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    • 专利摘要:
    The present invention relates to NHE-1 inhibitor crystals of formula (I), methods of using the NHE-1 inhibitor crystals, and pharmaceutical compositions containing the NHE-1 inhibitor crystals: Formula I NHE-1 inhibitor determinations are useful for alleviating tissue damage resulting from tissue ischemia.
    公开号:KR20020040918A
    申请号:KR1020027005366
    申请日:2000-10-09
    公开日:2002-05-30
    发明作者:브로스트롬라일로빈슨；코놀리테렌스죠셉；리젱제인；오릴수잔리；샤아바래트키리트쿠마르
    申请人:실버스타인 아써 에이.；화이자 프로덕츠 인코포레이티드；
    IPC主号:
    专利说明:

    SODIUM-HYDROGEN EXCHANGER TYPE 1 INHIBITOR CRYSTALS}
    [2] Myocardial ischemic injury may occur in the outpatient as well as in the outpatient environment and may result in sudden death, myocardial infarction or congestive heart failure. There is a medical need that has not yet been met to prevent or minimize myocardial ischemic injury, particularly myocardial infarction during surgery. The therapy is expected to save lives, reduce hospitalization, improve quality of life and reduce overall health care costs for patients at high risk.
    [3] Pharmacological heart protection will reduce the incidence and progression of myocardial infarction and dysfunction occurring in the surgical environment (during surgery). In addition to reducing myocardial damage and improving post-ischemic myocardial function in patients with ischemic heart disease, cardiac protection is also a "dangerous condition" (eg, age 65 and older) that requires non-cardiac surgery. , Coronary artery disease, diabetes, hypertension) will reduce the incidence of heart morbidity and mortality due to myocardial infarction and dysfunction.
    [4] The mechanism (s) responsible for myocardial damage observed after ischemia and reperfusion are not fully understood.
    [5] Various publications have disclosed the use of guanidine derivatives, for example, in the treatment of arrhythmias.
    [6] WO 99/43663 (International Application No. PCT / IB99 / 00206), recently published on September 2, 1999, discloses [5-cyclopropyl-1- (quinolin-5-yl). Various NHE-1 inhibitors are disclosed, including) -1H-pyrazole-4-carbonyl] guanidine. The publication also mentions that "preferred salts of the aforementioned compounds are mono- or di-mesylate salts".
    [7] International Application No. PCT / JP97 / 04650, published June 25, 1998, discloses N-[(substituted 5-membered heteroaryl)] guanidine compounds, which are inhibitors of Na + / H + exchange. It is disclosed that it is useful for treating various diseases such as hypertension, arrhythmia, angina pectoris, myocardial infarction, arteriosclerosis and diabetes complications.
    [8] Thus, there is a need in the art for compounds for the treatment of myocardial ischemia, i.e. new crystalline forms of such compounds, and there is a continuing investigation into them.
    [9] Summary of the Invention
    [10] The present invention relates to the determination of formula (I)
    [11]
    [12] Or the salt is referred to as the N- (5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl) -guanidine monomesylate salt.
    [13] Another aspect of the invention relates to the anhydrous crystalline form of the salt of formula (I).
    [14] Another aspect of the invention relates to anhydrous crystalline Form A of the salt of formula (I) having the X-ray diffraction d-spacings of Tables IIIa and IIIb below.
    [15] Another aspect of the invention relates to anhydrous crystalline Form A of the salt of formula (I) having an X-ray powder diffraction pattern as shown in FIG. 1.
    [16] Another aspect of the invention relates to the anhydrous crystalline Form D of the salt of formula (I) having the X-ray diffraction d-spacings of Tables IIa and IIb below.
    [17] Another aspect of the invention relates to anhydrous crystalline Form D of the salt of Formula (I) having an X-ray powder diffraction pattern as shown in FIG. 2.
    [18] Another aspect of the invention relates to a hemihydrate crystalline form of the salt of formula (I), preferably having the X-ray diffraction d-spacings of Tables IVa and IVb.
    [19] Another aspect of the invention relates to the hemihydrate crystalline form of the salt of formula (I) having an X-ray powder diffraction pattern as shown in FIG. 3.
    [20] Reference is made herein to the crystals of formula (I), including the following methods, pharmaceutical compositions, mixtures and kits. When the crystal is present in solution, it is understood that the crystalline form is absent (eg, in contrast to anhydrous tablet formulations), but the following methods, pharmaceutical compositions, mixtures and kits may be used in the processes or formulations derived from such crystals (e.g. For example, by administering an intravenous solution prepared from crystals).
    [21] Another aspect of the invention is a method of treating a mammal by administering a therapeutically effective amount of a crystal of formula (I) to a mammal (eg, a human) having a disease or condition mediated by NHE-1.
    [22] Another aspect of the invention provides for reducing tissue damage resulting from ischemia, comprising administering a therapeutically effective amount of a crystal of Formula (I) to a mammal (eg, a female or a male human) in need thereof. For example, to substantially prevent tissue damage, including tissue protection.
    [23] Ischemic tissues, individually or as a group, are heart, brain, liver, kidney, lung, digestive tract, skeletal muscle, spleen, pancreas, nerves, spinal cord, retinal tissue, blood vessels or intestinal tissue.
    [24] Particularly preferred ischemic tissue is heart tissue.
    [25] Particular preference is given to administering crystals to prevent myocardial ischemic injury during surgery.
    [26] Preferably, the crystals of the present invention are administered prophylactically.
    [27] Ischemic injury can occur in the organ or patient during organ transplantation.
    [28] Preferably, the crystals of the present invention are administered before cardiac surgery or non-cardiac surgery, during surgery and / or immediately after surgery.
    [29] In one embodiment of the invention, the crystal of formula (I) is administered topically.
    [30] Preferred dosages are about 0.001 to 100 mg / kg / day of crystal of formula (I). A particularly preferred dosage is about 0.01 to 50 mg / kg / day of crystal of formula (I).
    [31] Another aspect of the invention involves administering a therapeutically effective amount of a crystal of Formula (I) to a mammal (eg, a female or a male human), such as a coronary artery bypass implant (eg, coronary artery bypass). substantial reduction of myocardial tissue damage (eg, tissue protection) during grafting (CABG) surgery, vascular surgery, percutaneous transluminal coronary angioplasty (PTCA), organ transplantation or other non-cardiac surgery) To prevent tissue damage).
    [32] Another aspect of the invention involves administering to a mammal (eg, a female or a male human) a therapeutically effective amount of a crystal of formula (I), cardiac ischemia (acute coronary syndrome, eg, myocardial infarction or unstable angina) Or to alleviate myocardial tissue damage (eg, substantially prevent tissue damage, including tissue protection) in a patient with an ongoing brain ischemic state (eg, stroke).
    [33] Another aspect of the invention is a patient diagnosed with coronary heart disease (eg, prior myocardium) comprising administering to a mammal (eg, a female or a male human) a therapeutically effective amount of a crystal of Formula (I). Infarct or unstable angina) or in patients at high risk for myocardial infarction (e.g., age 65 or older and two or more risk factors for coronary heart disease) to reduce myocardial tissue damage (e.g., include tissue protection) To substantially prevent tissue damage).
    [34] Another aspect of the present invention relates to a method for preventing ischemic injury, comprising long-term oral administration of a therapeutically effective amount of a crystal of formula (I) to a mammal in need thereof.
    [35] Another aspect of the invention is directed to a method of treating cardiovascular disease comprising administering to a mammal (eg, a female or a male human) in a therapeutically effective amount of a crystal of formula (I).
    [36] Another aspect of the invention is directed to a method of treating atherosclerosis comprising administering to a mammal (eg, a female or a male human) a therapeutically effective amount of a crystal of Formula (I).
    [37] Another aspect of the invention relates to a method of treating hypertension, comprising administering to a mammal (eg, a female or a male human) in a therapeutically effective amount of a crystal of formula (I).
    [38] Another aspect of the invention relates to a method of treating arrhythmia comprising administering to a mammal (eg, a female or a male human) in a therapeutically effective amount of a crystal of formula (I).
    [39] Another aspect of the invention relates to a method for treating angina, comprising administering to a mammal (eg, a female or a male human) in a therapeutically effective amount of a crystal of formula (I).
    [40] Another aspect of the invention relates to a method of treating cardiac hypertrophy, comprising administering to a mammal (eg, a female or a male human) a therapeutically effective amount of a crystal of formula (I).
    [41] Another aspect of the invention relates to a method of treating kidney disease, comprising administering to a mammal (eg, a female or a male human) in a therapeutically effective amount of a crystal of formula (I).
    [42] Another aspect of the invention relates to a method of treating diabetic complications comprising administering to a mammal (eg, a female or a male human) a therapeutically effective amount of a crystal of formula (I).
    [43] Another aspect of the invention relates to a method of treating restenosis comprising administering to a mammal (eg, a female or a male human) in a therapeutically effective amount of a crystal of formula (I).
    [44] Another aspect of the invention is directed to a method of treating a cell proliferative disease comprising administering to a mammal (eg, a female or a male human) in a therapeutically effective amount of a crystal of formula (I).
    [45] Another aspect of the invention is directed to a method of treating a cancer disease comprising administering to a mammal (eg, a female or a male human) in a therapeutically effective amount of a crystal of formula (I).
    [46] Another aspect of the invention is directed to a method of treating fibrotic disease, comprising administering to a mammal (eg, a female or a male human) in a therapeutically effective amount of a crystal of formula (I).
    [47] Another aspect of the invention relates to a method of treating glomerular neurosis, comprising administering to a mammal (eg, a female or a male human) in a therapeutically effective amount of a crystal of formula (I).
    [48] Another aspect of the invention relates to a method of treating organ hypertrophy or hyperplasia, comprising administering to a mammal (eg, a female or a male human) a therapeutically effective amount of a crystal of formula (I).
    [49] Another aspect of the invention relates to a method of treating pulmonary fibrosis, comprising administering to a mammal (eg, a female or a male human) in a therapeutically effective amount of a crystal of formula (I).
    [50] Another aspect of the invention relates to a method of treating cerebral ischemic disorders comprising administering to a mammal (eg, a female or a male human) in a therapeutically effective amount of a crystal of formula (I).
    [51] Another aspect of the invention relates to a method of treating myocardial fainting comprising administering to a mammal (eg, a female or a male human) a therapeutically effective amount of a crystal of Formula (I).
    [52] Another aspect of the invention relates to a method of treating myocardial dysfunction comprising administering to a mammal (eg, a female or a male human) in a therapeutically effective amount of a crystal of formula (I).
    [53] Another aspect of the invention relates to a method for treating cerebrovascular disease, comprising administering to a mammal (eg, a female or a male human) in a therapeutically effective amount of a crystal of formula (I).
    [54] Another aspect of the invention relates to a method of treating organ hypertrophy or hyperplasia, comprising administering to a mammal (eg, a female or a male human) a therapeutically effective amount of a crystal of formula (I).
    [55] The invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a crystal of formula (I) and a pharmaceutically acceptable carrier, vehicle or diluent.
    [56] The invention also relates to pharmaceutical compositions for alleviating tissue damage resulting from ischemia, comprising a therapeutically effective amount of the crystal of formula (I) and a pharmaceutically acceptable carrier, vehicle or diluent.
    [57] Another aspect of the invention is a mixture of crystals of formula (I) with other compounds as described below.
    [58] Another aspect of the invention provides a therapeutically effective amount of a pharmaceutical composition comprising a crystal of formula (I) and a cardiovascular agent, and the above for alleviating tissue damage resulting from tissue ischemia in a mammal (eg, a male or female human). It relates to the use of the composition.
    [59] Another aspect of the invention provides a mammal (eg, a female or a male human) to (a) a crystal of formula (I); And (b) administering the cardiovascular agent in an amount that provides a therapeutic effect, thereby alleviating tissue damage that may result from or may result from ischemia (eg, tissue protection, including substantially tissue To prevent damage).
    [60] Another aspect of the present invention provides a pharmaceutical composition comprising (a) a crystal of Formula I of a first unit dosage form and a pharmaceutically acceptable carrier, vehicle or diluent; (b) a cardiovascular agent and a pharmaceutically acceptable carrier, vehicle or diluent of a second unit dosage form; And (c) means for containing said first and second dosage forms, wherein the amount of said first compound and said second compound is an amount that provides a therapeutic effect.
    [61] In the mixed compositions, mixing methods and kits, the cardiovascular agent is preferably, for example, a β-blocker (eg, acebutolol, atenolol, bopindolol, labetholol, mepindolol, nadolol, oxprene). Knol, pindolol, propranolol, sotalol), calcium channel blockers (e.g., amlodipine, nifedipine, nisoldipine, nirenedipine, verapamil), potassium channel openers, adenosine, adenosine agonists, ACE inhibitors (e.g. , Captopril, enalapril, nitrate (eg isosorbide dinitrate, isosorbide 5-monitrate, glyceryl trinitrate), diuretics (eg hydrochlorothiazide, Indamide, pyretanide, zipamide), glycosides (eg digoxin, methyldigoxin), thrombolytics (eg tPA), platelet inhibitors (eg leopro), aspirin, dipyrida Moles, Potassium Chloride, Clonidine, Prazo Or adenosine A 3 is a receptor agonist.
    [62] The invention also relates to crystals of formula (I) as first compounds; Glycogen phosphorylase inhibitors as second compounds; And / or optionally comprises a therapeutically effective amount of a composition comprising a pharmaceutical carrier, vehicle or diluent in a therapeutically effective amount.
    [63] Another aspect of the invention provides a mammal (eg, a female or a male human) to (a) a crystal of formula (I) as a first compound; And (b) administering a glycogen phosphorylase inhibitor as the second compound in an amount that provides a therapeutic effect (e.g., to reduce tissue damage that may or may result from ischemia. Including protecting, substantially preventing tissue damage).
    [64] Another aspect of the present invention provides a pharmaceutical composition comprising (a) a crystal of Formula I of a first unit dosage form and a pharmaceutically acceptable carrier, vehicle or diluent; (b) a glycogen phosphorylase inhibitor of a second unit dosage form and a pharmaceutically acceptable carrier, vehicle or diluent; And (c) means for containing said first and second dosage forms, wherein the amount of said first compound and said second compound is an amount that provides a therapeutic effect.
    [65] In the mixed compositions, mixing methods and kits, preferred glycogen phosphorylase inhibitors are as follows:
    [66] 5-Chloro-1H-indole-2-carboxylic acid [(1S)-((R) -hydroxy-dimethylcarbamoyl-methyl) -2-phenyl-ethyl] -amide;
    [67] 5,6-Dichloro-lH-indole-2-carboxylic acid [(1S)-[(R) -hydroxy- (methoxy-methyl-carbamoyl) -methyl] -2-phenyl-ethyl] -amide;
    [68] 5-Chloro-1H-indole-2-carboxylic acid [(1S)-[(R) -hydroxy- (methoxy-methyl-carbamoyl) -methyl] -2-phenyl-ethyl] -amide;
    [69] 5-Chloro-1H-indole-2-carboxylic acid ((1S)-[(R) -hydroxy-[(2-hydroxy-ethyl) -methyl-carbamoyl] -methyl] -2-phenyl-ethyl)- amides;
    [70] 5-Chloro-1H-indole-2-carboxylic acid [(1S)-[(R) -hydroxy- (methyl-pyridin-2-yl-carbamoyl) -methyl] -2-phenyl-ethyl] -amide;
    [71] 5-Chloro-1H-indole-2-carboxylic acid ((1S)-[(R) -hydroxy- [methyl- (2-pyridin-2-yl-ethyl) -carbamoyl] -methyl] -2-phenyl- Ethyl) -amide;
    [72] 5-Chloro-1H-indole-2-carboxylic acid [(1S) -benzyl- (2R) -hydroxy-3- (4-methyl-piperazin-1-yl) -3-oxo-propyl] -amide hydrochloride ;
    [73] 5-Chloro-1H-indole-2-carboxylic acid [(1S) -benzyl- (2R) -hydroxy-3- (3-hydroxy-azetidin-1-yl) -3-oxo-propyl] -amide;
    [74] 5-Chloro-1H-indole-2-carboxylic acid ((1S) -benzyl- (2R) -hydroxy-3-isoxazolidin-2-yl-3-oxo-propyl) -amide;
    [75] 5-Chloro-1H-indole-2-carboxylic acid ((1S) -benzyl- (2R) -hydroxy-3- [1,2] oxazinan-2-yl-3-oxo-propyl) -amide;
    [76] 5-Chloro-1H-indole-2-carboxylic acid [(1S) -benzyl- (2R) -hydroxy-3-((3S) -hydroxy-pyrrolidin-1-yl) -3-oxo-propyl] -amides;
    [77] 5-Chloro-1H-indole-2-carboxylic acid [(1S) -benzyl-3-((3R, 4S) -dihydroxy-pyrrolidin-1-yl)-(2R) -hydroxy-3-oxo -Propyl] -amide;
    [78] 5-Chloro-1H-indole-2-carboxylic acid [(1S) -benzyl-3-((3R, 4S) -dihydroxy-pyrrolidin-1-yl)-(2R) -hydroxy-3-oxo -Propyl] -amide;
    [79] 5-Chloro-1H-indole-2-carboxylic acid ((1S) -benzyl- (2R) -hydroxy-3-morpholin-4-yl-3-oxo-propyl) -amide;
    [80] 5-Chloro-1H-indole-2-carboxylic acid [(1S) -benzyl-2- (3-hydroxyimino-pyrrolidin-1-yl) -2-oxo-ethyl] -amide;
    [81] 5-Chloro-1H-indole-2-carboxylic acid [2- (cis-3,4-dihydroxy-pyrrolidin-1-yl) -2-oxo-ethyl] -amide;
    [82] 5-Chloro-1H-indole-2-carboxylic acid [2-((3S, 4S) -Dihydroxy-pyrrolidin-1-yl) -2-oxo-ethyl] -amide;
    [83] 5-Chloro-1H-indole-2-carboxylic acid [(1S) -benzyl-2- (cis-3,4-dihydroxy-pyrrolidin-1-yl) -2-oxo-ethyl] -amide;
    [84] 5-Chloro-1H-indole-2-carboxylic acid [2- (1,1-dioxo-thiazolidin-3-yl) -2-oxo-ethyl] -amide;
    [85] 5-Chloro-1H-indole-2-carboxylic acid (2-oxo-2-thiazolidin-3-yl-ethyl) -amide;
    [86] 5-Chloro-1H-indole-2-carboxylic acid [(1S)-(4-fluoro-benzyl) -2- (4-hydroxy-piperidin-1-yl) -2-oxo-ethyl] -amide ;
    [87] 5-Chloro-1H-indole-2-carboxylic acid [(1S) -benzyl-2-((3RS) -hydroxy-piperidin-1-yl) -2-oxo-ethyl] -amide;
    [88] 5-Chloro-1H-indole-2-carboxylic acid [2-oxo-2-((1RS) -oxo-1-thiazolidin-3-yl) -ethyl] -amide;
    [89] 5-Chloro-1H-indole-2-carboxylic acid [(1S)-(2-fluoro-benzyl) -2- (4-hydroxy-piperidin-1-yl) -2-oxo-ethyl] -amide ;
    [90] 5-Chloro-1H-indole-2-carboxylic acid [(1S) -benzyl-2-((3S, 4S) -dihydroxy-pyrrolidin-1-yl) -2-oxo-ethyl] -amide;
    [91] 5-Chloro-1H-indole-2-carboxylic acid [(1S) -benzyl-2- (3-hydroxy-azetidin-1-yl) -2-oxo-ethyl] -amide;
    [92] 5-Chloro-1H-indole-2-carboxylic acid [(1S) -benzyl-2- (3-hydroxyimino-azetidin-1-yl) -2-oxo-ethyl] -amide; And
    [93] 5-Chloro-1H-indole-2-carboxylic acid [(1S) -benzyl-2- (4-hydroxyimino-piperidin-1-yl) -2-oxo-ethyl] -amide.
    [94] The invention also relates to crystals of formula I as first compounds; Aldose reductase inhibitors as the second compound; And / or optionally comprises a therapeutically effective amount of a composition comprising a pharmaceutical carrier, vehicle or diluent in a therapeutically effective amount.
    [95] Another aspect of the invention provides a mammal (eg, a female or a male human) to (a) the determination of Formula I as a first compound; And (b) administering an aldose reductase inhibitor with the second compound in an amount that provides a therapeutic effect (e.g., tissue protection that results from ischemia or may result from ischemia). Including, substantially preventing tissue damage).
    [96] Another aspect of the present invention provides a pharmaceutical composition comprising (a) a crystal of Formula I of a first unit dosage form and a pharmaceutically acceptable carrier, vehicle or diluent; (b) an aldose reductase inhibitor of a second unit dosage form and a pharmaceutically acceptable carrier, vehicle or diluent; And (c) means for containing said first and second dosage forms, wherein the amount of said first compound and said second compound is an amount that provides a therapeutic effect.
    [97] In the above mixed compositions, mixing methods and kits, preferred aldose reductase inhibitors are Zopolest: 1-phthalazineacetic acid, 3,4-dihydro-4-oxo-3-[[(5-trifluoromethyl) -2-benzothiazolyl] methyl].
    [98] The invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of the crystal of formula (I) and a pharmaceutically acceptable carrier, diluent or excipient.
    [99] The invention also relates to pharmaceutical compositions for alleviating tissue damage resulting from ischemia, comprising a therapeutically effective amount of the crystal of formula (I) and a pharmaceutically acceptable carrier, diluent or excipient.
    [100] The term "mitigation" includes partial prophylaxis, or prophylaxis which is greater than that resulting from no compound or placebo administration, but substantially less than 100% other than the overall prophylaxis.
    [101] As used herein, the term “injury resulting from ischemia” is directly related to reduced blood flow to tissue, for example due to coagulation or closure of blood vessels that supply blood to a subject tissue, and above all Refers to a condition that causes decreased oxygen transport to tissues, reduced tissue performance, tissue dysfunction and / or necrosis. Or, if blood flow or organ perfusion can be quantitatively appropriate, the oxygen transport capacity of the blood or organ perfusion medium is reduced, for example, in a hypoxic environment, resulting in a decrease in oxygen supply to the tissue followed by a decrease in tissue performance, Tissue dysfunction and / or tissue necrosis may occur.
    [102] As used herein, the terms “treating”, “treat” or “treatment” include prophylactic (eg prophylactic) and conventional treatment.
    [103] "Pharmaceutically acceptable" means that the carrier, diluent, excipient and / or salt is compatible with the other ingredients of the combination and should not be harmful to its recipient.
    [104] As used herein, the expressions "reactive-inert solvent" and "inert solvent" refer to a solvent or mixture of solvents that does not interact in a way that adversely affects the yield of the starting product, reagent, intermediate or product with the desired product. Say.
    [105] It will be appreciated that the compounds of the present invention may exist in radiolabeled form, that is, the compounds may contain one or more atoms having an atomic mass or mass number that is different from the atomic mass or mass number commonly found in nature. . Radioisotopes for hydrogen, carbon, phosphorus, fluorine and chlorine include 3 H, 14 C, 32 P, 35 S, 18 F and 36 Cl, respectively. Compounds of the present invention containing such radioisotopes and / or other radioisotopes of other atoms are also included in the scope of the present invention. Tritium, ie 3 H and carbon-14, ie 14 C radioisotopes, are particularly preferred because of their ease of preparation and detectability. Radiolabelled compounds of formula (I) can generally be prepared by methods known to those skilled in the art. Conveniently, the radiolabeled compound can be prepared by performing the procedures described in the following schemes and / or examples by replacing non-radiolabeled reagents with readily available radiolabeled reagents.
    [106] Other features and advantages will be apparent from the description and claims describing the invention.
    [1] The present invention relates to sodium-hydrogen exchanger type 1 (NHE-1) inhibitors, and in particular to the determination of such inhibitors.
    [107] 1 is a characteristic x-ray powder showing that the anhydrous N- (5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl) -guanidine monomesylate salt of Form A is crystalline It is a diffraction pattern (vertical axis: intensity (CPS); horizontal axis: 2θ (°)).
    [108] FIG. 2 is a characteristic x-ray powder showing that the anhydrous N- (5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl) -guanidine monomesylate salt of Form D is crystalline It is a diffraction pattern (vertical axis: intensity (CPS); horizontal axis: 2θ (°)).
    [109] FIG. 3 is a characteristic x-ray powder diffraction pattern of Hemihydrate N- (5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl) -guanidine monomesylate salt of Form C Vertical axis: intensity (CPS); horizontal axis: 2θ (°).
    [110] In general, the crystals of the present invention can be prepared by methods including methods analogous to those known in the chemical art, in particular in light of the description contained herein. Particular methods of making the crystals of the present invention are provided as further features of the present invention and are illustrated by the following reaction formulae. Other methods are described in the experimental section.
    [111]
    [112] According to Scheme I, optionally p-toluenesulfone under pure conditions for about 1 to about 5 hours at a temperature of about 50 to about 110 ℃, preferably for about 1 to about 2 hours at a temperature of about 70 to about 80 ℃ The compound of formula IV is prepared by mixing a compound of formula II with an excess of a compound of formula III (N, N-dimethyl amide dimethyl acetal) in the presence of an acid catalyst such as an acid. The reaction can also be carried out in ethyl acetate.
    [113] The compound of formula (IV) is cyclized to a compound of formula (V) in an inert solvent such as ethanol at about 50 ° C. to about reflux temperature (78 ° C.) for about 1 to about 4 hours, preferably in the presence of an amine base such as triethylamine. To yield the pyrazole compound of formula VI. The reaction can also be carried out in ethyl acetate and methanol.
    [114] The pyrazole of formula (VI) is conveniently hydrolyzed with a base such as sodium hydroxide in a solvent such as methanol for about 1 to about 5 hours at ambient temperature or preferably at elevated temperature (eg reflux temperature). Prepare the acid.
    [115] In general, the acid of formula (VII) is coupled with guanidine in the presence of a suitable coupling agent. Suitable coupling agents are those which convert carboxylic acids into reactive species to form amide bonds upon reaction with amines.
    [116] The coupling agent may be a reagent that performs the condensation in a single pot process when mixed with carboxylic acid and guanidine. Exemplary coupling agents include 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride-hydroxybenzotriazole (EDC / HOBT), dicyclohexylcarbodiimide / hydroxybenzotriazole (HOBT) , 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) and diethylphosphoryl cyanide. The coupling is carried out in an inert solvent, preferably an aprotic solvent, in the presence of excess guanidine as base for about 1 to about 48 hours at a temperature of about -20 to about 50 ° C. Exemplary solvents include acetonitrile, dichloromethane, dimethylformamide and chloroform or mixtures thereof.
    [117] The coupling agent may be a substance that converts the carboxylic acid into an activated intermediate, which intermediate is isolated and / or produced in the first step and reacts with guanidine in the second step. Examples of such coupling agents and activating intermediates are thionyl chloride or oxalyl chloride to produce acid chloride, cyanuric fluoride to produce acid fluoride, or alkyl chloro such as isobutyl or isopropenyl chloroformate Propanephosphonic acid anhydride (propanephosphonic anhydride, PPA) (with tertiary amine bases) to produce mixed anhydrides with formate or carboxylic acid, or carbonyldiimidazole to produce acylimidazoles. If the coupling agent is oxalyl chloride, it is advantageous to use small amounts of dimethylformamide as co-solvent with other solvents (eg dichloromethane) to promote the production of acid chlorides. The activated acid derivative can be coupled by mixing with an intermediate in a suitable solvent with a suitable base. Suitable solvent / base mixtures are, for example, dichloromethane, dimethylformamide or acetonitrile or mixtures thereof in the presence of excess guanidine as base. Other suitable solvent / base mixtures include water or ((C 1 with a solvent such as dichloromethane, tetrahydrofuran or dioxane) and a base such as sodium, potassium or lithium hydroxide in an amount sufficient to consume the acid liberated in the reaction. -C 5 ) alcohols) or mixtures thereof. The use of such coupling agents and the appropriate choice of solvent and temperature are known to those skilled in the art or can be readily determined from the literature. Such and other exemplary conditions useful for coupling carboxylic acids are described in Houben-Weyl, Vol. XV, part II, E. Wunsch, Ed., G. Theime Verlag, Stuttgart (1974); M. Bodansky, Principles of Peptide Synthesis, Springer-Verlag, Berlin (1984); and The Peptides, Analysis, Synthesis and Biology (ed.E. Gross and J. Meienhofer), vols. 1-5 (Academic Press, NY, 1979-1983).
    [118] In a preferred embodiment, the acid of Formula VII is in excess in an aprotic solvent such as toluene for about 15 minutes to about 2 hours at a temperature of about 60 to about 90 ° C., preferably for about 1 to 2 hours at a temperature of about 75 ° C. Activated with thionyl chloride (eg 3 to 6 equivalents).
    [119] The activated acid chlorides of formula VIII in the resulting tetrahydrofuran anhydrous excess of guanidine hydrochloride and anhydrous tetrahydrochloride were warmed to ambient temperature for the last 1 hour at a temperature of about -20 to about 10 ° C. for about 1 to about 3 hours. Compounds of formula (IX) are prepared by mixing with an aqueous solution of an inorganic base (eg sodium hydroxide) in hydrofuran.
    [120] The compound of formula (IX) is a mixture of an aprotic solvent, preferably acetone and 1-methyl-2-pyrrolidinone, preferably about 90 to about 1 hour at a temperature of about 40 to about 80 ° C. Absence of illumination at about 20 to about 30 ° C. for about 3 to about 6 hours, preferably at about ambient temperature, after mixing with methanesulfonic acid in a mixture of 60% acetone and the remaining 1-methyl-2-pyrrolidinone Under stirring for about 3 hours. Preferably, the solid is reslurried in acetone for about 6 to about 18 hours. Salt formation can also be carried out in tetrahydrofuran. When selecting the solvent, 95% ethanol reslurry is preferred.
    [121] Starting materials and reagents for the aforementioned compounds are also readily available or can be readily synthesized by those skilled in the art using conventional organic synthesis methods. For example, most of the compounds used in the present invention are related to or are derived from compounds found in nature, which are of considerable scientific importance and are commercially needed, and therefore many such compounds are commercially available or documented. It is readily prepared from other commercially available materials by methods reported in or reported in the literature.
    [122] The anhydrous crystalline form (D) of the compounds of the invention is N- (5-cyclopropyl-1-quinolin-5-yl- at a temperature of about 30 to about 60 ° C., preferably at about 50 ° C. for about 1 to about 10 hours. Prepared by mixing an acetone solution of 1H-pyrazole-4-carbonyl) -guanidine and N-methyl pyrrolidinone with methanesulfonic acid, then stirring with cooling typically to a temperature of about 5 ° C., preferably less than 10 ° C. can do. Alternative solvents include organic solvents such as methanol, ethanol and isopropanol. If desired, the product is filtered and dried under vacuum for 24 to 72 hours at 55-60 ° C. until the solvent content is determined to be 0.5% or less by gas chromatography.
    [123] The anhydrous crystalline form (A) of the compounds of the invention is repulped (ie, partially dissolved) from acetone under stirring for about 2 to about 24 hours at a temperature of about 20 to about 25 ° C., preferably at ambient temperature, from the crystalline form (D) Mixed suspension of the prepared material) and then dried to a temperature of about 60 ° C, typically at a temperature of about 30 ° C. Alternative solvents include inert solvents such as acetonitrile, ethyl acetate and tetrahydrofuran.
    [124] The hemihydrate crystalline form (C) of the compound of the present invention is crystalline form (A) of 90% purity (as impurity N- (5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl-guanidine di Easy to contain mesylate salts), and can be prepared by repulping in ethanol or isopropanol / water for about 2 to about 24 hours at a temperature of about 20 to about 25 ° C., preferably at ambient temperature, preferably with stirring. Typically, the range is about 85 to about 95% ethanol and about 5 to about 15% water, with the ratio of 91% to 9% ethanol / water being preferred. Together are organic / water solvents such as acetonitrile, acetone, tetrahydrofuran, ethyl acetate.
    [125] Table I below shows amorphous N- (5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl) -guanidine monomesylate salt; Two anhydrous crystalline forms (A and B); And important properties for the four forms of semi-hydrated crystalline forms.
    [126] shape Melting Point (Starting Point) Property Remark Amorphous Amorphous A; Example 6 228 ℃ Cube Most stable anhydrous form D; Example 5 215 ℃ cube Stable anhydrous mode C; Example 7 140-170 ° C (Desolventization) 209 ° C cube Hemihydrate converts to Form D when dehydrated
    [127] Those skilled in the art will appreciate that the salts of formula (I) may exist in several tautomeric forms. All such tautomeric forms are considered part of this invention. For example, tautomeric forms of the carbonylguanidine residues of the salts of formula (I) are all included in the present invention.
    [128] Any aldose reductase inhibitor can be used as the second compound (active substance) of the invention for mixed therapy. The term aldose reductase inhibitor refers to a compound that inhibits the bioconversion of glucose to sorbitol, promoted by an aldose reductase enzyme. The inhibition is standard assay [J. Malone, "Red Cell Sorbitol, an Indicator of Diabetic Control", Diabetes , 29 : 861-864, 1980, can be readily measured by those skilled in the art. Various aldose reductase inhibitors are known to those skilled in the art.
    [129] An effective amount of aldose reductase inhibitor may be used for the activity of the present invention. Typically, an effective dosage of an aldose reductase inhibitor of the invention is about 0.1 to 100 mg / kg / day in a single dose or divided dose, preferably 0.1 to 20 mg / kg / day in a single dose or divided dose Range.
    [130] Any glycogen phosphorylase inhibitor can be used as the second compound of the present invention. The term glycogen phosphorylase inhibitor refers to any substance or agent, or any mixture of substances and / or agents, that reduces, delays or excludes the enzymatic action of glycogen phosphorylase. The enzymatic action of currently known glycogen phosphorylases is such that the glycogen macromolecule and the inorganic phosphate become glycogen macromolecules with one glucosyl residue shorter (forward of glycogenolysis) than glucose-1-phosphate and the original glycogen macromolecule. It is the decomposition of glycogen by the catalysis of the reaction. The action is readily determined by one skilled in the art according to standard assays. Various such compounds are included in published international patent applications PCT Application Publications WO 96/39384 and WO 96/39385. However, other glycogen phospholiase inhibitors will also be known to those skilled in the art.
    [131] In general, an effective dosage of a glycogen phosphorylase inhibitor to a pharmacologically mixed composition of the present invention, for example, an effective administration for ischemic damage alleviating activity of a mixture containing a glycogen phosphorylase inhibitor compound of the present invention. The amount is in the range of 0.005 to 50 mg / kg / day, preferably 0.01 to 25 mg / kg / day, most preferably 0.1 to 15 mg / kg / day.
    [132] Those skilled in the art will recognize other cardiovascular agents, such as β-blockers (e.g., acebutolol, atenolol, bopindolol, labetholol, mepindolol, nadolol, oxprenol, pindolol, propranolol , Sotalol), calcium channel blockers (e.g., amlodipine, nifedipine, nisoldipine, nirenedipine, verapamil), ACE inhibitors (e.g. captopril, enalapril), nitrates (e.g. iso Sorbide dinitrate, isosorbide 5-monitrate, glyceryl trinitrate), diuretics (e.g. hydrochlorothiazide, indamide, pyretanide, zipamide), glycosides (e.g. For example, digoxin, methyldigoxin), thrombolytics (eg tPA), platelet inhibitors (eg leopro), aspirin, dipyridamole, potassium chloride, clonidine, prazosin, aldose reductase inhibitors (eg For example, Zopolestat) and adenosine A 3 receptor It will be appreciated that the agonist may be used with the crystals of the present invention.
    [133] The crystals of the present invention is caused by the promotion of the sodium / proton (Na + / H +) sodium / proton (Na + / H +) exchange transport system suppresses exchange transport system disorders, for example, to open a disease It is useful as a therapeutic or prophylactic agent for cardiovascular diseases such as arteriosclerosis, hypertension, arrhythmia (e.g., ischemic arrhythmias, arrhythmia due to myocardial infarction, arrhythmias after PTCA or after thrombolysis), angina pectoris, cardiac hypertrophy, Myocardial infarction, heart failure (e.g. congestive heart failure, acute heart failure, hypertrophy, etc.), restenosis after PTCA, shock (e.g. hemorrhagic shock, endotoxin shock, etc.)], kidney disease (e.g. diabetes, diabetic kidney) Conditions, ischemic acute renal failure, etc.), ischaemia or a matrix disorder associated with ischemic reperfusion (eg, myocardial ischemic reperfusion-related disorder, acute renal failure, or coronary artery bypass graft (CABG) surgery, vascular surgery, organ transplantation, non-heart Disorders induced by surgery or surgical treatments such as percutaneous coronary angioplasty (PTCA)], cerebrovascular diseases (eg, ischemic stroke, hemorrhagic stroke, etc.), cerebral ischemic disorders (eg, disorders associated with cerebral infarction, Disorder or brain edema caused after stroke due to sequelae). The crystals of the present invention can also be used as a medicament for myocardial protection during coronary artery bypass graft (CABG) surgery, vascular surgery, percutaneous percutaneous coronary angioplasty (PTCA), organ transplantation or non-cardiac surgery.
    [134] Preferably, the crystals of the present invention are agents for myocardial protection before coronary artery bypass graft (CABG) surgery, vascular surgery, percutaneous cervical coronary angioplasty (PTCA), before organ transplantation or non-cardiac surgery, during or after surgery. Can be used as
    [135] Preferably, the crystals of the present invention can be used as a medicament for myocardial protection in patients with cardiac ischemia (acute coronary syndrome, eg myocardial infarction or unstable angina) or cerebral ischemic conditions (eg stroke). .
    [136] Preferably, the crystals of the present invention comprise patients who have been diagnosed with coronary heart disease (eg, prior myocardial infarction or unstable angina) or are at high risk for myocardial infarction (eg, age 65 and older and coronary heart disease). Two or more risk factors for) can be used as a medicament for long-term myocardial protection in patients.
    [137] In addition, the crystals of the present invention are noteworthy due to their strong inhibitory effect on the proliferation of cells, for example, the proliferation of fibroblasts and the proliferation of smooth muscle cells of blood vessels. For this reason, the crystals of the present invention are useful therapeutic agents for use in diseases in which cell proliferation is the main or secondary cause, and therefore, as anti-atherosclerosis, and late diabetic complications, cancer diseases, fibrotic diseases, such as lungs As a medicament for fibrosis, liver fibrosis or kidney fibrosis, glomerulonephritis, organ hypertrophy or hyperplasia, in particular, hyperplasia or hyperplasia of the prostate gland, pulmonary fibrosis, diabetic complications or recurrent stenosis after PTCA, or disease caused by endothelial cell damage Can be used.
    [138] Utility of the present invention as a medicament in the treatment of a disease as described herein above in a mammal (e.g. human), e.g. myocardial protection in patients undergoing cardiac or cerebral ischemic status during surgery or myocardial protection Protection, or long-term cardioprotection in patients diagnosed with coronary kidney disease, is evidenced by the activity of the crystals of the present invention in conventional preclinical cardioprotection assays (in vivo assays described in Klein, H. et al., Circulation) . , 92 : 912-917, 1995; isolated cardiac analysis is described in Scholz, W. et al., Cardiovascular Research , 29 : 260-268, 1995; arrhythmia analysis is described in Yasutake M. et al., Am . J. Physiol ., 36 : H2430-H2440, 1994; for NMR analysis, see Kolke et al., J. Thorac. Cardiovasc. Surg ., 112 : 765-775, 1996. The assays also provide a means by which the activity of the crystals of the present invention can be compared with that of other known crystals. The results of this comparison are useful for determining dosage levels for the treatment of these diseases in mammals, including humans.
    [139] Administering the crystals of the present invention may be by any method that preferentially delivers to the tissue of interest (eg, liver and / or cardiac tissue). Such methods include the oral route, parenteral, intraduodenal route, and the like. In general, the crystals of the present invention are administered in a single (eg, once daily) dose or in multiple doses, or via constant infusion in, for example, isotonic saline.
    [140] The crystals of the present invention can be used in any tissue (eg, heart, brain, lung, kidney, liver, for example) that may be susceptible to ischemia / reperfusion injury as a result of an ischemic state (eg myocardial infarction). Useful to mitigate or minimize damage directly to the digestive tract, skeletal muscle, and retina. Thus, the active compound is used to prevent, i.e., prematurely or prophylactically, prevent tissue damage (eg myocardial tissue) in patients at risk for ischemia (eg myocardial ischemia). This is useful for preventing or preventing.
    [141] In general, the crystals of the present invention are administered orally or parenterally (eg, intravenously, intramuscularly, subcutaneously or spinally). For example, topical administration may also be mentioned when the patient has a gastrointestinal disorder or when it is best to apply the drug to the surface of a tissue or organ as determined by the attending physician.
    [142] The dosage and time of administration of the crystal will of course depend on the subject being treated, the severity of the pain, the mode of administration and the judgment of the prescribing physician. Thus, due to the case-by-patient variability, the dosages shown below are only guidelines and can be titrated with a dose of drug to achieve a treatment which the physician considers appropriate for the patient. Given the degree of treatment desired, the physician must weigh a variety of factors, such as the age of the patient, the presence of an existing disease, as well as the presence of other diseases (eg cardiovascular disease).
    [143] Thus, for example, in one mode of administration, the determination of the present invention may be performed immediately before or after heart surgery (eg, within 24 hours before surgery) at risk of myocardial ischemia, during or after heart surgery (eg, after surgery). Within 24 hours). In a particularly preferred manner, the infusion is administered at a loading dose of about 1 to about 300 mg for about 1 minute to about 1 hour prior to surgery, followed by, for example, about 2 to about 7 days of postoperative treatment A constant infusion of about 1 to about 100 mg / kg / day is performed during the remaining preoperative, intraoperative and postoperative periods. The compounds of the present invention can also be administered in a daily manner over a long period of time.
    [144] An effective amount of the crystal of the invention is used to protect ischemia. Preferred dosages are from about 0.001 to about 100 mg / kg / day of crystal of the present invention. A particularly preferred dosage is about 0.01 to 50 mg / kg / day of the crystal of the present invention.
    [145] The crystals of the invention are generally administered in the form of a pharmaceutical composition comprising one or more crystals of the invention with a pharmaceutically acceptable vehicle or diluent. Thus, the crystals of the present invention can be administered separately or together in any conventional oral, parenteral, rectal or transdermal dosage form.
    [146] For oral administration, the pharmaceutical compositions may be in the form of solutions, suspensions, tablets, pills, capsules, powders and the like. Tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate, together with binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia, can be used in various disintegrants, for example starches, preferably Used with potato or tapioca starch and certain silicate complexes. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tableting purposes. Solid compositions of a similar type are also used as fillers in soft and hard filled gelatin capsules; Preferred materials in this regard also include lactose or lactose and high molecular weight polyethylene glycols. Where aqueous suspensions and / or elixirs are preferred for oral administration, the compounds of the present invention may be used in various sweeteners, flavorings, colorings, emulsifiers and / or suspending agents, as well as diluents such as water, ethanol, propylene glycol, glycerin and various similar mixtures thereof. It can be mixed with.
    [147] For parenteral administration, for example, solutions in sesame oil or peanut oil or solutions in aqueous propylene glycol, as well as sterile aqueous solutions of the corresponding water-soluble salts can be used. The aqueous solution can be suitably buffered if necessary, and the liquid diluent is first made isotonic with sufficient saline or glucose. The aqueous solution is particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection purposes. In this regard, the sterile aqueous media used are all readily obtained by standard techniques known to those skilled in the art.
    [148] For transdermal (eg topical) administration, dilute sterile aqueous solutions or partial aqueous solutions (typically from about 0.1 to 5% concentration) or similar aqueous solutions are prepared.
    [149] Methods of preparing various pharmaceutical compositions using specific amounts of active ingredients are known to those skilled in the art or will be apparent in light of the present disclosure. See Remington's Pharmaceutical Sciences , Mack Publishing Company, Easter, Pa., 15th Edition, 1975 for examples of methods of preparing pharmaceutical compositions.
    [150] The pharmaceutical composition according to the present invention may contain, for example, 0.0001 to 95% of the compound (s) of the present invention. In any case, the composition or formulation to be administered will contain an amount of the crystal (s) according to the invention in an amount effective to treat the disease / symptom of the subject to be treated.
    [151] Crystals of the invention will generally be administered in a convenient formulation. The following formulation examples are merely illustrative and do not limit the scope of the invention.
    [152] In the following formulations, "active ingredient" means the compound (s) (crystal (s)) of the present invention.
    [153] Formulation 1: Gelatin Capsule
    [154] Hard gelatine capsules are prepared using the following ingredients:
    [155] ingredient Amount (mg / capsules) Active ingredient 0.25-100 Starch (NF) 0-650 Starch (liquid powder) 0-50 Silicone Fluid (350 Centistokes) 0-15
    [156] Tablet formulations are prepared using the following ingredients:
    [157] Formulation 2: Tablet
    [158] ingredient Amount (mg / tablet) Active ingredient 0.25-100 Microcrystalline cellulose 200-650 Fumed silicon dioxide 10-650 Stearic acid 5-15
    [159] The tablets are prepared by blending and pressing the ingredients.
    [160] Alternatively, tablets containing 0.25 to 100 mg of active ingredient, respectively, are prepared as follows:
    [161] Formulation 3: Tablet
    [162] ingredient Amount (mg / tablet) Active ingredient 0.25-100 Starch 45 Microcrystalline cellulose 35 Polyvinylpyrrolidone (as a 10% solution in water) 4 Sodium carboxymethyl cellulose 4.5 Magnesium stearate 0.5 talc One
    [163] The active ingredient, starch and cellulose are passed through a US 45 mesh sieve and mixed thoroughly. A solution of polyvinylpyrrolidone is mixed with the resulting powder, which is then passed through a US 14 mesh sieve. The granules so produced are dried at 50-60 ° C. and passed through a US 18 mesh sieve. The sodium carboxymethyl starch, magnesium stearate and talc, which were previously passed through a US 60 mesh sieve, are then added to the granules, mixed and compressed on a tableting machine to obtain a tablet.
    [164] Suspensions each containing 0.25-100 mg of active ingredient per 5 ml dose are prepared as follows:
    [165] Formulation 4: Suspension
    [166] ingredient Volume (mg / 5 ml) Active ingredient 0.25-100 mg Sodium carboxymethyl cellulose 50 mg syrup 1.25 mg Benzoic acid solution 0.10 ml Spices Reference coloring agent Reference Purified water to be 5 ml
    [167] The active ingredient is passed through a US 45 mesh sieve and mixed with sodium carboxymethyl cellulose and syrup to produce a soft paste. The benzoic acid solution, fragrance and colorant are diluted with some water and added with stirring. Then sufficient water is added to make the required volume.
    [168] An aerosol solution containing the following ingredients is prepared:
    [169] Formulation 5: Aerosol
    [170] ingredient Volume (% by weight) Active ingredient 0.25 ethanol 25.75 Propellant 22 (chlorodifluoromethane) 74.00
    [171] The active ingredient is mixed with ethanol and the mixture is added to a portion of the propellant 22 cooled to 30 ° C. and transferred to the filling device. The required amount is then supplied to the stainless steel vessel and diluted with the remaining propellant. Subsequently, the valve unit is attached to the container.
    [172] Suppositories are prepared as follows:
    [173] Formulation 6: Suppositories
    [174] ingredient Amount (mg / suppository) Active ingredient 250 Saturated Fatty Acid Glyceride 2,000
    [175] The active ingredient is passed through a US 60 mesh sieve and suspended in pre-melted saturated fatty acid glycerides using minimal heat requirements. The mixture is then poured into suppository molds of nominal 2 g capacity and cooled.
    [176] Intravenous formulations are prepared as follows:
    [177] Formulation 7: Intravenous Solution
    [178] ingredient amount Active ingredient 25 mg Isotonic saline 1,000 ml
    [179] The solution of the above components is administered intravenously to the patient.
    [180] The active ingredient may also be a mixture of drugs.
    [181] Example 1
    [182] Methyl-3-cyclopropyl-3-oxopropanoate (15 g, 106 mmol, 1 equiv) and N, N-dimethylformamide dimethylacetal (14.7 mL, 111 mmol, 1.05 equiv) at 75 ° C. under N 2 Heated for 1.5 hours. The orange oil was then cooled to room temperature. TLC analysis (1: 1 EtOAc / hexanes) showed no starting material and slightly less polar and most more polar (methyl-3-cyclopropyl-2-dimethyleneamino-3-oxopropanoate ). The crude mixture was used as such in the next step.
    [183] Example 2
    [184] Crude methyl-3-cyclopropyl-2-dimethyleneamino-3-oxopropanoate (20.9 g, 106 mmol, 1.07 equiv) was diluted with ethanol (250 mL). Triethylamine (34.4 mL, 247 mmol, 2.5 equiv) followed by quinolin-5-yl-hydrazine (22.9 g, 98.6 mmol, 1 equiv) was added sequentially. Weak gas evolution was observed upon addition of quinolin-5-yl-hydrazine. The resulting heterogeneous mixture was heated to reflux (78 ° C.) under N 2 for 2 hours. The mixture became homogeneous and very thick after heating for about 3 minutes. The mixture was then cooled to room temperature. TLC analysis (1: 1 EtOAc / hexanes) showed a slightly less polar droplet (5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carboxylic acid methyl ester). APCI mass spectra also indicated the desired product. Then the reaction mixture was concentrated. To the residue was added EtOAc (300 mL) and 0.1 N HCl (400 mL). The emulsion was stirred for 10 minutes at room temperature and then filtered through a pad of Celite® to remove solids. The resulting biphasic mixture was separated. The aqueous layer was extracted with EtOAc (2 x 300 mL). The combined organic layers were washed with 0.1 N HCl (2 × 300 mL), dried over sodium sulfate and concentrated. To the residue was added hot isopropyl ether (80 mL). The cloudy solution was stirred for 2 minutes. Hexane (125 mL) was then added. The solid was granulated overnight. The solids were collected by filtration to give the product, 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carboxylic acid methyl ester, as a yellowish orange powder (20.8 g, 72% over two steps). It was.
    [185] Example 3
    [186] To a solution of 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carboxylic acid methyl ester (20 g, 68.2 mmol, 1 equiv) in MeOH (120 mL) 2N NaOH (54.5 mL, 109) Mmol, 1.6 equiv) was added. The resulting solution was heated to reflux (65 ° C.) under N 2 for 1.5 h and then cooled to room temperature. TLC analysis (1: 1 EtOAc / hexanes) showed no starting material. Methanol was removed under vacuum with mild heating (35 ° C.) on a rotary evaporator. The basic aqueous layer was then washed with EtOAc (2 x 100 mL). The resulting basic aqueous layer was slowly acidified to pH 1-2 with concentrated HCl. The product precipitated during acidification. The slurry was stirred at rt for 0.5 h and then the solids were collected by filtration. The solid was washed with 1 N HCl (2 × 25 mL) and dried to give the acid as a light brown solid (18.8 g, 99%).
    [187] Example 4
    [188] Thionyl chloride (32.6 mL, 448) in a stirred suspension of 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carboxylic acid (25 g, 89.5 mmol, 1 equiv) in toluene (250 mL) Mmol, 5 equivalents) was added. The resulting suspension was heated at 75 ° C. for 1.5 h under N 2 . The reaction mixture remained heterogeneous throughout. Solid acid chloride was collected by filtration. The brown solid was washed with toluene (3 x 50 mL) and dried under vacuum.
    [189] The suspension of acid chloride in THF (250 mL) was cooled to 0 ° C. A solution of guanidine hydrochloride (17.1 g, 179 mmol, 2 equiv) and 2 N NaOH (224 mL, 448 mmol, 5 equiv) was added over 5-10 minutes via a dropping funnel under N 2 . The reaction became homogeneous and biphasic upon addition of a basic aqueous solution of guanidine. The mixture was stirred with warming slowly to room temperature at 0 ° C. for 1 hour and then further stirred at room temperature for 1 hour. TLC analysis (4: 1 dichloromethane / methanol) resulted in more polar droplets (N- (5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl) -guanidine) and trace starting The presence of the material acid is indicated. The product was precipitated by removing THF under vacuum with mild heating (35 ° C.). The product was granulated by stirring the aqueous layer at room temperature for 1 hour. The solid was collected by filtration, washed with water (2 x 50 mL) and dried. The color of the product ranges from gray to medium brown. The batch was medium brown. Reslurried in MeOH (125 mL) for 30 min to give the desired product N- (5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl) -guanidine (22.6 g, 79% yield) Was obtained as a light brown solid.
    [190] Example 5
    [191] N- (5-cyclopropyl-1-quinolin-5-yl-1H-pyrazol-4-carbonyl) -guanidine (3.08 kg, 70.5, 9.61 mmol, 1 equiv) was suspended in acetone (30.8 kg). 1-methyl-2-pyrrolidinone (12.3 kg) was added to obtain a homogeneous solution. The preceding material was rinsed further with 4.8 kg of acetone (spectrum glass filtration). The reaction solution was warmed to 50 ° C. A solution of methanesulfonic acid (0.83 kg, 8.65 mol, 0.9 equiv) in acetone (8.3 kg) was added while maintaining the temperature below 55 ° C. The resulting slurry was stirred at 50 ° C. for 1-2 hours, then cooled and filtered. The filter cake was rinsed with acetone and dried to give N- (5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl) -guanidine monomesylate salt (3.24 kg, 81%) as gray Obtained as a solid. The product was then dried under vacuum to yield anhydrous crystals (form D) having the following properties: microscopy: birefringent plate / cube, crystallinity: completely crystalline, hygroscopic: non-hygroscopic, appearance: gray crystalline solid Melting point: 215 ° C. (starting temperature at 5 ° C./min). X-ray diffraction d-spacings are shown in Tables IIa and IIb below.
    [192] Form D Anode: CU-Wavelength 1: 1.54056, Wavelength 2: 1.54439 (Relative Strength: 0.500) Range # 1-Coupling: 3.000 to 40.000, Step Size: 0.040, Step Time: 1.00, Smooth Width: 0.300, Threshold: 1.0 d (A)l (relative value)d (A)l (relative value)d (A)l (relative value) 27.246712.85.990916.04.0087426.0 23.730932.25.6352525.53.928396.2 16.16249100.05.4716411.53.6962910.3 13.229891.75.2769939.93.604287.4 11.971801.55.1706418.33.5564023.3 8.705231.25.0366622.43.470399.6 8.069406.94.8180224.03.4087212.2 7.825137.24.4674817.03.3501112.3 7.252058.44.1729462.73.265033.6 6.7067010.24.0661310.7
    [193] Form D Anode: CU-Wavelength 1: 1.54056, Wavelength 2: 1.54439 (Relative Strength: 0.500) Range # 1-Coupling: 3.000 to 40.000, Step Size: 0.040, Step Time: 1.00, Smooth Width: 0.300, Threshold: 1.0 d (A)l (relative value)d (A)l (relative value) 3.219535.22.583672.4 3.136864.72.555402.3 3.093152.52.513953.1 2.9818110.22.467502.4 2.910784.22.403422.1 2.855273.62.369762.5 2.733173.42.334684.3 2.682095.62.305202.6 2.644232.62.266521.5
    [194] Example 6
    [195] 123 L (3.8 vol) of acetone was added to 3.165 kg of the product of Example 5. The slurry was stirred at rt for 20 h. The slurry was filtered and the solid was dried at 50 ° C. The product was anhydrous crystals (form A) (3.145 kg, 99%) having the following properties: Microscopic examination: Birefringent Cube, Crystallinity: Fully Crystalline, Hygroscopic: Non-Hygroscopic, Appearance: White crystalline solid, Melting Point: 228 ° C (starting temperature at 5 ° C / min). X-ray diffraction d-spacings are shown in Tables IIIa and IIIb below.
    [196] Form A Anode: CU-Wavelength 1: 1.54056, Wavelength 2: 1.5443 (Relative Strength: 0.500) Range # 1-Coupling: 3.000 to 40.000, Step Size: 0.040, Step Time: 1.00, Smooth Width: 0.300, Threshold: 1.0 d (A)l (relative value)d (A)l (relative value)d (A)l (relative value) 12.7880575.65.9848614.54.409689.1 10.119840.95.748177.74.2607735.9 9.549981.05.4416225.83.99060100.0 8.4810610.55.174676.23.701019.6 8.0605932.34.8869419.83.5689510.0 7.400353.74.805056.43.4564718.9 6.908919.94.7132912.33.395994.3 6.784587.14.641638.33.2850114.3 6.3944137.14.4748517.23.196738.2
    [197] Form A Anode: CU-Wavelength 1: 1.54056, Wavelength 2: 1.5443 (Relative Strength: 0.500) Range # 1-Coupling: 3.000 to 40.000, Step Size: 0.040, Step Time: 1.00, Smooth Width: 0.300, Threshold: 1.0 d (A)l (relative value)d (A)l (relative value) 3.1336028.12.647493.2 3.058197.22.586185.7 2.988636.22.558743.4 2.925594.52.510583.5 2.900633.72.441543.9 2.873773.52.377042.5 2.804123.02.319513.9 2.679415.62.296663.1
    [198] Example 7
    [199] 0.25 g of Sample A of approximately 90% pure (easy to contain N- (5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl) -guanidine dimesylate as impurity) To 1 ml ethanol (EtOH contained about 9% water) was added. The slurry was stirred at room temperature for about 21 hours. The slurry was then filtered and the solid was dried under vacuum at 50 ° C. for 90 minutes to give hemihydrate crystals (form C) having the following properties: microscopy: birefringent cube, crystallinity: fully crystalline, appearance: creamy Crystalline solid, melting point: 140 to 170 ° C. (desolvation), 209 ° C. (starting temperature at 5 ° C./min). X-ray diffraction d-spacings are shown in Tables IVa and IVb below.
    [200] Form C Anode: CU-Wavelength 1: 1.54056, Wavelength 2: 1.54439 (Relative Strength: 0.500) Range # 1-Coupling: 3.000 to 40.000, Step Size: 0.040, Step Time: 1.00, Smooth Width: 0.300, Threshold: 1.0 d (A)l (relative value)d (A)l (relative value)d (A)l (relative value) 23.843633.06.203708.04.3982321.9 12.7528526.75.9904716.84.2586215.7 11.420665.65.7442112.14.111406.0 10.47264100.05.4334417.73.9895078.6 9.132651.95.182818.53.815568.6 8.4698618.75.076214.83.7062213.3 8.0402535.74.8901813.83.604288.4 7.374625.94.788219.93.5641115.8 6.8980012.84.7122811.13.5063414.5 6.742437.24.6460411.83.4564322.6 6.3823513.64.4702914.63.3805310.5
    [201] Form C Anode: CU-Wavelength 1: 1.54056, Wavelength 2: 1.54439 (Relative Strength: 0.500) Range # 1-Coupling: 3.000 to 40.000, Step Size: 0.040, Step Time: 1.00, Smooth Width: 0.300, Threshold: 1.0 d (A)l (relative value)d (A)l (relative value) 3.2780915.22.679075.1 3.1307517.62.633334.0 3.098269.42.585306.0 3.050346.92.508193.7 2.983507.92.466206.4 2.918685.52.439724.6 2.871994.62.386774.7 2.813595.52.337084.3 2.743835.02.314203.9 2.709663.22.291623.3
    权利要求:
    Claims (38)
    [1" claim-type="Currently amended] Crystalline Form Of Salts Having Formula I:
    Formula I

    [2" claim-type="Currently amended] The method of claim 1,
    The crystal which is N- (5-cyclopropyl-1-quinolin-5-yl-1H-pyrazol-4-carbonyl) -guanidine monomesylate salt.
    [3" claim-type="Currently amended] The method of claim 1,
    A crystal which is anhydrous N- (5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl) -guanidine monomesylate salt.
    [4" claim-type="Currently amended] The method of claim 1,
    Anhydrous N- (5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl) -guanidine monomesylate salt with X-ray diffraction patterns of Tables IIa and IIb (crystalline Form D) Phosphorus determination:
    TABLE IIa
    Form D Anode: CU-Wavelength 1: 1.54056, Wavelength 2: 1.54439 (Relative Strength: 0.500) Range # 1-Coupling: 3.000 to 40.000, Step Size: 0.040, Step Time: 1.00, Smooth Width: 0.300, Threshold: 1.0 d (A) l (relative value) d (A) l (relative value) d (A) l (relative value) 27.24671 2.8 5.99091 6.0 4.00874 26.0 23.73093 2.2 5.63525 25.5 3.92839 6.2 16.16249 100.0 5.47164 11.5 3.69629 10.3 13.22989 1.7 5.27699 39.9 3.60428 7.4 11.97180 1.5 5.17064 18.3 3.55640 23.3 8.70523 1.2 5.03666 22.4 3.47039 9.6 8.06940 6.9 4.81802 24.0 3.40872 12.2 7.82513 7.2 4.46748 17.0 3.35011 12.3 7.25205 8.4 4.17294 62.7 3.26503 3.6 6.70670 10.2 4.06613 10.7
    TABLE IIb
    Form D Anode: CU-Wavelength 1: 1.54056, Wavelength 2: 1.54439 (Relative Strength: 0.500) Range # 1-Coupling: 3.000 to 40.000, Step Size: 0.040, Step Time: 1.00, Smooth Width: 0.300, Threshold: 1.0 d (A) l (relative value) d (A) l (relative value) 3.21953 5.2 2.58367 2.4 3.13686 4.7 2.55540 2.3 3.09315 2.5 2.51395 3.1 2.98181 10.2 2.46750 2.4 2.91078 4.2 2.40342 2.1 2.85527 3.6 2.36976 2.5 2.73317 3.4 2.33468 4.3 2.68209 5.6 2.30520 2.6 2.64423 2.6 2.26652 1.5
    [5" claim-type="Currently amended] The method of claim 1,
    Anhydrous N- (5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl) -guanidine monomesylate salt with X-ray diffraction patterns of Tables IIIa and IIIb (crystalline Form A) Phosphorus determination:
    TABLE IIIa
    Form A Anode: CU-Wavelength 1: 1.54056, Wavelength 2: 1.5443 (Relative Strength: 0.500) Range # 1-Coupling: 3.000 to 40.000, Step Size: 0.040, Step Time: 1.00, Smooth Width: 0.300, Threshold: 1.0 d (A) l (relative value) d (A) l (relative value) d (A) l (relative value) 12.78805 75.6 5.98486 14.5 4.40968 9.1 10.11984 0.9 5.74817 7.7 4.26077 35.9 9.54998 1.0 5.44162 25.8 3.99060 100.0 8.48106 10.5 5.17467 6.2 3.70101 9.6 8.06059 32.3 4.88694 19.8 3.56895 10.0 7.40035 3.7 4.80505 6.4 3.45647 18.9 6.90891 9.9 4.71329 12.3 3.39599 4.3 6.78458 7.1 4.64163 8.3 3.28501 14.3 6.39441 37.1 4.47485 17.2 3.19673 8.2
    TABLE IIIb
    Form A Anode: CU-Wavelength 1: 1.54056, Wavelength 2: 1.5443 (Relative Strength: 0.500) Range # 1-Coupling: 3.000 to 40.000, Step Size: 0.040, Step Time: 1.00, Smooth Width: 0.300, Threshold: 1.0 d (A) l (relative value) d (A) l (relative value) 3.13360 28.1 2.64749 3.2 3.05819 7.2 2.58618 5.7 2.98863 6.2 2.55874 3.4 2.92559 4.5 2.51058 3.5 2.90063 3.7 2.44154 3.9 2.87377 3.5 2.37704 2.5 2.80412 3.0 2.31951 3.9 2.67941 5.6 2.29666 3.1
    [6" claim-type="Currently amended] The method of claim 1,
    N- (5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl) -guanidine monomesylate hemihydrate.
    [7" claim-type="Currently amended] Acetone solution of N- (5-cyclopropyl-1-quinolin-5-yl-1H-pyrazol-4-carbonyl) -guanidine and N-methyl pyrrolidinone was methanesulfone at a temperature of about 30 to about 60 ° C. A process for preparing the crystals of claim 4 comprising cooling with a temperature of about ambient to about 35 ° C. after mixing with acid.
    [8" claim-type="Currently amended] A process for preparing the crystal of claim 5 comprising repulping anhydrous crystals of Form D having the X-ray diffraction patterns of Tables IIa and IIb below in acetone at a temperature of about 20 to about 25 ° C .:
    TABLE IIa
    Form D Anode: CU-Wavelength 1: 1.54056, Wavelength 2: 1.54439 (Relative Strength: 0.500) Range # 1-Coupling: 3.000 to 40.000, Step Size: 0.040, Step Time: 1.00, Smooth Width: 0.300, Threshold: 1.0 d (A) l (relative value) d (A) l (relative value) d (A) l (relative value) 27.24671 2.8 5.99091 6.0 4.00874 26.0 23.73093 2.2 5.63525 25.5 3.92839 6.2 16.16249 100.0 5.47164 11.5 3.69629 10.3 13.22989 1.7 5.27699 39.9 3.60428 7.4 11.97180 1.5 5.17064 18.3 3.55640 23.3 8.70523 1.2 5.03666 22.4 3.47039 9.6 8.06940 6.9 4.81802 24.0 3.40872 12.2 7.82513 7.2 4.46748 17.0 3.35011 12.3 7.25205 8.4 4.17294 62.7 3.26503 3.6 6.70670 10.2 4.06613 10.7
    TABLE IIb
    Form D Anode: CU-Wavelength 1: 1.54056, Wavelength 2: 1.54439 (Relative Strength: 0.500) Range # 1-Coupling: 3.000 to 40.000, Step Size: 0.040, Step Time: 1.00, Smooth Width: 0.300, Threshold: 1.0 d (A) l (relative value) d (A) l (relative value) 3.21953 5.2 2.58367 2.4 3.13686 4.7 2.55540 2.3 3.09315 2.5 2.51395 3.1 2.98181 10.2 2.46750 2.4 2.91078 4.2 2.40342 2.1 2.85527 3.6 2.36976 2.5 2.73317 3.4 2.33468 4.3 2.68209 5.6 2.30520 2.6 2.64423 2.6 2.26652 1.5
    [9" claim-type="Currently amended] A process for preparing the crystal of claim 6 comprising repulping anhydrous crystals of Form A having the X-ray diffraction patterns of Tables IIIa and IIIb below in ethanol or isopropanol / water at a temperature of about 20 to about 25 ° C.
    TABLE IIIa
    Form A Anode: CU-Wavelength 1: 1.54056, Wavelength 2: 1.5443 (Relative Strength: 0.500) Range # 1-Coupling: 3.000 to 40.000, Step Size: 0.040, Step Time: 1.00, Smooth Width: 0.300, Threshold: 1.0 d (A) l (relative value) d (A) l (relative value) d (A) l (relative value) 12.78805 75.6 5.98486 14.5 4.40968 9.1 10.11984 0.9 5.74817 7.7 4.26077 35.9 9.54998 1.0 5.44162 25.8 3.99060 100.0 8.48106 10.5 5.17467 6.2 3.70101 9.6 8.06059 32.3 4.88694 19.8 3.56895 10.0 7.40035 3.7 4.80505 6.4 3.45647 18.9 6.90891 9.9 4.71329 12.3 3.39599 4.3 6.78458 7.1 4.64163 8.3 3.28501 14.3 6.39441 37.1 4.47485 17.2 3.19673 8.2
    TABLE IIIb
    Form A Anode: CU-Wavelength 1: 1.54056, Wavelength 2: 1.5443 (Relative Strength: 0.500) Range # 1-Coupling: 3.000 to 40.000, Step Size: 0.040, Step Time: 1.00, Smooth Width: 0.300, Threshold: 1.0 d (A) l (relative value) d (A) l (relative value) 3.13360 28.1 2.64749 3.2 3.05819 7.2 2.58618 5.7 2.98863 6.2 2.55874 3.4 2.92559 4.5 2.51058 3.5 2.90063 3.7 2.44154 3.9 2.87377 3.5 2.37704 2.5 2.80412 3.0 2.31951 3.9 2.67941 5.6 2.29666 3.1
    [10" claim-type="Currently amended] The method of claim 9,
    The range is about 85 to about 95% ethanol and about 5 to about 15% water.
    [11" claim-type="Currently amended] [5-cyclopropyl-1- (quinolin-5-yl) -1H-pyrazole-4-carbonyl] guanidine monomesylate hemihydrate.
    [12" claim-type="Currently amended] From ischemia or hypoxia, comprising administering to a mammal in need thereof a pharmaceutical composition comprising a crystal of claim 1 and a pharmaceutically acceptable carrier, vehicle or diluent in a therapeutically effective amount. How to alleviate the caused tissue damage.
    [13" claim-type="Currently amended] The method of claim 12,
    The tissue is heart, brain, liver, kidney, lung, digestive tract, skeletal muscle, spleen, pancreas, nerve, spinal cord, retinal tissue, blood vessel or intestinal tissue.
    [14" claim-type="Currently amended] The method of claim 13,
    The amount of crystal of formula (I) is from about 0.01 to about 10 mg / kg / day.
    [15" claim-type="Currently amended] The method of claim 14,
    The mammal is a female or male human.
    [16" claim-type="Currently amended] The method of claim 15,
    The tissue is cardiac tissue.
    [17" claim-type="Currently amended] The method of claim 15,
    Wherein said tissue is brain tissue.
    [18" claim-type="Currently amended] The method of claim 15,
    Wherein said tissue is liver tissue.
    [19" claim-type="Currently amended] The method of claim 15,
    Wherein said tissue is kidney tissue.
    [20" claim-type="Currently amended] The method of claim 15,
    Wherein said tissue is lung tissue.
    [21" claim-type="Currently amended] The method of claim 15,
    Wherein said tissue is digestive tract tissue.
    [22" claim-type="Currently amended] The method of claim 15,
    And said tissue is skeletal muscle tissue.
    [23" claim-type="Currently amended] The method of claim 15,
    Wherein said tissue is a spleen tissue.
    [24" claim-type="Currently amended] The method of claim 15,
    Wherein said tissue is pancreatic tissue.
    [25" claim-type="Currently amended] The method of claim 15,
    Wherein said tissue is retinal tissue.
    [26" claim-type="Currently amended] The method of claim 15,
    Method of prophylactic administration of a compound.
    [27" claim-type="Currently amended] The method of claim 15,
    Method of administering the pharmaceutical composition before surgery.
    [28" claim-type="Currently amended] The method of claim 15,
    Method of administering the pharmaceutical composition before cardiac surgery.
    [29" claim-type="Currently amended] The method of claim 15,
    Method of administering the pharmaceutical composition during surgery.
    [30" claim-type="Currently amended] The method of claim 15,
    Method of administering the pharmaceutical composition during cardiac surgery.
    [31" claim-type="Currently amended] The method of claim 15,
    A method of administering a pharmaceutical composition within 24 hours after surgery.
    [32" claim-type="Currently amended] The method of claim 15,
    Method of administering the pharmaceutical composition within 24 hours after cardiac surgery.
    [33" claim-type="Currently amended] The method of claim 15,
    Tissue damage resulting from ischemia is an ischemic injury and occurs during organ transplantation.
    [34" claim-type="Currently amended] The method of claim 15,
    A method of administering the pharmaceutical composition to prevent myocardial ischemic injury during surgery.
    [35" claim-type="Currently amended] A pharmaceutical composition comprising a therapeutically effective amount of the crystal of claim 1 and a pharmaceutically acceptable carrier, vehicle or diluent.
    [36" claim-type="Currently amended] A pharmaceutical composition for reducing tissue damage resulting from ischemia or hypoxia, comprising a therapeutically effective amount of the crystal of claim 1 and a pharmaceutically acceptable carrier, vehicle or diluent.
    [37" claim-type="Currently amended] The method of claim 15,
    A method of administering the pharmaceutical composition before, during and after surgery.
    [38" claim-type="Currently amended] The method of claim 15,
    A method of administering the pharmaceutical composition prior to, during and after cardiac surgery.
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    同族专利:
    公开号 | 公开日
    HK1048472A1|2005-09-16|
    WO2001030759A2|2001-05-03|
    TNSN00210A1|2005-11-10|
    UA72002C2|2002-07-15|
    DK1224179T3|2004-10-25|
    HK1048472B|2005-09-16|
    PA8505501A1|2003-09-05|
    HU0204009A2|2003-03-28|
    BR0015275A|2002-07-16|
    CA2389020A1|2001-05-03|
    WO2001030759A3|2001-09-13|
    NZ517738A|2005-06-24|
    SK5312002A3|2003-01-09|
    PL354869A1|2004-03-08|
    HRP20020366A2|2004-02-29|
    CN1384829A|2002-12-11|
    YU31502A|2004-12-31|
    CN1636991A|2005-07-13|
    AR029402A1|2003-06-25|
    NO20021821D0|2002-04-18|
    CN1205205C|2005-06-08|
    AU7441500A|2001-05-08|
    EE200200227A|2003-06-16|
    CO5271714A1|2003-04-30|
    HU0204009A3|2004-07-28|
    CZ20021332A3|2002-10-16|
    IS6302A|2002-03-15|
    IL148581D0|2002-09-12|
    DE60012208D1|2004-08-19|
    EP1224179A2|2002-07-24|
    PE20010764A1|2001-07-23|
    EA200200416A1|2002-10-31|
    ZA200203295B|2003-06-25|
    AP200202493A0|2002-06-30|
    SI1224179T1|2004-10-31|
    TR200201167T2|2002-08-21|
    SV2002000209A|2002-07-16|
    GEP20043222B|2003-10-10|
    MA26840A1|2004-12-20|
    EA004937B1|2004-10-28|
    ES2222923T3|2005-02-16|
    AT271047T|2004-07-15|
    HRP20020366B1|2005-04-30|
    OA12080A|2003-08-25|
    DE60012208T2|2005-07-21|
    GT200000180A|2002-04-11|
    BG106729A|2002-12-29|
    EP1224179B1|2004-07-14|
    PT1224179E|2004-10-29|
    NO20021821L|2002-04-18|
    MXPA02004358A|2002-11-07|
    DZ3463A1|2001-05-03|
    KR100464526B1|2005-01-03|
    JP2003512455A|2003-04-02|
    AU778573B2|2004-12-09|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1999-10-29|Priority to US16237499P
    1999-10-29|Priority to US60/162,374
    2000-10-09|Application filed by 실버스타인 아써 에이., 화이자 프로덕츠 인코포레이티드
    2002-05-30|Publication of KR20020040918A
    2005-01-03|Application granted
    2005-01-03|Publication of KR100464526B1
    优先权:
    申请号 | 申请日 | 专利标题
    US16237499P| true| 1999-10-29|1999-10-29|
    US60/162,374|1999-10-29|
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