EP1330429A2 - Amides d'alkynyle et leurs applications therapeutiques - Google Patents

Amides d'alkynyle et leurs applications therapeutiques

Info

Publication number
EP1330429A2
EP1330429A2 EP01989847A EP01989847A EP1330429A2 EP 1330429 A2 EP1330429 A2 EP 1330429A2 EP 01989847 A EP01989847 A EP 01989847A EP 01989847 A EP01989847 A EP 01989847A EP 1330429 A2 EP1330429 A2 EP 1330429A2
Authority
EP
European Patent Office
Prior art keywords
propyl
hexynamide
compound
amino
oxoethyl
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Withdrawn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
EP01989847A
Other languages
German (de)
English (en)
Inventor
Youssef L. Bennani
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.)
Abbott Laboratories
Original Assignee
Abbott Laboratories
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 Abbott Laboratories filed Critical Abbott Laboratories
Publication of EP1330429A2 publication Critical patent/EP1330429A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/12—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—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
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C233/09—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to carbon atoms of an acyclic unsaturated carbon skeleton
    • 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

Definitions

  • the present invention relates to alkynyl amides, to the use of these compounds to treat seizures, migraine, and psychiatric disorders, and to the preparation of these compounds.
  • Valproic acid also referred to as VPA, valproate, di-n-propylacetic acid, DP A, 2-propylvaleric acid or 2-propylpentanoic acid
  • VPA valproic acid
  • DP A di-n-propylacetic acid
  • Migraine is defined as a periodically occurring vascular headache characterized by pain in the head (usually unilateral), nausea and vomiting, photophobia, phonophobia, vertigo and general weakness. Migraine is the most common type of vascular headache and affects as much as 15% of the world's population. Of the different types of migraines, classical migraine and common migraine are the two most prevalent. The major difference between .the two types of migraines is that classical migraines are preceded by the appearance of neurological symptoms before an attack whereas common migraines are not preceded by such symptoms. Migraine is caused by intermittent brain dysfunction. However, the precise pathophysiological mechanisms involved are not understood. The head pain is believed to involve blood vessel dilation.
  • Analgesics are often used to treat infrequent and mild migraines. Analgesics reduce the pain of a migraine and, in the case of aspirin, also discourage platelet aggregation. However, for moderate to severe migraines, stronger medications such as ergotamine and valproic acid are often necessary. Ergotamine tartrate is a vasoconstrictor which counteracts the painful dilation stage of the headache. When taken during the early stages of an attack, ergotamine tartrate helps to relieve the classic and common migraine symptoms. Valproic acid has been shown to be effective in prevention of migraine, however, its mechanism of anti-migraine action is unclear.
  • valproic acid increases brain gamma-aminobutyric acid (GAB A) levels and in doing so may activate the GABA receptor and suppresses migraine-related events.
  • GABA A brain gamma-aminobutyric acid
  • a number of psychiatric disorders may be treated with valproic acid, see: Loscher W., ed. Nalproate, Basel Switzerland: Birkhauser Nerlag, 1999; PostR.M., In Tasman A, Goldfinger, S.M., Kaufmann, C. A., eds. Review of psychiatry, volume 9, Washington DC: American Psychiatric Press, 1990, 170-202; and Jensen R., Brinck T., Olesen I, Neurology 44, 1994, 647.
  • Such psychiatric disorders include: i) Mood Disorders; ii) Anxiety Disorders; iii) Attention- Deficit and Disruptive Behavior Disorders; iv) Behavioral Disturbances associated with dementia; v) Behavioral Disturbances associated with autism; vi) Schizophrenia; vii) Impulse Control Disorders; viii) Personality Disorders; and ix) Substance-related Disorders.
  • Mood Disorders include, but are not limited to, Depressive Disorders and Bipolar Disorders such as Manic episodes and Mixed episodes.
  • Symptoms associated with Mood Disorders include, but are not limited to, depression, elevated, expansive or irritable mood, insomnia/hypersomnia, agitation and distractabiliry or impulsivity.
  • Anxiety Disorders include, but are not limited to, Panic Disorder, Posttraumatic Stress Disorder and Generalized Anxiety Disorder. Symptoms associated with Anxiety Disorders include, but are not limited to, anxious mood, panic attacks, irritability, outbursts of anger and exaggerated startle response.
  • Attention-Deficit and Disruptive Behavior Disorders include, but are not limited to, Attention-Deficit Hyperactivity Disorder Hyperactive-Impulsive Type, Conduct Disorder, Oppositional Defiant Disorder and Disruptive Behavior Disorder.
  • Symptoms associated with Attention-Deficit and Disruptive Behavior Disorders include, but are not limited to, impulsivity, aggression, anger and loss of temper.
  • Symptoms associated with Behavioral Disturbances for both dementia and autism include, but are not limited to, verbal and physical agitation and aggression.
  • Symptoms associated with Substance-related Disorders include but are not limited to, withdrawal and dependence.
  • Symptoms associated with schizophrenia include but are not limited to, positive symptoms, negative symptoms and agitation.
  • Impulse Control Disorders include, but are not limited to, Intermittent Explosive Disorder. Symptoms associated with Impulse Control Disorders, include but are not limited to, verbal or physical aggressive impulses. Personality Disorders include, but are not limited to, Borderline Personality Disorder. Symptoms associated with Personality Disorders, include but are not limited to, mood lability, irritability, agitation and aggression.
  • valproic acid may be used to treat general agitation or aggression not necessarily associated with any particular psychiatric disorder.
  • excitatory neurotransmitters such as glutamate and aspartate, as well as a variety of voltage-gated ion channels, are thought to play a central role in mediating cell death after a variety of cerebral insults including, but not limited to, ischemia, trauma, seizure and hypoglycemia.
  • excitatory neurotransmitters such as glutamate and aspartate, as well as a variety of voltage-gated ion channels
  • excitatory neurotransmitters such as glutamate and aspartate, as well as a variety of voltage-gated ion channels
  • excitatory neurotransmission for example, glutamate antagonists, ion channel blockers, anticonvulsants, and the like, elicit a neuroprotective effect in animal models of cerebral insults.
  • VPA neuroprotective protein B cell lymphoma protein-2
  • Neuropathic pain affects a significant number of patients suffering from disorders of the brain or spinal cord, such as stroke, trauma, multiple sclerosis, and diabetes.
  • Several known anticonvulsant compounds are efficacious in various analgesia models relevant to identifying therapeutic candidates for treating neuropathic pain (Lloyd and Morselli, in Psychopharmacology: The Third Generation of Progress, Raven Press, 1987).
  • the use of anticonvulsants like valproate to treat various pain states has been documented extensively (Swendlow, J. Clin. Neuropharmacol., 7, 1984, 51-82).
  • Restlessness syndrome denotes a somatic (non-mental) restlessness characterized by involuntary movement of the limbs, as well as by a sense of physical (rather than mental) agitation, which is independent of mood and, hence, is distinguished from restlessness per se, see (Sachdev et al., Austral. New Zealand J. Psychiatry 30, 1996, 38-53.
  • the genus of restlessness syndromes can be observed in association with many organic and non -organic psychiatric illnesses.
  • drug- induced restlessness (tardive, chronic, and withdrawal akathisias), such as drug-induced extrapyramidal symptoms, is one of the most common side effects of neuroleptic, drug therapy.
  • Idiopathic restless leg syndrome follows an autosomal dominant inheritance, with a variable clinical expression of symptoms.
  • ⁇ - adrenergic adrenoreceptor blockers which are effective against migraine are not useful for treating the other two syndromes and may even exasperate depression.
  • Ri is selected from the group consisting of alkyl and haloalkyl
  • R 2 is selected from the group consisting of hydrogen, alkyl and fluorine
  • R 3 is selected from the group consisting of hydrogen, alkyl and (NRARB)carbonylalkyl wherein R A and R B are each independently selected from the group consisting of hydrogen and alkyl; j is selected from the group consisting of hydrogen and alkyl; and R5 is selected from the group consisting of hydrogen and alkyl.
  • Ri is selected from the group consisting of alkyl and haloalkyl
  • R 2 is selected from the group consisting of hydrogen, alkyl and fluorine
  • R 3 is selected from the group consisting of hydrogen, alkyl and (NR A R B )carbonylalkyl wherein R A and R B are each independently selected from the group consisting of hydrogen and alkyl;
  • I is selected from the group consisting of hydrogen and alkyl
  • R 5 is' selected from the group consisting of hydrogen and alkyl.
  • compounds of the present invention have formula (I) wherein R 2 is hydrogen; Ri, R 3 , J and R5 are as defined in formula (I).
  • compounds of the present invention have formula (I) wherein R 2 is alkyl; Ri, R 3 , j and R5 are as defined in formula (I).
  • compounds of the present invention have formula (I) wherein R 2 is fluorine; Ri, R , t and R 5 are as defined in formula (I). In another preferred embodiment, compounds of the present invention have formula (I) wherein Ri is propyl; R5 is is methyl; and R 2 , R 3 and i are as defined in formula (I).
  • compounds of the present invention have formula (I) wherein Ri is propyl; R 3 is hydrogen; R 5 is methyl; and R 2 and R4. are as defined in formula (I).
  • compounds of the present invention have formula (I) wherein Ri is propyl; R 3 is (NRARB)carbonylalkyl; R5 is methyl; and R 2 and 4 are as defined in formula (I).
  • compounds of the present invention have formula (I) wherein Ri is propyl; R 2 is hydrogen; R is (NRARB)carbonylalkyl; R5 is methyl; and j is as defined in formula (I).
  • compounds of the present invention have formula (I) wherein Ri is propyl; R 2 is fluorine; R 3 is (NRAR ⁇ )carbonylalkyl; R5 is methyl; and Ri is as defined in formula (I).
  • compounds of the present invention have formula (I) wherein Ri is propyl; R 2 is alkyl; R 3 is (NRARB)carbonylalkyl; R5 is methyl; and R4. is as defined in formula (I).
  • Another embodiment of the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (I) in combination with a pharmaceutically acceptable carrier.
  • Another embodiment of the present invention relates to a method of treating epilepsy, migraine or a psychiatric disorder selected from Mood Disorders, Anxiety Disorders, Attention- Deficit and Disruptive Behavior Disorders, Behavioral Disturbances associated with dementia, Substance Abuse-related Disorders, Schizophrenia, Impulse Control Disorders, Personality Disorders and Behavioral Disturbances associated with autism in a mammal comprising administering to a mamml in need of such treatment a therapeutically effective amount of a compound of formula (I) in combination with a pharmaceutically acceptable carrier.
  • a psychiatric disorder selected from Mood Disorders, Anxiety Disorders, Attention- Deficit and Disruptive Behavior Disorders, Behavioral Disturbances associated with dementia, Substance Abuse-related Disorders, Schizophrenia, Impulse Control Disorders, Personality Disorders and Behavioral Disturbances associated with autism in a mammal comprising administering to a mamml in need of such treatment a therapeutically effective
  • a preferred embodiment of the present invention relates to a method of treating epilepsy, migraine or a psychiatric disorder selected from Mood Disorders, Anxiety Disorders, Attention- Deficit and Disruptive Behavior Disorders, Behavioral Disturbances associated with dementia, Substance Abuse-related Disorders, Schizophrenia, Impulse Control Disorders, Personality Disorders and Behavioral Disturbances associated with autism in a mammal comprising administering to a mamml in need of such treatment a therapeutically effective amount of (2R)- 2-propyl-4-hexynamide in combination with a pharmaceutically acceptable carrier.
  • a psychiatric disorder selected from Mood Disorders, Anxiety Disorders, Attention- Deficit and Disruptive Behavior Disorders, Behavioral Disturbances associated with dementia, Substance Abuse-related Disorders, Schizophrenia, Impulse Control Disorders, Personality Disorders and Behavioral Disturbances associated with autism in a mammal comprising administering to a mamml in need
  • Another preferred embodiment of the present invention relates to a method of treating epilepsy, migraine or a psychiatric disorder selected from Mood Disorders, Anxiety Disorders, Attention-Deficit and Disruptive Behavior Disorders, Behavioral Disturbances associated with dementia, Substance Abuse-related Disorders, Schizophrenia, Impulse Control Disorders, Personality Disorders and Behavioral Disturbances associated with autism in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound selected from (2R)-N-(2-amino-2-oxoethyl)-2-propyl-4-hexynamide; (2R)-N-[(lS)-l-(aminocarbonyl)-2-methylpro ⁇ yl]-2-propyl-4-hexynamide; (2R)-N-[(lS)-l- (aminocarbonyl)-3 -methylbutyl]-2-propyl-4-hexynamide;
  • alkyl refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms.
  • Representative examples of alkyl include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3- dimethylpentyl, heptyl, octyl, nonyl, and decyl.
  • halo or halogen, refers to -Cl, -Br, -I or -F.
  • haloalkyl refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of haloalkyl include, but are not limited to, trifluoromethyl, pentafluoroethyl, 3,3,3-trifluoropropyl, 2,2-difluoropropyl, 2,3-dif ⁇ uoropropyl, 2,2,3,3,3,- pentafluoropropyl and 2-chloro-3-fluoropentyl.
  • carbonyl refers to a -C(O)- group.
  • R A and R B are each independently selected from hydrogen and alkyl.
  • (NRARB)carbonyl refers to a -NRARB group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • (NRARB)carbonylalkyl refers to a (NRARs)carbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of (NR A RB)carbonylalkyl include, but are not limited to, 2- amino-2-oxoethyl, (lS)-2-amino-l-methyl-2-oxoethyl, (lR)-2-amino-l-methyl-2-oxoethyl, (1S)- 1 -(aminocarbonyl)-2-methylpropyl, (1R)-1 -(aminocarbonyl)-2-methylpropyl, (1 S)-l - (aminocarbonyl)-3-methylbutyl, (lR)-l-(aminocarbonyl)-3-methylbutyl, and (lS,2R)-4-amino-2- ethyl- l-is
  • Preferred compounds of formula (I) include,
  • a most preferred compound is (2R)-2-propyl-4-hexynamide.
  • the compounds of this invention can be prepared by a variety of synthetic routes.
  • Alkynyl amides of general formula (3) wherein Ri, R 3 , j and R5 are as defined in formula (I), may be prepared as described in Scheme 1.
  • Alkynyl acids of general formula (1) prepared according to US patent No. 5786380 hereby fully incorporated by reference, may be treated with oxalyl chloride and catalytic DMF in a solvent such as methylene chloride to provide crude acid chlorides.
  • the crude acid chlorides may then be treated with an amine of general formula (2) in a solvent such as methylene chloride to provide alkynyl amides of general formula of general formula (3).
  • Alkynyl amides of general formula (9), wherein Ri, R 3 , i and R5 are as defined in formula (I) and R 2 is alkyl, may be prepared as described in Scheme 2.
  • Alkynyl acids of general formula (1) may be treated with HCl in methanol to provide alkynyl esters of general formula (5).
  • Alkynyl esters of general formula (5) may be treated with lithium diisopropylamine and an alkyl halide to provide esters of general formula (6).
  • Esters of general formula (6) may be treated with aqueous base such as potassium hydroxide in a solvent such as water/ethanol to provide acids of general formula (7).
  • Acids of general formula (7) may be separated into individual enantiomers using chiral auxiliaries which is well known in the art such as the use of chiral oxazolidinones (Evans et al. J. Am. Chem. soc, (1982) 104 1737-1739) to provide chiral acids of general formula (8).
  • chiral auxiliaries which is well known in the art such as the use of chiral oxazolidinones (Evans et al. J. Am. Chem. soc, (1982) 104 1737-1739) to provide chiral acids of general formula (8).
  • An example of separation of similar acids is described in US Patent No. 5786380.
  • Chiral acids of general formula (8) may be processed as described in Scheme 1 to provide alkynyl amides of general formula (9).
  • Alkynyl amides of general formula (12), wherein Ri, R 3 , t and R 5 are as defined in formula (I), may be prepared as described in Scheme 3.
  • Esters of general formula (5) may be treated with lithium diisopropylamide and an electrophilic source of fluorine such as N-fluoro-N- [(trifluoromethyl)sulfonyl]trifluoromethanesulfonamide, other reagents known to be electrophilic sources of fluorine may be purchased commercially or prepared as described in (Chem. Rev., (1996) vol.
  • Fluorinated esters of general formula (11) may be processed as described in Scheme 2 to provide alkynyl amides of general formula (12).
  • mice Male GDI mice (Charles River, Portage, MI) weighing 25-35 g were used and during the experiment the mice were housed individually in clear polycarbonate cages for observation. For each experiment, ten mice were each pretreated intra-peritoneally with a compound of the present invention (1400 ⁇ mol/kg) prior to pentylenetetrazole (PTZ) (Sigma, St. Louis, MO) injection. Seizures were induced by the subcutaneous injection of PTZ (85 mg/kg) just below the nape of the neck. The animals were observed for 15 minutes and time to seizure was noted.
  • PTZ pentylenetetrazole
  • Table 1 represents the average time for PTZ induced seizure. Also noted were the number of mice out often that did not seize within the 15 minute period following PTZ injection. This data is shown in Table 2. Control animals were not pretreated with a compound of the present invention but were injected with PTZ (85 mg/kg) subcutaneously.
  • Tables 1 and 2 illustrate the anticonvulsant effect of compounds of the present invention in mammals.
  • mice Male CD1 mice (Charles River) weighing from 25-35 g were used. Mice were pretreated orally with compounds of the present invention prior to electrical stimulation. Mice were challenge by pulsed electrical stimulation (50 mA, 0.4 s duration, pulse width 0.5 ms, 60 pulses/sec) via comeal electrodes to induce seizure. The stimulation was delivered with an ECT Unit (Ugo Basile #7801). The electrodes of the unit were coated with electrocardiogram electrolyte (Signa Creme, Parker Labs #1708) to ensure good contact with the corneas. Mice were observed post-stimulation for the onset of seizures and death.
  • pulsed electrical stimulation 50 mA, 0.4 s duration, pulse width 0.5 ms, 60 pulses/sec
  • the stimulation was delivered with an ECT Unit (Ugo Basile #7801).
  • the electrodes of the unit were coated with electrocardiogram electrolyte (Signa Creme, Parker Labs #1708) to ensure good contact with the corneas. Mice were observed post
  • mice were considered to have had a seizure only if there was an extended extension (>90° from plane of body) of the hind legs. Mice were assigned scores of either "positive” or "negative.” A positive score indicates that seizure occurred; a negative score indicated that seizure did not occur. Animals which gave a positive seizure response were observed an additional 30 seconds for death. Those that did not seize were considered to be protected. The percent protection from seizures was calculated by dividing the number of protected mice by the total number of mice for the group. The percentage of mice protected from electrical shock induced seizures at doses of 600, 1200, 1800 and 2400 ⁇ mole/kg is illustrated in Table 3 for Example 1 and Example 6. The corresponding acid, (2R)-2-propyl-4-hexynoic acid, was also tested for comparison. Table 3
  • NT in Table 3 means Not Tested.
  • the data in Table 3 illustrates the ability of alkynyl amides of the present invention to protect mice from electrical shock induced seizures.
  • Alkynyl amides of the present invention unexpectedly protect a significantly higher percentage of mice when compared to the corresponding acid, (2R)-2-propyl-4-hexynoic acid.
  • the compounds of the present invention possess an anticonvulsant effect as demonstrated by the data illustrated in Tables 1-3.
  • the compounds of the present invention may be useful for the treatment of a variety of disorder such as seizures, epilepsy, migraine, psychiatric disorders, neuropathic pain and restlessness syndrome.
  • compounds of the present invention may be useful for providing neuroprotection.
  • psychiatric disorders such as Mood Disorders, Anxiety Disorders, Attention-Deficit and Disruptive Behavior Disorders, Behavioral Disturbances associated with dementia, Substance Abuse-related Disorders, Schizophrenia, Impulse Control Disorders, Personality Disorders and Behavioral Disturbances associated with autism
  • psychiatric disorders such as Mood Disorders, Anxiety Disorders, Attention-Deficit and Disruptive Behavior Disorders, Behavioral Disturbances associated with dementia, Substance Abuse-related Disorders, Schizophrenia, Impulse Control Disorders, Personality Disorders and Behavioral Disturbances associated with autism
  • the ability of the compounds of the invention, including but not limited to those specified in the examples, to treat neuropathic pain may be demonstrated according to the methods described in (Lloyd and Morselli, in Psychopharmacology: The Third Generation of Progress, Raven Press, 1987; and Swendlow, J. Clin. Neuropharmacol., 7, 1984, 51-82).
  • the ability of the compounds of the invention, including but not limited to those specified in the examples, to treat Restlessness Syndrome may be demonstrated according to the methods described in (O'Keefe, Arch. Intern. Med.
  • Stereoisomers of the present invention may exist as stereoisomers wherein, asymmetric or chiral centers are present. These stereoisomers are "R” or “S” depending on the configuration of substituents around the chiral carbon atom.
  • R and S used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., 1976, 45: 13-30.
  • the stereochemistry at the 2- position of the 4-hexynamides may be only (R) when R 2 is hydrogen or alkyl and may be only (S) when R 2 is fluorine.
  • R 3 is (NRARB)carbonylalkyl
  • the alkyl portion may contain one or two chiral centers.
  • the one or two chiral centers contained within the alkyl portion of ( R A R B )carbonylalkyl may be independently either (R) or (S), unless specifically noted otherwise.
  • the present invention does contemplate various stereoisomers and mixtures thereof and are specifically included within the scope of this invention.
  • Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers.
  • Individual stereoisomers of compounds of the present invention may be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution well-known to those of ordinary skill in the art.
  • the present invention contemplates prodrugs that are transformed by in vivo biotransformation into compounds of formula (I).
  • prodrug represents those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use.
  • Prodrugs of the present invention may be rapidly transformed in vivo to compounds of formula (I), for example, by hydrolysis in blood.
  • a thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, V. 14 of the A.C.S. Symposium Series; and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987.
  • pharmaceutically acceptable carrier means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen
  • the present invention provides pharmaceutical compositions which comprise compounds of the present invention formulated together with one or more non-toxic pharmaceutically acceptable carriers.
  • the pharmaceutical compositions can be formulated for oral administration in solid or liquid form, for parenteral injection or for rectal administration. Further included within the scope of the present invention are pharmaceutical compositions comprising one or more of the compounds of formula (I) prepared and formulated in combination with one or more non-toxic pharmaceutically acceptable compositions.
  • the pharmaceutical compositions can be formulated for oral administration in solid or liquid form, for parenteral injection or for rectal administration.
  • compositions of this invention can be administered to humans and other mammals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments or drops), bucally or as an oral or nasal spray.
  • parenterally refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intraarticular injection and infusion.
  • Pharmaceutical compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • aqueous and nonaqueous carriers, diluents, solvents or vehicles examples include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • a coating such as lecithin
  • surfactants for example, by the use of surfactants.
  • compositions may also contain adjuvants such as preservative agents, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride and the like. Prolonged abso ⁇ tion of the injectable pharmaceutical form may be brought about by the use of agents delaying abso ⁇ tion, for example, aluminum monostearate and gelatin.
  • the abso ⁇ tion of the drug in order to prolong the effect of a drug, it is often desirable to slow the abso ⁇ tion of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Suspensions in addition to the active compounds, may contain suspending agents, as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, and mixtures thereof.
  • the compounds of the present invention can be inco ⁇ orated into slow-release or targeted-delivery systems such as polymer matrices, liposomes, and microspheres. They may be sterilized, for example, by filtration through a bacteria-retaining filter or by inco ⁇ oration of sterilizing agents in the form of sterile solid compositions, which may be dissolved in sterile water or some other sterile injectable medium immediately before use.
  • the active compounds can also be in micro-encapsulated form, if appropriate, with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound can be admixed with at least one inert diluent such as sucrose, lactose, or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of such composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • injectable depot forms are made by forming microencapsulated matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides) Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by inco ⁇ orating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic, parenterally acceptable diluent or solvent such as a solution in 1,3-butanediol.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents such as paraffin); f) abso ⁇ tion accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol mon ⁇ ste
  • the dosage form may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benz
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Compounds of the present invention may also be administered in the form of liposomes.
  • liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes may be used.
  • compositions in liposome form may contain, in addition to the compounds of the present invention, stabilizers, preservatives, excipients, and the like.
  • the preferred lipids are the natural and synthetic phospholipids and phosphatidylcholines (lecithins) used separately or together.
  • compositions to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N Y., (1976), p 33 et seq.
  • pharmaceutically acceptable cation refers to a positively- charged inorganic or organic ion that is generally considered suitable for human consumption. Examples of pharmaceutically acceptable cations are hydrogen, alkali metal (lithium, sodium and potassium), magnesium, calcium, ferrous, ferric, ammonium, alkylammonium, dialkylammonium, trialkylammonium, tetraalkylammonium, diethanolammmonium, and choline. Cations may be interchanged by methods known in the art, such as ion exchange.
  • pharmaceutically acceptable salt refers to salts that are well known in the art.
  • S. MBerge et al. describe pharmaceutically acceptable salts in detail in (J. Pharmaceutical Sciences, 66:1-19 (1977)).
  • pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include nitrate, bisulfate, borate, formate, butyrate, valerate, 3-phenylpropionate, camphorate, adipate, benzoate, oleate, palmitate, stearate, laurate, lactate, fumarate, ascorbate, aspartate, nicotinate, p-toluenesulfonate, camphorsulfonate, methanesulfonate, 2-hydroxyethanesulfonate, gluconate, glucoheptonate, lactobionate, glycerophosphate, pectinate, lauryl sulfate, and the like, metal salts such as sodium, potassium, magnesium or calcium salts or amino salts such as ammonium, triethylamine salts, and the like, all of which may be prepared according to conventional methods.
  • Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants.
  • the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants which can be required.
  • Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention can be varied so as to obtain an amount of the active compound(s) which is effective to achieve the desired therapeutic response for a particular patient, compositions and mode of administration.
  • the selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
  • Aqueous liquid compositions of the present invention may be particularly useful for the treatment and prevention of seizures, in particular, seizures associated with epilepsy.
  • a therapeutically effective amount of one of the compounds of the present invention can be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt form.
  • the compound can be administered as a pharmaceutical composition containing the compound of interest in combination with one or more pharmaceutically acceptable excipients.
  • therapeutically effective amount of the compound of the invention means a sufficient amount of the compound to treat disorders, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgement.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
  • the total daily dose of the compounds of this invention administered to a human or lower animal may range from about 0.003 to about 30 mg/kg/day.
  • more preferable doses can be in the range of from about 0.01 to about 10 mg/kg/day.
  • the effective daily dose can be divided into multiple doses for pu ⁇ oses of administration; consequently, single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Anesthesiology (AREA)
  • Addiction (AREA)
  • Hospice & Palliative Care (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne des composés de formule (I), nouveaux et utiles permettant de traiter la crise, la migraine et les troubles psychiatriques.
EP01989847A 2000-11-01 2001-10-31 Amides d'alkynyle et leurs applications therapeutiques Withdrawn EP1330429A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US70377100A 2000-11-01 2000-11-01
PCT/US2001/045704 WO2002036546A2 (fr) 2000-11-01 2001-10-31 Amides d'alkynyle et leurs applications therapeutiques
US703771 2003-11-07

Publications (1)

Publication Number Publication Date
EP1330429A2 true EP1330429A2 (fr) 2003-07-30

Family

ID=24826711

Family Applications (1)

Application Number Title Priority Date Filing Date
EP01989847A Withdrawn EP1330429A2 (fr) 2000-11-01 2001-10-31 Amides d'alkynyle et leurs applications therapeutiques

Country Status (8)

Country Link
EP (1) EP1330429A2 (fr)
JP (1) JP4115835B2 (fr)
AU (1) AU2002228726A1 (fr)
CA (1) CA2427560C (fr)
MX (1) MXPA03003926A (fr)
PE (1) PE20020575A1 (fr)
UY (1) UY26997A1 (fr)
WO (1) WO2002036546A2 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005046659A2 (fr) * 2003-11-12 2005-05-26 Nps Pharmaceuticals, Inc. Traitement de la migraine comportant des composes d'isovaleramide et des agonistes de la serotonine
DE102005062987A1 (de) * 2005-12-28 2007-07-05 Grünenthal GmbH Substituierte Propiolsäureamide und ihre Verwendung zur Herstellung von Arzneimitteln

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5585358A (en) 1993-07-06 1996-12-17 Yissum Research Development Corporation Of The Hebrew University Of Jerusalem Derivatives of valproic acid amides and 2-valproenoic acid amides, method of making and use thereof as anticonvulsant agents

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0236546A2 *

Also Published As

Publication number Publication date
WO2002036546A3 (fr) 2002-10-10
UY26997A1 (es) 2002-07-31
MXPA03003926A (es) 2004-05-24
AU2002228726A1 (en) 2002-05-15
JP2004532804A (ja) 2004-10-28
CA2427560A1 (fr) 2002-05-10
JP4115835B2 (ja) 2008-07-09
WO2002036546A2 (fr) 2002-05-10
PE20020575A1 (es) 2002-06-25
CA2427560C (fr) 2010-12-07

Similar Documents

Publication Publication Date Title
JP3857714B2 (ja) α２δ−タンパク質へのアフィニティを有するアミノ酸
EP2268140B1 (fr) Nouveaux composés servant à traiter les maladies et troubles du système nerveux central
JP7036792B2 (ja) スピロ－ラクタムｎｍｄａ受容体修飾因子およびその使用
JP4555263B2 (ja) カルシウムチャンネルα２δサブユニットに親和性を有するプロリン誘導体
US20040034069A1 (en) Nitrogen-containing compounds and their use as glycine transport inhibitors
US8283375B2 (en) 2, 6 xylidine derivatives for the treatment of pain
JP2010535810A (ja) 癲癇の治療に有用なスルファミド誘導体
CA2427560C (fr) Amides d'alkynyle et leurs applications therapeutiques
US8846903B2 (en) Acyl-urea derivatives and uses thereof
US6521790B2 (en) Alkynyl amides and their therapeutic applications
US20130072533A1 (en) Compounds with both analgesic and anti-hyperalgesic efficacy
CN104710327B (zh) 有益于治疗中枢神经系统疾病和病症的化合物
CN104854083B (zh) 氨基环丁烷衍生物、其制备方法及其用作药物的用途
JP2007506726A (ja) α２δ−タンパク質に対する親和性を有するアミノ酸の使用方法
AU2019268209B2 (en) Compounds for the treatment of seizures and other central nervous system disorders and conditions
JP2008542198A (ja) β‐アミノ酸誘導体
WO2016141188A1 (fr) Composés pour moduler la fonction mitochondriale
WO2015118554A1 (fr) Dérivés de dithiolan-3-ylpentanoate, compositions pharmaceutiques et méthodes de traitement de la douleur
MXPA05000979A (es) Derivados de glicina sustituidos para uso como medicamentos.

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: 20030523

AK Designated contracting states

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO SI

17Q First examination report despatched

Effective date: 20070206

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

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: 20100914

REG Reference to a national code

Ref country code: HK

Ref legal event code: WD

Ref document number: 1058185

Country of ref document: HK