DK2612860T3 - Quinazolinderivater substitueret med anilin, fremgangsmåde til fremstilling og anvendelse deraf - Google Patents

Quinazolinderivater substitueret med anilin, fremgangsmåde til fremstilling og anvendelse deraf Download PDF

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DK2612860T3
DK2612860T3 DK11820990.7T DK11820990T DK2612860T3 DK 2612860 T3 DK2612860 T3 DK 2612860T3 DK 11820990 T DK11820990 T DK 11820990T DK 2612860 T3 DK2612860 T3 DK 2612860T3
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chloro
methyl
fluorophenylamino
substituted
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Zhenhua Huang
Yanyan Dong
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Xuanzhu Pharma Co Ltd
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Claims (12)

1. Forbindelse med den almene formel (I), et farmaceutisk acceptabelt salt deraf eller en stereoisomer deraf:
hvor R1 er valgt fra gruppen bestående af de følgende grupper, der ikke er substituerede eller er substitueret med 1 til 2 Qrsubstituenter;
hvor 1 til 3 carbonatomer på ringen kan erstattes med 1 til 3 heteroatomer og/eller grupper, der kan være ens eller forskellige og er udvalgt fra gruppen bestående af O, S(0)m, N(H)m, NCH3 og C(O), forudsat at efter udskiftningen, støder O og C(O) i ringen ikke op til hinanden, p er 0,1 eller 2, Qi er valgt fra gruppen bestående af halogen, hydroxyl, amino, carboxyl, en Ci_ 4-alkylgruppe, en Ci.4-alkoxylgruppe, en C1.4-alkylaminogruppe, en di(Ci^-alkyl)aminogruppe og en C3.6-cycloalkylgruppe; R2 er valgt fra gruppen bestående af hydrogen, en C^-alkylgruppe, som ikke er substitueret eller som er substitueret med 1 til 2 Q2-substituenter, en formylgruppe, der er substitueret med en Q2-substituent eller N(H)m, Q2 er valgt fra gruppen bestående af halogen, hydroxyl, amino, en Cm-alkylgruppe, en C^-alkoxylgruppe, en C^-alkylaminogruppe, en di(Ci.4- alkyl)aminogruppe, en C^-alkylcarbonyloxygruppe, en CM-alkylacylamino, en gruppe Ci^-alkylsulfonylgruppe, en Ci^-alkylsulfonylaminogruppe, en C3.5-cycloalkylgruppe og en mættet eller umættet 5-8-leddet heterocyclylgruppe, hvor C3.5-cycloalkylen, den mættet eller den umættede 5-8-leddede heterocyclyl kan være yderligere substitueret med 1 til 2 Q3-substituenter, Q3 er valgt fra gruppen bestående af halogen, hydroxyl, amino, en C^-alkylgruppe, en Ci.4-alkoxylgruppe, en Ci.4-alkylaminogruppe, en di(Ci_4- alkyl)aminogruppe, en Ci.4-alkylcarbonyloxygruppe, en Ci_4-alkylacylaminogruppe, en C-i^-alkylsulfonylgruppe, en C^-alkylsulfonylaminogruppe og en halogensubstitueret Cm-alkoxygruppe; R3 er valgt fra gruppen bestående af fluor, chlor, brom, en Ci_4-alkylgruppe eller en Ci.4-alkoxygruppe; R4, R5 og R6 er hver uafhængigt valgt fra gruppen bestående af hydrogen, fluor eller chlor; L er valgt fra gruppen bestående af en covalent binding, O, S(0)m eller N(H)m; n er 1, 2 eller 3; og m er 0, 1 eller 2.
2. Forbindelse ifølge krav 1, et farmaceutisk acceptabelt salt deraf eller en stereoisomer deraf, hvor R1 er valgt fra gruppen bestående af de følgende grupper, der ikke er substituerede eller er substitueret med 1 til 2 Q^substituenter:
p er O, 1 eller 2, Qi er valgt fra gruppen bestående af halogen, amino, en CM-alkylgruppe, en C^-alkylaminogruppe og en diiC^-alkylJaminogruppe; R2 er valgt fra gruppen bestående af hydrogen, methyl, der ikke er substitueret eller er substitueret med 1 til 2 Q2-substituenter eller ethyl, der ikke er substitueret eller er substitueret med 1 til 2 Q2-substituenter, en formylgruppe, der er substitueret med en Q2-substituent eller N(H)m, Q2 er valgt fra gruppen bestående af: (1) halogen, hydroxyl, amino, en Ci.4-alkoxylgruppe, en CM-alkylaminogruppe, en di(Ci.4-alkyl) aminogruppe, acetoxyl, acetamido, methylsulfonyl og methylsulfonylamino, (2) cyclopropyl, cyclopentyl, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, furyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, pyridyl, pyrazinyl og pyrimidinyl, disse Q2.grupper kan være yderligere substitueret med 1 til 2 Q3-substituenter, Q3 er valgt fra gruppen bestående af halogen, hydroxyl, amino, en C1-4-alkylgruppe, en Ci.4-alkoxylgruppe, en CM-alkylaminogruppe, en di(CM-alkyl) aminogruppe, en halogensubstitueret Ci^-alkoxyl, acetoxyl, acetamido, methylsulfonyl og methylsulfonylamino; R3 er valgt fra gruppen bestående af fluor eller chlor; R4, R5 og R6 er hydrogen; L er valgt fra gruppen bestående af en covalent binding eller O; n er 2; og m erO, 1 eller 2.
3. Forbindelse ifølge krav 1, et farmaceutisk acceptabelt salt deraf eller en stereoisomer deraf, hvor R1 er valgt fra gruppen bestående af:
R2 er valgt fra gruppen bestående af hydrogen, methyl, der ikke er substitueret eller er substitueret med 1 til 2 Q2-substituenter eller ethyl, der ikke er substitueret eller er substitueret med 1 til 2 Q2-substituenter, Q2 er valgt fra gruppen bestående af: (1) methoxy og en dKC^-alkylJaminogruppe, (2) piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, furyl, cyclopropyl, cyclopentyl, pyrrolyl, pyridyl, pyrimidinyl og thiazolyl, disse Q2 grupper kan være yderligere substitueret med 1 til 2 Q3-substituenter, Q3 er valgt fra gruppen bestående af halogen, hydroxy, amino, en CM-alkylgruppe, en Ci.4-alkoxylgruppe, en Ci_4-alkylaminogruppe, en dKC^-alkyl)aminogruppe og en halogensubstitueret C^-alkoxygruppe; R3 er valgt fra gruppen bestående af fluor eller chlor; R4, R5 og R6 er hydrogen; L er valgt fra gruppen bestående af en covalent binding eller O; og n er 2.
4. Forbindelse ifølge krav 1, et farmaceutisk acceptabelt salt deraf eller en stereoisomer deraf, hvor R1 er valgt fra gruppen bestående af:
R2 er valgt fra gruppen bestående af hydrogen, methyl, der ikke er substitueret eller er substitueret med 1 til 2 Q2-substituenter eller ethyl, der ikke er substitueret eller er substitueret med 1 til 2 Q2-substituenter, Q2 er valgt fra gruppen bestående af methoxy, dimethylamino, diethylamino, piperidinyl, piperazinyl og morpholinyl; R3 er valgt fra gruppen bestående af fluor eller chlor; R4, R5 og R6 er hydrogen; L er valgt fra gruppen bestående af en covalent binding eller O; og n er 2.
5. Forbindelse ifølge krav 1, et farmaceutisk acceptabelt salt deraf eller en stereoisomer deraf, hvilken forbindelsen er valgt fra gruppen bestående af: (f)-/V-[7-(8-oxabicyclo[3.2.1]octan-3-yloxy)-4-(3-chlor-4- fluorphenylamino)quinazolin-6-yl]-4-(piperidin-1-yl)-2-butenamid, (E)-/V-[7-(7-oxabicyclo[2.2.1]heptan-2-yloxy)-4-(3-chlor-4- fluorphenylamino)quinazoli-6-yl]-4-(piperidin-1-yl)-2-butenamid, (E)-A/-[4-(3-chlor-4-fluorphenylamino)-7-(2-methyl-2,7-diazaspiro[4,5]decan-7- yl)quinazolin-6-yl]-4-(piperidin-1-yl)-2-butenamid, N-[4-(3-chlor-4-fluorphenylamino)-7-(8-methyl-8-azabicyclo[3.2.1]octan-3- yloxy)quinazolin-6-yl]-acrylamid, /V-[4-(3-chlor-4-fluorphenylamino)-7-(8-methyl-1-oxa-8-azaspiro[4,5]decan-3- yloxy)quinazolin-6-yl]-acrylamid, /V-[4-(3-chlor-4-fluorphenylamino)-7-((8-methyl-1-oxa-8-azaspiro[4,5]decan-3-yl )methoxy)qu inazol in-6-yl]-acrylam id, /V-[4-(3-chlor-4-fluorphenylamino)-7-(8-methyl-1-oxa-8-azaspiro[4,5]decan-2-yl )methoxy)qu inazol in-6-yl]-acrylam id, /V-[4-(3-chlor-4-fluorophenylamino)-7-(2-((1R,5S,6S)-3-methyl-3-azabicyclo[3.1.0]hexan-6-ylethoxy)quinazolin-6-yl]-acrylamid, /\/-[4-(3-chlor-4-fluorophenylamino)-7-((2-methyloctahydrocyclopenta[c]pyrrol-4-yl )methoxy)qu inazol in-6-yl]-acrylam id, /V-[4-(3-chlor-4-fluorphenylamino)-7-((7-methyl-7-azabicyclo[2.2.1]heptan-2-yl)methoxy)qu inazol in-6-yl]-acrylam id, /V-[4-(3-chlor-4-fluorphenylamino)-7-(2-(3-methyl-3-azabicyclo[3.2.1]octan-8- yl)ethoxy)quinazolin-6-yl]-acrylamid, /V-[4-(3-chlor-4-fluorphenylamino)-7-((5-methyl-5-azaspiro[2.4]heptan-1-yl) methoxy)quinazolin-6-yl]-acrylamid, /V-[4-(3-chlor-4-fluorphenylamino)-7-((6-methyl-6-azaspiro[2.5]octan-1-yl) methoxy)quinazolin-6-yl]-acrylamid, /V-[4-(3-chlor-4-fluorphenylamino)-7-(2-(6-methyl-6-azaspiro[2.5]octan-1-yl) ethoxy)quinazolin-6-yl]-acrylamid, (E)-A/-[4-(3-chloro-4-fluorophenylamino)-7-(2-((1f?,5S,6S)-3-methyl-3-azabicyclo[3.1,0]hexan-6-yl)ethoxy)quinazolin-6-yl]-2-butenamid, (E)-A/-[4-(3-chlor-4-fluorphenylamino)-7-((7-methyl-7-azaspiro[3.5]nonan-2-yl)methoxy)quinazolin-6-yl]-2-butenamid, (E)-A/-[4-(3-chlor-4-fluorphenylamino)-7-((7-nnethyl-7-azaspiro[3.5]nonan-2- yl)methoxy)quinazolin-6-yl]-2-pentenamid, /V-[4-(3-chlor-4-fluorphenylamino)-7-((7-methyl-7-azaspiro[3.5]nonan-2- yl)methoxy)quinazolin-6-yl]-acrylamid, /S/-[4-(3-chlor-4-fluorphenylamino)-7-(2-(7-methyl-7-azaspiro[3.5]nonan-2-yl )ethoxy)quinazol in-6-yl]-acrylamid, (E)-A/-(4-(3-chlor-4-fluorphenylamino)-7-((7-methyl-7-azaspiro[3.5]nonan-2-yl)methoxy)quinazolin-6-yl)-4-dimethylamino-2-butenamid, (E)-A/-[4-(3-chlor-4-fluorphenylamino)-7-((2-(3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)ethoxy)quinazolin-6-yl)-4-dimethylamino]-crotonamid, (E)-/V-[4-(3-chlor-4-fluorphenylamino)-7-(((spiro[3.5]nonan-2- yl)methoxy)quinazolin-6-yl)-4-dimethylamino]-crotonamid,og (£)-A/-(7-(bicyclo[3.1.0]hexan-6-ylmethoxy)-4-(3-chlor-4- fluorphenylamino)quinazolin-6-yl)-4-(dimethylamino)but-2-enamid.
6. Fremgangsmåde til fremstilling af en forbindelse med den almene formel (I) ifølge krav 1, hvilken fremgangsmåde omfatter trinnene: Reaktionsprocedure
hvor R1, R2, R3, R4, R5, R6, L og n er som defineret i krav 1; udgangsmaterialet 2 = R1-LH; udgangsmaterialet 3 = R2CH=CH-C(0)CI eller R2CH=CH-COOH, (1) at opløse udgangsmaterialet 2 i et ikke-protonisk polært opløsningsmiddel, og at omsætte det med udgangsmaterialet 1 i nærvær af en base for at fremstille mellemproduktet 1; (2) at omsætte mellemproduktet 1 med et reduktionsmiddel eventuelt i nærvær af en syre for at fremstille mellemproduktet 2; og (3) at opløse mellemproduktet 2 i et organisk opløsningsmiddel, og at omsætte med udgangsmaterialet 3 i nærvær af en organisk base for at fremstille forbindelsen med formlen (I).
7. Farmaceutisk sammensætning, hvilken sammensætning indeholder en forbindelse ifølge ethvert af kravene 1-5, et farmaceutisk acceptabelt salt deraf eller en stereoisomer deraf.
8. Farmaceutisk sammensætning ifølge krav 7, hvilken sammensætning yderligere indeholder et andet terapeutisk middel valgt fra gruppen bestående af et antineoplastisk middel og et immunosuppressivt middel, hvilket andet terapeutiske middel er valgt fra gruppen bestående af en antimetabolit, der indbefatter capecitabin og gemcitabin; en vækstfaktorinhibitor, der indbefatter pazopanib og imatinib; et antistof, der indbefatter herceptin og bevacizumab; en mitotisk inhibitor, der indbefatter paclitaxel, vinorelbin, docetaxel, og doxorubicin; et antineoplastisk hormon, der indbefatter letrozol, tamoxifen, og fulvestrant; et alkyleringsmiddel, der indbefatter cyclophosphamid og carmustin; et metalplatin, der indbefatter carboplatin, cisplatin, og oxaliplatin; en topoismerase inhibitor, der indbefatter topotecan; og en immunosuppressant, der indbefatter everolimus.
9. Farmaceutisk formulering, der indeholder en forbindelse ifølge ethvert af kravene 1-5, et farmaceutisk acceptabelt salt deraf eller en stereoisomer deraf og et eller flere farmaceutisk acceptable bærere, hvilken formulering er i form af enhver farmaceutisk acceptabel doseringsform.
10. Anvendelse af en forbindelse ifølge et hvilket som helst af kravene 1-5, et farmaceutisk acceptabelt salt deraf eller en stereoisomer deraf til fremstilling af et lægemiddel til behandling af en hyperplasisygdom og en kronisk obstruktiv lungesygdom.
11. Anvendelse ifølge krav 10, hvor den nævnte hyperplasisygdom indbefatter en cancerøs sygdom og en ikke-cancerøs sygdom, hvilken cancerøs sygdom er valgt fra gruppen bestående af cerebroma, lungecancer, ikke-småcelle-lungecarcinoma, pladeepitel blærecarcinoma, gastrisk cancer, ovariecancer, peritoneal cancer, pancreascancer, brystcancer, hoved- og halscancer, cervikal cancer, endometriecancer, colorektal cancer, levercancer, renalt carcinom, adenocarcinom i spiserøret, pladeepitel kræft i spiserøret, fast tumor, non-Hodgkin-lymfom , centralnervesystem tumor (gliom, gliobastona multiforme, gliom sarcomatosum), prostatacarcinom eller thyreoideacarcinom; og ikke-cancersygdommen, for eksempel, er godartet hyperplasi i huden eller prostata.
12. Forbindelse ifølge ethvert af kravene 1-5, et farmaceutisk acceptabelt salt deraf eller en stereoisomer deraf til anvendelse som et medikament. endelse som et medikament.
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