WO1993020052A1 - Enantiomeric 1-phenyl-2-(2-pyridinyl)ethylamine for the treatment of neurodegenerative disorders - Google Patents

Enantiomeric 1-phenyl-2-(2-pyridinyl)ethylamine for the treatment of neurodegenerative disorders Download PDF

Info

Publication number
WO1993020052A1
WO1993020052A1 PCT/GB1993/000689 GB9300689W WO9320052A1 WO 1993020052 A1 WO1993020052 A1 WO 1993020052A1 GB 9300689 W GB9300689 W GB 9300689W WO 9320052 A1 WO9320052 A1 WO 9320052A1
Authority
WO
WIPO (PCT)
Prior art keywords
phenyl
pyridineethanamine
pharmaceutically acceptable
treatment
compound
Prior art date
Application number
PCT/GB1993/000689
Other languages
French (fr)
Inventor
Ronald Conrad Griffith
Robert John Murray
Michael Balestra
Original Assignee
Fisons Corporation
Fisons Plc
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
Priority claimed from GB929207339A external-priority patent/GB9207339D0/en
Priority claimed from GB929208290A external-priority patent/GB9208290D0/en
Application filed by Fisons Corporation, Fisons Plc filed Critical Fisons Corporation
Priority to RU94042465A priority Critical patent/RU2128650C1/en
Priority to DK93907975T priority patent/DK0633879T3/en
Priority to CA002133427A priority patent/CA2133427C/en
Priority to UA94095853A priority patent/UA29437C2/en
Priority to SK1177-94A priority patent/SK281258B6/en
Priority to KR1019940703465A priority patent/KR100259567B1/en
Priority to JP05517251A priority patent/JP3120810B2/en
Priority to EP93907975A priority patent/EP0633879B1/en
Priority to PL93305404A priority patent/PL180014B1/en
Priority to DE69317411T priority patent/DE69317411T2/en
Priority to ZA932415A priority patent/ZA932415B/en
Priority to TW082103364A priority patent/TW282455B/zh
Priority to GB939320273A priority patent/GB9320273D0/en
Publication of WO1993020052A1 publication Critical patent/WO1993020052A1/en
Priority to IL10910894A priority patent/IL109108A/en
Priority to ZA942140A priority patent/ZA942140B/en
Priority to PCT/GB1994/000651 priority patent/WO1994022831A1/en
Priority to DE69404974T priority patent/DE69404974T2/en
Priority to EP94911232A priority patent/EP0691957B1/en
Priority to SG1996007883A priority patent/SG48204A1/en
Priority to JP6521814A priority patent/JP3023987B2/en
Priority to ES94911232T priority patent/ES2105672T3/en
Priority to DK94911232.0T priority patent/DK0691957T3/en
Priority to PH48016A priority patent/PH30950A/en
Priority to AU63802/94A priority patent/AU682348B2/en
Priority to CA002159478A priority patent/CA2159478C/en
Priority to AT94911232T priority patent/ATE156813T1/en
Priority to DZ940029A priority patent/DZ1765A1/en
Priority to US08/221,076 priority patent/US5455259A/en
Priority to MA23459A priority patent/MA23154A1/en
Priority to CN94103739A priority patent/CN1047168C/en
Priority to AT94912016T priority patent/ATE156814T1/en
Priority to DE69404975T priority patent/DE69404975T2/en
Priority to ES94912016T priority patent/ES2105679T3/en
Priority to EP94912016A priority patent/EP0691958B1/en
Priority to AU64337/94A priority patent/AU682350B2/en
Priority to DK94912016.6T priority patent/DK0691958T3/en
Priority to CA002159480A priority patent/CA2159480C/en
Priority to PCT/GB1994/000716 priority patent/WO1994022832A1/en
Priority to JP6521865A priority patent/JP3023988B2/en
Priority to NO943645A priority patent/NO302170B1/en
Priority to FI944546A priority patent/FI105025B/en
Priority to NO951546A priority patent/NO304647B1/en
Priority to NO953846A priority patent/NO304648B1/en
Priority to FI954646A priority patent/FI109019B/en
Priority to FI954645A priority patent/FI109018B/en
Priority to GR970402722T priority patent/GR3025081T3/en
Priority to GR970402723T priority patent/GR3025082T3/en
Priority to HK98110056A priority patent/HK1009331A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • 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
    • A61P25/08—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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A61P25/10—Antiepileptics; Anticonvulsants for petit-mal
    • 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
    • A61P25/12—Antiepileptics; Anticonvulsants for grand-mal
    • 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
    • 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
    • A61P25/28—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

Definitions

  • This invention relates to an enantiomer of a known compound, its use as a pharmaceuti ⁇ cal, in particular in the treatment of neurodegenerative disorders, a process for its s production, and pharmaceutical formulations containing it.
  • European Patent Application 356035 discloses a large number of compounds for use in the treatment of neurodegenerative disorders, including ⁇ -phenyl-2-pyridineethanamine [referred to therein as l-phenyl-2-(2-pyridinyl)ethylamine],
  • substantially free from its (R)-enantiomer is meant that a sample of the (S)- enantiomer contains less than 10% by weight of the (R)-enantiomer (i.e. it is more than 90% enantiopure), more preferably less than 1% by weight of the (R)-enantiomer, and most preferably is pure (S)-enantiomer.
  • compositions include compounds which are suitable bioprecursors (prodrugs) of (S)- ⁇ -phenyl-2-pyridineethanamine, and of particular interest - acid addition salts.
  • Suitable bioprecursors of (+)- ⁇ -phenyI-2-pyridineethanamine include amino acid amide derivatives of the amino group, in particular ⁇ -am ⁇ no acid derivatives such as giycine derivatives.
  • Such derivatives may be prepared by conventional methods, for example amino acid amide derivatives may be prepared by the methods given in 'Advanced Organic Chemistry' by J March, 2nd edition, published by McGraw-Hill, page 1171.
  • Acid addition salts of (S)- ⁇ -phenyl-2-pyridineethanamine include salts of mineral acids, for example the dihydrochloride and dihydrobromide salts; and salts formed with organic acids such as formate, acetate, malate, benzoate and fumarate salts.
  • ⁇ -Phenyl-2-r- ⁇ dineethanamine may be prepared by conventional methods (for example, addition of the anion of 2-picoline to N-trimethylsilyl-benzaldimine).
  • (S)- ⁇ -phenyl-2- pyridineethanamine may then be prepared by one or more selective precipitations of a diastereomeric salt formed by reaction of ⁇ -phenyl-2-pyridineethanamine with a chiral salt, followed by one or more recrystallizations.
  • a process for the preparation of a compound of the invention which comprises selective precipitation of a diastereomeric salt formed between ⁇ -phenyl-2-pyridineethanamine and a chiral acid.
  • Chiral acids which may be mentioned include D- or L-tartaric acids and in particular S(+)- and R(-)-mandelic acids.
  • the precipitation may be carried out in an organic solvent which does not adversely affect the reaction (for example ethyl acetate), at or around room tempera ⁇ ture.
  • the compounds of the invention are indicated as pharmaceuticals, in particular as anticonvulsants and neuroprotective agents in the treatment of neurodegenerative disorders.
  • Specific neurodegenerative disorders include stroke, cerebral ischaemia, cerebral palsy, the effects of hypoglycaemia, epilepsy, AIDS-related dementia, Alzheimer's disease, Huntington's chorea, Olivo-ponto-cerebellar atrophy, perinatal asphyxia, Parkinson's disease, anoxia, neuronal damage associated with substance abuse (for example, narcotics or cocaine), retinopathies, schizophrenia, ischaemic states after cardiac arrest or surgical operations, intoxication or injuries of the spinal cord and amyotrophic lateral sclerosis.
  • Glutamate is an endogenous amino acid which has been characterized as a fast excitatory transmitter in the mammalian brain. Glutamate is also known as a powerful neurotoxin capable of killing CNS neurons under certain pathologic conditions which accompany stroke and cardiac arrest. It has been shown that the sensitivity of central neurons to hypoxia and ischaemia can be reduced by the specific antagonism of post synaptic glutamate receptors. Glutamate is characterized as a broad spectrum agonist having activity at four neuronal excitatory amino acid receptor sites.
  • Glutamate is believed to be a mixed agonist capable of binding to and exciting all four receptor types.
  • agents which selectively block or antagonise the action of glutamate at these receptors can prevent neurotoxic injury associated with anoxia, hypoxia or ischemia.
  • compounds which bind to the NMDA receptor site and selectively block the action of glutamate are useful in the prevention and treatment of neurodegenerative diseases.
  • NMDA blocking activity is measured by assessing a compound ' s ability to protect mice from convulsions induced by intravenous administration of 150mg/kg of NMDA according to the procedures of Czuczwar et al, (Neurotransmitters, Seizures and Epilepsy III, edited by G Nistico et al, Raven Press, New York 1986, pages 235-246). s Groups of mice are pretreated by 30 minutes with the test compound by the intra- peritoneal routes and then given NMDA. Animals were observed for convulsions as defined by loss of righting reflex and appearance of tonic/clonic seizures.
  • NMDA receptor antagonist activity may be measured in vitro by assaying a o compound's ability to inhibit binding of the receptor antagonist 10, 1 l-dihydro-5-methyl-
  • mice 5H-dibenzo[a,d]-cyclohepten-5,10-imine (MK 801) to the receptor. The method is described by Foster and Wong, Br J Pharmacol 91, 403-409 (1987).
  • NMDA and glycine receptor affinity may also be tested in the [ 3 H]L-glutamate and [ 3 H]glycine binding assays following the method of Monaghan & Cotman, PNAS, s 83, 7532, (1986) and Watson et al, Neurosci Res Comm, 2, 169, (1988).
  • Antihypoxia activity may be measured conveniently in mice. Groups of mice are tested at various times after the intraperitoneai administration of graded doses of the test compound.
  • the animals' survival time in a temperature-controlled hypoxic environment (96% nitrogen and 4% oxygen) is recorded. A statistical comparison is 0 made between coincident vehicle treated animals and the experimental group.
  • the dose-response and minimum active dose (MAD) for compounds are obtained [A A Artu and J D Michenf elder, Anaesthesia and Analgesia, 1981, 60, 867]. Other modes of administration can also be used.
  • Antiepileptic activity may be measured by assessing a compound's ability to 25 prevent the hind limb tonic extension component of the seizure in groups of mice or rats induced by maximal electroshock (MES) after oral, intraperitoneai, intravenous or subcutaneous administration, according to the procedures of the Epilepsy Branch, NINCDS as published by R J Porter, et al, Cleve Clin Quarterly 1984, 51, 293, and compared with the standard agents dilantin and phenobarbital.
  • MES maximal electroshock
  • the 4-vessel occlusion (4-VO) model of stroke is used to produce global ischaemia in the rat and is an essential technique to evaluate the effectiveness of compounds to prevent damage to areas of selective vulnerability in the brain, notably the CA1 pyramidal neurons of the hippocampus. This area is involved in the pathways for short term memory formation in both laboratory animals and humans.
  • the procedure consists of cauterizing the vertebral arteries and isolating the carotid arteries of rats maintained under anaesthesia on day 1. On day 2 the carotids are clamped for varying periods of time, ten minutes is sufficient to destroy the CAl neurons. The clamps are removed, reflow initiated and drugs administered at various times post reflow.
  • Body temperature is maintained at 37°C throughout the ischaemia and recovery periods.
  • the CAl neurons die off over a 48-72 hour period and normally the rats are treated for at least 3 days with drug (ip, iv, or po) and at 7 days the brains are removed for histology. Rating of CAl damage is accomplished using two methods, counting of viable CAl neurons and scoring of degree of gross pathology [W A Pulsinelli and A Buchan, 'The NMDA receptor/ion channel: Its importance to in vivo ischemia injury to selectively vulnerable neurons', Pharmacology of Cerebral Ischemia, edited by J Krieglstein and H Oberpichler, published by Academicliche Verlagsgesellschaft, Stuttgart, 1990, pl69].
  • SHR spontaneously hypertensive rats
  • a 2 hour focal ischemia is achieved in SHR by clamping the middle cerebral artery and the ipsilateral carotid while maintaining anaesthesia.
  • Drugs can be administered (usually ip) either before or various times after clamping the arteries or when reflow commences at 2 hours.
  • the brains are removed 24 hours after the experiment and frozen, sectioned and drug effects toward reducing infarct volume of the cerebral cortex is determined using a custom-built computer quantification system [A M Buchan, D Xue and A Slivka, Stroke, 1992, 23, 273.]
  • Toxicity of the compounds of the invention may be measured in the following tests.
  • Rats are dosed intravenously daily with progressively increasing doses of test compound until a maximum repeatable dose is found above which the incidence of convulsions and other abnormal clinical signs is unacceptable.
  • the inverted screen test [L L Cougenour, J R McLean, and R B Parker, Pharmacol Biochem Behav, 1977, 6, 351]. Mice are dosed with test compound and 30 minutes later are placed on a small wire platform which is inverted through an arc of 180°. Mice unable to climb to the upright position within 30 seconds are rated as failures.
  • rats are dosed orally with test compound (expressed as multiples of the oral ED 50 for protection in the MES test) and placed into individual clear plastic cages and observed over a 4 hour period for any incidence of 5 characteristic behaviours associated with PCP, namely hyperactivity, ataxia, circling, head weaving and retropulsion.
  • test compound expressed as multiples of the oral ED 50 for protection in the MES test
  • Five rats per treatment group are observed and compared to a control group receiving PCP.
  • a total incidence score would be 25, i.e. 5 rats exhibiting all 5 behaviours.
  • PCP at 10 times the ED S0 produces a score of 25 [W Koek, J H Woods, P Ornstein, 1987, Psychopharmacology, 91, 297].
  • Rats are placed on a narrow board (1.25cm wide suspended 40cm above the bench top) in a well lit entry cubicle which enters a progressively darkened box connected to a dark escape cubicle at the other end (board is 63cm long). A rat is impaired if it fails to negotiate the plank.
  • the task takes into account two known behaviours of rats, i.e. fear of height and seeking a dark environ ⁇ ment.
  • Linear pharmacokinetics may be detected in rats by evaluating the area under the plasma concentration v time curves obtained upon single intravenous administration of test compound at increasing doses (Smith et al, Xenobiotica, 20, 1187-1199, 1990). Blood was removed from a jugular vein catheter at various times over a 24 hour period. The plasma was separated by centrifugation and the concentration of test compound was determined using HPLC-UN chromatography. The plasma concentration v time values were plotted for each dose and the area under each curve estimated. Where linear pharmacokinetics are present, the area under the plasma concentration v time curve for a given dose is directly proportional to the dose administered. A finding of linear pharmacokinetics in rats indicates that linear pharmacokinetics would be found in humans (Leander et al, Epilepsia, 33, 696-704, 1992, at p703).
  • a method of treatment of a neurodegenerative disorder which comprises administering a therapeutically effective amount of a compound of the invention to a patient.
  • a method of treatment of a neurodegenerative disorder which comprises administering a therapeutically effective amount of a compound of the invention to a patient.
  • the dose of the compound administered is linearly proportional to the blood plasma concentration of the compound desired.
  • the dosage administered will, of course, vary with the compound employed, the mode of adniinistration and the treatment desired. However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of from about O.lmg to about 20mg per kg of animal body weight, preferably given in divided doses 1 to 4 times a day or in sustained release form.
  • the total daily dose is in the range of from 5mg to l,400mg, more preferably from lOmg to lOOmg
  • unit dosage forms suitable for oral administration comprise from 2mg to l,400mg of the compound admixed with a solid or liquid pharmaceutical carrier or diluent.
  • a pharmaceutical composition comprising preferably less than 80% and more preferably less than 50% by weight of a compound of the invention in admixture with a pharmaceutically acceptable adjuvant- diluent or carrier.
  • diluents and carriers are: for tablets and dragees: lactose, starch, talc, stearic acid: for capsules: tartaric acid or lactose; for injectable solutions: water, alcohols, glycerin, vegetable oils; for suppositories: natural or hardened oils or waxes.
  • An adjuvant of particular interest when the compound of the invention is to be used in the treatment of Parkinson's disease is L-dopa.
  • a compound of the invention as active ingredient in the manufacture of a medicament for the treatment of a neurodegenerative disorder.
  • the compounds of the invention may also have the advantage that they are less toxic, more efficacious, are longer acting, have a broader range of activity, are more potent, produce fewer side effects, are more easily absorbed or have other useful pharmacologi- cal properties, than compounds previously indicated in the therapeutic fields mentioned above.
  • the filtrate from the initial precipitation was neutralized with 25% NaOH solution in water, extracted with 2x250ml of CHC1 3 , dried over MgS0 4 , filtered and concentrated in vacuo.
  • the residue was dissolved in EtOAc (500ml) and to this solution was added a solution of R(-)-mandelic acid (6.5g, 0.043 moles) in EtOAc (500ml).
  • the precipitate was filtered off and recrystallized an additional three times.
  • the salt was basified with 25% NaOH solution in water, extracted with 3x100ml of chloroform, dried over MgS0 4 , filtered and concentrated in vacuo.
  • the enantiopurity may be determined by derivatizing either the mandelic acid or dihydrochloride salt with enantiopure (greater than 99.5%) methylbenzyl isocyanate, and then analyzing by HPLC using a normal phase column with ethanol hexane [6:94] as 1 solvent.
  • the enantiopurity of the enantiomers obtained above was shown to be greater than 99.5%.
  • Example 2 The compound of Example 1 was found to have an activity (ED S0 ) of 3.7mg/kg in the prevention of hind limb tonic extension in rats induced by maximal electroshock (MES) (described above) when administered orally. Its enantiomer had an ED 50 of 20.2mg/kg.
  • MES maximal electroshock

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Neurology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Psychology (AREA)
  • Psychiatry (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Epidemiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Steroid Compounds (AREA)

Abstract

(S)-α-phenyl-2-pyridineethanamine, and its pharmaceutically acceptable derivatives, are useful in the treatment of neurodegenerative disorders, and exhibit linear pharmacokinetics.

Description

Enantiomeri c l-phenyl -2-(2-pyridi ny . )ethy . ami ne for the treatment of neuro- degenerative di sorders
This invention relates to an enantiomer of a known compound, its use as a pharmaceuti¬ cal, in particular in the treatment of neurodegenerative disorders, a process for its s production, and pharmaceutical formulations containing it.
A major problem with existing drugs used to treat neurodegenerative disorders is a lack of predictability in the concentration of a drug in a patient's blood plasma resulting from administration of a given quantity of that drug, i.e. existing drugs do not exhibit linear 0 pharmacokinetics. It has been stated that an ideal drug in this field would show a linear relationship between blood plasma concentration and dose size so that a given change in dose would yield a predictable change in blood plasma concentration of the drug ['Pharmacokinetics of old, new and yet-to-be discovered antiepileptic drugs', R H Levy and B M Kerr, Epilepsia, vol 30, Supp 1, S35-S41, 1989]. S
European Patent Application 356035 discloses a large number of compounds for use in the treatment of neurodegenerative disorders, including α-phenyl-2-pyridineethanamine [referred to therein as l-phenyl-2-(2-pyridinyl)ethylamine],
Figure imgf000003_0001
0 Surprisingly, it has now been found that the (S)-enantiomer of this compound exhibits linear pharmacokinetics, whereas the racemate exhibits nonlinear pharmacokinetics.
Thus, according to the present invention, there is provided (S)-α-phenyl-2-pyridine- ethanamine,
25
Figure imgf000003_0002
substantially free from its (R)-enantiomer, and pharmaceutically acceptable derivatives thereof (hereinafter referred to together as "the compounds of the invention").
By "substantially free from its (R)-enantiomer", is meant that a sample of the (S)- enantiomer contains less than 10% by weight of the (R)-enantiomer (i.e. it is more than 90% enantiopure), more preferably less than 1% by weight of the (R)-enantiomer, and most preferably is pure (S)-enantiomer.
Pharmaceutically acceptable derivatives include compounds which are suitable bioprecursors (prodrugs) of (S)-α-phenyl-2-pyridineethanamine, and of particular interest - acid addition salts.
Suitable bioprecursors of (+)-α-phenyI-2-pyridineethanamine include amino acid amide derivatives of the amino group, in particular α-amϊno acid derivatives such as giycine derivatives. Such derivatives may be prepared by conventional methods, for example amino acid amide derivatives may be prepared by the methods given in 'Advanced Organic Chemistry' by J March, 2nd edition, published by McGraw-Hill, page 1171.
Acid addition salts of (S)-α-phenyl-2-pyridineethanamine include salts of mineral acids, for example the dihydrochloride and dihydrobromide salts; and salts formed with organic acids such as formate, acetate, malate, benzoate and fumarate salts.
α-Phenyl-2-r-^dineethanamine may be prepared by conventional methods (for example, addition of the anion of 2-picoline to N-trimethylsilyl-benzaldimine). (S)-α-phenyl-2- pyridineethanamine may then be prepared by one or more selective precipitations of a diastereomeric salt formed by reaction of α-phenyl-2-pyridineethanamine with a chiral salt, followed by one or more recrystallizations. Thus, according to a second aspect of the invention, there is provided a process for the preparation of a compound of the invention which comprises selective precipitation of a diastereomeric salt formed between α-phenyl-2-pyridineethanamine and a chiral acid. Chiral acids which may be mentioned include D- or L-tartaric acids and in particular S(+)- and R(-)-mandelic acids. The precipitation may be carried out in an organic solvent which does not adversely affect the reaction (for example ethyl acetate), at or around room tempera¬ ture.
The compounds of the invention are indicated as pharmaceuticals, in particular as anticonvulsants and neuroprotective agents in the treatment of neurodegenerative disorders. Specific neurodegenerative disorders that may be mentioned include stroke, cerebral ischaemia, cerebral palsy, the effects of hypoglycaemia, epilepsy, AIDS-related dementia, Alzheimer's disease, Huntington's chorea, Olivo-ponto-cerebellar atrophy, perinatal asphyxia, Parkinson's disease, anoxia, neuronal damage associated with substance abuse (for example, narcotics or cocaine), retinopathies, schizophrenia, ischaemic states after cardiac arrest or surgical operations, intoxication or injuries of the spinal cord and amyotrophic lateral sclerosis.
While not being limited by theory, neurodegeneration is thought to be caused or accelerated by certain excitatory amino acids found naturally in the central nervous system (CNS). Glutamate is an endogenous amino acid which has been characterized as a fast excitatory transmitter in the mammalian brain. Glutamate is also known as a powerful neurotoxin capable of killing CNS neurons under certain pathologic conditions which accompany stroke and cardiac arrest. It has been shown that the sensitivity of central neurons to hypoxia and ischaemia can be reduced by the specific antagonism of post synaptic glutamate receptors. Glutamate is characterized as a broad spectrum agonist having activity at four neuronal excitatory amino acid receptor sites. These receptor sites are named after the amino acids which selectively excite them: kainate (KA), N-methyl-D-aspartate (NMD A), quisqualate (QUIS) and 2-amino-4-phosphono- butyrate (APB). Glutamate is believed to be a mixed agonist capable of binding to and exciting all four receptor types. Thus, agents which selectively block or antagonise the action of glutamate at these receptors can prevent neurotoxic injury associated with anoxia, hypoxia or ischemia. In particular, compounds which bind to the NMDA receptor site and selectively block the action of glutamate are useful in the prevention and treatment of neurodegenerative diseases.
The pharmacological activity of the compounds of the invention may be measured in the tests set out below. a) NMDA blocking activity is measured by assessing a compound's ability to protect mice from convulsions induced by intravenous administration of 150mg/kg of NMDA according to the procedures of Czuczwar et al, (Neurotransmitters, Seizures and Epilepsy III, edited by G Nistico et al, Raven Press, New York 1986, pages 235-246). s Groups of mice are pretreated by 30 minutes with the test compound by the intra- peritoneal routes and then given NMDA. Animals were observed for convulsions as defined by loss of righting reflex and appearance of tonic/clonic seizures. Animals are kept for 60 minutes after NMDA dosing and mortality was recorded. b) NMDA receptor antagonist activity may be measured in vitro by assaying a o compound's ability to inhibit binding of the receptor antagonist 10, 1 l-dihydro-5-methyl-
5H-dibenzo[a,d]-cyclohepten-5,10-imine (MK 801) to the receptor. The method is described by Foster and Wong, Br J Pharmacol 91, 403-409 (1987). c) NMDA and glycine receptor affinity may also be tested in the [3H]L-glutamate and [3H]glycine binding assays following the method of Monaghan & Cotman, PNAS, s 83, 7532, (1986) and Watson et al, Neurosci Res Comm, 2, 169, (1988). d) Antihypoxia activity may be measured conveniently in mice. Groups of mice are tested at various times after the intraperitoneai administration of graded doses of the test compound. The animals' survival time in a temperature-controlled hypoxic environment (96% nitrogen and 4% oxygen) is recorded. A statistical comparison is 0 made between coincident vehicle treated animals and the experimental group. The dose-response and minimum active dose (MAD) for compounds are obtained [A A Artu and J D Michenf elder, Anaesthesia and Analgesia, 1981, 60, 867]. Other modes of administration can also be used. e) Antiepileptic activity may be measured by assessing a compound's ability to 25 prevent the hind limb tonic extension component of the seizure in groups of mice or rats induced by maximal electroshock (MES) after oral, intraperitoneai, intravenous or subcutaneous administration, according to the procedures of the Epilepsy Branch, NINCDS as published by R J Porter, et al, Cleve Clin Quarterly 1984, 51, 293, and compared with the standard agents dilantin and phenobarbital. 3o f) The 4-vessel occlusion (4-VO) model of stroke is used to produce global ischaemia in the rat and is an essential technique to evaluate the effectiveness of compounds to prevent damage to areas of selective vulnerability in the brain, notably the CA1 pyramidal neurons of the hippocampus. This area is involved in the pathways for short term memory formation in both laboratory animals and humans. The procedure consists of cauterizing the vertebral arteries and isolating the carotid arteries of rats maintained under anaesthesia on day 1. On day 2 the carotids are clamped for varying periods of time, ten minutes is sufficient to destroy the CAl neurons. The clamps are removed, reflow initiated and drugs administered at various times post reflow. Body temperature is maintained at 37°C throughout the ischaemia and recovery periods. The CAl neurons die off over a 48-72 hour period and normally the rats are treated for at least 3 days with drug (ip, iv, or po) and at 7 days the brains are removed for histology. Rating of CAl damage is accomplished using two methods, counting of viable CAl neurons and scoring of degree of gross pathology [W A Pulsinelli and A Buchan, 'The NMDA receptor/ion channel: Its importance to in vivo ischemia injury to selectively vulnerable neurons', Pharmacology of Cerebral Ischemia, edited by J Krieglstein and H Oberpichler, published by Wissenschaftliche Verlagsgesellschaft, Stuttgart, 1990, pl69]. g) In the Focal Model of Stroke, spontaneously hypertensive rats (SHR) are used as experimental subjects because of their relatively poor collateral brain circulation. A 2 hour focal ischemia is achieved in SHR by clamping the middle cerebral artery and the ipsilateral carotid while maintaining anaesthesia. Drugs can be administered (usually ip) either before or various times after clamping the arteries or when reflow commences at 2 hours. The brains are removed 24 hours after the experiment and frozen, sectioned and drug effects toward reducing infarct volume of the cerebral cortex is determined using a custom-built computer quantification system [A M Buchan, D Xue and A Slivka, Stroke, 1992, 23, 273.]
Toxicity of the compounds of the invention may be measured in the following tests.
a) Dose ranging studies based on those described by N W Spurling and P F Carey,
'A protocol for dose selection in repeat dose toxicity studies', poster presentation 974 at the Society of Toxicology annual meeting, Seattle, USA, 23-27 February 1992. Rats are dosed intravenously daily with progressively increasing doses of test compound until a maximum repeatable dose is found above which the incidence of convulsions and other abnormal clinical signs is unacceptable. b) The inverted screen test [L L Cougenour, J R McLean, and R B Parker, Pharmacol Biochem Behav, 1977, 6, 351]. Mice are dosed with test compound and 30 minutes later are placed on a small wire platform which is inverted through an arc of 180°. Mice unable to climb to the upright position within 30 seconds are rated as failures. Using sufficient doses and numbers of animals an appropriate TDS0 (dose in which 50% fail) can readily be determined. c) The observation test for 28 behavioral signs according to S Irwiπ [Psycho- pharmacology 1968, 13, 222]. Groups of 3 mice per dose are administered incremental amounts of test compound in the range 25-400 mg/kg and observed for 28 symptoms immediately after dosing, 30 minutes, 3 and 24 hours post dose. d) Test for Phencyclidine (PCP)-Like Behaviour. PCP-like behaviours are a side effect of potent competitive and non-competitive NMDA receptor antagonists. In a screen to determine whether a compound possesses this liability, rats are dosed orally with test compound (expressed as multiples of the oral ED50 for protection in the MES test) and placed into individual clear plastic cages and observed over a 4 hour period for any incidence of 5 characteristic behaviours associated with PCP, namely hyperactivity, ataxia, circling, head weaving and retropulsion. Five rats per treatment group are observed and compared to a control group receiving PCP. A total incidence score would be 25, i.e. 5 rats exhibiting all 5 behaviours. PCP at 10 times the EDS0 produces a score of 25 [W Koek, J H Woods, P Ornstein, 1987, Psychopharmacology, 91, 297]. e) Gang Plank Escape Test to measure neural impairment in rats [G E Garske et al, Epilepsy Research, 1991, 9, 161]. Rats are placed on a narrow board (1.25cm wide suspended 40cm above the bench top) in a well lit entry cubicle which enters a progressively darkened box connected to a dark escape cubicle at the other end (board is 63cm long). A rat is impaired if it fails to negotiate the plank. The task takes into account two known behaviours of rats, i.e. fear of height and seeking a dark environ¬ ment.
Linear pharmacokinetics may be detected in rats by evaluating the area under the plasma concentration v time curves obtained upon single intravenous administration of test compound at increasing doses (Smith et al, Xenobiotica, 20, 1187-1199, 1990). Blood was removed from a jugular vein catheter at various times over a 24 hour period. The plasma was separated by centrifugation and the concentration of test compound was determined using HPLC-UN chromatography. The plasma concentration v time values were plotted for each dose and the area under each curve estimated. Where linear pharmacokinetics are present, the area under the plasma concentration v time curve for a given dose is directly proportional to the dose administered. A finding of linear pharmacokinetics in rats indicates that linear pharmacokinetics would be found in humans (Leander et al, Epilepsia, 33, 696-704, 1992, at p703).
According to another aspect of this invention there is provided a method of treatment of a neurodegenerative disorder, which comprises administering a therapeutically effective amount of a compound of the invention to a patient. Of particular interest is such a method in which the dose of the compound administered is linearly proportional to the blood plasma concentration of the compound desired.
For the above-mentioned uses the dosage administered will, of course, vary with the compound employed, the mode of adniinistration and the treatment desired. However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of from about O.lmg to about 20mg per kg of animal body weight, preferably given in divided doses 1 to 4 times a day or in sustained release form. For man, the total daily dose is in the range of from 5mg to l,400mg, more preferably from lOmg to lOOmg, and unit dosage forms suitable for oral administration comprise from 2mg to l,400mg of the compound admixed with a solid or liquid pharmaceutical carrier or diluent.
The compounds of the invention may be used on their own or in the form of appropriate medicinal preparations for enteral or parenteral administration. According to a further aspect of the invention, there is provided a pharmaceutical composition comprising preferably less than 80% and more preferably less than 50% by weight of a compound of the invention in admixture with a pharmaceutically acceptable adjuvant- diluent or carrier.
Examples of diluents and carriers are: for tablets and dragees: lactose, starch, talc, stearic acid: for capsules: tartaric acid or lactose; for injectable solutions: water, alcohols, glycerin, vegetable oils; for suppositories: natural or hardened oils or waxes.
An adjuvant of particular interest when the compound of the invention is to be used in the treatment of Parkinson's disease is L-dopa.
According to a further aspect of the invention, there is provided the use of a compound of the invention as active ingredient in the manufacture of a medicament for the treatment of a neurodegenerative disorder.
The compounds of the invention may also have the advantage that they are less toxic, more efficacious, are longer acting, have a broader range of activity, are more potent, produce fewer side effects, are more easily absorbed or have other useful pharmacologi- cal properties, than compounds previously indicated in the therapeutic fields mentioned above.
The invention is illustrated by the following examples.
Example 1
Preparation of fSVo.-phenyl-2-pyridineethanamine dihydrochloride
a) g-Phenyl-2-pyridineethanamine dihydrochloride
To a cooled (0°C) solution of benzaldehyde (34.24g, 0.323 moles) in 600ml of tetrahydrofuran (THF) was added lithium bis(trimethylsiiyl)-amide (LHMDS) (323ml of a 1.0M solution in THF, 0.323 moles) dropwise over 30 minutes. This mixture was stirred at 0°C for three hours.
In a separate round bottom flask containing a cooled (-78°C) solution of 2-picoline (30.0g, 0.323 moles) in THF (600ml) was added n-butyllithium (n-BuLi) (129.2ml of a 2.5M solution in hexane) over twenty minutes. The first reaction mixture was allowed to warm to 0°C and remain there for an additional forty minutes. The second reaction mixture (containing the lithiated anion of 2-picoline) was cannulated into the first reaction mixture over 20 minutes. After 30 additional minutes the cold bath was removed and the mixture was allowed to warm to ambient temperature. After an additional one hour, the reaction mixture was poured into a separating funnel charged with ice (11) and 12 N HCl (200ml). The aqueous layer was washed with 3x200ml of diethyl ether (Et20) and then basified with 25% NaOH solution in water. The aqueous layer was extracted with 2x200ml of chloroform, the chloroform extracts dried over MgS04, filtered and concentrated in vacuo. The residue was dissolved in ethyl acetate (EtOAc) and acidified with a saturated solution of HCl/EtOAc. The solution was diluted with Et20 and the resulting white solid filtered and dried in vacuo to give the subtitle compound (37.08g, 43%), mp = 206-208°C.
b) (SVα-Phenyl-2-pyridineethanamine dihydrochloride
To a solution of racemic α-phenyl-2-pyridineethanamine (the free base of the product of step (a), obtained by neutralizing an aqueous solution of the product of step (a) with a 25% NaOH solution in water and extracting with chloroform) (10.96g, 0.0553 moles) in EtOAc (400ml) was added a solution of S(+)-mandelic acid (8.41g, 0.0553 moles) in EtOAc (300ml). The resulting precipitate was recrystallized from hot EtOAc (500ml) an additional three times. The salt was basified with a 25% NaOH solution in water, extracted with 3x100ml of chloroform, dried over MgS04, filtered and concentrated in vacuo. The residue was dissolved in EtOAc (300ml) and acidified with a saturated solution of HCl/EtOAc. The resulting white solid is filtered and dried in vacuo to give (-)-α-phenyl-2-pyridineethanamine dihydrochloride (5.5g), mp = 220-222°C, [α]D = -87.3° (c = 1.0, CH3OH).
The filtrate from the initial precipitation was neutralized with 25% NaOH solution in water, extracted with 2x250ml of CHC13, dried over MgS04, filtered and concentrated in vacuo. The residue was dissolved in EtOAc (500ml) and to this solution was added a solution of R(-)-mandelic acid (6.5g, 0.043 moles) in EtOAc (500ml). The precipitate was filtered off and recrystallized an additional three times. The salt was basified with 25% NaOH solution in water, extracted with 3x100ml of chloroform, dried over MgS04, filtered and concentrated in vacuo. The residue was dissolved in EtOAc (300ml) and acidified with a saturated solution of HCl/EtOAc. The resulting white solid was filtered and dried in vacuo to give the title compound (3.84g), mp = 220-222°C, [α]D = +87.1° (c = 1.1, CH3OH).
The enantiopurity may be determined by derivatizing either the mandelic acid or dihydrochloride salt with enantiopure (greater than 99.5%) methylbenzyl isocyanate, and then analyzing by HPLC using a normal phase column with ethanol hexane [6:94] as1 solvent. The enantiopurity of the enantiomers obtained above was shown to be greater than 99.5%.
X-ray crystallography showed the (+)-enantiomer to have (S)-absolute stereochemistry.
Example 2 The compound of Example 1 was found to have an activity (EDS0) of 3.7mg/kg in the prevention of hind limb tonic extension in rats induced by maximal electroshock (MES) (described above) when administered orally. Its enantiomer had an ED50 of 20.2mg/kg.

Claims

Claims:
1. (S)-α-pheπyl-2-pyridineethanamine, which is greater than 90% enantiopure, and pharmaceutically acceptable derivatives thereof.
2. (S)- -phenyl-2-pyridineethanamine, which is greater than 99% enantiopure, and pharmaceutically acceptable derivatives thereof.
3. (S)-α-phenyl-2-pyridineethanamine, and pharmaceutically acceptable derivatives thereof.
4. A pharmaceutical formulation comprising (S)-α-phenyl-2-pyridineethanamine as defined in any one of claims 1 to 3, or a pharmaceutically acceptable derivative thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
5. The use of (S)-α-phenyl-2-pyridineethanamine, as defined in any one of claims 1 to 3, or a pharmaceutically acceptable derivative thereof, as a pharmaceutical.
6. The use of (S)-α-phenyl-2-pyridineethanamine, as defined in any one of claims 1 to 3, or a pharmaceutically acceptable derivative thereof, as active ingredient in the manufacture of a medicament for the treatment of a neurodegenerative disorder.
7. A method of treatment of a neurodegenerative disorder, which comprises administering a therapeutically effective amount of (S)-α-phenyl-2-pyridineethanamine, as defined in any one of claims 1 to 3, or a pharmaceutically acceptable derivative thereof, to a patient.
8. A method of treatment as claimed in claim 7, wherein the dose of the compound administered is linearly proportional to the blood plasma concentration of the compound desired.
9. A process for the production of (S)-α-phenyl-2-pyridineethanamine as defined in any one of claims 1 to 3, or a pharmaceutically acceptable derivative thereof, which comprises selective precipitation of a diastereomeric salt formed between α-phenyl-2- pyridineethanamine and a chiral acid.
PCT/GB1993/000689 1987-02-06 1993-04-01 Enantiomeric 1-phenyl-2-(2-pyridinyl)ethylamine for the treatment of neurodegenerative disorders WO1993020052A1 (en)

Priority Applications (48)

Application Number Priority Date Filing Date Title
RU94042465A RU2128650C1 (en) 1992-04-03 1993-04-01 (S)-α-PHENYL-2-PYRIDINE ETHANEAMINE AND ITS SALT WITH INORGANIC ACIDS, METHOD OF THEIR SYNTHESIS, DRUG ON THEIR BASIS AND METHOD OF TREATMENT OF PATIENTS WITH CONVULSIONS
DK93907975T DK0633879T3 (en) 1992-04-03 1993-04-01 Enantiomeric 1-phenyl-2 (2-pyridinyl) ethylamine for the treatment of neurodegenerative diseases
CA002133427A CA2133427C (en) 1992-04-03 1993-04-01 Enantiomeric 1-phenyl-2-(2-pyridinyl) ethylamine for the treatment of neurodegenerative disorders
UA94095853A UA29437C2 (en) 1992-04-03 1993-04-01 (S)-a-phenyl -2-pyridinetamine or salt thereof with inorganic acid having anticonvulsant activity, a PROCESS for PREPARATION thereof, medicament on their basis and a method for treatment of convulsions
SK1177-94A SK281258B6 (en) 1992-04-03 1993-04-01 (s)-alpha-phenyl-2-pyridineethanamine, pharmaceutical composition containing thereof and use thereof
KR1019940703465A KR100259567B1 (en) 1992-04-03 1993-04-01 Enantiomeric 1-phenyl-2-(2-pyridinyl_ethylamine for the treatment of neurodegenerative disorders
JP05517251A JP3120810B2 (en) 1992-04-03 1993-04-01 Method for producing a compound for treating a neurodegenerative disease
EP93907975A EP0633879B1 (en) 1992-04-03 1993-04-01 Enantiomeric 1-phenyl-2-(2-pyridinyl)ethylamine for the treatment of neurodegenerative disorders
PL93305404A PL180014B1 (en) 1992-04-03 1993-04-01 (s)-alpha-phenyl-2-pyridodiethane amine and pharmaceutic composition containing it
DE69317411T DE69317411T2 (en) 1992-04-03 1993-04-01 ENANTIOMERE 1-PHENYL-2- (2-PYRIDINYL) ETHYLAMINE FOR THE TREATMENT OF NEURODEGENERATIVE DISORDERS
ZA932415A ZA932415B (en) 1992-04-03 1993-04-02 Compounds for the treatment of neurodegenerative disorders
TW082103364A TW282455B (en) 1992-04-03 1993-04-30
GB939320273A GB9320273D0 (en) 1993-04-01 1993-10-01 Compound useful in therapy
IL10910894A IL109108A (en) 1993-04-01 1994-03-24 (S)-alpha-phenyl-2-pyrideneethanamine (S)-malate its preparation and pharmaceutical compositions containing it
ZA942140A ZA942140B (en) 1993-04-01 1994-03-25 Salt of (S)-alpha-phenyl-2-pyridineethanamine useful in therapy
PCT/GB1994/000651 WO1994022831A1 (en) 1993-04-01 1994-03-29 (s)-alpha-phenyl-2-pyridineethanamine (s)-malate and its use as a medicament
DE69404974T DE69404974T2 (en) 1993-04-01 1994-03-29 (S) -ALPHA-PHENYL-2-PYRIDINETHANAMINE (S) -MALATE AND ITS USE AS A MEDICINAL PRODUCT
EP94911232A EP0691957B1 (en) 1993-04-01 1994-03-29 (s)-alpha-phenyl-2-pyridineethanamine (s)-malate and its use as a medicament
SG1996007883A SG48204A1 (en) 1993-04-01 1994-03-29 Salt of (s)-alpha-phenyl-2-pyridineethanamine useful in therapy
JP6521814A JP3023987B2 (en) 1993-04-01 1994-03-29 (S) -α-phenyl-2-pyridineethanamine (S) -malate and its use as a medicament
ES94911232T ES2105672T3 (en) 1993-04-01 1994-03-29 (S) -MALATE OF (S) -ALPHA-PHENYL-2-PYRIDINEETHANAMINE AND ITS USE AS A MEDICINAL PRODUCT.
DK94911232.0T DK0691957T3 (en) 1993-04-01 1994-03-29 (S) -alpha-phenyl-2-pyridinethanamine (S) -malate and its use as a drug.
PH48016A PH30950A (en) 1993-04-01 1994-03-29 Salt of (S) -alpha-phenyl-2-pyridineethanamine useful in therapy.
AU63802/94A AU682348B2 (en) 1993-04-01 1994-03-29 (S)-alpha-phenyl-2-pyridineethanamine (S)-malate and its use as a medicament
CA002159478A CA2159478C (en) 1993-04-01 1994-03-29 (s)-alpha-phenyl-2-pyridineethanamine (s)-malate and its use as a medicament
AT94911232T ATE156813T1 (en) 1993-04-01 1994-03-29 (S)-ALPHA-PHENYL-2-PYRIDINETHANAMIN(S)-MALATE AND ITS USE AS A MEDICINAL PRODUCT
DZ940029A DZ1765A1 (en) 1993-04-01 1994-03-30 Salt (s) -phenyl-2-pyridineethanamine useful for therapy.
US08/221,076 US5455259A (en) 1987-02-06 1994-03-31 Compounds for the treatment of neurodegenerative disorders
MA23459A MA23154A1 (en) 1993-04-01 1994-04-01 SALT OF (S) -PHENYL-2-PYRIDINEETHANAMIDE USEFUL FOR THEPAPIA.
CN94103739A CN1047168C (en) 1993-04-01 1994-04-01 Salt of (S)-a-phenyl-2-pyridineethanamine useful in therapy
AT94912016T ATE156814T1 (en) 1993-04-01 1994-04-05 (S)-ALPHA-PHENYL-2-PYRIDINETHANAMIN BENZOATE AND ITS USE AS A MEDICINAL PRODUCT
DE69404975T DE69404975T2 (en) 1993-04-01 1994-04-05 (S) -ALPHA-PHENYL-2-PYRIDINETHANAMINE BENZOATE AND ITS USE AS A MEDICINAL PRODUCT
ES94912016T ES2105679T3 (en) 1993-04-01 1994-04-05 (S) -ALPHA-PHENYL-2-PYRIDINEETHANAMINE BENZOATE AND ITS USE AS A MEDICINAL PRODUCT.
EP94912016A EP0691958B1 (en) 1993-04-01 1994-04-05 (s)-alpha-phenyl-2-pyridineethanamine benzoate and its use as a medicament
AU64337/94A AU682350B2 (en) 1993-04-01 1994-04-05 (S)-alpha-phenyl-2-pyridineethanamine benzoate and its use as a medicament
DK94912016.6T DK0691958T3 (en) 1993-04-01 1994-04-05 (S) -alpha-phenyl-2-pyridinethanamine benzoate and its use as a drug
CA002159480A CA2159480C (en) 1993-04-01 1994-04-05 (s)-alpha-phenyl-2-pyridineethanamine benzoate and its use as a medicament
PCT/GB1994/000716 WO1994022832A1 (en) 1993-04-01 1994-04-05 (s)-alpha-phenyl-2-pyridineethanamine benzoate and its use as a medicament
JP6521865A JP3023988B2 (en) 1993-04-01 1994-04-05 (S) -α-phenyl-2-pyridineethanamine benzoate and its use as a medicament
NO943645A NO302170B1 (en) 1992-04-03 1994-09-30 Enantiomeric 1-phenyl-2- (2-pyridinyl) ethylamine, pharmaceutical formulation and use thereof
FI944546A FI105025B (en) 1992-04-03 1994-09-30 Process for the preparation of (S) -alpha-phenyl-2-pyridinethanamine
NO951546A NO304647B1 (en) 1993-04-01 1995-09-28 (S) -alpha-phenyl-2-pyridinethanamine (S) -malate, pharmaceutical preparation containing this compound and its use in the manufacture of drug
NO953846A NO304648B1 (en) 1993-04-01 1995-09-28 (S) -alpha-phenyl-2-pyridinethanamine benzoate, pharmaceutical composition containing this compound and its use in the manufacture of drug
FI954646A FI109019B (en) 1993-04-01 1995-09-29 Process for the preparation of (S) -alpha-phenyl-2-pyridine-ethanamine-benzoate
FI954645A FI109018B (en) 1993-04-01 1995-09-29 Process for Preparation of (S) -alpha-phenyl-2-pyridinethanamine (S) -malate
GR970402722T GR3025081T3 (en) 1993-04-01 1997-10-17 (s)-alpha-phenyl-2-pyridineethanamine (s)-malate and its use as a medicament
GR970402723T GR3025082T3 (en) 1993-04-01 1997-10-17 (s)-alpha-phenyl-2-pyridineethanamine benzoate and its use as a medicament
HK98110056A HK1009331A1 (en) 1992-04-03 1998-08-21 Enantiomeric 1-phenyl-2-(2-pyridinyl) ethylamine for the treatment of neurodegenerative disorders

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB929207339A GB9207339D0 (en) 1992-04-03 1992-04-03 Pharmaceutical compound
GB9207339.4 1992-04-03
GB929208290A GB9208290D0 (en) 1992-04-15 1992-04-15 Pharmaceutical compound having neuroprotective properties
GB9208290.8 1992-04-15

Publications (1)

Publication Number Publication Date
WO1993020052A1 true WO1993020052A1 (en) 1993-10-14

Family

ID=26300643

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1993/000689 WO1993020052A1 (en) 1987-02-06 1993-04-01 Enantiomeric 1-phenyl-2-(2-pyridinyl)ethylamine for the treatment of neurodegenerative disorders

Country Status (29)

Country Link
EP (1) EP0633879B1 (en)
JP (2) JP3120810B2 (en)
KR (1) KR100259567B1 (en)
CN (1) CN1044367C (en)
AT (1) ATE163925T1 (en)
AU (2) AU3897693A (en)
CA (1) CA2133427C (en)
CZ (1) CZ288519B6 (en)
DE (1) DE69317411T2 (en)
DK (1) DK0633879T3 (en)
DZ (1) DZ1677A1 (en)
ES (1) ES2115055T3 (en)
FI (1) FI105025B (en)
HK (1) HK1009331A1 (en)
HU (1) HU211529A9 (en)
IL (1) IL105276A (en)
MA (1) MA22866A1 (en)
MX (1) MX9301935A (en)
MY (1) MY110149A (en)
NO (1) NO302170B1 (en)
NZ (1) NZ251384A (en)
PL (1) PL180014B1 (en)
RU (1) RU2128650C1 (en)
SG (1) SG47948A1 (en)
SK (1) SK281258B6 (en)
TW (1) TW282455B (en)
UA (1) UA29437C2 (en)
WO (1) WO1993020052A1 (en)
ZA (1) ZA932415B (en)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994022831A1 (en) * 1993-04-01 1994-10-13 Astra Aktiebolag (s)-alpha-phenyl-2-pyridineethanamine (s)-malate and its use as a medicament
WO1994022832A1 (en) * 1993-04-01 1994-10-13 Astra Aktiebolag (s)-alpha-phenyl-2-pyridineethanamine benzoate and its use as a medicament
EP0648745A1 (en) * 1988-08-12 1995-04-19 Astra Aktiebolag Arylalkylamine having anticonvulsant and neuroprotective properties
WO2000059496A1 (en) * 1999-04-06 2000-10-12 Astrazeneca Ab Use of low affinity nmda antagonists for the treatment of headache
WO2007017652A2 (en) * 2005-08-10 2007-02-15 Astrazeneca Ab Arylakylamines for the treatment of cancer
WO2010074647A1 (en) * 2008-12-24 2010-07-01 Astrazeneca Ab Ethanamine compounds and their use for treating depression
WO2013088135A1 (en) 2011-12-14 2013-06-20 Astrazeneca Ab Gabr-a2 diagnostic
WO2015067923A1 (en) 2013-11-05 2015-05-14 Astrazeneca Ab Nmda antagonist prodrugs
WO2021262779A1 (en) * 2020-06-23 2021-12-30 Biohaven Therapeutics Ltd. Topical formulations of (1s)-1-phenyl-2-pyridin-2-ylethanamine

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE9901077D0 (en) * 1999-03-23 1999-03-23 Astra Ab Novel use
SE9901340D0 (en) 1999-04-15 1999-04-15 Astra Pharma Prod Novel process

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0356035A2 (en) * 1988-08-12 1990-02-28 Astra Aktiebolag Arylkalkyl-amines and -amides having anticonvulsant and neuroprotective properties

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0356035A2 (en) * 1988-08-12 1990-02-28 Astra Aktiebolag Arylkalkyl-amines and -amides having anticonvulsant and neuroprotective properties

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
J.B. TAYLOR 'Comprehensive medicinal chemistry Vol.5 Biopharmaceutics' , PERGAMON PRESS , OXFORD *

Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0648745A1 (en) * 1988-08-12 1995-04-19 Astra Aktiebolag Arylalkylamine having anticonvulsant and neuroprotective properties
WO1994022831A1 (en) * 1993-04-01 1994-10-13 Astra Aktiebolag (s)-alpha-phenyl-2-pyridineethanamine (s)-malate and its use as a medicament
WO1994022832A1 (en) * 1993-04-01 1994-10-13 Astra Aktiebolag (s)-alpha-phenyl-2-pyridineethanamine benzoate and its use as a medicament
AU682350B2 (en) * 1993-04-01 1997-10-02 Astra Aktiebolag (S)-alpha-phenyl-2-pyridineethanamine benzoate and its use as a medicament
AU682348B2 (en) * 1993-04-01 1997-10-02 Astra Aktiebolag (S)-alpha-phenyl-2-pyridineethanamine (S)-malate and its use as a medicament
WO2000059496A1 (en) * 1999-04-06 2000-10-12 Astrazeneca Ab Use of low affinity nmda antagonists for the treatment of headache
WO2007017652A2 (en) * 2005-08-10 2007-02-15 Astrazeneca Ab Arylakylamines for the treatment of cancer
WO2007017652A3 (en) * 2005-08-10 2007-05-31 Astrazeneca Ab Arylakylamines for the treatment of cancer
CN102333762B (en) * 2008-12-24 2014-06-11 阿斯利康(瑞典)有限公司 Ethanamine compounds and application for treating depression
US9035065B2 (en) 2008-12-24 2015-05-19 Astrazeneca Ab Ethanamine compounds and methods of using the same
CN102333762A (en) * 2008-12-24 2012-01-25 阿斯利康(瑞典)有限公司 Ethylamine compounds and the purposes in the treatment dysthymia disorders thereof
AU2009330745B2 (en) * 2008-12-24 2012-04-05 Astrazeneca Ab Ethanamine compounds and their use for treating depression
US8013165B2 (en) 2008-12-24 2011-09-06 Astrazeneca Ab Ethanamine compounds and methods of using the same 545
EP2610246A1 (en) * 2008-12-24 2013-07-03 AstraZeneca AB Ethanamine compounds and methods of using the same
WO2010074647A1 (en) * 2008-12-24 2010-07-01 Astrazeneca Ab Ethanamine compounds and their use for treating depression
WO2013088135A1 (en) 2011-12-14 2013-06-20 Astrazeneca Ab Gabr-a2 diagnostic
US20150057317A1 (en) * 2011-12-14 2015-02-26 Astrazeneca Ab Gabr-a2 diagnostic
US10207994B2 (en) 2013-11-05 2019-02-19 Astrazeneca Ab NMDA antagonist prodrugs
CN105683180A (en) * 2013-11-05 2016-06-15 阿斯利康(瑞典)有限公司 Nmda antagonist prodrugs
US9822075B2 (en) 2013-11-05 2017-11-21 Astrazeneca Ab NMDA antagonist prodrugs
AU2014345407B2 (en) * 2013-11-05 2018-10-18 Astrazeneca Ab NMDA antagonist prodrugs
WO2015067923A1 (en) 2013-11-05 2015-05-14 Astrazeneca Ab Nmda antagonist prodrugs
EP3564234A1 (en) 2013-11-05 2019-11-06 AstraZeneca AB Nmda antagonist prodrugs
CN105683180B (en) * 2013-11-05 2020-01-21 阿斯利康(瑞典)有限公司 NMDA antagonist prodrugs
CN111187202A (en) * 2013-11-05 2020-05-22 阿斯利康(瑞典)有限公司 NMDA antagonist prodrugs
US10815199B2 (en) 2013-11-05 2020-10-27 Astrazeneca Ab NMDA antagonist prodrugs
EP4001272A1 (en) 2013-11-05 2022-05-25 Astrazeneca AB Nmda antagonist prodrugs
WO2021262779A1 (en) * 2020-06-23 2021-12-30 Biohaven Therapeutics Ltd. Topical formulations of (1s)-1-phenyl-2-pyridin-2-ylethanamine

Also Published As

Publication number Publication date
EP0633879B1 (en) 1998-03-11
TW282455B (en) 1996-08-01
AU3897693A (en) 1993-11-08
DK0633879T3 (en) 1998-09-28
SG47948A1 (en) 1998-04-17
EP0633879A1 (en) 1995-01-18
CN1081669A (en) 1994-02-09
NO302170B1 (en) 1998-02-02
NZ251384A (en) 1996-10-28
SK117794A3 (en) 1995-05-10
MA22866A1 (en) 1993-12-31
CZ240994A3 (en) 1995-12-13
CA2133427C (en) 2003-06-10
MX9301935A (en) 1994-08-31
ZA932415B (en) 1993-10-22
SK281258B6 (en) 2001-01-18
DE69317411T2 (en) 1998-07-30
CN1044367C (en) 1999-07-28
NO943645L (en) 1994-11-16
IL105276A0 (en) 1993-08-18
IL105276A (en) 1997-06-10
HU211529A9 (en) 1995-11-28
NO943645D0 (en) 1994-09-30
PL180014B1 (en) 2000-11-30
CA2133427A1 (en) 1993-10-14
FI944546A (en) 1994-09-30
FI944546A0 (en) 1994-09-30
AU7545696A (en) 1997-02-13
RU2128650C1 (en) 1999-04-10
JP2000319259A (en) 2000-11-21
CZ288519B6 (en) 2001-07-11
DE69317411D1 (en) 1998-04-16
AU705419B2 (en) 1999-05-20
JPH07505385A (en) 1995-06-15
HK1009331A1 (en) 1999-05-28
UA29437C2 (en) 2000-11-15
DZ1677A1 (en) 2002-02-17
MY110149A (en) 1998-02-28
KR100259567B1 (en) 2000-07-01
JP3120810B2 (en) 2000-12-25
FI105025B (en) 2000-05-31
ES2115055T3 (en) 1998-06-16
ATE163925T1 (en) 1998-03-15
RU94042465A (en) 1996-07-20

Similar Documents

Publication Publication Date Title
EP0633879B1 (en) Enantiomeric 1-phenyl-2-(2-pyridinyl)ethylamine for the treatment of neurodegenerative disorders
EP0691957B1 (en) (s)-alpha-phenyl-2-pyridineethanamine (s)-malate and its use as a medicament
US5455259A (en) Compounds for the treatment of neurodegenerative disorders
EP0691958B1 (en) (s)-alpha-phenyl-2-pyridineethanamine benzoate and its use as a medicament
CA2028645A1 (en) Use of arylalkylamides in the treatment of neurodegenerative diseases
TW390875B (en) (S) -<alpha>-phenyl-2-pyridineethanamine (S)-malate useful in therary, its perparing process and pharmaceutical composition comprising the same
EP1596852B1 (en) Drugs containing substituted 2-aryl-aminoacetic acid compounds
EP1596856A2 (en) Drugs containing substituted 2-aryl-aminoacetic acid compounds and/or substituted 2-heteroaryl-aminoacetic acid compounds

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AT AU BB BG BR CA CH CZ DE DK ES FI GB HU JP KP KR KZ LK LU MG MN MW NL NO NZ PL PT RO RU SD SE SK UA US VN

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
LE32 Later election for international application filed prior to expiration of 19th month from priority date or according to rule 32.2 (b)
EX32 Extension under rule 32 effected after completion of technical preparation for international publication
EX32 Extension under rule 32 effected after completion of technical preparation for international publication
LE32 Later election for international application filed prior to expiration of 19th month from priority date or according to rule 32.2 (b)
LE32 Later election for international application filed prior to expiration of 19th month from priority date or according to rule 32.2 (b)
LE32 Later election for international application filed prior to expiration of 19th month from priority date or according to rule 32.2 (b)
WWE Wipo information: entry into national phase

Ref document number: 1993907975

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 251384

Country of ref document: NZ

Ref document number: 117794

Country of ref document: SK

WWE Wipo information: entry into national phase

Ref document number: PV1994-2409

Country of ref document: CZ

Ref document number: 2133427

Country of ref document: CA

Ref document number: 944546

Country of ref document: FI

WWE Wipo information: entry into national phase

Ref document number: 1019940703465

Country of ref document: KR

WWP Wipo information: published in national office

Ref document number: 1993907975

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: PV1994-2409

Country of ref document: CZ

WWG Wipo information: grant in national office

Ref document number: 1993907975

Country of ref document: EP

WWG Wipo information: grant in national office

Ref document number: 944546

Country of ref document: FI

WWG Wipo information: grant in national office

Ref document number: PV1994-2409

Country of ref document: CZ