Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
CA 02355251 2001-06-13
1
NEW ~3-AMIDE AND L3-SULFONAMIDE CARBOXYLIC ACID
DERIVATIVES. THEIR PREPARATION AND THEIR USE AS
ENDOTHELIN RECEPTOR ANTAGONISTS
The present invention relates to novel carboxylic acid
derivatives, their preparation and use.
Endothelia is a peptide which is composed of 21 amino acids and
is synthesized and released by vascular endothelium. Endothelia
exists is three isoforms, ET-1, ET-Z and ET-3. "Endothelia" or
"ET" hereinafter refers to one or all isoforms of endothelia.
Endothelia is a potent vasoccnstzictor and has a strong effect on
vessel tone. It is known that this vasoconst=fiction is caused by
binding of endothelia to its receptor (Nature, ~, 411-415,
1988; FEeS Letters,~23 , 440-444, 19A8 and 8iochem. eiophys. Res.
Coauuun . . 1~. 8 6 B-8 7 5 . 19 8 A ) .
Elevated or abnormal release of endothelia causes persistent
vasoconstriction in peripheral. serial and cerebral blood vessels,
which may result in disotders. As reported in the literature,
errdothelin is involved in a number of disorders. These include:
hypertension, acute myocardial-infarct, pulte~onary hyper-
tension, Raynaud's syndrome, cerebral vasospasms, stroke, benign
prostate hypertrophy, atherosclerosis. asthma and prostate cancer
(J.~vaseular-.Med. Biology 2, 207 (1990), J. Am. Med. Associat3.on
264, 2868 (1990), lvature 344, 114 (1990), N. Engl. J. Med. 32~,
ZOS (1989), !'. Engl. J. Med. ,~28. 1732 (1993), Nephron 6~, 373
(1994), Stroke ~5_, 904 (1999), Nature ~, 759 (1993), J. Mol.
Cell. Cazdiol. Z7, A239 (1995); Cancer Research 56, 663 (1996),
Nature Medicine 1, 944,(1995)).
At least two endothelia receptor subtypes, ~T, and ETa receptors,
are curreatly,described in the literature (Nature ~$, 730
(1990), Nature 348, 732 (1990)). Accordingly, substance8 trhich
inhibit tlse binding of endothelia to one or both receptors ought
to antagonize the physiological effects of endothelia and
therefore represent valuable drugs.
DE 19726146.9 describes the preparation of l3-amino and !i-azido
carboxylic acid derivatives and their use as endothelia receptor
antagonists. Further investigation has revealed that related
aromatic carboxamides and sulfonamide derivatives have
advantageous properties in relation to receptor affinity and
receptor binding profile. The present patent relates to the
preparation and use the=eof.
CA 02355251 2001-06-13
Z
The invention relates to J3-amido and !3-sulfonamido carboxylic
acid derivatives of the formula I
R4 Rz
w-x
S N~C 0 ~ ~Q
i
I z =y
Rs Ri
R
Where Eil is tetrazolyl or a group
O
C-~R
where R has the following meaning:
a) a radical OR6, Where R6 is:
hydrogen, the cation of an alka7.i metal, the canon of an
alkaline earth metal or a physiologically tolerated organic
ammonium ion such as tertiary C1-C~-alkylaau~onium oz the
aaanoaium ion ; .
C3-Cs-cycloalkyl. Ci-Ce-alkyl, CHZ-ghenyl. Which may be
~5 substituted by one or mo=e of the following radicals:
halogen, aitro, eyano, C1-Cg-alkyl, Cl-C~-haloalkyl, hydroxyl,
Cl-C'-alkoxy, me=capto, C1-C~-alkylthio, amino,
'NB~C1-C,-alkyl , N(C1-Ca-alkyl)z;
3o a C3-CA-alkenyl o= C3-Ce-alkynyl group, it being possible far
these groups in turn to car=y one to five halogen atoass;
Rs can furthermore be a phenyl radical Which may carry one to
five~haloqen atoms andlor ova to three of the following
35 .radicals: vitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl,
hydroxyl. C1-Cs-alkoxy, mereapto, C1-C,-alkylthio, amino,
Ng(C1-C4-alkyl), N(Ci-C4-alkyl)z: ,
b) a 5-membered heteroaromatic systet~ linked via a nitrogen
qp atom, suca as pyrrolyl. pYrazolyl, imidazolyl and triazolyl,
erhich may carry one or two halogen atoms or one or two
C1-C~-alkyl or one or zoo Cl-C4-alkoxy groups:
q5
CA 02355251 2001-06-13
3
c) a group
_ C - ~ C~~ ~p 5 g,
where k can assume the values 0, 1 and 2, p the values 1, 2,
3 and 4, and R~ is
to
C1-Cd-alkyl. C3~Ca-cycloalkyl, C3-C'-alkenyl, C3-CB-alkynyl or
phenyl, Which may be substituted by one or more, eg. one to
three, of the following radicals:
halogen, nit=o, cyano, C1-Cq-alkyl, hydro~rl, C1-Cq-alkoxy,
Gl-Cq-alkylthiv, amino, NH(C1-Cs-alkyl). N(CI-Ca-alkyl)Z.
mercapta;
d~ a radical
p
- N 5 - ga
H II
O
whe=e RB is:
Cl-C4-alkyl. C3-C,-alkenyl, C3-Ca-alkynyl, C3-Ce-cycloalkyl, it
being possible for these radicals to carry .a C1-C,-alkoxy.
3p C1-C,-alkylthio and/or a phenyl radical as mentioned under c);
Ci-C,-haloalkyl or phenyl, u~substituted or substitated in
particular as mentioeed under c).
The_other substituents have the folloaring meanings:
W and Z, ~rhich may be identical or different a=e:
nitrogen or methine; with the proviso that Q = nitrogen if W
90 and 2 = methine;
g is nitrogen or CR9:
Y , is nitrogen or CRS°;
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4
Q is nitrogen or CRI~; ~,rith the proviso chat X = CR9 and Y
CRlo if Q = nitrogen;
Rz and R3, which may be identical or difFerent, are:
' phenyl or naphthyl, each of which may be substituted by one
or more of the following radier~ls: halogen, vitro, cyano,
hydroxyl, mercapto, C1-C,-alkyl, CZ-C,-alkenyl, C=-C4-alkynyl,
CI-C,-haloalkyl, C1-C,-alkoxy, phenoxy,, C=-C°-haloalkoxy,
C1-C,-alkylthio, amino, NH(C1-C9-alkyl), N(C~-C°-alkyl)2 yr
phenyl which may be substituted one or more times, eg. one to
three times, by halogen, vitro, eyano, C1-C,-alkyl,
Gl-Ca-haloalkyl, Ci-C,-alkoxy, Ci-C,-haloelkoxy or
C1-C,-alkylthio; or
I5 '
phenyl or naphthyl wdieh ase linked together in ortho
positions by a direct linkage, a methyleae, ethylene oz
ethenyleae group, an oxygen or sulfur atom or an SOZ, pe or
N-alkyl group;
Z0
C5-C6-cyeloalkyl, it being possible for these radicals to be
substituted in each case vne or more times by; halogen,
hy3roxyl, mereapto, carboxyl, vitro, eyano, C1-C~-alkyl,.
C=-Cq-alkenyl, C2-C°-alkynyl, Cl-C~-alkoxy, C1-C,-alkylthio,
IS Cl-C,-haloalkoxy;
R° a) a radical
0
30 Riz
with R1~ phenyl, naphthyl or a five- or six-rnembered
heteroaromatic system comprising one to three
nitrogen atoms and/or one sulfur or oxygen atom,
35 ,, it being possible for said radicals to be
substituted one or more times by: halogen,
vitro, cyano, hydroxyl, mercapto, C1-C°-alkyl,
C1-C°-hydroxyalkyl, Cl,-C°-haloalkyl,
Ci-C4-alko~cy, C~-C°-alkylcarbonyl, carboxyl,
40 Cl-C4-haloalkoxy, C1-C4-alkylthio,~amino,
NH(C1-Ca-alkyl), N(C1-C,-Slkyl)2, BZN50~,
(CI-C9-alkyl)NHSOZ, (C1-C4-alkyl)ZNSOZ, or phenoxy
or phenyl, each of which may be substituted one
or more times, e.g. one to three times, by
45 halogen, vitro, eyana, C1-Ca-alkyl,
CA 02355251 2001-06-13
C1-Ca-haloalkyl, CI-C9-alkoxy, C1-ca-haloalkoay
and/or Cl-C9-alkylthio
5
b) a radical
0
-S- Ria
to
0
with R13 C1-C9-alkyl. C1-C4-haloalkyl o= phenyl, it being
possible for the phenyl radical in turn to carry
one to five halogen atoms and/or one to three of
the follcwi~g radicals: C1-C~-alkyl,
C1-Ca-haloalkyl, C1-Ge-alkoxy, CL-C,-haloalkoxy
and/or C1-Cq-alkylthio;
RS is hydrogen, C1-C4-alkyl:
Zo
R~ and Rla(~,rhich may be identical or different) are:
hydrogen, halogen, Cl-C,-alkoxy, Cl-C'-haloalkoxy,
C3-C6-alkenyloxy. C3-C6-alkynyloxy, C1-C,-alkylthio,
Cl-C9-alkylcarbonyl, Ci-C4-alkoxycarbonyl, hydroxyl, N82,
NH(Cl-G~-alkyl), N(Ci-C~-alkyl)Z;
CI-C4-alkyl, CI-C~-alkenyl. C=-C,-alkynyl, it being possible
for these radicals to be Substituted by halogen, hydroxyl,
mercapto, carboxyl, cyano;
or CRS or CRla is linked to CR11 as indicated for R11 to give a
5- or 6-membeted ring,
R~i . is hydrogen, halogen, C1-C,-alkoxy, Cl-C~-haloalkoxy,
C3-Cd-alkenyloxy, c3-cs-alkynyloxy, Cy-C4-alkylthio,
C1-Ci-alkylcarbonyl, Cl-Ca-alkoxycarbonyl, P8(C1-Ca-alkyl),
N(C1-C4-alkyl)z, hydroxyl, carboxyl, cyano, amino, me=captv;
C~-C,-alkyl, CZ-CQ-alkenyl, CZ-Ca-alkynyl, it Deing possible
for these radicals to be substituted one or more times by:
halogen, hydroxyl, mercapto, carboxyl, cyano, amino,
C1-CQ-alkoxy;
~5 , or CR11 forms together With CRS or CRi° a 5- or 6-meaibered
alkylene or alkenylene ring which may be substituted by one
or two C1-C4-alkyl groups, and in which in each case one or
CA 02355251 2001-06-13
6
more methylene groups may be replaced by oxygen, sulfur. -NH
or -N(C1-Cq-alkyl).
The definitions applying herein and hereafter are:
an alkali metal is, for example, lithium. sodium, potassium;
as alkaline,earth metal is, for example, calcium, magnesium,
barium;
organic ammonium ions are protonated amines such as ethanolamine,
diethanolamine, ethyleaediamine, diethylamine or piperazine;
C3-Cs-cycloalkyl is, fot example, cyclopropyl, cyclobutyl,
cyclopeatyl, cyelohexyl, cycloheptyl or cyclooctyl;
~i-ce-haloalkyl can be linear or branched, eg. fluoromethyl,
d~fluoromethyl, trifluoromethyl, chlorodifluoromethyl,
dichlorofluoromethyl, trichloromethyl, 1-fluoroethyl,
I0 2-fluoroethyl, 2.Z-difluoroethll, 2,2,2-trifluoroethyl,
Z-chloro-2,2-difluoroethyl, Z,2-dichloro-Z-fluoroethyl,
Z,2,Z-ttichloroethyl or pentafluoroethyl;
Ci-Ca-haloalkoxy can be linear or branched, eg- difluorornethoxy,
Z5 trifluoromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy,
2,2-difluoroethoxy, 1,1,2,2-tetraflucroethoxy,
2,2,2-trifluotvethoxy, Z-cttloro-1,1,2-trifluoroethoxy,
Z-fluoroethoxy or pentafluoroethoxy;
30 ~y-C4-alkyl can be linear or branched, ag. methyl, ethyl,
1-propyl, 2-propyl, Z-methyl-Z-propyl, 2-methyl-1-propyl, 1-butyl
or Z-Dutyl;
C2-C,-alkenyl can be linear or brapched, eg. ethenyl,
35 1-p=open-3-yl, l-prvpen-2-yl, 1-pxopen-1-yl, Z-methyl-1-propenyl,
1-buzenyl or 2-butenyl;
C=-C,-alkynyl can be linear or branched, eg'. ethynyl,
1-propyn-1-yl, 1-propyn-3-yl, 1-butyn-4-yl or 2-butyn-4-yl;
40 Gl-Ca-alkoxy can be linear or branched, eg, methoxy, ethoxy,
ptopoxy, 1-methylethoacy, butoxy, 1-methylpropoxy, Z-methylpropoxy
or l,i-dimethylethoxy;
Cs-Cs-alkenYloxy can be linear or branched, eg. allyloxy,
45 2-buten-1-yloxy or 3-buten-2-yloxy;
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7
C3-C6-8lkynyloxy eaa be linear or branched, eg. 2-propyn-1-yloxy,
Z-butyn-I-yloacy or 3-butyn-Z-yloxy; .
C1-C9-alkylthio can be linear or branched, eg. methylthio,
ethylthio, propylthio, 1-methylethylthio, butyltnio,
' 1-methylpropylthio, 2-methylpropylthio or 1,1-dimethylethylthio;
C1-CS~alkylcarbonyl can be linear or branched, eg. acetyl,
ethylcarbonyl o= 2-propylcarbonyl;
C1-CB-alkyl can be linear or branched, eg. C1-Ca-alkyl, pentyl,
hexyl, heptyl or octyl;
C3-Ce-alkenyl can be linear or branched, eq. 1-propen-3-yl,
I-propen-2-yl, 1-propen-l-yl, 2-methyl-1-propeoyl, 1-buten-4-yZ,
2-bates-3-yl, 1-peatet~-5-yl, 1-hexes-6-yl, 3-hexes-6-yl,
2-hepten-7-yl or 1-octen-B-yl;
G3-CB-alkynyl can be linear or bra»ched, eg. 1-propyn-1-yl,
1-jp=opyn-3-yl, 1-butya-4-yl, Z-burins-4-yl, Z-pentyn-5-y',
3-hexyn-6-yl, 3-heptyn-7-yl, 2-oetyn-B-yl;
Halogen is, far example, flucrine, chlorine, bromine, iodine.
The invention further relates to those compounds from Which the
compounds of the formula I can be liberated (called prodrugsl.
Preferred prodrugs are those ~rhose release takes place under
conditions prevailing in certain compartments of the body, eg. in
the stomach, intestine, blood circulation, liver.
The compounds I and the irate=mediates for preparing them, eg, II
and I=I, may have one or more asymtnetrically substituted carbon
atoms. Compounds of this type can exist as pure enantiomers or
pure diastereomers or as mixture thereof. It is preferred to use
an enantioanerically pure compound as active ingredient.
the invention further relates to the use of the abovementioned
carboxylic acid derivatives to produce drugs, in particular to
produce inhibitors of ETa andloz ETB receptors. =he novel
compounds are suitable as antagonists as defined at the outset.
The compounds according to the invention with formula I can be
prepared via the routes described in DE 19726146.9.
A possible alternative to this is preparation via intermediates
of the general formula III; these derivatives can be synthesized
CA 02355251 2001-06-13
8
either by reducing azides of the formula II (see DE 19726146.9)
by generally known methods oz by opening the oxazoline
derivatives of the general formula IV Which are described in Wo
95/07266.
RZ Rz . R3
Ri
H R R=
p C-OH < N 0
io 3 R~ R3 Rl , IV
zi
xrz
The oxaxoline derivatives of the formula Iv can he opened by
treatment with aqueous solutions of strong acids such as
' hydrochlori.c acid, hydrobromic acid, sulfuric acid, perchloric
Z5 acid, trifluoroaeetic acid, toluenesulfonic acid, ~nethane'ulfonic
acid or trifluvramethanesulfonic acid in the presence of a
suitable solubiliZer. All water-miscible solvents can be used for
this purpose as long as they are inert toward the reagents used.
a0 Examples of such solubilizers are alcohols such as methanol,
ethanol. n-propanol, isopropanol; ethers such as tetrahydrofuran
or dioxane; nitrites sued as acetvnitrile or propionitrile;
amides such as dimethylformarnide -or ~aia~etbylacetamide; sulfoxides
and 3ulfones such as dimethyl sulfoxide.: carboxylic acids such as
25 acetic acid or propionic acid.
The reaction in this case is preferably carried out at a
temperature in the range between 0°C and the boiling point of the
solvent or solvent a~.ixture.
3D
Compounds according to the invention in ~rhich RqRSN is aromatic or
hetezoaromatic carboxamido can be prepared, for example, by
acylating III oe the nitrogen or, alternatively, acylating both
the amino group and the hydroxyl group in III and then
35 eliminating the ester acyl group using generally known methods.
For this purpose, the compound of the general fonttula III is
reacted with tl~e acylating reagent in the molar ratio of 1=1 to
1:6.in the presence of a suitable diluent. All solvents which are
inert toward the reagents used can be used for this purpose.
45
CA 02355251 2001-06-13
9
RZ O Rx
FI N C O I= ~ H
H w~ R N C OH
~ H
Ri R3 Ri
v
Examples of such solvents oz diluents are aliphatic, al icyclic
and aromatic hydrocarbons, Which may in each ease optionally be
chlorinated, such as hexane, cyclohexane, petroleum ether,
naphtha, benzene, toluene, xylene, methylene chloride,
chloroform, ethyl chloride and tricl~lotoethylene, ethers such as
diisopropyl ether, dibutyl etAer, methyl tent-butyl ethe=,
dioxane and tetrahydrofuran, nitriles ouch as acetonitrile and
prnpfonitrile, amides such as dimethyltormanide,
dimethylacetamide and N-methylpyrrolidone, sulfoxides and
sulfaaes such as dimethyl sulfoxide and sulfolane.
Z0 The reaction in this case is preferably carried out at a
temperature in the range between o°C and the boiling point of the
solvent or solvent mixture.
The presence of a zeaction catalyst may be~advantageous. A
Z5 suitable catalyst in this case is, for example,
dia~ethylaminopyridine.
the resulting compounds of the general formula V are converted
into the B-amido carboxylic acid derivatives according to the
30 iwention by zeacting the compounds of the general formula V faith
neterocycles of the general formula VI.
~n1_X W_X
p + ~ Ri 4 --~~ ~ Q -~1 R' g C 0 --~~ . Q
35 3 Rl Z =Y
2=Y
VI
Ia
R~' in formula vI is halogen or R15-501-, where R15 can be
40 C1-C4-alkyl, C1-C,-haloalkyl or phenyl, and the definitions of W,
X, Y, Z and Q are those given at the outset. The reaction
preferably takes place in an inert solvent or diluent with the
addition of a suitable base, i.e. a base ~rhich deprotonates the
intermediate V, at a temperature in the range from room
45 temperature to the boiling point of the solvent.
CA 02355251 2001-06-13
l
Compounds of the formula v= are known, and some of them can be
bought or they can be prepared in a generally known manner.
zf al in compounds of the general formula Ia is an ester, the
ester group can be cleaved with acid or base or by hydrogenolysis
to give the free carboxylic acids with R1 ~ COOH. Compounds of the
type Ia with Ri = C008 can, however, also be obtained directly by
dep=vtonating the intermediate V in which R1 = COON with three
equivalents of a suitablQ base and reacting with compounds of the
general formula VI. Once again, the reaction cakes place in an
inert solvent and at a temperature in the range from room
temperature to the boiling point of the solveat.
The base which caa be used is an alkali metal or alkaline earth
metal hydride such as sodium hydride, potassium hydride or
calcium hydride, a carbonate such as alkali metal carbonate, e.g.
sodium or potassium carbonate, an alkali metal or alkaline earth
metal hydroxide such as sodium or potassium hydroxide, an
orgaaou~etallic~compouad such as butyllithium or an alkali metal
amide such as lithium diisopropylamide or lithium amide.
The~compounds according to the invention of the general formula I
in which R4R5N is sulfonarnido can be obtained from anuLnee of the
general formula VII and are prepared as described in DE
I9~~61.46_9. For this purpose, VII i,s reacted by generally known
methods irith suLfonyl halides and, if Ri is an ester, the ester
group is cleaved arith acid or base or by hydrogenolysi5.
Rz Rx
R Hi X II ~ H u1 R
8 N ~ C O---~~ ~~Q ~ R13-5-N C -O ~ ~ Q
Z
IR1 8=Y ~~ N I Z=Y
Ra R7
Ib
Compounds o! the formula I caa also be prepared by startiDg front
the appropriate carboxylic acids, i.e. compounds of the formula I
in which Ri is COON, first converting them in a conventional way
in an activated form, such as an acid halide, anhydride ar
imidazolide, and then reacting the latter orith a~ appropriate
hydro~cyl compound HOR6 oz sulfonamide BiNSO2Re . This reaction can
be carried out in conventional solvents and often requites the
addition of a base, in which case those mentioned above are
suitable. These two steps can also be simplified, for example, by
allowing the carboxylic acid to act in the presence of a
dehydrating agent such as a carbodiimide on the hydroxyl compound
or the sulfonamide.
CA 02355251 2001-06-13
11
It is additionally possible to prepare compounds of the formula I
by starting from the salts of the appropriate carboxylic acids,
i.e, from compounds of the formula I in' which R1 is a group Coots,
where H can be an alkali metal cation or the equivalent of an
S alkaline earth metal cation_ These salts can be reacted With many
' compounds of the formula R-D where D is a conventional
nucleofugie leaving group, for example halogen such as chlorine,
bromine, iodine or optioeally halogen-, alkyl- or
haloalkyl-substituted aryl- or alkylsulfonyl .such as
toluenesulfonyl aid methylsulfoeyl or another equivalent leaving
group. Compounds of the formula R-D with a reactive substituent D
are known or can easily be obtained with general expert
knowledge. This reaction can be carried out in the conventional
solvents and is advantageously performed in the presence of a
base, in erhich case those mentioned above are suitable.
~ompouads of the forinula I in which Rt is tetrazolyl can be
prepared according to the methods described is WO 96/11914 from
the corresponding carboxylic acids (formula I with R1 ~ COOH).
Z0
In some cases, it is necessary to use generally knocan protective
group techniques to prepare the compounds I according to the
invention. If, for exaa~le. R4RSN = 9-8o-phenyl-CONS-, the
hydroxyl group can initially be protected as benzyl ether, which
is then cleaved az a suitable stage in the reaction sequence.
Compounds of the formula I and v can be obtained in
enantiornerically pure form by carrying out a classical raeersate
resolution ~rith suitable enantiomerically pure bases, such as
those described in wo 96/11914, ~rith racemic or diastereomeric
compounds of the formula I and v.
Glith a view to the biological effect, preferred carboxylic acid
derivatives of the general formula I - both as~pure enantiomers
or pure diasteteomers and as mixtures thereof ~ are those in
which the substitueaes have the following meanings:
R1 is tetrazolyl or a group
O
C-R
in ~ohich R has the following meaning:
a) a radical OR6, in Which R6 is:
CA 02355251 2001-06-13
12
hydrogen, the cation of as alkali metal, the cation of an
alkaline earth metal, a physSologically tolerated organic
ammonium ion such as tertiary C1-Ca-alkylaraswnium or the
ananonium ion;
C3-Ce-cycloalkyl, Cl-Ce-alkyl, CHi-phenyl, which can be
substituted by one or more of the follo~ring radicals:
halogen, C~-C4-alkyl, Cl-C!-haloalkyl, hydroxyl, C1-C~-alkoxy,
mercapto, C1-C,-alkylthio, NH(Cl-C4-alkyl), N(Cl-C,-alkyl)?;
to
a C3-CB-alkenyl or a C3-Ce-alkynyl group, it being possible
for these groups in turn to carry one to five halogen atoms;
Rs can also be a phenyl radical Which can carry vse to five
halogen atoms and/or one to three of the following radicals:
C1-C4-alkyl, C1-C~-haloalkyl, hydro~cyl, C1-C4-alkoxy,
mercapto, C1-C4-alkylthio, NH(C1.-~4-alkyl), N(Cl~~a-alkyl)?;
D) a 5-membered heteroaromatic system trhich is linked via a
nitrogen atom, such as pytazolyl, imidaaolyl and triazolyl,
which a~ay carry one or tmo halogen atoms or one or two
~ C~-C,-alkyl or. one or two C1-C,-alkoacy groups;
c~ a,group
(o)r '
I
- O - ( C8~ )p S R'
3o is Which k can assume the values 0, 1 and Z, p can assume the
values 1, 2, 3 and 4, and ~!~ is
ci-C,-alkyl, C3-C,-cycloalkyl, C3-Ce-alkenyl, C3-Ce-alkynyl or
pdenyl Which can be substituted by one or more, e.g. one to
, three, of the following radicals:
halogen, C1-C9-alkyl, hydroxyl. C1-C~-alkoxy, CZ-Ca-alkylthio,
NR ( C1-Ca-alkyl ) . N ( Cl--C4-alkyl ) z . a~ereapto;
d ) ~ a radical
O
-N 5- Ae
N
O
CA 02355251 2001-06-13
in which Re is:
Cl-C9-alkyl, C3-Ca-alkenyl, C3-CB-alkyayl, Cj-C8-cycloalkyl, it
being possible for these radicals to carry a Cl-Ca-alkcxy,
C1-C4-alkylthio and/or a phenyl radical as mentioned under c);
Cl-C,-haloalkyl or phenyl, optionally substituted in
particular as mentioned under c);
W and 2 (which may be identical or different):
nitrogen or methine; with the proviso that Q = nitrogen i.f W
and Z = methine;
X nitrogen or CR9;
Y nitrogen or CR»; '
Q nitrogen or CRil: With the proviso that X = CR9 and x =
CRl° if Q ~ nitrogen;
Rx and R3 (which may be identical or different):
phenyl or naphthyl. each of which may be substituted by one
Z5 or mote of the following radicals: halogen, eyano, hydroxyl.
mercapzo, C1-Cq-alkyl, C1-C4-haloalkyl,~Cl-C~-alkoxy, phenoxy,
Cl-C4-halvalkoxy. Cl-Cq-alkylthio, amino, Na(Cl-C~-alkyl),
N(C1-t4-alky112 or phenyl, ~rhich may be substituted one or
more times, e.g. one to three times, by halogen, cyano,
C1-Ca-alkyl, Ci-C4-haloalkyl, cl-Ca-alkoxy, Cl-Cq-haloalkoxy or
Cl-C4-alkylthiop or
phenyl or naphthyl, which are linked together in ortha
positions by direct linkage, a methylene, ethylene or
.etheaylene group. an oxygen or sulfur atorn,or an 50i, NH er
N-alkyl group;
Rd a) a radical
0
~z
R
With Rlz phenyl, naphthyl or a five-~or six-membered
heteroaromatic system comprising one to three
nitrogen atoms and/or one sulfur or oxygen atom,
it being possible for said radicals to be
substituted one or more times by halogen, eyano,
CA 02355251 2001-06-13
14
hydroxyl, mercapto, CI-Cq-alkyl,
C1-C~-hydroxyalkyl, C1-Cq-haloalkyl,
Cl-Ca-alkoxy, Cl-Ca-haloalkoxy, Cl-Cd-alkylthio,
amino, NH(C1-C4-alkyl), N(C1-C4-alkyllZ~ AzNSaz~
(Cl.Cq-alkyl)NHSOZ, (Cl-C4-alkyl)ZNSOZ, or phenoxy
' ~ or phenyl, each of which may be substituted one
or more times, e_g. one to three rimes, by
halogen, eyano, Cl-C,-alkyl. C1-C9-haloalkyl,
C1-C4-alkoxy, C1-Ca-haloalko~cy.and/or
Ci-Cq-alkylthio;
b1 a radical
O
-I5,_ Ri3
O
with Rl3 C~-Cq-alkyl, Cl-C4-haloalkyl or phenyl, it being
possible fvr tha phenyl sadieal in turn tv carry
one to five halogen atoms and/or one to three of
the following radicals: C1-C4-alkyl,
C1-Cq-haloalkyl, C1-C~-alkoxy;
R5 hydrogen, methyl;
R9 and Rl~(which may be identical or different):
. hydrogen, halogen, C1-Cq-alkoxy, C1-Cq-?raloal3co~cy,
C1-Ca-alkylthio, D~8(C1-Ca-alkyl), N(C1-Ca-alkyl)t;
C1-C,-alkyl. CZ-C,-alkenyl, it being possible fo= these
=adieals to be substituted by halogea, hydroacyl,
.mereapto, cyano;
or CR9 or CR1~ is linked to CRL1 as indicated fo= R11 to
give a 5- or 6-membered ring;
R11 hydrogen, halogen, C1-C4-alkoxy, Cl-Ca-haloalkoxy,
C1-C4-alkylthio, NH(C1-C4-alkyl), N(Ci-C4-alkyl)Z, eyano;
cl-C4-alkyl, CZ-Ca-alkenyl, it being possible for each of
these radicals to he substituted one or more times by:
halogen, cyano, C1-ca-alkoxy;
CA 02355251 2001-06-13
~ 15
or GR11 forma together with CR9 or CR1°~a 5- or 6-membered
alkylene or alkenylene ring v~ie?r may be substituted by
one or two C1-C,-alkyl groups, and in ~rhich in each case
one ar more methylene groups may be teplaeed by oxygen, .
sulfur, -Nii or -NtCl-C~-alkyl).
particularly preferred compounds of the formula I - both as
pure enantiomers oz pure diastereomers and as mixtures
thereof - are those in which the substituents have the
following meanings:
Ra is tetraaolyl or a group
0
C-R
is which R has the following meaning:
a) a radical OR6, in which R6 is.
Zo '
hydrogen, the cation of an al.7eali metal. ~e cgtion of an
' alkaline earth metal or the ammonium iorr:
C1-C8-alkyl, CB=-phenyl, Which can be substituted by one
Z5 . or more of the following radicals: halogen, C1-C4-alkyl,
C1-C~-haloalkyl, C1-Ca-alkoxy:
R6 can fuzthertnore be a phenyl radical which may carry
one to five halogen atoms and/or one to three of the
3o follooring radicals: C1-CQ-alkyl. C1-Cs-haloalkyl.
C1-C4-alkoxy~
b) a 5-membered heteroaromatic system linked via a nitrogcn~
atom, such as imidazolyl and triazvlyl, which may carry
35 ' one or !WO halogen atoms, or one or two Cl-C,-alkyl or
one or two C1-C4-alkoxy groups:
c) a group
(il)k
4o
-O-- (C8i)p S R'
in which k may assume the values 0, l and 2, p may assume
s5 the values 1, 2. 3 and 4, and R~ is
CA 02355251 2001-06-13
16
Cl-C4-alkyl, C3-CB-cycloalkyl or phenyl Which may be
substituted'by one or more, e.g_ one to three, of the
folloW,irg radicals:
halogen, CI-Cq~alkyl, Cl-C4-alkoxy;
d ) a radic al
O
SI
- N - --- R'
N
O
in which Re is.
l5
Cl-C4-alkyl, C3-Ce-eyeloelkyl, it being possible for these
radicals to carry a cl-C~-alkoxy and/oz a phenyl radical
as mentioned under c);
Z0 Cl-.C4-haloalkyl oz phenyl, optionally substituted, ici
particular as mentioned under c);
W and Z (which may be identical or different):
Z5 , nitrogen or methine; with the proviso that Q m nitrogen
if W and Z = methine;
X ,nitrogen or CR9; . .
Y nitrogen o= CRlo
30 Q nitrogen or CR11; with the proviso that X ~ CRS and Y
= CR1~ if Q = nitrogen;
RZ and Rj (which may be identical or different
phenyl groups which may be substituted by one or more of
35 the following radicals: halogen, C1-Cq-alkyl,
C1-Cq-haloalkyl, Cl-Ca-alkoxy, phenoxy, C1-C9-alkylthio,
NH(C1-Cq-alkyl), N(C~-C9-alkyl)z or phenyl, which may ba
substituted one or more times, e.g. one to three times,
by halogen, C1-co-alkyl, C1-C9-haloalkyl, C1-C~-alkoxy or
40 Ci-Cq-alkylthio; os
phenyl groups which are linked together in ortho
positions by a direct linkage, a methylene, ethylene or
ethenylene group, an oxygen or snlfar atom or an SOz-,
45 NH- or I~-alkyl group;
CA 02355251 2001-06-13
17
R4 a) a radical
D
giz
Nith Rlz phenyl or a five- or six-membered heteroaromatic
system comprising one to three nitrogen atoms
andlor one sulfur or oxygen atom, it being
possible for said radicals to be substituted one
or more times by: halogen, hydroxyl, Cl-Ca-alkyl,
C1-Cq-haloalkyl, Cl-Ca-alkoxy, Cl-C9-haloalkoxy,
phenoxy, Cl-Ca-alkylthio, NH(C1-c4-alkyl),
N(C1-Cq-alkyl)?, (C1-Ca-alkyl)N850z,
cl-C4-alkyl ) zpSOz or phenyl rrhieh can be
substituted one or more times, e.g. one to three
times, by halogen, Cl-C~-alkyl; C1-Ca-haloalkyl,
' Cl-Cd-alkoxy and/or C1-C4-haloalkoay;
D) a radical
'
O
- S _ Ri3
O
Z5
with Rl~ C1-C4-alkyl, C1-C,-haloalkyl or phenyl. it being
po9sible for the phenyl radical in tu=r to ea==y
one to five halogen atoms and/or otie to three of
the following radicals: C1-C~-alkyl,
Cl-C4-haloalkyl. Cl-Ca-alkoxy;
RS hydrogen, methyl;
40
R9 and Rla(vhieD may be identical or different):
hydrogen, C1-C4-alkoxy, C1-C4-alkylehio, N(Cl-C~-alkyl)i;
C1-Ca-alkyl, it being possible for these radicals to be
substituted by halogen;
or CR9 or CRl° is linked with CRil as indicated for R11 to
forea a 5- o= 6-me~nbered ring;
CA 02355251 2001-06-13
f8
R11 hydrogen, C1-C,-alkoxy, C1-Ca-alkylthio, cyano;
G1-C4-alkyl, it being possible for these radicals in each
case to be substituted one or more times by halogen;
or CRil forms together with CR9 or CRl~ a 5- or 6-membered
alkylene or alkeoylene ring which may be substituted by
one or two Cl-C4-alkyl groups and in which, fn each case,
one oz more methylene groups can be replaced by oxygen,
sulfur, -NH or -p(Ca-C4-alkyl).
The compounds of the present invention offer a~novel potential
treatment of hypertension, pulmonary hypertension, myocardial
infarct, chronic heart failure, angina pectoris, acute/ch;tonic
kidney failure, renal insufficiency, cerebral vasospasms,
cerebral ischemia, subarachnoid hemorrhages, migraine, asthma,
atherosclerosis, endotoxic shock, endotoxia-induced organ
failure, intzavascular coagulation, ~estenosis after angioplaaty,
benign prostate hyperplasis, ischemic and intoxication-induced
ZO kidney failaze or l~ype.rtension. cgclosporine-induced kidney
failure, erectile dysfunction, metastasis and gror.rth of
mesenchymal tumors, cancer, prostate cancer, contrast
agent-induced kidney failure, pancreatitis, gastrointestinah
ulcers.
The invention further relates to combination products consisting
of endothelin.receptor antagonists o~ the formula'I and
inhibitors of~the resin-aagiotensin system. Inhibitors of the
resin-angiotensin system are resin inhibitors, angiotensin Z=
ant8gonists and, in particular, angiotensin converting enzyme
(ACE) inhibitors.
These combination products are particularly suitable for treating
and preventing hypertension and its sequelae, and for treating
heart failure.
The good effect of the compounds can be shown in the following
teats:
Receptor-binding studies
Cloned human ETA or ET8 receptor-expressing C80 cells were
employed for binding studies.
CA 02355251 2001-06-13
- ~ 'i'9
Membrane preparation.--.
The ETa or ET8 receptor-e~cpressing CHO cells were grown is Dt~iEH
NUT MIX F12 medium (Gibco, No. 21331-020) with 10% fetal calf
serum (FRA Laboratories GtnbH, Lint, No. A15-022), 1 ml~i glutamine
. (Gibeo No. 25030-024), 100 U/ml penicillin and 100 )tg/ml
streptnmycia (Sigma No. P-07.81). After 48 hours, the cells were
washed with PBS and incubated with 0.05 trypsin-containing PHS
at 37°C for 5~ minutes. This was followed by neutralization with
medium, and the cells were collected by centrifugation at
300 x g.
For membrane preparation, the cells Were adjusted to a
concentration of l0e cells/ml of buffer (50 mri Tris-8C1 Duffer, pB
7_4) and then disintegrated with ultrasound (Branson 5onifier
250, 40-70 seconds/eonstant output 20).
83.nding assays
Z0 For the ETa and ETa receptor-binding assay, the membranes were
suspended in incubation buffer (50 mM Tris-5C1.~ pe 7.4 eith 5 mrl
' , MnCl2, 40 ~g/ml bacitraeia and 0.2% HSA) in a concentration of
50 ~:g of protein per assay mixture and incubated with ZS pM
yxsl~_gTl (HTA receptor assayl or ZS pM I1~5I7-FTC (ZTa receptor
assay) in the presence and absence of test suDstanee at 25°C. The
nonspecific bind~g Was determined using 10-1 M E"ry. After 30 min,
filtration through GF/B glass fiber filters (Whatman, England) in
a Skat=on cell harvester (5katron, Lier, Nox~rayl separated free
and bound radioliqand, and the filters were washed e.rith ice-cold
Tris-HC1 buffer, pH 7.4 with 0.2% HSA. The radioactivity
collected on the filters was quantified using a Packard 2200 GA
liquid scintillation counter_
Testing of ET antagonists in vivo:
Male SD tats weighing 250 - 300 g were anesthetized with
amobarbital, artificially ventilated, vagotomized and pithed_ The
carotid artery and jugular vein were cathezeri2ed.
In control animals, intravenous administzation of 1 mglk9 ETl
results in a marked rise in blood pressure r,~hich persists for a
lengthy period.
CA 02355251 2001-06-13
The test animals received i_v. injection (1 ml/kg) of the test
compounds 30 min before administration of ET1. To determine the
ET-antagonistic properties, the changes in blood pressure in the
test animals were compared with those in the control animals.
5
' Oral testing of ET receptor antagonists:
Male narmotensive tats (Sprague Dawlcy, Janvier) Weighing
250-350 g axe pretreated with the test substances orally. 80
l0 minutes later, the animals are anesthetized with urethane, and
the carotid artery (for measuring the blood pressure)~and the
jugular vein (administration of big endothelin/.endothelin 1) are
catheterized.
15 After a stabilization period, big endothelin (z0 (tg/kg, admin.
vol. 0.5 ml/kg) or ET1 (0.3 ~.g/kg, admin. vol. 0.5 atl/kg) is given
intravenously. Blood pressure and heart rate are recorded
continuously for 30 minutes. The marked and long-lasting changes
in blood pressure are calculated as the area under the curve
ZO (AQC). To detereu.ne the antagonistic effect of the test
substances, the ADC for the animals treated with substance is
compared with the AUC for the control animals.
Tre novel compounds can be admiriistered orally or parenterally
Z5 (subcutaneously, intravenously. intramuscularly,
intraperitoneally) in a conventional way. Administration can also
tekg place orith vapors or sprays tbrough the nasvpharyngesl
space.
The .dosage depends on the age, condition and weight of th~
patient and on the mode of administration. As a rule, the daily
dose of active ingredient is from about 0.5 to 50 mglkg of body
weight on oral administration and from about 0.1 to 10 tng/kg of
body weight art parenteral administration.
The novel compounds can be administered in conventional solid or
liquid pharmaceutical form" eg. as uneoated or (film-)coated
tablets, capsules, powders, granules, suppositories, solutions,
ointments, creams or sprays. These are produced in a conventional
way. The active ingredients can for this purpose be processed
with conventional pharmaceutical aids such as tablet binders,
bulking agents, preservatives, tablet disintegrants, flow
regulator, plasticizers, wetting agents, dispersants,
emulsifiers, solvents, release-slo~,ring agents. antioxidants
and/. or propellant gases (cf. H. Sucker et al.: PharmaZeutisehe
Technologic, Thieme-Verlag, Stuttgart. 1991)_ Tha administration
CA 02355251 2001-06-13
forms obtained i~ this way~AOrmally contain from 0.1 to 90% by
weight of active ingredie~.
Synthesis Examples '
s
Example l:
tiethyl 3-amino-Z-hydroxy-3,3-dipheaylpropionate
to O.Z g of a 10~ palladium/carboa hydrogenation catalyst gas added
to a solution of methyl 3-azido-2-hydroxy-3,3-diphenylpropioaate
(5.71 g; 19.2 aanol) in methanol (100 ml). The mixture was stirred
under a hydrogen atmosphere at zoom temperatu=e for 48 hours; the
catalyst was rhea filtered off and the solvent was distilled off.
i5 The residue Was taken up in 5% strength aqueous citric acid and
' the resulting solution eras extracted r~ith ether. The aqueous
phase ~as~then made alkalise with dilute sodium hydroxide
solution and again extracted ~rith ether. The extracts obtained
from the alkaline phase were dried over magnesium sulfate,~and
20 solvent was removed in vacuo. 4.03 g (14.9 muiol, 77% yield) t'f
the pure amine were obtained.
~ (200 M8a): 7.5 (m. 2 E1): 7.2-7.4 (m. 9 H). 5_0 (s, 1 H): 4.2
(s br, 1 E1). 3.4 (s, 3 ti): 2.0-2.9 (s bz, 2 Hl.
as
Example 2:
2-(4-Methoxybenzoylamino)-1-methoxycarbonyl-2.2-diphenylethyl
4-meehoxybenzaate
8yridine (1.17 g; 14.7 mmoll. a spatula tip of
di,methylarninopyridine, and pare-methoxybenzoyl chloride (2.52 g,
14.7 mmol) were successively added to a solution of methyl
3-amine-Z-hydroxy-3,3-diphenylpropioaate (2.00 g, 7.37 mmol) in
dichlorornethane (10 ml). The mixture Was stirzed at room
temperature for 4 hours and then, for vorkup, mixed ~rith mater
aad~extracted With ether. The combined organic phases were washed
with aqueous citric acid and saturated brine and then dried over
magnesium sulfate. The solvent was evaporated off is vacuo to
afford the crude bisacylation product. Which was employed without
further purification (1.37 g; 28% yield ~rith a purity of BZ%
according to HPLC).
CA 02355251 2001-06-13
22
Example 3:
Methyl 2-hydroxy-3-(4-methoxpbenzoylamino)-3,3-diphenylpropionate
Z-(4-Methoxybenzoylamino)-1-methoxycarbonyl-2,Z-diphenylethyl
4-rnethoxybenZOate (1.37 g; 2.08 mtnol with a parity of eZ%) vas
dissolved in methanol (20 ml), and potassium carbonate (B63 mg,
6. Z5 uunol) vas added. The resulting mixture was stirred at room
temperature for 16 hours and the solvent Was removed in vacuo.
id The residue vas taken up in water and extracted With ether; a
colorless solid precipitated during this and was isolated by .
filtration and was identical to the title compound. The aqueous
phase was then extracted again with ethyl ac~tate. The organic
phases were combined aad dried over magnesium sulfate, and the
solvent was removed in vacuo_ The crude product vas purified Dy
crystallization from diehloromethaae/ether/n-hexane, resulting in
a colorless solid (503 mg; 60$ yield).
Example 4.
2D
eeazyl 2-hydroxy-3-(4-methoxybenzoylaa~ino)-3,3-diphenyl-
propionate
2_11 ml of a 1 molar sodium hydroxide solution were added to a
15 solution of methyl Z-hydroxy-3-(4-methoxybenzoylamino)-3,3-di-
phenylpropionate (503 mg; 1. Z4 mmol) in 1:2 water/tetrahydrvfuran
(50 ml) and Stirred at room temperature for 60 hours. The
sta=ting material had been substantially.coavezted after this: to
complete the reaction, 1 molar sodi~un hydroxide solution (Z.11
30 ail) vas added again. and stirring was continued for one hour. The
mixture Was diluted with water, extracted with ether, acidified
with citric acid and again extracted with ether. The extracts
obtained from the acidic phase were dried ever magnesium sulfate
and the solvent was removed in vacuo. The residue (406 mg) eras
35 taken up in dimethylformamide (ZO ml), and potassium carbonate
(179 mg: 1.30 mmol) and benzyl bromide (195 mg; 1.14 mmol) Were
successively added. The resulting mixture vas stirred at room
temperature for 20 hours and then 5% strength aqueous citric acid
gas added. After dilution with water, ext=action r.ras carried out
40 with dichloromethane and then With ether (product is only
moderately soluble in ether). The combined organic extracts were
thoroughly washed With water aad then with saturated brine and
dried over magnesium sulfate, and the solvent was removed in
vacuo. Traces of benzyl bromide and dimethylformamide were
45 removed by washing the residue with a little 1:1 ether/n-hexane.
Qe? mg (?9$) of the pure benzyl ester were obtained.
CA 02355251 2001-06-13
23
Example 5:
Bentyl 2-14,6-diethyl[1,3,5]triazin-Z-yloxy)-3-(4-methoxy-
bentoyla~no)-3,3-diphenylpropionate
Poeassi~un carbonate (80 mq; 0.58 mmol) and
2-chloro-4,6-diethyl-[1,3.5]t=iazine (74 mg; 0_43 Col) were
successively added to a solution of. beezyl . . . . .~ , : t
2-hydroxy-3-(4-methoxybenzoylamino)-3,3-diphenylpropionate (139
to sng, 0 .29 nmol ) in dimethylformatni.de ( 15 ml ) . The mixture vas
heated to 6D°C and stirred at this temperature for .4 hours. The
reaction Haas stopped by adding 5% strength citric acid (10 ml).
Dilution with water Nas followed by extraction With ether, and
the combined organic phases ~~rere washed with saturated brine and
dried oyez magnesium sulfate. The solvent was distilled off; the
residua was purified by flash chromatograpby (eluent: ethyl
acetate irr cyclohexane 30-50%). 124 mg of the target compound
Were obtained with a purity of 90% (accordiaq to BYLC) (63%
. yield).
Example 6:
2-(4,6-Diethyl[1,3,5]triazin-Z-yioxy)-3-(9-metlioxybenzoylamino)-
3,3-diphenylpropionic acid (I-4)
A 10% palladium/carbon hydrogenation catalyst (spatula tip) was
added to a solution of benzyl 2-(4.6-diethyl-(1,3,5]triazin-2-
yloxy)-3-(4-methoxybenzoylamino)-3,3-diphenylpropionate 1124 mg,
0.18 a~ol with a purity of 90%) in ethyl acetate (15 ml) and
stirred under a hydrogen atu~osphere at room temperature for 3
hours. The catalyst was then filtered off and the solvent was
distilled off in vacuo. The residue was crystallized from
dichloromethane/ether/n-hexane, resulting in 99 mg (73% yield) of
the pure carboxylic acid.
1H_~1(yg (200 l~iflz): 7.8 (m. 3 H1: 7.6 ldd. 2 H): 7.1-7_4 (m, 8 R); 6_9
(d, Z H); 6.fi (s, 1 8); 3.B (s. 3 H); 2.7 (q, 4 H); 1.2 it, 6 H).
ESI-MS : h' - 526 .
The folloaring were synthesized analogously:
2-(4,6-Diethyl[1,3,5]triazin-2-yloxy)-3-(3,5-dimethoxybenzoyl-
amino)-3,3-diphenylpropivnic acid (I-327)
1H-NMR (200 l~lliz): 7.9 (s.l e); 7.6 (m. 2 H), 7.2-7,5 (m. B H): 6.9
(d, z H); 6.7 (s. 1 H). 6.6 (t. 1 H1: 3.B (s, 6 B): 2.7 (q. 4 8)
1.2 (t. 6 H)-
CA 02355251 2001-06-13
. 24
ESI-MS: M~ = 556.
3-(3,5-Dimethoxybenzoylamino)-Z-(4,6-dimethyl-Z-pyrimidinyloxy)-
3,3-diphenylpropionie acid (I-248)
5-
1H-NMR (Zo0 t~iz): A.l (s Dr. 1 N): 7.7 (m, 2 H); 7_Z-7.5 (sn. 8 H):
7.0 (d, 2 H); 6.70 (s, 1 a); 6.65 (s, 1 a): 6.60 (t, 1 g); 3.8 (s, 6
p); .2.3 (s, 6~ R) .
EST-MS: M' = 5Z7.
3-8enzoylatnino-2-(4,6-dimethyl-2-pyrimidinyloxy)-3,3-diphenyl-
p=opionie acid (I-66)
1g-gMg ( Z 0 0 I~JAz ) : 8 . Z ( s br, 1 H ) : 7 . 8 ( ai, 2 8 ) : 7 . 6 (:n.
Z 8 ) t
7.1-7.5 (gin. 11 H); 6.70 (s, 1 H): 6.6S (s. 1 8): ~2~3 (s, 6 R).
ESI-h5: M- ~ 467.
z-( 4, 6-Dimethyl-2-pY=i~dioyloxy)-3-( 4-mec,hylbenzoyla~nino)-3.3-
diphenylpropionic acid (I-199)
Zo
(Z00 ~z): e.o (s br. 1 H): 7.7 (d, Z S); 7.6 (m. Z M):
7.1-7.5 (m. l0 S); 6.7 ~s, 2 H)s 2,4 (s, 3 H): Z~3 (s~ 6
ESI-M5 : !t' - 4 B 1.
Example 7_
Henayl 2-methyl-4.4-Biphenyl-4,5-dihydrooxazole-5-ca=boxylate
Boron trifluoride etherate (8.04 g; 56.7 mmvll vas cautiously
added to a solution of beezyl 3,3-diphenyloxirane-Z-carboxylate
(10.D g; 28.3 rnmol) in acetonitrile (10D ml). The cttixture vas
' stirred at room temperature for an hour and then concentrated in
a rotary evaporator. The residue eras taken up in water, saturated
with sodium chloride aad extracted with ethyl acetate. The
organic phase was dried over magnesium sulfate, and the solvent
~sas removed in vacuo; the residue (13.5 g) vas employed further
Without purificasion-
Example e:
Benzyl 3-amino-2-hydroXy-3,3-diphenylpropionate
Benzyl 2-methyl-4.4-Biphenyl-4,5-dihydrooxazole-5-carboacylate
(13.5 g; crude) was stirred in a miacture of methanol (25 ml),
Water (50 ml) and concentrated hydzochlorie acid (50 ml) at t'oom
teznpesature for 60 hours. The solution vas then decanted off the
undissolved t~taterial: the residue Was stirred in the
CA 02355251 2001-06-13
2'S
abovementioned mixture again fot three hours. Recantation gas
repeated; the remaining residue was discarded. The two liquid
phasres weze eomb~ined and adjusted to pB e-9 with sodium hydroxide
solution, whereupon crystallization started. The crystals were
washed with ether and filtered aff with suction; 4.65 g of the
required amino alcohol were obtained in 97$ purity_
lE~-NMR (Z00 MHz)s T.4 (m, Z 8); 7_1-7.3 (a~, 11 H); 7.0 (m, 2 H); 5.0
(s, 1 9); 4.9 (d, 1 )i); 4.7 (d, 1 EI): 1.9-Z.5 (s br, Z ~1).
Example 9:
Benzyl 2-hydzoxy-3,3-diphenyl-3-(4-trifluvromethylbenzoylamino)-
propionate
pyridine ( 99 mg; 1. 00 aunol ) . a spatula tip of ditnethylauiino-
pyridiae, and pare-trifluoromethylbenzoyl chloride (215 mg,
1.00 miool) were successively added to a solution of benzyl
3-amino-2-hyd=oxy-3,3-diphenylpropionate (365 mg: 1.00 mmol) in
ZO dichloromethane (50 ml). The mixture vas sti=zed at room
temperature for 60 hours sad then Worked up by extracting with
dilute citric acid. The organic phase was dried over magnesium
Sulfate, and the solvent Was removed in vacuo..The residue (540
mg) Haas taken up in chlorofarm (50 m1) ard. after additiae of
pyridine ( 36 mg, 0 . 45 tnn~ol ) and a few crystals of
dimethylarninopyridine, refluxed for 4 hours. After cooling,
working up was carried out by extraction with dilute citric acid_
zhe organic phase gas dried over magnesium sulfate, and the
solvent eras removed in vacuo_ The residue ~,ras crystallized from
ethe=/n-hexane; 235 mg (45s yield) of the pure product were
obtained.
1H-NMR (200 Mgz): 7.7 (d. ~ H): 7.5 (d, Z H); 7.2-7.4 (m, 13 A); 7,1
(d, z H~; 5.5 (d b=, 1 e); s.o (on. 2 H): 4.6-4.6 (s br, 1 H)_
Example 10:
Benzyl 2-(4,6-dimethyl-2-pysimidinyloxy)-3,3-Biphenyl-3-(4-
tri~luoromethylbenzoylamino)propionate
Potassium carbonate (100 mg; o.7Z mu~ol) and 2-methylsulfonyl-
4,6-dia~ethylpyrimidine (96 mg; 0.51 mmol) were successively added
to a solution of benzyl 2-Qydroxy-3,3-Biphenyl-3-(4-trifluoro-
methylbenzoylamino)propionate (ZZO mg, 0.42 mmol) it
dimethylformamide (15 ml)_ The enixtuze was heated to 80°c and
stirred at this temperature for one hour. The reaction was
stopped by adding dilute citric acid acrd Water (200 ml)_ After
CA 02355251 2001-06-13
' 26
extraction with ether, the organic phase vas dried over magnesium
sulfate and concentrated in vaeuo. The residue vas crystalli2ed
from ether/n-hexane; 158 mg (60$) of the pure title compound were
obtained.
Example 11:
1~
2-(4,6-Dirnethyl-2-pyrimidinYloxyl-3,3-diphenyl-3-(4-trifluoro-
methylbenzoylamino)propionic acid (I-ZO1)
A 10% palladiurn/carbon hydrogenation catalyst (spatula tip) vas
added to a solution of benzrl 2-(9,6-dimethyl-2-pyzimidinyloxy)-
3,3lBiphenyl-3-(9-trifluoromettrylbenzoylamino)propionate (150 mg,
0.24 am,ol) in ethyl acetate (50 nl), and the mixture was stirred
under a hydrogen atmosphere at room temperature for 2 hours. The
catalyst was then filtered off and the solvent was distilled off
in vacuo. The residue vas crystallized from etbe=/n-hexane,
resulting in 100 mq (78%) of the pure carboxylic acid.
lH-PMR (200 MHx)a 8.3 (s br, 1 A); 7.9 ( d, 2 H); 7.7 gym, 4 H);
_ 7,1-7.4 (m. 8 a): 6.7 (s, 1 Hi; 6.6 (s, 1 g); 2.3 (s, 6 8).
ESI-rlS: !!~ = 535,
The follotaing were prepared analogously;
3-(3,4-Dimethoxybenzoylamino)-2-(4,6-dimethyl-2-pyrimidinyloxy)-
3.3-diphenylpropionic acid (I-48)
1H-pMit (200 LiHz): 8.Z (s br, 1 H); 7.? (m. 2 8); 7.1-7.5 (m, l0 R);
6.8 (d, 1 e): 6.7 (s, i g); 6.6 ~s, 1 E1); 3.9 (s, 3 B); 3.8 (s, 3
R1: 'Z.3 (s, 6 S).
ES.I-MS: H' ~ 527,
3-(3,4-Difluorobenzoylaruino)-2-(4,6-dimethyl-2~py=imidinyloxy)-
3,3-diphenylpropionic acid (I-340)
1H-NMR (200 l~z): B.Z~Is Dr. 1 8): 7.5-?.8 (m. 5 H): 7.1-7.4 (m,
88); 6.7 (s, 1 H): 6.6 (s. 1 H); 2.3 (s, 6 R).
ESI-MS: M' = 503.
2-(9,6-Dimethyl-2-pyriatidinyloxy)-3-(4-fluorobenzoylamino)-3,3-
diphenylpropionic acid (I-170)
1H-NriR (200 M8z): B.2 (s br, 1 H): 7.8 (dd, Z H): 7.6 (m, Z H);
7.0-7.5 (m, 10 H); 6.7 (s, 1 B); 6.6 (s, 1 H): 2.3 (s, 6 H).
ESI-MS: M' = 985.
CA 02355251 2001-06-13
27
Example 12:
Methyl 2-(4,6-dimethoxy-2-pyrimidinyloxy)-3-methanesulfonyl-
ami.no-3,3-diphenylp=opionate
Methanesulfonyl chloride (53 mg. 0.73 mmol). pyridine (82 mg;
1.04.aanol) and dimethylaminopyridine (spatula tip) were added to
a solution of methyl 3-amino-2-(4,6-dirnethoxy-Z-pyrimidinyl-
oxy)-3,3-diphenylpropionate (213 mg: 0.52 mcrol) in
dichloromethane (15 ml). The mixture was stirzed at room
temperature for one Week. Because conversion was incomplete, a
further 0.20 mole equivalent of methanesulfonyl ehlozide was ,
added, and stinting w86 again carried out at room temperature for
three days. For ~oorkup. the mixture a~as diluted dith ether and
washed successively pith dilute citric acid, $odiutn bicarbonate
solution and saturated brine. The organic phase was dried over
magnesium sulfate, and the solvent was removed in vacuo. The
citric acid extract was neutralized and extracted with ether; the
organic phases obtained therefrom were dried and evaporated as
described above. The residue (206 mg) was employed further
wsthoat further workup.
Example 13:
Z5 2-1A.6-Dimethoxy-Z-pytimidiayloxy)-3-methanesulfonylamino-3,3-di-
phenylpropionic acid (I-156)
0.5o ml of a 1 molar sodium hydroxide solution gas added to a
solution of methyl 2-(4.6-dimethoxy-2-pyrimidinyloxy)-3-methane-
3o sulfonylamiao-3,3-diphehylpropionate (1B1 mg, crude) in 1:Z
wate=/tetrahydrofuzan (30 rnl), and the mixture Was stixred at
room temperature'for 5 days. =o complete the reaction, a further
0.5 wale equivalent of 1 mole= sodium hydroxide solution was
added, and the mixture was again stirred for 29 hours. After the
35 dilution with eater and extraction with ether the aqueous phase
was acidified with citric acrd and again extracted with ether.
The extracts obtained from the acidic phase were dried over
magnesium sulfate, and the solvent Was removed in vacuo.
Crystallization of the residue from dichlozomethane/n-hexane
40 afforded the pure target compound (71 mg: 33% yield owe= two
stages).
lg-pMg (200 MRz): 7.6-7.7 (m. Z H); 7_3-7.S (m. B H), 6_S (s, 1 B)7
6.3 (s br, 1 H). 5.8 (s, 1 H): 3.9 (s, 6 H). 2.Z (s, 3 8).
45 E5=-HS: M' - 973.
CA 02355251 2001-06-13
The coc~pounds Listed in Table 1 can be prepared analogously or as
desc=ibed in the qerreral part.
l0
20
30
~ '
45
CA 02355251 2001-06-13
Z9
N
Z Z.'..Z Z Z vT.Z ZZ Z Z Z Z Z w
. ~ . J - a
' a a ?1 .~
N ~ L t1L' El t dl
alz v z ~ yar~ da y aralaralz
o so m o w mz o zz ~ z z a ~ o
1 I1 I I t II I 1I 1 1 1 1 I I
a
a aa a a a aa a ~a a a a a a a
d
.~ .~.~ T. _ _ E li
z aa z z a za a az a v a z z a
x
.a ~1 r .
y y y ~
dd y ~ art tvm al~ eD
O ZZ fe1O G7WT~O ZZ fJZ o D Z G
t
I 11 I 1 I 11 I 11 1 1 1 1 1 1
U Ua a G U aa a aa a V a V a a
=a z
x
I 11
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U Z2 z Z Z ZZ 2 Z2 Z t Z Z
o
~
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s z m s=x vv as s oca a a z
s ox z z :.1i z xx ; z z I 1 z
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d s v 1o a a ~ ~~.1a oo a a a a,~.a
1 -ra I I I cc 1 ac~I 1 1 c c 1
...1~I ri.r..ialO r~ 1I ~ rtrid a!r1
~.b.-m.~.~,s.c~, r...~.~,>,c ~ca.
C ~1?.C G C CW.C ?~?vC G C G.G.C
V 4r101W Q1I1 V rl~1LIN 411 1 11
s ~,o .e.er ~.~..s oo s r s w w
P.G.N GL04GII1 ~ NN i1G 0.1 1 Or
1 iId1 1 1 '~1~iI 10Ip1 1 1 -./ I
v ~~ ald aroo al .-~.1alm aro o d
z 1r z z z 11 z rs z ~ x 1 I z
o wH o 0 o a~no EE o 0 o a Ino
~ Irl1 1 1 1 11 1 I 1 1
p'L!1N Q Q C't'ff'1Q Na V'V'Q A 1"1Q'
' ~, ~1 r~rWl
C C C C
al CI0141
O:r1.1n ~ ..~.-I~n G rl.-/G L .C.-1..1
r1t~1~ ? w'~~r~~ Glr?W1a O~W ~.?~'~1
G CC C C C CC 1 GC I t I C C G
aldm alv al11m w mal~.w w m m al
r ,c~ .cr r .~r 1 tG 1 1 I s s t
p.WW CLG C~W0.a~ iL0.a v~v 0.i>.G.
0.'
s dx x s m acs x <=s s m m x z s
0 00 0 0 0 00 0 00 o v o 0 0 0
a o0 0 0 0 00 0 00 0 0 0 0 0 0
L~Ua a a U aU U UU U U V a a a
r N ~ Q'~ ~
~ . .~
.O z -~Nf1Q VI~D1~COQ~ . ...
fQ 1 11 r r 1 =r 1 11 1 r = r r
.....
.....
CA 02355251 2001-06-13
30
N ,L
z z z Z z ~ zZ Z z : z zz 2 Z Z x z.~ Zz a z
r~ .~ ..~~ra
.
~, a,a.
r r aral 41y d r,al ~ ~s w ar
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.
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t 1 I I 1 I iI 1 I 1 1 Z1 1 1 f t 1I 11 t I1
G a U a a V aa U a G a Va a a a U UU aC7 a aU
a
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s x I a s ~oa 1s x x s s 1I>;1 xz
z x v a z z a~ 1 v a 1 aa a a a a az aa a aa
x s
a C~
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s t
aJs of d da al al m al
z y o z ~r~ al alm xz al alarz arz z a gw
o cux o m v z z z oo z z z o zo o z or>J
1 1 1 1 1 1 I 1 1 11 1 1 I 1 11 I 1 1(
a a a a a a za a a aa a a a v aa za v ~a
3 '
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a z z z z v zz = z z z z z z z zz ~z z zz
z
Z Z
Z Z O O 2 2 O 2
d CIN O ON alU U alalO O alala OG! 4IO O CIm
Tr.U U~ ~ 1 I ~ ~a a ~ ~ I C~~ ~a a ~
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N titG,Oi01I IW 0aI 1 Orw1 1 CLCVI 1CL W1 1 WIL
rEipI 1 1 1 a1 1 N N I I1 1 1 I N N1 1-.~d (1
.i~ GI01C!D Om al1 1 4741A O N al1 1m a1A O dN
s ~ z x z 1 1z z m .,z ,a.I I z a z zz z1 1 xz
E E~O O O ~ ao o z a o oa a O O c~vO Oo a op
1 1 1 I 1 I 1 I 1 1 1 1 I 1 I1 1 11
v eva ara ehnv'w n yrv ae-1~ v a u1Inv v'n rn yrv
1
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~ ?~?~.~9r~~,l ?.~ ~ ?r~ 01 a ~ ?I?~?v ~1 ?. 0~1
C C G G C C CC C C G C CC ~ G G G GC Cd C 1.a
014101N ~ 07GIGI~ d14l01dl41O CIG!4!0lCJ 41~ d1 Isla
~I ri r-1
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?r ?,
W O.GI0.G~G iLOrC4~ d 0.W0rc GrG.CLWW WQ O. vN
C C C
d I
x s x z x x xx x x s x zx s s x m xx xo~ x sx
0 0 0 0 0 0 00 0 0 0 0 00 o v o 0 00 00 0 00
0 o a o 0 0 00 0 0 0 0 00 0 0 0 0 00 00 0 o0
v a a a a a aa a a v a aa a a a v aa aa a aa
O m a o --c~n v~ c r-m o v..N .,a
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r' '1
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CA 02355251 2001-06-13
N
22 Z Z Z Z 2Z Z Z z Z 2 Z Z: Z Z Z Z Z Z 2 Z2 2 2
.~ .r
~ ~ ~ ~ ~ y
m d d tU 0 4!1i 41 ma1ard f a~al~ Z mm ~ v
~m O ~ O ~ e7~ O ~ T z ~ fs7~~ ~ z O T z .~O z~ O ~
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a
V CJ CJ
U V C7 1 t 1
1 ~ 1 ~' 'r n
a v v
ms x x x x ~ aev a m x ~ x s 5es ~ a ws ~ x
aa a a a a z1 a 1 Z 1 V Z VZ ~ U V V v s V a~ = a
a v a
O O O = s
V V U
., .,a cl a ., , t 1
r c c ~' c' a
m ar d ~ m su rv~ ~r d ~
~ 4!Z ~ y y ~ Z y mm sVZ d ai Z dZ Z
Om O SrO Z W O O o w ~.~ ~ O Z ~ O ZO O
11 t 1 ~ ~ f 1 ~ r ~ 11 1 1 1 ~ 1 11 1
UV V U U v c7 a U U V UV U U V V V GV V
3
I s s
ZZ Z Z Z 2 ZZ Z Z V Z Z Z ZG Z ~ Z Z Z Z Z ,'LZ 2 Z
Z
Z Z Z Z 2 Z
s
s z ' u v a v v v
0 1 ~ 0 1 1 a~ 1
v x x -r...ims a s x ..1.,~ ...,
1 z z ~.~.zz r z z a,~.z
m o o c c oO s .-aO o c c o m x ~ a z x
~,z a a m arvv z ~.c~a o a~a z s arsv z x
.~o ~ ~ s s ~1 v .-~1 ~ s s 1 a o s ~ 0 0
oa .,..,w a..,.ra a - ., o.a~..-, v a a.o. a a
41 ?i?.1 t ?v?i1 4 ~ ?r 1 I ~Zs1 ~ z s 1 1 ~ S1 ~ x
4.iC C d C!GC ra1~C G dl41GZ ~ ~ z z aralz z.r~ a
a~,d d z z dd a ~.d a~ x x mc ~.>,o o z z o o~,~,o
w.as r o o rs -~o.r s o o sa ,cs ~ a o o c~c~.as a
vo o.a.~ 1 wc.0 1 0.a. 1 ~ a.1 ~r~r1 ~ 1 1 1 mr ~r1
NL11 1 r ~11I 1.1N 1 1 '1A fr ~ t ~ ~ "1~'~~ ~i'S r~
1i,~E!G1D O ~4!H 1 C101 D D C1~,G C.a ~ D O a ~.GrCL
Z>,F Z 1 1 Z~ ~,GI~Es t 1 ~C i0m C G 1 1 C CA A C
vo.v1N c~c'V~v10.a tnW a a cnorz z m m e~a 11a1z z d
1 ~ ~ 11 1 1 1 1 . ~s 1 ~ s r . .cs1 1 ~c
If1~VQ a f'1f'~Q4 N 1(14 C' f~11'7QW N N CLLLn f1GIC4!VN d1
1 ?~?~
d! C G
~.~.-IrW1 i1.~r1r~r~~irl0~ I ri~ini~ r~~CL r1rlrdr1.-1~ r~
?v? W,~ ~~ ?~~ ~ t ~ ?~?Wr7S~ G4a T ?v~ ~T ~ ?v
CC C C C C CC C C C -1 C C CC C C ~ ~ C G C GC G C
mm usm ara arv d d v a a~a1av asd c~uc~ald ruam a~d
a
sr s t .cs tt .cr ,cm, t s ss .~~ 1 1 .c.cs sr ~ c
aa.o.w a.o.o.a w w eya o,a aw w w ~ a w o.w wa.a.s>r
c
s
sx x s ca~cxz m z x x x s s~sz x x s x x s o~x x x
OO O O O ,OOO O O O O O O OO O O O O O O O OO O O
0o O O O O OO O O O O O O OO O O O O O O O OO O O
UV C~U U L UV U V U U U U VU U V U U U U V UU V U
0 nW ~ot~m aD - e1e~~a vwo ~m a o ~ N .,s ~wct~aoa
2 Qv a a v c wr,own v wn n n wn vi~o.o~ove.e.o~o~ovo
' ' ~
'.:.'." " ' ~ .:.:' .~ ".:~'...:' ~'. " ~ .:
y ~ ~i~ ~y
CA 02355251 2001-06-13
32
N
z z z z z = z z z z z ~ z z z z zz z z z
~ z z z
. .
,,., .r ~, r
s c a
t ar d ~ arv d a arN .
r
z v v s m sd ars s s m mv a~y a~ t zs v v y
a v
w o ~ S D Z S ~CO O O S SS T~w ~ a oO S S W
E S
a 1 I t i 1 t1 I 1 i 1 1 11 1 1 1 1 11 I 1 1
1
U U a a a C7 a a U U U U aa V a a a Va a U J
a C a
d
U
i
a a N u a a
v v
z 'r
i ~
N N ~ N , N l .r
~
x oa a = mv I a as xx x x a
c
2 a a Z i a ai z m i Z V Ia Z z l a C~U CrV V Z
x Z a s m Z
0 0 = 0 0 0
U
a a , a a - c~
v ~~ ~ i
~ v v m ~ z ~ v m d d s
r
m o s s s o 0 o z s m oo s o s m
( I t i 1 i 1 1 i I t 11 1 1 I 1
,u a a a a a a v a v a a a vv v a v a
Z Z Z Z 'L2 2Z U Z Z U Z Z?rZ ,Z Z 2 2Z : Z Z 2
d d s
Z
aG ~ 2 m z z s o
.
oc
V a U V V a V
=
r-,..r ~ ~ a o~ x x ~, a gs x x
a c s ~, . , a>,z : c v :z x s 2 z
a c
orai z .c m v 1r o o as s oo z z o 0
s r o y s s ..y a a c c,aa o o a v
m w v ~ o.o. ~,s 1 i w I ii a a i 1
1 1 Z Z 1 0.Z Z 1 1 t Z L'O...~..~1 r,.a.~1 ~ .-I.-1
r Z P'~~w TrQi~ ~ Z i~~ ~1~1 tfi 1~~1~1/r1~1~'1~1
o s z o o ~,zo o z z o o ,cz c a s a cc ~,o.G a
a o o a a s Ia v o o ~ a a.i v eu o o vd s .
1 t t I I iJN( 1 i i l i0tVJCZ I i t~GrJ~Jt .C
-,, .-,,-.,.c,.~.-1--Ia r.l...1zi a-o. --1 ...Ja.o~.t .corw
?~ C1D ~.~.O.41~,? D D a T 14i1 1 Q D 11 O.G 1 1
C i f G C to.~C G J i G C r1'~Z CC i 1 IC:ZA
01 c a d 01Z Od d a d'~ ~ aO O O a- a OO Z Z O O
r - Z s 1 1,J=s ~ t t1 I t . . I1 I 1 1 1
GW '1A1W 0rN ~f1G~0~rfn O~C~U1~ v a' ~'f n1C~cr.~.~~ .a~
a 1 1
0.'~ rV.a~I.-1.~r1..-1.-1.C.~..1.-i~1n1~ G~ CL r"I~1~In.lr-~ra~
~ ~r?~~.~ ~~ ?~W .1.?~'~?~?.~ 1 1 ~.7~~ ?~?~~
c c c C c a cC G 1 C C C GC G 4! ~ ~ CC C G C G
d aim alv m va ar~.arv v a~~iv s a svmaJv areJm
-J ..
a t c t s s .cs s 1 r t r ~c t 1 m, .n.c~ c s t s
>.
. ~ . W W iLGr0~P~Q'CLG.CLOrGLOrc' n W o.G~OrW oØ
GL iL C G
d 1
C
CJ
x s m ~ x zx z slx s s ss x x z s xs x m s s
o..0 0 0 0 0 00 0 0 0 0 0 00 0 0 0 0 00 0 0 0 0
o 0 0 0 o-a o0 0 0 0 0 0 00 0 0 0 0 0o a o 0 0
~.
a a a a a a aa a v v a a aa a a v a aa a a a a
N
er~ c ~wae~m avo - N e-~a ~n.p ~ aeao ern v
m ooa a v~a
r ~ r t~n e~e~t~t~m m m mm m m ao i ~
~ ~ ~~ ~ ~ ~
~ r ~ ~ ~ ~i ~ ~ ~ ~ ~r ~ ~m r
r n r w r rn~.~
CA 02355251 2001-06-13
33
Zz z z z za : = Z Z Z Z 2z ~ z z x ~ z z ~ z z z
'i ..~ .-r
c~ ar '' ~, a,
zm v 0lm zv d o~ y ~ d g y~ y ~ ~ a!of w r
o~ s w o o r ~ o 0 0 w
~ ~ ~ v~ ~ ~ ~~ ~,~ ~ o ~ 0 ~
~a a a v aa a a v v a v a a a a a
v v v a a a a a a
of
;' ;~ w a ' v a
,~ ", 1 1 1 1
n ~~ N Iv
s s s s ac a
' '
vv i s z ~; u z z u v uu ~ia a i' u s ~ u ~
z z c z u
,~
_n H N rl
a a a
0 0
a a .r cv v a
m a~ d ar s m d al~ ar a r
c
Sd S ofS 41 S ~ S 4! S US . S N au s al d
y Z it S
. r d
O.~ C S O S O CsiO F. O SO LY~1 O ~ O ts7 O It7 ~
1I 1 1 I 1 1 1 1 1 a 1I I 1 1 1 1 I 1 ,
1
aU V V a a a G U U U VU a a a a CJ a CJ a
3
x
ZZ Z a Z ZZ 2 U Z Z Z a ZZ Z Z Z z Z Z Z 2 Z Z 2 Z
Z ss m
2
GG OD 2 Z
U U
oG VV = ~ C 2
I ~ O O
~ ~1 ..1 O .rV O O a a
C = x V G r ~j ~j a ~
m0 2 Z s Z2 Z C C Z Z . p~ S x IC . . s
l Z 2 Z i
41 0! ..~z Z ~ ?~,2 Z r1.~Z Z ~ ~ Z
. CC O O Z ZO O C O O $ ~O
. , ,C , O t C O O ~ 9,O O G C O
a,n.a a o oa a v v o s
w ~,, a a o,ara v s .ca a ~ ar a
1 1 GJCI
~
, I 1 t i 1 i~.L1 I r C 1
nn .r.11 1.-1 r1 n n rl 1 ~IC .
. .~1r1n 4 .-1 ..v ~ ~ 1 .-~ 0~ 0. .1
w~.~,>,..1~-1~, >,w w ~, ~...1wa ~ r 1 .
.
, , =. a. ~, a v.~, ~, 1 1 ~.
aa a a ~.>, cc a a c c ~ ~CC C
, a Z C C ~ b C C Z S C
0o alm s ta~ ~I p O ~ ~ e zar
. d O o d of Z z al ~I o o ar
I( C C i~~t
. . i r I 1 s r a71r s 1 1 t .C 1 1 ~ ,C, 1 1 s
.
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,
AD 1 1 GLp,I 1 D O 1 1 p,11 I O O 1 1 I 1 1 I D C 1
11 t W E ~0Z s 1 I 1.1 W G S.rN 4 1 I il b Z Z 1~ 4 1 1 LI
aa p o z zo o a ~ m s z mm m Q ~ m m a o m m a a m
1 1 1 I1 1 r . 1 1 1 11 1 . . 1 1 1 1 I 1 . . 1
n-1a a .,.~ aa 1-, e-~a.a. , v~e e n r~a ~r W u,~ n ~ ,n
e - e
cc .r r,
I ~.
al C
0: 11 ~ .Ir~~) .C ~Inlrir~ ~ ~ ray 1 .~rrQI . ~ ~).W 1 1 Z
~ r ~ r r .
?~.~1~ ?Wf ~G. ~1 ~1 ?W~' ~1 ~ ~?.~ ~1?~1 ~ 'J'1 ~1?~?~11 CI'J'
1 . 1
CC C C G C1 G C C C C C CC C C C Ql G G C C C . 1 G
C
vararm almrrr m eu a m m m al~ ard alT m ~I alv ar al ~. ~I
~
rr t c r sI .e s t t s t rs s s .c1 t .c s r t tI t
. ~,
o .o.o.w w o.a c. w sLa. a. w v.aro.w o.v o, w o.w or o. n a.
c
s
it
x~ s s s ce>: x x x r~ x x sz x x z x x x s s s sl s x
o e
0 0 0 0 0 00 0 o a o 0 0 00 0 0 0 0 0 0 0 0 o a o 0
0 0 0 0 0 00 0 0 0 0 o a o0 0 0 0 0 0 0 0 0 0 0 0 0
C ~~ CJU C1aa U a U U U a UU U U a a CJ a U a a U V a
C
~ O~ ~ N ~ ~ "~ ~ ~ ~0 ~ O
O ~ _ - .. . e N
r T P P ~ ~O O O O ~ O ~ ~ .~~. ~ ~ .. . v
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. :..~ ..1. .1. ~ .r .. w
r
CA 02355251 2001-06-13
34
N
Z 2 Z Z Z : Z 2 2 22 Z Z~ U Z Z Z Z
ZZ Z Z Z ZZ 2
p.
.r
41 ?~
al~ eva al ~ al~ ~ s ~ y ~ ~
IVaral m ala ar~ of~ oralar
f o : w
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CA 02355251 2001-06-13
Example 14:
Receptor bindir~g data were measured for the compounds listed
S below using the binding assay described aboQe.
Tt~e results are shown in Table 2.
Table 2
Receptor binding data (R; values)
~o~mpound ETp [ nM ] ETB [ n!s ]
' I-C 74 2100
I-48 67 1400
I-66 63 >3000
I-156 337 >10000
I-170 140 4600
-
T-199 99 3400
Z0 I-ZOl 84 500
=-Z48 18 930
I-294 52 6700
I-340 Z25 5400
I5
35
45
