DK2356109T3 - Sammensætninger og fremgangsmåder til behandling af sygdomme i forbindelse med alkoholforbrug, smerter og andre sygdomme - Google Patents

Sammensætninger og fremgangsmåder til behandling af sygdomme i forbindelse med alkoholforbrug, smerter og andre sygdomme Download PDF

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DK2356109T3
DK2356109T3 DK09820030.6T DK09820030T DK2356109T3 DK 2356109 T3 DK2356109 T3 DK 2356109T3 DK 09820030 T DK09820030 T DK 09820030T DK 2356109 T3 DK2356109 T3 DK 2356109T3
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pain
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Jay Jie-Qiang Wu
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Vm Discovery Inc
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Claims (14)

1. Forbindelse med en strukturformel (Ila):
eller et salt eller solvat deraf, hvor: X er -CH2-; R1 er -C(0)NR5R6; R2 er hydrogen eller alkyl eventuelt substitueret med en eller med en eller flere substituenter R14;
-NR5R6 er udvalgt fra gruppen bestående af: ^ A3 (n er 1, 2 eller 3)
A5; A4 A5 Z1 er N; Z2 er CR12 eller N; R12 er udvalgt fra hydrogen eller alkyl eventuelt substitueret med en eller med en eller flere substituenter R14; n er et heltal fra 0 til 5; m erO; og hvert R11 uafhængigt er udvalgt fra gruppen bestående af acyl eventuelt substitueret med en eller flere substituenter R14, alkoxycarbonyl eventuelt substitueret med en eller flere substituenter R14, aryloxycarbonyl eventuelt substitueret med en eller flere substituenter R15, -C(0)NR11AR11B, ethyl, propyl, butyl, som hver især eventuelt er substitueret med en eller flere substituenter R14, aryl eventuelt substitueret med en eller flere substituenter R15, arylalkyl eventuelt substitueret med en eller flere substituenter R14, cycloheteroalkyl eventuelt substitueret med en eller flere substituenter R14, heteroaryl eventuelt substitueret med en eller flere substituenter R15, heteroarylalkyl eventuelt substitueret med en eller flere substituenter R14, heteroalkyl eventuelt substitueret med en eller flere substituenter R14, hvor R11A og R11B uafhængigt er hydrogen, alkyl eventuelt substitueret med en eller flere substituenter R14, aryl eventuelt substitueret med en eller flere substituenter R15, arylalkyl eventuelt substitueret med en eller flere substituenter R14, heteroaryl eventuelt substitueret med en eller flere substituenter R15, heteroarylalkyl eventuelt substitueret med en eller flere substituenter R14, heteroalkyl eventuelt substitueret med en eller flere substituenter R14, eller alternativt R11A og R11B sammen med nitrogenatomet, som de er bundet til, danner en 4-, 5-, 6- eller 7-leddet cycloheteroalkylring; hvor hver gruppe R14 uafhængigt er udvalgt fra -Ra, halogen, -O-, =0, -0Rb, -SRb, -S', =S, -NRCRC, =NRb, =N-ORb, trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -N02, =N2j -N3, -S(0)2Rb, -S(0)2NRb, -S(0)20-, -S(0)20Rb, -0S(0)2Rb, -0S(0)20-, -0S(0)20Rb, - P(0)(0')2, -P(0)(0Rb)(0'), -P(0)(ORb)(ORb), -C(0)Rb, -C(S)Rb, -C(NRb)Rb, -C(0)0-, -C(0) 0Rb, -C(S)ORb, -C(0)NRcRc, -C(NRb)NRcRc, -0C(0)Rb, -OC(S)Rb, -0C(0)0-, -0C(0)0Rb, -OC(S)ORb, -NRbC(0)Rb, -NRbC(S)Rb, -NRbC(0)0\ -NRbC(0)0Rb, -NRbC(S)ORb, -NRbC( 0)NRcRc, -NRbC(NRb)Rb og -NRbC(NRb)NRcRc, hver gruppe R15 uafhængigt er udvalgt fra -Ra, halogen, -O-, -0Rb, -SRb, -S', -NRCRC, trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -N02, -N3, -S(0)2Rb, -S(0)20‘, -S(0)20Rb, -OS (0)2Rb, -0S(0)20\ -0S(0)20Rb, -P(0)(0')2, -P(0)(0Rb)(0"), -P(0)(0Rb)(0Rb), -C(0)Rb, -C (S)Rb, -C(NRb)Rb, -C(0)0-, -C(0)0Rb, -C(S)ORb, -C(0)NRcRc, -C(NRb)NRcRc, -0C(0)Rb, - OC(S)Rb, -0C(0)0\ -0C(0)0Rb, -OC(S)ORb, -NRbC(0)Rb, -NRbC(S)Rb, -NRbC(0)0\ -NR bC(0)0Rb, -NRbC(S)ORb, -NRbC(0)NRcRc, -NRbC(NRb)Rb og -NRbC(NRb)NRcRc; hvor Ra er udvalgt fra gruppen bestående af alkyl, arylalkyl, alkyldiyl, aryl, heteroalkyl, heteroalkyldiyl, heteroaryl, heteroarylalkyl; hvert Rb uafhængigt er hydrogen eller Ra; og hvert Rc uafhængigt er Rb, eller alternativt de to Rc'er sammen med nitrogenatomet, som de er bundet til, danner en cycloheteroalkylring, som eventuelt kan omfatte fra 1 til 4 af de samme eller forskellige yderligere heteroatomer udvalgt fra gruppen bestående af O, N og S.
2. Forbindelse udvalgt fra gruppen bestående af:
eller et salt eller solvat deraf.
3. Farmaceutisk sammensætning omfattende en terapeutisk virksom mængde af en forbindelse eller et salt eller solvat deraf; og mindst et farmaceutisk acceptabelt vehikel; hvor forbindelsen er (A) en forbindelse med formel (Ile):
(Hc), eller et salt eller solvat deraf, hvor: X er -CH2-; R1 er -C(0)NR5R6; R2 er hydrogen eller alkyl eventuelt substitueret med en eller flere substituen-ter R14; -NR5R6 er udvalgt fra gruppen bestående af:
A4 A5
A5; Z1 er N; Z2 er CR12 eller N; R12 er udvalgt fra hydrogen eller alkyl eventuelt substitueret med en eller med en eller flere substituenter R14; n er et heltal fra 0 til 5; m erO; og hvert R11 uafhængigt er udvalgt fra gruppen bestående af halogen, acyl eventuelt substitueret med en eller flere substituenter R14, alkoxycarbonyl eventuelt substitueret med en eller flere substituenter R14, aryloxycarbonyl eventuelt substitueret med en eller flere substituenter R15, -C(0)NR11AR11B, alkyl eventuelt substitueret med en eller flere substituenter R14, aryl eventuelt substitueret med en eller flere substituenter R15, arylalkyl eventuelt substitueret med en eller flere substituenter R14, cycloheteroalkyl eventuelt substitueret med en eller flere substituenter R14, heteroaryl eventuelt substitueret med en eller flere substituenter R15, heteroarylalkyl eventuelt substitueret med en eller flere substituenter R14, heteroalkyl eventuelt substitueret med en eller flere substituenter R14, hvor R11A og R11B uafhængigt er hydrogen, alkyl eventuelt substitueret med en eller flere substituenter R14, aryl eventuelt substitueret med en eller flere substituenter R15, arylalkyl eventuelt substitueret med en eller flere substituenter R15, heteroaryl eventuelt substitueret med en eller flere substituenter R15, heteroarylalkyl eventuelt substitueret med en eller flere substituenter R14, heteroalkyl eventuelt substitueret med en eller flere substituenter R14 eller alternativt R11A og R11B sammen med nitrogenatomet, som de er bundet til, danner en 4-, 5-, 6- eller 7-leddet cycloheteroalkylring; hvor hver gruppe R14 og R15 er defineret i krav 1; eller (B) udvalgt fra gruppen bestående af:
eller et salt eller solvat deraf.
4. Farmaceutisk sammensætning omfattende en terapeutisk virksom mængde af en forbindelse eller et salt eller solvat deraf; og mindst et farmaceutisk acceptabelt vehikel, hvor forbindelsen er en forbindelse udvalgt fra gruppen bestående af:
eller et salt eller solvat deraf.
5. Farmaceutisk sammensætning ifølge krav 3 eller krav 4, formuleret til intradermal, intramuskulær, intraperitoneal, intravenøs, subkutan, intranasal, epidural, oral, sublingual, intranasal, intracerebral, intravaginal, transdermal, rektal, ved inhalering, eller topisk indgivelse.
6. Farmaceutisk sammensætning ifølge krav 3 eller krav 4, hvor forbindelsen: (i) inhiberer PKCs ikke-kompetitivt med ATP; eller (ii) inhiberer PKCs reversibelt med en IC5o på mindre end 1 μΜ.
7. Forbindelse ifølge krav 1 eller 2 eller et salt eller solvat deraf eller en farmaceutisk sammensætning ifølge et af kravene 3 til 6 til anvendelse i en fremgangsmåde til behandling.
8. Forbindelse med formel (Ild) eller (IIb) til anvendelse i en fremgangsmåde til behandling, hvor behandlingen er af en sygdom, lidelse, et symptom eller tilstand udvalgt fra akut smerte, kronisk smerte, inflammatorisk smerte, neu- ropatisk smerte, diabetisk neuropati, alkoholisk polyneuropati, kræft eller kræft- eller kemoterapi-induceret smerte, en generaliseret smertelidelse, tonisk smerte, vedvarende smerte, postoperativ smerte, kemisk-induceret smerte, lægemiddel-induceret smerte, migræne, angst, skeletmuskelkramper, konvulsive anfald, epilepsi, alkoholmisbrug og sygdom forbundet med alkoholisme, søvnløshed, smerte forbundet med alkohol-induceret hyperal-gesi, diabetes type 1 og type 2, diabetiske komplikationer, hepatisk steatose eller levercirrose, bipolar lidelse, mani, søvnbesvær, forbrænding, posttraumatisk stressforstyrrelse, hjertesygdom, inflammation og immun-medierede lidelser (herunder mikrobiel infektion og organtransplantation), kræft (herunder brystkræft, hoved- og halskræft, prostata- og lungekræft), maladaptiv rusmiddelforbrug, rusmiddelafhængighed, alkoholmisbrug, rusmiddelmisbrug, medicinmisbrug eller medicin-relaterede stimulerende, sedative, hypnotiske eller ataktiske virkninger og en kombination deraf, hvor forbindelsen har strukturformen (Ild):
(TTd), eller et salt eller solvat deraf, hvor:
R2 er hydrogen, halogen, acyl eventuelt substitueret med en eller med en eller flere substituenter R14, alkoxycarbonyl eventuelt substitueret med en eller med en eller flere substituenter R14, aryloxycarbonyl eventuelt substitueret med en eller med en eller flere substituenter R15, -C(0)NR5R6, alkyl eventuelt substitueret med en eller med en eller flere substituenter R14, aryl eventuelt substitueret med en eller med en eller flere substituenter R15, arylalkyl eventuelt substitueret med en eller med en eller flere substituenter R14, cy-cloheteroalkyl eventuelt substitueret med en eller med en eller flere substituenter R14, heteroaryl eventuelt substitueret med en eller med en eller flere substituenter R15, heteroarylalkyl eventuelt substitueret med en eller med en eller flere substituenter R14, heteroalkyl eventuelt substitueret med en eller med en eller flere substituenter R14; R5 og R6 uafhængigt er hydrogen, alkyl eventuelt substitueret med en eller med en eller flere substituenter R14, aryl eventuelt substitueret med en eller med en eller flere substituenter R15, arylalkyl eventuelt substitueret med en eller med en eller flere substituenter R14, heteroaryl eventuelt substitueret med en eller med en eller flere substituenter R15, heteroarylalkyl eventuelt substitueret med en eller med en eller flere substituenter R14, heteroalkyl eventuelt substitueret med en eller med en eller flere substituenter R14, eller alternativt R5 og R6 sammen med nitrogenatomet, som de er bundet til, danner en 4-, 5-, 6- eller 7-leddet cycloheteroalkylring; Z1 og Z2 uafhængigt er CR12 og N; R12 er udvalgt fra hydrogen eller alkyl eventuelt substitueret med en eller med en eller flere substituenter R14; n er et heltal fra 0 til 5; m er et heltal fra 0 til 8; og hvert R11 og R13 uafhængigt er udvalgt fra gruppen bestående af halogen, acyl, eventuelt substitueret med en eller med en eller flere substituenter R14, alkoxycarbonyl eventuelt substitueret med en eller med en eller flere substituenter R14, aryloxycarbonyl eventuelt substitueret med en eller med en eller flere substituenter R15, -C(0)NR5R6, alkyl eventuelt substitueret med en eller med en eller flere substituenter R14, aryl eventuelt substitueret med en eller med en eller flere substituenter R15, arylalky eventuelt substitueret med en eller med en eller flere substituenter R14, cycl o heteroalkyl, eventuelt substitueret med en eller med en eller flere substituenter R14, heteroaryl eventuelt substitueret med en eller med en eller flere substituenter R15, heteroarylalkyl eventuelt substitueret med en eller med en eller flere substituenter R14, heteroalkyl eventuelt substitueret med en eller med en eller flere substituenter R14; hvor hver gruppe R14 og R15 er som defineret i krav 1; eller forbindelsen haren strukturformel (IIb):
(Hb), eller et salt eller solvat deraf, hvor X, R1 og R2, n, R11 og R13 er som defineret i henhold til forbindelsen, som har strukturformlen (Ila), og m er et heltal fra 0 til 4.
9. Forbindelse med formel (Ild) eller (Mb) til anvendelse i en fremgangsmåde til behandling ifølge krav 8, hvor forbindelsen er udvalgt fra gruppen bestående af:
eller et salt eller solvat deraf.
10. Forbindelse til anvendelse inden for behandling ifølge krav 8 eller 9, til anvendelse i en fremgangsmåde til behandling af kræft eller kræft-induceret smerte.
11. Forbindelse til anvendelse inden for behandling ifølge krav 8 eller 9, til anvendelse i en fremgangsmåde til behandling af maldaptiv rusmiddelforbrug, rusmiddelafhængighed, alkoholmisbrug, rusmiddelmisbrug, medicinmisbrug eller medicin-relaterede stimulerende, sedative, hypnotiske eller ataktiske virkninger eller en kombination deraf.
12. Forbindelse til anvendelse inden for behandling ifølge krav 8 eller 9 eller et salt eller solvat deraf til anvendelse i en fremgangsmåde til behandling af et individ, som er ryger, en stofmisbruger, en maladaptiv rusmiddelbruger eller en alkoholmisbruger.
13. Forbindelse til anvendelse i en fremgangsmåde til behandling ifølge et af kravene 7 til 12, hvilken fremgangsmåde omfatter indgivelse af en terapeutisk virksom mængde af forbindelsen til patienten i kombination med mindst et yderligere aktivt middel udvalgt fra gruppen bestående af en inhibitor af proteinkinase A (PKA), en inhibitor af cAMP signalering, et ikke-steroidt anti-inflammatorisk lægemiddel, en prostaglandinsynteseinhibitor, et lokalt anæ-stetikum, et antikonvulsionsmiddel, et antidepressivt middel, en opioidrecep-toragonist, et neuroleptikum, en agonist af GABAa receptor, et smertestillen de middel, som virker ved en mekanisme, som er anderledes end en PKCs antagonist, et benzodiazepin, et barbiturat, et neurosteroid og et inhalerings-anæstetikum, et anæstetikum, et antikræft-lægemiddel, en modulator af mGluR5 receptor og en kombination deraf.
14. Farmaceutisk sammensætning ifølge et af kravene 3 til 6 omfattende mindst et yderligere aktivt middel udvalgt fra gruppen bestående af en inhibitor af proteinkinase A (PKA), en inhibitor af cAMP signalering, et ikke-steroidt anti-inflammatorisk lægemiddel, en prostaglandinsyntesteinhibitor, et lokalt anæstetikum, et antikonvulsionsmiddel, et antidepressivt middel, en opioidre-ceptoragonist, et neuroleptikum, en agonist af GABAA-receptor, et smertestillende middel, som virker ved en mekanisme, som er anderledes end en PKCs antagonist, et benzodiazepin, et barbiturat, et neurosteroid og et inha-leringsanæstetikum, et anæstetikum, et antikræft-lægemiddel, en modulator af mGluR5 receptor og en kombination deraf.
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PT3135672T (pt) 2020-04-02
CN106243100A (zh) 2016-12-21
EP2356109B1 (en) 2016-12-07
EP3135672A1 (en) 2017-03-01
ES2617873T3 (es) 2017-06-20
HRP20170357T1 (hr) 2017-05-05
CY1118665T1 (el) 2017-07-12
EP2356109A4 (en) 2012-05-30
ES2782376T3 (es) 2020-09-14
US8729081B2 (en) 2014-05-20
CN102177153A (zh) 2011-09-07
SI3135672T1 (sl) 2020-07-31
PL3135672T3 (pl) 2020-11-16
HUE050319T2 (hu) 2020-11-30
PL2356109T3 (pl) 2017-07-31
HUE033711T2 (en) 2017-12-28
EP2356109A2 (en) 2011-08-17
CY1123625T1 (el) 2022-03-24
CN106243100B (zh) 2019-04-09
LT3135672T (lt) 2020-05-25
SI2356109T1 (sl) 2017-04-26
WO2010042925A3 (en) 2010-07-29
EP3135672B1 (en) 2020-02-19
HRP20200552T1 (hr) 2020-07-10
US20110301149A1 (en) 2011-12-08
EP3135672B9 (en) 2020-05-20
CN102177153B (zh) 2016-09-21
DK3135672T3 (da) 2020-05-04

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