5-cyano-2-aminopyrimidine derivatives

Details 5-cyano-2-aminopyrimidine derivatives 5-cyano-2-aminopyrimidine derivatives

2000-06-16

2003-06-17

Shah, Mukund J. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C544S331000, C544S332000

Reexamination Certificate

active

06579983

ABSTRACT:

This invention relates to substituted 5-cyano-2-aminopyrimidines, to processes for their preparation, to pharmaceutical compositions containing them, and to their use in medicine.
Angiogenesis, the growth of capillaries from existing blood vessels, is an essential process in normal embryonic development, tissue repair and some aspects of female reproductive function. It is also associated with the development of several pathological disorders including solid tumour growth, metastasis, psoriasis and rheumatoid arthritis, as well as diabetic retinopathy and age related macular degeneration [Folkman, Nature Medicine, (1995) 1, 27-310].
Several growth factors have been shown to mediate angiogenesis through alteration of vascular permeability, including vascular endothelial growth factor [VEGF; G. Breier et al., Trends in Cell Biology, (1996), 6, 454-6], platelet derived growth factor (PDGF) and acidic and basic fibroblast growth factors (a & b FGF).
VEGF in dimeric form is a ligand that binds to two transmembrane tyrosine kinase associated receptors, expressed exclusively on proliferating endothelial cells, KDR (Flk-1 in mice) also known as VEGFR-2, and Flt-1 also known as VEGFR-1. Binding of VEGF to KDR/Flk and Fit leads to receptor dimerisation, kinase activation, autophosphorylation of the receptor and phosphorylation of intracellular substrates. An analogous series of events ensues after ligand occupancy of the more widely expressed tyrosine kinase associated FGFr receptor by aFGF or bFGF. Thus receptor tyrosine kinase activity initiates a cellular signalling pathway leading to proliferation.
Antagonism of VEGF with antibody completely suppresses neovascularisation and growth of human rhabdomyosarcoma A673 speroids in athymic mice [Borgstrom et al, Cancer Res., (1996), 56 4032-4039]. Suppression of bFGF gene expression by interferons a and b inhibits capillary density in mice, leading to pancreatic eyelet tumour suppression [Folkman et al, Proc. Natl. Acad.Sci. (1996), 93, 2002 and Singh et al Proc.Natl. Acad. Sci. (1995), 92, 10457). Other receptor associated kinases such as PDGF and EGFr may also have some role in mediating angiogenesis.
We have now found a series of substituted 5-cyano-2-aminopyrimidines which are potent and selective inhibitors of receptor tyrosine kinases involved in angiogenesis, especially KDR kinase and/or FGFr kinase. Selective inhibition of these kinases can be expected to have a beneficial effect and the compounds are thus of use in the prophylaxis and treatment of disease states associated with angiogenesis, as described hereinafter.
Thus, according to one aspect of the invention, we provide a compound of formula (1):
wherein
Ar is an optionally substituted aromatic or heteroaromatic group;
R
1
is a hydrogen atom or a straight or branched chain alkyl group;
R
2
is a —X
1
—R
3
group where X
1
is a direct bond or a linker atom or group, and
R
3
is an optionally substituted aliphatic, cycloaliphatic, heteroaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group; and the salts, solvates, hydrates and N-oxides thereof.
When Ar in the compounds of formula (1) is an aromatic group it may be for example an optionally substituted monocyclic or bicyclic fused ring C
6-12
aromatic group, such as an optionally substituted phenyl, 1- or 2-naphthyl, 1- or 2-tetrahydronaphthyl, indanyl or indenyl group.
When the group Ar in compounds of the invention is a heteroaromatic group it may be an optionally substituted C
1-13
heteroaromatic group, such as a C
1-9
heteroaromatic group, containing for example one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms.
In general, the heteroaromatic group may be for example an optionally substituted monocyclic heteroaromatic, or a bicyclic or tricyclic fused-ring heteroaromatic group. 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 nine- to thirteen-membered fused-ring heteroaromatic groups containing one, two or more heteroatoms selected from oxygen, sulphur or nitrogen atoms. Tricyclic heteroaromatic groups include for example ten- to fourteen-membered fused-ring heteroaromatic groups containing one, two or more heteroatoms selected from oxygen, sulphur or nitrogen atoms. The heteroaromatic group may be attached to the remainder of the compound of formula (1) through any of its ring carbon atoms.
Particular examples of heteroaromatic groups represented by Ar include optionally substituted pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, 1,2,5-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, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, indazolyl, imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxazolyl, quinolizinyl, quinazolinyl, phthalazinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl, quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8-tetrahydro-quinolyl, 5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl, xanthenyl or benzoquinolyl.
Optional substituents which may be present on the aromatic or heteroaromatic groups represented by Ar include one, two, three or more substituents, each represented by an atom or group —R
4
or -Alk(R
4
)
m
, where R
4
is a halogen atom, or an amino (—NH
2
), substituted amino, nitro, cyano, hydroxyl (—OH), substituted hydroxyl, formyl, carboxyl (—CO
2
H), esterified carboxyl, thiol (—SH), substituted thiol, —COR
5
[where R
5
is a -Alk(R
4
)
m
, aryl or heteroaryl group], —CSR
5
, —SO
3
H, —S
2
R
5
, —SO
2
NH
2
, —SO
2
NHR
5
, —SO
2
N[R
5
]
2
, —CONH
2
, —CSNH
2
, —CONHR
5
, —CSNHR
5
, —CON[R
5
]
2
, —CSN[R
5
]
2
, —NHSO
2
H, —NHSO
2
R
5
, —N[SO
2
R
5
]
2
, —NHSO
2
NH
2
, —NHSO
2
NHR
5
,
—NHSO
2
N[R
5
]
2
, —NHCOR
5
, —NHCONH
2
, —NHCONHR
5
, —NHCON[R
5
]
2
, —NHCSR
5
, —NHC(O)OR
5
, or optionally substituted cycloaliphatic, heteroycloaliphatic, aryl or heteroaryl group; Alk is a straight or branched C
1-6
alkylene, C
2-6
alkenylene or C
2-6
alkynylene chain, optionally interrupted by one, two or three —O— or —S— atoms atoms or groups selected from —S(O)—, —S(O)
2
— or —N(R
6
)— [where R
6
is a hydrogen atom or a straight or branched chain C
1-6
alkyl group]; and m is zero or an integer 1, 2 or 3.
When in the group -Alk(R
4
)
m
m is an integer 1, 2 or 3, it is to be understood that the substituent or substituents R
4
may be present on any suitable carbon atom in -Alk. Where more than one R
4
substituent is present these may be the same or different and may be present on the same or different atom in -Alk or in R
4
as appropriate. Thus for example, -Alk(R
4
)
m
may represent a —CH(R
4
)
2
group, such as a —CH(OH)Ar
1
group where Ar
1
is an aryl or heteroaryl group as defined below. Clearly, when m is zero and no substituent R
4
is present the alkylene, alkenylene or alkynylene chain represented by Alk becomes an alkyl, alkenyl or alkynyl group.
When R
4
is a substituted amino group it may be for example a group —NHR
5
[where R
5
is as defined above] or a group —N[R
5
]
2
wherein each R
5
group is the same or different.
When R
4
is a halogen atom it may be for example a fluorine, chlorine, bromine, or iodine atom.
When R
4
is a substituted hydroxyl or substituted thiol group it may be for example a group —OR
5
or —SR
5
respectively.
Esterified carboxyl groups represented by the group R
4
include groups of formula —CO
2
Alk
1
wherein Alk
1

Affiliated with

Also associated with

Rating

5-cyano-2-aminopyrimidine derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with 5-cyano-2-aminopyrimidine derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 5-cyano-2-aminopyrimidine derivatives will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3156501