CN1110489C - Benzisoelenazolone sulfamide derivative, its preparing process and its application in preparing medicines - Google Patents
Benzisoelenazolone sulfamide derivative, its preparing process and its application in preparing medicines Download PDFInfo
- Publication number
- CN1110489C CN1110489C CN 98124487 CN98124487A CN1110489C CN 1110489 C CN1110489 C CN 1110489C CN 98124487 CN98124487 CN 98124487 CN 98124487 A CN98124487 A CN 98124487A CN 1110489 C CN1110489 C CN 1110489C
- Authority
- CN
- China
- Prior art keywords
- benzisoelenazolone
- general formula
- sulfamide derivative
- phenyl
- ketone
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Abstract
The present invention relates to benzisoelenazolone sulfamide derivatives and a preparing method thereof. The benzisoelenazolone sulfamide derivatives can suppress the biosynthesis of leukotriene B4 and can be used for preparing medical compositions which are used for treating inflammatory and anaphylactic diseases which are relevant to the leukotriene B4.
Description
The present invention relates to novel Benzisoelenazolone sulfamide derivative and preparation method thereof, this compounds can suppress the biosynthesizing of leukotriene B4 (LTB4), can be used for preparing the pharmaceutical composition of the treatment struvite or anaphylactic disease relevant with LTB4.The invention still further relates to these compounds in the medicine of the above-mentioned disease of preparation treatment application and the pharmaceutical composition that comprises above-claimed cpd.
(Leukotrienes LTs) is the important arachidonic acid metabolite of a class that late nineteen seventies is found to leukotriene.Wherein leukotriene B4 (LTB4) can be induced leukocyte recruitment, change vascular permeability, relevant with the struvite and anaphylactic disease of many types of cardiovascular, lung, skin, kidney etc. to a great extent, these diseases comprise rheumatic arthritis, gout, asthma, ischemia reperfusion damage, psoriasis and enteritis.
There are several pieces of survey articles to relate to leukotriene B4 biosynthesis inhibitor or LTRA recently, as John A.Salmon, the Prog.DrugRes. of Lawrence G.Garland., 1991,37:9-90. and Clint D.W.Brooks, the J.Med.Chem. of James B.Summers., 1996,39 (14): 2629-2653.
U.S. Pat 4,755,524, US5,132,319, US5,514,702 and European patent EP 292,977 grades disclosed a series of leukotriene B4 biosynthesis inhibitors and leukotriene B42 receptor antagonist.
(Non-steroidal antiinflammatory drugs NSAIDs) is widely used for treating various acute and chronic inflammations to NSAID (non-steroidal anti-inflammatory drug).Yet oneself knows that NSAIDs all has serious GI irritation effect, can cause digestive tract ulcer the used overwhelming majority.Prostaglandin(PG) is important inflammatory mediator on the one hand, also be the important protectiveness factor that the protection gastrointestinal mucosal is avoided the Digestive system damage on the other hand, so life-time service NSAIDs will cause GI damage inevitably.In addition, steroidal class anti-inflammation analgesia medicine poor selectivity, side effect is also more.Therefore by new effect link and pharmacological mechanism seek efficiently, low toxicity, the little anti-inflammatory drug of side effect be the inexorable trend of current anti-inflammatory new drug research.
More existing use organic selenium compounds suppress the biosynthetic report of leukotriene B4 in the state of the art.Carl-Magnus Andersson etc. has reported that a class contains the diaryl selenide of substituted-amino, this compounds the biosynthesizing of external obvious inhibition leukotriene B4 (Free Rad.Bio.Med., 1994,16:17-28).It is anti-inflammatory, the anti-oxidation medicine of representative that particularly Japanese first drugmaker has developed with ebselen (Ebselen):
Because selenium atom directly links to each other with aromatic ring in the Ebselen molecular structure, selenium atom can not enter the selenium storehouse in metabolic process, thereby the very low (LD of toxicity
50＞6810 mg/kg mouse), do not have to limit usually the toxicity problem of organoselenium drug development, Japanese first drugmaker has finished the three phases clinical study of Ebselen at present.
Yet Bao Dao organoselenium class LTB4 biosynthesis inhibitor or the not high or water-soluble extreme difference of activity so far, thereby limited its clinical application.
The purpose of this invention is to provide the novel Benzisoelenazolone sulfamide derivative of a class, this analog derivative is applicable to the pharmaceutical composition of the struvite or anaphylactic disease that the preparation treatment is relevant with LTB4 suppressing to have high reactivity aspect the LTB4 biosynthesizing and having well water-solublely.
The present invention relates to the novel Benzisoelenazolone sulfamide derivative of a class, its general formula is as follows:
Wherein: R
1Be H or 1-5 carbon alkyl,
R
2, R
3Can be identical or different, be selected from H, halogen, 1-5 carbon alkyl and 1-5 carbon alkoxyl group,
R
4Be selected from H, halogen, nitro, hydroxyl, ethanoyl, 1-5 carbon alkyl and 1-5 carbon alkoxyl group.
Halogen is meant fluorine, chlorine, bromine, iodine among the present invention; Alkyl can be straight chained alkyl or branched-chain alkyl, as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group.
The present invention preferably has the following representative compounds of general formula (1):
N-(4-fluorophenyl)-2-(4-sulfamoyl phenyl)-1,2-benzisoxa selenazoles-3 (2H)-ketone
N-(4-methoxyphenyl)-2-(4-sulfamoyl phenyl)-1,2-benzisoxa selenazoles-3 (2H)-ketone
N-(3-fluorophenyl)-2-(4-sulfamoyl phenyl)-1,2-benzisoxa selenazoles-3 (2H)-ketone
N-(2-aminomethyl phenyl)-2-(4-sulfamoyl phenyl)-1,2-benzisoxa selenazoles-3 (2H)-ketone
N-methyl-N-phenyl-2-(4-sulfamoyl phenyl)-1,2-benzisoxa selenazoles-3 (2H)-ketone
General formula of the present invention (1) compound can prepare by following acidylate ring closure reaction:
Wherein, raw material 2-chlorine seleno Benzoyl chloride is synthetic referring to document: Bull.Chem.Soc.Jpn., 186,59:2179-2183.
Synthesizing of raw material 4-amino phenyl sulfonyl anilide (2) referring to document: J.Am.Chem.Soc., 1940,62:372-374.
The Benzisoelenazolone sulfamide derivative of general formula of the present invention (1) be by with above-mentioned two kinds of raw materials in organic solvent or organic solvent/water mixed system-kind as the alkali of acid binding agent in the presence of, obtain through the acidylate ring closure reaction.
In one embodiment of the invention; with above-mentioned two kinds of raw materials in organic solvent such as benzene, toluene, ether, tetrahydrofuran (THF), methylene dichloride, trichloromethane, tetracol phenixin, dioxane, acetonitrile, DMF or DMSO; with organic bases such as triethylamine, pyridine or hexahydropyridine is acid binding agent; through the acidylate ring closure reaction, obtain the Benzisoelenazolone sulfamide derivative of general formula (1).
In another embodiment of the invention, with above-mentioned two kinds of raw materials in ether and water mixed system, with mineral alkali such as NaHCO
3, Na
2CO
3Or NaOH is acid binding agent, through the acidylate ring closure reaction, obtains the Benzisoelenazolone sulfamide derivative of general formula (1).
Benzisoelenazolone sulfamide derivative of the present invention can suppress the biosynthesizing of LTB4, and this performance makes it can be used to control the illness of being brought out by source meta-bolites LTB4 within the arachidonic acid in the mammalian body.Above-mentioned thus Benzisoelenazolone sulfamide derivative can be used for preparing a kind of pharmaceutical composition, and this pharmaceutical composition can prevent and treatment and LTB4 diseases associated effectively.These diseases comprise rheumatic arthritis, gout, asthma, ischemia reperfusion damage, psoriasis and enteritis.
Pharmaceutical composition of the present invention comprises pharmaceutical carrier or vehicle and a certain amount of general formula
(1) Benzisoelenazolone sulfamide derivative.The compound (1) that contains the effect that is enough to suppress LTB4 in the composition.
When pharmaceutical composition uses with the form of solution or suspension, suitable pharmaceutical carrier or vehicle comprise: for Aquo System can be water, can be the mixture of ethanol, glycerine, propylene glycol, Semen Maydis oil, oleum gossypii seminis, peanut oil, sesame oil, whiteruss and they and water for non-Aquo System; For the pharmaceutical composition of solid form, suitable pharmaceutical carrier or vehicle can be crystalline cellulose, starch, Saccharum lactis; For the pharmaceutical composition of aerosol form, suitable pharmaceutical carrier can be monochlorodifluoromethane, chloro Halothane and compressed carbon dioxide.Described pharmaceutical composition also comprises: wedding agent, for example hydroxypropylcellulose, polyvinylpyrrolidone etc.; Lubricant, for example Magnesium Stearate and talcum etc.; Disintegrating agent, for example calcium carboxymethylcellulose etc.These additional components in addition, also can comprise other component such as stablizer, antioxidant, viscous regulator etc. in the pharmaceutical composition of the present invention, as long as can not have injurious effects for the therapeutic action of The compounds of this invention.
The route of administration of compound of the present invention for example can non-per os medication or per os medication.Non-per os drug formulation can be a kind of formulation in injection, suppository, emulsion, ointment, liniment, lotion, mashed prod and the drops etc. for example.The per os drug formulation can be a kind of formulation in tablet, granule, capsule, syrup, the suspension agent etc. for example.
General formula (1) Benzisoelenazolone sulfamide derivative in use, all be with atoxic, but the dosage that can suppress the main disease that is caused by LTB4 is included in the composition to be used.The dosage of compositions for use is 10 milligrams of-500 milligrams of active ingredients of each administration, but divides 1-4 administration every day.Dosage can be done suitable increase and decrease according to patient age, body weight and symptom.
Following embodiment is intended to further set forth the present invention.But should be clear and definite be the scope that the present invention is not limited to describe in detail below.
Embodiment 1:N-(4-fluorophenyl)-2-(4-sulfamoyl phenyl)-1,2-benzisoxa selenazoles-3 (2H)-ketone
2.66 gram (10 mmole) N-(4-fluorophenyl)-4-aminobenzene sulfonamides are suspended among 150 milliliters of ether, add 1.68 gram (20 mmole) NaHCO
350 ml water solution, slowly add 150 milliliters of diethyl ether solutions of 2.54 gram (10 mmole) 2-chlorine seleno Benzoyl chlorides in following 45 minutes of the ice-water bath.Continued stirring reaction 4 hours under the room temperature, filter, water and ether thorough washing, the dry crude product that gets gets white powder solid 3.09 grams, yield 69.1%, mp:221-224 ℃ through 95% ethyl alcohol recrystallization.
MS?m/z(％)：448(M+，100)，337(39)，184(71)，156(27)。
Embodiment 2:N-(4-methoxyphenyl)-2-(4-sulfamoyl phenyl)-1,2-benzisoxa selenazoles-3 (2H)-ketone
According to embodiment 1 similarity method, be raw material with 2.78 gram (10 mmole) N-(4-methoxyphenyl)-4-aminobenzene sulfonamides, with dioxane and water recrystallization, get 2.92 gram pale yellow crystals, yield 63.7%, mp:225.5-227.5 ℃.
MS?m/z(％)：460(M+，10)，337(15)，184(57)，156(39)，61(100)。
Embodiment 3:N-(3-chloro-phenyl-)-2-(4-sulfamoyl phenyl)-1,2-benzisoxa selenazoles-3 (2H)-ketone
According to embodiment 1 similarity method, (10 mmole) N-(3-aminophenyl)-the 4-aminobenzene sulfonamide is a raw material, uses the dehydrated alcohol recrystallization with 2.82 grams, gets the light yellow granular crystal of 3.54 grams, yield 76.4%, mp:212-214 ℃.
MS?m/z(％)：464(M+，74)，400(10)，338(51)，274(100)，194(95)，184(59)，156(35)。
Embodiment 4:N-(2-aminomethyl phenyl)-2-(4-sulfamoyl phenyl)-1,2-benzisoxa selenazoles-3 (2H)-ketone
According to embodiment 1 similarity method, be raw material with 2.62 gram (10 mmole) N-(2-aminomethyl phenyl)-4-aminobenzene sulfonamides, the dehydrated alcohol recrystallization gets 2.64 gram white needle-like crystals, yield 59.7%, mp:223-225 ℃.
MS?m/z(％)：444(M+，41)，380(11)，338(19)，184(31)，156(15)，106(100)。
Embodiment 5:N-methyl-N-phenyl-2-(4-sulfamoyl phenyl)-1,2-benzisoxa selenazoles-3 (2H)-ketone
According to embodiment 1 similarity method, methyl-4-amino phenyl sulfonyl anilide is a raw material with 2.62 gram (10 mmole) N-, and the dehydrated alcohol recrystallization gets 2.54 gram light yellow solids, yield 57.3%, mp:216-218 ℃.
MS?m/z(％)：444(M+，44)，380(94)，338(25)，274(100)，194(77)，184(46)，156(23)，106(59)。
Compound of the present invention can suppress the biosynthesizing of LTB4.This restraining effect by above-claimed cpd to the experiment of the LTB4 biosynthetic influence of rat thoracic cavity inflammatory leukocytes under calcium ion carrier A 23187 brings out and confirm.
Compound of the present invention has also been carried out following application testing:
(a) measure the influence of the leukocyte chemotaxis effect that general formula (1) Benzisoelenazolone sulfamide derivative brings out fMLPP;
(b) measure the influence of the mice ear that general formula (1) Benzisoelenazolone sulfamide derivative brings out Oleum Tiglii;
(c) measure of the influence of general formula (1) Benzisoelenazolone sulfamide derivative to the delayed allergy of dinitrofluorobenzene (DNFB) inductive mouse;
(d) measure general formula (1) Benzisoelenazolone sulfamide derivative is induced myeloperoxidase (MPO) to Oleum Tiglii influence;
(e) measure general formula (1) Benzisoelenazolone sulfamide derivative to the active influence of myeloperoxidase (MPO) in the delayed allergy of dinitrofluorobenzene inductive mouse.
Above-mentioned test can prove, compares The compounds of this invention water-soluble and all improve a lot as the activity of the biosynthesis inhibitor of LTB4 with the ebselen of prior art.Specifically referring to following experimental example:
Experimental example 1: Benzisoelenazolone sulfamide derivative is to the biosynthetic influence of LTB4
Get carrageenin inductive rat thoracic cavity neutrophil leucocyte, be suspended in no Ca
2+, no Mg
2+Du1becco ' ' s damping fluid in, concentration is 1.1 * 10
7Cells/ml.0.9 milliliter of obtained cell suspension adds testing compound, and 37 ℃ of temperature were incubated 10 minutes, added A23187 (final concentration 10 successively
-6Mol), arachidonic acid (final concentration 10
-5Mol), CaCl
2(final concentration 5 * 10
-4Mol), MgCl
2(final concentration 5 * 10
-4Mol).37 ℃ of temperature were incubated 5 minutes, added 2 milliliters of termination reactions of dehydrated alcohol, added PGB
220 nanograms.Centrifugal, get supernatant liquid, extract leukotriene B4 through the Sep-Pak chromatographic column, use eluent ethyl acetate, N
2Dry up, methyl alcohol redissolves, and analyzes with HPLC, and 280nm detects.The result is as follows: compound inhibiting rate (%) IC50
5 * 10
-71 * 10
-65 * 10
-61 * 10
-5(μ m) Ebselen 9 ± 9 White streptocides 2 ± 3 embodiment 1 10 41 96 100 4.21 embodiment 203 61 100 6.27
x±s，n＝2
The above results shows, the compound of embodiment 1 and embodiment 2 can obviously suppress the LTB4 biosynthesizing brought out by A23187, and its activity is much higher than prior art ebselen and White streptocide.In addition, test result illustrates that also Benzisoelenazolone sulfamide derivative of the present invention is not the Benzisoelenazolone of prior art and the simple adduction of sulphonamide, but a class is novel, highly active LTB4 biosynthesis inhibitor.
Experimental example 2: rabbit blood neutrophil leucocyte chemotactic experiment
Separate neutrophil leucocyte from rabbit blood, adopt Boyden chamber method: two chambers up and down, (fMLPP 5 * 10 for chemoattractant
-10Mol) in following chamber, cell is in last chamber (concentration: 3 * 10
6Individual/milliliter).Two Room separate (filter membrane aperture 3.0 μ m, 13 millimeters of φ) by filter membrane, at CO
2Cultivated 2 hours in the incubator, remove nut and filter membrane, with filter membrane dyeing, the cell count under the counting on the film of chamber.The result is as follows: compound inhibiting rate (%) IC
50
10
-1010
-910
-810
-710
-610
-5(mol) embodiment 1 44 55 59 87 82 92 1.2 * 10
-10Embodiment 2 40 55 47 70 86 85 1.3 * 10
-8
The above results explanation, the compound of embodiment 1 and embodiment 2 all can suppress the chemotaxis of the neutrophil leucocyte that brought out by fMLPP.
Experimental example 3: Oleum Tiglii causes mice ear experiment (I allergic reaction type)
With the kunming mice random packet, 10 every group, with testing compound coating medicine-feeding (1 milligram /), after 30 minutes, ear is coated with 2% Oleum Tiglii to a mouse left side, strikes bottom left auris dextra sheet after 4 hours, and diameter (8 millimeters) is weighed.The result is as follows: compound inhibiting rate (%) significance embodiment 1 80 * * (P＜0.01) embodiment 2 36 is not remarkable
By The above results as seen, the compound of embodiment 1 can significantly suppress the mice ear that caused by Oleum Tiglii.
Experimental example 4: dinitrofluorobenzene (dinitrofluro benzene, DNFB) inductive mouse delayed allergy experiment
Get the ICR mouse, random packet, 10 every group.Subcutaneous administration every day (50 mg/kg/day).Every mouse web portion unhairing is evenly smeared 1%DNFB solution 50 microlitres on it, strengthens once in second day.After 5 days, 1%DNFB solution 10 microlitres evenly are applied in mouse left side ear.After 24 hours, cut left and right sides auricular concha, striking down diameter with punch tool is 8 millimeters auricle, weighs.The result is as follows: the not remarkable embodiment 2 46 * * (P＜0.01) of compound inhibiting rate (%) significance embodiment 14
By The above results as seen, the compound of embodiment 2 can significantly suppress by the delayed allergy of dinitrofluorobenzene inductive mouse.
Experimental example 5: Oleum Tiglii is induced myeloperoxidase (MPO) experiment
With the kunming mice random packet, 10 every group, with testing compound coating medicine-feeding (1 milligram /), after 30 minutes, ear is coated with 2% Oleum Tiglii to a mouse left side, strikes bottom left auris dextra sheet after 4 hours, and diameter (8 millimeters) is weighed.Get the certainweight auricle, shred, add 2 milliliters of phosphoric acid buffers (pH6.0), high-speed homogenization 15 seconds, cryogenic freezing high speed centrifugation 15 minutes, supernatant discarded with scissors.Add the phosphoric acid buffer that contains 0.5% cetyl trimethylammonium bromide, high-speed homogenization 30 seconds, cryogenic freezing high speed centrifugation 15 minutes by 50 milligrams of tissue/milliliters.Get 0.1 milliliter of supernatant and add in 2.9 milliliters of colour developing liquid that contain the adjacent tolidine of hydrogen peroxide and 16.7 grams per liters O.001%, 460nm place mensuration 3 minutes.The result is as follows:
Compound inhibiting rate (%)
Embodiment 1 77
Embodiment 2 137
The above results shows that the compound of embodiment 1 and embodiment 2 all can suppress the activity of Oleum Tiglii inductive myeloperoxidase.
Experimental example 6: myeloperoxidase (MPO) activity experiment in the delayed allergy of dinitrofluorobenzene inductive mouse
Get the ICR mouse, random packet, 10 every group.Subcutaneous administration every day (50 mg/kg/day).Every mouse web portion unhairing is evenly smeared 1%DNFB solution 50 microlitres on it, strengthens once in second day.After 5 days, 1%DNFB solution 10 microlitres evenly are applied in mouse left side ear.After 24 hours, cut left and right sides auricular concha, striking down diameter with punch tool is 8 millimeters auricle, weighs.Get the certainweight auricle, shred, add 2 milliliters of phosphoric acid buffers (pH6.0), high-speed homogenization 15 seconds, cryogenic freezing high speed centrifugation 15 minutes, supernatant discarded with scissors.Add the phosphoric acid buffer that contains 0.5% cetyl trimethylammonium bromide, high-speed homogenization 30 seconds, cryogenic freezing high speed centrifugation 15 minutes by 50 milligrams of tissue/milliliters.Get 0.1 milliliter of supernatant and add in 2.9 milliliters of colour developing liquid that contain the adjacent tolidine of 0.001% hydrogen peroxide and 16.7 grams per liters, 460nm place mensuration 3 minutes.The result is as follows:
Compound inhibiting rate (%)
Embodiment 1 81
Embodiment 2-19
The above results shows that embodiment 1 compound can obviously suppress the activity by myeloperoxidase in the little genus delayed allergy of dinitrofluorobenzene inductive.
Claims (8)
1, the Benzisoelenazolone sulfamide derivative of general formula (1),
Wherein:
R
1Be H or 1-5 carbon alkyl,
R
2, R
3Can be identical or different, be selected from H, halogen, 1-5 carbon alkyl and 1-5 carbon alkoxyl group,
R
4Be selected from H, halogen, nitro, hydroxyl, ethanoyl, 1-5 carbon alkyl and 1-5 carbon alkoxyl group.
2, general formula as claimed in claim 1 (1) Benzisoelenazolone sulfamide derivative comprises:
N-(4-fluorophenyl)-2-(4-sulfamoyl phenyl)-1,2-benzisoxa selenazoles-3 (2H)-ketone
N-(4-methoxyphenyl)-2-(4-sulfamoyl phenyl)-1,2-benzisoxa selenazoles-3 (2H)-ketone
N-(3-fluorophenyl)-2-(4-sulfamoyl phenyl)-1,2-benzisoxa selenazoles-3 (2H)-ketone
N-(2-aminomethyl phenyl)-2-(4-sulfamoyl phenyl)-1,2-benzisoxa selenazoles-3 (2H)-ketone
N-methyl-N-phenyl-2-(4-sulfamoyl phenyl)-1,2-benzisoxa selenazoles-3 (2H)-ketone
3, the preparation method of the general formula of claim 1 (1) Benzisoelenazolone sulfamide derivative is characterized in that the 4-amino phenyl sulfonyl anilide with 2-chlorine seleno Benzoyl chloride and general formula (2) expression is a raw material,
In organic solvent or organic solvent/water mixed system, in the presence of a kind of alkali as acid binding agent,, obtain general formula (1) Benzisoelenazolone sulfamide derivative through closing ring-closing condensation reaction:
4, preparation method as claimed in claim 3 is characterized in that described organic solvent comprises benzene, toluene, ether, tetrahydrofuran (THF), methylene dichloride, trichloromethane, tetracol phenixin, dioxane, acetonitrile, DMF or DMSO; Described alkali as acid binding agent comprises triethylamine, pyridine or hexahydropyridine.
5, preparation method as claimed in claim 3 is characterized in that described organic solvent/water mixed system is the mixed system of ether and water; Described alkali as acid binding agent comprises NaHCO
3, Na
2CO
3Or NaOH.
6, the application of the Benzisoelenazolone sulfamide derivative of the general formula of claim 1 (1) expression in the pharmaceutical composition of preparation treatment and leukotriene B4 diseases associated, described and leukotriene B4 diseases associated is meant rheumatic arthritis, gout, asthma, ischemia reperfusion damage, psoriasis and enteritis.
7, the pharmaceutical composition of Benzisoelenazolone sulfamide derivative that contains general formula (1) expression of at least a claim 1.
8, according to the pharmaceutical composition of claim 7, its form is suitable for by oral administration, inhalation, intestines external administration, drug administration by injection and topical.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 98124487 CN1110489C (en) | 1998-11-11 | 1998-11-11 | Benzisoelenazolone sulfamide derivative, its preparing process and its application in preparing medicines |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 98124487 CN1110489C (en) | 1998-11-11 | 1998-11-11 | Benzisoelenazolone sulfamide derivative, its preparing process and its application in preparing medicines |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1253135A CN1253135A (en) | 2000-05-17 |
| CN1110489C true CN1110489C (en) | 2003-06-04 |
Family
ID=5228671
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 98124487 Expired - Fee Related CN1110489C (en) | 1998-11-11 | 1998-11-11 | Benzisoelenazolone sulfamide derivative, its preparing process and its application in preparing medicines |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1110489C (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1237969C (en) * | 2001-04-10 | 2006-01-25 | 日本新药株式会社 | Remedial agent for chronic articular rheumatism |
| US7820829B2 (en) | 2001-06-08 | 2010-10-26 | Peking University | Bisbenzisoselenazolonyl derivatives having antineoplastic, anti-inflammatory and antithrombotic activities as well as their use |
| CN1166651C (en) * | 2001-06-08 | 2004-09-15 | 北京大学药学院 | Anti-inflammatory and antineoplastic R-bis or glycophenylpropane isoselenazole substituted compound |
| CN103965188A (en) * | 2013-01-29 | 2014-08-06 | 中山大学 | Selenium-containing donepezil analogue |
-
1998
- 1998-11-11 CN CN 98124487 patent/CN1110489C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN1253135A (en) | 2000-05-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP3445757B1 (en) | Compounds and compositions for treating conditions associated with nlrp activity | |
| CN1032750C (en) | Process for prepn. of ureido derivatives of poly-4-amino-2-carboxy-1-methyl compounds | |
| DE69432984T2 (en) | THERAPEUTIC SUBSTITUTED GUANIDINE | |
| US20090062372A1 (en) | Glycopyrronium Salts and Their Therapeutic Use | |
| KR20090123882A (en) | Pleuromutilin derivatives for the treatment of diseases mediated by microbes | |
| IL160028A (en) | Thiophene carboxamide derivatives, process for their preparation, pharmaceutical compositions comprising them and their use in therapy | |
| BR0310106A (en) | Compound, process for producing a compound, pharmaceutical composition, use of the compound and method for treating a subject suffering from a pathological condition or disease | |
| JPS6281359A (en) | (n-substituted-2-hydroxy)benzamide and n-substituted-2-hydroxy-alpha-oxo-benzeneacetamide | |
| BR0314577A (en) | Triazole derivatives as transforming growth factor (tgf) inhibitors | |
| CN109152780B (en) | CXCR-2 inhibitors for the treatment of crystalline joint disorders | |
| SG183853A1 (en) | Modulators of hec1 activity and methods therefor | |
| TNSN05238A1 (en) | BENZENESULFONAMIDE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THEIR USE FOR THE TREATMENT OF PAIN | |
| EP2076519A2 (en) | Novel dithiolopyrrolones and their therapeutical applications | |
| CN86100761A (en) | The new 4H-1-chromene-4-ketone and the production method of sulfur containing analogs thereof | |
| JP2003502367A (en) | Indole compounds | |
| CN1511828A (en) | Sufonic aniline derivatives and their medicinal use | |
| IE913655A1 (en) | Synergistic agents | |
| CN1110489C (en) | Benzisoelenazolone sulfamide derivative, its preparing process and its application in preparing medicines | |
| US5010097A (en) | Novel compounds | |
| JPH0140837B2 (en) | ||
| CN1429108A (en) | Phosphate transport inhibitors | |
| JP2008528550A (en) | Anthelmintic imidazole-thiazole derivatives | |
| JPH01106839A (en) | Alkadiene derivatives, manufacture and pharmacological composition | |
| US20110077305A1 (en) | 5-lipoxygenase inhibitors | |
| JP2022541566A (en) | Cannabinoid derivatives as pharmaceutically active compounds and methods for their preparation |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C19 | Lapse of patent right due to non-payment of the annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |