AU691353B2 - Novel 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

S F Ref: 318676

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPEC FICATION FOR A STANDARD PATENT

ORIGINAL

Name and Address of Applicant: Actual Inventor(s): Address for Service: oeeo g e *6 *~s a c e F.Hoffmann-La Roche AG 124 Grenzacherstrasse CH-4002 Basle

SWITZERLAND

Volker Breu, Kaspar Burri, Jean-Marie Cassal, Martine Clozel, Georges Hirth, Bernd-Michael Loffler, Marcel Muller, Werner Neidhart and Heri Ramuz.

Spruson Ferguson, Patent Attorneys Level 33 St Martins Tower, 31 Market Street Sydney, New South Wales, 2000, Australia Novel Sulfonamides Invention Title: The following statement is a full description of this invention, including the best method of performing it known to me/us:a a 5845 IA The present invention is concerned with novel sulphonamides and their use as medicaments. in particular, the invention is concerned with novel compounds of the formula R'S0 2 NH R 4

R

R 2 0_O R6 R 3 R 8 R 7 wherein

R

1 signifies heterocyclyl; l0 R 2 signifies hydrogen, lower-alkyl, lower-alkoxy, lower-alkylthio, lower-alkoxy-lower-alkyl, lower-alkylsulphonyl-lower-alkoxy, phenyl, lower alkylphenyl, lower-alkoxy-phenyl, lower-alkylenedioxyphenyl, phenyl-lower alkyl, lower alkyl-phenyl-lower alkyl, lower alkoxy-phenyl-lower alkyl, lower alkylenedioxyphenyl-lower alkyl, heterocyclyl or heterocyclyl-lower alkyl;

R

3 signifies lower-alkyl, lower-alkoxy, formyl, halo-lower-alkyl, ~.hydroxy-lower-alkyl, amino-lower-alkyl or a residue -CH 2

O-A-

lower-alkyl, -(CH 2 )m-O-(CRaRb )nOH, -(CH2)m-OKCRaRb)nOR 9 2o .(CH 2 )m0O(CRaRb)nNH2 or -(CH 2 )m0O(CRaRb)n-B-R9

~:R

4

-R

8 signify hydrogen, lower-alkoxy or halogen;

R

9 signifies heterocyclyl; phenyl or phenyl substituted by loweralkyl, lower-alkoxy and/or halogen, or lower-alkyl; Ra and Rb signify hydrogen or lower-alkyl; A signifies a ketalized 1 ,2-dihydroxy-ethylene group; B signifies -NH(C(O)NH- or -NHC(O)O-: n signifies 2, 3 or 4; and m signifies 0 or 1.

The term "lower" used here denotes groups with 1-7 C atoms, preferably 1-4 C atoms. Alkyl, alkoxy and alkylthio groups as well as alkyl groups as components of alkanoyl groups can be straight-chain or branched. Methyl, ethyl, propyl, isopropyl, butyl, sec. and tert.

butyl are examples of such alkyl groups. Halogen denotes fluorine, chlorine, bromine and iodine, with chlorine being preferred. A loweralkylenedioxyphenyl residue is, for example, an ethylenedioxyphenyl residue. A ketalized 1,2-dihydroxyethylene group is, for example, the 2,2-dimethyl-1,3-dioxolan-4,5-diyl group. Examples of heterocyclyl residues are especially mono- or bicyclic which are mono- or disubstituted, e.g. by lower-alkyl, lower-alkanoyl, halogen, or by a further heterocyclic residue or unsubstituted and which have oxygen, nitrogen or sulphur as the hetero atom, such as 2- and 3-furyl, pyrimidinyl, 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 i:" quinazolyl. Examples of heterocyclyl residues R 1 are especially substituted snd unsubstituted pyridyl, pyrimidinyl, thienyl and isoxazolyl. Examples of heterocyclyl (sic) residues R 2 are especially pyrimidiyl and morpholino. Examples of heterocyclyl residues R 9 are especially pyridyl, pyrimidinyl and furyl.

Preferred compounds of formula I are those in which R 1 is a monocyclic, N- and/or 0-heterocyclic residue, especially pyridyl, 30 pyrimidinyl, isoxazolyl, furyl or thienyl which is unsubstituted or substituted by lower-alkyl, halogen, amino, mono- or di-loweralkylamino or lower-alkanoyl. Furthermore, there are preferred :..compounds of formula I in which R 2 is hydrogen, pyrimidinyl, pyridyl, morpholino, thiororpholino, piperidino, pyrrolidino, benzodioxolyl, lower-alkoxyphenyl or lower-alkylthio and those [in which] R 3 is a residue -0-(CRaRb)nOH, -O-(CRaRb)nNH 2 or a residue -O(CH2)2-B-R 9 and R 9 is a monocyclic N- and/or O-heterocyclic residue, especially pyridyl, pyrazinyl or furyl.

-1 -'II Of particular interest are compounds of formula I in which R 1 is a pyridyl residue substituted by lower-alkyl, R 2 is morpholino, R 3 is a residue -O(CH 2 )20C(O)NHR 9

R

4 is lower-alkoxy and R 5

-R

8 are hydrogen. Preferred residues R 9 are heterocyclyl residues, especially pyridyl residues such as 2-pyridyl.

The compounds of formula I given above are endothelin receptor inhibitors. They can therefore be used for the treatment of disorders which are associated with endothelin activities, especially o1 circulatory disorders such as hypertension, ischaemia, vasospasms and angina pectoris.

The compounds of formula I can be manufactured by a) reacting a compound of the formula

R'SO

2

NH

2 R 4

R

R

2 R-6 Hal

R

8

R

7 wherein R 1

R

2 and R4-R8 have the significance set forth above 20 and Hal is halogen, with a compound of the formula HO(CRaRb)nXH 25 wherein n, Ra and R b have the significance set forth above and X prpresents 0 or NH, or e -i hb) reacting a compound of the formula I~ C -4- Y R 4

R

R 2 0 R6 Is

R

3

R

8

R

7 wherein R 2

-R

8 have the significance set forth above, with a compound of the formula R1S02Z wherein R 1 has the significance set forth above and whereby Y represents halogen and Z represents amino or Y represents amino and Z represents halogen, or c) reacting a compound of the formula

R

1

SO

2 NH

R

4

R

N

R

2 R6 IV

*I

R

8 R R 7 S (CH 2 )m *a S* 5 O(CRaRb)nXH wherein R 1

R

2

R

4

-R

8 Ra, Rb, X, m and n have the significance "set forth above, cl) with an isocyanate of the formula R 9 NCO or a carbamoyl chloride of the formula R 9 NCOCI, wherein R 9 has the significance set forth above, or c2) with phosgene and thereafter with an alcohol of the formula 25 R 9 OH; or with a chloroformate of the formula R 9 OC(O)CI; or d) reacting a compound of formula I in which R 3 represents halolower-alkyl with a compound of the formula

I

HOCH2-A-lower-alkyl wherein A represents a ketalized 1,2-dihydroxy-ethylene group, and, if desired, modifying substituents present in the resulting compound of formula I and/or converting the compound of formula I obtained into a salt.

In the reaction of a compound of formula II with a compound of the formula HO(CRaRb)nXH, this is conveniently used as the alkali metal alcoholate. The corresponding glycol or the corresponding aminoalcohol, thus e.g. ethylene glycol or aminoethanol, when n 2, is preferably used as the solvent. The alkali metal alcoholate is preferably sodium alcoholate. The reaction is conveniently carried out while heating, e.g. to 40-1200C. In a preferred embodiment the compound HO(CRaRb)nXH is used as the mono-sodium salt of ethylene, propylene or butylene glycol or amino-ethanol, -propanol or -butanol.

The reaction of a compound of formula ilI with a compound of the formula R 1

SO

2Z can be carried out in a manner known per se for the manufacture of sulphonamides, e.g. in an inert organic solvent such as dimethyl sulphoxide, conveniently while heating and in a protective gas atmosphere, e.g. under argon.

The reaction in accordance with process variant cl) can be effected in a manner known per se preparation of carbamates and ureas from alcohols and, respectively, amines. Thus, a compound of formula IV can be converted into a compound of formula I in which B so is -OC(0)NH- with an isocyanate of the formula R 9 NCO in a suitable anhydrous organic solvent, e.g. a hydrocarbon such as toluene, conveniently while heating. The isocyanate can be generated in situ, e.g. from an azide of the formula RSCON3 by thermal decomposition.

Likewise, compounds of formula I with B -NHC(O)NH- can be obtained using compounds of formula IV in which B is NH.

According to process variant c2) a compound of formula IV in which B is oxygen can be reacted with phosgene and thereafter with an alcohol of the formula R9OH to [give] a compound of formula I in I which A is a residue A phosgene salt such as diphosgene

(CI-COOCCI

3 or triphosgene (CO(OCCI3)2 can be used in place of phosgene. Compounds of formula I with B -NHC(O)O- are obtained analogously starting from compounds of formula IV with B NH. The phosgene is conveniently used as a solution in an inert anhydrous organic solvent, e.g. a hydrocarbon such as toluene. The reaction with phosgene can be carried out at room temperature. The acid chloride obtained as an intermediate is reacted directly with the alcohol

R

9 0H, conveniently while heating.

The reaction in accordance with process variant d) can be carried out under the reaction conditions described for process variant a) and yields compounds of formula I in which R 3 is a residue -CH2O-A-lower-alkyl.

Substituents present in the thus-obtained compound of formula I can be modified. Thus, a methyl group R 3 can be converted into a formyl group by oxidation, the oxidation can be carried out in a manner known per se, e.g. with selenium dioxide. The formyl group in the thus-obtained compound can be reduced to the hydroxymethyl group. This reduction can be carried out in a manner known per se, e.g. by means of reducing agents such as NaBH4. The hydroxy,,iethyl group can be converted into a halomethyl group by reaction with a halogenating agent such as POCI3/PCI5. Furthermore, N-heterocyclic residues such as pyridile can be oxidized to N-oxides. All of these reactions can be carried out according to methods known per se. The compounds of formula I can be converted in a manner known per se into salts, e.g. alkali salts such as Na and K salts or alkaline earth metal salts such as Ca or Mg salts.

3o The compounds which are used at starting materials, insofar as they are not known or their preparation is described hereinafter, can be prepared in analogy to known methods or methods described in more details below.

The inhibitory activity of the compounds of formula I on endothelin receptors can be demonstrated using the test procedures described hereinafter:

I,_

I: Inhibition of endothelin binding to recombinant ETA receptors A cDNA coding for human ETA receptors of human placenta was cloned Adachi, Yang, Y. Furuichi and C. Miyamoto, BBRC 180, 1265-1272) and expressed in the baculovirus-insect cell system.

Baculovirus-infected insect cells from a 23 I fermenter are centrifuged off (3000 x g, 15 minutes, 40C) 60 hours after the infection, re-suspended in Tris buffer mM, pH 7.4, 1 mM MgCI2) and again centrifuged. After a further io re-suspension and centrifugation the cells are suspended in 800 ml of the same buffer and freeze-dried at -1200C. The cells disintegrate when the suspension in this hypotonic buffer mixture is thawed.

After a repeated freeze-drying/thawing cycle the suspension is homogenized and centrifuged (25000 x g, 15 minutes, 40C). After suspension in Tris buffer (75 mM, pH 7.4, 25 mM MgCI2, 250 mM saccharose) 1 ml aliquots (protein content about 3.5 mg/ml) are stored at -850C.

For the binding assay, the freeze-dried membrane preparations are thawed and, after centrifugation at 200C and 25000 g for minutes, re-suspended in assay buffer (50 mM Tris buffer, pH 7.4, containing 25 mM MnClz, 1 mM EDTA and 0.5% bovine serum albumin). 100 .1I of this membrane suspension containing 70 gg of protein are incubated with 50 ptl of 12 5 1-endothelin (specific 25 activity 2200 Ci/mMol) in assay buffer (25000 cpm, final concentration 20 pM) and 100 p l of assay buffer containing varying concentrations of test compound. The incubation is carried out at 200C for 2 hours or at 40C for 24 hours. The separation of free and membrane-bound radio- ligands is carried out by filtration over a 3 glass fibre filter.

The inhibitory activity of compounds of formula I determined in this test procedure is given in Table 1 as the ICso, i.e. as the concentration [nM] which is required to inhibit 50% of the specific binding of 1 2 5 1-endothelin.

Y p

_I_

Table 1 Compound of Example ICso [nM] 34 0.3 51 0.4 II. Inhibition of endothelin-induced contractions in isolated rat aorta rings Rings with a length of 5 mm were cut out from the thorax aorta of adult Wistar-Kyoto rats. The endothelium was removed by lightly rubbing the internal surface. Each ring was immersed at 370C in 10 ml of Krebs-Henseleit solution in an isolated bath while gassing with 95% Oz and 5% CO2. The isometric stretching of the rings was measured. The rings were stretched to a pre-tension of 3 g. After incubation for 10 minutes with the test compound or vehicle cumulative dosages of endothelin-1 were added. The activity of the test compound was ascertained by the observed shift to the right of the dosage-activity curve of endothelin-1 in the presence of different concentrations of antagonist. This shift to the right (or "dose ratio", DR) corresponds to the quotient from the ECso values of endothelin-1 in the presence and in the absence of antagonist, with 20 the EC 50 value denoting the endothelin concentration required for a half-maximum contraction.

The corresponding PA 2 value, which is a measure of the activity of the test compound, was calculated using a computer programme 25 according to the following equation from the "dose ratio" DR for each individual dosage-activity curve

S

pAz log(DR-1)-log(antagonist-concentration) 3o The EC50 of endothelin in the absence of test compounds is 0.3 nM.

The pA 2 values obtained with compounds of formula I are given in Table 2.

-Yb YI- -9- Table 2 Compound of Example Dose ratio (switch to the right) 34 9.7 51 9.2 On the basis of their capability of inhibiting endothelin binding, the compounds of formula I can be used as medicaments for the treatment of disorders which are associated with vasoconstriction of increasing frequencies. Examples of such disorders are high blood pressure, coronary disorders, cardiac insufficiency, renal and lo myocardial ischaemia, renal insufficiency, dialysis, cerebral ischaemia, cerebral infarct, migraine, subarachnoid haemorrhage, Raynaud syndrome and pulmonary high pressure. They can also be used in atherosclerosis, the prevention of restenosis after ballooninduced vascular dilation, inflammations, gastric and duodenal ulcers, ulcus cruris, gram-negative sepsis, shock, glomerulonephtritis, renal colic, glaucoma, asthma, in the therapy and prophylaxis of diabetic complications and complications in the administration of cyclosporin, as well cs other disorders associated with endothelin activities.

The compounds of formula I can be administered orally, rectally, parentally, e.g. intravenously, intramuscularly, subcutaneously, intrathecally or transdermally; or sublingually or as opththalmological preparations, or as an areosol. Capsules, tablets, 25 suspensions or solutions for oral administration, suppositories, injection solutions, eye drops, salves or spray solutions are examples of administration forms.

Intravenous, intramuscular or oral administration is a preferred 3o form of use. The dosages in which the compounds of formula I are administered in effective amounts depend on the nature of the specific active ingredient, the age and the requirements of the patient and the mode of administration. In general, dosages of about 0.1-100 mg/kg body weight per day come into consideration. The preparations containing the compounds of formula I can contain inert or also pharmacodynamically active additives. Tablets or granulates e.g. can contain a series of binders, fillers, carriers or diluents.

Liquid preparations can be present, for example, in the form of a sterile water-miscible solution. Capsules can contain a filler or thickener in addition to the active ingredient. Furthermore, flavourimproving additives as well as substances usually used as preserving, stabilizing, moisture-retaining and emulsifying agents as well as o1 salts for varying the osmotic pressure, buffers and other additives can also be present.

The previously mentioned carrier materials and diluents can comprise organic or inorganic substances, e.g. water, gelatine, lactose, starch, magnesium stearate, talc, gum arabic, polyalkylene glycols and the like. It is a prerequisite that all adjuvants used the manufacture of the preparations are non-toxic.

The following Examples illustrate the invention in more detail.

Example 1 1.29 g of Na were dissolved in 50 ml of ethylene glycol at 500C. Subsequently, 3.0 g of 5-tert-butyl-thiophene-2-sulphonic 25 acid 6-chloro-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin--ylamide were added portionwise at the same temperature and the mixture was heated at 10 OC for 4 1/2 hours. The clear reaction solution was poured on to ice/dilute HCI solution and the mixture was extracted 3 times with 0.2 i of ethyl acetate each time. The organic phase was 3 washed 3 times with water, dried over sodium sulphate and finally evaporated (sic) on a rotary evaporator. 5-tei t-Butyl-thiophene-2suiphonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2'bipyrimidin-4-ylamide was thus obtained as a pale yellow foam.

MS: 493 (M-S02).

Preparation of the starting compound: a) 2.0 g of 5-tert-butyl-thiophene-2-sulphonyl chloride were dissolved in 30 ml of ethanol at room temperature, treated with -11ml of 25% ammonia solution and heated at reflux for 4 1/2 hours. The mixture was concentrated on a rotary evaporator, the residue was treated with water, extracted with ethyl acetate (150 ml), dried over magnesium sulphate and again concentrated on a rotary evaporator. There was thus obtained 5-tert-butyl-2thiophene-2-sulphonamide as white crystals. MS: 219 The potassium salt was obtained therefrom with K tert,-butylate in methanol.

b) 3.49 g of 4,6-dichloro-5-(2-methoxy-phenoxy)-2,2'bipyrimidine were dissolved in 125 ml of dimethyl sulphoxide, 3.855 g of (5-tert-butyl-thiophene-2-sulphonamide) K were added at room temperature and the solution was subsequently stirred at room temperature for 20 hours. it was then treated with a further 1.285 g of (5-tert-butyl-thiophene-2-sulphonamide) K and left to react at room temperature for a further 2 hours. 200 ml of water [and] then 200 ml of ether were added to the reaction mixture while stirring vigorously, whereby a fine, white, crystalline precipitate formed and was filtered off under suction. The crystals were ao suspended in dilute, aqueous hydrochloric acid and stirred at room temperature for 1/2 hour, filtered off under suction and dried in a high vacuum. There was thus obtained 5-tert-butyl-thiophene-2sulphonic acid 6-chloro-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4ylamide as a white, crystalline solid.

25 MS: 523.4 Example 2 A solution of 3.23 g of 5-tert-butyl-thiophene-2-sulphonic acid 3 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4ylamide, 1.71 g of 2-pyridylcarboxylic acid azide and 70 mg of pdimethylaminopyridine in toluene (50 ml) was heated at 800C for 2 hours. The toluene was removed on a rotary evaporator and the residue was partitioned between methylene chloride (0.5 1) and 1N HCI solution (0.35 The organic phase was dried over magnesium sulphate, the solvent was finally removed on a rotary evaporator. The crude product was chromatographed over silica gel with methylene chloride/MeOH as the eluent. There was thus obtained pyridin- 2-ylcarbamic acid 2-[6-(5-tert-butyl-thiophen-2-ylsulphonylamino)- -12- 5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-yloxy]-ethyl ester as a pale yellow solid which was recrystallized from methylene chloride/MeOH.

MS: 678.3 Example 3 26 mg of sodium were dissolved in 2 ml of ethanolamine at 500C, treated portionwise at the same temperature with 150 mg of the compound from Example 1, paragraph and the solution was heated at 100 0 C for 4 hours. Subsequently, the mixture was poured on to ice/water, adjusted to pH 6 with 3N HCI, whereby there separated a pale yellow, crystalline solid which was filtered off under suction, washed with water and dried in a high vacuum. There was thus obtained 5-tert-butyl-thiophene-2-sulphonic acid 6-(2-aminoethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-ylamide as yellow crystals. MS: 557.4 Example 4 100 mg of 5-tert-butyl-thiophene-2-sulphonic acid 6-(2amino-ethoxy)-5-(2-me thoxy-phenoxy)-2,2'-bipyrimidin-4-ylamide were dissolved in 10 ml of toluene, treated with 53 mg of 2pyridylcarboxylic acid azide and the solution was heated at 1200C for 4 hours. The toluene was removed on a rotary evaporator and the residue was partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulphate and finally S..concentrated on a rotary evaporator. The residue was chromatographed on silica gel with methylene chloride/methanol 30 (30/1) as the eluent. There was thus obtained thiophen-2-sulphonic acid 5-(2-methoxy-phenoxy)-6-[2-(3-pyridin- 2-yl-ureido)-ethoxy]-2,2'-bipyrimidin-4-ylamide as a crystalline solid. MS: 677.4 Example 92 mg of NaH were added at room temperature to a solution of 162.5 mg of 4-amino-6-methoxy-5-(2-methoxyphenoxy)-2,2'-bipyrimidine in 10 ml of tetrahydrofuran, the solution -13was stirred at room temperature for 1 1/2 hours and subsequently 162.5 mg of 5-tert--butyl-thiophene-2-sulphonyl chloride were added at the same temperature. The mixture was stirred at room temperature for a further 2 hours, poured on to ice/water, extracted with ethyl acetate, the aqueous phase was acidified and extracted with methylene chloride. The combined, organic phases were dried over magnesium sulphate and concentrated on a rotary evaporator.

The residue was chromatographed over silica gel with methylene chloride/methanol (20/1) as the eluent. 5-tert--Butyl-N-[6o1 methoxy-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-yl]-thiophene- 2-sulphonamide was obtained as a yellow powder. MS: 463 (M-S02).

Preparation of the starting compounds: a) 2.09 g of 4,6-dichloro-5-(2-methoxy-phenoxy)-2,2'bipyrimidine (EP-A- 0 526 708) were suspended in 75 ml of methanol and 150 ml of ammonia were condensed at 750C using a feedpipe. The reaction mixture was left to come to room temperature overnight, concentrated in a water-jet vacuum and the residue was partitioned between a small amount of water and methylene chloride (500 mi). The organic phase was dried over sodium sulphate and concentrated on a rotary evaporator. The residue was triturated with ether, the resulting solid was separated and dried in a high vacuum.

The 4-amino-6-chloro-5-(2-methoxy-phenoxy)-2,2'-bipyrimidine was thus obtained as a fine, almost white powder. MS: 329 b) 6.55 g of sodium methylate were added at room temperature to a solution of 4-amino-6-chloro-5-(2-methoxy-phenoxy)-2,2'bipyrimidine in 200 ml of methanol and the solution was 30 subsequently heated at reflux for 32 hours. The methanol was removed on a rotary evaporator, the residue was taken up in methylene chloride and washed with 1N hydrochloric acid. The organic phase was dried over magnesium sulphate, the solvent was finally removed in a water-jet vacuum. The crude product was chromatographed on silica gel with methylene chloride/ methanol (10/1) as the eluent. 4-Amino-6-methoxy-5-(2-methoxy-phenoxy)- 2,2'-bipyrimidine was obtained as a lemon-yellow powder MS: 325 14- Example 6 In analogy to Example 1, from sodium glycolate and thiophene-2-sulphonic acid 6-chloro-5-(2-methoxy-phenoxy)-2,2'bipyrimidin-4-ylamide there was obtained 5-pentyl-thiophene-2sulphonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenioxy)-2,2'bipyrimidin-4-ylamide as a white solid. MS: 570.3 (M H).

Preparation of the starting compounds: a) (5 -n-Pentyl-thio phe ne-2-s ulph on amid e) K was obtained from (EP-A- 0 512 675) with ethanol/conc. HCI and salt formation with potassium tert.-butylate in methanol.

b) Analogously to Example 1, paragraph by reacting pentyl-thiophene-2-sulphonamide) K and 4,6-dichloro-5-(2-methoxyphenoxy)-2 ,2'-bipyrimidine there was obtained 2-sulphonic acid 6-chloro-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin- 2o 4-ylamide as a white solid. MS: 545 Example 7 Analogously to Example 2, from 2-pyridylcarboxylic acid azide and 5-pentyl-thiophene-2-sulphonic acid 6-(2-hydroxy-ethoxy)-5- (2-methoxy-phe noxy)-2,2'-i pyri midi n-4-yla mid e there was obtained *~:pyridin-2-ylcarbamic acid 2-r45-(2-methoxy-phenoxy)-6-(5-pentylth iophe n-2 -yls ulphonyl ami no)-2,2'-b ipyri mid in-4-yloxy] -ethyl ester as a white solid. MS: 692.4 analogy to Example 2, from sodium glycolate and 5-(2,2dimethyl-propionyl)-thiophene-2-sulphonic acid 6-chloro-5-(2methoxy-phenoxy)-2,2'-bipyrimidin-4-ylamide there was obtained (2,2-dimethyl-propionyl)-thiophene-2-sulphonic acid 6-(2-hydroxyethoxy)-5-(2-methoxy-phenoxy)-2,2 '-bipyrimidin-4-ylamide as a pink powder. MS: 586.3 Preparation of the starting compound: a) Analogously to Example 1, paragraph by reacting the potassium salt of 5-(2,2-dimetylpropanoyl)thiophene-2-sulphonamide (preparation: J Org. Chem., Vol 56, 4260 and 4,6-dichloro-5- (2-methoxy-phenoxy)-2,2'-bipyrimidine there was obtained 5-(2,2dimethyl-propionyl)-thiophene-2-sulphonic acid 6-chloro-5-(2methoxy-phenoxy)-2,2'-bipyrimidin-4-ylamide as a crystalline solid.

MS: 560.1 The potassium salt was obtained therefrom with o potassium tert.-butylate in methanol.

Example 9 Analogously to Example 2, from 2-pyridylcarboxylic acid azide and 5-(2,2-dimethyl-propionyl)-thiophene-2-sulphonic acid 6-(2hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-ylamide there was obtained the desired pyridin-2-ylcarbamic acod (2,2-dimethylpropionyl)-thiophen-2-ylsulphonylamino]-5-(2methoxy-phenoxy)-2,2'-bipyrimidin-4-yloxy]-ethyl ester as a beige 2o powder. MS: 704.3 w. 0 Example *0 we 1.75 g of Na were dissolved in 70 ml of ethylene glycol at ~25 50 0 C. Subsequently, 4.9 g of 5-isopropyl-pyridine-2-sulphonic acid 6-chloro-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-ylamide were added portionwise at the same temperature and the mixture was heated to :O00C for 4 hours. The clear reaction solution was poured into 200 ml of water, brought to pH 1 with 3N HCI, the separated 30 yellow crystals (sic) were filtered off under suction, washed with water, then with ether and finally dried in a high vacuum. There was thus obtained 5-lsopropyl-pyridine-2-sulphonic acid 6-(2-hydroxyethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-ylamide as a **jyellow, crystalline solid. MS: 537.3 Preparation of the starting compounds: a) 4.0 g of 5-isopropylpyridine-2-sulphonamide were dissolved (sic) in 40 ml of MeOH, 2.308 g of potassium tert.-butylate were

II

16added at room temperature and the solution was stirred for a further minutes. Subsequently, it was concentrated completely on a rotary evaporator and the thus-obtained potassium salt was dried in a high vacuum.

b) 3.49 g of 4,6-dichloro-5-(2-methoxy-phenoxy)-2,2'bipyrimidine were dissolved in 125 ml of dimethyl sulphoxide, 4.7 g of (5-isopropyl-pyridine-2-sulphonamide) K were added at room temperature and the solution was subsequently stirred at room lo temperature for 20 hours. It was poured into 350 ml of water and ml of ether while stirring vigorously, the solution was brought to pH 1 by the addition of 3N HCI. The white, crystalline precipitate was filtered off under suction and washed with water, then ether.

The crystals were suspended in dilute, aqueous hydrochloric acid (100 ml of water and 50 ml (sic) of 1N HCI) and stirred for minutes, filtered off under suction and again washed with water and dried in a high vacuum. There was thus obtained pyridine-2-sulphonic acid 6-chloro-5-(2-methoxy-phenoxy)-2,2'bipyrimidin-4-ylamide as a white, crystalline solid.

2o MS: 511.3 p Example 11 o* S 2.0 g of 5-isopropyl-pyridine-2-sulphonic acid 6-(2-hydroxy- 25 ethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-ylamide were dissolved in 80 ml of toluene, treated with 1.1 g of 2pyridylcarboxylic acid azide and the solution was subsequently heated at 900C for 4 hours. It was concentrated on a rotary evaporator and the residue was partitioned between 1N HCI and ethyl 3o acetate. The organic phase was dried over magnesium sulphate, the :solvent was removed in a water-jet vacuum and the residue was chromatographed on silica gel with methylene chloride/methanol (30/1) as the eluent. There was thus obtained pyridin-2-ylcarbamic acid 2-[6-(5-isopropyl-pyridin-2-ylsulphonylamino)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yloxy]-ethyl ester as yellow crystals.

MS: 657.3 For the preparation of the dihydrochloride, the compound was dissolved in methylene chloride and treated with the corresponding -e 17amount of 4.4N HCI in ethanol at room temperature. The solution was concentrated on a rotary evaporator, the separated, crystalline solid was isolated and dried in a high vacuum at 600C for 4 hours (sic).

Example 12 In analogy to Example 4, from 5-isopropyl-pyridine-2-sulphonic acid 6-(2-amino-ethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin- 4-ylamide and 2-pyridylcarboxylic acid azide there was obtained the to desired 5-isopropyl-pyridine-2-sulphonic acid 5-(2-methoxyphenoxy)-6-[2-(3-pyridin-2-yl-ureido)-ethoxy]-2,2'-bipyrimidin-4ylamide as yellow crystals. MS: 656.3 The starting compound was obtained analogously to Example 3 from ethanolamine and the compound from Example 10, paragraph b), as a yellow foam. MS: 538.3 Example 13 In analogy to Example 10, from pyridine-2-sulphonic acid 6chloro-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-ylamide and ethylene glycol there was pyridine-2-sulphonic acid 6-(2-hydroxyethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-ylamide as white crystals. MS: 615.4 Preparation of the starting compounds: a) 1.7 g of 2-pyridylsulphonyl chloride (J Org. Chem., Vol. 54, 389) were dissolved in 30 ml of ethanol, 30 ml of 25% ammonia solution 30 were added while cooling with ice and the mixture was subsequently heated at reflux for 4 hours. The reaction solution was concentrated on a rotary evaporator, the residue was partitioned between ethyl acetate and water, the organic phase was dried over magnesium sulphate and finally concentrated on a rotary evaporator, the 2pyridylsulphonamide separating as a beige, crystalline solid. MS: 469.2 The K salt was obtained therefrom with K tert.-butylate in methanol.

18 b) Analogously to Example 1 0, paragraph by reacting (2pyridylsulphonamide)-K and 4,6-dichloro-5-(2-methoxy-phenoxy)- 2,2'-bipyrimidine there was obtained pyridine-2-sulphonic acid 6chloro-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-yl2mide as white crystals. MS: 495.3 Example 14 In analogy to Example 11, from pyridine-2-s ul phonic acid 6-(2hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2, 2'-bipyrimidine-4ylamide and 2-pyridylcarboxylic acid azide there was obtained pyridin-2-ylcarbamic acid 2-I[5-(2-methoxy-phenoxy)-6-pyridin-2yls ulphonyla min o)-2,2 ipyri mid in-4-y loxy] -ethyl ester as white crystals. MS: 61 5.4 (M-H) Example 1 In analogy to Example 1 0, from pyridine-3-sulphonic acid 6chlom--5-(2-methoxy-phenoxy)-2 ,2 '-bipyrimidin-4-ylamide and 2c ethylene glycol there was obtained py'ridine-3-sulphonic acid 6-(2h y dro xy- e th oxy)- 5 -(2-mnne t hoxy- p he n oxy) b ipy r im id in -4-yIa m id e as white crystals. MS: 496 Preparation of the starting compounds: a) In analogy to Example 1 3, paragraph from 3-pyridylsulphonyl ~:chloride J Org. Chem., Vol. 54, 389) and ammonia there was obtained 2-pyridylsulphonamide as a white, crystalline solid, the potassium salt being obtained therefrom with potassium tert.-butylate in 3o methanol.

b) Analogously to Example 1 0, paragraph by reacting (3pyridylsulphonamide)-K and 4,6-dichloro-5-(2-methoxy-phenoxy)- 2,2-'-bipyrimidine there was obtained the desired pyridine-3as sulphonic acid 6-chloro-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4ylamide as white crystals. MS: 470 -19- Example 16 In analogy to Example 11, from pyridine-3-sulphonic acid 6-(2hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-ylamide and 2-pyridylcarboxylic acid azide there was obtained pyridin-2ylcarbamic acid 2-[5-(2-methoxy-phenoxy)-6-pyridin-3ylsulphonylamino)-2,2'-bipyrimidin-4-yloxy]-ethyl ester as white crystals. MS: 615.4(M-H).

Example 17 213 mg of 6-[2-(tert-butyl-dimethyl-silanoxy)-ethoxy]-5-(2chloro-5-methoxy-phenox.,)-pyrimidin-4-ylamine were dissolved in ml of tetrahydrofuran, treated at room temperature with 92 mg of NaH stirred at room temperature for 2 hours and then 155 mg of 5-tert-butyl-thiophene-2-sulphonyl chloride were added portionwise. The solution was stirred at room temperature for a further 2 hours, poured into ice-water and extracted twice with a total of 200 mi of ethyl acetate. After usual working-up of the 2o organic phase the silyl-protected crude product was chromatographed on silica gel with methylene chloride/ethyl acetate as the eluent.

The brownish foam obtained (219 mg) was dissolved in 15 ml 25 of acetonitrile, treated at room temperature with 1.5 ml of HF solution and stirred for 2 hours. The reaction mixture was partitioned between ethyl acetate and semi-saturated NaCI solution and the organic phase was worked-up as usual. The crude product was chromatographed on silica gel with methylene chloride/ethyl 3o acetate as the eluent and recrystallized from ether/hexane.

There was thus obtained 5-tert-butyl-thiophene-2-sulphonic acid (2-chloro-5--methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-pyrimidin-4ylamide as white crystals. MS: 449 (M-S02) Preparation of the starting compound a) 3-Methoxyphenol was converted with sulphuryl chloride into 2according to the procedure of M. Julia and I.

de Rosnay, Chimie Th6rapeutique 5 (1969), 334.

b) 18.2 g of 2-chloro-5-methoxyphenol werie dissolved in 150 ml of dry methanol. 9.3 g of MeONa were added, followed by 25 g of dimethyl chloromalonate. The reaction mixture was stirred at 500C for 2 hours. After distillation of the solvent the residue was partitioned between toluene and H20 in a separating funnel and washed neutral. After crystallization in ethanol there was obtained white crystals with m.p. 68-690C.

c) 1.43 g of Na were dissolved in 70 ml of MeOH. Then, 5.8 g of and 2.29 g of formamidine acetate were added; the reaction mixture was stirred under reflux for 1.5 hours. Then, the solvent was distilled off, the residue was taken up in H20, the aqueous phase was extracted with ethyl acetate, the organic phase was discarded and the aqueous phase was acidified to pH 4 with acetic acid, the 5-(2-chloro-5methoxy)phenoxy-4,6(1H,5H)-pyrimidinedione separating as a white powder. MS: m/e 268 d) A mixture of 3.75 g of 5-(2-chloro-5-methoxy)phenoxy- 4,6(1 H,5H)-pyrimidinedione, 5.4 g of N-ethyldiisopropylamine, 12.5 ml of POCI3 in 20 ml of dioxan was stirred under reflux for 18 hours. After distillation of the volatile components the residue was partitioned between ethyl acetate and H20 and washed neutral.

After distillation of the solvent the compound was purified on silica gel with CH2CI2 as the eluent. 4,6-Dichloro-5-(2-chloro-5-methoxyphenoxy)-pyrimidine was obtained as white crystals with m.p. 88- 890C after crystallization from EtOH.

9 e) About 500 ml of NH3 were conducted at -780C into a solution of 9.9 g of 4,6-dich!oro-5-(2-chloro-5-methoxy-phenoxy)-pyrimidine from Example le) in 400 ml of ethanol. Thereafter, the reaction mixture was stirred at -780C for 15 hours and at room temperature for 50 hours and finally evaporated. The residue was partitioned between ethyl acetate and water and the organic phase was workedup. 8.53 g of 6-chloro-5-(2-chloro-5-methoxy-phenoxy)-pyrimidin- 4-ylamine were thus obtained as yellow crystals. MS: 285 -21f) 8.53 of the previously obtained compound were added to a solution of 0.82 g of sodium in 100 ml of ethylene glycol at 50 0

C.

The solution was heated to 100OC for 20 hours, thereafter partitioned between semi-saturated NH4CI solution and CH2Cl2 and worked-up. There were obtained 8.3 g of 2-[6-amino-5-(2-chloro-5methoxy-phenoxy) 4-pyrimidin-4-yloxy]-1-ethanol as a white solid, which was silylated without further purification. For this purpose, the above material (8.3 g) was dissolved in 300 ml of methylene chloride, treated with 8.15 g of dimethylaminopyridine and finally at to room temperature with 10.05 g of t-butyldimethylchlorosilane. The reaction solution was stirred at room temperature for 5 hours. Then, it was filtered, the solution was concentrated, the evaporation residue was partitioned between semi-saturated NH4CI solution and ethyl acetate and the organic phase was worked-up. Subsequent crystallization from methylene chloride/hexane yielded 7 g of 6-[2- (tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-(2-chloro-5-methoxyphenoxy)-pyrimidin-4-ylamine. MS: 410 (M-CH3).

Example 18 In analogy to Example 2, from 5-tert-butyl-thiophene-2sulphonic acid 5-(2-chloro-5--methoxy-phenoxy)-6-(2-hydroxyethoxy)-pyrimidin-4-ylamide and 2-pyridylcarboxylic acid azide there was obtained pyridine-2-ylcarbamic acid 2-[6-(5-tert-butylthiophen-2-ylsulphonylamino)-5-(2-chloro-5-methoxy-phenoxy)pyrimidin-4-yloxy]-ethyl ester as white crystals. MS: 634.3 a.

Example 19 30 In analogy to Example 2, from the compound of Example 17 and 4-pyridylcarboxylic acid azide there wa; obtained pyridin-4ylcarbamic acid 2-[6-(5-tert-butyl-thiophen-2-ylsulphonylamino)-5- (2-chloro-5-methoxy-phenoxy)-pyrimidin-4-yloxy]-ethyl ester as white crystals. MS: 634.3 Example In analogy to Example 17, using 6-[2-(tert-butyl-dimethylsilanoxy)-ethoxy]-5-(2-methoxy-phenoxy)-pyrimidin-4-ylamine as -22the reaction component, there was obtained 2-sulphonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)pyrimidin-4-ylamide as a white solid. MS: 479 Example 21 180 mg of the compound from the foregoing step were added to a Na glycolate solution from 1.5 ml of ethylene glycol and 46 mg of Na. 1 ml of DMSO was added in order to complete the diss~oution.

The mixture was left to react at 900C for 3 hours. After cooling to room temperature the reaction medium was acidified to pH 4 with aqueous citric acid and the compound formed was subsequently extracted with ethyl acetate. After distillation of the ethyl acetate the N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)pyrimidin-4-yl]-5-isopropyl-pyridine-2-sulphonamide was crystallized from ethanol. There were obtained 175 mg of white crystals which decomposed at 180 0

C.

Preparation of the starting compound 306 mg of 4,6-dichloro-5-(2-chloro-5-methoxy-phenoxy)pyrimidine, 320 mg of 5-isopropyl-2-pyridine-sulphonamide and 180 mg of K tert.butylate dissolved in 2 ml of DMSO were reacted at 900C for 3 hours. After cooling to room temperature the reaction medium was acidified with aqueous citric acid; the compound was extracted with ethyl acetate and, after distillation of the solvent, crystallized from ethanol. 250 mg of N-[6-chloro-5-(2-chloro-5-methoxyihenoxy)-pyrimidin-4-yl]-5-isopropyl-pyridine-sulphonamide were obtained as white crystals with m.p. 174-1750C.

Example 22 100 mg of N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxyethoxy)-pyrimidin-4-yl]-5-isopropyl-pyridine-2-sulphonamide and 38.5 mg of 2-pyridyl-carboxylic acid azide were dissolved in 1 ml of dry dioxan. The solution was stirred at 950C for 2 hours, whereby N2 was liberated. After distillation of the solvent the compound was crystallized from ethanol. 115 mg of pyridin-2-yl-carbamic acid 2- [5-(2-chloro-5-methoxy-phenoxy)-6-(5-isopropyl-pyridin-2- I 23 ylsulphonylamino)-pyrimidin-4-yloxy]-ethyl ester were obtained as white crystals with m.p. 190-1910C.

ExampL 23 5-Isopropyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)- 2-(3 -methoxy-phenyl)-pyrimidin-4-yl] .pyridine-2-sulphonamide.

m.p. 1 39-1 400C (from ethanol), was obtained in analogy to Example 21.

Preparation of the starting compound 400 mg of N-[6-chloro-5-(2-methoxy-phenoxy)-2-(3-methoxyphenyl)-pyrimidin-4-yl]-5-isopropyl-pyridine-2-sulphonamide were obtained from 330 mg of 4,6-dichloro-2-(3-methoxy-phenyl)-5-(2methoxy-phenoxy)-pyrimidine and 420 mg of 2-sulphonamide) K in analogy to Examnple 21, second paragraph.

Example 24 In analogy to Example 22, from 11 5 mg of 5-isopropyl-N-[6-(2h hyd roxy-e t hoxy) 5-(2 -meth oxy- ph e noxy) 2 3-me thoxy-p h eny1)- **pyri mid in-4-yl] pyridi ne-2 -sul phon amide and 38.5 mg of 2-pyridylcarboxylic acid azide there were obtained 1 20 mg of pyridin-2-ylcarbamic acid 2-[6-(5-isopropyl-pyridin-2-ylsulphonylamino)-5-(2methoxy-phenoxy)-2-( 3-m-rethoxy-phe nyl)-pyrimidin-4-yloxy] -ethyl ester. M.p. 1 58-1 60 0 C (from ethanol).

Example a) N 6-C h Ioro- 5 -meth oxy- ph e noxy) -2 -me thy Isu Ip h any Ipyrirnid in-4-yl] -5 -iso pro pyl-pyrid ine-2-s ul phon amid e was obtained o from 4,6-dichloro-2-methylsulphanyl-5-(2-mr-thoxy-phenoxy)pyrimidine and (5-isopropyl-pyridine-2-suiphonamide) K in analogy to Example 21. M.p. 1 920C (from ethan'ol).

b) The compound was converted with Na glycolate into isopropyl-N-[6-(2-hydroxy-ethoxy)- 5-(2-metlhoxy-phenoxy)-2- -24methylsulIph anyl-pyrimid in-4-yl]-pyrid ine-2 -s ulph ona mide. M. P. 76- 780C (from EtOH).

Example 26 1 06 mg of pyridin-2-ylcarbamic acid 2-[6-(5-isopropylpyridin-2-ylsulphonylamino)-5-(2-methoxy-phenoxy)-2-methylsulphanyl-pyrimidin-4-yloxy]-ethyl ester were obtained from 1 00 mg of 5-isopropyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2methylsulphanyl-pyrimidin-4-yl]-pyridine-2-sulphonamide and 2pyridyl-carboxylic acid azide, in analogy to Example 22. M.p. 213- 21 4rc2 (from ethanol).

Example 27 a) N-[6-Chloro-2-(1 ,3-benzodioxol-5-yl)-5-(2-methoxy-phenoxy)pyrimidin-4-yl]-5-isopropyl-pyridine-2-sulphonamide was obtained from 4,6-dichloro-2-(1 ,3-benzodioxol-5-yl)-5-(2-methoxyphenoxy)-pyrimidine and (5-isopropyl-pyridine-2-sulphonamide) K.

b) This compound was converted with Na glycolate into ,3- -yl)-6-(2-hydroxy-ethoxy)-5 -(2-me-thoxy-phenoxy)- *~tpyrimidin-4-yl]-5-isopropyl-pyridine-2-sulphona-fiide. M.p. 1 840C (from EtOH).

C C 11 0 mg of pyridin-2-ylcarbamic acid yI)-6-(5-isopropyl-pyridin-2-ylsulphonylamino)-5-(2-methoxyp henoxy) -pyrimid in-4-yloxy] -ethyl ester were obtained from 11 6 mg of ,3-benzodiox<ol-5-yI)-6-(2-hydroxy-ethoxy)-5-(2methoxy-phenoxy)-pyrimidin-4-yI]-5-isopropyl-pyridine-2- .:*sulphonamide and 2-pyridyl-carboxylic acid in analogy to Exampie 22.

M.p. 1840C (from ethanol).

Example 2 9 a) N-[6-Chloro-5-(2-chloro-5-methoxy-phenoxy)-2-morpholin-4yl-pyrimidin-4-yl]-5-isopropyl-pyridin-2-sulphonamide was obtained from 4.6-dichloro-2-morpholin-4-yl-pyrimidine and isopropyl-pyridine-2-sulphonamide) K.

b) Reaction of this compound with Na glycolate yielded chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-2-morpholin-4yl-pyrimidin-4-yl]-5-isopropyl-pyridine-2-sulphonamide. M.p. 1 89- 19000 (from EtOH).

Example 11 6 mg of N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxyethoxy) -2 -mo rpho li n-4-yl-pyri mid in-4-yl]- 5-iso pro py I-pyrid ine-2 sulphonamide were converted with 2-pyridyl-carboxylic acid azide into pyridin-2-ylcarbamic acid 2-[5-(2-chloro-5-methoxy-phenoxy)- 6-(5-isopropyl-pyridin-2-ylsulphonylamino)-2-morpholin-4ylpyrimidin-4-yloxy] -ethyl ester in analogy to Example 22. From ethanol there were obtained 1 06 mg of white crystals which decomposed at 2400C.

Example 31 5-Methyl-pyridine-2-sulphonic acid 6-(2-hydroxy-ethoxy)-5- (2-methoxy-phenoxy)-2,2'-bipyrimidin-4-ylamide, m.p. 1 900C (from ethanol), was obtained from 5-methyl-pyridine-2-sulphonic acid [6- 25chloro-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-yl]-amide and Na glycolate in analogy to Example 21.

Preparation of the starting compound a) 2-Amino-5-methylpyridine wad diazotized and converted into 0 6: 2-bromo-5-methylpyridine according to the procedure of F.H. Case (JACS.68 (1 946), 2574).

b) 4.8 g of this compound in 40 ml of propylene glycol were reacted with 7.4 g of sodium hydrogen sulphide at 1 500C. After cooling to room temperature 5 ml of acetic acid were added dropwise to the reaction mixture, the formed separating as a yellow powder.

-26c) 50 ml of a 1.2 molar sodium hypochlorite solution were added dropwise within 30 minutes to a two-phase mixture of 40 ml of CH2C12, 20 ml of 37% aqueous HCI and 3 g of methylpyridine cooled to -1 00C. Subsequently, the organic phase was extracted three times with H20. The 5-methylpyridine sulphochloride was obtained as a yellowish liquid after distillation of the solvent.

d) Reaction of the sulphochloride with 25% MH 4 0H solution gave methylpyridine-2-sulphonamide.

e) 0.7 g of 4,6-dichloro-5-(2-methoxy-phenoxy)-2,2'bipyrimidine, 520 mg of 5-methylpyridine-2-sulphonamide and 320 mg of K tert. butylate dissolved in 2 ml of DMSO were stirred at 80 0

C

for 3 hours. After usual working-up of the reaction mixture 410 mg of 5-methyl-pyridine-2-sulphonic acid [6-chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl]-amide were obtained.

Example 32 In analogy to Example 22, from 105 mg of 5-methyl-pyridine-2sulphonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2'bipyridmin-4-ylamide and 30 mg of 2-pyridyl-carboxylic acid azide there were obained 100 mg of pyridin-2-ylcarbamic acid methoxy-phenoxy)-6-(5-methyl-pyridin-2-ylsulphonylamino)-2,2'- 25 bipyridimin-4-yloxy]-ethyl ester as beige crystals. M.p: decomposition at 1980C.

Example 33 o30 a) In analogy to Example 22, from 712 mg of 4,6-dichloro-5-(2minethoxy-phenoxy)-2-morpholin-4-yl-pyrimidine and pyridine-2-sulphonamide) K there were obtained 580 mg of Cmethyl-pyridine-2-sulphonic acid 6-chloro-5-(2-methoxy-phenoxy)m2-morpholin-4-yl-pyrimidin-4-ylamide.

b) Reaction of this compound with Na glycolate gave pyridine-2-sulphonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxyphenoxy)-2-morpholin-4-yl-pyrimidin-4-ylamide. M.p. 195-1960C (from ethanol).

-I I -27- Example 4 117 mg of pyridin-2-yl-carbamic acid 2-[5-(2-methoxyphenoxy)-6-(5-methyl-pyridin-2-ylsulphonylamino)-2-morpholin-4yl-pyrimidin-4-yloxy]-ethyl ester were obtained from 105 mg of methyl-pyridine-2-sulphonic acid 6-(2-hydroxy-ethoxy)-5-(2methoxy-phenoxy)-2-morpholin-4-ypyrimidin-4-ylamide and 2pyridyl-carboxylic acid azide in analogy to Example 22. M.p: io decomposition at 1750C.

Example 105 mg of 5-methyl-pyridine-2-sulphonic acid 6-(2-hydroxyethoxy)-5-(2-methoxy-phenoxy)-2-morpholin-4-y-pyrimidin-4ylamide in 2 ml of dichloromethane was treated with 3 ml of a 1.9 molar phosgene solution in toluene. After 1 hour at room temperature the chloroformate had formed completely. Then, the excess reagent was distilled off; the residue was taken up in a mixture of chloroform and pyridine; 0.5 g of 3-(hydroxymethyl)-furan was added and the mixture was left to react at 600C for 3 hours.

After the usual working-up the compound was purified on silica gel (dichloromethane-diethyl ether 4:1 by vol. as the eluent). 65 mg of carboxylic acid furan-3-ylmethyl ester 2-[5-(2-methoxy-phenoxy)- 6-(5-mnethyl-pyridin-2-sulphonyamino)-2-morpholin-4-ylpyrimidin-4-yloxy]-ethyl ester, MS: 640.5 were obtained.

Example 36 30 9.2 g of 4-[4-chloro-5-(2-chloro-5-methoxy-phenoxy)-6methyl-pyrimidin-2-yl]-morpholine and 17.8 g of pyridine-2-sulphonamide potassium in 130 ml of dry dimethyl sulphoxide were heated to 1200C under argon for 16 hours.

*i Thereafter, the dimethyl sulphoxide was distilled off, the residue was partitioned between ethyl acetate and 1N hydrochloric acid and the organic phase was washed neutral. The organic phase was dried, the solvent was evaporated and the residue was recrystallized from ethanol. 10.3 g of 5-isopropyl-pyridine-2-sulphonic acid 5-(2- I- -28chloro- 5-methoxy-phenoxy)-6-methyl-2-mo rpholin-4-yl-pyrimidin- 4-ylamide, MS: M 534, were obtained.

Example 37 1 g of the compound obtained in Example 36 and 2.1 g of selenium dioxide in 40 ml of dioxan were stirred in an autoclave at 1700C for 7 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was partitioned between ethyl io acetate and water. The organic phase was dried, the solvent was evaporated and the residue was purified over silica gel with ethyl acetate/hexane. 0.53 g of 5-isopropyl-pyridine-2-sulphonic acid (2-chloro-5-methoxy-phenoxy)-6-formyl-2-morpholin-4-ylpyrimidin-4-ylamide, m.p. 1940C, was obtained.

Example 38 0.1 g of the compound obtained in Example 37 in 3 mi of ethanol was treated with 0.014 g of sodium borohydride. The reaction 2o mixture was stirred at 80 0 C for 1 hour. Thereafter, the ethanol was distilled off and the residue was partitioned between chloroform and 1N HCI. The organic phase was washed with water and dried, the solvent was evaporated and the residue was chromatographed over silica gel with chloroform-methanol. After recrystallization from dichloromethane-ethanol there was obtained 0.072 g of pyridine-2-sulphonic acid 5-(2-chloro-5-methoxy-phenoxy)-6hydroxymethyl-2-morpholin-4-yl-pyrimidin-4-ylamide. M.p. 1050C.

Example 39 0# 00: 0.2 g of the compound obtained in Example 38 in 3.5 ml of POCI3 was stirred with 0.083 g of PCIS at 200C for 2 hours.

Thereafter, the POCI 3 was distilled off and the residue was partitioned between ethyl acetate and aqueous sodium bicarbonate (sic). The organic phase was washed with water, dried and the solvent was evaporated. The residue was chromatographed over silica gel with chloroform-methanol, thereafter recrystallized from dichloromethane-ethanol. 0.150 g of 5-isopropyl-pyridine-2s I s I 1 -r -29 suiphonic acid 5-(2-chloro-5-methoxy-phenoxy)-6-chororriethylk2morpholin-4-yl-pyrimidin-4-ylamide, m. p. 2050C, was obtained.

Example 0.130 g of the compound obtained in Example 39 was added to a sodium glycolate solution from 0.35 g of ethylene glycol and 0.021 g of sodium. The reaction mixture was stirred at 800C under argon for 2 hours. Thereafter, the ethylene glycol was distilled off and the lo residue was partitioned between ethyl acetate and 1 N hydrochloric acid. The organic phase was washed with water, dried over sodium sulphate and the solvent was distilled off. The residue was recrystallized in ether-petroleum ether. 0.104 g of 5-(2-chloro-5mehx-hnx)6(-yrx-toyehl--opoi--l pyrimidin-4-ylamide, m.p. 1 660C, was obtained.

Example 41 Pyridin-2-~ylcarbamic acid 2-[5-(2-chloro-5-methoxy- 2o phnx)6(-spoy-yiie2slhnlmn)2mrhln .4-yi-pyrimid in-4-yl-methoxy] -e thylI ester, MS: 71 3, was obtained in analogy to Example 2 from the compound obtained in Example 25* Example 42 Pyridin-2-ylcarbamic acid 5-(2-chloro-5-methoxy-phenoxy)-6- 5 s op ropy I -pyrid in -2 -y Is u Iph o ny Ia m ino) -2 m or pho Ii n 4 -y I pyrimidin-4-ylmethyl ester, MS: 669 was obtained in 3o analogy to Example 2 from the compound obtained in Example 38.

Example 43 5-lsopropyl-pyridine-2-sulphonic acid (RS)-5-(2-chloro-5methoxy-phenoxy)-6-(2,2-dimethyl-1 ,3-dioxolan-3-ylmethoxymethyl)-2-morpholin-4-yl-pyrimidin-4-ylamide, MS: 663, was obtained in analogy to Example 40 from the compound obtained in Example 39 and (RS)-2,2-dimethyl-1 ,3-dioxolan-4-methanoI Na.

Example 44 A solution of 0.05 g of the compound prepared in Example 43 in 2 ml of dioxan was treated with 2 ml of 1N HCI and heated to 800C for 1 5 minutes. After evaporation the residue was chromatographed over silica gel with chloroform-methanol and yielded pyridine-2-sulphonic acid (RS)-5-(2-chloro-5-methoxy-phenoxy)-6- (2,3-dihydroxy-propoxymethyl)-2-morpholin-4-yl-pyrimidin-4ylamide. M.p. 11 60C, MS: 623.

Example 345 mg of sodium were dissolved in 50 ml of abs. ethylene glycol at 800C. The solution was left to cool somewhat and 1.56 g of 5-isopropyl-pyridine-2-sulphonic acid 6-chloro-5-(2-methoxyphenoxy)-2-morpholin-4-yl-pyrimidin-4-ylamide were added. The resulting solution was stirred at 140 0 C for 24 hours, the solvent was removed in a high vacuum and the residue was dissolved in ml of water. After 4 hours at 50C the mixture was suction 2o filtered, the crystals were suspended in 40 ml of water, covered with ethyl acetate and treated dropwise while stirring with 1N aqueous HCI until the pH had fallen 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 NaCI solution. The combined organic phases were dried and concentrated until crystallization occurred (about 5 ml). The crystals were filtered off under suction, washed with ether and dried. There were obtained 1 144 g of white crystals of 5-isopropyl-pyridine-2-sulphonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-morpholin-4- 30 yl-pyrimidin-4-ylamide, m.p. 157-1600C, MS: 544.4.

Preparation of the starting compound A solution of 1.18 g of 4,6-dichloro-5-(2-methoxy-phenoxy)-2morpholin-4-yl-pyrimidine and 2.12 g (8.88 mmol) of pyridine-2-sulphonamide potassium salt in 25 ml of dry DMSO was heated to 800C for 3 hours until the dichloride had disappeared completely. The DMSO was removed in a high vacuum, the residue was taken up with 60 ml of water and the aqueous solution was washed I_ -31three times with diethyl ether. The solution was then acidified to pH with 1N HCI and the product was extracted three times with ethyl acetate. The organic phases were washed twice with water and finally once with saturated sodium chloride solution, combined, dried with sodium sulphate and evaporated. The crystalline residue was digested twice with absolute diethyl ether in order to completely remove a trace of 5-isopropyl-pyridine-2-sulphonamide. The crystals remaining behind were filtered off and dried. There were obtained 1.66 g of 5-isopropyl-pyridine-2-sulphonic acid lo 6-chloro-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4ylamide as white crystals of m.p. 168-1760C, MS: 518.3.

Example 46 5-tert.Butylthiophene-2-sulphonic acid 6-(2-hydroxy-ethoxy)- 5-(2-methoxy-phenoxy-2-morpholin-4-yl-pyrimidin-4-ylamide was obtained as a white solid foam in 54% yield, MS: 565.5 in analogy to Example 45 after a reaction period of 10 hours at 1200C with the addition of DMSO as the solubilizer (ethylene glycol:DMSO 5:2).

Example 47 2,5-Dichlorothiophene-3-sulphonic acid 6-(2-hydroxy-ethoxy)- 5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-ylamide was obtained as white crystals in 43% yield in analogy to Example after a reaction period of 3 hours at 1400C. MS: 575.3 30 Example 48 3,5-Dimethylisoxazole-4-sulphonic acid 6-(2-hydroxy-ethoxy)- 5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-ylamide, 0:.6:I white crystals of m.p. 144-1470C, MS: 520.4 was obtained in analogy to Example 45 after a reaction period of 3.5 hours at 1400C.

I

-32- Example 49 110 mg of sodium were dissolved in 2.5 ml of ethylene glycol at 500C. The solution was left to cool to room temperature and 260 mg of 2,5-dichlorothiophene-3-sulphonic acid 6-chloro-5-(2methoxy-phenoxy)-2,2'-bipyrimidin-4-ylamide were added. After heating to 500C for 2 hours the glycol was removed in a high vacuum and the solid residue was dissolved in 20 ml of water. The product was precipitated by adding 0.3 ml of acetic acid. After filtration, io washing with water and drying at 500C in a high vacuum 182 mg of pale beige crystals of 2,5-dichlorothiophene-3-sulphonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin- 4-ylamide, m.p. 157-1600C, MS: M+ (569), 470 were obtained.

Preparation of the starting 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-dichlorothiophene-3sulphonamide potassium salt in 5 ml of dry DMSO was held at room temperature for 16 hours. Thereafter, 0.112 g of K tert.-butylate was added, whereupon the reaction had finished within 5 hours. The P 0 reaction mixture was poured on to 40 ml of ice-water and extracted with 40 ml of diethyl ether in order to remove excess reagent. From 25 the aqueous phase by salting-out with saturated sodium chloride solution (20 ml) there was obtained 2,5-dichlorothiophene-3sulphonic acid 6-chloro-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4ylamide, [which was isolated] by filtration and washing with ether (0.54 g of beige powder).

In order to obtain the free sulphonamide, the Na salt was suspended in water and the suspension was acidified with acetic acid and extracted with ethyl acetate to which a small amount of CH2C2l had been added. The organic phase was washed twice with saturated 3s sodium chloride solution, dried with MgSO4 and evaporated under reduced pressure. The residue was washed briefly with diethyl ether and hexane and then dried. There was obtained 0.30 g as a beige powder of m.p. 1400C MS: 444 (M-(S02+CI)).

-33- In analogy, using 3,5-dimethylisoxazolyl-4-sulphonamide potassium there was obtained 3,5-dimethylisoxazole-4-sulphonic acid 6-chloro-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-ylamide in 71% yield as a beige, slightly reddish powder of m.p. 184-1870C. MS: M+ 488, 393 (M-(SO2+OCH3)).

Example 3,5-Dimethyl-isoxazole-4-sulphonic acid 6-(2-hydroxyo1 ethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-ylamide was obtained as a beige powder of m.p. 200-2040C, MS: 514 450 SOz), 419 (450-CH30), in analogy to Example 49.

Example 51 A solution of 888 mg of pyridine-2-carbonyl azide in 15 ml abs. dioxan was held at 800C for 15 minutes. The solution was left to cool somewhat, 1.09 g of the compound prepared in Example were added and the solution was held at 90 0 C for 4 hours.

2o Thereafter, it was evaporated to dryness, the residue was taken up with ethyl acetate, washed twice with water and once with saturated sodium chloride solution, the organic phases were combined, dried and concentrated, whereby crystals of the product separated. For definitive purification, it was chromatographed on silica gel with 25 EtOAc/CH2CI2 and there were obtained 931 mg of white crystals of pyridin-2-ylcarbamic acid 2-[6-(5-isopropyl-pyridin-2- S.I. ylsulphonyla mino)-5-(2-methoxy-phenoxy)-2-morpholin-4-ylpyrimidin-4-yloxy]ethyl ester of m.p. 200-2020C. MS: 664.4 IR (KBr) 1730 cm-1 (carbamate).

Example 52 .Pyridin-2-ylcarbamic acid 2-[6-(2,5-dichlorothiophen-3ylsulphonylamino)-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4yloxy]ethyl ester was obtained as white crystals of m.p.194-1970C, MS: 690.1 IR (KBr) 1732 cm- 1 (carbamate), in 61% yield in analogy to Example 51 from the compound prepared in Example 49.

II I L _L L- -34- Example 53 Pyridin-2-ylcarbamnic: acid 2-[5-(2-methoxy-phenoxy)-6-(3,5dimethyl-isoxazo l-4-ylsu lphonylamino)-2, 2'-bipyrimidin-4yloxy]ethyl ester was obtained as pale yellow crystals of m.p. 217- 21 8CC, MS: 635.3 IR (KBr) 1736 cm- 1 (carbamate), was obtained in 68% yield in analogy to Example 51 from the compound prepared in Example Example 54 Pyridin-2-ylcarbamic acid 2-16-(5-tert-butylthiophen-2ylsulphonylamino)-5-(2-methoxy-phenoxy)-2-morpholin-4-ylpyrimidin-4-yloxyl-ethyl ester was obtained as a white foam, MS: 683.5 in 90% yield in analogy to Example 51 from the compound prepared in Example 46.

Example Pyridin-2-ylcarbamic acid 2-[6-(2,5-dichloro-thiophen-3ylsulphonylamino)-5-(2-methoxy-phenoxy)-2-morpholin-4-ylpyrimidn-4-yloxy] -ethyl ester, white crystals of m.p. 1 94-1 960C, MS: 695.3 was obtained in 55% yield in analogy to Example 51 2 from the compound prepared in Example 47.

Example 56 Pyridin-2-ylcarbamic acid 2-[6-(3,5-dimethyl-isoxazol-4y Isu Iph on y Ia m ino 5 -rn9t h oxy -p h e noxy)- 2 -m orp h oIi n -4-yI- 3o pyrimidin-4-yloxy]-ethylester, white crystals of m.p. 1 06-1 09CC, MS: 640.4 was obtained in 70% yield in analogy to Example 51 from the compound prepared in Example 48.

Example 57 5-lsopropyl-pyridine-2-sulphonic acid 6-(2-hydroxy-ethoxy)- -(2-methoxy-phe noxy)-2-morpho li n-4-yl-pyri mid in-4-yla rnide (54.5 mg) was dissolved in N,N-dimethylacetamide (5 ml). 1 4.4 mg of NaH suspension were added at room temperature and the mixture BB~9~p- was stirred for 20 minutes. Finally, 2-chloropyrimidine (11.7 mg) was added. The reaction mixture was stirred for 18 hours at room temperature and poured into ice water. Saturated NH4CI solution was added and the mixture was extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulphate and evaporated. The residue was chromatographed over silica gel using methylene chloride/methanol (100/1) as the eluent. There was obtained 5-isopropyl-pyridine-2-sulphonic acid {5-(2-methoxyphenoxy)-2-morpholin-4-yl-6-[2-(pyrimidin-2-yloxy)-ethoxy]pyrimidin-4-yl}-amide as white crystals.

MS: 624 (M+H) Example 58 a) In analogy to Example 45, by reacting 5-isopropyl-pyridine-2sulphonic acid [6-chloro-2-(3-methoxy-benzyl)-5-(2-methoxyphenoxy)-pyrimidin-4-yl]-amide with Na in ethylene glycol there was obtained 5-isopropyl-pyridine-2-sulphonic acid [6-(2-hydroxyethoxy)-2-(3-methoxy-benzyl)-5-(2-methoxy-phenoxy)-pyrimidin-4- 2o yl]-amide as a white foam.

MS: 579.3 (M-H) Preparation of the starting material: b) 10.8 g of 3-methoxyphenylacetonitrile were dissolved in ethanol (100 ml) and the solution was saturated with hydrogen chloride at room temperature. The mixture was subsequently stirred for 12 hours a room temperature, the solution was cooled to 0 0 C and the precipitated crystals were sucked off. The crude product was so recrystallized from acetone/diethyl ether. There was thus obtained S. 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 hydrochloride (12 g) was dissolved in ethanol (100 ml) and treated at -75°C with 14 ml of liquid ammonia. The mixture was left to come to room temperature within 5 hours and was then evaporated in a rotary evaporator. The residue was suspended in acetone and the g c -36precipitated crystals were sucked off and dried under a high vacuum.

There was thus obtained 2-(3-methoxy-phenyl)-acetamidine hydrochloride as a white crystalline solid.

MS: 164 (M) d) Na (2.3 g) was dissolved in methanol (40 ml) and 2-(3-methoxyphenyl)-acetamidine hydrochloride (10 g) and (2-methoxyphenoxy)malonic acid dimethyl ester (12.67 g) were added in succession at room temperature. The mixture was stirred for 5 hours at room temperature, concentrated in a rotary evaporator and the crude product was added to water. The aqueous phase was washed with ethyl acetate, adjusted to pH 1 and the precipitated crystals were sucked off and dried under a high vacuum. There was thus obtained 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)-pyrimidine-4,6diol (14 g) was dissolved in acetonitrile (150 ml). Collidine (5.24 ml) and phosphorus oxychloride (21.7 ml) were added at room temperature and the mixture was stirred for 9 hours at room temperature. The mixture was poured into ice water and extracted with ethyl acetate.

SThe organic phase was washed with semi-saturated KHC03 solution, dried over magnesium sulhate and evaporated. The residue was taken up in hexane/diethyl ether, filtered and the filtrate was evaporated in a rotary evaporator. There was thus obtained 4,6-dichloro-2-(3methoxy-benzyl)-5-(2-methoxy-phenoxy)-pyrimidine as light brown crystals.

MS: 390 (M) f) in analogy to Example 45, by reacting 4,6-dichloro-2-(3-methoxybenzyl)-5-(2-methoxy-phenoxy)-pyrimidine with potassium isopropyl-pyridine-2-sulphonamide there was obtained pyridine-2-sulphonic acid [6-chloro-2-(3-methoxy-benzyl)-5-(2methoxy-phenoxy)-pyrimidin-4-yl]-amide as a yellow foam.

MS: 553.1 (M-H)

U

-37- Example 59 a) In analogy to Example 45, by reacting 5-isopropyl-pyridine-2suiphonic acid [6-chloro-2-(3-methoxy-benzyl)-5-phenoxypyrimidin-4-yl]-amide with Na in ethylene glycoi there was obtained 5-isopropyl-pyridine-2-sulphonic acid [6-(2-hydroxy-ethoxy)-2-(3methoxy-benzyl)-5-phenoxy-pyrimidin-4-yl]-amide as light yellow crystals.

MS: 549.2 (M-H) Preparatiorn of the starting material b) In analogy to Example 58d, by condensing 2-(3-methoxy-phenyl)acetamidine hydrochloride with phenoxymalonic: acid dimethyl ester there was obtained 2-(3-methoxy-benzyl)-5-phenoxypyrimidine-4,6diol as a yellow foam.

MS: 324 (M) c) In analogy to Example 58e, by chlorinating 2-(3-methoxy-benzyl)- 2o 5-phenoxypyrimidine-4,6-diol with phosphorus oxychloride there was obtained 4, 6-dichloro-2-(3-methoxy-benzyl)-5-phenoxypyrimidine as yellow crystals.

MS: 360 (M) 2 d) In analogy to Example 45, by reacting 4,6-dichloro-2-(3-methoxywith potassium 5-iso pro pyl-pyrid ine- ~'-sulphonamide there was obtained 5-isopropyl-pyridine-2sulphonic acid [6-chloro-2-(3-methoxy-benzyl)-5-phenoxypyrimidin-4-yl]-amide as a yellow foam.

MS: 523 (M-H) Example a:...:5-lsopropyl-pyridine-2-sulphonic acid [6-(2-hydroxy-ethioxy)- 2 -meth oxy-be nzyl) 5-phe noxy-pyrimid in-4-yl]-amid e (55 mg) was dissolved in dry methylene chloride (3 ml) .Boron tribromide mg in methylene chloride (2 was added at 0 0 C. The mixture was stirred for 2 hours at OTC and for a for a further 4 hours at room temperature, evaporated in a rotary evaporator and the residue -38was chrnmatographed over silica gel using methylene chloride/ethyl acetate as the eluent. There was obtained 5-isopropyl-pyridine-2sulphonic acid [2-(3-hydroxy-benzyl)-6-(2-hydroxy-ethoxy)-5phenoxy-pyrimidin-4-yl]-amide as white crystals. MS: 525.1 (M-H) Example A Tablets containing the following ingredients can be produced in a conventional manner: o1 Ingredients Per tablet Compound of formula I Lactose Corn starch Ta!c Magnesium stearate 10.0 100.0 mg 125.0 mg 75.0 mg 4.0 mg 1.0 mg Example B Capsules containing the following ingredients can be produced in a conventional manner: r o r r

I

Ingredients Compound of formula I Lactose Corn starch Talc Per capsule 25.0 mg 150.0 mg 20.0 mg 5.0 mg Example C Injection solutions can have the foilowing composition: o Compound of formula I Gelatine Phenol Water for injection 3.0 mg 150.0 mg 4.7 mg ad 1.0 mi -39- Example D 500 mg of compound of formula I are suspended in 3.5 ml of Myglyol 812 and 0.08 g of benzyl alcohol. This suspension is filled into a container having a dosage valve. 5.0 g of Freon 12 are filled into the container under pressure through the valve. The Freon is dissolved in the Myglyol-benzyl alcohol mixture by shaking. This spray container contains about 100 single doses which can be applied individually.

e

Claims (21)

1. Compounds of the formula, R 1 SO 2 NH R 4 R R 3 R 8 R 7 wherein R1 signifies heterocyclyl; R 2 signifies hydrogen, lower-alkyl, lower-alkrxy, lower-alkylthio, lower-alkoxy-lower-alkyl, lower-alkylsulphonyl-lower-alkoxy, phenyl, lower alkylphenyl, lower-alkoxy-phenyl, lovier-alkylene- dioxyphenyl, phenyl-lower alkyl, lower alkyl-phenyl-lower alkyl, lower alkoxy-phenyl-lower alkyl, lower alkylenedioxyphenyl-lower alkyl, heterocyclyl or heterocyclyl-lower alkyl; R 3 signifies lower-alkyl, lower-alkoxy, formyl, halo-lower-alkyl, hydroxy-lower-alkyl, amirio iower-alkyl or a residue -CH 2 O-A- *lower-alkyl, -(GH2)m0O(CRaRb)nOH, -(CH2)m0O(CRaRb)nOR 9 2o (CH2)m0O(CRaRb)nNH 2 or -(CH2)m0O(CRaRb)n-BR9; R 4 -R 8 signify hydrogen, lower-alkoxy or halogen; :R 9 signifies heterocyclyl; phenyl or phenyl substituted by lower- alkyl, lower-alkoxy and/or halogen, or lower-alkyl; Ra and Rb signify hydrogen or lower-alkyl; A signifies a ketalized 1 ,2-dihydroxy-ethylene group; *B signifies -NH(C(O)NH- or -NHC(O)O-: n signifies 2, 3 or 4; and M signifies 0 or 1. -41-

2. Compounds according to claim 1, wherein R 2 is hydrogen, lower-alkyl, lower-alkoxy, lower-alkyithia, lower-alkoxy-lower- alkyl, lower-alkylsulphonyl-lower-alkoxy, phenyl, lower-alkoxy- ,q phenyl, lower-alkylene-d~oxaphenyl or heterocyclyl, R 3 is lower- alkyl, lower-alkoxy, formyl, halo-lower-alkyl, hydroxy-lower-alkyl, amino-lower-alkyl or a residue -CH2O-A-lower-alkyl, -(CH2 )m-O (CRaRb)nOH, -(CH2)m0..(CRaRb)nNH2 or -(CH2)m0O(CRaRb)n-BR9 and R 1 ,P R 4 -R 9 Ra, Rb, A, B, n and m are as in claim 1.

3. Compounds according to claim 1 or 2, wherein R 1 is pyridyl, pyrimidinyl, isoxazolyl, furyl or thienyl which is unsubstituted or substituted by lower-alkyl, halogen, amino, mono- or di-lower-alkylamino or lower-alkanoyl.

4. Compounds according to any one of claims 1-3, wherein R 2 is hydrogen, pyrimidinyl, pyridyl, morpholino, thiomorpholino, piperidino, pyrrolidino, benzodioxolyl, lower-alkoxyphenyl or lower- a lkylthio. Compounds according to any one of claims 1-4, wherein R 3 is a residue -O-(CRaRb)nOH, -O-(CRaRb)nNH 2 or a residue -Q(CH2) 2 -B- R 9 and R 9 is pyridyl, pyrimidinyl or furyl. 25 6. Compounds according to claim 5, wherein R 3 is a residue -O(CH2)2-B-R 9 and B is Compounds according to claim 6, wherein R 9 is 2-pyridyl.

8. The compound according to claim 7, pyridin-2-ylcarbarnic acid ?-[6-(5-isopropyl-pyridin-2-ylsulphonylamino)-5-(2-methoxy- phenoxy)-2-morpholin-4-ypyrimid in-4-yloxy] ethyl ester.

9. The compounds according to claim 7, pyridin-2-ylcarbamic acid 2-[6-(5-tert-butyl-thiophen-2- ylsulphonylamino)-5-(2-methoxy-phenoxy)..2, 2'-bipyrimidin-4- yloxyj-ethyl ester, pyridin-2-ylcarbamic acid 2-[5-(2-m-rethoxy-phenoxy)-6-(5- -42 pentyl-th io ph en-2 -ylsulphonyl amino)-2 ,2'-bipyri mid in-4-yloxy] ethyl ester, pyridin-2-ylcarbamic acid 2-dimethyipropionyD)- thiophen-2-ylsulphonylamino]-5-(2-methoxy-phenoxy)-2 b ipyrim idi n-4-yloxy] -ethyl ester, pyridin-2-yfcarbamic acid 2.-[6-(5-isopropyl-pyridin-2- yls ulpho nyla mino)-5 -me thoxy-ph enoxy) -2,2 '-bipyri mid in-.4- yloxy]-ethyi ester, pyridin-2-ylcarbamic acid 2-[5-(2-methoxy-phenoxy)-6- pyridin-? -yls u pho nyla min o) bipyrimid in-4-yloxy]-e thyl ester, pyridin-2-ylcarbamic acid 2-[5-(2-methoxy-phenoxy)-6- pyridin-3 -yls ulpho nyla min o) -2,2'-bipyrim id in-4--yloxy] -ethyl ester, pyridin-2-ylcarbamic acid 2-[6-(5-tert-butyl-thiophen-2- ylsulphonyla mino)-5-(2-chloro-5-methoxy-phenoxy)-pyimidin-4- yloxy]-ethyl ester, pyridin-2-yl-carbamic acid 2-[6-(5-isopropyl-pyridin-2- yls ulpho nyla min 5-(2-methoxy-phe noxy) -2 -methoxy-phe nyl)- pyri mid in -4-yloxy] -ethyl ester, pyridin-2-ylcarbamic acid 2-[6-(5-isopropyl-pyridin-?- 2o ylsulphonylamino)-5-(2*--methoxy-phenoxy)-2-methylsulphanyl- pyrimidin-4-yloxy]-ethyl ester, pyridin-2-ylcarbamic acid 2-[2-QI ,3-benzodioxol-5-yl)-6-(5- iso propyl-pyridin-2 -yls u Iph onyla min o) -5 -methoxy-phe noxy)- pyrimid in-4-yloxy] -ethyl ester, pyridin-2-ylcarbamic acid 2-[5-(2-chloro-5-methoxy- phenoxy)-6-(5-isopropyl-pyridin-2-ylsulphonylamino)-2-morpholin- 4 4-yl pyrimid in -4-yloxy] -ethyl ester, pyridin-2-ylcarbamic acid 2-[5-(2-methoxy-phenoxy)-6-(5- mne t h yI-py r id in -2 -ylIs uIp h on y Ia m in o) 2- -b ipy r id imnin -4-yIo xy-e t hylI ester, a:...:pyridin-2-yI-carbamic acid 2-[5-(2-methoxy-phenoxy)-6-(5- methyl-pyridin-2-ylsulphonyla mino)-2-morpholin-4-yl-pyrimidin-4- :::.yloxy]-ethyl ester, pyridin-2-ylcarbamic acid 2-[5-(2-chloro-5-methoxy- phenoxy)-6-(5-isopropyl-pyridin-2-sulphonylamino)-2-morpholin-4- yl-pyrimid in-4-yl-rnethoxy] -ethyl ester, pyridin-2-ylcarbamic acid 5-(2-chloro-5-methoxy-phenoxy)-6- (5-isopropyl-pyridin-2-ylsulphonyla mino)-2-morpholin-4-yl- pyrimidin-4-ylmethyl ester, -43 pyridin-2-ylcarbamic acid 2-[6-(2,5-dichlorothiophen-3- ylsulphonylamino)-5-(2-methoxy-phenoxy)-2 ,2 '-bipyrimidin-4- yloxy]ethyl ester, pyridin-2-ylcarbamic acid 2-[5-(2-methoxy-phenoxy)-6-(3, dimethyl-isoxazol-4-ylsulphonylamino)-2,2'-bipyrimidin-4- yloxyjethyl ester, pyridin-2-ylcarbamic acid 2-[6-(5-tert-Butylthiophen-2- yisulphonyla mino)-5-(2-.methoxy-phe noxy)-2-morpholin-4-yl- pyrim:d in-4-yloxy] -ethyl ester, pyridin-2-ylcarbamic acid 2-[6-(2,5-dichloro-thiophen-3- (2-methoxy-phenoxy)-2-morpholin-4-y- pyrimidin-4-yloxy7 ijl ester, pyridin-2-ylcarbamic acid ,5-dimethyl-isoxazol-4- ylsulphonylamino)-5-(2-methoxy-phe noxy)-2-morpholin-4-yI- pyrimidin-4-yloxy]-ethyl ester. Compounds according to claim 6 wherein R 9 is 4-pyridyl.

11. The compound according to claim 1 0, pyridin-4- 2o ylcarbamic acid 2-[6-(5-tert-butyl-thiophen-2-ylsulphonylamino)-5- (2-chloro-5-methoxy-phenoxy)-pyrimidin-4-yloxy]-ethyl ester.

12. Compounds according to claim 5, wherein R 3 is a residue -0(CH2)2-B-R 9 and B is

13. The compound according to claim 1 2, carboxylic acid furan-3-ylmethyl ester 2-[5-(2-methoxy- 3o pyri midi n-4-yloxy] -ethyl ester. 5-isopropyl-pyridine-2-sulphonic acid {5-(2-methoxy- phenoxy)-2-morphiolin-4-yl-6-[2-.(pyrimidin-2-yloxy)-ethoxy]- pyrimidin-4-yl }-amide.

14. Compounds according to claim 5, wherein R 3 is a residue -O(CH2)2-B-R 9 and B is -NHC(0)NH-. The compounds according to claim 1 4, -44- 5-tert-butyl-thiophene-2-s ulphonic acid 5-(2-methoxy- phenoxy)-6- -pyridin-2-yl-ureido)-ethoxy]-2 ,2 '-bipyrimidin-4- ylamide, 5-isopropyl-pyridine-2-sulphonic acid 5-(2-methoxy-phenoxy)- 6-[2-(3-pyridin-2-yl-ureido)-ethoxy]-2,2'-bipyrimidin-4-ylamide.

16. Compounds according to claims 1-4, wherein R 3 is hydroxyethoxy.

17. The compounds according to claim 16, 5-tert-butyl-thiophene-2-sulphonic acid 6-(2-hydroxy- ethoxy)- 5-(2 -meth oxy-ph enoxy)-2 ,2 bipyri mid in-4-yla mide, 5-pentyl-thiophene-2-sulphonic acid 6-(2-hydroxy-ethoxy)-5- (2-methoxy-phenoxy)-2,2-bipyrimidin-4-ylamide, 5-(2 ,2-dimethyl-propionyl)-thiophene-2-sulphonic acid 6-(2- hydroxy-ethoxy) -5 -(2-methoxy-ph enoxy) -2 ,2 '-bipyrirmid in-4- ylamide, 5-isopropyl-pyridine-2-sulphonic acid 6-(2-hydroxy-ethoxy)- 5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-ylamide, pyridine-3-sulphonic acid 6-(2-hydroxy-ethoxy)-5-(2- methoxy-phenoxy)-2,2 '-bipyrimidin-4-ylamide, 5-tert-butyl-thiophene-2-sulphonic acid 5-(2-chloro-5-- meth oxy-ph enoxy) -6 -(2-hyd roxy-eth oxy) -pyrim id in-4-yla mid e, 5-tert-butyl-thiophene-2-sulphonic acid 6-(2-hydroxy- -(2-methoxy-phenoxy)-pyrimidin-4-ylamide, N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2 -hydroxy-ethoxy)- *py r im id in -4-y I] -5 iso pro p yI- py r idin e- 2 -s u Iph o na m id e, is opro pyI- N [6 hyd roxy- e t hoxy) -5 (2 -m e th oxy- ph e noxy) 2 -m e th oxy- p henyl1) -pyr im id in 4-yl I- py r id in e -2 sulIph on am ide, -iso pro py I-N [6 -h yd roxy- e th oxy) -5 -m e th oxy- ph e noxy) 2 -m e th yIs u p ha n y I-py r im id in -4-y I]py r id in e -2 su Iph on am ide, 1,3-benzodioxol-5-yI)-6-(2-hydroxy-ethoxy)-5-(2- m e th o xy -phe n o xy) -p yr im id in- 4 y 5 is o pr opyI- py r id in e- 2 sulphonamide, N 5 chIo ro- 5 -m e th oxy- ph e no xy) 6 -h ydro xy -e th oxy) -2 m or p hoIi n -4 -y I- py r im id in -4 y1-5 is o pro pyI- p yr id ine -2 sulphonamide, 5-methyl-pyridine-2-sulphonic acid 6-(2-hydroxy-ethoxy)-5- (2-methoxy-phenoxy)-2, 2'-bipyrimid in-4-yla mide, 5-methyl-pyridine-2-sulphonic acid 6-(2-hydroxy-ethoxy)-5- (2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-ylamide, 5-isopropyl-pyridine-2-sulphonic acid 6-(2-hydroxy-ethoxy)- 5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-ylamide, 5-tert.butylthiophene-2-sulphonic acid 6-(2-hydroxy-ethoxy)- 5-(2-methoxy-phenoxy-2-morpholin-4-yl-pyrimidin-4-yla mide, 2, 5-dichlorothiophene-3-sulphonic acid 6-(2-hydroxy-ethoxy)- -(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-ylamide, 3 ,5-dimethylisoxazole-4-sulphonic acid 6-(2-hyd roxy-ethoxy)- -(2-methoxy-phenoxy)-2-norpholin-4-yl-pyrimidin-4-ylamide, 2, 5-dichlorothiophene-3,-sulphonic acid 6-(2-hydroxy-ethoxy)- -(2-methoxy-phenoxy)-? ,2 '-bipyrimidin-4-yla mide, 3, 5-dimethyl-isoxazole-4-sulphonic acid 6-(2-hydroxy- ethoxy) -5-(2-rrnethoxy-phe noxy)-2,2'-b ipyri mid in-4 -yla mide, 5-isopropyl-pyridine-2-sulphonic acid [6-(2-hydroxy-ethoxy)- 2-(3-methoxy-benzyl)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]- amide, 5-isopropyl-pyridine-2-sulphonic acid [6-(2-hydroxy-ethoxy)- 2o 2-(3-methoxy-benzyl)-5-phenoxy-pyrimidin-4-yl]-amide, 5-isopropyl-pyridine-2-sulphonic acid [2-(3-hydroxy-benzyl)- 6 hyd roxy- e th oxy) -5 -p h en oxy- py r im id in -4-yI-a m id e.

18. Compounds according to claims 1-4, wherein R 3 is aminoethoxy.

19. The compound according to claim 18, 5-tert-butyl-thiophene-2-sulphonic acid 6-(2-amino-ethoxy)- 3o 5-(2-methoxy-phenoxy)-2,2-bipyrimidin-.4-ylamide. Compounds according to claims 1-4, wherein R 3 is lower- alkyl, lower-alkoxy, formyl, halo-lower-alkyl, hydroxy-lower-alkyl or -CH2O-A-lower-alkyl.

21. The compounds according to claim 5-Isopropyl-pyridine-2-sulphonic acid 5-(2-chloro-5-methoxy- phenoxy)-6-methyl-2-morpholiri-4-yl-pyrimidi n-4-ylamide, -46- 5-(2-chloro-5 -me thoxy-phenoxy)-6-f ormyl-2-morphoIin-4-yl- py rim idin -4 -y a mid e, 5-isopropyl-pyridine-2-sulphonic acid 5-(2-chloro-5-methoxy- p he noxy) -6 -hyd roxymethyl1-2 -mo rpho li n-4-yl-pyri mid i n-4-yl amide, 5-isopropyl-pyridine-2-sulphonic acid 5-(2-chloro-5-methoxy- phenoxy)-6-chloromethyl-2-morpholin-4-yl-pyrimidin-4-yamide, 5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxymethyl)- 2 -mo rpho lin-4-yl-pyrimidi n-4-yla mid e.

22. Compounds of the formula R 1 SO 2 NH 2 R 4 R 5 S Hal R 8 R 7 wherein RI, R 2 and R 4 -R 8 are as in claim 1 and Hal is halogen. Pharmaceutical preparations, containing a compound of claims 1-21 and usual carriers and adjuvants.

24. A process for the manufacture of compounds of claims 2o 1-21, characterized by reacting a compound of the formula 2 NH 2 R 4 R *Hal Re R 7 wherein RI, R 2 and R 4 -R 8 have the significance set forth above and Hal is halogen, with a compound of the formula -47- HO(CRaRb)nXH wherein n, Ra and Rb have the significance set forth above and X represents 0 or NH, or b) reacting a compound of the formula Y R 4 R R2-/ O R6 TI R 3 R 8 R 7 wherein R 2 -R 8 have the significance set forth above, with a compound of the formula RISO 2 Z wherein R 1 has the significance set forth above and whereby Y Srepresents halogen and Z represents amino or Y represents amino and Z represents halogen, 20 or c) reacting a compound of the formula SR'SONH 4 R 8 R 7 (CH 2 )m O(CRaRb)nXH wherein R 1 R 2 R 4 -R 8 Ra, Rb, X, m and n have the significance set forth above, 48 cl) with an isocyanate of the formula R 9 NCO or a carbamoyl chloride of the formula R 9 NCOC1, wherein R 9 has the significance set forth above, or c2) with phosgene and thereafter with an alcohol of the formula R 9 0H; or with a chloroformate of the formula R90C(O)CI; or d) reacting a compound of formula I in which R 3 represents halo-lower-alkyl with a compound of the formula HOCHz-A-lower-alkyl wherein A represents a ketalized 1,2-dihydroxy-ethylene group, and, if desired, modifying substituents present in the resulting compound of formula I and/or converting the compound of formula I obtained into a salt. Compounds according to any one of claims 1-21, whenever prepared by the process of claim 24.

26. Compounds of formula I substantially as hereinbefore described with reference to any one of the Examples. 15 27. A pharmaceutical composition including or consisting of an effective amount of at least one compound according to any one of claims 1-21, 25 or 26, together with a pharmaceutically acceptable carrier, diluent or adjuvant therefor.

28. A method for the treatment or prophylaxis of disorders which are associated with endothelin activities in a mammunal in need of such treatment or prophylaxis, which 20 mechod includes or consists of administering to said mammal an effective amount of at least one compound according to any one of claims 1-21, 25 or 26 or of a composition according to claim 27.

29. The method according to claim 28 wherein the disorders are circulatory S disorders.

30. The method according to claim 29 wherein the disorders are hypertension, ischaemia, vasospasms or angina pectoris. Dated 12 March, 1998 F Hoffmann-La Roche AG Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON t INALIBA100491:SSC Novel Sulfonamides Abstract Compounds of thle formula, R 0 NH R R R R 8 R E; wherein R' signifies heterocyclyl; R2signifies hydrogen, lower-alkyl, lower-alkoxy, lower-alkylthio, lower-alkoxy-lower- alkyl, lower-alkylsulphionyl-lower-alkoxy, phenyl, lower alkyiphenyl, lower-alkoxy- :phenyl, lower-alkylene-dioxyphenyl, phenyl-lower alyl lower alkyl-phenyl-lower alkcyl, lower alkoxy-phenyl-lower alkyl, lower alkylenedioxyphenyl-lower alkyl, heterocyclyl or heterocyclyb-lower alkcyl; R 3 signifies lower-alkyl, lower-alkoxy, formyl, halo-lower-alkyl, hydroxy-lower-alkcyl, amino-lower-alkyl or a residue -CH 2 0-A-lower-alkyl, aR b LOH, o (CH 2 aR b),OR 9, (CH 2 )m4O(CR aR b)nNH 2 or -(CH 2 )m4-Q(CR aR b)nWBR;9 R 4 _R 8 signify hydrogen, lower-alkoxy or halogen; R 9 signifies heterocyclyl; phenyl or phenyl substituted by lower-alkyl, lower-alkoxy .9 and/or halogen, or lower-,-dkyl; Ra and Rb signify hydrogen or lower-alkyl; A signifies a ketalized 1,2-dihydroxy-ethylene group; B signifies-OC(O)O-, -NH(C(O)NH- or-NHC(O)O-; n signifies 2, 3 or 4; and m signifies 0 or 1 are inhibitors for endothelin receptors. They can be used for the treatment of disorders which are associated with endothelin activities, especially circulatory disorders such as hypertension, ischaemia, vasospasmis and angina pectoris. It~ibFA~23G66:J0C I of 1