WO1995018088A1 - Derive d'acide benzoïque - Google Patents

Derive d'acide benzoïque Download PDF

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Publication number
WO1995018088A1
WO1995018088A1 PCT/JP1993/001907 JP9301907W WO9518088A1 WO 1995018088 A1 WO1995018088 A1 WO 1995018088A1 JP 9301907 W JP9301907 W JP 9301907W WO 9518088 A1 WO9518088 A1 WO 9518088A1
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WO
WIPO (PCT)
Prior art keywords
cells
compound
benzoic acid
mouse
group
Prior art date
Application number
PCT/JP1993/001907
Other languages
English (en)
Japanese (ja)
Inventor
Zong-Ru Guo
Rui Han
Feng-ming CHU
Xiao-qing HE
Li-juan XIA
Kazuya Kameo
Shiro Nakaike
Original Assignee
Taisho Pharmaceutical Co., Ltd.
Institute Of Materia Medica Chinese Academy Of Medical Sciences
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Taisho Pharmaceutical Co., Ltd., Institute Of Materia Medica Chinese Academy Of Medical Sciences filed Critical Taisho Pharmaceutical Co., Ltd.
Priority to PCT/JP1993/001907 priority Critical patent/WO1995018088A1/fr
Priority to AU57168/94A priority patent/AU5716894A/en
Publication of WO1995018088A1 publication Critical patent/WO1995018088A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
    • C07C65/28—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups having unsaturation outside the aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/19—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups having unsaturation outside the aromatic ring

Definitions

  • the present invention relates to benzoic acid derivatives useful for the prevention and treatment of malignant tumor growth (
  • Biminamine A acid and its analogs can be used systemically or locally for the prevention and treatment of malignant tumor growth and for the treatment of acne, psoriasis and other skin disorders.
  • German Patent Nos. 34344948, 3434492, European Patent No. 2110118 and H. Kagechika et al., J. Med. Chem, Volume 31. Pp. 218-2-2192 (1998) show that aromatic compounds such as vinylene groups substituted by aromatic rings, amide bonds, azo bonds, and ketene bonds, etc. It is described that a compound linked to ruponic acid has an effect of inducing cell differentiation and preventing and treating skin diseases.
  • An object of the present invention is to provide a compound having an antitumor effect and a differentiation-inducing effect that are superior to conventional ones. Disclosure of the invention
  • the present inventors have conducted intensive studies in view of the above object, and as a result, have found that a newly synthesized compound can achieve the above object, and have completed the present invention.
  • the present invention provides the following formula [1] [1]
  • R 1 and R 2 are the same or different and each represent a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.
  • a salt thereof
  • the alkyl group is a linear or branched alkyl group, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, and a pentyl group.
  • the salt of the compound according to the present invention means a pharmacologically acceptable salt, for example, a salt with an inorganic base such as potassium, sodium, magnesium, ammonia or an organic base such as triethylamine. .
  • the compound of the present invention has the formula [2]
  • the method of administering the compound of the present invention includes parenteral administration and oral administration.
  • the dosage forms are parenteral injections, tablets, granules, orally administered orally. It is any one dosage form selected from powders, capsules, syrups, and suspensions. C These dosage forms can be appropriately selected depending on the condition, age and purpose of treatment of the patient. In the preparation of various dosage forms, conventional excipients (eg, crystalline cellulose, starch,?
  • L sugar, mannitol, etc.), binders (eg, hydroxypropylcellulose, polyvinylpyrrolidone, etc.), lubrication Agents (eg, magnesium stearate, talc, etc.), disintegrants (eg, calcium carboxymethylcellulose), etc., can be used, and can be prepared using normal production methods (eg, the method specified in the Japanese Pharmacopoeia, 12th Edition) ) Can be used.
  • the dosage is 0.1 to 500 mg for the treatment of adults, and is to be administered once to three times a day. This dosage may be appropriately reduced depending on the age, weight and condition of the patient.
  • Example 1 As in Example 1, 0.65 g (2.62 mmo 1) of 3,5-di-tert-butyl-1-hydroxyacetophenone and 0.43 g (2.62 mmo 1) of methyl 2-forminolebenzoate were converted to 2- [3- (3,5-di-tert-butyl-4-hydroxyphenyl) -13-oxo-11-probenyl] 0.89 g of crude benzoic acid was obtained, which was crystallized from ethanol to give yellow crystals. 0.72 g was obtained. mp 105-: L 06 o C
  • Mouse P 3 8 8 leukemia cells (20000 ce 11 s / m 1), human nasopharyngeal carcinoma KB cells (l OOOO cell sZm l), human small cell lung cancer H 69 cells (5000 0 ce 11 s / m 1)
  • Human ovarian cancer A2780 cells (20000 ce11 s / m1) or human bladder cancer HT1197 cells (30000 ce11 s / ml) in 10% fetal serum-containing RPM1- After suspending in 1640 culture medium or MEM culture medium, add 0.1 ml to a 96-well culture plate. C, and cultured for 24 hours in a 5% carbon dioxide incubator.
  • Example 2 Various concentrations of the compound obtained in Example 2 dissolved in 0.5% DMS 0 were added in an amount of 0.1 ml, and the cells were further cultured for 48, 72, 120, 72 or 96 hours. After the culture, the reagent MTT [3- (4,5-dimethylthiazol-2-yl) -12,5-diphenyltetrazolium bromide] dissolved in PBS was added, and the cells were further cultured for 4 hours. After the completion of the culture, the medium was removed, DMS01501 was added, and the absorbance at 540 nm was measured using an Immunidai NJ2000.
  • HT1197 2.30 Test Example 2 [Effect of mouse colon cancer Co 1 on 26 on growth in vivo] Cell suspension of Co 1 on 26 prepared to 2.5 ⁇ 10 6 ce 11 s / m 1 0.2 m 1 in CDF One mouse was implanted subcutaneously at the back of the mouse. The compound obtained in Example 2 was suspended in 5% arabia gum and orally administered four times every other day from the third day after transplantation. Ten days after the transplantation, the size of the tumor was measured, and the tumor volume was calculated by the following formula.
  • the inhibition rate was calculated from the ratio of the tumor volume of the drug-administered group to the control.
  • Example 5 [Effect on in vivo growth of mouse B16 melanoma] Melanomas cells collected under aseptic conditions were transplanted under the mouse axilla and subcutaneous fossa. From the next day, the compound obtained in Example 2 at each concentration was orally administered three times every other day. On day 10 after transplantation, the tumor was excised and the tumor weight was measured to calculate the inhibition rate. The results are shown in Table 5.
  • the method was performed according to the method of Collins et al. (Canser. Res., Vol. 42, pp. 445-449, 1982).
  • the HL- 60 cells 1 X 10 5 cells Zm 1 to 10% fetal bovine serum added RPM I - 1640 medium, cultured in penicillin 10 OU / m 1, streptomycin 10 O / zg / mU 37 ° C, 5% C0 2 did.
  • the i-conjugation product and all-trans-vitamin A acid obtained in Example 1 were 1% and 0.1% ethanol solutions, and a 0.1% ethanol solution was used as a control.
  • the drug was added to each concentration, and after culturing for 5 days, the differentiation inducing activity was measured using the NBT reducing ability as an index. That is, after completion of the culture, the cells are collected by centrifugation at 1000 rpm, and 0.5 ml of a 0.1% NBT solution and 12-0-tetradecanoyl fluorbor Lou 13-acetate (TPA) 20 Ong was added and reacted at 37 ° C for 60 minutes. The cells after the reaction were collected by centrifugation to prepare a smear, which was stained with Wright-Giemsa staining solution. 200 cells per specimen were observed under a microscope, and those with a blue-violet formazan precipitate in the cytoplasm were identified as NBT-reducing ability-positive cells.
  • TPA 12-0-tetradecanoyl fluorbor Lou 13-acetate
  • GIT guanidine isothiocyanate
  • 6M guanidine isothiocyanate, 1 OmM sodium citrate (pH 7), 0.5% sarkosyl, 0.1 M2-mercaptoethanol The cells were suspended and shaken to break the cells.
  • the above cell lysate was overlaid on 5.7 M saline-0.1 M EDTA-Na (pH 7.5), and subjected to density gradient centrifugation at 17 4000 G at 20 ° C for 16 hours.
  • the compound of the present invention may significantly suppress the oncogene expression as compared to the control. found.
  • the anti-mutagenic effect of the compound of the present invention was evaluated by micronucleus formation test using mouse bone marrow cells. Micronucleus formation was induced by cyclophosphamide and DMBA, and the antagonism of the compound of the present invention was observed.
  • Each group consisted of 5 mice weighing 18-22 g, and the compound obtained in Example 1 was orally administered 5 Omg / Zkg or 10 Omg / kg once a day for 4 consecutive days.
  • micronucleus formation was induced by intraperitoneal injection of 100 mg / kg of cyclophosphamide or 25 mg of Zkg of DMBA, and a micronucleus test was conducted 24 hours later by a conventional method.
  • the compounds of the present invention significantly suppressed the micronucleus forming ability as compared with the positive control group.
  • mice weighing 18-22 g were randomly grouped into groups of 7 mice.
  • the compound obtained in Example 1 was orally administered SOmgZkg or 100 mgZkg once a day for 4 consecutive days, and after applying croton oil, holes were made in both ears. The difference between the swelling of the coated ear and the uncoated ear was used as an index.
  • Example 13 5 mgZkg or lOmgZkg of the compound obtained in Example 1 was continuously administered for 9 weeks. At 7 weeks, the tumor weight of the rats was measured. As a result, the tumor suppression rates of 5 mg / kg and 1 Omg / kg with respect to the control group were 98.7% and 100%, respectively. This result indicates that the compound of the present invention has a remarkable inhibitory effect on rat transplantable chondrosarcoma. Test Example 13
  • Mouse dermal papillomas caused by DMBA and croton oil were used as models to evaluate the antagonism of the compounds of the present invention against chemical carcinogens.
  • mice weighing 18-22 g were randomly divided into 30 groups of 30 mice per group, and the back was depilated with an 8% aqueous sodium sulfide solution.
  • 0.2 ml of a dimethylbenzanthracene monoacetone solution containing 150 ng DMBA was applied to each part where the hair had been removed, and administered twice a week for two weeks.
  • a 0.25% croton oil-acetone solution was applied 0.2 m 1Z times and administered twice a week for 12 weeks.
  • the compound obtained in Example 1 at 5 Omg / kg, 25 mg Xkg from the first week of DMBA application The article was administered directly to the back of the mouse.
  • the compound of the present invention was administered once every two days for 12 weeks, and the number of animals expressing papillomatosis ⁇ the number of animals that developed each week and the number of tumors that appeared in each animal were recorded. As a result, the compound of the present invention had a remarkable inhibitory effect as compared with the control, and the activity was dose-dependent (FIG. 2).
  • FIG. 1 shows the expression state of an oncogene by autoradiography in Test Example 9.
  • FIG. 2 shows the test results in Test Example 13. Industrial applicability
  • the compound of the present invention has an antitumor effect and a differentiation inducing effect, and is therefore useful for preventing and treating malignant tumor growth.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention se rapporte à un dérivé d'acide benzoïque représenté par la formule générale (I), et à un sel de celui-ci, formule dans laquelle R1 et R2 peuvent être identiques ou différents l'un de l'autre, et où chacun représente hydrogène ou alkyle C¿1?-C5. Le composé de l'invention présente des qualités supérieures par rapport aux composés classiques par son action antitumorale et son action induisant une différenciation.
PCT/JP1993/001907 1993-12-27 1993-12-27 Derive d'acide benzoïque WO1995018088A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/JP1993/001907 WO1995018088A1 (fr) 1993-12-27 1993-12-27 Derive d'acide benzoïque
AU57168/94A AU5716894A (en) 1993-12-27 1993-12-27 Benzoic acid derivative

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/JP1993/001907 WO1995018088A1 (fr) 1993-12-27 1993-12-27 Derive d'acide benzoïque

Publications (1)

Publication Number Publication Date
WO1995018088A1 true WO1995018088A1 (fr) 1995-07-06

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1993/001907 WO1995018088A1 (fr) 1993-12-27 1993-12-27 Derive d'acide benzoïque

Country Status (2)

Country Link
AU (1) AU5716894A (fr)
WO (1) WO1995018088A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4714776A (en) * 1985-07-22 1987-12-22 Riker Laboratories, Inc. Antiallergic agents

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4714776A (en) * 1985-07-22 1987-12-22 Riker Laboratories, Inc. Antiallergic agents

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF MEDICINAL CHEMISTRY, VoL. 32, No. 1, January 1989, pages 100-104. *

Also Published As

Publication number Publication date
AU5716894A (en) 1995-07-17

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