Note: Descriptions are shown in the official language in which they were submitted.
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Butyne Diol Derivatives
The present invention relates to novel butyne diol derivatives of the general
formula I and their use as active ingredients in the preparation of
pharmaceutical compositions. The invention also concerns related aspects
including processes for the preparation of the compounds, pharmaceutical
compositions containing one or more compounds of the general formula I and
especially their use as endothelin receptor antagonists.
Endothelins (ET-1, ET-2, and ET-3) are 21-amino acid peptides produced and
active in almost all tissues (Yanagisawa M et al.: Nature (1988) 332:411.
Endothelins are potent vasoconstrictors and important mediators of cardiac,
renal, endocrine and immune functions (McMillen MA et al.: J Am Coll Surg
(1995) 180:621 ). They participate in bronchoconstriction and regulate
neurotransmitter release, activation of inflammatory cells, fibrosis, cell
proliferation and cell differentiation (Rubanyi GM et al.: Pharmacol Rev
(1994)
46:328).
Two endothelin receptors have been cloned and characterized in mammals
(ETA, ETB) (Arai H et al.: Nature (1990) 348:730; Sakurai T et al.: Nature
(1990) 348:732). The ETA receptor is characterized by higher affinity for ET-1
and ET-2 than for ET-3. It is predominant in vascular smooth muscle cells and
mediates vasoconstricting and proliferative responses (Ohlstein EH et al.:
Drug Dev Res (1993) 29:108). In contrast, the ETB receptor has equivalent
affinity for the 3 endothelin isopeptides and binds the linear form of
endothelin, tetra-ala-endothelin, and sarafotoxin S6C (Ogawa Y et al.: BBRC
(1991 ) 178:248). This receptor is located in the vascular endothelium and
smooth muscles, and is also particularly abundant in lung and brain. The ETB
receptor from endothelial cells mediates transient vasodilator responses to
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ET-1 and ET-3 through the release of nitric oxide and/or prostacyclin whereas
the ETB receptor from smooth muscle cells exerts vasoconstricting actions
(Sumner MJ et al.: Brit J Pharmacol (1992) 107:858). ETA and ETB receptors
are highly similar in structure and belong to the superfamily of G-protein
coupled receptors.
A pathophysiological role has been suggested for ET-1 in view of its
increased plasma and tissue levels in several disease states such as
hypertension, sepsis, atherosclerosis, acute myocardial infarction, congestive
heart failure, renal failure, migraine and asthma. As a consequence,
endothelin receptor antagonists have been studied extensively as potential
therapeutic agents. Endothelin receptor antagonists have demonstrated
preclinical and/or clinical efficacy in various diseases such as cerebral
vasospasm following subarachnoid hemorrhage, heart failure, pulmonary and
systemic hypertension, neurogenic inflammation, renal failure and myocardial
infarction.
Today, no endothelin receptor antagonist is marketed yet, several are in
clinical trials. However, these molecules possess a number of weaknesses
such as complex synthesis, low solubility, high molecular weight, poor
pharmacokinetics or safety problems (e.g. liver enzyme increases).
Furthermore, the contribution of differential ETA / ETB receptor blockade to
the
clinical outcome is not known. Thus, tailoring of the physicochemical,
pharmacokinetic properties and the selectivity profile of each antagonist for
a
given clinical indication is mandatory. We have discovered a new class of
butyne-diol derivatives of the structure below and found that they allow the
specific tailoring described above.
The inhibitory activity of the compounds of formula I on endothelin receptors
can be demonstrated using the test procedures described hereinafter:
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For the evaluation of the potency and efficacy of the compounds of the
general formula I the following tests were used:
1) Inhibition of endothelin binding to membranes from CHO cells
carrying human ET receptors:
For competition binding studies, membranes of CHO cells expressing human
recombinant ETA or ETB receptors were used. Microsomal membranes from
recombinant CHO cells were prepared and the binding assay made as
previously described (Breu et al, FEBS Lett 1993; 334:210).
The assay was performed in 200 uL 50 mM Tris/HCI buffer, pH 7.4, including
mM MnCl2, 1 mM EDTA and 0.5% (w/v) BSA in polypropylene microtiter
plates. Membranes containing 0.5 ug protein were incubated for 2 h at
20°C
with 8 pM [251]ET-1 (4000 cpm) and increasing concentrations of unlabelled
20 antagonists. Maximum and minimum binding were estimated in samples
without and with 100 nM ET-1, respectively. After two h, the membranes were
filtered on filterplates containing GF/C filters (Unifilterplates from
Canberra
Packard S.A. Zurich, Switzerland). To each well, 50 uL of scintillation
cocktail
was added (MicroScint 20, Canberra Packard S.A. Zurich, Switzerland) and
25 the filter plates counted in a microplate counter (TopCount, Canberra
Packard
S.A. Zurich, Switzerland).
All the test compounds were dissolved, diluted and added in DMSO. The
assay was run in the presence of 2.5% DMSO which was found not to
interfere significantly with the binding. IC5o was calculated as the
concentration of antagonist inhibiting 50 % of the specific binding of ET-1.
For
reference compounds, the following IC5o values were found: ETA cells: 0.075
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nM (n=8) for ET-1 and 118 nM (n=8) for ET-3; ETB cells: 0.067 nM (n=8) for
ET-1 and 0.092 nM (n=3) for ET-3.
The IC5o values obtained with compounds of formula I are given in Table 1
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Table 1:
iC5o[nM]
Compound of
ETA ETB
Example 1 g 26 77
Example 2c 126 44
Example 3e 22 1520
Example 4d 53 2030
Example 5b 38 635
Example 9d 16 49
Example 11 d 49 97
Example 18 79 36
Example 19 112 45
Example 21 230 44
Example 58 7 123
Example 70 94 375
Example 71 13 28
Example 72 1 42
Example 81 1 197
Example 84 2 241
Example 89 13 1140
Example 94 13 107
2) Inhibition of endothelin-induced contractions on isolated rat aortic
rings (ETA receptors) and rat tracheal rings (ETB receptors):
The functional inhibitory potency of the endothelin antagonists was assessed
by their inhibition of the contraction induced by endothelin-1 on rat aortic
rings
(ETA receptors) and of the contraction induced by sarafotoxin S6c on rat
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tracheal (ETB receptors). Adult Wistar rats were anesthetized and
exsanguinated. The thoracic aorta or trachea were excised, dissected and cut
in 3-5 mm rings. The endothelium/epithelium was removed by gentle rubbing
of the intimal surface. Each ring was suspended in a 10 ml isolated organ
bath filled with Krebs-Henseleit solution (in mM; NaCI 115, KCI 4.7, MgS04
1.2, KH2P04 1.5, NaHC03 25, CaCl2 2.5, glucose 10) kept at 37°C and
gassed with 95% 02 and 5% C02. The rings were connected to force
transducers and isometric tension was recorded (EMKA Technologies SA,
Paris, France). The rings were stretched to a resting tension of 3 g (aorta)
or
2 g (trachea). Cumulative doses of ET-1 (aorta) or sarafotoxin S6c (trachea)
were added after a 10 min incubation with the test compound or its vehicle.
The functional inhibitory potency of the test compound was assessed by
calculating the concentration ratio, i.e. the shift to the right of the ECSo
induced by different concentrations of test compound. ECSO is the
concentration of endothelia needed to get a half-maximal contraction, pA2 is
the negative logarithm of the antagonist concentration which induces a two-
fold shift in the EC5o value.
The pA2 values obtained with compounds of formula I are given in Table 2.
Table 2:
pA2
Compound of
aortic rings trachea
Example 4d 7.15 5.89
Example 9d 7.11 6.47
Example 11 d 7.05 7.03
Example 19 <5 7.62
Example 58 7.57
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Example 59 7.70
Example 72 7.70
Example 81 7.56
Example 84 8.11
Because of their ability to inhibit the endothelin binding, the described
compounds can be used for treatment of diseases which are associated with
an increase in vasoconstriction, proliferation or inflammation due to
endothelin. Examples of such diseases are hypertension, coronary diseases,
cardiac insufficiency, renal and myocardial ischemia, renal failure, cerebral
ischemia, dementia, migraine, subarachnoidal hemorrhage, Raynaud's
syndrome, portal hypertension and pulmonary hypertension. They can also
be used for atherosclerosis, prevention of restenosis after balloon or stent
angioplasty, inflammation, stomach and duodenal ulcer, cancer, prostatic
hypertrophy, erectile dysfunction, hearing loss, amaurosis, chronic
bronchitis,
asthma, gram negative septicemia, shock, sickle cell anemia,
glomerulonephritis, renal colic, glaucoma, therapy and prophylaxis of diabetic
complications, complications of vascular or cardiac surgery or after organ
transplantation, complications of cyclosporin treatment, as well as other
diseases presently known to be related to endothelin.
The compounds can be administered orally, rectally, parenterally, e.g.
intravenously, intramuscularly, subcutaneously, intrathecally or
transdermally;
or sublingually or as ophthalmic preparation or administered as aerosol.
Examples of applications are capsules, tablets, oral administered
. suspensions or solutions, suppositories, injections, eye-drops, ointments or
aerosols/nebulizers.
Preferred applications are intravenous, intra-muscular, eye drops or oral
administrations. The dosage used depends upon the type of the specific
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active ingredient, the age and the requirements of the patient and the kind of
application. Generally, dosages of 0.1 - 50 mg / kg body weight per day are
considered. The preparations with compounds can contain inert or as well
pharmacodynamically active excipients. Tablets or granules, for example,
could contain a number of binding agents, filling excipients, carrier
substances or diluents.
The present invention relates to butyne diol derivatives of the general
formula
I,
~s~~
R~~ \NH
N ~ X\Rs
general formula I
R4 N O
wherein
R~ represents phenyl; mono-, di- or tri-substituted phenyl substituted with
phenyl, halogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower
alkoxy, lower alkenyloxy, lower alkynyloxy, lower alkylen or lower alkenylen
or
lower alkylenoxy or lower alkylendioxy forming with the phenyl ring a five- or
six-membered ring, hydroxy-lower alkyl, hydroxy-lower alkenyl, hydroxy-lower
alkynyl, lower alkyloxy-lower alkyl, lower alkyloxy-lower alkyloxy,
trifluoromethyl, trifluoromethoxy, cycloalkyl, hydroxy-cycloalkyl;
heterocyclyl;
five membered heteroaryl rings containing one or two nitrogen, sulfur or
oxygen atoms which may be mono- or di-substituted with halogen, lower
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alkyl, lower alkoxy, hydroxy-lower alkyl, halogen, trifluoromethyl; 2-pyridyl;
5-
substituted 2-pyridyl substituted with lower alkyl, lower alkoxy; benzyl; mono-
,
di- or tri-substituted benzyl substituted with phenyl, halogen, hydroxy, lower
alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower alkenyloxy, lower
alkynyloxy, lower alkylen or lower alkenylen or lower alkylenoxy or lower
alkylendioxy forming with the phenyl ring a five- or six-membered ring,
hydroxy-lower alkyl, hydroxy-lower alkenyl, hydroxy-lower alkynyl,
trifluoromethyl, trifluoromethoxy, cycloalkyl, hydroxy-cycloalkyl; five
membered heteroaryl rings containing one or two nitrogen, sulfur or oxygen
atoms; aryl; heteroaryl;
R2 represents hydrogen; lower alkyl; trifluoromethyl; phenyl; mono-, di- or
tri-
substituted phenyl substituted with phenyl, halogen, hydroxy, lower alkyl,
lower alkenyl, lower alkynyl, lower alkoxy, lower alkenyloxy, lower
alkynyloxy,
lower alkylen or lower alkenylen or lower alkylenoxy or lower alkylendioxy
forming with the phenyl ring a five- or six-membered ring, hydroxy-lower
alkyl,
hydroxy-lower alkenyl, hydroxy-lower alkynyl, lower alkyloxy-lower alkyl,
lower
alkyloxy-lower alkyloxy, trifluoromethyl, trifluoromethoxy, cycloalkyl,
hydroxy-
cycloalkyl; heterocyclyl; five membered heteroaryl rings containing one or two
nitrogen, sulfur or oxygen atoms which may be mono-or di-substituted with
halogen, lower alkyl, lower alkoxy; benzyl; mono-, di- or tri-substituted
benzyl
substituted with phenyl, halogen, hydroxy, lower alkyl, lower alkenyl, lower
alkynyl, lower alkoxy, lower alkenyloxy, lower alkynyloxy, lower alkylen or
lower alkenylen or lower alkylenoxy or lower alkylendioxy forming with the
phenyl ring a five- or six-membered ring, hydroxy-lower alkyl, hydroxy-lower
alkenyl, hydroxy-lower alkynyl, trifluoromethyl, trifluoromethoxy, cycloalkyl,
hydroxy-cycloalkyl; 2-pyrimidyl; mono- or di-substituted 2-pyrimidyl
substituted with lower alkyl, lower alkoxy, hydroxy-lower alkyl, halogen,
trifluoromethyl, five membered heteroaryl rings containing one or two
nitrogen, sulfur or oxygen atoms; aryl; heteroaryl; heterocyclyl; a group of
the
formula
-C(A)-B-Ra, wherein
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A represents O or S;
B represents NH or a bond; and
Ra represents lower alkyl; cycloalkyl; trifluoromethyl; phenyl; mono-, di- or
tri-
substituted phenyl substituted with phenyl, halogen, hydroxy, lower alkyl,
lower alkenyl, lower alkynyl, lower alkoxy, lower alkenyloxy, lower
alkynyloxy,
lower alkylen or lower alkenylen or lower alkylenoxy or lower alkylendioxy
forming with the phenyl ring a five- or six-membered ring, hydroxy-lower
alkyl,
hydroxy-lower alkenyl, hydroxy-lower alkynyl, lower alkyloxy-lower alkyl,
lower
alkyloxy-lower alkyloxy, trifluoromethyl, trifluoromethoxy, cycloalkyl,
hydroxy-
cycloalkyl; heterocyclyl; five membered heteroaryl rings containing one or two
nitrogen, sulfur or oxygen atoms which may be mono- or di-substituted with
halogen, lower alkyl, lower alkoxy, trifluoromehtyl, trifluoromethoxy; six
membered heteroaryl rings containing one or two nitrogen atoms which may
be mono-, di- or tri-substituted with halogen, lower alkyl, lower akyloxy,
trifluoromethyl;
R3 represents hydrogen, lower alkyl, phenyl; mono-, di- or tri-substituted
phenyl substituted with lower alkyl, lower alkenyl, lower alkynyl, lower
alkyloxy, amino, lower alkylamino, amino-lower alkyl, trifluoromethyl,
trifluoromethoxy, halogen, lower alkylthio, hydroxy, hydroxy-lower alkyl,
cyano, carboxyl, lower alkanoyl, formyl; benzofuranyl; heteroaryl; mono- or
disubstituted heteroaryl substituted with lower alkyl, lower alkenyl, lower
alkynyl, lower alkyloxy, amino, lower alkylamino, trifluoromethyl, halogen,
hydroxy, hydroxy-lower alkyl, cyano, carboxyl;
R4 represents hydrogen, halogen, trifluoromethyl, lower alkyl, lower
cycloalkyl,
lower alkyloxy, lower cycloalkyloxy, lower alkylthio, lower alkylthio-lower
alkyl,
hydroxy-lower alkyl, lower alkyl-oxy-lower alkyl, hydroxy-lower alkyl-oxy-
lower
alkyl, amino-lower alkyl, lower alkyl-amino-lower alkyl, amino, lower alkyl-
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amino, di-lower alkyl-amino; phenyl; mono-, di- or tri-substituted phenyl
substituted with phenyl, halogen, hydroxy, lower alkyl, lower alkoxy, lower
alkylen or lower alkenylen or lower alkylenoxy or lower alkylendioxy forming
with the phenyl ring a five- or six- membered ring, lower alkenyl, lower
alkenyloxy, trifluoromethyl, trifluoromethoxy, cycloalkyl, hydroxy-cycloalkyl;
aryl; aryl-amino; arylthio; aryloxy; aryl-lower alkyl; heteroaryl;
heterocyclyl;
X represents oxygen; sulfur; NH or a bond;
and pure enantiomers, enantiamerically pure diastereomers, mixtures of
diastereomers, diastereomeric racemates, mixtures of diastereomeric
racemates and pharmaceutically acceptable salts thereof.
In the definitions of the general formula I - if not otherwise stated - the
expression lower means straight and branched chain groups with one to
seven carbon atoms, preferably 1 to 4 carbon atoms. Examples of lower alkyl
and lower alkoxy groups are methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, sec.- butyl, tert.-butyl, pentyl, hexyl, heptyl, methoxy, ethoxy,
propoxy, butoxy, iso-butoxy, sec.-butoxy and tert.-butoxy. Lower
alkylendioxy-groups are preferably methylen-dioxy, ethylen-dioxy, propylen-
dioxy and butylen-dioxy- groups. Examples of lower alkanoyl-groups are
acetyl, propanoyl and butanoyl . Lower alkenylen means e.g.vinylen,
propenylen and butenylen. Lower alkenyl and lower alkynyl means groups
like ethylen, propylen, butylen, tert.-butylen(2-methyl-propenyl), and
acetylenyl, propinylen, butinylen, pentinylen, 2-methyl-pentinylen etc. Lower
alkenyloxy means allyloxy, vinyloxy, propenyloxy and the like. The expression
cycloalkyl means a saturated cyclic hydrocarbon ring with 3 to 6 carbon
atoms , e.g. cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl which may be
substituted with lower alkyl, hydroxy-lower alkyl, amino-lower alkyl, lower
alkoxy-lower alkyl and lower alkenylen groups. The expression heterocyclyl
means saturated or unsaturated ( but not aromatic ) five-, six- or seven-
membered rings containing one or two nitrogen, oxygen or sulfur atoms which
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may be the same or different and which rings may be substituted with lower
alkyl, amino, halogen, nitro, hydroxy, lower alkoxy, e.g. piperidinyl,
morpholinyl, piperazinyl, tetrahydropyranyl, dihydropyranyl, 1,4-dioxanyl,
pyrrolidinyl, tetrahydrofuranyl, dihydropyrrolyl, dihydroimidazolyl,
dihydropyrazolyl, pyrazolidinyl etc. and substituted derivatives of such rings
with substituents as outlined above. The expression heteroaryl means six-
membered aromatic rings containing one to four nitrogen atoms, benzofused
six-membered aromatic rings containing one to three nitrogen atoms, five-
membered aromatic rings containing one oxygen or one nitrogen or one sulfur
atom, benzo- fused five-membered aromatic rings containing one oxygen or
one nitrogen or one sulfur atom, five membered aromatic rings containig an
oxygen and nitrogen atom and benzo fused derivatives thereof, five membred
aromatic rings containing a sulfur, nitrogen or oxygen atom and benzo fused
derivatives thereof, five- membered aromatic rings containing two nitrogen
atoms and benzo fused derivatives thereof, five membered aromatic rings
containing three nitrogen atoms and benzo fused derivatives thereof or the
tetrazolyl ring, e.g. furanyl, thienyl, pyrrolyl, pyridinyl, indolyl,
quinolinyl,
isoquinolinyl, imidazolyl, triazinyl, thiazinyl, pyridazinyl, oxazolyl, etc.
whereby
such rings may be substituted with lower alkyl, amino, amino-lower alkyl,
halogen, hydroxy, lower alkoxy or trifluoromethyl. The expression aryl
represents mono-, di- or tri-substituted aromatic rings with 6 to 10 carbon
atoms like phenyl or naphthyl rings which may be substituted with phenyl,
halogen, hydroxy, lower alkoxy, lower alkyl, trifluoromethyl, lower
alkenyloxy,
trifluoromethoxy, cyclopropyl, hydroxy-cyclopropyl, lower alkylenoxy or lower
alkylendioxy.
The expression pharmaceutically acceptable salts encompasses either salts
with inorganic acids or organic acids like hydrohalogenic acids, e.g.
hydrochloric or hydrobromic acid; sulfuric acid, phosphoric acid, nitric acid,
citric acid, formic acid, acetic acid, malefic acid, tartaric acid,
methylsulfonic
acid, p- toluolsulfonic acid and the like or in case the compound of formula I
is
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acidic in nature with an inorganic base like an alkali or earth alkali base,
e.g.
sodium hydroxide, potassium hydroxide, calcium hydroxide etc.
The compounds of the general formula I might have one or more asymmetric
carbon atoms and may be prepared in form of optically pure enantiomers or
diastereomers, mixtures of enantiomers or diastereomers, diastereomeric
racemates, mixtures of diastereomeric racemates. The present invention
encompasses all these forms. Mixtures may be separated in a manner known
per se, i.e. by column chromatography, thin layer chromatography, HPLC,
crystallization etc.
Because of their ability to inhibit the endothelin binding, the described
compounds of the general formula I and their pharmaceutically acceptable
salts may be used for treatment of diseases which are associated with an
increase in vasoconstriction, proliferation or inflammation due to endothelin.
Examples of such diseases are hypertension, coronary diseases, cardiac
insufficiency, renal and myocardial ischemia, renal failure, cerebral
ischemia,
dementia, migraine, subarachnoidal hemorrhage, Raynaud's syndrome,
portal hypertension and pulmonary hypertension. They can also be used for
atherosclerosis, prevention of restenosis after balloon or stent angioplasty,
inflammation, stomach and duodenal ulcer, cancer, prostatic hypertrophy,
erectile dysfunction, hearing loss, amaurosis, chronic bronchitis, asthma,
gram negative septicemia, shock, sickle cell anemia, glomerulonephritis, renal
colic, glaucoma, therapy and prophylaxis of diabetic complications,
complications of vascular or cardiac surgery or after organ transplantation,
complications of cyclosporin treatment, as well as other diseases presently
known to be related to endothelin.
These compositions may be administered in enteral or oral form e.g. as
tablets, dragees, gelatine capsules, emulsions, solutions or suspensions, in
nasal form like sprays or rectically in form of suppositories. These compounds
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may also be administered in intramuscular, parenteral or intraveneous form,
e.g. in form of injectable solutions.
These pharmaceutical compositions may contain the compounds of formula I
as well as their pharmaceutically acceptable salts in combination with
inorganic andlor organic excipients which are usual in the pharmaceutical
industry like lactose, maize or derivatives thereof, talcum, stearinic acid or
salts of these materials.
For gelatine capsules vegetable oils, waxes, fats, liquid or half-liquid
polyols
etc. may be used. For the preparation of solutions and sirups e.g. water,
polyols, saccharose, glucose etc. are used. Injectables are prepared by using
e.g. water, polyols, alcohols, glycerin, vegetable oils, lecithin, liposomes
etc.
Suppositories are prepared by using natural or hydrogenated oils, waxes,
fatty acids (fats ), liquid or half-liquid polyols etc.
The compositions may contain in addition preservatives, stabilisation
improving substances, viscosity improving or regulating substances, solubility
improving substances, sweeteners, dyes, taste improving compounds, salts
to change the osmotic pressure, buffer, antioxidants etc.
The compounds of formula I may also be used in combination with one or
more other therapeutically useful substances e.g. a- and a-blockers like
Phentolamine, Phenoxybenzamine, Atenolol, Propranolol, Timolol,
Metoprolol, Carteolol etc.; Vasodilators like Hydralazine, Minoxidil,
Diazoxide,
Flosequinan etc.; Calcium-antagonists like Diltiazem, Nicardipine,
Nimodipine, Verapamil, Nifedipine etc.; ACE-inhibitors like Cilazapril,
Captopril, Enalapril, Lisinopril etc.; Potassium activators like Pinacidil
etc.
Angiotensin II antagonists; Diuretics like Hydrochlorothiazide,
Chlorothiazide,
Acetolamide, Bumetanide, Furosemide, Metolazone, Chlortalidone etc.;
Sympatholitics like Methyldopa, Clonidine, Guanabenz, Reserpine etc.; and
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other therapeutics which serve to treat high blood pressure or any cardiac
disorders.
The dosage may vary within wide limits but should be adapted to the specific
situation. In general the dosage given in oral form should daily be between
about 3 mg and about 3 g, preferably between about 10 mg and about 1 g,
especially preferred between 5 mg and 300 mg, per adult with a body weight
of about 70 kg. The dosage should be administered preferably in1 to 3 doses
per day which are of equal weight. As usual children should receive lower
doses which are adapted to body weight and age.
A preferred group of compounds are compounds of formula I wherein R~, R2,
and R4 are as defined above, and wherein
R3 represents phenyl; mono substituted phenyl substituted with lower alkyl,
lower alkyloxy, trifluoromethyl, trifluoromethoxy, halogen;
X represents oxygen or a single bond,
and pharmaceutically acceptable salts thereof.
Another preferred group of compounds are compounds of formula II
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Rs
formula II
O~ Rz
wherein R2, R3, R4, and X are as defined in formula I above,
and R5 represents lower alkyl,
and pharmaceutically acceptable salts of compounds of formula II.
Another group of preferred compounds are compounds of formula III
R~/ \NH
N
R4
R°
wherein R~, R3, R4, and X are as defined in formula I above,
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and R6, R7, and R8, each and independently represents hydrogen, lower alkyl,
lower alkenyl, lower alkynyl, lower alkyloxy, lower alkenyloxy, lower
alkynyloxy, halogen, trifluoromethyl, trifluoromethoxy or lower alkylthio;
and pharmaceutically acceptable salts thereof.
Yet another group of preferred compounds are compounds of formula IV
~s~
~ Rs
formula IV
H
O N~
Ra
O
wherein R~, R3, R4, Ra and X are as defined in formula I above,
and pharmaceutically acceptable salts thereof.
Another group of preferred compounds are compounds of formula I wherein
R~, R3, R4, and X are as defined in formula I above, and wherein R2
represents lower alkyl,
and pharmaceutically acceptable salts thereof.
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Another group of preferred compounds are the compounds described as final
products in the Examples 1 to 96 as given below, and pharmaceutically
acceptable salts thereof.
The compounds of the general formula 1 are prepared from compounds of the
formula V by one of the two pathways given below. The compounds VI are
reacted either with a compound R2-Y, where Y represents a reactive leaving
group such as chlorine, bromine, a sulfone, a sulfate, etc., or, in the case
where R2 represents a group of the formula C(A)-NH-Ra, with a compound
Ra-N=C=A where Ra and A are as defined in the general formula I.
Compounds of the formula VII can be prepared by reacting 2-butyne-1,4-diol
with R2-Y in the presence of a base (e.g. an alkali metal hydroxide, an alkali
metal alkoxide, sodium hydride, etc.) in a solvent such as DMSO, DMF, THF,
pyridine, water, etc. (e.g. Tetrahedron Letters 38 (1997), 7887-7890; Bull.
Chem. Soc. Jpn. 28 (1955), 80-82; J. Org. Chem. 18 (1953), 1601-1606).
Compounds of the formula VII can also be prepared by reacting a suitably
hydroxy-protected 1-chloro-4-hydroxy-2-butyne with an alkoxide, followed by
cleavage of the protecting group as described in the literature (e.g. Bull.
Chim. Soc. 1955, 502; J. Org. Chem. USSR (Engl. Transl.) 12 (1976), 505-
507; J. Org. Chem. 63 (1998), 4291-4298).
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~s/
// ~
/S\ R~/ NH
R, OH
NH
X~
N ~ R3
HO
~ 4
4 R
~
R N CI
V
OR2
HO
VII
Compounds V are prepared from the corresponding dichloro compounds VIII
(Bioorg. Med. Chem. Letters 7 (1997), 2223-2228, Chimia 50 (1996), 519-
524, and references cited therein).
X~R3
R4 /~ N/
VIII
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Treatment of VIII with an excess of the appropiate sulfonamide potassium salt
in the presence or absence of a base (e.g. triethylamine, Hunig's base) in a
solvent (e.g DMF, DMSO) at room temperature furnished the desired
compounds V. The sulfonamide potassiums salts may be prepared according
to e.g. Bioorg. Med. Chem. Letters 7 (1997), 2223-2228.
Compounds VIII could be prepared by treating the corresponding compounds
IX (or tautomeric forms thereof) at elevated temperatures (30-120°C)
with a
chlorinating agent such as POCI3, PCIS, or mixtures thereof, etc. each in the
presence or absence of a base such as N,N-dialkylaniline or benzyltriethyl
ammoniumchloride (e.g. Bioorg. Med. Chem. Lett., 7 (1997), 2223 - 2228; J.
Med. Chem., 41 (1998), 3793 - 3803; J. Chem. Soc. 1959, 2214; Bull. Soc.
Chim. Fr. 1959, 741-742).
O
N X~R3
R4 ~N ~O
H
IX
In a standard method as described by Pinner (for review see e.g. The
Pyrimidines, by D.J. Brown, Wiley Interscience, New York 1970), the
compounds IX resulted from condensation of the corresponding amidines X
(isolated as hydrochloride salts) with the appropriate malonic ester
derivatives
XI in the presence of a sodium alkoxide in a solvent such as methanol,
ethanol, etc. at room temperature (e.g. Bull. Soc. Chim. Fr. 1960, 1648).
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OMe, OEt OH
NH \R3 N ~ x\R3
HCI
4
R NH2 Me, OEt R4 N OH
X XI IX
The amidines X were prepared form the corresponding nitrites XII by
treatment of the nitrites XII either with sodium methylate in methanol
followed
by the addition of ammoniumchloride, or with lithium hexamethyldisilazan
followed by the addition of hydrochloric acid in isopropanol (Advanced
Organic Chemistry, by J. March, 3~d edtion, Wiley 1985, p. 803 and references
cited therein).
/N
R4/
XII
The malonic ester derivatives XI were either commercially available or were
prepared following the procedures found in the literature (e.g. J. Am. Chem.
Soc. 62 (1940), 1154, 1155; ibid. 74 (1952), 4466; J. Chem. Soc. Perkin 1,
1979, 2382-2386; Collect. Czech. Chem. Comm. 55 (1990), 1278-1289; J.
Med. Chem. Chim. Ther. 26 (1991 ), 599-604; Bull. Soc. Chim. Fr. 1973,
2065-2071 ).
As the case may be, compounds with one or more optically active carbon
atom are resolved into pure enantiomers or diastereomers, mixtures of
enantiomers or diastereomers, diastereomeric racemates, mixtures of
diastereomeric racemates in a manner known per se, and, if desired,
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synthesised compounds of formula I were converted into a pharmaceutically
acceptable salt in a manner known per se.
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Examples
The following examples illustrate the invention but do not at all limit the
scope
thereof. All temperatures are stated in °C.
The compounds given below were prepared according to the procedure
described above. All compounds were characterized by ~H-NMR (300MHz)
and occasionally by ~3C-NMR (75MHz) (Varian Oxford, 300MHz; chemical
shifts are given in ppm relative to the solvent used; multiplicities: s =
singlet, d
= doublet, t = triplet; m = multiplet), by LC-MS (Waters Micromass; ZMD-
platform with ESI-probe with Alliance 2790 HT; Column: 2x30mm, Gromsil
ODS4, 3~m, 120A; Gradient: 0 - 100% acetonitrile in water, 6 min, with
0.05% formic acid, flow: 0.45m1/min; tr is given in min, molecular mass of the
fraction at tr), by TLC (TLC-plates from Merck, silica gel 60 F254) and
occasionally by melting point. Abbreviations: DCM = dichloromethane, MeOH
= methanol, DMF = N,N-dimethylformamide, THF = tetrahydrofuran, DMSO =
dimethyl sulfoxide, DMPU - 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-
pyrimidinone, DMAP - 4-dimethylaminopyridine, DBU - 1,8-
diazabicyclo[5.4.0]undec-7-ene, min = minutes, h = hours.
Example 1
a) To a solution of 0.23 g sodium in 40 ml methanol was added 10.62 g 4-
cyanopyridine at room temperature. Stirring was continued for 6 h followed by
the addition of 5.9 g ammoniumchloride and stirring was continued for
another 10 h. Then 120 ml diethylether was added and the precipitate was
filtered off after 30 min and washed once with 20 ml of diethylether. The
product was dried under high vacuum. 14.95 g 4-amidino-pyridine
hydrochloride was obtained as a white powder.
b) 48 ml 2-methoxy-phenol (guajacol) were slowly added to a stirred
suspension of 70.8 g potassium carbonate in 480 ml acetone followed by
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heating to 45°C. Then 63.2 ml dimethylchloromalonate in 50 ml acetone
were
added within 20 min. The reaction mixture was heated to reflux for 16 h. The
solvent was evaporated under reduced pressure, the residue taken into water
and extracted with DCM. The combined organic layers were dried over
sodium sulfate and evaporated. The oily product was crystallized from methyl
tert.-butyl-ether. 86 g dimethyl-(o-methoxyphenoxy)malonate was obtained.
c) To a stirred solution of 9.7 g sodium methylate in 100 ml methanol a
solution of 21.7 g dimethyl-(o-methoxyphenoxy)malonate in 50 ml methanol
was added within 15 min and stirring was continued for 30 min followed by
the addition of 15.0 g 4-amidino-pyridine hydrochloride followed by stirring
at
room temperature for 20 h. The reaction mixture was concentrated in vacuo.
The solid residue was stirred with ether. The obtained powder was filtered off
and dissolved in 300 ml water. Acetic acid was added to pH = 4. The
precipitated product was filtered off, washed with water and dried in vacuo at
50°C. 20.1 g 5-(o-methoxyphenoxy)-4,6-dihydroxy-2-(4-pyridyl)-
pyrimidine (is
possibly also present as the tautomeric 5-(o-methoxyphenoxy)-2-(4-pyridyl)-
tetrahydropyrimidine-4,6-dion) was obtained as a white powder.
d) 10 g of the 5-(o-methoxyphenoxy)-4,6-dihydroxy-2-(4-pyridyl)-pyrimidine,
11.2 g N-ethyldiisopropylamine, 11 g tetraethylammoniumchloride and 13.8 g
phosphorous pentachloride were dissolved in 25 ml phosphorous oxychloride
and heated to reflux for 3 h. The mixture was evaporated in vacuo, toluene
was added and the mixture was again evaporated. The residue was taken
info DCM and poured onto ice/water. The layers were separated, the organic
layer was washed with water, dried over sodium sulfate and evaporated. After
recrystallization from acetone, 6.52 g of 4,6-dichloro-5-(o-methoxyphenoxy)-
2-(4-pyridyl)-pyrimidine was obtained.
e) 5-isopropyl pyridine-2-sulfonamide potassium salt was prepared according
to procedures disclosed in EP 0713875 A1 and Bioorganic & Medicinal
Chemistry Letters, 7 (1997), 2223-2228.
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f) 1 g of 4,6-dichloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidine and 1.43
g of 5-isopropyl pyridine-2-sulfonamide potassium salt were suspended in 20
ml of dry DMF. The mixture was stirred under argon at room temperature and
became clear within a few h. After 16 h at room temperature, most of the
solvent was removed by evaporation under reduced pressure. The residue
was taken up in 20 ml water and the pH was adjusted to 4-5 by adding about
1 ml of acetic acid. A precipitate formed. The precipitate was filtered off,
washed with water and dried. The yellow powder was further purified by
column chromatography on silica gel eluting first with hexane: ethyl acetate
1:1 then with DCM : MeOH 10 : 1. 1.43 g of 5-isopropyl-N-[6-chloro-5-(0-
methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide was
obtained as a slightly yellow powder. LC-MS: tR = 5.00 min, [M+1]+ = 512.19,
[M-1 ]- = 510.26.
g) At 0-5°C, 5.04 g of 2-butyne-1,4-diol was added portionwise to a
stirred
slurry of 0.7 g sodium hydride in 30 ml of dry DMF and 5 ml of DMPU. Stirring
was continued until the evolution of gas had ceased. To the resulting
suspension 1.5 g of 5-isopropyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(4-
pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide was added at room temperature
and the mixture was stirred at 95°C for 24 h. Eventually, the slurry
was
allowed to cool to room temperature, was then poured onto 100 ml of an
aqueous solution of 10% citric acid and extracted twice with 150 ml of ethyl
acetate. The combined organic layers were washed twice with 50 ml of water,
dried over MgS04 and evaporated. The remaining dark brown oil was purified
by column chromatography on 80 g of silica gel eluting with DCM containing
0-5% of methanol. This gave 0.82 g of 5-isopropyl-N-[6-(4-hydroxy-2-
butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine
sulfonamide as a pale yellow solid. LC-MS: tR = 4.39min, [M+1]+ = 562.29, [M-
1 ]- = 560.41.
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Example 2
a) A solution of 15.2 g of 4-tert.-butylbenzene sulfonyl chloride in 150 ml of
THF was cooled with an ice bath. 15.2 ml of 25% aqueous ammonium
hydroxide solution was added dropwise. After the addition was completed, the
solution was stirred at room temperature for 15 min. The solvent was
removed in vacuo. The residue was again dissolved in ethyl acetate and
washed twice with water. The organic phase was dried over Na2S04,
evaporated and dried. The resulting 14.8 g of a white powder was dissolved
in 75 ml of methanol and 7.5 g of potassium tert. butylate was added. The
solution was briefly stirred at room temperature and evaporated. The resulting
residue was carefully dried to give 16.3 g of 4-tert.-butylbenzene sulfonamide
potassium salt as a white solid.
b) To a solution of 6.1 g of 4,6-dichloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-
pyrimidine (Example 1, Section a) to d)) in 100 ml of dry DMF 8.8 g of 4-tert.-
butyl benzene sulfonamide potassium salt was added at room temperature.
The solution was stirred over night at room temperature. The solution was
added to a mixture of 150 ml of water and 100 ml of diethyl ether. The pH was
adjusted to 5 by adding acetic acid. The precipitate that formed was
collected,
washed with water and diethyl ether. The resulting powder was suspended in
boiling ethyl acetate. The mixture was allowed to cool in an icebath.
Eventually, the solid material was collected and dried to yield 6.6 g of 4-
tert.-
butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-benzene
sulfonamide as beige crystals. LC-MS: tR = 5.80 min, [M+1 ]+ = 525.31, [M-1 ]'
= 523.48
c) At room temperature, 6.9 g of 2-butyne-1,4-diol was added portionwise to a
stirred slurry of 0.96 g sodium hydride in 25 ml of dry DMF and 5 ml of dry
DMPU. Stirring was continued until the evolution of gas had ceased. To the
resulting suspension 2.1 g of 4-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-
2-(4-pyridyl)-4-pyrimidinyl]-benzene sulfonamide was added at room
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temperature and the mixture was stirred at 90°C for 48 h. Eventually,
the
solvent was removed under reduced pressure and the resulting oil was
treated with 150 ml of 10% aqueous acetic acid. The dark solution was
extracted with 150 ml of DCM. The organic layer was washed with water,
dried over MgS04 and evaporated. The resulting dark brown oil was further
purified by column chromatography on silica gel eluting with toluene : ethyl
acetate 4:1 to 1:4. This furnished 1.28 g of 4-tert.-butyl-N-[6-(4-hydroxy-2-
butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-benzene
sulfonamide as a beige foam. LC-MS: tR = 4.87 min, [M+1]+ = 575.32, [M-1]- _
573.45.
Example 3
a) To a suspension of 70 g of 2-bromo-5-methyl pyridine in 500 ml of water
200 ml 25% aqueous hydrochloric acid was added at room temperature. To
the clear solution 68 g of thiourea was added and the mixture ,was heated to
reflux. After 4 h another 34 g and after 18 h further 17 g of thiourea was
added. After 24 h the solution was cooled with an icebath and 360 ml of 4 N
sodium hydroxide solution was added. A precipitate formed which dissolved
upon adding 600 ml of DCM. The organic layer was separated and washed
with 500 ml of water. The aqueous phase was acidified to pH 3 using
hydrochloric acid and repeatedly extracted with DCM. The combined organic
layers were dried over MgS04, evaporated and dried under reduced
pressure. This gave 46.9 g of a yellow solid which was recrystallised from
boiling ethanol to furnish 37.6 g of 5-methyl-2-thin-pyridine in form of pale
yellow platelets which sinter at 168°C and gradually melt between 179
and
190°C. ~H-NMR(CDC13, 300 MHz): 2.17 (s, 3H); 7.24(dd, J=2.0, 8.8, 1H);
7.41 (t, J=1.0, 1 H); 7.47(d, J=8.8, 1 H); 14.03(s br, 1 H).
b) To a mixture of 100 ml of 25 % aqueous hydrochloric acid and 250 ml of
DCM was added 18 g of 5-methyl-2-thio-pyridine. While the mixture was
vigorously stirred and kept at -10°C 250 ml of an aqueous solution
containing
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13% of sodium hypochlorite was carefully added. Upon completion of the
addition, stirring was continued for 10 min. The organic layer was separated.
To the aqueous layer 250 ml of DCM was added and the mixture was again
treated as before with a further 250 ml batch of bleach. Upon completion of
the addition, the organic layer was separated. The aqueous layer was
extracted five times with 200 ml DCM. The organic layers were combined,
dried over MgS04 and evaporated. The resulting oil was dissolved in 125 ml
of THF and cooled to -20°C. 25 ml of saturated aqueous ammonium
hydroxide solution was slowly added. The mixture was stirred over night at
room temperature. Excess of ammonia was neutralised by adding
hydrochloric acid and the THF was removed in vacuo. The remaining
aqueous solution was extracted three times with 150 ml of ethyl acetate. The
combined organic layers were dried over MgS04 and the solvent was
evaporated. The remaining solid was recrystallised from boiling ethyl acetate
to yield 13.35 g of 5-methyl-2-pyridine sulfonamide in form of beige crystals.
~H-NMR(D6-DMSO, 300 MHz): 2.37(s, 3H); 7.36(s, 2H); 7.78-7.85(m, 2H);
8.53(s, 1 H); LC-MS: tR = 2.32 min, [M+1]+ = 173.04, [M-1]- = 171.10.
c) To a solution of 18.54 g of 5-methyl-2-pyridine sulfonamide in 400 ml of
methanol was added 12.08 g of potassium tert.-butylate. The solution was
stirred at room temperature for 5 min. The solvent was removed under
reduced pressure and the residue was dried under high vacuum to give 22.64
g of 5-methyl-2-pyridine sulfonamide potassium salt as a beige solid.
d) Under argon 4 g of 4,6-dichloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-
pyrimidine (Example 1, section a) to d)) was dissolved in 40 ml of dry DMF
and 3.62 g of 5-methylpyridine-2-sulfonamide potassium salt followed by 2.95
ml of Hunig's base was added. The dark solution was stirred at room
temperature for 22 h. A further portion of 0.75 g of 5-methylpyridine-2-
sulfonamide potassium salt was added and stirring was continued for 18 h.
The reaction mixture was poured onto 150 ml of 10% citric acid in water and
extracted four times with 150 ml of ethyl acetate. The combined organic
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phase was washed with water, dried over MgS04, and evaporated. The
resulting residue was suspended in 20 ml of methanol and 20 ml of acetone.
The precipitate was collected, washed with methanol:diethyl ether 1:1 and
dried. This furnished 4.56 g of 5-methyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-
(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide as a beige powder. LC-MS: tR
= 4.38 min, [M+1]+ = 484.58, [M-1]' = 482.51.
e) At room temperature, 8.0 g of 2-butyne-1,4-diol was added portionwise to a
stirred slurry of 0.99 g sodium hydride in 25 ml of dry DMF and 5 ml of dry
DMPU. Stirring was continued until the evolution of gas had ceased. To the
resulting suspension 2.0 g of 4-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-
2-(4-pyridyl)-4-pyrimidinyl]-benzene sulfonamide was added at room
temperature and the mixture was stirred at 90°C for 16 h. Eventually,
the
slurry was allowed to cool to room temperature, was then poured onto a
mixture of 200 ml of an aqueous solution of 10% citric acid and 200 ml of
ethyl acetate. A fine precipitate formed. The precipitate was filtered off,
washed with water and ethyl acetate. The organic layer was separated and
the aqueous layer was extracted two more times with ethyl acetate. The
combined organic layers were dried over MgS04 and the solvent was
removed to a volume of about 10 ml. The fine precipitate that formed was
collected, washed with ethyl acetate, and combined with the precipitate
isolated from the aqueous layer. This gave 1.65 g of 5-methyl-N-[6-(4-
hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-
pyridine sulfonamide as a beige powder. LC-MS: tR = 3.81 min, [M+1]+ -
534.63, [M-1 ]' = 532.54.
Example 4
a) 4,6-dihydroxy-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidine [or its
tautomer 5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-tetrahydropyrimidine-4,6
dion] was prepared as disclosed in EP 0 526 708 A1 from 2-amidino
pyrimidine and dimethyl-(o-methoxyphenoxy)malonate.
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b) 4,6-dichloro-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidine was pre-
pared as disclosed in EP 0 526 708 A1 from 4,6-dihydroxy-5-(o-
methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidine (which may also be present in
the tautomeric form 5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-tetrahydro-
pyrimidine-4,6-dione).
c) A solution of 3.5 g of 4,6-dichloro-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-
pyrimidine and 4.98 g of 5-isopropyl-2-pyridine sulfonamide potassium salt
(Example 1, section e) in 40 ml of DMSO was stirred at room temperature for
4 h. The mixture was poured onto water and extracted twice with diethyl
ether. The aqueous layer was acidified with acetic acid. The precipitate that
formed was collected, washed with water and diethyl ether and dried to
furnish 5.1 g of 5-isopropyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(2-
pyrimidinyl)-4-pyrimi-dinyl]-2-pyridine sulfonamide as a white solid. LC-MS:
tR
= 4.87 min, [M+1]+ = 513.32, [M-1]- = 511.26.
d) 273 mg of 5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxy-
phenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-pyridine sulfonamide was obtained
as a beige foam starting from 600 mg of 5-isopropyl-N-[6-chloro-5-(0-
methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-pyridine sulfonamide
following the procedure given in Example 1g. LC-MS: tR = 4.31 min, [M+1]+ -
563.71, [M-1 ]- = 561.59.
Example 5
a) 4-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimi-
dinyl]benzene sulfonamide was prepared as disclosed in EP 0 526 708 A1
from 4,6-dichloro-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidine and p-
tert.-butyl benzene sulfonamide potassium salt. LC-MS: tR = 5.50 min, [M+1]+
= 526.29, [M-1 ]- = 524.43.
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b) 295 mg of 4-tert.-butyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxy-
phenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene sulfonamide was obtained
as a beige foam starting from 1.4 g of 4-tert.-butyl-N-[6-chloro-5-(0-
-- methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene sulfonamide
following the procedure given in Example 1g. LC-MS: tR = 5.06 min, [M+1]+ -
576.33, [M-1 ]' = 574.45.
Example 6
a) To a suspension of 2.0 g of 4,6-dichloro-5-(o-methoxyphenoxy)-2-(2-
pyrimidinyl)-pyrimidine (Example 4 b) and 2.65 g of 5-methyl-2-pyridine
sulfonamide potassium salt (Example 3c) in 40 ml of DMF was added 10 ml
of DMSO. The mixture became clear and stirring was continued for 16 h at
room temperature. Upon pouring the mixture onto 50 ml of 10% citric acid in
water a white precipitate formed. The precipitate was collected, washed with
water and ethyl acetate, and dried. This furnished 2.67 g of 5-methyl-N-[6-
chloro-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-pyridine
sulfonamide as a white powder. LC-MS: tR = 4.23 min, [M+1]+ = 485.56, [M-1]-
= 483.48.
b) 347 mg of 5-methyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-
2-(2-pyrimidinyl)-4-pyrimidinyl]-2-pyridine sulfonamide was obtained as a pale
yellow foam starting from 1 g of 5-methyl-N-[6-chloro-5-(o-methoxyphenoxy)-
2-(2-pyrimidinyl)-4-pyrimidinyl]-2-pyridine sulfonamide following the
procedure
given in Example 1 g. LC-MS: tR = 3.90 min, [M+1]+ = 535.66, [M-1]- = 533.55.
Example 7
a) A solution of 10 g of dimethyl-(o-methoxyphenoxy)malonate (Example 1 b)
in 80 ml dry methanol was cooled to 0°C. 6.71 g of sodium methylate was
added portionenwise. To the suspension was added 2.84 g of acetamidine
hydrochloride and the mixture was stirred overnight at room temperature. The
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solvent was removed under reduced pressure and the residue was
suspended in 100 ml of diethyl ether. The solid was filtered off, washed with
another portion of 100 ml of diethyl ether and dissolved in 50 ml of water.
The
pH was adjusted to 4 by adding 25 ml of glacial acetic acid. The white
precipitate that formed was filtered off, washed with water and dried to yield
5.17 g of 5-(o-methoxyphenoxy)-4,6-dihydroxy-2-methyl-pyrimidine (or a
tautomer) as a white powder.
b) A solution of 10.9 g of 5-(o-methoxyphenoxy)-4,6-dihydroxy-2-methyl-
pyrimidine (or a tautomer) in 150 ml of POC13 was stirred at 50°C for
72 h.
The excess of POCI3 was evaporated, toluene was added to coevaporate
traces of POCI3. Eventually, an ice:water mixture was carefully added to the
residue and the pH was adjusted to 8 using 3 N sodium hydroxide solution.
The mixture was further diluted with 300 ml of water and extracted with 500
ml of DCM. The organic layer was separated, washed with 300 ml of water,
dried over Na2SO4 and evaporated. The residue was dissolved again in DCM
and filtered through a pad of silica gel eluting with DCM. The solvent was
removed in vacuo. The resulting residue was dried to furnish 8.7 g of 4,6-
dichloro-5-(o-methoxyphenoxy)-2-methyl-pyrimidine as a beige powder.
c) To a solution of 2.15 g of 4,6-dichloro-5-(o-methoxyphenoxy)-2-methyl-
pyrimidine in 40 ml of DMSO was added 3.59 g of 5-isopropyl-2-pyridine
sulfonamide potassium salt. The mixture was stirred for 72 h at room
temperature. The solution was diluted with 350 ml of water and extracted
twice with 200 ml of diehtyl ether. The organic layers were extracted twice
with water. The combined aqueous layers were acidified to pH 4 with 5 ml of
acetic acid and extracted twice with DCM. The organic layers were washed
with water, and dried over Na2S04. The solution was treated with activated
charcoal, filtered over Celite and evaporated. The residue was suspended in
30 ml of diethyl ether, filtered off and dried to give 3.15 g of 5-isopropyl-N-
[6-
chloro-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyridine sulfonamide
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as a pale beige powder. LC-MS: tR = 5.18 min, [M+1]+ = 449.25, [M-1]- -
447.31.
d) 440 mg of 5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(0-
methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyridine sulfonamide was
obtained as a beige foam starting from 600 mg of 5-isopropyl-N-[6-chloro-5-
(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyridine sulfonamide following
the procedure given in Example 1g, but stirring the reaction mixture for 48 h
at 95°C. LC-MS: tR = 4.74 min, [M+1]+ = 499.25, [M-1]- = 497.33
Example 8
a) At room temperature 2.95 g of 5-methyl-2-pyridine sulfonamide potassium
salt (Example 3c) was added to a suspension of 2 g of 4,6-dichloro-5-(0-
methoxyphenoxy)-2-methyl-pyrimidine (Example 7b) in 30 ml DMSO. The
mixture was stirred at room temperature for 48 h and was then poured onto
300 ml of water. The aqueous solution was extracted twice with 200 ml of
diethyl ether. The organic layers were extracted with water and the aqueous
layers were combined and acidified with 3 ml of acetic acid to pH 4.
Precipitation of the product was enhanced by adding 100 ml of saturated
aqueous sodium chloride and cooling the mixture to 0°C. Eventually, the
precipitate was filtered off, washed with cold water and dried under high
vacuum to give 2.26 g of 5-methyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-
methyl-4-pyrimidinyl]-2-pyridine sulfonamide as a beige powder. LC-MS: tR =
4.79 min, [M+1 ]+ = 421.42, [M-1 ]- = 419.46.
b) 584 mg of 5-methyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-
2-methyl-4-pyrimidinyl]-2-pyridine sulfonamide was obtained as a beige
powder starting from 950 mg of 5-methyl-N-[6-chloro-5-(o-methoxyphenoxy)-
2-methyl-4-pyrimidinyl]-2-pyridine sulfonamide following the procedure given
in Example 1g, but stirring the reaction mixture for 72 h at 95°C. LC-
MS: tR =
4.32 min, [M+1]+ = 471.57, [M-1]- = 469.40.
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Example 9
a) A solution of 32.75 g of dimethyl-(o-methoxyphenoxy)malonate (Example 1
b) in 250 ml of methanol was cooled to 0°C. 20.0 g sodium methylate was
added portionwise and upon completion of the addition the mixture was
stirred at room temperature for 6 h. Then 25.0 g of morpholinoformamidine
hydrobromide was added.and stirring was continued for 72 h. The solvent of
the beige suspension was evaporated and the residue was washed twice with
150 ml of diethyl ether. The remaining powder was dissolved in 200 ml of
water. Upon adjusting the pH to 4 with 50 ml of acetic acid a precipitate
formed. The precipitate was collected, washed with water and dried under
high vacuum to yield 17.01 g of 5-(o-methoxyphenoxy)-4,6-dihydroxy-2-(N-
morpholino)-pyrimidine (or a tautomer) as a slightly beige powder.
b) At 0°C 50 ml of POC13 was carefully added to 27.5 ml of Hunig's
base. To
this mixture 17 g of 5-(o-methoxyphenoxy)-4,6-dihydroxy-2-(N-morpholino)-
pyrimidine was added portionwise. The resulting mixture was stirred over
night at 130°C. The excess of reagents was evaporated and traces of
POCI3
were removed by coevaporation with toluene. The black residue was treated
with 50 ml of DCM and 50 ml of a water:ice mixture. After stirring for 15 min,
the mixture was diluted with 400 ml of water and 400 ml of DCM. The organic
layer was separated and washed with 300 ml of water. The aqueous layer
was extracted with 400 ml of DCM. The combined DCM layers were dried
over Na2S04 and the solvend was removed to a volume of about 100 ml. The
remaining solution was filtered over 50 g of silica gel eluting with DCM. The
filtrate was evaporated. The resulting residue was suspended in 50 ml of
diethyl ether. The solid was filtered off and dried to give 13.85 g of 4,6
dichloro-5-(o-methoxyphenoxy)-2-(N-morpholino)-pyrimidine as a white
crystalline powder.
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c) To a suspension of 4 g of 4,6-dichloro-5-(o-methoxyphenoxy)-2-(N-
morpholino)-pyrimidine in 60 ml of DMSO was added 5.32 g of 5-isopropyl-2-
pyridine sulfonamide potassium salt (Example 3c) and 0.98 ml of Hunig's
base. The mixture was stirred at 65°C for 72 h. The dark solution was
poured
onto 500 ml of water and quickly filtered through celite. The filtrate was
extracted with 500 ml and 250 ml of diethyl ether. The organic layers were
extracted with 100 ml of water. The aqueous layers were combined, acidified
with 3.5 ml of acetic acid and cooled to 0°C. The precipitate that
formed was
collected, washed with cold water and dried under high vacuum to furnish
4.94 g of 5-isopropyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-
pyrimidinyl]-2-pyridine sulfonamide as a brownish powder. LC-MS: tR = 5.46
min, [M+1 ]+ = 520.22, [M-1 ]- = 518.36.
d) At 0-5°C 3.97 g of 2-butyne-1,4-diol was added portionwise to a
stirred
slurry of 0.55 g sodium hydride in 30 ml of dry DMF and 7 ml of DMPU.
Stirring was continued until the evolution of gas had ceased. To the resulting
suspension 1.2 g of 5-isopropyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(N-
morpholino)-4-pyrimidinyl]-2-pyridine sulfonamide was added at room
temperature and the mixture was stirred at 95°C for 6 days. Eventually,
the
slurry was allowed to cool to room temperature, was then poured onto 100 ml
of an aqueous solution of 10% citric acid and extracted twice with 150 ml of
ethyl acetate. The combined organic layers were washed twice with 75 ml of
water, dried over MgS04 and evaporated. The remaining brown oil was
purified by column chromatography on 120 g of silica gel eluting with DCM
containing 0-2% of methanol. Fractions containing the desired compound
were combined, evaporated and the residue was further purified by
recrystallisation from diethyl ether : hexane. This gave 327 mg of 5-isopropyl-
N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-
pyrimidinyl]-2-pyridine sulfonamide as colourless crystals with a melting
point
of 196.0-197.5°C. LC-MS: tR = 4.89 min, [M+1]+ = 570.30, [M-1]- =
568.43.
Furthermore, 494 mg of the starting material was recovered as a beige foam.
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Example 10
a) At 5°C 12.7 g of sodium methylate was added portionwise to a
solution of
18.9 g of dimethyl-(o-methoxyphenoxy)malonate (Example 1 b) in 450 ml of
methanol. Upon completion of the addition stirring was continued at room
temperature for 30 min followed by the addition of 6 g of formamidine
hydrochloride. The mixture was stirred at room temperature for 72 h.
Eventually, the solvent was removed under reduced pressure and the
remaining residue was suspended in diethyl ether. The solid material was
filtered off and dissolved in 100 ml of water. The solution was acidified with
cone. hydrochloric acid. A white precipitate formed. The precipitate was
collected, washed with water and dried to give 15.1 g of 5-(0-
methoxyphenoxy)-4,6-dihydroxy-pyrimidine (or a tautomer) as a white
powder.
b) To a solution of 7.5 g of 5-(o-methoxyphenoxy)-4,6-dihydroxy-pyrimidine in
90 ml of POC13 24 ml of N,N-dimethylaniline was added. The mixture was
heated to 160°C and stirred for 2.5 h. Excess of POCI3 was distilled
off under
reduced pressure. Traces of POCI3 were coevaporated with toluene. The
remaining oil was treated with a water:ice mixture. The mixture was acidified
with 1 N hydrochloric acid and extracted twice with diethyl ether. The
combined organic layers were washed twice with dilute aqueous hydrochloric
acid, dried over MgS04 and evaporated. The remaining solid was washed
with methanol and dried. This gave 4.75 g of 4,6-dichloro-5-(0
methoxyphenoxy)-pyrimidine as a pale yellow powder.
c) To a solution of 2 g of 4,6-dichloro-5-(o-methoxyphenoxy)-pyrimidine in 40
ml of DMSO 3.7 g of 4-tert.butylbenzene sulfonamide potassium salt was
added. The resulting solution was stirred for 20 h at room temperature.
Eventually, the mixture was poured onto 400 ml of water and washed twice
with 200 ml of diethyl ether. The organic layers were extracted with 200 ml of
water. The combinded aqueous layers were acidified with cone. hydrochloric
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acid. The mixture was cooled to 0°C and 100 ml of brine was added. The
precipitate that formed was collected and dried to yield 2.7 g of 4-tert.-
butyl-N-
[6-chloro-5-(o-methoxyphenoxy)-4-pyrimidinyl]-benzene sulfonamide as a
white powder. LC-MS: tR = 5.80 min, [M+1]+ = 448.17, [M-1]- = 446.21.
d) To a slurry of 0.79 g of sodium hydride in 45 ml of DMF and 15 ml of
DMPU 5.68 g of 2-butyne-1,4-diol was added at 10°C. The mixture
was
stirred until no more gas evolved. Then 1.48 g of 4-tert.-butyl-N-[6-chloro-5-
(o-methoxyphenoxy)-4-pyrimidinyl]-benzene sulfonamide was added and the
mixture was stirred at 90°C for 72 h. The solvent was removed in vacuo
and
the residue was taken up in 150 ml of 10% aqueous acetic acid. The mixture
was extracted three times with 150 ml of ethyl acetate. The combined organic
layers were washed with water and brine, dried over MgS04 and evaporated.
The resulting brown oil was purified by column chromatography on silica gel
eluting with hexane:ethyl acetate 3:1 to 1:1. This furnished 320 mg of 4-tert.-
butyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-4-pyrimidinyl]-
benzene sulfonamide as a slightly brown foam. LC-MS: tR = 5.21 min, [M+1]+
= 498.35, [M-1 ]' = 496.49.
Example 'i'i
a) A solution of 6.8 g of sodium methylate in 200 ml of methanol was cooled
to 0°C. A solution of 10.3 g of diethyl 2-(p-tolyl)-malonate in 50 ml
of methanol
was slowly added. Upon completion of the addition the solution was allowed
to come to room temperature and 7.57 g of 4-amidino-pyridine hydrochloride
(Example 1 a) was added. The mixture was stirred at room temperature for 16
h. Eventually, the solvent was removed under reduced pressure and the
remaining residue was dissolved in 2 M hydrochloric acid. The solution was
extracted with diethyl ether, then adjusted to pH 5 with 10 M sodium
hydroxide solution. A precipitate formed. The precipitate was collected,
washed with cold water and dried at 60°C under high vacuum. This gave
8.77
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g of 4,6-dihydroxy-2-(4-pyridyl)-5-(p-tolyl)-pyrimidine (or a tautomer) as
orange crystals.
b) To a mixture of 8.0 g of 5-(p-tolyl)-4,6-dihydroxy-pyrimidine and 100 ml of
POC13 25 ml of diethylamine was added at room temperature. The mixture
was stirred for 16 h at 60°C. The excess of POCI3 was distilled off
under
reduced pressure. The remaining oil was dissolved in 300 ml of DCM and
treated with 300 ml of water. The aqueous layer was separated and extracted
three times with DCM. The combined organic layers were washed with water
and brine, dried over MgS04 and evaporated. The resulting residue was
suspended in isopropanol. The solid material was collected, washed with
isopropanol, and diethyl ether and dried to give 7.2 g of 4,6-dichloro-2-(4-
pyridyl)-5-(p-tolyl)-pyrimidine as a white crystalline powder.
c) A mixture of 654 mg of 4,6-dichloro-2-(4-pyridyl)-5-(p-tolyl)-pyrimidine
and
1051 mg of 5-isopropyl-2-pyridine sulfonamide potassium salt (Example 1 e)
in 20 ml of DMF was stirred for 16 h at room temperature. Eventually, the
solvent was distilled off under reduced pressure and the resulting residue was
treated with 100 ml of 10% aqueous acetic acid and 100 ml of DCM. The
layers were separated. The aqueous layer was extracted two more times with
DCM. The combined organic layers were washed once with water, dried over
MgS04 and evaporated. The remaining residue was crystallised from
isopropanol:diethyl ether. The yellow crystals were collected, washed with
cold isopropanol and diethyl ether, and dried under high vacuum to furnish
870 mg of 5-isopropyl-N-[6-chloro-5-(p-tolyl)-2-(4-pyridyl)-4-pyrimidinyl]-2-
pyridine sulfonamide. LC-MS: tR = 5.06 min, [M+1]+ = 480.40, [M-1]- = 478.48.
d) To a slurry of 0.34 g of sodium hydride in 15 ml of DMF and 4 ml of DMPU
2.4 g of 2-butyne-1,4-diol was added at room temperature. The mixture was
stirred until no more gas evolved. Then 0.67 g of 5-isopropyl-N-[6-chloro-5-(p-
tolyl)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide was added and the
mixture was stirred at 90°C for 48 h. The solvent was removed in vacuo
and
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the residue was taken up in 100 ml of 10% aqueous acetic acid. The mixture
was extracted three times with 100 ml of ethyl acetate. The combined organic
layers were washed with water and brine, dried over MgS04 and evaporated.
The resulting brown oil was purified by column chromatography on silica gel
eluting with DCM containing 4-10% of methanol. This furnished a fraction
which after recrystallisation from DCM : ethyl acetate gave 43 mg of 5-
isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(p-tolyl)-2-(4-pyridyl)-4-
pyrimidinyl]-
2-pyridine sulfonamide as pale yellow crystals. A second fraction gave 456
mg of 5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(p-tolyl)-2-(4-pyridy1)-4-
pyrimidinyl]-2-pyridine sulfonamide with about 90% purity as a brown oil. LC-
MS: tR = 4.53 min, [M+1 ]+ = 530.23, [M-1 ]- = 528.21.
Example 12
a) At 0°C a solution of 14.2 g of diethyl 2-(p-tolyl)-malonate in 50 ml
of
methanol was slowly added to a solution of 9.4 g of sodium methylate in 300
ml of methanol. Upon completion of the addition the reaction mixture was
allowed to warm up and 5.4 g of formamidine hydrochloride was added. The
mixture was stirred at room temperature for 16 h. The solvent was removed
under reduced pressure and the remaining residue was treated with 150 ml of
2 N hydrochloric acid. The suspension was stirred for 0.5 h. At 0-5°C,
the pH
was carefully adjusted to 4 using 10 N sodium hydroxide solution. The
precipitate was collected, washed with cold water, isopropanol, and diethyl
ether and dried under high vacuum at 65°C to give 11.2 g of 4,6-
dihydroxy-5-
(p-tolyl)-pyrimidine (or a tautomer) as a white powder.
b) At room temperature 10 ml of N,N-dimethylaniline was added to a mixture
of 5.1 g of 4,6-dihydroxy-5-(p-tolyl)-pyrimidine and 75 ml of POCI3. The
reaction mixture was stirred at 70°C for 16 h. The excess of POCI3 was
distilled off and the remaining oil was treated with a ice:water mixture and
extracted three times with diethyl ether. The combined organic layers were
washed with 1 N aqueous hydrochloric acid followed by brine, dried over
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MgS04 and evaporated. The remaining brown oil was crystallised from
isopropanol. The pale yellow crystals were collected, washed with cold
isopropanol and dried under high vacuum to furnish 4.1 g of 4,6-dichloro-5-(p-
tolyl)-pyrimidine.
c) A mixture of 0.8 g of 4,6-dichloro-5-(p-tolyl)-pyrimidine and 1.68 g of 4-
tert.-
butylbenzene sulfonamide potassium salt (Example 2a) in 20 ml of DMSO
was stirred at room temperature for 24 h. The mixture was poured onto 200
ml of water and extracted twice with 100 ml of diethyl ether. The organic
layers were extracted twice with 50 ml of water. The combined aqueous
layers were acidified hydrochloric acid. The resulting fine suspension was
extracted twice with ethyl acetate. The combined organic layers were dried
over Na2S04 and evaporated. The residue was dried under high vacuum to
give 1.34 g 4-tert.-butyl-N-[6-chloro-5-(p-tolyl)-4-pyrimidinyl]-benzene
sulfonamide as a white powder. LC-MS: tR = 5.92 min, [M+1]+ = 416.20, [M-1]-
= 414.24.
d) 700 mg of 4-tert.-butyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(p-tolyl)-4-
pyrimidinyl]-benzene sulfonamide was obtained as a brown glass starting
from 1.45 g of 4-tert.-butyl-N-[6-chloro-5-(p-tolyl)-4-pyrimidinyl]-benzene
sulfonamide following the procedure given in Example 10d. LC-MS: tR = 5.38
min, [M+1]+ = 466.24, [M-1]- = 464.32.
Example 13
a) A solution of 2.71 g of 4,6-dichloro-5-(o-methoxyphenoxy)-pyrimidine
(Example 10b) and 5.0 g of 5-isopropyl pyridine-2-sulfonamide potassium salt
(Example 1 e) in 50 ml of DMF was stirred at room temperature for 20 h. The
solvent was removed in vacuo, the residue was taken up in 200 ml of 10%
aqueous acetic acid and extracted three times with ethyl acetate. The
combined organic layers were washed with water and brine, dried over
MgS04 and evaporated. The crude product was crysallised from a mixture of
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2-propanol and diethyl ether. The crystals were collected, washed with cold 2-
propanol and diethyl ether and dried to give 2.8 g of 5-isopropyl-N-[6-chloro-
5-(o-methoxyphenoxy)-4-pyrimidinyl]-2-pyridine sulfonamide as white
crystals. LC-MS: tR = 4.99 min, [M+1]+ = 435.25, [M-1]- = 433.28.
b) To a solution of 11.02 g of 2-butyne-1,4-diol in 100 ml of DMF and 30 ml of
DMPU was added 2.8 g sodium hydride in portions. After completion of the
addition stirring was continued for 1.5 h followed by the addition of 2.78 g
of
5-isopropyl-N-[6-chloro-5-(o-methoxyphenoxy)-4-pyrimidinyl]-2-pyridine
sulfonamide. The mixture was heated to 90°C and stirred for 65 h. The
solvent was removed in vacuo, the residue was taken up in 250 ml of 10%
aqueous citric acid and extracted twice with 250 ml of ethyl acetate. The
organic phase was washed with water and brine, dried over MgS04 and
evaporated. Column chromatography of the crude product on silica gel eluting
with hexane:ethyl acetate 1:1 to 1:4 furnished 1.27 g of 5-isopropyl-N-[6-(4-
hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-4-pyrimidinyl]-2-pyridine
sulfonamide as a brown solid. Beige crystals were obtained for analytical
purposes after crystallisation of a part of the isolated product from 2-
propanol.
LC-MS: tR = 4.50 min, [M+1 ]+ = 485.27, [M-1 ]- = 483.41.
Example 14
a) A solution of 15.2 g of 4-tert.-butylbenzene sulfonyl chloride in 150 ml of
THF was cooled with an ice bath. 15.2 ml of 25% aqueous ammonium
hydroxide solution was added dropwise. After the addition was completed, the
solution was stirred at r.t. for 15 min. The solvent was removed in vacuo. The
residue was again dissolved in ethyl acetate and washed twice with water.
The organic phase was dried over Na2S04, evaporated and dried. The
resulting 14.8 g of a white powder was dissolved in 75 ml of methanol and 7.5
g of potassium tert. butylate was added. The solution was briefly stirred at
r.t.
and evaporated. The resulting residue was carefully dried to give 16.3 g of 4-
tert.-butylbenzene sulfonamide potassium salt as a white solid.
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b) A solution of 2.0 g of 4,6-dichloro-5-(2-methoxyphenoxy)-2-(N-morpholino)-
pyrimidine (Example 9b) and 2.96 g of 4-tart.-butylbenzene sulfonamide
potassium salt in 30 ml of DMSO was stirred at r.t. for 24 h. After 1 g of 4-
tart.-butylbenzene sulfonamide potassium salt had been added, stirring was
continued for another 24 h at r.t. followed by 16 h at 55°C.
Eventually, the
mixture was poured into 350 ml of water and 350 ml of ether. The mixture
was acidified by adding acetic acid. A white, sticky precipitate formed. The
mixture was stirred at 0°C for 1 h. The precipitate was filtered off,
washed
with water and ether and dissolved again in ethyl acetate. The solvent was
removed in vacuo and the remaining solid was suspended in 100 ml of diethyl
ether. The solid was filtered off, washed with additional diethyl ether and
dried
to give 2.57 g of 4-tart.-butyl-N-[6-chloro-5-(2-methoxy-phenoxy)-2-morpholin
4-yl-pyrimidin-4-yl]-benzene sulfonamide as a white powder. LC-MS: tR = 5.98
min, [M+1 ]+ = 533.29, [M-1 ]- = 531.41.
c) To a suspension of 675 mg of NaH in 45 ml of DMF and 5 ml of DMPU was
added 4.85 g of 2-butyne-1,4-diol. The mixture was stirred at room
temperature until evolution of gas had ceased. Then 1.5 g of 4-tart.-butyl-N-
[6-chloro-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-benzene
sulfonamide was added and the resulting mixture was heated to 95°C and
stirred for 5 days. Eventually, the mixture was pourred into 150 ml of 10%
aqueous citric acid and extracted three times with 150 ml of ethyl acetate.
The organic layers were washed with water and brine, dried over MgS04 and
evaporated. The resulting residue was purified by column chromatography on
silicagel eluting with hexane:ethyl acetate 1:1 to give 265 mg of 4-tart.-
butyl-
N-[6-(4-hydroxy-2-butynyloxy)-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-
pyrimidin-4-yl]-benzene sulfonamide as a beige foam along with 1.13 g of the
starting material 4-tart.-butyl-N-[6-chloro-5-(2-methoxy-phenoxy)-2-morpholin-
4-yl-pyrimidin-4-yl]-benzene sulfonamide. LC-MS: tR = 5.39 min, [M+1]+ _
583.41, [M-1 ]- = 581.35.
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Example 15
a) To a suspension of 4 g of 4,6-dichloro-5-(2-methoxyphenoxy)-2-(N-
morpholino)-pyrimidine (Example 9b) in 20 ml of DMSO was added 4.72 g of
5-methyl-2-pyridine sulfonamide potassium salt (Example 3c). The mixture
was stirred at 55°C for 17 h. The dark solution was poured into 500 ml
of
water and quickly filtered through celite. The filtrate was extracted with 500
ml
and 250 ml of diethyl ether. The organic layers were extracted with 100 ml of
water. The aqueous layers were combined, acidified with 3.5 ml of acetic acid
and cooled to 0°C. The precipitate that formed was collected, washed
with
cold water and dried under high vacuum to furnish 4.42 g of 5-methyl-N-[6-
chloro-5-(2-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridine
sulfonamide as a brownish powder..LC-MS: tR = 4.80 min, [M+1]+ = 492.31,
[M-1 ]- = 490.37.
b) To a suspension of 712 mg of NaH in 30 ml of DMF and 7 ml of DMPU was
added 5.11 g of 2-butyne-1,4-diol. The mixture was stirred at room
temperature until evolution of gas had ceased. Then 1.45 g of 5-methyl-N-[6-
chloro-5-(2-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridine
sulfonamide was added and the resulting mixture was heated to 95°C and
stirred for 4 days. Eventually, fihe mixture was pourred into 200 ml of 10%
aqueous citric acid and extracted three times with 200 ml of ethyl acetate.
The organic layers were washed with water and brine, dried over MgS04 and
evaporated. The resulting residue was purified by column chromatography on
silicagel eluting with a gradient of hexane:ethyl acetate 1:1 to ethyl acetate
to
give 470 mg of 5-methyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(2-
methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridine sulfonamide as
a beige powder along with 660 mg g of the starting material 5-methyl-N-[6-
chloro-5-(2-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridine
sulfonamide. LC-MS: tR = 4.33 min, [M+1]+ = 542.35, [M-1]- = 540.32.
Example 16
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a) A mixture of 10 g of 4,6-dichloro-5-(p-tolyl)-pyrimidine (Example 12b) and
4.8 g of 5-isopropyl pyridine-2-sulfonamide potassium salt (Example 1e) in
100 ml of DMF was stirred at room temperature for 72 h. The solvent was
partially removed in vacuo before the mixture was treated with 50 ml of
diethyl
ether. Under vigorous stirring, the pH of the aqueous phase was adjusted to 3
by adding a 10% aqueous citric acid solution. Stirring was continued for 15
min at 10°C. The precipitate that formed was collected, washed with
water
and diethtyl ether and dried under high vaccum at 50°C. This furnished
7.67 g
of 5-isopropyl-N-[6-chloro-5-(p-tolyl)-4-pyrimidinyl]-2-pyridine sulfonamide
as
a white powder. LC-MS: tR = 5.13 min, [M+1]+ = 403.24, [M-1]- = 401.28.
b) To a solution of 21.5 g of 2-butyne-1,4-diol in 200 ml of DMF and 50 ml of
DMPU was added in portions 5.5 g of NaH 55% in mineral oil. After the
evolution of gas had ceased 5.04 g of 5-isopropyl-N-[6-chloro-5-(p-tolyl)-4-
pyrimidinyl]-2-pyridine sulfonamide was added and the resulting mixture was
stirred for 80 h at 90°C. The solvent was removed in vacuo and the
residue
was partitioned between 300 ml of 10% aqueous citric acid and 300 ml of
ethyl acetate. The aqueous phase was extracte two more times with ethyl
acetate. The combined organic layers were washed with water and brine,
dried over MgS04 and evaporated. The crude product was purified by column
chromatography on silica gel eluting with hexane:ethyl acetate from 1:1 to 1:4
to give 2.0 g of 5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(p-tolyl)-4-
pyrimidinyl]-2-pyridine sulfonamide as a brown solid. LC-MS: tR = 4.64 min,
[M+1 ]+ = 453.28, [M-1 ]- = 451.40.
Example 17
To a suspension of 14 mg of a 55% sodium hydride dispersion in mineral oil
in 2 ml of dry DMF and 2 ml of dry THF 80 mg of 5-isopropyl-N-[6-(4-hydroxy-
2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl)-2-pyridine
sul-fonamide (Example 1 g) was added. After stirring for 10 min, 41 mg of 2-
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chloro-pyrimidine was added. Stirring was continued for 1 h at 70°C.
The
reaction mixture was poured onto 50 ml of 10% aqueous citric acid. The
solution was extracted twice with 50 ml of ethyl acetate. The combined
organic layers were twice washed with water, dried over MgS04 and
evaporated. The remaining residue was purified by column chromagraphy on
silica gel eluting with a gradient of 0-2% of methanol in DCM. This furnished
72 mg of 5-isopropyl-N-[6-(4-(2-pyrimidinyloxy)-2-butynyloxy)-5-(o-methoxy-
phenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide as a colourless
foam. LC-MS: tR = 4.74 min, [M+1]+ = 640.35, [M-1]- = 638.49.
Example 18
88 mg of 5-isopropyl-N-[6-(4-(4,6-dimethoxy-2-pyrimidinyloxy)-2-butynyloxy)-
5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide was
obtained as a pale yellow solid starting from 80 mg of 5-isopropyl-N-[6-(4-
hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl)-2-
pyridine sulfonamide (Example 1g) and 78 mg of 4,6-dimethoxy-2-methyl-
sulfonylpyrimidine following the procedure given in Example 17. LC-MS: tR =
5.34 min, [M+1]t = 700.42, [M-1]-= 698.52.
Example 19
To a suspension of 76 mg of a 55% sodium hydride dispersion in mineral oil
in 15 ml of dry THF 403 mg of 4-tert.-butyl-N-[6-(4-hydroxy-2-butynyloxy)-5-
(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-benzene sulfonamide
(Example 2c) was added. After stirring for 2 h, 91 mg of 2-chloropyrimidine
was added. Stirring was continued for 42 h at room temperature. The solvent
was evaporated and the remaining residue was partitioned between 50 ml of
10% aqueous acetic acid and 50 ml of ethyl acetate. The organic layer was
separated and the aqueous layer was extracted two more times with 50 ml of
ethyl acetate. The combined organic layers were washed with water and
brine, dried over MgS04 and evaporated. The remaining residue was purified
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by column chromagraphy on silica gel eluting with a gradient of 5-10% of
methanol in DCM. This furnished 256 mg of 4-tert.-butyl-N-[6-(4-(2-
pyrimidinyloxy)-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidi-
nyl]-benzene sulfonamide as a colourless foam. LC-MS: tR = 5.21 min, [M+1]+
= 653.69, [M-1 ]' = 651.78.
Example 20
200 mg of 4-tert.-butyl-N-[6-(4-(5-bromo-2-pyrimidinyloxy)-2-butynyloxy)-5-(0-
methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-benzene sulfonamide was
obtained in the form of beige crystals starting from 196 mg of 4-tert.-butyl-N-
[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidi-
nyl]-benzene sulfonamide (Example 2c) and 73 mg of 5-bromo-2-
chloropyrimidine following the procedure given in Example 19. However, the
crude product was purified by crystallisation from a methanol isopropanol
mixture. LC-MS: tR = 5.63 min, [M+1]+ = 731.65, [M-1]- = 729.66.
Example 21
A suspension of 400 mg of 4-tert.-butyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(0-
methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-benzene sulfonamide (Example
2c), 116 mg of 4,6-dimethoxy-2-methyl-sulfonylpyrimidine and 147 mg of
potassium carbonate in 15 ml of DMF was stirred at 90°C for 16 h.
Further 42
mg of 4,6-dimethoxy-2-methyl-sulfonylpyrimidine was added and stirring was
continued at 90°C for 24 h. Eventually, the solvent was removed in
vacuo,
and the resulting residue partitioned between 50 ml of 5% aqueous acetic
acid and 50 ml of DCM. The organic layer was separated and the aqueous
layer was extracted two more times with 50 ml of DCM. The combined
organic layers were washed with water, dried over MgS04 and evaporated.
The remaining oil was purified by column chromatography on silica gel eluting
with toluene : ethyl acetate 4:1 to 1:1. The product obtained was
recrystallised
from ethyl acetate : diethyl ether to give 76 mg of 4-tert.-butyl-N-[6-(4-(4,6-
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dimethoxy-2-pyrimidinyloxy)-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-
pyridyl)-4-pyrimidinyl]-benzene sulfonamide as white crystals. LC-MS: tR =
5.84 min, [M+1]+ = 713.35, [M-1]' = 711.45.
Example 22
To a suspension of 41 mg of a 55% sodium hydride dispersion in mineral oil
in 5 ml of dry DMF and 5 ml of dry THF 200 mg of 5-methyl-N-[6-(4-hydroxy-
2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine
sulfonamide (Example 3e) was added. After strirring for 10 min, 47 mg of 2-
chloropyrimidine was added. Stirring was continued for 20 h at room
temperature. Then another 20 mg of 2-chloropyrimidine was added and
stirring was continued for another 24 h. Eventually, the reaction mixture was
poured onto 50 ml of 10% aqueous citric acid. The solution was extracted
twice with 50 ml of ethyl acetate. The combined organic layers were twice
washed with water, dried over MgS04 and evaporated. The remaining residue
was purified by column chromagraphy on silica gel eluting with a gradient of
0-3% of methanol in DCM. This furnished 147 mg of 5-methyl-N-[6-(4-(2-
pyrimidinyloxy)-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidi-
nyl]-2-pyridine sulfonamide as a pale yellow powder. LC-MS: tR = 4.26 min,
[M+1 ]+ = 612.29, [M-1 ]' = 610.43.
Example 23
65 mg of 5-methyl-N-[6-(4-(5-bromo-2-pyrimidinyloxy)-2-butynyloxy)-5-(0-
methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide was
obtained as a pale yellow solid starting from 100 mg of 5-methyl-N-[6-(4-
hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-
pyridine sulfonamide (Example 3e) and 44 mg of 5-bromo-2-chloropyrimidine
following the procedure given in Example 22. LC-MS: tR = 4.77 min, [M+1]+ -
690.22, [M-1 ]' = 688.36.
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Example 24
91 mg of 5-methyl-N-[6-(4-(4,6-dimethoxy-2-pyrimidinyloxy)-2-butynyloxy)-5-
(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide was
obtained as a pale yellow solid starting from 100 mg of 5-methyl-N-[6-(4-
hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-
pyridine sulfonamide (Example 3e) and 82 mg of 4,6-dimethoxy-2-
methylsulfonylpyrimidine following the procedure given in Example 22. LC-
MS: tR = 4.80 min, [M+1]+ = 672.32, [M-1]- = 670.46.
Example 25
72 mg of 5-methyl-N-[6-(4-(4,6-dimethyl-2-pyrimidinyloxy)-2-butynyloxy)-5-(0-
methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide was
obtained as a pale yellow solid starting from 80 mg of 5-methyl-N-[6-(4-
hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-
pyridine sulfonamide (Example 3e) and 70 mg of 4,6-dimethyl-2-
methylsulfonylpyrimidine following the procedure given in Example 22. LC-
MS: tR = 4.68 min, [M+1 ]+ = 640.32, [M-1 ]' = 638.39.
Example 26
59 mg of 5-isopropyl-N-[6-(4-(2-pyrimidinyloxy)-2-butynyloxy)-5-(o-methoxy-
phenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-pyridine sulfonamide was obtained
as a beige foam starting from 80 mg of 5-isopropyl-N-[6-(4-hydroxy-2-
butynyloxy)-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-pyridine
sulfonamide (Example 4d) and 33 mg of 2-chloropyrimidine following the
procedure given in Example 22. LC-MS: tR = 4.55 min, [M+1]+ = 641.63, [M-1]-
= 639.47.
Example 27
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78 mg of 5-isopropyl-N-[6-(4-(5-bromo-2-pyrimidinyloxy)-2-butynyloxy)-5-(0-
methoxy-phenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-pyridine sulfonamide was
obtained as a beige foam starting from 80 mg of 5-isopropyl-N-[6-(4-hydroxy-
2-butynyloxy)-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidiny1]-2-
pyridine sulfonamide (Example 4d) and 55 mg of 5-bromo-2-chloropyrimidine
following the procedure given in Example 22. LC-MS: tR = 4.99 min, [M+1]+ -
719.56, [M-1 ]- = 717.28.
Example 28
65 mg of 4-tert.-butyl-N-[6-(4-(5-bromo-2-pyrimidinyloxy)-2-butynyloxy)-5-(0-
methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-benzene sulfonamide was
obtained as a beige foam starting from 75 mg of 4-tert.-butyl-N-[6-(4-hydroxy-
2-butynyloxy)-5-(o-methoxyphenoxy)-2-(2-pyrimidi-nyl)-4-pyrimidinyl]-
benzene sulfonamide (Example 5b) and 103 mg of 5-bromo-2-
chloropyrimidine following the procedure given in Example 22. LC-MS: tR =
5.83 min, [M+1 ]+ = 732.31, [M-1 ]- = 730.36.
Example 29
71 mg of 4-tert.-butyl-N-[6-(4-(4,6-dimethoxy-2-pyrimidinyloxy)-2-butynyloxy)-
5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-benzene sulfonamide
was obtained as a colourless foam starting from 75 mg of 4-tert.-butyl-N-[6-(4-
hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(2-pyrimi-dinyl)-4-
pyrimidinyl]-benzene sulfonamide (Example 5b) and 140 mg of 4,6-
dimethoxy-2-methylsulfonylpyrimidine following the procedure given in
Example 22. LC-MS: tR = 5.92 min, [M+1]+ = 714.42, [M-1]- = 712.50.
Example 30
20 mg of 5-methyl-N-[6-(4-(2-pyrimidinyloxy)-2-butynyloxy)-5-(o-methoxy-
phenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-pyridine sulfonamide was obtained
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as a colourless foam starting from 60 mg of 5-methyl-N-[6-(4-hydroxy-2-
butynyloxy)-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-pyridine
sulfonamide (Example 6b) and 36 mg of 2-chloropyrimidine following the
procedure given in Example 22. LC-MS: tR = 4.37 min, [M+1]+ = 613.29, [M-1]-
= 611.45.
Example 31
75 mg of 5-methyl-N-[6-(4-(5-bromo-2-pyrimidinyloxy)-2-butynyloxy)-5-(0-
methoxy-phenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-pyridine sulfonamide was
obtained as a colourless powder starting from 80 mg of 5-methyl-N-[6-(4
hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]
2-pyridine sulfonamide (Example 6b) and 120 mg of 5-bromo-2
chloropyrimidine following the procedure given in Example 22. LC-MS: tR =
4.64 min, [M+1 ]+ = 691.64, [M-1 ]- = 689.45.
Example 32
84 mg of 5-methyl-N-[6-(4-(4,6-dimethoxy-2-pyrimidinyloxy)-2-butynyloxy)-5-
(o-methoxy-phenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-pyridine sulfonamide
was obtained as a colourless powder starting from 80 mg of 5-methyl-N-[6-(4
hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]
2-pyridine sulfonamide (Example 6b) and 65 mg of 4,6-dimethoxy-2
methylsulfonylpyrimidine following the procedure given in Example 22. LC
MS: tR = 4.72 min, [M+1]+ = 673.70, [M-1]- = 671.53.
Example 33
73 mg of 5-isopropyl-N-[6-(4-(2-pyrimidinyloxy)-2-butynyloxy)-5-(o-methoxy-
phenoxy)-2-methyl-4-pyrimidinyl]-2-pyridine sulfonamide was obtained as a
colourless foam starting from 80 mg of 5-isopropyl-N-[6-(4-hydroxy-2-
butynyloxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyridine su(fon-
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amide (Example 7d) and 46 mg of 2-chloropyrimidine following the procedure
given in Example 17. LC-MS: tR = 5.18 min, [M+1]+ = 577.27, [M-1]- = 575.36.
Example 34
75 mg of 5-isopropyl-N-j6-(4-(4,6-dimethoxy-2-pyrimidinyloxy)-2-butynyloxy)-
5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyridine sulfonamide was
obtained as a colourless foam starting from 80 mg of 5-isopropyl-N-[6-(4-
hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-
pyridine sulfonamide (Example 7d) and 88 mg of 4,6-dimethoxy-2-
methylsulfonylpyrimidine following the procedure given in Example 17. LC-
MS: tR = 5.80 min, [M+1]+ = 637.31, [M-1]- = 635.40.
Example 35
76 mg of 5-isopropyl-N-[6-(4-(4,6-dimethyl-2-pyrimidinyloxy)-2-butynyloxy)-5-
(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyridine sulfonamide was
obtained as a colourless foam starting from 80 mg of 5-isopropyl-N-[6-(4-
hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyri-
dine sulfonamide (Example 7d) and 75 mg of 4,6-dimethyl-2-
methylsulfonylpyrimidine following the procedure given in Example 17. LC-
MS: tR = 5.51 min, [M+1 ]+ = 605.35, [M-1 ]- = 603.43.
Example 36
98 mg of 5-methyl-N-[6-(4-(5-bromo-2-pyrimidinyloxy)-2-butynyloxy)-5-(0-
methoxy-phenoxy)-2-methyl-4-pyrimidinyl]-2-pyridine sulfonamide was
obtained as a colourless foam starting from 80 mg of 5-methyl-N-[6-(4-
hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyri-
dine sulfonamide (Example 8b) and 96 mg of 5-bromo-2-chloropyrimidine
following the procedure given in Example 22. LC-MS: tR = 5.33 min, [M+1]+ -
627.20, [M-1 ]- = 625.27.
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Example 37
80 mg of 5-methyl-N-[6-(4-(4,6-dimethoxy-2-pyrimidinyloxy)-2-butynyloxy)-5-
(o-methoxy-phenoxy)-2-methyl-4-pyrimidinyl]-2-pyridine sulfonamide was
obtained as a colourless foam starting from 80 mg of 5-methyl-N-[6-(4-
hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyri-
dine sulfonamide (Example 8b) and 74 mg of 4,6-dimethoxy-2-
methylsulfonylpyrimidine following the procedure given in Example 22. LC-
MS: tR = 5.46 min, [M+1]+ = 609.31, [M-1]~ = 607.38.
Example 38
80 mg of 5-methyl-N-[6-(4-(4,6-dimethyl-2-pyrimidinyloxy)-2-butynyloxy)-5-(0-
methoxy-phenoxy)-2-methyl-4-pyrimidinyl]-2-pyridine sulfonamide was
obtained as a colourless foam starting from 80 mg of 5-methyl-N-[6-(4-
hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyri-
dine sulfonamide (Example 8b) and 79 mg of 4,6-dimethyl-2-
methylsulfonylpyrimidine following the procedure given in Example 22, LC-
MS: tR = 5.10 min, [M+1]+ = 577.30, [M-1]- = 575.41.
Example 39
To a suspension of 58 mg of a 55% sodium hydride dispersion in mineral oil
in 15 ml of dry THF 280 mg of 4-tert.-butyl-N-[6-(4-hydroxy-2-butynyloxy)-5-
(p-tolyl)-4-pyrimidinyl]-benzene sulfonamide (Example 12) was added. After
stirring for 1 h, 144 mg of 4,6-dimethoxy-2-methylsulfonylyrimidine was
added. Stirring was continued for 12 h at reflux. Eventually, the solvent was
evaporated and the remaining residue was partitioned between 50 ml of 10%
aqueous citric acid and 50 ml of ethyl acetate. The organic layer was
separated and the aqueous layer was extracted two more times with 50 ml of
ethyl acetate. The combined organic layers were washed with water and
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brine, dried over MgSO4 and evaporated. The remaining residue was purified
by column chromagraphy on silica gel eluting with a gradient of 10-20% of
ethyl acetate in toluene. The isolated yellow foam was further purified on a
preparative silica gel plate. This furnished 91 mg of 4-tert.-butyl-N-[6-(4-
(4,6-
dimethoxy-2-pyrimidinyloxy)-butynyloxy)-5-(p-tolyl)-4-pyrimidinyl]-benzene
sulfonamide as a colourless foam. LC-MS: tR = 6.32 min, [M+1]+ = 604.31, [M-
1 ]- = 602.43.
Example 40
To a suspension of 88 mg of a 55% sodium hydride dispersion in mineral oil
in 15 ml of dry THF 375 mg of 4-tert.-butyl-N-[6-(4-hydroxy-2-butynyloxy)-5-
(p-tolyl)-4-pyrimidinyl]-benzene sulfonamide (Example 12) was added. After
stirring for 1 h, 170 mg of 5-bromo-2-chloropyrimidine was added. Stirring
was continued for 60 h at 40°C. Eventually, the solvent was evaporated
and
the remaining residue was partitioned between 50 ml of 10% aqueous citric
acid and 50 ml of ethyl acetate. The organic layer was separated and the
aqueous layer was extracted two more times with 50 ml of ethyl acetate. The
combined organic layers were washed with water and brine, dried over
MgS04 and evaporated. The crude product was crystallised from 2-propanol
containing a small amount of diethyl ether to give 168 mg of 4-tert.-butyl-N-
[6-
(4-(5-bromo-2-pyrimidinyloxy)-butynyloxy)-5-(p-tolyl)-4-pyrimidinyl]-benzene
sulfonamide as beige crystals. LC-MS: tR = 6.22 min, [M+1]+ = 624.28.
Example 41
To a suspension of 29 mg of a 55% sodium hydride dispersion in mineral oil
in 15 ml of dry THF 150 mg of 4-tert.-butyl-N-[6-(4-hydroxy-2-butynyloxy)-5-
(o-methoxy-phenoxy)-4-pyrimidinyl]-benzene sulfonamide (Example 10) was
added. After stirring for 0.5 h, 64 mg of 5-bromo-2-chloropyrimidine was
added. Stirring was continued for 40 h at 40°C. Eventually, the solvent
was
evaporated and the remaining residue was partitioned between 50 ml of 10%
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aqueous citric acid and 50 ml of ethyl acetate. The organic layer was
separated and the aqueous layer was extracted two more times with 50 ml of
ethyl acetate. The combined organic layers were washed with water and
brine, dried over MgS04 and evaporated. The crude product was crystallised
from 2-propanol to give 126 mg of 4-tert.-butyl-N-[6-(4-(5-bromo-2-
pyrimidinyloxy)-2-butynyloxy)-5-(o-methoxy-phenoxy)-4-pyrimidinyl]-benzene
sulfonamide as beige crystals. LC-MS: tR = 6.07 min, [M+1]+ = 656.24, [M-1]+
= 654.34.
Example 42
126 mg of 4-tert.-butyl-N-[6-(4-(4,6-dimethoxy-2-pyrimidinyloxy)-2
butynyloxy)-5-(o-methoxy-phenoxy)-4-pyrimidinyl]-benzene sulfonamide was
obtained as a colourless foam starting from 150 mg of 4-tert.-butyl-N-[6-(4
hydroxy-2-butynyloxy)-5-(o-methoxy-phenoxy)-4-pyrimidinyl]-benzene
sulfonamide (Example 10) and 72 mg of 4,6-dimethoxy-2-
methylsulfonylpyrimidine following the procedure given in Example 41. LC-
MS: tR = 6.13 min, [M+1]+ = 635.81, [M-1]- = 633.77.
Example 43
To a suspension of 243 mg of K2C03 in 15 ml of DMF 450 mg of 5-isopropyl-
N-[6-(4-hydroxy-2-butynyloxy)-5-(p-tolyl)-2-(4-pyridyl)-4-pyrimidinyl]-2-
pyridine
sulfonamide (Example 11 ) was added. After stirring for 0.5 h at 90°C,
192 mg
of 4,6-dimethoxy-2-methylsulfonylpyrimidine was added and stirring was
continued for 16 h at 90°C. Eventually, the solvent was evaporated and
the
remaining residue was partitioned between 50 ml of 10% aqueous acetic acid
and 50 ml of DCM. The organic layer was separated and the aqueous layer
was extracted two more times with 50 ml of DCM. The combined organic
layers were washed with water and brine, dried over MgS04 and evaporated.
The crude product was purified by column chromatography on silica gel
eluting with DCM:methanol 20:1 to give 88 mg of 5-isopropyl-N-[6-(4-(4,6-
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dimethoxy-2-pyrimidinyloxy)-2-butynyloxy)-5-(p-tolyl)-2-(4-pyridyl)-4-
pyrimidinyl]-2-pyridine sulfonamide as a beige foam. LC-MS: tR = 5.54 min,
[M+1]+ = 668.38, [M-1]+ = 666.39.
Example 44
186 mg of 5-isopropyl-N-[6-(4-(5-bromo-2-pyrimidinyloxy)-2-butynyloxy)-5-(0-
methoxyphenoxy)-4-pyrimidinyl]-2-pyridine sulfonamide was obtained as
beige crystals starting from 250 mg of 5-isopropyl-N-[6-(4-hydroxy-2-
butynyloxy)-5-(o-methoxyphenoxy)-4-pyrimidinyl]-2-pyridine sulfonamide
(Example 13) and 194 mg of 5-bromo-2-chloropyrimidine following the
procedure given in Example 41. LC-MS: tR = 5.43 min, [M+1]+ = 643.18, [M-1]-
= 641.29.
Example 45
To a solution of 250 mg of 5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(0-
methoxyphenoxy)-4-pyrimidinyl]-2-pyridine sulfonamide (Example 13) in 15
ml of THF was added 48 mg of NaH. The mixture was stirred for 2 h at room
temperature before 120 mg of 4,6-dimethoxy-2-methylsulfonylpyrimidine was
added. Stirring was continued for 16 h at reflux. Eventually, the solvent was
evaporated and the remaining residue was partitioned between 50 ml of 10%
aqueous citric acid and 50 ml of ethyl acetate. The organic layer was
separated and the aqueous layer was extracted two more times with 50 ml of
ethyl acetate. The combined organic layers were washed with water and
brine, dried over MgS04 and evaporated. The crude product was purified by
chromatography on prep. tlc-plates coated with silica gel with ethyl
acetate:methanol: sat. aqueous ammonia 8:2:1 to give 71 mg of 5-isopropyl-
N-[6-(4-(4,6-dimethoxy-2-pyrimidinyloxy)-2-butynyloxy)-5-(0-
methoxyphenoxy)-4-pyrimidinyl]-2-pyridine sulfonamide as a beige foam. LC-
MS: tR = 5.50 min, [M+1]+ = 623.29, [M-1]+ = 621.40.
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Example 46
To a suspension of 9 mg of NaH 55% dispersion in mineral oil in 4 ml of
DMF:THF 1:1 was added 50 mg of 4-tert.-butyl-N-[6-(4-hydroxy-2-
butynyloxy)-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-benzene
sulfonamide (Example 14). After the evolution of gas had ceased, 42 mg of 5-
bromo-2-chloropyrimidine was added and the mixture was stirred for 1 h at
65°C before it was diluted with 50 ml of 10% aqueous citric acid and 50
ml of
ethyl acetate. The organic layer was separated, washed with 50 ml of water,
dried over MgS04 and evaporated. The crude product was purified by column
chromatography on silica gel eluting with hexane:ethyl acetate 3:2 to give 60
mg of 4-tert.-butyl-N-[6-(4-(5-bromo-2-pyrimidinyloxy)-2-butynyloxy)-5-(2-
methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-benzene sulfonamide as a
colourless foam. MS: tR = 6.14min, [M+1]+ = 739.18, [M-1]+ = 741.32.
Example 47
48 mg of 4-tert.-butyl-N-[6-(4-(4,6-dimethoxy-2-pyrimidinyloxy)-2-butynyloxy)-
5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-benzene sulfonamide
was obtained as a colourless foam starting from 50 mg of 4-tert.-butyl-N-[6-(4-
hydroxy-2-butynyloxy)-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-
yl]-benzene sulfonamide (Example 14) and 47 mg of 4,6-dimethoxy-2-
methylsulfonylpyrimidine following the procedure given in Example 46. LC-
MS: tR = 6.21 min, [M+1 ]+ = 721.44, [M-1 ]+ = 719.35
Example 48
37 mg of 5-methyl-N-[6-(4-(5-bromo-2-pyrimidinyloxy)-2-butynyloxy)-5-(2-
methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridine sulfonamide was
obtained as a beige powder starting from 50 mg of 5-methyl-N-[6-(4-hydroxy-
2-butynyloxy)-5-(2-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-
pyridine sulfonamide (Example 15) and 45 mg of 5-bromo-2-chloropyrimidine
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following the procedure given in Example 46. LC-MS: tR = 5.31 min, [M+1]+ -
700.34, [M-1 ]+ = 698.24.
Example 49
48 mg of 5-methyl-N-[6-(4-(4,6-dimethoxy-2-pyrimidinyloxy)-2-butynyloxy)-5-
(2-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridine sulfonamide
was obtained as a colourless solid starting from 50 mg of 5-methyl-N-[6-(4-
hydroxy-2-butynyloxy)-5-(2-methoxyphenoxy)-2-(N-morpholino)-4-
pyrimidinyl]-2-pyridine sulfonamide (Example 15) and 50 mg of 4,6-
dimethoxy-2-methylsulfonylpyrimidine following the procedure given in
Example 46. LC-MS: tR = 5.42 min, [M+1 ]+ = 680.43, [M-1 ]+ = 678.36.
Example 50
128 mg of 5-isopropyl-N-[6-(4-(5-bromo-2-pyrimidinyloxy)-2-butynyloxy)-5-(p-
tolyl)-4-pyrimidinyl]-2-pyridine sulfonamide was obtained as a beige foam
starting from 230 mg of 5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(p-fiolyl)-
4-pyrimidinyl]-2-pyridine sulfonamide (Example 16) and 194 mg of 5-bromo-2-
chloropyrimidine following the procedure given in Example 45. LC-MS: tR =
5.49 min, [M+1 ]+ = 611.25, [M-1 ]+ = 609.39.
Example 51
68 mg of 5-isopropyl-N-[6-(4-(4,6-dimethoxy-2-pyrimidinyloxy)-2-butynyloxy)-
5-(p-tolyl)-4-pyrimidinyl]-2-pyridine sulfonamide was obtained as a beige foam
starting from 230 mg of 5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(p-tolyl)-
4-pyrimidinylJ-2-pyridine sulfonamide (Example 16) and 120 mg of 4,6-
dimethoxy-2-methylsulfonylpyrimidine following the procedure given in
Example 45. LC-MS: tR = 5.60 min, [M+1 ]+ = 591.21, [M-1 ]+ = 589.24.
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Example 52
To a solution of 50 mg of 5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(0-
methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide
(Example 1g) and 10 mg of 4-dimethylaminopyridine in 5 ml of dry chloroform
25 p,1 of n-butyl isocyanate was added at room temperature. The mixture was
heated to 65°C and stirred for 42 h. After 6 h, 18 h, and 28 h another
portion
of 25 ~,I of n-butyl isocyanate was added. Eventually, the mixture was diluted
with 50 ml of ethyl acetate. The solution was washed twice with 20 ml of
water. The aqueous layers were extracted once with ethyl acetate. The
combined organic layers were dried over MgSO4 and evaporated. The
residue was purified by column chromatography on silica gel eluting first with
hexane : ethyl acetate 1:1 then with DCM containing 4% of methanol. This
gave 39 mg of n-butyl-carbamic acid 4-[6-(5-isopropyl-pyridine-2-
sulfonylamino)-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yloxy]-but-2-
ynyl ester as a pale yellow foam. LC-MS: tR = 5.17 min, [M+1]+ = 661.37, [M-
1 ]- = 659.51.
Example 53
To a solution of 50 mg of 5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(0-
methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide
(Example 1g) and 10 mg of 4-dimethylaminopyridine in 5 ml of dry chloroform
~,I of phenyl isocyanate was added at room temperature. The mixture was
25 heated to 65°C and stirred for 4 h. Eventually, the mixture was
diluted with 50
ml of ethyl acetate. The solution was washed twice with 20 ml of water. The
aqueous layers were extracted once with ethyl acetate. The combined
organic layers were dried over MgS04 and evaporated. The residue was
purified by column chromatography on silica gel eluting first with hexane
ethyl acetate 1:1 then with DCM containing 4% of methanol. This gave 40 mg
of phenyl-carbamic acid 4-[6-(5-isopropyl-pyridine-2-sulfonylamino)-5-(2-
methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yloxy]-but-2-ynyl ester as an off-
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white solid which melts at 163-164°C. LC-MS: tR = 5.15 min, [M+1]+ =
681.36,
[M-1 ]' = 679.51.
Example 54
39 mg of m-tolyl-carbamic acid 4-[6-(5-isopropyl-pyridine-2-sulfonylamino)-5-
(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yloxy]-but-2-ynyl ester was
obtained as an off-white solid starting from 50 mg of 5-isopropyl-N-[6-(4-
hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-
pyridine sulfonamide (Example 1g) and 25 ~.I of m-tolyl isocyanate following
the procedure given in Example 53. Melting point: 163-165°C. LC-MS: tR
=
5.33 min, [M+1 ]+ = 695.39, [M-1 ]- = 693.53.
Example 55
45 mg of (4-methoxyphenyl)-carbamic acid 4-[6-(5-isopropyl-pyridine-2-
sulfonylamino)-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yloxy]-but-2-
ynyl ester was obtained as a pale yellow foam starting from 50 mg of 5-
isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-
4-pyrimidinyl]-2-pyridine sulfonamide (Example 1g) and 25 p.1 of 4-
methoxyphenyl isocyanate following the procedure given in Example 53. LC-
MS: tR = 5.06 min, [M+1]+ = 711.35, [M-1]- = 709.48.
Example 56
27 mg of (2-methoxy-phenyl)-carbamic acid 4-[6-(5-isopropyl-pyridine-2-
sulfonylamino)-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yloxy]-but-2-
ynyl ester was obtained as a pale yellow foam starting from 50 mg of 5-
isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-
4-pyrimidinyl]-2-pyridine sulfonamide (Example 1g) and 25 ~,I of 2-
methoxyphenyl isocyanate following the procedure given in Example 53. LC-
MS: tR = 5.30 min, [M+1]+ = 711.36, [M-1]- = 709.49.
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Example 57
36 mg of (2-fluorophenyl)-carbamic acid 4-[6-(5-isopropyl-pyridine-2-
sulfonylamino)-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yloxy]-but-2-
ynyl ester was obtained as a white solid starting from 50 mg of 5-isopropyl-N-
[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-
pyrimidinyl]-2-pyridine sulfonamide (Example 1g) and 12 mg of 2-fluorophenyl
isocyanate following the procedure given in Example 53. LC-MS: tR = 5.16
min, [M+1 ]+ = 699.36, [M-1 ]- = 697.28.
Example 58
A solution of 50 mg of 2-picolinic acid azide (prepared from 2-picolinic acid
according to Chem. Pharm. Bull. 25 (1977) 1651-1657) and 10 mg of DMAP
in 8 ml of chloroform was stirred for 1 h at 75°C. 50 mg of 5-isopropyl-
N-[6-(4-
hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-
pyridine sulfonamide (Example 1g) followed by 3 ml of DMF was added and
the resulting clear solution was stirred for 16 h at 75°C. The mixture
was
diluted with 75 ml of ethyl acetate and washed with 50 ml of 10% aqueous
citric acid followed by 50 ml of water. The organic layer was evaporated and
the crude product was purified by chromatography on prep, tlc-plates with
dichlormethane:methanol 10:1 to give 41 mg of 2-pyridinyl-carbamic acid 4-
[6-(5-isopropyl-pyridine-2-sulfonylamino)-5-(2-methoxy-phenoxy)-2-pyridin-4-
yl-pyrimidin-4-yloxy]-but-2-ynyl ester as a white solid. LC-MS: tR = 4.74 min,
[M+1 ]+ = 682.47, [M-1 ]- = 680.41.
Example 59
271 mg of 2-pyrazinyl-carbamic acid 4-[6-(5-isopropyl-pyridine-2-
sulfonylamino)-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yloxy]-but-2-
ynyl ester was obtained as a white powder starting from 300 mg of 5-
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isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-
4-pyrimidinyl]-2-pyridine sulfonamide (Example 1 g) and 199 mg of pyrazine-2-
carbonyl azide (prepared from pyrazin-2-carboxylic acid according to Chem.
Pharm. Bull. 25 (1977) 1651-1657) following the procedure given in Example
58. LC-MS: tR = 4.73 min, [M+1]+ = 683.44, [M-1]- = 681.37.
Example 60
Under argon, a suspension of 50 mg of 5-methyl-N-[6-(4-hydroxy-2-
butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine
sulfonamide (Example 3), 10 mg of DMAP and 25 p1 of cyclohexylisocyanate
in 4 ml of chloroform and 3 ml of DMF was stirred for 72 h at 70°C. The
mixture was diluted with 50 ml of ethyl acetate and washed with 50 ml of 10%
aqueous citric acid and 2x25 mlf of water. The organic phase was dried over
MgS04 and evaporated. The crude product was purified by column
chromatography on silica gel eluting with a gradient of hexane:ethyl acetate
1:1 to ethyl acetate, then with DCM containing 4% of methanol to give 38 mg
of cyclohexylcarbamic acid 4-[6-(5-methylpyridine-2-sulfonylamino)-5-(2
methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yloxy]-but-2-ynyl ester as a
beige foam. LC-MS: tR = 4.89 min, [M+1]+ = 659.33, [M-1]- = 657.25.
Example 61
A suspension of 50 mg of 5-methyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(0-
methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide
(Example 3), 10 mg of DMAP and 25 p,1 of phenylisocyanate in 5 ml of
chloroform was refluxed for 15 minutes under argon. 1.5 ml of DMF was
added and stirring and heating was continued for 16 h. The clear solution was
diluted with 50 ml of ethyl acetate and washed with 50 ml of 10% aqueous
citric acid and 2x50 ml of water. The organic phase was dried over MgS04
and evaporated. The crude product was purified by column chromatography
on silica gel eluting first with hexane:ethyl acetate 1:1, then with DCM
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containing 4% of methanol to give 47 mg of phenylcarbamic acid 4-[6-(5-
methylpyridine-2-sulfonylamino)-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-
pyrimidin-4-yloxy]-but-2-ynyl ester as a slightly yellow solid. LC-MS: tR =
4.80
min, [M+1 J+ = 653.37, [M-1 ]- = 651.33.
Example 62
37 mg of (3-methylphenyl)-carbamic acid 4-[6-(5-methylpyridine-2-
sulfonylamino)-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yloxy]-but-2-
ynyl ester was obtained as a yellow solid starting from 50 mg of 5-methyl-N-
[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-
pyrimidinyl]-2-pyridine sulfonamide (Example 3) and 25 ~,I of 3-
methylphenylisocyanate following the procedure given in Example 61. MS: tR
= 4.95 min, [M+1]+ = 667.42, [M-1]- = 665.30.
Example 63
38 mg of (2-fluorophenyl)-carbamic acid 4-[6-(5-methylpyridine-2-
sulfonylamino)-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yloxy]-but-2-
ynyl ester was obtained as an off-white foam starting from 50 mg of 5-methyl-
N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-
pyrimidinyl]-2-pyridine sulfonamide (Example 3) and 25 ~,I of 2-
fluorophenylisocyanate following the procedure given in Example 61. MS: tR =
4.79 min, [M+1]+ = 671.34, [M-1]- = 669.28.
Example 64
42 mg of (4-fluorophenyl)-carbamic acid 4-[6-(5-methylpyridine-2-
sulfonylamino)-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yloxy]-but-2-
ynyl ester was obtained as an off white foam starting from 50 mg of 5-methyl-
N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-
pyrimidinyl]-2-pyridine sulfonamide (Example 3) and 25 ~,I of 4-
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fluorophenylisocyanate following the procedure given in Example 61. MS: tR =
4.89 min, [M+1 ]+ = 671.34, [M-1 ]- = 669.28.
Example 65
38 mg of 2-pyridinyl-carbamic acid 4-[6-(5-methyl-pyridine-2-sulfonylamino)-5-
(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yloxy]-but-2-ynyl ester was
obtained as a white powder starting from 50 mg of 5-methyl-N-[6-(4-hydroxy-
2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine
sulfonamide (Example 3) and 50 mg of 2-picolinic acid azide (prepared from
2-picolinic acid according to Chem. Pharm. Bull. 25 (1977) 1651-1657)
according to the procedure given in Example 58. MS: tR = 4.32 min, [M+1]+ _
654.39, [M-1 ]- = 652.33.
Example 66
18 mg of 2-pyridinyl-carbamic acid 4-[6-(5-isopropyl-pyridine-2-
sulfonylamino)-5-(2-methoxy-phenoxy)-2-(2-pyrimidinyl)-pyrimidin-4-yloxy]-
but-2-ynyl ester was obtained as a white solid starting from 50 mg of 5-
isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxy-phenoxy)-2-(2-
pyrimidinyl)-4-pyrimidinyl]-2-pyridine sulfonamide (Example 4) and 28 mg of
2-picolinic acid azide (prepared from 2-picolinic acid according to Chem.
Pharm. Bull. 25 (1977) 1651-1657) according to the procedure given in
Example 58. MS: tR = 4.84 min, [M+1]+ = 683.41.
Example 67
28 mg of 2-pyrazinyl-carbamic acid 4-[6-(5-isopropyl-pyridine-2-
sulfonylamino)-5-(2-methoxy-phenoxy)-2-(2-pyrimidinyl)-pyrimidin-4-yloxy]-
but-2-ynyl ester was obtained as a slightly yellow solid starting from 50 mg
of
5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxy-phenoxy)-2-(2-
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pyrimidinyl)-4-pyrimidinyl]-2-pyridine sulfonamide (Example 4) and 50 mg of
pyrazine-2-carbonyl azide (prepared from pyrazin-2-carboxylic acid according
to Chem. Pharm. Bull. 25 (1977) 1651-1657) following the procedure given in
Example 58. LC-MS: tR = 4.67 min, [M+1]+ = 684.42, [M-1]- = 682.39.
Example 68
24 mg of 2-pyridinyl-carbamic acid 4-[6-(4-tert.butylbenzenesulfonylamino)-5-
(2-methoxy-phenoxy)-2-(2-pyrimidinyl)-pyrimidin-4-yloxy]-but-2-ynyl ester was
obtained as a slightly yellow solid starting from 50 mg of 4-tert.-butyl-N-[6-
(4-
hydroxy-2-butynyloxy)-5-(o-methoxy-phenoxy)-2-(2-pyrimidinyl)-4-
pyrimidinyl]benzene sulfonamide (Example 5) and 50 mg of 2-picolinic acid
azide (prepared from 2-picolinic acid according to Chem. Pharm. Bull. 25
(1977) 1651-1657) following the procedure given in Example 58. LC-MS: tR =
5.44 min, [M+1 ]+ = 696.43, [M-1 ]- = 694.35.
Example 69
39 mg of 2-pyrazinyl-carbamic acid 4-[6-(4-tert.butylbenzenesulfonylamino)-5-
(2-methoxy-phenoxy)-2-(2-pyrimidinyl)-pyrimidin-4-yloxy]-but-2-ynyl ester was
obtained as a slightly yellow solid starting from 50 mg of 4-tert.-butyl-N-[6-
(4-
hydroxy-2-butynyloxy)-5-(o-methoxy-phenoxy)-2-(2-pyrimidinyl)-4-
pyrimidinyl]benzene sulfonamide (Example 5) and 50 mg of pyrazine-2-
carbonyl azide (prepared from pyrazin-2-carboxylic acid according to Chem.
Pharm. Bull. 25 (1977) 1651-1657) following the procedure given in Example
58. LC-MS: tR = 5.25 min, [M+1 ]+ = 697.44, [M-1 ]- = 695.35.
Example 70
To a solution of 50 mg of 5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(0-
methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyridine sulfonamide (Example
7d) in 5 ml of dry chloroform 25 p,1 of phenyl isocyanate followed by 20 mg of
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DMAP was added. The solution was stirred at 65°C for 3 h. The
solvent was
removed partially under reduced pressure and the remaining solution was
purified by column chromatography on 20 g of silica gel eluting with hexane
ethyl acetate 2:1. This gave 35 mg of phenyl-carbamic acid 4-[6-(5-isopropyl-
pyridine-2-sulfonylamino)-5-(2-methoxy-phenoxy)-2-methyl-pyrimidin-4-yloxy]-
but-2-ynyl ester as a colourless foam. LC-MS: tR = 5.62 min, [M+1]+ = 618.33,
[M-1 ]- = 616.45.
Example 71
43 mg of phenyl-carbamic acid 4-[6-(5-isopropyl-pyridine-2-sulfonylamino)-5-
(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yloxy]-but-2-ynyl ester was
obtained as a white foam starting from 50 mg of 5-isopropyl-N-[6-(4-hydroxy-
2-butynyloxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-
pyridine sulfonamide (Example 9) and 30 ~,I of phenylisocyanate following the
procedure given in Example 53. LC-MS: tR = 5.57 min, [M+1]+ = 689.38, [M-1]'
= 687.49.
Example 72
142 mg of 2-pyridinyl-carbamic acid 4-[6-(5-isopropyl-pyridine-2-
sulfonylamino)-5-(2-methoxy-phenoxy)-2-(N-morpholino)-pyrimidin-4-yloxy]-
but-2-ynyl ester was obtained as a colourless foam starting from 150 mg of 5-
isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(N-
morpholino)-4-pyrimidinyl]-2-pyridine sulfonamide (Example 9) and 100 mg of
2-picolinic acid azide (prepared from 2-picolinic acid according to Chem.
Pharm. Bull. 25 (1977) 1651-1657) following the procedure given in Example
58. LC-MS: tR = 5.37 min, [M+1]+ = 690.53, [M-1]- = 688.38.
Example 73
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To a solution of 570 mg of 5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(0-
methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridine sulfonamide
(Example 9) in 15 ml of DCM was added 0.37 ml of DBU, a catalytic amount
of DMAP and 70 ~,I of morpholine-4-carbonyl chloride. The mixture was stirred
at reflux for 16 h before it was evaporated. The residue was partitioned
between 75 ml of 10% aqueous citric acid and 75 ml of ethyl acetate. The
aqueous phase was extracted two more times with ethyl acetate, the
combined organic layers were washed with water and brine, dried over
MgS04 and evaporated. The crude product was purified on prep. tlc-plates
with toluene:ethyl acetate 1:1 to give 152 mg of morpholine-4-carbamic acid
4-[6-(5-isopropyl-pyridine-2-sulfonylamino)-5-(2-methoxy-phenoxy)-2-(N-
morpholino)-pyrimidin-4-yloxy]-but-2-ynyl ester as a beige foam. LC-MS: tR =
5.26 min, [M+1 ]+ = 683.43, [M-1 ]- = 681.57.
Example 74
170 mg of dimethyl-carbamic acid 4-[6-(5-isopropyl-pyridine-2-sulfonylamino)-
5-(2-methoxy-phenoxy)-2-(N-morpholino)-pyrimidin-4-yloxy]-but-2-ynyl ester
was obtained as white crystals (from 2-propanol/methanol) starting from 570
mg of 5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(N-
morpholino)-4-pyrimidinyl]-2-pyridine sulfonamide (Example 9) and 52 ~,I of
diemthylcarbamic acid chloride following the procedure given in Example 72.
LC-MS: tR = 5.29 min, [M+1 ]+ = 641.41, [M-1 ]- = 639.56.
Example 75
39 mg of phenyl-carbamic acid 4-[6-(5-isopropyl-pyridine-2-sulfonylamino)-5-
(2-methoxy-phenoxy)-pyrimidin-4-yloxy]-but-2-ynyl ester was obtained as a
colourless foam starting from 40 mg of 5-isopropyl-N-[6-(4-hydroxy-2-
butynyloxy)-5-(o-methoxyphenoxy)-4-pyrimidinyl]-2-pyridine sulfonamide
(Example 13) and 50 p1 of phenylisocyanate following the procedure given in
Example 53. LC-MS: tR = 5.38 min, [M+1]+ = 604.32, [M-1]- = 602.25.
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Example 76
50 mg of phenyl-carbamic acid 4-[6-(4-tert.-butyl-benzene-sulfonylamino)-5-
(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yloxy]-but-2-yny1 ester was
obtained as a colourless foam starting from 50 mg of 4-tert.-butyl-N-j6-(4-
hydroxy-2-butynyloxy)-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-
yl]-benzene sulfonamide (Example 14) and 50 ~,I of phenylisocyanate
following the procedure given in Example 53. LC-MS: tR = 6.07 min, [M+1]+ _
702.50, [M-1 ]- = 700.40.
Example 77
39 mg of 2-pyridinyl-carbamic acid 4-[6-(4-tert.-butyl-benzene-sulfonylamino)-
5-(2-methoxy-phenoxy)-2-(N-morpholino)-pyrimidin-4-yloxy]-but-2-ynyl ester
was obtained as a colourless foam starting from 50 mg of 4-tert.-butyl-N-[6-(4-
hydroxy-2-butynyloxy)-5-(2-methoxy-phenoxy)-2-(N-morpholino)-pyrimidin-4-
yl]-benzene sulfonamide (Example 14) and 50 mg of 2-picolinic acid azide
(prepared from 2-picolinic acid according to Chem. Pharm. Bull. 25 (1977)
1651-1657) according to the procedure given in Example 58. MS: tR = 5.63
min, [M+1 ]+ = 703.46, [M-1 ]- = 701.38.
Example 78
44 mg of n-butyl-carbamic acid 4-[6-(5-methyl-pyridine-2-sulfonylamino)-5-(2-
methoxy-phenoxy)-2-(N-morpholino)-pyrimidin-4-yloxy]-but-2-ynyl ester was
obtained as a white solid starting from 50 mg of 5-methyl-N-[6-(4-hydroxy-2-
butynyloxy)-5-(2-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridine
sulfonamide (Example 15) and 50 ~,I of n-butylisocyanate according to the
procedure given in Example 53. MS: tR = 5.24 min, [M+1]+ = 641.47, [M-1]- _
639.39.
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Example 79
53 mg of cyclohexyl-carbamic acid 4-[6-(5-methyl-pyridine-2-sulfonylamino)-
5-(2-methoxy-phenoxy)-2-(4-morpholino)-pyrimidin-4-yloxy]-but-2-ynyl ester
was obtained as a colourless foam starting from 50 mg of 5-methyl-N-[6-(4-
hydroxy-2-butynyloxy)-5-(2-methoxyphenoxy)-2-(4-morpholino)-4-pyrimidinyl]-
2-pyridine sulfonamide (Example 15) and 100 ~,I of cyclohexylisocyanate
according to the procedure given in Example 53. MS: tR = 5.32 min, [M+1]+ _
667.48, [M-1 ]- = 665.41.
Example 80
54 mg of phenyl-carbamic acid 4-[6-(5-methyl-pyridine-2-sulfonylamino)-5-(2-
methoxy-phenoxy)-2-(4-morpholino)-pyrimidin-4-yloxy]-but-2-ynyl ester was
obtained as a colourless foam starting from 50 mg of 5-methyl-N-[6-(4-
hydroxy-2-butynyloxy)-5-(2-methoxyphenoxy)-2-(4-morpholino)-4-pyrimidinyl]-
2-pyridine sulfonamide (Example 15) and 50 ~,I of phenylisocyanate according
to the procedure given in Example 53. MS: tR = 5.32 min, [M+1]+ = 661.43,
[M-1 ]- = 659.38.
Example 81
36 mg of 2-pyridinyl-carbamic acid 4-[6-(5-methyl-pyridine-2-sulfonylamino)-5-
(2-methoxy-phenoxy)-2-(4-morpholino)-pyrimidin-4-yloxy]-but-2-ynyl ester
was obtained as a white powder starting from 50 mg of 5-methyl-N-[6-(4
hydroxy-2-butynyloxy)-5-(2-methoxyphenoxy)-2-(4-morpholino)-4-pyrimidinyl]
2-pyridine sulfonamide (Example 15) and 50 mg of 2-picolinic acid azide
(prepared from 2-picolinic acid according to Chem. Pharm. Bull. 25 (1977)
1651-1657) according to the procedure given in Example 58. MS: tR = 4.90
min, [M+1]+ = 662.17, jM-1]- = 660.12.
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Example 82
40 mg of 3-pyridinyl-carbamic acid 4-[6-(5-methyl-pyridine-2-sulfonylamino)-5-
(2-methoxy-phenoxy)-2-(4-morpholino)-pyrimidin-4-yloxy]-but-2-yny1 ester
was obtained as a white powder starting from 50 mg of 5-methyl-N-[6-(4-
hydroxy-2-butynyloxy)-5-(2-methoxyphenoxy)-2-(4-morpholino)-4-pyrimidinyl]-
2-pyridine sulfonamide (Example 15) and 50 mg of nicotinic acid azide
(prepared from nicotinic acid according to Chem. Pharm. Bull. 25 (1977)
1651-1657) according to the procedure given in Example 58. MS: tR = 4.19
min, [M+1 ]+ = 662.39, [M-1 ]- = 660.59.
Example 83
7 mg of 4-pyridinyl-carbamic acid 4-[6-(5-methyl-pyridine-2-sulfonylamino)-5-
(2-methoxy-phenoxy)-2-(4-morpholino)-pyrimidin-4-yloxy]-but-2-yny1 ester
was obtained as a white solid starting from 50 mg of 5-methyl-N-[6-(4-
hydroxy-2-butynyloxy)-5-(2-methoxyphenoxy)-2-(4-morpholino)-4-pyrimidinyl]-
2-pyridine sulfonamide (Example 15) and 50 mg of isonicotinic acid azide
(prepared from isonicotinic acid according to Chem. Pharm. Bull. 25 (1977)
1651-1657) according to the procedure given in Example 58. MS: tR = 3.89
min, [M+1]+ = 662.39, [M-1]- = 660.33.
Example 84
204 mg of 4-pyrazinyl-carbamic acid 4-[6-(5-methyl-pyridine-2-sulfonylamino)-
5-(2-methoxy-phenoxy)-2-(4-morpholino)-pyrimidin-4-yloxy]-but-2-ynyl ester
was obtained as a white solid starting from 50 mg of 5-methyl-N-[6-(4-
hydroxy-2-butynyloxy)-5-(2-methoxyphenoxy)-2-(4-morpholino)-4-pyrimidinyl]-
2-pyridine sulfonamide (Example 15) and 50 mg of pyrazine-2-carbonyl azide
(prepared from pyrazin-2-carboxylic acid according to Chem. Pharm. Bull. 25
(1977) 1651-1657) following the procedure given in Example 58. MS: tR =
4.80 min, [M+1 ]+ = 663.43, [M-1 ]- = 661.36.
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Example 85
36 mg of phenyl-carbamic acid 4-[6-(5-isopropyl-pyridine-2-sulfonylamino)-5-
(p-tolyl)-pyrimidin-4-yloxy]-but-2-ynyl ester was obtained as an off white
foam
starting from 60 mg of 5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(p-tolyl)-4-
pyrimidinyl]-2-pyridine sulfonamide (Example 16) and 50 ~,I of
phenylisocyanate following the procedure given in Example 53. MS: tR = 5.50
min, [M+1 ]+ = 572.36, [M-1 ]' = 570.30.
Example 86
79 mg of N-methyl-N-phenyl-carbamic acid 4-[6-(5-isopropyl-pyridine-2-
sulfonylamino)-5-(p-tolyl)-pyrimidin-4-yloxy]-but-2-ynyl ester was obtained as
a beige foam starting from 230 mg of 5-isopropyl-N-[6-(4-hydroxy-2-
butynyloxy)-5-(p-tolyl)-4-pyrimidinyl]-2-pyridine sulfonamide (Example 16) and
95 mg of N-methyl-N-phenyl-carbamic acid chloride following the procedure
given in Example 72. LC-MS: tR = 5.44 min, [M+1]+ = 586.33, [M-1]-= 584.50.
Example 87
To a solution of 300 mg of 5-isopropyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-
(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide (Example 1f) and 1.47 g of 4-
methoxy-2-butynol (prepared starting from 2-butyn-1,4-diol and
dimethylsulfate following the procedure given in Bull. Chem. Soc. Japan 28
(1955), 80-83) in 15 ml of DMF was carefully added 234 mg of 55% NaH in
mineral oil. The brown solution stirred for 24 h at room temperature before
further 120 mg of 55% NaH in mineral oil was added. Stirring was continued
for 24 h. The mixture was diluted with 100 ml of 10% aqueous citric acid and
extracted four times with 50 ml of ethyl acetate. The combined organic
phases were washed twice with 50 ml of water, dried over MgS04 and
evaporated. The crude product was purified by column chromatography on
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silica gel eluting with ethyl acetate to give 154 mg of 5-isopropyl-N-[6-(4-
methoxy-but-2-ynyloxy)-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-
2-pyridine sulfonamide as a yellow solid. LC-MS: tR = 4.84 min, [M+1]+ _
576.42, [M-1 ]- = 574.37.
Example 88
To a solution of 300 mg of 5-isopropyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-
(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide (Example 1f) and 502 mg of
4-phenoxy-2-butyn-1-of (prepared starting from phenyl-propargylether and
para-formaldehyde following the procedure given in J. Chem. Soc. Perkin
Trans. 1, 1991, 1721-1727) in 15 ml of THF was added 228 mg of 55% NaH
in mineral oil. The orange suspension was stirred at room temperature for 1 h
before it was diluted with 100 ml of 10% aqueous citric acid. The mixture was
extracted three times with 50 ml of ethyl acetate. The combined organic
phases were washed with 50 ml of water, dried over MgS04 and evaporated.
The crude product was purified by chromatography on prep. tlc-plates with
ethyl acetate:methanolaat. aqueous ammonia 8:2:1 to give 241 mg of 5-
isopropyl-N-[6-(4-phenoxy-but-2-ynyloxy)-5-(2-methoxy-phenoxy)-2-pyridin-4-
yl-pyrimidin-4-yl]-2-pyridine sulfonamide as a slightly yellow foam. LC-MS: tR
= 5.95 min, [M+1 ]+ = 666.58, [M-1 ]- = 664.62
Example 89
To a mixture of 250 mg of 4-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-
(2-pyrimidinyl)-4-pyrimi-dinyl]benzene sulfonamide (Example 5a) and 1.11 g
of 4-methoxy-2-butynol (prepared starting from 2-butyn-1,4-diol and
dimethylsulfate following the procedure given in Bull. Chem. Soc. Japan 28
(1955), 80-83) in 15 ml THF was added 177 mg of 55% NaH in mineral oil.
The suspension was stirred for 16 h at reflux. The reaction mixture was
cooled, diluted with 100 ml 10% aqueous citric acid and extracted 4 times
with 50 ml of ethyl acetate. The combined organic phases were washed with
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water, dried over MgS04 and evaporated. The crude product was purified by
chromatography on prep. tlc-plates with ethyl acetate:methanolaat. aqueous
ammonia 8:2:1 to give 116 mg of 4-tert.-butyl-N-[6-(4-methoxy-2-butynyloxy)-
5-(o-methoxy-phenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene sulfonamide
as a slightly yellow foam. LC-MS: tR = 5.19 min, [M+1]+ = 590.40, [M-1]- _
588.39
Example 90
To a mixture of 260 mg of 4-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-
(2-pyrimidinyl)-4-pyrimidinyl]benzene sulfonamide (Example 5a) and 1.50 g of
4-phenoxy-2-butyn-1-of (prepared starting from phenyl-propargylether and
para-formaldehyde following the procedure given in J. Chem. Soc. Perkin
Trans. 1, 1991, 1721-1727) in 15 ml THF was added 184 mg of 55% NaH in
mineral oil. The suspension was stirred for 1 h at reflux. The reaction
mixture
was cooled, diluted with 100 ml 10% aqueous citric acid and extracted 4
times with 50 ml of ethyl acetate. The combined organic phases were washed
with water, dried over MgS04 and evaporated. The crude product was purified
by chromatography on prep. tlc-plates with ethyl acetate:methanolaat.
aqueous ammonia 8:2:1 to give 82 mg of 4-tert.-butyl-N-[6-(4-phenoxy-2-
butynyloxy)-5-(o-methoxy-phenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene
sulfonamide as a slightly yellow foam. LC-MS: tR = 5.60 min, [M+1]+ = 652.63,
[M-1 ]- = 650.58.
Example 91
To a solution of 390 mg of 4-benzyloxy-2-butyn-1-of (prepared starting from 2-
butyn-1,4-diol and benzylbromide in analogy to a procedure reported in
Tetrahedron Lett. 38 (1997), 7887-7890) in 5 ml DMF:THF 1:1 was added 97
mg of 55% NaH in mineral oil. After the evolution of gas had ceased, 250 mg
of 4-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-
pyrimidinyl]benzene sulfonamide (Example 5a) was added and the mixture
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was stirred at 50°C for 20 h before it was diluted with 75 ml of ethyl
acetate.
The mixture was washed with 75 ml of 10% aqueous citric acid and 75 ml of
water, and evaporated. The crude product was purified by chromatography on
prep. tlc-plates with ethyl acetate:methanolaat. aqueous ammonia 10:2:1 to
give 125 mg of 4-tert.-butyl-N-[6-(4-benzyloxy-2-butynyloxy)-5-(o-methoxy-
phenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene sulfonamide as a yellow
foam. LC-MS: tR = 5.93 min, [M+1]+ = 666.47, [M-1]- = 664.63.
Example 92
184 mg of 4-tert.-butyl-N-[6-(4-(4-methylbenzyloxy)-2-butynyloxy)-5-(0-
methoxy-phenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene sulfonamide was
obtained as a yellow foam starting from 250 mg of 4-tert.-butyl-N-[6-chloro-5-
(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene sulfonamide
(Example 5a) and 421 mg of 4-(4-methylbenzyloxy)-2-butyn-1-of (prepared
starting from 2-butyn-1,4-diol and 4-methylbenzylbromide in analogy to a
procedure reported in Tetrahedron Lett. 38 (1997), 7887-7890) following the
procedure given in Example 91. LC-MS: tR = 6.11 min, [M+1]+ = 680.51, [M-1]-
= 678.61.
Example 93
Crude 4-tert.-butyl-N-[6-(4-(3-methoxybenzyloxy)-2-butynyloxy)-5-(o-methoxy-
phenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene sulfonamide was obtained
starting from 300 mg of 4-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(2-
pyrimidinyl)-4-pyrimidinyl]benzene sulfonamide (Example 5a) and 1096 mg of
4-(3-methoxybenzyloxy)-2-butyn-1-of (prepared starting from 2-butyn-1,4-diol
and 3-methoxybenzylbromide in analogy to a procedure reported in
Tetrahedron Lett. 38 (1997), 7887-7890) following the procedure given in
Example 91. The compound was purified by column chromatography on silica
gel eluting with DCM containing 0-2.5% of methanol followed by
chromatography on prep. tlc-plates with DCM containing 5% of methanol. The
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resulting oil was dissolved in 10 ml of diethyl ether and treated with
pentane.
The precipitate was collected and dried to give 102 mg of 4-tert.-butyl-N-[6-
(4-
(3-methoxybenzyloxy)-2-butynyloxy)-5-(o-methoxy-phenoxy)-2-(2-
pyrimidinyl)-4-pyrimidinyl]benzene sulfonamide as an almost white powder.
LC-MS: tR = 5.74 min, [M+1]+ = 696.40, [M-1]' = 694.32.
Example 94
To a mixture of 250 mg of 5-isopropyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-
(N-morpholino)-4-pyrimidinyl]-2-pyridine sulfonamide (Example 9c) and 1.2 g
of 4-methoxy-2-butyn-1-of (prepared starting from 2-butyn-1,4-diol and
dimethylsulfate following the procedure given in Bull. Chem. Soc. Japan 28
(1955), 80-83) was added 192 mg of 55% NaH in mineral oil. After evolution
of gas had ceased, the brown suspension was refluxed for 16 h. Further 96
mg of 55% NaH in mineral oil was added and heating and stirring was
continued for another 3 h. The mixture was cooled, diluted with 50 ml of 10%
aqueous citric acid and extracted 4 times with 50 ml of ethyl acetate. The
combined organic phases were washed with water, dried over MgS04 and
evaporated. The crude product was purified by column chromatography on
silica gel eluting with hexane:ethyl acetate 1:3 and precipitated from diethyl
ether to give 114 mg of 5-isopropyl-N-[6-(4-methoxy-2-butynyloxy)-5-(0-
methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridine sulfonamide as
a white powder. LC-MS: tR = 5.19 min, [M+1]+ = 584.46, [M-1]- = 582.38.
Example 95
To a mixture of 300 mg of 4-tert.-butyl-N-[6-chloro-5-(p-tolyl)-4-pyrimidinyl]-
benzene sulfonamide (Example 12c) and 1.8 g of 4-methoxy-2-butyn-1-of
(prepared starting from 2-butyn-1,4-diol and dimethylsulfate following the
procedure given in Bull. Chem. Soc. Japan 28 (1955), 80-83) was added 288
mg of 55% NaH in mineral oil. After evolution of gas had ceased, the brown
suspension was stirred at room temperature for 24 h. Another 288 mg of 55%
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NaH in mineral oil was added and the mixture was stirred at 60°C
for 18 h.
The mixture was cooled, diluted with 50 ml of 10% aqueous citric acid and
extracted 4 times with 50 ml of ethyl acetate. The combined organic phases
were washed with water, dried over MgS04 and evaporated. The crude
product was purified by column chromatography on silica gel eluting with
hexane:ethyl acetate 1:1 and precipitated from diethyl ether to give 213 mg of
4-tert.-butyl-N-[6-(4-methoxy-2-butynyloxy)-5-(p-tolyl)-4-pyrimidinyl]-benzene
sulfonamide as a white powder. LC-MS: tR = 5.61 min, [M+1]+ = 480.30, [M-1]-
= 478.39.
Example 96
To a mixture of 282 mg of 4-tert.-butyl-N-[6-chloro-5-(p-tolyl)-4-pyrimidinyl]-
benzene sulfonamide (Example 12c) and 1.10 g of 4-phenoxy-2-butyn-1-of
(prepared starting from phenyl-propargylether and para-formaldehyde
following the procedure given in J. Chem. Soc. Perkin Trans. 1, 1991, 1721-
1727) in 15 ml THF was added 271 mg of 55% NaH in mineral oil. The
suspension was stirred for 4 h at reflux. The reaction mixture was cooled,
diluted with 100 ml 10% aqueous citric acid and extracted 4 times with 50 ml
of ethyl acetate. The combined organic phases were washed with water, dried
over MgS04 and evaporated. The crude product was purified by column
chromatography on silica gel eluting with heptane:ethyl acetate1:1 and
precipitated from diethyl ether to give 151 mg of 4-tert.-butyl-N-[6-(4-
phenoxy
2-butynyloxy)-5-(p-tolyl)-4-pyrimidinyl]-benzene sulfonamide as a white
powder. LC-MS: tR = 6.34 min, [M+1]+ = 542.48, [M-1]- = 540.15.
