JPH07507996A - Compound - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Compound The present invention relates to compounds based on an anthraquinone nucleus.

The inhibition of DNA) boisomerase, especially topoisomerase tt (topon), is currently , doxorubicin, mitoxantrone, VP16, cambutocin, tobotecan, The most critical product available, containing MAMSA, VM26, and eribinacin. It is considered to be an important component in the action mechanism of many clinically active anticancer drugs. is being given. These drugs are protein/drug/nucleic acid ternary complexes, i.e. In other words, it is thought that topo 11 is suppressed by stabilizing the degradable complex. It is being

However, although these drugs target topoisomerase, These drugs also have many other mechanisms of action, such as toxicity and poor treatment. Formation of DNA covalent adducts and free radicals resulting in therapeutic index This indicates the occurrence, etc. Furthermore, these drugs can treat major malignant diseases over a long period of time. If untreated, the existence of de novo resistance and the development of drug resistance may occur. Therefore, the condition will worsen.

U.S. Patent No. 4,894,451 discloses an asymmetrically substituted anthraform represented by the chemical formula (A). Sen-1,4-dinone compound: Here, B is a lower dialkylamino group, n is 3 to 5, and R is hydrogen, alkyl is noyl or alkylsulfonyl. These compounds are , intended for use against tumors. The present invention provides monosubstituted compounds The purpose is to provide something. At least the left-hand ring represented by the chemical formula (A>) was not previously possible.

It is an object of the present invention to provide improved clinically active agents. present invention A further object of the invention is to provide colored compounds which can be used as dyes.

According to the invention, chemical formula (1) Here, Y and Yl are each independently hydrogen or hydroxyl, and B and B1 is each independently oxo or hydrogen, R5 is hydrogen or hydroxyl and X is bonded to the ring via the nitrogen atom of the amino acid adjacent to the acid group of the amino acid. do. A compound represented by is an amino acid residue or a derivative of an α-amino acid is proposed. Served.

Obviously, if B or B1 is oxo, the line in the ring means a double bond. do.

゛　0 Amino Acid　 means here the group: R2-CR'H-NH2, in the formula, R1 is an amino acid residue, such as hydrogen, linear or branched Cl-6 a (e.g. methi-isopropyl, 2-methylpropyl or 1-methyl) propyl), hydroxyalkyl (e.g. -CH20H or 1-hydroxy ethyl), aralkyl (e.g. benzyl or 4-hydroxy-benzyl) ), thioalkyl (e.g. -CH2Sl(), alkylthioalkyl (and -CH2CH25CH3), acyl (e.g. -CH2COOH or - CH2CH2COOH), amidoalkyl (e.g. -C) (2C0NH2 or or -CH2CH2C0NH2), or linear or cyclic, aromatic or non- Aromatic, nitrogen-containing heterocyclic groups, e.g. tryptophan, lysine , a group forming an arginine or histidine moiety; and R2 is a group -c (= o) R3, where R3 is -0H1 or -0- bond or -N- bond group, For example, -〇-alkyl, -〇-alkylaminoalkyl, -〇-alkoxy alkyl or -NH-NHR4, where R4 is optionally -CN or -O Straight chain or branched alkyl groups optionally substituted with H, amide groups (e.g. -CON )(2) or a hydrazine group (for example, -(CH2)2NH(CH2)20 H). Examples of alkylaminoalkyl groups include CH3(CH3)NCH 2CH2- and CH3(CH3)NCH2CH2NHCH2CH2- are mentioned. It will be done.

°Alkyl° means up to 20 carbon atoms, preferably 1-10 carbon atoms, more preferably or straight chain or branched alkyl having 1-6 or 1-4 carbon atoms.

The common 20σ found in natural proteins and their D-isomers -Amino acids: uncommon natural a-amino acids found in proteins , for example, 4-hydroxyproline, 5-hydroxylysine, desmosine, ( N~methyllysine, 3-methylhistidine and isodesmosine and these D-isomer; natural amino acids not found in proteins, e.g. Nin, γ-aminobutyric acid, homocysteine, homoserine, citrulline, ornithine , canavanine, dienkolic acid, and β - cyanoalanines and their D-isomers; and these or other amino acids di-, tri-, tetra-, penta-, oligo- or polypeptides based on amino acids (provides that the amino acid attached to the anthracene ring is an α-amino acid) Preferably, the peptide has one amino acid group.

Therefore, for R1: hydrogen; straight chain or branched C1-4 alkyl (e.g. , methyl, isopropyl, isobutyl or 5ec-butyl); aryl-C 1-4 alkyl (e.g. benzyl, β-indolylmethyl, 4-hydroxy benzyl or 4-imidazolylmethyl): C14 alkylthio-('1-4 a alkyl (e.g. methylthioethyl); hydroxy-CI-4 alkyl (and For example, hydroxymethyl or 1-hydroxyethyl); mercapromethyl (such as For example, -CH2SH)': C1-4 amide (e.g. -CH2C(0)N H2 or -CH2CH2C(0)NH2); C1-4 alkyl carboxylate (e.g. -CH2C(0)OH or -CH2CH2C(0)OH): C1-6 alkyl amines (e.g. -(CH2)4N)12); and imino (CI-6) Alkylamine (e.g. (C)12)3NHC(=NH)NH 2) is mentioned.

Amino acid conductors include salts (acid or base adducts), esters, amides, means hydrazide, hydroxamic acid, and other derivatives; derivatives that tolerate the basic coloring properties or topoisomerase inhibitory properties of the compound. It shall not be reduced to the extent that it is not possible.

Salts that can usually be used in therapy include physiologically acceptable base salts, such as For example, a suitable base, such as an alkali metal (e.g. sodium), an alkali earth metals (e.g. magnesium), ammonium and NX4+ (where X is C1-4 alkyl) salts. Hydrochloric acid is a physiologically acceptable acid salt. Salts, sulfates, mesylate, besylate, phosphate, and glutamate are listed. can be lost.

The salts of the present invention can be prepared by conventional methods, for example, by adding the parent compound to a suitable base. to form the corresponding base salt by reacting with or inversely with a suitable acid. It can be prepared by allowing the corresponding acid salt to form.

Compounds of the invention can be prepared as substantially pure optical isomers. preferably is represented by the group: -NH-CRIH-R2, where R1=-CH2 C6J (40H, CH3, or -C) f208 and R2 = -C00C2 H5, -COOCH3, or -CONHNH2, or a derivative thereof .

Preferably, only one of Y and yl (preferably Yl) is hydrogen. Y-o Compounds in which both and Y] are hydrogen are considered novel. Y and Yl Some compounds in which at least one is -OH are new and have been previously described. , it is thought that its use against tumors was not proposed.

Preferably, B=Bl=oxo.

Preferred compounds are R+=-CH20H1 and R2=-CONHNH2. More preferably, RI=-CH20H1 and R2=-CONHNH2 , then B=B1=oxo and Y=Y1=H or Y--0) (and It is either Yl-H.

Furthermore, according to the present invention, a compound having the above structure and a pharmaceutically acceptable carrier are provided. A pharmaceutical formulation is provided comprising: Various suitable pharmaceutically acceptable carriers is available. The formulation is suitable for administration by the selected means. It is. Should be sterile, especially when used for injectable, non-pyrogenic purposes .

Compounds of the invention or formulations thereof may be administered enterally (e.g., orally and rectally) or non-intestinally. Orally (e.g., nasal or pulmonary delivery, or intravenous, arterial, cerebral, spinal, or pulmonary) It can be administered according to conventional methods, including intraperitoneal, intramuscular, or subcutaneous injection). be. This compound can be injected directly into the tumor. Processing can be done once or multiple times. It is possible to give. The dosage is to be determined by the physician, but 0.01 mg and 1.0 g/kg/day, e.g.　1 and 500mg/kg/ It is between days. At least some of the compounds of the invention may with particularly low toxicity and at very high doses, e.g. 50-300 mg/k g can be administered. (5 mg/kg in rodents and 1- Compare the maximum doxorubicin dose of 2 mg/kg. ) The compound of the present invention is Although the compounds of the present invention can be administered alone, the compounds of the present invention may be combined with one or more acceptable carriers. Both are preferably pharmaceutically acceptable formulations.

The carrier is compatible with the compounds of the invention and is not harmful to the receptor. It must be 'acceptable' in this sense.

The formulation is usually in unit dosage form and may be prepared in a variety of ways well known in the pharmaceutical field. It can be prepared by a method. Such a method involves injecting the active ingredient (compound of the invention) into including the step of combining with a carrier comprising one or more accessory ingredients. In general, These formulations carry the active ingredient in either a liquid carrier or a finely divided solid carrier. or both, and then formed into a product if necessary. It can be prepared from No. 2.

Preparations according to the invention for oral administration contain a predetermined amount of active ingredient. can be formed as separate units such as capsules, cachets or tablets; or as granules; as a solution or suspension in an aqueous or non-aqueous liquid or formed as an oil-in-water emulsion or a water-in-oil emulsion; It is something that The active ingredient can also be formed as a porous, lozenge, or paste. It is Noh.

A tablet can be made by compression or molding, optionally with one or more accessory ingredients. be. Compressed tablets are made by compressing the active ingredient into a free-flowing form, such as a powder or granules, in a suitable device. In some situations, optionally binders (e.g. povidone, gelatin, hydroxypropyl methyl cellulose), lubricants, inert diluents, preservatives, decomposition agents (e.g. starch Sodium glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cell It can be manufactured by compressing it together with loin), surfactants, dispersants, etc. Ru. Molded tablets are prepared by placing the compound in powdered form moistened with an inert liquid diluent in a suitable device. It can be prepared by molding a mixture of The tablet optionally has the desired release properties. For example, hydroxypropyl methyl cellulose in various proportions to obtain coating and molding for slow or controlled release of the active ingredient using It is possible.

Formulations suitable for topical administration in the mouth include a scented base, usually sucrose or lozenges consisting of the active ingredients in acacia and tragacanth; gelatin activity in bases such as phosphorus and glycerol or sucrose and acacia. a fragrance consisting of the ingredients; and a mouthwash consisting of the active ingredient in a suitable liquid carrier. One example is wash.

Formulations suitable for parenteral administration include antioxidants, buffers, bacteriostatic agents, and receptors. Aqueous and non-aqueous sterile formulations that can contain solutes to make preparations isotonic with blood. Sterile aqueous and non-aqueous solutions that can contain bacterial injection solutions; and suspending agents and thickening agents. Examples include suspensions. These formulations can be packaged in unit-dose or multi-dose containers, For example, it can be present in sealed ampoules and vials, and sterile liquid carriers. A. For example, a freeze-dried product that only needs to be added with water for injection just before use. It can be stored in Extemporaneous injection solutions and suspensions can be prepared from sterile powders, of the kind mentioned above. It can be prepared from granules and tablets.

Preferred dosage units are daily doses or units, daily subdoses of the active ingredient. , or an appropriate divided amount thereof.

Ingredients, in particular added to the formulations according to the invention as described above, are commonly used in the field of this formulation type. Other drugs can also be used. For example, flavors suitable for oral administration include It is possible to contain a bar agent.

At least some of the compounds are anticancer, antiviral, and/or anticancer agents. can be used as parasitic agents, and some of the anticancer compounds are It can be used for things.

Special tumors suitable for treatment according to the invention include erythroleukemia and cervical, cephalic and , neck, brain glioma, chest, lungs, intestines, prostate, skin, mouth, nose, stomach, liver, pancreas, and and these metastatic cancers.

Specific viral infections suitable for treatment according to the present invention include bovine virus I (H5VI); Bovine simplex virus II (H5VII); zoster Shin virus Ellen (VZVEllen): Bovine baby lomavirus ( BPV); and human immunodeficiency virus (HIV).

Particular protozoal infections suitable for treatment according to the invention include trichomoniasis; (particularly those caused by Plasmodium falciparum); trypanosomiasis and Trypanosoma cruzi); and Riesmaniasis. It will be done.

At least some of the compounds of the invention are useful as antibacterial agents.

At least some of the compounds of this invention are useful as dyes, carriers, diluted A lubricant or mordant for dyes, such as for dyeing cotton, nylon and paper. It is possible to combine with.

Furthermore, according to the present invention, there is provided a method for producing a compound having the above structure, and this production method (a) leucoquinizarin (or its 5'-0H1 and/or 8l- OH derivatives) and amino acids or amino acids in the leucoquinizaline ring in one of the carbonyl groups. -N82 group at the a-position of the carboxyl group so that the carboxyl group or its derivatives can be bonded Total oxidation of products obtained by reacting with amino acids or their derivatives ; (b) Chemical formula (a certain compound represented by D is converted into another chemical formula represented by chemical formula (1)) or (c) R5=-OH, B2=a2=oxo, and and Y=Y1=) (if the compound is represented by the chemical formula (IA), i.e. The final product of the compound represented by the chemical formula (where R5 is a protected -OH group, For example, to deprotect a compound protected by alkoxy such as methoxy? This is a method for producing a compound.

Leucoquinizarin is a compound represented by the following chemical formula (11>, where , Y=Y2=H and D=DI=-OH. This is combined with amino acids and dimethyl K2CO3 catalyst in an inert solvent such as formamide (DMF) at 80-100 °C. It is possible to carry out the reaction using a medium.

The reaction between leucoquinizarin and amino acids typically occurs between -10°C and 95°C. It will be done. Step (a) comprises a suitable oxidizing agent, preferably oxygen, hydrogen peroxide, or using chloranil in a miscible organic solvent/water system, e.g. Nor/water, a7tonitrile/water, or dimethyl sulfoxide/water or DM carried out in F/water at -10°C to 95°C, preferably 0-40°C. Ru. Adding a small amount of alkali (e.g. sodium hydroxide) accelerates oxidation. be done.

Step (b) may, for example, convert the ester to an amide, hydrazide, acid, salt or ester. The hydrogen atom adjacent to the carbonyl group bonded to the a-position of the nitrogen atom bonded to the intraquinone ring converting them into doloxamic acids or into other possibilities; or It consists of converting it into an ester. Such a transformation can be done, for example, by converting an ester into a The corresponding amide was obtained by reacting with ammonia (NH3, shielded tube, 100°C). By producing hydroxylamine (NH301(CI)/NaOM e, MeOH1 at room temperature for 1 week) to produce hydroxamic acid. and hydrazine hydrate (excess, methanol, perfusion, 2-3 hours) or React with other asymmetric monosubstituted hydrazine (NH2NHR4) to obtain the desired hydrazine. This is done by converting it into didos. The compound of the present invention can be obtained from an ester as a raw material. Using hydrazides, hydroxamic acids, or amide derivatives of amino acids as It can be prepared by

Compounds of the invention in which B and/or B1 are hydrogen may be subjected to a two-step process. It is best prepared from (1) where B=Bl=O.

Partial reduction in step 1 describes a method for reducing a mixture of known anthrones. Literature (L, Lieberman &^, Gimbcl Ber, Kan 887 ．． 20.1854). Here, A mixture of thoron is reacted with tin and hydrochloric acid in glacial acetic acid to form anthrone and this Here, a mixture of B and B1 in which either one is O is produced.

Stage 2 (Reference: L Cagliotli (+972) Organic S In the yn mountain eses 52, +22), the C=O group in the two compounds of the mixture is reacted with tosylhydrazine (NH2NHtosyl) to form the corresponding mixture. is converted into a mixture of tosylhydrazones, which is It can be prepared in situ and not isolated.

A reducing agent for the desired tosylhydrazone, such as sodium cyanoborohydride ( The reaction with Na(CN)BH3) was carried out in DMF at 50-100 °C to obtain the desired Structure (r; B=Bl=hydrogen), i.e. 9. lO-dihydro-anthra7ine is produced will be accomplished.

Reaction products of leucoquinizarin or its derivatives and amino acids or its derivatives Make the reaction mixture acidic, add excess water, and then extract with chloroform. Bye. Concentration of this chloroform extract yields crude leuko products, and in some cases can be crystallized from toluene or benzene. These intermediates are It is clearly contained. These intermediates are believed to have the structure of the chemical formula (II). Ru.

Here, Y, Yl, R5 and X are the same as in chemical formula (1), and E and Each El is independently hydrogen or hydroxyl. This compound is completely aromatic It is.

A compound of formula (m), where E=E1=OH, can be isolated as described above. , or can be synthesized by reduction reaction of (+). For example, sodium dithi onite in DMF and NaOH or NJIHCO3 aqueous solution at 0-100℃ or glacial acetic acid-ethanol at room temperature (perfusion). It can be synthesized by reacting with

These are anthraquinone 0) and 9.10-dihydroquine anthracene (0+). The rainbow onite reaction, which is a standard method for reducing ougin Ber (1906) 37.9.3563 and H, M, Cra wrrd e4 al (+952) J, Am, Chem, roc.

74.4087.

Compound (+++), where E=E1=H is a reaction obtained by a common method. cannot be isolated from the reaction mixture, but can only be produced by reduction of (r) to (m) above. It is. Anthraquinone to anthracene using ammonia/zinc reduction For methods such as conversion, please refer to the literature: J, T, Traxler (+970 ) Syr++hesis of Anthracenes (ram Artl hraquinones, 5ynthetic Communications 161-166.

Step (c) involves the use of various Lewis acids, such as boron trichloride (or boron tribromide). or boron trifluoride) in chloroform or dichloromethane, Performed at -78°C (dry ice) for 30-60 minutes.

The protected compound (IA) is described in U.S. Pat. No. 4,894,451 by Klapcho et al. Conversion of compound (11) to compound (m) described in (incorporated by reference) It can be manufactured by That is, instead of the tertiary amine (III) of the present application, , which uses the above amino acid derivative (having a free tertiary amine group) . The Roman numerals in the preceding sentence are not the chemical formulas of the patent application, but the chemical formulas of the US patent. corresponds to that of To avoid confusion, we will refer to these as K-11, etc. (K stands for K). (meaning of Rapcho). K-11 is 1,4-dialkoxy-anthrace 9,19-dione or similar 1,4-substituted compounds, as described in the literature: Karapch.

Described in eIal (+984) J, Org, Chem, 49.5254 It can be manufactured using the following method. The -IV synthesis reaction between K-11 and amino acids is , for example, using a 2-5 molar excess of the amino acid derivative in dichloromethane solution. It is carried out photochemically. This solution is irradiated to remove the solvent and remove the silica. Compounds purified by column chromatography are recrystallized from an appropriate solvent. be converted into The -1 compound (i.e. our formula IA) is then It can be converted into a chemical compound with the chemical formula 〇) as follows.

The invention will be explained in detail below with reference to the drawings.

Figure 1 shows the in vitro chemical sensitivity results (24 hours) of the compound of Example 10. (incubation period).

Figure 2 shows the in vitro chemical sensitivity results (24 hours) of the compound of Example 9. Incubate).

Figure 3 shows the results of the cross-resistance test using the compound of Example 1O (24 hours (incubation period).

Figure 4 shows the decatenation of topoisomerase 11. Showing the results of So-Nanai.

Figure 5 shows the results of the topoisomerase ■ relaxation assay.

Figure 6 shows topoisomerase! The results of relaxation 7 are shown.

General synthetic chemistry The N-anthra7yl amino acid of the present invention is a amino acid 1[2H,3H]-9 ゜lO-dihydroxyanthracene-1,4-dione or [2H]-9,1 0-dihydroxyanthracen-1-one (formula II) and then It can be synthesized by oxidizing the intermediate shown below.

(II) where D and DI are each independently hydrogen or hydroxyl, Y and Yl is the same as above.

Potassium carbonate is liberated from the hydrochloride to free amine N) 12cHRIR2. used for. Therefore, sodium carbonate, pyridine, triethylamine, or or diisopropylamine (however, some esters at R2 of the amine alkaline hydroxides or other bases that tend to hydrolyze the ter functionality. It can be replaced by other bases, including

DMF is DMA (dimethylacetamide), THF (tetravitrofura ), dioxane, HMPA (hydroxymethylphosphoramide) or other non- It can be replaced with a protic polar solvent. Alcohol-based solvents can also be used, but The scale of the reaction is leucoquinizarin (If, D=OH, DI=OH, Y= Limited due to low solubility of H, Yl=H).

The obtained product is mono-substituted, does not contain bis-substituted products, and is produced in high yield. It was found that These highly crystalline and virtually optically pure N-amples The tracenyl amino acid conductor is characterized by a range of analytical and spectroscopic methods. It is something.

General method Leucoquinosaline is commercially available from Yorkshire Chemicals, Reeve, UK, for example. is commercially available or quinizarin (available from Artri Noci). , for example, using sodium cythionite in sodium bicarbonate and DMF. It can be synthesized by reduction.

[28,3H]-2,3-dihydro-9,1O-dihydroxyanthracene-1 ,4-dione (leucoquinizarin), 2.4 g (0.01 mol) (Yokushi (Car Chemicals, Reeve, UK) in dimethylformamide (40 cm3). , a suitable a-amino acid derivative NH2CH(R1)R2 (0.01 mol) and water collecting carbonate A mixture of potassium (0.05 mol) was heated at 95° C. for 1 hour under an argon atmosphere. It was hot.

The reaction mixture was cooled to 25°C and ethanol (20 cm3) and water (2 cm3) were added. and aerated for 5 hours.

This solution was diluted with water (70 cm3) and extracted several times with chloroform. This extraction When the ingredients were combined, dried (magnesium sulfate), filtered, and concentrated, the result was a light purple color. of solid was obtained. This solid was dissolved in a minimum amount of toluene-ethyl acetate (9:1 to 4:1 1) and subjected to silica gel column chromatography (5 x 25 cm). It was eluted with the same mixed FG medium. Chloroform:methanol (9:10) or chloroform Roform:ethyl acetate (4:1) can be used instead.

The product-containing fractions were combined, filtered, and concentrated, leaving a solid residue. The resulting sample was analytically pure upon recrystallization in a suitable solvent. beauty salon Ethanol is the preferred solvent for the solvent.

Example 1: (S)-N-(4°-hydroxy-9°,10”-dihydro- 9°.

10'-dioxo-1°-anthryl)-L-alanine methyl ester. a As a raw material for amino acid derivatives, L-alanine methyl ester (Aldrich Co., Ltd.) (available from Michal Company, Poole, Dolcett, UK). The above compound was synthesized according to general methods.

Yield 58%; m, p, +70"C, e, i, 8% f-th+v+n/ z + = + 325 (M”), 266 (100%) M.

325,'Hnmryxtsw(CDCI,; 270 Ml(z)δ: 1. 7 (3H, d, CHCII,): 3.8 (3H.

s, 0CHx): 4.4 (lH, rn, CH) near, 05 (IH, d, H-2°): 7.27 (l H, d, H, 3°j: ^^'BB'- Shift+1/[δA7.7-7.9 (H-6,8-7): δ. 8.2.3. 4 (H-5', H-8') I: 10.5 (I) 1. dANHl: Grave 3.6 (IH9s, 4°-0H) i%+Bamboo: H@rg: , H,, No, C: 66.46: H: 4.6 2; N: 4.31% lO°-dioxo-1°-anthryl)-L-serine As a raw material for ethyl ester, serine ethyl ester (Aldrich) (available from The Chemical Company, Poole, Dollars, UK). It was synthesized according to the general method of Dr.

Yield: 63% m, p, 189°C (crystallized from ethanol) d, c, i, mass spec. Kutle m/z=356, (M”+1)’Hn1nr Snomuff + Shiki CDCl , ; 270MHz) δ: 1.3 (3H, +, CH,): 2.65 ( IH,br　s,CH,O)I,exch,D,O):　4.15　(2H, dB C1 (, OH); 4.3 (2H, q, CLi2CH,); 4.5 (I H, +n, CH); 7.13 (IH, d, H-2°j; 7.2+ Song, d, H-3'); AA'BB'-"A-++v-[6,, 1, 12-7 , 82 (2H, m, H-6°H-T): 06.8.28-8. :14 (2 H, m, H-5', )l-8') to 10.75 (IH, d, Nli, excel+, D, 0th: 1.52 iI H, s, 4'- 01(,exch,D!O),'i%4m:1jl(1:C,,H,,0 6N C: G423: HJ, 79. N394%=Jhfk-(k: C: 64.25 2H: 4.65: N: 3.85% where R'=ONm . This amine can be prepared by adding 1 equivalent of an aqueous sodium hydroxide solution to the a-amino acid. was obtained and used directly.

was prepared and then recrystallized from aqueous ethanol.

-dioxo-1°-anthryl)-glycylglycine, which can be prepared by the direct coupling method. It was prepared using a dipeptide derivative as a raw material.

After aeration, the crude product is isolated as a precipitate by pouring the reaction mixture into 2M hydrochloric acid. Separated.

Yield 47% m, p, 205°C 'Hnmr7A'? 1-+v (d6-DMSo, 270 MHz) 53.6 (2H, n+, C1i, C00HI: 4.15 (2H, d, NH-C1 i,), 7.28 (2H, m, H-2°, g・ 3'); 1.8 (2H, m, H-6', H-7:); 123 (2H , +n, H-5°, H-8': 10.4 (l) 1. 々煤@Ph-Nl1 l; 11.4 (lH, m, 4*’nM, C0-N output; 13.0 (2H, m, Yume qA4, C0OHt 4'-OH, 4t exch, C20).

1%, /, ; analysis udo, , H, 40, N, , C: 61.02. H: 3.95 ．． N: 7.91 view ＾ Biko: 61. +5°H: 3.90. N: 7.8 5% I got something.

Yield 37% m, p, 238°C 'Hnmr/'7) +v (d6-DMSO; 270 MHz) δ: 1 ．． 43 (3H, d, CH,); 4.21 (IH, m, C11) 7.0 1 (IH, +n, H-7'); F, 1-7.4 (2H, +n, H-2', H -5°): 7.53-7.90 (2H, +n, H-R',) (- 6'); 10.62 (I) (, m, N1d); 13.6+, 13.9 7.14.43 (3) 1.4°-OH, 8', OH, C0nH: %q　e+cch,　DqO).

Jin 1, Eikaginfu 2 to Fu 1--L/, 314 (M”), 299 (M-CH, ) i, r, Zca-+V,, (Br) cm”: 3400 (OH) 2920 (N, H), +590 (quinone) Nomigang C16H1□06N, ;Qq 5 colors 44; C: 61.1:) I. 3.75: N: 4.45% Example 7: (s) -N-(4°-hydroxy-9',10'-dihydro-9 °.

10”-dioxo-beanthryl)-L-trirosine ethyl ester was prepared from thi-trirosine ethyl ester in the same manner as in Example 1 above. .

Example 8: (S)-N-(4°-hydroxy-9°, 10°-dihyde Low-9°.

10'-dioxo-1'-anthryl)-L-alanine hydrazide, which is Prepared from shi-alanine hydrazide as in Example 1 above.

Example 9: (S)-N-(4'-hydroxy-9°,io'-dihyde Ro-9'.

10'-dioxo-1'-anthryl)-t,-1 lysine hydrazide This is , was prepared from L-)lyrosine hydrazide as in Example 1 above. (S )-N-(4°-hydroxy-9', 10'-dihydro-9', 10"-diox So-1°-anthryl)-L-)lyrosine ethyl ester (0,19g; 4 ．． 46XIO (4 moles) was dissolved in methanol (20 cm3). hydrazine hydration (0,045 g: 0 to 4 mol of 9XI) and perfused this solution for 3 hours. did. This solution was concentrated and dried, and the residue was recrystallized from absolute alcohol. An analytically pure sample of the title compound was obtained in 87% yield. Melting point: 284 ℃.

i, r syefu w+v y,,,, (25"*-+J Cm" 3320.: 1200 (NHNH2) 1640 (Co)/15n, 1StB C: 66.35. H: 4.57. N: 10.10% (or C, H, ,05N,; ]+lJC: 66.35: H: 4.3T゜ N・to, os%, M, 416° Example 10: (s) -N-(4°-hydroxy-9°, 10°-dihydro Rho-9゛]0°-dioxo-1°-anthryl)-L-serine hydrazide was prepared from L-7phosphorus hydrazide in the same manner as in Example 1 above.

Example 11: (S) -N-(9°, 10°-dihydro-9°, 10°-di Oxo-1°-anthryl)-L-serine ethyl ester (Method A) This is , chemical formula (1), Y=Y1=R5=H.

1-chloroanthracene-9,10-dione (0.01 mol) was dissolved in dimethylsulfonate. It was dissolved in oxide (50 cm3) and heated to 95°C. Anhydrous potassium carbonate (0, 0.05 mol) and then added L-serine ethyl ester hydrochloride (0.03 mol). mol) was added and heating continued for 1 hour under nitrogen atmosphere. The crude product is the reaction mixture was precipitated by addition of water, collected by filtration, and air dried.

The residue was dissolved in toluene-ethyl acetate (9:1) and subjected to silica gel column chromatography. Raffy was eluted with the same solvent. Combine the fractions containing the product, Filtration and concentration gave a red residue, which was recrystallized from ethanol. The title compound was obtained as analytically pure crystals.

Yield 1! 24% m, p, 158℃ l-Hydroxyanthraquinone (5 g) was added to 2% hydroxyl at 80°C under a nitrogen atmosphere. Dissolved in an aqueous sodium chloride solution (500 cm3). Sodium dithionite ( 8g) was added and heating continued for an additional 45 minutes. Adding excess 5M hydrochloric acid , crude leuko 1-hydroxyanthraquinone was precipitated. Filter this precipitate and add water and dried in vacuo. The leuco derivative was treated with dimethylformamide (50 cm3) and heated at 95°C to L-serine ethyl ester hydrochloride (3,8 g) and potassium carbonate (5 g) for 1 hour. The reaction mixture was then heated to 25 It was aerated for 4 hours at °C and diluted with water (500 cm3). Extract with chloroform and concentrate Upon reduction, the title compound was obtained as a crude product. Here, work up The treatment was carried out in the same manner as in Example 11.

Yield 54% m, p, 158°C l1tlr: t4c[:67.26; H: 5.01; N: 4.13% , JILIL C: 67.35; H: 4.95; m: 3.95%, d, c, i, *Qzw-zhy m/z = 340 (M4 + 1), 40%), 310 (70%); 224 (100%, 210 ( 60%) Example 13: (S)-N-(4'-hydroxy-9', 10°- Dihydro-9°.

10°-dioxo-1'-anthryl)-L-phenylalanine methyl varnish This compound uses L-phenylalanine methyl ester (aldo Rich) was prepared in the same manner as in Example 1.

e, i, '*%x to 1f l-1v m/z = 401 (M”); 310 (100%) M-CH2Ph; 250 (90%) 1M-(CHqPh, t C00C)(,),’Hnmr, LI%P71-117 (200MHz)in cDcl, 63.28 (2H.

+n, CH:); 3.75 (3H, s, CHs); 4.6 (IH9 q, CH)', 6.9Fi (IH, d, H-2°); @7.1B (IH .

d, H-3'); 7j (5H, s, Pl+); AA"BB'"/7'? + / [δA7.68-7.84 (H-6°, H-7'); ■A8.27- D, O1, m, p, 204°C4 Example! 4: (S) -N-(4°, 8°-dihydroxy-9', 10° -dihydro-9',10'-dioxo-1°-anthryl)-L-serine This compound uses L-serine ethyl ester as a raw material and the chemical formula ( 4), Y=OH; Yl=H; R5=OH; B=B1=oxo and X=-NHC Performed using RIH-R2, where R1=CH20H and R2=COOEt Prepared similarly to Example 6.

d, c, i, electric! Lzrx7sv m/z = 372. (M” + I) .

'Hnmr RV-n-Iv (CDCI,: 270 MHz) δ: 1 ．． 29 (3H, 1, CHl); 2.5 rlH, s.

CH, O ratio a<dh, D:O); 4.10 (2) (, d, Cli:OH ): 4.25 r2H, q, C1i, CH,); 4. T5 (l H.

m, CH); 7.05 (IH, m, H-7°): 10.5 (IH, +n, NH); 7.12-7.4 (2H, +n, H|2', H- 5’); 14.3 (2H, 4”-OH, l+’-OH, Q+, and- , D:O).

mp, 220'C.

Example 15: (S)-N-(4',8°-dihydroxy-9',10'-di Hydro-9°,10°-dioxo-1'-anthryl)-L-serine hydrazi This compound was prepared from the ethyl ester of Example 14 according to the method of Example 9. Prepared from

Example 15 is based on the chemical formula (in which Y=OH; Y1=H; R5=OH ; B=B1=oxo and X=-NHCRIH-R2, where R1=CH20 H and R2=CONHNH2.

m, p, 276℃ i, r, < wql-11/ vl, l,, (ZV*-J cm” 3320.3 195 (NHNH,), 1642 (Co)・;t’r　F(rmn11 C: 57.14. H: 4.76, N: 11.76% (cnH+5o bNy): Aq&I&C: 57.15. H: 4.5T゜ N: 11.65%, M, 357. d, c, i, real+1~7I-1 m1z=358 (M-+ II Example 16: (S) -N-(4°-Hi Droxy-9',10°-dihydro-9°.

10°-dioxo-1'-anthryl)-L-valine methyl ester example 1 from L-valine methyl ester.

'Hnmr shyzrIv (CDCL,; 270 MHz) δ 1.05 (3H, tl, CH,): 1.15 (3H, d.

CH,) + 3.7 (OCt(,): 4.05 (IH, m, CH): 7.1 (2H14r”-’RjLito, H-2’, j(-3’); 7 ．． 5- 7.8 (2H, m, ) (-6', H-7°): 8.1-8.3 (2H , m, ) I-5', H-8°): 10.5 (IH, пA N) 11: 13.45 (l)1. s, 0H) 1 "Sto-7←-V I-, a, (K Brl, can” 1745 (COOMel, 16201 doo non)ei’+ 14. She °2I-w +n/z = 353 (M-).

A linear or nearly linear relationship was observed for all 6 cell lines.

(Margin below) Topoisomerase assay Drug inhibition assays were performed using purified human Placenta topo Violet and ■, and purified He1a cell topo! ■Carried out in Ta.

In all assays, 1 pg/ml to 50 pg/ml (approximately 3 pM -15077M) in a pH 7.5 buffer system. The cells were incubated with enzyme and DNA substrate for 30-45 minutes at ℃. The reaction is The samples were then run on a 1% agarose gel. The specimens were placed in a pot, stained with ethidium bromide, and photographed. decatenation In the annosei, the kinedoplast of C. fasiculatm (kDN^) DNA extracted from the sample is the substrate; in the relaxation assay , supercoiled plasmid RGY is the substrate. appropriate positive con Troll inhibitors were used: Doxorubicin for Tovo II decatenation , Topo II relaxation VM26, and Topo 1 relaxation can Ptothecin.

IC5 of newly synthesized anthracenyl-peptide against all 6 cell lines o and ICgo values are shown in Table 2. Generally this compound is doxorbucin with values in the μM range, giving 10-100 times less potency than there were. The compound of Example 10 shows hypersensitivity to DR-1()vo II inhibitors. , see Figure 1), but other compounds with activity were less effective. (See Figure 2). In general, compounds are non-chlorinated in the MDR model. It shows noncross resistance (see Figure 3). This may be related to the high 1/% lipophilicity of the compound.

The compound of Example 15 was found to be non-inhibitory in the ADR Go cell line (resistant line due to topo-reduction). Always effective, it is one with high topo-activity.

It has been proven that there is.

Example C: Tablet formulation The following formulations A and of each ingredient were granulated using a solution of povidone. and then adding magnesium stearate and compressing. .

(a) Active ingredient 250 250 (b) Lactose B, P, 210 26 (c) Povidone B, P, 15 9 (d) Sodium starch glycolate 20 12 (e) Magnesium stearate Mu 53(a) Active ingredient 250 250 (b) Lactose 150 - (c) Avicel PHIOI 60 26 (d) Povidone B, P, 15 9 (e) Sodium starch glycolate 20 12 (r) Magnesium stearate Mu 53 active ingredients 100 Lactose 200 Starch 50 Povidone 5 Magnesium stearate 4 The following formulations and E are prepared by direct compression of the mixed active ingredients. . The lactose used in the formulation is of the direct compression type.

Active ingredient 250 Pregelatinized starch NF15 150 Active ingredient 250 Lactose 150 Avicel 100 Formulation F (controlled release formulation) This formulation consists of wet granulation of the following ingredients (below) in a solution of povidone. prepared by adding magnesium stearate and compressing. It will be done.

mg/tablet (a) Active ingredient 500 (b) Hydroxypropyl methylcellulose 112 (4M premium ) (c) Lactose B, P, 53 (d) Povidone B, P, C, 2g (e) Magnesium stearate 7 Drug release occurs over a period of approximately 6-8 hours and is complete after 12 hours.

The capsule formulation is made by mixing the ingredients of the formulation in Example C above, Prepared by filling gelatin capsules. Formulation B was prepared similarly. Ru.

(a) Active ingredient 250 (b) Lactice B, P, 143 (c) Sodium starch glycolate 25 (d) Magnesium stearate 2 (A active ingredient 250 (b) Macrogol 4000BP 350 capsules are Macrogol 4000B P is melted, the active ingredient is dispersed in this melt, and the active ingredient is dispersed in 2 bart hard gelatin capsules. It is prepared by filling a bottle.

formulation Active ingredient 250 Lecithin 100 Binatsuura 100 Capsules have the active ingredients dispersed in lecithin and peanut oil, and contain soft gelatin. It is prepared by filling capsules with this dispersion.

Formulation E (controlled release capsule) The following controlled release capsule formulation consists of ingredients a, b, c using an extruder. By extruding and then forming the extruded material into a pellet and drying it, It is prepared as follows. The resulting dry pellets are then coated with a release control membrane (d). and fill into two-piece hard gelatin capsules.

mg/capsule (a) Active ingredient 250 (b) Microcrystalline cellulose 125 (c) Lactose B, P, 125 (d) Ethylcellulose 13 Make up to 10 ml with sterile, pyrogen-free phosphate buffer (pH 7.0). .

The active ingredient is almost dissolved in phosphate buffer (35-40°C), and the total amount is diluted to 10%. ml, filter with a sterile microporous filter, and transfer to a sterile 10 ml amber glass vial. Place in Al (type 1) and seal.

Example F: Myomuscular injection Agent ingredient 0.20g Benzyl alcohol O, 10g Glucoflor 75 1.45g On the injection side, make up to 3.00ml with water.

The active ingredient is dissolved in glucofluor. Benzyl alcohol is then added to dissolve the Dissolve and add water to make 3 ml. This mixture is then filtered through a sterile microporous filter. Strain, place in a sterile 3 ml glass vial (type 1), and seal.

Example G: Sironop Suspension Active ingredient 0.2500g Sorbitol solution 1.5000g Glycerol 2.0000g Dispersible cellulose 0.0750g Sodium benzoate o, 0050g Fragrance, Beach 17.42.3169 0.0125ml Purified water9. s, 5.0 Make it 000ml.

Dissolve sodium benzoate in a portion of purified water and add sorbitol solution.

Add active ingredient and bring to fractions. Thickener (dispersible cellulose) in glycerol ) to disperse. Mix the two dispersions and make up the required volume with purified water. moreover, The required thickening properties can be obtained by applying shear force to the suspension. be.

Active ingredient (63μm) *250 Hard fat, BP 1770 (Witepsol H15-Guinami Soto Novel) *The active ingredient is in powder form. where at least 90% of the particles have a diameter of 63 μm or less.

One-fifth of Wytepsole H15 is placed in a steam jacket pan at a maximum temperature of 45℃. and melted. Active ingredients are passed through a 200pm sieve for smooth dispersion Silverson with a cutting head until the object is obtained. on) to the molten base while mixing. Keep the mixture at 45°C. While holding, add the remaining Witepsol H15 to the suspension and stir to make a homogeneous mixture. Get a mixture. The entire suspension was passed through a 250 μm stainless steel screen and Cool to 40° C. with continuous stirring. At a temperature of 38°C to 40’C, 2.02 Place the mixture in g into a suitable plastic mold. The resulting upper side is cooled to room temperature do.

Active ingredient 250 Dextrose anhydrous 380 Potato starch 363 Magnesium stearate 7 The above components are mixed directly and the resulting mixture is compressed directly to form a pellet. The saree is prepared.

Example J: Dye 1.0 g of the compound of Example 1 was added to 100 ml of an aqueous ethanol solution (50% v/v). Dissolve in and apply to cotton fabric.

lane 1 kDNA standard: lane 2 and and 12 topo II + kDNA; lanes 6-8.1-50 μg/ml Example 10: Lane 9-11.1-50 gg/ml Example 9 Explanation of Figure 5: (Newly synthesized Toboidomerase by anthracenyl peptide! ■Intervening relaxation Suppression); Lane 1 Super Carp J Redo; Lane 2 Topo ■ Summer + Super Carp J Redo ; Lane 4-54-5V; Lane 6-8.1-50 μg/ml Example 1O; 9 il, 1 50. ug/m1 Example 9゜Explanation of Figure 6: (Newly synthesized Inhibition of toboidomerase 1-mediated relaxase by anthracenyl peptide system); lane l super filled; lane 2 topo 1 + super coiled; lane 4+5 Cambutocin; Lane 6-8゜1 50 μg/ml Example 1O; 9-11,1 50 pg/ml Example 9 FIGURE 1 FIGURE 2 Ren maybe ゛yoke↓zu°l・ Continuation of front page (51) Int, C1,' Identification symbol Internal reference number C07C237108 CO9B 1/26 7306-4H (81) Designated countries EP (AT, BE, CH, DE.

DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), 0A (BF, BJ, CF, CG, CI, CM, GA, GN, ML , MR, SN, TD.

TG), AT, AU, BB, BG, BR, CA, CH.

DE, DK, ES, FI, GB, HU, JP, KP, KR, LK, LU, M G, MN, MW, NL, No, PL, RO, RU, SD, SE, UA , U.S.I. (72) Inventor Mincher, David John United Kingdom EHIO5DT Nibbinburgh Collington Road 10 Department of Applied Chemical and Physical Sciences Napier University of Nibuinburgh (no address)

Claims (1)

[Claims] 1. Chemical formula (I) (I) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Here, Y and Y1 are each independently, hydrogen or hydroxyl, and B and B1 are each independently oxo or hydrogen , R5 is hydrogen or hydroxyl, and X is an amino acid residue or This amino acid residue is a derivative of the amino acid adjacent to the acid group. is bonded to the ring via a nitrogen atom, A compound represented by 2, X is represented by the group: -N(R1)H-C(H)-R2, where R1=CH 2C6H4OH, -CH3, or -CH2OH, and R2=-COOC2 H5, -COOCH3, or -CONHNH2, or a derivative thereof , a compound according to claim 1. 3, R1=-CH2OH, and R2=-CONHNH2, or a derivative thereof The compound according to claim 2, which is 4. The compound according to any one of claims 1 to 3, wherein B=B1=oxo. . 5. The compound according to any one of claims 1 to 4, wherein Y=Y1=H. 6. The compound according to any one of claims 1 to 5 and a pharmaceutically acceptable compound. A pharmaceutical preparation consisting of a carrier. 7. The compound according to any one of claims 1 to 5 for pharmaceutical use. 8. The method according to claims 1 to 5 in the production of a drug for treating cancer in humans or mammals. Use of a compound according to any one of the preceding clauses. 9. The compound according to any one of claims 1 to 5, a dye composition diluent, and a dye composition diluent. A dye composition comprising a carrier or a mordant. 10. A method for producing the compound according to any one of claims 1 to 5, comprising: (a) Leucoquinizarin or its 5'-OH, 8'-OH, 5',8'-(O H) 2 derivative and an amino acid or amino acid attached to the leucoquinizaline ring in one of the carbonyl groups. or a derivative thereof has an -NH2 group at the α-position of the carboxyl group. Oxidize the product obtained by reacting with an amino acid or its derivative ;or, (b) converting a certain compound represented by chemical formula (I) into another chemical compound represented by chemical formula (I); convert to compound, A method for producing a compound, comprising: 11. Chemical formula (III): (III) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Here, Y, Y1, R5 and X is the same as in claim 1, and E and E1 each independently represent hydrogen or hydroxy. A compound represented by