WO2005016331A1 - Agent therapeutique contre les douleurs neuropathiques contenant un derive n-(benzoyl)amino acide comme principe actif - Google Patents

Agent therapeutique contre les douleurs neuropathiques contenant un derive n-(benzoyl)amino acide comme principe actif Download PDF

Info

Publication number
WO2005016331A1
WO2005016331A1 PCT/JP2004/011594 JP2004011594W WO2005016331A1 WO 2005016331 A1 WO2005016331 A1 WO 2005016331A1 JP 2004011594 W JP2004011594 W JP 2004011594W WO 2005016331 A1 WO2005016331 A1 WO 2005016331A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
pain
group
formula
methylalanine
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.)
Ceased
Application number
PCT/JP2004/011594
Other languages
English (en)
Japanese (ja)
Inventor
Yasushige Akada
Takuo Ogihara
Akihiro Okano
Yasushi Matsumura
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.)
Mochida Pharmaceutical Co Ltd
Original Assignee
Mochida Pharmaceutical Co Ltd
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 Mochida Pharmaceutical Co Ltd filed Critical Mochida Pharmaceutical Co Ltd
Publication of WO2005016331A1 publication Critical patent/WO2005016331A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/223—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of alpha-aminoacids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • a therapeutic agent for neuropathic pain containing an N- (benzoyl) amino acid derivative as an active ingredient
  • the present invention provides a method for preventing and / or preventing neuropathic monopathic pain, comprising an N- (benzoyl) amino acid derivative or an optically active form thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. Or regarding therapeutic agents. Further, the present invention provides (1) an N- (benzoinole) amino acid derivative or an optically active form thereof or a pharmaceutically acceptable salt thereof, and (2) gabapentin or pregaparin or a pharmaceutically acceptable form thereof. The present invention relates to a prophylactic and / or therapeutic agent for palsy pain characterized by combining at least one selected from the group consisting of a salt and a salt. Further, the present invention relates to a novel derivative or a salt thereof useful for these medicaments.
  • Pain includes unpleasant sensory-emotional experiences that occur based on substantial or potential injury to the tissue, and also includes sensory-emotional experiences described using such expressions.” Is defined. Pain is classified into nociceptive pain, neuropathic pain, and psychogenic pain.
  • Nociceptive pain is the physiological pain caused by mechanical, thermal, and chemical stimuli, and plays a role as a biosensor based on unpleasant sensory experiences to protect yourself from danger. You.
  • Neuropathic pain is pain caused by temporary damage or dysfunction caused by temporary damage to some part of the nerve transmission system from the periphery to the center (Illustrated Latest Anesthesia Science Series 4, Pain Clinical Chapter 1, Kenniro Dan, 1998, Medical View).
  • Nerve injuries that cause neuropathic pain are typically trauma or injuries to peripheral nerves, plexuses or perineural soft tissue, but may include central somatosensory pathways (spinal cord, brainstem, thalamus). Or ascending somatosensory pathways at the cortical level).
  • central somatosensory pathways spinal cord, brainstem, thalamus.
  • ascending somatosensory pathways at the cortical level For example, neurodegenerative disease, bone degenerative disease, metabolic disorder, cancer, It can be caused by staining, inflammation, post-surgical surgery, trauma, radiation therapy, treatment with anticancer drugs, etc.
  • its pathophysiology, and especially the molecular mechanism of its onset has not been fully elucidated.
  • arodyure is a condition in which a normal person feels pain with a stimulus that does not feel pain.
  • tactile stimulation causes pain, that is, there is a qualitative change in sensory response, and the threshold itself is considered to be a fundamental characteristic of arodinia.
  • post-herpetic neuralgia a representative of neuropathic pain, 87% of patients have arodyure.
  • the pain intensity of postherpetic neuralgia is said to be proportional to the degree of arodiure.
  • arodyure has been attracting attention as a treatment for postherpetic neuralgia.
  • neuropathic pain performing analgesic therapy for a patient who complains of chronic pain symptoms and the pain itself interferes with daily life is directly related to the quality of life (life). Quality of Life). It is said that central analgesics such as morphine, non-steroidal antiphlogistic analgesics and steroids are ineffective for neuropathic pain.
  • antidepressants such as amitriptyline are not used.
  • antiepileptic drugs such as gabapentin, pregabalin, carbamazepine and phenytoin, and antiarrhythmic drugs such as mexiletine have been diverted and prescribed.
  • amitriptyline such as low blood pressure, drowsiness, sedation, constipation, and difficulty urinating.
  • Carbamazepine and phenytoin have lightheadedness, rash, gastrointestinal symptoms, and cardiotoxicity. Is somnolence and dizziness, but mexiletine is known to have dizziness and gastrointestinal symptoms.
  • These drugs are not specific neuropathic pain remedies, and these drugs have a poor dissociation between efficacy and side effects, and their treatment satisfaction is low. Therefore, there is a need for a therapeutic agent for neuropathic pain which shows higher efficacy by oral administration and has fewer side effects.
  • Patent Document 1 discloses an amide derivative useful as a therapeutic agent for neuroretinal degenerative diseases.
  • Patent Document 2 discloses that 2-methyl-N— (4-trifluoro) is used as a synthetic intermediate of a novel acylamino-substituted acylylanilide derivative useful as an antiandrogen drug. It is known that romethylbenzoyl) alanine has been produced. It is known from Patent Document 3 that N-benzoyl-2-methylalanine was produced as a synthetic intermediate of an anticonvulsant.
  • Non-Patent Document 1 discloses that N-4-methylbenzoyl-2-methylalanine was produced as an intermediate in the conversion reaction between benzoic acid and salicylic acid. It is known. However, there is no disclosure in these prior arts for dieuropathy pain.
  • Patent Literature 4 discloses a salicylamide derivative having an analgesic effect, but does not disclose or suggest any effect on neuropathic pain (arodiure). Also, there is no report that these compounds have been successfully developed as pharmaceuticals.
  • Patent Document 5 discloses a therapeutic agent for pain in combination of gabapentin and pregabalin.
  • Patent Document 6 discloses that a compound having an antiepileptic effect and a compound selected from an N-methyl-D-aspartate (NMDA) receptor antagonist, a nonsteroidal anti-inflammatory drug (NSAID), an analgesic, and a combination thereof are disclosed.
  • NMDA N-methyl-D-aspartate
  • NSAID nonsteroidal anti-inflammatory drug
  • an analgesic an analgesic
  • a pain relief composition in combination with is disclosed.
  • the use of gabapentin with N- (benzoyl) amino acid derivatives is well known.
  • neuropathic pain treatments There are always comprehensive issues in the development of these drugs for neuropathic pain treatments.
  • neuropathic agents with less side effects and higher usefulness than those of the conventional drugs currently used for the treatment of neuropathic pain described above are used.
  • pain treatments There is a need for pain treatments
  • Patent Document 1 International Publication No. W099Z21543
  • Patent Document 2 International Publication No. W098Z22432
  • Patent Document 3 GB752692 published in the UK
  • Patent document 4 French publication FR M2137
  • Patent Document 5 International Publication WO01Z001983
  • Patent Document 6 International Publication WO00Z53225
  • Non-Patent Document 1 Synthsis 612-614, 1990
  • An object of the present invention is to provide a compound which is orally administrable, has few side effects, is more safe, and is effective for an analgesic having excellent efficacy and pharmacokinetic properties, especially a therapeutic agent for neuropathic pain.
  • Another object of the present invention is to provide a method for producing them, and a drug and a pharmaceutical composition containing them.
  • the above-mentioned problems in the prior art more specifically, rash and gastrointestinal symptoms, which are side effects of carbamazepine and phenytoin, such as side effects of amitriptyline, drowsiness, sedation, constipation, and difficulty urinating.
  • mexiletine such as somnolence and dizziness
  • gabapentin such as cardiotoxicity, and digestive symptoms. It is an object of the present invention to provide an analgesic which can be orally administered to mammals including humans, in particular, a preventive and / or therapeutic agent for neuropathic pain, which overcomes one or more of the problems.
  • the inventors of the present invention have conducted intensive studies to obtain compounds having an analgesic action with less side effects to solve the above problems, higher safety, and superior efficacy as a result of the formula (I) )so
  • the specified N- (benzoyl) amino acid derivative or its optically active form, or a pharmaceutically acceptable salt thereof has an excellent analgesic effect in the rat formalin test.
  • the first aspect of the present invention is to provide a compound represented by the following formula (I) or an optically active form thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof. It is a preventive and / or therapeutic agent for neuropathic pain characterized by containing as an ingredient.
  • Z represents -C (CH)-or -CH (CH (CH)) _;
  • n an integer of 02
  • R 1 represents a C 1-4 alkyl group, a hydroxyl group, a trifluoromethyl group or an acetyloxy group, and when n is 2, R 1 may be the same or different;
  • R 2 represents a hydrogen atom or a C 1-4 alkyl group. However, Z gar CH (CH (CH)) - a and, except when R 1 is 2-position of the hydroxy Honoré groups. )
  • R 1 in the above formula (I) is preferably a hydroxyl group, a trifluoromethyl group or an acetyloxy group, more preferably a hydroxy group or a trifluoromethyl group.
  • the substitution position of is expressed with the carbon atom to which CONH is bonded as position 1.
  • n 2, the 2nd and 3rd positions, 2nd and 4th positions, 2nd and 5th positions, 2nd and 6th positions, 3 And 4th, 3rd and 5th, 3rd and 6th, etc. And prefer to be fifth.
  • R 2 in the above formula (I) is preferably a hydrogen atom.
  • Z in the formula (I) is preferably -C (CH2)-.
  • Preferred examples of the compound represented by the formula (I) or an optically active form thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof are as follows.
  • N-benzoyl 2-methylalanine a pharmaceutically acceptable salt thereof, or a solvate thereof;
  • N- (P-toluoyl) 2-methylalanine a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • the second aspect of the present invention comprises, as an active ingredient, the compound represented by the formula (I) or an optically active form thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • An anti-arodiuretic agent characterized by the following:
  • a third aspect of the present invention relates to an agent for preventing and / or treating neuropathic pain
  • a neuropathic pain characterized by combining at least one selected from the group consisting of gabapentin or pregaparin, or a pharmaceutically acceptable salt thereof, or a solvate or a powerful group thereof.
  • a prophylactic and / or therapeutic agent characterized by combining at least one selected from the group consisting of gabapentin or pregaparin, or a pharmaceutically acceptable salt thereof, or a solvate or a powerful group thereof.
  • the compound represented by the formula (I) is preferred, preferred, a substituent or a preferable combination thereof, or a compound or an optically active compound is preferred.
  • the example is the same as the first embodiment.
  • a fourth aspect of the present invention provides:
  • the selected compound or optically active substance, a salt thereof, or a solvate thereof is selected compound or optically active substance, a salt thereof, or a solvate thereof.
  • a fifth aspect of the present invention is a medicament comprising, as an active ingredient, the compound or the optically active substance according to the fourth aspect, or a salt thereof, or a solvate thereof.
  • a sixth aspect of the present invention is characterized in that the compound or the optically active substance according to the fourth aspect, or a salt thereof, or a solvate thereof is contained as an active ingredient, New It is a preventive and / or therapeutic agent for bite-pathic pain.
  • an antibody comprising the compound or the optically active substance according to the fourth aspect, a salt thereof, or a solvate thereof as an active ingredient. It is a diuretic.
  • the "C1_4 alkyl group” means an alkyl group having 1 to 4 carbon atoms, and may be a methyl group, an ethyl group, which may have a linear structure or a branched structure.
  • the compound represented by the formula (I) used in the present invention may form a salt with a base .
  • bases are not particularly limited as long as they are pharmaceutically acceptable salts.
  • bases of metals such as sodium, potassium, magnesium, calcium, aluminum and the like, methinoleamine, ethylamine, ethanolamine And salts with organic bases such as pyridine, lysine, arginine, and ornithine, and ammonium salts.
  • salts can be obtained by a conventional method, for example, by mixing an equivalent amount of the compound of the present invention and a solution containing a desired base, and collecting the desired salt by filtration or distilling off the solvent. Further, the compound of the present invention or a salt thereof may form a solvate with a solvent such as water, ethanol and glycerol. The compound of the present invention or a salt thereof also includes these solvates.
  • the compound of the present invention may be crystalline or non-crystalline. That is, the compound represented by the above formula (I) of the present invention, its optically active form, or a salt or a solvate thereof also includes embodiments of crystals, non-crystals, and solvates thereof. .
  • the crystals also include polymorphs.
  • the present invention also includes the polymorph of the compound of the formula (I), a salt thereof, and a solvate thereof.
  • the compound represented by the formula (I) may have an asymmetric carbon atom, and various mixtures and isolated substances such as all optically active isomers (enantiomers and the like) may exist. Includes all of these.
  • the isolation and purification of such optical isomers can be achieved through preferential crystallization—optical resolution using column chromatography or asymmetric synthesis.
  • gabapentin is a general name of Neurotin commercially available in Europe and the United States, and refers to 2_ [1_ (aminomethyl) cyclohexane] acetic acid.
  • Pregabalin is a general name for (S) -3- (aminomethyl) -5-methylhexanoic acid.
  • the compound represented by the formula (I) in the present invention can be produced by a known method as a starting material by a combination of known methods. Among them, the method for producing the compound represented by the formula (I) is preferably the method described below.
  • R 1 , R 2 and Z have the same meaning as described above.
  • R 3 is an alkyl group, an aralkyl group, an aryl group, or a hydrogen atom Indicates.
  • R represents a C-14 alkyl group, a trifluoromethyl group, an acetyloxy group, or a protected hydroxyl group.
  • the production method comprises condensing an amino acid derivative represented by the formula (II) or a salt thereof with a benzoic acid derivative represented by the formula (III) to form an amide bond.
  • a compound represented by the formula (II) is obtained, and a compound represented by the formula (I) is obtained by converting a substituent (R 1A ) if necessary.
  • the reaction of condensing an amino acid derivative represented by the formula ( ⁇ ) with a benzoic acid derivative represented by the formula (III) to form an amide bond is a reaction commonly used in amide synthesis and peptide synthesis. It can be implemented in a known manner. For example, New Laboratory Chemistry Course “Synthesis and Reaction of Organic Compounds (11)” (Maruzen), Toshio Goto, Tetsuo Shiba, Teruo Matsuura “Supervising Organic Chemistry Experiment 4 -Synthetic Reaction [II]” )), And the like.
  • reaction (1) for forming an amide bond is carried out by a method of mixing and condensing a carboxylic acid or a carboxylic acid ester with an amine
  • the substrate is dissolved in a solvent having a boiling point of room temperature or higher. It is preferable to mix and heat or to condense by dehydration or dealcoholization by azeotropic distillation with a solvent.
  • reaction (2) for forming an amide bond is carried out by a method in which a carboxylic acid is converted into an acid halide or an active ester and reacted with an amine, the corresponding carboxylic acid is converted to a thional chloride-oxalic acid chloride or the like.
  • N-hydroxysuccinate converted to acid chloride using After conversion to various active esters using acid imide, N-hydroxybenzotriazole, 4-nitrophenol, pentafluorophenol, and the like, it is reacted with amine.
  • a base such as triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydrogencarbonate may be present.
  • the condensing agent may be, for example, N, N-dicyclohexylcarbodiimide.
  • DCC 1_ethyl_3_ (3-dimethylaminopropyl) carbodiimide
  • WSC benzotriazono-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate
  • B ⁇ P benzotriazono-1- Oxybenzotrispyrrolidinofosodium hexafluorophosphate
  • BOP-Cl bis (2-oxo-3-oxazolidinyl) phosphinic chloride
  • HBTU pentafluorophenyl diphenylphosphinate FDPP
  • condensation reaction together with the condensing agent, addition of l-hydroxybenzotriazole and 3,4-dihydro-3-hydroxy-14-oxo-1,2,3, benzotriazine, etc., lj, triethylamine, diisopropylamine
  • a base such as min, N-methylmorpholine, pyridine, sodium hydroxide, potassium hydroxide, sodium carbonate or sodium bicarbonate may be present.
  • Examples of more specific protecting groups include lower alkyl groups such as methyl group, ethyl group and t-butyl group; araalkyl groups such as benzyl group and 4-nitrobenzyl group; and substituted silyl groups such as trimethylsilyl group.
  • An acyl group such as an acetyl group or a benzoyl group; an arylsulfonyl group such as a benzenesulfonyl group or a tosyl group; a methoxymethyl group or a tetrahydropyranyl group.
  • the compound in which R 2 in the formula (I) is a hydrogen atom can be converted into an ester in which R 2 is a C 14 alkyl group by a conventional esterich reaction. Further, a compound in which R 2 in the formula (I) is a C14 alkyl group can be converted into a carboxylic acid in which R 2 in the formula (I) is a hydrogen atom by a conventional hydrolysis reaction. This conversion reaction can be appropriately performed in various steps.
  • the method was carried out according to the method of Doak et al. (Eur. J. Pharmacol., P. 281, p. 311, 1995).
  • a good mouth the rat's left paw is injected subcutaneously with 50% L of 0.5% formalin solution into the left paw, and the duration of the licking and pummeling action on the paw started immediately after is measured with a stopwatch. The integrated value of was recorded.
  • a biphasic characteristic pain response was induced by formalin induction, and pain detected within 10 minutes after induction was regarded as phase 1 and pain observed from 10 minutes to 45 minutes as phase 2 pain response .
  • the test compound was orally administered 30 minutes before the injection of formalin.
  • PRtest Pain response time (seconds) for formalin + test compound administration group
  • PRcontrol Pain response time (seconds) for formalin-induced control group
  • the compound of the present invention suppressed the formalin-induced pain response by oral administration. At the same time, there was no abnormality in general symptoms, indicating that the compound of the present invention had low toxicity.
  • Table 2 shows the results of examining the interaction between the test compound and gabapentin orally at the same time 30 minutes before the injection of formalin, and examining the interaction between them.
  • a sciatic nerve ligation model was prepared according to the method of Bennett et al. (Pain 33, 87, 1988). That is, the rat was anesthetized with pentobarbital sodium 4 Omg / kg, ip, the skin was incised, and the left biceps femoris was bluntly incised. Surrounding sciatic nerve After being detached from the weave and loosely squeezed at 4 lmm intervals using a surgical chromic gut (4-10 or 3-0), the operative site was sutured and returned to the breeding cage for rearing. In the sham operation group, the same treatment was performed until the sciatic nerve was detached.
  • the response threshold to tactile stimulation was measured using a von Frey filament.
  • the filament was pressed against the sole (from the vicinity of the heel to the center) in ascending order of stiffness, and the strength at which the elevation reaction was observed was determined as the response threshold (cut-off). : 28. 84 g). Table 3 shows the results.
  • the compound of the present invention increased the response threshold on the injury side where the sciatic nerve was strangled, but had little effect on the response threshold on the normal side.
  • gabapentin and Retin increased not only the injured side but also the normal side response threshold. Therefore, it has been clarified that the compound of the present invention exhibits a selective anti-arodiure effect on a nerve injury site.
  • Example 2 Oral administration of the compound of Example 2, Example 4, Example 5, or Example 6 to a 6-week-old female Wistar Hannover rat at a dose of 1000 mg / kg showed no abnormalities in general symptoms. No deaths were found.
  • Example 2 6-week-old female Wistar Hannover rats were treated with the conjugate of Example 2, Example 4, Example 5, and Example 6 at doses of 250, 500, and 1000 mg / kg / one time.
  • gavage oral administration at any dose no abnormalities were observed in any of the general symptoms observed and body weight and food consumption measurements, with no deaths until 24 hours after the end of the last dose at any dose.
  • No remarkable toxicological findings were observed in hematological tests, blood biochemical tests, weighing of major organs, and pathological composition tests.
  • Example 2 300 ⁇ mol / L
  • Example 5 300 ⁇ mol / L
  • Example 6 100 ⁇ mol / L
  • the compound of the present invention suppresses rat formalin-induced pain response by oral administration, and is effective in the rat sciatic nerve ligation model, which is a model of neuropathic pain. And showed a selective analgesic effect on the injured side. It was also shown that the combined use of the compound of the present invention and gabapentin enhanced the efficacy. Further, no abnormality was observed in the toxicity test, indicating that the compound of the present invention had extremely low toxicity. Further, the compound of the present invention did not show any inhibitory effect on the HERG channel. In addition, the compounds of the present invention were shown to have good pharmacokinetic properties.
  • the compound of the present invention has an excellent analgesic effect in an animal pain model, and has good pharmacokinetic properties with little side effects and high safety. It can be expected as a possible therapeutic agent for neuropathic pain or as a concomitant drug with gabapentin.
  • the compound of the present invention can be used for the following specific pain diseases, central neuropathy (for example, which can be caused by spinal cord injury), peripheral neuropathy (for example, reflex sympathetic dystrophy (RSD)) ), Acute herpes zoster and postherpetic neuralgia, diabetic neuropathy, trigeminal neuralgia, postoperative pain, cancer pain, low back pain-related neuropathy, pain after spinal cord injury, thalamic pain, lower limb pain, cow monkey, reflex sympathy It can be used for, but not limited to, neurogenic atrophy, chronic headache, toothache, shoulder periarthritis, osteoarthritis, arthritis, pain associated with rheumatism, and the like. It can also be used for the purpose of preventing or inhibiting the exacerbation of the signs of these chronic pain diseases over time.
  • central neuropathy for example, which can be caused by spinal cord injury
  • peripheral neuropathy for example, reflex sympathetic dystrophy (RSD)
  • RSD reflex sympathetic dystrophy
  • the compound of the present invention may be hyperalgesic (a phenomenon that excessively responds to a noxious stimulus), arodinia (a state in which even a slight touch is felt as pain), spontaneous pain (pain even though nothing is done). It is also effective for pain diseases showing symptoms such as
  • the compound of the present invention is useful not only for pain diseases, but also for convulsions, epilepsy, dementia (cerebrovascular, senile), acute phase of cerebral infarction, cerebral hemorrhage, transient cerebral ischemia, subarachnoid hemorrhage, head trauma, cerebral bleeding It can also be used for cerebrovascular disorders such as post-operative sequelae, cerebral arteriosclerosis sequelae, itch-related diseases, and irritable bowel syndrome.
  • the combined use of the compound of the present invention and gabapentin synergistically enhances the analgesic effect, especially the neuropathic pain suppressing effect. Therefore, an effect can be expected even for patients in whom gabapentin alone is ineffective. Also, because the dose of gabapentin can be reduced
  • drugs used in combination with the compound of the present invention include, in addition to gabapentin, antidepressants such as pregabalin or amitriptyline; antiepileptic drugs such as rubamazepine and phenytoin; and antiarrhythmic drugs such as mexiletine.
  • Drugs, etc. which are diverted to neuropathic pain and prescribed.
  • it is gabapentin or pregabalin.
  • the relative dose of the active ingredient to be combined (compound of the present invention: drug to be used in combination, mass ratio) can be changed in a wide range.
  • 100: 1 to 1: 100 may be mentioned, preferably 10: 1 to 1:10, and more preferably 5: 1 to 1: 5.
  • the compound of the present invention and a drug to be used in combination are used in combination, they may be separate preparations or a mixture. In the case of separate preparations, it is possible to take both at the same time or to administer them at staggered times.
  • the medicament of the present invention is administered in the form of a pharmaceutical composition.
  • the pharmaceutical composition of the present invention is prepared in combination with a pharmaceutically acceptable excipient containing at least one of the compounds represented by the formula (I) of the present invention. More specifically, excipients (eg, lactose, sucrose, mannitol, crystalline cellulose, caic acid, corn starch, potato starch), binders (eg, celluloses (hydroxypropylcellulose (HPC), hydroxypropyl Methylcellulose (HPMC)), crystalline cellulose, sugars (lactose, mannitol, sucrose, sorbitol, erythritol, xylitol), starches (corn starch, potato starch), pregelatinized starch, dextrin, polyvierpyrrolidone (PVP), macrogol , Polyvinyl alcohol (PVA)), lubricants (eg, magnesium stearate, calcium stearate, talc, carboxymethyl cellulose), disintegrants (eg, starches (corn starch, potato star
  • Various dosage forms include tablets, capsules, granules, powders, pills, ointments, patches, suppositories, injections, sublingual administrations, liquids, powders, suspensions, and nasal administrations. And sustained-release preparations. Oral, subcutaneous, intramuscular, transdermal, intravenous, intraarterial, perineural, epidural, intradural, intraventricular, rectal, intranasal administration And the like.
  • patient-controlled analgesia (PCA) infusers which allow patients to immediately administer analgesics when they feel pain, administration by simple infusers, administration by needle-free injectors, and transdermal administration of drugs by ion photolysis. Such a technique can also be used.
  • PCA patient-controlled analgesia
  • the dose of the compound of the present invention is usually 0.05 mg 30.0 g, preferably 0.1 mg per adult per day.
  • the dose is 5 mg 25 g, more preferably lmg 15 g.
  • the dose can be adjusted appropriately according to the symptoms or administration route.
  • the raw materials and reagents used in the present invention and Examples can be all prepared by a known method, or commercially available ones can be used.
  • the ratio by volume of the solvent in the column chromatography in the examples is shown by volume ratio.
  • N_ (4-acetoxybenzoyl) _2-methinolealanine ethylestenore synthesized in Example 1 A solution of sodium hydroxide (1.64 g) in water (30 mL) was dissolved in 400 g of ethanol (30 mL) at night. Was added, and the mixture was stirred at room temperature for 30 minutes and then heated and refluxed for 30 minutes. After concentrating the reaction solution, the residue was acidified with lmol / L aqueous hydrochloric acid and then extracted three times with ethyl acetate. The organic layer was washed successively with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was suspended in getyl ether and collected by filtration to give 2.97 g of the title compound as a white powder. (Yield 98%).
  • This solution was added dropwise to a solution of 2-methylalanine (5.00 g) in water (100 mL) under ice-cooling, and then diisopropylethylamine (16.9 mL) was added thereto, followed by stirring at room temperature for 6 hours.
  • the reaction solution was acidified with a 1 mol / L aqueous hydrochloric acid solution, and then extracted three times with ethyl acetate.
  • the organic layer was washed successively with water (twice) and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • the residue was suspended in getyl ether-hexane and collected by filtration to give 6.96 g of the title compound as a white powder. (Yield 42%)
  • Example 3 After weighing the above components, the compound of Example 3, lactose, crystalline cellulose, and partially arsenic starch are added and uniformly mixed, and an aqueous solution of hydroxypropylcellulose (HPC) is added. Produce the granules. The granules or fine granules are dried to obtain granules or fine granules.
  • HPC hydroxypropylcellulose
  • Example 2 After weighing the above components, the compound of Example 2 is dissolved in propylene glycol. Add sterile water for injection to make a total volume of 1, OOOmL, sterilize by filtration, dispense 5mL each into 10mL ampules, and seal to obtain injections.
  • Polyethylene glycolonole 1500 180g
  • Example 7 The compound of Example 7 was sufficiently polished in a mortar to obtain a fine powder, and then 1 g of each suppository was prepared by a melting method. Industrial applicability
  • the compounds of the present invention may be used in the following specific pain disorders, central neuropathy (for example, which may be caused by spinal cord injury), peripheral neuropathy (for example, reflex sympathetic dystrophy (RSD)), acute Herpes zoster and postherpetic neuralgia, diabetic neuropathy, trigeminal neuralgia, postoperative pain, cancer pain, low back pain-related neuropathy, pain after spinal cord injury, thalamic pain, lower limb pain, aubergi, reflex sympathetic atrophy Can be used for illness, chronic headache, toothache, shoulder periarthritis, osteoarthritis, arthritis, pain associated with rheumatism, etc. It can also be used for the purpose of preventing or inhibiting exacerbation of the signs of these chronic pain diseases over time.
  • central neuropathy for example, which may be caused by spinal cord injury
  • peripheral neuropathy for example, reflex sympathetic dystrophy (RSD)
  • RSD reflex sympathetic dystrophy
  • acute Herpes zoster and postherpetic neuralgia diabetic neuropathy,
  • the compound of the present invention can be used not only for pain diseases, but also for convulsions, epilepsy, dementia (cerebrovascular, senile), acute phase of cerebral infarction, cerebral hemorrhage, transient cerebral ischemia, subarachnoid hemorrhage, head trauma, cerebral bleeding It can also be used for cerebrovascular disorders such as post-operative sequelae and sequelae of cerebral atherosclerosis, diseases with itching, and irritable bowel syndrome.
  • the compound of the present invention in combination with gabapentin, it can be used for enhancing the efficacy of gabapentin or reducing side effects.

Landscapes

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

Abstract

L'invention concerne un agent préventif et/ou thérapeutique contre les douleurs neuropathiques, qui se caractérise en ce qu'il contient un composé de formule (I), un isomère optiquement actif du composé, ou un sel pharmaceutiquement acceptable du composé ou de l'isomère utilisé comme principe actif. Dans ladite formule, Z est -C(CH3)2 - ou -CH(CH(CH3)2)-; n est compris entre 0 et 2; R1 est alkyle C1-4, hydroxy, trifluorométhyle ou acétoxy; et R2 est hydrogène or alkyle C1-4, à condition que hydroxy soit exclu lorsque Z est -CH(CH(CH3)2)- et R1 se trouve à la position 2. L'agent de l'invention, qui peut être administré par voie orale, présente peu d'effets secondaires et offre plus de sécurité. Il est très efficace dans la prévention et/ou le traitement de douleurs neuropathiques et présente d'excellentes propriétés pharmaceutiques.
PCT/JP2004/011594 2003-08-13 2004-08-12 Agent therapeutique contre les douleurs neuropathiques contenant un derive n-(benzoyl)amino acide comme principe actif Ceased WO2005016331A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2003292918A JP2005060311A (ja) 2003-08-13 2003-08-13 Ｎ−（ベンゾイル）アミノ酸誘導体を有効成分とするニューロパシー性疼痛治療剤
JP2003-292918 2003-08-13

Publications (1)

Publication Number Publication Date
WO2005016331A1 true WO2005016331A1 (fr) 2005-02-24

Family

ID=34190969

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2004/011594 Ceased WO2005016331A1 (fr) 2003-08-13 2004-08-12 Agent therapeutique contre les douleurs neuropathiques contenant un derive n-(benzoyl)amino acide comme principe actif

Country Status (2)

Country Link
JP (1) JP2005060311A (fr)
WO (1) WO2005016331A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006114707A1 (fr) * 2005-04-28 2006-11-02 Pfizer Limited Derives d'acides amines
CN103002893A (zh) * 2010-07-30 2013-03-27 东丽株式会社 神经障碍性疼痛的治疗药或预防药
CN111196772A (zh) * 2018-11-16 2020-05-26 沈阳化工研究院有限公司 一种芳酰氨基异丁酰衍生物及其应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08291124A (ja) * 1995-04-19 1996-11-05 Microbial Chem Res Found 新規生理活性物質ヒドロスタチンａおよびその製造法と用途
JP2000502318A (ja) * 1995-06-23 2000-02-29 オゥクラホゥマ、メディカル、リサーチ、ファウンデイシャン Ｎ−Ｌ−α−アスパルチル−Ｌ−フェニルアラニン１−メチルエステルの鎮痛剤としての使用
JP2001501179A (ja) * 1996-09-03 2001-01-30 フアルマシア・エ・アツプジヨン・エツセ・ピー・アー キヌレニン―３―ヒドロキシラーゼ抑制活性を有するｎ―置換―２―アミノ―４―フェニル―４―オキソ―ブタン酸
JP2003503453A (ja) * 1999-07-02 2003-01-28 ワーナー−ランバート・カンパニー 相乗作用組成物：ガバペンチンおよびプレガバリン

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08291124A (ja) * 1995-04-19 1996-11-05 Microbial Chem Res Found 新規生理活性物質ヒドロスタチンａおよびその製造法と用途
JP2000502318A (ja) * 1995-06-23 2000-02-29 オゥクラホゥマ、メディカル、リサーチ、ファウンデイシャン Ｎ−Ｌ−α−アスパルチル−Ｌ−フェニルアラニン１−メチルエステルの鎮痛剤としての使用
JP2001501179A (ja) * 1996-09-03 2001-01-30 フアルマシア・エ・アツプジヨン・エツセ・ピー・アー キヌレニン―３―ヒドロキシラーゼ抑制活性を有するｎ―置換―２―アミノ―４―フェニル―４―オキソ―ブタン酸
JP2003503453A (ja) * 1999-07-02 2003-01-28 ワーナー−ランバート・カンパニー 相乗作用組成物：ガバペンチンおよびプレガバリン

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHIARUGI A ET AL: "Comparison of the Neurochemical and Behavioral Effects Resulting from the Inhibition of Kynurenine Hydroxylase and/or Kynureninase", JOURNAL OF NEUROCHEMISTRY, vol. 65, no. 3, 1995, pages 1176 - 1183, XP002904257 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006114707A1 (fr) * 2005-04-28 2006-11-02 Pfizer Limited Derives d'acides amines
JP2009040767A (ja) * 2005-04-28 2009-02-26 Pfizer Ltd アミノ酸誘導体
US7612226B2 (en) 2005-04-28 2009-11-03 Pfizer Inc. Amino acid derivatives
KR100925900B1 (ko) 2005-04-28 2009-11-09 화이자 리미티드 아미노산 유도체
AU2006238933B2 (en) * 2005-04-28 2011-12-01 Pfizer Limited Amino acid derivatives
CN103002893A (zh) * 2010-07-30 2013-03-27 东丽株式会社 神经障碍性疼痛的治疗药或预防药
RU2544552C2 (ru) * 2010-07-30 2015-03-20 Торэй Индастриз, Инк. Терапевтическое средство или профилактическое средство для нейропатической боли
CN103002893B (zh) * 2010-07-30 2017-05-10 东丽株式会社 神经障碍性疼痛的治疗药或预防药
CN111196772A (zh) * 2018-11-16 2020-05-26 沈阳化工研究院有限公司 一种芳酰氨基异丁酰衍生物及其应用
CN111196772B (zh) * 2018-11-16 2022-09-30 沈阳化工研究院有限公司 一种芳酰氨基异丁酰衍生物及其应用

Also Published As

Publication number Publication date
JP2005060311A (ja) 2005-03-10

Similar Documents

Publication Publication Date Title
US20060183786A1 (en) Injectable long-acting analgesic composition comprising an ester derivative of ketorolac
US8518979B2 (en) Alpha-halo- and alpha-alkyl-cyclopropylcarboxy compounds and uses thereof
ES2802977T3 (es) Compuesto para la modulación inmunológica, uso del mismo y composición farmacéutica que lo comprende
JPH0641475B2 (ja) 置換アルファアミノ酸、その製法および医薬
JPH0472821B2 (fr)
US20150080473A1 (en) N-Substituted Benzenepropanamide or Benzenepropenamide Derivatives for use in the Treatment of Pain and Inflammation
WO2010050577A1 (fr) Dérivé du cyclohexane et son utilisation pharmaceutique
TW202337456A (zh) Ｇｍ２神經節苷脂症之治療
US20140350099A1 (en) Method of Treating or Preventing Pain
US9802962B2 (en) Tricyclic pyrone compounds reduce amyloid beta aggregates
KR20090088442A (ko) 아미노알코올 유도체 및 그들의 치료적 용도
WO2011030205A1 (fr) Benzènepropanamide ou benzènepropénamide n substitués destinés à être utilisés dans le traitement de la douleur ou d'une inflammation
KR102235994B1 (ko) 환상 아민 유도체의 결정 및 그 의약 용도
JP2008179541A (ja) 神経因性疼痛治療薬
WO2005016331A1 (fr) Agent therapeutique contre les douleurs neuropathiques contenant un derive n-(benzoyl)amino acide comme principe actif
US10906864B2 (en) Nitroalkene non steroidal anti-inflammatory drugs (NA-NSAIDS) and methods of treating inflammation related conditions
JP6195100B2 (ja) プロテインキナーゼｇに対する高阻害活性を有する化合物及びその製造方法
CN117362200A (zh) 苯甲胺类化合物及其合成方法与应用
JPH08501557A (ja) Ａｃａｔ阻害剤としての１，２−二置換エチルアミド
JPH11509520A (ja) 鎮痛特性を有する新規のｎ−アセチル化４−ヒドロキシフェニルアミン誘導体及びそれを含む薬理組成物
JP2023518205A (ja) 酸化ストレスと関連した障害の処置およびこの処置のための化合物
US12357610B2 (en) Aryl-substituted acetamide and pyrrolidin-2-one derivatives and their use for the treatment of seizures
JPH0714871B2 (ja) 筋弛緩剤
KR20090018776A (ko) 염증성 질환 및 통증의 치료에서의 베타-아미노알콜의 용도
EP3732162B1 (fr) Médicaments anti-inflammatoires non stéroïdiens à base de nitroalcène (na-nsaids) et méthodes de traitement d'affections associées à une inflammation

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase