WO2007004510A1 - Médicament pour le traitement d'un infarctus cérébral - Google Patents

Médicament pour le traitement d'un infarctus cérébral Download PDF

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Publication number
WO2007004510A1
WO2007004510A1 PCT/JP2006/312996 JP2006312996W WO2007004510A1 WO 2007004510 A1 WO2007004510 A1 WO 2007004510A1 JP 2006312996 W JP2006312996 W JP 2006312996W WO 2007004510 A1 WO2007004510 A1 WO 2007004510A1
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WIPO (PCT)
Prior art keywords
morpholine
cerebral infarction
administration
hydroxyimidoformamide
thrombolytic
Prior art date
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PCT/JP2006/312996
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English (en)
Japanese (ja)
Inventor
Tomohiro Omura
Noriyuki Miyata
Shigeru Okuyama
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Taisho Pharmaceutical Co., Ltd.
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Application filed by Taisho Pharmaceutical Co., Ltd. filed Critical Taisho Pharmaceutical Co., Ltd.
Publication of WO2007004510A1 publication Critical patent/WO2007004510A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/49—Urokinase; Tissue plasminogen activator
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings

Definitions

  • the present invention relates to cerebral infarction treatment or cerebral infarction comprising N- (3 black mouth 4 monorephorin 1 4-inore) phenol-N, 1 hydroxymidformamide and a thrombolytic agent. It is related with the pharmaceutical excellent in the improvement of the dysfunction caused by this, or the neurological deficit symptom.
  • Cerebral infarction refers to cerebral dysfunction caused by ischemic necrosis in the brain, and is a disease requiring emergency treatment. Cerebral infarction is classified into thrombotic, embolic, and hemodynamic in terms of mechanism of action, and from clinical aspects, it is classified as atherothrombotic cerebral infarction, cardiogenic cerebral embolism, Lacna infarction, etc. Classified (see Non-Patent Document 1).
  • Ischemia occurs when cerebrovascular lesions such as arteriosclerosis or the local cerebral blood flow is blocked by cardiogenic thrombus, and neuronal cell death due to energy depletion is caused at the ischemic central site.
  • the blood flow through the accessory blood circulation remains around the ischemic center, and the nerve cells are alive but not functioning electrophysiologically.
  • this treatment is applied, this part of the nerve cell will die in the future, and pathologically, it will be a failure of cerebral infarction, and clinically, it will be impaired as a malfunction. Therefore, if the function of nerve cells in this part can be restored as early as possible, dysfunction can be treated.
  • This reversible incomplete ischemic region is called Benambra.
  • the purpose of treatment for the acute phase of cerebral infarction is to restore the function of neurons in this penumbra region, the outcome of which depends on the extent of ischemia and its duration. In other words, how quickly the blood flow is resumed in the penumbra area determines the outcome. It is said that neurons in this penumbra region can survive for 3 to 6 hours after onset.
  • the allowable time during which the nerve cells in the Benampura region can recover their function by treatment is called the treatable time.
  • rt-PA recombinant human tissue plasminogen activator
  • Non-Patent Document 2 rt PA is administered to patients within 3 hours of onset, and if no intracerebral hemorrhage is observed, first rapidly infuse 10% of the total dose (0.9 mg Zkg), and the rest for 1 hour. Continue intravenous infusion over the above.
  • 20-Hydroxyeico satetraenoic acid (20—HETE) is a product that is metabolized from arachidonic acid by cytochrome P450 4A or 4F (CYP), a 20-HETE-producing enzyme, and has a vasoconstrictive action (non-patented) Reference 3).
  • 20— HETE is also produced in the cerebral blood vessels and has a powerful cerebral vasoconstriction action based on Ca 2+ — activated K + — channel inhibition, thus regulating cerebral blood flow under physiological conditions It plays an important role as a factor. It has also been shown that it is also involved in cerebral vasoconstriction after subarachnoid hemorrhage (see Non-Patent Document 4).
  • N— (3 Black mouth— 4 Morpholine— 4—yl) phenol—N, —Hydroxyimidoformad (N— (3— Chloro— 4— morphlin— 4— yl) phenyl— N — Hydroxyimidofrmamide) is a selective and potent inhibitor of 20-HETE producing enzyme, which is compound 302 in Patent Document 1, and is represented by the following chemical formula.
  • N— (3-Chromosome— 4 Morpholine— 4—yl) phenol— N′-hydroxyimidoformamide exhibits a cerebral infarct volume-reducing action in a transient middle cerebral artery occlusion model in rats ( Non-special (Ref. In this model, the treatment time is 4 hours after the ischemic load, and the neurological deficit symptoms (sensory motor function, balance sensation, coordinated motor function) 7 days after the onset of symptoms are improved (Non-patent Document 6). reference). Based on the above, N- (3-chloro-4 morpholine-4yl) ferro-N, monohydroxyimidoformamide can improve dysfunction due to cerebral infarction when administered in the acute phase of cerebral infarction.
  • N- (3-Chrotine 1- 4-morpholine 1- 4-yl) file N and 1-hydroxyimide formamide were administered in combination. Furthermore, it is expected to enhance the therapeutic effect on cerebral infarction.
  • Patent Document l WO0lZ32164 Compound 302
  • Non-Patent Document 1 Stroke. 21, 637-676 (1990)
  • Non-Patent Document 2 N Eng J Med. 333, 1581-1587 (1995)
  • Non-Patent Document 3 Physio Rex. 82: 131-185 (2002)
  • Non-Patent Document 4 Stroke. 34: 1269-1275 (2003)
  • Non-Patent Document 5 J Pharmacol Exp Ther. 314: 77—85 (2005)
  • Non-patent literature 6 Neuroscience 2003 abstract number 741. 5 (2003)
  • Non-patent literature 7 J Neurosci Methods. 105: 45- 53 (2001)
  • An object of the present invention is to provide a medicament that is excellent in the treatment of cerebral infarction or the improvement of dysfunction or neurological deficits caused by cerebral infarction and with few side effects.
  • N (3—Black mouth 4 Morpholine 1 4-yl) Farm N, A drug for the treatment of cerebral infarction comprising a combination of 1 hydroxyimidoformamide and a thrombolytic agent,
  • N (3 black mouth 4 morpholine 1 4-yl) Farm N, a drug that improves dysfunction caused by cerebral infarction, which is a combination of hydroxyimidoformamide and a thrombolytic agent,
  • thrombolytic drug is one or more selected from urokinase, alteplase, tisokinase, nasalplase, nateplase, paminabrase, monteplase, and patroxobinka, or
  • FIG. 1 shows the effect of 3- (3 chloro-4 morpholine-4 yl) phenol ⁇ , -hydroxyimidoformamide on neuronal loss in a monkey cerebral embolism model. * ⁇ ⁇ 0. 05.
  • FIG. 2 Shows the effects on neuroleptic symptoms when combined with alteplase and N- (3 chloro-4 morpholine-4-yl) felt N, -hydroxyimidoformamide in a monkey cerebral embolism model. * p ⁇ 0. 05.
  • a cerebral infarction patient means a patient who develops cerebral infarction due to cerebral blood flow being blocked by a thrombus, and which requires or is administered a thrombolytic drug.
  • the patient is in the acute phase of cerebral infarction within 48 hours after onset, more preferably within 6 hours, and most preferably the patient in acute phase of cerebral infarction within 3 hours.
  • onset is defined as the time when a neurological symptom caused by cerebral infarction occurs, or when cerebral infarction occurs during sleep, and at the time of going to bed. Doctor's interview, medical examination, neurological evaluation and diagnostic imaging The time determined by the doctor.
  • Cerebral infarction treatment refers to the effect of preventing the progression of cerebral infarction in the acute phase of cerebral infarction, the effect of improving dysfunction or neurological deficits or subjective symptoms due to cerebral infarction, and Z or suppression of the development of psychiatric symptoms and seizures in the chronic phase. In addition, prevention of recurrence of stroke is also included.
  • the degree of cerebral infarction is determined by CT (Computed Tomography), MRI (Magnetic Resonance Imaging), cerebral vascular landscape, etc. at the time of diagnosis.
  • CT Computer Tomography
  • MRI Magnetic Resonance Imaging
  • cerebral vascular landscape etc. at the time of diagnosis.
  • obstruction site anterior cerebral artery region, middle cerebral artery region, posterior cerebral artery region, watershed region, brainstem cerebellum, etc., or left, right, or both sides of them
  • edema can be classified according to the degree of edema.
  • “Dysfunction caused by cerebral infarction” means neurological symptoms, daily life movement disorder, motor paralysis, etc. that occur in the acute phase of cerebral infarction. These symptoms include neurological assessments (evaluation of consciousness level, pupil symmetry and photoreaction, ataxia, sensory impairment, involuntary movement, etc.), modified Rankin Scale ⁇ Barthel Index, NIHSS, and Glasgow Scale. It can be expressed by an index of the degree of nerve function and disorder using. [0019] "Neural dropout symptom due to cerebral infarction” means a state in which a disorder is observed in one or more items listed in the following neurological symptoms.
  • index or objective evaluation indicating the degree of the symptom described above is compared with the state before drug administration, and the index or evaluation at a certain period of time after drug administration is It means to improve more than the floor.
  • Psychiatric Symptoms Nominal response to greetings, orientation, motivation, knowledge, computing power, voice tone, attitude, spontaneous behavior, spontaneous speech, attention, etc.
  • N- (3 black mouth-4 morpholine-4-yl) ferro-N, -hydroxyimidoformamide and thrombolytic drug may not be administered simultaneously.
  • the order of administration of (3—black mouth—4-morpholine—4-yl) phenol-N, -hydroxyimidoformamide and thrombolytic drug is not limited.
  • the medicament of the present invention uses a preparation in which each component of N- (3 black mouth-4 morpholine-4-yl) phenol-N, -hydroxyimide formamide and thrombolytic drug is independent, It can be used in combination therapy, and may be in the form of a kit that is packaged in combination with each other, or may be sold separately.
  • N- (3-chloro-4 morpholine-4-yl) ferro-N, mono-hydroxyimide formamide can be synthesized, for example, by the method described in WOO 1/32164. it can.
  • F-Nole N, 1 Hydroxyimidoformamide is sulfobutyl ether j8-cyclodextrin (SBE—j8 eye lodextrin) or a salt thereof and a potent formulation is preferred.
  • j8-cyclodextrin having a degree of substitution with a sulfobutyl group of about 7 on average is preferred, and a sodium salt is preferred.
  • Thrombolytic drugs include urokinase, alteplase, desmoteplase, tisokinase, nasarplase, nateplase, paminabrase, monteplase, patroxobin, and the like, and can be obtained based on methods described in the literature.
  • the preferred thrombolytic drug is alteplase.
  • Alteplase is a generic name for natural rt-PA developed by Genentech, and is available from Genentech as Activase (registered trademark). It is.
  • a pharmaceutical comprising a combination of N- (3-chloromono-4-monorefoline 4-4-inole) phenol-N, monohydroxyimidoformamide and a thrombolytic agent, used in the present invention, separately contains each active ingredient, It is mixed with physiologically acceptable carriers, excipients, binders, diluents, etc. and formulated, mainly for parenteral administration, specifically subcutaneous administration, intramuscular administration, intravenous administration, It can be administered in various dosage forms, such as dermal administration, intrathecal administration, epidural, intra-articular, and topical administration.
  • N— (3-chloro-1,4-morpholine 4-yl) phenol N, monohydroxyimidoformamide is administered within 4 hours after the start of administration of thrombolytic drug.
  • N- (3-Black mouth—4-morpholine—4-yl) Ferru N, -Hydroxyimidoformamide administration and simultaneous force Thrombolytic drug within 4 hours after the end of administration Is administered.
  • N (3—black mouth 4 morpholine 1—yl) phenol N, 1 hydroxyimidoformamide
  • the therapeutically effective amount of each case takes into account symptoms, age, sex, etc.
  • the dose is usually determined depending on the dose, but is usually 1 to 400 mg per day for adults, preferably about 120 mg per day.
  • Adults 1-400 mg per day may be administered once or divided into 2-4 times.
  • intravenous administration or continuous intravenous administration it may be administered for 1 to 24 hours per day.
  • the dosage is determined by various conditions. If effective, dosages below the above ranges can be used.
  • the dosage of the thrombolytic drug is appropriately determined according to the individual case in consideration of symptoms, age of the administration subject, sex, and the like. In the case of alteplase, it is usually 50- daily adult: LOOmg, preferably 0.9mgZkg.
  • the administration method is 50 to 1 per dose: LOOmg may be administered once, or divided into 2 to 4 times. In the case of intravenous administration or continuous intravenous administration, it may be administered from 1 to 24 hours per day. Preferably, 10% of the total dose (0.9 mg / kg) is rapidly administered intravenously with 1 to 2 components in 4 doses, and the remaining dose is continuously administered intravenously with 4 doses for 1 hour.
  • Surgical wounds were sutured under aseptic conditions, and mycillin sol Meiji (benzylpenicillin pro-in, dihydrostreptomycin sulfate mixed, Meiji Seika Co., Ltd.) was intramuscularly administered at 0.05 mLZkg. After surgery, 2 days were set for animal recovery. On the third day after surgery, venous blood was collected in force-yure (PE-240, Nippon Betaton Dickinson Co., Ltd.) approximately 3 hours before embolization and clotted by incubating at 37 ° C for 3 hours. did.
  • force-yure PE-240, Nippon Betaton Dickinson Co., Ltd.
  • Sevoflurane (Sevoflurane (registered trademark), Maruishi Pharmaceutical Co., Ltd.) Under inhalation anesthesia, a blood clot (diameter approx. 1 mm, length 10 cm) was injected from the force-Yule placed in the internal carotid artery, and 37 ° C An additional 1 mL of physiological saline solution (Otsuka Pharmaceutical Factory, Inc.) was added to the flask.
  • Alteplase (GRTPA (registered trademark), Mitsubishi Welpharma, 300,000 IU / kg) was rapidly administered 10% of the total dose into the internal carotid artery using a small infusion pump 1 hour after clot infusion, For the rest, continuous administration for 2 hours was performed.
  • the vehicle (11% SBE- ⁇ cyclodextrin) was administered in the same manner.
  • N- (3-Chloro-4 morpholine was not administered after thrombus injection without alteplase administration. 4) Ferruo N, -hydroxyimidoformamide alone or its vehicle was administered alone. In that case, the dose and method of administration of N- (3-Black mouth-4-morpholine-4-yl) felt N, -Hydroxyimidoformamide are as described above. From 1 hour after thrombus injection.
  • Nerve dropout symptoms were observed before clot injection and 1, 2, 3, 5, 7, 24 hours after clot injection. Observation of neurological deficits was performed using a score based on the apanese stroke scale (J Neurosci Methods. 105: 45-53 (2001)). Excluded were animals and deaths in which a score of 6 or less was observed in the item of consciousness level or muscle integration exercise 1 hour after clot injection.
  • the score of the neurological deficit symptom was shown by the mean value standard error. Mann- Whitney U test was performed between the two groups to compare the scores of neurological deficits. The significance level was set at 5%, and Windows® Stat View (Ver 5.0, SAS Institute Inc., Cary, NC, USA) was used for these tests. The test was conducted at each time point.
  • Figures 1 and 2 show the results of the effect on neurological deficits.
  • Figure 1 shows the effects of N- (3 chloro-4-morpholine-4-yl) phenol N and hydroxyimidoformamide alone on neurological deficits.
  • the score hardly improved until 24 hours after the thrombus injection (47.4 1.0).
  • the neurological loss symptom score 24 hours later was compared with the vehicle administration group (43.8 8 0, 8 p ⁇ 0. 05).
  • Figure 2 shows the effect of alteplase in combination with N- (3-chloroform-4-morpholine-4-yl) ferro-N, -hydroxyimidoformamide on neurological deficits.
  • the score was almost unchanged until 24 hours after the thrombus injection (46. 7 1.2).
  • N— (3 —Kuroguchi 1-morpholine 4-yl) Ferrain N and 1-hydroxyimidoformamide were combined with the vehicle at 7 hours after thrombus injection compared to the vehicle combination group at the same time.
  • Analysis by individual symptom showed a significant improvement in the consciousness level at 24 hours after thrombus infusion (Figure 3).
  • the present invention it is possible to obtain a therapeutic agent excellent in cerebral infarction, dysfunction caused by cerebral infarction, or neurological deficit symptoms.

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Abstract

La présente invention décrit un médicament dont l'effet thérapeutique sur l'infarctus cérébral est excellent et dont l'effet soulageant sur un dysfonctionnement ou un déficit neurologique induit par un infarctus cérébral est également excellent, ledit médicament ne présentant que des effets secondaires restreints. La présente invention décrit notamment un médicament comprenant une combinaison de N-(3-chloro-4-morpholin-4-yl)phényl-N’-hydroxyimidoformamide et d'un agent thrombolytique tel que l’urokinase, l’altéplase, la desmotéplase, la tisokinase, la nasaruplase, la natéplase, la pamitéplase, la montéplase ou la batroxobine.
PCT/JP2006/312996 2005-06-30 2006-06-29 Médicament pour le traitement d'un infarctus cérébral WO2007004510A1 (fr)

Applications Claiming Priority (2)

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JP2005190985A JP2008230968A (ja) 2005-06-30 2005-06-30 脳梗塞治療用の医薬
JP2005-190985 2005-06-30

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH11515010A (ja) * 1995-10-25 1999-12-21 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ 神経保護物質および血栓溶解剤の注射剤
WO2001032164A1 (fr) * 1999-11-01 2001-05-10 Taisho Pharmaceutical Co., Ltd. Inhibiteur pour enzyme de production de 20-hete
JP2003201238A (ja) * 2001-12-03 2003-07-18 Yamanouchi Pharmaceut Co Ltd 脳梗塞治療用医薬組成物
WO2003099288A1 (fr) * 2002-05-28 2003-12-04 Taisho Pharmaceutical Co., Ltd. Composition medicinale

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH11515010A (ja) * 1995-10-25 1999-12-21 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ 神経保護物質および血栓溶解剤の注射剤
WO2001032164A1 (fr) * 1999-11-01 2001-05-10 Taisho Pharmaceutical Co., Ltd. Inhibiteur pour enzyme de production de 20-hete
JP2003201238A (ja) * 2001-12-03 2003-07-18 Yamanouchi Pharmaceut Co Ltd 脳梗塞治療用医薬組成物
WO2003099288A1 (fr) * 2002-05-28 2003-12-04 Taisho Pharmaceutical Co., Ltd. Composition medicinale

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
TANAKA Y. ET AL.: "Effect of TS-011, an inhibitor of the synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE), on infarct size in models of ischemic stoke", JOURNAL OF PHARMACOLOGICAL SCIENCES, vol. 94, no. SUPPLEMENT 1, 2004, pages 292P, P-30685, XP008075717 *

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