CN1240354A - Use of condensated (hetaryl-substituted) 1-benzal-3-pyarzol derivates for treating special diseases of the cardiovascular and the central nerous systems - Google Patents
Use of condensated (hetaryl-substituted) 1-benzal-3-pyarzol derivates for treating special diseases of the cardiovascular and the central nerous systems Download PDFInfo
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- CN1240354A CN1240354A CN 97180632 CN97180632A CN1240354A CN 1240354 A CN1240354 A CN 1240354A CN 97180632 CN97180632 CN 97180632 CN 97180632 A CN97180632 A CN 97180632A CN 1240354 A CN1240354 A CN 1240354A
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- indazole
- hydroxymethylfurans
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- benzyl
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to the new use of 1-benzyl-3-(substituted hetaryl)-fused pyrazole derivatives, some of which are known, of the general formula (I)in which R1 to R4 have the meaning indicated in the description, as medicaments, and to new active compounds, in particular to their use as vasodilators, if appropriate in combination with organic nitrates and NO donors and if appropriate in combination with compounds which inhibit the degradation of cGMP.
Description
The present invention relates to the new application of 1-benzyl-3-substituted heteroaryl fused pyrazole derivatives, some chemical compounds wherein are known to medicine; The invention still further relates to the new reactive compound of these derivants, particularly they are as vasodilation.If suitable, these derivants organic nitrates capable of being combined and NO donor also can make up the chemical compound that suppresses the cGMP degraded and use.
Known in vitro tests, and the platelet aggregation that 1-benzyl-3-substituted heteroaryl fused pyrazole derivatives can suppress to be stimulated (referring to: EP-667345A1; C.-C.Wu etc., Britain medicine is learned magazine (Br.J.Pharmaco1) 1995; 116:1973-1978; F-N, Ko etc., blood (Blood) 1994; 84:4226-4223; S-U.Yu etc., blood (Blood) 1996,87:3758-3767).
Be surprised to find now: the 1-benzyl of general formula (I)-3-substituted heteroaryl fused pyrazole derivatives:
Wherein
R
1Represent hydrogen, halogen, hydroxyl or C
1-C
3-alkyl or C
1-C
3Alkoxyl,
R
2Represent the group of following general formula:
R wherein
5Represent hydrogen, halogen, carboxyl, C
1-C
3Alkyl, C
1-C
3-alkoxy carbonyl group or-CH
2-OR
6, R wherein
6Represent hydrogen or C
1-C
3Alkyl,
R
3And R
4Lump together and form the following formula building stone:
R wherein
7Represent hydrogen, halogen, hydroxyl or C
1-C
3-alkyl or C
1-C
3Alkoxyl,
And the isomer of these chemical compounds and salt,
Except weak anti-aggregation activity is arranged, also show significant vasorelaxation action, particularly hypotensive activity.Therefore, they are fit to some special cardiovascular system diseases of treatment, particularly treat various angina pectoriss, myocardial infarction, cardiac insufficiency, arteriosclerosis, apoplexy and hypertension.
According to the present invention, the chemical compound of general formula (I) can also exist with the form of salt.In general, the salt of mentioning here can refer to contain salt organic or inorganic base or acid.
In the present invention, preferred physiology goes up acceptable salt.According to the present invention, the last acceptable salt of physiology can be inorganic acid salt, carboxylate or sulfonate.Particularly preferred salt is: for example, and hydrochlorate, hydrobromate, sulfate, phosphate, mesylate, ethyl sulfonate, toluene fulfonate, benzene sulfonate, naphthalene sulfonate, acetate, propionate, lactate, tartrate, citrate, fumarate, maleate or benzoate.
According to the present invention, if chemical compound of the present invention has free carboxy, similarly, the last acceptable salt of physiology can be slaine or ammonium salt.Particularly preferred salt is: for example, sodium salt, potassium salt, magnesium salt or calcium salt, also have the deutero-ammonium salt of ammonia, or the deutero-ammonium salt of organic amine, organic amine wherein is as: ethamine, two or triethylamine, two or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine or ethylenediamine.
In the present invention, C
1-C
3Alkyl represent has the straight or branched alkyl of 1-3 carbon atom.Adducible example is: methyl, ethyl, propyl group and isopropyl.
In the present invention, C
1-C
3The alkoxyl representative has the straight or branched alkoxyl of 1-3 carbon atom.Adducible example is: methoxyl group, ethyoxyl, propoxyl group and isopropoxy.
In the present invention, C
1-C
3The alkoxy carbonyl representative has the straight or branched alkoxy carbonyl of 1-3 carbon atom.Adducible example is: methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl and isopropoxy carbonyl.
Preferably, in general formula of the present invention (I) chemical compound,
R
1Represent hydrogen, fluorine, chlorine, C
1-C
3Alkyl or C
1-C
3Alkoxyl,
R
2Represent the following formula group:
Wherein, R
5Represent hydrogen, chlorine, carbonyl, C
1-C
3Alkyl, C
1-C
3Alkoxy carbonyl or-CH
2-OR
6, R wherein
6Represent hydrogen or methyl,
R
3And R
4Lump together and form the following formula group:
Wherein, R7 represents hydrogen, fluorine, chlorine, C
1-C
3Alkyl or C
1-C
3Alkoxyl,
And the isomer of these chemical compounds or salt.
Particularly preferably, according to general formula of the present invention (I) chemical compound:
R
1Represent hydrogen, fluorine, chlorine or methoxyl group,
R2 represents the following formula group
Wherein, R
5Represent hydrogen, C
1-C
3Alkyl or-CH
2-OR
6, R wherein
6Represent hydrogen or methyl, R
3And R
4Lump together and be the following formula group:
R wherein
7Represent hydrogen, chlorine, fluorine, methyl or methoxy,
The perhaps isomer of these chemical compounds or salt,
Be used for the treatment of the specificity cardiovascular disease.
The invention still further relates to novel substance cited in the following table: table:
These in the present invention the known compound shown in the general formula (I) and noval chemical compound can prepare by usual way, as according to the described method of EP-667345A1.
And preferably, the present invention also comprises: the combination of general formula (I) chemical compound and organic nitrates and NO donor, the novel substance in general formula (I) chemical compound and the combination of organic nitrates and NO donor in addition.
In the present invention, organic nitrates and NO donor are some common materials, and they show its therapeutical effect by discharging NO or NO class material.Materials such as sodium nitroprusside (SNP), nitroglycerin, sorbide nitrate, isosorbide mononitrate, molsidomine and SIN-1 are preferred materials.
In addition, the present invention also comprises chemical compound of the present invention and other compound compositions, and wherein the latter can be able to suppress the degraded of cyclic guanosine monophosphate.These materials are phosphodiesterase 1,2 and 5 inhibitor (according to Beavo and Reifsnyder (1990) TIPS11, the nomenclature among the pp150-155) particularly.By these inhibitor, according to the present invention, the effect of these chemical compounds is reinforced, and needed pharmacotoxicological effect increases.
According to the present invention, the known compound and the noval chemical compound of used general formula (I) demonstrate unforeseeable and useful pharmacological action spectrum.For example, their induction of vascular diastoles cause the reduction of blood pressure, and coronary blood flow increasing.
Therefore, they are suitable for treating special cardiovascular system diseases, for example: various angina pectoriss, myocardial infarction, cardiac insufficiency, arteriosclerosis, apoplexy and hypertension.
In order to measure their cardiovascular effect, carried out following research: the cell that derives from blood vessel is carried out in vitro tests, using the NO donor and do not using under two kinds of situations of NO donor, testing of the influence of these chemical compounds the cGMP formation of guanylate cyclase-dependence; With phenylephrine pretreatment rabbit aorta ring, determine vasorelaxation action; In anesthetized rat, the research hypotensive activity.
In the former generation endotheliocyte, the stimulation of sGC
Handle porcine aorta with collagenase solution, therefrom isolate former generation endotheliocyte.Cultivating the cell that obtains in culture medium converges until reaching.For these research, discharge these cells, be connected in the Tissue Culture Dish, subculture is until converging.For the stimulating endothelial guanylate cyclase, the sucking-off culture medium is used Ringer ' s solution washing cell once, the NO donor is being arranged or do not having under the situation of NO donor existence then, is stimulating cultivation in the buffer (sodium nitroprusside, SNP, 1 μ M).Then, test substances (ultimate density 1 μ M) moves on the cell.After cultivating through 10 fens clock times, the sucking-off buffer was-20 ℃ of following dissolved cells 16 hours.The application of radiation immunological method is determined intercellular cGMP then.
Table A
| ?Ex.No. | %cGMP increases (NOSYNTH) |
| ?1 | ????＞1000 |
| ?2 | ????72 |
| ?3 | ????250 |
| ?4 | ????413 |
| ?7 | ????734 |
| ?8 | ????28 |
| ?10 | ????238 |
| ?11 | ????14 |
| ?14(YC-1) ?EP?667?345?A1 | ????＞906 |
Extracorporeal blood vessel diastole effect
Isolate the wide ring of some 1.5mm from rabbit aorta, be placed in the 5ml organ bath, organ bath wherein contains the Krebs-Henseleit solution that is filled with carbogen, and temperature is 37 ℃.Increase contractility and digitized, parallel record is in recorder with linear recording.In order to cause contraction, in this organ bath, add phenylephrine with the concentration that increases gradually.
Contrast all after dates through several, the material that institute will be studied in further process, the dosage to increase under every kind of situation is compared with the last contraction intensity that reaches of aforementioned process during contraction.Thereby, calculating concentration, this concentration must reduce control value 50% intensity (IE50).The standard dosage is 5 μ l.
Table B
| ?Ex.No. | ????Aorta?IC?50(μM) |
| ??1 | ????4.1 |
| ??3 | ????16 |
| ??4 | ????9.2 |
| ??14(YC-1) ??EP667?345?A | ????10 |
The blood pressure measurement of anesthetized rat
Male Wistar rat, body weight 300-350g with penthiobarbital (thiopental) (100mg/kg i.p.) anesthesia, after the tracheotomy, inserts femoral artery with conduit and measures blood pressure.The material of being tested, as the form of suspension in the Tylose solution, by stomach tube with the various dose oral administration.
Table C
| ?Ex.No. | Dosage | Maximum blood pressure reduction value | Time |
| ?1 | ?10mg/kg ?30mg/kg | -14mmHg -18mmHg | ?60min ?60min |
| ?14(YC-1) ?EP?667?345?A1 | ?10mg/kg ?30mg/kg | -10mmHg -18mmHg | ?60min ?60min |
In the present invention, described chemical compound is that the central nervous system disease of feature also is a reactive compound for control with the NO/cGMP unbalance of system.Specifically, their be fit to eliminate cognitive disappearance, improve the disorderly and treatment Alzheimer of learning and memory (Alzheimer ' s disease).Their also be fit to treatment central nervous system disorder as: the dyssomnias that anxiety, anxiety and depression, sexual disorder and central nervous system cause, they can also regulate the picked-up pathology obstacle of food, preference and other medicines.
And these reactive compounds also are fit to regulate cerebral circulation, therefore are the migrainous potent agents of control.
They also are fit to prevention and control cerebral infarction sequela (apoplexy) as apoplexy, brain local hemorrhage and craniocerebral trauma sequela.According to the present invention, similarly, these chemical compounds can be used to pain management.
The present invention includes the method for pharmaceutical preparation and these preparations of preparation.Described preparation also comprises one or more chemical compound of the present invention except containing pharmaceutically suitable inert non-toxic carrier; Perhaps these preparations are made up of one or more reactive compounds of the present invention.
Randomly, these chemical compounds can exist with microencapsulation form, contain one or more aforesaid carriers.
In aforesaid pharmaceutical preparation, the concentration of therapeutical active compound is about the 0.1-99.5% of total mixture weight, preferably about 0.5-95%.
Except containing chemical compound of the present invention, described pharmaceutical preparation can also comprise other pharmaceutically active compound.
In a word, for people's medicine or veterinary drug, following medication is favourable: for reactive compound of the present invention, and the per 24 hours about 0.5-500mg/kg body weight of administration total amount, preferred 5-100mg/kg body weight is if the form of suitable available plurality of single dosage produces a desired effect.One individually dosed, contains reactive compound of the present invention, the preferably about 1-80mg/kg body weight of its content, preferred especially 3-30mg/kg body weight.
Preparation embodiment
Embodiment 1
1-(2-luorobenzyl)-3-(5-hydroxymethylfurans-2-yl)-indazole
0.8g (2.5 moles) 1-(2-luorobenzyl)-3-(5-formoxyl-2-furyl)-indazole is suspended in the 40ml propanol, slowly adds the NaBH4 of 0.8g under 0 ℃ of temperature.Stirring at room 1 hour is added to the water the settled solution that obtains then, uses the ethyl acetate extraction mixture, the organic facies dried over sodium sulfate, and vacuum evaporation, residue carries out chromatography with silica gel, and wherein eluant is the toluene/ethyl acetate mixture.
Obtain crystal 6 20mg (productive rate 77%).
Fusing point: 83 ℃
Rf (SiO2, toluene/ethyl acetate 2: 1): 0.50
Table 1,2 similar: table 1 with embodiment preparation method in the table 3
1)Fusing point table 2
Table 3
Table 3 (on continuous)
Claims (9)
1, the 1-benzyl-3-substituted heteroaryl fused pyrazole derivatives of general formula (I) and the isomer of these chemical compounds and the purposes of salt:
R wherein
1Represent hydrogen, halogen, hydroxyl or C
1-C
3-alkyl or C
1-C
3Alkoxyl, R
2Represent the group of following general formula:
R wherein
5Represent hydrogen, halogen, carboxyl, C
1-C
3Alkyl, C
1-C
3-alkoxy carbonyl group or-CH
2-OR
6, R wherein
6Represent hydrogen or C
1-C
3Alkyl,
R
3And R
4Lump together and form the following formula building stone:
R wherein
7Represent hydrogen, halogen, hydroxyl or C
1-C
3-alkyl or C
1-C
3Alkoxyl,
They are used to prepare the medicine for the treatment of special cardiovascular system diseases.
2, the purposes of chemical compound according to claim 1 is used for the hypertensive medicine of preparation control.
3, the chemical compound that contains the described general formula of claim 1 (I), and the medicine of combination organic nitrates and NO donor.
4, purposes according to claim 1, the chemical compound combination organic nitrates and the NO donor of its formula of (I) are used to prepare the medicine for the treatment of cardiovascular disease.
5, purposes according to claim 1, the chemical compound combination of its formula of (I) can suppress the chemical compound of cGMP degraded, is used to prepare the medicine for the treatment of cardiovascular disease.
6, be selected from the noval chemical compound of following material:
1-(2-luorobenzyl)-3-(5-hydroxymethylfurans-2-yl)-indazole,
1-(4-luorobenzyl)-3-(5-hydroxymethylfurans-2-yl)-indazole,
3-(5-hydroxymethylfurans-2-yl)-1-(3-methoxy-benzyl)-indazole,
1-(3-luorobenzyl)-3-(5-hydroxymethylfurans-2-yl)-indazole,
3-(5-hydroxymethylfurans-2-yl)-1-(2-methoxy-benzyl)-indazole,
1-(3-benzyl chloride base)-3-(5-hydroxymethylfurans-2-yl)-indazole,
6-fluoro-1-(2 luorobenzyl)-3-(5-hydroxymethylfurans-2-yl)-indazole,
6-fluoro-3-(5-hydroxymethylfurans-2-yl)-1-(3-methoxy-benzyl)-indazole,
1-(3-benzyl chloride base)-6-fluoro-3-(5-hydroxymethylfurans-2-yl)-indazole,
1-benzyl-3-(5-methylfuran-2-yl) indazole,
1-benzyl-3-(5-hydroxymethyl thiophene-2-yl) indazole,
4-fluoro-1-(2-luorobenzyl)-3-(5-hydroxymethylfurans-2-yl)-indazole and
5-fluoro-1-(2-luorobenzyl)-3-(5-hydroxymethylfurans-2-yl)-indazole.
7, the medicine that contains the described material of claim 6.
8, the purposes of the described chemical compound of general formula (I), general formula (I) such as claim 1 definition, chemical compound wherein is used to prepare the medicine for the treatment of central nervous system disease.
9, purposes according to claim 8, medicine wherein is used for the treatment of cerebral infarction.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 97180632 CN1240354A (en) | 1996-10-14 | 1997-10-01 | Use of condensated (hetaryl-substituted) 1-benzal-3-pyarzol derivates for treating special diseases of the cardiovascular and the central nerous systems |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19642255.8 | 1996-10-14 | ||
| CN 97180632 CN1240354A (en) | 1996-10-14 | 1997-10-01 | Use of condensated (hetaryl-substituted) 1-benzal-3-pyarzol derivates for treating special diseases of the cardiovascular and the central nerous systems |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1240354A true CN1240354A (en) | 2000-01-05 |
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ID=5177774
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 97180632 Pending CN1240354A (en) | 1996-10-14 | 1997-10-01 | Use of condensated (hetaryl-substituted) 1-benzal-3-pyarzol derivates for treating special diseases of the cardiovascular and the central nerous systems |
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| Country | Link |
|---|---|
| CN (1) | CN1240354A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108727340A (en) * | 2017-04-11 | 2018-11-02 | 广东东阳光药业有限公司 | Fluorine-substituted indazole compounds and application thereof |
-
1997
- 1997-10-01 CN CN 97180632 patent/CN1240354A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108727340A (en) * | 2017-04-11 | 2018-11-02 | 广东东阳光药业有限公司 | Fluorine-substituted indazole compounds and application thereof |
| CN108727340B (en) * | 2017-04-11 | 2020-12-29 | 广东东阳光药业有限公司 | Fluorine substituted indazoles and use thereof |
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