U.S. patent application number 09/920206 was filed with the patent office on 2002-11-28 for 3-substituted isoquinolin-1-yl derivatives.
Invention is credited to Head, John Clifford, McKay, Catherine, Porter, John Robert.
Application Number | 20020177605 09/920206 |
Document ID | / |
Family ID | 26244781 |
Filed Date | 2002-11-28 |
United States Patent
Application |
20020177605 |
Kind Code |
A1 |
Head, John Clifford ; et
al. |
November 28, 2002 |
3-SUBSTITUTED ISOQUINOLIN-1-YL DERIVATIVES
Abstract
Squaric acid derivatives of formula (1) are described: 1 wherein
R.sup.1 is a hydrogen atom or a C.sub.1-6alkyl group; L.sup.1 is a
covalent bond or a linker atom or group; Alk.sup.1 is an optionally
substituted aliphatic chain; n is zero or the integer 1; R.sup.2 is
a hydrogen atom or an optionally substitued heteroaliphatic,
cycloaliphatic, heterocycloaliphatic, polycycloaliphatic,
heteropolycyclo-aliphatic, aromatic or heteroaromatic group; Alk is
a chain --CH.sub.2CH(R)--, --CH.dbd.C(R)--, 2 in which R is a
carboxylic acid (--CO.sub.2H) or a derivative or biostere thereof;
Ar.sup.2 is an optionally substituted aromatic or heteroaromatic
linking group; L.sup.2 is a covalent bond or a linker atom or
group; R.sup.16 is the group
-L.sup.3(Alk.sup.2).sub.tL.sup.4R.sup.20 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, Alk.sup.2 is
an optionally substituted aliphatic or heteroaliphatic chain and
R.sup.20 is an optionally substituted aromatic or heteroaromatic
group; The compounds are able to inhibit the binding of integrins
to their ligands and are of use in the prophylaxis and treatment of
immune or inflammatory disorders, or disorders including the
inappropriate growth or migration of cells.
Inventors: |
Head, John Clifford;
(Maidenhead, GB) ; McKay, Catherine;
(Rickansworth, GB) ; Porter, John Robert;
(Chinnor, GB) |
Correspondence
Address: |
Woodcock Washburn Kurtz
Mackiewicz & Norris LLP
One Liberty Place - 46th Floor
Philadelphia
PA
19103
US
|
Family ID: |
26244781 |
Appl. No.: |
09/920206 |
Filed: |
August 1, 2001 |
Current U.S.
Class: |
514/307 ;
546/146 |
Current CPC
Class: |
A61P 43/00 20180101;
A61P 1/04 20180101; A61P 3/10 20180101; A61P 29/00 20180101; C07D
401/12 20130101; A61P 19/02 20180101; A61P 17/06 20180101; A61P
25/00 20180101; C07D 401/14 20130101; A61P 11/06 20180101; A61P
17/00 20180101; C07D 413/12 20130101; C07D 217/22 20130101; A61P
7/00 20180101; A61P 37/06 20180101 |
Class at
Publication: |
514/307 ;
546/146 |
International
Class: |
C07D 217/12; A61K
031/47; A61K 031/4725 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 2, 2000 |
GB |
0018969.6 |
Nov 27, 2000 |
GB |
0028837.3 |
Claims
1. A compound of formula (1): 49wherein R.sup.1 is a hydrogen atom
or a C16alkyl group; L.sup.1 is a covalent bond or a linker atom or
group; Alk.sup.1 is an optionally substituted aliphatic chain; n is
zero or the integer 1; R.sup.2 is a hydrogen atom or an optionally
substitued heteroaliphatic, cycloaliphatic, heterocycloaliphatic,
polycycloaliphatic, heteropolycycloaliphatic, aromatic or
heteroaromatic group; Alk is a chain --CH.sub.2CH(R)--,
--CH.dbd.C(R)--, 50in which R is a carboxylic acid (--CO.sub.2H) or
a derivative or biostere thereof; Ar.sup.2 is an optionally
substituted aromatic or heteroaromatic linking group; L.sup.2 is a
covalent bond or a linker atom or group; R.sup.16 is the group
-L.sup.3(Alk.sup.2).sub.tL.sup.4R.sup.20 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, Alk.sup.2 is
an optionally substituted aliphatic or heteroaliphatic chain and
R.sup.20 is an optionally substituted aromatic or heteroaromatic
group; g is zero or the integer 1, 2, 3, 4 or 5; each R.sup.17
which may be the same or different is a hydrogen or halogen atom or
an optionally substituted straight or branched alkyl, alkoxy,
alkylthio or cycloalkyl aromatic or heteroaromatic group or a thiol
(--SH), hydroxyl (--OH), amino (--NH.sub.2), --N(R.sup.3)(R.sup.4)
[where R.sup.3 and R.sup.4 is each independently a hydrogen atom or
an optionally substituted alkyl group or together with the N atom
to which they are attached R.sup.3 and R.sup.4 alkyl groups are
joined to form a heterocyclic ring which may be optionally
interruped by a further --O-- or --S-- heteroatom or --N(R.sup.3)-
group], --CN, --CO.sub.2R.sup.3, --NO.sub.2,
--CON(R.sup.3)(R.sup.4), --CSN(R.sup.3)(R.sup.4), --COR.sup.3,
--N(R.sup.3)COR.sup.4, --N(R.sup.3)CSR.sup.4,
--SO.sub.2N(R.sup.3)(R.sup.- 4), --N(R.sup.3)SO.sub.2R.sup.4,
--N(R.sup.3)CON(R.sup.4)(R.sup.5) [where R.sup.5 is a hydrogen atom
or an optionally substituted alkyl group or together with the N
atom to which they are attached R.sup.4 and R.sup.5 alkyl groups
are joined to form a heterocyclic ring which may be optionally
interrupted by a further --O-- or --S-- heteroatom or --N(R.sup.3)
group] or --N(R.sup.3)SO.sub.2N(R.sup.4)(R.sup.5) group; and the
salts, solvates, hydrates and N-oxides thereof.
2. A compound according to claim 1 in which Alk is a chain 51or
--CH.sub.2CH(R)
3. A compound according to claim 1 in which R is a carboxylic acid
(--CO.sub.2H) group.
4. A compound according to claim 1 in which R is an esterified
carboxyl group of formula --CO.sub.2Alk.sup.7.
5. A compound according to claim 1 in which R.sup.1 is a hydrogen
atom.
6. A compound according to claim 1 in which L.sup.2 is a --O-- atom
or --N(R.sup.8)- group.
7. A compound according to claim 6 in which R.sup.8 is a hydrogen
atom or a methyl group.
8. 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.
9. A compound according to claim 8 in which R.sup.8 is a methyl,
ethyl or n-propyl group.
10. A compound according to claim 1 in which L.sup.1 is a covalent
bond.
11. A compound according to claim 1 in which n is the integer 1,
Alk.sup.1 is an optionally substituted straight or branched
C.sub.1-6alkylene chain and R.sup.2 is a hydrogen atom.
12. A compound according to claim 11 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.
13. A compound according to claim 1 in which L.sup.1 is a covalent
bond, n is zero and R.sup.2 is an optionally substituted
C.sub.5-7heterocycloalip- hatic group.
14. A compound according to claim 13 in which R.sup.2 is an
optionally substituted piperidinyl, homopiperidinyl,
heptamethyleneiminyl, pyrrolidinyl, piperazinyl, homopiperazinyl,
morpholinyl or thiomorpholinyl group.
15. A compound according to claim 1 of formula (2) 52wherein
R.sup.17a and R.sup.17b is each a hydrogen atom or an optional
substituent as previously defined for R.sup.17; and the salts,
solvates, hydrates and N-oxides thereof.
16. A compound according to claim 15 in which R.sup.16 is a group
-L.sup.3(Alk.sup.2).sub.tL.sup.4R.sup.20 in which R.sup.20 is an
optionally substituted phenyl, furyl, thienyl, imidazolyl, pyridyl
or pyrimidinyl group.
17. A compound according to claim 16 in which L.sup.3 is an --O--
or --S-- atom or a --C(O)-- or --N(R.sup.8)-- group in which
R.sup.8 is preferably a hydrogen atom or a methyl group.
18. A compound according to claim 17 in which t is the integer 1
and Alk.sup.2 is an optionally substituted C.sub.1-6alkylene
chain.
19. A compound according to claim 18 in which L.sup.4 is a covalent
bond.
20. A compound which is:
(S)-2-[(2-N,N-Diethylamino-3,4-dioxo-1-cyclobuten-
yl)amino]-3-{4-[3-phenyl- 1-isoquinolinylamino]phenyl}propanoic
acid;
(S)-2-[2-(2,5-Dimethylpyrrolidin-1-yl)-3,4-dioxo-1-cyclobutenyl)amino]-3--
{4-[3-phenyl-1-isoquinolinylamino]phenyl}propanoic acid;
(S)-2-[(2-(2,5-Dimethypyrrolidin-1-yl)-3,4-dioxo-1-cyclobutenyl)-
amino]-3-[4-(3-(4-fluorophenyl)isoquinolin-1-ylamino)phenyl]-propanoic
acid;
(S)-3-[4-(3-Phenyl-1-isoquinolinylamino)phenyl]-2-[(2-N-isopropyl-N-
-ethylamino-3,4-dioxocyclobut-1-enyl)amino]propanoic acid;
(S)-3-[4-(3-Phenyl-1-isoquinolinylamino)phenyl]-2-[(2-azepan-
1-yl-3,4-dioxocyclobut-1-enyl)amino]propanoic acid; and the salts,
solvates, hydrates, N-oxides and carboxylic acid ester,
particularly methyl, ethyl, propyl and i-propyl esters thereof.
21. A pharmaceutical composition comprising a compound according to
claim 1 together with one or more pharmaceutically acceptable
carriers, excipients or diluents.
22. A compound for the prophylaxis or treatment of a disease or
disorder in a mammal in which the extravasation of leukocytes plays
a role, comprising administering to a mammal suffering from such a
disease or disorder a therapeutically effective amount of a
compound according to claim 1.
23. A method according to claim 22 wherein said disease or disorder
is selected from the group consisting of inflammatory arthritis,
multiple sclerosis, allograft rejection, diabetes, inflammatory
dermatoses, asthma and inflammatory bowel disease.
24. A method according to claim 22 wherein said inflammatory
arthritis is selected from the group consisting of rheumatoid
arthritis, vasculitis and polydermatomyositis.
25. A method according to claim 22 wherein said inflammatory
dermatoses are selected from the group consisting of prosiasis and
dermatitis.
26. A method of inhibiting, in a mammal, the binding of (.alpha.4
integrins to the ligands thereof, comprising administering to the
mammal an effecting amount of a compound according to claim 1.
27. A method according to claim 25 wherein the .alpha.4 integrins
are selected from the group consisting of .alpha.4.beta.1 and
.alpha.4.beta.7 integrins.
Description
[0001] This invention relates to a series of 3-substituted
isoquinolin-1-yl 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, 346, 425, (1990); Springer, T. A., Cell, 76, 301, (1994)].
Specific cell surface molecules collectively referred to as cell
adhesion molecules mediate many of these interactions.
[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 16 different
integrin alpha chains and 8 different integrin beta chains have
been identified [Newman, P. et al, Molecular Medicine Today, 304,
(1996)]. The members of the family are typically named according to
their heterodimer composition although trivial nomenclature is
widespread in the field. Thus the integrin.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
VLA-4. 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 to date [Sonnenberg, A., Current Topics
in Microbiology and Immunology, 184, 7, (1993)].
[0004] 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 [Marlin, S. D. et al,
J. Exp. Med. 164, 855, (1986)]. Patients suffering 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 integrin family) there is a defect in blood clotting
(Hodivala-Dilke, K. M., J. Clin. Invest. 103, 229, (1999)].
[0005] 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 antibodies and
peptides that block various functions of these molecules [e.g.
Issekutz, T. B., J. Immunol. 149, 3394, (1992); Li, Z. et al, Am.
J. Physiol. 263, L723, (1992); Mitjans, F. 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 Res36, 408 (1997)]. A number of monoclonal
antibodies which block integrin function are currently being
investigated for their therapeutic potential in human disease, and
one, ReoPro, a chimeric antibody against the platelet integrin
.alpha.llb.beta.3 is in use as a potent anti-thrombotic agent for
use in patients with cardiovascular complications following
coronary angioplasty. Integrins recognize both cell surface and
extracellular matrix ligands, and ligand specificity is determined
by the particular alpha-beta subunit combination of the molecule
[Newman, P., ibid]. One particular integrin subgroup of interest
involves the .alpha.4 chain which can pair with two different beta
chains .beta.1 and .beta.7 [Sonnenberg, A., ibid]. The
.alpha.4.beta.1 pairing occurs on many circulating leukocytes (for
example lymphocytes, monocytes, eosinophils and basophils) although
it is absent or only present at low levels on circulating
neutrophils. .alpha.4.beta.1 binds to an adhesion molecule
(Vascular Cell Adhesion Molecule-1 also known as VCAM-1) frequently
up-regulated on endothelial cells at sites of inflammation
[Osborne, L., Cell, 62, 3, (1990)]. The molecule has also been
shown to bind to at least three sites in the matrix molecule
fibronectin [Humphries, M. J. et al, Ciba Foundation Symposium,
189, 177, (1995)]. Based on data obtained with monoclonal
antibodies in animal models it is believed that the interaction
between .alpha.4.beta.1 and ligands on other cells and the
extracellular matrix plays an important role in leukocyte migration
and activation [Yednock, T. A. et al, Nature, 356, 63, (1992);
Podolsky, D. K. etal, J. Clin. Invest. 92, 372, (1993); Abraham, W.
M. etal, J. Clin. Invest. 93, 776, (1994)].
[0006] The integrin generated by the pairing of .alpha.4 and
.beta.7 has been termed LPAM-1 [Holzmann, B. and Weissman, I. L.,
EMBO J. 8, 1735, (1989)]. The .alpha.4.beta.7 pairing is expressed
on certain sub-populations of T and B lymphocytes and on
eosinophils [Erle, D. J. et al, J. Immunol. 153, 517 (1994)]. Like
.alpha.4.beta.1, .alpha.4.beta.7 binds to VCAM-1 and fibronectin.
In addition, .alpha.4.beta.7 binds to an adhesion molecule believed
to be involved in the homing of leukocytes to mucosal tissue termed
MAdCAM-1 [Berlin, C. et al, Cell, 74, 185, (1993)]. The interaction
between .alpha.4.beta.7 and MAdCAM-1 may also be important sites of
inflammation outside of mucosal tissue [Yang, X.-D. et al, PNAS,
91, 12604, (1994)].
[0007] Regions of the peptide sequence recognizeded by
.alpha.4.beta.1 and .alpha.4.beta.7 when they bind to their ligands
have been identified. .alpha.4.beta.1 seems to recognise LDV, IDA
or REDV peptide sequences in fibronectin and a QIDSP sequence in
VCAM-1 [Humphries, M. J. et al, ibid] whilst .alpha.4.beta.7
recognises a LDT sequence in MAdCAM-1 [Birskin, M. J. et al, J.
Immunol. 156, 719, (1996)]. There have been several reports of
inhibitors of these interactions being designed from modifications
of these short peptide sequences [Cardarelli, P. M. etal, J. Biol.
Chem., 269, 18668, (1994); Shorff, H. N. et al, Biorganic Med.
Chem. Lett., 6, 2495, (1996); Vanderslice, P. et al, J. Immunol.,
158, 1710, (1997)]. It has also been reported that a short peptide
sequence derived from the .alpha.4.beta.1binding site in
fibronectin can inhibit a contact hypersensitivity reaction in a
trinitrochlorobenzene sensitised mouse [Ferguson, T. A., etal,
PNAS, 88, 8072, (1991)].
[0008] Since the alpha 4 subgroup of integrins are predominantly
expressed on leukocytes their inhibition can be expected to be
beneficial in a number of immune or inflammatory disease states.
However, because of the ubiquitous distribution and wide range of
functions performed by other members of the integrin family it is
important to be able to identify selective inhibitors of the alpha
4 subgroup.
[0009] We have now found a group of 3-substituted isoquinlin-1-yl
derivatives which are potent and selective inhibitors of
.alpha.4-integrins. Members of the group are able to inhibit
.alpha.4 integrins such as .alpha.4.beta.1 and .alpha.4.beta.7 at
concentrations at which they generally have no or minimal
inhibitory action on .alpha. integrins of other subgroups. The
3-substituted isoquinlin-1-yl derivatives show unexpectedly high
inhibition of .alpha.4-integrins when compared to unsubstituted
isoquinolin-1-yl derivatives. Additionally, the 3-substituted
isoquinolin-1-yl derivatives of the invention show a surprisingly
improved pharmacokinetic profile in comparison to unsubstituted
isoquinolin-1-yl derivatives, particularly improved
bioavailability. The compounds are thus of use in medicine, for
example in the prophylaxis and treatment of immune or inflammatory
disorders as described hereinafter.
[0010] Thus according to one aspect of the invention we provide a
compound of formula (1): 3
[0011] wherein
[0012] R.sup.1 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] Alk.sup.1 is an optionally substituted aliphatic chain;
[0015] n is zero or the integer 1;
[0016] R.sup.2 is a hydrogen atom or an optionally substitued
heteroaliphatic, cycloaliphatic, heterocycloaliphatic,
polycycloaliphatic, heteropolycyclo-aliphatic, aromatic or
heteroaromatic group;
[0017] Alk is a chain --CH.sub.2CH(R)--, --CH.dbd.C(R)--, 4
[0018] in which R is a carboxylic acid (--CO.sub.2H) or a
derivative or biostere thereof;
[0019] Ar.sup.2 is an optionally substituted aromatic or
heteroaromatic linking group;
[0020] L.sup.2 is a covalent bond or a linker atom or group;
[0021] R.sup.16 is the group
-L.sup.3(Alk.sup.2).sub.tL.sup.4R.sup.20 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, Alk.sup.2 is
an optionally substituted aliphatic or heteroaliphatic chain and
R.sup.20 is an optionally substituted aromatic or heteroaromatic
group;
[0022] g is zero or the integer 1, 2, 3, 4 or 5;
[0023] each R.sup.17 which may be the same or different is a
hydrogen or halogen atom or an optionally substituted straight or
branched alkyl, alkoxy, alkylthio or cycloalkyl aromatic or
heteroaromatic group or a thiol (--SH), hydroxyl (--OH), amino
(--NH.sub.2), --N(R.sup.3)(R.sup.4) [where R.sup.3 and R.sup.4 is
each independently a hydrogen atom or an optionally substituted
alkyl group or together with the N atom to which they are attached
R.sup.3 and R.sup.4 alkyl groups are joined to form a heterocyclic
ring which may be optionally interruped by a further --O-- or --S--
heteroatom or --N(R.sup.3)-- group], --CN, --CO.sub.2R.sup.3,
--NO2, --CON(R.sup.3)(R.sup.4), --CSN(R.sup.3)(R.sup.4),
--COR.sup.3, --N(R.sup.3)COR.sup.4, --N(R.sup.3)CSR.sup.4,
--SO.sub.2N(R.sup.3)(R.sup.- 4), --N(R.sup.3)SO.sub.2R.sup.4,
--N(R.sup.3)CON(R.sup.4)(R.sup.5) [where R.sup.5 is a hydrogen atom
or an optionally substituted alkyl group or together with the N
atom to which they are attached R.sup.4 and R.sup.5 alkyl groups
are joined to form a heterocyclic ring which may be optionally
interrupted by a further --O-- or --S-- heteroatom or --N(R.sup.3)
group] or --N(R.sup.3)SO.sub.2N(R.sup.4)(R.sup.5) group;
[0024] and the salts, solvates, hydrates and N-oxides thereof.
[0025] 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. In addition, compounds of formula (1)
may exist as tautomers, for example keto (CH.sub.2C.dbd.O)-enol
(CH.dbd.CHOH) tautomers. Formula (1) and the formulae hereinafter
are intended to represent all individual tautomers and mixtures
thereof, unless stated otherwise. Optionally substituted aromatic
and heteroaromatic groups represented by R.sup.20 in the group
-L.sup.3(Alk.sup.3).sub.tL.sup.4R.sup.20 include those optionally
substituted aromatic and heteroaromatic groups as described
hereinafter for the group R.sup.2, for example C.sub.6-12
monocyclic aromatic groups or C.sub.1-9 monocyclic heteroaromatic
groups. Optional substituents (R.sup.18) that may be present on
such aromatic and heteroaromatic groups include those optional
substituents as described hereinafter for R.sup.2 aromatic and
heteroaromatic groups.
[0026] 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 alkyl 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.
[0027] When R.sup.8 is present as an alkyl 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 or a C.sub.1-8cycloalkyl
group particularly a C.sub.3-6cycloalkyl group e.g. a cyclopropyl,
cyclobutyl, cyclopentyl or cyclohexyl group. Optional substituents
which may be present on such 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.
[0028] 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 chains described for Alk.sup.1 or
heteroaliphatic groups described for R.sup.2 in which one of the
terminal hydrogen atoms is replaced by a bond.
[0029] Examples of the substituent represented by
-L.sup.3(Alk.sup.2).sub.- tL.sup.4R.sup.20 which is present at the
3-position of the isoquinoline ring as the group R.sup.16 in
compounds of the invention include atoms or groups
-L.sup.3Alk.sup.2L.sup.4R.sup.20, -L.sup.3Alk.sup.2R.sup.20,
-L.sup.3R.sup.20, -R.sup.20 and -Alk.sup.2R.sup.20 wherein L.sup.3,
Alk.sup.2, L.sup.4 and R.sup.20 are as defined above. Particular
examples of such substituents include
-L.sup.3CH.sub.2L.sup.4R.sup.20,
-L.sup.3CH(CH.sub.3)L.sup.4R.sup.20, -L.sup.3
(CH.sub.2).sub.2L.sup.4R.su- p.20, -L.sup.3 CH.sub.2R.sup.20,
-L.sup.3CH(CH.sub.3)R.sup.20, -L.sup.3(CH.sub.2).sub.2R.sup.20,
--CH.sub.2R.sup.20, --CH(CH.sub.3)R.sup.20,
--(CH.sub.2).sub.2R.sup.20 and -R.sup.20 groups.
[0030] Particular examples of R.sup.20 optionally substituted
aromatic and heteroaromatic groups when present in the group
-L.sup.3(Alk.sup.3).sub.t- L.sup.4R.sup.20 include optionally
substituted phenyl, furyl, thienyl, triazolyl, imidazolyl, pyridyl,
pyrimidinyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl,
pyrazolyl and triazinyl groups.
[0031] Particular examples of R.sup.16 substituents represented by
-L.sup.3(Alk.sup.2).sub.tL.sup.4R.sup.20 in compounds of the
invention include optionally substitued phenyl, furyl, thienyl,
triazolyl, imidazolyl, pyridyl, pyrimidinyl, thiazolyl, oxazolyl,
isoxazolyl, isothiazolyl, pyrazolyl, triazinyl, benzyl,
furylmethyl, thienylmethyl, imidazolyl methyl, pyridylmethyl,
pyrimidinyl methyl, benzyloxy, furylmethyloxy, thienylmethyloxy,
imidazolylmethyloxy, pyridylmethyloxy, pyrimidinylmethyloxy,
phenyloxy, furyloxy, thienyloxy, pyridyloxy, pyrimidinyloxy,
phenyltio, furylthio, thienylthio, pyridylthio, pyrimidinylthio,
phyenylmethylthio, furylmethylthio, thienylmethylthio,
pyridylmethylthio, pyrimidinylmethylthio, phenylamino, furylamino,
thienylamino, pyridylamino. pyrimidinylamino, phenylmethylamino,
furylmethylamino, thienylmethylamino, pyridylmethylamiino,
pyrimidinylmethylamino, N-methylphenylmethylamino,
N-methylfurylmethylamino, N-methylthienylmethylamino,
N-methylpyridylmethylamino, N-methylpyridinylmethylamino,
phenylcarbonyl, furylcarbonyl, thienylcarbonyl, pyridylcarbonyl and
pyrimidinylcarbonyl groups.
[0032] When the substituent R.sup.17 is an optionally substituted
alkyl group it may be for example an optionally substituted
C.sub.1-6alkyl group, e.g. an optionally substituted methyl, ethyl,
propyl or isopropyl group. Optional substituents which may be
present on R.sup.17 alkyl groups include those optional
substituents as described in relation to R.sup.2 heteroaliphatic
chains hereinafter. Particular examples of optionally substituted
R.sup.17 alkyl groups include --CF.sub.3, --CHF.sub.2, --CH.sub.2F,
--CCl.sub.3, --CHCl.sub.2, --CH.sub.2Cl, --CH.sub.2OCH.sub.3 and
--CH.sub.2OCH.sub.2CH.sub.3 groups. When the substituent R.sup.17
is an optionally substituted alkoxy group it may be for example an
optionally substituted methoxy, ethoxy, propoxy or isopropoxy
group. Optional substituents that may be present include those just
described for R.sup.17 alkyl groups. Particular examples of
R.sup.17 optionally substituted alkoxy groups include --OCF.sub.3,
--OCHF.sub.2, --OCHF, --OCCl.sub.3, --OCHCl.sub.2, --OCH.sub.2Cl,
--OCH.sub.2OCH.sub.3 and --OCH.sub.2OCH.sub.2CH.sub.3 groups. When
R.sup.17 is an optionally substituted alkylthio group it may be for
example an optionally substituted methylthio, ethylthio or
isopropylthio group. Optional substituents which may be present
include those optional substituents as just described for R.sup.17
alkyl groups. When R.sup.17 is an optionally substituted cycloalkyl
group it may be for example an optionally substituted
C.sub.3-8cycloalkyl group, especialy a C.sub.3-6cycloalkyl group
e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Optional
substituents which may be present include those optional
substituents just described for R.sup.17 alkyl groups. When
R.sup.17 is an optionally substituted aromatic or heteroaromatic
group it may be any aromatic or heteroaromatic group as described
hereinafter for the group R.sup.2. Optional substituents which may
be present on R.sup.17 aromatic and heteroaromatic groups include
those optional substituents described for R.sup.2 aromatic and
heteroaromatic groups. Particular examples of optionally
substituted aromatic groups include optionally substituted phenyl,
furyl, thienyl, pyridyl and pyrimidinyl groups.
[0033] When R.sup.3, R.sup.4 and/or R.sup.5 is present in R.sup.17
groups as an optionally substituted alkyl group it may be any
optionally substituted alkyl group as previously described for
R.sup.8.
[0034] When the groups R.sup.3 and R.sup.4 or R.sup.4 and R.sup.5
are both optionally substituted alkyl groups e.g. optionally
substituted 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.3)-. Particular examples of such heterocyclic rings
include piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl,
imidazolidinyl and piperazinyl rings.
[0035] Where desired, two R.sup.17 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.
[0036] L.sup.2 when present in compounds of the invention may be a
linker atom or group L.sup.2aor 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, L.sup.2a is a covalent bond or a linker atom
or group as described above for L.sup.3 and L.sup.4, and y is zero
or the integer 1.
[0037] Optionally substituted aromatic or heteroaromatic linking
groups represented by Ar.sup.2 include those aromatic or
heteroaromatic groups described hereinafter in relation to R.sup.2
aromatic or heteroaromatic groups respectively where said groups
become divalent linking groups, for example phenylene, pyridinylene
or pyrimidinylene groups. The optional substituents which may be
present on these groups include one, two, three or four optional
substituents (R.sup.17a, R.sup.17b, R.sup.17c and R.sup.17d) where
said substituents include those R.sup.17 optional substituents
described hereinbefore.
[0038] When the group R is present 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.3R.sup.4 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] Esters (--CO.sub.2Alk.sup.7) and amide (--CONR.sup.3R.sup.4)
derivatives of the carboxylic acid group (--CO.sub.2H) in compounds
of formula (1) may advantageously be used as prodrugs of the active
compound. Such prodrugs are compounds which undergo
biotransformation to the corresponding carboxylic acid prior to
exhibiting their pharmacological effects and the invention
particularly extends to prodrugs of the acids of formula (1). Such
prodrugs are well known in the art, see for example International
Patent Application No. W000/23419, Bodor, N. (Alfred Benzon
Symposium, 1982, 17, 156-177), Singh, G. et al (J. Sci. Ind. Res.,
1996, 55, 497-510) and Bundgaard, H., (Design of Prodrugs, 1985,
Elsevier, Amsterdam).
[0040] Esterified carboxyl groups represented by the group
R.sup.13ainclude groups of formula --CO.sub.2Alk.sup.7 wherein
Alk.sup.7 is a straight or branched optionally substituted
C.sub.18alkyl group such as a methyl, ethyl, n-propyl, i-propyl,
n-butyl, i-butyl, s-butyl or t-butyl group; an optionally
substituted C.sub.2-8alkenyl group such as a propenyl e.g.
2-propenyl or butenyl e.g. 2-butenyl or 3-butenyl group, an
optionally substituted C.sub.2-8alkynyl group such as a ethynyl,
propynyl e.g. 2-propynyl or butynyl e.g. 2-butynyl or 3-butynyl
group, an optionally substituted C.sub.3-8cycloalkyl group such as
a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl
group; an optionally substituted C.sub.3-8cycloalkylC.sub.1-8alkyl
group such as a cyclopentylmethyl, cyclohexylmethyl or
cyclohexylethyl group; an optionally substituted
C.sub.3-8heterocycloalkylC.sub.1-6alkyl group such as a
morpholinyl-N-ethyl, thiomorpholinyl-N-methyl,
pyrrolidinyl-N-ethyl, pyrrolidinyl-N-propyl, piperidinyl-N-ethyl,
pyrazolidinyl-N-methyl or piperazinyl-N-ethyl group; an optionally
substituted C.sub.1-6alkyloxyC.sub.1-6alkyl group such as a
methyloxyethyl or propyloxyethyl group; an optionally substituted
C.sub.1-6alkylthioC.sub.1- -6alkyl group such as an ethylthioethyl
group; an optionally substituted
C.sub.1-6alkylsulfinylC.sub.1-6alkyl group such as an
methylsulfinylethyl group; an optionally substituted
C.sub.1-6alkylsulfonylC.sub.1-6alkyl group such as an
methylsulfonylmethyl group; an optionally substituted
C.sub.3-8cycloalkyloxyC.sub.1-6alkyl group such as a
cyclohexyloxy-methyl group; an optionally substituted
C.sub.3-8cycloalkylthioC.sub.1-6alkyl group such as a
cyclopentylthiomethyl group; an optionally substituted
C.sub.3-8cycloalkylsulfinylC.sub.1-6alkyl group such as a
cyclopentylsulfinylmethyl group; an optionally substituted
C.sub.3-8cycloalkylsulfonylC.sub.1-6alkyl group such as a
cyclopentylsulfonylmethyl group; an optionally substituted
C.sub.1-6alkyloxycarbonylC.sub.1-6alkyl group such as
isobutoxycarbonylpropyl group; an optionally substituted
C.sub.1-6alkyloxycarbonylC.sub.1-6alkenyl group such as
isobutoxycarbonylpentenyl group; an optionally substituted
C.sub.1-6alkyloxycarbonyloxyC.sub.1-6alkyl group such as an
isopropoxycarbonyloxyethyl e.g a 1-(isopropoxycarbonyloxy)ethyl,
2-(isopropoxycarbonyloxy)ethyl or ethyloxycarbonyloxymethyl group;
an optionally substituted
C.sub.1-6alkyloxycarbonyloxyC.sub.1-6alkenyl group such as a
isopropoxycarbonyloxybutenyl group, an optionally substituted
C.sub.3-8cycloalkyloxycarbonyloxyC.sub.1-6alkyl group such as a
cyclohexyloxycarbonyloxyethyl, e.g. a
2-(cyclohexyloxycarbonyloxy)ethyl group, an optionally substituted
N-di-C.sub.1-8alkylaminoC.sub.1-8alkyl group such as a
N-dimethylaminoethyl or N-diethylaminoethyl group; an optionally
substituted N-C.sub.6-12aryl-N-C.sub.1-6alkylaminoC.sub.1-6alk- yl
group such as a N-phenyl-N-methylaminomethyl group; an optionally
substituted N-di-C.sub.1-8alkylcarbamoylC.sub.1-8alkyl group such
as a N-diethylcarbamoyl-methyl group; an optionally substituted
C.sub.6-10arylC.sub.1-6alkyl group such as an optionally
substituted benzyl, phenylethyl, phenylpropyl, 1-naphthylmethyl or
2-naphthylmethyl group; a C.sub.6-10aryl group such as an
optionally substituted phenyl, 1-naphthyl or 2-naphthyl group; a
C.sub.6-10aryloxyC.sub.1-8alkyl group such as an optionally
substituted phenyloxymethyl, phenyloxyethyl, 1-naphthyloxymethyl,
or 2-naphthyloxymethyl group; a C.sub.6-12arylthioC.sub.1-8alkyl
group such as an optionally substituted phenylthioethyl group; a
C.sub.6-12arylsulfinylC.sub.1-8alkyl group such as an optionally
substituted phenylsulfinylmethyl group; a
C.sub.6-12arylsulfonylC.sub.1-8alkyl group such as an optionally
substituted phenylsulfonylmethyl group; an optionally substituted
C.sub.1-8alkanoyloxyC1-8alkyl group, such as a acetoxymethyl,
ethoxycarbonyloxyethyl, pivaloyloxymethyl, propionyloxyethyl or
propionyloxypropyl group; an optionally substituted
C.sub.4-8imidoC.sub.1-8alkyl group such as a succinimidomethyl or
phthalamidoethyl group; a C.sub.6-12aroyloxyC.sub.1-8alkyl group
such as an optionally substituted benzoyloxyethyl or
benzoyloxypropyl group or a triglyceride such as a 2-substituted
triglyceride e.g. a 1,3-di-C.sub.1-8alkylglycerol-2-yl group such
as a 1,3-diheptylglycerol-2-yl group. Optional substituents present
on the Alk.sup.7 group include R.sup.13a substituents described
above.
[0041] It will be appreciated that in the forgoing list of
Alk.sup.7 groups the point of attachment to the remainder of the
compound of formula (1) is via the last described part of the
Alk.sup.7 group. Thus, for example a methoxyethyl group would be
attached by the ethyl group, whilst a morpholinyl-N-ethyl group
would be attached via the N-ethyl group.
[0042] It will be further appreciated that in the forgoing list of
Alk.sup.7 groups, where not specifically mentioned, alkyl groups
may be replaced by alkenyl or alkynyl groups where such groups are
as previously defined for Alk.sup.1. Additionally these alkyl,
alkenyl or alkynyl groups may optionally be interrupted by one, two
or three linker atoms or groups where such linker atoms and groups
are as previously defined for L.sup.3.
[0043] When the group R.sup.1 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.
[0044] 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.
[0045] 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.
[0046] 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
--(CH2).sub.2CCH-- groups.
[0047] Heteroaliphatic groups represented by the group R.sup.2 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.3CH.sub.3
and --(CH.sub.2).sub.2L.sup.5CH.sub.2CH.sub.3 groups.
[0048] The optional substituents which may be present on aliphatic
chains or heteroaliphatic groups represented by Alk.sup.1 and
R.sup.2 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
alkyl group as defined above for R.sup.8, --CONHR.sup.9,
--CON(R.sup.9).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.
[0049] Optionally substituted cycloaliphatic groups represented by
the group R.sup.2 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.
[0050] Optionally substituted heterocycloaliphatic groups
represented by the group R.sup.2 include optionally substituted
C.sub.3-10heterocycloali- phatic groups. Particular examples
include optionally substituted C.sub.3-10heterocycloalkyl, e.g.
C.sub.3-7heterocycloalkyl, or C.sub.3-10heterocycloalkenyl, e.g.
C.sub.3-7hetercycloalkenyl groups, each of said groups containing
one, two, three or four heteroatoms or heteroatom-containing groups
L.sup.5 as defined above.
[0051] Optionally substituted polycycloaliphatic groups represented
by the group R.sup.2 include optionally substitued C.sub.7-10 bi-
or tricycloalkyl or C.sub.7-10 bi- or tricycloalkenyl groups.
Optionally substituted heteropolycycloaliphatic groups represented
by the group R.sup.2 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.
[0052] Particular examples of cycloaliphatic, polycycloaliphatic,
heterocycloaliphatic and heteropolycycloaliphatic groups
represented by the group R.sup.2 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,
homopiperidinyl, heptamethyleneiminyl, piperidinone, 1,4-dioxanyl,
morpholinyl, morpholinone, 1,4-dithianyl, thiomorpholinyl,
piperazinyl, homopiperazinyl. 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.
[0053] The optional substituents which may be present on the
cycloaliphatic, polycycloaliphatic, heterocycloaliphatic or
heteropolycycloaliphatic groups represented by the group R.sup.2
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.11, --N(R.sup.11)CSR.sup.11,
--SO.sub.2N(R.sup.11).s- ub.2, --N(R.sup.11)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 Additionally, when the
group R.sup.2 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,
heteropolycycloaliphatic, aromatic or heteroaromatic group.
[0054] Optionally substituted aliphatic or heteroaliphatic chains
represented by Alk.sup.5 include those optionally substituted
chains described above for Alk.sup.2.
[0055] Cycloaliphatic, heterocycloaliphatic, polycycloaliphatic or
heteropolycyclo-aliphatic groups represented by R.sup.12 include
those groups just described for the group R.sup.2. Optional
substituents which may be present on these groups include those
described above in relation to Alk.sup.1 and R.sup.2 aliphatic and
heteroaliphatic chains. Optionally substituted aromatic or
heteroaromatic groups represented by R.sup.12 include those
optionally substituted R.sup.2 aromatic and heteroaromatic groups
as described hereinafter.
[0056] Optionally substituted aromatic groups represented by
R.sup.2 include for example optionally substituted monocyclic or
bicyclic fused ring C.sub.6-12aromatic groups, such as phenyl, 1-
or 2-naphthyl, 1- or 2-tetrahydronaphthyl, indanyl or indenyl
groups.
[0057] Optionally substituted heteroaromatic groups represented by
the group R.sup.2 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.
[0058] Particular examples of heteroaromatic groups of these types
include pyrrolyl, furyl, thienyl, imidazolyl,
N-C.sub.1-6alkylimidazolyl, 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, quinoxalinyl, 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.
[0059] Optional substituents which may be present on the aromatic
or heteroaromatic groups represented by the group R.sup.2 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
-Alk6(R.sup.13a)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)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].sub.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).sub.2, --N(R.sup.11 )CSNH.sub.2, --N(R.sup.11
)CSNHR.sup.14, --N(R.sup.1 1)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.1 1)Het.sup.2,
--N(R.sup.11)CSN(R.sup.1 1)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)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.
[0060] When in the group -Alk.sup.6(R.sup.13a)m m is an integer 1,
2 or 3, it is to be understood that the substituent or substituents
R.sup.13amay 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.
[0061] 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.14).sub.2 wherein each R.sup.14 group is the
same or different.
[0062] When R.sup.13a is a halogen atom it may be for example a
fluorine, chlorine, bromine, or iodine atom.
[0063] 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(=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 where Alk.sup.7 is a group as
defined hereinbefore.
[0064] 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.
[0065] 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.3-10heterocycloaliphatic groups described above for
R.sup.2.
[0066] 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.1-9heteroaromatic groups
as described above for the group R.sup.2. 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.
[0067] 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 optional
substituents described hereinbefore for R.sup.2
heterocycloaliphatic groups.
[0068] 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.1-6alkyl, 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.1-6 alkylamino, e.g.
3-morpholinopropylamino, C.sub.1-6alkylaminoC.sub.1-6alkyl, e.g.
ethylaminoethyl, C.sub.1-6dialkyl-aminoC.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 propylsuilphonyl, 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.sup.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, Cl 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.1-6 dialkylaminoC.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.
[0069] 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.
[0070] 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.2.
[0071] 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.
[0072] 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.
[0073] 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.
[0074] Particularly useful salts of compounds according to the
invention include pharmaceutically acceptable salts, especially
acid addition pharmaceutically acceptable salts.
[0075] In compounds according to the invention the group R.sup.16
is a L.sup.3(Alk.sup.2).sub.tL.sup.4R.sup.20 group. In compounds of
this type R.sup.20 is preferably an optionally substituted aromatic
group such as an optionally substituted phenyl group or an
optionally substituted monocyclic hetero-aromatic group.
Particularly useful monocyclic heteroaromatic groups are optionally
substituted five- or six-membered heteroaromatic groups as
previously described, especially five- or six-membered
heteroaromatic groups containing one, two, three or four
heteroatoms selected from oxygen, sulphur or nitrogen atoms.
Patrticularly useful optional substituents that may be present on
these R.sup.20 groups include halogen atoms or optionally
substituted alkyl, alkoxy, alkylthio, --NR.sup.3R.sup.4, --CN,
--CO.sub.2R.sup.3, --COR.sup.3 or --N(R.sup.3)COR.sup.4 groups, as
described above in relation to the compounds of formula (1).
[0076] A particularly useful group of compounds according to the
invention has the formula (2): 5
[0077] wherein R.sup.17a and R.sup.17b is each a hydrogen atom or
an optional substituent as previously defined for R.sup.17;
R.sup.16, R.sup.17, g, L.sup.1, L.sup.2, Ar.sup.2, Alk, R.sup.1,
Alk.sup.1, n and R.sup.2 are as defined for formula (1); and the
salts, solvates, hydrates and N-oxides thereof.
[0078] Particularly useful optionally substituted monocyclic
heteroaromatic groups represented by R.sup.20 in the group R.sup.16
include optionally substituted furyl, thienyl, imidazolyl, pyridyl
and pyrimidinyl groups. Most especially useful R.sup.20 aromatic
groups include optionally substituted phenyl groups and most
especially useful R.sup.20 monocyclic heteroaromatic groups include
thienyl and pyridyl groups.
[0079] In one preferred class of compounds of formula (2) R.sup.16
is the group -L.sup.3(Alk.sup.2).sub.tL.sup.4R.sup.20 in which
R.sup.20 is preferably a group as just defined, L.sup.3 is
preferably an --O-- or --S-- atom or a --C(O)-- or --N(R.sup.8)--
group in which R.sup.8 is preferably a hydrogen atom or a methyl
group, t is the integer 1 and Alk.sup.2 is preferably an optionally
substituted aliphatic chain, most preferably an optionally
substitued C.sub.1-6alkylene chain, especially an optionally
substituted --CH.sub.2--, --(CH.sub.2).sub.2- or
--CH(CH.sub.3)CH.sub.2- chain , and L.sup.4 is preferably a
covalent bond.
[0080] In another preferred class of compounds of formula (2)
R.sup.16 is the group -L.sup.3(Alk.sup.2).sub.tL.sup.4R.sup.20 in
which R.sup.20 is preferably a group as just defined, t is zero and
L.sup.3 and L.sup.4 is each a covalent bond.
[0081] Most particularly useful optional substituents which may be
present on R.sup.20 aromatic and heteroaromatic grops include
halogen atoms, especially fluorine and chlorine atoms, and
C.sub.16alkyl groups, especially methyl, ethyl and i-propyl groups
and --CF.sub.3 --OCH.sub.3 --OCH.sub.2CH.sub.3,
--OCH(CH.sub.3).sub.2, --OCF.sub.3, --SCH.sub.3, --NHCH.sub.3,
--N(CH.sub.3).sub.2, --CN, --CO.sub.2CH.sub.3, --COCH.sub.3 and
--N(CH.sub.3)COCH.sub.3 groups.
[0082] Alk in compounds of the invention is preferably: 6
[0083] or, especially, --CH.sub.2CH(R)-.
[0084] In one prefered class of compounds of formulae (1) and (2) R
is a --CO.sub.2H group.
[0085] In another prefered class of compounds of formulae (1) and
(2) R is an esterified carboxyl group of formula
--CO.sub.2Alk.sup.7. In this class of compound Alk.sup.7 is
preferably a C.sub.1-8alkyl group, especially a methyl, ethyl,
propyl or i-propyl group, an optionally substituted C.sub.6-10aryl
group, especially a phenyl group, an optionally substituted
C.sub.6-10arylC1-6alkyl group, especially a benzyl group, a
C.sub.3-8heterocycloalkylC.sub.1-6alkyl group, especially a
morpholinyl-N-ethyl group or a C.sub.1-6alkyloxyC.sub.1-6alkyl
group, especially a methyloxyethyl group. Especially preferred
esterified carboxyl groups include --CO.sub.2CH.sub.3,
--CO.sub.2CH.sub.2CH.sub.3, --CO.sub.2CH.sub.2CH.sub.2CH.sub.3 and
--CO.sub.2CH(CH.sub.3).sub.2 groups.
[0086] In general in compounds of formulae (1) and (2) R.sup.1 is
preferably a hydrogen atom.
[0087] In general in compounds of formulae (1) and (2) L.sup.2 is
preferably L2a where L.sup.2a is a --O-- atom or --N(R.sup.8)--
group in which R.sup.8 is preferably a hydrogen atom or methyl
group. An especially useful --N(R.sup.8)-- group is --NH--.
[0088] In general in compounds of formula (2) R.sup.17, R.sup.17a
and R.sup.17b when present as an optional substituent is each
preferably a halogen atom, especially a fluorine or chlorine atom
or an C.sub.1-6alkyl group, especially methyl, ethyl, propyl or
isopropyl group, a haloC.sub.1-6alkyl group, especially --CF.sub.3,
a C.sub.1-6alkoxy group, especially a methoxy, ethoxy, propoxy or
isopropoxy group a haloC.sub.1-6alkoxy group, especially a
trifluoromethoxy or difluoromethoxy group, --CN, --COR.sup.3,
especially --COCH.sub.3, a C.sub.1-6alkylthio group especially a
methylthio or ethylthio group, a C.sub.3-8cycloalkyl group,
especially a cyclopentyl or cyclohexyl group or a
C.sub.1-6alkylenedioxy group, especially a methylenedioxy or
ethylenedioxy group.
[0089] In one preferred class of compounds of formula (2) g is
zero.
[0090] In another preferred class of compounds of formula (2) g is
the integer 1 and 2.
[0091] In general in compounds of formulae (1) and (2) when n is
zero or the integer 1 the group R.sup.2 may especially be 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 cyclopropyl or cyclohexyl, optionally
substituted C.sub.5-7heterocycloaliphatic, especially optionally
substituted pyrrolidinyl or thiazolidinyl, especially optionally
substituted phenyl and optionally substituted
C.sub.5-7heteroaromatic, especially optionally substituted pyridyl
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 -(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, thiazolidinyl pyrrolidinoyl, piperidinyl,
homopiperidinyl, heptamethyleneiminyl, morpholinyl, piperazinyl or
homopiperazinyl 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. 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.
[0092] In one preferred class of compounds of formulae (1) and (2)
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.2 in this class of compounds is
preferably a hydrogen atom.
[0093] In another preferred class of compounds of formulae (1) and
(2) 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--, --CH(CH.sub.3)CH.sub.2-- and
especially --C(CH.sub.3).sub.2CH.sub.2-- chains. R.sup.2 in this
class of compounds is preferably a hydrogen atom. A most especially
useful optionally substituted Alk.sup.1R.sup.2 group is
--C(CH.sub.3).sub.3.
[0094] In another preferred class of compounds of formulae (1) and
(2), L.sup.1 is a covalent bond, n is zero and R.sup.2 is an
optionally substituted C.sub.5-7heterocycloaliphatic group.
Especially useful C.sub.5-7heterocycloaliphatic groups include
optionally substituted piperidinyl, homopiperidinyl,
heptamethyleneiminyl, pyrrolidinyl, piperazinyl, homopiperazinyl,
morpholinyl and thiomorpholinyl groups. Most preferred
C.sub.5-7heterocycloaliphatic groups are those linked via a ring
nitrogen atom to the remainder of the compund of formulae (1) or
(2). Most especially useful C.sub.5-7heterocycloaliphatic groups
include optionally substituted pyrolidin-1-yl, piperidin-1-yl and
homopiperidin-1-yl groups. Especially useful optional substituents
on these C.sub.5-7heterocycloaliphatic groups include optionally
substituted C.sub.1-6alkyl groups, especially methyl, ethyl or
i-propyl groups. Most preferred optionally substituted
C.sub.5-7heterocycloaliphatic groups include
2-methylpyrrolidin-1-yl, cis and trans 2,5-dimethylpyrrolidin-1-y-
l, 2-methylpiperidin-yl and 2,6-dimethylpiperidin-1-yl,
homopiperidin-1-yl, 2-methylhomopiperidin-1 -yl and cis and trans
2,7-dimethylhomopiperidin-1 -yl groups.
[0095] Particularly useful compounds of the invention include:
[0096] (S)-2-[(2-N ,N-Diethylamino-3,4-dioxo-1
-cyclobutenyl)amino]-3-{4-[- 3-phenyl- 1
-isoquinolinylamino]phenyl}propanoic acid
[0097] (S)-2-[2-(2,5-Dimethylpyrrolidin-1 -yl)-3,4-dioxo- 1
-cyclobutenyl)amino]-3-{4-[3-phenyl- 1
-isoquinolinylamino]phenyl}propano- ic acid
[0098] (S)-2-[(2-(2,5-Dimethypyrrolidin-1 -yl)-3,4-dioxo-1
-cyclobutenyl)amino]-3-[4-(3-(4-fluorophenyl)isoquinolin-1-ylamino)phenyl-
]propanoic acid
[0099] (S)-3-[4-(3-Phenyl- 1
-isoquinolinylamino)phenyl]-2-[(2-N-isopropyl-
-N-ethylamino-3,4-dioxocyclobut-1-enyl)amino]propanoic acid;
[0100] (S)-3-[4-(3-Phenyl-1
-isoquinolinylamino)phenyl]-2-[(2-azepan- 1 -yl-3,4-dioxocyclobut-1
-enyl)amino]propanoic acid;
[0101] and the salts, solvates, hydrates, N-oxides and carboxylic
acid ester, particularly methyl, ethyl, propyl and i-propyl esters
thereof.
[0102] Compounds according to the inventions are potent and
selective inhibitors of .alpha.4 integrins and have advantageous
clearance properties, especially those compounds where R is a
carboxylic ester or amide. The ability of the compounds to act in
this way may be simply determined by employing tests such as those
described in the Examples hereinafter.
[0103] The compounds are of use in modulating cell adhesion and in
particular are of use in the prophylaxis and treatment of diseases
or disorders involving inflammation in which the extravasation of
leukocytes plays a role and the invention extends to such a use and
to the use of the compounds for the manufacture of a medicament for
treating such diseases or disorders.
[0104] 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.
[0105] 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.
[0106] 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.
[0107] 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.
[0108] Preparations for oral administration may be suitably
formulated to give controlled release of the active compound.
[0109] For buccal administration the compositions may take the form
of tablets or lozenges formulated in conventional manner.
[0110] The compounds for 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.
[0111] 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.
[0112] 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.
[0113] 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.
[0114] 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 100mg/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.
[0115] 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.2, Alk, R.sup.1, R.sup.2, 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.
[0116] 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,
1999]. 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).
[0117] 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): 7
[0118] Where Ar.sup.1 represents a group: 8
[0119] in which b signifies the point of attachment to the
remainder of the compound of formula (3); and Alk represents a
group --CH.sub.2CH(CO.sub.2R.sup.y)--,
--CH.dbd.CH(CO.sub.2R.sup.y)--, 9
[0120] [where R.sup.y is an alkyl group for example a
C.sub.1-6alkyl group]
[0121] The hydrolysis may be performed using either an acid or a
base depending on the nature of RY, 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.
[0122] 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
[0123] where R.sup.a is a leaving group, with an amine
Ar.sup.1L.sup.2Ar.sup.2AIkN(R.sup.1)H 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.
[0124] 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
Ar.sup.1L.sup.2Ar.sup.2AlkN(R.sup.1)H is used, an organic base such
as diisopropyl-ethylamine can be added.
[0125] Any carboxylic acid group present in the intermediate of
formula (4) or the amine Ar.sup.1L.sup.2Ar.sup.2AlkN(R.sup.1)H 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.
[0126] It will be appreciated that the displacement reaction may
also be performed on a compound of formula (5): 11
[0127] where R.sup.b is a leaving group as defined for R.sup.a
using an intermediate R.sup.2(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.
[0128] Where desired the displacement reaction may also be
performed on an intermediate of formulae (4) or (5), Ar.sup.1
L.sup.2Ar.sup.2AlkN(R.sup.1- )H or R.sup.2(Alk.sup.1).sub.nL.sup.1H
which is linked, for example via its Ar.sup.1 or R.sup.2 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.
[0129] Intermediates of formulae (4) and (5) are either readily
available or may be prepared from an intermediate of formula (6):
12
[0130] where R.sup.a and R.sup.b are as previously defined and an
amine Ar.sup.1L.sup.2Ar.sup.2AlkN(R.sup.1)H or
R.sup.2(Alk.sup.1).sub.nN(R.sup.- 8)H by displacement as just
described for the preparation of compounds of formula (1).
[0131] Intermediates of formulae Ar.sup.1
L.sup.2Ar.sup.2AlkN(R.sup.1)H and
R.sup.2(Alk.sup.1).sub.nN(R.sup.8)H 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.
[0132] 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.2(Alk.sup.1)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.
[0133] 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.
[0134] Intermediates of formula Ar.sup.1X.sup.1 and
R.sup.2(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 Ar.sup.1 represents a 3-substituted
isoquinolin-1-yl group may be prepared from alcohols of formula
Ar.sup.1 OH by reaction with a halogenating agent, for example a
phosphorous oxyhalide such as phosphorous oxychloride at an
elevated temperature e.g. 110.degree. C. Intermediate alcohols of
formula Ar.sup.1 OH in which Ar.sup.1 represents a 3-substituted
isoquinolin-1-yl group may be prepared by methods well known to a
person skilled in the art, e.g. by the methods of Wu M.-J. et al
Tetrahedron, 55, 13193-200 (1999), Hiebl J. et al Tetrahedron Lett.
40, 7935-8 (1999), Nagarajan A. et al Indian J. Chem., Sect. B,
28B, 67-78 (1989), Brun E. M. et al Synlett, 7, 1088-90 (1999) and
Brun, E. M. et al Synthesis, 273-280 (2000).
[0135] In a further example intermediates of formula Ar.sup.1
L.sup.2Ar.sup.2AlkN(R.sup.1)H may be obtained by reaction of a
compound of formula Ar.sup.1 L.sup.2H with a compound of formula
X.sup.1Ar.sup.2AlkN(R.sup.1)H under the reaction conditions just
described Compounds of formula Ar.sup.1 L.sup.2H in which, for
example Ar.sup.1 represents a 3-substituted isoquinolin-1-yl group
and L.sup.2 is a --N(R.sup.8)-- group, may be prepared by the
methods of Bordner, J. et al J. Med. Chem. 31, 1036-9 (1988), Tovar
J. D. et al J. Org. Chem., 64, 6499-6504 (1999), Karser E. M. et al
Synetheis, 11, 805-6 (1974), and Molino, P et al J. Chem. Soc.
Perkin Trans. 1 1727-31 (1990).
[0136] In another example, compounds containing a -L.sup.1 H 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.2or
--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-methyl-morpholine, 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
[0137] 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.
[0138] 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. In a
further example, ester groups --CO.sub.2R.sup.3, --CO.sub.2R.sup.11
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.3, R.sup.11
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.
[0139] 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.
[0140] 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.2R.sup.3 or
CO.sub.2R.sup.11] 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.
[0141] 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.14OH in a solvent such
as tetrahydrofuran in the presence of a phosphine, e.g.
triphenylphosphine and an activator such as diethyl-, diisopropyl-,
or dimethylazodicarboxylate.
[0142] Aminosulphonylamino [--NHSO.sub.2NHR.sup.2 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.2NHSO.sub.2NH.sub.2 or
Ar.sup.1NHSO.sub.2NH.sub.2 in the presence of an organic base such
as pyridine at an elevated temperature, e.g. the reflux
temperature.
[0143] In another example compounds containing a --NHCSAr.sup.1,
--CSNHAr.sup.1, --NHCSR.sup.2 or --CSNHR.sup.2 may be prepared by
treating a corrsponding compound containing a --NHCOAr.sup.1,
--CONHAr.sup.1, --NHCOR.sup.2 or --CONHR.sup.2 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.
[0144] 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.
[0145] 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.
[0146] 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.
[0147] 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.
[0148] 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.
[0149] 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 Ar.sup.1L.sup.2Ar.sup.2AlkN(R.sup.1)H- , using
such well know and commonly used palladium mediated reaction
conditions as are to be found in the general reference texts Rodd's
Chemistry of Carbon Compounds, Volumes 1-15 and Supplementals
(Elsevier Science Publishers, 1989), Fieser and Fieser's Reagents
for Organic Synthesis, Volumes 1-19 (John Wiley and Sons, 1999),
Comprehensive Heterocyclic Chemistry, Ed. Katritzky et al, Volumes
1-8, 1984 and Volumes 1-11, 1994 (Pergamon), Comprehensive Organic
Functional Group Transformations, Ed. Katritzky et al, Volumes 1-7,
1995 (Pergamon), Comprehensive Organic Synethesis, Ed. Trost and
Flemming, Volumes 1-9, (Pergamon, 1991), Encyclopedia of Reagents
for Organic Synthesis, Ed. Paquette, Volumes 1-8 (John Wiley and
Sons, 1995), Larock's Comprehensive Organic Transformations (VCH
Publishers Inc., 1989) and March's Advanced Organic Chemistry (John
Wiley and Sons, 1992).
[0150] 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.
[0151] 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.
[0152] 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.
[0153] 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.
[0154] 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.
[0155] 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.
[0156] 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-fluorenylmethoxycarbonyl; TFA -
trifluoroacetic acid;
[0157] All NMR's were obtained at 300MHz, unless otherwise
indicated.
INTERMEDIATE 1
3-Phenylisoguinolone
[0158] o-Toluic acid (5g, 36.7mmol) in THF (120 ml) was cooled to
-78.degree.and sec-BuLi (56.5 ml, 1.3M in cyclohexanes) added
slowly. The solution was warmed to 0.degree. for 0.5 h then cooled
to -78.degree. and benzonitrile (3.75 ml) in THF (20 ml) added. The
reaction mixture was allowed to warm to RT and stirred for 16 h
then water (150 ml) was added to give a white precipitate which was
isolated by filtration and dried to give the title compound (3.68
g, 45%) as a white solid. .delta.H (CDCl.sub.3) 10.34 (1H, br s),
8.41 (1H, d, J 8.0Hz), 7.76 (2H, d, J 8.3Hz), 7.67 (1H, t, J
8.0Hz), 7.60 (1 H, d, J 7.0Hz), 7.48 (4H, m) 6.80 (1H, s). m/z
(ES+, 70V) 222 (MH+).
INTERMEDIATE 2
1-Chloro-3-Phenylisoquinoline
[0159] Intermediate 1 (3.68 g 16.7 mmol) was dissolved in
phosphorus oxychloride (10 ml) and heated at 80.degree. for 2.5 h.
The solution was cooled and concentrated, the residue dissolved in
DCM and washed with ice cold aqueous NaHCO.sub.3, water, dried
(NaSO.sub.4), concentrated in vacuo to give the title compound
(3.71 g, 93%) which was used directly in the next reaction.
.delta.H (CDCI.sub.3) 8.34 (1H, d, J 8.4Hz), 8.10 (2H, d, J 8.5Hz),
8.01 (1H, s), 7.89 (1H, d, J 8.5Hz), 7.76 (1H, t, J 8.5Hz), 7.67
(1H, t, J 8.5Hz), 7.51 (3H, m). mL/Z (ES+, 70V) 240 (MH+).
INTERMEDIATE 3
1-Chloro-3-(4-fluorophenyl)isoquinoline
[0160] Prepared in a similar manner to the compound of Intermediate
2. .delta.H (DMSO-d.sup.6) 8.52 (1H, s), 8.31-8.24 (3H, m), 8.14
(1H, d, J 8.2Hz), 7.93 (1H, dt, J 7.0, 1.1Hz), 7.83 (1H, d, J 7.0,
1.1Hz), 7.40 (2H, t, J 8.9Hz), m/z (ES+, 70V) 271 (MH+).
EXAMPLE 1
Ethyl
(S)-2-[(2-isopropoxy-3,4-dioxo-1-cyclobutenylamino]-3-{4-[3-phenyl-1-
-isoquinolinylamino]phenyl}propanoate
[0161] Ethyl
(S)-[(tert-butoxycarbonyl)amino]-3-(4-aminophenyl)propanoate (926
mg, 3.0 mmol) and Intermediate 2 (800 mg, 3.3 mmol) in
2-ethoxy-ethanol were heated at 120.degree. for 4.5 h. The solution
was cooled, concentrated then dissolved in EtOAc and MeOH and an
excess of HCI(g) bubbled through. After 30 min the solvent was
removed and the precipitate filtered and washed with EtOAc. The
precipitate was dissolved in MeOH and treated with
3,4-diisopropoxy-3-cyclobuten-1,2-dione (407 mg, 1.5 mmol) and
DIPEA (0.8 ml) and stirred for 16 h. The mixture was concentrated,
dissolved in DCM, washed with water, dried (Na.sub.2SO.sub.4),
concentrated and purified by chromatography (SiO.sub.2; 2%
MeOH/DCM) to give the title compound (1.02 g, 84%) as a brown oil.
.delta.H (DMSO-d.sup.6, 350K) 9.03 (1H, s), 8.77 (1H, m), 8.51 (1H,
d, J 8.3Hz), 8.13 (2H, d, J 8.5Hz), 7.96 (2H, m), 7.89 (1H, d, J
8.3Hz), 7.75 (1 H, s), 7.71 (1H, t, J 8.3Hz), 7.59 (1H, t, J
8.3Hz), 7.48 (2H, t, J 7.3Hz), 7.39 (1 H, t, J 7.3Hz), 7.26 (2H, d,
J 8.6Hz), 5.22 (1H, m), 4.65 (1H, m), 4.19 (2H, q, J 7.1Hz), 3.25
(1H, dd, J 14.2, 5.0Hz), 3.06 (1H, dd, J 14.0, 9.7Hz), 1.36 (6H, d,
J 6.2Hz), 1.24 (3H, t, J 7.1Hz). mLz (ES+, 70V) 550 (MH+).
EXAMPLE 2
Methyl
(S)-2-[2-N,N-diethylamino-3,4-dioxo-1-cyclobutenyl)amino]-3-{4-[3-p-
henyl-1-isoquinolinylamino]phenyl}propanoate
[0162] The compound of Example 1 (500 mg, 0.91 mmol) in MeOH (4 ml)
was treated with diethylamine (0.19 ml) and stirred for 16 h. The
solvent was removed and the residue dissolved in DCM, washed with
water, dried (Na.sub.2SO.sub.4), concentrated and the crude product
purified by chromatography (SiO.sub.2; DCM/MeOH 100:1) to give the
title compound (422 mg, 85%) as a brown oil. 8H (DMSO-d.sup.6,
350K) 9.01 (1H, s), 8.51(1H, d, J 7.0Hz), 8.14 (2H, d, J 7.0Hz),
7.92 (2H, d, J 8.6Hz), 7.90 (1H, m), 7.74 (1H, s), 7.73 (1H, t, J
7.0Hz), 7.58 (1H, t, J 7.0Hz), 7.47 (2H, t, J 6.0Hz), 7.37 (1H, m),
7.26 (2H, d, J 8.6Hz), 5.29 (1H, m), 3.74 ( 3H, s), 3.55 (4H, m),
3.27 (1H, dd, J 14.1, 5.1Hz), 3.11 (1H, dd, J 14.1, 9.8Hz), 1.14
(6H, t, J 7.1Hz). m/z (ES+, 70V) 549 (MH+).
EXAMPLE 3
(S)-2-[(2-N,N-Diethylamino-3.4-dioxo-1-cyclobutenyl)amino]-3-{4-[-3-phenyl-
-1-isoquinolinylamino]phenyl}propanoic acid
[0163] The compound of Example 2 (422 mg, 0.77 mmol) was dissolved
in THF (2 ml) and water (2 ml) and treated with lithium hydroxide
(49 mg) and stirred for 4 h. The solvent was removed and the
residue purified by chromatography (SiO.sub.2;
DCM/MeOH/AcOH/H.sub.2O 200:20:3:2) to give the title compound (275
mg, 67%) as a pale brown oil. .delta.H (DMSO-d.sup.6, 350K) 9.00
(1H, s), 8.51 (1H, dd, J 8.4, 0.7Hz), 8.14 (2H, dd, J 7.4, 0.7Hz),
7.92 (1H, m), 7.90 (2H, d, J 8.6Hz), 7.74 (1H, s), 7.70 (1, t, J
7.4Hz), 7.58 (1H, t, J 7.4Hz), 7.49 (2H, t, J 7.4Hz), 7.39 (1 H, t,
J 7.4Hz), 7.27 (2H, d, J 8.6Hz), 7.27 (2H, d, J 8.6Hz), 5.16 (1H,
m), 3.54 (4H, m), 3.27 (1H, dd, J 14.0, 4.6Hz), 3.08 (1H, dd, J
14.0, 9.8Hz), 1.14 (6H, t, J 7.1Hz). m/z (ES+, 70V), 535 (MH+).
EXAMPLE 4
Methyl (S)-2-[(2-N.N-dipropylamino-3,4-dioxo-1-cyclobutenyl)
amino]-3-{4-[3-phenyl-1-isoquinolinylamino]phenyl}propanoate
[0164] Prepared in a similar manner to that described for Example 2
starting from the compound of Example 1 and dipropylamine. .delta.H
(DMSO-d.sup.6, 350K) 9.01 (1H, s), 8.52 (1H, d, J 8.6Hz), 8.14 (2H,
d, J 7.0Hz), 7.93 (4H, m), 7.74 (1H, s), 7.70 (1H, td, J 7.0,
1.1Hz), 7.56 (1H, m), 7.37 (1H, m), 7.32 (1H, d, J 8.9Hz), 7.25
(2H, d, J 8.5Hz), 5.28 (1H, m), 3.75 (3H, s), 3.46 (4H, m), 3.28
(1H, dd, J 14.1, 5.0Hz), 3.11 (1H, dd, J 14.1, 9.8Hz), 1.53 (4H, q,
J 7.3Hz), 0.84 (6H, t, J 7.3Hz). m/z (ES+, 70V) 577 (MH+).
EXAMPLE 5
(S)-2-[(2-N.N-Dipropylamino-3,4-dioxo-1-cyclobutenyl)amino]-3-{4-[3-phenyl-
-1-isoquinolinylamino]phenyl}propanoic acid
[0165] Prepared in a similar manner to that described for the
compound of Example 3 from the compound of Example 4 to give the
title compound. 6H (DMSO-d.sup.6, 350K) 9.00 (1H, s), 8.51 (2H, d,
J 8.4Hz), 8.12 (2H, d, J 7.2Hz), 7.93 (2H, m), 7.74 (1H, s), 7.70
(1H, td, J 6.9,1.1 Hz), 7.59 (1H, t, J 6.9Hz), 7.48 (2H, t, J
7.3Hz), 7.39 (1H, t, J 7.3Hz), 7.25 (2H, d, J 8.4Hz), 7.21 (1H, d,
J 8.9Hz), 5.17 (1H, m), 3.43 (4H, m), 3.27 (1H, dd, J 14.2, 4.7Hz),
3.10 (1H, dd, J 14.2, 9.0Hz), 1.56 (2H, sextet, J 7.5Hz), 1.54 (2H,
sextet, J 7.5Hz), 0.83 (6H, t, J 7.5Hz). m/z (ES+, 70V) 563
(MH+).
EXAMPLE 6
Methyl
(S)-2-[2-(2,5-dimethylpyrrolidin-1-yl)3,4-dioxo-1-cyclobutenyl)
amino]-3-{4-[(-phenyl-1-isoquinolinylamino]phenyl}propanoate
[0166] Prepared in a similar manner to that described for Example 2
from the compound of Example 1 and 2,5-dimethyl pyrrolidine to give
the title compound as an orange oil. .delta.H (DMSO-d.sup.6) 9.22
(1H, s), 8.53 (1H, d, J 8.3Hz), 8.15 (2H, d, J 8.3Hz), 7.92 (3H,
m), 7.80 (1H, s), 7.72 (2H, m), 7.63 (1H, m), 7.53 (2H, m), 7.47
(1H, m), 7.27 (2H, d, J 8.5Hz), 5.23 (1H, m), 4.19 (2H, m), 3.73
(3H, s), 3.26 (1H, dd, J 14.1, 4.3Hz), 3.06 (1H, dd, J 14.1,
11.0Hz), 2.05 (2H, m,), 1.66 (2H, m), 1.22 (3H, d, J 6.3Hz), 1.21
(3H, d, J 6.3Hz). m/z (ES+, 70V) 575 (MH+).
EXAMPLE 7
(S)-2-[2-(2,5-Dimethylpyrrolidin-1-yl)-3,4-dioxo-1-cyclobutenyl)amino]-3-{-
4-[3-phenyl-1-isoguinolinylamino]phenyl}propanoic acid
[0167] Prepared in a similar manner to that described for Example 3
from the compound of Example 6 to give the title compound as a
yellow glassy solid. .delta.H (DMSO-d.sup.6, 340K) 9.04 (1H, s),
8.52 (1H, d, J 8.3Hz), 8.13 (2H, d, J 8.5Hz), 7.90 (3H, m), 7.74
(1H, s), 7.71 (1H, m), 7.58 (1H, m), 7.49 (2H, m), 7.39 (1H, m),
7.26 (2H, d, J 8.5Hz), 7.17 (1H, m), 5.07 (1H, m), 4.19 (2H, m),
3.26 (1H, dd, J 14.0, 4.7Hz), 3.12 (1H, dd, J 14.0, 9.3Hz), 2.05
(2H, m), 1.68 (2H, m), 1.27 (3H, d, J 6.4Hz), 1.23 (3H, d, J
6.4Hz). 5 m/z (ES+, 70V) 561 (MH+).
EXAMPLE 8
Ethyl-(S)-2-[(2-isopropoxy-3.4-dioxo-1-cyclobutenyl)amino]-3-[4-(3-[4-fluo-
rophenyl]-1-isoquinolinylamino)phenyl]propionate
[0168] Prepared in a similar manner to the compond of Example 1
from the compound of Intermediate 3 and ethyl
(S)-t-butoxycarbonylamino)-3-(4-amin- ophenyl)propanoate, to give
the title compound .delta.H (DMSO-d.sup.6) 8.91 (1H, s), 8.51 (1H,
m), 8.15 (2H, m), 7.88 (3H, m), 7.69 (3H, m), 7.57 (2H, m), 7.25
(4H, m), 5.25 (1H, m), 4.74 (1H, br d), 4.22 (2H, q, J 7.1Hz), 3.27
(1H, dd, J 14.2, 5.3Hz), 3.09 (1H, dd, J 14.2, 9.4Hz), 1.38 (6H,
m), 1.25 (3H, t, J 7.1 Hz); mLz (ES+, 70V) 568 (MH+).
EXAMPLE 9
Ethyl
(S)-2-[(2-(2.5-dimethypyrrolidin-1-yl)-3.4-dioxocyclobut-l-enyl)-ami-
no]-3-(4-[3-(4-fluorophenyl)isoguinolin-1
-ylamino)phenyl]propanoate
[0169] Prepared in a similar manner to the compound of Example 2
from the compound of Example 8 and 2,5-dimethylpyrrolidine to give
the title compound. .delta.H (CDCI.sub.3) 8.10 (2H, m), 7.93 (1H,
m), 7.81-7.57 (4H, m), 7.54 (2H, m), 7.10 (5H,m ), 5.36 (2H, m),
4.27 (2H, q, J 7.2Hz), 4.13 (1H, m), 3.29 (2H, m), 2.05 (2H, m),
1.67 (2H, m), 1.59 (2H, m), 1.33 (9H, m). m/z (ES+, 70V) 607
(MH+).
EXAMPLE 10
(S)-2-[(2-(2,5-Dimethypyrrolidin-1-yl)-3,4-dioxo-1-cyclobutenyl)amino]-3-[-
4-(3-(4-fluorophenyl)isogui nolin-1-ylamino)phenyl]propanoic
acid
[0170] Prepared in a similar fashion to the compound of Example 3
from the compound of Example 9 to give the title compound..
.delta.H (DMSO-d.sup.6) 9.27 (1H, s), 8.58 (1H, d, J 8.4Hz), 8.22
(2H, m), 7.94 (3H, m), 7.79 (2H, m), 7.60 (2H, m), 7.33 (4H, m),
5.16 (1H, m), 4.24 (2H, m), 3.29 (1H, m), 3.08 (1H, m), 2.16 (2H,
m), 1.73 (2H, m), 1.26 (6H, m). m/z (ES+, 70V) 579 (MH+).
EXAMPLE 11
Ethyl (s)-2-[(2-(2-methylpiperidin-1
-yl)3,4-dioxocyclobut-1-enyl)amino]-3-
-[4-(3-(4-fluorophenyl)isoquinolin-1-ylamino)phenyl]propanoate
[0171] Prepared in a similar manner to the compound of Example 2
from the compound of Example 8 and 2-methylpiperidine to give the
title compound. .delta.H (DMSO-d.sup.6) 9.07 (1H, s), 8.51 (1H, d,
J 8.4Hz), 8.16 (2H, m), 7.89 (3H, m), 7.72-7.56 (3H, m), 7.27 (4H,
m), 5.24 (1H, m), 4.46 (1H, m), 4.19 (2H, m), 4.05 (1H, m), 3.29
(2H, m), 1.72-1.44 (6H, m), 1.24 (3H, t, J 7.1Hz), 1.21 (3H, t, J
7.1Hz); m/z (ES+, 70V) 551 (MH+).
EXAMPLE 12
(S)-2-[(2-(2-Methylpiperidin-1-yl)-3,4-dioxocyclobut-1-enyl)amino]-3-[4-(3-
-(4-fluorophenyl)isoguinolin-1-enylamino)phenyl]propanoic acid
[0172] Prepared in a similar manner to the compound of Example 3
from the compound of Example 11 to give the title compound.
.delta.H (DMSO-d.sup.6) 9.92 (1H, s), 8.58 (1H, d, J 8.4Hz), 8.22
(2H, m), 7.94-7.75 (5H, m), 7.65 (1H, m), 7.32 (4H, m), 5.23 (1H,
s), 4.50 (1H, s), 4.10 (1H, s), 3.20 (2H, m), 3.18 (1H, m),
1.73-1.46 (4H, m), 1.23 (3H, m). m/z (ES+, 70V) 579 (MH+).
EXAMPLE 13
(S)-3-[4-(3-Phenyl-1-isoquinolinylamino)phenyl]-2-(2-morpholino-3,4-dioxoc-
yclobut-1-enylamino)propanoic acid
[0173] A solution of methyl
(S)-3-[4-(3-phenyl-1-isoquinolinylamino)phenyl-
]-2-(2-isopropoxy-3,4-dioxocyclobut-1-enylamino)propanoate (20 mg,
0.08 mmol) [prepared in a similar manner to the compound of Example
1] in MeOH (0.2 ml) was treated with morpholine (0.011 ml, 0.12
mmol) and the resulting mixture heated at 600 for 24 h. The mixture
was concentrated to dryness then redissolved in anhydrous THF (1.0
ml) and treated with polystyrene methylisocyanate resin (Argonaut
Technologies, 120 mg, 2.0 mmol/g, 0.24 mmol) at room temperature
for 24 h. The resulting mixture was filtered, and the resin was
washed with MeOH(1.0 ml). The combined filtrate was evaporated to
dryness then redissolved in THF (0.2 ml) and treated with an
aqueous solution of lithium hydroxide monohydrate (0.2 ml of a
solution of 100 mg in 4.0 ml water, 0.12 mmol) at room temperature
for 24 h. The reaction mixture was quenched with glacial acetic
acid (0.007 ml, 0.12 mmol), then evaporated to dryness to give the
crude product which was purified by preparative HPLC to afford the
title compound . HPLC-MS Retention time 3.50 min, MH+549.
[0174] LC-MS Conditions: Lunca C18(2) 50.times.4.6 mm (3 um)
column, running a gradient of 95% [0.1% aqueous formic acid], 5%
[0.1% formic acid in acetonitrile] to 5% [0.1% aqueous formic
acid], 95% [0.1% formic acid in acetonitrile ] over 3 min, then
maintaining the mobile phase at that ratio for a further 2 min.
Flow rate 1.0 m/min. MS was acquired by API electrospray in
positive ion mode, at 80V, scanning from 120 to 1000 amu.
[0175] The compounds of Examples 14-48 shown in Table 1 were
prepared from methyl
(S)-3-[4-(3-phenyl-1-isoquinolinylamino)phenyl]-2-(2-isopropoxy-3,-
4-dioxocyclobut-1-enylamino)propanoate in a similar manner to the
compound of Example 13 using the appropriate amine in place of
morpholine.
[0176] In Table 1 the letter X.sub.1 indicates the point of
attachment of the amine fragment (R1) to the square in the
structure at the head of the table.
2TABLE 1 13 HPLC Retention R1 MH+ Time (min) EXAMPLE 14 14 535 3.82
EXAMPLE 15 15 537 3.45 EXAMPLE 16 16 575 4.11 EXAMPLE 17 17 589
4.27 EXAMPLE 18 18 589 4.36 EXAMPLE 19 19 561 3.96 EXAMPLE 20 20
621 4.01 EXAMPLE 21 21 521 3.65 EXAMPLE 22 22 549 3.92 EXAMPLE 23
23 535 3.77 EXAMPLE 24 24 591 4.41 EXAMPLE 25 25 577 3.82 EXAMPLE
26 26 589 4.36 EXAMPLE 27 27 547 3.82 EXAMPLE 28 28 595 3.82
EXAMPLE 29 29 561 4.02 EXAMPLE 30 30 591 4.49 EXAMPLE 31 31 610
3.01 EXAMPLE 32 32 598 3.01 EXAMPLE 33 33 615 4.39 EXAMPLE 34 34
601 4.42 EXAMPLE 35 35 597 4.16 EXAMPLE 36 36 561 3.95 EXAMPLE 37
37 565 3.81 EXAMPLE 38 38 577 3.82 EXAMPLE 39 39 519 3.58 EXAMPLE
40 40 575 4.18 EXAMPLE 41 41 521 3.74 EXAMPLE 42 42 595 3.67
EXAMPLE 43 43 611 3.85 EXAMPLE 44 44 576 2.48 EXAMPLE 45 45 662 3.6
EXAMPLE 46 46 551 3.39 EXAMPLE 47 47 597 3.74 EXAMPLE 48 48 561
3.48
[0177] 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.
.alpha..sub.4.beta..sub.1 Integrin-dependent Jurkat cell adhesion
to VCAM-Ig
[0178] 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 4.degree.. The plates were washed (3.times.)
in phosphate-buffered saline (PBS) and then blocked for 1 h in
PBS/1% BSA at room temperature 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 room
temperature 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.
[0179] Each plate was washed (2.times.) with medium and the
adherent cells were fixed with 100.mu.l methanol for 10 minutes
followed by another wash. 100.mu.l 0.25% Rose Bengal (Sigma R4507)
in PBS was added for 5 minutes at room temperature 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. .alpha..sub.4.beta..sub.7 Integrin-dependent
JY cell adhesion to MAdCAM-Ig
[0180] 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 subline 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..sup.1 integrin assay.
.alpha..sub.5.beta..sub.1 Integrin-dependent K562 cell adhesion to
fibronectin 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 room temperature 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.
.alpha..sub.m.beta..sub.2-dependent human polymorphonuclear
neutrophils adhesion to plastic
[0181] 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-ac- etate, and in the presence or absence
of test compounds, and incubated for 20 min at 37.degree. C.
followed by 30 min at room temperature. 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 room
temperature 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.
.alpha.llb/.beta..sub.3-dependent human platelet aggregation
[0182] 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
220xg 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: NaCI 8.0;
MgCI.sub.2H.sub.2O 0.427; CaCI.sub.2 0.2; KCI 0.2; D-glucose 1.0;
NaHCO.sub.3 1.0; NaHPO.sub.42H.sub.2O 0.065). Aggregation was
monitored following addition of 2.5.mu.M ADP (Sigma) in the
presence or absence of inhibitors.
[0183] In the above assays the preferred compounds of the invention
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 .alpha. 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.
[0184] The advantageous clearance properties (improved
bioavailability) of compounds according to the invention may be
demonstrated as follows:
[0185] 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 an indicator
of high first-pass hepatic clearance after oral administration and
therefore low oral bioavailability.
[0186] 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.
[0187] The total plasma clearance of a compound according to the
invention can be determined as follows:
[0188] 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 (CL.sub.p) is
calculated by dividing the intravenous dose(D.sub.iv) by the
AUC.sub.iv for the blood plasma concentration--time course of a
drug administered by the intravenous route: CL.sub.p=D.sub.iv
AUC.sub.iv
[0189] 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 and/or the carboxylic
ester or amide R group of compounds of formula (1) is not
present.
* * * * *