EP1551789A1 - Intermediaires utilises dans la preparation d'acides amines bicycliques fusionnes a action therapeutique - Google Patents

Intermediaires utilises dans la preparation d'acides amines bicycliques fusionnes a action therapeutique

Info

Publication number
EP1551789A1
EP1551789A1 EP03799019A EP03799019A EP1551789A1 EP 1551789 A1 EP1551789 A1 EP 1551789A1 EP 03799019 A EP03799019 A EP 03799019A EP 03799019 A EP03799019 A EP 03799019A EP 1551789 A1 EP1551789 A1 EP 1551789A1
Authority
EP
European Patent Office
Prior art keywords
pain
formula
compound
carboxylic acid
preparation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP03799019A
Other languages
German (de)
English (en)
Inventor
I. R. c/o Pfizer Global Research & Dev. GLADWELL
A. J. c/o Pfizer Global Research & Dev. PETTMAN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Ltd
Pfizer Inc
Original Assignee
Pfizer Ltd
Pfizer Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pfizer Ltd, Pfizer Inc filed Critical Pfizer Ltd
Publication of EP1551789A1 publication Critical patent/EP1551789A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/608—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a ring other than a six-membered aromatic ring in the acid moiety
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/353—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by isomerisation; by change of size of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
    • C07C53/132—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen containing rings
    • C07C53/136—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen containing rings containing condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/26—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/14—All rings being cycloaliphatic
    • C07C2602/20—All rings being cycloaliphatic the ring system containing seven carbon atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • This invention relates to intermediates of novel cyclic amino derivatives useful as pharmaceutical agents and to processes for their production.
  • WO 99/21824 discloses cyclic amino acids that are useful in the treatment of epilepsy, faintness attacks, neurodegenerative disorders, depression, anxiety, panic, pain, neuropathological disorders, gastrointestinal disorders such as irritable bowel syndrome (DBS) and inflammation, especially arthritis.
  • the compounds disclosed include those of the formula:
  • R is hydrogen or a lower alkyl
  • Ri to R > are each independently selected from hydrogen, straight or branched alkyl of from 1 to 6 carbons, phenyl, benzyl, fluorine, chlorine, bromine, hydroxy, hydroxymethyl,
  • R is a straight or branched alkyl of from 1 to
  • n is an integer of from 1 to 4, where there are stereocentres, each center may be independently R or S, preferred compounds being those of Formulae I-IN above in which n is an integer of from 2 to 4.
  • the compounds are disclosed as being useful in treating a variety of disorders including epilepsy, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, pain, neuropathological disorders, and sleep disorders.
  • Patent application number EP 01400214.1 discloses the use of compounds of formula I to IN above for preventing and treatment of visceral pain, and gastrointestinal disorders.
  • R 1 and R 2 are each independently selected from H, straight or branched alkyl of 1-6 carbon atoms, cycloalkyl of from 3-6 carbon atoms, phenyl and benzyl, subject to the proviso that, except in the case of a tricyclooctane compound of formula (XVII), R 1 and R 2 are not simultaneously hydrogen; for use in the treatment of a number of indications, including pain.
  • the application discloses, as Method H, preparation of the following compounds:
  • the compound of formula (70) may be prepared by Method A described in PCT/IB02/01146, illustrated here from compound (9), a known compound, see L.Y.Chen, L.Ghosez, Tetrahedron Letters, 1990, 31, 4467; C. Houge,
  • the present invention provides a racemic intermediate of formula (I) or (IA):
  • R represents H or a suitable carboxylic acid protecting group, such as C 1-6 alkyl or benzyl.
  • the invention provides a process for the preparation of a compound of formula (I) or (IA), comprising reaction of a compound of formula (It) or (UA), respectively, with a compound of formula (HI)
  • R 1 represents a suitable phosphonyl ether group, such as Ci- ⁇ alkyl
  • R represents a suitable carboxylic acid protecting group, such as C ⁇ -6 alkyl or benzyl, followed by optional deprotection of the R group.
  • the compounds of formula (I) & (IA) are useful in the preparation of therapeutic compounds disclosed in PCT/IB02/01146.
  • the present invention provides the use of a compound of formula (I) or (IA) in the preparation of a therapeutic compound of formula (XII)
  • R represents H or a suitable carboxylic acid protecting group, such as C ⁇ -6 alkyl or benzyl, comprising:
  • R is a carboxylic acid protecting group, enzymatic esterification a compound of formula (I) or (IA) where R is H; or (iii) chromatographic resolution of the isomers of a compound of formula (I) or (IA); or (iv) where R is a carboxylic acid protecting group, by enzymatic hydrolysis of a compound of formula (I) or (IA) where R is a carboxylic acid protecting group, followed by re-esterification; or (v) where R is a carboxylic acid protecting group, by removal of the undesired stereoisomer of a compound of formula (I) or (IA) where R is a carboxylic acid protecting group by enzymatic hydrolysis.
  • Sutiable carboxylic acid protecting groups are well known to those skilled in the art and include C ⁇ -6 alkyl or benzyl groups or related derivatives. Suitable protecting groups are described in 'Protective Groups In Organic Synthesis', 3 r Edn., by Greene and Wuts, Wiley Interscience Publishing, ISBN 0-471-16019-9, particularly the list of substituted methyl esters, 2-substituted ethyl esters, 2,6- dialkylphenyl esters, substituted benzyl esters, silyl esters, activated esters, miscellaneous derivatives, stannyl esters, amides and hydrazides at page 369-372 and the description, with references, from page 372-422, which is incorporated herein by reference.
  • Suitable enzymes for enzymatic hydrolysis include Altus 13, Altus 57, Chirazyme L2 solution, Thermomyces Langinosus or Mucor Meihei, preferably Novozyme 435.
  • a suitable compound of formula (I) is selected from:
  • a suitable compound of formula (IA) is selected from:
  • 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.
  • the compounds of the present invention possess one or more chiral centers. 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 compounds of the invention may form base 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 therapeutic compounds formed from the intermediates of the present invention are useful as agents for treating or relieving the symptoms of neurodegenerative disorders.
  • neurodegenerative disorders include, for example, Alzheimer's disease, 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: stroke, head trauma, and asphyxia. Stroke refers to a cerebral vascular disease and may also be referred to as a cerebral vascular accident (CVA) and includes acute thromboembolic stroke. Stroke includes both focal and global ischemia. Also, included are transient cerebral ischemic attacks and other cerebral vascular problems accompanied by cerebral ischemia.
  • CVA cerebral vascular accident
  • vascular disorders may occur in a patient undergoing carotid endarterectomy specifically or other cerebrovascular or vascular surgical procedures in general, or diagnostic vascular procedures including cerebral angiography and the like.
  • 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, in cardiac arrest, and status epilepticus.
  • the therapeutic compounds described are also 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) and 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.
  • Pain tend to be quite heterogeneous and may present with various pain symptoms. There are a number of typical pain subtypes: 1) spontaneous pain which may be dull, burning, or stabbing; 2) pain responses to noxious stimuli are exaggerated (hyperalgesia); 3) pain is produced by normally innocuous stimuli (allodynia) (Meyer et al., 1994 Textbook of Pain 13-44). Although patients with back pain, arthritis pain, CNS trauma, or neuropathic pain may have similar symptoms, the underlying mechanisms are different and, therefore, may require different treatment strategies. Therefore 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 have both nociceptive 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.
  • postchemotherapy syndromes chronic postsurgical pain syndromes, post radiation syndromes
  • back pain which may be due to herniated or ruptured intervertabral discs or abnormalities of the lumber facet joints, sacroiliac joints, paraspinal muscles or the posterior longitudinal ligament.
  • 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. These include but are not limited to, Diabetic neuropathy, Post herpetic neuralgia, Back pain, Cancer neuropathy, HTV neuropathy, Phantom limb pain, Carpal Tunnel Syndrome, chronic alcoholism, hypothyroidism, trigeminal neuralgia, uremia, or vitamin deficiencies. Neuropathic pain is pathological as it has no protective role.
  • neuropathic pain are difficult to treat, as they are often heterogeneous even between patients with the same disease (Woolf & Decosterd 1999 Pain Supp. 6: S141-S147; Woolf and Mannion 1999 Lancet 353: 1959-1964). They include spontaneous pain, which can be continuous, or paroxysmal and abnormal evoked pain, such as hyperalgesia (increased sensitivity to a noxious stimulus) and allodynia (sensitivity to a normally innocuous stimulus).
  • 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 is a common cause of disability. 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).
  • - 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, scleredoma, scleredoma, skeletal muscle ischemia;
  • 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 can be divided into digestive visceral pain and non-digestive visceral pain. Commonly encountered gastrointestinal (GI) disorders include the functional bowel disorders (FBD) and the inflammatory bowel diseases (IBD).
  • GI gastrointestinal
  • BBD functional bowel disorders
  • IBD inflammatory bowel diseases
  • GI 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 therapeutic compounds are also expected to be useful in the treatment of anxiety and of panic as demonstrated by means of standard pharmacological procedures.
  • the biological activity of the therapeutic compounds of the invention may be measured in a radioligand binding assay using [ ⁇ HJgabapentin and the o ⁇ subunit derived from porcine brain tissue (Gee N.S., Brown J.P., Dissanayake V.U.K., Offord J., Thuriow R., Woodruff G.N., J. Biol. Chem., 1996;271:5879- 5776). Results may be expressed in terms of ⁇ M or nM ⁇ 2 ⁇ binding affinity.
  • the therapeutic compounds can be administered, for example but not limited to the following route: orally, buccally or sublingually in the form of tablets, capsules, multi-and nano-particulates, gels, films (incl. muco-adhesive), powder, ovules, elixirs, lozenges (incl. liquid-filled), chews, solutions, suspensions and sprays.
  • the compounds of the invention 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 as described in Ashley Publications, 2001 by Liang and Chen
  • the therapeutic compounds can also be administered by injection, that is, intravenously, intramuscularly, intracutaneously, intraduodenally, or intraperitoneally, intraarterially, intrathecally, intraventricularly, intraurethrally, intrasternally, intracranially, intraspinally or subcutaneously, or they may be administered by infusion, needle-free injectors or implant injection techniques.
  • the therapeutic compounds can be administered intranasally or by inhalation.
  • the therapeutic compounds may be administered topically to the skin, mucosa, 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, microemulsions and combinations thereof.
  • the therapeutic compounds can be administered rectally, for example in the form of a suppository or pessary. They may also be administered by vaginal route.
  • the therapeutic compounds may also be administered by the ocular route. They may also be administered in the ear, using for example but not limited to the drops.
  • the therapeutic compounds may also be used in combination with a cyclodextrin.
  • 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 of the therapeutic compounds 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 capsules, 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.
  • racemic ester 1.0 g; 5.6mmol
  • tert- butanol 4 ml
  • the resulting slurry was stirred for 5 minutes at 30°C.
  • Novozyme 435 500mg
  • immobilized Candida Antarctica lipase B was added to the reaction and the suspension was then stirred at the 30°C for 10 hours.
  • the heterogeneous mixture was filtered to recover the immobilized enzyme.
  • the filtrate was extracted three times with ethyl acetate (100ml) to remove the undesired enantiomer as the ester.
  • aqueous solution was then acidified to pH 3.5 with dilute hydrochloric acid and extracted three times with ethyl acetate (100ml), the combined organic phases were dried with sodium sulfate and concentrated in vacuo to give the title compound.
  • Example 2 The compound of Example 2 was dissolved in ethanol (20ml) and concentrated sulfuric acid was added. The reaction was heated to 80°C and stirred for 18 hours. The solvent was removed in vacuo to yield the title compound as an oil.
  • Triethylphosphonoacetate (96.2g; 429mmol) was added to a suspension of
  • the two phase filtrate was separated and the aqueous phase re- extracted with tert-butylmethyl ether (0.50 L).
  • the combined organic phases were extracted with a IM aqueous solution of sodium hydroxide (0.4 L).
  • the aqueous solution was then adjusted to pH 1-2 by the addtion of concentrated hydrochloric acid (40 ml) and extracted twice with tert-butylmethyl ether (0.40 L, then 0.20 L).
  • the combined organic phases were washed with demineralised water (0.40 L) and concentrated in vacuo to give the title compound (56.5 g) in 33.5% yield as a pale yellow oil which crystallised on standing.
  • Example 5 The compound of Example 5 (10.5 Kg; 69.0 mol) was dissolved in absolute ethanol (52.5 L) and 98wt% sulfuric acid (0.525Kg; 5.36 mol) was added at 20-25°C. The reaction mixture was then heated to 75°C over 0.5 hours and stirred for 24 hours. The reaction mixture was cooled to 10°C and a 40wt% solution of sodium hydroxide (3.17L) diluted with demineralised water (28.6 L) was added slowly to maintain the reaction temperature below 20°C. n-Heptane (31.5 L) was added and the phases were separated. The aqueous phase was then extracted again with n-heptane (31.5 L).
  • n-heptane solution (12.5L) of the acrylic ester of Example 6 (0.921 Kg; 5.11 mol) was concentrated by distillation at atmospheric pressure to 36% of its original volume. The n-heptane was then replaced with tetrahydrofuran by atmospheric azeotropic distillation at constant volume. The reaction mixture was cooled to 20-25°C, then tetrabutylammonium fluoride trihydrate (2.10Kg; 6.64 mol) and nitromethane (0.499 Kg, 8.18 mol) were added. The resulting brown solution was stirred at 20-25°C for 17 hours.
  • the cyclohexylamine salt of the nitro acid of Example 10 (100 g; 320 mmol) was added to a mixture of ethyl acetate (680 ml) and a 2M aqueous solution of hydrochloric acid (340 ml). The mixture was stirred vigorously for 10 minutes and the phases were separated. The organic layer was further washed with demineralised water (340 ml). The organic layer was separated and demineralised water (1360 ml) was added, to this two phase mixture 5% platinum on carbon as a 50% water wet catalyst (13.65 g) was added. The reaction mixture was then hydrogenated at 50°C and a hydrogen pressure of 150 psi for 24 hours.
  • the hydrogen was purged with nitrogen and the reaction mixture was heated to 70°C.
  • the reaction mixture was filtered through Celite at 70°C and the filter pad was washed with hot demineralised water (50 ml).
  • the filtrate was allowed to settle and phases were separated at 70°C, the lower aqueous phase was removed and concentrated by distillation at atmospheric pressure to a sixth of its original volume.
  • the white slurry was cooled to 50°C and isopropanol (705 ml) was then added over a period of 1.7 hours.
  • the white slurry was then cooled to between +5°C and +10°C over 90 minutes and stirred for 2.5 hours.
  • the solid was collected by filtration and the damp filter cake washed with isopropanol (60 ml).
  • a solution of nitro acid of Example 8 (928 g; 4.35 mol) in ethyl acetate (9.6L) was dried by atmospheric azeotropic distillation at constant volume. After cooling the solution to 40°C, cyclohexylamine (423 g; 4.26 mol) was added over 15 minutes. The resultant slurry was cooled to 20°C over 4 hours and left to stir for 13 hours at 20°C. The solid was collected by filtration and the damp filter cake washed with ethyl acetate (1.3 L). The isolated solid was then dried in vacuo at 30°C for 18 hours to give the title compound as a white solid (1.205 Kg) in 91% yield.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention présente des composés correspondant à la formule (I) dans laquelle R représente H ou un groupe protecteur à base d'acide carboxylique, qui sont des intermédiaires dans la préparation d'acides aminés bicycliques fusionnés à action thérapeutique.
EP03799019A 2002-10-04 2003-09-22 Intermediaires utilises dans la preparation d'acides amines bicycliques fusionnes a action therapeutique Withdrawn EP1551789A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB0223070 2002-10-04
GBGB0223070.4A GB0223070D0 (en) 2002-10-04 2002-10-04 Intermediates in the preparation of therapeutic fused bicyclic amino acids
PCT/IB2003/004179 WO2004031115A1 (fr) 2002-10-04 2003-09-22 Intermediaires utilises dans la preparation d'acides amines bicycliques fusionnes a action therapeutique

Publications (1)

Publication Number Publication Date
EP1551789A1 true EP1551789A1 (fr) 2005-07-13

Family

ID=9945336

Family Applications (1)

Application Number Title Priority Date Filing Date
EP03799019A Withdrawn EP1551789A1 (fr) 2002-10-04 2003-09-22 Intermediaires utilises dans la preparation d'acides amines bicycliques fusionnes a action therapeutique

Country Status (8)

Country Link
EP (1) EP1551789A1 (fr)
JP (1) JP2006501296A (fr)
AU (1) AU2003263487A1 (fr)
BR (1) BR0315046A (fr)
CA (1) CA2499863A1 (fr)
GB (1) GB0223070D0 (fr)
MX (1) MXPA05003638A (fr)
WO (1) WO2004031115A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110818550A (zh) * 2019-11-25 2020-02-21 东华理工大学 一种选择性酶促水解反应制备右旋异丁苯丙酸的方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TNSN03094A1 (fr) * 2001-04-19 2005-12-23 Warner Lambert Co Amino-acides condenses bicycliques ou tricycliques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2004031115A1 *

Also Published As

Publication number Publication date
GB0223070D0 (en) 2002-11-13
BR0315046A (pt) 2005-08-16
MXPA05003638A (es) 2005-06-03
JP2006501296A (ja) 2006-01-12
AU2003263487A1 (en) 2004-04-23
WO2004031115A1 (fr) 2004-04-15
CA2499863A1 (fr) 2004-04-15

Similar Documents

Publication Publication Date Title
EP1226110B1 (fr) Acides amines bicycliques utilises comme agents pharmaceutiques
JP5610600B2 (ja) 二環性化合物の製造方法
WO2000031020A1 (fr) Analogues d'acide gamma-aminobutyrique ameliores
JP2002516312A (ja) カルシウムチャンネルのα２δサブユニットに対する親和性を有する立体配座的に制約されたアミノ酸化合物
ZA200502305B (en) Proline derivatives having affinity for the calcium channel alpha-2-delta subunit
WO2010079668A1 (fr) Oléfine
AU2006238933B2 (en) Amino acid derivatives
US6911555B2 (en) Cyclic nitromethyl acetic acid derivatives
US7018818B2 (en) Intermediates in the preparation of therapeutic fused bicyclic amino acids
EP1551789A1 (fr) Intermediaires utilises dans la preparation d'acides amines bicycliques fusionnes a action therapeutique
US20040092498A1 (en) Substituted glycine derivatives for use as medicaments

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20050504

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL LT LV MK

DAX Request for extension of the european patent (deleted)
RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: PFIZER INC.

Owner name: PFIZER LIMITED

17Q First examination report despatched

Effective date: 20081112

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20090323