SI9300075A - 3-(1h-tetrazol-5-yl)-4h-pyrido(1,2a)pyrimidin-4-ones, pharmaceutical preparations comprising the same and process pro their preparing - Google Patents

3-(1h-tetrazol-5-yl)-4h-pyrido(1,2a)pyrimidin-4-ones, pharmaceutical preparations comprising the same and process pro their preparing Download PDF

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SI9300075A
SI9300075A SI19939300075A SI9300075A SI9300075A SI 9300075 A SI9300075 A SI 9300075A SI 19939300075 A SI19939300075 A SI 19939300075A SI 9300075 A SI9300075 A SI 9300075A SI 9300075 A SI9300075 A SI 9300075A
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general formula
tetrazol
pharmaceutically acceptable
hydrogen
alkyl
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SI19939300075A
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Slovenian (sl)
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Istvan Hermecz
Judit Sipos
Lelle Vasvari-Debreczy
Zoltan Kapui
Agnes Horvath
Maria Balogh
Geza Kereszturi
Kinga Boer
Aniko Pajor
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Chinoin Gyogyszer-
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Abstract

The invention relates to partly new 3-(1H &cir& _-tetrazol-5-yl)-4H &cir& _-pyrido[1,2-a &cir& _]pyrimidin-4-ones of general formula (I) and pharmaceutically acceptable salts and/or hydrates and the preparation thereof. These compounds possess significant antiallergic or antiulcer activity. The subjects of our invention are compounds of general formula (I) and pharmaceutically acceptable salts and/or hydrates thereof, wherein R stands for hydrogenatom, C1-4 alkyl group, or C6-10 aryl group; R<1> stands for hydrogenatom, C1-4 alkyl group, halogenatom, hydroxyl group, nitro group, carboxyl group, C2-5 alkoxycarbonyl group or C7-12 aralkoxy group; R<2> represents hydrogenatom, C1-4 alkyl group, or halogenatom; and a process for the preparation thereof. The invention also relates to a process for the preparation of compounds of general formula (I) and pharmaceutically acceptable salts and/or hydrates thereof, which comprises cyclising a 3-(2-pyridylamino)-2-(1H &cir& _-tetrazol-5-yl)acrylnitrile of general formula (II), (wherein the meanings of R, R<1> and R<2> are the same as defined above) in acidic media and converting the compound of general formula (I) thus obtained into a pharmaceutically acceptable salt thereof or, if desired, liberating the base from its salt, or converting it into another salt thereof in a way known per se.

Description

CHINOIN GYOYSZER- ES VEGYESZETI TERMEKEK GyXrA RT.CHINOIN GYOYSZER- ES VEGYESZETI TERMEKEK GyXrA RT.

3-(lH-tetrazol-5-il)-4H-pirido[l,2-a]pirimidin-4-oni, farmacevtski sestavki, ki jih vsebujejo in njihova priprava3- (1H-tetrazol-5-yl) -4H-pyrido [1,2-a] pyrimidin-4-ones, pharmaceutical compositions containing them and their preparation

Predloženi izum se nanaša na delno nove 3-(lH-tetrazol-5-il)-4H-pirido[l,2a]pirimidin-4-one s splošno formulo (I), na njihove farmacevtsko sprejemljive soli in/ali hidrate in njihovo pripravo. Te spojine imajo pomembno antialergijsko ali antiulkusno učinkovitostThe present invention relates to partially novel 3- (1H-tetrazol-5-yl) -4H-pyrido [1,2a] pyrimidin-4-ones of the general formula (I), to their pharmaceutically acceptable salts and / or hydrates and their preparation. These compounds have significant anti-allergic or antiulcer efficacy

3-(lH-tetrazol-5-il)-4H-pirido[l,2-a]pirimidin-4-oni s splošno formulo (I), kjer R predstavlja atom vodika, so opisani v US-PS št. 4122274 in 4209620 kot antialergijska sredstva, medtem ko v US-PS št. 4457932 kot antiulkusna sredstva.3- (1H-tetrazol-5-yl) -4H-pyrido [1,2-a] pyrimidin-4-ones of the general formula (I), wherein R represents a hydrogen atom, are described in US-PS no. 4122274 and 4209620 as anti-allergic agents, whereas in US-PS no. 4457932 as an antiulcer agent.

Izhodne snovi in postopki, uporabljeni v zgornjih patentnih opisih, pa niso zelo ugodni za pripravo spojin s splošno formulo (I), kjer R stoji za vodik, ker dajejo zelo nizke dobitke, celo nižje kot je prikazano v opisu in/ali navajajo uporabo nevarnih reaktantov, kot npr. zmesi aluminijevega klorida - natrijevega azida 1:3 v tetrahidrofuranu.The starting materials and processes used in the foregoing patent descriptions are not, however, very advantageous for the preparation of compounds of general formula (I) wherein R stands for hydrogen because they give very low yields, even lower than shown in the description and / or indicate the use of dangerous reactants such as e.g. aluminum chloride - sodium azide 1: 3 mixture in tetrahydrofuran.

Reaktanti in reakcijski pogoji, navedeni v US-PS št. 4474953 so bolj ugodni, vendar se 60-70 % dobitki, navedeni v primerih ne nanašajo na čiste (lH-tetrazol-5-il)-4Hpirido[l,2-a]pirimidin-4-one s splošno formulo (I), Iger R stoji za vodik. Po ponovitvi postopka smo identificirani in izolirali iz produkta s približno 30 % dobitkom izomemo zmes, ki sestoji iz 3-(2-etil-tetrazol-5-il) derivata s splošno formulo (III) in 3-(l-etil-tetrazol-5-il) derivata s splošno formulo (IV). Ta dva izomera lahko ločimo med seboj s kristalizacijo.The reactants and reaction conditions specified in US-PS no. 4474953 are more advantageous, but 60-70% of the yields given in the examples do not relate to pure (1H-tetrazol-5-yl) -4Hpyrido [1,2-a] pyrimidin-4-ones of general formula (I), Iger R stands for hydrogen. After repeating the process, an isomer mixture consisting of a 3- (2-ethyl-tetrazol-5-yl) derivative of the general formula (III) and 3- (1-ethyl-tetrazole- 5-yl) derivative of general formula (IV). These two isomers can be separated by crystallization.

Identifikacijo spojine s splošno formulo (IV) potrdimo z rentgensko difraktometrijo. Tvorbo teh spojin lahko razložimo z reakcijo etiliranja, kjer etanol, ki nastane pri reakciji zapiranja obroča etil-[3-(2-piridilamino)-2-(lH-tetrazol-5-il)akrilatov s splošno formulo (V) v polifosforjevi kislini, alkilira produkte zaprtja obroča, t.j. spojine s splošno formulo (I), kjer R stoji za vodik. Torej poleg spojine s splošno formulo (I) dobimo tudi pomembno količino spojin s splošnimi formulami (III) in (IV).The identification of a compound of general formula (IV) is confirmed by X-ray diffractometry. The formation of these compounds can be explained by an ethylation reaction, where the ethanol resulting from the ring-closing reaction of ethyl- [3- (2-pyridylamino) -2- (1H-tetrazol-5-yl) acrylates of the general formula (V) in polyphosphoric acid , alkylates ring closure products, i compounds of general formula (I) wherein R is hydrogen. Thus, in addition to the compound of general formula (I), a significant amount of the compounds of general formulas (III) and (IV) are also obtained.

Osnova našega izuma je nepričakovano odkritje, da akrilnitrile s splošno formulo (II) lahko pretvorimo na enostaven način z dobrim dobitkom in brez tvorbe stranskih produktov v pirido-[l,2-a]pirimidine s splošno formulo (I).The basis of our invention is the unexpected discovery that acrylonitriles of general formula (II) can be converted easily by good yield and without the formation of by-products to pyrido- [1,2-a] pyrimidines of general formula (I).

Predmet našega izuma so spojine s splošno formulo (I)The subject of our invention are compounds of general formula (I)

in njihove farmacevtsko sprejemljive soli in/ali hidrati, kjerand their pharmaceutically acceptable salts and / or hydrates, wherein

R stoji za atom vodika, CM alkilno skupino ali C610 arilno skupino;R represents a hydrogen atom, a C M alkyl group or a C 610 aryl group;

R1 stoji za atom vodika, alkilno skupino, atom halogena, hidroksilno skupino, nitro skupino, karboksilno skupino, C2 5 alkoksikarbonilno skupino ali C712 aralkoksi skupino;R 1 stands for hydrogen atom, alkyl group, halogen atom, hydroxyl group, nitro group, carboxyl group, C 2 5 alkoxycarbonyl group or C 712 aralkoxy group;

R2 predstavlja atom vodika, alkilno skupino ali atom halogena;R 2 represents a hydrogen atom, an alkyl group or a halogen atom;

in postopek za njihovo pripravo.and the process for preparing them.

Kot uporabljamo tukaj, izraz Cw alkilna skupina pomeni sam kot tak ali v deležih npr. v alkoksi skupinah, ravno ali razvejeno verigo alifatskih nenasičenih ogljikovodičnih skupin z 1 do 4 atomi ogljika (kot npr. metilna, etilna, n-propilna in terc.butilna skupina).As used herein, the term C w alkyl group means alone as such or in portions e.g. in alkoxy groups, a straight or branched chain aliphatic unsaturated hydrocarbon groups having 1 to 4 carbon atoms (such as methyl, ethyl, n-propyl and tert-butyl).

Kot uporabljamo tukaj, izraz C6 W arilna skupina pomeni fenilno skupino ali naftilno skupino, ki v danem primeru nosi ClJ( alkilno skupino.As used herein, the term C 6 W aryl group means a phenyl group or a naphthyl group which optionally bears a C 1J ( alkyl group).

Spojine s splošno formulo (I) lahko dajo ravnotežno zmes spojin s splošno formulo (IA) kot je prikazano s shemo A.Compounds of general formula (I) can give an equilibrium mixture of compounds of general formula (IA) as shown in Scheme A.

Shema AScheme A

Predloženi izum se nanaša tudi na postopek za pripravo spojin s splošno formulo (I) in njihovih farmacevtsko sprejemljivih soli in/ali hidratov, ki obsega ciklizacijo 3-(2piridilammo)-2-(lH-tetrazol-5-il)akrilnitrila s splošno formulo (II)The present invention also relates to a process for the preparation of compounds of general formula (I) and their pharmaceutically acceptable salts and / or hydrates, comprising the cyclization of 3- (2-pyridylamino) -2- (1H-tetrazol-5-yl) acrylonitrile of the general formula (II)

(II) (kjer so pomeni za R, R1 in R2 enaki kot je definirano zgoraj) v kislem mediju in pretvorbo tako dobljene spojine s splošno formulo (I) v njeno farmacevtsko sprejemljivo sol ali, če želimo, sprostitev baze iz njene soli ali pretvorbo le-te v njeno drugo sol po postopku znanem po sebi.(II) (where R, R 1 and R 2 are as defined above) in an acidic medium and converting the compound of the formula (I) thus obtained into its pharmaceutically acceptable salt or, if desired, releasing the base from its salt or converting it to another salt by a process known per se.

Uporaba spojin s splošno formulo (Π) obsega uporabo spojin s splošno formulo (ΠΑ) (Iger so R, R1 in R2 enaki kot je definirano zgoraj), ki predstavljajo tavtomeme ravnotežne zmesi spojin s splošno formulo (II) (glej shemo B) kot tudi tavtomere tetrazolnega obroča spojin s splošnimi formulami (Π) in (ΠΑ) in E-Z geometrične izomere spojin s splošno formulo (II).The use of compounds of general formula (Π) involves the use of compounds of general formula (ΠΑ) (Iger, R, R 1, and R 2 are the same as defined above), which represent the tautomatic equilibrium mixtures of compounds of general formula (II) (see Scheme B ) as well as tautomers of the tetrazole ring of compounds of the general formulas (Π) and (ΠΑ) and EZ geometric isomers of the compounds of general formula (II).

Kot kislinska sredstva lahko uporabimo organske in anorganske kisline. Če želimo lahko reakcijo izvedemo v prisotnosti topila prednostno v prisotnosti vode.Organic and inorganic acids can be used as acidic agents. If desired, the reaction can be carried out in the presence of a solvent, preferably in the presence of water.

Kot organske kisline lahko uporabimo alkankarboksilne kisline in arilsulfonske kisline. Kot neorganske kisline prednostno lahko uporabimo vodikove halogenide, sulfonsko kislino in razne kisline fosforja. Reakcijo lahko izvršimo, če želimo, pri povišani temperaturi. Temperaturo lahko izberemo v skladu z lastnostmi kislinskega sredstva in, če reakcijo izvedemo v prisotnosti topila, v skladu z lastnostmi topila. Reakcijo prednostno izvedemo pri temperaturi, kije različna od sobne temperature.As organic acids, alkanecarboxylic acids and arylsulfonic acids can be used. Hydrogen halides, sulfonic acid and various phosphoric acids can preferably be used as inorganic acids. The reaction can be carried out, if desired, at elevated temperature. The temperature can be selected according to the properties of the acidic agent and, if the reaction is carried out in the presence of a solvent, according to the properties of the solvent. The reaction is preferably carried out at a temperature different from room temperature.

Spojino s splošno formulo (I), ki jo dobimo pri reakciji, oborimo iz reakcijske zmesi po razredčenju z vodo ali potem, ko naravnamo pH reakcijske zmesi tako, da je nevtralen in jo lahko ponovno dobimo npr. s filtriranjem.The compound of general formula (I) obtained in the reaction is precipitated from the reaction mixture after dilution with water or after adjusting the pH of the reaction mixture to be neutral and readily obtainable e.g. by filtering.

Spojine s splošno formulo (I), če želimo lahko pretvorimo v njihove farmacevtsko sprejemljive soli in/ali hidrate z učinkovanjem kislin ali baz. Baze lahko sprostimo iz soli in, če želimo, pretvorimo v njihove druge soli. S tem postopkom lahko prednostno pripravimo kislinske adicijske soli npr. s klorovodikovo kislino, bromovodikovo kislino, žveplovo kislino, ocetno kislino, citronsko kislino itd. kot tudi natrijeve, kalijeve in kalcijeve soli.Compounds of general formula (I), if desired, can be converted into their pharmaceutically acceptable salts and / or hydrates by the action of acids or bases. The bases can be released from the salts and, if desired, converted to their other salts. Preferably, the acid addition salts of e.g. with hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, citric acid, etc. as well as sodium, potassium and calcium salts.

Spojino s splošno formulo (I) ali njene farmacevtsko sprejemljive soli lahko terapevtsko uporabimo v obliki farmacevtskih sestavkov, ki vsebujejo aktivni ingridient pomešan z inertnimi netoksičnimi trdnimi ali tekočimi razredčili in nosilci.The compound of general formula (I) or its pharmaceutically acceptable salts can be therapeutically used in the form of pharmaceutical compositions containing the active ingredient mixed with inert non-toxic solid or liquid diluents and carriers.

Te farmacevtske sestavke lahko formuliramo kot trdne snovi (tableta, kapsula, draže) ali kot tekočine (raztopina, suspenzija, emulzija).These pharmaceutical compositions can be formulated as solids (tablet, capsule, irritants) or as liquids (solution, suspension, emulsion).

Kot nosilce lahko uporabimo običajne snovi (kot npr. smukec, kalcijev karbonat, magnezijev stearat, vodo, polietilenglikol.As carriers, conventional substances (such as talc, calcium carbonate, magnesium stearate, water, polyethylene glycol may be used.

Pripravki, če želimo, lahko vsebujejo dodatne snovi, kot npr. emulgatorje ali snovi za raztapljanje.The preparations may, if desired, contain additional substances such as e.g. emulsifiers or dissolving substances.

Izhodne snovi s splošnimi formulami (Π) in (HA), ki tvorijo tavtomeme ravnotežne zmesi (glej shemo B)Starting materials of the general formulas (Π) and (HA) that form the tautomé equilibrium mixtures (see scheme B)

Shema B lahko pripravimo iz malonitrilov s splošno formulo (VI) (kjer so R, R1 in R2 enaki kot so definirani zgoraj), ki dajo tavtomeme ravnotežne zmesi s 3-ciano-4-imino-4Hpirido[l,2-a]pirimidini s splošno formulo (VIA) (glej shemo C)Scheme B can be prepared from malonitriles of the general formula (VI) (where R, R 1 and R 2 are the same as defined above) which yield tautomic equilibrium mixtures with 3-cyano-4-imino-4Hpyrido [1,2-a ] pyrimidines of general formula (VIA) (see Scheme C)

(VI) (VIA)(VI) (VIA)

Shema C z reakcijo z amonijevim azidom.Scheme C by reaction with ammonium azide.

Spojine s splošnimi formulami (VI) in (VIA) lahko sintetiziramo na enostaven način znan iz literature [Journal of Organic Chemistry, 1986, 51, 2988] z reakcijoCompounds of general formulas (VI) and (VIA) can be synthesized in a simple manner known from the literature [Journal of Organic Chemistry, 1986, 51, 2988] by reaction

2-amino-piridinov, malonitrila in ortoestrov, ki so na voljo na tržišču.Commercially available 2-amino-pyridines, malonitrile and orthoesters.

R1 R 1

Predloženi izum je podrobno prikazan z naslednjimi primeri, ki pa ga ne omejujejoThe present invention is illustrated in detail with the following examples, but not limited thereto

PRIMERIEXAMPLES

PrimeriExamples

53.3 g (0,25 mol) 3-(2-piridilamino)-2-(lH-tetrazol-5-il)-akrilnitrila segrevamo v 500 ml konc. klorovodikove kisline ob refluksu 1 uro. Po 10-15 minutnem segrevanju se originalni kristali raztopijo in nastanejo kristali produkta. Nastalo suspenzijo ohladimo, razredčimo s 1000 ml vode in nevtraliziramo s 25 % vodno raztopino amoniaka. Kristale zberemo in izperemo z vodo.53.3 g (0.25 mol) of 3- (2-pyridylamino) -2- (1H-tetrazol-5-yl) -acrylonitrile were heated in 500 ml of conc. hydrochloric acid at reflux for 1 hour. After 10-15 minutes of heating, the original crystals are dissolved and product crystals are formed. The resulting suspension was cooled, diluted with 1000 ml of water and neutralized with a 25% aqueous ammonia solution. The crystals were collected and washed with water.

Produkt: 41,48 g (87,9 %) 3-(lH-tetrazol-5-il)-4-okso-4H-pirido[l,2-a]pirimidina.Product: 41.48 g (87.9%) of 3- (1H-tetrazol-5-yl) -4-oxo-4H-pyrido [1,2-a] pyrimidine.

Tal.: 316°C (razp.)Melting point: 316 ° C (dec.)

Analiza za C9H6N6O izrač.: C 50,47%; H 2,82%; N 39,24%;Analysis for C 9 H 6 N 6 O Calc .: C 50.47%; H, 2.82%; N, 39.24%;

ugot.: C 49,73%; H 2,77%; N 39,48%.found: C, 49.73%; H, 2.77%; N, 39.48%.

Primer 2Example 2

23,7 g (0,1 mol) 3-[(3-metil-2-piridil)amino]-2-(lH-tetrazol-5-il)-akrilnitrila segrevamo v 200 ml konc. klorovodikove kisline ob refluksu 1 uro. Po 10-15 minutnem segrevanju se originalni kristali raztopijo in nastanejo kristali produkta. Nastalo suspenzijo ohladimo, razredčimo s 400 ml vode in nevtraliziramo s 25 % vodno raztopino amoniaka (pH = 6,5). Kristale zberemo in izperemo z vodo.23.7 g (0.1 mol) of 3 - [(3-methyl-2-pyridyl) amino] -2- (1H-tetrazol-5-yl) -acrylonitrile were heated in 200 ml of conc. hydrochloric acid at reflux for 1 hour. After 10-15 minutes of heating, the original crystals are dissolved and product crystals are formed. The resulting suspension was cooled, diluted with 400 ml of water and neutralized with 25% aqueous ammonia solution (pH = 6.5). The crystals were collected and washed with water.

Produkt: 19,57 g (85,76 %) 3-(lH-tetrazol-5-il)-9-metil-4-okso-4H-pirido[l,2ajpirimidina.Product: 19.57 g (85.76%) of 3- (1H-tetrazol-5-yl) -9-methyl-4-oxo-4H-pyrido [1,2-pyrimidine.

Tal.: 312°C razp. (dimetilformamid)Melting point: 312 ° C dec. (dimethylformamide)

Analiza za C10HgN6O izrač.: C 52,62%; H 3,53%; N 36,83%;Analysis for C 10 H g N 6 O calcd: C 52.62%; H, 3.53%; N, 36.83%;

ugot.: C 52,66%; H 3,44%; N 37,27%.Found: C, 52.66%; H, 3.44%; N, 37.27%.

Primer 3Example 3

13.3 g (0,059 mol) 3-[(6-metil-2-piridil)amino]-2-(lH-tetrazol-5-il)akrilnitrila dodamo ob mešanju k 70 g polifosfoijeve kisline pri 60°C. Reakcijsko zmes segrevamo in mešamo v oljni kopeli pri 130-140°C 2 uri, nato jo ohladimo na 3040°C, previdno razredčimo z 210 ml vode in nevtraliziramo ob hlajenju z ledom s 75 ml 25 % vodne raztopine amoniaka (pH = 6,5-7). Oborjene kristale zberemo in izperemo z vodo.13.3 g (0.059 mol) of 3 - [(6-methyl-2-pyridyl) amino] -2- (1H-tetrazol-5-yl) acrylonitrile were added while stirring to 70 g of polyphosphoic acid at 60 ° C. The reaction mixture was heated and stirred in an oil bath at 130-140 ° C for 2 hours, then cooled to 3040 ° C, carefully diluted with 210 ml of water and neutralized by ice-cooling with 75 ml of 25% aqueous ammonia (pH = 6, 5-7). The precipitated crystals were collected and washed with water.

Produkt: 12,7 g (94,8 %) 3-(lH-tetrazol-5-il)-6-metil-4-okso-4H-pirido[l,2ajpirimidina.Product: 12.7 g (94.8%) of 3- (1H-tetrazol-5-yl) -6-methyl-4-oxo-4H-pyrido [1,2-pyrimidine.

Tal.: 286°C razp. (dimetilformamid)Melting point: 286 ° C dec. (dimethylformamide)

Analiza za C10HgN6O izrač.: C 52,62 %; H 3,53 %; N 36,83 %;Analysis for C 10 HgN 6 O calcd: C 52.62%; H, 3.53%; N, 36.83%;

ugot.: C 52,80%; H 3,48%; N 37,01%.found: C 52.80%; H, 3.48%; N, 37.01%.

Primer 4Example 4

2,41 g (0,01 mol) 3-metil-3-[(6-metil-2-piridil)-amino]-2-(lH-tetrazol-5il)akrilnitrila dodamo ob mešanju k 20 g polifosforjeve kisline pri 60°C. Reakcijsko zmes segrevamo in mešamo v oljni kopeli pri 130-140°C 4 ure, nato jo ohladimo na 50-60°C, previdno razredčimo z 28 ml vode in nevtraliziramo ob hlajenju z ledom s 28 ml 25 % vodne raztopine amoniaka (pH = 7). Oborjene kristale zberemo in izperemo z vodo.2.41 g (0.01 mol) of 3-methyl-3 - [(6-methyl-2-pyridyl) -amino] -2- (1H-tetrazol-5yl) acrylonitrile was added while stirring to 20 g of polyphosphoric acid at 60 ° C. The reaction mixture was heated and stirred in an oil bath at 130-140 ° C for 4 hours, then cooled to 50-60 ° C, carefully diluted with 28 ml of water and neutralized by ice-cooling with 28 ml of 25% aqueous ammonia (pH = 7). The precipitated crystals were collected and washed with water.

Produkt: 1,47 g (60,8 %) 3-(lH-tetrazol-5-il)-2,6-dimetil-4-okso-4H-pirido[l,2ajpirimidina.Product: 1.47 g (60.8%) of 3- (1H-tetrazol-5-yl) -2,6-dimethyl-4-oxo-4H-pyrido [1,2-pyrimidine.

Tal.: 258-260°C razp. (dimetilformamid)Melting point: 258-260 ° C dec. (dimethylformamide)

Analiza za CnH10N6O izrač.: C 54,54%; H 4,16%; N 34,70%;Analysis for C n H 10 N 6 O calcd: C 54.54%; H, 4.16%; N, 34.70%;

ugot.: C 54,58%; H 4,12%; N 34,33%.found: C 54.58%; H, 4.12%; N, 34.33%.

Primer 5Example 5

2,47 g (0,01 mol) 3-[(5-kloro-2-piridil)-amino]-2-(lH-tetrazol-5-il)akrilnitrila dodamo ob mešanju k 12 g polifosforjeve kisline pri 60°C. Reakcijsko zmes segrevamo in mešamo v oljni kopeli pri 130-140°C 1 uro, nato jo ohladimo na 5060°C, previdno razredčimo s 50 ml vode in nevtraliziramo ob hlajenju z ledom s 25 ml 25 % vodne raztopine amoniaka (pH = 6,5-7). Oborjene kristale zberemo in izperemo z vodo.2.47 g (0.01 mol) of 3 - [(5-chloro-2-pyridyl) -amino] -2- (1H-tetrazol-5-yl) acrylonitrile was added while stirring to 12 g of polyphosphoric acid at 60 ° C. . The reaction mixture was heated and stirred in an oil bath at 130-140 ° C for 1 hour, then cooled to 5060 ° C, carefully diluted with 50 ml of water and neutralized by ice-cooling with 25 ml of 25% aqueous ammonia (pH = 6, 5-7). The precipitated crystals were collected and washed with water.

Produkt: 1,7 g (68,6 %) 3-(lH-tetrazol-5-il)-7-kloro-4-okso-4H-pirido[l,2ajpirimidma.Product: 1.7 g (68.6%) of 3- (1H-tetrazol-5-yl) -7-chloro-4-oxo-4H-pyrido [1,2-pyrimidine.

Tal.: 304°C razp.Melting point: 304 ° C dec.

Analiza za C9H5N6OC1 izrač.: C 43,48%; H 2,03%; N 33,80%; Cl 14,26%;Analysis for C 9 H 5 N 6 OC 1 calculated: C 43.48%; H, 2.03%; N, 33.80%; Cl, 14.26%;

ugot.: C 43,71%; H 2,50%; N 33,53% Cl 14,60%.found: C 43.71%; H, 2.50%; N 33.53% Cl 14.60%.

PrimeriExamples

2,27 g (0,01 mol) 3-[(5-metil-2-piridil)-amino]-2-(lH-tetrazol-5-il)akrilnitrila dodamo ob mešanju k 12 g poiifosforjeve kisline pri 60°C. Reakcijsko zmes segrevamo in mešamo v oljni kopeli pri 140°C 1 uro, nato jo ohladimo na sobno temperaturo, previdno razredčimo s 50 ml vode in nevtraliziramo ob hlajenju z ledom s 20 ml 25 % vodne raztopine amoniaka. Oborjene kristale zberemo in izperemo z vodo.2.27 g (0.01 mol) of 3 - [(5-methyl-2-pyridyl) -amino] -2- (1H-tetrazol-5-yl) acrylonitrile was added while stirring to 12 g of polyphosphoric acid at 60 ° C. . The reaction mixture was heated and stirred in an oil bath at 140 ° C for 1 hour, then cooled to room temperature, carefully diluted with 50 ml of water and neutralized by ice-cooling with 20 ml of 25% aqueous ammonia solution. The precipitated crystals were collected and washed with water.

Produkt: 2,3 g (93,5 %) 3-(lH-tetrazol-5-il)-7-metil-4-okso-4H-pirido[l,2ajpirimidina monohidrata.Product: 2.3 g (93.5%) of 3- (1H-tetrazol-5-yl) -7-methyl-4-oxo-4H-pyrido [1,2-pyrimidine monohydrate.

Tal.: 297°C razp.Melting point: 297 ° C dec.

Analiza za C10HgN6O.H2O izrač.: C 48,78%; H 4,09%; N 34,13%;Analysis for C 10 H g N 6 OH 2 O calcd: C 48.78%; H, 4.09%; N, 34.13%;

ugot.: C 49,34%; H 4,18%; N 34,57%.found: C, 49.34%; H, 4.18%; N, 34.57%.

Primer 7Example 7

2,27 g (0,01 mol) 3-[(4-metil-2-piridil)-amino]-2-(lH-tetrazol-5-il)akrilnitrila dodamo ob mešanju k 20 g poiifosforjeve kisline pri 60°C. Reakcijsko zmes segrevamo in mešamo v oljni kopeli pri 140°C 1 uro, nato jo ohladimo na sobno temperaturo, previdno razredčimo s 60 ml vode in nevtraliziramo ob hlajenju z ledom z 28 ml 25 % vodne raztopine amoniaka (pH = 6,5-7). Oborjene kristale zberemo in izperemo z vodo.2.27 g (0.01 mol) of 3 - [(4-methyl-2-pyridyl) -amino] -2- (1H-tetrazol-5-yl) acrylonitrile was added while stirring to 20 g of polyphosphoric acid at 60 ° C. . The reaction mixture was heated and stirred in an oil bath at 140 ° C for 1 hour, then cooled to room temperature, carefully diluted with 60 ml of water and neutralized by ice-cooling with 28 ml of 25% aqueous ammonia (pH = 6.5-7 ). The precipitated crystals were collected and washed with water.

Produkt: 2,24 g (94,5 %) 3-(lH-tetrazol-5-il)-8-metil-4-okso-4H-pirido[l,2ajpirimidina hemihidrata.Product: 2.24 g (94.5%) of 3- (1H-tetrazol-5-yl) -8-methyl-4-oxo-4H-pyrido [1,2-pyrimidine hemihydrate.

Tal.: 288°C razp.Melting point: 288 ° C dec.

Analiza za C^H^OJ/^O izrač.: C 50,63%; H 3,82%; N 35,42%;Analysis for C 25 H 18 F 3 O 3 O Calc .: C 50.63%; H, 3.82%; N, 35.42%;

ugot.: C 50,26%; H 3,90%; N 35,38%.Found: C, 50.26%; H, 3.90%; N, 35.38%.

Primer 8Example 8

2,41 g (0,01 mol) 3-[(4,6-dimetil-2-piridil)-amino]-2-(lH-tetrazol-5-il)akrilnitrila dodamo ob mešanju k 12 g polifosforjeve kisline pri 60°C. Reakcijsko zmes segrevamo in mešamo v oljni kopeli pri 140°C 1 uro, nato jo ohladimo na sobno temperaturo, previdno razredčimo s 50 ml vode in nevtraliziramo ob hlajenju z ledom z 18 ml 25 % vodne raztopine amoniaka. Oborjene kristale zberemo in izperemo z vodo.2.41 g (0.01 mol) of 3 - [(4,6-dimethyl-2-pyridyl) -amino] -2- (1H-tetrazol-5-yl) acrylonitrile was added while stirring to 12 g of polyphosphoric acid at 60 ° C. The reaction mixture was heated and stirred in an oil bath at 140 ° C for 1 hour, then cooled to room temperature, carefully diluted with 50 ml of water and neutralized by ice-cooling with 18 ml of 25% aqueous ammonia solution. The precipitated crystals were collected and washed with water.

Produkt: 1,43 g (59,1 %) 3-(lH-tetrazol-5-il)-6,8-dimetil-4-okso-4H-pirido[l,2ajpirimidina.Product: 1.43 g (59.1%) of 3- (1H-tetrazol-5-yl) -6,8-dimethyl-4-oxo-4H-pyrido [1,2-pyrimidine.

Tal.: 350°C razp.Mp .: 350 ° C dec.

Analiza za C^H^N^O izrač.: C 54,54%; H 4,16%; N 34,69%;Analysis for C 25 H 28 N 4 O calc .: C 54.54%; H, 4.16%; N, 34.69%;

ugot.: C 54,35%; H 4,21%; N 33,94%.found: C 54.35%; H 4.21%; N, 33.94%.

Primer 9Example 9

2,3 g (0,01 mol) 3-[(3-hidroksi-2-piridil)-amiho]-2-(lH-tetrazol-5-il)akrilnitrila segrevamo v 20 ml konc. klorovodikove kisline ob refluksu 1 uro. Reakcijsko zmes ohladimo na sobno temperaturo in zlijemo v 30 ml vode ter pH naravnamo na 6,5 s 10 ml 25 % vodne raztopine amonika. Kristale zberemo in izperemo z vodo.2.3 g (0.01 mol) of 3 - [(3-hydroxy-2-pyridyl) -amino] -2- (1H-tetrazol-5-yl) acrylonitrile are heated in 20 ml of conc. hydrochloric acid at reflux for 1 hour. The reaction mixture was cooled to room temperature and poured into 30 ml of water and the pH adjusted to 6.5 with 10 ml of 25% aqueous ammonia solution. The crystals were collected and washed with water.

Produkt: 2,4 g (90,2 %) hidrokloridne soli 3-(lH-tetrazol-5-il)-9-hidroksi-4-okso-4Hpirido[l,2-a]pirimidina.Product: 2.4 g (90.2%) of the 3- (1H-tetrazol-5-yl) -9-hydroxy-4-oxo-4H-pyrido [1,2-a] pyrimidine hydrochloride salt.

Tal.: 324°C razp.Melting point: 324 ° C dec.

Analiza za C^N^^HCl izrač.: C 40,54%; H 2,65%; N 31,52%;Analysis for C 26 H 26 HCl Calc .: C, 40.54%; H 2.65%; N, 31.52%;

ugot.: C 40,82%; H 2,78%; N 31,26%.found: C, 40.82%; H, 2.78%; N, 31.26%.

Primer 10Example 10

1,1 g (0,004 mol) 3-[(3,5-dikloro-2-piridil)-amino]-2-(lH-tetrazol-5-il)akrilnitrila dodamo ob mešanju k 12 g polifosforjeve kisline pri 60°C. Reakcijsko zmes segrevamo in mešamo v oljni kopeli pri 130-140°C 30 minut, nato jo ohladimo na 60°C, previdno razredčimo s 50 ml vode in nevtraliziramo ob hlajenju z ledom s 15 ml % vodne raztopine raztopine amonika (pH = 7). Oborjene kristale zberemo in izperemo z vodo.1.1 g (0.004 mol) of 3 - [(3,5-dichloro-2-pyridyl) -amino] -2- (1H-tetrazol-5-yl) acrylonitrile was added while stirring to 12 g of polyphosphoric acid at 60 ° C. . The reaction mixture was heated and stirred in an oil bath at 130-140 ° C for 30 minutes, then cooled to 60 ° C, diluted carefully with 50 ml of water and neutralized by cooling with ice with 15 ml% aqueous ammonia solution (pH = 7). . The precipitated crystals were collected and washed with water.

Produkt: 1,04 g (90,4 %) 3-(lH-tetrazol-5-il)-dikloro-4-okso-4H-pirido[l,2ajpirimidina.Product: 1.04 g (90.4%) of 3- (1H-tetrazol-5-yl) -dichloro-4-oxo-4H-pyrido [1,2-pyrimidine.

Tal.: 291°C razp. (dimetilformamid).Melting point: 291 ° C dec. (dimethylformamide).

Analiza za C9H4N6C12O izrač.: C 38,19%; H 1,42%; N 29,69%; Cl 25,05%;Analysis for C 9 H 4 N 6 C1 2 O calcd: C 38.19%; H, 1.42%; N, 29.69%; Cl 25.05%;

ugot.: C 37,80%; H 1,58%; N 29,77% Cl 25,02%.found: C 37.80%; H, 1.58%; N, 29.77%; Cl, 25.02%.

PrimerilPrimer

1,25 g (4 mmol) 3-(5-bromo-2-piridilamino)-2-(lH-tetrazol-5-il)akrilnitrila segrevamo v 10 ml konc. klorovodikove kisline ob refluksu 1 uro. Reakcijsko zmes ohladimo na sobno temperaturo in zlijemo v 30 ml vode ter nevtraliziramo z 10 ml 25 % vodne raztopine amoniaka (pH = 7). Kristale zberemo in izperemo z vodo. Produkt: 1,25 g (99,0 %) 3-(lH-tetrazol-5-il)-7-bromo-4-okso-4H-pirido[l,2ajpirimidina.1.25 g (4 mmol) of 3- (5-bromo-2-pyridylamino) -2- (1H-tetrazol-5-yl) acrylonitrile were heated in 10 ml of conc. hydrochloric acid at reflux for 1 hour. The reaction mixture was cooled to room temperature and poured into 30 ml of water and neutralized with 10 ml of 25% aqueous ammonia solution (pH = 7). The crystals were collected and washed with water. Product: 1.25 g (99.0%) of 3- (1H-tetrazol-5-yl) -7-bromo-4-oxo-4H-pyrido [1,2-pyrimidine.

Tal.: 298-300°C razp.Melting point: 298-300 ° C dec.

Analiza za C9H5N6BrO izrač.: C 36,88%; H 1,72%; N 28,67%; Br 27,26%;Analysis for C 9 H 5 N 6 BrO Calc .: C 36.88%; H, 1.72%; N, 28.67%; Br 27.26%;

ugot.: C 36,76%; H 1,62%; N 28,86% Br 27,13%.found: C 36.76%; H, 1.62%; N, 28.86%; Br, 27.13%.

Primer 12Example 12

1,41 g (4,6 mmol) 3-fenil-[(6-metil-2-piridil)-amino]-2-(lH-tetrazol-5-il)akrilnitrila dodamo ob mešanju k 12 g polifosfoijeve kisline pri 60°C. Reakcijsko zmes segrevamo in mešamo v oljni kopeli pri 130-140°C 1 uro, nato jo ohladimo na 60°C, previdno razredčimo s 60 ml vode in nevtraliziramo ob hlajenju z ledom s 14 ml 25 % vodne raztopine amonika (pH = 7). Oborjene kristale zberemo in izperemo z vodo. Produkt: 1,05 g (75,0 %) 3-(lH-tetrazol-5-il)-2-fenil-6-metil-4-okso-4H-pirido[l,2ajpirimidina.1.41 g (4.6 mmol) of 3-phenyl - [(6-methyl-2-pyridyl) -amino] -2- (1H-tetrazol-5-yl) acrylonitrile was added while stirring to 12 g of polyphosphoic acid at 60 ° C. The reaction mixture was heated and stirred in an oil bath at 130-140 ° C for 1 hour, then cooled to 60 ° C, carefully diluted with 60 ml of water and neutralized by cooling with ice with 14 ml of 25% aqueous ammonia solution (pH = 7) . The precipitated crystals were collected and washed with water. Product: 1.05 g (75.0%) of 3- (1H-tetrazol-5-yl) -2-phenyl-6-methyl-4-oxo-4H-pyrido [1,2-pyrimidine.

Tal.: 280°C razp. (dimetilformamid).Melting point: 280 ° C dec. (dimethylformamide).

Analiza za C16H12N6O izrač.: C 63,15%; H 3,97%; N 27,62%;Analysis for C 16 H 12 N 6 O Calc .: C 63.15%; H, 3.97%; N, 27.62%;

ugot.: C 63,39%; H 3,66%; N 27,72%.found: C 63.39%; H, 3.66%; N, 27.72%.

Primer 13Example 13

0,65 g (2,5 mmol) 3-(3-nitro-2-piridilamino)-2-(lH-tetrazol-5-il)akrilnitrila segrevamo v 10 ml konc. klorovodikove kisline ob refluksu 1 uro. Reakcijsko zmes ohladimo na sobno temperaturo in zlijemo v 35 ml vode ter nevtraliziramo z 9 ml 25 % vodne raztopine amoniaka (pH = 7). Kristale zberemo in izperemo z vodo. Produkt: 0,49 g (75,0 %) 3-(lH-tetrazol-5-il)-9-nitro-4-okso-4H-pirido[l,2ajpirimidina.0.65 g (2.5 mmol) of 3- (3-nitro-2-pyridylamino) -2- (1H-tetrazol-5-yl) acrylonitrile was heated in 10 ml of conc. hydrochloric acid at reflux for 1 hour. The reaction mixture was cooled to room temperature and poured into 35 ml of water and neutralized with 9 ml of 25% aqueous ammonia solution (pH = 7). The crystals were collected and washed with water. Product: 0.49 g (75.0%) of 3- (1H-tetrazol-5-yl) -9-nitro-4-oxo-4H-pyrido [1,2-pyrimidine.

Tal.: 283-285°C razp.Melting point: 283-285 ° C dec.

Analiza za C9H5N7O3 izrač.: C 41,71%; H 1,94%; N 37,83 %;Analysis for C 9 H 5 N 7 O 3 Calc: C 41.71%; H, 1.94%; N, 37.83%;

ugot.: C 41,20%; H 2,30%; N 38,20%.found: C 41.20%; H 2.30%; N, 38.20%.

Primer 14Example 14

1,4 g (0,005 mol) 3-[(3-etoksikarbonil-2-piridil)-amino]-2-(lH-tetrazol-5il)akrilnitrila dodamo ob mešanju k 12 g polifosforjeve kisline pri 60°C. Reakcijsko zmes segrevamo in mešamo v oljni kopeli pri 130-140°C 1 uro, nato jo ohladimo na 60°C, previdno razredčimo s 50 ml vode in nevtraliziramo ob hlajenju z ledom s 16 ml 25 % vodne raztopine amonika (pH = 7). Oborjene kristale zberemo in izperemo z vodo.1.4 g (0.005 mol) of 3 - [(3-ethoxycarbonyl-2-pyridyl) -amino] -2- (1H-tetrazol-5yl) acrylonitrile were added while stirring to 12 g of polyphosphoric acid at 60 ° C. The reaction mixture was heated and stirred in an oil bath at 130-140 ° C for 1 hour, then cooled to 60 ° C, diluted carefully with 50 ml of water and neutralized by ice-cooling with 16 ml of 25% aqueous ammonia (pH = 7). . The precipitated crystals were collected and washed with water.

Produkt: 3-(lH-tetrazol-5-il)-9-etoksikarbonil-6-metil-4-okso-4H-pirido[l,2-a]pirimidin.Product: 3- (1H-Tetrazol-5-yl) -9-ethoxycarbonyl-6-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine.

Tal.: 247-250°C razp.Melting point: 247-250 ° C dec.

Analiza za C12H1QN6O izrač.: C 50,35%; H 3,52%; N 29,36%;Analysis for C 12 H 1Q N 6 O calcd: C 50.35%; H, 3.52%; N, 29.36%;

ugot.: C 50,12%; H 3,45%; N 29,87%.found: C, 50.12%; H, 3.45%; N, 29.87%.

Primer 15Example 15

Priprava 50,100,200 in 400 mg tablet.Preparation of 50,100,200 and 400 mg tablets.

750 mg kalijeve soli 3-(lH-tetrazol-5-il)-2,6-dimetil-4-okso-4H-pirido[l,2ajpirimidina homogeniziramo s 1050 g kristalne celuloze in 15 g amidopektina.750 mg of the potassium salt of 3- (1H-tetrazol-5-yl) -2,6-dimethyl-4-oxo-4H-pyrido [1,2-pyrimidine is homogenized with 1050 g of crystalline cellulose and 15 g of amidopectin.

Zmes granuliramo s 150 g Eudragit-lac raztopine, nato jo posušimo pri 40°C in ponovno granuliramo. Granulat homogeniziramo s praškasto zmesjo, ki sestoji iz 20 g smukca in 20 g magnezijevega stearata, nato jo s postopkom znanim po sebi z ustreznimi pripravami za stiskanje, stisnemo v tablete 50,100,200 in 400 mg.The mixture was granulated with 150 g of Eudragit-lac solution, then dried at 40 ° C and granulated again. The granulate is homogenized with a powder mixture consisting of 20 g of talc and 20 g of magnesium stearate, and then compressed into 50,100,200 and 400 mg tablets by a process known per se with suitable compression preparations.

Claims (7)

PATENTNI ZAHTEVKIPATENT APPLICATIONS 1. Spojine s splošno formulo (I)1. Compounds of general formula (I) N-N HN-N H O (I) ali njihove farmacevtsko sprejemljive soli in/ali hidrati, kjerO (I) or pharmaceutically acceptable salts and / or hydrates thereof, wherein R stoji za vodik, CM alkil ali C610 aril;R is hydrogen, C M alkyl, or C 610 aryl; R1 stoji za vodik, CM alkil, halogen, hidroksil, nitro, karboksil, C2 5 alkoksikarbonil ali C? 12 aralkoksi;R 1 stands for hydrogen, C 1-4 alkyl, halogen, hydroxyl, nitro, carboxyl, C 2-5 alkoxycarbonyl or C ? 12 aralkoxy; R2 predstavlja vodik, alkil ali halogen;R 2 represents hydrogen, alkyl or halogen; s pridržkom, da če R stoji za vodik, je R1 različen od vodika, alkila ali halogena.with the proviso that if R stands for hydrogen, R 1 is different from hydrogen, alkyl or halogen. 2. Farmacevtski sestavek, označen s tem, da kot aktivni ingredient obsega spojino s splošno formulo (I) ali njene farmacevtsko sprejemljive soli in/ali hidrate, pri čemer so R, R1 in R2 enaki kot so definirani v zahtevku 1.2. A pharmaceutical composition comprising as active ingredient a compound of general formula (I) or pharmaceutically acceptable salts and / or hydrates thereof, wherein R, R 1 and R 2 are the same as defined in claim 1. 3. Postopek za pripravo spojine s splošno formulo (I) (I) ali njenih farmacevtsko sprejemljivih soli in/ali hidratov, pri čemerA process for the preparation of a compound of general formula (I) (I) or its pharmaceutically acceptable salts and / or hydrates, wherein R stoji za vodik, CM alkil ali C610 aril;R is hydrogen, C M alkyl, or C 610 aryl; R1 stoji za vodik, C14 alkil, halogen, hidroksil, nitro, karboksil, C2 5 alkoksikarbonil ali C? 12 aralkoksi;R 1 stands for hydrogen, C 14 alkyl, halogen, hydroxyl, nitro, carboxyl, C 2 5 alkoxycarbonyl or C ? 12 aralkoxy; R2 predstavlja vodik, CM alkil ali halogen;R 2 represents hydrogen, C 1-4 alkyl or halogen; označen s tem, da obsega ciklizacijo 3-(2-piridil-amino)-2-(lH-tetrazol-5-il)-akrilnitrila s splošno formulo (II), pri čemer so pomeni za R, R1 in R2 definirani zgoraj, v kislinskem mediju, in pretvorbo tako dobljene spojine s splošno formulo (I) v njeno farmacevtsko sprejemljivo sol in/ali hidrat ali sprostitev baze iz soli in pretvorbo le-te v drugo sol s postopkom, znanim po sebi.characterized in that it comprises the cyclization of 3- (2-pyridyl-amino) -2- (1H-tetrazol-5-yl) -acrylonitrile of the general formula (II), wherein R, R 1 and R 2 are defined above, in an acidic medium, and converting the compound of the formula (I) thus obtained into its pharmaceutically acceptable salt and / or hydrate or releasing the base from the salt and converting it to another salt by a process known in the art. 4. Postopek po zahtevku 3, označen s tem, da obsega uporabo organskih ali anorganskih kislin, kot npr. alkankarboksilne kisline, arilsulfonske kisline, vodikovega halogenida, žveplove kisline ali fosforjeve kisline kot kislinskega medija.Process according to claim 3, characterized in that it comprises the use of organic or inorganic acids, such as e.g. alkanecarboxylic acid, arylsulfonic acid, hydrogen halide, sulfuric acid or phosphoric acid as the acidic medium. 5. Postopek po zahtevku 3, označen s tem, da obsega ciklizacijo spojine s splošno formulo (II) (II) pri čemer so pomeni za R, R1 in R2 enaki kot so definirani v zahtevku 1, v prisotnosti topila.A process according to claim 3, characterized in that it comprises cyclization of a compound of general formula (II) (II) wherein R, R 1 and R 2 are the same as defined in claim 1 in the presence of a solvent. 6. Postopek po zahtevku 3, označen s tem, da obsega uporabo vode kot topila.A process according to claim 3, characterized in that it comprises the use of water as a solvent. 7. Postopek po zahtevkih 3-4, označen s tem, da obsega izvajanje ciklizacije pri temperaturi med 25-50°C.The process according to claims 3-4, characterized in that it comprises performing the cyclization at a temperature between 25-50 ° C. ZaFor CHINOIN GYOYSZER- ES VEGYESZETI TERMEKEK GYARA RT.:CHINOIN GYOYSZER- ES VEGYESZETI TERMEKEK GYARA RT .: 22609-II-93-MD22609-II-93-MD PATENTNA PIS&SNA LJUBL^NA zwrPATENT LETTER & SNA LJUBL ^ NA with wr POVZETEKSUMMARY 3-(lH-tetrazol-5-il)-4H-pirido[l,2-a]pirimidin-4-oni, farmacevcevtski sestavki, ki jih vsebujejo in njihova priprava3- (1H-tetrazol-5-yl) -4H-pyrido [1,2-a] pyrimidin-4-ones, pharmaceutical compositions containing them and their preparation Predloženi izum se nanaša na delno nove 3-(lH-tetrazol-5-il)-4Hpirido[l,2a]pirimidin-4-one s splošno formulo (I) in njihove farmacevtsko sprejemljive soli in/ali hidrate ter njihovo pripravo. Te spojine imajo pomembno antialergijsko ali antiulkusno učinkovitost.The present invention relates to partially novel 3- (1H-tetrazol-5-yl) -4Hpyrido [1,2a] pyrimidin-4-ones of the general formula (I) and their pharmaceutically acceptable salts and / or hydrates and their preparation. These compounds have significant anti-allergic or antiulcer efficacy. Predmet našega izuma so spojine s splošno formulo (I) in njihove farmacevtsko sprejemljive soli in/ali hidrati, kjerThe subject of our invention are compounds of general formula (I) and their pharmaceutically acceptable salts and / or hydrates, wherein R stoji za vodik, C1-t alkil ali C610 aril;R stands for hydrogen, C 1-t alkyl or C 610 aryl; R1 stoji za vodik, CM alkil, halogen, hidroksil, nitro, karboksil, C25 alkoksikarbonil ali C712 aralkoksi;R 1 stands for hydrogen, C M alkyl, halogen, hydroxyl, nitro, carboxyl, C 25 alkoxycarbonyl or C 712 aralkoxy; R2 predstavlja vodik, CM alkil ali halogen;R 2 represents hydrogen, C 1-4 alkyl or halogen; in postopek za njihovo pripravo.and the process for preparing them. Predloženi izum se nanaša tudi na postopek za pripravo spojin s splošno formulo (I) in njihovih farmacevtsko sprejemljivih soli in/ali hidratov, pri čemer obsega ciklizacijo 3-(2-piridilamino)-2-(lH-tetrazol-5-il)akrilnitrila v kislinskem mediju in pretvorbo tako dobljene spojine s splošno formulo (I) v njeno farmacevtsko sprejemljivo sol ali, če želimo, sprostitev baze iz njene soli ali pretvorbo le-te v drugo njeno sol po postopku znanem po sebi.The present invention also relates to a process for the preparation of compounds of general formula (I) and their pharmaceutically acceptable salts and / or hydrates, comprising the cyclization of 3- (2-pyridylamino) -2- (1H-tetrazol-5-yl) acrylonitrile in an acidic medium and converting the compound of the formula (I) thus obtained into its pharmaceutically acceptable salt or, if desired, releasing the base from its salt or converting it to another salt thereof by a process known per se.
SI19939300075A 1992-02-13 1993-02-12 3-(1h-tetrazol-5-yl)-4h-pyrido(1,2a)pyrimidin-4-ones, pharmaceutical preparations comprising the same and process pro their preparing SI9300075A (en)

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HU9200432A HUT64064A (en) 1992-02-13 1992-02-13 Process for producing puyrido/1,2-a/pyrimidine derivatives and pharmaceutical compositions comprising same as active ingredient

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ITMI20011764A1 (en) * 2001-08-10 2003-02-10 Dinamite Dipharma Spa HIGH PURITY PEMIROLAST METHOD
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TWI490219B (en) 2009-06-29 2015-07-01 Incyte Corp Pyrimidinones as pi3k inhibitors
US8759359B2 (en) 2009-12-18 2014-06-24 Incyte Corporation Substituted heteroaryl fused derivatives as PI3K inhibitors
EP2558463A1 (en) 2010-04-14 2013-02-20 Incyte Corporation Fused derivatives as i3 inhibitors
WO2011163195A1 (en) 2010-06-21 2011-12-29 Incyte Corporation Fused pyrrole derivatives as pi3k inhibitors
TW201249844A (en) 2010-12-20 2012-12-16 Incyte Corp N-(1-(substituted-phenyl)ethyl)-9H-purin-6-amines as PI3K inhibitors
WO2012125629A1 (en) 2011-03-14 2012-09-20 Incyte Corporation Substituted diamino-pyrimidine and diamino-pyridine derivatives as pi3k inhibitors
US9126948B2 (en) 2011-03-25 2015-09-08 Incyte Holdings Corporation Pyrimidine-4,6-diamine derivatives as PI3K inhibitors
TWI543980B (en) 2011-09-02 2016-08-01 英塞特控股公司 Heterocyclylamines as pi3k inhibitors
AR090548A1 (en) 2012-04-02 2014-11-19 Incyte Corp BICYCLIC AZAHETEROCICLOBENCILAMINS AS PI3K INHIBITORS
US10077277B2 (en) 2014-06-11 2018-09-18 Incyte Corporation Bicyclic heteroarylaminoalkyl phenyl derivatives as PI3K inhibitors
LT3831833T (en) 2015-02-27 2023-02-27 Incyte Holdings Corporation Processes for the preparation of a pi3k inhibitor
US9988401B2 (en) 2015-05-11 2018-06-05 Incyte Corporation Crystalline forms of a PI3K inhibitor
WO2016183060A1 (en) 2015-05-11 2016-11-17 Incyte Corporation Process for the synthesis of a phosphoinositide 3-kinase inhibitor

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