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WO1993016076A1 - 3-(1H^_-TETRAZOL-5-YL)-4H^_-PYRIDO[1,2-a^_]PYRIMIDINE-4-ONES, COMPOSITIONS PHARMACEUTIQUES LES CONTENANT, ET LEUR PREPARATION - Google Patents

3-(1H^_-TETRAZOL-5-YL)-4H^_-PYRIDO[1,2-a^_]PYRIMIDINE-4-ONES, COMPOSITIONS PHARMACEUTIQUES LES CONTENANT, ET LEUR PREPARATION Download PDF

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Publication number
WO1993016076A1
WO1993016076A1 PCT/HU1993/000009 HU9300009W WO9316076A1 WO 1993016076 A1 WO1993016076 A1 WO 1993016076A1 HU 9300009 W HU9300009 W HU 9300009W WO 9316076 A1 WO9316076 A1 WO 9316076A1
Authority
WO
WIPO (PCT)
Prior art keywords
general formula
tetrazol
stands
hydrogen
pharmaceutically acceptable
Prior art date
Application number
PCT/HU1993/000009
Other languages
English (en)
Inventor
István HERMECZ
Judit Sipos
Lelle VASVÁRY
Zoltán Kapui
ágnes Horváth
Mária BALOGH
Géza KERESZTURI
Kinga Boér
Anikó PAJOR
Original Assignee
Chinoin Gyógyszer- És Vegyészeti Termékek Gyára Rt.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chinoin Gyógyszer- És Vegyészeti Termékek Gyára Rt. filed Critical Chinoin Gyógyszer- És Vegyészeti Termékek Gyára Rt.
Publication of WO1993016076A1 publication Critical patent/WO1993016076A1/fr

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Classifications

    • 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

Definitions

  • the invention relates to partly new 3-(lH-tetrazol- -5-yl)-4H-pyrido[l,2-a]pyrimidin-4-ones of the general formula (I) and pharmaceutically acceptable salts and/or hydrates and the preparation thereof. These compounds possess significant antiallergic or antiulcer activity.
  • 3-(lH-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4- -ones of general formula (I) where R represents hydrogenatom, are described in US-PS Nos. 4122274 and 4209620 as antiallergic agents, whereas in US-PS No. 4457932 as antiulcer agents.
  • the basis of our invention is the unexpected dis ⁇ covery that the acrylnitriles of general formula (II) may be transformed in a simple manner, in good yield, and without the formation of by-products into the pyrido- [l,2-a]pyrimidines of general formula (I).
  • R stands for hydrogenatom, C 1 _ 4 alkyl group, or c 6 - 10 ar Yl group
  • R 1 stands for hydrogenatom, - ⁇ ⁇ _ % alkyl group, halogen- atom, hydroxyl group, nitro group, carboxyl group, C2-5 alkoxycarbonyl group or C ⁇ ⁇ i2 aralkoxy group
  • R 2 represents hydrogenatom, C 1 -4 alkyl group, or halogenatom; and a process for the preparation thereof.
  • C1--.4 alkyl group means - in itself or in moieties, for instance in alkoxy groups - straight or branched chain aliphatic saturated hydrocarbon groups having one to four carbon atoms (such as e.g. methyl, ethyl, n-propyl and tert.-butyl group).
  • C 6 _ ⁇ o aryl group means phenyl group or naphthyl group, optionally bearing a ⁇ - ⁇ alkyl group.
  • the present 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-(lH-tetrazol-5-yl)acrylnitrile of general formula (II)
  • organic and inorganic acids may be applied. If desired, the reaction may be carried out in the presence of solvent, preferably in the presence of water. As for organic acids alkanecarboxylic acids and arylsulfonic acids may be used. For inorganic acids preferably hydrogenhalides, sulfonic acid and various acids of the phosphor may be applied.
  • the reaction may be accomplished, if desired, at elevated temperature. The temperature may be chosen according to the properties of the acidic agent and, if the reaction is carried out in the presence of solvent, according to the properties of the solvent. The reaction is preferably carried out at a temperature different from room temperature.
  • the compound of general formula (I) obtained in the reaction precipitates from the reaction mixture after dilution with water or after adjusting the pH of the reaction mixture to neutral and may be recovered for instance by filtration.
  • Compounds of general formula (I) may be converted into their pharmaceutically acceptable salts and/or hydrates on the effect of acids or bases. From the salts the bases may be liberated and, if desired, converted into another salt thereof.
  • acid addition salts with e.g. hydrochloric acid, hydrobromic acid, sulphuric acid, acetic acid, citric acid ets. may favourably be prepared, as well as the sodium, potassium and calcium salts.
  • the compound of general formula (I) or its pharma- ceutically acceptable salts may therapeutically be used in the form of pharmaceutical compositions containing the active ingredient in an admixture with inert non- toxic solid or liquid diluents and carriers.
  • compositions may be formulated as solids (tablet, capsule, dragee) or as liquids (solution, suspension, emulsion) .
  • the usual materials such as e.g. talc, calcium carbonate, magnesium stearate, water, poly(ethylene glycol) may be used.
  • the preparations may contain supplementary materials such as e.g. emulsifying agents, or dissolution materials.
  • Example 1 53 . 3 g ( 0. 25 mol) of 3- ( 2-pyridylamino) -2- ( 1H- -tetrazol-5-yl)-acrylnitrile are heated in 500 ml of cone, hydrochloric acid under reflux conditions for 1 hour. After 10-15 mins of heating the original crystals dissolve, and the crystals of the product appear. The resulting suspension is cooled, diluted with 1000 ml of water, and neutralized with 25 % aqueous ammonia solution. The crystals are collected, washed with water.
  • Example 5 ⁇ 2.47 g (0.01 mol) of 3-[ (5-chloro-2-pyridyl)- -amino]-2-(lH-tetrazol-5-yl)acrylnitrile are added under stirring to 12 g of polyphosphoric acid at 60 °C.
  • the mixture is granulated with the help of 150 g of Endragit-lac solution, then it is dried at 40 °C and re- granulated.
  • the granulatum is homogenized with a powder mixture consisting of 20 g of talc and 20 g of magnesium stearate, then in a method known per se, with the help of the appropriate pressure tools, it is pressed into tablets of 50, 100, 200 and 400 mg.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

3-(1H^_-tétrazol-5-yl)-4H^_-pyrido[1,2-a^_]pyrimidin-4-ones partiellement nouveaux répondant à la formule générale (I), leurs hydrates et/ou sels pharmaceutiquement acceptables, et leur préparation. Ces composés présentent une activité antiallergique ou antiulcéreuse importante. On a mis au point des composés répondant à la formule (I), et leurs hydrates et/ou sels pharmaceutiquement acceptables, dans laquelle R représente un atome d'hydrogène, un groupe alkyle C1-4 ou un groupe aryle C6-10; R1 représente un atome d'hydrogène, un groupe alkyle C¿1-4?, un atome d'halogène, un groupe hydroxyle, un groupe nitro, un groupe carboxyle, alcoxycarbonyle C2-5 ou un groupe araloxy C7-12; R?2¿ représente un atome d'hydrogène, un groupe alkyle C¿1-4?, ou un atome d'halogène; et leur procédé de préparation. On a également mis au point un procédé de préparation des composés de la formule générale (I) et leurs hydrates et/ou sels pharmaceutiquement acceptables. Il consiste à cycliser un 3-(2-pyridylamino)-2-(1H^_-tétrazol-5-yl)acrylnitrile répondant à la formule (II) (dans laquelle R, R?1 et R2¿ ont les mêmes notations que ci-dessus) dans des milieux acides, et à transformer le composé de la formule générale (I) ainsi obtenu en son sel pharmaceutiquement acceptable ou, le cas échéant, à libérer la base de son sel, ou à la transformer de manière connue en soi en un autre de ses sels.
PCT/HU1993/000009 1992-02-13 1993-02-12 3-(1H^_-TETRAZOL-5-YL)-4H^_-PYRIDO[1,2-a^_]PYRIMIDINE-4-ONES, COMPOSITIONS PHARMACEUTIQUES LES CONTENANT, ET LEUR PREPARATION WO1993016076A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HUP9200432 1992-02-13
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

Publications (1)

Publication Number Publication Date
WO1993016076A1 true WO1993016076A1 (fr) 1993-08-19

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Country Status (7)

Country Link
CN (1) CN1080289A (fr)
AU (1) AU3573793A (fr)
HU (1) HUT64064A (fr)
IL (1) IL104706A0 (fr)
MX (1) MX9300779A (fr)
SI (1) SI9300075A (fr)
WO (1) WO1993016076A1 (fr)

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20030014619A (ko) * 2001-08-10 2003-02-19 디나미테 디파르마 에스.피.아. 고순도 페미로라스트의 제조방법
WO2007093184A3 (fr) * 2006-02-13 2007-10-25 Astion Pharma As Traitement de l'acne et autres maladies
EP1818058A3 (fr) * 2006-02-13 2007-11-07 Astion Pharma A/S Traitement de l'acné et autres maladies
EP2210892A3 (fr) * 2002-10-04 2010-10-27 Prana Biotechnology Limited Composés actifs neurologiquement
US8940752B2 (en) 2009-06-29 2015-01-27 Incyte Corporation Pyrimidinones as PI3K inhibitors
US9062055B2 (en) 2010-06-21 2015-06-23 Incyte Corporation Fused pyrrole derivatives as PI3K inhibitors
US9096600B2 (en) 2010-12-20 2015-08-04 Incyte Corporation N-(1-(substituted-phenyl)ethyl)-9H-purin-6-amines as PI3K inhibitors
US9108984B2 (en) 2011-03-14 2015-08-18 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
US9193721B2 (en) 2010-04-14 2015-11-24 Incyte Holdings Corporation Fused derivatives as PI3Kδ inhibitors
US9199982B2 (en) 2011-09-02 2015-12-01 Incyte Holdings Corporation Heterocyclylamines as PI3K inhibitors
US9309251B2 (en) 2012-04-02 2016-04-12 Incyte Holdings Corporation Bicyclic azaheterocyclobenzylamines as PI3K inhibitors
US9403847B2 (en) 2009-12-18 2016-08-02 Incyte Holdings Corporation Substituted heteroaryl fused derivatives as P13K inhibitors
US9732097B2 (en) 2015-05-11 2017-08-15 Incyte Corporation Process for the synthesis of a phosphoinositide 3-kinase inhibitor
US9988401B2 (en) 2015-05-11 2018-06-05 Incyte Corporation Crystalline forms of a PI3K inhibitor
US10077277B2 (en) 2014-06-11 2018-09-18 Incyte Corporation Bicyclic heteroarylaminoalkyl phenyl derivatives as PI3K inhibitors
US10336759B2 (en) 2015-02-27 2019-07-02 Incyte Corporation Salts and processes of preparing a PI3K inhibitor
US12226418B2 (en) 2018-06-01 2025-02-18 Incyte Corporation Dosing regimen for the treatment of PI3K related disorders

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HU209793B (en) * 1990-09-25 1994-11-28 Chinoin Gyogyszer Es Vegyeszet Process for the production of pyrido[1,2-a]pyrimidine-derivatives and pharmaceutical compositions containing the same

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0462834A1 (fr) * 1990-06-21 1991-12-27 Wako Pure Chemical Industries, Ltd Procédé pour la préparation de dérivés de pyrido[1,2-a]pyrimidine

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0462834A1 (fr) * 1990-06-21 1991-12-27 Wako Pure Chemical Industries, Ltd Procédé pour la préparation de dérivés de pyrido[1,2-a]pyrimidine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAl ABSTRACTS, Twelfth Collective Index, Volumes 106-115, 1987-1991, page 80, 214CS; & CHEMICAL ABSTRACTS 111:89 703n, YAKURI TO CHIRYO, 1989, 17(4), 14727-32, (Japan). *

Cited By (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20030014619A (ko) * 2001-08-10 2003-02-19 디나미테 디파르마 에스.피.아. 고순도 페미로라스트의 제조방법
EP2210892A3 (fr) * 2002-10-04 2010-10-27 Prana Biotechnology Limited Composés actifs neurologiquement
WO2007093184A3 (fr) * 2006-02-13 2007-10-25 Astion Pharma As Traitement de l'acne et autres maladies
EP1818058A3 (fr) * 2006-02-13 2007-11-07 Astion Pharma A/S Traitement de l'acné et autres maladies
US8940752B2 (en) 2009-06-29 2015-01-27 Incyte Corporation Pyrimidinones as PI3K inhibitors
US9975907B2 (en) 2009-06-29 2018-05-22 Incyte Holdings Corporation Pyrimidinones as PI3K inhibitors
US10428087B2 (en) 2009-06-29 2019-10-01 Incyte Corporation Pyrimidinones as PI3K inhibitors
US10829502B2 (en) 2009-06-29 2020-11-10 Incyte Corporation Pyrimidinones as PI3K inhibitors
US9434746B2 (en) 2009-06-29 2016-09-06 Incyte Corporation Pyrimidinones as PI3K inhibitors
US11401280B2 (en) 2009-06-29 2022-08-02 Incyte Holdings Corporation Pyrimidinones as PI3K inhibitors
US9403847B2 (en) 2009-12-18 2016-08-02 Incyte Holdings Corporation Substituted heteroaryl fused derivatives as P13K inhibitors
US9193721B2 (en) 2010-04-14 2015-11-24 Incyte Holdings Corporation Fused derivatives as PI3Kδ inhibitors
US9062055B2 (en) 2010-06-21 2015-06-23 Incyte Corporation Fused pyrrole derivatives as PI3K inhibitors
US9815839B2 (en) 2010-12-20 2017-11-14 Incyte Corporation N-(1-(substituted-phenyl)ethyl)-9H-purin-6-amines as PI3K inhibitors
US9527848B2 (en) 2010-12-20 2016-12-27 Incyte Holdings Corporation N-(1-(substituted-phenyl)ethyl)-9H-purin-6-amines as PI3K inhibitors
US9096600B2 (en) 2010-12-20 2015-08-04 Incyte Corporation N-(1-(substituted-phenyl)ethyl)-9H-purin-6-amines as PI3K inhibitors
US9108984B2 (en) 2011-03-14 2015-08-18 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
US9199982B2 (en) 2011-09-02 2015-12-01 Incyte Holdings Corporation Heterocyclylamines as PI3K inhibitors
US10646492B2 (en) 2011-09-02 2020-05-12 Incyte Corporation Heterocyclylamines as PI3K inhibitors
US12201636B2 (en) 2011-09-02 2025-01-21 Incyte Corporation Heterocyclylamines as PI3K inhibitors
US11819505B2 (en) 2011-09-02 2023-11-21 Incyte Corporation Heterocyclylamines as PI3K inhibitors
US11433071B2 (en) 2011-09-02 2022-09-06 Incyte Corporation Heterocyclylamines as PI3K inhibitors
US10092570B2 (en) 2011-09-02 2018-10-09 Incyte Holdings Corporation Heterocyclylamines as PI3K inhibitors
US9707233B2 (en) 2011-09-02 2017-07-18 Incyte Holdings Corporation Heterocyclylamines as PI3K inhibitors
US10376513B2 (en) 2011-09-02 2019-08-13 Incyte Holdings Corporation Heterocyclylamines as PI3K inhibitors
US9730939B2 (en) 2011-09-02 2017-08-15 Incyte Holdings Corporation Heterocyclylamines as PI3K inhibitors
US9309251B2 (en) 2012-04-02 2016-04-12 Incyte Holdings Corporation Bicyclic azaheterocyclobenzylamines as PI3K inhibitors
US10259818B2 (en) 2012-04-02 2019-04-16 Incyte Corporation Bicyclic azaheterocyclobenzylamines as PI3K inhibitors
US9944646B2 (en) 2012-04-02 2018-04-17 Incyte Holdings Corporation Bicyclic azaheterocyclobenzylamines as PI3K inhibitors
US10479803B2 (en) 2014-06-11 2019-11-19 Incyte Corporation Bicyclic heteroarylaminoalkyl phenyl derivatives as PI3K inhibitors
US11130767B2 (en) 2014-06-11 2021-09-28 Incyte Corporation Bicyclic heteroarylaminoalkyl phenyl derivatives as PI3K inhibitors
US10077277B2 (en) 2014-06-11 2018-09-18 Incyte Corporation Bicyclic heteroarylaminoalkyl phenyl derivatives as PI3K inhibitors
US11999751B2 (en) 2014-06-11 2024-06-04 Incyte Corporation Bicyclic heteroarylaminoalkyl phenyl derivatives as PI3K inhibitors
US10336759B2 (en) 2015-02-27 2019-07-02 Incyte Corporation Salts and processes of preparing a PI3K inhibitor
US11084822B2 (en) 2015-02-27 2021-08-10 Incyte Corporation Salts and processes of preparing a PI3K inhibitor
US12024522B2 (en) 2015-02-27 2024-07-02 Incyte Corporation Salts and processes of preparing a PI3K inhibitor
US10125150B2 (en) 2015-05-11 2018-11-13 Incyte Corporation Crystalline forms of a PI3K inhibitor
US9988401B2 (en) 2015-05-11 2018-06-05 Incyte Corporation Crystalline forms of a PI3K inhibitor
US9732097B2 (en) 2015-05-11 2017-08-15 Incyte Corporation Process for the synthesis of a phosphoinositide 3-kinase inhibitor
US12226418B2 (en) 2018-06-01 2025-02-18 Incyte Corporation Dosing regimen for the treatment of PI3K related disorders

Also Published As

Publication number Publication date
HU9200432D0 (en) 1992-04-28
HUT64064A (en) 1993-11-29
SI9300075A (en) 1993-09-30
AU3573793A (en) 1993-09-03
IL104706A0 (en) 1993-06-10
CN1080289A (zh) 1994-01-05
MX9300779A (es) 1993-09-30

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