DK2640721T3 - Agonister til forbedret binding af integrin-udtrykkende celler til integrinreceptorer - Google Patents

Agonister til forbedret binding af integrin-udtrykkende celler til integrinreceptorer Download PDF

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DK2640721T3
DK2640721T3 DK11841201.4T DK11841201T DK2640721T3 DK 2640721 T3 DK2640721 T3 DK 2640721T3 DK 11841201 T DK11841201 T DK 11841201T DK 2640721 T3 DK2640721 T3 DK 2640721T3
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thienylmethyl
amino
bis
methyl
carbamate
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Ronald J Biediger
Iv C William Gundlach
Robert V Market
Michael M Savage
Peter Vanderslice
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Texas Heart Inst
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Claims (14)

1. Kemisk forbindelse med den almene formel (I)
hvor R1 er udvalgt fra gruppen bestående af phenyl, thienyl, fiiryl, pyridyl, thiazolyl, oxazolyl og isoxazolyl, R2 er alkyl, aryl eller aralkyl, M1 er CH2, M2 er CO, M3 er O eller S, M4 er CH2, M5 er (CRUR12), hvor R11 er hydrogen, R12 er udvalgt fra gruppen bestående af NR21CONR22R23, NR21COR24 og NR21COOR24, R21 og R22, når de er til stede, er uafhængigt udvalgt fra gruppen bestående af hydrogen eller Ci-C6-alkyl, R23, når de er til stede, er udvalgt fra gruppen bestående af hydroxyalkyl, alkoxyalkyl, alkyl, aryl, aralkyl og alkoxycarbonylalkyl, R24, når de er til stede, er udvalgt fra gruppen bestående af alkyl og heterocyclyl, M6 er (CH2)q, hvor q er et heltal fra 0 til 6, R3 er udvalgt fra gruppen bestående af hydrogen, NR15COOR16, alkyl og aryl, hvor R15, når de er til stede, er hydrogen eller Ci-C6-alkyl, R16, når de er til stede, er udvalgt fra gruppen bestående af alkyl og aralkyl, og R1 og R2 kan uafhængigt enten være usubstitueret eller substitueret med én eller flere substituenter, der er udvalgt fra gruppen bestående af alkyl, hydroxy, alkoxy, azido, haloalkoxy, halo, haloalkyl, amino, alkylamino, dialkylamino, og R3 kan enten være usubstitueret eller substitueret med én eller flere substituenter udvalgt fra gruppen bestående af alkyl, aryl, aralkyl, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, hydroxyaryl, alkoxyaryl, halo, amino, alkylamino, dialkylamino, -NHCO(alkyl), -NHCO(aryl), -NHCO(aralkyl), -NHCO(haloalkyl), -NHS02(alkyl), -NHS02(aryl), - NHS02(aralkyl), alkoxycarbonyl, hvor begrebet ”aryl” refererer til en carbocyklisk aromatisk gruppe med 6 til 12 carbonatomer eller en heterocyklisk aromatisk gmppe, og hvor begrebet ’’aralkyl” refererer til et arylsubstitueret alkylradikal, hvor begrebet ”aryl” er som defineret ovenfor.
2. Forbindelse ifølge krav 1 udvalgt fra gruppen bestående af Methyl-(6S, 10S)-10-(l ,3-benzodioxol-5-yl)-6-butyl-3,8-dioxo-1 -(2-thienyl)-2-(2-thienylmethyl)-4-oxa-2,7,9-triazadodecan-12-oat; methyl-(6S, 1 OR)-10-( 1,3-benzodioxol-5-yl)-6-butyl-3,8-dioxo-1 -(2-thienyl)-2-(2-thienylmethyl)-4-oxa-2,7,9-triazadodecan-12-oat; methyl-(6S,10S)-10-(l,3-benzodioxol-5-yl)-6-butyl-7-methyl-3,8-dioxo-l-(2-thienyl)- 2-(2-thienylmethyl)-4-oxa-2,7,9-triazadodecan-12-oat; methyl-(6S,10S)-10-(l,3-benzodioxol-5-yl)-6-butyl-9-methyl-3,8-dioxo-l-(2-thienyl)- 2-(2-thienylmethyl)-4-oxa-2,7,9-triazadodecan-12-oat; ethyl-(6S,10R)-10-(l,3-benzodioxol-5-yl)-6-butyl-7-methyl-3,8-dioxo-l-(2-thienyl)-2-(2-thienylmethyl)-4-oxa-2,7,9-triazadodecan-12-oat; methyl-(10S)-10-(l,3-benzodioxol-5-yl)-3,8-dioxo-l-(2-thienyl)-2-(2-thienylmethyl)-4-oxa-2,7,9-triazadodecan-l 2-oat; methyl-3,8-dioxo-1 -(2-thienyl)-2-(2-thienylmethyl)-4-oxa-2,7,9-triazadodecan-12-oat; methyl-(6S, 10S)-10-(1,3-benzodioxol-5-yl)-6-butyl-2-methyl-3,8-dioxo-1 -(2-thienyl)- 4-oxa-2,7,9-triazadodecan-l 2-oat; methyl-(6S)-6-butyl-3,8-dioxo-l-(2-thienyl)-2-(2-thienylmethyl)-4-oxa-2,7,9-triazadodecan-12-oat; (2S)-2-{[(l,3-benzodioxol-5-yl-methyl)carbamoyl]amino}hexyl-bis(2- thienylmethyl)carbamat; methyl-(6S, 10S)-6-butyl-3,8-dioxo-10-phenyl-l -(2-thienyl)-2-(2-thienylmethyl)-4-oxa-2,7,9-triazadodecan-l 2-oat; (2S)-2-( {[(IS)-1 -(1,3-benzodioxol-5-yl)-3-hydroxypropyl]carbamoyl} amino)hexyl-bis(2-thienylmethyl)carbamat; (2S)-2-[(benzylcarbamoyl)amino]hexyl-bis(2-thienylmethyl)carbamat; (2S)-2-[(morpholin-4-yl-carbonyl)amino]hexyl-bis(2-thienylmethyl)carbamat; (2S)-2-{[(3-methoxypropyl)carbamoyl]amino}hexyl-bis(2-thienylmethyl)carbamat; (2S)-2-{[(2-methoxyethyl)carbamoyl]amino}hexyl-bis(2-thienylmethyl)carbamat; tert-butyl-[(2S)-l-{[bis(2-thienylmethyl)carbamoyl]oxy}hexan-2-yl]carbamat; (2S)-2-[(tert-butylcarbamoyl)amino]hexyl-bis(2-thienylmethyl)carbamat; (2S)-2-[(isopropylcarbamoyl)amino]hexyl-bis(2-thienylmethyl)carbamat; (2S)-2-[(methylcarbamoyl)amino]hexyl-bis(2-thienylmethyl)carbamat; tert-butyl-[(2R)-l-{[bis(2-thienylmethyl)carbamoyl]oxy}hexan-2-yl]carbamat; benzyl- {(5S)-6-{[bis(2-thienylmethyl)carbamoyl]oxy}-5-[(tert-butoxycarbonyl)amino]hexyl}carbamat; methyl-(9S, 13S)-13-(l,3-benzodioxol-5-y 1)-9-( {[bis(2-thienylmethyl)carbamoyl]oxy}methyl)-3,11 -dioxo-1 -phenyl-2-oxa-4,10,12-triazapcntadccan-15-oat; (2S)-2-acetamidohexyl-bis(2-thienylmethyl)carbamat; methyl-(6R, 1 OS)-10-(l ,3-benzodioxol-5-yl)-6-butyl-3,8-dioxo-l -(2-thienyl)-2-(2-thienylmethyl)-4-oxa-2,7,9-triazadodecan-12-oat; methyl-(6R, 10R)-10-( 1,3-benzodioxol-5-yl)-6-butyl-3,8-dioxo-1 -(2-thienyl)-2-(2-thienylmethyl)-4-oxa-2,7,9-triazadodecan-12-oat; benzyl- {(5 S)-6- {[bis(4-methoxybenzyl)carbamoyl]oxy} -5 -[(tert-butoxycarbonyl)amino]hexyl}carbamat; tert-butyl-[(2S)-1 - {[bis(4-methoxybenzyl)carbamoyl]oxy} hexan-2-yl]carbamat; methyl-(6S, 10S)-10-(1,3-benzodioxol-5-yl)-6-butyl-2-(4-methoxybenzyl)-1 -(4-methoxyphenyl)-3,8-dioxo-4-oxa-2,7,9-triazadodecan-12-oat; (2S)-2-({[(lS)-l-(l,3-benzodioxol-5-yl)-3-hydroxypropyl]carbamoyl}amino)hexyl- bis(4-methoxybenzyl)carbamat; (2S)-2-[(tert-butoxycarbonyl)amino]hexyl-dibenzylcarbamat; methyl-(6S,10S)-10-(l,3-benzodioxol-5-yl)-2-benzyl-6-butyl-3,8-dioxo-l-phenyl-4-oxa-2,7,9-triazadodecan-l 2-oat; tert-butyl-[(2S)-l-{[bis(4-methylbenzyl)carbamoyl]oxy}hexan-2-yl]carbamat; methyl-(6S, 10S)-10-(1,3-benzodioxol-5-yl)-6-butyl-2-(4-methylbenzyl)-1 -(4-methylphenyl)-3,8-dioxo-4-oxa-2,7,9-triazadodecan-12-oat; tert-butyl-[(2 S)-1 - {[bis(4-chlorbenzyl)carbamoyl]oxy} hexan-2-yl] carbamat; methyl-(6S, 10S)-10-(1,3-benzodioxol-5-yl)-6-butyl-2-(4-chlorbenzyl)-1 -(4-chlorphenyl)-3,8-dioxo-4-oxa-2,7,9-triazadodecan-12-oat; (2S)-2-[(tert-butoxycarbonyl)amino]hexyl-(4-brombenzyl)(2-thienylmethyl)carbamat; methyl-(6S, 1 OS)-10-(1,3-benzodioxol-5-yl)-2-(4-brombenzyl)-6-butyl-3,8-dioxo-1 -(2-thienyl)-4-oxa-2,7,9-triazadodecan-12-oat; methyl-(6S, 10S)-2-(4-azidoobenzyl)-10-(1,3-benzodioxol-5-yl)-6-butyl-3,8-dioxo-1 -(2-thienyl)-4-oxa-2,7,9-triazadodecan-12-oat; (2S)-2-[(tert-butoxycarbonyl)amino]hexylphenyl(2-thienylmethyl)carbamat; Methyl-(6S, 10S)-10-(1,3-benzodioxol-5-yl)-6-butyl-3,8-dioxo-2-phenyl-l -(2-thienyl)- 4-oxa-2,7,9-triazadodecan-12-oat; tert-butyl-[(2S)-l-{[bis(3-thienylmethyl)carbamoyl]oxy}hexan-2-yl]carbamat; methyl-(6S, 10S)-10-(1,3-benzodioxol-5-yl)-6-butyl-3,8-dioxo-1 -(3-thienyl)-2-(3-thienylmethyl)-4-oxa-2,7,9-triazadodecan-12-oat; benzyl- [(5 S)-5 - [(tert-butoxycarbonyl)amino] -6- {[butyl(2-thienylmethyl)carbamoyl]oxy}hexyl]carbamat; (2S)-2-[(tert-butoxycarbonyl)amino]hexylbutyl(2-thienylmethyl)carbamat; Methyl-(3S,7S)-3-(l ,3-benzodioxol-5-yl)-7-butyl-5,10-dioxo-l 1 -(2-thienylmethyl)-9-oxa-4,6,11 -triazapentadecan-1 -oat; benzyl- [(5 S)-5 - [(tert-butoxycarbonyl)amino]-6- {[(2-methoxyethyl)(2-thienylmethyl)carbamoyl]oxy}hexyl]carbamat; (2S)-2-[(tert-butoxycarbonyl)amino]hexyl-(2-methoxyethyl)(2-thienylmethyl)carbamat; Methyl-(9S, 13S)-13-(1,3-benzodioxol-5-yl)-9-butyl-6,11 -dioxo-5-(2-thienylmethyl)-2,7-dioxa-5,10,12-triazapentadecan-15-oat; (2S)-2-[({3-[(methylsulfonyl)amino]benzyl}carbamoyl)amino]hexyl-(2- methoxyethyl)(2-thienylmethyl)carbamat; (2S)-2-{[(4-brombenzyl)carbamoyl]amino}hexyl-bis(2-thienylmethyl)carbamat; (2S)-2-{[(4-azidobenzyl)carbamoyl]amino}hexyl-bis(2-thienylmethyl)carbamat; tert-butyl-[(2S)-l-{[bis(2-thienylmethyl)carbamoyl]thio}hexan-2-yl]carbamat og methyl-(6S, 1 OS)-10-( 1,3-benzodioxol-5-yl)-6-butyl-3,8-dioxo-1 -(2-thienyl)-2-(2-thienylmethyl)-4-thia-2,7,9-triazadodecan-12-oat.
3. Forbindelse udvalgt fra gruppen bestående af tert-butyl-[(2S)-1 - {[bis(cyclopropylmethyl)carbamoyl]oxy} hexan-2-yl]carbamat; (2S)-2-[(tert-butoxycarbonyl)amino]hexyldiisobutylcarbamat; methyl-(8S,12S)-12-(l,3-benzodioxol-5-yl)-8-butyl-4-isobutyl-2-methyl-5,10-dioxo-6-oxa-4,9,11 -triazatetradecan-14-oat; benzyl-{(5S)-6-[bis(cyclopropylmethyl)amino]-5-[(tert-butoxycarbonyl)amino]-6-oxohexyl} carbamat; methyl-(2S)-2- {[bis(2-thienylmethyl)-carbamoyl]amino} hexanoat; methyl-(2R)-2- {[bis(2-thienylmethyl)carbamoyl] amino} hexanoat; methyl-(2S)-6-{[(benzyloxy)carbonyl]amino}-2-{[bis(2-thienylmethyl)carbamoyl] amino } hexanoat; methyl- {[bis(2-thienylmethyl)carbamoyl] (methyl)amino} acetat; methyl- {[bis(2-thienylmethyl)carbamoyl] amino } acetat; methyl- {[bis(2-thienylmethyl)carbamoyl] (butyl)amino} acetat; methyl-(2R)- {[bis(2-thienylmethyl)carbamoyl] amino} (phenyl)acetat; tert-butyl- {[bis(2-thienylmethyl)carbamoyl]amino} acetat; tert-butyl- {[bis(2-thienylmethyl)carbamoyl](butyl)amino} acetat.
4. Farmaceutisk sammensætning, der omfatter: en forbindelse ifølge et hvilket som helst af kravene 1-3 eller et farmaceutisk acceptabelt salt deraf; og en farmaceutisk acceptabel bærer.
5. Fremgangsmåde til behandling af integrin-udtrykkende celler, der omfatter: (a) etablering af kontakt mellem mindst en integrinudtrykkende celle in vitro og en agonist af integrinen, hvor agonisten er en forbindelse ifølge et hvilket som helst af kravene 1 til 3.
6. Fremgangsmåde ifølge krav 5, hvor integrinen er udvalgt ffa gruppen bestående af α4β1, α5β1, α4β7, ανβ3 og αίβ2.
7. Fremgangsmåde til forbedret binding af celler til en integrin-bindende ligand, hvilken fremgangsmåde omfatter: behandling af integrin-udtrykkende celler in vitro med en agonist af integrin ifølge fremgangsmåden ifølge krav 6, hvor integrinen er udvalgt fra gruppen bestående af α4β1, α5β1, α4β7, ανβ3 og αίβ2; og etablering af kontakt mellem de behandlede celler og en integrin-bindende ligand.
8. Fremgangsmåde ifølge krav 7, hvor agonisten af integrin er en forbindelse ifølge krav 2 eller krav 3.
9. Fremgangsmåde ifølge krav 7, hvor de integrin-udtrykkende celler er udvalgt fra gruppen bestående af voksne stamceller, embryostamceller, progenitorceller og inducerede pluripotente stamceller.
10. Fremgangsmåde ifølge krav 7, hvor etablering af kontakt mellem de behandlede celler og en integrin-bindende ligand indbefatter etablering af kontakt mellem en overflade, der omfatter en integrin-bindende ligand, og de agonist-behandlede celler for at binde de agonist-behandlede celler til overfladen, hvor binding af de agonist-behandlede celler forbedres i forhold til binding af integrin-udtrykkende celler, der ikke er behandlet ved hjælp af denne fremgangsmåde.
11. Fremgangsmåde ifølge krav 10, hvor mindst 3 gange flere agonist-behandlede celler bindes til overfladen end integrin-udtrykkende celler, der ikke er behandlet med agonisten.
12. Fremgangsmåde ifølge krav 10, hvor overfladen er på et væv, der omfatter et integrin-bindende protein, der er udvalgt fra gruppen bestående af vaskulær celleadhæsionsmolekyle-1 (VCAM-1), fibronectin, slimhindespecifikt cellulært adhæsionsmolekyle-1 (MAdCAM-1), intercellulært adhæsionsmolekyle-1 (ICAM-1), intercellulært adhæsionsmolekyle-2 (ICAM-2) og vitronectin.
13. Agonist af integrin til anvendelse i en fremgangsmåde til forbedret retention af eksogent introducerede celler på et målsted in vivo på et pattedyr, hvilken fremgangsmåde omfatter: (a) behandling af integrin-udtrykkende celler in vitro med agonisten af integrin; (b) indføring af de agonist-behandlede celler i et målsted in vivo i pattedyret; og (c) at bevirke, at et større antal af de introducerede agonist-behandlede celler forbliver på målstedet i forhold til antallet af tilbageholdte celler, hvis integrin-udtrykkende celler, der ikke var behandlet med agonisten, bliv indført i målstedet; hvor agonisten er en forbindelse som defineret i krav 1-3.
14. Agonist-behandlede integrin-udtrykkende stamceller eller progenitorceller til anvendelse i en fremgangsmåde til behandling af et pattedyrs beskadigede eller sygdomsramte vaskulære væv, hvilken fremgangsmåde omfatter: (a) administration til et beskadiget eller sygdomsramt vaskulært sted, der indbefatter knoglemarv, i et kar hos pattedyret af en flerhed af de agonist-behandlede integrin- udtrykkende stamceller eller progenitorceller; (b) at bevirke, at et større antal af de administrerede agonist-behandlede celler forbliver på det vaskulære sted i forhold til antallet af celler, der tilbageholdes, hvis integrin-udtrykkende celler, der ikke var behandlet med agonisten, blev administreret til det beskadigede eller sygdomsramte vaskulære sted, hvor stedet omfatter celler, der bærer en integrin-bindende ligand på en celleoverflade; og (c) at tillade, at celler på det vaskulære sted opformeres/differentieres og/eller frigiver parakrine faktorer; hvor de agonist-behandlede integrin-udtrykkende stamceller eller progenitorceller er blevet behandlet ifølge fremgangsmåden ifølge krav 5, hvor integrinen er udvalgt fra gruppen bestående af α4β1, α5β1, α4β7, ανβ3 og αίβ2.
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