CN1207392A - Viformyl cumarins compound, process for preparing same and pharmaceutical composition contg. same - Google Patents

Viformyl cumarins compound, process for preparing same and pharmaceutical composition contg. same Download PDF

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CN1207392A
CN1207392A CN 97116602 CN97116602A CN1207392A CN 1207392 A CN1207392 A CN 1207392A CN 97116602 CN97116602 CN 97116602 CN 97116602 A CN97116602 A CN 97116602A CN 1207392 A CN1207392 A CN 1207392A
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compound
coch
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alkyl
formyl radical
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CN1108297C (en
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徐世平
韩锐
李兰敏
曹西华
徐嵩
夏丽娟
刘红岩
尤胜权
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Institute of Materia Medica of CAMS
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Abstract

The viformylcumarin compounds, their preparing process, their salts acceptable pharmacologically and their medicinal composition are disclosed.

Description

Viformyl cumarins compound and preparation method thereof and the pharmaceutical composition that contains this compound
The present invention relates to a kind of Viformyl cumarins compound, the preparation method of this compound and the pharmaceutical composition that contains this compound, especially for the Viformyl cumarins compound of illness such as change and tetter before treatment tumour or the cancer, the preparation method of this compound and the pharmaceutical composition that contains this compound.
R8923 all has vital role to epithelial cell growth and differentiation and blocking-up precancerous lesion or make it to reverse etc.Xu's generation equality is that the functional design of improving R8923 has been synthesized a series of retinoic acid derivatives (Acta Pharmaceutica Sinica 16 (9): 678-685 (1981)) wherein Viaminate (RI) and N-(4-carboxyphenyl)retinamide (RII) are respond well at aspects such as carcinogenesis, and toxicity is lower, be fit to cancer chemoprevention, the treatment precancerous lesion.The mice model of forestomach cancer that the anti-sarcosine ethyl nitrosamine of these compounds of discoveries such as Cai Haiying is brought out has remarkable restraining effect (Acta Pharmaceutica Sinica 16 (9): 648-652 (1981)).These R8923s of discoveries such as Wang Ruizhen suppress esophageal cancer cell remarkable activity (Chinese tumour magazine 5 (4): 243-248 (1983)).Du from grade compared the toxicity of Viaminate (RI), N-(4-carboxyphenyl)retinamide (RII), vitamin A acid and R8923s such as anti-tinea spirit and Accutane, find that RI and RII toxicity are lower, this shows that it is suitable for treating the application of precancerous lesion (Acta Pharmaceutica Sinica 17:333-337 (1982)).Song strives the induction of differentiation (Acta Pharmaceutica Sinica 19:576-581 (1984)) that equality is found RI and RII.Han Rui etc. have reported RII treatment precancerous lesion, as oral cavity day shift, white diseases of vulva, uterine neck and atypical hyperplasia of gastric mucosa and Preleukemia etc. good result (In Vivio 4:153-160 (1990)) are arranged all.The medium discovery RI of Lin Pei is in Lin County esophageal carcinoma high risk area, and big crowd's esophageal precancerous lesion is carried out the barrier treatment, makes the esophageal carcinoma sickness rate 43.2% (Proc.CAMS that descends in 5 years; PUMC5 (3): 121-129 (1990)).The report that a large amount of relevant retinoids research aspects are also arranged abroad.Isotretinoin (Accutane) and etretinnate (anti-tinea spirit) as dermatological department medication go on the market.Gander etc., U.S. Patent No. 4,126,693 is also used above-mentioned pharmacological agent precancerous lesion.All there is suitable toxic side effect in most of retinoids medicines when patient takes.Toxic side effect is little, and activity is often too low again.So need constantly development new, the R8923 that activity is high, effective, toxic side effect is low is so that the clinical better medicament that provides is provided.Smith etc.,, J.Clin.Oncol.10 (5): 839-864 (1992) has summarized the therapeutic action of application, the especially vitamin A acid (RA) of R8923 aspect the treatment cancer to human promyelocytic leukemia (APL).As Blazsek etc., Biomed.Pharmacother.45:169-177 (1991); Degos etc., Biomed.Pharmather46:210-209 (1992); Castaigne etc., Blood74 (9): 1704-1709 (1990) Chomienne etc., Blood76 (9): 1710-1717 (1990): Lo Coco etc., Blood77 (8): 1657-1659 (1991) proves by the differentiation therapy retinoid compounds and can treat APL.Kizaki etc., Cancer Res.40:3413-3425 (1980), ester, amine and the acid amides effect aspect cancer chemoprevention of report vitamin A acid.Shealy etc., U.S. Patent No. 5,124,083, the induction and the cancer chemoprevention effect of proof retinoic acid derivative, and be published in J.Clin.Invest.21:574-579 (1991) and Loev etc., U.S. Patent No. 4,532,042, all prove the differentiation-inducing action of R8923.Gander, U.S. Patent No. 4,323,581 proves the effect of 4-HPR treatment mammary gland precancerous lesion.Nair etc., Carcinogenesis12 (1): 65-69 (1991) proves the antitumous effect of coumarin kind compound.Ishizuka etc., U.S. Patent No. 5,096,924 proves that the tonka-bean that replaces have antitumous effect.Marshall, etc., J.Biol.Resp.Mo is (1989) d.8:62, the raise immunity of report tonka bean camphor.As cancer patients's monocyte is significantly increased, thereby increase anti-cancer ability.Preuss-Ueberschar etc., Drug Res.34:1305-1313 (1984) proves that tonka bean camphor is a teratogenesis not.Quote these documents as reference of the present invention.
Though obtaining certain progress aspect the R8923 research, some has been used for clinical, does not also reach the requirement of hope far away.Show as the compound with greater activity on the one hand, its toxic side effect is too big; Its activity of the compound that toxicity is little also decreases on the other hand, and all difficult level, particularly R8923 that reaches practical application has stronger teratogenesis, brings inconvenience to the women of child-bearing age.
The purpose of this invention is to provide a kind ofly had suitable superiority than former R8923, particularly not teratogenesis and have the new R8923 of antitumor and induction of differentiation and pharmacology on acceptable salt.
Another object of the present invention provides a kind of pharmaceutical composition that contains acceptable salt on new R8923 of the present invention and the pharmacology thereof.
A further object of the present invention provides a kind of Mammals that is used for, especially for people's the pharmaceutical composition that contains R8923 of the present invention.
A further object of the invention provides R8923 of the present invention and/or contains the synthetic method of this compound compositions.
Brief Description Of Drawings
Fig. 1 represents the papillomatous exercising result of mouse skin that the compound of the embodiment of the invention 13 brings out DMBA/ Oleum Tiglii.
Fig. 2 represents the papillomatous exercising result of mouse skin that the compound of the embodiment of the invention 13 brings out DMBA/ Oleum Tiglii.
The restraining effect result of the mouse skin ornithine decarboxylase (ODC) that the compound that Fig. 3 represents the embodiment of the invention 13 brings out Oleum Tiglii.
The invention provides a kind of anticancer and bioactive Viformyl cumarins compound of cancer chemoprevention of having, the structure of this compound is as shown in the formula shown in the I:
Figure A9711660200081
Wherein, R1Be H, C1～C 18, be preferably C1-C 4Alkyl, aralkyl and haloalkyl, CXYR7, wherein, X is H, N, NH, C, CH, O, and Y is H, N, NH, C, CH, O, and Y is O or N, R7Be H, halogen, OH, C1-C 18, be preferably C1-C 4Alkyl or alkoxyl, alkyl or alkoxyl, haloalkyl, replacement, the single replacement or polysubstituted phenyl,, wherein the substituting group on the phenyl ring can be C1-C 4Alkyl, haloalkyl, alkoxyl, OH, halogen, CO2H, ester group, NO2、CF 3、SO 3H、NR 8R 9R wherein8And R9Identical or different, difference is H, alkyl or cycloalkyl and heterocycle etc. independently;
R 2Be H, OH, C1～C 18Alkyl, haloalkyl, alkoxyl are preferably C1～ C 4Alkyl or alkoxyl, not replacement or substituted aryl or aralkyl, the substituting group on the phenyl ring is same as described above, CXYR7Or OR, R is dimension formoxyl, X, Y and R7As defined above;
R 3Be H, OH, CH3, OR or CH2OR，CXYR 7, wherein X, Y, R and R7As defined above;
R 4Be H, halogen, be preferably Cl and Br, C 1～C 18Alkyl (preferred C 1-C 4Alkyl or alkoxyl group), OH, OR or CXYR 7, wherein X, Y, R and R 7As defined above;
R 5Be H, C 1-C 18Alkyl or haloalkyl, alkoxyl group, OR, or CXYR 7, wherein R, X, Y and R 7As defined above;
R 6Be H, C 1=C 18Alkyl or haloalkyl, alkoxyl group, OR, or CXYR 7, wherein R, X, Y or R 7As defined above.
In the compound of the present invention, R 1Be preferably H or COR 7, R wherein 7Be CH 3, OC 2H 5, OH or NHR 10, R wherein 10Be H or substituted-phenyl etc.
In the compound of the present invention, R 2Be preferably H, OR, Cl, CH 3, Ph, C=NR 10, CH=CHR 10Wherein R and R 10As defined above.
In the compound of the present invention, R 3Be preferably H, OR, CO 2H, CO 2Et, COC 12H 25, CXYR 7Or CH 2OR, wherein X, Y, R and R 7As above definition.
In the compound of the present invention, R 4Be preferably H, C 2H 5, CHO, COCH 3, C 4H 9, PhCO, CO 2H, Cl, Br, CH=CHR 10, R wherein 10As defined above.
In the compound of the present invention, R 5Be preferably H, CH 3, OR, CHO, CH=NR 10, CH=CHR 10, wherein R and R 10As defined above.
In the compound of the present invention, R 6Be preferably H, CH 3, OR, COCH 3, CO 2H, BR, CHO, CH=NR 10, CH=CHR 10, wherein R and R 10As defined above.
According to the present invention, R 1, R 2, R 3, R 4, R 5And R 6The example of some preferably combination as follows: R 1=COCH 3, R 2=R 4=R 6=H, R 3=R 5=OR, R=ties up formyl radical; R 1=COCH 3, R 2=R 4=R 6=H, R 3=CO 2H, R 5=OR, R=ties up formyl radical; R 1=COCH 3, R 2=R 3=R 4=H, R 5=R 6=OR, R=ties up formyl radical; R 1=COCH 3, R 2=R 5=R 6=H, R 3=OR, R 4=CO 2H, R=ties up formyl radical; R 1=COCH 3, R 2=R 3=R 4=H, R 5=OR, R 6=CO 2H, R=ties up formyl radical; R 1=COCH 2, R 2=R 4=R 6=H, R 3=CO 2H, R 5=OR, R=ties up formyl radical; R 1=COCH 3, R 2=R 3=R 6=H, R 4=Cl, R 5=OR, R=ties up formyl radical.According to the present invention, the chemical formula of dimension formyl radical is as follows:
Figure A9711660200101
The invention still further relates to the preparation method of above-claimed cpd, this method comprises:
(1) by the phenolic compound of following formula (II) expression and respective compound react replacement and contain the coumarin kind compound (III) of hydroxyl
Wherein, R 1, R 2, R 2, R 4, R 5And R 6As defined above, but wherein have at least one to be OH simultaneously for OH or two substituting groups;
(2) resulting compound (III) and vitamin A acid reaction are obtained compound of the present invention (I): Wherein, R 1, R 2, R 3, R 4, R 5And R 6As defined above, R is the dimension formyl radical.
According to method of the present invention, described replacement and the coumarin kind compound (III) that contains hydroxyl can adopt method preparation known to a person of ordinary skill in the art.
Compound of the present invention has anticancer and the active class of cancer chemoprevention is newly tieed up the first compound, can be used in the body and/or all class diseases of external treatment cancer, precancerous lesion and Dermatology Department.
The invention further relates to the pharmaceutical composition that contains acceptable salt on the Viformyl cumarins compound of the present invention for the treatment of effective dose and the pharmacology thereof.
But the route of administration oral medication of compound of the present invention or non-oral medication or both are used in combination.The formulation of non-oral medication can be an injection, various paste, film class preparation, suppository, embedding formulation, liniment, and other formulation of non-oral medication.The formulation of oral medication for example can be a tablet, granule, and capsule, syrup, suspension agent, and electuary etc.Used formulation can be according to patient's symptom, the age, and sex, therapeutic purpose, physical appearances etc. are selected.
When using compound of the present invention to prepare above-mentioned forms of pharmaceutical compositions, can add various assistant agent as known in the art, vehicle for example, wedding agent, lubricant, disintegrating agent etc. as activeconstituents.
Vehicle can be a vehicle commonly used in the pharmacy field, for example can be crystalline cellulose, starch, sucrose, lactose, glucose, N.F,USP MANNITOL etc.; Wedding agent can be a hydroxypropylcellulose, polyvinylpyrrolidone, etc.; Lubricant for example can be a Magnesium Stearate, talcum powder etc.; Disintegrating agent for example can be a calcium carboxymethylcellulose etc.
Drug combination preparation of the present invention can prepare with ordinary method as known in the art.
The consumption of compound of the present invention is preferably the 0.001-100mg/kg body weight, and more preferably the 0.1-50mg/kg body weight is preferably the 1-10mg/Kg body weight especially.
The present invention is further illustrated by the following examples.But the present invention is not limited to these embodiment.
Synthesizing of embodiment 1 3-ethanoyl-5 carboxyls-7-dimension methanoyl tonka bean camphor
To magnetic stirring bar is installed, add 0.6g (0.002 mole) vitamin A acid, 20ml benzene and 0.12ml (0.0013 mole) PCl in the 100ml round-bottomed bottle of reflux condensing tube and drying tube 3, at N 2Stirring at room is 1 hour under the protection.Reaction mixture is concentrated and join in the absolute anhydrous diethyl ether of handling with sodium Metal 99.5 standby.
In the 100ml there-necked flask prolong is installed, feed hopper also makes it become dehumidification system.Add 0.5g (0.002 mole) 3-ethanoyl-5-carboxyl-umbelliferone then, the absolute anhydrous diethyl ether of 0.5ml anhydrous pyridine and 20ml under agitation drips the anhydrous ether solution that above-mentioned steps obtains.Stir after two hours, filter the solid that collection produces, dry back is refining with ethanol, gets the 0.5g title compound.
Fusing point 158-161 ℃.
1H-NMR (CDCl 3); δ 1.03 (s, 6H, 1 '-2CH 3); 1.38-2.14 (m, 6H, alicyclic ring CH 2); 1.71 (s, 3H, 5 '-CH 3); 2.02 (s, 3H, 9 '-CH 3); 2.42 (s, 3H, 13 '-CH 3); 2.70 (s, 3H, 3-COCH 3); 4.76 (b, 1H, 5-CO 2H); 5.93-6.41 and 6.97-7.26 (m, 6H, the two key hydrogen of dimension first); 7.50 (d, 1H, 8-H); 7.85 (d, 1H, 6-H); 9.51 (s, 1H, 4-H).
MS:(C 32H 34O 7=530 (M +), 282 (dimension formyl radicals), 248 (tonka bean camphors), 233 (248-CH 3).
Synthesizing of embodiment 2 3-ethanoyl-5-ethoxycarbonyl-7-dimension methanoyl tonka bean camphor
Adopt preparation method, equipment and the reaction conditions identical to carry out with embodiment 1; raw material adopts 0.56g (0.002 mole) 3-ethanoyl-5-ethoxycarbonyl 070 Hydroxycoumarin and 0.6g (0.002 mole) vitamin A acid, obtains 0.5g title compound (through ethanol purification).
Fusing point: 162-64 ℃.
1H-NMR (CDCl 3); δ 1.04 (s, 6H, 1 '-2CH 3); 1.44 (t, 3H, 5-ester-CH 3); 1.14-2.12 (m, 6H, alicyclic ring CH 2); 1.72 (s, 3H, 5 '-CH 3); 2.03 (s, 3H, 9 '-CH 3); 2.42 (s, 3H, 13 '-CH 3); 2.70 (s, 3H, 3-COCH 3); 4.24 (q, 2H, 5-ester group CH 2); 5.88-6.48 and 6.98-7.25 (m, 6H, the two key hydrogen of dimension first); 7.36 (d, 1H, 8-H); 7.73 (d, 1H, 6-H); 9.47 (s, 1H, 4-H).
MS:(C 34H 38O 7=558 (M +, nearly base peak), 283,276,261,233,231,175 (base peak, 231-28-28).
The preparation of embodiment 3 4-dimension methanoyl-6-tertiary butyl tonka bean camphor
Adopt preparation method, equipment and the reaction conditions identical with embodiment 1 to carry out, raw material employing 0.6g4-hydroxyl-6-tertiary butyl tonka bean camphor and 1.0g vitamin A acid make the 0.6g title compound.
Fusing point: 142-144 ℃.
1H NMR (CDCl 3): δ 1.05 (s, 6H, 1 '-2CH 3); (1.37 s, 9H, t-butyl); 1.48,1.62 and 2.04 (m, 6H, alicyclic ring CH 2); 1.73 (s, 3H, 5 '-CH 3); 2.05 (s, 3H, 9 '-CH 3); 2.46 (s, 3H, 13 '-CH 3); 6.06 (s, 1H, 3-H); 6.16-6.52 and 7.16-7.26 (m, 6H, the two key hydrogen of dimension first); 7.30 (d, 1H, Ar-H); 7.61 (m, 2H, Ar-H).
MS：500(M +)，282，203，175，161。
Synthesizing of embodiment 4 4-dimension methanoyl-7-methylcoumarin
Adopt preparation method, equipment and the reaction conditions identical with embodiment 1 to carry out, raw material employing 0.4g4-hydroxyl-7-methyl-tonka bean camphor and 1.0g vitamin A acid makes the 0.5g title compound.
Fusing point: 115-117 ℃.
1H NMR (CDCl 3): δ 1.03 (s, 6H, 1 '-2CH 3); 1.32-2.14 (m, 6H, alicyclic ring CH 2); 1.731 (s, 3H, 5 '-CH 3); 2.30 (s, 3H, 9 '-CH 3); 2.42 (s, 6H, 7,13 '-2CH 3); 5.92 (s, 1H, 3-H); 5.96-6.50 and 6.92-7.26 (m, 6H, the two key hydrogen of dimension first); 7.10 (d, 1H, Ar-H); 7.48 (d, 1H, Ar-H).
MS：458(M +)，430，355，321，307，282，267，175，159，147。
Embodiment 54, and 8-dimethyl-7-ties up the synthetic of methanoyl tonka bean camphor
Adopt preparation method, equipment and the reaction conditions identical to carry out with embodiment 1.With 0.57g 4,8-dimethyl-7-hydroxyl-tonka bean camphor and 1.0g vitamin A acid make the 0.5g title compound.
Fusing point: 178-80 ℃.
1H NMR (CDCl 3); δ 1.04 (s, 6H, 1 '-2CH 3); 1.16-2.28 (m, 6H, alicyclic ring CH 2); 1.73 (s, 3H, 5 '-CH 3); 2.01 (s, 3H, 9 '-CH 3); 2.28 (s, 3H, 13 '-CH 3); 2.41 (s, 6H, 4,8-2CH 3); 5.99 (s, 1H, 3-H); 6.01-6.56 and 6.86-7.28 (m, 6H, the two key hydrogen of dimension first); 7.06 (d, 1H, Ar-H); 7.40 (d, 1H, Ar-H).
MS：472(M +)，283，190，175，161。
Embodiment 6-45
Adopt preparation method, equipment and the reaction conditions identical, select corresponding raw material, obtain R respectively with embodiment 1 1, R 2, R 3, R 4, R 5And R 6Be the The compounds of this invention shown in the following table.
Table 1
Embodiment ????R 1 ??R 2 ??R 3 ??R 4 ??R 5 ??R 6 Fusing point (℃)
??1 ??2 ??3 ??4 ??5 ??6 ??7 ??8 ??9 ??10 ??11 ??12 ??13 ??14 ??15 ??16 ??17 ??18 ??19 ??20 ??21 ??22 ??COCH 3??COCH 3??COOC 2H 5??H ??H ??COCH 3??COCH 3??H ??COCH 3??COCH 3??COCH 3??COCH 3??COCH 3??COCH 3??COCH 3??COOC 2H 5??H ??COOC 2H 5??COOC 2H 5??COOC 2H 5??COOC 2H 5??COOC 2H 5 ??H ??H ??H ??OR ??CH3 ??H ??H ??Ph ??H ??H ??H ??H ??H ??H ??H ??H ??Ph ??H ??H ??H ??H ??H ??COOH ??CO 2C 2H 5??H ??H ??H ??CH 3??H ??H ??CH 3??H ??OR ??H ??OR ??H ??H ??H ??OR ??H ??H ??COOH ??H ??OR ??H ??H ??H ??H ??H ??H ??H ??H ??H ??Cl ??COOH ??H ??H ??C 2H 5??n-Hex ??H ??H ??H ??Cl ??H ??H ??H ??OR ??OR ??OR ??CH 3??OR ??OR ??OR ??OR ??OR ??OR ??H ??OR ??OR ??OR ??OR ??OR ??OR ??OR ??OR ??OR ??OR ??OR ??H ??H ??COCH 3??H ??CH 3??H ??CH 3??H ??COOH ??H ??H ??OR ??H ??H ??H ??CH 3??H ??H ??H ??H ??OR ??H ????158-61 ????162-64 ????141 ????115 ????178 ????179-81 ????174-76 ????113-16 ????174-76 ????167-69 ????185-87 ????136-38 ????156-58 ????149-50 ????112-14 ????122-24 ????112-14 ????174-76 ????124 ????150 ????78-80 ????138-40
(continuous table 1)
Embodiment ????R 1 ??R 2 ????R 3 ????R 4 ?R 5 ??R 6 Fusing point (℃)
??23 ??24 ??25 ??26 ??27 ??28 ??29 ??30 ??31 ??32 ??33 ??34 ??35 ??36 ??37 ??38 ??39 ??40 ??41 ??42 ??43 ??44 ??45 ?H ?COOC 2H 5?COOH ?CONH 2?CONH 2?H ?H ?H ?H ?H ?H ?H ?H ?H ?H ?H ?H ?CO 2H ?H ?COCH 3?H ?H ?H ??OR ??H ??H ??H ??H ??OR ??CH 3??CH 3??CH 3??CH 3??OR ??CH 3??CH 3??CH 3??CH 3??OR ??OR ??H ??OR ??H ??CH 3??CH 3??Ph ????H ????OR ????H ????COOH ????H ????H ????H ????H ????OR ????H ????H ????H ????H ????H ????H ????CH 3????H ????CO 2H ????H ????CO 2Et ????H ????H ????H ???n-Hex ???C 6H 5CO ???n-Hex ???H ???Cl ???t-But ???C 2H 5???H ???H ???n-Hex ???CH 3???H ???Cl ???H ???Br ???H ???H ???H ???H ???H ???H ???H ???H ?OR ?OR ?OR ?OR ?OR ?H ?OR ?OR ?OR ?OR ?OR ?OR ?OR ?OR ?OR ?CH 3?OR ?OR ?H ?OR ?OR ?NHR ?OR ??H ??H ??H ??H ??H ??H ??H ??H ??H ??H ??H ??OR ??H ??H ??H ??H ??CH 3??OR ??H ??OR ??CO 2H ??H ??CH 3 ????100 ????106 ????159 ????191 ????198 ????142 ????120 ????154 ????134 ????114 ????104 ????106 ????126 ????161-62 ????160-62 ????133 ????153 ????235 ????88 ????122-38 ????145 ????239 ????154
Measure the antitumour activity of The compounds of this invention and/or composition with known in vivo test.These methods are known, conventional testss.Compound of the present invention has specific antitumour activity.
Below be that the screening method that is used for formula of the present invention (I) Viformyl cumarins compound is given an example, but be not limited to these.
Compound biological activity test of the present invention comprises (being not limited to these):
1) induces the human promyelocytic leukemia cytodifferentiation;
2) anticancer (MTT test).
3) suppress the mouse skin papilloma and form (comprising the experiment that carcinogenesis and anti-promoting combine);
4) anti-mutagenesis;
5) marrow that endoxan is brought out is bitten the restraining effect that the polychromatophilia micronucleus in erythrocytes forms;
6) the mouse ear swelling restraining effect that Oleum Tiglii is brought out;
7) the active inhibition that raises of mouse skin ornithine decarboxylase (ODC) that Oleum Tiglii is brought out;
8) to the chondrosarcomatous restraining effect of rat;
9) teratology testing.
No matter the said treatment of animal or human or prophylactic effect (reduction sickness rate) are needed not to be completely or eradicate, but compare with control compound, can provide improve (P 〉=0.05) of statistical significance, also symptom serious or acute attack be had the effect of alleviating.Route of administration can oral and/or parenterai administration, as in subcutaneous, vein, intracutaneous, intramuscular injection, peritonaeum, the nose, approach such as encephalic, transdermal, mouth spray suction, the use that can be used alternatingly or cooperatively interact of each route of administration.
Experimental example 1 Viformyl cumarins compound is to the differentiation-inducing action of the white sick HL-60 cell of the early young grain of people
People's promyelocyte (HL-60) is in the RPMI-1640 nutrient solution that contains 10% calf serum, penicillin 100U/ml and Streptomycin sulphate 100 μ g/ml, in 37 ℃, 5%CO 2Cultivate in the incubator and go down to posterity.Will be by logarithmic growth, concentration is 1.2 * 10 5-1.4 * 10 5/ ml cell inoculation contains in the culturing bottle of 5ml nutrient solution, 3 bottles every group.After 24 hours, the cell growth concentration reaches 2.5 * 10 5Ml, experimental group adds the medicine that is dissolved in the alcoholic acid different concns, capacity ethanol such as control group adding (the ethanol final concentration is no more than 0.01%, and under this concentration, ethanol cell growth and differentiation do not have influence), the whole process of experimental implementation is all carried out under the lucifuge condition.Collect each 250 μ l of administration and cellular control unit every day, add (no calcium magnesium) phosphoric acid buffer that equivalent contains 0.2%NBT, every ml contains TPA600mg, and 37 ℃, 5%CO 2Insulation is three hours in the incubator, adds a certain amount of cold phosphoric acid buffer termination reaction.Under 4 ℃ of conditions, cell counting takes a morsel.Have blue purple solids precipitation in the cell and be NBT reacting positive cell, every sample is checked 200 cells at least, the counting positive rate, and obtain ED 50(seeing Table 2)
Table 2 The compounds of this invention is to HL-60 cell induction Analytical Chemical Experiment result
Compound Concentration (M) NBT (+) % ED 50(M)
Embodiment 6 embodiment 1 embodiment 7 embodiment 9 embodiment 10 embodiment 11 embodiment 12 embodiment 13 ?10 -4????????77????3×10 -6?10 -5????????72 ?10 -6????????49 ?10 -7????????8 ?10 -5????????92????7×10 -8?10 -6????????84 ?10 -7????????73 ?10 -8????????15 ?10 -5????????88????8×10 -7?10 -6????????77 ?10 -7????????12 ?10 -5????????89????2.8×10 -7?10 -6????????69 ?10 -7????????41 ?10 -4????????96????6×10 -7?10 -5????????81 ?10 -6????????78 ?10 -7????????31 ?10 -5????????98????5.9×10 -8?10 -6????????69 ?10 -7????????55 ?10 -8????????34 ?10 -5????????96????6.5×10 -8?10 -6????????88 ?10 -7????????55 ?10 -8????????31 ?6.4×10 -6???99????1.3×10 -8?6.4×10 -7???96 ?6.4×10 -8???82 ?6.4×10 -9???33 ?6.4×10 -10??10
(continuous table 2)
Compound Concentration (M) NBT (+) % ED 50(M)
Embodiment 2 embodiment 16 embodiment 18 embodiment 19 embodiment 20 embodiment 22 embodiment 26 embodiment 27 ??10 -4??????77????3×10 -6??10 -5??????72 ??10 -6??????49 ??10 -7??????8 ??10 -5??????93????2.6×10 -7??10 -6??????84 ??10 -7??????46 ??10 -8??????12 ??10 -5??????84????1×10 -6??10 -6??????54 ??10 -7??????2 ??10 -5??????44????1×10 -5??10 -6??????8 ??10 -4??????92????9×10 -6??10 -5??????84 ??10 -6??????5 ??10 -5??????94????2.5×10 -7??10 -6??????80 ??10 -7??????41 ??10 -8??????17 ??10 -5??????97????8.0×10 -8??10 -6??????91 ??10 -7??????53 ??10 -8??????34 ??10 -5??????88????5.5×10 -7??10 -6??????80 ??10 -7??????17
Experimental example 2 compounds of the present invention are to the cytotoxicity (MTT experiment) of HL-60 cell
The logarithmic phase cell is pressed 10 4Ml is inoculated in 96 orifice plates.Abandon substratum next day and change the substratum that contains different concns medicine and coordinative solvent contrast, establish 3-5 parallel hole for every group, cultivate after 4-5 days for 37 ℃, abandon supernatant liquor, every hole adds the serum free medium that the fresh preparation of 0.2ml contains 0.2mg/ml MTT, continues to cultivate 4 hours.Carefully abandon supernatant liquor and add 200 μ l DMSO dissolving MTT first hairpin precipitation,, on MR700 type microplate reader, measure the optical density value at 570mm place, be calculated as follows cell survival rate, and calculate ED with miniature ultrasonic vibrator mixing 50(seeing Table 3)
Figure A9711660200211
Table 3 The compounds of this invention is to the MT experimental result of HL-60 cell
Compound Concentration (M) inhibiting rate % ED 50(M)
Embodiment 9 embodiment 11 embodiment 12 embodiment 15 embodiment 16 embodiment 22 embodiment 26 ??10 -5????51.6±0.0????8.5×10 -6??10 -6????34.1±7.1 ??10 -7????11.5±4.2 ??10 -5????63.9±2.9????1×10 -7??10 -6????54.0±1.9 ??10 -7????50.5±0.9 ??10 -8????29.7±1.4 ??10 -5????61.5±1.9????9.5×10 -7??10 -6????50.6±0.5 ??10 -7????48.8±0.5 ??10 -8????28.0±5.2 ??10 -5????52.6±1.3????9.0×10 -6??10 -6????30.4±1.4 ??10 -7????10.4±2.4 ??10 -5????54.5±2.8????9×10 -7??10 -6????48.8±1.3 ??10 -7????34.6±0.0 ??10 -8????16.2”2.4 ??10 -5????61.2±2.4????1×10 -6??10 -6????49.9±2.5 ??10 -7????32.5±1.1 ??10 -8????21.8±3.1 ??10 -5????68.7±0.2????9×10 -7??10 -6????52.6±0.5 ??10 -7????43.8±1.3 ??10 -8????9.4±3.7
Experimental example 3 suppresses mouse skin papilloma experiment (carcinogenesis and anti-promoting are in conjunction with experiment)
Kunming mice male and female dual-purpose, body weight 18-22g, back wool is sloughed with trichogen, random packet (seeing Table 4), 20 every group, male and female half and half in first three sky of experiment beginning.With DMBA acetone solution (150 μ g/200 μ l), each 200 μ l finished up to experiment for 2 times weekly control group in experiment the 1st, 7,14 day, and experiment was carried out for 12 weeks altogether.During this period, papilloma number and tumor-bearing mice number are write down in the end weekly.The oral various dose of full kind; (10mg/Kg is 20mg/Kg) with contrast medicine RII (40mg/Kg) for the compound of embodiment 14.Administration group DMBA is identical with control group with Oleum Tiglii smearing method and tumour observation method of counting.
Table 4 embodiment 13 compounds are to the treatment plan of carcinogenic and short cancer in conjunction with experiment
Group Start the stage (4 week) Protect the cancer stage (8 week)
??1 ??2 ? ??3 ? ??4 ? ??5 ? ??6 ? DMBA DMBA+ embodiment 13 compounds (10mg/Kg/2 days) DMBA+ embodiment 13 compounds (20mg/Kg/2 days) DMBA+ embodiment 13 compounds (20mg/Kg/2 days) DMBA DMBA+RII (40mg/Kg/2 days) Croton oil croton oil+embodiment 13 compounds (10mg/Kg/2 days) croton oil+embodiment 13 compounds (20mg/Kg/2 days) croton oil croton oil+embodiment 13 compounds (20mg/Kg/2 days) croton oil+RII (40mg/Kg/2 days)
Experimental result
Cutaneous papilloma from took place in the 5th week in control group, and after this mouse tumor incidence and average lotus knurl number are 6.75/.It is oral that (the tumour incidence reduces, and the average lotus knurl of mouse number is obviously reduced, and is a certain amount of effect relationship for 10mg/Kg, the 20mg/Kg) prolongation of latency that the mouse skin papilloma is taken place to embodiment 14 compound groups.Its effect is better than similar medicine R II (seeing Fig. 1 and 2).
The experiment of experimental example 4 mouse ear swellings
The administration group that the ICR mouse is divided at random contrast and various dose.The compound of obtaining in advance the oral embodiment 14 of mouse, 1 time/day, continuous three days.For the third time half an hour after the administration, be coated with Oleum Tiglii solution (containing 2% Oleum Tiglii, 20% ethanol, 73% ether and 5% water) 25 μ l for the mouse right ear two sides.Mouse is put to death in dislocation after 6 hours, and ears punch with keratome, and the weigh difference of left and right sides ear weight of auricle is the swelling degree.The results are shown in Table 5.
The effect (n=10) of the mouse ear swelling that table 5 embodiment 13 compounds bring out Oleum Tiglii
Group Dosage (mg/Kg) mouse ear swelling (mg) inhibiting rate
Comparative examples 13 compounds ????????????????16.5±1.4 ????50??????????14.2±2.8?????13.9* ????100?????????12.3±3.0?????31.5**
*p＜0.05
**p＜0.01
The active restraining effect that raises of the mouse back face tissue ornithine decarboxylase (ODC) that 5 pairs of Oleum Tigliis of embodiment bring out
Male ICR mouse 18-22g is divided into blank group, positive controls and administration group at random.The compound of obtaining in advance the oral embodiment 13 of mouse, dosage is the 50mg/Kg body weight, 1 time/day, continuous 2 days.After the 2nd administration 1 hour, be coated with 1% Oleum Tiglii acetone solution, 200 μ l to the mouse back of depilation in advance.Put to death animal after 5 hours, cut skin of back, be dipped in earlier in the ice-cold physiological saline, immersed again in 52 ℃ of hot water 30 seconds, immerse at last in the ice-cold salt solution.Strike off the corium part with scalpel, epidermis shredded the back add an amount of extracting solution, with refiner under ice bath after the high-speed homogenizationization, centrifugal 30 minutes of 30,000 * g, the gained supernatant liquor carries out determining the protein quantity and enzyme assay.Unit of enzyme activity is with nmol CO 2/ 30 minutes/mg albumen is represented.Experimental result as shown in Figure 3.
6 pairs of chondrosarcomatous restraining effect of transplantability rat of experimental example
Get well-grown rat chondrosarcoma and shred under aseptic condition, by dilution in 1: 3, in 60-80g Wistar rat oxter, 0.4ml/ only with No. 16 needle inoculations.Next day the random packet oral administration, the next day once, altogether administration is 18 times.Put to death rat on the 37th day in the inoculation back, claim knurl and body weight after the stripping knurl.The result estimates with tumor control rate.Experimental result such as table 6: table 6 embodiment 11 compounds and vitamin A acid are to the chondrosarcomatous restraining effect of transplantability rat
Group The heavy inhibiting rate (%) of dosage body weight knurl
Comparative examples 11 compound vitamin A acids ??????245.7???15.34 ??5???262.3???2.68**????82.5 ?10???262.3???0.39**????97.5 ?20???244.0???0.03**????99.8 ?20???222.0???0.00**????100.0
**p＜0.01
The mouse bone marrow cells that embodiment 7 CTX cause is bitten many when incarnadining the restraining effect that cell micronucleus forms
50 of male ICR mouses, 18-22g are divided into 4 groups at random; Control group is not done any processing; Endoxan mutagenesis group and two administration groups.The compound that the administration group obtains in advance the embodiment 13 of the oral various dose of mouse, 1 time/day, continuous three days.After the administration 2 hours for the third time, equal intraperitoneal injection of cyclophosphamide 100mg/Kg except that control group, in the injection CTX after 24 hours, 48 hours and 71 hours, 5 of the dead mouse in every component other places, get the femur bone marrow smear, Wright-Giemsa dyeing, microscopically counting marrow is bitten polychromatophilia red corpuscle (PCE) micronucleus and is formed number, and every 1000 of operation counting is bitten the polychromatophilia red corpuscle.
The compound of obtaining in advance the embodiment 13 of the oral various dose of mouse can obviously reduce CTX and bring out the micronucleus rate of formation and be the mouse bone marrow cells that a certain amount of effect relationship (seeing Table 7) table 7 embodiment 13 compounds bring out CTX and bite the inhibition (n=5) that the polychromatophilia micronucleus in erythrocytes forms
Group Dosage CTX marrow micronucleus forms 1000 PCE
Control group CTX embodiment 13 compounds+CTX ??mg/kg????mg/kg????24h?????????48h????????72h ????????????????????4.0±1.6 ???????????100??????25.6±2.9???33.2±5.9??23.6±4.0 ??50???????100??????12.9±2.0???17.0±3.2??11.4±2.3** ??100??????100??????8.6±2.6????11.8±2.9??7.2±1.9**
The CTX=endoxan
PCE＝ploychromadic?erythrocytes
* p＜0.01 experimental example, 8 Ames experiment
Salmonellas reverse mutation experiment according to Ames is carried out, bacterial strain uses therefor is TA97 and TA98, experiment adopts flat board to mix method, detection system contains the compound that the embodiment 14 of 0.1ml bacterium liquid 80 μ l different concns obtains, in the anti-mutation experiment, also add the positive mutagen of 20 μ l simultaneously, or control solvent DMSO, 0.5ml PBS (pH7.4) and the soft agar-agar of 0.2ml.Glass dish is upside down in 37 ℃ of incubators and cultivated 48 hours, counts time change colony number of bacterium then and cause prominent experimental result to see Table 8,9 and 10.
Table 8 embodiment 13 compounds are led to the effect (n=3) of Salmonellas TA97 mutation reverse mutation to 4-NQO
Group Concentration 4NQO reverse mutation number/ware inhibiting rate
DMSO Rubomycin C embodiment 13 compounds μ l/ ware μ l/ ware X ± SD % 80 μ l/ wares 0 111 ± 16 1 552 ± 93 50 1 429 ± 62 27.9 100 1 302 ± 35** 56.7 200 1 265 ± 7** 65.1
**p＜0.01
Table 9 embodiment 13 compounds are led to the effect (n=3) of Salmonellas TA97 mutation reverse mutation to Rubomycin C
Group Concentration 4NQO reverse mutation number/ware inhibiting rate
DMSO Rubomycin C embodiment 13 compounds μ l/ ware μ l/ ware X ± SD % 80 μ l/ wares 0 24 ± 25 107 ± 13 50 5 67 ± 9** 48.2 100 5 52 ± 6** 66.3 200 5 43 ± 4**, 77.1 300 5 38 ± 8** 83.1
**p＜0.01
Table 10 embodiment 13 compounds are to the mutagenic test (n=3) of Salmonellas mutation TA97TA98
Concentration sudden change number/ware
Group DMSO embodiment 13 compounds μ l/ ware TA97 TA98 μ l/ 111 ± 24 ± 2 200 101 ± 32 300 21 ± 4
Experiment shows that embodiment 13 compounds have anti-mutagenesis, and than itself not having mutagenesis under the heavy dose.
The teratology testing of the compound of experimental example 9 embodiment 13 and the compound of embodiment 12
Select healthy, sexually matured mouse, 29 ± 2g mates by male and female 2: 1 (or 1: 1).Check the cloudy bolt of female mouse every morning, to find one day 0 day (D of sperm for becoming pregnant 0).Pregnant mouse is assigned randomly in each experimental group and the control group.Divide into groups single cage of pregnant mouse is raised, and male mouse is then put into female mouse cage mating every night, every group long-pendingly stops mating when having 15-20.Every pregnant mouse is all in the 7th day gastric infusion 40mg/Kg of gestation and two dosage of 20mg/Kg, the contrast medicine be RA once a day, continuous 10 days.The normal control group is given equivalent physiological saline.Pregnant mouse is from D 0Rise and weighed once, adjust dosage according to body weight change every three days.Positive controls is given vitamin A acid 10mg/Kg.(D before childbirth 18) adopt the vertebra dislocation method to put to death female mouse, cut open the belly, open the uterus, take out the tire mouse that lives, and record absorbs the tire number.Observe tire mouse profile, and claim litter weight.With tire mouse separated into two parts at random, a part is liquid-solid fixed with BouinsShi, in good time the cut sections for microscopic examination internal organ.Another part is fixed with 95% ethanol, and through sodium alizarinsulfonate dyeing, decolouring and process such as transparent check that skeleton development situation, experimental result see Table 11 and table 12.The teratology testing of table 11 embodiment 13 and 12 compound (to absorbing the influence of tire) (n=10)
Group The dosage tire absorbs (%) tire mouse body weight
Contrast Tween80 embodiment 13 embodiment 12 vitamin A acids Mg/Kg absorbs number/implantation number tire mouse sum body weight average (0/,135 135 1.2 ± 0.2 0.3% 0/,104 104 1.2 ± 0.2 40 0/,107 107 1.1 ± 0.2 20 0/,104 104 1.1 ± 0.2 40 0/,119 119 1.1 ± 0.2 20 0/,113 113 1.1 ± 0.2 10 73/99 (73.7%) 26* 0.7 ± 0.1** of gX ± SD)
* p＜0.001 table 12 embodiment 13 and 12 compound are to the influence (n=10) of tire mouse bone and internal organ
Tire mouse pillow breastbone Ossified poor (%) Tire mouse tricorn enlarges (%)
Group contrast Tween80 embodiment 13 embodiment 12 vitamin A acids Dosage 40 20 40 20 10 Several 0/79 (0) 0/69 (0) 15/81 (18.1) 22/61 (33.3) 3/77 (3.9) 0/75 (0) 16/16 (100) * of occipitalization difference/examined Several 0/79 (0) 0/69 (0) 20/81 (24.7) 14/66 (21.2) 2/77 (2.6) 0/75 (0) 16/16 (100) * of breastbone difference/examined Several 0/54 (0) 0/34 (0) 0/39 (0) 0/38 (0) 0/43 (0) 0/38 (0) 1/3 (33.3) * of lateral ventricle number/examined Lateral ventricle number/total tire several 0/10 (0) 0/10 (0) 0/10 (0) 0/10 (0) 0/10 (0) 0/10 (0) 0/10 (0)
*p＜0.001

Claims (16)

1, acceptable salt on a kind of Viformyl cumarins compound of representing by following formula I and the pharmacology thereof:
Figure A9711660200021
(I)
In the formula, R 1Be H, C 1-C 18Alkyl, aralkyl and haloalkyl, CXYT 7, wherein X is H, N, NH, C, CH, O, and Y is H, N, NH, C, CH, O, and XY is O, R 7Be H, halogen, OH, C 1-C 18Alkyl, haloalkyl, alkoxyl group, ester group, replacement, the single replacement or polysubstituted phenyl,, wherein the substituting group on the phenyl ring can be C 1-C 4Alkyl, haloalkyl, alkoxyl group, OH, halogen, CO 2H, ester group, NO 2, CF 3, SO 3H, NR 8R 9, R wherein 8And R 9Identical and inequality, independently form heterocycle etc. respectively for H, alkyl, cycloalkyl and both;
R 2Be H, C 1-C 18Alkyl, haloalkyl, alkoxyl group, ester group, halogen, OH, phenyl or substituted-phenyl, CXYR 7, OR wherein X, Y and R 7As defined above, R=dimension formyl radical;
R 3Be H, OH, CHC 2OH, halogen, C 1-C 18Alkyl, haloalkyl, ester group, alkoxyl group, OR, CH 2OR or CXYR 7, wherein R, X, Y and R 7As defined above;
R 4Be H, halogen, C 1-C 18Alkyl, haloalkyl, alkoxyl group, ester group, OH, CXYR 7, wherein X, Y and R 7As defined above;
R 5Be H, C 1-C 18Alkyl, haloalkyl, alkoxyl group, halogen, ester group, OR or CXYR 7, R wherein 7, X, Y and R as defined above;
R 6Be H, C 1-C 18Alkyl, haloalkyl, alkoxyl group, halogen, ester group, OH, OR, CXYR 7, wherein R, X, Y and R 7As defined above;
2, compound as claimed in claim 1 is characterized in that R 1Be H or COR 7, R wherein 7Be CH 3, OC 2H 5, OH, NHR 10, R wherein 10=H or substituted-phenyl.
3, compound as claimed in claim 1 is characterized in that R 2Be H, OR, Cl, CH 3, ph, CH=NR 10, CH=CHR 10, R wherein 10As defined above.
4, compound as claimed in claim 1 is characterized in that R 3Be H, CH 3, CO 2H, CO 2Et, CO 2C 12H 25Or CH 2OR, CXYR 7, wherein X, Y, R 7Be the dimension formyl radical with R.
5, compound as claimed in claim 1 is characterized in that R 4Be H, CH 3, CH 3, COCH 3, C 4H 9, phCO, CO 2H, Cl, Br, CH=NR 10, CH=CHR 10, R wherein 10As defined above.
6, compound as claimed in claim 1 is characterized in that R 5Be H, CH 3, OR, CHO, CH=NR 10, CH=CHR 10, wherein R and R 10As defined above.
7, compound as claimed in claim 1 is characterized in that R 6Be H, OR, COCH 3, CO 2H, Br, CHO, CH=NR 10, CH=CHR 10, CXYR 7, wherein X, Y, R 7, R and R 10As defined above.
8, compound as claimed in claim 1 is characterized in that R 1=COCH 3, R 2=R 4=R 6=H, R 3=R 5=OR, R=ties up formyl radical.
9, compound as claimed in claim 1 is characterized in that R 1=COCH 3, R 2=R 4=R 6=H, R 3=CO 2H, R 5=OR, R=ties up formyl radical.
10, compound as claimed in claim 1 is characterized in that R 1=COCH 3, R 2=R 3=R 4=H, R 5=R 6=OR, R=ties up formyl radical.
11, compound as claimed in claim 1 is characterized in that R 1=COCH 3, R 2=R 5=R 6=H, R 3=OR, R 5=CO 2H, R=ties up formyl radical.
12, compound as claimed in claim 1 is characterized in that R 1=COCH 3, R 2=R 3=R 4=H, R 6=CO 2H, R 5=OR, R=ties up formyl radical.
13, compound as claimed in claim 1 is characterized in that R 1=COCH 3, R 2=R 4=R 6=H, R 3=CO 2H, R 5=OR, R=ties up formyl radical.
14, compound as claimed in claim 1 is characterized in that R 1=COCH 3, R 2=R 3=R 6=H, R 4=C1, R 5=OR, R=ties up formyl radical.
15, preparation is characterized in that as the method for the said compound of claim 1:
(1) by the phenolic compound of following formula (II) expression and respective compound react replacement and contain the coumarin kind compound (III) of hydroxyl
Wherein, R 1, R 2, R 3, R 4, R 5And R 6As defined above, but wherein have at least one to be OH simultaneously for OH or two substituting groups;
(2) resulting compound (III) and vitamin A acid reaction are obtained compound of the present invention (I):
Figure A9711660200052
Wherein, R 1, R 2, R 3, R 4, R 5And R 6As defined above, R is the dimension formyl radical.
16, the pharmaceutical composition that contains acceptable salt on the R8923 as claimed in claim 1 for the treatment of effective dose and the pharmacology thereof.
CN97116602A 1997-07-31 1997-07-31 Viformyl cumarins compound, process for preparing same and pharmaceutical composition contg. same Expired - Fee Related CN1108297C (en)

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