DK2542542T3 - Isotopisk berigede arylsulfonamid-ccr3-antagonister - Google Patents

Isotopisk berigede arylsulfonamid-ccr3-antagonister Download PDF

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DK2542542T3
DK2542542T3 DK11707755.2T DK11707755T DK2542542T3 DK 2542542 T3 DK2542542 T3 DK 2542542T3 DK 11707755 T DK11707755 T DK 11707755T DK 2542542 T3 DK2542542 T3 DK 2542542T3
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certain embodiments
deuterium
optionally substituted
substituents
nr1br1c
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Tai Wei Ly
Garrett Thomas Potter
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Axikin Pharmaceuticals Inc
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/26—Sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P35/00—Antineoplastic agents
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds

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Claims (15)

1. Forbindelse med formel I:
eller en enantiomer, en blanding af enantiomerer, en blanding af to eller flere diastereomerer, en tautomer eller en blanding af to eller flere tautomerer deraf; eller et farmaceutisk acceptabelt salt, solvat eller hydrat deraf; hvor: R1, R2, R3, R4, R5 og R8 hver for sig er (a) hydrogen, deuterium, halo, cyano, nitro eller guanidin; (b) Ci_6alkyl, C2_ 6alkenyl, C2_6alkynyl, C3-7cycloalkyl, C6-i4aryl, C7_i5aralkyl, heteroaryl eller heterocyclyl; eller (c) -C(0)Rla, -C(0)0Rla, - C (0) NRlbRlc, -C (NRla)NRlbRlc, -0Rla, -0C(0)Rla, -0C(0)0Rla, OC (0) NRlbRlc, -0C (=NRla) NRlbRlc, -0S(0)Rla, -OS (0) 2Rla, OS (0) NRlbRlc, -OS (0) 2NRlbRlc, -NRlbRlc, -NRlaC (0) Rld, -NRlaC (0) 0Rld, -NRlaC (0)NRlbRlc, -NRlaC (=NRld) NRlbRlc, -NRlaS (0) Rld, -NRlaS (0) 2Rld, -NRlaS (0) NRlbRlc, -NRlaS (0) 2NRlbRlc, -SRla, -S(0)Rla, -S (0) 2Rla, S (0) NRlbRlc eller -S (0) 2NRlbRlc; R6, R7 og R9 hver er deuterium; R10 og R11 hver for sig er (a) hydrogen; eller (b) Ci-6alkyl, C2_ 6alkenyl, C2_6alkynyl, C3_7cycloalkyl, C6-i4aryl, C7-isaralkyl, heteroaryl eller heterocyclyl; eller R10 og R11 er koblet sammen til frembringelse af heterocyclyl; R12 er (a) hydrogen; (b) Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, C3-7cycloalkyl, C6-i4aryl, C7-isaralkyl, heteroaryl eller heterocyclyl; eller (c) -C(0)Rla, -C(0)0Rla, -C (0) NRlbRlc, - C (NRla) NRlbRlc, -S(0)Rla, -S(0)2Rla, -S(0)NRlbRlc eller S (0) 2NRlbRlc; L er Ci_6alkylen; X er 0 eller S; og Rla, Rlb, Rlc og Rld hver for sig er hydrogen, deuterium, Ci_ 6alkyl, C2-6alkenyl, C2-6alkynyl, C3_7cycloalkyl, C6-i4aryl, heteroaryl eller heterocyclyl; eller hvert par af Rlb og Rlc sammen med N-atomet, hvortil de er bundet, uafhængigt danner heteroaryl eller heterocyclyl; hvor hver alkyl, alkylen, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl og heteroaryl i R1, R2, R3, R4, R5, R8, R10, R11, R12, Rla, Rlb, Rlc, Rld eller L eventuelt er substitueret med en eller flere substituenter Q, hvor hver Q er udvalgt uafhængigt blandt (a) deuterium, cyano, halo og nitro; (b) Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3_7cycloalkyl, C6-i4aryl, C7-isaralkyl, heteroaryl og heterocyclyl, som hver eventuelt yderligere er substitueret med en eller flere substituenter Qa; og (c) -C (0) Ra, -C (0) 0Ra, -C(0)NRbRc, -C (NRa) NRbRc, -0Ra, OC (0) Ra, -0C (0) 0Ra, -0C(0)NbR°, -0C (=NRa) NRbR°,-OS (0) Ra, 0S(0)2Ra, -0S(0)NbRc, -OS (0) 2NRbRc, -NRbRc, -NRaC (0) Rd, NRaC (0) 0Rd, -NRaC (0) NRbRc, -NRaC (=NRd) NRbRc, -NRaS (0) Rd, NRaS(0)2Rd, -NRaS (0)NRbRc,-NRaS (0) 2NRbRc, -SRa, -S(0)Ra, -S(0)2Ra, -S(0)NRbRc og -S (0) 2NRbRc, hvor hver Ra, Rb, Rc og Rd uafhængigt er (i) hydrogen eller deuterium; (ii) Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C6-i4aryl, C7-i5aralkyl, heteroaryl eller heterocyclyl, som hver eventuelt er substitueret med en eller flere substituenter Qa; eller (iii) hvert par af Rb og Rc sammen med N-atomet, hvortil de er bundet, danner heterocyclyl, der eventuelt er substitueret med en eller flere substituenter Qa; hvor hver Qa er udvalgt uafhængigt fra gruppen, der består af (a) deuterium, cyano, halo og nitro; (b) Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C6-i4aryl, 07-isaralkyl, heteroaryl og heterocyclyl; og (c) -C(0)Re, -C(0)0Re, -C (0) NRfRg, -C (NRe) NRfRg, -0Re, -0C(0)Re, -OC (0) 0Re, -0C(0)NRfRg, -OC (=NRe) NRfRg, -0S(0)Re, -0S(0)2Re, -OS (0) NRfRg, -OS (0) 2NRfRg, -NRfRg, -NReC (0) Rh, NReC (0) 0Rf, -NReC (0) NRfRg, -NReC (=NRh) NRfRg, -NReS(0)Rh, NReS(0)2Rh, -NReS (0) NRfRg, -NReS (0) 2NRfRg, -SRe, -S(0)Re, -S(0)2Re, -S(0)NRfRg og -S (0) 2NRfRg; hvor hver Re, Rf, Rg og Rb uafhængigt er (i) hydrogen eller deuterium; (ii) Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, C3_7cycloalkyl, C6-i4aryl, C7-i5aralkyl, heteroaryl eller heterocyclyl; eller (iii) hvert par af Rf og Rg sammen med N-atomet, hvortil de er bundet, danner heterocyclyl.
2. Forbindelse ifølge krav 1, der har strukturen med formel II:
eller en enantiomer, en blanding af enantiomerer, en blanding af to eller flere diastereomerer, en tautomer eller en blanding af to eller flere tautomerer deraf; eller et farmaceutisk acceptabelt salt, solvat eller hydrat deraf; hvor: R13 er (a) hydrogen, deuterium, halo, cyano, nitro, oxo eller guanidin; (b) Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, C3-7cycloalkyl, C6-i4aryl, C7-i5aralkyl, heteroaryl eller heterocyclyl, som hver eventuelt er substitueret med en eller flere substituenter Q; eller (c) -C (0) Rla,-C (0) 0Rla, -C (0) NRlbRlc, -C (NRla) NRlbRlc, -0Rla, -0C (0) Rla, -0C (0) 0Rla,-0C (0) NRlbRlc, -0C (=NRla) NRlbRlc, -0S(0)Rla, -OS (0) 2Rla, -OS (0) NRlbRlc,-OS (0) 2NRlbRlc, -NRlbRlc, -NRlaC (0) Rld, NRlaC (0) 0Rlcl, -NRlaC (0)NRlbRlc, -NRlaC (=NRlcl) NRlbRlc, -NRlaS (0) Rlcl, -NRlaS (0) 2Rla, -NRlaS (0) NRlbRlc,-NRlaS (0) 2NRlbRlc, -SRla, -S (0) Rla, -S (0) 2Rla, -S(0)NRlbRlc eller -S (0) 2NRlbRlc; hvor Rla, Rlb, Rlc og Rld hver er som defineret heri; m er et helt tal på 0, 1, 2 eller 3; n er et helt tal på 1, 2 eller 3; og p er et helt tal på 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 eller 16.
3. Forbindelse ifølge krav 1 eller 2, hvor R1, R2, R3, R4 og R5 hver for sig er hydrogen, deuterium, halo eller Ci_6alkyl, der eventuelt er substitueret med en eller flere substituenter Q.
4. Forbindelse ifølge krav 3, hvor to af R1, R2, R3, R4 og R5 er halo eller Ci-galkyl, der eventuelt er substitueret med en eller flere substituenter Q; og de resterende tre er hydrogen eller deuterium.
5. Forbindelse ifølge krav 3, hvor to af R1, R2, R3, R4 og R5 er chlor, methyl, -CH2D, -CHD2 eller -CD3; og de resterende tre er hydrogen eller deuterium.
6. Forbindelse ifølge et hvilket som helst af kravene 1 til 5, hvor R2 er chlor, eller hvor R2 er methyl, -CH2D, -CHD2 eller -CD3; og/eller hvor R4 er chlor, eller hvor R4 er methyl, -CH2D, -CHD2 eller -CD3; og/eller hvor R1 er hydrogen, eller hvor R1 er deuterium; og/eller hvor R3 er hydrogen, eller hvor R3 er deuterium; og/eller hvor R5 er hydrogen, eller hvor R5 er deuterium; og/eller hvor R8 er cyano eller nitro, eller hvor R8 er -13CN; og/eller hvor R12 er Ci_6alkyl eller C3_7cycloalkyl, som hver eventuelt er substitueret med en eller flere substituenter Q, eller hvor R12 er -CD3 eller cyclopentyl.
7. Forbindelse ifølge et hvilket som helst af kravene 2 til 6, hvor m er 1; og/eller hvor n er 1 eller 2.
8. Forbindelse ifølge et hvilket som helst af kravene 1 til 7, hvor X er 0; eller hvor X er S.
9. Forbindelse ifølge krav 1, hvor forbindelsen er 3 — (4 — cyclopentylpiperazin-l-ylsulfonyl)-4-(3,5-dichlorphenoxy)- 2,5,6-trideuteriumbenzonitril eller et farmaceutisk acceptabelt salt, solvat eller hydrat deraf.
10. Forbindelse ifølge et hvilket som helst af kravene 1 til 9, hvor forbindelsen er carbon-13-beriget; og/eller hvor mindst ét af atomerne, der er specificeret som isotopisk beriget, har en isotopisk berigelse på mindst ca. 5 %.
11. Forbindelse ifølge et hvilket som helst af kravene 1 til 10, hvor forbindelsen er et hydrochloridsalt.
12. Farmaceutisk præparat, der omfatter en forbindelse ifølge et hvilket som helst af kravene 1 til 11 eller en enantiomer, en blanding af enantiomerer, en blanding af to eller flere diastereomerer, en tautomer eller en blanding af to eller flere tautomerer deraf; eller et farmaceutisk acceptabelt salt, solvat eller hydrat deraf; og et eller flere farmaceutisk acceptable bærematerialer eller excipienser; og eventuelt yderligere omfatter et andet terapeutisk middel.
13. Farmaceutisk præparat ifølge krav 12, hvor præparatet er formuleret til enkeltdosisadministration; eventuelt hvor præparatet er formuleret i en oral, parenteral eller intravenøs doseringsform, hvor den orale doseringsform fortrinsvis er en tablet eller en kapsel.
14. Forbindelse ifølge et hvilket som helst af kravene 1 til 11 eller farmaceutisk præparat ifølge krav 12 eller 13 til anvendelse i: en fremgangsmåde til behandling, forebyggelse eller bedring af et eller flere symptomer på en CCR3-medieret forstyrrelse, sygdom eller tilstand; eller en fremgangsmåde til behandling, forebyggelse eller bedring af et eller flere symptomer på en eosinofilforbundet forstyrrelse, sygdom eller tilstand; eller en fremgangsmåde til behandling, forebyggelse eller bedring af et eller flere symptomer på en basofilforbundet forstyrrelse, sygdom eller tilstand; eller en fremgangsmåde til behandling, forebyggelse eller bedring af et eller flere symptomer på en mastcelleforbundet forstyrrelse, sygdom eller tilstand; eller en fremgangsmåde til behandling, forebyggelse eller bedring af et eller flere symptomer på en inflammationssygdom.
15. Forbindelsen eller farmaceutisk præparat til anvendelse ifølge krav 14, hvor forstyrrelsen, sygdommen eller tilstanden er udvalgt fra gruppen, der består af astma, allergisk astma, anstrengelsesastma, allergisk rhinitis, helårsbetinget allergisk rhinitis, sæsonbetinget allergisk rhinitis, atopisk dermatitis, kontaktoverfølsomhed, kontaktdermatitis, konjunktivitis, allergisk konjunktivitis, eosinofil bronkitis, fødevareallergier, eosinofil gastroenteritis, inflammatorisk tarmsygdom, ulcerativ colitis, Crohns sygdom, mastocytose, hyper-IgE-syndrom, systemisk lupus erythematous, psoriasis, akne, multipel sklerose, allograftafstødning, reperfusionsskade, kronisk obstruktiv lungesygdom, Churg-Strauss-syndrom, sinusitis, basofil leukæmi, kronisk urticaria, basofil leukocytosis, psoriasis, eksem, KOL (kronisk obstruktiv lungesygdom), arthritis, rheumatoid arthritis, psoriatisk arthritis, osteoarthritis og kardiovaskulære forstyrrelser; eller hvor forstyrrelsen, sygdommen eller tilstanden er astma, anstrengelsesastma, allergisk rhinitis, atopisk dermatitis, kronisk obstruktiv lungesygdom eller allergisk konjunktivitis.
DK11707755.2T 2010-03-02 2011-03-01 Isotopisk berigede arylsulfonamid-ccr3-antagonister DK2542542T3 (da)

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WO2012051090A1 (en) * 2010-10-11 2012-04-19 Axikin Pharmaceuticals, Inc. Salts of arylsulfonamide ccr3 antagonists
EP2892884A1 (en) * 2012-09-07 2015-07-15 Axikin Pharmaceuticals, Inc. Isotopically enriched arylsulfonamide ccr3 antagonists

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US20110218207A1 (en) 2011-09-08
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