US 2004O242565A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0242565 A1 Toshima et al. (43) Pub. Date: Dec. 2, 2004
(54) MEDICINAL COMPOSITION FOR (57) ABSTRACT PREVENTION OF OR TREATMENT FOR A pharmaceutical composition comprising at least one of CEREBROWASCULAR DISORDER AND components (a) and at least one of components (b) shown in CARDOPATHY below: (76) Inventors: Yoshinori Toshima, Shizuoka (JP); (a) a compound represented by the general formula (I) Asako Hitomi, Shizuoka (JP); (I) Shin-ichi Satoh, Shizuoka (JP); Ichiro Ikegaki, Shizuoka (JP) r SON NH Correspondence Address: BRCH STEWART KOLASCH & BRCH N PO BOX 747 FALLS CHURCH, VA 22040-0747 (US) 2N
(21) Appl. No.: 10/488,699 R1 (22) PCT Fed: Jul. 30, 2002 (wherein R1 represents a hydrogen atom or a hydroxyl (86) PCT No.: PCT/JP02/07712 group) or an acid addition Salt or hydrate thereof, and (b) an ameliorant of cerebral circulation, a vasodilator, a cerebral protecting drug, an brain metabolic Stimu (30) Foreign Application Priority Data lants, an anticoagulant, an antiplatelet drug, a throm bolytic drug, an amelirant of psychiatric Symptom, a Sep. 11, 2001 (JP)...... 2001-274846 antihypertensive drug, an antianginal drug, a diuretic, a cardiotonic, an antiarrhythmic drug, an antihyperlipidemic drug, an immunosuppreSSant, or Publication Classification a pharmaceutically acceptable Salt (except the com ponents shown in (a)). It is useful as a preventive or (51) Int. Cl...... A61K 31/551 remedy for cerebrovascular disorders and cardiac (52) U.S. Cl...... 514/218 diseases. US 2004/0242565 A1 Dec. 2, 2004
MEDICINAL COMPOSITION FOR PREVENTION immunosuppressant until the pharmaceutical composition of OF OR TREATMENT FOR CEREBROWASCULAR the present invention is disclosed. DISORDER AND CARDIOPATHY DISCLOSURE OF THE INVENTION TECHNICAL FIELD 0006 An object of the present invention is to provide a 0001) The present invention relates to a pharmaceutical pharmaceutical composition that has a marked effect than composition that is effective against prevention or treatment that obtained when a preventive drug or a treatment drug is of diseases Such as a cerebrovascular disorder and a cardiac administered singly for prevention or treatment of a cere disease. brovascular disorder, a cardiac disease, and the like. 0007. In view of the above-mentioned circumstances, the RELATED ART inventors of the present invention have found that the 0002 For prevention or treatment of diseases such as a compound represented by the general formula (I) exerts cerebrovascular disorder and a cardiac disease, there have particularly significant effect that was not obtained when been used drugs such as an ameliorant of cerebral circula administering the compound singly for, e.g., drug effect, tion, a vasodilator, a cerebral protecting drug, an brain Safeness, stability, dosage, dosage form, usage, or the like by metabolic stimulants, an anticoagulant, an antiplatelet drug, using the compound in combination with an ameliorant of a thrombolytic drug, an amelirant of psychiatric symptom, a cerebral circulation, avasodilator, an cerebral protecting antihypertensive drug, an antianginal drug, a diuretic, a drug, an brain metabolic stimulants, an anticoagulant, an cardiotonic, an antiarrhythmic drug, an antihyperlipidemic antiplatelet drug, a thrombolytic drug, an amelirant of psy drug, and an immunosuppressant. chiatric Symptom, a antihypertensive drug, an antianginal drug, a diuretic, a cardiotonic, an antiarrhythmic drug, an 0003) On the other hand, it has been already known that antihyperlipidemic drug, or an immunosuppressant. Thus, a compound represented by the general formula (I): the inventors have accomplished the present invention based on the knowledge. (I) 0008 That is, the present invention relates to the follow r ings: SON NH 0009 (1) A pharmaceutical composition including at least one of components (a) and at least one of components N (b) shown in below. 0010) (a) A compound represented byy the following 2N. general formula (I): r (I) 0004 (wherein R1 represents a hydrogen atom or a SON NH hydroxyl group) has an inhibitory activity against a kinase Such as a Rho kinase, a myosin light chain kinase, or a protein kinase C, shows a vascular N Smooth muscle relaxation effect, a blood flow increasing effect, an antihypertensive effect, a cere 2N. bral protective effect, a cardiac protective effect, or the like; and is an effective Substance in a vasodilator R1 agent (particularly as a treating agent for angina), a cerebral protecting agent, a cardiac protecting agent, or the like (for example, JP 61-227581 A, JP 0011) (wherein R1 represents a hydrogen atom or a 02-256617 A, JP 06-056668A, JP 07-080854B, EP hydroxyl group) 0187371, WO 98/06433, Br. J. Pharmacol., 98, 1091 0012 (b) An ameliorant of cerebral circulation, a (1989), J. Pharmacol. Exp. Ther..., 259, 738 (1991), Vasodilator, a cerebral protecting drug, an brain Circulation, 96, 4357 (1997), Cardiovasc. Res., 43, metabolic stimulants, an anticoagulant, an antiplate 1029 (1999)). let drug, a thrombolytic drug, an amelirant of psy 0005. In the aforementioned documents, the single use of chiatric Symptom, a antihypertensive drug, an anti the compound represented by the general formula (I) is anginal drug, a diuretic, a cardiotonic, an disclosed. However, there have been no report regarding antiarrhythmic drug, an antihyperlipidemic drug, and concomitant use or a plan of concomitant use of the com an immunosuppressant (except the components pound with an ameliorant of cerebral circulation, a vasodi shown in (a)). lator, a cerebral protecting drug, an brain metabolic stimu 0013 Note that, in the present invention, the components lants, an anticoagulant, an antiplatelet drug, a thrombolytic (a) include, in addition to the compound represented by the drug, an amelirant of psychiatric Symptom, a antihyperten general formula (I), hydrates thereof (for example, 1/2 Sive drug, an antianginal drug, a diuretic, a cardiotonic, an hydrates, 1 hydrates, and 3 hydrates) and acid addition salts antiarrhythmic drug, an antihyperlipidemic drug, or an thereof. US 2004/0242565 A1 Dec. 2, 2004
0014) Moreover, the drug of components (b), which is and psychiatric Symptom, neurologic Symptom, disorder in used together with the component (a) represented by the activities of daily living disability, amnesia, and dementia, general formula (I) according to the present invention, which are based on those diseases. includes pharmaceutically acceptable Salts thereof. 0027 (14) The pharmaceutical composition according to 0.015 (2) The pharmaceutical composition according to item (12), in which the cerebrovascular disorder is selected item (1), in which the vasodilator shown in (b) is a calcium from the group consisting of cerebral infarction and cere channel blocking drug and the calcium channel blocking bral vasospasm; and a neurologic Symptom and disorder in drug is nimodipine. activities of daily living disability, which are based on those 0016 (3) The pharmaceutical composition according to diseases. item (1), in which the thrombolytic drug shown in (b) is a 0028 (15) The pharmaceutical composition according to tissue plasminogen activator and the tissue plasminogen item (12), in which the cerebrovascular disorder is selected activator is alteplase. from the group consisting of cerebral vasospasm developed 0017 (4) The pharmaceutical composition according to after Subarachnoid hemorrhage; and neurologic Symptom item (1), in which the antiplatelet drug shown in (b) is and disorder in activities of daily living disability, which are clopidogrel or aspirin. asSociated with those diseases. 0018 (5) The pharmaceutical composition according to 0029 (16) The pharmaceutical composition according to item (1), in which the antianginal drug shown in (b) is a item (3), which is provided for prevention or treatment of a calcium channel blocking drug and the calcium channel cerebrovascular disorder. blocking drug is amlodipine or nifedipine. 0030) (17) The pharmaceutical composition according to item (16) in which the cerebrovascular disorder is selected 0019 (6) The pharmaceutical composition according to from the group consisting of cerebral infarction, cerebral item (1), in which the antianginal drug shown in (b) is a thrombosis, celebral embolism, and transient ischemic nitrate drug and the nitrate drug is isosorbide. attack, and neurologic Symptom and disorder in activities of 0020 (7) The pharmaceutical composition according to daily living disability, which are based on those diseases. item (1), in which the antianginal drug shown in (b) is a 0031 (18) The pharmaceutical composition according to B-adrenaline receptor antagonist and the B-adrenaline recep item (4), which is provided for prevention or treatment of a tor antagonist is atenolol. cerebrovascular disorder. 0021 (8) The pharmaceutical composition according to 0032 (19) The pharmaceutical composition according to item (1), which is provided for prevention or treatment of a item (18), in which the cerebrovascular disorder is selected cerebrovascular disorder. from the group consisting of cerebral infarction, cerebral 0022 (9) The pharmaceutical composition according to thrombosis, celebral embolism, cerebral hemorrhage, cere item (8), in which the cerebrovascular accident is selected bral vasospasm, Subarachnoid hemorrhage, transient from the group consisting of cerebral infarction, cerebral ischemic attack, cerebral arteriosclerosis, head trauma, and thrombosis, cerebral embolism, cerebral hemorrhage, cere cerebral edema; and psychiatric Symptom, neurologic Symp bral vasospasm, Subarachnoid hemorrhage, transient tom, disorder in activities of daily living disability, amnesia, ischemic attack, cerebral arteriosclerosis, head trauma, and and dementia, which are based on those diseases. cerebral edema; and psychiatric Symptom, neurologic Symp 0033 (20) The pharmaceutical composition according to tom, disorder in activities of daily livingdisability, amnesia, item (1), which is provided for prevention or treatment of a and dementia, which are based on those diseases. cardiac disease. 0023 (10) The pharmaceutical composition according to 0034 (21) The pharmaceutical composition according to item (8), in which the cerebrovascular disorder is selected item (20), in which the cardiac disease is selected from the from the group consisting of cerebral infarction and cere group consisting of myocardial ischemia, angina pectoris, bral vasospasm; and neurologic Symptom and disorder in myocardial infarction, complication of myocardial infarc activities of daily living disability, which are based on those tion, reperfusion injury in treatment of myocardial infarc diseases. tion, and cardiac failure. 0024 (11) The pharmaceutical composition according to 0035 (22) The pharmaceutical composition according to item (8), in which the cerebrovascular disorder is selected from the group consisting of cerebral vasospasm developed item (20), in which the cardiac disease is angina pectoris. after Subarachnoid hemorrhage; and neurologic Symptom 0036 (23) The pharmaceutical composition according to and disorder in activities of daily living disability, which are item (5), which is provided for prevention or treatment of a asSociated with those diseases. cardiac disease. 0025 (12) The pharmaceutical composition according to 0037 (24) The pharmaceutical composition according to item (2), which is provided for prevention or treatment of a item (23), in which the cardiac disease is selected from the cerebrovascular disorder. group consisting of myocardial ischemia, angina pectoris, myocardial infarction, complication of myocardial infarc 0026 (13) The pharmaceutical composition according to tion, reperfusion injury in treatment of myocardial infarc item (12), in which the cerebrovascular disorder is selected from the group consisting of cerebral infarction, cerebral tion, and cardiac failure. thrombosis, celebral embolism, transient ischemic attack, 0038 (25) The pharmaceutical composition according to cerebral arteriosclerosis, head trauma, and cerebral edema, item (23), in which the cardiac disease is angina pectoris. US 2004/0242565 A1 Dec. 2, 2004
0039 (26) The pharmaceutical composition according to Sulfuric acid; and Salts of organic acids Such as acetic acid, item (6), which is provided for prevention or treatment of a citric acid, tartaric acid, lactic acid, Succinic acid, fumaric cardiac disease. acid, maleic acid, and methaneSulfonic acid. 0040 (27) The pharmaceutical composition according to 0052 Examples of the ameliorant of cerebral circulation item (26), in which the cardiac disease is selected from the to be used together with the compound of the present group consisting of myocardial ischemia, angina pectoris, invention shown in (a) include oZagrel, argatroban, nicer myocardial infarction, complication of myocardial infarc goline, concentrated glycerin/fructose, meclofenoxate, tion, reperfusion injury in treatment of myocardial infarc nizofenone, dihydroergotoxine, ibudilast, ifenprodil. tion, and cardiac failure. Examples of the vasodilator include bencyclane, cinnariz ine, citicoline, cyclandelate, cyclonicate, ebumamonine, 0041) (28) The pharmaceutical composition according to phenoxeZyl, flunarizine, ibudilast, ifenprodil, lomerizine, item (26), in which the cardiac disease is angina pectoris. naphlole, nikamate, noSergoline, nimodipine, papaverine, 0.042 (29) The pharmaceutical composition according to pentifylline, nofedoline, Vincamin, Vinpocetine, Vichizyl, item (4), which is provided for prevention or treatment of a pentoxifylline, prostacyclin derivatives (Such as prostaglan cardiac disease. din E1 and prostaglandin I2), an endothelin receptor block ing drug (Such as bosentan), diltiazem, nicorandil, and 0043 (30) The pharmaceutical composition according to nitroglycerin. Examples of the cerebral protecting drug item (29), in which the cardiac disease is selected from the include radical Scavengers (such as edaravone, Vitamin E, group consisting of myocardial ischemia, angina pectoris, and Vitamin C), glutamate antagonists, AMPA antagonists, myocardial infarction, complication of myocardial infarc kainate antagonists, NMDA antagonists, GABA agonists, tion, reperfusion injury in treatment of myocardial infarc growth factors, opioid antagonists, phosphatidylcholine pre tion, and cardiac failure. cursors, serotonin agonists, Na"/Ca" channel inhibitory 0044 (31) The pharmaceutical composition according to drugs, and K channel opening drugs. Examples of the brain item (29), in which the cardiac disease is angina pectoris. metabolic Stimulants include amantadine, tiapride, and y-aminobutyric acid. Examples of the anticoagulant include 0045 (32) The pharmaceutical composition according to heparins (such as heparin Sodium, heparin potassium, dalte item (7), which is provided for prevention or treatment of a parin Sodium, dalteparin calcium, heparin calcium, parna cardiac disease. parin Sodium, reviparin Sodium, and danaparoid Sodium), 0046 (33) The pharmaceutical composition according to warfarin, enoxaparin, argatroban, batroxobin, and sodium item (32), in which the cardiac disease is selected from the citrate. Examples of the antiplatelet drug include ticlopidine group consisting of myocardial ischemia, angina pectoris, hydrochloride, dipyridamole, ciloStaZol, ethyl icosapentate, myocardial infarction, complication of myocardial infarc Sarpogrelate hydrochloride, dilazep hydrochloride, trapidil, tion, reperfusion injury in treatment of myocardial infarc a nonsteroidal antiinflammatory agent (Such as aspirin), tion, and cardiac failure. beraprostSodium, iloprost, and indobufene. Examples of the thrombolytic drug include urokinase, tissue-type plasmino 0047 (34) The pharmaceutical composition according to gen activators (Such as alteplase, tisokinase, nateplase, pam item (32), in which the cardiac disease is angina pectoris. iteplase, monteplase, and rateplase), and nasaruplase. 0.048 (35) A use of a certain amount of the compound Examples of the amelirant of psychiatric Symptom include shown in (a) and a certain amount of at least one treatment treatment agents for Schizophrenia (Such asphenothiazine agent of the drugs shown in (b) or a pharmaceutically drugs, butyrophenone drugs, benzamide drugs, and risperi acceptable Salt thereof for prevention or treatment of a done), antianxiety agents (Such as thienodiazepine drugs, cerebrovascular disorder and a cardiac disease. benzodiazepine drugs, and tandospirone), antidepressants (fluvoxamine, milnacipran, iminobenzyl derivatives, diben 0049 (36) A method of treating a cerebrovascular disor Zocycloheptadiene derivatives, maprotiline, mianserin, and der or a cardiac disease using a certain amount of the Setiptiline), and antidementia drugs (Such as donepezil). compound shown in (a) and a certain amount of at least one Examples of the antihypertensive drug include angiotensin treatment agent of the components shown in (b) or a converting enzyme inhibitors (such as captopril, alacepril, pharmaceutically acceptable Salt thereof. lisinopril, imidapril, quinapril, temocapril, delapril, benazepril, cilaZapril, trandolapril, enalapril, ceronapril, 0050 (37) A document which describes that a certain foSinopril, imadapril, mobertpril, perindopril, ramipril, Spi amount of the compound shown in (a) and a certain amount rapril, and randolapril), angiotensin II antagonists (Such as of at least one treatment agent of the drugs shown in (b) or losartan, candesartan, Valsartan, eprosartan, and irbesartan), a pharmaceutically acceptable Salt thereof can or should be calcium channel blocking drugs (Such as aranidipine, used for prevention or treatment of a cerebrovascular dis efonidipine, nicardipine, bamidipine, benidipine, manid order and a cardiac disease; and a package including the ipine, cilnidipine, nisoldipine, nitrendipine, nifedipine, nil document. Vadipine, felodipine, amlodipine, diltiazem, bepridil, clen 0051. The compound of the present invention represented tiazem, phendilin, galopamil, mibefradil, prenylamine, by the general formula (I) can be synthesized in accordance Semotiadil, terodiline, Verapamil, cilnidipine, elgodipine, with a well known in the method described in, for example, isradipine, lacidipine, lercanidipine, nimodipine, cinnariz Chem. Pharam. Bull, 40, (3) 770-773 (1992); JP 61-152658 ine, flunarizine, lidoflazine, lomerizine, bencyclane, A, or the like. In addition, an acid addition Salt thereof is etafenone, and perhexiline), f-adrenaline receptor blocking preferably a pharmaceutically acceptable nontoxic Salt. drugs (propranolol, pindolol, indenolol, carteolol, buni Examples of the Salt include: Salts of inorganic acids Such as trolol, atenolol, acebutolol, metoprolol, timolol, nipradillol, hydrochloric acid, hydrobromic acid, phosphoric acid, and penbutolol, nadolol, tilisolol, carvedilol, bisoprolol, betaX US 2004/0242565 A1 Dec. 2, 2004 olol, celiprolol, bopindolol, bevantolol, labetalol, alprenolol, SuppreSSant include azathioprine, mizoribine, cycloSporine, amoSulalol, arotinolol, befunolol, bucumolol, bufetolol, tacrolimus, gusperimus, and methotrexate. buferalol, buprandolol, butylidine, butofilolol, carazolol, 0053. In addition, examples of the drugs of the present cetamolol, cloranolol, dilevalol, epanolol, levobunolol, invention shown in (b) to be used together with the com mepindolol, metipranolol, moprolol, nadoxolol, nevibolol, pound shown in (a) or pharmaceutically acceptable Salts oXprenolol, practol, pronetalol, Sotalol, Sufinalol, talindolol, thereof include carperitide, eplerenone, Vatanidipine, lemil tertalol, toliprolol, xybenolol, and eSmolol), a-receptor dipine, cleVidipine, Zofenopril, olmesartan, KRH-594, Oma blocking drugs (Such as amoSulalol, prazosin, terazosin, patrilat, fasidotril, ecadotril, Sampatrilat, MDL-100240, doxazosin, bunaZoSin, urapidil, phentolamine, arotinolol, Z-13752A, Xamoterol, molsidomine, ivabradine, cariporide, dapiprazole, fenspiride, indoramin, labetalol, naftopidil, etomoxir, HMR-1098, eniporide, BIII-890, SL-65.1708, tri nicergoline, tamsulosin, tolazoline, trimaZosin, and yohim flusal, tinzaparin, pamicogrel, tirofiban, eptifibatide, abcix bine), Sympathetic nerve inhibitors (Such as clonidine, guan imab, YM-33, BGC-728, CI-1031, NAPc2, SB-249417, facine, guanabenz, methyldopa, and reserpine), hydralazine, nesiritide, urodilatin, BG-9928, DTI-0017, monosialogan todralazine, budralazine, and cadralazine. Examples of the glioside GM-1, tirilazad, nicaraven, EGb-761, ebselen, antianginal drug include nitrate drugs (Such as amyl nitrite, NXY-059, EPC-K1, Sitaxsentan, tezosentan, ambrisentan, nitroglycerin, and isosorbide), f-adrenaline receptor block Zonampanel, enrasentan, darusentan, J-104132, BMS ing drugs (such as propranolol, pindolol, indenolol, car 207940, BSF-302146, TBC-3711, ABT-546, Ro-61-1790, teolol, bunitrolol, atenolol, acebutolol, metoprolol, timolol, aliskiren, vepalimomab, VPA-985, SR-121463, toborinone, nipradillol, penbutolol, nadolol, tilisolol, carvedilol, biso MCC-135, MCI-154, treprostinol, repinotan, SUN-N4057, prolol, betaxolol, celiprolol, bopindolol, bevantolol, labe dexanabinol, UK-315716, irampanel, DY-9760e, pexeli talol, alprenolol, amoSulalol, arotinolol, befunolol, bucu Zumab, UK-279276, and NS-7. molol, bufetolol, buferalol, buprandolol, butylidine, butofilolol, carazolol, cetamolol, cloranolol, dilevalol, 0054 The pharmaceutical composition of the present epanolol, levobunolol, mepindolol, metipranolol, moprolol, invention includes not only a mixture in which at least one nadoxolol, nevibolol, Oxprenolol, practol, pronetalol, of the above-mentioned components (a) and at least one of Sotalol, Sufinalol, talindolol, tertalol, toliprolol, andxy the above-mentioned components (b) have been mixed benolol), calciumchannel blocking drugs (such as aranid previously, but also a nonmixed combination Such as a form ipine, efonidipine, nicardipine, bamidipine, benidipine, of a kit or a pharmaceutical package. manidipine, cilnidipine, niSoldipine, nitrendipine, nife 0055. On preparing the pharmaceutical composition of dipine, nilvadipine, felodipine, amlodipine, diltiazem, bepri the present invention as a formulation having a form Suitable dil, clentiazem, phendiline, galopamil, mibefradil, preny for administration, there may be mixed: the compound lamine, Semotiadil, terodiline, Verapamil, cilnidipine, represented by the general formula (I) (wherein R1 repre elgodipine, isradipine, lacidipine, lercanidipine, nimodipine, Sents a hydrogen atom or a hydroxyl group) provided as an cinnarizine, flunarizine, lidoflazine, lomerizine, bencyclane, active ingredient or an acid addition Salt or hydrate thereof; etafenone, and perhexiline) trimetazidine, dipyridamole, at least one treatment agent of the drugs shown in (b) or a etafenone, dilaZep, trapidil, nicorandil, enoxaparin, and aspi pharmaceutically acceptable Salt thereof, and a pharmaceu rin. Examples of the diuretic include thiazide diuretics (Such tically acceptable carrier which is known as a Supplementary as hydrochlorothiazide, methyclothiazide, trichlormethiaz component. Examples of the carrier include: gelatin; sac ide, benzylhydrochlorothiazide, and penflutizide), loop charides Such as lactose and glucose, Starches Such as wheat, diuretics (Such as furosemide, etacrynic acid, bumetanide, rice, and corn Starch; fatty acids Such as Stearic acid; fatty piretanide, azosemide, and torasemide), K'Sparing diuretics acid Salts. Such as calcium Stearate and magnesium Stearate; (spironolactone, triamterene, and potassiumcanrenoate), talc, vegetable oils, alcohols Such as Stearic alcohol and osmotic diuretics (Such as isosorbide, D-mannitol, and glyc benzyl alcohol, gum, and polyalkylene glycol. erin), nonthiazide diuretics (Such as meticrane, tripamide, chlorthalidone, and mefruside), and acetazolamide. 0056 Moreover, general examples of a liquid carrier Examples of the cardiotonic include digitalis formulations include: water, physiological Saline; a Solution containing (Such as digitoxin, digoxin, methyldigoxin, deslanoside, dextrose or a Similar Saccharide; and glycols Such as ethyl Vesnarinone, lanatoside C, and proscillaridin), Xanthine for ene glycol, propylene glycol, polyethylene glycol, and mulations (such as aminophylline, choline theophylline, polypropylene glycol. When the pharmaceutical composi diprophylline, and proxyphylline), catecholamine formula tion of the present invention is prepared as a capsule, tions (such as dopamine, dobutamine, and docarpamine), typically, gelatin is preferably used. PDE III inhibitors (such as amrinone, olprinone, and mil 0057 The pharmaceutical composition of the present rinone), denopamine, ubidecare none, pimobendan, levosi invention, which is composed of the carrier provided as a mendan, aminoethylsulfonic acid, Vesnarinone, carperitide, Supplementary component; the compound represented by and colforsin daropate. Examples of the antiarrhythmic drug the general formula (I) (wherein R1 represents a hydrogen include ajmaline, pirmenol, procainamide, cibenzoline, dis atom or a hydroxyl group) provided as an active ingredient opyramide, quinidine, aprindine, mexiletine, lidocaine, phe or an acid addition Salt or hydrate thereof, and at least one nyloin, pilsicainide, propafenone, flecainide, atenolol, ace treatment agent of the drugs shown in (b) or a pharmaceu butolol, Sotalol, propranolol, metoprolol, pindolol, tically acceptable Salt thereof, includes an active ingredient amiodarone, nifekalant, diltiazem, bepridil, and Verapamil. in an amount of, typically 0.01 wt % or more and 80 wt % Examples of the antihyperlipidemic drug include atorvasta or less, preferably 60 wt % or less, for example. tin, Simvastatin, pravastatin Sodium, fluvastatin Sodium, clinofibrate, clofibrate, Simfibrate, fenofibrate, bezafibrate, 0058. In addition, the present invention relates to a colestimide, and colestyramine. Examples of the immuno method of treating a cerebrovascular disorder or a cardiac US 2004/0242565 A1 Dec. 2, 2004 disease using a certain amount of the compound shown in (a) maceutical composition of the present invention. That is, the above and a certain amount of at least one treatment agent present invention relates to a medical kit for prevention or of the drugs shown in (b) or a pharmaceutically acceptable treatment of a cerebrovascular disorder and a cardiac dis Salt thereof. Those may be simultaneously administered as a ease, which is characterized by including a first container mixture and may be separately administered Successively as containing a certain amount of the compound shown in (a) a different pharmaceutical form. In the case of the repetitive and a Second container containing a certain amount of at administration, the time interval between administrations is least one treatment agent of the drugs shown in (b) or a preferably 48 hours or less. Moreover, the compound shown pharmaceutically acceptable Salt thereof. By using Such a in (a) and the drug shown in (b) may have different admin kit, the present invention facilitates a use of the pharmaceu istration routes from each other. tical composition of the present invention, and also facili 0059) That is, when one has an oral administration, and tates accurate administration of a Suitable active ingredient the other may have a parenteral administration. to a patient with accurate dosage by a physician. 0066 Moreover, other means that facilitate to understand 0060) Examples of the administration method include and use the pharmaceutical composition of the present oral administration and parenteral administration. Examples invention include a briefing document and a package. That of a dosage form Suitable for the oral administration include is, a document which describes the use of a certain amount a tablet, a capsule, a powder, a granule, a liquid agent, and of the compound shown in (a) together with a certain amount an elixir. of at least one treatment agent of the drugs shown in (b) or 0061 Examples of a dosage form suitable for the a pharmaceutically acceptable Salt thereof for prevention or parenteral administration include a liquid agent. treatment of a cerebrovascular disorder and a cardiac dis 0062) When the pharmaceutical composition is parenter ease, and a package which includes the document. The ally administered by intramuscular injection, intravenous document and the package which includes the document injection, or Subcutaneous injection, the composition can be facilitate to understand and use the pharmaceutical compo administered in the form of a sterile Solution that is added Sition of the present invention, and also facilitates accurate with another Solute Such as Sodium chloride or glucose. administration of a Suitable active ingredient to a patient When the pharmaceutical composition is administered by with accurate dosage by a physician. injection, the composition is preferably dissolved in Steril ized water, a lidocaine hydrochloride Solution (for intramus BEST MODE FOR CARRYING OUT THE cular injection), physiological Saline, glucose, a Solution for INVENTION intravenous injection, or an electrolyte Solution (for intra 0067. The present invention will next be described more venous injection). Specifically by way of examples, formulation example, and 0.063. When the composition is dissolved in such a man kit example. However, the present invention is not limited ner, the Solution may be regulated So as to contain an active thereto. ingredient in an amount of, typically 0.01 wt % or more and 20 wt % or less, preferably 0.1 wt % or more and 10 wt % EXAMPLE 1. or less. In the case of a liquid agent for oral administration, preferable examples include a Suspension or Syrup that Effect on Dog Delayed Cerebral Vasospasm Model contains an active ingredient in an amount of 0.01 to 20 wt 0068 An adult mongrel dog was anesthetized with pen %. Examples of a carrier to be used in Such a case include tobarbital and 5 ml of autologous blood was injected into an aqueous diluents Such as perfume, Syrup, or pharmaceu cisterna magna (on the first day). On the third day, 5 ml of tical micell. autologous blood was injected into cisterna magna under thiamyral anesthesia. Before the injection of autologous 0064. The dosage of the pharmaceutical composition of blood on the first day and on the Seventh day, angiographin the present invention depends on age of a patient to be was injected into vertebral artery, followed by photograph administered, health condition, body weight, degree of ing blood vessel of basilar artery. The blood vessel photo Symptom, type of treatment if any Simultaneous treatment is graph on the Seventh day confirmed occurrence of delayed performed, frequency of treatment, property of desired cerebral vasospasm on the photograph. Then, a hydrochlo effect, administration route, or administration plan. Typi ride of the compound represented by the general formula (I) cally, effective dosage of the compound of the present (wherein R1 represents a hydrogen atom) (0.3 mg/kg) and invention represented by the general formula (I) (wherein nimodipine (0.1 mg/kg or 1 mg/kg) were separately admin R1 represents a hydrogen atom or a hydroxyl group) or an istered into vein over 30 minutes continuously (separate acid addition salt or hydrate thereof is 0.01 to 20 mg/kg day administration group). Alternatively, a hydrochloride of the in the case of parenteral administration, and 0.02 to 40 compound represented by the general formula (I) (wherein mg/kg day in the case of oral administration. Effective R1 represents ahydrogen atom) (0.3 mg/kg) and nimodipine dosage of the drug shown in (b) or a pharmaceutically (0.1 mg/kg) were concomitantly administered into vein over acceptable salt thereof is typically 0.0001 to 100 mg/kg day. 30 minutes continuously (concomitant administration In addition, effective dosage in the case where the vasodi group). As a control, physiological Saline was administered lator shown in (b) is a calcium channel blocking drug and the into vein over 30 minutes continuously. After the adminis calcium channel blocking drug is nimodipine is 0.1 to 3 tration of each drug, the blood vessel was photographed to mg/kg day in the case of parenteral administration, and 0.3 measure the diameter of basilar artery. Table 1 shows the to 30 mg/kg day in the case of oral administration. percentage (%) of the blood vessel diameter after the admin 0065. The present invention also provides a kit, package, istration of each drug based on the blood vessel diameter or document for convenient and effective use of the phar before the injection of autologous blood (on the first day). US 2004/0242565 A1 Dec. 2, 2004
the fourth day. On the fifth day, the brain was extracted and TABLE 1. the size of a cerebral infarction was histopathologically measured. In the case of the Separate administration of the Basilar artery diameter (diameter before blood hydrochloride of the compound represented by the general Compound injection: 100%) formula (I) (wherein R1 represents a hydrogen atom) (1 Physiological saline 59.9% mg/kg) and Sodium oZagrel (10 mg/kg), the cerebral infarc Hydrochloride of general formula (I) 60.5% tion was not inhibited. On the other hand, in the case of the compound (wherein R1 represents a hydrogen concomitant administration of the hydrochloride of the atom) 0.3 mg/kg Nimodipine 0.1 mg/kg 55.7% compound represented by the general formula (I) (wherein Nimodipine 1 mg/kg 58.0% R1 represents a hydrogen atom) (1 mg/kg) and Sodium Hydrochloride of general formula (I) 68.8% oZagrel (10 mg/kg), the cerebral infarction was inhibited. compound (wherein R1 represents a hydrogen Also, the inhibitory effect of cerebral infarction was con atom) 0.3 mg/kg + Nimodipine 0.1 mg/kg firmed in the case of the concomitant administration of a certain amount of the hydrochloride and Sodium OZagrel that had not caused the inhibitory effect of cerebral infarction 0069. The diameter of basilar artery measured before the when administering those Separately. It was confirmed that drug administration (on the Seventh day) decreased to about 60% compared with that measured before the autologous the concomitant administration of the hydrochloride of the blood injection (on the first day), and occurrence of delayed compound represented by the general formula (I) (wherein cerebral vasospasm was confirmed. When the hydrochloride R1 represents a hydrogen atom) and Sodium oZagrel caused of the compound represented by the general formula (I) a Synergistic effect. It was indicated that the concomitant (wherein R1 represents a hydrogen atom) (0.3 mg/kg) and administration of the compound represented by the general nimodipine (0.1 mg/kg or 1 mg/kg) were separately admin formula (I) (wherein R1 represents a hydrogen atom) and istered, the vasospasm was not improved. When the hydro Sodium OZagrel was effective for improvement and preven chloride of a compound represented by the general formula tion of cerebral infarction. (I) (wherein R1 represents a hydrogen atom) (0.3 mg/kg) and nimodipine (0.1 mg/kg or 1 mg/kg) were concomitantly EXAMPLE 3 administered, an vasospasm improving effect was observed. Effect on Neuronal Death Model by Transient 0070 Also, an vasospasm improving effect was observed Occlusion of Both Common Carotid Arteries of in the case of the concomitant administration of a certain Mongolian Gerbil amount of the hydrochloride and nimodipine that had not 0073. Both common carotid arteries of a Mongolian caused vasospasm improving effect when administering gerbil were occluded for 5 minutes to cause transient brain those Separately. ischemic condition. Immediately after restarting blood flow, 0071 Those results confirmed that the concomitant a hydrochloride of the compound represented by the general administration of the hydrochloride of the compound rep formula (I) (wherein R1 represents a hydrogen atom) (0.3 resented by the general formula (I) (wherein R1 represents mg/kg) or nimodipine (3 mg/kg or 10 mg/kg) was separately a hydrogen atom) and nimodipine caused a Synergistic administered intraperitoneally (separate administration effect. Also, those results indicated that the concomitant group). administration of the compound represented by the general 0074 Alternatively, a hydrochloride of the compound formula (I) (wherein R1 represents a hydrogen atom) and represented by the general formula (I) (wherein R1 repre nimodipine was effective for improvement and prevention of Sents a hydrogen atom) (0.3 mg/kg) and nimodipine (0.3 cerebral vasospasm. mg/kg) were administered intraperitoneally (concomitant administration group). EXAMPLE 2 0075. On the seventh day, the number of pyramidal cells Inhibitory Effect of Cerebral Infarction in Rat in a hippocampuS CA1 region was counted. The brain Cerebral Infarction Model ischemia decreased the number of pyramidal cells to about 0.072 A rat brain microthromboembolism model 10%. The separate administration of the hydrochloride of the described in Stroke, 31, 224.5-2255 (2000) was used as a compound represented by the general formula (I) (wherein cerebral infarction model. Physiological Saline, a hydrochlo R1 represents a hydrogen atom) (0.3 mg/kg) and nimodipine ride of a compound represented by the general formula (I) (3 mg/kg) did not inhibit neuronal death. The concomitant (wherein R1 represents a hydrogen atom) (1 mg/kg), or administration of the hydrochloride of the compound rep Sodium OZagrel provided as an ameliorant of cerebral cir resented by the general formula (I) (wherein R1 represents culation (10 mg/kg) was separately administered intraperi a hydrogen atom) (0.3 mg/kg) and nimodipine (3 mg/kg) toneally to a rat provided as a cerebral infarction model inhibited neuronal death. Also, the brain inhibitory effect of (separate administration group) Alternatively, a hydrochlo neuronal death was confirmed in the case of the concomitant ride of a compound represented by the general formula (I) administration of a certain amount of the hydrochloride and (wherein R1 represents a hydrogen atom) (1 mg/kg) and nimodipine that had not caused the brain inhibitory effect of Sodium OZagrel (10 mg/kg) were administered intraperito neuronal death when administering those Separately. neally (concomitant administration group). After the model 0076 Those results confirmed that the concomitant was prepared, each drug was administered once a day until administration of the hydrochloride of the compound rep US 2004/0242565 A1 Dec. 2, 2004
resented by the general formula (I) (wherein R1 represents FORMULATION EXAMPLE a hydrogen atom) and nimodipine caused a Synergistic 0078 Apharmaceutical composition, which includes (a), effect. In addition, those results indicated that the concomi a compound represented by the general formula (I): tant administration of the compound represented by the general formula (I) (wherein R1 represents a hydrogen atom) and nimodipine was effective for improvement and (I) prevention of cerebral infarction. r SON NH EXAMPLE 4 Effect on Vasopressin Induced Rat Angina Pectoris N Model 2N 0077. A rat was orally administered with physiological Saline, a hydrochloride of the compound represented by the R1 general formula (I) (wherein, R1 is a hydrogen atom) (3 mg/kg), nifedipine provided as a calcium channel blocking drug (3 mg/kg), propranolol provided as a f-adrenaline 0079 (wherein R1 represents a hydrogen atom or a receptor blocking drug (100 mg/kg), or isosorbide nitrate hydroxyl group) or an acid addition Salt or hydrate provided as a nitrate drug (30 mg/kg) separately (separate thereof and which includes at least one of (b) an ameliorant of cerebral circulation, a vasodilator, a administration group). Alternatively, a rat was orally admin cerebral protecting drug, an brain metabolic Stimu istered with one compound of a hydrochloride of the com lants, an anticoagulant, an antiplatelet drug, a throm pound represented by the general formula (I) (wherein, R1 bolytic drug, an amelirant of psychiatric Symptom, a is a hydrogen atom) (3 mg/kg), nifedipine (3 mg/kg), antihypertensive drug, an antianginal drug, propranolol (100 mg/kg), and isosorbide nitrate (30 mg/kg) diuretic, a cardiotonic, an antiarrhythmic drug, an (concomitant administration group). Half an hour later, antihyperlipidemic drug, and an immunosuppreSSant vasopressin (0.5 U/kg) was intravenously administered. The can be produced in accordance with, for example, the ST segment depression was used as an indeX showing the formulation shown below. degree of a myocardial ischemia. On the Seventh day, the ST Segment in an electrocardiogram was measured for com 0080) 1. Sterile Injectable parison with a ST Segment before the vasopressin adminis 0081. A preferable amount of at least one of the drugs tration. It was found that the vasopressin administration shown in (b) was added to the components shown in Table caused the ST Segment depression. In addition, occurrence 2 below and those compounds were dissolved in distilled of a myocardial ischemia was observed. The ST segment water for injection. Subsequently, the Solution was regulated depression was not improved by the Separate administration to have a required final weight by addition of distilled water of the hydrochloride of the compound represented by the for injection and an ampule containing 2 ml of the Solution general formula (I) (wherein, R1 is a hydrogen atom), was Sealed, followed by heat Sterilization. nifedipine, propranolol, and isosorbide nitrate. The ST Seg ment depression was improved by the concomitant admin TABLE 2 istration of the hydrochloride of the compound represented Active ingredient by the general formula (I) (wherein, R1 is a hydrogen atom) Component content and nifedipine; the hydrochloride of the compound repre 10 mg formulation Hydrochloride of general 10 mg Sented by the general formula (I) (wherein, R1 is a hydrogen formula (I) compound atom) and propranolol, or the hydrochloride of the com (wherein R1 represents a pound represented by the general formula (I) (wherein, R1 hydrogen atom) Sodium chloride 16 mg is a hydrogen atom) and isosorbide nitrate. The improving Distilled water Proper amount effect of myocardial ischemia was confirmed in the case of Total amount was the concomitant administration of a certain amount of the regulated to 2 ml 30 mg formulation Hydrochloride of general 30 mg hydrochloride, nifedipine, propranolol, and isosorbide formula (I) compound nitrate that had not caused the improving effect of myocar (wherein R1 represents a dial ischemia when administering those Separately. Those hydrogen atom) Sodium chloride 16 mg results confirmed that the concomitant administration of any Distilled water Proper amount of the hydrochloride of the compound represented by the Total amount was general formula (I) (wherein R1 represents a hydrogen regulated to 2 ml 60 mg formulation Hydrochloride of general 60 mg atom), nifedipine, propranolol, and isosorbide nitrate caused formula (I) compound a Synergistic effect. In addition, those results indicated that (wherein R1 represents a the concomitant administration of any of the hydrochloride hydrogen atom) Sodium chloride 16 mg of the compound represented by the general formula (I) Distilled water Proper amount (wherein R1 represents a hydrogen atom), nifedipine, pro Total amount was pranolol, and isosorbide nitrate was effective for improve regulated to 2 ml ment and prevention of angina pectoris. US 2004/0242565 A1 Dec. 2, 2004
TABLE 2-continued TABLE 3-continued Active ingredient Component Amount Component content Lactose 98.5 mg 10 mg formulation Hydrochloride of general 10 mg Magnesium stearate 1.5 mg formula (I) compound Carboxymethylcellulose calcium 5.0 mg (wherein R1 represents a hydroxyl group) Total 150.0 mg Sodium chloride 16 mg Distilled water Proper amount Total amount was regulated to 2 ml KIT EXAMPLE 30 mg formulation Hydrochloride of general 30 mg formula (I) compound (wherein R1 represents a 0084. A kit of pharmaceutical composition, which hydroxyl group) includes (a), a compound represented by the general formula Sodium chloride 16 mg (I): Distilled water Proper amount Total amount was regulated to 2 ml (I) 60 mg formulation Hydrochloride of general 60 mg formula (I) compound (wherein, R1 represents a hydroxyl ...O. group) Sodium chloride 16 mg Distilled water Proper amount N Total amount was regulated to 2 ml l
R1 0082) 2. Tablet 0.083. A preferable amount of at least one of the drugs 0085 (wherein R1 represents a hydrogen atom or a shown in (b) was added to the components shown in Table hydroxyl group) or an acid addition Salt or hydrate thereof 3 below to prepare a tablet in accordance with a general and which includes at least one of (b) an ameliorant of method. cerebral circulation, a vasodilator, a cerebral protecting drug, an brain metabolic Stimulants, an anticoagulant, an TABLE 3 antiplatelet drug, a thrombolytic drug, an amelirant of psy chiatric Symptom, a antihypertensive drug, an antianginal Component Amount drug, a diuretic, a cardiotonic, an antiarrhythmic drug, an 10 mg formulation Hydrochloride of general formula 10.0 mg antihyperlipidemic drug, and an immunosuppressant can be (I) compound (wherein R1 represents a hydrogen atom) provided in a form shown below, for example. Crystalline cellulose 25.0 mg Lactose 108.5 mg 0086. At least one of pharmaceutical dosage form units Magnesium stearate 1.5 mg shown in Table 4 and at least one of pharmaceutical dosage Carboxymethylcellulose calcium 5.0 mg form units shown in Table 5 were separately packed in a Total 150.0 mg divided bottle or a divided foil packet, and the bottle or the 20 mg formulation Hydrochloride of general formula 20.0 mg packet was Stored in a package container. (I) compound (wherein R1 represents a hydrogen atom) TABLE 4 Crystalline cellulose 25.0 mg Lactose 98.5 mg Active Magnesium stearate 1.5 mg ingredient Carboxymethylcellulose calcium 5.0 mg Component content Total 150.0 mg 1. Ampule agent 10 mg formulation Hydrochloride of general formula 10.0 mg (I) compound (wherein R1 10 mg formulation Hydrochloride of general 10 mg represents a hydroxyl group) formula (I) compound (wherein Crystalline cellulose 25.0 mg R1 represents a hydrogen atom) Lactose 108.5 mg 30 mg formulation Hydrochloride of general 30 mg Magnesium stearate 1.5 mg formula (I) compound (wherein Carboxymethylcellulose calcium 5.0 mg R1 represents a hydrogen atom) 60 mg formulation Hydrochloride of general 60 mg Total 150.0 mg formula (I) compound (wherein 20 mg formulation Hydrochloride of general formula 20.0 mg R1 represents a hydrogen atom) (I) compound (wherein R1 10 mg formulation Hydrochloride of general 10 mg represents a hydroxyl group) formula (I) compound (wherein Crystalline cellulose 25.0 mg R1 represents a hydroxyl group) US 2004/0242565 A1 Dec. 2, 2004
(a) a compound represented by the general formula (I) TABLE 4-continued (I) Active ingredient r Component content SON NH 30 mg formulation Hydrochloride of genera 30 mg ormula (I) compound (wherein N R1 represents a hydroxyl group) 60 mg formulation Hydrochloride of genera 60 mg ormula (I) compound (wherein 2N R1 represents a hydroxyl group) 2. Tablet R1 10 mg formulation Hydrochloride of genera 10.0 mg ormula (I) compound (wherein (wherein R1 represents a hydrogen atom or a hydroxyl R1 represents a hydrogen atom) group) or an acid addition salt or hydrate thereof, and 20 mg formulation Hydrochloride of genera 20.0 mg ormula (I) compound (wherein (b) an ameliorant of cerebral circulation, a vasodilator, a R1 represents a hydrogen atom) cerebral protecting drug, an brain metabolic Stimulants, 10 mg formulation Hydrochloride of genera 10.0 mg an anticoagulant, an antiplatelet drug, a thrombolytic ormula (I) compound (wherein drug, an amelirant of psychiatric Symptom, a antihy R1 represents a hydroxyl group) pertensive drug, an antianginal drug, a diuretic, a 20 mg formulation Hydrochloride of genera 20.0 mg cardiotonic, an antiarrhythmic drug, an antihyperlipi ormula (I) compound (wherein demic drug, an immunosuppreSSant, or a pharmaceuti R1 represents a hydroxyl group) cally acceptable Salt (except the components shown in (a)). 2. A pharmaceutical composition according to claim 1, 0087 which is provided for prevention or treatment of a cere brovascular disorder. TABLE 5 3. A pharmaceutical composition according to claim 2, wherein the cerebrovascular disorder is selected from the Active ingredient group consisting of cerebral infarction, cerebral thrombosis, Component content cerebral embolism, cerebral hemorrhage, cerebral vasos pasm, Subarachnoid hemorrhage, transient ischemic attack, 1. Ampule agent cerebral arteriosclerosis, head trauma, and cerebral edema, 10 mg formulation Nimodipine 10 mg and psychiatric Symptom, neurologic Symptom, disorder in 2. Tablet activities of daily living disability, amnesia, and dementia, which are based on those diseases. 30 mg formulation Nimodipine 30 mg 4. A pharmaceutical composition according to claim 3, 60 mg formulation Nimodipine 60 mg 100 mg formulation Nimodipine 100 mg wherein Sodium OZagrel is used as an ameliorant of cerebral 3. capsule circulation shown in claim 1 (b). 5. A pharmaceutical composition according to claim 3, 30 mg formulation Nimodipine 30 mg wherein nimodipine is used as a vasodilator Shown in claim 1 (b). 6. A pharmaceutical composition according to claim 1, INDUSTRIAL APPLICABILITY which is provided for prevention or treatment of a cardiac disease. 0088. The present invention can provide a pharmaceuti 7. A pharmaceutical composition according to claim 6, cal composition that is useful as a preventive or treatment is wherein the cardiac disease is Selected from the group consisting of myocardial ischemia, angina pectoris, myocar useful as a preventive or treatment agent for a cerebrovas dial infarction, complication of myocardial infarction, rep cular disorder and a cardiac disease. erfusion injury in myocardial infarct treatment, and cardiac failure. 8. A pharmaceutical composition according to claim 7, wherein nifedipine, propranolol, or isosorbide nitrate is used 1. A pharmaceutical composition comprising at least one as an antianginal drug shown in claim 1 (b). of components (a) and at least one of components (b) shown in below: