WO2004014357A2 - Utilisation therapeutique de derives d'acide amine d'aryle - Google Patents

Utilisation therapeutique de derives d'acide amine d'aryle Download PDF

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WO2004014357A2
WO2004014357A2 PCT/IB2003/003193 IB0303193W WO2004014357A2 WO 2004014357 A2 WO2004014357 A2 WO 2004014357A2 IB 0303193 W IB0303193 W IB 0303193W WO 2004014357 A2 WO2004014357 A2 WO 2004014357A2
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alkyl
compound
formula
disorders
pain
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WO2004014357A3 (fr
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Graham Nigel Maw
David James Rawson
Lisa Rosemary Thompson
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Pfizer Ltd Great Britain
Pfizer Inc
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Pfizer Ltd Great Britain
Pfizer Inc
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Priority to JP2004527144A priority Critical patent/JP2006507238A/ja
Priority to AU2003247056A priority patent/AU2003247056A1/en
Priority to MXPA05001534A priority patent/MXPA05001534A/es
Priority to BR0313284-6A priority patent/BR0313284A/pt
Priority to CA002495108A priority patent/CA2495108A1/fr
Priority to EP03784335A priority patent/EP1528919A2/fr
Publication of WO2004014357A2 publication Critical patent/WO2004014357A2/fr
Publication of WO2004014357A3 publication Critical patent/WO2004014357A3/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C07D271/07—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/22—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from lactams, cyclic ketones or cyclic oximes, e.g. by reactions involving Beckmann rearrangement
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1

Definitions

  • This invention relates to novel aryl amino acid derivatives useful as pharmaceutical agents, to processes for their production, to pharmaceutical compositions containing them, and to their use for the treatment of the conditions set out below.
  • Gabapentin is an anti-convulsant agent that is useful in the treatment of epilepsy and has recently been shown to be a potential treatment for neurogenic pain. It is 1-(aminomethyl)-cyclohexylacetic acid of structural formula:
  • Gabapentin is one of a series of compounds of formula
  • R is hydrogen or a lower alkyl radical and n is 4, 5, or 6.
  • R is hydrogen or a lower alkyl radical and n is 4, 5, or 6.
  • the present invention provides aryl amino acid derivatives and their prodrugs, and pharmaceutically acceptable salts and solvates useful in the treatment of a variety of disorders including faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, neuropathic pain, sleep disorders and neuropathological disorders.
  • the compounds provided may also be useful in the treatment of premenstrual syndrome.
  • the invention provides the use of compounds of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease selected from faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, neuropathic pain, sleep disorders and neuropathological disorders:
  • R 1 is H, C ⁇ -C 6 alkyl or C 3 -Ce cycloalkyl;
  • X is -(CH 2 ) n -C(R 7 )(R 8 )-;
  • Y is a direct link or -(CH 2 )m-C(R 9 )(R 10 )-;
  • R 7 , R 8 , R 9 and R 10 are independently H or C C 6 alkyl; or R 8 and R 1 can be taken together with the nitrogen to which R 1 is attached to form a 4-
  • R 10 and R 1 can be taken together with the nitrogen to which R 1 is attached to form a
  • R 8 and R 10 can be taken together with the carbons to which they are attached to form a 4-8- membered carbocyclic ring; n is 0, 1 or 2; m is 0, 1 or 2;
  • R 2 , R 3 , R 4 and R 5 are independently selected from H, CrC 6 alkyl, C ⁇ -C 6 alkoxy, hydroxy, halogen, hydroxycarbonyl, C ⁇ -C 6 alkoxycarbonyl, cyano, sulfonyl, C ⁇ -C 6 alkylsulfonyl, thio, C ⁇ -C ⁇ alkylthio, sulfonamide, perfluoro- Ci-C ⁇ alkyl, perfluoro- C Ce alkoxy, C 3 -C 8 cycloalkyl, 4-8 membered heterocycloalkyl, amino, (Ci-C ⁇ alkyl or di- C ⁇ - C ⁇ alkyl)amino, aminocarbonyl, (C ⁇ -C ⁇ alkyl or di- CI-CQ alkyl)aminocarbonyl, C ⁇ -C 6 acylamino, (N- Ci-C ⁇ alkyl)C ⁇ -C 6 acylamino, pheny
  • R 6 is hydroxycarbonyl or a carboxylic acid biostere or a prodrug thereof.
  • R 1 is suitably H.
  • Y is suitably a direct link.
  • X is suitably -C(R 7 )(R 8 )-, or R 7 is suitably H and R 8 is suitably H or C C 6 alkyl, e.g. methyl, or R 8 and R 2 suitably form a 4-8- membered carbocyclic ring, preferably a 5-membered carbocyclic ring, e.g. cyclopentyl, or R 8 and
  • R 1 suitably form a 4-8- membered heterocycloalkyl ring, preferably a 5-membered heterocycloalkyl ring, e.g. a tetrahydropyran ring.
  • R 2 , R 3 , R 4 and R 5 are suitably independently selected from H and halogen, e.g. bromide or chloride.
  • R 6 is preferably hydroxycarbonyl, tetrazole or oxazolidinone, most preferably hydroxycarbonyl.
  • a preferred subgroup according to the present invention is represented by a compound of formula (II):
  • R 7 and R 8 are independently H or C ⁇ -C 6 alkyl
  • R 2 , R 3 , R 4 and R 5 are independently selected from H, C C 6 alkyl, C- ⁇ -C 6 alkoxy, hydroxy, halogen, hydroxycarbonyl, C Ce alkoxycarbonyl, cyano, Ci-C ⁇ alkylsulfonyl, perfluoro- C ⁇ -C 6 alkyl, perfluoro- C ⁇ -C 6 alkoxy, C 3 -C 8 cycloalkyl and 4-8 membered heterocycloalkyl; or R 8 and R 2 can be taken together with the carbons to which they are attached to form a 4-8- membered carbocyclic or heterocycloalkyl ring.
  • Particularly preferred examples of the compounds of formula (I) are; 2-aminomethyl-5-chloro-benzoic acid; 2-aminomethyl-4,5-dichloro-benzoic acid; 2-aminomethyl-3-bromo-benzoic acid; 2-aminomethyl-6-chloro-benzoic acid; 2-(1-aminoethyl)-benzoic acid; 2,3-dihydro-1H-isoindole-4-carboxylic acid; and 3-(2-aminomethyl-5-chloro-phenyl)-4H-[1,2,4]oxadiazol-5-one; or a pharmaceutically acceptable salt thereof.
  • halo means fluoro, chloro, bromo or iodo.
  • Alkyl and alkoxy groups containing the requisite number of carbon atoms, except where indicated, can be unbranched- or branched-chain. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl. Examples of alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy and t- butoxy.
  • heterocycloalkyl when used herein refers to a single saturated or partially unsaturated ring system containing at least one ring heteroatom independently selected from O, S and N.
  • Suitable heterocycloalkyl groups include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, isoxazolidinyl, 1 ,3-oxazolidin-3-yl, isothiazolidinyl, 1,3- thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, piperidinyl, thiomorpholinyl, 1 ,2-tetrahydrothiazin-2-yl, 1 ,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl,
  • Monocyclic heteroaryl when used herein refers to a single aromatic ring containing at least one ring heteroatom independently selected from O, S and N.
  • Suitable heteroaryl groups include furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1 ,3,5-oxadiazolyl, 1,2,4- oxadiazolyl, 1 ,2,3-oxadiazolyl, 1 ,3,5-thiadiazolyl, 1 ,2,3-thiadiazolyl, 1 ,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1 ,2,4-triazinyl, 1 ,2,3-triazinyl, 1 ,3,5-triazinyl, etc.
  • C 3 -C 8 cycloalkyl refers to a single saturated or partially unsaturated carbocyclic ring.
  • Suitable cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl groups.
  • Carboxylic acid biostere when used herein refers to a group functionally equivalent to a carboxylic acid. Suitable biosteres include tetrazolyl, oxazolidinonyl, sulfonic acid, sulfinic acid, phosphonic acid, phosphinic acid, hydantoinyl, pyrrolidionyl and 3-isoxazolyl.
  • the present compounds can exist in unsolvated forms as well as solvated forms, including hydrated forms.
  • the solvated forms, including hydrated forms which may contain isotopic substitutions (e.g. D2O, d6-acetone, d6-DMSO), are equivalent to unsolvated forms and are encompassed within the scope of the present invention.
  • Certain of the compounds of the present invention possess one or more chiral centers and each center may exist in the R(D) or S(L) configuration.
  • the present invention includes all enantiomeric and epimeric forms as well as the appropriate mixtures thereof. Separation of diastereoisomers or cis and trans isomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or H.P.L.C. of a stereoisomeric mixture of a compound of the invention or a suitable salt or derivative thereof.
  • An individual enantiomer of a compound of the invention may also be prepared from a corresponding optically pure intermediate or by resolution, such as by H.P.L.C. of the corresponding racemate using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of the corresponding racemate with a suitable optically active acid or base, as appropriate.
  • the present invention also includes all suitable isotopic variations of a compound of the invention or a pharmaceutically acceptable salt thereof.
  • An isotopic variation of a compound of the invention or a pharmaceutically acceptable salt thereof is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • isotopes that can be incorporated into compounds of the invention and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F and 36 CI, respectively.
  • isotopic variations of the compounds of the invention and pharmaceutically acceptable salts thereof are useful in drug and/or substrate tissue distribution studies.
  • Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • substitution with isotopes such as deuterium, i.e., 2 H may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances.
  • Isotopic variations of the compounds of the invention and pharmaceutically acceptable salts thereof of this invention can generally be prepared by conventional procedures such as by the illustrative methods or by the preparations described in the Examples and Preparations hereafter using appropriate isotopic variations of suitable reagents.
  • pharmacologically compatible salts can be salts of appropriate non-toxic inorganic or organic acids or bases.
  • Suitable acid addition salts are the hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, sulphate, bisulphate, nitrate, phosphate, hydrogen phosphate, acetate, fumarate, aspartate, besylate, bicarbonate/carbonate, camsylate, D and L-lactate, D and L- tartrate, edisylate, mesylate, malonate, orotate, gluceptate, methylsulphate, stearate, glucuronate, 2-napsylate, tosylate, hibenzate, nicotinate, isethionate, malate, maleate, citrate, gluconate, succinate, saccharate, benzoate, esylate, and pamoate salts.
  • Suitable base salts are formed from bases which form non-toxic salts and examples are the sodium, potassium, aluminium, calcium, magnesium, zinc, choline, diolamine, olamine, arginine, glycine, tromethamine, benzathine, lysine, meglumine and diethylamine salts. Salts with quaternary ammonium ions can also be prepared with, for example, the tetramethyl-ammonium ion.
  • the compounds of the invention may also be formed as a zwitterion.
  • a suitable salt of compounds of the present invention is the hydrochloride salt.
  • Prodrugs of the above compounds are included in the scope of the instant invention.
  • the effectiveness of an orally administered drug is dependent upon the drug's efficient transport across the mucosal epithelium and its stability in entero-hepatic circulation.
  • Drugs that are effective after parenteral administration but less effective orally, or whose plasma half-life is considered too short, may be chemically modified into a prodrug form.
  • a prodrug is a drug which has been chemically modified and may be biologically inactive at its site of action, but which may be degraded or modified by one or more enzymatic or other in vivo processes to the parent bioactive form.
  • This chemically modified drug, or prodrug should have a different pharmacokinetic profile to the parent, enabling easier absorption across the mucosal epithelium, better salt formulation and/or solubility, improved systemic stability (for an increase in plasma half- life, for example).
  • These chemical modifications may be (1 ) Ester or amide derivatives which may be cleaved by, for example, esterases or lipases.
  • ester derivatives the ester is derived from the carboxylic acid moiety of the drug molecule by known means.
  • the amide may be derived from the carboxylic acid moiety or the amine moiety of the drug molecule by known means.
  • (2) Peptides which may be recognized by specific or nonspecific proteinases. A peptide may be coupled to the drug molecule via amide bond formation with the amine or carboxylic acid moiety of the drug molecule by known means.
  • the quaternary salt is termed a "soft" quaternary salt since, unlike normal quaternary salts, e.g., R-N + (CH3)3, it can release the active drug on hydrolysis.
  • "Soft" quaternary salts have useful physical properties compared with the basic drug or its salts. Water solubility may be increased compared with other salts, such as the hydrochloride, but more important there may be an increased absorption of the drug from the intestine.
  • Increased absorption is probably due to the fact that the "soft" quaternary salt has surfactant properties and is capable of forming micelles and unionized ion pairs with bile acids, etc., which are able to penetrate the intestinal epithelium more effectively.
  • the prodrug, after absorption, is rapidly hydrolyzed with release of the active parent drug.
  • Aminoacyl-glycolic and -lactic esters are known as prodrugs of amino acids (Wermuth C.G., Chemistry and Industry, 1980:433-435).
  • the carbonyl group of the amino acids can be esterified by known means.
  • Prodrugs and soft drugs are known in the art (Palomino E., Drugs of the Future, 1990;15(4):361-368). The last two citations are hereby incorporated by reference.
  • the invention also relates to therapeutic use of the present compounds as agents for treating or relieving the symptoms of neurodegenerative disorders.
  • neurodegenerative disorders include, for example, Huntington's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis.
  • the present invention also covers treating neurodegenerative disorders termed acute brain injury. These include but are not limited to: head trauma, and asphyxia. Other incidents are head trauma, spinal cord trauma, or injury from general anoxia, hypoxia, hypoglycemia, hypotension as well as similar injuries seen during procedures from embole, hyperfusion, and hypoxia.
  • the instant invention would be useful in a range of incidents, for example, during cardiac bypass surgery, in incidents of intracranial hemorrhage, in perinatal asphyxia and in cardiac arrest.
  • the compounds of the present invention are useful for the general treatment of pain, particularly neuropathic pain.
  • Physiological pain is an important protective mechanism designed to warn of danger from potentially injurious stimuli from the external environment.
  • the system operates through a specific set of primary sensory neurones and is exclusively activated by noxious stimuli via peripheral transducing mechanisms (Millan 1999 Prog. Neurobio. 57: 1-164 for an integrative Review).
  • These sensory fibres are known as nociceptors and are characterised by small diameter axons with slow conduction velocities. Nociceptors encode the intensity, duration and quality of noxious stimulus and by virtue of their topographically organised projection to the spinal cord, the location of the stimulus.
  • nociceptive nerve fibres of which there are two main types, A-delta fibres (myelinated) arid C fibres (non-myelinated).
  • A-delta fibres myelinated
  • C fibres non-myelinated.
  • the activity generated by nociceptor input is transferred after complex processing in the dorsal horn, either directly or via brain stem relay nuclei to the ventrobasal thalamus and then on to the cortex, where the sensation of pain is generated.
  • Intense acute pain and chronic pain may involve the same pathways driven by pathophysiological processes and as such cease to provide a protective mechanism and instead contribute to debilitating symptoms associated with a wide range of disease states. Pain is a feature of many trauma and disease states. When a substantial injury, via disease or trauma, to body tissue occurs the characteristics of nociceptor activation are altered. There is sensitisation in the periphery, locally around the injury and centrally where the nociceptors terminate. This leads to hypersensitivity at the site of damage and in nearby normal tissue. In acute pain these mechanisms can be useful and allow for the repair processes to take place and the hypersensitivity returns to normal once the injury has healed. However, in many chronic pain states, the hypersensitivity far outlasts the healing process and is normally due to nervous system injury.
  • pain can be divided into a number of different areas because of differing pathophysiology, these include nociceptive, inflammatory, neuropathic pain etc. It should be noted that some types of pain have multiple aetiologies and thus can be classified in more than one area, e.g. Back pain, Cancer pain can have nociceptive inflammatory and neuropathic components.
  • Nociceptive pain is induced by tissue injury or by intense stimuli with the potential to cause injury. Pain afferents are activated by transduction of stimuli by nociceptors at the site of injury and sensitise the spinal cord at the level of their termination. This is then relayed up the spinal tracts to the brain where pain is perceived (Meyer et al., 1994 Textbook of Pain 13-44).
  • the activation of nociceptors activates two types of afferent nerve fibres. Myelinated A-delta fibres transmitted rapidly and are responsible for the sharp and stabbing pain sensations, whilst unmyelinated C fibres transmit at a slower rate and convey the dull or aching pain.
  • Moderate to severe acute nociceptive pain is a prominent feature of, but is not limited to pain from strains/sprains, post-operative pain (pain following any type of surgical procedure), posttraumatic pain, burns, myocardial infarction, acute pancreatitis, and renal colic. Also cancer related acute pain syndromes commonly due to therapeutic interactions such as chemotherapy toxicity, immunotherapy, hormonal therapy and radiotherapy.
  • Moderate to severe acute nociceptive pain is a prominent feature of, but is not limited to, cancer pain which may be tumour related pain, (e.g. bone pain, headache and facial pain, viscera pain) or associated with cancer therapy (e.g.
  • Neuropathic pain is defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system (IASP definition). Nerve damage can be caused by trauma and disease and thus the term 'neuropathic pain' encompasses many disorders with diverse aetiologies.
  • Neuropathic pain is pathological as it has no protective role. It is often present well after the original cause has dissipated, commonly lasting for years, significantly decreasing a patients quality of life (Woolf and Mannion 1999 Lancet 353: 1959-1964). The symptoms of neuropathic pain are difficult to treat, as they are often heterogeneous even between patients with the same disease (Woolf & Decosterd 1999 Pain Supp.
  • the inflammatory process is a complex series of biochemical and cellular events activated in response to tissue injury or the presence of foreign substances, which result in swelling and pain (Levine and Taiwo 1994: Textbook of Pain 45-56).
  • Arthritic pain makes up the majority of the inflammatory pain population.
  • Rheumatoid disease is one of the commonest chronic inflammatory conditions in developed countries and rheumatoid arthritis (RA) is a common cause of disability.
  • RA rheumatoid arthritis
  • the exact aetiology of RA is unknown, but current hypotheses suggest that both genetic and microbiological factors may be important (Grennan & Jayson 1994 Textbook of Pain 397-407).
  • IBD inflammatory bowel diseases
  • Musculo-skeletal disorders including but not limited to myalgia, fibromyalgia, spondylitis, sero-negative (non-rheumatoid) arthropathies, non-articular rheumatism, dystrophinopathy, Glycogenolysis, polymyositis, pyomyositis.
  • Central pain or 'thalamic pain' as defined by pain caused by lesion or dysfunction of the nervous system including but not limited to central post-stroke pain, multiple sclerosis, spinal cord injury, Parkinson's disease and epilepsy.
  • Heart and vascular pain including but not limited to angina, myocardical infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, sclerodoma, skeletal muscle ischemia.
  • Visceral pain and gastrointestinal disorders.
  • the viscera encompasses the organs of the abdominal cavity. These organs include the sex organs, spleen and part of the digestive system. Pain associated with the viscera may be neuropathic, nociceptive as well as inflammatory and can be divided into digestive visceral pain and non-digestive visceral pain.
  • Commonly encountered gastrointestinal (Gl) disorders include the functional bowel disorders (FBD) and the inflammatory bowel diseases (IBD).
  • Gl disorders include a wide range of disease states that are currently only moderately controlled, including - for FBD, gastro-esophageal reflux, dyspepsia, the irritable bowel syndrome (IBS) and functional abdominal pain syndrome (FAPS), and - for IBD, Crohn's disease, ileitis, and ulcerative colitis, which all regularly produce visceral pain.
  • Other types of visceral pain include the pain associated with dysmenorrhea, pelvic pain, cystitis and pancreatitis.
  • Head pain including but not limited to migraine, migraine with aura, migraine without aura, cluster headache, tension-type headache.
  • Orofacial pain including but not limited to dental pain, temporomandibular myofascial pain.
  • the compounds of formula (I) are preferably used for the treatment of neuropathic pain.
  • the compounds of the invention are also expected to be useful in the treatment of depression.
  • Depression can be the result of organic disease, secondary to stress associated with personal loss, or idiopathic in origin. There is a strong tendency for familial occurrence of some forms of depression suggesting a mechanistic cause for at least some forms of depression.
  • the diagnosis of depression is made primarily by quantification of alterations in patients' mood. These evaluations of mood are generally performed by a physician or quantified by a neuropsychologist using validated rating scales, such as the Hamilton Depression Rating Scale or the Brief Psychiatric Rating Scale. Numerous other scales have been developed to quantify and measure the degree of mood alterations in patients with depression, such as insomnia, difficulty with concentration, lack of energy, feelings of worthlessness, and guilt.
  • the standards for diagnosis of depression as well as all psychiatric diagnoses are collected in the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) referred to as the DSM.
  • a method for treating a disease selected from faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, neuropathic pain, sleep disorders, and neuropathological disorders comprising administering a therapeutically effective amount of a compound of formula (I) to a mammal in need of said treatment.
  • the biological activity of the compounds of the invention may be measured in a radioligand binding assay using [ ⁇ Hjgabapentin and the a ⁇ S subunit derived from porcine brain tissue (Gee N.S., Brown J.P., Dissanayake V.U.K., Offord J., Thurlow R., Woodruff G.N., J. Biol. Chem., 1996;271:5776-5879). Results may be expressed in terms of ⁇ M or nM ⁇ 2 ⁇ binding affinity.
  • the compounds of the instant invention may be administered in combination, either separately, simultaneously or sequentially, with one or more other pharmacologically active agents.
  • Suitable agents particularly for the treatment of neuropathic pain, include:
  • opioid analgesics e.g. morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine and pentazocine;
  • opioid analgesics e.g. morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, n
  • nonsteroidal antiinflammatory drugs e.g. aspirin, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen.ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, sulindac, tolmetin, zomepirac, and their pharmaceutically acceptable salts;
  • NSAIDs nonsteroidal antiinflammatory drugs
  • barbiturate sedatives e.g. amobarbital, aprobarbital, butabarbital, butabital, mephobarbital, metharbital, methohexital, pentobarbital, phenobartital, secobarbital, talbutal, theamylal, thiopental and their pharmaceutically acceptable salts;
  • benzodiazepines having a sedative action, e.g.
  • Hi antagonists having a sedative action e.g. diphenhydramine, pyrilamine, promethazine, chlorpheniramine, chlorcyclizine and their pharmaceutically acceptable salts
  • miscellaneous sedatives such as glutethimide, meprobamate, methaqualone, dichloralphenazone and their pharmaceutically acceptable salts
  • skeletal muscle relaxants e.g.
  • NMDA receptor antagonists e.g. dextromethorphan ((+)-3-hydroxy-N- methylmorphinan) and its metabolite dextrorphan ((+)-3-hydroxy-N- methylmorphinan), ketamine, memantine, pyrroloquinoline quinone and cis-4-
  • alpha-adrenergic active compounds e.g. doxazosin, tamsulosin, clonidine and 4- amino-6,7-dimethoxy-2-(5-methanesulfonamido-1 ,2,3,4-tetrahydroisoquinol-2-yl)- 5-(2-pyridyl) quinazoline;
  • tricyclic antidepressants e.g. desipramine, imipramine, amytriptiline and nortriptiline
  • anticonvulsants e.g. carbamazepine, gabapentin, pregabalin and valproate
  • serotonin reuptake inhibitors e.g. fluoxetine, paroxetine, citalopram and sertraline
  • coal-tar analgesics in particular, paracetamol
  • neuroleptics such as droperidol
  • Vanilloid receptor agonists e.g. resinferatoxin
  • Beta-adrenergic compounds such as propranolol
  • Local anaesthetics such as mexiletine
  • Corticosteriods such as dexamethasone
  • Combinations of the compounds of the present invention and other therapeutic agents may be administered separately, sequentially or simultaneously.
  • the present invention extends to a kit comprising a compound of formula (I), one or more other therapeutic agents, such as those listed above, and a suitable container.
  • the compounds of the invention can be administered alone or in combination with other drugs but will generally be administered in an admixture with suitable pharmaceutical excipient(s), diluent(s) or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • suitable pharmaceutical excipient is used herein to describe any ingredient other than the compound of the invention. If appropriate, auxiliaries can be added. Auxiliaries are preservatives, anti-oxidants, flavours or colourants.
  • the compounds of the invention may be administered in a composition of the immediate-, delayed-, modified-, sustained-, pulsed- or controlled- release type.
  • the compounds of formula (I) can be administered, for example but not limited to the following routes: orally, buccally or sublingually in the form of tablets, capsules, multi- and nano-particulates, liquids, gels, films (incl. muco-adhesive), powders, ovules, elixers, lozenges (incl. liquid-filled), chews, solutions, suspensions and sprays.
  • the compounds of formulae (I) may also be administered as osmotic dosage form, or in the form of a high energy dispersion or as coated particles or fast-dissolving, fast- disintegrating dosage form such as those described in Expert Opinion in Therapeutic Patents, H(6), 981-986 by Liang and Chen (2001).
  • the compounds of the formula (I) may be administered as crystalline or amorphous products. They may be obtained, for example as solid plugs, powders or films, by methods such as precipitation, crystallization, freeze drying, spray drying or evaporative drying. Microwave or radio frequency drying may also be used for this purpose. Suitable formulations of the compounds of formula (I) may be in hydrophilic or hydrophobic matrix, ion-exchange resin complex, coated or uncoated form and other types as described in US 6,106,864 as desired.
  • Such pharmaceutical compositions may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine and starch (preferably corn, potato or tapioca starch), mannitol, disintegrants such as sodium starch glycolate, crosscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), triglycerides, hydroxypropylcellulose (HPC), bentonite sucrose, sorbitol, gelatin and acacia.
  • excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine and starch (preferably corn, potato or tapioca starch), mannitol, disintegrants such as sodium starch glycolate, crosscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrroli
  • lubricating agents may be added to solid compositions, for example magnesium stearate, stearic acid, glyceryl behenate, PEG and talc or wetting agents, such as sodium lauryl sulphate or preservatives, anti-oxidants, flavours and colourants.
  • wetting agents such as sodium lauryl sulphate or preservatives, anti-oxidants, flavours and colourants.
  • polymers such as carbohydrates, phospholipids and proteins may be included.
  • Fast dispersing or dissolving dosage formulations may contain the following ingredients: aspartame, acesulfame potassium, citric acid, croscarmellose sodium, crospovidone, diascorbic acid, ethyl acrylate, ethyl cellulose, gelatin, hydroxypropylmethyl cellulose, magnesium stearate, mannitol, methyl methacrylate, mint flavouring, polyethylene glycol, fumed silica, silicon dioxide, sodium starch glycolate, sodium stearyl fumarate, sorbitol or xylitol.
  • dispersing or dissolving as used herein to describe FDDFs are dependent upon the solubility of the drug substance used, i.e.
  • the solid dosage forms such as tablets are manufactured using standard processes known to a forumaltionchemist, for example, by direct compression, wet, dry or melt granulation, melt congealing or extrusion.
  • the tablet cores which may be mono or multi-layer may be coated with appropriate overcoats known in the art.
  • Solid formulations for oral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • Suitable modified release formulations for the purposes of the invention are described in US Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in Verma et al., Pharmaceutical Technology On-line, 25(2), 1-14 (2001 ).
  • Solid compositions of a similar type may also be employed as fillers in capsules such as gelatin, starch or HPMC capsules.
  • Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols.
  • Liquid compositions may be employed as fillers in soft or hard capsules, such as gelatin capsule, and typically comprise a carrier, for example water, ethanol, propylene glycol, methylcellulose or a suitable oil, and one or more emulsifying agents and/or suspending agents.
  • a carrier for example water, ethanol, propylene glycol, methylcellulose or a suitable oil
  • emulsifying agents and/or suspending agents for aqueous and oily suspensions, solutions, syrups and/or elixirs, the compounds of the invention may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol, methylcellulose, alginic acid or sodium alginate, glycerin, oils, hydrocolloid agents and combinations thereof.
  • formulations containing these compounds and excipients may be presented as a dry product for reconstitution with water or other suitable vehicles
  • Liquid form preparations include solutions, suspensions, syrups, elixirs and emulsions, for example, water or water propylene glycol solutions.
  • liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
  • the compounds of the present invention can also be administered by injection, that is, intravenously, intramuscularly, intracutaneously, intraduodenally, or intraperitoneally, intra-arterially, intrathecally, intraventricularly, intraurethrally, intrasternally, intracranially, intraspinally or subcutaneously.
  • Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors, infusion or implant injection techniques.
  • needle injectors including microneedle injectors, needle-free injectors, infusion or implant injection techniques.
  • parenteral administration they are best used in the form of a sterile aqueous solution, suspension or emulsion (or system so that can include micelles) which may contain other substances known in the art, for example, enough salts or carbohydrates, such as glucose to make the solution isotonic with blood.
  • aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary.
  • parenteral administration they may be used in the form of a sterile non-aqueous system such as fixed oils, including mono- or diglycerides, and fatty acids, including oleic acid.
  • suitable parenteral formulations under sterile conditions for example lyophilisation is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art.
  • the active ingredient may be in a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • solubility of compounds of formula (I) used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.
  • Formulations for parenteral administration may be formulated to be immediate and/or modified release.
  • compounds of formula (I) may be formulated in a more solid form for administration as an implanted depot providing long-term release of the active compound.
  • the compounds of the present invention can be administered intranasally or by inhalation. They are conveniently delivered in the form of a dry powder (either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids) from a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist) or nebuliser, with or without the use of a suitable propellant, e.g.
  • a dry powder either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids
  • atomiser preferably an atomiser using electrohydrodynamics to produce a fine mist
  • nebuliser e.g.
  • a hydrofluoroalkane such as 1 ,1 ,1 ,2-tetralfuoroethane (HFA 134A [trade mark]) or 1 ,1 ,1,2,3,3,3-heptafluoropropane (HFA 227EA [trade mark])
  • carbon dioxide a further perfluorinated hydrocarbon such as Perflubron [trade mark] or other suitable gas.
  • the pressurised container, pump, spray, atomiser or nebuliser may contain a solution or suspension of the active compound, for example using a mixture of ethanol (optionally, aqueous ethanol) or a suitable agent for dispersing, solubilising or extending release and the propellant as the solvent, which may additionally contain a surfactant, such as sorbitan trioleate or an oligolactic acid.
  • a surfactant such as sorbitan trioleate or an oligolactic acid.
  • Capsules, blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as l-leucine, mannitol or magnesium stearate.
  • the dosage unit is determined by means of a valve which delivers a metered amount.
  • the compound of the invention Prior to use in a dry powder formulation or suspension formulation for inhalation the compound of the invention is micronised to a size suitable for delivery by inhalation (typically considered as less than 5 microns). Micronisation may be achieved by any appropriate comminuting method, for example spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation or by spray drying.
  • a suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1 ⁇ g to 10mg of the compound of the invention per actuation and the actuation volume may vary from 1 /I to 100 ⁇ l.
  • a typical formulation may comprise a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride.
  • Alternative solvents may be used in place of propylene glycol, for example glycerol or polyethylene glycol.
  • Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release.
  • the compounds of the invention may be administered topically to the skin or mucosa, either dermally or transdermally, for example, in the form of a gel, hydrogel, lotion, solution, cream, ointment, dusting powder, dressing, foam, film, skin patch, wafers, implant, sponges, fibres, bandage, microemulsion and combinations thereof.
  • Liposomes may also be used.
  • the compounds formula (I) can be suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, glycerin, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid, water, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, alcohols such as ethanol.
  • penetration enhancers may be used- see, for example J. Pharm.
  • the following may also be used polymers, carbohydrates, proteins, phospholipids in the form of nanoparticles (such as niosomes or liposomes) or suspended or dissolved. In addition, they may be delivered using iontophoresis, electroporation, phonophoresis and sonophoresis.
  • topical administration include delivery by iontophoresis, electroporation, phonophoresis, sonophoresis and needle-free or microneedle injection.
  • Formulations for topical administration may be formulated to be immediate and/or modified release.
  • the compounds of the invention can be administered rectally, for example in the form of a suppository, pessary or enema. They may also be administered by vaginal route.
  • these compositions may be prepared by mixing the drug with a suitable non-irritant excipients, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the cavity to release the drug.
  • Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release.
  • the compounds of the invention may also be administered directly to the eye or ear.
  • the compounds of formula (I) can be formulated as micronised suspensions or solutions in isotonic, pH adjusted, sterile saline.
  • a polymer may be added such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer (e.g. hydroxypropylmethylcellulose, hydroxyethylcellulose or methyl cellulose), or a heteropolysaccharide polymer (e.g. gelan gum).
  • they may be formulated in an ointment such as petrolatum or mineral oil, incorporated into bio-degradable (e.g.
  • Formulations may be optionally combined with a preservative, such as benzalkonium chloride. In addition, they may be delivered using iontophoresis.
  • Formulations for ocular/aural administration may be formulated to be immediate and/or modified release.
  • the compounds of the invention may also be used in combination with soluble macromolecular entities such as cyclodextrin or polyethylene glycol-containing polymers to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability.
  • Drug-cyclodextrin complexes are generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used.
  • the cyclodextrin may be used as an auxiliary additive, e.g. as a carrier, diluent or solubiliser.
  • Alpha-, beta- and gamma- cyclodextrins are most commonly used and suitable examples are described in WO-A- 91/11172, WO-A-94/02518 and WO-A-98/55148.
  • the term 'administered' includes delivery by viral or non-viral techniques.
  • Viral delivery mechanisms include but are not limited to adenoviral vectors, adeno- associated viral (AAV) vectors, herpes viral vectors, retroviral vectors, lentiviral vectors, and baculoviral vectors.
  • Non-viral delivery mechanisms include lipid mediated transfection, lipsomes, immunoliposomes, lipofectin, cationic facial amphiphiles (CFAs) and combinations thereof.
  • the routes for such delivery mechanisms include but are not limited to mucosal, nasal, oral, parenteral, gastrointestinal, topical or sublingual routes.
  • the pharmaceutical preparation is preferably in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 1 g according to the particular application and the potency of the active component. In medical use the drug may be administered three times daily as, for example, capsules of 100 or 300 mg.
  • the compounds utilized in the pharmaceutical method of this invention are administered at the initial dosage of about 0.01 mg to about 100 mg/kg daily.
  • a daily dose range of about 0.01 mg to about 100 mg/kg is preferred.
  • the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.
  • the pharmaceutical composition according to the present invention can, if desired, also contain one or more other compatible therapeutic agents.
  • the composition can be combined with any one or more compounds useful in the treatment of pain, such as those listed above.
  • the present invention presents a pharmaceutical composition comprising a compound of formula (I) or (II) one or more other pharmacologically active agents and one or more pharmaceutically acceptable carriers.
  • a compound of formula (I) may be prepared by ring opening of a lactam of formula (III);
  • PG is H or a suitable protecting group, such as ferf-butoxycarbonyl
  • a suitable acid such as hydrochloric acid in a suitable solvent such as dioxan or by base mediated ring opening using a hydroxide source, such as lithium hydroxide, in a suitable solvent such as tetrahydrofuran, followed by deprotection of any protecting group present by methods known in the art, for example treatment with an acid such as hydrochloric acid in a suitable solvent such as diethyl ether or dioxan.
  • a compound of formula (I) may be prepared by deprotection of a compound of formula (IV) by methods known in the art; where PG is a suitable protecting group.
  • deprotection may be carried out by treatment with an acid such as hydrochloric acid in a suitable solvent such as diethyl ether or dioxan.
  • a compound of formula (IV) may be prepared from a compound of formula (V) according to Scheme 1.
  • a compound of formula (I) may be prepared from a compound of formula (IX) according to Scheme 2.
  • a compound of formula (I) may be prepared from a compound of formula (XI) according to Scheme 3.
  • a lactam of formula (III) may be prepared from a compound of formula (XIII);
  • a lactam of formula (III) can be prepared from a compound of formula (XIV);
  • lactam formation using a suitable ammonia source such as ammonium hydroxide in a suitable solvent such as tetrahydrofuran or ethanol at 0-25°C.
  • a suitable ammonia source such as ammonium hydroxide
  • a suitable solvent such as tetrahydrofuran or ethanol at 0-25°C.
  • a lactam of formula (III) can be prepared from a compound of formula (XV);
  • (XV) by treatment of (XV) with a suitable hydroxylamine source such as hydroxylamine hydrochloride and base such as pyridine in a suitable solvent such as methanol or ethanol at elevated temperatures to form a benzo[d][1 ,2]oxain-1-one, followed by ring opening and lactam formation by treatment with a suitable reducing agent such as zinc in an acid such as glacial acetic acid or hydrochloric acid at elevated temperatures.
  • a suitable hydroxylamine source such as hydroxylamine hydrochloride and base such as pyridine
  • a suitable solvent such as methanol or ethanol
  • protecting groups are present, these will be generally interchangeable with other protecting groups of a similar nature, e.g. where an amine is described as being protected with a fetf-butoxycarbonyl group, this may be readily interchanged with any suitable amine protecting group.
  • a pharmaceutically acceptable salt of a compound of the invention may be readily prepared by mixing together solutions of a compound of the invention and the desired acid or base, as appropriate.
  • the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • the invention provides:- (i) a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or pro-drug thereof; (ii) a pharmaceutical composition including a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or pro-drug thereof, together with a pharmaceutically acceptable excipient, diluent or carrier;
  • a method for the treatment of any of the conditions mentioned herinbefore which comprises administering to a patient in need of such treatment, either simultaneously, separately or sequentially, a combination of a compound of formula (I) and a further pain agent.
  • a combination of a compound of formula (I) and a further therapeutic agent for the manufacture of a medicament for the treatment of any of the conditions mentioned herinbefore; and
  • a product containing a compound of formula (I) and a further therapeutic agent as a combined preparation for simultaneous, separate or sequential use in the treatment of any of the conditions mentioned herinbefore.
  • Cai, Sui Xiong Zhou, Zhang-Lin: Huang, Jin-Cheng; Whittermore, Edward R; Egbuwoku, Zizi O; J. Med. Chem.; 39, 17, 1996, 3248-3255.
  • the previously prepared diazonium solution was added to the Cu(l)CN at 60°C over a period of 30 mins.
  • the reaction mixture was heated to 70°C for an additional 1 hour, then cooled to room temperature.
  • the brown mixture was diluted with ethyl acetate (70 ml), filtered through a pad of celiteTM, washed with ethyl acetate (3 x 20 ml), the combined organics washed with brine (50 ml), dried over magnesium sulfate, filtered and the solvent removed by evaporation under reduced pressure to give a dark orange solid.
  • the aqueous fraction was extracted with ethyl acetate (10 ml), the organics combined, washed with brine (10 ml), dried over magnesium sulfate, filtered and the solvent removed by evaporation under reduced pressure to give an orange oil.
  • the oil was taken into minimum amount of dichloromethane and purified by flash chromatography on silica gel eluting with a solvent gradient of heptane:ethyl acetate (3:1) to give the title compound (0.57 g, 57 %) as a pale yellow oil.
  • the active compound can be any compound of formula (I) and/or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.
  • compositions A and B can be prepared by wet granulation of ingredients (a) to (c) and (a) to (d) with a solution of povidone, followed by addition of the magnesium stearate and compression.
  • Composition A m ⁇ /tablet mq/tablet
  • Composition B m ⁇ /tablet mq/tablet
  • composition C mq/tablet Active ingredient 100
  • compositions D and E can be prepared by direct compression of the admixed ingredients.
  • the lactose used in formulation E is of the direct compression type.
  • Composition F Controlled release composition
  • composition can be prepared by wet granulation of ingredients (a) to (c) with a solution of povidone, followed by addition of the magnesium stearate and compression.
  • Composition G Enteric-coated tablet
  • Enteric-coated tablets of Composition C can be prepared by coating the tablets with 25mg/tablet of an enteric polymer such as cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethyl-cellulose phthalate, or anionic polymers of methacrylic acid and methacrylic acid methyl ester (Eudragit L). Except for Eudragit L, these polymers should also include 10% (by weight of the quantity of polymer used) of a plasticizer to prevent membrane cracking during application or on storage. Suitable plasticizers include diethyl phthalate, tributyl citrate and triacetin.
  • enteric polymer such as cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethyl-cellulose phthalate, or anionic polymers of methacrylic acid and methacrylic acid methyl ester (Eudragit L). Except for Eudragit L, these polymers should also include 10% (by weight of the quantity of polymer used) of a plasticizer
  • Composition H Enteric-coated controlled release tablet
  • Enteric-coated tablets of Composition F can be prepared by coating the tablets with 50mg/tablet of an enteric polymer such as cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethyl- cellulose phthalate, or anionic polymers of methacrylic acid and methacrylic acid methyl ester (Eudgragit L). Except for Eudgragit L, these polymers should also include 10% (by weight of the quantity of polymer used) of a plasticizer to prevent membrane cracking during application or on storage. Suitable plasticizers include diethyl phthalate, tributyl citrate and triacetin.
  • enteric polymer such as cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethyl- cellulose phthalate, or anionic polymers of methacrylic acid and methacrylic acid methyl ester (Eudgragit L). Except for Eudgragit L, these polymers should also include 10% (by weight of the quantity of polymer used
  • Capsules can be prepared by admixing the ingredients of Composition D above and filling two-part hard gelatin capsules with the resulting mixture.
  • Composition B (infra) may be prepared in a similar manner.
  • Capsules can be prepared by melting the Macrogol 4000 BP, dispersing the active ingredient in the melt and filling two-part hard gelatin capsules therewith.
  • Capsules can be prepared by dispersing the active ingredient in the lecithin and arachis oil and filling soft, elastic gelatin capsules with the dispersion.
  • Composition E Controlled release capsule
  • the controlled release capsule formulation can be prepared by extruding mixed ingredients (a) to (c) using an extruder, then spheronising and drying the extrudate. The dried pellets are coated with a release controlling membrane (d) and filled into two- part, hard gelatin capsules.
  • Composition F Enteric capsule
  • the enteric capsule composition can be prepared by extruding mixed ingredients (a) to (c) using an extruder, then spheronising and drying the extrudate. The dried pellets are coated with an enteric membrane (d) containing a plasticizer (e) and filled into two-part, hard gelatin capsules.
  • Composition G Enteric-coated controlled release capsule
  • Enteric capsules of Composition E can be prepared by coating the controlled-release pellets with 50mg/capsule of an enteric polymer such as cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate, or anionic polymers of methacrylic acid and methacrylic acid methyl ester (Eudragit L). Except for Eudragit L, these polymers should also include 10% (by weight of the quantity of polymer used) or a plasticizer to prevent membrane cracking during application or on storage. Suitable plasticizers include diethyl phthalate, tributyl citrate and triacetin. (iii) Intravenous injection composition
  • the active ingredient is dissolved in most of the phosphate buffer at 35-40°C, then made up to volume and filtered through a sterile micropore filter into sterile 10 ml glass vials (Type 1) which are sealed with sterile closures and overseals.
  • the active ingredient is dissolved in the glycofurol.
  • the benzyl alcohol is then added and dissolved, and water added to 3 ml.
  • the mixture is then filtered through a sterile micropore filter and sealed in sterile 3 ml glass vials (Type 1 ).
  • Witepsol H15 is melted in a steam-jacketed pan at 45°C maximum.
  • the active ingredient is sifted through a 200lm sieve and added to the molten base with mixing, using a Silverson fitted with a cutting head, until a smooth dispersion is achieved. Maintaining the mixture at 45°C, the remaining Witepsol H15 is added to the suspension which is stirred to ensure a homogenous mix.
  • the entire suspension is then passed through a 250lm stainless steel screen and, with continuous stirring, allowed to cool to 40°C. At a temperature of 38-40°C, 2.02g aliquots of the mixture are filled into suitable plastic moulds and the suppositories allowed to cool to room temperature.
  • Hydroxyethyl cellulose The active ingredient and alcohol USP are gelled with hydroxyethyl cellulose and packed in a transdermal device with a surface area of 10cm .

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  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Psychology (AREA)
  • Anesthesiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Indole Compounds (AREA)

Abstract

Selon cette invention, les composés de formule (I) sont utilisés dans le traitement d'attaques de lipothymie, d'hypocinésie, de troubles crâniens, de troubles neurodégénératifs, de dépression, d'anxiété, de panique, de douleurs neuropathiques, de troubles neuropathologiques et de troubles du sommeil. Ladite invention a aussi trait à des processus de préparation des produits finaux et d'intermédiaires utilisés dans le traitement, ainsi que des compositions pharmaceutiques renfermant au moins un desdits composés.
PCT/IB2003/003193 2002-08-09 2003-07-29 Utilisation therapeutique de derives d'acide amine d'aryle Ceased WO2004014357A2 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
JP2004527144A JP2006507238A (ja) 2002-08-09 2003-07-29 アリールアミノ酸誘導体の治療的使用
AU2003247056A AU2003247056A1 (en) 2002-08-09 2003-07-29 Therapeutic use of aryl amino acid derivatives
MXPA05001534A MXPA05001534A (es) 2002-08-09 2003-07-29 Uso terapeutico de derivados arilo de aminoacidos.
BR0313284-6A BR0313284A (pt) 2002-08-09 2003-07-29 Utilização terapêutica de derivados de aril-aminoácidos
CA002495108A CA2495108A1 (fr) 2002-08-09 2003-07-29 Utilisation therapeutique de derives d'acide amine d'aryle
EP03784335A EP1528919A2 (fr) 2002-08-09 2003-07-29 Utilisation therapeutique de derives d'acide amine d'aryle

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB0218590.8A GB0218590D0 (en) 2002-08-09 2002-08-09 Therapeutic use of aryl amino acid derivatives
GB0218590.8 2002-08-09

Publications (2)

Publication Number Publication Date
WO2004014357A2 true WO2004014357A2 (fr) 2004-02-19
WO2004014357A3 WO2004014357A3 (fr) 2004-07-01

Family

ID=9942061

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2003/003193 Ceased WO2004014357A2 (fr) 2002-08-09 2003-07-29 Utilisation therapeutique de derives d'acide amine d'aryle

Country Status (8)

Country Link
EP (1) EP1528919A2 (fr)
JP (1) JP2006507238A (fr)
AU (1) AU2003247056A1 (fr)
BR (1) BR0313284A (fr)
CA (1) CA2495108A1 (fr)
GB (1) GB0218590D0 (fr)
MX (1) MXPA05001534A (fr)
WO (1) WO2004014357A2 (fr)

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0759750A4 (fr) * 1994-05-11 1998-05-27 Howard K Shapiro Compositions pour le traitement de maladies inflammatoires chroniques

Also Published As

Publication number Publication date
WO2004014357A3 (fr) 2004-07-01
GB0218590D0 (en) 2002-09-18
EP1528919A2 (fr) 2005-05-11
BR0313284A (pt) 2005-07-12
MXPA05001534A (es) 2005-04-19
AU2003247056A1 (en) 2004-02-25
JP2006507238A (ja) 2006-03-02
CA2495108A1 (fr) 2004-02-19

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