OA11957A - Metalloprotease inhibitors. - Google Patents

Metalloprotease inhibitors. Download PDF

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OA11957A
OA11957A OA1200100319A OA1200100319A OA11957A OA 11957 A OA11957 A OA 11957A OA 1200100319 A OA1200100319 A OA 1200100319A OA 1200100319 A OA1200100319 A OA 1200100319A OA 11957 A OA11957 A OA 11957A
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methylphenyl
piperidin
compound
methyl
préparation
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OA1200100319A
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Kevin Neil Dack
Michael Jonathan Fray
Mark Liewellyn Lewis
Nicholas Murray Thomson
Gavin Alistair Whitlock
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Pfizer
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    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
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Claims (39)

172 119 5 7 CLAIMS 1. N-Hydroxy 4-{[4-(4-{6-[2-hydroxyethoxy]pyridin-2-yl]-3-methylphenyI)piperidin-l-yl]sulphonyl]tetrahydro-2H-pyran-4-carboxamide and the pharmaceutically acceptablesalts thereof, and solvatés thereof.
2. A compound selected from : N-hydroxy 2-[(4- {4-[6-(2-hydroxyethoxy)pyridin-2-yl]-3-methylphenyl]piperidin-l -yl)sulphonyl]-2-methylpropanamide; N-hydroxy 2-{[4-(4-{6-[2-(methoxy)ethoxy]pyridin-2-yl}-3-methylphenyl)piperidin-l-yl]sulphonyl]-2-methylpropanamide; N-hydroxy 4- {[4-(4- {6-[2-hydroxyethoxy]pyridin-2-yl} -3-methylphenyl)piperidin-1 -yl] sulphonyl} tetrahydro-2H-pyran-4-carboxamide; N-hydroxy 4-{[4-(4-{6-[(2S)-2,3-dihydroxy-l-propoxy]pyridin-2-yl}-3-methylphenyl)piperidin-1 -yl] sulphonyl} tetrahydro-2H-pyran-4-carboxamide;N-hydroxy 4- {[4-(4- {6-[(2R)-2,3-dihydroxy-1 -propoxy]pyridin-2-yl} -3-methylphenyl)piperidin-1 -yl] sulphonyl} tetrahydro-2H-pyran-4-carboxamide;N-hydroxy 4- {[4-(4- {6- [2-hydroxyethoxy]pyridin-2-yl} -3 -methylphenyl)piperidin-1 -yl] sulphonyl} -piperidine-4-carboxamide dihydrochloride; N-hydroxy 4- {[4-(4- {6-[2-hydroxyethoxy]pyridin-2-yl}-3-methylphenyl)piperidin-l-yl]sulphonyl} -1 -methyl-piperidine-4-carboxamide; N-hydroxy 2- [4-(4- {3 - [ (2S)-2,3 -dihydroxy-1 -propoxy]phenyl} -3 -methylphenyl)-piperidin-1 -ylsulphonyl] -2-methylpropanamide; N-hydroxy 4-{4-[4-(3-[(2R)-2,3-dihydroxy-l-propoxy]phenyl)-3-methylphenyl]-piperidin-1 -ylsulphonyl} -tetrahydro-(2H)-pyran-4-carboxamide; N-hydroxy 4- {4-[4-(3- {(2S)-2-hydroxy-2-hydroxymethyl]ethoxyphenyl)-3-methylphenyl] -piperidin-1 -ylsulphonyl} -tetrahydro-2H-pyran-4-carboxamide;N-hydroxy 4-{4-[4-(3-{l,3-dihydroxy-2-propoxyphenyl)-3-methylphenyl]-piperidin-l-ylsulphonyl} -tetrahydro-2H-pyran-4-carboxamide; N-hydroxy 2- {[4-(4- {3-[2-(methylamino)ethoxy]phenyl} -3-methylphenyl)-piperidin-l -yl] sulphonyl]-2-methylpropanamide hydrochloride; H3 H957 N-hydroxy 2-(4-(4- {3-(2-aminoethoxy)phenyl} -3-methylphenyl)-piperidin-1 -ylsulphonyl]-2-methylpropanamide hydrochloride; N-Hydroxy 4- {[4-(-4- {3-[2-anrinoethoxy]phenyl}-3-rnethylphenyl)piperidin-l -yl]sulphonyl} tetrahydro-2H-pyran-4-carboxamide hydrochloride; N-hydroxy 2-(4-(4- {3-(2-N,N-dimethylaminoethoxy)phenyl} -3-methylphenyl)-piperidin-l-ylsulphonyl]-2-methylpropanamide; N-Hydroxy 4-{[4-(4-{3-(N-methylaminomethyl)phenyl}-3-methylphenyl)piperidin-l-yl]sulphonyl} tetrahydro-2H-pyran-4-carboxamide hydrochloride; N-hydroxy 4- {[4-(3-methyl-4- {3-[4-morpholinylmethyl]}phenyl)piperidin-1 -yl]sulphonyl}tetrahydro-2H-pyran-4-carboxamide; N-hydroxy 2-( {4-[4-(3-methoxy-1 H-pyrazol-1 -yl)-3-methylphenyl]piperidin-1 -yl}sulphonyl)-2-methylpropanamide; N-hydroxy 2-[(4-{4-[3-(2-hydroxyethoxy)-lH-pyrazol-l-yl]-3-methylphenyl}piperidin- l-yl)sulphonyl)-2-methylpropanamide; N-hydroxy 2-methyl-2-( {4-[3-methyl-4-( 1,3-thiazol-2-yl)phenyl]piperidin-1 -yl} sulphonyl)propanamide; (la,3a,4a)-Ar,3,4-trihydroxy-l-[(4-{4-[6-(2-hydroxyethoxy)pyridin-2-yl]-3- methylphenyl}piperidin-l-yl)sulfonyl]cyclopentanecarboxamide; (1 a, 3a,4a)-1 -( {4-[4-(6-ethoxypyridin-2-yl)-3-methylphenyl]piperidin-1 -yl} sulfonyl)-7V,3,4-trihydroxycyclopentanecarboxamide; (1 α,3β,4β)-1 -( {4-[4-(6-ethoxypyridin-2-yl)-3-methylphenyl]piperidin-l -yl} sulfonyl)-7V,3,4-trihydroxycyclopentanecarboxamide; ( 1 a,3a,4a)-N,3,4-trihydroxy-1 - {4-(4-(3 -methoxyphenyl)-3 -methylphenyljpip eridin-1 -ylsulfonyl} cyclopentanecarboxamide; and (1 a,3 β,4β)-Λζ3,4-trihydroxy-1 - {4-[4-(3-methoxyphenyl)-3-methylphenyl]piperidin-l -ylsulfonyl} cyclopentanecarboxamide, and the pharmaceutically acceptable salts thereof, and solvatés thereof.
3. N-Hydroxy 4- {[4-(4- {6-[2-hydroxyethoxy]pyridin-2-yl} -3-methylphenyl)piperidin-1 - yl]sulphonyl}-piperidine-4-carboxamide and the pharmaceutically acceptable salts thereof, and solvatés thereof. 174 ”957
4. N-Hydroxy 4-{[4-(-4-{6-[2-aminoethoxy]pyridin-2-yl}-3-methylphenyl)piperidin-l-yl]sulphonyl}tetrahydro-2H-pyran-4-carboxamide and the pharmaceutically acceptablesalts thereof, and solvatés thereof.
5 wherein R3, X and R are as defined in any one of daims 5,6 or 7, Rp is as defined indaim 31, and P and P1 are OH-protecting groups which may be taken independently ortogether.
5. A compound of formula (I):
and pharmaceutically-acceptable salts thereof, and solvatés thereof,wherein 10 the dotted line represents an optional bond; X is a monocyclic aromatic linker moiety selected ffom pyrazolylene, thiazolylene,pyrazinylene, pyridazinylene, pyrrolylene, oxazolylene, isoxazolylene, oxadiazolylene,thiadiazolylene, imidazolylene, triazolylene, or tetrazolylene; R is H, Ci-4 alkyl optionally substituted by Cm alkoxy or NR4R5 or OH, or 15 Cm alkoxy optionally substituted by 1 or 2 substituents selected from (Cm alkyloptionally substituted by OH), Cm alkoxy, OH and NR4R5; R1 and R2 are each independently H, Cm alkyl optionally substituted by OH or Cmalkoxy, or C2-6 alkenyl; 20 or R1 and R2 are taken, together with the C atom to which they are attached, to form a β-ίο 7-membered ring optionally incorporating a hetero- moiety selected ffom O, S, SO,SO2 and NR6, and which 3- to 7-membered ring is optionally substituted by one or moreOH; R3 is H, halo, methyl, or methoxy; doi 173 ί î 9 5 7 R4 and R5 are each independently H or Ci to C6 alkyl optionally substituted by OH, Cito C4 alkoxy or aryl, or R4 and R5 can be taken together with the N atom to which they are attached, to forma 3- to 7-membered ring, optionally incorporating a further hetero- moiety selected from 5 O, S, SQ2 and NR7; and R6 and R7 are each independently H or Ci to C4 alkyl.
6. A compound of formula (I):
7. A compound of formula (I):
and pharmaceutically-acceptable salts thereof, and solvatés thereof,wherein 15 the dotted line represents an optional bond, X is a monocyclic aromatic linker moiety selected from phenylene, pyridinylene,pyrazolylene, thiazolylene, thienylene, furylene, pyrimidinylene, pyrazinylene,pyridazinylene, pyrrolylene, oxazolylene, isoxazolylene, oxadiazolylene,thiadiazolylene, imidazolylene, triazolylene, or tetrazolylene; 20 R is H, Cm alkyl optionally substituted by Cm alkoxy, NR4R5 or OH, or Cm alkoxy optionally substituted by 1 or 2 substituents selected from (Cm alkyloptionally substituted by OH), Cm alkoxy, OH and NR4R5; R1 and R2 are each independently Cm alkyl substituted by OH; m H 9 5 7 or R1 and R2 are taken together, with the C atom to which they are attached, to form a 3-to 7-membered ring optionally incorporating a hetero- moiety selected from O, S, SO,SO2 and NR6, and which 3- to 7-membered ring is substituted by one or more OH; R3 is H, halo, methyl, or methoxy; R4 and R5 are each independently H or Ci to Cô alkyl optionally substituted by OH, Cito C4 alkoxy or aryl, or R4 and R5 can be taken together with the N atom to which they are attached , to forma 3- to 7-membered ring, optionally incorporating a further hetero- moiety selected fromO, S, SO2 and NR7, and R6 and R7 are each independently H or Ci to C4 alkyl.
8. A compound, sait or solvaté according to claim 6 or claim 7 where X is phenylene,pyridinylene, pyrazolylene or thiazolylene.
9. A compound, sait or solvaté according to claim 8 wherein X is 1,3-phenylene, 2,6-pyridinylene, 1,3-pyrazolylene or 2,5-thiazolylene.
10. A compound, sait or solvaté according to claim 5 wherein X is pyrazolylene orthiazolylene.
10 and pharmaceutically-acceptable salts thereof, and solvatés thereof,wherein the dotted line represents an optional bond; X is a monocyclic aromatic linker moiety selected from phenylene, pyridinylene,pyrazolylene, thiazolylene, thienylene, furylene, pyrimidinylene, pyrazinylene, 15 pyridazinylene, pyrrolylene, oxazolylene, isoxazolylene, oxadiazolylene,thiadiazolylene, imidazolylene, triazolylene, or tetrazolylene; R is Cm alkyl substituted by NR4R5, Cm alkoxy substituted by NR4R5, or Ci .4 alkoxysubstituted by 2 substituents selected from (Cm alkyl optionally substituted by OH), Ci4 alkoxy, OH and NR4R5; 20 R1 and R2 are each independently H, Cm alkyl optionally substituted by OH or Cmalkoxy, orC2-6 alkenyl; or R1 and R2 are taken together, with the C atom to which they are attached, to form a 3to 7-membered ring optionally incorporating a hetero- moiety selected from O, S, SO, 11957 SOz and NR6, and which 3- to 7-membered ring is optionally substituted by one or moreOH; R3 is H, halo, methyl, or methoxy; R4 and R5 are each independently H or Cj to Cô alkyl optionally substituted by OH, Ci5 to C4 alkoxy or aryl, or R4 and R5 can be taken together with the N atom to which they are attached, to foraia 3- to 7-membered ring, optionally incorporating a further hetero- moiety selected fromO, S, SO2 andNR7, and R6 and R7 are each independently H or Ci to C4 alkyl. 0
11. A compound, sait or solvaté according to claim 10 wherein X is 1,3-pyrazolylene or 2,5-thiazolylene.
12. A compound, sait or solvaté according to claim 5 or claim 7 wherein R is H,methoxy, O(CH2)2OH, O(CH2)2OCH3, O(CH2)2N(CH3)2, O(CH2)2NHCH3,O(CH2)2NH2, CH2NHCH3, morpholinomethyl, 2-morpholinoethoxy, 2R-2,3-dihydroxy- 1-propyloxy, 2S-2,3-dihydroxy-l-propyloxy or l,3-dihydroxy-2-propyloxy.
13. A compound, sait or solvaté according to claim 12 wherein R is 0(CH2)2OH orO(CH2)2NH2. 178 119 5 7
14. A compound, sait or solvaté according to claim 6 wherein R is O(CH2)2N(CH3)2,O(CH2)2NHCH3, O(CH2)2NH2, CH2NHCH3, morpholinomethyl, 2-morpholinoethoxy,2R-2,3-dihydroxy-l-propyloxy, 2S-2,3-dihydroxy-l-propyloxy or l,3-dihydroxy-2-propyloxy. 5
15. A compound, sait or solvaté according to claim 14 wherein R is O(CH2)2NH2.
16.. A compound, sait or solvaté according to claim 5 or claim 6 wherein R1 and R2 areeach independently C1-6 alkyl optionally substituted by OH, 10 or R1 and R2 are taken together, with the C atom to which they are attached, to form a 3-to 7-membered ring optionally incorporating a hetero- moiety selected frorn O, S, SO,SO2 and NRb, and which 3- to 7-membered ring is optionally substituted by one or moreOH. 15
17. A compound, sait or solvaté according to claim 16 wherein R1 and R2 are each CH3, 1 2 or R and R are taken together, with the C atom to which they are attached, to form atetrahydropyran-4-ylidene, piperidin-4-ylidene, l-methylpiperidin-4-ylidene, or 3,4-dihydroxycyclopentylidene moiety. 20
18. A compound, sait or solvaté according to claim 17 wherein R1 and R2 are taken together, with the C atom to which they are attached, to form a tetrahydropyran-4-ylidene, cz's-3,4-dihydroxycyclopentylidene, Zrazw-3,4-dihydroxycyclopentylidene orpiperidin-4-ylidene moiety. 25
19. A compound, sait or solvaté according to claim 18 wherein R1 and R2 are taken together, with the C atom to which they are attached, to form a tetrahydropyran-4-ylidene, piperidin-4-ylidene, or cz's-3,4-dihydroxycyclopentylidene where the hydroxysubstituents hâve a czs-relationship to the hydroxamate moiety. ’OC i»ç 175 119 5 γ
20. A compound, sait or solvaté according to claim 7 wherein R1 and R2 are takentogether, with the C atom to which they are attached, to form a 3,4-dihydroxycyclopentylidene moiety.
21. A compound, sait or solvaté according to claim 20 wherein R1 and R2 are takentogether, with the C atom to which they are attached, to form a czs-3,4-dihydroxycyclopentylidene group where the hydroxy substituents hâve a cA-relationshipto the hydroxamate moiety.
22. A compound, sait or solvaté according to any one of daims 5 to 21 wherein R3 ismethyl and the optional double bond depicted as a dotted line in formula (I) is absent.
23. A pharmaceutical composition comprising a substance according to any one ofdaims 1 to 22 and a pharmaceutically acceptable diluent, adjuvant or carrier.
24. A substance according to any one of daims 1 to 22 for use as a médicament.
25. The use of a substance according to any one of daims 1 to 22 in the manufacture ofa médicament for the treatment of a MMP-mediated disease, condition or process.
26. A compound seiected from: methyl 4-(4-oxo-piperidin-1 -ylsulphonyl)tetrahydro-2H-pyran-4-carboxylate;methyl 4- {[4-(4-bromo-3-methylphenyl)-4-hydroxy-l-piperidin-l-yl]sulfonyl}tetrahydro-2/f-pyran-4-carboxylate; methyl 4- {[4-(4- {6-[2-(fôri-butoxy)ethoxy]pyridin-2-yl} -3-methylphenyl)piperidin-1 -yl]sulfonyl}tetrahydro-27/-pyran-4-carboxylate; 4- {[4-(4- {6-[2-tert-butoxyethoxy]pyridin-2-yl} -3-methylphenyl)piperidin-1 -yl]sulfonyl}-tetrahydro-2H-pyran-4-carboxylic acid; and A-hydroxy-4-[(4-{4-[6-(2-/erZ-butoxyethoxy)pyridin-2-yl]-3-methylphenyl}piperidin-l- yl)sulfonyl]tetrahydro-277-pyran-4-carboxamide. 1 19 5 7
27. A compound selected from: N-hydroxy 1 -(tert-butoxycarbonyl)-4- {[4-(4- {6-[2-hydroxyethoxy]pyridin-2-yl) -3-methylphenyl)piperidin-1 -yl] sulphonyl} -piperidine-4-carboxamide; 1 -(tert-butoxycarbonyl)- 4-[4-(4- {6-[2-hydroxyethoxy]pyridin-2-yl} -3- methylphenyl)piperidin-1 -ylsulphonyl]-piperidine-4-carboxylic acid; methyl 1 -(tert-butoxycarbonyl)- 4- {(4-(4- {6-[2-hydroxyethoxy]pyridin-2-yl} -3- methylphenyl)piperidin-1 -yl] sulphonyl) -4-piperidinecarboxylate; methyl 4- {(4-(4- {6-[2-hydroxyethoxy]pyridin-2-yl} -3-methylphenyl)piperidin-l - yl ]sulphonyl} -piperidine-4-carboxylate; methyl 1 -benzyl-4- {[4-(4- {6-[2-benzyloxyethoxy]pyridin-2-yl}-3- methylphenyl)piperidin-l-yl]suIphonyl}-piperidin-4-carboxylate; methyl 1 -benzyl-4-[4-(4-bromo-3-methylphenyl)piperidin-1 -ylsulphonyl] -4-piperidinecarboxylate; and methyl 2-[4-(4-bromo-3-methylphenyl)piperidin-1 -ylsulphonyl] acetate.
28. A compound selected from: N-hydroxy 4-(4-(4-{3-(2-[(N-tert-butoxycarbonyl)amino]ethoxy)phenyl}-3-methylphenyl)-piperidin-1 -ylsulphonyl] -tetrahydro-2H-pyran-4-carboxamide; N-hydroxy 4-(4-(4- {3-(2-[(tert-butoxycarbonyl)amino]ethoxy)phenyl} -3-methylphenyl)-piperidin-1 -ylsulphonyl] -tetrahydro-2H-pyran-4-carboxylate; methyl 4-(4-(4- {3-(2-((tert-butoxycarbonyl)amino]ethoxy)phenyl} -3-methylphenyl)- piperidin-1 -ylsulphonyl]-tetrahydro-2H-pyran-4-carboxylate; methyl 4-(4-(4-{3-(2-aminoethoxy)phenyl)-3-methylphenyl)-piperidin-l-ylsulphonyl]- tetrahydro-2H-pyran-4-carboxylate; methyl 4-(4-(4- {3-(2-(N-benzylamino]ethoxy)phenyl}-3-methylphenyl)-piperidin-l-ylsulphonyl]-tetrahydro-2H-pyran-4-carboxylate; methyl 4-(4-(4- {3-(2-oxoethoxy)phenyl}-3-methylphenyl)-piperidin-l-ylsulphonyl]-tetrahydro-2H-pyran-4-carboxylate; and methyl 4-(4-(4- (3-(2,2-diethoxyethoxy)phenyl) -3-methylphenyl)-piperidin-l -ylsulphonyl]-tetrahydro-2H-pyran-4-carboxylate. tet 119 5 7
29. A compound selected from: 4-[4-(4- {6-[2-hydroxyethoxy]pyridin-2-yl} -3-methylphenyl)piperidin-1 -ylsulphonyl]tetrahydro-2H-pyran-4-carboxylic acid; methyl 4- {[4-(4- {6-[2-hydroxyethoxy]pyridin-2-yl} -3-methylphenyl)piperidin-1 -5 yl]sulphonyl} tetrahydro-2H-pyran-4-carboxylate; methyl 4-[4-(4- {6-[2-benzyloxy]ethoxypyridin-2-yl} -3-methylphenyl)-1,2,3,6-tetrahydropyridin-1 -ylsulphonyl]tetrahydro-2H-pyran-4-carboxylate; andmethyl 4-[4-(4-bromo-3 -methylphenyl)-1,2,3,6-tetrahydropyridin-1 -ylsulphonyl]tetrahydro-2H-pyran-4-carboxylate. 10
30. A compound of formula (VI):
(VI) 15 wherein the substituents R1, R2, R3, X and R are as defined above in relation to any oneof claims 5, 6 or 7.
31. A compound of formula (VH): - 5 HONH
(VII) _ ι 119 5 7 wherein R1, R2, R3 and X are as defined in any one of daims 5,6 or 7, and where Rp is aNH- and/or OH-protected version of the corresponding compound of formula (I) asdefined in any one of daims 5, 6 or 7, and Avhere the corresponding compound of 5 formula (I) as defined in any one of daims 5,6 or 7 contains a free NH, NH2 or OHgroup.
32. A process for making a compound of formula (I) as defined in any one of daims 5, 6or 7 where R contains a free NH, NH2 or OH group, which comprises deprotecting a 10 corresponding compound of formula (VIT) as defined in daim 31.
33. A compound of formula (VUI) or (IX):
where R3, X and R are as defined in any one of daims 5, 6 or 7. 119 5 7
34. A compound of formula (X) or (XI) :
35. A compound of formula (ΧΠ): 10 HONH
R (XII) 184 119 5 7 wherein R3, X and R are as defined in any one of daims 5, 6 or 7 and Rlp and R2p is aN- and/or O-protected precursor which, on deprotection would give a correspondingcompound of formula (I) as defined in the corresponding claim 5,6 or 7. 5
36. A process for making a compound of formula (I) as defined in any one of daims 5,6 or 7 where R1 and/or R2 contains a ffee NH, NH2 or OH group, which comprisesdeprotecting a corresponding compound of formula (XH) as defined in claim 35.
37. A compound of formula (H) :
(H) 12 3 where R , R , R , X and R are as defined in any one of daims 5,6 or 7, and where Z is aleaving group such as chloro, bromo, iodo, C1.3 alkyloxy or HO. 15
38. A process for making a compound of formula (I) as defined in any one of daims 5, 6or 7, which comprises reaction of a compound of formula (Π) as defined in claim 37with hydroxylamine. 20
39. A compound of formula (ΧΙΠ): <iof
wherein R3, X and R are as defined in any one of daims 5, 6 or 7 and RIp, R2p and Rpare independently a N- and/or O-protected precursor which, on deprotection would givea corresponding compound of formula (I) as defined in the corresponding daims 5, 6 or 5 7 where R1, R2 and R contain a free NH, NH2 and/or OH group.
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