EP1332146A2 - Spiro-pyrimidine-2,4,6-trione metalloproteinase inhibitors - Google Patents

Spiro-pyrimidine-2,4,6-trione metalloproteinase inhibitors

Info

Publication number
EP1332146A2
EP1332146A2 EP01978721A EP01978721A EP1332146A2 EP 1332146 A2 EP1332146 A2 EP 1332146A2 EP 01978721 A EP01978721 A EP 01978721A EP 01978721 A EP01978721 A EP 01978721A EP 1332146 A2 EP1332146 A2 EP 1332146A2
Authority
EP
European Patent Office
Prior art keywords
group
pyridin
alkyl
spiro
triaza
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01978721A
Other languages
German (de)
English (en)
French (fr)
Inventor
Brian Scott Pfizer Global Res. a. Devel. BRONK
Mark Carl Pfizer Global Res. a. Devel. NOE
Martin James Pfizer Global Res. a. Devel WYTHES
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Products Inc
Original Assignee
Pfizer Products Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pfizer Products Inc filed Critical Pfizer Products Inc
Publication of EP1332146A2 publication Critical patent/EP1332146A2/en
Withdrawn legal-status Critical Current

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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
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Definitions

  • alkyl as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched moieties, or combinations thereof. Alkyl groups, wherever they occur, may be optionally substituted by a suitable substituent.
  • alkenyl as used herein, unless otherwise indicated, includes hydrocarbon radicals containing at least one olefin linkage and having straight, branched moieties, or combinations thereof.
  • heterocyclyl includes an organic radical derived from a non-aromatic heterocyclic compound by removal of one or more hydrogens, such as 3-azabicyc!o[3.1.0]hexa ⁇ yl, 3-azabicyclo[4.1.0]-heptanyl, azetidinyl, dihydrofuranyl, dihydropyra ⁇ yl, dihydrothienyl, dioxanyl, 1 ,3-dioxolanyI, 1,4-dithianyl, hexahydroazepinyl, hexahydropyrimidine, imidazolidiny), imidazolinyl, isoxazolidinyl, morpholinyl, oxazolidinyl, piperazinyl, pjperidinyl, 2H-pyranyl, 4H-pyra ⁇ yl, pyrazolidinyl, pyrazolinyl, pyrroli
  • X is (d-C 10 )heteroaryl selected from the group consisting of imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl; preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; more preferably X is pyridinyl.
  • Y is selected from the group consisting of a bond, oxygen, sulfur, -CH 2 -, >S0 2 , -OCH 2 - and -CH 2 0-; preferably Y is oxygen, -OCH 2 - or -CH 2 0-; more preferably Y is oxygen.
  • each of R 5 , R 6 , R 7 and R 8 is selected from the group consisting of hydrogen, (d-C 4 )alkyl, (C ⁇ -d)alkenyl, (C C 4 )a
  • Z is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, N-methyl-3-azetidinyl, piperazinyl, piperidinyl, N-methylpiperidinyl and morpholinyl.
  • more preferably Z is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl and tetrahydropyranyl.
  • most preferably Z is selected from the group consisting of cyclopentyl, cyclohexyl, tetrahydrofuranyl and tetrahydropyranyl.
  • G is R 15 -(CR 16 R 17 ) P -; wherein p is 1; R 15 is
  • either X or Z is not substituted by any optional substituents.
  • Azetidine-1-carboxylic acid 4-[5-(2,2,6,8,10-pentaoxo-2 ⁇ 6 -thia-1 ,7,9-triaza- spiro[4.5]dec-1-yl)-pyridin-2-yloxy]-benzylamide; 2,2-Dioxo-1 -[6-(4-pyrazol-1 -ylmethyl-phenoxy)-pyridin-3-yl]-2 ⁇ 6 -thia-1 ,7,9-triaza- spiro[4.5]decane-6,8,10-trione;
  • Methodabolic diseases refers to disorders such as diabetes (including non-insulin dependent diabetes mellitus, diabetic retinopathy, insulin resistance, diabetic ulceration).
  • Central Nervous System CNS disorders as used herein refers to disorders such as head trauma, spinal cord injury, Inflammatory diseases of the central nervous system, neuro- degenerative disorders (acute and chronic), Alzheimer's disease, demyelinating diseases of the nervous system, Huntington's disease, Parkinson's disease, peripheral neuropathy, pain, cerebral amyloid angiopathy, nootropic or cognition enhancement, amyotrophic lateral sclerosis, multiple sclerosis, migraine, depression and anorexia.
  • Suitable agents to be used in combination include standard non-steroidal anti-inflammatory agents (hereinafter NSAlD's) such as piroxicam, diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, apazone, pyrazolones such as phenylbutazone, salicylates such as aspirin, COX-2 inhibitors such as celecoxib, valdecoxib, paracoxib, etoricoxib and rofecoxib, analgesics, steroids, glucosamines, chondrosamines/ sulfates, gabapentin, A-agonists, IL-1 process and release inhibitors, CCR-1 antagonists, LTD-4, L
  • NSAlD's standard non-steroidal anti-inflammatory agents
  • piroxicam
  • L 1 and L 2 are leaving groups such as alkoxy, preferably methoxy, ethoxy or benzyloxy, more preferably methoxy or ethoxy and wherein L 3 is a suitable leaving group, such as halo, para-tolylsulfonyloxy (OTs), or methylsulfonyloxy (OMs), preferably halo, such as bromo or iodo, with a suitable base in a polar solvent.
  • Suitable bases include tertiary amines, .such as triethylamine.
  • Other suitable bases include a strongly basic macro-reticular resin or gel type resin, such as Amberlyst 400 ® resin (hydroxide form).
  • Suitable solvents include alcoholic solvents, preferably ethanol.
  • the aforesaid reaction can be conducted at a temperature of about -10 °C to about 50 °C, preferably about 20 °C, for a period of about 6 to about 36 hours.
  • a compound of formulae lllm-llln, respectively, can be prepared by reacting a compound of formulae IVm-IVn, respectively:
  • the compounds of formula H 2 N-X- Y-Z-G are commercially available or can be made by methods well known to those skilled in the art. Alternatively, the compounds of formula H 2 N-X- Y-Z-G can be prepared as described i ⁇ Scheme 3.
  • Scheme 2 refers to the preparation of a compound of the formula I, wherein the heterocyclic ring "A" has the formula o, i.e., a compound of formula lo.
  • a compound of formula lo: lo can be prepared by reacting a compound of the formula lllo, wherein L 1 and L 2 are leaving groups, with a urea of formula II (i.e., H 2 N-(CO)-NH 2 ) in the presence of a suitable base in a polar solvent.
  • Suitable leaving groups include methoxy, ethoxy, or benzyloxy, preferably ethoxy.
  • Bovine nasal cartilage is a tissue that is very similar to articular cartilage, i.e. chondrocytes surrounded by a matrix that is primarily type II collagen and aggrecan. The tissue is used because it: (1 ) is very similar to articular cartilage, (2) is readily available, (3) is relatively homogeneous and (4) degrades with predictable kinetics after IL-1 stimulation.
  • One group of preferred compounds possesses selective activity towards MMP-13 over MMP- 1.
  • Another preferred group of compounds possesses selective activity towards MMP-13 over MMP-1 , MMP-3 and MMP-7.
  • Another preferred group of compounds possesses selective activity towards MMP-13 over MMP-1 , MMP-3, MMP-7 and MMP-17.
  • Another preferred group of compounds possesses selective activity towards MMP-13 over MMP-1 , MMP-2, MMP-3, MMP-7, MMP-9 and MMP-14
  • Another preferred group of compounds possesses selective activity towards MMP-13 over MMP- 2 and MMP-14.
  • a sterile injectable solution of the active ingredient is usually prepared.
  • Solutions of a therapeutic compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed.
  • the aqueous solutions should be suitably adjusted and buffered, preferably at a pH of greater than 8, if necessary and the liquid diluent first rendered isotonic.
  • These aqueous solutions are suitable intravenous injection purposes.
  • the oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes.
  • the preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
  • compounds can be administered intramuscularly or subcutaneously at dosage levels of about 0.1 to 50 mg/kg/day, advantageously 0.2 to 10 mg/kg/day given in a single dose or up to 3 divided doses.

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EP01978721A 2000-10-26 2001-10-23 Spiro-pyrimidine-2,4,6-trione metalloproteinase inhibitors Withdrawn EP1332146A2 (en)

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IS6762A (is) 2003-03-27
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