U.S. patent application number 10/768970 was filed with the patent office on 2006-10-05 for methods and compounds for inhibiting beta-amyloid peptide release and/or its synthesis.
This patent application is currently assigned to Elan Pharmaceuticals, Inc.. Invention is credited to James E. Audia, Thomas C. Britton, James J. Droste, Clark Norman Eid, Beverly K. Folmer, George W. Huffman, Varghese John, Lee H. Latimer, Thomas E. Mabry, Jeffrey S. Nissen, Warren J. Porter, Jon K. Reel, William Leonard Scott, Eugene D. Thorsett, Jay S. Tung, Jing Wu.
Application Number | 20060223761 10/768970 |
Document ID | / |
Family ID | 25523957 |
Filed Date | 2006-10-05 |
United States Patent
Application |
20060223761 |
Kind Code |
A1 |
Audia; James E. ; et
al. |
October 5, 2006 |
Methods and compounds for inhibiting beta-amyloid peptide release
and/or its synthesis
Abstract
Disclosed are compounds which inhibit .beta.-amyloid peptide
release and/or its synthesis, and, accordingly, have utility in
treating Alzheimer's disease Also disclosed pharmaceutical
compositions comprising a compound which inhibits .beta.-amyloid
peptide release and/or its synthesis as well as methods for
treating Alzheimer's disease both prophylactically and
therapeutically with such pharmaceutical compositions.
Inventors: |
Audia; James E.;
(Indianapolis, IN) ; Britton; Thomas C.; (Carmel,
IN) ; Droste; James J.; (Indianapolis, IN) ;
Folmer; Beverly K.; (Newark, DE) ; Huffman; George
W.; (Carmel, IN) ; John; Varghese; (San
Francisco, CA) ; Latimer; Lee H.; (Oakland, CA)
; Mabry; Thomas E.; (Indianapolis, IN) ; Nissen;
Jeffrey S.; (Indianapolis, IN) ; Porter; Warren
J.; (Indianapolis, IN) ; Reel; Jon K.;
(Carmel, IN) ; Thorsett; Eugene D.; (Moss Beach,
CA) ; Tung; Jay S.; (Belmont, CA) ; Wu;
Jing; (San Mateo, CA) ; Eid; Clark Norman;
(Cheshire, CT) ; Scott; William Leonard;
(Indianapolis, IN) |
Correspondence
Address: |
BUCHANAN, INGERSOLL & ROONEY PC
POST OFFICE BOX 1404
ALEXANDRIA
VA
22313-1404
US
|
Assignee: |
Elan Pharmaceuticals, Inc.
South San Francisco
CA
Eli Lilly & Company
Indianapolis
IN
|
Family ID: |
25523957 |
Appl. No.: |
10/768970 |
Filed: |
February 2, 2004 |
Related U.S. Patent Documents
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Application
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Patent Number |
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10309569 |
Dec 3, 2002 |
6861558 |
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10768970 |
Feb 2, 2004 |
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09789487 |
Feb 20, 2001 |
6888022 |
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10309569 |
Dec 3, 2002 |
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08976289 |
Nov 21, 1997 |
6191166 |
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10309569 |
Dec 3, 2002 |
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60108166 |
Nov 22, 1996 |
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60064859 |
Feb 28, 1997 |
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60108161 |
Feb 28, 1997 |
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60098558 |
Feb 28, 1997 |
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Current U.S.
Class: |
514/17.8 ;
514/21.91; 514/310; 514/317; 514/419; 514/423 |
Current CPC
Class: |
C07K 5/06191 20130101;
A61K 31/47 20130101; C07K 5/06078 20130101; A61K 31/445 20130101;
A61K 38/06 20130101; A61K 31/4015 20130101; A61K 31/00 20130101;
A61K 31/405 20130101; A61K 38/05 20130101 |
Class at
Publication: |
514/019 ;
514/310; 514/317; 514/419; 514/423 |
International
Class: |
A61K 38/04 20060101
A61K038/04; A61K 31/47 20060101 A61K031/47; A61K 31/405 20060101
A61K031/405; A61K 31/4015 20060101 A61K031/4015; A61K 31/445
20060101 A61K031/445 |
Claims
1. A method for inhibiting p-amyloid peptide release and/or its
synthesis in a cell which method comprises administering to such a
cell an amount of a compound or a mixture of compounds effective in
inhibiting the cellular release and/or synthesis of .beta.-amyloid
peptide wherein said compounds are represented by formula I:
##STR11## wherein R.sup.1 is selected from the group consisting of
alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted
alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl
and heterocyclic; R.sup.2 is selected from the group consisting of
hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and
heterocyclic; each R.sup.3 is independently selected from the group
consisting of hydrogen and methyl and R.sup.3 together with R.sup.4
can be fused to form a cyclic structure of from 3 to 8 atoms which
is optionally fused with an aryl or heteroaryl group; each R.sup.4
is independently selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl,
heteroaryl, heterocyclic, substituted alkyl, substituted alkenyl
and substituted alkynyl; each R.sup.5 is selected from hydrogen and
methyl or together with R4 forms a cycloalkyl group of from 3 to 6
carbon atoms; X is selected from the group consisting of --C(O)Y
and --C(S)Y where Y is selected from the group consisting of (a)
alkyl or cycloalkyl, (b) substituted alkyl with the proviso that
the substitution on said substituted alkyl do not include
.alpha.-haloalkyl, .alpha.-diazoalkyl, .alpha.-OC(O)alkyl, or
.alpha.-OC(O)aryl groups, (c) alkoxy or thioalkoxy, (d) substituted
alkoxy or substituted thioalkoxy, (e) hydroxy, (f) aryl, (g)
heteroaryl, (h) heterocyclic, (i) --NR'R'' where R' and R'' are
independently selected from hydrogen, alkyl, alkenyl, alkynyl,
substituted alkyl, substituted alkenyl, substituted alkenyl,
cycloalkyl, aryl, heteroaryl, heterocyclic, where one of R' or R''
is hydroxy or alkoxy, and where R' and R'' are joined to form a
cyclic group having from 2 to 8 carbon atoms optionally containing
1 to 2 additional heteroatoms selected from oxygen, sulfur and
nitrogen and optionally substituted with one or more alkyl, alkoxy
or carboxylalkyl groups, (j) --NHSO2-R.sup.8 where R.sup.8 is
selected from alkyl, substituted alkyl, alkenyl, substituted
alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic, (k)
--NR.sup.9NR.sup.10R.sup.10 where R.sup.9 is hydrogen or alkyl, and
each R.sup.10 is independently selected from hydrogen, alkyl,
substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl,
heteroaryl, heterocyclic, and (I) --ONR.sup.9[C(O)O].sub.zR.sup.10
where z is zero or one, R.sup.9 and R.sup.10 are as defined above;
X can also be --CR.sup.6R.sup.6Y' where each R.sup.6 is
independently selected from the group consisting of hydrogen,
alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and
heterocyclic and Y' is selected from the group consisting of
hydroxyl, amino, thiol, alkoxy, substituted alkoxy, thioalkoxy,
substituted thioalkoxy, --OC(O)R.sup.7, --SSR.sup.7,
--SSC(O)R.sup.7 where R.sup.7 is selected from the group consisting
of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and
heterocyclic, X' is hydrogen, hydroxy, or fluoro; X'' is hydrogen,
hydroxy or fluoro, or X' and X'' together form an oxo group, Z is
selected from the group consisting of a bond covalently linking
R.sup.1 to --CX'X''--, oxygen and sulfur; n is an integer equal to
1 or 2; and pharmaceutically acceptable salts thereof with the
provisos that: A. when R.sup.1 is phenyl or 3-nitrophenyl, R.sup.2
is methyl, R.sup.3 is hydrogen, R.sup.4 is --CH(OH)CH.sup.3,
R.sup.5 is hydrogen, X' and X'' are hydrogen, Z is a bond, and n is
1, then X is not --C(O)OH; B. when R.sup.1 is phenyl, R.sup.2 is
methyl, R.sup.3 is hydrogen, R.sup.4 is --CH(OH)CH.sub.3 derived
from D-threonine, R.sup.5 is hydrogen, X' and X'' are hydrogen, Z
is a bond, and n is 1, then X is not --C(O)OH or --C(O)OCH.sub.3;
C. when R.sup.1 is phenyl, R.sup.2 is methyl, R.sup.4 is benzyl,
R.sup.5 is hydrogen, X is methoxycarbonyl, X' and X'' are hydrogen,
Z is a bond, and n is 1, then R.sup.3 is not methyl; D. when
R.sup.1 is iso-propyl, R.sup.2 is --CH.sub.2C(O)NH.sub.2, R.sup.3
is hydrogen, R.sup.4 is iso-butyl, R.sup.5 is hydrogen, X' and X''
are hydrogen, Z is a bond, and n is 1, then X is not
--C(O)OCH.sub.3; E. when R.sup.1 is phenyl, R.sup.2 is methyl,
R.sup.5 is hydrogen, X is --C(O)OCH.sub.3, X' and X'' are hydrogen,
Z is a bond, and n is 1, then R.sup.3, the nitrogen atom attached
to R.sup.3, and R.sup.4 do not form
1,2,3,4-tetrahydroiso-quinolin-2-yl or pyrrolidin-2-yl; F. when
R.sup.1 is phenyl, R.sup.2 is methyl, R.sup.3 is hydrogen, R.sup.5
is hydrogen, X is --C(O)OCH.sub.3, X' and X'' are hydrogen, Z is a
bond, and n is 1, then R.sup.4 is not 4-amino-n-butyl; G. when
R.sup.1 is 3-nitrophenyl, R.sup.2 is methyl, R.sup.3 is hydrogen,
R.sup.4 is --CH(OH)CH.sub.3, R.sup.5 is hydrogen, X' and X'' are
hydrogen, Z is a bond, and n is 1, then X is not --C(O)NH.sub.2 or
--CH.sub.2OH; H. when R.sup.1 is phenyl, R.sup.2 is methyl, R.sup.3
is hydrogen, R.sup.5 is hydrogen, X is --CH.sub.2OCH.sub.3, X' and
X'' are hydrogen, Z is a bond, and n is 1, then R.sup.4 is not
benzyl or ethyl; I. when R.sup.1 is 3,5-difluorophenyl, R.sup.2 is
methyl, R.sup.3 is methyl, R.sup.4 is methyl, R.sup.5 is hydrogen,
X' and X'' are hydrogen, Z is a bond, and n is 1, then X is not
--CHOH.phi.; J. when R.sup.1 is 3,5-difluorophenyl, R.sup.2 is
methyl, R.sup.3 is hydrogen, R.sup.4 is phenyl derived from
D-phenylglycine, R.sup.5 is hydrogen, X' and X'' are hydrogen, Z is
a bond, and n is 1, then X is not --CHOH.phi. or --CH2OH; K. when
R.sup.1 is N-(2-pyrrolidinonyl), R.sup.2 is methyl, R.sup.3 is
hydrogen, R.sup.4 is benzyl, R.sup.5 is hydrogen, X' and X'' are
hydrogen, Z is a bond, and n is 1, then X is not --C(O)OCH.sub.3;
L. when R.sup.1 is 3,5-difluorophenyl, R.sup.2 is methyl derived
from D-alanine, R.sup.3 is hydrogen, R.sup.4 is phenyl derived from
D-phenylglycine, R.sup.5 is hydrogen, X' and X'' are hydrogen, Z is
a bond, and n is 1, then X is not --C(O)NH-benzyl; M. when R.sup.1
is 3,5-difluorophenyl, R.sup.2 is methyl, R.sup.3 is hydrogen,
R.sup.4 is hydrogen, R.sup.5 is hydrogen, X' and X'' are hydrogen,
Z is a bond, and n is 1, then X is not --CH.sub.2OH; N. when
R.sup.1 is 3,5-difluorophenyl, R.sup.2 is methyl, R.sup.3 is
hydrogen, R.sup.4 is 4-phenylphenyl, R.sup.5 is hydrogen, X' and
X'' are hydrogen, Z is a bond, and n is 1, then X is not
--C(O)NHC(CH.sub.3).sub.3; and O. when R.sup.1 is
3,5-difluorophenyl, R.sup.2 is methyl, R.sup.3 is hydrogen, R.sup.4
is phenyl derived from D-phenylglycine, R.sup.5 is hydrogen, X' and
X'' are hydrogen, Z is a bond, and n is 1, then X is not
--C(O)NHCH(CH.sub.3).sub..phi..
2-89. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of the following U.S.
Provisional Applications:
[0002] 1. U.S. Provisional Application No. 60/______ which was
converted pursuant to 37 C.F.R. .sctn.1.53(b)(2)(ii) from U.S.
patent application Ser. No. 08/755,442, filed Nov. 22, 1996;
[0003] 2. U.S. Provisional Application No. 60/______ which was
converted pursuant to 37 C.F.R. .sctn.1.53(b)(2)(ii) from U.S.
patent application Ser. No. 08/808,528, filed Feb. 28, 1997;
[0004] 3. U.S. Provisional Application No. 60/______ which was
converted pursuant to 37 C.F.R. .sctn.1.53(b)(2)(ii) from U.S.
patent application Ser. No. 08/807,528, filed Feb. 28, 1997;
and
[0005] 4. U.S. Provisional Application No. 60/______ which was
converted pursuant to 37 C.F.R. .sctn.1.53(b)(2)(ii) from U.S.
patent application Ser. No. 08/807,427, filed Feb. 28, 1997.
[0006] Each of these applications are incorporated herein by
reference in their entirety.
BACKGROUND OF THE INVENTION
Field of the Invention
[0007] This invention relates to methods which inhibit cellular
.beta.-amyloid peptide release and/or its synthesis, and,
accordingly, have utility in treating Alzheimer's disease. This
invention also relates to pharmaceutical compositions comprising
such compounds as well as methods for inhibiting release of
.beta.-amyloid peptide.
REFERENCES
[0008] The following publications, patents and patent applications
are cited in this application as superscript numbers:
[0009] .sup.1Glenner, et al., "Alzheimer's Disease: Initial Report
of the Purification and Characterization of a Novel Cerebrovascular
Amyloid Protein", Biochem. Biophys. Res. Commun., 120:885-890
(1984).
[0010] .sup.2 Glenner, et al., "Polypeptide Marker for Alzheimer's
Disease and its Use for Diagnosis", U.S. Pat. No. 4,666,829 issued
May 19, 1987.
[0011] .sup.3 Selkoe, "The Molecular Pathology of Alzheimer's
Disease", Neuron, 6:487-498 (1991).
[0012] .sup.4 Goate, et al., "Segregation of a Missense Mutation in
the Amyloid Precursor Protein Gene with Familial Alzheimer's
Disease", Nature, 349:704-706 (1990).
[0013] .sup.5 Chartier-Harlan, et al., "Early-Onset Alzheimer's
Disease Caused by Mutations at Codon 717 of the .beta.-Amyloid
Precursor Protein Gene", Nature, 353:844-846 (1989).
[0014] .sup.6 Murrell, et al., "A Mutation in the Amyloid Precursor
Protein Associated with Hereditary Alzheimer's Disease", Science,
254:97-99 (1991).
[0015] .sup.7 Mullan, et al., "A Pathogenic Mutation for Probable
Alzheimer's Disease in the APP Gene at the N-Terminus of
.beta.-Amyloid, Nature Genet., 1:345-347 (1992).
[0016] .sup.8 Schenk, et al., "Methods and Compositions for the
Detection of Soluble .beta.-Amyloid Peptide", International Patent
Application Publication No. WO 94/10569, published 11 May 1994.
[0017] .sup.9 Selkoe, "Amyloid Protein and Alzheimer's Disease",
Scientific American, pp. 2-8, November, 1991.
[0018] .sup.10 Losse, et al., Tetrahedron, 27:1423-1434 (1971).
[0019] .sup.11 Citron, et al., "Mutation of the .beta.-Amyloid
Precursor Protein in Familial Alzheimer's Disease Increases
.beta.-Protein Production, Nature, 360:672-674.(1992).
[0020] .sup.12 Hansen, et al., "Reexamination and Further
Development of a Precise and Rapid Dye Method for Measuring Cell
Growth/Cell Kill", J. Immun. Meth., 119:203-210 (1989).
[0021] .sup.13 P. Seubert, Nature (1992) 359:325-327
[0022] .sup.14 Johnson-Wood et al., PNAS USA (1997)
94:1550-1555
[0023] .sup.15 Tetrahedron Letters, 34(48), 7685 (1993))
[0024] All of the above publications, patents and patent
applications are herein incorporated by reference in their entirety
to the same extent as if each individual publication, patent or
patent application was specifically and individually indicated to
be incorporated by reference in its entirety.
STATE OF THE ART
[0025] Alzheimer's Disease (AD) is a degenerative brain disorder
characterized clinically by progressive loss of memory, cognition,
reasoning, judgment and emotional stability that gradually leads to
profound mental deterioration and ultimately death. AD is a very
common cause of progressive mental failure (dementia) in aged
humans and is believed to represent the fourth most common medical
cause of death in the United States. AD has been observed in races
and ethnic groups worldwide and presents a major present and future
public health problem. The disease is currently estimated to affect
about two to three million individuals in the United States alone.
AD is at present incurable. No treatment that effectively prevents
AD or reverses its symptoms and course is currently known.
[0026] The brains of individuals with AD exhibit characteristic
lesions termed senile (or amyloid) plaques, amyloid angiopathy
(amyloid deposits in blood vessels) and neurofibrillary tangles.
Large numbers of these lesions, particularly amyloid plaques and
neurofibrillary tangles, are generally found in several areas of
the human brain important for memory and cognitive function in
patients with AD. Smaller numbers of these lesions in a more
restrictive anatomical distribution are also found in the brains of
most aged humans who do not have clinical AD. Amyloid plaques and
amyloid angiopathy also characterize the brains of individuals with
Trisomy 21 (Down's Syndrome) and Hereditary Cerebral Hemorrhage
with Amyloidosis of the Dutch Type (HCHWA-D). At present, a
definitive diagnosis of AD usually requires observing the
aforementioned lesions in the brain tissue of patients who have
died with the disease or, rarely, in small biopsied samples of
brain tissue taken during an invasive neurosurgical procedure.
[0027] The principal chemical constituent of the amyloid plaques
and vascular amyloid deposits (amyloid angiopathy) characteristic
of AD and the other disorders mentioned above is an approximately
4.2 kilodalton (kD) protein of about 39-43 amino acids designated
the .beta.-amyloid peptide (.beta.AP) or sometimes A.beta.,
A.beta.P or .beta./A4. .beta.-Amyloid peptide was first purified
and a partial amino acid sequence was provided by Glenner, et
al..sup.1 The isolation procedure and the sequence data for the
first 28 amino acids are described in U.S. Pat. No.
4,666,829.sup.2.
[0028] Molecular biological and protein chemical analyses have
shown that the .beta.-amyloid peptide is a small fragment of a much
larger precursor protein (APP), that is normally produced by cells
in many tissues of various animals, including humans. Knowledge of
the structure of the gene encoding the APP has demonstrated that
.beta.-amyloid peptide arises as a peptide fragment that is cleaved
from APP by protease enzyme(s). The precise biochemical mechanism
by which the .beta.-amyloid peptide fragment is cleaved from APP
and subsequently deposited as amyloid plaques in the cerebral
tissue and in the walls of the cerebral and meningeal blood vessels
is currently unknown.
[0029] Several lines of evidence indicate that progressive cerebral
deposition of .beta.-amyloid peptide plays a seminal role in the
pathogenesis of AD and can precede cognitive symptoms by years or
decades. See, for example, Selkoe.sup.3. The most important line of
evidence is the discovery that missense DNA mutations at amino acid
717 of the 770-amino acid isoform of APP can be found in affected
members but not unaffected members of several families with a
genetically determined (familial) form of AD (Goate, et al..sup.4;
Chartier-Harlan, et al..sup.5; and Murrell, et al..sup.6) and is
referred to as the Swedish variant. A double mutation changing
lysine.sup.595-methionine.sup.596 to
asparagine.sup.595-leucine.sup.596 (with reference to the 695
isoform) found in a Swedish family was reported in 1992 (Mullan, et
al..sup.7). Genetic linkage analyses have demonstrated that these
mutations, as well as certain other mutations in the APP gene, are
the specific molecular cause of AD in the affected members of such
families. In addition, a mutation at amino acid 693 of the
770-amino acid isoform of APP has been identified as the cause of
the .beta.-amyloid peptide deposition disease, HCHWA-D, and a
change from alanine to glycine at amino acid 692 appears to cause a
phenotype that resembles AD is some patients but HCHWA-D in others.
The discovery of these and other mutations in APP in genetically
based cases of AD prove that alteration of APP and subsequent
deposition of its .beta.-amyloid peptide fragment can cause AD.
[0030] Despite the progress which has been made in understanding
the underlying mechanisms of AD and other .beta.-amyloid peptide
related diseases, there remains a need to develop methods and
compositions for treatment of the disease(s). Ideally, the
treatment methods would advantageously be based on drugs which are
capable of inhibiting .beta.-amyloid peptide release and/or its
synthesis in vivo.
SUMMARY OF THE INVENTION
[0031] This invention is directed to the, discovery of a class of
compounds which inhibit .beta.-amyloid peptide release and/or its
synthesis and, therefore, are useful in the prevention of AD in
patients susceptable to AD and/or in the treatment of patients with
AD in order to inhibit further deterioration in their condition.
The class of compounds having the described properties are defined
by formula I below: ##STR1##
[0032] wherein R.sup.1 is selected from the group consisting of
alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted
alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl
and heterocyclic;
[0033] R.sup.2 is selected from the group consisting of hydrogen,
alkyl, substituted alkyl alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, cycloalkyl, aryl, heteroaryl and
heterocyclic;
[0034] each R.sup.3 is independently selected from the group
consisting of hydrogen and methyl and R.sup.3 together with R.sup.4
can be fused to form a cyclic structure of from 3 to 8 atoms which
is optionally fused with an aryl or heteroaryl group;
[0035] each R.sup.4 is independently selected from the group
consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
cycloalkenyl, heteroaryl, heterocyclic, substituted alkyl,
substituted alkenyl and substituted alkynyl;
[0036] each R.sup.5 is selected from hydrogen and methyl or
together with R.sup.4 forms a cycloalkyl group of from 3 to 6
carbon atoms;
[0037] X is selected from the group consisting of --C(O)Y and
--C(S)Y where Y is selected from the group consisting of
[0038] (a) alkyl or cycloalkyl,
[0039] (b) substituted alkyl with the proviso that the substitution
on said substituted alkyl do not include .alpha.-haloalkyl,
.alpha.-diazoalkyl, .alpha.-OC(O)alkyl, or .alpha.-OC(O)aryl
groups,
[0040] (c) alkoxy or thioalkoxy,
[0041] (d) substituted alkoxy or substituted thioalkoxy,
[0042] (e) hydroxy,
[0043] (f) aryl,
[0044] (g) heteroaryl,
[0045] (h) heterocyclic,
[0046] (i) --NR'R'' where R' and R'' are independently selected
from hydrogen, alkyl, alkenyl, alkynyl, substituted alkyl,
substituted alkenyl, substituted alkenyl, cycloalkyl, aryl,
heteroaryl, heterocyclic, where one of R' or R'' is hydroxy or
alkoxy, and where R' and R'' are joined to form a cyclic group
having from 2 to 8 carbon atoms optionally containing 1 to 2
additional heteroatoms selected from oxygen, sulfur and nitrogen
and optionally substituted with one or more alkyl, alkoxy or
carboxylalkyl groups,
[0047] (j) --NHSO.sub.2--R.sup.8 where R.sup.8 is selected from
alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl,
aryl, heteroaryl and heterocyclic;
[0048] (k) --NR.sup.9NR.sup.10R.sup.10 where R.sup.9 is hydrogen or
alkyl, and each R.sup.10 is independently selected from hydrogen,
alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl,
aryl, heteroaryl, heterocyclic, and
[0049] (l) --ONR.sup.9[C(O)O].sub.zR.sup.10 where z is zero or one,
R.sup.9 and R.sup.10 are as defined above;
[0050] X can also be --CR.sup.6R.sup.6Y' where each R.sup.6 is
independently selected from the group consisting of hydrogen,
alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and
heterocyclic and Y' is selected from the group consisting of
hydroxyl, amino, thiol, alkoxy, substituted alkoxy, thioalkoxy,
substituted thioalkoxy, --OC(O)R.sup.7, --SSR.sup.7,
--SSC(O)R.sup.7 where R.sup.7 is selected from the group consisting
of alkyl, substituted alkyl cycloalkyl, aryl, heteroaryl and
heterocyclic,
[0051] X' is hydrogen, hydroxy, or fluoro;
[0052] X'' is hydrogen, hydroxy or fluoro, or X' and X'' together
form an oxo group,
[0053] Z is selected from the group consisting of a bond covalently
linking R.sup.1 to --CX'X''--, oxygen and sulfur;
[0054] n is an integer equal to 1 or 2; and
[0055] pharmaceutically acceptable salts thereof
[0056] with the provisos that:
[0057] A. when R.sup.1 is phenyl or 3-nitrophenyl, R.sup.2 is
methyl, R.sup.3 is hydrogen, R.sup.4 is --CH(OH)CH.sub.3, R.sup.5
is hydrogen, X' and X'' are hydrogen, Z is a bond, and n is 1, then
X is not --C(O)OH;
[0058] B. when R.sup.1 is phenyl, R.sup.2 is methyl, R.sup.3 is
hydrogen, R.sup.4 is --CH(OH)CH.sub.3 derived from D-threonine,
R.sup.5 is hydrogen, X' and X'' are hydrogen, Z is a bond, and n is
1, then X is not --C(O)OH or --C(O)OCH.sub.3;
[0059] C. when R.sup.1 is phenyl, R.sup.2 is methyl, R.sup.4 is
benzyl, R.sup.5 is hydrogen, X is methoxycarbonyl, X' and X'' are
hydrogen, Z is a bond, and n is 1, then R.sup.3 is not methyl;
[0060] D. when R.sup.1 is iso-propyl, R.sup.2 is
--CH.sub.2C(O)NH.sub.2, R.sup.3 is hydrogen, R.sup.4 is iso-butyl,
R.sup.5 is hydrogen, X' and X'' are hydrogen, Z is a bond, and n is
1, then X is not --C(O)OCH.sub.3;
[0061] E. when R.sup.1 is phenyl, R.sup.2 is methyl, R.sup.5 is
hydrogen, X is --C(O)OCH.sub.3, X' and X'' are hydrogen, Z is a
bond, and n is 1, then R.sup.3, the nitrogen atom attached to
R.sup.3, and R.sup.4 do not form
1,2,3,4-tetrahydroiso-quinolin-2-yl or pyrrolidin-2-yl;
[0062] F. when R.sup.1 is phenyl, R.sup.2 is methyl, R.sup.3 is
hydrogen, R.sup.5 is hydrogen, X is --C(O)OCH.sub.3, X' and X'' are
hydrogen, Z is a bond, and n is 1, then R.sup.4 is not
4-amino-n-butyl;
[0063] G. when R.sup.1 is 3-nitrophenyl, R.sup.2 is methyl, R.sup.3
is hydrogen, R.sup.4is --CH(OH)CH.sub.3, R.sup.5 is hydrogen, X'
and X'' are hydrogen, Z is a bond, and n is 1, then X is not
--C(O)NH.sub.2 or --CH.sub.2OH;
[0064] H. when R.sup.1 is phenyl, R.sup.2 is methyl, R.sup.3 is
hydrogen, R.sup.5 is hydrogen, X is --CH.sub.2OCH.sub.3, X' and X''
are hydrogen, Z is a bond, and n is 1, then R.sup.4 is not benzyl
or ethyl;
[0065] I. when R.sup.1 is 3,5-difluorophenyl, R.sup.2 is methyl,
R.sup.3 is methyl, R.sup.4 is methyl, R.sup.5 is hydrogen, X' and
X'' are hydrogen, Z is a bond, and n is 1, then X is not
--CHOH.phi.;
[0066] J. when R.sup.1 is 3,5-difluorophenyl, R.sup.2 is methyl,
R.sup.3 is hydrogen, R.sup.4 is phenyl derived from
D-phenylglycine, R.sup.5 is hydrogen, X' and X'' are hydrogen, Z is
a bond, and n is 1, then X is not --CHOH.phi. or --CH.sub.2OH;
[0067] K. when R.sup.1 is N-(2-pyrrolidinonyl), R.sub.2 is methyl,
R.sub.3 is hydrogen, R.sub.4 is benzyl, R.sup.5 is hydrogen, X' and
X'' are hydrogen, Z is a bond, and n is 1, then X is not
--C(O)OCH.sub.3;
[0068] L. when R.sup.1 is 3,5-difluorophenyl, R.sup.2 is methyl
derived from D-alanine, R.sup.3 is hydrogen, R.sup.4 is phenyl
derived from D-phenylglycine, R.sup.5 is hydrogen, X' and X'' are
hydrogen, Z is a bond, and n is 1, then X is not
--C(O)NH-benzyl;
[0069] M. when R.sup.1 is 3,5-difluorophenyl, R.sup.2 is methyl,
R.sup.3 is hydrogen, R.sup.4 is hydrogen, R.sup.5 is hydrogen, X'
and X'' are hydrogen, Z is a bond, and n is 1, then X is not
--CH.sub.2OH;
[0070] N. when R.sup.1 is 3,5-difluorophenyl, R.sup.2 is methyl,
R.sup.3 is hydrogen, R.sup.4 is 4-phenylphenyl, R.sup.5 is
hydrogen, X' and X'' are hydrogen, Z is a bond, and n is 1, then X
is not --C(O)NHC(CH.sub.3).sub.3; and
[0071] O. when R.sup.1 is 3,5-difluorophenyl, R.sup.2 is methyl,
R.sup.3 is hydrogen, R.sup.4 is phenyl derived from
D-phenylglycine, R.sup.5 is hydrogen, X' and X'' are hydrogen, Z is
a bond, and n is 1, then X is not --C(O)NHCH(CH.sub.3).phi..
[0072] Preferably, the compounds of this invention are derived from
L-amino acids and, accordingly, are represented by formula IA:
##STR2##
[0073] Accordingly, in one of its method aspects, this invention is
directed to a method for inhibiting .beta.-amyloid peptide release
and/or its synthesis in a cell which method comprises administering
to such a cell an amount of a compound or a mixture of compounds of
formula I above effective in inhibiting the cellular release and/or
synthesis of .beta.-amyloid peptide.
[0074] Because the in vivo generation of .beta.-amyloid peptide is
associated with the pathogenesis of AD.sup.8,9, the compounds of
formula I can also be employed in conjunction with a pharmaceutical
composition to prophylactically and/or therapeutically prevent
and/or treat AD. Accordingly, in another of its method aspects,
this invention is directed to a prophylactic method for preventing
the onset of AD in a patient at risk for developing AD which method
comprises administering to said patient a pharmaceutical
composition comprising a pharmaceutically inert carrier and an
effective amount of a compound or a mixture of compounds of formula
I above.
[0075] In yet another of its method aspects, this invention is
directed to a therapeutic method for treating a patient with AD in
order to inhibit further deterioration in the condition of that
patient which method comprises administering to said patient a
pharmaceutical composition comprising a pharmaceutically inert
carrier and an effective amount of a compound or a mixture of
compounds of formula I above.
[0076] Compounds suitable for use in the claimed methods include,
by way of example only, the following: [0077]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanoate
methyl ester [0078]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-histidine methyl
ester [0079]
N-benzyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanam-
ide [0080]
N-2-(N,N-dimethylamino)ethyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl-
]-(S)-2-aminohexanamide [0081]
N-(2-methoxyethyl)-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-am-
inohexanamide [0082]
N-2-(N,N-dimethylamino)ethyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl-
]-L-phenylalaninamide [0083]
N-(4-pyridyl)methyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-pheny-
lalaninamide [0084]
N-(3-pyridyl)methyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-pheny-
lalaninamide [0085]
N-(4-pyridyl)methyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-a-
minohexanamide [0086]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanoate
tert-butyl ester [0087]
N--[N-(pent-4-enoyl)-L-alaninyl]-L-phenylalanine methyl ester
[0088] N--[N-(dec-4-enoyl)-L-alaninyl]-L-phenylalanine methyl ester
[0089]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-[3-(N,N-dimethylamino)pr-
opoxy]phenylalanine methyl ester [0090]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-[(tert-butyloxycarbonyl)-
methoxy]phenylalanine methyl ester [0091]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-tyrosine methyl
ester [0092]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(carboxymethoxy)-
phenylalanine methyl ester [0093]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4(2-morpholinoethoxy)pheny-
lalanine methyl ester [0094]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-6-(N,N-dimethyla-
mino)hexanoate methyl ester [0095]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(2-pyridyl)pro-
pionate methyl ester [0096]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(3-pyridyl)pro-
pionate methyl ester [0097]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-proline methyl ester
[0098]
1-[N-(3,5-difluorophenylacetyl)-L-alaninyl]piperidine-2-carboxyla-
te methyl ester [0099]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(4-pyridyl)pro-
pionate methyl ester [0100]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-methoxypropionate
methyl ester [0101]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-morpholinopropiona-
te methyl ester [0102]
N-(2-methoxyethyl)-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(2-m-
orpholinoethoxy)phenylalaninamide [0103]
N-(2-methoxyethyl)-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino--
3-methoxypropionamide [0104]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine methyl ester
[0105]
N-(2-methoxyethyl)-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino--
3-(4-pyridyl)propionamide [0106]
N-(2-methoxyethyl)-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino--
3-(2-pyridyl)propionamide [0107]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(thiazol-4-yl)-
propionate methyl ester [0108]
2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-1,2,3,4-tetrahydroisoquinolin-
e-3-carboxylate methyl ester [0109]
N-(3-methoxybenzyl)-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-pheny-
lalaninamide [0110]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(
1-naphthyl)propionate methyl ester [0111]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(2-naphthyl)pr-
opionate methyl ester [0112]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(2-thienyl)pro-
pionate methyl ester [0113]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine benzyl
ester [0114]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine
3-bromo-propyl ester [0115]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine
3-iodopropyl ester [0116]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-leucine tert-butyl
ester [0117]
N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-pyridyl)acetam-
ide [0118]
N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-pyridyl)acetam-
ide [0119]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-N-(tert-butoxycarbonyl)-L-ly-
sine methyl ester [0120] methyl
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-4-phenylbutanoat-
e [0121] N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine
2-phenylethyl ester [0122]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine 3-phenylpropyl
ester [0123]
N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4-pyridy-
l)acetamide [0124] N--[N-(phenylacetyl)-L-alaninyl]-L-threonine
methyl ester [0125] N'--[N-(phenylacetyl)-L-alaninyl]-L-leucinamide
[0126] N'--[N-(phenylacetyl)-L-alaninyl]-L-alaninamide [0127]
N'--[N-(phenylacetyl)-L-alaninyl]-L-phenylalaninamide [0128]
N'--[N-(phenylacetyl)-L-alaninyl)-L-valinamide [0129]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-pyridyl)acetate
ethyl ester [0130]
N-methyl-N'--[N-(phenylacetyl)-L-alaninyl]-L-leucinamide [0131]
N,N-dimethyl-N'--[N-(phenylacetyl)-L-alaninyl]-L-phenylalaninamide
[0132] N,N-dimethyl-N'--[N-(phenylacetyl)-L-alaninyl]-L-leucinamide
[0133] N,N-dimethyl-N'--[N-(phenylacetyl)-L-alaninyl]-L-valinamide
[0134]
N-methyl-N'--[N-(phenylacetyl)-L-alaninyl]-L-phenylalaninamide
[0135] N-methyl-N'--[N-(phenylacetyl)-L-alaninyl]-L-valinamide
[0136]
N-methyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanam-
ide [0137]
N,N-dimethyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohex-
anamide [0138]
N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamide
[0139]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-methoxy-
phenyl)acetate methyl ester [0140]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4-methoxyphenyl)a-
cetate methyl ester [0141]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-pyridyl)acetate
ethyl ester [0142]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4-pyridyl)acetate
ethyl ester [0143]
N--[N-(cyclohexylacetyl)-L-alaninyl]-L-phenylalanine methyl ester
[0144] N--[N-(cyclopentylacetyl)-L-alaninyl]-L-phenylalanine methyl
ester [0145]
N--[N-(cyclohex-1-enylacetyl)-L-alaninyl]-L-phenylalanine methyl
ester [0146]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-1-aminocyclopropane-1-carbox-
ylate methyl ester [0147]
N-2-(N,N-dimethylamino)ethyl-N-methyl-N'--[N-(3,5-difluorophenylacetyl)-L-
-alaninyl]-L-alaninamide [0148]
N--[N-(cyclopropylacetyl)-L-alaninyl]-L-phenylalanine methyl ester
[0149] N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine benzyl
ester [0150] N--[N-(isovaleryl)-L-phenylglycinyl]-L-alanine ethyl
ester [0151]
N--[N-(3-nitrophenylacetyl)-L-alaninyl]-L-phenylalanine methyl
ester [0152] N--[N-(3-nitrophenylacetyl)-L-alaninyl]-L-alanine
ethyl ester [0153] N--[N-(3-nitrophenylacetyl)-L-alaninyl]glycine
ethyl ester [0154]
N-hydroxy-N'--[N-(3-nitrophenylacetyl)-L-alaninyl]-D,L-threonina-
mide [0155] N--[N-(isovaleryl)-L-phenylglycinyl]-L-alanine
iso-butyl ester [0156]
N--[N-(3-nitrophenylacetyl)-L-alaninyl]-2-amino-3-(3-hydroxyphenyl)propio-
nate methyl ester [0157]
N--[N-(3-nitrophenylacetyl)-L-alaninyl]-L-tyrosine ethyl ester
[0158] N--[N-(isovaleryl)-L-isoleucinyl]-L-alanine iso-butyl ester
[0159]
N--[N--[N-(isovaleryl)-L-valinyl]-L-phenylglycinyl]-L-alanine
iso-butyl ester [0160]
N--[N-(isovaleryl)-L-phenylalaninyl]-L-alanine iso-butyl ester
[0161] N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine ethyl
ester [0162]
1-[N-(3-nitrophenylacetyl)-L-alaninyl]-indoline-(S)-2-carboxylate
ethyl ester [0163]
N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide [0164]
N-methoxy-N-methyl-N'--[N-(isovaleryl)-L-phenylglycinyl]-L-alaninamide
[0165]
N-iso-butyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alani-
namide [0166]
N,N-di-n-propyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninami-
de [0167]
N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-valinamide [0168]
N-(4-nitrophenyl)-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-
-alaninamide [0169]
N'--[N--[N-(isovaleryl)-L-phenylglycinyl]-L-alaninyl]-L-phenylalaninamide
[0170] N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine
methyl ester [0171]
N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamide
[0172]
N-iso-butyl-N'--[N-(isovaleryl)-L-phenylglycinyl]-L-alaninamide
[0173]
N-(2-methoxyethyl)-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenyl-
alaninamide [0174]
N-(4-nitrobenzyl)-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanina-
mide [0175]
N-(4-nitrophenyl)-N'--[N--[N-(isovaleryl)-L-phenylglycinyl]-L-alaninyl]-L-
-alaninamide [0176]
N-(4-nitrophenyl)-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenyla-
laninamide [0177]
N-benzyl-N-methyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanina-
mide [0178]
N-(3,5-difluorobenzyl)-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-al-
aninamide [0179]
N-(3-nitrobenzyl)-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanina-
mide [0180]
N-benzyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide
[0181]
N-(4-nitrobenzyl)-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-
-phenylalaninamide [0182]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-tryptophan methyl
ester [0183]
N-(4-methoxybenzyl)-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-
-L-alaninamide [0184]
N-N-(phenylacetyl)-L-phenylglycinyl]-L-alanine ethyl ester [0185]
N--[N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninyl]-L-phen-
ylglycine methyl ester [0186]
N--[N-(cyclohexylacetyl)-L-phenylglycinyl]-L-alanine ethyl ester
[0187] N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycine
methyl ester [0188]
N--[N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninyl]-L-p-
henylglycine methyl ester [0189]
N-(2-phenylethyl)-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl)-L-alanina-
mide [0190]
N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-tryptophanamide
[0191]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-cyclohexylprop-
ionate methyl ester [0192]
N-(2-methoxyethyl)-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-am-
ino-3-(4-nitrophenyl)propionamide [0193]
N--[N-(3-nitrophenylacetyl)-L-alaninyl]-L-serine ethyl ester [0194]
N--[(R)-.alpha.-methylbenzyl]-N'--[N-(3,5-difluorophenylacetyl)-L-alaniny-
l]-L-alaninamide [0195]
N--[(S)-.alpha.-methylbenzyl]-N'--[N-(3,5-difluorophenylacetyl)-L-alaniny-
l]-L-alaninamide [0196]
N-(4-fluorobenzyl)-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanin-
amide [0197]
N-(4-pyridylmethyl)-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alani-
namide [0198]
N-(4-trifluoromethylbenzyl)-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-
-L-alaninamide [0199]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-phenylpropionate
ethyl ester [0200]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine
tert-butyl ester [0201]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-methylpropionate
methyl ester [0202]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl[-2-amino-2-cyclohexylacetate
ethyl ester [0203]
N-(2-methoxyethyl)-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenyl-
glycinamide [0204]
N--[N-(isovaleryl)-2-amino-2-cyclohexylacetyl]-L-alanine ethyl
ester [0205]
N-2-(N,N-dimethylamino)ethyl-N'--[N-(3,5-difluorophenylacetyl)-L--
alaninyl]-L-phenylglycinamide [0206]
N-(2-pyridylmethyl)-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-pheny-
lglycinamide [0207]
N--[N-(3-pyridylacetyl)-L-alaninyl]-L-phenylalanine methyl ester
[0208] N--[N-(2-pyridylacetyl)-L-alaninyl]-L-phenylalanine methyl
ester [0209] N--[N-(4-pyridylacetyl)-L-alaninyl]-L-phenylalanine
methyl ester [0210]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4-fluorophenyl)ac-
etate ethyl ester [0211]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-fluorophenyl)ac-
etate ethyl ester [0212]
N--[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-alanine ethyl
ester [0213]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-phthalimid-
opropionate ethyl ester [0214]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycine
neopentyl ester [0215]
N-tert-butyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycin-
amide [0216]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycine
tert-butyl ester [0217]
N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide
[0218]
4-[N--[N-(3-nitrophenylacetyl)-L-alaninyl]-L-valinyl]morpholine
[0219] N--[N-(3-nitrophenylacetyl)-L-alaninyl]-L-valine ethyl ester
[0220] N--[N-(3-nitrophenylacetyl)-L-alaninyl]-L-threonine methyl
ester [0221]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminopentanoate
methyl ester [0222]
4-[N--[N-(3-nitrophenylacetyl)-L-alaninyl]-(S)-2-amino-3-tert-butoxybutyr-
yl]morpholine [0223]
4-[N--[N-(3-nitrophenylacetyl)-L-alaninyl]-L-isoleucinyl]morpholine
[0224] N--[N-(3-nitrophenylacetyl)-L-alaninyl]-L-isoleucine methyl
ester [0225] N--[N-(3-nitrophenylacetyl)-L-alaninyl]-L-isoleucine
[0226]
N--[N--[N-(3-nitrophenylacetyl)-L-alaninyl]-L-threoninyl]-L-valine
ethyl ester [0227]
N--[N-(3-nitrophenylacetyl)-L-alaninyl]-(S)-2-aminopentanoate
methyl ester [0228]
N--[N-(3-nitrophenylacetyl)-L-alaninyl]-L-leucine methyl ester
[0229] N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-leucine
methyl ester [0230]
N-2-methoxyethyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninam-
ide [0231]
N-2-(N,N-dimethylamino)ethyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl-
]-L-alaninamide [0232]
N-cyclohexyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide
[0233]
N-neopentyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alani-
namide [0234]
N-tetrahydrofurfuryl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alan-
inamide [0235]
N-2-pyridylmethyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanina-
mide [0236]
3-[N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninyl]thiazolidine
[0237]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl-(S)-2-aminobutanoate
methyl ester [0238]
N--[N-(3-nitrophenylacetyl)-L-alaninyl]-(S)-2-aminobutanoate methyl
ester [0239]
N--(R)-sec-butyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl-L--
alaninamide [0240]
1-[N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninyl]pyrrolidine
[0241]
N--(S)-sec-butyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L--
alaninamide [0242]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-valine methyl ester
[0243]
N-2-fluoroethyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninami-
de [0244]
N--[(S)-6-methyl-3-oxohept-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninam-
ide [0245]
N-4-nitrobenzyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-
butyramide [0246]
N-4-nitrobenzyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-
pentanamide [0247]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-fluorophenyl)ac-
etate methyl ester [0248]
N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)ac-
etamide [0249] N
--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(5-chlorobenzothioph-
en-2-yl)acetate methyl ester [0250]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(benzothiophen-2-y-
l)acetate ethyl ester [0251]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(benzothiophen-3-y-
l)acetate methyl ester [0252]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-thienyl)acetate
methyl ester [0253]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(benzothiophen-5-y-
l)acetate ethyl ester [0254]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)ace-
tate methyl ester [0255]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)ace-
tate tert-butyl ester [0256]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)ace-
tic acid [0257]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(1H-tetrazol-5-yl)-
acetate methyl ester [0258]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(6-methoxy-2-n-
aphthyl)acetate methyl ester [0259]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-trifluoromethyl-
phenyl)acetate methyl ester [0260]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4,5,6,7-tetrahydr-
obenzothiophen-2-yl)acetate methyl ester [0261]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(thieno[2,3-b]thio-
phen-2-yl)acetate methyl ester [0262]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-methylthiazol-4-
-yl)acetate methyl ester [0263]
(3S,4S)--N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-4-amino-3-hydroxy-5-
-phenylpentanoate methyl ester [0264]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohex-4-enoate
methyl ester [0265]
N--[N-(cyclopropylacetyl)-L-alaninyl]-L-phenylglycine tert-butyl
ester [0266]
N-tert-butyl-N'--[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2--
amino-2-(4-phenylphenyl)acetamide [0267]
N--[N-(3,5-difluorophenylacetyl)-(S)-2-aminobutanoyl]-L-phenylglycine
tert-Butyl Ester [0268]
N--[N-(3,5-difluorophenylacetyl)-L-valinyl]-L-phenylglycine
tert-butyl ester [0269]
N--[N-(3,5-difluorophenylacetyl)-L-methioninyl]-L-phenylglycine
methyl ester [0270]
N--[N-(3,5-difluorophenylacetyl)-L-valinyl]-L-phenylglycine methyl
ester [0271]
N--[N-(3,5-difluorophenylacetyl)-2-aminobutanoyl]-L-phenylglycine
methyl ester [0272]
N--[N-(3,5-difluorophenylacetyl)-L-leucinyl]-L-phenylglycine methyl
ester [0273]
N--[N-(3,5-difluorophenylacetyl)-L-phenylalaninyl]-L-phenylglyci-
ne methyl ester [0274]
N--[N-(3,5-difluorophenylacetyl)glycinyl]-L-phenylglycine methyl
ester [0275]
N--[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycin-
e methyl ester [0276] N--[N-(phenylacetyl)-L-alaninyl]-L-alanine
methyl ester [0277] N--[N-(phenylacetyl)-L-alaninyl]-L-leucine
methyl ester [0278] N--[N-(phenylacetyl)-L-alaninyl]-L-isoleucine
methyl ester [0279] N--[N-(phenylacetyl)-L-alaninyl]-L-proline
methyl ester [0280]
N--[N-(phenylacetyl)-L-alaninyl]-L-phenylalanine methyl ester
[0281]
N--[N-(phenylacetyl)-L-alaninyl]-N-(tert-butoxycarbonyl)-L-lysine
methyl ester [0282] N--[N-(phenylacetyl)-L-alaninyl]-glycine methyl
ester [0283] N--[N-(phenylacetyl)-L-alaninyl]-L-valine methyl ester
[0284] N--[N-(phenylacetyl)-L-alaninyl]-(S)-2-aminobutanoate methyl
ester [0285] N--[N-(phenylacetyl)-L-alaninyl]-(S)-2-aminopentanoate
methyl ester [0286]
N--[N-(3-nitrophenylacetyl)-L-alaninyl]-L-valine [0287]
N--[N-(phenylacetyl)-L-alaninyl]-L-N-methylaniline methyl ester
[0288] N--[N-(isovaleryl)-L-phenylglycinyl]-L-alanine iso-butyl
ester [0289] N--[N-(isovaleryl)-L-isoleucinyl]-L-alanine tert-butyl
ester [0290]
N-Cyclohexyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycin-
amide [0291]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-hydroxyproline
ethyl ester [0292]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-lysine methyl ester
[0293] N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-glutamide
[0294]
1-[N-(3,5-difluorophenylacetyl)-L-alaninyl]piperidine-2-carboxylate
methyl ester [0295]
N--[(S)-3-hydroxy-6-methylhept-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alan-
inamide [0296]
N--[(S)-2-hydroxy-1-phenyleth-1-yl]-N'-(3,5-difluorophenylacetyl)-L-alani-
namide [0297]
N--[N-(3,5-difluorophenyl-.alpha.-fluoroacetyl)-L-alaniny]-L-phenylglycin-
e tert-butyl ester [0298]
N--[N-(3,5-difluorophenylacetyl)-2-(S)-aminocyclohexylacetyl]-L-phenylgly-
cine methyl ester [0299]
N-[(1R,2S)-1-hydroxy-1-phenylprop-2-yl]-N'-(3,5-difluorophenylacetyl)-L-a-
laninamide [0300]
N-[(1R,2S)-1-hydroxy-1,2-diphenyleth-2-yl]-N'-(3,5-difluorophenylacetyl)--
L-alaninamide [0301]
N-[(1S,2R)-1-hydroxy-1-phenylprop-2-yl]-N'-(3,5-difluorophenylacetyl)-L-a-
laninamide [0302]
N-2-methoxyethyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-glycinamid-
e [0303]
N--[(S)-.alpha.-hydroxy-.alpha.-phenyl-iso-propyl]-N'-(3,5-difl-
uorophenylacetyl)-L-alaninamide [0304]
N--[(S)-2-hydroxy-1,2-diphenylethyl]-N'-(3,5-difluorophenylacetyl)-L-alan-
inamide [0305]
N--[(S)-1-hydroxyhex-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide
[0306]
N-[.alpha.-hydroxy-.alpha.'-(4-hydroxyphenyl)-iso-propyl]-N'-(3,5-
-difluorophenylacetyl)-L-alaninamide [0307]
N-2-pyridylmethyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenyla-
laninamide [0308]
N-[.alpha.-hydroxy-.alpha.'-pyrid-2-yl-iso-propyl]-N'-(3,5-difluorophenyl-
acetyl)-L-alaninamide [0309]
N-[.alpha.-hydroxy-.alpha.'-pyrid-4-yl-iso-propyl]-N'-(3,5-difluorophenyl-
acetyl)-L-alaninamide [0310]
N--[(S)-1-hydroxy-4-methylpent-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alan-
inamide [0311]
N-[.alpha.-methoxy-prop-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide
[0312]
N-[1-hydroxy-3-methyl-but-2-yl]-N'-(3,5-difluorophenylacetyl)-L--
alaninamide [0313]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(6-aminopyrid-2-yl-
)acetate methyl ester [0314]
N-[1-hydroxy-prop-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide
[0315]
N--[(S)-2-methoxy-1-phenyleth-1-yl]-N'-(3,5-difluorophenylacetyl)-
-L-alaninamide [0316]
N--[(S)-1-methoxy-2-phenyl-prop-2-yl]-N'-(3,5-difluorophenylacetyl)-L-ala-
ninamide [0317]
N--[(S)-1-acetoxyhex-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide
[0318]
N--[(S)-1-(tert-butylcarbonyloxy)-hex-2-yl]-N'-(3,5-difluoropheny-
lacetyl)-L-alaninamide [0319]
N-[2-hydroxy-1-(thien-2-yl)ethyl]-N'-(3,5-difluorophenylacetyl)-L-alanina-
mide [0320]
N--[(S)-2-hydroxy-2-methyl-1-phenylprop-1-yl]-N'-(3,5-difluorophenylacety-
l)-L-alaninamide [0321]
N--[N-(3,5-difluorophenylacetyl)-L-(thien-2-yl)glycinyl]-L-phenylalanine
tert-butyl ester [0322]
N--[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl-L-phenylglycinol
[0323]
N--[N-(cyclopropaneacetyl)-L-phenylglycinyl]-L-phenylglycinol
[0324]
N--[N-(cyclopentaneacetyl)-L-phenylglycinyl]-L-phenylglycinol
[0325]
N--[N-(3,5-difluorophenylacetyl)-D,L-phenylglycinyl]-D,L-phenylgl-
ycinamide [0326]
N--[N-(3,5-difluorophenylacetyl)-D,L-valinyl]-D,L-phenylglycinamide
[0327] N--[N-(2-thienylacetyl)-L-alaninyl]-L-phenylglycinamide
[0328] N--[N-(n-caprotyl)-L-alaninyl]-L-phenylglycinamide [0329]
N--[N-(3,5-difluorophenylacetyl)-L-norleucinyl]-L-phenylglycine
methyl ester [0330]
N--[N-(3,5-difluorophenylacetyl)-L-norvalinyl]-L-phenylglycine
methyl ester [0331]
N--[N-(3,5-difluorophenylacetyl)-L-tert-leucinyl]-L-phenylglycine
methyl ester [0332]
N--[N-(3,5-difluorophenylacetyl)-L-isoleucinyl]-L-phenylglycine
methyl ester [0333]
N--[N-(3,5-difluorophenylacetyl)-L-cyclohexylalaninyl]-L-phenylglycine
methyl ester [0334]
N--[N-(3,5-difluorophenylacetyl)-(S)-2-amino-2-(cyclopropyl)acetyl]-L-phe-
nylglycine methyl ester [0335]
N--[N-(3,5-difluorophenylacetyl)-(S)-2-amino-2-(thien-3-yl)acetyl]-L-phen-
ylglycine methyl ester [0336]
N--[N-(3,5-difluorophenylacetyl)-(S)-2-amino-2-(thien-2-yl)acetyl]-L-phen-
ylglycine methyl ester [0337]
N--[N-(3,5-difluorophenylacetyl)-L-(4-fluorophenyl)glycinyl]-L-phenylglyc-
ine methyl ester [0338]
N--[N-(3,5-difluorophenylacetyl)-D-(4-fluorophenyl)glycinyl]-L-phenylglyc-
ine methyl ester [0339]
N--[N-(3,5-difluorophenylacetyl)-L-(4-methoxyphenyl)glycinyl]-L-phenylgly-
cine methyl ester [0340]
N--[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycine
tert-butyl ester [0341]
N--[N-(cyclopropylacetyl)-L-phenylglycinyl]-L-phenylglycine
tert-butyl ester [0342]
N--[N-(cyclopentylacetyl)-L-phenylglycinyl]-L-phenylglycine
tert-butyl ester [0343]
N--[N-(tert-butylacetyl)-L-alaninyl]-L-phenylglycinamide [0344]
N-tert-butyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(5-b-
romothien-2-yl)glycinamide [0345]
N-tert-butyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-(5-bromothie-
n-2-yl)glycinamide [0346]
N-tert-butyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(4-bromothie-
n-2-yl)glycinamide [0347]
N-tert-butyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(thien-2-yl)-
glycinamide [0348]
N-tert-butyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-(thien-2-yl)-
glycinamide [0349]
N-tert-butyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(thien-3-yl)-
glycinamide [0350]
N-tert-butyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-(thien-2-yl)-
glycinamide [0351]
N-tert-butyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-phenylglycin-
amide [0352]
N-tert-butyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycin-
amide [0353]
N-tert-butyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-(5-chlorot-
hien-2-yl)glycinamide [0354]
N-Cyclohexyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-4-(phenyl)ph-
enylglycinamide [0355]
N-tert-butyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-3-(phenoxy)p-
henylglycinamide [0356]
N--(S)-(-)-.alpha.-methylbenzyl-N--[N-(3,5-difluorophenylacetyl)-L-alanin-
yl]-D,L-phenylglycinamide [0357]
N-tert-butyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-3-(phenyl)ph-
enylglycinamide [0358]
N-tert-butyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(ethyl)phe-
nylglycinamide [0359]
N-tert-butyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-2-(phenyl)ph-
enylglycinamide [0360]
N-tert-butyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-2-(benzyl)ph-
enylglycinamide [0361]
N-tert-butyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-4-bromophe-
nylglycinamide [0362]
N-tert-butyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(cyclohexy-
l)phenylglycinamide [0363]
N-tert-butyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(4-ethylph-
enyl)phenylglycinamide [0364]
N-tert-butyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-4-(tert-bu-
tyl)phenylglycinamide [0365]
N-tert-butyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-3-(4-chlor-
ophenoxy)phenylglycinamide [0366]
N-cyclohexyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(phenyl)ph-
enylglycinamide [0367]
N--[N-(3,5-difluorophenyl-.alpha.-hydroxyacetyl)-L-alaninyl]-L-phenylglyc-
ine tert-butyl ester [0368]
N-tert-butyl-N'--[N-(3,5-difluorophenyl-.alpha.,.alpha.-difluoroacetyl)-L-
-alaninyl]-L-phenylglycinamide [0369]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-phenylglycine
tert-butyl ester [0370]
N--[(S)-1-oxo-1-phenylprop-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninam-
ide [0371]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-(pyrid-3-yl)glycine
tert-butyl ester [0372]
[N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinyl]morpholi-
ne [0373]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-(2-methoxy)phenylglycine
methyl ester [0374]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine
N-tert-butoxycarbonyl(hydroxyl amine) ester [0375]
N-neopentyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglyci-
namide [0376]
N-tetrahydrofurfuryl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-ph-
enylglycinamide [0377]
N-methoxy-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycina-
mide [0378]
[N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinyl]azetidin-
e [0379]
N-iso-butyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-p-
henylglycinamide [0380]
N-cyclopropanemethyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-ph-
enylglycinamide [0381]
N-methoxy-N-methyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phen-
ylglycinamide [0382]
N-2-methylprop-2-enyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-p-
henylglycinamide [0383]
N-(pyrid-3-yl)methyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-ph-
enylglycinamide [0384] N-(pyrid-4-yl)
methyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamid-
e [0385]
N-furfuryl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-ph-
enylglycinamide [0386]
N-cyclopentyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylgly-
cinamide [0387]
N-1-benzylpiperidin-4-yl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,-
L-phenylglycinamide [0388]
N,N-dimethyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglyc-
inamide [0389]
N-2,2,6,6-tetramethylpiperidin-4-yl-N'--[N-(3,5-difluorophenylacetyl)-L-a-
laninyl]-D,L-phenylglycinamide [0390]
N-2-methylcyclohexyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-ph-
enylglycinamide [0391]
N-4-methylcyclohexyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-ph-
enylglycinamide [0392]
N-1-ethoxycarbonylpiperidin-4-yl-N'--[N-(3,5-difluorophenylacetyl)-L-alan-
inyl]-D,L-phenylglycinamide [0393]
N-methyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamid-
e [0394]
N-tert-butoxy-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-
-phenylglycinamide [0395]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine
N-tert-butyl(hydroxylamine) ester [0396]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycine
hydrazide [0397]
N-(1-ethoxyethen-1-yl)-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]-
-L-phenylglycine hydrazide [0398]
N--[N-(phenylacetyl)-L-alaninyl]-L-phenylglycine tert-butyl ester
[0399]
N-4-(phenyl)butyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenyl-
glycinamide [0400]
N-3-(4-iodophenoxy)propyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-
-phenylglycinamide [0401]
N-6-(amino)hexyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenyl-
glycinamide Hydrochloride [0402]
N-1-(phthalimido)pent-2-yl-N'-(3,5-difluorophenylacetyl)-L-alaninamide
[0403]
N--[N-(3,5-difluorophenylacetyl)-L-(3,5-difluorophenyl)glycinyl]--
L-(3,5-difluorophenyl)glycine methyl ester [0404]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-norleucine [0405]
N--[N-(cyclopentaneacetyl)-L-alaninyl]-L-phenylglycine tert-butyl
ester [0406]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-fluorophenylglyc-
ine iso-propyl ester [0407]
N-(isopropyl)N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycin-
amide [0408] N--[N-(cyclopentylacetyl)-L-alaninyl]-L-phenylalanine
tert-butyl ester [0409]
N--[N-(cyclopropylacetyl)-L-alaninyl]-L-phenylalanine tert-butyl
ester [0410]
N--[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-phenylglycine
iso-butyl ester [0411]
N--[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D-phenylglycine methyl
ester [0412]
N--[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-(3-.alpha.-phenyl-
)proline methyl ester [0413] N
--[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-azetidine methyl
ester [0414]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-(5-chlorob-
enzothiophen-2-yl)acetate methyl ester [0415]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(thiazol-4-yl)-
propionate tert-butyl ester [0416]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide
tert-butyl ester [0417]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-(thien-2-yl)glycinamide
[0418]
N--[N-(3,4-dichlorophenylacetyl)-L-alaninyl]-D-phenylglycinamide
[0419] N--[N-(3-chlorophenylacetyl)-L-alaninyl]-D-phenylglycinamide
[0420] N--[N-(3-bromophenylacetyl)-L-alaninyl]-D-phenylglycinamide
[0421] N--[N-(3-fluorophenylacetyl)-L-alaninyl]-D-phenylglycinamide
[0422] N--[N-(4-fluorophenylacetyl)-L-alaninyl]-D-phenylglycinamide
[0423] N--[N-(3-methylphenylacetyl)-L-alaninyl]-D-phenylglycinamide
[0424] N--[N-(4-methylphenylacetyl)-L-alaninyl]-D-phenylglycinamide
[0425]
N--[N-(3-trifluoromethylphenylacetyl)-L-alaninyl]-D-phenylglycina-
mide [0426]
N--[N-(3-methoxyphenylacetyl)-L-alaninyl]-D-phenylglycinamide
[0427] N--[N-(2-chlorophenylacetyl)-L-alaninyl]-D-phenylglycinamide
[0428] N--[N-(1-naphthylacetyl)-L-alaninyl]-D-phenylglycinamide
[0429] N--[N-(2-naphthylacetyl)-L-alaninyl]-D-phenylglycinamide
[0430] N--[N-(phenylacetyl)-L-alaninyl]-D-phenylglycinamide [0431]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-phenylglycine [0432]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-phenylglycinamide
[0433]
N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-furanyl)ac-
etamide [0434]
N'--[N-(3,5-difluorphenylacetyl)-D-alaninyl]-D-phenylglycinamide
[0435]
N'--[N-(3,4-difluorophenylacetyl)-D-alaninyl]-D-phenylglycinamide
[0436]
N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanin-N-methylsul-
fonamide [0437]
N''-methyl-N''-phenyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-glyci-
namide [0438]
N''-methyl-N''-phenyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-ala-
ninamide [0439]
N'--[N-(3,5-difluorophenylacetyl)-L-methioninyl]-L-phenylglycinamide
[0440]
N''-methyl-N''-benzyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaniny-
l]-glycinamide [0441]
N''-4-fluorobenzyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenyl-
glycinamide [0442]
N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(4-fluoro)phenylglycine
neopentyl ester [0443]
N--[N-(2,3,4,5,6-pentafluorophenylacetyl)-L-alaninyl]-L-(pyrid-3-yl)glyci-
ne methyl ester [0444]
N--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(pyrid-3-yl)glycine
tert-butyl ester [0445]
N--[N-(3,5-difluorophenylacetyl)-L-(O-benzyl)serinyl]-L-phenylglycine
methyl ester [0446]
N--[N-(3,5-difluorophenylacetyl)-L-(O-benzyl)threoninyl]-L-phenylglycine
methyl ester [0447]
N--[N-(3,5-difluorophenylacetyl)-L-threoninyl]-L-phenylglycine
methyl ester [0448]
N--[N-(3,5-difluorophenylacetyl)-L-serinyl]-L-phenylglycine methyl
ester [0449]
N''-4-methylphenyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]--
L-phenylglycinamide [0450]
N''-tetrahydrofurfuryl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-ph-
enylglycinamide [0451]
N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-fluorophenyl-glycinamid-
e [0452]
N'--[N-(3,5-difluorophenylacetyl)-L-methionyl]-L-phenylglycinam-
ide [0453]
N--[N-(3,5-difluorophenylacetyl)-2-aminobutanoyl]-L-phenylglycinamide
[0454]
N'--[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglyci-
namide [0455]
N--[N-(3,5-difluorophenylacetyl)-L-valinyl]-L-phenylglycinamide
[0456]
N--[(R)-.alpha.-methylbenzyl]-N'--[N-(3,5-difluorophenylacetyl)-L-alaniny-
l]-L-phenylglycinamide [0457]
N-[1-phenyl-2-oxo-3-methylbutan-1-yl]-N'-(3,5-difluorophenylacetyl)-L-ala-
ninamide [0458]
N-[1-phenyl-2-oxo-propan-1-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamid-
e [0459]
N-[1-phenyl-2-oxo-pentan-1-yl]-N'-(3,5-difluorophenylacetyl)-L--
alaninamide [0460]
N-[1-phenyl-2-oxo-2-phenyl-ethan-1-yl]-N'-(3,5-difluorophenyl-acetyl)-L-a-
laninamide [0461]
N-[1-phenyl-2-oxo-butan-1-yl]-N'-(3,5-difluorophenyl-acetyl)-L-alaninamid-
e [0462]
N-[1-phenyl-2-oxo-4-methylpentan-1-yl]-N'-(3,5-difluorophenyl-a-
cetyl)-L-alaninamide [0463]
N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-.alpha.-hydroxyphenylalan-
ine methyl ester [0464]
N''-[4-((2-hydroxy-4-azido)-phenyl)-NHC(O)-)butyl]N'--[N-(3,5-difluorophe-
nylacetyl)-L-alaninyl]-L-phenylglycinamide [0465]
N--[(S)-1-phenyl-2-oxo-2-phenyl-ethan-1-yl]-N'-(3,5-difluorophenyl-acetyl-
)-L-alaninamide [0466]
N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-fluorophenylglycine
tert-butyl ester [0467]
N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-phenylphenylglycine
tert-butyl ester [0468]
[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(2,
3-benzo[b]proline)methyl ester [0469]
N''-tert-butyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-n-butylp-
henylglycinamide [0470]
N''-tert-butyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-4-(pheny-
lacetenyl)phenylglycinamide [0471]
N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinthioamide
[0472]
N-[1,3-diphenyl-2-oxo-propan-1-yl]-N'-(3,5-difluorophenylacetyl)--
L-alaninamide [0473]
N-[1-phenyl-2-oxo-2-cyclopentylethan-1-yl]-N'-(3,5-difluorophenylacetyl)--
L-alaninamide [0474]
N-[1-phenyl-2-oxo-hexan-1-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide
[0475]
N-[1-phenyl-2-oxo-3-methylpentan-1-yl]-N'-(3,5-difluorophenylace-
tyl)-L-alaninamide [0476]
N''-n-hexyl-6-biotinamidyl-N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]--
D,L-phenylglycinthioamide [0477]
N'--[N-(3,5-difluorophenylacetyl)-L-methioninyl]-L-methionine
[0478]
N'--[N-(2-tert-BOC-amino)propionyl)-L-alaninyl]-L-phenylglycine
methyl ester [0479] N''-tert-butyl
N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-2-fluorophenylglycinamide
[0480]
N'--[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-2-phenylglycin- e
methyl ester [0481]
N--[(S)-1-phenyl-2-oxo-3-phenylpropan-1-yl]-N'-(3,5-difluorophenylacetyl)-
-L-alaninamide [0482]
N'--[N-(3,5-difluorophenylacetyl)-D,L-thien-3-ylglycinyl]-D,L-2-phenylgly-
cine [0483]
N'--[N-(3,5-difluorophenylacetyl)-D,L-thien-3-ylglycinyl]-D,L-2-phenylgly-
cine tert-butyl ester [0484]
N'--[N-(3,5-difluorophenylacetyl)-L-thien-3-ylglycinyl-L-2-phenylglycine
[0485]
N'--[N-(3,5-difluorophenylacetyl)-L-thien-3-ylglycinyl-L-2-phenyl-
glycine tert-butyl ester [0486]
N-[2-hydroxy-1-(S)phenyleth-1-yl]-N'-[(3,5-difluorophenylacetyl)-L-phenyl-
glycinyl]-L-alaninamide [0487]
N-[2-hydroxyeth-1-yl]-N'-[(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenyl-
glycinamide [0488]
N'--[N-(3,5-difluorophenyl-2-oxo-acetyl)-L-alaninyl]-L-2-phenylglycine
tert-butyl ester [0489]
[N-(2,5-dichlorophenoxyacetyl)-L-alaninyl]-L-phenylglycine methyl
ester [0490]
[N-(3,5-dichlorophenoxyacetyl)-L-alaninyl]-L-phenylglycine methyl
ester [0491]
[N-(3,4-dichlorothiophenoxyacetyl)-L-alaninyl]-L-phenylglycine
methyl ester [0492]
[N-(3-aminoproprionyl)-L-alaninyl]-L-phenylglycine tert-butyl ester
[0493]
[N-(3-tert-butoxycarbonylamino)propionyl)-L-alaninyl]-L-phenylglycine
tert-butyl ester
[0494] The pharmaceutical compositions described above comprise a
pharmaceutically inert carrier and a compound of the formula I
above.
[0495] In formula I above, X'' is preferably hydrogen and X' is
preferably hydrogen or fluoro.
[0496] In formula I above, Z is preferably a covalent bond linking
R.sup.1 to --CX'X''--.
[0497] In formula I above, preferred R.sup.1 unsubstituted aryl
groups include, for example, phenyl, 1-naphthyl, 2-naphthyl, and
the like.
[0498] Preferred R.sup.1 substituted aryl groups include, for
example, monosubstituted phenyls (preferably 3 or 5 substituents);
disubstituted phenyls (preferably 3,5 substituents); and
trisubstituted phenyls (preferably 3,4,5 substituents). Preferably,
the substituted phenyl groups do not include more than 3
substituents.
[0499] Examples of substituted phenyls include, for instance,
4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl,
4-methylphenyl, 3-methoxyphenyl, 3-nitrophenyl, 3-fluorophenyl,
3-chlorophenyl, 3-bromophenyl, 3-thiomethoxyphenyl, 3-methylphenyl,
3-trifluoromethylphenyl, 2-hydroxyphenyl, 2-methylphenyl,
2-fluorophenyl, 2-chlorophenyl, 3,4difluorophenyl,
2,3,4,5,6-pentafluorophenyl, 3,4-dibromophenyl, 3,4-dichlorophenyl,
3,4-methylene-dioxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl,
2,4-dichlorophenyl, and 2,5-difluorophenyl.
[0500] Preferred R.sup.1 alkaryl groups include, by way of example,
benzyl, 2-phenylethyl, 3-phenyl-n-propyl, and the like.
[0501] Preferred R.sup.1 alkyl, substituted alkyl, alkenyl,
cycloalkyl and cycloalkenyl groups include, by way of example,
iso-propyl, n-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,
--CH.sub.2CH.dbd.CH.sub.2,
--CH.sub.2CH.dbd.CH(CH.sub.2).sub.4CH.sub.3, cyclopropyl,
cyclobutyl, cyclohexyl, cyclopentyl, cyclohex-1-enyl,
--CH.sub.2-cyclopropyl, --CH.sub.2-cyclobutyl,
--CH.sub.2-cyclohexyl, --CH.sub.2-cyclopentyl,
--CH.sub.2CH.sub.2-cyclopropyl, --CH.sub.2CH.sub.2-cyclobutyl,
--CH.sub.2CH.sub.2-cyclohexyl, --CH.sub.2CH.sub.2-cyclopentyl,
aminomethyl, N-tert-butoxycarbonylaminomethyl, and the like.
[0502] Preferred R.sup.1 heteroaryls and substituted heteroaryls
include, by way of example, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl,
fluoropyridyls (including 5-fluoropyrid-3-yl), chloropyridyls
(including 5-chloropyrid-3-yl), thien-2-yl, thien-3-yl,
benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, -furan-2-yl,
benzofuran-2-yl, thionaphthen-2-yl, 2-chlorothiophen-5-yl,
3-methylisoxazol-5-yl, 2-(thiophenyl)thiophen-5-yl,
6-methoxythionaphthen-2-yl, 3-phenyl-1,2,4-thiooxadiazol-5-yl,
2-phenyloxazol-4-yl, and the like.
[0503] Preferably R.sup.2 is selected from the group consisting of
hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl
and heterocyclic. Particularly preferred R.sup.2 substituents
include, by way of example, methyl, ethyl, n-propyl, iso-propyl,
n-butyl, iso-butyl, sec-butyl, phenyl, 4-fluorophenyl,
3,5-difluorophenyl, 4-methoxyphenyl, benzyl, cyclopropyl,
cyclohexyl, cyclopentyl, cycloheptyl, thien-2-yl, thien-3-yl,
--CH.sub.2CH.sub.2SCH.sub.3, --CH.sub.2OCH.sub.2.phi.,
--CH(CH.sub.3)OCH.sub.2.phi., --CH(OH)CH.sub.3, --CH.sub.2OH and
the like. As noted below, R.sup.2 (as well as R.sup.4) is
preferably the side chain of an L-amino acid.
[0504] Preferably, R.sup.3 is hydrogen, methyl or together with
R.sup.4 and the nitrogen to which R.sup.3 is attached forms
pyrrolidin-2-yl, 2,3-dihydroindol-2-yl, piperidin-2-yl,
4-hydroxy-pyrrolidin-2-yl, 1,2,3,4-tetrahydroisoquinolin-3-yl, and
the like.
[0505] Preferred R.sup.4 substituents include, for example,
hydrogen, methyl, ethyl, iso-propyl, n-propyl, n-butyl, sec-butyl,
iso-butyl, cyclopentyl, cyclohexyl, allyl, iso-but-2-enyl,
3-methylpentyl, --CH.sub.2-cyclopropyl, --CH.sub.2-cyclohexyl,
--CH.sub.2-indol-3-yl, phenyl, p-(phenyl)phenyl, m-(phenyl)phenyl
o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, p-bromophenyl,
m-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl,
m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl,
m-trifluoromethylphenyl,
p-(CH.sub.3).sub.2NCH.sub.2CH.sub.2CH.sub.2O-benzyl,
p-(CH.sub.3).sub.3COC(O)CH.sub.2O-benzyl, p-phenylphenyl,
3,5-difluorophenyl, p-(HOOCCH.sub.2O)-benzyl, 2-aminopyrid-6-yl,
4-(N-morpholino-CH.sub.2CH.sub.2O)-benzyl,
--CH.sub.2CH.sub.2C(O)NH.sub.2, --CH.sub.2-imidazol-4-yl,
--CH.sub.2-(3-tetrahydrofuranyl), --CH.sub.2-thien-2-yl,
--CH.sub.2-thiazol-4-yl, --CH.sub.2(1-methyl)cyclopropyl,
--CH.sub.2-thien-3-yl, thien-3-yl, thien-2-yl,
--CH.sub.2--C(O)O-t-butyl, --CH.sub.2--C(CH.sub.3).sub.3,
--CH.sub.2CH(CH.sub.2CH.sub.3).sub.2, 2-methylcyclopentyl,
-cyclohex-2-enyl, --CH[CH(CH.sub.3).sub.2]COOCH.sub.3,
--(CH.sub.2).sub.2SCH.sub.3, --CH.sub.2CH.sub.2N(CH.sub.3).sub.2,
--CH.sub.2C(CH.sub.3).dbd.CH.sub.2, --CH.sub.2CH.dbd.CHCH.sub.3
(cis and trans), --CH.sub.2OH, --CH(OH)CH.sub.3,
--CH(O-t-butyl)CH.sub.3, --CH.sub.2OCH.sub.3,
--(CH.sub.2).sub.4NH-Boc, --(CH.sub.2).sub.4NH.sub.2,
--(CH.sub.2).sub.4N(CH.sub.3).sub.2, --CH.sub.2-pyridyl (e.g.,
2-pyridyl, 3-pyridyl and 4-pyridyl), pyridyl (2-pyridyl, 3-pyridyl
and 4-pyridyl), --CH.sub.2-naphthyl (e.g., 1-naphthyl and
2-naphthyl), --CH.sub.2--(N-morpholino),
p-(N-morpholino-CH.sub.2CH.sub.2O)-benzyl, benzo[b] thiophen-2-yl,
benzo[b] thiophen-3-yl, 5-chlorobenzo[b]thiophen-2-yl,
4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl,
tetrazol-5-yl, 5-chlorobenzo[b]thiophen-3-yl,
benzo.differential.b]thiophen-5-yl, 6-methoxynaphth-2-yl,
--CH.sub.2--N-phthalimidyl, 2-methylthiazol-4-yl, and
thieno[2,3-b]thiophen-2-yl, 5-bromothien-2-yl, 4-bromothien-2-yl,
5-chlorothien-2-yl, 3-phenoxyphenyl, 2-phenoxyphenyl,
4-ethylphenyl, 2-benzylphenyl, (4-ethylphenyl)phenyl,
4-tert-butylphenyl, 4-n-butylphenyl, o-(4-chlorophenoxy)phenyl,
furan-2-yl, 4-phenylacetylenylphenyl and the like.
[0506] Preferably, R.sup.5 is hydrogen. However, in another
embodiment, R.sup.4 and R.sup.5 are fused to form a cycloalkyl
group including, for example, cyclopropyl, cyclobutyl, and the
like.
[0507] One preferred X substituent is --C(O)Y. Preferably Y is
hydroxy, alkoxy or substituted alkoxy such as methoxy, ethoxy,
n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy,
neo-pentoxy, benzyloxy, 2-phenylethoxy, 3-phenyl-n-propoxy,
3-iodo-n-propoxy, 4-bromo-n-butoxy, --ONHC(O)OC(CH.sub.3).sub.3,
--ONHC(CH.sub.3).sub.3 and the like. Another preferred Y group is
--NR'R'' where R' and R'' are as defined above. Such preferred Y
groups include, by way of example, amino (--NH.sub.2,
--NH(iso-butyl), --NH(sec-butyl), N-methylamino, N,N-dimethylamino,
N-benzylamino, N-morpholino, azetidino, N-thiomorpholino,
N-piperidinyl, N-hexamethyleneimino, N-heptamethylene-imino,
N-pyrrolidinyl, --NH-methallyl, --NHCH.sub.2-(furan-2-yl),
--NHCH.sub.2-cyclopropyl, --NH(tert-butyl), --NH(p-methylphenyl),
--NHOCH.sub.3, --NHCH.sub.2(p-fluorophenyl),
--NHCH.sub.2CH.sub.2OCH.sub.3, --NH-cyclopentyl, --NH-cyclohexyl,
--NHCH.sub.2CH.sub.2N(CH.sub.3).sub.2,
--NHCH.sub.2C(CH.sub.3).sub.3, --NHCH.sub.2-(pyrid-2-yl),
--NHCH.sub.2-(pyrid-3-yl), --NHCH.sub.2-(pyrid-4-yl),
N-thiazolindinyl, --N(CH.sub.2CH.sub.2CH.sub.3).sub.2,
--N[CH.sub.2CH(CH.sub.3).sub.2].sub.2, --NHOH,
--NH(p-NO.sub.2-.phi.), --NHCH.sub.2(p-NO.sub.2-.phi.),
--NHCH.sub.2(m-NO.sub.2-.phi.), --N(CH.sub.3)OCH.sub.3,
--N(CH.sub.3)CH.sub.2-.phi., --NHCH.sub.2-(3,5-di-fluorophenyl),
--NHCH.sub.2CH.sub.2F, --NHCH.sub.2(p-CH.sub.3O-.phi.),
--NHCH.sub.2(m-CH.sub.3O-.phi.), --NHCH.sub.2(p-CF.sub.3-.phi.),
--N(CH.sub.3)CH.sub.2CH.sub.2OCH.sub.3, --NHCH.sub.2CH.sub.2.phi.,
--NHCH(CH.sub.3).phi., --NHCH.sub.2-(p-F-.phi.),
--N(CH.sub.3)CH.sub.2CH.sub.2N(CH.sub.3).sub.2,
--NHCH.sub.2-(tetrahydrofuran-2-yl),
--NHCH.sub.2(p-trifluoromethylphenyl),
--NHCH.sub.2C(CH.sub.3).dbd.CH.sub.2, --NH-[(p-benzyl)pyrid-4-yl],
--NH-[(2,6-dimethyl)pyrid-4-yl], --NH-(2-methylcyclohexyl),
--NH-(4-methylcyclohexyl), --NH--[N-ethoxycarbonyl]-piperidin-4-yl,
--NHOC(CH.sub.3).sub.3, --NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2-.phi.,
--C(O)NH(CH.sub.2).sub.3O-(p-CH.sub.3).phi.,
--C(O)NH(CH.sub.2).sub.6NH.sub.2, --NH-(tetrahydrofuran-2-yl),
--N(CH.sub.3).phi.,
--NH(CH.sub.2).sub.4NHC(O)-(2-hydroxy-4-azido)-phenyl,
--NH(CH.sub.2).sub.6-(biotinamidyl), and the like.
[0508] Another preferred Y group is an alkyl group such as methyl,
ethyl, iso-propyl, n-propyl, iso-butyl, n-butyl, sec-butyl,
tert-butyl, --CH.sub.2CH.sub.2CH(CH.sub.3).sub.2,
--CH.sub.2-pyridy-2-yl, --CH.sub.2-pyridy-3-yl,
--CH.sub.2-pyridy-4-yl, --CH.sub.2-fur-2-yl, and the like; a
substituted alkyl group such as benzyl; a cycloalkyl group such as
cyclopentyl; and an aryl group such as phenyl.
[0509] Still another preferred Y group is --NHSO.sub.2--R where R
is selected from alkyl, substituted alkyl, alkenyl, substituted
alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic. Such groups
are exemplified by NH--SO.sub.2--CH.sub.3.
[0510] Preferred Y' groups include a substituted alkyl group such
as --CH.sub.2OH, --CH(OH)CH.sub.2CH.sub.2CH(CH.sub.3).sub.2,
--CH(OH).phi., --CH(OH)CH.sub.2C(O)OCH.sub.3,
--C(OH)(CH.sub.3).sub.2, --CH.sub.2OCH.sub.3,
--CH.sub.2OC(O)OCH.sub.3, --CH.sub.2OC(O)C(CH.sub.3).sub.3, and the
like.
[0511] Preferred compounds for use in the methods of this invention
include those set forth in the tables below: TABLE-US-00001
##STR3## R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.5 X t-butyl
--CH.sub.3 H -.phi. H --C(O)NH.sub.2 thien-2-yl --CH.sub.3 H -.phi.
H --C(O)NH.sub.2 n-butyl --CH.sub.3 H -.phi. H --C(O)NH.sub.2
cyclopentyl --CH.sub.3 H -.phi. H --C(O)OC(CH.sub.3).sub.3
3,5-di-F-.phi.- --CH.sub.3 H --CH.sub.2CH.sub.2CH.sub.2CH.sub.3 H
--C(O)OCH.sub.3 3,5-di-F-.phi.- --CH.sub.3 H
--CH.sub.2-imidazol-4-yl H --C(O)OCH.sub.3 3,5-di-F-.phi.-
--CH.sub.3 H --CH.sub.2CH.sub.2CH.sub.2CH.sub.3 H
--C(O)NHCH.sub.2-.phi. 3,5-di-F-.phi.- --CH.sub.3 H
--(CH.sub.2).sub.3CH.sub.3 H
--C(O)NHCH.sub.2CH.sub.2N(CH.sub.3).sub.2 3,5-di-F-.phi.-
--CH.sub.3 H --(CH.sub.2).sub.3CH.sub.3 H
--C(O)NHCH.sub.2CH.sub.2OCH.sub.3 3,5-di-F-.phi.- --CH.sub.3 H
--CH.sub.2-.phi. H --C(O)NHCH.sub.2CH.sub.2N(CH.sub.3).sub.2
3,5-di-F-.phi.- --CH.sub.3 H --CH.sub.2-.phi. H
--C(O)NHCH.sub.2-(pyrid-4-yl) 3,5-di-F-.phi.- --CH.sub.3 H
--CH.sub.2-.phi. H --C(O)NHCH.sub.2-(pyrid-3-yl) 3,5-di-F-.phi.-
--CH.sub.3 H --(CH.sub.2).sub.3CH.sub.3 H
--C(O)NHCH.sub.2-pyrid-4-yl 3,5-di-F-.phi.- --CH.sub.3 H
--CH.sub.2CH.sub.2CH.sub.2CH.sub.3 H --C(O)OC(CH.sub.3).sub.3
CH.sub.2.dbd.CHCH.sub.2-- --CH.sub.3 H --CH.sub.2.phi. H
--C(O)OCH.sub.3 CH.sub.3(CH.sub.3).sub.4CH.dbd.CHCH.sub.2--
--CH.sub.3 H --CH.sub.2.phi. H --C(O)OCH.sub.3 3,5-di-F-.phi.-
--CH.sub.3 H p-(CH.sub.3).sub.2NCH.sub.2CH.sub.2CH.sub.2O- H
--C(O)OCH.sub.3 benzyl 3,5-di-F-.phi.- --CH.sub.3 H
p-(CH.sub.3).sub.3COC(O)CH.sub.2O- H --C(O)OCH.sub.3 benzyl
3,5-di-F-.phi.- --CH.sub.3 H p-hydroxybenzyl- H --C(O)OCH.sub.3
3,5-di-F-.phi.- --CH.sub.3 H p-HOOCCH.sub.2O-benzyl H
--C(O)OCH.sub.3 3,5-di-F-.phi.- --CH.sub.3 H p-(N-morpholino- H
--C(O)OCH.sub.3 CH.sub.2CH.sub.2O-benzyl- 3,5-di-F-.phi.-
--CH.sub.3 H --(CH.sub.2).sub.4--N(CH.sub.3).sub.2 H
--C(O)OCH.sub.3 3,5-di-F-.phi.- --CH.sub.3 H
--CH.sub.2-(pyrid-2-yl) H --C(O)OCH.sub.3 3,5-di-F-.phi.-
--CH.sub.3 H --CH.sub.2-(pyrid-3-yl) H --C(O)OCH.sub.3
3,5-di-F-.phi.- --CH.sub.3 R.sub.3/R.sub.4 and N = H
--C(O)OCH.sub.3 L-pyrrolidinyl .phi.- --CH.sub.3 R.sub.3/R.sub.4
and N = H --C(O)OCH.sub.3 piperidin-2-yl 3,5-di-F-.phi.- --CH.sub.3
H --CH.sub.2-(pyrid-4-yl) H --C(O)OCH.sub.3 3,5-di-F-.phi.-
--CH.sub.3 H --CH.sub.2OCH.sub.3 H --C(O)OCH.sub.3 3,5-di-F-.phi.-
--CH.sub.3 H --CH.sub.2--(N-morpholino) H --C(O)OCH.sub.3
3,5-di-F-.phi.- --CH.sub.3 H p-(N-morpholino- H
--C(O)NHCH.sub.2CH.sub.2OCH.sub.3 CH.sub.2CH.sub.2--O)-benzyl-
3,5-di-F-.phi.- --CH.sub.3 H --CH.sub.2OCH.sub.3 H
--C(O)NHCH.sub.2CH.sub.2OCH.sub.3 3,5-di-F-.phi.- --CH.sub.3 H H H
--C(O)OCH.sub.3 3,5-di-F-.phi.- --CH.sub.3 H --CH.sub.2-pyrid-4-yl
H --C(O)NHCH.sub.2CH.sub.2OCH.sub.3 3,5-di-F-.phi.- --CH.sub.3 H
--CH.sub.2-pyrid-2-yl H --C(O)NHCH.sub.2CH.sub.2OCH.sub.3
3,5-di-F-.phi.- --CH.sub.3 H --CH.sub.2-thiazol-4-yl H
--C(O)OCH.sub.3 3,5-di-F-.phi.- --CH.sub.3 R.sub.3/R.sub.4 and N =
H --C(O)OCH.sub.3 1,2,3,4-tetrahydro- isoquinolin-3-yl
3,5-di-F-.phi.- --CH.sub.3 H --CH.sub.2-.phi. H
--C(O)NHCH.sub.2-(m-CH.sub.3O-.phi.) 3,5-di-F-.phi.- --CH.sub.3 H
--CH.sub.2-1-naphthyl H --C(O)OCH.sub.3 3,5-di-F-.phi.- --CH.sub.3
H --CH.sub.2-2-naphthyl H --C(O)OCH.sub.3 3,5-di-F-.phi.-
--CH.sub.3 H --CH.sub.2-thien-2-yl H --C(O)OCH.sub.3
3,5-di-F-.phi.- --CH.sub.3 H --CH.sub.2-.phi. H
--C(O)OCH.sub.3-.phi. 3,5-di-F-.phi.- --CH.sub.3 H --CH.sub.2-.phi.
H --C(O)OCH.sub.2CH.sub.2CH.sub.2CH.sub.2Br 3,5-di-F-.phi.-
--CH.sub.3 H --CH.sub.2-.phi. H --C(O)OCH.sub.2CH.sub.2CH.sub.2I
3,5-di-F-.phi.- --CH.sub.3 H --CH.sub.2CH(CH.sub.3).sub.2 H
--C(O)OC(CH.sub.3).sub.3 3,5-di-F-.phi.- --CH.sub.3 H pyrid-2-yl H
--C(O)NH.sub.2 3,5-di-F-.phi.- --CH.sub.3 H pyrid-3-yl H
--C(O)NH.sub.2 3,5-di-F-.phi.- --CH.sub.3 H
--(CH.sub.2).sub.4--NHC(O)OC(CH.sub.3).sub.3 H --C(O)OCH.sub.3
3,5-di-F-.phi.- --CH.sub.3 H --CH.sub.2CH.sub.2-.phi. H
--C(O)OCH.sub.3 3,5-di-F-.phi.- --CH.sub.3 H H H
--C(O)OCH.sub.2CH.sub.2.phi. 3,5-di-F-.phi.- --CH.sub.3 H H H
--C(O)OCH.sub.2CH.sub.2CH.sub.2.phi. 3,5-di-F-.phi.- --CH.sub.3 H
pyrid-4-yl H --C(O)NH.sub.2 .phi.- --CH.sub.3 H --CH(OH)CH.sub.3 H
--C(O)OCH.sub.3 .phi.- --CH.sub.3 H --CH.sub.2CH(CH.sub.3).sub.2 H
--C(O)NH.sub.2 .phi.- --CH.sub.3 H --CH.sub.3 H --C(O)NH.sub.2
.phi.- --CH.sub.3 H --CH.sub.2-.phi. H --C(O)NH.sub.2 .phi.-
--CH.sub.3 H --CH(CH.sub.3).sub.2 H --C(O)NH.sub.2 3,5-di-F-.phi.-
--CH.sub.3 H pyrid-3-yl H --C(O)OCH.sub.2CH.sub.3 .phi.- --CH.sub.3
H --CH.sub.2CH(CH.sub.3).sub.2 H --C(O)NHCH.sub.3 .phi.- --CH.sub.3
H --CH.sub.2-.phi. H --C(O)N(CH.sub.3).sub.2 .phi.- --CH.sub.3 H
--CH.sub.2CH(CH.sub.3).sub.2 H --C(O)N(CH.sub.3).sub.2 .phi.-
--CH.sub.3 H --CH(CH.sub.3).sub.2 H --C(O)N(CH.sub.3).sub.2 .phi.-
--CH.sub.3 H --CH.sub.2-.phi. H --C(O)NHCH.sub.3 .phi.- --CH.sub.3
H --CH.sub.2(CH.sub.3).sub.2 H --C(O)NHCH.sub.3 3,5-di-F-.phi.-
--CH.sub.3 H --CH.sub.2CH.sub.2CH.sub.2CH.sub.3 H --C(O)NHCH.sub.3
3,5-di-F-.phi.- --CH.sub.3 H --CH.sub.2CH.sub.2CH.sub.2CH.sub.3 H
--C(O)N(CH.sub.3).sub.2 3,5-di-F-.phi.- --CH.sub.3 H
--CH.sub.2CH.sub.2CH.sub.2CH.sub.3 H --C(O)NH.sub.2 3,5-di-F-.phi.-
--CH.sub.3 H m-CH.sub.3O-.phi.- H --C(O)OCH.sub.3 3,5-di-F-.phi.-
--CH.sub.3 H p-CH.sub.3O-.phi.- H --C(O)OCH.sub.3 3,5-di-F-.phi.-
--CH.sub.3 H pyrid-2-yl H --C(O)OCH.sub.2CH.sub.3 3,5-di-F-.phi.-
--CH.sub.3 H pyrid-4-yl H --C(O)OCH.sub.2CH.sub.3 cyclohexyl
--CH.sub.3 H --CH.sub.2-.phi. H --C(O)OCH.sub.3 cyclopentyl
--CH.sub.3 H --CH.sub.2-.phi. H --C(O)OCH.sub.3 cyclohex-1-enyl
--CH.sub.3 H --CH.sub.2-.phi. H --C(O)OCH.sub.3 3,5-di-F-.phi.-
--CH.sub.3 H R.sup.4/R.sup.5 = -cyclopropyl --C(O)OCH.sub.3
3,5-di-F-.phi.- --CH.sub.3 H --CH.sub.3 H
--C(O)N(CH.sub.3)CH.sub.2CH.sub.2N(CH.sub.3).sub.2 cyclopropyl
--CH.sub.3 H --CH.sub.2.phi. H --C(O)OCH.sub.3 3,5-di-F-.phi.-
--CH.sub.3 H H H --C(O)OCH.sub.2-.phi. (CH.sub.3).sub.2CH-- -.phi.
H --CH.sub.3 H --C(O)OCH.sub.2CH.sub.3 3-NO.sub.2-.phi.- --CH.sub.3
H --CH.sub.2-.phi. H --C(O)OCH.sub.3 3-NO.sub.2-.phi.- --CH.sub.3 H
--CH.sub.3 H --C(O)OCH.sub.2CH.sub.3 3-NO.sub.2-.phi.- --CH.sub.3 H
H H --C(O)OCH.sub.2CH.sub.3 3-NO.sub.2-.phi.- --CH.sub.3 H
--CH(OH)CH.sub.3 H --C(O)NHOH (CH.sub.3).sub.2CH-- -.phi. H
--CH.sub.3 H --C(O)OCH.sub.2CH(CH.sub.3).sub.2 3-NO.sub.2-.phi.-
--CH.sub.3 H m-hydroxybenzyl H --C(O)OCH.sub.3 3-NO.sub.2-.phi.-
--CH.sub.3 H p-hydroxybenzyl H --C(O)OCH.sub.2CH.sub.3
(CH.sub.3).sub.2CH-- --CH(CH.sub.3)CH.sub.2CH.sub.3 H --CH.sub.3 H
--C(O)OCH.sub.2CH(CH.sub.3).sub.2 (CH.sub.3).sub.2CH--
--CH.sub.2-.phi. H --CH.sub.3 H --C(O)OCH.sub.2CH(CH.sub.3).sub.2
3,5-di-F-.phi.- --CH.sub.3 H --CH.sub.3 H --C(O)OCH.sub.2CH.sub.3
3-NO.sub.2-.phi.- --CH.sub.3 R.sub.3/R.sub.4 and N = H
--C(O)OCH.sub.2CH.sub.3 2,3-dihydro- indol-2-yl 3,5-di-F-.phi.-
--CH.sub.3 H --CH.sub.3 H --C(O)NH.sub.2 (CH.sub.3).sub.2CH--
-.phi. H --CH.sub.3 H --C(O)N(CH.sub.3)--OCH.sub.3 3,5-di-F-.phi.-
--CH.sub.3 H --CH.sub.3 H --C(O)NHCH.sub.2CH(CH.sub.3).sub.2
3,5-di-F-.phi.- --CH.sub.3 H --CH.sub.3 H
--C(O)N(CH.sub.2CH.sub.2CH.sub.3).sub.2 3,5-di-F-.phi.- --CH.sub.3
H --CH(CH.sub.3).sub.2 H --C(O)NH.sub.2 3,5-di-F-.phi.- --CH.sub.3
H --CH.sub.3 H --C(O)NH-(p-NO.sub.2-.phi.) 3,5-di-F-.phi.-
--CH.sub.3 H --CH.sub.2-.phi. H --C(O)OCH.sub.3 3,5-di-F-.phi.-
--CH.sub.3 H --CH.sub.2-.phi. H --C(O)NH.sub.2 (CH.sub.3).sub.2CH--
-.phi. H --CH.sub.3 H --C(O)NHCH.sub.2CH(CH.sub.3).sub.2
3,5-di-F-.phi.- --CH.sub.3 H --CH.sub.2-.phi. H
--C(O)NHCH.sub.2CH.sub.2OCH.sub.3 3,5-di-F-.phi.- --CH.sub.3 H
--CH.sub.3 H --C(O)NHCH.sub.2-(p-NO.sub.2-.phi.) 3,5-di-F-.phi.-
--CH.sub.3 H --CH.sub.2-.phi. H --C(O)NH-(p-NO.sub.2-.phi.)
3,5-di-F-.phi.- --CH.sub.3 H --CH.sub.3 H
--C(O)N(CH.sub.3)CH.sub.2-.phi. 3,5-di-F-.phi.- --CH.sub.3 H
--CH.sub.3 H --C(O)NHCH.sub.2-(3,5-di-F-.phi.) 3,5-di-F-.phi.-
--CH.sub.3 H --CH.sub.3 H --C(O)NHCH.sub.2-(m-NO.sub.2-.phi.)
3,5-di-F-.phi.- --CH.sub.3 H --CH.sub.3 H --C(O)NHCH.sub.2-.phi.
3,5-di-F-.phi.- --CH.sub.3 H --CH.sub.2-.phi. H
--C(O)NHCH.sub.2-(p-NO.sub.2-.phi.) 3,5-di-F-.phi.- --CH.sub.3 H
--CH.sub.2-indol-3-yl H --C(O)OCH.sub.3 3,5-di-F-.phi.- --CH.sub.3
H --CH.sub.3 H --C(O)NHCH.sub.2-(p-OCH.sub.3-.phi.) .phi.- -.phi. H
--CH.sub.3 H --C(O)OCH.sub.2CH.sub.3 cyclohexyl- -.phi. H
--CH.sub.3 H --C(O)OCH.sub.2CH.sub.3 3,5-di-F-.phi.- --CH.sub.3 H
-.phi. H --C(O)OCH.sub.3 3,5-di-F-.phi.- --CH.sub.3 H --CH.sub.3 H
--C(O)NHCH.sub.2CH.sub.2-.phi. 3,5-di-F-.phi.- --CH.sub.3 H
--CH.sub.2-indol-3-yl H --C(O)NH.sub.2 3,5-di-F-.phi.- --CH.sub.3 H
--CH.sub.2-cyclohexyl H --C(O)OCH.sub.3 3,5-di-F-.phi.- --CH.sub.3
H p-NO.sub.2-benzyl- H --C(O)NHCH.sub.2CH.sub.2OCH.sub.3
3-NO.sub.2-.phi.- --CH.sub.3 H --CH.sub.2OH H
--C(O)OCH.sub.2CH.sub.3 3,5-di-F-.phi.- --CH.sub.3 H --CH.sub.3 H
--C(O)NHCH(CH.sub.3).phi. 3,5-di-F-.phi.- --CH.sub.3 H --CH.sub.3 H
--C(O)NHCH(CH.sub.3).phi. 3,5-di-F-.phi.- --CH.sub.3 H --CH.sub.3 H
--C(O)NHCH.sub.2-(p-F-.phi.) 3,5-di-F-.phi.- --CH.sub.3 H
--CH.sub.3 H --C(O)NHCH.sub.2-(pyrid-4-yl) 3,5-di-F-.phi.-
--CH.sub.3 H --CH.sub.3 H --C(O)NHCH.sub.2-(p-F.sub.3C-.phi.)
3,5-di-F-.phi.- --CH.sub.3 H -.phi. --CH.sub.3
--C(O)OCH.sub.2CH.sub.3 3,5-di-F-.phi.- --CH.sub.3 H
--CH.sub.2-.phi. H --C(O)OC(CH.sub.3).sub.3 3,5-di-F-.phi.-
--CH.sub.3 H --CH.sub.3 --CH.sub.3 --C(O)OCH.sub.3 3,5-di-F-.phi.-
--CH.sub.3 H cyclohexyl H --C(O)OCH.sub.2CH.sub.3 3,5-di-F-.phi.-
--CH.sub.3 H -.phi. H --C(O)NHCH.sub.2CH.sub.2OCH.sub.3
(CH.sub.3).sub.2CH-- cyclohexyl H --CH.sub.3 H
--C(O)OCH.sub.2CH.sub.3 3,5-di-F-.phi.- --CH.sub.3 H -.phi. H
--C(O)NHCH.sub.2CH.sub.2N(CH.sub.3).sub.2 3,5-di-F-.phi.-
--CH.sub.3 H -.phi. H --C(O)NHCH.sub.2-(pyrid-2-yl) pyrid-3-yl
--CH.sub.3 H --CH.sub.2-.phi. H --C(O)OCH.sub.3 pyrid-2-yl
--CH.sub.3 H --CH.sub.2-.phi. H --C(O)OCH.sub.3 pyrid-4-yl
--CH.sub.3 H --CH.sub.2-.phi. H --C(O)OCH.sub.3 3,5-di-F-.phi.-
--CH.sub.3 H p-F-.phi. H --C(O)OCH.sub.2CH.sub.3 3,5-di-F-.phi.-
--CH.sub.3 H o-F-.phi. H --C(O)OCH.sub.2CH.sub.3 3,5-di-F-.phi.-
-.phi. H --CH.sub.3 H --C(O)OCH.sub.2CH.sub.3 3,5-di-F-.phi.-
--CH.sub.3 H --CH.sub.2--N-phthalimidyl H --C(O)OCH.sub.2CH.sub.3
3,5-di-F-.phi.- --CH.sub.3 H p-F-.phi. H
--C(O)OCH.sub.2C(CH.sub.3).sub.3 3,5-di-F-.phi.- --CH.sub.3 H
-.phi. H --C(O)OCH.sub.2C(CH.sub.3).sub.3 3,5-di-F-.phi.-
--CH.sub.3 H -.phi. H --C(O)NHC(CH.sub.3).sub.3 3,5-di-F-.phi.-
--CH.sub.3 H -.phi. H --C(O)OC(CH.sub.3).sub.3 3,5-di-F-.phi.-
--CH.sub.3 H -.phi. H --C(O)OC(CH.sub.3).sub.3 3,5-di-F-.phi.-
--CH.sub.3 H -.phi. H --C(O)NH.sub.2 3-NO.sub.2-.phi.- --CH.sub.3 H
--CH(CH.sub.3).sub.2 H --C(O)--N-morpholino 3-NO.sub.2-.phi.-
--CH.sub.3 H --CH(CH.sub.3).sub.2 H --C(O)OCH.sub.2CH.sub.3
3-NO.sub.2-.phi.- --CH.sub.3 H --CH(OH)CH.sub.3 H --C(O)OCH.sub.3
3-NO.sub.2-.phi.- --CH.sub.3 H ##STR4## H --C(O)--N-morpholino
3-NO.sub.2-.phi.- --CH.sub.3 H --CH(CH.sub.3)CH.sub.2CH.sub.3 H
--C(O)--N-morpholino 3-NO.sub.2-.phi.- --CH.sub.3 H
--CH(CH.sub.3)CH.sub.2CH.sub.3 H --C(O)OCH.sub.3 3-NO.sub.2-.phi.-
--CH.sub.3 H --CH(CH.sub.3)CH.sub.2CH.sub.3 H --C(O)OH
3-NO.sub.2-.phi.- --CH.sub.3 H --CH.sub.2CH.sub.2CH.sub.3 H
--C(O)OCH.sub.3 3-NO.sub.2-.phi.- --CH.sub.3 H
--CH.sub.2CH(CH.sub.3).sub.2 H --C(O)OCH.sub.3 3,5-di-F-.phi.-
--CH.sub.3 H --CH.sub.2CH(CH.sub.3).sub.2 H --C(O)OCH.sub.3
3,5-di-F-.phi.- --CH.sub.3 H --CH.sub.3 H
--C(O)NHCH.sub.2CH.sub.2OCH.sub.3 3,5-di-F-.phi.- --CH.sub.3 H
--CH.sub.3 H --C(O)NHCH.sub.2CH.sub.2N(CH.sub.3).sub.2
3,5-di-F-.phi.- --CH.sub.3 H --CH.sub.3 H --C(O)NH-cyclohexyl
3,5-di-F-.phi.- --CH.sub.3 H --CH.sub.3 H
--C(O)NHCH.sub.2C(CH.sub.3).sub.3 3,5-di-F-.phi.- --CH.sub.3 H
--CH.sub.3 H --C(O)NHCH.sub.2-(tetra- hydrofuran-2-yl
3,5-di-F-.phi.- --CH.sub.3 H --CH.sub.3 H
--C(O)NHCH.sub.2-(pyrid-2-yl) 3,5-di-F-.phi.- --CH.sub.3 H
--CH.sub.3 H --C(O)--(N-thiazolidinyl) 3,5-di-F-.phi.- --CH.sub.3 H
--CH.sub.2CH.sub.3 H --C(O)OCH.sub.3 3,5-di-F-.phi.- --CH.sub.3 H
--CH.sub.2CH.sub.2CH.sub.3 H --C(O)OCH.sub.3 3,NO.sub.2-.phi.-
--CH.sub.3 H --CH.sub.2CH.sub.3 H --C(O)OCH.sub.3 3,5-di-F-.phi.-
--CH.sub.3 H --CH.sub.3 H --C(O)NHCH(CH.sub.3)CH.sub.2CH.sub.3
3,5-di-F-.phi.- --CH.sub.3 H --CH.sub.3 H --C(O)--(N-pyrrolidinyl)
3,5-di-F-.phi.- --CH.sub.3 H --CH.sub.3 H
--C(O)NHCH(CH.sub.3)CH.sub.2CH.sub.3 3,5-di-F-.phi.- --CH.sub.3 H
--CH(CH.sub.3).sub.2 H --C(O)OCH.sub.3 3,5-di-F-.phi.- --CH.sub.3 H
--CH.sub.3 H --C(O)NHCH.sub.2CH.sub.2--F 3,5-di-F-.phi.- --CH.sub.3
H --CH.sub.3 H --C(O)CH.sub.2CH.sub.2CH(CH.sub.3).sub.2
3,5-di-F-.phi.- --CH.sub.3 H --CH.sub.2CH.sub.3 H
--C(O)NHCH.sub.2-(p-NO.sub.2-.phi.)
3,5-di-F-.phi.- --CH.sub.3 H --CH.sub.2CH.sub.2CH.sub.3 H
--C(O)NHCH.sub.2-(p-NO.sub.2-.phi.) 3,5-di-F-.phi.- --CH.sub.3 H
m-F-.phi.- H --C(O)OCH.sub.3 3,5-di-F-.phi.- --CH.sub.3 H
thien-2-yl H --C(O)NH.sub.2 3,5-di-F-.phi.- --CH.sub.3 H thien-2-yl
H --C(O)NH.sub.2 3,5-di-F-.phi.- --CH.sub.3 H
5-chlorobenzo[b]thiophen- H --C(O)OCH.sub.3 2-yl 3,5-di-F-.phi.-
--CH.sub.3 H benzo[b]thiophen-6-yl H --C(O)OCH.sub.2CH.sub.3
3,5-di-F-.phi.- --CH.sub.3 H benzo[b]thiophen-2-yl H
--C(O)OCH.sub.2CH.sub.3 3,5-di-F-.phi.- --CH.sub.3 H
benzo[b]thiophen-2-yl H --C(O)OCH.sub.2CH.sub.3 3,5-di-F-.phi.-
--CH.sub.3 H benzo[b]thiophen-3-yl H --C(O)OCH.sub.3
3,5-di-F-.phi.- --CH.sub.3 H thien-2-yl H --C(O)OCH.sub.3
3,5-di-F-.phi.- --CH.sub.3 H benzo[b]thiophen-5-yl H
--C(O)OCH.sub.2CH.sub.3 3,5-di-F-.phi.- --CH.sub.3 H thien-2-yl H
--C(O)OCH.sub.3 3,5-di-F-.phi.- --CH.sub.3 H thien-2-yl H
--C(O)OC(CH.sub.3).sub.3 3,5-di-F-.phi.- --CH.sub.3 H thien-2-yl H
--C(O)OH 3,5-di-F-.phi.- --CH.sub.3 H tetrazol-5-yl H
--C(O)OCH.sub.3 3,5-di-F-.phi.- --CH.sub.3 H 2-aminopyrid-6-yl H
--C(O)OCH.sub.3 3,5-di-F-.phi.- --CH.sub.3 H 6-methoxynaphth-2-yl H
--C(O)OCH.sub.3 3,5-di-F-.phi.- --CH.sub.3 H m-CF.sub.3-.phi.- H
--C(O)OCH.sub.3 3,5-di-F-.phi.- --CH.sub.3 H 4,5,6,7-tetrahydro- H
--C(O)OCH.sub.3 benzo[b]thiophen-2-yl 3,5-di-F-.phi.- --CH.sub.3 H
thieno[2,3-b]thiophen-2-yl H --C(O)OCH.sub.3 3,5-di-F-.phi.-
--CH.sub.3 H 2-methylthiazol-4-yl H --C(O)OCH.sub.3 3,5-di-F-.phi.-
--CH.sub.3 H --CH.sub.2CH.dbd.CHCH.sub.3 H --C(O)OCH.sub.3 (trans)
cyclopropyl --CH.sub.3 H -.phi. H --C(O)OC(CH.sub.3).sub.3
3,5-di-F-.phi.- --CH.sub.3 H (p-.phi.)-.phi. H
--C(O)NHC(CH.sub.3).sub.3 3,5-di-F-.phi.- --CH.sub.2CH.sub.3 H
-.phi. H --C(O)OC(CH.sub.3).sub.3 3,5-di-F-.phi.-
--CH(CH.sub.3).sub.2 H -.phi. H --C(O)OC(CH.sub.3).sub.3
3,5-di-F-.phi.- --CH.sub.2CH.sub.2SCH.sub.3 H -.phi. H
--C(O)OCH.sub.3 3,5-di-F-.phi.- --CH(CH.sub.3).sub.2 H -.phi. H
--C(O)OCH.sub.3 3,5-di-F-.phi.- --CH.sub.2CH.sub.3 H -.phi. H
--C(O)OCH.sub.3 3,5-di-F-.phi.- --CH.sub.2CH(CH.sub.3).sub.2 H
-.phi. H --C(O)OCH.sub.3 3,5-di-F-.phi.- --CH.sub.2.phi. H -.phi. H
--C(O)OCH.sub.3 3,5-di-F-.phi.- --H H -.phi. H --C(O)OCH.sub.3
3,5-di-F-.phi.- -.phi. H -.phi. H --C(O)OC(CH.sub.3).sub.3
3,5-di-F-.phi.- -.phi. H -.phi. H --C(O)OCH.sub.3 .phi.- --CH.sub.3
H --CH.sub.3 H --C(O)OCH.sub.3 .phi.- --CH.sub.3 H
--CH.sub.2CH(CH.sub.3).sub.2 H --C(O)OCH.sub.3 .phi.- --CH.sub.3 H
--CH(CH.sub.3)CH.sub.2CH.sub.3 H --C(O)OCH.sub.3 .phi.- --CH.sub.3
R.sub.3/R.sub.4 and N = H --C(O)OCH.sub.3 L-pyrrolidinyl .phi.-
--CH.sub.3 H --CH.sub.2-.phi. H --C(O)OCH.sub.3 .phi.- --CH.sub.3 H
--(CH.sub.2).sub.4NHC(O)O- H --C(O)OCH.sub.3 t-butyl .phi.-
--CH.sub.3 H H H --C(O)OCH.sub.3 .phi.- --CH.sub.3 H
--CH(CH.sub.3).sub.2 H --C(O)OCH.sub.3 .phi.- --CH.sub.3 H
--CH.sub.2CH.sub.2 H --C(O)OCH.sub.3 .phi.- --CH.sub.3 H
--CH.sub.2CH.sub.2CH.sub.3 H --C(O)OCH.sub.3 3,NO.sub.2-.phi.-
--CH.sub.3 H --CH(CH.sub.3).sub.2 H --C(O)OH .phi.- --CH.sub.3
--CH.sub.3 --CH.sub.3 H --C(O)OCH.sub.3 (CH.sub.3).sub.2CH-- -.phi.
H --CH.sub.3 H --C(O)OCH.sub.2CH(CH.sub.3).sub.2
(CH.sub.3).sub.2CH-- --CH(CH.sub.3)CH.sub.2CH.sub.3 H --CH.sub.3 H
--C(O)OCH.sub.2CH(CH.sub.3).sub.2 3,5-di-F-.phi.- --CH.sub.3 H
-.phi. H --C(O)NH-cyclohexyl 3,5-di-F-.phi.- --CH.sub.3
R.sup.3/R.sup.4 and N = H --C(O)OCH.sub.2CH.sub.3 4-.beta.-hydroxy-
pyrrolidin-2-yl 3,5-di-F-.phi.- --CH.sub.3 H
--(CH.sub.2).sub.4NH.sub.2 H --C(O)OCH.sub.3 3,5-di-F-.phi.-
--CH.sub.3 H --CH.sub.2CH.sub.2C(O)NH.sub.2 H --C(O)NH.sub.2
3,5-di-F-.phi.- --CH.sub.3 R.sub.3/R.sub.4 and N = H
--C(O)OCH.sub.3 piperidin-2-yl 3,5-di-F-.phi.- --CH.sub.3 H H H
--C(O)NHCH.sub.2CH.sub.2OCH.sub.3 3,5-di-F-.phi.- -cyclohexyl H
-.phi. H --C(O)OCH.sub.3 3,5-di-F-.phi.- --CH.sub.3 H
--CH.sub.2-.phi. H --C(O)NHCH.sub.2-pyrid-2-yl 3,5-di-F-.phi.-
-thien-2-yl H -.phi. H --C(O)OC(CH.sub.3).sub.3 3,5-di-F-.phi.-
.phi. H -.phi. H --C(O)NH.sub.2 3,5-di-F-.phi.-
--CH(CH.sub.3).sub.2 H -.phi. H --C(O)NH.sub.2 -thienyl --CH.sub.3
H -.phi. H --C(O)NH.sub.2 CH.sub.3(CH.sub.2).sub.2-- --CH.sub.3 H
-.phi. H --C(O)NH.sub.2 3,5-di-F-.phi.- --(CH.sub.2).sub.3CH.sub.3
H -.phi. H --C(O)OCH.sub.3 3,5-di-F-.phi.-
--(CH.sub.2).sub.2CH.sub.3 H -.phi. H --C(O)OCH.sub.3
3,5-di-F-.phi.- --C(CH.sub.2).sub.3 H -.phi. H --C(O)OCH.sub.3
3,5-di-F-.phi.- --C(CH.sub.3)CH.sub.2CH.sub.3 H -.phi. H
--C(O)OCH.sub.3 3,5-di-F-.phi.- --CH.sub.2.phi. H -.phi. H
--C(O)OCH.sub.3 3,5-di-F-.phi.- -cyclopropyl H -.phi. H
--C(O)OCH.sub.3 3,5-di-F-.phi.- -thien-3-yl H -.phi. H
--C(O)OCH.sub.3 3,5-di-F-.phi.- -thien-2-yl H -.phi. H
--C(O)OCH.sub.3 3,5-di-F-.phi.- p-F-.phi. H -.phi. H
--C(O)OCH.sub.3 3,5-di-F-.phi.- p-OCH.sub.3-.phi. H -.phi. H
--C(O)OCH.sub.3 3,5-di-F-.phi.- -.phi. H -.phi. H
--C(O)OC(CH.sub.3).sub.3 -cyclopropyl -.phi. H -.phi. H
--C(O)OC(CH.sub.3).sub.3 -cyclopentyl -.phi. H -.phi. H
--C(O)OC(CH.sub.3).sub.3 --C(CH.sub.3).sub.3 --CH.sub.3 H -.phi. H
--C(O)NH.sub.2 3,5-di-F-.phi.- --CH.sub.3 H 5-bromothien-2-yl H
--C(O)NHC(CH.sub.3).sub.3 3,5-di-F-.phi.- --CH.sub.3 H
4-bromothien-2-yl H --C(O)NHC(CH.sub.3).sub.3 3,5-di-F-.phi.-
--CH.sub.3 H thien-2-yl H --C(O)NHC(CH.sub.3).sub.3 3,5-di-F-.phi.-
--CH.sub.3 H thien-3-yl H --C(O)NHC(CH.sub.3).sub.3 3,5-di-F-.phi.-
--CH.sub.3 H -.phi. H --C(O)NHC(CH.sub.3).sub.3 3,5-di-F-.phi.-
--CH.sub.3 H 5-chlorothien-2-yl H --C(O)NHC(CH.sub.3).sub.3
3,5-di-F-.phi.- --CH.sub.3 H (p-.phi.)-.phi.- H --C(O)NH-cyclohexyl
3,5-di-F-.phi.- --CH.sub.3 H (m-phenoxy)-.phi.- H
--C(O)NHC(CH.sub.3).sub.3 3,5-di-F-.phi.- --CH.sub.3 H -.phi. H
--C(O)NH-cyclohexyl 3,5-di-F-.phi.- --CH.sub.3 H (m-.phi.)-.phi.- H
--C(O)NHC(CH.sub.3).sub.3 3,5-di-F-.phi.- --CH.sub.3 H
(p-CH.sub.3CH.sub.2)-.phi.- H --C(O)NHC(CH.sub.3).sub.3
3,5-di-F-.phi.- --CH.sub.3 H (p-.phi.)-.phi.- H
--C(O)NHC(CH.sub.3).sub.3 3,5-di-F-.phi.- --CH.sub.3 H
(p-benzyl)-.phi.- H --C(O)NHC(CH.sub.3).sub.3 3,5-di-F-.phi.-
--CH.sub.3 H (p-Br)-.phi.- H --C(O)NHC(CH.sub.3).sub.3
3,5-di-F-.phi.- --CH.sub.3 H (p-.phi.)-.phi.- H
--C(O)NHC(CH.sub.3).sub.3 3,5-di-F-.phi.- --CH.sub.3 H
(p-CH.sub.3CH.sub.2.phi.)-.phi.- H --C(O)NHC(CH.sub.3).sub.3
3,5-di-F-.phi.- --CH.sub.3 H (p-tert-butyl)-.phi.- H
--C(O)NHC(CH.sub.3).sub.3 3,5-di-F-.phi.- --CH.sub.3 H
p-(4-Cl-phenoxy)-.phi.- H --C(O)NHC(CH.sub.3).sub.3 3,5-di-F-.phi.-
--CH.sub.3 H (p-.phi.)-.phi.- H --C(O)NH-cyclohexyl 3,5-di-F-.phi.-
--CH.sub.3 H -.phi. H --C(O)OC(CH.sub.3).sub.3 3,5-di-F-.phi.-
--CH.sub.3 H --CH.sub.3 H --C(O)-.phi. 3,5-di-F-.phi.- --CH.sub.3 H
pyrid-3-yl H --C(O)OC(CH.sub.3).sub.3 3,5-di-F-.phi.- --CH.sub.3 H
-.phi. H --C(O)-morpholino 3,5-di-F-.phi.- --CH.sub.3 H
(m-methoxy)-.phi. H --C(O)OCH.sub.3 3,5-di-F-.phi.- --CH.sub.3 H
-.phi. H --C(O)ONHC(O)OC(CH.sub.3).sub.3 3,5-di-F-.phi.- --CH.sub.3
H -.phi. H --C(O)NHC(CH.sub.3).sub.3 3,5-di-F-.phi.- --CH.sub.3 H
-.phi. H --C(O)NHCH.sub.2-furan-2-yl 3,5-di-F-.phi.- --CH.sub.3 H
-.phi. H --C(O)NHOCH.sub.3 3,5-di-F-.phi.- --CH.sub.3 H -.phi. H
--C(O)-cyclobutylamide 3,5-di-F-.phi.- --CH.sub.3 H -.phi. H
--C(O)NHCH.sub.2CH(CH.sub.3).sub.2 3,5-di-F-.phi.- --CH.sub.3 H
-.phi. H --C(O)NHCH.sub.2-cyclopropyl 3,5-di-F-.phi.- --CH.sub.3 H
-.phi. H --C(O)N(CH.sub.3)OCH.sub.3 3,5-di-F-.phi.- --CH.sub.3 H
-.phi. H --C(O)NCH.sub.2C(CH.sub.3).dbd.CH.sub.2 3,5-di-F-.phi.-
--CH.sub.3 H -.phi. H --C(O)CH.sub.2-pyrid-3-yl 3,5-di-F-.phi.-
--CH.sub.3 H -.phi. H --C(O)CH.sub.2-pyrid-4-yl 3,5-di-F-.phi.-
--CH.sub.3 H -.phi. H --C(O)CH.sub.2-fur-2-yl 3,5-di-F-.phi.-
--CH.sub.3 H -.phi. H --C(O)NH-cyclopentyl 3,5-di-F-.phi.-
--CH.sub.3 H -.phi. H --C(O)NH-[(p-benzyl)-pyrid-4-yl]
3,5-di-F-.phi.- --CH.sub.3 H -.phi. H --C(O)N(CH.sub.3).sub.2
3,5-di-F-.phi.- --CH.sub.3 H -.phi. H
--C(O)NH-[2,6-dimethylpyrid-4- yl] 3,5-di-F-.phi.- --CH.sub.3 H
-.phi. H --C(O)NH-(2-methylcyclohexyl) 3,5-di-F-.phi.- --CH.sub.3 H
-.phi. H --C(O)NH-(4-methylcyclohexyl) 3,5-di-F-.phi.- --CH.sub.3 H
-.phi. H --C(O)NH--[N-ethoxycarbonyl]- piperidin-4-yl
3,5-di-F-.phi.- --CH.sub.3 H -.phi. H --C(O)NHCH.sub.3
3,5-di-F-.phi.- --CH.sub.3 H -.phi. H --C(O)NHOC(CH.sub.3).sub.3
3,5-di-F-.phi.- --CH.sub.3 H -.phi. H --C(O)ONHC(CH.sub.3).sub.3
3,5-di-F-.phi.- --CH.sub.3 H -.phi. H --C(O)NHNH.sub.2
3,5-di-F-.phi.- --CH.sub.3 H -.phi. H
--C(O)NHN.dbd.C(CH.sub.3)OCH.sub.2CH.sub.3 -.phi. --CH.sub.3 H
-.phi. H --C(O)OC(CH.sub.3).sub.3 3,5-di-F-.phi.- --CH.sub.3 H
-.phi. H --C(O)NH(CH.sub.2).sub.4-.phi. 3,5-di-F-.phi.- --CH.sub.3
H -.phi. H --C(O)NH(CH.sub.2).sub.3O-(p-CH.sub.3).phi.
3,5-di-F-.phi.- --CH.sub.3 H -.phi. H
--C(O)NH(CH.sub.2).sub.6NH.sub.2 3,5-di-F-.phi.- 3,5-di-F-.phi.- H
3,5-di-F-.phi.- H --C(O)OCH.sub.3 3,5-di-F-.phi.- --CH.sub.3 H
--CH.sub.2CH.sub.2CH.sub.2CH.sub.3 H --C(O)OH -cyclopentyl
--CH.sub.3 H -.phi. H --C(O)OC(CH.sub.3).sub.3 3,5-di-F-.phi.-
thien-2-yl H -.phi. H --C(O)OC(CH.sub.3).sub.3 3,5-di-F-.phi.-
--CH.sub.3 R.sub.3/R.sub.4 and N = H --C(O)OCH.sub.3
L-(3-.alpha.-phenyl)- pyrrolidinyl 3,5-di-F-.phi.- --CH.sub.3
R.sub.3/R.sub.4 and N = H --C(O)OCH.sub.3 L-azetidin-2-yl
3,5-di-F-.phi.- --CH.sub.3 H 5-chlorobenzo[b]thiophen- H
--C(O)OCH.sub.3 3-yl 3,5-di-F-.phi.- --CH.sub.3 H
--CH.sub.2-thiazol-4-yl H --C(O)OC(CH.sub.3).sub.3 3,5-di-F-.phi.-
--CH.sub.3 H -.phi. H --C(O)NHC(CH.sub.3).sub.3 3,5-di-F-.phi.-
--CH.sub.3 H thien-2-yl H --C(O)NH.sub.2 3,5-di-Cl-.phi.-
--CH.sub.3 H -.phi. H --C(O)NH.sub.2 3-Cl-.phi.- --CH.sub.3 H
-.phi. H --C(O)NH.sub.2 3-Br-.phi.- --CH.sub.3 H -.phi. H
--C(O)NH.sub.2 3-F-.phi.- --CH.sub.3 H -.phi. H --C(O)NH.sub.2
4-F-.phi.- --CH.sub.3 H -.phi. H --C(O)NH.sub.2 3-CH.sub.3-.phi.-
--CH.sub.3 H -.phi. H --C(O)NH.sub.2 4-CH.sub.3-.phi.- --CH.sub.3 H
-.phi. H --C(O)NH.sub.2 3-CF.sub.3-.phi.- --CH.sub.3 H -.phi. H
--C(O)NH.sub.2 3-CH.sub.3O-.phi.- --CH.sub.3 H -.phi. H
--C(O)NH.sub.2 2-Cl-.phi.- --CH.sub.3 H -.phi. H --C(O)NH.sub.2
1-naphthyl --CH.sub.3 H -.phi. H --C(O)NH.sub.2 2-naphthyl
--CH.sub.3 H -.phi. H --C(O)NH.sub.2 .phi.- --CH.sub.3 H -.phi. H
--C(O)NH.sub.2 3,5-di-F-.phi.- --CH.sub.3 H -.phi. H --COOH
3,5-di-F-.phi.- --CH.sub.3 H furan-2-yl H --C(O)NH.sub.2
3,4-di-F-.phi.- --CH.sub.3 H -.phi. H --C(O)NH.sub.2
3,5-di-F-.phi.- --CH.sub.3 H --CH.sub.2-.phi. H
--C(O)NH--SO.sub.2--CH.sub.3 3,5-di-F-.phi.- --CH.sub.3 H H H
--C(O)N(CH.sub.3).phi. 3,5-di-F-.phi.- --CH.sub.3 H --CH.sub.3 H
--C(O)N(CH.sub.3).phi. 3,5-di-F-.phi.- --CH.sub.2CH.sub.2SCH.sub.3
H -.phi. H --C(O)NH.sub.2 3,5-di-F-.phi.- --CH.sub.3 H H H
--C(O)N(CH.sub.3)CH.sub.2.phi. 3,5-di-F-.phi.- --CH.sub.3 H -.phi.
H --C(O)NHCH.sub.2(p-F-.phi.) 3,5-di-F-.phi.- --CH.sub.3 H
4-fluorophenyl H --C(O)OCH.sub.2C(CH.sub.3).sub.3
2,3,4,5,6-penta-F-.phi.- --CH.sub.3 H -.phi. H --C(O)OCH.sub.3
3,5-di-F-.phi.- --CH.sub.2OCH.sub.2-.phi. H -.phi. H
--C(O)OCH.sub.3 3,5-di-F-.phi.- --CH(CH.sub.3)OCH.sub.2-.phi. H
-.phi. H --C(O)OCH.sub.3 3,5-di-F-.phi.- --CH(OH)CH.sub.3 H -.phi.
H --C(O)OCH.sub.3 3,5-di-F-.phi.- --CH.sub.2OH H -.phi. H
--C(O)OCH.sub.3 3,5-di-F-.phi.- --CH.sub.3 H -.phi. H
--C(O)NH-(4-methylphenyl) 3,5-di-F-.phi.- --CH.sub.3 H -.phi. H
--C(O)NH-2-tetrahydrofurfuryl 3,5-di-F-.phi.- --CH.sub.3 H
4-fluoro-.phi. H --C(O)NH.sub.2 3,5-di-F-.phi.-
--CH.sub.2CH.sub.2SCH.sub.3 H -.phi. H --C(O)NH.sub.2
3,5-di-F-.phi.- --CH.sub.2CH.sub.3 H -.phi. H --C(O)NH.sub.2
3,5-di-F-.phi.- -.phi. H -.phi. H --C(O)NH.sub.2 3,5-di-F-.phi.-
--CH(CH.sub.3).sub.2 H -.phi. H --C(O)NH.sub.2 3,5-di-F-.phi.-
--CH.sub.3 H -.phi. H --C(O)NHCH(CH.sub.3).phi. 3,5-di-F-.phi.-
--CH.sub.3 H -.phi. H --C(O)CH(CH.sub.3).sub.2 3,5-di-F-.phi.-
--CH.sub.3 H -.phi. H --C(O)CH.sub.3 3,5-di-F-.phi.- --CH.sub.3 H
-.phi. H --C(O)CH.sub.2CH.sub.2CH.sub.3 3,5-di-F-.phi.- --CH.sub.3
H -.phi. H --C(O)-.phi. 3,5-di-F-.phi.- --CH.sub.3 H -.phi. H
--C(O)CH.sub.2CH.sub.3 3,5-di-F-.phi.- --CH.sub.3 H -.phi. H
--C(O)CH.sub.2CH(CH.sub.3).sub.2 3,5-di-F-.phi.- --CH.sub.3 H
-.phi. H --C(O)OCH.sub.3 3,5-di-F-.phi.- --CH.sub.3 H -.phi. H
--C(O)NH(CH.sub.2).sub.4NHC(O)- (2-hydroxy-4-azido)- phenyl
3,5-di-F-.phi.- --CH.sub.3 H 4-fluoro-.phi. H
--C(O)OC(CH.sub.3).sub.3 3,5-di-F-.phi.- --CH.sub.3 H
4-.phi.-.phi.- H --C(O)OC(CH.sub.3).sub.3 3,5-di-F-.phi.-
--CH.sub.3 R.sub.3/R.sub.4 and N = H --C(O)OCH.sub.3 3,3-dihydro-
2-isobenzazolyl 3,5-di-F-.phi.- --CH.sub.3 H 4-n-butylphenyl H
--C(O)NHC(CH.sub.3).sub.3 3,5-di-F-.phi.- --CH.sub.3 H
4-phenylacetylenylphenyl H --C(O)NHC(CH.sub.3).sub.3
3,5-di-F-.phi.- --CH.sub.3 H -.phi. H --C(S)NH.sub.2
3,5-di-F-.phi.- --CH.sub.3 H -.phi. H --C(O)CH.sub.2-.phi.
3,5-di-F-.phi.- --CH.sub.3 H -.phi. H --C(O)-cyclopentyl
3,5-di-F-.phi.- --CH.sub.3 H -.phi. H --C(O)-n-butyl
3,5-di-F-.phi.- --CH.sub.3 H -.phi. H
--C(O)CH(CH.sub.3)CH.sub.2CH.sub.3 3,5-di-F-.phi.- --CH.sub.3 H
-.phi. H --C(O)NH(CH.sub.2).sub.6-(biotinamidyl) 3,5-di-F-.phi.-
--CH.sub.2CH.sub.2SCH.sub.3 H --CH.sub.2CH.sub.2SCH.sub.3 H
--C(O)OCH.sub.3 t-BOC-NH--CH.sub.2-- --CH.sub.3 H -.phi. H
--C(O)OCH.sub.3 3,5-di-F-.phi.- --CH.sub.3 H 2-F-.phi.- H
--C(O)NHC(CH.sub.3).sub.3 3,5-di-F-.phi.- --CH.sub.3 H -.phi. H
--C(O)OCH.sub.3 3,5-di-F-.phi.- thien-3-yl H -.phi. H --C(O)OH
3,5-di-F-.phi.- thien-3-yl H -.phi. H --C(O)OC(CH.sub.3).sub.3
(2,5-di-Cl-.phi.)-O-- --CH.sub.3 H -.phi. H --C(O)OCH.sub.3
(3,5-di-F-.phi.)-O-- --CH.sub.3 H -.phi. H --C(O)OCH.sub.3
(3,4-di-Cl-.phi.)-S-- --CH.sub.3 H -.phi. H --C(O)OCH.sub.3
[0512] TABLE-US-00002 ##STR5## R.sup.1 R.sup.2 R.sup.3 R.sup.4 Y'
Y'' 3,5-di-F-.phi.- --CH.sub.3 H --CH.sub.2.phi.
--CH.sub.2C(O)OCH.sub.3 H 3,5-di-F-.phi.- --CH.sub.3 H --CH.sub.3
--CH.sub.2CH.sub.2CH(CH.sub.3).sub.2 H 3,5-di-F-.phi.- --CH.sub.3 H
-.phi. H H 3,5-di-F-.phi.- --CH.sub.3 H --CH.sub.2.phi. H H
3,5-di-F-.phi.- --CH.sub.3 H --CH.sub.3 H H 3,5-di-F-.phi.-
--CH.sub.3 H --CH.sub.3 -.phi. H 3,5-di-F-.phi.- --CH.sub.3 H
-.phi. -.phi. H 3,5-di-F-.phi.- --CH.sub.3 H
--(CH.sub.2).sub.3CH.sub.3 H H 3,5-di-F-.phi.- --CH.sub.3 H
--CH.sub.2-(p- H H hydroxyphenyl) 3,5-di-F-.phi.- --CH.sub.3 H
2-pyridyl H H 3,5-di-F-.phi.- --CH.sub.3 H 4-pyridyl H H
3,5-di-F-.phi.- --CH.sub.3 H --CH.sub.2CH(CH.sub.3).sub.2 H H
3,5-di-F-.phi.- --CH.sub.3 H --CH(CH.sub.3).sub.2 H H
3,5-di-F-.phi.- --CH.sub.3 H --CH.sub.3 H H 3,5-di-F-.phi.-
--CH.sub.3 H thien-2-yl H H 3,5-di-F-.phi.- --CH.sub.3 H -.phi.
--CH.sub.3 --CH.sub.3 3,5-di-F-.phi.- -.phi. H -.phi. H H
-cyclopropyl -.phi. H -.phi. H H -cyclopentyl -.phi. H -.phi. H
H
[0513] TABLE-US-00003 ##STR6## R.sup.1 R.sup.2 R.sup.3 R.sup.4 Q Y'
3,5-di-F-.phi.- --CH.sub.3 H --CH.sub.3 --OCH.sub.3 H
3,5-di-F-.phi.- --CH.sub.3 H -.phi. --OCH.sub.3 H 3,5-di-F-.phi.-
--CH.sub.3 H --CH.sub.2.phi. --OCH.sub.3 H 3,5-di-F-.phi.-
--CH.sub.3 H --CH.sub.2CH.sub.2CH.sub.2CH.sub.3 --OC(O)CH.sub.3 H
3,5-di-F-.phi.- --CH.sub.3 H --CH.sub.2CH.sub.2CH.sub.2CH.sub.3
--OC(O)C(CH.sub.3).sub.3 H 3,5-di-F-.phi.- --CH.sub.3 H
--CH.sub.2CH.sub.2CH.sub.3 -phthalimido H
[0514] TABLE-US-00004 ##STR7## R.sup.1 R.sup.2 R.sup.4' R.sup.4 X
(CH.sub.3).sub.2CH-- (CH.sub.3).sub.2CH-- -.phi. --CH.sub.3
--C(O)OCH.sub.2CH(CH.sub.3).sub.2 (CH.sub.3).sub.2CH-- -.phi.
--CH.sub.3 --CH.sub.2-.phi. --C(O)NH.sub.2 (CH.sub.3).sub.2CH
-.phi. --CH.sub.3 --CH.sub.3 --C(O)NH(p-NO.sub.2-.phi.)
3,5-di-F-.phi.- --CH.sub.3 --CH.sub.2-.phi. -.phi. --C(O)OCH.sub.3
3,5-di-F-.phi.- --CH.sub.3 --CH.sub.3 -.phi. --C(O)OCH.sub.3
3-NO.sub.2-.phi.- --CH.sub.3 --CH(OH)CH.sub.3 --CH(CH.sub.3).sub.2
--C(O)OCH.sub.2CH.sub.3 3,5-di-F-.phi.- -.phi. --CH.sub.3 -.phi.
--CH.sub.2OH 3,5-di-F-.phi.- --CH.sub.3 -.phi. H --CH.sub.2OH
[0515] TABLE-US-00005 ##STR8## R.sup.1 X' X'' R.sup.2 R.sup.4 X
3,5-di-F-.phi.- --OH H --CH.sub.3 -.phi. --C(O)NHC(CH.sub.3).sub.3
3,5-di-F-.phi.- --F F --CH.sub.3 -.phi. --C(O)NHC(CH.sub.3).sub.3
3,5-di-F-.phi.- X'/X'' = --CH.sub.3 -.phi. --C(O)OC(CH.sub.3).sub.3
.dbd.O
DETAILED DESCRIPTION OF THE INVENTION
[0516] As above, this invention relates to methods for inhibiting
.beta.-amyloid peptide release and/or its synthesis, and,
accordingly, have utility in treating Alzheimer's disease. However,
prior to describing this invention in further detail, the following
terms will first be defined.
Definitions
[0517] The term ".beta.-amyloid peptide" refers to a 39-43 amino
acid peptide having a molecular weight of about 4.2 kD, which
peptide is substantially homologous to the form of the protein
described by Glenner, et al..sup.1 including mutations and
post-translational modifications of the normal .beta.-amyloid
peptide. In whatever form, the .beta.-amyloid peptide is an
approximate 39-43 amino acid fragment of a large membrane-spanning
glycoprotein, referred to as the .beta.-amyloid precursor protein
(APP). Its 43-amino acid sequence is: TABLE-US-00006 1 Asp Ala Glu
Phe Arg His Asp Ser Gly (SEQ ID NO: 1) Tyr 11 Glu Val His His Gln
Lys Leu Val Phe Phe 21 Ala Glu Asp Val Gly Ser Asn Lys Gly Ala 31
Ile Ile Gly Leu Met Val Gly Gly Val Val 41 Ile Ala Thr
or a sequence which is substantially homologous thereto.
[0518] "Alkyl" refers to monovalent alkyl groups preferably having
from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms.
This term is exemplified by groups such as methyl, ethyl, n-propyl,
iso-propyl, n-butyl, iso-butyl, n-hexyl, and the like.
[0519] "Substituted alkyl" refers to an alkyl group, preferably of
from 1 to 10 carbon atoms, having from 1 to 3 substituents selected
from the group consisting of alkoxy, substituted alkoxy, aryloxy,
heteroaryloxy, heterocyclyloxy, acyl, acylamino, amino, aminoacyl,
aminocarboxy esters, cyano, cycloalkyl, halogen, hydroxyl,
carboxyl, carboxylalkyl, oxyacyl, oxyacylamino, thiol, thioalkoxy,
substituted thioalkoxy, aryl, heteroaryl, heterocyclic, nitro, and
mono- and di-alkylamino, mono- and di-(substituted alkyl)amino,
mono- and di-arylamino, mono- and di-heteroarylamino, mono- and
di-heterocyclic amino, and unsymmetric di-substituted amines having
different substituents selected from alkyl, substituted alkyl,
aryl, heteroaryl and heterocyclic.
[0520] "Alkylene" refers to divalent alkylene groups preferably
having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon
atoms. This term is exemplified by groups such as methylene
(--CH.sub.2--), ethylene (--CH.sub.2CH.sub.2--), the propylene
isomers (e.g., --CH.sub.2CH.sub.2CH.sub.2-- and
--CH(CH.sub.3)CH.sub.2--), and the like.
[0521] "Alkaryl" refers to -alkylene-aryl groups preferably having
from 1 to 10 carbon atoms in the alkylene moiety and from 6 to 10
carbon atoms in the aryl moiety. Such alkaryl groups are
exemplified by benzyl, phenethyl and the like.
[0522] "Alkoxy" refers to the group "alkyl-O--". Preferred alkoxy
groups include, by way of example, methoxy, ethoxy, n-propoxy,
iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy,
n-hexoxy, 1,2-dimethylbutoxy, and the like.
[0523] "Substituted alkoxy" refers to the group "substituted
alkyl-O--" where substituted alkyl is as defined above.
[0524] "Alkylalkoxy" refers to the group "-alkylene-O-alkyl" where
alkylene and alkyl are as defined above. Such groups include, by
way of example, methylenemethoxy (--CH.sub.2OCH.sub.3),
ethylenemethoxy (--CH.sub.2CH.sub.2OCH.sub.3),
n-propylene-iso-propoxy
(--CH.sub.2CH.sub.2CH.sub.2OCH(CH.sub.3).sub.2), methylene-t-butoxy
(--CH.sub.2--O--C(CH.sub.3).sub.3) and the like.
[0525] "Alkylthioalkoxy" refers to the group "-alkylene-S-alkyl"
wherein alkylene and alkyl are as defined above. Such groups
include, by way of example methylthiomethoxy (--CH.sub.2SCH.sub.3),
ethylthiomethoxy (--CH.sub.2CH.sub.2SCH.sub.3),
n-propyl-iso-thiopropoxy
(--CH.sub.2CH.sub.2CH.sub.2SCH(CH.sub.3).sub.2),
methylthio-t-butoxy (--CH.sub.2SC(CH.sub.3).sub.3) and the
like.
[0526] "Alkenyl" refers to alkenyl groups preferably having from 2
to 10 carbon atoms and more preferably 2 to 6 carbon atoms and
having at least 1 and preferably from 1-2 sites of alkenyl
unsaturation. Preferred alkenyl groups include ethenyl
(--CH.dbd.CH.sub.2), n-propenyl (--CH.sub.2CH.dbd.CH.sub.2),
iso-propenyl (--C(CH.sub.3).dbd.CH.sub.2), but-2-enyl
(--CH.sub.2CH.dbd.CHCH.sub.3), and the like.
[0527] "Substituted alkenyl" refers to an alkenyl group as defined
above having from 1 to 3 substituents selected from the group
consisting of alkoxy, substituted alkoxy, acyl, acylamino, amino,
aminoacyl, aminocarboxy esters, cyano, halogen, hydroxyl, carboxyl,
carboxylalkyl, cycloalkyl, oxyacyl, oxyacylamino, thiol,
thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic,
nitro, and mono- and di-alkylamino, mono- and di-(substituted
alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino,
mono- and di-heterocyclic amino, and unsymmetric di-substituted
amines having different substituents selected from alkyl,
substituted alkyl, aryl, heteroaryl and heterocyclic.
[0528] "Alkynyl" refers to alkynyl groups preferably having from 2
to 10 carbon atoms and more preferably 2 to 6 carbon atoms and
having at least 1 and preferably from 1-2 sites of alkynyl
unsaturation. Preferred alkynyl groups include ethynyl
(--CH.ident.CH.sub.2), propargyl (--CH.sub.2C.ident.CH) and the
like.
[0529] "Substituted alkynyl" refers to an alkenyl group as defined
above having from 1 to 3 substituents selected from the group
consisting of alkoxy, substituted alkoxy, acyl, acylamino, amino,
aminoacyl, aminocarboxy esters, cyano, halogen, hydroxyl, carboxyl,
carboxylalkyl, cycloalkyl, oxyacyl, oxyacylamino, thiol,
thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic,
nitro, and mono- and di-alkylamino, mono- and di-(substituted
alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino,
mono- and di-heterocyclic amino, and unsymmetric di-substituted
amines having different substituents selected from alkyl,
substituted alkyl, aryl, heteroaryl and heterocyclic.
[0530] "Acyl" refers to the groups alkyl-C(O)--, substituted
alkyl-C(O)--, cycloalkyl-C(O)--, aryl-C(O)--, heteroaryl-C(O)-- and
heterocyclic-C(O)-- where alkyl, substituted alkyl, cycloalkyl,
aryl, heteroaryl and heterocyclic are as defined herein.
[0531] "Acylamino" refers to the group --C(O)NRR where each R is
independently hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl,
heteroaryl, and heterocyclic and where each of alkyl, substituted
alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic are as defined
herein.
[0532] "Aminoacyl" refers to the group --NRC(O)R where each R is
independently hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl,
heteroaryl, and heterocyclic and where each of alkyl, substituted
alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic are as defined
herein.
[0533] "Oxyacyl" refers to the groups --OC(O)-alkyl, --OC(O)-aryl,
--C(O)O-heteroaryl-, and --C(O)O-heterocyclic where alkyl, aryl,
heteroaryl and heterocyclic are as defined herein.
[0534] "Oxyacylamino" refers to the groups --OC(O)NR-alkyl,
--OC(O)NR-substituted, alkyl, --OC(O)NR-aryl,
--OC(O)NR-heteroaryl-, and --OC(O)NR-heterocyclic where R is
hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl,
and heterocyclic and where each of alkyl, substituted alkyl,
cycloalkyl, aryl, heteroaryl and heterocyclic are as defined
herein.
[0535] "Aminocarboxy esters" refers to the groups --NRC(O)O-alkyl,
--NRC(O)O-substituted alkyl, --NRC(O)O-aryl, --NRC(O)O-heteroaryl,
and --NRC(O)O-heterocyclic where R is hydrogen, alkyl, substituted
alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic and where
each of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and
heterocyclic are as defined herein.
[0536] "Aryl" refers to an unsaturated aromatic carbocyclic group
of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or
multiple condensed rings (e.g., naphthyl or anthryl). Preferred
aryls include phenyl, naphthyl and the like.
[0537] Unless otherwise constrained by the definition for the aryl
substituent, such aryl groups can optionally be substituted with
from 1 to 5 and preferably 1 to 3 substituents selected from the
group consisting of hydroxy, biotinamidyl, acyl, alkyl, alkoxy,
alkenyl, alkynyl, substituted alkyl, substituted alkoxy,
substituted alkenyl, substituted alkynyl, amino, aminoacyl,
aminocarboxy esters, alkaryl, aryl, aryloxy, azido, carboxyl,
carboxylalkyl, acylamino, cyano, halo, nitro, heteroaryl,
heterocyclic, oxyacyl, oxyacylamino, thioalkoxy, substituted
thioalkoxy, trihalomethyl, mono- and di-alkylamino, mono- and
di-(substituted alkyl)amino, mono- and di-arylamino, mono- and
di-heteroarylamino, mono- and di-heterocyclic amino, and
unsymmetric di-substituted amines having different substituents
selected from alkyl, substituted alkyl, aryl, heteroaryl and
heterocyclic, and the like. Preferred substituents include alkyl,
alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy.
[0538] "Aryloxy" refers to the group aryl-O-- wherein the aryl
group is as defined above including optionally substituted aryl
groups as also defined above.
[0539] The term "carboxy terminal R.sup.4 group" refers to that
R.sup.4 group in compounds of formula I which, when n is two, is
closest to the X group.
[0540] "Carboxyalkyl" refers to the groups "C(O)O-alkyl and
"C(O)O-substituted alkyl where alkyl and substituted alkyl are as
defined above.
[0541] "Cycloalkyl" refers to cyclic alkyl groups of from 3 to 10
carbon atoms having a single cyclic ring or multiple condensed
rings which can be optionally substituted with from 1 to 3 alkyl
groups. Such cycloalkyl groups include, by way of example, single
ring structures such as cyclopropyl, cyclobutyl, cyclopentyl,
cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl,
2-methylcyclooctyl, and the like, or multiple ring structures such
as adamantanyl, and the like.
[0542] "Cycloalkenyl" refers to cyclic alkenyl groups of from 4 to
8 carbon atoms having a single cyclic ring and at least one point
of internal unsaturation which can be optionally substituted with
from 1 to 3 alkyl groups. Examples of suitable cycloalkenyl groups
include, for instance, cyclobut-2-enyl, cyclopent-3-enyl,
cyclooct-3-enyl and the like.
[0543] "Halo" or "halogen" refers to fluoro, chloro, bromo and iodo
and preferably is either chloro or bromo.
[0544] "Heteroaryl" refers to a monovalent aromatic group of from 2
to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen,
nitrogen and sulfur within the ring.
[0545] Unless otherwise constrained by the definition for the
heteroaryl substituent, such heteroaryl groups can be optionally
substituted with 1 to 3 substituents selected from the group
consisting of hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl,
substituted alkyl, substituted alkoxy, substituted alkenyl,
substituted alkynyl, amino, aminoacyl, aminocarboxy esters,
alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, aminoacyl, cyano,
halo, nitro, heteroaryl, heterocyclic, oxyacyl, oxyacylamino,
thioalkoxy, substituted thioalkoxy, trihalomethyl, mono- and
di-alkylamino, mono- and di-(substituted alkylamino, mono- and
di-arylamino, mono- and di-heteroarylamino, mono- and
di-heterocyclic amino, and unsymmetric di-substituted amines having
different substituents selected from alkyl, substituted alkyl,
aryl, heteroaryl and heterocyclic, and the like. Preferred
substituents include alkyl, alkoxy, halo, cyano, nitro,
trihalomethyl, and thioalkoxy.
[0546] Such heteroaryl groups can have a single ring (e.g., pyridyl
or furyl) or multiple condensed rings (e.g., indolizinyl or
benzothienyl). Preferred heteroaryls include pyridyl, pyrrolyl and
furyl.
[0547] "Heteroaryloxy" refers to the group heteroaryl-O-- wherein
the heteroaryl group is as defined above including optionally
substituted heteroaryl groups as also defined above.
[0548] "Heterocycle" or "heterocyclic" refers to a monovalent
(i.e., one point of attachment) saturated or unsaturated group
having a single ring or multiple condensed rings, from 1 to 8
carbon atoms and from 1 to 4 hetero atoms selected from nitrogen,
sulfur or oxygen within the ring.
[0549] Unless otherwise constrained by the definition for the
heterocyclic substituent, such heterocyclic groups can be
optionally substituted with 1 to 4 substituents selected from the
group consisting of hydroxy, acyl, allyl, alkoxy, alkenyl, alkynyl,
substituted alkyl, substituted alkoxy, substituted alkenyl,
substituted alkynyl, amino, aminoacyl, aminocarboxy esters,
alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, aminoacyl, cyano,
halo, nitro, heteroaryl, heterocyclic, oxyacyl, oxyacylamino,
thioalkoxy, substituted thioalkoxy, trihalomethyl, mono- and
di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and
di-arylamino, mono- and di-heteroarylamino, mono- and
di-heterocyclic amino, and unsymmetric di-substituted amines having
different substituents selected from alkyl, substituted alkyl,
aryl, heteroaryl and heterocyclic, and the like. Such heterocyclic
groups can have a single ring or multiple condensed rings.
Preferred heteroaryls include morpholino, piperidinyl, and the
like.
[0550] Examples of heterocycles and heteroaryls include, but are
not limited to, furan, thiophene, thiazole, oxazole, pyrrole,
imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine,
indolizine, isoindole, indole, indazole, purine, quinolizine,
isoquinoline, quinoline, phthalazine, naphthylpyridine,
quinoxaline, quinazoline, cinnoline, pteridine, carbazole,
carboline, phenanthridine, acridine, phenanthroline, isothiazole,
phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine,
imidazoline, piperidine, piperazine, indoline, phthalimide,
1,2,3,4-tetrahydroisoquinoline,
4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine,
thiophene, benzo[b]thiophene, morpholino, piperidinyl, pyrrolidine,
tetrahydrofuranyl, and the like.
[0551] "Heterocyclyloxy" refers to the group heterocyclyl-O--
wherein the heterocyclic group is as defined above including
optionally substituted heterocyclic groups as also defined
above.
[0552] "Oxyacyl" refers to the groups --OC(O)-alkyl, --OC(O)-aryl,
--C(O)O-heteroaryl-, and --C(O)O-heterocyclic where alkyl, aryl,
heteroaryl and heterocyclic are as defined herein.
[0553] "Oxyacylamino" refers to the groups --OC(O)NH-alkyl,
--OC(O)NH-substituted alkyl, --OC(O)NH-aryl, --OC(O)NH-heteroaryl-,
and --OC(O)NH-heterocyclic where alkyl, aryl, heteroaryl and
heterocyclic are as defined herein.
[0554] "Thiol" refers to the group --SH.
[0555] "Thioalkoxy" refers to the group --S-alkyl.
[0556] "Substituted thioalkoxy" refers to the group --S-substituted
alkyl.
[0557] "Thioaryloxy" refers to the group aryl-S-- wherein the aryl
group is as defined above including optionally substituted aryl
groups also defined above.
[0558] "Thioheteroaryloxy" refers to the group heteroaryl-S--
wherein the heteroaryl group is as defined above including
optionally substituted aryl groups as also defined above.
[0559] "Pharmaceutically acceptable salt" refers to
pharmaceutically acceptable salts of a compound of Formula I which
salts are derived from a variety of organic and inorganic counter
ions well known in the art and include, by way of example only,
sodium, potassium, calcium, magnesium, ammonium,
tetraalkylammonium, and the like; and when the molecule contains a
basic functionality, salts of organic or inorganic acids, such as
hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate,
oxalate and the like.
Compound Preparation
[0560] The compounds of formula I are readily prepared via several
divergent synthetic routes with the particular route selected
relative to the ease of compound preparation, commercial
availability of starting materials, etc.
[0561] A first synthetic method involves conventional coupling of
an acetic acid derivative with a primary amine of an esterified
amino acid as shown in reaction (1) below: ##STR9## wherein
R.sup.1, R.sup.2, R.sup.3, X' and X'' are as defined above, and X
is either oxygen or --NH--.
[0562] Reaction (1) merely involves coupling of a suitable acid
derivative 1 with the primary amine of amino acid ester 2 under
conditions which provide for the N-acetyl derivative 3. This
reaction is conventionally conducted for peptide synthesis and
synthetic methods used therein can also be employed-to prepare the
N-acetyl amino acid esters 3 of this invention. For example, well
known coupling reagents such as carbodiimides with or without the
use of well known additives such as N-hydroxysuccinimide,
1-hydroxybenzotriazole, etc. can be used to facilitate coupling.
The reaction is conventionally conducted in an inert aprotic
diluent such as dimethylformamide, dichloromethane, chloroform,
acetonitrile, tetrahydrofuran and the like. Alternatively, the acid
halide of compound 1 can be employed in reaction (1) and, when so
employed, it is typically employed in the presence of a suitable
base to scavenge the acid generated during the reaction. Suitable
bases include, by way of example, triethylamine,
diisopropylethylamine, N-methylmorpholine and the like.
[0563] Reaction (1) is preferably conducted at from about 0.degree.
C. to about 60.degree. C. until reaction completion which typically
occurs within 1 to about 24 hours. Upon reaction completion,
N-acetyl amino acid ester 3 is recovered by conventional methods
including precipitation, chromatography, filtration and the like or
alternatively is hydrolyzed to the corresponding acid without
purification and/or isolation other than conventional work-up
(e.g., aqueous extraction, etc.). Alternatively, the synthesis
described above in reaction (1) can be conducted on the amino acid
(XR.sup.3.dbd.OH) and subsequent to N-acetyl formation as described
above.
[0564] In any event, if an N-acetyl amino acid ester is formed, it
is converted to the corresponding acid prior to the coupling step
with another amino acid ester/amide, HNR.sup.3CR.sup.4R.sup.5C(O)Y.
Coupling is accomplished using well known peptide coupling
chemistry with well known coupling reagents such as carbodiimides
with or without the use of well known additives such as
N-hydroxysuccinimide, 1-hydroxybenzotriazole, etc. which can be
used to facilitate coupling. The reaction is conventionally
conducted in an inert aprotic polar diluent such as
dimethylformamide, dichloromethane, chloroform, acetonitrile,
tetrahydrofuran and the like.
[0565] Such coupling yields compounds of formula I where n is 1.
The synthesis of compounds of formula I where n is 2 is
accomplished via a second coupling reaction. Specifically, in the
first coupling reaction, HNR.sup.3CR.sup.4R.sup.5C(O)Y is selected
to be an amino acid ester. That is to say that Y is --O-alkyl.
After coupling, the ester is hydrolyzed via conventional conditions
well known in the art to provide for the corresponding carboxylic
acid which can now be used to couple a second amino acid
ester/amide.
[0566] In reaction (1), each of the reagents (compound 1 and amino
acid ester 2 are well known in the art with a plurality of each
being commercially available.
[0567] Alternatively, the compounds of formula I can be prepared by
first forming the dipeptide ester and then N-acylating these
esters. That is to say that the amino acid ester or amide
HNR.sup.3CR.sup.4R.sup.5C(O)Y is coupled to the N-blocked amino
acid BlockNHCHR.sup.2COOH via conventional coupling conditions to
provide for the dipeptide
BlockNHCHR.sup.2C(O)N(R.sup.3)CR.sup.4R.sup.5C(O)Y. The blocking
group is then removed via conventional conditions to provide for
the free amine which is then N-acylated in the manner described
above to provide for the compounds of formula I.
[0568] After coupling and N-acylation (in whatever order) is
complete, the resulting esters and amides can be derivatized via
conventional chemistry to provide for derivatives of the
synthesized compounds. For example, conventional reduction of a
terminal ester group with lithium borohydride leads to the terminal
--CH.sub.2OH group. Alternatively, an ester group can be converted
to a primary amide [--C(O)NH.sub.2] by reaction with ammonia in
methanol with a catalytic amount of sodium cyanide while
heating.
[0569] Similarly, reactive functionality which is blocked on either
R.sup.2 and/or R.sup.3 groups can be deblocked and then
derivatized. For example, the a BOC protected amino group on
R.sup.3 (e.g., lysine side chain) can be deblocked after synthesis
and the amino group acylated or otherwised derivatized.
[0570] Additionally, a terminal ester can be subjected to
transesterification techniques to provide for other esters.
Numerous techniques are known in the art to effect
transesterification and each technique merely replaces one ester
group with a different ester group derived from the corresponding
alcohol or thioalcohol and, in some cases, a catalyst such as
titanium (IV) iso-propoxide is used to facilitate reaction
completion. In one technique, the alcohol or thioalcohol is first
treated with sodium hydride in a suitable diluent such as toluene
to form the corresponding sodium alkoxide or thioalkoxide which is
then employed to effect transesterification. The efficiency of this
technique makes it particularly useful with high boiling and/or
expensive alcohols or thioalcohols.
[0571] In another transesterification technique, the ester to be
transesterified is placed in a large excess of the alcohol or
thioalcohol which effects transesterification. A catalytic amount
of sodium hydride is then added and the reaction proceeds quickly
under conventional conditions to provide the desired
transesterified product. Because this protocol requires the use of
a large excess of alcohol or thioalcohol, this procedure is
particularly useful when the alcohol or thioalcohol is
inexpensive.
[0572] Transesterification provides a facile means to provide for a
multiplicity of different ester substituents on the compounds of
formula I above. In all cases, the alcohols and thioalcohols
employed to effect transesterification are well known in the art
with a significant number being commercially available.
[0573] Other methods for preparing the esters of this invention
include, by way of example, first hydrolyzing the ester to the free
acid followed by O-alkylation with a halo-R.sup.3 group in the
presence of a base such as potassium carbonate. Alternatively, for
esterification procedures for alcohols containing an ester group
can be achieved by using the methods of Losse, et al..sup.11
[0574] The compounds described herein can also be prepared by use
of polymer supported forms of carbodiimide peptide coupling
reagents. A polymer supported form of EDC, for example, has been
described (Tetrahedron Letters, 34(48), 7685 (1993)).sup.10.
Additionally, a new carbodiimide coupling reagent, PEPC, and its
corresponding polymer supported forms have been discovered and are
very useful for the preparation of the compounds of the present
invention.
[0575] Polymers suitable for use in making a polymer supported
coupling reagent are either commercially available or may be
prepared by methods well known to the artisan skilled in the
polymer arts. A suitable polymer must possess pendant sidechains
bearing moieties reactive with the terminal amine of the
carbodiimide. Such reactive moieties include chloro, bromo, iodo
and methanesulfonyl. Preferably, the reactive moiety is a
chloromethyl group. Additionally, the polymer's backbone must be
inert to both the carbodiimide and reaction conditions under which
the ultimate polymer bound coupling reagents will be used.
[0576] Certain hydroxymethylated resins may be converted into
chloromethylated resins useful for the preparation of polymer
supported coupling reagents. Examples of these hydroxylated resins
include the 4-hydroxymethyl-phenylacetamidomethyl resin (Pam Resin)
and 4-benzyloxybenzyl alcohol resin (Wang Resin) available from
Advanced Chemtech of Louisville, Ky., USA (see Advanced Chemtech
1993-1994 catalog, page 115). The hydroxymethyl groups of these
resins may be converted into the desired chloromethyl groups by any
of a number of methods well known to the skilled artisan.
[0577] Preferred resins are the chloromethylated
styrene/divinylbenzene resins because of their ready commercial
availability. As the name suggests, these resins are already
chloromethylated and require no chemical modification prior to use.
These resins are commercially known as Merrifield's resins and are
available from Aldrich Chemical Company of Milwaukee, Wisc., USA
(see Aldrich 1994-1995 catalog, page 899). Methods for the
preparation of PEPC and its polymer supported forms are outlined in
the following scheme. ##STR10##
[0578] Such methods are described more fully in U.S. Patent
Application Ser. No. 60/019,790 filed Jun. 14, 1996 which
application is incorporated herein by reference in its entirety.
Briefly, PEPC is prepared by first reacting ethyl isocyanate with
1-(3-aminopropyl)pyrrolidine. The resulting urea is treated with
4-toluenesulfonyl chloride to provide PEPC. The polymer supported
form is prepared by reaction of PEPC with an appropriate resin
under standard conditions to give the desired reagent.
[0579] The carboxylic acid coupling reactions employing these
reagents are performed at about ambient temperature to about
45.degree. C., for from about 3 to 120 hours. Typically, the
product may be isolated by washing the reaction with CHCl.sub.3 and
concentrating the remaining organics under reduced pressure. As
discussed supra, isolation of products from reactions where a
polymer bound reagent has been used is greatly simplified,
requiring only filtration of the reaction mixture and then
concentration of the filtrate under reduced pressure.
[0580] Still other methods for the preparation of esters are
provided in the examples below.
[0581] Compounds where X is --CR.sup.6R.sup.6Y' are readily
prepared by coupling, e.g., an amino alcohol
H.sub.2NCR.sup.4R.sup.5CR.sup.6R.sup.6OH, to the carboxyl group of
R.sup.1ZCX'X''C(O)NHCHR.sup.2C(O)OH under standard coupling
conditions well known in peptide coupling chemistry which can use
well known coupling reagents such as carbodiimides with or without
the use of well known additives such as N-hydroxysuccinimide,
1-hydroxybenzotriazole, etc. If necessary, well known blocking
groups on Y' can be employed to protect the group during coupling.
Such blocking groups are particularly desirable when Y' is an amino
group.
[0582] The reaction is conventionally conducted in an inert aprotic
polar diluent such as dimethylformamide, dichloromethane,
chloroform, acetonitrile, tetrahydrofuran and the like. Upon
reaction completion, any blocking groups on Y' are selectively
removed to provide for the desired compound.
[0583] When Y' is --OH or --SH, post-synthetic conversion of these
groups to the corresponding esters (i.e., --OC(O)R.sup.7),
disulfides (i.e., --SSR.sup.7) and --SSC(O)R.sup.7 groups is
accomplished using well known chemistry. For example, ester
synthesis requires only reaction with a suitable acid such as
acetic acid (R.sup.7=methyl), acid halide (e.g., acid chloride) or
acid anhydride under suitable esterification conditions.
[0584] When one of R.sup.6 is hydrogen, post-synthetic oxidation of
the --CHR.sup.6OH group leads to the ketone derivatives.
Alternatively, such ketones can be prepared by coupling the
suitable aminoketone HCl salt with the terminal carboxyl group of
the amino acid as illustrated in Example 168 below.
[0585] In these synthetic methods, the starting materials can
contain a chiral center (e.g., alanine) and, when a racemic
starting material is employed, the resulting product is a mixture
of R,S enatiomers. Alternatively, a chiral isomer of the starting
material can be employed and, if the reaction protocol employed
does not racemize this starting material, a chiral product is
obtained. Such reaction protocols can involve inversion of the
chiral center during synthesis.
[0586] Accordingly, unless otherwise indicated, the products of
this invention are a mixture of R,S enatiomers or diasteriomers.
Preferably, however, when a chiral product is desired, the chiral
product corresponds to the L-amino acid derivative. Alternatively,
chiral products can be obtained via purification techniques which
separate enatiomers from a R,S mixture to provide for one or the
other stereoisomer. Such techniques are well known in the art.
Pharmaceutical Formulations
[0587] When employed as pharmaceuticals, the compounds of formula I
are usually administered in the form of pharmaceutical
compositions. These compounds can be administered by a variety of
routes including oral, rectal, transdermal, subcutaneous,
intravenous, intramuscular, and intranasal. These compounds are
effective as both injectable and oral compositions. Such
compositions are prepared in a manner well known in the
pharmaceutical art and comprise at least one active compound.
[0588] This invention also includes pharmaceutical compositions
which contain, as the active ingredient, one or more of the
compounds of formula I above associated with pharmaceutically
acceptable carriers. In making the compositions of this invention,
the active ingredient is usually mixed with an excipient, diluted
by an excipient or enclosed within such a carrier which can be in
the form of a capsule, sachet, paper or other container. When the
excipient serves as a diluent, it can be a solid, semi-solid, or
liquid material, which acts as a vehicle, carrier or medium for the
active ingredient. Thus, the compositions can be in the form of
tablets, pills, powders, lozenges, sachets, cachets, elixirs,
suspensions, emulsions, solutions, syrups, aerosols (as a solid or
in a liquid medium), ointments containing, for example, up to 10%
by weight of the active compound, soft and hard gelatin capsules,
suppositories, sterile injectable solutions, and sterile packaged
powders.
[0589] In preparing a formulation, it may be necessary to mill the
active compound to provide the appropriate particle size prior to
combining with the other ingredients. If the active compound is
substantially insoluble, it ordinarily is milled to a particle size
of less than 200 mesh. If the active compound is substantially
water soluble, the particle size is normally adjusted by milling to
provide a substantially uniform distribution in the formulation,
e.g. about 40 mesh.
[0590] Some examples of suitable excipients include lactose,
dextrose, sucrose, sorbitol, mannitol, starches, gum acacia,
calcium phosphate, alginates, tragacanth, gelatin, calcium
silicate, microcrystalline cellulose, polyvinylpyrrolidone,
cellulose, sterile water, syrup, and methyl cellulose. The
formulations can additionally include: lubricating agents such as
talc, magnesium stearate, and mineral oil; wetting agents;
emulsifying and suspending agents; preserving agents such as
methyl- and propylhydroxy-benzoates; sweetening agents; and
flavoring agents. The compositions of the invention can be
formulated so as to provide quick, sustained or delayed release of
the active ingredient after administration to the patient by
employing procedures known in the art.
[0591] The compositions are preferably formulated in a unit dosage
form, each dosage containing from about 5 to about 100 mg, more
usually about 10 to about 30 mg, of the active ingredient. The term
"unit dosage forms" refers to physically discrete units suitable as
unitary dosages for human subjects and other mammals, each unit
containing a predetermined quantity of active material calculated
to produce the desired therapeutic effect, in association with a
suitable pharmaceutical excipient. Preferably, the compound of
formula I above is employed at no more than about 20 weight percent
of the pharmaceutical composition, more preferably no more than
about 15 weight percent, with the balance being pharmaceutically
inert carrier(s).
[0592] The active compound is effective over a wide dosage range
and is generally administered in a pharmaceutically effective
amount. It, will be understood, however, that the amount of the
compound actually administered will be determined by a physician,
in the light of the relevant circumstances, including the condition
to be treated, the chosen route of administration, the actual
compound administered, the age, weight, and response of the
individual patient, the severity of the patient's symptoms, and the
like.
[0593] For preparing solid compositions such as tablets, the
principal active ingredient is mixed with a pharmaceutical
excipient to form a solid preformulation composition containing a
homogeneous mixture of a compound of the present invention. When
referring to these preformulation compositions as homogeneous, it
is meant that the active ingredient is dispersed evenly throughout
the composition so that the composition may be readily subdivided
into equally effective unit dosage forms such as tablets, pills and
capsules. This solid preformulation is then subdivided into unit
dosage forms of the type described above containing from, for
example, 0.1 to about 500 mg of the active ingredient of the
present invention.
[0594] The tablets or pills of the present invention may be coated
or otherwise compounded to provide a dosage form affording the
advantage of prolonged action. For example, the tablet or pill can
comprise an inner dosage and an outer dosage component, the latter
being in the form of an envelope over the former. The two
components can separated by enteric layer which serves to resist
disintegration in the stomach and permit the inner component to
pass intact into the duodenum or to be delayed in release. A
variety of materials can be used for such enteric layers or
coatings, such materials including a number of polymeric acids and
mixtures of polymeric acids with such materials as shellac, cetyl
alcohol, and cellulose acetate.
[0595] The liquid forms in which the novel compositions of the
present invention may be incorporated for administration orally or
by injection include aqueous solutions suitably flavored syrups,
aqueous or oil suspensions, and flavored emulsions with edible oils
such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as
well as elixirs and similar pharmaceutical vehicles.
[0596] Compositions for inhalation or insufflation include
solutions and suspensions in pharmaceutically acceptable, aqueous
or organic solvents, or mixtures thereof, and powders. The liquid
or solid compositions may contain suitable pharmaceutically
acceptable excipients as described supra. Preferably the
compositions are administered by the oral or nasal respiratory
route for local or systemic effect. Compositions in preferably
pharmaceutically acceptable solvents may be nebulized by use of
inert gases. Nebulized solutions may be breathed directly from the
nebulizing device or the nebulizing device may be attached to a
face masks tent, or intermittent positive pressure breathing
machine. Solution, suspension, or powder compositions may be
administered, preferably orally or nasally, from devices which
deliver the formulation in an appropriate manner.
[0597] The following formulation examples illustrate the
pharmaceutical compositions of the present invention.
Formulation Example 1
[0598] Hard gelatin capsules containing the following ingredients
are prepared: TABLE-US-00007 Quantity Ingredient (mg/capsule)
Active Ingredient 30.0 Starch 305.0 Magnesium stearate 5.0
[0599] The above ingredients are mixed and filled into hard gelatin
capsules in 340 mg quantities.
Formulation Example 2
[0600] A tablet formula is prepared using the ingredients below:
TABLE-US-00008 Quantity Ingredient (mg/tablet) Active Ingredient
25.0 Cellulose, microcrystalline 200.0 Colloidal silicon dioxide
10.0 Stearic acid 5.0
[0601] The components are blended and compressed to form tablets,
each weighing 240 mg.
Formulation Example 3
[0602] A dry powder-inhaler formulation is prepared containing the
following components: TABLE-US-00009 Ingredient Weight % Active
Ingredient 5 Lactose 95
[0603] The active ingredient is mixed with the lactose and the
mixture is added to a dry powder inhaling appliance.
Formulation Example 4
[0604] Tablets, each containing 30 mg of active ingredient, are
prepared as follows: TABLE-US-00010 Quantity Ingredient (mg/tablet)
Active Ingredient 30.0 mg Starch 45.0 mg Microcrystalline cellulose
35.0 mg Polyvinylpyrrolidone 4.0 mg (as 10% solution in sterile
water) Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg
Talc 1.0 mg Total 120 mg
[0605] The active ingredient, starch and cellulose are passed
through a No. 20 mesh U.S. sieve and mixed thoroughly. The solution
of polyvinyl-pyrrolidone is mixed with the resultant powders, which
are then passed through a 16 mesh U.S. sieve. The granules so
produced are dried at 50.degree. to 60.degree. C. and passed
through a 16 mesh U.S. sieve. The sodium carboxymethyl starch,
magnesium stearate, and talc, previously passed through a No. 30
mesh U.S. sieve, are then added to the granules which, after
mixing, are compressed on a tablet machine to yield tablets each
weighing 150 mg.
Formulation Example 5
[0606] Capsules, each containing 40 mg of medicament are made as
follows: TABLE-US-00011 Quantity Ingredient (mg/capsule) Active
Ingredient 40.0 mg Starch 109.0 mg Magnesium stearate 1.0 mg Total
150.0 mg
[0607] The active ingredient, starch, and magnesium stearate are
blended, passed through a No. 20 mesh U.S. sieve, and filled into
hard gelatin capsules in 150 mg quantities.
Formulation Example 6
[0608] Suppositories, each containing 25 mg of active ingredient
are made as follows: TABLE-US-00012 Ingredient Amount Active
Ingredient 25 mg Saturated fatty acid glycerides to 2,000 mg
[0609] The active ingredient is passed through a No. 60 mesh U.S.
sieve and suspended in the saturated fatty acid glycerides
previously melted using the minimum heat necessary. The mixture is
then poured into a suppository mold of nominal 2.0 g capacity and
allowed to cool.
Formulation Example 7
[0610] Suspensions, each containing 50 mg of medicament per 5.0 ml
dose are made as follows: TABLE-US-00013 Ingredient Amount Active
Ingredient 50.0 mg Xanthan gum 4.0 mg Sodium carboxymethyl
cellulose (11%) 50.0 mg Microcrystalline cellulose (89%) Sucrose
1.75 g Sodium benzoate 10.0 mg Flavor and Color q.v. Purified water
to 5.0 ml
[0611] The active ingredient, sucrose and xanthan gum are blended,
passed through a No. 10 mesh U.S. sieve, and then mixed with a
previously made solution of the microcrystalline cellulose and
sodium carboxymethyl cellulose in water. The sodium benzoate,
flavor, and color are diluted with some of the water and added with
stirring. Sufficient water is then added to produce the required
volume.
Formulation Example 8
[0612] TABLE-US-00014 Quantity Ingredient (mg/capsule) Active
Ingredient 15.0 mg Starch 407.0 mg Magnesium stearate 3.0 mg Total
425.0 mg
[0613] The active ingredient, starch, and magnesium stearate are
blended, passed through a No. 20 mesh U.S. sieve, and filled into
hard gelatin capsules in 560 mg quantities.
Formulation Example 9
[0614] A subcutaneous formulation may be prepared as follows:
TABLE-US-00015 Ingredient Quantity Active Ingredient 5.0 mg corn
oil 1 ml
Formulation Example 10
[0615] A topical formulation may be prepared as follows:
TABLE-US-00016 Ingredient Quantity Active Ingredient 1-10 g
Emulsifying Wax 30 g Liquid Paraffin 20 g White Soft Paraffin to
100 g
[0616] The white soft paraffin is heated until molten. The liquid
paraffin and emulsifying wax are incorporated and stirred until
dissolved. The active ingredient is added and stirring is continued
until dispersed. The mixture is then cooled until solid.
[0617] Another preferred formulation employed in the methods of the
present invention employs transdermal delivery devices ("patches").
Such transdermal patches may be used to provide continuous or
discontinuous infusion of the compounds of the present invention in
controlled amounts. The construction and use of transdermal patches
for the delivery of pharmaceutical agents is well known in the art.
See. e.g., U.S. Pat. No. 5,023,252, issued Jun. 11, 1991, herein
incorporated by reference. Such patches may be constructed for
continuous, pulsatile, or on demand delivery of pharmaceutical
agents. Frequently, it will be desirable or necessary to introduce
the pharmaceutical composition to the brain, either directly or
indirectly. Direct techniques usually involve placement of a drug
delivery catheter into the host's ventricular system to bypass the
blood-brain barrier. One such implantable delivery system used for
the transport of biological factors to specific anatomical regions
of the body is described in U.S. Pat. No. 5,011,472 which is herein
incorporated by reference.
[0618] Indirect techniques, which are generally preferred, usually
involve formulating the compositions to provide for drug
latentiation by the conversion of hydrophilic drugs into
lipid-soluble drugs. Latentiation is generally achieved through
blocking of the hydroxy, carbonyl, sulfate, and primary amine
groups present on the drug to render the drug more lipid soluble
and amenable to transportation across the blood-brain barrier.
Alternatively, the delivery of hydrophilic drugs may be enhanced by
intra-arterial infusion of hypertonic solutions which can
transiently open the blood-brain barrier.
[0619] Other suitable formulations for use in the present invention
can be found in Remington's Pharmaceutical Sciences, Mace
Publishing Company, Philadelphia, Pa., 17th ed. (1985).
Utility
[0620] The compounds and pharmaceutical compositions of the
invention are useful in inhibiting .beta.-amyloid peptide release
and/or its synthesis, and, accordingly, have utility in treating
Alzheimer's disease in mammals including humans.
[0621] As noted above, the compounds described herein are suitable
for use in a variety of drug delivery systems described above.
Additionally, in order to enhance the in vivo serum half-life of
the administered compound, the compounds may be encapsulated,
introduced into the lumen of liposomes, prepared as a colloid, or
other conventional techniques may be employed which provide an
extended serum half-life of the compounds. A variety of methods are
available for preparing liposomes, as described in, e.g., Szoka, et
al., U.S. Pat. Nos. 4,235,871, 4,501,728 and 4,837,028 each of
which is incorporated herein by reference.
[0622] The amount of compound administered to the patient will vary
depending upon what is being administered, the purpose of the
administration, such as prophylaxis or therapy, the state of the
patient, the manner of administration, and the like. In therapeutic
applications, compositions are administered to a patient already
suffering from AD in an amount sufficient to at least partially
arrest further onset of the symptoms of the disease and its
complications. An amount adequate to accomplish this is defined as
"therapeutically effective dose." Amounts effective for this use
will depend on the judgment of the S attending clinician depending
upon factors such as the degree or severity of AD in the patient,
the age, weight and general condition of the patient, and the like.
Preferably, for use as therapeutics, the compounds described herein
are administered at dosages ranging from about 1 to about 500
mg/kg/day.
[0623] In prophylactic applications, compositions are administered
to a patient at risk of developing AD (determined for example by
genetic screening or familial trait) in an amount sufficient to
inhibit the onset of symptoms of the disease. An amount adequate to
accomplish this is defined as "prophylactically effective dose."
Amounts effective for this use will depend on the judgment of the
attending clinician depending upon factors such as the age, weight
and general condition of the patient, and the like. Preferably, for
use as prophylactics, the compounds described herein are
administered at dosages ranging from about 1 to about 500
mg/kg/day.
[0624] As noted above, the compounds administered to a patient are
in the form of pharmaceutical compositions described above. These
compositions may be sterilized by conventional sterilization
techniques, or may be sterile filtered. The resulting aqueous
solutions may be packaged for use as is, or lyophilized, the
lyophilized preparation being combined with a sterile aqueous
carrier prior to administration. The pH of the compound
preparations typically will be between 3 and 11, more preferably
from 5 to 9 and most preferably from 7 and 8. It will be understood
that use of certain of the foregoing excipients, carriers, or
stabilizers will result in the formation of pharmaceutical
salts.
[0625] The following synthetic and biological examples are offered
to illustrate this invention and are not to be construed in any way
as limiting the scope of this invention. Unless otherwise stated,
all temperatures are in degrees Celsius.
EXAMPLES
[0626] In the examples below, the following abbreviations have the
following meanings. If an abbreviation is not defined, it has its
generally accepted meaning.
[0627] BOC=tert-butoxycarbonyl
[0628] BOP=benzotriazol-1-yloxy-tris(dimethylamino)phosphonium
[0629] hexafluorophosphate
[0630] bd=broad doublet
[0631] bs=broad singlet
[0632] c=concentration (g/mL)
[0633] CDI=1,1'-carbonyldiimidazole
[0634] d=doublet
[0635] dd=doublet of doublets
[0636] DCM=dichloromethane
[0637] DEAD=diethyl azodicarboxylate
[0638] DMF=dimethylformamide
[0639] DMSO=dimethylsulfoxide
[0640] EDC=1-(3-dimethylaminopropyl)-3-ethylcarbodimide
[0641] hydrochloride
[0642] EEDQ=2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline
[0643] eq.=equivalents
[0644] EtOAc=ethyl acetate
[0645] EtOH=ethanol
[0646] g=grams
[0647] L=liter
[0648] m=multiplet
[0649] max=maximum
[0650] MeOH=methanol
[0651] meq=milliequivalent
[0652] mg=milligram
[0653] mL=milliliter
[0654] mm=millimeter
[0655] mmol=millimole
[0656] N/A=not available
[0657] N=normal
[0658] ng=nanogram
[0659] nm=nanometers
[0660] OD=optical density
[0661] .phi.=phenyl
[0662] PEPC=1-(3-(1-pyrrolidinyl)propyl)-3-ethylcarbodiimide
[0663] psi=pounds per square inch
[0664] q=quartet
[0665] quint=quintet
[0666] rpm=rotations per minute
[0667] s=singlet
[0668] t=triplet
[0669] TFA=trifluoroacetic acid
[0670] THF=tetrahydrofuran
[0671] tlc=thin layer chromatography
[0672] .mu.L=microliter
[0673] UV=ultraviolet
[0674] In the examples below, all temperatures are in degrees
Celcius (unless otherwise indicated) and each of the compounds set
forth in these examples was prepared by one of the following
general procedures, unless otherwise indicated.
[0675] Additionally, the term "Aldrich" indicates that the compound
or reagent used in the following procedures is commercially
available from Aldrich Chemical Company, Inc., 1001 West Saint Paul
Avenue, Milwaukee, Wis. 53233 USA; the term "Fluka" indicates that
the compound or reagent is commercially available from Fluka
Chemical Corp., 980 South 2nd Street, Ronkonkoma N.Y. 11779 USA;
the term "Lancaster" indicates that the compound or reagent is
commercially available from Lancaster Synthesis, Inc., P.O. Box 100
Windham, N.H. 03087 USA; the term "Sigma" indicates that the
compound or reagent is commercially available from Sigma, P.O. Box
14508, St. Louis Mo. 63178 USA; the term "Chemservice" indicates
that the compound or reagent is commercially available from
Chemservice Inc., Westchester, Pa.; the term "Bachem" indicates
that the compound or reagent is commercially available from Bachem
Biosciences Inc., 3700 Horizon Drive, Renaissance at Gulph Mills,
King of Prussia, Pa. 19406 USA; the term "Maybridge" indicates that
the compound or reagent is commercially available from Maybridge
Chemical Co. Trevillett, Tintagel, Cornwall PL34 OHW United
Kingdom; and the term "TCI" indicates that the compound or reagent
is commercially available from TCI America, 9211 North Harborgate
Street, Portland Oreg. 97203; the term "Alfa" indicates that the
compound or reagent is commercially available from Johnson Matthey
Catalog Company, Inc. 30 Bond Street, Ward Hill, Mass. 01835-0747;
the term "Novabiochem" indicates that the compound or reagent is
commercially available from Calbiochem-Novabiochem Corp. 10933
North Torrey Pines Road, P.O. Box 12087, La Jolla Calif.
92039-2087; the term "Oakwood" indicates that the compound or
reagent is commercially available from Oakwood, Columbia, S.C.; the
term "Advanced Chemtech" indicates that the compound or reagent is
commercially available from Advanced Chemtech, Louisville, Ky.; and
the term "Pfaltz & Bauer" indicates that the compound or
reagent is commercially available from Pfaltz & Bauer,
Waterbury, Conn., USA.
[0676] The following General Procedures A'-P' and Examples A1-A74
illustrate the synthesis of N-(aryl/heteroarylacetyl)amino acid
esters which can be hydrolyzed to provide for
N-(aryl/heteroarylacetyl)amino acid starting materials of this
invention. Other N-(aryl/heteroarylacetyl)amino acid esters can be
prepared using these procedures from commerically available or
known starting materials.
General Procedure A'
Coupling of R'C(X')(X'')C(O)Cl with
H.sub.2NCH(R.sup.2)C(O)XR.sup.3
[0677] To a stirred solution of (D,L)-alanine iso-butyl ester
hydrochloride (from Example B below) (4.6 mmol) in 5 mL of pyridine
was added 4.6 mmol of an acid chloride. Precipitation occurred
immediately. The mixture was stirred for 3.5 h, diluted with 100 mL
of diethyl ether, washed with 10% HCl three times, brine once, 20%
potassium carbonate once and brine once. The solution was dried
over magnesium sulfate, filtered, and evaporated at reduced
pressure to yield the product. Other amino acid esters may also be
employed in this procedure.
General Procedure B'
Coupling of R'C(X')(X'')C(O)OH with
H.sub.2NCH(R.sup.2)C(O)XR.sup.3
[0678] A solution of the acid (3.3 mmol) and CDI in 20 mL THF was
stirred for 2 h. L-alanine iso-butyl ester hydrochloride (from
Example B below) (3.6 mmol) was added, followed by 1.5 mL (10.8
mmol) of triethylamine. The reaction mixture was stirred overnight.
The reaction mixture was diluted with 100 mL of diethyl ether,
washed with 10% HCl three times, brine once, 20% potassium
carbonate once and brine once. The solution was dried over
magnesium sulfate, filtered, and evaporated at reduced pressure to
yield the product. Other amino acid esters may also be employed in
this procedure.
General Procedure C'
Esterification of R'C(X')(X'')C(O)NHCH(R.sup.2)C(O)OH With
HOR.sup.3
[0679] To a stirred solution of phenylacetylvaline (1.6470 g, 7.0
mmol) in 20 mL THF was added CDI (1.05 g, 6.5 mmol) and the mixture
was stirred for 1.5 h. 2-Methylbutanol (0.53 g, 6 mmol) was added
the mixture, followed by addition of NaH (0.16 g, 6.5 mmol).
Bubbling occurred immediately. The reaction mixture was stirred
overnight. The reaction mixture was diluted with 100 mL of diethyl
ether, washed with 10% HCl three times, brine once, 20% potassium
carbonate once and brine once. The solution was dried over
magnesium sulfate, filtered, and evaporated at reduced pressure to
yield the product. Other N-acyl amino acids and alcohols may also
be employed in this procedure.
General Procedure D'
Ester Hydrolysis to the Free Acid
[0680] Ester hydrolysis to the free acid was conducted by
conventional methods. Below are two examples of such conventional
de-esterification methods. To the ester in a 1:1 mixture of
CH.sub.3OH/H.sub.2O was added 2-5 equivalents of K.sub.2CO.sub.3.
The mixture was heated to about 50.degree. C. for about 0.5 to 1.5
hours until tic showed complete reaction. The reaction was cooled
to room temperature and the methanol was removed at reduced
pressure. The pH of the remaining aqueous solution was adjusted to
about 2, and ethyl acetate was added to extract the product. The
organic phase was then washed with saturated aqueous NaCl and dried
over MgSO. The solution was stripped free of solvent at reduced
pressure to yield the product.
[0681] The amino acid ester was dissolved in dioxane/water (4:1) to
which was added LiOH (.about.2 eq.) that was dissolved in water
such that the total solvent after addition was about 2:1
dioxane:water. The reaction mixture was stirred until reaction
completion and the dioxane was removed under reduced pressure. The
residue was diluted with EtOAc, the layers were separated and the
aqueous layer acidified to pH 2. The aqueous layer was back
extracted with EtOAc, the combined organics were dried over
Na.sub.2SO.sub.4 and the solvent was removed under reduced pressure
after filtration. The residue was purified by conventional methods
(e.g., recrystallization).
[0682] The following exemplifies this later example. The methyl
ester of 3-NO.sub.2 phenylacetyl alanine 9.27 g (0.0348 mols) was
dissolved in 60 mL dioxane and 15 mL of H.sub.2O and adding LiOH
(3.06 g, 0.0731 mol) that has been dissolved in 15 mL of H.sub.2O.
After stirring for 4 hours, the dioxane was removed under reduced
pressure and the residue diluted with EtOAc, the layers were
separated and the aqueous layer acidified to pH 2. The aqueous
layer was back extracted with EtOAc (4.times.100 mL), the combined
organics were dried over Na.sub.2SO.sub.4 and the solvent was
removed under reduced pressure after filtration. The residue was
recrystallized from EtOAc/isooctane giving 7.5 g (85%) of
3-nitrophenylacetyl alanine. C.sub.11H.sub.12N.sub.2O.sub.5
requires C=52.38, H=4.80, and N=11.11 Analysis found C=52.54,
H=4.85, and N=11.08. [.alpha.].sub.23 =29.9 @589 nm.
General Procedure E'
Low Temperature BOP Coupling of Acid and Alcohol
[0683] A solution of methylene chloride containing the carboxylic
acid (100M %) and N-methyl morpholine (150M %) was cooled to
-20.degree. C. under nitrogen. BOP (105M %) was added in one
portion and the reaction mixture was maintained at -20.degree. C.
for 15 minutes. The corresponding alcohol (120M %) was added and
the reaction mixture was allowed to warm to room temperature and
stirred for 12 hours. The reaction mixture was then poured into
water and extracted with ethyl acetate (3.times.). The combined
ethyl acetate portions were backwashed with saturated aqueous
citric acid (2.times.), saturated aqueous sodium bicarbonate
(2.times.), brine (1.times.), dried over anhydrous magnesium
sulfate or sodium sulfate and the solvent removed under reduced
pressure to yield the crude product.
General Procedure F'
EDC Coupling of Acid and Amine
[0684] The acid derivative was dissolved in methylene chloride. The
amine (1 eq.), N-methylmorpholine (5 eq.), and hydroxybenzotriazole
monohydrate (1.2 eq.) were added in sequence. The reaction was
cooled to about 0.degree. C. and then 1.2 eq. of
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was
added. The solution was allowed to stir overnight and come to room
temperature under N.sub.2 pressure. The reaction mix was worked up
by washing the solution with saturated, aqueous Na.sub.2CO.sub.3,
0.1M citric acid, and brine before drying with Na.sub.2SO.sub.4 and
removal of solvents to yield crude product. Pure products were
obtained by flash chromatography in an appropriate solvent.
General Procedure G'
EDC Coupling of Acid and Amine
[0685] A round bottom flask was charged with carboxylic acid (1.0
eq.), hydroxy-benzotriazole hydrate (1.1 eq.) and amine (1.0 eq.)
in THF under nitrogen atmosphere. An appropriate amount (1.1 eq.
for free amines and 2.2 eq. for hydrochloride amine salts) of base,
such as Hunig's base was added to the well stirred mixture followed
by EDC (1.1 eq.). After stirring from 4 to 17 hours at room
temperature the solvent was removed at reduced pressure, the
residue taken up in EtOAc (or similar solvent)/water. The organic
layer was washed with saturated aqueous sodium bicarbonate
solution, 1N HCl, brine and dried over anhydrous sodium sulfate. In
some cases, the isolated product was analytically pure at this
stage while, in other cases, purification via chromatography and/or
recrystallization was required prior to biological evaluation.
General Procedure H'
Coupling of R'C(X')(X'')C(O)Cl with
H.sub.2NCH(R.sup.2)C(O)XR.sup.3
[0686] An excess of oxalyl chloride in dichlorbmethane was added to
the acid derivative together with one drop of DMF. The resulting
mixture was stirred for about 2 hours or until bubbling ceases. The
solvent was then removed under reduced pressure and rediluted with
dry methylene chloride. To the resulting solution was added about
1.1 eq. of the appropriate amino acid ester and triethylamine (1.1
eq. in methylene chloride). The system was stirred at room
temperature for 2 hours and then the solvent was removed under
reduced pressure. The residue was dissolved in ethyl acetate,
washed with 1N HCl followed by 1N NaOH. The organic layer was dried
over anhydrous sodium sulfate, filtered and the solvent removed
under reduced pressure to provide for the desired product.
General Procedure I'
P-EPC Coupling
[0687] P-EPC coupling employs an amino acid ester and a substituted
acetic acid compound. The acetic acid derivative is well known in
the art and is typically commercially available. The amino acid
ester is prepared by conventional methods from the known and
typically commercially available N-BOC amino acid as described in
General Procedure I' below.
[0688] Specifically, the appropriate amino ester free base (0.0346
mmols) and substituted phenylacetic acid (0.069 mmols) were
dissolved in 2.0 mL CHCl.sub.3 (EtOH free), treated with 150 mg of
P-EPC (0.87 meq./g) and the reaction was mixed for 4 days at
23.degree. C. The reaction was filtered through a plug of cotton,
rinsed with 2.0 mL of CHCl.sub.3 and the filtrate evaporated under
a stream of nitrogen. The purity of each sample was determined by
.sup.1H NMR and ranged from 50% to >95%. Between 8.0 and 15.0 mg
of final product was obtained from each reaction and was tested
without additional purification.
General Procedure J'
Synthesis of Amino Acid Esters From the Corresponding N-BOC Amino
Acid
A. Esterification of the Acid.
[0689] The N-BOC amino acid was dissolved in dioxane and treated
with an excess of alcohol (.about.1.5 eq.) and catalytic DMAP (100
mg) at 0.degree. C. Stirring was continued until reaction
completion whereupon the product was recovered by conventional
methods.
B. Removal of N-BOC Group.
[0690] The N-BOC protected amino acid was dissolved in methylene
chloride (0.05M) and treated with 10 eq. of TFA at room temperature
under a nitrogen atmosphere. The reaction was monitored by tic
until starting material was consumed usually within 1-5 hours. An
additional 10 eq. of TFA was added to the reaction if the starting
material was still present after 5 hours. The reaction was
carefully neutralized with Na.sub.2CO.sub.3, separated, the organic
layer washed with brine and dried over anhydrous Na.sub.2SO.sub.4.
The crude amine was then used without purification.
[0691] Specific exemplification of these procedures are as
follows:
[0692] 1. Racemic (.+-.)-N-BOC-.alpha.-amino butyric acid (Aldrich)
(9.29 g, 0.0457 mol) was dissolved in 100 mL of dioxane and treated
with iso-butyl alcohol (6.26 mL, 0.0686 mol), EDC (8.72 g, 0.0457)
and catalytic DMAP (100 mg) at 0.degree. C. After stirring for 17
hours, the organics were evaporated at reduced pressure, the
residue diluted with EtOAc washed with NaHCO.sub.3, brine and dried
over Na.sub.2SO.sub.4. Evaporation yields 8.42 g (71%) of an oil.
C.sub.13H.sub.25NO.sub.4 requires: C=60.21, H=9.72, and N=5.40.
Anal found: C=59.91, H=9.89, and N=5.67.
[0693] The above N-BOC amino acid ester (8.00 g, 0.032 mol) was
deprotected as above giving 3.12 g (61%) of the free base as a
colorless oil which solidifies upon standing.
[0694] 2. L-N-BOC-alanine (Aldrich) (8.97 g, 0.047 mol) was
dissolved in 100 mL of CH.sub.2Cl.sub.2, iso-butyl alcohol (21.9
mL, 0.238 mol) and treated with DMAP (100 mg) and EDC (10.0 g, 0.52
mol) at 0.degree. C. The mixture was stirred for 17 hours, diluted
with H.sub.2O, washed with 1.0 N HCl, NaHCO.sub.3, then brine and
the organics were dried over Na.sub.2SO.sub.4. Filtration and
evaporation yields 11.8 g (quantitative) of L-N-BOC alanine
iso-butyl ester which is contaminated with a small amount of
solvent. A sample was vacuum dried for analytical analysis.
C.sub.12H.sub.23NO.sub.4 requires: C=58.79, H=9.38, and N=5.71.
Anal found: C=58.73, H=9.55, and N=5.96.
[0695] The above N-BOC amino acid ester (11.8 g, 0.0481 mol) was
deprotected as above. The free base was converted to the
corresponding HCl salt using saturated HCl (g)/EtOAc to give
L-N-alanine iso-butyl ester hydrochloride. Obtained 4.2 g (48%) of
a colorless solid. C.sub.7H.sub.15NO.sub.2. HCl requires: C=46.28,
H=8.88, and N=7.71. Anal found: C=46.01, H=8.85, and N=7.68.
General Procedure K'
Methyl Ester Formation From Amino Acids
[0696] The amino acid (amino acid or amino acid hydrochloride) is
suspended in methanol and chilled to 0.degree. C. HCl gas is
bubbled through this solution for 5 minutes. The reaction is
allowed to warm to room temperature then stirred for 4 hours. The
solvents are then removed at reduced pressure to afford the desired
amino acid methyl ester hydrochloride. This product is usually used
without further purification.
Example A'
Synthesis of Free and Polymer Bound PEPC
N-ethyl-N'-3-(1-pyrrolidinyl)propylurea
[0697] To a solution of 27.7 g (0.39 mol) ethyl isocyanate in 250
mL chloroform was added 50 g (0.39 mol)
3-(1-pyrrolidinyl)propylamine dropwise with cooling. Once the
addition was complete, the cooling bath was removed and the
reaction mixture stirred at room temperature for 4 hours. The
reaction mixture was then concentrated under reduced pressure to
give 74.5 g (96.4%) of the desired urea as a clear oil.
1-(3-(1-pyrrolidinyl)propyl)-3-ethylcarbodiimide (P-EPC)
[0698] To a solution of 31.0 g (0.156 mol)
N-ethyl-N'-3-(1-pyrrolidinyl)propyl-urea in 500 mL dichloromethane
was added 62.6 g (0.62 mol) triethylamine and the solution was
cooled to 0.degree. C. To this solution were then added 59.17 g
(0.31 mol) 4-toluenesulfonyl chloride in 400 mL dichloromethane
dropwise at such a rate as to maintain the reaction at 0-5.degree.
C. After the addition was complete, the reaction mixture was warmed
to room temperature and then heated to reflux for 4 hours. After
cooling to room temperature, the reaction mixture was washed with
saturated aqueous potassium carbonate (3.times.150 mL). The aqueous
phases were combined and extracted with dichloromethane. All
organic phases were combined and concentrated under reduced
pressure. The resultant orange slurry was suspended in 250 mL
diethyl ether and the solution decanted off from the solid. The
slurry/decantation process was repeated 3 more times. The ether
solutions were combined and concentrated under reduced pressure to
give 18.9 g (67%) of the desired product as a crude orange oil. A
portion of the oil was distilled under vacuum to give a colorless
oil distilling at 78-82.degree. C. (0.4 mm Hg).
Preparation of a Polymer Supported Form of
1-(3-(1-pyrrolidinyl)propyl)-3-ethylcarbodiimide (P-EPC)
[0699] A suspension of 8.75 g (48.3 mmol)
1-(3-(1-pyrrolidin-yl)propyl)-3-ethylcarbodiimide and 24.17 g
(24.17 mmol) Merrifield's resin (2% cross-linked, 200-400 mesh,
chloromethylated styrene/divinylbenzene copolymer, 1 meq. Cl/g) in
dimethylformamide was heated at 100.degree. C. for 2 days. The
reaction was cooled and filtered and the resulting resin washed
sequentially with 1 L DMF, 1 L THF and 1 L diethyl ether. The
remaining resin was then dried under vacuum for 18 hours.
Example B'
Preparation of Alanine Iso-Butyl Ester Hydrochloride
[0700] A mixture of 35.64 g (0.4 mol) of (D,L)-alanine (Aldrich)
(or L-alanine (Aldrich)); 44 mL (0.6 mol) of thionyl chloride
(Aldrich) and 200 mL of isobutanol was refluxed for 1.5 hours and
the volatiles were removed completely on a rotavapor of 90.degree.
C. under reduced pressure to give (D,L)-alanine iso-butyl ester
hydrochloride (or L-alanine iso-butyl ester hydrochloride), which
was pure enough to be used for further transformations.
Example C'
Preparation of 3,5-dichlorophenylacetic acid
[0701] To a solution of 3.5 g of 3,5-dichlorobenzyl alcohol
(Aldrich) in 75 mL of dichloromethane at 0.degree. C. was added 1.8
mL of methane sulfonylchloride followed by 3.5 mL of triethylamine
added dropwise. After 2 hours the solution was diluted to 150 mL
with dichloromethane, washed with 3N HCl, saturated aqueous
NaHCO.sub.3 dried with Na.sub.2SO.sub.4 and the solvents removed to
yield the desired 3,5-dichlorobenzyl methanesulfonate as a yellow
oil that was used without purification.
[0702] The crude sulfonate was dissolved in 50 mL of DMF at
0.degree. C. and then 3 g of KCN was added. After 2 hours an
additional 50 mL of DMF was added and the solution was stirred for
16 hours. The red solution was diluted with 1 L of H.sub.2O and
acidified to pH 3 with 3N HCl. The aqueous solution was extracted
with dichloromethane. The combined organics were washed with 3N
HCl, dried with Na.sub.2SO.sub.4 and the solvents removed at
reduced pressure to yield crude 3,5-dichlorophenylacetonitrile
which was used without purification.
[0703] The nitrile was added to a mixture of 40 mL of concentrated
sulfuric acid and 50 mL H.sub.2O and heated to reflux for 48 hours,
cooled to room temperature and stirred for 48 hours. The reaction
was diluted into 1 L of crushed ice, warmed to room temperature and
extracted with 2.times.200 mL of dichloromethane and 2.times.200 mL
of ethylacetate. Both sets of organics were combined and washed
with saturated aqueous NaHCO.sub.3. The NaHCO.sub.3 fractions were
combined and acidified to pH 1 with 3N HCl. The white solid was too
fine to filter and was extracted out with 2.times.200 mL of
dichloromethane. The combined organics were dried with
Na.sub.2SO.sub.4 and the solvents removed at reduced pressure to
yield crude 3,5-dichlorophenylacetic acid as a white solid. The
solid was slurried with hexane and filtered to get 1.75 g of white
solid.
[0704] NMR (CDCl.sub.3): (in ppm) 3.61 (s, 2H), 7.19 (s,1H), 7.30
(s, 1H)
Example D'
Synthesis of N-(3-chlorophenylacetyl)alanine
[0705] The title compound was prepared using L-alanine (Nova
Biochem) and 3-chlorophenyl acetic acid (Aldrich) by following
General Procedures F' or G', followed by hydrolysis using General
Procedure D'.
[0706] Example A1
Synthesis of N-(phenylacetyl)-D,L-alanine iso-butyl ester
[0707] Following General Procedure A' above and using phenylacetyl
chloride (Aldrich) and D,L-alanine iso-butyl ester hydrochloride
(from Example B' above), the title compound was prepared. The
reaction was monitored by tlc on silica gel and purification was by
extraction with Et2O followed by washes with aqueous
K.sub.2CO.sub.3 and aqueous HCl.
[0708] NMR data was as follows:
[0709] .sup.1H-nmr (CDCl.sub.3): .delta.=7.23-7.36 (m, 5H), 6.18
(d, 1H), 4.58 (t, J=7.3 Hz, 1H), 3.87 (m, 2H), 3.57 (s, 2H), 1.90
(m, 1H), 1.34 (d, J=7.2 Hz, 3H), 0.89 (d, J=6.8 Hz, 6H).
[0710] .sup.13C-nmr (CDCl.sub.3): .delta.=172.7, 170.3, 134.5,
129.2, 128.8, 127.2, 71.3, 48.1, 43.4, 27.5, 18.8, 18.3.
[0711] C.sub.15H.sub.21NO.sub.3 (MW=263.34; Mass Spectroscopy
(MH.sup.+=264))
Example A2
Synthesis of N-(3-phenylpropionyl)-D,L-alanine iso-butyl ester
[0712] Following General Procedure A' above and using
3-phenylpropionyl chloride (Aldrich) and D,L-alanine iso-butyl
ester hydrochloride (from Example B' above), the title compound was
prepared as a solid having a melting point of from
51.degree.-54.degree. C. The reaction was monitored by tic on
silica gel and purification was by extraction with Et.sub.2O
followed by washes with aqueous K.sub.2CO.sub.3 and aqueous
HCl.
[0713] NMR data was as follows:
[0714] .sup.1H-nmr (CDCl.sub.3): .delta.=7.25 (m, 2H), 7.19 (m,
3H), 6.28 (d, J=7.2 Hz, 1H), 4.58 (quint., J=7.2 Hz, 1H), 3.89 (m,
2H), 2.95 (t, J=7.7 Hz, 2H), 2.50 (m, 2), 1.92 (m, 1H), 1.33 (d,
J=7.1 Hz, 3H), 0.91 (d, J=6.7 Hz, 6H).
[0715] .sup.13C-nmr (CDCl.sub.3): .delta.=173.0, 171.5, 140.6,
128.3, 128.1, 126.0, 71.2, 47.8, 37.9, 31.4, 27.5, 18.79, 18.77,
18.3.
[0716] C.sub.16H.sub.23NO.sub.3 (MW=277.37, Mass Spectroscopy
(MH.sup.+ 278))
Example A3
Synthesis of N-(3-methylpentanoyl)-L-alanine iso-butyl ester
[0717] Following General Procedure B' and using 3-methylpentanoic
acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from
Example B' above), the title compound was prepared as an oil. The
reaction was monitored by tlc on silica gel and purification was by
extraction with EtO followed by washes with aqueous K.sub.2CO.sub.3
and aqueous HCl.
[0718] NMR data was as follows:
[0719] .sup.1H-nmr (CDCl.sub.3): .delta.=6.08 (d, J=5.9 Hz, 1H),
4.62 (quint., J=7.3 Hz, 1H), 3.92 (m, 2H), 2.22 (m, 1H), 1.84-2.00
(m, 3H), 1.40 (d, J=7.2 Hz, 3H), 1.35 (m, 1H), 1.20 (m, 1H),
0.85-0.96 (m, 12H).
[0720] .sup.13C-nmr (CDCl.sub.3): .delta.=173.3, 172.1, 71.4, 47.9,
43.9, 32.3, 29.38, 29.35, 27.6, 19.10, 19.06, 18.93, 18.91, 18.72,
18.67, 11.3.
[0721] C.sub.13H.sub.25NO.sub.3 (MW=243.35, Mass Spectroscopy
(MH.sup.+ 244))
Example A4
Synthesis of N-[(4-chlorophenyl)acetyl]-L-alanine iso-butyl
ester
[0722] Following General Procedure B' and using
4-chlorophenylacetic acid (Aldrich) and L-alanine iso-butyl ester
hydrochloride (from Example B' above), the title compound was
prepared as a solid having a melting point of
111.degree.-113.degree. C. The reaction was monitored by tlc on
silica gel and purification was by extraction with Et.sub.2O
followed by washes with aqueous K.sub.2CO.sub.3 and aqueous
HCl.
[0723] NMR data was as follows:
[0724] .sup.1H-nmr (CDCl.sub.3): .delta.=7.30 (d, J=8.2 Hz, 2H),
7.21 (d, J=8.3 Hz, 2H), 6.18 (d, J=5.5 Hz, 1H), 4.57 (quint., J=7.2
Hz, 1H), 3.88 (m, 2H), 3.53 (s, 2H), 1.91 (m, 1H), 1.36 (d, J=7.1
Hz, 3H), 0.90 (d, J=6.8 Hz, 6H).
[0725] .sup.13C-nmr (CDCl.sub.3): .delta.=172.8, 169.8, 133.1,
133.0, 130.6, 128.9, 71.4, 48.2, 42.6, 27.6, 18.85, 18.82,
18.4.
[0726] C.sub.15H.sub.20NO.sub.3Cl (MW=297.78, Mass Spectroscopy
(MH.sup.+ 298))
Example A5
Synthesis of N-[(3,4-dichlorophenyl)acetyl]-L-alanine iso-butyl
ester
[0727] Following General Procedure B' and using
3,4-dichlorophenylacetic acid (Aldrich) and L-alanine isobutyl
ester hydrochloride (from Example B' above), the title compound was
prepared as a solid having a melting point of 81.degree.-83.degree.
C. The reaction was monitored by tlc on silica gel and purification
was by extraction with Et.sub.2O followed by washes with aqueous
K.sub.2CO.sub.3 and aqueous HCl.
[0728] NMR data was as follows:
[0729] .sup.1H-nmr (CDCl.sub.3): .delta.=0.90 (d, J=6.8 Hz, 6H),
1.38 (d, J=7.1 Hz, 3H), 1.91 (m, 1H), 3.50 (s, 2H), 3.90 (m, 2H),
4.57 (quint., J=7.1 Hz, 1H), 6.31 (d, J=4.9 Hz, 1H),7.12 (m, 1H),
7.38 (m, 2H).
[0730] .sup.13C-nmr (CDCl.sub.3): .delta.=18.4, 18.8, 18.9, 27.6,
42.2, 48.3, 71.5, 128.6, 130.6, 131.2, 131.3, 132.6, 134.7, 169.2,
172.8.
[0731] C.sub.15H.sub.19NO.sub.3Cl.sub.2 (MW=332.23, Mass
Spectroscopy (MH.sup.+ 332))
Example A6
Synthesis of N-[(4-methylphenyl)acetyl]-D,L-alanine iso-butyl
ester
[0732] Following General Procedure B' and using
4-methylphenylacetic acid (Aldrich) and D,L-alanine iso-butyl ester
hydrochloride (from Example B' above), the title compound was
prepared as a solid having a melting point of
102.degree.-104.degree. C. The reaction was monitored by tlc on
silica gel (Rf=0.6 in 33% ethyl acetate/hexanes) and purification
was by extraction with Et.sub.2O followed by washes with aqueous
K.sub.2CO.sub.3 and aqueous HCl.
[0733] NMR data was as follows:
[0734] .sup.1H-nmr (CDCl.sub.3): .delta.=0.90 (d, J=6.7 Hz, 6H),
1.35 (d, J=7.2 Hz, 3H), 1.91 (m, 1H), 2.34 (s, 3H), 3.55 (s, 2H),
3.88 (m, 2H), 4.58 (m, 1H), 6.05 (bd, 1H), 7.16 (s, 4H).
[0735] .sup.13C-nmr (CDCl.sub.3): .delta.=18.5, 18.85, 18.87, 21.0,
27.6, 43.1, 48.1, 71.3, 129.2, 129.6, 131.3, 136.9, 170.6,
172.8.
[0736] C.sub.16H.sub.23NO.sub.3 (W=277.37, Mass Spectroscopy
(MH.sup.+ 278))
Example A7
Synthesis of N-[(3-pyridyl)acetyl]-D,L-alanine iso-butyl ester
[0737] Following General Procedure F' and using 3-pyridylacetic
acid hydrochloride (Aldrich) and D,L-alanine iso-butyl ester
hydrochloride (from Example B' above), the title compound was
prepared as a solid having a melting point of 62.degree.-64.degree.
C. The reaction was monitored by tlc on silica gel (Rf=0.48 10%
methanol/dichloromethane) and purification was by silica gel
chromatography.
[0738] NMR data was as follows:
[0739] .sup.1H-nmr (CDCl.sub.3): .delta.=8.40 (d, J=2.8, 2H); 7.6
(m, 1H): 7.16 (m, 2H); 14.5 (quint., J=7.2, 7.2, 1H); 3.8 (m, 2H);
3.48 (s, 2H); 1.8 (m, 1H); 1.30 (d, J=7.2, 3H); 0.81 (d, J=6.7,
6H).
[0740] .sup.13 C-nmr (CDCl.sub.3): .delta.=173.4, 170.1, 150.6,
148.8, 137.4, 131.4, 124.1, 71.9, 48.9, 40.6, 28.1, 19.5, 19.4,
18.6.
[0741] C.sub.14H.sub.20N.sub.2O.sub.3 (MW=264, Mass Spectroscopy
(MH.sup.+ 265))
Example A8
Synthesis of N-[(1-naphthyl)acetyl]-L-alanine iso-butyl ester
[0742] Following General Procedure B' and using 1-naphthylacetic
acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from
Example B' above), the title compound was prepared as a solid
having a melting point of 69.degree.-73.degree. C. The reaction was
monitored by tlc on silica gel and purification was by extraction
with Et.sub.2O followed by washes with aqueous K.sub.2CO.sub.3 and
aqueous HCl.
[0743] NMR data was as follows:
[0744] .sup.1H-nmr (CDCl.sub.3): .delta.=0.83 (m, 6M); 1.25 (d,
J=7.1 Hz, 3H), 1.81 (m, 1H), 3.79 (m, 2H), 4.04 (2s, 2H), 4.57
(quint., J=7.3 Hz, 1H), 5.99 (d, J=7.1 Hz, 1H), 7.44 (m, 2H), 7.53
(m, 214), 7.85 (m, 2H), 7.98 (m, 1H).
[0745] .sup.13C-nmr (CDCl.sub.3): .delta.=18.2, 18.81, 18.83, 27.5,
41.5, 48.2, 71.3, 123.7, 125.6, 126.1, 126.6, 128.2, 128.5, 128.7,
130.7, 132.0, 133.9, 170.3, 172.5.
[0746] C.sub.19H.sub.23NO.sub.3 (MW=313.40, Mass Spectroscopy
(MH.sup.+ 314))
Example A9
Synthesis of N-[(2-naphthyl)acetyl]-L-alanine iso-butyl ester
[0747] Following General Procedure B' and using 2-naphthylacetic
acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from
Example B' above), the title compound was prepared as a solid
having a melting point of 128.degree.-129.degree. C. The reaction
was monitored by tlc on silica gel and purification was by
extraction with Et.sub.2O followed by washes with aqueous
K.sub.2CO.sub.3 and aqueous HCl.
[0748] NMR data was as follows:
[0749] .sup.1H-nmr (CDCl.sub.3): .delta.=0.86 (m, 6H), 1.35 (d,
J=7.1 Hz, 3H), 1.78 (m, 1H, 3.76 (s, 2H), 3.87 (m, 2H), 4.62
(quint., J=7.2 Hz, 1H), 6.13 (d, J=7.1 Hz, 1H), 7.41 (m, 1H), 7.48
(m, 2H), 7.74 (s, 1H), 7.83 (m, 3H).
[0750] .sup.13C-nmr (CDCl.sub.3): .delta.=18.4, 18.82, 18.85, 27.6,
43.7, 48.2, 71.4, 125.9, 126.3, 127.2, 127.6, 127.7, 128.2, 128.7,
132.0, 132.5, 133.5, 170.3, 172.8.
[0751] C.sub.19H.sub.23NO.sub.3 (MW=313.40, Mass Spectroscopy
(MH.sup.+ 314)).
Example A10
Synthesis of N-(4-phenylbutanoyl)-L-alanine iso-butyl ester
[0752] Following General Procedure B' and using 4-phenylbutanoic
acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from
Example B' above), the title compound was prepared as an oil. The
reaction was monitored by tlc on silica gel and purification was by
extraction with Et.sub.2O followed by washes with aqueous
K.sub.2CO.sub.3 and aqueous HCl.
[0753] NMR data was as follows:
[0754] .sup.1H-nmr (CDCl.sub.3): .delta.=0.92 (d, J=6.7 Hz, 6H),
1.38 (d, J=7.1 Hz, 3H), 1.96 (m, 3H), 2.21 (t, J=7.1 Hz, 2H), 2.64
(t, J=7.3 Hz, 2H), 3.90 (m, 2H), 4.59 (quint., J=7.2 Hz, 1H), 6.31
(d, 1H), 7.16 (m, 3H), 7.24 (m, 2H).
[0755] .sup.13C-nmr (CDCl.sub.3): .delta.=18.3, 18.75, 18.78, 26.8,
27.5, 34.9, 35.3, 47.8, 71.2, 125.7, 128.2, 128.3, 141.3, 172.1,
173.0.
[0756] C.sub.17H.sub.25NO.sub.3 (MW 291.39, Mass Spectroscopy
(MH.sup.+ 292)).
Example A11
Synthesis of N-(5-phenylpentanoyl)-L-alanine iso-butyl ester
[0757] Following General Procedure B' and using 5-phenylpentanoic
acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from
Example B' above), the title compound was prepared as an oil. The
reaction was monitored by tlc on silica gel and purification was by
extraction with Et.sub.2O followed by washes with aqueous
K.sub.2CO.sub.3 and aqueous HCl.
[0758] NMR data was as follows:
[0759] .sup.1H-nmr (CDCl.sub.3): .delta.=7.23 (m, 2H), 7.17 (m,
3H), 6.30 (d, 1H), 4.59 (quint., J=7.3 Hz, 1H), 3.91 (m, 2H), 2.61
(t, J=7.2 Hz, 2H), 2.22 (t, J=7.2 Hz, 2H), 1.93 (m, 1H), 1.66 (m,
4Th, 1.38 (d, J=7.2 Hz, 3H), 0.92 (d, J=6.7 Hz, 6H).
[0760] .sup.13C-nmr (CDCl.sub.3): .delta.=173.1, 172.3, 142.0,
128.2, 128.1, 125.6, 71.2, 47.8, 36.1, 35.5, 30.8, 27.5, 25.0,
18.80, 18.77, 18.4.
[0761] C.sub.18H.sub.27NO.sub.3 (MW=305.39, Mass Spectroscopy
(MH.sup.+ 306)).
Example A12
Synthesis of N-[(4-pyridyl)acetyl]-D,L-alanine iso-butyl ester
[0762] Following General Procedure F' and using 4-pyridylacetic
acid hydrochloride (Aldrich) and (D,L)-alanine iso-butyl ester
hydrochloride (from Example B' above), the title compound was
prepared as a solid having a melting point of 64.degree.-66.degree.
C. The reaction was monitored by tlc on silica gel (Rf=0.43 10%
methanol/dichloromethane) and purification was by silica gel
chromatography.
[0763] NMR data was as follows:
[0764] .sup.1H-nmr (CDCl.sub.3): .delta.=8.51 (dd, J=1.6, 2.8, 1.6,
2H); 7.23 (dd, J=4.3, 1.6, 4.4, 2H); 6.71 (d, J=6.8, 1H); 4.56
(quint., J=7.3, 7.2, 1H); 3.88 (m, 2H); 3.53 (s, 2H); 1.89 (m, 1H);
1.36 (d, J=7.2, 3H); 0.88 (d, J=6.7, 6H).
[0765] .sup.13C-nmr (CDCl.sub.3): .delta.=173.5, 169.3, 150.5,
144.4, 125.1, 72.1, 48.9, 43.0, 28.2, 19.5, 19.5, 18.9.
[0766] C.sub.14H.sub.20N.sub.2O.sub.3 (MW=264, Mass Spectroscopy
(MH.sup.+ 265))
Example A13
Synthesis of N-(phenylacetyl)-L-alanine iso-butyl ester
[0767] Following General Procedure B' and using phenylacetyl
chloride (Aldrich) and L-alanine iso-butyl ester hydrochloride
(from Example B' above), the title compound was prepared as a solid
having a melting point of 45.degree.-47.degree. C. The reaction was
monitored by tlc on silica gel and purification was by extraction
with Et.sub.2O followed by washes with aqueous K.sub.2CO.sub.3 and
aqueous HCl.
[0768] NMR data was as follows:
[0769] .sup.1H-nmr (CDCl.sub.3): a=7.24-7.39 (m, 5H), 6.14 (d,
1H),. 4.58 (t, J=7.3 Hz, 1H), 3.88 (m, 2H), 3.58 (s, 2H), 1.90 (m,
1H), 1.35 (d, J=7.2 Hz, 3H), 0.89 (d, J=6.7 Hz, 6H).
[0770] .sup.13C-nmr (CDCl.sub.3): .delta.=172.8, 170.4, 134.5,
129.3, 128.9, 127.2, 71.3, 48.1, 43.5, 27.5, 18.9, 18.8, 18.4.
[0771] C.sub.15H.sub.21NO.sub.3 (MW=263.34, Mass Spectroscopy
(MH.sup.+ 264)).
Example A14
Synthesis of 2-[(3,4dichlorophenyl)acetamido]butyric acid isobutyl
ester
[0772] Following General Procedure I' above and using
3,4-dichlorophenylacetic acid (Aldrich) and iso-butyl
2-aminobutyrate (prepared following General Procedure J' above) the
title compound was prepared. The reaction was monitored by tlc on
silica gel and purification was by filtration as described in the
general procedure.
[0773] NMR data was as follows:
[0774] .sup.1H-nmr (CDCl.sub.3): a=7.36 (m, 3H), 6.03 (bd, 1M),
4.54 (m, 1H), 3.87 (m, 2H), 3.49 (s, 2H), 1.93 (m, 2H), 1.72 (m,
1H), 0.88 (d, 6H), 0.80 (t, 3H).
Example A15
Synthesis of .sup.2-[(3-methoxyphenyl)acetamido]butyric acid
iso-butyl ester
[0775] Following General Procedure I' above and using
3-methoxyphenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate
(prepared following General Procedure J' above), the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[0776] NMR data was as follows:
[0777] .sup.1H-nmr (CDCl.sub.3): .delta.=6.75 (m, 4H), 5.93 (bd,
1H), 4.51 (m, 1H), 3.83 (m, 2H), 3.75 (s, 2H), 3.52 (s, 2H), 1.82
(m, 2H), 1.60 (m, 1H), 0.84 (d, 6H), 0.74 (t, 3H).
[0778] C.sub.17H.sub.25NO.sub.4 MW=307.39, Mass Spectroscopy
(MH.sup.+ 309)).
Example A16
Synthesis of 2-[(4nitrophenyl)acetamido]butyric acid iso-butyl
ester
[0779] Following General Procedure I' above and using
4-nitrophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate
(prepared following General Procedure J' above), the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[0780] NMR data was as follows:
[0781] .sup.1H-nmr (CDCl.sub.3): .delta.=8.16 (d, 2H), 7.44 (d,
2H), 6.04 (bd, 1H), 4.55 (m, 1H), 3.86 (m, 2H), 3.66 (s, 2H), 1.86
(m,.2H), 1.67 (m, 1H), 0.85 (d, 6H), 0.81 (t, 3H).
[0782] C.sub.16H.sub.22N.sub.2O.sub.5 (MW=322.36, Mass Spectroscopy
(MH.sup.+ 323)).
Example A17
Synthesis of 2-[(3,4-methylenedioxyphenyl)acetamido]butyric acid
iso-butyl ester
[0783] Following General Procedure I' above and using
3,4-(methylenedioxy)-phenyl acetic acid (Aldrich) and iso-butyl
2-aminobutyrate (prepared following General Procedure J' above),
the title compound was prepared. The reaction was monitored by tlc
on silica gel and purification was by filtration as described in
the general procedure.
[0784] NMR data was as follows:
[0785] .sup.1H-nmr (CDCl.sub.3): .delta.=6.72 (m, 3H), 5.92 (bd,
1H), 4.54 (m, 1H), 3.86 (m, 2H), 3.66 (s, 2H), 1.86 (m, 2H), 1.66
(m, 1H), 0.89 (d, 6H), 0.79 (t, 3H).
Example A18
Synthesis of 2-[(thien-3-yl)acetamido]butyric acid iso-butyl
ester
[0786] Following General Procedure I' above and using
3-thiopheneacetic acid (Aldrich) and iso-butyl 2-aminobutyrate
(prepared following General Procedure J' above), the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[0787] NMR data was as follows:
[0788] .sup.1H-nmr (CDCl.sub.3): .delta.=7.37 (m, 1H), 7.16 (m,
1H), 7.04 (m, 1H), 6.05 (bd, 1H), 4.57 (m, 1H), 3.66 (s, 2H), 1.93
(m, 2H), 1.67 (m, 1H), 0.91 (d, 6H), 0.86 (t, 3H).
Example A19
Synthesis of 2-[(4chlorophenyl)acetamido]butyric acid iso-butyl
ester
[0789] Following General Procedure I' above and using
4-chlorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate
(prepared following General Procedure I' above), the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[0790] NMR data was as follows:
[0791] .sup.1H-nmr (CDCl.sub.3): .delta.=7.22 (m, 2H), 7.11 (m,
2H), 5.80 (m, 1H), 4.44 (m, 1H), 3.78 (m, 2H), 3.43 (s, 2H), 1.77
(m, 2H), 1.56 (m, 1H), 0.83 (d, 6H) 0.71 (t, 3H).
Example A20
Synthesis of 2-[(3nitrophenyl)acetamido]butyric acid iso-butyl
ester
[0792] Following General Procedure I' above and using
3-nitrophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate
(prepared following General Procedure J' above), the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[0793] NMR data was as follows:
[0794] .sup.1H-nmr (CDCl.sub.3): .delta.=8.15 (m, 2H), 7.65 (m,
1H), 6.08 (m, 1H), 4.46 (m, 1H), 3.92 (m, 2H), 3.68 (s, 2H), 1.91
(m, 2H), 1.75 (m, 1H), 0.98 (d, 6H) 0.71 (t, 3H).
Example A21
Synthesis of 2-[(2-hydroxyphenyl)acetamido]butyric acid iso-butyl
ester
[0795] Following General Procedure I' above and using
2-hydroxyphenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate
(prepared following General Procedure 3' above), the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[0796] NMR data was as follows:
[0797] .sup.1H-nmr (CDCl.sub.3): .delta.=7.14 (m, 1H), 7.01 (m,
1H), 6.93 (m, 1H), 6.79 (m, 1H), 6.46 (m, 1H), 4.51 (m, 1H), 3.87
(m, 2H), 3.57 (s, 2H), 2.01 (m, 2H), 1.75 (m, 1H), 0.89 (d, 6H),
0.85 (t, 3H).
Example A22
Synthesis of 2-[(2-naphthyl)acetamido]butyric acid iso-butyl
ester
[0798] Following General Procedure I' above and using
2-naphthylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate
(prepared following General Procedure J' above); the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[0799] NMR data was as follows:
[0800] .sup.1H-nmr (CDCl.sub.3): .delta.=7.83 (m, 7H), 5.95 (m,
1H), 4.58 (m, 1H), 3.84 (m, 2H), 3.75 (s, 2H), 1.89 (m, 2H), 1.63
(m; 1H), 0.91 (d, 6H), 0.81 (t, 3H).
[0801] C.sub.20H.sub.25NO.sub.3 (MW=327.42, Mass Spectroscopy
(MH.sup.+ 328)).
Example A23
Synthesis of 2[(2,4-dichlorophenyl)acetamido]butyric acid iso-butyl
ester
[0802] Following General Procedure I' above and using
2,4-dichlorophenylacetic acid (Aldrich) and iso-butyl
2-aminobutyrate (prepared following General Procedure J' above),
the title compound was prepared. The reaction was monitored by tlc
on silica gel and purification was by filtration as described in
the general procedure.
[0803] NMR data was as follows:
[0804] .sup.1H-nmr (CDCl.sub.3): .delta.=7.49 (m, 1H), 7.22 (m, 2H)
5.98 (m, 1H), 4.52 (m, 1H), 3.86 (m, 2H), 3.61 (s, 2H), 1.84 (m,
2H), 1.62 (m, 1H) 0.87 (d, 6H), 0.80 (t, 3H).
Example A24
Synthesis of 2-[(4-bromophenyl)acetamido]butyric acid iso-butyl
ester
[0805] Following General Procedure I' above and using
4-bromophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate
(prepared following General Procedure I' above), the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[0806] NMR data was as follows:
[0807] .sup.1H-nmr (CDCl.sub.3): .delta.=7.43 (d, 2H), 7.19 (d, 2H)
5.85 (m, 1H), 4.51 (m, 1H), 3.81 (m, 2H), 3.47 (s, 2H), 1.84 (m,
2H), 1.61. (m, 1H) 0.84 (d, 6H), 0.76 (t, 3H).
[0808] C.sub.16H.sub.22NO.sub.3Br (MW=356.26, Mass Spectroscopy
(MH.sup.+ 358)).
Example A25
Synthesis of 2-[(3-chlorophenyl)acetamido])butyric acid iso-butyl
ester
[0809] Following General Procedure I' above and using
3-chlorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate
(prepared following General Procedure J' above), the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[0810] NMR data was as follows:
[0811] .sup.1H-nmr (CDCl.sub.3): .delta.=7.25 (m, 3H), 7.12 (m, 1H)
5.80 (m, 1H), 4.52 (m, 1H); 3.86 (m, 2H), 3.50 (s, 2H), 1.87 (m,
2H), 1.67 (m, 1H) 0.88 (d, 6H), 0.77 (t, 3H).
[0812] C.sub.16H.sub.22NO.sub.3Cl (MW=311.81 Mass Spectroscopy
(MH.sup.+ 313)).
Example A26
Synthesis of 2-[(3-fluorophenyl)acetamido]butyric acid iso-butyl
ester
[0813] Following General Procedure I' above and using
3-fluorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate
(prepared following General Procedure J' above), the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[0814] NMR data was as follows:
[0815] .sup.1H-nmr (CDCl.sub.3): .delta.=7.31 (m, 1H), 7.01 (m, 3H)
5.95 (m, 1), 4.54 (m, 1H), 3.84 (m, 2H), 3.54 (s, 2H), 1.88 (m, 2H,
1.65 (m, 1H) 0.87 (d, 6H, 0.81 (t, 3H).
[0816] C.sub.16H.sub.22NO.sub.3F (MW=295.35 Mass Spectroscopy
(MH.sup.+ 296)).
Example A27
Synthesis of 2-[(benzothiazol-4-yl)acetamido]butyric acid iso-butyl
ester
[0817] Following General Procedure I' above and using
4-benzothiazol-4-yl acetic acid (Chemservice) and iso-butyl
2-aminobutyrate (prepared following General Procedure I' above),
the tide compound was prepared. The reaction was monitored by tlc
on silica gel and purification was by filtration as described in
the general procedure.
[0818] NMR data was as follows:
[0819] .sup.1H-nmr (CDCl.sub.3): .delta.=7.82 (m, 1H), 7.51-7.21
(m, 4H) 5.84 (m, 1H), 4.51 (m, 1H), 3.90 (s, 2H), 3.79 (m, 2H),
1.78 (m, 21), 1.58 (my 1H) 0.80 (d, 6H), 0.66 (t, 3H).
Example A28
Synthesis of 2-[(2-methylphenyl)acetamido]butyric acid iso-butyl
ester
[0820] Following General Procedure I' above and using
2-methylphenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate
(prepared following General Procedure J' above), the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[0821] NMR data was as follows:
[0822] .sup.1H-nmr (CDCl.sub.3): .delta.=7.18 (m, 4H), 5.79 (m,
1H), 4.54 (m, 1H), 3.85 (m, 2M), 3.59 (s, 2H), 3.29 (s, 3H), 1.81
(m, 2H), 1.59 (m, 1H) 0.87 (d, 6H), 0.77 (t, 3H).
[0823] C.sub.17H.sub.25NO.sub.3 (MW=291.39 Mass Spectroscopy
(M.sup.+ 291)).
Example A29
Synthesis of 2-[(2-fluorophenyl)acetamido]butyric acid iso-butyl
ester
[0824] Following General Procedure I' above and using
2-fluorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate
(prepared following General Procedure I' above), the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[0825] NMR data was as follows:
[0826] .sup.1H-nmr (CDCl.sub.3): .delta.=7.28 (m, 1H), 7.09 (m, 3H)
6.03 (m, 1H), 4.54 (m, 1H), 3.87 (m, 2H), 3.57 (s, 2H), 1.89 (m,
2H), 1.64 (m, 1H) 0.88 (d, 6H), 0.80 (t, 3H).
Example A30
Synthesis of 2-[(4-fuorophenyl)acetamido]butyric acid iso-butyl
ester
[0827] Following General Procedure I' above and using
4-fluorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate
(prepared following General Procedure J' above), the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[0828] NMR data was as follows:
[0829] .sup.1H-nmr (CDCl.sub.3): .delta.=7.20 (m, 2H), 6.97 (m, 2H)
5.87 (m, 1H), 4.492 (m, 1H), 3.83 (m, 2H), 3.48 (s, 2H), 1.86 (m,
2H), 1.60 (m, 1H) 0.87 (d, 6H), 0.78 (t, 3H).
[0830] C.sub.16H.sub.22NO.sub.3F (MW=295.35 Mass Spectroscopy
(MH.sup.+ 296)).
Example A31
Synthesis of 2-[(3-bromophenyl)acetamido]butyric acid iso-butyl
ester
[0831] Following General Procedure I' above and using
3-bromophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate
(prepared following General Procedure J' above), the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[0832] NMR data was as follows:
[0833] .sup.1H-nmr (CDCl.sub.3): .delta.=7.45 (m, 2H), 7.23 (m, 2H)
5.95 (m, 1H), 4.55 (m, 1H) 3.84 (m, 2H) 3.55 (s, 2H), 1.89 (m, 2H),
1.68 (m, 1H) 0.91 (d, 6H), 0.81 (t, 3H).
[0834] C.sub.16H.sub.22NO.sub.3Br (MW=356.26 Mass Spectroscopy
(M.sup.+ 357)).
Example A32
Synthesis of 2-[(3-trifluoromethylphenyl)acetamido]butyric acid
iso-butyl ester
[0835] Following General Procedure I' above and using
3-trifluoromethyl-phenylacetic acid (Aldrich) and iso-butyl
2-aminobutyrate (prepared following General Procedure I' above),
the title compound was prepared. The reaction was monitored by tlc
on silica gel and purification was by filtration as described in
the general procedure.
[0836] NMR data was as follows:
[0837] .sup.1H-nmr (CDCl.sub.3): .delta.=7.52 (m, 1H), 7.47 (m, 2H)
6.01 (m, 1H), 4.56 (m, 1H), 3.86 (m, 2H), 3.61 (s, 2H), 1.84 (m,
2H), 1.62 (m, 1H) 0.87 (d, 6H), 0.80 (t, 3H).
[0838] C.sub.17H.sub.22NO.sub.3F.sub.3 (MW=345.36 Mass Spectroscopy
(MH.sup.+ 345)).
Example A33
Synthesis of 2-[(2-thienyl)acetamido]butyric acid iso-butyl
ester
[0839] Following General Procedure I' above and using
2-thiopheneacetic acid (Aldrich) and iso-butyl 2-aminobutyrate
(prepared following General Procedure J' above), the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[0840] NMR data was as follows:
[0841] .sup.1H-nmr (CDCl): .delta.=6.89 (m, 3H), 6.07 (bd, 1H),
4.50 (m, 1H), 3.82 (m, 2H), 3.71 (s, 2H), 1.85 (m, 2H), 1.62 (m,
1H), 0.81 (d, 6H), 0.75 (t, 3H).
[0842] C.sub.14H.sub.21NO.sub.3S (MW=283.39, Mass Spectroscopy
(MH.sup.+ 284)).
Example A34
Synthesis of 2-(phenylacetamido)butyric acid iso-butyl ester
[0843] Following General Procedure H' above and using phenylacetic
acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following
General Procedure J' above), the title compound was prepared. The
reaction was monitored by tlc on silica gel and purification was by
chromatography on silica gel using 9:1 toluene:EtOAc as the
eluant.
[0844] NMR data was as follows:
[0845] .sup.1H-nmr (CDCl.sub.3): .delta.=7.17-7.28 (m, 5H), 6.23
(bd, 1H), 4.51 (m, 1H), 3.86 (m, 2H), 3.54 (s, 2H), 1.87 (m, 2H),
1.62 (m, 1H), 0.87 (d, 6H), 0.78 (t, 3H).
[0846] C.sub.16H.sub.23NO.sub.3 (MW=277.36, Mass Spectroscopy
(MH.sup.+ 277)).
Example A35
Synthesis of N-(phenylacetyl)valine 2-methylbutyl ester
Step A. Preparation of N-(phenylacetyl)valine
[0847] To a stirred solution of 5.15 g (44 mmol) of valine (Bachem)
in 50 mL (100 mmol) of 2N NaOH cooled to 0.degree. C. was added
dropwise 5.3 mL (40 mmol) of phenylacetyl chloride (Aldrich). A
colorless oil precipitated. The reaction mixture was allowed to
warm to room temperature and stirred for 18 hours, washed with 50
mL diethyl ether, acidified to pH 2-3 with aqueous HCl. The white
precipitate formed was filtered off, washed thoroughly with water,
followed by diethyl ether to give 7.1 g (30 mmol, 69% yield) of the
title compound.
[0848] NMR data was as follows:
[0849] .sup.1H-nmr (DMSO-d.sub.6): .delta.=12.63 (s, 1H), 8.25 (d,
J=8.6 Hz, 1H), 7.27 (m, 5H), 4.15 (m, 1H), 3.56 (d, J=13.8 Hz, 1H),
3.47 (d, J=13.8 Hz, 1H), 2.05 (m, 1H), 0.87 (d, J=6.8, Hz, 3H),
0.84 (d, J=6.8 Hz, 3)
[0850] .sup.13C-nmr (DMSO-d.sub.6): .delta.=173.2, 170.4, 136.6,
129.0, 128.2, 126.3, 57.1, 41.9, 30.0, 19.2, 18.0
[0851] C.sub.13H.sub.17NO.sub.3 (MW=235.29; Mass Spectroscopy
(MH.sup.+=236))
Step B. Synthesis of N-(phenylacetyl)valine 2-methylbutyl ester
[0852] Following General Procedure C' and using the
N-(phenylacetyl)valine prepared in Step A above and
2-methylbutan-1-ol (Aldrich), the title compound was prepared as a
diastereomeric mixture. The reaction was monitored by tlc on silica
gel and purification was by filtration as described in the general
procedure.
[0853] NMR data was as follows:
[0854] .sup.1H-nmr (CDCl.sub.3): .delta.=7.25-7.40 (m, 5H), 5.95
(d, 1H), 4.56 (m, 1H), 3.84-4.00 (m, 2H), 3.61 (s, 2H), 2.10 (m,
1H), 1.68 (m, 1H), 1.38 (m, 1H), 1.15 (m 1H), 0.82-0.94 (m, 9H),
0.76 (d, 3H).
[0855] .sup.13C-nmr (CDCl.sub.3): .delta.=171.84, 171.81, 170.7,
134.6, 129.31, 129.27, 128.9, 127.3, 69.8, 57.0, 43.7, 33.9, 31.3,
25.9, 25.8, 18.9, 17.4, 16.34, 16.27, 11.12, 11.07.
[0856] C.sub.18H.sub.27NO.sub.3 (MW=305.42, Mass Spectroscopy (MH
306)).
Example A36
Synthesis of N-(phenylacetyl)-L-methionine iso-butyl ester
[0857] L-Methionine (0.129 g, 0.869 mmols) (Aldrich) was taken-up
in dioxane (5.0 mL) and treated with a saturated solution of sodium
bicarbonate (5.0 mL) followed by phenylacetyl chloride (Aldrich)
(0.114 mL, 0.822 mmols). After stirring for 17 hours at room
temperature the mixture was diluted with ethyl acetate, the layers
separated and the aqueous layer acidified to pH 2 with 5N HCl. The
crude product was extracted into ethyl acetate, dried over sodium
sulfate, vacuum dried and used without further purification.
[0858] N-phenylacetyl-L-methionine (0.1285 g, 0.447 mmol) was
dissolved in 3.0 mL dioxane and iso-butyl alcohol (0.2 mL) and
treated with EDC (0.094 g, 0.492 mmol), and catalytic DMAP (0.015
g). After stirring for 17 hours at 23.degree. C., the mixture was
evaporated at reduced pressure to an oil, the residue was diluted
in EtOAc and washed with 0.1 N HCl and saturated sodium
bicarbonate. Chromatography on silica gel using 98:2
CHCl.sub.3/MeOH as eluant provided the pure product.
[0859] NMR data was as follows:
[0860] .sup.1H-nmr (CDCl.sub.3): .delta.=7.4-7.23 (m, 5H), 6.14
(bd, 1H), 4.70 (m, 1H), 3.89 (d, 2H), 3.62 (s, 2H), 2.43 (m, 2H),
2.12 (m, 1H), 1.93 (m, 2H), 0.94 (d, 6H).
[0861] C.sub.17H.sub.25NO.sub.3S (MW=323.17, Mass Spectroscopy
(M.sup.+ 323)
Example A37
Synthesis of N-(phenylacetyl)-L-leucine iso-butyl ester
[0862] L-Leucine (Aldrich) (0.114 g, 0.869 mmols) was taken-up in
dioxane (5.0 mL) and treated with a saturated solution of sodium
bicarbonate (5.0 mL) followed by phenylacetyl chloride (Aldrich)
(0.114 mL, 0.822 mmols). After stirring for 17 hours at room
temperature the mixture was diluted with ethyl acetate, the layers
separated and the aqueous layer acidified to pH 2 with 5N HCl. The
crude product was extracted into ethyl acetate, dried over sodium
sulfate, vacuum dried and used without further purification.
[0863] N-Phenylacetyl-L-leucine (0.0081 g, 0.038 mmol) was
dissolved in 2.0 mL CHCl.sub.3 (EtOH free) and iso-butyl alcohol
(0.055 mL) and treated with-P-EPC (100 mg, 0.87 milliequivalents).
The mixture was rotated for 4 days, filtered through a plug of
cotton and the filtrate evaporated at reduced pressure to an oil
which was sufficiently pure for testing.
[0864] NMR data was as follows:
[0865] .sup.1H-nmr (CDCl.sub.3): .delta.=7.22 (m, 5H), 5.57 (d,
1H), 4.35 (m, 1H), 3.35 (m, 3H), 1.35 (m, 4H), 0.68 (m, 9H).
[0866] C.sub.18H.sub.22NO.sub.3 (MW=305.40, Mass Spectroscopy
(M.sup.+ 305)).
Example A38
Synthesis of N-[(3-chlorophenyl)acetyl]alanine 3-methylbut-2-enyl
ester
[0867] Following General Procedure C' above and using
N-(3-chlorophenylacetyl alanine (from Example D' above) and
3-methylbut-2-en-1-ol (Aldrich), the title compound can be
prepared. The reaction was monitored by tlc on silica gel and
purification was by liquid chromatography using 30% EtOAc/hexane as
the eluant.
[0868] NMR data was as follows:
[0869] .sup.1H-nmr (CDCl.sub.3): .delta.=7.39-7.16 (m, 4H), 6.06
(bd, 1H), 5.38-5.29 (m, 1H), 4.63 (d, J=9Hz, 2H), 3.56 (s, 2H),
1.79 (s, 3H), 1.7 (s, 3H), 1.39 J=9 Hz, 3H).
Example A39
Synthesis of N-[(3-chlorophenyl)acetyl]alanine cyclopropylmethyl
ester
[0870] Following General Procedure C' above, and using
N-(3-chlorophenylacetyl alanine (from Example D' above) and
cyclopropylmethanol (Aldrich), the title compound can be prepared.
The reaction was monitored by tlc on silica gel and purification
was by liquid chromatography using 3:7 EtOAc:hexane as the
eluant.
[0871] NMR data was as follows:
[0872] .sup.1H-nmr (CDCl.sub.3): .delta.=7.2-7.1 (m, 4H), 6.09 (bs,
1H), 4.6 (dq, J=9 Hz, 1H), 3.96 (dd, J=9 Hz, 2H), 3.59 (s, 2H), 1.2
(d, J=9 Hz, 3H), 1.2-1.0 (m, 1H), 0.603-0.503 (m, 2H), 0.300-0.203
(m, 2H).
Example A40
Synthesis of N-[(3-chlorophenyl)acetyl]alanine 2-thienylmethyl
ester
[0873] Following General Procedure C' above, and using
N-(3chlorophenylacetyl alanine (from Example D' above) and
2-thiophenemethanol (Aldrich) the title compound can be prepared.
The reaction was monitored by tlc on silica gel and purification
was by liquid chromatography using 3:7 EtOAc:hexane as the
eluant.
[0874] NMR data was as follows:
[0875] .sup.1H-nmr (CDCl.sub.3): .delta.=7.37-6.97 (m, 7H), 5.97
(q, J=14 Hz, 2H), 4.6 (dq, J=9 Hz, 1H), 3.76 (s, 2H), 1.38 (d, J=9
Hz, 3H).
Example A41
Synthesis of N-[(3-chlorophenyl)acetyl]alanine
(1-methylcyclopropyl)methyl ester
[0876] Following General Procedure C' above, and using
N-(3-chlorophenylacetyl alanine (from Example D' above) and
(1-methylcyclopropyl)methanol (Aldrich) the title compound can be
prepared. The reaction was monitored by tlc on silica gel and
purification was by liquid chromatography using 3:7 EtOAc:hexane as
the eluant.
[0877] NMR data was as follows:
[0878] .sup.1H-nmr (CDCl.sub.3): .delta.=8.6. (bd, J=9 Hz, 1H),
3.86 (q, J=14 Hz, 2H), 3.4 (s, 2H), 2.29 (q, J=9 Hz, 1H), 1.3 (d,
J=9 Hz, 3H), 1.03 (s, 3H), 0.5-0.4 (m, 2H), 0.4-0.28 (m, 2H).
Example A42
Synthesis of N-[(3-chlorophenyl)acetyl]alanine 3-thienylmethyl
ester
[0879] Following General Procedure C' above, and using
N-(3-chlorophenylacetyl alanine (from Example D' above) and
3-thiophenemethanol (Aldrich) the title compound can be prepared.
The reaction was monitored by tlc on silica gel and purification
was by liquid chromatography using 3:7 EtOAc:hexane as the
eluant.
[0880] NMR data was as follows:
[0881] .sup.1H-nmr (CDCl.sub.3): .delta.=8.03 (bd, J=9 Hz, 1H),
7.56-7.5 (m, 1H), 7.47 (bs, 1H), 7.4-7.17 (m, 4H), 7.06 (d, J=9 Hz,
1H), 5.1 (5, 2H), 4.3 (dq, 1H), 1.3 (d, J=9 Hz, 3H).
Example A43
Synthesis of N-[(3-chlorophenyl)acetyl]alanine 2-methylcyclopentyl
ester
[0882] Following General Procedure C' above, and using
N-(3-chlorophenylacetyl alanine (from Example D' above) and
2-methylcyclopentanol (Aldrich) the title compound can be prepared.
The reaction was monitored by tlc on silica gel and purification
was by liquid chromatography using 3:7 EtOAc:hexane as the
eluant.
[0883] NMR data was as follows:
[0884] .sup.1H-nmr (CDCl.sub.3): .delta.=7.39-7.16 (m, 4H), 6.3
(bd, 1H), 4.79-4.7 (m, 1H), 4.6-4.25 (m, J=9 Hz, 1H), 3.577 (s,
2H), 2.09-1.8 (m, 2H), 1.74-1.6 (m, 2H), 1.39 (dd, J=9 Hz, 3H), 1.2
(dt, J=9 Hz, 1H), 0.979 (dd, J=9 Hz, 2H)
[0885] C.sub.17H.sub.22NO.sub.3Cl (MW=323.82, Mass Spectroscopy
(MH.sup.+ 323).
Example A44
Synthesis of N-[(3-chlorophenyl)acetyl]alanine 2-methylprop-2-enyl
ester
[0886] Following General Procedure C' above, and using
N-(3-chlorophenylacetyl alanine (from Example D' above) and
2-methylprop-2-en-1-ol (Aldrich) the title compound can be
prepared. The reaction was monitored by tlc on silica gel and
purification was by liquid chromatography using 3:7 EtOAc:hexane as
the eluant.
[0887] NMR data was as follows:
[0888] .sup.1H-nmr (CDCl.sub.3): .delta.=7.39-7.16 (m, 4H), 6.03
(bs, 1H), 4.77 (s, 2H), 4.7-4.29 (m, 3H), 2.59 (s, 2H), 1.73 (s,
3H), 1.43 (d, J=9 Hz, 3H)
[0889] C.sub.15H.sub.18NO.sub.3Cl (MW=295.76, Mass Spectroscopy
(MH.sup.+ 295)).
Example A45
Synthesis of N-[(3-chlorophenyl)acetyl]alanine cyclohex-2-enyl
ester
[0890] Following General Procedure C' above, and using
N-(3-chlorophenylacetyl alanine (from Example D' above) and
cyclohex-2-en-1-ol (Aldrich) the title compound can be prepared.
The reaction was monitored by tlc on silica gel and purification
was by liquid chromatography using 3:7 EtOAc:hexane as the
eluant.
[0891] NMR data was as follows:
[0892] .sup.1H-nmr (CDCl.sub.3): .delta.=8.6 (bd, J=9 Hz, 1H),
7.4-7.2 (m, 4H), 6.0-5.8 (m, 1H), 5.7-5.5 (m, 1H), 5.1 (bs, 1H),
4.13-4.29 (m, 1H), 3.5 (s, 2H), 2.1-1.9 (m, 2H), 1.8-1.69 (m, 1H),
1.69-1.49 (m, 4H), 1.3 (dd, J=9 Hz, 3H)
[0893] C.sub.17H.sub.20NO.sub.3Cl (MW=321.8, Mass Spectroscopy
(MH.sup.+ 321.2)).
Example A46
Synthesis of N-[(2-phenylbenzoxazol-5-yl)acetyl]alanine iso-butyl
ester
[0894] Following General Procedure I' above, and using
5-(2-phenylbenzoxazol)-yl-acetic acid (CAS# 62143-69-5) and alanine
iso-butyl ester (prepared following General Procedure J' above),
the tide compound was prepared.
[0895] NMR data was as follows:
[0896] .sup.1H-nmr (CDCl.sub.3): .delta.=8.24 (m, 3H), 7.68 (m,
1H), 7.51 (m, 5H), 6.04 (m, 1H), 4.58 (m, 1H), 3.85 (m, 2H), 3.68
(s, 2H), 1.9 (m, 1H), 1.35 (d, 3H), 0.87 (d, 6H).
[0897] C.sub.22H.sub.24N.sub.2O.sub.4 (MW=380, Mass Spectroscopy
(MH.sup.+ 381)).
Example 47
Synthesis of N-[(3-methylthiophenyl)acetyl]alanine iso-butyl
ester
[0898] Following General Procedure I' above, and using
3-methylthiophenylacetic acid (CAS# 18698-73-2) and amine iso-butyl
ester (prepared following General Procedure J' above), the title
compound was prepared. The reaction was monitored by tlc on silica
gel and purification was by filtration as described in the general
procedure.
[0899] NMR data was as follows:
[0900] .sup.1H-nmr (CDCl.sub.3): .delta.=7.14 (m, 2H), 7.01 (m,
1H), 4.56 (m, 1H), 3.88 (m, 2H), 3.54 (s, 2H), 2.46 (s, 3H), 1.89
(m, 1H), 1.35 (d, 3H) 0.85 (d, 6H).
[0901] C.sub.16H.sub.23NO.sub.3S (MW=309, Mass Spectroscopy
(MH.sup.+ 310)).
Example A48
Synthesis of N-4-[(2-furyl)acetyl]alanine iso-butyl ester
[0902] Following General Procedure I' above, and using
2-furylacetic acid (CAS# 2745-26-8) and alanine iso-butyl ester
(prepared following General Procedure J' above), the tide compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[0903] NMR data was as follows:
[0904] .sup.1H-nmr (CDCl.sub.3): .delta.=7.36 (m, 1H), 6.34 (m,
1H), 6.21 (m, 1H), 4.56 (m, 1H), 3.91 (m, 2H), 3.61 (s, 2H), 1.92
(m, 1H), 1.38 (d, 3H) 0.89 (d, 6H).
[0905] C.sub.13H.sub.19NO.sub.4 (MW=253, Mass Spectroscopy
(MH.sup.+ 254)).
Example A49
Synthesis of N-[(benzofuran-2-yl)acetyl]alanine iso-butyl ester
[0906] Following General Procedure I' above, and using
benzofuran-2-ylacetic acid (Maybridge) and alanine iso-butyl ester
(prepared following General Procedure J' above), the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[0907] NMR data was as follows:
[0908] .sup.1H-nmr (CDCl.sub.3): b=7.51 (m, 1H), 7.44 (m, 1H), 7.25
(m, 2H), 6.67 (s, 1H), 4.60 (m, 1H), 3.87 (m, 2H), 3.77 (s, 2H),
1.88 (m, 1H), 1.38 (d, 3H), 0.87 (d, 6H).
[0909] C.sub.17H.sub.21NO.sub.4 (MW=303, Mass Spectroscopy
(MH.sup.+ 304)).
Example A50
Synthesis of N-[(benzothiophen-3-yl)acetyl]alanine iso-butyl
ester
[0910] Following General Procedure I' above, and using
thianaphthen-3-ylacetic acid (Lancaster) and alanine iso-butyl
ester (prepared following General Procedure J' above), the title
compound was prepared. The reaction was monitored by tlc on silica
gel and purification was by filtration as described in the general
procedure.
[0911] NMR data was as follows:
[0912] .sup.1H-nmr (CDCl.sub.3): .delta.=7.89 (m, 1H), 7.76 (m,
1H), 7.38 (m, 3H), 6.07 (m, 1H), 4.57 (m, 1H), 3.92 (m, 2H), 3.82
(s, 4H), 1.84 (m, 1H), 1.32 (d, 3H) 0.85 (d, 6H).
[0913] C.sub.17H.sub.21NO.sub.3S (MW=319, Mass Spectroscopy
(MH.sup.+ 320)).
Example A51
Synthesis of N-[(2-chloro-5-thienyl)acetyl]alanine iso-butyl
ester
[0914] Following General Procedure I' above, and using
5-chloro-2-thienyl)acetic acid (CAS# 13669-19-7) and alanine
iso-butyl ester (prepared following General Procedure J' above),
the title compound was prepared. The reaction was monitored by tlc
on silica gel and purification was by filtration as described in
the general procedure.
[0915] NMR data was as follows:
[0916] .sup.1H-nmr (CDCl.sub.3): .delta.=6.77 (m, 1H), 6.68 (d,
1H), 6.31 (bm, 1H), 4.59 (m, 1H), 3.91 (m, 2H), 3.38 (s, 2H), 1.90
(m, 1H), 1.39 (d, 3H) 0.89 (d, 61).
[0917] C.sub.13H.sub.18NO.sub.3SCl (MW=303, Mass Spectroscopy
(MH.sup.+ 303)).
Example A52
Synthesis of N-[(3-methylisoxazol-5-yl)acetyl]alanine iso-butyl
ester
[0918] Following General Procedure I' above, and using
(3-methyl-isoxazol-5-yl)acetic acid (CAS# 19668-85-0) and alanine
isobutyl ester (prepared following General Procedure J' above), the
title compound was prepared. The reaction was monitored by tlc on
silica gel and purification was by filtration as described in the
general procedure.
[0919] NMR data was as follows:
[0920] .sup.1H-nmr (CDCl.sub.3): .delta.=6.07 (s, 2H), 4.56 (m,
1H), 3.92 (m, 2H), 3.68 (s, 2H), 2.29 (s, 3H), 1.94 (m, 1H), 1.89
(d, 3H) 0.91 (d, 6H).
[0921] C.sub.13H.sub.20N.sub.2O.sub.4 (MW=268, Mass Spectroscopy
(MH.sup.+ 269)).
Example A53
Synthesis of N-[(2-phenylthiothienyl)acetyl]alanine iso-butyl
ester
[0922] Following General Procedure I' above, and using
(2-phenyl-thiothienyl)acetic acid and alanine iso-butyl ester
(prepared following General Procedure J' above), the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[0923] NMR data was as follows:
[0924] .sup.1H-nmr (CDCl.sub.3): .delta.=7.21-7.11 (m, 6H), 6.92
(d, 1H), 4.56(m, 1H), 3.87 (m, 2H), 3.72 (s, 2H), 1.94 (m, 1H),
1.38 (d, 3H) 0.89 (d, 6H).
[0925] C.sub.19H.sub.23NO.sub.3S.sub.2 (MW 377, Mass Spectroscopy
(MH.sup.+ 378)).
Example A54
Synthesis of N-[(6-methoxybenzothiophen-2yl)acetyl]alanine isobutyl
ester
[0926] Following General Procedure I' above, and using
(6-methoxythianaphthen-2-yl)acetic acid and alanine iso-butyl ester
(prepared following General Procedure J' above), the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[0927] NMR data was as follows:
[0928] .sup.1H-nmr (CDCl.sub.3): .delta. 7.59 (d, 1H), 7.33 (d,
1H), 7.16 (s, 1H), 7.03 (dd, 1H), 4.56 (m, 1H), 3.87(s, 3H), 3.84
(m, 2H), 3.76 (s, 2H), 1.85 (m, 1H), 1.30 (d, 3H) 0.86 (d, 6H).
[0929] C.sub.18H.sub.23NO.sub.4S (MW=349, Mass Spectroscopy
(MH.sup.+ 350)).
Example A55
Synthesis of N-[(3-phenyl-1,2,4-thiadiazol-5-yl)acetyl]alanine
iso-butyl ester
[0930] Following General Procedure I' above, and using
(3-phenyl-1,2,4-thiadiazol-5-yl)acetic acid (CAS# 907710&5) and
alanine iso-butyl ester (prepared following General Procedure I'
above), the title compound was prepared. The reaction was monitored
by tlc on silica gel and purification was by filtration as
described in the general procedure.
[0931] NMR data was as follows:
[0932] .sup.1H-nmr (CDCl.sub.3): .delta.=7.47 (m, 5H), 4.66 (m,
1H), 4.16 (s, 2H), 3.91 (m, 2H), 1.93 (m, 1H), 1.48 (d, 3H) 0.93
(d, 6H).
[0933] C.sub.17H.sub.21N.sub.3O.sub.3S (MW=347, Mass Spectroscopy
(MH.sup.+ 348)).
Example A56
Synthesis of N-[2-phenyloxazol-4-yl)acetyl]alanine iso-butyl
ester
[0934] Following General Procedure I' above, and using
(2-phenyloxazol4-yl)acetic acid (CAS# 22086-89-1) and alanine
iso-butyl ester (prepared following General Procedure I' above),
the title compound was prepared. The reaction was monitored by tlc
on silica gel and purification was by filtration as described in
the general procedure.
[0935] NMR data was as follows:
Example A57
Synthesis of N-[(3-methylphenyl)acetyl]alanine iso-butyl ester
[0936] Following General Procedure I' above, and using
3-methylphenylacetic acid (Aldrich) and alanine iso-butyl ester
(prepared following General Procedure J' above), the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[0937] NMR data was as follows:.
[0938] .sup.1H-nmr (CDCl.sub.3): .delta.=7.21 (m, 1H), 7.07 (m,
3H), 4.54 (m, 1H), 3.83 (m, 2H), 3.52 (s, 2H), 2.35 (s, 3H), 1.87
(m, 1H), 1.32 (d, 3H), 0.88 (d, 6R).
[0939] C.sub.16H.sub.23NO.sub.3 (MW=277, Mass Spectroscopy
(MH.sup.+ 278)).
Example A58
Synthesis of N-[(2,5-difluorophenyl)acetyl]alanine iso-butyl
ester
[0940] Following General Procedure I' above, and using
2,5-difluorophenylacetic acid (Aldrich) and alanine iso-butyl ester
(prepared following General Procedure J' above), the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[0941] NMR data was as follows:
[0942] .sup.1H-nmr (CDCl.sub.3): .delta.=7.08-6.94 (m, 3H), 4.57
(m, 1H)-3.91 (m, 2H), 3.56 (s, 2H), 1.92 (m, 1H), 1.41 (d, 3H) 0.91
(d, 6H).
[0943] C.sub.15H.sub.19NO.sub.3F.sub.2 (MW=299, Mass Spectroscopy
(MH.sup.+ 300)).
Example A59
Synthesis of N-[(3,5-diflurophenyl)acetyl]alanine iso-butyl
ester
[0944] Following General Procedure I' above, and using
3,5-difluorophenylacetic acid (Aldrich) and alanine iso-butyl ester
(prepared following General Procedure J' above), the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[0945] NMR data was as follows:
[0946] .sup.1H-nmr (CDCl.sub.3): .delta.=6.81 (m, 2H), 6.74 (m,
1H), 6.06 (m, 1H), 4.57 (m, 1H), 3.92 (m, 2H), 3.51 (s, 2H), 1.94
(m, 1H), 1.36 (d, 3H) 0.87 (d, 6H).
[0947] C.sub.15H.sub.19NO.sub.3F.sub.2 (MW=299, Mass Spectroscopy
(MH.sup.+ 300)).
Example A60
Synthesis of N-[(3-thienyl)acetyl]alanine iso-butyl ester
[0948] Following General Procedure I' above, and using
3-thiopheneacetic acid (Aldrich) and alanine iso-butyl ester
(prepared following General Procedure J' above), the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[0949] NMR data was as follows:
[0950] .sup.1H-nmr (CDCl.sub.3): .delta.=7.33 (m, 1H), 7.14 (m,
1H), 7.01 (m, 1H), 6.09 (m, 1H), 4.58 (m, 1H), 3.88 (m, 2H), 3.60
(s, 2H), 1.91 (m, 1H), 1.37 (d, 3H) 0.92 (d, 6H).
[0951] Optical Rotation: [.alpha.].sub.23 -52 (c 1MeOH) @ 589
nm.
[0952] C.sub.13H.sub.19NO.sub.3S (MW=269, Mass Spectroscopy
(MH.sup.+ 269)).
Example A61
Synthesis of N-[(4methylphenyl)acetyl]-L-alanine iso-butyl
ester
[0953] Following General Procedure I' above, and using
4-methylphenylacetic acid (Aldrich) and L-alanine iso-butyl ester
(prepared following General Procedure J' above), the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[0954] NMR data was as follows:
[0955] .sup.1H-nmr (CDCl.sub.3): .delta.=7.11 (s, 4H), 5.93 (m,
1H), 4.58 (m, 1H), 3.88 (m, 2H), 3.54 (s, 2H), 2.33 (s, 3H), 1.89
(m, 1H), 1.32 (d, 3H), 0.89 (d, 6H).
[0956] C.sub.16H.sub.23NO.sub.3 (MW=277.35, Mass Spectroscopy
(MH.sup.+ 278)).
Example A62
Synthesis of N-(phenylacetyl)-L-alanine S-1-(methoxycarbonyl)
iso-butyl ester
[0957] Following General Procedure K' and using
(S)-(+)-2-hydroxy-2-methylbutyric acid (Aldrich) in place of the
amino acid, methyl (S)-(+)-2-hydroxy-2-methylbutyrate was
prepared.
[0958] Methyl (S)-(+)-2-hydroxy-2-methylbutyrate was then coupled
with carbobenzyloxy-L-alanine (Aldrich) using General Procedure E'
to provide carbobenzyloxy-L-alanine S-1-(methoxycarbonyl)iso-butyl
ester.
[0959] Carbobenzyloxy-L-alanine S-1-(methoxycarbonyl)iso-butyl
ester (1.0 g) was then dissolved in 20 mL of methanol and 6N HCl
(0.5 mL) and 10% palladium on carbon (0.1 g) were added. This
reaction mixture was hydrogenated at 40 psi of hydrogen on a Parr
apparatus for 5 hours at room temperature and then filtered through
a pad of Celite. The filtrate was concentrated at reduced pressure
to provide L-alanine S-1-(methoxycarbonyl) iso-butyl ester
hydrochloride (98% yield).
[0960] L-Alanine S-1-(methoxycarbonyl)iso-butyl ester hydrochloride
was then coupled to phenylacetic acid using General Procedure G' to
provide the title compound.
[0961] NMR data was as follows:
[0962] .sup.1H-nmr (CDCl.sub.3): .delta.=7.35-7.20 (m, 5}I, 6.22
(bd, 1H), 4.83 (d, 1H), 4.65 (p, 1H), 3.68 (s, 3H), 3.55 (s, 2H),
2.21 (m, 1H), 1.40 (d, 3H), 0.97 (d, 3H), 0.93 (d, 3H).
[0963] .sup.13C-nmr (CDCl.sub.3): .delta.=173.25, 171.18, 170.22,
135.11, 129.94, 129.50, 127.88, 52.67, 48.49, 43.98, 30.53, 19.21,
18.75, 17.58.
Example A63
Synthesis of N-[(3-nitrophenyl)acetyl]-L-alanine iso-butyl
ester
[0964] Following General Procedure H' above and using
3-nitrophenylacetic acid (Aldrich) and L-alanine iso-butyl ester
hydrochloride (from Example B' above), the title compound was
prepared. The reaction was monitored by tlc on silica gel and
purification was by recrystallization from butyl chloride.
[0965] NMR data was as follows:
[0966] .sup.1H-nmr (CDCl.sub.3): .delta.=8.17 (m, 2H), 7.68 (d,
1H), 7.52 (t, 1H), 6.18 (m, 1H), 4.48 (m, 1H), 3.94 (m, 2H), 3.67
(s, 2H), 1.93 (m, 1H), 1.42 (d, 3H), 0.91 (d, 3H);
[0967] Optical Rotation: [.alpha.].sub.23 -49 (c 5, MeOH).
Example A64
Synthesis of N-[(3,5-difluorophenyl)acetyl]alanine ethyl ester
[0968] Following General Procedure G' and using
3,5-difluorophenylacetic acid (Aldrich) and alanine ethyl ester
(Aldrich), the title compound was prepared as a solid with a
melting point of 93.degree.-95.degree. C. The reaction was
monitored by tlc on silica gel (Rf=0.8 in EtOAC) and purification
was by chromatography on silica gel using. EtOAc as the eluant
followed by recrystallization from 1-chlorobutane.
[0969] NMR data was as follows:
[0970] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.30 (d, 3H); 3.52 (s,
2H).
[0971] C.sub.13H.sub.25NO.sub.3F.sub.2 (MW=271.26, Mass
Spectroscopy (MH.sup.+ 271)).
Example A65
Synthesis of N-[(3-nitrophenyl)acetyl]methionine ethyl ester
[0972] Following General Procedure G' above and using
3-nitrophenylacetic acid (Aldrich) and methionine ethyl ester
hydrochloride (Aldrich), the title compound was prepared. The
reaction was monitored by tlc on silica gel and purification was by
recrystallization from butyl chloride.
[0973] NMR data was as follows:
[0974] .sup.1H-nmr (CDCl.sub.3): .delta.=8.18 (s, 1H), 8.15 (d, 1H)
7.66 (d, 1H), 7.48 (t, 1H), 6.30 (m, 1H), 4.67 (m, 1H), 4.21 (t,
2H), 3.67 (s, 2H), 2.47 (t, 2H), 2.12. (m, 2 H), 2.08 (s, 3H), 1.27
(t, 3H).
[0975] Optical Rotation: [.alpha.].sub.23 -30 (c 5, MeOH).
Example A66
Synthesis of N-[(3-chlorophenyl)acetyl]alanine iso-butyl ester
[0976] Following General Procedure G' above and using
3-chlorophenylacetic acid (Aldrich) and alanine iso-butyl ester
(prepared following General Procedure I' above), the title compound
was prepared. The reaction was monitored by tlc on silica gel.
[0977] NMR data was as follows:
[0978] .sup.1H-nmr (CDCl.sub.3): .delta.=7.29 (m, 3H), 7.18 (m,
1H), 6.0 (m, 1H), 4.56 (m, 1H), 3.89 (m, 2H), 3.53 (s, 2H), 1.91
(m, 1H), 1.39 (d, 3 H), 0.91 (d, 3H).
[0979] Optical Rotation: [.alpha.].sub.23 -45 (c 5, MeOH).
[0980] C.sub.15H.sub.20NO.sub.3Cl (MW=297.78, Mass Spectroscopy
(MH.sup.+ 297)).
Example A67
Synthesis of N-[(3-chlorophenyl)acetyl]alanine
2-(N,N-dimethylamino)ethyl ester
[0981] Following General Procedure C' above, and using
N-(3-chlorophenyl-acetyl)alanine (from Example D' above) and
2-(N,N-dimethyl amino)ethanol (Aldrich), the title compound can be
prepared. The reaction was monitored by tic on silica gel and
purification was by liquid chromatography using 0.1:2:0.79
NH.sub.4OH:EtOH:CHCl.sub.3 as the eluant.
[0982] NMR data was as follows:
[0983] .sup.1H-nmr (CDCl.sub.3): 7.37 (s, 1H), 7.33-7.2 (m, 3H),
4.675-4.6 (m, 1H), 4.5-4.37 (m, 1H), 4.25-4.13 (m, 1H), 3.6 (d, J=7
Hz, 2H), 2.86 (bs, 2H), 2.3 (s, 6H), 1.23 (d, J=9 Hz, 3H).
[0984] C.sub.15H.sub.21N.sub.2O.sub.3Cl (MW=313.799, Mass
Spectroscopy (M.sup.+ 313)).
Example A68
Synthesis of 2-[(3,5-dichlorophenyl)acetamido]hexanoic acid methyl
ester
[0985] Following General Procedure F' above, an using
3,5-dichlorophenylacetic acid (from Example C' above) and
L-norleucine methyl ester hydrochloride (Bachem), the title
compound was prepared as a solid having a melting point of
77.degree.-78.degree. C. The reaction was monitored by tlc on
silica gel (Rf=0.70 in 40% EtOAC/hexanes) and purification was by
flash chromatography on silica gel using 40% EtOAc/hexanes as the
eluant.
[0986] NMR data was as follows:
[0987] .sup.1H-nmr (CDCl): .delta.=7;20 (s), 7.18 (s), 6.6 (m),
4.55 (m), 3.7 (s), 3.5 (s), 3.4 (s), 2.0 (s), 1.8 (m), 1.6 (m), 1.2
(m), 0.8 (t).
[0988] .sup.13C-nmr (CDCl.sub.3): .delta.=173.54, 169.67, 138.43,
135.72, 128.33, 128.07, 78.04, 77.62, 77.19, 53.04, 52.90, 43.14,
32.57, 27.87, 22.81, 14.41.
Example A69
Synthesis of N-[(3,5-diclorophenyl)acetyl]-L-alanine iso-butyl
ester
[0989] Following General Procedure F' above, and using
3,5-dichlorophenylacetic acid (from Example C' above) and L-alanine
iso-butyl ester hydrochloride (from Example B' above), the
title-compound was prepared as a solid having a melting point of
115.degree.-116.degree. C. The reaction was monitored by tlc on
silica gel (Rf=0.40 in 3% methanol/dichloromethane) and
purification was by flash chromatography on silica gel using 3%
methanol/dichloromethane as the eluant.
[0990] NMR data was as follows:
[0991] .sup.1H-nmr (CDCl.sub.3): .delta.=7.27 (d, J=2 Hz, 1H), 7.19
(s, 2H), 6.22 (d, J=6 Hz, 1H), 4.59 (quint., J=7 Hz, 1H), 3.9 (q,
J=4 Hz, 2H), 3.5 (s, 2H), 1.9 (m, 1H), 1.4 (d, J=7 Hz, 3H), 0.91
(d, J=7 Hz, 6H).
[0992] .sup.13C-nmr (CDCl.sub.3): .delta.=173.45, 169.37, 138.31,
135.75, 128.39, 128.11, 78.04, 77.61, 77.19, 72.19, 54.03, 48.97,
43.12, 28.24, 19.52, 19.49, 19.09.
[0993] C.sub.15H.sub.19NO.sub.3Cl.sub.2 (MW=331.9, Mass
Spectroscopy (MH.sup.+ 332)).
Example A70
Synthesis of N-(cyclohexylacetyl)-L-alanine iso-butyl ester
[0994] Following General Procedure B' above, and using
cyclohexylacetic acid (Aldrich) and L-alanine iso-butyl ester
hydrochloride (from Example B' above), the title compound was
prepared as a solid having a melting point of 92.degree.
C.-93.degree. C. The reaction was monitored by tlc on silica gel
(Rf=0.39 in 1:3 EtOAc:hexane) and purification was by extraction
with EtO followed by washes with aqueous K.sub.2CO.sub.3 and
aqueous HCl.
[0995] NMR data was as follows:
[0996] .sup.1H-nmr (CDCl.sub.3): .delta.=0.93 (d, J=6.7 Hz, 6H),
0.85-1.01 (m, 2H), 1.05-1.35 (m, 3H), 1.40 (d, J=7.1 Hz, 3H),
1.60-1.85 (m, 6H), 1.95 (m, 1H), 2.06 (d, J=7.0 Hz, 2H), 3.92 (m,
2H), 4.61 (m, 1H), 6.08 (bd, 1H).
[0997] .sup.13C-nmr (CDCl.sub.3): .delta.=18.7, 18.9, 26.0, 26.1,
27.6, 33.0, 35.3, 44.6, 47.9, 71.4, 171.8, 173.3.
[0998] C.sub.15H.sub.27NO.sub.3 (MW=269.39, Mass Spectroscopy
(MH.sup.+ 270)).
Example A71
Synthesis of N-(cyclopentylacetyl)-L-alanine iso-butyl ester
[0999] Following General Procedure B' above, and using
cyclopentylacetic acid (Aldrich) and L-alanine iso-butyl ester
hydrochloride (from Example B' above), the title compound was
prepared as a solid having a melting point of 62.degree.
C.-64.degree. C. The reaction was monitored by tlc on silica gel
(Rf=0.37 in 1:3 EtOAc:hexane) and purification was by extraction
with EtO followed by washes with aqueous K.sub.2CO.sub.3 and
aqueous HCl.
[1000] NMR data was as follows:
[1001] .sup.1H-nmr (CDCl.sub.3): .delta.=0.87 (d, J=6.8 Hz, 6H),
1.01-1.17 (m, 2H), 1.34 (d, J=7.2,Hz, 3H), 1.40-1.62 (m, 4H),
1.70-1.83 (m, 2H), 1.89 (m, 1H), 2.15 (m, 3H), 3.86 (m, 2H), 4.55
(m, 1H), 6.30 (d, J=7.1 Hz, 1H).
[1002] .sup.13C-nmr (CDCl.sub.3): .delta.=18.4, 18.78, 18.80, 24.8
(very high), 27.5, 32.27, 32.32, 36.9, 42.5, 47.7, 71.2, 172.2,
173.2.
[1003] Elemental Analysis-Calc (%): C, 65.85; H, 9.87; N, 5.49;
Found (%) C, 66.01; H, 10.08; N, 5.49.
[1004] C.sub.14H.sub.25NO.sub.3 (MW=255.36, Mass Spectroscopy
(MH.sup.+ 256)).
Example A72
Synthesis of N-[(cyclohex-1-enyl)acetyl]-L-alanine iso-butyl
ester
[1005] Following General Procedure B' above, and using
cyclohex-1-enyl acetic acid (Alfa) and L-alanine iso-butyl ester
hydrochloride (from Example B' above), the title compound was
prepared as a solid having a melting point of 49.degree.
C.-51.degree. C. The reaction was monitored by tlc on silica gel
(Rf=0.40 in 1:3 EtOAc:hexane) and purification was by extraction
with Et.sub.2O followed by washes with aqueous K.sub.2CO.sub.3 and
aqueous HCl.
[1006] NMR data was as follows:
[1007] .sup.1H-nmr (CDCl.sub.3): .delta.=0.91 (d, J=4.5 Hz, 3H),
0.93 (d, J=6.7 Hz, 3H), 1.40 (d, J=7.2 Hz, 3H), 1.52-1.70 (m, 4H),
1.97 (m, 3H), 2.06 (bs, 2H), 2.89 (s, 2H), 3.92 (m, 2H), 4.59 (m,
1H), 5.65 (s, 1H), 6.33 (d, J=6.6 Hz, 1H).
[1008] .sup.13C-nmr (CDCl.sub.3): .delta.=18.7, 18.91, 18.93, 21.9,
22.7, 25.3, 27.6, 28.3, 46.1, 47.9, 71.4, 127.1, 132.5, 170.6,
173.1.
[1009] Elemental Analysis-Calc (%): C, 67.38; H, 9.42; N, 5.24;
Found (%): C, 67.34; H, 9.54; N, 5.16.
[1010] C.sub.15H.sub.25NO.sub.3 (MW=267.37, Mass Spectroscopy
(MH.sup.+ 268)).
Example A73
Synthesis of N-[(3-chlorophenyl)acetyl]alanine 3-methylbut-2-enyl
thioester
[1011] Following General Procedure C' above, and using
N-((3-chlorophenyl)acetyl]alanine and 3-methyl-2-butene thioester
(TCI), the title compound can be prepared. The reaction was
monitored by tlc on silica gel and purification was by liquid
chromatography using 3:7 EtOAc:Hexane as the eluant.
[1012] NMR data was as follows:
[1013] .sup.1H-nmr (DMSO-d.sub.6): .delta.=5.2-5.075 (m, 1H), 4.37
(dq, J=9 Hz, 1H), 3.56 (s), 3.43 (d, J=12 Hz, 2H), 1.266. (d, J=12
Hz, 6H) 1.3 (d, J=9 Hz, 3H).
[1014] C.sub.16H.sub.20NO.sub.2ClS (MW=325.86, Mass Spectroscopy
(M+325)).
Example A74
Synthesis of N-[(2-phenyl)-2-fluoroacetyl]alanine ethyl ester
[1015] Following General Procedure F' above, and using
.alpha.-fluorophenyl acetic acid (Aldrich) and alanine ethyl ester
(Aldrich), the title compound was prepared. The reaction was
monitored by tlc on silica gel (=0.75 in 1:1 EtOAc:hexane) and
purification was by chromatography on silica gel using 1:2 ethyl
acetate/hexanes as the eluent.
[1016] NMR data was as follows:
[1017] .sup.1H-nmr (DMSO-d,): .delta.=1.14. (q, 3H), 1.34 (d, 3H),
4.07 (m, 2H), 4.33 (m, 1H), 5.84 (d, 1H),;6.01 (d, 1H), 7.40-7.55
(m, 5H), 8.87 (m, 1H).
[1018] C.sub.13H.sub.16NO.sub.3F (MW=253.27, Mass Spectroscopy
(MH.sup.+ 253)).
Example A75
Synthesis of N-(3,5-difluorophenylacetyl)-L-phenylglycine methyl
ester
[1019] Following General Procedure F above, and using
3,5-difluorophenylacetic acid (Aldrich) and L-phenylglycine methyl
ester hydrochloride (Bachem), the title compound was prepared.
[1020] NMR data was as follows:
[1021] .sup.1H-nmr (CDCl.sub.3): .delta.=7.4-7.3 (m, 5H), 6.9-6.7
(m, 3H), 6.55 (d 1H, 7.1 Hz), 5.56 (d 1H 7 Hz), 3.72 (s 3H), 3.57
(s 2H)
[1022] .sup.13C-nmr (CDCl.sub.3): .delta.=197.6, 177.6, 171.8,
169.3, 136.7, 129.6, 129.3, 127.8, 113.0, 112.9, 112.7, 111.4,
103.8, 103.5, 65.1, 57.2, 53.5, 45.1, 43.3, 43.3
[1023] C.sub.17H.sub.15NO.sub.3F, (MW=319.31, Mass Spectroscopy (MH
+320)).
Example 76
Synthesis of N-(3,5-difluorophenylacetyl)-L-phenylglycine iso-butyl
ester
[1024] The 3,5-difluorophenylacetic acid (Aldrich) was EDC coupled
to L-phenylglycine methyl ester hydrochloride (Bachem) via General
Procedure F above.
[1025] The resulting compound was placed in a large excess of the
desired alcohol. A catalytic amount of dry NaH was added, and the
reaction was followed by tlc until the presence of starting
material was no longer detected. The reaction was quenched with a
few milliliters of 1N HCl, and after a few minutes of stirring
saturated aqueous NAHCO, was added. The volume of the reaction
mixture was reduced on a rotary evaporator until the excess alcohol
was removed and then the remaining residue was taken up in ethyl
acetate and additional water was added. The organic phase was
washed with saturated aqueous NaCl and dried over MgSO.sub.4. The
solution was stripped free of solvent on a rotary evaporator, and
the crude product residue was then further purified by
chromatography.
[1026] NMR data was as follows:
[1027] .sup.1H-nmr (CDCl.sub.3): .delta.=7.35-7.3 (m 5H), 6.8-6.7
(m 3H) 6.60 (d 1H, 7 Hz), 5.55 (d 1H 7.1 Hz), 3.9 (m 2H), 3.60 (s
2H), 1.85 (m 1H 7 Hz), 0.8 (q 6H 7 Hz)
[1028] .sup.13C-nmr (CDCl.sub.3): .delta.=171.3, 169.3, 165.4,
138.5, 137.0, 129.5, 129.2, 127.6, 113.1, 113.0, 112.8, 112.7,
103.8, 103.5, 103.2, 75.5, 57.2, 43.4, 43.3, 28.2, 19.3
[1029] C.sub.20H.sub.21NO.sub.3F.sub.2 (MW=361.39, Mass
Spectroscopy (MH +362)).
Example A77
Synthesis of N-(cyclopentylacetyl)-L-phenylglycine methyl ester
[1030] Following General Procedure D' above, and using
cyclopentylacetic acid (Aldrich) with L-phenylglycine methyl ester
hydrochloride (Bachem) the title compound was prepared.
[1031] NMR data was as follows:
[1032] .sup.1H-nmr (CDCl.sub.3): .delta.=7.35 (s, 5H), 6.44 (bd,
1H), 5.6 (d, 1H), 3.72 (s, 3H), 2.24 (bs, 3H), 1.9-1.4 (m, 6H),
1.2-1.05 (m, 2H)
[1033] .sup.13C-nmr (CDCl.sub.3): .delta.=172.3, 171.7, 136.7,
129.0, 128.6, 127.3, 56.2, 52.7, 42.5, 36.9, 32.40, 32.38, 24.8
Example A78
Synthesis of N-(cyclopentylacetyl)-L-alanine methyl ester
[1034] Following General Procedure D' above, and using
cyclopentylacetic acid (Aldrich) with L-alanine methyl ester
hydrochloride (Sigma) the title compound was prepared.
[1035] NMR data was as follows:
[1036] .sup.1H-nmr (CDCl.sub.3): .delta.=6.38 (d, 1H), 4.50 (m,
1H), 3.65 (s, 3H), 2.13 (bs, 3H), 1.80-1.00 (m (includes d at 1.30,
3H), 11H)
[1037] .sup.13C-nmr (CDCl.sub.3): .delta.=173.7, 172.5, 52.1, 47.6,
42.3, 36.8, 32.15, 32.14, 18.0
[1038] C.sub.11H.sub.19NO.sub.3 (MW=213.28, Mass Spectroscopy
(MH.sup.+ 214)).
Example A79
Synthesis of N-(cyclopropylacetyl)-L-phenylglycine methyl ester
[1039] Following General Procedure D' above, and using
cyclopropylacetic acid (Aldrich) with L-phenylglycine methyl ester
hydrochloride (Bachem), the title compound was prepared.
[1040] NMR data was as follows:
[1041] .sup.1H-nmr (CDCl.sub.3): .delta.=7.35 (m, 5H) 6.97 (bd,
J=7.2 Hz, 1H) 5.59 (d, J=7.8 Hz, 1H), 3.71 (s, 3H), 2.17 (m, 2H),
1.05-0.95 (m, 1H), 0.62 (m, 2H), 0.02 (m,.2H)
[1042] .sup.13C-nmr (CDCl.sub.3): .delta.=171.9, 174.6, 136.6,
129.0, 128.5, 127.2, 56.1, 52.7, 41.0, 6.9, 4.37, 4.33
Example A80
Synthesis of N-(cyclopropylacetyl)-L-alanine methyl ester
[1043] Following General Procedure D' above, and using
cyclopropylacetic acid (Aldrich) with L-alanine methyl ester
hydrochloride (Sigma), the title compound was prepared.
[1044] NMR data was as follows:
[1045] .sup.1H-nmr (CDCl.sub.3): .delta.=6.60 (d, 1H), 4.55 (m,
1H), 3.69 (s, 3H), 2.10 (m, 2H), 1.34 (d, 3H), 0.95 (m, 1H), 0.58
(m, 2H) 0.15 (m, 2H)
[1046] .sup.13C-nmr (CDCl.sub.3): .delta.=173.7, 172.3, 52.3, 47.7,
41.0, 18.2, 6.7, 4.27, 4.22
Example A81
Synthesis of N-[(3-nitrophenyl)acetyl]-L-methionine iso-butyl
ester
[1047] Following General Procedure H' above, and using
nitrophenylacetic acid (Aldrich) and L-methionine (Aldrich), the
title compound was prepared as a tan oil. The reaction was
monitored by tlc on silica gel.
[1048] NMR data was as follows:
[1049] .sup.1H-nmr (CDCl.sub.3): .delta.=8.16 (m,2H) 7.67 (d, 1H)
7.32 (t, 1H), 6.31 (bd, 1H), 4.69 (m, 1H), 3.90 (d, 2H), 3.68 (s,
2H), 2.47 (t, 2H), 2.15 (m, 1H), 2.02 (s, 3H), 1.90 (m, 2H), 0.91
(d, 6H).
[1050] C.sub.17H.sub.24N.sub.2O.sub.5S (MW 368.4, Mass Spectroscopy
(MH.sup.+ 368)).
[1051] The following General Procedures A''-B'' and Examples B1-B2
illustrate the synthesis of N-(aryl/heteroarylacetyl)amino acid
starting materials useful in this invention. Other
N-(aryl/heteroarylacetyl)amino acids can be prepared using these
procedures from commerically available or known starting
materials.
General Procedure A''
Acid Chloride Preparation
[1052] 3,5-Difluorophenylacetic acid (30 g, 0.174 mol) (Aldrich)
was dissolved in dichloromethane and this solution was cooled to
0.degree. C. DMF (0.5 mL, catalytic) was added followed by the
dropwise addition of oxalyl chloride (18 mL, 0.20 mol) over a 5
minute period. The reaction was stirred for 3 h and then
rotoevaporated at reduced pressure to a residue which was placed on
a high vacuum pump for 1 h to afford 3,5-difluorophenylacetyl
chloride as a thin yellow oil. Other acid chlorides can be prepared
in a similar manner.
General Procedure B''
Schotten-Bauman Procedure
[1053] 3,5-Difluorophenylacetyl chloride (from General Procedure
A'') was added dropwise to a 0.degree. C. solution of L-alanine
(Aldrich) (16.7 g, 0.187 mol) in 2 N sodium hydroxide (215 mL, 0.43
mol). The reaction was stirred for 1 h at 0.degree. C. and then
overnight at room temperature. The reaction was diluted with water
(100 mL), then extracted with ethyl acetate (3.times.150 mL). The
organic layer was then washed with brine (200 mL), dried over
MgSO.sub.4, and rotoevaporated at reduced pressure to a residue.
Recrystallization of the residue from ethyl. acetate/hexanes
afforded the desired product (34.5 g, 82% yield). Other acid
chlorides may be used in this procedure to provide for
intermediates useful in this invention.
Example B1
Synthesis of N-(Phenylacetyl)-L-alanine
[1054] Following General Procedure B" above, title compound was
prepared from phenylacetyl chloride (Aldrich) and L-alanine
(Aldrich) as a solid having a melting point of 102-104.degree.
C.
[1055] NMR data was as follows:
[1056] .sup.1H-nmr (CDCl.sub.3): .delta.=9.14 (br s, 1H), 7.21-7.40
(m, 5H), 6.20 (d, J=7.0 Hz, 1H), 4.55 (m, 1H), 3.61 (s, 2H), 1.37
(d, J=7.1 Hz, 3H).
[1057] .sup.13C-nmr (CDCl.sub.3): d=176.0, 171.8, 134.0, 129.4,
127.5, 48.3, 43.2, 17.9.
Example B2
Synthesis of N-(3,5-Difluorophenylacetyl)-L-alanine
[1058] Following General Procedure B'' above, the title compound
was prepared from 3,5-difluorophenylacetyl chloride (from General
Procedure A'' above) and L-alanine (Aldrich).
[1059] NMR data was as follows:
[1060] .sup.1H-nmr (CD.sub.3OD): .delta.=8.32 (br s, 0.3H), 6.71
(m, 2H), 6.60 (m, 1H), 4.74 (br s, 1.7H), 4.16 (m, 1H), 3.36 (s,
2H), 1.19 (d, J=7.3 Hz, 3H).
[1061] .sup.13C-nmr (CD.sub.3OD): .delta.=175.9, 172.4, 164.4 (dd,
J=13.0, 245.3 Hz), 141.1, 113.1 (dd, J=7.8, 17.1 Hz), 102.9 (t,
J=25.7 Hz), 49.5, 42.7, 17.5.
[1062] The following General Procedures A'''-C''' and Examples
C1-C8 illustrate the synthesis of dipeptide ester starting
materials useful in this invention. Other dipeptide esters can be
prepared using these procedures from commerically available or
known starting materials.
General Procedure A'''
EDC Coupling Procedure
[1063] A round bottom flask containing a magnetic stir bar under an
atmosphere of nitrogen at 0.degree. C. or room temperature was
charged with THF, carboxylic acid (1.0 eq), an amine or amine
hydrochloride (1.1 eq.), 1-hydroxybenzotriazole hydrate (1.15-1.2
eq.), N,N-diisopropylethylamine (2.2-2.9 eq.), followed by
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC)
(1.15-1.2 eq.). The cooling bath was removed and the mixture
allowed to warm to room temperature with stirring for 10-20 hours.
The mixture was diluted with EtOAc and washed with 0.5 N aqueous
HCl (2.times.), dilute aqueous NaHCO.sub.3 (1.times.), brine
(1.times.) and dried over either Na.sub.2SO.sub.4 or MgSO.sub.4.
The drying agent was removed by filtration and the filtrate
concentrated in vacuo. The residue was either used without further
purification or purified using standard procedures, such as flash
chromatography on silica gel and/or recrystallization.
General Procedure B'''
Removal of the N-tert-Boc Protecting Group
[1064] The N-tert-Boc-amine was dissolved in a suitable dry solvent
(such as 1,4-dioxane or ethyl acetate) and the solution was cooled
in an ice bath. Gaseous HCl was introduced into the solution until
the mixture was saturated with HCl. The mixture was then stirred
until the reaction was complete. The resulting mixture was
concentrated under reduced pressure to yield the amine
hydrochloride. The amine hydrochloride was used without
purification or was triturated using, for example, diethyl ether
and the resulting solid was collected by filtration.
General Procedure C'''
EEDO Coupling Procedure
[1065] A round bottom flask containing a magnetic stir bar under as
atmosphere of nitrogen at room temperature was charged with THF, a
carboxylic acid (1 eq.), an amine hydrochloride (1.1 eq.), and
2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) (1.1 eq). The
reaction mixture was allowed to stir for 15 minutes and then
4-methylmorpholine (1.1 eq) was added and stirring was continued at
room temperature for 15-20 hours. The reaction mixture was
concentrated in vacuo and the resulting residue was partitioned
between ethyl acetate and water. The organic phase was separated
and washed with saturated aqueous NH.sub.4Cl (2.times.), saturated
aqueous NaHCO.sub.3 (2.times.), followed by brine (1.times.). The
organic phase was then dried over Na.sub.2SO.sub.4 and the drying
agent was removed by filtration and the filtrate concentrated in
vacuo. The residue was either used without further purification or
purified using standard procedures, such as flash chromatography on
silica gel and/or recrystallization.
Example C1
Synthesis of N-(L-Methionine)-L-phenylglycine Methl Ester
Hydrochloride
[1066] Following General Procedure A''' and using
N-(tert-butoxycarbonyl)-L-methionine (Sigma) and L-phenylglycine
methyl ester hydrochloride (Bachem), the Boc-protected dipeptide
was prepared as a crude solid or foam. The resulting crude
dipeptide was deprotected using General Procedure B''' to afford
the title compound as a crude solid or foam.
Example C2
Synthesis of N-(2-Aminobutanoyl)-L-phenylglycine-Methl Ester
Hydrochloride
[1067] Following General Procedure A''' and using
N-(tert-butoxycarbonyl)-2-aminobutyric acid (Sigma) and
L-phenylglycine methyl ester hydrochloride (Bachem), the
Boc-protected dipeptide was prepared as a crude solid or foam. The
resulting crude dipeptide was deprotected using General Procedure
B' to afford the title compound as a crude solid or foam.
Example C3
Synthesis of N-(Leucine)-L-phenylglycine Methl Ester
Hydrochloride
[1068] Following General Procedure A' and using
N-(tert-butoxycarbonyl)-L-leucine (Sigma) and L-phenylglycine
methyl ester hydrochloride (Bachem), the Boc-protected dipeptide
was prepared as a crude solid or foam. The resulting crude
dipeptide was deprotected using General Procedure B''' to afford
the title compound as a crude solid or foam.
Example C4
Synthesis of N-(L-Phenylalanine)-L-phenylglycine Methl Ester
Hydrochloride
[1069] Following General Procedure A' and using
N-(tert-butoxycarbonyl)-L-phenylalanine (Sigma) and L-phenylglycine
methyl ester hydrochloride (Bachem), the Boc-protected dipeptide
was prepared as a crude solid or foam. The resulting crude
dipeptide was deprotected using General Procedure B' to afford the
title compound as a crude solid or foam.
Example C5
Synthesis of N-(Glycine)-L-phenylglycine Methl Ester
Hydrochloride
[1070] Following General Procedure A''' and using
N-(tert-butoxycarbonyl)glycine (Sigma) and L-phenylglycine methyl
ester hydrochloride (Bachem), the Boc-protected dipeptide was
prepared as a crude solid or foam. The resulting crude dipeptide
was deprotected using General Procedure B''' to afford the title
compound as a crude solid or foam.
Example C6
Synthesis of N-(L-Phenylglycine)-L-phenylglycine Methl Ester
Hydrochloride
[1071] Following General Procedure C' and using
N-(tert-butoxycarbonyl)-L-phenylalanine (Sigma) and L-phenylglycine
methyl ester hydrochloride (Bachem), the Boc-protected dipeptide
was prepared as a crude solid or foam. The resulting crude
dipeptide was deprotected using General Procedure B' to afford the
title compound as a crude solid or foam.
Example C7
Synthesis of N-(L-Valine)-L-phenylglycine Methl Ester
Hydrochloride
[1072] Following General Procedure A''' and using
N-(tert-butoxycarbonyl)-L-valine (Sigma) and L-phenylglycine methyl
ester hydrochloride (Bachem), the Boc-protected dipeptide was
prepared as a crude solid or foam. The resulting crude dipeptide
was deprotected using General Procedure B''' to afford the title
compound as a crude solid or foam.
Example C8
Synthesis of N-[(S)-2-Aminocyclohexylacetyl)-L-phenylglycine Methl
Ester Hydrochloride
[1073] Following General Procedure A' and using
N-(tert-butoxycarbonyl)-(S)-aminocyclohexylacetic acid (e.g.,
Boc-L-cyclohexylglycine) and L-phenylglycine methyl ester
hydrochloride (Bachem), the Boc-protected dipeptide was prepared as
a crude solid or foam. The resulting crude dipeptide was
deprotected using General Procedure B''' to afford the title
compound as a crude solid or foam.
[1074] The following Examples D1-D4 illustrate the synthesis of
various intermediates useful as starting materials for this
invention. Similar intermediates can be prepared using these
procedures and commerically available or known starting
materials.
Example D 1
Synthesis of 3,5-Difluorophenyl-.alpha.-fluoroacetic Acid
[1075] Methyl 3,5-difluoromandelate was prepared following General
Procedure G below and using commerically available
3,5-difluoromandelic acid. The resultant .alpha.-hydroxy methyl
ester was fluorinated according to the general procedure described
in W. J. Middleton, et al., Org. Synth. Col. Vol. VI, 835.
Specifically, a solution of diethylaminosulfur trifluoride (1.1 eq)
in CH.sub.2Cl.sub.2 was cooled to 0.degree. C. and treated with
methyl 3,5-difluoromandelate (1.0 eq) as a solution in
CH.sub.2Cl.sub.2. After 10 min. the cooling bath was removed and
the reaction was stirred at ambient temperature for 30 min. The
reaction was monitored by tlc (Rf=0.65, 1:1 ethyl acetate/hexanes).
The mixture was then poured onto ice and the layers separated. The
organic phase was washed with saturated aqueous NaHCO.sub.3 and
brine. The organic layer was dried over Na.sub.2SO.sub.4, filtered,
and concentrated in vacua. The product was purified by LC2000
chromatograpy (180 mL/min) using 10% EtoAc/hexanes as the eluent.
The resulting methyl 3,5-difluorophenyl-.alpha.-fluoroacetate was
hydrolyzed by dissolving the ester in 70% aqueous dioxane and
treating with lithium hydroxide (2.0 eq.). No starting material
remained by tlc after 2 h. The dioxane was removed via rotary
evaporation. The aqueous mixture was first washed with ethyl
acetate and then acidified with 0.01 N HCl. The aqueous layer was
extracted with ethyl acetate. The organic phase was washed with
brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated. The
crude solid was recrystallized from ethyl acetate/hexanes affording
3,5-difluorophenyl-.alpha.-fluoroacetic acid as a white solid
having a melting point of 90-110.degree. C.
[1076] C.sub.8H.sub.5F.sub.3O.sub.2 (MW=190.1); mass spectroscopy:
190.1.
Example D2
Synthesis of (S)-2-Hydroxy-2-methyl-1-phenylprop-1-ylamine
[1077] (S)-2-Hydroxy-2-methyl-1-phenylprop-1-ylamine was prepared
by adding 5.0 equivalents of methyl magnesium bromide to a solution
of L-phenylglycine methyl ester hydrochloride in THF at 0.degree.
C. The reaction mixture was stirred for 1 hour and then quenched
with sodium bicarbonate. After standard work-up conditions, the
residue was purified by silica gel chromatography using 10%
MeOH/CHCl.sub.3 as the eluent.
Example D3
Synthesis of Methyl (S)-2-Amino-2-(6-methoxy-2-naphthyl)acetate
[1078]
(S)-2-(tert-Butoxycarbonylamino)-2-(6-methoxy-2-naphthyl)acetic
acid was prepared from 2-(6-methoxy-2-naphthyl)acetic acid
according to the general method described by D. A. Evans, et al.,
J. Amer. Chem. Soc., (1990), 112, 4011-4030. Briefly,
(S)-3-(6-methoxy-2-naphthylacetyl)4-benzyl-2-ozazolidinone was
converted to
(S)-3-[(S)-6-methoxy-2-naphthyl-.alpha.-azidoacetyl)-4-benzyl-2-ozazol-
idinone via standard enolate azidation procedures using potassium
1,1,1,3,3,3-hexa-methyldisilazane and trimethylsilyl azide at
-78.degree. C. Treatment of the azide derivative with 3 equivalents
of lithium hydroxide in THF then provided
(S)-2-azido-2-(6-methoxy-2-naphthyl)acetic acid. Reduction of this
intermediate, as its sodium salt, in 1:1 1,4-dioxane/water (0.05 M)
with. 1 atm of hydrogen, 10% Pd/C at 25.degree. C. afforded
(S)-2-azido-2-(6-methoxy-2-naphthyl)acetic acid, which was then
converted, without isolation, to its N-Boc derivative on treatment
with 1.4 equivalents of di-tert-butyl dicarbonate and 0.47
equivalents of sodium carbonate. The product was isolated by the
acidification to pH 2 with 1 N NaHSO.sub.4 and extraction with
three portions of ethyl acetate. The product was recrystallized
from ethyl acetate/hexanes to afford a white solid,
m.p.=176.degree. C. (shrink); 197-199.degree. C. (dec).
[1079] NMR data was as follows:
[1080] .sup.1H NMR (DMSO-d.sub.6): .delta.=12.78 (s, 1H), 7.84-7.77
(m, 3H), 7.62 (d, J=8 Hz, 1H), 7.49 (d, J=8 Hz, 1H), 7.31 (d, J=2
Hz, 1H), 7.17 (dd, J=9, 2 Hz, 1H), 5.22.(d, J=8 Hz, 1H), 3.87 (s,
3H), 1.39.(s, 9H).
[1081]
(S)-2-(tert-Butoxycarbonylamino)-2-(6-methoxy-2-naphthyl)acetic
acid was then converted into the methyl ester using General
Procedure G below. The methyl ester was then dissolved in
CH.sub.2Cl.sub.2 and this solution cooled to 0.degree. C.
Trifluoroacetic acid (50 molar eq.) was added and the reaction was
allowed to warm to room temperature and stirring was continued for
2 hrs. The reaction mixture was then concentrated and the residue
extracted into CH.sub.2Cl.sub.2 and washed with sodium bicarbonate
solution. The organic layer was dried over Na.sub.2SO.sub.4,
filtered and concentrated to yield methyl
(S)-2-amino-2-(6-methoxy-2-naphthyl)acetate.
Example D4
Synthesis of Methyl
2-Amino2-(thieno[2,3-b]thiophen-2-yl)acetate
[1082] To a 3.75 mole equivalents of sodium hydride (oil free) was
added DMF and the resulting mixture was cooled to 0.degree. C. A
solution of methyl thieno[2,3-b]thiophen-2-carboxylate (1 mole eq.)
and methyl methylsulfinyl methyl sulfide (1.1 mole eq.) in DMF was
then added dropwise and the reaction mixture was stirred at
0.degree. C. for 30 min and then allowed to warm to room
temperature and stirring was continued for 3 h. The reaction was
then quenched with methanol - and the product extracted into EtOAc.
The organic extracts were washed with water followed by brine, and
then dried over Na.sub.2SO.sub.4, filtered and concentrated to give
a gummy brown oil. The residue was slurried in diethyl ether and
the resulting solid collected. The solid was then dissolved in hot
ethyl acetate and decolorizing carbon was added. The mixture was
then filtered and solvent removed to give a solid, which was used
without further purification.
[1083] Acetic anhydride (10 mole eq.) and acetic acid (1.8 mole
eq.) were mixed together and heated to 70.degree. C. for 15 min.
and then cooled to 65.degree. C. The solid sulfone from above was
added in portions and the reaction was allowed to stir at
70.degree. C. for 30 min. and then cooled and concentrated. The
resulting solid was taken up in ethyl acetate and washed with
sodium bicarbonate solution, followed by 1 N Na.sub.2S.sub.2O.sub.3
solution. The solution was then dried over MgSO.sub.4, filtered and
concentrated to give methyl
2-keto-2-(thieno[2,3-b]thiophen-2-yl)thioacetate as a solid, which
was used without further purification.
[1084] To the 2-keto compound (0.0165 moles) (4.0 g) was added 270
mL of methanol and 16.5 mL of 1 N NaOH. The reaction was allowed to
stir for 6 h at room temperature and then methoxyamine (1.38 g,
0.0165 moles) was added and stirring was continued for 18 h. The
reaction mixture was then concentrated and the residue dissolved in
ethyl acetate and washed with water. The aqueous layer was then
acidified with in HCl and the oily product was extracted into ethyl
acetate and washed with brine. The organic layer was dried over
MgSO.sub.4, filtered and concentrated to give 4.0 g of
2-(hydroxyimino)-2-(thieno(2,3-b]thiophen-2-yl)acetic acid as a
yellow solid. The methyl ester was then prepared using General
Procedure G below and the oxime was reduced to an amino group using
General Procedure R below to afford methyl
2-amino-2-(thieno(2,3-b]thiophen-2-yl)acetate.
Example D5
Synthesis of N-Methyl-N'-BOC-Leucinamide
[1085] A solution of 0.9968 g (4 mmol) of N-BOC-leucine (Bachem)
and 1.2323 g (7.6 mmol) of CDI in 40 mL of THF was stirred for 1
hour, and then 0.5402 g (8 mmol) of methylamine hydrochloride
(Aldrich) and 0.8092 g (8 mmol) of N-methylmorpholine were added.
The mixture was stirred for 16 hours, evaporated at reduced
pressure to dryness, and the residue was washed thoroughly with
water, 1N NaOH, water, followed by diethyl ether to yield 0.886 g
(3.09 mmol, 70%) of the title compound.
Example D6
Synthesis of N-BOC-Norleucine amide
[1086] To a stirred mixture of 3.47 g (15 mmol) of BOC-norleucine
(Bachem), 3.44 g (22.5 mmol) of 1-hydroxybenzotriazole monohydrate
and 50 mL of dichloromethane at 0.degree. C. was added 3.45 g (1.2
mmol)-of EDC. The resulting mixture was stirred at 0.degree. C. for
1 hour and then ammonia gas was bubbled through the mixture for 10
min. The cooling bath was allowed to warm to room temperature and
the mixture stirred for 18 hours. The mixture was evaporated at
reduced pressure to dryness, triturated with 20% Na.sub.2CO.sub.3.
The resulting solid was collected by filtration and washed with
water to yield 2.69 g (11.7 mmol, 78%) of the title compound.
Example D7
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-alanine
[1087] The title compound was prepared by dissolving 1.98 g (0.006
mols) of N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine
ethyl ester (from Example 85 below) in 60 mL dioxane and 15 mL of
H.sub.2O and adding LiOH (0.25 g, 0.006 mol) that-has been
dissolved in 15 mL of H.sub.2O. After stirring for 3 hours, the
dioxane was removed under reduced pressure and the residue diluted
with EtOAc, the layers were separated and the aqueous layer
acidified to pH 2. The aqueous layer was back extracted with EtOAc
(4.times.100 ml), and the combined organics were dried over
Na.sub.2SO.sub.4 and the solvent was removed under reduced pressure
after filtration. The residue was recrystallized from
EtOAc/isooctane giving 1.7 g (90%).
C.sub.14H.sub.16F.sub.2N.sub.2O.sub.4 requires C, 53.50 H, 5.13 N,
8.91. Anal found C, 53.30 H, 5.26 N, 8.98.
Example D8
Synthesis of m-Nitrophenylacetyl-L-alanine 2,4,5-Trichlorophenyl
Ester
[1088] m-Nitrophenylacetyl-L-alanine (1 eq.) and
2,4,5-tricholophenol (1.3 eq.) were stirred in dicholomethane. A
1.0 M solution of 1,3-dicyclohexylcarbcdiimide in dichloromethane
(1.2 eq.) was added and the mixture was stirred at ambient
temperature for 16 hours. The resulting mixture was filtered and
the filtrate was concentrated under reduced pressure. The resulting
oil was purified by silica gel chromatography using 1:2 ethyl
acetate/hexanes as the eluant to provide the title -compound as a
pink solid. For C.sub.17H.sub.13Cl.sub.3N.sub.2O.sub.5: Calc.
47.30% C, 3.04% H, 6.49% N. Found 47.57% C, 3.18% H, 6.47% N.
Example D9
Synthesis of D,L-.alpha.-Methylphenylglycine Ethyl Ester
[1089] The title was prepared using the procedures described in J.
J. Fitt and H. W. Gschwend, J. Org. Chem., 42, No. 15, 2639 (1977).
More specifically, D,L-phenylglycine (Aldrich) was stirred in
dimethylformamide dimethylacetal and the mixture was heated at
reflux under an atmosphere of dry nitrogen for 4 hours. After
cooling, the mixture was concentrated under reduced pressure to
provide a yellow oily solid. The mixture was slurried in diethyl
ether and filtered through Celite. The filtrate was concentrated to
an orange oil which was purified by vacuum distillation to provide
a yellow oil which solidified. The yellow solid was stirred in dry
THF at -20 C under dry nitrogen. Lithium -bis(trimethylsilyl)amide
(1.05 eq, 1.0M solution in THF) was added dropwise. The resulting
mixture was allowed to warm to -10 C and stirring was continued for
1 hour at that temperature. Methyl iodide (1.05 eq) was added and
the mixture was allowed to warm ambient temperature with stirring.
After 14 hours, the mixture was concentrated. The residue was
partitioned between aqueous potassium carbonate and chloroform. The
organic portion was dried (sodium sulfate) and concentrated under
reduced pressure. The product was purified by silica gel
chromatography to yield a yellow oil. The yellow oil was stirred in
absolute ethanol. Dry zinc chloride (4 eq.) was added and the
mixture was heated at reflux. After 14 hours, the mixture was
concentrated under reduced pressure to provide a yellow oil. The
oil was partitioned between aqueous potassium carbonate and
chloroform. The organic portion was dried (sodium sulfate) and
concentrated under reduced pressure. The title compound was
purified by silica gel chromatography.
Example D10
Synthesis of D,L-Phthalimidoalanine Ethyl Ester Hydrochloride
[1090] N-(Diphenylmethylene)glycine ethyl ester (1 eq.) (Aldrich)
was stirred in dry THF at -78.degree. C. under-an atmosphere of dry
nitrogen. Lithium bis(trimethylsiyl)amide (1.02 eq, 1.0 M solution
in THF) was added dropwise. The resulting mixture was stirred 1
hour at -78.degree. C. A THF solution of N-(bromomethyl)phthalimide
(1.1 eq) (Aldrich) was added and the mixture was allowed to warm to
ambient temperature and then stirring was continued for 1 hour.
Hydrochloric acid (600 mL, 2N) was added and the mixture was
stirred for 20 minutes. The THF was removed on a rotoevaporator.
The resulting aqueous mixture was washed with diethyl ether, and
then concentrated (to 100 mL) to yield a thick slurry. A white
solid was collected, washed with cold water and dried in a vacuum
oven to yield the title compound which was used without further
purification.
Example D 11
Synthesis of N-(3-Nitrophenylacetyl)-L-alanine
[1091] The title compound was prepared by dissolving 9.27 g (0.0348
mols) of the N-(3-nitrophenylacetyl)-L-alanine methyl ester in 60
mL of dioxane and 15 mL of H.sub.2O and adding LiOH (3.06 g, 0.0731
mol) that has been dissolved in 15 mL of H.sub.2O. After stirring
for 4 hours, the dioxane was removed under reduced pressure and the
residue diluted with EtOAc, the layers were separated and the
aqueous layer acidified to pH 2. The aqueous layer was back
extracted with EtOAc (4.times.100 ml)., the combined organics were
dried over Na.sub.2SO.sub.4 and the solvent was removed under
reduced pressure after filtration. The residue was recrystallized
from EtOAc/isooctane giving 7.5 g (85 %).
C.sub.11H.sub.12N.sub.12O.sub.5 requires C, 52.38 H, 4.80 N. 11.11.
Anal found C, 52.54 H, 4.85 N, 11.08. [.alpha.].sub.23 =-29.9 @ 589
nm.
Example D12
Synthesis of Methyl 2-Amino-2-(3-fluorophenyl)acetate
Hydrochloride.
[1092] Potassium cyanide (6.3, 0.1 mol) and ammonium carbonate
(15.7 g, 0.2 mol) were dissolved in 50 mL of water (in a well
ventilated fume hood). 3-Fluorobenzaldehyde (5.0 g, 0.04 mol) was
dissolved in 50 mL of EtOH and added to the reaction. After
stirring at reflux under nitrogen atmosphere for 17 hours, the
reaction was cooled to 23.degree. C., the pH adjusted to 2.0 by the
addition of 5 N HCl and cooled to 5.degree. C. The resulting
hydantoin was collected, rinsed with cold water and vacuum dried
giving 3.59 of an off-white solid. The hydantoin was hydrolyzed at
reflux using 1 N NaOH giving 2-amino-2-(3-fluorophenyl)acetic acid
which was esterified via Procedure H in methanol to give the title
compound.
Example D13
Synthesis of N-[N-(S)-2-Aminobutanoyl]-L-phenylglycine tert-Butyl
ester
[1093] A mixture of
N-[N-(benzyloxycarbonyl)-(S)-2-aminobutanoyl]-L-phenylglycine
tert-butyl ester (4.13 g) (prepared from
N-(benzyloxycarbonyl)-(S)-2-aminobutanoic acid (Novabiochem) and
L-phenylglycine tert-butyl ester hydrochloride (Novabiochem) using
General Procedure D) and 20% Pd(OH).sub.2/C (0.360 g) in EtOH (200
mL) was shaken in a Parr Apparatus under a hydrogen atmosphere (40
psi) for 4 hours. The solids were removed by filtration through a
plug of Celite, while rinsing with EtOH. The filtrate was
concentrated to an off-white oil, which was used without further
purification. .sup.1H-NMR in CDCl.sub.3 revealed that -10%
trans-esterification to the ethyl occurred during this reaction.
The ethyl ester was removed by flash chromatography after
subsequent reaction of this compound.
Example D14
Synthesis of N-[N-L-Valinyl]-L-phenylglycine tert-Butyl ester
[1094] A mixture of
N-[N-(benzyloxycarbonyl)-L-valinyl]-L-phenylglycine tert-butyl
ester (4.63 g) (prepared from N-(benzyloxycarbonyl)-L-valine
(Aldrich) and L-phenylglycine tert-butyl ester hydrochloride
(Novabiochem) using General Procedure D) and 20% Pd(OH).sub.2/C
(0.360 g) in EtOH (200 mL) was shaken in a Parr Apparatus under a
hydrogen atmosphere (40 psi) for 4 hours. The solids were removed
by filtration through a plug of Celite, while rinsing with EtOH.
The filtrate was concentrated to an off-white solid, which was used
without further purification. .sup.1H-NMR in CDCl.sub.3 revealed
that .about.1% trans-esterification to the ethyl occurred during
this reaction. The ethyl ester was removed by flash chromatography
after subsequent reaction of this compound.
Example D15
Synthesis of (S)-Phenylglycinol Methyl Ether
[1095] (S)-(+)-r2-phenylglycinol (1 eq.) (Aldrich) was stirred in
dry THF under an atmosphere of dry nitrogen. Sodium hydride (1 eq.)
was added and the resulting mixture was stirred for l hour at
ambient temperature. A THF solution of iodomethane (1 eq.) was
added and the mixture was stirred for 1 hour. The mixture was
concentrated to provide a residue which was taken up in water and
extracted with chloroform. The organic extracts were concentrated
under reduced pressure to yield the title compound as an oil which
was purified by silica gel chromatography to yield a crude product
which was used without further purification.
Example D16
Synthesis of (S)-2-Hydroxy-2-methyl-1-phenylprop-1-ylamine
[1096] To a stirred, cooled (0.degree. C.) suspension of 5.6 g
(27.8 mmol) of L-phenylglycine methyl ester hydrochloride (Aldrich)
in 200 mL of dry THF was added methylmagnesium bromide (46.3 mL,
138.9 mmol, 3.0 M in diethyl ether). During the addition, the
internal-temperature increased to 24.degree. C. Stirring was
continued for 1 hour, after which the reaction was carefully
quenched by addition of saturated sodium bicarbonate solution. The
reaction mixture was partitioned between ethyl acetate and aqueous
sodium bicarbonate solution, back extracting the aqueous layer with
3 volumes of ethyl acetate. The combined organics were dried over
anhydrous sodium sulfate and concentrated under reduced pressure.
The product was purified by flash chromatography on silica gel,
eluting with 10% methanol in chloroform (neutralized with ammonium
hydroxide) to afford 1.96 g to the title compound.
Example D17
Synthesis of 5Chloro-2-thiophenecarboxaldehyde
[1097] A solution of 2-chlorothiophene (Aldrich; 1 molar eq.) in
THF was cooled to -78.degree. C. and treated with n-butyllithium
(1.6M in hexanes; 1.1 molar eq.) in a dropwise manner. The
resultant yellow solution was stirred at -78.degree. C. for 40
minutes. Dimethylformamide (1.1 molar eq.) was added dropwise and
the reaction stirred and additional 30 minutes. The mixture was
diluted with methylene chloride and washed with 10% acetic acid, 1M
potassium carbonate, and brine. The organic phase was dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified by HPLC eluting with 15% ethyl acetate/hexanes to afford
the title compound.
Example D18
Synthesis of (S)-(-)-.alpha.-Methylbenzylisocyanide
[1098] Prepared according to the general procedure of Wolber, E. K.
A.; Ruchardt, C. Chem. Ber. 1991, 124, 1667. To a suspension of
1,1'-carbonyldiimidazole (1.6 molar eq.; Aldrich) in acetonitrile
at 0.degree. C. was treated with methanesulfonic acid (3.2 molar
eq.; Aldrich) in a dropwise fashion. A very thick suspension
results. S-(-)-.alpha.-Methylbenzyl formamide (1 molar eq.; from
Example D19 below) was added as a solution in acetonitrile via
cannulation. The mixture was stirred overnight at ambient
temperature. The suspension was filtered, washing with
acetonitrile. The filtrate was concentrated and purified via flash
chromatography eluting with 30% ethyl acetate/hexanes. The oil was
further purified via bulb-to-bulb distillation (80.degree. C., 0.04
mm Hg) giving a pale yellow oil in 51% yield. Calcd for
C.sub.9H.sub.9N: C, 82.41; H, 6.92; N, 10.68. Found: C, 82.56; H.
6.82; N, 10.71.
Example D19
Synthesis of (S)-(-)-.alpha.-Methylbenzyl formamide
[1099] (S)-(-)-.alpha.-Methylbenzylamine (1 molar eq.) was treated
with ethyl formate (80 molar eq.; Aldrich). A precipitate formed
immediately. The suspension was heated to reflux (55.degree. C.)
for 3 hours. The precipitate went into solution upon heating. The
solution was cooled to ambient temperature and concentrated via
rotary evaporation. The resultant solid was used without
purification.
Example D20
Synthesis of 3-(Phenyl)benzaldehyde
[1100] A solution of 3-bromobiphenyl (Aldrich; 1 molar eq.) in dry
THF was cooled to -78.degree. C. and treated with tert-butyllithium
(Aldrich; 1.7 M in hexanes, 2 molar eq.) in a dropwise manner. The
reaction was allowed to stir at -78.degree. C. for 40 minutes.
Dimethylformamide (Aldrich; 2.5 molar eq.) was added and stirring
continued an additional 20 minutes. The mixture was partitioned in
a separatory funnel between methylene chloride and water. The
organic layer was dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The residue was purified via HPLC eluting with 5%
ethyl acetate/hexanes. The desired aldehyde was obtained in 71 %
yield.
Example D21
Synthesis of 4-(Cyclohexyl)benzaldehyde
[1101] 18-Crown-6 (Aldrich; 4 molar eq.) and pyridinium
chlorochromate. (Aldrich; 4 molar eq.) were added together in
chloroform and stirred for 20 minutes. 4-Cyclohexylbenzylalcohol
(from Example D22 below; 1 molar eq.) was added and stirring
continued for 3 hours. Ether was added and the mixture filtered
through a plug of silica eluting with ether. The solvent was
removed via rotary evaporation. The residue was dissolved in ether
and washed with water. The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated.
Example D22
Synthesis of 4(Cyclohexyl)benzyl Alcohol
[1102] To a solution of 4-cyclohexylbenzoic acid (Aldrich; 1 molar
eq.) in toluene was added diiso-butylaluminum hydride (Aldrich; 1 M
in toluene; 4 molar eq.) over a 2 hour period. After addition was
complete, the reaction was heated to 60.degree. C. for 1 hour. The
reaction was cooled to 5.degree. C. and quenched with saturated
aqueous ammonium chloride. The layers were separated and the
aqueous layer extracted with ethyl acetate. The combined organics
were filtered to remove salts-and concentrated.
Example D23
Synthesis of 3,5-Difluorophenyl-.alpha.,.alpha.-difluoroacetic
Acid
[1103] A solution of ethyl
3,5-difluorophenyl-.alpha.,.alpha.-difluoroacetate (from Example
D24 below; 1 molar eq.) in 50% aqueous ethanol was treated with
lithium hydroxide (1.5 molar eq.). The solution was stirred for 3
hours at ambient temperature then concentrated via rotary
evaporation. The residue was taken up in water; a small amount of 1
N NaOH was added to make basic. The aqueous mixture was extracted
with ether. The aqueous layer was acidified to pH 3 with 1 N HCl.
The acid was extracted thrice with methylene chloride. The combined
methylene chloride extracts were dried over Na.sub.2SO.sub.4,
filtered, and concentrated.
Example D24
Synthesis of Ethyl 3,5-Difluorophenyl-.alpha.,
.alpha.-difluoroacetate
[1104] Ethyl 3,5-difluorophenyl-.alpha.-ketoacetate (Rieke Metals,
Inc. #14014; 1 molar eq.) was treated. with (diethylamino)sulfur
trifluoride (DAST) (2.5 molar eq.). The reaction was stirred at
ambient for 72 hours then heated to 50.degree. C. for 6 hours. The
mixture was poured over ice and extracted with methylene chloride.
The organic layer was washed with saturated sodium bicarbonate,
dried over Na.sub.2SO.sub.4, filtered, and concentrated. The
residue was purified via HPLC eluting with 2% ethyl
acetatelhexanes.
Example D25
Synthesis of
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine
[1105] N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycine
methyl ester (from Example 111 below) was hydrolyzed according to
Procedure AF. The acid was recrystallized from isooctane/EtOAc
providing a mixture of diastereomers at the phenylglycine center.
Elemental analysis; C.sub.19H.sub.18F.sub.2N.sub.4O.sub.4 requires
C, 60.63 H, 4.82 N, 7.44. Found; C, 60.65 H, 5.02 N, 7.37. Mass
spectroscopy (MH.sup.+377).
Example D26
Synthesis of 3-(4Iodophenyl)propylamine
[1106] N-(3-bromopropyl)phthalimide (1 eq., Aldrich) and
4-iodophenol (1 eq., Aldrich) and potassium carbonate (2 eq.) was
stirred in acetonitrile. The mixture was heated at reflux. After 64
hour, the reaction mixture was concentrated to a thick mixture
which was slurried in water. A white solid was collected, washed
with water and vacuum dried.
[1107] The white solid was stirred in ethanol. Anhydrous hydrazine
(2 eq.) was added and mixture was heated at reflux for 18 hours.
The reaction mixture was concentrated to yield a solid which was
treated with 1N NaOH and extracted with CHCl.sub.3. The organic
portion was dried, concentrated then diluted with ether. The
mixture was treated with dry HCl. The title compound was collected
as a white solid and vacuum dried.
Example D27
Synthesis of 2-Amino-1-phthalimidopentane Hydrochloride
[1108] 2-Amino-1-pentanol was stirred in a mixture of chloroform
and saturated aqueous sodium bicarbonate. Di-tert-butyl dicarbonate
(1.05 eq.) was added in one portion and the mixture was stirred
until starting material was consumed. The organic portion was
separated, dried (sodium sulfate) and concentrated. The crude
material was purified by silica gel chromatrography using 1:1 ethyl
acetate/hexanes.
[1109] The product was dissolved in THF. Triethylamine (1.1 eq.)
was added and the mixture was cooled in an ice bath.
Methanesulfonyl chloride (1.1 eq.) was added dropwise and the
mixture was stirred until starting material was consumed. The
mixture was concentrated under reduced pressure then was
partitioned between ethyl acetate and water. The organic portion
was separated, dried (sodium sulfate) and concentrated to yield a
white solid which was chromatographed on silica gel using 30% ethyl
acetate in hexanes and finally crystallized from
1-chlorobutane/hexanes.
[1110] The crystalline product was stirred in dry DMF and potassium
phtalimide (1.1 eq.) was added. The mixture was stirred for 18
hours then was concentrated under reduced pressure. The residue was
partitioned between ethyl acetate and water. The organic portion
was dried and concentrated to yield a white solid. The solid was
taken up in chloroform and filtered through a plug of silica.
Eluent containing product was concentrated to yield the crude
product as a white solid.
[1111] The white solid was taken up in dry dioxane and resulting
solution was saturated with gaseous HCl. After stirring for 30
minutes, the mixture was concentrated to yield a white solid which
was triturated in ether. The title compound was collected, washed
with ether and dried in a vacuum oven.
Example D28
Synthesis of D,L-3,5-Difluorophenylglycine
[1112] KOH (11.76 grams), LiCl (2.95 grams), saturated aqueous
ammonia (20 mL), and benzyltriethylammonium chloride (0.805 grams)
were stirred and chilled in CH.sub.2Cl.sub.2 (17 mL). Gaseous
ammonia was bubbled into this mixture with chilling (0.degree. C.)
to saturation. To the resulting mixture was added
3,5-difluorobenzaldehyde (5.0 grams) (Lancaster) and chloroform
(4.46 mL), dissolved in CH.sub.2Cl.sub.2 (17.5 mL) with concurrent
saturation with ammonia gas. The resulting mixture was stirred cold
for 4 hours and at 22.5.degree. C. for 96 hours. Water (60 mL) and
CH.sub.2Cl.sub.2 (20 mL) were added; the layers separated, and the
aqueous layer was extracted 3 times more with CH.sub.2Cl.sub.2. The
aqueous layer was _ reduced in vacuo by 50%. The pH was adjusted to
6.5 with cold conc. HCl whereupon white crystals of D,L-3,5
difluorophenylglycine formed (3.4343 grams).
Example D29
Synthesis of L-3,5-Difluorophenylglycine Methyl Ester Tartate
Salt
[1113] 3.43 Grams of D,L-3,5 difluorophenylglycine (from Example
D28 above) was slurried in 50 mL methanol and 2.5 mL conc.
H.sub.2SO.sub.4. The reaction mixture was heated under gentle
reflux for 18 hours. The mixture was chilled in and ice bath and
the pH of the solution was adjusted to 7.0 with saturated aqueous
ammonia. The volatile organic solvents were removed in vacua and
the aqueous portion was extracted three times with
CH.sub.2Cl.sub.2; the combined organic layers dried, filtered, and
reduced in vacua to provide 2.680 grams of crude ester. This ester,
benzaldehyde (1.4085 grams), and (-) tartaric acid (1.9921 grams),
were dissolved in 20.5 mL of hot ethanol and stirred slowly for 72
hours as the title compound crystallized. The product was filtered
and dried to provide 3.4805 grams of the (-) tartarate salt.
Example D30
Synthesis of
N-(3,5-Difluorophenylacetyl)-L-3,5-difluorophenylglycine
[1114] L-3,5-Difluorophenylglycine (0.4291 g) (prepared from
L-3,5-difluorophenylglycine (-)-tartarate salt (from Example D29
above) by neutralization) and 3,5-difluoroacetic acid 0.367 gram
were dissolved in THE. FEDQ coupling using General Procedure AN
afforded 0.7441 grams of the title compound as the methyl ester.
The ester was dissolved in 1,4 dioxane (10 mL), chilled and
LiOH.H.sub.2O (89.0 mg) in water (10 mL) was added slowly and the
mixture was stirred for 2 hours at 22.5.degree. C. EtOAc (30 mL)
and 1N HCl were added and the aqueous layer extracted two times.
The combined organic layers were dried (MgSO.sub.4) and reduced in
vacuo to provide the title compound (700.8 mg).
[1115] Each of the compounds set forth in the following examples
was prepared by one of the following general procedures, unless
otherwise indicated.
General Procedure A
EDC Coupling Procedure I
[1116] To a 1:1 mixture of the corresponding carboxylic acid and
amino ester/amide in CH.sub.2Cl.sub.2 or DMF at 0.degree. C. was
added 1.5 equivalents triethylamine, followed by 2.0 equivalents
hydroxybenzotriazole monohydrate, then 1.25 equivalents of
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC).
The reaction mixture was stirred overnight at room temperature and
then transferred to a separatory funnel. The mixture was washed
with water, saturated aqueous NaHCO.sub.3, 1 N aqueous hydrochloric
acid, and saturated aqueous sodium chloride, and then dried over
MgSO.sub.4. The solution was stripped free of solvent on a rotary
evaporator to yield the crude product.
General Procedure B
EDC Coupling Procedure II
[1117] The carboxylic acid was dissolved in methylene chloride in a
round-bottomed flask. The amino acid (1 eq.), N-methylmorpholine (5
eq.) and hydroxybenzotriazole monohydrate (1.2 eq.) were added in
sequence. A cooling bath was applied to the round-bottomed flask
until the solution reached 0.degree.. At that time, 1.2 eq. of
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was
added. The solution was then allowed to stir overnight and come to
room temperature under N.sub.2 pressure. The reaction mixture was
then washed with saturated aqueous Na.sub.2CO.sub.3, 0.1 M citric
acid, and brine before drying with Na.sub.2SO.sub.4 and removing
the solvents to yield the crude product. Pure products were
typically obtained by-flash chromatography in an appropriate
solvent.
General Procedure C
EDC Coupling Procedure III
[1118] A round-bottomed flask was- charged with the appropriate
carboxylic acid (1.0 eq), hydroxybenzotriazole hydrate (1.1 eq) and
the appropriate amine. (1.0 eq) in THF under a nitrogen atmosphere.
An appropriate amount (1.1 eq. for the free amine and 2.2 eq. for
amine hydrochloride salt) of a suitable base, such as Hunig's base
was added to the stirred mixture, followed by
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC)
(1. 1 eq). After stirring for about 4 h to 17 h at room
temperature, the solvent was removed at reduced pressure and the
residue taken up in EtOAc (or a similar solvent)/H.sub.2O. The
extracts were washed with saturated NaHCO.sub.3, 1 N aqueous
hydrochloric acid, brine and dried over Na.sub.2SO.sub.4. In some
cases, the isolated product required further purification using
standard procedures, such as chromatography and/or
recrystallisation.
General Procedure D
EDC Coupling Procedure IV
[1119] A round bottom flask containing a magnetic stir bar under an
atmosphere of nitrogen at 0.degree. C. was charged with THF, an
amine or amine hydrochloride (1.0 eq.), carboxylic acid (1.1 eq.),
1-hydroxybenzotriazole hydrate (1.15-1.2 eq),
N,N-diisopropylethylamine (2.3 eq.), followed by
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC)
(1.15-1.2 eq.).
[1120] The cooling bath was removed and the mixture allowed to warm
to room temperature with stirring for 10-20 hours. The mixture was
diluted with EtOAc and washed with 0.5 N aqueous. HCl (2.times.),
dilute aqueous NaHCO.sub.3 (1.times.), brine (1.times.) and dried
over either Na.sub.2SO.sub.4 or MgSO.sub.4. The drying agent was
removed by filtration and the filtrate concentrated in vacuo. The
residue was either used without further purification or purified by
standard procedures, such as flash chromatography on silica gel
and/or recrystallization.
General Procedure E
EDC Coupling Procedure V
[1121] A round bottom flask containing a magnetic stir bar under an
atmosphere of nitrogen at 0.degree. C. or room temperature was
charged with THF, carboxylic acid (1.0 eq), an amine or amine
hydrochloride (1.0-1.1 eq.), 1-hydroxybenzotriazole hydrate
(1.1-1.2 eq.), N,N-diisopropylethylamine (2.2-2.9 eq.), followed by
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC)
(1.1-1.2 eq.). The cooling bath was removed and the mixture allowed
to warm to room temperature with stirring for 10-20 hours. The
mixture was diluted with EtOAc and washed with 0.5 N aqueous HC.
(2.times.), dilute aqueous NaHCO.sub.3 (1.times.), brine (1.times.)
and dried over either Na.sub.2SO.sub.4 or MgSO.sub.4. The drying
agent was removed by filtration and the filtrate concentrated in
vacuo. The residue was either used without further purification or
purified using standard procedures, such as flash chromatography on
silica gel and/or recrystallization.
General Procedure F
EDC Coupling Procedure VI
[1122] A round bottom flask containing a magnetic stir bar under an
atmosphere of nitrogen at 0.degree. C. was charged with THF,
carboxylic acid (1.0 eq.), an amine or amine hydrochloride (1.1
eq.), N,N-diisopropylethylamine (2.2-2.3 eq.), followed by
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC)
(1.1-1.2 eq.). The cooling bath was removed and the mixture allowed
to warm to room temperature with stirring for 10-20 hours. The
mixture was diluted with EtOAc and washed with 0.2 N aqueous HCl
(2.times.), dilute aqueous NaHCO.sub.3 (1.times.), brine (1.times.)
and dried over either Na.sub.2SO.sub.4 or MgSO.sub.4. The drying
agent was removed by filtration and the filtrate concentrated in
vacui. The residue was either used without further purification or
purified using standard procedures, such as flash chromatography on
silica gel and/or recrystallization.
General Procedure G
Methyl Ester Preparation
[1123] To 1-methyl-3-nitro-1-nitrosoguanidine (1.2 eq.) in diethyl
ether cooled to 0.degree. C. was added 40% KOH until bubbling
ceased. This mixture was then decanted into a plastic tube
containing KOH pellets as a drying agent. The solution was then
added to the appropriate carboxylic acid and the mixture was
stirred until the reaction was complete (as determined, for
example, by tlc). The reaction was then quenched with acetic acid
and extracted into EtOAc. Removal of the solvent afforded the
desired methyl ester.
General Procedure H
[1124] Carboxylic Acid Ester Preparation
[1125] To the appropriate amino acid or carboxylic acid in the
appropriate alcohol was bubbled anhydrous HCl gas until the
solution was saturated. The reaction was stirred overnight at
25.degree. C. and the solvent was then removed under reduced
pressure. The residue was then dissolved in EtOAc and this solution
was washed with sodium bicarbonate solution. The organic layer were
then dried over sodium sulfate, filtered and solvent removed to
afford the desired ester.
General Procedure I
tert-Butyl Ester Preparation I
[1126] To a solution of an N-CBZ-protected amino acid in
CH.sub.2Cl.sub.2 was added 1.5 equivalents of
N,N'-diisopropyl-O-t-butylisourea (prepared by standard literature
methods such as those found in Synthesis (1979), p. 561), and the
reaction was heated to reflux for 17 h. An additional 1.5
equivalents of isourea were then added, and reflux was continued
for another 7 h. The reaction was then cooled to room temperature
and filtered through a bed of Celite 545, then stripped to dryness
to leave a clear oil. The residue was dissolved in hexanes and
filtered to remove solids, and the filtrate was washed with
saturated aqueous NaHCO.sub.3, water, saturated aqueous NaCl, and
dried over MgSO.sub.4. The solution was concentrated under reduced
pressure to leave the product.
General Procedure J
tert-Butyl Ester Preparation II
[1127] The reaction was conducted in a sealed tube using the
appropriate carboxylic acid, a catalytic amount of H.sub.2SO.sub.4
(0.03 eq.) and an excess of condensed iso-butylene in dioxane or
CH.sub.2Cl.sub.2 at -20.degree. C. The reaction times varied from
about 48 hours to about 120 hours. When the reaction was complete,
the solvent was removed under reduced pressure and the residue
dissolved in diethyl ether. This solution was washed with sodium
bicarbonate solution and the organic layer dried over sodium
sulfate, filtered and solvent removed. The resulting product was
purified using standard procedures, such as HPLC or titration
using, for example, diethyl ether/hexanes.
General Procedure K
Amide Preparation I
[1128] To a solution of 3 equivalents of the desired amine in
1,2-dichloroethane was added 5.2 equivalents triethylaluminum
subsurface. After stirring for 30 minutes at room temperature, a
solution of the desired ester dissolved in 1,2-dichloroethane was
added. The reaction was refluxed until tlc showed complete
conversion, typically 3 h. The reaction was then cooled to
0.degree. C. and quenched with 10% aqueous hydrochloric acid (Note:
the acid should be added slowly as some foaming occurs during its
addition). The mixture was transferred to a separatory funnel and
the layers were separated. The aqueous phase was washed with ethyl
acetate, and the organic phases were washed with saturated aqueous
NaCl, dried over MgSO.sub.4, and concentrated under reduced
pressure to leave the crude product..
[1129] Alternatively, if the product is acid soluble, after the
reaction is quenched, the reaction volume was reduced to about
one-third of its initial volume under reduced pressure. To the
resulting solution was added 20% aqueous potassium sodium tartrate
(Rochelle's salt) and ethyl acetate. The pH of the solution was
then adjusted to -13, and the aluminum salts dissolved in the
aqueous solution. The organic phase was separated, and the aqueous
phase was extracted with ethyl acetate. The combined organic
solution was washed with saturated aqueous NaCl, dried over
MgSO.sub.4, and concentrated under reduced pressure to leave the
crude product.
General Procedure L
Amide Preparation II
[1130] The carboxamide was prepared from its corresponding ester
using the procedure described in Hogberg, T., et. al., J. Organic
Chem., 1987, 52, 2033-2036.
General Procedure M
Amide Preparation III
[1131] To the appropriate carboxylic acid (1.0 eq.) in THF was
added N-methylmorpholine (1.1 eq.) and the solution was cooled to
-20.degree. C. to 0.degree. C. iso-butyl chloroformate (1.1 to 2.1
eq.) was then added and the reaction mixture was stirred at
-20.degree. C. to 0.degree. C. for 30 min. A mixture of the
appropriate amino acid, water and 1.5 eq. of potassium carbonate
was then added, and the resulting mixture was allowed to warm to
room temperature and stir for 2 hrs. The reaction mixture was then
poured into water and washed with EtOAc. The pH of the water layer
was then adjusted to 2.0 with 5 N HCl and the water layer was
extracted with EtOAc. The combined organic layers were dried over
sodium sulfate, filtered and the solvent removed under reduced
pressure. The resulting crude amide was used without further
purification or purified using standard procedures such as
chromatography or titration using, for example, diethyl
ether/hexanes or EtOAc/hexanes.
General Procedure N
Hydrolysis of Carboxylic Acid Esters
[1132] To the ester in a 1:1 mixture of CH.sub.3OH/H.sub.2O was
added 2-5 equivalents of K.sub.2CO.sub.3. The mixture was heated to
50.degree. C. for 0.5-1.5 h until tlc showed complete reaction. The
reaction was cooled to room temperature and the _ methanol was
removed on a rotary evaporator. The pH of the remaining aqueous
solution was adjusted to about 2, and ethyl acetate was added to
extract the product. The organic phase was then washed with
saturated aqueous NaCl and dried over MgSO.sub.4. The solution was
stripped free of solvent on a rotary evaporator to yield the
product.
General Procedure O
Removal of N-Carbobenzyloxy (CBZ) Protecting Groups
[1133] The N-CBZ-protected compound was dissolved in ethanol in a
hydrogenation flask and a catalytic amount of 10% Pd/C was added.
The mixture was hydrogenated at 20 psi H.sub.2 on a Parr shaker for
30 min. The reaction was then filtered through a pad of Celite 545
and stripped free of solvent on a rotary evaporator to yield the
product.
General Procedure P
Removal of the N-tert-Boc Protecting Group
[1134] The N-tert-Boc-amine was dissolved in a suitable dry solvent
(such as 1,4-dioxane or ethyl acetate) and the solution was cooled
in an ice bath. Gaseous HCl was introduced into the solution until
the mixture was saturated with HCl. The mixture was then stirred
until the reaction was complete. The resulting mixture was
concentrated under reduced pressure to yield the amine
hydrochloride. The amine hydrochloride was used without
purification or was triturated using, for example, diethyl ether
and the resulting solid was collected by filtration.
General Procedure Q
Halide Exchange (Einkelstein) Reaction
[1135] The corresponding alkyl bromide or alky chloride was
dissolved in 20 mL of methyl ethyl ketone and 1 eq. of NaI was
added. The reaction was heated to 60.degree. C. and stirred
overnight. The cooled reaction mixture was extracted with
dichloromethane (2.times.30 mL) and the combined extracts were
roto-evaporated at reduced pressure to give the crude product. Pure
products were typically obtained by flash chromatography in an
appropriate solvent.
General Procedure R
Oxime Reduction I
[1136] To the oxime ester in the alcohol corresponding to the ester
was added formic acid (500 eq.) and water (500 eq.). The reaction
mixture cooled to 5.degree. C. and zinc dust (3.8 eq.) was added in
portions over 20 min. The reaction was then allowed to warm to room
temperature and stirring was continued for 3 hours. The reaction
was then filtered over HYFLO and the solvent removed under reduced
pressure. The residue was dissolved in EtOAc and this solution
washed with saturated sodium bicarbonate solution. The organic
layer was then dried over sodium sulfate, filtered and solvent
removed to afford the product.
General Procedure S.
Reduction of Esters to Alcohols
[1137] To a 0.degree. C. solution of the starting ester in
anhydrous THF was added 1.0 equivalents of LiBH.sub.4 in THF. The
reaction was stirred at room temperature overnight and then
quenched with water. The THF was removed on a rotary evaporator and
ethyl acetate was added. The phases were separated and the organic
phase was washed with saturated aqueous sodium chloride solution,
dried over magnesium sulfate, and concentrated under reduced
pressure to afford the alcohol product.
General Procedure T
CDI Coupling Procedure
[1138] A solution of the appropriate acid (3.3 mmol) and
1,1'-carbodiimidazole (CDI) in 20 mL THF was stirred for 2 h. The
amino acid ester hydrochloride (3.6 mmol) was added, followed by
1.5 mL (10.8 mmol) of triethylamine. The reaction mixture was
stirred overnight and then dissolved in 100 mL of diethyl ether,
washed with 10% HCl three times, brine once, 20% potassium
carbonate once and brine once. The solution was dried over
magnesium sulfate, filtered, and evaporated at reduced pressure to
yield the product.
General Procedure U
EDC Coupling Procedure VII
[1139] A mixture of the appropriate carboxylic acid (1 eq.), 1
hydroxybenzotriazole (1.6 eq.), the appropriate amine (1 eq.),
N-methylmorpholine (3 eq.) and dichloromethane (or DMF for
insoluble substrates), cooled in an ice-water bath, was stirred
until a clear solution was obtained. EDC (1.3 eq.) was added to the
reaction mixture and the cooling bath was allowed-to warm to
ambient temperature over 1-2 h. The reaction was then stirred
overnight. The reaction mixture was then evaporated at reduced
pressure to dryness under vacuum and 20% aqueous potassium
carbonate was added to the residue. The mixture was shaken
vigorously and allowed to stand for hours or overnight, if
necessary, until the oily product to solidify. The solidified
product was then filtered off, washed thoroughly with 20% potassium
carbonate, water, 10% HCl, and water to give the product. No
racemization was observed using this procedure.
General Procedure V
O-Acylation of Alcohols
[1140] To a solution of the alcohol (e.g.,
N-[(S)-1-hydroxyhex-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide
from Example 228 below) in pyridine was added 4 equivalents of
acetic anhydride and the reaction was stirred at room temperature
for 2.5 h. The reaction was quenched onto ice and then ethyl
acetate was added and the phases were separated. The organic phase
was washed with 10% HCl, water, saturated aqueous NaCl, and dried
over MgSO.sub.4. The solution was stripped free of solvent on a
rotary evaporator to yield the product.
General Procedure W
O-Esterification of Alcohols
[1141] To a suspension of 0.95 equivalents of NaH in THF was added
an alcohol (e.g.,
N-[(S)-1-hydroxyhex-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide
from Example 228 below) dissolved in THF. This solution was cooled
to 0.degree. C., then 1.1 equivalents of an acyl chloride (e.g.
trimethylacetyl chloride) was added. The reaction was stirred at
room temperature overnight, then was quenched with water and ethyl
acetate. The organic phase was washed with - water, saturated
aqueous NaCl, and dried over MgSO.sub.4. The solution was stripped
free of solvent on a rotary evaporator to yield the crude
product.
General Procedure X
BOP Coupling Procedure
[1142] A solution of the carboxylic acid (1.0 eq.) and N-methyl
morpholine. (1.5 eq.) in dichloromethane was cooled to -20.degree.
C. under nitrogen. BOP (1.05 eq.) was added in one portion and the
reaction mixture was maintained at -20.degree. C. for 15 minutes.
The appropriate alcohol (1.2 eq.) was added and the reaction
mixture was allowed to warm to room temperature and stirring was
continued for 12 hours. The reaction mixture was then poured into
water and extracted with ethyl acetate (3.times.) and the combined
organic layers were washed with saturated aqueous citric acid
(2.times.), saturated aqueous sodium bicarbonate (2.times.), brine
(1.times.), and then rotoevaporated at reduced pressure to provide
the crude product.
General Procedure Y
BOC Removal Using TFA
[1143] The Boc-protected compound was added to a 1:1 mixture of
dichloromethane and trifluoroacetic acid (TFA) and the reaction
mixture was stirred until tlc indicated complete conversion,
typically 2 hours. The solution was then stripped to dryness. The
residue was suspended in dichloromethane and again stripped to
dryness to remove excess TFA. The residue was placed under high
vacuum for several hours to afford the desired TFA salt.
General Procedure Z
Amide Preparation IV
[1144] The trichlorophenyl ester (1 eq.) was stirred in DMF or THF
and the oxime or amine (1.2 eq.) was added. The mixture was stirred
at ambient temperature for 14 hours. In cases where the
hydrochloride salt form of an amine was used, a suitable base such
as diisdpropylethylamine (1.2 eq.) was also added. The resulting
mixture was concentrated under reduced pressure to yield an oil or
residue which was used without further purification or was purified
by standard procedures, such as silica gel chromatography and/or
recrystallization.
General Procedure AA
Sodium Borohydride Reduction
[1145] The ketone was dissolved in MeOH and treated with 1.0
equivalent of sodium borohydride. The reaction was stirred until
tlc showed the starting material was consumed, typically 1 hour.
The reaction mixture was then evaporated at reduced pressure and
chromatographed to afford the alcohol product.
General Procedure AB
Preparation Amino Acid Derivatives Using Chiral Amines
[1146] (S)-(+)-.alpha.-Methylbenzyl amine was added dropwise to a
solution of 4-(phenyl)benzaldehyde (1 molar eq.) in THF followed by
the addition of 1.0 molar eqivalent of zinc chloride. The reaction
mixture was allowed to stir at room temperature for 5 h. The cloudy
mixture was then cooled to -30.degree. C. and treated with
tert-butylisocyanide (1.05 molar eq.). After 20 minutes,
N-(3,5-difluorophenylacetyl)-L-alanine was added and stirring was
continued at -30.degree. C. for 120 h. The reaction mixture was
then poured into a seperatory funnel and diluted with
CH.sub.2Cl.sub.2, washed with sodium bicarbonate. The organic layer
was then washed with 0.5 N HCl, followed by brine. The organic
layer was then dried over Na.sub.2SO.sub.4, filtered and
concentrated to give
N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-N'-(S)-.alpha.--
methylbenzyl-2-amino-2-(4-phenylphenyl)acetamide, as a mixture of
isomers. At this stage, the isomers were typically separated by
HPLC chromatography using, for example, a gradient of 30 to 35%
EtOAc/hexanes. The .alpha.-methylbenzyl protecting group was then
removed from the S,S isomer by added 10 molar equivalents of
triethylsilane and 20 molar equivalents of trifluoroacetic acid to
the S,S isomer. The reaction was then heated to 37.degree. C. for 3
h and then poured into ethyl acetate and washed with sodium
bicarbonate. The organic layer was dried over Na.sub.2SO.sub.4,
filtered and concentrated. The residue was purified by
recrystallisation from ethyl acetate or ethyl acetate/hexanes.
Various other aldehydes and carboxylic acids can be used in this
procedure to provide for a variety of compounds useful in this
invention.
General Procedure AC
Oxime Reduction II
[1147] To a solution of the oxime ester in the alcohol
corresponding to the ester was added a catalytic amount of acetic
acid and 0.1 mole equivalent of 10% Pd/C. The reaction vessel (Parr
shaker)-was charged with hydrogen to 40 PSI and this mixture was
shaken for 3 h. The reaction mixture was then filtered over HyFlo
and concentrated. The residue was dissolved in ethyl acetate and
washed with a saturated solution of sodium bicarbonate. The organic
layer was then dried over Na.sub.2SO.sub.4, filtered and
concentrated to give the desired amine.
General Procedure AD
Mitsunobu Reaction
[1148] To a solution of
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-tyrosine methyl ester
in 20 mL of THF was added 1.3 equivalents each of
triphenylphosphine and diethyl azodicarboxylate (DEAD), and 1.0
equivalents - of an alcohol. The mixture was stirred a room
temperature overnight and the solvent was then removed. The residue
was purified by standard procedures, such as chromatography and/or
recrystallizadton.
General Procedure AE
O-Alkylation of Tyrosine Derivatives
[1149] To a solution of
N-[N-(3,5-difluorophenylacetyl)-L-alaniyl]-L-tyrosine methyl ester
in 20 mL of acetone was added 1.3 equivalents of an alkyl bromide
and 3.0 equivalents of potassium carbonate as a fine powder and a
catalytic amount of sodium iodide. The reaction mixture was stirred
at room temperature overnight and then partitioned between DCM and
water. The organic layer was dried over anhydrous sodium sulfate,
stripped of solvents and purified using standard procedures, such
as chromatography and/or recrystallization.
General Procedure AF
Hydrolysis of Carboxylic Acid Esters
[1150] A solution of the carboxylic acid ester (1.0 eq.) and
lithium hydroxide (1.1 eq.) in 1:2 water/dioxane was stirred at
23.degree. C. for 1 hour. The reaction mixture was then acidified
to pH 3 with 1 N HCl and extracted with ethyl acetate.
Concentration of the ethyl acetate extracts provided the product.
In some cases, the product was further purified using standard
procedures, such as chromatography and/or recrystallization.
General Procedure AG
Methyl Ester Formation from Amino Acids
[1151] The amino acid (amino acid or amino acid hydrochloride) is
suspended in methanol and chilled to 0.degree. C. HCl gas is
bubbled through this solution for 5 minutes. The reaction is
allowed to warm to room temperature then stirred for 4 hours. The
solvents are then removed to afford the desired amino acid methyl
ester hydrochloride. This product is usually used without further
purification.
General Procedure AH
FEDO Coupling Procedure
[1152] A round bottom flask containing a magnetic stir bar under as
atmosphere of nitrogen at room temperature was charged with THF,
the carboxylic acid (1 eq.), the amine hydrochloride (1.1 eq.) and
EEDQ (1.1 eq.) and the reaction mixture was allowed to stir for 15
minutes. 4-Methylmorpholine (1.1 eq.) was added to the reaction and
stirring was continued at room temperature for 15-20 hours. The
reaction mixture was then concentrated in vacua and the resulting
residue was partitioned between ethyl acetate and water. The
organic phase was separated and washed with saturated aq.
NH.sub.4Cl (2.times.), saturated aq. NaHCO.sub.3 (2.times.),
followed by brine (1.times.). Organic phase dried over
Na.sub.2SO.sub.4. The drying agent was removed by filtration and
the filtrate concentrated in vacuo. The residue was either used
without further purification or purified using standard procedures,
such as flash chromatography on silica gel and/or
recrystallization.
General Procedure AI
N-tert-BOC Protection of Amino Acids
[1153] A round bottom flask containing a magnetic stir bar under an
atmosphere of nitrogen at room temperature was charged with
dioxane, water, 1.0 N aq. sodium hydroxide, and the amino acid (1
eq). Stirring was initiated and the flask was cooled in an ice
bath. Di-t-butyldicarbonate (1.1 eq) was added to the reaction
mixture, followed by removal of the ice bath and slow warming to
room temperature over 1 hour. The reaction was partially
concentrated on the rotary evaporator followed by the addition of
ethyl acetate. The flask was re-cooled in an ice bath and the
mixture was acidified to a pH of 2-3 through the addition of
potassium bisulfate. The reaction was transferred into a seperatory
funnel and the organic layer was separated. The aqueous layer was
extracted with ethyl acetate and the combined organic layers were
dried over Na.sub.2SO.sub.4. The drying agent was removed by
filtration and the filtrate concentrated in vacuo. The solid was
used without further purification.
General Procedure AJ
Removal of N-Carbobenzyloxy (CBZ) Protecting Groups
[1154] A round bottom flask containing a magnetic stir bar under an
atmosphere of nitrogen at room temperature was charged with
methanol, tetrahydrofuran, 20% Pd(OH).sub.2/C (1 mass eq.), and the
CBZ-protected dipeptide. Stirring was initiated and the flask was
purged (3.times.) with hydrogen. The reaction mixture was allowed
to stir at room temperature overnight under an atmosphere of
hydrogen. The reaction was filtered and the filtrate was
concentrated in vacua. The resulting solid was used as is or
purified via silica gel chromatography.
General Procedure AK
Addition of N-Carbobenzyloxy (CBZ) Protecting Groups
[1155] A round bottom flask containing a magnetic stir bar under an
atmosphere of nitrogen at room temperature was charged with water,
sodium carbonate (2.2 eq.), and amino acid (1.0 eq.). The slurry
was stirred at room temperature for 1 hour. Benzylchloroformate was
added to the reaction and stirring was continued overnight. The
reaction mixture was extracted with CH.sub.2Cl.sub.2 (3.times.) and
the combined organic extracts were acidified to a pH of 2-3. The
resulting solid was isolated via vacuum filtration.
General Procedure AL
Preparation of Amino Acid Derivatives Using Chiral Amines II
[1156] A solution of aryl aldehyde (1 molar eq.) in THF was treated
with S-(-)-.alpha.-methylbenzylamine (1 molar eq.), followed by
MgSO.sub.4. The reaction mixture was stirred for 1 hour then
treated with tert-butylisocyanide (1.5-2.0 molar eq.) and
N-(3,5-difluorophenylacetyl)-L-alanine (1.5-2.0 molar eq.). The
reaction was allowed to stir for 60 hours. The reaction was diluted
with methylene chloride and washed with 0.01 N HCl and saturated
aqueous NaHCO.sub.3. Each aqueous wash was back-extracted with
methylene chloride. The combined organics were washed with brine,
dried over Na.sub.2SO.sub.4, filtered and concentrated to give
N-terr-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-N'-R-.alpha.-me-
thylbenzyl-2-amino-2-DL-(aryl)acetamide. At this stage, the isomers
were separated if possible by HPLC chromatography using, for
example, a gradient : of 20 to 25 % ethyl acetate/hexaries. The
.alpha.-methylbenzyl protecting group was then removed from the
peptide by adding 10 molar equivalents of triethylsilane and 20
molar equivalents of trifluoroacetic acid to the compound. The
reaction was heated to 37.degree. C. for 3 hours and then poured
into ethyl acetate and washed with sodium bicarbonate. The organic
layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated.
The residue was purified by trituration with ether or
ether/hexanes. Various other aldehydes, isocyanides, and carboxylic
acid can be used in this procedure to provide for a variety of
compounds useful in this invention.
General Procedure AM
Preparation of Amino Acid Derivatives Using Chiral Amines III
[1157] A solution of an aromatic aldehyde (3 molar eq.) and
S-(-)-.alpha.-methylbenzylamine (1 molar eq.) in methanol was
treated with titanium(IV) isopropoxide (1.5 molar eq.). After
stirring the mixture at ambient temperature for 6 hours,
tert-butylisocyanide (1.1 molar eq.) was added followed by
N-(3,5-difluorophenylacetyl)-L-alanine (1.2 molar eq.) 40 minutes
later. The reaction mixture was stirred for 72 hours. The methanol
was removed via rotary evaporation. The residue was dissolved in
methylene chloride and washed with 0.01 N HCl. The emulsion was
filtered through celite washing with methylene chloride. The layers
were separated; the organic phase was washed with saturated
NaHCO.sub.3 and brine. The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated to give N-tert
butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-N'-R-.alpha.-methylben-
zyl-2-amino-2-DL-(aryl)acetamide. At this stage the isomers were
separated if possible by HPLC chromatography using, for example, a
gradient of 20 to 25% ethyl acetate/hexanes. The
.alpha.-methylbenzyl protecting group was then removed from the
peptide by adding 10 molar equivalents of triethylsilane and 20
molar equivalents of trifluoroacetic acid to the compound. The
reaction was heated to 37.degree. C. for 3 hours and then poured
into ethyl acetate and washed with sodium bicarbonate. The organic
layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated.
The residue was purified by trituration with ether or
ether/hexanes. Various other aldehydes, isocyanides, and carboxylic
acid can be used in this procedure to provide for a variety of
compounds useful in this invention.
General Procedure AN
EEDO Coupling-Procedure II
[1158] To a 1:1 mixture of the corresponding carboxylic acid and
amino ester/amide in THF at 0.degree. C. was added 1.1 equivalents
of EEDQ. The reaction mixture was stirred for 18 hours at
22.5.degree. C. The solvent was removed under reduced pressure or
under a stream of nitrogen and the residue dissolved in EtOAc. The
organic solution was washed 1 time with saturated NaHCO.sub.3
solution, 1 time with N HCl, and dried over MgSO.sub.4. The organic
solution was reduced in vacua to yield the product.
General Procedure AO
Preparation of Primary Amides
[1159] A sealable pressure tube containing a magnetic stir bar
under an atmosphere of nitrogen at room temperature was charged
with a methyl ester (1 eq.), sodium cyanide (0.1 eq.) and a 7M
solution of ammonia in methanol. The tube was sealed and heated to
45.degree. C. with stirring for 18 hours. The reaction was allowed
to cool to room temperature and the resulting precipitate was
isolated by vacuum filtration. The solid was either washed with
methanol or recrystallyzed from ethyl acetate/methanol.
Example 1
Synthesis of Methyl
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanoate
[1160] Following General Procedure A (without the 1N HCl wash) and
using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2).and
norleucine methyl ester hydrochloride (Sigma), the title compound
was prepared as a solid (mp=142-143.degree. C.). The reaction was
monitored by tlc (Rf=0.71 in 10% CH.sub.3OH/CH.sub.2Cl.sub.2, 0.22
in 50% EtOAc/hexanes) and the product was purified by silica plug
chromatography using CH.sub.2Cl.sub.2 as the eluent.
[1161] NMR data was as follows:
[1162] .sup.1H-nmr (CDCl.sub.3): .delta.=6.90 (d, J=7.69 Hz, 1H),
6.80 (m, 3H), 6.70 (m, 1H), 4.62 (quint, 3=7.2 Hz, 1H), 4.48 (m,
1H, 3.72 (s, 3H), 3.51 (s, 2H), 1.78 (m, 1H), 1.60 (m, 1H), 1.36
(d, J=7.02 Hz, 3H), 1.25 (m, 4H), 0.85 (m, 3H).
[1163] .sup.13C-nmr (CDCl.sub.3): .delta.=173.23, 172.69, 169.97,
165.30, 165.12, 162.00, 139.01, 138.88, 138.76, 112.93, 112.83,
112.70, 112.60, 103.63, 103.30, 102.97, 52.94, 49.38, 43.28, 32.32,
27.95, 22.75, 19.23, 14.35.
[1164] C.sub.18H.sub.24F.sub.2N.sub.2O.sub.4 (MW=370.40); mass
spectroscopy (MH.sup.+) 371.
Example 2
Synthesis of N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-histidine
Methyl Ester
[1165] Following General Procedure A and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2) and
L-histidine methyl ester dihydrochloride (Sigma), the title
compound was prepared as a solid (mp=195-197.degree. C.). The
reaction was monitored by tlc (Rf=0.29 in 10%
CH.sub.3OH/CH.sub.2Cl.sub.2).sup.-. NMR data was as follows:
[1166] .sup.1H-nmr (CD.sub.3OD): 3=7.60 (s, 1H), 7.00-6.81 (m, 4H),
4.70 (t, 1H), 4.39 (q, 1H), 3.72 (s, 3H), 3.60 (s, 2H), 3.22-3.00
(m, 2H), 1.38 (d, 3H).
[1167] .sup.13C-nmr (CD.sub.3OD): .delta.=175.46, 172.56, 172.94,
166.64, 166.47, 163.38, 163.20, 141.73, 141.60, 141.47, 136.85,
113.92, 113.82, 113.70, 113.59, 103.89, 103.55, 103.21, 54.55,
53.31, 51.00, 43.21, 43.19, 30.36, 18.44.
[1168] C.sub.18H.sub.20F.sub.2N.sub.4O.sub.4 (MW=394.38); mass
spectroscopy (MH.sup.+) 395.
Example 3
Synthesis of
N-Benzyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanami-
de
[1169] Following General Procedure K and using methyl
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanoate
(from Example 1 above) and benzylamine (Aldrich), the title
compound was prepared as a solid (mp=>200.degree. C). The
reaction was monitored by tlc (Rf=0.29 in 5% CH.sub.3O
H/CH.sub.2Cl.sub.2) and the product was purified by preparative
plate chromatography.
[1170] NMR data was as follows:
[1171] .sup.1H-nmr (CDCl.sub.3): 3=7.05 (m,5H), 6.65 (m, 3H), 4.10
(m, 4H), 3.35 (d, 2H), 1.35 (m, 9H), 0.65 (m, 3H).
[1172] .sup.13C-nmr (CDCl.sub.3): .delta.=175.48, 174.75, 173.16,
166.64, 166.46, 163.37, 141.55, 141.42, 140.38, 130.04, 129.95,
129.05, 128.95, 128.73, 113.94, 113.83, 113.71, 113.60, 103.90,
103.88, 103.56, 103.22, 55.43, 51.26, 44.53, 43.21, 33.38, 29.56,
23.91, 18.28, 14.78.
[1173] C.sub.24H.sub.29F.sub.2N.sub.3O.sub.3 (MW 445.51); mass
spectroscopy (MH.sup.+) 446.
Example 4
Synthesis of
N-2-(N,N-Dimethylamino)ethyl-N'-[N-(3,5difluorophenylacetyl)-L-alaninyl]--
(S)-2-aminohexanamide
[1174] Following General Procedure K and using methyl
N-(N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanoate
(from Example 1 above) and N,N-dimethylethylenediamine (Aldrich),
the title compound was prepared as a solid (mp=182-187.degree. C.).
The reaction was monitored by tlc (Rf=0.51 in 15 % CH.sub.3O
H/CH.sub.2Cl.sub.2) and the product was purified by preparative
plate chromatography using 15% CH.sub.3OH/CH.sub.2C.sub.2 as the
eluent.
[1175] NMR data was as follows:
[1176] .sup.1H-nmr (CDCl.sub.3): .delta.=7.21 (d, 1H), 6.80 (m,
5H), 4.64 (m, 1H), 4.48 (q, 1H), 3.57 (s, 2H), 3.30 (q, 2H), 2.41
(t, 2H), 2.22 (s, 6H), 1.70 (m, 2H), 1.32 (m, 7H), 0.87 (m,
3H).
[1177] .sup.13C-nmr (CDCl.sub.3): .delta.=172.2, 172.0, 170.0,
165.4, 165.3, 163.9, 162.1, 162.0, 139.1, 138.8, 113.1, 112.8,
103.6, 103.3, 103.0, 58.1, 54.0, 49.7, 45.7, 43.3, 38.1, 33.2,
28.2, 23.0, 19.2, 14.4.
[1178] C.sub.21H.sub.32F.sub.2N.sub.4O.sub.3 (MW=426.51); mass
spectroscopy (MH.sup.+) 427.
Example 5
Synthesis of
N-(2-Methoxyethyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-ami-
nohexanamide
[1179] Following General Procedure K and using methyl
N-(N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanoate
(from Example 1 above) and 2-methoxyethylamine (Aldrich), the title
compound-was prepared as a solid (mp=>200.degree. C.). The
reaction was monitored by tlc (Rf=0.42 in 10%
CH.sub.3OH/CH.sub.2Cl.sub.2) and the product was purified by flash
chromatography using 12% CH.sub.3OH/CH.sub.2Cl.sub.2 as the
elueht.
[1180] NMR data was as follows:
[1181] .sup.1H-nmr (CDCl.sub.3): .delta.=7.85 (bd, J=8.79 Hz,
0.5H), 7.64 (bd, J=7.81 Hz, 0.5H), 7.35 (m, 1H), 7.16 (bd, J=7.27
Hz, 0.5H), 7.06 (bs, 0.5H), 6.83 (m, 2H), 6.68 (m, 1H), 4.70 (m,
2H), 3.56 (d, J=9.89 Hz, 2H), 3.40 (m, 7H), 1.57 (m, 10H), 0.84 (m,
3H).
[1182] .sup.13C-nmr (CDCl.sub.3): .delta.=172.62, 172.58, 172.14,
172.04, 170.02, 169.91, 165.33, 165.15, 162.08, 112.99, 112.92,
112.82, 112.77, 112.66, 112.59, 103.54, 103.34, 103.31, 103.29,
71.46, 71.44, 59.27, 59.24, 53:76, 49.64, 49.43, 43.29, 39.79,
33.26, 33.22, 28.10, 28.03, 22.97, 22.91, 19.71, 19.61, 19.56,
19.51; 14.46, 14.43.
[1183] C.sub.20H.sub.29F.sub.2N.sub.3O.sub.4 (MW=413.47); mass
spectroscopy (MH.sup.+) 414.
Example 6
Synthesis of N-2-(N,N-Dimethylamino)ethyl-N
'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamide
[1184] Following General Procedure K and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine methyl
ester (from Example 94 below) and N,N-dimethylethylenediamine
(Aldrich), the title compound was prepared as a solid
(mp=174-182.degree. C.). The reaction was monitored by tlc (Rf=0.31
in 10% CH.sub.3OH/CH.sub.2Cl.sub.2) and the product was purified by
preparative plate chromatography using 10%
CH.sub.3OH/CH.sub.2Cl.sub.2 as the eluent.
[1185] NMR data was as follows:
[1186] .sup.1H-nmr (CD.sub.3OD): .delta.=7.22 (m, 5h), 6.85 (m,
3H), 4.51 (m, 1H), 4.18 (m, 1H), 3.57 (m, 2H), 3.50-2.45 (m, 6H),
2.39 (s, 6H), 1.26 (d, 2.4H), 1.10. (d, 0.6H).
[1187] .sup.13C-nmr (CD.sub.3OD): .delta.=176.03, 175.50, 174.20,
173.99, 173.50, 173.22, 166.63, 166.46, 163.36, 163.19, 141.65,
141.52, 141.39, 139.38, 139.00, 130.90, 130.74, 130.05, 130.01,
128.37, 128.30, 114.03, 113.93, 113.80, 113.70, 103.96, 103.62,
103.57, 103.28, 59.18, 59.14, 56.78, 56.51, 51.93, 51.74, 45.53,
45.47, 43.21, 43.18, 42.92, 38.84, 38.65 37.94, 37.85, 18.09,
17.73.
[1188] C.sub.24H.sub.30F.sub.2N.sub.4O.sub.3 (MW=460.53); mass
spectroscopy (MH.sup.+) 461.
Example 7
Synthesis or
N-(4-Pyridyl)methyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenyl-
alaninamide
[1189] Following General Procedure K and using
N-(N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine methyl
ester (from Example 94 below) and 4-(aminomethyl)pyridine
(Aldrich), the tide compound was prepared as a solid
(mp.=>200.degree. C.). The reaction was monitored by tlc
(Rf=0.46 in 10% CH.sub.3O H/CH.sub.2Cl.sub.2) and the product was
purified by recrystallization from ethyl acetate.
[1190] NMR data was as follows:
[1191] .sup.1H-nmr (CD.sub.3OD): .delta.=8.37 (d, 2H), 7.25 (m,
5H), 7.11 (d, 2H), 6.85 (m, 3H), 4.56 (t, 1H), 4.29 (m, 3H), 3.64
(s, 2H), 3.08 (m, 2H), 1.30 (d, 3H).
[1192] .sup.13C-nmr (CD.sub.3OD): .delta.=175.46, 174.04, 173.26,
166.60, 166.43, 163.34, 163.16, 150.97, 150.44, 141.59, 141.45,
138.84, 130.95, 130.13, 128.44, 124.28, 113.98, 113.87, 113.75,
113.64, 103.91, 103.57, 103.23, 62.08, 57.01, 43.33, 43.12, 38.93,
21.41, 18.16, 15.02.
[1193] C.sub.26H.sub.26F.sub.2N.sub.4O.sub.3 (MW=480.52); mass
spectroscopy (MH.sup.+) 481.
Example 8
Synthesis of
N-(3-Pyridyl)methyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenyl-
alaninamide
[1194] Following. General Procedure K and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine methyl
ester (from Example 94 below) and 4-(aminomethyl)pyridine
(Aldrich), the tide compound was prepared as a solid
(mp=199-210.degree. C.). The reaction was monitored by tlc (Rf=0.46
in 10% CH.sub.3O H/CH.sub.2Cl.sub.2, minor isomer Rf=0.50) and the
product was purified by preparative plate chromatography using 10%
CH.sub.3OH/CH.sub.2Cl.sub.2 as the eluent.
[1195] NMR data was as follows:
[1196] .sup.1H-nmr (CD.sub.3OD): .delta.=8.42 (m, 2H), 7.61 (m,
1H), 7.29 (m, 6H), 6.90 (m, 3H), 4.61 (m, 1H), 4.33 (m, 3H), 3.58
(s, 1.5H), 3.54 (s, 0.5H), 3.10 (m, 2H), 1.33 (d, 2.25H), 1.15 (d,
0.75H).
[1197] .sup.13C-nmr (CD.sub.3OD): .delta.=176.00, 175.34, 174.03,
173.81, 173.23, 166.61, 166.44, 163.35, 163.17, 149.93, 149.20,
141.48, 139.20, 138.72, 138.10, 138.03, 136.88, 136.79, 130.89,
130.70, 130.06, 130.02, 128.40, 128.33, 125.71, 113.97, 113.87,
113.74, 113.64, 103.92, 103.58, 103.53, 103.23, 56.88, 56.66,
55.74, 53.21, 43.22, 43.15, 42.89, 42.06, 41.98, 39.04, 38.88,
38.77, 18.18, 17.79.
[1198] C.sub.26H.sub.26F.sub.2N.sub.4O.sub.3 (MW=480.52); mass
spectroscopy (MH.sup.+) 481.
Example 9
Synthesis of
N-(4Pyridyl)methyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-ami-
nohexanamide
[1199] Following General Procedure K and using methyl
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamide
(from Example 1 above) and 4-(aminomethyl)pyridine (Aldrich), the
title compound was prepared as a solid (mp=181-205.degree. C.). The
reaction was monitored by tlc (Rf=0.51 in 10%
CH.sub.3OH/CH.sub.2Cl.sub.2) and the product was purified by
preparative plate chromatography using 10%
CH.sub.3OH/CH.sub.2Cl.sub.2 as the eluent.
[1200] NMR data was as follows:
[1201] .sup.1H-nmr (CD.sub.3OD): .delta.=8.48 (m, 0.8H), 8.42 (m,
1.2H), 7.37 (d, J=6.10, 0.8H), 7.28 (d, J=6.11, 1.2H), 6.85 (m,
3H), 4.39 (m, 4H), 3.61 (s, 0.8H), 3.53 (d, J=2.99, 1.2H),
2.05-1.25 (m, 9H); 0.90 (m, 3H).
[1202] .sup.13C-nmr (CD.sub.3OD): .delta.=176.61, 175.71, 175.33,
175.29, 173.32, 173.24, 166.49, 166.32, 163.22, 163.05, 151.30,
151.24, 150.55, 150.41, 141.54, 141.41, 124.35, 124.20, 113.95,
113.85, 113.72, 113.62, 103.86, 103.57, 103.52, 103.18, 55.72,
55.64, 51.98, 43.38, 43.19, 42.82, 33.07, 32.57, 29.87, 29,67,
23.90, 23.82, 18.24, 17.86, 14.80.
[1203] C.sub.23H.sub.28F.sub.2N.sub.4O.sub.3 (MW=446.50); mass
spectroscopy (MH.sup.+) 447.
Example 10
Synthesis of tert-butyl
N-[N-(3,5Difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanoate
Step A--t-Butyl Ester Formation
[1204] To a solution of Z-norleucine-OH in CH.sub.2Cl.sub.2 was
added 1.5 equivalents of N,N'-diisopropyl-O-t-butylisourea
(prepared by the method of Synthesis (1979) p.561 for review) and
the reaction was heated to reflux for 17 hours. An additional 1.5
equivalents of isourea was then added, and reflux was continued for
another 7 hours. The reaction was then cooled to room temperature
and filtered through a bed of Celite 545, then stripped to dryness
to leave a clear oil. The residue was dissolved in hexanes and
filtered to remove solids, and the filtrate was washed with
saturated aqueous NaHCO, water, saturated aqueous NaCl, and dried
over MgSO.sub.4. The solution was concentrated under reduced
pressure to leave the product.
Step B--CBZ Removal
[1205] The CBZ-protected amino ester was dissolved in ethanol in a
hydrogenation flask and a catalytic amount of 10% Pd/C was added.
The mixture was hydrogenated at 20 psi H.sub.2 on a Parr shaker for
30 min. The reaction was then filtered through a pad of Celite 545
and stripped free of solvent on a rotary evaporator to yield the
product, norleucine tert-butyl ester hydrochloride.
Step C
[1206] Following General Procedure D and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
the norleucine tert-butyl ester hydrochloride, the title compound
was prepared as a semi-solid. The reaction was monitored by tlc
(Rf=0.41 in 50% EtOAc/hexanes) and the product was purified by
flash chromatography using 50% EtOAc/hexanes as the eluent,
followed by preparative plate chromatography using 50%
EtOAc/hexanes as the eluent.
[1207] NMR data was as follows:
[1208] .sup.1H-nmr (CDCl.sub.3): .delta.=7.63 (d, J=7.7 Hz, 1H),
7.34 (d, J=7.7 Hz, 1H), 6.8 (m, 2H), 6.7 (m, 1H), 4.8 (m, 1H), 4.36
(q, J=5.6 Hz, 1H), 3.52 (s, 2H), 1.8-1.1 (m, 15H), 0.8 (m, 3H).
[1209] .sup.13C-nmr (CDCl.sub.3): 67 =173.0, 171.8, 170.2, 165.1,
165.0, 161.9, 161.7, 139.6., 139.4, 139.3, 112.8, 112.7, 112.6,
112.5, 103.2, 102.9, 102.6, 82.3, 53.6, 49.3, 43.0, 32.2, 28.4,
27.8, 22.7, 19.4, 14.7, 14.2.
[1210] C.sub.21H.sub.30F.sub.2N.sub.2O.sub.4 (MW=412.48); mass
spectroscopy (MH.sup.+) 413.
Example 11
Synthesis of N-[N-(Pent-4enoyl)-alaninyl]-L-phenylalanine Methyl
Ester
[1211] Following General Procedure A and using
N-(L-alaninyl)-L-phenylalanine methyl ester (prepared by coupling
N-BOC-L-alanine (Sigma) and L-phenylalanine methyl ester (Sigma)
using General Procedure A, followed by removal of the BOC-group
using General Procedure Y) and pent-4-enoic acid (Aldrich), the
title compound was prepared as a solid (mp=125.5-126.5.degree. C.).
The reaction was monitored by tlc (Rf=0.32 in 50% EtOAc/hexanes;
0.51 in 10% CH.sub.3OH/CH.sub.2Cl.sub.2) and the product was
purified by flash chromatography using 10% CH.sub.3O
H/CH.sub.2Cl.sub.2 as the eluent.
[1212] NMR data was as follows:
[1213] .sup.1H-nmr (CDCl.sub.3): .delta.=7.27 (bd, J=7.82 Hz, 1H),
7.25-7.05 (m, 5H), 6.72 (bd, J=7.57 Hz, 1H), 5.75 (m, 1H), 4.96 (m,
2H), 4.59 (quint, J=7.2 Hz, 1H), 3.65 (s, 3H), 3.05 (m, 4H),
2.40-2.18 (m, 4H), 1.28 (d, J=7.02 Hz, 3H). .sup.13C-nmr
(CDCl.sub.3): .delta.=173.06, 172.77, 172.36, 137.47, 136.53,
129.76, 129.07, 116.09, 54.10, 52.87, 49.06, 38.31, 25.93, 30.03,
19.17.
[1214] C.sub.18H.sub.24N.sub.2O.sub.4 (MW=332.40); mass
spectroscopy (MNa.sup.+) 355.0.
Example 12
Synthesis of N-[N-(Dec-4-enoyl)-L-alaninyl]-L-phenylalanine Methyl
Ester
[1215] Following General Procedure A and using
N-(L-alaninyl)-L-phenylalanine methyl ester (prepared by coupling
N-BOC-L-alanine (Sigma) and L-phenylalanine methyl ester (Sigma)
using General Procedure A, followed by removal of the BOC-group
using General Procedure Y) and dec-4-enoic acid (prepare from ethyl
dec-4-enoate (ICM) using General Procedure N), the title compound
was prepared as a solid (mp=115.5-117.5.degree. C.). The reaction
was monitored by tlc (Rf=0.52 in 50% EtOAc/hexanes; 0.60 in 10%
CH.sub.3O H/CH.sub.2Cl.sub.2) and the product was purified by flash
chromatography using 10% CH.sub.3O H/CH.sub.2Cl.sub.2 as the
eluent.
[1216] NMR data was as follows:
[1217] .sup.1H-nmr (CDCl.sub.3): .delta.=7.54 (bd, J=7.69 Hz, 1H),
7.22-7.04 (m, 5H), 6.91 (bd, J=7.69 Hz, 1H), 5.37 (m, 2H), 4.73 (q,
J=6.9 Hz, 1H), 4.63 (quint, J=7.2 Hz, 1H), 3.61 (s, 3H), 3.02 (m,
2H), 2.40-2.10 (m, 4H), 1.89 (m, 2H), 1.35-1.13 (m, 9H), 0.82 (m,
3H).
[1218] .sup.13C-nmr (CDCl.sub.3): .delta.=173.26, 173.05, 172.38,
136.65, 132.30, 129.74, 128.99, 128.68, 127.48, 54.19, 52.74,
48.97, 38.28, 36.70, 33.04, 31.93, 29.68, 29.09, 23.06, 19.23,
14.61.
[1219] C.sub.23H.sub.34N.sub.2O.sub.4 (MW=402.54); mass
spectroscopy (MNa.sup.+) 425.0.
Example 13
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-4-[3-(N,N-dimethylamino)propo-
xy]phenylalanine Methyl Ester
[1220] Following General Procedure A and using
N-(3,5difluorophenylacetyl)-L-alanine (from Example B2) and
L-4-[3-(N,N-dimethylamino)propoxy)-phenylalanine methyl ester
(prepared from N-BOC-L-tyrosine methyl ester (Bachem) and
3-dimethylamino-1-propanol (Aldrich) using a Mitsunobu procedure
essentially as: described in General Procedure AD, followed by
removal of the BOC-group using General Procedure Y), the title
compound was prepared as a solid (mp=153-155.degree. C.). The
reaction was monitored by tlc (Rf=0.36 in 10% MeOH/DCM/1%TEA) and
the product was purified by acid/base washes.
[1221] NMR data was as follows:
[1222] .sup.13-nmr (CDCl.sub.3): .delta.=6.973-6.947 (d, 2H);
6.794-6.766 (d, 2H); 6.743-6.714 (d, 2H); 6.735-6.676 (t, 1H);
4.761-4.735 (q, 1H); 4.511-4.463 (q, 1H); 3.967-3.924 (t, 2H);
3.703 (s, 3H); 3473 (s, 2H); 3.019-2.977 (t, 2H); 2.443-2.394 (t,
2H); 2.233 (s, 6H); 1.944-1.897 (t, 2H); 1.319-1.296 (d, 3H).
[1223] .sup.13C-nmr (CDCl.sub.3): .delta.=172.292; 172.256;
169.808; 158.747; 130.731; 127.887; 115.149; 112.900; 112.672;
66.690; 56.945; 54.039; 52.971; 49.400; 46.105; 43.302; 37.421;
28.129; 19.029.
[1224] C.sub.26H.sub.33F.sub.2N.sub.3O.sub.5 (MW=505); mass
spectroscopy (MH.sup.+) 506.
Example 14
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-4[(tert-butyloxycarbonyl)me-
thoxy]phenylalanine Methyl Ester
[1225] Following General Procedure AE and using tert-butyl
bromoacetate (Aldrich) and
N-(N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-tyrosine methyl ester
(from Example 15 below), the title compound was prepared as a solid
(mP=116-119.degree. C.). The reaction was monitored by tlc (Rf=0.54
in 50% EtOAc/hexanes) and the product was purified by silica gel
column chromatography.
[1226] NMR data was as follows:
[1227] .sup.1H-nmr (CDCl.sub.3): .delta.=7.648-7.615 (d, 1H);
7.513-7.407 (d, 1H); 6.943-6.914 (d, 2H); 6.756-6.669 (d+t, 4H);
6.621-6.562 (t, 1H); 4.662-4.590 (q+quintex, 2H); 4.382 (s, 2H);
3.571 (s, 3H); 3.406 (s, 2H); 3.006-2.648 (m, 2H); 1.417 (s,. 9H);
1.243-1.221 (d, 3H).
[1228] .sup.13C-nmr (CDCl.sub.3): .delta.=173.14; 173.001;
172.294;. 170.273; 168.614; 168.546; 165.107; 161.816; 157.428;
139.493; 130.749; 129.385; 115.077; 112.803; 103.250; 828.270;
66.039; 54.361; 52.730; 49.172; 42.832; 37.288; 28.509; 19.018.
[1229] C.sub.27H.sub.32F.sub.2N.sub.2O.sub.7 (MW=534); mass
spectroscopy (MH.sup.+) 535.
Example 15
Synthesis of N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-tyrosine
Methyl Ester
[1230] Following General Procedure A and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
L-tyrosine methyl ester (Bachem), the title compound was prepared
as a solid (mp=85-88.degree. C.). The reaction was monitored by tlc
(Rf=0.27 in 50% EtOAc/hexanes) and the product was purified by
silica gel column chromatography.
[1231] NMR data was as follows:
[1232] .sup.1H-nmr (CDCl.sub.3): 67 =8.036 (b, 1H); 7.369-7.344 (d,
1H); 7.205-7.151 (d, 1M); 6.869-6.841 (d, 2H); 6.763-6.738 (d, 2H);
6.657-6.615 (m, 3H); 4.741-4.697 (q, 1H); 4.566-4.491 (q, 1H);
3.671 (s, 3H); 3.415 (s, 2H); 3.061-2.771 (dm, 2H); 1.271-1.250 (d,
3H).
[1233] .sup.13C-nmr (CDCl.sub.3): .delta.173.049; 172.666; 172.444;
170.768; 165.211; 161.917; 156.098, 130.862; 127.542; 116.093,
112.990; 112.659; 103.236; 61.112; 54.306;.49.441; 42.947;
18.923.
[1234] C.sub.21H.sub.22F.sub.2N.sub.2O.sub.5 (MW 420); mass
spectroscopy (MH.sup.+) 421.
Example 16
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-4-(carboxymethoxy)phenylala-
nine Methyl Ester
[1235] Following General Procedure N and using
N-(N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-[(tert-butyloxycarbonyl)m-
ethoxy]phenylalanine methyl ester (from Example 14 above), the
title compound was prepared. The reaction was monitored by tlc
(Rf=0.49 in 10% MeOH/DCM+1% AcOH) and the product was purified by
silica gel column chromatography.
[1236] NMR data was as follows:
[1237] .sup.1H-nmr (CDCl.sub.3): .delta.=7.817 (s, 1H); 7.648-7622
(d, 1H); 7.544-7.520 (d, 1H), 6.956-6.914 (d, 2H); 6.762-6.703
(d+d, 4H); 6.650-6.590 (t, 1H); 4.678-4.636 (q, 1H); 4.567-4.503
(quinex+s, 3H); 3.622 (s, 3H); 3.431 (s, 2H); 2.987-2.811 (m, 2H);
1.241-1.219 (d, 3H).
[1238] .sup.13C-nmr (CDCl.sub.3): .delta.=173.618; 173.534;
172.215; 171.209; 171.108; 165.148; 164.973; 161.855; 161.683;
157.309; 139.052; 130.887; 129.376; 115.104;. 112.895; 112.667;
103.083; 65.324; 54.155; 52.933; 50.538; 49.384; 42.683; 37.168;
18.678.
[1239] C.sub.23H.sub.24F.sub.2N.sub.2O.sub.7 (MW=478); mass
spectroscopy (MH.sup.+) 479.
Example 17
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-4-(2-morpholinoethoxy)pheny-
lalanine Methyl Ester
[1240] Following General Procedure AD and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-tyrosine methyl ester
(from Example 15 above) and 4-(2-hydroxyethyl)morpholine (Aldrich),
the title compound was prepared as a solid (mp=138-141.degree. C.).
The reaction was monitored by tlc (Rf=0.56 in 10% MeOH/DCM+1% TEA)
and the product was purified by silica gel column chromatography,
followed by trituation using diethyl ether. NMR data was as
follows:
[1241] .sup.1H-nmr (CDCl.sub.3): .delta.=6.974-6.945 (d, 2H);
6.795-6.726 (d+t, 2H); 6.697-6.682 (t, 1H); 4.755-4.689 (q, 1H);
4.535-4.468 (quintex, 1H); 4.0504.012 (t, 2H); 3.723-3.606 (t+s,
7H); 3.463 (s, 2H); 3.039-2.892 (m, 2H); 2.779-2.741 (t, 2H);
2.562-2.531 (t, 4H); 1.297-1.274 (d, 3H).
[1242] .sup.13C-nmr (CDCl.sub.3): .delta.=1721.477; 172.428;
172.303; 169.925; 158.397; 130.778; 128.504; 115.179; 112.988;
112.769; 112.659; 67.457; 66.249; 58.187; 54.631; 54.119; 52.956;
49.358; 43.202; 37.496; 19.028.
[1243] C.sub.27H.sub.33F.sub.2N.sub.3O.sub.6 (MW=533); mass
spectroscopy (MH.sup.+) 534.
Example 18
Synthesis of Methyl
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-6(N,N-dimethylami-
no)hexanoate
[1244] Following General Procedure A and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
N.epsilon.,N.epsilon.-dimethyl-L-lysine methyl ester hydrochloride
(Bachem), the title compound was prepared as a solid
(mp=123-126.degree. C.). The reaction was monitored by tlc (Rf=0.22
in 10% MeOH/DCM+1% TEA) and the product was purified by silica gel
column chromatography.
[1245] NMR data was as follows:
[1246] .sup.1H-nmr (CDCl.sub.3): .delta.=7.019-6.993 (d, 1H);
6.828-6.801 (dd, 2H); 6.753-6.723 (m, 1H); 6.617-6.592 (d, 1H);
4.557-4.447 (q+q, 2H); 3.730 (s, 3H); 3.522 (s, 2H); 2.593-2.572
(m, 2H); 2.196 (s, 6H); 1.837-1.642 (m, 2H); 1.486-1.344 (m+d,
7H).
[1247] .sup.13C-nmr (CDCl.sub.3): .delta.=173.070; 172.544,
169.809; 112.986; 112.655; 103.384: 59.393; 52.991; 49.368; 45.947;
43.427; 43.403; 43.375; 31.870; 27.376; 23.378; 19.155.
[1248] C.sub.20H.sub.29F.sub.2N.sub.3O.sub.4 (MW=413); mass
spectroscopy (MH.sup.+) 414.
Example 19
Synthesis of Methyl
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(2-pyridyl)
propionate
[1249] Following General Procedure A and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2) and methyl
(S)-2-amino-3-(2-pyridyl)propionate hydrochloride (Synthetech), the
title compound was prepared as a solid (mp=121-124.degree. C.). The
reaction was monitored by tlc (Rf=0.39 in 10% MeOH/DCM) and the
product was purified by silica gel column chromatography.
[1250] NMR data was as follows:
[1251] .sup.1H-nmr (CDCl.sub.3): .delta.=8.474-8.458 (d, 1H);
7.767-7.631 (m, 1H); 7.625-7.574 (t, 1H); 7.178-7.102 (t+d, 2H);
6.818-6.811 (d, 2H); 6.73-6.667 (t, 1H); 6.593-6.542 (m, 1H);
4.933-4.873 (m, 1H); 4.566-4.496 (m, 1H); 3.646 (s, 3H); 3.499 (s,
2H); 3.375-3.196 (m, 2H); 1.393-1.370 (d, 3H).
[1252] .sup.13C-nmr (CDCl.sub.3): .delta.=172.453; 172.020;
169.527; 157.454; 149.608; 137.449; 124.366; 124.328; 122.694;
113.032; 112.992; 112.661; 103.333; 53.032; 52.997; 52.349; 52.252;
49.427; 49.405; 43.464, 43.437, 38.486; 19.548; 19.232.
[1253] C.sub.20H.sub.21F.sub.2N.sub.3O.sub.4 (MW=405); mass
spectroscopy (MH.sup.+) 406.
Example 20
Synthesis of Methyl
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-amino3-(3-pyridyl)propi-
onate
[1254] Following General Procedure A and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2) and methyl
(S)-2-amino-3-(3-pyridyl)propionate hydrochloride (Synthetech), the
title compound was prepared as a solid (mp=101-103.degree. C.).
The-reaction was monitored by tlc (Rf=0.48 in 10% MeOH/DCM) and the
product was purified by silica gel column chromatography.
[1255] NMR data was as follows:
[1256] .sup.1H-nmr (CDCl.sub.3): .delta.8.492-8.396 (m, 1H);
8.359-8.322 (m, 1H); 7.505-7.452 (m, 1H); 7.248-7.170 (m, 1H);
6.976-6.908 (m, 1H); 6.855-6.668 (m, 3H); 6.352-6.288 (m, 1H);
4.866-4.798 (m, 1H); 4.784-4.429 (m, 1H); 3.750 (s, 3H); 3.513 (s,
2H); 3.2202.964 (m, 2H); 1.310-1.287 (d, 3H).
[1257] .sup.13C-nmr (CDCl.sub.3): .delta.=172.867; 171.831;
170.307; 161.942; 150.892; 150.753; 148.907; 148.750; 137.523;
137.388; 132.460; 124.106; 124.034; 112.981; 112.754; 103.228;
53.623; 53.461; 53.146; 49.368; 49.259; 43.137; 43.115; 43.086;
35.485; 18.664.
[1258] C.sub.20H.sub.21F.sub.2N.sub.3O.sub.4 (MW=405); mass
spectroscopy (MH.sup.+) 406.
Example 21
Synthesis of N-(N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-proline
Methyl Ester
[1259] Following General Procedure A and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
L-proline methyl ester hydrochloride (Bachem), the title compound
was prepared as a viscous solid. The reaction was monitored by tlc
(Rf=0.57 in 10% MeOH/DCM) and the product was purified by acid/base
washes.
[1260] NMR data was as follows:
[1261] .sup.1H-nmr (CDCl.sub.3): .delta.=7.524-7.498 (d, 1H);
6.813-6.793 (d, 2H); 6.681-6.613 (m, 1H); 4.788-4.717 (m, 1H);
4.484-4.442 (m, 1H);-3.705-3.590 (m+s, 4H); 3.465(s, 2H);
2.217-1.902 (m, 5H); 1.332-1.309 (d, 3H).
[1262] .sup.13C-nmr (CDCl.sub.3): .delta.=172.753; 172.152;
169.843; 165.185; 161.894; 112.953; 112.850; 112.727; 112.624;
103.331, 102.996, 102.662; 59.352; 52.735; 47.495; 47.267; 43.069;
29.472; 25.403; 18.243.
[1263] C.sub.17H.sub.2OF.sub.2N.sub.2O.sub.4 (MW=354); mass
spectroscopy (MH.sup.+) 355.
Example 22
Synthesis of Methyl
1-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]piperidine-2-carboxylate
[1264] Following General Procedure B and using-
N-(phenylacetyl)-L-alanine (from Example B1 above) and methyl
pipecolinate hydrochloride (Aldrich), the title compound was
prepared as an oil. The reaction was monitored by tlc (Rf=0.30 in
50% EtOAc/hexanes) and the product was purified by silica gel
chromatography.
[1265] NMR data was as follows:
[1266] .sup.1H-nmr (CDCl.sub.3): .delta.=7.2 (m, 5H), 6.95 (dd,
J=7.2, 15.2, 7.2 Hz, 1H), 5.21 (dd, J=5.0, 11.0, 5.0 Hz, 1H), 4.89
(q, J=7.1, 7;l Hz, 1H), 3.7 (m, 1H), 3.59 (s, 3H), 3.47 (s, 2H),
3.1 (m, 1H), 2.16 (d, J=11.5 Hz, 1H), 1.4 (m, 4H), 1.22 (dd, J=1.3,
4.4, 1.2 Hz, 3H).
[1267] .sup.13C-nmr (CDCl.sub.3): .delta.=172.6, 171.8, 170.7,
135.5, 129.8, 129.3, 127.6, 52.9, 52.8, 46.0, 43.9, 27.1,.26.8,
25.6, 21.4, 19.9, 18.5.
[1268] C.sub.18H.sub.24N.sub.2O.sub.4 (MW=332); mass spectroscopy
(MH.sup.+) 333.
Example 23
Synthesis of. Methyl
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3(4pyridyl)propio-
nate
Step A--Preparation of 3-(3-pyridyl)alanine methyl ester
dihydrochloride
[1269] Sodium metal (1.40 g, 61 mmol) was dissolved in EtOH (100
mL) and diethyl acetamidomalonate (6.62 g, 30.5 mmol) and
3-picolylchloride hydrochloride (5.00 g, 30.5 mmol) were added. The
mixture was heated to reflux for 6 hours, and then cooled and
filtered to remove NaCl (washed with EtOH). The solvent was removed
in vacuo and the mixture was taken up into saturated aqueous
NaHCO.sub.3 (100 mL) and extracted with EtOAc (3.times.100 m
[1270] The solvent was removed and the residue purified by silica
gel flash chromatography (95:5 CH.sub.2Cl.sub.2/MeOH) to give
diethyl 2-(3-pyridylmethyl)-2-acetamidomalonate (2.84 g, 30%).
[1271] Diethyl 2-(3-pyridylmethyl)-2-acetamidomalonate was
dissolved in 6N HCl (30 mL) and heated to reflux for 19 hours
whereupon it was cooled to room temperature and the HCl solution
was removed by evaporation in vacua. The intermediate amino acid
dihydrochloride salt was taken up into MEOH (30 ML) saturated with
HC1 gas and stirred for 3.5 hours. The MeOH/HCl was removed by
evaporation in vacuo to give 3-(3-pyridyl)alanine methyl ester
dihydrochloride (2.235 g, 100%).
Step B--Preparation of Methyl
N-[N-(3,5Difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(4pyridyl)propio-
nate
[1272] Following General Procedure A and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
methyl (S)-2-amino-3-(4-pyridyl)propionate hydrochloride (prepared
by the method set forth above using 4-picolylchloride
hydrochloride),,the title compound was prepared as a solid. The
reaction was monitored by tlc (Rf=0.49 in 10% MeOH/DCM) and the
product was purified by silica gel column chromatography.
[1273] NMR data was as follows:
[1274] .sup.1H-nmr (CDCl.sub.3): .delta.=8.423-8.335 (dd, 2H);
7.832-7.754 (q, 1H); 7.342-7.246 (dd, 1H); 7.032-6.972 (dd, 2H);
6.764-6.667 (t, 2H); 6.659-6.599 (m, 1H); 4.837-4.768 (m, 1H);
4.590-4.515 (m, 1H); 3.675 (s, 3H); 3.426 (s, 2H); 3.112-2.804 (m,
2H); 1.256-1.106 (dd, 3H).
[1275] .sup.13C-nmr (CDCl.sub.3): .delta.=173.037; 171.739;
170.258; 170.225; 165.201; 165.012; 161.904; 161.721; 150.183;
150.063; 146.115; 146.012; 139.100; 125.180; 125.122; 112.951;
112.915; 112.846; 103.492; 103.153; 53.088, 49.318; 42.977, 37.593;
37.547; 19.297; 18.882.
[1276] C.sub.2OH.sub.21F.sub.2N.sub.3O.sub.4 (MW=405); mass
spectroscopy (MH.sup.+) 406.
Example 24
Synthesis of Methyl
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino-3-methoxypropionate
[1277] Following General Procedure A and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
methyl 2-amino-3-methoxypropionate hydrochloride (Bachem), the tide
compound was prepared as a solid (mp=165-168.degree. C.). The
reaction was monitored by tlc (Rf=0.48 in 10% MeOH/DCM) and the
product was purified by acid/base washes.
[1278] NMR data was as follows:
[1279] .sup.1H-nmr (CDCl.sub.3): .delta.=6.971-6.944 (d, 1H);
6.813-6.801 (m, 2H); 6.741-6.678 (m, 1H); 6.585-6.526 (m, 1H);
4.692-4.561 (quintex+q, 2H); 3.83-3.802 (m, 1H); 3.738 (s, 3H);
3.592-3.516 (m+ds, 3H); 3.312 (s, 3H); 1.408-1.355 (dd, 3H).
[1280] .sup.13C-nmr (CDCl.sub.3): .delta.=172.705; 172.680;
170.908; 113.019; 112.978; 112.687; 112.646; 103.347;. 72.434;
72.405; 59.885; 59.837; 53.263; 53.240; 49.413; 49.329; 19.389;
18.9196.
[1281] C.sub.16H.sub.20F.sub.2N.sub.2O.sub.5 (MW=358); mass
spectroscopy (MH.sup.+) 359.
Example 25
Synthesis of Methyl
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino-3-morpholinopropionat-
e
Step A methyl (2-N-CBZ-amino)-3-morpholino-propionate
[1282] To a solution of N-CBZ-dehydro-alanine methyl ester (Sigma)
in acetonitrile was added 2.0 equivalent of morpholine and 0.25
equivalents of anhydrous ferric chloride. The mixture was stirred
for 16 hours and monitored by TLC. The solvent was stripped off and
the residue extracted with ethyl acetate and washed with 1N HCl.
The aqueous layer was basified with 1N potassium carbonate to pH=9
and extracted with ethyl acetate again, dried over sodium sulfate
and rotovapped to dryness to give methyl
(2-N-CBZ-amino)-3-morpholino-propionate as a clear tan oil. See
Perez et al., Tetrahedron 51(3) 8355-62 (1995)
Step B Methyl
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino-3-morpholinopropionat-
e
[1283] Following General Procedure A and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
methyl 2-amino-3-morpholinopropionate hydrochloride (prepared by
General Procedure O above from methyl
(2-N-CBZ-amino)-3-morpholino-propionate), the title compound was
prepared as a viscous solid. The reaction was monitored by tlc
(Rf=0.44 in 10% MeOH/DCM) and the product was purified by acid/base
washes.
[1284] NMR data was as follows:
[1285] .sup.1H-mnr (CDCl.sub.3): .delta.=7.408-7.384 (d, 1H);
7.247-7.173 (m, 1H); 6.774-6.614 (m+t, 3H); 4.605-4.468 (m, 1H);
3.667 (s, 3H); 3.642 (s, 2H); 3.576-3.561 (t, 4H); 3.479-3.461
(s+s, 2H); 2.639-2.618 (d, 2H); 2.395-2.366 (m, 4H); 1.344-1.307
(t, 3H).
[1286] .sup.13C-nmr (CDCl.sub.3): .delta.=173.120; 172.245;
172.192; 170.275; 170.159; 165.189;. 165.020; 161.897; 161.727;
139.167; 112.937; 112.863; 112.759; 112.610; 112.533; 103.103;
102.774; 67.379; 67.301; 59.346; 59.110; 54.030; 52.936; 51.116;
49.283; 43.053; 18.980; 18.921.
[1287] C.sub.19H.sub.26F.sub.2N.sub.3O.sub.5 (MW=413); mass
spectroscopy (MH.sup.+) 414.
Example 26
Synthesis of
N-(2-Methoxyethyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4(2-mor-
pholinoethoxy)phenylalaninamide
[1288] Following General Procedure K and using 2-methoxyethylamine
(Aldrich) and
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(2-morpholinoethoxy)-phen-
ylalanine methyl ester (from Example 17 above), the title compound
was prepared as a solid (mp=165-168.degree. C.). The reaction was
monitored by tlc (Rf=0.67 in 10% MeOH/DCM+1% TEA), and the product
was purified by acid/base washes.
[1289] NMR data was as follows:
[1290] .sup.1H-nmr (CDCl.sub.3): .delta.=8.258-8.232 (d, 1H);
8.014-7.989 (d, 1H); 7.532-7.370 (t, 1H); 7.035-7.008 (d, 2H);
6.842-6.630 (m, 5H); 4.980-4.905 (m, 1H); 4.794-4.772 (m, 1H);
4.026-3.992 (t, 2H); 3.713-3.642 (t, 4H); 3.594-3.453 (dd, 2H);
3.404-3.267 (t, 2H); 3.179 (s, 3H); 2.930-2.914 (t, 2H);
2.763-2.731 (t, 2H); 2.538-2.502 (m, 4H) 1.335-1.314 (d, 3H).
[1291] .sup.13C-nmr (CDCl.sub.3): .delta.=172.956; 172.918;
171.756; 170.142; 161.677; 158.131; 130.973; 129.270; 1.14.968;
114.875; 112.908; 112.696; 112.571; 71.423; 71.367; 67.440; 66.164;
59.072; 58.232; 58.188; 54.636; 42.827; 42.800; 39.757; 39.642;
20.449; 20.135.
[1292] C.sub.29H.sub.38F.sub.2N.sub.4O.sub.6 (MW=576); mass
spectroscopy (MH.sup.+) 577.
Example 27
Synthesis of
[1293]
N-(2-Methoxyethyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2--
amino-3-methoxypropionamide
[1294] Following General Procedure K and using 2-methoxyethylamine
(Aldrich) and methyl
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-methoxypropionate
(from Example 24 above), the title compound was prepared as a solid
(mp=181-184.degree. C.). The reaction was monitored by tlc (Rf=0.43
in 10% MeOH/DCM) and the product was purified by acid/base
washes.
[1295] NMR data was as follows:
[1296] .sup.1H-nmr (CDCl.sub.3): .delta.=6.728-6.706 (d, 2H);
6.648-6.586 (t, 1H); 4.244-4213 (m, 1H); 4.092-4.068 (m, 1H);
3.553-3.503 (m, 2H); 3.393-3.347 (m, 2H); 3.210-3.073 (m+s, 7H);
3.053 (s, 3H); 1.183-1.138 (d, 3H).
[1297] .sup.13C-nmr (CDCl.sub.3): .delta.=176.31; 173.28; 172.59;
141.65; 114.02; 113.79; 113.69; 109.467; 103.528; 80.369; 73.210;
72.265; 72.011; 59.839; 59.801; 59.374; 55.584; 51.773;.51.731;
51.445; 42.915; 40.846; 17.751.
[1298] C.sub.18H.sub.25F.sub.2N.sub.3O.sub.5 (MW=401); mass
spectroscopy (MH.sup.+) 402.
Example 28
Synthesis of N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]glycine
Methyl Ester
[1299] Following General Procedure A and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
glycine methyl ester hydrochloride (Bachem), the title compound was
prepared as a solid (mp=158-160.degree. C.). The reaction was
monitored by tlc (Rf=0.61 in 10%MeOH/DCM) and the product was
purified by silica gel chromatography.
[1300] NMR data was as follows:
[1301] .sup.1H-nmr (CDCl.sub.3): .delta.6.882-6.866 (m, 1H);
6.827-6.794 (m, 2H); 6.748-6.689 (t, 1H); 6.520-6.494 (d, 1H);
4.611-4.563 (quintex, 1H); 4.00-3.99 (d, 2H); 3.746 (s, 3H); 3.528
(s, 2H); 1.389-1.366 (d, 3H).
[1302] .sup.13C-nmr (CDCl.sub.3): .delta.=172.926; 172.524;
170.524; 113.056; 112.951; 112.723; 103.769; 103.437; 103.214;
103.105; 85.309; 53.009; 49.333; 43.292; 41.692; 18.810.
[1303] C.sub.14H.sub.16F.sub.2N.sub.2O.sub.4 (MW 314); mass
spectroscopy (MH.sup.+) 315.
Example 29
Synthesis of
N-(2-Methoxyethyl)-N-'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino--
3-(4pyridyl)propionamide
[1304] Following General Procedure K and using 2-methoxyethylamine
and methyl
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(4-pyrid-
yl)propionate (from Example 23 above), the title compound was
prepared as a sold (mp=202-206.degree. C.). The reaction was
monitored by tlc (Rf=0.72 in 10%MeOH/DCM) and the product was
purified by acid/base washes.
[1305] NMR data was as follows:
[1306] .sup.1H-nmr (CDCl.sub.3): .delta.=8.214-8.198 (d, 2H);
7.117-7.100 (d, 2H); 6.707-6.687 (m, 2H); 6.638-6.576 (t, 1H);
4.498-4.448 (m, 1H); 3.985-3.939 (q, 1H); 3.386 (s, 2H);
3.190-3.084 (m, 4H); 3.060 (s, 3H); 2.918-2.629 (m, 2H);
1.077-0.905 (d, 3H).
[1307] .sup.13C-nmr (CDCl.sub.3): .delta.=175.831; 173.229;
150.440; 150.249; 126.887; 113.995; 113.662; 103.662; 103.529;
72.081; 59.370; 55.201; 51.674; 42.949; 40.889; 38.350; 17.933.
[1308] C.sub.22H.sub.26F.sub.2N.sub.4O.sub.4 (MW=448); mass
spectroscopy (MH.sup.+) 449.
Example 30
Synthesis of N-(2-Methoxyethyl)-N
'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-(2-pyridyl)
propionamide
[1309] Following General Procedure K and using 2-methoxyethylamine
and methyl
N-(N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(2-pyrid-
yl)propionate (from Example 19 above), the title compound was
prepared as a solid (mp 183-187.degree. C.). The reaction was
monitored by tlc (Rf=0.39 in 10% MeOH/DCM) and the product was
purified by recrystallization from MeOH/DCM.
[1310] NMR data was as follows:
[1311] .sup.1H-nmr (CDCl.sub.3): .delta.=8.457-8.442 (d, 1H);
8.029-8.005 (d, 1.H); 7.642-7.585 (t, 1H); 7.395-7.379 (m, 1H);
7.267-7.141 (d+t, 2H); 6.828-6.802 (m, 2H); 6.754-6.679 (t, 1H);
6.604-6.581 (m, 1H); 4.871-4.809 (q, 1H); 4.532-4.485 (quintex,
1H); 3.537 (s, 2H); 3.342-3.118 (m, 6H); 3.248 (s, 3H); 1.394-1.371
(d, 3H).
[1312] .sup.13C-nmr (CDCl.sub.3): .delta.=172.360; 171.140; 158.43;
149.113; 137.59; 124.98; 122.54; 113.02; 112.69; 103.40; 71.376;
59.203; 53.143; 49.984; 43.355; 43.328; 39.685; 39.626; 19.295.
[1313] C.sub.22H.sub.26F.sub.2N.sub.4O.sub.4 (MW=448); mass
spectroscopy (MH.sup.+) 449.
Example 31
Synthesis of Methyl
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(thiazol-4yl)pr-
opionate
[1314] Following General Procedure A and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
methyl (S)-2-amino-3-(thiazol-4-yl)propionate hydrochloride
(General Procedure H with methanol and HCl on methyl
(S)-2-amino-3-(thiazol-4-yl)propyl acid (Synthetech)), the title
compound was prepared as a solid (mp=136-139.degree. C.). The
reaction was monitored by tlc (Rf=0.4 in 10% MeOH/DCM) and the
product was purified by recrystallization from DCM.
[1315] NMR data was as follows: .sup.1H-nmr (CDCl.sub.3):
.delta.=8.737-8.731 (d, 1H); 7.410-7.385 (d, 1H); 7.065-7.059 (d,
1H); 6.828-6.802 (m, 2H); 6.747-6.687 (m, 1H); 6.542-6.518 (d, 1H);
4.904-4.844 (q, 1H); 4.553-4.505 (quintex, 1R); 3.678 (s, 3H);
3.515 (s, 2H); 3.402-3.232 (dq, 2H); 1.384-1.361 (d, 3H).
[1316] .sup.13-nmr (CDCl.sub.3): .delta.=172.497; 171.726; 169.619;
153.831; 152.613; 116.431; 113.019; 112.688; 112.014; 103.396;
53.113; 52.625; 49.476; 43.460.; 43.435; 32.850; 19.422.
[1317] C.sub.18H.sub.19F.sub.2N.sub.3O.sub.4S (MW=411); mass
spectroscopy (MH.sup.+) 412.
Example 32
Synthesis of Methyl
2-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-1,2,3,-tetrahydroisoquinoline-
-3-carboxylate
[1318] Following General Procedure A and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
methyl 1,2,3,4-tetrahydroisoquinoline-3-carboxylate (Aldrich), the
title compound was prepared as a solid (mp=37-40.degree. C.). The
reaction was monitored by tlc (Rf=0.64 in 10% MeOH/DCM).
[1319] NMR data was as follows:
[1320] .sup.1H-nmr (CDCl.sub.3): .delta.=7.500-7.475 (d, 1H);
7.161-7.057 (m, 4H); 6.815-6.795 (dm, 2H); 6.656-6.596 (t, 1H);
5.336-5.088 (m, 2H); 4.924-4.841 (m, 1H); 4.718-4.453 (m, 1H);
3.530 (s, 3H); 3.500 (s, 2H); 3.329-3.058 (m, 2H); 1.423-1.400,
1.327-1.304 (d, 3H).
[1321] .sup.13C-nmr (CDCl.sub.3): .delta.=173.428; 173.329;
171.690; 171.559; 169.558; 165.020; 161.899; 161.728; 139.368;
132.549; 128.912; 127.723; 126.648; 112.929; 103.360; 60.915;
53.318; 53.001; 46.377; 43.121; 31.027; 21.537; 19.545; 18.771;
14.716.
[1322] C.sub.22H.sub.22F.sub.2N.sub.2O.sub.4 (MW=416); mass
spectroscopy (MH.sup.+) 417.
Example 33
Synthesis of
N-(3-Methoxybenzyl)-N'-[N-(3,5difluorophenylacetyl)-L-alaninyl]-L-phenyla-
laninamide
[1323] Following General Procedure B and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine
(prepared by coupling N-(3,5-difluorophenylacetyl)-L-alanine (from
Example B2 above) with L-phenylalanine methyl ester hydrochloride
(Sigma) using General Procedure E, followed by hydrolysis using
General Procedure C) and 3-methoxybenzylamine (TCI), the title
compound was prepared as a solid (mp=117-130.degree. C.). The
reaction was monitored by tlc (Rf=0.8 in 3% MeOH/methylene
chloride) and the product was purified by recrystallization from
MeOH.
[1324] NMR data was as follows:
[1325] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.4 (t, 1H), 8.32 (d,
1H), 8.1 (d, 1H), 6.95-7.2 (m, 9H), 6.7 (m, 3H), 4.5 (m, 1H), 4.2
(m, 3H), 3.7 (s, 3H), 3.5 (s, 2H), 3.3 (d, 2H), 3.0 (m, 2H), 2.5
(s, 3H), 1.2 (m, 4H).
[1326] .sup.13C-nmr (DMSO-d.sub.6): .delta.=172.40, 171.08, 169.28,
159.62, 141.09, 138.06, 129.62, 129.51, 128.41, 126.63, 119.56,
112.97, 112.79, 112.59, 112.46, 55.31, 48.77, 40.69, 40.42, 40.28,
40.14, 40.03, 39.86, 39.70, 39.58, 39.46, 39.44, 39.31, 39.20,
39.03, 18.45.
[1327] C.sub.28H.sub.29N.sub.3O.sub.4F.sub.2 (MW=509); mass
spectroscopy (MH.sup.+) 509.
Example 34
Synthesis of Methyl
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(1-naphthyl)pro-
pionate
[1328] Following General Procedure B and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
methyl (S)-2-amino-3-(1-naphthyl)propionate hydrochloride (Bachem),
the tide compound was prepared as a solid (mp=103-130.degree. C.).
The reaction was monitored by dc (Rf=0.8 in 5% MeOH/methylene
chloride) and the product was purified by flash column
chromatography using 6% MeOH/methylene chloride as the eluent.
[1329] NMR data was as follows:
[1330] .sup.1H-nmr (CDCl.sub.3): .delta.=8.10 (d, 1H), 7.85 (d,
1H), 7.71 (d, 1H), 7.50 (m, 3H), 7.35 (t, 1H), 7.20 (d, 1H), 6.70
(m, 4H), 6.30 (d, 1H), 4.90 (m, 1H), 4.45-(m, 1H), 3.3-3.7 (m, 8H),
1.7 (bs, 1H), 1.3 (d 3H).
[1331] .sup.13C-nmr (CDCl.sub.3): .delta.=172.43, 172.29, 169.77,
134.41, 132.61, 132.58, 129.51, 128.63, 128.33, 128.28, 128.06,
126.97, 126.80, 126.42, 126.29, 125.94; 125.86, 124.06, 123.90,
112.96, 112.63, 103.44, 78.03, 77.61, 77.19, 61.01,.54.02, 53.83,
52.99, 51.40, 49.33, 43.29, 35.64, 18.82, 14.77.
[1332] C.sub.24H.sub.24N.sub.2O.sub.4F.sub.2 (MW=442); mass
spectroscopy (MH.sup.+) 442.
Example 35
Synthesis of Methyl
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(2-naphthyl)pro-
pionate
[1333] Following General Procedure B and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
methyl (S)-2-amino-3-(2-naphthyl)propionate hydrochloride (Bachem),
the title compound was prepared as a solid (mp=166.degree. C.). The
reaction was monitored by dc (Rf=0.55 in 5% MeOH/methylene
chloride) and the product was purified by preparative tlc using 5%
MeOH/methylene chloride as the eluent.
[1334] NMR data was as follows:
[1335] .sup.1H-nmr (CDCl.sub.3): .delta.=1.3 (d, 3H), 3.2 (m, 2H),
3.3 (s, 2H)., 3.7 (s, 3H), 4.55 (m, 1H), 4.9 (quart, 1H), 6.7 (m,
4H), 7.05 (d, 1H), 7.20 (d, 1H), 7.45 (m, 2H), 7.55 (s, 1H), 7.80
(m, 3H).
[1336] .sup.13C-nmr (CDCl.sub.3): .delta.=172.43, 172.26, 169.86,
133.93, 133.76, 133.02, 128.86, 128.64, 128.23, 128.20, 127.69,
126.85, 126.45, 112.95, 112.62, 103.37, 78.05, 77.62, 77.20, 53.93,
53.05, 49.37, 43.12, 38.46, 18.81.
[1337] C.sub.24H.sub.24N.sub.2O.sub.4F.sub.2 (MW=442); mass
spectroscopy (MH.sup.+) 442.
Example 36
Synthesis of Methyl
N-(N-(3,5Difluorophenylacetyl)-L-alaninyl]-(S)-2-amino3-(2-thienyl)propio-
nate
[1338] Following General Procedure B and using
N-(3,5difluorophenylacetyl)-L-alanine (from Example B2 above) and
methyl (S)-2-amino-3-(2-thienyl)-propionate (Bachem), the title
compound was prepared as a solid (mp=145-147.degree. C.). The
reaction was monitored by tlc (Rf=0.9 in 100% EtOAc) and the
product was purified by preparative tlc using EtOAc as the
eluent.
[1339] NMR data was as follows:
[1340] .sup.1H-nmr (CDCl.sub.3): .delta.=7.15 (d, 1H), 6.9 (t, 1H),
6.7-6.8 (m, 5H); 6.3 (d, 1H), 4.8 (m, 1H), 4.5 (m, 1H), 3.8 (s,
3H), 3.5 (s, 2H), 3.35 (d, 2H), 1.35 (d, 3H).
[1341] .sup.13C-nmr (CDCl.sub.3): .delta.=172.22, 171.56, 169.79,
137.47, 127.71, 125.55, 113.04, 112.71, 103.48, 78.03, 77.60,
77.18, 53.78, 53.25, 49.51, 43.41, 32.37, 18.97.
[1342] C.sub.19H20N.sub.2O.sub.4F.sub.2S (MW=410); mass
spectroscopy (MH.sup.+) 410.
Example 37
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-phenylalanine Benzyl
Ester
[1343] Following General Procedure B and
using-N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2
above) and L-phenylalanine benzyl ester hydrochloride (Bachem), the
title compound was prepared as a solid (mp=170-171.degree. C.). The
reaction was monitored by tlc (Rf=0.7 in 5% MeOH/methylene
chloride) and the product was purified by recrystallization from
MeOH.
[1344] NMR data was as follows:
[1345] .sup.1H-nmr (MeOH): .delta.=7.3 (m, 10H), 6.9 (m, 3H), 5.2
(s, 2H), 4.75 (t, J=7 Hz, 1H), 4.4 (quart, J=6 Hz, 1H), 3.6 (s,
2H), 3.1 (m, J=6 Hz, 1.35 (d, J=7 Hz, 3H).
[1346] .sup.13C-nmr (MeOH): .delta.175.29, 173.09, 172.78, 141.54,
138.35, 137.53, 130.88, 130.08, 130.05, 129.92, 128.42, 113.93,
113.83, 113.60, 103.90, 103.55, 103.21,.68.59, 55.87.
[1347] C.sub.27H.sub.26N.sub.2O.sub.4F.sub.2 (MW=480); mass
spectroscopy (MH.sup.+) 480.
Example 38
Synthesis of
N-(N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-phenylalanine
3-Bromopropyl Ester
[1348] Following General Procedure B and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine
(prepared by coupling N-(3,5-difluorophenylacetyl)-L-alanine (from
Example B2 above) and L-phenylalanine (Aldrich) using General
Procedure B) and 3-bromo-1-propanol (Aldrich), the title compound
was prepared as a solid (mp.=138-142.degree. C.). The reaction was
monitored by tlc (Rf 0.75 in 60% EtOAc/hexanes) and the product was
purified by flash column chromatography using 60% EtOAc/hexanes as
the eluent.
[1349] NMR data was as follows:
[1350] .sup.1H-nmr (CDCl.sub.3): .delta.=7.3-6.6 (m, 10H), 4.8 (m,
1H), 4.55 (m, 1H), 4.2 (t, J=6 Hz, 2H), 3.51 (s, 2H), 3.3 (m, 2H),
3.05 (m, J=6 and 8 Hz, 2H), 2.1 (m, 2H), 1.3-1.2,(m, J=7 Hz,
3H).
[1351] .sup.13C-nmr (CDCl.sub.3): .delta.=172.49, 171.78, 171.71,
170.01, 169.96, 165.31, 162.02, 161.84, 138.91, 138.78, 138.66,
136.26, 136.19, 129.76, 129.72, 129.22, 129.18, 127.80, 113.04,
113.02, 112.93, 112.91, 112.82, 112.79, 112.71, 112.69, 103.72,
103.69, 103.36, 103.05, 103.03, 63.75, 63.70, 54.11, 53.91, 49.38,
49.32, 43.26, 38.56, 38.51, 31,92, 29.76, 29.71, 19.14, 19.06.
[1352] C.sub.23H.sub.25N.sub.2O.sub.4F.sub.2Br (MW=511.1); mass
spectroscopy (MH.sup.+) 512.
Example 39
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl-L-phenylalanine
3-Iodopropyl Ester
[1353] Following General Procedure B and using
N-(N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine
(prepared by coupling N-(3,5-difluorophenylacetyl)-L-alanine (from
Example B2 above) and L-phenylalanine (Aldrich) using General
Procedure B) and 3-iodo-1-propanol (Aldrich), the title compound
was prepared as a solid. The reaction was monitored by tlc (Rf=0.45
in 5% MeOH/methylene chloride) and the product was purified by
preparative tlc using 5% MeOH/methylene chloride.
[1354] NMR data was as follows:
[1355] .sup.1H-nmr (CDCl.sub.3): .delta.=7.4-7.0 (m, 5H), 6.9-6.6
(m, 4H), 6.3 (m, 1H), 4.8 (m, 1H), 4.5 (m, 1H), 4.2 (t, 2H), 3.5
(s, 2H), 3.1 (m, 4H), 2.1 (m, 2H), 1.7 (s, 1H), 1.35-1.25 (m,
3H).
[1356] .sup.13C-nmr (CDCl.sub.3): .delta.=172:24, 171.72, 169.95,
136.12, 136.09, 129.77, 129.75, 129.28; 129.24, 127.87, 113.06,
113.02, 112.73, 112.70, 103.80, 103.49, 103.47, 65.73, 65.70,
54.00, 53.84, 49.42, 49.33, 43.38, 38.54, 38.50, 32.57, 18.97,
18.91.
Example 40
Synthesis of N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-leucine
tert-Butyl Ester
[1357] Following General Procedure B and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
L-leucine tert-butyl ester hydrochloride (Bachem), the title
compound was prepared as a solid (mp=128.degree. C.). The reaction
was monitored by tlc (Rf=0.85 in 5% MeOH/methylene chloride) and
the product was purified by flash column chromatography using 5%
MeOH/methylene chloride as the eluent.
[1358] NMR data was as follows:
[1359] .sup.1H-nmr (CDCl.sub.3): .delta.=6.9-6.5 (m, 5H), 4.6 (m,
1H), 4.4 (m, 1H), 3.5 (s, 2H), 1.7-1.4 (m, 15H); 0.9 (t, 6H).
[1360] .sup.13C-nmr (CDCl.sub.3): .delta.=172.41, 172.20, 169.87,
165.30, 162.00, 161.83, 139.01, 138.89, 112.92, 112.82, 112.69,
112.59, 103.62, 103.29, 102.95, 82.50, 78.03, 77.61, 77.18, 52.12,
49.39, 43.34, 41.86, 28.52, 25.42, 23.26, 22.46, 19.18.
[1361] C.sub.27H.sub.30N.sub.2O.sub.4F.sub.2 (MW=412.48); mass
spectroscopy (MH.sup.+) 413.
Example 41
Synthesis of
N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-pyridyl)acetami-
de
[1362] Following General Procedure L and using ethyl
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-pyridyl)acetate
(from Example 65 below), the title compound was prepared as a
solid. The reaction was monitored by tlc (Rf=0.1 in 9:1
CHCl.sub.3/MeOH) and the product was purified by recrystallization
from EtOH.
[1363] NMR data was as follows:
[1364] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.54 (m, 1H), 8.43 (d,
1H), 7.77 (m, 1H), 7.59 (bs, 1H), 7.46 (m, 1H), 7.33 (m, 1H), 7.22
(m, 1H), 7.09 (m, 1H), 6.98 (m, 2H), 5.41 (m, 1H), 4.46 (m, 1H),
4.46 (m, 1H), 3.52 (s, 2H), 1.26 (m, 3H).
[1365] C.sub.18H.sub.17N.sub.3O.sub.3F.sub.2 (MW=376.3); mass
spectroscopy (MH.sup.+) 377.
Example 42
Synthesis of
N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-pyridyl)acetami-
de
[1366] Following General Procedure L and using ethyl
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-pyridyl)acetate
(from Example 53 below), the title compound was prepared as a
solid. The reaction was monitored by tlc (Rf=0.1 in 9:1
CHCl.sub.3/MeOH) and the product was purified by recrystallization
from EtOH.
[1367] NMR data was as follows:
[1368] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.64 (m, 1H), 8.55 (d,
1H), 8.52 (d, 1H), 8.41 (d, 1H), 7.79 (m, 1H), 7.37 (m, 1H), 7.32
(m, 1H), 7.09 (m, 1H), 6.98 (m, 2H), 5.42 (m, 1H), 4.42 (m, 1H),
3.53 (s, 2H), 1.26 (m, 3H).
[1369] C.sub.18H.sub.17N.sub.4O.sub.3F.sub.2 (MW 376.3); mass
spectroscopy (MH.sup.+) 377.
Example 43
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-N,-(tert-butoxycarbonyl)-L-ly-
sine Methyl Ester
[1370] Following General Procedure A and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
NE-(tert-butoxycarbonyl)-L-lysine methyl ester (Bachem), the title
compound was prepared as an oil. The reaction was monitored by tlc
(Rf=0.40 in 50% EtOAc/hexanes) and the product was purified by
flash chromotography using 50% EtOAc/hexanes as the eluent.
[1371] NMR data was as follows:
[1372] .sup.1H-nmr (CDCl.sub.3): .delta.=6.80 (d, 2H), 6.66 (t,
1H), 4.82 (bs, 1H), 3.73 (s, 3H), 3.52 (s, 2H), 3.04 (bs, 2H),
1.60-1.15 (m, 2H), 1.38 (s, 9H), 1.32 (d, 2H), 1.20-1.30 (m,
2H).
[1373] .sup.13C-nmr (CDCl.sub.3): .delta.=173.00, 172.80,.165.28,
165.1l, 161.98, 161.78, 156.79, 138.95, 129.06, 128.72, 103.59,
103.26, 102.92, 79.81, 52.99, 52.76, 49.44, 43.25, 31.92,
29.98,-28.99, 22.95, 18.94.
[1374] C.sub.23H.sub.33F.sub.2N.sub.3O.sub.6 (MW=485.53); mass
spectroscopy (MH.sup.+) N/A.
Example 44
Synthesis of Methyl
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-phenylbutanoate
[1375] Following General Procedure A and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
methyl (S)-2-amino4-phenylbutanoate (prepared from
(+)-.alpha.-amino-4-phenylbutyric acid (Bachem) using General
Procedure AG), the tide compound was prepared as a solid
(mp=147-149.5.degree. C.). The reaction was monitored by tlc
(Rf=0.32 in 50% EtOAc/hexanes) and the product was purified by
flash chromatography using EtOAc/hexanes as the eluent.
[1376] NMR data was as follows:
[1377] .sup.1H-nmr (CDCl.sub.3): .delta.=7.63 (bd, 2H), 7.04.(m,
5H), 6.56-6.82 (m, 3H), 4.80 (p, 1H), 4.48 (q, 1H), 3.65 (s, 3H),
3.49 (s, 2H), 2.50-2.65 (m, 2H), 1.80-2.16 (m, 2H), 1.29 (d,
3H).
[1378] .sup.13C-nmr (CDCl.sub.3): .delta.=173.48, 172.89, 170.43,
165.17, 161.71, 140.91, 139.34, 129.07, 129.01, 128.89, 126.81,
126.76, 112.90, 112.67, 103.37, 103.03, 102.69, 52.86, 52.71,
49.36, 42.99, 33.79, 32.21, 19.34.
[1379] C.sub.22H.sub.24F.sub.2N.sub.2O.sub.4 (MW=418.44); mass
spectroscopy (MH.sup.+) 419.
Example 45
Synthesis of N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]glycine
2-Phenylethyl Ester
[1380] Following General Procedure X and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine (prepared from
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine-benzyl ester
(from Example 73 below) using General Procedure O) and
2-phenylethanol (Aldrich), the title compound was prepared as a
solid (mp=154.0-155.2.degree. C.). The reaction was monitored by
tlc (Rf=0.15 in 15% EtOAc/hexanes) and the product was purified by
flash chromotography using 15% EtOAc/hexanes as the eluent.
[1381] NMR data was as follows:
[1382] .sup.1H-nmr (CDCl.sub.3): .delta.=7.35-7.20 (m, 5H), 6.76
(bs, 1H), 6.72-6.67 (m, 3H), 6.54 (bd,,1H), 4.58 (p, 1H), 4.34 (t,
2H), 3.96 (d, 2H), 3.52 (s, 2H), 2.93 (t, 2H), 1.26 (d, 3H).
[1383] .sup.13C-nmr (CDCl.sub.3): .delta.=172.9, 170.1, 169.9,
137.8, 129.4, 129.1, 127.3, 112.94, 103.4, 103.0, 65.5, 49.3, 43.2,
41.8, 35.4, 18.8.
[1384] C.sub.21H.sub.22N.sub.2O.sub.4F.sub.2 (MW=404.42); mass
spectroscopy (MH.sup.+) 405.
Example 46
Synthesis of N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]glycine
3-Phenylpropyl Ester
[1385] Following General Procedure X and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine (prepared from
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine benzyl ester
(from Example 73 below) using General Procedure O) and and
3-phenyl-1-propanol (Aldrich), the title compound was prepared as a
solid (mp=137.degree. C.). The reaction was monitored by tlc
(Rf=0.15 in 50% EtOAc/hexanes) and the product was purified by
flash chromatography using 50% EtOAc/hexanes as the eluent.
[1386] NMR data was as follows:
[1387] .sup.1H-nmr (CDCl.sub.3): .delta.=7.55-7.32 (m, 5H), 6.73
(d,.2H), 6.65 (m, 1H), 4.74 (p, 1H), 4.14 (t, 2H), 3.93 (m, 2H),
3.49 (s, 2H), 2.66 (t, 2H), 194 (p, 2H), 1.41 (d, 3H).
[1388] .sup.13C-nmr (CDCl.sub.3): .delta.=173.8, 170.5, 170.1,
165.2, 165.0, 161.9, 161.7, 141.5, 139.2, 129.1, 128.9, 126.7,
112.9, 112.8, 103.4, 103.1, 102.8, 65.4, 49.3, 42.9, 41.8, 32.6,
30.6, 19.3.
[1389] C.sub.22H.sub.24N.sub.2O.sub.4F.sub.2 (MW=418.44); mass
spectroscopy (MH.sup.+) 419.
Example 47
Synthesis of
N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl-2-amino-2-(4pyridyl)acetamide
[1390] Following General Procedure L and using ethyl
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4-pyridyl)acetate
(from Example 66), the title compound was prepared as a solid. The
reaction was monitored by tlc. (Rf=0.1 in CHCl.sub.3/MeOH 9:1) and
the product was purified by silica gel chromatography using 9:1
CHCl.sub.3/MeOH as the eluent.
[1391] NMR data was as follows:
[1392] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.53 (m, 2H), 8.88 (bs,
1H), 7.41 (m, 2H), 7.12 (m, 1H), 7.02 (m, 2H), 5.46 (m, 1H), 4.46
(m, 1H), 3.55 and 3.52 (s, 2H), 1.21 (m, 3H).
[1393] C.sub.18H.sub.18N.sub.4O.sub.3F.sub.2 (MW=376.3); mass
spectroscopy (MH.sup.+) 377.
Example 48
Synthesis of N-[N-(Phenylacetyl)-L-alaninyl]-L-threonine Methyl
Ester
[1394] Following General Procedure U and-using
N-(phenylacetyl)-L-alanine (from Example B1 above) and L-threonine
methyl ester hydrochloride (Bachem), the title compound was
prepared as a solid.
[1395] NMR data was as follows:
[1396] .sup.1H-nmr (CDCl.sub.3): .delta.=7.45 (d, J=8.9 Hz, 1H),
7.11-7.27 (m, 6H), 4.55 (quintet, J=7.2 Hz, 1H), 4.43 (dd,
J=2.6,8.8 Hz, 1H), 4.20 (m, 1H), 3.62 (s, 3H), 3.46 (s, 2H), 1.29
(d, J=7.0 Hz, 3H), 1.04 (d; J=6.4 Hz, 3H).
[1397] .sup.13C-nmr (CDCl.sub.3): .delta.=172.8, 171.1, 170.9,
134.5, 128.9, 128.4, 126.8, 67.5, 57.7, 52.1, 48.7, 42.8, 19.6,
18.3.
[1398] C.sub.16H.sub.22N.sub.2O.sub.5 (MW=322.36); mass
spectroscopy (MH.sup.+) 323.
Example 49
Synthesis of N-[N-(Phenylacetyl)-L-alaninyl]-L-leucinamide
[1399] Following General Procedure T and using
N-(phenylacetyl)-L-alanine (from Example B1 above) and
L-leucinamide hydrochloride (Aldrich), the title compound was
prepared as a solid (mp=207-209.degree. C.). The product was
purified by extraction with EtOAc and washing with aqueous
potassium carbonate and aqueous hydrochloric acid.
[1400] NMR data was as follows:
[1401] .sup.1H-nmr (CD.sub.3OD): .delta.=7.00-7.12 (m, 5H),
4.10-4.20 (m, 2H), 3.34 (s, 2H), 1.30-1.50 (m, 2H), 1.12-1.23 (m,
4H), 0.65-0.76 (m, 6H).
[1402] .sup.13C-nmr (CD.sub.3OD): .delta.=177.5, 174.9, 174.1,
136.8, 130.1, 129.6, 127.9, 52.8, 50.7, 43.4, 41.9, 25.8, 23,.5,
21.8, 17.7.
Example 50
Synthesis of N'-[N-(Phenylacetyl)-L-alaninyl]-L-alaninamide
[1403] Following General Procedure U and using
N-(phenylacetyl)-L-alanine (from Example B-1 above) and
L-alaninamide hydrochloride (Bachem), the title compound was
prepared as a solid (mp=>260.degree. C.). The product was
purified by washing with aqueous sodium hydroxide and aqueous
hydrochloric acid.
[1404] NMR data was as follows:
[1405] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.27 (d, J=7.1 Hz, 1H),
7.88 (d, J=7.6 Hz, 1H), 7.26 (m, 6H), 6.99 (s, 1H), 4.25 (quintet,
J=7.1 Hz, 1H), 4.16 (quintet, J=7.1 Hz, 1H), 3.46 (s, 2H), 1.19 (t,
J=6.3 Hz, 6H).
[1406] .sup.13C-nmr (DMSO-d.sub.6): .delta.=174.1, 171.8, 170.0,
136.3, 129.0, 128.1, 126.3, 48.3, 47.9, 42.0, 18.3, 18.1.
Example 51
Synthesis of
N'-[N-(Phenylacetyl)-L-alaninyl]-L-phenylalaninamide
[1407] Following General Procedure T and using
N-(phenylacetyl)-L-alanine (from Example B1 above) and
L-phenylalaninamide (Bachem), the title compound was prepared as a
solid (mp=224-225.degree. C.).
[1408] NMR data was as follows:
[1409] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.24 (d, J=7.2 Hz, 1H),
7.89 (d, J=8.2 Hz, 1H), 7.36 (s, 1H), 7.13-7.34 (m, 10H), 7.1-1 (s,
1H), 4.40 (m, 1H), 4.21 (quintet, J=7.1 Hz, 1H), 3.44 (d, 2H), 3.01
(dd, J=4.9, 13.7 Hz, 1H), 2.82 (dd, J=9.0, 13.7 Hz, 1H), 1.13 (d,
J=6.9 Hz, 3H).
[1410] .sup.13C-nmr (DMSO-d.sub.6): .delta.=172.7, 172.0, 170.0,
137.8, 136.3, 129.2, 129.0, 128.2, 128.0, 126.3, 126.2, 53.6, 48.5,
41.9, 37.3, 18.0.
Example 52
Synthesis of N'-[-(Phenylacetyl)-L-alaninyl)-L-valinamide
[1411] Following General Procedure T and using
N-(phenylacetyl)-L-alanine (from Example B1 above) and L-valinamide
hydrochloride (Bachem), the title compound was prepared as a solid
(mp=>261.degree. C.).
[1412] NMR data was as follows:
[1413] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.31 (d, J=7.5 Hz, 1H),
7.62 (d, J=9.0 Hz, 1H), 7.38 (s, 1H), 7.15-7.30 (m; 5H), 7.05 (s,
1H), 4.34 (quintet, J=7.2 Hz, 1H), 4.08 (dd, J=6.4, 15.3 Hz, 1H),
3.45 (s, 2H), 1.91 (m, 1H), 1.19 (d, J=7.0 Hz, 3H), 0.79 (d, J=6.7
Hz, 3H), 0.76 (d, J=6.8 Hz, 3H).
[1414] .sup.13C-nmr (DMS-d.sub.6): .delta.32 172.8, 172.1, 170.0,
136.3, 129.0, 128.2, 126.3, 57.2, 48.2, 42.0, 30.5, 19.2, 17.9,
17.8.
Example 53
Synthesis of Ethyl
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-pyridyl)acetate
[1415] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
ethyl 2-amino-2-(3-pyridyl)acetate (prepared as described in P.
Kolar et al., J. Heterocyclic Chem., 28, 1715 (1991) and references
cited therein), the title compound was prepared as a solid
(mp=146-157.degree. C.). The reaction was monitored by tlc (Rf=0.1
in CHCl.sub.3/MeOH 98:2) and the product was purified by silica gel
chromatography using 959:5 CHCl.sub.3/MeOH as the eluent, followed
by recrystallization from chlorobutane.
[1416] NMR data was as follows:
[1417] .sup.1H-nmr (CDCl.sub.3): .delta.=8.60 (m, 1H), 8.56 and
8.52 (m, 1H), 7.91 (m, 1H), 7.63 (m, 1 H), 7.22 (m, 1H), 6.90 (m,
1H), 6.74 (m, 2H), 5.55 (m, 1H), 4.69 (m, 1H), 4.17 (m, 2H), 3.50
and 3.41 (s, 2H), 1.33 and 1.29 (d, 3H), 1.21 (m, 3H), 1.18 (m,
3H).
[1418] C.sub.20H.sub.21N.sub.3O.sub.4F.sub.2 (MW=405.4); mass
spectroscopy (MH.sup.+) 405.
Example 54
Synthesis of
N-Methyl-N'-[N-(phenylacetyl)-L-alaninyl]-L-leucinamide
[1419] Following General Procedure U and using
N-(phenylacetyl)-L-alanine (from Example B1 above) and
N-methyl-L-leucinamide (prepared from N-methyl-N'-BOC-L-Leucinamide
(from Example D5 above) using General Procedure Y), the title
compound was prepared as a solid (mp=233-235.degree. C.). The
product was purified by recrystallization from MeOH.
[1420] NMR data was as follows:
[1421] .sup.1H-nmr (CDCl.sub.3/CD.sub.3OD): .delta.=7.25-7.40 (m,
5H), 4.36 (quartet, J=7.2 Hz, 1H), 4.27 (dd, J=5.1, 14.6 Hz, 1H),
3.56 (s, 2H), 2.72 (s, 3H), 1.40-1.61 (m, 2H), 1.32 (d, J=7.1 Hz,
3H), 0.89 (d, J=6.2 Hz, 3H), 0.86 (d, J=6.2 Hz, 3H).
Example 55
Synthesis of
N,N-Dimethyl-N'-[N-(phenylacetyl)-L-alaninyl]-L-phenylalaninamide
[1422] Following General Procedure U and using
N-(phenylacetyl)-L-alanine (from Example B1 above) and
N,N-dimethyl-L-phenylalaninamide (prepared by coupling
N-BOC-L-phenylalanine (Bachem) with dimethylamine hydrochloride
(Aldrich) using General Procedure B, followed by removal of the
BOC-group using General Procedure Y), the title compound was
prepared as a solid (mp=152-155.degree. C.). The product was
purified by extraction with EtOAc, washing with aqueous sodium
carbonate and aqueous hydrochloric acid, and trituration with
Et.sub.2O.
[1423] NMR data was as follows:
[1424] .sup.1H-nmr (CDCl.sub.3): .delta.=7.49 (d, J=8.2 Hz, 1H),
7.20-7.26 (m, 8H), 7.14 (m, 2H), 6.45 (d, J=7.5 Hz, 1H), 5.08
(quartet, J=8.0 Hz, 1H), 4.60 (quintet, J=7.3 Hz, 1H), 3.56 (s,
2H), 2.95 (m, 2H), 2.86 (s, 3H), 2.61 (s, 3H), 1.26 (d, J=6.9 Hz,
3H).
[1425] .sup.13C-nmr.(CDCl.sub.3): .delta.=171.6, 170.8, 170.4,
136.0, 134.7, 129.3, 129.2, 128.9, 128.8, 128.3, 127.1, 50.2, 48.7,
43.4, 39.5, 36.8, 35.6, 18.8.
Example 56
Synthesis of
N,N-Dimethyl-N'-[N-(phenylacetyl)-L-alaninyl]-L-leucinamide
[1426] Following General Procedure U and using
N-(phenylacetyl)-L-alanine (from Example B1 above) and
N,N-dimethyl-L-leucinamide (prepared by coupling N-BOC-L-leucine
(Bachem) with dimethylamine hydrochloride (Aldrich) using General
Procedure B, followed by removal of the BOC-group using General
Procedure Y), the title compound was prepared as a solid
(mp=130-132.degree. C.). The product was purified by extraction by
EtOAc, washing with aqueous sodium carbonate and aqueous
hydrochloric acid, and trituration with EtO.
[1427] NMR data was as follows:
[1428] .sup.1H-nmr (CDCl.sub.3): .delta.=7.23-7.36 (m, 5H), 7.04
(d, J=8.7 Hz, 1H), 6.30 (d, J=7.6 Hz, 1H), 4.92 (m, 1H), 4.56
(quintet, J=7.2 Hz, 1H), 3.56 (s, 2H), 3.07 (s, 3H), 2.94 (s, 3H),
1.33-1.64 (m, 3H), 1.27 (d, J=6.9 Hz, 3H), 0.94 (d, J=6.4 Hz, 3H),
0.88 (d, J=6.5 Hz, 3H).
[1429] .sup.13C-nmr (CDCl.sub.3): .delta.=172.0, 171.7, 170.4,
134.6, 129.2, 128.8, 127.2, 48.7, 47.3, 43.5, 42.1, 36.9, 35.8,
24.6, 23.3, 21.8, 18.6.
Example 57
Synthesis of
N,N-Dimethyl-N'-[N'-(phenylacetyl)-L-alaninyl]-L-valinamide
[1430] Following General Procedure U and using
N-(phenylacetyl)-L-alanine (from Example B1 above) and
N,N-dimethyl-L-valinamide (prepared by coupling N-BOC-L-valine
(Bachem) with dimethylamine hydrochloride (Aldrich) using General
Procedure B, followed by removal of the BOC-group using General
Procedure Y), the title compound was prepared as a solid
(mp=147-149.degree. C.). The product was purified by extraction by
EtOAc, washing with aqueous sodium carbonate and aqueous
hydrochloric acid, and trituration with EtO.
[1431] NMR data was as follows:
[1432] .sup.1H-nmr (CDCl.sub.3): .delta.=7.24-7.38 (m, 5H), 6.64
(d, 1H), 6.05 (d, 1H), 4.74 (dd, J=5.9, 8.9 Hz, 1H), 4.50 (quintet,
J=7.1 Hz, 1H), 3.59 (s, 2H), 3.08 (s, 3H), 2.96 (s, 3H), 1.97 (m,
1H), 1.28 (d, J=7.0 Hz, 3H), 0.91 (d, J=6.8 Hz, 3H), 0.84 (d, J=6.8
Hz, 3H).
[1433] .sup.13C-nmr (CDCl.sub.3): .delta.=172.3, 171.4, 170.4,
134.6, 129.0, 128.5, 126.8, 53.5, 48.5, 43.2, 37.3, 35.6, 31.2,
19.2, 18.6, 17.5.
[1434] C.sub.18H.sub.27N.sub.3O.sub.3 (MW=333.43); mass
spectroscopy (MH.sup.+) 334.
Example 58
Synthesis of
N-Methyl-N'-(N-(phenylacetyl)-L-alaninyl]-L-phenylalaninamide
[1435] Following General Procedure U and using
N-(phenylacetyl)-L-alanine (from Example B1 above) and
N-methyl-L-phenylalaninamide (prepared by coupling
N-BOC-L-phenylalanine (Bachem) with methylamine hydrochloride
(Aldrich) using General Procedure B, followed by removal of the
BOC-group using General Procedure Y), the title compound was
prepared as a solid. The product was purified by washing with
aqueous sodium carbonate and aqueous hydrochloric acid.
[1436] NMR data was as follows:
[1437] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.23 (d, J=7.0 Hz, 1H),
7.95 (d, J=8.2 Hz, 1H), 7.79 (d, J=4.4 Hz, 1H), 7.10-7.32 (m, 10H),
4.37 (quintet, J=5.4 Hz, 1H), 4.19 (quintet, J=7.1 Hz, 1H), 3.44
(s, 2H), 2.96 (dd, J=5.5, 13.7 Hz, 1H), 2.78 (dd, J=9.2, 13.7 Hz,
1H), 2.52 (d, J=4.4 Hz, 3H), 1.11 (d, J=7.0 Hz, 3H).
[1438] .sup.13C-nmr (DMSO-d.sub.6): .delta.=172.0, 171.0, 170. 1,
137.8, 136.3, 129.11, 129.07, 128.2, 128.1, 126.31, 126.26, 53.9,
48.5, 41.9, 37.5, 25.5, 18.0.
Example 59
Synthesis of
N-Methyl-N'-[N-(pheylacetyl)-L-alaninyl]-L-valinamide
[1439] Following General Procedure U and using
N-(phenylacetyl)-L-alanine (from Example B1 above) and
N-methyl-L-valinamide (prepared by coupling N-BOC-L-valine (Bachem)
with methylamine hydrochloride (Aldrich) using General Procedure B,
followed by removal of the BOC-group using General Procedure Y),
the title compound was prepared as a solid. The product was
purified by washing with aqueous sodium carbonate and aqueous
hydrochloric acid.
[1440] NMR data was as- follows:
[1441] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.30 (d, J=7.6 Hz, 1H),
7.88 (d, J=4.7 Hz, 1H), 7.69 (d, J=9.1 Hz, 1H), 7.17-7.32 (m, 5H),
4.34 (quintet, J=7.2 Hz, 1H), 4.04 (dd, J=7.0, 8.9 Hz, 1H), 3.45
(s, 2H), 2.56 (d, J=4.6 Hz, 3H), 1.87 (m, 1H), 1.18 (d, J=7.0 Hz,
3H), 0.76 (d, J=6.6 Hz, 3H), 0.75 (d, J=6.7 Hz, 3H).
[1442] .sup.13C-nmr (DMSO-d.sub.6): .delta.=172.0, 171.1, 170.0,
136.3, 129.0, 128.1, 126.3, 57.6, 48.2, 42.0, 30.6, 25.4, 19.2,
18.1, 17.9.
Example 60
Synthesis of
N-Methyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanami-
de
[1443] Following General Procedure U and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
N-methyl-L-norleucinamide (prepared by coupling N-BOC-L-norleucine
(Bachem) with methylamine hydrochloride (Aldrich) using General
Procedure B, followed by removal of the BOC-group using General
Procedure Y), the title compound was prepared as a solid. The
product was purified by washing with aqueous sodium carbonate and
aqueous hydrochloric acid.
[1444] NMR data was as follows:
[1445] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.37 (d, 7.1, 1H), 7.88
(d, 8.1, 1H), 7.78 (d, 4.4, 1H), 7.08 (t, 9.5 , 1H), 6.98 (d, 6.90,
2H), 4.27 (quintet, 7.0, 1H), 4.13 (quartet, 5.5, 1H), 3.51 (s,
2H), 2.54 (d, 4.4, 3H), 1.58 (m, 1H), 1.46 (m, 1H), 1.19 (m, 7H),
0.81 (t, 6.5, 3H).
[1446] .sup.13C-nmr (DMSO-d.sub.6): .delta.=172.0, 171.9, 169.0,
162.2(dd, J=13.6, 244.0 Hz), 140.7, 112.2(dd, J=8.3, 17.0 Hz),
101.9(t, J=25.5 Hz), 52.4, 48.4, 41.3, 31.8, 27.4, 25.5, 21.8,
17.9, 13.8.
[1447] C.sub.18H.sub.25N.sub.3O.sub.3F.sub.2 (MW=369.42); mass
spectroscopy (MH.sup.+) 384.
Example 61
Synthesis of
N,N-Dimethyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexa-
namide
[1448] Following General Procedure U and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
N)N-dimethyl-L-norleucinamide -(prepared by coupling
N-BOC-L-norleucine (Bachem) with dimethylamine hydrochloride
(Aldrich) using General Procedure B followed by removal of the
BOC-group using General Procedure Y), the title compound was
prepared as a solid (mp=138-140.degree. C.). The product was
purified by extraction with EtOAc and washing with aqueous sodium
carbonate and aqueous hydrochloric acid.
[1449] NMR data was as follows:
[1450] .sup.1H-nmr (CDCl.sub.3): .delta.=7.11 (d, 8.1, 1H), 6.81
(m, 2H), 6.71 (m, 1H), 6.60 (d, 7.6, 1H), 4.89 (q, J=5.0, 1H), 4.57
(quint, J=7.1, 1H), 3.53 (s, 2H), 3.08 (s, 3H), 2.97 (s, 3H), 1.70
(m, 1H), 1.55 (m, 1H), 1.201.38 (m, 7H), 0.85 (t, 6.9, 3H).
[1451] .sup.13C-nmr (CDCl.sub.3): .delta.=171.6, 171.5, 168.9,
163.0 (dd, J=12.9, 247.3 Hz), 138.4, 112.2 (dd, J=7.8, 17.0 Hz),
102.7 (t, J=25.0 Hz), 49.1, 48.9, 42.9, 37.1, 35.8, 32.6 27.1,
22.4, 19.1, 13.8.
[1452] C.sub.19H.sub.27N.sub.3O.sub.3F.sub.2 (MW=383.44); mass
spectroscopy (MH.sup.+) 384.
Example 62
Synthesis of
N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamide
[1453] Following General Procedure U and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
L-norleucinamide (prepared from N-BOC-L-norleucinamide (from
Example D6 above) using General Procedure Y), the title compound
was prepared as a solid (mp=>215.degree. C.). The product was
purified by precipitation from water.
[1454] NMR data was as follows:
[1455] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.37 (d, 7.4 , 1H), 7.83
(d, 8.0, 1H), 7.29 (s, 1H), 6.95-7.14 (m, 4H), 4.29 (quintet,
J=7.2, 1H), 4.14 (quartet, J=5.0, 1H), 3.52 (s, 2H), 1.61 (m, 1H),
1.46 (m, 1H), 1.21 (m, 7H), 0.82 (m, 3H).
[1456] .sup.13C-nmr (DMSO-d.sub.6): .delta.=173.6, 171.9, 168.9,
162.0 (dd), 140.7, 112.2 (dd, J=7.5, 16.6 Hz), 101.9 (t), 52.2,
48.3, 41.3, 31.8, 27.4, 21.8, 18.0, 13.8.
[1457] C.sub.17H.sub.23N.sub.3O.sub.3F.sub.2 (MW=355.39); mass
spectroscopy (MH.sup.+) 356.
Example 63
Synthesis of Methyl
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino2-(3-methoxyphenyl)ace-
tate
[1458] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
methyl 2-amino-2-(3-methoxyphenyl)acetate hydrochloride (prepared
by the Bucherer Modification of the Strecker procedure as described
in J. P. Greenstein et al., "The Chemistry of Amino Acids", Vol. 1,
p. 698, Wiley, New York (1961)), the title compound was prepared as
a solid (mp=163-170.degree. C.). The reaction was monitored by tlc
(Rf=0.45 in 9:1 CHCl.sub.3/MeOH) and the product was purified by
silica gel chromatography using 97:3 CHCl.sub.3/MeOH as the
eluent.
[1459] NMR data was as follows:
[1460] .sup.1H-nmr (CDCl.sub.3): .delta.=7.27 (m, 1H), 7.18 and
7.06 (m, 1H), 6.87-6.67 (m, 6H), 6.25 (m, 1H),.5.46 (m, 1H), 4.58
(m, 1H), 3.82 (s, 3H), 3.71 and 3.69 (s, 3H), 3.53 and 3.48 (s,
3H), 1.39 and 1.30 (d, 3H). C.sub.21H.sub.22N.sub.2O.sub.5F.sub.2
(MW=420.42); mass spectroscopy (M+) 421.
Example 64
Synthesis of Methyl
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4methoxyphenyl)ace-
tate
[1461] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
methyl 2-amino-2-(4-methoxyphenyl)acetate hydrochloride (prepared
by the Bucherer Modification of the Strecker procedure as described
in J. P. Greenstein et al., "The Chemistry of Amino Acids", Vol. 1,
p. 698, Wiley, New York (1961)), the title compound was prepared as
a solid (mp=170-174.degree. C.). The reaction was monitored by tlc
(Rf=0.1 in 98:2 CHCl.sub.3/MeOH) and the product was purified by
silica gel chromatography using 98:2 CHCl.sub.3/MeOH as the eluent.
NMR data was as follows:
[1462] .sup.1H-nmr (CDCl.sub.3): .delta.=7.26 (m, 2H), 7.01-6.68
(m, 5H), 6.14 (m, 1H), 5.41 (m, 1H), 4.56 (m, 1H), 3.80 (s, 3H),
3.74 and 3.71 (s, 3H), 3.54 and 3.47 (s, 3H), 1.39 and 1.29 (d,
3H).
[1463] C.sub.21H.sub.22N.sub.2O.sub.5F.sub.2 (MW=420.42); mass
spectroscopy (MH.sup.+) 421.
Example 65
Synthesis of Ethyl
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino2-(2-pyridyl)acetate
[1464] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
ethyl 2-amino-2-(2-pyridyl)acetate hydrochloride (prepared as
described in P. Kolar et al., J. Heterocyclic Chem., 28, 1715
(1991) and references cited therein), the tide compound was
prepared as a solid (mp=123-125.degree. C.). The reaction was
monitored by tlc (Rf=0.1 in 98:2 CHCl.sub.3/MeOH) and the product
was purified by silica gel chromatography using 95:5
CHCl.sub.3/MeOH as the eluent, followed by recrystallization from
chlorobutane.
[1465] NMR data was as follows:
[1466] .sup.1H-nmr (CDCl.sub.3): .delta.=8.53 (m, 1H), 7.70 (m,
2H), 7.48 (m, 1H), 7.27 (m, 1H), 6.86 (m, 2H), 6.74 (m, 1H), 6.52
(m, 1H), 5.58 (m, 1H), 4.67 (m, 1H), 4.18 (m, 2H), 3.54 and 3.50
(s, 2H), 1.48 and 1.39 (d, 3H), 1.21 (m, 3H).
[1467] C.sub.20H.sub.21N.sub.3O.sub.4F.sub.2 (MW=405.4);
massctroscopy (MH.sup.+) 405.
Example 66
Synthesis of Ethyl
N-[N-(3,5Difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4pyridyl)acetate
[1468] Following General Procedure C and using
N-(3,5difluorophenylacetyl)-L-alanine (from Example B2 above) and
ethyl 2-amino-2-(4-pyridyl)acetate hydrochloride (prepared as
described in P. Kolar et al., J. Heterocyclic Chem., 28, 1715
(1991) and references cited therein), the title compound was
prepared as a solid (mp=175-181 .degree. C.). The reaction was
monitored by tlc (Rf=0.1 in 98:2 CHCl.sub.3/MeOH) and the product
was purified by silica gel chromatography using 95:5
CHCl.sub.3/MeOH as the eluent, followed by recrystallization from
chlorobutane.
[1469] NMR data was as follows:
[1470] .sup.1H-nmr (CDCl.sub.3): .delta.=8.59 (m, 2H), 7.39 (m,
1H), 7.26 (m, 21D, 6.80 (m, 3H), 6.21 (m, 1H), 5.51 (m, 1H), 4.62
(m, 1H), 4.21 (m, 2H), 3.57 and 3.51 (s, 2H), 1.38 (m, 3H), 1.23
(m, 3H).
[1471] C.sub.20H.sub.21N.sub.3O.sub.4F.sub.2 (MW=405.4); mass
spectroscopy (MH.sup.+) 405.
Example 67
Synthesis of N-[N-(Cyclohexylacetyl)-L-alaninyl]-L-phenylalanine
Methyl Ester
[1472] Following General Procedure U and using cyclohexylacetic
acid (Aldrich) and N-(L-alaninyl)-L-phenylalanine methyl ester
(prepared by coupling N-BOC-L-alanine (Bachem) with L-phenylalanine
methyl ester hydrochloride (Bachem) using General Procedure U,
followed by removal of the BOC-group using General Procedure Y),
the title compound was prepared as a solid (mp=156-158.degree. C.).
The reaction was monitored by tlc (Rf=0.25 in 1:1
EtOAc/hexanes).
[1473] NMR data was as follows:
[1474] .sup.1H-nmr (CDCl.sub.3): .delta.=0.95 (m, 2H), 1.10-1.38
(m, 3H), 1.33 (d, J=7.0 Hz, 3H), 1.60-1.86 (m, 6H), 2.02 (d, J=7 5
Hz, 2H), 3.10 (m, 2H), 3.71 (s, 3H), 4.49 (m, 1H), 4.81 (m, 1H),
6.10 (d, J=7.3 Hz, 1H), 6.65 (d, J=7.7 Hz, 1H), 7.11 (m, 2H), 7.26
(m, 3H).
[1475] .sup.13C-nmr (CDCl.sub.3): .delta.=18.4, 26.0, 26.1, 33.0,
33.1, 35.3, 37.8, 44.5, 48.5, 52.4, 53.3, 127.1, 128.6, 129.2,
135.6, 171.6, 172.0, 172.2.
[1476] C.sub.21H.sub.30N.sub.2O.sub.4 (MW=374.48); mass
spectroscopy (MH.sup.+) 375.
Example 68
Synthesis of N-[N-(Cyclopentylacetyl)-L-alaninyl]-L-phenylalanine
Methyl Ester
[1477] Following General Procedure U and using cyclopentylacetic
acid (Aldrich) and N-(L-alaninyl)-L-phenylalanine methyl ester
(prepared by coupling N-BOC-L-alanine (Bachem) with L-phenylalanine
methyl ester hydrochloride (Bachem) using General Procedure U,
followed by removal of the BOC-group using General Procedure Y),
the title compound was prepared as a solid (mp=137-139.degree. C.).
The reaction was monitored by tlc (Rf=0.23 in 1:1
EtOAc/hexanes).
[1478] NMR data was as follows:
[1479] .sup.1H-nmr (CDCl.sub.3): .delta.=1.13 (m, 2H), 1.33 (d,
J=7.0 Hz, 3H), 1.58 (m, 4H), 1.80 (m, 2H), 2.17 (m, 3H), 3.10 (m,
2H), 3.71 (s, 3H), 4.50 (m, 1H), 4.83 (m, 1H), 6.12 (d, J=7.4 Hz,
1H), 6.69 (d, J=7.7 Hz, 1H), 7.2 (m, 2H), 7.25 (m, 3H).
[1480] .sup.13C-nmr (CDCl.sub.3): .delta.=18.3, 24.9, 32.4, 32.5,
37.0, 37.7, 42.7, 48.4, 52.3, 53.3, 127.1, 128.5, 129.2, 135.7,
171.6, 172.0, 172.6.
[1481] C.sub.20H.sub.28N.sub.2O.sub.4 (MW=360.46); mass
spectroscopy (MH.sup.+) 361.
Example 69
Synthesis of
N-[N-(Cyclobex-1-enylacetyl)-L-alaninyl]-L-phenylalanine Methyl
Ester
[1482] Following General Procedure U and using
cyclohex-1-enylacetic acid (Alfa) and
N-(L-alaninyl)-L-phenylalanine methyl ester (prepared by coupling
N-BOC-L-alanine (Bachem) with L-phenylalanine methyl ester
hydrochloride (Bachem) using General Procedure U, followed by
removal of the BOC-group using General Procedure Y), the title
compound-was prepared as a solid (mp=139-142.degree. C.). The
reaction was monitored by tlc (Rf=0.27 in 1:1 EtOAc/hexanes).
[1483] NMR data was as follows:
[1484] .sup.1H-nmr (CDCl.sub.3): .delta.=1.31 (d, J=7.0 Hz, 3H),
1.58 (m, 4H), 1.89 (m, 2H), 2.04 (br s, 2H), 2.83 (s, 2H),
3.00-3.20 (m, 2H), 3.71 (s, 3H), 4.47 (m, 1H), 4.81 (m, 1H), 5.60
(s, 1H), 6.26 (d, J=7.3 Hz, 1H), 6.67 (d, J=7.7 Hz, 1H), 7.11 (m,
2H), 7.26 (m,3H).
[1485] .sup.13C-nmr (CDCl.sub.3): .delta.=18.1, 21.9, 22.7, 25.3,
28.3, 37.7, 46.0, 48.4, 52.3, 53.3, 127.1, 127.2, 128.5, 129.1,
132.2, 135.7, 171.0, 171.6, 171.8.
[1486] C.sub.21H.sub.28N.sub.2O.sub.4 (MW=372.47); mass
spectroscopy (MH.sup.+) 373.
Example 70
Synthesis of Methyl
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-1-aminocyclopropane-1-carboxy-
late
[1487] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
methyl 1-aminocyclopropane-1-carboxylate hydrochloride (Sigma), the
title compound was prepared as a solid.
[1488] The reaction was monitored by tlc (Rf=0.3 in 95:5
CHCl.sub.3/MeOH) and the product was purified by silica gel
chromatography using 97:3 CHCl.sub.3/MeOH as the eluent.
[1489] NMR data was as follows:
[1490] .sup.1H-nmr (CDCl.sub.3): .delta.=6.96 (bs, 1H), 6.82 (m,
2H), 6.69 (m, 1H), -6.48 (d, 1H), 4.50 (m, 1H), 3.67 (s, 3H), 3.54
(s, 2H), 1.58 (m, 2H), 1.40 (d, 2H), 1.12 (m, 2H).
[1491] Optical Rotation: [.alpha.].sub.23=.about.18.degree. (c 1,
MeOH).
Example 71
Synthesis of
N-2-(N,N-Dimethylamino)ethyl-N-methyl-N'-[N-(3,5-difluorophenylacetyl)-L--
alaninyl]-L-alaninamide
[1492] Following General Procedure C and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (from Example
D7 above) and N,N,N'-trimethylethylene-diamine (Aldrich), the title
compound was prepared as a solid.
[1493] NMR data was as follows:
[1494] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.37 (m, 2H), 8.19 (d,
1H), 8.08 (d, 2H), 7.10 (m, 1H), 6.99 (m, 2H), 4.67 (m, 1H), 4.30
(m, 1H), 3.52 (s, 2H), 3.01 and 2.86 (s, 3H), 2.47 (t, 1H), 2.31
(t, 1H), 2.15 (s, 6H), 1.19 (m, 6H).
[1495] Optical Rotation: [.alpha.].sub.23=-85.degree. (c 1,
MeOH).
[1496] C.sub.19H.sub.28N.sub.4O.sub.3F.sub.2 (MW=398.45); mass
spectroscopy (MH.sup.+) 398.
Example 72
Synthesis of N-[N-(Cyclopropylacetyl)-L-alaninyl]-L-phenylalanine
Methyl Ester
[1497] Following General Procedure U and using cyclopropylacetic
acid (Lancaster) and N-(L-alaninyl)-L-phenylalanine methyl ester
(prepared by coupling N-BOC-L-alanine (Bachem) with L-phenylalanine
methyl ester hydrochloride Pachem) using General Procedure U,
followed by removal of the BOC-group using General Procedure Y),
the title compound was prepared as a solid (mp=128-131.degree. C.).
The reaction was monitored by tlc (Rf=0.14 in 1:1
EtOAc/hexanes).
[1498] NMR data was as follows:
[1499] .sup.1H-nmr (CDCl.sub.3): .delta.=0.17 (m, 2H), 0.59 (m,
2H), 0.92 (m, 11), 1.35 (d, J=7.0 Hz, 3H), 2.11 (m, 2H), 3.05 (dd,
J=6.7, 13.9 Hz, 1H), 3.16 (dd, J=5.5, 13.9 Hz, 1H), 3.73 (s, 3H),
4.52 (m, 1H), 4.82 (m, 1H), 6.47 (d, J=7.1 Hz, 1H), 6.70 (d, J=7.5
Hz, 1H), 7.12 (m, 2H), 7.28 (m, 3H).
[1500] .sup.13C-nmr (CDCl.sub.3): .delta.=4.6, 6.9, 18.2, 37.7,
41.2, 48.4, 52.4, 53.2, 127.1, 128.5, 129.2, 135.7, 171.7, 171.9,
172.3.
[1501] C.sub.18H.sub.24N.sub.2O.sub.4 (MW=332.40); mass
spectroscopy (MH.sup.+) 333.
Example 73
Synthesis of N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]glycine
Benzyl Ester
[1502] Following General Procedure A and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
glycine benzyl ester (prepared from N-BOC-glycine (Bachem) and
benzyl alcohol (Aldrich) using General Procedure X, followed by
removal of the BOC-group using General Procedure Y), the title
compound was prepared as a solid (mp=167.5.degree. C). The reaction
was monitored by tlc (Rf=0.35 in 2% MeOH/CH.sub.2Cl.sub.2) and the
product was purified by flash chromotography using 2%
MeOH/CH.sub.2Cl.sub.2 as the eluent.
[1503] NMR data was as follows:
[1504] .sup.1H-nmr (CDCl.sub.3): .delta.=7.12 (m, 5H), 6.71 (m,
3H), 6.60 (m, 2H), 4.95 (s, 2H), 4.18 (q, 1H), 3.76 (dd, 2H), 3.35
(s, 2H), 1.13 (d, 3H).
[1505] .sup.13C-nmr (CDCl.sub.3): .delta.=176.0, 172.9, 171.5,
166.46, 163.30, 141.54, 137.70, 130.11, 129.88, 113.98, 113.87,
113.75, 113.64, 103.89, 103.55, 103.21, 68.44, 50.93, 43.25, 42.61,
18.65.
[1506] C.sub.20H.sub.20N.sub.2O.sub.4F.sub.2 (MW=390.39); mass
spectroscopy (MH.sup.+) 391.
Example 74
Synthesis of N-[N-(Isovaleryl)-L-phenylglycinyl]-L-alanine Ethyl
Ester
[1507] Following General Procedure C and using
N-(isovaleryl)-L-phenylglycine (prepared from isovaleric acid
(Aldrich) and L-phenylglycine methyl ester hydrochloride (Aldrich)
using General Procedure C, followed by hydrolysis using General
Procedure AF) and L-alanine ethyl ester hydrochloride (Sigma), the
title compound was prepared as a solid (mp=198-201.degree. C.). The
reaction was monitored by tlc (Rf=0.3 in 1:1 EtOAc/hexanes) and the
product was purified by silica gel chromatography using 5%
MeOH/CHCl.sub.3 as the eluent, followed by rerystallization from
EtOAc.
[1508] NMR data was as follows:
[1509] .sup.1H-nmr (DMSO-d.sub.6)(1:5 mixture of diastereomers):
.delta.=1.25 and 1.30 (two d, 3H), 5.57 (d, 1H), 5.60 (d, 1H).
[1510] C.sub.18H.sub.26N.sub.2O.sub.4 (MW=334.42); mass
spectroscopy (MH.sup.+) 335.
Example 75
Synthesis of N-[N-(3-Nitrophenylacetyl)-L-alaninyl]-L-phenylalanine
Methyl Ester
[1511] Following General Procedure Z and using
N-(3-nitrophenylacetyl)-L-alanine 2,4,5-trichlorophenyl ester (from
Example D8 above) and L-phenylalanine methyl ester hydrochloride
(Sigma), the title compound was prepared as a solid
(mp=154-158.degree. C.). The reaction was monitored by tlc (Rf=0.3
in 1:1 EtOAc/hexanes) and the product was purified by silica gel
chromatography using 50-100% EtOAc/hexanes as the eluent.
[1512] NMR data was as follows:
[1513] .sup.1H-nmr (DMSO-d.sub.6)(1:3 mixture of diastereomers):
.delta.=1.00 and 1.18 (two d, 3H), 2.96 (m, 2H).
[1514] C.sub.21H.sub.23N.sub.3O.sub.6 (MW=413.43); mass
spectroscopy (MH.sup.+) 413.
Example 76
Synthesis of N-[N-(3-Nitrophenylacetyl)-L-alaninyl]-L-alanine Ethyl
Ester
[1515] Following General Procedure Z and using
N-(3-nitrophenylacetyl)-L-alanine 2,4,5-trichlorophenyl ester (from
Example D8 above) and L-alanine ethyl ester hydrochloride (Sigma),
the title compound was prepared as a solid (mp=193-195.degree. C.).
The reaction was monitored by tlc (Rf=0.4 in EtOAc) and the product
was purified by silica gel chromatography using EtOAc as the
eluent.
[1516] NMR data was as follows:
[1517] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.20 (m, 9H), 3.65 (s,
2H); 4.05 (m, 2H).
[1518] Optical Rotation: [.alpha.].sub.20=-27.3.degree.@589 nm,
(c=1.02, DMSO).
[1519] C.sub.16H.sub.21N.sub.3O.sub.6 (MW=351.36); mass
spectroscopy (MH.sup.+) 352.
Example 77
Synthesis of N-[N-(3-Nitrophenylacetyl)-L-alaninyl]glycine Ethyl
Ester
[1520] Following General Procedure C and using
N-(3-nitrophenylacetyl)-L-alanine (prepared from
3-nitrophenylacetic acid (Aldrich) and L-alanine ethyl ester
hydrochloride (Sigma) using General Procedure C, followed by
hydrolysis using General Procedure AF) and glycine ethyl ester
hydrochloride (Sigma), the title compound was prepared as a solid
(mp=164-165.degree. C.). The product was purified by silica gel
chromatography using EtOAc as the eluent, followed by
recrystallization from EtOAc.
[1521] NMR data was as follows:
[1522] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.20 (m, 6H), 4.08 (q,
2H); 4.32 (m, 1H).
[1523] Optical Rotation: [.alpha.].sub.20=-25.degree.@589 nm,
(c=1.00, DMSO).
[1524] C.sub.15H.sub.19N.sub.3O.sub.6 (MW=337.33); mass
spectroscopy (MH.sup.+) 338.
Example 78
Synthesis of
N-Hydroxy-N'-[N-(3-nitrophenylacetyl)-L-alaninyl]-D,L-threoninamide
[1525] Following General Procedure Z and using
N-(3-nitrophenylacetyl)-L-alanine 2,4,5-trichlorophenyl ester (from
Example D8 above) and D,L-threonine hydroxamnate (Sigma), the title
compound was prepared as a solid (mp=180-183.degree. C.). The
reaction was monitored by tlc (Rf=0.25 in 15% MeOH/CHCl.sub.3) and
the product was purified by silica gel chromatography using 15%
MeOH/CHCl.sub.3 as the eluent, followed by recrystallization from
EtOAc.
[1526] NMR data was as follows:
[1527] .sup.1H-nmr (DMSO-d.sub.6)(1:1 mixture of diastereomers):
.delta.=1.22 (m, 3H); 0.98 (m, 3H).
[1528] C.sub.15H.sub.20N.sub.4O.sub.7 (MW=368.35); mass
spectroscopy (MH.sup.+) 368.
Example 79
Synthesis of N-[N-(Isovaleryl)-L-phenylglycinyl]-L-alanine
iso-butyl Ester
[1529] Following General Procedure C and using
N-(isovaleryl)-L-phenylglycine (prepared from isovaleric acid
(Aldrich) and L-phenylglycine methyl ester hydrochloride (Aldrich)
using General Procedure C, followed by hydrolysis using General
Procedure AF) and L-alanine iso-butyl ester hydrochloride (prepared
from N-BOC-L-alanine (Sigma) and 2-methyl-1-propanol (Aldrich)
using General Procedure C (with catalystic DMAP), followed by
removal of the BOC-group using General Procedure P), the title
compound was prepared as a solid (mp=181-186.degree. C.). The
reaction was monitored by tic (Rf=0.4 in 1:1 EtOAc/hexanes) and the
product was purified by silica gel chromatography using 1:1
EtOAc/hexanes as the eluent.
[1530] NMR data was as follows:
[1531] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.31 (d, 3H); 5.59 (d,
1H).
[1532] Optical Rotation: [.alpha.].sub.20=+19.0.degree.@589 nm,
(c=1.03, DMSO).
[1533] C.sub.20H.sub.29N.sub.2O.sub.4 (MW=362.47); mass
spectroscopy (MH.sup.+) 363.
Example 80
Synthesis of Methyl
N-[N-(3-nitrophenylacetyl)-L-alaninyl]-2-amino-3-(3-hydroxyphenyl)propion-
ate
[1534] Following General Procedure C and using
N-(3-nitrophenylacetyl)-L-alanine (prepared from
3-nitrophenylacetic acid (Aldrich) and L-alanine ethyl ester
hydrochloride (Sigma) using General Procedure C, followed by
hydrolysis using General Procedure AF) and methyl
2-amino-3-(3-hydroxyphenyl)propionate (prepared from
2-amino-3-(3-hydroxyphenyl)propionate (Biosynth AG, Switzerland)
and methanol using General Procedure H), the title compound was
prepared as a solid (mp=155-159.degree. C.). The reaction was
monitored by tic (Rf=0.4 in EtOAc) and the product was purified by
silica gel chromatography using EtOAc as the eluent.
[1535] NMR data was as follows:
[1536] .sup.1H-nmr (DMSO-d.sub.6)(1:1 mixture of diastereomers):
.delta.=1.02 and 1.20 (two d, 3H); 3.62 (2 s, 3H).
[1537] C.sub.21H.sub.23N.sub.2O (MW=429.43); mass spectroscopy
(MH.sup.+) 429.
Example 81
Synthesis of N-[N-(3-Nitrophenylacetyl)-L-alaninyl]-L-tyrosine
Ethyl Ester
[1538] Following General Procedure C and using
N-(3-nitrophenylacetyl)-L-alanine (prepared from
3-nitrophenylacetic acid (Aldrich) and L-alanine ethyl ester
hydrochloride (Sigma) using General Procedure C, followed by
hydrolysis using General Procedure AF) and L-tyrosine ethyl ester
(Sigma), the title compound was prepared as a solid
(mp=117-119.degree. C.). The reaction was monitored by tic (Rf=0.5
in EtOAc) and the product was purified by silica gel chromatography
using EtOAc as the eluent.
[1539] NMR data was as follows:
[1540] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.07 (t, 3H); 1.20 (d,
3H); 9.23 (s, 1H).
[1541] Optical Rotation: [.alpha.].sub.20=-13.1.degree.@589 nm,
(c=1.08, DMSO).
[1542] C.sub.22H.sub.25N.sub.3O.sub.7 (MW=443.46); mass
spectroscopy (MH.sup.+) 443/444.
Example 82
Synthesis of N-[N-(Isovaleryl)-L-isoleucinyl]-L-alanine iso-butyl
Ester
[1543] Following General Procedure C and using
N-(isovaleryl)-L-isoleucine (prepared from isovaleric acid
(Aldrich) and L-isoleucine methyl ester hydrochloride (Aldrich)
using General Procedure C, followed by hydrolysis using General
Procedure AF) and L-alanine iso-butyl ester hydrochloride (prepared
from N-BOC-L-alanine (Sigma) and 2-methyl-1-propanol (Aldrich)
using General Procedure C (with catalystic DMAP), followed by
removal of the BOC-group using General Procedure P), the title
compound was prepared as a solid (mp=142-146.degree. C.). The
reaction was monitored by tic (Rf. 0.4 in 1:1 EtOAc/hexanes) and
the product was purified by silica gel chromatography using 1:1
EtOAc/hexanes as the eluent.
[1544] NMR data was as follows:
[1545] .sup.1H-nmr (DMSO-d.sub.6)(1:4 mixture of diastereomers):
.delta.=1.26 (d, 3H), 7.70, 7.80 (doublets, 1H); 8.30, 8.40
(doublets, 1H).
[1546] C.sub.18H.sub.34N.sub.2O.sub.4 (MW 342.48); mass
spectroscopy (MH.sup.+) 343.
Example 83
Step A--Synthesis of
N-[N-[N-(tert-Butoxycarbonyl)-L-valinyl]-D,L-phenylglycinyl]-L-alanine
iso-butyl Ester
[1547] Following General Procedure A and using
N-[N-BOC-L-valinyl]-D,L-phenylglycine (prepared by coupling
N-BOC-L-valine (Bachem) and L-phenylglycine methyl ester
hydrochloride (Sigma) using General Procedure C, followed by
hydrolysis of the methyl ester using General Procedure AF) and
L-alanine iso-butyl ester hydrochloride (prepared from
N-BOC-L-alanine (Sigma) and 2-methyl-1-propanol (Aldrich) using
General Procedure C (with catalytic DMAP), followed by removal of
the BOC-group using. General Procedure P), the title compound was
prepared. The reaction was monitored by tlc (Rf=0.3 in 5%
MeOH/CH.sub.2Cl.sub.2) and the product was purified by silica gel
chromatography using 5% MeOH/CH.sub.2Cl.sub.2 as the eluent.
[1548] NMR data was as follows:
[1549] .sup.1H-nmr (DMSO-d.sub.6)(1:1 mixture of diastereomers):
.delta.=1.25 (d, 3H); 5.58 (d, 1H).
[1550] C.sub.25H.sub.39N.sub.3O.sub.6 (MW=477.61); mass
spectroscopy (MH.sup.+) 478.
Step B--Synthesis of N-[N-(L-Valinyl)-D-L-phenylglycinyl]-L-alanine
iso-butyl Ester Hydrochloride
[1551] Following General Procedure P and using the product from
Example 83--Step A above, the title compound was prepared as a
solid (mp=225-232.degree. C.). The product was purified by
trituration in Et.sub.2O.
[1552] NMR data was as follows: .sup.1H-nmr (DMSO-d.sub.6)(1:2
mixture of diastereomers): .delta.=1.26, 1.32 (doublets, 3H); 5.60,
5.65 (doulets, 1H).
[1553] C.sub.20H.sub.32N.sub.3O.sub.4Cl (MW=413.94); mass
spectroscopy (MH.sup.+) 378 (free base).
Step C--Synthesis of
N-[N-[N-(Isovaleryl)-L-valinyl]-L-phenylglycinyl]-L-alanine
isobutyl Ester
[1554] Following General Procedure C and using isovaleric acid
(Aldrich) and the product from Example 83--Step B above, the title
compound was prepared as a solid (mp=217-221.degree. C.). The
reaction was monitored by tlc (Rf=0.25 in 5% MeOH/CHCl.sub.3) and
the product was purified by silica gel chromatography using 5%
MeOH/CHCl.sub.3) as the eluent.
[1555] NMR data was as follows:
[1556] .sup.1H-nmr (DMSO-d.sub.6)(1:3 mixture of diastereomers):
.delta.=5.52, 5.58 (doublets, 1H).
[1557] C.sub.25H.sub.39N.sub.3O.sub.5 (MW=461.60); mass
spectroscopy (MR.sup.+) 462.
Example 84
Synthesis of N-(N-(Isovaleryl)-L-phenylalaninyl]-L-alanine
iso-butyl Ester
[1558] Following General Procedure C and using isovaleric acid
(Aldrich) and N-(L-phenylalaninyl)-L-alanine iso-butyl ester
hydrochloride (prepared from N-BOC-L-phenylalanine (Sigma) and
L-alanine iso-butyl ester hydrochloride (prepared as described in
Example 83A above) using General Procedure C, followed by removal
of the BOC-group using General Procedure P), the tide compound was
prepared as a solid (mp=135-138.degree. C.). The reaction was
monitored by tic (Rf=0.3 in 3% MeOH/CHCl.sub.3) and the product was
purified by silica gel chromatography using 3% MeOH/CHCl.sub.3 as
the eluent.
[1559] NMR data was as follows:
[1560] .sup.1H-nmr (DMSO-d.sub.6): .delta.=0.75 (d, 3H), 0.84 (d,
3H); 0.90 (d, 6H); 1.33 (d, 3H).
[1561] Optical Rotation: [.alpha.].sub.20=+4.71.degree.@589 nm,
(c=1.02, DMSO).
[1562] C.sub.21H.sub.32N.sub.2O.sub.4 (MW=376.50); mass
spectroscopy (MH.sup.+) 376.
Example 85
Synthesis of N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-alanine
Ethyl Ester
[1563] Following General Procedure C and using
3,5-difluorophenylacetic acid (Oakwood) and L-alanine ethyl ester
hydrochloride (Sigma), the title compound was prepared as a solid
(mp=197-199.degree. C.). The reaction was monitored by tlc (Rf=0.6
in EtOAc) and the product was purified from bi-products by silica
gel chromatography using EtOAc as the eluent, followed by
recrystallization from EtOAc.
[1564] NMR data was as follows:
[1565] .sup.1H-nmr (DMSO-d.sub.6): .delta.1.22 (m, 9H); 3.52 (s,
2H).
[1566] Optical Rotation: [.alpha.].sub.20=-76.1.degree.@589 nm,
(c=1.01, DMSO).
[1567] C.sub.16H.sub.20N.sub.2O.sub.4F.sub.2 (MW=342.34); mass
spectroscopy (MH.sup.+) 343.
Example 86
Synthesis of Ethyl
1-[N-(3-Nitrophenylacetyl)-L-alaninyl]indoline-(S)-2-carboxylate
[1568] Following General Procedure C and using
N-(3-nitrophenylacetyl)-L-alanine (prepared from
3-nitrophenylacetic acid (Aldrich) and L-alanine ethyl ester
hydrochloride-(Sigma) using General Procedure C, followed by
hydrolysis using General Procedure AF) and ethyl
(S)-indoline-2-carboxylate (prepared from (S)-indoline-2-carboxylic
acid (Aldrich) and ethanol using General Procedure H), the title
compound was prepared as a solid. The reaction was monitored by tic
(Rf=0.4 in 2:1 EtOAc/hexanes) and the product was purified by
silica gel chromatography using 2:1 EtOAc/hexanes as the
eluent.
[1569] NMR data was as follows:
[1570] .sup.1H-nmr (DMSO-d.sub.6)(1:2 mixture of diastereomers):
.delta.=1.05, 1.17 (triplets, 3H); 1.29, 1.39 (doublets, 3H).
[1571] C.sub.22H.sub.23N.sub.3O.sub.6 (MW=425.44); mass
spectroscopy (MH.sup.+) 425.
Example 87
Synthesis of
N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-alaninamide
[1572] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
L-alaninamide hydrochloride (Sigma), the title compound was
prepared as a solid (mp=285-288.degree. C.). The reaction was
monitored by tic (Rf=0.35 in 10% MeOHlCHCl.sub.3) and the product
was purified by silica gel chromatography using 10% MeOH/CHCl.sub.3
as the eluent, followed by recrystallization from EtOH.
[1573] NMR data was as follows:
[1574] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.21 (m, 6H); 7.95 (d,
1H); 8.37 (d, 1H).
[1575] Optical Rotation: [.alpha.].sub.20=-26.84.degree.@589 nm,
(c=1.01, DMSO).
[1576] C.sub.14H.sub.17N.sub.3O.sub.3F.sub.2 (MW=313.31); mass
spectroscopy (MH.sup.+) 314.
Example 88
Synthesis of
N-Methoxy-N-methyl-N'-[N-(isovaleryl)-L-phenylglycinyl]-L-alaninamide
[1577] Following General Procedure C and using
N-[N-(isovaleryl)-L-phenylglycinyl]-L-alanine (prepared from
N-[N-(isovaleryl)-L-phenylglycinyl]-L-alanine ethyl ester (from
Example 74 above) using General Procedure AF) and
N,O-dimethylhydroxylamine (Aldrich), the title compound was
prepared as a solid. The reaction was monitored by tlc (Rf=0.6 in
EtOAc) and the product was purified by silica gel chromatography
using EtOAc as the eluent.
[1578] NMR data -was as follows:
[1579] .sup.1H-nmr (DMSO-d.sub.6)(1:1 mixture of diastereomers):
.delta.=3.67, 3.73 (singlets, 3H), 5.62.(m, 1H).
[1580] C.sub.18H.sub.27N.sub.3O.sub.4 (MW=349.43); mass
spectroscopy (MH.sup.+) 350.
Example 89
Synthesis of
N-iso-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide
[1581] Following General Procedure C and using
N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (prepared
from N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine ethyl
ester (from Example 85 above) using General Procedure AF) and
isobutylamine (Aldrich), the title compound was prepared as a solid
(mp 258-260.degree. C.). The reaction was monitored by tic (Rf=0.4
in 10% MeOH/CHCl.sub.3) and the product was purified by silica gel
chromatography using 10% MeOH/CHCl.sub.3 as the eluent.
[1582] NMR data was as follows:
[1583] .sup.1H-nmr (DMSO-d.sub.6): .delta.=0.80 (d, 6H); 1.20 (m,
6H).
[1584] Optical Rotation: [.alpha.].sub.20=-30.4.degree.@589 nm,
(c=1.01, DMSO).
[1585] C.sub.18H.sub.25N.sub.3O.sub.3F.sub.2 (MW=369.41); mass
spectroscopy (MH.sup.+) 369.
Example 90
Synthesis of
N,N-Di-n-propyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide
[1586] Following General Procedure C and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (prepared
from N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine ethyl
ester (from Example 85 above) and di-n-propylamine (Aldrich), the
title compound was prepared as a solid (mp=137-146.degree. C.). The
reaction was monitored by tic (Rf=0.5 in 10% MeOH/CHCl.sub.3) and
the product was purified by silica gel chromatography using 5%
MeOH/CHCl.sub.3 as the eluent.
[1587] NMR data was as follows:
[1588] .sup.1H-nmr (DMSO-d.sub.6)(1:2 mixture of diastereomers):
.delta.=3.50 (s, 2H), 4.30 (m, 1H), 4.63 (m, 1H).
[1589] C.sub.20H.sub.29N.sub.3O.sub.3F.sub.2 (MW=397.46); mass
spectroscopy (MH.sup.+) 397.
Example 91
Synthesis or
N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-valinamide
[1590] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
L-valinamide hydrochloride (Sigma), the title compound was prepared
as a solid. The reaction was monitored by tlc (Rf=0.3 in 10%
MeOH/CHCl.sub.3) and the product was purified by silica gel
chromatography using 10% MeOH/CHCl.sub.3 as the eluent.
[1591] NMR data was as follows:
[1592] .sup.1H-nmr (DMSO-d.sub.6)(1:4 mixture of diastereomers):
.delta.=1.22 (m, 3H); 1.97 (m, 1H).
[1593] C.sub.16H.sub.21N.sub.3O.sub.3F.sub.2 (MW=341.36) mass
spectroscopy (MH.sup.+) 342.
Example 92
Synthesis of
N-(4-Nitrophenyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninam-
ide
[1594] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
N-(4-nitrophenyl)-L-alaninamide hydrochloride (Fluka), the title
compound was prepared as a solid (mp=242-244.degree. C.). The
reaction was monitored by tlc (Rf=0.4 in 10% MeOH/CHCl.sub.3) and
the product was purified by silica gel chromatography using 10%
MeOH/CHCl.sub.3 as the eluent, followed by recrystallization from
acetonitrile.
[1595] NMR data was as follows:
[1596] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.24 (d, 3H); 1.33 (d,
3H).
[1597] Optical Rotation: [.alpha.].sub.20=-5.18.degree.@589 nm,
(c=1.00, DMSO).
[1598] C.sub.20H.sub.20N.sub.4O.sub.5F.sub.2 (MW=434.40); mass
spectroscopy (MH.sup.+) 434.
Example 93
Synthesis of
N'-[N-[N-(Isovaleryl)-L-phenylglycinyl]-L-alaninyl]-L-phenylalaninamide
[1599] Following General Procedure C and using
N-(isovaleryl)-L-phenylglycine (prepared from isovaleric acid
(Aldrich) and L-phenylglycine methyl ester hydrochloride (Aldrich)
using General Procedure C, followed by hydrolysis using General
Procedure AF) and N'-(L-alaninyl)-L-phenylalaninamide hydrochloride
(prepared from N-BOC-L-alanine (Sigma) and L-phenylalaninamide
(Sigma) using General Procedure C, followed by removal of the
BOC-group using General Procedure P), the title compound was
prepared as a solid. (mp=272-276.degree. C.). The reaction was
monitored by tlc (Rf=0.25 in 10% MeOH/CHCl.sub.3) and the product
was purified by silica gel chromatography using 10% MeOH/CHCl.sub.3
as the eluent.
[1600] NMR data was as follows:
[1601] .sup.1H-nmr (DMSO-d.sub.6)(1:1 mixture of diastereomers):
.delta.=1.07, 1.17 (doublets, 3H); 5.40, 5.52 (doublets, 1H).
[1602] C.sub.25H.sub.32N.sub.4O.sub.4 (MW=452.55); mass
spectroscopy (MH.sup.+) 453.
Example 94
Synthesis of
N-(N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-phenylalanine Methyl
Ester
[1603] Following General Procedure C and using
3,5-difluorophenylacetic acid (Oakwood) and
N-(L-alaninyl)-L-phenylalanine methyl ester hydrochloride (prepared
from N-BOC-L-alanine (Sigma) and L-phenylalanine methyl ester
hydrochloride (Sigma) using General Procedure C, followed by
removal of the BOC-group using General Procedure P), the title
compound was prepared as a solid (mp=173-175.degree. C.). The
reaction was monitored by tlc (Rf=0.6 in 10% MeOH/CHCl.sub.3) and
the product was purified by silica gel chromatography using 4%
MeOH/CHCl.sub.3 as the eluent, followed by recrystallization from
1-chlorobutane/acetonitrile.
[1604] NMR data was as follows:
[1605] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.17 (d, 3H); 3.48 (s,
2H).
[1606] Optical Rotation: [.alpha.].sub.20=-32.47.degree.@589 nm,
(c=1.01, MeOH).
[1607] C.sub.21H.sub.22N.sub.2O.sub.4F.sub.2 (MW=404.41); mass
spectroscopy (MH.sup.+) 404.
Example 95
Synthesis of
N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamide
[1608] Following General Procedure C and using
3,5-difluorophenylacetic acid (Oakwood) and
N'-(L-alaninyl)-L-phenylalaninamide hydrochloride (prepared from
N-BOC-L-alanine (Sigma) and L-phenylalaninamide (Sigma) using
General Procedure C, followed by removal of the BOC-group using
General Procedure P), the title compound was prepared as a solid
(mp=252-253.degree. C.). The reaction was monitored by tic (Rf=0.5
in 15% MeOH/CHCl.sub.3) and the product was purified by silica gel
chromatography using 15% MeOH/CHCl.sub.3 as the eluent, followed by
recrystallization from EtOH.
[1609] NMR data was as follows:
[1610] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.15 (d, 3H); 3.51 (s,
2H).
[1611] Optical Rotation: [.alpha.].sub.20=-24.4.degree.@589 nm,
(c=1.01, DMSO).
[1612] C.sub.20H.sub.21N.sub.3O.sub.3F.sub.2 (MW=389.41); mass
spectroscopy (MH.sup.+) 389.
Example 96
Synthesis of
N-iso-butyl-N'-(N-(isovaleryl)-L-phenylglycinyl]-L-alaninamide
[1613] Following General Procedure C and using
N-[N-(isovaleryl)-L-phenylglycinyl]-L-alanine (prepared from
N-[N-(isovaleryl)-L-phenylglycinyl]-L-alanine ethyl ester (from
Example 74 above) using General Procedure AF) and iso-butylamine
(Aldrich), the title compound was prepared as a solid
(mp=227-232.degree. C.). The reaction was monitored by tic (Rf=0.3
in 5% MeOH/CHCl.sub.3) and the product was purified by silica gel
chromatography using 5% MeOH/CHCl.sub.3 as the eluent, followed by
recrystallization from acetonitrile.
[1614] NMR data was as follows:
[1615] .sup.1H-nmr (DMSO-d.sub.6)(1:4 mixture of diastereomers):
.delta.=1.58 (m, 1H); 1.95 (m, 1H); 5.55 (d, 1H).
[1616] C.sub.20H.sub.31N.sub.3O.sub.3 (MW=361.48); mass
spectroscopy (MH.sup.+) 361.
Example 97
Synthesis of
N-(2-Methoxyethyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl)-L-phenyla-
laninamide
[1617] Following General Procedure C and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine
(prepared from
N-N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine methyl
ester (from Example 94) using General Procedure AF) and
2-methoxyethylamine (Aldrich), the title compound was prepared as a
solid (mp=206-208.degree. C.). The reaction was monitored by tlc
(Rf=0.3 in 10% MeOH/CHCl.sub.3) and the product was purified by
silica gel chromatography using 10% MeOH/CHCl.sub.3 as the eluent,
followed by recrystallization from 1-chlorobutane/acetonitrile.
[1618] NMR data was as follows:
[1619] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.14 (d, 3H); 4.22 (m,
1H); 4.45 (m, 1H).
[1620] Optical Rotation: [.alpha.].sub.20=-25.degree.@589 nm,
(c=1.00, DMSO).
[1621] C.sub.23H.sub.27N.sub.3O.sub.4F.sub.2 (MW=447.49); mass
spectroscopy (MH.sup.+) 447.
Example 98
Synthesis of
N-(4Nitrobenzyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninami-
de
[1622] Following General Procedure C and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (prepared
from N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine ethyl
ester (from Example 85 above) using General Procedure AF) and
4-nitrobenzylamine (Aldrich), the tide compound was prepared as a
solid (mp=257-259.degree. C.). The reaction was monitored-by tic
(Rf=0.4 in 10% MeOH/CHCl.sub.3) and the product was purified by
silica gel chromatography using 10% MeOH/CHCl.sub.3 as the eluent,
followed by recrystallization from EtOH/acetonitrile.
[1623] NMR data was as follows:
[1624] .sup.1H-nmr (DMSO-d.sub.6): .delta.=3.53 (s, 2H); 4.39 (d,
2H).
[1625] Optical Rotation: [.alpha.].sub.20=-29.3.degree.@589 nm,
(c=1.00, DMSO).
[1626] C.sub.21H.sub.22N.sub.4O.sub.5F.sub.2 (MW=448.43); mass
spectroscopy (MH.sup.+) 448.
Example 99
Synthesis of
N-(4Nitrophenyl)-N'-[N-(N-(isovaleryl)-L-phenylglycinyl]-L-alaninyl]-L-al-
aninamide
[1627] Following General Procedure C and using
N-[N-(isovaleryl)-L-phenylglycinyl]-L-alanine (prepared from
N-[N-(isovaleryl)-L-phenylglycinyl]-L-alanine ethyl ester (from
Example 74 above) using General Procedure AF) and
N-(4-nitrophenyl)-L-alaninamide hydrochloride (Fluka), the title
compound was prepared as a solid (mp=255-257.degree. C.). The
reaction was monitored by tlc (Rf=0.5 in 10% MeOH/CHCl.sub.3) and
the product was purified by silica gel chromatography using 10%
MeOH/CHCl.sub.3 as the eluent, followed by recrystallization from
1-chlorobutane/acetonitrile.
[1628] NMR data was as follows:
[1629] .sup.1H-nmr (DMSO-d.sub.6)(1:2 mixture of diastereomers):
.delta.=5.45, 5.55 (doublets, 1H); 10.20, 10.54 (singlets, 1H).
[1630] C.sub.25H.sub.31N.sub.4O.sub.6 (MW=497.56); mass
spectroscopy (MH.sup.+) 497.
Example 100
Synthesis of
N-(4-Nitrophenyl)-N'-(N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylal-
aninamide
[1631] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
N-(4-nitrophenyl)-L-phenylalaninamide hydrochloride (Lancaster),
the title compound was prepared as a solid (mp=253-254.degree. C.).
The reaction was monitored by tic (Rf=0.5 in 10% MeOH/CHCl.sub.3)
and the product was purified by silica gel chromatography using 8%
MeOH/CHCl.sub.3 as the eluent.
[1632] NMR data was as follows:
[1633] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.17 (d, 3H); 10.52 (s,
1H).
[1634] Optical Rotation: [.alpha.].sub.20=+40.6.degree.@589 nm,
(c=1.00, DMSO).
[1635] C.sub.26H.sub.24N.sub.4O.sub.5F.sub.2 (MW=510.50); mass
spectroscopy (MH.sup.+) 510.
Example 101
Synthesis of
N-Benzyl-N-methyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninam-
ide
[1636] Following General Procedure C and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (prepared
from N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine ethyl
ester (from Example 85 above) using General Procedure AF) and
N-benzyl-N-methylamine (Aldrich), the title compound was prepared
as a solid (mp 167-169.degree. C.). The reaction was monitored by
tlc (Rf=0.4 in 5% MeOH/CHCl.sub.3) and the product was purified by
silica gel chromatography using 5% MeOH/CHCl.sub.3 as the eluent,
followed by recrystallization from acetonitrile.
[1637] NMR data was as follows:
[1638] .sup.1H-nmr (DMSO-d.sub.6)(1:3 mixture of diastereomers):
.delta.=3.52 (singlets, 2H); 2.95 (s, 2H).
[1639] Optical Rotation: [.alpha.].sub.20=-55.8.degree.@589 nm,
(c=1.01, DMSO).
[1640] C.sub.22H.sub.25N.sub.3O.sub.3F.sub.2 (MW=417.45); mass
spectroscopy (MH.sup.+) 417.
Example 102
Synthesis of
N-(3,5-Difluorobenzyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-ala-
ninamide
[1641] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
N-(3,5-difluorobenzyl)-L-alaninamide hydrochloride (prepared from
N-BOC-L-alanine (Sigma) and 3,5-difluorobenzylamine (Lancaster)
using General Procedure C, followed by removal of the BOC-group
using General Procedure P), the title compound was prepared as a
solid (mp=267-269.degree. C.). The reaction was monitored by tlc
(Rf=0.25 in 10% MeOH/CHCl.sub.3) and the product was purified by
silica gel chromatography using 10% MeOH/CHCl.sub.3 as the eluent,
followed by recrystallization from acetonitrile.
[1642] NMR data was as follows:
[1643] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.21 (d, 3H), 1.24 (d,
3H).
[1644] Optical Rotation: [.alpha.].sub.20=+26.9.degree.@589 nm,
(c=1.01, DMSO).
[1645] C.sub.21H.sub.21N.sub.3O.sub.3F.sub.4 (MW=439.41); mass
spectroscopy (MH.sup.+) 439.
Example 103
Synthesis of
N-(3-Nitrobenzyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninam-
ide
[1646] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
N-(3-nitrobenzyl)-L-alaninamide hydrochloride (prepared from
N-BOC-L-alanine (Sigma) and 3-nitrobenzylamine hydrochloride
(Aldrich) using General Procedure C, followed by removal of the
BOC-group using General Procedure P), the title compound was
prepared as a solid (mp=245-247.degree. C.). The reaction was
monitored by tlc (Rf=0.4 in 10% MeOH/CHCl.sub.3) and the product
was purified by silica gel chromatography using 10% MeOH/CHCl.sub.3
as the eluent, followed by recrystallization from acetonitrile.
[1647] NMR data was as follows:
[1648] .sup.1H-nmr (DMSO-d6): .delta.=1.21 (d, 3H); 1.25 (d,
3H).
[1649] Optical Rotation: [.alpha.].sub.20=-32.8.degree.@589 nm,
(c=1.00, DMSO).
[1650] C.sub.21H.sub.22N.sub.4O.sub.5F.sub.2 (MW=448.43); mass
spectroscopy (MH.sup.+) 449.
Example 104
Synthesis of
N-Benzyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide
[1651] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
N-benzyl-L-alaninamide hydrochloride (prepared from N-BOC-L-alanine
(Sigma) and benzylamine (Aldrich) using General Procedure C,
followed by removal of the BOC-group using General Procedure P),
the title compound was prepared as a solid (mp 260-262.degree. C.).
The reaction was monitored by tic (Rf=0.3 in 10% MeOH/CHCl.sub.3)
and the product was purified by silica gel chromatography using 10%
MeOH/CHCl.sub.3 as the eluent, followed by recrystallization from
acetonitrile.
[1652] NMR data was as follows:
[1653] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.20 (d, 3H); 1.24 (d,
3H).
[1654] Optical Rotation: [.alpha.].sub..degree.=-29.3.degree.@589
nm, (c=1.03, DMSO).
[1655] C.sub.21H.sub.23N.sub.3O.sub.3F.sub.2 (MW=403.43); mass
spectroscopy (MH.sup.+) 403.
Example 105
Synthesis of
N-(4-Nitrobenzyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylala-
ninamide
[1656] Following General Procedure C and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine
(prepared from
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine methyl
ester (from Example 94) using General Procedure AF) and
4-nitrobenzylamine hydrochloride (Aldrich), the title compound was
prepared as a solid (mp=248-250.degree. C.). The reaction was
monitored by tlc (Rf=0.4 in 12% MeOH/CHCl.sub.3) and the product
was purified by silica gel chromatography using 12% MeOH/CHCl.sub.3
as the eluent, followed by recrystallization from acetonitrile.
[1657] NMR data was as follows:
[1658] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.15 (d, 3H); 7.35 (d,
2H); 8.12 (d, 2H).
[1659] Optical Rotation: [.alpha.].sub.20=-27.6.degree.@589 nm
(c=1.01, DMSO).
[1660] C.sub.27H.sub.26N.sub.4O.sub.5F.sub.2 (MW=524.52); mass
spectroscopy (MH.sup.+) 524.
Example 106
Synthesis of
N-(N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-tryptophan Methyl
Ester
[1661] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
L-tryptophan methyl ester hydrochloride (Sigma), the title compound
was prepared as a solid (mp=191-193.degree. C.). The reaction was
monitored by tlc (Rf=0.4 in 10% MeOH/CHCl.sub.3) and the product
was purified by silica gel chromatography using 5% MeOH/CHCl.sub.3
as the eluent, followed by recrystallization from
1-chlorobutane/acetonitrile.
[1662] NMR data was as follows:
[1663] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.20 (d, 3H); 3.55 (s,
3H).
[1664] Optical Rotation: [.alpha.].sub.20=-8.82.degree.@589 nm
(c=1.02, DMSO).
[1665] C.sub.23H.sub.23N.sub.3O.sub.4F.sub.2 (MW=443.45); mass
spectroscopy (MH.sup.+) 443.
Example 107
Synthesis of
N-(4-Methoxybenzyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanin-
amide
[1666] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
N-(4-methoxybenzyl)-L-alaninamide hydrochloride (prepared from
N-BOC-L-alanine (Sigma) and 4-methoxybenzylamine hydrochloride
(Aldrich) using General Procedure C, followed by removal of the
BOC-group using General Procedure P), the title compound was
prepared as a solid (mp 234-236.degree. C.). The reaction was
monitored by tic (Rf=0.3 in 10% MeOH/CHCl.sub.3) and the product
was purified by silica gel chromatography using 10% MeOH/CHCl.sub.3
as the eluent, followed by recrystallization from
EtOH/acetonitrile.
[1667] NMR data was as follows:
[1668] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.20 (d, 6H); 3.51 (s,
2H); 3.72 (s, 3H).
[1669] Optical Rotation: [.alpha.].sub.20=+27.9.degree.@589 nm
(c=1.00, DMSO).
[1670] C.sub.22H.sub.25N.sub.3O.sub.4F.sub.2 (MW=433.46); mass
spectroscopy (MH.sup.+) 433.
Example 108
Synthesis of N-[N-(Phenylacetyl)-L-phenylglycinyl]-L-alanine Ethyl
Ester
[1671] Following General Procedure C and using phenylacetic acid
(Aldrich) and N-(L-Phenylglycinyl)-L-alanine ethyl ester
hydrochloride (prepared from N-BOC-L-phenylglycine (Advanced
Chemtech) and L-alanine ethyl ester hydrochloride (Aldrich) using
General Procedure C, followed by removal of the BOC-group using
General Procedure P), the title compound was prepared as a solid
(mp=208-210.degree. C.). The reaction was monitored by tic (Rf=0.4
in 5% MeOH/CHCl.sub.3) and the product was purified by silica gel
chromatography using 5% MeOH/CHCl.sub.3 as the eluent, followed by
recrystallization from 1-chlorobutane/acetonitrile.
[1672] NMR data was as follows:
[1673] .sup.1H-nmr (DMSO-d.sub.6): .delta.=3.55 (s, 2H); 5.55 (d,
1H).
[1674] Optical Rotation: [.alpha.].sub.20=+44.8.degree.@589 nm
(c=1.02, DMSO).
[1675] C.sub.21H.sub.24N.sub.2O.sub.4 (MW=368.43); mass
spectroscopy (MH.sup.+) 369.
Example 109
Synthesis of
N-[N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-phenylalaninyl]-L-phenyl-
glycine Methyl Ester
[1676] Following General Procedure C and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine
(prepared from
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine methyl
ester (from Example 94) using General Procedure AF) and
L-phenylglycine methyl ester hydrochloride (Aldrich), the title
compound was prepared as a solid (mp=203-207.degree. C.). The
reaction was monitored by tlc (Rf=0.3 in 10% MeOH/CHCl.sub.3) and
the product was purified by silica gel chromatography using 10%
MeOH/CHCl.sub.3 as the eluent, followed by trituration using
1-chlorobutane.
[1677] NMR data was as follows:
[1678] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.13 (d, 3H); 3.62 (s,
3H).
[1679] Optical Rotation: [.alpha.].sub.20=+42.1.degree.@589 nm
(c=1.03, DMSO).
[1680] C.sub.29N.sub.3O.sub.5F.sub.2 (MW=537.56); mass spectroscopy
(MH.sup.+) 537.
Example 110
Synthesis of N-(N-(Cyclohexylacetyl)-L-phenylglycinyl]-L-alanine
Ethyl Ester
[1681] Following General Procedure C and using cyclohexylacetic
acid (Aldrich) and N-(L-phenylglycinyl)-L-alanine ethyl ester
hydrochloride (prepared from N-BOC-L-phenylglycine (Advanced
Chemtech) and L-alanine ethyl ester hydrochloride (Aldrich) using
General Procedure C, followed by removal of the BOC-group using
General Procedure P), the title compound was prepared as a solid
(mp=196-198.degree. C.). The reaction was monitored by tlc (Rf=0.3
in 5% MeOH/CHCl.sub.3) and the product was purified by silica gel
chromatography using 5% MeOH/CHCl.sub.3 as the eluent, followed by
trituration using 1-chlorobutane.
[1682] NMR data was as follows:
[1683] .sup.1H-nmr (DMSO-d.sub.6): .delta.=2.08 (d, 2H); 5.56 (d,
1H).
[1684] Optical Rotation: [.alpha.].sub.20=+26.3.degree.@589 nm
(c=1.01, DMSO).
[1685] C.sub.21H.sub.30N.sub.2O.sub.4 (MW=374.48); mass
spectroscopy (MH.sup.+) 375.
Example 111
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-phenylglycine Methyl
Ester
[1686] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
L-phenylglycine methyl ester hydrochloride (Aldrich), the title
compound was prepared as a solid (mp=198-200.degree. C.). The
reaction was monitored by tic (Rf=0.4 in 4% MeOH/CHCl.sub.3) and
the product was purified by silica gel chromatography using 4%
MeOH/CHCl.sub.3 as the eluent, followed by recrystallization from
1-chlorobutane/acetonitrile.
[1687] NMR data was as follows:
[1688] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.26 (d,.3H); 3.64 (s,
3H).
[1689] Optical Rotation: (DMSO) [.alpha.].sub.20=+69.9.degree.@589
nm (c=1.01, DMSO).
[1690] C.sub.20H.sub.20N.sub.2O.sub.4F.sub.2 (MW=390.39), mass
spectroscopy (MH.sup.+) 391.
Example 112
Synthesis of
N-[N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-alaninyl]-L-phenylglycine
Methyl Ester
[1691] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
N-(L-alaninyl)-L-phenylglycine methyl ester hydrochloride (prepared
from N-BOC-L-alanine (Sigma) and L-phenylglycine methyl ester
hydrochloride (Aldrich) using General Procedure C, followed by
removal of the BOC-group using General Procedure P), the title
compound was prepared as a solid (mp=243-245.degree. C.). The
reaction was monitored by tic (Rf=0.5 in 10% MeOH/CHCl.sub.3) and
the product was purified by silica gel chromatography using 10%
MeOH/CHCl.sub.3 as the eluent, followed by recrystallization from
acetonitrile.
[1692] NMR data was as follows:
[1693] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.19 (d, 3H); 1.24 (d,
3H).
[1694] Optical Rotation: [.alpha.].sub.20=+38.2.degree.@589 nm
(c=1.02, DMSO).
[1695] C.sub.23H.sub.25N.sub.3O.sub.5F.sub.2 (MW=461.46); mass
spectroscopy (MH.sup.+) 461.
Example 113
Synthesis of
N-(2-Phenylethyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-4L-alanina-
mide
[1696] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
N-(2-phenylethyl)-L-alaninamide hydrochloride (prepared from
N-BOC-L-alanine (Sigma) and phenethylamine (Aldrich) using General
Procedure C, followed by removal of the BOC-group using General
Procedure. P), the title compound was prepared as a solid
(mp=241-243.degree. C.). The reaction was monitored by tlc (Rf=0.3
in 8% MeOH/CHCl.sub.3) and the product was purified by silica gel
chromatography using 8% MeOH/CHCl.sub.3 as the eluent, followed by
recrystallization from acetonitrile.
[1697] NMR data was as follows:
[1698] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.14 (d, 3H); 1.21 (d,
3H).
[1699] Optical Rotation: [.alpha.].sub.20=-33.7.degree.@589 nm
(c=1.00, DMSO).
[1700] C.sub.22H.sub.25N.sub.3O.sub.3F.sub.2 (MW=417.45); mass
spectroscopy (MH.sup.+) 417.
Example 114
Synthesis of
N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-tryptophanamide
[1701] Following General Procedure C and using
3,5-difluorophenylacetic acid (Oakwood) and
N'-(-alaninyl)-L-tryptophanamide hydrochloride (prepared from
N-BOC-L-alanine (Sigma) and L-tryptophanamide hydrochloride (Sigma)
using General Procedure C, followed by removal of the BOC-group
using General Procedure P), the title compound was prepared as a
solid (mp=199-202.degree. C.). The reaction was monitored by tlc
(Rf=0.3 in 15% MeOH/CHCl.sub.3) and the product was purified by
silica gel chromatography using 15% MeOH/CHCl.sub.3 as the eluent,
followed by recrystallization from acetonitrile.
[1702] NMR data was as follows:
[1703] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.17 (d, 3H); 4.26 (m,
1H); 4.44 (m, 1H).
[1704] Optical Rotation: [.alpha.].sub.20=-31.0.degree.@589 nm
(c=1.05, DMSO).
[1705] C.sub.22H.sub.22N.sub.4O.sub.3F.sub.2 (MW=428.44); mass
spectroscopy (MH.sup.+) 428.
Example 115
Synthesis of Methyl
N-(N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-cyclohexylpropi-
onate
[1706] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
methyl (S)-2-amino-3-cyclohexylpropionate (Novabiochem), the title
compound was prepared as a solid (mp=116-119.degree. C.). The
reaction was monitored by tic (Rf=0.4 in 4% MeOH/CHCl.sub.3) and
the product was purified by silica gel chromatography using 4%
MeOH/CHCl.sub.3 as the eluent, followed by recrystallization from
1-chlorobutane/hexanes.
[1707] NMR data was as follows:
[1708] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.22 (d, 3H); 3.62 (s,
3H).
[1709] Optical Rotation: [.alpha.].sub.20=-21.2.degree.@589 nm
(c=1.01, DMSO).
[1710] C.sub.21H.sub.27N.sub.2O.sub.4F.sub.2 (MW=410.46); mass
spectroscopy (MH.sup.+) 411.
Example 116
Synthesis of
N-(2-Methoxyethyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-ami-
no-3-(4-nitrophenyl)propionamide
[1711] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
N-(2-methoxyethyl)-(S)-2-amino-3-(4-nitrophenyl)propionamide.
hydrochloride (prepared from N-BOC-L-4-nitrophenylalanine (Advanced
Chemtech) and 2-methoxyethylamine (Aldrich) using General Procedure
C, followed by removal of the BOC-group using General Procedure P),
the title compound was prepared as a solid (mp=263-265.degree. C.).
The reaction was monitored by tlc (Rf=0.5 in 10% MeOH/CHCl.sub.3)
and the product was purified by silica gel chromatography using 10%
MeOH/CHCl.sub.3 as the eluent, followed by recrystallization from
EtOH/acetonitrile.
[1712] NMR data was as follows:
[1713] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.15 (d, 3H); 4.23 (m,
1H); 4.54 (m, 1H).
[1714] Optical Rotation: [.alpha.].sub.20=-19.9.degree.@589 nm
(c=1.00, DMSO).
[1715] C.sub.23H.sub.26N.sub.4O.sub.6F.sub.2 (MW=492.48); mass
spectroscopy (MH.sup.+) 493.
Example 117
Synthesis of N-[N-(3-Nitrophenylacetyl)-L-alaninyl]-L-serine Ethyl
Ester
[1716] Following General Procedure C and using
N-(3-nitrophenylacetyl)-L-alanine (prepared from
3-nitrophenylacetic acid (Aldrich) and L-alanine ethyl ester
hydrochloride (Sigma) using General Procedure C, followed by
hydrolysis using General Procedure AF) and L-serine ethyl ester
hydrochloride (Sigma), the title compound was prepared as a solid
(mp=179-181.degree. C.). The reaction was monitored by tlc (Rf=0.2
in 5% MeOH/CHCl.sub.3) and the product was purified by silica gel
chromatography using 5% MeOH/CHCl.sub.3 as the eluent.
[1717] NMR data was as follows:
[1718] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.20 (m, 6H); 4.30 (m,
1H); 4.41 (m, 1H); 5.04 (t, 1H).
[1719] Optical Rotation: [.alpha.].sub.20=-19.7.degree.@589 nm
(c=1.01, DMSO).
[1720] C.sub.16H.sub.21N.sub.3O (MW=367.36); mass spectroscopy
(M.sup.+) 368.
Example 118
Synthesis of
N-[(R)-.alpha.-Methylbenzyl]-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-
-L-alaninamide
[1721] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
N-(R)-.alpha.-methylbenzyl-L-alaninamide hydrochloride (prepared
from N-BOC-L-alanine (Sigma) and (R)-.alpha.-methylbenzylamine
(Aldrich) using General Procedure C, followed by removal of the
BOC-group using General Procedure P), the title compound was
prepared as a solid (mp=240-242.degree. C.). The reaction was
monitored by tic (Rf=0.4 in 10% MeOH/CHCl.sub.3) and the product
was purified by silica gel chromatography using 9% MeOH/CHCl.sub.3
as the eluent, followed by recrystallization from acetonitrile.
[1722] NMR data was as follows:
[1723] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.19 (t, 6H);.1.31 (d,
3H).
[1724] Optical Rotation: [.alpha.].sub.20=+1.0.degree.@589 nm
(c=1.00, DMSO).
[1725] C.sub.22H.sub.25N.sub.3O.sub.3F.sub.2 (MW=417.45); mass
spectroscopy (MH.sup.+) 417.
Example 119
Synthesis of
N-[(S)-.alpha.-Methylbenzyl]-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-
-L-alaninamide
[1726] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
N-(S)-.alpha.-methylbenzyl-L-alaninamide hydrochloride (prepared
from N-BOC-L-alanine (Sigma) and (R)-.alpha.-methylbenzylamine
(Aldrich) using General Procedure C, followed by removal of the
BOC-group using General Procedure P), the title compound was
prepared as a solid (mp=293-295.degree. C.). The reaction was
monitored by tlc (Rf=0.4 in 10% MeOH/CHCl.sub.3) and the product
was purified by silica gel chromatography using 10% MeOH/CHCl.sub.3
as the eluent, followed by recrystallization from acetonitre.
[1727] NMR data was as follows:
[1728] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.20 (m, 6H); 1.30 (d,
3H).
[1729] Optical Rotation: [.alpha.].sub.20=-65.9.degree.@589 nm
(c=1.05, DMSO).
[1730] C.sub.22H.sub.25N.sub.3O.sub.3F.sub.2 (MW=417.45); mass
spectroscopy (MH.sup.+) 417.
Example 120
Synthesis of
N-(4-Fluorobenzyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanina-
mide
[1731] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
N-(4-fluorobenzyl)-L-alaninamide hydrochloride (prepared from
N-BOC-L-alanine (Sigma) and 4-fluorobenzylamine (Aldrich) using
General Procedure C, followed by removal of the BOC-group using
General Procedure P), the title compound was prepared as a solid
(mp=257-259.degree. C.). The reaction was monitored by tlc (Rf=0.4
in 10% MeOH/CHCl.sub.3) and the product was purified by silica gel
chromatography using 9% MeOH/CHCl.sub.3 as the eluent, followed by
trituration using 1-chlorobutane.
[1732] NMR data was as follows:
[1733] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.20 (m, 6H); 3.52 (s,
2H).
[1734] Optical Rotation: [.alpha.].sub.20=-28.7.degree.@589 nm
(c=1.00, DMSO).
[1735] C.sub.21H.sub.22N.sub.3O.sub.3F.sub.3 (MW=421.42); mass
spectroscopy (MH.sup.+) 421.
Example 121
Synthesis of
N-(4-Pyridylmethyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanin-
amide
[1736] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
N-(4-pyridylmethyl)-L-alaninamide dihydrochloride (prepared from
N-BOC-L-alanine (Sigma) and 4 (aminomethyl)pyridine (Aldrich) using
General Procedure C, followed by removal of the BOC-group using
General Procedure P), the title compound was prepared as a solid
(mp 244-247.degree. C.). The reaction was monitored by tlc (Rf=0.3
in 10% MeOH/CHCl.sub.3) and the product was purified by silica gel
chromatography using 10% MeOH/CHCl.sub.3 as the eluent, followed by
recrystallization from acetonitrile.
[1737] NMR data was as follows:
[1738] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.21 (d, 3H); 1.26 (d,
3H).
[1739] Optical Rotation: [.alpha.].sub.20=-30.3.degree.@589 nm
(c=1.00, DMSO).
[1740] C.sub.27H.sub.22N.sub.4O.sub.3F.sub.2 (MW=404.42); mass
spectroscopy (MH.sup.+) 405.
Example 122
Synthesis of
N-(4-Trifluoromethylbenzyl)-N'-(N-(3,5-difluorophenylacetyl)-L-alaninyl]--
L-alaninamide
[1741] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
N-(4-trifluoromethylbenzyl)-L-alaninamide hydrochloride (prepared
from N-BOC-L-alanine.(Sigma) and 4-(trifluoromethyl)benzylamine
(Aldrich) using General Procedure C, followed by removal of the
BOC-group using General Procedure P), the title compound was
prepared as a solid (mp=244-247.degree. C.). The reaction was
monitored by tlc (Rf=0.4 in 10% MeOH/CHCl.sub.3) and the product
was purified by silica gel chromatography using 8% MeOH/CHCl.sub.3
as the eluent, followed by triturated using 1-chlorobutane.
[1742] NMR data was as follows:
[1743] .sup.1H-nmr (DMSO-d.sub.6): .delta.=3.52 (s, 2H); 4.35 (d,
2H).
[1744] Optical Rotation: [.alpha.].sub.20=-27.4.degree.@589 nm
(c=1.05, DMSO).
[1745] C.sub.22H.sub.22N.sub.3O.sub.3F.sub.5 (MW=471.43); mass
spectroscopy (MH.sup.+) 471.
Example 123
Synthesis of Ethyl
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino-2-phenylpropionate
[1746] Following General Procedure C and using
3,5-difluorophenylacetic acid (Oakwood) and ethyl
N-(L-alaninyl)-2-amino-2-phenylpropionate hydrochloride (prepared
from N-BOC-L-alanine (Sigma) and D,L-.alpha.-methylphenylglycine
ethyl ester (from Example D9 above) using General Procedure C,
followed by removal of the BOC-group using General Procedure P),
the title compound was prepared as a solid (mp=128-130.degree. C.).
The reaction was monitored by tlc (Rf=0.2 in 3% MeOH/CHCl.sub.3)
and the product was purified by silica gel chromatography using 3%
MeOH/CHCl.sub.3 as the eluent.
[1747] NMR data was as follows:
[1748] .sup.1H-nmr (DMSO-d.sub.6)(1:1 mixture of diastereomers):
.delta.=1.72, 1.77 (singlets, 3H); 3.52 (s, 2H).
[1749] C.sub.22H.sub.24N.sub.2O.sub.4F.sub.2 (MW=418.44); mass
spectroscopy (MH.sup.+) 418.
Example 124
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-phenylalanine
tert-Butyl Ester
[1750] Following General Procedure C and using
3,5-difluorophenylacetic acid (Oakwood) and
N-(L-alaninyl)-L-phenylalanine tert-butyl ester hydrochloride
(prepared from N-BOC-L-alanine (Sigma) and L-phenylalanine
tert-butyl ester hydrochloride (Advanced Chemtech) using General
Procedure C, followed by removal of the BOC-group using General
Procedure P), the title compound was prepared as a gel. The
reaction was monitored by tlc (Rf=0.5 in 4% MeOH/CHCl.sub.3) and
the product was purified by silica gel chromatography using 4%
MeOH/CHCl.sub.3 as the eluent.
[1751] NMR data was as follows:
[1752] .sup.1H-nmr (DMSO-.sub.6): .delta.=1.19 (d, 3M); 1.30 (s,
9H).
[1753] C.sub.24H.sub.25N.sub.2O.sub.4F.sub.2 (MW=446.50); mass
spectroscopy (MH.sup.+) 446.
Example 125
Synthesis of Methyl
N-(N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-methylpropionate
[1754] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
methyl 2-aminoisobutyrate (prepared from 2-aminoisobutyric acid
(Aldrich) using General Procedure H), the tide compound was
prepared as a solid. The reaction was monitored by tlc (Rf=0.25 in
CHCl.sub.3/MeOH 95:5).
[1755] NMR data was as follows:
[1756] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.32 (m, 3H), 7.13 (m,
1H), 7.00 (m, 2H), 4.31 (m, 1H), 3.53 (m, 5H), 7.08 (m, 1H), 1.36
(s, 3H), 1.34 (s, 3H), 1.19 (d, 3H).
[1757] Optical Rotation: [.alpha.].sub.23=-25.degree. (c 1,
MeOH).
[1758] C.sub.16H.sub.20N.sub.2O.sub.4F.sub.2 (MW=342.34); mass
spectroscopy (MH.sup.+) 343.
Example 126
Synthesis of Ethyl
N-(N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino2-cyclohexylacetate
[1759] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
ethyl 2-amino-2-cyclohexylacetate hydrochloride (prepared from
cyclohexylglycine (Advanced Chemtech) using General Procedure H),
the title compound was prepared as a solid (mp=146-150.degree. C.).
The reaction was monitored by tlc (Rf=0.3 in 3% MeOH/CHCl.sub.3)
and the product was purified by silica gel chromatography using 3%
MeOH/CHCl.sub.3 as the eluent.
[1760] NMR data was as follows:
[1761] .sup.1H-nmr (DMSO-d.sub.6)(1:1 mixture of diastereomers):
.delta.=1.60 (m, 6H); 3.50 (s, 2H).
[1762] C.sub.21H.sub.28N.sub.2O.sub.4F.sub.2 (MW=410.46); mass
spectroscopy (MH.sup.+) 410.
Example 127
Synthesis of
N-(2-Methoxyethyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylg-
lycinamide
[1763] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
N-(2-methoxyethyl)-L-phenylglycinamide hydrochloride (prepared from
N-BOC-L-phenylglycine (Advanced Chemtech) and 2-methoxyethylamine
(Aldrich) using General Procedure C, followed by removal of the
BOC-group using General Procedure P), the title compound was
prepared as a solid (mp=252-254.degree. C.). The reaction was
monitored by tlc (Rf=0.3 in 10% MeOH/CHCl.sub.3) and the product
was purified by silica gel chromatography using 10% MeOH/CHCl.sub.3
as the eluent, followed by recrystallization from acetonitrile.
[1764] NMR data was as follows:
[1765] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.22 (d, 3H); 5.43 (d,
1H).
[1766] Optical Rotation: [.alpha.].sub.20=+6.17.degree.@589 nm
(c=1.04, DMSO).
[1767] C.sub.22H.sub.25N.sub.3O.sub.4F.sub.2 (MW=433.46); mass
spectroscopy (MH.sup.+) 434.
Example 128
Synthesis of
N-(N-(Isovaleryl)-2-amino-2-cyclohexylacetyl]-L-alanine Ethyl
Ester
[1768] Following General Procedure C and using
N-(isovaleryl)-2-amino-2-cyclohexylacetic acid (prepared from
isovaleric acid (Aldrich) and D,L-.alpha.-cyclohexylglycine ethyl
ester hydrochloride (prepared from cyclohexylglycine. (Advanced
Chemtech) and ethanol using General Procedure H) using General
Procedure C, followed by removal of the BOC-group using General
Procedure P) and L-alanine ethyl ester hydrochloride (Sigma), the
title compound was prepared as a solid (mp 220-224.degree. C.). The
reaction was monitored by tlc (Rf=0.2 in 5% MeOH/CHCl.sub.3) and
the product was purified by silica gel chromatography using 5%
MeOH/CHCl.sub.3 as the eluent, followed by recrystallization from
1-chlorobutane/acetonitrile.
[1769] NMR data was as follows:
[1770] .sup.1H-nmr (DMSO-d.sub.6): .delta.=0.85 (d, 6H); 4.04 (m,
2H).
[1771] C.sub.18H.sub.32N.sub.2O.sub.4 (MW=340.46); mass
spectroscopy (MH.sup.+) 341.
Example 129
Synthesis of
N-2-(N,N-Dimethylamino)ethyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-
-L-phenylglycinamide
[1772] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
N-2-(N,N-dimethylamino)ethyl-L-phenylglycinamide dihydrochloride
(prepared from N-BOC-L-phenylglycine (Advanced Chemtech) and
N,N-dimethylethylenediamine (Aldrich) using General Procedure C,
followed by removal of the BOC-group using General Procedure P),
the title compound was prepared as a solid (mp=234-236.degree. C.).
The reaction was monitored by tlc (Rf=0.3 in 15% MeOH/CHCl.sub.3)
and the product was purified by silica gel chromatography using 10%
MeOH/CHCl.sub.3, followed by slurrying in acetonitrile.
[1773] NMR data was as follows:
[1774] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.22 (d, 3H); 5.41 (d,
1H).
[1775] Optical Rotation: [.alpha.].sub.20=+5.7.degree.@589 nm
(c=1.01, DMSO).
[1776] C.sub.23H.sub.28N.sub.4O.sub.3F.sub.2 (MW=446.50); mass
spectroscopy (MH.sup.+) 446.
Example 130
Synthesis of
N-(2-Pyridylmethyl)-N'-(N-(3,5difluorophenylacetyl)-L-alaninyl]-phenylgly-
cinamide
[1777] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
N-(2-pyridylmethyl)-L-phenylglycinamide dihydrochloride (prepared
from N-BOC-L-phenylglycine (Advanced Chemtech) and
2-(aminomethyl)pyridine (Aldrich) using General Procedure C,
followed by removal of the BOC-group using General Procedure P),
the title compound was prepared as a solid (mp=272-275.degree. C.).
The reaction was monitored by tlc (Rf=0.4 in 10% MeOH/CHCl.sub.3)
and the product was purified by silica gel chromatography using 10%
MeOH/CHCl.sub.3 as the eluent, followed by recrystallization from
acetonitrile.
[1778] NMR data was as follows:
[1779] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.24 (d, 3H); 5.50 (d,
1H).
[1780] Optical Rotation: [.alpha.].sub.20=+12.4.degree.@589 nm
(c=1.02, DMSO).
[1781] C.sub.25H.sub.24N.sub.4O.sub.3F.sub.2 (MW=466.49); mass
spectroscopy (MH.sup.+) 467.
Example 131
Synthesis of N-[N-(3-Pyridylacetyl)-L-alaninyl]-L-phenylalanine
Methyl Ester
[1782] Following General Procedure C and using 3-pyridylacetic acid
hydrochloride (Aldrich) and N-(L-alaninyl)-L-phenylalanine methyl
ester hydrochloride (prepared from N-BOC-L-alanine (Sigma) and
L-phenylalanine methyl ester hydrochloride (Sigma) using General
Procedure C, followed by removal of the BOC-group using General
Procedure P), the title compound was prepared as a solid
(mp=150-152.degree. C.). The reaction was monitored by tlc (Rf=0.3
in 10% MeOH/CHCl.sub.3) and the product was purified by silica gel
chromatography using 10% MeOH/CHCl.sub.3 as the eluent, followed by
recrystallization from acetonitrile.
[1783] NMR data was as follows:
[1784] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.16 (d, 3H); 347 (s,
2H).
[1785] Optical Rotation: [.alpha.].sub.20=-19.0.degree.@589 nm
(c=1.03, DMSO).
[1786] C.sub.20H.sub.23N.sub.3O.sub.4 (MW=369.42); mass
spectroscopy (MH.sup.+) 369.
Example 132
Synthesis of N-[N-(2-Pyridylacetyl)-L-alaninyl]-L-phenylalanine
Methyl Ester
[1787] Following General Procedure C and using 2-pyridylacetic acid
hydrochloride (Aldrich) and N-(L-alaninyl)-L-phenylalanine methyl
ester hydrochloride (prepared from N-BOC-L-alanine (Sigma) and
L-phenylalanine methyl ester hydrochloride (Sigma) using General
Procedure C, followed by removal of the BOC-group using General
Procedure P), the title compound was prepared as a solid
(mp=137-139.degree. C.). The reaction was monitored by tlc (Rf=0.4
in 8% MeOH/CHCl.sub.3) and the product was purified by silica gel
chromatography using 8% MeOH/CHCl.sub.3 as the eluent, followed by
recrystallization from 1-chlorobutane/acetonitrile.
[1788] NMR data was as follows:
[1789] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.17 (d, 3H); 3.65 (s,
2H).
[1790] Optical Rotation: [.alpha.].sub.20=-17.48.degree.@589 nm
(c=1.09, DMSO).
[1791] C.sub.20H.sub.23N.sub.3O.sub.4 (W=369.42); mass spectroscopy
(MH.sup.+) 369.
Example 133
Synthesis of N-[N-(4-Pyridylacetyl)-L-alaninyl]-L-phenylalanine
Methyl Ester
[1792] Following General Procedure C and using 4-pyridylacetic acid
hydrochloride (Aldrich) and N-(L-alaninyl)-L-phenylalanine methyl
ester hydrochloride (prepared from N-BOC-L-alanine (Sigma) and
L-phenylalanine methyl ester hydrochloride (Sigma) using General
Procedure C, followed by removal of the BOC-group using General
Procedure P), the title compound was prepared as a solid
(mp=152-154.degree. C.). The reaction was monitored by tlc (Rf=0.4
in 10% MeOH/CHCl.sub.3) and the product was purified by silica gel
chromatography using 10% MeOH/CHCl.sub.3 as the eluent, followed by
recrystallization from 1-chlorobutane/acetonitrile.
[1793] NMR data was as follows:
[1794] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.17 (d, 3H); 3.47 (s,
2H).
[1795] Optical Rotation: [.alpha.].sub.20=-17.degree.@589 nm
(c=1.00, DMSO).
[1796] C.sub.20H.sub.23N.sub.3O.sub.4 (MW=369.42); mass
spectroscopy (MH.sup.+) 369.
Example 134
Synthesis of Ethyl
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4fluorophenyl)acet-
ate
[1797] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
ethyl 2-amino-2-(4-fluorophenyl)acetate hydrochloride (prepared
from 4-fluorophenylglycine (Fluka) and ethanol using General
Procedure H), the title compound was prepared as a solid
(mp=169-183.degree. C.). The reaction was monitored by tlc (Rf=0.3
in 4% MeOH/CHCl.sub.3) and the product was purified by silica gel
chromatography using 4% MeOH/CHCl.sub.3 as the eluent, followed by
recrystallization from 1-chlorobutane/acetonitrile.
[1798] NMR data was as follows:
[1799] .sup.1H-nmr (DMSO-d.sub.6)(1:1 mixture of diastereomers):
.delta.=3.49, 3.53 (singlets, 2H); 5.40 (m, 1H).
[1800] C.sub.21H.sub.21N.sub.2O.sub.4F.sub.3 (MW=422.4); mass
spectroscopy (MH.sup.+) 422.
Example 135
Synthesis of Ethyl
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino2-(2-fluorophenyl)acet-
ate
[1801] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
ethyl 2-amino-2-(2-fluorophenyl)acetate hydrochloride (prepared
from 2-fluorophenylglycine (Fluka) and ethanol using General
Procedure H), the title compound was prepared as a solid
(mp=153-170.degree. C.). The reaction was monitored by tlc (Rf=0.3
in 5% MeOH/CHCl.sub.3) and the product was purified by silica gel
chromatography using 5% MeOH/CHCl.sub.3 as the eluent, followed by
recrystallization from 1-chlorobutane/acetonitrile.
[1802] NMR data was as follows:
[1803] .sup.1H-nmr (DMSO-d.sub.6)(1:1 mixture of diastereomers):
.delta.=3.50, 3.54 (singlets, 2H), 5.66 (m, 1H).
[1804] C.sub.21H.sub.21N.sub.2O.sub.4F.sub.3 (MW=422.40); mass
spectroscopy (MH.sup.+) 422.
Example 136
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-L-phenylglycinyl]-L-alanine Ethyl
Ester
[1805] Following General Procedure C and using
3,5-difluorophenylacetic acid (Oakwood) and
N-(L-phenylglycinyl)-L-alanine ethyl ester hydrochloride (prepared
from N-BOC-L-phenylglycine (Advanced Chemtech) and L-alanine ethyl
ester hydrochloride (Aldrich) using General Procedure C, followed
by removal of the BOC-group using General Procedure P), the title
compound was prepared as a solid. The reaction was monitored by tlc
(Rf=0.3 in 3% MeOH/CHCl.sub.3) and the product was purified by
silica gel chromatography using 3% MeOH/CHCl.sub.3 as the eluent,
followed by recrystallization from 1-chlorobutane/acetonitrile.
[1806] NMR data was as follows:
[1807] .sup.1H-nmr (DMSO-d.sub.6): .delta.=3.50 (s, 2H), 5.53 (d,
1H).
[1808] C.sub.21H.sub.22N.sub.2O.sub.4F.sub.2 (MW=404.42); mass
spectroscopy (MH.sup.+) 405.
Example 137
Synthesis of Ethyl
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino-3-phthalimidopropiona-
te
[1809] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
ethyl 2-amino-3-phthalimidopropionate hydrochloride (from Example
D10 above), the title compound was prepared as a solid
(mp=197-201.degree. C.). The reaction was monitored by tlc (Rf=0.5
in 10% MeOH/CHCl.sub.3) and the product was purified by silica gel
chromatography using 5% MeOH/CHCl.sub.3 as the eluent.
[1810] NMR data was as follows:
[1811] .sup.1H-nmr (DMSO-d.sub.6)(1:1 mixture of diastereomers):
.delta.=7.88 (m, 4H), 8.29 (t, 1H), 8.48, 8.55 (doublets, 1H).
[1812] C.sub.24H.sub.23N.sub.3O.sub.6F.sub.2 (MW=487.46); mass
spectroscopy (MH.sup.+) 487.
Example 138
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-phenylglycine
Neopentyl Ester
[1813] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
L-phenylglycine neopentyl ester hydrochloride (prepared from
N-BOC-L-phenylglycine (Advanced Chemtech) and
2,2-dimethyl-1-propanol (Aldrich) using-General Procedure C (with
catalytic DMAP), followed by removal of the BOC-group using General
Procedure P), the title compound was prepared as a solid
(mp=133-136.degree. C.). The reaction was monitored by tlc (Rf=0.7
in 10% MeOH/CHCl.sub.3) and the product was purified by silica gel
chromatography using 4% MeOH/CHCl.sub.3 as the eluent, followed by
recrystallization from 1-chlorobutane/hexanes.
[1814] NMR data was as follows:
[1815] .sup.1H-nmr (DMSO-d.sub.6): .delta.=3.50 (s, 2H), 5.42 (d,
1H).
[1816] Optical Rotation: [.alpha.].sub.20=+45.9.degree.@589 nm (c
1.02, DMSO).
[1817] C.sub.24H.sub.28N.sub.2O.sub.4F.sub.2 (MW=446.50); mass
spectroscopy (MH.sup.+) 446.
Example 139
Synthesis of
N-tert-Butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycina-
mide
[1818] Following General Procedure AB and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above),
S-(+)-.alpha.-methylbenzylamine (Aldrich), benzaldehyde (Aldrich)
and tert-butylisocyanide (Aldrich), the title compound was prepared
as a solid (mp=233-235.degree. C.). The reaction was monitored by
tlc (Rf=0.4 in 10% MeOH/CHCl.sub.3) and the product was purified by
silica gel chromatography using 8% MeOH/CHCl.sub.3 as the eluent,
followed by recrystallization from 1-chlorobutane/acetonitrile.
[1819] NMR data was as follows:
[1820] .sup.1H-nmr (DMSO-d.sub.6)(1:1 mixture of diastereomers):
.delta.=3.52 (s, 2H), 5.40 (m, 1H).
[1821] C.sub.23H.sub.27N.sub.3O.sub.3F.sub.2 (MW=431.49); mass
spectroscopy (MH.sup.+) 432.
Example 140
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-phenylglycine
tert-Butyl Ester
[1822] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
L-phenylglycine tert-butyl ester hydrochloride (Advanced Chemtech),
the title compound was prepared as a solid (mp=145-147.degree. C.).
The reaction was monitored by tlc (Rf=0.5 in 5% MeOH/CHCl.sub.3)
and the product was purified by silica gel chromatography using
2.5% MeOH/CHCl.sub.3 as the eluent, followed by recrystallization
from 1-chlorobutane/hexanes.
[1823] NMR data was as follows:
[1824] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.26 (d, 3H); 5.20 (d,
1H).
[1825] Optical Rotation: [.alpha.].sub.20=+14.8.degree.@589 nm
(c=1.01, MeOH).
[1826] C.sub.23H.sub.26N.sub.2O.sub.4F.sub.2 (MW=432.47); mass
spectroscopy (MH.sup.+) 433.
Example 141
Synthesis of
N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide
[1827] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
L-phenylglycinamide hydrochloride (prepared from
N-BOC-L-phenylglycine (Advanced Chemtech) and ammonia using General
Procedure C, followed by removal of the BOC-group using General
Procedure P), the title compound was prepared as a solid
(mp=288-290.degree. C.). The reaction was monitored by tlc (Rf=0.4
in 15% MeOH/CHCl.sub.3) and the product was purified by silica gel
chromatography using 15% MeOH/CHCl.sub.3 as the eluent, followed by
recrystallization from EtOH.
[1828] NMR data was as follows:
[1829] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.22 (d, 3H), 5.56 (d,
1H).
[1830] Optical Rotation: [.alpha.].sub.20=+27.5.degree.@589 nm
(c=1.03, DMSO).
[1831] C.sub.19H.sub.19N.sub.3O.sub.3F.sub.2 (MW=375.38); mass
spectroscopy (MH.sup.+) 376.
Example 142
Synthesis of
4-N-[N-(3-Nitrophenylacetyl)-L-alaninyl]-L-valinyl]morpholine
[1832] Following General Procedure C and using
N-(3-nitrophenylacetyl)-L-alanine (from Example D11 above) and
4-(L-valinyl)morpholine (prepared from N-BOC-L-valine (Aldrich) and
morpholine (Aldrich) using General Procedure M, followed by removal
of the BOC-group using General Procedure P), the title compound was
prepared as a solid. The reaction was monitored by tlc (Rf=0.5 in
9:1 CHCl.sub.3/MeOH) and the product was purified by silica gel
chromatography using 98:2 CHCl.sub.3/MeOH as the eluent.
[1833] NMR data was as follows:
[1834] .sup.1H-nmr (CDCl.sub.3): .delta.=8.12 (d, 2H), 8.08 (dd,
1H), 7.59 (d, 1H, J=7 Hz), 7.42 (t, 1H), 7.32 (d, J=88 Hz, 1H),
7.03(d, J=8 Hz, 1H), 4.78 (m, 1H), 4.68 (m, H), 3.61 (m, 10H), 1.90
(m, 1H), 1.96 (d, 3H), 1.31 (d, 3H), 0.88 (d, 3H), 0.80 (d,
3H),
[1835] Optical Rotation: [.alpha.].sub.23=-5 (c 5, MeOH).
Example 143
Synthesis of N-[N-(3-Nitrophenylacetyl)-L-alaninyl]-L-valine Ethyl
Ester
[1836] Following General Procedure C and using
N-(3-nitrophenylacetyl)-L-alanine (from Example D11 above) and
L-valine ethyl ester hydrochloride (Aldrich), the title compound
was prepared as a solid. The reaction was monitored by tlc (Rf=0.2
in 97:3 CHCl.sub.3/MeOH) and the product was purified by silica gel
chromatography using 97:3 CHCl.sub.3/MeOH as the eluent.
[1837] NMR data was as follows:
[1838] .sup.1H-nmr (CDCl.sub.3): .delta.=8.13 (m, 2H), 7.62 (d, J=7
Hz, 1H), 7.47 (t, 1H), 6.52 (m, 2H), 4.57 (m, 1H), 4.46 (m, 1H),
4.19 (m, 2H), 3.65 (s, 2H), 2.13 (m, 1H), 1.38 (d, 3H), 1.22 (t,
3H), 0.82 (d, 3H).
[1839] Optical Rotation: [.alpha.].sub.23=-24.3.degree.@589 nm (c
1, DMSO).
[1840] C.sub.18H.sub.25N.sub.3O.sub.6 (MW=379.42); mass
spectroscopy (MH.sup.+) 380.
Example 144
Synthesis of N-N-(3-Nitrophenylacetyl)-L-alaninyl]-L-threonine
Methyl Ester
[1841] Following General Procedure C and using
N-(3-nitrophenylacetyl)-L-alanine (from Example D11 above) and
L-threonine methyl ester hydrochloride (Aldrich), the title
compound was prepared as a solid. The reaction was monitored by tlc
(Rf=0.1 in 95:5 CHCl.sub.3/MeOH) and the product was purified by
silica gel chromatography using 95:5 CHCl.sub.3/MeOH as the
eluent.
[1842] NMR data was as follows:
[1843] .sup.1H-nmr (CDCl.sub.3): .delta.=8.08 (d, 1H), 7.96 (d,
1H), 7.59 (d, 1H), 7.45 (d, 1H), 7.34 (t, 1H), 7.20 (d, 1H), 4.43
(m, 1H), 4.39 (dd, 1H), 4.13 (m, 1H), 3.59 (s, 3H), 3.51 (s, 2H),
1.20 (d, 3H), 1.03 (d, 3H).
[1844] Optical Rotation: [.alpha.].sub.23=-20.8.degree. (c 5,
MeOH).
[1845] C.sub.16H.sub.20N.sub.2O.sub.7 (MW=367.3); mass spectroscopy
(MH.sup.+) 368.
Example 145
Synthesis of
4-[N-[N-(3-Nitrophenylacetyl)-L-alaninyl]-(S)-2-amino-3-tert-butoxybutyry-
l]morpholine
[1846] Following General Procedure C and using
N-(3-nitrophenylacetyl)-L-alanine (from Example D11 above) and
4-((S)-2-amino-3-tert-butoxybutyryl]-morpholine (prepared from
N-BOC-O-tert-butyl-L-threonine (Sigma) and morpholine (Aldrich)
using General Procedure M, followed by removal of the BOC-group
using General Procedure P), the title compound was prepared as a
solid. The reaction was monitored by tlc (Rf=0.1 in 95:5
CHCl.sub.3/MeOH) and the product was purified by silica gel
chromatography using 96:4 CHCl.sub.3/MeOH as the eluent.
[1847] NMR data was as follows:
[1848] .sup.1H-nmr (CDCl.sub.3): .delta.=8.12 (m, 22H), 7.66 (d,
1H), 7.47 (t, 1H), 6.88 (d, 1H), 6.32 (d, 1H), 4.78 (m, 1H), 4.50
(m, 1H), 3.90-3.40 (m, 1H), 1.40 (d, 3H), 1.18 (s, 9H), 1.0 (d,
3H).
[1849] C.sub.23H.sub.33N.sub.3O.sub.7 (MW=478.5); mass spectroscopy
(MH.sup.+) 479.
Example 146
Synthesis of
4[N-[N-(3-Nitrophenylacetyl)-L-alaninyl]-L-isoleucinyl]morpholine
[1850] Following General Procedure C and using
N-(3-nitrophenylacetyl)-L-alanine (from Example D11 above) and
4-(L-isoleucinyl)morpholine (prepared from N-BOC-L-isoleucine
(Aldrich) and morpholine (Aldrich) using General Procedure M,
followed by removal of the BOC-group using General Procedure P),
the title compound was prepared as a solid (mp=156-160.degree. C.).
The reaction was monitored by tlc (Rf=0.45 in 9:1 CHCl.sub.3/MeOH)
and the product was purified by silica gel chromatography using
98:2 CHCl.sub.3/MeOH as the eluent.
[1851] NMR data was as follows:
[1852] .sup.1H-nmr (CDCl.sub.3): .delta.=8.16 (di 1H), 8.09 (d,
1H), 7.63 (d, 1H), 7.45 (t, 1H), 7.30 (d, 11), 6.89 (d, 1H), 4.78
(m, 1H), 4.62 (m, 1H), 3.6 (m, 10H), 1.65 (m, 1H), 1.4 (m, 1HE),
1.29 (d, 3H), 1.03 (d, 3H), 0.90-0.76 (m, 6H).
[1853] Optical Rotation: [.alpha.].sub.23=-55.degree.@589 nm (c 1,
MeOH).
Example 147
Synthesis of N-[N-(3-Nitrophenylacetyl)-L-alaninyl]-L-isoleucine
Methyl Ester
[1854] Following General Procedure C and using
N-(3-nitrophenylacetyl)-L-alanine (from Example D11 above) and
L-isoleucine methyl ester hydrochloride (Aldrich), the title
compound was prepared as a solid. The reaction was monitored by tlc
(Rf=0.15 in 97:3 CHCl.sub.3/MeOH) and the product was purified by
silica gel chromatography using 97:3 CHCl.sub.3/MeOH as the
eluent.
[1855] NMR data was as follows:
[1856] .sup.1H-nmr (CDCl.sub.3): .delta.=8.12 (m, 2H), 7.66 (d,
1H), 7.49 (t, 1H), 6.50 (m, 2H), 4.52 (m, 2H), 3.72 (s, 3H), 3.61
(s, 2H), 1.87 (m, 1H), 1.32 (m; 4H), 1.07 (m, 1H), 0.81(d, 6H).
[1857] Optical Rotation: [.alpha.].sub.23-7.3.degree. (c 5,
MeOH).
[1858] C.sub.18H.sub.25N.sub.2O.sub.6 (MW=379); mass spectroscopy
(MH.sup.+) 379.
Example 148
Synthesis of
N-[N-(3-Nitrophenylacetyl)-L-alaninyl]-L-isoleucine
[1859] Following General Procedure AF and using
N-(N-(3-nitrophenylacetyl)-L-alaninyl]-L-isoleucine methyl ester
(from Example 147 above), the title compound was prepared as a
solid.
[1860] NMR data was as follows:
[1861] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.41 (d, 1H), 8.15 (s,
1H), 8.07 (d, 1H); 7.91 (d, 1H), 7.68 (d, 1H), 7.53 (t, 1H), 4.36.
(m, 1H), 4.12 (m, 1H), 3.62 (s, 2H), 1.71 (m, 1H), 1.31 (m, 1H),
1.18 (d, 3H), 1.07 (m, 1H), 0.79 (m, 6H).
[1862] Optical Rotation: [.alpha.].sub.23=42.degree. (c 5,
MeOH).
[1863] C.sub.17H.sub.23N.sub.2O.sub.6 (MW=365.3); mass spectroscopy
(MH.sup.+) 366.
Example 149
Synthesis of
N-[N-[N-(3-Nitrophenylacetyl)-L-alaninyl]-threoninyl]-L-valine
Ethyl Ester
[1864] Following General Procedure C and using
N-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-threonine (prepared from
N-(N-(3-nitrophenylacetyl)-L-alaninyl]-L-threonine methyl ester
(from Example 144 above) using General Procedure AF) and L-valine
ethyl ester hydrochloride (Aldrich), the title compound was
prepared as a solid. The reaction was monitored by tlc (Rf=0.1 in
96:4 CHCl.sub.3/MeOH) and the product was purified by silica gel
chromatography using 96:4 CHCl.sub.3/MeOH as the eluent.
[1865] NMR data was as follows:
[1866] .sup.1H-nmr (CDCl.sub.3): .delta.=8.12 (m, 1H), 7.60 (d,
1H), 7.48 (t, 1H), 7.05 (d, 1H), 6.98.(d, 1H), 6.48 (d, 1H), 4.60
(m, 1H), 4.47 (m, 3H), 4.22 (m, 2H) 3.65 (s, 2H), 2.19 (m, 1H),
1.38 (d, 3H), 1.28 (t, 3H), 1.09 (d, 3H), 0.87 (m 6H).
[1867] Optical Rotation: [.alpha.].sub.23=-85.degree. (c 5,
MeOH).
Example 150
Synthesis of Methyl
N-[N-(3-nitrophenylacetyl)-L-alaninyl]-(S)-2-aminopentanoate
[1868] Following General Procedure C and using
N-(3-nitrophenylacetyl)-L-alanine (from Example D11 above) and
methyl (S)-2-aminopentanoate hydrochloride (prepared from
(S)-2-aminopentanoic acid (Novabiochem) using General Procedure H),
the title compound was prepared as a solid. The reaction was
monitored by tlc (Rf=0.4 in 9:1 CHCl.sub.3/MeOH).
[1869] NMR data was as follows:
[1870] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.39 (m, 1H), 8.28 (m,
1H), 8.19 (m, 1H), 8.11 (m, 1H), 7.73 (d, 1H), 7.61 (d, 1H), 4.36
(m, 1H), 4.22 (m, 1H); 3.64 (m, 5H), 1.62 (m, 2H), 1.26 (m, 2H),
1.22 (d, 3H), 0.86 (m, 3H).
[1871] Optical Rotation: [.alpha.].sub.23=-29.degree. (c 1,
MeOH).
[1872] C.sub.17H.sub.23N.sub.3O.sub.6 (MW=365); mass spectroscopy
(MH.sup.+) 366.
Example 151
Synthesis of N-[N-(3-Nitrophenylacetyl)-L-alaninyl]-L-leucine
Methyl Ester
[1873] Following General Procedure C and using
N-(3-nitrophenylacetyl)-L-alanine (from Example D11 above) and
L-leucine methyl ester hydrochloride (Aldrich), the title compound
was prepared as a solid. The reaction was monitored by tlc (Rf=0.75
in 9:1 CHCl.sub.3/MeOH) and the product was purified by silica gel
chromatography using 97:3 CHCl.sub.3/MeOH as the eluent.
[1874] NMR data was as follows:
[1875] .sup.1H-nmr (CDCl.sub.3): .delta. 8.12 (m, 2H), 8.04 (m,
1H), 7.58 (m, 1H), 7.48-7.30 (m, 2H), 7.11 (d, 1H), 4.63 (m, 1H),
4.48 (m, 1H), 3.68 (s, 2H) 3.64 (s, 3H), 1.63 (m, 1H), 1.31 (m,
2H), 0.85 (d, 3H), 0.82 (m, 3H).
[1876] Optical Rotation: [.alpha.].sub.23=-32.degree. (c 1,
MeOH).
[1877] C.sub.18H.sub.25N.sub.3O.sub.6 (MW=379); mass spectroscopy
(MH.sup.+) 380.
Example 152
Synthesis of N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-leucine
Methyl Ester
[1878] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
L-leucine methyl ester hydrochloride (Aldrich), the title compound
was prepared as a solid. The reaction was monitored by tlc (Rf=0.5
in 9:1 CHCl.sub.3/MeOH).
[1879] NMR data was as follows:
[1880] .sup.1H-nmr (CDCl.sub.3): .delta.=6.78 (m, 2H), 6.69 (m,
1H), 4.52 (m, 2H), 3.73 (m, 1H), 3.52 (d, 2H), 1:63 (m, 2H), 1.36
(m, 3H), 0.88 (m, 3H).
[1881] Optical Rotation: [.alpha.].sub.23=-34.degree. (c 1,
MeOH).
[1882] C.sub.18H.sub.24N.sub.2O.sub.4F.sub.2 (MW=370); mass
spectroscopy (MH.sup.+) 370.
Example 153
Synthesis of
N-2-Methoxyethyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninami-
de
[1883] Following General Procedure C and using
N-[N-(3,S-difluorophenylacetyl)-L-alaninyl]-L-alanine (from Example
D7 above) and 2-methoxyethylamine (Aldrich), the title compound was
prepared as a solid. The reaction was monitored by tlc (Rf=0.35 in
9:1 CHCl.sub.3/MeOH).
[1884] NMR data was as follows:
[1885] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.32 (m, 1H), 7.98 (d,
1H), 7.82 (m, 1H), 7.07 (m, 1H), 6.97 (m, 2H), 4.25 (m, 2H), 3.52
(s, 2H), 3.32 (m, 3H), 3.20 (m, 4H), 1.19 (m, 6H).
[1886] Optical Rotation: [.alpha.].sub.23=-50.degree. (c 1,
MeOH).
[1887] C.sub.17H.sub.23N.sub.3O.sub.4F.sub.2 (MW=371); mass
spectroscopy (MH.sup.+) 372.
Example 154
Synthesis of
N-2-(N,N-Dimethylamino)ethyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-
-L-alaninamide
[1888] Following General Procedure C and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (from Example
D7 above) and N,N-dimethylethylenediamine (Aldrich), the title
compound was prepared as a solid. The reaction was monitored by tlc
(Rf=0.05 in, 9:1 CHCl.sub.3/MeOH).
[1889] NMR data was as follows:
[1890] .sup.1H-nmr (DMSO-d.sub.6): .delta.8.38 (m, 1H), 8.02 (m,
1H), 7.66 (m, 1H), 7.09 (m, 1H), 6.97 (m, 2H), 4.22 (m, 2H), 3.53
(s, 2H), 3.08 (m, 2H), 2.22 (m, 2H), 2.11 (m, 6H), 1.21 (d,
6H).
[1891] Optical Rotation: [.alpha.].sub.23=-55.degree. (c 1,
MeOH).
[1892] C.sub.18H.sub.26N.sub.4O.sub.3F.sub.2 (MW=384); mass
spectroscopy (MH.sup.+) 384.
Example 155
Synthesis of
N-Cyclohexyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide
[1893] Following General Procedure C and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (from Example
D7 above) and cyclohexylamine (Aldrich), the title compound was
prepared as a solid (mp=239-244.degree. C.). The reaction was
monitored by tlc (Rf=0.25 in 9:1 CHCl.sub.3/MeOH).
[1894] NMR data was as follows:
[1895] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.39 (m, 1H), 7.94 (m,
1H), 7.56 (m, 1H), 7.08 (m, 1H), 6.97 (m, 2H), 4.20 (m, 2H), 3.32
(s, 2H), 3.27 (m, 1H), 1.64 (m, 4H), 1.54 (m, 2H), 1.20 (m,
10H).
[1896] Optical Rotation: [.alpha.].sub.23=-58.degree. (c 1,
MeOH).
[1897] C.sub.20H.sub.27N.sub.3O.sub.3F.sub.2 (MW=395); mass
spectroscopy (MH.sup.+) 395.
Example 156
Synthesis of
N-Neopentyl-N'-[N-(3,5difluorophenylacetyl)-L-alaninyl]-L-alaninamide
[1898] Following General Procedure C and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (from Example
D7 above) and neopentylamine (Aldrich), the title compound was
prepared as a solid. The reaction was monitored by tlc (Rf=0.25 in
9:1 CHCl.sub.3/MeOH).
[1899] NMR data was as follows:
[1900] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.37 (d, 1H), 8.01 (m,
1H), 7.67 (m, 1H), 7.11 (m, 1H), 6.98 (m, 2H), 4.28 (m, 2H), 3.51
(s, 2H), 2.88 (m, 2H), 1.23 (d, 3H), 0.80 (m, 9H).
[1901] Optical Rotation: [.alpha.].sub.23=-54.degree. (c 1,
MeOH).
[1902] C.sub.19H.sub.27N.sub.3O.sub.3F.sub.2 (MW=383); mass
spectroscopy (MH.sup.+) 383.
Example 157
Synthesis of
N-Tetrahydrofurfuryl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alani-
namide
[1903] Following General Procedure C and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (from Example
D7 above) and tetrahydrofurfurylamine (Aldrich), the title compound
was prepared as a solid. The reaction was monitored by tlc (Rf=0.20
in 9:1 CHCl3/MeOH).
[1904] NMR data was as follows:
[1905] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.36 (d, 1H), 8.01 (m,
1H), 7.81 (m, 1H), 7.11 (m, 1H), 6.99 (m, 2H), 4.25 (m, 2H), 3.77
(m, 2H), 3.58 (m, 1H), 3.51 (s, 2H), 3.21 (m, 1H), 1.78 (m, 4H),
1.46 (m, 1H), 1.19 (m, 6H).
[1906] Optical Rotation: [.alpha.].sub.23-76.degree. (c 1,
MeOH).
[1907] C.sub.19H.sub.25N.sub.3O.sub.4F.sub.2 (MW=397); mass
spectroscopy (MH.sup.+) 398.
Example 158
Synthesis of
N-2-Pyridylmethyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninam-
ide
[1908] Following General Procedure C and using
N-(N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (from Example
D7 above) and 2-(aminomethyl)pyridine (Aldrich), the title compound
was prepared as a solid. The reaction was monitored by tlc (Rf=0.1
in 9:1 CHCl.sub.3/MeOH).
[1909] NMR data was as follows:
[1910] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.49 (m, 1H), 8.41 (m,
2H), 8.14 (d, 1H), 7.74 (m, 1H), 7.28 (m, 2H), 7.09 (m, 1H.), 6.98
(m, 2H), 4.33 (m, 4H), 3.52 (s, 2H), 1.24 (m, 6H).
[1911] Optical Rotation: [.alpha.].sub.23=-68.degree. (c 5,
MeOH).
[1912] C.sub.20H.sub.22N.sub.4O.sub.3F.sub.2 (MW=404); mass
spectroscopy (MH.sup.+) 405.
Example 159
Synthesis of
3[N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-alaninyl]thiazolidine
[1913] Following General Procedure C and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (from Example
D7 above) and thiazolidine (Aldrich), the title compound was
prepared as a solid. The reaction was monitored by tlc (Rf=0.25 in
9:1 CHCl.sub.3/MeOH).
[1914] NMR data was as follows:
[1915] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.34 (m, 2H), 8.22 (m,
1H), 7.09 (m, 1H), 6.98 (m, 2H), 4.68-4.23 (m, 4H), 3.81-3.6 (m,
2H), 3.52 (s, 2H), 3.01 (m, 2H), 1.19 (m, 6H).
[1916] Optical Rotation: [.alpha.].sub.23=-67.degree.(c 1,
MeOH).
[1917] C.sub.17H.sub.21N.sub.3O.sub.3F.sub.2 (MW=385); mass
spectroscopy (MH.sup.+) 385.
Example 160
Synthesis of Methyl
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminobutanoate
[1918] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
methyl (S)-2-aminobutanoate hydrochloride (prepared from
(S)-(+)-2-aminobutyric acid (Aldrich) using General Procedure H),
the title compound was prepared as a solid (mp=103-106.degree.
C.).
[1919] NMR data was as follows:
[1920] .sup.1H-nmr (CDCl.sub.3): .delta.=6.83 (m, 2H), 6.72 (m,
1H), 6.49 (d, 1H), 4.55 (m, 1H), 4.48 (m, 1H), 3.72 (s, 3H), 3.49
(s, 2H), 1.85 (m, 1H), 1.69 (m, 1H), 1.39 (d, 3H), 0.86 (t,
3H).
[1921] Optical Rotation: [.alpha.].sub.23=-70.degree. (c 1,
MeOH).
[1922] C.sub.16H.sub.20N.sub.2O.sub.4F.sub.2 (MW=342.35); mass
spectroscopy (MH.sup.+) 342.
Example 161
Synthesis of Methyl
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminopentanoate
[1923] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
methyl (S)-2-aminopentanoate hydrochloride (prepared from
(S)-2-aminopentanoic acid (Novabiochem) using General Procedure H),
the title compound was prepared as a solid (mp 154-155.degree.
C.)
[1924] NMR data was-as follows:
[1925] .sup.1H-nmr (CDCl.sub.3): .delta.=6.80 (m, 2H), 6.69 (m,
1H), 6.45 (d, 1H), 6.28 (d, 1H), 4.52 (m, 2H), 3.71 (s, 3H), 3.51
(s, 2H), 1.77 (m, 1H), 1.58 (m, 1H), 1.35 (d, 3H), 1.27 (m, 2H),
0.87 (t, 3H).
[1926] Optical Rotation: [.alpha.].sub.23=-69.degree. (c 1,
MeOH).
Example 162
Synthesis of Methyl
N-[N-(3-nitrophenylacetyl)-L-alaninyl]-(S)-2-aminobutanoate
[1927] Following General Procedure C and using
N-(3-nitrophenylacetyl)-L-alanine (from Example D11 above) and
methyl (S)-2-aminobutanoate hydrochloride (prepared from
(S)-(+)-2-aminobutyric acid (Aldrich) using General Procedure H),
the title compound was prepared as a solid (mp=154-157.degree.
C.).
[1928] NMR data was as follows:
[1929] .sup.1H-nmr (CDCl.sub.3): .delta.=8.13 (m, 1H), 8.04 (m,
1H), 7.57 (m, 1H), 7.38 (m, 1H), 4.72 (m, 1H), 4.39 (m, 1H), 3.69
(s, 3H), 3.41 (s, 2H), 1.73 (m, 1H), 1.61 (m, 1H), 1.34 (d, 3H),
0.79 (t, 3H).
[1930] Optical Rotation: [.alpha.].sub.23=-75.degree. (c 1,
MeOH).
Example 163
Synthesis of
N-(R)-sec-Butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamid-
e
[1931] Following General Procedure C and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (from Example
D7 above) and (R)-(-)-sec-butylamine (Aldrich), the title compound
was prepared as a solid. The reaction was monitored by tlc (Rf=0.15
in 95:5 CHCl.sub.3/MeOH) and the product was purified by silica gel
chromatography using 95:5 CHCl.sub.3 MeOH as the eluent.
[1932] NMR data was as follows:
[1933] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.39 (m, 1H), 7.95 (m,
1H), 7.49 (m, 1H), 7.09 (m, 1H), 7.0.1 (m, 2H), 4.20 (m, 4H), 3.61
(m, 1H), 3.52 (s, 2H), 1.34 (m, 2H), 1.21 (m, 6H), 0.97 (d, 3H),
0.79 (m, 3H).
[1934] Optical Rotation: [.alpha.].sub.23=-50.degree. (c 1,
MeOH).
[1935] C.sub.18H.sub.25N.sub.3O.sub.3F.sub.2 (MW=369.41); mass
spectroscopy (MH.sup.+) 370.
Example 164
Synthesis of
1-[N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-alaninyl]pyrrolidine
[1936] Following General Procedure C and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (from Example
D7 above) and pyrrolidine (Aldrich), the title compound was
prepared as a solid. The reaction was monitored by tlc (Rf=0.15 in
95:5 CHCl.sub.3/MeOH) and the product was purified by silica gel
chromatography using CHCl.sub.3/MeOH as the eluent.
[1937] NMR data was as follows:
[1938] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.31 (m, 1H), 8.08 (m,
1H), 7.09 (m, 1H), 6.99 (m, 2H), 4.48 (m, 1H), 4.29 (m, 1H),
3.51_(s, 2H), 3.44-3.22 (m, 4H), 1.80 (m, 4H), 1.27 (m, 6H).
[1939] C.sub.18H.sub.23N.sub.3O.sub.3F.sub.2 (MW=367.40); mass
spectroscopy (MH.sup.+) 367.
Example 165
Synthesis of
N-(S)-sec-Butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamid-
e
[1940] Following General Procedure C and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (from Example
D7 above) and (S)-(+)-sec-butylamine (Aldrich), the tide compound
was prepared as a solid. The reaction was monitored by tlc (Rf=0.25
in 9:1 CHCl.sub.3/MeOH) and the product was purified by silica gel
chromatography using CHCl.sub.3/MeOH as the eluent.
[1941] NMR data was as follows:
[1942] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.38 (m, 1H), 7.92 (m,
1H), 7.30 (m, 1H), 7.18 (m, 1H), 6.99 (m, 2H), 4.20 (m, 4H), 3.62
(m, 1H), 3.52 (s, 211), 1.34 (m, 2H), 1.20 (m, 6H), 1.01 (m, 3H),
0.81 (t, 3H).
[1943] Optical Rotation: [.alpha.].sub.23=-52 (c 1, MeOH).
[1944] C.sub.19H.sub.25N.sub.3O.sub.3F.sub.2 (MW=369.41); mass
spectroscopy (MH.sup.+) 370.
Example 166
Synthesis of N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-valine
Methyl Ester
[1945] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
L-valine methyl ester hydrochloride (Aldrich), the title compound
was prepared as a solid.
[1946] NMR data was as follows:
[1947] .sup.1H-nmr (CDCl.sub.3) .delta.=6.81 (m, 2H), 6.73 (m, 1H),
6.48 (d, 1H), 6.22 (d, 1H), 4.48 (m, 2H), 3.70 (s, 3H), 3.51 (s,
2H), 2.16 (m, 1H), 1.37 (m, 1H), 0.87.(t, 3H).
[1948] Optical Rotation: [.alpha.].sub.23=-65.degree. (c 1,
MeOH).
[1949] C.sub.17H.sub.22N.sub.2O.sub.4F.sub.2 (MW=356.37); mass
spectroscopy (MH.sup.+) 360.
Example 167
Synthesis of
N-2-Fluoroethyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamid-
e
[1950] Following General Procedure C and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (from Example
D7 above) and 2-fluoroethylamine hydrochloride (Aldrich), the title
compound was prepared as a solid (mp=230-235.degree. C.).
[1951] NMR data was as follows:
[1952] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.38 (d, 1H), 8.04 (m,
2H), 7.07 (m, 1H), 6.99 (m, 2H), 4.39 (m, 2H), 4.24 (m, 1H), 3.53
(s, 2H), 3.35 (m, 2H), 1.20 (m, 6H).
[1953] Optical Rotation: [.alpha.].sub.23=-33.degree. (c 1,
MeOH).
[1954] C.sub.16H.sub.20N.sub.3O.sub.3F.sub.3 (MW=359.37); mass
spectroscopy (MH.sup.+) 359.
Example 168
Synthesis of
N-[(S)-6Methyl-3-oxohept-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamid-
e
[1955] Following General Procedure M and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
(S)-6-methyl-3-oxohept-2-ylamine hydrochloride (prepared by
treating N-BOC-L-alanine N-methoxy-N-methyl amide (Weinreb et al.,
Tetrahedron Lett., 22, 3815 (1981)) with isopropyl magnesium
bromide (Aldrich), followed by removal of the BOC group using
General Procedure P), the title compound was prepared as a solid.
The product was purified by silica gel chromatography using
CHCl.sub.3/MeOH as the eluent.
[1956] NMR data was as follows:
[1957] .sup.1H-nmr (CDCl.sub.3): .delta.=6.84 (m, 2H), 6.69 (m,
1H), 6.31 (m, 1H), 4.50 (m, 2H), 3.51 (s, 21), 2.48 (m, 2H),
1.47.(m,-2H), 1.32 (m, 7H), 0.90 (d, 6H).
[1958] Optical Rotation: [.alpha.].sub.23=-42.degree. (c 1,
MeOH).
[1959] C.sub.19H.sub.26N.sub.2O.sub.3F.sub.2 (MW=368); mass
spectroscopy (MH.sup.+) 368.
Example 169
Synthesis of
N-4-Nitrobenzyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminob-
utyramide
[1960] Following General Procedure C and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminobutyric acid
(prepared from methyl
N-(N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminobutanoate
(from Example 160 above) using General Procedure AF) and
4-nitrobenzylamine (Aldrich), the title compound was prepared as a
solid. The reaction was monitored by tlc (Rf=0.3 in 95:5
CHCl.sub.3/MeOH) and the product was purified by silica gel
chromatography using 97:3 CHCl.sub.3/MeOH as the eluent.
[1961] NMR data was as follows:
[1962] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.57 (t, 1H), 8.40-(d,
1H), 8.21 (d, 2H), 8.02 (d, 1H), 7.50 (d, 2H), 7.08 (m, 1H), 6.98
(m, 2H), 4.42 (d, 2H), 4.37 (m, 1H), 4.17 (m, 1H), 3.53 (s, 2H),
1.64 (m, 2H), 1.21 (m, 3H), 0.83 (t, 3H).
[1963] Optical Rotation: [.alpha.].sub.23=-42.degree. (c 1,
MeOH).
[1964] C.sub.22H.sub.24N.sub.4O.sub.5F.sub.2 (MW=462.45); mass
spectroscopy (MH.sup.+) 462.
Example 170
Synthesis of
N-4-Nitrobenzyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminop-
entanamide
[1965] Following General Procedure C and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminopentanoic
acid (prepared from methyl
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminopentanoate
(from Example 161 above) using General Procedure AF) and
4-nitrobenzylamine (Aldrich), the title compound was prepared as a
solid. The reaction was monitored by tlc (Rf=0.3 in 95:5
CHCl.sub.3/MeOH) and the product was purified by recrystallization
from acetonitrile.
[1966] NMR data was as follows:
[1967] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.57 (m, 1H), 8.41 (d,
1H), 8.22 (d, 2H), 8.06 (d, 1I), 7.51 (d, 2H), 7.12 (m, 1H), 7.00
(m, 2H), 4.43 (d, 2H), 4.30 (m, 2H), 3.56 (s, 2H), 1.65 (m, 2H),
1.29 (m, 5H), 0.91 (t, 3H).
[1968] Optical Rotation: [.alpha.].sub.23=+97.degree. (c 1,
MeOH).
[1969] C.sub.23H.sub.26N.sub.4O.sub.5F.sub.2 (MW=476.4); mass
spectroscopy (MH.sup.+) 476.
Example 171
Synthesis of Methyl
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-fluorophenyl)ace-
tate
[1970] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
methyl 2-amino-2-(3-fluorophenyl)acetate hydrochloride (from
Example D12 above), the title compound was prepared as a solid. The
reaction was monitored by tlc (Rf=0.2 in 95:5 CHCl.sub.3/MeOH) and
the product was purified by silica gel chromatography using 95:5
CHCl.sub.3/MeOH as the eluent.
[1971] NMR data was as follows:
[1972] .sup.1H-nmr (CDCl.sub.3): .delta.=7.36 (m, 1H), 7.18 (m,
1H), 7.13 (m, 1H), 7.06 (m, 1H), 6.87 (m, 2H), 6.74 (m, 1H), 6.09
(m, 1H), 5.49 (d, 1H), 4.59 (m, 1H), 3.74 (s, 3H), 3.57 (s, 2H),
1.35 (d, 3H), 0.97 (d, 3H).
[1973] C.sub.20H.sub.19N.sub.2O.sub.4F.sub.3 (MW=408.38); mass
spectroscopy (MH.sup.+) 408.
Example 172
Synthesis of
N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-amino2-(2-thienyl)acet-
amide
[1974] Following General Procedure L and using methyl
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)acet-
ate (from Example 178 below), the title compound was prepared as a
solid (mp=decomposition at 190.degree. C.). The product was
purified by preparative LC 2000 chromatography using 8:2
EtOAc/hexanes as the eluent.
[1975] NMR data was as follows:
[1976] .sup.1H-nmr (CDCl.sub.3/DMSO-d.sub.6): .delta.=8.9-6.14
(Ar+NH's 10 H), 5.43-5.39 (m, 1H), 4.16-4.10 (m, J=7 Hz, 1H), 3.19
(s, 2H), 1.15 (d, J=7.05 Hz, 3H).
[1977] C.sub.17H.sub.17F.sub.2N.sub.3O.sub.3S (MW=381.4); mass
spectroscopy (MH.sup.+) 381.
Example 173
Synthesis of Methyl
N-(N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino-2-(5-chlorobenzothiop-
hen-2-yl)acetate
[1978] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
methyl 2-amino-2-(5-chlorobenzothiophen-2-yl)acetate (prepared from
5-chlorobenzothiophene-2-acetic acid [CAS No. 23799-65-71 using
General Procedure G, followed by amination using a procedure
essentially the same as that described in Example D4 above), the
title compound was prepared as a solid (mp=189-190.degree. C.). The
product was purified by titration using Et.sub.2O/hexanes.
[1979] NMR data was as follows:
[1980] .sup.1H-nmr (CDCl.sub.3): .delta.=7.7-7.63 (m, 2H),
7.33-7.17 (m, 2H), 6.89-6.63 (m, 3H), 6.16-6.03 (m, 1H), 5.85 (dd,
1H), 4.7-4.53 (m, 1H), 3.83 (s, 1.5H), 3.8 (s, 1.5H), 3.59 (s, 1H),
3.5 (s, 1H), 1.4 (dt, 3H).
[1981] C.sub.22H.sub.19ClF.sub.2N.sub.2O.sub.4S (MW=481); mass
spectroscopy (MH.sup.+) 480.
Example 174
Synthesis of Ethyl
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino2-(benzothiophen-2-yl)-
acetate
[1982] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
ethyl 2-amino-2-(benzothiophen-2-yl)acetate [CAS No. 98800-64-7],
the title compound was prepared as a solid (mp=189-190.degree. C.).
The product was purified by preparative LC-2000 chromatography
using 2:8 EtOAc/hexanes as the eluent.
[1983] NMR data was as follows:
[1984] .sup.1H-nmr (CDCl.sub.3): .delta.=7.8-7.75 (m, 2H),
7.34-7.27 (m, 2H), 7.25-7.09 (m, 3H), 6.81-6.76 (m, 1H), 6.76-6.63
(m, 1H), 6.23 (dd, J=7 Hz, 1H), 5.84(d, J=7.07 Hz, 1H), 4.61-4.59
(m, 1H),.4.33-4.2 (m, 2H), 3.54 (s, 1H), 3.50 (s, 1H), 1.70 (d,
J=11.9 Hz, 1.5H), 1.38 (d, J=11.9 Hz, 1.5 H), 1.36-1.23 (dt,
3H).
[1985] C.sub.23H.sub.22N.sub.2O.sub.4SF.sub.2 (MW=460.49); mass
spectroscopy (MH.sup.+) 460.
Example 175
Synthesis of Methyl
N-[N-(3,5Difluorophenylacetyl)-L-alaninyl]-2-amino-2(benzothiophen-3-yl)a-
cetate
[1986] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
methyl 2-amino-2-(benzothiophen-3-yl)acetate (prepared from
2-amino-2-(benzothiophen-3-yl)acetic acid (CAS. 95834-94-9] using
General Procedure H), the title compound was prepared as a solid
(mp=185-186.degree. C.).
[1987] NMR data was as follows:
[1988] .sup.1H-nmr (CDCl.sub.3): .delta.=7.86 (m, 2H),-7.4-7.3 (m,
3H), 7.4-7.2 (m, 2H), 6.9-6.6 (m, 3H), 6.3-6.13 (m, 1H), 5.95-5.85
(m, 1H), 4.55-4.5 (m, 1H), 3.75 (s, 1.5H), 3.65 (s, 1.5H), 3.55 (s,
1H), 3.35 (s, 1H), 1.4 (d, 1.5M, 1.3 (d, 1.5H).
[1989] C.sub.22H.sub.20N.sub.2O.sub.4F.sub.2S (MW=446); mass
spectroscopy (MH.sup.+) 446.
Example 176
Synthesis of Methyl
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-thienyl)acetate
[1990] Following General Procedure C and using
N-(3,5difluorophenylacetyl)-L-alanine (from Example B2 above) and
methyl 2-amino-2-(2-thienyl)acetate (prepared from
L-2-thienylglycine (Sigma) using General Procedure G), the title
compound was prepared as a solid (mp=161-162.degree. C.). The
product was purified by preparative LC 2000 chromatography using
1:4 EtOAc/hexanes.
[1991] NMR data was as follows:
[1992] .sup.1H-nmr (CDCl.sub.3): .delta.=7.3-6.65 (Ar, 7H), 6.25
(bt, 1H), 5.8 (dd, 1H), 4.68-4.5 (m, 1H), 3.85 (s, 1H), 3.75 (s,
1H), 3.52 (s, 1H), 3.5 (s, 1H), 1.35 (overlaying d, 3H).
[1993] C.sub.18H.sub.18N.sub.2O.sub.4F.sub.2S (MW=396); mass
spectroscopy (MH.sup.+) 396.1.
Example 177
Synthesis of Ethyl
N-(N-(3,5Difluorophenylacetyl)-L-alaninyl]-2-amino-2-(benzothiophen-5yl)a-
cetate
[1994] Following Genera Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
ethyl 2-amino-2-(benzothiophen-5-yl)acetate (prepared as described
in S. Kukolja et al., J. Med. Chem., 198.5, 28, 1896-1903), the
title compound was prepared as a solid (mp 126.5-127.5.degree. C.).
The product was purified by preparative LC 2000 chromatography
using 1:1 hexanes/EtOAc as the eluent.
[1995] NMR data was as follows:
[1996] .sup.1H-nmr (CDCl.sub.3): .delta.=8.1 (s, 1H), 8.05 (s, 1H),
7.67.5 (m, 2H), 7.4-7.25 (m, 3H), 7.15 (bd, J=12 Hz, 5H), 7.05 (bd,
J=12 Hz, 5H), 6.89-6.675 (m, 2H), 6.225 (bd, J=12 Hz, 5H), 6.075
(bd, J=12 Hz, 5H), 4.55 (q, J=7.5 Hz, 1H), 4.2 (dq, 2H), 3.575 (s,
1H), 3.242 (s, 1H), 1.4 (d, J=7.05 Hz, 1.5H), 1.15 (d, J=7.05 Hz,
1.5H).
[1997] C.sub.23H.sub.22N.sub.2O.sub.4F.sub.2S (MW=460); mass
spectroscopy (MH.sup.+) 460.1.
Example 178
Synthesis of Methyl
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)acet-
ate
[1998] Following General Procedure G and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)acet-
ic acid (from Example 180 below), the title compound was prepared
as a solid (mp=180-181.degree. C.). The product was purified by
preparative LC 2000 chromatography using 6:4 EtOAc/hexanes as the
eluent.
[1999] NMR data was as follows:
[2000] .sup.1H-nmr (CDCl.sub.3): .delta.=7.3-6.6 (Ar+NH, 7H), 6.37
(bd, J=7 Hz, 1H), 5.77 (d, J=7 Hz, 1H), 4.6-4.56 (m, J=7 Hz, 1H),
3.7 (s, 3H), 3.4 (s, 2H), 1.38.(d, J=7 Hz, 3H).
[2001] C.sub.18H.sub.18N.sub.2O.sub.4SF.sub.2 (MW=396); mass
spectroscopy (MH.sup.+) 396.1.
Example 179
Synthesis of tert-Butyl
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)acet-
ate
[2002] Following General Procedure J and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)acet-
ic acid (from Example 180 below), the title compound was prepared
as a solid (mp=117-118.degree. C.). The product was purified by
tituraration using ether/hexanes.
[2003] NMR data was as follows:
[2004] .sup.1H-nmr (CDCl.sub.3): .delta.=7.24 (d, J=6.5 Hz, 1H),
7.05-6.63 (m, 6H), 6.19 (bd, J=7.2 Hz, 1H), 5.66 (d, J=7.5 Hz, 1H),
4.6-4.5 (m, 1H), 3.5 (s, 2H), 1.44 (s, 9H), 1.38 (d, J=7.1 Hz,
3H).
[2005] C.sub.21H.sub.24N.sub.2O.sub.4SF.sub.2 (MW=438.5); mass
spectroscopy (MH.sup.+) 438.
Example 180
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)acet-
ic Acid
[2006] Following General Procedure M and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
L-.alpha.-2-thienylglycine (Sigma), the title compound was prepared
as a solid. The product was purified by tituration using
EtOAc/hexanes.
[2007] NMR data was as follows:
[2008] .sup.1H-nmr (DMSO-d6): .delta.=8.73 (d, J=7 Hz, 1H), 8.38
(d, J=7 Hz, 1H), 7.56-7.4 (m, 1H), 7.2-6.9 (m, 4H), 5.54 (d, J=8
Hz, 1H), 4.5-4.3 (m, 1H), 3.33 (s, 2H), 1.23 (d, J=7 Hz, 3H).
[2009] C.sub.17H.sub.16N.sub.2O.sub.4SF.sub.2(MW=382); mass
spectroscopy (MH.sup.+) 382.
Example 181
Synthesis of Methyl
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino-2-(1H-tetrazol-5-yl)a-
cetate
[2010] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
methyl 2-amino2-(1H-tetrazol-5-yl)acetate (prepared from ethyl
1H-tetrazole-5-acetate [CAS 173367-99-2] using procedures
essentially the same as those described in S. Kukolja, J. Med.
Chem., 1985, 28, 1886-1896), the title compound was prepared as a
solid. The reaction was product was purified by tituration using
EtOAc/hexanes.
[2011] NMR data was as follows:
[2012] .sup.1H-nmr (DMSO-d.sub.6): .delta.=9.13 (d, J=7.6 Hz, 1H),
8.39 (t, J=7 Hz, 1H), 7.1-6.95 (m, 3H), 5.9 (dd, 1H), 4.4-4.3 (m,
1H), 4.14 (q, J=7 Hz, 2H), 3.5 (s, 3H), 1.27-1.11 (m, 6H).
[2013] C.sub.16H.sub.18N.sub.6O.sub.4F.sub.2 (MW=396.3); mass
spectroscopy (MH.sup.+) 396.3.
Example 182
Synthesis of Methyl
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(6-methoxy-2-na-
phthyl)acetate
[2014] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
methyl (S)-2-amino-2-(6-methoxy-2-naphthyl)acetate (from Example D3
above), the title compound was prepared as a solid
(mp=177-178.degree. C.). The product was purified by tituration
using hexanes/EtOAc.
[2015] NMR data was as follows:
[2016] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.84 (d, J=9 Hz, 1H),
8.4 (d, J=9 Hz, 1H), 7.90-7.76 (m, 2H), 7.247-6.90 (m, 5H), 5.5
(J=7 Hz, 1H), 4.243 (d, J=3.5 Hz, 1H), 3.86 (s, 3H), 3.6 (s, 3H),
3.29 (s, 2H), 1.26 (d, J=7.5 Hz, 3H).
[2017] C.sub.25H.sub.24N.sub.2O.sub.5F.sub.2 (MW=470.48); mass
spectroscopy (MH.sup.+) 470.
Example 183
Synthesis of Methyl
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-trifluoromethylp-
henyl)acetate
[2018] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
methyl 2-amino-2-(3-trifluoromethylphenyl)acetate (prepared from
2-(hydroxyimino)-2-(3-trifluoromethylphenyl)acetlc acid [CAS
179811-81-S] using General Procedures G and R above), the title
compound was prepared as a solid (mp=133-134.degree. C.). The
product was purified by tituration from EtOAc/hexanes.
[2019] NMR data was as follows:
[2020] .sup.1H-nmr (CDCl.sub.3): .delta.=7.57-7.37 (m, 4H), 6.8-6.6
(m, 3H), 6.05 (BA, 1H), 5.5 (A, J=7.5Hz, 1H), 3.7 (s, 1.5H), 3.675
(s, 1.5H), 3.5 (s, 1H), 3.45 (s, 1H), 1.33 (d, J=7.5 Hz, 1.5H),
1.275 (d, J=7.5 Hz, 1.5H).
[2021] C.sub.21H.sub.19N.sub.2O.sub.4F.sub.5 (MW=458.39); mass
spectroscopy (MH.sup.+) 459.
Example 184
Synthesis of Methyl
N-(N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4,5,6,7-tetrahydro-
benzothiophen-2-yl)acetate
[2022] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
methyl 2-amino-2-(4,5,6,7-tetrahydrobenzothiophen-2-yl)acetate
(prepared from
N-Boc-2-amino-2-(4,5,6,7-tetrahydrobenzothiophen-2-yl)acetlc acid
[CAS 95361-97-0] using General Procedures G above and the Boc
removal procedure described in Example D3 above), the title
compound was prepared as a solid. The product was purified by
tituration using Et.sub.2O/hexanes.
[2023] NMR data was as follows:
[2024] .sup.1H-nmr (CDCl.sub.3): .delta.=7.05 (d, J=5 Hz, 1H), 7.02
(d, J=5 Hz, 1H), 6.82-6.66 (m, 3H), 6.31 (bd, J=8 Hz, 1H), 5.66
(dd, J=7.2 Hz, 1H), 4.63-4.55 (m, 1H), 3.76 (s, 1.5H), 3.75 (s,
1.5H), 3.52 (s, 1H), 3.50 (s, 1H), 2.67-2.65 (m, 2H), 2.54-2.52 (m,
2H), 1.77-1.7 (m, 4H), 1.36 (dd, J=7 Hz, 3H).
[2025] C.sub.22H.sub.24N.sub.2O.sub.4F.sub.2S (MW=450); mass
spectroscopy (MH.sup.+) 450.
Example 185
Synthesis of Methyl
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino-2-(thieno[2,3-b]thiop-
hen-2-yl)acetate
[2026] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
methyl 2-amino-2-(thieno[2,3-b]thiophen-2-yl)acetate (from Example
D4 above), the title compound was prepared as a solid. The product
was purified by titruation from Et.sub.2O/hexanes.
[2027] NMR data was as follows:
[2028] .sup.1H-nmr (CDCl.sub.3): .delta.=7.35 (d, J=7.5 Hz, 1H),
7.2-7.0 (m, 3H), 6.9-6.69 (m, 3H), 6.13-6.0 (m, 1H), 5.8 (dd, 1H),
4.63-4.5 (m, 1H), 3.8 (s, 3H), 3.58 (s, 1H), 3.469 (1H), 1.4 (dd,
3H).
[2029] C.sub.20H.sub.18N.sub.2O.sub.4F.sub.2S.sub.2 (MW=452); mass
spectroscopy (MH.sup.+) 452.
Example 186
Synthesis of Methyl
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-methylthiazolyl)-
acetate
[2030] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
methyl 2-amino-2-(2-methylthiazol-4-yl)acetate (prepared from
N-Boc-2-amino-2-(2-methylthiazol-4-yl)acetlc acid [CAS 105381-90-6]
using General Procedure H above), the title compound was prepared
as a solid. The product was purified by tituration using
Et.sub.2O/hexanes.
[2031] NMR data was as follows:
[2032] .sup.1H-nmr (CDCl.sub.3): .delta.=7.2-6.66 (pr+NH, 5H),
5.69-5.6 (m, 1H), 4.8-4.69 (m, 1H), 3.76 (s, 3H), 3.56 (s, 1H), 3.5
(s, 1H), 2.69 (s, 3H), 1.4 (d, J=14 Hz, 1.5H), 1.35 (s, J=14 Hz,
1.5H).
[2033] C.sub.18H.sub.19N.sub.3O.sub.4F.sub.2S (MW=411); mass
spectroscopy (MH.sup.+) 411.
Example 187
Synthesis of Methyl
(3S,4S)-N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-4-amino-3-hydroxy-5-p-
henylpentanoate
[2034] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
methyl (3S,4S)-4-amino-3-hydroxy-5-phenylpentanoate (Novabiochem),
the title compound was prepared as a solid. The reaction was
monitored by tlc (Rf=0.2 in 95:5 CHCl.sub.3MeOH) and the product
was purified by flash column chromatography using 95:5
CHCl.sub.3/MeOH as the eluent.
[2035] NMR data was as follows:
[2036] .sup.1H-nmr (CDCl.sub.3): .delta.=8.29 (d, 1H), 7.65 (d,
1H), 7.40-7.20 (m, 5H), 7.10 (m, 1H), 6.99 (m, 2H), 5.27 (d, 1H),
4.47 (bs, 2H), 4.09 (m, 2H), 3.57 and 3.51 (m, 3H), 2.72 (m, 2H),
2.31 (m, 2H), 1.19 (m, 2H).
[2037] Optical Rotation: [.alpha.].sub.23=-66.degree. (c 1,
MeOH).
[2038] C.sub.23H.sub.26N2O.sub.5F.sub.2 (MW=448); mass spectroscopy
(MH.sup.+) 449.
Example 188
Synthesis of Methyl
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohex-4-enoate
Step A--Synthesis of
(S)-3-(Hex-4-enoyl)-4-(phenylmethyl)-2-oxazolidinone
[2039] To a mechanically stirred solution of 9.50 g (83.2 mmol,
1.10 equiv.) of 4-hexenoic acid (commercially available from
Lancaster, Catalog #252-427-6) and 13.9 mL (10.1 g, 99.7 mmol, 1.33
equiv.) of triethylamine in 150 mL of dry THF, cooled to
-78.degree. C. under dry N.sub.2, was added 10.71 mL (10.49 g, 87.0
mmol, 1.15 equiv.) of pivaloyl chloride (Aldrich). The mixture was
warmed to 0.degree. C. for 60 min, and then recooled to -78.degree.
C. A solution of 13.4 g (75.6 mmol, 1.00 equiv) of
(S)-(-)-(phenylmethyl)-2-oxazolidone (Aldrich) and 22 mg of
triphenylmethane (indicator) in 150 mL of dry THF, stirred at
-30.degree. C. to 45.degree. C. under N.sub.2, was treated dropwise
with n-butyllithium (.about.2.5 M in hexanes) (Aldrich) until an
orange color persisted (.about.30 mL required). The resulting
solution was cooled to -78.degree. C. and then added, via rapid
cannulation, to the above stirred mixture containing the mixed
anhydride. The residual lithiated oxazolidone was rinsed in with
two 10-mL portions of dry THF and the resulting mixture was stirred
at -78.degree. C. for 1.5 h, and then at 0.degree. C. for 1 h. The
mixture was partitioned between CH.sub.2Cl.sub.2 and pH 7 phosphate
buffer. The CH.sub.2Cl.sub.2 phase was washed with saturated
aqueous NaHCO.sub.3 followed by half-saturated aqueous NaCl, dried
(MgSO.sub.4), and evaporated in vacuo. The residual S cream-colored
solid (22.4 g) was chromatographed (Waters Prep 2000, 5.0
cm.times.25 cm 10 .mu. Kromasil KR60-10SIL-5025 column) in two
batches eluting with 85:15 hexanes/EtOAc. The chromatographed
product, was recrystallized from hexane to yield 14.34 g (first
crop, 69%) of the title compound as fine white needles. .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 7.37-7.20 (m, 5H, --C.sub.6H.sub.5),
5.60-5.43(m, 2H, CH.dbd.CHCH.sub.3), 4.71-4.63(m, 1H, NCH(Ph)
CH.sub.2O), 4.23-4.14(m, 2H, NCH(Ph)CH.sub.2O), 3.295(dd, J=13.3,
3.3 Hz, 1H, CHHC.sub.6H.sub.5), 3.11-2.90 (m, 2H, CH.sub.2C.dbd.O),
2.758 (dd, J=13.3, 9.6 Hz, 1H, CHHC.sub.6H.sub.5), 2.42-2.34 (m,
2H, CH.dbd.CHCH.sub.2), 1.67-1.65 (m, 2H, CH.dbd.CHCH.sub.3).
Step B--Synthesis of
(4S)-3-[(S)-2-Azidohex-4-enoyl]-4-(phenylmethyl)-2-oxazolidinone
[2040] A solution of 5.47g (20.0 mmol, 1.00 equiv) of the product
from Step A above in 60 mL of dry THF, stirred at -78.degree. C.
under dry N.sub.2, was added via rapid cannulation to a stirred,
cooled (-78.degree. C.) solution of 43.6 mL (22.0 mmol, 1.10 equiv)
of potassium hexamethyldisilazide (0.505 M in toluene) (Aldrich)
and 60 mL of dry THF. The residual imide solution was rinsed in
with two 5-mL portions of dry THF. The resulting solution was
stirred at -78.degree. C. for 30 min. To the above solution of the
K-enolate, stirred at -78.degree. C. under dry N.sub.2, was added a
cooled (-78.degree. C.) solution of 7.43 g (24.0 mmol, 1.2 equiv)
of trisyl azide (prepared as described in R. E. Harmon et al., J.
Org. Chem., 1973, 38, 11-16) in 60 mL of dry THP via rapid
cannulation. (Note the reaction exothermed to -68.degree.C. during
the addition). After 1-2 min, 4.24 mL (4.45 g, 74.1 mmol, 3.7
equiv) of glacial acetlc acid was added in one portion. The
resulting mixture was stirred at -78.degree. C. for 15 min, and was
then allowed to warm to 25.degree. C. on stirring overnight. The
mixture was partitioned between CH.sub.2Cl.sub.2 and pH 7 phosphate
buffer. The aqueous phase was extracted with CH.sub.2Cl.sub.2
(3.times.) and the organic extracts were combined, washed with
dilute aqueous NaHCO.sub.3, dried (MgSO.sub.4), and evaporated in
vacuo. The residual oil (9.55 g) was chromatographed (Waters Prep
2000, 5.0 cm.times.25 cm 10 .mu. Kromasil KR60-10SIL-5025 column)
eluting with a 3 L linear gradient from 30:70 to 80:20
CH.sub.2Cl.sub.2/hexanes. After rechromatographing the mixed
fractions (2.times.), a total of 5.27 g (84% yield) of the title
compound (faster eluting, major diastereomer) was isolated as a
colorless, viscous oil. .sup.1H NMR (300 MHz; CDCl.sub.3)
.delta.7.38-7.20 (m, 5H, --C.sub.6H.sub.5), 5.73-5.62 (m, 1H,
CH.dbd.CHCH.sub.3), 5.52-5.41 (m, 1H, CH.dbd.CHCH.sub.3), 5.011
(dd, J=8.3, 5.5 Hz, 1H, CH(N.sub.3) C=0), 4.71-4.63 (m, 1H,
NCH(Ph)CH.sub.2O), 4.236 (d, J=5.1 Hz, 2H, NCH(Ph)CH.sub.2O), 3.338
(dd, J=13.4, 3.3. Hz, 1H, CHHC.sub.6H.sub.5), 2.827 (dd, J=13.4,
9.5 Hz, 1H, CHHC.sub.6H.sub.5), 2.64-2.46 (m, 2H,
CH.sub.2CH.dbd.CHCH.sub.3), 1.694 (dd, J=6.4, 1.1 Hz, 3H,
CH.dbd.CHCH.sub.3).
Step C--Synthesis of (S)-2-Azidohex-4enoic Acid
[2041] A solution of 5.00 g (15.91 mmol) of the product from Step B
above in 240 mL of THF and 80 mL of deionized water, stirred at
0.degree. C. under N.sub.2, was treated with 762 mg (31.8 mmol,
2.00 equiv) of LiOH (anhydrous powder). After stirring at 0.degree.
C. for 30 min, 100 mL of 0.5 N aqueous NAHCO was added and the THF
was removed by rotary evaporation in vacua. The residue was diluted
to 400-500 mL with H.sub.2O and extracted with 5 portions of
CH.sub.2Cl.sub.2. The aqueous phase was acidified to pH 1-2 by the
cautious addition of 5 N HCl, and then was extracted with 4
portions of EtOAc. The EtOAc extracts were combined, dried
(Na.sub.2SO.sub.4), and evaporated in vacuo to yield 2.45 g (99%)
of the title compound as a light amber oil. .sup.1H NMR (300 MHz,
CDCl.sub.3) a 11.38 (br s, 1H, CO.sub.2H), 5.73-5.62 (m, 1H,
CH.sub.3CH.dbd.CH), 5.48-5.38 (m, 1H, CH.dbd.CHCH.sub.2), 3.928
(dd, I=7.8, 5.4 Hz, 1H, CH(N.sub.3)CO.sub.2H), 2.66-2.47(m, 2H,
CH.dbd.CHCH.sub.2), 1.703 (dd, J=6.4, 1.1 Hz, 3H, CH.sub.3.
Step D--Methyl
N-[N-tert-Butoxycarbonyl-L-alaninyl]-(S)-2-aminohex-4-enoate
[2042] A solution of 504.7 mg (3.25 mmol) of the product from Step
C above in diethyl ether, cooled to 0.degree. C., was treated
dropwise with ethereal diazomethane (prepared as described in L. F.
Fieser et al., "Reagents for Organic Synthesis", Vol. 1, p. 191,
Wiley & Sons. (1967)) until a yellow color persisted. The
excess diazomethane was removed by entraining with N.sub.2, and the
ether was evaporated under a stream of N.sub.2. The residual oil
was dissolved in 10 mL of anhydrous methanol. The solution was
cooled to 0.degree. C. under dry N.sub.2 and 1.24 g (6.54 mmol, 2.0
equiv) of anhydrous SnCl.sub.2 was added. The mixture was stirred
at .ltoreq.25.degree. C. for 4 h, and the solvent was evaporated in
vacuo to afford a solid tin-amine complex.
[2043] A solution of 1.23 g (6.50 mmol, 2.00 equiv.) of
N-Boc-L-alanine (Sigma) and 0.715 mL (0.658 g, 6.50 mmol, 2.0
equiv.) of 4-methylmorpholine (redistilled, 99.5%) (Aldrich) in 15
mL of anhydrous THF, cooled to -15 to -20.degree. C. under dry
N.sub.2, was treated dropwise with 0.861 mL (0.907 g, 6.50 mmol,
2.00 equiv.) of iso-butyl chloroformate (Aldrich). After stirring
at '115 to -20.degree. C. for 20 min, the resulting mixture
containing the mixed anhydride was added via cannulation to the
solid tin-amine complex (vide supra). The residual mixed anhydride
was rinsed in with 7 mL of THF and 1.1 g (13.1 mmol, 4.0 equiv.) of
NaHCO.sub.3 powder and 5 mL of H.sub.2O was added. The mixture was
stirred at 0.degree. C. for 5 h. An additional 1.1 g (13.1 mmol,
4.0 equiv.) of NaHCO.sub.3 powder and 5 mL of H.sub.2O was added
and the mixture was stirred at 20.degree. C. for 1.5 h. The mixture
was filtered to remove the gelatinous precipitate, and the filter
cake was washed with several portions of EtOAc. The filtrate was
washed with saturated aqueous NaHCO.sub.3 (the aqueous phase was
back-extracted with 3 portion of EtOAc), followed by pH 4-5
phosphate buffer (the aqueous phase was back-extracted with 3
portions of EtOAc). The organic phase was dried (Na.sub.2SO.sub.4)
and evaporated in vacuo. The residual straw colored oil (1.21 g)
was chromatographed (Waters Prep 2000, 5.0 cm.times.25 cm 10 .mu.
Kromasil KR60-10SIL-5025 column) eluting with a 3-L linear-gradient
from 80:20 to 40:60 hexane/EtOAc to yield 0.9088 g (89%) of the
title compound as a white solid. Tlc R.sub.f 0.25 [silica,
hexane/EtOAc 6:4)]; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.61
(d, J=7.6 Hz, 1H, NH), 5.60-5.48(m, 1H, CH.dbd.CHCH.sub.3),
5.33-5.23 (m, 1H, CH.dbd.CHCH.sub.3), 5.08 (d, J=7.3 Hz, 1H, NH),
4.591 (dt, J.sub.d=7.8 Hz, J.sub.t=5.7 Hz, 1H,
HNCH(CH.sub.2CH.dbd.CHCH.sub.3)), 4;19 (br m, 1H, HNCH(CH.sub.3),
3.74(s, 3H, OCH.sub.3), 2.56-2.39 (sym m, 2H,
CH.sub.2CH.dbd.CHCH.sub.3), 1,658 (dd, J=6.4, 1.2 Hz, 3H,
CH.sub.2CH.dbd.CHCH.sub.3), 1.454 (s, 9H, OC(CH.sub.3).sub.3, 1.358
(d, J=7.1 Hz, 3H, HNCH(CH.sub.3)).
Step E--Synthesis of Methyl
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohex-4-enoate
[2044] A solution of 0.811 g (2.58 mmol) of the product from Step D
above in 5 mL of CH.sub.2Cl.sub.2 was cooled to 0.degree. C. under
dry N.sub.2 and 5 mL of trifluoroacetic acid was introduced by
syringe at .ltoreq.4.degree. C. The solution was stirred at
0.degree. C. for 40 min. Toluene (15 mL) was added and the mixture
was evaporated in vacua on the rotary evaporator. The addition of
toluene and solvent evaporation was repeated. The residue was
dissolved in 20 mL of CH.sub.2Cl.sub.2 and the solution was cooled
to 0.degree. C. under dry N.sub.2. To this was added 1.35 mL (1.00
g, 7.74 mmol, 3.0 equiv) of ethyldiisopropylamine (Aldrich),
followed by the dropwise addition at .ltoreq.6.degree. C. of 0.728
mL (0.938 g, 5.16 mmol, 2.0 equiv) of 3,5-difluorophenylacetyl
chloride (prepared from 3,5-difluorophenylacetic acid (Aldrich)
using General Procedure H'). The resulting solution was stirred at
0.degree. C. for 2 h. Excess saturated aqueous NaHCO.sub.3 was
added and the two phase mixture was stirred in an ice bath for 30
min. The mixture was diluted with CH.sub.2Cl.sub.2 and washed
successively with aqueous NaHCO.sub.3/Na.sub.2CO.sub.3 (pH 10), 1 N
aqueous NaHSO.sub.4, and saturated aqueous NaCl., The
CH.sub.2Cl.sub.2 solution was dried (Na.sub.2SO.sub.4) and
evaporated in vacuo to afford 1.17 g of a yellow solid. This was
recrystallized from EtOAc to yield 602 mg (63%) of the title
compound as a fluffy white solid. This material was found by 300
mHz .sup.1H NMR analysis to consist of a 92:8 mixture of E and Z
isomers, respectively.
[2045] NMR data was as follows:
[2046] .sup.1H-nmr (300 MHz, CDCl.sub.3): .delta.=6.85-6.69 (m,
3H), 6.335 (br d, J=7.8 Hz, 1H), 6.289 (br d, J=7.0 Hz, 1H),
5.58-5.47 (m, 1H), 5.28-5.18 (m, 1H), 4.58-4.45 (m, 2H) 3.745. (s,
3H), 3.528 (s, 2H), 2.457 (apparent t, J=6.4 Hz, 2H), 1.650 (dd,
J=6.5, 1.3Hz, 3H), 1.58 (dm, J=6.5 Hz, 0.08H), 1.375 (d, J=7.0 Hz,
3H).
[2047] IR (CHCl.sub.3) 3421, 1742, 1667, 1626, 1597, 1503, and 1120
cm.sup.-1
[2048] Anal. Calcd for C.sub.18H.sub.22F.sub.2N.sub.2O.sub.4: C,
58.69; H, 6.02; N, 7.60. Found: C, 58.83, H, 5.89; N, 7.67.
[2049] C.sub.18H.sub.22F.sub.2N.sub.2O.sub.5 (MW=368); mass
spectroscopy (MH.sup.+) 368.
Example 189
Synthesis of N-[N-(Cyclopropylacetyl)-L-alaninyl]-L-phenylglycine
tert-Butyl Ester
[2050] Following General Procedure U and using cyclopropylacetic
acid (Lancaster) and N-(L-alaninyl)-L-phenylglycine ter-butyl ester
(General Procedure U of Z-alanine (Bachem) to phenylglycine-t-butyl
(Novabio) and then General Procedure O), the title compound was
prepared as a solid (mp=105-107.degree. C.). The reaction was
monitored by tlc (Rf=0.33 in 1:1 EtOAc/hexane, 0.13 in 5%
MeOH/DCM).
[2051] NMR data was as follows:
[2052] .sup.1H-nmr (CDCl.sub.3): .delta.=0.15 (m, 2H), 0.56 (m,
2H), 0.91 (m, 1H), 1.38 (m, 12H), 2.09 (d, J 7.1 Hz, 2H), 4.62 (m,
1H), 5.39 (d, J =7.2 Hz, 1H), 6.52 (d, J =7.2 Hz, 1H), 7.31 (m,
6H).
[2053] .sup.13C-nmr (CDCl.sub.3): .delta.=4.53, 4.55, 6.9, 18.4,
27.8, 41.21 48.4, 57.1, 82.6, 127.0, 128.2, 128.7, 136.8, 169.4,
171.4, 172.3.
[2054] C.sub.20H.sub.23N.sub.2O.sub.4 (MW=360.46); mass
spectroscopy (MH.sup.+) 361.
Example 190
Synthesis of
N-tert-Butyl-N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(-
4-phenylphenyl)acetamide
[2055] Following General Procedure AB and using
3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
4-biphenylcarboxaldehyde (Aldrich), the title compound was prepared
as a solid (mp=266-267.degree. C.). The product was purified by
recrystallization from EtOAc and/or EtOAc/hexanes.
[2056] NMR data was as follows:
[2057] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.42 (d, 1H, J=7 Hz),
8.31 (d, 1H, J=7 Hz), 7.91 (s, 1H), 7.6-7.56 (m, 4H), 7.42-7.59 (m,
5H), 7.2-7.69 (m, 3H), 5.42 (d, 1H, J=8 Hz), 4.42 (pentet, 1H, J=8
Hz), 3.5 (s, 1H), 1.2 (doublet on top of a singlet, 12H).
[2058] C.sub.29H.sub.31N.sub.3O.sub.3F.sub.2 (MW=508); mass
spectroscopy (MH.sup.+) 508.4.
Example 191
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-(S)-2-aminobutanoyl]-L-phenylglycine
tert-Butyl Ester
[2059] Following General Procedure D and using
3,5-difluorophenylacetic acid (Aldrich) and
N-C(S)-2-aminobutanoyl]-L-phenylglycine tert-butyl ester (from
Example D13 above), the title compound was prepared as a solid
(mp=138.7-140.0.degree. C.). The reaction was monitored by tlc
(Rf=0.24 in 2/1 hexanes:EtOAc) and the product was purified by
flash chromromatography and HPLC.
[2060] NMR data was as follows:
[2061] .sup.1H-nmr (DMSO-d.sub.6, 250 MHz): .delta.=8.66 (d, J=6.75
Hz, 1H), 8.30 (d, J=8.26 Hz, 1H), 7.37 (bs, 5H), 7.11-6.96 (m, 3H),
5.23 (d, J=7.00 Hz, 1H), 4.36 (td, J=7.88, 5.50 Hz, 1H), 3.53
(AB.sub.q, J.sub.AB=14.05 Hz, .DELTA.v.sub.AB=7.75 Hz, 2H),
1.85-1.48 (m, 2H), 1.34 (s, 9H), 0.88 (t, J=7.38 Hz, 3H).
[2062] Optical Rotation: [.alpha. .sub.20=21.8.degree. (c 1.0,
MeOH).
[2063] C.sub.24H.sub.28N.sub.2O.sub.4F.sub.2 (MW=446.50); mass
spectroscopy (MH.sup.+, minus CO.sub.2-tBu) 345.2.
Example 192
Synthesis of
N-(N-(3,5-Difluorophenylacetyl)-t-valinyl]-L-phenylglycine
tert-Butyl Ester
[2064] Following General Procedure D and using
3,5-difluorophenylacetic acid (Aldrich) and
N-(L-valinyl)-L-phenylglycine tert-butyl ester (from Example D14
above), the title compound was prepared as a solid
(mp=170.5-171.8.degree. C.): The reaction was monitored by tlc
(Rf=0.39 in 2:1 hexanes/EtOAc) and the product was purified by
flash chromromatography and HPLC.
[2065] NMR data was as follows:
[2066] .sup.1H-nmr (DMSO-d.sub.6, 250 MHz): .delta.=8.71 (d, J=6.75
Hz, 1H), 8.22 (d, J=9.26 Hz, 1H), 7.37 (bs, 5H), 7.11-6.96 (m, 3H),
5.23 (d, J=6.50 Hz, 1H), 4.36 (dd, J=8.88, 6.38 Hz, 1H), 3.55
(AB.sub.q, J.sub.AB=13.88 Hz, .DELTA.v.sub.AB=21.56 Hz, 2H),
2.10-1.95 (m, 1H), 1.34 (s, 9H), 0.88 (d, J=6.75 Hz, 3H), 0.86 (d,
J=6.50 Hz, 3H).
[2067] Optical Rotation: [.alpha.].sub.20=20.8.degree. (c 1.0,
MeOH).
[2068] C.sub.25H.sub.30N.sub.2O.sub.4F.sub.2 (MW=460.53); mass
spectroscopy (MH.sup.+, minus CO.sub.2-tBu) 359.2.
Example 193
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-L-methioninyl]-L-phenylglycine
Methyl Ester
[2069] Following General Procedure E and using
3,5-difluorophenylacetic acid (Aldrich) and
N-(L-methioninyl)-L-phenylglycine methyl ester hydrochloride
(prepared from N-BOC-L-methionine (Sigma) and L-phenylglycine
methyl ester hydrochloride (Aldrich) using General Procedure E,
followed by removal of the BOC-group using General Procedure P),
the title compound was prepared as a solid (mp=189.3.degree. C.).
The reaction was monitored by tlc (Rf=0.53 in 5:95
MeOH/CH.sub.2Cl.sub.2) and the product was purified by
recrystallization from ethyl acetate/hexanes.
[2070] NMR data was as follows:
[2071] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.85 (d, J=6.7 Hz, 1H),
8.41 (d, J=8.1 Hz, 1H), 7.38 (m, 5H), 7.09 (m, 1H), 6.98 (m, 2H),
5.38 (d, J=6.6 Hz, 1H), 4.47 (m, J=8.2 Hz, 1H), 3.62 (s, 3H), 3.51
(d, 2H), 2.46 (t, 2H), 2.04 (s, 3H), 1.89 (m, 2H).
[2072] .sup.13C-nmr (DMSO-d.sub.6): .delta. 172.036, 171.729,
169.883, 164.658, 164.479; 161.406, 161.227, 141.689, 141.557,
141.427, 136.524, 129.512, 129.213, 128.717, 126.274, 113.187,
113.085, 112.961, 112.862, 103.023, 102.684, 102.340, 93.065,
57.205, 53.063, 42.231, 33.075, 30.221, 15.465.
[2073] CHH.sub.24N.sub.2O.sub.4F.sub.2S (MW=450.51); mass
spectroscopy (MH.sup.+) 450.
Example 194
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-L-valinyl]-L-phenylglycine Methyl
Ester
[2074] Following General Procedure E and using
3,5-difluorophenylacetic acid (Aldrich) and
N-(L-valinyl)-L-phenylglycine methyl ester hydrochloride (prepared
from N-BOC-L-valine (Sigma) and L-phenylglycine methyl ester
hydrochloride (Aldrich) using General Procedure E, followed by
removal of the BOC-group using General Procedure P), the title
compound was prepared as a solid (mp=226.5.degree. C.). The
reaction was monitored by tlc (Rf=0.49 in 5:95
MeOH/CH.sub.2Cl.sub.2) and the product was purified by flash
chromatography using MeOH/CH.sub.2Cl.sub.2 as the eluent.
[2075] NMR data was as follows:
[2076] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.84 (d, J=6.2 Hz, 1H),
8.23 (d, J=8.8 Hz, 1H), 7.38 (m, 5H), 7.07 (m, 1H), 6.98 (m, 2H),
5.37 (d, J=6.5 Hz, 1H), 4.34 (m, J=8.9 Hz, 1H), 3.55 (m, 5H), 2.01
(m, 1H), 0.87 (m, 6H).
[2077] .sup.13 C-nmr (DMSO-d.sub.6): .delta.=171.988, 171.690,
169.861, 164.633, 164.456, 161.382, 161.204, 141.987, 141.859,
141.727, 136.553, 129.470, 129.192, 128.791, 113.128, 113.026,
112.902, 112.803, 102.961, 102.619, 102.281, 57.914, 57.262,
52.935, 42.274, 31.728, 19.845, 18.815.
[2078] C.sub.22H.sub.24N.sub.2O.sub.4F.sub.2 (MW=418.44); mass
spectroscopy (MH.sup.+) 418.1.
Example 195
Synthesis of
N-(N-(3,5-Difluorophenylacetyl)-2-aminobutanoyl]-L-phenylglycine
Methyl Ester
[2079] Following General Procedure E and using
3,5-difluorophenylacetic acid (Aldrich) and
N-(2-aminobutanoyl)-L-phenylglycine methyl ester hydrochloride
(prepared from N-BOC-L-aminobutyric acid (Sigma) and
L-phenylglycine methyl ester hydrochloride (Aldrich) using General
Procedure E, followed by removal of the BOC-group using General
Procedure P), the title compound was prepared as a solid
(mp=215.3.degree. C.). The reaction was monitored by dc (Rf=0.46 in
5:95 MeOH/CH.sub.2Cl.sub.2) and the product was purified by
recrystallization from ethyl acetate/hexanes.
[2080] NMR data was as follows:
[2081] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.83 (d, J=6.8 Hz, 1H),
8.32 (d, J=8.1 Hz, 1H), 7.38 (m, 5H), 7.08 (m, 1H), 6.98 (m, 2H),
5.38 (d, J=6.8 Hz, 1H), 4.35 (m, J=7.9 Hz, 1H), 3.61 (s, 3H), 3.52
(d, 2H), 1.64 (m, 2H), 0.88 (t, 3H).
[2082] .sup.13C-nmr (DMSO-d.sub.6): .delta.=171.684, 170.934,
168.984, 164.193, 163.980, 160.295, 160.083, 141.059, 140.902,
140.743, 135.857, 128.689, 128.372, 127.892, 112.387, 112.257,
112.131, 111.999, 102.254, 101.845, 101.438, 56.351, 53.441,
52.212, 41.436, 25.675, 10.067.
[2083] C.sub.21H.sub.22N.sub.2O.sub.4F.sub.2 (MW=404.42); mass
spectroscopy (MH.sup.+) 405.1.
Example 196
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-L-leucinyl]-L-phenylglycine Methyl
Ester
[2084] Following General Procedure E and
using-3,5-difluorophenylacetic acid (Aldrich) and
N-(L-leucinyl)-L-phenylglycine methyl ester hydrochloride (prepared
from N-BOC-L-leucine (Aldrich) and L-phenylglycine methyl ester
hydrochloride (Aldrich) using General Procedure E, followed by
removal of the BOC-group using General Procedure P), the title
compound was prepared as a solid (mp=178.4.degree. C.). The
reaction was monitored by tlc (Rf=0.51 in 5:95
MeOH/CH.sub.2Cl.sub.2) and the product was purified by flash
chromotograph using MeOH/CH.sub.2Cl.sub.2 as the eluent.
[2085] NMR data was as follows:
[2086] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.85 (d, J=6.8 Hz, 1H),
8.33 (d, J=8.3 Hz, 1H), 7.37 (m, 5H), 7.08 (m, 1H), 6.95 (m, 2H),
5.37 (d, J=6.8 Hz, 1H), 4.46 (m, J=8.3 Hz, 1H), 3.60 (s, 3H), 3.49
(d, 2H),. 1.55 (m, 3H), 0.89 (d, 3H), 0.82 (d, 3H).
[2087] .sup.13C-nmr (DMSO-d.sub.6): .delta.=172.225, 170.899,
168.888, 164.197, 163.984, 160.298, 160.086, 141.029, 140.887,
140.723, 135.875, 128.657, 128.348, 127.944, 112.340, 112.207,
112.084, 111.951, 102.251, 101.842, 101.435, 56.343, 52.214,
50.697, 41.510, 40.982, 24.449, 23.056, 21.575.
[2088] C.sub.23H.sub.26N.sub.2O.sub.4F.sub.2 (MW=432.47); mass
spectroscopy (MH.sup.+) 432.1.
Example 197
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-L-phenylalaninyl]-L-phenylglycine
Methyl Ester
[2089] Following General Procedure E and using
3,5-difluorophenylacetic acid (Aldrich) and
N-(L-phenylalaninyl)-L-phenylglycine methyl ester hydrochloride
(prepared from N-BOC-L-phenylalanine (Aldrich) and L-phenylglycine
methyl ester hydrochloride (Aldrich) using General Procedure E,
followed by removal of the BOC-group using General Procedure P),
the title compound was prepared as a solid (mp=188.3.degree. C.).
The reaction was monitored by tlc (Rf=0.59 in 5:95
MeOH/CH.sub.2Cl.sub.2) and the product was purified by flash
chromatography using MeOH/CH.sub.2Cl.sub.2 as the eluent.
[2090] NMR data was as follows:
[2091] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.99 (d, J=6.9 Hz, 1H),
8.44 (d, J=8.6 Hz, 1H), 7.4 (m, 5H), 7.21 (m, 5H), 7.03 (m, 1H),
6.77 (m, 2H), 5.42 (d, J=6.9 Hz, 1H), 4.70 (m, J=8.5 Hz, 1H), 3.63
(s, 3H), 3.40 (m, 2H), 3.08 (m, 1H), 2.76 (m, 1H).
[2092] .sup.13C-nmr (DMSO-d.sub.6): .delta.=171.428, 170.896,
168.853, 164.127, 163.915, 160.222, 160.010, 140.756, 140.601,
140.438, 137.662, 135.918, 130.638, 129.247, 128.737, 128.415,
127.908, 126.281, 112.147, 112.025, 111.892, 102.189, 101.782,
101.373, 56.411, 53.461, 52.306, 41.513, 37.796.
[2093] C.sub.26H.sub.24N.sub.2O.sub.4F.sub.2 (MW=466.49); mass
spectroscopy (MH.sup.+) 466.
Example 198
Synthesis of
N-[N-(3,5Difluorophenylacetyl)glycinyl]-L-phenylglycine Methyl
Ester
[2094] Following General Procedure E and using
3,5-difluorophenylacetic acid (Aldrich) and
N-(glycinyl)-L-phenylglycine methyl ester hydrochloride (prepared
from N-BOC-glycine (Aldrich) and L-phenylglycine methyl ester
hydrochloride (Aldrich) using General Procedure E, followed by
removal of the BOC-group using General Procedure P), the title
compound was prepared as a solid (mp 142.3.degree. C.). The
reaction was monitored by tlc (Rf=0.33 in 5:95
MeOH/CH.sub.2Cl.sub.2) and the product was purified by
recrystallization from diethyl ether/hexanes.
[2095] NMR data was as follows:
[2096] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.82 (d, J=7.2 Hz, 1H),
8.39 (t, 1H), 7.37 (m, 5H), 7.05. (m, 3H), 5.44 (d, 7.1 Hz, 1H),
3.83 (d, 2H), 3.62 (s, 3H), 3.53 (s, 2H).
[2097] .sup.13C-nmr (DMSO-d): .delta.=170.956, 169.427, 168.788,
164.226, 164.013, 160.329, 160.115, 140.817, 140.663, 140.499,
136.222, 128.728, 128.338, 127.687, 112.494, 112.360, 112.238,
112.104, 102.310, 101.900, 101.492, 56.200, 52.321, 41.731,
41.464.
[2098] C.sub.19H.sub.18N.sub.2O.sub.4F.sub.2 (MW=376.36); mass
spectroscopy (MH.sup.+) 376.0.
Example 199
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycine
Methyl Ester
[2099] Following General Procedure E and using
3,5-difluorophenylacetic acid (Aldrich) and
N-(L-phenylglycinyl)-L-phenylglycine methyl ester hydrochloride
(prepared from N-BOC-L-phenylglycine (Novabiochem) and
L-phenylglycine methyl ester hydrochloride (Aldrich) using General
Procedure AH, followed by removal of the BOC-group using General
Procedure P), the title compound was prepared as a solid
(mp=222.8.degree. C.). The reaction was monitored by tlc (Rf=0.61
in 5:95 MeOH/CH.sub.2Cl.sub.2) and the product was purified by
recrystallization from ethyl acetate.
[2100] NMR data was as follows:
[2101] .sup.1H-nmr (DMSO-d.sub.6): .delta.=9.22 (d, J=6.8 Hz, 1H),
8.85 (d, J=8.2 Hz, 1H), 7.37 (m, 10H), 7.08 (m, 1H), 6.97 (d, 2H),
5.69 (d, J=8.2 Hz, 1H), 5.43 (d, J=6.8 Hz, 1H), 3.61 (d, 2H), 3.55
(s, 3H).
[2102] .sup.13C-nmr (DMSO-d.sub.6): .delta.=170.606, 169.727,
168.777, 164.194, 163.982, 160.296, 160.082, 140.920, 140.757,
140.603, 138.391, 135.900, 128.732, 128.425, 128.233, 127.871,
127.556, 127.222, 112.467, 112.340, 112.209, 112.082, 102.292,
101.884, 101.475, 56.431, 55.621, 52.203; 41.205.
[2103] C.sub.25H.sub.22N.sub.2O.sub.4F.sub.2 (MW=452.46); mass
spectroscopy (MH.sup.+) 452.2.
Example 200
Synthesis of N-[N-(Phenylacetyl)-L-alaninyl]-L-alanine Methyl
Ester
[2104] Following General Procedure A and using
N-(phenylacetyl)-L-alanine (from Example B1 above) and L-alanine
methyl ester hydrochloride (Aldrich), the title compound was
prepared as a solid (mp=140.5-142.degree. C.). The reaction was
monitored by tlc (Rf=0.17 in 50% EtOAc/hexanes).
[2105] NMR data was as follows:
[2106] .sup.1H-nmr (CDCl.sub.3): .delta.=1.3-1.4 (m, 6H), 3.55 (s,
2H), 3.75 (s, 3H), 4.4-4.6 (m, 2H), 6.1-6.3 (brd, 1H), 6.6-6.7
(brd, 1H), 7.2-7.4 (m, 5H).
[2107] .sup.13C-nmr (CDCl.sub.3): .delta.=18.4, 19.0, 44.1, 48.6,
49.3, 53.0, 127.9, 129.5, 129.8, 135.1, 171.5, 172.4, 173.6.
[2108] C.sub.15H.sub.20N.sub.2O.sub.4 (MW=292.34); mass
spectroscopy (MH.sup.+) 293.
Example 201
Synthesis of N-[N-(Phenylacetyl)-L-alaninyl]-L-leucine Methyl
Ester
[2109] Following General Procedure A and using
N-(phenylacetyl)-L-alanine (from Example B1 above) and L-leucine
methyl ester hydrochloride (Aldrich), the tide compound was
prepared as a solid (mp 102.5-105.degree. C.). The reaction was
monitored by tlc (Rf=0.25 in 50% EtOAc/hexanes).
[2110] NMR data was as follows:
[2111] .sup.1H-nmr (CDCl.sub.3): .delta.=0.8-0.95 (m, 6H}, 1.3 (d,
J=7 Hz, 3H), 1.4-1.6 (m, 3H), 3.58 (s, 2H), 3.75 (s, 3H), 4.4-4.6
(m, 2H), 6.2 (brd, 1H), 6.7 (brd, 1H), 7.2-7.4 (m, 5H).
[2112] .sup.13C-nmr (CDCl.sub.3): .delta. 18.7, 22.3, 23.4, 25.3,
41.5, 44.1, 49.2, 51.4, 52.8, 127.9, 129.5, 129.8, 135.0, 171.5,
172.6, 173.7.
[2113] C.sub.18H.sub.26N.sub.2O.sub.4 (MW=334.42); mass
spectroscopy (MH.sup.+) 335.
Example 202
Synthesis of N-[N-(Phenylacetyl)-L-alaninyl]-L-isoleucine Methyl
Ester
[2114] Following General Procedure A and using
N-(phenylacetyl)-L-alanine (from Example B1 above) and L-isoleucine
methyl ester hydrochloride (Sigma), the title compound was
prepared. The reaction was monitored by tlc (Rf=0.24 in 50%
EtOAc/hexanes).
[2115] NMR data was as follows:
[2116] .sup.1H-nmr (CDCl.sub.3): .delta.=0.8-0.95 (m, 6H), 1.0-1.2
(m, 1H), 1.2-1.4 (m, including 1.3 (d, J=7 Hz, 4H)), 1.8-1.9 (m,
1H), 3.58 (s, 2H), 3.75 (s, 3H), 4.4-4.6 (m, 2H), 6.2 (brd, 1H),
6.7 (brd, 1H), 7.2-7.4 (m, 5H).
[2117] .sup.13C-nmr (CDCl.sub.3): .delta.=12.1, 16.0, 18.5, 25.6,
38.1, 44.1, 49.3, 52.7, 57.2, 127.9, 129.6, 129.8, 135.0, 171.5,
172.5, 172.6.
[2118] C.sub.18H.sub.26N.sub.2O.sub.4 (MW=334.42); mass
spectroscopy (MH.sup.+) 335.
Example 203
Synthesis of N-(N-(Phenylacetyl)-L-alaninyl]-L-proline Methyl
Ester
[2119] Following General Procedure A and using
N-(phenylacetyl)-L-alanine (from Example B1 above) and L-proline
methyl ester hydrochloride (Bachem), the title compound was
prepared as an oil. The reaction was monitored by tlc (Rf=0.12 in
50% EtOAc/hexanes).
[2120] NMR data was as follows:
[2121] .sup.1H-nmr (CDCl.sub.3): .delta.=1.33 (d, J=7 Hz, 3H),
1.9-2.1 (m, 3H), 2.1-2.25 (m, 1H), 3.5-3.8 (m including 3.58 (s)
and 3.75 (s), total 7H), 44.4 (m, 1H), 4.7-4.8 (m, 1H), 6.5 (brd,
1H), 7.2-7.4 (m, 5H).
[2122] .sup.13C-nmr (CDCl.sub.3): .delta.=18.5, 25.5, 29.5, 44.1,
47;3, 47.4, 52.8, 59.3, 127.8, 129.42, 129.48, 129.9, 135.2, 170.9,
171.8, 172.8.
[2123] C.sub.17H.sub.22N.sub.2O.sub.4 (MW=318.38); mass
spectroscopy (MH.sup.+) 319.
Example 204
Synthesis of N-(N-Phenylacetyl)-L-alaninyl]-L-phenylalanine Methyl
Ester
[2124] Following General Procedure A and using
N-(phenylacetyl)-L-alanine (from Example B1 above) and
L-phenylalanine methyl ester hydrochloride (Aldrich), the title
compound was prepared as a solid (mp=148-149.5.degree. C.). The
reaction was monitored by tlc (Rf=0.24 in 50% EtOAc/hexanes) and
the product was not purified.
[2125] NMR data was as follows:
[2126] .sup.1H-nmr (CDCl.sub.3): .delta.=1.25 (d, J=7 Hz, 3H), 3.02
(dd, J=7, 14Hz, 1H), 3.12 (dd, J=5, 14 Hz, 1H), 3.53 (s, 2H), 3.72
(s, 3H), 4.4-4.5 (m, 1H), 4.75-4.85 (m, 1H), 5.9 (brd, 1H), 6.5
(brd, 1H), 7.0-7.5 (m, 10H).
[2127] .sup.13C-nmr (CDCl.sub.3): .delta.=18.6, 38.3, 44.0, 49.2,
52.9, 53.9, 127.7, 128.0, 129.1, 129.6, 129.8, 129.9, 135.0, 136.3,
171.4, 172.2, 172.3.
[2128] C.sub.21H.sub.24N.sub.2O.sub.4 (MW=368.44); mass
spectroscopy (MH.sup.+) 369.
Example 205
Synthesis of
N-[N-(Phenylacetyl)-L-alaninyl]-N-(tert-butoxycarbonyl)-L-lysine
Methyl Ester
[2129] Following General Procedure A and using
N-(phenylacetyl)-L-alanine (from Example B1 above) and
N,-(tert-butoxycarbonyl)-L-lysine methyl ester hydrochloride
(Bachem), the title compound was prepared as a solid (mp
119-121.degree. C.). The reaction was monitored by tlc (Rf=0.46 in
90:10:1 CH.sub.2Cl.sub.2\MeOH\NH.sub.4OH).
[2130] NMR data was as follows:
[2131] .sup.1H-nmr (CDCl.sub.3): .delta.=1.2-1.9 (m, 18H)(includes
1.3 (d, J=7 Hz) and 1.4 (s)), 3.0-3.15 (m, 2H), 3.12 (dd, J=5, 14
Hz, 1H), 3.57 (s, 2H), 3.72 (s, 3H), 4.4-4.5 (m, 2H), 4.75-4.85 (m,
1H), 6.2 (brd, 1H), 6.75 (brd, 1H), 7.2-7.4 (m, 5H).
[2132] .sup.13C-nmr (CDCl.sub.3): .delta.=18.6, 22.9, 29.0, 29.9,
32.0, 40.5, 44.0, 49.4, 52.7, 53.0, 79.8, 127.9, 129.5, 129.8,
135.1, 156.7, 171.6, 172.7, 173.0.
[2133] C.sub.23H.sub.35N.sub.3O.sub.6 (MW=449.55); mass
spectroscopy (MH.sup.+)=450.
Example 206
Synthesis of N-[N-(Phenylacetyl)-L-alaninyl]glycine Methyl
Ester
[2134] Following General Procedure A and using
N-(phenylacetyl)-L-alanine (from Example B1 above) and glycine
methyl ester hydrochloride (Aldrich), the title compound was
prepared as a solid (mp=152-153.5.degree. C.). The reaction was
monitored by tlc (Rf=0.10 in 50% EtOAc/hexanes).
[2135] NMR data was as follows: p .sup.1H-nmr (CDCl.sub.3):
.delta.=1.33 (d, J=7 Hz, 3H), 3.59 (s, 2H), 3.75 (s, 3H), 3.97 (d,
J=6.5 Hz, 2H), 4.5-4.6 (m, 1H), 6.1 (brd, 1H), 6.8 (brs, 1H),
7.2-7.6 (m, 5H).
[2136] .sup.13C-nmr (CDCl.sub.3): .delta.=18.7, 41.6, 43.9, 49.2,
52.9, 127.9, 129.5, 129.9, 135.0, 170.6, 171.7, 173.2.
[2137] C.sub.14H.sub.18N.sub.2O.sub.4 (MW=278.31); mass
spectroscopy (MH.sup.+) 279.
Example 207
Synthesis of N-[N-(Phenylacetyl)-L-alaninyl]-L-valine Methyl
Ester
[2138] Following General Procedure A and using
N-(phenylacetyl)-L-alanine (fromo Example B1 above) and L-valine
methyl ester hydrochloride (Aldrich), the title compound was
prepared as a solid (mp=112-115.degree. C.). The reaction was
monitored by tlc (Rf=0.33 in 50% EtOAc/hexanes) and the product was
not purified.
[2139] NMR data was as follows:
[2140] .sup.1H-nmr (CDCl.sub.3): .delta.=0.8-0.9.(overlapping d
appearing as t, J=6 Hz, 6H), 2.0-2.2 (m, 1H), 3.57 (s, 2H), 3.72
(s, 3H), 4.4-4.5 (m, 1H), 4.5-4.65 (m, 1H), 6.2 (brd, 1H), 6.75
(brd, 1H), 7.2-7.4 (m, 5H).
[2141] .sup.13C-nmr (CDCl.sub.3): .delta.=18.3, 18.5, 19.5, 31.5,
44.1, 49.3, 52.7, 57.9, 127.9, 129.5, 129.8, 135.0, 171.5, 172.7,
172.7.
[2142] C.sub.17H.sub.24N.sub.2O.sub.4 (MW=320.39); mass
spectroscopy (MH.sup.+) 321.
Example 208
Synthesis of Methyl
N-[N-(Phenylacetyl)-L-alaninyl]-2-(S)-aminobutanoate
[2143] Following General Procedure A and using
N-(phenylacetyl)-L-alanine (from Example B1 above) and methyl
L-2-aminobutanoate hydrochloride (prepared from L-2-aminobutanoic
acid (Bachem) using General Procedure H (without extractions)), the
title compound was prepared as a solid (mp=120.degree. C.). The
reaction was monitored by tlc (Rf=0.2 in 50% EtOAc/hexanes).
[2144] NMR data was as follows:
[2145] .sup.1H-nmr (CDCl.sub.3): .delta.=0.85 (t, J=6 Hz, 3H), 1;32
(d, J=7 Hz, 3H), 1.6-1.9 (m, 2H), 3.57 (s, 2H), 3.72 (s, 3H),
4.4-4.6 (m, 2H), 6.2 (brd, 1H, 6.75 (brd, 1H), 7.2-7.4.(m, 5H).
[2146] .sup.13C-nmr (CDCl.sub.3): .delta.=10.2, 18.9, 25.8, 44.0,
49.3, 52.8, 54.0, 127.9, 129.5, 129.8, 135.1, 171.5, 172.7,
173.0.
[2147] C.sub.16H.sub.22N.sub.2O.sub.4 (MW=306.36); mass
spectroscopy (M.sup.+) 307.
Example 209
Synthesis of Methyl
N-[N-(Phenylacetyl)-L-alaninyl]-2-(S)-aminopentanoate
[2148] Following General Procedure A and using
N-(phenylacetyl)-L-alanine (from Example B1 above) and methyl
2-(S)-aminopentanoate hydrochloride (prepared from L-2-aminovaleric
acid (Bachem) using General Procedure H (without extractions)), the
title compound was prepared as a solid (mp=135-137.degree. C.). The
reaction was monitored by tlc (Rf=0.30 in 50% EtOAc/hexanes).
[2149] NMR data was as follows:
[2150] .sup.1H-nmr (CDCl.sub.3): .delta.=0.87 (t, J=6 Hz, 3H),
1.2-1.4 (m with d, J=7 Hz, 5H), 1.5-1.8 (m, 2H), 3.57 (s, 2H), 3.72
(s, 3H), 4.4-4.5 (m, 2H), 6.4 (brd, 1H), 7.0 (brd, 1H), 7.2-7.4 (m,
5H).
[2151] .sup.13 C-nmr (CDCl.sub.3): .delta.=14.2, 19.0, 19.2, 34.5,
44.0, 49.2, 52.7, 52.8, 127.8, 129.4, 129.8, 135.2, 171.5, 172.8,
173.3.
[2152] C.sub.17H.sub.24N.sub.2O.sub.4 (MW=320.39); mass
spectroscopy (MH.sup.+) 321.
Example 210
Synthesis of N-[N-(3-Nitrophenylacetyl)-L-alaninyl]-L-valine
[2153] Following General Procedure AF and using
N-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-valine ethyl ester (from
Example 143 above), the title compound was prepared as a solid. The
reaction was monitored by tlc (Rf=0.05 in 9:1 CHCl.sub.3/MeOH).
[2154] NMR data was as follows:
[2155] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.41 (d, 1H), 8.13 (s,
1H), 8.09 (d, 1H), 7.91 (d, 1H), 7.68 (d, 1H), 7.56 (t, 1H), 4.4
(m, 1H), 4.10 (m, 1H), 3.63 (s, 2H), 2.01 (m, 1H), 1.19 (m, 3H),
0.89 (d, 6H).
[2156] Optical Rotation: [.alpha.].sub.23=-49.degree. (c 1,
MeOH).
[2157] C.sub.16H.sub.21N.sub.3O.sub.6 (MW=351.3); mass spectroscopy
(MH.sup.+) 352.
Example 211
Synthesis of N-[N-(Phenylacetyl)-L-alaninyl]-L-N-methylalanine
Methyl Ester
[2158] Following General Procedure A and using
N-(phenylacetyl)-L-alanine (from Example B1 above) and
L-N-methylalanine methyl ester hydrochloride (prepared from
L-N-methylalanine hydrochloride (Bachem) using General Procedure H
(without extractions)), the title compound was prepared as an oil.
The reaction was monitored by tlc (Rf=0.13 in 50% EtOAc/hexanes)
and the product was purified by column chromatography using 60%
EtOAc/hexanes as the eluent.
[2159] NMR data was as follows:
[2160] .sup.1H-nmr (CDCl.sub.3): .delta.=1.2-1.6 (m including 1.32
(d, J=7 Hz, 6H), 2.97 (s (rotomers), 3H), 3.57.(s, 2H), 3.7-3.8 (s
(rotomers), 3M), 4.4-5.2 (m, 2H), 6.6 (brd, 1H), 7.2-7.4 (m,
5H).
[2161] .sup.13C-nmr (CDCl.sub.3): .delta.=14.7, 15.0, 18.8, 19.1,
31.6, 32.3, 44.3, 46.2, 46.3, 52.7, 52.88, 52.93, 53.6, 127.81,
127.85, 129.45, 129.48, 129.9, 135.2, 170.60, 170.67, 172.19,
172.4, 173.25, 173.31.
[2162] C.sub.16H.sub.22N.sub.2O.sub.4 (MW=306.36); mass
spectroscopy (MH.sup.+) 307.
Example 212
Synthesis of N-[N-(Isovaleryl)-L-phenylglycinyl]-L-alanine Isobutyl
Ester
[2163] Following General Procedure C and using
N-(isovaleryl)-L-phenylglycine (prepared from isovaleric acid
(Aldrich) and L-phenylglycine methyl ester hydrochloride (Aldrich)
using General Procedure C, followed by hydrolysis using General
Procedure AF) and L-alanine isobutyl ester hydrochloride (prepared
from N-BOC-L-alanine (Sigma) and 2-methyl-1-propanol (Aldrich)
using General Procedure C (with catalystic DMAP), followed by
removal of the BOC-group using General Procedure P), the tide
compound was prepared as a solid (mp=181-186.degree. C.). The
reaction was monitored by tlc (Rf=0.4 in 1:1 EtOAc/hexanes) and the
product was purified by silica gel chromatography using 1:1
EtOAc/hexanes as the eluent.
[2164] NMR data was as follows:
[2165] .sup.1H-nmr (CDCl.sub.3): .delta.=1.31 (d, 3H), 5.59 (d,
1H).
[2166] Optical Rotation: [.alpha.].sub.20=+19.degree. @ 589 nm (c
1.03, DMSO).
[2167] C.sub.20H.sub.30N.sub.2O.sub.4 (MW=362); mass spectroscopy
(MH.sup.+) 363.
Example 213
Synthesis of N-[N-(Isovaleryl)-L-isoleucinyl]-L-alanine Isobutyl
Ester
[2168] Following General Procedure C and using
N-(isovaleryl)-L-isoleucine (prepared from isovaleric acid
(Aldrich) and L-isoleucine methyl ester hydrochloride (Aldrich)
using General Procedure C, followed by hydrolysis using General
Procedure AF) and L-alanine isobutyl ester hydrochloride (prepared
from N-BOC-L-alanine (Sigma) and 2-methyl-1-propanol (Aldrich)
using General Procedure C (with catalystic DMAP), followed by
removal of the BOC-group using General Procedure P), the title
compound was prepared as a solid (mp=142-146.degree. C.). The
reaction was monitored by tlc (Rf=0.4 in 1:1 EtOAc/hexanes) and the
product was purified by silica gel chromatography using 1:1
EtOAc/hexanes as the eluent to provide a 1:4 mixture of
diastereomers.
[2169] NMR data was as follows:
[2170] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.26 (d, 3H), 7.70 (d,
1H), 7.80 (d, 1H), 8.30 (d, 1H), 8.40 (d, 1H).
[2171] C.sub.18H.sub.34N.sub.2O.sub.4 (MW=342.48); mass
spectroscopy (MH.sup.+) 343.
Example 214
Synthesis of N-Cyclohexyl-N'-
N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide
[2172] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
N-cyclohexyl-L-phenylglycinamide (prepared from
N-BOC-L-phenylglycine (Advanced Chemtech) and cyclohexylamine
(Aldrich) using General Procedure M, followed by removal of the
BOC-group using General Procedure P), the title compound was
prepared as a solid. The reaction was monitored by tlc (Rf=0.5 in
9:1 CHCl.sub.3/MeOH) and the product was purified by trituration
from ethanol.
[2173] NMR data was as follows:
[2174] .sup.1H-nmr (CDCl.sub.3): .delta.=8.55 (m, 2H), 8.08 (d,
1H), 7.30 (m, 5H), 7.08 (m, 1H), 6.97 (d, 2H), 5.37 (m, 1M, 3.47
(s, 2H), 1.8-1.6 (m, 6H), 1.23-0.98 (m, 7H).
[2175] Optical Rotation: [.alpha.].sub.23=32.7.degree. (c 1;
MeOH).
[2176] C.sub.25H.sub.29F.sub.2N.sub.3O.sub.3 (MW=457); mass
spectroscopy (MH.sup.+) 458.
Example 215
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-4-hydroxyproline
Ethyl Ester
[2177] Following General Procedure F and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
L-4-hydroxyproline ethyl ester hydrochloride (Pfaltz & Bauer),
the title compound was prepared as a foam. The reaction was
monitored by tlc (Rf=0.32 in 95:5 CH.sub.2Cl.sub.2/MeOH) and the
product was purified by flash column chromatography.
[2178] NMR data was as follows:
[2179] .sup.1H-nmr (CDCl.sub.3, 250 Mz): .delta.=7.31 (d, 1H,
J=7.00 Hz), 6.83-6.64 (m, 3H), 4.67 (p, 1H, J=7.09 Hz), 4.58 (t,
1H, J=8.26 Hz), 4.47 (bs, 1H), 4.25-4.06 (m, 2H), 3.81 (bd, 1H,
J=11.01 Hz), 3.62 (dd, 1H, J=10.76, 3.75 Hz), 3.46 (s, 2H), 2.30
(dd, 1H, J=13.51, 8.26 Hz), 1.96(ddd, 1H, J=13.44, 8.82, 4.56 Hz),
1.33 (d, 3H, J=6.75. Hz), 1.24 (t, 3H, J=7.13 Hz).
[2180] C.sub.18H.sub.23F.sub.2N.sub.2O.sub.5 (MW=384.38); mass
spectroscopy (MH.sup.+) 385.1.
Example 216
Synthesis of N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-lysine
Methyl Ester
[2181] Following General Procedure Y and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-N.sub.4-(tert-butoxycarbonyl)-
-L-lysine methyl ester (from Example 43 above), the title compound
was prepared as an oil. The title compound was isolated as the
trifluoroacetic acid salt (containing about 5% excess
trifluoroacetic acid).
[2182] NMR data was as follows:
[2183] .sup.1H-nmr (CDCl.sub.3+2 drops of CD.sub.3OD):
.delta.=6.40-6.52 (m, 3H), 4.17 (t, 1H), 4.40 (q, 1H), 3.42 (s,
3H), 3.23 (s, 3H), 2.53 (bs, 2H), 1.60 (m, 1H), 1.32 (m, 3H),
1.02-1.13 (m, 2H), 1.10 (d, 2H).
[2184] .sup.13C-nmr (CDCl.sub.3+2 drops of CD.sub.3OD):
.delta.=174.1, 166.4, 166.2, 163.1, 163.0, 141.3, 113.8, 113.7,
113.5, 103.5, 55.2, 56.3, 43.0, 40.9, 32.2, 28.1, 24.0, 18.2.
[2185] C.sub.21H.sub.26F.sub.5N.sub.3O.sub.6 (MW=511.4); mass
spectroscopy (MH.sup.+) 512.
Example 217
Synthesis of
N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-glutamide
[2186] Following General Procedure B and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
L-glutamide hydrochloride (Bachem), the title compound was prepared
as a solid (mp=260-263.degree. C.). The reaction was monitored by
tlc (Rf=0.77 in 10% MeOH/DCM) and the product was purified by
silica gel chromatography.
[2187] NMR data was as follows:
[2188] .sup.1H-nmr (CDCl.sub.3): .delta.=8.40 (d, J=7.1 Hz, 1H),
8.02 (d, J=6.9, 1H), 7.2 (m, 2H), 7.0 (m, 4H), 6.76 (s, 1H), 4.2
(m, 1H), 3.56 (s, 2H), 2.1 (m, 2H), 1.9 (m, 2H), 1.21 (d, J=7.0 Hz,
3H).
[2189] .sup.13C-nmr (CDCl.sub.3): .delta.=173.5, 172.4, 169.5,
112.5, 110.4, 102.3, 52.5, 49.0, 41.6, 35.7, 31.8, 28.1, 18.4.
[2190] C.sub.16H.sub.20F.sub.2N.sub.4O.sub.4 (MW=370); mass
spectroscopy (MH.sup.+) 371.
Example 218
Synthesis of
Methyl
1-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]piperidine-2-carboxylate
[2191] Following General Procedure A and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
methyl pipecolinate hydrochloride (Aldrich), the title compound was
prepared as a solid (mp=114-118.degree. C.). The reaction was
monitored by tlc (Rf=0.71 in 10% MeOH/DCM) and the product was
purified by acid/base washes.
[2192] NMR data was as follows:
[2193] .sup.1H-nmr (CDCl.sub.3): .delta.=6.95 (dd, J=7.1, 7.1, 7.1
Hz; 1H), 6.81 (d, J=6.1 Hz, 2H), 6.7 (m, 1H), 5.28 (dd, J=5.0 Hz,
12.6, 5.4, 1H), 4.93 (q, J=7.0, 6.9, 7.0 Hz, 1H), 3.75 (s, 1H),
3.70 (s, 3H), 3.50 (s, 2H), 3.2 (m, 1H), 2.27 (d, J=33.5 Hz, 1H),
1.5 (m, 5H), 1.31 (d, J=5.2 Hz, 3H).
[2194] .sup.13C-nmr (CDCl.sub.3): .delta.=172.8; 172.6; 171.7;
171.6; 169.2; 169.1; 112.9; 112.8; 112.7; 112.6; 103.2; 102.8;
53.0; 52.9; 52.9; 52.7; 46.2; 46.1; 43.9; 43.9; 27.1; 26.8; 25.6;
21.4; 19.9; 18.5.
[2195] C.sub.18H.sub.22F.sub.2N.sub.2O.sub.4 (MW=368); mass
spectroscopy (MH.sup.+) 369.
Example 219
Synthesis of
N-[(S)-3-Hydroxy-6-methylhept-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alani-
namide
[2196] Following General Procedure AA and using
N-[(S)-6-methyl-3oxohept-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamid-
e (from Example 168 above), the title compound was prepared as a
solid. The reaction was monitored by tlc (Rf=0.75 in 9:1
CHCl.sub.3/MeOH) and the product was purified by silica gel
chromatography using 99:1 CHCl.sub.3/MeOH as the eluent.
[2197] NMR data was as follows:
[2198] .sup.1H-nmr (CDCl.sub.3): .delta.=6.81 (m, 1H), 6.72 (m,
2H), 6.39 (m, 2H), 4.45 (m, 1H), 3.97 (m, 1H), 3.60 (m, 1H), 3.52
(s, 2H), 1.54 (m, 1H), 1.4 (m, 5H), 1.09 (m, 3H), 0.9 (m, 6H).
[2199] Optical Rotation: [.alpha.].sub.23=-39.degree. (c 1,
MeOH).
[2200] C.sub.19H.sub.28F.sub.2N.sub.2O.sub.3 (MW=448); mass
spectroscopy (MH.sup.+) 449.
Example 220
Synthesis of
N-[(S)-2-Hydroxy-1-phenyleth-1-yl]-N'-(3,5-Difluorophenylacetyl)-L-alanin-
amide
[2201] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
(S)-2-hydroxy-1-phenyleth-1-ylamine (e.g., (S)-phenylglycinol)
(Aldrich), the title compound was prepared as a solid
(mp=204-206.degree. C.). The reaction was monitored by tlc (Rf=0.5
in 10% MeOH/CHCl.sub.3) and the product was purified by silica gel
chromatography using 5 % MeOH/CHCl.sub.3 as the eluent, followed by
recrystallization from acetonitrile.
[2202] NMR data was as follows:
[2203] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.24 (d, 3H), 4.38 (m,
1H), 4.80 (m, 2H).
[2204] Optical Rotation: [.alpha.].sub.20=+3.56.degree. @ 589 nm (c
1.10, DMSO).
[2205] C.sub.19H.sub.20F.sub.2N.sub.2O.sub.3 (MW=362.38); mass
spectroscopy (MH.sup.+) 363.
Example 221
Synthesis of
N-[N-(3,5-Difluorophenyl-.alpha.-fluoroacetyl)-L-alaniny]-L-phenylglycine
tert-Butyl Ester
[2206] Following General Procedure M and using
3,5-difluorophenyl-.alpha.-fluoroacetic acid (from Example D1
above) and N-(L-alaniny)-L-phenylglycine tert-butyl ester (prepared
using N-BOC-L-alanine (Sigma) and L-phenylglycine tert-butyl ester
hydrochloride (Bachem) using General Procedure C, followed by
removal of the BOC group using General Procedure P), the title
compound was prepared as a clear oil. The reaction was monitored by
tlc (Rf=0.44 and 0.51 in 1:1 EtOAc/hexanes) and the product was
purified by LC 2000. chromatography using 20% EtOAc/hexanes as the
eluent.
[2207] NMR data was as follows:
[2208] .sup.1H-nmr (CDCl.sub.3)(1:1 mixture of diasteromers):
.delta.=1.37 (s, 9H), 1.39 (s, 9H), 1.42 (d, J=7.0 Hz, 3H), 1.48
(d, J=7.0 Hz, 3H), 3.80 (d, J=7.0 Hz, 1H), 4.62 (pent, J=7.0 Hz,
2H), 5.36 (d, J=7.1 Hz, 1H), 5.42 (d, J=7.2 Hz, 1H), 5.60 (d, J=4.7
Hz, 1H), 5.73 (d, J=4.7 Hz, 1H), 6.80 (m, 2H), 6.97 (m, 4H),
7.20-7.33 (m, 12H).
[2209] C.sub.23H.sub.25F.sub.3N.sub.2O.sub.4 (MW=450.2); mass
spectroscopy (MH.sup.+) 451.
Example 222
Synthesis of
N-[(S)-.alpha.-Hydroxy-.alpha.'-phenylisopropyl]-N'-(3,5-difluorophenylac-
etyl)-L-alaninamide
[2210] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
(S)-.alpha.-hydroxy-.alpha.'-phenylisopropylamine (e.g.,
L-phenylalaninol) (Aldrich), the title compound was prepared as a
solid. The reaction was monitored by tlc (Rf=0.5 in 9:1
CHCl.sub.3/MeOH) and the product was purified by silica gel
chromatography using 95:5 CHCl.sub.3/MeOH as the eluent.
[2211] NMR data was as follows:
[2212] .sup.1H-nmr (CDCl.sub.3): .delta.=7.33-7.17 (m, 5H), 6.72
(m, 3H), 6.62 (d, 1H), 6.32 (d, 1H), 4.43 (m, 1H), 4.10 (m, 1H),
3.61 (m, 2H), 3.45 (s, 2H), 2.84 (m, 2H), 1.32 (d, 3H).
[2213] Optical Rotation: [.alpha.].sub.23=-60.degree. (c 1,
MeOH).
[2214] C.sub.20H.sub.22F.sub.2N.sub.2O.sub.3 (MW=376); mass
spectroscopy (MH.sup.+) 377.
Example 223
Synthesis of
N-[(1S,2R)-1-Hydroxy-1-phenylprop-2-yl]-N'-(3,5-difluorophenylacetyl)-L-a-
laninamide
[2215] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
(1S,2R)-1-hydroxy-1-phenylprop-2-ylamine hydrochloride (e.g.,
(1S,2R)-norephedrine hydrochloride) (Aldrich), the title compound
was prepared as a solid. The reaction was monitored by tlc (Rf=0.5
in 9:1 CHCl.sub.3/MeOH) and the product was purified by silica gel
chromatography using 98:2 CHCl.sub.3/MeOH as the eluent.
[2216] NMR data was as follows:
[2217] .sup.1H-nmr (CDCl.sub.3): .alpha.=7.31 (m, 5H), 6.84-6.64
(m, 4H), 4.86 (m, 1H), 4.51 (m, 1H), 4.23 (m, 1H), 3.52 (s, 2H),
1.38 (d, 3H), 0.97 (d, 3H).
[2218] Optical Rotation: [.alpha.].sub.23=-44.degree. (c 1,
MeOH).
[2219] C.sub.20H.sub.22F.sub.2N.sub.2O.sub.3 (MW=376); mass
spectroscopy (MH.sup.+) 377.
Example 224
Synthesis of
N-2-Methoxyethyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycinamide
[2220] Following General Procedure K and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine methyl ester
(from Example 28 above) and 2-methoxyethylamine (Aldrich), the
title compound was prepared as a solid (mp=148-151.degree. C.). The
reaction was monitored by tlc+(Rf=0.53 in 10% MeOH/DCM+1% TEA) and
the product was purified by silica gel chromatography.
[2221] NMR data was as follows:
[2222] .sup.1H-nmr (CDCl.sub.3): .delta.=8.2 (m, 1H), 7.1 (m, 1H),
6.6 (m, 8H0, 4.7 (m, 1H), 4.0 (m, 1R), 3.6 (m, 2H), 3.39 (s, 2H),
3.2 (m, 4H), 3.1 (s, 3H), 1.17 (d, J=7.2 Hz, 3H).
[2223] .sup.13C-nmr (CDCl.sub.3): .alpha.=176.3, 173.4, 172.2,
166.5, 163.4, 150.4, 141.6, 114.1, 114.0, 113.9, 113.8, 103.9,
103.5, 72.2, 72.1, 59.4, 51.9, 44.0, 43.0, 40.7, 17.9.
[2224] C.sub.16H.sub.21F.sub.2N.sub.3O.sub.4 (MW=357); mass
spectroscopy (MH.sup.+) 358.
Example 225
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-2-(S)-aminocyclohexylacetyl]-L-phenylglyc-
ine Methyl Ester
[2225] Following General Procedure E and using
3,5-difluorophenylacetic acid (Aldrich) and
N-[2-(S)-aminocyclohexylacetyl]-L-phenylglycine methyl ester
hydrochloride (prepared from N-BOC-L-cyclohexylglycine (Sigma) and
L-phenylglycine methyl ester hydrochloride (Aldrich) using General
Procedure E, followed by removal of the BOC-group using General
Procedure P), the title compound was prepared as a solid
(mp=234.4.degree. C.). The reaction was monitored by tlc (Rf=0.65
in 5:95 MeOH/DCM) and the product was purified by recrystallization
from ethyl acetate.
[2226] NMR data was as follows:
[2227] .sup.1H-nmr (DMSO-d.sub.3): .delta.=8.85 (d, J=6.5 Hz, 1H),
8.21 (d, J=8.9 Hz, 1H), 7.37 (s, 5H), 7.07 (m, 1H), 6.97 (d, 2H),
5.36 (d, J=6.4 Hz, 1H), 4.35 (t, J=7.7 Hz, 1H), 3.53 (m, 5H), 1.65
(m, 6H), 1.06 (m, 5H).
[2228] .sup.13C-nmr (DMSO-d.sub.3): .delta.=171.065, 170.865,
168.953, 164.179, 163.967, 160.282, 160.070, 141.210, 141.058,
135.766, 128.657, 128.374, 128.004, 112.371, 112.238, 112.115,
111.981, 102.217, 101.808, 101.399, 56.568, 56.471, 41.467, 40.354,
28.884, 28.025, 25.926, 25.669.
[2229] C.sub.25H.sub.28N.sub.2O.sub.4F.sub.2 (MW=458.51); mass
spectroscopy (MH.sup.+) 458.1.
Example 226
Synthesis of
N-[(1R,2S)-1-Hydroxy-1-phenylprop-2-yl]-N'-(3,5-difluorophenylacetyl)-L-a-
laninamide
[2230] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
(1R,2S)-1-hydroxy-1-phenylprop-2-ylamine hydrochloride (e.g.,
(1R,2S)-norephedrine hydrochloride) (Aldrich), the title compound
was prepared as a foam. The reaction was monitored by tlc (Rf=0.5
in 9:1 CHCl.sub.3/MeOH).
[2231] NMR data was as follows:
[2232] .sup.1H-nmr (CDCl.sub.3): .delta.=7.35 (m, 51), 7.75 (m,
3H), 6.57 (d, 1H), 4.47 (d, 1H), 4.26 (m, 1H), 3.48 (s, 2H), 1.32
(d, 3H), 1.01 (d, 3H).
[2233] Optical Rotation: [.alpha.].sub.23=-64.degree. (c 1,
MeOH).
[2234] C.sub.20H.sub.22F.sub.2N.sub.2O.sub.3 (MW=376); mass
spectroscopy (MH.sup.+) 377.
Example 227
Synthesis of
N-[(1R,2S)-1-hydroxy-1,2-diphenyleth-2-yl]-N'-(3,5-difluorophenylacetyl)--
L-alaninamide
[2235] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
(1R,2S)-2-amino-1,2-diphenylethanol (Aldrich), the title compound
was prepared as a solid (mp=217-219.degree. C.). The reaction was
monitored by tlc (Rf=0.4 in 10% MeOH/CHCl.sub.3) and the product
was purified by silica gel chromatography using 7% MeOH/CHCl.sub.3
as the eluent, followed by recrystallization from acetonitrile.
[2236] NMR data was as follows:
[2237] .sup.1H-nmr (DMSO-d.sub.6): .delta.=0.76 (d, 3H), 5.43 (d,
1H).
[2238] Optical Rotation: [.alpha.].sub.20=-6.9.degree. @ 589 nm (c
1.10, DMSO).
[2239] C.sub.25H.sub.24F.sub.2N.sub.2O.sub.3 (MW=438.48); mass
spectroscopy (MH.sup.+) 439.
Example 228
Synthesis of
N-[(S)-1-Hydroxyhex-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide
[2240] Following General Procedure S and using methyl
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanoate
(from Example 1 above), the title compound was prepared as a solid
(mp=157-158.5.degree. C.). The reaction was monitored by tlc
(Rf=0.62 in 10% CH.sub.3OH/CH.sub.2Cl.sub.2).
[2241] NMR data was as follows:
[2242] .sup.1H-nmr (CD.sub.3OD): .delta.=5.9 (m, 2H), 5.8 (m, 1H),
4.37 (q, 1H), 3.8 (m, 1H), 3.58.(s, 2H), 3.5 (m, 2H), 1.4 (m, 9H),
0.9 (m, 3H).
[2243] .sup.13C-nmr (CD.sub.3OD): .delta.=175.4, 172.9, 166.7,
166.5, 163.5, 163.2, 141.8, 141.7, 113.9, 113.8, 113.7, 113.6,
103.9, 103.6, 103.2, 65.6, 53.2, 51.2, 43.3, 32.3, 29.7, 24.1,
18.7, 14.9.
[2244] C.sub.17H.sub.24F.sub.2N.sub.2O.sub.3 (MW=342.39); mass
spectroscopy (MH.sup.+) 343.
Example 229
Synthesis of
N-[.alpha.-Hydroxy-.alpha.'-(4-hydroxyphenyl)isopropyl]-N'-(3,5-difluorop-
henylacetyl)-L-alaninamide
[2245] Following General Procedure S and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-tyrosine methyl ester
(from Example 15 above), the title compound was prepared as a solid
(mp=179-183.degree. C.). The reaction was monitored by tlc (Rf=0.42
in 10% MeOH/DCM) and the product was purified by recrystallization
from MeOH/diethyl ether.
[2246] NMR data was as follows:
[2247] .sup.1H-nmr (CDCl.sub.3): .delta.=6.82 (d; J=8.3 Hz, 2H),
6.7 (m, 2H), 6.62 (t, J=9.1, 9.1 Hz, 1H), 6.47 (d, J=8.5 Hz, 2H),
4.1 (m, 1H), 3.7 (m, 1H), 3.34 (s, 2H), 3.2 (m, 2H), 2.5 (m, 2H);
1.08-0.94 (dd, J=7.1, 36.0, 7.1 Hz, 3H).
[2248] .sup.13C-nmr (CDCl.sub.3): .delta.=175.0, 172.8, 157.4,
131.8, 131.8, 130.7, 116.6, 116.5, 113.9, 113.5, 64.1, 54.9, 51.1,
43.3, 37.4, 18.6.
[2249] C.sub.20H.sub.22F.sub.2N.sub.2O.sub.4 (MW=392); mass
spectroscopy (MH.sup.+)=393.
Example 230
Synthesis of
N-2-Pyridylmethyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylal-
aninamide
[2250] Following General Procedure K and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine methyl
ester (from Example 94 above) and 2-(aminomethyl)pyridine
(Aldrich), the title compound was prepared.
[2251] NMR data was as follows:
[2252] .sup.1H-nmr (CD.sub.3OD): .delta.=8.45 (d, 1H), 7.75 (t,
1H), 7.2-7.4 (m, 6H), 7.1 (d, 1H), 6.8-7.0 (m, 3H) 4.63 (t,
1H).4.45 (s, 2H), 4.2-4.35 (m, 1H), 3.6 (s, 2H), 3.6 (s, 2H),
3.0-3.25 (m, 2H), 1.30 (d, 3H)
[2253] .sup.13C-nmr (CD.sub.3OD): .delta.=175.4, 174.0, 173.3,
166.6, 163.3, 163.2, 159.5, 150.0, 141.4, 139.4, 138.9, 130.9,
130.1, 128.4, 124.2, 123.2, 114.0, 113.9, 113.7, 113.6, 103.9,
103.2, 56.9, 51.4, 45.8, 43.1, 39.0, 18.2
[2254] C.sub.26H.sub.26F.sub.2N.sub.4O.sub.3 (MW=480.52); mass
spectroscopy (MH.sup.+)=481.
Example 231
Synthesis of
N-[.alpha.-Hydroxy-.alpha.'-pyrid-2-ylisopropyl]-N'-(3,5-difluorophenylac-
etyl)-L-alaninamide
[2255] Following General Procedure S and using methyl
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(2-pyridyl)prop-
ionate (from Example 19 above), the title compound was prepared as
a solid (mp=225-229.degree. C.). The reaction was monitored by tlc
(Rf=0.66 in 10% MeOH/DCM) and the product was purified by
recrystallization from MeOH/diethyl ether.
[2256] NMR data was as follows:
[2257] .sup.1H-nmr (CDCl.sub.3): .delta.=8.21 (d, J=4.5 Hz, 1H),
7.46 (t, J=6.3, 7.6 Hz, 1H), 7.11 (d, J=7.6 Hz, 1H), 7.01 (t,
J=5.5, 7.1 Hz, 1H), 6.70 (d, J=6.3 Hz, 2H), 6.62 (t, J=9.6, 9.0 Hz,
1H), 4.1 (m,- 1H), 3.4 (m, 1H), 3.33 (s, 2H), 3.3 (m, 2H), 1.06 (d,
J=7.0 Hz, 3H).
[2258] .sup.13C-nmr (CDCl.sub.3): .delta.=172.754, 160.222,
150.134, 139.137, 126.198, 123.680, 113.936, 113.602, 103.578,
64.854, 53.689, 51.191, 43.304, 40.394, 18.769.
[2259] C.sub.19H.sub.21F.sub.2N.sub.3O.sub.3 (MW=377); mass
spectroscopy (MH.sup.+) 378.
Example 232
Synthesis of
N-[.alpha.-Hydroxy-.alpha.'-pyrid-4ylisopropyl]-N'-(3,5-difluorophenylace-
tyl)-L-alaninamide
[2260] Following General Procedure S and using methyl
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(4-pyridyl)prop-
ionate (from Example 23 above), the title compound was prepared as
a solid (mp=189-193.degree. C.). The reaction was monitored by tlc
(Rf=0.47 in 10% MeOH/DCM) and the product was purified by silica
gel chromatography.
[2261] NMR data was as follows:
[2262] .sup.1H-nmr (CDCl.sub.3): .delta.=8.18 (d, J=5.6 Hz, 2H),
7.27 (d, J=5.6 Hz, 2H), 6.7 (m, 2H), 6.6 (m, 1H), 4.0 (m, 1H), 3.9
(m, 1H), 3.32 (s, 2H), 3.10 (s, 2H), 2.9 (m, 2H), 1.07 (d, J=7.2,
3H).
[2263] .sup.13C-nmr (CDCl.sub.3): .delta.=175.8, 150.4, 150.2,
126.8, 113.9, 113.6, 103.6, 103.5, 72.0, 59.3, 55.2, 51.6, 42.9,
40.8, 38.3, 17.9.
[2264] C.sub.19H.sub.21F.sub.2N.sub.3O.sub.3 (MW=377); mass
spectroscopy (MH.sup.+) 378.
Example 233
Synthesis of
N'-[(S)-1-Hydroxy-4-methylpent-2-yl]-N'-(3,5difluorophenylacetyl)-L-alani-
namide
[2265] Isomer A:
[2266] Following General Procedure B and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
(S)-1-hydroxy-4-methylpent-2-ylamine (leucinol) (Bachem), the title
compound was prepared as a solid (mp=141-151.degree. C.). The
reaction was monitored by tlc (Rf=0.5 in 5% MeOH/methylene
chloride) and the product was purified by recrystallization from
EtOAc/hexanes.
[2267] NMR data was as follows:
[2268] .sup.1H-nmr (CD.sub.3OD): .delta.=8.15 (s 1H), 7.5 (t, J=8
Hz, 1H), 6.80-6.55 (m, 3H), 4.15 (m, J=3.5 Hz, 1H), 3.7 (m 1H),
3.35 (s 2H), 3.22 (t, J=3 Hz, 2H), 1.4 (m, 1H), 1.1 (m, 5H), 0.7
(m, 6H).
[2269] .sup.13C-nmr (CD.sub.3OD): .delta.=175.4, 175.3, 173.0,
113.9, 113.9, 113.6, 113.5, 103.9, 103.6, 103.2, 66.1, 51.6, 51.4,
51.3, 51.3, 43.4, 41.7, 41.6, 26.5, 26.3, 24.3, 22.8, 22.7, 19.0,
18.7, 18.6.
[2270] C.sub.17H.sub.24N.sub.2O.sub.3F.sub.2 (MW=342.19); mass
spectroscopy (MH.sup.+) 343.
[2271] Isomer B:
[2272] Following General Procedure B and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
(S)-1-hydroxy-4-methylpent-2-ylamine (leucinol) (Aldrich), the
title compound was prepared as a solid (mp=151--153.degree. C.).
The reaction was monitored by tlc (Rf=0.8 in 10% MeOH/DCM) and the
product was purified by recrystallization, followed by flash column
chromatography, followed by a preparative tlc using 10% MeOH/DCM as
the eluent.
[2273] NMR data was as follows:
[2274] .sup.1H-nmr (CD.sub.3OD): .delta.=8.15.(s 1H), 7.5 (t, J=8
Hz, 1H), 6.80-6.55 (m, 3H), 4.15 (m, J=3.5 Hz, 1H), 3.7 (m, 1H),
3.35 (s, 2H), 3.22 (t, J=3 Hz, 2H), 1.4 (m, 1H), 1.1(m, 5H), 0.7
(m, 6H).
[2275] .sup.13C-nmr (CD.sub.3OD): .delta.=175.2, 172.9, 166.6,
166.5, 141.7, 113.9, 113.9, 113.8, 113.6, 113.6, 103.9, 103.6,
103.2, 66.1, 51.2, 50.4, 50.1, 50.0, 49.8, 49.7, 49.6, 49.4, 49.38,
49.3, 49.0, 48.7, 43.4, 43.3, 41.7, 26.3, 24.3, 22.8, 18.7.
[2276] C.sub.17H.sub.24N.sub.2O.sub.3F.sub.2 (MW=342.19); mass
spectroscopy (MH.sup.+) 342.
Example 234
Synthesis of
N-[1-Methoxyprop-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide
[2277] Following General Procedure B and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
2-amino-1-methoxypropane (Aldrich), the title compound was prepared
as a solid (mp=152.degree. C.). The reaction was monitored by tlc
(Rf=0.45 in 5% MeOH/DCM) and the product was purified by
recrystallization from methanol/water.
[2278] NMR data was as follows:
[2279] .sup.1H-nmr (CDCl.sub.3): .delta.=6.9-6.7 (m, 3H), 6.6 (d,
J=7 Hz, 1H), 6.3 (m, 1H), 4.5 (m, J=7 Hz, 1H), 4.1 (m, 1H), 3.5 (s,
2H), 3.3 (m, 5H), 1.4 (d, J=7 Hz, 3H), 1.15 (t, J=8 Hz, 3H).
[2280] .sup.13C-nmr (CDCl.sub.3): .delta.=172.0, 113.0, 112.9,
112.62, 112.60, 103.7, 103.4, 78.0, 77.6, 77.2, 75.8, 75.7, 59.6,
59.58, 49.6,.49.5, 45.6, 45.6, 43.4, 19.4, 19.38, 18.9, 18.0.
[2281] C.sub.17H.sub.20N.sub.2O.sub.3F.sub.2 (MW=314.14); mass
spectroscopy (MH.sup.+) 315.
Example 235
Synthesis of
N-[1-Hydroxy-3-methylbut-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamid-
e
[2282] Following General Procedure B and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
valinol (Bachem), the title compound was prepared as a solid
(mp=176-179.degree. C.). The reaction was monitored by tlc (Rf=0.4
in 5% MeOH/DCM) and the product was purified by recrystallization
from EtOAc/hexanes.
[2283] NMR data was as follows:
[2284] .sup.1H-nmr (CD.sub.3OD): .delta.=7.5 (d, J=9 Hz, 1H),
6.8-6.5 (m, 3H), 4.15 (m, 1H), 3.45 (m, 2H), 3.35 (m, 3H), 1.65 (m,
J=7 Hz, 1H), 1.20 (d, J=5 Hz, 3H), 0.7 (m, 6H).
[2285] .sup.13C-nmr (acetone-d.sub.6): .delta.=113.7, 113.4, 103.0,
63.3, 57.7, 57.69, 50.5, 50.4, 43.2, 31.1, 30.8, 30.6, 30.5, 30.3,
30.2, 30.1, 29.9, 29.9, 29.8, 29.7, 29.6, 20;5, 20.4, 19.5, 19.1,
19.0, 18.8.
[2286] C.sub.16H.sub.22N.sub.2O.sub.3F.sub.2 (MW=329.19); mass
spectroscopy (MH.sup.+) 329.
Example 236
Synthesis of Methyl
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino-2-(6aminopyrid-2-yl)a-
cetate
[2287] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
methyl 2-amino-2-(6-aminopyrid-2-yl)acetate (prepared from
2-(methoxyimino)-2-(6-aminopyrid-2-yl)acetic acid [CAS 71470-33-2]
using. General Procedures G and AC above); the title compound was
prepared. The product was purified by LC 2000 preparative column
chromatography using. 1:1 EtOAc/hexanes as the eluent.
[2288] NMR data was as follows:
[2289] .sup.1H-nmr (CDCl.sub.3): .delta.=7.65-6.5 (m, 6H), 6.4 (d,
J=8.19 Hz, 1H), 5.49-5.33 (m, 1H), 4.8-4.5 (m, 2H), 3.7 (s, 3H),
3.6 (s, 1H), 3.5 (s, 1H), 2.06 (bs, 2H), 1.44 (d, J=7.06 Hz, 1.5
H), 1.35 (d, 7.06 Hz, 1.5H).
[2290] C.sub.19H.sub.20N.sub.4O.sub.4F.sub.2 (MW=406.39); mass
spectroscopy (MH.sup.+) 406.3.
Example 237
Synthesis of
N-[1-Hydroxyprop-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide
[2291] Following General Procedure B and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
alanol (Bachem), the title compound was prepared as a solid
(mp=158-163.degree. C.). The reaction was monitored by tlc (Rf=0.7
in 10% MeOH/DCM) and the product was purified by recrystallization
from ethyl acetate, followed by flash column chromatography using
10% MeOH/DCM.
[2292] NMR data was as follows:
[2293] .sup.1H-nmr (CD.sub.3OD): .delta.=8.2 (m, 1H), 7.6 (m, 1H),
4.1 (m, J=7 Hz, 1H), 3.7 (m, J=5 Hz, 1H), 3.35 (s, 2H), 3.25 (m,
2H), 1.15 (d, J=7 Hz, 3H), 0.9 (d, J=7 Hz, 3H).
[2294] .sup.13C-nmr (CD.sub.3OD): .delta.=175.1, 175.06, 172.9,
166.6, 166.5, 163.4, 163.2, 141.6, 113.9, 113.8, 113.7, 113.6,
103.9, 103.6, 103.2, 66.5, 51.4, 51.3, 51.3, 51.2, 50.4, 50.1,
49.8, 49.77, 49.6, 49.5, 49.3, 49.1, 49.0, 48.7, 43.3, 18.8,
17.5.
[2295] C.sub.14H.sub.18N.sub.2O.sub.3F.sub.2 (MW=300); mass
spectroscopy (MH.sup.+) 301.
Example 238
Synthesis of
N-[(S)-2-methoxy-1-phenyleth-1-yl]-N'-(3,5-difluorophenylacetyl)-L-alanin-
amide
[2296] Following General Procedure C and using
3,5-difluorophenylacetic acid (Oakwood) and
N-[(S)-2-methoxy-1-phenyleth-1-yl]-L-alaninamide (prepared from
N-BOC-L-alanine (Sigma) and (S)-phenylglycinol methyl ether (from
Example D15 above) using General Procedure C, followed by removal
of the BOC-group using General Procedure P), the title compound was
prepared as a solid (mp=180-182.degree. C.). The reaction was
monitored by tlc (Rf=0.4 in 10% MeOH/CHCl.sub.3) and the product
was purified by silica gel chromatography using 5% MeOH/CHCl.sub.3
as the eluent, followed by recrystallization from
1-chlorobutane/acetonitrile.
[2297] NMR data was as follows:
[2298] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.22 (d, 3H), 3.23 (s,
3H).
[2299] Optical Rotation: [.alpha.].sub.20=+12.3.degree. @ 589 nm (c
1.04, DMSO).
[2300] C.sub.20H.sub.22F.sub.2N.sub.2O.sub.3 (MW=376.41); mass
spectroscopy (MH.sup.+) 377.
Example 239
Synthesis of
N-{(S)-1-Methoxy-2-phenylprop-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alani-
namide
[2301] Following General Procedure B and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
L-phenylalaninol methyl ether hydrochloride (Fluka), the title
compound was prepared as a fluffy solid. The product was purified
by recrystallization from MeOH/EtOAc.
[2302] NMR data was as follows:
[2303] .sup.1H-nmr (CDCl.sub.3): .delta.=1.31 (d, J=7 Hz, 3H), 2.8
(d, J=7 Hz, 2H), 3.28 (d, J=3 Hz, 2H), 3.32 (s, 3H), 3.47 (s, 2H),
4.15-4.3 (m, 1H), 4.35-4.5 (m, 1H), 6.3-6.5 (m, 2H), 6.6-6.9 (m,
3H), 7.1-7.35 (m, 5H).
[2304] .sup.13C-nmr (CDCl.sub.3): .delta.=19.1, 37.8, 43.4, 49.6,
51.0, 59.6, 72.7, 103.4, 112.6, 113.0, 127.1, 129.0, 129.9, 138.3,
169.8, 172.1.
Example 240
Synthesis of
N-[(S)-1-Acetoxyhex-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide
[2305] Following General Procedure V and using
N-[(S)-1-hydroxyhex-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide
(from Example 228 above), the title compound was prepared as a
solid (mp=144-145.degree. C.). The reaction was monitored by tlc
(Rf=0.42 in 10% CH.sub.3OH/CH.sub.2Cl.sub.2).
[2306] NMR data was as follows:
[2307] .sup.1H-nmr (CD.sub.3OD): .delta.=6.7 (m, 2H), 6.6 (m, 1H),
4.09 (q, 1H), 3.9-3.7 (m, 3H), 3.35 (s, 2H), 1.79 (s, 3H), 1.4-1.0
(m, 9H), 0.6 (m, 3H).
[2308] .sup.13C-nmr (CD.sub.3OD): .delta.=175.5, 173.2, 172.8,
166.6, 166.5, 163.4, 163.2, 141.8, 141.7, 141.5, 113.9, 113.8,
113.7, 113.6, 103.9, 103.5, 103.2, 67.5, 51.2, 43.28, 43.26, 32.2,
29.6, 24.0, 21.3, 18.8, 14.8.
[2309] C.sub.19H.sub.26F.sub.2N.sub.2O.sub.4 (MW=384.43); mass
spectroscopy (MH.sup.+) 385.
Example 241
Synthesis of
N-[(S)-1-(tert-Butylcarbonyloxy)-hex-2-yl]-N'-(3,5difluorophenylacetyl)-L-
-alaninamide
[2310] Following General Procedure W and using
N-[(S)-1-hydroxyhex-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide
(from Example 228 above) and timethylacetyl chloride (Aldrich), the
title compound was prepared as a solid (mp=104-107.5.degree. C.).
The reaction was monitored by tlc (Rf=0.43 in 10%
CH.sub.3OH/CH.sub.2Cl.sub.2) and the product was purified by
preparative thin layer chromatography using. 10%
CH.sub.3OH/CH.sub.2Cl.sub.2 as the eluent.
[2311] NMR data was as follows:
[2312] .sup.1H-nmr (CD.sub.3OD): .delta.=7.67 (bd, 1H), 6.7 (m,
2H), 6.6 (m, 1H), 4.14 (q, 1H), 3.9-3.6 (m, 3H), 3.35 (s, 2H),
1.4-1.0 (m, 9H), 0.98 (s, 9H), 0.6 (m, 3H).
[2313] .sup.13C-nmr (CD.sub.3OD): .delta.=180.3, 175.3, 175.2,
172.8, 166.6, 166.5, 163.4, 163.2, 141.8, 141.7, 141.5, 133.9,
113.8, 113.7, 113.6, 103.9, 103.6, 103.2, 67.6, 51.1, 51.0, 43.3,
40.4, 32.4, 32.3, 29.5, 28.2, 24.0, 19.0, 14.9.
[2314] C.sub.22H.sub.32F.sub.2N.sub.2O.sub.4 (MW=426.51); mass
spectroscopy (MH.sup.+) 427.5.
Example 242
Synthesis of
N-[2-Hydroxy-1-(thien-2-yl)ethyl]-N'-(3,5-difluorophenylacetyl)-L-alanina-
mide
[2315] Following General Procedure S and using methyl
N-[N-(3,5-difuorophenlacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)acetat-
e (from Example 178 above), the title compound was prepared as a
solid (mp=201-202.degree. C.). The product was purified by
trituration using 1:1 hexanes/EtOAc.
[2316] NMR data was as follows:
[2317] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.4-8.25 (m, 2H),
7.4-7.35 (m, 2H), 7.3-6.91 (m, 4H), 5.1-4.85 (m, 1H), 4.4-4.3 (m,
1H), 3.7-3.5 (m, 2H), 3.51 (s, 1H), 3.50 (s, 1H), 1.23-1.19
(overlaying doublets, 3H).
[2318] C.sub.21H.sub.23F.sub.2N.sub.2O.sub.3 (MW=368.4); mass
spectroscopy (MH.sup.+) 368.
Example 243
Synthesis of
N-[(S)-2-hydroxy-2-methyl-1-phenylprop-1-yl]-N'-(3,5-difluorophenylacetyl-
)-L-alaninamide
[2319] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
(S)-2-hydroxy-2-methyl-1-phenylprop-1-ylamine (from Example D16
above), the title compound was prepared as a solid. The product was
purified by recrystallization from methanol/ethyl acetate.
[2320] NMR data was as follows:
[2321] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.32 (d, 1H), 8.11 (d,
1H), 7.20-7.33 (m, 5H), 7.08 (m, 1H), 6.96 (m, 2H), 4.68 (d, 1H),
4.53 (s, 1H), 4.95 (m,1H), 3.50 (d, 2H), 1.25 (d, 3H), 1.08 (s,
3H), 0.98 (s, 3H).
[2322] Optical Rotation: [.alpha.].sub.23=-11.degree. (c 1,
MeOH).
[2323] C.sub.21H.sub.24F.sub.2N.sub.2O.sub.3 (MW=390.42); mass
spectroscopy (MH.sup.+) 391.
Example 244
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-L-(thien-2-yl)glycinyl]-L-phenytalanine
tert-Butyl Ester
[2324] Following General Procedure E and using
3,5-difluorophenylacetic acid (Aldrich) and
L-(2-thienyl)glycinyl-L-phenylglycine tert-butyl ester (prepared
using N-(9-florenylmethoxycarbonyl)-L-(2-thienyl)glycine (prepared
as described below) and L-phenylglycine tert-butyl ester
hydrochloride using General Procedure AH, followed by deprotection
using dicyclohexylamine in DMF and THF), the tide compound was
prepared as a solid (mp=176-177.degree. C.). The product was
purified by flash chromatography using EtOAc/dichloromethane as the
eluent.
[2325] C.sub.26H.sub.26N.sub.2O.sub.4F.sub.2 (MW=500.56); mass
spectroscopy (MH.sup.+) 500.
Preparation of
N-(9-Fluorenylmethoxycarbonyl)-L-(2-Thienyl)glycine
[2326] A round bottom flask containing a magnetic stir bar under an
atmosphere of nitrogen at room temperature was charged with water,
dioxane, sodium carbonate (2.5 eq.) and
L-.alpha.-(2-thienyl)glycine (1.0 eq.) (Sigma). Stirring was
initiated and the slurry was cooled in an ice bath.
9-Flurenylmethyl chloroformate was added portionwise to the
reaction and stirring was continued in an ice bath for 4 hours
followed by 8 hours at room temperature. The reaction mixture was
poured onto water and extracted with diethyl ether. The aqueous
layer was cooled in an ice bath and acidified with vigorous
stirring to a pH of 2. The resulting solid was isolated via vacuum
filtration, washed with water (3.times.) and dried under reduced
pressure.
Example 245
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycinol
[2327] Following General Procedure E and using
3,5-difluorophenylacetic acid (Aldrich) and
L-phenylglycinyl-L-phenylglycinol (prepared from
N-BOC-L-phenylgycine (Novabiochem) and L-phenylglycinol
(Novabiochem) using General Procedure AH, followed by removal of
the BOC-group using General Procedure P), the title compound was
prepared as a solid (mp=231.4.degree. C.). The product was purified
by crystallization from ethyl acetate.
[2328] C.sub.24H.sub.22N.sub.2O.sub.3F.sub.2 (MW=424.45); mass
spectroscopy (MH.sup.+) 424.9.
Example 246
Synthesis of
N-[N-(Cyclopropaneacetyl)-L-phenylglycinyl]-L-phenylglycinol
[2329] Following General Procedure E and using cyclopropaneacetic
acid (Aldrich) and L-phenylglycinyl-L-phenylglycinol (prepared from
N-BOC-L-phenylgycine (Novabiochem) and L-phenylglycinol
(Novabiochem) using General Procedure AH, followed by removal of
the BOC-group using General Procedure P), the title compound was
prepared as a solid (mp=202.5.degree. C.). The product was purified
by crystallization from ethyl acetate.
[2330] C.sub.21H.sub.24N.sub.2O.sub.3 (MW=352.43); mass
spectroscopy (MH.sup.+) 353.2.
Example 247
Synthesis of
N-[N-(Cyclopentaneacetyl)-L-phenylglycinyl]-L-phenylglycinol
[2331] Following General Procedure E and using cyclopentaneacetic
acid (Aldrich) and L-phenylglycinyl-L-phenylglycinol (prepared from
N-BOC-L-phenylgycine (Novabiochem) and L-phenylglycinol
(Novabiochem) using General Procedure AH, followed by removal of
the BOC-group using General Procedure P), the title compound was
prepared as a solid (mp=201.4.degree. C.). The product was purified
by flash chromatography using MeOH/CH.sub.2CH.sub.2 as the
eluent.
[2332] C.sub.23H.sub.28N.sub.2O.sub.3 (MW=380.49); mass
spectroscopy (MH.sup.+) 381.4.
Example 248
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-D,L-phenylglycinyl]-D,L-phenylglycinamide
[2333] Following General Procedure AO and using
N-[N-(3,5-difluorophenylacetyl)-D,L-phenylglycinyl]-D,L-phenylglycine
methyl ester (from Example 99 above), the title compound was
prepared as a solid (mp=285.5-288.5.degree. C.).
[2334] C.sub.24H.sub.21N.sub.3O.sub.3F.sub.2 (MW=437.45); mass
spectroscopy (MH.sup.+) 437,1.
Example 249
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-D,L-valinyl]-D,L-phenylglycinamide
[2335] Following General Procedure AO and using
N-(N-(3,5-difluorophenylacetyl)-L-valinyl]-L-phenylglycine methyl
ester. (from Example 94 above), the title compound was prepared as
a solid (mp=260.3-264.3.degree. C.). The product was purified by
recrystallization from ethyl acetate/methanol.
[2336] C.sub.21H.sub.23N.sub.3O.sub.3F.sub.2 (MW=403.43); mass
spectroscopy (MH.sup.+) 404.
Example 250
Synthesis of
N-[N-(2-Thienylacetyl)-L-alaninyl]-L-phenylglycinamide
[2337] Following the General Procedures described herein, the title
compound was prepared.
Example 251
Synthesis of N-[N-(n-Caproyl)-L-alaninyl]-L-phenylglycinamide
[2338] Following the General Procedures described herein, the title
compound was prepared.
Example 252
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-L-norleucinyl]-L-phenylglycine
Methyl Ester
[2339] Following General Procedure E and using
3,5-difluorophenylacetic acid (Aldrich) and
L-phenylglycinyl-L-phenylglycine methyl ester hydrochloride
(prepared from N-BOC-L-norleucine (Lancaster) and L-phenylglycine
methyl ester hydrochloride (Aldrich) using General Procedure E,
followed by removal of the BOC-group using General Procedure P),
the title compound was prepared as a solid (mp=188-189.5.degree.
C.). The product was purified by flash chromatography using ethyl
acetate/hexanes as the eluant.
[2340] C.sub.23H.sub.26N.sub.2O.sub.4F.sub.2 (MW=432.47); mass
spectroscopy (MH.sup.+) 432.
Example 253
Synthesis of
N-[N-(3,5Difluorophenylacetyl)-L-noryalinyl]-phenylglycine Methyl
Ester
[2341] Following General Procedure E and using
3,5-difluorophenylacetic acid (Aldrich) and
L-norvalinyl-L-phenylglycine methyl ester hydrochloride (prepared
from N-BOC-L-norvaline (Lancaster) and L-phenylglycine methyl ester
hydrochloride (Aldrich) using General Procedure E, followed by
removal of the BOC-group using General Procedure P), the title
compound was prepared as a solid (mp 204-205.degree. C.). The
product was purified by flash chromatography using ethyl
acetate/hexanes as the eluent.
[2342] C.sub.22H.sub.24N.sub.2O.sub.4F.sub.2 (MW=418.44); mass
spectroscopy (MH.sup.+) 418.3.
Example 254
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-L-tert-leucinyl]-L-phenylglycine
Methyl Ester
[2343] Following General Procedure E and using
3,5-difluorophenylacetic acid (Aldrich) and
L-tert-leucinyl-L-phenylglycine methyl ester hydrochloride
(prepared from N-BOC-L-tert-leucine (Bachem) and L-phenylglycine
methyl ester hydrochloride (Aldrich) using General Procedure E,
followed by removal of the BOC-group using General Procedure P),
the title compound was prepared as a solid (mp=176.4.degree. C.).
The product was purified by flash chromatography using ethyl
acetate/hexanes as the eluent.
[2344] C.sub.23H.sub.26N.sub.2O.sub.4F.sub.2 (MW=432.47); mass
spectroscopy (MH.sup.+) 432.0.
Example 255
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-L-isoleucinyl]-L-phenylglycine
Methyl Ester
[2345] Following General Procedure E and using
3,5-difluorophenylacetic acid (Aldrich) and
L-isoleucinyl-L-phenylglycine methyl ester hydrochloride (prepared
from N-BOC-L-isoleucine (Aldrich) and L-phenylglycine methyl ester
hydrochloride (Aldrich) using General Procedure E, followed by
removal of the BOC-group using General Procedure P), the title
compound was prepared as a solid (mp=228.8.degree. C.). The product
was purified by flash chromatography using ethyl acetate/hexanes as
the eluent.
[2346] C.sub.23H.sub.26N.sub.2O.sub.4F.sub.2 (MW=432.46); mass
spectroscopy (MH.sup.+) 433.4.
Example 256
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-L-cyclohexylalaninyl]-L-phenylglycine
Methyl Ester
[2347] Following General Procedure E and using
3,5-difluorophenylacetic acid (Aldrich) and
L-cyclohexylalaninyl-L-phenylglycine methyl ester hydrochloride
(prepared from N-BOC-L-cyclohexylalanine (Sigma) and
L-phenylglycine methyl ester hydrochloride (Aldrich) using General
Procedure E, followed by removal of the BOC-group using General
Procedure P), the title compound was prepared as a solid
(mp=174.8.degree. C.). The product was purified by flash
chromatography using ethyl acetate/hexanes as the eluent.
[2348] C.sub.26H.sub.30N.sub.2O.sub.4F.sub.2 (MW=472.53); mass
spectroscopy (MH.sup.+) 473.2.
Example 257
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-(S)-2-amino-2-(cyclopropyl)acetyl]-L-phen-
ylglycine Methyl Ester
[2349] Following General Procedure E and using
3,5-difluorophenylacetic acid (Aldrich) and
(S)-2-amino-2-(cyclopropyl)acetyl-L-phenylglycine methyl ester
hydrochloride (prepared from N-BOC-(S)-2-amino-2-cyclopropylacetic
acid (prepared from cyclopropylacetic acid (Lancaster) and
(4S)4-benzyl-2-oxaxolidinone (Aldrich) using the procedures
described in Evans et al., J. Am. Chem. Soc., 1990, 112, 4011-4030
and references cited therein) and L-phenylglycine methyl ester
hydrochloride (Aldrich) using General Procedure E, followed by
removal of the BOC-group using General Procedure P), the title
compound was prepared as a solid (mp=225-226.5.degree. C.). The
product was purified by flash chromatography using MeOH/CHCl.sub.3
as the eluent.
[2350] C.sub.22N.sub.2O.sub.4F.sub.2 (MW=416.42); mass spectroscopy
(MH.sup.+) 417.3.
Example 258
Synthesis of
N-[N-(3,5Difluorophenylacetyl)-(S)-2-amino-2(thien-3-yl)acetyl]-L-phenylg-
lycine Methyl Ester
[2351] Following General Procedure E and using
3,5-difluorophenylacetic acid (Aldrich) and
L-(S)-2-amino-2-(thien-3-yl)acetyl-L-phenylglycine methyl ester
hydrochloride (prepared from N-BOC-L-thien-3-ylglycine (prepared
from L-.alpha.-2-thienylglycine (Sigma) using General Procedure AJ)
and L-phenylglycine methyl ester hydrochloride (Aldrich) using
General Procedure E, followed by removal of the BOC-group using
General Procedure P), the title compound was prepared as a solid
(mp=229.3.degree. C.). The product was purified by crystallization
from ethyl acetate/hexanes.
[2352] C.sub.23H.sub.20N.sub.2O.sub.4SF.sub.2 (MW=458.49); mass
spectroscopy (MH.sup.+) 458.
Example 259
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-(S)-2-amino-2-(thien-2-yl)acetyl]-L-pheny-
lglycine Methyl Ester
[2353] Following General Procedure AH and using
3,5-difluorophenylacetic acid (Aldrich) and
L-(S)-2-amino-2-(thien-2-yl)acetyl-L-phenylglycine methyl ester
hydrochloride (prepared from N-BOC-L-thien-2-ylglycine (prepared
from L-.alpha.-(thien-2-yl)glycine (Sigma) using General Procedure
AI) and L-phenylglycine methyl ester hydrochloride (Aldrich) using
General Procedure E, followed by removal of the BOC-group using
General Procedure P), the tide compound was prepared as a solid
(mp=230.8.degree. C.). The product was purified by flash
chromatographyl using MeOH/CH.sub.2CH.sub.2 as the eluant.
[2354] C.sub.23H.sub.20N.sub.2O.sub.4F.sub.2S(MW=458.49); mass
spectroscopy (MH.sup.+) 458.
Example 260
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-L-(4fluorophenyl)glycinyl]-L-phenylglycin-
e Methyl Ester
[2355] Following General Procedure E and using
3,5-difluorophenylacetic acid (Aldrich) and
L-(4-fluorophenyl)glycinyl-L-phenylglycine methyl ester
hydrochloride (prepared from N-Cbz-(4-fluorophenyl)glycine
(prepared from (4-fluorophenyl)glycine (prepared as described
below) using General Procedure AK) and L-phenylglycine methyl ester
hydrochloride (Aldrich) using General Procedure E, followed by
silica gel chromatography using 5% ethyl acetate/toluene as the
eluant and removal of the Cbz-group using. General Procedure AJ),
the title compound was prepared as a solid (mp=213.1.degree. C.).
The product was purified by flash chromatography using ethyl
acetate/CHCl.sub.3 as the eluent.
[2356] C.sub.25H.sub.21N.sub.2O.sub.4F.sub.2 (MW=470.44); mass
spectroscopy (MH.sup.+) 470.1.
Preparation of (4-fluorophenyl)glycine
[2357] (S)-(-)-4-Benzyl-2-oxazolidinone (15.0 g, 93 mmol) (Aldrich)
was dissolved in THF (100 mL). The solution was cooled to
-70.degree. C. and reaction flask was purged twice with nitrogen.
n-Butyl lithium (44.6 mL, 2.0M, 89 mmol) was added to form a solid
precipitate which broke up on stirring wo afford a slurry.
4-Fluorophenylacetyl chloride 16.1 g, 93 mmol) (Aldrich) was added
to afford a light green solution and stirring was continued for 45
minutes. The reaction mixture was then stirred at room temperature
for 1 hour. The reaction mixture was then treated with saturated
sodium bisulfate (100 mL) and ethyl acetate (100 mL). The organic
phase was washed with water, followed by brine. The organic phase
was then dried over anhydrous sodium sulfate and concentrated under
reduced pressure to afford an oil. The oil was crystallized to
afford 24.4 g of
1-(4-fluorophenylacetyl)-(S)-(-)-4-Benzyl-2-oxazolidinone.
[2358] Potassium hexamethyldisilazane (140 mL, 0.5M, 70.0 mmol) was
added to THF (80 mL). The solution was cooled to -50.degree. C.
under nitrogen and a cold solution (-60.degree. C.) of
1-(4-fluorophenylacetyl)-(S)-(-)-4-benzyl-2-oxazolidinone (15.0 g,
46 mmol) in THF (100 mL). The resulting mixture was allowed to stir
at -70.degree. C. for 1 hour and to warm to about -20.degree. C.
The mixture was re-cooled to -70.degree. C. and a cold solution
(-65.degree. C.) of trasyl azide (21.6 g, 70.0 mmol) was added. The
mixture was allowed to stir for about 15 min. while warming to
-45.degree. C. and then glacial acetic acid (18 mL) was added. The
mixture was then stirred at about 30.degree. C. for 3 hours. A
precipitate formed and was removed by filtration. The filtrate was
concentrated by 50 and then washed with water, saturated sodium
bicarbonate solution and brine. The organic phase was dried over
sodium sulfate, concentrated under reduced pressure to afford 37.7
g of crude
1-[2-(4-fluorophenyl)-2-azidoacetyl]-(S)-(-)-4-benzyl-2-oxazolidinone.
[2359] Crude
1-[2-(4-fluorophenyl)-2-azidoacetyl]-(S)-(-)-4-benzyl-2-oxazolidinone
(10.0 g, 28.0 mmol) was dissolved in 100 mL of THF and 100 mL of
methanol and trifluoroacetic acid (4.31 mL, 75.3 mmol) was added.
Pallidium on carbon (10%, 2.0 g) was added and the mixture was
hydrogenated on a Paar shaker at 50 psi overnight at room
temperature. The reaction mixture was then filtered through a plug
of Celite and the solid cake was rinsed with 100 mL of methanol.
The filterate was concentrated to afford
1-[2-(4-fluorophenyl)-2-aminoacetyl]-(S)-(-)-4-benzyl-2-oxazolidinone
trifluoroacetate salt as a yellowish oil.
[2360] To a mixture of THF and de-ionized water (50 mL/50 mL) was
added
1-[2-(4-fluorophenyl)-2-aminoacetyl]-(S)-(-)4-benzyl-2-oxazolidinone
trifluoroacetate salt (4.14 g, 9.7 mmol) and lithium hydroxide
monohydrate (1.22 g, 29 mmol). The homogenous solution was stirred
for 2 hours at room temperature at which time Tlc indicated
complete disappearance of starting material. The mixture was
extracted with dichloromethane (3.times.100 mL) and the aqueous
phase was acidified to pH 2-3 while cooling in an ice-bath. A
precipitate formed. The mixture was then cooled in an ice-bath for
1.5 hours and then filtered. The solid was washed with water
followed by pentane to afford 4-fluorophenylglycine
hydrochloride.
Example 261
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-D-(4-fluorophenyl)glycinyl]-L-phenylglyci-
ne Methyl Ester
[2361] Following General Procedure E and using
3,5-difluorophenylacetic acid (Aldrich) and
D-(4-fluorophenyl)glycinyl-L-phenylglycine methyl ester
hydrochloride (prepared from N-Cbz-(4-fluorophenyl)glycine
(prepared from (4-fluorophenyl)glycine (prepared as in Example 260)
using General Procedure AK) and L-phenylglycine methyl ester
hydrochloride (Aldrich) using General Procedure E, followed by
silica gel chromatography using 5% ethyl acetate/toluene as the
eluant and removal of the Cbz-group using General Procedure AJ),
the title compound was prepared as a solid (mp=188.0.degree. C.).
The product was purified by flash chromatography using ethyl
acetate/CHCl.sub.3 as the eluent.
[2362] C.sub.25H.sub.21N.sub.2O.sub.4F.sub.3 (MW=470.44); mass
spectroscopy (MH.sup.+) 470.1.
Example 262
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-L-(4-methoxyphenyl)glycinyl]-L-phenylglyc-
ine Methyl Ester
[2363] Following General Procedure E and using
3,5-difluorophenylacetic acid (Aldrich) and
L-(4-methoxyphenyl)glycinyl-L-phenylglycine methyl ester
hydrochloride (prepared from N-Cbz-L-(4-methoxyphenyl)glycine
(prepared from (4-methoxyphenyl)glycine (prepared by the Bucherer
modification of the Strecker procedure as described in Greenstein
et al., "The Chemistry of Amino Acid", Vol. 1, p. 698, Wiley, New
York (1961)) using General Procedure AK) and L-phenylglycine methyl
ester hydrochloride (Aldrich) using General Procedure E, followed
by removal of the Cbz-group using General Procedure AJ), the title
compound was prepared as a solid (mp=224.6.degree. C.). The product
was purified by flash chromatography using MeOH/CHCl.sub.3 as the
eluent.
[2364] C.sub.26H.sub.24N.sub.2O.sub.5F.sub.2 (MW=482.48); mass
spectroscopy (MH.sup.+) 482.1.
Example 263
Synthesis of N-[N-
(3,5-Difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycine
tert-Butyl Ester
[2365] Following General Procedure E and using
3,5-difluorophenylacetic acid (Aldrich) and
L-phenylglycinyl-L-phenylglycine tert-butyl ester (prepared from
N-Cbz-L-phenylglycine (Novabiochem) and L-phenylglycine tert-butyl
ester hydrochloride (Novabiochem) using General Procedure AH,
followed by removal of the Cbz-group using General Procedure AJ),
the title compound was prepared as a solid (mp=185.0.degree. C.).
The product was purified by flash chromatography using ethyl
acetate/CH.sub.2CH.sub.2 as the eluant.
[2366] C.sub.28H.sub.28N.sub.2O.sub.4F.sub.2 (MW=494.54); mass
spectroscopy (MH.sup.+, minus CO.sub.2-t-Bu) 393.
Example 264
Synthesis of
N-[N-(Cyclopropylacetyl)-L-phenylglycinyl]-L-phenylglycine
tert-Butyl Ester
[2367] Following General Procedure E and using cyclopropylacetic
acid (Aldrich) and L-phenylglycinyl-L-phenylglycine tert-butyl
ester hydrochloride (prepared from N-Cbz-L-phenylglycine
(Novabiochem) and L-phenylglycine tert-butyl ester hydrochloride
(Novabiochem) using General Procedure AH, followed by removal of
the Cbz-group using General Procedure AJ), the title compound was
prepared as a solid (mp=187.5.degree. C.). The product was purified
by crystallization from ethyl acetate.
[2368] C.sub.25H.sub.30N.sub.2O.sub.4 (MW=422.53); mass
spectroscopy (MH.sup.+) 423.4.
Example 265
Synthesis of
N-[N-(Cyclopentylacetyl)-L-phenylglycinyl]-L-phenylglycine
tert-Butyl Ester
[2369] Following General Procedure E and using cyclopropylacetic
acid (Aldrich) and L-phenylglycinyl-L-phenylglycine tert-butyl
ester hydrochloride (prepared from N-Cbz-L-phenylglycine
(Novabiochem) and L-phenylglycine tert-butyl ester hydrochloride
(Novabiochem) using General Procedure AH, followed by removal of
the Cbz-group using General Procedure AJ), the title compound was
prepared as a solid (mp=190.8.degree. C.). The product was purified
by crystallization from ethyl acetate.
[2370] C.sub.27H.sub.34N.sub.2O.sub.4 (MW=450.58); mass
spectroscopy (MH.sup.+) 451.
Example 266
Synthesis of
N-[N-(t-Butylacetyl)-L-alaninyl]-L-phenylglycinamide
[2371] Following the General Procedures described herein, the title
compound was prepared.
Example 267
Synthesis of
N-tert-Butyl-N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-(5-bromothien-
-2-yl)glycinamide
[2372] Following General Procedure AB and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above),
5-bromo-2-thiophenecarboxaldehyde (Aldrich),
(S)-(+)-.alpha.-methylbenzylamine (Aldrich) and
tert-butylisocyanide (Aldrich), the title compound was prepared as
a solid (mp=227-228.degree. C.). The product was purified by
recrystallization from ethyl acetate/hexanes.
[2373] C.sub.21H.sub.24N.sub.3O.sub.3BrS (MW=515); mass
spectroscopy (MH.sup.+) 515, 415.
Example 268
Synthesis of
N-tert-Butyl-N'-[N-(3,5-Difluorophenylacetyl)-1-alaninyl]-D(5-bromothien--
2-yl)glycinamide
[2374] Following General Procedure AB and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above),
5-bromo-2-thiophenecarboxaldehyde (Aldrich),
(S)-(+)-.alpha.-methylbenzylamine (Aldrich) and
tert-butylisocyanide (Aldrich), the title compound was prepared as
a solid (mp=216-217.degree. C.). The product was purified by
recrystallization from ethyl-acetate/hexanes.
[2375] C.sub.21H.sub.24N.sub.3O.sub.3BrS (MW=515); mass
spectroscopy (MH.sup.+) 515, 415.
Example 269
Synthesis of
N-tert-Butyl-N'-[N-(3,5-Difluorophenylacetyl)-1-alaninyl]-L-(4bromothien--
2-ylglycinamide
[2376] Following General Procedure AB and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above),
4-bromo-2-thiophenecarboxaldehyde (Aldrich),
(S)-(+)-.alpha.-methylbenzylamine (Aldrich) and
tert-butylisocyanide (Aldrich), the title compound was prepared as
a solid (mp=246-247.degree. C.). The product was purified by
recrystallization from ethyl acetate/hexanes.
[2377] C.sub.21H.sub.24N.sub.3O.sub.3BrS (MW=515); mass
spectroscopy (MH.sup.+) 515, 415.
Example 270
Synthesis of
N-tert-Butyl-N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-(thien-2-yl)g-
lycinamide
[2378] Following General Procedure AB and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above),
2-thiophenecarboxaldehyde (Aldrich),
(S)-(+)-.alpha.-methylbenzylamine (Aldrich) and
tert-butylisocyanide (Aldrich), the title compound was prepared as
a solid (mp=241-242.degree. C.). The product was purified by
recrystallization from ethyl acetate/hexanes.
[2379] C.sub.21H.sub.25N.sub.3O.sub.3F.sub.2S (MW=438); mass
spectroscopy (MH.sup.+) 438, 338.
Example 271
Synthesis of
N-tert-Butyl-N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D-(thien-2-yl)g-
lycinamide
[2380] Following General Procedure AB and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above),
2-thiophenecarboxaldehyde (Aldrich),
(S)-(+)-.alpha.-methylbenzylamine (Aldrich) and
tert-butylisocyanide (Aldrich), the title compound was prepared as
a solid (mp=235-236.degree. C.). The product was purified by
recrystallization from ethyl acetate/hexanes.
[2381] C.sub.21H.sub.25N.sub.3O.sub.3F.sub.2S (MW=438); mass
spectroscopy (MH.sup.+) 438, 338.
Example 272
Synthesis of
N-tert-Butyl-N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-(thien-3-yl)g-
lycinamide
[2382] Following General Procedure AB and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above),
3-thiophenecarboxaldehyde (Aldrich),
(S)-(+)-.alpha.-methylbenzylamine (Aldrich) and
tert-butylisocyanide (Aldrich), the title compound was prepared as
a solid (mp=240-241.degree. C.). The product was purified by
recrystallization from ethyl acetate/hexanes.
[2383] C.sub.21H.sub.25N.sub.3O.sub.3F.sub.2S (MW=438); mass
spectroscopy (MH.sup.+) 438, 338.
Example 273
Synthesis of
N-tert-Butyl-N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D-(thien-3-yl)g-
lycinamide
[2384] Following General Procedure AB and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above),
3-thiophenecarboxaldehyde (Aldrich),
(S)-(+)-.alpha.-methylbenzylamine (Aldrich) and
tert-butylisocyanide (Aldrich), the title compound was prepared as
a solid (mp=245-246.degree. C.). The product was purified by
recrystallization from ethyl acetate/hexanes.
[2385] C.sub.21H.sub.25N.sub.3O.sub.3F.sub.2S (MW=438); mass
spectroscopy (MH.sup.+) 438, 338.
Example 274
Synthesis of
N-tert-Butyl-N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D-phenylglycina-
mide
[2386] Following General Procedure AB and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above),
benzaldehyde (Aldrich), (S)-(+)-.alpha.-methylbenzylamine (Aldrich)
and tert-butylisocyanide (Aldrich), the title compound was prepared
as a solid (mp=239-240.degree. C.). The reaction was monitored by
tlc (Rf=0.25 in 50% ethyl acetate/hexanes).
[2387] C.sub.23H.sub.27N.sub.3O.sub.3F.sub.2 (MW=431.53); mass
spectroscopy (MH.sup.+) 432.
Example 275
Synthesis of
N-tert-Butyl-N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-phenylglycina-
mide
[2388] Following General Procedure AL and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above),
benzaldehyde (Aldrich), (S)-(+)-.alpha.-methylbenzylamine (Aldrich)
and tert-butylisocyanide (Aldrich), the title compound was prepared
as a solid (mp=240-241.degree. C.).
[2389] C.sub.23H.sub.27N.sub.3O.sub.3F.sub.2 (MW=431.53); mass
spectroscopy (MH.sup.+) 432.
Example 276
Synthesis of
N-tert-Butyl-N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-(5-chloroth-
ien-2-yl)glycinamide
[2390] Following General Procedure AB and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above),
5-chloro-2-thiophenecarboxaldehyde (from Example D17 above),
(S)-(+)-.alpha.-methylbenzylamine (Aldrich) and
tert-butylisocyanide (Aldrich), the title compound was prepared as
a solid (mp=195-198.degree. C.). The-reaction was monitored by tlc
(Rf=0.15 in 50% ethyl acetatelhexanes).
[2391] C.sub.21H.sub.24N.sub.3O.sub.3F.sub.2Cl (MW=472); mass
spectroscopy (MH.sup.+) 472.
Example 277
Synthesis of
N-Cyclohexyl-N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-4-(phenyl)
phenylglycinamide
[2392] Following General Procedure AB and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above),
4-biphenylcarboxaldehyde (Aldrich),
(S)-(+)-.alpha.-methylbenzylamine (Aldrich) and
cyclohexylisocyanide (Aldrich), the tide compound was prepared as a
solid (mp=300.degree. C. (dec.)). The reaction was monitored by tlc
(Rf=0.23 in 50% ethyl acetate/hexanes).
[2393] C.sub.31H.sub.33N.sub.3O.sub.3F.sub.2 (MW=533.62); mass
spectroscopy MH.sup.+, minus cyclohexylamide) 408.2.
Example 278
Synthesis of
N-tert-Butyl-N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-1,3-(phenoxy)
phenylglycinamide
[2394] Following General Procedure AM and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above),
3-phenoxybenzaldehyde (Aldrich), (S)-(+)-.alpha.-methylbenzylamine
(Aldrich) and tert-butylisocyanide (Aldrich), the tide compound was
prepared. The reaction was monitored by tlc (Rf=0.29 in 50% ethyl
acetate/hexanes).
[2395] C.sub.29H.sub.31N.sub.3O.sub.4F.sub.2 (MW=523.63); mass
spectroscopy (MH.sup.+) 524.24.
Example 279
Synthesis of
N-(S)-(-)-.alpha.-Methylbenzyl-N'-[N-(3,5-Difluorophenylacetyl)-L-alaniny-
l]-D,L-phenylglycinamide
[2396] Following General Procedure AB and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above),
benzaldehyde (Aldrich), (S)-(+)-.alpha.-methylbenzylamine (Aldrich)
and (S)-(-)-.alpha.-methylbenzylisocyanide (from Example D18
above), the title compound was prepared.
[2397] C.sub.27H.sub.27N.sub.3O.sub.3F.sub.2 (MW=479.53); mass
spectroscopy (MH.sup.+) 480.21.
[2398] By following the procedures set forth above,
N-(R)-(+)-.alpha.-Methylbenzyl-N'-[N-(3,5-Difluorophenylacetyl)-L-alaniny-
l]-D,L-phenylglycinamide was prepared merely by substitution of the
appropriate isomer.
[2399] C.sub.27H.sub.27N.sub.3O.sub.3F.sub.2 (MW=479.53); mass
spectroscopy (MH.sup.+) 480.1.
Example 280
Synthesis of
N-tert-Butyl-N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-3-(phenyl)phe-
nylglycinamide
[2400] Following General Procedure AM and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above),
3-phenylbenzaldehyde (from Example D20 above),
(S)-(+)-.alpha.-methylbenzylamine (Aldrich) and
tert-butylisocyanide (Aldrich), the title compound was prepared.
The reaction was monitored by tlc. (Rf=0.25 in 50% ethyl
acetate/hexanes).
[2401] C.sub.29H.sub.31N.sub.3O.sub.3F.sub.2 (MW=507.63); mass
spectroscopy (MH.sup.+) 508.2.
Example 281
Synthesis of
N-tert-Butyl-N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-4-(ethyl)phen-
ylglycinamide
[2402] Following General Procedure AM and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above),
4-ethylbenzaldehyde (Aldrich), (S)-(+)-.alpha.-methylbenzylamine
(Aldrich) and tert-butylisocyanide (Aldrich), the title compound
was prepared. The reaction was monitored by tlc (Rf=0.20 in 50%
ethyl acetate/hexanes).
[2403] C.sub.25H.sub.31N.sub.3O.sub.3F.sub.2 (MW=459.59); mass
spectroscopy (MH.sup.+) 460.2.
Example 282
Synthesis of
N-tert-Butyl-N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-2-(phenyl)phe-
nylglycinamide
[2404] Following General Procedure AM and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above),
2-phenylbenzaldehyde (Aldrich), (S)-(+)-.alpha.-methylbenzylamine
(Aldrich) and tert-butylisocyanide (Aldrich), the title compound
was prepared. The reaction was monitored by tlc (Rf=0.15 in 50%
ethyl acetate/hexanes).
[2405] C.sub.29H.sub.31N.sub.3O.sub.3F.sub.2 (MW=507.63); mass
spectroscopy (MH.sup.+, minus tert-butylamide) 409.
Example 283
Synthesis of
N-tert-Butyl-N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-2-(benzyl)phe-
nylglycinamide
[2406] Following General Procedure AM and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above),
2-(benzyl)benzaldehyde (Aldrich), (S)-(+)-.alpha.-methylbenzylamine
(Aldrich) and tern-butylisocyanide (Aldrich), the title compound
was prepared. The reaction was monitored by tlc (Rf=0.19 in 50%
ethyl acetate/hexanes).
[2407] C.sub.30H.sub.33N.sub.3O.sub.3F.sub.2 (MW=521.66); mass
spectroscopy (MH.sup.+) 522.26.
Example 284
Synthesis of
N-tert-Butyl-N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-4-bromophen-
ylglycinamide
[2408] Following General Procedure AM and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above),
4-bromobenzaldehyde (Aldrich), (S)-(+)-.alpha.-methylbenzylamine
(Aldrich) and tert-butylisocyanide (Aldrich), the title compound
was prepared. The reaction was monitored by tlc (Rf=0.06 in 50%
ethyl acetate/hexanes).
[2409] C.sub.23H.sub.26N.sub.3O.sub.3F.sub.2 (MW=510.42); mass
spectroscopy (MH.sup.+) 512.1.
Example 285
Synthesis of
N-tert-Butyl-N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-4-(cyclohexyl-
)phenylglycinamide
[2410] Following General Procedure AL and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above)
4-(cyclohexyl)benzaldehyde (from Example D21 above),
(S)-(+)-.alpha.-methylbenzylamine (Aldrich) and
tert-butylisocyanide (Aldrich), the title compound was prepared as
a solid (mp=232-235.degree. C.).
[2411] C.sub.29H.sub.37N.sub.3O.sub.3F.sub.2 (MW=513.69); mass
spectroscopy (MH.sup.+) 514.29.
Example 286
Synthesis of
N-tert-Butyl-N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-4-(4-ethylphe-
nyl)phenylglycinamide
[2412] Following General Procedure AL and using
N-(3,5-difluorophenylacetyl)-L-alanine (from, Example B2 above),
4,4'-ethylbiphenylcarboxaldehyde (Aldrich),
(S)-(+)-.alpha.-methylbenzylamine (Aldrich) and
tert-butylisocyanide (Aldrich), the title compound was prepared as
a solid (mp=231-233.degree. C.).
[2413] C.sub.31H.sub.35N.sub.3O.sub.3F.sub.2 (MW=513.69); mass
spectroscopy (MH.sup.+) 514.29.
Example 287
Synthesis of
N-tert-Butyl-N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-4-(tert-but-
yl)phenylglycinamide
[2414] Following General Procedure AL and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above),
4-(tert-butyl)benzaldehyde (Aldrich),
(S)-(+)-.alpha.-methylbenzylamine (Aldrich) and
tert-butylisocyanide (Aldrich), the title compound was prepared as
a solid (mp=280.degree. C. (dec.)). The reaction was monitored by
tlc (Rf=0.13 in 50% ethyl acetate/hexanes).
[2415] C.sub.27H.sub.35N.sub.3O.sub.3F.sub.2 (MW=487.65); mass
spectroscopy (MH.sup.+) 488.27.
Example 288
Synthesis of
N-tert-Butyl-N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-3-(4-chloro-
phenoxy)phenylglycinamide
[2416] Following General Procedure AL and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above),
3-(4-chlorophenoxy)benzaldehyde (Aldrich),
(S)-(+)-.alpha.-methylbenzylamine (Aldrich) and
tert-butylisocyanide (Aldrich), the title compound was prepared as
a solid (mp=192-195.degree. C.).
[2417] C.sub.29H.sub.30N.sub.3O.sub.4F.sub.2Cl (MW=558.07); mass
spectroscopy (MH.sup.+) 558.20.
Example 289
Synthesis of
N-Cyclohexyl-N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D-4-(phenyl)phe-
nylglycinamide
[2418] Following General Procedure AB and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above),
4-biphenylcarboxaldehyde (Aldrich),
(S)-(+)-.alpha.-methylbenzylamine (Aldrich) and
cyclohexylisocyanide (Aldrich), the title compound was prepared as
a solid (mp=290-291.degree. C.).
[2419] C.sub.31H.sub.33N.sub.3O.sub.3F.sub.2 (MW=533.62); mass
spectroscopy (MH.sup.+) 534.3.
Example 290
Synthesis of
N-([N-(3,5-Difluorophenyl-.alpha.-hydroxyacetyl)-L-alaninyl]-L-phenylglyc-
ine tert-Butyl Ester
[2420] Following General Procedure C and using 3,5-difluoromandelic
acid (Fluorochem) and N-(L-alaninyl)-L-phenylglycine tert-butyl
ester (prepared using N-BOC-L-alanine (Sigma) and L-phenylglycine
tert-butyl ester hydrochloride (Bachem) using General Procedure C,
followed by removal of the BOC group using General Procedure P),
the title compound was prepared.
[2421] C.sub.23H.sub.26N.sub.2O.sub.5F.sub.2 (MW=479.53). Elemental
analysis: Calc. (%) C, 61.60; H 5.84; N, 6.25. Found (%) C, 61.32;
H, 6.02; N, 6.17.
Example 291
Synthesis of
N-tert-Butyl-N'-[N-(3,5-Difluorophenyl-.alpha.,.alpha.-difluoroacetyl)-L--
alaninyl]-L-phenylglycinamide
[2422] Following General Procedure C and using
3,5-difluorophenyl-.alpha.,.alpha.-difluoroacetic acid (from
Example D23 above) and N-(L-alaninyl)-L-phenylglycine tert-butyl
ester (prepared using N-BOC-L-alanine (Sigma) and L-phenylglycine
tert-butyl ester hydrochloride (Bachem) using General Procedure C,
followed by removal of the BOC group using General Procedure P),
the title compound was prepared. The reaction was monitored by tlc
(Rf=0.39 in 30% ethyl acetate/hexanes) and the product was purified
by HPLC using 17% ethyl acetate/hexanes as the eluent.
[2423] C.sub.23H.sub.24N.sub.2O.sub.4F.sub.4 (MW=468.49); mass
spectroscopy (MH.sup.+) 469.17.
Example 292
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D-phenylglycine
tert-Butyl Ester
[2424] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
D-phenylglycine tert-butyl ester (prepared from D-phenylglycine
(Sigma) using General Procedure J), the title compound was
prepared. The reaction was monitored by tlc (Rf=0.1 in 10%
MeOH/CHCl.sub.3).
[2425] NMR data was as follows:
[2426] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.64 (d, 1H), 8.38 (d,
1H), 7.34 (m, 5), 7.09 (m, 1H), 6.99 (m, 2H), 5.27 (d, 1H), 4.45
(m, 1H), 3.32 (s, 2H) 1.28 (s, 9H), 1.18 (d, 3H).
[2427] Optical Rotation: [.alpha.].sub.20=-103.58 (c=1, MeOH).
[2428] C.sub.23H.sub.26N.sub.2O.sub.4F.sub.2 (MW=432.47); mass
spectroscopy (MH.sup.+) 433.
Example 293
Synthesis of
N-[(S)-1-Oxo-1-phenylprop-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninami-
de
[2429] By oxidation of
N-[(1R,2S)-1-hydroxy-1-phenylprop-2-yl]-N'-(3,5-difluorophenylacetyl)-L-a-
laninamide (from Example 226 above) using Jones reagent in acetone,
the title compound was prepared. The reaction was monitored by tlc
(Rf=0.7 in 9:1 CHCl.sub.3/MeOH) and the product was purified by
flash chromatography using 97:3 chloroform/methanol as, the
eluent.
[2430] NMR data was as follows:
[2431] .sup.1H-nmr (CDCl.sub.3): .delta.=7.98 (m, 2H), 7.26 (m,
1H), 7.50 (m, 2H), 6.84 (m, 2H), 6.72 (m, 1H), 6.25 (d, 1H); 5.49
(m, 3H), 4.54 (m, 3H), 3.54 (s, 2H), 1.41 (d, 3H), 1.38 (d,
3H).
[2432] Optical Rotation: [.alpha.].sub.20=-106.degree. @ 589 nm (c
1, MeOH).
[2433] C.sub.20H.sub.20F.sub.2N.sub.2O.sub.3 (MW=374.39); mass
spectroscopy (MH.sup.+) 374.
Example 294
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-L-]-D-L-(pyrid-3-yl)glycine
tert-Butyl Ester
[2434] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
tert-butyl 2-amino-2-(3-pyridyl)acetate (prepared as described in
Kolar et al., J. Heterocyclic Chem., 28, 171 (1991) and reference
cited therein), the title compound was prepared. The reaction was
monitored by tlc (Rf=0.2 in 5% MeOH/CHCl.sub.3) and the product was
purified by flash chromatography using 5 % MeOH/CHCl.sub.3 as the
eluent.
[2435] NMR data was as follows:
[2436] .sup.1H-nmr (CDCl.sub.3): .delta.=8.63 (m, 1H), 8.54 (m,
1H), 7.62 (m, 1H); 7.45 (t, 1H), 7.26 (m, 1H), 6.82(m, 2H), 6.71
(m, 1H), 6.47 and 6.36 (d, 1H), 5.42 (d, 1H), 4.59 (m, 1H), 3.52
and 3.47 (two s, 2H), 1.38 and 1.36 (s, 9H), 1.34 and 1.28 (two d,
3H).
[2437] C.sub.22H.sub.25N.sub.3O.sub.4F.sub.2 (MW=433.46); mass
spectroscopy (MH.sup.+) 434.
Example 295
Synthesis of
[N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinyl]morpholin-
e
[2438] Following General Procedure C and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (from
Example D25 above) and morpholine (Aldrich), the title compound was
prepared. The reaction was monitored by tlc (Rf=0.4 in 10%
MeOH/CHCl.sub.3) and the product was purified by flash
chromatography using 5% MeOH/CHCl.sub.3 as the eluent.
[2439] NMR data was as follows:
[2440] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.60 and 8.49 (two d's,
1H), 8.49 (m, 1H), 7.25 (m, 5H), 7.18 (m, 2H), 6.95 (m, 1H), 5.82
(m, 1H), 4.38 (m, 1H), 3.52 (m, 10H), 1.21 and 1.12 (two d's,
3H).
[2441] C.sub.23H.sub.25N.sub.3O.sub.4F.sub.2 (MW=445.47); mass
spectroscopy (MH.sup.+) 446.
Example 296
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-(2-methoxy)phenylglycine
Methyl Ester
[2442] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
methyl 2-amino-2-(2-methoxy)acetate (prepared from
2-methoxybenzaldehyde (Aldrich) using the Bucherer modification of
the Strecker procedure as described in J. P. Greenstein et al.,
"The Chemistry of Amino Acids", Wiley: New York, 1961, Vol. 1, p.
698), the title compound was prepared. The reaction was monitored
by tlc (Rf=0.3 in 10% MeOH/CHCl.sub.3) and the product was purified
by flash chromatography using 10% MeOH/CHCl.sub.3 as the
eluent.
[2443] NMR data was as follows:
[2444] .sup.1H-nmr (CDCl.sub.3): .delta.=7.28 (m, 2H), 6.93 (d,
1H), 6.88 (m, 2H), 6.69 (m, 2H), 6.34 (m, 1H), 5.67 (m, 1H), 4.52
(m, 1H), 3.81 (two s, 3H), 3.68 (two s, 3H), 3.59 and 3.45 (two s,
3H) 1.41 and 1.28 (two d, 3H).
[2445] C.sub.21H.sub.22N.sub.2O.sub.5F.sub.2(MW=420.42); mass
spectroscopy (MH.sup.+) 420.
Example 297
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine
N-tert-Butoxycarbonyl(hydroxyl amine) Ester
[2446] Following General Procedure C and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (from
Example D25 above) and N-BOC hydroxyl amine (Aldrich), the title
compound was prepared. The reaction was monitored by tlc (Rf=0.35
in 10% MeOH/CHCl.sub.3) and the product was purified by flash
chromatography using 2% MeOH/CHCl.sub.3 as the eluent.
[2447] NMR data was as follows:
[2448] .sup.1H-nmr (CDCl.sub.3): .delta.=7.79 (m, 1H), 7.41-7.28
(m, 5H), 6.78-6.59 (m, 3H), 5.52 (m, 1H), 4.69 (m, 1H), 3.38 (two
s, 1H), 1.38 (d, 3H), 1.30 (s, 9H).
[2449] C.sub.24H.sub.27N.sub.3O.sub.6F.sub.2 (MW=491.49); mass
spectroscopy (MH.sup.+) 492.
Example 298
Synthesis of
N-Neopentyl-N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycin-
amide
[2450] Following General Procedure M and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (from
Example D25 above) and neopentylamine (Aldrich), the title compound
was prepared. The reaction was monitored by tlc (Rf=0.4 in 10%
MeOH/CHCl.sub.3) and the product was purified by flash
chromatography using 10% MeOH/CHCl.sub.3 as the eluent.
[2451] NMR data was as follows:
[2452] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.44 (m, 1H), 7.41 (m,
2H), 7.31 (m, 3H), 7.12 (m, 1H), 6.99 (m, 2H), 5.50 (m, 1H), 4.47
(m, 1H), 3.52 (two s, 2H), 2.84 (m, 2H), 1.22 (m, 3H), 0.71 (s,
9H).
[2453] C.sub.24H.sub.29N.sub.3O.sub.3F.sub.2 (MW=460); mass
spectroscopy (MH.sup.+) 460.
Example 299
Synthesis of
N-Tetrahydrofurfuryl-N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-phe-
nylglycinamide
[2454] Following General Procedure M and using
N-(N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (from
Example D25 above) and tetrahydrofurfurylamine (Aldrich), the title
compound was prepared. The reaction was monitored by tlc (Rf=0.4 in
10% MeOH/CHCl.sub.3) and the product was purified by flash
chromatography using 10% MeOH/CHCl.sub.3 as the eluent.
[2455] NMR data was as follows:
[2456] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.41 (m, 2H), 7.32 (m,
5H), 7.08 (m, 1H), 6.99 (m, 2H), 5.48 (m, 1H), 4.42 (m, 1H),
3.85-3.54 (m, 3H), 3.48 (two s, 2H), 3.14 (m, 2H), 1.76 (m, 4H),
1.21 (m, 3H).
[2457] C.sub.24H.sub.27N.sub.3O.sub.4F.sub.2 (MW=459.49); mass
spectroscopy (MH.sup.+) 460.
Example 300
Synthesis of
N-Methoxy-N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinam-
ide
[2458] Following General Procedure M and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (from
Example D25 above) and methoxyamine hydrochloride (Aldrich), the
title compound was prepared. The reaction was monitored by tlc
(Rf=0.35 in 10% MeOH/CHCl.sub.3) and the product was purified by
flash chromatography using 10% MeOH/CHCl.sub.3 as the eluent.
[2459] NMR data was as follows:
[2460] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.63 (m, 1H), 8.35 (m,
1H), 7.34 (m, 5H), 7.12 (m, 1H), 6.99 (m, 2H), 5.23 (d, 1H), 4.42
(m, 1H), 3.58 (s, 3H), 3.51 (two s, 2H), 1.22 (d, 3H).
[2461] C.sub.20H.sub.21N.sub.3O.sub.4F.sub.2 (MW=405); mass
spectroscopy (MH.sup.+) 405.
Example 301
Synthesis of
[N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinyl]azetidine
[2462] Following General Procedure M and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (from
Example D25 above) and azetidine (Aldrich), the title compound was
prepared. The reaction was monitored by tlc (Rf=0.6 in 10%
MeOH/CHCl.sub.3) and the product was purified by flash
chromatography using 10% MeOH/CHCl.sub.3 as the eluent.
[2463] NMR data was as follows:
[2464] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.61 and 8.46 (two d,
1H), 8.33 (m, 1H), 7.34 (m, 5H), 7.19 (m, 1H), 6.99 (m, 2H), 5.36
(two d, 1H), 4.42 (m, 1H), 4.31 (m, 1H), 3.88 (m, 3H), 3.5 (two s,
2H), 2.36 (m, 2H), 1.18 (two d, 3H).
[2465] C.sub.22H.sub.23N.sub.3O.sub.3F.sub.2 (MW=415.44); mass
spectroscopy (MH.sup.+) 416.
Example 302
Synthesis of
N-Isobutyl-N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycina-
mide
[2466] Following General Procedure M and using N-[N-(3,5-
difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (from Example
D25 above) and isobutylamine (Aldrich), the title compound was
prepared. The reaction was monitored by tlc (Rf=0.65 in 10%
MeOH/CHCl.sub.3) and the product was purified by flash
chromatography using 10% MeOH/CHCl.sub.3 as the eluent.
[2467] NMR data was as follows:
[2468] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.41 (m, 1H), 8.22 (m, 1
H), 7.38 (m, 2H), 7.09 (m, 1H), 6.98 (m, 2H), 5.52 (two d, 1H),
4.41 (m, 1H), 3.34 (two s, 2H), 2.85 (s, 2H), 1.61 (m, 1H), 1.20
(m, 3H), 0.92 (m, 6H).
[2469] C.sub.23H.sub.27N.sub.3O.sub.3F.sub.2 (MW=431.48); mass
spectroscopy (MH.sup.+) 432.
Example 303
Synthesis of
N-Cyclopropanemethyl-N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-phe-
nylglycinamide
[2470] Following General Procedure M and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (from
Example D25 above) and (aminomethyl)cyclopropane (Aldrich), the
title compound was prepared. The reaction was monitored by tlc
(Rf=0.25 in 10% MeOH/CHCl.sub.3) and the product was purified by
flash chromatography using 10% MeOH/CHCl.sub.3 as the eluent.
[2471] C.sub.23H.sub.25N.sub.3O.sub.3F.sub.2 (MW=429.47); mass
spectroscopy (MH.sup.+) 374.
Example 304
Synthesis of
N-Methoxy-N-methyl-N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-pheny-
lglycinamide
[2472] Following General Procedure C and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (from
Example D25 above) and N-methoxy-N-methylamine hydrochloride
(Aldrich), the title compound was prepared. The reaction was
monitored by tlc (Rf=0.3 in 10% MeOH/CHCl.sub.3) and the product
was purified by flash chromatography using 2 % MeOH/CHCl.sub.3 as
the eluent.
[2473] NMR data was as follows:
[2474] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.65 and 8.53 (two d,
1H), 8.37 (m, 1H), 7.31 (m, 5H), 7.12 (m, 1H), 6.98 (m, 2H), 5.91
and 5.82 (two d, 1H), 4.49 (m, 1H), 3.60-3.42 (m, 5H), 3.08 (two s,
3H), 1.21 and 1.16 (two d, 3H).
[2475] C.sub.21H.sub.23N.sub.3O.sub.4F.sub.2 (MW=419); mass
spectroscopy (MH.sup.+) 420.
Example 305
Synthesis of
N-2-Methylprop-2-enyl-N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-ph-
enylglycinamide
[2476] Following General Procedure M and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (from
Example D25 above) and 1-amino-2-methylprop-2-ene (Aldrich), the
title compound was prepared. The reaction was monitored by tic
(Rf=0.45 in 10% MeOH/CHCl.sub.3) and the product was purified by
flash chromatography using 3% MeOH/CHCl.sub.3 as the eluent.
[2477] NMR data was as follows:
[2478] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.43 (m, 2H), 7.40 (m,
2H), 7.29 (m, 3H), 7.11. (m, 1H), 6.98 (m, 2H), 5.46 (d, 1H),
4.68-(m, 2H), 4.42 (m, 1H), 3.6 (m, 2H), 3.49 (s, 2H), 1.56 (s,
3H), 1.21 (d, 3H).
[2479] C.sub.23H.sub.25N.sub.3O.sub.3F.sub.2 (MW=429.47); mass
spectroscopy (MH.sup.+) 430.
Example 306
Synthesis of
N-(Pyrid-3-yl)methyl-N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-phe-
nylglycinamide
[2480] Following General Procedure C and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (from
Example D25 above) and 3-(aminomethyl)pyridine (Aldrich), the title
compound was prepared. The reaction was monitored by tlc (Rf=0.1 in
10% MeOH/CHCl.sub.3) and the product was purified by flash
chromatography using 3% MeOH/CHCl.sub.3 as the eluent.
[2481] NMR data was as follows:
[2482] .sup.1H-nmr (DMSO.sub.6): .delta.=8.82 (m, 1H), 8.55 (m,
1H), 8.42 (m, 3H), 7.52 (m, 1H), 7.35 (m, 5H), 7.10 (m, 1H), 6.99
(m, 2H), 5.43 (d, 2H), 4.44 (m, 1H), 4.30 (bd, 2H) 3.52 (s, 2H)
1.26 (d, 3H).
[2483] C.sub.23H.sub.24N.sub.4O.sub.3F.sub.2 (MW=466.49); mass
spectroscopy (MH.sup.+) 467.
Example 307
Synthesis of
N-(Pyrid-4-yl)methyl-N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-phen-
ylglycinamide
[2484] Following General Procedure C and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (from
Example D25 above) and 4-(aminomethyl)pyridine (Aldrich), the title
compound was prepared. The reaction was monitored by tlc (Rf=0.1 in
10% MeOH/CHCl.sub.3) and the product was purified by flash
chromatography using 3% MeOH/CHCl.sub.3 as the eluent.
[2485] NMR data was as follows:
[2486] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.88 (m, 1H), 8.54 (d,
1H), 8.43 (m, 3H), 7.37 (m, 4H), 7.12 (m, 3H), 6.9(m, 1H), 5.44 (d,
1H), 4.45 (m, 1H), 4.31 (d, 2H), 3.51 (s, 2H), 1.25 (d, 3H).
[2487] C.sub.23H.sub.24N.sub.4O.sub.3F.sub.2 (MW=466.49); mass
spectroscopy (MH.sup.+) 467.
Example 308
Synthesis of
N-Furfuryl-N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycina-
mide
[2488] Following General Procedure C and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (from
Example D25 above) and furfurlamine (Aldrich), the title compound
was prepared. The reaction was monitored by tlc (Rf=0.5 in 10%
MeOH/CHCl.sub.3) and the product was purified by flash
chromatography using 3% MeOH/CHCl.sub.3 as the eluent.
[2489] NMR data was as follows:
[2490] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.66 (m, 1H), 8.45 (d,
1H), 8.39 (m, 1H), 7.57 (s, 1H), 7.33 (m, 5H), 7.09 (m, 1H), 6.99
(m, 2H), 6.36 (m, 1H), 6.12 (s, 1H), 5.41 (d, 1H), 4.22 (m, 1H),
3.52 (s, 2H) 1.24 (d, 3H).
[2491] C.sub.24H.sub.23N.sub.3O.sub.4F.sub.2 (MW=455); mass
spectroscopy (MH.sup.+) 456.
Example 309
Synthesis of
N-Cyclopentyl-N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-phenylglyc-
inamide
[2492] Following General Procedure C and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (from
Example D25 above) and cyclopentylamine (Aldrich), the title
compound was prepared. The product was purified by
recrystallization from ethanol.
[2493] NMR data was as follows:
[2494] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.32 (m, 2H), 8.16 (m,
1H), 7.33-7.20 (m, SR), 7.04 (m, 1H), 6.93 (m, 2H), 5.34 (d, 1H),
4.37 (m, 1H), 3.9 (m, 1H), 3.49 (s, 2H), 1.80-1.29 (m, 8H), 1.19
(d, 3H).
[2495] C.sub.24H.sub.27N.sub.3O.sub.3F.sub.2 MW=443.49); mass
spectroscopy (MH.sup.+) 444.
Example 3190
Synthesis of
N-1-Benzylpiperidin-4yl-N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-
D,L-phenylglycinamide
[2496] Following General Procedure C and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (from
Example D25 above) and 4-amino-1-benzylpiperdine (Aldrich), the
title compound was prepared. The reaction was monitored by tlc
(Rf=0.2 in 10% MeOH/CHCl.sub.3) and the product was purified by
flash chromatography using 3% MeOH/CHCl.sub.3 as the eluent.
[2497] NMR data was as follows:
[2498] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.39 (m, 2H), 8.21 (m,
1H), 7.30 (m, 5H), 7.11 (m 1H), 6.98 (m, 2H), 5.39 (d, 1H), 4.21
(m, 1H), 3.54 (bm, 3H), 3.42 (bs, 2H), 2.70 (bm, 2H), 1.89 (bm,
2H), 1.71 (bm, 2H), 1.42 (3H), 1.22 (m, 3H).
[2499] C.sub.31H.sub.34N.sub.4O.sub.3F.sub.2 (MW=548.64); mass
spectroscopy (MH.sup.+) 548.
Example 311
Synthesis of
N,N-Dimethyl-N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-phenylglyci-
namide
[2500] Following General Procedure C and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (from
Example D25 above) and dimethylamine (Aldrich), the title compound
was prepared. The reaction was monitored by tlc (Rf=0.65 in 10%
MeOH/CHCl.sub.3) and the product was purified by flash
chromatography using 5% MeOH/CHCl.sub.3 as the eluent.
[2501] NMR data was as follows:
[2502] .sup.1H-nmr (MSO-d.sub.6): .delta.=8.13 and 8.01 (two d,
1H), 7.32 (m, 5H), 6.78 (m, 2H), 6.63 (m, 1H), 5.88 (m, 1H), 4.72
(m, 1H), 3.45 (two s, 2H), 2.94 (two s, 6H), 1.32 and 1.17 (two d,
3H).
[2503] C.sub.21H.sub.23N.sub.3O.sub.3F.sub.2 (MW=403.43); mass
spectroscopy (MH.sup.+) 404.
Example 312
Synthesis of
N-2,2,6,6-Tetramethylpiperidin-4-yl-N'-[N-(3,5-Difluorophenylacetyl)-L-al-
aninyl]-D,L-phenylglycinamide
[2504] Following General Procedure C and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (from
Example D25 above) and 4-amino-2,2,6,6,-tetramethylpiperidine
(Aldrich), the title compound was prepared. The reaction was
monitored by tlc (Rf=0.2 in 2% MeOH/CHCl.sub.3) and the product was
purified by flash chromatography using 2% MeOH/CHCl.sub.3 as the
eluent.
[2505] NMR data was as follows:
[2506] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.46 (d, 1H), 8.33 (d,
1H), 8.12 (bm, 1H), 7.33 (m, 5H), 7.13 (m, 1H), 6.99 (m, 2H),
5.37.(d, 1H), 4.41 (m, 1H), 3.98 (m,1H), 3.52 (s, 2H), 1.67 (bm,
1H), 1.44 (bm, 1H), 1.22 (d, 3H), 1.01 (bm, 14H).
[2507] C.sub.28H.sub.36N.sub.4O.sub.3F.sub.2 (MW=514.62); mass
spectroscopy (MH.sup.+) 514.
Example 313
Synthesis of
N-2-Methylcyclohexyl-N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-phe-
nylglycinamide
[2508] Following General Procedure C and using N-[N-(3,5-
difluorophenrylacetyl)-L-alaninyl]-D,L-phenylglycine (from Example
D25 above) and 2-methylcyclohexylamine (Aldrich), the title
compound was prepared. The reaction was monitored by tlc (Rf=0.4 in
2% MeOH/CHCl.sub.3).
[2509] NMR data was as follows:
[2510] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.41 (m, 2H), 8.0 (m,
1H), 7.33 (m, 5H), 7.11 (m, 1H), 6.99 (m, 2H), 5.35 (m, 1H), 4.41
(m, 1H), 3.52 (s, 2H), 3.18 (m,1H), 1.78-0.82 (m 11H), 0.81 (m,
3H).
[2511] C.sub.26H.sub.31N.sub.3O.sub.3F.sub.2 (MW=472.5); mass
spectroscopy (MH.sup.+) 472.
Example 314
Synthesis of
N-4-Methylcyclohexyl-N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-phe-
nylglycinamide
[2512] Following General Procedure C and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (from
Example D25 above) and 4-methylcyclohexylamine (Aldrich), the title
compound was prepared. The reaction was monitored by tlc (Rf=0.2 in
2% MeOH/CHCl.sub.3) and the product was purified by flash
chromatography using 2% MeOH/CHCl.sub.3 as the eluent.
[2513] NMR data was as follows:
[2514] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.38 (m; 2H), 8.08 (m,
1H), 7.33 (m, 5H), 7.09 (m, 1H), 7.01 (m, 2H), 5.54 and 5.36 (two
d, 1H), 4.43 (m, 2H), 3.76 (m, 1H), 3.52 (s, 2H), 1.79-1.17 (m,
11H), 0.84 (d, 3H).
[2515] C.sub.26H.sub.31N.sub.3O.sub.3F.sub.2 (MW=472.5); mass
spectroscopy (MH.sup.+) 472.
Example 315
Synthesis of
N-1-Ethoxycarbonylpiperidin-4-yl-N'-[N-(3,5-difluorophenylacetyl)-L-alani-
nyl]-D,L-phenylglycinamide
[2516] Following General Procedure C and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (from
Example D25 above) and 4-amino-1-ethoxycarbonylpiperdine (Aldrich),
the title compound was prepared. The reaction was monitored by tlc
(Rf=0.2 in 2% MeOH/CHCl.sub.3) and the product was purified by
flash chromatography using 2% MeOH/CHCl.sub.3 as the eluent.
[2517] NMR data was as follows:
[2518] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.42 (m, 2H), 8.23 (m,
1H), 7.33 (m, 5H), 7.09 (m, 1H), 6.98 (m, 2H), 5.38 (m, 1H), 4.41
(m, 1H), 4.01 (q, 2H), 3.9-3.64 (m, 3H), 3.49 (s, 2H), 2.88 (bm,
2H), 1.75 (m,1H), 1.54 (m,1H), 1.2 (m, 6H).
[2519] C.sub.27H.sub.32N.sub.4O.sub.5F.sub.2 (MW=530.57); mass
spectroscopy (MH.sup.+) 531.
Example 316
Synthesis of
N-Methyl-N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide
[2520] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)- L-alanine (from Example B2 above) and
N-methyl-(S)-2-amino-2-phenylacetamide [CAS 129213-83-8], the
title-compound was prepared. The reaction was monitored by tlc
(Rf=0.2 in 5% MeOH/CHCl.sub.3) and the product was purified by
flash chromatography using 5% MeOH/CHCl.sub.3 as the eluent.
[2521] NMR data was as follows:
[2522] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.43 (m, 2H), 8.21 (m,
1M), 7.36 (m, 5H), 7.09 (m, 1H), 6.95 (m, 2H), 5.36 (m, 1H), 4.40
(m, 1H), 3.41 (s, 2H), 2.56 (d, 3H), 1.22 (d, 3H).
[2523] Optical Rotation: [.alpha.].sub.20=-67 (c=1, MeOH).
[2524] C.sub.20H.sub.21N.sub.3O.sub.3F.sub.2.0.75 H.sub.2O
(MW=403.43); mass spectroscopy (MH.sup.+) 404.
Example 317
Synthesis of
N-tert-Butoxy-N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-phenylglyc-
inamide
[2525] Following General Procedure C and using
-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine
(from Example D25 above) and O-(tert-butoxy)hydroxylamine
(Aldrich), the title compound was prepared. The reaction was
monitored by tlc (Rf=0.65in 10% MeOH/CHCl.sub.3).
[2526] NMR data was as follows:
[2527] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.72 and 8.58 (two d,
1H), 8.39 (m, 1H), 7.37 (m, 5H), 7.10 (m, 1H), 6.99 (m, 2H), 5.41
(m, 1H), 4.46 (m, 1H), 3.51 (two s, 3H), 1.22 (m, 3H), 1.09 (s,
9H).
[2528] C.sub.23H.sub.27N.sub.3O.sub.4F.sub.2 (MW=447.48); mass
spectroscopy (MH.sup.+) 448.
Example 318
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine
N-tert-Butyl(hydroxylamine) Ester
[2529] Following General Procedure C and using
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (from
Example D25 above) and N-(tert-butoxy)hydroxylamine (Aldrich), the
title compound was prepared. The reaction was monitored by tlc
(Rf=0.65 in 10% MeOH/CHCl.sub.3).
[2530] C.sub.23H.sub.27N.sub.3O.sub.4F.sub.2.0.25 H.sub.2O
(MW=447.48); mass spectroscopy (MH.sup.+) 448.
Example 319
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-phenylglycine
Hydrazide
[2531] N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycine
methyl ester (2.0 g, 5.1 mmol) (from Example 111 above) was stirred
in ethanol (40 mL) and anhydrous hydrazine (0.3 mL, 10 mmol)
(Aldrich) was added. The solution was heated at reflux for 12 hours
and then allowed to cool to ambient temperature with stirring. A
title compound was collected as a white solid by filtration,
washing with ethanol and during in a vacuum oven (52% yield).
[2532] NMR data was as follows:
[2533] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.20 (t, 3H), 5.41 (m,
1H).
[2534] C.sub.19H.sub.20N.sub.3O.sub.4F.sub.2 (MW=390.39); mass
spectroscopy (MH.sup.+) 390.
Example 320
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-phenylglycine
Acetobydrazonate
[2535] N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-phenylglycine
hydrazide (0.5 g, 1.3 mmol) (from Example 319 above) was heated at
reflux in triethylorthoacetate (40 mL). After 14 hours, the
reaction mixture was concentrated under reduced pressure to afford
the title compound as a white solid (84% yield). The reaction was
monitored by tlc (Rf=0.65. in 10% MeOH/CHCl.sub.3) and the product
was purified by silica gel chromatography using 5% MeOH/CHCl.sub.3
as the eluent.
[2536] NMR data was as follows:
[2537] .sup.1H-nmr (DMSO-d.sub.6): .delta.=4.03 (q, 2H), 5.54 (m,
1H).
[2538] C.sub.23H.sub.26N.sub.4O.sub.4F.sub.2 (MW=460.49); mass
spectroscopy (MH.sup.+) 460.
Example 321
Synthesis of N-[N-(Phenylacetyl)-L-alaninyl]-L-phenylglycine
tert-Butyl Ester
[2539] Following General Procedure C and using phenylacetic acid
(AIdrich) and L-alaninyl-L-phenylglycine tert-butyl ester (prepared
using N-BOC-L-alanine (Sigma) and L-phenylglycine tert-butyl ester
hydrochloride (Bachem) using General Procedure C, followed by
removal of the BOC group using General Procedure P), the title
compound was prepared. The reaction was monitored by tlc (Rf=0.25
in 3 % MeOH/CHCl.sub.3) and the product was purified by
crystallization from chlorobutane/hexanes.
[2540] NMR data was as follows:
[2541] .sup.1H-nmr (DMSO-d.sub.6): .delta.=4.43 (m, 1H), 5.20 (d,
1H).
[2542] C.sub.23H.sub.28N.sub.2O.sub.4 (MW=396.49); mass
spectroscopy (MH.sup.+) 397.
Example 322
Synthesis of
N-4-(phenyl)butyl-N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-phenylgl-
ycinamide
[2543] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
N-4-(phenyl)butyl-L-phenylglycinamide (prepared from
N-BOC-L-phenylglycine (Advanced Chemtech) and 4-phenylbutylamine
(Aldrich) using General Procedure C, followed by removal of the
BOC-group using General Procedure P), the title compound was
prepared. The reaction was monitored by tlc (Rf=0.45 in 5%
MeOH/CHCl.sub.3) and the product was purified by trituration in
water, followed by trituration in acetonitrile.
[2544] NMR data was as follows:
[2545] .sup.1H-nmr (DMSO-d.sub.6): .delta.=4.42 (m, 1H), 5.37 (d,
1H).
[2546] C.sub.29H.sub.31N.sub.3O.sub.3F.sub.2 (MW=507.5); mass
spectroscopy (MH.sup.+) 507.
Example 323
Synthesis of
N-3-(4-Iodophenyl)propyl-N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-p-
henylglycinamide
[2547] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
N-3-(4-iodophenyl)propyl-L-phenylglycinamide (prepared from
N-BOC-L-phenylglycine (Advanced Chemtech) and
3-(4-iodophenyl)propylamine (from Example D26 above) using General
Procedure C, followed by removal of the BOC-group using General
Procedure P), the title compound was prepared. The product was
purified by trituration in water, followed by trituration in
ethanol.
[2548] NMR data was as follows:
[2549] .sup.1H-nmr DMSO-d.sub.6): .delta.=4.41 (q, 2H), 5.35 (m,
1H).
[2550] C.sub.28H.sub.28N.sub.3O.sub.4F.sub.2I (MW=635.45); mass
spectroscopy (MH.sup.+) 635.
Example 324
Synthesis of
N-6-(Amino)hexyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylg-
lycinamide Hydrochloride
[2551] Following General Procedure C and using
N-(N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (from
Example D25 above) and N-BOC-1,6-hexanediamine (Fluka), followed by
removal of the BOC-group using General Procedure P, the title
compound Was prepared. The product was isolated as a white
solid.
[2552] NMR data was as follows:
[2553] .sup.1H-nmr (DMSO-d.sub.6): .delta.=4.41 (m, 1H), 5.40 (t,
1H).
[2554] C.sub.25H.sub.32N.sub.4O.sub.3F.sub.2 (MW=474.56); mass
spectroscopy (MH.sup.+) 475.
Example 325
Synthesis of
N-1-(Phthalimido)pent-2-yl-N'-(3,5-difluorophenylacetyl)-L-alaninamide
[2555] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
2-amino-1-phthalimidopentane hydrochloride (from Example D27
above), the title compound was prepared. The reaction was monitored
by tlc (Rf=0.3 in 5% MeOH/CHCl.sub.3) and the product was purified
by silica gel chromatography using 5% MeOH/CHCl.sub.3 as the
eluent, followed by recrystallization from
chlorobutane/acetonitrile.
[2556] NMR data was as follows:
[2557] .sup.1H-nmr (DMSO-d.sub.6): .delta.=4.1 (m, 2H), 7.83 (bs,
4H).
[2558] C.sub.24H.sub.25N.sub.3O.sub.4F.sub.2 (MW=457.48); mass
spectroscopy (MH.sup.+) 457.
Example 326
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-L-(3,5-difluorophenyl)glycinyl]-L-(3,5-di-
fluorophenyl)glycine Methyl Ester
[2559] Following General Procedure AN and using
N-(3,5-difluorophenylacetyl)-L-(3,5-difluorophenyl)glycine (from
Example D30 above) and L-3,5-difluorophenylglycine methyl ester
(from Example D29 above), the title compound was prepared. The
product was purified by crystallization.
[2560] NMR data was as follows:
[2561] .sup.1H-nmr (DMSO-d.sub.6): .delta.=9.40 (m, 1H), 9.0 (m,
1H), 6.80-7.70 (m, 9H), 5.45 (d, 1H), 5.25 (m, 1H), 3.55-365 (m,
5H).
Example 327
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-alaninyl]-L-norleucine
[2562] Following General Procedure AF and using THF/H.sub.2O (1:1)
on N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-norleucine methyl
ester, the title compound was prepared as a solid
(mp=158.5-160.5.degree. C.). The reaction was monitored by tlc
(Rf=0.29 in 10% MeOH/CH.sub.2Cl.sub.2).
[2563] NMR data was as follows:
[2564] .sup.1H-nmr (CD.sub.3OD): .delta.=8.46 (bd, J=6.71, 1H),
8.25(bd, J=7.69, 1H), 7.00-6.79 (m, 3H), 4.50-4.35 (m, 2H), 3.61
(d, 2H), 1.94-1.79 (m, 1H), 1.78-1.60 (m, (includes d at 1.40,
J=7.14, 3H), 0.92 (m, 3H).
[2565] .sup.13C-nmr (CD.sub.3OD): .delta.=176.0, 175.5, 172.9,
166.6, 166.5, 163.4, 163.2, 141.7, 141.6, 141.5, 113.9, 113.8,
113.7, 113.6, 103.9, 103.6, 103.2, 54.1, 50.9, 43.3, 32.9, 29.4,
23.8, 18.6, 14.8.
[2566] C.sub.17H.sub.22N.sub.2O.sub.4F.sub.2 (MW=356.37); mass
spectroscopy (MH.sup.+) 357.
Example 328
Synthesis of N-[N-(Cyclopentaneacetyl)-L-alaninyl]-L-phenylglycine
tert-Butyl Ester
[2567] Following General Procedure D and using cyclopentylacetic
acid (Aldrich) and L-alaninyl-L-phenylgycine tert-butyl ester
(prepared from N-CBZ-L-alanine (Sigma) and L-phenylglycine
tert-butyl ester hydrochloride (Bachem) using General Procedure C,
followed by removal of the CBZ-group using General Procedure Y),
the title compound was prepared as a solid (mp=133-138.degree. C.).
The reaction was monitored by tlc (Rf=0.48 in 50% EtOAc/hexanes)
and the product was purified by flash chromatography using 25-50%
EtOAc/hexanes as the eluent.
[2568] NMR data was as follows:
[2569] .sup.1H-nmr (CDCl.sub.3): .delta.=7/86 (bd, J=7.2 Hz, 1H),
7.30-7.15 (m, 5H), 6.81 (bd, J=7.82 Hz, 1H), 5.34 (d, J=7.20 Hz,
1H0, 4.72 (quint, J=7.2 Hz, 1H), 2.04 (m, 3H), 1.75-1.28 (m
(includes s at 1.34, 9H) 18H), 1.1-0.9 (m, 2H).
[2570] .sup.13C-nmr (CDCl.sub.3): .delta.=173.3, 172.8, 170.0,
137.1, 129.2, 128:6, 127.7, 82.7, 57.7, 48.9, 43.0, 37.6, 32.9,
28.3, 25.4, 19.3.
[2571] C.sub.22H.sub.32N.sub.2O.sub.4 (MW=388.51); mass
spectroscopy (MH.sup.+) 389.5.
Example 329
Synthesis of
N-[N-(2,5-Dichlorophenylmercaptoacetyl)-L-alaninyl]-L-phenylglycine
Methyl Ester
[2572] 2,5-Dichlorophenylmercaptoacetic acid (TCl America,
Portland, Oreg.) (237 mg) was converted to the acid chloride as
described in the General Procedure A'' and utilized to acylate
methyl L-alaninyl-L-phenylglycinate as described in General
Procedure B''. The title compound (210 mg) was isolated as crystals
from ethyl ether.
[2573] NMR data was as follows:
[2574] .sup.1H-nmr (DMSO-d.sub.6) .delta.=8.85 (d, 1H), 8.20 (d,
1H), 6.70-7.45 (m, 8H), 5.45 (d, 1H), 4.45-4.65 (m, 3H), 3.65 (s,
3H), 1.30 (d, 3H).
[2575] C.sub.20H.sub.20Cl.sub.2N.sub.2O.sub.4S (MW=455.363) mass
spectroscopy (MH.sup.+) 454.1.
[2576] Anal. Calcd. for C.sub.20H.sub.20Cl.sub.2N.sub.2O.sub.4S: C,
52.75 H, 4.42 N, 6.15; Found: C, 53.58 H, 5.01, N, 6.34.
Example 330
Synthesis of
N-[N-(3,4-Dichlorophenylmercptoacetyl)-L-alaninyl]-L-phenylglycine
Methyl Ester
[2577] 3,4-Dichlorophenylmercaptoacetic acid (J. Med. Chem., 15(9),
940-944 (1972)) (237 mg) was converted to the acid chloride as
described in the General Procedure A'' and utilized to acylate
methyl L-alaninyl-L-phenylglycinate as described in General
Procedure B''. The title compound (182 mg) was isolated as crystals
from ethyl ether.
[2578] NMR data was as follows:
[2579] .sup.1H-nmr (DMSO-d.sub.6) .delta.=8.8 (d, 1H), 8.40 (d,
1H), 7.25-7.65 (m, 8H), 5.40 (d, 1H), 4.45 (m, 1H), 3.80 (m, 2H),
3.65 (s, 3H), 1.25 (d, 3H).
[2580] C.sub.20H.sub.20Cl.sub.2N.sub.2O.sub.4S (MW=455.363); mass
spectroscopy (MH.sup.+) 454.1
[2581] Anal. Calcd. for C.sub.20H.sub.20Cl.sub.1N.sub.2O.sub.4S: C,
52.75 H, 4.42 N, 6.15; Found: C, 53.05 H,
[2582] 4.67 N, 6.26.
Example 331
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-phenylglycine Methyl
Ester
[2583] 3,5-Difluorophenoxyacetic acid (prepared by refluxing an
aqueous mixture of 3,5-difluorophenol (Aldrich), 2-chloroacetic
acid, and NaOH] (188 mg) was converted to the acid chloride as
described in the General Procedure A'' and utilized to acylate
methyl L-alaninyl-L-phenylglycinate as described in General
Procedure B''. The title compound (210 mg) was isolated as crystals
from ethyl ether.
[2584] NMR data was as follows:
[2585] .sup.1H-nmr (DMSO-d.sub.6) .delta.=8.85 (d, 1H), 8.20 (d,
1H), 6.70-7.45 (m, 8H), 5.45 (d, 1H), 4.45-4.65 (m, 3H), 3.65 (s,
3H), 1.30 (d, 3H).
[2586] C.sub.20H.sub.20F.sub.2N.sub.2O.sub.5 (MW=406.39); mass
spectroscopy (MH.sup.+) 406.3.
[2587] Anal. Calcd. for C.sub.20H.sub.20F.sub.2N.sub.2O.sub.5: C,
59.11 H, 4.96 N, 6.89; Found: C, 53.34 H, 4.80 N, 6.94.
Example 332
Synthesis of Methyl
N-[N-(3,5-Difluorophenoxyacetyl)-L-alaninyl]-L-2,3-dihydroisoindole-1carb-
oxylate
[2588] Following General Procedure AN,
L-2,3-Dihydro-1H-isoindole-1-carboxylic acid methyl ester
hydrochloride (Gazz. Chim. Ital., 106 (1-2) p. 65-75 (1976)) (417
mg) was coupled to N-(3,5-difluorophenylacetyl-L-alanine (from
Example B2) to provide the title compound (150 mg).
[2589] NMR data was as follows:
[2590] .sup.1H-nmr (DMSO-d.sub.6) .delta.=8.55 (d, 1H), 6.85-7.45
(m, 7H), 5.50(m, 1H), 4.95(s, 1H),
[2591] 4.55-4.90(m, 2+H), 3.65 (m, 3H), 1.30 (m, 3H).
[2592] C.sub.21H.sub.20F.sub.2N.sub.2O.sub.4 (MW=402.40); mass
spectroscopy (MH.sup.+) 402.3.
Example 333
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-1-amino-1,3-diphenylpropane-2-
-one
[2593] To a solution of 200 mg of
N-methoxy-N-methyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-pheny-
lglycinamide (from Example 304 above) in THF was added 1.91 mL of a
2M solution of benzyl magnesium bromide in THF (Aldrich) at
0.degree. C. The reaction mixture was stirred at ambient
temperature for 72 hours, and was subsequently quenched by addition
of water. The reaction mixture was partitioned between ethyl
acetate and water and the organic phase was washed with 1N HCl
solution. Following removal of solvent under reduced pressure, the
crude ketone was purified by chromatography on silica gel, eluting
with ethyl acetate, to afford 62 mg of the title compound as a 1:1
mixture of phenyl diastereomers.
[2594] NMR data was as follows:
[2595] .sup.1H-Nmr (CDCl.sub.3) (approx 1:1 mixture of
diastereomers) .delta.=7.2-7.5 (m, 8H), 7.0-7.1 (m, 2H), 6.7-6.9
(m, 4H), 6.2 (m, 1H), 5.5(t, 1H), 3.5-3.6 (m, 2H), 1.28-1.45
(doublets in 1:1 ratio, 3H).
Example 334
Synthesis of
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine
Thiocarboxamide
Step A--Preparation of t-butoxycarbonyl-phenylglycine
thiocarboxamide
[2596] To a suspension of 500 mg (2.00 mmol)
t-butoxycarbonyl-L-phenylglycine carboxamide (prepared as in
Example 141) in 50 mL of dry toluene was added 808 mg (2.00 mmol)
Lawesson's reagent (Aldrich). The reaction mixture was heated to
95.degree. C. for 5 min. Cooling to ambient temperature and
dilution with 1:1 ethyl acetate/hexanes resulted in precipitation
of insoluble material. Removal of the soluble phase, followed by
additional washing of the solids and combination of the soluble
phase, and removal of solvent afforded crude thiocarboxamide as a
semisolid. Purification by chromatography on silica gel, eluting
with ethyl acetate afforded 364 mg of thiocarboxamide.
Step B--Preparation of Phenylglycine Thiocarboxamide
Hydrobromide
[2597] A solution of 364 mg of t-butoxycarbonyl phenylglycine
thiocarboxamide in 4 mL 30% HBr in acetic acid was stirred for 1
hour. The volitile materials were removed under reduced pressure
and the crude phenylglycine thiocarboxamide hydrobromide was
obtained as a pale solid. The material was utilized without further
purification.
[2598] To a stirred solution of 486 mg of
(3,5-difluorophenylacetyl)-L-alanine (from B2) in 30 mL of
dichoromethane was added 383 mg of EDCI, 270 mg of HOBT hydrate,
followed by 350 .mu.L of diisopropylethylamine. To this suspension
was added phenylglycine thiocarboxamide hydrobromide in
dichloromethane. The reaction mixture was stirred at ambient
temperature for 72 hours. The reaction mixture was partioned
between water and dichloromethane and the organic phase was washed
with 1N HCl solution, followed by saturated aqueous sodium
bicarbonate solution. Removal of solvent afforded the crude
product, which was purified by chromatography on silica gel,
eluting with ethyl acetate, to afford 271 mg of the title compound
(approximately 3:2 mixture of phenylglycine diastereomers) as a
pale solid.
[2599] NMR data was as follows:
[2600] .sup.1H-Nmr (CDCl.sub.3) (approx 3:2 mixture of
diastereomers): .delta.=7.3-7.7 (m, 8H), 6.7-6.8 (m, 4H).
Example 335
Synthesis of
N-[N-(3,5-Difluorophenyl-2-oxoacetyl)-L-alaninyl]-L-phenylglycine
tert-Butyl Ester
[2601] Following General Procedure C and using
L-alaninyl-L-phenylglycine tert-butyl ester (prepared as described
in Example 321) and 3,5-difluorophenylglyoxylate (prepared as
described in J. Org. Chem., 45(14), 28883 (1980)), the title
compound was prepared as a solid. The product was purified by
slurrying with EtOAc/hexanes.
[2602] Elemental Anal.: Calc.(%) C, 61.88, H, 5.42, N, 6.27; Found:
C, 62.15, H, 5.51, N, 6.18.
Example 336
Synthesis of
N-(2-Hydroxy-1-phenyleth-1-yl)-N'-[N-(3,5-Difluorophenylacetyl)-L-phenylg-
lycinyl]-L-alaninamide
[2603] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-phenylglycinyl-L-alanine (prepared
from N-(3,5-difluorophenylacetyl)-L-phenylglycinyl-L-alanine ethyl
ester) and (S)-phenylglycinot (Aldrich), the title compound was
prepared (m.p.=269-272.degree. C.). The reaction was monitored by
tlc (Rf=0.3 in 10% MeOH/CHCl.sub.3) and the product was purified by
chromatography using 10% MeOH/CHCl.sub.3 as the eluent.
[2604] NMR data was as follows:
[2605] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.25 (d, 3H), 8.01 (d,
1H), 8.52 (d, 1H), 8.82 (d, 1H).
[2606] Optical Rotation: [.alpha.].sub.20=-62.7 @ 589 nm (c=1.02,
DMSO).
[2607] C.sub.27H.sub.27N.sub.3O.sub.3F.sub.2 (MW=495.53); mass
spectroscopy (MH.sup.+) 496.
Example 337
Synthesis of
N-(2-Hydroxyeth-1-yl)-N'-[N-(3,5-Difluorophenylacetyl)-L-alanyl]-L-phenyl-
glycinamide
[2608] Following General Procedure C and using
N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and
L-phenylglycine (2-hydroxyethyl)amide hydrochloride (prepared from
N-BOC-L-phenylglycine (Bachem) and 2-aminoethanol (Aldrich) using
General Procedure C, followed by removal of the BOC group using
General Procedure P), the title compound was prepared. The product
was purified by chromatography using 10% MeOH/CHCl.sub.3 as the
eluent, followed by crystallization from EtOH.
[2609] NMR data was as follows:
[2610] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.22 (d, 3H), 5.42 (d,
1H).
[2611] Optical Rotation: [.alpha.].sub.20=+8.77 @ 589 nm (c 1.03,
DMSO).
[2612] C.sub.21H.sub.23N.sub.3O.sub.4F.sub.2 (MW=419.43); mass
spectroscopy (MH.sup.+) 420.
Example 338
Synthesis of
N-(4-(4-Azido-2-hydroxybenzmido)but-1-yl)-N'-[N-(3,5-Difluorophenylacetyl-
)-L-alanyl]-L-phenylglycinamide
[2613] Following General Procedure A and using
N-(3,5-difluorophenylacetyl)-L-alanyl-L-phenylglycine (prepared as
described herein) and 4-(4-azidosalicylamido)butylamine (Pierce
Chemical), the title compound was prepared as a light sensitive
solid. The reaction was conducted under low light conditions and
the reaction vessel was protected from light. The reaction was
monitered by tlc (R.sub.f0.2 in 2.5% MeOH/dichloromethane).
[2614] NMR data was as follows:
[2615] .sup.1H-nmr (CD.sub.3OH/CDCl.sub.3): .delta.=7.72 (d, 2H),
7.30 (m, 5H), 6.84 (m, 2H), 6.73 (m, 1H), 6.54 (m, 2H), 5.34 (s,
1H), 4.39 (q, 1H), 3.56 (s, 2H), 3.31 (bs, 2H), 3.21 (bs, 2H), 1.57
(bs, 4H), 1.35 (d, 2H).
Example 339
Synthesis of
N-(Methanesulfonyl)-N'-[N-(3,5-Difluorophenylacetyl)-L-alanyl]-L-phenylal-
anamide
[2616] N-Cbz-L-Phenylalanine (Sigma) was coupled to
N-hydroxysuccinimide (Aldrich) using DCC in dicloromethane. The
resulting intermediate was reacted with methanesulfonamide in DMF
with diisopropylethylamine to provide
N-methanesulfonyl-N'-Cbz-L-phenylalanamide amide. The Cbz group was
removed using General Procedure O and the resulting intermediate
was coupled to N-(3,5-difluorophenylacetyl)-L-alanine (from Example
B2 above) using General Procedure B to give the title compound,
m.p. =203-205.degree. C.
Examples 340-407
[2617] By following the procedures set forth above, the following
additional compounds were prepared:
[2618] N-[N-(3 5-Difluorophenylacetyl)-L-alaninyl]-D-phenylglycine
methyl ester (Ex 340)
[2619]
N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-(3-.alpha.-phenyl)pr-
oline methyl ester (Ex. 341)
[2620] N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-azetidine
methyl ester (Ex. 342)
[2621] methyl
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-(5-chlorobenzothiop-
hen-2-yl)acetate (Ex. 343)
[2622] t-butyl
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(thiazol-4-yl)p-
ropionate (Ex. 344)
[2623] t-butyl
-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide
(Ex. 345)
[2624]
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-(thien-2-yl)glycinam-
ide (Ex. 346)
[2625]
N-[N-(3,4-dichlorophenylacetyl)-L-alaninyl]-D-phenylglycinamide
(Ex. 347)
[2626] N-[N-(3-chlorophenylacetyl)-L-alaninyl]-D-phenylglycinamide
(Ex. 348)
[2627] N-[N-(3-bromophenylacetyl)-L-alaninyl]-D-phenylglycinamide
(Ex. 349)
[2628] N-[N-(3-fluorophenylacetyl)-L-alaninyl]-D-phenylglycinamide
(Ex. 350)
[2629] N-[N-(4-fluorophenylacetyl)-L-alaninyl]-D-phenylglycinamide
(Ex. 351)
[2630] N-[N-(3-methylphenylacetyl)-L-alaninyl]-D-phenylglycinamide
(Ex. 352)
[2631] N-[N-(4-methylphenylacetyl)-L-alaninyl]-D-phenylglycinamide
(Ex. 353)
[2632]
N-[N-(3-trifluoromethylphenylacetyl)-L-alaninyl]-D-phenylglycinami-
de (Ex. 354)
[2633] N-[N-(3-methoxyphenylacetyl)-L-alaninyl]-D-phenylglycinamide
(Ex. 355)
[2634] N-[N-(2-chlorophenylacetyl)-L-alaninyl]-D-phenylglycinamide
(Ex. 356)
[2635] N-[N-(1-naphthylacetyl)-L-alaninyl]-D-phenylglycinamide (Ex.
357)
[2636] N-[N-(2-naphthylacetyl)-L-alaninyl]-D-phenylglycinamide (Ex.
358)
[2637] N-[N-(phenylacetyl)-L-alaninyl]-D-phenylglycinamide (Ex.
359)
[2638] N-[N-(3,5-difluorophenylacety)-L-alaninyl]-D-phenylglycine
(Ex. 360)
[2639]
N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-fura-
nyl)acetamide (Ex. 361)
[2640]
N'-[N-(3,4-difluorophenylacetyl)-D-alaninyl]-D-phenylglycinamide
(Ex. 362)
[2641]
N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenlalanin-N-methy-
lsulfonamide (Ex. 363)
[2642]
N''-methyl-N''-phenyl-N'-(N-(3,5-difluorophenylacetyl)-L-alaninyl]-
-glycinamide (Ex. 364)
[2643]
N''-methyl-N''-phenyl-N'-(N-(3,5-difluorophenylacetyl)-L-alaninyl]-
-L-alaninamide (Ex. 365)
[2644]
N'-[N-(3,5-difluorophenylacetyl)-L-methioninyl]-L-phenylglycinamid-
e (Ex. 366)
[2645]
N''-methyl-N''-benzyl-N'-(N-(3,5-difluorophenylacetyl)-L-alaninyl]-
-glycinamide (Ex. 367)
[2646]
N''-4-fluorobenzyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L--
phenylglycinamide (Ex. 368)
[2647]
N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(4-fluoro)phenylgly-
cine neopentyl ester (Ex. 369)
[2648]
N-[N-(2,3,4,5,6-pentafuorophenylacetyl)-L-alaninyl]-L-(pyird-3-yl)-
glycine methyl ester (Ex. 370)
[2649]
N-[N-(3,5-difluorophenylacetyl)-L-(O-benzyl)serinyl]-L-phenylglyci-
ne methyl ester (Ex. 371)
[2650]
N-[N-(3,5-difluorophenylacetyl)-L-(O-benzyl)threoninyl]-L-phenylgl-
ycine methyl ester (Ex. 372)
[2651]
N-[N-(3,5-difluorophenylacetyl)-L-threoninyl]-L-phenylglycine
methyl ester (Ex. 373)
[2652] N-[N-(3,5-difluorophenylacetyl)-L-serinyl]-L-phenylglycine
methyl ester (Ex. 374)
[2653]
N''-4-methylphenyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L--
phenylglycinamide (Ex. 375)
[2654]
N''-tetrahydrofurfuryl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl-
]-L-phenylglycinamide (Ex. 376)
[2655]
N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]L-4-flurophenyl-glycin-
amide (Ex. 377)
[2656]
N'-[N-(3,5-difluorophenylacetyl)-L-methonyl]-L-phenylglycinamide
(Ex. 378)
[2657]
N-[N-(3,5-difluorophenylacetyl)-2-aminobutanoyl-L-phenylglyciamide
(Ex. 379)
[2658]
N'-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycina-
mide (Ex. 380)
[2659]
N-[N-(3,5-difluorophenylacetyl)-L-valinyl]-L-phenylglycinamide (Ex.
381)
[2660]
N-[(R)-.alpha.-methylbenzyl]-N'-[N-(3,5-difluorophenylacetyl)-L-al-
aninyl]-L-phenylglycinamide (Ex. 382)
[2661] N-[1-phenyl-2-oxo-3-methylbutan-1
-yl]-N-(3,5-difluorophenylacetyl)-L-alaninamide (Ex. 383)
[2662]
N-[1-phenyl-2-oxo-propan-1-yl]-N'-(3,5-difluorophenylacetyl)-L-ala-
ninamide (Ex. 384)
[2663]
N-[1-phenyl-2-oxo-pentan-1-yl]-N'-(3,5-difluorophenylacetyl)-L-ala-
ninamide (Ex. 385)
[2664] N-[1 -phenyl-2-ox-2-phenyl-ethan-1
-yl]-N'-(3,5-difluorophenyl-acetyl)-L-alaninamide (Ex. 386)
[2665]
N-[1-phenyl-2-oxo-butan-1-yl]-N'-(3,5-difluorophenyl-acetyl)-L-ala-
ninamide (Ex. 387).
[2666] N-[1
-phenyl-2-oxo-4-methylpentan-1-yl]-N'-(3,5-difluorophenyl-acetyl)-L-alani-
namide (Ex. 388)
[2667]
N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-.alpha.-hydroxyphen-
ylalanine methyl ester (Ex. 389)
[2668] N''-[4-((2-hydroxy-4-azido)-phenyl)-NHC(O)-)butyl]
N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide
(Ex. 390)
[2669]
N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-fluorophenylglyci-
ne t-butyl ester (Ex. 391)
[2670]
N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L4-phenylphenylglycin-
e t-butyl ester (Ex. 392)
[2671]
[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(2,3-benzo[b]proline)m-
ethyl ester (Ex. 393)
[2672]
N''-t-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-n-but-
ylphenylglycinamide (Ex. 394)
[2673]
N''-t-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-4-(ph-
enylacetenyl)phenylglycinamide (Ex. 395)
[2674]
N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinthioa-
mide (Ex. 396)
[2675]
N-[1,3-diphenyl-2-oxopropan-1-yl]-N'-(3,5-difluorophenylacetyl)-L--
alaninamide (Ex. 397)
[2676]
N-[1-phenyl-2-oxo-2-cyclopentylethan-1-yl]-N'-(3,5-difluorophenyla-
cetyl)-L-alaninamide (Ex. 398)
[2677] N-[1
-phenyl-2-oxo-hexan-1-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide
(Ex. 399).
[2678]
N-[1-phenyl-2-oxo-3-methylpentan-1-yl]-N'-(3,5-difluorophenylacety-
l)-L-alaninamide (Ex. 400)
[2679]
N'-n-hexyl-6-biotinamidyl-N'-[N-(3,5-difluorophenylacetyl)-L-alani-
nyl]-D,L-phenylglycinthioamide (Ex. 401)
[2680]
N'-[N-(3,5-difluorophenylacetyl)-L-methioninyl]-L-methionine(Ex.
402)
[2681] N'-[N-(2-t-BOC-amino)propionyl)-L-alaninyl]-L-phenylglycine
methyl ester (Ex. 403)
[2682] N''-t-butyl
N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-2-fluorophenylglycinamide
(Ex. 404)
[2683]
N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-2-phenylglycine
methyl ester (Ex. 405)
[2684]
N'-[N-(3,5-difluorophenylacetyl)-D,L-thien-3-ylglycinyl]-D,L-2-phe-
nylglycine (Ex. 406)
[2685]
N'-[N-(3,5-difluorophenylacetyl)-D,L-thien-3-ylglycinyl]-D,L-2-phe-
nylglycine t-butyl ester (Ex. 407)
Example 408
[2686] Following the procedures set forth above, the following
compounds of formula I were or could be prepared:
[2687] R.sup.1 is 3,5-difluorophenyl; X' and X'' are hydrogen;
R.sup.2 is methyl; R.sup.3 is hydrogen; R.sup.4 is p-fluorophenyl;
R.sup.5 is hydrogen; Z is a bond, X is
--C(O)OCH.sub.2C(CH.sub.3).sub.3; and n is 1;
[2688] R.sup.1 is 3,5-difluorophenyl; X' and X'' are hydrogen;
R.sup.2 is methyl; R.sup.3 is hydrogen; R.sup.4 is
p-(phenyl)phenyl; R.sup.5 is hydrogen; X is
--C(O)NHC(CH.sub.3).sub.3; Z is a bond; and n is 1;
[2689] R.sup.1 is cyclopentyl; X' and X'' are hydrogen; R.sup.2 is
methyl; R.sup.3 is hydrogen; R.sup.4 is phenyl; R.sup.5 is
hydrogen; X is --C(O)OC(CH.sub.3).sub.3; Z is a bond; and n is
1;
[2690] R.sup.1 is cyclopropyl; X' and X' are hydrogen; R.sup.2 is
methyl; R.sup.3 is hydrogen; R.sup.4 is phenyl; R.sup.5 is
hydrogen; X is --C(O)OC(CH.sub.3).sub.3; Z is a bond; and n is 1;
and
[2691] R.sup.1 is 3,5-difluorophenyl; X' and X' are hydrogen;
R.sup.2 is methyl; R.sup.3 is hydrogen; R.sup.4 is phenyl; R.sup.5
is hydrogen; X is --C(O)OCH.sub.2C(CH.sub.3).sub.3; Z is a bond;
and n is 1.
Example 409
Cellular Screen for the Detection of Inhibitors of .beta.-Amyloid
Production
[2692] Numerous compounds of formula I above were assayed for their
ability to inhibit .beta.-amyloid production in a cell line
possessing the Swedish mutation. This screening assay employed
cells (K293=human kidney cell line) which were stably transfected
with the gene for amyloid precursor protein 751 (APP751) containing
the double mutation Lys.sub.651Met.sub.652 to
Asn.sub.651Leu.sub.652 (APP751 numbering) in the manner described
in International Patent Application Publication No. 94/10569.sup.8
and Citron et al..sup.12. This mutation is commonly called the
Swedish mutation and the cells, designated as "293 751 SWE", were
plated in Corning 96-well plates at 1.5-2.5.times.10.sup.4 cells
per well in Dulbecco's minimal essential media plus 10% fetal
bovine serum. Cell number is important in order to achieve
.beta.-amyloid ELISA results within the linear range of the assay
(.about.0.2 to 2.5 ng per mL).
[2693] Following overnight incubation at 37.degree. C. in an
incubator equilibrated with 10% carbon dioxide, media were removed
and replaced with 200 .mu.L of a compound of formula I (drug)
containing media per well for a two hour pretreatment period and
cells were incubated as above. Drug stocks were prepared in 100%
dimethylsulfoxide such that at the final drug concentration used in
the treatment, the concentration of dimethylsulfoxide did not
exceed 0.5% and, in fact, usually equaled 0.1%.
[2694] At the end of the pretreatment period, the media were again
removed and replaced with fresh drug containing media as above and
cells were incubated for an additional two hours. After treatment,
plates were centrifuged in a Beckman GPR at 1200 rpm for five
minutes at room temperature to pellet cellular debris from the
conditioned media. From each well, 100 .mu.L of conditioned media
or appropriate dilutions thereof were transferred into an ELISA
plate precoated with antibody 266.sup.14 against amino acids 13-28.
of .beta.-amyloid peptide as described in International Patent
Application Publication No. 94/105699 and stored at 4.degree. C.
overnight. An ELISA assay employing labelled antibody 6C6.sup.14
against amino acids 1-16 of .beta.-amyloid peptide was run the next
day to measure the amount of .beta.-amyloid peptide produced.
[2695] Cytotoxic effects of the compounds were measured by a
modification of the method of Hansen, et al..sup.13. To the cells
remaining in the tissue culture plate was added 25 .mu.L of a
3,(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide (MTT)
stock solution (5 mg/mL) to a final concentration of 1 mg/mL. Cells
were incubated at 37.degree. C. for one hour, and cellular activity
was stopped by the addition of an equal volume of MTT lysis buffer
(20% w/v sodium dodecylsulfate in 50% dimethylformamide, pH 4.7).
Complete extraction was achieved by overnight shaking at room
temperature. The difference in the OD.sub.562 nm and the OD.sub.650
nm was measured in a Molecular Device's UV.sub.max microplate
reader as an indicator of the cellular viability.
[2696] The results of the .beta.-amyloid peptide ELISA were fit to
a standard curve and expressed as ng/mL .beta.-amyloid peptide. In
order to normalize for cytotoxicity, these results were divided by
the MTT results and expressed as a percentage of the results from a
drug free control. All results are the mean and standard deviation
of at least six replicate assays.
[2697] The test compounds were assayed for .beta.-amyloid peptide
production inhibition activity in cells using this assay. The
results of this assay demonstrate that, each of the compounds
within this invention tested reduced .beta.-amyloid peptide
production by at least 30% as compared to control.
Example 410
In Vivo Suppression of .beta.-Amyloid Release and/or Synthesis
[2698] This example illustrates how the compounds of this invention
could be tested for in vivo suppression of .beta.-amyloid release
and/or synthesis. For these experiments, 3 to 4 month old PDAPP
mice are used [Games et al., (1995) Nature 373:523-527]. Depending
upon which compound is being tested, the compound is usually
formulated at either 5 or 10 mg/ml. Because of the low solubility
factors of the compounds, they may be formulated with various
vehicles, such as corn oil (Safeway, South San Francisco, Calif.);
10% EtOH in corn oil (Safeway); 2-hydroxypropyl-.beta.-cyclodextrin
(Research Biochemicals International, Natick Mass.); and
carboxy-methyl-cellulose (Sigma Chemical Co., St. Louis Mo.).
Specifically, for example 141 the vehicle was
carboxy-methyl-cellulose (Sigma).
[2699] The mice are dosed subcutaneously with a 26 gauge needle and
3 hours later the animals are euthanized via CO.sub.2 narcosis and
blood is taken by cardiac puncture using a 1 cc 25G 5/8''
tuberculin syringe/needle coated with solution of 0.5 M EDTA, pH
8.0. The blood is placed in a Becton-Dickinson vacutainer tube
containing EDTA and spun down for 15 minutes at 1500.times.g at
5.degree. C. The brains of the mice are then removed and the cortex
and hippocampus are dissected out and placed on ice.
1. Brain Assay
[2700] To prepare hippocampal and cortical tissue for enzyme-linked
immunosorbent assays (ELISAs) each brain region is homogenized in
10 volumes of ice cold guanidine buffer (5.0 M guanidine-HCl, 50 mM
Tris-HCl, pH 8.0) using a Kontes motorized pestle (Fisher,
Pittsburgh Pa.). The homogenates are gently rocked on a rotating
platform for three to four hours at room temperature and stored at
-20.degree. C. prior to quantitation of .beta.-amyloid.
[2701] The brain homogenates are diluted 1:10 with ice-cold casein
buffer [0.25% casein, phosphate buffered saline (PBS), 0.05% sodium
azide, 20 .mu.g/ml aprotinin, 5 mM EDTA, pH 8.0, 10 .mu.g/ml
leupeptin], thereby reducing the final concentration of guanidine
to 0.5 M, before centrifugation at 16,000.times.g for 20 minutes at
4.degree. C. The .beta.-amyloid standards (1-40 or 1-42 amino
acids) were prepared such that the final composition equaled 0.5 M
guanidine in the presence of 0.1% bovine serumalbumin (BSA).
[2702] The total .beta.-amyloid-sandwich ELISA, quantitating both
.beta.-amyloid (aa 1-40) and .beta.-amyloid (aa 1-42) consists of
two monoclonal antibodies (mAb) to .beta.-amyloid. The capture
antibody, 266.sup.14, is specific to amino acids 13-28 of
.beta.-amyloid. The antibody 3D6.sup.15, which is specific to amino
acids 1-5 of .beta.-amyloid, is biotinylated and served as the
reporter-antibody in the assay. The 3D6 biotinylation procedure
employs the manufacturer's (Pierce, Rockford Ill.) protocol for
NHS-biotin labeling of immunoglobulins except that 100 mM sodium
bicarbonate, pH 8.5 buffer is used. The 3D6 antibody does not
recognize secreted amyloid precursor protein (APP) or full-length
APP but detects only .beta.-amyloid species with an amino terminal
aspartic acid. The assay has a lower limit of sensitivity of
.about.50 pg/ml (11 pM) and shows no cross-reactivity to the
endogenous murine .beta.-amyloid peptide at concentrations up to 1
ng/ml.
[2703] The configuration of the sandwich ELISA quantitating the
level of .beta.-amyloid (aa 142) employs the mAb 21F12.sup.15
(which recognizes amino acids 33-42 of .beta.-amyloid) as the
capture antibody. Biotinylated 3D6 is also the reporter antibody in
this assay which has a lower limit of sensitivity of .about.125
pg/mi (28 pM.
[2704] The 266 and 21F12 capture mAbs are coated at 10 .mu.g/ml
into 96 well immunoassay plates (Costar, Cambridge Mass.) overnight
at room temperature. The plates are then aspirated and blocked with
0.25% human serum albumin in PBS buffer for at least 1 hour at room
temperature, then stored desiccated at 4.degree. C. until use. The
plates are rehydrated with wash buffer (Tris-buffered saline, 0.05%
Tween 20) prior to use. The samiples and standards are added to the
plates and incubated overnight at 4.degree. C. The plates are
washed .gtoreq.3 times with wash buffer between each step of the
assay. The biotinylated 3D6, diluted to 0.5 .mu.g/ml in casein
incubation buffer (0.25% casein, PBS, 0.05% Tween 20, pH 7.4) is
incubated in the. well for 1 hour at room temperature. Avidin-HRP
(Vector, Burlingame Calif.) diluted 1:4000 in casein incubation
buffer is added to the wells for 1 hour at room temperature. The
calorimetric substrate, Slow TMB-ELISA (Pierce, Cambridge Mass.),
is added and allowed to react for 15 minutes, after which the
enzymatic reaction is stopped with addition of 2 N H2SO.sub.4.
Reaction product is quantified using a Molecular Devices Vmax
(Molecular Devices, Menlo Park Calif.) measuring the difference in
absorbance at 450 nm and 650 nm.
2. Blood Assay
[2705] The EDTA plasma is diluted 1:1 in specimen diluent (0.2 gm/l
sodium phosphate.H.sub.2O (monobasic), 2.16 gm/l sodium
phosphate.7H.sub.2O (dibasic), 0.5 gm/l thimerosal, 8.5 gm/l sodium
chloride, 0.5 ml TritonX-405, 6.0 g/l globulin-free bovine serum
albumin; and water). The samples and standards in specimen diluent
are assayed using the total .beta.-amyloid assay (266 capture/3D6
reporter) described above for the brain assay except the specimen
diluent was used instead of the casein diluents described.
[2706] From the foregoing description, various modifications and
changes in the composition and method will occur to those sidlied
in the art. All such modifications coming within the scope of the
appended claims are intended to be included therein.
* * * * *