FI117896B - New sulfonamides - Google Patents

Abstract

4-sulphonylamino-5-phenoxy-pyrimidine derivs. of formula (I) are new: R1 = heterocyclyl; R2 = H, alkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulphonyl alkoxy, phenyl, alkylphenyl, alkoxyphenyl, alkylenedioxyphenyl, phenylalkyl, alkylphenylalkyl, alkoxyphenylalkyl, alkylenedioxyphenylalkyl, heterocyclyl or heterocyclylalkyl; R3 = alkyl (opt. substd. by halo, OH or amino), alkoxy, HCO, CH2OA-alkyl or (CH2)mO-(CRaRb)nX; X = OH, OR9, NH2 or B-R9; R4-R8 = H, alkoxy or halo; R9 = heterocyclyl, phenyl (opt. substd. by alkyl, alkoxy and/or halo) or alkyl; Ra, Rb = H or alkyl; A = ketalised 1,2-dihydroxyethylene; B = OCOO, OCONH, NHCONH or NHCOO; n = 2-4 m = 0-1.

Description

117896 /

New sulfonamides

The present invention relates to novel sulfonainides of the formula R1SO2HH for use as a medicament. R 4 R 5 O-R R 3 R * R 7 R 1 where R 1 is heterocyclyl 1 which is a mono- or bicyclic heterocyclic group containing oxygen, nitrogen or sulfur as a heteroatom selected from 2-furyl, 3-fu-10 ryl, pyrimidinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 1,2-diazinyl, 1,4-diazinyl, morpholino, 2-thienyl, 3-thienyl, isoxazolyl, oxazolyl, thiazolyl, imidazolyl, pyrrolyl, benzofuranyl, benzothienyl, indolyl, purinyl, quinolyl, isoquinolyl and quinazolyl; or a heterocyclic group as defined above mono- or di-substituted with C 1-7 -alkyl, C 1-7 -alkanoyl, halogen, amino, mono-C 1-7 -alkylamino * * * * * *, di -C1-7 alkylamino or another heterocyclic group as defined above; R 2 is hydrogen, C 1-7 -alkyl, C 1-7 -alkoxy, C 1-7 -alkyl, C 1-7 -thio, C 1-7 -alkoxy-C 1-7 -alkyl, C 1-7 -alkylsulfonyl-C 1 -7-: alkoxy, phenyl, C 1-7 -alkyl-phenyl, C 1-7 -alkoxy-phenyl-C 1-7 -alkylenedioxyphenyl, phenyl-C 1-7 -alkyl, C 1-7 -alkyl -phenyl-C 1-7 -alkyl, C 1-7 -alkoxy-phenyl-C 1-7 -alkyl: ·. 25 l, C 1-7 alkylenedioxyphenyl C 1-7 alkyl or heterocyclyl / which is a mono- or bicyclic heterocyclic group having oxygen, nitrogen or sulfur as a heteroatom selected from 2-furyl, 3-furyl, pyrimidinyl, * ·· 2-pyridyl, 3-pyridyl, 4-pyridyl, 1,2-diazinyl,. 1,4-diazinyl, morpholino, 2-thienyl, 3-thienyl, isox- * · * zazolyl, oxazolyl, thiazolyl, imidazolyl, pyrrolyl, benzofuranyl, benzothienyl, indolyl, purine-117,796-yl, thiomorpholino, piperidino, pyrrolidino, benzodioxolyl, quinolyl, isoquinolyl and quinazolyl; or a heterocyclic group as defined above mono- or di-substituted with C 1-7 alkyl, C 1-7 alkanoyl, halo: or another heterocyclic group as defined above; or heterocyclyl2-C1-7-alkyl, whereby heterocyclyl2 has the same meaning as above; R 3 is C 1-7 alkyl, C 1-7 alkoxy, formyl, halo C 1-7 alkyl, hydroxy C 1-7 alkyl, aminoC 1-7 alkyl, or a group -CH 2 O -A- C 1-7 alkyl, - (CH 2) m -O- (CR a R b) n OH, - (CH 2) m -O- (CR a R b) m R 9, - (CH 2) m -O- (CR a R b) n NH 2 or - (CH 2) m O - (CR 4) n B -R 9; R 4 to R 8 represent hydrogen, C 1-7 alkoxy or halogen; R 9 is heterocyclyl 3, which is a mono- or bicyclic-15 heterocyclic group containing oxygen, nitrogen or sulfur as a heteroatom selected from 2-furyl, 3-furyl, pyrimidinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 1,2-diazinyl, 1,4-diazinyl, morpholino, 2-way.

ynyl, 3-thienyl, isoxazolyl, oxazolyl, thiazolyl, imidazolyl, pyrrolyl, pyrazinyl, benzofuranyl, benzothienyl, indolyl, purinyl, quinolyl,? -isoquinolyl and quinazolyl; or an instant as defined above; ; *: a cyclic group mono- or di-substituted with C 1-7 * t ·. . *. alkyl, C 1-7 alkanoyl, halogen or the like

Iti; . ·. A heterocyclic group as defined above; or phenyl substituted with C 1-7 alkyl, C 1-7 alkoxy and / or halogen; or C 1-7 alkyl; ** R a and R b represent hydrogen or C 1-7 alkyl; 7-alkyl; A is a ketalized 1,2-dihydroxy-ethylene group; B is -OC (O) O-, -OC (O) NH-, -NHC (O) NH- or -NHC (O) O-: • * · · ... * n is 2, 3 or 4, and *: m is 0 or 1.

• * · • *. · **. The invention also relates to pharmaceutical compositions containing the compounds of the formula I and to the use of the compounds of the formula I in the manufacture of medicaments for use in the treatment of diseases. 117896 with endothelin activating properties, particularly circulatory disorders such as hypertension, ischemia, vasospasm and angina pectoris.

The term "lower" as used below refers to groups containing 1 to 7 C atoms, preferably 1 to 4 C atoms. Alkyl, alkoxy and alkylthio groups and alkyl groups as part of alkanoyl groups may be straight-chain or branched. Examples of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl. Halogen is fluorine, chlorine, bromine and iodine, with chlorine being preferred. A lower alkylenedioxyphenyl group is, for example, an ethylenedioxyphenyl group. The ketalized 1,2-dihydroxyethylene group is, for example, the 2,2-dimethyl-1,3-dioxolane-4,5-diyl group.

Examples of heterocyclyl groups are in particular substituted, for example, mono- or di-substituted or unsubstituted mono- or bicyclic 5- and 6-membered heterocyclic groups by lower alkyl, lower alkanoyl, halogen or any other heterocyclic group. containing oxygen, nitrogen or sulfur as heteroatoms, such as 2- and 3-furyl, pyrimidinyl, 2-, 3- and: • · · • • * 4-pyridyl, 1,2- and 1 , 4-diazinyl, morpholino, 2- and 3- * * * *: · thienyl, isoxazolyl, oxazolyl, thiazolyl, imidazolyl, pyrrolyl, benzofuranyl, benzothienyl, · ·: indolyl, purinyl, quinolyl, isoquinolyl and kinazo • · - ·. · · lyl. Examples of heterocyclyl groups R are specifically * r *; unsubstituted and unsubstituted pyridyl, pyrimidinyl, thienyl and isoxazolyl. Examples of heterocyclyl groups R2 include, in particular, pyrimidinyl and morpho-. lino. Examples of heterocyclyl groups R 9 are in particular pyridyl, pyrimidinyl and furyl.

Preferred compounds of the formula I * * * are those wherein R 1 is a monocyclic S, N and / or · -. 35 O-heterocyclic group, especially unsubstituted or [* * * '·! . ···. lower alkyl, halogen, amino, mono- or di-. ! * · * · · 4 117896 pyridyl, pyrimidinyl, isoxazolyl, furyl or thienyl substituted by lower alkylamino or lower alkanoyl. Further preferred are compounds of formula I wherein R 2 is hydrogen, pyrimidinyl, pyridyl, morpholino, thiomorpholino, piperidino, pyrrolidino, benzodioxolyl, lower alkoxy-phenyl or lower alkylthio and those wherein R 3 is -O- ( CR a R b) n H, -O- (CR a R b) n NH 2 or a group -O (CH 2) 2 -B-R 9, and R 9 is a monocyclic N- and / or O-heterocyclic group, in particular pyridyl, pyrazinyl or furyl.

Of particular interest are compounds of formula I wherein R 1 is lower alkyl substituted py-; a ridyl group, R 1 is morpholino, R 3 is -O (CH 2) 2 OC (O) NHR 9, R 4 is lower alkoxy and R 5 -R 8 are hydrogen. Preferred pi-15 groups R 9 are heterocyclyl groups, especially pyridyl groups such as 2-pyridyl.

The compounds of formula I above are inhibitors of endothelin receptors. They can therefore be used in the treatment of diseases with en-20 dothelin activating properties, in particular circulatory diseases such as hypertension, ischemia, vascular spasms and angina pectoris.

• »· *. Compounds of Formula I may be prepared by: • * · * · ί. ' 25 a) a compound of the formula • *. ·; ·: R, so! P r <r »ii · *.

«· 1 I

• * *: where R1, R2 and R4 - R8 are as defined above and Hal is · · * halogen, is reacted with a compound of the formula Φ · · * «« «

HO (CRaRb) nXH

5 117896 wherein n, Ra and Rb are as defined above and X is O or NH, or b) reacting a compound of formula Y R4 R5 R3 R8 R7 wherein R2 to R8 are as defined above with a compound of formula wherein R 1 is as defined above and wherein Y is halogen and Z is amino, or Y is amino and Z is halogen; or c) reacting a compound of the formula R 10a R 2 R 8 R 7 ) m

v; I

OiCR ^ nXH

* 1 ·

Iti · · ·: where R 1, R 2, R 4 - R 8, R a, R b, X, m and n have the same 4 1 1 ··· J 15 as above, • 1 i el) is reacted with an isocyanate of the formula

* 1 1 Q

V · R with NCO or carbamoyl chloride of formula R9NCO0C1, wherein R9 has the same meaning as above, or · 2 to c2) is reacted with phosgene followed by 1-3, 20 alcohols of formula R8OH; or chlorine ants-

··· G

.1. an acid ester of the formula ROC (O) C1; or • 1 · 1 · 2 · 1 · 2 · 3 · · 6 117896 d) a compound of formula I wherein R 3 is halo-lower alkyl, is reacted with a compound of the formula H 0 CH 2 -A-lower alkyl 5; wherein A is a ketalized 1,2-dihydroxy-ethylene group, and the substituents of the optionally obtained compound of formula I are modified and / or the resulting compound of formula I is converted into a salt.

The present invention also relates to a compound of formula II.

In the reaction of a compound of formula II with a compound of formula HO (CRaRb) nXH, the latter is conveniently used as an alkali metal alcoholate.

Preferably, the solvent used is the corresponding glycol or the corresponding amino alcohol, for example ethylene glycol or aminoethanol, if n is 2. The alkali metal alcohol is preferably sodium alcoholate. The reaction is conveniently carried out with heating, e.g. at 40-120 ° C. In a preferred embodiment, the compound HO (CRaRb) nXH uses ethylene, propylene or butylene glycol or ... amino-ethanol, -propanol or -butanol mono-sodium * · * *. salt.

• · ·

** "* Reaction of compound of formula III with formula R1SO2Z

The compound of formula * 25 may be prepared from sulfonamides in a manner known per se, for example. .

· ,; ; in an inert organic solvent, such as dimethylsulfoxide, under appropriate heating, and in a protective gas atmosphere, e.g., an argon atmosphere.

· * ·., 30 Reaction according to method variant cl) ***. may be carried out in a manner known per se, known from the preparation of carbamates and ureas from alcohols • · - * • · * * · "or amines. This allows the compound of formula IV to be reacted with the formula R9NCO in a suitable anhydrous organic solvent, e.g.

• · · · ''. ···. in a hydrocarbon such as toluene, conveniently by heating to a compound of formula I wherein B is -OC (O) NH-. The isocyanate can then be obtained in situ, e.g. from an azide of formula R9CON3 by thermal decomposition. Similarly, compounds of formula IV wherein B is NH can be obtained using compounds of formula I wherein B is -NHC (O) NH-.

According to process variant c2), the compound of formula IV wherein B is oxygen can be reacted with phosgene followed by the alcohol R 10 OH to form a compound of formula I wherein A is -OC (O) 0-. Instead of phosgene, a phosgene salt such as diphosgene (Cl-COOCCl3) or triphosgene (CO (OCC13) 2 may be used. Similarly, starting from compounds of formula IV wherein B is NH, compounds of formula I wherein B is -NHC (0) 0. Phosgene is then conveniently used as a solution in an inert anhydrous organic solvent, e.g., a hydrocarbon such as toluene, The reaction with the phosgene may be carried out at room temperature Intermediate-obtained acid-20 chloride is reacted immediately with the alcohol R90H.

... The reaction of process variant d) can be carried out in the reaction conditions described in process variant a) to give compounds of formula I, * * * 3 * ·: · * Wherein R is -CH 2 O -A-lower alkyl.

In the compound of formula I thus obtained, the substituents present therein may be modified. In this way, the style R * can be converted to the formyl group by oxidation. The oxidation may be carried out in a manner known per se, for example with selenium dioxide. In the compound thus obtained, the formyl group can be reduced to a hydroxymethyl group.

This reduction can be accomplished in a manner known per se, for example by the use of reducing agents such as NaBH4. The hydroxymethyl group can be converted to a halomethyl group, •. *. 35 by reacting with a halogenating agent such as POCls / PCls. with. Further, N-heterocyclic groups such as pyridyl may be oxidized to N-oxides. All of these reactions may be carried out according to methods known per se. The compounds of the formula I can be converted into salts, e.g., alkali salts, such as Na-5 and K salts, or alkaline-earth metal salts, such as Ca or Mg salts, in a manner known per se.

Compounds used as starting materials may be prepared if they are not known or are prepared according to methods known in the art, known or described below.

The inhibitory effect on endothelin receptors of the compounds of formula I can be demonstrated by the following experimental protocols: I: Inhibition of endothelin binding to the recombinant ETA receptor cDNA encoding the human placental human ETD receptor was cloned (M. Adachi, Y Y-Yang, Y Furuichi, and C.

Miyamoto, BBRC 180, 1265-1272) and expressed in a Baculovirus insect cell system. 20 Baculovirus-infected insect cells from a 23-liter fermenter are centrifuged 60 hours after infection (3000 xg, 15 minutes, S * · 4 ° C), resuspended in Tris buffer (5 mM, pH 7.4, · · · 1) mM MgCl 2) and centrifuged again. After being resuspended and centrifuged, the cells are resuspended in 800 ml of the same buffer and frozen at -120 ° C. Violation of the ί ί field occurs by thawing the suspension in this s · i .:: hypotonic buffer mixture After a repeated freeze / thaw, the suspension is homogenized and centrifuged (25,000 xg, 15 minutes, 4 ° C). · * · 30 suspended in Tris buffer (75 mM, pH 7.4, 25 mM MgCl 2, 250; *** mM mM sucrose) are maintained in 1 ml aliquots (protein content ···, * approx. 3.5 mg / ml) at -85 ° C.

• · * * · [· Frozen membrane preparations for the Binding test • · * ··· * thawed and centrifuged at 25,000 x g; j *. 35 times for 10 minutes at 20 ° C, resuspended • · ·

assay buffer (50 mM Tris buffer pH 7.4 containing 25 mM

·· «9 117896

MnCl2, 1 mM EDTA and 0.5% bovine serum albumin). 100 μΐ of this membrane suspension containing 70 pg protein is incubated with 50 μl 125 I-endothelin (specific activity 2 200 Ci / mMol) in assay buffer (25,000 cpm, 5 final concentration 20 pM) and 100 μl of assay buffer contains varying concentrations of test compound. This is incubated for 2 hours at 20 ° C or 24 hours at 4 ° C. The separation of free and membrane bound radioligands occurs by filtration through a glass fiber filter.

Table 1 shows the inhibitory effect of the compounds of formula I obtained in this experimental set-up as the IC 50, i. at the concentration [nM] required to inhibit 50% of the specific binding of 125 I-endothelin. '.

Table 1 Compound from Example IC50 [nM] 34 0.3 51: 0.4 II: Inhibition of Endothelin-Induced Vascular Contraction in Isolated Rat Aortic Rings 5 mm long rings were removed from the aorta of adult Wistar-Kyoto rats. The endothelium was removed by ... gently rubbing the inner surface. Each ring was submerged *, placed in a 37 ° C isolated organ bath containing 10 ml of Krebs-Henseleit solution, gasified with a mixture of 95% by weight. C > 2 and 5% CC > 2. The isometric tension of the tires was measured. The rings were stretched until the initial load * * ·. · · Was 3 g. After incubation for 10 minutes with: t test compound or vehicle, cumulative doses of endothelin-1, Test compound act * were added. 30 was obtained by determining the detectable endothelin-1, · · · · · ·, · · · · · · · · · · ·, · · · · · · · · · · · ·, Dose-curve right shift in the presence of different antagonist concentrations. then the partial ···.

. the amount obtained from the EC50 values of endothelin-1 administered. In the presence of 35 gonists, with and without an antagonist, the EC50-kuvaa ······························································································

The "Dose-ratio" of the DR values was calculated using the PC software using the corresponding pÄ2 value for each individual dose-effect curve according to the equation below, which describes the amount of activity of the test compound.

pÄ2 = log (DR-1) -log (antagonist concentration) 10 The EC 50 value of endothelin in the absence of test compounds is 0.3 nM,

The values of pA2 thus obtained for the compounds of formula I are reported in Table 2.

Table 2 Compound Example Example Dose Ratio (Right Shift) 34 9.7 51 9.2

The compounds of the formula I can be used as pharmaceuticals for the treatment of diseases in which vasoconstriction is increased because they are capable of inhibiting endothelin binding. Examples of such diseases * · · are hypertension, coronary heart disease, heart failure * * * · **, renal and myocardial ischaemia, kidney function, dialysis, cerebral ischemia, cerebral infarction, migraine, * » i I *: subarachnoidal or submucosal haemorrhage, • · ii i Raynaud's disease and elevated pulmonary artery pressure, they can also be used in atherosclerosis, to prevent vasoconstriction after balloon dilatation, in lungs, gastric and duodenal ulcers, leg ulcers, blood, gram-negative bacteria, · · ♦. *, intoxication, shock, inflammation of the kidneys, • • ♦ '· ”· feminine pain, glaucoma. * 9 * ··· 'in the treatment and prevention of comorbidities, asthma, diabetes-related complications, and cyclosporin * * * · * ". dose prevention and prophylaxis of <· · 117896 and other diseases with endothelin activating properties.

The compounds of formula I can be administered orally, rectally, parenterally, for example, 5 intravenous, intramuscular, subcutaneous tissue, the intrathecal space or transdermally via a skin; or through the surface of the tongue, or as a preparation for the treatment of ophthalmic diseases, or as an aerosol. Examples of different modes of administration include capsules, tablets, oral suspensions or solutions, suppositories, injection solutions, eye drops, ointments or spray solutions.

A preferred mode of use is intravenous, intramuscular, or oral injection. The dosage at which the compounds of Formula I are administered in effective amounts will depend on the type of specific active agent, the age and needs of the patient, and the route of administration.

Generally, dosages of from about 0.1 to about 100 mg / kg body weight / day are suitable. Preparations containing compounds of the formula I may contain inert or also pharmacodynamically active additives. The tablets or dragees may contain a number of binders, fillers, ···. carriers, or diluents. Liquid formulations may be, for example, in the form of a sterile, water-soluble solution. The capsules may contain, in addition to the active ingredient, a filler or a thickener.

• · ·: * '· Further, preparations may contain flavoring additives, · M, as well as substances commonly used as preservatives, stabilizers, wetting agents, emulsifying agents and emulsifying agents, and also salts for altering the osmotic pressure. , buffers! * · .. 30 and other additives.

· * '* · The above carriers and diluents ···. *. may consist of organic or inorganic substances, e.g., water, gelatines, milk sugar, starch, magnesium stearate, talc, acacia, polyal-, 35 xylene glycols and the like. It is a prerequisite that all the auxiliaries used in the preparation of the preparations are non-toxic.

The following examples further illustrate the invention. Example 1 1.29 g of Na were dissolved in 50 ml of ethylene glycol at 50 ° C. Thereafter, 3.0 g of 5-tert-butyl-thiophene-2-sulfonic acid-6-chloro-5- (2-methoxy-phenoxy) -2,2'-bipyrimidin-4-ylamide were added portionwise at the same temperature and was heated for 4 1/2 hours at 100 ° C.

The clear reaction solution was poured into ice / dilute HCl solution and extracted 3 times with 0.2 L acetic acid ester each time, the organic phase was washed three times with water, dried over sodium sulfate and finally evaporated in a rotary evaporator. There was thus obtained 5-tert-butyl-thiophene-2-sulfonic acid-6- (2-hydroxy-ethoxy) -5- (2-methoxy-phenoxy) -2,2'-bipyrimidin-4-ylamide as a pale yellow foam.

MS: 493 (M-SO 2).

Preparation of the starting compound: 20 a) 2.0 g of 5-tert-butyl-thiophene-2-sulfonic acid chloride were dissolved in 30 ml of ethanol at room temperature, ··· 50 ml of 25% ammonia solution and -> · · · was lost for 4 1/2 hours under reflux. The residue was then evaporated in a rotary evaporator, water was added to the residue, extracted with ethyl acetate (150 ml), dried over magnesium sulfate. · Sodium sulfate and again evaporated in a rotary evaporator. There was thus obtained 5-tert-butyl-thiophene-2-sulfonamide

»M

V ϊ as white crystals. MS: 219 (M) @ +. The potassium salt was obtained from this with K-tert-butylate in methanol.

B) 3.49 g of 4,6-dichloro-5- (2-methoxy-phenoxy) -2,2 '- 3'-bipyrimidine was dissolved in 125 ml of dimethylsulfoxide, *. *. *. to this was added at room temperature 3.855 g of (5-tert-butyl-thiophene-2-sulfonamide) -K and the solution was then stirred for 20 hours at room temperature. Then: 1.285 g of (5-tert-butyl-thiophene-2- • · ·, 3-sulfonamide) -K were further added and the reaction was allowed to react for a further 2 ··· 13 for 1 7896 hours. 200 ml of water and then 200 ml of ether were added to the reaction mixture with vigorous stirring to form a fine white crystalline precipitate which was filtered off with suction. The crystals were suspended in dilute aqueous hydrochloric acid and stirred for 1/2 hour at room temperature, then suction filtered and dried under high vacuum.

There was thus obtained 5-tert-butyl-thiophene-2-sulfonic acid-6-chloro-5- (2-methoxy-phenoxy) -2,2'-bipyrimidin-4-ylamide as a white crystalline solid.

MS: 523.4 (M + H).

Example 2

A solution of 3.23 g of 5-tert-butyl-thiophene-2-sulfonic acid-6- (2-hydroxy-ethoxy) -5- (2-methoxy-phenoxy) -2,2'-bipyrimidin-4-ylamide , 1.71 g of 2-pyridylcarboxyl-15-fatty acid azide and 70 mg of p-dimethylaminopyridine in toluene (50 ml) were heated at 80 ° C for 2 hours. Tolu-; The ene was removed on a rotary evaporator and the residue was partitioned between methylene chloride (0.5 L) and In HCl solution (0.35 L). The organic phase was dried over magnesium sulfate, the solvent was finally removed in a rotary evaporator. The crude product was chromatographed on silica gel using methylene chloride / MeOH (5/1) as eluent. This resulted in a * * · · · · *. din-2-ylcarbamic acid 2- [6- (5-tert-butyl-thiophen-2-yl] * *, '··· * sulfonylamino) -5- (2-methoxy-phenoxy) -2,2' - bipyrimidine • · · * ·! · * 25 4-yloxy] -ethyl ester as a pale yellow solid which was recrystallized from methylene chloride / MeOH.

MS: 678.3 (M + H) @ +.

* * *::: Example 3 26 mg of sodium was dissolved at 50 ° C in 2 ml of ethanolamine, portions of which were added at the same temperature. ** ·. only 150 mg of the compound of Example 1 (b) and solution were heated for 4 hours at 100 ° C. Subsequently, r • · - * * * * was poured.

* · "In ice / water, the pH was adjusted to 6 with 3N HCl,

M1 was purchased as a light yellow crystalline solid, which was filtered off with suction. The reaction mixture was dried, washed with water and dried under high vacuum.

* * *. ···. . There was thus obtained 5-tert-butyl-thiophene-2-sulfonic acid-6- (2- • 4 · 1417896 amino-ethoxy) -5- (2-methoxy-phenoxy) -2,2'-bipyrimidine-4- ylamide as yellow crystals.

MS: 557.4 (M + H).

Example 4 100 mg of 5-tert-butyl-thiophene-2-sulfonic acid-6- (2-amino-ethoxy) -5- (2-methoxy-phenoxy) -2,2'-bipyrimidin-4-yl-amide were dissolved. To 10 ml of toluene, 53 ΐ mg of 2-pyridylcarboxylic acid azide was added thereto and the solution was heated at 120 ° C for 4 hours. The toluene was removed in a rat-10 thio evaporator and the residue partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate and finally evaporated in a rotary evaporator. The residue was chromatographed on silica gel using methylene chloride / methanol (30/1) as eluent. There was thus obtained 5-tert-butyl-thiophene-2-sulfonic acid-5- (2-methoxy-phenoxy) -6- [2- (3-pyridin-2-yl-ureido) -ethoxy] -2,2'- bipyrimidin-4-yl-amide as a crystalline solid.

MS: 677.4 (M + H) @ +.

Example 5 To a solution of 162.5 mg of 4-amino-6-methoxy-5- (2-methoxy-phenoxy) -2,2'-bipyrimidine in 10 ml of tetrahydrofuran was added 92 mg at room temperature. NaH (65- * · * * \ *%), the solution was stirred for 1 1/2 hours at room temperature and then added at the same temperature 162.5 · · · 25 mg 5 tert-butyl-thiophene-2-sulfonyl chloride. Stirring was continued for 2 hours at room temperature, poured into ice / water, extracted with ethyl acetate, aqueous phase: T: acidified and extracted with methylene chloride. The combined organic phases were dried over magnesium sulfate 30 and evaporated in a rotary evaporator. The residue is chromato- • ♦ · *. ···. was graphed on silica gel using methylene chloride- (2/1) di / methanol (20/1) as eluent. There was thus obtained 5-tert-butyl-N- [6-methoxy-5- (2-methoxy-phenoxy) -2,2'-bipyrimidin-4-yl] -thiophene -2-sulfonamide as a yellow powder.

. ! ·. 35 MS: 463 (M-SO2).

Preparation of starting compounds: a) 2.09 g of 4,6-dichloro-5- (2-methoxy-phenoxy) -2,2 '- bipyrimidine (EP-A-0 526 708) was suspended in 75 of any ethanol and condensed at -75 ° C with 150 mL of ammonia in 5 risers. The reaction mixture was allowed to warm to room temperature overnight, evaporated in a water jet vacuum and the residue partitioned between water and methylene chloride (500 mL). The organic phase was dried over sodium sulfate and evaporated in a rotary evaporator. The residue was stirred with 10 ether, the resulting solid separated and dried under high vacuum. 4-amino-6-chloro-5- (2-methoxy-phenoxy) -2,2'-bipyrimidine was thus obtained as a fine, almost white powder. MS: 329 (M) @ +.

b) To a solution of 2.0 g of 4-amino-6-chloro-5-15 (2-methoxy-phenoxy) -2,2'-bipyrimidine in 200 ml of methanol was added 6.55 g of sodium methyl and then the solution was heated under reflux for 32 hours. The methanol was removed on a rotary evaporator, the residue was dissolved in methylene chloride and washed with In 20 hydrochloric acid. The organic phase was dried over magnesium sulfate, and the solvent was finally removed under water jet vacuum.

... The crude product was chromatographed on silica gel using methyl • 1 · *. lenium chloride / methanol (10/1) as eluent. There was thus obtained 4-amino-6-methoxy-5- (2-methoxy-phenoxy) -2,21-bipyrimidine • · 1 * ·: 25 lemon as a yellow powder. MS: 325 (M) @ +.

• · • · ·: Example. Similarly as in Example 1 was obtained from sodium glycolate and 5-pentylthiophene-2-sulfonic acid-6-chloro-5- (2-methoxy-phenoxy) -. 2,2'-bipyrimidin-4-ylamide 5-: 1 · 30 pentyl-thiophene-2-sulfonic acid-6- (2-hydroxyethoxy) -5- (2- .2,2-methoxy-phenoxy) -2, 2'-Bipyrimidin-4-ylamide as a white solid. MS: 570.3 (M + H) @ +.

* 1 1 * · '1 Preparation of starting compounds: a) from 2-pentyl-5- (t-butylsulfonamido) thiophene *. 35 (EP-A-0 512 675) gave ethanol / conc. With HCl and form-

m · · J

1 Ie 1 7896 club salt with potassium tert-butylate in methanol (5-n-pentyl-thiophene-2-sulfonic acid amide) -K.

b) Similarly as in Example 1 (b), (5-n-pentyl-thiophene-2-sulfonic acid-5-di) -K and 4,6-dichloro-5- (2-methoxy-phenoxy) -2 , 2'-Bipyrimidine reacted with 5-pentyl-thiophene-2-sulfonic acid-6-chloro-5- (2-methoxy-phenoxy) -2,2'-bipyrimidin-4-ylamide as a white solid. MS: 545 (M).

Example 7 10 Similarly to Example 2, 2-pyridylcarboxylic acid azide and 5-pentylthiophene-2-sulfonic acid-6- (2-hydroxy-ethoxy) -5- (2-methoxy-phenoxy) -2,2 'were obtained. -Biopyrimidin-4-ylamide, pyridin-2-ylcarbamic acid 2- [5- (2-methoxy-phenoxy) -6- (5-pentyl-thiophen-2-ylsulfonyl-15-amino) -2,2'-bipyrimidine -4-yloxy] -ethyl ester as a white solid. MS: 692.4 (M + H) @ +.

Example 8

Similarly as in Example 1, sodium glycolate and 5- (2,2-dimethyl-propionyl) -thiophene-2-20 sulfonic acid-6-chloro-5- (2-methoxy-phenoxy) -2,2'-bipyrimidine were obtained. din-4-ylamide 5- (2,2-dimethyl-propionyl) -thiophene-2-sulfonic acid-β- (2-hydroxy-ethoxy) -5- (2-methoxy-phenoxy) - • 1 · 2,2 ' -bipyrimidin-4-ylamide as a pink powder. MS: *, 586.3 (M + H).

Preparation of the starting compound: · · ·: a) Similarly to Example 1 b), · · * was obtained by administering 5- (2,2-dimethylpropionyl) -thiophene-2 · · · ί. ί; of the potassium salt of the sulfonamide (prepared by J. Org. Chem., Vol. 56, 4260) and 4,6-dichloro-5- (2-methoxy-phenoxy) -2,2'-bipyrid-1 · 30 -midine react with 5- (2,2-Dimethyl-propionyl) -thiophene-2-3. sulfonic acid 6-chloro-5- (2-methoxy-phenoxy) -2,2'-bipyrimidin-4-yl-4-yl-amide as a crystalline solid. MS: 560.1 · · · * · 1 · (M + H). The potassium salt was obtained here with potassium tert-butylate in methanol.

· • · · * 1 1 «· · 2 • · 3 • · * 1 1 117896 π

Example 9

Similarly as in Example 2, 2-pyridylcarboxylic acid azide and 5- (2,2-dimethyl-propionyl) -thiophene-2-sulfonic acid-6- (2-hydroxy-ethoxy) -5-5 (2-methoxy- phenoxy) -2,2'-bipyrimidin-4-ylamide, pyridin-2-ylcarbamic acid 2- [6- [5- (2,2-dimethyl-propionyl) -thiophen-2-ylsulfonylamino] -5- (2-methoxy) (phenoxy) -2,2'-bipyrimidin-4-yloxy] -ethyl ester as a beige powder. MS: 704.3 (M + H) @ +.

Example 10 1.75 g of Naita was dissolved at 50 ° C in 70 ml of ethylene glycol. Thereafter, the same heat was added thereto; at room temperature, 4.9 g of 5-isopropyl-pyridine-2-sulfonic acid-6-chloro-5- (2-methoxy-phenoxy) -2,2'-bipyrimidin-4-15-ylamide were heated at 100 ° C for 4 hours. :in. The clear reaction solution was poured into 200 mL of water, the pH was adjusted to 1 with 3N HCl, the precipitated yellow crystals were suction filtered, washed with water, then with ether and then dried under high vacuum. There was thus obtained 5-isopropyl-20-pyridine-2-sulfonic acid-6- (2-hydroxy-ethoxy) -5- (2-methoxy-phenoxy) -2,2'-bipyrimidin-4-ylamide as a yellow crystalline solid. as that solid.

• ♦ · * *; MS: 537.3 (M-II).

Preparation of the starting compounds: a) 4.0 g of 5-isopropyl-pyridine-2-sulfonamide were dissolved in 40 ml of MeOH, to which room temperature was added. 2.308 g of potassium tert-butylate was added and the solution was further stirred for 20 minutes. Subsequently, it was completely evaporated in a rotary evaporator and the potassium salt thus obtained was dried under high vacuum.

B. 3.49 g of 4,6-dichloro-5- (2-methoxy-phenoxy) -2,2 '- bipyrimidine was dissolved in 125 ml of dimethylsulfoxide, *. *: 4.7 g of (5-isopropyl- * ·· pyridine-2-sulfonamide) -K were added at room temperature and the solution was stirred. After 35 hours at room temperature. Then the solution is poured - · · ·, ···. was stirred under vigorous stirring in 350 ml of water and 90 ml of «*» ··· 1,17896 ether, the pH was adjusted to 1 by addition of 3N HCl. The white crystalline precipitate was suction filtered and washed with water and then ether. The crystals were suspended in dilute aqueous hydrochloric acid (100 ml water and 50 ml In HCl) and stirred for 5 minutes, then suction filtered and washed again with water and dried under high vacuum. There was thus obtained 5-isopropyl-pyridine-2-sulfonic acid-6-chloro-5- (2-methoxy-phenoxy) -2,2'-bipyrimidin-4-ylamide as a white crystalline solid.

MS: 511.3 (M-H).

Example 11 2.0 g of 5-isopropyl-pyridine-2-sulfonic acid-6- (2-hydroxy-ethoxy) -5- (2-methoxy-phenoxy) -2,2'-bipyrimidin-4-ylamide were dissolved in 80 ml: To toluene, 1.1 g of 2-pyridylcarboxylic acid azide were added thereto and the solution was then heated for 4 hours at 90 ° C. It was then evaporated in a rotary evaporator and the residue was partitioned between In HCl and ethyl acetate. The organic phase was dried over magnesium sulfate, the solvent was removed in a water jet vacuum and the residue was chromatographed on silica gel using methylene chloride / methanol (30/1) as eluent. There was thus obtained ··· 'pyridin-2-ylcarbamic acid 2- [6- (5-isopropyl-pyridin-1 · *, 2-ylsulfonylamino) -5- (2-methoxy-phenoxy) -2,2'-bipyrim - • · · ** ·) 2-Din-4-yloxy] -ethyl ester as yellow crystals.

MS: 657.3 (M + H).

2: To prepare the dihydrochloride, the compound was dissolved in 1. · Methylene chloride and to this was added at room temperature • · 2! corresponding amount of 4.4 N HCl in ethanol. The solution was evaporated in a rotary evaporator, the precipitated crystalline solid was isolated and dried for 4 hours at 60 ° C in a high vacuum. where.

• · • · ·

Example 12 * t · 12 "Similarly to Example 4, 5-isopropyl-pyridine-2-sulfonic acid-6- (2-amino-ethoxy) -5- (2-meth-3-yl) -oxide was obtained. -phenoxy) -2,2'-bipyrimidin-4-ylamide and 2-pyridyl-1,1'-lecarboxylic acid azide, the desired 5-isopropyl-pyrrolo-4-yl-19,178,696-din-2-sulfonic acid-5- (2-Methoxy-phenoxy) -6- [2- (3-pyridin-2-yl-ureido) -ethoxy] -2,2'-bipyrimidin-4-yl-amide as yellow crystals MS: 656.3 (MH).

Similarly, as in Example 5 cat 3, the starting compound was obtained from ethanolamine and the compound of Example 10 (b) as a yellow foam. MS: 538.3 (M + H) @ +.

Example 13

Similarly as in Example 10, pyridine-2-sulfonic acid-6-chloro-5- (2-methoxy-phenoxy) -2,2'-10-bipyrimidin-4-ylamide and ethylene glycol were obtained from pyridine-2-sulfonic acid-6- ( 2-hydroxy-ethoxy) -5- (2-methoxy-phenoxy) -2,21-bipyrimidin-4-ylamide as white crystals.

MS: 615.4 (M-H).

Preparation of the starting compounds: 15 a) 1.7 g of 2-pyridylsulfonic acid chloride (J. Org.

Chem., Vol. 54, 389) was dissolved in 30 ml of ethanol, to which was added 30 ml of 25% ammonia solution under ice-cooling, and then heated under reflux for 4 hours. The reaction solution was evaporated in a rotary evaporator, the residue was partitioned between ethyl acetate and water, the organic phase was dried over magnesium sulfate and finally evaporated in a rotary evaporator to precipitate 2-pyridylsulfonic * ♦ · acid amide as a beige, crystalline solid. , 2 (MH) The K-salt was obtained from this with K-tert.- · · · '***** 25 butylate in methanol.

* 1 »: 1 b) Similarly as in Example 10, b), • ·: was obtained by the administration of (2-pyridylsulfonamide) -K and 4,6- • * * dichloro-5- (2- of methoxy-phenoxy) -2,2'-bipyrimidine with pyridine-2-sulfonic acid-6-chloro-5- (2-methoxy-phenoxy) -2,2'- · * · 30 bipyrimidin-4-ylamide as white crystals .

*. MS: 495.3 (M-H) -.

• · ·. Example 14 '· * · Similarly as in Example 11, pyridine-* · n-2-sulfonic acid-6- (2-hydroxy-ethoxy) -5- (2-methoxy-phenoxy *: *) was obtained. 2,2'-bipyrimidin-4-ylamide and 2-pyridylcarboxylic acid. from the acylic acid azide pyridin-2-ylcarbamic acid 2- [5- (2- • · ·: 20 117896 methoxy-phenoxy) -6-pyridin-2-ylsulfonylamino) -2,2'-bi-pyrimidin-4-yloxy] -ethyl ester in the form of white crystals.

MS: 615.4 (M-H).

Example 15 Similarly to Example 10, pyridine-3-sulfonic acid-6-chloro-5- (2-methoxy-phenoxy) -2,2'-bipyrimidin-4-ylamide and ethylene glycol were obtained from pyridine-3-sulfonic acid-6. - (2-Hydroxy-ethoxy) -5- (2-methoxy-phenoxy) -2,2'-bipyrimidin-4-ylamide as white crystals.

MS: 496 (M).

Preparation of Starting Compounds: a) Similarly to Example 13, a) was obtained from 3-pyridylsulfonic acid chloride (J. Org. Chem., Vol. 54, 389) and ammonia 2-pyridylsulfonic acid amide 15 as a white crystalline solid. The potassium salt was obtained from this with potassium tert-butylate in methanol.

b) Similarly as in Example 10, b), (3-pyridylsulfonamide) -K and 4,6-dichloro-5- (2-methoxy-phenoxy) -2,2'-bipyrimidine were reacted with the desired pyridine-3 -sulfonic acid ~ 6-chloro-5- (2-methoxyphenoxy) -2,2'-bipyrimidin-4-ylamide as white crystals.

... MS: 470 (M).

• · · * • »·

Example 16 • * · * * * * "Similarly to Example 11, there was obtained pyridine · * · · * 25 ni-3-sulfonic acid-6- (2-hydroxy-ethoxy) -5- (2 -methoxy-phenoxy- (2-yl) -2,2'-bipyrimidin-4-ylamide and 2-pyridylcarboxylic acid azide, pyridin-2-ylcarbamic acid 2- [5- (2- * * * N * -methoxy) phenoxy) -6-pyridin-3-ylsulfonylamino) -2,2'-bipyrimidin-4-yloxy] ethyl ester as white crystals.

MS: 615.4 (M-H).

*** · Example 17 • · * * *. *, 213 mg of [6-2- (tert-butyl-dimethylsilaneoxy) - * * * '· * · ethoxy] -5- (2-chloro) 5-Methoxy-phenoxy) -pyrimidin-4-yl * - *. * Amine was dissolved in 15 ml of tetrahydrofuran, at room temperature, 35 mg of NaH (65%) was added thereto. , se- »« *. ***. after stirring for 2 hours at room temperature, then * · * 1,178,696 was added portionwise to 155 mg of 5-tert-butyl-thiophene-2-sulfonyl chloride. The solution was stirred for a further 2 hours at room temperature, poured into ice water and extracted twice with a total of 200 ml of ethyl acetate. After further treatment of the or-5 gaseous phase by conventional means, the silyl protected crude product was chromatographed on silica gel using methylene chloride / acetic ester (8/1) as eluent.

The resulting brownish foam (219 mg) was dissolved in 10 ml of acetonitrile, to which 1.5 ml of HF solution (40%) was added at room temperature and stirred for 2 hours. The re-reaction mixture was partitioned between ethyl acetate and half-saturated NaCl solution and the organic phase was further worked up in the usual manner. The crude product was chromatographed on silica gel using methylene chloride / ethyl acetate (4/1) as eluent and recrystallized from ether / hexane. There was thus obtained 5-tert-butyl-thiophene-2-sulfonic acid-5- (2-chloro-5-methoxy-phenoxy) -6- (2-hydroxy-ethoxy) -pyrimidin-4-ylamide as white crystals. MS: 449 (M-SO 2). ! Preparation of the starting compound (a) 3-Methoxyphenol was modified according to M. Julia * · · and I. de Rosnay, Chimie Threpeutigue, 5 (1969), 334, guideline · · · ** · with sulfuryl chloride 2-chloro-5. -methoxypheno- ***** 25 residues.

B) 18.2 g of 2-chloro-5-methoxyphenol were dissolved in 150 ml of dry methanol. To this was added 9.3 g of MeONa * · · ί.ϊ ϊ followed by 25 g of chlormalonic acid dimethyl ester. The reaction mixture was stirred for 2 hours at 50 ° C. Solvent · * ·,. After 30 distillations, the residue was partitioned in a toluene funnel. ene and Η2 <0: η and washed neutral. After crystallization from ethanol, (2-chloro-5-methoxymethyl) phenoxy-dimethyl malonate was obtained as white crystals, m.p.

den sp. was 68-69 ° C.

c) 1.43 g of Na was dissolved in 70 ml of MeOH. Sit- * * «. ***. To this was added 5.8 g of (2-chloro-5-methoxy) phenoxy ··· 117896 22 dimethyl malonate and 2.29 g of formamidine acetate. The re-reaction mixture was stirred at reflux for 1.5 hours.

The solvent was then distilled off, the residue was dissolved in the skin, the aqueous phase was extracted with ethyl acetate, the organic phase was discarded, and the aqueous phase was adjusted to pH 4 with acetic acid to give 5- (2-chloro-5-methoxy) -phenoxy-4,6- (1H). , (5H) -pyrimidinedione precipitated as a white powder. MS: m / e = 268 (M +).

d) A mixture of 3.75 g of 5- (2-chloro-5-10 methoxy) phenoxy-4,6- (1H, 5H) -pyrimidinedione, 5.4 g of N-ethyldiisopropylamine and 5 mL of POCl 3 in 20 mL of dioxane was stirred at reflux for 18 hours. After distillation of the volatile components, the residue was partitioned between ethyl acetate and foO and washed to neutral. After distilling off the solvent, the compound was purified on silica gel using CfCl2 as the eluent.

After crystallization from EtOH, 4,6-dichloro-5- (2-chloro-5-methoxy-phenoxy) -pyrimidine was obtained as white crystals having m.p. 88-89 ° C. , 20 e) To a solution of 9.9 g of 4,6-dichloro-5- (2-chloro-5-methoxy-phenoxy) -pyrimidine in Example l) in 400 ml of ethanol was introduced At 500 ° C, about 500 ml • · · NH 3. * A. The reaction mixture was then stirred for 15 hours at -78 ° C and 50 hours at room temperature and finally evaporated. The residue was partitioned between ethyl acetate and water and the organic phase was further worked up. There was thus obtained 6-chloro-5- (2-chloro-5-methoxy-phenoxy) -pyrimidine · · · · 4-Ylamine as yellow crystals. MS: 285 (M) @ +.

f) 8.53 g of the above compound was added at 50 ° C to a solution of 0.82 g of sodium in 100 ml. ethylene glycol. The solution was heated for 20 hours at 100 ° C, then partitioned between half saturated NH 4 Cl solution and CH 2 Cl 2 and worked up.

* ·

8.3 g of 2- [6-amino-5- (2-chloro-5-methoxy-phenoxy) -4-; **: 35 Pyrimidin-4-yloxy] -1-ethanol as a white solid. nena, which was silylated without further purification. For this purpose, the above material (8.3 g) was dissolved in 300 ml of methylene chloride, 8.15 g of dimethylaminopyridine was added thereto, and finally 10.05 g of t-butyldimethylchlorosilane were added at room temperature. The reaction solution was stirred for 5 hours at room temperature. It was then filtered, the solution evaporated, the evaporation residue partitioned between half saturated NH 4 Cl solution and ethyl acetate and the organic phase was further worked up. Subsequent crystallization from methylene chloride / hexane gave 7 g of 6- [2-10 (tert-butyl-dimethylsilanyloxy) -ethoxy] -5- (2-chloro-5-methoxy-phenoxy) -pyrimidin-4-ylamine.

MS: 410 (M-CH 3).

Example 18

Similarly as in Example 2, 5-tert-butyl-thiophene-2-sulfonic acid-5- (2-chloro-5-methoxy-phenoxy) -6- (2-hydroxy-ethoxy) -pyrimidine-4- was obtained. of the ylamide and 2-pyridylcarboxylic acid azide, pyridin-2-ylcarbamic acid 2- [6- (5-tert-butyl-thiophen-2-ylsulfonylamino) -5- (2-chloro-5-methoxy-phenoxy) -pyrimidin-4 -yloxy] -ethyl ester as white crystals.

MS: 634.3 (M + H) @ +.

... Example 19 • »· *. Similarly as in Example 2, the compound of Example · · * *** · “17 and 4-pyridylcarboxylic acid azide gave pyridin-4-ylcarbamic acid 2- [6- (5-tert-butyl). thiophen-2- • ·: ylsulfonylamino) -5- (2-chloro-5-methoxy-phenoxy) - • · i: pyrimidin-4-yloxy] -ethyl ester as white crystals.

MS: 634.3 (M + H) @ +.

Example 20 • 30 Similarly to Example 17 was obtained using **. 6- [2- (tert-Butyl-dimethylsilanyloxy) -ethoxy] -5- (2- • · · • methoxy-phenoxy) -pyrimidin-4-ylamine Reaction Component * · · * · tert-Butyl-thiophene-2-sulfonic acid-6- (2-hydroxy-4-ethoxy) -5- (2-methoxy-phenoxy) -pyrimidin-4-ylamide as a solid.

MS: 479 (M).

• «• · * 24 1 1 7 8 9 6

Example 21

To a solution of Na-glycolate consisting of 1.5 ml of ethylene glycol and 46 mg of Na was added 180 mg of the compound of the above step. For complete dissolution, 1 mL of DMSO was added. The reaction was then allowed to proceed for 3 hours at 90 ° C. After cooling to room temperature, the pH of the reaction medium was adjusted to 4 with aqueous citric acid and the resulting compound was then extracted with ethyl acetate. After distillation of the ethyl acetate distillate, N- [5- (2-chloro-5-methoxy-phenoxy) -6- (2-hydroxy-ethoxy) -pyrimidin-4-yl] -5-isopropyl-pyridine-2-sulfonamide was crystallized. ethanol. 175 mg of white crystals were obtained, which decomposed at 180 ° C.

Preparation of the starting compound 15 306 mg of 4,6-dichloro-5- (2-chloro-5-methoxy-phenoxy) -pyrimidine, 320 mg of 5-isopropyl-2-pyridine-2-sulfonamide and 180 mg of K-tert. butylate was dissolved in 2 mL of DMSO and allowed to react for 3 hours at 90 ° C. After cooling to room temperature, the reaction dye was acidified with aqueous citric acid; the compound was extracted with acetic ester and solvent distilled. after crystallization from ethanol. There was obtained N- [6-chloro- * · * 5- (2-chloro-5-methoxy-phenoxy) -pyrimidin-4-yl] -5-isoprop- * * *** -yl-pyridine-2-sulfonamide as white crystals having m.p.

25 was 174-175 ° C.

* · * · * I.; : Example 22 • ·: 100 mg of N- [5- (2-chloro-5-methoxy-phenoxy) -6- (2-hydroxy-4-oxy-ethoxy) -pyrimidin-4-yl] -5- isopropyl-pyridine-2-sulfonamide and 38.5 mg of 2-pyridylcarboxylic acid azide were dissolved in 1 ml of dry dioxane. The solution is stirred- *. · **. for 2 hours at 95 ° C, whereupon N 2 was released. Soluble- • «· /. after distillation, the compound was crystallized from ethanol.

· * * * · "115 mg of pyridin-2-yl-carbamic acid 2- [5- (2- [*] ... * chloro-5-methoxy-phenoxy) -6- (5-isopropyl-pyridine) were obtained. 2-yl- (* · 35 sulfonylamino) -pyrimidin-4-yloxy] -ethyl ester as white crystals having m.p. 190-191 ° C.

117896 25

Example 23

Similarly as in Example 21, 5-isopropyl-N- [6- (2-hydroxy-ethoxy) -5- (2-methoxy-phenoxy) -2- (3-methoxy-phenyl) -pyrimidin-4-yl] - was obtained. pyridine-2-sulfone-5 amide. The melting point was 139-140 ° C (from ethanol). 'Production of departure compound

Similarly as in Example 21, Part Two, 400 mg of N- [6-chloro-5- (2-methoxy-phenoxy) -2- (3-methoxy-phenyl) -pyrimidin-4-yl] -5-isopropyl-pyridine were obtained. 10 2-sulfonamide from 330 mg of 4,6-dichloro-2- (3-methoxy-phenyl) -5- (2-methoxy-phenoxy) -pyrimidine and 420 mg (5-isopropyl-pyridine-2) sulfonamide) -K added.

Example 24

Similarly as in Example 22, 115 mg of 5-isopropyl-N- [6- (2-hydroxy-ethoxy) -5- (2-methoxy-phenoxy) -2- (3-methoxy-phenyl) -pyrimidine were obtained. 4-yl] -pyridine-2-sulfonamide and 38.5 mg of 2-pyridylcarboxylic acid azide in 120 mg of pyridin-2-ylcarbamic acid 2- [6- (5-isopropyl-pyridin-2-ylsulfonylamino) -5- (2-methoxy-phenoxy) -2- (3-methoxy-phenyl) -pyrimidin-4-yloxy] -ethyl ester. Sp. 158-160 ° C (from ethanol).

· .. Example 25 »·» • · · *. a) Similarly as in Example 21, N- [6- ···· '* · ** chloro-5- (2-methoxy-phenoxy) -2-methylsulfanyl-pyrimidin-4 · -yl-4-yl was obtained. ] -5-Isopropyl-pyridine-2-sulfonamide from 4,6-dichloro * -: 2-methylsulfanyl-5- (2-methoxy-phenoxy) -pyrimidine and

Pk ': · · (5-isopropyl-pyridine-2-sulfonamide) -K.

: Melting point 192 ° C (from ethanol).

b) The compound was converted to Na-glycolate with 5-isopropyl-N- [6- (2-hydroxy-ethoxy) -5- (2-methoxy-phenoxy) -2-methyl-2-methyl. . phenylsulfanyl-pyrimidin-4-yl] pyridine-2-sulfonamide.

Mp: 76-78 ° C (from EtOH).

* · * I Example 26 • · *

Similarly as in Example 22, 106 mg was obtained. 35 Pyridin-2-yl-carbamic acid 2- [6- (5-isopropyl-pyridin-2H-2H-2-ylsulfonylamino) -5- (2-methoxy-phenoxy) -2-methylsulfur · · · ♦ 117896 26 Fanyl-pyrimidin-4-yloxy] -ethyl ester from 100 mg of 5-iso-propyl-N- [6- (2-hydroxy-ethoxy) -5- (2-methoxy-phenoxy) -2-methylsulfanyl -pyrimidin-4-yl] -pyridine-2-sulfonamide and 2-pyridylcarboxylic acid azide.

5 M.p. 213-214 ° C (from ethanol).

Example 27 a) From 4,6-dichloro-2- (1,3-benzodioxol-5-yl) -5- (2'-methoxy-phenoxy) -pyrimidine and (5-isopropyl-pyridine-2-sulfonamide) -K gave N- [6-chloro-2- (1,3-benzodioxol-5-yl) -5- (2-methoxy-phenoxy) -pyrimidin-4-yl] -5-iso-propyl pyridine-2-sulfonamide.

b) This compound was converted to Na-glycolate with N- [2- (1,3-benzodioxol-5-yl) -6- (2-hydroxy-ethoxy) -5- (2-methoxy-phenoxy) -pyrimidin-4-yl. ] -5-isopropyl-pyridine-2-sulfonamide. Mp: 184 ° C (from EtOH).

Example 28

Similarly as in Example 22, 110 mg of pyridin-2-yl-carbamic acid 2- [2- (1,3-benzodioxol-5-yl) -6- (5-isopropyl-pyridin-2-ylsulfonylamino) -5-20 were obtained. (2-Methoxy-phenoxy) -pyrimidin-4-yloxy] -ethyl ester from 116 mg of N- [2- (1,3-benzodioxol-5-yl) -6- (2-hydroxyethoxy) -5- ( 2-methoxy-phenoxy) -pyrimidin-4-yl] -5-isopropyl, pyridine-2-sulfonamide and 2-pyridyl-carboxyl * * * acid azide. Sp. 184 ° C (from ethanol).

* ··· * Example 29 • ·: (a) 4,6-Dichloro-2-morpholin-4-yl-pyrimidine and * · · · (5-isopropyl-pyridine-2-sulfonamide) -K N- [6-chloro-5- (2-chloro-5-methoxy-phenoxy) -2-morpholin-4-yl-pyrimidin-4-yl] -5-isopropyl-pyridine-2-sulfonamide was obtained.

ί * · ί # 30 b) By reacting this compound with Na-gly, ···. with cholate gave N- [5- (2-chloro-5-methoxy-4'-phenoxy) -6- (2-hydroxy-ethoxy) -2-morpholin-4-yl-pyrimidin * * *. "din-4-yl] -5-isopropyl-pyridine-2-sulfonamide.

Mp: 189-190 ° C (from EtOH).

• 9 9 m m • · · »» · * ·· • 9 9 m 999

Example 30 27 1 7896

Similarly as in Example 22, 116 mg of N- [5- (2-chloro-5-methoxy-phenoxy) -6- (2-hydroxy-ethoxy) -2-morpholin-4-yl-pyrimidin-4 -yl] -5-isopropyl-pyridine-2-sulfonamide with 2-pyridylcarboxylic acid azide pyridine-2-ylcarbamic acid 2- [5- (2-chloro-5-methoxy-phenoxy) - 6- (5-isopropyl-pyridine-2-yylisul-alkylsulfonylamino) -2-morpholin-4-yl-pyrimidin-4-yloxy] -ethyl ester. 106 mg of white crystals were obtained from ethanol which decomposed at 240 ° C.

Example 31

Similarly as in Example 21, 5-methyl-pyridine-2-sulfonic acid [6-chloro-5- (2-methoxy-phenoxy) -2,2'-bipyrimidin-4-yl] -amide and Na of glycolate 5-methyl-pyridine-2-sulfonic acid-6- (2-hydroxy-ethoxy) -5- (2-methoxy-phenoxy) -2,2'-bipyrimidin-4-ylamide. The melting point was 190 ° C (from ethanol).

Preparation of the starting compound a) 2-Amino-5-methylpyridine was diazotized and converted to 2-bromo-5-methylpyridine in F.H.

Case (JACS 68 (1946), 2574).

b) 4.8 g of this compound were reacted in 40 µl of propylene glycol with 7.4 g of sodium hydrogen sulfide at 150 ° C. After cooling at room temperature. · · [··· 25 patients, 5 ml of acetic acid was added dropwise to the reaction mixture to precipitate the resulting 2-mercapto-5-methylpyridine as a yellow powder.

• * * ί, ί: c) In a biphasic mixture consisting of 40 ml CH2Cl2, 20 ml 37% aqueous HCl and "... 30 g of 2-mercapto-5- methyl pyridine, cooled to -10 ° C, was treated with 50 ml * · ·. ·. 1,2 molar sodium hypochlorite solution over 30 min. phase was shaken three times with Η2 <0: η.

9 m · · · * .. · * After distillation of the solvent, 5-methylpyridine was obtained; 35 sulphochloride as a yellowish liquid.

D) Reaction of the sulfochloride with 25% NH 4 OH solution yielded 5-methylpyridine-2-sulfonamide.

e) 0.7 g of 4,6-dichloro-5- (2-methoxy-phenoxy) -2,2'-5-bipyrimidine, 520 mg of 5-methyl-pyridine-2-sulfonamide. and 320 mg of K-tert-butylate was dissolved in 2 ml of DMSO and stirred at 80 ° C for 3 hours. After further working up the reaction mixture in a conventional manner, 410 mg of 5-methylpyridine-2-sulfonic acid [6-10] chloro-5- (2-methoxy-phenoxy) -2,2'-bipyrimidine-4- was obtained. yl] -amide.

Example 32

Similarly as in Example 22, 105 mg of 5-methyl-pyridine-2-sulfonic acid-6- (2-hydroxy-15-ethoxy) -5- (2-methoxy-phenoxy) -2,2'-bipyrimidine-4- was obtained. ylamide and 30 mg of 2-pyridylcarboxylic acid azide 100 mg of pyridin-2-ylcarbamic acid 2- [5- (2-methoxyphenoxy) -6- (5-methylpyridin-2-ylsulfonylamino) -2, 2'-Bipyrimidin-4-yloxy] -ethyl ester as beige crystals. Melting point-20 te: decomposition at 198 ° C.

Example 33 ... Similar to Example 22, 712 µmg of 4,6-dichloro-5- (2-methoxy-phenoxy) -2-morpholin-4-yl was obtained. • · · * · * 1-Pyrimidine and (5-methylpyridine-2-sulfonamide) -K * «« ** 5 5 580 mg of 5-methylpyridine-2-sulfonic acid-6-chloro- 5- (2- *: Methoxy-phenoxy) -2-morpholin-4-yl-pyrimidin-4-ylamide.

• · · b) Reaction of this compound with Na-glycol-· · · · · · · · · · · · · · · · · · · · · · · · · · Formate to give 5-methylpyridine-2-sulfonic acid-6- ) -2-

· * ·> 30 morpholin-4-yl-pyrimidin-4-ylamide. Sp. 195-196 ° C

. * ··. (From ethanol).

· * · * Example 34 • · * · "Similarly to Example 22, 117 mg of · · · pyridin-2-yl-carbamic acid 2- [5- (2-methoxy-phenoxy) -6- * were obtained. 35 (5 -methyl-pyridin-2-ylsulfonylamino) -2-morpholin-4-yl-· · * · ··· pyrimidin-4-yloxy] -ethyl ester from 105 mg of 5-methyl-· · »· · 117896 29 pyridine -2-sulfonic acid-6- (2-hydroxy-ethoxy) -5- (2-methoxy-phenoxy) -2-morpholin-4-yl-pyrimidin-4-ylamide and 2-pyridyl-carboxylic acid azide. At 175 ° C. v 5 Example 35 To 105 mg of 5-methyl-pyridine-2-sulfonic acid-6- (2-hydroxy-ethoxy) -5- (2-methoxy-phenoxy) -2-morpholine-4- Ylpyrimidin-4-ylamide In 2 ml of dichloromethane, 3 ml of a 1.9 molar solution of phosgene in toluene was added, after 1 hour at room temperature the chloroformate had formed completely. to a mixture of chloroform and pyridine, to which was added 0.5 g of 3- (hydroxymethyl) -furan and reacted for 3 hours at 60 ° C. After conventional further treatment, the compound was purified on silica gel (dichloromethane-diethyl ether 4: 1 as eluent). 65 mg of carboxylic acid-furan-3-ylmethyl ester-2- [5- (2-methoxy-phenoxy) -6- (5-methyl-pyridine-2-sulfonylamino) -2-morpholin-4-yl- were obtained. 20 Pyrimidin-4-yloxy] -ethyl ester.

MS: 640.5 [M-H] -].

«·· Example 36 • ·.

♦ · 1 *. 9.2 g of 4- [4-chloro-5- (2-chloro-5-methoxy-phenoxy) -? · · **; 16-methyl-pyrimidin-2-yl] -morpholine and 17.8 g of -iso- * 1 · * ·· 2 Propyl-pyridine-2-sulfonamide-potassium was heated • · · ** · · ·: in 130 mL of dry dimethyl sulfoxide under argon atmosphere · 1 · · 16 h at 120 ° C. . The dimethylsulfoxyl was then distilled off, the residue was partitioned between ethyl acetate and IN hydrochloric acid and the organic phase was washed with neutral 30 µl. The organic phase was dried and the solvent evaporated. and the residue was recrystallized from ethanol. 10.3.1 g of 5-isopropyl-pyridine-2-sulfonic acid-5- (2-chloro-5 ', 11'-methoxy-phenoxy) -6-methyl-2-morpholin-4-yl- was obtained. pyrimidin-4- • · ·: ... ...-ylamide MS: M = 534.

• · · * · s 2 • · ♦ ··

Example 37 1 g-7896 1 g of the compound obtained in Example 36 and 2.1 g of selenium dioxide in 40 ml of dioxane were stirred in an autoclave at 170 ° C for 7 hours. The reaction mixture was filtered and the filtrate was evaporated. The residue was partitioned between ethyl acetate and water. The organic phase was dried, the solvent evaporated and the residue was purified on silica gel using ethyl acetate-hexane. 0.53 g of 5-isopropyl-pyridine-2-sulfonic acid-5- (2-chloro-5-methoxy-phenoxy) -6-10-formyl-2-morpholin-4-yl-pyrimidin-4-ylamide is obtained, m.p. . 194 ° C.

Example 38 To 0.1 g of the compound obtained in Example 37 in 3 ml of ethanol was added 0.014 g of sodium borohydride. The reaction mixture was stirred at 80 ° C for 1 hour. The ethanol was then distilled off and the residue partitioned between chloroform and 1N HCl. The organic phase was washed with water and dried, the solvent was evaporated and the residue was chromatographed on silica gel using chloroform-methanol. After recrystallization from dichloromethane-ethanol, 0.072 g of 5-isopropyl-pyridine-2-sulfonic acid-5- (2-chloro-5-methoxy-phenoxy) -6-hydroxymethyl * -2,2-morpholine was obtained. -4-yl-pyrimidin-4-ylamide, m.p. 105 ° C.

2 · 0.2 g of the compound obtained in Example 38 in 3.5 ml of ß.ί: POCl3 were mixed with 0.083 g of PCl 20 at 20 ° C. at 2 · · I hours. The POCl3 was then distilled off and the residue was partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with water, dried, and the solvent evaporated. The residue was chromatographed * .3. on silica gel using chloroform-methanol, followed by recrystallization from dichloromethane-ethanol.

• · · * · 1 · 0.150 g of 5-isopropyl-pyridine-2-sulfonic acid-5- • · (2-chloro-5-methoxy-phenoxy) -6-chloromethyl-2-morpholine-4-yl were obtained; 35 yl-pyrimidin-4-ylamide, m.p. 205 ° C.

• · · • · · 2 • · 3 • · · · · 117896 31

Example 40

To a sodium glycolate solution containing 0.35 g of ethylene glycol and 0.021 g of sodium was added 0.130 g of the compound obtained in Example 39. The reaction mixture was stirred under an argon atmosphere for 2 hours at 80 ° C. Subsequently, the ethylene glycol was distilled off and the residue was partitioned between ethyl acetate and 1N hydrochloric acid. The organic phase was washed with water, dried over sodium sulfate and the solvent was evaporated. The residue was recrystallized from ether-Petro-10. 0.104 g of 5- (2-chloro-5-methoxy-phenoxy) -6- (2-hydroxy-ethoxymethyl) -2-morpholin-4-yl-pyrimidin-4-ylamide, m.p. was 166 ° C.

Example 41

Similarly as in Example 2, the compound obtained in Example-15 gave pyridin-2-ylcarbamic acid 2- [5- (2-chloro-5-methoxy-phenoxy) -6- (5-isopropyl-pyridine-2-sulfonylamino) - 2-morpholin-4-yl-pyrimidin-4-yl-metoxymethoxyphenyl-si] -ethyl ester. MS: (M-H) - = 713.

Example 42 Similarly to Example 2, the compound obtained in Example 38 gave pyridin-2-ylcarbamic acid 5-tert-2-chloro-5-methoxy-phenoxy) -6- (5-isopropyl-pyridin-2-one). yl * * * * (sulfonylamino) -2-morpholin-4-yl-pyrimidin-4-ylmethyl • * * * * * ester. MS: (M-H) - = 669.

***** 25 Example 43 • * • * * ί.ί ί Similarly to Example 40, a compound of Example 39 and (RS) -2,2-dimethyl-1,3-cat were obtained. • · · ί, ί! from dioxolan-4-methanol-Na 5-isopropyl-pyridine-2-sulfonic acid (RS) -5- (2-chloro-5-methoxy-phenoxy) -6- (2,2-dimethyl-30-yl) -1,3-dioxolan-3-ylmethoxymethyl) -2-morpholin-4-yl-, 3'-pyrimidin-4-ylamide. MS: (M-H) - = 663.

···. ·, Example 44 • * # * · "To a solution of 0.05 g in Example 43 was prepared.

* ... * in 2 mL of dioxane, 2 mL of IN was added

* • j *; HCl and heated for 15 minutes at 80 ° C. After evaporation, the residue was chromatographed on silica gel using 32-17896 with chloroform-methanol to give 5-isopropyl-pyridine-2-sulfonic acid (RS) -5- (2-chloro-5-). methoxy-phenoxy) -6- (2,3-dihydroxy-propoxymethyl) -2-morpholin-4-yl-pyrimidin-4-ylamide. Melting point: 116 ° C, MS: (M-H) - = 623.

Example 45 345 mg of sodium was dissolved at 80 ° C in 50 ml of absolute ethylene glycol. The mixture was allowed to cool slightly and then 1.56 g of 5-isopropyl-pyridine-2-sulfonic acid-6-chloro-5- (2-methoxy-phenoxy) -2-morpholin-4-yl-10H-pyrimidin-4- was added. ylamide. The resulting solution was stirred for 24 hours at 140 ° C, the solvent was removed under high vacuum and the residue was dissolved in 40 ml of water. After 4 hours at 5 ° C, suction was filtered, the crystals were suspended in 40 ml of water, layered with ethyl acetate, and 1N aqueous HCl was added dropwise with stirring until the pH had dropped to 3.5. The aqueous phase was extracted three times with ethyl acetate and the organic phases were washed twice with water and once with saturated NaCl solution. The combined organic phases were dried and evaporated until crystallization started (about 5 ml). It was then suction filtered, washed with ether and dried. There were obtained 1.144 g (70%) of 5-isopropyl-pyridine-1, 2, 2-sulfonic acid-6- (2-hydroxy-ethoxy) -5- (2-methoxy-phenoxy) - 1, 2, 3 Morpholin-4-yl-pyrimidin-4-ylamide as white crystals. Melting point: 157-160 ° C, MS: (M-H) - = 544.4.

Preparation of the starting compound • A solution of 1.18 g of 4,6-dichloro-5- (2H-methoxy-phenoxy) -2-morpholin-4-yl-pyrimidine and 2.12 g (8.88 mMol) of 5-isopropyl-pyridine-2-sulfonamide-potassium salt in 25 ml of dried DMDO were heated for 3 hours. at 80 ° C until the dichloride had disappeared completely ···. *. ti. The DMSO was removed under high vacuum, the residue was dissolved in 60 ml of water, and the aqueous solution was washed three times

* ··· * with diethyl ether. The pH of the solution was then adjusted to IN

35 · HCl to 3.5 and the product was extracted three times with ethyl acetate. The organic phases were washed twice with water · · · 33 · 1 7 896 and finally once with saturated brine, dried over sodium sulfate and evaporated. The crystalline residue was digested twice with absolute diethyl ether to completely remove traces of 5-iso-5-propyl-pyridine-2-sulfonamide. The remaining crystals were filtered off and dried. 1.66 g (96%) of 5-isopropyl-pyridine-2-sulfonic acid-6-chloro-5- (2-methoxy-phenoxy) -2-morpholin-4-yl-pyrimidin-4-ylamide are obtained as white crystals. having a melting point of 168-176 ° C. 10 MS: (MH) - = 518.3.

Example 46

Similarly as in Example 45, after being allowed to react for 10 hours at 120 ° C, DMSO was added as a solvent mediator (ethylene glycol: DMSO = 5: 2), 5-15 tert-butylthiophene-2-sulfonic acid-6- (2). -hydroxy-ethoxy) -5- (2-methoxy-phenoxy) -2-morpholin-4-yl-pyrimidin-4-yl-amide as a white solid foam in 54% yield.

MS: 565.5 (M + H) +.

Example 47 20 Similarly to Example 45, after 2,5 hours at 140 ° C, 2,5-, ··· dichlorothiophene-3-sulfonic acid-6- (2-hydroxy-ethoxy) -5 was obtained. - (* (2-methoxy-phenoxy) -2-morpholin-4-yl-pyrimidin-4-ylamine) as white crystals in a yield of 43%. Melting point: * ' ·: ··· 2580-1833. MS: 575.3 (MH) ”.

J · S ·! ί Example 48

I I

Similarly as in Example 45, 3,5-dimethyl-isoxazole-4-sulfonic acid-6- (2-hydroxy-1) was obtained after 3.5 hours at 140 ° C. Ethoxy) -5- (2-methoxy-phenoxy) -2-morpholin-4-yl-pyrimidin-4'-ylamide as white crystals, m.p. 144-147 ° C. MS: 520, 4 (MH) -.

EXAMPLE 49 110 mg of sodium was dissolved at 50 ° C in 2.5 ml: 35 ethylene glycol. Allowed to cool to room temperature and

»M

. ***. then 260 mg of 2,5-dichlorothiophene-3-sul-··· 117896 34 phonic acid-6-chloro-5- (2-methoxy-phenoxy) -2,2'-bipyrimidin-4-ylamide was added. After heating for 2 hours at 50 ° C, the glycol was removed under high vacuum and the solid residue was dissolved in 20 ml of water. The product was precipitated by addition of 0.3 ml of acetic acid. After filtration, washed with water and dried under high vacuum at 50 ° C, 182 mg (67%) of 2,5-dichlorothiophene-3-sulfonic acid-6- (2-hydroxy-ethoxy) -5- (2-methoxy) were obtained. -phenoxy) -2,2'-bipyrimidin-4-ylamide as light beige crystals 10 m.p. 157-160 ° C. MS: M + (569), 470 (M + - (SO 2 + Cl)).

Preparation of departure compound:

A solution of 0.349 g of 4,6-dichloro-5- (2-methoxy-phenoxy) -2,2'-bipyrimidine and 0.405 g of 2,5-dichloro-rithiophene-3-sulfonamide potassium salt in 5 ml: dried DMSO was kept for 16 hours at room temperature. Then 0.112 g of K. tert-butylate was added, after which the reaction was completed within 5 hours. The reaction mixture was poured into 40 mL of ice water and extracted with 40 mL of diethyl ether to remove excess reagent. From the aqueous phase, a solution of 2,5-dichlorothiophene-3-sulfonic acid-6-? · * Chloro-5- (2-methoxy-phenoxy) -2,2'-bipyrimidin-4-ylamide was obtained by salting with saturated brine (20 mL).

4 · I

** ·; * sodium salt by filtration and washing with ether (0.54 g • * '* * ·! · * 25 beige powder).

• «: To obtain the free sulfonamide, the Na salt was suspended. * was added to water and the suspension was acidified with acetic acid and extracted with ethyl acetate with a small amount of CH2Cl2. The organic phase was washed twice with saturated brine, dried over MgSO 4, and shaken under reduced pressure. The residue was briefly washed with diethyl ether and hexane and then dried.

* * * * · "0.30 g (54%) was obtained as a beige powder with a melting point of 140 ° C (with decomposition), MS: 444 (M- (SO 2 + Cl)).

Similarly, 3,5-dimethylisoxazole-potassium 3,5-dimethylisoxazole-4-sulfone was obtained using 3,5-dimethylisoxazole-4 · sulfonamide potassium. 7896 35 phonic acid 6-chloro-5- (2-methoxy-phenoxy) -2,2'-bipyrimidin-4-yl-amide in 71% yield as a beige, slightly reddish powder, m.p. 184-187 ° C. MS: M + = 488, 393 (M - (SO 2 + OCH 3)).

5 Example 50 ''

Similarly as in Example 49, 3,5-dimethylisoxazole-4-sulfonic acid-6- (2-hydroxy-ethoxy) -5- (2-methoxy-phenoxy) -2,2'-bipyrimidin-4-yl-amide was obtained. beige powder, m.p. was 200-204 ° C. MS: 514 (M +), 450 (M + -SO 2), 419 (450-CH 3 O).

Example 51

A solution of 888 mg of pyridine-2-carbonyl azide in 15 ml of abs. dioxane was held for 15 min. at 80 ° C. After allowing to cool slightly, 1.09 g of the compound prepared in Example 45 was added thereto and the solution was kept at 90 ° C for 4 hours. It was then evaporated to dryness, then dissolved in ethyl acetate, washed twice with water and once with brine, the organic phases were combined, dried and evaporated to give a crystalline product. For final purification, silica gel chromatography using EtOAc / CH2Cl2 (1: 1) gave 931 mg (70%) of pyrimidin-2-ylcarbamic acid 2- [6- (5-isopropyl) -pyridin-2-yl- • * * '* sulfonylamino) -5- (2-methoxy-phenoxy) -2-morpholin-4-yl- • · · -2u] ·: · * pyrimidine-4- yloxy] -et yy lie s as white crystals, j *:: having m.p. was 200-202 ° C. MS: 664.4 (M-H) -. IR (KBr): 1730 cm -1 (carbamate).

·· «· Example 52

Similarly as in Example 51, the compound prepared in Example 49 in 61% yield was 61% pyrimidine-2-ylcarbamic acid 2- [6- (2,5-dichlorothiophen-3-yl). sulfonylamino) -5- (2-methoxy-phenoxy) -2,2'-bipyrimidine-4- (trans-yloxy) -ethyl ester as white crystals, m.p. 194-197 ° C. MS: 690.1 (M + H) +. IR (KBr) 1732 cm &lt; 1 &gt;

• * · • · · «« • * • · 36 1 1 7896

Example 53

Similarly as in Example 51, the compound prepared in Example 50 in 68% yield was pyridin-2-ylcarbamic acid 2- [5- (2-methoxy-phenoxy) -6-5 (3,5-dimethyl-isoxazol-4-ylsulfonylamino). ) -2,2'-Bipyrimidin-4-yloxy] -ethyl ester as pale yellow crystals, m.p. 217-218 ° C. MS: 635.3 (M + H) - IR (KBr) 1736 cm -1 (carbamate).

Example 54 10 Similarly to Example 51, the compound prepared in Example 46 was obtained in 90% yield using pyridine-2-ylcarbamic acid 2- [6- (5-tert-butylthiophen-2-ylsulfonylamino) -5- (2-methoxy). -phenoxy) -2-morpholin-4-yl-pyrimidin-4-yloxy] -ethyl ester as a white foam. MS: 683.5 (M-H) -.

Example 55

Similarly as in Example 51, the compound prepared in Example 47 was obtained in 55% yield in pyridine-2-ylcarbamic acid 2- [6- (2,5-dichlorothiophen-3-yl-20-sulfonylamino) -5- (2-methoxy). -phenoxy) -2-morpholin-4-yl-pyrimidin-4-yloxy] -ethyl ester as white crystals, m.p. 194-196 ° C. MS: 695.3 (M-H) -.

* · ·

Example 56 • · · · **; Similarly as in Example 51, the compound of Example 48 was obtained in 70% yield with pyrid-1-yl-pyridin-2-ylcarbamic acid 2- [6- (3,5-dimethyl) isoxazole: 4-ylsulfonylamino) -5- (2-methoxy-phenoxy) -2-morpholin-4- [3,1'-1'-yl-pyrimidin-4-yloxy] -ethyl ester as white crystals, m.p. 106-109 ° C. MS: 640.4 (M-H) -.

EXAMPLE 57 5-Isopropyl-pyridine-2-sulfonic acid-6- (2-hydroxy-1,1,1-Si-ethoxy) -5- (2-methoxy-phenoxy) -2-morpholine-4 -yl-pyrimidin-1 · * · 1 · din-4-ylamide (54.5 mg) was dissolved in N, N-dimethylacetamide • (5 ml), to which 14.4 mg was added at room temperature. · '; 35% NaH suspension, was further stirred for 20 minutes. at room temperature and finally 2-chloro was added thereto.

IM

117896 37 ripyrimidine (11.7 rag). The reaction mixture was stirred for 18 hours at room temperature, poured into ice water, treated with saturated NH 4 Cl solution and extracted with ethyl acetate.

The organic phase was washed with water, dried over magnesium sulphate and finally evaporated in a rotary evaporator.

The residue was chromatographed on silica gel using methylene chloride / methanol (100/1) as eluent. There was thus obtained 5-isopropyl-pyridine-2-sulfonic acid {5- (2-methoxy-phenoxy) -2-morpholin-4-yl-6- [2- (pyrimidin-2-yloxy) -10-ethoxy] -pyrimidine- 4-yl} amide as white crystals. MS: 624 (M + H) @ +.

Example 58 a) Similarly to Example 45, 5-isopropyl-pyridine-2-sulfonic acid [6-chloro-2- (3-methoxy-benzyl) -5- (2-methoxy-phenoxy) -pyrimidine-4 was obtained. -I-yl] amide with Na in ethylene glycol 5-iso-propyl-pyridine-2-sulfonic acid [6- (2-hydroxy-ethoxy) -2- (3-methoxy-benzyl) -5- (2- methoxy-phenoxy) -pyrimidin-4-yl] -amide as a white foam. MS: 579.3 (M-H) -.

Preparation of the starting compounds: b) 10.8 g of 3-raethoxyphenylacetonitrile were dissolved in ethanol (100 ml) and the solution was saturated with hydrogen chloride.

Sat at room temperature. Subsequently, the mixture was stirred for 12 hours at room temperature, the solution was cooled to 0 ° C, and the precipitated crystals were suction filtered. The crude product was recrystallized from acetone / diethyl ether. There was thus obtained 2- (3- • ·: methoxy-phenyl) -acetimidic acid-ethyl ester hydrochloride * * • as a white crystalline solid.

MS: 193 (M) @ +.

C) 2- (3-methoxy-phenyl) -acetimidic acid ethyl ester ***. R 1 hydrochloride (12 g) was dissolved in ethanol (100 ml) and to this was added 14 ml of liquid ammonia at -75 ° C. The mixture was allowed to warm to room temperature over an hour and evaporated in a rotary evaporator. The residue was slurried in acetone. 35 so, the precipitated crystals were suction filtered and dried to a high density. keavakuumissa. There was thus obtained 2- (3-methoxy-phenyl) -acetamide- * * * * 38 1 17896 dinine hydrochloride as a white crystalline solid. MS: 164 (M) @ +.

d) Na (2.3 g) was dissolved in methanol (40 ml) and 2- (3-methoxy-phenyl) -acetamidine hydrochloride (10 g) and (2-methoxy-phenoxy) malonic acid dimethyl ester were added successively at room temperature. 12.67 g) and stirred for 5 hours at room temperature. Subsequently, it was evaporated in a rotary evaporator and the crude product was poured into water. The aqueous phase was washed with ethyl acetate, then brought to pH 1 and then the precipitated crystals were suction filtered and dried under high vacuum. This gave 2- (3-methoxy-benzyl) -5- (2-methoxy-phenoxy) -pyrimidine-4,6-diol as beige crystals, MS: 354 (M).

e) 2- (3-Methoxy-benzyl) -5- (2-methoxy-phenoxy) -15-pyrimidine-4,6-diol (14 g) was dissolved in acetonitrile (150 ml) and collidine (5.24 ml) was added at room temperature. ), phosphorus oxychloride (21.7 mL) and stirred for 9 hours at room temperature. Poured into ice water and extracted with ethyl acetate. The organic phase was washed with half saturated KHCO3 solution, dried over magnesium sulfate and evaporated. The residue was dissolved in hexane / diethyl ether, filtered and evaporated in a rotary evaporator. tiohaihduttimessa. There was thus obtained 4,6-dichloro-2- (3-methoxy-Φ · · * · *; ’benzyl) -5- (2-methoxy-phenoxy) -pyrimidine as light brown crystals. MS: 390 (M).

♦ ·: .ϊ: f) In a similar manner to Example 45, 4,6-dichloro-2- (3-methoxy-benzyl) -5- (2-methoxy-

f M

: Reaction of phenoxy) -pyrimidine with 5-isopropyl-pyridine-2-sulfonamide-potassium salt of 5-isopropyl-pyridine-2- [3 ', 4-sulfonic acid [6-chloro-2- (3-methoxy-benzyl) -5- (2-Methoxy-4,8-bis-phenoxy) -pyrimidin-4-yl] -amide as a yellow foam.

MS: 553.1 (M-H).

• * · * * · Example 59 * Φ · a) Similarly to Example 45, an-; 35 clubs 5-isopropyl-pyridine-2-sulfonic acid [6-chloro-2- ♦ · ·. * ··. (3-methoxy-benzyl) -5-phenoxy-pyrimidin-4-yl] -amide ··· 117896 with Na in ethylene glycol 5-isopropyl-pyridine-2-sulfonic acid [6- (2-hydroxy-ethoxy) - 2- (3-Methoxy-benzyl) -5-phenoxy-pyrimidin-4-yl] -amide as pale yellow crystals. MS: 549.2 (M-H) -.

Preparation of Starting Compounds: b) Similarly to Example 58d), a conc. by densifying 2- (3-methoxy-phenyl) -acetamidine hydrochloride with phenoxymalonic acid dimethyl ester 2- (3-methoxybenzyl) -5-phenoxypyrimidine-4,6-diol as a yellow foam.

MS: 324 (M).

c) Similarly as in Example 58e), 2- (3-methoxy-benzyl) -5-phenoxy-pyrimidine-4,6-diol was chlorinated with 4,6-dichloro-2- (3-methoxy-benzyl) -5- phenoxy-pyrimidine as yellow crystals.

MS: 360 (M).

d) Similarly as in Example 45) was obtained by reacting 4,6-dichloro-2- (3-methoxy-benzyl) -5-phenoxy-pyrimidine with 5-isopropyl-pyridine-2-sulfonamide-potassium salt. isopropyl-pyridine-2-sulfonic acid [6-20] chloro-2- (3-methoxy-benzyl) -5-phenoxy-pyrimidin4-yl] -amide as a yellow foam. MS: 523 (M-H) -.

··. Example 60 • · · * · · *. 5-Isopropyl-pyridine-2-sulfonic acid [6- (2-hydroxy-4 · 2,1-ethoxy) -2- (3-methoxy-benzyl) -5-phenoxy-pyrimidine-4- • · · * ··· 1 25 yl] amide (55 mg) was dissolved in dry methylene chloride: (3 ml) and boron tribromide (50 mg) was added at 0 ° C: · methylene chloride (2 ml). The mixture was then stirred for 2 hours at 2 ° C, at 0 ° C and for a further 4 hours at room temperature, evaporated in a rotary evaporator and chromatographed on the residue. 30 was carried out on silica gel using methylene chloride-ethyl ester .3. eluant. There was thus obtained 5-isopropyl-pyridine-2- • · · · sulfonic acid [2- (3-hydroxy-benzyl) -6- (2-hydroxy-ethoxy) - • · · * ”5-phenoxy-pyrimidine-4- yl] amide as white crystals.

t · · MS: 525.1 (M-H).

»1 · • · · • · · · ♦ · 2 •« 3 117896 40

Example A

Tablets containing the following ingredients may be prepared in conventional manner:

Ingredients Per Tablet 5 Compound of Formula I 10.0 - 100.0 mg lactose 125.0 mg corn starch 75.0 mg talc 4.0 mg magnesium stearate 1.0 mg

Example B

Capsules containing the following ingredients may be prepared in conventional manner:

Ingredients per Capsule

Compound of Formula I 25.0 mg 15 lactose 150.0 mg corn starch 20.0 mg 4 talc 5.0 mg magnesium stearate 1.0 mg

Example C

The composition of the injection solutions may be as follows: ... t Compound of Formula I 3.0 mg t · * Gelatins 150.0 mg • · i * · ** 'Phenol 4.7 mg • · ·' ··· * 25 Water for Injections ad 1.0 ml • i 3.5 ml myglyol 812 and 0.08 g benzyl # 4 ·,: · alcohol are suspended in 500 mg of the compound of formula I V *. This suspension is sealed in a container with a metering valve. 5.0 g of freon-12 are passed under pressure · * · .. 30 valves into the container. Freon dissolves when shaken. **. myglyol-bentsyylialkoholiseokseen. This aerosol dispenser contains approximately 100 single doses which can be dispensed in one at a time.

* · · * 4 * 4 444 4 4 · 4 4 4 444 4 4 4 444 4 4 4 4 44 *

Claims (16)

A compound of formula I R 'SOMH R <Rs 0_M R. R3 R® R7 wherein R 1 is a heterocyclyl1 which is a mono- or bicyclic heterocyclic group having oxygen, nitrogen or sulfur as a heteroatom and which is selected from the group 2-furyl, 3-furyl, pyrimidinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 1,2-diazinyl, 1,4-diazinyl, morpholino, 2-thienyl, 3-thienyl , iso-xazolyl, oxazolyl, thiazolyl, imidazolyl, pyrrolyl, benzofuranyl, benzothienyl, indolyl, purinyl, quinolyl, isoquinolyl and quinazolyl; or a heterocyclic group defined above which is mono- or di-substituted with C 1-7 alkyl, C 1-7 alkanoyl, halogen, amino, mono-C 1-7 alkylamino, di-C 1-7 alkylamino or with another hetero-cyclic group defined above; ij]; R 2 is hydrogen, C 1-7 alkyl, C 1-7 alkoxy, C 1-7 alkylthio, C 1-7 alkoxy-C 1-7 alkyl, C 1-7 alkylsulfonyl-C 1-7 alkoxy, phenyl, * * * C 1-7 alkyl phenyl, C 1-7 alkoxy phenyl, C 1-7 alkylenedioxyphenyl, phenyl C 1-7 alkyl, C 1-7 alkyl phenyl C 1-7 alkyl, C 1-7 alkoxy [Phenyl-C 1-7 alkyl, C 1-7 alkylenedioxyphenyl-C 1-7 alkyl or a heterocyclyl 2 which is a mono- or bicyclic heterocyclic group which has oxygen, nitrogen or sulfur as a hetero- * atom in the atom selected from the group 2-furyl, 3-furyl, pyrimidinyl, 2-pyridyl, 3-pyridyl, 4 -pyridyl, 1,2-diazinyl, 1,4-; diazinyl, morpholino, 2-thienyl, 3-thienyl, isoxazolyl, oxa · zolyl, thiazolyl, imidazolyl, pyrrolyl , benzofuranyl, benzothienyl, indolyl, purinyl, thiomorpholino, piperidino, pyrroleino, benzodioxolyl, quinolyl, isoquinolyl and quinazolyl, or a heterocyclic defined above group, which is mono- or di-substituted with C 1-7 alkyl, C 1-7 alkanoyl, halogen or with another heterocyclic group defined above; or heterocyclyl 2 -C 1-7 alkyl, wherein heterocyclyl 2 represents the same as above; A compound according to claim 1, wherein R 2 is hydrogen, C 1-7 alkyl, C 1-7 alkoxy, C 1-7 alkylthio, C 1-7 alkoxy-C 1-7 alkyl, C 1-7 alkylsulfonyl-C 1 -7-alkoxy, phenyl, C 1-7 alkoxy-phenyl, C 1-7. ···. alkylenedioxyphenyl or heterocyclyl; Wherein · heterocyclyl 2 represents the same as in patent *. *: claim 1; R 3 is C 1-7 alkyl, C 1-7 alkoxy, formyl, halogen C 1-7 alkyl,. Hydroxy-C 1-7 alkyl, amino-C 1-7 alkyl or the group -CH 2 O -A-C 1-7 alkyl, - (CH 2) a-O- (CR 2 R b) nOH, - (CH 2) m-O- (CRaRb) nNH2 or (CH2) m-O- (CRaRb) nB-R9 and R1, R4-R9, Ra, Rb, A, B, n and m denote the acid as claimed. 1st A compound according to claim 1 or 2, wherein R 3 is a group -O (CH 2) 2 -B-R 9 and B is - (O) C (O) NH-. 5 The compound of claim 3 which is pyridin-2-ylcarbamic acid 2- [6- (5-isopropyl-pyridin-2-ylsulfonylamino) -5- (2-methoxy-phenoxy) -2-morpholine-4 yl-pyrimidine-4-yloxy] -ethyl ester. A compound according to claim 3 which is pyridin-2-ylcarbamic acid 2- [6- (5-tert-butyl-thiophen-2-ylsulfonylamino) -5- (2-methoxy-phenoxy) -2,2'- bipyrimidin-4-yloxy] ethyl ester, pyridin-2-ylcarbamic acid 2- [5- (2-methoxy-phenoxy) -6- (5-pentyl-thiophen-2-ylsulfonylamino) -2,2'-bipyrimidine-4 -yloxy] -ethyl ester, pyridin-2-ylcarbamic acid 2- [6- [5- (2,2-dimethyl-propionyl) -thiophen-2-ylsulfonylamino] -5- (2-methoxy-phenoxy) -2, 2'-bipyrimidin-4-yloxy] ethyl ester, pyridin-2-ylcarbamic acid 2- [6- (5-isopropyl-pyridin-2-ylsulfonylamino) -5- (2-methoxy-phenoxy) -2, 2'-bipyrimidin-4-yloxy] ethyl ester, pyridin-2-ylcarbamic acid 2- [5- (2-methoxy-phenoxy) -6-, pyridin-2-ylsulfonylamino) -2,2'- bipyrimidin-4-yloxy] -ethyl-ester · pyridin-2-ylcarbamic acid 2- [5- (2-methoxy-phenoxy) -6- • :: pyridin-3-ylsulfonylamino) -2,2'-bipyrimidin-4-yloxy] -ethyl-ester: pyridin-2-ylcarbamic acid 2- [6- (5-tert. butyl-thiophen-2-ylsulfonylamino) -5- (2-chloro-5-methoxy-phenoxy) 2) pyridin-2-ylcarbamic acid 2- [6- (5-isopropyl-pyridin-2,3-ylsulfonylamino) -5- (2- methoxy-phenoxy) -2- (3-methoxy-phenyl) - * "pyrimidin-4-yloxy] ethyl ester, pyridin-2-ylcarbamic acid 2- [6- (5-isopropyl-pyridine) 2-ylsulfonylamino) -5- (2-methoxy-phenoxy) -2-methylsulfanyl-pyridine. midin-4-yloxy] ethyl ester, pyridin-2-yl-carbamic acid 2- [2- (1,3-benzodioxol-5-yl) -6- (5-isopropyl-pyridin-2-ylsulfonylamino) - 5- (2-methoxy-phenoxy) -pyrimidin-4-yloxy] -ethyl ester, pyridin-2-yl-carbamic acid 2- [5- (2-chloro-methoxy-phen-oxy) -6- (5- isopropyl-pyridin-2-ylsulfonylamino) -2-morpholin-4-ylpyrimidin-4-yloxy] ethyl ester, pyridin-2-yl-carbamic acid 2- [5- (2-methoxy-phenoxy) -6- (5- methyl-pyridin-2-ylsulfonylamino) -2,2'-bipyrimidin-4-ylo-xi] -cytyl ester, pyridin-2-yl-carbamic acid 2- [5- (2-methoxy-phenoxy) -6-amine (5-Methyl-pyridin-2-ylsulfonylamino) -2-morpholin-4-yl-pyrimidin-4-yloxy] ethyl ester, pyridin-2-yl-carbamic acid 2- [5- (2-chloro-5) -methoxy-phenoxy) - 6- (5-isopropyl-pyridin-2-sulfonylamino) -2-morpholin-4-yl-pyrimidin-4-ylmethoxy] -ethyl ester, pyridin-2-yl-carbamic acid-5- (2 -chloro-5-methoxy-phenoxy) -6- (5-isopropyl-pyridin-2-ylsulfonylamino) -2-morpholin-4-yl-pyrimidin-4-yl-methyl ester, pyridin-2-yl-carbamic acid 2- [6- (2,5-Dichlorothiophene-3-ylsulfonylamino) -5- (2-methoxy-phenoxy) -2,2'-bipyrimidine-4 yloxy] ethyl ester, pyridin-2-yl-carbamic acid 2- [5- (2-methoxy-phenoxy) -6- (*) (3,5-dimethyl-isoxatesol-4-ylsulfonylamino) -2,2'-bipyrimidine- * δ · 4-yloxy] ethyl ester, * pyridin-2-ylcarbamic acid 2- [6- (5-tert. -butylthiophene- (2-ylsulfonylamino) -5- (2-methoxy-phenoxy) -2-morpholin-4-yl-pyrimidin-4-yloxy] -ethyl ester, * · * pyridin-2 -yl-carbamic acid 2- [6- (2,5-dichloro-thiophen-3-ylsulfonylamino) -5- (2-methoxy-phenoxy) -2-morpholin-4-yl-pyridine. 30midin-4-yloxy] ethyl ester or pyridin-2-ylcarbamic acid 2- [6- (3,5-dimethyl-isoxate-2-yl-4-ylsulfonylamino) - 5- (2-Methoxy-phenoxy) -2-morpholin-4-yl-2-pyrimidin-4-yloxy] -ethyl ester. R 3 is C 1-7 alkyl, C 1-7 alkoxy, formyl, halogen C 1-7 alkyl, hydroxy C 1-7 alkyl, amino C 1-7 alkyl, or a group -CH 2 O -A-C 1-7 -alkyl, - (CH2) m-O- (CRaRb) nOH, - (CH2) m -O- (CRaRb) nOR9, - (CH2) m -O- (CRaRb) nNH2 or - (CH2) m-O - (CRaRb) nB-R9; R 4 -R 8 represents hydrogen, C 1-7 alkoxy or halogen; A compound according to claim 1 or 2, wherein R is. ] ·. And a group is -O (CH 2) 2 -B-R 9 and B is - (O) C (O) 0-. ♦ · * * · · • «« • · • · • ♦ «117896 The compound of claim 6 which is carboxylic acid furan-3-ylmethyl ester-2- [5- (2-methoxyphenoxy) -6- (5-methyl-pyridine-2-sulfonylamino) -2-morpholine-4- yl-pyrimidin-4-yloxy] ethyl ester or 5-isopropyl-pyridine-2-sulfonic acid (5- (2-methoxy-phenoxy) -2-morpholin-4-yl-6- [2- (pyrimidine 2-yloxy) ethoxy] -pyrimidin-4-yl} -amide. A compound according to claim 1 or 2, wherein R 3 is a group -O (CH 2) 2 -B-R9 and B is -NHC (O) NH-. 10 The compound of claim 8, which is 5-tert-butyl-thiophene-2-sulfonic acid 5- (2-methoxy-phenoxy) -6- [2- (3-pyridin-2-yl-ureido) -ethoxy ] -2,2'-bipyrimidin-4-yl-amide, or 5-isopropyl-pyridine-2-sulfonic acid-5- (2-methoxy-phenoxy) -15- [2- (3-pyridin-2-yl) -ureido) -ethoxy] -2,21-bipyrimidin-4-yl-amide. 'I The compound of claim 1, wherein R 3 is hydroxyethoxy. R 9 is a heterocyclyl 3 which is a mono- or bicyclic heterocyclic group having oxygen, nitrogen or sulfur as a heteroatom and selected from the group 2-furyl, 3-furyl, pyrimidinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 1,2-diazinyl, 1,4-diazinyl, morpholino, 2-thienyl, 3-thienyl, isoxazolyl, oxazolyl, thiazolyl, imidazolyl, pyrrolyl, pyrazinyl, benzofuranyl, benzothienyl, indolyl , purinyl, quinolyl, isoquinolyl and quinazolyl; or a heterocyclic group defined above which is mono- or di-substituted with C 1-7 alkyl, C 1-7 alkanoyl, halogen or with another heterocyclic group defined above; or phenyl, or phenyl, which is substituted by C 1-7 alkyl, C 1-7 alkoxy ... and / or halogen; or C 1-7 alkyl; R *** and Rb represent hydrogen or C 1-7 alkyl; A is a ketalized 1,2-dihydroxyethylene group; B is -OC (O) O-, -OC (O) NH-, -NHC (O) NH- or -NHC (O) O-: * *:.: N is 2, 3 or 4; and ::: m is 0 or 1. «M f The compound of claim 10 which is 5-tert.-butyl-thiophene-2-sulfonic acid-6- (2-hydroxy-ethoxy) -5- (2-methoxy-phenoxy) -2,2'-bipyrimidine 4-ylamide, 5-pentylthiophene-2-sulfonic acid 6- (2-hydroxyethoxy) -5- (2-methoxy-phenoxy) -2,2'- bipyrimidin-4-ylamide, 5- (2,2-dimethyl-propionyl) -thiophene-2-sulfonic acid-6- (2-, hydroxy-ethoxy) -5- (2) -methoxy-phenoxy) -2,2 '-bipyrimidin-4-ylamide, Φ *: 5-isopropyl-pyridine-2-sulfonic acid 6- (2-hydroxy-ethoxy) - · · 5- (2) -methoxy-phenoxy) -2,2'-bipyrimidin-4-ylamide,: *: pyridine-3-sulfonic acid-6- (2-hydroxy-ethoxy) -5- (2-methoxy-phenoxy) -2, 2'-bipyrimidin-4-ylamide, 5-tert.-butyl-thiophene-2-sulfonic acid-5- (2-chloro-5-methoxy-, 2-phenoxy) -6- (2-hydroxy-ethoxy) ) -pyrimidin-4-ylamide, 5-yl-tert-butyl-thiophene-2-sulfonic acid-6- (2-hydroxy-ethoxy) - * - 5- (2-methoxy-phenoxy) -pyrimidine-4 N-[5- (2-chloro-5-methoxy-phenoxy) -6- (2-hydroxy-ethoxy) -. Pyrimidin-4-yl] -5-isopropyl-pyridine-2-sulfonamide, 5 · isopropyl-N- [6- (2-hydroxyethoxy) -5- (2-methoxyphenylamino) -5 phenoxy) -2- (3-methoxy-phenyl) -pyrimidin-4-yl] -pyridine-2-sulfonamide, 5-isopropyl-N- [6- (2-hydroxy-ethoxy) - 5- (2-methoxy-phenoxy) -2-methylsulfanyl-pyrimidin-4-yl] -pyridin-2-sulfonamide, N- [2- (1,3-benzodioxol-5-yl) -6- (2- hydroxyethoxy) -5-5 (2-methoxy-phenoxy) -pyrimidin-4-yl] -5-isopropyl-pyridine-2-sulfonamide, N- [5- (2-chloro-5-methoxy-phenoxy) -6- (2-hydroxy-ethoxy) -2-morpholin-4-yl-pyrimidin-4-yl] -5-isopropyl-pyridin-2-sulfonamide, 5-methyl-pyridine-2-sulfonic acid-6- (2 -hydroxy-ethoxy) -5- (2-methoxy-phenoxy) -2,2'-bipyrimidin-4-ylamide, 5-methyl-pyridine-2-sulfonic acid-6- (2-hydroxy-ethoxy) -5- { 2-methoxy-phenoxy) -2-morpholin-4-yl-pyrimidin-4-yl-amide, 5-isopropyl-pyridine-2-sulfonic acid-6- (2-hydroxy-ethoxy)-5- (2-methoxy) -phenoxy) -2-morpholin-4-yl-pyrimidin-4-yl-amide, 5-tert.-butyl-thiophene-2-sulfonic acid-6- (2-hydroxy-ethoxy) -5- (2-methoxy) phenoxy) -2-morpholin-4-yl-pyrimidine-4- yl-amide, 2,5-dichlorothiophen-3-sulfonic acid-6- (2-hydroxy-ethoxy) -5- (2-methoxy-phenoxy) -2-morpholin-4-yl-pyrimidin-4-yl-amide, 3,5-Dimethyl-isoxatosole-4-sulfonic acid-6- (2-hydroxyethoxy) -5- (2-methoxy-phenoxy) -2-morpholin-4-yl-pyrimidin-4-yl-amide, * · · · · 2,5-dichlorothiophene-3-sulfonic acid 6- (2-hydroxy-ethoxy) - ·· ·. 5- (2-methoxy-phenoxy) -2,2 '-bipyrimidin-4-ylamide, 3,5-dimethyl-isoxatosole-4-sulfonic acid-6- (2-hydroxy-ethoxy) -5- (2-methoxy-phenoxy) -2,2 '-bipyrimidin-4-ylamide, -1 * 5 * -isopropyl-pyridine-2-sulfonic acid [6- (2-hydroxy-ethoxy) - *** 2- (3-methoxy-benzyl) -5- (2-methoxy-phenoxy) -pyrimidin-4-yl] -amide, φ · · · 5-isopropyl-pyridine-2-sulfonic acid [ 6- (2-Hydroxy-ethoxy) - ··· 2- (3-methoxy-benzyl) -5-phenoxy-pyrimidin-4-yl] -amide, or t. *. 5-isopropyl-pyridin-2 sulfonic acid [2- (3-hydroxy-benzyl) -6- (2-hydroxy-ethoxy) -5-phenoxy-pyrimidin-4-yl] -amide. A compound according to claim 1, wherein R 3 is C 1-7 alkyl, C 1-7 alkoxy, formyl, halo-C 1-7 alkyl, hydroxy-C 1-7 alkyl, -CH 2 O -A-C 1 -7-alkyl or amino-ethoxy The compound of claim 12 which is 5-isopropyl-pyridine-2-sulfonic acid 5- (2-chloro-5-methoxyphenoxy) -6-methyl-2-morpholin-4-yl-pyrimidin-4-ylamide 5- (2-Chloro-5-methoxy-phenoxy) -6-formyl-2-morpholine-4-5-yl-pyrimidin-4-ylamide, 5-isopropyl-pyridine-2-sulfonic acid 5- (2-chloro) -5-methoxy-phenoxy) -6-hydroxymethyl-2-morpholin-4-yl-pyrimidin-4-ylamide, 5-isopropyl-pyridine-2-sulfonic acid 5- (2-chloro-5-methoxy-phenoxy) 6-Chloromethyl-2-morpholin-4-yl-pyrimidin-4-ylamide, 5- (2-chloro-5-methoxy-phenoxy) -6- (2-hydroxy-ethoxymethyl) -2-morpholin-4-yl -pyrimidin-4-ylamide, 5-tert-butyl-thiophene-2-sulfonic acid 6- (2-amino-ethoxy) -5- (2-methoxy-phenoxy) -2,2'-bipyrimidin-4-ylamide. Compounds of formula Hal 'R8 R7 wherein R1, R2 and R4-R8 denote sarana as in claim 1 and Hai are halogen. ···; 15. Pharmaceutical preparations, characterized by * · ♦:, ·. that they contain a compound according to any of the claims 1 · 13 and conventional carrier and adjuvants. Use of a compound according to any of the claims 1-13 as an active substance in the manufacture of drugs used for the treatment of diseases associated with the disease. ; * ** with endothelin activating properties, especially blood circulation * ... · lational diseases, such as hypertension, ischemia, seizures *. ! in the blood vessels and angina pectoris. • ♦ a · a. • a ♦ · • · · a • * · • * * • a · 1 • · aa ··