DK2813502T3 - Bradykininreceptorantagonister og farmaceutiske sammensætninger indeholdende dem - Google Patents

Bradykininreceptorantagonister og farmaceutiske sammensætninger indeholdende dem Download PDF

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DK2813502T3
DK2813502T3 DK13172137.5T DK13172137T DK2813502T3 DK 2813502 T3 DK2813502 T3 DK 2813502T3 DK 13172137 T DK13172137 T DK 13172137T DK 2813502 T3 DK2813502 T3 DK 2813502T3
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methylphenyl
oxo
ethyl
amino
ylmethyl
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Andrea Rosario Beccari
Gianluca Bianchini
Michela Fani'
Mara Zippoli
Chiara Liberati
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Dompé Farm S P A
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    • C07—ORGANIC CHEMISTRY
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    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

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Claims (15)

1. Forbindelse med formel (I):
(i) og farmaceutisk acceptable salte deraf, hvor X og Y er forskellig fra hinanden og er O eller NH; R1 er valgt fra gruppen bestående af Ci-Ce-alkyl; Cs-Ce-cycloalkyl og halo Ci-C3-alkyl. R2 er valgt fra gruppen bestående af: - Ci-Ce alkyl; - C3-C6 cycloalkyl; - phenyl usubstitueret eller substitueret med mindst én gruppe valgt fra -
0-Ci-C4-akyl og Ci-C4-alkyl; - benzothiophen; - en 5- eller 6-leddet heteroaromatisk ring valgt fra pyridin og pyrrol. R3 er valgt fra gruppen bestående af: - Ci-Ce alkyl; - (CH2)mCOCH3, hvor m er et heltal bestående mellem 1 og 4; - (CH2)n-Z, hvor n er et heltal bestående mellem 1 og 3 og Z er valgt fra gruppen bestående af dialkylamin, C3-C6-cycloalkyl, benzotriazol, isoindol-l,3(2H)-dion-2-yl, imidazol, triazol, indol, furan, og phenyl, den sidstnævnte er usubstitueret eller substitueret med én eller flere grupper valgt fra halo, C1-C3 alkyl, O-C1-C3 alkyl og C1-C3 alkylamino; - C3-C6 cycloalkyl usubstitueret eller substitueret med én eller flere grupper valgt fra halo, og C1-C3 alkyl; - 2-methyl-l,3-oxazol-4-yl; - phenyl usubstitueret eller substitueret med én eller flere grupper valgt fra C1-C3 alkyl, hydroxyl, halo og nitro til anvendelse som et medikament.
2. Forbindelse til anvendelse ifølge krav 1, hvor X er O og Y er NH.
3. Forbindelse til anvendelse ifølge kravene 1 eller 2, hvor R1 er valgt fra methyl, cyclopropyl og trifluormethyl og/eller R2 er valgt fra methoxyphenyl, methylphenyl, l-benzothiophen-3-yl, 1-ethylpropyl, l-methyl-lF/-pyrrol-2-yl, 2-methylethyl, pyridin-3yl, cyclopentyl og cyclohexyl og/eller R3 er valgt fra: C2-C4 alkyl; 4-yl-butan-2-on; -CH2-Z, hvor Z er dimethylamino, cyclopentyl, benzotriazol-l-yl, isoindol-1, 3(2H)-dion-2-yl, imidazol-4-yl, 1,2,3-triazol-l-yl, indol-l-yl, furan-2-yl, eller phenyl, usubstitueret eller substitueret med én eller flere grupper valgt fra F, methyl, methoxy og dimethylamino; C3-C6 cycloalkyl usubstitueret eller substitueret med én eller flere grupper valgt fra F og methyl; 2-methyl-l,3-oxazol-4-yl; phenyl usubstitueret eller substitueret med én eller flere grupper valgt fra methyl, hydroxy, F og nitro; dimethylamino.
4. Forbindelse til anvendelse ifølge kravene 1 til 3, hvor R3 er valgt fra 1- methylen-lH-benzotriazol, 2-methyl-l,3-oxazol-4-yl, 2-methylen-lH-isoindol-l,3(2H)-dion, N,N-dimethyl-l-methylenamin, 4-methylen-lH-imidazol, 4-yl-butan-2-on, l-methylen-lH-l,2,3-triazol; 1-methylen-lH-indol, benzyl, 2- methoxybenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2,3-difluorbenzyl, 4-fluorbenzyl, 2,6-difluorbenzyl, 4-N,N-dimethylaminobenzyl, 4-methylphenyl, 4-hydroxyphenyl, 4-nitrophenyl, 2-nitrophenyl, 4-fluorphenyl, 2-methylenfuran, ethyl, butyl, isobutyl, phenyl, 4,4-difluorcyclohexyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, l-yl-2-methylcyclopropan, methylencyclopentyl.
5. Forbindelse til anvendelse ifølge kravene 1 til 4, valgt fra: 2-(lH-benzotriazol-l-yl)-N-(2-methoxybenzyl)-N-{l-(4-methylphenyl)-2- oxo-2-[(tetrahydrofuran-2-ylmethyl)amino]ethyl}acetamid; 2-methyl-N-(2-methoxybenzyl)-N-{l-(4-methylphenyl)-2-oxo-2- [(tetrahydrofuran-2-ylmethyl)amino]ethyl}-l,3-oxazol-4-carboxamid; 2-(2,3-difluorphenyl)-N-(2-methoxybenzyl)-N-{l-(4-methylphenyl)-2-oxo- 2-[(tetrahydrofuran-2-ylmethyl)amino]ethyl}acetamid; N-(2-methoxybenzyl)-N-{l-(4-methylphenyl)-2-oxo-2-[(tetrahydrofuran-2- ylmethyl)amino]ethyl}furan-2-carboxamid; 2-(2,4-difluorphenyl)-l\l-(2-methoxybenzyl)-N-{l-(4-methylphenyl)-2-oxo- 2-[(tetrahydrofuran-2-ylmethyl)amino]ethyl}acetamid; 2-(2,6-difluorphenyl)-N-(2-methoxybenzyl)-N-{l-(4-methylphenyl)-2-oxo- 2- [(tetrahydrofuran-2-ylmethyl)amino]ethyl}acetamid; N-(2-methoxybenzyl)-N-{l-(4-methylphenyl)-2-oxo-2-[(tetrahydrofuran-2- ylmethyl)amino]ethyl>-2-phenylacetamid; 3- methyl-N-(2-methoxybenzyl)-N-{(l-(4-methylphenyl)-2-oxo-2-[(tetrahydrofuran-2-ylmethyl)amino]ethyl}butanamid; 2-(2-methylphenyl)-N-(2-methoxybenzyl)-N-{(l-(4-methylphenyl)-2-oxo- 2-[(tetrahydrofuran-2-ylmethyl)amino]ethyl}acetamid; 2-(l,3-dioxoisoindolin-2-yl)-N-(2-methoxybenzyl)-N-{l-(4-methylphenyl)- 2-oxo-2-[(tetrahydrofuran-2-ylmethyl)amino]-ethyl}acetamid; 2-(dimethylamino)-N-(2-methoxybenzyl)-{l-(4-methylphenyl)-2-oxo-2- [(tetrahydrofuran-2-ylmethyl)amino]ethyl}acetamid; 2-(lH-imidazol-4-yl)-N-(2-methoxybenzyl)-N-{l-(4-methylphenyl)-2-oxo- 2-[(tetrahydrofuran-2-ylmethyl)amino]ethyl}acetamid; 2-(2-methoxylphenyl)-l\l-(2-methoxybenzyl)-N-{(l-(4-methylphenyl)-2- oxo-2-[(tetrahydrofuran-2-ylmethyl)amino]ethyl}acetamid; N-(2-methoxybenzyl)-N-{l-(4-methylphenyl)-2-oxo-2-[(tetrahydrofuran-2- ylmethyl)amino]ethyl>pentanamid; N-(2-methoxybenzyl)-N-{l-(4-methylphenyl)-2-oxo-2-[(tetrahydrofuran-2- ylmethyl)amino]ethyl>cyclopentancarboxamid; 4-hydroxy-N-(2-methoxybenzyl)-N-{l-(4-methylphenyl)-2-oxo-2- [(tetrahydrofuran-2-ylmethyl)amino]ethyl}benzamid; 4-oxo-N-(2-methoxybenzyl)-N-{l-(4-methylphenyl)-2-oxo-2- [(tetrahydrofuran-2-ylmethyl)amino]ethyl}pentanamid; 2-(3-methylphenyl)-N-(2-methoxybenzyl)-N-{(l-(4-methylphenyl)-2-oxo- 2-[(tetrahydrofuran-2-ylmethyl)amino]ethyl}acetamid; 2-(4-methylphenyl)-N-(2-methoxybenzyl)-N-{(l-(4-methylphenyl)-2-oxo- 2-[(tetrahydrofuran-2-ylmethyl)amino]ethyl}acetamid; 4-methyl-N-(2-methoxybenzyl)-N-{l-(4-methylphenyl)-2-oxo-2- [(tetrahydrofuran-2-ylmethyl)amino]ethyl}benzamid; 2-(4-fluorphenyl)-N-(2-methoxybenzyl)-N-{(l-(4-methylphenyl)-2-oxo-2- [(tetrahydrofuran-2-ylmethyl)amino]ethyl}acetamid; 4-fluor-N-(2-methoxybenzyl)-N-{l-(4-methylphenyl)-2-oxo-2- [(tetrahydrofuran-2-ylmethyl)amino]ethyl}benzamid; 4,4-difluor-N-(2-methoxybenzyl)-N-{l-(4-methylphenyl)-2-oxo-2- [(tetrahydrofuran-2-ylmethyl)amino]ethyl}cyclohexancarboxamid; N-(2-methoxybenzyl)-N-{l-(4-methylphenyl)-2-oxo-2-[(tetrahydrc>furan-2- ylmethyl)amino]ethyl}propanamid; N-(2-methoxybenzyl)-N-{l-(4-methylphenyl)-2-oxo-2-[(tetrahydrofuran-2- ylmethyl)amino]ethyl}cyclobutancarboxamid; N-(2-methoxybenzyl)-2-nitro-N-{l-(4-methylphenyl)-2-oxo-2- [(tetrahydrofuran-2-ylmethyl)amino]ethyl}benzamid; N-(2-methoxybenzyl)-N-{l-(4-methylphenyl)-2-oxo-2-[(tetrahydrofuran-2- ylmethyl)amino]ethyl>cyclopropancarboxamid; N-(2-methoxybenzyl)-4-nitro-l\l-{l-(4-methylphenyl)-2-oxo-2- [(tetrahydrofuran-2-ylmethyl)amino]ethyl}benzamid; 2-[(4-dimethylamino)phenyl]-N-(2-methoxybenzyl)-N-{ 1-(4- methylphenyl)-2-oxo-2-[(tetrahydrofuran-2- ylmethyl)amino]ethyl>acetamid; N-(2-methoxybenzyl)-N-{l-(4-methylphenyl)-2-oxo-2-[(tetrahydrofuran-2- ylmethyl)amino]ethyl>-2-(lH-l,2,3-triazol-l-yl)acetamid; 2-(lH-indol-l-yl)-N-(2-methoxybenzyl)-N-{l-(4-methylphenyl)-2-oxo-2- [(tetrahydrofuran-2-ylmethyl)amino]ethyl}acetamid; N-(cyclopentylmethyl)-2-(lH-imidazol-4-yl)-N-{l-(4-methylphenyl)-2-oxo- 2-[(tetrahydrofuran-2-ylmethyl)amino]ethyl>acetamid; N-(cyclohexylmethyl)-2-(2-methylphenyl)-N-{l-(4-methylphenyl)-2-oxo-2- [(tetrahydrofuran-2-ylmethyl)amino]ethyl}acetamid; N-(cyclohexylamino)-2-(dimethylamino)-N-{l-(4-methylphenyl)-2-oxo-2- [(tetrahydrofuran-2-ylmethyl)amino]ethyl}acetamid; 2-(dimethylamino)-N-(3-methylbenzyl)-N-{l-(4-methylphenyl)-2-oxo-2- [(tetrahydrofuran-2-ylmethyl)amino]ethyl}acetamid; N-(cyclohexylmethyl)-2-(lH-imidazol-4-yl)-N-{l-(4-methylphenyl)-2-oxo- 2-[(tetrahydrofuran-2-ylmethyl)amino]ethyl}acetamid; N-(cyclohexylmethyl)-2-phenyl-N-{l-(4-methylphenyl)-2-oxo-2- [(tetrahydrofuran-2-ylmethyl)amino]ethyl}acetamid; 2-methyl-N-(3-methylbenzyl)-N-{l-(4-methylphenyl)-2-oxo-2- [(tetrahydrofuran-2-ylmethyl)amino]ethyl}cyclopropancarboxamid; N-(l-benzothiophen-3-ylmethyl)-2-(d imethylamino)-N-{ 1-(4- methylphenyl)-2-oxo-2-[(tetrahydrofuran-2- ylmethyl)amino]ethyl}acetamid; N-(cyclohexylmethyl)-2-(3-methylphenyl)-N-{l-(4-methylphenyl)-2-oxo-2- [(tetrahydrofuran-2-ylmethyl)amino]ethyl}acetamid; N-(2-ethylbutyl)-2-(2-methylphenyl)-N-{l-(4-methylphenyl)-2-oxo-2- [(tetrahydrofuran-2-ylmethyl)amino]ethyl}acetamid; N-(2-ethylbutyl)-2-(4-fluorlphenyl)-N-{l-(4-methylphenyl)-2-oxo-2- [(tetrahydrofuran-2-ylmethyl)amino]ethyl}acetamid; 2-(dimethylamino)-N-[(l-methyl-lH-pyrrol-2-yl)methyl]-N-{l-(4- methylphenyl)-2-oxo-2-[(tetrahydrofuran-2- ylmethyl)amino]ethyl}acetamid; N-(cyclopentylmethyl)-2-(2-methylphenyl)-N-{l-(4-methylphenyl)-2-oxo- 2-[(tetrahydrofuran-2-ylmethyl)amino]ethyl}acetamid; N-(cyclopentylmethyl)-2-(3-methylphenyl)-N-{l-(4-methylphenyl)-2-oxo- 2-[(tetrahydrofuran-2-ylmethyl)amino]ethyl>acetamid; 2-(2-methylphenyl)-N-(pyridin-3-ylmethyl)-N-{l-(4-methylphenyl)-2-oxo- 2-[(tetrahydrofuran-2-ylmethyl)amino]ethyl}acetamid; N-(cyclopentylmethyl)-N-{l-(4-methylphenyl)-2-oxo-2-[(tetrahydrofuran- 2-yl)methylamino]ethyl>2-phenylacetamid; N-(cyclohexylmethyl)-2-cyclopentyl-N-{l-(4-methylphenyl)-2-oxo-2- [(tetrahydrofuran-2-ylmethyl)amino]ethyl}acetamid; 2-(lH-imidazol-4-yl)-N-(2-methylpropyl)-N-{l-(4-methylphenyl)-2-oxo-2- [(tetrahydrofuran-2-ylmethyl)amino]ethyl}acetamid; N-(2-ethylbutyl)-N-{l-(4-methylphenyl)-2-oxo-2-[(tetrahydrofuran-2- ylmethyl)amino]ethyl}cyclohexancarboxamid; 2-cyclopentyl-N-cyclopentylmethyl-N-{l-(4-methylphenyl)-2-oxo-2- [(tetrahydrofuran-2-ylmethyl)amino]ethyl}acetamid; N-(2-methoxybenzyl]-N-[l-(4-cyclopropylphenyl)-2-oxo-2- [(tetrahydrofuran-2-yl)methylamino]ethyl)-3-methylbutanamid; 2-(lH-benzotriazol-l-yl)-N-(2-methoxybenzyl)-N-{l-(4- trifluormethylphenyl)-2-oxo-2-[(tetrahydrofuran-2- ylmethyl)amino]ethyl>acetamid; N-[(2-methoxybenzyl]-N-{l-[4-(trifluormethyl)phenyl]-2-oxo-2- [(tetrahydrofuran-2-yl)methylamino]ethyl}3-methylbutanamid; N-(2-methoxybenzyl)-N-{(lR)-l-(4-methylphenyl)-2-oxo-2-[(2R)- (pyrrolidin-2-ylmethyl)amino]ethyl}-2-(lH-l,2,3-triazol-l-yl)acetat.
6. Forbindelser til anvendelse ifølge kravene 1 til 5, i R,R-konfiguration eller som 4 som en blanding af stereoisomerer.
7. Forbindelser ifølge kravene 1 til 6, til anvendelse i forebyggelsen, nedsættelse af risikoen for, forbedring og/eller behandling af sygdomme valgt fra smerterelaterede lidelser, inflammatoriske og/eller neuropatiske tilstande.
8. Forbindelser ifølge kravene 1 til 7, til anvendelse i forebyggelsen, nedsættelse af risikoen for, forbedring og/eller behandling af sygdomme valgt fra visceral smerte; neuropatisk smerte, post herpetisk neuralgi, nervebeskadigelse, centrale smertesyndromer forårsaget af en læsion af nervesystemet, postkirurgiske smertesyndromer, knogle- og ledsmerte, gentagen bevægesmerte, dental smerte, cancer smerte, myofascial smerte, fibromyalgi, perioperativ smerte, kronisk smerte, dysmenorrhe, smerte forbundet med angina og inflammatorisk smerte, inflammatorisk smerte er smerte forbundet med osteoarthritis, rheumatoid arthritis, reumatisk sygdom, gigt, hyper-reaktive luftveje, luftvejssygdom, inflammatoriske tarmsygdomme; inflammatorisk hudlidelser; ødem stammende fra forbrændinger, forstuvninger og frakturer; cerebral ødem og angioødem; diabetisk vaskulopati; diabetisk neuropati; diabetisk retinopati; diabetiske symptomer forbundet med insulitis; leversygdom; multipel sclerose; kardiovaskular sygdom; kongestiv hjertefejl; myokardial infarkt; neurodegenerative sygdomme; epilepsi; septisk chok; hovedpine herunder klyngehovedpine, migræne herunder profylaktisk og akut anvendelse; lukket hovedtraume; cancer; sepsis; gingivitis; osteoporose; benign hyperplasi og hyperaktiv blære.
9. Forbindelse med formel (I):
(i) og farmaceutisk acceptable salte deraf, hvor X og Y er forskellig fra hinanden og er O eller NH; R1 er valgt fra gruppen bestående af Ci-Ce-alkyl; Cs-Ce-cycloalkyl og halo Ci-C3-alkyl. R2 er valgt fra gruppen bestående af: - Ci-Ce alkyl; - C3-C6 cycloalkyl; - phenyl usubstitueret eller substitueret med mindst én gruppe valgt fra -0-Ci-C4-akyl og Ci-C4-alkyl; - benzothiophen; - en 5- eller 6-leddet heteroaromatisk ring valgt fra pyridin og pyrrol. R3 er valgt fra gruppen bestående af: - Ci-Ce alkyl; - (CH2)mCOCH3, hvor m er et heltal bestående mellem 1 og 4; - (CH2)n-Z, hvor n er et heltal bestående mellem 1 og 3 og Z er valgt fra gruppen bestående af dialkylamin, C3-C6-cycloalkyl, benzotriazol, isoindol-l,3(2H)-dion-2-yl, imidazol, triazol, indol, furan, og phenyl, den sidstnævnte er usubstitueret eller substitueret med én eller flere grupper valgt fra halo, C1-C3 alkyl, O-C1-C3 alkyl og C1-C3 alkylamino; - C3-C6 cycloalkyl usubstitueret eller substitueret med én eller flere grupper valgt fra halo, og C1-C3 alkyl; - 2-methyl-l,3-oxazol-4-yl; - phenyl usubstitueret eller substitueret med én eller flere grupper valgt fra C1-C3 alkyl, hydroxyl, halo og nitro, forudsat at denne forbindelse ikke er valgt fra: lH-benzotriazol-l-acetamid, N-[(2-methoxyphenyl)methyl]-N-[l-(4-methylphenyl)-2-oxo-2-[[(tetrahydro-2-furanyl)methyl]amino]ethyl; lH-benzotriazol-l-acetamid, N-[(4-methoxyphenyl)methyl]-N-[l-(4-methylphenyl)-2-oxo-2-[[(tetrahydro-2-furanyl)methyl]amino]ethyl; lH-benzotriazol-l-acetamid, N-[l-[4-(l-methylethyl)phenyl]-2-oxo-2-[[(tetrahydro-2-furanyl)methyl]amino]ethyl-N-(2-thienylmethyl); lH-benzotriazol-l-acetamid, N-(2-furanylmethyl)-N-[l-[4-(l-methylethyl)phenyl]-2-oxo-2-[[(tetrahydro-2-furanyl)methyl]amino]ethyl; lH-benzotriazol-l-acetamid, N-[l-[4-(l-methylethyl)phenyl]-2-oxo-2-[[(tetrahydro-2-furanyl)methyl]amino]ethyl-N-(3-pyridinylmethyl); lH-benzotriazol-l-acetamid, N-[l-(4-methylphenyl)-2-oxo-2-[[(tetrahydro-2-furanyl)methyl]amino]ethyl-N-(2-thienylmethyl); lH-benzotriazol-l-acetamid, N-[(2-furanylmethyl)-N-[l-(4-methylphenyl)-2-oxo-2-[[(tetrahydro-2-furanyl)methyl]amino]ethyl; 1 H-benzotriazol-l-acetamid, N-[(2-methoxyphenyl)methyl]-N-[ 1-(2-methylphenyl)-2-oxo-2-[[(tetrahydro-2-furanyl)methyl]amino]ethyl; 1 H-benzotriazol-l-acetamid, N-(2-furanylmethyl)-N-[l-(2-methylphenyl)-2-oxo-2-[[(tetrahydro-2-furanyl)methyl]amino]ethyl; 1 H-benzotriazol-l-acetamid, N-[l-(2-methylphenyl)-2-oxo-2-[[(tetrahydro-2-furanyl)methyl]aminoethyl]-N-(2-thienylmethyl).
10. Forbindelse ifølge krav 9, hvor X er O og Y er NH.
11. Forbindelse ifølge kravene 9 eller 10, hvor R1 er valgt fra methyl, cyclopropyl og trifluormethyl og/eller R2 er valgt fra methoxyphenyl, methylphenyl, l-benzothiophen-3-yl, 1-ethylpropyl, l-methyl-lW-pyrrol-2-yl, 2-methylethyl, pyridin-3yl, cyclopentyl og cyclohexyl og/eller R3 er valgt fra: C2-C4 alkyl; 4-yl-butan-2-on; -CH2-Z, hvor Z er dimethylamino, cyclopentyl, benzotriazol-l-yl, isoindol-1, 3(2H)-dion-2-yl, imidazol-4-yl, 1,2,3-triazol-l-yl, indol-l-yl, furan-2-yl, eller phenyl, usubstitueret eller substitueret med én eller flere grupper valgt fra F, methyl, methoxy og dimethylamino; C3-C6 cycloalkyl usubstitueret eller substitueret med én eller flere grupper valgt fra F og methyl; 2-methyl-l,3-oxazol-4-yl; phenyl usubstitueret eller substitueret med én eller flere grupper valgt fra methyl, hydroxy, F og nitro; dimethylamino.
12. Forbindelse ifølge kravene 9 til 11, hvor R3 er valgt fra 1-methylen-lH-uenzotriazol, 2-methyl-l,3-oxazol-4-yl, 2-methylen-lH-isoindol-l,3(2H)-dion, N,N-dimethyl-l-methylenamin, 4-methylen-lH-imidazol, 4-yl-butan-2-on, 1-Tiethylen-lH-l,2,3-triazol; 1-methylen-lH-indol, benzyl, 2-methoxybenzyl, 2-nethylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2,3-difluorbenzyl, 4-fluorbenzyl, 2,6-difluorbenzyl, 4-N,N-dimethylaminobenzyl, 4-methylphenyl, 4-hydroxyphenyl, 4-nitrophenyl, 2-nitrophenyl, 4-fluorphenyl, 2-methylenfuran, ethyl, butyl, sobutyl, phenyl, 4,4-difluorcyclohexyl, cyclohexyl, cyclopentyl, cyclobutyl, :yclopropyl, l-yl-2-methylcyclopropan, methylencyclopentyl.
13. Forbindelse ifølge kravene 9 to 12, valgt fra: 2-methyl-N-(2-methoxybenzyl)-N-{l-(4-methylphenyl)-2-oxo-2- [(tetrahydrofuran-2-ylmethyl)amino]ethyl}-l,3-oxazol-4-carboxamid; 2-(2,3-difluorphenyl)-N-(2-methoxybenzyl)-N-{l-(4-methylphenyl)-2-oxo- 2-[(tetrahydrofuran-2-ylmethyl)amino]ethyl>acetamid; N-(2-methoxybenzyl)-N-{l-(4-methylphenyl)-2-oxo-2-[(tetrahydrofuran-2- ylmethyl)amino]ethyl>furan-2-carboxamid; 2-(2,4-difluorphenyl)-N-(2-methoxybenzyl)-N-{l-(4-methylphenyl)-2-oxo- 2-[(tetrahydrofuran-2-ylmethyl)amino]ethyl}acetamid; 2-(2,6-difluorphenyl)-N-(2-methoxybenzyl)-N-{l-(4-methylphenyl)-2-oxo- 2- [(tetrahydrofuran-2-ylmethyl)amino]ethyl}acetamid; N-(2-methoxybenzyl)-N-{l-(4-methylphenyl)-2-oxo-2-[(tetrahydrofuran-2- ylmethyl)amino]ethyl}-2-phenylacetamid; 3- methyl-N-(2-methoxybenzyl)-N-{(l-(4-methylphenyl)-2-oxo-2-[(tetrahydrofuran-2-ylmethyl)amino]ethyl}butanamid; 2-(2-methylphenyl)-N-(2-methoxybenzyl)-N-{(l-(4-methylphenyl)-2-oxo- 2-[(tetrahydrofuran-2-ylmethyl)amino]ethyl>acetamid; 2-(l,3-dioxoisoindolin-2-yl)-N-(2-met:hoxybenzyl)-N-{l-(4-methylphenyl)- 2-oxo-2-[(tetrahydrofuran-2-ylmethyl)amino]-ethyl}acetamid; 2-(dimethylamino)-N-(2-methoxybenzyl)-{l-(4-methylphenyl)-2-oxo-2- [(tetrahydrofuran-2-ylmethyl)amino]ethyl}acetamid; 2-(lH-imidazol-4-yl)-N-(2-methoxybenzyl)-N-{l-(4-methylphenyl)-2-oxo- 2-[(tetrahydrofuran-2-ylmethyl)amino]ethyl}acetamid; 2-(2-methoxylphenyl)-l\l-(2-methoxybenzyl)-N-{(l-(4-methylphenyl)-2- oxo-2-[(tetrahydrofuran-2-ylmethyl)amino]ethyl>acetamid; N-(2-methoxybenzyl)-N-{l-(4-methylphenyl)-2-oxo-2-[(tetrahydrofuran-2- ylmethyl)amino]ethyl>pentanamid; N-(2-methoxybenzyl)-N-{l-(4-methylphenyl)-2-oxo-2-[(tetrahydrofuran-2- ylmethyl)amino]ethyl}cyclopentancarboxamid; 4-hydroxy-N-(2-methoxybenzyl)-N-{l-(4-methylphenyl)-2-oxo-2- [(tetrahydrofuran-2-ylmethyl)amino]ethyl}benzamid; 4-oxo-N-(2-methoxybenzyl)-N-{l-(4-methylphenyl)-2-oxo-2- [(tetrahydrofuran-2-ylmethyl)amino]ethyl}pentanamid; 2-(3-methylphenyl)-N-(2-methoxybenzyl)-N-{(l-(4-methylphenyl)-2-oxo- 2-[(tetrahydrofuran-2-ylmethyl)amino]ethyl}acetamid; 2-(4-methylphenyl)-N-(2-methoxybenzyl)-N-{(l-(4-methylphenyl)-2-oxo- 2-[(tetrahydrofuran-2-ylmethyl)amino]ethyl}acetamid; 4-methyl-N-(2-methoxybenzyl)-N-{l-(4-methylphenyl)-2-oxo-2- [(tetrahydrofuran-2-ylmethyl)amino]ethyl}benzamid; 2-(4-fluorphenyl)-N-(2-methoxybenzyl)-N-{(l-(4-methylphenyl)-2-oxo-2- [(tetrahydrofuran-2-ylmethyl)amino]ethyl}acetamid; 4-fluor-N-(2-methoxybenzyl)-N-{l-(4-methylphenyl)-2-oxo-2- [(tetrahydrofuran-2-ylmethyl)amino]ethyl}benzamid; 4,4-difluor-N-(2-methoxybenzyl)-N-{l-(4-methylphenyl)-2-oxo-2- [(tetrahydrofuran-2-ylmethyl)amino]ethyl}cyclohexancarboxamid; N-(2-methoxybenzyl)-N-{l-(4-methylphenyl)-2-oxo-2-[(tetrahydrofuran-2- ylmethyl)amino]ethyl}propanamid; N-(2-methoxybenzyl)-N-{l-(4-methylphenyl)-2-oxo-2-[(tetrahydrofuran-2- ylmethyl)amino]ethyl}cyclobutancarboxamid; N-(2-methoxybenzyl)-2-nitro-l\l-{l-(4-methylphenyl)-2-oxo-2- [(tetrahydrofuran-2-ylmethyl)amino]ethyl}benzamid; N-(2-methoxybenzyl)-N-{l-(4-methylphenyl)-2-oxo-2-[(tetrahydrofuran-2- ylmethyl)amino]ethyl>cyclopropancarboxamid; N-(2-methoxybenzyl)-4-nitro-l\l-{l-(4-methylphenyl)-2-oxo-2- [(tetrahydrofuran-2-ylmethyl)amino]ethyl}benzamid; 2-[(4-dimethylamino)phenyl]-N-(2-methoxybenzyl)-l\l-{ 1-(4- methylphenyl)-2-oxo-2-[(tetrahydrofuran-2- ylmethyl)amino]ethyl>acetamid; N-(2-methoxybenzyl)-N-{l-(4-methylphenyl)-2-oxo-2-[(tetrahydrofuran-2- ylmethyl)amino]ethyl>-2-(lH-l,2,3-triazol-l-yl)acetamid; 2-(lH-indol-l-yl)-N-(2-methoxybenzyl)-N-{l-(4-methylphenyl)-2-oxo-2- [(tetrahydrofuran-2-ylmethyl)amino]ethyl}acetamid; N-(cyclopentylmethyl)-2-(lH-imidazol-4-yl)-N-{l-(4-methylphenyl)-2-oxo- 2-[(tetrahydrofuran-2-ylmethyl)amino]ethyl}acetamid; N-(cyclohexylmethyl)-2-(2-methylphenyl)-N-{l-(4-methylphenyl)-2-oxo-2- [(tetrahydrofuran-2-ylmethyl)amino]ethyl}acetamid; N-(cyclohexylamino)-2-(dimethylamino)-N-{l-(4-methylphenyl)-2-oxo-2- [(tetrahydrofuran-2-ylmethyl)amino]ethyl}acetamid; 2-(dimethylamino)-N-(3-methylbenzyl)-N-{l-(4-methylphenyl)-2-oxo-2- [(tetrahydrofuran-2-ylmethyl)amino]ethyl}acetamid; N-(cyclohexylmethyl)-2-(lH-imidazol-4-yl)-N-{l-(4-methylphenyl)-2-oxo- 2-[(tetrahydrofuran-2-ylmethyl)amino]ethyl}acetamid; N-(cyclohexylmethyl)-2-phenyl-N-{l-(4-methylphenyl)-2-oxo-2- [(tetrahydrofuran-2-ylmethyl)amino]ethyl}acetamid; 2-methyl-N-(3-methylbenzyl)-N-{l-(4-methylphenyl)-2-oxo-2- [(tetrahydrofuran-2-ylmethyl)amino]ethyl}cyclopropancarboxamid; N-(l-benzothiophen-3-ylmethyl)-2-(dimethylamino)-N-{ 1-(4- methylphenyl)-2-oxo-2-[(tetrahydrofuran-2- ylmethyl)amino]ethyl}acetamid; N-(cyclohexylmethyl)-2-(3-methylphenyl)-l\l-{l-(4-methylphenyl)-2-oxo-2- [(tetrahydrofuran-2-ylmethyl)amino]ethyl}acetamid; N-(2-ethylbutyl)-2-(2-methylphenyl)-N-{l-(4-methylphenyl)-2-oxo-2- [(tetrahydrofuran-2-ylmethyl)amino]ethyl}acetamid; N-(2-ethylbutyl)-2-(4-fluorlphenyl)-N-{l-(4-methylphenyl)-2-oxo-2- [(tetrahydrofuran-2-ylmethyl)amino]ethyl}acetamid; 2-(dimethylamino)-N-[(l-methyl-lH-pyrrol-2-yl)methyl]-N-{l-(4- methylphenyl)-2-oxo-2-[(tetrahydrofuran-2- ylmethyl)amino]ethyl}acetamid; N-(cyclopentylmethyl)-2-(2-methylphenyl)-N-{l-(4-methylphenyl)-2-oxo- 2-[(tetrahydrofuran-2-ylmethyl)amino]ethyl>acetamid; N-(cyclopentylmethyl)-2-(3-methylphenyl)-N-{l-(4-methylphenyl)-2-oxo- 2-[(tetrahydrofuran-2-ylmethyl)amino]ethyl}acetamid; 2-(2-methylphenyl)-N-(pyridin-3-ylmethyl)-N-{l-(4-methylphenyl)-2-oxo- 2-[(tetrahydrofuran-2-ylmethyl)amino]ethyl>acetamid; N-(cyclopentylmethyl)-N-{l-(4-methylphenyl)-2-oxo-2-[(tetrahydrofuran- 2-yl)methylamino]ethyl}2-phenylacetamid; N-(cyclohexylmethyl)-2-cyclopentyl-N-{l-(4-methylphenyl)-2-oxo-2- [(tetrahydrofuran-2-ylmethyl)amino]ethyl}acetamid; 2-(lH-imidazol-4-yl)-N-(2-methylpropyl)-N-{l-(4-methylphenyl)-2-oxo-2- [(tetrahydrofuran-2-ylmethyl)amino]ethyl}acetamid; N-(2-ethylbutyl)-N-{l-(4-methylphenyl)-2-oxo-2-[(tetrahydrofuran-2- ylmethyl)amino]ethyl>cyclohexancarboxamid; 2-cyclopentyl-N-cyclopentylmethyl-N-{l-(4-methylphenyl)-2-oxo-2- [(tetrahydrofuran-2-ylmethyl)amino]ethyl}acetamid; N-(2-methoxybenzyl]-N-[l-(4-cyclopropylphenyl)-2-oxo-2- [(tetrahydrofuran-2-yl)methylamino]ethyl)-3-methylbutanamid; 2-(lH-benzotriazol-l-yl)-N-(2-methoxybenzyl)-N-{l-(4- trifluormethylphenyl)-2-oxo-2-[(tetrahydrofuran-2- ylmethyl)amino]ethyl>acetamid; N-[(2-methoxybenzyl]-N-{l-[4-(trifluormethyl)phenyl]-2-oxo-2- [(tetrahydrofuran-2-yl)methylamino]ethyl}3-methylbutanamid; N-(2-methoxybenzyl)-N-{(lR)-l-(4-methylphenyl)-2-oxo-2-[(2R)- (pyrrolidin-2-ylmethyl)amino]ethyl}-2-(lH-l,2,3-triazol-l-yl)acetat.
14. Forbindelse ifølge kravene 9 til 13, i Rekonfigurationen ellersom en blanding af stereoisomerer.
15. Farmaceutisk sammensætning omfattende mindst én forbindelse ifølge kravene 9 til 14 i kombination med farmaceutisk acceptable excipienser og/eller fortyndingsmidler.
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