DK2185515T3 - Derivater af 1-phenyl-2-pyridinylalkylalkoholer som phosphodiesteraseinhibitorer - Google Patents

Derivater af 1-phenyl-2-pyridinylalkylalkoholer som phosphodiesteraseinhibitorer Download PDF

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DK2185515T3
DK2185515T3 DK08784827.1T DK08784827T DK2185515T3 DK 2185515 T3 DK2185515 T3 DK 2185515T3 DK 08784827 T DK08784827 T DK 08784827T DK 2185515 T3 DK2185515 T3 DK 2185515T3
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alkyl
optionally substituted
halogen atoms
branched
linear
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DK08784827.1T
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Maurizio Delcanale
Gabriele Amari
Elisabetta Armani
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Chiesi Farma Spa
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    • C07—ORGANIC CHEMISTRY
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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Claims (19)

1. Forbindelse med den almene formel (I)
hvor: Z er udvalgt fra gruppen bestående af (CH2)m, hvor m = 0, 1 eller 2; og CR4R5, hvor R4 uafhængigt er udvalgt fra H eller et lineært eller forgrenet (CrC4)-alkyl eventuelt substitueret med et eller flere halogenatomer eller med et (CrC4)-cycloalkyl, og R5 uafhængigt er udvalgt fra gruppen bestående af - lineært eller forgrenet (CrC4)-alkyl eventuelt substitueret med et eller flere halogenatomer; - phenyl; - benzyl; - NH2; og - HNCOOR', hvor R' er et lineært eller forgrenet (CrC4)-alkyl eventuelt substitueret med et eller flere halogenatomer. Ri og R2 er forskellige eller det samme og uafhængigt er udvalgt fra gruppen bestående af -H; - lineært eller forgrenet (CrC6)-alkyl, eventuelt substitueret med en eller flere substituenter udvalgt fra halogenatomer, (C3-C7)-cycloalkyl eller (C5-C7)-cycloalkenyl; - (C3-C7)-cycloalkyl; - (C5-C7)-cycloalkenyl; - lineært eller forgrenet (C2-C6)-alkenyl; og - lineært eller forgrenet (C2-C6)-alkynyl. R3 er en eller flere substituenter uafhængigt udvalgt fra gruppen bestående af H, CN, N02, CF3 og halogenatomer. A er et phenyl, som eventuelt er substitueret med en eller flere Rx-grupper, eller A er en heteroarylring, som eventuelt er substitueret med en eller flere Rx-grupper, hvor A er en heteroarylring udvalgt fra gruppen bestående af pyrrol, pyrazol, furan, thiophen, imidazol, oxazol, isoxazol, thiazol, pyridin, pyrimidin, pyrazin, pyridazin og pyran, hvor den eventuelle substituent Rx i A-ringsystemet kan være en eller flere, kan være den samme eller forskellig, og uafhængigt er udvalgt fra gruppen bestående af: - lineært eller forgrenet (CrC6)-alkyl eventuelt substitueret med et eller flere halogenatomer eller (C3-C7)-cycloalkyl; - lineært eller forgrenet (C2-C6)-alkenyl eventuelt substitueret med et eller flere (C3-C7)-cycloalkyl; - lineært eller forgrenet (C2-C6)-alkynyl eventuelt substitueret med et eller flere (C3-C7)-cycloalkyl; - (C5-C7)-cycloalkenyl; - phenyl; - (C3-C7)-heterocycloalkyl; - OR7, hvor R7 er udvalgt fra gruppen bestående af -H; - (C-i-C-io)-alkyl eventuelt substitueret med et eller flere halogenatomer eller (C3-C7)-cycloalkyl; - (C3-C7)-cycloalkyl; - (CrC4)-alkylen-(C3-C7)-heterocycloalkyl; - CO-(CrC6)-alkyl, hvor (CrC6)-alkylet eventuelt er substitueret med et eller flere halogenatomer; - COO-(CrC6)-alkyl, hvor (CrC6)-alkylet eventuelt er substitueret med et eller flere halogenatomer; - phenyl; - benzyl; - (CrCio)-alkyl-NR8R9, hvor R8 og R9 uafhængigt er udvalgt fra gruppen bestående af H, lineært eller forgrenet (CrC6)-alkyl, som eventuelt er substitueret med et eller flere halogenatomer, og de danner sammen med nitrogenatomet, som de er bundet til, en mættet, delvist mættet eller umættet ring; og - halogenatomer; -CN; - N02; - NR10R11, hvor R-io og Ru er forskellige eller det samme og uafhængigt er udvalgt fra gruppen bestående af -H; - lineært eller forgrenet (CrC6)-alkyl, eventuelt substitueret med et eller flere halogenatomer, phenyl eller (C3-C7)-cycloalkyl; - COC6H5; - CO-(CrC4)-alkyl, hvor (CrC4)-alkylet eventuelt er substitueret med et eller flere halogenatomer; - COO-(CrC4)-alkyl, hvor (CrC4)-alkylet eventuelt er substitueret med et eller flere halogenatomer; - CONH-(CrC6)-alkyl-R12, hvor R12 er udvalgt fra gruppen bestående af -H; - (CrC4)-alkyl eventuelt substitueret med et eller flere halogenatomer; - OR4R5; og - CONH (C-i-C4) alkyl-N(CrC4)-alkyl, hvor N(CrC4)-alkylet eventuelt er substitueret med et eller flere halogenatomer; eller de danner sammen med nitrogenatomet, som de er bundet til, en mættet eller delvist mættet ring. - (Ci-C4)-alkyl-NR10Rn; - COR-i2, hvor R12 er phenyl eller lineært eller forgrenet (CrC6)-alkyl eventuelt substitueret med et eller flere halogenatomer; - oxo; - HNS02Ri3, hvor R13 er (CrC4)-alkyl eventuelt substitueret med et eller flere halogenatomer eller et phenyl eventuelt substitueret med halogenatomer eller med en (CrC4)-alkylgruppe eventuelt substitueret med et eller flere halogenatomer; - S02Ri4, hvor R14 er (C-|-C4)-alkyl eventuelt substitueret med et eller flere halogenatomer, OH eller NR10Rn, hvor R10 og Ru er som ovenfor defineret; - SOR-15, hvor R-15 er phenyl eller (CrC4)-alkyl eventuelt substitueret med et eller flere halogenatomer; - SR-ie, hvor R16 er H, phenyl eller (CrC4)-alkyl eventuelt substitueret med et eller flere halogenatomer; - COOR-17, hvor R17 er H, (CrC4)-alkyl eventuelt substitueret med et eller flere halogenatomer, phenyl eller benzyl; og - (CH2)qORi8, hvor q=1,2, 3 eller 4, og Ri8 er H eller (CrC4)-cycloalkyl. og farmaceutisk acceptable salte og N-oxider på pyridinringen deraf.
2. Forbindelse ifølge krav 1, hvor det ene eller flere halogenatomer, som eventuelt substituerer (CrC4)-alkylet, (CrC6)-alkylet og (C-i-C-io)-alkylet, er udvalgt fra et eller flere klor- eller fluoratomer
3. Forbindelse ifølge krav 1 og 2, hvor R3 er et halogenatom.
4. Forbindelse ifølge krav 3, hvor R3 er klor.
5. Forbindelse ifølge krav 4 med den almene formel (II)
6. Forbindelse ifølge krav 5, hvor Z er (CH2)m med m lig med 0.
7. Forbindelse ifølge krav 6, som er 3-cyclopropylmethoxy-4-difluormethoxy-benzoesyre 1-(3-cyclopropylmethoxy-4-difluormethoxyphenyl)-2-(3,5-dichlor-1-oxy-pyridin-4-yl)ethylester (forbindelse 14).
8. Forbindelse ifølge krav 6, som er 3-cyclopropylmethoxy-4-difluormethoxy-benzoesyre 1-(3-cyclopropylmethoxy-4-difluormethoxyphenyl)-2-(3,5-dichlor-pyridin-4-yl)ethylester (forbindelse 11).
9. Forbindelse ifølge krav 5, hvor Z er CHR5, hvor R5 er et lineært eller forgrenet C-i-Cralkyl eventuelt substitueret med et eller flere halogenatomer.
10. Forbindelse ifølge krav 5, hvor Z er CR4R5, hvor R4 og R5 begge er lineært eller forgrenet CrC4-alkyl, som eventuelt er substitueret med et eller flere halogenatomer, og de danner en ring med carbonatomet, som de er bundet til, med 3, 4, 5 eller 6 carbonatomer.
11. Fremgangsmåde til fremstilling af en forbindelse ifølge et af de foregående krav, hvilken fremgangsmåde omfatter trinnet, hvor der tilsættes en syre med formel AZCOOH eller et acylchlorid med formel AZCOCI eller et isocyanat med formel AZNCO, hvor A og Z er som ovenfor defineret, til en opløsning af et alkoholderivat med den almene formel (2)
j hvor R-ι, R2 og R3 er som ovenfor defineret.
12. Farmaceutisk sammensætning omfattende en forbindelse ifølge et af kravene 1 til 10 som aktivstof med iblanding af et eller flere farmaceutisk acceptable bærestoffer og/eller hjælpestoffer.
13. Farmaceutisk sammensætning ifølge krav 12, egnet til indgivelse ved inhalering.
14. Farmaceutisk sammensætning ifølge krav 12 eller 13, hvor sammensætningen endvidere omfatter et yderligere aktivstof udvalgt fra klasserne af be-ta2-agonister, corticosteroider og antikolinerg- eller antimuscarinmidler.
15. Forbindelse ifølge et af kravene 1 til 10 til anvendelse som et medikament.
16. Forbindelse ifølge et af kravene 1 til 10 til anvendelse ved forebyggelse og/eller behandling af en sygdom, som er karakteriseret ved phosphodiesterase 4 (PDE4)-overaktivitet, og/eller hvor en inhibition af PDE4-aktivitet er ønskelig.
17. Forbindelse ifølge krav 16 til anvendelse ved forebyggelse og/eller behandling af en sygdom i luftvejene karakteriseret ved luftvejsobstruktion.
18. Forbindelse ifølge krav 17 til anvendelse ved forebyggelse og/eller behandling af en sygdom udvalgt fra gruppen bestående af astma eller kronisk bronkitis eller kronisk obstruktiv lungesygdom.
19. Forbindelse med den almene formel (2)
hvor R1, R2 og R3 er defineret som i krav 1.
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