U.S. patent application number 10/319272 was filed with the patent office on 2003-08-28 for squaric acid derivatives.
Invention is credited to Alexander, Rikki Peter, Archibald, Sarah Catherine, Head, John Clifford, Langham, Barry John, Linsley, Janeen Marsha, Porter, John Robert, Warrellow, Graham John.
Application Number | 20030162799 10/319272 |
Document ID | / |
Family ID | 26243599 |
Filed Date | 2003-08-28 |
United States Patent
Application |
20030162799 |
Kind Code |
A1 |
Langham, Barry John ; et
al. |
August 28, 2003 |
Squaric acid derivatives
Abstract
Squaric acid Derivatives of formula (1) are described: 1 wherein
R.sup.1 is an integrin binding group; R.sup.2 is a hydrogen atom or
a C.sub.1-6alkyl group; L.sup.1 is a covalent bond or a linker atom
or group; n is zero or the integer 1; Alk.sup.1 is an optionally
substituted aliphatic chain; R.sup.3 is a hydrogen atom or an
optionally substituted heteroaliphatic, cycloaliphatic,
heterocycloaliphatic, polycycloaliphatic, polyheterocycloaliphatic,
aromatic or heteroaromatic group: and the salts, solvates, hydrates
and N-oxides thereof. The compounds are able to inhibit the binding
of integrins to their ligands and are of use in the prophylaxis and
treatment of immune of inflammatory disorders, or disorders
involving the inappropriate growth or migration of cells.
Inventors: |
Langham, Barry John;
(Reading, GB) ; Alexander, Rikki Peter; (High
Wycombe, GB) ; Head, John Clifford; (Maidenhead,
GB) ; Linsley, Janeen Marsha; (High Wycombe, GB)
; Porter, John Robert; (Chinnor, GB) ; Archibald,
Sarah Catherine; (Maidenhead, GB) ; Warrellow, Graham
John; (Northwood, GB) |
Correspondence
Address: |
WOODCOCK WASHBURN LLP
ONE LIBERTY PLACE, 46TH FLOOR
1650 MARKET STREET
PHILADELPHIA
PA
19103
US
|
Family ID: |
26243599 |
Appl. No.: |
10/319272 |
Filed: |
December 13, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10319272 |
Dec 13, 2002 |
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09579317 |
May 25, 2000 |
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6518283 |
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Current U.S.
Class: |
514/266.1 ;
514/300; 514/357; 514/650; 544/283; 546/122; 546/335; 564/336 |
Current CPC
Class: |
A61P 29/00 20180101;
C07C 229/34 20130101; A61P 43/00 20180101; C07C 235/16 20130101;
C07C 255/57 20130101; C07C 271/22 20130101; C07D 239/42 20130101;
C07C 271/28 20130101; C07C 233/81 20130101; C07D 295/135 20130101;
C07D 471/04 20130101; A61P 37/00 20180101; C07D 213/79 20130101;
C07C 233/55 20130101; C07C 2601/04 20170501; C40B 40/00 20130101;
C07C 235/56 20130101; C07D 215/42 20130101; C07C 237/40 20130101;
C07D 239/34 20130101; C07C 2603/18 20170501; C07D 333/70 20130101;
A61P 7/00 20180101; C07C 235/84 20130101; C07C 271/58 20130101;
C07D 241/42 20130101; C07C 229/36 20130101; C07D 241/44 20130101;
C07D 217/22 20130101; C07B 2200/07 20130101; C07C 235/64 20130101;
C07D 213/81 20130101 |
Class at
Publication: |
514/266.1 ;
514/300; 514/357; 514/650; 544/283; 546/122; 546/335; 564/336 |
International
Class: |
C07D 471/02; A61K
031/517; C07D 239/72; A61K 031/44; A61K 031/137 |
Foreign Application Data
Date |
Code |
Application Number |
May 28, 1999 |
GB |
9912640.1 |
Feb 8, 2000 |
GB |
0002858.9 |
Claims
1. A compound of formula (1): 13wherein R.sup.1 is an integrin
binding group; R.sup.2 is a hydrogen atom or a C.sub.1-6alkyl
group; L.sup.1 is a covalent bond or a linker atom or group; n is
zero or the integer 1; Alk.sup.1 is an optionally substituted
aliphatic chain; R.sup.3 is a hydrogen atom or an optionally
substituted heteroaliphatic, cycloaliphatic, heterocycloaliphatic,
polycycloaliphatic, polyheterocycloaliphatic, aromatic or
heteroaromatic group; and the salts, solvates, hydrates and
n-oxides thereof:
2. A compound according to claim 1 in which R.sup.1 is an
.alpha..sub.4-integrin binding group.
3. A compound according to claim 1 in which R.sup.1 is a group of
formula Ar.sup.1L.sup.2Ar.sup.2Alk-, where Ar.sup.1 is an
optionally substituted aromatic or heteroaromatic group, L.sup.2 is
a linker atom or group, Ar.sup.2 is an optionally substituted
phenylene or nitrogen-containing six-membered heteroarylene group
and Alk is a chain from: --CH.sub.2--CH(R)--, --CH.dbd.C(R)--,
14where R is a carboxylic acid (--CO.sub.2H) or a derivative or
biostere thereof.
4. A compound according to claim 3 in which Alk is a chain selected
from --CH.sub.2--CH(R)--, or 15
5. A compound according to claim 4 in which R is a carboxylic acid
(--CO.sub.2H) group.
6. A compound according to claim 3 in which Ar.sup.2 is an
optionally substituted 1,4-phenylene group.
7. A compound according to claim 3 in which Ar.sup.1 is an
optionally substituted phenyl, monocyclic heteroaromatic or
bicycl1c heteroaromatic group.
8. A compound according to claim 7 in which Ar.sup.1 is an
optionally substituted pyridyl and pyrimidinyl group.
9 A compound according to claim 8 in which L.sup.2 is a
--CON(R.sup.8)-- group where R.sup.8 is a hydrogen atom or an
optionally substituted C.sub.1-6alkyl group.
10. A compound according to claim 9 in which R.sup.8 is a hydrogen
atom.
11. A compound according to claim 7 in which Ar.sup.1 is an
optionally substituted 2,6-naphthyridinyl and 4quinazolinyl
groups.
12. A compound according to claim 11 in which L.sup.2 is an --O--
or --N(R.sup.8)-- group where R.sup.8 is a hydrogen atom or an
optionally substituted C.sub.1 6alkyl group.
13. A compound according to claim 12 in which R.sup.8 is a hydrogen
atom.
14. A compound according to claim 1 in which L.sup.1 is a
--N(R.sup.8)-- group where R.sup.8 is a hydrogen atom or an
optionally substituted C.sub.1-6alkyl group.
15. A compound according to claim 14 in which R.sup.8 is a hydrogen
atom or methyl, ethyl or n-propyl group.
16. A compound according to claim 1 in which L.sup.1 is a covalent
bond.
17. A compound according to any one of claim 1 in which n is the
integer 1 and Alk.sup.1 is an optionally substituted straight or
branched C.sub.1-6alkylene chain.
18. A compound according to claim 17 in which Alk.sup.1 is a
--CH.sub.2--, --CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2--,
--CH(CH.sub.3)CH.sub.2-- or --C(CH.sub.3).sub.2CH.sub.2--
chain.
19. A compound according to claim 18 in which R.sup.3 is a hydrogen
atom.
20. A compound according to claim 3 of formula (2a): 16wherein
--W=is --CH= or --N.dbd.; R.sup.16 and R.sup.17, which may be the
same or different is each a hydrogen atom or group
-L.sup.3(Alk.sup.2).sub.tL.sup- .4(R.sup.4).sub.u in which: L.sup.3
is a covalent bond or a linker atom or group; Alk.sup.2 is an
aliphatic or heteroaliphatic chain; t is zero or the integer 1;
L.sup.4 is a covalent bond or a linker atom or group; R.sup.4 is a
hydrogen or halogen atom or a group selected from optionally
substituted C.sub.1-6alkyl or C.sub.3-8 cycloalkyl, --OR.sup.5
(where R.sup.5 is a hydrogen atom, an optionally substitued
C.sub.1-6alkyl or C.sub.3-8 cycloalkyl group], --SR.sup.5,
--NR.sup.5R.sup.6 [where R.sup.6 is as just defined for R.sup.5 and
may be the same or different], --NO.sub.2, --CN, --CO.sub.2R.sup.5,
--SO.sub.3H, --SOR.sup.5, --SO.sub.2R.sup.5, --SO.sub.3R.sup.5,
--OCO.sub.2R.sup.5, --CONR.sup.5R.sup.6, --OCONR.sup.5R.sup.6,
--CSNR.sup.5R.sup.6, --COR.sup.5, --OCOR.sup.5,
--N(R.sup.5)COR.sup.6, --N(R.sup.5)CSR.sup.6,
--SO.sub.2N(R.sup.5)(R.sup.6), --N(R.sup.5)SO.sub.2R.sup.6,
N(R.sup.5)CON(R.sup.6)(R.sup.7) [where R.sup.7 is a hydrogen atom,
an optionally substituted C.sub.1-6alkyl or C.sub.3-8cycloalkyl
group], --N(R.sup.5)CSN(R.sup.6)(R.sup.7) or
--N(R.sup.5)SO.sub.2N(R.sup.6)(R.sup- .7), provided that when t is
zero and each of L.sup.3 and L.sup.4 is a covalent bond then u is
the integer 1 and R.sup.4 is other than a hydrogen atom; and the
salts, solvates, hydrates and N-oxides thereof.
21. A compound according to claim 3 of formula (2b) 17wherein
R.sup.16 is a hydrogen atom or a group
-L.sup.3(Alk.sup.2).sub.tL.sup.4(R.sup.4).sub.- u in which L.sup.3
is a covalent bond or a linker atom or group; Alk.sup.2 is an
aliphatic or heteroaliphatic chain; t is zero or the integer 1;
L.sup.4 is a covalent bond or a linker atom or group; R.sup.4 is a
hydrogen or halogen atom or a group selected from optionally
substituted C.sub.1-6alkyl or C.sub.3-8 cycloalkyl, --OR.sup.5
[where R.sup.5 is a hydrogen atom, an optionally substitued
C.sub.1-6alkyl or C.sub.3-8 cycloalkyl group], --SR.sup.5,
--NR.sup.5R.sup.6 [where R.sup.6 is as just defined for R.sup.5 and
may be the same or different], --NO.sub.2, --CN, --CO.sub.2R.sup.5,
--SO.sub.3H, --SOR.sup.5, --SO.sub.2R.sup.5, --SO.sub.3R.sup.5,
--OCO.sub.2R.sup.5, --CONR.sup.5R.sup.6, --OCONR.sup.5R.sup.6,
--CSNR.sup.5R.sup.6, --COR.sup.5, --OCOR.sup.5,
--N(R.sup.5)COR.sup.6, --N(R.sup.5)CSR.sup.6,
--SO.sub.2N(R.sup.5)(R.sup.- 6), --N(R.sup.5)SO.sub.2R.sup.6,
N(R.sup.5)CON(R.sup.6)(R.sup.7) [where R.sup.7 is a hydrogen atom,
an optionally substituted C.sub.1-6alkyl or C.sub.3-9cycloalkyl
group], --N(R.sup.5)CSN(R.sup.6)(R.sup.7) or
--N(R.sup.5)SO.sub.2N(R.sup.6)(R.sup.7), provided that when t is
zero and each of L.sup.3 and L.sup.4 is a covalent bond then u is
the integer 1 and R.sup.4 is other than a hydrogen atom; g is zero
or the integer 1, 2, 3 or 4; and the salts, solvates, hydrates and
N-oxides thereof.
22. A compound according to claim 3 of formula (2c) 18wherein
R.sup.16 is a hydrogen atom or a group in which L.sup.3 is a
covalent bond or a linker atom or group; Alk.sup.2 is an aliphatic
or heteroaliphatic chain; t is zero or the integer 1; L.sup.4 is a
covalent bond or a linker atom or group; R.sup.4 is a hydrogen or
halogen atom or a group selected from optionally substituted
C.sub.1-6alkyl or C.sub.3-8 cycloalkyl, --OR.sup.5 [where R.sup.5
is a hydrogen atom, an optionally substitued C.sub.1-6alkyl or
C.sub.3-8 cycloalkyl group], --SR.sup.5, --NR.sup.5RO [where
R.sup.6 is as just defined for R.sup.5 and may be the same or
different], --NO.sub.2, --CN, --CO.sub.2R.sup.5, --SO.sub.3H,
--SOR.sup.5, --SO.sub.2R.sup.5, O.sub.3R.sup.5, --OCO.sub.2R.sup.5,
--CONR.sup.5R.sup.6, --OCONR.sup.5R.sup.6, --CSNR.sup.5R.sup.6,
--COR.sup.5, COR.sup.5-N(R.sup.5)COR.sup.6, --N(R.sup.5)CSR.sup.5,
--SO.sub.2N(R.sup.5)(R.sup.6), --N(R.sup.5)SO.sub.2R.sup.6,
N(R.sup.5)CON(R.sup.6)(R.sup.7) [where R.sup.7 is a hydrogen atom,
an optionally substituted C.sub.1-6alkyl or C.sub.3-8cycloalkyl
group], --N(R.sup.5)CSN(R.sup.6)(R.sup.7) or
--N(R.sup.5)SO.sub.2N(R.sup.6)(R.sup- .7), provided that when t is
zero and each of L.sup.3 and L.sup.4 is a covalent bond then u is
the integer 1 and R.sup.4 is other than a hydrogen atom; g is zero
or the integer 1, 2, 3 or 4; and the salts, solvates, hydrates and
N-oxides thereof.
23. A compound which is:
(S)-3-[4-(3,5-Dichloro4-pyridylcarboxamido)phenyl-
]-2-(2-propylamino-3,4-dioxocyclobut-1-enyl)amino]propanoic acid;
(S)-3-[4-(3,5-Dichloro4-pyridylcarboxamido)phenyl]-242-t-butyl-3,4-dioxoc-
yclobut-1 enyl)amino]propanoic acid;
(S)-3-{4[(6,7-Dimethoxy4qunazolinyl)a-
mino]phenyl}2-[(2-N,N-diethylamino-3,4-dioxocyclobut-1-enyl)amino]propanoi-
c acid;
(S)-3-[4-([2,6-Naphthyridin-1-yl]amino)phenyl]-2-[(2-N,N-diethylam-
ino-3,4-dioxocyclobut-1-enyl)amino]propanoic acid;
(S)-3-[4-([6,7-Dimethox-
y-4qunazolinyl)oxy]phenyl]-2-[(2-N,N-diethylamino-3,4-dioxocyclobut-1-enyl-
)amino]propanoic acid;
(S)-3-[4-([6,7-Methoxy4-qunazolinyl]amino)phenyl]-2-
[(2-N,N-diethylamino-3,4-dioxocyclobut-1-enyl)amino]propanoic acid;
(S)-3-[4-([2,6-Naphthyridin-1-yl]amino)phenyl]-2-[(2-N,N-dipropylamino-3,-
4-dioxocyclobut-1enyl)amino]propanoic acid;
(S)-3-[4-([2,6-Naphthyridin-1--
yl]oxy)phenyl]-2-[(2-N,N-diethylamino-3,4-dioxocyclobut-1-enyl)amino]propa-
noic acid;
(S)-3-[4-([2,6-Naphthyridin-1-yl]amino)phenyl]-2-[(2-piperidin--
1-yl-3,4-dioxocyclobut-1-enyl)amino]propanoic acid;
(R)-3-{4-(3,5-Dichloro4-pyridylcarboxamido)phenyl)}3-[(2-N,N-diethylamino-
-3,4-dioxocyclobut-1-enyl)amino]propanoic acid;
(S)-3-[4-([2,6-Naphthyridi-
n-1-yl]oxy)phenyl]-2-[(2-N,N-dipropylamino-3,4-dioxocyclobut-1-enyl)amino]-
propanoic acid;
(S)-3-[4([2,6-Naphthyridin-1-yl]amino)phenyl]-2-[(2-N,
-ethyl-N-isopropylamino3,4-dioxocyclobut-1-enyl)amino]propanoic
acid; and the salts, solvates, hydrates and N-oxides thereof.
24. A pharmaceutical composition comprising a compound according to
Claim 1 together with one or more pharmaceutically acceptable
carriers, excipients or diluents.
Description
[0001] This invention relates to a series of squaric acid
derivatives, to compositions containing them, to processes for
their preparation, and to their use in medicine.
[0002] Over the last few years it has become increasingly clear
that the physical interaction of inflammatory leukocytes with each
other and other cells of the body plays an important role in
regulating immune and inflammatory responses [Springer, T A.
Nature, X, 425, (1990); Springer, T. A. Cell 76, 301, (1994)]. Many
of these interactions are mediated by specific cell surface
molecules collectively referred to as cell adhesion molecules.
[0003] The adhesion molecules have been sub-divided into different
groups on the basis of their structure. One family of adhesion
molecules which is believed to play a particularly important role
in regulating immune and inflammatory responses is the integrin
family. This family of cell surface glycoproteins has a typical
non-covalently linked heterodimer structure. At least 14 different
integrin alpha chains and 8 different integrin beta chains have
been identified [Sonnenberg, A Current Topics in Microbiology and
Immunology, 184, 7, (1993)]. The members of the family are
typically named according to their heterodimer composition although
trivial nomenclature is widespread in this field. Thus the integrin
termed .alpha.4.beta.1 consists of the integrin alpha 4 chain
associated with the integrin beta 1 chain, but is also widely
referred to as Very Late Antigen 4 or VLA4.
[0004] Some integrin chains are capable of pairing with more than
one partner. For example, the .alpha..sub.v chain has been reported
to pair with the beta 1 chain, the beta 3 chain, the beta 5 chain,
the beta 6 chain and the beta 8 chain to give molecules which bind
to different sets of ligands and which are referred to respectively
as the integrins
.alpha..sub.v.beta..sub.1,.alpha..sub.v.beta..sub.3,
.alpha..sub.v.beta..sub.5, .alpha..sub.v.beta..sub.6, and
.alpha..sub.v.beta..sub.8. Not all of the potential pairings of
integrin alpha and beta chains have yet been observed in nature and
the integrin family has been subdivided into a number of subgroups
based on the pairings that have been recognised [Sonnenberg, A.
ibid].
[0005] The importance of integrin function in normal physiological
responses is highlighted by two human deficiency diseases in which
integrin function is defective. Thus in the disease termed
Leukocyte Adhesion Deficiency (LAD) there is a defect in one of the
families of integrins expressed [on leukocytes. Patients suffereing
from this disease have a reduced ability to recruit leukocytes to
inflammatory sites and suffer recurrent infections which in extreme
cases may be fatal. In the case of patients suffering from the
disease termed Glanzman's thrombasthenia,(a defect in a member of
the beta 3 integer famly) there is a defect in blood clotting.
[0006] The potential to modify integrin function in such a way as
to beneficially modulate cell adhesion has been extensively
investigated in animal models using specific monoclonal antibodies
and peptides that block various functions of these molecules [e.g.
Issekutz, T. B. J. Immunol. 3394, (1992); Li, Z. et al. Am. J.
Physiol. 263, L723, (1992); Mitjans et al J. Cell Sci. 108, 2825
(1995), Brooks P.C. et al J. Clin. Invest. 96, 1815 (1995), Binns,
R. M. et al J. Immunol. 157, 4094, (1996), Hammes, H-P, et al
Nature Medicine 2, 529 (1996), Srivata, S. et al Cardiovascular
Res. 3, 408 (1997)]. A number of monoclonal antibodies which block
integrin function are currently being investigated for their
therapeutic potential in human disease.
[0007] Inhibition of integrin-mediated cell interaction can be
expected to be beneficial in a number of disease states, and in
addition to the monoclonal antibodies and peptides just mentioned
there has been great interest in selective low molecular weight
inhibitors of integrin function. Thus, for example selective
.alpha..sub.4 integrin inhibitors have been described in
International patent Specifications Nos. WO96122966, WO97/03094, WO
98/04247, WO98/04913, WO98/53814, WO98/53817, WO98/53818,
WO98/54207, WO98/58902, WO99/06390, WO99/06431-06437, WO99/10312,
WO99/10313, WO99/67230, WO 99/26922, WO99/60015, WO99/26921,
WO9936393, WO99/52898 and WO99/64395. Numerous selective
.alpha..sub.v integrin inhibitors have also been described, for
example in International Patent Specifications Nos. WO97/08145,
WO97/23480, WO97/36858, WO97/36859, WO97/36861, WO97/36862,
WO97/44333, WO97/47618, WO98/31359, WO98/25892, WO98/18460,
WO99/44994, WO99/30709, WO99/31061, WO 99126945, WO99152896,
WO99/52879, WO99/32457, WO99/31099, WO00/07544, WO00/00486,
WO00/06169, WO0/17197 and WO00/01383.
[0008] While it is clearly possible to obtain selective integrin
inhibitors, their usefulnesses in medicine may be limited due to
poor pharmacokinetic properties. Thus, for example, in our hands,
integrin inhibitors falling within the general structural types
featured in the above-mentioned patent specifications are not
particularly attractive for development as medicines since they can
be cleared rapidly from the body. In order to overcome this problem
we have made use of a squaric acid framework which can be readily
adapted to provide potent and selective integrin inhibitors using
recognised integrin binding groups (for example as described herein
and in the patent specifications listed above), which
advantageously possess good pharmacokinetic properties, especially
low plasma clearance.
[0009] Thus according to one aspect of the invention we provide a
compound of formula (1) 2
[0010] wherein
[0011] R.sup.1 is an integrin binding group;
[0012] R.sup.2 is a hydrogen atom or a C.sub.1-6alkyl group;
[0013] L.sup.1 is a covalent bond or a linker atom or group;
[0014] n is zero or the integer 1;
[0015] Alk.sup.1 is an optionally substituted aliphatic chain;
[0016] R.sup.3 is a hydrogen atom or an optionally substituted
heteroaliphatic, cycloaliphatic, heterocycloaliphatic,
polycycloaliphatic, polyheterocycloaliphatic, aromatic or
heteroaromatic group:
[0017] and the salts, solvates, hydrates and N-oxides thereof.
[0018] It will be appreciated that compounds of formula (1) may
have one or more chiral centres, and exist as enantiomers or
diastereomers. The invention is to be understood to extend to all
such enantiomers, diastereomers and mixtures thereof, including
racemates. Formula (1) and the formulae hereinafter are intended to
represent all individual isomers and mixtures thereof. unless
stated or shown otherwise.
[0019] In the compounds according to the invention,
integrin-binding groups represented by R.sup.1 include for example
those which are able to bind .alpha..sub.4- or
.alpha..sub.v-integrins. Particular examples of such integrins
include .alpha..sub.4.beta..sub.1, .alpha..sub.4.beta..sub- .7 and
.alpha..sub.v.beta..sub.3 integrins.
[0020] In general, the term integrin-binding group is used herein
in relation to R.sup.1 to mean any group which when part of the
compound of formula (1) is able to interact with an integrin to
modulate cell adhesion in vivo and achieve a therapeutic response.
Typically the R.sup.1 group may bind to the integrin in such a way
that it modulates the interaction of the integrin with its ligand.
Thus for example the R.sup.1 group may inhibit binding of the
ligand and decrease cell adhesion. Such a response enables
appropriate R.sup.1 groups to be readily identified using small
scale routine in vitro screening assays to determine the degree of
inhibition of integrin-ligand binding in the presence of a compound
of formula (1). Examples of such screening assays are widely
reported in the literature, for example in the papers and
International patent specifications described above, and in the
Examples hereinafter.
[0021] Thus in general R.sup.1 may be any group which when present
in a compound of formula (1) is able to bind to an integrin such
that the compound of formula (1) inhibits the binding of the
integrin with its ligand with an IC.sub.50 of 10 .mu.M or below,
particularly 1 .mu.M or below, especially 500 nM or below, e.g. in
the range 0.001-500 nM.
[0022] Particular R.sup.1 groups in compounds of the invention
include those of formula Ar.sup.1L.sup.2Ar.sup.2Alk- wherein
Ar.sup.1 is an optionally substituted aromatic or heteroaromatic
group, L.sup.2 is a linker atom or group, Ar.sup.2 is an optionally
substituted phenylene or nitrogen-containing six-membered
heteroarylene group and Alk is a chain: 3
[0023] where R is a carboxylic acid (--CO.sub.2H) or a derivative
or biostere thereof. R.sup.1 groups of this type are particularly
useful for binding .alpha..sub.4 integrins and compounds of formula
(1) incorporating the Ar.sub.1L.sup.2Ar.sup.2Alk- function can be
expected to inhibit (.alpha..sub.4 integrins such as
.alpha..sub.4.beta..sub.1 and/or .alpha..sub.4.beta..sub.7 at
concentrations at which they generally have no or minimal
inhibitory action on integrins of other ax subgroups. Such
compounds are of use in medicine, for example in the prophylaxis
and treatment of immune or inflammatory disorders as described
hereinafter.
[0024] Optionally substituted aromatic groups represented by
Ar.sub.1 when present in the group R.sup.1 include for example
optionally substituted monocyclic or bicyclic fused ring C.sub.6-12
aromatic groups, such as phenyl, 1- or 2-naphthyl, 1- or
2-tetrahydronaphthyl, indanyl or indenyl groups.
[0025] Optionally substituted heteroaromatic groups represented by
the group Ar.sup.1 when present in the group R.sup.1 include for
example optionally substituted C.sub.1-9 heteroaromatic groups
containing for example one, two, three or four heteroatoms selected
from oxygen, sulphur or nitrogen atoms. In general, the
heteroaromatic groups may be for example monocyclic or bicyclic
fused ring, heteroaromatic groups. Monocyclic heteroaromatic groups
include for example five- or six-membered heteroaromatic groups
containing one, two, three or four heteroatoms selected from
oxygen, sulphur or nitrogen atoms. Bicyclic heteroaromatic groups
include for example eight- to thirteen-membered fused-ring
heteroaromatic groups containing one, two or more heteroatoms
selected from oxygen, sulphur or nitrogen atoms.
[0026] Particular examples of heteroaromatic groups of these types
include pyrrolyl, furyl, thienyl, imidazolyl,
N--C.sub.1-16alkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,
1,3,4-oxadiazolyl, 1,3,4-thiadiazole, pyridyl, pyrimidinyl,
pyridazinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl,
1,2,3-triazinyl, benzofuryl, [2,3-dihydro]benzofuryl,
[2,3-dihydro]benzothienyl, benzothienyl, benzotriazolyl, indolyl,
isoindolyl, benzimidazolyl, imidazo[1,2-a]pyridyl, benzothiazolyl,
benzoxazolyl, benzopyranyl, [3,4-dihydro]benzopyranyl,
quinazolinyl, qiunoxalinyl, naphthyridinyl, especially
2,6-naphthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl,
pyrido[4,3-b]-pyridyl, quinolinyl, isoquinolinyl, tetrazolyl,
5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetrahydroisoquinolinyl, and
imidyl, e.g. succinimidyl, phthalimidyl, or naphthalimidyl such as
1,8-naphthalimidyl.
[0027] Each aromatic or heteroaromatic group represented by the
group Ar.sup.1 may be optionally substituted on any available
carbon or, when present, nitrogen atom. One, two, three or more of
the same or different substituents may be present and each
substituent may be selected for example from an atom or group
-L.sup.3(Alk.sup.2).sub.tL.sup.4(R.sup.4).s- ub.u in which L.sup.3
and L.sup.4, which may be the same or different, is each a covalent
bond or a linker atom or group, t is zero or the integer 1, u is an
integer 1, 2 or 3, Alk.sup.2 is an aliphatic or heteroaliphatic
chain and R.sup.4 is a hydrogen or halogen atom or a group selected
from optionally substituted C.sub.1-6alkyl or C.sub.3-8 cycloalkyl,
--OR.sup.5 [where R.sup.5 is a hydrogen atom, an optionally
substitued C.sub.1-6alkyl or C.sub.3-8 cycloalkyl group],
--SR.sup.5, --NR.sup.5R.sup.6 [where R.sup.6 is as just defined for
R.sup.5 and may be the same or different], --NO.sub.2, --CN,
--CO.sub.2R.sup.5, --SO.sub.3H, --SOR.sup.5, --SO.sub.2R.sup.5,
--SO.sub.3R.sup.5, --OCO.sub.2R.sup.5, --CONR.sup.5R.sup.6,
--OCONR.sup.5R.sup.6, --CSNR.sup.5R.sup.6--COR.sup.5, --OCOR.sup.5,
--N(R.sup.5)COR.sup.6, --N(R.sup.5)CSR.sup.6,
--SO.sub.2N(R.sup.5)(R.sup.6), --N(R.sup.5)SO.sub.2RS,
N(R.sup.5)CON(R.sup.6)(R.sup.7) [where R.sup.7 is a hydrogen atom,
an optionally substituted C.sub.1-6alkyl or C.sub.3-8cycloalkyl
group], --N(R.sup.5)CSN(R.sup.6)(R.sup.7) or
--N(R.sup.5)SO.sub.2N(R.sup.6)(R.sup.7), provided that when t is
zero and each of L.sup.3 and L.sup.4 is a covalent bond then u is
the integer 1 and R.sup.4 is other than a hydrogen atom.
[0028] When L.sup.3 and/or L.sup.4 is present in these substituents
as a linker atom or group it may be any divalent linking atom or
group. Particular examples include --O-- or --S-- atoms or
--C(O)--, --C(O)O--, --OC(O)--, --C(S)--, --S(O)--, --S(O).sub.2--,
--N(R.sup.8)-[where R.sup.8 is a hydrogen atom or an optionally
substituted C.sub.1-6alkyl group], --N(R.sup.8)O--, --N(R.sup.8)N--
--CON(R.sup.8)--, --OC(O)N(R.sup.8)--, --CSN(R.sup.8)--,
--N(R.sup.8)CO--, --N(R.sup.8)C(O)O--, --N(R.sup.8)CS--,
--S(O).sub.2N(R.sup.8)--, --N(R.sup.8)S(O).sub.2--,
--N(R.sup.8)CON(R.sup.8)--, --N(R.sup.8)CSN(R.sup.8)--, or
--N(R.sup.8)SO.sub.2N(R.sup.8)-- groups. Where the linker group
contains two R.sup.8 substituents, these may be the same or
different.
[0029] When R.sup.4, R.sup.5, R.sup.6, R.sup.7 and/or R.sup.8 is
present as a C.sub.1-6alkyl group it may be a straight or branched
C.sub.1-6alkyl group, e.g. a C.sub.1-3alkyl group such as a methyl
or ethyl group. C.sub.3-8cycloalkyl groups represented by R.sup.4,
R.sup.5, R.sup.6, R.sup.7 and/or R.sup.8 include
C.sub.3-6cycloalkyl groups e.g. cyclopropyl, cyclobutyl,
cyclopentyl and cyclohexyl groups. Optional substituents which may
be present on such alkyl and cycloalkyl groups include for example
one, two or three substituents which may be the same or different
selected from halogen atoms, for example fluorine, chlorine,
bromine or iodine atoms, or hydroxy or C.sub.1-6alkoxy e.g. methoxy
or ethoxy groups.
[0030] When the groups R.sup.5 and R.sup.6 or R.sup.6 and R.sup.7
are both C.sub.1-6alkyl groups these groups may be joined, together
with the N atom to which they are attached, to form a heterocyclic
ring. Such heterocyclic rings may be optionally interrupted by a
further heteroatom selected from --O--, --S-- or --N(R.sup.5)--.
Particular examples of such heterocyclic rings include piperidinyl,
morpholinyl, thiomorpholinyl, pyrrolidinyl, imidazolidinyl and
piperazinyl rings.
[0031] When Alk.sup.2 is present as an aliphatic or heteroaliphatic
chain it may be for example any, divalent chain corresponding to
the below-mentioned aliphatic or heteroaliphatic group described
for Alk.sup.1 or R.sup.3 respectively.
[0032] Halogen atoms represented by R.sup.4 in the optional
Ar.sup.1 substituents include fluorine, chlorine, bromine, or
iodine atoms.
[0033] Examples of the substituents represented by
-L.sup.3(Alk.sup.2).sub- .tL.sup.4(R.sup.4).sub.u when present in
Ar.sup.1 groups in compounds of the invention include atoms or
groups -L.sup.3Alk.sup.2L.sup.4R.sup.4, -L.sup.3Alk.sup.2R.sup.4,
-L.sup.3R.sup.4, --R.sup.4 and -Alk.sup.2R.sup.4 wherein L.sup.3,
Alk.sup.2, L.sup.4 and R.sup.4 are as defined above. Particular
examples of such substituents include
-L.sup.3CH.sub.2L.sup.4R.sup.4, -L.sup.3CH(CH.sub.3)L.sup.4R.sup.4,
-L.sup.3CH(CH.sub.2).sub.2L.sup.4R.sup.4, -L.sup.3CH.sub.2R.sup.4,
-L.sup.3CH(CH.sub.3)R.sup.4, -L.sup.3(CH.sub.2).sub.2R.sup.4,
--CH.sub.2R.sup.4, --CH(CH.sub.3)R.sup.4, --(CH.sub.2).sub.2R.sup.4
and --R.sup.4 groups.
[0034] Thus Ar.sup.1 in compounds of the invention may be
optionally substituted for example by one, two, three or more
halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms,
and/or C.sub.1-6alkyl, e.g. methyl, ethyl, n-propyl, i-propyl,
n-butyl or t-butyl, C.sub.3-8cycloalkyl, e.g. cyclopropyl,
cyclobutyl, cyclopentyl or cyclohexyl, C.sub.1-6hydroxyalkyl, e.g.
hydroxymethyl, hydroxyethyl or --C(OH)(CF.sub.3).sub.2,
carboxyC.sub.1-6alkyl, e.g. carboxyethyl, C.sub.1-6alkylthio e.g.
methylthio or ethylthio, carboxyC.sub.1-6alkylthi- o, e.g.
carboxymethylthio, 2-carboxyethylthio or 3-carboxy-propylthio,
C.sub.1-6alkoxy, e.g. methoxy or ethoxy, hydroxyC.sub.1-6alkoxy,
e.g. 2-hydroxyethoxy, haloC.sub.1-6alkyl, e.g. --CF.sub.3,
--CHF.sub.2, CH.sub.2F, haloC.sub.1-6alkoxy, e.g. --OCF.sub.3,
--OCHF.sub.2, --OCH.sub.2F, C.sub.1-6alkylamino, e.g. methylamino
or ethylamino, amino (--NH.sub.2), aminoC.sub.1-6alkyl, e.g.
aminomethyl or aminoethyl, C.sub.1-6dialkylamino, e.g.
dimethylamino or diethylamino, C.sub.1-6alkylaminoC.sub.1-6alkyl,
e.g. ethylaminoethyl, C.sub.1-6 dialkylaminoC.sub.1-6alkyl, e.g.
diethylaminoethyl, aminoC.sub.1-6alkoxy, e.g. aminoethoxy,
C.sub.1-6alkylaminoC.sub.1-6alkoxy, e.g. methylaminoethoxy,
C.sub.1-6dialkylaminoC.sub.1-6alkoxy, e.g. dimethylaminoethoxy,
diethylaminoethoxy, isopropylaminoethoxy, or dimethylaminopropoxy,
nitro, cyano, amidino, hydroxyl (--OH), formyl [HC(O)-], carboxyl
(--CO.sub.2H), --CO.sub.2Alk.sup.3 (where Alk.sup.3 is as defined
below for Alk.sup.7], C.sub.1-6 alkanoyl e.g. acetyl, thiol (--SH),
thioC.sub.1-6alkyl, e.g. thiomethyl or thioethyl, sulphonyl
(--SO.sub.3H), --SO.sub.3Alk.sup.3, C.sub.1-6alkylsulphinyl, e.g.
methylsulphinyl, C.sub.1-6alkylsulphonyl, e.g. methylsulphonyl,
aminosulphonyl (--SO.sub.2NH.sub.2), C.sub.1-6 alkylaminosulphonyl,
e.g. methylaminosulphonyl or ethylaminosulphonyl,
C.sub.1-6dialkylaminosulphon- yl, e.g. dimethylaminosulphonyl or
diethylaminosulphonyl, phenylaminosulphonyl, carboxamido
(--CONH.sub.2), C.sub.1-6alkyl aminocarbonyl, e.g.
methylaminocarbonyl or ethylaminocarbonyl,
C.sub.1-6dialkylaminocarbonyl, e.g. dimethylaminocarbonyl or
diethylaminocarbonyl, aminoC.sub.1-6alkylaminocarbonyl, e.g.
aminoethylaminocarbonyl,
C.sub.1-6dialkylaminoC.sub.1-6alkylaminocarbonyl- , e.g.
diethylaminoethylaminocarbonyl, aminocarbonylamino,
C.sub.1-6alkylaminocarbonylamino, e.g. methylaminocarbonylamino or
ethylaminocarbonylamino, C.sub.1-6dialkylaminocarbonylamino, e.g.
dimethylaminocarbonylamino or diethylaminocarbonylamino,
C.sub.1-6alkylaminocabonylC.sub.1-6 alkylamino, e.g.
methylaminocarbonylmethylamino aminothiocarbonylamino,
C.sub.1-6alkylaminothiocarbonylamino, e.g.
methylaminothiocarbonylamino or athylaminothiocarbonylamino,
C.sub.1-6dialkylaminothiocarbonylamino, e.g.
dimethylaminothiocarbonylamino or diethylaminothiocarbonylamino,
C.sub.1-6alkylaminothiocarbonylC.sub.1-6alkylamino, e.g.
ethylaminothiocarbonylmethylamino, C.sub.1-6alkylsulphonytamino,
e.g. methylsulphonylamino or ethylsulphonylemino,
C.sub.1-6dialkylsulphonylami- no, e.g. dimethylsulphonylamino or
diethyl-sulphonylamino, aminosulphonylamino (--NHSO.sub.2NH.sub.2),
C.sub.1-6alkylamino-sulphonyl- amino, e.g.
methylaminosulphonylamino or ethylaminosulphonylamino,
C.sub.1-6dialkylaminosulphonylamino, e.g.
dimethylaminosulphonylamino or diethylaminosulphonylamino,
C.sub.1-6alkanoylamino, e.g. acetylamino,
aminoC.sub.1-6alkanoylamino e.g. aminoocetylamino,
C.sub.1-6dialkylaminoC.sub.1-6alkanoylamino, e.g.
dimethylaminoacetylamin- o, C.sub.1-6alkanoylaminoC.sub.1-6alkyl,
e.g. acetylaminomethyl, C.sub.1-6alkanoylaminoC.sub.1-6alkylamino,
e.g. acetamidoethylamino, C.sub.1-6alkoxycarbonylamino, e.g:
methoxycarbonylamino, ethoxycarbonylamino or t-butoxycarbonylamino
groups.
[0035] L.sup.2 when present as part of the group R.sup.1 in
compounds of the invention may be a linker atom or group L.sup.2a
or a linker -Alk.sup.a(L.sup.2a).sub.y-, where Alk.sup.a is an
optionally substituted aliphatic or heteroaliphatic chain as
previously defined for Alk.sup.2, and L.sup.2a is a linker atom or
group as described above for L.sup.3 and L.sup.4 and y is zero or
the integer 1.
[0036] Optionally substituted nitrogen-containing six-membered
heteroarylene groups represented by Ar.sup.2 when present as part
of the group R.sup.1 include optionally substituted pyridiyl,
pyrimidindiyl, pyridazindiyl, pyrazindiyl and triazindiyl groups.
Each group may be attached to the remainder of the molecule through
any available ring carbon atoms.
[0037] The phenylene and nitrogen-containing heteroarylene groups
represented by Ar.sup.2 may be optionally substituted by one or two
substituents selected from the atoms or groups
-L.sup.3(Alk.sup.2).sub.tL- .sup.4(R.sup.4).sub.u described herein.
Where two of these atoms or groups are present they may be the same
or different.
[0038] When the group R is present in R.sup.1 in compounds of the
invention as a derivative of a carboxylic acid it may be for
example a carboxylic acid ester or amide. Particular esters and
amides include --CO.sub.2Alk.sup.7 and --CONR.sup.5R.sup.6 groups
as defined herein. When R is a biostere of a carboxylic acid it may
be for example a tetrazole or other acid such as phosphonic acid,
phosphinic acid, sulphonic acid, sulphinic acid or boronic acid or
an acylsulphonamide group.
[0039] When the group R.sup.2 is present in compounds of the
invention as a C.sub.1-6alkyl group it may be for example a
straight or branched C.sub.1-6alkyl group, e.g. a C.sub.1-3alkyl
group such as a methyl or ethyl group.
[0040] The linker atom or group represented by L.sup.1 in compounds
of formula (1) may be any linker atom or group as described above
for the linker atom or group L.sup.3.
[0041] When the group Alk.sup.1 is present in compounds of formula
(1) as an optionally substituted aliphatic chain it may be an
optionally substituted C.sub.1-10 aliphatic chain. Particular
examples include optionally substituted straight or branched chain
C.sub.1-6 alkylene, C.sub.2-6 alkenylene, or C.sub.2-6 alkynylene
chains.
[0042] Particular examples of aliphatic chains represented by
Alk.sup.1 include optionally substituted --CH.sub.2--,
--(CH.sub.2).sub.2--, --CH(CH.sub.3)CH.sub.2--,
--(CH.sub.2).sub.2CH.sub.2--, --(CH.sub.2).sub.3CH.sub.2--,
--CH(CH.sub.3)(CH.sub.2).sub.2--, --CH.sub.2CH(CH.sub.3)CH.sub.2--,
--C(CH.sub.3).sub.2CH.sub.2--,
--CH.sub.2C(CH.sub.3).sub.2CH.sub.2--,
--(CH.sub.2).sub.2C(CH.sub.3).sub.- 2CH.sub.2--,
--(CH.sub.2).sub.4CH.sub.2--, --(CH.sub.2).sub.5CH.sub.2--,
--CHCH--, --CHCHCH.sub.2--, --CH.sub.2CHCH--,
--CHCHCH.sub.2CH.sub.2--, --CH.sub.2CHCHCH.sub.2--,
--(CH.sub.2).sub.2CHCH--, --CC--, --CCCH.sub.2--, --CH.sub.2CC--,
--CCCH.sub.2CH.sub.2--, --CH.sub.2CCCH.sub.2-- or
--(CH.sub.2).sub.2CCH-- groups.
[0043] Heteroaliphatic groups represented by the group R.sup.3 in
the compounds of formula (1) include the aliphatic chains just
described for Alk.sup.1 but with each containing a terminal
hydrogen atom and additionally containing one, two, three or four
heteroatoms or heteroatom-containing groups. Particular heteroatoms
or groups include atoms or groups L.sup.5 where L.sup.5 is as
defined above for L.sup.3 when L.sup.3 is a linker atom or group.
Each L.sup.5 atom or group may interrupt the aliphatic group, or
may be positioned at its terminal carbon atom to connect the group
to an adjoining atom or group. Particular examples include
optionally substituted -L.sup.5CH.sub.3, --CH.sub.2L.sup.5CH.sub.3,
-L.sup.5CH.sub.2CH.sub.3, --CH.sub.2L.sup.5CH.sub.2CH.sub.3,
--(CH.sub.2).sub.2L.sup.5CH.sub.3,
--(CH.sub.2).sub.3L.sup.5CH.sub.3, -L.sup.5(CH.sub.2).sub.3, and
--(CH.sub.2).sub.2L.sup.5CH.sub.2CH.sub.3 groups.
[0044] The optional substituents which may be present on aliphatic
or heteroaliphatic chains represented by Alk.sup.1 and R.sup.3
respectively include one, two, three or more substituents where
each substituent may be the same or different and is selected from
halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or
--OH, --CO.sub.2H, --CO.sub.2R.sup.9, where R.sup.9 is an
optionally substituted straight or branched C.sub.1-6alkyl group as
defined above for R.sup.4, --CONHR.sup.9, --CON(R.sup.a).sub.2,
--COCH.sub.3, C.sub.1-6alkoxy, e.g. methoxy or ethoxy, thiol,
--S(O)R.sup.9, --S(O).sub.2R.sup.9, C.sub.1-6alkylthio e.g.
methylthio or ethylthio, amino or substituted amino groups.
Substituted amino groups include --NHR.sup.9 and --N(R.sup.9).sub.2
groups. Where two R.sup.9 groups are present in any of the above
substituents these may be the same or different.
[0045] Optionally substituted cycloaliphatic groups represented by
the group R.sup.3 in compounds of the invention include optionally
substituted C.sub.3-10 cycloaliphatic groups. Particular examples
include optionally substituted C.sub.3-10 cycloalkyl, e.g.
C.sub.3-7 cycloalkyl or C.sub.3-10 cycloalkenyl, e.g C.sub.3-7
cycloalkenyl groups.
[0046] Optionally substituted heterocycloaliphatic groups
represented by the group R.sup.3 include optionally substituted
C.sub.3-10heterocycloali- phatic groups. Particular examples
include optionally substituted C.sub.3-10heterocycloalkyl, e.g.
C.sub.3-7 heterocycloalkyl, or C.sub.3-10heterocycloalkenyl, e.g.
C.sub.3-7 hetercycloalkenyl groups, each of said groups containing
one, two, three or four heteroatoms or heteroatom-containing groups
L.sup.5 as defined above.
[0047] Optionally substituted polycycloaliphatic groups represented
by the group R.sup.3 include optionally substitued C.sub.7-10 bi-
or tricycloalkyl or C.sub.7-10bi- or tricycloalkenyl groups.
Optionally substituted polyheterocycloaliphatic groups represented
by the group R.sup.3 include the optionally substituted
polycycloalkyl groups just described, but with each group
additionally containing one, two, three or four L.sup.5 atoms or
groups.
[0048] Particular examples of cycloaliphatic, polycycloaliphatic,
heterocycloaliphatic and polyheterocycloaliphatic groups
represented by the group R.sup.3 include optionally substituted
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
2-cyclobuten-1-yl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl,
adamantyl, norbornyl, norbornenyl, tetrahydrofuranyl, pyrroline,
e.g. 2- or 3-pyrrolinyl, pyrrolidinyl, pyrrolidinone, oxazolidinyl,
oxazolidinone, dioxolanyl, e.g. 1,3-dioxolanyl, imidazolinyl, e.g.
2-imidazolinyl, imidazolidinyl, pyrazolinyl, e.g. 2-pyrazolinyl,
pyrazolidinyl, pyranyl, e.g. 2- or 4-pyranyl, piperidinyl,
piperidinone, 1,4-dioxanyl, morpholinyl, morpholinone,
1,4-dithianyl, thiomorpholinyl, piperazinyl, 1,3,5-trithianyl,
oxazinyl, e.g. 2H-1,3-, 6H-1,3-, 6H-1,2-, 2H-1,2- or
4H-1,4-oxazinyl, 1,2,5-oxathiazinyl, isoxazinyl, e.g. o- or
p-isoxazinyl, oxathiazinyl, e.g. 1,2,5 or 1,2,6-oxathiazinyl, or
1,3,5,-oxadiazinyl groups.
[0049] The optional substituents which may be present on the
cycloaliphatic, polycycloaliphatic, heterocycloaliphatic or
polyheterocycloaliphatic groups represented by the group R.sup.3
include one, two, three or more substituents each selected from
halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or
C.sub.1-6alkyl, e.g. methyl or ethyl, haloC.sub.1-6alkyl, e.g.
halomethyl or haloethyl such as difluoromethyl or trifluoromethyl,
optionally substituted by hydroxyl, e.g. --C(OH)(CF.sub.3).sub.2,
C.sub.1-6alkoxy, e.g. methoxy or ethoxy, haloC.sub.1-6alkoxy, e.g.
halomethoxy or haloethoxy such as difluoromethoxy or
trifluoromethoxy, thiol, C.sub.1-6alkylthio e.g. methylthio or
ethylthio, or -(Alk.sup.4).sub.vR.sup.10 groups in which Alk.sup.4
is a straight or branched C.sub.1-3alkylene chain, v is zero or an
integer 1 and R.sup.10 is a --OH, --SH, --N(R.sup.11).sub.2, (in
which R.sup.11 is an atom or group as defined herein for R.sup.8)
--CN, --CO.sub.2R.sup.11, --NO.sub.2, --CON(R.sup.11).sub.2,
--CSN(R.sup.11).sub.2, --COR.sup.11, --CSN(R.sup.11).sub.2,
--N(R.sup.11)COR.sup.1 1, --N(R.sup.11)CSR.sup.11,
--SO.sub.2N(R.sup.11).sub.2, --N(R 1)SO.sub.2R.sup.11,
--N(R.sup.11)CON(R.sup.11).sub.2, --N(R.sup.11)CSN(R.sup.11),
N(R.sup.11)SO.sub.2N(R.sup.11).sub.2 or optionally substituted
phenyl group. Where two R.sup.11 atoms or groups are present in
these substituents these may be the same or different. Optionally
substituted phenyl groups include phenyl substituted by one, two or
three of the R.sup.13 groups described below
[0050] Additionally, when the group R.sup.3 is a
heterocycloaliphatic group containing one or more nitrogen atoms
each nitrogen atom may be optionally substituted by a group
-(L.sup.6).sub.p(Alk.sup.5).sub.qR.sup.- 12 in which L.sup.6 is
--C(O)--, --C(O)O--, --C(S)--, --S(O).sub.2--, --CON(R.sup.11)--,
--CSN(R.sup.11)-- or SO.sub.2N(R.sup.11)--; p is zero or an integer
1; Alk.sup.5 is an optionally substituted aliphatic or
heteroaliphatic chain; q is zero or an integer 1; and R.sup.12 is a
hydrogen atom or an optionally substituted cycloaliphatic,
heterocycloaliphatic, polycycloaliphatic, polyheterocycloaliphatic,
aromatic or heteroaromatic group.
[0051] Optionally substituted aliphatic or heteroaliphatic chains
represented by Alk.sup.5 include those optionally substituted
chains described above for Alk.sup.1 and R.sup.3 respectively.
[0052] Cycloaliphatic, heterocycloaliphatic, polycycloaliphatic or
polyheterocycloaliphatic groups represented by R.sup.12 include
those groups just described for the group R.sup.3. Optional
substituents which may be present on these groups include those
described above in relation to Alk.sup.1 and R.sup.3 aliphatic and
heteroaliphatic chains.
[0053] When the group R.sup.3 is an optionally substituted aromatic
or heteroaromatic group it may be for example an aromatic or
heteroaromatic group as described herein for the group
Ar.sup.1.
[0054] Optional substituents which may be present on the aromatic
or heteroaromatic, groups represented by the group R.sup.3 include
one, two, three or more substituents, each selected from an atom or
group R.sup.13 in which R.sup.13 is --R.sup.13a or
-Alk.sup.6(R.sup.13a).sub.m, where R.sup.13a is a halogen atom, or
an amino (--NH.sub.2), substituted amino, nitro, cyano, amidino,
hydroxyl (--OH), substituted hydroxyl, formyl, carboxyl
(--CO.sub.2H), esterified carboxyl, thiol (--SH), substituted
thiol, --COR.sup.14 [where R.sup.14 is an
-Alk.sup.6(R.sup.13a).sub.m, cycloaliphatic, heterocycloaliphatic,
aryl or heteroaryl group], --CSR.sup.14, --SO.sub.3H, --SOR.sup.14,
--SO.sub.2R.sup.14, --SO.sub.3R.sup.14, --SO.sub.2NH.sub.2,
--SO.sub.2NHR.sup.14 SO.sub.2N(R.sup.14).sub.2, --CONH.sub.2,
--CSNH.sub.2, --CONHR.sup.14, --CSNHR.sup.14, --CON[R.sup.14]2,
--CSN(R.sup.14).sub.2, --N(R.sup.11)SO.sub.2R.sup.14,
--N(SO.sub.2R.sup.14).sub.2, --NH(R.sup.11)SO.sub.2NH.sub.2,
--N(R.sup.11)SO.sub.2NHR.sup.14,
--N(R.sup.11)SO.sub.2N(R.sup.14).sub.2, --N(R.sup.11)COR.sup.14,
--N(R.sup.11)CONH.sub.2, --N(R.sup.11)CONHR.sup.14,
--N(R.sup.11)CON(R.sup.14), --N(R.sup.11)CSNH.sub.2,
--N(R.sup.11)CSNHR.sup.14, --N(R.sup.11)CSN(R.sup.14).sub.2,
--N(R.sup.11)CSR.sup.14, --N(R.sup.11)C(O)OR.sup.14,
--SO.sub.2NHet.sup.1 [where --NHet.sup.1 is an optionally
substituted C.sub.5-7cyclicamino group optionally containing one or
more other --O-- or --S-- atoms or --N(R.sup.11)--, --C(O)--,
--C(S)--, S(O) or --S(O).sub.2 groups], --CONHet.sup.1,
--CSNHet.sup.1, --N(R.sup.11)SO.sub.2NHet.sup.1,
--N(R.sup.11)CONHet.sup.1, --N(R.sup.11)CSNHet.sup.1.
--SO.sub.2N(R.sup.11)Het.sup.2 [where Het.sup.2 is an optionally
substituted monocyclic C.sub.5-7carbocyclic group optionally
containing one or more --O-- or --S-- atoms or --N(R.sup.11)--,
--C(O)-- or --C(S)-- groups], -Het.sup.2, --CON(R.sup.11)Het.sup.2,
--CSN(R.sup.11)Het.sup.2, --N(R.sup.11)CON(R.sup.11)Het.sup.2,
--N(R.sup.11)CSN(R.sup.11)Het.sup.2, cycloaliphatic,
heterocycloaliphatic, aryl or heteroaryl group; Alk.sup.6 is a
straight or branched C.sub.1-6alkylene, C.sub.2-6alkenylene or
C.sub.2-6alkynylene chain, optionally interrupted by one, two or
three --O-- or --S-- atoms or S(O).sub.n [where n is an integer 1
or 2] or --N(R.sup.15)-- groups [where R.sup.15 is a hydrogen atom
or C.sub.1-6alkyl, e.g. methyl or ethyl group]; and m is zero or an
integer 1, 2 or 3. It will be appreciated that when two R.sup.11 or
R.sup.14 groups are present in one of the above substituents, the
R.sup.11 or R.sup.14 groups may be the same or different.
[0055] When in the group -Alk.sup.6(R.sup.13a).sub.m m is an
integer 1, 2 or 3, it is to be understood that the substituent or
substituents R.sup.13a may be present on any suitable carbon atom
in -Alk.sup.6. Where more than one R.sup.13a substituent is present
these may be the same or different and may be present on the same
or different atom in -Alk.sup.6. Clearly, when m is zero and no
substituent R.sup.13a is present the alkylene, alkenylene or
alkynylene chain represented by Alk.sup.6 becomes an alkyl, alkenyl
or alkynyl group.
[0056] When R.sup.13a is a substituted amino group it may be for
example a group --NHR.sup.14 [where R.sup.14 is as defined above]
or a group --N(R.sup.142 wherein each R.sup.14 group is the same or
different.
[0057] When R.sup.13a is a halogen atom it may be for example a
fluorine, chlorine, bromine, or iodine atom.
[0058] When R.sup.13a is a substituted hydroxyl or substituted
thiol group it may be for example a group --OR.sup.14 or a
--SR.sup.14 or --SC(.dbd.NH)NH.sub.2 group respectively. Esterified
carboxyl groups represented by the group R.sup.13a include groups
of formula --CO.sub.2Alk.sup.7 wherein Alk.sup.7 is a straight or
branched, optionally substituted C.sub.1-8alkyl group such as a
methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or
t-butyl group; a C.sub.6-12arylC.sub.1-8alkyl group such as an
optionally substituted benzyl, phenylethyl, phenylpropyl,
1-naphthylmethyl or 2-naphthylmethyl group; a CeC.sub.1-2aryl group
such as an optionally substituted phenyl, 1-naphthyl or 2-naphthyl
group; a C.sub.6-12aryloxyC.sub.1-8alkyl group such as an
optionally substituted phenyloxymethyl, phenyloxyethyl,
1-naphthyloxymethyl, or 2-naphthyloxymethyl group; an optionally
substituted C.sub.1-8alkanoyloxyC.sub.1-8alkyl group, such as a
pivaloyloxymethyl, propionyloxyethyl or propionyloxypropyl group;
or a C.sub.6-12aroyloxyC.sub.1-18alkyl group such as an optionally
substituted benzoyloxyethyl or benzoyloxypropyl group. Optional
substituents present on the Alk.sup.7 group include R.sup.13a
substituents described above.
[0059] When Alk.sup.6 is present in or as a substituent it may be
for example a methylene, ethylene, n-propylene, i-propylene,
n-butylene, i-butylene, s-butylene, t-butylene, ethenylene,
2-propenylene, 2-butenylene, 3-butenylene, ethynylene,
2-propynylene, 2-butynylene or 3-butynylene chain, optionally
interrupted by one, two, or three --O-- or --S--, atoms or
--S(O)--, --S(O).sub.2-- or --N(R.sup.9)-- groups. Cycloaliphatic
or heterocycloaliphatic groups represented by the groups R.sup.13a
or R.sup.14 include those optionally substituted
C.sub.3-10cycloaliphatic or C.sub.3-10 heterocycloaliphatic groups
described above for R.sup.3.
[0060] Aryl or heteroaryl groups represented by the groups
R.sup.13a or R.sup.14 include mono- or bicyclic optionally
substituted C.sub.6-12 aromatic or C.sub.1-9 heteroaromatic groups
as described above for the group Ar.sup.1. The aromatic and
heteroaromatic groups may be attached to the remainder of the
compound of formula (1) by any carbon or hetero e.g. nitrogen atom
as appropriate.
[0061] When --NHet.sup.1 or -Het.sup.2 forms part of a substituent
R.sup.13 each may be for example an optionally substituted
pyrrolidinyl, pyrazolidinyl, piperazinyl, morpholinyl,
thiomorpholinyl, piperidinyl or thiazolidinyl group. Additionally
Het.sup.2 may represent for example, an optionally substituted
cyclopentyl or cyclohexyl group. Optional substituents which may be
present on --NHet.sup.1 or -Het.sup.2 include those R.sup.7
substituents described above.
[0062] Particularly useful atoms or groups represented by R.sup.13
include fluorine, chlorine, bromine or iodine atoms, or
C.sub.1-6alkyl, e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl or
t-butyl, optionally substituted phenyl, pyridyl, pyrimidinyl,
pyrrolyl, furyl, thiazolyl, thienyl, morpholinyl, thiomorpholinyl,
piperazinyl, e.g. t-butyloxycarbonylpiperazinyl, pyrrolidinyl,
dioxolanyl, dioxanyl, oxazolidinyl, thiazolidinyl, imidazolidinyl
or piperidinyl, C.sub.1-6hydroxyalkyl, e.g. hydroxymethyl or
hydroxyethyl, carboxyC.sub.1-6alkyl, e.g. carboxyethyl,
C.sub.1-6alkylthio e.g. methylthio or ethylthio,
carboxyC.sub.1-6alkylthio, e.g. carboxymethylthio,
2-carboxyethylthio or 3-carboxypropylthio, C.sub.1-6alkoxy, e.g.
methoxy or ethoxy, hydroxyC.sub.1-6alkoxy, e.g. 2-hydroxyethoxy,
optionally substituted phenoxy, pyridyloxy, thiazolyoxy, phenylthio
or pyridylthio, C.sub.4-7cycloalkyl, e.g. cyclobutyl, cyclopentyl,
C.sub.5-7cycloalkoxy, e.g. cyclopentyloxy, haloC.sub.1-16alkyl,
e.g. trifluoromethyl, haloC.sub.1-6alkoxy, e.g. trifluoromethoxy,
C.sub.1-6alkylamino, e.g. methylamino, ethylamino or propylamino,
C.sub.6-12arylC.sub.1-6alkylamino, e.g. benzylamino,
4-fluorobenzylamino or 4-hydroxyphenylethylamino, amino
(--NH.sub.2), aminoC.sub.1-6alkyl, e.g. aminomethyl or aminoethyl,
C.sub.1-6dialkylamino, e.g. dimethylamino or diethylamino,
aminoC.sub.1-6alkylamino, e.g. aminoethylamino or aminopropylamino,
optionally substituted Het.sup.1NC.sub.1-6alkylamino, e.g.
3-morpholinopropylamino, C.sub.1-6alkylaminoC.sub.1-6alkyl, e.g.
ethylaminoethyl, C.sub.1-6dialkylaminoC.sub.1-6alkyl, e.g.
diethylaminoethyl, aminoC.sub.1-6alkoxy, e.g. aminoethoxy,
C.sub.1-6alkylaminoC.sub.1-6alkoxy, e.g. methylaminoethoxy,
C.sub.1-6dialkylaminoC.sub.1-6alkoxy, e.g. dimethylaminoethoxy,
diethylaminoethoxy, diisopropylaminoethoxy, or
dimethylaminopropoxy, hydroxyC.sub.1-6alkylamino, e.g.
2-hydroxyethylamino, 3-hydroxypropylamino or 3-hydroxybutylamino,
imido, such as phthalimido or naphthalimido, e.g.
1,8-naphthalimido, nitro, cyano, amidino, hydroxyl (--OH), formyl
[HC(O)--], carboxyl (--CO.sub.2H), --CO.sub.2Alk.sup.7 [where
Alk.sup.7 is as defined above], C.sub.1-6 alkanoyl e.g. acetyl,
propyryl or butyryl, optionally substituted benzoyl, thiol (--SH),
thioC.sub.1-6alkyl, e.g. thiomethyl or thioethyl,
--SC(.dbd.NH)NH.sub.2, sulphonyl (--SO.sub.3H),
--SO.sub.3Alk.sup.7, C.sub.1-6alkylsulphinyl, e.g. methylsulphinyl,
ethylsulphinyl or propylsulphinyl, C.sub.1-6alkylsulphonyl, e.g.
methylsulphonyl, ethylsulphonyl or propylsulphonyl, aminosulphonyl
(--SO.sub.2NH.sub.2), C.sub.1-6alkylaminosulphonyl, e g
methylaminosulphonyl, ethylaminosulphonyl or propylaminosulphonyl
C.sub.1-6dialkylaminosulphony- l, e.g. dimethylaminosulphonyl or
diethylaminosulphonyl, phenylaminosulphonyl, carboxamido
(--CONH.sub.2), C.sub.1-6alkylaminocarb- onyl, e.g.
methylaminocarbonyl, ethylaminocarbonyl or propylaminocarbonyl,
C.sub.1-6dialkylaminocarbonyl, e.g. dimethylaminocarbonyl or
diethylaminocarbonyl, aminoC.sub.1-6alkylaminocarbonyl, e.g.
aminoethylaminocarbonyl,
C.sub.1-6alkylaminoC.sub.1-6alkylaminocarbonyl, e.g.
methylaminoethylaminocarbonyl,
C.sub.1-6dialkylaminoC.sub.1-6alkylam- inocarbonyl, e.g.
diethylaminoethylaminocarbonyl, aminocarbonylamino,
C.sub.1-6alkylaminocarbonylamino, e.g. methylaminocarbonylamino or
ethylaminocarbonylamino, C.sub.1-6dialkylaminocarbonylamino, e.g.
dimethylaminocarbonylamino or diethylaminocarbonylamino,
C.sub.1-6alkylaminocabonylC.sub.1-6alkylamino, e.g.
methylaminocarbonylmethylamino, aminothiocarbonylamino,
C.sub.1-6alkylaminothiocarbonylamino, e.g.
methylaminothiocarbonylamino or ethylaminothiocarbonylamino,
C.sub.1-6dialkylaminothiocarbonylamino, e.g.
dimethylaminothiocarbonylamino or diethylaminothiocarbonylamino,
C.sub.1-6alkylaminothiocarbonylC.sub.1-6alkylamino, e.g.
ethylaminothiocarbonylmethylamino, --CONHC(.dbd.NH)NH.sub.2,
C.sub.1-6alkylsulphonylamino, e.g. methylsulphonylamino or
ethylsulphonylamino, haloC.sub.1-6alkylsulphonylamino, e.g.
trifluoromethylsulphonylamino, C.sub.1-6dialkylsulphonylamino, e.g.
dimethylsulphonylamino or diethylsulphonylamino, optionally
substituted phenylsulphonylamino, aminosulphonylamino
(--NHSO.sub.2NH.sub.2), C.sub.1-6alkylaminosulphonylamino, e.g.
methylaminosulphonylamino or ethylaminosulphonylamino,
C.sub.1-6dialkylaminosulphonylamino, e.g.
dimethylaminosulphonylamino or diethylaminosulphonylamino,
optionally substituted morpholinesulphonylamino or
morpholinesulphonylC.sub.1-6alkyl- amino, optionally substituted
phenylaminosulphonylamino, C.sub.1-6alkanoylamino, e.g.
acetylamino, aminoC.sub.1-6alkanoylamino e.g. aminoacetylamino,
C.sub.1-6dialkylaminoC.sub.1-6alkanoylamino, e.g.
dimethylaminoacetylamino, C.sub.1-6alkanoylaminoC.sub.1-6alkyl,
e.g. acetylaminomethyl, C.sub.1-6alkanoylaminoC.sub.1-6alkylamino,
e.g. acetamidoethylamino, C.sub.1-6alkoxycarbonylamino, e.g.
methoxycarbonylamino, ethoxycarbonylamino or t-butoxycarbonylamino
or optionally substituted benzyloxy, pyridylmethoxy,
thiazolylmethoxy, benzyloxycarbonylamino,
benzyloxycarbonylaminoC.sub.1-6alkyl e.g.
benzyloxycarbonylaminoethyl, thiobenzyl, pyridylmethylthio or
thiazolylmethylthio groups.
[0063] Where desired, two R.sup.13 substituents may be linked
together to form a cyclic group such as a cyclic ether, e.g. a
C.sub.1-6alkylenedioxy group such as methylenedioxy or
ethylenedioxy.
[0064] It will be appreciated that where two or more R.sup.13
substituents are present, these need not necessarily be the same
atoms and/or groups. In general, the substituent(s) may be present
at any available ring position in the aromatic or heteroaromatic
group represented by R.sup.3.
[0065] The presence of certain substituents in the compounds of
formula (1) may enable salts of the compounds to be formed.
Suitable salts include pharmaceutically acceptable salts, for
example acid addition salts derived from inorganic or organic
acids, and salts derived from inorganic and organic bases.
[0066] Acid addition salts include hydrochlorides, hydrobromides,
hydroiodides, alkylsulphonates, e.g. methanesulphonates,
ethanesulphonates, or isothionates, arylsulphonates, e.g.
p-toluenesulphonates, besylates or napsylates, phosphates,
sulphates, hydrogen sulphates, acetates, trifluoroacetates,
propionates, citrates, maleates, fumarates, malonates, succinates,
lactates, oxalates, tartrates and benzoates.
[0067] Salts derived from inorganic or organic bases include alkali
metal salts such as sodium or potassium salts, alkaline earth metal
salts such as magnesium or calcium salts, and organic amine salts
such as morpholine, piperidine, dimethylamine or diethylamine
salts.
[0068] Particularly useful salts of compounds according to the
invention include pharmaceutically acceptable salts, especially
acid addition pharmaceutically acceptable salts.
[0069] In the compounds according to the invention the group
R.sup.1 is preferably an Ar.sup.1L.sup.2Ar.sup.2Alk-group. In
compounds of this type Ar.sup.1 is preferably an optionally
substituted phenyl, monocyclic heteroaromatic or bicyclic
heteroaromatic group. Particularly useful monocyclic heteroaromatic
groups are optionally substituted five- or six-membered
heteroaromatic groups as described previously, especially five- or
six-membered heteroaromatic groups containing one or two
heteroatoms selected from oxygen, sulphur or nitrogen atoms.
Nitrogen-containing groups are especially useful, particularly
pyridyl or pyrimidinyl groups. Particularly useful substituents
present on these Ar.sup.1 groups include halogen atoms or
optionally-substituted alkyl, --OR.sup.5, --SR.sup.5,
--NR.sup.5R.sup.6, --CO.sub.2H, --CO.sub.2CH.sub.3, --NO.sup.2 or
--CN groups as described above in relation to the compounds of
formula (1). Particularly useful bicyclic heteroaromatic groups
represented by Ar.sup.1 include optionally substituted ten-membered
fused-ring heteroaromatic groups containing one or two heteroatoms,
especially nitrogen atoms. Particular examples include optionally
substituted naphthyridinyl, especially 2,6-naphthyridinyl,
quinolinyl and isoquinolinyl, especially isoquinolin-1-yl groups.
Particular optional substituents include those just described for
monocyclic heteroaromatic groups.
[0070] A particularly useful group of compounds according to the
invention has the formula (2a): 4
[0071] wherein --W.dbd. is --CH.dbd. or --N.dbd.;
[0072] R.sup.16 and R.sup.17, which may be the same or different is
each a hydrogen atom or an atom or group
-L.sup.3(Alk.sup.2).sub.tL.sup.4(R.sup.- 4).sub.u in which L.sup.3,
Alk.sup.2, t, L.sup.4 R.sup.4 and u are as defined previously;
[0073] L.sup.1, L.sup.2, Ar.sup.2, Alk, R.sup.2, Alk.sup.1, n and
R.sup.3 are as defined for formula (1);
[0074] and the salts, solvates, hydrates and N-oxides thereof.
[0075] --W.dbd. in compounds of formula (2a) is preferably
--N.dbd..
[0076] R.sup.16 and R.sup.17 in compounds of formula (2a) is each
preferably as particularly described above for compounds of formula
(1), other than a hydrogen atom. Particularly useful R.sup.16 and
R.sup.17 substituents include halogen atoms, especially fluorine or
chlorine atoms, or methyl, halomethyl, especially --CF.sub.3,
--CHF.sub.2 or --CH.sub.2F, methoxy or halomethoxy, especially
--OCF.sub.3, --OCHF.sub.2 or --OCH.sub.2F groups.
[0077] A further particularly useful group of compounds according
to the invention has the formula (2b): 5
[0078] wherein R.sup.16, L.sup.1, L.sup.2, Ar.sup.2, Alk, R.sup.2,
Alk.sup.1, n and R.sup.3 are as defined for formula (2a);
[0079] g is zero or the integer 1, 2, 3 or 4;
[0080] and the salts, solvates, hydrates and N-oxides thereof.
[0081] Each R.sup.16 atom or group in compounds of formula (2b) may
be independently selected from an atom or group
-L.sup.3(Alk.sup.2).sub.tL.s- up.3(R.sup.4).sub.u in which L.sup.3,
Alk.sup.2, t, L.sup.4, R.sup.4 and u are as previously defined.
Particularly useful R.sup.16 substituents when present in compounds
of formula (2b) include halogen atoms; especially fluorine,
chlorine or bromine atoms, or methyl, halomethyl, especially
--CF.sub.3, methoxy or halomethoxy, especially --OCF.sub.3, --CN,
--CO.sub.2Me; --NO.sub.2, amino (--NH.sub.2), substituted amino
(--NR.sup.5R.sup.6) and --N(R.sup.5)COCH.sub.3, especially
--NHCOCH.sub.3 groups.
[0082] In one preferred group of compounds of formula (2b) each
R.sup.16 is a hydrogen atom.
[0083] Another particularly useful group of compounds according to
the invention has the formula (2c): 6
[0084] wherein R.sup.16, g, L.sup.1, L.sup.2, Ar.sup.2, Alk,
R.sup.2, Alk.sup.1, n and R.sup.3 are as defined for formula
(2b);
[0085] and the carbon atoms at positions 6 and 7 of the
naphthyridine ring are indicated with the appropriate numerals;
[0086] and the salts, solvates, hydrates and N-oxides thereof.
[0087] Each R.sup.16 atom or group in compounds of formula (2c) may
be independently selected for an atom or group
-L.sup.3(Alk.sup.2).sub.tL.su- p.4(R.sup.4).sub.u in which L.sup.3,
Alk.sup.2, t, L.sup.4, R.sup.4 and u are as previously defined.
Particularly useful R.sup.16 substituents when present in compounds
of formula (2c) include halogen atoms, especially fluorine or
chlorine atoms, methyl, halomethyl, especially --CF.sub.3, methoxy
or halomethoxy, especially --OCF.sub.3, --CN, --CO.sub.2Me,
--NO.sub.2, amino (--NH.sub.2), substituted amino
(--NR.sup.5R.sup.6) and --N(R.sup.5)COCH.sub.3, especially
--NHCOCH.sub.3 groups.
[0088] In one preferred group of compounds of formula (2c) g is the
integer 1 and R.sup.16 is a methoxy group, especially a methoxy
group present at the 6-position. In another preferred group of
compounds of formula (2c) g is the integer 2 and each R.sup.16
group is a methoxy group, especially a methoxy group present at the
6- and 7-positions.
[0089] Alk in compounds of the invention is preferably: 7
[0090] or, especially, --CH.sub.2CH(R)--.
[0091] R in the compounds of formulae (1), (2a), (2b) and (2c) is
preferably a --CO.sub.2H group.
[0092] In general in compounds of formulae (1), (2a), (2b) and (2c)
R.sup.2 is preferably a hydrogen atom.
[0093] In general in compounds of formula (2a) L.sup.2 is
preferably L.sup.2a where L.sup.2a is a --CON(R.sup.8)-- group,
especially --CONH--
[0094] In general in compounds of formulae (2b) and (2c) L.sup.2 is
preferably L.sup.2a where L.sup.2a is an --O-- atom or
--N(R.sup.8)-- group. An especially useful --N(R.sup.8)-- group is
--NH--.
[0095] The group Ar.sup.2 in compounds of formulae (1), (2a), (2b)
and (2c) is preferably an optionally substituted phenylene group.
Particularly useful groups include optionally substituted
1,4-phenylene groups.
[0096] In general in compounds of formulae (1), (2a), (2b) and (2c)
when n is zero or the integer 1 the group R.sup.3 may especially be
a hydrogen atom or an optionally substituted heteroaliphatic,
cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic
group as defined herein. Particularly useful groups of this type
include optionally substituted C.sub.2-6heteroalkyl, particularly
C.sub.1-3alkoxyC.sub.1-3alkyl, especially methoxypropyl, optionally
substituted C.sub.3-7cycloalkyl, especially optionally substituted
cyclopropyl, cyclobutyl, cyclopentyl, cyclopropyl or cyclohexyl,
optionally substituted C.sub.5-7heterocycloali- phatic, especially
optionally substituted pyrrolidinyl, piperidinyl or thiazolidinyl,
especially optionally substituted phenyl and optionally substituted
C.sub.5-7heteroaromatic, especially optionally substituted pyridyl,
pyrimidinyl or triazinyl groups. Optional substituents on these
groups include in particular R.sup.13 atoms or groups where the
group is an aromatic or heteroaromatic group and halogen atoms or
C.sub.1-6alkyl, especially methyl, haloC.sub.1-6alkyl, especially
trifluoromethyl, C.sub.1-6alkoxy, especially methoxy,
haloC.sub.1-6alkoxy, especially trifluoromethoxy or
-(L.sup.6).sub.p(Alk.sup.5).sub.qR.sup.12 groups as described
earlier where the group is a nitrogen-containing
heterocycloaliphatic group such as a pyrrolidinyl, piperidinyl or
thiazolidinyl group. Particularly useful
-(L.sup.6).sub.p(Alk.sup.5).sub.- qR.sup.12 groups include those in
which L.sup.6 is a --CO-- group. Alk.sup.5 in these groups is
preferably present (i.e. q is preferably an integer 1) and in
particular is a --CH.sub.2-- chain.
[0097] Compounds of this type in which R.sup.12 is a hydrogen atom
or an optionally substituted aromatic or heteroaromatic group,
especially an optionally substituted phenyl, pyridyl or imidazolyl
group are particularly preferred.
[0098] In one preferred class of compounds of formulae (1), (2a),
(2b) and (2c) L.sup.1 is present as a --N(R.sup.8)-- group.
Particularly useful --N(R.sup.8)-- groups include --NH--,
--N(CH.sub.3)--, --N(CH.sub.2CH.sub.3)-- and
--N(CH.sub.2CH.sub.2CH.sub.3)-- groups. In this class of compounds
n is preferably the integer 1 and Alk.sup.1 is preferably an
optionally substituted straight or branched C.sub.1-6alkylene
chain. Particularly useful Alk.sup.1 chains include --CH.sub.2--,
--CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2--,
--CH(CH.sub.3)CH.sub.2-- and --C(CH.sub.3).sub.2CH.sub.2--. R.sup.3
in this class of compounds is preferably a hydrogen atom.
[0099] In another preferred class of compounds of formulae (1),
(2a), (2b) and (2c) L.sup.1 is a covalent bond, n is the integer 1
and Alk.sup.1 is an optionally substituted straight or branched
C.sub.1-6alkylene chain. Particularly useful Alk.sup.1 chains
include optionally substituted --CH.sub.2--, --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2-- and --CH(CH.sub.3)CH.sub.2-- and
especially --C(CH.sub.3).sub.2CH.sub.2-- chains. R.sup.3 in this
class of compounds is preferably a hydrogen atom. A most especially
useful optionally substituted Alk.sup.1 R.sup.3 group is
--C(CH.sub.3).sub.3.
[0100] In another preferred class of compounds of fomulae (1),
(2a), (2b) and (2c), L.sup.1 is a covalent bond, n is zero and
R.sup.3 is an optionally substituted C.sub.5-7heterocycloaliphatic,
especially an optionally substituted piperidinyl group. A most
especially useful optionally substituted piperidinyl group is an
optionally substituted piperidin-1-yl group.
[0101] Particularly useful compounds of the invention include:
[0102]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-(2-propylamin-
o-3,4-dioxocyclobut-1-enyl)amino]propanoic acid;
[0103]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-(2-t-butyl-3,-
4-dioxocyclobut-1-enyl)amino]propanoic acid;
[0104]
(S)-3-{4-[(6,7-Dimethoxy4-quinazolinyl)amino]phenyl}-2-[(2-N,N-diet-
hylamino-3,4-dioxocyclobut-1-enyl)amino]propanoic acid;
[0105]
(S)-3-[4-([2,6-Naphthyridin-1-yl]amino)phenyl]-2-[(2-N,N-diethylami-
no-3,4-dioxocyclobut-1-enyl)amino]propanoic acid;
[0106]
(S)-3-[4-([6,7-Dimethoxy-4-quinazolinyl)oxy]phenyl]-2-[(2-N,N-dieth-
ylamino-3,4-dioxocyclobut-1-enyl)amino]propanoic acid;
[0107]
(S)-3-[4-([6,7-Methoxy4-quinazolinyl]amino)phenyl]-2-[(2-N,N-diethy-
lamino-3,4-dioxocyclobut-1-enyl)amino]propanoic acid;
[0108]
(S)-3-[4-([2,6-Naphthyridin-1-yl]amino)phenyl]-2-[(2-N,N-dipropylam-
ino-3,4-dioxocyclobut-1-enyl)amino]propanoic acid;
[0109]
(S)-3-[4-([2,6-Naphthyridin-1-yl]oxy)phenyl]-2-[(2-N,N-diethylamino-
-3,4-dioxocyclobut-1-enyl)amino]propanoic acid;
[0110]
(S)-3-[4-([2,6-Naphthyridin-1-yl]amino)phenyl]-2-[(2-piperidin-1-yl-
-3,4-dioxocyclobut-1-enyl)amino]propanoic acid;
[0111]
(R)-3-{4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl}-3-[(2-N,N-dieth-
ylamino-3,4-dioxocyclobut-1-enyl)amino]propanoic acid;
[0112]
(S)-3-[4-([2,6-Naphthyridin-1-yl]oxy)phenyl]-2-[(2-N,N-dipropylamin-
o-3,4-dioxocyclobut-1-enyl)amino]propanoic acid;
[0113] (S)-3-[4-([2,6-Naphthyridin-1-yl]amino)phenyl]-2-[(2-N,
-ethyl-N-isopropylamino-3,4-dioxocyclobut-1-enyl)amino]propanoic
acid;
[0114] and the salts, solvates, hydrates and N-oxides thereof.
[0115] The compounds according to the invention are generally of
use in modulating cell adhesion. Thus for example when R.sup.1 in
compounds of the invention is an .alpha..sub.4-integrin binding
groups the compounds are of use in the prophylaxis and treatment of
diseases or disorders involving inflammation in which the
extravasation of leukocytes plays a role.
[0116] Diseases or disorders of this type include inflammatory
arthritis such as rheumatoid arthritis vasculitis or
polydermatomyositis, multiple sclerosis, allograft rejection,
diabetes, inflammatory dermatoses such as psoriasis or dermatitis,
asthma and inflammatory bowel disease.
[0117] In another example when R.sup.1 is an .alpha..sub.v-integrin
binding group the compounds may be of use in the prophylaxis and
treatment of diseases or disorders involving inappropriate growth
or migration of cells. Particular diseases include inflammatory
diseases, and diseases involving angiogenesis, bone resorption or
cllular or matrix over-expression.
[0118] Particular uses to which these compounds of the invention
may be put include the treatment or inhibition of tumour growth and
metastasis; retinopathy; macular degeration psoriasis; rheumatoid
arthritis; osteoporosis; bone resorption following or due to joint
replacement, hypercalcemia or malignancy, Paget's disease,
glucocorticoid treatment, immonilisation-induced osteopenia,
hyperparathyroidism or peridontal disease, vascuar restenosis,
atherosclerosis; inflammatory bowel disease; and psoriasis.
[0119] For the prophylaxis or treatment of disease the compounds
according to the invention may be administered as pharmaceutical
compositions, and according to a further aspect of the invention we
provide a pharmaceutical composition which comprises a compound of
formula (1) together with one or more pharmaceutically acceptable
carriers, excipients or diluents.
[0120] Pharmaceutical compositions according to the invention may
take a form suitable for oral, buccal, parenteral, nasal, topical
or rectal administration, or a form suitable for administration by
inhalation or insufflation.
[0121] For oral administration, the pharmaceutical compositions may
take the form of, for example, tablets, lozenges or capsules
prepared by conventional means with pharmaceutically acceptable
excipients such as binding agents (e.g. pregelatinised maize
starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose);
fillers (e.g. lactose, microcrystalline cellulose or calcium
hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or
silica); disintegrants (e.g. potato starch or sodium glycollate);
or wetting agents (e.g. sodium lauryl sulphate). The tablets may be
coated by methods well known in the art. Liquid preparations for
oral administration may take the form of, for example, solutions,
syrups or suspensions, or they may be presented as a dry product
for constitution with water or other suitable vehicle before use.
Such liquid preparations may be prepared by conventional means with
pharmaceutically acceptable additives such as suspending agents,
emulsifying agents, non-aqueous vehicles and preservatives. The
preparations may also contain buffer salts, flavouring, colouring
and sweetening agents as appropriate.
[0122] Preparations for oral administration may be suitably
formulated to give controlled release of the active compound.
[0123] For buccal administration the compositions may take the form
of tablets or lozenges formulated in conventional manner.
[0124] The compounds of formula (1) may be formulated for
parenteral administration by injection e.g. by bolus injection or
infusion. Formulations for injection may be presented in unit
dosage form, e.g. in glass ampoule or multi dose containers, e.g.
glass vials. The compositions for injection may take such forms as
suspensions, solutions or emulsions in oily or aqueous vehicles,
and may contain formulatory agents such as suspending, stabilising,
preserving and/or dispersing agents. Alternatively, the active
ingredient may be in powder form for constitution with a suitable
vehicle, e.g. sterile pyrogen-free water, before use. For particle
mediated administration the compounds of formula (1) may be coated
on particles such as microscopic gold particles.
[0125] In addition to the formulations described above, the
compounds of formula (1) may also be formulated as a depot
preparation. Such long acting formulations may be administered by
implantation or by intramuscular injection.
[0126] For nasal administration or administration by inhalation,
the compounds for use according to the present invention are
conveniently delivered in the form of an aerosol spray presentation
for pressurised packs or a nebuliser, with the use of suitable
propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethan- e, carbon dioxide or other suitable gas
or mixture of gases.
[0127] The compositions may, if desired, be presented in a pack or
dispenser device which may contain one or more unit dosage forms
containing the active ingredient. The pack or dispensing device may
be accompanied by instructions for administration.
[0128] The quantity of a compound of the invention required for the
prophylaxis or treatment of a particular condition will vary
depending on the compound chosen, and the condition of the patient
to be treated. In general, however, daily dosages may range from
around 100 ng/kg to 100 mg/kg e.g. around 0.01 mg/kg to 40 mg/kg
body weight for oral or buccal administration, from around 10 ng/kg
to 50 mg/kg body weight for parenteral administration and around
0.05 mg to around 1000 mg e.g. around 0.5 mg to around 1000 mg for
nasal administration or administration by inhalation or
insufflation.
[0129] The compounds of the invention may be prepared by a number
of processes as generally described below and more specifically in
the Examples hereinafter. In the following process description, the
symbols Ar.sup.1, Ar.sup.2, Alk, R.sup.1, R.sup.2, R.sup.3,
L.sup.1, L.sup.2, Alk.sup.1 and n when used in the formulae
depicted are to be understood to represent those groups described
above in relation to formula (1) unless otherwise indicated. In the
reactions described below, it may be necessary to protect reactive
functional groups, for example hydroxy, amino, thio or carboxy
groups, where these are desired in the final product, to avoid
their unwanted participation in the reactions. Conventional
protecting groups may be used in accordance with standard practice
[see, for example, Green, T. W. in "Protective Groups in Organic
Synthesis", John Wiley and Sons, 1991]. In some instances,
deprotection may be the final step in the synthesis of a compound
of formula (1) and the processes according to the invention
described hereinafter are to be understood to extend to such
removal of protecting groups. For convenience the processes
described below all refer to a preparation of a compound of formula
(1) but clearly the description applies equally to the preparation
of compounds of formula (2).
[0130] Thus according to a further aspect of the invention, a
compound of formula (1) in which R is a --CO.sub.2H group may be
obtained by hydrolysis of an ester of formula (3): 8
[0131] where Alk represents a group
--CH.sub.2CH(CO.sub.2R.sup.y)--, --CH.dbd.CH(CO.sub.2R.sup.y)--,
9
[0132] [where R.sup.y is an alkyl group for example a
C.sub.1-6alkyl group]
[0133] The hydrolysis may be performed using either an acid or a
base depending on the nature of R.sup.y, for example an organic
acid such as trifluoroacetic acid or an inorganic base such as
lithium, sodium or potassium hydroxide optionally in an aqueous
organic solvent such as an amide e.g. a substituted amide such as
dimethylformamide, an ether e.g. a cyclic ether such as
tetrahydrofuran or dioxane or an alcohol e.g. methanol at a
temperature from ambient to the reflux temperature. Where desired,
mixtures of such solvents may be used.
[0134] According to a further aspect of the invention a compound of
formula (1) may be prepared by displacement of a leaving group from
a compound of formula (4): 10
[0135] where R.sup.a is a leaving group, with an amine
R.sup.1R.sup.2NH or a salt thereof. Suitable leaving groups
represented by R.sup.a include halogen atoms, especially chlorine
and bromine atoms, or alkoxy, e.g. methoxy, ethoxy or isopropoxy,
aryloxy, e g. dinitrophenyloxy, or aralkoxy, e g. benzyloxy,
groups.
[0136] The reaction may be performed in an inert solvent or mixture
of solvents, for example a substituted amide such as
dimethylformamide, an alcohol such as ethanol and/or a halogenated
hydrocarbon such as dichloromethane, at a temperature from
0.degree. C. to the reflux temperature. Where necessary, for
example when a salt of an amine R.sup.1, R.sup.2NH is used, an
organic base such as diisopropylethylamine can be added.
[0137] Any carboxylic acid group present in the intermediate of
formula (4) or the amine R.sup.1R.sup.2NH may need to be protected
during the displacement reaction, for example as an ethyl ester.
The desired acid may then be obtained through subsequent
hydrolysis, for example as particularly described above and
generally described below.
[0138] It will be appreciated that the displacement reaction may
also be performed on a compound of formula (5): 11
[0139] where R.sup.b is a leaving group as defined for R.sup.a
using an intermediate R.sup.3(Alk.sup.1).sub.nL.sup.1H where
-L.sup.1H is a functional group such as an amine (--NH.sub.2) using
the reaction conditions just described.
[0140] Where desired the displacement reaction may also be
performed on an intermediate of formulae (4) or (5),
R.sup.1R.sup.2NH or R.sup.3(Alk.sup.1).sub.nL.sup.1H which is
linked, for example via its R.sup.1 or R.sup.3 group, to a solid
support, such as a polystyrene resin. After the reaction the
desired compound of formula (1) may be displaced from the support
by any convenient method, depending on the original linkage chosen.
Intermediates of formulae (4) and (5) are either readily available
or may be prepared from an intermediate of formula (6): 12
[0141] where R.sup.a and R.sup.b are as previously defined and an
amine R.sup.1R.sup.2NH or intermediate
(R.sup.3(Alk.sup.1).sub.nL.sup.1H by displacement as just described
for the preparation of compounds of formula (1).
[0142] Intermediates of formulae R.sup.1R.sup.2NH and
R.sup.3(Alk.sup.1).sub.nL.sup.1H may be obtained from simpler,
known compounds by one or more standard synthetic methods employing
substitution, oxidation, reduction or cleavage reactions.
Particular substitution approaches include conventional alkylation,
arylation, heteroarylation, acylation, thioacylation, halogenation,
sulphonylation, nitration, formylation and coupling procedures. It
will be appreciated that these methods may also be used to obtain
or modify other compounds of formulae (1) and (2) where appropriate
functional groups exist in these compounds.
[0143] Thus compounds of the invention and intermediates thereto
may be prepared by alkylation, arylation or heteroarylation. For
example, compounds containing a -L.sup.1H or -L.sup.2H group (where
L.sup.1 and L.sup.2 is each a linker atom or group) may be treated
with a coupling agent R.sup.3(Alk.sup.1).sub.nX.sup.1 or
Ar.sup.1X.sup.1 respectively in which X.sup.1 is a leaving atom or
group such as a halogen atom, e.g. a fluorine, bromine, iodine or
chlorine atom or a sulphonyloxy group such as an alkylsulphonyloxy,
e.g. trifluoromethylsulphonyloxy or arylsulphonyloxy, e.g.
p-toluenesulphonyloxy group.
[0144] The reaction may be carried out in the presence of a base
such as a carbonate, e.g. caesium or potassium carbonate, an
alkoxide, e.g. potassium t-butoxide, or a hydride, e.g. sodium
hydride, or an organic amine e.g. triethylamine or
N,N-diisopropylethylamine or a cyclic amine, such as
N-methylmorpholine or pyridine, in a dipolar aprotic solvent such
as an amide, e.g. a substituted amide such as dimethylformamide or
an ether, e.g. a cyclic ether such as tetrahydrofuran.
[0145] Intermediates of formula Ar.sup.1X.sup.1 and
R.sup.3(Alk.sup.1).sub.nX.sup.1 are generally known, readily
available compounds or may be prepared from known compounds by
standard substitution and other synthetic procedures, for example
as described herein. Thus for example compounds of formula
Ar.sup.1X.sup.1 in which, for example, Ar.sup.1 represents a
2,6-naphthyridine group may be prepared from alcohols of formula
Ar.sup.1OH by reaction with a halogenating agent, for example a
phosphorous oxyhalide such as phosphorous oxychloride at an
elevated temperature e.g. 110.degree. C.
[0146] Intermediate alcohols of formula Ar.sup.1OH in which, for
example, Ar.sup.1 represents a 2,6-naphthyridine group may be
prepared by methods well known to a person skilled in the art, e.g.
by the method of Sakamoto, T. et al [Chem. Pharm. Bull. 3, 626-633,
(1985)].
[0147] Alternatively alkylating agents of formula Ar.sup.1X.sup.1
in which, for example, Ar.sup.1 represents a 2,6-naphthyridine
group may be prepared by reaction of a 2,6-naphthyridine N-oxide or
N,N'-dioxide with a halogenating agent, e.g. a phosphorous
oxyhalide such as phosphorous oxychloride to give a 1-halo or
1,5-dihalo-2,6-napthyridine respectively. In the case of
1,5-dihalo-2,6-napthyridines each halogen atom may be substituted
separately by a reagent such as HL.sup.2Ar.sup.2AlkN(R.sup.2)- H or
HL.sup.3(Alk.sup.2).sub.tL.sup.4(R.sup.4).sub.u by the particular
methods just described above.
[0148] 2,6-Napthyridine N-oxides and N,N'-dioxides may be generated
from the corresponding 2,6-napthyridines group by the general
methods of synthesis of N-oxides described below or they may be
synthesised by the methods of Numata, A. et al (Synthesis, 1999,
306-311).
[0149] Further alkylating agents of formula Ar.sup.1X.sup.1 in
which, for example, Ar.sup.1 represents a 2,6-naphthyridine, may be
prepared by the methods of Giacomello G. et al (Tetrahedron Letters
1965, 1117-1121), Tan, R. and Taurins, A. (Tetrahedron Letters
1965, 2737-2744), Ames, D. E. and Dodds, W. D. (J. Chem. Soc.
Perkin 1 1972. 705-710) and Alhaique, F. et al (Tetdrahedron
Letters, 1975, 173-174).
[0150] In a further example intermediates of formula R.sup.1,
R.sup.2NH may be obtained by reaction of a compound of formula
Ar.sup.1 L.sup.2H with a compound of formula X.sup.1
Ar.sup.2AlkN(R.sup.2)H under the reaction conditions just
described
[0151] Compounds of formula Ar.sup.1L.sup.2H in which, for example
Ar.sup.1 represents a 2,6-naphthyridine and L.sup.2 is a
--N(R.sup.8)-- group, may be prepared from substituted
4-cyano-3-cyanomethylpyridines by the methods of Alhaique, F. et al
(ibid and Gazz. Chim. Ital. 1975, 105, 1001-1009) or from
3-fomylpyridines by the methods of Molina, P. at al (Tetrahedron
1992, 48, 4601-4616).
[0152] In another example, compounds containing a -L.sup.1H or
-L.sup.2H or group as defined above may be functionalised by
acylation or thioacylation, for example by reaction with one of the
alkylating agents just described but in which X.sup.1 is replaced
by a --C(O)X.sup.2, C(S)X.sup.2, --N(R.sup.8)COX.sup.2 or
--N(R.sup.8)C(S)X.sup.2 group in which X.sup.2 is a leaving atom or
group as described for X.sup.1. The reaction may be performed in
the presence of a base, such as a hydride, e.g. sodium hydride or
an amine, e.g. triethylamine or N-methylmorpholine, in a solvent
such as a halogenated hydrocarbon, e.g. dichloromethane or carbon
tetrachloride or an amide, e.g. dimethylformamide, at for example
ambient temperature. Alternatively, the acylation may be carried
out under the same conditions with an acid (for example one of the
alkylating agents described above in which X.sup.1 is replaced by a
--CO.sub.2H group) in the presence of a condensing agent, for
example a diimide such as
1-(3-dimethylaminopropyl)-3-ethylcarbodiimi- de or
N,N'-dicyclohexylcarbodiimide, advantageously in the presence of a
catalyst such as a N-hydroxy compound e.g. a N-hydroxytriazole such
as 1-hydroxybenzotriazole. Alternatively the acid may be reacted
with a chloroformate, for example ethylchloroformate, prior to the
desired acylation reaction
[0153] In a further example compounds may be obtained by
sulphonylation of a compound containing an --OH group by reaction
with one of the above alkylating agents but in which X.sup.1 is
replaced by a --S(O)Hal or --SO.sub.2Hal group in which Hal is a
halogen atom such as chlorine atom] in the presence of a base, for
example an inorganic base such as sodium hydride in a solvent such
as an amide, e.g. a substituted amide such as dimethylformamide at
for example ambient temperature.
[0154] In another example, compounds containing a -L.sup.1H or
-L.sup.2H group as defined above may be coupled with one of the
alkylation agents just described but in which X.sup.1 is replaced
by an --OH group in a solvent such as tetrahydrofuran in the
presence of a phosphine, e.g. triphenylphosphine and an activator
such as diethyl, diisopropyl- or dimethylazodicarboxylate.
[0155] In a further example, ester groups --CO.sub.2R.sup.5,
--CO.sub.2Alk.sup.3 or --CO.sub.2Alk.sup.7 in the compounds may be
converted to the corresponding acid [-CO.sub.2H] by acid- or
base-catalysed hydrolysis depending on the nature of the groups
R.sup.5, Alk.sup.3 or Alk.sup.7. Acid- or base-catalysed hydrolysis
may be achieved for example by treatment with an organic or
inorganic acid, e.g. trifluoroacetic acid in an aqueous solvent or
a mineral acid such as hydrochloric acid in a solvent such as
dioxan or an alkali metal hydroxide, e.g. lithium hydroxide in an
aqueous alcohol, e.g. aqueous methanol.
[0156] In a further example, --OR.sup.5 or --OR.sup.14 groups
[where R.sup.5 or R.sup.14 each represents an alkyl group such as
methyl group] in compounds of formula (1) may be cleaved to the
corresponding alcohol --OH by reaction with boron tribromide in a
solvent such as a halogenated hydrocarbon, e.g. dichloromethane at
a low temperature, e.g. around -78.degree. C.
[0157] Alcohol [--OH] groups may also be obtained by hydrogenation
of a corresponding --OCH.sub.2R.sup.14 group (where R.sup.14 is an
aryl group) using a metal catalyst, for example palladium on a
support such as carbon in a solvent such as ethanol in the presence
of ammonium formate, cyclohexadiene or hydrogen, from around
ambient to the reflux temperature. In another example, --OH groups
may be generated from the corresponding ester [CO.sub.2Alk.sup.5 or
CO.sub.2R.sup.5] or aldehyde [--CHO] by reduction, using for
example a complex metal hydride such as lithium aluminium hydride
or sodium borohydride in a solvent such as methanol.
[0158] In another example, alcohol --OH groups in the compounds may
be converted to a corresponding --OR.sup.5 or --OR.sup.14 group by
coupling with a reagent R.sup.5OH or R.sup.140H in a solvent such
as tetrahydrofuran in the presence of a phosphine, e.g.
triphenylphosphine and an activator such as diethyl-, diisopropyl-,
or dimethylazodicarboxylate.
[0159] Aminosulphonylamino [--NHSO.sub.2NHR.sup.3 or
--NHSO.sub.2NHAr.sup.1] groups in the compounds may be obtained, in
another example, by reaction of a corresponding amine [--NH.sub.2]
with a sulphamide R.sup.3NHSO.sub.2NH.sub.2 or Ar.sup.1
NHSO.sub.2NH.sub.2 in the presence of an organic base such as
pyridine at an elevated temperature, e.g. the reflux
temperature.
[0160] In another example compounds containing a --NHCSAr.sup.1,
--CSNHAr.sup.1, --NHCSR.sup.3 or --CSNHR.sup.3 may be prepared by
treating a corrsponding compound containing a --NHCOAr.sup.a,
--CONHAr.sup.1, --NHCOR.sup.3 or --CONHR.sup.3 group with a
thiation reagent, such as Lawesson's Reagent, in an anhydrous
solvent, for example a cyclic ether such as tetrahydrofuran, at an
elevated temperature such as the reflux temperature.
[0161] In a further example amine (--NH.sub.2) groups may be
alkylated using a reductive alkylation process employing an
aldehyde and a borohydride, for example sodium triacetoxyborohyride
or sodium cyanoborohydride, in a solvent such as a halogenated
hydrocarbon, e.g. dichloromethane, a ketone such as acetone, or an
alcohol, e.g. ethanol, where necessary in the presence of an acid
such as acetic acid at around ambient temperature.
[0162] In a further example, amine [--NH.sub.2] groups in compounds
of formula (1) may be obtained by hydrolysis from a corresponding
imide by reaction with hydrazine in a solvent such as an alcohol,
e.g. ethanol at ambient temperature.
[0163] In another example, a nitro [--NO.sub.2] group may be
reduced to an amine [--NH.sub.2], for example by catalytic
hydrogenation using for example hydrogen in the presence of a metal
catalyst, for example palladium on a support such as carbon in a
solvent such as an ether, e.g. tetrahydrofuran or an alcohol e.g.
methanol, or by chemical reduction using for example a metal, e.g.
tin or iron, in the presence of an acid such as hydrochloric
acid.
[0164] Aromatic halogen substituents in the compounds may be
subjected to halogen-metal exchange with a base, for example a
lithium base such as n-butyl or t-butyl lithium, optionally at a
low temperature, e.g. around -78.degree. C., in a solvent such as
tetrahydrofuran and then quenched with an electrophile to introduce
a desired substituent. Thus, for example, a formyl group may be
introduced by using dimethylformamide as the electrophile; a
thiomethyl group may be introduced by using dimethyldisulphide as
the electrophile.
[0165] In another example, sulphur atoms in the compounds, for
example when present in a linker group L.sup.1 or L.sup.2 may be
oxidised to the corresponding sulphoxide or sulphone using an
oxidising agent such as a peroxy acid, e.g. 3-chloroperoxybenzoic
acid, in an inert solvent such as a halogenated hydrocarbon, e.g.
dichloromethane, at around ambient temperature.
[0166] In another example compounds of formula Ar.sup.1X.sup.1
(where X.sup.1 is a halogen atom such as a chlorine, bromine or
iodine atom) may be converted to such compounds as
Ar.sup.1CO.sub.2R.sup.20 (in which R.sup.20 is an optionally
substituted alkyl, aryl or heteroaryl group), Ar.sup.1CHO,
Ar.sup.1CHCHR.sup.20, Ar.sup.1CCR.sup.20, Ar.sup.1N(R.sup.20)H,
Ar.sup.1N(R.sup.20).sub.2, for use in the synthesis of for example
compounds of formula R.sup.1R.sup.2NH, using such well known and
commonly used palladium mediated reaction conditions as are to be
found in the general reference texts Encyclopedia of Reagents for
Organic Synthesis, Editor-in Chief Paquette, L. A., John Wiley and
Sons, 1995 and Comprehensive Organic Functional Group
Transformations, Editors-in-Chief Katritzky, A R. et al, Pergamon,
1995.
[0167] N-oxides of compounds of formula (1) may be prepared for
example by oxidation of the corresponding nitrogen base using an
oxidising agent such as hydrogen peroxide in the presence of an
acid such as acetic acid, at an elevated temperature, for example
around 70.degree. C. to 80.degree. C, or alternatively by reaction
with a peracid such as peracetic acid in a solvent, e.g.
dichloromethane, at ambient temperature.
[0168] Salts of compounds of formula (1) may be prepared by
reaction of a compound of formula (1) with an appropriate base in a
suitable solvent or mixture of solvents e.g. an organic solvent
such as an ether e.g. diethylether, or an alcohol, e.g. ethanol
using conventional procedures.
[0169] Where it is desired to obtain a particular enantiomer of a
compound of formula (1) this may be produced from a corresponding
mixture of enantiomers using any suitable conventional procedure
for resolving enantiomers.
[0170] Thus for example diastereomeric derivatives, e.g. salts, may
be produced by reaction of a mixture of enantiomers of formula (1)
e.g. a racemate, and an appropriate chiral compound, e.g. a chiral
base. The diastereomers may then be separated by any convenient
means, for example by crystallisation and the desired enantiomer
recovered, e.g. by treatment with an acid in the instance where the
diastereomer is a salt.
[0171] In another resolution process a racemate of formula (1) may
be separated using chiral High Performance Liquid Chromatography.
Alternatively, if desired a particular enantiomer may be obtained
by using an appropriate chiral intermediate in one of the processes
described above.
[0172] Chromatography, recrystallisation and other conventional
separation procedures may also be used with intermediates or final
products where it is desired to obtain a particular geometric
isomer of the invention.
[0173] The following Examples illustrate the invention. All
temperatures are in .degree. C. The following abbreviations are
used:
1 NMM N-methylmorpholine; EtOAc ethyl acetate; MeOH methanol; BOC
butoxycarbonyl; DCM dichloromethane; AcOH acetic acid; DIPEA
diisopropylethylamine; EtOH ethanol; Pyr pyridine; Ar aryl; DMSO
dimethylsulphoxide; iPr isopropyl; Et.sub.2O diethylether; Me
methyl; THF tetrahydrofuran, DMF N,N-dimethylformamide; FMOC
9-fluorenylmethoxy- br broad; carbonyl; obs obscured; app apparent;
dil dilute; RT room temperature; Bu butyl; DIPEA
diisopropylethylamine
[0174] All NMR's were obtained at 300 mHz.
[0175] Intermediate 1
[0176] 3,5-Dichloropyridine-4-carboxylic acid
[0177] A solution of 3,5-dichloropyridine (5.00 g, 33.8 mmol) in
THF (25 ml) was added to a solution of LDA [generated from nBuLi
(2.5M solution in hexanes, 14.9 ml, 37.2 mmol) and diisopropylamine
(4.10 g, 5.7 ml, 40.6 mmol)] in THF (25 ml) at -78.degree. under
nitrogen, to give a yellow/brown slurry. The reaction was stirred
for 30 min at -780 then CO.sub.2 gas was bubbled through to give a
clear brown solution that slowly gave a precipitate, warmed to RT
over 2 h, then quenched with water (20 ml) and partitioned between
Et.sub.2O (100 ml) and 1M NaOH (100 ml). The aqueous layer was
separated and acidified to pH 1 with concentrated hydrochloric acid
and then extracted with 10% MeOH in DCM (100 ml.times.3). The
combined organic layers were dried (MgSO.sub.4) and the solvent
removed under vacuum to give a brown solid that was recrystallised
from ethanol and dried under vacuum to give the title compound as
pinkish crystals (2.63 g, 41%). .delta..sub.H (DMSO-d.sup.6) 8.74
(2H, s). .delta.C (DMSO-d.sup.6) 163.5, 147.7, 141.0, 126.7
[0178] Intermediate 2
[0179] Ethyl
(S)-3-(4-[3,5-dichloropyrid4-ylcarboxamido]phenyl)-2-(t-butox-
ycarbonyl amino)propionate
[0180] A slurry of the compound of Intermediate 1 (51.2 g, 0.267
mol) in DCM (195 ml) and thionyl chloride (195 ml, 2.67 mol) was
treated with DMF (5 drops) and heated to reflux for 4 h. The
reaction was concentrated in vacuo and azeotroped with toluene
(2.times.50 ml) to give a yellow solid which was used without
further purification. A solution of
ethyl-(S)-3-(4-aminophenyl)-2-(t-butoxycarbonyl amino)propionate
(130.8 g, 0.425 mol) in DCM (800 ml) was cooled to 0.degree. and
treated with NMM (56.0 ml, 0.51 mol), stirred 5 minutes and then a
solution of the acid chloride (98.3 g, 0.468 mol) in DCM (200 ml)
was added dropwise keeping the reaction temperature below 50. The
reaction was stirred for 1 h, quenched with NaHCO.sub.3 solution
(500 ml), the organic layer separated, washed with NaHCO.sub.3
solution (500 ml), 10% citric acid solution (500 ml) and
NaHCO.sub.3 solution (500 ml), dried (MgSO.sub.4)and concentrated
in vacuo to give a yellow solid which was recrystallised
(EtOAc/hexane) to give the title compound, 140 g, 69%.
.delta..sub.H (DMSO d6), 8.8 (2H, s), 7.55 (2H, d, J 8.5 Hz), 7.23
(2H, d, J 8.5 Hz), 4.0 (3H, m), 3.4 (2H, b s), 2.9 (1H, m), 2.8
(1H, m), 1.3 (9H, s), 1.25 (3H, t). m/z (ES.sup.+, 70V) 504
(MNa.sup.+).
[0181] Intermediate 3
[0182] Ethyl (S)-3-[4(3,5-dichloropyrid4-yl
carboxamido)phenyl]-2-amino propionate hydrochloride
[0183] A solution of the compound of Intermediate 2 (70 g, 0.146
mol) in EtOAc (500 ml) and 1,4-dioxan (50 ml) was treated with a
solution of HCl in EtOAc (500 ml, 3M), and stirred at RT for 4 h.
The reaction was concentrated in vacuo to give a yellow solid which
was triturated with Et.sub.2O then recrystallised (EtOAc/hexane) to
give the title compound (59.3 g, 92%). .delta..sub.H (DMSO
d.sup.6), 11.10 (1H, s), 8.70 (2H, s), 7.55 (2H, d, J 8.4 Hz), 7.25
(2H, d, J 8.4 Hz), 4.10 (3H, m), 3.10 (2H, m), 1.10 (3H, m). m/z
(ES.sup.+, 70V) 382 (MH.sup.+).
[0184] Intermediate 4
[0185] 3-(tert-Butyl)-4-isopropoxy-3-cyclobutene-1,2-dione
tert-Butyl lithium (2.29 ml of a 1.7M solution in pentane, 3.9
mmol) was added to a solution of
3,4-diisopropoxy-3-cyclobutene-1,2-dione (594 mg, 3 mmol) in THF
(30 ml) at -78.degree. C. After 5 h trifluoroactic anhydride (636
.mu.l, 4.5 mmol) was added and stirring continued at -78.degree. C.
for 30 min. The cold mixture was poured into NH.sub.4Cl(aq),
extraced with EtOAc, dried (Na.sub.2SO.sub.4) and evaporated in
vacuo. Column chromatography (S)O.sub.2; EtOAc/hexane, 15:85) gave
the title compound as a mobile yellow oil (408 mg, 69%). 5H
(CDCl.sub.3) 5.43 (1H, sept, 16.2 Hz), 1.45 (6H, d, 16.2 Hz) and
1.33 (9H, s); m/z (ES.sup.+, 70V) 197 (M.sup.++H).
[0186] Intermediate 5
[0187] 1-Chloro-2,6-naphthyridine
[0188] 1-Hydroxy-2,6-naphthyridine (550 mg) [prepared according to
the method of Sakamoto, T. et al Chem. Pharm. Bull. 33, 626,
(1985)] was stirred with phosphorous oxychloride (10 ml) at
110.degree. for 5 h. The volatiles were removed in vacuo and the
residue treated carefully with ice. After diluting with water (to
.about.25 ml), solid NaHCO.sub.3 was added to neutralise and the
product extracted into EtOAc (2.times.80 ml). The combined organic
extracts were dried (MgSO.sub.4), evaporated in vacua, and the
crude product chromatographed (S)O.sub.2; EtOAc) affording the
title compound as a slightly yellow solid (420 mg, 68%).
.delta..sub.H (CDCl.sub.3) 9.35 (1H, s), 8.82 (1H, d, J 5.9 Hz),
8.48 (1H, d, 15.6 Hz), 8.00 (1H, d, 15.9 Hz), 7.74 (1H, d, J 5.6
Hz); m/z (ES.sup.+, 70V) 165 and 167 (MH.sup.+).
[0189] Intermediate 6
[0190] Ethyl
(S)-3-{4-[(2,6-naphthyridin-1-yl)amino]phenyl}-2-[N-(t-butylo- xy
carbonyl) amino]propanoate
[0191] Ethyl
(S)-3-(4-aminophenyl)-2-[N-(t-butyloxycarbonyl)amino]propanoa- te
(600 mg, 1.95 mmol), Intermediate 5 (350 mg, 2.13 mmol) and DIPEA
(276 mg, 372 .mu.l, 2.13 mmol) in 2-ethoxyethanol (0.5 ml) were
stirred at 130.degree. under N.sub.2 for several hours. The
reaction was partitioned between EtOAc (70 ml) and saturated
aqueous NaHCO.sub.3 (30 ml). The phases were separated and the
aqueous layer re-extracted with EtOAc (3.times.30 ml). The combined
organic extracts were washed with brine (10 ml), dried (MgSO.sub.4)
and evaporated in vacuo to afford a dark oil. Chromatography
(S)O.sub.2; 3% MeOH/DCM) gave the title compound as a dull orange
foam (360 mg, 42%). .delta..sub.H (CDCl.sub.3) 9.19 (1H, s), 8.67
(1H, d, J 5.9 Hz), 8.24 (1H, d, J 5.8 Hz), 7.66 (1H, d, J 5.9 Hz),
7.65 (2H, d, J 8.5 Hz), 7.21 (1H, d, J 5.8 Hz), 7.16 (2H, d, J 8.5
Hz), 7.15 (1H, obscured s), 5.05-4.97 (1H, m), 4.60-4.51 (1H, m),
4.19 (2H, q, 17.1 Hz), 3.17-3.04 (2H, m), 1.44 (9H, s), 1.27 (3H,
t, J 7.1 Hz); m/z (ES.sup.+, 70V) 459 (MNa.sup.+), 437
(MH.sup.+).
[0192] Intermediate 7
[0193] Ethyl
(S)-2-amino-3-{4-[(2,6-naphthyridin-1-yl)amino]phenyl}propano-
ate
[0194] Intermediate 6 (360 mg) was treated with a solution of
trifluoroacetic acid (10 ml) and DCM (10 ml) and stirred at RT for
2 h. The volatiles were removed in vacuo and the residue was
partitioned between EtOAc (80 ml) and saturated aqueous NaHCO.sub.3
(30 ml). The phases were separated and the aqueous layer
re-extracted with EtOAc (3.times.30 ml). The combined organic
extracts were dried (MgSO.sub.4) and evaporated in vacuo to afford
the title compound as a dark orange viscous oil (280 mg, 100%).
.delta..sub.H (CDCl.sub.3) 9.18 (1H, s), 8.66 (1H, d, J 5.9 Hz),
8.22 (1H, d, J 5.8 Hz), 7.67 (1H, d, J 5.9 Hz), 7.64 (2H, d, J 8.5
Hz), 7.22 (2H, d, J 8.5 Hz), 7.19 (1H, d, J 5.8 Hz), 4.20 (2H, q, J
7.1 Hz), 3.73 (1H, dd, J 7.9, 5.1 Hz), 3.10 (1H, dd, J 13.6, 5.2
Hz), 2.87 (1H, dd, J 13.6, 7.9 Hz), 1.70 (3H, br s), 1.28 (3H, t,
7.1 Hz); m/z (ES.sup.+, 70V) 337 (MH.sup.+).
[0195] Intermediate 8
[0196] Methyl
(S)-2-(t-butyloxycarbonylamino)-3-[4-(2,6-naphthyridin-1-ylo-
xy)phenyl]propanoate
[0197] To N-(t-butyloxycarbonyl) tyrosine methyl ester (1.42 g,
4.82 mmol) in dry DMF (10 ml) was added 1-chloro-2,6 naphthyridine
(0.79 g, 4.82 mmol) and cesium carbonate (1.65 g, 5.06 mmol) and
the reaction stirred at 450 under N.sub.2 for 2 days. The DMF was
evaporated, EtOAc added and washed (3.times.) with water, dried
(MgSO.sub.4), and evaporated in vacuo. The residue was
chromatographed (SiO.sub.2; 40 to 100% EtOAc/isohexane) to afford
the tile compound as white foam (1.61 g, 82%). .delta..sub.H
(CDCl.sub.3) 9.29 (1H, s), 8.76 (1H, d, J 5.74 HZ), 8.17 (1H, d, J
5.74 Hz), 8.11 (1H, d, J 5.8 Hz), 7.43 (1H, d, J 5.8 Hz), 7.22-7.18
(3H, m), 5.03 (1H, br s), 4.61 (1H, br s), 3.75 (3H, s), 3.15-3.05
(2H, m), 1.44 (9H, s); m/z (ES.sup.+, 70V) MH.sup.+ 424.
[0198] Intermediate 9
[0199] Ethyl
(S)-2-(N-t-butyloxycarbonylamino)-3-[4-(isoquinolin-1-ylamino- )
phenyl]propanoate
[0200] A stirred solution of ethyl
(S)-3-(4-aminophenyl)-2-(N-4-butyloxyca- rbonylamino)propanoate
(3.08 g, 10.0 mmol), 1-chloroisoquinoline (1.80 g, 11.0 mmol) and
N,N-diisopropylethylamine (1.42 g, 1.91 ml, 11.0 mmol) in
2-ethoxyethanol (1.0 ml) was heated at 130.degree. for 4 h. The
volatiles were removed in vacuo and the residue partitioned between
EtOAc (120 ml) and saturated aqueous NaHCO.sub.3 (50 ml). The
phases were separated and the aqueous layer was re-extracted with
EtOAc (80 ml). The combined organic extracts were washed with brine
(30 ml), dried (MgSO.sub.4) and evaporated in vacuo. The obtained
dark oil was chromatographed (Silica; 20-30% EtOAc/hexane) to
afford the title compound as a pink oil which crystallised on
standing (2.78 g, 64%). .delta..sub.H (CDCl.sub.3) 8.07 (1H, d, J
5.8 Hz), 7.93 (1H, d, J 8.4 Hz), 7.72 (1H, d, J 7.5 Hz), 763 (1H,
d), 7.61 (2H, d, B 8.5 Hz), 7.51 (1H, t, J 6.8 Hz), 7.23 (1H, br
s), 7.10 (1H, br s), 7.10 (2H, d, J 6.8 Hz), 5.02 (1H, br d, J 8.0
Hz), 4.54 (1H, br m), 4.16 (2H, t, J 7.1 Hz), 3.05 (2H, br m), 1.43
(9H, s), 1.25 (3H, t, J 7.1 Hz); m/z (ES.sup.+, 60V) 436
(MH.sup.+).
[0201] Intermediate 10
[0202] (S)-Ethyl
2-amino-3-[4-(isoquinolin-1-ylamino)phenyl]propanoate
[0203] A stirred solution of Intermediate 9 (2.709) in EtOAc (100
ml) was treated with HCl gas until turbidity and precipitation was
seen to occur. The reaction mixture was stirred at ambient
temperatue for an addition 0.5 h. The reaction was purged with
nitrogen then diluted with EtOAc (50 ml) and saturated aqueous
NaHCO.sub.3 (50 ml). Sufficient solid NaHCO.sub.3 was added to
ensure full neutrality. The phases were separated and the aqueous
layer re-extracted with EtOAc (2.times.40 ml). The combined organic
extracts were washed with brine (20 ml), dried (MgSO.sub.4) and
evaporated in vacuo to afford the title compound as a light orange
oil (2.10 g, q). .delta.H (CDCl.sub.3) 8.06 (1H, d, J 5.8 Hz), 7.91
(1H, d, 18.3 Hz), 7.71 (1H, d, J 7.9 Hz), 7.63 (1H, obs. signal),
7.59 (2H, d, J 8.4 Hz), 7.49 (1H, app.t, J 7.8 HZ), 7.25 (1H, br
s), 7.15 (1H, d, J 8.4 Hz), 7.09 (1H, d, J 5.8 Hz), 4.17 (2H, q, J
7.2 Hz), 3.68 (1H, dd, J 7.7, 5.1 Hz), 3.06 (1H, dd, J 14.6, 5.1
Hz), 2.81 (1H, dd, J 13.6, 7.9 Hz), 1.58 (2H, br s), 1.26 (3H, t,
v7.0 Hz); m/z (ES.sup.+, 60V) 435.9 (MH.sup.+).
[0204] Intermediate 11
[0205] Ethyl
(E)-3-{4-[(tert-Butoxycarbonyl)amino]phenyl}-2-propenoate
[0206] Ethyl 4-aminocinnamate (2.5 g, 13.1 mmol) was dissolved in
THF (25 ml) and treated with di-tert-butyl dicarbonate (3.14 g).
The solution was refluxed for 16 h and then allowed to cool. The
product was extracted into EtOAc and washed with water and brine,
dried over Na.sub.2SO.sub.4, filtered and the solvent removed. The
crude product was purified by column chromatography (S)O.sub.2;
EtOAc/hexane 1:9) to give the title compound (2.82 g, 74%) as a
white solid. .delta..sub.H (CDCl.sub.3) 7.62 (1H, d, J 16.0 Hz),
7.45 (2H, d, 8.8 Hz), 7.38 (2H, d, 18.8 Hz), 6.63 (1H, br s), 6.33
(1H, d, J 16.0 Hz), 4.12 (2H, q, J 7.1 Hz), 1.52 (9H, s), 1.25 (3H,
t, J 7.1 Hz). m/z (ES.sup.+, 70V) 314 (MNa.sup.+).
[0207] Intermediate 12
[0208] Ethyl
(3S)-3-{4-[(tert-Butoxycarbonyl)amino]phenyl}3-{N-benzyl[(1R)-
-1-phenylethyl]amino}propanoate
[0209] Intermediate 11 (1.0 g, 3.44 mmol) was dissolved in THF (25
ml), treated with sodium hydride and left to stir for 20 mins.
(R)-(+)--N-Benzyl-(methylbenzylamine (1.44 ml) in THF (25 ml) at
0.degree. was treated with n-butyllithium (2.75 ml, 2.5M in
hexanes) and the purple solution left to stir for 20 mins then
cooled to -78.degree. and the ester anion added slowly. The
reaction mixture was stirred at -78.degree. C. for 4 h then
quenched with ammonium chloride solution, extracted into EtOAc,
washed with water and brine, dried (Na.sub.2SO.sub.4), filtered and
the solvent removed. The crude product was purified by column
chromatography (S)O.sub.2; CH.sub.2Cl.sub.2) to give the title
compound (1.14 g, 66%) as a white solid. .delta..sub.H (CDCl.sub.3)
7.42-7.17 (14H, m), 6.45 (1H, br s), 4.39 (1H, dd, J 9.4, 5.5 Hz),
3.99 (1H, q, J 6.9 Hz), 3.93 (2H, qd, J 7.1, 2.4 Hz), 3.72 (1H, d,
J 14.7 Hz), 3.64 (1H, d, J 14.7 Hz), 2.63 (1H, dd, J 14.7, 5.5 Hz),
2.52 (1H, dd, J 14.7, 9.5 Hz), 1.52 (9H, s), 1.22 (3H, d, J 6.9
Hz), 1.06 (3H, t, 17.1 Hz). m/z (ES.sup.+, 70V) 503 (MH.sup.+).
[0210] Intermediate 13
[0211] Ethyl
(3S)-3-amino-3-{4-[(tert-Butoxycarbonyl)amino]}phenyl-propano-
ate
[0212] Intermediate 12 (312 mg, 0.62 mmol) in MeOH (5 ml) was
treated with formic acid (0.1 ml) and 10% palladium on carbon. The
reaction mixture was heated to reflux for 30 mins then cooled,
filtered through celite.TM. and the solvent removed to give the
title compound (195 mg, 100%) as an oil. .delta..sub.H (CDCl.sub.3)
8.05 (2H, br s), 7.28 (2H, d, J 8.5 Hz), 7.21 (2H, d, J 8.5 Hz,),
6.92 (1H, brs), 4.48 (1H, dd, J 8.4, 5.7 Hz), 4.05 (2H, q, J 7.1
Hz), 3.6 (1H, dd, J 17.2, 8.4 Hz), 2.79 (1H, dd, J 17.2, 5.7 Hz),
1.44 (9H, s), 1.14 (3H, t, J 7.1 Hz). m/z (ES.sup.+, 70V) 331
(MNa.sup.+).
[0213] Intermediate 14
[0214] Methyl
(R)-3-[(tert-Butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propan-
oate
[0215] Methyl (3R)-(3-amino)-3-(4-hydroxyphenyl)propanoate [S. G.
Davies and 0. Ichihara, Tetrahedron Asymmetry, (1991), 2, 183-186]
(346 mg, 1.78 mmol) was dissolved in dioxan (5 ml) and sodium
bicarbonate solution (5 ml) added. The solution was treated with
di-tert-butyl dicarbonate (407 mg, 1.86 mmol) and stirred
vigourously for 16 h. The solution was diluted with water, and the
product extracted into EtOAc (.times.2), washed with water, brine,
dried (Na.sub.2SO.sub.4), filtered and the solvent removed. The
product was purified by column chromatography (S)O.sub.2;
CH.sub.2Cl.sub.2/MeOH 20:1) to give the title compound (211 mg,
42%) as a white solid. .delta..sub.H (CDCl.sub.3) 7.06 (2H, d, J
8.6 Hz), 6.66 (2H, d, J 8.6 Hz), 5.48 (1H, br), 4.98 (2H, br m),
3.61 (3H, s), 2.78 (2H, m), 1.42 (9H, s). m/z (ES.sup.+, 70V) 318
(MNa.sup.+).
[0216] Intermediate 15
[0217] Methyl
(3R)-3-[(tert-Butoxycarbonyl)amino]-3-{4-[(6,7-dimethoxy-4-q-
uinazolinyl)oxy] phenyl}propanoate
[0218] Intermediate 14 (420 mg, 1.42 mmol) in DMF (4 ml) was
treated with potassium carbonate (394 mg) and
4-chloro-6,7-dimethoxyquinazoline (320 mg). The solution was
stirred for 48 h and then water (20 ml) was added. The mixture was
extracted with EtOAc (.times.2), washed with water (.times.3),
brine, dried (Na.sub.2SO.sub.4), filtered and the solvent removed
to give the title compound (657 mg, 96%) as a foamy yellow solid.
.delta..sub.H (DMSO d.sup.6) 8.53 (1H, s), 7.53 (1H, s), 7.40 (2H,
d, J 8.6 Hz), 7.37 (1H, s), 7.24 (2H, d, J 8.6 Hz), 4.96 (1H;, m,
CH), 3.98 (3H, s), 3.95 (3H, s), 3.57 (3H, s), 2.77 (2H, m), 1.36
(9H, s). m/z (ES.sup.+, 70V) 484 (MH.sup.+).
[0219] Intermediate 16
[0220] Methyl
(3R)-3-Amino-3-{4-[(6,7-dimethoxy4-quinazolinyl)oxy]phenyl}p-
ropanoate
[0221] Intermediate 15 (650 mg, 1.35 mmol) was dissolved in EtOAc
(10 ml) and HCl gas was bubbled through. The reaction mixture was
stirred for 2 h and the solvent removed to give the title compound
(589 mg, 100%) as an oil. .delta..sub.H (DMSO d.sup.6) 8.66 (1H,
s), 7.65 (2H, d, J 8.7 Hz), 7.58 (1H, s), 7.44 (1H, s), 7.39 (2H,
d, J 8.7 Hz), 3.99 (3H, s), 3.97 (3H, s), 3.58 (3H, s), 3.22 (1H,
dd, J 16.3, 6.1 Hz), 3.05 (1H, dd, J 16.3, 8.5 Hz). m/z (ES.sup.+,
70V) 384 (MH.sup.+).
[0222] Intermediate 17
[0223] Methyl (S)-3-{4-[(3-phenyl-1
quinazolinyl)amino]-phenyl}-[2-(tert-b-
utoxycarbonyl)amino]-propanoate
[0224] Methyl
(2S)-[2-(tert-butoxycarbonyl)amino]-3-(4-aminophenyl)propano- ate
(500 mg, 1.7 mmol) and 4-chloro-2-phenylquinazoline (408 mg) were
dissolved in 2-ethoxyethanol (5 ml) with Hunigs base (0.6 ml) and
the solution heated at 120.degree. C. for 16 h. The solution was
cooled and concentrated. The residue was purified by column
chromatography (S)O.sub.2; CH.sub.2Cl.sub.2/MeOH 25:1) to give the
title compound (682 mg, 81%) as a brown foamy solid. .delta..sub.H
(CDCl.sub.3) 8.56 (2H, dd, J 7.5, 3.7 Hz), 8.10 (1H, m), 7.95 (1H,
m), 7.88 (2H, d, J 8.5 Hz), 7.80 (1H, m), 7.70 (1H, m), 7.50 (3H,
m), 7.23 (2H, d, J 8.5 Hz), 5.05 (1H, m), 4.65 (1H, m), 3.72 (3H,
s), 3.49 (1H, m), 3.15 (2H, m), 1.45 (9H, s). m/z (ES.sup.+, 70V)
499 (MH.sup.+).
[0225] Intermediate 18
[0226] Methyl (S)-2-Amino-3-{4-[(3-phenyl-1-quinazolinyl
amino]phenyl}propanoate
[0227] Intermediate 17 (678 mg, 1.36 mmol) in EtOAc (30 ml) was
saturated with HCl gas and stirred for 45 mins. The brown
precipitate was filtered off and dried to give the title compound
(518 mg, 96%) as a brown foamy solid. 5H (DMSO d.sup.6) 9.12 (1H,
d, J 8.6 Hz), 8.83 (2H, m), 8.50 (1H, d, J 8.1 Hz), 8.44 (2H, d, J
7.1 Hz), 8.14 (1H, d, J 8.1 Hz), 8.10 (1H, t, J 8.1 Hz), 7.84 (2H,
d, u 8.6 Hz), 7.70 (1H, d, J 7.1 Hz), 7.63 (2H, t, J 17.1 Hz), 7.40
(2H, d, J 8.5 Hz), 3.70 (3H, s), 3.67 (1H, m), 3.30 (1H, dd, J
14.0, 5.5 Hz), 3.18 (1H, dd, J 14.0, 7.4 Hz). m/z (ES.sup.+, 70V)
399 (MH.sup.+).
[0228] Intermediate 19
[0229] Ethyl
(R)-3-Amino-3-[4-(tert-butoxycarbonyl)aminophenyl]propanoate
[0230] Ethyl
(3R)-3-{Benzyl[(1S)-1-phenylethyl]amino}-3-[4-(tert-butoxycar-
bonyl) amino phenyl]propanoate (1.18 g, 2.35 mmol) was dissolved in
MeOH (10 ml) and formic acid (1 ml) and 10% palladium on carbon
added and the mixture refluxed for 2 h. The reaction mixture was
cooled, filtered through Celite.RTM. and concentrated to give the
crude title compound which was used immediately in the next
reaction. .delta..sub.H (CDCl.sub.3) 7.34 (2H, d, J 8.1 Hz), 7.27
(2H, d, J 8.1 Hz), 7.10 (1H, br s), 4.59 (1H, m), 4.11 (2H, q, J
7.1 Hz), 3.14 (1H, dd, J 16.8, 7.9 Hz), 2.86 (1H, dd, J 16.8, 12.0
Hz), 1.20 (3H, t, J 7.1 Hz).
[0231] Intermediate 20
[0232] Ethyl (R)-3-amino-3-(4-aminophenyl)propanoate Intermediate
19 was dissolved in EtOAc (25 ml) and the solution saturated with
HCl gas. The solution was stirred at RT for 90 mins whilst a white
precipitate formed. The solid was filtered and dried to give the
title compound (570 mg, 88% over 2 steps) as a white solid. AH
(DMSO d6) 8.79 (2H, br s), 7.63 (2H, d, J 8.4 Hz), 7.36 (2H, d, J
8.4 Hz, 4.58 (1H, m), 3.98 (2H, q, J 7.1 Hz), 3.19 (1H, dd, J 16.3,
5.6 Hz), 2.99 (1H, dd, J 16.3, 9.1 Hz), 1.08 (3H, t, 17.1 Hz). m/z
(ES.sup.+, 70V) 192 (M-NH.sub.3).
[0233] Intermediate 21
[0234] Ethyl (R)-3-(4-Aminophenyl)-3-(tert-butoxycarbonylamino)
propanoate
[0235] Intermediate 20 (550 mg, 1.96 mmol) was dissolved in dioxan
(10 ml) and treated with sodium bicarbonate (1 g), water (10 ml)
and di-tert-butyl dicarbonate (427 mg) and the mixture stirred for
16 h. Water was added and the product extracted into EtOAc
(.times.2), washed with brine, dried (Na.sub.2SO.sub.4), filtered
and concentrated to give the crude product which was purified by
column chromatography (S)O.sub.2; CH.sub.2Cl.sub.2/MeOH 20:1) to
give the title compound (296 mg, 49%) as an oil. .delta..sub.H
(CDCl.sub.3) 7.07 (2H, d, J 8.3 Hz), 6.64 (2H, d, J 8.3 Hz), 5.28
(1H, br s), 4.99 (1H, m), 4.05 (2H, q, J 7.1 Hz), 2.82 (1H, dd, J
5.1, 6.5 Hz), 2.73 (1H, dd, J 15.1, 6.5 Hz), 1.42 (9H, s), 1.17
(3H, t, J 7.1 Hz). m/z (ES.sup.+, 70V) 331 (MNa.sup.+).
[0236] Intemediate 22
[0237] Ethyl
(3R)-3-[(tert-Butoxycarbonylamino)]-3-[4-(2,6-naphthyridin-1--
ylamino)phenylpropanoate
[0238] Intermediate 21 (250 mg, 0.81 mmol) in 2-ethoxyethanol (2
ml) was treated with 1-chloro-2,6-naphthyridine (134 mg) and heated
at 120.degree. for 15 mins, then 100.degree. C. for 1 h, then
cooled and concentrated. The residue was extracted into EtOAc (x
3), washed with sodium bicarbonate solution, brine, dried
(Na.sub.2SO.sub.4), filtered and concentrated to give the crude
product. The products were purified by column chromatography
(S)O.sub.2; CH.sub.2Cl.sub.2/MeOH 50:1-20:1-10:1) to give the
deprotected compound (106 mg, 30%) as a brown gum and the title
compound (98 mg, 36%) as a yellow gum. .delta..sub.H (CDCl.sub.3)
9.18 (1H, s), 8.66 (1H, d, J 5.9 Hz), 8.20 (1H, d, J 58 Hz), 7.73
(1H, d, J 5.9 Hz), 7.65 (2H, d, J 8.5 Hz), 7.30 (2H, d, J 8.5 Hz),
7.19 (1H, d, J 5.8 Hz), 5.47 (1H, m), 5.08 (1H, m), 4.09 (2H, q, J
7.1 Hz), 2.83 (2H, t, 16.4 Hz), 1.44 (9H, s), 1.20 (3H, t, 17.1
Hz). m/z (ES.sup.+, 70V) 437 (MH.sup.+).
[0239] Intermediate 23
[0240] Ethyl (R)-3-Amino-3-[4-(2,6-naphthyridin-1-ylamino)phenyl
propanoate
[0241] Intermediate 22 (100 mg, 1 mmol) was dissolved in EtOAc (5
ml) and saturated with HCl gas. The reaction mixture was stirred to
give a precipitate which was filtered and dried to give the title
compound which was combined with the material isolated from the
previous reaction. 5H (CDCl.sub.3) 9.18 (1H, s), 8.65 (1H, d, J 5.9
Hz), 7.65 (2H, d, J 8.5 Hz,), 7.37 (2H, d, J 8.5 Hz), 7.19 (1H, d,
J 5.7 Hz), 4.44 (1H, t, J 6.8 Hz), 4.15 (2H, q, J 7.1 Hz), 2.68
(2H, d, J 6.8 Hz), 1.25 (3H, t, J 1-7.1 Hz).
[0242] Intermediate 24
[0243] N--BOC--O-(2-Pyrimidinyl)-L-tyrosine methyl ester
[0244] A solution of N--BOC-L-tyrosine methyl ester (3.0 g, 10.2
mmol) in DMF (5 ml) was added to a suspension of NaH (60% in oil,
11.2 mmol, 447 mg) in DMF (10 ml). After 10 min, a solution of
2-chloropyrimidine (11.2 mmol, 1.28 g) in DMF (3 ml) was added and
the mxiture stirred overnight. The reaction was quenched with
water, diluted EtOAc and washed with water and brine. The EtOAc
layer was dried (Na.sub.2SO.sub.4) and concentrated in vacuo.
Purification by column chromatography [SiO.sub.2, EtOAc/hexane,
1:1] gave the title compound. .delta..sub.H (DMSO d6) 8.62 (2H, d,
J 4.8 Hz), 7.37 (1H, d, J 8.1 Hz), 7.28 (2H, d, J 8.4 Hz), 7.24
(1H, t, J 4.8 Hz), 7.09 (2H, d, J 8.4 Hz), 4.18 (1H, m), 3.01 (1H,
dd, J 13.8, 4.6 Hz), 1.33 (9H, s).
[0245] Intermediate 25
[0246] O-(2-Pyrimidinyl)-L-tyrosine methyl ester hydrochloride
[0247] Removal of BOC group from Intermediate 24 (HCl/EtOAc) gave
the title compound as a white solid. .delta.H (DMSO d.sub.6) 8.69
(3H, m), 8.63 (2H, d, J 4.9 Hz), 7.31-7.25 (3H, m), 7.15 (2H, d, J
8.6 Hz), 4.30 (1H, m), 3.69 (3H, s), 3.19 (1H, dd, J 14.5, 6.4 Hz),
3.12 (1H, dd, J 14.3, 7.2 Hz).
[0248] Intermediate 26
[0249] N BOC-O-(3,5-Dichloroisonicotinoyl)-L-tyrosine methyl
ester
[0250] A solution of N-BOC-L-tyrosine methyl ester (2.95 g, 10
mmol) in THF (10 ml) was added to a suspension of NaH (60% in oil,
11 mmol, 440 mg) in THF (30 ml) at 0.degree.. After 10 min, a
solution of 3,5-dichloroisonicotinoyl chloride (11 mml, 2.32 g) in
THF (10 ml) was added and the mixture stirred at RT for 4 h.
NH.sub.4Cl (aq) was added and the mixture extracted with DCM. The
DCM extracts were dried (Na.sub.2SO.sub.4) and concentrated in
vacua. Recrystallisation (EtOAc/hexane) gave the title compound as
white crystals (3.61 g, 77%). .delta.H (DMSO d.sub.6) 8.89 (2H, s),
7.39 (2H, d, J 8.5 Hz), 7.32 (1H, d, J 8.2 Hz), 7.23 (2H, d, J 8.5
Hz), 4.21 (1H, m), 3.62 (3H, s), 3.05 (1H, dd, J 13.8, 4.9 Hz),
2.89 (1H, dd, J 13.8, 10.5 Hz), 1.31 (9H). m/z (ES.sup.+, 70V) 410
(M++Na).
[0251] Intermediate 27
[0252] O-(3,5-Dichloroisonicotinoyl)-L-tyrosine methyl ester
hydrochloride
[0253] Intermediate 26 (3.61 g) in EtOAc (150 ml) was treated with
HCl/EtOAc (3m, 50 ml). The white precipitate produced was filtered
off and dried to give the title compound as a white solid (1.93 g).
.delta.H (DMSO d.sub.6) 8.90 (2H, s), 8.74 (3H, br), 7.42 (2H, d, J
8.5 Hz), 7.28 (2H, d, J 8.6 Hz), 4.31 (1H, m), 3.67 (3H, s), 3.25
(1H, dd, J 14.2, 6.0 Hz), 3.17 (1H, dd, J 14.1, 7.2 Hz). m/z
(ES.sup.+, 70V) 369 (MH.sup.+).
[0254] Intermediate 28
[0255] 3-Butyl4-methoxy-3-cyclobutene-1,2-dione
[0256] n-BuLi (8.13 ml of a 1.6M solution in hexane, 13 mmol) was
added slowly to a solution of 3,4-dimethoxy-3-cyclobutene-1,2-dione
(1.42 g, 10 mmol) in THF (100 ml) at -78.degree.. After 2 h,
trifluoroacetic anhydride (2.12 ml, 15 mmol) was added. After a
further 30 min the cold solution was poured into NH.sub.4Cl(aq)
(100 ml) and EtOAc (100 ml) and stirred well. The aqueous layer was
extracted with EtOAc. The organic extracts were washed with brine,
dried (Na.sub.2SO.sub.4) and concentrated in vacuo. Column
chromatography (S)O.sub.2, EtOAc/hexane, 30:70) gave the title
compound as a yellow oil (803 mg, 48%). .delta.H (CDCl.sub.3) 4.42
(3H, s), 2.60 (2H, t, 17.6 Hz), 1.71-1.61 (2H, m), 1.44-1.32 (2H,
m), 0.94 (3H, t, J 7.3 Hz). m/z (ES.sup.+, 70V) 169 (MH.sup.+).
[0257] Intermediate 29
[0258] Methyl
(Z)-2-[(tert-butoxycarbonyl)amino]-3-(3-methoxy-4-nitropheny-
l)-2-propenoate
[0259] Activated manganese IV oxide (26 g) was added to a mixture
of 3-methoxy-4-nitrobenzylalcohol (5.26 g, 28.7 mmol),
N-(t-Butyloxycarbonyl)<-(diethylphosphono)glycine methylester
(described in WO99/47547) (8.91 g, 27.4 mmol) and DBU (4.29 ml,
28.7 mmol) in DCM (150 ml) at 00. The mixture was stirred at RT
overnight then filtered. The filtrate was washed with dil. HCl,
dried (Na.sub.2SO.sub.4) and evaporated in vacuo. Recrystallisation
from MeOH gave the title compound as pale brown crystals (4.6 g).
6H (DMSO d.sub.6) 8.94 (1H, br s), 7.91 (1H; d, J 18.4 Hz), 7.56
(1H, d, J 1.5 Hz), 7.36 (1H, dd, 18.5, 1.3 Hz), 7.12 (1H, br s),
3.92 (3H, s), 3.75 (3H, s), 1.37 (9H, s). M/Z (ES.sup.+, 70V) 375
(M.sup.++Na).
[0260] Intermediate 30
[0261] Methyl
3-(4-amino-3-methoxyphenyl)-2-[(tert-butoxycarbonyl)amino]-2-
-propanoate
[0262] A mixture of Intermediate 29 (2.30 g, 6.53 mmol) and
palladium on charcoal (10% Pd on carbon, 230 mg) in MeOH (65 ml)
was stirred under a hydrogen atmosphere at RT overnight. The
catalyst was filtered off and the filtrate concentrated in vacuo.
Recrystallisation (Et.sub.2O/hexane) gave the title compound as
dark pink needles (1.62 g, 77%). .delta.H (DMSO d.sub.6) 7.12 (1H,
d, J 7.9 Hz), 6.65 (1H, s), 6.51 (2H, s), 4.52 (1H, s), 4.49 (1H,
s), 4.07 (1H, m), 3.72 (3H, s), 3.59 (3H, s), 2.81 (1H, dd, J 13.7,
5.4 Hz), 2.69 (1H, dd, J 13.1, 9.5 Hz), 1.32 (9H, s). m/z
(ES.sup.+, 70V) 347 (MNa.sup.+).
[0263] Intermediate 31
[0264] Methyl
3-{4-[(6,7-dimethoxy-4-quinazolinyl)amino]-3-methoxyphenyl}--
2-[(tert-butoxycarbonyl)amino]propanoate
[0265] A mixture of Intermediate 30 (486 mg, 15 mmol),
4-chloro-6,7-dimethoxy quinazoline (337 mg, 1.5 mmol) and
diisopropylethylamine (2610, 1.5 mmol) in ethoxyethanol (1.5 ml)
was heated at 120.degree. for 24 h. The mixture was diluted with
DCM, washed with dil. HCl and water, dried (Na.sub.2SO.sub.4) and
concentrated in vacuo. Column chromatography (S)O.sub.2: MeOH/DCM,
5:95) gave the title compound as a brown gum (720 mg, 94%) .delta.H
(DMSO d6) 9.10 (1H, s, ArNH), 8.34 (1H, d, J 1.0 Hz), 7.85 (1H, d,
J 1.4 Hz), 7.47-7.44 (2H, m), 7.40 (1H, d, J 8.0 Hz), 7.47-7.44
(2H, m), 7.40 (1H, d, J 8.0 Hz), 7.20 (1H, s), 7.07 (1H, s), 6.91
(1H, d, J 8.0 Hz), 4.344.28 (1H, m), 3.98 (3H, s), 3.98 (3H,
s),3.82 (3H, s) 3.70 (3H, s), 3.09 (1H, dd, J 13.8, 5.0 Hz), 2.95
(1H, dd, J 13.7, 10.0 Hz), 1.42 (9H, s). m/z (ES.sup.+, 70V) 573
(MH.sup.+).
[0266] Intermediate 32
[0267] Methyl
2-amino-3-{4-[(6,7-dimethoxy4-quinazolinyl)amino]-3-methoxyp-
henyl}propanoate hydrochloride Dry HCl was bubbled into a solution
of Intermediate 31 (715 mg, 1.4 mmol) in EtOAc (30 ml) for a few
seconds. The mixture was stirred at RT for 1 h. The precipitate was
filtered off and dried to give the title compound as a brown solid
(534 mg, 85%). .delta.H (DMSO d.sub.6, 370K) 8.57 (1H, s), 8.23 (1H
br s), 7.43 (1H, d, J 7.9 Hz), 7.15 (1H, s), 6.95 (1H, dd, J 8.0,
1.5 Hz), 4.28 (1H, dd, J 7.1, 6.2 Hz), 4.02 (3H, s), 4.01 (2H, s),
3.82 (3H, s), 3.75 (3H, s), 3.31 (1H, dd, J 14.2, 6.1 Hz), 3.24
(1H, dd, J 14.2, 7.1 Hz). m/z (ES.sup.+, 70V) 413 (MH.sup.+).
[0268] Intermediate 33
[0269] Methyl
(S)-2-[(tert-butoxycarbonyl)amino]-3-{4-[2-(2,6-dichlorophen-
yl)ethynyl]phenyl}propanoate
[0270] Nitrogen was bubbled through a solution of
N--BOC-L-4-iodophenylala- nine methyl ester (1.50 g, 3.69 mmol) in
toluene (20 ml) and triethylamine (10 ml).
Bis(triphenylphosphine)palladium (II) chloride (10 mol %, 260 mg)
and copper (I) iodide (20 mol %, 140 mg) were added. A solution of
2,6-dichlorophenylacetylene (949 mg, 5.55 mmol) in toluene (10 ml)
was added by syringe-pump over 3 h. The mixture was stirred at RT
for a further 3 h. The mixture was diluted with EtOAc, washed with
dil. HCl and brine, dried (Na.sub.2SO.sub.4) and evaporated in
vacuo. Column chromatography (S)O.sub.2; EtOAc/hexane, 20:80) gave
the title compound as a brown gum (1.61 g, 97%). .delta.H (DMSO
d.sub.6), 7.60-7.58 (2H, m), 7.51 (2H, d, J 8.1 Hz), 7.42 (1H, dd,
J 8.8, 7.4 Hz), 7.33 (2H, d, J 8.1 Hz), 4.21 (1H, br m), 3.73 (3H,
s), 3.04 (1H, dd, J 13.8, 5.0 Hz), 2.88 (1H, dd, J 13.7, 10.0 Hz)
and 1.31 (9H, s): m/z (ES.sup.+, 70V) 470 (M.sup.++Na).
[0271] Intermediate 34
[0272] Methyl
(S)-2-amino-3-{4-[2-(2,6-dichlorophenyl)ethynyl]phenyl}propa- noate
hydrochloride
[0273] HCl gas was bubbled through a solution of the compound of
Example 33 (1.6 g, 3.57 mmol) in EtOAc (70 ml) for 5 min. The
mixture was stirred for 1 h at RT. The precipitate formed was
filtered off and washed with ether to give the title compound as an
off-white solid (1.21 g, 88%). .delta.H (DMSO d6), 8.73 (3H, br s),
7.60 (2H, d, J 8.0 Hz), 7.56 (2H, d, J 8.1 Hz), 7.44 (1H, dd, J
8.7, 7.6 Hz), 7.35 (2H, d, J 8.1 Hz), 4.30 (1H, t, J 6.6 Hz), 3.68
(3H, s), 3.25 (1H, dd, J 14.2, 6.1 Hz), 3.16 (1H, dd, J 14.0, 7.2
Hz); m/z (ES.sup.+, 70V) 348 (M.sup.++H).
[0274] Intermediate 35
[0275] 5-Methyl4-[3H]quinazolinone
[0276] 6-Methylanthranilic acid (5 g, 33 mmol) and formamidine
acetate (0.4 g, 41 mmol) were refluxed in 2-ethyoxyethanol (50 ml)
for 16 h. On cooling the solvent was removed in vacuo, the residue
slurried in diethyl ether, the solid filtered, washed with diethyl
ether and dried to yield 3.6 g of the title compound. .delta.H
(DMSO d.sub.6), 7.97 (1H, s), 7.60 (1H, dd, J 7.9, 7.6 Hz), 7.43
(1H, d, J 8.0 Hz), 7.21 (1H, d, J 7.3 Hz), 2.76 (3H, s); m/z
(ES.sup.+ 70V)161 (MH.sup.+).
[0277] Intermediate 36
[0278] 4-Chloro-5-methylquinazoline
[0279] The compound of Intermediate 35 (4.1 g, 26 mmol) was
refluxed in phosphorous oxychloride (60 ml) for 5 h. On cooling the
phosphorous oxychloride was removed in vacuo and the residue
quenched in ice cold saturated sodium bicarbonate. The resulting
mixture was extracted with EtOAc (3.times.50 ml), washed with
brine, dried (Mg.sub.2SO.sub.4), the solvent removed and the
residue purified by column chromatography (Silica 1:1
ethylacetate/isohexane) to yield the title compound as white solid.
.delta..sub.H (DMSO d.sub.6), 8.5 (1H, s), 7.7 (1H, dd) 7.8 (1H,
d), 7.3 (1H, m)
[0280] Intermediate 37
[0281]
Ethyl-(S)-3-{4-([5-methyl-4-quinazolinyl]amino)phenyl}-2-(t-butoxy--
carbonyl)amino propanoate
[0282]
Ethyl-(S)-3-(4-aminophenyl)-2-[(t-butoxycarbonyl)amino]propanoate
(413 mg, 1.4 mmol) and Intermediate 36 (250 mg, 1.4 mmol) were
heated at reflux in EtOH (10 ml). The solution was cooled, solvent
removed in vacuo, residue stirred in EtOAc (10 ml) and sat. sodium
bicarbonate (10 ml), organic layer isolated, washed with sodium
bicarbonate, brine, dried (MgSO.sub.4) and the solvent removed, to
yield the title compound as an off white solid (520 mg). .delta.H
(CDCl.sub.3) 8.6 (1H, s), 7.8 (1H, br, s), 7.7 (1H, d, J 7.8 Hz),
7.6 (2H, m), 7.3 (1H, d, J 7.2 Hz), 7.2 (2H, d, J 8.7 Hz), 5.2 (1H,
br m), 4.6 (1H, br m) 4.2 (2H, q, 7.2 Hz), 3.15 (2H, br m), 3.1
(3H, s), 1.4 (9H, s), 1.25 (3H, t, J 7.2 Hz).
[0283] Intermediate 38
[0284]
Ethyl-(S)-3-(4-[(5-methyl4-quinazolinyl)amino]phenyl)-2-aminopropan-
oate
[0285] The compound of Intermediate 37 (1.1 g, 2.5 mmol) in DCM (4
ml) and trifluoroacetic acid (2 ml) was stirred for 1 h. The
solution was poured onto saturated sodium bicarbonate and extracted
with EtOAc (.times.3). The extracts were washed with brine, dried
(MgSO.sub.4), solvent removed in vacuo to give the title compound
as yellow oil. .delta.H (CDCl.sub.3), 8.6 (1H, s), 7.8 (1H, br s),
7.7 (1H, d, J 8.4 Hz), 7.6 (3H, m), 7.3 (3H, m) 4.2 (2H, q, J 7.2
Hz), 3.7 (1H, m), 3.1 (1H, dd, J 13.6, 8.4 Hz), 3.0 (1H, s), 2.8
(1H, dd, J 13.6, 7.9 Hz), 1.3 (3H, t, J 7.2 Hz). m/z (ES.sup.+,
70V) 351 (MH.sup.+)
[0286] Intermediate 39
[0287] Methyl-2-amino-5-(trifluoromethoxy)benzoate
[0288] A mixture of 2-Bromo-4-trifluoromethoxy aniline (2.7 g, 10.6
mmol) palladium (II) acetate (360 mg,) triethylamine (9 ml) and
1,3-bis (diphenylphosphino) propane (651 mg) in anhydrous methanol
(10 ml) and anhydrous dimethyl formamide (10 ml) were cooled in
ice/methanol bath, and carbon monoxide gas was bubbled through for
10 min. The mixture was heated at 700 under a partially inflated
balloon of carbon monoxide for 17 h. On cooling nitrogen was
bubbled through the solution to dispense excess carbon monoxide,
and the mixture was poured onto water (50 ml) and EtOAc (50 ml),
filtered through Celite.RTM., the organic layer isolated, and
aqueous phase was extracted with EtOAc. The organic layers were
combined, washed with water (.times.2), brine (.times.2), dried
(MgSO.sub.4), and the solvent removed in vacuo. The residue was
distilled and the fraction boiling at 170.degree., 0.08 mbar
collected to yield 1.8 g of a yellow liquid. 5H (CDCl.sub.3), 7.7
(1H, m), 7.1 (1H, m), 6.6 (1H, d, 19.0 Hz), 3.9 (3H, s).
[0289] Intermediate 40
[0290] 6-(Trifluoromethoxy)-4-[3H]-quinazoline,
[0291] Prepared in a similar manner to the compound of intermediate
35 from the compound of Intermediate 39. .delta..sub.H (DMSO d6),
8.1 (1H, s), 7.9 (1H, s), 7.8 (2H, m).
[0292] Intermediate 41
[0293] 4-Chloro-6-(trifluoromethoxy)quinazoline.
[0294] Prepared from the compound of Intermediate 40 in a similar
manner to that described for Intermediate 36. .delta..sub.H
(CDCl.sub.3), 9.1 (1H, s), 8.1 (1H, d, J 9.2 Hz), 80 (1H, m), 7.8
(1H, m); m/z (EI.sup.+, 70V) 249/251.
[0295] Intermediate 42
[0296]
Ethyl-(S)-3-(4-{[6-trifluoromethoxy4-quinazolinyl]amino}phenyl-2-[(-
t-butoxycarbonyl)amino]propanoate
[0297] Prepared from Intermediate 41 in a similar manner to that
described for Intermediate 37. .delta..sub.H (CDCl.sub.3), 8.7 (1H,
s), 8.0 (1H, d, J 9.1 Hz), 7.8 (1H, br s), 7.6 (314, m), 7.2 (2H,
d, J 8.5 Hz), 5.0 (1H, br s) 4.5 (1H, br s), 4.2 (2H, q, J 7.2 Hz),
3.1 (2H, br s), 1.4 (9H, s), 1.2 (3H, t, J 7.2 Hz).
[0298] Intermediate 43
[0299] Ethyl
(S)-3-(4-{[6-trifluoromethoxy)4-quinazolinyl]amino}phenyl)-2--
aminopropanoate
[0300] Prepared from the compound of Intermediate 42 in a similar
manner to that described for Intermediate 38. .delta..sub.H
(CDCl.sub.3), 8.7 (1H, s), 7.9 (1H, d, J 9.2 Hz), 7.7 (1H, br m),
7.6 (3H, m), 7.2 (2H, d, J 7.1 Hz), 4.2 (2H, q, J 7.2 Hz), 3.8 (1H,
m), 3.1 (1H, m), 2.9 (1H, m), 1.3 (3H, t, J 7.2 Hz); m/z (EI.sup.+,
70V) 421 (MH.sup.+)
[0301] Intermediate 44
[0302] 3-Amino-4-methoxy-3-cyclobutene-1,2-dione
[0303] 3,4-Dimethoxy-3-cyclobutene-1,2-dione (1.3 g, 9.2 mmol) in
of MeOH (10.0 ml) was treated with aqueous ammonia (10.0 ml of a
2.0M solution) and stirred at ambient temperature for 2 h. The
yellow precipitate thus formed was recovered by filtration, washed
with MeOH and Et.sub.2O and dried in vacuo to afford the title
compound (0.87 g, 75%) as an amorphous yellow powder .delta.H
(d.sup.6 DMSO) 8.32 (2H, br s), 4.28 (3H, s). m/z (ES.sup.+, 70V)
127 (MH.sup.+).
[0304] Intermediate 45
[0305]
Methyl-(S)-3-{4-[(2-chloro-6,7-dimethoxy-4-quinazolinyl)amino]pheny-
l}-2-[(t-butoxycarbonyl)amino]propanoate
[0306] Prepared in a similar manner to the compound of Intermediate
9 from
methyl-(S)-3-(4-aminophenyl)-2-(N-t-butoxycarbonylamino)propanoate
and 2,4-dichloro6,7-dimethoxyquinazoline. .delta.H (CD.sub.3OD)
7.72 (1H, s), 7.69 (2H, d, J 8.4 Hz), 7.25 (2H, d, J 8.4 Hz), 7.05
(1H, s), 4.34 (1H, m), 4.15 (2H, m, J 7.1 Hz), 4.00 (3H, s), 3.96
(3H, s), 3.08 (1H, m), 2.97 (1H, m), 1.40 (9H, s), 1.23 (3H, t, J
7.1 Hz). m/z (ESI.sup.+ 531 (MH.sup.+).
EXAMPLE 1
[0307] Ethyl
(S)-3-[4-(3,5-dichloro-4-pyridylcarboxamido)phenyl]-242-isopr-
opoxy-3,4-dioxocylobut-1-enylamino)propanoate
[0308] A solution of Intermediate 3 (2.1 g, 5 mmol) in EtOH (25 ml)
was treated with DIPEA (0.96 ml, 5.5 mmol) and
3,4-diisopropoxy-3-cyclobutene- -1,2-dione (1.1 g; 5.5 mmol) and
heated to reflux for 16 h. The reaction mixture was cooled and
concentrated in vacuo. The residue was taken up in EtOAc (50 ml)
and washed with 10% aqueous citric acid (2.times.50 ml),
NaHCO.sub.3 solution (2.times.30 ml) and brine (30 ml), dried
(MgSO.sub.4) and the solvent evaporated in vacuo to give a pale
yellow oil, which was purified by column chromatography
(S)O.sub.2,EtOAc:hexane 1:1) to give the title compound as a white
foam 1.62 g, 62%). .delta.H (DMSO d.sup.6), 10.45 (1H, s), 8.69
(2H, s), 8.52 (1H, d, J 8.4 Hz), 7.57 (2H, d, J 7.6 Hz), 7.25 (2H,
d, J 7.6 Hz), 5.22 (1H, m), 4.69 (1H, m), 4.19 (2H, q, J 7.1 Hz),
3.25 (1H, dd, J 14.3, 5.2 Hz), 3.07 (1H, dd, J 14.3, 9.4 Hz), 1.38
(6H, dd, J 6.2, 3.9 Hz), 1.23 (3H, t, J 7.1 Hz).
EXAMPLE 2
[0309]
Ethyl-(S)-3-[4-(3,5-dichloro4-pyridylcarboxamido)phenyl]-2-(2-[3-me-
thoxypropylamine]-3,4-dioxocyclobut-1-enylamino)propanoate
[0310] A solution of the compound of Example 1 (1.55 g, 2.99 mmol)
in EtOH (25 ml) was treated with 3-methoxypropylamine (0.34 ml, 3.3
mmol) and stirred for 16 h at RT. The white solid was isolated by
filtration, and washed with cold Et.sub.2O (3.times.10 ml) to give
the title compound (1.38 g, 84%). .delta.H (DMSO d.sup.6),10.89
(1H, s), 8.80 (2H, s), 7.59 (2H, d, J 8.4 Hz), 7.25 (2H, br m),
7.18 (2H, d, J 18.4 Hz), 4.99 (1H, m), 4.18 (2H, q, J 7.1 Hz), 3.54
(2H, m), 3.37 (2H, t, J 6.3 Hz), 3.23 (3H, s), 3.16.(1H, m), 3.06
(1H, m), 1.75 (2H, q. 16.3 Hz), 1.22 (3H, t, J 7.1 Hz). m/z
(ES.sup.+, 70V) 549 (MH.sup.+).
EXAMPLE 3
[0311]
(S)-3-[4-(3,5-Dichloro4-pyridylcarboxamido)phenyl]-2-[2-(3-methoxyp-
ropylamino]-3,4-dioxocyclobut-1-enylamino)propanoic acid
[0312] A solution of the compound of Example 2 (1.30 g, 2.48 mmol)
in THF (40 ml) and water (25 ml) was treated with LiOH.H.sub.2O
(125 mg, 2.98 mmol) and stirred for 3 h at RT. The reaction mixture
was concentrated in vacuo, and acidified to pH 2 with 1M
hydrochloric acid. The resulting solid was isolated by filtration,
washed with water and dried in vacuo to give the title compound
(1.15 g, 85%). .delta.H (DMSO d.sup.6), 10.89 (1H, s), 8.79 (2H,
s), 7.58 (3H, m), 7.19 (2H, d, J 8.1 Hz), 4.92 (1H, m), 3.54 (2H,
m), 3.23 (3H, s), 3.16 (1H, dd, J 13.9, 5.1 Hz), 3.05 (1H, dd, J
13.9, 7.4 Hz) and 1.74 (2H, t, J 6.4 Hz). m/z (ES.sup.+, 70V) 521
(MH.sup.+).
EXAMPLE 4
[0313]
Ethyl-(S)-3-[4-(3,5-dichloro-4-pyridylcarboxamido)phenyl]-2-(2-prop-
ylamino-3,4-dioxocyclobut-1-enylamino)propanoate
[0314] A solution of the compound of Example 1 (1 g, 1.93 mmol) in
EtOH (25 ml) was treated with n-propylamine (0.18 ml, 2.12 mmol)
and stirred at RT for 16 h. The resulting white solid was isolated
by filtration and washed with cold Et.sub.2O (2.times.20 ml) to
give the title compound (0.689, 68%). .delta.H (DMSO d.sup.6),
10.87 (1H, s), 8.78 (2H, s), 7.57 (4H, m,), 7.16 (2H, d, J 8.3 Hz),
4.97 (1H, m), 4.16 (2H, q, J 7.1 Hz), 3.44 (2H, m), 3.11 (2H, m),
1.50 (2H, m), 1.20 (3H, t, J 7.1 Hz), 0.86 (3H, t, J 7.1 Hz). m/z
(ES.sup.+, 70V) 519 (MH.sup.+).
EXAMPLE 5
[0315] (S)-3-[4-(3,5-Dichloro
4-pyridylcarboxamido)phenyl]-2-(2-propylamin-
o-3,4-deoxocyclobut-1-enylamino)propanoic acid.
[0316] The title compound (0.67 g, 99%) was prepared from the
compound of Example 4 (0.66 g, 1.27 mmol) in a similar manner to
the compound of Example 3. .delta.H (DMSO d.sup.6), 10.51 (1H, s),
8.71 (2H, s), 7.56 (2H, d, J 8.3 Hz), 7.36 (1H, m), 7.31 (1H, d, J
9.0 Hz), 7.22 (2H, d, J 8.3 Hz), 4.96 (1H, m), 3.49 (2H, q, 16.7
Hz), 3.20 (1H, dd, J 14.1, 5.6 Hz), 3.09 (1H, dd, J 14.1, 7.4 Hz),
1.57 (2H, m), 0.92 (3H, t, J 7.4 Hz). m/z (ES.sup.+, 70V) 491
(MH.sup.+).
EXAMPLE 6
[0317] Ethyl
(S)-3-[4-(3,5-dichloro4-pyridylcarboxamido)phenyl]-2-[(2-tert-
-bukyl)-3,4-dioxo-1-cyclobutenylamino]propanoate
[0318] A mixture of the compound of Intermediate 4 (392 mg, 2
mmol), Intermediate 3 (837 mg, 2 mmol) and DIPEA (348 .mu.l, 2
mmol) in abs. ethanol (20 ml) was heated at reflux for 24 h. The
solvent was removed in vacuo and the residue dissolved in DCM,
washed with HCl (1M), dried (Na.sub.2SO.sub.4) and evaporated in
vacuo. Column chromatography (S)O.sub.2; MeOH/DCM, 5:95) gave the
title compound as a yellow foam (741 mg, 72%). .delta.H (DMSO
d.sub.6), 10.83 (1H, s), 8.77 (2H, s), 8.54 (1H, d, J 8.6 Hz,),
7.54 (2H, d, J 8.4 Hz), 7.23 (2H, d, J 8.5 Hz), 5.01 (1H, m), 4.17
(2H, q, J 7.1 Hz), 3.25 (1H, dd, J 4.6 Hz), 3.04 (1H, dd, J 13.7,
10.9 Hz), 1.21 (9H, s), 1.21 (3H, t, J 7.1 Hz) m/z (ES.sup.+, 70V)
518 (M.sup.++H).
EXAMPLE 7
[0319]
(S)-3-[4-[3,5-Dichloro4-pyridylcarboxamido)phenyl]-2-[(2-tert-butyl-
)-3,4-dioxo-1-cyclobutenylamino]propanoate
[0320] Lithium hydroxide monohydrate (66 mg, 1.56 mmol) was added
to the compound of Example 6 (735 mg, 1.42 mmol) in THF (14 ml) and
water (14 ml). After 2.5 h at RT the THF was removed in vacuo. The
aqueous residue was acidified (pH1, 1M HCl) and the precipitate
filtered off, washed with water and dried to give the title
compound as a pale brown solid (625 mg, 90%). .delta.H (DMSO
d.sub.6), 13.29 (1H, br s), 10.85 (1H, s), 8.78 (2H, s), 8.49 (1H,
d, J 9.2 Hz), 7.55 (2H, d, J 8.5 Hz), 7.24 (2H, d, J 8.5 Hz), 4.95
(1H, ddd, J 11.0, 9.3, 4.2 Hz), 3.28 (1H, dd, J 13.8, 4.1 Hz), 3.04
(1H, dd, J 13.7, 1.1 Hz), 1.22 (9H, s); m/z (ES.sup.+, 70V) 490
(M.sup.++H).
EXAMPLE 8
[0321] Methyl
(S)-3-{4-[(3,5-dichloroisonicotinoyl)oxy]phenyl}-2-(2-propyl-
amino-3,4-dioxocyclbut-1-enylamino)propanoate
[0322] In a similar manner to that described for Example 1 and
Example 2 the title compound was prepared from the compound of
Intermediate 27 as a white solid. .delta.H (DMSO d.sub.6, 390K)
8.81 (2H, s), 7.36 (2H, d, J 8.7 Hz), 7.26 (2H, d, J 8.7 Hz),
5.11-5.05 (1H, m), 3.78 (3H, d), 3.52-3.47 (2H, m) 3.29 (1H, dd, J
14.2, 5.9 Hz), 3.18 (1H, dd, J 14.2, 9.7 Hz), 1.63-1.54 (2H, m),
0.93 (3H, t, 17.4 Hz,). m/z (ES.sup.+, 70V) 506 (MH.sup.+).
EXAMPLE 9
[0323]
(S)-3-{(4-[(3,5-Dichloroisonicotinoyl)oxy]phenyl}-2-(2-propylamino--
3,4-dioxocyclobut-1-enylamino)propanoic acid
[0324] In a similar manner to that described for Example 3 the
title compound was prepared from Example 8 as a white solid.
.delta..sub.H (DMSO d.sub.6, 390K) 13.31 (1H, br), 8.80 (2H, s),
7.38 (2H, d, J 8.6 Hz), 7.25 (2H, d, J 8.6 Hz), 5.0-4.98 (1H, m),
3.52-3.47 (2H, m,) 3.29 (1H, dd, J 14.2, 5.7 Hz), 3.16 (1H, dd, J
14.2, 7.5 Hz), 2.51-2.50 (2H, m), 0.93 (3H, t, J 7.4 Hz). m/z
(ES.sup.+, 70V) 494 (MH.sup.+).
EXAMPLE 10
[0325] Ethyl
(S)-3-[4-(3,5-dichloro-4-pyridylcarboxamido)phenyl]-2-(2-buty-
l-3,4-dioxo-1-cyclobutenylamino)propanoate
[0326] A mixture of Intermediate 28 (336 mg, 2 mmol), Intermediate
3 (837 mg, 2 mmol) and DIPEA (700 .mu.l, 4 mmol) in EtOH (2 ml) was
heated at reflux for 2 h. The solvent was removed in vacuo. The
residue was dissolved in DCM (150 ml), washed with dil. HCl, dried
(Na.sub.2SO.sub.4) and concentrated in vacuo. Column chromatography
(S)O.sub.2: MeOH/DCM, 5:95) gave the title compound as a yellow
foam (904 mg, 87%). .delta.H (DMSO d.sub.6, 390K) 10.39 (1H, br s),
8.68 (2H, s), 8.59 (1H, br d, J 7.8 Hz), 7.55 (2H, br s), 7.26 (2H,
d, J 8.3 Hz), 4.84 (1H, br s), 4.21 (2H, q, J 7.1 Hz), 3.28 (1H,
dd, J 14.3, 5.3 Hz), 3.10 (1H, dd, J 14 3, 9.2 Hz), 2.5 (2H, m),
1.62-1.54 (2H, m), 1 38-1.29 92H), 1.24 (3H, t, J 7.1 Hz,
CO.sub.2CH.sub.2CH.sub.3), 0.91 (3H, t, J 7.3 Hz). m/z (ES.sup.+,
70V) 518 (MH.sup.+).
EXAMPLE 11
[0327] (S)-3-{4-(Dichloro-4-pyridylcarboxamido)phenyl]-2-(2
butyl-3,4-dioxo-1-cyclobutenylamino)propanoic acid
[0328] In a similar manner to that described for Example 3 the
title compound was prepared from the compound of Example 10 as a
pale yellow solid. 5H (DMSO d.sub.6, 370K), 10.48 (1H, s), 8.70
(2H, s), 8.5 (1H, v br), 7.55 (2H, d, J 7.8 Hz), 7.25 (2H, d, J 7.9
Hz), 4.85 (1H, v br), 3.29-3.22 (1H, m), 3.09-3.03 (1H, m), 2.5
(2H, m), 1.57-1.51 (2H, m), 1.36-1.27 (2H, m), 0.90 (3H, t, J 7.3
Hz). m/2 (ES, 70V) 490 (MH.sup.+).
EXAMPLE 12
[0329] Ethyl
(S)-3-{4-[(2,6-naphthyridin-1-yl)amino]phenyl}2-[(2-isopropox-
y-3,4-dioxocyclobut-1-enyl)amino]propanoate
[0330] A solution of Intermediate 7 (280 mg, 0.84 mmol) and
3,4-diisopropoxy-3-cyclobuten-1,2-dione (200 mg, 1.01 mmol) in
absolute ethanol (5 ml) was stirred at RT for 8 h then at 500 for
18 h. The volatiles were removed in vacuo and the residue
chromatographed (Silica, 80% EtOAc/Hexane to 100% EtOAc) affording
the title compound as a dull yellow foam (250 mg, 63%). .delta.H
(CDCl.sub.3) 9.18 (1H, s), 8.66 (1H, d, J 5.9 Hz), 8.21 (1H, d, J
5.7 Hz), 7.72 (1H, d, J 5.9 Hz), 7.66 (2H, d, 18.5 Hz), 7.22 (1H,
obs. s), 7.20 (1H, d, 15.7 Hz), 7.14 (2H, d, J 8.5 Hz), 6.37, 5.90,
5.18 and 4.60 (together 1H, br m's), 4.27 (2H, q, J 7.1 Hz),
3.31-3.10 (2H, br m), 1.42 (3H, d, J. 6.2 Hz), 1.41 (3H, d, 16.2
Hz), 1.32 (3H, t, J 7.1 Hz); m/z (ES.sup.+, 70V) 475
(MH.sup.+).
EXAMPLE 13
[0331] Ethyl
(S)-3-{4-[(2,6-naphthyridin-1-yl)amino]phenyl}2-{[2-N,N-dieth-
ylamino-3,4-dioxocyclobut-1-enyl]amino}propanoate
[0332] The compound of Example 12 (240 mg, 0.51 mmol) and
diethylamine (74 mg, 105 .mu.l, 1.01 mmol) in absolute ethanol (2
ml) was stirred at 45.degree. under an atmosphere of N.sub.2 for 18
h. The volatiles were removed in vacuo and the residue
chromatographed (Silica, gradiant elution 1 to 3% EtOH/EtOAc) to
afford the title compound as a yellow foam (240 mg, 97%). .delta.H
(CDCl.sub.3) 9.17 (1H, s), 8.65 (1H, d, J 5.9 Hz), 8.19 (1H, d, J
5.7 Hz), 7.78 (1H, d, J 5.9 Hz), 7.68 (2H, d, J 8.4 Hz), 7.48 (1H,
s), 7.18 (1H, d, J 5.7 Hz), 7.13 (2H, d, J 8.4 Hz), 5.45-5.35 (2H,
overlapping signals), 4.25 (2H, q, J 7.1 Hz), 3.68-3.31 (4H, br m),
3.30-3.18 (2H, m), 1.31 (3H, t, J 7.1 Hz), 1.22 (6H, t, J 7.1 Hz);
m/z (ES.sup.+, 70V) 488 (MH.sup.+).
EXAMPLE 14
[0333]
(S)-3-{4-[(2,6-Naphthyridin-1-yl)amino]phenyl}2-{[2-N,N-diethylamin-
o-3,4-dioxocyclobut-1-enyl]amino}propanoic acid
[0334] The compound of Example 13 (230 mg, 0.47 mmol) was treated
with a solution of LiOH.H.sub.2O (25 ml, 0.60 mmol) in water (4 ml)
and dioxan (4 ml) at RT for 1.5 h. A few drops of AcOH were added
and the volatiles removed in vacuo. The residue was chromatographed
[silica, gradiant elution, DCM (200 to 120), MeOH (20), AcOH (3),
H.sub.2O (2)] to afford the product as a yellow oil. Freeze-drying
from aqueous MeOH afforded the title compound as a bright yellow
amorphous solid (165 mg, 76%). .delta..sub.H (d.sub.6 DMSO) 9.28
(1H, s), 9.20 (1H, s), 8.65 (1H, d, J 5.9 Hz), 8.37 (1H, d, J 5.8
Hz), 8.12 (1H, d, J 5.8 Hz), 7.78 (2H, d, J 8.5 Hz), 7.66 (1H, d, J
9.0 Hz), 7.26 (1H, d, J 5.8 Hz), 7.22 (2H, d, J 8.5 Hz), 5.15-5.05
(1H, m), 3.70-3.30 (4H, br m), 3.22 (1H, dd, J 13.9, 4.0 Hz), 3.00
(1H, dd, J 13.9, 10.9 Hz), 1.09 (6H, t, J 7.1 Hz); m/z (ES.sup.+,
70V) 460 (MH.sup.+).
EXAMPLE 14A.
[0335]
(S)-3-{4-[(2,6-Naphthyridin-1-yl)amino]phenyl}-2-{[2-N,N-diethylami-
no-3,4-dioxocyclobut-1-enyl]amino}propanoic acid, sodium salt
[0336] A solution of the compound of Example 14 (250 mg, 0.55 mmol)
in water (3 ml) and THF (2 ml) was treated with sodium hydroxide
solution (0.1M, 5.5 mmol) and stirred for 10 mins. The solution was
freeze dried to give the title compound as a bright orange solid
(250 mg, 95%). .delta..sub.H (d.sub.6 DMSO) 8.43 (1H, s), 8.06 (2H,
s), 7.48 (1H, d, J 5.6 Hz), 7.16 (2H, d, J 8.3 Hz), 6.93 (2H, d, J
8.4 Hz), 5.88 (1H, d, J 5.6 Hz), 3.73 (1H, t, J 6.7 Hz), 3.88-3.83
(2H, m), 3.55-3.50 (2H, m), 2.86 (1H, dd, J 13.3, 6.5 Hz), 2.67
(1H, m), 1.12 (6H, t, J 7.1 Hz). (ES.sup.+, 70V)460(MH.sup.+).
[0337] In a similar manner to that described for Examples 13 and 14
were prepared the Examples 15 to 28:
EXAMPLE 15
[0338] Ethyl
(S)-3-[4-(2,6-naphthyridin-1-ylamino)phenyl]2-[2-(piperadin-1-
-yl)-3,4-dioxocyclobut-1-enylamino]propanoate
[0339] .delta.H (CDCl.sub.3) 9.18 (1H, s), 8.67 (1H, d, J 5.9 Hz),
8.20 (1H, d, J 5.9 Hz), 7.74 (1H, d, J 5.9 Hz), 7.67 (2H, d, J 8.5
Hz), 7.35 (1H, s), 7.20 (1H, d, J 5.9 Hz), 7.13 (2H, d, J 8.5 Hz),
5.40 (2H, narrow m), 4.25 (2H, q, J 7.2 Hz), 3.69-3.50 (4H, br m),
3.22 (2H, narrow m), 1.67 (6H, narrow m), 1.31 (3H, t, J 7.2 Hz);
m/z (ES.sup.+, 70V) (MH.sup.+) 500.
EXAMPLE 16
[0340]
(S)-3-[4-(2,6-Naphthyridin-1-ylamino)phenyl]-2-[2-(piperidin-1-yl)--
3,4-dioxocyclobut-1-enylamino]propanoic acid
[0341] .delta.H (d.sub.6 DMSO) 9.29 (1H, s), 9.21 (1H, s), 8.65
(1H, d, J 5.9 Hz), 8.38 (1H, d, J 5.9 Hz), 8.12 (1H, d, J 5.8 Hz),
7.77 (2H, d, J 8.4 Hz), 7.76 (1H, obs. signal), 7.26 (1H, d, J 5.8
Hz), 7.21 (2H, d, J 8.4 Hz), 5.07 (1H, narrow m), 3.72-3.48 (4H, br
m), 3.20 (1H, dd, J 14.0, 4.1 Hz), 2.98 (1H, dd, J 14.0, 10.6 Hz),
1.68-1.49 (6H, br m); m/z (ES.sup.+, 70V) (MH.sup.+) 472.
EXAMPLE 17
[0342] Ethyl
(S)-3-[4-(2,6-naphthyridin-1-ylamino)phenyl]-2-(2-N,N-di-n-pr-
opylamino-3,4-dioxocyclobut-1-enylamino)propanoate
[0343] .delta.H (CDCl.sub.3) 9.18 (1H, s), 8.70 (1H, d, 15.9 Hz),
8.15 (1H, s), 7.85 (1H, br s), 7.64 (2H, d, J 8.3 Hz), 7.19-7.13
(3H, m), 5.40-5.30 (1H, m), 4.35-4.20 (2H, m), 3.60-3.10 (6H, m),
1.65-1.55 (4H, m), 1.33 (3H, t, J 7.1 Hz), 0.9 (6H, t, J 7.35 Hz),
m/z (ES.sup.+, 70V) MH.sup.+ 516.
EXAMPLE 18
[0344]
(S)-3-[4-(2,6-Naphthyridin-1-ylamino)phenyl]-2-(2-N,N-di-n-propylam-
ino-3,4-dioxocyclobut-1-enylamino)propanoic acid
[0345] .delta.H (d.sub.6 DMSO, 370K) 9.19 (1H, s), 9.0 (1H, br s),
8.64 (1H, d, 18.6 Hz), 8.34 (1H, d, J 5.9 Hz), 8.14 (1H, d, J 5.7
Hz), 7.79 (2H, d, J 8.4 Hz), 7.25-7.21 (1H, m), 7.23 (2H, d, J 8.7
Hz), 7.05 (1H, br s), 5.15 (1H, br s), 3.56-3.40 (4H, m), 3.27 (1H,
dd, J 14.2, 4.9 Hz), 3.10 (1H, dd, J 14.2, 9.4 Hz), 1.65-1.50 (4H,
m), 0.86 (6H, t, 17.3 Hz), m/z (ES.sup.+, 70V) MH.sup.+ 488.
EXAMPLE 19
[0346]
(S)-3-[4-(2,6-naphthyridin-1-ylamino)phenyl]2-(2-tert-butyl-3,4-dio-
xocyclobut-1-enylamino)-propanoic acid
[0347] .delta..sub.H (d.sub.6 DMSO) 9.29 (1H, s), 9.22 (1H, s),
8.67 (1H, d, J 5.8 Hz), 8.51 (1H, d, J 9.1 Hz), 8.40 (1H, d, J 0.8
Hz), 8.38 (1H, d, J 0.8 Hz), 8.13 (1H, dd, J 5.6, 1.3 Hz), 7.78
(2H, nr m), 7.26 (1H, d, 15.8 Hz), 7.19 (1H, d, 18.6 Hz), 4.95 (1H,
brs), 3,4-3.2 (1H, m), 3.04 (1H, dd, J 13.6, 11.1 Hz), 1.23 (9H,
s). m/z (ES.sup.+, 70V) (MH.sup.+) 445.2.
EXAMPLE 20
[0348]
(S)-3-[4-(2,6-Naphthyridin-1-ylamino)phenyl]-2-[2-N-methyl-N-butyla-
mino)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[0349] .delta.H (d6 DMSO, 390K) 9.19 (1H, s), 9.08 (1H, s), 8.65
(1H, d, 15.9 Hz), 8.35 (1H, d, J 5.9 Hz), 8.35 (1H, d, J 5.9 Hz),
8.14 (1H, d, J 5.7 Hz), 7.78 (2H, d, J 8.3 HZ), 7.25-7.20 (3H, m),
5.06 (1H, br s), 3.58-3.42 (2H, m), 3.24 (1H, dd, J 14.1, 4.7 Hz),
3.16 (3H, s), 3.06 (1H, dd, J 14.1, 9.5 Hz), 1.54-1.50 (2H, m),
1.27 (2H, dd, J 15.1, 7.4 Hz), 0.87 (3H, t, J 7.31 HZ). M/Z
ES.sup.+, 70V) 474 (MH.sup.+).
EXAMPLE 21
[0350]
(S)-3-[4-(2,6-Naphthyridin-1-yl-N-methylamino)phenyl]-2-[2-N,N-diet-
hylamino-3,4-dioxocyclobut-1-enylamino)propanoic acid
[0351] .delta..sub.H (d.sub.6 DMSO; 350K) 9.23 (1H, d, J 1.0 Hz),
8.36 (1H, d, J 5.6 Hz), 8.22 (1H, d, J 6.0 Hz), 7.49 (1H, dd, J
5.7, 0.9 Hz), 7.30 (1H, br d, 18.0 Hz), 7.21 (2H, d, J 8.5 Hz),
7.05 (1H, d, J 6.0 Hz), 6.93 (2H, d, J 8.5 Hz), 5.12-5.09 (1H,
narrow m), 3.66-3.45 (4H, m), 3.49 (3H, s), 3.24 (1H, dd, J
14.0-4.5 Hz), 3.03 (1H, dd, J 14.0, 10.1 Hz), 1.10 (6H, t, J 7.1
Hz) m/z (ES.sup.+, 70V) 474 (MH.sup.+).
EXAMPLE 22
[0352]
(S)-3-[4-(2,6-Naphthyridin-1-ylamino)phenyl]-2-[(2,5-dimethyl-3-pyr-
rolin-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[0353] .delta.H (DMSO d.sub.6, 350K); 9.19 (1H, d, J 0.9 Hz), 9.09
(1H, s), 8.65 (1H, d, J 5.9 Hz), 8.35 (1H, d, J 5.9 Hz), 8.14 (1H,
d, J 5.7 Hz), 7.78 (2H, d, J 8.3 Hz), 7.26-7.18 (4H, m), 5.90 (2H,
s), 5.09 (1H, br s), 4.85 (2H, q, J 12.8, 6.4 Hz), 3.27 (1H, dd, J
14.1, 4.8 Hz), 3.11 (1H, dd, J 14.1, 9.5 Hz), 1.35 (3H, d, J 6.4
Hz), 1.31 (3H, d, J 16.4 Hz), m/z (ES.sup.+, 70V) 484
(MH.sup.+).
EXAMPLE 23
[0354]
(S)-3-[4-(2,6-Naphthyridin-1-ylamino)phenyl]2-[2-(N-methyl-N-propyl-
amino)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[0355] .delta.H (DMSO d.sub.6, 350K), 9.20 (1H, s), 9.10 (1H, s),
8.65 (1H, d, J 5.85 Hz), 8.35 (1H, d, J 5.92 Hz), 8.14 (1H, d, J
5.68 Hz), 7.79 (2H, d, J 8.03 Hz), 7.36 (1H, d, J 9.0 Hz),
7.26-7.22 (3H, m), 5.16 (1H, br s), 3.50-3.39 (2H, m), 3.25 (1H,
dd, J 14.09, 4.83 Hz), 3.17 (3H, s), 3.07 (1H, dd, J 14.1, 9.9 Hz),
1.61-1.52 (2H, m), 0.84 (3H, t, J 7.35 Hz); m/z (ES.sup.+, 70V)
460.(MH.sup.+).
EXAMPLE 24
[0356]
(S)-3-[4-(2,6-Naphthyridin-1-ylamino)phenyl]-2-[(2-(S)-(2-methoxyme-
thyl)pyrrolidin-1-yl]-3,4-dioxocyclobut-1-enyl)amino[propanoic
acid
[0357] .delta.H (DMSO d.sub.6, 350K) 9.20 (1H, s), 9.10 (1H, s),
8.65 (1H, d, J 5.9 Hz), 8.35 (1H, d, J 5.9 Hz), 8.14 (1H, d, 0.15.7
Hz), 7.80 (2H, d, J 8.3 Hz), 7.27-7.20 (4H, m), 5.07 (1H, br s),
4.20 (1H, d, J 5.2 Hz), 3.85-3.64 (2H, m), 3.35-3.32 (2H, m), 3.25
(3H, s), 3.25-3.01 (2H, m), 2.03-1.75 (4H, m); m/z (ES+, 70V), 502
(MH.sup.+).
EXAMPLE 25
[0358]
(S)-3-[4-(2,6-Naphthyridin-1-ylamino)phenyl]-2-[2-(N-ethyl-N-iso-pr-
opylamino)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[0359] .delta.H (DMSO d.sub.6, 350K); 9.20 (1H, s), 9.09 (1H, s),
8.64 (1H, d, J 5.9 Hz), 8.35 (1H, d, J 5.9 Hz), 8.15 (1H, d, J 5.7
Hz), 7.78 (2H, d, J 8.3 Hz), 7.26-7.20 (4H, m), 5.18 (1H, brs),
4.44-4.37 (1H, m), 3.45 (2H, q, J 7.2, 2.4 Hz), 3.25 (1H, dd, J
14.1, 4.7 Hz), 3.08 (1H, dd, J 14.1, 9.8 Hz), 1.20 (6H, q, J 6.7,
3.3 Hz), 1.14 (3H, t, 17.1 Hz), m/z (ES.sup.+, 70V), 474
(MH.sup.+).
EXAMPLE 26
[0360]
(S)-3-[4-(2,6-Naphthyridin-1-ylamino)phenyl]-2-[2-(methyl-N-iso-pro-
pylamino)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[0361] .delta.H (DMSO d.sub.6, 350K) 9.20 (1H, s), 9.09 (1H, s),
8.65 (1H, d, J 5.9 Hz), 8.35 (1H, d, 15.9 Hz), 8.14 (1H, d, J 5.6
Hz), 7.79 (2H, d, J 8.3 Hz), 7.38 (1H, d, J 8.1 Hz), 7.26-7.22 (3H,
m), 5.12 (1H, br s), 4.46-4.40 (1H, m), 3.25 (1H, dd, J 4.1, 4.8
Hz), 3.05 (1H, dd, J 14.2, 4.6 Hz), 3.06 (3H, s). 1.82 (3H, d, J
2.58 Hz, 1.65 (3H, d, J 2.6 Hz); m/z (ES.sup.+, 70V) 460
(MH.sup.+,).
EXAMPLE 27
[0362]
(S)-3-[4-(2,6-Naphthyridin-1-ylamino)phenyl]-2-[2-(2,5-dimethylpyrr-
olidin-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[0363] .delta.H (DMSO d.sub.6, 350K) 9.20 (1H, d, J 0.9 Hz), 9.10
(1H, s), 8.65 (1H, d, J 5.9 Hz), 8.35 (1H, d, J 5.9 Hz), 8.14 (1H,
d, J 5.7 Hz), 7.79 (2H, d, J 8.3 Hz), 7.26-7.23 (3H, m), 3.26 (1H,
dd, J 14.2, 4.8 Hz), 3.1 (1H, dd, J 14.2, 9.7 Hz), 2.15-2.09 (2H,
m), 1.73-1.66 (2H, m), 1.28 (3H, d, J 6.4 Hz), 1.25 (3H, d, J 6.4
Hz); m/z (ES.sup.+, 70V) 486 (MH.sup.+).
EXAMPLE 28
[0364]
(S)-3-[4-(2,6-Naphthyridin-1-ylamino)phenyl]-2-[2-(2-methylpiperdin-
-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[0365] .delta.H (DMSO d.sub.6, 370K), 9.19 (1H, s), 9.03 (1H, s),
8.64 (1H, d, J 5.8 Hz), 8.33 (1H, d, J 5.9 Hz), 8.14 (1H, d, J 5.6
Hz), 7.78 (2H, q, J 8.4, 2.3 Hz), 7.25-7.22 (4H, m), 5.13 (1H, br
s), 4.45 (1H, br s), 4.04 (1H, d, J 13.7 Hz), 3.25-3.20 (2H, m),
3.11-3.05 (1H, m), 1.76-1.49 (6H, m), 1.24 (3H, q, J 6.9, 5.2 Hz),
m/z (ES.sup.+, 70V) 486 (MH.sup.+).
EXAMPLE 29
[0366] Methyl
(S)-3-[4-(2,6-naphthyrodin-1-yloxy)phenyl]-2-(2-N,N-diethyla-
mino-3,4-dioxocyclobut-1-enylamino)propanoate
[0367] To methyl
(S)-2-(2-isopropoxy-3,4-dioxocyclobut-1-enylamino)-3-[4-(-
2,6-naphthyridin-1-yloxy)phenyl]-propanoate (prepared from the
compound of Intermediate 8 in a similar manner to the compound of
Example 1) (0.20 g, 0.44 mmol) in methanol (3 ml) was added 2
equivalents of diethylamine (0.09 ml) and the solution was stirred
at 65.degree. overnight. The solution was cooled and then
evaporated. The solid was chromatographed (Silica, EtOAc/isohexane
50-100%) to afford the title com pound (0.15 g, 73%) as a white
solid. .delta.H (CDCl.sub.3) 9.30 (1H, s), 8.77 (1H, d, J 5.7 Hz),
8.19 (1H, d, 15.8 Hz), 8.08 (1H, d, J 5.79 Hz), 7.44 (1H, d, J 5.8
Hz), 7.24-7.18 (4H, m), 5.46 (1H, m), 5.35 (1H, m), 3.83 (3H, s),
3.70-3.40 (4H, br s), 3.31 (2H, d, J 5.3 Hz), 1.24 (6H, t, J 7.2
Hz). m/z (ES.sup.+, 70V) MH.sup.+ 475.
EXAMPLE 30
[0368]
(S)-3-[4-(2,6-Naphthyridin-1-yloxy)phenyl]-2-(2-N,N-diethylamino-3,-
4-dioxocyclobut-1-enylamino)propanoic acid
[0369] The compound of Example 29 (0.137 g, 0.29 mmol) in dioxan (2
ml) and water (2 ml) was treated with LiOH.H.sub.2O (0.02 g) and
stirred at RT for 4 h, a few drops of glacial acetic acid were
added and the solution was then evaporated in vacuo. The product
was chromatographed (Silica; DCM 200:MeH 20:HOAc 3:H.sub.2O 2) to
afford the title compound as an off-white solid (0.10 g, 78%).
.delta..sub.H (d.sub.6 DMSO, 350K), 9.40 (1H, s), 8.76 (1H, d, J
5.7 Hz), 8.15-8.09 (2H, m), 7.65 (1H, dd, J 5.8, 0.9 Hz), 7.37 (1H,
s), 7.36 (2H, d, J 8.6 Hz), 7.20 (2H, d, J 8.6 Hz), 5.15 (1H, br
s), 3.59-3.51 (4H, m), 3.32 (1H, dd, J 4.1, 4.8 Hz), 3.13 (1H, dd,
J 14.1, 9.9 Hz), 1.14 (6H, t, J 7.1 Hz). m/z (ES.sup.+, 70V)
MH.sup.+ 461.
[0370] The compounds of Examples 31 to 33 were prepared in a
similar manner to the compounds of Examples 29 and 30.
EXAMPLE 31
[0371]
(S)-3-[4-(2,6-Naphthyridin-1-yloxy)phenyl]-2-[2-piperidin-1-yl-3,4--
dioxocyclobut-1-enylamino]propanoiac acid
[0372] .delta.H (d.sub.6 DMSO, 370K) 9.39 (1H, s), 8.76 (1H, d, J
5.7 Hz), 8.13 (2H, nr m), 7.65 (1H, dd, J 5.7, 0.9 Hz), 7.34 (2H,
d, J 8.6 Hz), 7.21 (2H, d, J 8.6 Hz), 5.16 (1H, br s), 3.64-3.59
(5H, m), 3.31 (1H, dd, J 14.1, 5.0 Hz), 3.12 (1H, dd, J 14.1, 9.6
Hz), 1.63-1.57 (5H, m); m/z (ES.sup.+, 70V) MH.sup.+ 473.
EXAMPLE 32
[0373]
Methyl-(S)-3-[4-(2,6-naphthyridin-1-yloxy)phenyl]-2-(2-N,N-di-n-pro-
pylamino-3,4-dioxocyclobut-1-enylamino)propanoic acid
[0374] .delta.H (d.sub.6 DMSO) 9.41 (1H, s), 8.76 (1H, d, J 5.7
Hz), 8.14 (1H, d, J 5.7 Hz), 8.07 (1H, d, J 5.7 Hz), 7.74 (1H, d, J
8.9 Hz), 7.67 (1H, d, J 5.8 Hz), 7.33 (2H, d, J 8.5 Hz), 7.18 (2H,
d, J 8.5 Hz), 5.23 (1H, m), 3.72 (3H, s), 3.37 (5H, br m), 3.11
(1H, m), 1.48 (4H, br m), 0.80 (6H, t, J 7.3 Hz).
EXAMPLE 33
[0375]
(S)-3-[4-(2,6-Naphthyrodin-1-yloxy)phenyl]-2-(2-N,N-di-n-propylamin-
o-3,4-dioxocyclobut-1 enylamino)propanoic acid
[0376] .delta.H (d.sub.6 DMSO 350K) 9.41 (1, d, J 1.0 Hz), 8.77 (1H
d, J 8.7 Hz), 8.14 (1H, d, J 5.7 Hz), 8.11 (1H, d, J 5.7 Hz), 7.67
(1H, dd, J 5.8, 0.9 Hz), 7.35 (2H, d, J 8.6 Hz), 7.27 (1H, d, J 8.9
Hz), 7.21 (2H, d, J 8.6 Hz), 5.20 (1H, m), 3.47 (4H, m), 3.33 (1H,
dd, J 14.1, 4.8 Hz), 3.13 (1H, dd, J 14.1, 10.0 Hz), 1.55 (4H, m),
0.86 (6H, t, J 7.4 Hz). m/z (ES.sup.+, 70V) 489 (MH.sup.+).
EXAMPLE 34
[0377]
Methyl-(S)-3-{4-[2-(2,6-dichlorophenyl)ethynyl]phenyl}-2-[(2-isopro-
poxy-3,4-dioxo-1-cyclobutenyl)amino]propanoate
[0378] A mixture of the compound of Intermediate 34 (1.17 g, 3.04
mmol), 3,4-diisopropoxy-3-cyclobutene-1,2-diene (632 mg, 3.19 mmol)
and DIPEA (540 .mu.l, 3.1 mmol) in MeOH (30 ml) was stirred at RT
for 3 days. The solvent was removed in vacuo. The residue was
dissolved in DCM, washed with dil. HCl, dried (Na.sub.2SO.sub.4)
and evaporated in vacuo. Column chromatography (S)O.sub.2;
MeOH/DCM, 3:97) gave the title compound as a yellow gum (1.45 g,
98%). .delta.H (DMSO d.sub.6, 390K), 8.47 (1H, d, J 7.9 Hz),
7.53-7.50 (3H, m), 7.38 (1H, dd, J 8.7, 7.5 Hz), 7.33 (2H, d, J 8.2
Hz), 5.21 (1H, sept. J 6.2 Hz), 4.78-4.72 (1H, m), 3.72 (3H, s),
3.31 (1H, dd, J 14.2, 5.2 Hz), 3.13 (1H, dd, J 14.2, 9.4 Hz), 1.38
(3H, d, J 6.1 Hz). 1.37 (3H, d, J 6.2 Hz); m/z (ES.sup.+, 70V) 486
(M.sup.++H).
EXAMPLE 35
[0379] Methyl
(S)-3-{4-[2-(2,6-dichlorophenyl)ethynyl]phenyl}-2-[2-propyla-
mino-3,4-dioxocyclobut-1-enylamino]propanoate
[0380] Propylamine (96 .mu.l, 1.18 mmol) was added to a solution of
the compound of Example 34 (475 mg, 0.98 mmol) in MeOH (10 ml). The
reaction mixture was stirred at RT overnight. Volatiles were
removed in vacuo and the resulting solid triturated with boiling
MeOH. The solid was filtered off to give the title compound as a
white solid (335 mg, 71%). .delta.H (DMSO-d.sub.6, 390K) 7.57-7.53
(4H, m), 7.44-7.40 (1H, m), 7.33 (2H, d, J 8.3 Hz), 7.3 (1H, br m)
7.2 (1H, br m), 5.10 (1H, m). 3.76 (3H, s), 3.54-3.49 (2H, m), 3.30
(1H, dd, J 14.1, 5.9 Hz), 3.18 (1H, dd, J 14.1, 7.7 Hz), 1.60 (2H,
sept. J 7.1 Hz), 0.95 (3H, t, 17.4 Hz); m/z (ES.sup.+, 70V) 485
(M.sup.++H).
EXAMPLE 36
[0381]
(S)-3-{4-[2-(2,6-Dichloropheny)ethynyl]phenyl}-2-(2-propylamino-3,4-
-dioxocyclobut-1-enylamino)propanoic acid
[0382] Lithium hydroxide monohydrate (34 mg, 0.81 mmol) was added
to the compound of Example 35 (325 mg, 0.671 mmol) in a mixture of
THF (7 ml) and water (7 ml). After 1 h at RT the THF was removed in
vacuo. The aqueous residue was acidified (pH 1-2, dil. HCl) and the
precipitated filtered off, washed with water and dried to give the
title compound as a yellow solid (315 mg, 90%). .delta.H (DMSO
d.sub.6, 390K), 7.37-7.31 (4H, m), 7.21 (1H, dd, J 8.6, 7.5 Hz),
7.14 (2H, d, J 8.4 Hz), 7.1 (2H, br m), 4.82 (1H, m), 3.33-3.29
(2H, m), 3.11 (1H, dd, J 4.1, 5.7 Hz), 2.98 (1H, dd, J 14.1, 7.6
Hz), 1.39 (2H, sept. J 7.1 Hz). 0.75 (3H, t, J 7.4 Hz); m/z
(ES.sup.+, 70V) 471 (M.sup.++H).
EXAMPLE 37
[0383] Methyl
(S)-3-{4-[2-(2,6-dichlorophenyl)ethynyl]phenyl}-2-(2-N,N-die-
thylamino-3,4-dioxocyclobut-1-enylamino)propanoate
[0384] A mixture of the compound of Example 34 (470 mg, 0.969 mmol)
and diethylamine (401 .mu.l, 3.88 mmol) in MeOH (10 ml) was heated
at 50.degree. C. overnight. The solvent was removed in vacuo and
the residue purified by column chromatography (S)O.sub.2; MeOH/DCM,
5:95) to give the title compound as a light brown foam (450 mg,
93%). .delta.H (DMSO d.sub.6, 390K), 7.55-7.50(4H, m), 7.42-7.35
(3H, m), 7.16 (1H, d, J 8.5 Hz), 5.63 (1H, m), 3.74 (3H, s), 3.55
(4H, q, J 7.1 Hz), 3.34 (1H, dd, J 14.2, 5.3 Hz), 3.20 (1H, dd, J
14.2, 9.4 Hz), 1.17 (6H, t, J 7.1 Hz); m/z (ES.sup.+, 70V) 499
(M.sup.++H).
EXAMPLE 38
[0385]
(S)-3-{4-[2-(2,6-Dichlorophenyl)ethynyl]phenyl}-2-(2-N,N-diethylami-
no-3,4-dioxocyclobut-1-enylamino)propanoic acid
[0386] Obtained as an off-white solid from the compound of Example
37 by ester hydrolysis using the method described above for Example
36. .delta.H (DMSO-d.sub.6, 390K), 7.42-7.37 (4H, m), 7.29-7.24
(3H, m,), 6.91 (1H, br d, J 8.7 Hz), 3.43 (4H, q, J 7.1 Hz), 3.22
(1H, dd, J 14.2, 5.1 Hz), 3.06 (1H, dd. J 14.2, 9.4 Hz), 1.04 (6H,
t J 7.1 Hz). m/z (ES.sup.+, 70V) 485 (M.sup.++H).
[0387] The compounds of Examples 39 to 44 were prepared from
methyl-(S)-3-(4-aminophenyl)-2-(N-t-butyloxycarbonylamino)propanoate
and the appropriate reagent in a similar manner to that described
for Intermediate 3 then derivatised in a manner analogous to that
described for Examples 1, 2 and 3.
EXAMPLE 39
[0388]
(S)-3-[4-(Benzylcarboxamido)phenyl]-2-(2-n-propylamino-3,4-dioxocyc-
lobut-1-enylamino)propanoic acid .delta.H (d.sub.6 DMSO 390K); 9.25
(1H, s), 7.86 (1H, s), 7.44 (2H, d, J 8.4 Hz), 7.40-7.15 (5H, m),
7.08 (2H, d, J 8.4 Hz), 7.0 (1H, d, 18.0 Hz), 4.94 (1H, br s), 3.62
(2H, s), 3.47 (2H, nr m), 3.14 (1H, dd, J 14.1, 5.7 Hz), 3.04 (1H,
dd, J 14.1, 6.8 Hz), 1.57 (2H, dd, J 14.3, 7.1 Hz), 0.92 (3H, t, J
7.3 Hz); m/z (ES.sup.+, 70V) 436 (MH.sup.+).
EXAMPLE 40
[0389]
(S)-3-[4-(2,4,6-Trifluorobenzylamino)phenyl]-2-(2-n-propylamino-3,4-
-dioxocyclobut-1-enylaminopropanoic acid
[0390] .delta.H (d.sub.6 DMSO 390K) 7.88 (1H, s), 7.12 (1H, br s),
6.97 (1H, br s), 6.92 (2H, d, J 8.3 Hz), 6.78 (2H, nr m), 6.58 (2H,
d, J 8.3 Hz), 4.89 (1H, br s)m 4.27 (2H, s), 3.46-3.48 (2H, nr m),
3.04 (1H, dd, J 14.18, 5.7 Hz), 2.95 (1H, dd, J 14.2, 6.68 Hz),
1.62-1.53 (2H, Nr m), 0.92 (3H, t, J 7.38 Hz); m/z (ES.sup.+, 70V),
462 (MH.sup.+).
EXAMPLE 41
[0391]
(S)-3-[4(2,6-Dichlorobenzylamino)phenyl]-2-(2-n-propylamino-3,4-dio-
xocyclobut-1 enylamino)propanoic acid
[0392] .delta.H (d.sub.6 DMSO) 7.26 (2H, s), 7.17 (1H, d, J 7.3
Hz), 7.14 (1H, br s), 6.95 (1H, br s), 6.8 (2H, d, J 8.4 Hz), 6.5
(2H, d, J 8.47 Hz), 4.70 (1H, br s), 4.31 (3H, s), 3.13 (2H, m),
2.89 (1H, dd, J 14.2, 5.6 Hz), 2.79 (1H, dd, J 14.2, 7.1 Hz), 2.85
(1H, br s), 1.44 (2H, dd, J 14.2, 7.1 Hz), 0.76 (3H, t, J 7.4 Hz);
m/z (ES.sup.+, 70V) 476 (MH.sup.+).
EXAMPLE 42
[0393] (S)-3-[4-(2,4,6-Trichlorobenzylamino)phenyl]-2-(2-n-propyl
amino-3,4-dioxocyclobut-1-enylamino)propanoic acid
[0394] .delta..sub.H (d.sub.6 DMSO) 7.55 (2H, s),7.23 (1H, br s),
7.09 (1H, br d, J 8.4 Hz), 6.96 (2H, d, J 8.4 Hz), 6.66 (2H, d, J
8.5 Hz), 4.90 (1H, br s), 4.44 (2H, s), 3.48 (2H, m), 3.07 (1H, dd,
J 14.1, 5.5 Hz), 2.95 (1H, dd, J 14.2, 7.2 Hz), 1.60 (2H, dd, J
14.3, 7.0 Hz), 0.93 (3H, t, J 7.4 Hz); m/z (ES.sup.+, 70V) 509
(MH.sup.+).
EXAMPLE 43
[0395]
(S)-3-[4-(3-Chlorothiophen-2-ylcarboxamido)phenyl]-2-(2-n-propylami-
no-3,4-dioxocyclobut-1-enylamino]propanoic acid
[0396] .delta.H (d.sub.6 DMSO) 9.50 (1H, s), 7.79 (1H, d, J 5.2
Hz), 7.57 (2H, d, J 8.4 Hz), 7.21 (2H, d, J 8.4 Hz), 7.12 (1H, br
s), 7.11 (1H, d, J 5.2 Hz), 4.96 (1H, br s), 3.49 (2H, m),
3.25-3.02 (2H, m), 1.59 (2H, dd, J 14.3, 7.1 Hz), 0.93 (3H, t, J
7.4 HZ), m/z (ES.sup.+, 70V) 461 (MH.sup.+).
EXAMPLE 44
[0397]
(S)-3-[4-(3-Chlorobenzo[b]thiophen-2-ylcarboxamido)phenyl]-2-(2-n-p-
ropylamino-3,4-dioxocyclobut-1-enylamino)propanoic acid .delta.H
(d6 DMSO, 400K) 9.98 (1H, s), 8.07 (1H, nr, m), 7.94 (1H, nr m),
7.6 (5H, m), 7.23 (2H, d, 18.4 Hz), 7.1 (1H, br s), 4.98 (1H, br
s), 3.5 (2H, m), 2.35 (1H, dd, J 14.2, 5.7 Hz), 3.3 (1H, dd, J
14.2, 5.7 Hz), 1.59 (2H, hex, J 7.3 Hz), 0.94 (3H, t, J 7.3 Hz).
m/z (ES.sup.+, 70V) 512 (MH.sup.+).
[0398] The compounds of Examples 45 to 47 were prepared from methyl
(S)-3-(4-aminophenyl)-2-(N-t-butoxycarbonylamino)propanoate and the
appropriate reagent in a similar manner to that described for
Intermediate 6 then derivatised in a similar manner to that
described for Examples 11, 13 and 14.
EXAMPLE 45
[0399]
(S)-3-[4-(Pyrimidin-2-ylamino)phenyl]-2-(2-n-propylamino-3,4-dioxoc-
yclobut-1-enylamino)propanoic acid
[0400] .delta.H ((d.sub.6 DMSO, 390K) 8.86 (1H, br s), 8.41 (2H, d,
J 4.8 Hz), 7.64 and 7.62 (2H, dd, J 1.8, 1.4 Hz), 7.15 (1H, br s),
7.12 (2H, d, J 8.6 Hz), 6.77 (1H, t, J 4.8 Hz), 4.93 (1H, br s),
3.48 (2H, t, J 6.8 Hz), 3.18 (1H, dd, J 14.1, 5.5 Hz), 3.05 (1H,
dd, J 14.2, 7.3 Hz), 1.58 (2H, dd, J 14.2, 7.0 Hz), 0.92 (3H, t,
17.4 Hz), m/z (ES.sup.+, 70V) 396 (MH.sup.+).
EXAMPLE 46
[0401]
(S)-3-{4-[(2-Benzyl-6-chloropyrimidin4-yl)amino]phenyl}-2-{[2-N,N-d-
iethylamino-3,4-dioxocyrclobut1 enyl]amino}propanoic acid
[0402] .delta.H (DMSO, 370K) 9.40 (1H, s), 7.48 (2H, d J 2.3 Hz),
7.38 (4H, s), 7.35-7.25 (2H, m), 7.24 (2H, d, 18.5 Hz), 6.64 (1H,
s), 5.15 (1H, br s), 4.07 (2H, s), 3.60 (2H, q, J 7.2, 4.7 Hz), 3.3
0(1H, dd, J 14.2, 4.9 Hz), 3.10 (1H, dd, J 14.1, 9.4 Hz), 1.2 (6H,
t, J 7.1 Hz); m/z (ES.sup.+, 70V) 534 (MH.sup.+).
EXAMPLE 47
[0403]
(S)-3-[4-(Quinolin4-ylamino)phenyl]-2-{[2-N,N-diethylamino-3,4-diox-
o-1-cyclobutenyl]amino}propanoic acid
[0404] .delta.H (DMSO, 390K) 8.48 (1H, d, J 5.2 Hz), 8.39 (1H, d, J
7.1 Hz), 7.93 (1H, dd, J 8.4, 0.8 Hz), 7.71 (1H, d, J 5.4 Hz),
7.54-7.50 (1H, m), 7.32 (2H, d, J 8.4 Hz), 7.24 (2H, d, J 8.5 Hz),
6.83 (1H, d, J 5.2 Hz), 4.68 (1H, m), 3.70-3.50 (4H, m), 3.32 and
3.29 (1H, dd, J 13.8, 5.5 Hz), 3.24 and 3.21 (1H, dd, J 13.8, 6.3
Hz), 1.23 (6H, t, J 7.2 Hz), m/z (ES.sup.+, 70V), 459
(MH.sup.+).
[0405] The compounds of Examples 48 to 55 were prepared from
N-BOC-L-tyrosine methyl ester and the appropriate reagent in the
manner described for Intermediate 24 then derivatised in a manner
analogous to that described for Examples 12 to 14.
EXAMPLE 48
[0406] Methyl
(S)-3-[4-(2,6-Dichlorobenzyloxy)phenyl]-2-(2-N,N-diethylamin-
o-3,4-dioxocyclobut-1-enylamino)propanoate
[0407] .delta.H (DMSO d.sub.6), 7.71 (1H, d, 19.0 Hz), 7.55-7.52
(2H, m), 7.47-7.42 (1H, d), 7.18 (2H, d, J 8.7 Hz), 6.95 (2H, d, J
8.7 Hz), 5.17 (2H, s), 5.15 (1H, m), 3.70 (3H, s), 3.55 (4H, br),
3.20 (1H, dd, J 4.6 Hz), 3.01-2.93 (1H, m), 1.07 (6H, t, J 7.1 Hz);
m/z (ES.sup.+, 70V) 505 (MH.sup.+).
EXAMPLE 49
[0408]
(S)-3-[4-(2,6-Dichlorobenzyloxy)phenyl]-2-(2-N,N-diethylamino-3,4-d-
ioxocyclobut-1-enylamino)propanoic acid
[0409] .delta.H (DMSO d.sub.6) 13.08 (1H, br), 8.31-8.24 (2H, m),
8.22-8.04 (1H, m), 8.02 (2H, d, J 8.8 Hz), 7.77 (2H, d, J 8.7 Hz),
6.07 (2H, s), 7.70 (1H, br), 5.95 (1H, br m), 4.49-4.40 (4H, m),
4.05 (1H, dd, J 14.3, 5.1 Hz), 3.89 (1H, dd, J 14.2, 9.1 Hz), 1.97
(6H, t, J 7.1 Hz); m/z (ES.sup.+, 70V) 491 (MH.sup.+).
EXAMPLE 50
[0410] Methyl
(S)-3-[4-(2,6-dichlorobenzyloxy)phenyl]-2-(2-propylamino-3,4-
-dioxocyclobut-1-enylamino)propanoate
[0411] .delta.H (DMSO d6) 7.60 (1H, br), 7.56 (2H, m), 7.47-7.42
(1H, m,), 7.09 (2H, d, J 8.3 Hz), 6.97 (2H, d, J 8.7 Hz), 5.17 (2H,
s), 4.99 (1H, m), 3.70 (3H, s), 3.70 (2H, m), 3.12 (1H, dd, J 5.2
partly obscured), 1.54-1.47 (2H, m), 0.86 (3H, t, J 7.4 Hz). M/Z.
(ES, 70V) 491 (MH.sup.+).
EXAMPLE 51
[0412]
(S)-3-[4-(2,6-Dichlorobenzyloxy)phenyl]-2-(2-propylamino-3,4-dioxoc-
yclobut-1-enylamino)propanoic acid
[0413] .delta.H (DMSO d.sub.6, 390K), 7.42-7.40 (2H, m), 7.35-7.31
(1H, m), 7.09 (1H, br), 7.08-7.06 (2H, m), 6.89-6.86 (2H, m),5.17
(2H, s), 4.82 (1H, br), 3.39-3.38 (2H, m), 3.09 (1H, dd, J 14.2,
5.6 Hz), 2.96 (1H, dd, J 14.2, 7.4 Hz), 1.52-1.47 (2H, m), 0.84
(3H, t, 17.4H.sub.3); m/z (ES.sup.+, 70V) 477 (MH.sup.+).
EXAMPLE 52
[0414] Methyl
(S)-3-[4-12-pyrimidinyloxy)phenyl]-2-(2-N,N-diethylamino-3,4-
-dioxocyclobut-1-enylamino)propanoate
[0415] .delta.H (DMSO d.sub.6, 390K) 860 (2H, d, J 4.8 Hz), 7.31
(2H, d, J 8.6 Hz,), 7.20 (1 Ha, t, J 4.8 Hz). 7.10 (2H, d, J 8.6
Hz), 5.28-5.23 (1H, m), 3.74 (3H, s), 3.56 (4H, q, J 7.1 Hz), 3.31
(1H, dd, J 14.3, 5.4 Hz), 3.17 (1H, dd, J 14.2, 9.2 Hz), 1.17 (6H,
t, J 17.1 Hz); m/z (ES.sup.+, 70V) 425 (MH.sup.+).
EXAMPLE 53
[0416]
(S)-3-[4-(2-Pyrimidinyloxy)phenyl]-2-(2-N,N-diethylamino-3,4-dioxoc-
yclobut-1-enylamino)propanoic acid
[0417] .delta.H (DMSO d6, 390K) 13.10 (1H, br), 8.60 (2H, d, 4.8
Hz), 7.31 (2H, d, J 8.7 Hz), 7.20 (1H, d, 14.8 Hz), 7.09 (2H, d, J
8.7 Hz), 6.97 (1H, br), 5.18-5.17 (1H, m), 3.60-3.59 (4H, m), 3.31
(1H, dd, J 14.3, 5.2 Hz), 3.16 (1H, dd, J 14.3, 9.1 Hz); m/z
(ES.sup.+, 70V), 411 (MH.sup.+).
EXAMPLE 54
[0418] Methyl
(S)-3-[4-(2-pyrimidinyloxy)phenyl]-2-(2-propylamino-3,4-diox-
ocyclobut-1-enylamino)propanoate
[0419] .delta.H (DMSO d.sub.6, 390K) 8.61 (2H, d, J 4.8 Hz), 7.70
(1H, br), 7.55 (1H, br), 7.26-7.19 (3H, m), 7 10 (2H, d, J 8.5 Hz),
5.02 (1H, m), 3.71 (3H, s), 3.44 (2H, br), 3.18 (1H, dd, J 14.0,
5.4 Hz, CH.sub.AH.sub.BAr), 3.08 (1H, dd, J 14.0, 8.0 Hz,
CH.sub.AH.sub.BAr), 1.54-1.46 (2H, m, NHCH.sub.2CH.sub.2CH.sub.3),
0.86 (3H, t, J 7.4, NCH.sub.2CH.sub.2CH.sub.3); m/z (ES.sup.+, 70V)
411 (MH.sup.+).
EXAMPLE 55
[0420]
(s)-3-[4-(2-Pyrimidinyloxy)phenyl]-2-(2-propylamino-3,4-dioxocyclob-
ut-1-enylamino)propanoic acid
[0421] .delta.H (DMSO d.sub.6, 390K) 8.67 (2H, d, J 4.8 Hz), 7.33
(2H, d, J 8.6 Hz), 7.27 (1H, d, J 4.7 Hz), 7.16 (2H, d, J 8.6 Hz),
5.06-5.02 (1H, m), 3.58-3.53 (2H, m), 3.31 (1H, dd, J 14.3, 5.6
Hz), 3.18 (1H, dd, J 14.2, 7.5 Hz,), 1.67-1.62 (2H, m), 0.99 (3H,
t, J 7.4 Hz); m/z (ES.sup.+, 70V) 397 (MH.sup.+).
EXAMPLE 56
[0422] Methyl (S)-3-{4-[(3-phenyl-1
quinazolinyl)amino]phenyl}-[(2-isoprop-
oxy-3,4-dioxocyclobut-1-enyl)amino]propanoate
[0423] Intermediate 18 (518 mg, 1.3 mmol) was dissolved in MeOH (5
ml) and DIPEA base (0.5 ml), treated with
3,4-diisopropoxy-3-cyclobutene-1,2-dion- e (309 mg) and stirred at
RT for 16 h. The solution was concentrated, dissolved in DCM (20
ml), washed with water, dried (Na.sub.2SO.sub.4), filtered and
concentrated. The crude product was purified by column
chromatography (S)O.sub.2:CH.sub.2Cl.sub.2/MeOH 50:1) to give the
title compound (550 mg, 1.0 mmol, 79%) as a brown foamy solid.
.delta.H (DMSO) 8.44 (1H, m), 8.43 (2H, m), 7.80 (2H, m), 7.75 (2H,
m), 7.50 (2H, m), 7.49 (2H, m), 7.33 (2H, d, J 8.6 Hz), 5.23 (1H,
septet, J 6.2 Hz), 4.80 (1H, m), 3.76 (3H, s), 3.30 (1H, dd, J
14.2, 5.3 Hz), 3.13 (1H, dd, J 14.2, 9.3 Hz), 1.38 (3H, d, 16.2
Hz), 1.37 (3H, d, 16.2 Hz); m/z (ESI, 70V) 537 (MH.sup.+).
EXAMPLE 57
[0424] Methyl
(S)-3-{4-[(2-phenyl-4-quinazolinyl)amino]phenyl}-[2-N,N-diet-
hylamino-3,4-dioxo-1-cyclobutenyl)amino]propanoate
[0425] The compound of Example 56 (550 mg, 1.0 mmol) and
diethylamine (0.21 ml) in MeOH (5 ml) was stirred at RT for 16 h
and the solution then concentrated. The residue was purified by
column chromatography (S)O.sub.2; DCM/MeOH 100:1) to give the title
compound (375 mg, 0.68 mmol, 68%) as a brown foamy solid. .delta.H
(DMSO, 390K) 8.45 (3H, m), 7.85 (4H, m), 7.56 (1H, m), 7.48 (3H,
m), 7.35 (2H, d, J 8.7H, 5.33 (1H, m), 3.76 (3H, s), 3.56 (2H, q, J
7.2 Hz), 3.54 (2H, q, J 7.2 Hz), 3.33 (1H, dd, J 14.2, 5.3 Hz),
3.20 (1H, dd, J 14.2, 9.2 Hz), 1.17 (6H, t, J 7.1 Hz); m/z;
(ES.sup.+, 70V) 550 (MH.sup.+).
EXAMPLE 58
[0426]
(S)-3-{-[2-Phenyl-4-quinazolinyl)amino]phenyl}-[2-N,N-diethylamino--
3,4-dioxo-t-cyclobutenyl)amino]propanoic acid
[0427] Example 57 (360 mg, 0.66 mol) was dissolved in THF (2 ml)
and water (2 ml) and treated with lithium hydroxide (41 mg). The
solution was stirred at RT or 90 mins and concentrated. The residue
was dissolved in water and slowly acidified to pH 2 with dilute
hydrochloric acid to give a yellow precipitate which was filtered
and dried to give the title compound (237 mg, 67%). .delta.H (DMSO
d.sub.6) 9.75 (1H, br m), 8.60 (1H, d, 18.7 Hz), 8.43 (2H, m), 7.92
(4H, m), 7.62 (1H, m), 7.52 (3H, m), 7.38 (2H, d, J 8.6 Hz), 5.21
(1H, m), 3.57 (2H, q, J 7.1 Hz), 3.55 (2H, q, J 7.1 Hz), 3.3 (1H,
dd, J 14.1, 4.6 Hz), 3.15 (1H, dd, J 14.1, 10.1 Hz), 1.14 (3H, t, J
7.1 Hz); M/Z (ES+, 70V) 536 (MH.sup.+).
[0428] The compounds of Examples 59 to 64 were prepared from
methyl-(S)-3-(4-aminophenyl)-24N-t-butoxycarbonyl)aminopropanoate
and the appropriate quinazoline in a manner similar to that
described for Intermediate 18 and then derivatised in a manner
similar to that described for Examples 56, 57 and 58.
EXAMPLE 59
[0429]
Methyl-(S)-3-[4(Quinazolin-4-ylamino)phenyl]-2-(2-N,N-diethylamino--
3,4-dioxocyclobut-1-enylamino)propanoic acid
[0430] .delta.H (CDCl.sub.3) 8.73 (1H, s), 8.0 (1H, d, J 8.5 Hz),
7.91 (1H, d, J 8.3 Hz), 7.83-7.54 (6H, m), 7.15 (2H, d, J 8.5 Hz),
5.41 (1H, br s), 3.8 (3H, s), 3.70-3.35 (4H, br m), 3.35-3.15 (2H,
m), 1.23 (6H, t, J 7.2 Hz); m/z (ES.sup.+, 70V) 474 (MH.sup.+).
EXAMPLE 60
[0431]
(S)-3-[4-(Quinazolin-4-ylamino)phenyl]-2-(2-N,N-diethylamino-3,4-di-
oxocyclobut-1-enylamino)propanoic acid
[0432] .delta.H (d.sub.6 DMSO, 390K) 8.62 (1H, s), 8.55 (1H, d,
18.8 Hz), 7.90-7.82 (5H, m), 7.66-7.62 (1H, nr m), 7.34 (2H, d, J
8.5 Hz), 7.09 (1H, br s), 5.25 (1H, brs), 3.64-3.56 (4H, m), 3.35
(1H, dd, J 14.2, 5.1 Hz), 3.20 (1H, dd, J 14.2, 9.1 Hz), 1.23 (6H,
t, J 17.15 Hz); m/z (ES.sup.+, 70V) 460 (MH.sup.+).
EXAMPLE 61
[0433]
(S)-3-{4-[(6,7-Dimethoxyquinazolin-4-yl)amino]phenyl}-2-{[2-N,N-die-
thylamino-3,4-dioxo-1-cyclobutenyl]amino}propanoic acid
[0434] .delta.H (CDCl.sub.3) 9.39 (1H, s), 8.41 (1H, s), 7.81 (1H,
s), 7.67 (3H, dd, J 8.5, 3.8 Hz), 7.25 (2H, d, J 8.4 Hz), 7.16 (1H,
s), 5.12 (1H, br s), 3.93 (3H, s), 3.91 (3H, s), 3.60-3.40 (4H, m),
3.20-2.90 (2H, m), 1.09 (6H, t, J 7.0 Hz); m/z (ES.sup.+, 70V) 520
(MH.sup.+).
EXAMPLE 62
[0435]
(S)-3-{4-{(6,7-Dimethoxyquinazolin-4-yl)amino]phenyl}2-{[2-n-propyl-
amino)-3,4-dioxo-1-cyclobutenyl]amino}propanoic acid
[0436] .delta.H (DMSO) 9.40 (1H, s), 8.42 (1H, s), 7.81 (1H, s),
7.70 (1H, s), 7.66 (2H, d, 18.3 Hz), 7.16 (2H, d, J 7.9 Hz), 7.15
(1H, s), 4.82 (1H, br s), 3.93 (3H, s), 3.91 (3H, s), 3.6-2.9 (4H,
m), 1.49 (2H, dd, J 14.1, 7.0 Hz), 0.86 (3H, t, J 7.3 Hz); m/z
(ES.sup.+, 70V) 506 (MH.sup.+).
EXAMPLE 63
[0437] Methyl
(S)-3-[4-(6-methoxyquinazolin-4-ylamino)phenyl]-2-(2-N,N-die-
thylamino-3,4-dioxocyclobut-1-enylamino)propanoate
[0438] .delta.H (CDCl.sub.3) 8.65 (1H, s), 7.83 (1H, d, J 9.1 Hz),
7.69 (3H, s, d, J 8.0 Hz), 7.45 (1H, dd, 19.2, 2.6 Hz), 7.13 (2H,
d, J 8.5 Hz), 5.40 (1H, br s), 3.95 (3H, s), 3.79 (3H, s), 3.6-3.41
(4H, br m), 3.48 (1H, dd, J 14.1, 5.5 Hz), 3.22 (1H, dd, J 14.1,
7.0 Hz), 1.29 (6H, t, 17.2 Hz); m/z (ES.sup.+, 70V) 504
(MH.sup.+).
EXAMPLE 64
[0439]
(S)-3-[4-(6-Methoxyquinazolin-4-ylamino)phenyl]-2-(2-N,N-diethylami-
no-3,4-dioxocyclobut-1-enylamino)propanoic acid
[0440] .delta..sub.H (d.sub.6 DMSO, 370K); 9.35 (1H, br s), 8.40
(1H, s), 7.89 (1H, d, J 2.7 Hz, 7.54 (2H, d, J 8.6 Hz), 7.71 (1H,
s), 7.49 (1H, d, J 2.7 Hz), 7.28 (2H, d, J 8.5 Hz), 7.15 (1H, br
s), 5.14 (1H, br s), 3.97 (3H, s), 3.42-3.6 (4H, m), 3.28 (1H, dd,
J 14.1, 4.9 Hz), 3.60-3.42 (4H, m), 3.28 (1H, dd, J 14.1, 4.9 Hz),
3.14 (1H, dd, J 14.1, 9.2 Hz), 1.16 (6H, t, 17.1 Hz); m/z
(ES.sup.+, 70V) 490 (MH.sup.+)
[0441] The compounds of Examples 65 to 68 were prepared from
Intermediate 32 in a manner similar to that described for Examples
56 to 58.
EXAMPLE 65
[0442] Methyl
3-{4-[(6,7-dimethyoxy-4-quinazolinyl)amino]-3-methoxyphenyl}-
-2-(2-propylamino-3,4-dioxocyclobut-1-enylamino)propanoate
[0443] .delta.H (DMSO d.sub.6, 390K) 8.54 (1H, br s), 8.38 (1H,
s,), 7.75 (1H, d, J 7.8 Hz), 7.66 (1H, s), 7.34 (1H, br d J 8.5
Hz), 7.25 (1H, br s), 7.20 (1H, s), 6.97 (1H, d, J 1.9 Hz), 6.85
(1H, br s), 5.15-5.09 (1H, m), 3.97 (3H, s), 3.96 (3H, s), 3.78
(3H, s), 3.76 (3H, s), 3.52-3.47 (2H, m), 3.26 (1H, dd, J 14.1, 5.6
Hz), 3.12 (1H, dd, J 14.1, 8.0 Hz), 1.59 (2H, sext, J 7.2 Hz), 0.93
(3H, t, J 7.4 Hz); m/z (ES.sup.+ 70V) 550 (MH.sup.+).
EXAMPLE 66
[0444]
3-{4-[(6,7-Dimethoxy-4-quinazolinyl)amino]-3-methoxyphenyl}2-(2
propylamino-3,4-dioxocyclobut-1-enylamino)propanoic acid
[0445] .delta.H (DMSO d.sub.6, 390K) 8.38 (1H, s), 7.73 (1H, d, J
8.0 Hz), 7.66 (1H, s), 7.27 (1H, br s), 7.20 (1H, s), 6.99 (1H, d,
J 1.18 Hz), 6.87 (1H, dd, J 8.0, 1.9 Hz), 5.02 (1H, m), 3.97 (3H,
s), 3.96 (3H, s), 3.83 (3H, s), 3.49 (2H, q, J 6.3 Hz), 3.27 (1H,
dd, J 14.1, 5.4 Hz), 3.11 (1H, dd, J 14.1, 7.8 Hz), 1.59 (2H, sext.
J 76.2 Hz), 0.93 (3H, t, 17.4 Hz); m/z (ES.sup.+, 70V) 536
(MH.sup.+.
EXAMPLE 67
[0446] Methyl
3-{4-[(6,7-dimethoxy-4-quinazolinyl)amino]-3-methoxyohenyl}--
2(2-N,N-diethylamino-3,4-dioxocyclobut-1-enylamino)propanoate
.delta.H (DMSO d.sub.6, 390K) 8.33 (1H, br s), 8.15 (1H, s), 7.51
(1H, d, 18.1 Hz), 7.44 (1H, s), 6.98 (1H, s), 6.92 (1H, d, 19.0
Hz), 6.82 (1H, d, J 1. Hz), 6.69 (1H, dd, J 8.0, 1.9 Hz), 5.15-5.09
(1H, m), 3.76 (3H, s), 3.75 (3H, s), 3.61 (3H, s), 3.55 (3H, s),
3.35 (4H, q, J 71 Hz), 3.11 (1H, dd, J 14.2, 51 Hz), 2.94 (1H, dd,
J 14.2, 9.5 Hz), 0.96 (6H, t, J 7.1 Hz); m/z (ES.sup.+, 70V) 564
(MH.sup.+).
EXAMPLE 68
[0447]
3-{4[(6,7-Dimethoxy-4-quinazolinyl)amino]-3-methoxyphenyl}-2-(2-N,N-
-diethylamino-3,4-dioxocyclobut-1-enylamino)propanoic acid
[0448] .delta.H (DMSO d.sub.6, 390K), 8.49 (1H, s,), 7.97 (1H, br
s), 7.51-7.49 (1H, m), 7.38 (1H, s), 7.21 (1H, br d), 7.12 (1H, s),
6.96 (1H, dd, J 7.9, 1.3 Hz), 5.28-5.25 (1H, m), 4.00 (6H, s), 3.81
(3H, s), 3.58 (1H, q, J 7.1 Hz), 3.35 (1H, dd, J 14.2, 4.8 Hz),
3.20 (1H, dd, J 14.2, 9.7 Hz), 1.18 (6H, t, J 7.1 Hz); m/z
(ES.sup.+, 70V) 550 (MH.sup.+).
EXAMPLE 69
[0449] Methyl
(S)-3-{4-[(6,7-dimethoxy4-quinazolinyl)amino]phenyl}-2-(2-te- rt
butyl-3,4-dioxocyclobut-1-enylamino)propanoate
[0450] A mixture of
methyl-(S).sub.4-[(6,7-dimethoxy-4-quinazolinyl)amino]-
phenyl}-2-amino propanoate (332 mg, 0.869 mmol) and Intermediate 4
(171 mg, 0.87 mmol) in MeOH (10 ml) was heated at reflux for 5
days. The solvent was removed in vacuo. The residue was dissolved
in DCM, washed with dil. HCl, dried (Na.sub.2SO.sub.4) and
concentrated in vacuo. Column chromatography (S)O.sub.2; MeOH/DCM,
7:93) gave the title compound as a brown glass (275 mg). .delta.H
(DMSO d.sub.6) 9.39 (1H, s), 8.62 (1H, br d), 8.40 (1H, d, J 1.2
Hz), 7.81 (1 h, s), 7.69-7.65 (2H, m), 7.22 (2H, d, 8.5 Hz), 5.08
(1H, m), 3.94 (3H, s), 3.91 (3H, s), 3.74 (3H, s), 3.30 (1H, m),
3.02 (1H, dd, J 13.5, 11.2 Hz), 1.22 (9H, s); m/z (ES.sup.+, 70V)
519 (MH.sup.+).
EXAMPLE 70
[0451]
Ethyl-(S)-3-{4-[(3-chloro-6,7-dimethoxy4-quinazolinyl)amino]phenyl}-
-2-[(2-isopropoxy-3,4-dioxocyclobut-1-enylamino)propanoate
[0452] Prepared in a similar manner to the compound of Example 56
from the Intermediate 45. .delta.H (CD.sub.3OD) 7.73 (2H, d, J 8.6
Hz), 7.73 (1H, s), 7.27 (2H, d, J 8.6 Hz), 7.06 (1H, s), 5.28 (1H,
m), 5.07 and 4.62 (1H, br), 4.23 (2H, q), 4.00 (3H, s), 3.97 (3H,
s), 3.35 (1H, m) 3.05 (1H, m), 1.40 (6H, d, J 6.2 Hz), 1.30 (3H, t,
J 7.3 Hz).
EXAMPLE 71
[0453]
Ethyl-(S)-3-{4-{(3-chloro-6,7-dimethoxy4-quinazolinyl)amino[phenyl)-
-2-E(2-N,N-diethylamino-3,4-dioxocyclobut-1-enylamino]propanoate
[0454] Prepared in a similar manner to the compound of the Example
57 from the compound of Example 70. .delta..sub.H (CD.sub.3OD) 7.72
(1H, s), 7.70 (2H, d, J 8.6 Hz), 7.29 (2H, d, 18.6 Hz), 7.04 (1H,
s), .delta. 33 (1H, dd), 4.25 (2H, q, J 7.1 Hz), 3.99 (3H, s), 3.96
(3H, s), 3.58 (4H, br), 3.44 (1H, dd), 3.10 (1H, dd), 1.30 (3H, t,
17.1 Hz), 1.20 (6H, t, J 7.2 Hz).
EXAMPLE 72
[0455]
(S)-3-{4-[(3-Chloro-6,7-dimethoxy-4-quinazolinyl)amino]phenyl}-2-[(-
2-N,N-diethylamino-cyclobut-1-enyl)amino]propanoic acid
[0456] Prepared in a similar manner to the compound of Example 58
from the compound of Example 71. .delta.H (d.sub.6 DMSO) 7.86 (1H,
s), 7.65 (2H, d, J 8.6 Hz), 7.31 (2H, d, J 8.6 Hz), 7.16 (1H, s),
5.15 (1H, m), 3.97 (3H, s), 3.95 (3H, s), 3.53 (4H, m), 3.20 (1H,
m), 3.13 (1H, m), 1.50 (6H, t, J 7.1 Hz). m/z (ES.sup.+) 554
(MH.sup.+).
EXAMPLE 73
[0457]
(S)-3-{4-[(6,7-Dimethoxy-4-quinazolinyl)amino]phenyl}-2-(2-t-butyl--
3,4-dioxocyclobut-1-enylamino)propanoic acid
[0458] Prepared in a similar manner to the compound of Example 58
from the compound of Example 69. .delta..sub.H (DMSO d.sub.6, 370K)
8.40 (1H, s), 7.94 (1H, d, 19.2 Hz), 7.83 (1H, s), 7.58 (2H, d,
18.5 Hz), 7.17 (2H, d, 18.6 Hz), 7.14 (1H, s), 4.96-4.90 (1H, m),
3.89 (3H, s), 3.87 (3H, s), 3.22 (1H, dd, J 14.1, 4.5 Hz),3.04 (1H,
dd, J 14.0, 10.2 Hz), 1.17 (9H, s). m/z (ES.sup.+, 70V) 505
(MH.sup.+).
EXAMPLE 74
[0459]
Ethyl-(S)-3-(4-[5-methyl-4-quinazolinyl)amino]phenyl)-2-[(2-isoprop-
oxy-3,4-dioxocyclobut-1-enyl)amino]propanoate
[0460] Intermediate 38 (800 mg, 2.3 mmol) and
3,4-diisopropoxy-3-cyclobute- n 1,2-dione (453 mg, 1 equiv) were
stirred at RT in anhydrous MeOH (5 m) for 17 h. The solvent was
removed in vacuo and the residue purified by column chromatography
(Silica, 75:25 EtOAc-isohexane) to give the title compound.
.delta.H (DMSO d6; 350K), 8.70 (broad signal), 8.50 (1H, s), 7.60
(4H, m), 7.30 (1H, d, J 7.0 Hz), 7.20 (2H, d, 8.4 Hz), 5.20 (1H,
m). 5.60 (1H, broad s), 4.20 (2H, m), 3.20 (1H, m), 3.10 (1H, m),
3.00 (3H, s), 1.30 (6H, d, J 6.2 Hz), 1.20 (3H, m); m/z (ES.sup.+,
70V) 489 (MH.sup.+).
EXAMPLE 75
[0461] Ethyl
(S)-3(4-[(5-methyl4:quinazolinyl)amino]phenyl)-2-[2-N,N-dieth-
ylamino-3,4-dioxocyclobut-1-enyl)amino]propanoate
[0462] The compound of Example 74 (250 mg, 0.5 mmol) and
N,N-diethylamine were stirred at RT in anhydrous (5 ml) MeOH for 17
h. The solvent was removed in vacuo and the residue purified by
column chromatography (Silica; EtOAc to 95% EtOAc: 5% MeOH) to
isolate the title compound (200 mg) as an off-white solid. .delta.H
(DMSO d.sub.6), 8.60 (1H, s), 8.50 (1H, s), 7.80 (1H, d, J 9.1 Hz),
7.60 (4H, m), 7.40 (1H, d, J 7,0 Hz), 7.20 (2H, d, 6.8 Hz), 5.20
(1H, m), 4.00 (1H, m), 3.70 (3H, s), 3.50 (4H, broad signal), 3.20
(1H, m), 3.00 (1H, m), 2.90 (3H, s), 1.20 (6H, m). m/z (ES.sup.+,
70V) 488 (MH.sup.+).
EXAMPLE 76
[0463]
(S)-3-(4-[(5-Methyl4-quinazolinyl)amino]phenyl)-2-[(2-N,N-diethylam-
ino-3,4-dioxocyclobut-1-enyl)amino]propanoic acid
[0464] The compound of Example 75 (190 mg, 0.38 mmol) and lithium
hydroxide monohydrate (19 mg) were stirred in a solvent mixture of
MeOH (3 ml), THF (1.5 ml), and water (1.5 ml) for 17 h. The solvent
was removed in vacuo and the residue dissolved in water, the
solution neutralised with HCl, concentrated in vacuo and the
residue purified by column chromatography (Silica; 200:20:3:2
DCM:MeOH:AcOH:H.sub.2O) to isolate the title compound as yellow
solid. .delta.H (DMSO d.sub.6, 350K), 8.50 (1H, broad signal), 7.70
(3H, broad signal), 7.40-7.20 (3H, m), 5.10 (1H, m), 3.6 (4H, m),
3.30 (1H, m), 3.10 (1H, m), 1.10 (6H, t, J 7.2 Hz), m/z (ES.sup.+,
70V) 474 (MH.sup.+).
[0465] Also prepared in a similar manner to that described for
Examples 75 and 76 from the compound of Example 74 were the
compounds of Examples 77 and 78:
EXAMPLE 77
[0466] Methyl
(S)-3-(4-[(5-methyl-4-quinazolinyl)amino]phenyl)-2-[(2-N,N-d-
i-n-propylamine-3,4-dioxocyclobut-1-enyl)amino]propanoate
[0467] .delta.H (DMSO d.sub.6, 350K), 8.50 (1H, broad s), 7.80-7.60
(4H, m), 7.40 (1H, m), 7.30 (2H, m), 5.30 (1H, m), 3.70 (3H, s),
3.50 (4H, m), 3.40 (1H, m), 3.20 (1H, m), 3.10 (3H, s), 1.60 (4H,
m), 0.90 (6H, t, J 7.4 Hz), m/z (ES.sup.+, 70V) 516 (MH.sup.+)
EXAMPLE 78
[0468]
(S(-3-(4-[(5-Methyl-4-quinazolinyl)amino]phenyl)-2-[(2-N,N-di-n-pro-
pylamino-3,4-dioxocyclobut-1-enyl)amino]propanoic acid .delta.H
(DMSO d.sub.6, 350K), 8.70 (1H, s), 7.80 (2H, m), 7.70-7.40 (3H,
m), 7.40 (2H, d, J 8.5 Hz), 5.20 (1H, m), 3.60 (4H, m), 3.40 (1H,
m), 3.20 (1H, m), 3.00 (3H, s), 1.50 (4H, m), 0.90 (6H, t, J 7.3
Hz), ml/z (ES.sup.+, 70V) 502 (MH.sup.+).
EXAMPLE 79
[0469]
Ethyl-(S)-3-(4-([6-(trifluoromethoxy)-4-quinazolinyl]amino)phenyl]--
2-[(2-isopropoxy-3,4-dioxocyclobut-1-enyl)amino]propanoate
[0470] Prepared in a similar manner to Example 74 from the compound
of Intermediate 43. .delta..sub.H (DMSO d.sub.6, 300K), 9.20-9.00
(1H, m), 8.70 (2H, m), 8.00 (2H, m), 7.80 (2H, m), 7.30 (2H, m),
5.20 (1H, m), 5.00 (1H, m), 4.50 and 4.20 (1H, 2, sets m), 3.80
(3H, m), 3.30 (1H, m), 3.00 (1H, m), 1.30 (6H, m), m/z (ES.sup.+,
70V) 545 (MH.sup.+).
EXAMPLE 80
[0471] Methyl
(S)-3-(4([6-(trifluoromethoxy)-4-quinazolinyl]amino)phenyl)--
2-[(2-N,N-diethylamino-3,4-dioxocyclbut-1-enyl)amino]propanoate
[0472] Prepared from the compound of Example 79 in a similar manner
to that described for Example 75. .delta..sub.H (CD.sub.3OD), 8.50
(1H, s), 8.40 (1H, s), 7.90 (1H, d, 19.1 Hz), 7.80 (1H, m), 7.70
(2H, d, J 8.6 Hz), 7.30 (2H, d, J 8.6 Hz), 5.50 (1H, m), 3.80 (3H,
s), 3.60 (4H, broad signal), 3.50 (1H, m), 3.10 (1H, m), 1.20 (6H,
t, J 7.2 Hz), m/z (ES.sup.+, 70V) 544 (MH.sup.+).
EXAMPLE 81
[0473]
(S)-3-(4-([6-(Trifluoromethoxy)-4-quinazolinyl]amino)phenyl)-2-[(2--
diethylamino-3,4-dioxocyclobut-1-enyl)amino]propanoic acid
[0474] Prepared from Example 80 in a similar manner to that
described for Example 76. .delta.H (DMSO, 340K), 9.80 (bd s), 8.60
(2H, m), 8.00-7.70 (4H, m), 7.30 (2H, d), 5.20 (1H, m), 3.50 (4H,
m), 3.30 (1H, m), 3.10 (1H, m), 1 20 (6H, t, 17.1 Hz) m/z
(ES.sup.+, 70V) 544 (MH.sup.+).
EXAMPLE 82
[0475]
Methyl-(S)-3-(4([6-(trifluoromethoxy)-4-quinazolinyl]amino)phenyl)--
2-[(2-N,N-di-n-propylamino-3,4-dioxocyclobut-1-enyl)amino]propanoate
[0476] Prepared from the compound of Example 79 in a similar manner
to that described for Example 75. .delta.H (CD.sub.3OD), 8.50 (1H,
s), 8.40 (1H, broad signal), 7.90 (1H, d, 9.2 Hz), 7.85-7.70 (3H,
m), 7.30 (1H, d, 18.5 Hz), 5.40 (1H, m), 3.80 (3H, s), 3.60 (5H,
broad signal), 3.10 (1H, m), 1.60 (4H, m), 0.90 (3H, t, J 7.4 Hz),
m/z (ES.sup.+, 70V) 586 (MH.sup.+).
EXAMPLE 83
[0477]
(S)-3-(4-([6-(Trifluoromethoxy)-4-quinazolinyl]amino)phenyl)-2-[(2--
N,N-di-n-propylamino-3,4-dioxocyclobut-1-enyl)amino]propanoic
acid
[0478] Prepared from the compound of Example 82 in a similar manner
to that described for Example 76. .delta.H (DMSO d.sub.6, 350K),
9.70 (broad signal), 8.60 (2H, m), 7.90 (1H, d, J 9.2 Hz), 7.70
(3H, m), 7.30 (2H, d, J 8.0 Hz), 5.20 (1H, m), 3.50 (4H, m), 3.30
(1H, m), 3.200 (1H, m), 1.60 (4H, m), 0.90 (3H, t, J 7.4 Hz), m/z
(ES.sup.+, 70V) 572 (MH.sup.+).
[0479] The compounds of Examples 84 to 89 were prepared in a
similar manner to that described for the preparation of
Intermediate 8 from N-BOC-L-tyrosine methyl ester and the
appropriate quinazoline and then derivatised in a manner similar to
that described for Examples 56 to 58.
EXAMPLE 84
[0480] Methyl
(S)-3-[4-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]-2-(2-N,N-d-
iethylamino-3,4-dioxocyclobut-1-enylamino)propanoate
[0481] .delta..sub.H (CDCl.sub.3) 8.57 (1H, s), 7.54 (1H, s), 7.33
(1H, s), 7.25-7.17 (5H, m), 5.55-4.9 (1H, m), 4.07 (6H, s), 3.83
(3H, s), 3.55-3.4 (5H, m), 3.31 (1H, dd, J 9.0, 5.5 Hz), 1.25 (6H,
t, 17.2 Hz), m/z (ES.sup.+, 70V) 535 (MH.sup.+).
EXAMPLE 85
[0482]
(S)-3-{4-[(6,7-Dimethoxyquinazolin-4-yl)oxy]phenyl}-2-{[2-N,N-dieth-
ylamino-3,4-dioxo-1-cyclobutenyl]amino}propanoic acid
[0483] .delta.H (d.sub.6 DMSO, 370K) 8.58 (1H, s), 7.64 (1H, s),
7.44-7.40 (3H, m), 7.28 (2H, d, J 8.5 Hz), 5.23 (1H, br s), 4.06
(3H, s), 4.04 (3H, s), 3.66-3.56 (4H, m), 3.39 (1H, dd, J 14.1, 4.6
Hz), 3.21 (1H, dd, J 14.1, 9.6 Hz). 1.22 (6H, t, J 7.1 Hz), m/z
(ES.sup.+, 70V) 521 (MH.sup.+),
EXAMPLE 86
[0484] Methyl
(S)-3-[4-(6-methoxyquinazolin-4-yloxy)phenyl]-2-(2-N,N-di-n--
propylamino-3,4-dioxocyclobut-1-enylamino)propanoate.
[0485] .delta..sub.H (CDCl.sub.3) 8.62 (1H, s), 7.95 (2H, d, 9.0
Hz), 7.59-7.54 (2H, m), 7.26-7.18 (3H, m), 5.47-5.42 (1H, m), 5.30
(1H, d, J 8.4 Hz), 3.99 (3H, s), 3.83 (3H, s), 3.60-3.10 (6H, m),
1.67-1.60 (4H, m), 0.92 (6H, t, J 7.4 Hz); m/z (ES.sup.+, 70V) 533
(MH.sup.+).
EXAMPLE 87
[0486]
(S)-3-[4-(6-Methoxyquinazolin-4-yloxy)phenyl]-2-(2-N,N-di-n-propyla-
mino-3,4-dioxocyclobut-1-enylamino)propanoic acid
[0487] (d.sub.6 DMSO) 8.57 (1H, s), 7.92 (1H, d, J 10.0 Hz), 7.65
(2H, d, J 7.3 Hz), 7.37 (2H, d, J 8.7 Hz), 7.24 (2H, d, J 8.6 Hz),
7.09 (1H, br s), 5.13 (1H, br s), 3.98 (3H, s), 3.59-3.39 (4H, m),
3.35 (1H, dd, J 14.5, 5.0 Hz), 3.17 (1H, dd, J 14.1, 9.4 Hz),
1.67-1.50 (4H, m), 0.87 (6H, t, J 7.3 Hz); m/z (ES.sup.+, 70V) 519
(MH.sup.+)
EXAMPLE 88
[0488]
(S)-3-[4-(6-Methoxyquinazolin-4-yloxy)phenyl]-2-(2-n-propylamino-3,-
4-dioxocyclobut-1-enylamino)propanoic acid .delta..sub.H (de DMSO,
370K) 8.59 (1H, s), 7.92 (1H, d, J 9.8Jz), 7.65 (2H, d, J 7.3 Hz),
7.35-7.24 (5H, m), 4.97 (1H, br s), 3.99 (3H, s), 3.50 (2H, t, J
6.3 Hz), 3.29 (1H, dd, J 14.0, 5.4 Hz), 3.13 (1H, dd, J 14.1, 7.4
Hz), 1.58 (2H, dd, J 14.2, 7.1 Hz), 0.92 (3H, t, J 7.4 Hz); m/z
(ES.sup.+, 70V) 477 (MH.sup.+).
EXAMPLE 89
[0489]
(S)-3-[4-(6-Methoxyquinazolin-4-yloxy)phenyl]-2-(2-N,N-diethylamino-
-3,4-dioxocyclobut-1-enylamino)propanoic acid .delta..sub.H (DMSO,
370K) 8.58 (1H, s), 7.92 (1H, d, J 9.9 Hz), 7.65 (2H, d, J 4.7 Hz),
7.39 (2H, d, 18.5 Hz), 7.25 (2H, d, 18.8 Hz), 5.21 (1H, br s), 3.98
(3H, s), 3.6-3.5 (4H, m), 3.34 (1H, dd, J 14.2, 5.1 Hz), 3.17 (1H,
dd, J 14.1, 9.9 Hz), 1.17 (6H, t, 17.1 Hz); m/z (ES.sup.+, 70V) 461
(MH.sup.+).
EXAMPLE 90
[0490]
(S)-Ethyl-3-[4-(isoquinolin-1-ylamino)phenyl]-2-[(2-isopropoxy-3,4--
dioxocyclobut-1-enyl)amino]propanoate
[0491] A solution of Intermediate 10 (426 mg, 1.27 mmol) and
3,4-diisopropoxy-3-cyclobutene-1,2-dione (301 mg, 1.52 mmol) in
absolute ethanol (5.0 ml) was stirred at 400 under N.sub.2 for 18
h. The volatiles were removed in vacuo and the residue
chromatographed (S)O.sub.2; 25-50% EtOAc/hexane) to afford the
title compound as a pale orange foam (585 mg, 97%). .delta.H
(CDCl.sub.3) 8.04 (1H, d, J 5.8 Hz), 7.98 (1H, d, J 8.4 Hz), 7.72
(1H, d, J 7.8 Hz), 7.62 (1H, obscured m), 7.61 (2H, d, J 8.3 Hz),
7.52 (1H, app.t, J 7.0 Hz), 7.35 (1H, br s), 7.12-7.08 (3H, m),
6.60, 6.03, 5.13 and 4.59 (together 1H, m), 5.32 (1H, m), 4.24 (2H,
q, J 7.1 Hz), 3.25-3.01 (2H, br m), 1.39 (6H, d, J 6.1 Hz), 1.30
(3H, t, J 7.1 Hz); m/z (ES.sup.+, 70V) 474 (MH.sup.+).
EXAMPLE 91
[0492] Ethyl (S)-3-[4
isoquinolin-1-ylamino)phenyl]2-{[2-N,N-diethylamino--
3,4-dioxo-1-cyclobutenyl]amino}propanoate A solution of the
compound of Example 90 (585 mg, 1.24 mmol) and diethylamine (181
mg, 225 .mu.l, 2.48 mmol) in absolute ethanol (2 ml) was heated at
500 under N.sub.2 for 18 h. The volatiles were removed in vacuo
affording the title compound as a dull orange foam (520 mg).
.delta.H (CDCl.sub.3) 8.05 (1H, d, 15.8 Hz), 7.96 (1H, d, J 8.3
Hz), 7.75 (1H, d, J 7.6 Hz), 7.65 (1H, m), 7.63 (2H, d, J 8.5 Hz),
7.55 (1H, app.t, J 7.0 Hz), 7.23 (1H, br s), 7.11 (1H, m), 7.10
(2H, d, J 8.5 Hz), 5.39 (1H, narrow m), 4.25 (2H, q, J 7.1 Hz),
3.65-3.35 (4H, br m), 1.32 (3H, t, J 7.1 Hz), 1.22 (6H, t, J 7.2
Hz); m/z (ES.sup.+, 70V) 487 (MH.sup.+).
EXAMPLE 92
[0493]
(S)-3-[4-(Isoquinolin-1-ylamino)phenyl]-2-{[2-N,N-diethylamino-3,4--
dioxo-1-cyclobutenyl]amino}propanoic acid
[0494] A solution of Example 91 (510 mg, 1.05 mmol) and
LiOH.H.sub.2O (53 mg, 1.26 mmol) in water (8 ml) and dioxan (8 ml)
was stirred at room temperatue for 1.5 h. Several drops of AcOH
were added and the volatiles were removed in vacuo. The residue was
chromatographed [silica, DCM (200-120), MeOH (20), AcOH (3),
H.sub.2O(2)]. Freeze-drying from aqueous MeOH afforded the title
compound as a pale yellow amorphous solid (230 mg, 48%). .delta.H
(d.sup.6 DMSO) 9.07 (1H, br s), 8.49 (1H, d, 18.3 Hz), 7.95 (1H, d,
J 5.7H), 7.79-7.75 (3H, m's), 7.70-7.64 (2H, m's), 7.58 (1H, td, J
8.3, 1.3 Hz), 7.20 (2H, d, 18.4 Hz), 7.13 (1H, d, 15.6 Hz), 5.11
(1H, m), 3.65-3.38 (4H, br m), 3.22 (1H, dd, J 13.9, 4.0 Hz), 2.99
(1H, dd, J 13.9, 11.0 Hz) and 1.09 (6H, t, J 7.0 Hz); m/z
(ES.sup.+, 70V) 459 (MH.sup.+).
EXAMPLE 93
[0495] Ethyl
(3S)-3-{4-[(tert-Butoxycarbonyl)amino]phenyl}-3-[(2-isopropox-
y-3,4-dioxocyclobut-1-enyl)amino]propanoate
[0496] Intermediate 12 (190 mg, 0.62 mmol) in MeOH was treated with
3,4-diisopropoxy-3-cyclobutene-1,2-dione (122 mg) and
N-methyl-morpholine (0.1 ml) and stirred at RT for 16 h. The
solvent was removed and the product purified by column
chromatography (S)O.sub.2;CH.sub.2Cl.sub.2/MeO- H 20:1) to give the
title compound (176 mg, 64%) as a white foamy solid. .delta.H
(DMSO) 7.41 (2H, d, J 8.6 Hz), 7.24 (2H, d, J 8.6 Hz, 5.29 (1H, m),
5.25 (1H, septet, J 6.2 Hz), 4.06 (2H, q, J 7.1 Hz), 2.99 (1H, dd,
J 15.8, 8.8 Hz), 2.86 (11H, dd, J 15.8, 6.0 Hz), 1.40 (3H, d, J 6.2
Hz), 1.36 (3H, d, 16.2 Hz), 1.16 (3H, t, J 7.1 Hz); m/z (ESI, 70V)
469 (MNa.sup.+).
EXAMPLE 94
[0497] Ethyl
(3S)-3-(4-aminophenyl)-3-[(2-isopropoxy-3,4-dioxocyclobut-1-e-
nyl)amino]propanoate
[0498] The compound of Example 93 (176 mg, 0.39 mmol) was dissolved
in EtOAc (10 ml) and HCl gas was bubbled through. The reaction
mixture was stirred for 2 h and the solvent removed to give the
title compound (130 mg, 0.34 mmol, 87%) as an oil. .delta.H (DMSO
360K) 7.38 (2H, d, J 8.5 Hz), 7.21 (2H, d, J 8.5 Hz), 5.30 (1H, br
m), 5.25 (1H, septet, J 6.2 Hz), 4.08 (2H, q, J 7.1 Hz), 2.99 (11H,
dd, J 15.8, 8.8 Hz), 2.85 (1H, dd, J 15.8, 6.0 Hz), 1.40 (3H, d, J
6.2 Hz), 1.36 (3H, d, J 6.2 Hz), 1.15 (3H, t, J 7.1 Hz).
EXAMPLE 95
[0499] Ethyl
(3S)-3-{4-(3,5-dichloro4-pyridylcarboxamido)phenyl}-3-[(2-iso-
propoxy-3,4-dioxocyclobut-1-enyl)amino]propanoate
[0500] The compound of Example 94 (max 2 mmol) was dissolved in DCM
(5 ml) and N-methylmorpholine (1 equiv) and cooled to 0.degree..
3,5-dichloroisonicotinoyl chloride (463 mg) was added and the
reaction mixture stirred at RT for 16 h then quenched with sodium
bicarbonate solution. The organic layer was washed with dilute
hydrochloric acid, water, dried (Na.sub.2SO.sub.4), filtered and
the solvent removed. The product was purified by column
chromatography (S)O.sub.2; CH.sub.2Cl.sub.2/MeOH 20:1) to give the
title compound (636 mg, 61%) as an oil. .delta.H (DMSO, 390K) 10.47
(1H, br s), 8.69 (2H, s), 7.62 (2H, d, 18.4 Hz), 7.39 (2H, d, J 8.4
Hz), 5.38 (1H, m), 5.25 (1H, septet, J 6.1 Hz), 4.10 (2H, q, 17.1
Hz), 3.05 (1H, dd, J 15.8, 8.6 Hz), 1.42 (3H, d, J 6.1 Hz), 1.38
(3H, d, J 6.1 Hz), 1.18 (3H, t, J 7.1 Hz);; m/z (ES.sup.+, 70V) 522
(MH.sup.+)
EXAMPLE 96
[0501] Ethyl
(3S)-3d4-(3,5-dichloropyrid-4-ylcarboxamido)phenyl}-3-{[2-N,N-
-diethylamino-3,4-dioxo-1-cyclobutenyl]amino}propanoate
[0502] The compound of Example 95 (318 mg, 0.61 mmol) was dissolved
in MeOH (5 ml) and diethylamine (0.13 ml). The solution was stirred
for 16 h to give a white precipitate which was isolated by
filtration and dried to give the title compound (247 mg, 78%) as a
white solid. .delta.H (DMSO, 370K) 10.93 (1H, br s), 8.78 (2H, s),
7.61 (2H, d, J 9.0 Hz), 7.41 (2H, d, J 9.0 Hz), 5.83 (1H, m), 3.59
(3H, s), 3.53 (4H, br m), 3.08 (1H, dd, J 16.0, 9.0 Hz), 2.95 (1H,
dd, J 16.0, 6.0 Hz), 1.10 (6H, t, 16.0 Hz); m/z (ES.sup.+, 70V) 521
(MH.sup.+).
EXAMPLE 97
[0503]
(3S)-3-{4-(3,5-Dichloropyrid-4-yl-carboxamido)phenyl}-3-{[2-N,N-die-
thylamino-3,4-dioxo-1-cyclobutenyl]amino}propanoic acid
[0504] The compound of Example 96 (235 mg, 0.45 mmol) was dissolved
in THF (5 ml) and water (5 ml) and lithium hydroxide (21 mg) added.
The solution was stirred at RT for 3 h and the solvent removed in
vacuo. The residue was dissolved in water (10 ml) and acidified to
pH 2 with dil. HCl to give a white precipitate (198 mg, 0.39 mmol,
87%) which was filtered and dried to afford the title compound.
.delta.H (DMSO, 390K) 10.43 (1H, br s), 8.69 (2H, s), 7.60 (2H, d,
J 8.5 Hz), 7.45 (2H, d, J 8.5 Hz), 7.29 (1H, br s), 5.82 (1H, m),
3.60 (2H, q, J 7.0 Hz), 3.58 (2H, q, J 7.0 Hz), 3.02 (1H, dd, J
15.8, 8.2 Hz,), 2.90 (1H, dd, J 15.8, 6.1 Hz), 1.20 (6H, t, J 7.0
Hz); m/z (ES.sup.+, 70V) 507 (MH.sup.+). Analysis by chiral HPLC on
Chirobiotic T column eluting with MeOH/0.6%HOAc gave single peak
eluting at 5.58 minutes.
EXAMPLE 98
[0505]
(3R)-3-{4-(3,5-Dichloropyrid4-ylcarboxamido)phenyl-3-{[2-N,N-(dieth-
ylamino)-3,4-dioxo-1-cyclobutenyl]amino}propanoic acid
[0506] This was prepared by the same route as the (S)-enantiomer
Example 97 using the appropriate chiral amine. Analysis by chiral
HPLC on Chirobiotic T column eluting with MeOH/0.6%HOAc gave single
peak eluting at 6.54 minutes.
EXAMPLE 99
[0507] Methyl
(3R)-3-[(2-Isopropoxy-3,4-dioxocyclobut-1-enyl)amino]-3-{4-[-
(6,7-dimethoxy4-quinazolinyl)oxy]phenyl}propanoate
[0508] Intermediate 16 (580 mg, 1.38 mmol) was dissolved in MeOH (6
ml) and DIPEA (0.53 ml) and 3,4-diisopropoxy-3-cyclobuten-1,2-dione
(300 mg) added. The solution was stirred for 16 h and the solvent
removed. The residue was purified by column chromatography
(S)O.sub.2; CH.sub.2Cl.sub.2/MeOH 50:1) to give the title compound
(539 mg, 75%) as a yellow oil. .delta.H (DMSO, 350K) 8.99 (1H, br
m), 8.54 (1H, s), 7.57 (1H, s), 7.49 (2H, d, J 8.6 Hz), 7.38 (1H,
s), 7.32 (2H, d, 8.6 Hz), 5.40 (11H, m), 5.27 (1H, septet, J 6.2
Hz), 4.01 (3H, s), 3.98 (3H, s), 3.64 (3H, s), 3.10 (1H, dd, J
16.1, 5.8 Hz,), 2.97 (1H, dd, J 16.1, 5.8 Hz), 1.42 (3H, d, J 6.2
Hz), 1.38 (3H, d, J 6.2 Hz); m/z (ES.sup.+, 70V) 522
(MH.sup.+).
EXAMPLE 100
[0509] Methyl
(3R)-3-{[2-N,N-diethylamino-3,4-dioxo-1-cyclobutenyl]amino}--
3-{4-[(6,7-dimethoxy4-quinazolinyl)oxy]phenyl}propanoate
[0510] The compound of Example 99 (265 mg, 0.51 mmol) was dissolved
in MeOH (3 ml) and diethylamine added (0.1 ml). The solution was
stirred for 16 h giving a white precipitate. The precipitate was
filtered and dried to give the title compound (177 mg, 65%) as a
white solid. .delta.H (DMSO, 370K) 8.55 (1H, s), 7.59 (1H, s), 7.54
(2H, d, J 8.5 Hz), 7.32 (1H, s), 7.30 (2H, d, J 8.5 Hz, 5.94 (1H,
m), 4.02 (3H, s), 3.99 (3H, s), 3.64 (3H, s), 3.60 (4H, septet, J
7.1 Hz), 3.15 (1H, dd, J 15.7, 8.9 Hz), 3.03 (1H, dd, J 15.7, 5.9
Hz), 1.19 (6H, t, J 7.1 Hz),; m/z (ES.sup.+, 70V) 535
(MH.sup.+).
EXAMPLE 101
[0511] (R)-3-{[2-N,N-7Diethylamino-3,4-dioxo-1
cyclobutenyl]amino}-3-{4
[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}propanoic acid
[0512] The compound of Example 100 (170 mg, 0.32 mmol) was
dissolved in THF (2 ml) and water (2 ml) and lithium hydroxide (20
mg) was added. The solution was stirred at RT for 3 h and the
solvent removed. The residue was dissolved in water (10 ml) and
acidified to pH 2 with dil. HCl to give a white precipitate (42 mg,
25%) which was filtered and dried-.delta.H (DMSO, 400K) 8.56 (1H,
s), 7.60 (1H, s), 7.54 (2H, d, J 8.6 Hz), 7.39 (1H, s), 7.31 (2H,
d, J 8.6 Hz), 5.90 (1H, m), 4.03 (3H, s), 3.99 (3H, s), 3.62 (2H,
q, J 7.1 Hz), 3.60 (2H, q, J 7.1 Hz), 3.06 (1H, dd, J 15.8, 8.2
Hz), 2.95 (1H, dd, J 5.8, 6.1 Hz), 1.21 (3H, t, J 7.1 Hz),; m/z
(ES.sup.+ 70V) 521 (MH.sup.+).
EXAMPLE 102
[0513] Ethyl
(R)-3-[(2-Isopropoxy-3,4-dioxo-1-cyclobutenyl)amino-3-[4-(2,6-
-naphthyridin-1-ylamino)phenylpropanoate
[0514] Intermediate 23 (178 mg, 0.53 mmol) was dissolved in MeOH (5
ml) and DIPEA (0.2 ml), treated with
3,4-diisopropoxy-3-cyclobuten-1,2-dione (126 mg) and stirred at RT
for 16 h. The solution was concentrated, dissolved in DCM (20 ml),
washed with water, dried (Na.sub.2SO.sub.4), filtered and
concentrated. The crude product was purified by column
chromatography (S)O.sub.2, CH.sub.2Cl.sub.2/MeOH 50:1) to give the
title compound (150 mg, 60%) as an oil. (H (DMSO, 370K) 9.21 (1H,
s), 9.09 (1H, br s), 8.70 (1H, br m), 8.65 (1H, d, J 5.9), 8.33
(1H, d, J 5.9 Hz), 8.16 (1H, d, J 5.7 Hz), 7.87 (2H, d, J 8.5 Hz),
7.35 (2H, d, J 8.5 Hz), 7.28 (1H, d, J 5.7 Hz), 5.37 (1H, m), 5.27
(1H, septet, J 6.2 Hz), 4.10 (2H, qd, J 7.1, 0.4 Hz), 3.05 (1H, dd,
J 15.8, 8.9Ht), 2.93 (1H, dd, J 15.8, 5.9), 1.43 (3H, d, J 6.2 Hz),
1.39 (3H, d, J 6.2H)), 1.18 (3H, t, 17.1 Hz); m/z (ES.sup.+, 70V)
475 (MH.sup.+).
EXAMPLE 103
[0515] Methyl
(3R)-3-[(2-N,N-Diethylamino-3,4-dioxo-1-cyclobutenyl)amino-3-
-[4-(2,6-naphthyridin-1-ylamino)phenyl]propanoate
[0516] The compound of Example 102 (145 mg, 0.3 mmol) in MeOH (2
ml) was treated with diethylamine (0.07 ml) and stirred at RT for
16 h. The solvent was removed and the residue was purified by
column chromatography (S)O.sub.2, CH.sub.2Cl.sub.2/MeOH 100:1) to
give the title compound (140 mg, 98%) as a yellow oil. .delta.H
(DMSO, 370K) 9.21 (1H, s), 9.08 (1H, br s), 8.65 (1H, d, J 5.9 Hz),
8.33 (1H, d, 15.9 Hz). 8 16 (1H, d, J 5.7 Hz), 7.86 (2H, d, J 8.5
Hz), 7.40 (2H, d, J 8.5 Hz), 7.27 (1H, d, J 5.7 Hz), 5.87 (1H, m),
3.63 (3H, s), 3.59 (2H, q, J 7.1 Hz), 3.57 (2H, q, J 7.1 Hz), 3.12
(1H, dd, J 15.6, 8.8 Hz), 2.99 (1H, dd, J 15.6, 6.0 Hz), 1.21 (3H,
t, J 7.1 Hz), 1.18 (3H, t, J 7.1 Hz), m/z (ES.sup.+, 70V) 474
(MH.sup.+).
EXAMPLE 104
[0517]
(3R)-3-[(2-N,N-Diethylamino-3,4-dioxo--cyclobutenyl)amino-3-[4-(2,6-
-naphthyridin-1-ylamino)phenylpropanoic acid
[0518] The compound of Example 103 (140 mg, 0.29 mmol) was
dissolved in THF (1 ml) and water (1 ml) and treated with lithium
hydroxide (18 mg). The solution was stirred at RT for 90 mins and
concentrated in vacuo. The residue was dissolved in water and
slowly acidified to pH 4.5 with dilute HCl acid to give a yellow
precipitate which was filtered and dried to give the title compound
(60 mg). .delta.H (DMSO, 350K) 9.22 (1H, d, J 0.8 Hz), 8.66 (1H, d,
J 5.8 Hz), 8.36 (11H, dd, J 5.9, 0.8 Hz), 8.15 (1H, d, J 5.8 Hz),
7.84 (2H, d, J 8.5 Hz), 7.40 (2H, d, J 8.5 Hz), 7.29 (1H, d, J 5.8
Hz), 5.83 (1H, m), 3.59 (2H, q, J 7.1 Hz), 3.57 (2H, q, J 7.1 Hz),
3.02 (1H, dd, J 15.7, 8.8 Hz, 2.90 (1H, dd, J 15.7, 5.9 Hz), 1.18
(6H, t, J 7.1 Hz), m/z (ES.sup.+, 70V) 460 (MH.sup.+).
[0519] The following derivatised resins were prepared to enable the
preparation of compounds of the invention by solid phase
synthesis:
[0520] Resin bound
(S)-3-(4-Aminophenyl)-2-(9-fluorenylmethoxy-carbonylami-
no)propanoic acid (1)
[0521] Paramax Wang resin (Advanced Chemtech, 10 g, 1.0 mmol/g, 10
mmol equivalent) in DMF (150 ml) was treated with
N-.alpha.-FMOC4-nitro-L-phen- ylalanine (22 g, 50 mmol),
2,6-dichlorobenzoyl chloride (7.0 ml, 50 mmol) and pyridine (4.0
ml, 50 mmol) and the mixture agitated under nitrogen at RT for 24
h. The resin was filtered and washed with DMF and DCM then
unreacted resin sites were capped with 20% acetic anhydride in DMF
for 30 mins at RT. The resin was filtered and washed as before then
treated with a 1 M solution of stannous chloride dihydrate in DMF
(100 ml) at RT for 12 h and washed with DMF and DCM to give the
derivatised resin (1).
[0522] Resin bound
(S)-3-[4-(3,5-dichloro4-pyridylcarboxamido)phenyl]-2-am-
inopropanoic acid (2)
[0523] Derivatised resin (1) from the above procedure was swollen
in DCM (50 ml) then treated with DIPEA (5.1 ml, 29 mmol) and
3,5-dichloropyridine-4-carbonylchloride (6.2 ml, 29 mmol) and
agitated under nitrogen at RT for 12 h. The resin was washed as
before then treated with a 20% solution of piperidine in DMF (100
ml) for 30 mins at RT followed by thorough washing with DMC and DCM
to give the derivatised resin (2).
[0524] Resin bound
(S)-3-[4-(3,5-dichloro-4-pyridylcarboxamido)phenyl]-2-(-
2-methoxy-3,4-dioxocyclobut-1-enylamino)propanoic acid (3)
[0525] Derivatised resin (2) from the above procedure in DMF (100
ml) was treated with 3,4-dimethoxy-3-cyclobutene-1,2-dione (4.1 g,
29 mmol) for 12 h at 70.degree. then filtered and washed with DMF
and DCM to give the derivatised resin (3).
[0526] Resin bound
(RS)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-3--
(2-methoxy-3,4-dioxocyclobut-1-enylamino)propanoic acid (4)
[0527] Derivatised resin (4) was prepared in a similar manner to
derivatised resin (3) from
(RS)-3-(9-fluorenylmethoxycarbonylamino)-3-(4-- nitrophenyl)
propanoic acid. The latter was prepared as follows: A cold (O)
solution of (RS)-3-Amino-3-(4-nitrophenyl)propanoic acid [D. M.
Kalvin and R. W. Woodward; J. Org. Chem. (1985) 50, 2259] (3.2 g,
15 mmol) in 10% aqueous sodium carbonate (60 ml) and 1,4-dioxane
(30 ml) was treated portion-wise with
9-fluorenylmethoxycarbonyl-N-hydroxysuccinimide (5.6 g, 17 mmol) in
1,4-dioxane (15 ml) and the mixture stirred at RT for 12 h. The
mixture was poured into water (300 ml) and the aqueous phase washed
3 times with Et.sub.2O. The aqueous layer was then acidified with
solid citric acid and extracted into Et.sub.2O. The combined
organic layers were dried (MgSO.sub.4) and evaporated to a yellow
oil. then triturated from hexane and EtOAc to afford
(RS)-3-(9-fluorenylmethoxy-car-
bonylamino)-3-(4-nitrophenyl)propanoic acid as a yellow solid (1.8
g); m/z (ES.sup.+, 70V) 432.
[0528] Resin bound
(S)-3d4-Aminophenyl)-2-(2-propylamino-3,4-dioxocyclobut-
-1-enylamino) propanoic acid (5)
[0529] Paramax Wang resin (Advanced Chemtech, 10 g, 1.0 mmol/g, 10
mmol equivalent) in DMF(150 ml) was treated with
N-.alpha.-FMOC4-nitro-L-pheny- lalanine (22 g, 50 mmol),
2,6-dichlorobenzoyl chloride (7.0 ml, 50 mmol) and pyridine (4.0
ml, 50 mmol) and the mixture agitated under nitrogen at RT for 24
h. The resin was filtered and washed with DMF and DCM then
unreacted resin sites were capped with 20% acetic anhydride in DMF
for 30 mins at RT. The resin was filtered and washed as before. A
portion (4 g) was treated with a 20% solution of piperidine in DMF
(100m) for 30 mins at RT then filtered and washed with DMF and DCM.
The resin was treated with 3,4-dimethoxy-3-cyclobutene-1,2-dione
(1.9 g, 13.4 mmol) in DMF (50 ml) for 12 h at 70.degree. C. then
filtered and washed with DMF and DCM. The resin was swollen in DCM
(10 ml) and EtOH (40 ml) and treated with propylamine (1.6 ml, 19.2
mmol). The solution was agitated for 12 h at RT then filtered and
washed thoroughly with DCM. The resin was treated with a 1 M
solution of stannous chloride dihydrate in DMF (50 ml) at RT for 8
h then washed with DMF and DCM to give derivatised resin (5).
[0530] Resin bound diethylphosphono-.alpha.-diazoacetate (6)
[0531] Wang resin (Advanced Chem tech, 1.0 g, 0.7 mmol/g, 0.7 mmol
equivalent) was treated with diethyl-phosphonoacetate (0.68 g, 3.5
mmol), N,N'-diisopropylcarbodiimide 0.55 ml, 3.5 mmol) and
4-N,N-dimethylamino-pyridine (0.09 g, 0.7 mmol), in DCM (5.0m). The
mixture was agitated at ambient temperature for 16 h. The resin was
filtered and washed with DMF, MeOH and DCM. The resulting resin
(1.0 g) was treated with 4-acet-amidobenzenesulfonyl azide (0.43 g,
1.86 mmol) and diazabicyclo-undec-7-ene (0.09 g, 0.62 mmol) in
acetonitrile at ambient temperature for 16 h. The resin was washed
with DMF, MeOH and DCM to give derivatised resin (6) [FTIR (ATR)
.nu..sub.max 2132 cm.sup.-1].
[0532] Resin bound
(S)-3-[4-(1-isoquinolylamino)phenyl]-2-(9-fluorenylmeth-
oxycarbonylamino)propanoic acid (7)
[0533] Wang resin (Advanced Chemtech, 3.0 g, 0.7 mmol/g, 2.1 mmol
equivalent) in DMF (50 ml) was treated with
($)-3-[4-(1-isoquinolylamino)-
phenyl]-2-(9-fluorenylmethoxycarbonylamino)propanoic acid (3.3 g,
6.3 mmol), 2,6-dichlorobenzoyl chloride (1.5 ml, 10.5 mmol) and
pyridine (0.8 ml, 10.5 mmol) and the mixture agitated under
nitrogen at RT for 24 h. The resin was filtered and washed with DMF
and DCM then unreacted resin sites were capped with 20% acetic
anhydride in DMF for 30 mins at RT. The resin was filtered and
washed as before to give derivatised resin (7).
[0534] Resin bound (S)-3-[4-(1
isoquinolylamino)phenyl]-2-(2-methoxy-3,4-d-
ioxocyclobut-1-enylaminopropanoic acid (8)
[0535] Derivatised resin (7) from the above procedure was treated
with a 20% solution of piperidine in DMF (100 ml) for 30 mins at RT
followed by thorough washing with DMF and DCM. The resin was
treated with 3,4-dimethoxy-3-cyclobutene-1,2-dione (4.7 g, 33 mmol)
for 12 h at 70.degree. in DMF (50 ml) then filtered and washed as
before to give derivatised resin (8).
[0536] Resin bound
(S)-3-(4-benzoylphenyl)-2-(2-methoxy-3,4-dioxocyclobut--
1-enyl)aminopropanoic acid (9b
[0537] N-.alpha.-FMOC-L-benzoylphenylalanine Wang resin (Advanced
Chemtech, 400 mg, 0.5 mmol/g, 0.2 mmol equivalent) was treated with
a 20% solution of piperidine in DMF (5 ml) for 30 mins at RT then
filtered and washed thoroughly with DMF and DCM. The resin was
treated with 3,4-dimethoxy-3-cyclobutene-1,2-dione (200 mg, 1.4
mmol) for 12 h at 700 in DMF (5 ml) then filtered and washed as
before to give derivatised resin (9).
[0538] HPLC-MS
[0539] HPLC-M& was performed on a Hewlett Packard 1100/MSD ES
Single Quadropole system with diode array detector using
either:
[0540] Conditions A: A Luna C18(2) 50.times.4.6 mm (3am particle
size) column, running a gradient of 95% [20 mM ammonium formate, pH
3.5], 5% [0.1% formic acid in acetonitrile] to 10% [20 mM ammonium
formate, pH 3.5], 90% (0.1% formic acid in acetonitrile] over 3
min, then maintaining the mobile phase at that ratio for a further
2 min. Flow rate 0.8 ml/min.; or
[0541] Conditions B: A Luna C18(2) 50.times.2.0 mm (3 gm) column,
running a gradient of 95% [0.1% aqueous formic acid], 5% [0.1%
formic acid in acetonitrile] to 10% [0.1% aqueous formic acid], 90%
[0.1% formic acid in acetonitrile] over 2 min, then maintaining the
mobile phase at that ratio for a further 1 min. Flow rate 0.8
ml/min. MS was acquired by API electrospray in positive ion mode,
at 70V, scanning from 150 to 750 amu.
EXAMPLE 105
[0542]
(S)-3-4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl1-212-cyclohexylam-
ino-3,4-dioxocyclobut-1-enylamino)ppropanoic acid
[0543] To the derivatised resin (3), (120 mg) was added DCM (0.2
ml), EtOH (0.8 ml) and a 1M solution of cyclohexylamine in DCM (0.5
ml). The solution was agitated for 12 h at RT followed by
filtration and multiple washes with DCM. The resin was treated with
60% trifluoroacetic acid in DCM (1.5 ml) for 3 h with agitation and
then filtered. The filtrate was evaporated in vacuo to give the
crude product which was purified by preparative HPLC to afford the
title compound (5 mg).
[0544] HPLC-MS (Conditions A) Retention time 3.5 min MH.sup.+
531.
[0545] The following compounds of Examples 106 to 179 and 183 to
195 were prepared in a similar manner to the compound of Example
105, each using the starting material shown. For examples where the
amine was added as a salt, 1 mol equivalent of DIPEA was also
added.
EXAMPLE 106
[0546]
(S)-3-[4-(3,5-Dichloro4-pyridylcarboxamido)phenyl]-2-[2-(1-adamanty-
lamino)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[0547] 1-Adamantylamine gave the title compound (4 mg)
[0548] HPLC-MS (Conditions A) Retention time 3.9 min MH.sup.+
583
EXAMPLE 107
[0549]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-[2-(2-methoxy-
ethylamino)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[0550] 2-Methoxyethylamine gave the title compound (10 mg)
[0551] HPLC-MS (Conditions A) Retention time 3.1 min MH.sup.+
507
EXAMPLE 108
[0552]
(S)-3-[4-(3.-Dichloro-4-pyridylcarboxamido)phenyl]-2-[2-(3-methoxyp-
ropylamino)-3,4-dioxocyclobut-1-enylamino]propanoic acid
3-Methoxypropylamine gave the title compound (9 mg)
[0553] HPLC-MS (Conditions A) Retention time 3.2 min MH.sup.+
521
EXAMPLE 109
[0554]
(S)-3-[4-(3,5-Dichloro-4-1pyridylcarboxamido)phenyl]-2-[2-[2-thieny-
lmethylamino)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[0555] 2-(Aminomethyl)thiophene gave the title compound (4 mg)
[0556] HPLC-MS (Conditions A) Retention time 3.4 min MH.sup.+
545
EXAMPLE 110
[0557]
(S)-3-[4-(3,5-Dichloro4-pyridylcarboxamido)phenyl]-2-[2-(4-morpholi-
noethylamino)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[0558] N-(2-Aminoethyl)morpholine gave the title compound (8
mg)
[0559] HPLC-MS (Conditions A) Retention time 2.9 min MH.sup.+
562
EXAMPLE 111
[0560]
(S)-3-[4-(3,5-Dichloro-4-2pyridylcarboxamido)phenyl]-2-[2-(3,4,5-tr-
imethoxybenzylamino)-3,4-dioxocyclobut-1-enylamino]propanoic
acid
[0561] 3,4,5-Trimethoxybenzylamine gave the title compound (3
mg)
[0562] HPLC-MS (Conditions A) Retention time 3.4 min MH.sup.+
629
EXAMPLE 112
[0563]
(S)-3-[4-(3,5-Dichloro4-pyridylcarboxamido)phenyl]-2-[2-(1-piperidi-
noethylamino)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[0564] 1-(2-Aminoethyl)piperidine gave the title compound (11
mg)
[0565] HPLC-MS (Conditions A) Retention time 2.9 min MH.sup.+
560
EXAMPLE 113
[0566]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-[2-[3-(2-oxop-
yrrolidin-1-yl)propylamino)-3,4-dioxocyclobut-1-enylamino propanoic
acid
[0567] 1-(3-Aminopropyl)-2-pyrrolidinone gave the title compound
(12 mg)
[0568] HPLC-MS (Conditions A) Retention time 3.1 min MH.sup.+
574
EXAMPLE 114
[0569]
(S)-3-4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-[2-(3phenylpro-
pylamino)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[0570] 3-Phenylpropylamine gave the title compound (8 mg)
[0571] HPLC-MS (Conditions A) Retention time 3.7 min MH.sup.+
567
EXAMPLE 115
[0572]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-[2-(3-(1-imid-
azolyl)propylamino)-3,4-dioxocyclobut-1-enylamino]propanoic
[0573] N-(3-Aminopropyl)imidazole gave the title compound (9
mg)
[0574] HPLC-MS (Conditions A) Retention time 2.8 min MH.sup.+
557
EXAMPLE 116
[0575]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-[2-piperponyl-
amino-3,4-dioxocyclobut-1-enylamino]propanoic acid
[0576] Piperonylamine gave the title compound (3 mg)
[0577] HPLC-MS (Conditions A) Retention time 3.5 min MH.sup.+
583
EXAMPLE 117
[0578]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-[2-(1-benzyl--
4-piperidinylamino)-3,4-dioxocyclobut-1-enylamino]ppropanoic
acid
[0579] 4-Amino-1-benzylpiperidine gave the title compound (12
mg)
[0580] HPLC-MS (Conditions A) Retention time 3.1 min MH.sup.+
622
EXAMPLE 118
[0581]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-[2-(2-pyridyl-
methylamino)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[0582] 2-(Aminomethyl)pyridine gave the title compound (14 mg)
[0583] HPLC-MS (Conditions A) Retention time 3.2 min MH.sup.+
540
EXAMPLE 119
[0584]
(S)-3-[4-(3,5-Dichloro-4-pyrdylcarboxamido)phenyl]-2-(2-cyclopentyl-
amino-3,4-dioxocyclobut-1-enylamino)propanoic acid
[0585] Cyclopentylamine gave the title compound (8 mg)
[0586] HPLC-MS (Conditions A) Retention time 3.4 min MH.sup.+
517
EXAMPLE 120
[0587]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-[2-(4-phenylb-
utylamino)-3,4-dioxocyclobut-1 enylamino]propanoic acid
[0588] 4-Phenylbutylamine gave the title compound (4 mg)
[0589] HPLC-MS (Conditions A) Retention time 3.8 min MH.sup.+
581
EXAMPLE 121
[0590]
(s)-3-[4-(3,5-Dichloro-4-1pyridylcarboxamido)phenyl]-2-[2-(3-pyridy-
lmethylamino)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[0591] 3-(Aminomethyl)pyridine gave the title compound (7 mg)
[0592] HPLC-MS (Conditions A) Retention time 3.0 min MH.sup.+
540
EXAMPLE 122
[0593]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-[2-(3,3-dimet-
hylbutylamino)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[0594] 3,3-Dimethylbutylamine gave the title compound (7 mg)
[0595] HPLC-MS (Conditions A) Retention time 3.6 min MH.sup.+
533
EXAMPLE 123
[0596]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-[2-(3,4-dichl-
orobenzylamino)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[0597] 3,4-Dichlorobenzylamine gave the title compound (11 mg)
[0598] HPLC-MS (Conditions A) Retention time 3.8 min MH.sup.+
607
EXAMPLE 124
[0599]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-[2-(2-(1-pipe-
razinyl)ethylamino)-3,4-dioxocyclobut-1-enylamino]propanoic
[0600] N-(2-aminoethyl)piperazine gave the title compound (5
mg)
[0601] HPLC-MS (Conditions A) Retention time 2.8 min MH.sup.+
561
EXAMPLE 125
[0602]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-[2-(2-(1-pyrr-
olidinyl)ethylamino)-3,4-dioxocyclobut-1-enylamino]propanoic
[0603] 1-(2-aminoethyl)pyrrolidine gave the title compound (9
mg)
[0604] HPLC-MS (Conditions A) Retention time 2.9 min MH.sup.+
546
EXAMPLE 126
[0605]
(S)-3-[4-(3,5-Dichloro4-pyridylcarboxamido)phenyl]-2-[2-(3-hydroxyp-
ropylamino)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[0606] 3-Hydroxypropylamine gave the title compound (4 mg)
[0607] HPLC-MS (Conditions A) Retention time 3.0 min MH.sup.+
507
EXAMPLE 127
[0608]
(S)-3-[4-(3,5-Dichloro4-pyridylcarboxamido)phenyl]-2-[244cyclohexyl-
anilino)3,4-dioxocyclobut-1-enylamino]propanoic acid
[0609] 4-Cyclohexylaniline gave the title compound (3 mg)
[0610] HPLC-MS (Conditions A) Retention time 4.3 min MH.sup.+
607
EXAMPLE 128
[0611]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-[2-(4-morphol-
inoanilino)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[0612] 4-Morpholinoaniline gave the title compound (5 mg)
[0613] HPLC-MS (Conditions A) Retention time 3.4 min MH.sup.+
610
EXAMPLE 129
[0614]
(S)-3-[4:(3,5-Dichloro4-pyridylcarboxamido)phenyl]-242-isopropylami-
no-3,4-dioxocyclobut-1-enylamino)propanoic acid
[0615] Isopropylamine gave the title compound (2 mg)
[0616] HPLC-MS (Conditions B) Retention time 2.3 min MH.sup.+
491
EXAMPLE 130
[0617]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-242-tert-butyla-
mino-3,4-dioxocyclobut-1-enylamino)propanoic acid
[0618] Tert-butylamine gave the title compound (1 mg)
[0619] HPLC-MS (Conditions B) Retention time 2.39 min MH.sup.+
505
EXAMPLE 131
[0620]
(S)-3-[4-(3,5-Dichloro-4-pyrodylcarboxamido)phenyl]-2-(2-propylamin-
o-3,4-dioxocyclobut-1-enylamino)propanoic acid
[0621] Propylamine gave the title compound (5 mg)
[0622] HPLC-MS (Conditions B) Retention time 2.3 min MH.sup.+
491
EXAMPLE 132
[0623]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-(2-benzylamin-
o-3,4-dioxocyclobut-1-enylamino)propanoic acid
[0624] Benzylamine gave the title compound (4 mg)
[0625] HPLC-MS (Conditions B) Retention time 2.43 min MH.sup.+
539
EXAMPLE 133
[0626]
(S)-3-[4-(3,5-Dichloro4-pyrodylcarboxamido)phenyl]-2-[-2-(3-(dimeth-
ylamino)propylamino)-3,4-dioxocyclobut-1-enylamino]propanoic
acid
[0627] 3-(Dimethylamino)propylamine gave the title compound (5
mg)
[0628] HPLC-MS (Conditions B) Retention time 1.92 min MH.sup.+
534
EXAMPLE 134
[0629]
(S)-3-[4-(3,5-Dichloro4-pyridylcarboxamido)phenyl]-2-[2-(3-isopropo-
xypropylamino]-3,4-dioxocyclobut-1-enylamino]propanoic
[0630] 3-Isopropoxypropylamine gave the title compound (5 mg)
[0631] HPLC-MS (Conditions B) Retention time 2.37 min MH.sup.+
549
EXAMPLE 135
[0632]
(S)-3-[4-(3,5-Dichloro4-pyridylcarboxamido)phenyl]-2-[2-(3-ethoxypr-
opylamino)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[0633] 3-Ethoxypropylamine gave the title compound (5 mg)
[0634] HPLC-MS (Conditions B) Retention time 2.3 min MH.sup.+
535
EXAMPLE 136
[0635]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-[2-(2-(3-indo-
lyl)ethylamino)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[0636] 2-(3-indolyl)ethylamine gave the title compound (1 mg)
[0637] HPLC-MS (Conditions B) Retention time 2.15 min MH.sup.+
592
EXAMPLE 137
[0638]
(S)-3-[4(3,5-Dichloro-4-pyridylcarboxamido)phenyl-2-(2-cyclobutylam-
ino-3,4-dioxocyclobut-1-enylamino]propanoic acid
[0639] Cyclobutylamine gave the title compound (4 mg)
[0640] HPLC-MS (Conditions B) Retention time 2.35 min MH.sup.+
503
EXAMPLE 138
[0641]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-(2-cyclopropy-
lamino-3,4-dioxocyclobut-1-enylamino)propanoic acid
[0642] Cyclopropylamine gave the title compound (5 mg)
[0643] HPLC-MS (Conditions B) Retention time 2.26 min MH.sup.+
489
EXAMPLE 139
[0644]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-[2-(4-(1,2,3--
thiadiazol-4-yl)benzylamino)-3,4-dioxocyclobut-1-enylamino]propanoic
acid
[0645] 4-(1,2,3-Thiadiazol4-yl)benzylamine gave the title compound
(5 mg)
[0646] HPLC-MS (Conditions B) Retention time 2.46 MH.sup.+ 623
EXAMPLE 140
[0647]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-[2(3-nitroben-
zylamino)-3,4dioxocyclobut-1-enylamino]propanoic acid
[0648] 3-Nitrobenzylamine hydrochloride gave the title compound (4
mg)
[0649] HPLC-MS (Conditions B) Retention time 2.46 min MH.sup.+
584
EXAMPLE 141
[0650]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-[2-(4-(methyl-
sulfonyl)benzylamino)-3,4-dioxocyclobut-1-enylamino]propanoic
acid
[0651] 4-(Methylsulfonyl)benzylamine hydrochloride gave the title
compound (1 mg)
[0652] HPLC-MS (Conditions B) Retention time 2.31 min MH.sup.+
617
EXAMPLE 142
[0653]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-[2-(2-(benzyl-
thio)ethylamino)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[0654] 2-(Benzylthio)ethylamine hydrochloride gave the title
compound (7 mg)
[0655] HPLC-MS (Conditions B) Retention time 2.56 min MH.sup.+
599
EXAMPLE 143
[0656]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-[2-(2-(4-nitr-
ophenyl)ethylamino)-3,4dioxocyclobut-1-enylamino]propanoic acid
[0657] 2-(4-Nitrophenyl)ethylamine hydrochloride gave the title
compound (1 mg)
[0658] HPLC-MS (Conditions B) Retention time 2.47 min MH.sup.+
598
EXAMPLE 144
[0659]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-[2-(1-piperid-
inyl)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[0660] Piperidine gave the title compound (5 mg).
[0661] HPLC-MS (Conditions B) Retention time 2.36 min MH.sup.+
517
EXAMPLE 145
[0662]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-(2-morpholino-
-3,4-dioxocyclobut-1-enylamino)propanoic acid
[0663] Morpholine gave the title compound (7 mg)
[0664] HPLC-MS (Conditions B) Retention time 2.24 min MH.sup.+
519
EXAMPLE 146
[0665]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-(2-thiomorpho-
lino-3,4-dioxocyclobut-1-enylamino)propanoic acid
[0666] Thiomorpholine gave the title compound (1 mg)
[0667] HPLC-MS (Conditions B) Retention time 2.36 min MH.sup.+
535
EXAMPLE 147
[0668]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-(2-diethylami-
no-3,4-dioxocyclobut-1-enylamino)propanoic acid
[0669] Diethylamine gave the title compound (4 mg)
[0670] HPLC-MS (Conditions B) Retention time 2.34 min MH.sup.+
505
EXAMPLE 148
[0671]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-[2-(1-pyrroli-
dinyl)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[0672] Pyrrolidine gave the title compound (2 mg)
[0673] HPLC-MS (Conditions B) Retention time 2.29 min MH.sup.+
503
EXAMPLE 149
[0674]
(S)-3-14-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-[2-(4-ethyl-1-
-piperazinyl)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[0675] 1-Ethylpiperazine gave the title compound (6 mg)
[0676] HPLC-MS (Conditions B) Retention time 1.96 min MH.sup.+
546
EXAMPLE 150
[0677]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-[2-(4-(hydrox-
ypropyl)-1-piperazinyl)-3,4-dioxocyclobut-1-enylamino]propanoic
acid
[0678] 1-Piperazinepropanol gave the title compound (6 mg)
[0679] HPLC-MS (Conditions B) Retention time 1.94 min MH.sup.+
576
EXAMPLE 151
[0680]
(S)-3-[4(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-[2-((S)-3-dime-
thylamino-1-pyrrolidinyl)-3,4-dioxocyclobut-1-enylamino]propanoic
acid
[0681] (S)-3-(Dimethylamino)pyrrolidine gave the title compound (8
mg)
[0682] HPLC-MS (Conditions B) Retention time 1.94 min MH.sup.+
546
EXAMPLE 152
[0683]
(S)-3-[4-(3,5-Dichloro4-pyridylcarboxamido)phenyl]-2-[24(S)-2-(meth-
oxymethyl)-1-pyrrolidinyl)-3,4-dioxocyclobut-1-enylamino]propanoic
acid
[0684] (S)-2-(Methoxymethyl)pyrrolidine gave the title compound (2
mg)
[0685] HPLC-MS (Conditions B) Retention time 2.37 min MH.sup.+
547
EXAMPLE 153
[0686]
(S)-3-[4-(3,5-Dichloro-4-2pyridylcarboxamido)1phenyl-2-2-(1-piperaz-
inyl)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[0687] Piperazine gave the title compound (1 mg)
[0688] HPLC-MS (Conditions B) Retention time 1.93 min MH.sup.+
518
EXAMPLE 154
[0689]
(S)-3-[4-(3,5-Dichloro4-pyridylcarboxamido)phenyl]-2-[2d(RS)-3-diet-
hylamino-1-pyrrolidinyl)-3,4-dioxocyclobut-1-enylamino]propanoic
acid
[0690] 3-(Diethylamino)pyrrolidine gave the title compound (6
mg)
[0691] HPLC-MS (Conditions B) Retention time 1.98 min MH.sup.+
574
EXAMPLE 155
[0692]
(S)-3-[4-(3,5-Dichloro4-pyridylcarboxamido)phenyl]-2-[2-(4-(4-nitro-
phenyl)-1-piperazinyl)-3,4-dioxocyclobut-1-enylamino]propanoic
[0693] 1-(4-Nitrophenyl)piperazine gave the title compound (2
mg)
[0694] HPLC-MS (Conditions B) Retention time 2.54 min MH.sup.+
639
EXAMPLE 156
[0695]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-(2-butylamino-
-3,4-dioxocyclobut-1-enylamino)propanoic acid
[0696] Butylamine gave the title compound (3 mg)
[0697] HPLC-MS (Conditions B) Retention time 2.37 min MH.sup.+
505
EXAMPLE 157
[0698]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-(2-pentylamin-
o-3,4-dioxocyclobut-1-enylamino)propanoic acid
[0699] Pentylamine gave the title compound (2 mg)
[0700] HPLC-MS (Conditions B) Retention time 2.44 min MH.sup.+
519
EXAMPLE 5
[0701]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-[2-((RS)-1-me-
thylpropylamino)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[0702] 1-Methylpropylamine gave the title compound (9 mg)
[0703] HPLC-MS (Conditions B) Retention time 2.34 min MH.sup.+
505
EXAMPLE 159
[0704]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2(2-isobutylami-
no)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[0705] Isobutylamine gave the title compound (3 mg)
[0706] HPLC-MS (Conditions B) Retention time 2 35 min MH.sup.+
505
EXAMPLE 160
[0707] (S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-[2
N-methyl-N-isopropylamino)-3,4-dioxocyclobut-1-enylamino]propanoic
acid
[0708] Methylisopropylamine gave the title compound (4 mg)
[0709] HPLC-MS (Conditions B) Retention time 2.31 min MH.sup.+
505
EXAMPLE 161
[0710]
(S)-3-4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-[2-(N-ethyl-N--
methylamino)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[0711] N-Ethylmethylamine gave the title compound (6 mg)
[0712] HPLC-MS (Conditions B) Retention time 2.26 min MH.sup.+
491
EXAMPLE 162
[0713] (S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-[24
N-methyl-N-propylamino)-3,4-dioxocyclobut-1-enylamino]propanoic
acid
[0714] N-Methylpropylamine gave the title compound (3 mg)
[0715] HPLC-MS (Conditions B) Retention time 2.32 min MH.sup.+
505
EXAMPLE 163
[0716]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-(2-cyclopropa-
nemethylamino-3,4-dioxocyclobut-1-enylamino)propanoic
[0717] Cyclopropanemethylamine gave the title compound (4 mg)
[0718] HPLC-MS (Conditions B) Retention time 2.32 min MH.sup.+
503
EXAMPLE 164
[0719]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-[2-(propynyla-
mino)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[0720] 2-Propynylamine gave the title compound (5 mg)
[0721] HPLC-MS (Conditions B) Retention time 2.26 min MH.sup.+
487
EXAMPLE 165
[0722]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-(2-isopentyla-
mino-3,4-dioxocyclobut-1-enylamino)propanoic acid
[0723] Isopentylamine gave the title compound (1 mg)
[0724] HPLC-MS (Conditions B) Retention time 2.44 min MH.sup.+
519
EXAMPLE 166
[0725]
(s)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-[2((RS)-2-met-
hylbutylamino)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[0726] 2-Methylbutylamine gave the title compound (2 mg)
[0727] HPLC-MS (Conditions B) Retention time 2.42 min MH.sup.+
519
EXAMPLE 167
[0728]
(S)-3-[4-(3,5-Dichloro4-pyridylcarboxamido)phenyl]-2-[2((RS)-1,3-di-
methylbutylamino)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[0729] 1,3-Dimethylbutylamine gave the title compound (3 mg)
[0730] HPLC-MS (Conditions B) Retention time 2.49 min MH.sup.+
533
EXAMPLE 168
[0731]
(S)-3-[4-(3,5-Dichloro4-pyridylcarboxamido)phenyl]-2-[2-(N-methyl-N-
-butylamino)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[0732] N-Methylbutylamine gave the title compound (3 mg)
[0733] HPLC-MS (Conditions B) Retention time 2.39 min MH.sup.+
519
EXAMPLE 169
[0734]
(S)-3-[4-(3,5-Dichloro4-pyridylcarboxamido)phenyl]-2-[2((RS)-1-meth-
ylbutylamino)-3,4-dioxocyclobut-1-enylamino]propanoic acid
1-Methylbutylamine gave the title compound (3 mg)
[0735] HPLC-MS (Conditions B) Retention time 2.41 min MH.sup.+
519
EXAMPLE 170
[0736]
(S)-3-[4-(3,5-Dichloro4-pyridylcarboxamido)phenyl]-2-(2-allylamino--
3,4-dioxocyclobut-1-enylamino)propanoic acid
[0737] Allylamine gave the title compound (3 mg)
[0738] HPLC-MS (Conditions B) Retention time 2.27 min MH.sup.+
489
EXAMPLE 171
[0739]
(S)-3-[4-(3,5-Dichloro-4-1pyridylcarboxamido)phenyl]-2-[2-(2-(methy-
lthio)ethylamino)-3,4-dioxocyclobut-1-enylamino]propanoic
[0740] 2-(Methylthio)ethylamine gave the title compound (3 mg)
[0741] HPLC-MS (Conditions B) Retention time 2.30 min MH.sup.+
523
EXAMPLE 172
[0742]
(S)-3-[4-(3,5-Dichloro-4-1pyridylcarboxamido)phenyl]-2-(2-carboxyet-
hylamino-3,4-dioxocyclobut-1-enylamino)propanoic acid
[0743] .beta.-Alanine hydrochloride gave the title compound (4
mg)
[0744] HPLC-MS (Conditions B) Retention time 2.19 min MH.sup.+
521
EXAMPLE 173
[0745]
(S)-3-[4-(3,5-Dichloro-4-1pyridylcarboxamido)phenyl]-2-[2((S)-1-car-
boxy-3-methylbutylamino)-3,4-dioxocyclobut-1-enylamino]propanoic
acid
[0746] L-Leucine hydrochloride gave the title compound 0.5 mg
[0747] HPLC-MS (Conditions B) Retention time 2.35 min MH.sup.+
563
EXAMPLE 174
[0748]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl-2-[2-(carboxymet-
hylamino)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[0749] Glycine hydrochloride gave the title compound (2 mg)
[0750] HPLC-MS (Conditions B) Retention time 2.19 min MH.sup.+
507
EXAMPLE 175
[0751]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl-2-[2((S)-1-carbo-
xy-2-methylpropylamino)-3,4-dioxocyclobut-1-enylamino)propanoic
acid
[0752] L-Valine hydrochloride gave the title compound (3 mg)
[0753] HPLC-MS (Conditions B) Retention time 2.28 min MH.sup.+
549
EXAMPLE 176
[0754]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-[2((S)-1-carb-
oxy-2-phenylethylamino)-3,4-dioxocyclobut-1-enylamino]propanoic
acid
[0755] L-Phenylalanine gave the title compound (0.5 mg)
[0756] HPLC-MS (Conditions B) Retention time 2.38 min MH.sup.+
597
EXAMPLE 177
[0757]
(S)-3-[4-3,5-Dichloro4-pyridylcarboxamido)phenyl]-2-(2ethylamino-3,-
4-dioxocyclobut-1-enylamino)propanoic acid
[0758] Ethylamine hydrochloride gave the title compound (3 mg)
[0759] HPLC-MS (Conditions B) Retention time 2.22 min MH.sup.+
477
EXAMPLE 178
[0760]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-[2-methylamin-
o-3,4-dioxocyclobut-1-enylamino]propanoic acid
[0761] Methylamine hydrochloride gave the title compound (2 mg)
[0762] HPLC-MS (Conditions B) Retention time 2.17 MH.sup.+ 463
EXAMPLE 179
[0763]
(S)-3-[4-(3,5-Dichloro4-pyridylcarboxamido)phenyl]-2-(2-dimethylami-
no-3,4-dioxocyclobut-1-enylamino)propanoic acid
[0764] Dimethylamine hydrochloride gave the title compound (6
mg)
[0765] HPLC-MS (Conditions B) Retention time 2.20 min MH.sup.+
477
EXAMPLE 180
[0766]
(S)-3-[4(3,5-Dichloro4-12pyridylcarboxamido)phenyl]-2-(2-anilino-3,-
4-dioxocyclobut-1-enylamino]propanoic acid
[0767] Derivatised resin (2), (320 mg) in DMF (10 ml), was treated
with 4-anilino-3-ethoxy-3-cyclobutene-1,2-dione (400 mg, 1.86 mmol)
for 12 h at 70.degree. then filtered and washed with DMF and DCM.
The resin was treated with 60% trifluoroacetic acid in DCM (1.5 ml)
for 3 h with agitation then filtered. The filtrate was evaporated
in vacuo to give the crude product which was purified by
preparative HPLC to afford the title compound (2 mg)
[0768] HPLC-MS (Conditions B) Retention time 2.46 min MH.sup.+
525
EXAMPLE 181
[0769]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl-2-(2-phenyl-3,4--
dioxocyclobut-1-enylamino)propanoic acid
[0770] By the same method as the compound of Example 180,
3-methoxy4-phenyl-3-cyclobutene-1,2-dione was used to give the
title compound (13 mg).
[0771] HPLC-MS (Conditions B) Retention time 2.53 min MH.sup.+
510
EXAMPLE 182
[0772]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-(2-methoxy-3,-
4-dioxocyclobut-1-enylamino)propanoic acid
[0773] Derivatised resin (3), (120 mg) was treated with 60%
trifluoroacetic acid in DCM (1.5 ml) for 3 h with agitation then
filtered. The filtrate was evaporated in vacuo to give the crude
product which was purified by preparative HPLC to afford the title
compound (2 mg)
[0774] HPLC-MS (Conditions B) Retention time 2.26 min MH.sup.+
465
EXAMPLE 183
[0775]
(S)-3-[4-(3,5-Dichloro-4-1pyridylcarboxamido)phenyl]-2-(2-(1-decahy-
droquinolyl)-3,4-dioxocyclobut-1-enylamino)propanoic acid
[0776] Decahydroquinoline gave the title compound (1 mg).
[0777] HPLC-MS (Conditions B) Retention time 2.53 min MH.sup.+
571
EXAMPLE 184
[0778] (S)-3-[4-3,5-Dichloro4-pyridylcarboxamido)1phenyl-2-[24
N-benzyl-N-butylamino]-3,4-dioxocyclobut-1 enylamino]propanoic
acid
[0779] N-Benzylbutylamine gave the title compound (5 mg)
[0780] HPLC-MS (Conditions B) Retention time 2.60 min MH.sup.+
595
EXAMPLE 185
[0781]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-[2-(N-(2-cyan-
oethyl)-N-methylamino)-3,4-dioxocyclobut-1-enylamino]propanoic
acid
[0782] N-Methyl-beta-alanine nitrile gave the title compound (3
mg)
[0783] HPLC-MS (Conditions B) Retention time 2.22 min MH.sup.+
516
EXAMPLE 186
[0784]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-[2-(N-(2-(2-p-
yridyl)ethyl)-N-methylamino)-3,4-dioxocyclobut-1-enylamino]propanoic
acid
[0785] 2-(2-Methylaminoethyl)pyridine gave the title compound (6
mg)
[0786] HPLC-MS (Conditions B) Retention time 2.03 min MH.sup.+
568
EXAMPLE 187
[0787]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-[2-(1,2,3,6-t-
etrahydro-1-pyridyl)-3,4-dioxocyclobut-1-enylamino]propanoic
acid
[0788] 1,2,3,6-Tetrahydropyridine gave the title compound (3
mg)
[0789] HPLC-MS (Conditions B) Retention time 2.32 min MH.sup.+
515
EXAMPLE 188
[0790]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-[2-(N-methyl--
N-(phenylethyl)amino)-3,4-dioxocyclobut-1-enylamino]propanoic
acid
[0791] N-Methylphenylethylamine gave the title compound (6 mg)
[0792] HPLC-MS (Conditions B) Retention time 2.45 min MH.sup.+
567
EXAMPLE 189
[0793]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-(2-N,N-dibuty-
lamino-3,4-dioxocyclobut-1-enylamino)propanoic acid
[0794] Dibutylamine gave the title compound (5 mg)
[0795] HPLC-MS (Conditions B) Retention time 2.58 min MH.sup.+
561
EXAMPLE 190
[0796]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-[2-(3.3.3-tri-
fluoropropylamino)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[0797] 3,3,3-Trifluoropropylamine gave the title compound (7
mg)
[0798] HPLC-MS (Conditions B) Retention time 2.35 min MH.sup.+
545
EXAMPLE 191
[0799]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-[2-(N-ethyl-N-
-(4pyridylmethyl)amino)-3,4-dioxocyclobut-1-enylamino]propanoic
[0800] 4-(Ethylaminomethyl)pyridine gave the title compound (4
mg)
[0801] HPLC-MS (Conditions B) Retention time 2.01 min MH.sup.+
568
EXAMPLE 192
[0802]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-[2-(3-thiazol-
idinyl)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[0803] Thiazolidine gave the title compound (2 mg)
[0804] HPLC-MS (Conditions B) Retention time 2.29 min MH.sup.+
521
EXAMPLE 193
[0805]
(S)-3-[4-(3,5-Dichloro4-pyridylcarboxamido)phenyl-2-[2-(N-allyl-N-m-
ethylamino)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[0806] N-Methylallylamine gave the title compound (4 mg)
[0807] HPLC-MS (Conditions B) Retention time 2.29 min MH.sup.+
503
EXAMPLE 194
[0808]
(S)-3-[4-(3,5-Dichloro4-pyridylcarboxamido)phenyl]-2-[2(N-benzyl-N--
methylamino)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[0809] N-Benzylmethylamine gave the title compound (2 mg)
[0810] HPLC-MS (Conditions B) Retention time 2.42 min MH.sup.+
553
EXAMPLE 195
[0811]
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-(2-N,N-iallyl-
amino-3,4-dioxocyclobut-1-enylamino)propanoic acid
[0812] Diallylamine gave the title compound (5 mg)
[0813] HPLC-MS (Conditions B) Retention time 2.39 min MH.sup.+
529.
EXAMPLE 196
[0814]
(S)-3-[4(1-Isoquinolylamino)phenyl]-2-(2-N,N-diethylamino-3,4-dioxo-
cyclobut-1-enylamino)propanoic acid
[0815] To the derivatised resin (8), (100 mg) was added ethanol
(1.0 ml) and a 1M solution of diethylamine in DCM (0.7 ml). The
solution was agitated for 18 h at RT then filtered and washed
thoroughly with DCM. The resin was treated with 95% trifluoroacetic
acid in DCM (2.0 ml) for 3 h with agitation and then filtered: The
filtrate was evaporated in vacuo to give the crude product which
was purified by preparative HPLC to afford the title compound (2
mg).
[0816] HPLC-MS (Conditions B) Retention time 2.0 min MH.sup.+
459
[0817] The following compounds of Examples 197 to 231 were prepared
in a similar manner to the compound of Example 196, each using the
starting material shown. For examples where the amine was added as
a salt, 1 mol equivalent of DIPEA was also added.
EXAMPLE 197
[0818]
(S)-3-[4-(1-Isoquinolylamino)phenyl]-2-(2-(3-methoxypropylamino)-3,-
4-dioxocyclobut-1-enylamino)propanoic acid
[0819] 3-Methoxypropylamine gave the title compound (4 mg)
[0820] HPLC-MS (Conditions B) Retention time 2.0 min MH.sup.+
475
EXAMPLE 198
[0821]
(S)-3-[4-(1-Isoquinolylamino)phenyl]-2-[2-(1-piperidinyl)-3,4-dioxo-
cyclobut-1-enylamino]propanoic acid
[0822] Piperidine gave the title compound (2 mg)
[0823] HPLC-MS (Conditions B) Retention time 2.1 min MH.sup.+
471
EXAMPLE 199
[0824] (S)-3-[4-(1-Isoquinolylamino)phenyl]-2-[2-(1
piperazinyl)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[0825] Piperazine gave the title compound (2 mg)
[0826] HPLC-MS (Conditions B) Retention time 1.7 min MH.sup.+
472
EXAMPLE 200
[0827]
(S)-3-[4-(1-Isoquinolylamino)phenyl]-2-(2-pentylamino-3,4-dioxocycl-
obut-1-enylamino)propanoic acid Pentylamine gave the title compound
(3 mg)
[0828] HPLC-MS (Conditions B) Retention time 2.2 min MH.sup.+
473
EXAMPLE 201
[0829]
(S)-3-[4-(1-Isoquinolylamino)phenyl]-2-(2-propylamino-3,4-dioxocycl-
obut-1-enylamino)propanoic acid
[0830] Propylamine gave the title compound (1 mg)
[0831] HPLC-MS (Conditions B) Retention time 2.0 min MH.sup.+
445
EXAMPLE 202
[0832]
(S)-3-[4-(1-Isoquinolylamino)phenyl]-2-(2-(1-decahydroquinolinyl)-3-
,4-dioxocyclobut-1-enylamino)propanoic acid
[0833] Decahydroquinoline gave the title compound (5 mg)
[0834] HPLC-MS (Conditions B) Retention time 2.2 min MH.sup.+
525
EXAMPLE 203
[0835]
(S)-3-[4-(1-Isoquinolylamino)phenyl]-2-{2[-N-ethyl-N-(4-pyridylmeth-
yl)amino]-3.4dioxocyclobut-1-enylamino}propanoic acid
[0836] 4-(Ethylaminomethyl)pyridine gave the title compound (2
mg)
[0837] HPLC-MS (Conditions B) Retention time 1.8 min MH.sup.+
522
EXAMPLE 204
[0838]
(S)-3-[4(1-Isoquinolylamino)phenyl]-2-(2-tert-butylamino-3,4-dioxoc-
yclobut-1-enylamino)propanoic acid
[0839] Tert-Butylamine gave the title compound (1 mg)
[0840] HPLC-MS (Conditions B) Retention time 2.1 min MH.sup.+
459
EXAMPLE 205
[0841]
(S)-3-[4:(1-Isoquinolylamino)phenyl]-2-(2-cyclobutylamino-3,4-dioxo-
cyclobut-1-enylamino)propanoic acid
[0842] Cyclobutylamine gave the title compound (1 mg)
[0843] HPLC-MS (Conditions B) Retention time 2.1 min MH.sup.+
457
EXAMPLE 206
[0844]
(S)-3-[4(1-Isoquinolylamino)phenyl]-2-(2-thiomorpholino-3,4-dioxocy-
clobut-1-enylamino)propanoic acid
[0845] Thiomorpholine gave the title compound (2 mg)
[0846] HPLC-MS (Conditions B) Retention time 2.1 min MH.sup.+
489
EXAMPLE 207
[0847]
(S)-3-[4-(1Isoquinolylamino)phenyl]-2-(2-allylamino-3,4-dioxocyclob-
ut-1-enylamino)propanoic acid
[0848] Allylamine gave the title compound (0.3 mg)
[0849] HPLC-MS (Conditions B) Retention time 2.0 min MH.sup.+
443
EXAMPLE 208
[0850]
(S)-3-[4-(1-Isoquinolylamino)phenyl]-2-[2-(N-benzyl-N-methylamino)--
3,4-dioxocyclobut-1enylamino]propanoic acid
[0851] N-Benzylmethylamine gave the title compound (5 mg)
[0852] HPLC-MS (Conditions B) Retention time 2.2 min MH.sup.+
507
EXAMPLE 209
[0853]
(S)-3-[4-(1-Isoquinolylamino)phenyl]-2-(2-cyclohexylamino-3,4-dioxo-
cyclobut-1-enylamino)propanoic acid
[0854] Cyclohexylamine gave the title compound (3 mg)
[0855] HPLC-MS (Conditions B) Retention time 2.2 min MH.sup.+
485
EXAMPLE 210
[0856]
(S)-3-[4-(1-Isoquinolylamino)phenyl]-2-(2-benzylamino-3,4-dioxocycl-
obut-1-enylamino)propanoic acid
[0857] Benzylamine gave the title compound (2 mg)
[0858] HPLC-MS (Conditions B) Retention time 2.l min MH.sup.+
493
EXAMPLE 211
[0859]
(S)-3-[4-(1-Isoquinolylamino)phenyl]-2-{2-[3-(dimethylamino)propyl]-
amino-3,4-dioxocyclobut-1-enylamino}propanoic acid
[0860] 3-(Dimethylamino)propylamine gave the title compound (2
mg)
[0861] HPLC-MS (Conditions B) Retention time 1.7 min MH.sup.+
488
EXAMPLE 212
[0862]
(S)-3-[4(1-Isoquinolylamino)phenyl]-2-[(2-pyridylmethyl)amino-3,4-d-
ioxocyclobut-1-enylamino]propanoic acid
[0863] 2(Aminomethyl)pyridine gave the title compound (4 mg)
[0864] HPLC-MS (Conditions B) Retention time 1.9 min MH.sup.+
494
EXAMPLE 213
[0865]
(S)-3-[4-(1-Isoquinolylamino)phenyl]-2-[2(3-pyridylmethyl)amino-3,4-
-dioxocyclobut-1enylamino]propanoic acid
[0866] 3-(Aminomethyl)pyridine gave the title compound (1 mg)
[0867] HPLC-MS (Conditions B) Retention time 1.8 min MH.sup.+
494
EXAMPLE 214
[0868]
(S)-3-[4-(1-Isoquinolylamino)phenyl]-2-[2-(4-pyridylmethyl)amino-3,-
4-dioxocyclobut-1-enylamino]propanoic acid
[0869] 4-(Aminomethyl)pyridine gave the title compound (5 mg)
[0870] HPLC-MS (Conditions B) Retention time 1.8 min MH.sup.+
494
EXAMPLE 215
[0871]
(s)-3-[4-1-Isoquinolylamino)phenyl]-2-[2-(2-(benzylthio)ethylamino)-
-3,4-dioxocyclobut-1enylamino]propanoic acid
[0872] 2-(Benzylthio)ethylamine hydrochloride gave the title
compound (4 mg)
[0873] HPLC-MS (Conditions B) Retention time 2.2 min MH.sup.+
553
EXAMPLE 216
[0874]
(S)-3-[4(1-Isoquinolylamino)phenyl]-2-(2-dimethylamino-3,4-dioxocyc-
lobut-1-enylamino)propanoic acid
[0875] Dimethylamine gave the title compound (24 mg)
[0876] HPLC-MS (Conditions B) Retention time 1.9 min MH.sup.+
431
EXAMPLE 217
[0877]
(S)-3-[4-(1-Isoquinolylamino)phenyl]-2-(2-morpholino-3,4-dioxocyclo-
but-1-enylamino)propanoic acid
[0878] Morpholine gave the title compound (3 mg)
[0879] HPLC-MS (Conditions B) Retention time 2.0 min MH.sup.+
473
EXAMPLE 218
[0880]
(S)-3-[4-(1-Isoquinolylamino)phenyl]-2-[2-(N-methyl-N-butylamino)-3-
,4-dioxocyclobut-1enylamino]propanoic acid
[0881] N-Methylbutylamine gave the title compound (5 mg)
[0882] HPLC-MS (Conditions B) Retention time 2.2 min MH.sup.+
473
EXAMPLE 219
[0883]
(S)-3-[4(1-Isoquinolylamino)phenyl]-2-{2-[(RS)-2-methylbutylamino]--
3,4-dioxocyclobut-1 enylamino}propanoic acid
[0884] 2-Methylbutylamine gave the title compound (4 mg)
[0885] HPLC-MS (Conditions B) Retention time 2.2 min MH.sup.+
473
EXAMPLE 220
[0886] (S)-3-[4
(1-Isoquinolylamino)phenyl]-2-(2-butylamino-3,4-dioxocyclo-
but-1-enylamino)propanoic acid
[0887] Butylamine gave the title compound (4 mg)
[0888] HPLC-MS (Conditions B) Retention time 2.2 min MH.sup.+
459
EXAMPLE 221
[0889]
(S)-3-[4-(1-Isoquinolylamino)phenyl]-2-{2-[(RS)-1,3-dimethylbutylam-
ino]-3,4-dioxocyclobut-1-enylamino}propanoic acid
[0890] 1,3-Dimethylbutylamine gave the title compound (5 mg)
[0891] HPLC-MS (Conditions B) Retention time 2.3 min MH.sup.+
487
EXAMPLE 222
[0892]
(S)-3-[4-(1-Isoquinolylamino)phenyl]-2-[2-(N-methyl-N-isopropylamin-
o)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[0893] Methylisopropylamine gave the title compound (3 mg)
[0894] HPLC-MS (Conditions B) Retention time 2.1 min MH.sup.+
459
EXAMPLE 223
[0895]
(S)-3-[4-(1-Isoquinolylamino)phenyl]-2-{2-[(RS)-1-methylbutylamino]-
-3,4-dioxocyclobut-1-enylamino}propanoic acid
[0896] 1-Methylbutylamine gave the title compound (6 mg)
[0897] HPLC-MS (Conditions B) Retention time 2.2 min MH.sup.+
473
EXAMPLE 224
[0898]
(S)-3-[4-(1-Isoquinolylamino)phenyl]-2-(2-isobutylamino-3,4-dioxocy-
clobut-1-enylamino)propanoic acid
[0899] Isobutylamine gave the title compound (4 mg)
[0900] HPLC-MS(Conditions B) Retention time 2.1 min MH.sup.+
459
EXAMPLE 225
[0901]
(S)-3-[4(1-Isoquinolylamino)phenyl]-2-(2-dipropylamino-3,4-dioxocyc-
lobut-1-enylamino)propanoic acid
[0902] Dipropylamine gave the title compound (4 mg)
[0903] HPLC-MS (Conditions B) Retention time 2.2 min MH.sup.+
487
EXAMPLE 226
[0904]
(S)-3-[4(1-Isoquinolylamino)phenyl]-2-{2-[(RS)-2-methylpropylamino]-
-3,4-dioxocyclobut-1-enylamino}propanoic acid
[0905] 1-Methylpropylamine gave the title compound (4 mg)
[0906] HPLC-MS (Conditions B) Retention time 2.1 min MH.sup.+
459
EXAMPLE 227
[0907]
(S)-3-[4-(1-Isoquinolylamino)phenyl]-2-[2-(N-ethyl-N-methylamino)
3,4-dioxocyclobut-1-enylamino]propanoic acid
[0908] N-Ethylmethylamine gave the title compound (1 mg)
[0909] HPLC-MS (Conditions B) Retention time 2.0 min MH.sup.+
445
EXAMPLE 228
[0910]
(S)-3-[4-(2,3,4-Trimethoxybenzoylamino)phenyl]-2-(2-propylamino-3,4-
-dioxocyclobut-1-enylamino)propanoic acid
[0911] To the derivatised resin (5), (120 mg) was added DCM (5 ml),
DIPEA (0.1 ml, 0.6 mmol) and 2,3,4-trimethoxybenzoyl chloride (138
mg, 0.6 mmol). The solution was agitated for 12 h at RT then
filtered and washed thoroughly with DCM. The resin was treated with
60% trifluoroacetic acid in DCM (1.5 ml) for 3 h with agitation and
then filtered. The filtrate was evaporated in vacuo to give the
crude product which was purified by preparative HPLC to afford the
title compound (0.5 mg).
[0912] HPLC-MS (Conditions B) Retention time 2.34 min MH.sup.+
512
[0913] The following compounds of Examples 229 to 241 were prepared
in a similar manner to the compound of Example 228, each using the
starting material shown.
EXAMPLE 229
[0914]
(S)-3-[4-(2,4-Dimethoxybenzoylamino)phenyl]-2(2-propylamino-3,4-dio-
xocyclobut-1-enylamino)propanoic acid
[0915] 2,4-Dimethoxybenzoylchloride gave the title compound (2
mg)
[0916] HPLC-MS (Conditions B) Retention time 2.41 min MH.sup.+
482
EXAMPLE 230
[0917]
(S)-3-[4-(4-Bromobenzoylamino)phenyl]-2-(2-propylamino-3,4-dioxocyc-
lobut-1-enylamino)propanoic acid
[0918] 4-Bromobenzoylchloride gave the title compound (3 mg)
[0919] HPLC-MS (Conditions B) Retention time 2.49 min MH.sup.+
500
EXAMPLE 231
[0920]
(S)-3-[4-(2-Thienylcarbonylamino)phenyl]-2-(2-propylamino-3,4-dioxo-
cyclobut-1-enylamino)propanoic acid
[0921] Thiophene-2-carbonylchloride gave the title compound (0.5
mg)
[0922] HPLC-MS (Conditions B) Retention time 2.31 min MH.sup.+
428
EXAMPLE 232
[0923]
(S)-3-[4-(trans-Cinnamoylamino)phenyl]-2-(2-propylamino-3,4-dioxocy-
clobut-1-enylamino)propanoic acid
[0924] trans-Cinnamoylchloride gave the title compound (1 mg)
[0925] HPLC-MS (Conditions B) Retention time 2.44 min MH.sup.+
448
EXAMPLE 233
[0926]
(S)-3-[4-(Phenylacetylamino)phenyl]-2-(2-propylamino-3,4-dioxocyclo-
but-1-enylamino)propanoic acid
[0927] Phenacetylchloride gave the title compound (0.5 mg)
[0928] HPLC-MS (Conditions B) Retention time 2.34 min MH.sup.+
436
EXAMPLE 234
[0929]
(S)-3-[4-(2,6-Dichlorobenzoylamino)phenyl]-2-(2-propylamino-3,4-dio-
xocyclobut-1-enylamino)propanoic acid
[0930] 2,6-Dichlorobenzoylchloride gave the title compound (3
mg)
[0931] HPLC-MS (Conditions B) Retention time 2.39 min MH.sup.+
490
EXAMPLE 235
[0932]
(S)-3-[4(2,6-Dimethylbenzoylamino)phenyl]-2-(2-propylamino-3,4-diox-
ocyclobut-1-enylamino)propanoic acid
[0933] 2,6-Dimethylbenzoylchloride gave the title compound (1
mg)
[0934] HPLC-MS (Conditions B) Retention time 2.38 min MH.sup.+
450
EXAMPLE 236
[0935]
(S)-3-[4-(Benzyloxyacetylamino)phenyl]-2-(2-propylamino-3,4-dioxocy-
clobut-1-enylamino)propanoic acid
[0936] Benzyloxyacetylchloride gave the title compound (1 mg)
[0937] HPLC-MS (Conditions B) Retention time 2.41 min MH.sup.+
466
EXAMPLE 237
[0938]
(S)-3-[4-14-Cyanobenzoylamino)phenyl]-2-(2-propylamino-3,4-dioxocyc-
lobut-1-enylamino)propanoic acid
[0939] 4-Cyanobenzoylchloride gave the title compound (1 mg)
[0940] HPLC-MS (Conditions B) Retention time 2.33 min MH.sup.+
447
EXAMPLE 238
[0941]
(S)-3-[4-(6-Chloro-3-pyridylcarboxamido)phenyl]-2-(2-propylamino-3,-
4-dioxocyclobut-1-enylamino)propanoic acid
[0942] 6-Chloronicotinylchloride gave the title compound (1 mg)
[0943] HPLC-MS (Conditions B) Retention time 2.3 min MH.sup.+
457
EXAMPLE 239
[0944]
(S)-3-[4-12-Chloro-3-pyridylcarboxamido)phenyl]-2-(2-propylamino-3,-
4-dioxocyclobut-1-enylamino)propanoic acid
2-Chloronicotinylchloride gave the title compound (0.5 mg)
[0945] HPLC-MS (Conditions B) Retention time 2.18 min MH.sup.+
457
EXAMPLE 240
[0946]
(S)-3-[4-(2-Fluorobenzoylamino)phenyl]-2-(2-proplyamino-3,4-dioxocy-
clobut-1-enylamino)propanoic acid
[0947] 2-Fluorobenzoylchloride gave the title compound (1 mg)
[0948] HPLC-MS (Conditions B) Retention time 2.33 min MH.sup.+
440
EXAMPLE 241
[0949]
(S)-3-[4-(3,4-Dimethoxybenzoylamino)phenyl-2-(2-propylamino-3,4-dio-
xocyclobut-1-enylamino)propanoic acid
[0950] 3,4-Dimethoxybenzoylchloride gave the title compound (2
mg)
[0951] HPLC-MS (Conditions B) Retention time 2.28 min MH.sup.+
482
EXAMPLE 242
[0952]
(S)-3-[4-(4-Methoxyphenoxycarbonylamino)phenyl]-2-(2-propylamino-3,-
4-dioxocyclobut-1-enylamino)propanoic acid
[0953] To the derivatised resin (5), (120 mg) was added 1,4-dioxan
(4.5 ml), DIPEA (0.2 ml, 1.2 mmol), water (0.5 ml) and
4-methoxyphenylchlorofo- rmate (0.2 ml, 0.6 mmol). The solution was
agitated for 12 h at RT then filtered and washed thoroughly with
DCM. The resin was treated with 60% trifluoroacetic acid in DCM
(1.5 ml) for 3 h with agitation and then filtered. The filtrate was
evaporated in vacuo to give the crude product which was purified by
preparative HPLC to afford the title compound (2 mg).
[0954] HPLC-MS (Conditions B) Retention time 2.42 min MH.sup.+
468
[0955] The following compounds of Examples 243 to 246 were prepared
in a similar manner to the compound of Example 242, each using the
starting material shown.
EXAMPLE 243
[0956]
(S)-3-[4-(4-Methylphenoxycarbonylamino)phenyl]-2-(2-propylamino-3,4-
-dioxocyclobut-1-enylamino)propanoic acid
[0957] p-Tolylchloroformate gave the title compound (0.5 mg)
[0958] HPLC-MS (Conditions B) Retention time 2.50 min MH.sup.+
452
EXAMPLE 244
[0959]
(S)-3-[4-(4-Fluorophenoxycarbonylamino)phenyl]-2-(2-propylamino-3,4-
-dioxocyclobut-t-enylamino)propanoic acid
4-Fluorophenylchloroformate gave the title compound (2 mg)
[0960] HPLC-MS (Conditions B) Retention time 2.45 min MH.sup.+
456
EXAMPLE 245
[0961] (S)-3-[44
Phenoxycarbonylamino)phenyl]-2-(2-propylamino-3,4-dioxocy-
clobut-1-enylamino)propanoic acid
[0962] Phenylchloroformate gave the title compound (2 mg)
[0963] HPLC-MS (Conditions B) Retention time 2.42 min MH.sup.+
438
EXAMPLE 246
[0964]
(S)-3-[4-(4-Nitrobenzyloxycarbonylamino)phenyl]-2-(2-propylamino-3,-
4-dioxocyclobut-1-enylamino)propanoic acid
[0965] 4-Nitrobenzylchloroformate gave the title compound (1
mg)
[0966] HPLC-MS (Conditions B) Retention time 2.47 min MH.sup.+
497
EXAMPLE 247
[0967]
(S)-3-(4-3enzoylphenyl)-2-(2-propylamino-3.4dioxocyclobut-1-enylami-
no)propanoic acid
[0968] To the derivatised resin (9), (200 mg) was added ethanol
(1.6 ml), DCM (0.4 ml) and propylamine (0.08 ml, 1 mmol). The
solution was agitated for 12 h at RT then filtered and washed
thoroughly with DCM. The resin was treated with 95% trifluoroacetic
acid in DCM (2.0 ml) for 3 h with agitation and then filtered. The
filtrate was evaporated in vacuo to give the crude product which
was purified by preparative HPLC to afford the title compound (4
mg).
[0969] HPLC-MS (Conditions B) Retention time 2.4 min MH.sup.+
407.
[0970] The following compound of Example 248 was prepared in a
similar manner to the compound of Example 247 using the starting
material shown.
EXAMPLE 248
[0971]
(S)-3-(4-Benzoylphenyl)-2-(2-morpholino-3,4-dioxocyclobut-1-enylami-
no)propanoic acid
[0972] Morpholine gave the title compound (5 mg)
[0973] HPLC-MS (Conditions B) Retention time 2.3 min MH.sup.+
435
EXAMPLE 249
[0974]
(S)-3-[4-(1-Isoquinolylcarboxamido)phenyl]-2-(2-propylamino-3,4-dio-
xocyclobut-1-enylamino)propanoic acid
[0975] A slurry of derivatised resin (5) (prepared from Wang resin
(0.7 mmol/g), 100 mg) in DCM (5 ml) was treated with 1-isoquinoline
carboxylic acid (56 mg, 0.30 mmol), DIEA (45 .mu.l, 0.25 mmol) and
[O-(7-azabenzotriazol-1-yl)-1,1,3,3-Tetramethyluronium-hexafluorophosphat-
e] (HATU) (95 mg, 0.25 mmol). The mixture was agitated for 16 h at
RT then filtered and washed thoroughly with DCM, DMF, MeOH, DMF
then DCM. The resin was treated with 50% trifluoroacetic acid in
DCM (5 ml) for 3 h with agitation and then filtered. The resin was
washed with a further portion of DCM (5 ml). The combined filtrate
was evaporated in vacuo to give the crude product which was
purified by preparative HPLC to afford the title compound (7.3
mg).
[0976] HPLC-MS (Conditions B). Retention time 2.47 min, MH.sup.+
473 The following compounds of Examples 250 to 281 were prepared in
a similar manner to the compound of Example 249, each using the
starting material shown.
EXAMPLE 250
[0977]
(S)-3-}4-[2-Benzo(b)furanylcarboxamido]phenyl}-2-(2-propylamino-3,4-
-dioxocyclobut-1-enylamino)propanoic acid
[0978] 2-Benzo(b)furancarboxylic acid gave the title compound (1.0
mg)
[0979] HPLC-MS (Conditions B). Retention time 2.45 min, MH.sup.+
462
EXAMPLE 251
[0980]
(S)-3-[4-(4-Methoxy-2-quinolylcarboxamido)phenyl]-2-(2-propylamino--
3,4-dioxocyclobut-1-enylamino)propanoic acid
[0981] 4-Methoxy-2-quinolinecarboxylic acid gave the title compound
(5.3 mg)
[0982] HPLC-MS (Conditions B). Retention time 2.59 min, MH.sup.+
503
EXAMPLE 252
[0983]
(S)-3-{4-[4-(4-Oxo4,5,6,7,-tetrahydrobenzo(b)furan-3-ylcarboxamido]-
phenyl}-2-(2-propylamino-3,4-dioxocyclobut-1-enylamino)propanoic
acid
[0984] 4-Oxo-4,5,6,7-tetrahydrobenzo(b)furan-3-carboxylic acid gave
the title compound (8.2 mg)
[0985] HPLC-MS (Conditions B). Retention time 2.37 min, MH.sup.+
480
EXAMPLE 253
[0986]
(S)-3-[4-(2-(1-Pyrrolyl)-5-pyridylcarboxamido)phenyl]-2-(2-propylam-
ino-3,4-dioxocyclobut-1-enylamino)propanoic acid
[0987] 2-(1-Pyrrolyl)-5-pyridinecarboxylic acid gave the title
compound (1.7 mg)
[0988] HPLC-MS (Conditions B). Retention time 2.45 min, MH.sup.+
488
EXAMPLE 254
[0989]
(S)-3-[4-(3-Indazolylcarboamido)phenyl]-2-(2-propylamino-3,4-dioxoc-
yclobut-1-enylamino)propanoic acid
[0990] 3-Indazolecarboxylic acid gave the title compound (5.0
mg)
[0991] HPLC-MS (Conditions B). Retention time 2.34 min, MH.sup.+
462
EXAMPLE 255
[0992]
(S)-3-[4-(4-Fluorobenzoylamino)phenyl]-22-propylamino-3,4-dioxocycl-
obut-1-enylamino)propanoic acid
[0993] 4-Fluorobenzoic acid gave the title compound (3.7 mg)
[0994] HPLC-MS (Conditions B). Retention time 2.37 min, MH.sup.+
440
EXAMPLE 256
[0995]
(S)-3-[4-(4-Methoxybenzoylamino)phenyl]-2-(2-propylamino-3,4-dioxoc-
yclobut-1-enylamino)propanoic acid
[0996] 4-Methoxybenzoic acid gave the title compound (0.3 mg)
[0997] HPLC-MS (Conditions B). Retention time 2.34 min, MH.sup.+
452
EXAMPLE 257
[0998]
(S)-3-[4-(4-Acetamidobenzoylamino)phenyl]-2-(2-propylamino-3,4-diox-
ocyclobut-1-enylamino)propanoic acid
[0999] 4-Acetamidobenzoic acid gave the title compound (3.7 mg)
[1000] HPLC-MS (Conditions B). Retention time 2.16 min, MH.sup.+
479
EXAMPLE 258
[1001]
(S)-3-[4-(4-Acetylbenzoylamino)phenyl]-2-(2-propylamino-3,4-dioxocy-
clobut-1-enylamino)propanoic acid
[1002] 4-Acetylbenzoic acid gave the title compound (2.0 mg)
[1003] HPLC-MS (Conditions B). Retention time 2.28 min, MH.sup.+
461
EXAMPLE 259
[1004]
(S)-3-[4-(4-Nitrobenzoylamino)phenyl]-2-(2-propylamino-3,4-dioxocyc-
lobut-1-enylamino)propanoic acid
[1005] 4-Nitrobenzoic acid gave the title compound (4.3 mg)
[1006] HPLC-MS (Conditions B). Retention time 2.39 min, MH.sup.+
467
EXAMPLE 260
[1007]
(S)-3-{4-[4-(4-Hydroxyphenyl)benzoylamino]phenyl}-2-(2-propylamino--
3,4-dioxocyclobut-1-enylaminolpropanoic acid
[1008] 4-Hydroxybiphenyl carboxylic acid gave the title compound
(0.8 mg)
[1009] HPLC-MS (Conditions B). Retention time 2.36 min, MH.sup.+
514
EXAMPLE 261
[1010]
(S)-3-[4-(4-Cyanobenzoylamino)phenyl]-2-(2-propylamino-3,4-dioxocyc-
lobut-1-enylamino)propanoic acid
[1011] 4-Cyanobenzoic acid gave the title compound (6.5 mg)
[1012] HPLC-MS (Conditions B). Retention time 2.32 min, MH.sup.+
447
EXAMPLE 262
[1013]
(S)-3-[4-(4-Trifluoromethylbenzoylamino)phenyl]-2-(2-propylamino-3,-
4-dioxocyclobut-1-enylamino)propanoic acid
[1014] 4-Trifluoromethylbenzoic acid gave the title compound (5.4
mg)
[1015] HPLC-MS (Conditions B). Retention time 2.55 min, MH.sup.+
560
EXAMPLE 263
[1016]
(S)-3-[4-(N-Oxo4-pyridylcarboxamido)phenyl]-2-(2-propylamino-3,4-di-
oxocyclobut-1-enylamino)propanoic acid
[1017] 4-Pyridyl-N-oxide carboxylic acid gave the title compound
(4.7 mg)
[1018] HPLC-MS (Conditions B). Retention time 1.97 min, MH.sup.+
439
EXAMPLE 264
[1019]
(S)-3-[4-(2,6-Dichloro-3-pyridylcarboxamido)phenyl]-2-(2-propylamin-
o-3,4-dioxocyclobut-1-enylamino)propanoic acid
[1020] 2,6, Dichloronicotinic acid gave the title compound (4.7
mg)
[1021] HPLC-MS (Conditions B). Retention time 2.31 min, MH.sup.+
493
EXAMPLE 265
[1022]
(S)-3-[4-(2-(Methoxycarbonyl)benzoylamino)phenyl]-2-(2-propylamino--
3,4-dioxocyclobut-1-enylamino)propanoic acid
[1023] 2-Methoxycarbonylbenzoic acid gave the title compound (3.4
mg)
[1024] HPLC-MS (Conditions B). Retention time 2.28 min, MH.sup.+
480
EXAMPLE 266
[1025]
(S)-3-{4-[5-Methyl-2-(trifluoromethyl)-3furanylcarboxamido]phenyl}--
2-(2-propylamino-3,4-dioxocyclobut-1-enylamino)propanoic acid
[1026] 5-Methyl-2-(trifluoromethyl)-3-furancarboxylic acid gave the
title compound (5.6 mg)
[1027] HPLC-MS (Conditions B). Retention time 2.48 min, MH.sup.+
494
EXAMPLE 267
[1028]
(S)-3-[4-(2-Acetyl-3-thienylcarboxamido)phenyl]-2-(2-propylamino-3,-
4-dioxocyclobut-1-enylamino)propanoic acid
[1029] 2-Acetyl-3-thiophenecarboxylic acid gave the title compound
(5.2 mg)
[1030] HPLC-MS (Conditions B). Retention time 2.28 min, MH.sup.+
470
EXAMPLE 268
[1031]
(S)-3-{4-[((R)-2-Oxothiazolidin-4-ylcarboxamido]phenyl}-2-[2-propyl-
amino-3,4-dioxocyclobut-1-enylamino)propanoic acid
[1032] (R)-2-Oxothiazolidine-4-carboxylic acid gave the title
compound (5.4 mg)
[1033] HPLC-MS (Conditions B). Retention time 2.07 min, MH.sup.+
447
EXAMPLE 269
[1034]
(S)-3-[4-(4-Nitro-3-pyrazolylcarboxamido)phenyl]-2-(2-propylamino-3-
,4-dioxocyclobut-1-enylamino)propanoic acid
4-Nitro-3-pyrazolecarboxylic acid gave the title compound (3.0
mg)
[1035] HPLC-MS (Conditions B). Retention time 2.14 min, MH.sup.+
457
EXAMPLE 270
[1036]
(S)-3-[4-(5-Chloro-2-thienylcarboxamido)phenyl]-2-(2-propylamino-3,-
4-dioxocyclobut-1-enylamino)propanoic acid
[1037] 5-Chloro-2-thiophenecarboxylic acid gave the title compound
(5.3 mg)
[1038] HPLC-MS (Conditions B). Retention time 2.48 min, MH.sup.+
462
EXAMPLE 271
[1039] (S)-3-[4-(1-Methyl-5-nitro-4-pyrazolylcarboxamido)
phenyl]-2-(2-propylamino-3,4-dioxocyclobut-1-enylamino)propanoic
acid
[1040] 1-Methyl-5-nitro-4-pyrazolecarboxylic acid gave the title
compound (6.1 mg)
[1041] HPLC-MS (Conditions B). Retention time 2.23 min, MH.sup.+
471
EXAMPLE 272
[1042]
(S)-3-[4-(2-Furoylamino)phenyl]-2-(2-propylamino-3,4-dioxocyclobut--
1-enylamino)propanoic acid
[1043] 2-Furoic acid gave the title compound (3.7 mg)
[1044] HPLC-MS (Conditions B). Retention time 2.23 min, MH.sup.+
412
EXAMPLE 273
[1045]
(S)-3-[4-(2,4-Dimethyl-5-thiazolylcarboxamido)phenyl]-2-(2-propylam-
ino-3,4-dioxocyclobut-1-enylamino)propanoic acid
[1046] 2,4-Dimethyl-5-thiazolecarboxylic acid gave the title
compound (4.2 mg)
[1047] HPLC-MS (Conditions B). Retention time 2.18 min, MH.sup.+
457
EXAMPLE 274
[1048]
(S)-3-[4-(1,2,3-thiadiazol-4-ylcarboxamido)phenyl]-2-(2-propylamino-
-3,4-dioxocyclobut-1-enylamino)propanoic acid
[1049] 1,2,3,Thiadiazole-5-carboxylic acid gave the title compound
(4.9 mg)
[1050] HPLC-MS (Conditions B). Retention time 2.20 min, MH.sup.+
430
EXAMPLE 275
[1051]
(S)-3-[4-(2-Thienylcarboxamido)phenyl]-2-(2-propylamino-3,4-dioxocy-
clobut-1-enylamino)propanoic acid
[1052] 2-Thiophenecarboxylic acid gave the title compound (5.0
mg)
[1053] HPLC-MS (Conditions B). Retention time 2.31 min, MH.sup.+
428
EXAMPLE 276
[1054]
(S)-3-[4-(2-Pyrazinylcarboxamido)phenyl]-2-(2-propylamino-3,4-dioxo-
cyclobut-t-enylamino)propanoic acid
[1055] 2-Pyrazinecarboxylic acid gave the title compound (4.2
mg)
[1056] HPLC-MS (Conditions B). Retention time 2.16 min, MH.sup.+
424
EXAMPLE 277
[1057]
(S)-3-{4-[(2-Furyl)oxalylamino]phenyl}-2-(2-propylamino-3,4-dioxocy-
clobut-1-enylamio)propanoic acid
[1058] .alpha.-Oxo-2-furanacetic acid gave the title compound (4.8
mg)
[1059] HPLC-MS (Conditions B). Retention time 2.3 min, MH.sup.+
440.
EXAMPLE 278
[1060]
(S)-3-[4-(3-Methyl-2-thienylcarboxamido)phenyl]-2-(2-2propylamino-3-
,4-dioxocyclobut-1-enylaminolpropanoic acid
[1061] 3-Methyl-2-thiophenecarboxylic acid gave the title compound
(2.0 mg)
[1062] HPLC-MS (Conditions B). Retention time 2.37 min, MH.sup.+
442
EXAMPLE 279
[1063]
(S)-3-[4-(4-Methyl-1,2,3-thiadiazol-5-ylcarboxamido)phenyl]-2-(2-pr-
opylamino-3,4-dioxocyclobut-1-enylamino)propanoic acid
[1064] 4-Methyl-1,2,3-thiazole-5carboxylic acid gave the title
compound (4.0 mg)
[1065] HPLC-MS (Conditions B). Retention time 2.24 min, MH.sup.+
444
EXAMPLE 280
[1066]
(S)-3-[4-(5-Phenyl-4-oxazolylcarboxamido)phenyl]-2-(2-propylamino-3-
,4-dioxocyclobut-1-enylamino)propanoic acid
[1067] 5-Phenyl-4-oxazolecarboxylic acid gave the title compound
(5.9 mg)
[1068] HPLC-MS (Conditions B). Retention time 2.51 min, MH.sup.+
489
EXAMPLE 281
[1069]
(S)-3-[4-(3-Methyl-5-trifluoromethyl-4-isoxazolylcarboxamido)phenyl-
]-2-(2-propyl amino-3,4-dioxocyclobut-1-enylamino)propanoic
acid
[1070] 3-Methyl-5-trifluoromethyl-4-isoxazolecarboxylic acid gave
the title compound (5.8 mg)
[1071] HPLC-MS (Conditions B). Retention time 2.43 min, MH.sup.+
495.
[1072] The following compounds of Examples 282 to 323 were prepared
in a similar manner to the compound of Example 105, using
derivatised resin (4) and the starting material shown. For examples
where the amine was added as a salt 1 mol equivalent of DIPEA was
also added.
EXAMPLE 282
[1073]
(RS)-3-[4-(3,5-Dichloro-4-pyrodylcarboxamido)phenyl]-3-[2-(2-morpho-
linoethylamino)-3,4-dioxocyclobut-1 enylamino]propanoic acid
[1074] N-(2-Aminoethyl)morpholine gave the title compound (2
mg)
[1075] HPLC-MS (Conditions B) Retention time 1.98 min MH.sup.+
562
EXAMPLE 283
[1076]
(RS)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-3-[2-(2-piperd-
inoethylamino)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[1077] 1-(2-Aminoethyl)piperidine gave the title compound (2mg)
[1078] HPLC-MS (Conditions B) Retention time 2.02 min MH.sup.+
560
EXAMPLE 284
[1079]
(RS)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-3-[2-(3-(2-oxo-
pyrrolidin-1-yl)propylamino)-3,4-dioxocyclobut-1-enylamino]propanoic
acid
[1080] 1-(3-Aminopropyl)-2-pyrrolidinone gave the title compound (1
mg)
[1081] HPLC-MS (Conditions B) Retention time 2.14 min MH.sup.+
574
EXAMPLE 285
[1082]
(RS)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)1phenyl-3-[2-(3-(1-imi-
dazolyl)propylamino)-3,4-dioxocyclobut-1-enylamino]propanoic
[1083] N-(3-Aminopropyl)imidazole gave the title compound (3
mg)
[1084] HPLC-MS (Conditions B) Retention time 1.98 min MH.sup.+
557
EXAMPLE 286
[1085]
(RS)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl-3-[2-(1-benzyl--
4-piperidinylamino]-3,4-dioxocyclobut-1-enylamino]propanoic
acid
[1086] 4-Amino-1-benzylpiperidine gave the title compound (6
mg)
[1087] HPLC-MS (Conditions B) Retention time 2.13 min MH.sup.+
622
EXAMPLE 287
[1088]
(RS)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-3-[2-(2-pyridy-
lmethylamino)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[1089] 2-(Aminomethyl)pyridine gave the title compound (6 mg)
[1090] HPLC-MS (Conditions B) Retention time 2.17 min MH.sup.+
540
EXAMPLE 288
[1091]
(RS)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-3-[2-(3-pyridy-
lmethylamino)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[1092] 3-(Aminomethyl)pyridine gave the title compound (3 mg)
[1093] HPLC-MS (Conditions B) Retention time 2.07 min MH.sup.+
540
EXAMPLE 289
[1094]
(RS)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-3-[2-(3,3-dime-
thylbutylamino)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[1095] 3,3-Dimethylbutylamine gave the title compound (3 mg)
[1096] HPLC-MS (Conditions B) Retention time 2.45 min MH.sup.+
533
EXAMPLE 290
[1097]
(RS)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-3-[2-(3,4-dich-
lorobenzylamino)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[1098] 3,4-Dichlorobenzylamine gave the title compound (4 mg)
[1099] HPLC-MS (Conditions B) Retention time 2.51 min MH.sup.+
607
EXAMPLE 291
[1100]
(RS)-3-[4-(3,5-Dichloro4-pyridylcarboxamido)phenyl]-3-[2-(2-(1-pipe-
razinyl)ethylamino)-3,4-dioxocyclobut-1-enylamino]propanoic
[1101] N-(2-Aminoethyl)piperazine gave the title compound (1
mg)
[1102] HPLC-MS (Conditions B) Retention time 1.97 min MH.sup.+
561
EXAMPLE 292
[1103]
(RS)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-3-(2-isopropyl-
amino-3,4-dioxocyclobut-1-enylamino)1propanoic acid
[1104] Isopropylamine gave the title compound (1 mg)
[1105] HPLC-MS (Conditions B) Retention time 2.25 min MH.sup.+
491
EXAMPLE 293
[1106]
(RS)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-3-(2-propylami-
no-3,4-dioxocyclobut-1-enylamino)propanoic acid
[1107] Propylamine gave the title compound (2 mg)
[1108] HPLC-MS (Conditions B) Retention time 2.25 min MH.sup.+
491
EXAMPLE 294
[1109]
(RS)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-3-(2-tert-buty-
lamino-3,4-dioxocyclobut-1-enylamino)propanoic acid
[1110] Tert-Butylamine gave the title compound (0.5 mg)
[1111] HPLC-MS (Conditions B) Retention time 2.33 min MH.sup.+
505
EXAMPLE 295
[1112]
(RS)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-3-(2-benzylami-
no-3,4-dioxocyclobut-1-enylamino)propanoic acid
[1113] Benzylamine gave the title compound (1 mg)
[1114] HPLC-MS (Conditions B) Retention time 2.37 min MH.sup.+
539
EXAMPLE 296
[1115]
(RS)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-3-[2-(3-(dimet-
hylaminoloropylamino)-3,4-dioxocyclobut-1-enylamino]propanoic
acid
[1116] 3-(Dimethylamino)propylamine gave the title compound (0.5
mg)
[1117] HPLC-MS (Conditions B) Retention time 1.89 min MH.sup.+
534
EXAMPLE 297
[1118]
(RS)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-3-[2-(3-isopro-
poxypropylamino)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[1119] 3-Isopropoxypropylamine gave the title compound (1 mg)
[1120] HPLC-MS (Conditions B) Retention time 2.3 min MH.sup.+
549
EXAMPLE 298
[1121]
(RS)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-3-[2-(3-ethoxy-
propylamino)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[1122] 3-Ethoxypropylamine gave the title compound (2 mg)
[1123] HPLC-MS (Conditions B) Retention time 2.23 min MH.sup.+
535
EXAMPLE 299
[1124]
IRS)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-3-[2-(2methoxy-
ethylamino)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[1125] 2-Methoxyethylamine gave the title compound (0.5 mg)
[1126] HPLC-MS (Conditions B) Retention time 2.16 min MH.sup.+
507
EXAMPLE 300
[1127]
(RS)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-3-[2-(3-methox-
yoropylamino)-3,4-dioxocyclobut-1enylaminolpropanoic acid
[1128] 3-Methoxypropylamine gave the title compound (0.5 mg)
[1129] HPLC-MS (Conditions B) Retention time 2.18 min MH.sup.+
521
EXAMPLE 301
[1130]
(RS)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-3-(2-cyclobuty-
lamino-3,4-dioxocyclobut-1-enylamino)propanoic acid
[1131] Cyclobutylamine gave the title compound (2 mg)
[1132] HPLC-MS (Conditions B) Retention time 2.28 min MH.sup.+
503
EXAMPLE 302
[1133]
(RS)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-3-(2-cycloprop-
ylamino-3,4-dioxocyclobut-1-enylamino)propanoic acid
[1134] Cyclopropylamine gave the title compound (2 mg)
[1135] HPLC-MS (Conditions B) Retention time 2.19 min MH.sup.+
489
EXAMPLE 303
[1136]
(RS)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-3-2-(2-(benzyl-
thio)ethylamino)-3,4-dioxocyclobut-1-enylamino]propanoic
[1137] 2-(Benzylthio)ethylamine hydrochloride gave the title
compound (0.5 mg)
[1138] HPLC-MS (Conditions B) Retention time 2.46 min MH.sup.+
599
EXAMPLE 304
[1139] (RS)-3-[4
(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-3-[2-(4-(1,2,3-
-thiadiazol4-yl)benzylamino)-3,4-dioxocyclobut-1-enylamino]propanoic
acid
[1140] 4-(1,2,3-Thiadiazol4-yl)benzylamine gave the title compound
(2 mg)
[1141] HPLC-MS (Conditions B) Retention time 2.38 min MH.sup.+
623
EXAMPLE 305
[1142]
(RS)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-3-(2-cyclohexy-
lamino-3,4-dioxocyclobut-1-enylamino)propanoic acid
[1143] Cyclohexylamine gave the title compound (0.5 mg)
[1144] HPLC-MS (Conditions B) Retention time 2.39 min MH.sup.+
531
EXAMPLE 306
[1145]
(RS)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-3-[2-piperidin-
yl-3,4-dioxocyclobut-1-enylamino]propanoic acid
[1146] Piperidine gave the title compound (2 mg)
[1147] HPLC-MS (Conditions A) Retention time 2.32 min MH.sup.+
517
EXAMPLE 307
[1148]
(RS)-3-[4-(3,5-Dichloro-4-2pyridylcarboxamido)phenyl]-3-(2-thiomorp-
holino-3,4-dioxocyclobut-1-enylamino)propanoic acid
[1149] Thiomorpholine gave the title compound (1 mg)
[1150] HPLC-MS (Conditions A) Retention time 2.32 min MH.sup.+
535
EXAMPLE 308
[1151]
(RS)-3-[4-(3,5-Dichloro4-pyridylcarboxamido)phenyl]-3-[2-(4-methyl--
1-piperazinyl)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[1152] 1-Methylpiperazine gave the title compound (3 mg)
[1153] HPLC-MS (Conditions A) Retention time 1.93 min MH.sup.+
532
EXAMPLE 309
[1154]
(RS)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-3-(2-diethylam-
ino-3,4-dioxocyclobut-1-enylamino)propanoic acid
[1155] Diethylamine gave the title compound (2 mg)
[1156] HPLC-MS (Conditions A) Retention time 2.29 min MH.sup.+
505
EXAMPLE 310
[1157]
(RS)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-3-[2-(1-pyrrol-
idinyl)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[1158] Pyrrolidine gave the title compound (1 mg)
[1159] HPLC-MS (Conditions A) Retention time 2.24 min MH.sup.+
503
EXAMPLE 311
[1160]
(RS)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-3-[2-(4-ethyl--
1-piperazinyl)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[1161] 1-Ethylpiperazine gave the title compound (1 mg)
[1162] HPLC-MS (Conditions A) Retention time 1.94 min MH.sup.+
546
EXAMPLE 312
[1163]
(RS)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-3-[2-(4-(hydro-
xyoropyl)-1-piperazinyl)-3,4-dioxocyclobut-1-enylamino]propanoic
acid
[1164] 1-Piperazinepropanol gave the title compound (3 mg)
[1165] HPLC-MS (Conditions A) Retention time 1.93 min MH.sup.+
576
EXAMPLE 313
[1166]
(RS)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-3-[2-(1-pipera-
zinyl)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[1167] Piperazine gave the title compound (4 mg)
[1168] HPLC-MS (Conditions A) Retention time 1.92 min MH.sup.+
518
EXAMPLE 314
[1169]
(RS)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-3-[2-((S)
3-dimethylamino-1-pyrrolidinyl)-3,4-dioxocyclobut-1-enylamino]propanoic
acid
[1170] (S)-3-(Dimethylamino)pyrrolidine gave the title compound (3
mg)
[1171] HPLC-MS (Conditions A) Retention time 1.92 min MH.sup.+
546
EXAMPLE 315
[1172]
(RS)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-3-[2-((RS)-3-d-
iethylamino-1-pyrrolidinyl)-3,4-dioxocyclobut-1-enylamino]propanoic
acid
[1173] 3-(Diethylamino)pyrrolidine gave the title compound (3
mg)
[1174] HPLC-MS (Conditions A) Retention time 1.95 min MH.sup.+
574
EXAMPLE 316
[1175]
(RS)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-3-(2-butylamin-
o-3,4-dioxocyclobut-1-enylamino]propanoic acid
[1176] Butylamine gave the title compound (0.1 mg)
[1177] HPLC-MS (Conditions A) Retention time 2.33 min MH.sup.+
505
EXAMPLE 317
[1178]
(RS)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-3-(2-pentylami-
no-3,4-dioxocyclobut-1enylamino)propanoic acid
[1179] Pentylamine gave the title compound (1 mg)
[1180] HPLC-MS (Conditions A) Retention time 2.40 min MH.sup.+
519
EXAMPLE 3198
[1181]
(RS)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-3-[2-((RS)-2-b-
utylamino)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[1182] 1-Methylpropylamine gave the title compound (2 mg)
[1183] HPLC-MS (Conditions A) Retention time 2.31 min MH.sup.+
505
EXAMPLE 319
[1184]
(RS)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-3-(2-isobutyla-
mino-3,4-dioxocyclobut-1-enylamino)propanoic acid
[1185] Isobutylamine gave the title compound (2 mg)
[1186] HPLC-MS (Conditions A) Retention time 2.31 min MH.sup.+
505
EXAMPLE 320
[1187]
(RS)-3-[4(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-3-[2-(N-methyl--
N-isopropylamino)-3,4-dioxocyclobut-1-enylamino)propanoic acid
[1188] Methylisopropylamine gave the title compound (2 mg)
[1189] HPLC-MS (Conditions A) Retention time 2.3 min MH.sup.+
505
EXAMPLE 321
[1190]
(RS)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-3-[2-(N-ethyl--
N-methylamino)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[1191] N-Ethylmethylamine gave the title compound (0.2 mg)
[1192] HPLC-MS (Conditions A) Retention time 2.24 min MH.sup.+
491
EXAMPLE 322
[1193]
(RS)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-3-[2-(N-methyl-
-N-butylamino)-3,4-dioxocyclobut-1-enylamino]propanoic acid
[1194] N-Methylbutylamine gave the title compound (0.3 mg)
[1195] HPLC-MS (Conditions A) Retention time 2.38 min MH.sup.+
519
EXAMPLE 323
[1196]
(RS)-3-[4(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-3-[2-(N-ethyl-N-
-(pyridylmethyl)amino]-3,4-dioxocyclobut-1-enylamino]propanoic
acid
[1197] 4-(Ethylaminomethyl)pyridine gave the title compound (1
mg)
[1198] HPLC-MS (Conditions A) Retention time 2.01 min MH.sup.+
568
EXAMPLE 324
[1199]
3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl-2-(2-isopropylamino--
3,4-dioxocyclobut-1-enylamino)propanoic acid
[1200] Derivatised resin 6 (1.0 g) was treated with the
Intermediate 44 (0.4 g, 3.0 mmol) and a catalytic amount of
dirhodiumtetraacetate in toluene (10 ml) at 1200 for 2.5 h. The
resin was then filtered and washed with DMF and DCM to give resin
bound .alpha.-(2-methoxy-3,4-dioxocyclo-bu-
t-1-enylamino)diethylphosphonoacetate. This resin was then treated
with 4-(3,5-dichloro-4-pyridylcarboxamido)benzaidehyde (0.53 g, 1.5
mmol) and diazabicycloundec-7-ene (DBU) (0.1 g, 1.2 mmol) in DCM
(5.0 ml). The mixture was agitated at ambient temperature for 72 h
then filtered and the resin washed thoroughly with DCM. A 90 mg
portion of this resin was treated with 2-propylamine (0.045 mL, 0.6
mmol), in DCM (0.2 mL) and MeOH (0.8 mL). The mixture was agitated
at ambient temperature for 16 h then filtered and washed thoroughly
with DCM, MeOH, DMF, MeOH and DCM. The resin was treated with 50%
trifluoroacetic acid in DCM (2 ml) for 3 h with agitation and then
filtered. The resin was washed with a further portion of DCM (2 ml)
and the combined filtrate was evaporated in vacuo to give the crude
product which was purified by preparative HPLC to afford the title
compound (0.9 mg).
[1201] HPLC-MS (Conditions B). Retention time 2.29 min, MH.sup.+
489 The following compound of Example 325 was prepared in an
identical manner to the compound of Example 324, using the starting
material shown.
EXAMPLE 325
[1202]
3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-(2-cyclobutylamin-
o-3,4-dioxocyclobut-1-enylamino)prop-2-enoic acid
[1203] Cyclobutylamine gave the title compound (0.4 mg)
[1204] HPLC-MS (Conditions B). Retention time 2.33 min, MH.sup.+
501.
[1205] The following assays can be used to demonstrate the potency
and selectivity of the compounds according to the invention. In
each of these assays an IC.sub.50 value was determined for each
test compound and represents the concentration of compound
necessary to achieve 50% inhibition of cell adhesion where
100%=adhesion assessed in the absence of the test compound and
0%=absorbance in wells that did not receive cells.
[1206] .alpha..sub.4.beta..sub.1 Integrin-dependent Jurkat cell
adhesion to VCAM-Ig
[1207] 96 well NUNC plates were coated with F(ab).sub.2 fragment
goat anti-human IgG Fc.gamma.-specific antibody [Jackson Immuno
Research 109-006-098: 100 .mu.l at 2 .mu.g/ml in 0.1M NaHCO.sub.3,
pH 8.4], overnight at 40. The plates were washed (3.times.) in
phosphate-buffered saline (PBS) and then blocked for 1 h in PBS/1%
BSA at RT on a rocking platform. After washing (3.times.in PBS) 9
ng/ml of purified 2d VCAM-Ig diluted in PBS/1% BSA was added and
the plates left for 60 minutes at RT on a rocking platform. The
plates were washed (3.times.in PBS) and the assay then performed at
370 for 30 min in a total volume of 200 .mu.l containing
2.5.times.10.sup.5 Jurkat cells in the presence or absence of
titrated test compounds.
[1208] Each plate was washed (2.times.) with medium and the
adherent cells were fixed with 100 .mu.l MeOH for 10 minutes
followed by another wash. 100 .mu.l 0.25% Rose Bengal (Sigma R4507)
in PBS was added for 5 minutes at RT and the plates washed
(3.times.) in PBS. 100 .mu.l 50% (v/v) ethanol in PBS was added and
the plates left for 60 min after which the absorbance (570 nm) was
measured.
[1209] .alpha..sub.4.beta..sub.7Integrin-dependent JY cell adhesion
to MAdCAM-Ig
[1210] This assay was performed in the same manner as the
.alpha..sub.4.beta..sub.1 assay except that MAdCAM-Ig (150 ng/ml)
was used in place of 2d VCAM-Ig and a sub-line of the .beta.-lympho
blastoid cell-line JY was used in place of Jurkat cells. The
IC.sub.50 value for each test compound was determined as described
in the .alpha..sub.4.beta..sub.1 integrin assay.
[1211] .alpha.5.beta..sub.1 Integrin-dependent K562 cell adhesion
to fibronectin
[1212] 96 well tissue culture plates were coated with human plasma
fibronectin (Sigma F0895) at 5 .mu.g/ml in phosphate-buffered
saline (PBS) for 2 hr at 37.degree. C. The plates were washed
(3.times.in PBS) and then blocked for 1 h in 100 .mu.l PBS/1% BSA
at RT on a rocking platform. The blocked plates were washed
(3.times.in PBS) and the assay then performed at 37.degree. C. in a
total volume of 200 .mu.l containing 2.5.times.10.sup.5 K562 cells,
phorbol-12-myristate-13-acetate at 10 ng/ml, and in the presence or
absence of titrated test compounds. Incubation time was 30 minutes.
Each plate was fixed and stained as described in the
.alpha..sub.4.beta..sub.1 assay above
[1213] .alpha..sub.m.beta..sub.2-dependent human polymorphonuclear
neutrophils adhesion to plastic
[1214] 96 well tissue culture plates were coated with RPMI 1640/10%
FCS for 2 h at 37.degree. C. 2.times.10.sup.5 freshly isolated
human venous polymorphonuclear neutrophils (PMN) were added to the
wells in a total volume of 200 .mu.l in the presence of 10 ng/ml
phorbol-12-myristate-13-a- cetate, and in the presence or absence
of test compounds, and incubated for 20 min at 37.degree. C.
followed by 30 min at RT. The plates were washed in medium and 100
.mu.l 0.1% (w/v) HMB (hexadecyl trimethyl ammonium bromide, Sigma
H5882) in 0.05M potassium phosphate buffer, pH 6.0 added to each
well. The plates were then left on a rocker at RT for 60 min.
Endogenous peroxidase activity was then assessed using tetramethyl
benzidine (TMB) as follows: PMN lysate samples mixed with 0.22%
H.sub.2O.sub.2 (Sigma) and 50 .mu.g/ml TMB (Boehringer Mannheim) in
0.1M sodium acetate/citrate buffer, pH 6.0 and absorbance measured
at 630 nm.
[1215] .alpha.llb/.beta..sub.3-dependent human platelet
aggregation
[1216] Human platelet aggregation was assessed using impedance
aggregation on the Chronolog Whole Blood Lumiaggregometer. Human
platelet-rich plasma (PRP) was obtained by spinning fresh human
venous blood anticoagulated with 0.38% (v/v) tri-sodium citrate at
220.times.g for 10 min and diluted to a cell density of
6.times.10.sup.8/ml in autologous plasma. Cuvettes contained equal
volumes of PRP and filtered Tyrode's buffer (g/liter: NaCl 8.0;
MgCl.sub.2.H.sub.2O 0.427; CaCl.sub.2 0.2; KCl 0.2; D-glucose 1.0;
NaHCO.sub.3 1.0; NaHPO.sub.4.2H.sub.2O 0.065). Aggregation was
monitored following addition of 2.5CM ADP (Sigma) in the presence
or absence of inhibitors.
[1217] In the above assays the preferred compounds of the invention
in which R.sup.1 is an .alpha..sub.4 integrin binding group, such
as the compounds of the Examples generally have IC.sub.50 values in
the .alpha..sub.4.beta..sub.1 and .alpha..sub.4 .beta..sub.7 assays
of 1 .mu.M and below. In the other assays featuring at integrins of
other subgroups the same compounds had IC.sub.50 values of 50 .mu.M
and above thus demonstrating the potency and selectivity of their
action against .alpha..sub.4 integrins.
[1218] The following assays may be used to determine the ability of
compounds according to the invention to inhibit
.alpha..sub.v.beta..sub.3 and .alpha..sub.v.beta..sub.5
function.
[1219] .alpha..sub.v.beta..sub.3-Dependent Direct Binding Assay
[1220] 96 Well NUNC immunoplates were coated overnight with a
non-blocking anti-.beta..sub.3 monoclonal antibody at 2 .mu.g/ml in
Dulbecco's phosphate buffered saline (PBS) and subsequently blocked
with 5% 9W/v)BSA in PBS (Sigma, fraction V) for 60 min. at RT.
After washing in Tris-buffered saline (TBS: 20 mM Tris/150 mM NaCl,
pH 7.5), plates then received 100 .mu.l of a lysate prepared from
JY cells and were incubated for 3 h at RT. The lysate was made by
lysing JY B-lymphoblastoid cells at 5.times.10.sup.7 cells were ml
in TBS containing 1 mM MnCl.sub.2, 1% (V/v) BSA/0.1% (v/v) Tween 20
and were incubated for a further 2 hours at RT. Inhibitors were
titrated into the fibronectin prior to addition to plates. After
washing, streptavidin-peroxidase (Amersham) at 1:500 in TBS/1%
(W/v) BSA/0.1% (v/v)Tween 20 was added and plates incubated for 1 h
at RT. Finally 100 .mu.l TMB substrate was added and Absorbance
(630 nm) measured after 10-15 miunbutes. IC.sub.50 values for
inhibition of adhesion were calculated on the Activity Base curve
fitting programme.
[1221] .alpha..sub.v.beta..sub.3-Dependent Cell Adhesion Assay
[1222] This was a modification of a published method [Stupack et
al., Exp. Cell. Tes. 203, 443-448 (1992)] and employed the JY cell
line. These cells are maintained in RPMI 1640+10% FCS+2 mM
L-glutamine and, when used for assay, were washed in assat medium
(RPMI 1640+10% FCS), suspended at 4.times.10.sup.6/ml in the same
medium and pretreated with a blocking monoclonal antibody to CD18
(6.5E, F(ab').sub.2 fragment) for 10 min at RT. 96 Well NUNC
immunoplates were coated with 100 .mu.l 2.5uk/.mu.l human
vitronectin in PBS per well for 2 h at 37.degree. C.; they were
then washed 2.times.in PBS and blocked with 1% (w/v) BSA in PBS for
60 min at RT and washed 2.times.more in PBS. 2.times.1-5 JY per
well were added to wells containing compounds serially titrated
across the plate and, finally, phorbol-12-myristate-13-acetate at
10 ng/ml was added in a final volume of 200 .mu.l. After incubation
at 370C for 30 min, non-adherent cells were removed by washing
3.times.in assay medium, adherent cells were fixed in MeOH and
stained with 0.25% (W/v) Rose Bengal in PBS for 5 min, unbound dye
was removed by 3 further washes in PBS and cell-bound dye was
released with 1:1 PBS:ethanol. Absorbance at 570 nm was then
measured. IC.sub.50 values for inhibition of adhesion were
calculated as described above for the direct binding assay.
[1223] .alpha..sub.v.beta..sub.5-Dependent Cell Adhesion Assay
[1224] This assay was based on a published method [Koivunen et al,
J. Bio. Chem. 268, 20205-20210 (1993)] and employed the human colon
adenocarcinoma cell line HT-29. HT-29 Cells were routinely
maintained in DMEM+10% FCS+2 mM L-glutamine and were removed from
flasks using trypsin/EDTA, washed 2.times.in assay medium and
suspended at 4.times.10.sup.6/ml in the same medium. The cells were
allowed to `rest` for 15 min. at RT before being added
(2.times.10.sup.5/well) to wells containing compounds serially
titrated across the plate in a final volume of 200 .mu.l. The 96
well NUNC immunoplates had been coated with human vit ronectin as
described above for the .alpha..sub.v.beta..sub.3 assay. After
incubation at 37.degree. C. for 60 min, adhesion was assessed as
described above for the .alpha..sub.v.beta..sub.3 assay.
[1225] In the above assays the preferred compounds of the invention
generally have IC.sub.50 values of 1 .mu.M and below.
[1226] The advantageous clearance properties of compounds according
to the invention may be demonstrated as follows:
[1227] Hepatic clearance, whether metabolic or biliary, can make a
substantial contribution to the total plasma clearance of a drug.
The total plasma clearance is a principal parameter of the
pharmacokinetic properties of a medicine. It has a direct impact on
the dose required to achieve effective plama concentrations and has
a major impact on the elimination half-life and therefore the
dose-interval. Furthermore, high hepatic clearance is 3n indicator
of high first-pass hepatic clearance after oral administration and
therefore low oral bioavailability.
[1228] Many peptidic and non-peptidic carboxylic acids of
therapeutic interest are subject to high hepatic clearance from
plasma. Except for drugs which function in the liver, hepatic
uptake from blood or plasma is undesirable because it leads to high
hepatic clearance if the compound is excreted in bile or
metabolised, or if the substance is not cleared from the liver, it
may accumulate in the liver and interfere with the normal function
of the liver.
[1229] The total plasma clearance of a compound according to the
invention can be determined as follows:
[1230] a small dose of the compound in solution is injected into a
vein of a test animal. Blood samples are withdrawn from a blood
vessel of the animal at several times after the injection, and the
concentration of compound in the bleed or plasma is measured using
a suitable assay. The area under the curve (AUCiv) is calculated by
non-compartmental methods (for example, the trapezium method) or by
pharmacokinetic modelling. The total plasma clearance (CLp) is
calculated by dividing the intravenous dose(Div) by the AUCiv for
the blood plasma concentration--time course of a drug administered
by the intravenous route: CLp =Div.div.AUCiv
[1231] When tested in this manner, compounds according to the
invention are not rapidly or extensively extracted by the liver and
have low total plasma clearance where low is defined as less than
10 ml/min/kg in the laboratory rat (Sprague Dawley CD). This
compares favourably with functionally equivalent integrin binding
compounds in which the squaric acid framework of compounds of
formula (1) is not present.
* * * * *