Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
CA 02382850 2002-02-25
Novel inhibitors of the integrin a"(33
The invention relates to novel compounds of the
formula I
X-Y-Z-R1-CHz-R2 (R4) -CHz-CO-RS I
in which '
X is H2N-C (=NH) -, HZN-C (=NH) -NH-, A-C (=NH) -NH-, Hetl-
or Hetl-NH-,
where the primary amino groups can also be
provided with conventional amino protective
groups,
Y is \
-(CH2)n- ~ -(CHZ)rt, tC~"'~2)0-
R3
in which one, two, three or four methylene groups
can be replaced by N, 0 and/or S,
Z is absent, -O-, -NH-, -NA-, -CH(OH)-, -CH(OA)-,
-CHA-, -CAZ- or -S-,
R1 is phenylene which is unsubstituted or mono-, di-
or trisubstituted by F, Cl, Br, A, OA, OCF3 or CN,
Rz is N, CH or CA,
R3 is H, F, C1, Br, A, OA or OCF3,
R4 is phenyl, naphthyl or Het2, mono- or poly-
substituted by F, Cl, Br, A, aryl, OA, SA, CO-A,
CN, COOA, CONHZ , CONHA, CONA2 or N02 ,
RS is OH, OA, NH2, NHA or NA2,
CA 02382850 2002-02-25
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Hetl is a mono- or binuclear heterocycle having 1 to 4
N atoms, which can be unsubstituted or mono- or
disubstituted by NHz,
Hetz is an aromatic mono- or binuclear heterocycle
having 1 to 3 N, O and/or S atoms, which can be
unsubstituted or mono- or disubstituted by F, C1,
Br, A, OA, SA, OCF3, -CO-A, CN, COOA, CONHz, CONHA,
CONAZ or NOZ ,
aryl is phenyl or naphthyl, unsubstituted or mono- or
polysubstituted by Hal, A, OA, OH, CO-A, CN, COOA,
COOH, CONHz , CONHA, CONA2 or N02 ,
A is alkyl having 1-12 C atoms,
n is 1, 2, 3, 4, 5 or 6,
m, o in each case independently of one another are 0,
l, 2, 3, 4, 5 or 6,
with the proviso that R4 ~ a phenyl or naphthyl radical
monosubstituted by A or aryl,
and their physiologically acceptable salts and
solvates.
The invention was based on the object of discovering
novel compounds having valuable properties, in
particular those which can be used for the production
of medicaments.
It has been found that the compounds of the formula I
and their salts have very valuable pharmacological
properties, together with good tolerability. They act
especially as integrin inhibitors, in particular
inhibiting the interactions of the a~ integrin
receptors with ligands. The compounds exhibit
particular activity in the case of the integrins oc"~33
CA 02382850 2002-02-25
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and a"(35. The compounds are very particularly active as
adhesion receptor antagonists for the receptor oc~,(33.
This action can be demonstrated by the method which is
described by J.W. Smith et al., in J. Biol. Chem. 265,
11008-11013 and 12267-12271 (1990).
The inhibition of vitronectin binding to the receptor
a~(33 was confirmed experimentally for 3- (4-fluoro-
phenyl)-4-f4-[3-(pyridin-2-ylamino)propoxy]phenyl)-
butyric acid.
In Curr. Opin. Cell. Biol. 5, 864 (1993),
B. Felding-Habermann and D.A. Cheresh describe the
importance of the integrins as adhesion receptors for a
wide variety of phenomena and syndromes, especially
with respect to the receptor av(33.
Other inhibitors of the integrin av(33 are described in
EP 0820988. Vitronectin receptor antagonists are also
described in WO 97/24124 and in EP 0820991.
The dependence of the origin of angiogenesis on the
interaction between vascular integrins and
extracellular matrix proteins is described by
P.C. Brooks, R.A. Clark and D.A. Cheresh in Science
264, 569-71 (1994).
The possibility of the inhibition of this interaction
and thus for the initiation of apoptosis (programmed
cell death) of angiogenic vascular cells by a cyclic
peptide is described by P.C. Brooks, A.M. Montgomery,
M. Rosenfeld, R.A. Reisfeld, T.-Hu, G. Klier and
D.A. Cheresh in Cell 79, 1157-64 (1994).
The experimental proof that the compounds according to
the invention also prevent the adhesion of living cells
to the corresponding matrix proteins and accordingly
also the adhesion of tumour cells to matrix proteins
can be furnished in a cell adhesion test which is
carried out analogously to the method of F. Mitjans et
al., J. Cell Science 108, 2825-2838 (1995).
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In J. Clin. Invest. 96, 1815-1822 (1995), P.C. Brooks
et al. describe oc~,(33 antagonists for the control of
cancer and for the treatment of tumour-induced
angiogenic diseases.
The compounds of the formula I according to the
invention can therefore be employed as pharmaceutical
active compounds, in particular for the treatment of
oncoses, osteoporosis, osteolytic disorders and for the
suppression of angiogenesis.
Compounds of the formula I which block the interaction
of integrin receptors and ligands, such as, for
example, of fibrinogen, on the fibrinogen receptor
(glycoprotein IIb/IIIa), prevent, as GPIIb/IIIa
antagonists, the spread of tumour cells by metastasis.
This is confirmed by the following observations:
The spread of tumour cells from a local tumour into the
vascular system takes place through the formation of
microaggregates (microthrombi) by interaction of the
tumour cells with blood platelets. The tumour cells are
screened by the protection in the microaggregate and
are not recognized by the cells of the immune system.
The microaggregates can attach to vessel walls, owing
to which further penetration of tumour cells into the
tissue is facilitated. Since the formation of the
microthrombi is mediated by fibrinogen binding to the
fibrinogen receptors on the activated blood platelets,
the GPIIb/IIIa antagonists can be regarded as effective
metastasis inhibitors.
In addition to the binding of fibrinogen, fibronectin
and of the von Willebrand factor to the fibrinogen
receptor of the blood platelets, compounds of the
formula I also inhibit the binding of further adhesive
proteins, such as vitronectin, collagen and laminin, to
the corresponding receptors on the surface of various
cell types. In particular, they prevent the formation
of blood platelet thrombi and can therefore be employed
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for the treatment of thromboses, apoplexy, cardiac
infarct, inflammation and arteriosclerosis.
The properties of the compounds can also be
demonstrated by methods which are described in
EP-A1-0 462 960. The inhibition of fibrinogen binding
to the fibrinogen receptor can be demonstrated by the
method which is given in EP-Al-0 381 033.
The platelet aggregation-inhibiting action can be
demonstrated in vitro by the method of Born (Nature
4832, 927-929, 1962). The inhibition of bone resorption
by the compounds of the invention can be confirmed with
the aid of a osteoclast resorption test analogously to
WO 95/32710.
The invention accordingly relates to the compounds of
the formula I according to Claim 1 and/or their
physiologically acceptable salts for the production of
a medicament for use as an integrin inhibitor. The
invention relates in particular to compounds of the
formula I according to Claim 1 and/or their acceptable
salts for the production of a medicament for the
control of pathologically angiogenic disorders,
tumours, osteoporosis, inflammations and infections.
The compounds of the formula I can be employed as
pharmaceutical active compounds in human and veterinary
medicine, for the prophylaxis and/or therapy of
thrombosis, myocardial infarct, arteriosclerosis,
inflammation, apoplexy, angina pectoris, oncoses,
osteolytic diseases such as osteoporosis,
hypercalcaemia, pathologically angiogenic diseases such
as, for example, inflammation, ophthalmological
diseases, diabetic retinopathy, macular degeneration,
myopia, ocular histoplasmosis, rheumatoid arthritis,
osteoarthritis, rubeotic glaucoma, ulcerative colitis,
Crohn's disease, atherosclerosis, psoriasis, restenosis
after angioplasty, viral infection, bacterial
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infection, fungal infection, in acute kidney failure
and in wound healing for assisting the healing
processes.
The compounds of the formula I can be employed as
antimicrobially active substances in operations where
biomaterials, implants, catheters or heart pacemakers
are used. They have an antiseptic action here. The
efficacy of the antimicrobial activity can be
demonstrated by the process described by
P. Valentin-Weigund et al., in Infection and Immunity,
2851-2855 (1988).
The invention also relates to the hydrates and
solvates, e.g. alcoholates, of these compounds.
The invention further relates to a process for the
preparation of compounds of the formula I according to
Claim 1, and their salts, characterized in that
a) a compound of the formula I is set free from its
functional derivatives by treating with a
solvolysing, reducing or hydrogenolysing agent,
or
b) a radical X and/or RS is converted into another
radical X and/or R5,
by, for example,
i) converting an amino group into a guanidino
group by reaction with an amidinating agent,
ii) hydrolysing an ester,
iii) converting a hydroxyamidine into an amidine
by hydrogenation,
and/or converting a base or acid of the formula I into
one of its salts.
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The compounds of the formula I can have a chiral centre
and can therefore occur in a number of stereoisomeric
forms. All these forms (e. g. D and L forms) and their
mixtures (e.g. the DL forms) are included in the
formula I.
So-called prodrug derivatives are also included in the
compounds according to the invention, i.e. compounds of
the formula I modified with, for example, alkyl or acyl
groups, sugars or oligopeptides, which are rapidly
cleaved in the body to the active compounds according
to the invention.
The abbreviations mentioned above and below stand for:
Ac acetyl
BOC tert-butoxycarbonyl
CBZ or Z benzyloxycarbonyl
DCCI dicyclohexylcarbodiimide
DMF dimethylformamide
EDCI N-ethyl-N,N'-(dimethylaminopropyl)carbo-
diimide
Et ethyl
Fmoc 9-fluorenylmethoxycarbonyl
HOBt 1-hydroxybenzotriazole
Me methyl
Mtr 4-methoxy-2,3,6-trimethylphenylsulfonyl
HONSu N-hydroxysuccinimide
OBut tert-butyl ester
Oct octanoyl
OMe methyl ester
OEt ethyl ester
POA phenoxyacetyl
TFA trifluoroacetic acid
Trt trityl (triphenylmethyl).
It applies to the whole invention that all radicals
which occur a number of times, such as, for example, A,
CA 02382850 2002-02-25
can be identical or different, i.e. are independent of
one another.
A is alkyl and has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or
12 C atoms and is preferably methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, sec-butyl or tert-butyl,
additionally also pentyl, 1-, 2- or 3-methylbutyl,
1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl,
1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-,
2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-
1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2-,
1,2,2-trimethylpropyl, heptyl, octyl, nonyl or decyl,
undecyl or docecyl. A is also alkyl substituted by
halogen, preferably CF3.
X is preferably, for example, pyrimidin-2-ylamino,
pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino,
benzimidazol-2-ylamino, 4,5-dihydroimidazol-2-ylamino,
2-aminoimidazol-5-ylamino, 2-aminopyridin-6-ylamino,
2-aminoimidazol-5-yl or 2-aminopyridin-6-yl.
Y is preferably, for example, ethylene, propylene or
butylene.
Z is preferably, for example, O.
R1 is preferably, for example, 1,4-phenylene.
R2 is preferably, for example, CH or N, very
particularly CH.
R4 is preferably, for example, phenyl mono- or
polysubstituted by F.
RS is preferably, for example, OH.
Hetl is preferably 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or
5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 3- or
4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, unsubstituted
or mono- or disubstituted by A, NHA and/or NH2,
furthermore preferably 1,2,3-triazol-1-, -4- or -5-yl,
1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl,
3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6-
or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-,
4-, 5-, 6- or 7-benzopyrazolyl, 2-, 3-, 4-, 5-, 6-, 7-
CA 02382850 2002-02-25
_ g _
or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl,
3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7-
or 8-quinazolinyl, 1H-imidazo[4,5-b]pyridin-2-yl or
1,8-naphthyridin-7-yl.
The heterocyclic radicals can also be partially or
completely hydrogenated.
Hetl can thus, for example, also be 2,3-dihydro-1-,
-2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-,
-4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetra-
hydro-1-, -2- or -4-imidazolyl, 4,5-dihydroimidazol-
2-yl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl,
tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-,
-2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-,
-3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or
4-piperidinyl, hexahydro-1-, -3- or -4-pyridazinyl,
hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or
3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-,
-5-, -6-, -7- or -8-quinolyl, 1,2,3,4-tetrahydro-1-,
-2-, -3-, -4-, -5-, -6-, -7- or -8-isoquinolyl or
1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl.
Hydrogenated or partially hydrogenated Hetl radicals
can additionally be substituted by =NH or carbonyl
oxygen.
Het2 is preferably 2,3-, 2,4-, 2,5- or 3,4-thienyl,
2,3-, 2,4-, 2,5- or 3,4-pyrrolyl, 2,4-, 2,5- or
4,5-imidazolyl, 2,3-, 2,4-, 2,6- or 3,5-pyridyl, 2,4-,
2,5-, 2,6-, 4,5- or 5,6-pyrimidinyl, unsubstituted or
monosubstituted by F, Cl, Br, A, OA or OCF3.
n is preferably 2, 3, 4, 5 or 6, very particularly
preferably n is 3, 4 or 5.
m and o are preferably, in each case independently of
one another, 0, 1 or 2, very particularly preferably
they are 0.
Substituted "one or more times" means mono-, di-, tri-
or tetrasubstituted.
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Aryl is phenyl which is unsubstituted, preferably - as
indicated - monosubstituted, specifically preferably
phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-,
m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-,
m- or p-tert-butylphenyl, o-, m- or p-cyanophenyl, o-,
m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m-
or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or
p-chlorophenyl, o-, m- or p-methylthiophenyl, o-, m- or
p-methylsulfinylphenyl, o-, m- or p-methylsulfonyl
phenyl, o-, m- or p-aminophenyl, o-, m- or p-methyl
aminophenyl, o-, m- or p-dimethylaminophenyl, o-, m- or
p-nitrophenyl, o-, m- or p-acetylphenyl, o-, m- or
p-methoxycarbonylphenyl, o-, m- or p-aminocarbonyl
phenyl,
further preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or
3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or
3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or
3,5-dibromophenyl, 2-chloro-3-methyl-, 2-chloro-
4-methyl-, 2-chloro-5-methyl-, 2-chloro-6-methyl-,
2-methyl-3-chloro-, 2-methyl-4-chloro-, 2-methyl-
5-chloro-, 2-methyl-6-chloro-, 3-chloro-4-methyl-,
3-chloro-5-methyl- or 3-methyl-4-chlorophenyl, 2-bromo-
3-methyl-, 2-bromo-4-methyl-, 2-bromo-5-methyl-,
2-bromo-6-methyl-, 2-methyl-3-bromo-, 2-methyl-4-bromo-,
2-methyl-5-bromo-, 2-methyl-6-bromo-, 3-bromo-
4-methyl-, 3-bromo-5-methyl- or 3-methyl-4-bromophenyl,
2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl,
2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichloro-
phenyl, 2,4,6-tri-tert-butylphenyl, 2,5-dimethylphenyl,
p-iodophenyl, 4-fluoro-3-chlorophenyl, 4-fluoro-3,5-di
methylphenyl, 2-fluoro-4-bromophenyl, 2,5-difluoro
4-bromophenyl, 2,4-dichloro-5-methylphenyl, 3-bromo
6-methoxyphenyl, 3-chloro-6-methoxyphenyl, 2-methoxy
5-methylphenyl, 2,4,6-triisopropylphenyl.
Amino protective group is preferably formyl, acetyl,
propionyl, butyryl, phenylacetyl, benzoyl, toluyl, POA,
methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxy-
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carbonyl, BOC, 2-iodoethoxycarbonyl, CBZ ("carbo-
benzoxy"), 4-methoxybenzyloxycarbonyl, FMOC, Mtr or
benzyl.
Accordingly, the present invention relates in
particular to those compounds of the formula I in which
at least one of the radicals mentioned has one of the
preferred meanings indicated above. Some preferred
groups of compounds can be expressed by the following
subformulae Ia to Im, which correspond to the formula I
and in which the radicals not designated in greater
detail have the meaning indicated in the formula I, but
in which
in a) X is pyrimidin-2-ylamino, pyridin-2-yl-
amino, imidazol-1-yl, imidazol-2-yl-
amino, benzimidazol-2-ylamino, 4,5-di-
hydroimidazol-2-ylamino, 2-amino-
imidazol-5-ylamino, 2-aminopyridin-
6-ylamino, 2-aminoimidazol-5-yl or
2-aminopyridin-6-yl;
in b) X is pyrimidin-2-ylamino, pyridin-2-yl-
amino, imidazol-1-yl, imidazol-2-yl-
amino, benzimidazol-2-ylamino or 4,5-di-
hydroimidazol-2-ylamino,
Y is - (CHZ) n-,
n is 2, 3 or 4;
in c) X is pyrimidin-2-ylamino, pyridin-2-yl-
amino, imidazol-1-yl, imidazol-2-yl-
amino, benzimidazol-2-ylamino or 4,5-di-
hydroimidazol-2-ylamino,
Y 1S - (CH2) n-.
n is 2, 3 or 4;
in d) X is pyrimidin-2-ylamino, pyridin-2-yl-
amino, imidazol-1-yl, imidazol-2-yl-
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amino, benzimidazol-2-ylamino or 4,5-di-
hydroimidazol-2-ylamino,
Y is - (CH2) n-.
n is 2, 3 or 4,
Z is O;
in e) X is pyrimidin-2-ylamino, pyridin-2-yl
amino, imidazol-1-yl, imidazol-2-yl
amino, benzimidazol-2-ylamino or 4,5-di
hydroimidazol-2-ylamino,
Y 1 S - ( CH2 ) n- ,
n is 2, 3 or 4,
Z is O,
R2 is N or CH;
in f) X is pyrimidin-2-ylamino, pyridin-2-yl-
amino, imidazol-1-yl, imidazol-2-yl-
amino, benzimidazol-2-ylamino or 4,5-di-
hydroimidazol-2-ylamino,
Y is - (CH2) n-,
n is 2, 3 or 4,
Z is O,
R2 is N or CH,
R4 is phenyl which is mono- or poly
substituted by F, Cl, Br, OA, OCF3,
-CO-A, CN, COOA, CONHz or NO2;
in g) X is pyrimidin-2-ylamino, pyridin-2-yl-
amino, imidazol-1-yl, imidazol-2-yl-
amino, benzimidazol-2-ylamino or 4,5-di-
hydroimidazol-2-ylamino,
Y is - (CH2) n-,
n is 2, 3 or 4,
Z is O,
RZ is N or CH,
R4 is phenyl which is mono- or poly-
substituted by F, Cl, Br, OA or OCF3;
RS is OA or OH;
CA 02382850 2002-02-25
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in h) X is pyrimidin-2-ylamino, pyridin-2-yl-
amino, imidazol-1-yl, imidazol-2-yl-
amino, benzimidazol-2-ylamino or 4,5-di-
hydroimidazol-2-ylamino,
Y is - (CHZ) n- i
n is 2, 3 or 4,
Z is O,
R2 is N or CH,
R4 is phenyl which is mono- or poly-
substituted by F,
RS is OA or OH;
in i) X is pyrimidin-2-ylamino, pyridin-2-yl-
amino, imidazol-1-yl, imidazol-2-yl-
amino, benzimidazol-2-ylamino or 4,5-di-
hydroimidazol-2-ylamino,
Y is - (CH2)n-,
n is 2, 3 or 4,
Z is O,
R2 is N or CH,
R4 is phenyl which is mono- or poly-
substituted by Hal, A or aryl,
RS is OA or OH
with the proviso that R4 is not equal to a
phenyl or naphthyl radical monosubstituted by A
or aryl;
in k) X is pyrimidin-2-ylamino, pyridin-2-yl-
amino, imidazol-1-yl, imidazol-2-yl-
amino, benzimidazol-2-ylamino or 4,5-di-
hydroimidazol-2-ylamino,
Y is - (CH2)n-,
n is 2, 3 or 4,
Z is O,
R2 is N or CH,
R4 is phenyl which is substituted by Hal
and aryl,
RS is OA or OH
CA 02382850 2002-02-25
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with the proviso that R4 is not equal to a
phenyl or naphthyl radical monosubstituted by A
or aryl;
in 1) X is pyrimidin-2-ylamino, pyridin-2-yl-
amino, imidazol-1-yl, imidazol-2-yl-
amino, benzimidazol-2-ylamino or 4,5-di-
hydroimidazol-2-ylamino,
Y is - (CHZ) n-.
n is 2, 3 or 4,
Z is O,
R2 is N or CH,
R4 is phenyl which is substituted by Hal
and aryl,
RS is OA or OH,
aryl is phenyl which is mono-, di- or
trisubstituted by Hal, A, OA, CF3, CN
or
N02
with t he proviso that R4 is not equal to a
phenyl or naphthyl radical monosubstituted by
A
or aryl;
in m) X is pyrimidin-2-ylamino, pyridin-2-yl-
amino, imidazol-1-yl, imidazol-2-yl-
amino, benzimidazol-2-ylamino, 4,5-di-
hydroimidazol-2-ylamino, 2-amino-
imidazol-5-ylamino, 2-aminopyridin-6-yl-
amino, 2-aminoimidazol-5-yl or 2-amino-
pyridin-6-yl,
Y iS - (CHZ) n-,
n is 2, 3 or 4,
Z is O,
R2 is N or CH,
R4 is phenyl which is mono- or poly-
substituted by Hal, A or aryl,
RS is OA or OH
with t he proviso that R4 is not equal to a
phenyl or naphthyl radical monosubstituted by
A
or aryl.
CA 02382850 2002-02-25
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The compounds of the formula I and also the starting
substances for their preparation are otherwise prepared
by methods known per se, such as are described in the
literature (e.g. in the standard works such as
Houben-Weyl, Methoden der organischen Chemie [Methods
of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart),
namely under reaction conditions which are known and
suitable for the reactions mentioned. Use can also be
made in this case of variants which are known per se,
but not mentioned here in greater detail.
If desired, the starting substances can also be formed
in situ, such that they are not isolated from the
reaction mixture, but immediately reacted further to
give the compounds of the formula I.
Compounds of the formula I can preferably be obtained
by liberating compounds of the formula I from one of
their functional derivatives by treating with a
solvolysing or hydrogenolysing agent.
Preferred starting substances for the solvolysis or
hydrogenolysis are those which otherwise correspond to
the formula I, but instead of one or more free amino
and/or hydroxyl groups contain corresponding protected
amino and/or hydroxyl groups, preferably those which,
instead of an H atom which is linked to an N atom,
carry an amino protective group, in particular those
which, instead of an HN group, carry an R' N group in
which R' is an amino protective group, and/or those
which, instead of the H atom of a hydroxyl group, carry
a hydroxyl protective group, e.g. those which
correspond to the formula I, but instead of a group
-COOH carry a group -COOR", in which R" is a hydroxyl
protective group.
It is also possible for a number of - identical or
different - protected amino and/or hydroxyl groups to
CA 02382850 2002-02-25
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be present in the molecule of the starting substances.
If the protective groups present are different from one
another, in many cases they can be removed selectively.
The expression "amino protective group" is generally
known and relates to groups which are suitable for
protecting (or blocking) an amino group from chemical
reactions, but which are easily removable after the
desired chemical reaction has been carried out at other
positions in the molecule. Typical groups of this type
are, in particular, unsubstituted or substituted aryl,
aryl, aralkoxymethyl or aralkyl groups. Since the amino
protective groups are removed after the desired
reaction (or reaction sequence), their nature and size
is otherwise not critical; however, those having 1-20,
in particular 1-8, C atoms are preferred. The
expression "aryl group" is to be interpreted in the
widest sense in connection with the present process. It
includes acyl groups derived from aliphatic,
araliphatic, aromatic or heterocyclic carboxylic acids
or sulfonic acids, and, in particular, alkoxycarbonyl,
aryloxycarbonyl and especially aralkoxycarbonyl groups.
Examples of acyl groups of this type are formyl or
alkanoyl such as acetyl, propionyl, butyryl; aralkanoyl
such as phenyl acetyl; aroyl such as benzoyl or toluyl;
aryloxyalkanoyl such as POA; alkoxycarbonyl such as
methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxy-
carbonyl, BOC, 2-iodoethoxycarbonyl; aralkyloxycarbonyl
such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxy-
carbonyl, Fmoc; arylsulfonyl such as Mtr. Preferred
amino protective groups are BOC and Mtr, additionally
CBZ, Fmoc, benzyl, formyl and acetyl.
The removal of the amino protective group takes place -
depending on the protective group used - e.g. using
strong acids, expediently using TFA or perchloric acid,
but also using other strong inorganic acids such as
hydrochloric acid or sulfuric acid, strong organic
carboxylic acids such as trichloroacetic acid or
CA 02382850 2002-02-25
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sulfonic acids such as benzene- or p-toluenesulfonic
acid. The presence of an additional inert solvent is
possible, but not always necessary. Suitable inert
solvents are preferably organic solvents, for example
carboxylic acids such as acetic acid, ethers such as
tetrahydrofuran or dioxane, amides such as DMF,
halogenated hydrocarbons such as dichloromethane,
additionally also alcohols such as methanol, ethanol or
isopropanol, and also water. Mixtures of the above-
mentioned solvents are additionally suitable. TFA is
preferably used in an excess without addition of a
further solvent, perchloric acid in the form of a
mixture of acetic acid and 70% perchloric acid in the
ratio 9:1. The reaction temperatures for the cleavage
are expediently between approximately 0 and
approximately 50°; the reaction is preferably carried
out at between 15 and 30° (room temperature).
The groups BOC, OBut and Mtr can preferably be removed,
for example, using TFA in dichloromethane or using
approximately 3 to 5N HC1 in dioxane at 15-30°, the
Fmoc group using an approximately 5 to 50% strength
solution of secondary amines such as dimethylamine,
diethylamine or piperidine in DMF at 15-30°.
Hydrogenolytically removable protective groups (e. g.
CBZ or benzyl) can be removed, for example, by treating
with hydrogen in the presence of a catalyst (e . g . of a
noble metal catalyst such as palladium, expediently on
a support such as carbon). Suitable solvents here are
those indicated above, in particular, for example,
alcohols such as methanol or ethanol or amides such as
DMF. As a rule, the hydrogenolysis is carried out at
temperatures between approximately 0 and 100° and
pressures between approximately 1 and 200 bar,
preferably at 20-30° and 1-10 bar. Hydrogenolysis of
the CBZ group takes place well, for example, on 5 to
10% Pd/C in methanol or using ammonium formate (instead
of hydrogen) on Pd/C in methanol/DMF at 20-30°.
CA 02382850 2002-02-25
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Suitable inert solvents are, for example, hydrocarbons
such as hexane, petroleum ether, benzene, toluene or
xylene; chlorinated hydrocarbons such as trichloro-
ethylene, 1,2-dichloroethane, carbon tetrachloride,
chloroform or dichloromethane; alcohols such as
methanol, ethanol, isopropanol, n-propanol, n-butanol
or tert-butanol; ethers such as diethyl ether,
diisopropyl ether, tetrahydrofuran (THF) or dioxane;
glycol ethers such as ethylene glycol monomethyl or
monoethyl ether (methyl glycol or ethyl glycol),
ethylene glycol dimethyl ether (diglyme); ketones such
as acetone or butanone; amides such as acetamide,
dimethylacetamide or dimethylformamide (DMF); nitriles
such as acetonitrile; sulfoxides such as dimethyl
sulfoxide (DMSO); carbon disulfide; carboxylic acids
such as formic acid or acetic acid; nitro compounds
such as nitromethane or nitrobenzene; esters such as
ethyl acetate, water or mixtures of the solvents
mentioned.
It is furthermore possible to hydrolyse an ester of the
formula I. Expediently, this is carried out by
solvolysis or hydrogenolysis, as indicated above, e.g.
using LiOH in methanol, NaOH or KOH in dioxane/water at
temperatures between 0 and 60°C, preferably between 10
and 40°C.
The conversion of a cyano group into an amidino group
is carried out by reaction with, for example, hydroxyl-
amine and subsequent reduction of the N-hydroxyamidine
with hydrogen in the presence of a catalyst such as,
for example, Pd/C.
It is furthermore possible to replace a conventional
amino protective group by hydrogen by removing the
protective group, as described above, solvolytically or
hydrogenolytically or by liberating an amino group
protected by a conventional protective group by
solvolysis or hydrogenolysis.
CA 02382850 2002-02-25
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For the preparation of compounds of the formula I in
which X is HzN-C(=NH)-NH-, an appropriate amino
compound can be treated with an amidinating agent. A
preferred amidinating agent is 1-amidino-3,5-di-
methylpyrazole (DPFN), which is particularly employed
in the form of its nitrate. The reaction is expediently
carried out with addition of a base such as tri-
ethylamine or ethyldiisopropylamine in an inert solvent
or solvent mixture, e.g. water/dioxane at temperatures
between 0 and 120°C, preferably between 60 and 120°C.
For the preparation of an amidine of the formula I
(X = -C (=NH) -NH2) , ammonia can be added to a nitrile of
the formula I (X = CN). The addition is preferably
carried out in a number of stages by a) converting the
nitrile in a manner known per se using HzS into a
thioamide, which is converted using an alkylating
agent, e.g. CH3I, into the corresponding S-alkyl-
imidothioester, which for its part reacts with NH3 to
give the amidine, b) converting the nitrile using an
alcohol , a . g . ethanol in the presence of HCl , into the
corresponding imidoester and treating this with
ammonia, or c) reacting the nitrile with lithium bis-
(trimethylsilyl)amide and then hydrolysing the product.
The release of the compounds of the formula I from an
oxidized precursor, by, for example, reducing an oxy-
heterocycle using a reducing agent such as, for
example, phosphorus trichloride in an inert solvent, is
furthermore preferred.
Furthermore, free amino groups can be acylated in the
customary manner using an acid chloride or anhydride or
alkylated using an unsubstituted or substituted alkyl
halide, expediently in an inert solvent such as
dichloromethane or THF and/or in the presence of a base
such as triethylamine or pyridine at temperatures
between -60 and +30°.
CA 02382850 2002-02-25
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A base of the formula I can be converted into the
associated acid addition salt using an acid, for
example by reaction of equivalent amounts of the base
and of the acid in an inert solvent such as ethanol and
subsequent evaporation. For this reaction, suitable
acids are in particular those which yield
physiologically acceptable salts. Thus inorganic acids
can be used, e.g. sulfuric acid, nitric acid,
hydrohalic acids such as hydrochloric acid or
hydrobromic acid, phosphoric acids such as
orthophosphoric acid, sulfamic acid, in addition
organic acids, in particular aliphatic, alicyclic,
araliphatic, aromatic or heterocyclic mono- or
polybasic carboxylic, sulfonic or sulfuric acids, e.g.
formic acid, acetic acid, propionic acid, pivalic acid,
diethylacetic acid, malonic acid, succinic acid,
pimelic acid, fumaric acid, malefic acid, lactic acid,
tartaric acid, malic acid, citric acid, gluconic acid,
ascorbic acid, nicotinic acid, isonicotinic acid,
methane- or ethanesulfonic acid, ethanedisulfonic acid,
2-hydroxyethanesulfonic acid, benzenesulfonic acid,
p-toluenesulfonic acid, naphthalenemono- and disulfonic
acids, laurylsulfuric acid. Salts with physiologically
unacceptable acids, e.9. picrates, can be used for the
isolation and/or purification of the compounds of the
formula I.
On the other hand, an acid of the formula I can be
converted into one of its physiologically acceptable
metal or ammonium salts by reaction with a base.
Possible salts here are, in particular, the sodium,
potassium, magnesium, calcium and ammonium salts, in
addition substituted ammonium salts, e.g. the
dimethyl-, diethyl- or diisopropylammonium salts,
monoethanol-, diethanol- or diisopropylammonium salts,
cyclohexyl-, dicyclohexylammonium salts, dibenzyl-
ethylenediammonium salts, furthermore, for example,
salts with arginine or lysine.
CA 02382850 2002-02-25
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The compounds of the formula I contain one or more
chiral centres and can therefore be present in racemic
or in optically active form. Racemates obtained can be
separated into the enantiomers mechanically or
chemically by methods known per se. Preferably,
diastereomers are formed from the racemic mixture by
reaction with an optically active resolving agent.
Suitable resolving agents are, for example, optically
active acids, such as the D and L forms of tartaric
acid, diacetyltartaric acid, dibenzoyltartaric acid,
mandelic acid, malic acid, lactic acid or the various
optically active camphorsulfonic acids such as
(3-camphorsulfonic acid. Resolution of enantiomers with
the aid of a column packed with an optically active
resolving agent (e.g. dinitrobenzoylphenylglycine) is
also advantageous; a suitable eluent is, for example, a
mixture of hexane/isopropanol/acetonitrile, e.g. in the
volume ratio 82:15:3.
Of course, it is also possible to obtain optically
active compounds of the formula I according to the
methods described above, by using starting substances
which are already optically active.
The invention includes not only the compounds mentioned
but also mixtures and preparations which, in addition
to these compounds according to the invention, also
contain other pharmacological active compounds or
adjuvants which can influence the primary
pharmacological action of the compounds according to
the invention in the desired manner. These can be used
as therapeutics, diagnostics or as reagents. They can
be given to man or animals locally or systemically,
orally, intravenously, intraperitoneally,
intramuscularly, subcutaneously, transdermally,
nasally, buccally, or iontophoretically, which includes
formulations in suspensions, emulsions or solutions,
liposomes, ointments, pastes, biodegradable polymers or
CA 02382850 2002-02-25
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as nanoparticles, tablets, capsules or pills, granules
or powders, as an aerosol for inhaling, as intranasal
drops or sprays. A combination of the novel products
with other techniques, such as surgery, irradiation,
diagnosis, radiotherapy, photodynamic therapy and gene
therapy, as well as with other medicaments is also
possible. Such medicaments can originate, for example,
from the cardiovascular, central nervous system or
oncology fields. They can be tumour agents, such as
angiogenesis inhibitors or cytostatics,
chemotherapeutics of the groups alkylating agents,
antibiotics, antimetabolites, biologicals and
immunomodulators, hormones and their antagonists,
mustard gas derivatives, alkaloids and others, where
these substances can be of low molecular weight or high
molecular weight. They can be lipids, carbohydrates or
proteins. Also included amongst these are cytokines,
toxins, fusion proteins, monoclonal antibodies and
vaccines.
The invention accordingly relates to compounds of the
formulae defined above and below and also in the
claims, including their physiologically acceptable
salts, as medicaments, diagnostics or reagents.
The invention relates in particular to corresponding
medicaments as inhibitors for the control of disorders
which are based indirectly or directly on expression of
the a,~(33 integrin receptor, thus in particular in the
case of pathologically angiogenic disorders,
thromboses, cardiac infarcts, coronary heart disorders,
arteriosclerosis, tumours, osteoporosis, inflammations,
infections and also for influencing wound-healing
processes.
The invention also relates to corresponding
pharmaceutical preparations which contain at least one
medicament of the formula I and, if appropriate,
vehicles and/or excipients.
CA 02382850 2002-02-25
- 23 -
The invention furthermore relates to the use of the
compounds and/or their physiologically acceptable salts
according to the claims and the description for the
production of a medicament for the control of disorders
which are based indirectly or directly on expression of
the a"(33 integrin receptor, thus in particular in the
case of pathologically angiogenic disorders,
thromboses, cardiac infarcts, coronary heart disorders,
arteriosclerosis, tumours, osteoporosis, inflammations,
infections and for influencing wound-healing processes.
The medicaments according to the invention or
pharmaceutical preparations comprising them can be used
as medicaments in human or veterinary medicine.
Suitable vehicles are organic or inorganic substances
which are suitable for enteral (e.g. oral) or
parenteral administration or topical application or for
application in the form of an inhalation spray and do
not react with the novel compounds, for example water,
vegetable oils, benzyl alcohols, alkylene glycols,
polyethylene glycols, glycerol triacetate, gelatin,
carbohydrates such as lactose or starch, magnesium
stearate, talc, petroleum jelly. Tablets, pills, coated
tablets, capsules, powders, granules, syrups, juices or
drops are used for oral administration, suppositories
are used, in particular, for rectal administration,
solutions, preferably oily or aqueous solutions, in
addition suspensions, emulsions or implants, are used
for parenteral administration and ointments, creams or
powders are used for topical application. The novel
compounds can also be lyophilized and the lyophilizates
obtained used, for example, for the production of
injection preparations. The preparations indicated can
be sterilized and/or can contain excipients such as
glidants, preservatives, stabilizing and/or wetting
agents, emulsifiers, salts for affecting the osmotic
pressure, buffer substances, colourants, flavourings
and/or one or more further active compounds, e.g. one
or more vitamins.
CA 02382850 2002-02-25
- 24 -
For administration as an inhalation spray, sprays can
be used which contain the active compound either
dissolved or suspended in a propellant or propellant
mixture (e. g. COZ or chlorofluorohydrocarbons).
Expediently, the active compound is used here in
micronized form, it being possible for one or more
additional physiologically tolerable solvents to be
present, e.g. ethanol. Inhalation solutions can be
administered with the aid of customary inhalers.
As a rule, the substances according to the invention
can be administered in analogy to other known,
commercially available preparations (e.g. described in
US-A-4 472 305), preferably in doses between
approximately 0.05 and 500 mg, in particular between
0.5 and 100 mg, per dose unit. The daily dose is
preferably between approximately 0.01 and 20 mg/kg of
body weight. The specific dose for each patient
depends, however, on all sorts of factors, for example
on the efficacy of the specific compound employed, on
the age, body weight, general state of health and sex,
on the diet, on the time and route of administration,
and on the excretion rate, pharmaceutical combination
and severity of the particular disorder to which the
therapy applies. Parenteral administration is
preferred.
Above and below, all temperatures are given in °C.
The HPLC analyses (retention time Rt) were carried out
in the following systems:
column 3 ~m silica rod with a 210 second gradient of 20
to 100% water/acetonitrile/0.01% trifluoroacetic acid,
at 2.2 ml/min flow and detection at 220 nm.
Mass spectrometry (MS): EI (electron impact ionization) M+
FAB (fast atom bombardment) (M+H)+
CA 02382850 2002-02-25
- 25 -
Example 1
Synthesis of 3- (4-fluorophenyl) -4-{4- [3- (pyridin-
2-ylamino)propoxy]phenyl~butyric acid
835 mg of Mg are suspended in 5 ml of abs. THF. A
solution of 2.0 g of 4-benzyloxybenzyl chloride in 5 ml
of abs. tetrahydrofuran is then added dropwise. After
addition is complete, the turbid solution is stirred at
room temperature for 1 hour, then a solution of 1.73 g
of ethyl 2-cyano-3-(4-fluorophenyl)acrylate in 10 ml of
abs. toluene is added and the mixture is refluxed for
16 hours. The solvent is removed and, after customary
working up, ethyl 4-(4-benzyloxyphenyl)-2-cyano
3-(4-fluorophenyl)butyrate ("AA") is obtained.
8.27 g of "AA" are suspended in a mixture of 80 ml of
acetic acid and 80 ml of cons. HCl and the mixture is
then refluxed for 16 hours. After customary working up,
4-(4-hydroxyphenyl)-3-(4-fluorophenyl)butyric acid ("AB")
is obtained.
A solution of 1.0 g of "AB" in 10 ml of abs. methanol
is treated with 0.4 ml of thionyl chloride and stirred
at room temperature for 16 hours. After customary
working up, methyl 4-(4-hydroxyphenyl)-3-(4-fluoro-
phenyl)butyrate ("AC") is obtained.
0.62 ml of diethyl azodicarboxylate is added dropwise
to a suspension of 0.4 g of "AC", 0.5 g of 3-(1-oxy-
pyridin-2-ylamino)propan-1-of and 1.23 g of polymer-
bound triphenylphosphine (loading about 3 mmol/g) in
17 ml of abs. THF and the mixture is subsequently
stirred for 16 hours. After filtration and removal of
the solvent, the residue is purified by means of HPLC.
Methyl 3-(4-fluorophenyl)-4-{4-[3-(1-oxypyridin-2-yl-
amino)propoxy]phenyl~butyrate ("AD") is obtained.
CA 02382850 2002-02-25
- 26 -
A solution of 0.45 g of "AD" in 30 ml of chloroform is
treated with 0.59 g of phosphorus trichloride, and
stirred for 2 hours at room temperature and for a
further 2 hours under reflux. After customary working
up, the residue is treated in 15 ml of methanol with
0.2 g of lithium hydroxide and stirred at room
temperature for 16 hours. After removal of the solvent,
the residue is treated with 0.66 ml of trifluoroacetic
acid and purified by means of HPLC. 3-(4-Fluorophenyl)-
4-{4-[3-pyridin-2-ylamino)propoxy]phenyl}butyric acid,
trifluoroacetate, is obtained
H
N N
OH
Test results of the a,V~3 inhibition by 3-4-fluoro-
phenyl)-4-{4-[3-pyridin-2-ylamino)propoxy]phenyl~-
butyric acid
The ICso value, i.e. the concentration in nmol/litre
which inhibits 50% of the vitronectin binding to the
corresponding isolated receptor, is given for the
vitronectin binding test (method of Smith et al., J.
Biol. Chem. 265, 12267-71, 1990).
ICso 0c"(33: 10.
The pharmacological data confirm the antagonistic
activity of the compound according to the invention for
the receptor a"(33.
The compounds below were obtained analogously to the
synthesis scheme described above
3- (4-fluorophenyl) -4-{4- [2- (pyrimidin-2-ylamino) -
ethoxy]phenyl~butyric acid, trifluoroacetate;
CA 02382850 2002-02-25
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3-(4-fluorophenyl)-4-{4-[3-(pyrimidin-2-ylamino)-
propoxy]phenyl~butyric acid, trifluoroacetate;
3- (4-fluorophenyl) -4-{4- [4- (pyrimidin-2-ylamino) -
butoxy]phenyl~butyric acid, trifluoroacetate;
3- (4-fluorophenyl) -4-{4- [2- (pyridin-2-ylamino) ethoxy] -
phenyl)butyric acid, trifluoroacetate;
3- (4-fluorophenyl) -4-{4- [4- (pyridin-2-ylamino)butoxy] -
phenyl}butyric acid, trifluoroacetate;
3- (4-fluorophenyl) -4-{4- [3- (imidazol-1-yl)propoxy] -
phenyl~butyric acid;
3-(4-fluorophenyl)-4-{4-[3-(4,5-dihydro-1H-imidazol-
2-ylamino)propoxy]phenyl}butyric acid;
3- (4-fluorophenyl) -4-{4- [3- (imidazol-2-ylamino) -
propoxy]phenyl~butyric acid;
3-(4-fluorophenyl)-4-{4-[3-(benzimidazol-2-ylamino)-
propoxy]phenyl~butyric acid;
3-(4-fluorophenyl)-4-{4-[3-(2-aminopyridin-6-ylamino)-
propoxy]phenyl)butyric acid,
3-(4-fluorophenyl)-4-{4-[3-(2-aminoimidazol-5-ylamino)-
propoxy]phenyl}butyric acid.
Example 2
Synthesis of (4-fluorophenyl-{4-[3-(pyridin-2-ylamino)-
propoxy]benzyl~amino)acetic acid
40.0 g of 4-hydroxybenzaldehyde are dissolved in 400 ml
of abs. THF under a protective gas atmosphere, and the
solution is treated with 55.1 g of dihydropyran and
13.7 g of pyridinium p-toluenesulfonate and stirred at
CA 02382850 2002-02-25
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room temperature overnight. The solvent is removed on a
rotary evaporator, the residue is worked up in the
customary manner and 4-(tetrahydropyran-2-yloxy)-
benzaldehyde ("BA") is obtained as a colourless oil.
A solution of 2.0 g of "BA" in 20 ml of abs. methanol
is treated with 1.17 g of 4-fluoroaniline and stirred
at 60° for 3 hours. 0.79 g of sodium cyanoborohydride
are added at room temperature, and the reaction soluion
is refluxed for 16 hours. After removal of the solvent,
customary working up and purification by
chromatography, 4-fluorophenyl-[4-(tetrahydropyran-
2-yloxy)benzyl]amine ("BB") is obtained as a colourless
liquid.
8.0 g of "BB" and 10.36 g of methyl bromoacetate are
dissolved in 100 ml of abs. THF under an Nz atmosphere,
treated with 12.0 g of potassium carbonate and refluxed
for 16 hours. After removal of the solvent, customary
working up and purification by chromatography, methyl
( [4-fluorophenyl] - [4- (tetrahydropryan-2-yloxy) benzyl] -
amino}acetate ("BC") is obtained as a colourless solid.
A solution of 0.5 g of "BC" in 25 ml of methanol and
5 ml of dichloromethane is treated with 2.76 ml of
conc. HCl and stirred at room temperature for
5 minutes. After removal of the solvents and customary
working up, the residue is dissolved in 16 ml of abs.
THF together with 0.47 g of 3-(1-oxypyridin-2-yl-
amino)propan-1-of and then treated with 1.17 g of
polymeric triphenylphosphine (loading about 3 mmol/g).
0.62 ml of diethyl azodicarboxylate is then added
dropwise. The suspension is then stirred at room
temperature for 16 hours. After filtration and removal
of the solvent, the residue is purified by means of
HPLC. Methyl (~4-[3-(1-oxypyridin-2-ylamino)propoxy]-
benzyl}-(4-fluorophenyl)amino)acetate ("BD") is
obtained.
CA 02382850 2002-02-25
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A solution of 0.44 g of "BD" in 30 ml of chloroform is
treated with 0.57 g of phosphorus trichloride, and
stirred for 2 hours at room temperature and for a
further 2 hours under reflux. After customary working
up, the residue is treated in 15 ml of methanol with
0.27 g of lithium hydroxide and stirred at room
temperature for 16 hours. After removal of the solvent,
0.66 ml of trifluoroacetic acid is added and the
mixture is purified by means of HPLC. ((4-Fluoro-
phenyl)-{4-[3-(pyridin-2-ylamino)propoxy]benzyl~amino)-
acetic acid, bistrifluoroacetate is obtained
F
N N.~.-~.O .~ ( ~ O
p t ~ .
N OH
The compounds below are obtained analogously
((4-fluorophenyl)-~4-[2-(pyrimidin-2-ylamino)ethoxy]-
benzyl~amino)acetic acid,
((4-fluorophenyl)-~4-[3-(pyrimidin-2-ylamino)propoxy]-
benzyl}amino)acetic acid,
( (4-fluorophenyl) -{4- [4- (pyrimidin-2-ylamino) butoxy] -
benzyl~amino)acetic acid,
( (4-fluorophenyl) -~4- [2- (pyridin-2-ylamino) ethoxy] -
benzyl~amino)acetic acid,
( (4-fluorophenyl) -{4- [4- (pyridin-2-ylamino) butoxy] -
benzyl~amino)acetic acid,
((4-fluorophenyl)-f4-[3-(imidazol-1-yl)propoxy]benzyl~-
amino)acetic acid,
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((4-fluorophenyl)-{4-[3-(4,5-dihydro-1H-imidazol-2-yl-
amino)propoxy]benzyl}amino)acetic acid,
( (4-fluorophenyl) -{4- [3- (imidazol-2-ylamino)propoxy] -
benzyl}amino)-acetic acid,
( (4-fluorophenyl) -{4- [3- (benzimidazol-2-ylamino) -
propoxy]benzyl}amino)acetic acid.
Example 3
The compounds below are obtained analogously to
Example 1
3-(3-chloro-4-phenyl)phenyl)-4-{4-[3-(pyridin-2-yl-
amino)propoxy]phenyl}butyric acid,
H
N\ NCO
OH
3-(2-bromo-phenyl)-4-{4-[3-(pyridin-2-ylamino)propoxy]-
phenyl}butyric acid,
3-(3,4-dichloro-phenyl)-4-{4-[3-(pyridin-2-yl-
amino)propoxy]phenyl}butyric acid,
3-(4-bromo-phenyl)-4-{4-[3-(pyridin-2-ylamino)propoxy]-
phenyl}butyric acid,
3-(2,3-dichloro-phenyl)-4-{4-[3-(pyridin-2-yl-
amino)propoxy]phenyl}butyric acid,
CA 02382850 2002-02-25
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3-(2,4-dichloro-phenyl)-4-{4-[3-(pyridin-2-yl-
amino)propoxy]phenyl~butyric acid,
3-(3-bromo-phenyl)-4-{4-[3-(pyridin-2-ylamino)propoxy]-
phenyl}butyric acid,
3-(2,6-difluoro-phenyl)-4-{4-[3-(pyridin-2-yl-
amino)propoxy]phenyl}butyric acid,
3-(3,5-dichloro-phenyl)-4-{4-[3-(pyridin-2-yl-
amino)propoxy]phenyl}butyric acid.
The following examples relate to pharmaceutical
preparations:
Example A: Injection vials
A solution of 100 g of 3-(4-fluorophenyl)-
4-{4-[3-(pyridin-2-ylamino)propoxy]phenyl~butyric acid
and 5 g of disodium hydrogenphosphate is adjusted to pH
6.5 in 3 1 of double-distilled water using 2 N
hydrochloric acid, sterile-filtered, filled into
injection vials, lyophilized under sterile conditions
and aseptically sealed. Each injection vial contains
5 mg of active compound.
Example B: Suppositories
A mixture of 20 g of 3-(4-fluorophenyl)-
4-{4-[3-(pyridin-2-ylamino)propoxy]phenyl~butyric acid
is fused with 100 g of soya lecithin and 1400 g of
cocoa butter, poured into moulds and allowed to cool.
Each suppository contains 20 mg of active compound.
Example C: Solution
A solution is prepared from 1 g of 3- (4-fluorophenyl) -
4-{4-[3-(pyridin-2-ylamino)propoxy]phenyl~butyric acid,
CA 02382850 2002-02-25
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9.38 g of NaH2P04 ~ 2 H20, 28.48 g of Na2HP04 ~ 12 HZO
and 0.1 g of benzalkonium chloride in 940 ml of double
distilled water. The solution is adjusted to pH 6.8,
made up to 1 1 and sterilized by irradiation. This
solution can be used in the form of eye drops.
Example D: Ointment
500 mg of 3- (4-fluorophenyl) -4-{4- [3- (pyridin-2-yl
amino)propoxy]phenyl~butyric acid are mixed with 99.5 g
of petroleum jelly under aseptic conditions.
Example E: Tablets
A mixture of 1 kg of 3-(4-fluorophenyl)
4-{4-[3-(pyridin-2-ylamino)propoxy]phenyl~butyric acid,
4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of
talc and 0.1 kg of magnesium stearate is compressed in
a customary manner to give tablets such that each
tablet contains 10 mg of active compound.
Example F: Coated tablets
Analogously to Example E, tablets are pressed and are
then coated in a customary manner with a coating of
sucrose, potato starch, talc, tragacanth and colourant.
Example G: Capsules
2 kg of 3-(4-fluorophenyl)-4-~4-[3-(pyridin-2-ylamino)-
propoxy]phenyl}butyric acid are filled into hard
gelatin capsules in a customary manner such that each
capsule contains 20 mg of the active compound.
Example H: Ampoules
A solution of 1 kg of 3-(4-fluorophenyl)-
4-f4-[3-(pyridin-2-ylamino)propoxy]phenyl}butyric acid
in 60 1 of double-distilled water is sterile-filtered,
CA 02382850 2002-02-25
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filled into ampoules, lyophilized under sterile
conditions and aseptically sealed. Each ampoule
contains 10 mg of active compound.
Example I: Inhalation spray
14 g of 3-(4-fluorophenyl)-4-{4-[3-(pyridin-2-yl-
amino)propoxy]phenyl~butyric acid are dissolved in 10 1
of isotonic NaCl solution and the solution is filled
into commercially available spray containers having a
pump mechanism. The solution can be sprayed into the
mouth or nose. One puff of spray (approximately 0.1 ml)
corresponds to a dose of approximately 0.14 mg.
