NZ243959A

NZ243959A - Substituted pyrazine derivatives and pharmaceutical compositions thereof

Info

Publication number: NZ243959A
Application number: NZ243959A
Authority: NZ
Inventors: Herbert Koppe; Georg Speck; Klaus Stockhaus
Original assignee: Boehringer Ingelheim Int
Priority date: 1991-08-16
Filing date: 1992-08-14
Publication date: 1995-07-26
Also published as: WO1993004048A1; HK1003137A1; FI940696A; IL102814A0; DE59208974D1; ES2108129T3; NO940523D0; GR3025742T3; AU669122B2; EP0598770B1; HU9400430D0; RU94015265A; CZ280760B6; FI940696A0; RU2124008C1; SK17594A3; HUT67661A; CZ33794A3; MX9204637A; NO940523L

Abstract

Disclosed are new compounds of formula (I) (R<1> to R<6> being defined in the description) which can be prepared by conventional methods. The compounds are suitable for use as active ingredients in drugs.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £43959 24 39 59 Priority Date(s): . Jfc.?. 3L. .'A .1; JU.. Specification Filed: /W.4r.?.£« Ctnns: 13q. .c.9.<V>.4^5 I iv,. /^.V^\.V,7iAw<.i.5r ."TCV-f Publication Date: .^Wv.1995 p f) jo>«rnal. N^: .... .1.Sh NO OHJTOSS r; 14 AUG 1932 Patents Form No. 5 I RL NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION NEW PYRAZINE DERIVATIVES, THE PREPARATION AND USE THEREOF WE, BOEHRINGER INGELHEIM INTERNATIONAL GMBH., a German company of D-6507 Ingelheim am Rhein, FEDERAL REPUBLIC OF GERMANY hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: - 1 - (followed by page la) - la - New pyrazine derivatives, the preparation and use chereof The invention relates to new tetra-substituted pyrazine 5 derivatives, the preparation thereof and their use in the production of pharmaceutical substances or drugs. According to one aspect of the invention, we provide compounds of the formula (I) 10 NH R1 / W N ([ CI-,/ ""^S-CO -NH-C-NH, R2 20 wherein, independently of one another, R1 represents H or a (C^b) alkyl group; R2 represents 25 a straight-chained or branched (Cj.,,) alkyl chain which is substituted, a) by a phenoxy group which may in turn be mono-or polysubstituted by F, CI, (Ci.2) alkyl or 30 (Ci.2) alkoxy; b) by a phenoxy-((Cj^)alkyl)-amino or a phenoxy- ( (C^) alkyl) - (methylamino) group, in which the (C^) alkyl group may be mono- or poly-35 substituted by hydroxy, and in which the phenoxy group may be mono- or poly-substituted by F, CI, (C^) alkyl or (Cr_2) alkoxy ; (followed by pag£ 2) ' -4 \ 'J* ' %j r? - 2 - or an amidino group of the formula -c-NHR11 (V), ! NH 5 wherein R11 represents a phenyl group which is mono-or polysubstituted by F, CI or a (C^)alkyl group,- or Rx and R2 together denote, together with the 10 nitrogen atom to which they are bound, a piperazine ring which is substituted in the 4-position by or nh2 i N/V/V_ och3 3 and acid addition salts thereof. The preferred substituents in phenyl or phenoxy groups are alkyl or alkoxy groups having one or two carbon 5 atoms as well as F and CI. Whilst R1 is preferably hydrogen or methyl, R2 preferably represents larger groups, e.g. a group selected from 10 / 3 CH 3 15 \—/ —i 0-CH2-CH(OH)-CH2-N(CH3)-(CH2) CI 20 and F 25 CH 3 NH Z4 3 0 •» Q 15 20 25 30 - 4 - or R1 and R2 form a substituted heterocyclic group with the nitrogen to which they are bound, e.g. Nil. CH_0 10 According to a further aspect of the invention, we provide a process for preparing compounds of formula (I), as hereinbefore defined, in which a) a pyrazine carboxylic acid ester of formula /V CI _/ Xvl— C02-alkyl R^R*N !' \—NH \,^ 1 <VII> wherein R1, R2 are as hereinbefore defined and alkyl represents a (C^.,) alkyl group is reacted with a guanidine of formula H2N-C=NH I NH2 (VIII) or b) a pyrazine derivative of formula 35 y~" . ' < \ • s-4KAY 1995 '• - 5 - 24 3 10 15 Cl_/ V.-CO- NH-C=NH l li L, (xi)^ is reacted with an amine of formula HNRXR2 (VI), wherein R1 and R2 are as hereinbefore defined, followed, if desired, by conversion of any base of formula I obtained into an acid addition salt. 20 In reaction (a) , the compounds of general formula VII may be prepared by the reaction of a lower alkyl ester of 3-amino-5,6-dichloropyrazine-2-carboxylic acid with an amine of formula VI, as defined above, under anhydrous conditions. This 2 5 reaction may be carried out using methods generally known from the literature in an inert solvent at elevated temperature in the presence of an acid acceptor. The amine component is generally used in equimolar amounts. However, it is also possible to 3 0 use the amine component as the acid acceptor and solvent. Preferably, however, the solvent used is dimethylformamide or dimethylsulphoxide or mixtures thereof. The reaction temperature is not crucial. As a rule, the reaction is carried out at a 35 temperature in the range from 80 - 100°C depending on the reactivity of the amine used. Under these conditions the reaction is finished after about 1 to 2 hours. Organic and inorganic bases may be 243959 - 6 - used as acid acceptors. Preferably, tertiary amines such as pyridine, N-methylpiperidine, dimethylaniline or triethylamine are used. 5 The 3,5-diaminopyrazine carboxylic acid esters of formula VII prepared in this way may, if desired, be subjected to subsequent treatment, e.g. a reaction of acylation or alkylation. 10 Acylation is carried out by known methods, e.g. by reacting a diamine of formula VII with a reactive carboxylic acid derivative. 15 The alkylation is used, for example, in the preparation of corresponding phenoxypropanolamine derivatives. For this purpose, a diamino compound of the substructure IX of formula VII: 20 .CC>2 alkyl _ NH. (IX) 25 (alk = (Ci^) alkyl, R3 = H or Me) is reacted in a suitable solvent e.g. with a phenoxypropyleneoxide of general formula 30 35 V V-O-CH -CH-CH 2 \ / 2 O (X) . v\ £i» /' / #• ; 3 ' , -41 \ f) /< "i* ZD - 7 - Z = (C:.2) alkoxy, at ambient temperature or slightly elevated temperature. Generally, the reaction is complete 5 in about 0.5 to 1 hour. However, the direct method of synthesis described above is preferred. 10 In reaction a) above, in order to prepare the end products of formula I the 3,5-diaminopyrazine carboxylic acid esters of formula VII are reacted with a guanidine of formula VIII in a suitable solvent with heating. Simple alcohols 15 are particularly suitable as the solvent. Preferably, the reaction is carried out in methanol at boiling temperature. Under these conditions the reaction is generally complete after about 30 to 90 minutes. 20 25 In reaction (b) , the reaction is preferably carried out at elevated temperature in a polar solvent, if possible anhydrous, e.g. dimethylformamide, dimethylsulphoxide. The starting compounds of formula XI are obtained by conventional methods. They may for example be obtained according to process a) if pyrazine carboxylic acid esters are used which are of 3 0 similar construction to the esters of formula VII but contain a chlorine atom instead of NR*R2 in the 5-position. The compounds of formula I may be used as active 3 5 substances in pharmaceutical preparations or may be used as intermediate products for preparing such active substances. The new compounds inhibit the Na+/H+- and Na"VLi +-exchange, inter alia. The active substaqies 4 /r "4 I; k: v: r 1 243959 according to the invention may be used as antihypertensives, mucolytics, diuretics and cancerostatics; they may also be used in diseases connected with ischaemia (for example: cardiac, 5 cerebral, gastrointestinal, pulmonary and renal ischaemia, ischaemia of the liver, ischaemia of the skeletal musculature). Corresponding diseases include, for example, coronary heart disease, angina pectoris, embolisms in the circulation of the lungs, acute or 10 chronic kidney failure, chronic kidney insufficiency, cerebral infarct, chronic circulatory disorders of the brain. During reperfusion of the ischaemic heart (e.g. after an attack of angina pectoris or a cardiac infarct) irreversible damage may occur to cardiomyocytes in the 15 affected region. The compounds according to the invention may be used in such cases for cardioprotection. The prevention of damage which may occur as a result of 2 0 reduced circulation during transplants should also be included in the field of ischaemia. According to a yet further aspect of the invention, we provide pharmaceutical compositions comprising a 2 5 compound of formula (I) as hereinbefore defined together with a pharmaceutically acceptable excipient, carrier or diluent. The active substances may be administered in 3 0 conventional forms, e.g. plain or coated tablets, capsules, granules, injectable solutions, and possibly nasally administered preparations, the active substance generally being present in an amount of 1 to 200 mg, preferably 20 to 100 mg per dosage unit. These 35 pharmaceutical preparations are produced in a manner known per se. The following Examples illustrate aspects of the invention but should not be construed as limiting: * % 1C.» \ ^ r'» r.» I J s ,*% I f* * r «• • Pharmacy Examples - 9 - ^^959 1. Tablets (Composition) 5 Compound according to Example Corn starch Sec. calcium phosphate Magnesium stearate 40.0 mg 144.0 mg 115.0 mg 1 ■0 mg 300.0 mg 10 2. Gelatine capsules The contents of a capsule consist of 50.0 mg of a corn starch. Note: Under the headings "Form" the Tables which follow indicate whether the preparation is a salt (HC1 = 20 hydrochloride, 2.HC1 = dihydrochloride, etc.) or the base (BS). 15 compound according to the invention and 150.0 mg of t ^-4 HAY 1395 •' r 243959 - 10 - Example 1 a) Methyl 3-amino-6-chloro-5-(2-[1-(2,6-dimethyl-phenoxy) ] propylamino) -pyrazine-2-carboxylate 5 4.44 g (20 mmol) of methyl 3-amino-5,6-dichloropyrazine-2-carboxylate, 3.6 g (20 mmol) of 2-amino-l-(2, 6-dimethylphenoxy)propane and 2.2 g (22 mmol) of triethylamine are heated to 95 - 100*C 10 in 40 ml of anhydrous dimethylformamide for 1M hours. After the solvent has been distilled off in vacuo the residue is purified on silica gel (eluant: ethyl acetate/isopropanol/NH3 (70:30:1). Yield 7.3 g 15 b) N-amidino-3-amino-6-chloro-5-(2-[1-(2,6-dimethylphenoxy) ] propylamino) pyrazine-2-carboxamide-hydrochloride 20 7.3 g (0.02 mmol) of pyrazine carboxylic acid ester from Example la) are dissolved in 50 ml of methanol and heated with 80 ml of a 1 molar mechanolic guanidine solution for 45 minutes over a boiling water bath. The solvent is distilled off in vacuo 2 5 and the residue is purified over a silica gel column (eluant: ethyl acetate/isopropanol/NH3 (70:30:5) and the hydrochloride of the end product is prepared. Yield 4.9 g; melting point 267 - 270#C. 30 :< a " j <v -4 WAV 1395 • 24 3 P 5 Q - 11 - Example .1 a) Methyl 3-amino-6-chloro-5-[N1-(5-fluoro-2- methyl)phenyl]-guanidino-pyrazine-2-carboxylate 5 13.3 g <60 mmol) of methyl 3-amino-5,6-dichloropyrazine-2-carboxylate, 15 g (90 mmol) of (5-fluoro-2-methyl)-phenylguanidine and 6 g of triethylamine are stirred into 100 ml of DMSO for 2 10 hours at 90"C. After cooling, 100 ml of CH2C12 are added. 100 ml of water are added dropwise, with cooling, the CH2C12 phase is separated off and the aqueous phase is extracted with 150 ml of CH2C12. The CH2C12 phases collected are washed with a little 15 water, dried over MgS04 and concentrated by evaporation. The residue is purified over silica gel (eluant: ethyl acetate/isopropanol (95:5). Yield: 12.6 g 20 b) N-Amidino-3-amino-6-chloro-5-[N'-(5-fluoro-2- methyl) -phenyl]guanidino-pyrazine-2-carboxamide 5.5 g of 2-methylpyrazinecarboxylate from Example 2a) are dissolved in 25 ml of anhydrous 25 dimethyl formamide, 50 ml of a 1.2 molar methanolic guanidine solution are added and the resulting mixture is refluxed for 30 minutes. Then the methanol is distilled off and the residue is purified on silica gel (eluant: ethyl 30 acetate/isopropanol/NH3 (70:30:5)) and the reaction product is converted into the hydrochloride. Yield: 8.7 g; m.p. 242°C. 35 Example 3 N-Amidino-3-amino-6-chloro-5-[4- [ (4-amino-6, 7- ■ f c ^ i dimethoxy) -2-quinazolinyl] -1-piperazinyl] -pyrazine-2-" q'\. carboxamide-dihydrochloride / f' . "41?!AY 1995 " " A ^ O ^ *^959 12 13.1 g (45.3 mmol) of N- [ (4-amino-6,7-dimethoxy)-2-quinazolinylJ-piperazine, 10 g (45.3 mmol) of methyl 3-amino-5, 6-dichloropyrazine-2-carboxylate and 7 ml of triethylamine are reacted in 60 ml of dimethylsulphoxide 5 for 2 hours at 80'C. After cooling, the reaction product is precipitated by the addition of 100 ml of water, suction filtered, dried and converted into the end product without any further purification using the method described in Example la) by reacting with 10 guanidine. Yield: 10.5 g; m.p. > 290"C. The compounds listed in the Tables which follow may be obtained analogously to the above Examples and in 15 accordance with the remarks in the specification. If the compounds take the form of the base the abbreviation BS appears in the column "Form", otherwise the acid with which the salt is formed is specified. - 13 - Tflble 1 Compounds of formula CI. ■\X3C 1^ N. ^OONH-C-NH, NH 1 NH, Nr. R1 R2 fJ959 Form mP { -C i ai3 ai3 - ii ai2^>~oai: IICl >280 2 * IICl amorph I'jC ch(ch3)-<«2 ii ai(ai3)-ai2 "3C 5 ai3 ai(a{3)-ai2 HCl 250-253 HCl 278 HCl 232-235 6 h at 2-oi2~o-\ y oai 7 H ai2-cn2-o-/~\ci ci^ 8 CH3 a{2-af2 -Q oar HCl 145-148 2 • HCl 122-125 HCl 141-143 {tNr / . \> ^V r; \ ~4 li.hi 3295 r ct j if Qy 14 r-'i • k' I^2 f orm mp.l-CI DQI3 cj m ai2-a!<?-H(ai3)-ai2-ai(on)-cn2-o-/ y 2 • iici 110-120 ci 10 11 cn^-ai2-H(ai3)~ai(ai)-qi2-o-^~^ IK «3-07 ci 1 i 1 ^ ii oi2-oi2-(jii-ai-ai(ai3)-ai2-<3^^ 2 . nci arnph i'3c 11 ai2^i2^l2^(ab)^'2^(aj)"<H2"<H\_/<:1 05 anorph CI 243959 - 15 - Table 2 Compounds of formula C1 v^-N^CONH-C-NH. II A. RN-C—N N NH " kt* l:orm _inp.l*C| 2 • IICl 237-210 2 • IICl 264-267 2 • IICl 239-242 2 * IICl 242 BS 177-180 Nr Ii 2 Cl ■P '/ V-Cl Cl b M Cl Cl F //•» « ^ r (" -41.:Ay i995 ' r-o ■ I? p J»' </div>

Claims

<div class="application article clearfix printTableText" id="claims"> ^0959 - 16 Table 3 Compounds of formula OONH-C-NH. Mi Ni Form__ mP- | 2 - iiCl 274 2 - HCl 225-2: - 17 WHAT WE CLAIM IS: 10

1. Compounds of formula N NH CU, /^V-CO-NH-C-NHj / N. N _NH. R 243959 (I) 15 wherein, independently of one another, R1 R2 represents H or a alkyl group; represents 20 a straight-chained or branched (Cx.4) alkyl chain which is substituted, a) by a phenoxy group which may in turn be mono-or polysubstituted by F, Cl, (Ci-2)alkyl or (Ci.j) alkoxy ; 30 b) by a phenoxy- ((C^) alkyl) -amino or a phenoxy-((Cx.4) alkyl) - (methylamino) group, in which the (C^) alkyl group may be mono- or polysubstituted by hydroxy, and in which the phenoxy group may be mono- or poly-substituted by F, Cl, (Ci.j) alkyl or (C^) alkoxy; or an amidino group of the formula 35 -C-NHR11 I NH (V), wherein R11 represents a phenyl group which is mono-4. 7 \ ^'<UY)935 r ;C * •,r sj z j y 18 or polysubstituted by F, Cl or a (C^)alkyl group,- 5 or R1 and R2 together denote, together with the nitrogen atom to which they are bound, a piperazine ring which is substituted in the 4-position by S nh2 N/\/y -0CH3 10 or 15 and acid addition salts thereof.

2 . N-Amidino-3-amino-6-chloro-5-[4-[(4-amino-6,7-dimethoxy) -2-quinazolinyl] -1-piperazinyl] -pyrazine-2-carboxamide and acid addition salts thereof. 20

3 . N-Amidino-3-amino-6-chloro-2- [N' - (5-fluoro-2-methyl)-phenyl]guanidinopyrazine-2-carboxamide and acid addition salts thereof. 25

4. N-Amidino-3-amino-6-chloro-5-[2-[1-(2,6-dimethyl-phenoxy) ] propylamino] pyrazine-2-carboxamide and acid addition salts thereof.

5. A pharmaceutical composition comprising a compound 3 0 as claimed in any one of claims 1 to 4 together with a pharmaceutically acceptable excipient, carrier or diluent.

6. The use of a compound as claimed in any of claims 3 5 l, 2, 3 or 4 in the preparation of pharmaceutical compositions having an antihypertensive, mucolytic, diuretic, cancerostatic and PAF-antagonistic activity.^ [>:A / i395 ctoy59 - 19 - 10 15

7. A process for preparing compounds of formula (I) as claimed in claim 1 in which a) a pyrazine carboxylic acid ester of formula /N\ Cl & —C02-alkyl J— (VII) N' 2 I R R N wherein R1, R2 are as defined in claim 1 and alkyl represents a (Cx.4) alkyl group is reacted with a guanidine of formula H2N-C=NH I NH2 (VIII) 20 or b) a pyrazine derivative of formula 25 l-AV f z (XI) , ,_CO- NH-C=NH ,H2 NHj 30 35 is reacted with an amine of formula HNR1R2 (VI) , wherein R1 and R2 are as defined in claim 1, '43959 followed, if desired, by conversion of any base of formula (I) obtained into an acid addition salt.

8. A process as claimed in claim 7 substantially as 5 hereinbefore described.

9. A process as claimed in claim 7 substantially as hereinbefore described and with reference to Examples 1 to 3 and the Tables. 0

10. Compositions as claimed in claim 5 substantially as hereinbefore described and with reference to the Pharmacy Examples. BOEHRINGER INGELHEIM INTERNATIONAL GmbH y Their Attorneys BALDWIN# SON & CAREY i l </div>