CN1098258C - Isocoumarin derivatives and use thereof in drugs - Google Patents
Isocoumarin derivatives and use thereof in drugs Download PDFInfo
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- CN1098258C CN1098258C CN96180334A CN96180334A CN1098258C CN 1098258 C CN1098258 C CN 1098258C CN 96180334 A CN96180334 A CN 96180334A CN 96180334 A CN96180334 A CN 96180334A CN 1098258 C CN1098258 C CN 1098258C
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Abstract
The present invention provides a compound represented by the right formula (I) and a medicinal preparation thereof. In the formula, R represents a hydrogen atom or C(1-6) alkyl group, n is integer 0 or 1. The medicinal preparation can be used for preventing or curing the maladjustment of the immunoregulation functions or diseases caused by blood vessel neogenesis.
Description
Technical field
The present invention relates to different coumarin derivative and in pharmaceutically application, in more detail, relate to the different coumarin derivative that is used to prevent and treat the disease that immunoregulation effect imbalance and angiogenesis cause.
Background technology
Different coumarin derivative, the 3-methylol of representing with following formula-6-methoxyl group-8-hydroxyl-1H-2-chromene-1-ketone particularly, at first found as the compound that eurocidin streptoverticillium (Streptoverticillium eurocidium) produces, as various zooblasts and human cancer cell are shown that the microbiotic MI 43-37F 11 of proliferation inhibition activity attracts much attention (spy opens flat 3-2177 number).Thereafter, chemical synthesis process to above-mentioned microbiotic MI 43-37F11 (hereinafter to be referred as MI 43) is studied, 3 at the Isocoumarin 〉97 skeleton have the methyl that contains the disengaging base with benzyloxymethyl or monochloromethyl etc., make intermediate (spy opens flat 4-112884 number) with this different coumarin derivative etc., in addition, also provide (spy opens flat 5-97841 number) to have at above-mentioned 3
Different coumarin derivative (the R in the formula of base
3And R
4Be respectively replacement or unsubstituted alkyl, alkoxyl group, alkanol oxygen base, one or disubstituted amido, thiophenyl or N independently
3In base, it shows the pharmacologically active same with MI 43.
In addition, oral MI 43 can suppress adjuvant arthritis of big white mouse and the collagen-induced arthritis of mouse effectively, so there is the people to propose as immunomodulator (spy opens flat 6-183966 number).Yet MI 43 demonstrates suitable validity as immunomodulator, and, still exist as active compound or the medical needs of supplying with.
Originally as medicaments such as the steroid hormone preparation for the treatment of autoimmune diseases use, golden preparation, Beracilline, LEVAMISOLE HCL, sulfasalazines, sometimes can cause adrenal insufficiency, infect severe side effect such as disease, renal tubal dysfunction, hematopoietic disorder or gastrointestinal dysfunction, it be used produce very big restriction.
Under such background, the purpose of this invention is to provide side effect little, to effective with the Mammals headed by the mankind, the good pharmaceutical preparation of bioavailability particularly.
Disclosure of an invention
The inventor studies the pharmacological action and the bioavailability of various different coumarin derivatives for achieving the above object.The result is, find 3 direct bonded carboxyls with MI 43, perhaps use the different coumarin derivative of the methylol on 3 that pass through methylene radical or methyne bonded carboxyl replacement MI 43, for example, demonstrate goodly or be not less than its immunoregulation effect, also find its low toxicity simultaneously, and show extremely good bioavailability than MI 43.And, it is shocking that the compound of this specific character is arranged, when Mammals is oral, find that it shows very high stability in vivo.In addition, find that also above-claimed cpd can suppress mammiferous angiogenesis effectively.Also having, is in the original technical literature not compound of record by methylene radical or methyne in conjunction with the different coumarin derivative of carboxyl at above-mentioned 3.
Thereby, the invention provides the pharmaceutical preparation that contains the adjuvant that allows on the pharmacopedics and constitute with significant quantity on the pharmacology of the salt that allows on the compound of following formula (I) expression or its pharmacopedics:
(in the formula, R is hydrogen atom or C
1-6Alkyl, n are 0 or 1).Prevention particularly is provided or treats the immunoregulation effect imbalance or the pharmaceutical preparation of the disease that angiogenesis causes.
In other words, provide the salt that allows on the compound that adopts above-mentioned formula (I) expression or its pharmacopedics, the pharmaceutical preparation of the disease that preparation prevention or the imbalance of treatment immunoregulation effect or angiogenesis cause.
Again in other words, provide immunoregulation effect to lack of proper care or the prevention of the disease that angiogenesis causes or the method for treatment, this method comprises the pharmacology significant quantity with the salt that allows on the compound of following formula (I) expression or its pharmacopedics, gives the operation of the Mammals administration headed by the mankind.
In addition, provide a kind of novel cpd in following formula (I) compound, i.e. the compound or its salt of representing with following formula (I-a).
(in the following formula, R is hydrogen atom or C
1-6Alkyl).
In addition, the present invention also provides the compound that can effectively use following formula (II) expression as the synthetic intermediate of making following formula (I-a) compound.
(in the following formula, R is hydrogen atom or C
1-6Alkyl, and A is hydrogen atom or protecting group).
The simple declaration of accompanying drawing
Fig. 1 be compound 3 of the present invention when mouse is oral, this compound and metabolite concentration curve over time in the blood plasma.
Fig. 2 is MI 43 (comparative compound) when mouse is oral, the concentration of this compound and metabolite curve over time in blood plasma.
The detailed description of invention
Formula of the present invention (I) compound is characterized in that, directly combines carboxyl especially on 3 on Isocoumarin 〉97 skeleton, and perhaps (R is C for methylene radical (R is a hydrogen atom) by 1 carbon atom is only arranged or methyne
1-6Alkyl) combines carboxyl indirectly.Here, R is C
1-6During alkyl, can enumerate as the object lesson of alkyl, for example, methyl, ethyl, just or sec.-propyl, just-, different-, secondary-or the tertiary butyl, n-pentyl, isopentyl and n-hexyl etc.In formula (I) compound, when R was abovementioned alkyl, especially bioavailability was for example stable in vivo high, the trend that also has validity to increase when oral.
The spendable particular compound of the present invention is as shown in the table.When referring to The compounds of this invention below, with the sequence number of these compounds.
Table: the specific examples of compound
| Compound N o. n R |
| 1 0 - 2 1 |
Above-mentioned formula (I) compound can use the salt form of its carboxyl and basic cpd, as long as these salt pairs purpose of the present invention does not have baneful influence, any salt is all available.Yet, preferably, generally contain the salt that allows on the pharmacopedics of medicine of carboxyl, preferably the salt that generates with basic cpd.Do not limit, but concrete salt can enumerate lithium, sodium, and alkaline-earth metal such as basic metal, calcium and magnesium such as potassium, and the salt of organic basess such as methylamine, ethamine, dimethylamine, Trimethylamine 99, triethylamine, pyridine, piperazine and piperidines.
In the compound of the present invention, compound 1 is known compound (Yamazaki, et al., the Chem.Pharm.Bull. that separates from the metabolite of reddish brown aspergillus (Aspergillus ochraceus)
20(10) 2276～2278 (1972)), still, also can prepare by following reaction process I.
Reaction process I
In addition, the new compound with formula (II) expression for example, can prepare by following reaction process II.
Reaction process II
More particularly, the operation of above-mentioned reaction process I, for example, according to J.Org.Chem., Vol.54, the method for 4218～4220,1989 records is made initial compounds 1, then, represented various reaction process can be implemented by the known method of people among the above-mentioned flow process I.These operate in the spy and open in the flat 5-163263 communique write up, if desired, please refer to this communique.Quote the content of the content of this communique as this specification sheets.
Secondly, reaction process II is, for example, and wushu
4Or
53 halogenated methyl different coumarin derivatives place methyl-sulphoxide, dimethyl formamide, tetrahydrofuran (THF) isopolarity solvent, with cyaniding basic metal (for example, KCN or NaCN) reaction, generate corresponding to
8Nitrile compound.Then; at organic bases (for example; imidazoles, lutidine etc. exist down; the nitrile compound that obtains here with place; for example the silylation agent in the organic solvents such as dimethyl formamide, methylene dichloride, toluene (for example; TERT-BUTYL DIMETHYL CHLORO SILANE, t-butyldimethylsilyl ト リ Off レ-ト etc.) reaction; behind 8 hydroxyl protection; in reaction solvents such as methylene dichloride-aqueous systems; in the presence of alternate moving catalyst and alkali metal hydroxide (for example sodium hydroxide, potassium hydroxide etc.); with halohydrocarbons reaction, production
9Nitrile compound.If necessary, 8 of the Isocoumarin 〉97 skeleton hydroxyl protections also can break away from.Above-mentioned reaction generally is to carry out under the reflux temperature of 0 ℃～solvent for use.
The formula that obtains like this
8And
9, with and the compound that removes hydroxyl protecting group all are compounds of report not in original technical literature, for example, can be used as the synthetic intermediate of formula of the present invention (II) compound.Therefore, can use trimethyl silyl, ethanoyl, propionyl, benzoyl, methoxymethyl, methoxy ethoxy methyl and benzyloxymethyl etc. to replace above-mentioned silyl as hydroxyl protecting group, therefore, the present invention also provides the formula of these protecting groups
8And
9Compound.
From formula
8Or
9Compound comes synthesis type (II) compound to be formula
8Or
9Compound, carried out in 50～150 ℃ of stirrings in the mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid at organic acids such as tosic acid, methylsulfonic acids in 1～20 hour.When this was reflected at hydroxyl protecting group in the above-claimed cpd and breaks away from, cyan-hydrolysis was transformed into carboxyl.
The salt of the carboxylic acid derivative that obtains like this according to the known salt-forming reaction of people, generates with corresponding basic cpd.
The salt that allows on the compound of the invention described above or its pharmacopedics, describe in detail as the back, for example, demonstration has restraining effect to collagen-induced arthritis, and old friends infer that it can be used for preventing or treat the disease of main autoimmunization regulating effect imbalance such as autoimmune disease such as chronic rheumatoid joint disease, systemic lupus erythematosus, Sjogren's syndrome disease, periarteritis nodosa, ulcerative colitis and teenager's property diabetes or malignant tumour, severe infection disease etc.
In addition, for example, in the subcutaneous method of mouse back, demonstrate restraining effect to the angiogenesis of tumor promotion.People infer that it mainly also is applicable to the disease that prevention and treatment angiogenesis cause, angiogenesis, particularly arteriosclerosis that for example propagation of malignant solid tumour and transfer, diabetic retinopathy, chronic eczema, corneal transplantation cause.
In addition, compound of the present invention is compared with known MI 43, and it demonstrates the immunoregulation effect that is had and has high stability in vivo.When particularly oral, show good bioavailability based on effective high stability in the organism.And, almost find no toxicity, can be effectively, safe handling.
Compound of the present invention can be separately as prevention or treatment, and for example immunoregulation effect is lacked of proper care or the pharmaceutical preparation of the disease that angiogenesis causes, yet it is preferred being used in combination with the adjuvant that allows on the pharmacopedics.As such adjuvant, can enumerate this technical field weighting agent commonly used at present, extender, tackiness agent, thinner or vehicle such as wetting Agent for Printing Inks, disintegrating agent, disintegration inhibitor, tensio-active agent, lubricant.These pharmaceutical preparations can be selected various doses of shapes according to its therapeutic purpose.On behalf of agent shape, it can enumerate tablet, pill, powder, solution, suspendible syrup, emulsion, granule, capsule, suppository, injection (solution, suspensoid etc.) etc.In addition, the good especially administering mode of performance The compounds of this invention effect, think oral, so in above-mentioned dose of shape, it is preferred that oral preparation shape is provided.
When the tablet moulding, can be extensive use of known carrier, for example, lactose, white sugar, sodium-chlor, glucose, urea, starch, lime carbonate, potter's clay, crystalline cellulose, vehicle such as silicic acid, water, ethanol, propyl alcohol, simple syrup, Glucose Liquid, starch fluid, gelatin solution, carboxymethyl cellulose, shellac, methylcellulose gum, potassiumphosphate, wedding agents such as Polyvinylpyrolidone (PVP), dry starch, sodium alginate, agar powder, the laminarin powder, sodium bicarbonate, lime carbonate, polyoxy ethane sorbitan-fatty acid ester class, Sodium Lauryl Sulphate BP/USP, glyceryl monostearate, starch, disintegrating agents such as lactose, white sugar, cocoa cream, hydrogenation wet goods disintegration inhibitor, quaternary ammonium salt, absorption enhancers such as Sodium Lauryl Sulphate BP/USP, glycerine, wetting Agent for Printing Inkss such as starch, starch, lactose, potter's clay, wilkinite, sorbent materials such as colloidal silicic acid, Talc, stearate, boric acid powder, lubricants such as polyoxyethylene glycol etc.
And, as required, tablet is wanted dressing usually, for example, can make coated tablet, gelatine glaze sheet, film covering piece, double-layer tablets and multilayer tablet.When being configured as the pill form, but the original known carrier in this field of widespread use, for example, vehicle such as glucose, lactose, starch, cocoa cream, hardened vegetables oil, potter's clay, talcum, wedding agents such as gum Arabic powder, powdered tragacanth, gelatin, ethanol, disintegrating agents such as laminarin, agar or the like.
When being shaped to the suppository form, can be extensive use of the carrier of this field previously-known, polyoxyethylene glycol for example, the ester class of cocoa cream, higher alcohols, gelatin, semisynthetic glyceryl ester etc.
Occasion at the preparation injection, solution and suspensoid sterilization, and isoosmotic with blood is preferred, when these solutions of preparation, suspensoid, can be extensive use of this field thinner commonly used, for example can water, ethanol, propylene glycol, the isooctadecanol of ethoxylation, polyoxygenated isooctadecanol, polyoxy ethane sorbitan-fatty acid ester class.Also have, when this isotonic solution of preparation, also can contain sodium-chlor, glucose or the glycerine of capacity in the preparation, in addition, also can use general solubilizing agent, buffer reagent, analgesic agent etc.When oral, as required, also can contain tinting material, preservatives, spices, flavour agent, sweeting agent etc. or other drug in the said preparation.
The amount of contained above-claimed cpd of the present invention is not particularly limited in the pharmaceutical preparation of the present invention, can in very large range select, but, general tablet, during solid preparation such as granule and capsule, compounds content in the said preparation composition is 1～70% (weight), 5～50% (weight) preferably, and compounds content is 0.1～10% (weight) in the liquid preparations such as solution, injection and suspensoid.
The medication of The compounds of this invention is not done special restriction, should according to the form of various preparations, patient's age, surname not, the weight of other conditions and disease waits to determine medication.For example, tablet, pill, solution, suspendible syrup, emulsion, granule and capsule can be oral.As mentioned above, oral administration is preferred, yet, when be injection liquid, can use separately, or inject with general nutritive medium mixing posterior vein such as glucose, amino acid, and, can be as required, but also muscle, intracutaneous, subcutaneous or intraperitoneal administration.When being suppository, but rectal administration.
The dosage of The compounds of this invention, can according to usage, patient age, surname not, suitably increases and decreases such as other conditions, disease weight, yet, in by the administration animal body, reach effective concentration on the pharmacology for making, for example, when oral, every day 0.3～300mg/kg body weight, non-when oral, 0.03～30mg/kg body weight is suitable.
In the compound of the present invention, compound 1, compound 2 and compound 3, give 8 oral or intraperitoneal administrations of DBA/1J mouse with the 100mg/kg body weight respectively, confirm not have dead individual, also find the individuality of poisoning.This shows that the compound that the present invention uses does not show acute toxicity fully or shows extremely low toxicity.In addition, compound 1 is pressed the 100mg/kg body weight or compound 3 is pressed the 30mg/kg body weight, give oral 40 days of above-mentioned 8 mouse respectively, do not have dead individuality, the individuality that shows acute symptom is not arranged fully yet.Therefore, compound of the present invention shows subacute toxicity hardly.In addition, can infer meeting because of other The compounds of this invention and show same situation, so can use safely by the utmost point with the The compounds of this invention of formula (I) expression.
And, concrete is as described below, compound of the present invention is being used for the animal pattern test of arthropathic animal pattern of chronic rheumatoid and angiogenesis, show significant curative effect, in addition, cause the enzyme that material produced of other inflammation, for example, epoxy oxydase (perhaps prostaglandin endoperoxides enzyme) and lipoxidase, and the carrageenin edema of acute inflammation animal pattern do not shown antagonistic action (or restraining effect) fully.Therefore, pharmaceutical preparation of the present invention is characterized in that showing the action effect of highly selective.In addition, concrete is as described below, and compound of the present invention has shown high Plasma Concentration through 8 hours when mouse is oral, have the good characteristic of oral administration especially.
Enumerate some object lessons below and illustrate in greater detail the present invention, but the present invention is not so limited.About the restraining effect (its 1) of action effect to collagen-induced arthritis
Investigate the morbidity preventive effect of collagen-induced arthritis with one group of 5～8 DBA/1J mouse.That is, the II Collagen Type VI with isopyknic Freund emulsification, is made into the soup of giving of 1mg/ml, the intradermal administration 0.1ml at mouse tail has an effect it.After 21 days,, emulsive II Collagen Type VI 0.1ml is administered to the intraperitoneal of mouse, carries out supplementary immunization, bring out sacroiliitis with same working method.
Compound 1 is by 10 and the 30mg/kg body weight, from the 1st secondary action day of II Collagen Type VI, every day 1 time, oral administration 43 days.In addition, compound 2 and 3 is by 1 and the 10mg/kg body weight, same every day 1 time respectively, intraperitoneal administration 43 days.The inhibition effect of collagen-induced arthritis is by being estimated with the foot plate thickness of digital calipers results of regular determination hind leg.The results are shown in table 1.The restraining effect of table 1 pair collagen-induced arthritis
The restraining effect of collagen-induced arthritis (its 2)
| Test compound dosage vola thickness (about add up to, mm) is after (mg/kg/ day) 37 days |
| Contrast (being untreated)-8.02 ± 0.82 |
| Compound 1 10 6.44 ± 0.40 ** 30 6.12±0.22 ** |
| Compound 21 6.81 ± 1.07 * 10 7.19±0.40 * |
| Compound 31 7.08 ± 0.16 * 10 6.78±0.98 * |
With one group of 7～8 animal, with the above-mentioned sacroiliitis of bringing out equally, compound 3 is by 1,3 and the 10mg/kg body weight; Other one group, MI 43 (comparison) presses the 30mg/kg body weight, behind the difference supplementary immunization, oral 1 time of every day, obeys altogether 21 days.By following standard,, estimate inhibition effect to collagen-induced arthritis with 0～4 grade (the highest 16 grades) according to rubescent, the swelling of the forelimb of laboratory animal and hind leg, tetanic degree.
Grade(ス コ ア)
0: do not find symptom fully;
1: little joints such as the finger of four limbs have only 1 rubescent, swelling;
2: little joint has more than 2, or bigger rubescent, the swelling in joint such as wrist, carpus;
3:1 hand or sufficient whole rubescent, swelling;
4:1 hand or sufficient whole swelling reach at utmost, and with joint stiffness.
The results are summarized in the following table 2.
The restraining effect of table 2 pair collagen-induced arthritis (its 2)
| Test compound dosage progression after (mg/kg/ day) 34 days |
| Contrast (being untreated)-9.25 ± 1.35 compound 31 6.50 ± 1.49 3 5.00 ± 1.61 10 3.50 ± 0.63 **MI 43 (comparison) 30 5.29 ± 1.77 |
Mean+/-standard error
And the obvious errors between the control group
*: P＜0.01
The compounds of this invention in the last table can significantly suppress collagen-induced arthritis, simultaneously, when oral, comparative compound (MI43) is although can not effectively suppress arthritic progression by the administration of 30mg/kg body weight, but, can effectively suppress arthritic progression by the administration of 10mg/kg body weight.The effect of the subcutaneous method angiogenesis inhibiting of mouse back
With the subcutaneous method of mouse back, inquire into the inhibition effect of The compounds of this invention 1 and 3 pairs of mouse transplanting tumor S180 induced tumor angiogenesiss respectively.That is, stick the millipore filter of aperture 0.45 μ m on the two sides of micropore ring, toward this indoor injection 1 * 10 of making
7Individual S180 cell.After clogging inlet, this chamber is moved in the air bag of the subcutaneous formation in back that ICR is a female mice (9～10 week age).0.5% cmc soln of tested compound and control solvent, from moving oral 5 days of beginning in worthwhile day.At the 5th day that transplants, peel off skin, be sidelong the O shape ring of putting and encircle same shape, internal diameter 10mm at the skin one of this chamber of contact, under stereomicroscope, observe, and the photography of taking a picture.
, bending distinctive according to tumor vessel reaches the blood vessel number more than the 3mm, and the angiogenesis intensity of gained photo is divided into 0,1,2,3 four-stages, judges grade according to following standard.
Grade
0: tumor vessel several 0;
1: 1 of tumor vessel;
2: 2 of tumor vessels;
3: tumor vessel is more than 3.
Result when using compound 1 is as shown in table 3 below
The angiogenesis restraining effect (compound 1) of table 3 in the subcutaneous method of mouse back
A: inject phosphoric acid buffer group (normal group);
B: inject S180 tumour cell+injection group of solvents (control group)
C: inject S180 tumour cell+compound 1, press 100mg/kg body weight administration group.
The results are shown in following table 4 when using compound 3.
Table 4 in the subcutaneous method of mouse back to the restraining effect (compound 3) of angiogenesis
A: inject phosphoric acid buffer group (normal group)
B: inject S180 tumour cell+injection group of solvents (control group)
C: inject S180 tumour cell+compound 3, administration 0.3mg/kg group
D: inject S180 tumour cell+compound 3, the 1.0mg/kg group;
E: inject S180 tumour cell+compound 3, the 3mgg/g group;
F: inject S180 tumour cell+compound 3, the 10mg/kg group;
G: inject S180 tumour cell+M 143,100mg/kg organizes (comparison)
*: P＜0.05,
*: P＜0.01 (" student " t check)
From last table 3 and 4 as seen, it is oral that compound 1 is pressed the 100mg/kg body weight, and compound 3 is oral by 1～10mg/kg body weight, and in the subcutaneous method of mouse back, tumour cell S180 brings out angiogenesis and is effectively suppressed.The concentration of tested compound in blood plasma during oral administration
The analysis condition of HPLC (eastern ソ-(strain) CCTP system) is, with YMC A-312 post (ODS6 * 150mm (strain) ヮ イ エ system シ one), during compound 3, as mobile phase is acetonitrile: the 1%TFA aqueous solution=60: 40, during MI 43, as mobile phase is acetonitrile: the 0.1%TFA aqueous solution=40: 60, use flow velocity 1.0ml/min respectively, and measure at UV244nm.
Shown in table 5 and table 6, it is shown in Fig. 1 and Fig. 2 over time in the concentration in the blood plasma for compound 3 and MI 43.The not variation body of compound 3 presents reduction, and also observed high Plasma Concentration at 8 hours after showing maximum in 30 minutes after the administration.Yet, be low-down value at 24 hours.In addition, the not variation body of MI 43 presents decline rapidly behind the demonstration maximum after 5 minutes.Other 5 kinds of MI 43 metabolites have been confirmed.
The concentration (do not change bulk concentration) (μ g/ml) of table 5 compound 3 in blood plasma
| Times 5 (branch) 30 (branch) 4 (hour) 8 (hour) 24 (hour) |
| Mean value 122.54 131.34 63.01 38.41 0.19 standard deviations 16.11 14.01 8.44 6.87 0.12 |
| (not determining metabolite) |
| Mean value 2.61 12.78 26.28 30.29 0.80 standard deviations 2.29 3.78 5.12 4.19 0.36 |
The concentration (do not change bulk concentration) (μ g/ml) of table 6 MI 43 (comparison) in blood plasma
| Times 5 (branch) 30 (branch) 4 (hour) 8 (hour) |
| Mean value 0.811 0.155 0.048-standard deviation 0.225 0.059 0.016- |
| Metabolite A |
| Mean value 6.23 1.71 0.184 0.102 standard deviations 2.68 0.622 0.123 0.076 |
| Metabolite B |
| Mean value 2.15 0.466--standard deviation 0.637 0.106-- |
| Metabolite C |
| Mean value 6.14 1.91 0.329 0.345 standard deviations 1.795 1.045 0.055 |
| Metabolite D |
| Mean value 0.177 0.063--standard deviation 0.074 0.021-- |
| Do not determine metabolite |
| Mean value 0.292 0.142--standard deviation 0.093 0.028-- |
Metabolite A:3 position-COOH conversion body
The sulphate of metabolite B:8 position hydroxyl
The compound of the glucuronic acid of metabolite C:8 position hydroxyl
Metabolite D:6 position-OH conversion body
-: below detection limit to the effect of carrageenin edema
With one group of 6～7 ICR is the effect of mice study to the carrageenin edema.That is, according to 3 and 30mg/kg body weight or make it oral according to 20mg/kg with the positive control drug Warner-Lambert), after 30 minutes, it is subcutaneous that 1% carrageenin liquid, 25 μ l are injected the right hind foot plate with compound 3.After 2 hours, measure foot plate thickness in the carrageenin administration, compare, calculate edema rate (%) with the thickness before the administration with digital calipers.The results are shown in table 7.
The effect of table 7 pair carrageenin edema
| Tested compound administration amount (mg/kg) edema rate (%) |
| Contrast (5% cmc soln)-47.4 ± 2.8 compounds 33 41.7 ± 3.1 30 46.1 ± 4.2 Warner-Lambert)s 20 18.5 ± 3.5 ** |
Mean+/-standard error
And the obvious errors between the control group
*P＜0.01
By table as seen, compound 3 presses 3 and the 30mg/kg administration, and the carrageenin edema is not had restraining effect fully.In addition, the Warner-Lambert) 20mg/kg of antiphlogistic drug shows effectively inhibition effect.Effect to epoxy oxydase and lipoxidase
Press the method (Biochemical Pharmacology 36.:2035～2037,1987) of Evans and studied the active restraining effect of 3 pairs of epoxy oxydase of compound (or prostaglandin(PG) endoperoxidase).That is, the enzyme sample that obtains from the smart gland of sheep is in the presence of the arachidonic acid of 500 μ M and 300 μ M compounds 3, in 27 ℃ of hatchings 1.5 minutes.Add trichoroacetic acid(TCA) in this reaction solution, reaction is stopped, measuring the absorbancy of 532nm.
In addition, with method (Joumalof Biological Chemistry, the 260:11554～11,559 1985) research of Egan etc. restraining effect to the 5-lipoxidase.The enzyme that use is obtained by the basophilic leukemia cell (RBL-1) of big white mouse.Enzyme sample and 30 μ M compounds 3 after 5 minutes, add linolenic acid in the room temperature hatching.Then.After 8 minutes, the hydro-oxidation sodium solution stops reaction, measures the absorbancy of 234nm in the room temperature hatching.
The results are shown in following table 8.
Table 8 pair epoxy oxydase and the active effect of lipoxidase
| Test compound inhibiting rate (%) |
| Epoxy oxydase 5-lipoxidase |
| Compound 3-4.0 21.0 |
n＝2
By table as seen, 30 μ M of compound 3 and 300 μ M, there is restraining effect any also demonstration to epoxy oxydase and lipoxidase.Preparation example
The preparation of example 1:8-hydroxyl-6-methoxyl group-1-oxo-1H-2-chromene-3-carboxylic acid (compound 1)
3.60g MI43 (16.20mmol) is dissolved among the acetone 100ml, adds Jones (Jones) reagent 14ml down, stirred 10 minutes in 0 ℃ ice-cooled.Add water 500ml in reaction solution, with ethyl acetate 1000ml, 500ml extraction.Wash organic layer 3 times with 20% salt solution 200ml.Use ethyl acetate 200ml aqueous layer extracted again, with 20% salt solution 100ml washing 2 times.After extraction liquid and extraction fluid merged, with 5% sodium bicarbonate aqueous solution 300ml counterextraction 4 times.After adding water and making cumulative volume reach 1400ml, add concentrated hydrochloric acid, regulate pH to 3.0.The white precipitate that leaching generated after the vacuum-drying, is dissolved in hot acetone, filters, removes insoluble substance, concentrated filtrate.Make resulting solid suspension in 10% methanol aqueous solution 40ml, reflux is after 10 minutes, with ice-cooled.Filter the white precipitate that is generated, drying under reduced pressure obtains 2.36g (yield 62%) compound 1.
1H-NMR spectrum (400MHz, DMSO-d
6): main absorption is as follows.δTMS(ppm)：3.88(3H，s)、6.70(1H，d，J＝2.0Hz)、6.95(1H，d，J＝2.0Hz)、7.59(1H，s)、10.98(1H，s)
The preparation of example 2:3-chloromethyl-8-hydroxyl-6-methoxyl group-1-oxo-1H-2-chromene
The MI 43 of 5.00g (22.50mmol) and triphenylphosphine 10.0g (38.25mmol) are dissolved in tetrahydrofuran (THF) 50ml, add tetracol phenixin 30ml (244mmol), reflux 30 minutes.The concentrating under reduced pressure reaction solution adds ethanol 47ml in resulting residue 18.46g, carries out recrystallization, obtains title compound 4.72g (yield: 87%).
1H-NMR spectrum (400MHz, CDCl
3): mainly absorb as follows: δ TMS (ppm): 3.88 (3H, s), 4.33 (2H, s), 6.40 (1H, d, J=2.4Hz), 6.51 (1H, s), 6.53 (1H, d, J=2.4Hz), 11.00 (1H, s) preparations of routine 3:3-cyanogen methyl-8-hydroxyl-6-methoxyl group-1-oxo-1H-2-chromene
3-chloromethyl-8-hydroxyl-6-methoxyl group-1-oxo-1H-2-chromene 5.00g (20.78mmol) that example 2 is obtained is dissolved in dimethyl formamide 70ml, adds sodium cyanide 4.29g (83.11mmol), in nitrogen atmosphere; Stirred 30 minutes in 15 ℃.Add water 300ml in reaction solution, use ethyl acetate 600ml, 250ml extraction 3 times.Behind 20% salt solution 300ml washing organic layer 3 times, use anhydrous sodium sulfate drying, be evaporated to about 300ml.Add the 3g gac in this solution, reflux 10 minutes.Use diatomite filtration, remove gac, filtrate and washing lotion are concentrated into about 100ml.Reflux after the crystallization that dissolving is separated out, with ice-cooled, is filtered the crystallization that separates out again, obtains title compound 4.08g (yield 84%).
1H-NMR spectrum (400MHz, DMSO-d
6): mainly absorb as follows: δ TMS (ppm): 3.65 (2H, d, J=1.1Hz), 3.89 (3H, s), 6.42 (1H, d, J=2.4Hz), 6.54 (1H, d, J=2.4Hz), 6.58 (1H, s), 10.82 (1H, s)
Example 4:(8-hydroxyl-6-methoxyl group-1-oxo-1H-2-chromene-3-yl) preparation of acetate (compound 2)
3-cyano group-8-hydroxyl-6-methoxyl group-1-oxo-1H-2-chromene 1.50g (6.49mmol) that example 3 is obtained is suspended among acetate 8ml and the concentrated hydrochloric acid 8ml, and in 70 ℃ of stirrings 5.5 hours, concentration of reaction solution was with ethyl acetate 150ml extraction.After washing organic layer 3 times with 20% salt solution 50ml, use anhydrous sodium sulfate drying, concentrating under reduced pressure, then, vacuum-drying obtains black powder.Add ethanol 20ml, gac 0.3g in this black powder, reflux 30 minutes.Remove gac, the white crystals that generates is filtered in cooling, and drying under reduced pressure obtains title compound (compound 2) 1.30g (yield 80%).
IR absorption spectrum (KBr): the following (unit: cm of characteristic absorbance
-1).ν max：1238、1574、1626、1651、1690、1723
1H-NMR spectrum (400MHz, DMSO-d
6): mainly absorb as follows: δ TMS (ppm): 3.62 (2H, s), 3.86 (3H, s), 6.56 (1H, d, J=2.4Hz), 6.63 (1H, d, J=2.4Hz), 6.66 (1H, s), 10.90 (1H, s)
The preparation of example 5:8-t-butyldimethylsilyl oxygen-3-cyanogen methyl-6-methoxyl group-1-oxo-1H-2-chromene
(A: tertiary butyl dimethylsilane)
3-cyanogen methyl-8-hydroxyl-6-methoxyl group-1-oxo-1H-2-chromene 2.70g (11.68mmol) that example 3 is obtained is dissolved in dimethyl sulfoxide 25ml, under ice-cooled, add imidazoles 1.59g (23.4mmol), chlorination tertiary butyl dimethylsilane 2.82g (18.7mmol) successively, stirred 2 hours.Reaction adds toluene in reaction solution after finishing, and washes 1 time with 10% salt solution 50ml, washes 2 times with 20% salt solution 50ml.The toluene layer anhydrous sodium sulfate drying, concentrating under reduced pressure, then, vacuum-drying with ethanol 20ml recrystallization, obtains title compound 3.77g (yield 93%) to the residue 4.08g that obtains.
1H-NMR spectrum (400MHz, CDCl
3): main absorption is as follows: δ TMS (ppm): 0.28 (6H, s), 1.05 (9H, s), 3.59 (2H, d, J=1.6Hz), 3.87 (3H, s), 6.45 (3H, m)
The preparation of example 6 8-t-butyldimethylsilyl oxygen-3-(1-cyanoethyl)-6-methoxyl group-1-oxo-1H-2-chromenes
8-t-butyldimethylsilyl oxygen-3-cyanogen methyl-6-methoxyl group-1-oxo-1H-2-chromene 2.50g (7.24mmol) that example 5 is obtained is dissolved in methylene dichloride 80ml, adds 1M aqueous sodium hydroxide solution 100ml, is cooled to 0 ℃.High degree of agitation Yi Bian add tetrabutylammonium fluoride 584mg (1.81mmol), is added the methylene dichloride 10ml that contains methyl iodide 0.92ml (14.47mmol) then on one side, stirs 30 minutes.After reaction finished, the separate dichloromethane layer was used anhydrous sodium sulfate drying, concentrating under reduced pressure, the residue of gained silica gel column chromatography (ワ コ one gel C-200,130g, developping agent: hexane/ethyl acetate=5/1) purify, obtain title compound 1.01g (yield 39%).
1H-NMR spectrum (400MHz, CDCl
3): main absorption is as follows: δ TMS (ppm): 0.28 (6H, s), 1.05 (9H, s), 1.68 (3H, d, J=7.2Hz), 3.73 (1H, q, J=7.2Hz), 3.87 (3H, s), 6.45 (1H, d, J=2.0Hz), 6.46 (1H, d, J=2.0Hz), 6.48 (1H, s)
The preparation of example 7:2-(8-hydroxyl-6-methoxyl group-1-oxo-1H-2-chromene-3-yl) propionic acid (compound 3)
8-t-butyldimethylsilyl oxygen-3-(1-cyanoethyl)-6-methoxyl group-1-oxo-1H-2-chromene 1.63g (4.72mmol) that example 6 is obtained is dissolved in acetate 5ml and concentrated hydrochloric acid 5ml stirred 12 hours in 70 ℃.The cooling reaction solution adds water 10ml, makes and separates out crystallization.Leach crystallization, washing, drying under reduced pressure obtains title compound coarse crystallization 1.21g.Add ethanol 8ml in coarse crystallization, after the reflux, cooling leaches the faint yellow crystallization that is generated, and drying under reduced pressure obtains title compound (compound 3) 1.04g (yield 80%).
1H-NMR spectrum (400MHz, DMSO-d
6): main absorption is as follows: δ TMS (ppm): 1.40 (3H, d, J=7.2Hz), 3.70 (1H, q, J=7.2Hz), 3.86 (3H, s), 6.56 (1H, d, J=1.6Hz), 6.67 (1H, d, J=1.6Hz), 6.68 (1H, s), 10.90 (1H, s)
The manufacturing of example 8 capsules
The compound 1 that method with example 1 record is made be 20mg, with lactose 180mg, Magnesium Stearate 1mg (being per 1 capsule) uniform mixing, each capsule is filled to No. 3 hard gelatin capsules that contain the about 200mg of mixture that obtains.
The preparation of example 9 tablets
The compound 2 of the method preparation of example 4 record be 10mg, with lactose 120mg, W-Gum 57mg (each tablet amounts) the fine mixing.This mixture and 10% starch paste are mixed into particle, add W-Gum 60mg and Magnesium Stearate 3mg (every content) inward, make fine mixing.Make the tablet of diameter 8mm, the about 250mg of weight.
The preparation of example 10 syrup suspensoids
The compound 3 of the method preparation of use-case 7 record for 100mg, with Xylo-Mucine 100mg, methyl p-hydroxybenzoate 14mg, ethyl p-hydroxybenzoate 6mg, simple syrup 40ml, distilled water 10ml (being every bottle of content) the fine mixing, make suspendibleization, the medicine bottle of packing into.
The possibility of industrial utilization
The invention provides immunoregulation effect and angiogenesis inhibitory action good compound or pharmaceutical preparation. Therefore, the present invention can use in pharmaceuticals industry.
Claims (15)
1. a pharmaceutical preparation wherein contains the adjuvant that allows on the pharmacopedics, and the significant quantity on the pharmacology with the salt that allows on the compound of following formula (I) expression or its pharmacopedics,
In the following formula, R represents hydrogen atom or C
1-6Alkyl, n are 0 or 1.
2. the pharmaceutical preparation of record in the claim 1, the preparation of the disease that it causes for prevention or treatment immunoregulation effect imbalance or angiogenesis.
In the claim 1 or 2 record pharmaceutical preparation, wherein n is an integer 1.
In the claim 2 record pharmaceutical preparation, the disease of its treatment is an autoimmune disease.
In the claim 3 record pharmaceutical preparation, the disease of its treatment is an autoimmune disease.
In the claim 1,2 or 4 record pharmaceutical preparation, its preparation is an oral dosage form.
In the claim 3 record pharmaceutical preparation, its preparation is an oral dosage form.
In the claim 5 record pharmaceutical preparation, its preparation is an oral dosage form.
9. the application of the salt that allows in following formula (I) compound or its pharmacy in the pharmaceutical preparation of the disease that preparation prevention or the imbalance of treatment immunoregulation effect or angiogenesis cause,
In the following formula, R is hydrogen atom or C
1-6Alkyl, n are 0 or 1.
10. the application of record in the claim 9, wherein n is an integer 1.
11. the application of record in claim 9 or 10, wherein disease is an autoimmune disease.
12. the application of record in claim 9 or 10, wherein preparation is an oral dosage form.
13. the application of claim 11 record, wherein preparation is an oral dosage form.
14. with the compound or its salt of following formula (I-a) expression,
In the following formula, R is hydrogen atom or C
1-6Alkyl.
15. with the compound of following formula (II) expression,
In the following formula, R is hydrogen atom or C
1-6Alkyl, A are hydrogen atom or protecting group.
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|---|---|---|---|
| CN96180334A CN1098258C (en) | 1996-06-17 | 1996-06-17 | Isocoumarin derivatives and use thereof in drugs |
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| Application Number | Priority Date | Filing Date | Title |
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| CN96180334A CN1098258C (en) | 1996-06-17 | 1996-06-17 | Isocoumarin derivatives and use thereof in drugs |
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| CN1222149A CN1222149A (en) | 1999-07-07 |
| CN1098258C true CN1098258C (en) | 2003-01-08 |
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ID=5127808
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| CN100358519C (en) * | 2003-05-15 | 2008-01-02 | 中国科学院上海有机化学研究所 | Medicine against fungus |
| CN107998127B (en) * | 2015-04-08 | 2020-07-03 | 华中科技大学 | Application of 2H-1-benzopyran-2-ketone in preparing medicine for inhibiting lymphocyte proliferation |
| CN110183460A (en) * | 2019-04-30 | 2019-08-30 | 四川轻化工大学 | Rhizoma Dioscoreae Septemlobae phenanthrene compounds and application and extraction method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH032177A (en) * | 1989-05-31 | 1991-01-08 | Microbial Chem Res Found | New anticancer antibiotic m143-37f11 and production thereof |
| JPH04112884A (en) * | 1990-08-31 | 1992-04-14 | Mercian Corp | Production of antibiotic m143-37f11 and production intermediate |
| JPH0597841A (en) * | 1991-10-04 | 1993-04-20 | Mercian Corp | Isocoumarin derivative |
| JPH06183966A (en) * | 1992-12-18 | 1994-07-05 | Mercian Corp | Immunoregulator |
-
1996
- 1996-06-17 CN CN96180334A patent/CN1098258C/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH032177A (en) * | 1989-05-31 | 1991-01-08 | Microbial Chem Res Found | New anticancer antibiotic m143-37f11 and production thereof |
| JPH04112884A (en) * | 1990-08-31 | 1992-04-14 | Mercian Corp | Production of antibiotic m143-37f11 and production intermediate |
| JPH0597841A (en) * | 1991-10-04 | 1993-04-20 | Mercian Corp | Isocoumarin derivative |
| JPH06183966A (en) * | 1992-12-18 | 1994-07-05 | Mercian Corp | Immunoregulator |
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