WO2009074518A1 - Combinaisons formées de modulateurs au prolinamide du récepteur p2x7 et d'autres agents thérapeutiques - Google Patents

Combinaisons formées de modulateurs au prolinamide du récepteur p2x7 et d'autres agents thérapeutiques Download PDF

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WO2009074518A1
WO2009074518A1 PCT/EP2008/066890 EP2008066890W WO2009074518A1 WO 2009074518 A1 WO2009074518 A1 WO 2009074518A1 EP 2008066890 W EP2008066890 W EP 2008066890W WO 2009074518 A1 WO2009074518 A1 WO 2009074518A1
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methyl
mmol
treatment
therapeutic agent
mixture
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PCT/EP2008/066890
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Anton Duval Michel
Daryl Simon Walter
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Glaxo Group Limited
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Priority claimed from GB0821840A external-priority patent/GB0821840D0/en
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Publication of WO2009074518A1 publication Critical patent/WO2009074518A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/402—1-aryl substituted, e.g. piretanide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • 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
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • 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
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to combinations of heterocyclic (prolinamide) derivatives which modulate P2X7 receptor function and are capable of antagonizing the effects of ATP at the P2X7 receptor (P2X7 receptor antagonists) together with a further therapeutic agent or agents; to pharmaceutical compositions containing the combinations; and to the use of such combinations in therapy.
  • heterocyclic (prolinamide) derivatives which modulate P2X7 receptor function and are capable of antagonizing the effects of ATP at the P2X7 receptor (P2X7 receptor antagonists) together with a further therapeutic agent or agents; to pharmaceutical compositions containing the combinations; and to the use of such combinations in therapy.
  • the P2X7 receptor is a ligand-gated ion-channel which is expressed in cells of the hematopoietic lineage, e.g. macrophages, microglia, mast cells, and lymphocytes (T and B) (see, for example, CoIIo, et al., Neuropharmacology, Vol.36, pp1277-1283 (1997)), and is activated by extracellular nucleotides, particularly adenosine triphosphate (ATP).
  • ATP adenosine triphosphate
  • IL- 1 ⁇ interleukin 1 beta
  • TNF ⁇ tumour necrosis factor alpha
  • P2X7 receptors are also located on antigen presenting cells, keratinocytes, parotid cells, hepatocytes, erythrocytes, erythroleukaemic cells, monocytes, fibroblasts, bone marrow cells, neurones, and renal mesangial cells. Furthermore, the P2X7 receptor is expressed by presynaptic terminals in the central and peripheral nervous systems and has been shown to mediate glutamate release in glial cells (Anderson, C. et al., Drug. Dev. Res., Vol.50, page 92 (2000)).
  • P2X7 receptor antagonists in the treatment of a wide range of diseases including pain and neurodegenerative disorders.
  • Recent preclinical in vivo studies have directly implicated the P2X7 receptor in both inflammatory and neuropathic pain (Del ⁇ Antonio et al., Neurosci. Lett, Vol.327, pp87-90 (2002),. Chessell, I. P., et al., Pain, Vol.1 14, pp386-396 (2005), Honore et al., J. Pharmacol. Exp.
  • R 1 represents C 1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3_6 cycloalkyl, C3_6 cycloalkylmethyl- or pyridinylmethyl-, any of which is optionally substituted with 1 , 2 or 3 halogen atoms; or unsubstituted phenyl or benzyl;
  • R 2 and R 3 independently represent hydrogen, halogen, Ci -5 alkyl, arylmethyl-, C 2-6 alkenyl, C 2 _ 6 alkynyl or C 3-6 cycloalkylmethyl-; and any of said C 1 ⁇ 3 alkyl, arylmethyl-, C 2-6 alkenyl, C 2-6 alkynyl or C 3 . 6 cycloalkylmethyl- is optionally substituted with 1 , 2 or 3 halogen atoms;
  • R 4 , R 5 and R 6 independently represent hydrogen, fluorine or methyl; and R 7 , R 8 , R 9 , R 10 and R 11 independently represent hydrogen, halogen, cyano, C 1-5 alkyl, C 2-6 alkenyl, C 2 . 6 alkynyl, C 3-6 cycloalkyl or phenyl, and any of said C 1-6 alkyl, C 2-6 alkenyl, C 2 . 6 alkynyl, C 3 .
  • R 6 cycloalkyl or phenyl is optionally substituted with 1 , 2 or 3 halogen atoms; or R 10 and R 11 together with the carbon atoms to which they are attached form a benzene ring which is optionally substituted with 1 , 2 or 3 halogen atoms; with the proviso that when R 7 and R 11 are both selected from hydrogen or fluorine, at least one of R 8 , R 9 and R 10 is a halogen atom, or R 8 , R 9 and R 10 are selected from the group consisting of hydrogen and CF 3 and one, but not more than one, of R 8 , R 9 and R 10 is CF 3 ; together with a further therapeutic agent or agents.
  • the further therapeutic agent or agents may be medicaments claimed to be useful in the treatment of a condition which is mediated by P2X7 receptors as described herein.
  • Suitable examples of other such therapeutic agents may include a ⁇ 2-agonist (also known as ⁇ 2 adrenoceptor agonists; e.g. formoterol) and/or a corticosteroid (e.g. budesonide, fluticasone (e.g. as propionate or furoate esters), mometasone (e.g. as furoate), beclomethasone (e.g. as 17-propionate or 17,21 -dipropionate esters), ciclesonide, triamcinolone (e.g. as acetonide), flunisolide, rofleponide or butixocort (e.g. as propionate ester)), for the treatment of a respiratory disorder (such as asthma or chronic obstructive pulmonary disease (COPD)), e.g. as described in WO 2007/008155 and/or WO 2007/008157.
  • a respiratory disorder such as asthma or chronic obstructive pulmonary
  • a further therapeutic agent may include a 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor (e.g. atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, or simvastatin), for the treatment of a cardiovascular disorder (such as atherosclerosis), e.g. as described in WO 2006/083214.
  • HMG CoA 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor
  • atorvastatin e.g. atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, or simvastatin
  • a cardiovascular disorder such as atherosclerosis
  • a further therapeutic agent may include a non-steroid anti-inflammatory drug (NSAID; e.g. ibuprofen, naproxen, aspirin, celecoxib, diclofenac, etodolac, fenoprofen, indomethacin, ketoprofen, ketoralac, oxaprozin, nabumetone, sulindac, tolmetin, rofecoxib, valdecoxib, lumaricoxib, meloxicam, etoricoxib or parecoxib; or e.g.
  • NSAID non-steroid anti-inflammatory drug
  • Celecoxib (a COX-2 inhibitor) can for example be administered orally at a dosage regimen of 100 mg or 200 mg (measured as the free base) once or twice daily.
  • a further therapeutic agent may in particular include a tumour necrosis factor ⁇ (TNF ⁇ ) inhibitor (e.g. etanercept or an anti- TNF ⁇ antibody such as infliximab and adalimumab) (e.g. for parenteral administration such as subcutaneous or intravenous administration), for the treatment of an inflammatory disease or disorder (such as rheumatoid arthritis or osteoarthritis, and/or inflammatory pain), e.g. as described in
  • TNF ⁇ tumour necrosis factor ⁇
  • etanercept or an anti- TNF ⁇ antibody such as infliximab and adalimumab
  • parenteral administration such as subcutaneous or intravenous administration
  • an inflammatory disease or disorder such as rheumatoid arthritis or osteoarthritis, and/or inflammatory pain
  • a further therapeutic agent may in particular include an anti-CD20 monoclonal antibody (e.g. for parenteral such as intravenous administration), such as ofat
  • hA20 Immunomedics, Inc.
  • hA20 Immunomedics, Inc.
  • rituximab in particular ofatumumab or rituximab.
  • This further therapeutic agent can e.g. be for the treatment of an inflammatory disease or disorder (such as rheumatoid arthritis or osteoarthritis, and/or inflammatory pain).
  • an inflammatory disease or disorder such as rheumatoid arthritis or osteoarthritis, and/or inflammatory pain.
  • a further therapeutic agent may include 2-hydroxy-5- [ [4- [ (2- pyridinylamino) sulfonyl] phenyl] azo] benzoic acid (sulfasalazine) for the treatment of an inflammatory disease or disorder (such as rheumatoid arthritis or osteoarthritis; in particular rheumatoid arthritis), e.g. as described in WO 2004/105797.
  • an inflammatory disease or disorder such as rheumatoid arthritis or osteoarthritis; in particular rheumatoid arthritis
  • a further therapeutic agent may in particular include N-[4-[[(2, 4-diamino-6-pteridinyl) methyl] methylamino] benzoyl]- L-glutamic acid (methotrexate) for the treatment of an inflammatory disease or disorder (such as rheumatoid arthritis or osteoarthritis; in particular rheumatoid arthritis), e.g. as described in WO 2004/105796.
  • an inflammatory disease or disorder such as rheumatoid arthritis or osteoarthritis; in particular rheumatoid arthritis
  • a further therapeutic agent may include an inhibitor of pro TNF ⁇ convertase enzyme (TACE), for the treatment of an inflammatory disease or disorder (such as rheumatoid arthritis or osteoarthritis; in particular rheumatoid arthritis), e.g. as described in WO 2004/073704.
  • TACE pro TNF ⁇ convertase enzyme
  • a further therapeutic agent may in particular include:
  • an inhibitor of p38 kinase e.g. for oral administration
  • an anti-IL-6-receptor antibody e.g. an anti-IL-6-receptor monoclonal antibody (e.g. for parenteral such as intravenous administration)
  • anakinra e.g. an anti-IL-1 (e.g. I L-1 ⁇ ) monoclonal antibody (e.g.
  • an inhibitor of JAK3 protein tyrosine kinase i) an anti-macrophage colony stimulation factor (M-CSF) monoclonal antibody
  • M-CSF anti-macrophage colony stimulation factor
  • an anti-CD20 monoclonal antibody e.g. for parenteral such as intravenous administration
  • rituximab, ofatumumab HuMax-CD20 TM, developed in part by Genmab AS) (e.g. ofatumumab for intravenous administration), PRO70769, AME- 133 (Applied Molecular Evolution), or hA20 (Immunomedics, Inc.); in particular rituximab or ofatumumab;
  • IL-1 e.g. IL-1 ⁇
  • IL-1 ⁇ IL-1 ⁇
  • IL-1 ⁇ IL-1 ⁇
  • inflammatory or neuropathic pain e.g. as described in WO 2006/003517.
  • the further therapeutic agent includes a non-steroid anti-inflammatory drug (NSAI D) (e.g. ibuprofen, naproxen, aspirin, celecoxib, diclofenac, etodolac, fenoprofen, indomethacin, ketoprofen, ketoralac, oxaprozin, nabumetone, sulindac, tolmetin, rofecoxib, valdecoxib, lumaricoxib, meloxicam, etoricoxib or parecoxib; or e.g.
  • NSAI D non-steroid anti-inflammatory drug
  • the non-steroid anti-inflammatory drug and/or the combination comprising the non-steroid anti-inflammatory drug is for the treatment of an inflammatory disease or disorder.
  • the further therapeutic agent does not include a non-steroid anti-inflammatory drug (NSAID) (e.g. ibuprofen, naproxen, aspirin, celecoxib, diclofenac, etodolac, fenoprofen, indomethacin, ketoprofen, ketoralac, oxaprozin, nabumetone, sulindac, tolmetin, rofecoxib, valdecoxib, lumaricoxib, meloxicam, etoricoxib or parecoxib; or e.g. paracetamol, loxoprofen or aceclofenac).
  • NSAID non-steroid anti-inflammatory drug
  • the further therapeutic agent does not include ethanol, cocaine, nicotine, or an opioid (typically a dependence-inducing opioid, e.g. morphine).
  • the further therapeutic agent does not include an opioid (typically a dependence-inducing opioid, e.g. morphine), or nicotine, or a dependence-inducing CNS depressant (e.g. ethanol), or a dependence-inducing psychostimulant (e.g. cocaine).
  • the further therapeutic agent does not include a dependence- inducing agent (e.g. an opioid such as morphine, or nicotine, or a dependence- inducing CNS depressant such as ethanol, or a dependence-inducing psychostimulant such as cocaine).
  • CNS means central nervous system.
  • the further therapeutic agent does not include a cancer chemotherapeutic agent.
  • the further therapeutic agent or agents can be a therapeutic agent or agents capable of treating inflammatory pain, such as paracetamol and/or an opioid (such as morphine, fentanyl, oxycodone, tramadol, hydrocodone, hydromorphone, oxymorphone, methadone or buprenorphine; in particular morphine, fentanyl, oxycodone, or tramadol).
  • This/these therapeutic agent(s), and/or the combination comprising this/these therapeutic agent(s) can be for the treatment of inflammatory pain, e.g. in a mammal such as a human.
  • paracetamol can be administered at a human oral dosage regimen of 500 mg to 1000 mg (e.g. 500 mg, 650 mg or 1000 mg, in particular 650 mg) of paracetamol (measured as the free base / free compound), administered two, three or four times daily.
  • a human oral dosage regimen 500 mg to 1000 mg (e.g. 500 mg, 650 mg or 1000 mg, in particular 650 mg) of paracetamol (measured as the free base / free compound), administered two, three or four times daily.
  • the further therapeutic agent or agents can be a therapeutic agent or agents capable of treating neuropathic pain, such as:
  • an opioid such as morphine, fentanyl, oxycodone, tramadol, hydrocodone, hydromorphone, oxymorphone, methadone or buprenorphine; in particular morphine, fentanyl, oxycodone, or tramadol
  • opioid such as morphine, fentanyl, oxycodone, tramadol, hydrocodone, hydromorphone, oxymorphone, methadone or buprenorphine; in particular morphine, fentanyl, oxycodone, or tramadol
  • a monoamine reuptake inhibitor such as duloxetine or amytriptyline
  • This/these therapeutic agent(s), and/or the combination comprising this/these therapeutic agent(s), can be for the treatment of neuropathic pain, e.g. in a mammal such as a human.
  • pregabalin can be administered orally e.g. for neuropathic pain; e.g. at a human oral dosage regimen of 150 mg to 600 mg total pregabalin per day (measured as the free base), split between two to three doses per day.
  • pregabalin can be administered at a starting oral dosage regimen of 150 mg total pregabalin per day (split between 2 or 3 doses per day), escalating (e.g. in about one week) to an oral dosage regimen of 300 mg pregabalin total per day, and optionally escalating up to a maximum oral dosage regimen of 600 mg total pregabalin per day.
  • an oral dosage regimen of 150 mg to 300 mg total pregabalin per day can be administered.
  • an oral dosage regimen of 150 mg to 450 mg (e.g. 300 or 450 mg) total pregabalin per day can be administered.
  • Pregabalin can e.g. be administered separately from the compound of formula (I) or the salt thereof.
  • gabapentin can be administered orally, e.g. for neuropathic pain.
  • Oral dosage units can e.g. contain 100 mg, 300 mg, 400 mg, 600 mg or 800 mg of gabapentin (measured as the free base/acid).
  • the gabapentin dosage regimen for neuropathic pain can e.g. be from 300 mg once, twice or three times per day up to a total dose of 3600 mg / day. Some gradual up-titration of the dosage regimen is usually performed.
  • Slower titration of gabapentin dosage may be appropriate for individual patients.
  • the minimum time to reach a total dose of 1800 mg / day is typically one week, to reach 2400 mg / day is typically a total of 2 weeks, and to reach 3600 mg / day is typically a total of 3 weeks.
  • Gabapentin can e.g. be administered separately from the compound of formula (I) or the salt thereof.
  • gabapentin enacarbil (XP13512, ( ⁇ )-1-([( ⁇ - isobutanoyloxyethoxy)carbonyl]-aminomethyl)-1-cyclohexane acetic acid, which is a prodrug of gabapentin) can be administered orally, e.g. to a human, e.g. separately from the compound of formula (I) or the salt thereof.
  • gabapentin enacarbil (XP13512) is for example administered orally, e.g. to a human such as a human adult, e.g.
  • a 600 mg dose of gabapentin enacarbil contains the molar equivalent of 312 mg of gabapentin. See also K.C. Cundy et al., "Clinical Pharmacokinetics of XP13512, a Novel Transported Prodrug of Gabapentin", J. CHn.
  • the opioid and/or the combination comprising the opioid is for the treatment of pain, in particular inflammatory or neuropathic pain, e.g. in a mammal such as a human.
  • the compounds When the compounds are used in combination with other therapeutic agents, the compounds may be administered either sequentially or simultaneously by any convenient route.
  • the individual components of the combination of the invention may be present as separate pharmaceutical formulations / compositions, or may be present as a combined pharmaceutical formulation / composition (e.g. may be together in a single combined oral dosage form, e.g. a single combined tablet or capsule).
  • the individual components of this combination can for example be administered either sequentially in separate pharmaceutical formulations / compositions (e.g. oral), or simultaneously in separate or combined pharmaceutical formulation(s) / composition(s) (e.g. oral); in a particular embodiment they are administered sequentially in separate pharmaceutical formulations / compositions (e.g. oral).
  • compositions comprising a combination as defined herein together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention.
  • the individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
  • a combination comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof:
  • R 1 represents C 1-6 alkyl, C 2-6 alkenyl, C 2 _ 6 alkynyl, C 3-5 cycloalkyl or C 3-6 cycloalkylmethyh any of which may be optionally substituted with 1 , 2 or 3 halogen atoms; or unsubstituted phenyl or benzyl;
  • R 2 and R 3 independently represent hydrogen, halogen, C 1-6 alkyl, arylmethyl-, C 2-6 alkenyl, C 2 . 6 alkynyl or C 3-6 cycloalkylmethyl-; and any of said C 1 ⁇ 3 alkyl, arylmethyl-,
  • C 2-6 alkenyl, C 2 . 6 alkynyl or C 3-6 cycloalkylmethyl- may be optionally substituted with 1 ,
  • R 4 , R 5 and R 6 independently represent hydrogen or fluorine
  • R 7 , R 8 , R 9 , R 10 and R 11 independently represent hydrogen, halogen, cyano, C 1-6 alkyl,
  • a combination comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof:
  • R 1 represents Ci -6 alkyl, C 2 . 6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkylmethyl- or pyridinylmethyl-, any of which is optionally substituted with 1 , 2 or 3 halogen atoms; or unsubstituted phenyl or benzyl;
  • R 2 and R 3 independently represent hydrogen, halogen, C- ⁇ -6 alkyl, arylmethyl-, C2-6 alkenyl, C 2 . 6 alkynyl or C3-6 cycloalkylmethyl-; and any of said C1-3 alkyl, arylmethyl-, C2-6 alkenyl, C 2- 6 alkynyl or C3.6 cycloalkylmethyl- is optionally substituted with 1 , 2 or 3 halogen atoms; R 4 , R 5 and R 6 independently represent hydrogen, fluorine or methyl; and
  • R 7 , R 8 , R 9 , R 10 and R 11 independently represent hydrogen, halogen, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2 . 6 alkynyl, C 3-6 cycloalkyl or phenyl, and any of said C 1-6 alkyl, C 2-6 alkenyl, C 2 . 6 alkynyl, C 3 .
  • R 6 cycloalkyl or phenyl is optionally substituted with 1 , 2 or 3 halogen atoms; or R 10 and R 11 together with the carbon atoms to which they are attached form a benzene ring which is optionally substituted with 1 , 2 or 3 halogen atoms; with the proviso that when R 7 and R 11 are both selected from hydrogen or fluorine, at least one of R 8 , R 9 and R 10 is a halogen atom, or not more than one of R 8 , R 9 and R 10 is a CF 3 group; together with a further therapeutic agent or agents.
  • alkyl refers to a straight or branched hydrocarbon chain containing the specified number of carbon atoms.
  • C 1 ⁇ alkyl means a straight or branched hydrocarbon chain containing at least 1 and at most 6 carbon atoms.
  • alkyl include, but are not limited to; methyl (Me), ethyl (Et), n-propyl, i-propyl, n-hexyl and i-hexyl.
  • alkenyl refers to a straight or branched hydrocarbon chain containing the specified number of carbon atoms wherein at least one carbon-carbon bond is a double bond.
  • alkenyl include, but are not limited to ethenyl, propenyl, n-butenyl, i-butenyl, n-pentenyl and i-pentenyl.
  • alkynyl refers to a straight or branched hydrocarbon chain containing the specified number of carbon atoms wherein at least one carbon-carbon bond is a triple bond.
  • alkynyl include, but are not limited to ethynyl, propynyl, butynyl, i-pentynyl, n-pentynyl, i-hexynyl and n-hexynyl.
  • 'cycloalkyl' unless otherwise stated means a closed 3 to 6 membered non- aromatic ring, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • 'aryl' refers to a C ⁇ -io monocyclic or bicyclic hydrocarbon ring wherein at least one ring is aromatic. Examples of such groups include phenyl and naphthyl.
  • 'halogen' is used herein to describe, unless otherwise stated, a group selected from fluorine, chlorine, bromine or iodine.
  • R 1 represents C 1 ⁇ alkyl, C 2 _ 6 alkenyl, C 2-6 alkynyl, C 3 . 6 cycloalkyl or pyridinylmethyl-, any of which is optionally substituted with 1 , 2 or 3 halogen atoms; or unsubstituted phenyl or benzyl.
  • R 1 represents unsubstituted C 1-6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 6 cycloalkyl, pyridinylmethyl-, phenyl or benzyl.
  • R 1 represents unsubstituted Ci -4 alkyl, C 3-5 cycloalkyl, pyridinylmethyl-, phenyl or benzyl. In yet another embodiment, R 1 represents methyl or ethyl.
  • R 2 and R 3 independently represent hydrogen, halogen, Ci -6 alkyl, benzyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-6 cycloalkylmethyl-; and any of said Ci -6 alkyl, benzyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl or C 3-6 cycloalkylmethyl- may be optionally substituted with 1 , 2 or 3 halogen atoms.
  • R 2 and R 3 independently represent hydrogen or halogen; unsubstituted Ci_ 6 alkyl, benzyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl or C 3 ⁇ cycloalkylmethyl-.
  • R 2 and R 3 independently represent hydrogen, fluorine or methyl. In a further embodiment, R 2 and R 3 both represent hydrogen.
  • R 4 and R 5 independently represent hydrogen or methyl.
  • R 6 represents hydrogen or methyl.
  • R 4 , R 5 and R 6 all represent hydrogen.
  • R 7 , R 8 , R 9 , R 10 and R 11 independently represent hydrogen, halogen, cyano, trifluoromethyl or unsubstituted Ci -6 alkyl; or R 10 and R 11 together with the carbon atoms to which they are attached form an unsubstituted benzene ring.
  • R 7 , R 8 , R 9 , R 10 and R 11 independently represent hydrogen, halogen, cyano, methyl or trifluoromethyl; or R 10 and R 11 together with the carbon atoms to which they are attached form an unsubstituted benzene ring.
  • R 7 , R 8 , R 9 , R 10 and R 11 independently represent hydrogen, chlorine, fluorine, bromine, methyl or trifluoromethyl.
  • R 1 represents unsubstituted C 1-4 alkyl, C 2 - 4 alkenyl, C 3-5 cycloalkyl, pyridinylmethyl-, phenyl or benzyl;
  • R 2 and R 3 both represent hydrogen
  • R 4 , R 5 and R 6 independently represent hydrogen or methyl
  • R 7 , R 8 , R 9 , R 10 and R 11 independently represent hydrogen, chlorine, fluorine, bromine, methyl or trifluoromethyl; with the proviso that when R 7 and R 11 are both selected from hydrogen or fluorine, at least one of R 8 , R 9 and R 10 is a halogen atom, or R 8 , R 9 and R 10 are selected from the group consisting of hydrogen and CF 3 and one, but not more than one, of R 8 , R 9 and
  • R 10 is CF 3 .
  • Particular compounds of formula (I) include the compounds of Examples 1-136 as shown below, or a pharmaceutically acceptable salt thereof.
  • the compound of formula (I) or the pharmaceutically acceptable salt thereof is ⁇ /- ⁇ [2-chloro-3-(trifluoromethyl)phenyl]methyl ⁇ -1-methyl-5-oxoprolinamide:
  • the compound of formula (I) or the pharmaceutically acceptable salt thereof is /V- ⁇ -chloro-S- ⁇ rifluoromethylJphenylJmethylJ-i-methyl-S-oxo-/.- prolinamide:
  • the compound of formula (I) or the pharmaceutically acceptable salt thereof is ⁇ /- ⁇ [2-chloro-3- (trifluoromethyl)phenyl]methyl ⁇ -1 -methyl-5-oxo-L-prolinamide:
  • a ⁇ 2-agonist also known as ⁇ 2 adrenoceptor agonists; e.g. formoterol
  • a corticosteroid e.g. budesonide, fluticasone (e.g. as propionate or furoate esters), mometasone (e.g. as furoate), beclomethasone (e.g. as 17-propionate or 17,21- dipropionate esters), ciclesonide, triamcinolone (e.g. as acetonide), flunisolide, rofleponide or butixocort (e.g. as propionate ester)), e.g. for the treatment of a respiratory disorder (such as asthma or chronic obstructive pulmonary disease (COPD)); or
  • COPD chronic obstructive pulmonary disease
  • HMG CoA reductase inhibitor e.g. atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, or simvastatin
  • a cardiovascular disorder such as atherosclerosis
  • NSAID non-steroid anti-inflammatory drug
  • NSAID non-steroid anti-inflammatory drug
  • ibuprofen e.g. ibuprofen, naproxen, aspirin, celecoxib, diclofenac, etodolac, fenoprofen, indomethacin, ketoprofen, ketoralac, oxaprozin, nabumetone, sulindac, tolmetin, rofecoxib, valdecoxib, lumaricoxib, meloxicam, etoricoxib or parecoxib; or e.g.
  • NSAID non-steroid anti-inflammatory drug
  • celecoxib in particular celecoxib, paracetamol, ibuprofen or diclofenac; more particularly celecoxib administered orally at a dosage regimen of 100 mg or 200 mg (measured as the free base) once or twice daily; e.g. for the treatment of an inflammatory disease or disorder (such as rheumatoid arthritis or osteoarthritis, and/or inflammatory pain); and/or
  • tumour necrosis factor ⁇ (TNF ⁇ ) inhibitor e.g. etanercept or an anti- TNF ⁇ antibody such as infliximab and adalimumab
  • parenteral administration such as subcutaneous or intravenous administration
  • an inflammatory disease or disorder such as rheumatoid arthritis or osteoarthritis, and/or inflammatory pain
  • inflammatory disease or disorder such as rheumatoid arthritis or osteoarthritis, and/or inflammatory pain
  • sulfasalazine e.g. for the treatment of an inflammatory disease or disorder (such as rheumatoid arthritis or osteoarthritis; in particular rheumatoid arthritis); and/or e.g. for the treatment of an IL-1 (e.g. IL-1 ⁇ ) mediated disease (such as rheumatoid arthritis or osteoarthritis, and/or inflammatory or neuropathic pain; in particular rheumatoid arthritis); and/or
  • TACE - pro TNF ⁇ convertase enzyme
  • statin e.g. for oral administration
  • a statin such as atorvastatin, lovastatin, pravastatin, simvastatin, fluvastatin, cerivastatin, crilvastatin, dalvastatin, rosuvastatin, tenivastatin, fluindostatin, velostatin, dalvastatin, nisvastatin, bervastatin, pitavastatin, rivastatin, glenvastatin, eptastatin, tenivastatin, flurastatin, rosuvastatin or itavastatin; e.g. for the treatment of an IL-1 (e.g. IL-1 ⁇ ) mediated disease (such as rheumatoid arthritis); and/or
  • a glucocorticoid agent e.g. for oral or skin-topical administration
  • a glucocorticoid agent such as dexamethasone, methylprednisolone, prednisolone, prednisone and hydrocortisone
  • an I L- 1 e.g. IL-1 ⁇
  • mediated disease such as rheumatoid arthritis
  • an inhibitor of p38 kinase e.g. for oral administration
  • e.g. for the treatment of an IL-1 (e.g. IL-1 ⁇ ) mediated disease such as rheumatoid arthritis
  • IL-1 e.g. IL-1 ⁇
  • mediated disease such as rheumatoid arthritis
  • an anti-IL-6-receptor antibody e.g. an anti-IL-6-receptor monoclonal antibody (e.g. for parenteral such as intravenous administration); e.g. for the treatment of an IL-1 (e.g. IL-1 ⁇ ) mediated disease (such as rheumatoid arthritis); and/or
  • anakinra e.g. for the treatment of an IL-1 (e.g. I L- 1 ⁇ ) mediated disease (such as rheumatoid arthritis); and/or
  • an anti-IL-1 e.g. I L-1 ⁇
  • monoclonal antibody e.g. for parenteral such as intravenous administration
  • an IL-1 e.g. I L-1 ⁇
  • mediated disease such as rheumatoid arthritis
  • an inhibitor of JAK3 protein tyrosine kinase e.g. for the treatment of an IL-1 (e.g. IL- 1 ⁇ ) mediated disease (such as rheumatoid arthritis); and/or
  • M-CSF anti-macrophage colony stimulation factor
  • an anti-CD20 monoclonal antibody e.g. for parenteral such as intravenous administration
  • parenteral such as intravenous administration
  • a monoclonal antibody e.g. for parenteral such as intravenous administration
  • humanMax-CD20 TM developed in part by Genmab AS
  • rituximab e.g. ofatumumab for intravenous administration
  • PRO70769 e.g. ofatumumab for intravenous administration
  • AME-133 Applied Molecular Evolution
  • hA20 Immunomedics, Inc.
  • IL-1 e.g.
  • IL-1 ⁇ IL-1 ⁇
  • disease such as rheumatoid arthritis or osteoarthritis, and/or inflammatory or neuropathic pain; in particular rheumatoid arthritis
  • inflammatory disease or disorder such as rheumatoid arthritis or osteoarthritis, and/or inflammatory pain
  • a therapeutic agent or agents capable of treating inflammatory pain such as paracetamol (e.g. oral paracetamol, e.g. 500 mg to 1000 mg for oral administration two, three or four times daily) and/or an opioid (such as morphine, fentanyl, oxycodone, tramadol, hydrocodone, hydromorphone, oxymorphone, methadone or buprenorphine; in particular morphine, fentanyl, oxycodone, or tramadol); and e.g. this/these therapeutic agent(s), and/or the combination comprising this/these therapeutic agent(s), can be for the treatment of inflammatory pain, e.g. in a mammal such as a human; and/or
  • paracetamol e.g. oral paracetamol, e.g. 500 mg to 1000 mg for oral administration two, three or four times daily
  • an opioid such as morphine, fentanyl, oxycodone, tramadol,
  • a therapeutic agent or agents capable of treating neuropathic pain such as an opioid (such as morphine, fentanyl, oxycodone, tramadol, hydrocodone, hydromorphone, oxymorphone, methadone or buprenorphine; in particular morphine, fentanyl, oxycodone, or tramadol); a monoamine reuptake inhibitor (such as duloxetine or amytriptyline); pregabalin (e.g. for oral administration e.g. as described herein), gabapentin (e.g. for oral administration e.g. as described herein), gabapentin enacarbil (XP13512) (e.g.
  • this/these therapeutic agent(s), and/or the combination comprising this/these therapeutic agent(s), can be for the treatment of neuropathic pain, e.g. in a mammal such as a human.
  • the ⁇ /- ⁇ [2-chloro-3- (trifluoromethyl)phenyl]methyl ⁇ -1 -methyl-5-oxo-L-prolinamide and the further therapeutic agent or agents may be present as separate pharmaceutical formulations
  • compositions may be present as a combined pharmaceutical formulation / composition (e.g. may be together in a single combined oral dosage form, e.g. a single combined tablet or capsule).
  • These components of this combination can be administered either sequentially in separate pharmaceutical formulations / compositions (e.g. oral), or simultaneously in separate or combined pharmaceutical formulation(s) / composition(s) (e.g. oral); in a particular embodiment they are administered sequentially in separate pharmaceutical formulations / compositions
  • Antagonists of P2X7 may be useful in preventing, treating, or ameliorating a variety of pain states (e.g. neuropathic pain, inflammatory pain (e.g. chronic), and visceral pain), inflammation and neurodegeneration, in particular Alzheimer's disease.
  • P2X7 antagonists may also constitute useful therapeutic agents in the management of rheumatoid arthritis and inflammatory bowel disease.
  • Compounds of formula (I) or salts thereof, within the combinations of the present invention modulate P2X7 receptor function and are capable of antagonizing the effects of ATP at the P2X7 receptor ("P2X7 receptor antagonists"), and may be competitive antagonists, inverse agonists, or negative allosteric modulators of P2X7 receptor function.
  • Certain compounds of formula (I) may in some circumstances form acid addition salts thereof. It will be appreciated that for use in medicine compounds of formula (I) may be used as salts, in which case the salts should be pharmaceutically acceptable. Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse , J. Pharm. ScL, 1977, 66, 1-19.
  • a pharmaceutically acceptable salt is formed from a pharmaceutically acceptable acid such as an inorganic or organic acid.
  • a pharmaceutically acceptable acid such as an inorganic or organic acid.
  • Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
  • the pharmaceutically acceptable acid is benzenesulfonic, camphorsulfonic, ethanesulfonic, hydrobromic, hydrochloric, methanesulfonic, nitric, phosphoric, sulfuric, or p-toluenesulfonic acid.
  • Examples of pharmaceutically acceptable salts include those formed from maleic, fumaric, benzoic, ascorbic, pamoic, succinic, hydrochloric, sulfuric, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, propionic, tartaric, salicylic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, cyclohexylsulfamic, phosphoric and nitric acids.
  • the compounds of formula (I) or pharmaceutically acceptable salts thereof may be prepared in crystalline or non-crystalline form (e.g. in crystalline or amorphous solid form), and, in particular if crystalline, may optionally be solvated, e.g. as the hydrate.
  • This invention includes within its scope solvates (e.g. hydrates) of compounds of formula (I) or pharmaceutically acceptable salts thereof, for example stoichiometric solvates (e.g. hydrates); as well as compounds or salts containing variable amounts of solvent (e.g. water).
  • Compounds of formula (I) or salts thereof may be capable of existing in stereoisomeric forms (e.g.
  • stereoisomeric forms and to mixtures thereof including racemates.
  • the different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis.
  • the stereochemical composition of the final product has been determined by chiral HPLC (more specifically by methods (A), (B), (C) or (D) as set out in the Examples), the corresponding stereospecific name and structure have been assigned to the final product where the enantiomeric excess of said product is greater than 70%. Assignment of absolute stereochemistry is based on the known chirality of the starting material.
  • the stereochemistry of the final product has not been indicated.
  • the chirality of the main component of the product mixture will be expected to reflect that of the starting material and the enatiomeric excess will depend on the synthetic method used and is likely to be similar to that measured for an analogous example (where such an example exists).
  • compounds shown in one chiral form are expected to be able to be prepared in the alternative chiral form using the appropriate starting material.
  • racemic starting materials it would be expected that a racemic product would be produced and the single enatiomers could be separated by the usual methods.
  • the invention also extends to any tautomeric forms and mixtures thereof.
  • the combinations of the subject invention may also include isotopically-labeled compounds, which are identical to those recited in formula (I) or salts thereof, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.
  • isotopes that can be incorporated into compounds or salts within the combinations of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, iodine, and chlorine, such as 3H, 11 C, 14C,
  • Isotopically-labeled compounds or salts within the combinations of the present invention are potentially useful in drug and/or substrate tissue distribution assays.
  • Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are for example optionally chosen for their (in some cases) ease of preparation and detectability.
  • 1 1 C and 8F isotopes can be useful in PET (positron emission tomography), and 1251 isotopes can be useful in SPECT (single photon emission computerized tomography). PET and SPECT can be useful in brain imaging.
  • lsotopically labeled compounds of formula (I) or salts thereof within this invention are in one embodiment and in some cases prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting an available isotopically labeled reagent for a non-isotopically labeled reagent.
  • the compound of formula (I) or the pharmaceutically acceptable salt thereof is not a radioactive isotopically-labelled compound or salt.
  • the compound or salt is not an isotopically-labelled compound or salt.
  • Compounds of formula (I) or a pharmaceutically acceptable salt thereof may be prepared according to the following process comprising process (a), (b), (c) or (d) (described below), and optionally preparing a pharmaceutically acceptable salt of the compound.
  • the process comprises: (a) Coupling of a carboxylic acid of formula (2) (or an activated derivative thereof) with an amine of formula (3) (see Scheme 1 ), wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are as defined above.
  • Compounds (2) and (3) are optionally protected;
  • the coupling of an acid of formula (2) and an amine of formula (3) typically comprises the use of activating agents, such as N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride or polymer-supported carbodiimide, 1- hydroxybenzotriazole (HOBT) or 1 -hydroxy-7-azabenzotriazole (HOAt), and optionally a suitable base such as a tertiary alkylamine (e.g. diisopropylethylamine, N-ethyl morpholine, triethylamine) or pyridine, in a suitable solvent such as DMF and/or dichloromethane and at a suitable temperature e.g.
  • activating agents such as N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride or polymer-supported carbodiimide, 1- hydroxybenzotriazole (HOBT) or 1
  • the coupling of (2) and (3) may be accomplished by treatment with O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate and a suitable tertiary alkylamine such as diisopropylethylamine in a suitable solvent such as dimethylformamide at a suitable temperature such as room temperature.
  • the compound of formula (2) may be employed as an activated derivative (e.g. acid chloride, mixed anhydride, active ester (e.g.
  • process (a) typically comprises treatment of said activated derivative with an amine (Ogliaruso, M.A.; Wolfe, J. F. in The Chemistry of Functional Groups (Ed. Patai, S.) Suppl.B: The Chemistry of Acid Derivatives, Pt. 1 (John Wiley and Sons, 1979), pp442-8; Beckwith, A.L.J, in The Chemistry of Functional Groups (Ed. Patai, S.) Suppl.B: The Chemistry of Amides (Ed. Zabricky, J.j(John Wiley and Sons, 1970), pp 73 ff).
  • Step (i) typically comprises initial treatment of (7) with a base such as sodium hydroxide in a suitable solvent such as methanol at a suitable temperature such as 0 0 C followed by reductive alkylation which typically comprises subsequent treatment with an aldehyde or ketone and an acid, such as acetic acid, and then addition of a reducing agent such as sodium borohydride at a suitable temperature such as between 0°C and room temperature.
  • a base such as sodium hydroxide in a suitable solvent such as methanol at a suitable temperature such as 0 0 C
  • reductive alkylation typically comprises subsequent treatment with an aldehyde or ketone and an acid, such as acetic acid, and then addition of a reducing agent such as sodium borohydride at a suitable temperature such as between 0°C and room temperature.
  • Step (ii) may occur spontaneously, in which case (9) is isolated directly from the reaction of (7) as described in step (i) above, but more typically compound (8) is heated at a suitable temperature, such as 1 10 0 C, in a suitable solvent, such as toluene, to afford compound (9) .
  • a suitable temperature such as 1 10 0 C
  • a suitable solvent such as toluene
  • Deprotection step (iii) typically comprises a standard procedure for conversion of a carboxylic ester to an acid, such as use of an appropriate hydroxide salt (e.g. sodium hydroxide) in an appropriate solvent such as methanol at a suitable temperature such as between O 0 C and room temperature.
  • an appropriate hydroxide salt e.g. sodium hydroxide
  • an appropriate solvent such as methanol
  • R 6 H or F
  • L 1 is a suitable group such as halogen (e.g. chlorine or bromine) or a boronic acid or boronic ester
  • P 3 represents a suitable protecting groups such as C 1-6 alkyl.
  • Step (i) typically comprises treatment of (10) with a base such as sodium hydride and an alkylating agent such as an alkyl halide in a suitable solvent such as tetrahydrofuran at a suitable temperature such as between 0 0 C and room temperature or alternatively it may comprise treatment of (10) with an aryl halide or aryl or alkenyl boronic acid (or ester) in a suitable solvent such as toluene in the presence of a suitable catalyst such as a mixture of tris(dibenzylideneacetone)dipalladium(0) and XantphosTM (9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene) and a suitable base such as cesium carbonate at a suitable temperature such as 120 0 C.
  • a base such as sodium hydride and an alkylating agent such as an alkyl halide in a suitable solvent such as tetrahydrofuran at a suitable temperature such as between
  • Deprotection (ii) typically comprises a standard procedure for conversion of a carboxylic ester to an acid, such as use of an appropriate hydroxide salt (e.g. sodium hydroxide) in an appropriate solvent such as methanol at a suitable temperature such as between 0 0 C and room temperature; or use of an appropriate acid (e.g. trifluoroacetic acid) in an appropriate solvent such as dichloromethane at a suitable temperature such as between O 0 C and room temperature.
  • an appropriate hydroxide salt e.g. sodium hydroxide
  • an appropriate solvent such as methanol
  • an appropriate acid e.g. trifluoroacetic acid
  • Step (i) typically comprises heating (12) in an autoclave or sealed tube in a suitable solvent, such as water, and at a suitable temperature such as from 100-140 0 C with or without microwave irradiation.
  • a suitable solvent such as water
  • Step (i) typically comprises protection of (13) by standard protocols such as treatment with an alkoxycarbonyl anhydride, such as di-tertbutyl dicarbonate, and a base such as triethylamine and a catalyst such as 4-dimethylaminopyridine in a suitable solvent such as dichloromethane at a suitable temperature such as room temperature.
  • an alkoxycarbonyl anhydride such as di-tertbutyl dicarbonate
  • a base such as triethylamine
  • a catalyst such as 4-dimethylaminopyridine
  • a suitable solvent such as dichloromethane
  • Step (ii) typically comprises treatment of (14) with a base such as lithium bis(trimethylsilyl)amide and an alkylating agent such as an alkyl halide in a suitable solvent such as tetrahydrofuran at a suitable temperature such as between -78 0 C and room temperature.
  • a base such as lithium bis(trimethylsilyl)amide
  • an alkylating agent such as an alkyl halide
  • a suitable solvent such as tetrahydrofuran
  • Step (iii) typically comprises deprotection of (15) by standard protocols such as, for the case when P 5 is a tertbutoxy carbonyl group, treatment with hydrogen chloride in a suitable solvent such as dioxane and at a suitable temperature such as room temperature.
  • Step (iv) typically comprises the process described above for the steps shown in Scheme 4.
  • P 5 , P 6 and P 7 represent suitable protecting groups, for example P 5 can be a C 1-6 alkoxycarbonyl and P 6 and P 7 can be C 1 ⁇ alkyl (P 6 and P 7 need not be the same).
  • L 1 is a suitable leaving group such as halogen (e.g. chlorine or bromine).
  • Step (i) typically comprises treatment of (17) with a suitable base, such as potassium hexamethyldisilazide, and an alkylating agent such as an alkyl halide in a suitable solvent such as tetrahydrofuran at a suitable temperature such as between -78°C and room temperature.
  • a suitable base such as potassium hexamethyldisilazide
  • an alkylating agent such as an alkyl halide
  • a suitable solvent such as tetrahydrofuran
  • Step (N) typically comprises a standard procedure for conversion of a carboxylic ester to an acid, such as treatment with a suitable acid (e.g. trifluoroacetic acid) in an appropriate solvent such as dichloromethane at a suitable temperature such as room temperature.
  • a suitable acid e.g. trifluoroacetic acid
  • dichloromethane e.g. dichloromethane
  • P 8 , P 9 and P 10 represent suitable protecting groups such as Ci -6 alkyl in the cases of P 8 and P 9 (P 8 and P 9 need not be the same) and a group derived from a suitable acyclic or cyclic ketone in the case of P 10 .
  • Step (i) typically comprises treatment of (19) with a suitable ketone, such as (1 R,2R,5f?)-2-hydroxypinan-3-one, and a lewis acid such as boron trifluoride etherate in a suitable solvent such as toluene at a suitable temperature such as 1 10 0 C.
  • a suitable ketone such as (1 R,2R,5f?)-2-hydroxypinan-3-one
  • a lewis acid such as boron trifluoride etherate
  • a suitable solvent such as toluene
  • Step (ii) typically comprises treatment of (20) with a Grignard reagent, such as methyl magnesium bromide, and a base, such as 1 ,8-diazabicyclo[5.4.0]undec-7-ene, followed by treatment with an unsaturated ester (21 ), such as ethyl crotonate in a suitable solvent such as tetrahydrofuran at a suitable temperature such as -3O 0 C.
  • a Grignard reagent such as methyl magnesium bromide
  • a base such as 1 ,8-diazabicyclo[5.4.0]undec-7-ene
  • Step (iii) typically comprises a standard procedure for conversion of an imine to an amine, such as treatment with a suitable acid (e.g. 15% aqueous citric acid) in an appropriate solvent such as tetrahydrofuran at a suitable temperature such as room temperature.
  • a suitable acid e.g. 15% aqueous citric acid
  • an appropriate solvent such as tetrahydrofuran
  • Step (iv) typically comprises heating (23) in a suitable solvent, such as toluene, at a suitable temperature such as between room temperature and 12O 0 C.
  • a suitable solvent such as toluene
  • Step (v) typically comprises the process described above for the steps shown in Scheme 4.
  • Step (i) typically comprises treatment of (25) with a base such as sodium hydride and an alkylating agent such as an alkyl halide in a suitable solvent such as dimethylformamide at a suitable temperature such as between 0 0 C and room temperature.
  • Step (ii) typically comprises treatment of (26) with a base such as lithium diisopropylamide and an alkylating agent such as an alkyl halide in a suitable solvent such as tetrahydrofuran at a suitable temperature such as between -78°C and room temperature.
  • a base such as lithium diisopropylamide
  • an alkylating agent such as an alkyl halide
  • a suitable solvent such as tetrahydrofuran
  • Step (iii) typically comprises treatment of (27) with a base such as lithium diisopropylamide and an alkylating agent such as an alkyl halide in a suitable solvent such as tetrahydrofuran at a suitable temperature such as between -78°C and room temperature.
  • a base such as lithium diisopropylamide and an alkylating agent such as an alkyl halide
  • a suitable solvent such as tetrahydrofuran
  • Step (iv) typically comprises a standard procedure for deprotecting an alcohol.
  • P 11 is a trityl group
  • Step (v) typically comprises a standard protocol for oxidation of an alcohol to the corresponding carboxylic acid such as treatment of the alcohol (29) with an oxidising agent such as a combination of sodium chlorite, TEMPO (2,2,6,6-tetramethyl-1- piperidinyloxy free radical) and bleach (sodium hypochlorite solution) in a suitable solvent such as a mixture of aqueous sodium phosphate monobasic buffer solution and acetonitrile at a suitable temperature such as 40 0 C.
  • an oxidising agent such as a combination of sodium chlorite, TEMPO (2,2,6,6-tetramethyl-1- piperidinyloxy free radical) and bleach (sodium hypochlorite solution) in a suitable solvent such as a mixture of aqueous sodium phosphate monobasic buffer solution and acetonitrile at a suitable temperature such as 40 0 C.
  • (21 ) and (25) are typically either available from commercial sources or can be prepared by a person skilled in the art using methods described in the chemical literature (or using analogous methods).
  • compositions may be prepared conventionally by reaction with the appropriate acid or acid derivative.
  • the compounds of formula (I) or the pharmaceutically acceptable salts thereof within the combinations of the present invention modulate P2X7 receptor function and are capable of antagonizing the effects of ATP at the P2X7 receptor, they may be useful in the treatment of pain, including acute pain, chronic pain, chronic articular pain, musculoskeletal pain, neuropathic pain, inflammatory pain, visceral pain, pain associated with cancer, pain associated with migraine, tension headache and cluster headaches, pain associated with functional bowel disorders, lower back and neck pain, pain associated with sprains and strains, sympathetically maintained pain; myositis, pain associated with influenza or other viral infections such as the common cold, pain associated with rheumatic fever, pain associated with myocardial ischemia, post operative pain, cancer chemotherapy, headache, toothache and dysmenorrhea.
  • pain including acute pain, chronic pain, chronic articular pain, musculoskeletal pain, neuropathic pain, inflammatory pain, visceral pain, pain associated with cancer, pain associated with migraine, tension
  • the chronic articular pain condition can be rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis (ankylosing spondylitis), gouty arthritis or juvenile arthritis.
  • the inflammatory pain condition can be rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis (ankylosing spondylitis) or fibromyalgia.
  • the compounds of formula (I) or pharmaceutically acceptable salts thereof, and/or the combinations of the present invention may be useful in the treatment or prevention of pain (e.g. inflammatory pain) in arthritis, such as pain (e.g. inflammatory pain) in rheumatoid arthritis or osteoarthritis.
  • pain e.g. inflammatory pain
  • arthritis such as pain (e.g. inflammatory pain) in rheumatoid arthritis or osteoarthritis.
  • Pain associated with functional bowel disorders includes non-ulcer dyspepsia, non- cardiac chest pain and irritable bowel syndrome.
  • the neuropathic pain condition can be: diabetic neuropathy (e.g. painful diabetic neuropathy), sciatica, non-specific lower back pain, trigeminal neuralgia, multiple sclerosis pain, fibromyalgia, HIV-related neuropathy, post-herpetic neuralgia, trigeminal neuralgia, or lumbar radiculopathy; or pain resulting from physical trauma, amputation, phantom limb syndrome, spinal surgery, cancer, toxins or chronic inflammatory conditions.
  • diabetic neuropathy e.g. painful diabetic neuropathy
  • sciatica non-specific lower back pain
  • trigeminal neuralgia multiple sclerosis pain
  • fibromyalgia HIV-related neuropathy
  • post-herpetic neuralgia trigeminal neuralgia
  • lumbar radiculopathy or pain resulting from physical trauma, amputation, phantom limb syndrome, spinal surgery, cancer, toxins or chronic inflammatory conditions.
  • the neuropathic pain can be: pain associated with normally non-painful sensations such as "pins and needles" (paraesthesias and dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static, thermal or cold allodynia), increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia), or an absence of or deficit in selective sensory pathways (hypoalgesia).
  • normally non-painful sensations such as "pins and needles” (paraesthesias and dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static, thermal or cold allodynia), increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia), or an absence of or deficit in selective sensory pathways (hypoalgesia).
  • the acute pain condition can be post-surgical pain or dysmenorrhea (e.g. primary dysmenorrhea).
  • dysmenorrhea e.g. primary dysmenorrhea
  • ⁇ conditions which could potentially be treated by the combinations of the present invention include fever, inflammation, immunological diseases, abnormal platelet function diseases (e.g. occlusive vascular diseases), impotence or erectile dysfunction; bone disease characterised by abnormal bone metabolism or resorbtion; hemodynamic side effects of non-steroidal anti-inflammatory drugs (NSAI D's) such as cyclooxygenase-2 (COX-2) inhibitors, cardiovascular diseases; neurodegenerative diseases and neurodegeneration, neurodegeneration following trauma, tinnitus, dependence on a dependence-inducing agent such as opioids (e.g. morphine), CNS (central nervous system) depressants (e.g. ethanol), psychostimulants (e.g.
  • opioids e.g. morphine
  • CNS central nervous system
  • psychostimulants e.g.
  • Type I diabetes e.g. hepatitis, cirrhosis
  • gastrointestinal dysfunction e.g. diarrhoea
  • colon cancer e.g. overactive bladder and urge incontinence.
  • Depression and alcoholism could potentially also be treated by the combinations of the present invention.
  • Inflammation and the inflammatory conditions associated with said inflammation include arthritis (in particular rheumatoid arthritis or osteoarthritis), skin conditions
  • ophthalmic diseases such as glaucoma, retinitis, retinopathies, uveitis and of acute injury to the eye tissue (e.g. conjunctivitis), inflammatory lung disorders (e.g. asthma, allergic rhinitis, respiratory distress syndrome, pigeon fancier's disease, farmer's lung, chronic obstructive pulmonary disease (COPD, which includes bronchitis and/or emphysema), or airways hyperresponsiveness); gastrointestinal tract disorders (e.g.
  • organ transplantation and other conditions with an inflammatory component such as vascular disease, migraine, periarteritis nodosa, thyroiditis, aplastic anaemia, Hodgkin's disease, sclerodoma, myaesthenia gravis, multiple sclerosis, sorcoidosis, nephrotic syndrome, Bechet's syndrome, gingivitis, myocardial ischemia, pyrexia, systemic lupus erythematosus, polymyositis, tendinitis, bursitis, and Sjogren's syndrome.
  • Inflammation or an inflammatory condition associated with said inflammation can in particular be arthritis (e.g. rheumatoid arthritis or osteoarthritis).
  • Immunological diseases include autoimmune diseases, immunological deficiency diseases or organ transplantation.
  • Bone diseases characterised by abnormal bone metabolism or resorbtion include osteoporosis (especially postmenopausal osteoporosis), hyper-calcemia, hyperparathyroidism, Paget's bone diseases, osteolysis, hypercalcemia of malignancy with or without bone metastases, rheumatoid arthritis, periodontitis, osteoarthritis, ostealgia, osteopenia, cancer cacchexia, calculosis, lithiasis (especially urolithiasis), solid carcinoma, gout and ankylosing spondylitis, tendinitis and bursitis.
  • osteoporosis especially postmenopausal osteoporosis
  • hyper-calcemia especially hyperparathyroidism
  • Paget's bone diseases osteolysis
  • hypercalcemia of malignancy with or without bone metastases rheumatoid arthritis
  • periodontitis osteoarthritis
  • osteoarthritis ostealgia
  • osteopenia cancer ca
  • Cardiovascular diseases include hypertension or myocardiac ischemia; atherosclerosis; functional or organic venous insufficiency; varicose therapy; haemorrhoids; and shock states associated with a marked drop in arterial pressure (e.g. septic shock).
  • Neurodegenerative diseases include dementia, particularly degenerative dementia (such as senile dementia, dementia with Lewy bodies, Alzheimer's disease, Pick's disease, Huntingdon's chorea, Parkinson's disease and Creutzfeldt-Jakob disease, ALS, or motor neuron disease; in particular Alzheimer's disease); vascular dementia (including multi-infarct dementia); as well as dementia associated with intracranial space occupying lesions; trauma; infections and related conditions (including HIV infection, meningitis and shingles); metabolism; toxins; anoxia and vitamin deficiency; and mild cognitive impairment e.g. associated with ageing, particularly age associated memory impairment.
  • degenerative dementia such as senile dementia, dementia with Lewy bodies, Alzheimer's disease, Pick's disease, Huntingdon's chorea, Parkinson's disease and Creutzfeldt-Jakob disease, ALS, or motor neuron disease; in particular Alzheimer's disease
  • vascular dementia including multi-infarct dementia
  • the neurodegenerative disease e.g. to be treated by the compound of formula (I) or salt thereof or by the combination, can for example be degenerative dementia (in particular Alzheimer's disease), vascular dementia (in particular multi-infarct dementia), or mild cognitive impairment (MCI) e.g. MCI associated with ageing such as age associated memory impairment.
  • degenerative dementia in particular Alzheimer's disease
  • vascular dementia in particular multi-infarct dementia
  • MCI mild cognitive impairment
  • the combinations of the present invention may also be useful as neuroprotectants and in the treatment of neurodegeneration following trauma such as stroke, cardiac arrest, pulmonary bypass, traumatic brain injury, spinal cord injury or the like.
  • the combinations of the present invention may also be useful in the treatment of malignant cell growth and/or metastasis, and myoblastic leukaemia.
  • Type 1 diabetes Complications of Type 1 diabetes include diabetic microangiopathy, diabetic retinopathy, diabetic nephropathy, macular degeneration, glaucoma, nephrotic syndrome, aplastic anaemia, uveitis, Kawasaki disease and sarcoidosis.
  • Kidney dysfunction includes nephritis, glomerulonephritis, particularly mesangial proliferative glomerulonephritis and nephritic syndrome.
  • a combination as defined herein for use in the treatment or prevention (e.g. treatment) of a condition which is mediated by P2X7 receptors can be for use in the treatment or prevention (e.g. treatment) of pain, inflammation (e.g. rheumatoid arthritis or osteoarthritis) or a neurodegenerative disease, in particular for use in the treatment of inflammatory pain, neuropathic pain, visceral pain, rheumatoid arthritis or osteoarthritis; e.g. in a mammal such as a human.
  • a method of treating a human or animal (e.g. rodent e.g. rat) subject for example a human subject, suffering from a condition which is mediated by P2X7 receptors, for example a condition or disease disclosed herein (in particular pain, inflammation, rheumatoid arthritis, osteoarthritis or a neurodegenerative disease, more particularly pain such as inflammatory pain, neuropathic pain or visceral pain), which comprises administering to said subject an effective amount of a combination as defined herein.
  • a condition which is mediated by P2X7 receptors for example a condition or disease disclosed herein (in particular pain, inflammation, rheumatoid arthritis, osteoarthritis or a neurodegenerative disease, more particularly pain such as inflammatory pain, neuropathic pain or visceral pain)
  • a condition or disease disclosed herein in particular pain, inflammation, rheumatoid arthritis, osteoarthritis or a neurodegenerative disease, more particularly pain such as inflammatory pain, neuropathic
  • a method of treating a human or animal subject suffering from pain, inflammation e.g. rheumatoid arthritis or osteoarthritis
  • a neurodegenerative disease more particularly rheumatoid arthritis or osteoarthritis, and/or pain such as inflammatory pain, neuropathic pain or visceral pain
  • administering comprises administering to said subject an effective amount of a combination as defined herein.
  • a method of treating a human or animal (e.g. rodent e.g. rat) subject for example a human subject, suffering from inflammatory pain, neuropathic pain or visceral pain (e.g. pain, such as inflammatory pain, in arthritis (e.g. rheumatoid arthritis or osteoarthritis)), which method comprises administering to said subject an effective amount of a combination as defined herein.
  • rodent e.g. rat
  • visceral pain e.g. pain, such as inflammatory pain, in arthritis (e.g. rheumatoid arthritis or osteoarthritis)
  • a method of treating a subject for example a human subject, suffering from Alzheimer's disease which method comprises administering to said subject an effective amount of a combination as defined herein.
  • a combination as defined herein for the manufacture of a medicament for the treatment or prevention (e.g. treatment) of a condition which is mediated by the action of P2X7 receptors, for example a condition or disease disclosed herein, e.g. in a mammal such as a human or rodent e.g. human or rat e.g. human.
  • a combination as defined herein for the manufacture of a medicament for the treatment or prevention (e.g. treatment) of pain (e.g. inflammatory pain, neuropathic pain or visceral pain), inflammation (e.g. rheumatoid arthritis or osteoarthritis), or a neurodegenerative disease; e.g. in a mammal such as a human or rodent e.g. human or rat e.g. human.
  • pain e.g. inflammatory pain, neuropathic pain or visceral pain
  • inflammation e.g. rheumatoid arthritis or osteoarthritis
  • a neurodegenerative disease e.g. in a mammal such as a human or rodent e.g. human or rat e.g. human.
  • a combination as defined herein for the manufacture of a medicament for the treatment or prevention (e.g. treatment) of inflammatory pain, neuropathic pain or visceral pain (in particular inflammatory pain or neuropathic pain; such as inflammatory pain in arthritis such as rheumatoid arthritis or osteoarthritis); e.g. in a mammal such as a human or rodent e.g. human or rat e.g. human.
  • a combination as defined herein for the manufacture of a medicament for the treatment or prevention (e.g. treatment) of Alzheimer's disease; e.g. in a mammal such as a human or rodent e.g. human or rat e.g. human.
  • a combination as defined herein for the treatment of humans and/or other mammals it can optionally be formulated in accordance with pharmaceutical practice as a pharmaceutical composition. Therefore in another aspect of the invention there is provided a pharmaceutical composition comprising a combination as defined herein, adapted for use in human or veterinary medicine.
  • a combination as defined herein in therapy it can optionally be formulated into a pharmaceutical composition in accordance with pharmaceutical practice.
  • the present invention also provides a pharmaceutical composition, which comprises a combination as defined herein, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising the combination of the invention, and/or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier (but not comprising the further therapeutic agent(s)), which may be prepared by admixture, e.g. at ambient temperature and/or at atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of a tablet, a capsule, an oral liquid preparation, a powder, a granule, a lozenge, a reconstitutable powder, an injectable or infusable solution or suspension, or a suppository.
  • An orally administrable pharmaceutical composition comprising the combination of the invention, and/or an orally administrable pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier (but not comprising the further therapeutic agent(s)), are generally preferred.
  • Tablets and capsules for oral administration may be in unit dose form, and may contain one or more excipients, such as a binding agent (e.g. hydroxypropylmethylcellulose or povidone), a filler(s) (e.g. lactose monohydrate, anhydrous lactose, and/or microcrystalline cellulose), a lubricant e.g. tabletting lubricant (e.g. magnesium stearate or calcium stearate), a disintegrant (e.g. croscarmellose sodium), and/or an acceptable wetting agent.
  • a binding agent e.g. hydroxypropylmethylcellulose or povidone
  • a filler(s) e.g. lactose monohydrate, anhydrous lactose, and/or microcrystalline cellulose
  • a lubricant e.g. tabletting lubricant (e.g. magnesium stearate or calcium stearate)
  • a disintegrant e.g. cros
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain additive(s) such as suspending agent(s), emulsifying agent(s), non-aqueous vehicle(s) such as edible oil(s), preservative(s), and/or, if desired, flavouring(s) or colourant(s).
  • fluid unit dosage forms are typically prepared utilising a compound or salt within the combination of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle.
  • the compound or salt within the combination can e.g. be either suspended or dissolved in the vehicle.
  • the compound or salt within the combination can e.g. be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • an adjuvant(s) such as a local anaesthetic, a preservative(s) and/or a buffering agent(s) are dissolved in the vehicle.
  • the composition can e.g.
  • Parenteral suspensions are typically prepared in substantially the same manner, except that the compound or salt within the combination is suspended in the vehicle instead of being dissolved, and sterilization is not usually accomplished by filtration.
  • the compound or salt within the combination can be sterilised, e.g. by exposure to ethylene oxide, before suspension in a sterile vehicle.
  • a surfactant or wetting agent is included in the composition, e.g. to facilitate uniform distribution of the compound or salt.
  • the composition contains from 0.1% to 99% (by weight of the composition), in particular from 0.1 to 60% or from 1 to 60% or from 10 to 60% by weight, of the active material (e.g. the compound of formula (I) or pharmaceutically acceptable salt of the invention), e.g. depending on the method of administration.
  • the carrier(s) and/or excipient(s) contained in the composition can for example be present in from 1% to 99.9%, e.g. from 10% to 99%, by weight of the composition.
  • the dose of the compound of formula (I) or the pharmaceutically acceptable salt thereof (e.g. of /V- ⁇ [2-chloro-3-(trifluoromethyl)phenyl]methyl ⁇ -1-methyl-5-oxo-/.- prolinamide) within the combination, e.g. as used in the treatment of the aforementioned disorders, may vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors.
  • suitable unit doses e.g.
  • orally-administrable unit doses may be 0.05 to 2000 mg or 0.05 to 1000 mg, for example 0.05 to 200 mg, or may be for example 0.3 to 2000 mg or 10 to 2000 mg or 10 to 1000 mg or 20 to 1000 mg such as 20 to 40 mg, of the compound of formula (I) or the pharmaceutically acceptable salt thereof (e.g. of /V- ⁇ [2-chloro-3-(trifluoromethyl)phenyl]methyl ⁇ -1 -methyl-5-oxo-/--prolinamide).
  • such unit doses are typically administered once a day, or more than once a day (e.g. twice a day); e.g. orally and/or e.g. to a human.
  • Such therapy may for example extend for a number of days, weeks, months or years.
  • ⁇ /- ⁇ [2-Chloro-3-(trifluoromethyl)phenyl]methyl ⁇ -1-methyl-5-oxo-L- prolinamide can for example be administered to a human at an oral dosage regimen of 0.3 mg to 2000 mg once or twice per day, e.g. 10 mg to 2000 mg once or twice per day, e.g. 10 mg to 1000 mg once or twice per day or 20 mg to 1000 mg once or twice per day.
  • the treatment may for example extend for a number of days, weeks, months or years.
  • 5-Oxo-i -(phenylmethyl)-proline (0.176 g, 0.80 mmol, prepared as described below) was dissolved in dichloromethane (3 ml) and to this was added 1- hydroxybenzotriazole (0.119 g, 0.88 mmol), triethylamine (0.1 13 ml, 0.81 mmol), [(2- chloro-4-fluorophenyl)methyl]amine (0.134 g, 0.84 mmol) and N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.169 g, 0.88 mmol) under an atmosphere of argon. The mixture was stirred at room temperature overnight.
  • Methyl 5-oxo-1-(phenylmethyl)-prolinate (0.212 g, 0.91 mmol) was dissolved in water (3 ml) and methanol (0.5 ml) and treated with 2M aqueous sodium hydroxide (0.682 ml, 1.36 mmol). The mixture was stirred overnight at room temperature and then washed with dichloromethane. The aqueous layer was evaporated and the residue treated with an excess of 1 M hydrogen chloride in ether ( ⁇ 5 ml). The mixture was evaporated once more and the residue was triturated with dichloromethane.
  • 1-(1-Methylethyl)-5-oxo-proline (0.060 g, 0.35 mmol, prepared as described below) was dissolved in dichloromethane (3 ml) and dimethylformamide (1 ml) and to this was added 1-hydroxybenzotriazole (0.052 g, 0.39 mmol), [(2-chloro-4- fluorophenyl)methyl]amine (0.061 g, 0.39 mmol) and N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (0.074 g, 0.39 mmol) under an atmosphere of argon. The mixture was stirred at room temperature overnight.
  • the 1-(1-methylethyl)-5-oxo-proline used in the above procedure was prepared as follows: (i) Dimethyl L-glutamate hydrochloride (0.500 g, 2.37 mmol) was dissolved in methanol (4 ml) and tetrahydrofuran (8 ml)and the mixture was then treated with crushed sodium hydroxide (0.099 g, 2.49 mmol) for 10 minutes. At this stage acetic acid (0.136 ml, 2.37 mmol) and acetone (0.261 ml, 3.55 mmol) were added together to the mixture as a solution in tetrahydrofuran (1 ml).
  • Methyl 1-ethyl-5-oxo-prolinate (0.135 g, 0.79 mmol, prepared as described below) was dissolved in methanol (4 ml) and treated with 2M aqueous sodium hydroxide (0.592 ml, 1.18 mmol). The mixture was stirred for ⁇ 4 hrs at room temperature and then evaporated to give a residue which was then treated with an excess of 1 M hydrogen chloride in ether ( ⁇ 5 ml) for 10 minutes. The mixture was evaporated once more and the residue was dissolved in dichloromethane (4 ml) and dimethylformamide (2 ml) and filtered to remove solids.
  • 5-0X0-1 -phenyl-proline (0.047 g, 0.23 mmol, prepared as described below) was dissolved in dichloromethane ( ⁇ 2 ml) and dimethylformamide (1 ml) and to this was added 1-hydroxybenzotriazole (0.034 g, 0.25 mmol), [(2-chloro-4- fluorophenyl)methyl]amine (0.040 g, 0.25 mmol), N-ethyl morpholine (0.032 ml, 0.25 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.048 g, 0.25 mmol). The mixture was stirred at room temperature for 4.5 hrs.
  • the 5-OXO-1 -phenyl-proline used in the above procedure was prepared as follows: (i) Methyl 5-oxo-L-prolinate (0.204 ml, 1.75 mmol) was dissolved in toluene (5 ml) and treated with tris(dibenzylideneacetone)dipalladium (0) (0.024 g, 0.03 mmol), bromobenzene (0.184 ml, 1.75 mmol), cesium carbonate (0.795 g, 2.45 mmol) and XantphosTM (0.040 g, 0.07 mmol). The resulting mixture was heated at 120 0 C for -18 hrs and then allowed to cool to room temperature.
  • Methyl 5-oxo-1 -phenylprolinate (0.054 g, 0.25 mmol) was combined with 2M aqueous sodium hydroxide (0.160 ml, 0.32 mmol) in methanol (1 ml) and stirred overnight at room temperature. The solvent was then evaporated and the residue taken up in ethyl acetate and washed with 2M aqueous hydrogen chloride. The aqueous layer was separated and washed twice more with ethyl acetate and then the combined ethyl acetate layers were dried using a phase separator and evaporated to give 5-OXO-1 -phenyl-proline (0.047 g) as a clear oil.
  • the mixture was stirred at room temperature (20 0 C) under argon for 3 hrs and then overnight.
  • the mixture was diluted with more dichloromethane (25 ml) and washed sequentially with 2M aqueous hydrogen chloride (20 ml), saturated aqueous sodium hydrogen carbonate (20 ml), 10% aqueous sodium carbonate (20 ml) and brine (20 ml).
  • the organic layer was filtered through a hydrophobic frit and then evaporated to give the crude product.
  • the 1 -methyl-5-oxo-proline used in the above procedure was prepared as follows: (i) /V-methyl-L-glutamic acid (0.500 g, 3.1 mmol) was dissolved in water (1 ml) and heated in a sealed tube at 14O 0 C for 30 minutes in a microwave reactor. The water was then evaporated and the residue triturated with ether to give, after drying, 1 - methyl-5-oxo-proline (0.298 g) as a white solid.
  • ⁇ /-[(2,4-dichlorophenyl)methyl]-1-methyl-5-oxo-prolinamide can also be prepared as described below:
  • the organic layer was dried by passing through a hydrophobic frit and then concentrated under vacuum to give 65g of pink solids.
  • the solids had formed large lumps so the crude material was ground up in a pestle and mortar. These were then triturated with diethyl ether (400ml) and the solids filtered off and washed with further Et 2 O (2 x 200ml). Drying then gave 52.96g of pale pink solids.
  • This material was combined with 2 further batches, prepared in the same way, (141.42g total) and then suspended in ethanol (430ml) and water (715ml) and gradually warmed to 65°C (temperature of solution). The mixture gave an almost clear solution (deep pink), except for a very fine solid suspension.
  • Enantiomeric excess 99.5%, as determined by chiral chromatography method A, indicative of ⁇ /-[(2,4-dichlorophenyl)methyl]-1-methyl-5-oxo-L-prolinamide
  • the 1 -methyl-5-oxo-proline used in the above procedure was prepared as follows: (i) (7-J-pyroglutamic acid methyl ester (1 g, 6.99 mmol) was dissolved/mixed with tetrahydrofuran (10 ml) and cooled to 0 0 C using an ice-bath. Sodium hydride (0.201 g of a 60% suspension in oil, 8.38 mmol) was added to the mixture. After bubbling stopped, methyl iodide (0.522 ml, 8.38 mmol) was added and the mixture was allowed to warm to room temperature and then stirred for 1 hr. The solvent was evaporated and water was added (1 ml).
  • 1-Ethyl-5-oxo-proline (0.050 g, 0.32 mmol) was dissolved in anhydrous dichloromethane ( ⁇ 7 ml) and dimethylformamide (1 ml) and to this was added 1- hydroxybenzotriazole (0.052 g, 0.38 mmol), [(2,3,4-trifluorophenyl)methyl]amine (0.103 g, 0.64 mmol), N-ethyl morpholine (0.151 ml, 0.95 mmol) and N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.073 g, 0.38 mmol). The mixture was shaken at room temperature over the weekend.
  • 1 -ethyl-5-oxo-proline may be prepared as follows (Method B):
  • This material was purified by automated silica flash-column chromatography (Biotage SP4), eluting with a 15- 100% gradient of ethyl acetate in hexane, to give 1 ,1-dimethylethyl 1 -ethyl-5-oxo- prolinate.
  • 1 -ethyl-5-oxo-proline may be prepared as follows (Method C): (i) 1 -(1 ,1 -Dimethylethyl) 5-methyl-L-glutamate hydrochloride (5.0 g, 19.71 mmol) was dissolved in a mixture of methanol (30 ml) and tetrahydrofuran (60 ml) and the mixture was then treated with crushed, powdered sodium hydroxide (0.828 g, 20.69 mmol) under argon at room temperature.
  • the enantiomeric excess (e.e.) of the isomer shown is also listed along with its stereospecific name, the chiral separation method used in parantheses and the corresponding retention time (r.t.) in that method.
  • the mixture was allowed to warm to -10 0 C and then water (500 ml) was added to quench the reaction.
  • the mixture was diluted with diethyl ether (250 ml) and the two resulting layers were separated.
  • the aqueous layer was acidified to pH1 using concentrated aqueous hydrogen chloride and then extracted with 2 x 500 ml aliquots of diethyl ether.
  • the combined organic extracts were passed through a hydrophobic frit and reduced in vacuo to give a yellow solid.
  • Methyl-5-oxo-4-(phenylmethyl)-prolinate (0.205 g, 0.88 mmol) was dissolved in tetrahydrofuran (2.5 ml) and treated with ethyl iodide (0.077 ml, 0.97 mmol). The mixture was then cooled to 0 0 C and treated with sodium hydride (0.037 g of a 60% suspension in oil, 0.92 mmol). After stirring at O 0 C for 10-15 minutes the solution was warmed to room temperature and stirred for a further 3.5 hrs. The mixture was then treated with saturated aqueous ammonium chloride solution ( ⁇ 2 ml) and subsequently diluted with dichloromethane (5 ml).
  • the mixture was quenched with saturated aqueous ammonium chloride and then extracted with ethyl acetate (x3).
  • the combined organic extracts were then washed with water and then with saturated aqueous sodium chloride solution (x2), dried over anhydrous magnesium sulphate, and concentrated to a crude oil (1 .27 g).
  • the crude solid was purified by automated flash silica-gel column chromatography (Biotage SP4), eluting with a 0-100% gradient of ethyl acetate in hexane, to give the desired product (i.e.
  • the resin was filtered off, washing with more methanol, and the filtrate was concentrated to a gum (0.625 g).
  • the gum was purified by automated flash silica-gel column chromatography (Biotage SP4), eluting with a 0-100% gradient of ethyl acetate in hexane, to give 1-ethyl-5- (hydroxymethyl)-3-(phenylmethyl)-2-pyrrolidinone (0.170 g) which was used in the next step.
  • the mixture was then treated with saturated aqueous sodium hydrogen carbonate (20 ml) and stirred vigorously.
  • the aqueous layer was removed using a phase separator and then the solvent was removed from the organic layer using an argon blow-down unit.
  • the resulting residue was treated with a mixture of water and ethylacetate (25 ml, 1 :1 ) and the aqueous layer was subsequently discarded.
  • the organic layer was filtered through a phase separator and evaporated to give an oil.
  • the 1-(1-Methylethyl)-5-oxoproline used in the above procedure was prepared in an analogous manner to that described previously for the synthesis of methyl 1-ethyl-5- oxo-prolinate (see example 3) but using acetone in the place of acetaldehyde and with the addition of a subsequent ester deprotection step (using standard conditions, i.e. sodium hydroxide in methanol) being carried out (as opposed to the combined deprotection and amide coupling described in example 3).
  • 1-ethyl-5-oxoproline (0.080 g, 0.51 mmol, prepared in an analogous manner to that described for example 12, method A) was dissolved in dichloromethane (5 ml) and to this was added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.1 17 g, 0.61 mmol), N-ethyl morpholine (0.195 ml, 1 .53 mmol), and 2,3-dimethyl benzylamine (0.082 g, 0.61 mmol). The mixture was stirred for -17 hrs and then left to stand over the weekend.
  • the 1-methyl-5-oxoproline used as the starting material was prepared in the following manner:
  • /V- ⁇ [2-chloro-3-(thfluoromethyl)phenyl]methyl ⁇ -1 -methyl-5-oxoprolinamide may also be prepared as described below:
  • 1-Methyl-5-oxoproline 49.0 g, 0.342 mol, prepared as described above
  • DCM 600ml
  • EEDQ 2-ethoxy-1-ethoxycarbonyl-1 ,2-dihydroquinoline, 75.26 g, 0.359 mol, 1.05eq
  • 1-methyl-5-oxoproline (0.060 g, 0.42 mmol, prepared as described above for example 51 ) was dissolved in dichloromethane (5 ml) and to this was added N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.096 g, 0.5 mmol), 1- hydroxybenzotriazole (0.068 g, 0.5 mmol), and N-ethyl morpholine (0.160 ml, 1.26 mmol).
  • example 62-64 The amines required for the synthesis of example 62-64 were prepared according to the procedures described, respectively, below:
  • Aqueous sodium hydroxide solution was added until the pH of the mixture was between 8-9 and then the mixture was extracted with ethyl acetate (3 x 30 ml). The combined organic layers were filtered through a hydrophobic frit and then evaporated under vacuum. The residue was redissolved in dichloromethane, filtered through a hydrophobic frit and evaporated to give a yellow oil. The oil was dissolved in 2M aqueous hydrogen chloride. A white precipitate formed and this was collected by vacuum filtration and then loaded equally onto 4 x 10 g SCX columns. The columns were flushed with methanol and water and then aqueous ammonia was used to wash off the product. These latter fractions were reduced under vacuum to give a yellow oil (0.4 g).
  • Table 5 The examples tabulated below (Table 5) were prepared in a manner analogous to that described for Example 12 by substituting the appropriate amine (or salt thereof) for the [(2,3,4-trifluorophenyl)methyl]amine used in the procedure described for example 12. All of the amines used ito make the compounds shown in Table 5 are available from commercial sources or can be prepared using routes described previously in the chemical literature unless stated otherwise.
  • the 1 -ethyl-5-oxo- proline used to prepare these examples was in turn prepared using method C as described for example 12 apart from in the case of example 65 where method A was used.
  • 1-ethyl-5-oxoproline (0.100 g, 0.64 mmol) was dissolved in a mixture of dichloromethane (3 ml) and dimethylformamide (0.5 ml) and to this was added N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.147 g, 0.77 mmol), 1- hydroxybenzotriazole (0.104 g, 0.77 mmol), and N-ethyl morpholine (0.244 ml, 1.92 mmol). The mixture was stirred for 10 minutes and then 2-chloro-4- fluorobenzylamine was added to the mixture and stirring continued overnight (-16 hrs) at room temperature.
  • Ethyl 1 -ethyl-5-oxoprolinate (1.33 g, 7.18 mmol) was dissolved in ethanol (10 ml) and cooled to 0 0 C in an ice bath. To this was added 12.5M aqueous sodium hydroxide solution (1.72 ml, 21.53 mmol) and the mixture was stirred for ⁇ 4 hours at 0 0 C. The ethanol was evaporated under vacuum and the aqueous residue was acidified with 2N aqueous hydrogen chloride to pH1. The volume of the aqueous phase was reduced to ⁇ 3 ml under vacuum and then extracted with a 3:1 mixture of chloroform and isopropanol using a phase separator. The combined organic layers were concentrated to a pale yellow oil which on drying in vacuo crystallized to give 1 - ethyl-5-oxoproline as a white solid (1.12 g).
  • ⁇ /- ⁇ [4-fluoro-2-(trifluoromethyl)phe ⁇ yl]methyl ⁇ -1-methyl-5-oxoprolinamide was prepared in a manner analogous to that described above for the synthesis of ⁇ /-[(2- chloro-4-fluorophenyl)methyl]-1 -ethyl-5-oxoprolinamide (Example 70) but 1-methyl-5- oxoproline (prepared as describe below) was substituted for 1-ethyl-5-oxoproline and ⁇ [4-fluoro-2-(trifluoromethyl)phenyl]methyl ⁇ amine was substituted for 2-chloro-4- fluorobenzylamine.
  • D-pyroglutamic acid ethyl ester (4.0 g, 25.5 mmol) was dissolved in tetrahydrofuran (25 ml) and cooled to 0 0 C .
  • Methyl iodide (1.66 ml, 26.7 mmol) was added and stirring continued for 10 minutes under argon at 0 0 C.
  • Sodium hydride (60% in oil, 1.6 g, 26.7 mmol) was then added portionwise (allowing each portion to react). After addition of all the sodium hydride the mixture was allowed to warm to room temperature and stirred overnight under argon. The mixture was then treated with saturated aqueous ammonium chloride solution (-15 ml) and stirred for 4 hrs.
  • Ethyl 1 -methyl-5-oxoprolinate (0.27 g, 1.58 mmol) was dissolved in ethanol (5 ml) and cooled to 0 0 C in an ice bath. To this was added 2M aqueous sodium hydroxide solution (3 ml) and the mixture was stirred for ⁇ 4 hours at 0 0 C. The ethanol was evaporated under vacuum and the aqueous residue was acidified with 2N aqueous hydrogen chloride to pH1. The volume of the aqueous phase was reduced to ⁇ 3 ml under vacuum and then extracted with a 3:1 mixture of chloroform and isopropanol using a phase separator. The combined organic layers were concentrated to give 1 - methyl-5-oxoproline which was used without further purification. Examples 84-90
  • Example 7 Furthermore, and also in a manner analogous to that described for Example 70 above the compounds tabulated below (Table 7) were prepared by substituting the appropriate amine (or salt thereof) for the 2-chloro-4-fluorobenzylamine used in Example 70. All of the amines used to make the compounds shown in Table 7 are available from commercial sources or can be prepared using routes described previously in the chemical literature unless stated otherwise.
  • 1-Methyl-5-oxoproline (prepared as describe above for example 81 ) was substituted for the 1-ethyl-5- oxoproline used in Example 70.
  • the enantiomeric excess (e.e.) of the isomer shown is also listed along with its stereospecific name, the chiral separation method used in parantheses and the corresponding retention time (r.t.) in that method.
  • 5-0X0-1 -phenyl-proline (0.072 g, 0.35 mmol, prepared as described below) was dissolved in dichloromethane ( ⁇ 2 ml) and dimethylformamide (0.5 ml) and to this was added N-(3-dimethylaminopropyl)-N'-ethylcarbodiirnide hydrochloride (0.081 g, 0.42 mmol), 1-hydroxybenzotriazole (0.057 g, 0.42 mmol), and N-ethyl morpholine (0.134 ml, 1.05 mmol).
  • the 5-OXO-1 -phenyl-proline used in the above procedure was prepared as follows: (i) D-pyroglutamic acid ethyl ester (0.200 g, 1.27 mmol) was dissolved in dioxane (5 ml) and treated with tris(dibenzylideneacetone)dipalladium (0) (0.058 g, 0.06 mmol), bromobenzene (0.351 ml, 1.53 mmol), cesium carbonate (0.621 g, 1.91 mmol) and XantphosTM (0.1 10 g, 0.19 mmol). The resulting mixture was heated at reflux overnight and then allowed to cool to room temperature. The mixture was diluted with methanol and filtered.
  • Methyl 5-oxo-1-phenylprolinate (0.078 g, 0.36 mmol) was combined with 2N aqueous sodium hydroxide (2 ml) in ethanol (2 ml) at 0 0 C. The mixture was stirred at between -10 0 C and 0°C for 5 hours. The solvent was then evaporated in vacuo and the residue was acidified to pH1 by the addition of 2M aqueous hydrogen chloride. To this was added dichloromethane and the mixture was passed through a phase separator.
  • 5-0X0-1 -(phenylmethyl)proline (0.100 g, 0.46 mmol, prepared as described below) was dissolved in a mixture of dichloromethane (2.5 ml) and dimethylformamide (0.5 ml) and to this were added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.105 g, 0.55 mmol), 1-hydroxybenzotriazole (0.074 g, 0.55 mmol), and N-ethyl morpholine (0.143 ml, 1.37 mmol).
  • D-glutamic acid (1 .47 g, 10 mmol) was dissolved in 2N aqueous sodium hydroxide (10 ml, 20 mmol) and stirred for 15 minutes. The mixture was then treated with a solution of benzaldehyde (1.1 ml, 10 mmol) in ethanol (3 ml) and stirred at room temperature for 30 minutes. The mixture was cooled to O 0 C and treated with sodium borohydride (0.030 g). The mixture was allowed to warm to room temperature with stirring over 4 hrs and then washed with diethyl ether (three times) before acidifying with concentrated hydrochloric acid to pH2.
  • i-Cyclopentyl-5-oxoproline (0.100 g, 0.51 mmol, prepared as described below) was dissolved in a mixture of dichloromethane (2.5 ml) and dimethylformamide (0.5 ml) and to this were added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.1 17 g, 0.61 mmol), 1-hydroxybenzotriazole (0.082 g, 0.61 mmol), and N-ethyl morpholine (0.2 ml, 1.52 mmol).
  • the ethanol was then evaporated under vacuum and the aqueous residue was acidified to pH1 by the addition of 2N aqueous hydrogen chloride.
  • the volume of resulting aqueous mixture was reduced under vacuum to ⁇ 3 ml and this was then extracted with a 3:1 mixture of chloroform and isopropanol respectively using a phase separator.
  • the aqueous layer was washed with more dichloromethane and then the combined organic fractions were evaporated to give crude 1 -cyclopentyl-5-oxoproline which was used in subsequent reactions without further purification.
  • the 1-(2,2-dimethylpropyl)-5-oxoproline used in the method described above was prepared as follows:
  • L-glutamic acid (1.47 g, 10 mmol) was dissolved in 2N aqueous sodium hydroxide (10 ml, 20 mmol) and treated with a solution of trimethylacetaldehyde (1 .09 ml, 10 mmol) in ethanol (5 ml) and then stirred at room temperature for 30 minutes. The mixture was cooled to O 0 C and treated with sodium borohydride (0.130 g). The mixture was allowed to warm to room temperature with stirring over 4 hrs and then acidified to neutral pH. Concentration in vacuo was followed by slurrying in ethanol and azeotroping three times with more ethanol. Finally the remaining material was suspended in ethanol (50 ml) and heated at reflux for 48 hrs.
  • ⁇ /- ⁇ [2-chloro-3-(trifluoromethyl)phenyl]methyl ⁇ -5-oxo-1-(phenylmethyl)-D-prolinamide was prepared in an analogous manner to that described for the synthesis of ⁇ /- ⁇ [2- chloro-3-(trifluoromethyl)phenyl]methyl ⁇ -1-(2,2-dimethylpropyl)-5-oxoprolinamide (example 100) above but using 5-oxo-1 -(phenylmethyl)proline in the place of 1-(2,2- dimethylpropyl)-5-oxoproline.
  • 5-OXO-1 -(phenylmethyl)proline was prepared in an analogous manner to that described above for the synthesis of 1-(2,2-dimethylpropyl)-5-oxoproline (example 100) but using benzaldehyde in the place of trimethylacetaldehyde.
  • N-[(2,4-dichlorophenyl)methyl]-1-methyl-5-oxoprolinamide was prepared in a manner analogous to that described above for the synthesis of ⁇ /- ⁇ [4-fluoro-2- (trifluoromethyl)phenyl]methyl ⁇ -1 -methyl-5-oxoprolinamide (Example 83) but [(2,4- dichlorophenyl)methyl]amine was substituted for ⁇ [4-fluoro-2-
  • Example 9 The examples tabulated below (Table 9) were prepared in a manner analogous to that described for Example 12 by substituting the appropriate amine (or salt thereof) for the [(2,3,4-trifluorophenyl)methyl]amine used in the procedure described for Example 12. All of the amines used to make the compounds shown in Table 9 are available from commercial sources or can be prepared using routes described previously in the chemical literature unless stated otherwise. The 1 -ethyl-5-oxo- proline used to prepare these examples was in turn prepared using method C as described for Example 12.
  • Example 1 10 1 -methyl- ⁇ /-(1-naphthalenylmethyl)-5-oxoprolinamide (E110)
  • 1-methyl-5-oxoproline (0.050 g, 0.35 mmol, prepared in a manner analogous to that described above for example 51 ), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.081 g, 0.42 mmol), 1-hydroxybenzotriazole (0.057 g, 0.42 mmol), N- ethyl morpholine (0.166 ml, 1 .05 mmol) and (i-naphthalenylmethyl)amine were combined in dichloromethane ( ⁇ 8 ml) and the mixture was stirred for -20 hrs at room temperature.
  • Example 1 1 1 ⁇ /- ⁇ [2-chloro-4-fluoro-3-(trifluoromethyl)phenyl]methyl ⁇ -1-methyl-5- oxoprolinamide (E111)
  • Ammonium hydroxide (4.15 ml, 75 mmol) was added slowly to a solution of 1- hydroxybenzotriazole (10 g, 74 mmol) in tetrahydrofuran (100 ml) at 0 0 C (ice-bath) and stirred for 2 hrs. Filtration and washing with tetrahydrofuran gave ammonium 1/-/-1 ,2,3-benzotriazol-1-olate (10.57 g) as a white solid.
  • Example 1 12 ⁇ /- ⁇ [2-chloro-3-(trifluoromethyl)phenyl]methyl ⁇ -1 -cyclobutyl-5- oxoprolinamide (E112)
  • i-Cyclobutyl-5-oxoproline (0.238 g, 0.82 mmol) was suspended in dichloromethane (3 ml) and to this was added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.188 g, 0.98 mmol), 1 -Hydroxybenzotriazole (0.132 g, 0.98 mmol), and N-ethyl morpholine (0.313 ml, 2.46 mmol). The mixture was stirred at room temperature for 30 minutes and then ⁇ [2-chloro-3-
  • the i-Cyclobutyl-5-oxoproline used in the above procedure was prepared in an analogous manner to that described previously for the synthesis of methyl 1-ethyl-5- oxo-prolinate (see example 3) but using cyclobutanone in the place of acetaldehyde and with the addition of a subsequent ester deprotection step (using standard conditions, i.e. sodium hydroxide in methanol) being carried out (as opposed to the combined deprotection and amide coupling described in example 3).
  • N- ⁇ [2-chloro-3-(trifluoromethyl)phenyl]methyl ⁇ -1 -(2,2-dimethylpropyl)-5- oxoprolinamide was prepared in an analogous manner to that described for example 100 but using 1-(2,2-dimethylpropyl)-5-oxoproline prepared as described below.
  • the 1-(2,2-dimethylpropyl)-5-oxoproline used in the method described above was prepared as follows: D-glutamic acid (2.21 g, 15 mmol) was dissolved in 2N aqueous sodium hydroxide (15 ml, 30 mmol), cooled to 0 0 C, and treated with a solution of trimethylacetaldehyde (1.63 ml, 15 mmol) in ethanol (3 ml) and then stirred at room temperature for 45 minutes. The mixture was again cooled to 0 0 C and treated portion-wise with sodium borohydride (0.189 g, 5 mmol).
  • D-glutamic acid (2.21 g, 15 mmol) was dissolved in 2N aqueous sodium hydroxide (15 ml, 30 mmol) at O 0 C and then treated with pyridine-2-carboxaldehyde (1.43 ml, 15 mmol). The mixture was stirred at room temperature for 45 minutes and then cooled to 0°C and treated with sodium borohydride (0.189 g, 5 mmol). The mixture was allowed to warm to room temperature with stirring over 4 hrs then after washing twice with diethyl ether it was acidified to pH5-6.
  • D-glutamic acid (2.21 g, 15 mmol) was dissolved in 2N aqueous sodium hydroxide (15 ml, 30 mmol) at 0°C and then treated with pyridine-3-carboxaldehyde (1.41 ml, 15 mmol) in ethanol (3 ml). The mixture was stirred at room temperature for 30 minutes and then cooled to 0 0 C and treated portion-wise with sodium borohydride (0.189 g, 5 mmol). The mixture was allowed to warm to room temperature with stirring over 4 hrs then after washing with diethyl ether it was acidified to pH5-6 using concentrated hydrochloric acid.
  • Oxygen was bubbled through the mixture for a further 5 minutes followed by argon for 10 minutes.
  • Dimethylsulphide (2.23 ml, 30.4 mmol) was then added to the mixture and the mixture was removed from the cooling bath and stirred for 2.5 hrs.
  • the 1 ,3-dimethyl-5-oxoproline used in the above procedure was prepared as follows: (i) (f?,f?,f?)-2-hydroxypinen-3-one (10.9 g, 64.8 rmmol) and glycine-t-butyl ester (13 g, 97.2 mmol) in anhydrous toluene (200 ml) was treated with boron trifluoride-diethyl etherate (0.460 g, 3.24 mmol) and then heated, under argon, for 6 hrs at reflux. The mixture was then cooled to room temperature and stirred overnight.
  • the impure material was further purified, again using automated flash silica-gel column chromatography (Biotage SP4), but eluting with a gradient of 0-25% ethyl acetate in hexane (0-15% over 10 column volumes and 15- 25% over 5 column volumes), to give a further crop of 1 ,1-dimethylethyl N- [(I R ⁇ R. ⁇ R ⁇ -hydroxy ⁇ e.e-trimethylbicyclo ⁇ .i .i lhept-S-ylidenet ⁇ lycinate (1.73 g).
  • Diazabicyclo[5.4.0]undec-7-ene (7.78 g, 51 .1 mmol) was then added and the mixture was stirred for an additional 20 minutes at -30 0 C. The mixture was then treated with ethyl crotonate and stirring continued for 1 hr. The mixture was quenched by addition of saturated aqueous ammonium chloride solution (35 ml) and then extracted with ethyl acetate (3 x 100 ml). The combined organic extracts were dried over sodium sulphate, filtered and evaporated to give a yellow oil.
  • This material was purified by automated flash silica-gel column chromatography (using a Biotage SP4), eluting with a gradient of 0-20% (over 5 column volumes) then 20-35% (over 14 column volumes) ethyl acetate in hexane, to give 1-(1 ,1-dimethylethyl) 5-ethyl N- [(1 R,2f?,5R)-2-hydroxy-2,6,6-trimethylbicyclo[3.1.1 ]hept-3-ylidene]-3-methylglutamate (4.2 g) which was used in the next step.
  • aqueous phase was then adjusted to pH ⁇ 7 using aqueous sodium hydrogen carbonate solution and then extracted with diethyl ether (3 x 100 ml). The organic fractions were combined, dried over sodium sulphate, filtered and evaporated to give 1 -(1 , 1 -dimethylethyl) 5-ethyl 3-methylglutamate (1.1 g) as a yellow oil which was used in the next step without further purification, (iv) 1-(1 ,1-Dimethylethyl) 5-ethyl 3-methylglutamate (1.1 g, 4.5 mmol) was left to stand, attached to a high vacuum line, overnight and then over a weekend.
  • the mixture was then cooled to 0 0 C and treated portion-wise with sodium hydride (60% in oil, 0.170 g, 4.36 mmol). The mixture ceased bubbling after 30 minutes at 0 0 C and was then allowed to warm to room temperature and stirred overnight. The mixture was quenched by addition of saturated aqueous ammonium chloride solution (10 ml) and the organic layer was separated and put aside. The aqueous layer was extracted with dichloromethane (3 x 20 ml) and the combined extracts were dried using a hydrophobic frit.
  • sodium hydride 50% in oil, 0.170 g, 4.36 mmol
  • 1-ethyl-4,4-dimethyl-5-oxoproline (0.130 g, 0.702 mmol, prepared as described below), 1-Hydroxybenzotriazole (0.161 g, 1.053 mmol), and N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.202 g, 1.053 mmol) were dissolved in dichloromethane (5 ml) and stirred for 15 minutes at room temperature.
  • 1-Ethyl-5-oxo-4,4-bis(phenylmethyl)proline was prepared in a manner analogous to that described for 1-ethyl-4,4-dimethyl-5-oxoproline in example 130 above but using 1-ethyl-3,3-bis(phenylmethyl)-5- ⁇ [(triphenylmethyl)oxy]methyl ⁇ -2- pyrrolidinone (isolated as a side-product in method B, Example 37) in place of 1 - ethyl-3,3-dimethyl-5- ⁇ [(triphenylmethyl)oxy]methyl ⁇ -2-pyrrolidinone.
  • /V-(2-biphenylylmethyl)-1 -ethyl-5-oxoprolinamide was prepared in a manner analogous to that described above for the synthesis of ⁇ /-[(2,3- dimethylphenyl)methyl]-1-ethyl-5-oxoprolinamide (E50) but using (2- biphenylylmethyl)amine in place of 2,3-dimethyl benzylamine.
  • the microwave reactor used was a Biotage InitiatorTM . Reactions were carried out using normal power output unless specified otherwise.
  • HPLC HPLC was carried out using the following apparatus and conditions:
  • the columns used are Waters Atlantis, the dimensions of which are 19mm x 100mm (small scale) and 30mm x 100mm (large scale).
  • the stationary phase particle size is 5 ⁇ rm.
  • Aqueous solvent Water + 0.1 % Formic Acid
  • the column used is a Waters Atlantis, the dimensions of which are 4.6mm x 50mm.
  • the stationary phase particle size is 3 ⁇ m.
  • Organic solvent Acetonitrile + 0.05% Formic Acid
  • the above method has a flow rate of 3ml/mins.
  • the injection volume for the generic method is 5ul.
  • the column temperature is 30deg.
  • the UV detection range is from 220 to 330nm.
  • Immediate release tablets for oral administration containing ⁇ /- ⁇ [2-Chloro-3- (trifluoromethyl)phenyl]methyl ⁇ -1-methyl-5-oxo-/.-prolinamide (a compound of formula (I), which e.g. can optionally be prepared as described in Example 51 ) as the active therapeutic agent (P2X7 receptor antagonist) at 0.3 mg, 1 mg, 5 mg, 25 mg and 125 mg doses, are prepared according to the compositions shown in the table below.
  • the active agent is ⁇ /- ⁇ [2-chloro-3-(trifluoromethyl)phenyl]methyl ⁇ -1-methyl-5-oxo-/-- prolinamide.
  • the purified water is removed during processing, does not appear in final product.
  • Opadry® White OY-S-28876 contains titanium dioxide (E171 ), macrogol 400, and hypromellose (hydroxypropylmethylcellulose).
  • /V- ⁇ [2-Chloro-3-(trifluoromethyl)phenyl]methyl ⁇ -1-methyl-5-oxo-L-prolinamide tablets are manufactured using a process of wet granulation and drying, compression and tablet coating.
  • the manufacture process contains the following steps:
  • the screened granules from 3) are blended with the required amount of extragranular excipient(s) in a low shear mixer.
  • the platform granules containing 1.484% w/w of drug substance are used to make the blend; whereas for the 25 mg and 125 mg dose tablets, the platform granules containing 37.1 1 % w/w of drug substance are used to make the blend.
  • the blend from 4) is lubricated with magnesium stearate.
  • one or more of one dose of these tablets can optionally be used as one half (the P2X7 receptor antagonist half) of the separate combinations disclosed in the Combination Examples 1 , 2 and 3 given below.
  • the following two therapeutic agents are administered to a human suffering from rheumatoid arthritis, e.g. a human adult suffering from severe, active, classical or definite rheumatoid arthritis, as a separate combination and using the following dosage regimens, with the two therapeutic agents being administered either at substantially the same time of the day and/or at different times of the day as appropriate:
  • Therapeutic agent 1 (a compound of formula (I))
  • ⁇ /- ⁇ [2-Chloro-3-(trifluoromethyl)phenyl]methyl ⁇ -1-methyl-5-oxo-/--prolinamide is administered to the human at an oral dosage regimen of 0.3 mg to 2000 mg once or twice per day, e.g. 10 mg to 2000 mg once or twice per day, e.g. 20 mg to 1000 mg once or twice per day.
  • oxo-L-prolinamide ( ) can be prepared as described in
  • Methotrexate is administered separately to the human at a dosage regimen of 7.5 mg orally once weekly, or using divided oral doses of 2.5 mg at 12 hour intervals for 3 doses (7.5 mg) as a course once weekly.
  • the schedule can be adjusted gradually to achieve an optimal response, but typically should not exceed a total weekly oral dose of 20mg of methotrexate. Once a response has been achieved, the methotrexate dose is typically reduced to the lowest possible effective dose.
  • the following two therapeutic agents are administered to a human, for the treatment of neuropathic pain in the human, as a separate combination and using the following dosage regimens, with the two therapeutic agents being administered either at substantially the same time of the day and/or at different times of the day as appropriate:
  • Therapeutic agent 1 (a compound of formula (I))
  • ⁇ /- ⁇ [2-Chloro-3-(trifluoromethyl)phenyl]methyl ⁇ -1-methyl-5-oxo-/--prolinamide is administered to the human at an oral dosage regimen of 0.3 mg to 2000 mg once or twice per day, e.g. 10 mg to 2000 mg once or twice per day, e.g. 20 mg to 1000 mg once or twice per day.
  • oxo-L-prolinamide ( ) can De prepared as described in
  • Pregabalin is administered separately to the human at an oral dosage regimen of 150 mg to 600 mg total pregabalin per day (measured as the free base), split between two to three doses per day.
  • pregabalin can be administered at a starting oral dosage regimen of 150 mg total pregabalin per day (split between 2 or 3 doses per day), escalating (e.g. in about one week) to an oral dosage regimen of 300 mg pregabalin total per day, and optionally escalating up to a maximum oral dosage regimen of 600 mg total pregabalin per day.
  • an oral dosage regimen of 150 mg to 300 mg total pregabalin per day can be administered.
  • an oral dosage regimen of 150 mg to 450 mg (e.g. 300 or 450 mg) total pregabalin per day can be administered.
  • the following two therapeutic agents are administered to a human, for the treatment of osteoarthritis and/or inflammatory pain in the human, as a separate combination and using the following dosage regimens, with the two therapeutic agents being administered either at substantially the same time of the day and/or at different times of the day as appropriate:
  • Therapeutic agent 1 (a compound of formula (I))
  • /V- ⁇ [2-Chloro-3-(trifluoromethyl)phenyl]methyl ⁇ -1-methyl-5-oxo--.-prolinamide is administered to the human at an oral dosage regimen of 0.3 mg to 2000 mg once or twice per day, e.g. 10 mg to 2000 mg once or twice per day, e.g. 20 mg to 1000 mg once or twice per day.
  • oxo-L-prolinamide ( ) can De prepared as described in
  • Paracetamol is administered separately to the human at an oral dosage regimen of 500 mg to 1000 mg (e.g. 500 mg, 650 mg or 1000 mg, in particular 650 mg) of paracetamol (measured as the free base / free compound), administered two, three or four times daily.
  • 500 mg to 1000 mg e.g. 500 mg, 650 mg or 1000 mg, in particular 650 mg
  • paracetamol administered two, three or four times daily.
  • the combination treatment is optionally continued for a number of days, weeks, months or years.
  • HEK293 cells expressing human recombinant P2X7 receptors, were grown in poly-L-lysine pretreated 96 well plates for 18-24 h. (The cloning of the human P2X7 receptor is described in US 6,133,434). The cells were washed twice with 350 ⁇ l of assay buffer before addition of 50 ⁇ l of test compound.
  • the cells were then incubated at room temperature (19-21 0 C) for 30 min before addition of ATP and ethidium (100 ⁇ M final assay concentration).
  • the ATP concentration was chosen to be close to the EC 80 for the receptor type and was 1 mM for studies on the human P2X7 receptor. Incubations were continued for 8 or 16 min and were terminated by addition of 25 ⁇ l of 1.3M sucrose containing 5mM of the P2X7 receptor antagonist reactive black 5 (Aldrich).
  • HEK293 cells expressing human recombinant P2X7 receptors, were grown in poly- L-lysine pretreated 384 well plates for 42-48h.
  • the cloning of the human P2X7 receptor is described in US 6,133,434.
  • the cells were washed three times with 80 ⁇ l of assay buffer, loaded for 1 h at 37°C with 2 ⁇ M Fluo4 (Teflabs), washed three times again, and left with 30 ⁇ l buffer before the addition of 10 ⁇ l of 4x concentrated test compound.
  • the cells were then incubated at room temperature for 30 mins before addition (online, by FLIPR384 or FLIPR3 instrument (Molecular Devices)) of
  • BzATP Benzoylbenzoyl-ATP 60 ⁇ M final assay concentration.
  • the BzATP concentration was chosen to be close to the EC 8O for the receptor type.
  • Incubations and reading were continued for 90sec, and intracellular calcium increase was determined by measuring fluorescence (excitation wavelength of 488nm and emission wavelength of 516nm) from below the plate, with FLIPR CCD camera.
  • Antagonist plC 50 values for blocking BzATP responses were determined using iterative curve fitting techniques.
  • the compounds of Examples 1-136 were tested in the FLIPR Ca Assay and/or the Ethidium Accumulation Assay for human P2X7 receptor antagonist activity and found to have plC50 values > 4.7 in the FLIPR Ca Assay and/or plC50 values > 5.5 in the Ethidium Accumulation Assay.
  • a peripheral mononeuropathy By placing loosely constrictive ligatures around the common sciatic nerve, a peripheral mononeuropathy can be produced, which thereby provides a rat model of neuropathic pain, Bennet et ai, Pain, Vol.33, pp87-107 (1988).
  • Adult male Random Hooded rats 180-20Og from Charles River, UK were anaesthetised with isoflurane (3%).
  • the sciatic nerve in the left leg was exposed at mid thigh level and 4 loose ligatures of Chromic 4.0 gut tied around the nerve as described by Bennet et ai, Pain, Vol.33, pp87-107 (1988).
  • the wound was closed and secured with staples. Sham rats underwent the same procedure but loose ligatures were not applied.
  • FCA Freund's complete adjuvant
  • FCA Freund's Complete Adjuvant

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Abstract

La présente invention concerne une combinaison qui comprend un composé représenté par la formule (I) ou un sel pharmaceutiquement acceptable de ce dernier de formule (I), ainsi qu'au moins un autre agent thérapeutique; et l'utilisation de la combinaison dans le traitement ou la prévention de la douleur, de l'inflammation ou d'une maladie neurodégénérative. Les composés représentés par la formule (I) sont présumés être des antagonistes du récepteur P2X7. Le composé représenté par la formule (I) est de préférence le N-{[2-chloro-3-(trifluorométhyl)phényl]méthyl}- 1 -méthyl-5-oxo-L-prolinamide. L'autre agent thérapeutique peut être par exemple, le méthotrexate, un AINS, un inhibiteur du TNFα, la sulfasalazine, une statine, un agent glucocorticoïde, un anticorps monoclonal anti-IL-1 ou un anticorps monoclonal anti-CD20, utile par exemple pour traiter la polyarthrite rhumatoïde. L'autre agent thérapeutique peut être capable de traiter la douleur inflammatoire ou neuropathique, tel que par exemple du paracétamol, un opioïde (par exemple, la morphine, le fentanyl, l'oxycodone, ou le tramadol), la prégabaline, la gabapentine, la gabapentine enacarbil ou la carbamazépine.
PCT/EP2008/066890 2007-12-12 2008-12-05 Combinaisons formées de modulateurs au prolinamide du récepteur p2x7 et d'autres agents thérapeutiques WO2009074518A1 (fr)

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WO2013090591A1 (fr) * 2011-12-15 2013-06-20 Dow Global Technologies Llc Procédé de préparation d'acides alkylpyroglutamiques
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WO2019006074A1 (fr) * 2017-06-28 2019-01-03 Indiana University Research And Technology Corporation Agent pharmaceutique qui se lie au récepteur p2x7
CN109180552A (zh) * 2018-09-26 2019-01-11 沈阳药科大学 取代的5-氧代吡咯烷类衍生物及其制备方法和应用
US10342786B2 (en) 2017-10-05 2019-07-09 Fulcrum Therapeutics, Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD
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