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DK2668160T3 - Trpm8-receptorantagonister - Google Patents

Trpm8-receptorantagonister Download PDF

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DK2668160T3
DK2668160T3 DK12705078.9T DK12705078T DK2668160T3 DK 2668160 T3 DK2668160 T3 DK 2668160T3 DK 12705078 T DK12705078 T DK 12705078T DK 2668160 T3 DK2668160 T3 DK 2668160T3
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chloronaphthalen
oxy
methyl
ylmethyl
amine
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DK12705078.9T
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Alessio Moriconi
Gianluca Bianchini
Laura Brandolini
Andrea Aramini
Chiara Liberati
Silvia Bovolenta
Andrea Beccari
Simone Lorenzi
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Dompé Farmaceutici S P A
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Claims (12)

1. Forbindelser med formlen (I):
(I) og farmaceutisk acceptable salte deraf, hvor: R er valgt fra: - H, Br, CN, NO2, SO2NH2, S02NHR' og S02N(R')2, hvor R' er valgt fra lineær eller forgrenet C1-C4 alkyl; X er valgt fra: - F, Cl, C1-C3 alkyl, NH2 og OH Y er valgt fra: - -O-, CH2, NH og SO2 RI og R2, uafhængigt fra hinanden, er valgt fra - H, F og lineær eller forgrenet C1-C4 alkyl; R3 og R4, uafhængigt fra hinanden, er valgt fra - H og lineær eller forgrenet C1-C4 alkyl; Z er valgt fra: - NR6 og R6R7N+, hvor R6 og R7, uafhængigt fra hinanden, er valgt fra: • H og lineær eller forgrenet C1-C4 alkyl R5 er en gruppe valgt fra: - H og lineær eller forgrenet C1-C4 alkyl Het er en heteroaryl gruppe valgt fra pyrrolyl, N-methylpyrrolyl, thiophenyl, furyl og pyridinyl, ikke-substitueret eller substitueret med en eller flere substituenter valgt fra F, Cl, CH3, NH2 og OH.
2. Forbindelserne ifølge krav 1, hvor, uafhængigt fra hinanden: R er valgt fra H, Br og CN. X er valgt fra F, Cl og C1-C3 alkyl; Y er valgt fra -O- , CH2, NH og SO2, RI og R2, uafhængigt fra hinanden, er valgt fra H, F og Chb; R3 og R4, uafhængigt fra hinanden, er valgt fra H og Chb; Z er valgt fra NR6 og R6R7N+, hvor R6 og R7, uafhængigt fra hinanden, er valgt fra H og Chb; R5 er valgt fra H og Chb;
3. Forbindelserne ifølge krav 1 eller 2, hvor, uafhængigt fra hinanden, R er valgt fra H og CN; X er valgt fra F og Cl; Y er valgt fra CH2, O og SO2; Z er valgt fra NH og N + (CH3)2; R5 er H, Het er substitueret med mindst en substituent valgt fra F, Cl og CH3.
4. Forbindelserne ifølge et hvilket som helst af kravene 1 til 3, hvor Het er 5-substitueret pyrrol-2-yl, 5-substitueret N-methylpyrrol-2-yl, 5- substitueret thiophen-2-yl eller 5- substitueret fur-2-yl.
5. Forbindelserne ifølge et hvilket som helst af kravene 1 til 4 valgt fra gruppen bestående af: 2-[(l-chloronaphthalen-2-yl)oxy]-N-(furan-2-ylmethyl)ethanaminium chlorid (1) 2-[(l-chloronaphthalen-2-yl)oxy]-N-[(5-methylfuran-2-yl)methyl]ethanaminium chlorid (2) N-[(5-chlorofuran-2-yl)methyl]-2-[(l-chloronaphthalen-2-yl)oxy]ethanaminium (3) 2-[(l-chloronaphthalen-2-yl)oxy]-N-[(5-chlorothiophen-2-yl)methyl]ethanaminium (4) 2-[(l-chloronaphthalen-2-yl)oxy]-N-(thiophen-2-ylmethyl)ethana minium (5) 2-[(l-chloronaphthalen-2-yl)oxy]-N-(pyridin-2-ylmethyl)ethanaminium (6) 2-[(l-chloronaphthalen-2-yl)oxy]-N-[(l-methyl-lH-pyrrol-2-yl)methyl]ethanaminium (7) l-[(l-chloronaphthalen-2-yl)oxy]-N-(furan-2-ylmethyl)-2-methylpropan-2-amin (8) l-[(l-chloronaphthalen-2-yl)oxy]-2-methyl-N-[(5-methylfuran-2-yl)methyl]propan-2-amin (9) N-[(5-chlorofuran-2-yl)methyl]-l-[(l-chloronaphthalen-2-yl)oxy]-2-methylpropan-2-amin (10) l-[(l-chloronaphthalen-2-yl)oxy]-N-[(5-chlorc>thiophen-2-yl)methyl]-2-methylpropan-2-amin (11) l-[(l-chloronaphthalen-2-yl)oxy]-2-methyl-N-(thiophen-2-ylmethyl)propan-2-amin (12) 1- [(l-chloronaphthalen-2-yl)oxy]-2-methyl-N-(pyridin-2-ylmethyl)propan- 2- amin (13) 1- [(l-chloronaphthalen-2-yl)oxy]-2-methyl-N-[(l-methyl-lH-pyrrol-2-yl)methyl]propan-2-amin (14) 2- [(l-chloronaphthalen-2-yl)oxy]-N-(furan-2-ylmethyl)propan-l-amin (15) 2-[(l-chlorc)naphthalen-2-yl)oxy]-N-[(5-methylfuran-2-yl)methyl] propan- 1- amin (16) N-[(5-chlorofuran-2-yl)methyl]-2-[(l-chloronaphthalen-2-yl)oxy]propan-l-amin (17) 2- [(l-chloronaphthalen-2-yl)oxy]-N-[(5-chlorothiophen-2-yl)methyl]propan-l-amin (18) 2-[(l-chloronaphthalen-2-yl)oxy]-N-(thiophen-2-ylmethyl)propan-1-amin (19) l-[(l-chloronaphthalen-2-yl)oxy]-N-(furan-2-ylmethyl)propan-2-amin (20) 1- [(l-chloronaphthalen-2-yl)oxy]-N-[(5-methylfuran-2-yl)methyl]propan- 2- amin (21) N-[(5-chlorofuran-2-yl)methyl]-l-[(l-chloronaphthalen-2-yl)oxy]propan-2-amin (22) l-[(l-chloronaphthalen-2-yl)oxy]-N-[(5-chlorothiophen-2-yl)methyl]propan-2-amin (23). 1- [(l-chloronaphthalen-2-yl)oxy]-N-(thiophen-2-ylmethyl)propan-2-amin (24) 2- [(l-chloronaphthalen-2-yl)sulfonyl]-N-(furan-2-ylmethyl)ethanamin (25) 2-[(l-chloronaphthalen-2-yl)sulfonyl]-N-[(5-methylfuran-2-yl)methyl]ethanamin (26) N-[(5-chlorofuran-2-yl)methyl]-2-[(l-chloronaphthalen-2-yl)sulfonyl]ethanamin (27) 2-[(l-chloronaphthalen-2-yl)sulfonyl]-N-[(5-chlorothiophen-2-yl)methyl]ethanamin (28) 2-[(l-chloronaphthalen-2-yl)sulfonyl]-N-(thiophen-2-ylmethyl)ethanamin (29) 2-[(l-chloronaphthalen-2-yl)sulfonyl]-N-(pyridin-2-ylmethyl)ethanamin (30) 2- [(l-chloronaphthalen-2-yl)sulfonyl]-N-[(l-methyl-lH-pyrrol-2-yl)methyl] ethanamin (31) 3- (l-chloronaphthalen-2-yl)-N-(furan-2-ylmethyl)propan-l-amin (32) 3-( l-chloronaphthalen-2-yl)-N-[(5-methylfu ran-2-yl)methyl] propan- 1-amin (33) N-[(5-chlorofuran-2-yl)methyl]-3-(l-chloronaphthalen-2-yl)propan-1-amin (34) 3-(l-chloronaphthalen-2-yl)-N-[(5-chlorothiophen-2-yl)methyl]propan-l-amin (35) 3-(l-chloronaphthalen-2-yl)-N-(thiophen-2-ylmethyl)propan-l-amin (36) 3-(l-chloronaphthalen-2-yl)-N-(pyridin-2-ylmethyl)propan-l-amin (37) 2-[(l-chloronaphthalen-2-yl)oxy]-N-(furan-2-ylmethyl)-N-methylethanamin (38) 2-[(l-chloronaphthalen-2-yl)oxy]-N-(fiiran-2-ylmethyl)-N,N-dimethylethanaminiumiodid (39) N-{2-[(l-chloronaphthalen-2-yl)oxy]ethyl}-l-(5-methylfuran-2-yl)ethanamin (40) N-(l-chloronaphthalen-2-yl)-N'-(furan-2-ylmethyl)ethan-l,2-diamin (41) N-(l-chloronaphthalen-2-yl)-N'-[(5-methylfuran-2-yl)methyl]ethan-l,2-diamin (42) N-[(5-chlorofuran-2-yl)methyl]-N'-(l-chloronaphthalen-2-yl)ethan-l,2-diamin (43) N-(l-chloronaphthalen-2-yl)-N'-[(5-chlorothiophen-2-yl)methyl]ethan-l,2-diamin (44) N-(l-chloronaphthalen-2-yl)-N'-(thiophen-2-ylmethyl)ethan-l,2-diamin (45) N-(l-chloronaphthalen-2-yl)-N'-(pyridin-2-ylmethyl)ethan-l,2-diamin (46) N-(l-chloronaphthalen-2-yl)-N'-[(l-methyl-lH-pyrrol-2-yl)methyl]ethan-1,2-diamin (47) 2-[(l-fluoronaphthalen-2-yl)oxy]-N-(furan-2-ylmethyl)ethanamin (48) 2-[(l-fluoronaphthalen-2-yl)oxy]-N-[(5-methylfuran-2-yl)methyl]ethanamin (49) N-[(5-chlorofuran-2-yl)methyl]-2-[(l-fluoronaphthalen-2-yl)oxy]ethanamin (50) N-[(5-chlorothiophen-2-yl)methyl]-2-[(l-fluoronaphthalen-2-yl)oxy]ethanamin (51) 2-[(l-fluoronaphthalen-2-yl)oxy]-N-(thiophen-2-ylmethyl)ethanamin (52) 2-[(l-fluoronaphthalen-2-yl)oxy]-N-(pyridin-2-ylmethyl)ethanamin (53) 2-[(l-fluoronaphthalen-2-yl)oxy]-N-[(l-methyl-lH-pyrrol-2-yl)methyl]ethanamin (54) 5-chloro-6-{2-[(pyridin-2-ylmethyl)amino]ethoxy}naphthalen-2-carbonitril (55) 5-chloro-6-{2-[(furan-2-ylmethyl)amino]ethoxy}naphthalen-2-carbonitril (56) 5-chloro-6-(2-{[(5-methylfuran-2-yl)methyl]amino}ethoxy)naphthalen-2-carbonitril (57) 5-chloro-6-(2-{[(5-chlorofuran-2-yl)methyl]amino}ethoxy)naphthalen-2-carbonitril (58) 5-chloro-6-(2-{[(5-chlorothiophen-2-yl)methyl]amino}ethoxy)naphthalen-2-carbonitril (59) 5-chloro-6-{2-[(thiophen-2-ylmethyl)amino]ethoxy}naphthalen-2-carbonitril (60). 2-[(l-ethylnaphthalen-2-yl)oxy]-N-(furan-2-ylmethyl)ethanamin (61) 2,2-difluoro-2-[(l-fluoronaphthalen-2-yl)oxy]-N-(furan-2-ylmethyl)ethanamin (62) 2-[(6-bromo-l-fluoronaphthalen-2-yl)oxy]-N-(furan-2-ylmethyl)ethanamin (63)
6. Forbindelserne ifølge et hvilket som helst af kravene 1 til 5, valgt fra gruppen bestående af: 2-[(l-chloronaphthalen-2-yl)oxy]-N-(furan-2-ylmethyl)ethanaminium chlorid (1) 2-[(l-chloronaphthalen-2-yl)oxy]-N-(thiophen-2-ylmethyl)ethana minium (5) 2-[(l-chloronaphthalen-2-yl)oxy]-N-(pyridin-2-ylmethyl)ethanaminium (6) l-[(l-chloronaphthalen-2-yl)oxy]-N-(furan-2-ylmethyl)-2-methylprc>pan-2-amin (8) 1- [(l-chloronaphthalen-2-yl)oxy]-2-methyl-N-(pyridin-2-ylmethyl)prc>pan- 2- amin (13) 1- [(l-chloronaphthalen-2-yl)oxy]-2-methyl-N-[(l-methyl-lH-pyrrol-2-yl)methyl]propan-2-amin (14) 2- [(l-chloronaphthalen-2-yl)sulfonyl]-N-(furan-2-ylmethyl)ethanamin (25) 3- (l-chloronaphthalen-2-yl)-N-(furan-2-ylmethyl)propan-l-amin (32) 3-(l-chloronaphthalen-2-yl)-N-[(5-methylfuran-2-yl)methyl]propan-l-amin (33) N-[(5-chlorofuran-2-yl)methyl]-3-(l-chloronaphthalen-2-yl)propan-l-amin (34) 3-(l-chloronaphthalen-2-yl)-N-[(5-chlorothiophen-2-yl)methyl]propan-l-amin (35) 2-[(l-fluoronaphthalen-2-yl)oxy]-N-(furan-2-ylmethyl)ethanamin (48) 2-[(l-fluoronaphthalen-2-yl)oxy]-N-(thiophen-2-ylmethyl)ethanamin (52) 2-[(l-fluoronaphthalen-2-yl)oxy]-N-(pyridin-2-ylmethyl)ethanamin (53) 5-chloro-6-{2-[(pyridin-2-ylmethyl)amino]ethoxy}naphthalen-2-carbonitril (55) 5-chloro-6-{2-[(thiophen-2-ylmethyl)amino]ethoxy}naphthalen-2-carbonitril (60).
7. Forbindelserne ifølge et hvilket som helst af kravene 1 til 6, til anvendelse i forebyggelsen og/eller behandlingen af lidelser og/eller sygdomme forbundet med aktiviteten af TRPM8 (Transient Receptor Potential kationkanal underfamilie M medlem 8), hvor lidelsen og/eller sygdommene, er valgt fra gruppen bestående af: inflammatoriske lidelser, iskæmi, smerte, urologiske sygdomme, slagtilfælde, psykiatriske lidelser og neurodegeneration.
8. Forbindelserne til anvendelse ifølge krav 7, hvor lidelsen og/eller sygdommene, er valgt fra kronisk smerte, neuropatisk smerte inklusiv kold allodyni og diabetisk neuropatisk smerte, postoperativ smerte, osteoartritisk smerte, rheumatoid arthritisk smerte, cancersmerte, neuralgi, fibromyalgi, neuropatier, algesi, nerveskade, migræne, hovedpine, kløe, irritable tyktarm og luftvejssygdomme, blæresyndrom, interstitial cystitis, detrusor overaktivitet (overaktiv blære), urinær inkontinens, neurogenisk detrusor overaktivitet (detrusor hyperreflexia), idiopatisk detrusor overaktivitet (detrusor instabilitet), godartet prostatisk hyperplasi, nedre urinvejssygdomme og nedre urinvejssymptomer angst og depression.
9. Farmaceutisk sammensætning omfattende som den aktive ingrediens mindst en forbindelse ifølge et hvilket som helst af kravene 1 til 8 i kombination med egnede excipienser og/eller fortyndingsmidler.
10. Den farmaceutiske sammensætning ifølge krav 9, egnet til at blive administreret intravesikalt, intravenøst, dermalt, oralt, og inhalatorisk.
11. Den farmaceutiske sammensætning ifølge et af kravene 9 eller 10, i formen af kontrolleret frigivelses formulering.
12. Fremgangsmåde til fremstilling af forbindelserne ifølge et hvilket som helst af kravene 1 til 8, omfattende de følgende trin: - at omsætte det aminiske mellemprodukt IA :
CIA) hvor X, RI, R2, R3, R4 og Z har de samme betydninger som de med formel (I) og Y'= O, CH2, NH og S, with R5CO-Het, hvor Het og R5 har de samme betydninger som de med formel (I), og efterfølgende tilføjer til reaktionsblandingen et mildt reduktionsmiddel, fortrinsvis natriumborhydrid, for derved at opnå forbindelsen (IB)
(IB) som sammenfalder med den endelige forbindelse med formel (I) i tilfældet Y'= O, CH2, NH, og i tilfældet Y'=S fremgangsmåden endvidere omfatter det følgende trin: - at oxidere forbindelsen (IB) for at opnå forbindelsen med formel (I) med Y=SC>2.
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