Cardio-cerebrovascular drugs and their uses

Abstract

The present invention provides cardio-cerebrovascular drugs and their use.Specifically, the compound of the present invention has the structure represented by formula (I), where each group is defined as described in the specification.The present invention also discloses the use of said compound in treating thrombotic disease, anti-inflammation and treating neurological injury. [Formula 1] JPEG2024545920000054.jpg4242

Description

[Technical field]

[0001] The present invention relates to the field of medicines, and more specifically to cardio-cerebrovascular drugs and their uses. [Background technology]

[0002] In China, the incidence of cardiovascular disease is increasing, and the current number of patients with cardiovascular disease is estimated to be 330 million. The incidence of stroke in China is on the rise, with new cases accounting for about 40% of the world's total, deaths accounting for about 30% of the world's total, and stroke patients surviving with pre-existing conditions accounting for 13 million, making China the country with the highest lifetime risk of stroke and the heaviest disease burden. In the next decade, the incidence of coronary heart disease in China is expected to continue to rise, and the incidence of acute myocardial infarction is also expected to rise sharply, with China expected to have more than 20 million acute myocardial infarction patients after 2030. Acute pulmonary embolism is the third most common acute cardiovascular syndrome in the world after myocardial infarction and stroke, with the annual incidence of pulmonary embolism being (39-115) people / 100,000, and the incidence rate showing a tendency to increase in recent years.

[0003] When thrombotic diseases occur, surgical thrombectomy, thrombolysis, and antithrombotic therapy are mainly used in clinical practice. Commonly used thrombolytic drugs include urokinase, streptokinase, alteplase, reteplase, etc. Commonly used antithrombotic drugs include antiplatelet drugs and anticoagulants. Thrombolytic drugs and orally administered antithrombotic drugs have good preventive and therapeutic effects, but the disadvantage is that they all lead to the risk of bleeding, so the blood coagulation mechanism needs to be closely monitored during the use period.

[0004] During the occurrence of a stroke, vascular occlusion occurs in the brain, cutting off the blood supply and damaging neuronal cells, so in clinical practice there is a need to treat the damaged neuronal cells.

[0005] Edaravone was developed and marketed in Japan to treat acute attacks of cerebral infarction and improve neurological symptoms, daily living activity ability and functional impairment due to acute cerebral infarction. It has been approved for sale in China but has not been approved in major countries in Europe and the United States. Some positive results were obtained in Phase III clinical studies of Edaravone composition (Edaravone-Dexborneol), and it has been approved for sale in China, but it has not been approved by the US FDA or recommended by the guidelines because the design of its clinical protocol does not match the requirements of current overseas official clinical research guidelines for neuroprotective agents.

[0006] The Chinese guidelines for diagnosis and treatment of ischemic stroke only recommend butylphthalide as a class II drug for improving cerebral microcirculation, and there are no recommended neuroprotective agents in clinical guidelines abroad. The field of mainstream medically approved neuroprotective agents in the world is still blank.

[0007] Therefore, the present inventor conceived of developing a new therapeutic drug for stroke-induced nerve damage that can effectively perform thrombolytic therapy for thrombotic diseases and at the same time protect the brain nerves, thereby filling the gap in the field of neuroprotective agents and satisfying the unmet needs in clinical practice in the field of cardiovascular and cerebrovascular diseases, and has important clinical significance and practical value. Summary of the Invention [Problem to be solved by the invention]

[0008] It is an object of the present invention to provide cardio-cerebrovascular drugs and uses thereof. [Means for solving the problem]

[0009] In a first aspect of the invention there is provided the use of a compound of formula I or a pharma- ceutically acceptable salt thereof for the manufacture of a pharmaceutical composition or formulation, said pharmaceutical composition or formulation comprising a compound of formula I as an active ingredient, and said pharmaceutical composition or formulation comprising: (a) prevention and / or treatment of thrombosis-related diseases; (b) anti-inflammatory treatment; and / or (c) Treatment of neuronal damage caused by cerebral infarction, brain trauma, cerebral hemorrhage, or brain tumor surgery Provide for use. [ka] (In the formula, R1 is a hydroxy group, a C1-C6 alkoxy group, a halogen, a substituted or unsubstituted -O-C1-C6 alkyl group, [ka] wherein said substitution is with a sulfonic acid group or a hydroxy group. Here, m is a positive integer from 1 to 6. [ka] In [ka] is a chiral carbon atom, and the chirality is [ka] Selected from. R4 is Na + , K + , Li + or Cs + The metal ion is selected from the group consisting of: R5 is a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, an aryl group or a heteroaryl group. R2 and R3 are each independently H, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C3-C8 cycloalkyl group, a C2-C6 hydroxyalkyl group, or -(C1-C3 alkylene group)-COOH. n is a positive integer between 6 and 12.)

[0010] In another preferred embodiment, the pharmaceutical composition is for preventing thrombosis, thrombolytic therapy, or preventing and / or treating cerebral ischemia-reperfusion injury, suppressing ferroptosis of neurons caused by cerebral ischemia-reperfusion, or resolving vascular inflammation. In another preferred embodiment, the thrombus is selected from the group consisting of vascular endothelium-damaging thrombus, arteriovenous shunt thrombosis, cerebral ischemia-reperfusion injury, or a combination thereof.

[0011] In another preferred embodiment, the cerebral ischemia-reperfusion injury includes cerebral infarction, cerebral edema, and / or ferroptosis of neural cells. In another preferred embodiment, the anti-inflammatory treatment is an anti-vascular inflammatory treatment. In another preferred embodiment, the vascular inflammation includes vascular inflammation caused by high sugar and high fat.

[0012] In another preferred embodiment, the pharmaceutical composition or formulation is for the prevention and / or treatment of thrombosis-related diseases. In another preferred embodiment, the thrombosis-related disease is selected from the group consisting of cerebral thrombosis, cerebral infarction (acute ischemic stroke) and the neuronal damage caused thereby in nervous tissue, cerebral edema, myocardial infarction, pulmonary embolism, or a combination thereof. In another preferred embodiment, the thrombosis-related disease comprises an infarction-related disease.

[0013] In another preferred embodiment, the pharmaceutical composition or formulation is for anti-inflammatory treatment. In another preferred embodiment, the pharmaceutical composition or preparation is for treating neuronal damage caused by cerebral infarction, cerebral trauma, cerebral hemorrhage or brain tumor surgery.

[0014] In another preferred embodiment, R1 is a hydroxy group, a methoxy group, [ka] is selected from the group consisting of:

[0015] In another preferred embodiment, m=1. In another preferred embodiment, R4 is Na + It is. In another preferred embodiment, R5 is CH3. In another preferred embodiment, n is 6, 7 or 8.

[0016] In another preferred embodiment, R1 is a hydroxy group, a methoxy group, [ka] is selected from the group consisting of: In another preferred embodiment, R2 and R3 are each independently H, a methyl group, a hydroxypropyl group, a hydroxyethyl group, or a carboxymethyl group.

[0017] In another preferred embodiment, the compound of formula I is selected from the group consisting of methylcyclodextrin, carboxymethylcyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, or sulfobutyl-β-cyclodextrin. In another preferred embodiment, the mother nucleus of the compound of formula I is a cyclodextrin.

[0018] In another preferred embodiment, the compound of formula I is [ka] It is.

[0019] In another preferred embodiment, the compound of formula I is selected from the group consisting of: [ka]

[0020] In another preferred embodiment, the pharmaceutical composition further comprises another active ingredient. In another preferred embodiment, the additional active ingredient is selected from the group consisting of butylphthalide, urokinase, edaravone, or a combination thereof. In another preferred embodiment, the pharmaceutical composition or formulation comprises a compound of formula (I) or a pharma- ceutically acceptable salt as an active ingredient, and a pharma- ceutically acceptable carrier.

[0021] In another preferred embodiment, the dosage form of the pharmaceutical composition or formulation is selected from the group consisting of injection solution, lyophilized powder injection, sustained release, controlled release, enteric coated tablets or capsules, and granules. In another preferred embodiment, the pharmaceutical composition or formulation contains, as an active ingredient, 0.001-99 wt%, preferably 0.1-90 wt%, more preferably 1-80 wt%, of the compound of formula I or a pharma- ceutically acceptable salt thereof, calculated by the total weight of the composition.

[0022] In a second aspect of the present invention, there is provided the use of a composition of a compound of formula I and urokinase for the manufacture of a medicament for treating a thrombosis-related disorder. In a third aspect of the present invention, there is provided the use of a composition of a compound of formula I and butylphthalide for the manufacture of a medicament for treating neurological damage due to cerebral infarction.

[0023] In a fourth aspect of the invention, there is provided a pharmaceutical composition or formulation comprising: (a) an active ingredient comprising a compound of formula I or a pharma- ceutically acceptable salt thereof; and (b) a pharma- ceutically acceptable carrier; (1) Prevention and / or treatment of thrombosis-related diseases, (2) Anti-inflammatory treatment, and / or (3) Treatment of neuronal damage caused by cerebral infarction, brain trauma, cerebral hemorrhage, or brain tumor surgery The present invention provides a pharmaceutical composition or formulation for

[0024] In another preferred embodiment, when the active ingredient comprises two components, the weight ratio of the two components is from 1:20 to 20:1, preferably from 1:10 to 10:1, more preferably from 1:5 to 5:1.

[0025] In a fifth aspect of the present invention there is provided a kit comprising: (1) a first pharmaceutical composition comprising a first container, and within said container, a first compound, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier; (2) an nth pharmaceutical composition comprising an nth container, and within said container, an nth compound or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier; where n is any positive integer from 2 to 8; wherein the first compound and the nth compound are both compounds of formula I or a pharma- ceutically acceptable salt thereof, or the first compound is a compound of formula I or a pharma- ceutically acceptable salt thereof and at least one of the nth compounds is another active agent, wherein the compound of formula I is as defined in claim 1; and / or (3) optionally, instructions for use.

[0026] In a sixth aspect of the present invention there is provided a method for treating a disease, said disease being as defined in claim 1, comprising administering to a subject in need thereof a compound of formula I or a pharma- ceutically acceptable salt thereof, wherein the compound of formula I is as defined in claim 1. In another preferred embodiment, the subject is a mammal. In another preferred embodiment, the subject is a human.

[0027] Of course, it is understood that within the scope of the present invention, the above technical features of the present invention and the technical features specifically described below (for example, in the Examples) can be combined with each other to form new or preferred technical solutions, which will not be described here one by one due to space limitations. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0028] Specific embodiments The inventors have conducted extensive and in-depth research and have unexpectedly found that the compound represented by formula I has a remarkable effect on the prevention and / or treatment of thrombus-related diseases, anti-inflammatory treatment, and neuronal damage caused by cerebral infarction, brain trauma, cerebral hemorrhage, or brain tumor surgery. Experiments have shown that the compound of formula I has a good therapeutic effect on brain nerve damage caused by stroke. The compound of formula I of the present invention can be used for the prevention of thrombus and thrombolysis in thrombotic diseases, anti-inflammatory treatment, etc. Based on this, the present invention has been completed.

[0029] term: The term "halogen" refers to F, Cl, Br and I. The term "C1-C6 alkyl group" refers to a straight or branched chain alkyl group having from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, neopentyl, t-pentyl, or the like.

[0030] The term "C2-C6 alkenyl group" refers to a straight or branched alkenyl group having 2 to 6 carbon atoms and containing one double bond, including, but not limited to, vinyl, propenyl, butenyl, isobutenyl, pentenyl, and hexenyl groups. The term "C2-C6 alkynyl group" refers to a straight or branched chain alkynyl group having 2 to 6 carbon atoms and containing a triple bond, including, but not limited to, ethynyl, propargyl, butynyl, isobutynyl, pentynyl, and hexynyl groups.

[0031] The term "C1-C6 hydroxyalkyl group" refers to a straight or branched chain alkyl group having 1-6 carbon atoms and containing one hydroxy group, including, but not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, etc., with C1-C3 hydroxyalkyl groups being preferred. The term "C3-C8 cycloalkyl group" refers to a cyclic alkyl group having 3-8 carbon atoms in the ring, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

[0032] The term "C1-C6 alkoxy" refers to a straight or branched chain alkoxy group having 1-6 carbon atoms, including, but not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, etc. C1-C4 alkoxy groups are preferred. The terms "aromatic ring" and "aryl group" have the same meaning, with "C6-C10 aryl group" being preferred. The term "C6-C10 aryl group" refers to an aromatic ring group having 6-10 carbon atoms without any heteroatoms in the ring, such as phenyl and naphthyl groups.

[0033] The term "heteroaryl group" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, which may be nitrogen, oxygen, or S(O)r, where r is an integer 0, 1, or 2, e.g., a 4-8 membered heteroaryl group is a heteroaromatic system containing 4-8 ring atoms, a 4-10 membered heteroaryl group is a heteroaromatic system containing 4-10 ring atoms, including, but not limited to, pyrrolyl, furyl, thienyl, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, isoxazolyl, pyridyl, pyranyl, pyridazyl, pyrimidinyl, pyrazinyl, benzimidazolyl, triazolyl, and the like.

[0034] Unless specifically described as "substituted or unsubstituted", any of the groups described in the present invention may be substituted with a substituent selected from the group consisting of halogen, acyloxy, cyano, amino, nitro, carboxy, amido, carboxymethyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C1-C6 haloalkynyl, hydroxy, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, hydroxyC1-C4 alkyl, C5-C7 cycloalkenyl, phenyl, and naphthyl. [ka] represents the attachment position of the group.

[0035] active substance As used herein, the terms "compounds of the invention" and "active ingredients of the invention" are used interchangeably and refer to compounds of Formula I. [ka]

[0036] The present invention further includes pharma- ceutically acceptable salts of the compounds of formula I. The term "pharma- ceutically acceptable salts" refers to salts that are suitable for use as drugs, formed between the compounds of the present invention and an acid or base. Pharmaceutically acceptable salts include inorganic salts and organic salts. One type of suitable salt is the salt formed between the compounds of the present invention and an acid. The acids suitable for forming salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, etc., organic acids such as formic acid, acetic acid, propanoic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, phenylmethanesulfonic acid, benzenesulfonic acid, etc., and acidic amino acids such as aspartic acid, glutamic acid, etc.

[0037] The compound of formula I of the present invention can be prepared by methods well known to those skilled in the art, and the reaction parameters of each step are not particularly limited. In addition, the typical compound of the present invention can be obtained as a commercial product. As used herein, in compounds of Formula I, when a chiral carbon atom is present, the chiral carbon atom may be of the R configuration, the S configuration, or a mixture of both.

[0038] In the present invention, the active ingredient is a compound of formula I. [ka] (In the formula, R1 is a hydroxy group, a C1-C6 alkoxy group, a halogen, a substituted or unsubstituted -O-C1-C6 alkyl group, [ka] wherein said substitution is with a sulfonic acid group or a hydroxy group. Here, m is a positive integer from 1 to 6. [ka] In [ka] is a chiral carbon atom, and the chirality is [ka] Selected from. R4 is Na + , K + , Li + or Cs + The metal ion is selected from the group consisting of: R5 is a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, an aryl group or a heteroaryl group. R2 and R3 are each independently H, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C3-C8 cycloalkyl group, a C2-C6 hydroxyalkyl group, or -(C1-C3 alkylene group)-COOH. n is a positive integer between 6 and 12.)

[0039] In one embodiment, R1 is a hydroxy group, a methoxy group, [ka] is selected from the group consisting of:

[0040] In another embodiment, m=1. In another embodiment, R4 is Na + It is. In another embodiment, R5 is CH3. In another embodiment, n is 6, 7 or 8.

[0041] In another embodiment, R1 is a hydroxy group, a methoxy group, [ka] is selected from the group consisting of: In another embodiment, R2 and R3 are each independently H, a methyl group, a hydroxypropyl group, a hydroxyethyl group, or a carboxymethyl group.

[0042] In another embodiment, the compound of formula I is selected from the group consisting of methyl cyclodextrin, carboxymethyl cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, or sulfobutyl-β-cyclodextrin. In another embodiment, the mother nucleus of the compound of formula I is a cyclodextrin.

[0043] In another embodiment, the compound of formula I is [ka] It is. In another embodiment, the compound of formula I is selected from the group consisting of: [ka]

[0044] Drug Compositions and Methods of Application The present invention also provides pharmaceutical compositions comprising a pharma- ceutically acceptable carrier and a safe and effective amount of one or more compounds according to the present invention. Since the compound of the present invention has excellent antithrombotic activity, the compound of the present invention and various crystal forms thereof, pharma- ceutically acceptable inorganic or organic salts, hydrates or solvates thereof, as well as pharmaceutical compositions containing the compound of the present invention as a main active ingredient, are useful for the treatment, prevention and alleviation of diseases associated with embolism.

[0045] The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharma- ceutically acceptable salt in a safe effective amount range and a pharma- ceutically acceptable excipient or carrier. Here, the "safe effective amount" refers to the amount of the compound that is sufficient to significantly improve the disease condition and does not cause severe side effects. Usually, the pharmaceutical composition contains the compound of the present invention in an amount of 1-2000 mg / formulation, preferably 10-1000 mg / formulation. Preferably, the "formulation" is a capsule or tablet.

[0046] "Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gel substances that must be applicable to humans and have sufficient purity and sufficiently low toxicity. "Compatible" refers to the ability of each component in the composition to be blended with and among the compounds of the present invention without significantly reducing the effectiveness of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyhydric alcohols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., tallow, glyceryl ... R ), humectants (e.g., sodium dodecyl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, and pyrogen-free distilled water.

[0047] The pharmaceutical composition is in the form of injection, capsule, tablet, pill, powder, or granule. The mode of administration of the pharmaceutical composition of the present invention is not particularly limited, but representative modes of administration include, but are not limited to, oral administration, intratumoral administration, rectal administration, parenteral gastrointestinal administration (intravenous, intramuscular, or subcutaneous administration), and topical administration.

[0048] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is usually mixed with at least one inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or may contain (a) a filler or compatibilizer, such as starch, lactose, sucrose, glucose, mannitol, or silicic acid; (b) a binder, such as hydromethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, or gum arabic; (c) a humectant, such as glycerin; and (d) a disintegrant, such as agar, calcium carbonate, or the like. The pharmaceutical composition may be mixed with ingredients such as calcium, potato starch or tapioca starch, alginic acid, certain complex silicates or sodium carbonate, (e) solution retardants such as paraffin, (f) absorption promoters such as ammonium compounds, (g) wetting agents such as cetanol or glycerin monostearate, (h) adsorbents such as kaolin, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0049] Solid dosage forms, such as tablets, pills, capsules, pills, and granules, can be prepared with coatings or shells, such as enteric coatings and other materials known in the art. Opacifying agents may be included, and in such compositions, the release of the active or compound may be delayed in a certain part of the digestive tract. Examples of embedding materials that can be used include polymeric and wax-based materials. If necessary, the active compound may also be formed into a microcapsule with one or more of the above excipients.

[0050] Liquid dosage forms for oral administration include pharma- ceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, compatibilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn oil, olive oil, castor oil, or sesame oil, or mixtures of these substances.

[0051] Besides these inert diluents, the composition may also include adjuvants, such as wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, and perfumes. In addition to the active compound, suspensions may contain suspending agents such as ethoxylated isooctadecanol, polyoxyethylene sorbitol or sorbitan esters, microcrystalline cellulose, aluminum methoxyl or agar, or mixtures of these substances.

[0052] Compositions for parenteral injection include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous or non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols, and suitable mixtures thereof. Dosage forms of the compounds of the present invention for topical administration include ointments, powders, poultices, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required.

[0053] The compounds of the present invention may be administered alone or in combination with other pharma- ceutically acceptable compounds (eg, antithrombotic agents). The treatment methods of the present invention may be administered alone or in combination with other therapeutic procedures or agents. When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (such as a human) in need of treatment, and the dosage is a pharmacologically effective dosage, and for a human weighing 60 kg, the daily dosage is usually 1-2000 mg, preferably 50-1000 mg. Of course, the specific dosage should further consider factors such as the mode of administration and the health condition of the patient, all of which are within the skill of a skilled doctor.

[0054] The main advantages of the present invention are: (a) The compound of formula I of the present invention has a good therapeutic effect on cranial nerve damage caused by stroke. (b) The compounds of formula I of the present invention can be used for the prevention and thrombolysis of thrombotic diseases and do not lead to bleeding. (c) The compounds of formula I of the present invention have anti-inflammatory effects. (d) Among the compounds of formula I of the present invention, compound 1 has excellent safety and low toxicity and side effects.

[0055] The present invention will be further described below with reference to specific examples. It is understood that these examples are only used to illustrate the present invention and do not limit the scope of the present invention. Experimental methods for which no specific conditions are given in the following examples are generally performed according to standard conditions, such as those described in Sambrook et al., "Molecular Cloning: A Laboratory Manual" (New York, Cold Spring Harbor Laboratory Press, 1989), or according to the manufacturer's recommended conditions. Unless otherwise stated, percentages and parts are by weight.

[0056] Example 1: Experiment to evaluate the preventive effect of samples against vascular endothelium-damaging thrombosis Experimental method: 420 5 dpf wild-type AB strain zebrafish were randomly placed in a 6-well plate, with 30 in each well (experimental group). Compound (1), compound (2), compound (3), compound (4), compound (5), compound (6), compound (7), compound (8), compound (9), compound (10) and compound (11) (see Table 1 for the structural formula) were administered by injection at a dose of 4.00 ng / animal, and the positive control drug acetylsalicylic acid was administered in aqueous solution at a concentration of 30.0 μg / mL. At the same time, a normal control group (i.e., zebrafish treated with standard dilution water) and a model control group were set up, with the volume of each well (experimental group) being 3 mL. In addition to the normal control group, all other experimental groups were administered with ponatinib in aqueous solution to induce vascular endothelial injury thrombosis model in zebrafish. Samples were incubated at 28°C and treated with ponatinib for a set time period, then stained with o-dianisidine.

[0057] After staining, 10 zebrafish were randomly selected from each group and photographed under a microscope. The staining intensity of the red blood cells in the zebrafish hearts was analyzed using NIS-Elements D 3.20 advanced image processing software. The statistical results of the staining intensity of the red blood cells in the hearts were used to evaluate the preventive effect of the samples against vascular endothelium-damaging thrombosis.

[0058] The formula for calculating the thromboprophylactic effect is as follows:

number

[0059] Test Results: [Table 1-1] [Table 1-2]

[0060] Experimental results: The staining intensities of zebrafish cardiac red blood cells in the 4.00 ng / animal dose groups of compound (1), compound (2), compound (3), compound (4), compound (5), compound (6), compound (7), compound (8), compound (9), compound (10) and compound (11) were 4397, 3655, 3045, 4300, 4340, 4938, 4584, 4580, 4709, 4326 and 4749 pixels, respectively.

[0061] Compared with the model control group, the thromboprophylaxis effect of compound (3) at 4.00 ng / mouse was 17% (p > 0.05), and the thromboprophylaxis effect of compound (1), compound (2), compound (4), compound (5), compound (6), compound (7), compound (8), compound (9), compound (10) and compound (11) at 4.00 ng / mouse was 66%, 39%, 63%, 64%, 86%, 73%, 73%, 78%, 64% and 79% (p < 0.01, p < 0.05, p < 0.001, p < 0.001, p < 0.001, p < 0.001, p < 0.001, p < 0.01, p < 0.001), respectively.

[0062] Experimental conclusion: Compound (1), compound (2), compound (4), compound (5), compound (6), compound (7), compound (8), compound (9), compound (10) and compound (11) have obvious preventive effects on zebrafish against endothelial injury thrombosis induced by ponatinib under the conditions of this experiment. In particular, compound (6), compound (11), compound (9), compound (7), compound (8) and compound (1) had very significant preventive effects on zebrafish of endothelial damage induced by ponatinib in the 4.00 ng / animal dose group, with the index of thrombosis prevention effect (%) being 66%-86%, while the index of thrombosis prevention effect of 30 μg / ml acetylsalicylic acid was 101%.

[0063] Example 2: Assessment of allergy risk by sample Experimental method: 2 dpf wild-type AB strain zebrafish were randomly placed in a 24-well plate, and 6 duplicate wells were set up for each group, with 10 zebrafish treated in each well. The samples were administered intravenously at a dose of 500 ng / animal, and the positive control "C48 / 80" was administered at a concentration of 1.5 μg / mL. A normal control group was also set up, with the volume of each well being 1 mL. BAPNA was administered as an aqueous solution to each experimental group. After one day of treatment at 28°C, the liquid was transferred to a 96-well plate, and 200 μL / well of the liquid was used to detect the relative absorbance value (OD value) of the tryptase expression level in each experimental group using a microplate reader. The allergy risk of the samples was evaluated based on the statistical analysis of the OD value. The statistical results are shown as the mean ± standard error.

number

[0064] [Table 2]

[0065] Experimental results: The tested compounds of the present invention had low allergy risk even at a dose 125 times higher (i.e., 500 ng / animal) than the dose of 4 ng / animal in Example 1. Representatively, as shown in Table 2, the tested compounds (1), (2), and (10) of the present invention all had significantly lower allergy risk than the positive control. Among these, “compound (2)” and “compound (1)” had no or almost no allergic risk, while “compound (10)” had a low allergic risk.

[0066] Experimental conclusion: Combining the experimental results of Examples 1 and 2, that is, taking into consideration safety and efficacy comprehensively, the present invention selected compound (1) as the preferred compound for further experiments.

[0067] Example 3 Evaluation of the preventive effect of Compound 1 against vascular endothelium-damaging thrombosis Experimental method: Wild-type AB strain zebrafish were treated with 4 μg / mL ponatinib for 18 h to establish a zebrafish vascular endothelial injury thrombosis model. 150 5 dpf wild-type AB strain zebrafish were randomly placed in a 6-well plate, with 30 in each well (experimental group). Compound (1) was administered by injection at doses of 2.06 and 6.18 ng / animal, and the positive control drug acetylsalicylic acid was administered in aqueous solution at a concentration of 30 μg / mL. At the same time, a normal control group (i.e., zebrafish treated with standard dilution water) and a model control group were set up, with the volume of each well (experimental group) being 3 mL. Except for the normal control group, all other experimental groups were administered with aqueous solution of ponatinib to induce a zebrafish vascular endothelial injury thrombosis model. Incubate at 28 ℃, compound (1) is treated with ponatinib for a certain time, then stained with o-dianisidine. After staining, randomly select 10 zebrafish from each group and take photos under a microscope. Analyze the staining intensity of red blood cells in the zebrafish heart using NIS-Elements D 3.10 advanced image processing software. Based on the statistical results of the staining intensity of red blood cells in the heart, evaluate the preventive effect of compound (I) against vascular endothelium damage thrombosis. The formula for the prevention of thrombosis is as follows:

number

[0068] [Table 3]

[0069] Experimental results: In the 2.06 ng / animal and 6.18 ng / animal dose groups of compound (1), the zebrafish heart red blood cell staining intensity was 4601 and 5044 pixels, respectively, with p < 0.001 compared to the model control group, and the thrombosis prevention effect was 83% and 99%, respectively. Experimental conclusion: Compound (1) has a significant preventive effect on endothelial injury thrombosis induced by ponatinib in zebrafish, and the preventive effect has a certain dose-dependence. Compound (1) has a better preventive effect on endothelial injury thrombosis than the positive control acetylsalicylic acid.

[0070] Example 4 Effect of Compound (1) on Arteriovenous Shunt Thrombus in Rats Testing Method: Grouping: 10 mice / group divided into 5 groups. The model control group was administered with the solvent, while the test compound (1) and the positive control group were administered with the compound (1) by intravenous injection for three consecutive days, and the model was constructed once a day, 30 minutes after the last administration. Model construction: 50 SD male rats were anesthetized with pentobarbital sodium 60 mg / kg ip. They were fixed in a supine position, the skin was incised from the middle of the neck, the fascia and muscle tissue were separated, the left common carotid artery and the right external jugular vein were isolated, and an arteriovenous (AV) bypass operation was performed using a polyethylene tube with a thread. The proximal part of the carotid artery was clamped with an arterial clip, and one end of the polyethylene was inserted into the artery and the other end into the vein to complete the bypass operation. 30 min after the last administration, the arterial clip was opened, and blood flowed from the left common carotid artery through the bypass tube to the right external jugular vein, and the blood flow was connected to the shunt circulation, and the thrombus was removed 15 min later.

[0071] Detection index: After 15 minutes, the blood flow was released, the thread was taken out, the remaining liquid was sucked up, the weight of the thread with the thrombus was measured, and the wet weight of the thrombus was calculated. The thread was dried by heating in an oven at 50°C, and the dry weight of the thrombus was calculated by measuring it. The thrombus formation inhibition rate was calculated. After the test was completed, the tail was cut to detect the bleeding time. [Table 4]

[0072] Experimental results: Compared with the model control group, intravenous injection of compound (1) at 10 mg / kg, 20 mg / kg, and 40 mg / kg could inhibit the thrombus formation in rat arteriovenous shunt to different degrees, and the inhibition rates of the wet and dry thrombus weights were 19.4% (P>0.005), 15.9% (P>0.005); 21.9% (P<0.001), 26.8% (P<0.001); 34.3% (P<0.001), and 37.8% (P<0.001), respectively. Intravenous administration of ozagrel at 16 mg / kg inhibited the wet and dry thrombus weights by 34% (P<0.001) and 34.1% (P<0.01). Experimental conclusion: The antithrombotic effect of compound (1) is dose-dependent, and its antithrombotic effect is comparable to or better than that of ozagrel.

[0073] [Table 5]

[0074] Experimental results: Compared with the model control group, intravenous administration of different doses of compound (1) had no significant effect on the bleeding time of rats. In the positive control, intravenous administration of ozagrel significantly prolonged the bleeding time of rats (P<0.01). Experimental Conclusion: Bleeding experiments with compound (1) showed no dose dependency, thus proving that compound (1) does not pose any significant bleeding risk.

[0075] Example 5 Effect of preventive administration of compound (1) on cerebral ischemia-reperfusion injury in rats Experimental method: SD rats were randomly divided into six groups: a sham operation group, a model control group, a positive control drug ozagrel (6 mg / kg) group, and groups receiving high (67.5 mg / kg), medium (22.5 mg / kg), and low (7.5 mg / kg) doses of the test compound (1). In the treatment group, the drug was administered via tail vein injection in advance, while in the sham operation group and model control group, an equal volume of saline was administered once a day for three consecutive days. Ten minutes after the last administration, a rat MCAO / R model was constructed, and reperfusion was performed after 2 hours of ischemia. Twenty-four hours after MCAO / reperfusion, the rats were scored for neurobehavioral characteristics to measure the rats' neurological functions. The cerebral infarction rate and brain water content of the rats were measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining method.

[0076] [Table 6]

[0077] [Table 7]

[0078] [Table 8]

[0079] Experimental results: All doses of compound (1) and the positive drug ozagrel group were able to reduce the neurological function score, cerebral infarction rate and cerebral water content in MCAO / R rats. Experimental conclusion: Prophylactic administration of compound (1) can reduce the cerebral infarction rate and cerebral water content in cerebral ischemia-reperfusion injury in rats, and improve the neuromotor function in rats.

[0080] Example 6 Effect of the combined use of compound (1) and urokinase (iv) on autothrombosis and thromboplastin-induced ischemic brain damage in rats Experimental method: Using the method of injecting autologous thrombus and thromboplastin into the internal carotid artery via the external carotid artery to embolize the artery in the rat cerebral cortex, SD rat cerebral ischemia injury model was established, and the rats were randomly divided into 5 groups according to behavioral scores: sham operation group (external carotid artery was only isolated), model control group (both groups were administered equal volumes of saline), urokinase (5000 U / kg) group, and compound (1) (22.5 mg / kg) group, with 20 rats in each group (10 rats were used for detecting cerebral infarction rate, and 10 rats were used for pathological detection). 2 h after the model was established, the rats were slowly injected (1 mL / min) once through the tail vein, and the blood flow reduction at 120 min after injection was monitored. After 24 h, the rats were scored for neurobehavior and the rats' neurological functions were measured. The cerebral infarction rate and cerebral water content of the rats were measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining method, and the cerebral pathological damage of the rats 2 h after cerebral ischemia was observed by hematoxylin-eosin (HE) staining method.

[0081] Test Results: [Table 9]

[0082] (Data are shown as mean ± standard deviation, n = 10) [Table 10]

[0083] [Table 11]

[0084] [Table 12]

[0085] After establishing a model of cerebral ischemic injury caused by autologous thrombosis and thromboplastin, intravenous administration of compound (1), urokinase and compound (1) + urokinase could significantly reduce the percentage decrease in cerebral blood flow, the cerebral infarction area and cerebral water content in the model rats, and improve the pathological injury and behavioral changes, among which compound (1) + urokinase showed the most obvious improvement level of cerebral ischemic injury caused by autologous thrombosis and thromboplastin.

[0086] Experimental conclusion: Compound (1)(iv) and its combination with urokinase can reduce the cerebral infarction rate, cerebral water content and pathological damage in rats with cerebral ischemic injury caused by thrombosis and thromboplastin, and improve the neuromotor function of rats, showing good anti-ischemic brain injury effect.

[0087] Example 7 Effect of therapeutic administration of compound (1) on cerebral ischemia-reperfusion injury in rats Experimental method: SD rats were randomly divided into 11 groups, including a sham operation group, a model control group, a positive control edaravone intravenous injection group (6 mg / kg, iv), a positive control butylphthalide injection solution intravenous injection group (5 mg / kg, iv), a high dose of compound (1) intravenous injection group (24 mg / kg, iv), a medium dose of compound (1) intravenous injection group (12 mg / kg, iv), a low dose of compound (1) intravenous injection group (6 mg / kg, iv), a positive drug butylphthalide soft capsule intragastric administration group (60 mg / kg, ig), a high dose of compound (1) intragastric administration group (60 mg / kg, ig), a medium dose of compound (1) intragastric administration group (30 mg / kg, ig), and a low dose of compound (1) intragastric administration group (15 mg / kg, ig). A middle cerebral artery occlusion (MCAO) cerebral ischemia-reperfusion model was established in male rats using the internal carotid artery suture occlusion method, and reperfusion was performed after 90 min of ischemia. One hour after reperfusion, the rats were administered once via tail vein and orally, and 24 h later, neurobehavioral scores were performed on the rats to measure their neurological function. The cerebral infarction rate and brain water content of the rats were measured using the 2,3,5-triphenyltetrazolium chloride (TTC) staining method.

[0088] [Table 13]

[0089] [Table 14]

[0090] [Table 15]

[0091] Experimental results: Each dose group of compound (1) and each positive drug group could reduce the neurological function score, cerebral infarction rate and brain water content of MCAO / R rats to different degrees, among which, the compound (1) (24 mg / kg, iv) group and compound (1) (60 mg / kg, ig) group showed the most obvious effects. Experimental conclusion: The therapeutic administration of compound (1) can reduce the cerebral infarction rate and cerebral water content of cerebral ischemia-reperfusion injury in rats, and improve the neuromotor function of rats.

[0092] Example 8 Study on the inhibition of ferroptosis of neuronal cells during cerebral ischemia-reperfusion by Compound 1, Compound 3 and Compound 5 Experimental method: Primary neuron cells were incubated in medium containing elastin (final concentration 50 μM) for 24 h, and then incubated in medium containing different concentrations of the test drug and elastin (final concentration 50 μM) for another 24 h. After the incubation, real-time PCR was used to detect the mRNA expression of GPX4 in the cells of each group, CCK8 experiment was used to detect the cell vitality of the cells of each group, C11-BODIPY probe method was used to detect the lipid ROS level in the cells of each group, and PGSK probe method was used to detect the iron content in the cells. The experimental data were expressed as mean ± SD, and statistical differences between groups were analyzed using one-way ANOVA and Tukey's test, with a p value of <0.05 considered to be significant.

[0093] Test Results: [Table 16]

[0094] After the incubation, the cell vitality of the cells in each group was detected by CCK8 assay. The results are shown as mean ± SD. Compared with the model control group, ***p < 0.0001. Compared with the model control group, # p<0.05, ## p<0.01. As can be seen from Table 16, in the model group, cell vitality was significantly decreased compared to the control group (p<0.0001), when the concentration of compound 3 was greater than 10 μM, cell vitality was obviously improved compared to the model group (p<0.05), and when the concentrations of compound 5 and compound 1 were greater than 5 μM, cell vitality was obviously increased compared to the model group (p<0.05).

[0095] [Table 17]

[0096] After the incubation, the lipid ROS levels in the cells of each group were detected by the C11-BODIPY probe method. The results are shown as mean ± SD. Compared with the control group, ***p<0.0001, and compared with the model group, # p<0.05, ## p<0.01. As can be seen from Table 17, in the model group, the intracellular lipid ROS level was significantly increased compared to the control group (p<0.0001), when the concentration of compound 3 was more than 10 μM, the intracellular lipid ROS level was significantly decreased compared to the model group (p<0.05), and when the concentration of compound 5 and compound 1 was more than 5 μM, the intracellular lipid ROS level was significantly decreased compared to the model group (p<0.01).

[0097] [Table 18]

[0098] After the incubation, the intracellular iron content was detected by the PGSK probe method. The results are shown as mean ± SD. Compared with the control group, ***p<0.0001, and compared with the model group, # p<0.05, ## p<0.01. As can be seen from Table 18, in the model group, the cellular PGSK probe fluorescence intensity was obviously decreased compared to the control group, and the iron content was significantly increased (p<0.0001); when the concentration of compound 3 was more than 10 μM, the intracellular iron content was obviously decreased compared to the model group (p<0.05); when the concentrations of compound 5 and compound 1 were more than 5 μM, the intracellular iron content was significantly decreased compared to the model group (p<0.05).

[0099] [Table 19]

[0100] After the incubation, GPX4 mRNA expression in the cells of each group was detected by real-time PCR. The results are shown as mean ± SD. Compared with the control group, *** p<0.0001 compared with the model group. # p<0.05, ## p<0.01. As can be seen from Table 19, in the model group, cellular GPX4 mRNA expression was significantly decreased compared to the control group (p<0.0001), when the compound 3 concentration was higher than 5 μM, the cellular GPX4 mRNA expression level was obviously increased compared to the model group (p<0.05), and when the compound 5 and compound 1 concentrations were higher than 2.5 μM, the cellular GPX4 mRNA expression level was significantly increased compared to the model group (p<0.01).

[0101] Experimental conclusion: Compound 1, compound 3 and compound 5 all significantly increased the cell vitality and GPX4 mRNA expression of rat neuronal cells induced by erastin, and significantly reduced the intracellular lipid ROS level and iron content. The above research results show that compound 1, compound 3 and compound 5 all can inhibit the ferroptosis of rat neuronal cells induced by erastin.

[0102] Example 9 Evaluation of the relieving effect of Compound 1, Compound 3 and Compound 5 on vascular inflammation Experimental method: 360 5 dpf macrophage fluorescent zebrafish were randomly selected and placed in beakers, and 30 fish were placed in each beaker, and compound (1), compound (3), and compound (5) were administered by intravenous injection. In the positive control group, atorvastatin calcium was administered in aqueous solution at a concentration of 30 μg / mL, and at the same time, a normal control group (zebrafish were treated with breeding water) and a model control group were set up, and the volume of each beaker (experimental group) was 25 mL. Except for the normal control group, high-sugar and high-fat feed was administered in aqueous solution. Compound (1), compound (3), and compound (5) were treated with high-sugar and high-fat feed for 30 h until 9 dpf, and 10 zebrafish were randomly selected from each experimental group, and the macrophage fluorescence intensity in and around the tail vein of the zebrafish was detected under a fluorescent microscope, and the effects of compound (1), compound (3), and compound (5) on vascular inflammation in the high-sugar and high-fat model zebrafish were evaluated based on the results of statistical analysis.

number

[0103] Test Results: [Table 20]

[0104] Experimental conclusion: Under the dosage conditions of this experiment, compound (1), compound (3) and compound (5) have a significant relieving effect on vascular inflammation in a high-sugar, high-fat model of zebrafish.

[0105] Example 10 Preparation of injection solution [Table 21]

[0106] Take 80% of the total amount of water for injection, add the formulated amounts of sodium chloride, sodium citrate dihydrate, glycerin, and compound (1) in that order, stir to dissolve, and adjust the solution pH value to 5.0-6.5 with 0.1M hydrochloric acid or sodium hydroxide. Make up to the specified volume with water for injection. Divide into 10ml glass bottles, sterilize by heating and pressure, and obtain an injection solution of the compound. Each bottle contains 20mg of compound (1).

[0107] Example 11 Preparation of freeze-dried powder injection [Table 22]

[0108] The compound (1) was added to 80% of the amount of water for injection, stirred to dissolve, and water for injection was added to the amount of the compound. Activated carbon (0.1-0.5%) was added to the above drug solution and stirred for several tens of minutes. The drug solution was decolorized with activated carbon and filtered to remove the carbon. The pH value of the drug solution was adjusted with lithium hydroxide solution (or hydrochloric acid solution). The semi-finished product was sampled and detected. Secondary filtration was performed using a 0.22 μm filter and bottled. The product was freeze-dried with the specified freeze-drying parameters, pressed, sealed with a lid, and packaged.

[0109] All documents related to the present invention are incorporated herein by reference as if each document were incorporated individually. After reading the above content of the present invention, it will be understood that those skilled in the art can make various changes and modifications to the present invention, and that equivalent forms thereof are within the scope of the claims of the present invention.

Claims

1. 2. Use of a compound of formula I or a pharma- ceutically acceptable salt thereof for the manufacture of a pharmaceutical composition or formulation, said pharmaceutical composition or formulation comprising a compound of formula I as an active ingredient, and said pharmaceutical composition or formulation comprising: (a) prevention and / or treatment of thrombosis-related diseases, (b) anti-inflammatory treatment; and / or (c) Treatment of neuronal damage due to cerebral infarction, brain trauma, cerebral hemorrhage, or brain tumor surgery. The above-mentioned use, characterized in that it is for the purpose of: 【Chemistry 1】 (In the formula, R １ represents a hydroxy group, a C1-C6 alkoxy group, a halogen atom, a substituted or unsubstituted —O—C1-C6 alkyl group, 【Chemistry 2】 wherein said substitution is with a sulfonic acid group or a hydroxy group. Here, m is a positive integer from 1 to 6. 【Chemistry 3】 In 【Chemistry 4】 is a chiral carbon atom, and the chirality is 【Chemistry 5】 Selected from. R ４ is Na ＋ , K ＋ , Li ＋ or Cs ＋ The metal ion is selected from the group consisting of: R ５ is a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, an aryl group or a heteroaryl group. R ２ and R ３ are each independently H, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C3-C8 cycloalkyl group, a C2-C6 hydroxyalkyl group, or -(C1-C3 alkylene group)-COOH. n is a positive integer between 6 and 12.

2. 2. The use according to claim 1, characterized in that the thrombosis-related disease is selected from the group consisting of cerebral thrombosis, cerebral infarction (acute ischemic stroke) and the neuronal damage caused thereby in the nervous tissue, cerebral edema, myocardial infarction, pulmonary embolism, or a combination thereof.

3. The use according to claim 1, characterized in that the pharmaceutical composition or formulation is for the prevention and / or treatment of thrombosis-related diseases.

4. The use according to claim 1, characterized in that the pharmaceutical composition or preparation is for the treatment of neuronal damage due to cerebral infarction, cerebral trauma, cerebral hemorrhage or brain tumor surgery.

5. The use according to claim 1, characterized in that the dosage form of the pharmaceutical composition or formulation is selected from the group consisting of injection solution, lyophilized powder injection, sustained release, controlled release, enteric coated tablets or capsules, and granules.

6. 20. The use of a composition of a compound of formula I and urokinase, characterized in that it is used in the manufacture of a medicament for treating a thrombosis-related disease.

7. 2. Use of a composition of the compound of formula I and butylphthalide, characterized in that it is for the treatment of neuronal damage caused by cerebral infarction, cerebral trauma, cerebral hemorrhage or brain tumor surgery.

8. A pharmaceutical composition or formulation comprising: (a) an active ingredient comprising a compound of formula I or a pharma- ceutically acceptable salt thereof; and (b) a pharma- ceutically acceptable carrier; (1) Prevention and / or treatment of thrombosis-related diseases, (2) Anti-inflammatory treatment, and / or (3) Treatment of neuronal damage caused by cerebral infarction, brain trauma, cerebral hemorrhage, or brain tumor surgery The pharmaceutical composition or formulation is characterized in that it is for the purpose of:

9. 1. A drug kit comprising: (1) a first pharmaceutical composition comprising a first container, and within said container, a first compound, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier; (2) an nth pharmaceutical composition comprising an nth container; and within said container, an nth compound or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier; where n is any positive integer from 2 to 8; wherein the first compound and the nth compound are both compounds of formula I or a pharma- ceutically acceptable salt thereof, or the first compound is a compound of formula I or a pharma- ceutically acceptable salt thereof and at least one of the nth compounds is another active agent, wherein the compound of formula I is as defined in claim 1; and / or (3) optional instructions for use. The drug kit comprising:

10. A method for treating a disease, said disease being as defined in claim 1, comprising the step of administering to a subject in need thereof a compound of formula I or a pharma- ceutically acceptable salt thereof, wherein the compound of formula I is as defined in claim 1.

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