Substituted pyrazole compound, preparation method, pharmaceutical composition and application thereof
阅读说明：本技术 取代吡唑类化合物、其制备方法、药物组合物及用途 (Substituted pyrazole compound, preparation method, pharmaceutical composition and application thereof ) 是由 韩建斌 温翔 李泽东 杨金娜 杨柳 于 2018-08-22 设计创作，主要内容包括：一种式I所示的取代吡唑类化合物、其制备方法、药物组合物及用途。所述化合物具有良好的稳定性、溶解性优异,对细胞毒性小,对神经保护作用效果显著,能够有效预防和治疗神经细胞损伤,是一种理想的预防或治疗：脑卒中,脑栓塞,脑卒中后遗症,脑卒中运动机能障碍,线粒体脑肌病,肌萎缩性脊髓侧索硬化症的药用化合物。<Image he="464" wi="505" file="DDA0001773516260000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(A substituted pyrazole compound shown in formula I, a preparation method, a pharmaceutical composition and application thereof. The compound has good stability, excellent solubility, small cytotoxicity and obvious neuroprotective effect, and can be effectively usedThe prevention and treatment of nerve cell damage is an ideal prevention or treatment: the medicinal compound for treating cerebral apoplexy, cerebral embolism, cerebral apoplexy sequelae, cerebral apoplexy motor dysfunction, mitochondrial encephalomyopathy and amyotrophic lateral sclerosis.)
1. A substituted pyrazole compound shown in formula (I) or pharmaceutically acceptable salt thereof, or solvate of the substituted pyrazole compound and the pharmaceutically acceptable salt,
wherein:
R1represents hydrogen or alkyl;
x represents-O-, -S-or-NH-;
R2represents H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted non-aromatic heterocyclic group, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, or optionally substituted heteroaralkyl,
the term "optionally substituted" refers to unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxy, alkoxy, aryloxy, arylalkoxy, halogen, alkanoyloxy, alkoxyacyloxy, unsubstituted or alkyl substituted amino;
alternatively, the first and second electrodes may be,
Forming a group represented by the following formula (ii),
in the formula (ii), n is 1 or 2, m is 1,2,3 or 4,
each R is3Independently of one another, hydroxy, hydroxymethyl, alkanoyloxy (preferably acetoxy), benzoyloxy (preferably benzoyloxy, p-chlorobenzoyloxy) optionally substituted by halogen, alkanoylAn oxymethyl group (preferably an acetoxymethyl group), a benzoyloxymethyl group (preferably a benzoyloxymethyl group, a p-chlorobenzoyloxymethyl group) optionally substituted with halogen, an alkoxy group, an alkoxymethyl group, or an amino group which is unsubstituted or mono-or di-substituted with a group selected from the group consisting of an alkyl group, an alkanoyl group (preferably an acetyl group), a benzoyl group (preferably a benzoyl group, a p-chlorobenzoyl group) optionally substituted with halogen;
optionally, the "alkyl" and the alkyl moiety in "aralkyl", "heteroaralkyl", "alkoxy", "arylalkoxy", "alkanoyloxy", "alkoxyacyloxy", "alkanoyloxymethyl" are each independently C1-20Straight or branched alkyl, optionally C1-17Straight or branched alkyl, optionally C1-8Straight or branched alkyl, optionally C1-6Straight or branched alkyl, optionally C1-4A straight or branched chain alkyl group, alternatively methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, heptyl, n-octyl, n-nonyl, n-decyl, dodecyl, pentadecyl or hexadecyl;
alternatively, said "cycloalkyl" is C3-8Cycloalkyl, alternatively, is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
alternatively, the "non-aromatic heterocyclyl" is a non-aromatic C containing 1-2 heteroatoms selected from O, N, S3-8A heterocyclyl group, optionally, an oxirane group, an oxetanyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a piperidinyl group, a piperazinyl group, or a morpholinyl group;
alternatively, the aryl group in the "aryl", "aralkyl" is phenyl, or naphthyl;
alternatively, the heteroaryl moiety in said "heteroaryl", and "heteroaralkyl" are each independently a 5-10 membered monocyclic or bicyclic fused aromatic heterocyclic group containing 1-2 heteroatoms selected from O, N, S, alternatively pyrrolyl, furanyl, pyridinyl, pyrazinyl, or pyrimidinyl.
2. The substituted pyrazole compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof,
R1represents hydrogen or methyl;
x represents-O-or-NH-;
R2is C1-C17Branched or straight-chain alkyl of (C)3-6Cycloalkyl, phenyl C1-C6Alkyl, pyridyl, optionally substituted by one or more groups selected from hydroxy, C1-6Alkanoyloxy group, C1-6Phenyl substituted by an alkoxyacyloxy group or a group of the formula-NR ' R ' in which R ' are each independently C1-C6Straight or branched alkyl.
Alternatively, the first and second electrodes may be,
in the formula (ii), n is 1 or 2, m is 2,3 or 4,
each R is3Independently of one another, hydroxy, hydroxymethyl, or unsubstituted or substituted by C1-6Alkanoyl monosubstituted amino.
3. The substituted pyrazole compound of formula (I) or a pharmaceutically acceptable salt thereof, or a solvate of the compound or the salt according to claim 1 or 2, wherein the substituted pyrazole compound of formula (I) is a compound of formula II, III or IV,
wherein R is2As defined in claim 1 or 2And (5) defining.
4. The substituted pyrazole compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, or a solvate thereof,
wherein the moiety of formula (I) in formula (I) forms a group of formula (iii) or (iv),
wherein R'1Is hydrogen atom, hydroxymethyl, C1-4An alkanoyloxymethyl group; r'2Is hydroxy or C1-4An alkanoyloxy group; r'3Is hydrogen, hydroxy, C1-4Alkanoyloxy, amino, or C1-4An alkanoylamino group.
5. The substituted pyrazole compound of formula (I) or a pharmaceutically acceptable salt thereof, or a solvate thereof according to claim 4, wherein the moiety of formula (I) in formula (I) forms a group of formula,
6. the substituted pyrazole compound of formula (I) or a pharmaceutically acceptable salt thereof, or a solvate thereof according to claim 1, wherein the compound of formula (I) is selected from the group consisting of:
7. a process for producing the substituted pyrazole compound of the formula (I) or pharmaceutically acceptable salt thereof, or solvate thereof according to any one of claims 1 to 6, which comprises reacting the compound of the formula (A) with edaravone under basic conditions,
in the formula, R1、X、A、R2、As defined in claims 1-6, Y is halogen, preferably Cl or Br.
8. The production method according to claim 7, wherein,
the compound of formula (I) is a compound shown in formula (II), the synthetic route of the preparation method is shown as follows,
the preparation method comprises the following steps:
1) reacting the compound of formula (C) with acetaldehyde in the presence of a catalyst to obtain a compound of formula (B);
2) reacting the compound shown in the formula (B) with edaravone under alkaline conditions to obtain a compound shown in a formula (II);
optionally, the preparation method of the formula (C) comprises reacting the compound of the formula (D) with thionyl chloride;
alternatively, the first and second electrodes may be,
wherein the compound of the formula (I) is a compound shown in a formula (III), the synthetic route of the preparation method is shown as follows,
the preparation method comprises the following steps:
1) reacting the compound shown in the formula (D) with chloromethyl chlorosulfonate to obtain a compound shown in a formula (E);
2) reacting the compound of the formula (E) with edaravone under alkaline conditions to obtain a compound of a formula (III);
alternatively, the first and second electrodes may be,
wherein the compound of the formula (I) is a compound shown in a formula (IV), the synthetic route of the preparation method is shown as follows,
the preparation method comprises the following steps:
1) reacting a compound shown in a formula (H) with formaldehyde to obtain a compound shown in a formula (G);
2) reacting a compound of formula (G) with PCl5/POCl3The compound of the formula (F) is prepared by reaction,
3) reacting the compound of the formula (F) with edaravone under alkaline conditions to obtain a compound of a formula (IV);
alternatively, the first and second electrodes may be,
wherein the compound of the formula (I) is a compound shown as the following formula (V), the synthetic route of the preparation method is shown as follows,
wherein Y is Cl or Br,
the preparation method comprises the steps of reacting the compound shown in the formula (M) with edaravone under alkaline conditions to obtain a compound shown in the formula (V);
in the above structural formula, R2、R3M, n are as defined in claim 1 or 2.
9. A pharmaceutical composition comprising one or more of the substituted pyrazoles of formula (I) or pharmaceutically acceptable salts thereof, or solvates thereof according to any one of claims 1-6, and optionally a pharmaceutically acceptable carrier.
10. Use of the substituted pyrazoles of formula (I) according to any one of claims 1-6 or their pharmaceutically acceptable salts, or their solvates, or the pharmaceutical composition according to claim 9, for the preparation of a medicament for the prevention or treatment of stroke, cerebral embolism, stroke sequelae, stroke motor dysfunction, mitochondrial encephalomyopathy, and/or amyotrophic lateral sclerosis.
Technical Field
The invention relates to a substituted pyrazole compound, a preparation method, a pharmaceutical composition and application thereof.
Background
Cerebrovascular diseases are known to have four high morbidity, high disability rate, high mortality rate, high recurrence rate and the like. China is a country with high incidence of cerebrovascular diseases, wherein stroke (or called cerebral infarction or cerebral stroke) is the most important clinical cerebrovascular disease. Statistics of the Chinese cerebral apoplexy prevention and treatment report-2015 show that the number of patients suffering from cerebral apoplexy in China is as many as 700 thousands, and the number of patients dying from cerebral apoplexy diseases per year exceeds 130 thousands, so that the patients become the first death cause in China. In addition, the annual new patients with Stroke in China exceeds 200 million, the annual rate is continuously increased at a rate close to 9 percent, the Incidence rate of male Stroke is the third world and the Incidence rate of female Stroke is the second world in China (reference: the Committee for the prevention and treatment of national health Committee of the Ministry of public health of China: the China Stroke epidemic report 2015, Beijing, the Chinese collaboration university Press 2015, Wang W, Jiang B, Sun H, RuX, Sun D, Wang Wang, Wang Wang, Jiang Y, Li Y, Wang Y.Presence, Inc and mortality of Stroke in China: research from a national Stroke position-base survey of 480,687 Adulates.circulation 2017 and 135: 759-).
The pathological mechanism of stroke is a disease in which brain tissue is damaged due to sudden rupture of cerebral vessels or failure of blood flow into the brain due to vascular occlusion, and includes ischemic and hemorrhagic stroke. The stroke disease not only has high mortality rate, but also is the leading cause of disability of adults in China. The pathological mechanism of the sequelae of the cerebral apoplexy and the disabilities after treatment is that a large amount of active oxygen and free radicals are generated around a brain focus during blood reperfusion after cerebral ischemia, and the free radicals can cause irreversible damage to nerve cells and brain cells through the forms of cell membrane damage, protein damage, nucleic acid/DNA damage, generation of various inflammation mediators and the like, and finally cause the death of the nerve cells or the brain cells (reference documents: oxygen free radicals and ischemic stroke, Chinese medicine information 2010; (10) 210. sup. 210. and dynamic of free radial process involved chemical stroke: fluent on neurological status and heart.J.Clin. Neurosci.2004, Jun,11(5) 501. sup. 506). Therefore, if only the intravenous or arterial thrombolysis treatment is emphasized in the clinical treatment of the cerebral apoplexy, the problems and the hidden troubles of sequelae and disabilities brought by the free radical nerve injury to patients are difficult to completely solve and prevent.
Similar to stroke, Amyotrophic Lateral Sclerosis (ALS) is also a disease characterized pathologically by damaged atrophy and death of nerve cells. ALS is also commonly referred to as progressive freezing, and although its pathogenesis itself is currently unknown, it has been biologically demonstrated that the disease is associated with at least Superoxide Dismutase (SOD). SOD is a metalloenzyme widely present in living bodies, and among them, SOD1 has a detoxifying effect by oxidizing harmful substances such as radicals in mitochondria and decomposing them into water through disproportionation. It is currently widely accepted by the scientific community that mutation of SOD1 superoxide dismutase is one of the causes of amyotrophic lateral sclerosis (ref: Supportive and systematic management of amyotrophic lateral sclerosis. Nature reviews. neurology.2016, (9): 526-38.).
Mitochondrial encephalomyopathy is a group of diseases in which the mitochondrial structure is abnormal due to deletion or mutation of mitochondrial genes or nuclear genes, resulting in dysfunction of the brain and striated muscles. The disease is similar to epilepsy, cerebral infarction, encephalitis, cerebral dysplasia and other diseases clinically, and is a disease which seriously affects the health and life of patients. As mitochondria is one of organelles which are most sensitive to various injuries, pathological studies show that the mitochondria is attacked by oxygen free radicals to cause dysfunction and further involve the central nervous system to form the mitochondrial encephalomyopathy (reference: development of imaging study of the mitochondrial encephalomyopathy, northwest national defense medicine journal, 32 nd 2 nd vol. 2011).
The amyotrophic lateral sclerosis and the mitochondrial encephalomyopathy are clearly specified in the 'notice on publishing the first group of rare diseases' (published by national medical service No. [ 2018 ] No. 10) jointly issued by the national health committee, the scientific and technical department, the industry and informatization department, the national drug administration and the national traditional Chinese medicine administration, and are also called autism as rare diseases in China. As a rare disease, although the incidence rate of ALS is low, the population base of China is large, the number of patients suffering from the disease is about 10-20 ten thousand according to incomplete statistics, and a medicine capable of radically treating the disease is not developed successfully at present. The incidence of mitochondrial encephalomyopathy is around 1/4300 in adults and up to 1/2000 in children. Therefore, the development of therapeutic drugs capable of improving the patient's condition for such rare diseases is one of the common struggle targets of scientists in the biomedical field and important issues in the medical and health fields of China. (reference: progress in clinical diagnosis of amyotrophic lateral sclerosis [ Yan John Fan Dong L., China journal of modern neurological diseases 2012.6 Vol 12, No. 3; current situation of epidemiological research of amyotrophic lateral sclerosis [ J ]. J., China journal of neurology, 2015,48(6):542-
Disclosure of Invention
The inventor elaborately develops a novel substituted pyrazole compound which can effectively prevent and/or treat nerve cell injury.
Therefore, the invention provides a substituted pyrazole compound shown in formula (I) or pharmaceutically acceptable salt thereof, or solvate of the substituted pyrazole compound and the pharmaceutically acceptable salt,
wherein:
R1represents hydrogen or alkyl;
x represents-O-, -S-or-NH-;
R2represents H, optionally substituted alkyl, optionally substitutedCycloalkyl, optionally substituted non-aromatic heterocyclic group, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, or optionally substituted heteroaralkyl,
the term "optionally substituted" refers to unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxy, alkoxy, aryloxy, arylalkoxy, halogen, alkanoyloxy, alkoxyacyloxy, unsubstituted or alkyl substituted amino;
alternatively, the first and second electrodes may be,
Forming a group represented by the following formula (ii),
in the formula (ii), n is 1 or 2, m is 1,2,3 or 4,
each R is3Independently of one another, is hydroxy, hydroxymethyl, alkanoyloxy (preferably acetoxy), benzoyloxy (preferably benzoyloxy, p-chlorobenzoyloxy) optionally substituted by halogen, alkanoyloxymethyl (preferably acetoxymethyl), benzoyloxymethyl (preferably benzoyloxymethyl, p-chlorobenzoyloxymethyl) optionally substituted by halogen, alkoxy, alkoxymethyl, or amino which is unsubstituted or mono-or di-substituted by a group selected from alkyl, alkanoyl (preferably acetyl), benzoyl (preferably benzoyl, p-chlorobenzoyl) optionally substituted by halogen.
Optionally, the "alkyl" and the alkyl moiety in "aralkyl", "heteroaralkyl", "alkoxy", "arylalkoxy", "alkanoyloxy", "alkoxyacyloxy", "alkanoyloxymethyl" are each independently C1-20Straight or branched alkyl, optionally C1-17Straight or branched alkyl, optionally C1-8Straight or branched alkyl, optionally C1-6Straight or branched alkyl, optionally C1-4A straight or branched chain alkyl group, alternatively methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, heptyl, n-octyl, n-nonyl, n-decyl, dodecyl, pentadecyl, or hexadecyl;
alternatively, said "cycloalkyl" is C3-8Cycloalkyl, alternatively, is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
alternatively, the "non-aromatic heterocyclyl" is a non-aromatic C containing 1-2 heteroatoms selected from O, N, S3-8A heterocyclyl group, optionally, an oxirane group, an oxetanyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a piperidinyl group, a piperazinyl group, or a morpholinyl group;
alternatively, the aryl group in the "aryl", "aralkyl" is phenyl, or naphthyl;
alternatively, the heteroaryl moiety in said "heteroaryl", and "heteroaralkyl" are each independently a 5-10 membered monocyclic or bicyclic fused aromatic heterocyclic group containing 1-2 heteroatoms selected from O, N, S, alternatively pyrrolyl, furanyl, pyridinyl, pyrazinyl, or pyrimidinyl.
Alternatively, in the substituted pyrazole compound shown in the formula (I) or the pharmaceutically acceptable salt thereof, or the solvate of the substituted pyrazole compound and the pharmaceutically acceptable salt,
R1represents hydrogen or methyl;
x represents-O-or-NH-;
represents a double bond, A is O;
R2is C1-C17Branched or straight-chain alkyl of (C)3-6Cycloalkyl, phenyl C1-C6Alkyl, pyridyl, optionally substituted by one or more substituentsFrom hydroxy, C1-6Alkanoyloxy group, C1-6Phenyl substituted by an alkoxyacyloxy group or a group of the formula-NR ' R ' in which R ' are each independently C1-C6Straight or branched alkyl.
Alternatively, the first and second electrodes may be,
in the formula (ii), n is 1 or 2, m is 2,3 or 4,
each R is3Independently of one another, hydroxy, hydroxymethyl, or unsubstituted or substituted by C1-6Alkanoyl monosubstituted amino.
Alternatively, in the substituted pyrazole compound shown in the formula (I) or the pharmaceutically acceptable salt or the solvate thereof, the substituted pyrazole compound shown in the formula (I) is a compound shown in the formula II, III or IV,
wherein R is2As defined above.
Alternatively, in the substituted pyrazole compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, or a solvate thereof, the moiety of the formula (I) in the formula (I) forms a group represented by the following formula (iii) or (iv),
wherein R'1Is hydrogen atom, hydroxymethyl, C1-4An alkanoyloxymethyl group; r'2Is hydroxy or C1-4An alkanoyloxy group; r'3Is hydrogen, hydroxy, C1-4Alkanoyloxy, amino, or C1-4An alkanoylamino group.
Alternatively, in the substituted pyrazole compound represented by the formula (I) or the pharmaceutically acceptable salt thereof, or the solvate of the substituted pyrazole compound or the pharmaceutically acceptable salt thereof, the moiety represented by the formula (I) in the formula (I) forms a group represented by the following formula,
alternatively, in the substituted pyrazole compound represented by the formula (I) or the pharmaceutically acceptable salt thereof, or the solvate of the substituted pyrazole compound, the compound represented by the formula (I) is selected from the following compounds:
alternatively, the substituted pyrazole compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, or a solvate of the substituted pyrazole compound or the pharmaceutically acceptable salt can be in various optical isomer forms, and can be in α configuration or β configuration for glycoside compounds, for example, the compounds 33-40 can be in α configuration or β configuration.
In another aspect, the present inventors provide a process for producing a substituted pyrazole compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof, or a solvate thereof, comprising a step of reacting a compound of the formula (a) with edaravone under basic conditions,
in the formula, R1、X、A、R2、
Alternatively, in the above-mentioned production method,
the compound of formula (I) is a compound shown in formula (II), the synthetic route of the preparation method is shown as follows,
the preparation method comprises the following steps:
1) reacting the compound of formula (C) with acetaldehyde in the presence of a catalyst to obtain a compound of formula (B);
2) reacting the compound shown in the formula (B) with edaravone under alkaline conditions to obtain a compound shown in a formula (II);
optionally, the preparation method of the formula (C) comprises reacting the compound of the formula (D) with thionyl chloride;
alternatively, the first and second electrodes may be,
the compound of the formula (I) is a compound shown in a formula (III), and the synthetic route of the preparation method is shown as follows,
the preparation method comprises the following steps:
1) reacting the compound shown in the formula (D) with chloromethyl chlorosulfonate to obtain a compound shown in a formula (E);
2) reacting the compound of the formula (E) with edaravone under alkaline conditions to obtain a compound of a formula (III);
alternatively, the first and second electrodes may be,
the compound of the formula (I) is a compound shown in a formula (IV), and the synthetic route of the preparation method is shown as follows,
the preparation method comprises the following steps:
1) reacting a compound shown in a formula (H) with formaldehyde to obtain a compound shown in a formula (G);
2) reacting a compound of formula (G) with PCl5/POCl3The compound of the formula (F) is prepared by reaction,
3) reacting the compound of the formula (F) with edaravone under alkaline conditions to obtain a compound of a formula (IV); alternatively, the first and second electrodes may be,
the compound of the formula (I) is a compound shown as the following formula (V), and the synthetic route of the preparation method is shown as follows,
wherein Y is Cl or Br,
the preparation method comprises the steps of reacting the compound shown in the formula (M) with edaravone under alkaline conditions to obtain a compound shown in the formula (V);
in the above structural formula, R2、R3M, n are as defined above.
Alternatively, various optical isomer forms of the substituted pyrazole compounds represented by the formula (I) or pharmaceutically acceptable salts thereof, or solvates thereof can be synthesized by different methods, or obtained by separation, and the α configuration and the β configuration of the compounds, such as the α configuration or the β configuration of the compounds 33, 34, 35, 36, 37, 38, 39 and 40, can be prepared by different synthetic methods, or obtained by separation.
In another aspect, the present invention provides a pharmaceutical composition, which includes one or more of the substituted pyrazoles of formula (I) or pharmaceutically acceptable salts thereof, or solvates thereof, and optionally a pharmaceutically acceptable carrier.
The administration mode of the substituted pyrazole compound shown in the formula (I) or the pharmaceutically acceptable salt thereof or the solvate of the substituted pyrazole compound comprises the following steps: parenteral administration, oral administration, inhalation, and the like, and at least one of these compounds can be used alone or in admixture with pharmaceutically acceptable carriers, adjuvants, vehicles, excipients, diluents, and the like. The pharmaceutical composition may be in the form of, for example, injection, capsule, powder, granule, tablet, pill, syrup, emulsion, suspension, solution, etc., and may be formulated according to a conventional method.
Parenteral administration includes subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection or infusion. Injectable preparations, for example sterile aqueous or oleaginous suspensions, may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be in the form of a sterile injectable solution, suspension or lyophilized powder for injection in a parenterally-acceptable diluent or solvent, for example, as an aqueous solution. Suitable carriers or solvents that may be employed include water, ringer's solution and isotonic sodium chloride solution. In addition, the sterile essential oils may also be employed as a solvent or suspending medium. Different types of nonvolatile oils or fatty acids may be used for this purpose, including natural, synthetic or semi-synthetic fatty oils or acids, and natural, synthetic or semi-synthetic mono-, di-or triglycerides.
Oral solid dosage forms include the above powders, granules, tablets, pills and capsules. In these solid dosage forms, the active compound may be mixed with at least one additive, such as sucrose, lactose, cellulose, mannitol, maltose, dextrin, starch, agar, alginate, chitin, chitosan, pectin, donkey-hide gelatin, collagen, casein, albumin, and synthetic or semi-synthetic polymers or glycerides. These dosage forms may also include substances other than inert carriers, for example, lubricants such as magnesium stearate, preservatives such as benzoates (Parabens) and sorbitol, antioxidants such as ascorbic acid, tocopherol and cysteine, disintegrants, binders, thickeners, buffers, sweeteners, flavorants and odorants. The tablet and pill can be prepared by adding outer coating.
Oral liquid dosage forms include pharmaceutical emulsions, syrups, suspensions, solutions containing diluents commonly used in the art, such as water.
On the other hand, the present inventors provide a substituted pyrazole compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, or a solvate of the compound or the pharmaceutical composition for use in the preparation of a medicament for preventing or treating diseases such as stroke, cerebral embolism, stroke sequelae, stroke motor dysfunction, mitochondrial encephalomyopathy, and amyotrophic lateral sclerosis.
On the other hand, the present inventors provide a substituted pyrazole compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, or a solvate of the compound or the pharmaceutical composition for use in the prevention or treatment of diseases such as stroke, cerebral embolism, stroke sequelae, stroke motor dysfunction, mitochondrial encephalomyopathy, and/or amyotrophic lateral sclerosis.
The specific dosage for any particular patient will depend upon a variety of factors including the activity of the compound employed, the age, body weight, general health, sex, diet, time of administration, mode of administration, rate of secretion, drug combination and the particular condition being treated. The dosage varies with the disease, symptom, subject and route of administration to be treated, and for adult treatment, 1-300mg per day is administered orally or 1-100mg is administered intravenously in 2-3 divided doses. For example, for the treatment of ischemic stroke, the active ingredient is administered orally in an appropriate amount, e.g., about 10-200 mg/time, or intravenously in an amount of about 5-100 mg/time, in 2 or 3 equal doses per day.
The substituted pyrazole compound shown in the formula (I) or pharmaceutically acceptable salt thereof or solvate of the substituted pyrazole compound can effectively prevent and treat nerve cell injury.
In one aspect, a substituted pyrazole compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or a solvate of either thereof has excellent stability.
On the other hand, the substituted pyrazole compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, or a solvate of the compound or the salt has excellent water solubility.
On the other hand, the substituted pyrazole compound shown in the formula (I) or the pharmaceutically acceptable salt thereof, or the solvate of the compound or the pharmaceutically acceptable salt has low cytotoxicity.
On the other hand, the substituted pyrazole compound shown in the formula (I) or the pharmaceutically acceptable salt or the solvate thereof has a remarkable neuroprotective effect, and can be effectively used for preventing or treating cerebral apoplexy, cerebral embolism, cerebral apoplexy sequelae, cerebral apoplexy motor dysfunction, mitochondrial encephalomyopathy and/or post-amyotrophic lateral sclerosis.
Drawings
FIG. 1 is a drop latency-time curve for each group of ALS mice in a rod transfer experiment.
Figure 2 is a drop latency-time curve for suspension experiments in groups of ALS mice.
Detailed Description
The present invention is illustrated below by examples, which should not be construed as limiting the scope of the invention.
Representative exemplary compounds of the invention are listed in table 1. TABLE 1
Abbreviations
TBTU: O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate
DMF: n, N-dimethylformamide
ED: edaravone
DBU: 1, 8-diazabicyclo [5.4.0] undec-7-ene
TMSOTF: trimethylsilyl trifluoromethanesulfonate
SOD (superoxide dismutase): superoxide dismutase
MCAO: focal cerebral ischemia reperfusion injury model
ALS: amyotrophic lateral sclerosis
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