WO2001005391A2 - Method for treating chronic pain using mek inhibitors - Google Patents

Method for treating chronic pain using mek inhibitors Download PDF

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Publication number
WO2001005391A2
WO2001005391A2 PCT/US2000/018346 US0018346W WO0105391A2 WO 2001005391 A2 WO2001005391 A2 WO 2001005391A2 US 0018346 W US0018346 W US 0018346W WO 0105391 A2 WO0105391 A2 WO 0105391A2
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Prior art keywords
methyl
phenyl
iodo
phenylamino
fluoro
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PCT/US2000/018346
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English (en)
French (fr)
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WO2001005391A3 (en
Inventor
Stephen Douglas Barrett
Alexander James Bridges
Haile Tecle
Alistair Dixon
Kevin Lee
Robert Denham Pinnock
Lu-Yan Zhang
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Warner-Lambert Company
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Application filed by Warner-Lambert Company filed Critical Warner-Lambert Company
Priority to IL14761700A priority Critical patent/IL147617A0/xx
Priority to AU57859/00A priority patent/AU5785900A/en
Priority to PL00352705A priority patent/PL352705A1/xx
Priority to KR1020027000665A priority patent/KR20020015379A/ko
Priority to JP2001510448A priority patent/JP2003504399A/ja
Priority to CA002377100A priority patent/CA2377100A1/en
Priority to EP00943382A priority patent/EP1202732A2/en
Publication of WO2001005391A2 publication Critical patent/WO2001005391A2/en
Publication of WO2001005391A3 publication Critical patent/WO2001005391A3/en
Priority to HK02108607.6A priority patent/HK1047039A1/zh

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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/428—Thiazoles condensed with carbocyclic rings
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Definitions

  • the invention features a method for treating chronic pain using MEK inhibitors.
  • Chronic pain includes neuropathic pain, and chronic inflammatory pain.
  • neuropathic pain may be, for example, a deep ache, a burning sensation, or hypersensitivity to touch.
  • Diseases or conditions associated with neuropathic pain include, without limitation, diabetic neuropathy, causalgia, plexus avulsion, neuroma, vasculitis, crush injury, viral infections (e.g., herpes virus infection or HIV), constriction injury, tissue injury, nerve injury from the periphery to the central nervous system, limb amputation, hypothyroidism, uremia, chronic alcoholism, post-operative pain, arthritis, back pain, and vitamin deficiencies.
  • Infections such as herpes zoster (shingles) can cause nerve inflammation and produce postherpetic neuralgia, a chronic burning localized to the area of viral infection.
  • Hyperalgesia is when an already noxious stimulus becomes more painful, and allodynia, when a previously non-noxious stimulus becomes painful (such as contact of clothing or a breeze).
  • Reflex sympathetic dystrophy is accompanied by swelling and sweating or changes in local blood flow, tissue atrophy, or osteoporosis.
  • Causalgia including severe burning pain and swelling, sweating, and changes in blood flow, may follow an injury or disease of a major nerve such as the sciatic nerve.
  • neuropathic pain may also be induced by cancer or chemotherapy.
  • Neuropathic pain is currently treated with anticonvulsants such as carbamazepine and antidepressants such as amitryptaline.
  • NSAIDS and opioids generally have little effect (Fields et al 1994 Textbook of Pain p 991- 996 (pub: Churchill Livingstone), James & Page 1994 J.Am. Pediatr. Med.Assoc, 8: 439-447, Galer, 1995 Neurology 45 S 17-S25.
  • Neuropathic conditions that have been treated with gabapentin include: postherpetic neuralgia, postpoliomyelitis, CPRM, HIV-related neuropathy, trigeminal neuralgia, and reflex sympathetic dystrophy (RSD).
  • the generally weak efficacy of antiinflammatory agents suggests that the mechanism for chronic pain is separate from hyperalgesia.
  • the invention features a method for treating chronic pain, which method includes the step of administering a composition including a MEK inhibitor to a patient in need of such treatment.
  • Chronic pain includes neuropathic pain, idiopathic pain, and pain associated with vitamin deficiencies, uremia, hypothyroidism post-operative pain, arthritis, back pain, and chronic alcoholism.
  • the invention also features compositions as disclosed, formulated for the treatment of chronic pain.
  • Such a composition may include one or more MEK inhibitor compounds having a structure disclosed in patent application PCT/US99/30416, international filing date December 21 , 1999.
  • MEK inhibitors include a compound having the formula (I) below:
  • W is one of the following formulae (i) - (xiii):
  • X1 is O, S, or NR F .
  • X 2 is OH, SH, or NHR E .
  • Each of R E and R F is H or C 1-4 alkyl; each of R1 and R 2 is independently selected from H, F, NO 2 , Br and Cl; R ⁇ [ can also be SO2NRGR H , or and R 2 together with the benzene ring to which they are attached constitute an indole, isoindole, benzofuran, benzothiophene, indazole, benzimidazole, or benzthioazole.
  • R 3 is selected from H and F; each of RG, RH, and R 4 is independently selected from H, Cl and CH 3 .
  • R 5 is H or C 1-4 alkyl.
  • Each hydrocarbon radical above is optionally substituted with between 1 and 3 substituents independently selected from halo, hydroxyl, amino, (amino)sulfonyl, and NO 2 .
  • Each heterocyclic radical above is optionally substituted with between 1 and 3 substituents independently selected from halo, C 1 . 4 alkyl, C 3 - 6 cycloalkyl, C 3 .
  • the invention also features a pharmaceutically acceptable salt or C ⁇ - ⁇ ester of a disclosed compound.
  • said MEK inhibitor has a structure selected from: 2,4-bis-(2-chloro-4-iodo- phenylamino)-3-fluoro-5-nitro-benzoic acid; 5-[3,4difluoro-2-(4-iodo-2-methyl- phenylamino)-phenyl]-[1 ,3,4]oxadiazol-2-ylamine; 5-[4-fluoro-2-(4-iodo-2- methyl-phenylamino)-phenyl]-[1 ,3,4]oxadiazol-2-ol; (2,3-difluoro-6- [1 ,3,4]oxadiazol-2-yl-phenyl)(-(4-iodo-2-methyl-phenyl)-amine; 5-[3,4-difluoro- 2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1 ,3,4]oxadiazole-2-thio
  • said MEK inhibitor has the structure selected from: 2,4-bis-(2-chloro-4- iodo-phenylamino)-3-fluoro-5-nitro-benzoic acid.
  • FIG. 1 is a bar graph representing the paw withdrawal threshold (PWT) in grams as a function of time in days.
  • the empty, cross-hatched, and single- hatched bars are vehicle, PD 198306, and pregabalin, respectively.
  • the arrows indicate time of drug administration (30 mg/kg, p.o.).
  • FIG 2. is a bar graph representing the force required in grams to elicit paw withdrawal using von Frey hair filaments as a function of time in days.
  • FIG. 3. is a bar graph representing the force required in grams to elicit paw withdrawal using von Frey hair filaments as a function of time in days.
  • FIG. 4. is a bar graph representing the force required in grams to elicit paw withdrawal using von Frey hair filaments as a function of time in days.
  • Baseline (BL) measurements were taken before treatment. Animals received a single i.t. administration of PD 198306 (1-30 ⁇ g/10 ⁇ l), or pregabalin
  • FIG. 5. is a bar graph representing the force required in grams to elicit paw withdrawal using von Frey hair filaments as a function of time in days.
  • FIG. 6 is a bar graph representing the force required in grams to elicit paw withdrawal using von Frey hair filaments as a function of time in days .
  • FIG. 7. is a bar graph representing the force required in grams to elicit paw withdrawal using von Frey hair filaments as a function of time in days.
  • FIG. 8 is a bar graph representing the force required in grams to elicit paw withdrawal using von Frey hair filaments.
  • the compounds disclosed herein are pharmaceutically active, for example, they inhibit MEK.
  • MEK enzymes are dual specificity kinases involved in, for example, immunomodulation, inflammation, and proliferative diseases such as cancer and restenosis.
  • Proliferative diseases are caused by a defect in the intracellular signaling system, or the signal transduction mechanism of certain proteins.
  • Defects include a change either in the intrinsic activity or in the cellular concentration of one or more signaling proteins in the signaling cascade .
  • the cell may produce a growth factor that binds to its own receptors, resulting in an autocrine loop, which continually stimulates proliferation. Mutations or overexpression of intracellular signaling proteins can lead to spurious mitogenic signals within the cell. Some of the most common mutations occur in genes encoding the protein known as Ras, a G-protein that is activated when bound to GTP, and inactivated when bound to GDP.
  • Ras leads in turn to the activation of a cascade of serine/threonine kinases.
  • One of the groups of kinases known to require an active Ras-GTP for its own activation is the Raf family. These in turn activate MEK (e.g., MEK-
  • MEK e.g., MEK-
  • MAP kinase e.g., MEK-
  • Activation of MAP kinase by mitogens appears to be essential for proliferation; constitutive activation of this kinase is sufficient to induce cellular transformation.
  • Blockade of downstream Ras signaling for example by use of a dominant negative Raf-1 protein, can completely inhibit mitogenesis, whether induced from cell surface receptors or from oncogenic Ras mutants.
  • Ras is not itself a protein kinase, it participates in the activation of Raf and other kinases, most likely through a phosphorylation mechanism.
  • Raf and other kinases phosphorylate MEK on two closely adjacent serine residues, s218 anc
  • MEK in turn phosphorylates MAP kinase on both a tyrosine, ⁇ 185 anc
  • MAP kinase This double phosphorylation activates MAP kinase at least 100-fold. Activated MAP kinase can then catalyze the phosphorylation of a large number of proteins, including several transcription factors and other kinases. Many of these MAP kinase phosphorylations are mitogenically activating for the target protein, such as a kinase, a transcription factor, or another cellular protein. In addition to Raf-1 and MEKK, other kinases activate MEK, and MEK itself appears to be a signal integrating kinase. Current understanding is that MEK is highly specific for the phosphorylation of MAP kinase.
  • MEK does not phosphorylate peptides based on the MAP kinase phosphorylation sequence, or even phosphorylate denatured MAP kinase.
  • MEK also appears to associate strongly with MAP kinase prior to phosphorylating it, suggesting that phosphorylation of MAP kinase by MEK may require a prior strong interaction between the two proteins.
  • the effect of the MEK inhibitor PD 198306 has been investigated in two animal models of neuropathic pain by assessing static allodynia with von Frey hairs.
  • Oral administration of PD 198306 (3-30mg/kg) had no effect in the model of chronic constriction injury of the sciatic nerve (CCI). However, after repeated administration (3 doses over two days) it had a transient effect in the diabetic neuropathy model (streptozocin). This may be due to disorders of the blood- brain barrier induced by the diabetic condition in these animals, thus allowing central action of the compound.
  • Intrathecal administration of PD 198306 (1- 30 ⁇ g) dose-dependently blocked static allodynia in both the streptozocin and the CCI models of neuropathic pain, with minimum effective doses (MED) of 3 and 10 ⁇ g respectively. The highest dose used (30 ⁇ g) totally blocked the maintenance of static allodynia, for up to 1h.
  • MED minimum effective doses
  • MEK inhibitors as potential new therapeutic tools for chronic pain.
  • the study of potential side-effects, especially related to memory, of future brain-penetrant MEK inhibitors will indicate the therapeutic window for this novel class of compounds in the treatment of pain.
  • Alkyl groups include aliphatic (i.e., hydrocarbyl or hydrocarbon radical structures containing hydrogen and carbon atoms) with a free valence. Alkyl groups are understood to include straight chain and branched structures. Examples include methyl, ethyl, propyl, isopropyl, butyl, n-butyl, isobutyl, t- butyl, pentyl, isopentyl, 2,3-dimethylpropyl, hexyl, 2, 3-d i methyl hexyl, 1 ,1- dimethylpentyl, heptyl, and octyl. Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Alkyl groups can be substituted with 1 , 2, 3 or more substituents which are independently selected from halo (fluoro, chloro, bromo, or iodo), hydroxy, amino, alkoxy, alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy, arylalkyloxy, heterocyclic radical, and (heterocyclic radical)oxy.
  • substituents are independently selected from halo (fluoro, chloro, bromo, or iodo), hydroxy, amino, alkoxy, alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy, arylalkyloxy, heterocyclic radical, and (heterocyclic radical)oxy.
  • alkenyl groups are analogous to alkyl groups, but have at least one double bond (two adjacent sp 2 carbon atoms).
  • alkynyl groups have at least one triple bond (two adjacent sp carbon atoms).
  • Unsaturated alkenyl or alkynyl groups may have one or more double or triple bonds, respectively, or a mixture thereof; like alkyl groups, unsaturated groups may be straight chain or branched, and they may be substituted as described both above for alkyl groups and throughout the disclosure by example.
  • alkenyls, alkynyls, and substituted forms include cis-2-butenyl, trans-2-butenyl, 3-butynyl, 3-phenyl-2-propynyl, 3-(2'-fluorophenyl)-2-propynyl, 3-methyl(5-phenyl)-4-pentynyl, 2-hydroxy-2-propynyl, 2-methyl-2-propynyl, 2- propenyl, 4-hydroxy-3-butynyl, 3-(3-fluorophenyl)-2-propynyl, and 2-methyl-2- propenyl.
  • alkenyls and alkynyls can be C 2- or C 2-8, for example, and are preferably C 3 - 4 or C 3-8 .
  • substituted hydrocarbon radicals include hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxycycloalkyl, hydroxyaryl, and corresponding forms for the prefixes amino-, halo- (e.g., fluoro-, chloro-, or bromo-), nitro-, alkyl-, phenyl-, cycloalkyl- and so on, or combinations of substituents.
  • halo- e.g., fluoro-, chloro-, or bromo-
  • substituted alkyls include hydroxyalkyl, aminoalkyl, nitroalkyl, haloalkyl, alkylalkyl (branched alkyls, such as methylpentyl), (cycloalkyl)alkyl, phenylalkyl, alkoxy, alkylaminoalkyl, dialkylaminoalkyl, arylalkyl, aryloxyalkyl, arylalkyloxyalkyl, (heterocyclic radical)alkyl, and (heterocyclic radical)oxyalkyl.
  • R 1 thus includes hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxycycloalkyl, hydroxyaryl, aminoalkyl, aminoalkenyl, aminoalkynyl, aminocycloalkyl, aminoaryl, alkylalkenyl, (alkylaryl)alkyl, (haloaryl)alkyl, (hydroxyaryl)alkynyl, and so forth.
  • RA includes hydroxyalkyl and aminoaryl
  • RB includes hydroxyalkyl, aminoalkyl, and hydroxyalkyl(heterocyclic radical)alkyl.
  • Heterocyclic radicals which include but are not limited to heteroaryls, include: furyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, pyrrolyl, imidazolyl, 1 ,3,4-triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, indolyl, and their nonaromatic counterparts.
  • heterocyclic radicals include piperidyl, quinolyl, isothiazolyl, piperidinyl, morpholinyl, piperazinyl, tetrahydrofuryl, tetrahydropyrrolyl, pyrrolidinyl, octahydroindolyl, octahydrobenzothiofuranyl, and octahydrobenzofuranyl.
  • Selective MEK 1 or MEK 2 inhibitors are those compounds which inhibit the MEK 1 or MEK 2 enzymes, respectively, without substantially inhibiting other enzymes such as MKK3, PKC, Cdk2A, phosphorylase kinase, EGF, and PDGF receptor kinases, and C-src.
  • a selective MEK 1 or MEK 2 inhibitor has an IC 50 for MEK 1 or MEK 2 that is at least one-fiftieth (1/50) that of its IC 50 for one of the above-named other enzymes.
  • a selective inhibitor has an IC 50 that is at least 1/100, more preferably 1/500, and even more preferably 1/1000, 1/5000, or less than that of its IC 5 o or one or more of the above-named enzymes.
  • One aspect of the invention features the disclosed compounds shown in formula (I) in the Summary section.
  • Embodiments of the invention include compounds wherein: (a) Ri is bromo or chloro; (b) R2 is fluoro; (c) R3 is H; (d) each of R2 and R 3 is H; (e) each of R 2 and R 3 is fluoro; (f) R1 is bromo; (g) each of R ⁇ R 2 and R 3 is fluoro; (h) R 2 is nitro; (i) R 3 is H; (j) R 4 is chloro; (k) R 4 is methyl; (I) R 5 is H; (m) R 5 is CH 3 ; (n) Xi is O or S; (o) X1 is NH or NCH 3 ; (p) X 2 is OH, SH, or NH 2 ; (q) X 2 is OH; (r) X 2 is NHR E ; (s) R 4 is H; (t) R 4 is chloro or methyl; or combinations thereof.
  • the double or triple bond, respectively, is not adjacent the point of attachment when it is a heteroatom.
  • the substituent is preferably prop-2-ynyl, or but-2 or 3-enyl, and less preferably prop-1-ynyl or but-1-enyl.
  • Examples of compounds include: [5-fluoro-2-(1 H-tetrazol-5-yl)- phenyl]-(4-iodo-2-methyl-phenyl)-amine; [2,3-difluoro-6-(1 H-tetrazol-5-yl)- phenyl]-(4-iodo-2-methyl-phenyl)- amine; (4-iodo-2-methyl-phenyl)-[2,3,4- trifluoro-6-(1 H-tetrazol-5-yl)-phenyl]-amine; [4-bromo-2,3-difluoro-6-(1 H- tetrazol-5-yl)-phenyl]-(4-iodo-2-methyl-phenyl)-amine; [5-fluoro-4-nitro-2-(1 H- tetrazol-5-yl)-phenyl]-(4-iodo-2-methyl-phenyl)-amine; [2-
  • Additional examples are: 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)- phenyl]-isothiazol-3-ol; 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)- phenyl]-isothiazol-3-ol; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)- phenyl]-isothiazol-3-ol; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-phenyl]-isothiazol-3-ol; 5-[4-fluoro-2-(4-iodo-2-methyl- phenylamino)-5-nitro-phenyl]-isothiazol-3-ol; 5-[4-fluoro-2-(4-iodo-2-
  • the invention also features compounds such as: 5-[2-(2-amino-4-iodo- phenylamino)-4-fluoro-phenyl]-1 -methyl-1 H-[1 ,2,3]triazol-4-ol; 5-[2-(2-amino-4- iodo-phenylamino)-3,4-difluoro-phenyl]-1 -methyl-1 H-[1 ,2,3]triazol-4-ol; 5-[2-(2- amino-4-iodo-phenylamino)-3,4,5-trifluoro-phenyl]-1 -methyl-1 H-[1 ,2,3]thazol- 4-ol; 5-[2-(2-amino-4-iodo-phenylamino)-5-bromo-3,4-difluoro-phenyl]-1- methyl-1 H-[1 ,2,3]thazol-4-ol; 5-[2-(2-amino-4-iodo-phenyla
  • Further examples of the invention include 3-[4-fluoro-2-(4-iodo-2- methyl-phenylamino)-phenyl]-2H-isoxazol-5-one; 3[3,4-difluoro-2-(4-iodo-2- methyl-phenylamino)-phenyl]-2H-isoxazol-5-one; 3-[3,4,5-trifluoro-2-(4-iodo-2- methyl-phenylamino)-phenyl]-2H-isoxazol-5-one; 3-[5-bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino)-phenyl]-2H-isoxazol-5-one; 3-[4-fluoro-2-(4- iodo-2-methyl-phenylamino)-5-nitro-phenyl]-2H-isoxazol-5-one; [5-fluoro-2-(2- ox
  • R-i can also be SO2NRGRH, or Ri and R 2 together with the benzene ring to which they are attached constitute an indole, isoindole, benzofuran, benzothiophene, indazole, benzimidazole, or benzthioazole, include the following groups:
  • the disclosed compounds can be synthesized according to Schemes 1-25 or analogous variants thereof. These synthetic strategies are further exemplified in Examples 1-8 below.
  • the solvent between compounds 4 and 5 in Scheme 1 is toluene (PhMe).
  • compositions are useful as both prophylactic and therapeutic treatments for diseases or conditions relating to chronic pain, including neuropathic pain, as provided in the Summary section, as well as diseases or conditions modulated by the MEK cascade.
  • the disclosed method relates to postoperative pain, phantom limb pain, burn pain, gout, trigeminal neuralgia, acute herpetic and postherpetic pain, causalgia, diabetic neuropathy, plexus avulsion, neuroma, vasculitis, crush injury, constriction injury, tissue injury, post-surgical pain, arthritis pain, or limb amputation
  • local injuries can be treated with local or topical administration.
  • Chronic pain affecting the entire body such as diabetic neuropathy can be treated with systemic administration (injection or orally) of a disclosed composition.
  • Treatment for chronic pain (e.g., post-operative pain) confined to the lower body can be administered centrally, e.g., epidurally.
  • Formulations and methods of administration can include the use of more than one MEK inhibitor, or a combination of a MEK inhibitor and another pharmaceutical agent, such as an anti-inflammatory, analgesic, muscle relaxing, or anti-infective agent.
  • Preferred routes of administration are oral, intrathecal or epidural, subcutaneous, intravenous, intramuscular, and, for non-human mammals, intraplantar, and are preferably epidural.
  • an effective amount will be between 0.1 and 1000 mg/kg per day, preferably between 1 and 300 mg/kg body weight, and daily dosages will be between 10 and 5000 mg for an adult subject of normal weight.
  • Commercially available capsules or other formulations such as liquids and film-coated tablets) of 100 mg, 200 mg, 300 mg, or 400 mg can be administered according to the disclosed methods.
  • Dosage unit forms include tablets, capsules, pills, powders, granules, aqueous and nonaqueous oral solutions and suspensions, and parenteral solutions packaged in containers adapted for subdivision into individual doses. Dosage unit forms can also be adapted for various methods of administration, including controlled release formulations, such as subcutaneous implants. Administration methods include oral, rectal, parenteral (intravenous, intramuscular, subcutaneous), intracisternal, intravaginal, intraperitoneal, intravesical, local (drops, powders, ointments, gels, or cream), and by inhalation (a buccal or nasal spray).
  • Parenteral formulations include pharmaceutically acceptable aqueous or nonaqueous solutions, dispersion, suspensions, emulsions, and sterile powders for the preparation thereof.
  • carriers include water, ethanol, polyols (propylene glycol, polyethylene glycol), vegetable oils, and injectable organic esters such as ethyl oleate. Fluidity can be maintained by the use of a coating such as lecithin, a surfactant, or maintaining appropriate particle size.
  • Carriers for solid dosage forms include (a) fillers or extenders, (b) binders, (c) humectants, (d) disintegrating agents, (e) solution retarders, (f) absorption acccelerators, (g) adsorbants, (h) lubricants, (i) buffering agents, and (j) propellants.
  • Compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents; antimicrobial agents such as parabens, chlorobutanol, phenol, and sorbic acid; isotonic agents such as a sugar or sodium chloride; absorption-prolonging agents such as aluminum monostearate and gelatin; and absorption-enhancing agents. 3. Related compounds
  • the invention provides the disclosed compounds and closely related, pharmaceutically acceptable forms of the disclosed compounds, such as salts, esters, amides, hydrates or solvated forms thereof; masked or protected forms; and racemic mixtures, or enantiomerically or optically pure forms.
  • Pharmaceutically acceptable salts, esters, and amides include carboxylate salts (e.g., C ⁇ alkyl, cycloalkyl, aryl, heteroaryl, or non-aromatic heterocyclic), amino acid addition salts, esters, and amides which are within a reasonable benefit/risk ratio, pharmacologically effective, and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response.
  • Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate, and laurylsulfonate.
  • alkali metal and alkali earth cations such as sodium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations such as tetramethyl ammonium, methylamine, trimethylamine, and ethylamine.
  • alkali metal and alkali earth cations such as sodium, potassium, calcium, and magnesium
  • non-toxic ammonium, quaternary ammonium, and amine cations such as tetramethyl ammonium, methylamine, trimethylamine, and ethylamine.
  • amine cations such as tetramethyl ammonium, methylamine, trimethylamine, and ethylamine.
  • Representative pharmaceutically acceptable amides of the invention include those derived from ammonia, primary C ⁇ - 6 alkyl amines and secondary di (C ⁇ alkyl) amines.
  • Secondary amines include 5- or 6-membered heterocyclic or heteroaromatic ring moieties containing at least one nitrogen atom and optionally between 1 and 2 additional heteroatoms.
  • Preferred amides are derived from ammonia, C 1 . 3 alkyl primary amines, and di (C 1-2 alkyl)amines.
  • Representative pharmaceutically acceptable esters of the invention include C 1 - 7 alkyl, C 5 . 7 cycloalkyl, phenyl, and phenyl(C ⁇ - 6 )alkyl esters.
  • Preferred esters include methyl esters.
  • the invention also includes disclosed compounds having one or more functional groups (e.g., hydroxyl, amino, or carboxyl) masked by a protecting group. Some of these masked or protected compounds are pharmaceutically acceptable; others will be useful as intermediates. Synthetic intermediates and processes disclosed herein, and minor modifications thereof, are also within the scope of the invention.
  • Hydroxyl protecting groups include: ethers, esters, and protection for 1 ,2- and 1 ,3-diols.
  • the ether protecting groups include: methyl, substituted methyl ethers, substituted ethyl ethers, substituted benzyl ethers, silyl ethers and conversion of silyl ethers to other functional groups. Substituted Methyl Ethers
  • Substituted methyl ethers include: methoxymethyl, methylthiomethyl, t- utylthiomethyl, (phenyldimethylsilyl) methoxymethyl, benzyloxymethyl, p- ethoxybenzyloxymethyl, (4-methoxyphenoxy) methyl, guaiacolmethyl, t- butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis(2-chloro- ethoxy)methyl, 2-
  • Substituted Ethyl Ethers include: 1-ethoxyethyl, 1-(2,chloroethoxy)ethyl, 1 -methyl-1 -methoxyethyl, 1 -methyl-1 -benzyloxyethyl, 1 -methyl-1 -benzyloxy-2- fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilyethyl, 2-(phenylselenyl)ethyl, t- butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, and benzyl.
  • Substituted Benzyl Ethers include: p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- and 4-picolyl, 3-methyl-2-picolyl ⁇ /-oxido, diphenylmethyl, p, p -dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, ⁇ -naphthyldiphenyl- methyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri-(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxy)phenyldiphenylmethyl, 4,4',4"-tris(
  • Silyl Ethers Silyl ethers include: trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t- butyldimethylsilyl, f-butyldiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl, and -butylmethoxyphenylsilyl.
  • Esters protecting groups include: esters, carbonates, assisted cleavage, miscellaneous esters, and sulfonates.
  • esters examples include: formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p- chlorophenoxyacetate, p-P-phenylacetate, 3-phenylpropionate, 4- oxopentanoate (levulinate), 4,4-(ethylenedithio) pentanoate, pivaloate, adamantoate,crotonate,4-methoxycrotonate, benzoate, p-phenylbenzoate, and 2,4,6-trimethylbenzoate (mesitoate).
  • Carbonates include: formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p- chlor
  • Carbonates include: methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl) ethyl, 2-(phenylsulfonyl) ethyl, 2-(triphenylphosphonio) ethyl, isobutyl, vinyl, allyl, p-nitrophenyl, benzyl, p-methoxybenzyl, 3,4- dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, S-benzyl thiocarbonate, 4- ethoxy-1 -naphthyl, and methyl dithiocarbonate.
  • assisted Cleavage protecting groups include: 2-iodobenzoate, 4- azido-butyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl) benzoate, 2- formylbenzene-sulfonate, 2-(methylthiomethoxy) ethyl carbonate, 4- (methylthiomethoxymethyl) benzoate, and 2-(methylthiomethoxymethyl) benzoate.
  • miscellaneous esters include: 2,6-dichloro-4- methylphenoxyacetate, 2,6-dichloro-4-(1 ,1 ,3,3-tetramethylbutyl) phenoxyacetate,
  • Sulfonates Protective sulfates includes: sulfate, methanesulfonate(mesylate), benzylsulfonate, and tosylate.
  • the protection for 1 ,2 and 1 ,3-diols group includes: cyclic acetals and ketals, cyclic ortho esters, and silyl derivatives. Cyclic Acetals and Ketals
  • Cyclic acetals and ketals include: methylene, ethylidene, 1-f-butylethylidene, 1-phenylethylidene, (4-methoxyphenyl) ethylidene, 2,2,2-trichloroethylidene, acetonide (isopropylidene), cyclopentylidene, cyclohexylidene, cycloheptylidene, benzylidene, p-methoxybenzylidene, 2,4- dimethoxybenzylidene, 3,4-dimethoxybenzylidene, and 2-nitrobenzylidene.
  • Cyclic ortho esters include: methoxymethylene, ethoxymethylene, dimethoxy- methylene, 1-methoxyethylidene, 1-ethoxyethylidine, 1 ,2- dimethoxyethylidene, ⁇ -methoxybenzylidene, 1-( ⁇ /, ⁇ /-dimethylamino)ethylidene derivative, -(N,N- dimethylamino) benzylidene derivative, and 2-oxacyclopentylidene.
  • Ester protecting groups include: esters, substituted methyl esters, 2- substituted ethyl esters, substituted benzyl esters, silyl esters, activated esters, miscellaneous derivatives, and stannyl esters. Substituted Methyl Esters
  • Substituted methyl esters include: 9-fluorenylmethyl, methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxy-methyl, benzyloxymethyl, phenacyl, p-bromophenacyl, ⁇ -methylphenacyl, p-methoxyphenacyl, carboxamidomethyl, and N- phthalimidomethyl.
  • 2-Substituted Ethyl Esters include: 2,2,2-trichloroethyl, 2-haloethyl, I- chloroalkyl, 2-(trimethylsily)ethyl, 2-methylthioethyl, 1 ,3-dithianyl-2-methyl, 2(p-nitrophenylsulfenyl)-ethyl, 2-(p-toluenesulfonyl)ethyl, 2-(2'-pyridyl)ethyl, 2- (diphenylphosphino)ethyl, 1 -methyl-1 -phenylethyl, f-butyl, cyclopentyl, cyclohexyl, allyl, 3-buten-1-yl, 4-(trimethylsily)-2-buten-1-yl, cinnamyl, ⁇ - methylcinnamyl, phenyl, p-(trimethylsily)ethyl, 2-methyl
  • Substituted Benzyl Esters include: triphenylmethyl, diphenylmethyl, bis(o-nitrophenyl)methyl, 9-anthrylmethyl, 2-(9,10-dioxo)anthrylmethyl, 5- dibenzo-suberyl, 1 -pyrenylmethyl,2-(trifluoromethyl)-6-chromylmethyl, 2,4,6- trimethylbenzyl, p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl, p- methoxybenzyl, 2,6-dimethoxybenzyl, 4-(methylsulfinyl)benzyl, 4-sulfobenzyl, piperonyl, and 4-P-benzyl. Silyl Esters
  • Silyl esters include: trimethylsilyl, triethylsilyl, f-butyldimethylsilyl, / ' - propyldimethylsilyl, phenyldimethylsilyl, and di- f-butylmethylsilyl.
  • Miscellaneous Derivatives includes: oxazoles, 2-alkyl-1 ,3-oxazolines, 4-alkyl- 5-OXO-1 , 3-oxazolidines, 5-alkyl-4-oxo-1 ,3-dioxolanes, ortho esters, phenyl group, and pentaaminocobalt(lll) complex.
  • Stannyl Esters include: trimethylsilyl, triethylsilyl, f-butyldimethylsilyl, / ' - propyldimethylsilyl, phenyldimethylsilyl, and di- f-butylmethylsilyl.
  • stannyl esters examples include: triethylstannyl and tri-n-butylstannyl.
  • Amides include: N,N -dimethyl, pyrrolidinyl, piperidinyl, 5,6- dihydrophenanthridinyl, o-nitroanilides, ⁇ /-7-nitroindolyl, ⁇ /-8-nitro-1 , 2,3,4- tetrahydroquinolyl, and p-P-benzenesulfonamides.
  • Hydrazides include: N- phenyl, N,N '-diisopropyl and other dialkyl hydrazides.
  • Carbamates include: carbamates, substituted ethyl, assisted cleavage, photolytic cleavage, urea-type derivatives, and miscellaneous carbamates.
  • Carbamates Carbamates include: methyl and ethyl, 9-fluorenylmethyl, 9-(2- sulfo)fluorenylmethyl, 9-(2,7-dibromo)fluorenylmethyl, 2,7-di-f-butyl-[9-(10,10- dioxo-10,10,10,10-tetrahydro- thioxanthyl)]methyl, and 4-methoxyphenacyl.
  • Substituted Ethyl protective groups include: 2,2,2-trichloroethyl, 2- t methylsilylethyl, 2-phenylethyl, 1-(1-adamantyl)-1-methylethyl, 1 ,1-dimethyl- 2-haloethyl, 1 ,1dimethyl-2,2-dibromoethyl, 1 ,1-dimethyl-2,2,2-trichloroethyl, 1- methyl-1 -(4-biphenylyl)ethyl, 1 -(3,5-di-f-butylphenyl)-1 -methylethyl, 2-(2'-and 4'-pyridyl)ethyl, 2-( ⁇ /, ⁇ /-icyclohexylcarboxamido)- ethyl, f-butyl, 1-adamantyl, vinyl, silyl, 1-isopropylally
  • Assisted Cleavage Protection via assisted cleavage includes: 2-methylthioethyl, 2-methylsulfonylethyl, 2-(p-toluenesu ⁇ fonyl)ethyl, [2-(1 ,3-dithianyl)]methyl, 4-methylthiophenyl, 2,4-dimethyl-thiophenyl, 2-phosphonioethyl,
  • Photolvtic Cleavage uses groups such as: m-nitrophenyl, 3,5- dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, and phenyl(o- nitrophenyl)methyl.
  • Urea-Type Derivatives examples include: phenothiazinyl-(10)-carbonyl derivative, N '-p-toluenesulfonylaminocarbonyl, and N '- phenylaminothiocarbonyl.
  • miscellaneous carbamates include: f-amyl, S-benzyl thiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropylmethyl, p-decyloxy-benzyl, diisopropylmethyl, 2,2- dimethoxycarbonylvinyl, o-( ⁇ /, ⁇ /-dimethyl-carboxamido)-benzyl, 1 ,1-dimethyl- 3( ⁇ /, ⁇ /-dimethylcarboxamido)propyl, 1 ,1-dimethyl-propynyl, di(2-pyridyl)methyl, 2-furanylmethyl, 2-iodoethyl, isobornyl, isobutyl, isonicotinyl, p(p - methoxyphenyl- azo)benzyl, 1-methylcyclo
  • Amides includes: ⁇ /-formyl, ⁇ /-acetyl, ⁇ /-chloroacetyl, ⁇ /-trichloroacetyl, ⁇ /-trifluoroacetyl, ⁇ /-phenylacetyl, ⁇ /-3-phenylpropionyl, ⁇ /-picolinoyl, ⁇ /-3- pyridyl-carboxamide, ⁇ /-benzoylphenylalanyl derivative, ⁇ /-benzoyl, and ⁇ /-p- phenylbenzoyl.
  • Assisted Cleavage Assisted cleavage groups include: ⁇ /-o-nitrophenylacetyl, N-o- nitrophenoxyacetyl, ⁇ /-acetoacetyl, ( ⁇ /-dithiobenzyloxycarbonylamino)acetyl, ⁇ /-3-(p-hydroxphenyl) propionyl, ⁇ /-3-(o-nitrophenyl)propionyl, ⁇ /-2-methyl-2- (o-nitrophenoxy)propionyl, ⁇ /-2-methyl-2-(o-phenylazophenoxy)propionyl, ⁇ /-4- chlorobutyryl, ⁇ /-3-methyl-3-nitrobutyryl, ⁇ /-o-nitrocinnamoyl, N- acetylmethionine derivative, ⁇ /-o-nitrobenzoyl, N-o- (benzoyloxymethyl)benzoyl, and 4,5-diphenyl-3-oxazolin-2-
  • Cyclic imide derivatives include: ⁇ /-phthalimide, ⁇ /-dithiasuccinoyl, ⁇ /-2,3-diphenyl-maleoyl, ⁇ /-2,5-dimethylpyrrolyl, ⁇ /-1 ,1 ,4,4-tetramethyldisilylazacyclopentane adduct, 5-substituted 1 ,3-dimethyl-1 ,3,5-triazacyclohexan-2-one, 5-substituted 1 ,3-dibenzyl- 1 ,3,5-triazacyclohexan-2-one, and 1-substituted 3,5-dinitro-4-pyridonyl.
  • Protective groups for - NH include: ⁇ /-alkyl and ⁇ /-aryl amines, imine derivatives, enamine derivatives, and ⁇ /-hetero atom derivatives (such as N- metal, N-N, N-P, N-Si, and N-S), ⁇ /-suifenyl, and ⁇ /-sulfonyl.
  • ⁇ /-alkyl and ⁇ /-aryl amines include: ⁇ /-methyl, ⁇ /-allyl,
  • Imine derivatives include: ⁇ /-1 ,1-dimethylthiomethylene, ⁇ /-benzylidene, ⁇ /-p-methoxybenzylidene, ⁇ /-diphenylmethylene,
  • An example of an enamine derivative is ⁇ /-(5,5-dimethyl-3-oxo-1-cyclohexenyl).
  • ⁇ /-Hetero Atom Derivatives include: ⁇ /-borane derivatives, ⁇ /-diphenylborinic acid derivative, ⁇ /-[phenyl(pentacarbonylchromium- or -tungsten)]carbenyl, and ⁇ /-copper or ⁇ /-zinc chelate.
  • N-N derivatives include: ⁇ /-nitro, ⁇ /-nitroso, and ⁇ /-oxide.
  • ⁇ /-P derivatives include: /-diphenylphosphinyl, /V-dimethylthiophosphinyl, ⁇ /-diphenylthiophosphinyl, ⁇ /-dialkyl phosphoryl, ⁇ /-dibenzyl phosphoryl, and ⁇ /-diphenyl phosphoryl.
  • ⁇ /-sulfenyl derivatives include: ⁇ /-benzenesulfenyl, ⁇ /-o-nitrobenzenesulfenyl, ⁇ /-2,4-dinitrobenzenesulfenyl, ⁇ /-pentachlorobenzenesulfenyl, ⁇ /-2-nitro-4-methoxy-benzenesulfenyl, N- triphenylmethylsulfenyl, and ⁇ /-3-nitropyridinesulfenyl.
  • ⁇ /-sulfonyl derivatives include: ⁇ /-p-toluenesulfonyl, ⁇ /-benzenesulfonyl, ⁇ /-2,3,6-trimethyl- 4-methoxybenzenesulfonyl, ⁇ /-2,4,6-trimethoxybenzenesulfonyl, N-
  • Disclosed compounds which are masked or protected may be prodrugs, compounds metabolized or otherwise transformed in vivo to yield a disclosed compound, e.g., transiently during metabolism.
  • This transformation may be a hydrolysis or oxidation which results from contact with a bodily fluid such as blood, or the action of acids, or liver, gastrointestinal, or other enzymes.
  • mice Male Sprague Dawley rats (250-300g), obtained from Bantin and Kingman, (Hull, U.K.) were housed in groups of 3. All animals were kept under a 12h light/dark cycle (lights on at 07h OOmin) with food and water ad libitum. All experiments were carried out by an observer blind to drug treatments.
  • PD 198306 [N-Cyclopropylmethoxy-3,4,5-trifluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide] and CI-1008 (pregabalin) were synthesized at Parke-Davis (Ann Arbor, Ml, USA). PD 198306 was suspended in cremophor:ethanol:water (1 :1 :8) vehicle. Pregabalin was dissolved in water. Both compounds were administered orally. Streptozocin (Aldrich, UK) was dissolved in 0.9% w/v NaCl and administered intraperitoneally. Drug administrations were made in a volume of 1 ml/kg.
  • Diabetes was induced in rats by a single i.p. injection of streptozocin (50mg/kg) as described previously (Courteix et al., 1993).
  • PD 198306 and pregabalin were administered intrathecally in a volume of 10 ⁇ l using a 100 ⁇ l Hamilton syringe by exposing the spine of the rats under brief isoflurane anaesthesia. Injections were made into the intrathecal space between lumbar region 5-6 with a 10 mm long 27 gauge needle. Penetrations were judged successful if there was a tail flick response. The wound was sealed with an autoclip and rats appeared fully awake within 2-3 min following injection.
  • Static allodynia was assessed with von Frey hairs, before (baseline, BL) and 0.5h, 1 h and 2h after intrathecal or intraplantar administration of PD 198306 (1-30 ⁇ g, i.t), vehicle (cremophor:ethanol:water, 1 :1 :8) or pregabalin (10 ⁇ g, i.t).
  • static allodynia was assessed with von Frey hairs, before (baseline, BL) and 1h after oral administration of PD 198306 (3-30mg/kg, p.o.), vehicle (cremophor:ethanol:water, 1 :1 :8) or pregabalin (30mg/kg, p.o.).
  • Static allodynia was assessed before and 1 h after the morning administration. In the afternoon static allodynia was assessed before, 1h, 2h and 3h after administration for streptozocin treated animals. CCI animals were assessed before, 1 h and 2h after administration
  • PD 198306 and pregabalin were synthesised at Parke-Davis (Ann Arbor, Ml, USA).
  • PD 198306 was suspended in cremophor:ethanol:water (1 :1 :8) vehicle.
  • Pregabalin was dissolved in water. Both compounds were administered orally, intrathecally or intraplantar in volumes of 1 ml/kg, 10 ⁇ l and 100 ⁇ l respectively.
  • Streptozocin (Aldrich, UK) was dissolved in 0.9% w/v NaCl and administered intraperitoneally in a volume of 1 ml/kg.
  • the animals and methods for developing chronic constriction injury in the rat, injecting test compounds, and evaluation of static allodynia were according to Example 2 above.
  • PD219622, PD297447, PD 184352, PD 254552 and pregabalin were administered intrathecally at doses of 30 ⁇ g for all PD compounds and 100 ⁇ g for pregabalin.
  • Static allodynia was assessed with von Frey hairs, before (baseline, BL) and 0.5h, 1h and 2h after intrathecal administration of the compounds
  • PD297447, PD219622, PD 254552, PD 184352 (CI-1040), and pregabalin were synthesised at Parke-Davis (Ann Arbor, Ml, USA).
  • PD297447, PD219622, PD 254552, PD 184352 (CI-1040), and pregabalin were synthesised at Parke-Davis (Ann Arbor, Ml, USA).
  • PD219622, PD 254552 and PD 184352 were suspended in cremophor:ethanol:water (1 :1 :8) vehicle.
  • Pregabalin was dissolved in water. All compounds were administered intrathecally in a 10 ⁇ l volume.
  • the antiallodynic effect was only evident for 30min post-injection and thus, shorter than the one observed for pregabalin (100 ⁇ g). The magnitude of the effect was similar for 30 ⁇ g of PD 184352 and 100 ⁇ g of pregabalin.
  • Phenyl-H 6.42-6.46(1 H, m, Phenyl-H); 5.02(2H, s, -NH 2 ), 2.20(3H, s, CH 3 ).

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WO2001005391A3 (en) 2001-07-19
IL147617A0 (en) 2002-08-14
KR20020015379A (ko) 2002-02-27
UY26248A1 (es) 2000-10-31
ZA200109903B (en) 2003-05-28
EP1202732A2 (en) 2002-05-08
AU5785900A (en) 2001-02-05
CO5190702A1 (es) 2002-08-29
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HUP0202381A2 (hu) 2002-11-28
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