EP0914318A1 - Pyrazines - Google Patents

Pyrazines

Info

Publication number
EP0914318A1
EP0914318A1 EP97920835A EP97920835A EP0914318A1 EP 0914318 A1 EP0914318 A1 EP 0914318A1 EP 97920835 A EP97920835 A EP 97920835A EP 97920835 A EP97920835 A EP 97920835A EP 0914318 A1 EP0914318 A1 EP 0914318A1
Authority
EP
European Patent Office
Prior art keywords
formula
group
pyrazine
compound
catalyst
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP97920835A
Other languages
German (de)
English (en)
Inventor
Frank Hibbert
Keith Jones
Martine Max-Planck-Institut KEENAN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kings College London
Original Assignee
Kings College London
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
Priority claimed from GBGB9609972.6A external-priority patent/GB9609972D0/en
Priority claimed from GBGB9624653.3A external-priority patent/GB9624653D0/en
Application filed by Kings College London filed Critical Kings College London
Publication of EP0914318A1 publication Critical patent/EP0914318A1/fr
Withdrawn legal-status Critical Current

Links

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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/20—Nitrogen atoms

Definitions

  • the present invention relates to novel pyrazines and to methods of their use in preparing further imidazopyrazine compounds.
  • the luminescent chromophores such as Coelenterazine which can be isolated from Aequora Victoria, as described in the Article by Shimomura O, Johnson Fitt. and Morisett in Biochemistry 1974, 13,3278-3286, contain the imidazopyrazine ring system.
  • Coelenterazine has been extensively studied because of the bioluminescent process which is triggered by calcium ions and has proved to be a sensitive method for the detection and quantification of calcium ions.
  • Coelenterazine and analogues have been prepared by the "Kishi route", as described in the Article by Shimomura O, Musieki B. Kishi Y, Biochem J., 1989, 261,913-920.
  • the aromatic groups Ar which can be used include groups such as phenyl, naphthyl and thiophenyl.
  • the substituted aromatic groups include alkyl, aryl and substituted aryl, alkaryl, halides, halide substituted aryl groups and groups such as trifiuoromethyl, fluoro and alkoxy groups.
  • the Ph group can be substituted by any of the substituents listed above.
  • the invention also provides pyrazines of the formula
  • Ph is an aromatic or substituted aromatic group e.g.as Ar in (I).
  • the invention further provides pyrazines of formula
  • the compounds (I) of the present invention can be prepared by the reaction of the 5-halo substituted pyrazine:-
  • the catalysts which can be used in the process of the present invention include, but are not limited to, platinum groups catalysts, particularly palladium compounds.
  • the preferred palladium catalysts are Pd(II) complexes, particularly organic palladium compounds such as diphenyl phosphino complexes of Pd(II) e.g. [l ,4-bis(diphenylphosphino)butane]palladium(II) chloride and [1,1 bis(diphenylphosphino)ferrocene]palladium(II) acetate.
  • reaction of compound B with the arylboronic acid preferably takes place in a solvent which will depend on the nature of the catalyst used.
  • solvents which can be used are toluene, tetrahydrofuran, dimethyl formamide, optionally in the presence of co-solvents such as water or an amine such as triethylamine.
  • the reaction can be illustrated as follows:
  • Preferred Ar groups are 4-MeOC 6 H 4 , C 6 H 5 , naphthyl, 4-FC 6 H 4 , 4-CF 3 C 6 H 4 and 2-thienyl.
  • Compound B can be prepared by bromination of the corresponding pyrazine:-
  • the pyrazine C can be prepared by known methods, for example, as described in the Article by Turek A, Mojovie L, Queguiner G, Synthesis 1988, 881-884.
  • 2-chloropyrazine was metallated using lithium tetramethylpiperidide and reacted with benzaldehyde to afford the alcohol (3) in 88% yield.
  • Oxidation of (3) using freshly-prepared MnO 2 gave the ketone (4) in 93% yield.
  • Introduction of the amino group was achieved by heating ketone (4) with a solution of ammonia in ethanol at 120°C overnight leading to aminopyrazine (5) in 63% yield.
  • the preferred method for cleaving the methyl aryl ether is by reaction with ethanethiolate.
  • the phenol (II) obtained can be converted to the phenol (III) by reduction.
  • Any reduction which reduces the ketone group can be used such as using a metallic catalyst such as platinum or palladium or carbon, treatment with zinc and hydrochloric acid under usual Clemenson conditions (M Lucas and F Solano, Anal. Biochem, 1992 206,273).
  • Reduction of the ketone to alcohol e.g. using NaBH 4 in methanol followed by treatment of the alcohol with Et 3 SiH and trifluoracetic acid.
  • a preferred method is a Wolff-Kishner reduction by reaction with hydrazine hydrate and potassium hydroxide in ethylene glycol.
  • the above compounds of the present invention can be used as intermediates to prepare compounds containing the imidazopyrazine ring system such as coelenterazine by reduction of the benzoyl substituent to benzyl, condensation with 4-methoxybenzylglyoxal and cleavage of the methyl ethers using pyridinium bromide or by reaction with a ketoaldehyde.
  • compounds containing the imidazopyrazine ring system such as coelenterazine by reduction of the benzoyl substituent to benzyl, condensation with 4-methoxybenzylglyoxal and cleavage of the methyl ethers using pyridinium bromide or by reaction with a ketoaldehyde.
  • the ⁇ -ketoaldehyde can be prepared by known methods, for example by the route described by S Inove, S Sugiura, H Kakoi and K Hasizume. Chem. Letters 1975, 141. In this route the phenol group in 4-hydroxy phenyl acetic acid is acylated, converted to the acid chloride (with SOCU) and reacted with diazomethane to give the ⁇ -diazoketone.
  • the ⁇ -diazoketone was reacted with dry HBr to give the bromomethyl ketone which is reacted with silver nitrate in acetonitrile to give the nitrate ester which is reacted with sodium acetate to give the ⁇ -ketoaldehyde.
  • the compound (V) is found to exist mainly in the enol form in solution in many solutions.
  • Example 1 The invention is further described in the following Examples in which Examples 1 to 7 describe the preparation of the novel pyrazines of the invention and Example 8 illustrates the production of coelenterazine with the preparation of the 2-amino-3-benzoyl-5-(4'-methoxyphenyl)pyrazine used in Example 8 prepared as in Example 1.
  • Example 1
  • Phenyl and naphthylboronic acids reacted cleanly with (6) and gave the heterobiaryl products 7b and 7c in very high yields (entries 3 and 4).
  • the introduction of electron-withdrawing substituents on the boronic acid moiety presented no problems and both the 4-fluoro and the 4-trifluoromethyl-substituted boronic acids reacted within a reasonable timescale to give the respective coupled products 7d and 7e in high yields.
  • Diazald (7.4 g, 0.02 mol) in dry diethyl ether (82 ml) was added dropwise to a warm solution of aqueous potassium hydroxide (7.4 g, in 12 ml of H 2 O) and di(ethyleneglycol)ethyl ether (17 ml). Diazomethane was collected as a co-distillate with diethyl ether.
  • Ethanethiol (0.6 ml. 8 mmol), dissolved in dry DMF (3 ml) was added to a suspension of sodium hydride (5.5 equiv) in dry DMF (2 ml) under an atmosphere or argon. The mixture was stirred for 5 mins before a solution of 2-amino-3 -benzoyl -5-(p-methoxyhenyl)pyrazine (520 mg, 1.7 mmol) in DMF (4 ml) was added. The solution was heated at 100°C for 8 hours. On cooling, the mixture was acidified with 10% aqueous HC1 and washed with EtOAc. The aqueous phase was made alkaline (10% aqueous NaOH) and extracted with EtOAc.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

On décrit de nouvelles pyrazines et un procédé de fabrication de ces dernières selon lequel on fait réagir des pyrazines 5-halo substituées avec un acide arylboronique. Les nouvelles pyrazines peuvent être utilisées dans la synthèse de la coelentérazine.
EP97920835A 1996-05-11 1997-05-06 Pyrazines Withdrawn EP0914318A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
GB9609972 1996-05-11
GBGB9609972.6A GB9609972D0 (en) 1996-05-11 1996-05-11 Pyrazines
GBGB9624653.3A GB9624653D0 (en) 1996-11-27 1996-11-27 Synthesis of coelenterazine
GB9624653 1996-11-27
PCT/GB1997/001227 WO1997043267A1 (fr) 1996-05-11 1997-05-06 Pyrazines

Publications (1)

Publication Number Publication Date
EP0914318A1 true EP0914318A1 (fr) 1999-05-12

Family

ID=26309321

Family Applications (1)

Application Number Title Priority Date Filing Date
EP97920835A Withdrawn EP0914318A1 (fr) 1996-05-11 1997-05-06 Pyrazines

Country Status (3)

Country Link
EP (1) EP0914318A1 (fr)
CA (1) CA2253910A1 (fr)
WO (1) WO1997043267A1 (fr)

Families Citing this family (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1383765B1 (fr) 2001-04-25 2006-12-13 Lilly Icos LLC Dérives de carboline en tant qu'inhibiteurs de phosphodiesterase 5 (PDE 5) pour le traitement des maladies cardiovasculaires et le dysfonctionnement érectile
EP1501514B1 (fr) * 2002-05-03 2012-12-19 Exelixis, Inc. Modulateurs de proteine-kinases et leurs methodes d'utilisation
US7704995B2 (en) 2002-05-03 2010-04-27 Exelixis, Inc. Protein kinase modulators and methods of use
US8263585B2 (en) 2007-05-04 2012-09-11 Novartis Ag Organic compounds
US8268834B2 (en) 2008-03-19 2012-09-18 Novartis Ag Pyrazine derivatives that inhibit phosphatidylinositol 3-kinase enzyme
ES2921576T3 (es) 2008-12-19 2022-08-29 Vertex Pharma Compuestos útiles como inhibidores de la quinasa ATR
US9334244B2 (en) 2010-05-12 2016-05-10 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9062008B2 (en) * 2010-05-12 2015-06-23 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
NZ603477A (en) 2010-05-12 2014-09-26 Vertex Pharma Compounds useful as inhibitors of atr kinase
EP2723747A1 (fr) 2011-06-22 2014-04-30 Vertex Pharmaceuticals Inc. Composés utiles comme inhibiteurs de la kinase atr
US9309250B2 (en) 2011-06-22 2016-04-12 Vertex Pharmaceuticals Incorporated Substituted pyrrolo[2,3-b]pyrazines as ATR kinase inhibitors
CN108685922A (zh) 2011-09-30 2018-10-23 沃泰克斯药物股份有限公司 用atr抑制剂治疗胰腺癌和非小细胞肺癌
CN106496173A (zh) 2011-09-30 2017-03-15 沃泰克斯药物股份有限公司 用于制备可用作atr激酶抑制剂的化合物的方法
WO2013049722A1 (fr) 2011-09-30 2013-04-04 Vertex Pharmaceuticals Incorporated Composés utiles comme inhibiteurs de kinase atr
WO2013049720A1 (fr) 2011-09-30 2013-04-04 Vertex Pharmaceuticals Incorporated Composés utiles en tant qu'inhibiteurs de kinase atr
US8846918B2 (en) 2011-11-09 2014-09-30 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
CN102432614A (zh) * 2011-11-16 2012-05-02 泰州凯美迪生物医药技术有限公司 腔肠素的合成方法
CN108478577A (zh) 2012-04-05 2018-09-04 沃泰克斯药物股份有限公司 可用作atr激酶抑制剂的化合物及其组合疗法
DK2904406T3 (en) 2012-10-04 2018-06-18 Vertex Pharma METHOD OF DETERMINING THE ATR INHIBITION, INCREASED DNA DAMAGE
EP2909202A1 (fr) 2012-10-16 2015-08-26 Vertex Pharmaceuticals Incorporated Composés utiles en tant qu'inhibiteurs de la kinase atr
SI2941432T1 (en) 2012-12-07 2018-07-31 Vertex Pharmaceuticals Incorporated 2-AMINO-6-FLUORO-N- (5-FLUORO-4- (4- (4- (OXETHAN-3-YL) PIPERAZIN-1-CARBONYL) PIPERIDIN-1-YLIPRIDIN-3-YL) 1,5 ALFA) PYRIMIDINE-3-CARBOXAMIDE AS ATR KINAZE INHIBITOR
WO2014143240A1 (fr) 2013-03-15 2014-09-18 Vertex Pharmaceuticals Incorporated Dérivés de pyrazolopyrimidine fusionnés utiles en tant qu'inhibiteurs de la kinase atr
PT3077397T (pt) 2013-12-06 2020-01-22 Vertex Pharma Composto de 2-amino-6-fluoro-n-[5-fluoro-piridin-3-il]pirazolo[1,5-a]pirimidin-3-carboxamida útil como inibidor da atr quinase, a sua preparação, diferentes formas sólidas e derivados radiomarcados do mesmo
MX373102B (es) 2014-06-05 2020-04-17 Vertex Pharma Derivados radiomarcados de un compuesto de 2-amino-6-fluoro-n-[5-fluoro-piridin-3-il]-pirazolo[1,5-a]pirimidin-3-carboxamida útil como inhibidor de ataxia telangiectasia mutada y rad3 relacionado (atr) cinasa, preparación de tal compuesto y diferentes formas sólidas del mismo.
SG11201610500WA (en) 2014-06-17 2017-01-27 Vertex Pharma Method for treating cancer using a combination of chk1 and atr inhibitors
AU2016331955B2 (en) 2015-09-30 2022-07-21 Vertex Pharmaceuticals Incorporated Method for treating cancer using a combination of DNA damaging agents and ATR inhibitors
CN105968114B (zh) * 2016-05-27 2018-11-09 山东大学 一种腔肠素类似物及其制备方法与应用
BR112020018094A2 (pt) 2018-03-08 2020-12-22 Incyte Corporation Compostos de aminopirazina diol como inibidores de pi3k-¿
US11046658B2 (en) 2018-07-02 2021-06-29 Incyte Corporation Aminopyrazine derivatives as PI3K-γ inhibitors
CN118891255A (zh) * 2022-03-16 2024-11-01 阿鲁姆治疗公司 新化合物及其抑制检查点激酶2的用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9743267A1 *

Also Published As

Publication number Publication date
WO1997043267A1 (fr) 1997-11-20
CA2253910A1 (fr) 1997-11-20

Similar Documents

Publication Publication Date Title
EP0914318A1 (fr) Pyrazines
Kondo et al. Palladium-catalyzed indole and benzofuran ring formation accompanying carbonylation
Gassman et al. Generation of azasulfonium salts from halogen-sulfide complexes and anilines. Synthesis of indoles, oxindoles, and alkylated aromatic amines bearing cation stabilizing substituents
KR100901402B1 (ko) 14-히드록시노르모르피논 유도체의 제조 방법
CN112174823B (zh) 一种合成2,2-二甲基-3-氧杂环丁酮的中间体及其制备方法和应用
Ohta et al. Syntheses and reactions of some 2, 5-disubstituted pyrazine monoxides
EP1045823B1 (fr) Procede de preparation de certains composes d'acide benzoique
CN111253395B (zh) 萘并[1′,2′:4,5]咪唑并[1,2-a]吡啶-5,6-二酮化合物的合成方法
Morrow et al. Intramolecular cyclization of 2'-olepinic side-chains on anodically oxidized 4-phenylphenols. The effect of olefin substituents on carbon—carbon bond formation
JP4660862B2 (ja) アルコキシピラジン誘導体の製造方法
JP4399870B2 (ja) ３−アルコキシ−５−アルキルピラジン−２−アミン類の製造方法
WO2005021465A1 (fr) Procede de production de compose insature aromatique
Rogers et al. Improved syntheses of 6‐hydroxy‐5‐methoxy‐and 5‐hydroxy‐6‐methoxyindoles and their O‐acetates, analogs of natural eumelanin precursors
HU195659B (en) Process for producing cotarnine
EP0008951B1 (fr) Intermédiaire de stéroide, procédé pour sa préparation et procédé pour préparer à partir de celui-ci un autre intermédiaire de stéroide
CN115710227B (zh) 一种茚并异喹啉衍生物的制备方法
Cho et al. Palladium‐catalyzed synthesis of 3‐oxo‐1, 3‐dihydro‐1‐isobenzofuranyl alkanoates from 2‐bromobenzaldehyde and sodium alkanoates
WO2003082860A1 (fr) Procedes de production de compose indole
US8168799B2 (en) Process for the preparation of tetrazolytetrahydrocyclopentapyrazoles
HUP0303846A2 (hu) Eljárás kinolin-karboxaldehid-származék és közbenső termék előállítására
Mohajer A new catalyst for the synthesis of 2-substituted perimidines catalyzed by FePO4 [enter Paper Title]
JPH09239275A (ja) イミン化合物合成用触媒、及びこれを用いたイミン化合物の製造法
JP4659240B2 (ja) ヒドロキシアルデヒドの製造方法
CN106554307B (zh) 一种海洋真菌来源的抗病毒喹啉酮生物碱类衍生物的制备方法
WO2024187498A1 (fr) Procédé de catalyse d'une oléfine méta-hydrocarbonée d'un dérivé d'acide benzoïque par du palladium

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19981130

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN

18W Application withdrawn

Withdrawal date: 19991013