WO2015085968A1 - 用于心脑血管疾病的喹唑啉衍生物 - Google Patents

用于心脑血管疾病的喹唑啉衍生物 Download PDF

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WO2015085968A1
WO2015085968A1 PCT/CN2015/072662 CN2015072662W WO2015085968A1 WO 2015085968 A1 WO2015085968 A1 WO 2015085968A1 CN 2015072662 W CN2015072662 W CN 2015072662W WO 2015085968 A1 WO2015085968 A1 WO 2015085968A1
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alkyl
alkoxy
group
thf
compound according
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French (fr)
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刘磊
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北京融鑫创业投资中心（有限合伙）
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a class of quinazoline derivatives useful for cardiovascular and cerebrovascular diseases, and to new pharmaceutical uses of quinazoline derivatives, in particular to quinazoline derivatives such as terazosin, for preparation in cardiovascular and cerebrovascular diseases. Use in medicines for diseases.
  • Cardiovascular disease and heart disease are among the most widespread diseases affecting human health.
  • Typical cerebral vascular diseases such as cerebral thrombosis, cerebral ischemia, cerebral infarction, and cardiovascular diseases such as myocardial infarction, myocardial ischemia, coronary heart disease, angina pectoris or heart failure.
  • Cerebral thrombosis refers to blockage of blood vessels in the brain caused by various reasons, causing cerebral vascular dysfunction and causing related symptoms. Due to severe stenosis or occlusion of the blood vessels in the brain, cerebral blood flow is blocked and the brain tissue is attenuated and softened. There are many causes of cerebral thrombosis, mainly cerebral vascular occlusion and blood circulation disorder in the brain, that is, the result of the joint action of cerebral blood vessels and blood. There are also multiple factors in its formation. Cerebral thrombosis is usually associated with three factors: vascular disease, changes in blood components, or changes in hemodynamics.
  • cerebral ischemia also known as ischemic stroke and cerebral infarction
  • Ischemic brain injury includes primary injury during ischemia and secondary injury during reperfusion.
  • the pathogenesis of the pathological process is ischemia.
  • Restoration of blood perfusion is the basis of treatment, but reperfusion is secondary.
  • Sexual damage is inevitable.
  • Ischemic cerebrovascular disease is extremely harmful. According to the data, 40 out of 57 countries have listed the mortality rate of ischemic cerebrovascular disease in the top three, with Japan and China ranking first.
  • Cardiovascular diseases associated with myocardial ischemia include myocardial infarction, coronary heart disease, angina pectoris or heart failure.
  • Myocardial infarction is generally understood to be local myocardial necrosis due to a complete interruption or significant decrease in the persistence of regional blood supply.
  • thrombolytic and fibrinolysis treatments are especially used in acute myocardial infarction, with the aim of passing as much as possible through the ischemic area ( The primary) reperfusion protects the ischemic myocardium from the last cell death (ie, the last necrosis) and thus limits the infarct size to as small an area as possible.
  • the use of other (assisted) methods during the acute myocardial infarction phase and after myocardial infarction may help to improve myocardial conditions, especially in the area of infarction.
  • cardiovascular and cerebrovascular diseases such as cerebral thrombosis, cerebral ischemia, cerebral infarction and other cerebrovascular diseases as well as myocardial infarction, myocardial ischemia, coronary heart disease, angina pectoris, heart strength Cardiovascular diseases such as exhaustion.
  • the present inventors have surprisingly found that a class of quinazoline derivatives are effective in the treatment and/or prevention of cerebrovascular diseases, cardiovascular diseases and/or heart diseases, particularly cerebrovascular diseases such as cerebral thrombosis, cerebral ischemia, and cerebral infarction.
  • cerebrovascular diseases such as cerebral thrombosis, cerebral ischemia, and cerebral infarction.
  • cardiovascular diseases such as myocardial infarction, myocardial ischemia, coronary heart disease, angina pectoris, and heart failure.
  • the present invention relates to a compound of formula I, or a pharmaceutically acceptable salt, prodrug, solvate thereof, such as a hydrate or ester, for use in the prevention and/or treatment of cerebrovascular diseases, cardiovascular diseases and / or the application of drugs for heart disease,
  • R 1a and R 1b are each independently selected from H, NH 2 , OH, C 1-6 alkyl-, C 1-6 alkoxy-C 1-6 alkyl-, C 2-6 alkenyl-, C 2-6 alkynyl -, C 1-6-alkoxy -, C 1-6 acyl alkyl -, aryl acyl -, C 6-10 aryl - C 5-6 cycloalkyl or -, the alkyl
  • the base is optionally substituted with from 1 to 3 substituents selected from the group consisting of hydroxy or halogen;
  • R 1a and R 1b together with the nitrogen atom to which they are attached form a 5- or 6-membered ring;
  • R 2 and R 3 are each independently selected from H, halogen, C 1-6 alkyl-, halo C 1-6 alkyl-, C 2-6 alkenyl-, C 2-6 alkynyl-, CN, NO 2 , NH 2 , OH, C 1-6 alkoxy-, C 1-6 alkoxy-C 1-6 alkoxy-, C 1-6 alkanoyloxy-, C 1-6 alkanoyl Amino-, arylacylamino-, saturated or unsaturated 5- or 6-membered carbocyclic or heterocyclic, saturated or unsaturated 5- or 6-membered carbocyclyloxy or heterocyclic oxy Or C 1-6 alkyl acyl-; or
  • R 2 and R 3 together with the ring atom to which they are attached form a 5- or 6-membered carbocyclic or heterocyclic ring;
  • R 4 and R 5 are each independently selected from H, halogen, CN, NO 2 , NH 2 , OH, C 1-6 alkyl-, C 1-6 alkoxy-C 1-6 alkoxy-, C 1-6 alkanoyloxy-, halo C 1-6 alkyl-, C 2-6 alkenyl-, C 2-6 alkynyl-, C 1-6 alkoxy-, C 1-6 alkanoyl Amino-, arylacylamino-, saturated or unsaturated 5- or 6-membered carbocyclic or heterocyclic, saturated or unsaturated 5- or 6-membered carbocyclyloxy- or heterocyclic oxygen Base- or C 1-6 alkyl acyl-.
  • the present invention further provides some preferred technical solutions.
  • R 1a and R 1b in formula (I) are each independently selected from H, NH 2 , OH, C 1-6 alkyl-, C 1-4 alkoxy-C 1-4 alkyl -, C 2-4 alkenyl-, C 2-4 alkynyl-, C 1-4 alkoxy-, C 1-4 alkyl acyl-, phenyl acyl-, phenyl- or C 5-6 ring alkyl, wherein alkyl optionally substituted with 1-3 substituents selected from the group consisting of: a hydroxyl group or a halogen; or, form a 5- or 6-membered ring together with the nitrogen atom to which R 1a and R 1b which they are attached.
  • R 2 and R 3 in formula (I) are each independently selected from H, halo, C 1-6 alkyl-, halo C 1-6 alkyl-, C 1-6 alkoxy. -, C 1-6 alkoxy-C 1-6 alkoxy-, C 1-6 alkanoyloxy-, C 1-6 alkanoylamino-, aryl acylamino-, saturated or unsaturated 5 a - or 6-membered carbocyclic or heterocyclic group or a saturated or unsaturated 5- or 6-membered carbocyclic or heterocyclic oxy group; alternatively, said R 2 and R 3 together with the ring atom to which they are attached form 5 - or a 6-membered carbocyclic or heterocyclic ring.
  • R 4 and R 5 in formula (I) are each independently selected from H, halo, C 1-6 alkyl-, C 1-6 alkoxy-C 1-6 alkoxy-, C 1-6 alkanoyloxy-, halo C 1-6 alkyl-, C 1-6 alkoxy-, C 1-6 alkanoylamino-, aryl acylamino-, saturated or unsaturated 5 Or a 6-membered carbocyclic or heterocyclic group or a saturated or unsaturated 5- or 6-membered carbocyclic oxy or heterocyclic oxy group.
  • R 2 and R 3 in formula (I) are each independently selected from H, CH 3 O-, -CH 2 -O-CH 2 -, -O(CH 2 ) 2 OC 2 H 5 , -OC(O)CH 3 , -F, -CF 3 , And 1,2-pyridine ring, -NHCOCH 3 , -(CH 2 ) 2 CH 3 , -NHCOPh, Alternatively, the R 2 together form a 5-membered heterocyclic ring containing two oxygen ring atom and R 3 which they are attached.
  • R 4 and R 5 in formula (I) are each independently selected from H, —O(CH 2 ) 2 OC 2 H 5 , —OC(O)CH 3 , —OCH 3 , -CF 3 , -F, -NHCOCH 3 , -(CH 2 ) 3 CH 3 , -NHCOPh or
  • R 1a and R 1b in formula (I) are each independently selected from H, NH 2 , OH, C 1-6 alkyl-, C 1-6 alkoxy-C 1-6 alkyl -, C 2-6 alkenyl-, C 2-6 alkynyl-, C 1-6 alkyl acyl- or C 5-6 cycloalkyl, wherein the alkyl group is optionally substituted with from 1 to 3 Substituent: hydroxyl or halogen; or, R 1a and R 1b together with the nitrogen atom to which they are attached form a 6-membered ring.
  • R 2 and R 3 in formula (I) are each independently selected from halo, C 1-6 alkyl-, halo C 1-6 alkyl-, C 1-6 alkoxy-, C 1-6 alkoxy-C 1-6 alkoxy-, C 1-6 alkanoyloxy- or C 1-6 alkanoylamino-.
  • R 4 and R 5 in formula (I) are each independently selected from H, halo, C 1-6 alkyl-, C 1-6 alkoxy-C 1-6 alkoxy-, C 1-6 alkanoyloxy-, halo C 1-6 alkyl-, C 1-6 alkoxy- or C 1-6 alkanoylamino-.
  • R 1a and R 1b in Formula (I) are each independently selected from H, NH 2 , OH, C 1-6 alkyl-, C 1- 4 -alkoxy-C 1-4 alkyl-, C 2-4 alkenyl-, C 2-4 alkynyl-, C 1-4 alkyl acyl-, phenyl- or C 5-6 cycloalkyl, Wherein the group is optionally substituted with from 1 to 3 substituents selected from the group consisting of hydroxyl or halogen.
  • R 2 and R 3 in formula (I) are each independently selected from halo, C 1-6 alkyl-, halo C 1-6 alkyl-, C 1-6 alkoxy-, C 1-6 alkoxy-C 1-6 alkoxy-, C 1-6 alkanoyloxy- or C 1-6 alkanoylamino-.
  • R 4 and R 5 in formula (I) are each independently selected from H, halo, C 1-6 alkyl-, C 1-6 alkoxy-C 1-6 alkoxy-, C 1-6 alkanoyloxy-, halo C 1-6 alkyl-, C 1-6 alkoxy- or C 1-6 alkanoylamino-.
  • R 1a and R 1b in formula (I) are each independently selected from H, —NH 2 , —OH.
  • R 4 and R 5 in formula (I) are each independently selected from H.
  • the compound of Formula (I) is selected from the group consisting of the compounds of Co. 1 to Co. 33, or a pharmaceutically acceptable salt, prodrug, solvate thereof, such as a hydrate or ester.
  • the C 2-6 alkenyl group is selected from C 2-5 alkenyl, C 2-4 alkenyl groups such as vinyl, propenyl, allyl.
  • the C 2-6 alkynyl group is selected from the group consisting of C 2-5 alkynyl, C 2-4 alkynyl.
  • the C 5-6 cycloalkyl group is selected from the group consisting of a cyclopentyl group and a cyclohexyl group.
  • the aryl group or an aryl group on the aryl acyl group selected from the group consisting of phenyl, naphthyl, preferably phenyl.
  • the halogen is selected from the group consisting of fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.
  • the present invention provides a preferred use of the above pharmaceutical uses:
  • the cerebrovascular disease includes, but is not limited to, cerebral thrombosis, cerebral ischemia, and/or cerebral infarction.
  • the cardiovascular disease and/or heart disease includes, but is not limited to, myocardial infarction, myocardial ischemia, myocardial damage, coronary heart disease, angina pectoris, or heart failure.
  • the myocardial damage includes, but is not limited to, myocardial damage caused by acute myocardial infarction, chronic myocardial infarction, and/or treatment following myocardial infarction.
  • the present invention also provides a method for treating a cerebrovascular disease, a cardiovascular disease and/or a heart disease in a mammal, wherein the mammal is at a daily dose of less than 100 ⁇ g/kg (for example, 0.1 to 100 ⁇ g/kg).
  • the drug provided by the present invention is administered for at least 7 consecutive days.
  • the invention also provides a preferred embodiment of the method of treatment: for example, the mammal is administered a compound of the invention in an amount of less than 75 ⁇ g/kg per day (eg, 0.1 to 75 ⁇ g/kg) for at least 7 consecutive days, such as a mammal.
  • the compound of the present invention is administered in an amount of less than 50 ⁇ g/kg per day (0.1 to 50 ⁇ g/kg) for at least 7 consecutive days.
  • the present invention also provides a method of the above medicament for treating a cerebrovascular disease, a cardiovascular disease and/or a heart disease in a mammal, the mammalian mammal administering the compound in an amount which reduces the leukocyte within an acceptable range.
  • the term "lower white blood cell count is within an acceptable range” means that the number of white blood cells in the blood of the mammal after 7 days of daily administration and continuous administration of the compound is relative to the number of white blood cells in the blood prior to administration of the compound.
  • the percentage is above 30%, for example above 40%, for example above 50%. Of course, it will usually be below 150%, for example below 130%.
  • the percentage (the white blood cell concentration in the blood after 7 days of administration, the leukocyte concentration in the blood before administration) x 100%, and may also be referred to herein as "the percentage of white blood cells on the 7th".
  • the number of white blood cells in the blood ie the concentration of white blood cells in the blood, is usually expressed in terms of the number of white blood cells per unit volume. This data is extremely common and readily available in clinical laboratory tests, for example, it can be easily detected by examining peripheral blood. obtain.
  • the mammal is administered the compound of the invention continuously for at least 7 days in a daily dose of less than 100 ⁇ g/kg, for example at a daily dose of less than 75 ⁇ g/kg for at least 7 days, for example in
  • the compound of the present invention is administered continuously for at least 7 days in an amount of less than 50 ⁇ g/kg per day; in particular, the mammal is administered the compound of the present invention continuously in an amount of 0.1 to 100 ⁇ g/kg per day for at least 7 days, for example, daily.
  • the compound of the present invention is administered continuously in an amount of 0.1 to 75 ⁇ g/kg for at least 7 days, for example, by continuously administering the compound of the present invention in an amount of 0.1 to 50 ⁇ g/kg per day for at least 7 days, in which not only excellent prevention and the like can be obtained.
  • the leukopenia in the blood of the mammal can be obtained within an acceptable range, in particular
  • the percentage of white blood cells on the 7th day is 30% or more, for example, 40% or more, for example, 50% or more. For example, it will usually be below 150%, for example below 130%. This result of avoiding side effects of the drug while obtaining excellent prevention and/or treatment of cerebral thrombosis effects is completely unexpected.
  • the compound of the formula I also includes terazosin or a pharmaceutically acceptable salt thereof or a solvate thereof such as a hydrate.
  • terazosin or a pharmaceutically acceptable salt thereof or a solvate thereof such as a hydrate.
  • it may be the hydrochloride salt of terazosin or a hydrate thereof, for example, a dihydrate of terazosin hydrochloride.
  • Myocardial infarction is generally understood to be local myocardial necrosis due to a complete interruption of the regional blood supply or a critical reduction.
  • thrombolytic and fibrinolysis treatments are especially used in acute myocardial infarction, with the aim of passing as much as possible through the ischemic area ( The primary reperfusion protects the ischemic myocardium from the last cell death (ie, the last necrosis) and thus limits the infarct size to as small an area as possible.
  • the use of other (assisted) methods during the acute myocardial infarction phase and after myocardial infarction may help to improve myocardial conditions, especially in the area of infarction.
  • the compounds of the present invention for use in the treatment of myocardial damage caused by myocardial infarction are generally suitable for use in the treatment of myocardial infarction in this case.
  • these compounds can be used in the treatment of acute myocardial infarction and especially after myocardial infarction, either in patients who have undergone fibrinolytic therapy or in patients who have not undergone such dissolution therapy.
  • the compounds of the present invention are effective in the treatment, especially in the prevention of cardiac insufficiency (myocardial insufficiency), in patients after infarction undergoing dissolution therapy. This also applies to that Some patients who have been treated with p-adrenergic receptor blockers.
  • SNS sympathetic nervous system
  • preventing or prohibiting excessive sympathetic activation may be a valuable strategy for the treatment of patients with myocardial infarction, especially for the prevention of heart failure after myocardial infarction.
  • the compounds of the invention for use in the treatment of myocardial infarction and/or myocardial infarction produce a human heart function in the chronic phase of patients with myocardial infarction, especially after myocardial infarction.
  • Administration of the compounds of the invention after myocardial infarction reduced cardiac weight and decreased sympathetic activation as measured by plasma-norepinephrine levels.
  • the compounds of the invention are therefore suitable for reducing excessive hypertrophy of the heart, particularly in the later stages of treatment of patients after myocardial infarction.
  • the compounds of the invention lower plasma-norepinephrine-levels, thereby making it extremely effective to normalize sympathetic stimulation following myocardial infarction.
  • the compounds of the invention may be administered orally (since the compounds of the invention are known to be readily absorbed by the gastrointestinal tract), intramuscularly, intravenously, to treat myocardial damage caused by myocardial infarction.
  • brain diseases such as cerebral thrombosis and cerebral ischemia and heart disease such as myocardial infarction and myocardial ischemia are related to organ blood supply disorders
  • both brain and heart organs have great working modes.
  • the difference between the treatment of the two types of diseases is usually not the same or similar, especially the well-known many drugs for heart disease can not be applied to brain diseases at all; similarly, many drugs for brain diseases can not be applied at all.
  • Heart disease The disease, the treatment of the two organs, is not related.
  • the compounds of the present invention which are useful in brain diseases such as the present invention are also applicable to certain heart diseases.
  • the term "effective amount” refers to a dose that can achieve treatment, prevention, alleviation, and/or alleviation of a disease or condition described herein in a subject.
  • the term “drug” includes a compound, and pharmaceutically acceptable salts, prodrugs, solvates thereof, such as hydrates or esters, and also includes these compounds, and pharmaceutically acceptable salts, prodrugs thereof, A pharmaceutical composition of a solvate such as a hydrate or an ester.
  • pharmaceutical composition which may be used interchangeably with “composition,” which means that it can be used to achieve treatment, prevention, alleviation and/or alleviation of the present invention in a subject.
  • the term "subject” or “patient” may refer to an animal that receives the compositions and extracts of the invention to treat, prevent, alleviate and/or alleviate the diseases, disorders, symptoms of the invention, particularly It is a mammal, such as a human, a dog, a monkey, a cow, a horse, and the like.
  • disease or symptom refers to a physical state of the subject that is associated with the disease or condition described herein.
  • % generally refers to a weight/weight percentage for a solid material as a solid and generally refers to a weight/volume percentage for a liquid when the total material is a liquid.
  • the percentage characterizing the liquid solute generally refers to the volume/volume percentage.
  • Terazosin (TZ, (4-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperazin-1-yl)(tetrahydrofuran-2-yl)methanone, C 19 H 25 N 5 O 4 ) which is a compound of the number Co.33 according to the invention.
  • terazosin when terazosin is mentioned, it includes not only the Co.33 compound shown by the above structure, but also a pharmaceutically acceptable salt (for example, hydrochloride) of the above structural compound, and the above structural compound and A solvate of a salt thereof such as a hydrate such as a dihydrate.
  • the terazosin refers to terazosin hydrochloride dihydrate.
  • the present invention has been extensively studied using terazosin as a typical example of a compound of formula I to demonstrate the surprising effect of the present invention; in the following experiments, particularly biological tests, the test reagents used are not mentioned, unless otherwise indicated. It refers to terazosin hydrochloride dihydrate, but it is well known whether it is in the form of a salt and in the form of a salt and whether it is a hydrate. These elements usually do not affect the therapeutic effect of the drug.
  • Figure 1 Results of rat MCAO model test.
  • Step 1 Ammonia gas was introduced into a solution of Compound 1a (50 mmol) in 200 mL of tetrahydrofuran, and the reaction was carried out at 25 ° C for 36 hours. A large amount of white solid was precipitated from the system, and the white solid obtained by filtration was washed with tetrahydrofuran to give the final product 1f, yield: 63%.
  • Step 2 15 mL of acetic anhydride was added to the compound 1f (10 mmol), and the mixture was refluxed for 2 hr. After cooling to room temperature, a large amount of white solid was precipitated from the system, and the white solid obtained by filtration was washed with tetrahydrofuran to obtain 1 g of the final product in a yield of 63%.
  • Step 3 In the case of an argon atmosphere, 1 d (2 mmol) was added to a solution in which 1 g (2 mmol) of 1-pentanol was dissolved. After the reaction system was refluxed for 4.5 hours, it was allowed to stand in an environment of 0 to 5 ° C to stand for crystallization. The obtained white crystals were washed twice with 10 mL of acetone, and then recrystallized from diethyl ether/methanol to give the final product 1i as compound Co.1, yield: 60%.
  • Step 1 Compound 1b (20 mmol) was added to a solution of Compound 1a (20 mmol) in 100 mL of methanol, and the reaction was carried out at 25 ° C for 4 hours. After the thin plate chromatography indicated that the conversion of 1a was completed, 100 mL of diethyl ether was added to the system, and the mixture was mixed and placed in an environment of -20 ° C to stand for crystallization. The obtained white solid was recrystallized from petroleum ether / ethyl acetate to give the final product 1c, yield: 41%.
  • Step 2 In the case of an argon atmosphere, 1 d (2 mmol) was added to a solution of 1 c (2 mmol) of 1-pentanol. After the reaction system was refluxed for 4.5 hours, it was allowed to stand in an environment of 0 to 5 ° C to stand for crystallization. The obtained white crystals were washed twice with 10 mL of acetone, and then recrystallized from diethyl ether/methanol to give the product (1) as compound Compounds.
  • Step 1 To a solution of Compound 1a (20 mmol) in 100 mL of methanol was added hydrazine hydrate (20 mmol), and the reaction was carried out at 25 ° C for 4 hours. After the thin plate chromatography indicated that the conversion of 1a was completed, 100 mL of diethyl ether was added to the system, and the mixture was mixed and placed in an environment of -20 ° C to stand for crystallization. The obtained white solid was recrystallized from petroleum ether / ethyl acetate to give the final product 3a, yield: 61%.
  • Step 2 In the case of an argon atmosphere, 1 d (2 mmol) was added to a solution of 3a (2 mmol) in 1-pentanol. After the reaction system was refluxed for 4.5 hours, it was allowed to stand in an environment of 0 to 5 ° C to stand for crystallization. The obtained white crystals were washed twice with 10 mL of acetone, and then recrystallized from diethyl ether/methanol to give the product 3b as the compound Co.3, yield: 31%.
  • Step 1 An aqueous solution of hydroxylamine (20 mmol) was added to a solution of Compound 1a (20 mmol) in 100 mL of methanol, and the reaction was carried out at 25 ° C for 3 hours. After the thin plate chromatography indicated that the conversion of 1a was completed, 100 mL of diethyl ether was added to the system, and the mixture was mixed and placed in an environment of -20 ° C to stand for crystallization. The obtained white solid was recrystallized from petroleum ether / ethyl acetate to give the final product 4a, yield: 88%.
  • Step 2 In the case of an argon atmosphere, 1 d (2 mmol) was added to a solution in which 4a (2 mmol) of 1-pentanol was dissolved. After the reaction system was refluxed for 4.5 hours, it was allowed to stand in an environment of 0 to 5 ° C to stand for crystallization. The obtained white crystals were washed twice with 10 mL of acetone, and then recrystallized from diethyl ether/methanol to give the final product 4b as compound Co. 4 in a yield of 75%.
  • Step 1 Allylamine (22 mmol) was added to a solution of Compound 1a (20 mmol) in 100 mL of methanol, and the reaction was carried out at 25 ° C for 8 hours. After the thin plate chromatography indicated that the conversion of 1a was completed, 100 mL of diethyl ether was added to the system, and the mixture was mixed and placed in an environment of -20 ° C to stand for crystallization. The obtained white solid was recrystallized from petroleum ether / ethyl acetate to give the final product 5a, yield: 31%.
  • Step 2 In the case of an argon atmosphere, 1 d (2 mmol) was added to a solution in which 5a (2 mmol) of 1-pentanol was dissolved. After the reaction system was refluxed for 4.5 hours, it was allowed to stand in an environment of 0 to 5 ° C to stand for crystallization. The obtained white crystals were washed twice with 10 mL of acetone, and then recrystallized from diethyl ether/methanol to give the final product 5b as compound Co. 5 in a yield of 75%.
  • Step 1 Propargylamine (28 mmol) was added to a solution of Compound 1a (20 mmol) in 100 mL of methanol, and the reaction was carried out at 25 ° C for 10 hours. After the thin plate chromatography indicated that the conversion of 1a was completed, 100 mL of diethyl ether was added to the system, and the mixture was mixed and placed in an environment of -20 ° C to stand for crystallization. The obtained white solid was recrystallized from petroleum ether / ethyl acetate to give the final product 6a, yield: 44%.
  • Step 2 In the case of an argon atmosphere, 1 d (2 mmol) was added to a solution in which 6a (2 mmol) of 1-pentanol was dissolved. After the reaction system was refluxed for 4.5 hours, it was allowed to stand in an environment of 0 to 5 ° C to stand for crystallization. The obtained white crystals were washed twice with 10 mL of acetone, and then recrystallized from diethyl ether/methanol to give the product 6b as compound Co. 6 in a yield of 75%.
  • Step 1 Compound 7a (20 mmol) was added to a solution of Compound 1a (20 mmol) in 100 mL of methanol, and the reaction was carried out at 25 ° C for 3 hours. After the thin plate chromatography indicated that the conversion of 1a was completed, 100 mL of diethyl ether was added to the system, and the mixture was mixed and placed in an environment of -20 ° C to stand for crystallization. The obtained white solid was recrystallized from petroleum ether / ethyl acetate to give the final product 7b.
  • Step 2 In the case of an argon atmosphere, 1 d (2 mmol) was added to a solution in which 7b (2 mmol) of 1-pentanol was dissolved. After the reaction system was refluxed for 4.5 hours, it was allowed to stand in an environment of 0 to 5 ° C to stand for crystallization. The obtained white crystals were washed twice with 10 mL of acetone, and then recrystallized from diethyl ether/methanol to give the product, product, 7.
  • Step 1 Compound 8a (20 mmol) was added to a solution of Compound 1a (20 mmol) in 100 mL of methanol, and the reaction was carried out at 25 ° C for 1.5 hours. After the thin plate chromatography indicated that the conversion of 1a was completed, 100 mL of diethyl ether was added to the system, and the mixture was mixed and placed in an environment of -20 ° C to stand for crystallization. The obtained white solid was recrystallized from petroleum ether / ethyl acetate to give the final product 8b.
  • Step 2 In the case of an argon atmosphere, 1 d (2 mmol) was added to a solution in which 8b (2 mmol) of 1-pentanol was dissolved. After the reaction system was refluxed for 4.5 hours, it was allowed to stand in an environment of 0 to 5 ° C to stand for crystallization. The obtained white crystals were washed twice with 10 mL of acetone, and then recrystallized from diethyl ether/methanol to give the product, product, 8.
  • Step 1 Compound 9a (20 mmol) was added to a solution of Compound 1a (20 mmol) in 100 mL of methanol, and the reaction was carried out at 25 ° C for 2.5 hours. After the thin plate chromatography indicated that the conversion of 1a was completed, 100 mL of diethyl ether was added to the system, and the mixture was mixed and placed in an environment of -20 ° C to stand for crystallization. The obtained white solid was recrystallized from petroleum ether / ethyl acetate to give the final product 9b.
  • Step 2 In the case of an argon atmosphere, 1 d (2 mmol) was added to a solution in which 9b (2 mmol) of 1-pentanol was dissolved. After the reaction system was refluxed for 4.5 hours, it was allowed to stand in an environment of 0 to 5 ° C to stand for crystallization. The obtained white crystals were washed twice with 10 mL of acetone, and then recrystallized from diethyl ether/methanol to give the final product 9c as compound Co.9, yield: 43%.
  • Step 1 Compound 10a (20 mmol) was added to a solution of Compound 1a (20 mmol) in 100 mL of methanol, and the reaction was carried out at 25 ° C for 5 hours. After the thin plate chromatography indicated that the conversion of 1a was completed, 100 mL of diethyl ether was added to the system, and the mixture was mixed and placed in an environment of -20 ° C to stand for crystallization. The obtained white solid was recrystallized from petroleum ether / ethyl acetate to give the final product 10b, yield: 36%.
  • Step 2 In the case of an argon atmosphere, 1 d (2 mmol) was added to a solution in which 10b (2 mmol) of 1-pentanol was dissolved. After the reaction system was refluxed for 4.5 hours, it was allowed to stand in an environment of 0 to 5 ° C to stand for crystallization. The obtained white crystals were washed twice with 10 mL of acetone, and then recrystallized from diethyl ether/methanol to give the product of the product 10.
  • Step 1 To a solution of compound 1a (20 mmol) in 100 mL of methanol was added compound 11a (20 mmol). The reaction was carried out at 25 ° C for 5 hours. After the thin plate chromatography indicated that the conversion of 1a was completed, 100 mL of diethyl ether was added to the system, and the mixture was mixed and placed in an environment of -20 ° C to stand for crystallization. The obtained white solid was recrystallized from petroleum ether / ethyl acetate to give the final product 11b.
  • Step 2 In the case of an argon atmosphere, 1 d (2 mmol) was added to a solution in which 11b (2 mmol) of 1-pentanol was dissolved. After the reaction system was refluxed for 4.5 hours, it was allowed to stand in an environment of 0 to 5 ° C to stand for crystallization. The obtained white crystals were washed twice with 10 mL of acetone, and then recrystallized from diethyl ether/methanol to give the final product 11c as compound Co.11, yield: 62%.
  • Step 1 In the case of an argon atmosphere, 1 d (2 mmol) was added to a solution in which 12a (2 mmol) of 1-pentanol was dissolved. After the reaction system was refluxed for 4.5 hours, it was allowed to stand in an environment of 0 to 5 ° C to stand for crystallization. The obtained white crystals were washed twice with 10 mL of acetone, and then recrystallized from diethyl ether/methanol to give the product 12b as the compound Co.12, yield: 62%.
  • Step 1 20 mL of 13a was added to compound 1f (10 mmol), and the reaction was refluxed for 2 hr. After cooling to room temperature, a large amount of white solid was precipitated from the system, and the white solid obtained by filtration was washed with tetrahydrofuran to obtain the final product 13b in a yield of 82%.
  • Step 2 In the case of an argon atmosphere, 1 d (2 mmol) was added to a solution in which 13b (2 mmol) of 1-pentanol was dissolved. After the reaction system was refluxed for 5.5 hours, it was allowed to stand in an environment of 0 to 5 ° C to stand for crystallization. The obtained white crystals were washed twice with 10 mL of acetone, and then recrystallized from diethyl ether/methanol to give the product 13.
  • Step 1 22 mL of 14a was added to compound 1f (10 mmol), and the reaction was refluxed for 2 hr. After cooling to room temperature, a large amount of white solid was precipitated from the system, and the obtained white solid was washed with tetrahydrofuran to give the final product 14b in a yield of 55%.
  • Step 2 In the case of an argon atmosphere, 1 d (2 mmol) was added to a solution in which 14b (2 mmol) of 1-pentanol was dissolved. After the reaction system was refluxed for 4.5 hours, it was allowed to stand in an environment of 0 to 5 ° C to stand for crystallization. The obtained white crystals were washed twice with 10 mL of acetone, and then recrystallized from diethyl ether/methanol to give the product of the product 14.
  • Step 1 In the case of an argon atmosphere, 1 d (2 mmol) was added to a solution in which 15a (2 mmol) of 1-pentanol was dissolved. After the reaction system was refluxed for 4.5 hours, it was allowed to stand in an environment of 0 to 5 ° C to stand for crystallization. The obtained white crystals were washed twice with 10 mL of acetone, and then recrystallized from diethyl ether/methanol to give the final product 15b as compound Co. 15 in a yield of 55%.
  • Step 1 In the case of an argon atmosphere, 1 d (2 mmol) was added to a solution in which 16a (2 mmol) of 1-pentanol was dissolved. After the reaction system was refluxed for 4.5 hours, it was allowed to stand in an environment of 0 to 5 ° C to stand for crystallization. The obtained white crystals were washed twice with 10 mL of acetone, and then recrystallized from diethyl ether/methanol to give the product 16b as compound Co.16 in a yield of 45%.
  • Step 1 In the case of an argon atmosphere, 1 d (2 mmol) was added to a solution in which 17a (2 mmol) of 1-pentanol was dissolved. After the reaction system was refluxed for 4 hours, it was allowed to stand in an environment of 0 to 5 ° C to stand for crystallization. The obtained white crystals were washed twice with 10 mL of acetone, and then recrystallized from diethyl ether/methanol to give the final product 17b as compound Co.17 in a yield of 55%.
  • Step 1 In the case of an argon atmosphere, 1 d (2 mmol) was added to a solution in which 18a (2 mmol) of 1-pentanol was dissolved. After the reaction system was refluxed for 3 hours, it was allowed to stand in an environment of 0 to 5 ° C to stand for crystallization. The obtained white crystals were washed twice with 10 mL of acetone, and then recrystallized from diethyl ether/methanol to give the product 18b as the compound Co. 18 in a yield of 75%.
  • Step 1 In the case of an argon atmosphere, 1 d (2 mmol) was added to a solution in which 19a (2 mmol) of 1-pentanol was dissolved. After the reaction system was refluxed for 3 hours, it was allowed to stand in an environment of 0 to 5 ° C to stand for crystallization. The obtained white crystals were washed twice with 10 mL of acetone, and then recrystallized from diethyl ether/methanol to give the product 19b as the compound Co.19 in a yield of 54%.
  • Step 1 In the case of an argon atmosphere, 1 d (2 mmol) was added to a solution in which 20a (2 mmol) of 1-pentanol was dissolved. After the reaction system was refluxed for 3 hours, it was allowed to stand in an environment of 0 to 5 ° C to stand for crystallization. The obtained white crystals were washed twice with 10 mL of acetone, and then recrystallized from diethyl ether/methanol to give the product 20b as the compound Co. 20 in a yield of 54%.
  • Step 1 In the case of an argon atmosphere, 1 d (2 mmol) was added to a solution in which 21a (2 mmol) of 1-pentanol was dissolved. After the reaction system was refluxed for 4 hours, it was allowed to stand in an environment of 0 to 5 ° C to stand for crystallization. The obtained white crystals were washed twice with 10 mL of acetone, and then recrystallized from diethyl ether/methanol to give the product of the product of the product 21b as a compound.
  • Step 1 In the case of an argon atmosphere, 1 d (2 mmol) was added to a solution in which 22a (2 mmol) of 1-pentanol was dissolved. After the reaction system was refluxed for 5 hours, it was allowed to stand in an environment of 0 to 5 ° C to stand for crystallization. The obtained white crystals were washed twice with 10 mL of acetone, and then recrystallized from diethyl ether/methanol to give the product 22b as the compound Co.22 in a yield of 61%.
  • Step 1 In the case of an argon atmosphere, 1 d (2 mmol) was added to a solution in which 23a (2 mmol) of 1-pentanol was dissolved. After the reaction system was refluxed for 5 hours, it was allowed to stand in an environment of 0 to 5 ° C to stand for crystallization. The obtained white crystals were washed twice with 10 mL of acetone, and then recrystallized from diethyl ether/methanol to give the product 23b as the compound Co.23 in a yield of 48%.
  • Step 1 In the case of an argon atmosphere, 1 d (2 mmol) was added to a solution in which 24a (2 mmol) of 1-pentanol was dissolved. After the reaction system was refluxed for 4 hours, it was allowed to stand in an environment of 0 to 5 ° C to stand for crystallization. The obtained white crystals were washed twice with 10 mL of acetone, and then recrystallized from diethyl ether/methanol to give the product 24b as the compound Co.24 in a yield of 24%.
  • Step 1 In the case of an argon atmosphere, 1 d (2 mmol) was added to a solution in which 25a (2 mmol) of 1-pentanol was dissolved. After the reaction system was refluxed for 4.5 hours, it was allowed to stand in an environment of 0 to 5 ° C to stand for crystallization. The obtained white crystals were washed twice with 10 mL of acetone, and then recrystallized from diethyl ether/methanol to give the product 25b as the compound Co.25 in a yield of 45%.
  • Step 1 In the case of an argon atmosphere, 1 d (2 mmol) was added to a solution in which 26a (2 mmol) of 1-pentanol was dissolved. After the reaction system was refluxed for 4 hours, it was allowed to stand in an environment of 0 to 5 ° C to stand for crystallization. The obtained white crystals were washed twice with 10 mL of acetone, and then recrystallized from diethyl ether/methanol to give the product 26b as compound Co.26 in a yield of 55%.
  • Step 1 In the case of an argon atmosphere, 1 d (2 mmol) was added to a solution in which 27a (2 mmol) of 1-pentanol was dissolved. After the reaction system was refluxed for 3 hours, it was allowed to stand in an environment of 0 to 5 ° C to stand for crystallization. The obtained white crystals were washed twice with 10 mL of acetone, and then recrystallized from diethyl ether/methanol to give the product 27b as Compounds.
  • Step 1 In the case of an argon atmosphere, 1 d (2 mmol) was added to a solution in which 28a (2 mmol) of 1-pentanol was dissolved. After the reaction system was refluxed for 3 hours, it was allowed to stand in an environment of 0 to 5 ° C to stand for crystallization. The obtained white crystals were washed twice with 10 mL of acetone, and then recrystallized from diethyl ether/methanol to give the product 28b as the compound Co. 28 in a yield of 75%.
  • Step 1 In the case of an argon atmosphere, 1 d (2 mmol) was added to a solution in which 29a (2 mmol) of 1-pentanol was dissolved. After the reaction system was refluxed for 3 hours, it was allowed to stand in an environment of 0 to 5 ° C to stand for crystallization. The obtained white crystals were washed twice with 10 mL of acetone, and then recrystallized from diethyl ether/methanol to give the final product 29b as compound Co.29 in a yield of 44%.
  • Step 1 In the case of an argon atmosphere, 1 d (2 mmol) was added to a solution in which 30a (2 mmol) of 1-pentanol was dissolved. After the reaction system was refluxed for 5 hours, it was allowed to stand in an environment of 0 to 5 ° C to stand for crystallization. The obtained white crystals were washed twice with 10 mL of acetone, and then recrystallized from diethyl ether/methanol to give the final product 30b as compound Co.30 in a yield of 65%.
  • Step 1 In the case of an argon atmosphere, 1 d (2 mmol) was added to a solution in which 31a (2 mmol) of 1-pentanol was dissolved. After the reaction system was refluxed for 4 hours, it was allowed to stand in an environment of 0 to 5 ° C to stand for crystallization. The obtained white crystals were washed twice with 10 mL of acetone, and then recrystallized from diethyl ether/methanol to give the product 31b as Compounds.
  • Step 1 In the case of an argon atmosphere, 1 d (2 mmol) was added to a solution in which 32a (2 mmol) of 1-pentanol was dissolved. After the reaction system was refluxed for 4 hours, it was allowed to stand in an environment of 0 to 5 ° C to stand for crystallization. The obtained white crystals were washed twice with 10 mL of acetone, and then recrystallized from diethyl ether/methanol to give the product 32b as the compound Co.32 in a yield of 45%.
  • Test Example 1 drug therapy for cerebral thrombosis
  • the compound Co.33 (formulated as a sterile injectable solution) was administered to patients in the acute phase and subacute phase of cerebral thrombosis by the following method.
  • Subject patient Acute patient who was diagnosed with cerebral thrombosis and within 7 days after onset, and subacute patients who were (more than 7 days) less than 1 month old.
  • Compound Co.33 was formulated into a 0.5 mg/ml injection using water for injection according to a conventional injection preparation method.
  • Test agent and dose The above formulated drug was diluted with 100 ml of 0.9% sodium chloride injection, and the amount of compound Co.33 was 20 ⁇ g/kg/day by weight, once a day, intravenously infused over 30 minutes.
  • the degree of improvement in the course of treatment is shown in Table 1 (after 7 days of administration) and Table 2 (after 14 days of administration), the number outside the parentheses in the table is the number of patients, and the percentage in parentheses is the total number of patients in this case. percentage.
  • the degree of improvement can be judged by the following methods: for the neurological symptoms, activities of daily living, mental symptoms, self-conscious symptoms, levels of consciousness, etc., the symptoms are classified into five stages in the normal and severe cases. The symptoms of the patient before administration and the symptoms of the patient at the time of withdrawal were judged separately, and the results of the determined grades were judged to be mildly improved, moderately improved, and significantly improved. The overall improvement degree is comprehensively obtained from the judgment results of each item.
  • Peripheral blood was taken from each patient before administration, and the white blood cells in the blood were counted according to the conventional cell counting method (using a blood routine analyzer manufactured by Coulter Co., USA).
  • the number of white blood cells at this time point was WN0 (ie, blood).
  • the leukocyte concentration the same below; followed by examination of the white blood cell count after 7 days of administration, the number of white blood cells at this time point was WN7; then the white blood cell count was checked after 14 days of administration, and the number of white blood cells at this time point was WN14.
  • RESULTS The mean percentage of white blood cells on the 7th was 78%, and the average of the percentage of white blood cells on the 14th was 86%, both above 50%, indicating that the administration of the compound of the present invention to treat the brain plug according to the above dosing regimen is not only effective but also does not appear. Unacceptable side effects.
  • the security summary is based on the security of side effects.
  • the compound of the present invention such as terazosin can be used as an effective cerebral thrombosis therapeutic agent.
  • the compounds of the present invention are particularly effective for the treatment of acute and subacute cerebral thrombosis and exhibit low side effects.
  • the compound Co. 33 of Test Example 1 was administered to each group at a dose of 2 ⁇ g/kg/day, 50 ⁇ g/kg/day, and 400 ⁇ g/kg/day, respectively, according to the administration method of Test Example 1, for 14 consecutive days.
  • Test Example 3 Rat MCAO model was investigated for the treatment of cerebral infarction
  • Control 1000 400 100 50 10 1 0.1 Infarct volume (%) 27% 26% twenty four% 14% 8% 5% 7% 9%
  • terazosin has a significant effect in rat MCAO.
  • the white brain region represents mitochondrial function damage and is incapable of reacting to produce formazan (a red substance) (left).
  • terazosin (TZ) significantly reduced cell damage, and the infarct size was significantly lower than that of the control group (right panel).
  • Co.1, Co.14, Co.15, and Co.17 were respectively tested according to the results of Table 5 above, and it was also found that some of the compounds can be used at a dose of 0.1 to 100 ⁇ g/kg.
  • the infarct volume was reduced to less than 15%, especially at doses of 0.1-75 ⁇ g/kg, which reduced the infarct volume to less than 10%, which was significantly different from the control group (p ⁇ 0.05). It was also found that the completely surprising result was When the drug dose was greater than 250 ⁇ g/kg, the infarct volume was above 25%, showing no significant difference from the control group.
  • Test Example 3 In combination with the results of Test Example 1 above, it is fully expected that when the compound of the present invention is used in a human cerebral thrombosis patient, the compound of the present invention is continuously administered in an amount of less than 100 ⁇ g/kg per day for at least 7 days.
  • the compound of the present invention is administered continuously in an amount of 0.1 to 100 ⁇ g/kg for at least 7 days, for example, by continuously administering the compound of the present invention in an amount of 0.1 to 75 ⁇ g/kg per day for at least 7 days, for example, at a daily dose of 0.1 to 50 ⁇ g/kg.
  • the continuous administration of the compound of the present invention for at least 7 days will provide an effective treatment for cerebral infarction and will have a low adverse effect on the human body.
  • Test Example 4 Mouse anti-cerebral thrombosis model test
  • Test Example 5 Treatment effect on myocardial infarction
  • the beneficial effects of the compounds of the invention in the treatment of myocardial infarction, especially after myocardial infarction, can be demonstrated in a standard test by pharmacological characterization of the effect of the test substance on factors affecting the functional state of the myocardium after myocardial infarction.
  • MI-rat animal model
  • Plasma norepinephrine levels were found to rise sharply after myocardial infarction. Plasma norepinephrine levels continue to rise during periods of increased cardiac insufficiency.
  • the MI-rat test showed that even after three weeks of infarction, the heart rate was increased after the so-called recovery phase (in vivo unrestricted state determination, awake rats), while remaining plasma norepinephrine levels It is also about 50% higher than sham-operated rats (see below: sham-operated rats without ligating coronary arteries).
  • sham-operated rats see below: sham-operated rats without ligating coronary arteries.
  • elevated metabolism is observed in the hypothalamus and blue plaques adjacent to the ventricles, in which the sympathetic nerves are regulated by the surrounding system. Behavioral studies have shown increased fear in infarcted rats. These observations therefore indicate the presence of slowly elevated sympathetic activation in this infarcted rat model.
  • mice Male Wister rats (270-320 grams). The rats were housed in a 12 hour light/dark cycle and fed with standard rat chow and water (both freely available). These animals will be subjected to coronary artery ligation (MI-rat) or unligated sham-operated rats (pse-rat). After 24 hours, MI-rats were randomly divided, and then an osmotic micropump (Alzet, model 2001) was transplanted to give the compound of the present invention (terazosin hydrochloride, TZ, subcutaneously) at a dose per ⁇ g/kg/day. Formulated as a sterile injectable solution with physiological saline or only with a excipient. Treatment of the compounds of the invention will continue until the third weekend after surgery.
  • MI-rat coronary artery ligation
  • pse-rat unligated sham-operated rats
  • the rats were anesthetized with pentobarbital 19 days after the surgery to occlude the coronary artery, and a catheter (PE-10, thermally welded with PE-50) was inserted through the femoral artery into the abdominal aorta.
  • the catheter is guided from the skin down to the neck of the animal, allowing it to pass out from there and secure and close it. Let the rats rest for two days.
  • the catheter was lengthened with a heparin-treated, saline-filled hose on the day of sample collection and two 1 ml blood samples were taken after at least 60 minutes.
  • the blood was collected in a pre-cooled sample vial (syringe) containing 10 ⁇ l of EDTA (0.1 M).
  • the vials were stored at -80 °C.
  • the plasma concentration of norepinephrine, epinephrine and dopamine will be determined by HPLC while on the other hand the concentration of ANF is analyzed by the RIA-test.
  • the amount of interstitial collagen was determined by randomly selecting 6 to 7 hearts from each experimental group. To this end, the heart was fixed by perfusion of 3.6% by weight of phosphate buffered formaldehyde. After removal of the atria and large blood vessels, the ventricles were cut from the apex to the bottom of the heart into 4 pieces and the sections were preserved for at least 24 hours in formaldehyde. After fixation, the sections were dehydrated and packaged in paraffin.
  • the 5 ⁇ m thin elbow with paraffin removed was incubated with 0.2% w/v phosphomolybdic acid aqueous solution for 5 minutes, and then incubated with 0.1% by weight of Sirius Red F3BA (Polysciencies Inc., UK) in saturated trinitrophenol solution for 45 minutes. Then, it was washed with 0.01 M hydrochloric acid for 2 minutes, dehydrated, and incorporated into Entellan (Merk, Germany) for microscopic examination. The infarcted area was removed, and the interstitial collagen of each heart was measured at 40-fold magnification in the septum between the ventricles as a Sirius red-positive area.
  • Sirius Red F3BA Polysciencies Inc., UK
  • the infarcted rats treated with the compounds of the present invention showed a slight weight loss as compared with the untreated infarcted rats, but the body weight was significantly decreased as compared with the pseudo-rats.
  • the infarcted rats treated with the compounds of the invention had significantly lower cardiac weight than untreated infarcted rats. From these data it is concluded that administration of the compounds of the invention prevents excessive cardiac hypertrophy.
  • the neurotransmitter activity measured according to plasma-norepinephrine levels and ANF levels was significantly elevated in untreated infarcted rats. Rats treated with the compounds of the invention had no change in ANF-plasma levels compared to untreated infarcted rats. Treatment with the compounds of the invention reduced plasma norepinephrine levels to approximately half of the plasma norepinephrine levels measured in pseudo-rats.
  • Plasma norepinephrine levels measured in untreated infarcted rats were significantly elevated and were up to three times the measured values of pseudo-rats.
  • plasma norepinephrine levels were reduced to almost half of the false rat values.
  • Plasma norepinephrine levels were significantly reduced in the 5 ⁇ g/kg/day group. This indicates that the compounds of the present invention at doses of 50 ⁇ g/kg/day and 5 ⁇ g/kg/day are effective in reducing the activation of sympathetic nerves after myocardial infarction in rats.
  • Heart rate measured in awake animals was significantly higher in infarcted rats than in sham rats.
  • Administration of the compounds of the invention not only reduced tachycardia, but the treated infarcted rats showed slower cardiac activity (hypopnea) compared to the pseudo-rats.
  • Table 6 Test results of sham-operated control animals (SHAM), untreated infarcted rats (INFARKT) and infarcted rats treated with the compound of the present invention (INF+TZ); doses of 50 ⁇ g/kg/day and 5 ⁇ g/kg/day
  • MPA mean arterial blood pressure
  • NA norepinephrine
  • ANF arterial natriuretic factor
  • * significantly different from pseudo-rat
  • # significantly different from untreated infarcted rats
  • Co.1, Co.14, Co.15, and Co.17 were used to test according to the results of Table 6 above. It was also found that some compounds could be reached at a dose of 25 ⁇ g/kg/day. The range of results presented above for the doses of terazosin 5 ⁇ g/kg/day and 50 ⁇ g/kg/day.
  • the results of the above tests indicate that the compounds of the present invention exert a beneficial, promoting healing and/or recovery effect on the myocardium state following myocardial infarction and are therefore suitable for treating acute myocardial infarction in humans and large mammals.
  • Myocardial damage caused by myocardial infarction is also treated within the scope and especially within the therapeutic range after myocardial infarction.
  • the compounds of the present invention are particularly effective in the treatment range after myocardial infarction.
  • the dosage of the compound of the present invention may vary depending on the individual case and naturally varies depending on the type of the condition to be treated and the form of administration.
  • the daily dose for oral administration or injection administration for the treatment of human myocardial infarction or after myocardial infarction is generally 0.01 to 5 mg, for example, 0.01 to 3 mg.

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Abstract

提供一种式I所示的化合物，或其药学可接受的盐、溶剂合物例如水合物、酯、前药，在制备用于预防和/或治疗哺乳动物脑血管疾病包括但不限于脑血栓、脑缺血、脑梗塞等，以及用于心血管疾病及心脏病包括但不限于心肌梗塞、心肌缺血、心肌损伤、冠心病、心绞痛、心力衰竭等中的用途。

Description

用于心脑血管疾病的喹唑啉衍生物 技术领域
本发明涉及一类可用于心脑血管疾病的喹唑啉衍生物，还涉及喹唑啉衍生物的新制药用途，特别涉及喹唑啉衍生物例如特拉唑嗪等在制备用于心脑血管疾病的药物中的用途。
背景技术
心脑血管疾病和心脏病是影响人类健康最广泛的疾病之一。典型的有脑血栓、脑缺血、脑梗塞等脑血管疾病以及心肌梗塞、心肌缺血、冠心病、心绞痛或心力衰竭等心血管疾病。
脑血栓是指由于各种原因导致的脑内血管堵塞，致使脑血管功能障碍，引起相关症状。由于脑内血管严重狭窄或闭塞，导致脑血流阻断而使脑组织发生缺血坏死和软化。引起脑血栓的原因较多，主要的是脑血管阻塞及脑部血液循环障碍，即脑血管和血液共同作用的结果。它的形成也有多重因素。脑血栓形成通常与以下三方面因素有关：血管病变、血液成分的改变或血液动力学改变有关。
此外，与脑血栓有关联的病症是，脑缺血又称缺血性卒中、脑梗塞，是一类由于脑血流供应障碍引起缺血、缺氧、导致脑局限性坏死或脑软化的疾病。缺血性脑损伤包括缺血期原发性损伤和再灌注期继发性损伤，其病理过程中的始动环节是缺血，恢复脑组织的血液灌注是其治疗基础，但再灌注继发性损伤则不可避免。缺血性脑血管病危害极大。资料显示，在57个国家中，有40个国家把缺血性脑血管疾病的死亡率列入了前3位，其中在日本和中国已居首位。在发达国家，急性缺血性脑卒中死亡率超过多种恶性肿瘤，是第2大致死病因，也是致成人长期严重残疾的最常见疾病。除了对患者及家庭的打击外，还造成了沉重的经济负担。国内每年死于中风(脑卒中)者有160万之众，并有新发病例150万人，总患病人数超过1500万人，其中缺血性中风的发病率远高于出血性脑中风，占中风总数的70％-80％，而且随着人口老龄化的进程，缺血性脑卒中发病率逐年上升。因此，研究脑缺血及再灌注损伤机制，研究和开发防治脑缺血及再灌注损伤的药物，降低缺血性脑血管病的死亡率和致残率，研究一种治疗心脑血管疾病，并且特别用于治疗缺血性脑病 的药物，是当前是卫生工作和科学研究的一项重要课题。
与心肌缺血有关的心血管疾病有心肌梗塞、冠心病、心绞痛或心力衰竭等。心肌梗塞一般应理解为由于区域性血液供应的持续性完全中断或显著性降低造成的局部心肌区域坏死。除一般的治疗方法(镇痛和镇静、供氧、卧床及特种饮食)外，在急性心肌梗塞中尤其还采用血栓溶解及纤维蛋白溶解的治疗，其目的在于通过局部缺血区域尽可能多(首要的)的再灌注使局部缺血的心肌免于最后的细胞死亡(即最后的坏死)并因此将梗塞面积限制在尽可能小的区域。在急性心肌梗塞阶段和在心肌梗塞后应用其它(辅助的)方法可能有助于改善心肌状态，尤其是在梗塞的区域内。
迄今为止，临床上仍然需要有有效的药物以应用治疗和/或预防心脑血管疾病例如脑血栓、脑缺血、脑梗塞等脑血管疾病以及心肌梗塞、心肌缺血、冠心病、心绞痛、心力衰竭等心血管疾病。
发明内容
本发明的目的是提供治疗和/或预防哺乳动物脑血管疾病、心血管疾病和/或心脏疾病的新药物。本发明人惊奇地发现，一类喹唑啉衍生物可以有效治疗和/或预防脑血管疾病、心血管疾病和/或心脏疾病，特别是例如脑血栓、脑缺血、脑梗塞等脑血管疾病以及心肌梗塞、心肌缺血、冠心病、心绞痛、心力衰竭等心血管疾病。
本发明涉及式I所示的化合物，或其药学上可接受的盐、前药、溶剂合物例如水合物或酯，在制备用于预防和/或治疗哺乳动物脑血管疾病、心血管疾病和/或心脏疾病的药物中的应用，
Figure PCTCN2015072662-appb-000001
其中
R1a和R1b各自独立地选自H、NH2、OH、C1-6烷基-、C1-6烷氧基-C1-6烷基-、C2-6烯基-、C2-6炔基-、C1-6烷氧基-、C1-6烷基酰基-、芳基酰基-、C6-10芳基-或C5-6环烷基-，所 述烷基任选地被1-3个选自下列的取代基取代：羟基或卤素；或者
R1a和R1b与它们连接的氮原子一起形成5-或6-元环；
R2和R3各自独立地选自H、卤素、C1-6烷基-、卤代C1-6烷基-、C2-6烯基-、C2-6炔基-、CN、NO2、NH2、OH、C1-6烷氧基-、C1-6烷氧基-C1-6烷氧基-、C1-6烷酰基氧基-、C1-6烷酰基氨基-、芳基酰基氨基-、饱和或不饱和的5-或6-元碳环基或杂环基、饱和或不饱和的5-或6-元碳环基氧基或杂环基氧基或者C1-6烷基酰基-；或者
R2和R3与它们连接的环原子一起形成5-或6-元碳环或杂环；
R4和R5各自独立地选自H、卤素、CN、NO2、NH2、OH、C1-6烷基-、C1-6烷氧基-C1-6烷氧基-、C1-6烷酰基氧基-、卤代C1-6烷基-、C2-6烯基-、C2-6炔基-、C1-6烷氧基-、C1-6烷酰基氨基-、芳基酰基氨基-、饱和或不饱和的5-或6-元碳环基或杂环基、饱和或不饱和的5-或6-元碳环基氧基-或杂环基氧基-或C1-6烷基酰基-。
关于由式(I)所示化合物制备的药物，本发明进一步提供了一些优选的技术方案。
一些实施方式中，式(I)中的R1a和R1b各自独立地选自H、NH2、OH、C1-6烷基-、C1-4烷氧基-C1-4烷基-、C2-4烯基-、C2-4炔基-、C1-4烷氧基-、C1-4烷基酰基-、苯基酰基-、苯基-或者C5-6环烷基，其中烷基任选被1-3个选自下列的取代基取代：羟基或卤素；或者，所述R1a和R1b与它们连接的氮原子一起形成5-或6-元环。
一些实施方式中，式(I)中的R2和R3各自独立地选自H、卤素、C1-6烷基-、卤代C1-6烷基-、C1-6烷氧基-、C1-6烷氧基-C1-6烷氧基-、C1-6烷酰基氧基-、C1-6烷酰基氨基-、芳基酰基氨基-、饱和或不饱和的5-或6-元碳环或杂环基或者饱和或不饱和的5-或6-元碳环或杂环基氧基；或者，所述R2和R3与它们连接的环原子一起形成5-或6-元碳环或杂环。
一些实施方式中，式(I)中的R4和R5各自独立地选自H、卤素、C1-6烷基-、C1-6烷氧基-C1-6烷氧基-、C1-6烷酰基氧基-、卤代C1-6烷基-、C1-6烷氧基-、C1-6烷酰基氨基-、芳基酰基氨基-、饱和或不饱和的5-或6-元碳环基或杂环基或者饱和或不饱和的5-或6-元碳环基氧基或杂环基氧基。
一些实施方式中，式(I)中的R1a和R1b各自独立地选自H、-NH2、-OH、CH3C(O)-、-(CH2)2-O-(CH2)2-OH、-CH2-CH＝CH2、-CH2-C≡CH、-(CH2)5CH3、-(CH2)4-CF3、环己基、-CH2-(CH2)3-CH2-、-(CH2)2O(CH2)2-OH、-Ph、CH3、-C(O)-CF3或-C(O)-Ph。
一些实施方式中，式(I)中的R2和R3各自独立地选自H、CH3O-、-CH2-O-CH2-、 -O(CH2)2OC2H5、-OC(O)CH3、-F、-CF3、
Figure PCTCN2015072662-appb-000002
并1,2-吡啶环、-NHCOCH3、-(CH2)2CH3、-NHCOPh、
Figure PCTCN2015072662-appb-000003
或者，所述R2和R3与它们连接的环原子一起形成含有2个氧的5元杂环。
一些实施方式中，式(I)中的R4和R5各自独立地选自H、-O(CH2)2OC2H5、-OC(O)CH3、-OCH3、
Figure PCTCN2015072662-appb-000004
-CF3、-F、-NHCOCH3、-(CH2)3CH3、-NHCOPh或
Figure PCTCN2015072662-appb-000005
一些实施方式中，式(I)中的R1a和R1b各自独立地选自H、NH2、OH、C1-6烷基-、C1-6烷氧基-C1-6烷基-、C2-6烯基-、C2-6炔基-、C1-6烷基酰基-或C5-6环烷基，其中烷基任选被1-3个选自下列的取代基取代：羟基或卤素；或者，所述R1a和R1b与它们连接的氮原子一起形成6元环。
一些实施方式中，式(I)中的R2和R3各自独立地选自卤素、C1-6烷基-、卤代C1-6烷基-、C1-6烷氧基-、C1-6烷氧基-C1-6烷氧基-、C1-6烷酰基氧基-或C1-6烷酰基氨基-。
一些实施方式中，式(I)中的R2和R3与它们连接的环原子一起形成5-或6-元杂环。
一些实施方式中，式(I)中的R4和R5各自独立地选自H、卤素、C1-6烷基-、C1-6烷氧基-C1-6烷氧基-、C1-6烷酰基氧基-、卤代C1-6烷基-、C1-6烷氧基-或C1-6烷酰基氨基-。
一些实施方式中，式(I)中的一些实施方式中，式(I)中的R1a和R1b各自独立地选自H、NH2、OH、C1-6烷基-、C1-4烷氧基-C1-4烷基-、C2-4烯基-、C2-4炔基-、C1-4烷基酰基-、苯基-或C5-6环烷基，其中所述基任选被1-3个选自下列的取代基取代：羟基或卤素。
一些实施方式中，式(I)中的R2和R3各自独立地选自卤素、C1-6烷基-、卤代C1-6烷基-、C1-6烷氧基-、C1-6烷氧基-C1-6烷氧基-、C1-6烷酰基氧基-或C1-6烷酰基氨基-。
一些实施方式中，式(I)中的R4和R5各自独立地选自H、卤素、C1-6烷基-、C1-6烷氧基-C1-6烷氧基-、C1-6烷酰基氧基-、卤代C1-6烷基-、C1-6烷氧基-或C1-6烷酰基氨基-。
一些实施方式中，式(I)中的R1a和R1b各自独立地选自H、-NH2、-OH。
一些实施方式中，式(I)中的R4和R5各自独立地选自H。
一些实施方式中，式(I)中的化合物选自编号Co.1至Co.33的化合物或其药学可接受的盐、前药、溶剂合物例如水合物或酯。
本发明中，所述烷基、烯基和炔基，或者所述烷氧基、烷基酰基等基团部分上的烷基，它们是直链或者支链的。在一个实施方案中，所述C1-6烷基或者所述C1-6烷氧基、C1-6烷基酰基等基团部分上的C1-6烷基部分，其选自C1-5烷基、C1-4烷基，例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基。在一些实施方式中，所述C2-6烯基选自C2-5烯基、C2-4烯基，例如乙烯基、丙烯基、烯丙基。在一些实施方式中，所述C2-6炔基选自C2-5炔基、C2-4炔基。所述C5-6环烷基选自环戊基和环己基。所述芳基或者所述芳基酰基上的芳基，其选自苯基、萘基，优选苯基。所述卤素选自氟、氯、溴和碘，优选氟和氯。
进一步地，本发明提供了上述药物用途的优选用途：
所述脑血管疾病包括但不限于脑血栓、脑缺血和/或脑梗塞。
所述心血管疾病和/或心脏疾病包括但不限于心肌梗塞、心肌缺血、心肌损伤、冠心病、心绞痛或心力衰竭。
所述心肌损伤包括但不限于急性心肌梗塞、慢性心肌梗塞和/或心肌梗塞后的治疗造成的心肌损伤。
本发明还提供了上述药物用于治疗哺乳动物所患脑血管疾病、心血管疾病和/或心脏疾病的方法，哺乳动物是以每日剂量低于100μg/kg的量(如0.1～100μg/kg)施用本发明提供的药物，至少连续施用7日。本发明还提供了此治疗方法的优选技术方案：例如哺乳动物以每日剂量低于75μg/kg的量(如0.1～75μg/kg)施用本发明化合物，至少连续施用7日，再如哺乳动物以每日剂量低于50μg/kg的量(0.1～50μg/kg)施用本发明化合物，至少连续施用7日。
本发明还提供了上述药物用于治疗哺乳动物所患脑血管疾病、心血管疾病和/或心脏疾病的方法，哺乳动物述哺乳动物以白细胞降低在可接受范围内的量施用所述化合物。其中，所述术语“白细胞降低在可接受范围内”是指：所述哺乳动物在每日施用并连续施用所述化合物7日之后时血中白细胞数量相对于施用所述化合物之前血中白细胞数量的百分数，该百分数在30％以上，例如在40％以上，例如在50％以上。当然通常会在150％以下，例如在130％以下。即，该百分数＝(用药7日后血中白细胞浓度÷用药前血中白细胞浓度)×100％，在本文中亦可称为“7日白细胞百分数”。该百分数越接近于100％(例如在50～150％范围内，特别是在70％～130％范围内)则表明动物血中白细胞数变化越小，对于 维持人体正常生理功能是有益的；但是当该百分数降低时，表明用药之后血中白细胞浓度降低。血中白细胞数量，即血中白细胞浓度，通常是以单位体积中白细胞的数目表示的，这种数据在临床实验室检查中是极普遍并且容易获得的，例如是可以容易地通过检查外周血而获得。
已经发现，所述哺乳动物以每日剂量低于100μg/kg的量连续施用本发明化合物至少7日，例如以每日剂量低于75μg/kg的量连续施用本发明化合物至少7日，例如以每日剂量低于50μg/kg的量连续施用本发明化合物至少7日；特别是所述哺乳动物是以每日剂量0.1～100μg/kg的量连续施用本发明化合物至少7日，例如以每日剂量0.1～75μg/kg的量连续施用本发明化合物至少7日，例如以每日剂量0.1～50μg/kg的量连续施用本发明化合物至少7日，在此施用方式下不但可以获得优良的预防和/或治疗脑血栓的效果，而且可以避免因使用所述化合物而引起的白细胞减少的不良反应，特别是在上述施用方式下可以获得所述哺乳动物血液中的白细胞降低在可接受范围内，特别是所述7日白细胞百分数在30％以上，例如在40％以上，例如在50％以上。例如通常会在150％以下，例如在130％以下。这种在获得优良预防和/或治疗脑血栓效果的基础上同时避免药物副作用的结果是完全出人意料的。
本发明中，所述式I化合物也包括特拉唑嗪或其药学可接受的盐或者其溶剂合物如水合物。例如可以是特拉唑嗪的盐酸盐或其水合物，例如是特拉唑嗪盐酸盐的二水合物。
心肌梗塞一般应理解为由于区域性血液供应的持续性完全中断或关键性的减低造成的局部心肌区域坏死。除一般的治疗方法(镇痛和镇静、供氧、卧床及特种饮食)外，在急性心肌梗塞中尤其还采用血栓溶解及纤维蛋白溶解的治疗，目的在于，通过局部缺血区域尽可能多(首要的)的再灌注使局部缺血的心肌免于最后的细胞死亡(即最后的坏死)，并因此将梗塞面积限制在尽可能小的区域。在急性心肌梗塞阶段和在心肌梗塞后应用其它(辅助的)方法可能有助于改善心肌状态，尤其是在梗塞的区域内。
本发明的为治疗心肌梗塞造成的心肌损伤而使用的本发明化合物在这种情况下一般适合于在心肌梗塞治疗范围内应用。因此这些化合物可以在治疗急性心肌梗塞并且特别在心肌梗塞后的治疗范围內，既可以在已经进行了纤维蛋白溶解治疗的病人中使用，又可以在没有进行这种溶解治疗的病人中使用。在进行了溶解治疗的梗塞后病人中本发明化合物对治疗，特别是还对预防形成心肌造成的心机能不全(心肌机能不全)有效。这也适用于那 些已经用p—肾上腺素能受体阻断剂进行过治疗的病人。
没有进行溶解的梗塞后的病人转入心肌梗塞的慢性阶段。对于处于慢性阶段的梗塞后病人特别有意义的是：交感神经系统(SNS)在心血管的调节中起重要的作用。交感神经的刺激是提高心脏喷射特别重要的机制，因为这一刺激既提高心肌收缩力又提高心率。此外，怠性心肌梗塞导致SNS的激活以维持灌注压力及组织灌注。这种急性状态可发展成更慢性阶段，在这一阶段中交感神经的激活会导致未受伤害的心肌的肥大和重建(Remodeling)。但这一过程可能超过所希望的程度并且由于各种原因持续的SNS激活可能是有害的：(1)考虑到心脏机能不全的发展可认为中枢交感神经系统的慢性激活是不利的。在持续性肾上腺素能的刺激中会导致心脏上补偿性的肾上腺素能受体的减少。但这种免于长久提高儿茶酚胺水平的心脏保护机制的后果是心率和心力通过自主神经系统调节的严重损害。(2)SNS-刺激提高血管紧张并因此提高心脏的后持续(Nachlast)。(3)升高的、循环的儿茶酚胺水平引起心脏中病灶坏死并促进心的肥大的产生。(4)升高的血浆-儿茶酚胺水平促进心率的不利的提高和有生命危险的心率不齐的时而出现。
因此，阻止或禁止过强的交感神经激活可能是治疗心肌梗塞病人，特别也是预防性治疗心肌梗塞后心脏衰弱的发展有价值的策略。
现已令人惊奇地发现，本发明用于治疗心肌梗塞和/或心肌梗塞后所用的本发明化合物由于其对心肌梗塞病人，尤其是心肌梗塞后的病人在慢性阶段的心肌功能状态产生令人惊奇的、促进康复和/或恢复的、有益的影响而出众。在心肌梗塞后给以本发明化合物使心脏重量减少并降低交感神经的激活，通过血浆-去甲肾上腺素-水平测得。因此本发明化合物适合于减少心脏的过度肥大，特别是在心肌梗塞后病人的后期治疗阶段。此外，本发明化合物降低血浆-去甲肾上腺素-水平，由此极为有效的使心肌梗塞后交感神经刺激正常化。
可通过口服(因为已知本发明化合物可容易地通过胃肠道吸收)、肌注、静脉注射方式施用本发明化合物，以治疗心肌梗塞引起的心肌损伤。
此外，尽管脑血栓、脑缺血等脑部疾病与心肌梗塞、心肌缺血等心脏部位疾病均与器官供血障碍有关，然而众所周知的，由于脑和心脏两种器官在工作模式等方面有极大的差异，两类疾病的治疗方式通常并不相同或相似，特别是众所周知的许多用于心脏疾病的药物根本不能适用于脑部疾病；同样地许多用于脑部疾病的药物亦根本不能适用于心脏疾 病，即两个器官的治疗方式并不任何关联性。然而在本发明中完全出人意料地发现，可用于如本发明所述脑部疾病的本发明化合物，还可适用于某些心脏疾病。
本发明任一方面或该任一方面的任一实施方案所具有的特征同样适用于其它任一方面或该其它任一方面的任一实施方案，只要它们不会相互矛盾，当然在相互之间适用时，必要的话可对相应特征作适当修饰。
下面对本发明的各个方面和特点作进一步的描述。
本发明所引述的所有文献，它们的全部内容通过引用并入本文，并且如果这些文献所表达的含义与本发明不一致时，以本发明的表述为准。此外，本发明使用的各种术语和短语具有本领域技术人员公知的一般含义，即便如此，本发明仍然希望在此对这些术语和短语作更详尽的说明和解释，提及的术语和短语如有与公知含义不一致的，以本发明所表述的含义为准。
本文中使用的术语“约”，其通常是指包括本领域允许的误差范围，例如±10％，例如±5％，例如±2％。
如本文所述的，术语“有效量”是指可在受试者中实现治疗、预防、减轻和/或缓解本发明所述疾病或病症的剂量。
如本文所述的，术语“药物”包括化合物及其药学上可接受的盐、前药、溶剂合物例如水合物或酯，还包括含有这些化合物及其药学上可接受的盐、前药、溶剂合物例如水合物或酯的药物组合物。术语“药物组合物”，其可与“组合物”互换使用，“药物”或“药物组合物”是指可用于在受试者中实现治疗、预防、减轻和/或缓解本发明所述疾病、病症、症状的物质。
如本文所述的，术语“受试者”或“患者”，可以指接受本发明组合物和提取物以治疗、预防、减轻和/或缓解本发明所述疾病、病症、症状的动物，特别是哺乳动物，例如人、狗、猴、牛、马等。
如本文所述的，术语“疾病或症状”是指所述受试者的一种身体状态，该身体状态与本发明所述疾病或症状有关。
如本文所述的，“％”，如未特别指明，对于总物料是固体时一般是指重量/重量的百分比，对于总物料是液体时一般是指重量/体积的百分比。当然，对于总物料是液体并且溶质是液体时，表征该液态溶质的百分比一般是指体积/体积的百分比。
特拉唑嗪(Terazosin，TZ，(4-(4-氨基-6,7-二甲氧基喹唑啉-2-基)哌嗪-1-基)(四氢呋喃-2-基)甲酮，C19H25N5O4)，其为本发明所述编号Co.33的化合物。在本发明中，当提及特拉唑嗪时，其不但包括以上结构所示的Co.33化合物，还包括上述结构化合物的药学可接受的盐(例如盐酸盐)，以及上述结构化合物及其盐的溶剂合物例如水合物例如二水合物。在本发明的一个优选实施方案中，所述特拉唑嗪是指盐酸特拉唑嗪二水合物。本发明下文使用作为式I化合物典型示例的特拉唑嗪进行了大量研究以表明本发明出人意料的效果；在下文试验特别是生物学试验中，如未另外指明，所用的试药特拉唑嗪是指盐酸特拉唑嗪二水合物，但众所周知的，是否呈盐形式以及呈何种盐形式以及是否是水合物，这些要素通常并不影响药物的治疗效果。
附图说明
图1：大鼠MCAO模型试验结果。
具体实施方式
以下详细实例用于描述本发明，但并不是用于限制本发明范围。
A、化合物实施例部分
以下实施例示例性地制备了本发明的部分式I化合物，各化合物分别以Co.1至Co.32表示，而Co.33表示特拉唑嗪，其是已知化合物(购自贵州威门，国药准字H20103323)。以下实施例的反应流程中，“reflux”表示回流，“1-pentanol”表示1-戊醇。
实施例1：Co.1的制备
Figure PCTCN2015072662-appb-000006
步骤1：向溶有化合物1a(50mmol)的200mL四氢呋喃溶液中通入氨气，反应在25℃下进行36小时。体系中有大量白色固体析出，过滤所得白色固体用四氢呋喃洗涤后得最终产品1f，产率为：63％。
Figure PCTCN2015072662-appb-000007
步骤2：向化合物1f(10mmol)加入15mL醋酸酐，反应回流2小时。冷却到室温，体系中有大量白色固体析出，过滤所得白色固体用四氢呋喃洗涤后得最终产品1g，产率为：63％。
Figure PCTCN2015072662-appb-000008
步骤3：在氩气氛的情况下，向溶有1g(2mmol)的1-戊醇的溶液中加入1d(2mmol)。反应体系回流4.5小时后，将其置于0-5℃环境中静置结晶。用10mL丙酮洗涤所得白色晶体两次，再用乙醚/甲醇重结晶后得最终产品1i即为化合物Co.1，产率为：60％。1H NMR(300MHz,CDCl3):1.84(m,2H,thf-H),2.03(m,2H,thf-H),d 2.61(s,3H,CH3),3.474.07(m,11H,thf-H,pip-H和CH2CH2O),3.93(s,3H,OCH3),3.97(s,3H,OCH3),4.82(m,1H,thf-2H),7.16(s,1H,Ar-5H),7.72(s,1H,Ar-8H)；HR-MS(ESI-正性):430.20928(M+H)(计算值：430.20904)；元素分析：(C,58.74；H,6.34；N,16.30；O,18.63)；计算值：(C,58.73；H,6.34；N,16.31；O,18.63)。
实施例2：Co.2的制备
Figure PCTCN2015072662-appb-000009
步骤1：向溶有化合物1a(20mmol)的100mL甲醇溶液中加入化合物1b(20mmol)，反应在25℃下进行4小时。薄板层析指示1a转化完全后，向体系中加入100mL乙醚，混匀后放在-20℃环境中静置结晶。所得白色固体用石油醚/乙酸乙酯重结晶后得最终产品1c，产率为：41％。
Figure PCTCN2015072662-appb-000010
步骤2：在氩气氛的情况下，向溶有1c(2mmol)的1-戊醇(1-pentanol)的溶液中加入1d(2mmol)。反应体系回流(reflux)4.5小时后，将其置于0-5℃环境中静置结晶。用10mL丙酮洗涤所得白色晶体两次，再用乙醚/甲醇重结晶后得最终产品1e即为化合物Co.2，产率为：62％。1H NMR(300MHz,DMSO-d6):1.84(m,2H,thf-H),2.03(m,2H,thf-H),3.474.07(m,14H,thf-H,pip-H和CH2CH2O),3.84(s,3H,OCH3),3.87(s,3H,OCH3),4.73(m,1H,thf-2H),7.16(s,1H,Ar-5H),7.72(s,1H,Ar-8H)；13C NMR(DMSO-d6):d 25.2,27.9,40.9,44.1,44.6,55.8,56.2,60.1,68.1,68.2,72.1,74.9,102.4,104.4,106.9,146.2,154.4,154.2,158.6,169.6；HR-MS(ESI-正性):476.25120(M+H)(计算值：476.25091)；元素分析：C,58.08；H,7.00；N,14.73；O,20.19；计算值：(C,58.09；H,6.99；N,14.73；O,20.19)。
实施例3：Co.3的制备
Figure PCTCN2015072662-appb-000011
步骤1：向溶有化合物1a(20mmol)的100mL甲醇溶液中加入水合肼(20mmol)，反应在25℃下进行4小时。薄板层析指示1a转化完全后，向体系中加入100mL乙醚、混匀后放入-20℃环境中静置结晶。所得白色固体用石油醚/乙酸乙酯重结晶后得最终产品3a，产率为：61％。
Figure PCTCN2015072662-appb-000012
步骤2：在氩气氛的情况下，向溶有3a(2mmol)的1-戊醇溶液中加入1d(2mmol)。反应体系回流4.5小时后，将其置于0-5℃环境中静置结晶。用10mL丙酮洗涤所得白色晶体两次，再用乙醚/甲醇重结晶后得最终产品3b即为化合物Co.3，产率为：31％。1H NMR(300MHz,DMSO-d6):d 1.87(m,2H,thf-H),2.03(m,2H,thf-H),3.434.07(m,6H,thf-H,pip-H),3.86(s,3H,OCH3),3.88(s,3H,OCH3),4.63(m,1H,thf-2H),7.16(s,1H,Ar-5H), 7.82(s,1H,Ar-8H)；HR-MS(ESI-正性):403.20938(M+H)(计算值：403.20946)。
实施例4：Co.4的制备
Figure PCTCN2015072662-appb-000013
步骤1：向溶有化合物1a(20mmol)的100mL甲醇溶液中加入羟氨(20mmol)水溶液，反应在25℃下进行3小时。薄板层析指示1a转化完全后，向体系中加入100mL乙醚、混匀后放入-20℃环境中静置结晶。所得白色固体用石油醚/乙酸乙酯重结晶后得最终产品4a，产率为：88％。
Figure PCTCN2015072662-appb-000014
步骤2：在氩气氛的情况下，向溶有4a(2mmol)的1-戊醇的溶液中加入1d(2mmol)。反应体系回流4.5小时后，将其置于0-5℃环境中静置结晶。用10mL丙酮洗涤所得白色晶体两次，再用乙醚/甲醇重结晶后得最终产品4b即为化合物Co.4，产率为：75％。1H NMR(300MHz,DMSO-d6):1.81(m,2H,thf-H),2.03(m,2H,thf-H),3.474.07(m,6H,thf-H,pip-H),3.87(s,3H,OCH3),3.94(s,3H,OCH3),4.43(m,1H,thf-2H),7.26(s,1H,Ar-5H),7.74(s,1H,Ar-8H)；HR-MS(ESI-正性):404.19339(M+H)(计算值：404.19341)。
实施例5：Co.5的制备
Figure PCTCN2015072662-appb-000015
步骤1：向溶有化合物1a(20mmol)的100mL甲醇溶液中加入烯丙基胺(22mmol)，反应在25℃下进行8小时。薄板层析指示1a转化完全后，向体系中加入100mL乙醚、混匀后放入-20℃环境中静置结晶。所得白色固体用石油醚/乙酸乙酯重结晶后得最终产品5a，产率为：31％。
Figure PCTCN2015072662-appb-000016
步骤2：在氩气氛的情况下，向溶有5a(2mmol)的1-戊醇的溶液中加入1d(2mmol)。反应体系回流4.5小时后，将其置于0-5℃环境中静置结晶。用10mL丙酮洗涤所得白色晶体两次，再用乙醚/甲醇重结晶后得最终产品5b即为化合物Co.5，产率为：75％。1H NMR(300MHz,DMSO-d6):1.82(m,2H,thf-H),2.03(m,2H,thf-H),3.474.07(m,6H,thf-H,pip-H),3.87(s,3H,OCH3),3.94(s,3H,OCH3),4.04(d,2H),4.43(m,1H,thf-2H),5.19-5.23(m,2H),5.82-5.88(m,1H),7.26(s,1H,Ar-5H),7.74(s,1H,Ar-8H)；HR-MS(ESI-正性):428.22978(M+H)(计算值：428.22986)。
实施例6：Co.6的制备
Figure PCTCN2015072662-appb-000017
步骤1：向溶有化合物1a(20mmol)的100mL甲醇溶液中加入炔丙基胺(28mmol)，反应在25℃下进行10小时。薄板层析指示1a转化完全后，向体系中加入100mL乙醚、混匀后放入-20℃环境中静置结晶。所得白色固体用石油醚/乙酸乙酯重结晶后得最终产品6a，产率为：44％。
Figure PCTCN2015072662-appb-000018
步骤2：在氩气氛的情况下，向溶有6a(2mmol)的1-戊醇的溶液中加入1d(2mmol)。反应体系回流4.5小时后，将其置于0-5℃环境中静置结晶。用10mL丙酮洗涤所得白色晶体两次，再用乙醚/甲醇重结晶后得最终产品6b即为化合物Co.6，产率为：75％。1H NMR(300MHz,DMSO-d6):1.82(m,2H,thf-H),2.03(m,2H,thf-H),3.474.07(m,6H,thf-H,pip-H),3.80(s,2H)，3.87(s,3H,OCH3),3.94(s,3H,OCH3),4.04(d,2H),4.43(m,1H,thf-2H),7.26(s,1H,Ar-5H),7.74(s,1H,Ar-8H)；HR-MS(ESI-正性):426.21413(M+H)(计 算值：426.21408)。
实施例7：Co.7的制备
Figure PCTCN2015072662-appb-000019
步骤1：向溶有化合物1a(20mmol)的100mL甲醇溶液中加入化合物7a(20mmol)，反应在25℃下进行3小时。薄板层析指示1a转化完全后，向体系中加入100mL乙醚、混匀后放入-20℃环境中静置结晶。所得白色固体用石油醚/乙酸乙酯重结晶后得最终产品7b，产率为：61％。
Figure PCTCN2015072662-appb-000020
步骤2：在氩气氛的情况下，向溶有7b(2mmol)的1-戊醇的溶液中加入1d(2mmol)。反应体系回流4.5小时后，将其置于0-5℃环境中静置结晶。用10mL丙酮洗涤所得白色晶体两次，再用乙醚/甲醇重结晶后得最终产品7c即为化合物Co.7，产率为：62％。1H NMR(300MHz,DMSO-d6):0.86-1.62(m,11H,)，1.84(m,2H,thf-H),2.03(m,2H,thf-H),3.464.07(m,8H,thf-H,pip-H),3.86(s,3H,OCH3),3.83(s,3H,OCH3),4.75(m,1H,thf-2H),7.16(s,1H,Ar-5H),7.72(s,1H,Ar-8H)；HR-MS(ESI-正性):472.29238(M+H)(计算值：472.29229)。
实施例8：Co.8的制备
Figure PCTCN2015072662-appb-000021
步骤1：向溶有化合物1a(20mmol)的100mL甲醇溶液中加入化合物8a(20mmol)，反应在25℃下进行1.5小时。薄板层析指示1a转化完全后，向体系中加入100mL乙醚、混匀后放入-20℃环境中静置结晶。所得白色固体用石油醚/乙酸乙酯重结晶后得最终产品8b，产率为：71％。
Figure PCTCN2015072662-appb-000022
步骤2：在氩气氛的情况下，向溶有8b(2mmol)的1-戊醇的溶液中加入1d(2mmol)。反应体系回流4.5小时后，将其置于0-5℃环境中静置结晶。用10mL丙酮洗涤所得白色晶体两次，再用乙醚/甲醇重结晶后得最终产品8c即为化合物Co.8，产率为：42％。1H NMR(300MHz,DMSO-d6):1.22-1.72(m,11H,)，1.84(m,2H,thf-H),2.03(m,2H,thf-H),3.474.05(m,8H,thf-H,pip-H),3.82(s,3H,OCH3),3.73(s,3H,OCH3),4.43(m,1H,thf-2H),7.54(s,1H,Ar-5H),7.86(s,1H,Ar-8H)；HR-MS(ESI-正性):512.24846(M+H)(计算值：512.24859)。
实施例9：Co.9的制备
Figure PCTCN2015072662-appb-000023
步骤1：向溶有化合物1a(20mmol)的100mL甲醇溶液中加入化合物9a(20mmol)，反应在25℃下进行2.5小时。薄板层析指示1a转化完全后，向体系中加入100mL乙醚、混匀后放入-20℃环境中静置结晶。所得白色固体用石油醚/乙酸乙酯重结晶后得最终产品9b，产率为：21％。
Figure PCTCN2015072662-appb-000024
步骤2：在氩气氛的情况下，向溶有9b(2mmol)的1-戊醇的溶液中加入1d(2mmol)。反应体系回流4.5小时后，将其置于0-5℃环境中静置结晶。用10mL丙酮洗涤所得白色晶体两次，再用乙醚/甲醇重结晶后得最终产品9c即为化合物Co.9，产率为：43％。1H NMR(300MHz,DMSO-d6):1.32-1.52(m,10H,)，1.86(m,2H,thf-H),2.03(m,2H,thf-H),3.47 4.07(m,9H,thf-H,pip-H),3.82(s,3H,OCH3),3.79(s,3H,OCH3),4.46(m,1H,thf-2H),7.33(s,1H,Ar-5H),7.78(s,1H,Ar-8H)；HR-MS(ESI-正性):470.27673(M+H)(计算值：470.27658)。
实施例10：Co.10的制备
Figure PCTCN2015072662-appb-000025
步骤1：向溶有化合物1a(20mmol)的100mL甲醇溶液中加入化合物10a(20mmol)，反应在25℃下进行5小时。薄板层析指示1a转化完全后，向体系中加入100mL乙醚、混匀后放入-20℃环境中静置结晶。所得白色固体用石油醚/乙酸乙酯重结晶后得最终产品10b，产率为：36％。
Figure PCTCN2015072662-appb-000026
步骤2：在氩气氛的情况下，向溶有10b(2mmol)的1-戊醇的溶液中加入1d(2mmol)。反应体系回流4.5小时后，将其置于0-5℃环境中静置结晶。用10mL丙酮洗涤所得白色晶体两次，再用乙醚/甲醇重结晶后得最终产品10c即为化合物Co.10，产率为：43％。1HNMR(300MHz,DMSO-d6):1.33-1.47(m,6H,)，1.86(m,2H,thf-H),2.04(m,2H,thf-H),3.574.09(m,12H,thf-H,pip-H),3.82(s,3H,OCH3),3.77(s,3H,OCH3),4.48(m,1H,thf-2H),7.37(s,1H,Ar-5H),7.79(s,1H,Ar-8H)；HR-MS(ESI-正性):456.26108(M+H)(计算值：456.26119)。
实施例11：Co.11的制备
Figure PCTCN2015072662-appb-000027
步骤1：向溶有化合物1a(20mmol)的100mL甲醇溶液中加入化合物11a(20mmol)， 反应在25℃下进行5小时。薄板层析指示1a转化完全后，向体系中加入100mL乙醚、混匀后放入-20℃环境中静置结晶。所得白色固体用石油醚/乙酸乙酯重结晶后得最终产品11b，产率为：41％。
Figure PCTCN2015072662-appb-000028
步骤2：在氩气氛的情况下，向溶有11b(2mmol)的1-戊醇的溶液中加入1d(2mmol)。反应体系回流4.5小时后，将其置于0-5℃环境中静置结晶。用10mL丙酮洗涤所得白色晶体两次，再用乙醚/甲醇重结晶后得最终产品11c即为化合物Co.11，产率为：62％。1H NMR(300MHz,DMSO-d6):1.79(m,2H,thf-H),2.06(m,2H,thf-H),3.274.08(m,17H,thf-H,pip-H和CH2CH2O),3.85(s,3H,OCH3),3.88(s,3H,OCH3),4.73(m,1H,thf-2H),7.26(s,1H,Ar-5H),7.72(s,1H,Ar-8H)；HR-MS(ESI-正性):490.26656(M+H)(计算值：490.26658)。
实施例12：Co.12的制备
Figure PCTCN2015072662-appb-000029
步骤1：在氩气氛的情况下，向溶有12a(2mmol)的1-戊醇的溶液中加入1d(2mmol)。反应体系回流4.5小时后，将其置于0-5℃环境中静置结晶。用10mL丙酮洗涤所得白色晶体两次，再用乙醚/甲醇重结晶后得最终产品12b即为化合物Co.12，产率为：62％。1HNMR(300MHz,DMSO-d6):1.79(m,2H,thf-H),2.06(m,2H,thf-H),3.474.08(m,11H,thf-H,pip-H),3.85(s,3H,OCH3),3.88(s,3H,OCH3),4.73(m,1H,thf-2H),6.86-7.62(m,7H,Ar-H)；HR-MS(ESI-正性):464.22978(M+H)(计算值：464.22996)。
实施例13：Co.13的制备
Figure PCTCN2015072662-appb-000030
步骤1：向化合物1f(10mmol)加入20mL 13a，反应回流2小时。冷却到室温，体系中有大量白色固体析出，过滤所得白色固体用四氢呋喃洗涤后得最终产品13b，产率为：82％。
Figure PCTCN2015072662-appb-000031
步骤2：在氩气氛的情况下，向溶有13b(2mmol)的1-戊醇的溶液中加入1d(2mmol)。反应体系回流5.5小时后，将其置于0-5℃环境中静置结晶。用10mL丙酮洗涤所得白色晶体两次，再用乙醚/甲醇重结晶后得最终产品13c即为化合物Co.13，产率为：62％。1HNMR(300MHz,CDCl3):1.80(m,2H,thf-H),2.06(m,2H,thf-H),3.474.07(m,13H,thf-H,pip-H),3.93(s,3H,OCH3),3.97(s,3H,OCH3),4.82(m,1H,thf-2H),7.16(s,1H,Ar-5H),7.72(s,1H,Ar-8H)；HR-MS(ESI-正性):484.18078(M+H)(计算值：484.18084)。
实施例14：Co.14的制备
Figure PCTCN2015072662-appb-000032
步骤1：向化合物1f(10mmol)加入22mL 14a，反应回流2小时。冷却到室温，体系中有大量白色固体析出，过滤所得白色固体用四氢呋喃洗涤后得最终产品14b，产率为：55％。
Figure PCTCN2015072662-appb-000033
步骤2：在氩气氛的情况下，向溶有14b(2mmol)的1-戊醇的溶液中加入1d(2mmol)。反应体系回流4.5小时后，将其置于0-5℃环境中静置结晶。用10mL丙酮洗涤所得白色晶体两次，再用乙醚/甲醇重结晶后得最终产品14c即为化合物Co.14，产率为：48％。1HNMR(300MHz,CDCl3):d 1.84(m,2H,thf-H),2.03(m,2H,thf-H),3.454.47(m,13H,thf-H,pip-H),3.93(s,3H,OCH3),3.97(s,3H,OCH3),4.82(m,1H,thf-2H),6.89-7.72(m,7H,Ar-H)；HR-MS(ESI-正性):492.22469(M+H)(计算值：492.22478)。
实施例15：Co.15的制备
Figure PCTCN2015072662-appb-000034
步骤1：在氩气氛的情况下，向溶有15a(2mmol)的1-戊醇的溶液中加入1d(2mmol)。反应体系回流4.5小时后，将其置于0-5℃环境中静置结晶。用10mL丙酮洗涤所得白色晶体两次，再用乙醚/甲醇重结晶后得最终产品15b即为化合物Co.15，产率为：55％。1HNMR(300MHz,CDCl3):1.84(m,2H,thf-H),2.03(m,2H,thf-H),3.494.27(m,13H,thf-H,pip-H),4.82(m,1H,thf-2H),6.07(s,2H,CH2OCH2)7.27(s,1H,Ar-5H),7.68(s,1H,Ar-8H)；HR-MS(ESI-正性):372.16718(M+H)(计算值：372.16726)。
实施例16：Co.16的制备
Figure PCTCN2015072662-appb-000035
步骤1：在氩气氛的情况下，向溶有16a(2mmol)的1-戊醇的溶液中加入1d(2mmol)。反应体系回流4.5小时后，将其置于0-5℃环境中静置结晶。用10mL丙酮洗涤所得白色晶体两次，再用乙醚/甲醇重结晶后得最终产品16b即为化合物Co.16，产率为：45％。1HNMR(300MHz,CDCl3):1.15-1.26(t,6H,CH3-H)1.87(m,2H,thf-H),2.03(m,2H,thf-H),3.454.17(m,25H,thf-H,pip-H),4.79(m,1H,thf-2H),7.27(s,1H,Ar-5H),7.68(s,1H,Ar-8H)；HR-MS(ESI-正性):504.28215(M+H)(计算值：504.28221)。
实施例17：Co.17的制备
Figure PCTCN2015072662-appb-000036
步骤1：在氩气氛的情况下，向溶有17a(2mmol)的1-戊醇的溶液中加入1d(2mmol)。反应体系回流4小时后，将其置于0-5℃环境中静置结晶。用10mL丙酮洗涤所得白色晶体两次，再用乙醚/甲醇重结晶后得最终产品17b即为化合物Co.17，产率为：55％。1H NMR(300MHz,CDCl3):1.83(m,2H,thf-H),2.03(m,2H,thf-H),d 2.61(s,3H,CH3),3.474.07(m,11H,thf-H,pip-H和CH2CH2O),3.94(s,3H,OCH3),4.82(m,1H,thf-2H),7.18(s,1H,Ar-5H),7.72(s,1H,Ar-8H)；HR-MS(ESI-正性):416.19344(M+H)(计算值：416.19339)。
实施例18：Co.18的制备
Figure PCTCN2015072662-appb-000037
步骤1：在氩气氛的情况下，向溶有18a(2mmol)的1-戊醇的溶液中加入1d(2mmol)。反应体系回流3小时后，将其置于0-5℃环境中静置结晶。用10mL丙酮洗涤所得白色晶体两次，再用乙醚/甲醇重结晶后得最终产品18b即为化合物Co.18，产率为：75％。1H NMR(300MHz,CDCl3):1.80(m,2H,thf-H),2.03(m,2H,thf-H),3.574.07(m,11H,thf-H,pip-H),3.94(s,3H,OCH3),4.85(m,1H,thf-2H),7.23(s,1H,Ar-5H),7.80(s,1H,Ar-8H)；HR-MS(ESI-正性):376.17853(M+H)(计算值：376.17849)。
实施例19：Co.19的制备
Figure PCTCN2015072662-appb-000038
步骤1：在氩气氛的情况下，向溶有19a(2mmol)的1-戊醇的溶液中加入1d(2mmol)。反应体系回流3小时后，将其置于0-5℃环境中静置结晶。用10mL丙酮洗涤所得白色晶 体两次，再用乙醚/甲醇重结晶后得最终产品19b即为化合物Co.19，产率为：54％。1H NMR(300MHz,CDCl3):1.15-1.26(m,6H),1.89(m,2H,thf-H),2.03(m,2H,thf-H),3.074.07(m,15H,thf-H,pip-H),4.85(m,1H,thf-2H),7.63(s,1H,Ar-5H),7.89(s,1H,Ar-8H)；HR-MS(ESI-正性):479.23836(M+H)(计算值：479.23823)。
实施例20：Co.20的制备
Figure PCTCN2015072662-appb-000039
步骤1：在氩气氛的情况下，向溶有20a(2mmol)的1-戊醇的溶液中加入1d(2mmol)。反应体系回流3小时后，将其置于0-5℃环境中静置结晶。用10mL丙酮洗涤所得白色晶体两次，再用乙醚/甲醇重结晶后得最终产品20b即为化合物Co.20，产率为：54％。1H NMR(300MHz,CDCl3):1.83(m,2H,thf-H),2.03(m,2H,thf-H),3.074.07(m,11H,thf-H,pip-H),4.88(m,1H,thf-2H),7.58(m,1H,Ar-H),7.63(s,1H,Ar-H),7.89(s,1H,Ar-H),8.38(d,1H,Ar-H)8.83(d,1H,Ar-H)；HR-MS(ESI-正性):379.18833(M+H)(计算值：379.18825)。
实施例21：Co.21的制备
Figure PCTCN2015072662-appb-000040
步骤1：在氩气氛的情况下，向溶有21a(2mmol)的1-戊醇的溶液中加入1d(2mmol)。反应体系回流4小时后，将其置于0-5℃环境中静置结晶。用10mL丙酮洗涤所得白色晶体两次，再用乙醚/甲醇重结晶后得最终产品21b即为化合物Co.21，产率为：54％。1H NMR(300MHz,CDCl3):1.86(m,2H,thf-H),2.01(m,2H,thf-H),2.62(s,3H,CH3),3.174.07(m,11H,thf-H,pip-H),3.97(s,3H,OCH3),4.85(m,1H,thf-2H),7.89(s,1H,Ar-H),8.83(d,1H,Ar-H)；HR-MS(ESI-正性):379.18833(M+H)(计算值：379.18825)。
实施例22：Co.22的制备
Figure PCTCN2015072662-appb-000041
步骤1：在氩气氛的情况下，向溶有22a(2mmol)的1-戊醇的溶液中加入1d(2mmol)。反应体系回流5小时后，将其置于0-5℃环境中静置结晶。用10mL丙酮洗涤所得白色晶体两次，再用乙醚/甲醇重结晶后得最终产品22b即为化合物Co.22，产率为：61％。1H NMR(300MHz,CDCl3):0.88-0.93(t,3H)，1.62(m,2H)，1.88(m,2H,thf-H),2.03(m,2H,thf-H),2.64(t,2H)，3.574.07(m,11H,thf-H,pip-H),3.94(s,3H,OCH3),4.85(m,1H,thf-2H),7.23(s,1H,Ar-5H),7.82(s,1H,Ar-8H)；HR-MS(ESI-正性):400.23464(M+H)(计算值：400.23486)。
实施例23：Co.23的制备
Figure PCTCN2015072662-appb-000042
步骤1：在氩气氛的情况下，向溶有23a(2mmol)的1-戊醇的溶液中加入1d(2mmol)。反应体系回流5小时后，将其置于0-5℃环境中静置结晶。用10mL丙酮洗涤所得白色晶体两次，再用乙醚/甲醇重结晶后得最终产品23b即为化合物Co.23，产率为：48％。1H NMR(300MHz,CDCl3):1.87(m,2H,thf-H),2.01(m,2H,thf-H),3.174.07(m,11H,thf-H,pip-H),3.97(s,3H,OCH3),4.87(m,1H,thf-2H),6.86-7.62(m,7H,Ar-H)；HR-MS(ESI-正性):477.22497(M+H)(计算值：477.22503)。
实施例24：Co.24的制备
Figure PCTCN2015072662-appb-000043
步骤1：在氩气氛的情况下，向溶有24a(2mmol)的1-戊醇的溶液中加入1d(2mmol)。反应体系回流4小时后，将其置于0-5℃环境中静置结晶。用10mL丙酮洗涤所得白色晶 体两次，再用乙醚/甲醇重结晶后得最终产品24b即为化合物Co.24，产率为：24％。1H NMR(300MHz,CDCl3):1.86(m,2H,thf-H),1.94-2.58(m,8H),3.174.07(m,12H,thf-H,pip-H),3.97(s,3H,OCH3),4.85(m,1H,thf-2H),5.56(m,2H),7.15(s,1H,Ar-5H),7.71(s,1H,Ar-8H)；HR-MS(ESI-正性):454.24499(M+H)(计算值：454.24543)。
实施例25：Co.25的制备
Figure PCTCN2015072662-appb-000044
步骤1：在氩气氛的情况下，向溶有25a(2mmol)的1-戊醇的溶液中加入1d(2mmol)。反应体系回流4.5小时后，将其置于0-5℃环境中静置结晶。用10mL丙酮洗涤所得白色晶体两次，再用乙醚/甲醇重结晶后得最终产品25b即为化合物Co.25，产率为：45％。1HNMR(300MHz,CDCl3):1.15-1.26(t,6H,CH3-H)1.88(m,2H,thf-H),2.03(m,2H,thf-H),3.444.17(m,25H,thf-H,pip-H),3.85(s,3H,OCH3),3.87(s,3H,OCH3),4.87(m,1H,thf-2H),7.27(s,1H,Ar-5H),7.68(s,1H,Ar-8H)；HR-MS(ESI-正性):564.30330(M+H)(计算值：564.30334)。
实施例26：Co.26的制备
Figure PCTCN2015072662-appb-000045
步骤1：在氩气氛的情况下，向溶有26a(2mmol)的1-戊醇的溶液中加入1d(2mmol)。反应体系回流4小时后，将其置于0-5℃环境中静置结晶。用10mL丙酮洗涤所得白色晶体两次，再用乙醚/甲醇重结晶后得最终产品26b即为化合物Co.26，产率为：55％。1H NMR(300MHz,CDCl3):1.86(m,2H,thf-H),2.03(m,2H,thf-H),d 2.61(s,3H,CH3),3.474.07(m,11H,thf-H,pip-H和CH2CH2O),3.91(s,3H,OCH3),3.95(s,3H,OCH3),3.99(s,3H,OCH3),4.82(m,1H,thf-2H),7.16(s,1H,Ar-5H),7.72(s,1H,Ar-8H)；HR-MS(ESI-正性):476.21445(M+H)(计算值：476.21452)。
实施例27：Co.27的制备
Figure PCTCN2015072662-appb-000046
步骤1：在氩气氛的情况下，向溶有27a(2mmol)的1-戊醇的溶液中加入1d(2mmol)。反应体系回流3小时后，将其置于0-5℃环境中静置结晶。用10mL丙酮洗涤所得白色晶体两次，再用乙醚/甲醇重结晶后得最终产品27b即为化合物Co.27，产率为：53％。1H NMR(300MHz,CDCl3):1.15-1.26(m,6H),1.88(m,2H,thf-H),2.03(m,2H,thf-H),3.074.07(m,15H,thf-H,pip-H),3.86(s,3H,OCH3),3.88(s,3H,OCH3),4.85(m,1H,thf-2H),7.63(s,1H,Ar-5H),7.89(s,1H,Ar-8H)；HR-MS(ESI-正性):539.25942(M+H)(计算值：539.25936)。
实施例28：Co.28的制备
Figure PCTCN2015072662-appb-000047
步骤1：在氩气氛的情况下，向溶有28a(2mmol)的1-戊醇的溶液中加入1d(2mmol)。反应体系回流3小时后，将其置于0-5℃环境中静置结晶。用10mL丙酮洗涤所得白色晶体两次，再用乙醚/甲醇重结晶后得最终产品28b即为化合物Co.28，产率为：75％。1H NMR(300MHz,CDCl3):1.78(m,2H,thf-H),2.03(m,2H,thf-H),3.574.07(m,11H,thf-H,pip-H),3.86(s,3H,OCH3),3.88(s,3H,OCH3),3.94(s,3H,OCH3),4.85(m,1H,thf-2H),7.23(s,1H,Ar-5H),7.82(s,1H,Ar-8H)；HR-MS(ESI-正性):436.19955(M+H)(计算值：436.19962)。
实施例29：Co.29的制备
Figure PCTCN2015072662-appb-000048
步骤1：在氩气氛的情况下，向溶有29a(2mmol)的1-戊醇的溶液中加入1d(2mmol)。反应体系回流3小时后，将其置于0-5℃环境中静置结晶。用10mL丙酮洗涤所得白色晶体两次，再用乙醚/甲醇重结晶后得最终产品29b即为化合物Co.29，产率为：44％。1H NMR(300MHz,CDCl3):1.84(m,2H,thf-H),2.01(m,2H,thf-H),2.62(s,3H,CH3),3.174.07(m,11H,thf-H,pip-H),3.82(s,3H,OCH3),3.85(s,3H,OCH3),3.97(s,3H,OCH3),4.85(m,1H,thf-2H),7.89(s,1H,Ar-H),8.83(d,1H,Ar-H)；HR-MS(ESI-正性):475.23050(M+H)(计算值：475.23051)。
实施例30：Co.30的制备
Figure PCTCN2015072662-appb-000049
步骤1：在氩气氛的情况下，向溶有30a(2mmol)的1-戊醇的溶液中加入1d(2mmol)。反应体系回流5小时后，将其置于0-5℃环境中静置结晶。用10mL丙酮洗涤所得白色晶体两次，再用乙醚/甲醇重结晶后得最终产品30b即为化合物Co.30，产率为：65％。1H NMR(300MHz,CDCl3):0.88-0.93(t,3H)，1.62(m,2H)，1.84(m,2H,thf-H),2.03(m,2H,thf-H),2.64(t,2H)，3.574.07(m,11H,thf-H,pip-H),3.71(s,3H,OCH3),3.76(s,3H,OCH3),3.91(s,3H,OCH3),4.85(m,1H,thf-2H),7.23(s,1H,Ar-5H),7.82(s,1H,Ar-8H)；HR-MS(ESI-正性):400.23464(M+H)(计算值：474.27164)。
实施例31：Co.31的制备
Figure PCTCN2015072662-appb-000050
步骤1：在氩气氛的情况下，向溶有31a(2mmol)的1-戊醇的溶液中加入1d(2mmol)。反应体系回流4小时后，将其置于0-5℃环境中静置结晶。用10mL丙酮洗涤所得白色晶体两次，再用乙醚/甲醇重结晶后得最终产品31b即为化合物Co.31，产率为：24％。1H NMR (300MHz,CDCl3):1.864(m,2H,thf-H),1.93-2.58(m,8H),3.174.07(m,12H,thf-H,pip-H),3.80(s,3H,OCH3),3.83(s,3H,OCH3),3.94(s,3H,OCH3),4.85(m,1H,thf-2H),5.56(m,2H),7.15(s,1H,Ar-5H),7.71(s,1H,Ar-8H)；HR-MS(ESI-正性):536.25085(M+H)(计算值：536.25091)。
实施例32：Co.32的制备
Figure PCTCN2015072662-appb-000051
步骤1：在氩气氛的情况下，向溶有32a(2mmol)的1-戊醇的溶液中加入1d(2mmol)。反应体系回流4小时后，将其置于0-5℃环境中静置结晶。用10mL丙酮洗涤所得白色晶体两次，再用乙醚/甲醇重结晶后得最终产品32b即为化合物Co.32，产率为：45％。1H NMR(300MHz,CDCl3):1.860(m,2H,thf-H),1.95-2.58(m,8H),3.174.07(m,12H,thf-H,pip-H),3.80(s,3H,OCH3),3.86(s,3H,OCH3),3.93(s,3H,OCH3),4.85(m,1H,thf-2H),5.56(m,2H),7.15(s,1H,Ar-5H),7.71(s,1H,Ar-8H)；HR-MS(ESI-正性):514.26655(M+H)(计算值：514.26656)。
B、生物学试验例部分
试验例1、脑血栓症的药物治疗
用以下的方法，对于脑血栓症的急性期及亚急性期患者，给与化合物Co.33(配制成无菌注射液)。
对象患者：经明确诊断为脑血栓且在发病后7日以内的急性患者、以及(超过7日)未满1个月的亚急性期患者。
药剂：化合物Co.33用注射用水按常规的注射液配制方法配制成0.5mg/ml的注射液。
试验药剂和剂量：以上配制的药剂用100ml的0.9％氯化钠注射液稀释，按体重计给予化合物Co.33的量为20μg/kg/天，每日一次，在30min内静脉点滴输注。
给药时间：14天
分析对象的例数：109例
i)病情改善程度
治疗进程中的改善程度如表1(给药7天后)及表2(给药14天后)所示，表中括号外的数字是患者例数，括号内的百分数是该例数占总患者的百分数。
表1：给药7天后
显著改善 中等程度改善 轻度改善 不变 恶化 合计
5(4.6％) 44(40.4％) 41(37.6％) 12(11.0％) 7(6.4％) 109(100％)
表2：给药14天后
显著改善 中等程度改善 轻度改善 不变 恶化 合计
10(9.2％) 63(57.8％) 29(26.6％) 5(4.6％) 2(1.8％) 109(100％)
另外，在给药后3天时初步统计，显著改善+中等程度改善+轻度改善的患者总数低于10％，远低于7日时达82％以上的改善效果。可见，以上述20μg/kg/天的剂量给药时间达7天或7天以上时是有益的。
其中，改善程度可用以下方式判断：对于神经症状、日常生活活动障碍、精神症状、自觉症状、意识水平等各项、预先在正常和重症间分为5个阶段的症状等级。把给药前患者的症状及停药时患者的症状分别判定等级，判定的等级的结果来判断轻度改善、中等程度改善及明显改善。从各项的判断结果综合地求出全面改善程度。
ii)白细胞变化
每名患者在给药前取外周血，按常规细胞计数法(使用美国Coulter公司生产的血常规自动分析仪测定)对血中的白细胞计数，该时间点的白细胞数计为WN0(即血中白细胞浓度，下同)；接着在给药7天后检查白细胞计数，该时间点的白细胞数计为WN7；接着在给药14天后检查白细胞计数，该时间点的白细胞数计为WN14。
对于每名患者，用下式计算其7日白细胞百分数和14日白细胞百分数：
7日白细胞百分数＝(WN7÷WN0)×100％；
14日白细胞百分数＝(WN14÷WN0)×100％
然后计算在7日时全部患者7日白细胞百分数的平均值，以及在14日时全部患者14日白细胞百分数的平均值。结果：7日白细胞百分数的平均值为78％，14日白细胞百分数的平均值86％，均在50％以上，表明按上述给药方案施用本发明化合物以治疗脑栓不但疗效确切，而且未出现不能令人接受的副作用。
iii)安全性汇总
结果见表3所示，从表3可以看出"基本安全”和“安全”约占98％。
表3：
安全 基本安全 安全上有问题 不安全 合计
94(86.2％) 13(11.9％) 2(1.8％) 0(0％) 109(100％)
此外，安全性汇总是考虑了发生副作用的安全性。
可见本发明化合物例如特拉唑嗪可以用作有效脑血栓治疗剂。本发明化合物对于急性和亚急性脑血栓的治疗特别有显著效果，并且显示出低的副作用。
试验例2、副作用考察
18～25岁男性健康志愿者12人，随机分组，每组4人。
使用试验例1的化合物Co.33药剂，以2μg/kg/天、50μg/kg/天、400μg/kg/天的剂量，参照试验例1的给药方法分别给予各组，连续14天。
参照试验例1的计算方法计算各组7日白细胞百分数的平均值、14日白细胞百分数的平均值，结果见表4。
表4：
  2μg/kg/天组 50μg/kg/天组 400μg/kg/天组
7日白细胞百分数的平均值 114％ 106％ 36％
14日白细胞百分数的平均值 97％ 91％ 13％
可见，对于低于50μg/kg/天的给药组，在给药14天后仍未见有白细胞显著降低的现象，然而对于400μg/kg/天的给药组，在给药7天后即见有显著的白细胞降低现象，已经脱离了正常的范围，这是不可接受的。
试验例3、大鼠MCAO模型考察治疗脑梗塞的效果
本试验例进行大鼠MCAO模型即中脑动脉闭塞(middle cerebral artery occlusion)模型试验，使用成年雄性Sprague-Dawley大鼠(250～270g，北京维通利华公司)，照文献O'Donnell,M.E.,Tran,L.,Lam,T.I.,Liu,X.B.& Anderson,S.E.Bumetanide inhibition of the blood-brain barrier Na-K-Cl cotransporter reduces edema formation in the rat middle cerebral artery occlusion model of stroke.J Cereb Blood Flow Metab 24,1046-56(2004)，以及文献Zuo,X.L., Wu,P.& Ji,A.M.Nylon filament coated with paraffin for intraluminal permanent middle cerebral artery occlusion in rats.Neurosci Lett 519,42-6(2012)中公开的方法进行试验。简而言之，将缝线穿过麻醉大鼠的左颈外动脉进行处理。使用激光多普勒血流监视仪以确认成功实现梗塞(由卒中前基线下降>80％)。为了检测特拉唑嗪的效果，在梗塞操作之前30min，将特拉唑嗪(以0.9％氯化钠注射液配制成适应浓度，无菌)和0.9％氯化钠注射液(对照)腹腔注射，剂量及组别见表5和图1(10μg/kg剂量组)。4小时之后通过TTC染色(1％，37℃，15min)，使用Image 2软件进行分析。
表5
剂量组(μg/kg) 对照 1000 400 100 50 10 1 0.1
梗塞体积(％) 27％ 26％ 24％ 14％ 8％ 5％ 7％ 9％
以上表5结果，完全令人意外的是，特拉唑嗪在低剂量下显示出抗血栓有效的结果，而高剂量时反而完全未显示出抗血栓效果。在极低的浓度下(低于50μg/kg)，腹腔注射特拉唑嗪就可以抑制大鼠脑卒中过程中的组织损伤。
另外，从图1结果可见，在大鼠MCAO中，特拉唑嗪具有明显疗效。这种TTC染色中，白色的脑区代表线粒体功能已损伤，无法反应而产生甲腊(formazan，一种红色物质)(左图)。与对照组相比，特拉唑嗪(TZ)明显减少了细胞损伤，梗塞面积显著低于对照组(右图)。
在增加的试验中，分别使用Co.1、Co.14、Co.15、Co.17照上述表5结果的方法进行测试，同样发现象些化合物均在0.1～100μg/kg的剂量时可使梗塞体积降到15％以下，特别是0.1～75μg/kg的剂量时可使梗塞体积降到10％以下，与对照组有显著性差异(p<0.05)；同样发现完全令人意外的结果是当药物剂量大于250μg/kg时梗塞体积均在25％以上，显示与对照组没有显著性差异。
本试验例3的结果结合上文试验例1的结果，完全可以预期，当本发明化合物用于人类脑血栓患者时，以每日剂量低于100μg/kg的量连续施用本发明化合物至少7日，例如是以每日剂量低于75μg/kg的量连续施用本发明化合物至少7日，例如是以每日剂量低于50μg/kg的量连续施用本发明化合物至少7日；或者，以每日剂量0.1～100μg/kg的量连续施用本发明化合物至少7日，例如是以每日剂量0.1～75μg/kg的量连续施用本发明化合物至少7日，例如是以每日剂量0.1～50μg/kg的量连续施用本发明化合物至少7日，将可以获得有效的治疗脑梗塞效果，并且对人体将具有低的不良影响。
试验例4、小鼠抗脑血栓模型试验
制作小鼠脑血栓模型，在小鼠因血栓死亡后，对脑组织进行染色，结果显示在脑片中部呈现白色(其为脑死亡的典型现象)；在一次注射特拉唑嗪(0.4mg/kg i.p.)时可明显降低死亡组织面积。对结果进行统计，以％死亡组织＝白色区域面积/总面积为考察指标，每种条件下小鼠数量＝6。结果：血栓组的％死亡组织平均值为13％，血栓+TZ组的％死亡组织平均值为6％，经t-检验，P<0.05，表明特拉唑嗪可以明显降低脑死亡组织的面积。但是在该试验中，参照上文试验例2的方法测定动物在给药前后的白细胞变化，结果显示给药后(相对于给药前)的白细胞百分数均值为1.2％，表明呈现完全不能令人接受的白细胞降低的不良反应。
试验例5、对心肌梗塞的治疗效果
本发明化合物在心肌梗塞尤其是心肌梗塞后的治疗中的有益作用，可在标准试验中通过测定测试物质对那些影响经历心肌梗塞后心肌的功能状态的因素的作用的药理学表征来证明。对证明特别是在心肌梗塞的慢性阶段影响心肌的功能状态的因素的作用合适的动物模型例如有慢性心肌梗塞(MI)的Wister-大鼠。
用这一动物模型(MI-大鼠)发现血浆去甲肾上腺素水平在心肌梗塞后急剧上升。在心脏机能不全的病情加重阶段血浆去甲肾上腺素水平会继续上升。MI-大鼠试验能看出甚至梗塞三周后，即在所谓的恢复阶段后仍显示出心率提高(体内非限制的状态测定，醒着的大鼠)，同时剩余的血浆去甲肾上腺素水平还比假手术大鼠高出约50％(见下文：假动过手术的大鼠，没有结扎冠状动脉)。此外，在这种动物的中枢神经系统中，在脑室旁的下丘脑和蓝斑中观察到升高的代谢，在其中的交感神经对周围系统作用被调节。行为研究表明在梗塞大鼠中恐惧感升高。因此这些观察结果表明在这种梗塞大鼠模型中存在缓慢升高的交感神经活化。
(1)试验动物和剂量：
下列试验是在雄性Wister大鼠(270-320克)上进行的。这些大鼠用12小时照明/黑暗循环并用标准大鼠饲料和水(都可随意获取)饲养。这些动物将经受冠状动脉结扎(MI-大鼠)或者未结扎的假手术大鼠(假-大鼠)。24小时后将MI-大鼠随机分开，然后移植渗透微泵(Alzet，型号2001)，以按每μg/kg/天的剂量皮下给以本发明化合物(盐酸特拉唑嗪，TZ， 用生理盐水配制成无菌注射液)或只给以赋型剂。本发明化合物治疗将连续进行直到手术后第三个周末。
(2)冠状动脉结扎：
在戊巴比妥麻醉(60m/kg，i.p.)下进行左前下行冠状动脉结扎。简而言之：在气管插管后在第四肋间区做一皮肤切口。将平滑肌分开并固定到一边。然后对动物进行正压换气(频率65-70/分钟，活塞排气量3ml)，并且其胸腔通过分开肋间肌肉而打开。打开心包，心脏就地保持并用6-0丝线在左冠状动脉下侧在肺动脉开始的附近缝合。将缝拉紧。假大鼠也进行相同的过程，但不进行真正的结扎。将肋骨用3-0丝线集中到一起，然后将肌肉恢复原位并缝合皮肤。
(3)血液样品的准备和采集：
在使冠状动脉结扎的外科手术后19天重新用戊巴比妥将大鼠麻醉，并将一根导管(PE-10，用PE-50热焊接)经股动脉插到腹部主动脉。将该导管从皮下引导至动物脖颈，让它从那里向外穿出并将其固定并封闭。让大鼠休息两天。在取样品那天用一根肝素处理的、充满盐水的软管将导管加长并在至少60分钟后取2个1毫升的血样。将血液收集在预冷却的样品小瓶(注射器)中，里面含有10μl的EDTA(0.1M)。离心后将血浆收集到预冷的、装有或者1.2mg谷胱甘肽(Gluthation)或者10μl抑肽酶(100KIU；KIU＝千国际单位)的小管中，以测定儿茶酚胺或前房的促尿钠排泄因子(ANF)。将小管在-80℃保存。去甲肾上腺素的血浆浓度、肾上腺素和多巴胺将通过HPLC测定，同时在另一方面用RIA-试验分析ANF的浓度。
(4)心的胶原蛋白的测定：
随机从每个实验组中选取6到7个心脏测定间质胶原蛋白的量。为此通过灌注3.6％重量的磷酸盐缓冲的甲醛固定心脏。在除去心房和大血管后，将心室从心尖开始到心底切成4片并至少在甲醛中保存切片24小时。固定后将切片脱水并包入石蜡中。将去掉石蜡的5μm薄肘用0.2％重量/体积的磷钼酸水溶液温育5分钟，然后用0.1％重量的天狼星红F3BA(Polysciencies Inc.，英国)的饱和三硝基苯酚溶液温育45分钟，然后用0.01M的盐酸洗涤2分钟，去水，并为了显微镜检测包入Entellan(Merk公司，德国)中。除去梗塞区域，在心室间的隔膜作为天狼星红阳性区域在40倍的放大倍数下测定每个心脏的间质胶原蛋白。
(5)数据处理：
若无另外说明，所得数据用组平均值±S.E.M(标准平均偏差)表示。只处理带包含左心室自由心壁的主要部分的梗塞区域的梗塞心脏的数据，因为较小的梗塞区域通常在血液动力学上被全部代偿。通过“变量的单向分析(Einweganalyse)(ANOVA)”，随后按照Bonferroni的post-hoc-Analyse分析这些数据。在本发明化合物治疗过的和未治疗过的梗塞心脏中血管的结构参数的差别用学生t试验(Student'st-Test)对两组分别确定。
(6)结果：
对4组大鼠进行了研究：两组为本发明化合物(TZ)治疗过的梗塞大鼠(剂量为5μg/kg/天和50μg/kg/天)，一组未治疗过的梗塞大鼠和一组假手术对照大鼠(假大鼠或假-大鼠或类似称谓)。冠状动脉结扎产生左心室自由心壁主梗塞。试验动物的总死亡率为28％并且在两组梗塞大鼠之间没有区别。将50μg/kg/天和5μg/kg/天剂量的试验的结果概括于表6中并将在随后说明。在表6中给出的结果包含每组大鼠为7-14只的组数据，胶原蛋白测定除外，其数据是基于每组大鼠为6-7只的数据。
尽管实验动物在试验开始时体重近似，但本发明化合物治疗的梗塞大鼠与未治疗的梗塞大鼠相比显示出微小的体重降低，但与假-大鼠相比体重明显下降。本发明化合物治疗的梗塞大鼠的心脏重量明显低于未治疗的梗塞大鼠。从这些数据得出的结论是给以本发明化合物可阻止过度的心肌肥大。
根据血浆-去甲肾上腺素水平和ANF水平测得的神经递质的活性在未治疗的梗塞大鼠中明显升高。用本发明化合物治疗的大鼠的ANF-血浆水平与未治疗的梗塞大鼠相比没有变化。通过本发明化合物治疗使血浆去甲肾上腺素水平降低到约为对假大鼠测得的血浆去甲肾上腺素水平的一半。
在未治疗的梗塞大鼠中测得的血浆去甲肾上腺素水平明显升高而且高达假大鼠测定值的三倍。通过在50μg/kg/天组中用本发明化合物治疗，血浆去甲肾上腺素水平降低到几乎是假大鼠值的一半。在5μg/kg/天组中血浆去甲肾上腺素水平明显下降。这表明50μg/kg/天和5μg/kg/天剂量的本发明化合物能在大鼠心肌梗塞后有效降低交感神经的活化。
对于50μg/kg/天和5μg/kg/天剂量组，从表6中同样可获得心的胶原蛋白的测定结果。
在醒着的动物中测得的心率为梗塞大鼠比假大鼠明显升高。给以本发明化合物不仅降低心动过速，而且经过治疗的梗塞大鼠与假大鼠相比显示出心脏活动变慢(心动徐缓)。
表6：假手术对照动物(SHAM)、未治疗梗塞大鼠(INFARKT)和本发明化合物治疗的梗塞大鼠(INF+TZ)的试验结果；剂量为50μg/kg/天和5μg/kg/天
  SHAM INFARKT INF+TZ(5μg/kg/d) INF+TZ(50μg/kg/d)
试验动物数 8-14 7-12 7 6-7
体重(g) 332±7 322±9 314±5 307±8*
心脏重(mg) 1173±36 1543±74* 1123±45# 1078±23#
心脏重/体重比 3.5±0.2 4.7±0.3* 3.8±0.4# 3.6±0.2#
心率(次/分钟) 352±16 387±8* 334±12# 321+6*#
MAP(mmHg) 113±2 98±3* 94±3 102±5
血浆NA-水平(pg/ml) 198±30 578±143* 136±48# 96±20#
血浆ANF(pg/ml) 39±4 53±5 56±2 60±7
间质胶原蛋白(％) 1.3±0.1 2.2±0.4* 1.6±0.2 1.4±0.1
缩写：MPA＝平均动脉血压；NA＝去甲肾上腺素；ANF＝动脉促尿钠排泄因子；*＝与假-大鼠明显不同；#＝与未治疗的梗塞大鼠明显不同
在增加的试验中，分别使用Co.1、Co.14、Co.15、Co.17照上述表6结果的方法进行测试，同样发现象些化合物均在25μg/kg/天的剂量时可以达到以上表6特拉唑嗪5μg/kg/天和50μg/kg/天剂量所呈现的结果范围。
这些试验结果清楚地表明，在心肌梗塞治疗范围内尤其是在心肌梗塞后的治疗范围内，通过给以本发明化合物对心肌的功能状态产生了有益的影响。从测得的血浆儿茶酚胺水平可以看出本发明化合物能有效地使心肌梗塞大鼠的交感神经活化正常。这些结果可通过心率数据(体内，在醒着的大鼠上测得)证明，因为在本发明化合物治疗的大鼠中，心率甚至低于假-大鼠的心率值。这可能更是归因于本发明化合物的慢性作用而不是急性作用，因为在急性治疗中心率的降低伴随着动脉血压平均值的上升，这种情况在缓慢治疗中没有观察到。考虑到本发明化合物的作用，虽然测得的心脏重/体重比(肥大)的积极效果看起来不显著并且间质胶原蛋白的测定最多能推断出小的重建(Remodeling)效应，但这些结果表明本发明化合物对心的肥大和不希望的重建有明显的预防作用趋势。
因此上述试验结果表明，本发明化合物对经受心肌梗塞后的心肌状态产生有益的、促进康复和/或恢复的影响并因此适合于在人类和大的哺乳动物中、在治疗急性心肌梗塞的 范围内并且特别是也在心肌梗塞后的治疗范围内治疗心肌梗塞造成的心肌损伤。此外，考虑到心肌梗塞后心脏衰弱(例如心力衰减)的进行，本发明化合物特别能在心肌梗塞后的治疗范围内也起到预防作用。本发明化合物的应用剂量可依个别情况而异并自然随要治疗的状态的类型和给药形式而变。一般对人类心肌梗塞治疗或心肌梗塞后的治疗口服或注射给药的日剂量为0.01～5mg，例如0.01～3mg。

Claims (23)

  1. 式I所示的化合物，
    Figure PCTCN2015072662-appb-100001
    或其药学上可接受的盐、溶剂合物、水合物、酯或前药，在制备用于预防和/或治疗哺乳动物脑血管疾病、心血管疾病和/或心脏疾病的药物中的应用；
    其特征在于：
    R1a和R1b各自独立地选自H、NH2、OH、C1-6烷基-、C1-6烷氧基-C1-6烷基-、C2-6烯基-、C2-6炔基-、C1-6烷氧基-、C1-6烷基酰基-、芳基酰基-、C6-10芳基-或C5-6环烷基-，所述烷基任选地被1-3个选自下列的取代基取代：羟基或卤素；或
    R1a和R1b与它们连接的氮原子一起形成5-或6-元环；
    R2和R3各自独立地选自H、卤素、C1-6烷基-、卤代C1-6烷基-、C2-6烯基-、C2-6炔基-、CN、NO2、NH2、OH、C1-6烷氧基-、C1-6烷氧基-C1-6烷氧基-、C1-6烷酰基氧基-、C1-6烷酰基氨基-、芳基酰基氨基-、饱和或不饱和的5-或6-元碳环基或杂环基、饱和或不饱和的5-或6-元碳环基氧基或杂环基氧基或者C1-6烷基酰基-；或者
    R2和R3与它们连接的环原子一起形成5-或6-元碳环或杂环；
    R4和R5各自独立地选自H、卤素、CN、NO2、NH2、OH、C1-6烷基-、C1-6烷氧基-C1-6烷氧基-、C1-6烷酰基氧基-、卤代C1-6烷基-、C2-6烯基-、C2-6炔基-、C1-6烷氧基-、C1-6烷酰基氨基-、芳基酰基氨基-、饱和或不饱和的5-或6-元碳环基或杂环基、饱和或不饱和的5-或6-元碳环基氧基或杂环基氧基或C1-6烷基酰基。
  2. 根据权利要求1所述的化合物的应用，其特征在于：所述R1a和R1b各自独立地选自H、NH2、OH、C1-6烷基-、C1-4烷氧基-C1-4烷基-、C2-4烯基-、C2-4炔基-、C1-4烷氧基-、C1-4烷基酰基-、苯基酰基-、苯基-或者C5-6环烷基，其中烷基任选被1-3个选自下列的取代基取代：羟基或卤素；或者
    所述R1a和R1b与它们连接的氮原子一起形成5-或6-元环。
  3. 根据权利要求1所述的化合物的应用，其特征在于：所述R2和R3各自独立地选自H、卤素、C1-6烷基-、卤代C1-6烷基-、C1-6烷氧基-、C1-6烷氧基-C1-6烷氧基-、C1-6烷酰基氧基-、C1-6烷酰基氨基-、芳基酰基氨基-、饱和或不饱和的5-或6-元碳环或杂环基或者饱和或不饱和的5-或6-元碳环或杂环基氧基；或者
    所述R2和R3与它们连接的环原子一起形成5-或6-元碳环或杂环。
  4. 根据权利要求1所述的化合物的应用，其特征在于：所述R4和R5各自独立地选自H、卤素、C1-6烷基-、C1-6烷氧基-C1-6烷氧基-、C1-6烷酰基氧基-、卤代C1-6烷基-、C1-6烷氧基-、C1-6烷酰基氨基-、芳基酰基氨基-、饱和或不饱和的5-或6-元碳环基或杂环基或者饱和或不饱和的5-或6-元碳环基氧基或杂环基氧基。
  5. 根据权利要求1所述的化合物的应用，其特征在于：
    所述R1a和R1b各自独立地选自H、-NH2、-OH、CH3C(O)-、-(CH2)2-O-(CH2)2-OH、-CH2-CH＝CH2、-CH2-C≡CH、-(CH2)5CH3、-(CH2)4-CF3、环己基、-CH2-(CH2)3-CH2-、-(CH2)2O(CH2)2-OH、-Ph、CH3、-C(O)-CF3或-C(O)-Ph。
  6. 根据权利要求1所述的化合物的应用，其特征在于：所述R2和R3各自独立地选自H、CH3O-、-CH2-O-CH2-、-O(CH2)2OC2H5、-OC(O)CH3、-F、-CF3、
    Figure PCTCN2015072662-appb-100002
    并1,2-吡啶环、-NHCOCH3、-(CH2)2CH3、-NHCOPh、
    Figure PCTCN2015072662-appb-100003
    或者
    所述R2和R3与它们连接的环原子一起形成含有2个氧的5元杂环。
  7. 根据权利要求1所述的化合物的应用，其特征在于：所述R4和R5各自独立地选自H、-O(CH2)2OC2H5、-OC(O)CH3、-OCH3、
    Figure PCTCN2015072662-appb-100004
    -CF3、-F、-NHCOCH3、-(CH2)3CH3、-NHCOPh或
    Figure PCTCN2015072662-appb-100005
  8. 根据权利要求1所述的化合物的应用，其特征在于：所述R1a和R1b各自独立地选自H、NH2、OH、C1-6烷基-、C1-6烷氧基-C1-6烷基-、C2-6烯基-、C2-6炔基-、C1-6烷基酰基-或C5-6环烷基，其中烷基任选被1-3个选自下列的取代基取代：羟基或卤素；或者
    所述R1a和R1b与它们连接的氮原子一起形成6元环。
  9. 根据权利要求1所述的化合物的应用，其特征在于：所述R2和R3各自独立地选自卤素、C1-6烷基-、卤代C1-6烷基-、C1-6烷氧基-、C1-6烷氧基-C1-6烷氧基-、C1-6烷酰基氧基-或C1-6烷酰基氨基-；或者
    所述R2和R3与它们连接的环原子一起形成5-或6-元杂环。
  10. 根据权利要求1所述的化合物的应用，其特征在于：所述R4和R5各自独立地选自H、卤素、C1-6烷基-、C1-6烷氧基-C1-6烷氧基-、C1-6烷酰基氧基-、卤代C1-6烷基-、C1-6烷氧基-或C1-6烷酰基氨基-。
  11. 根据权利要求1所述的化合物的应用，其特征在于：所述R1a和R1b各自独立地选自H、NH2、OH、C1-6烷基-、C1-4烷氧基-C1-4烷基-、C2-4烯基-、C2-4炔基-、C1-4烷基酰基-、苯基-或C5-6环烷基，其中所述基任选被1-3个选自下列的取代基取代：羟基或卤素。
  12. 根据权利要求1所述的化合物的应用，其特征在于：所述R2和R3各自独立地选自卤素、C1-6烷基-、卤代C1-6烷基-、C1-6烷氧基-、C1-6烷氧基-C1-6烷氧基-、C1-6烷酰基氧基-或C1-6烷酰基氨基-。
  13. 根据权利要求1所述的化合物的应用，其特征在于：所述R4和R5各自独立地选自H、卤素、C1-6烷基-、C1-6烷氧基-C1-6烷氧基-、C1-6烷酰基氧基-、卤代C1-6烷基-、C1-6烷氧基-或C1-6烷酰基氨基-。
  14. 根据权利要求1所述的化合物的应用，其特征在于：所述化合物选自编号Co.1至Co.33的化合物或其药学可接受的盐、前药、溶剂合物例如水合物或酯。
  15. 根据权利要求1-14任一项所述的化合物的应用，其特征在于：所述脑血管疾病为脑血栓、脑缺血和/或脑梗塞。
  16. 根据权利要求1-14任一项所述的化合物的应用，其特征在于：所述心血管疾病和/或心脏疾病为心肌梗塞、心肌缺血、心肌损伤、冠心病、心绞痛或心力衰竭。
  17. 根据权利要求16所述的化合物的应用，其特征在于：所述心肌损伤是急性心肌梗塞、慢性心肌梗塞和/或心肌梗塞后的治疗造成的心肌损伤。
  18. 根据权利要求1-17任一项所述的化合物的应用，其特征在于：所述哺乳动物为人。
  19. 一种用于治疗哺乳动物所患脑血管疾病、心血管疾病和/或心脏疾病的方法，其 特征在于：所述哺乳动物以每日剂量低于100μg/kg施用权利要求1-18任一项所述的药物，至少连续施用7日。
  20. 根据权利要求19所述的方法，其特征在于：所述每日剂量为0.1～100μg/kg。
  21. 根据权利要求19所述的方法，其特征在于：所述每日剂量为0.1～75μg/kg。
  22. 根据权利要求19所述的方法，其特征在于：所述每日剂量为0.1～50μg/kg。
  23. 一种用于治疗哺乳动物所患脑血管疾病、心血管疾病和/或心脏疾病的方法，其特征在于：所述哺乳动物以白细胞降低在可接受范围内的量施用权利要求1-18任一项所述的药物。
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