TWI278455B - Novel xanthone compounds, their preparation and use as medicament - Google Patents

Abstract

This invention relates to novel xanthone compounds, their preparation and use as medicament. More particularly this invention is directed to the isolation of the novel xanthone natural product sootepenseone from Dasymaschalon sootepense Craib, Annonaceae, its identification and derivatization, and the use of sootepenseone and its derivatives as anticancer agents.

Description

1278455 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed A7 B7 V. INSTRUCTIONS (1) Introduction The present invention relates to novel alpha ketone compounds, their methods of preparation, and the use of the drugs. In particular, the present invention relates to the novel natural product Sustin sne (s ο 〇tepense ο ne ), from the Dasymaschalon sootepense Craib, Annonaceae (the species of the genus Annona) Identification and derivation, and the use of sootepenseone and its derivatives as anticancer agents. Areas of invention Cancer is probably one of the most active anti-human factors in the world, and the entire scientific community is working hard to prevent and eradicate cancer. Novel agents with chemotherapeutic valence in combating cancer are clearly a highly important medical problem. However, the emergence of new drugs in the field of cancer is a difficult task because anticancer agents must kill or render tumor cells incapable, but they must not cause excessive damage to normal cells. In the current state of knowledge in the fields of cancer biology and medicinal chemistry, it is impossible to ensure that new types of molecules can be designed as effective antitumor agents. Although there has been considerable progress in cancer biology, molecular pharmacology, pharmacokinetics, medicinal chemistry, and related fields, the knowledge sought is still unclear. In recent decades, the concept of chemotherapy for malignant diseases has reached the forefront, and scientists around the world have done in-depth research on the use of botanical ingredients and their derivatives as novel anti-tumor inhibitors. An example of an important anticancer agent from plants is the alkaloid vinblastine (this paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). -4- I---------- -------Book---------Line (please read the note on the back and fill out this page) 1278455 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (2 ) vinbla stine) and Changchun new test (vincristine), both of which are separated from Changchun. A description of natural products as anticancer agents can be found in Shradha Sinha and Audha Jain, "Progress in Drug Research, Vol. 42, pages 53-132 (1 994) Basel (Switzerland) o General Description of the Invention The present invention provides Novel cytotoxic a-ketone compound R1 represented by formula (I)

Or a tautomer thereof, a mirror image isomer, a stereoisomer or a physiologically acceptable salt or solvate or a mixture thereof, wherein R1 is a hydrogen atom; methyl (-CH3), C2-C6 alkane Base residue, formazan group (a CHO); acetamyl residue (a C〇CH3), -C〇一C2-6 yard base, C〇一C3-8 ring yard base, a c〇一C6 - 18-square or -C〇-C7-24 square-based residue, each of which has one or more substituents selected from the group consisting of: one H, one SH, the paper scale applicable to the Chinese National Standard (CNS) A4 size (210 X 297 mm) -5- I-------!!^^装|__|订·-------^线 (please read the notes on the back and fill in this Page) 1278455 A7 B7 V. INSTRUCTIONS (3) Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives - N Η 2 - NHC 1 - 6 yard base - Ν (C 1 - 6 yard base) 2 > — N Η c 6 -1 4 aryl, —Ν (C 6 - i 4 aryl) 2, —N ( c 1 -6 alkyl) (C 6 — 14 4 aryl), _ -Ν HC 〇R — N 〇 2 — CN, —(C〇) R 3 , —( CS ) R 4 — F , — c 1 , —B r , —I — —0 — C 1 - 6 alkane , - 〇 - c 6 - 1 4 aryl, mono-(C 0 ) R '; -S-C alkyl> - s - C 6 - 1 4 aryl, - S 〇 R 6 , and S 〇 2 R wherein R 2 to R 7 each independently represent a hydrogen atom, a C 1 -6 yard, - 〇 - C 1 - 6 alkyl, - 0 - 6 - 1 4 aryl ' - Ν Η 2, N Η C 1 - 6 alkyl, one N (C 1 - 6 alkyl) 2 Λ - N Η C 6 - 1 4 aryl, one N (C 6 - 1 4 square) 2 ' - N ( C 1 —e ; alkyl” (C 6 - • 1 4 aryl), -s - c 1 - group, — S — c 6-14; aryl residue y -coo- _ C 1 - 6 It has one or more substituents selected from the group consisting of: 〇Η, —S Η — —NHC 1 -6 alkyl, —N(Ci-6)yl 2, —N Η c 6 - 1 4 aryl, -N ( c 6 -1 4 aryl) 2 ^ — N ( c 1 -6 alkyl) (C 6 - 1 4 aryl), _ -Ν HC 〇R - N 〇 2 > — C Ν , —(C〇) R 9, —( CS ) R 1 0 — F > — c 1 , Β r , —I Λ —0 — C 1 - 6 alkyl, —〇— c 6 ... 1 4 aryl, one 〇 (C 〇) R 1 1, s - C 1 - 6, a s-C 6 - 1 4 : aryl; a group, a S 〇 R 1 2 and - S 〇 2 . R 1 3 , wherein R 8 to R 13 each independently represent a hydrogen atom Λ C 1 - - 6 alkyl, mono-C 1 e ; alkyl, mono-C 6 - 1 4 : aryl: -NH2, - NHCi - 6 alkyl, -N (Ci - 6 alkyl 2) The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) _ 6 - I----------•装--------Book (please first Read the notes on the back and fill out this page)

1278455 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Invention description (4) —NHC6 - 14 square base, —N (C6-14 square base) 2, —N (Cl-6 yard base) (C6 — 14 aryl), —S — Cl-6, a S—C 6-14 aryl residue; a C 〇 NR 14 R 15 residue, wherein R 14 and R 15 each independently represent a hydrogen atom, —C i — 6 alkyl, 〇C 1 -6 alkyl, 〇-C6 -14 aryl, one NH2, one NHCl-6, -N (Cl-6), 2, N HC6-14 aryl, -N (C6-14 aryl) 2, —N(Cl-6 alkyl)(C6-14 aryl), an S-Cl-6 substituent, an S-C6-14 aryl residue; or selected from The following balanced cations: alkali or alkaline earth metals, such as Li, Na, K, Ca, Mg, NR16R17R18R19 ( + ), wherein R16 to R19 each independently represent a hydrogen atom or a Cl - c6 substituent; R2 and R3 A part of the C 17 = C 18 double bond is formed or each is hydrogen. In the case where the aforementioned compound of formula I forms a phenate with a di- or polyvalent equilibrium cation, the remaining positive charge can be combined with a physiologically acceptable anion such as C 1 - or 〇Η. To be compensated. A novel compound of the formula I wherein R1 is a hydrogen atom and R2 and R3 form part of a C17-C18 double bond is designated as sootepenseone (1)0 Another system of the invention Provided is a method for the preparation of a compound of formula I which is isolated from the leaves of a Susten paper by the leaves of Dasymaschalon sootepenseone Craib, Annonaceae (Approx sinensis) for the Chinese National Standard (CNS) A4 Specifications (210 X 297 mm) I------------------ Order i 丨! ! _ line (please read the note on the back and fill out this page) 1278455 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed A7 B7 V. Description of the Invention (5) Sootepenseone and subsequent derivatization of the compound Come on. The invention also provides the use of a compound of formula (I) as a medicament, especially for the treatment of cancer. The invention also provides a pharmaceutical composition comprising an effective amount of a compound of formula (I) for use in treating a subject in need thereof. Herein, an effective amount of the compound of the formula (I) is defined as: inhibiting the growth of a tumor cell, killing a malignant cell, reducing the volume or size of the tumor, or self-treatment after administration to the patient. The amount of the compound that completely removes the tumor in the patient. Thus, by using a pharmaceutically acceptable carrier, the substantially pure compound of the present invention can be formulated into a dosage form for administration to a patient in need of oncolytic treatment by oral, topical or parenteral administration. In a preferred system, the patient is a mammal, especially a human. The effective amount administered to a patient will generally depend on the surface area of the body, the weight of the patient, and the condition of the patient. Interrelationships between doses for animals or humans (based on mg/m2 (body surface area)) are described in FI. Elreich, E.J. et al., Cancer Chemother. Rep., 50(4) 219 (1966). The body surface area can be roughly determined by the patient's height and weight (see, for example, ' Scientific Tables, Geigy Pharmaceuticals, Ardly, N.Y. pages 537-538 (1 970)). The preferred dosage level will also depend on the attending physician's assessment of the nature of the particular cancer condition of the patient and the overall physical state of the patient. The effective antitumor dose of the ketone compound of the present invention is between 1 // g/kg (patient weight) to about 5,000 // g/kg ' — I----^---- --·装--------Book---------Line· (Please read the note on the back and fill out this page) This paper scale applies to China National Standard (CNS) A4 specification ( 210 X 297 mm) _ 8 - A7 B7 1278455 V. INSTRUCTIONS (6) The better is between 2 // g and about 1 0 0 0 // g/kg (patient weight). As known to those skilled in the art, the effective dose will also be used with the route of administration, the use of excipients, and the presence or absence of other treatments (including the use of other antineoplastic agents and radiation therapy). The pharmaceutical composition of the present invention can be administered intravenously, intramuscularly, intracutaneously, subcutaneously, intraperitoneally or topically in the form of microlipids. Examples of dosage forms include aqueous solutions of the active ingredient in isotonic saline, 5% glucosamine, and other known pharmaceutically acceptable liquid carriers. Other solubilizing agents known to those skilled in the art can be used as pharmaceutical excipients for the delivery of active agents. Additionally, the compounds of the present invention may also be chemically modified to increase water solubility, e.g., by the formation of pharmaceutically acceptable phenates. The compounds of the present invention can also be formulated into dosage forms for other routes of administration by known methods. The pharmaceutical composition can be formulated, for example, as a capsule, gel seal or tablet for oral administration. The capsule may comprise any known pharmaceutically acceptable material, such as a gelatin or cellulose derivative. The tablets may be formulated according to conventional procedures, i.e., a mixture of a compressed active agent with a solid carrier and a lubricant known to those skilled in the art. Examples of solid carriers include starch, sugar, and bentonite. The compounds of the present invention may also be administered as a hard outer layer of a tablet or sachet containing, for example, lactose or mannitol (as a binding agent) as well as conventional elixirs and tablets. The Chinese National Standard (CNS) A4 specification (210 X 297 mm) is applied to the paper scales used in the treatment of animals. "Isolation" ("Efficient" or "Effective Dose") I---------- Loading -------- order --------- line (please read the note on the back and then fill out this page) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing -9 - 1278455 A7 B7 five , invention description (7) (please read the note on the back and then fill out this page) The term in this article refers to the amount of alkaloid that inhibits the growth of cancer in animals but does not cause intolerable toxicity after administration to animals. The effective amount will vary depending on the mode of administration, the schedule of administration, the type of tumor, and other related factors, and such factors may be varied without departing from the scope or practice of the invention. In general, the effective dose is in the range of about 0 001 to 100 〇 mg/kg (body weight) per day. The terms "cancer" or "tumor" as used herein include (but are not limited to the following) Adrenal cancer, glioblastoma (and other brain tumors), breast cancer, uterine cancer, colorectal cancer, endometrial cancer, stomach cancer, liver cancer, lung cancer (small cells and non-small cells), lymphoma ( Including non-malignant granuloma, Burkitt's, diffuse large cells, hair follicles and diffuse malignant granuloma), melanoma (metastatic), neuroblastoma, osteosarcoma, ovarian tumor, retinoblastoma , soft tissue sarcoma, sputum and other tumors that respond to chemotherapy. Other objects and advantages of the invention will be readily apparent from the description. The Ministry of Economic Affairs, Intellectual Property Office, Employees' Consumer Cooperatives, Printing Inventions, and the compounds of the present invention shown in the formula (I) have a five-ring alpha ketone ring system (the paradox can be found in: Sultanbawa, MUS, Xanthonoids of tropical plants, Tetrahedron 36 (1 980) 1456- 1 506 ). The following published natural compounds have a similar ring system: Gaboric acid (2), isolated from Garcinia hanburyi (this paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) - 10 - 1278455 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed A7 _ B7__ V. Description of Invention (8) See Amorosa, M. et al., Ann. Chim. (Rome), 1 966, 56, 232; Ahmad, AS et al., J. Chem. Soc. (C), 1 966,772 (Structure); Arnone, A. et al., Tetr· Lett, 1967, 4201 (pmr data, structure)); Lan Ruilin (morellin) (3), single out of Garcinia morella (see: Rao, BS, J. Chem. Soc, 1 937, 853 (single); Kartha, G· et al., Tetr Lett. 1963, 459 (crystal structure. structure); Nair, PM et al., India J. Chem., 1 964, 2, 402 (structure)); Hanburin (4), from Garcinia Single departure (see: Asano, J. et al, Phytochemistry, 1 996, 41, 815 (individual, uv, ir, pmr, cmr data) and fobesone (forbesione) (5), from broadleaf Garcinia (Garci Nia forbesii) is isolated (see: Yu an - W ahe ong, Leslie J. Harrison, Graham J. Bennett and Hugh T.-W. Tan, J. Chem. Research (S) 1 996, 392-393). These compounds have isoprene side chains at the C-5 position and also have hydrogen bonded to the phenolphthalein group. Both momerin (3) and gebraric acid (2) have a terpene ring. System. All compounds (2) to (5) have a bicyclo[2 · 2 · 2] octene carbon structure fused to the 2,2-dimethyl-tetrahydrofuran ring system. However, the formula of the present invention In contrast to the compounds of the invention, the compounds are significantly different in structure from the compounds of the invention: 1) in (3), the C-pentadiene side chain is oxidized to an aldehyde, and in (2) , the C 5-pentadiene side chain is oxidized to a carboxylic acid; 2) the fused dihydrofuran ring at the 3,4 position does not appear in (4) 'or, as in (3), instead , piperonone appears in the 3,4 position; this paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -11 - ----------- Pack--- -----Order---------Line (please read first Note on the back page again) 1278455 A7 _____B7 _ V. INSTRUCTIONS (9) 3) As in (3) and (5), the ring system is in the c-5 position and is further isoprene Replaced by side chains. In contrast, the compound of the present invention contains a dihydrofuran ring which is completely substituted except for carbon 2, which is fused to the modified π-ketone ring. Regarding the taxonomy of Dasymaschalon sootepense Craib, see V.H. Heyhood, "Flowering Plants of the World", University Press, Oxford, 1 97 8 o Surprisingly, the compounds of the present invention exhibit significant antitumor activity. Furthermore, the compounds of the invention are less toxic. Therefore, the β-ketone compound of the present invention is novel and progressive. The structures of compounds (2) to (5) are shown below: (Please read the notes on the back and fill out this page.) Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperatives Printed -12- This paper scale applies to China National Standards (CNS) A4 size (210 X 297 mm) 1278455 A7 B7 V. Description of invention (10)

Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperative, printing

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-----------•装---------Book---------Line· (Please read the notes on the back and fill in this page) Paper size Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 13· 1278455 A7 ________B7 V. Invention description (11)

Suter Testosterone Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperative Printed Example 1 From Dasymaschalon sootepense Single Sootpenseone (1 »VR-3016, D~25637) Plant material is based on 1 9 9 The winners were collected in Doitung in the province of Chiangrai in northern Thailand in January and January. The leaves of the plant were air-dried for three days under the sun (about 3 〇 - 3 5 〇c ) and stored in a bag. The dried powdery leaves of D. sootepense were extracted continuously with ancestors (110 liters), chloroform (107 liters) and methanol (igQ liters) to obtain 2 〇 4 · 2 mg, 192 · 7 mg and 1187 · 〇 mg respectively. Crude extract. The crude methanol extract is further partitioned into ethyl acetate (12 liters) of water (4 · 35 liters) and n-butanol (10 liters) of water (10 liters) to obtain 1 0 respectively. 3 · 6 mg of ethyl acetate extract, 3 8 8 · 7 mg of n-butanol extract and 4 0 1 · 8 mg of water extract. The ethyl acetate extract (100 mg) was subjected to silica gel chromatography ((Please read the back note first and then fill out this page). This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). -14- 1278455 A7 B7 V. INSTRUCTIONS (12) (Please read the notes on the back and fill out this page)

Merck No.: 7 7 3 4,1 · 6 2 kg of sand, the extract was premixed with 18 μg of tannin), eluted with a mixture of hexane-ethyl acetate and ethyl acetate-methanol. . The fractions (each 300) were combined on the basis of T L C to produce a total of 19 fractions (F i to F i 9 ). The fractions F 7 (1·10 g) and F8 (〇·84 mg) eluted with 7-8 % ethyl acetate-hexane were chromatographed again, using hexane-ethyl acetate as solvent. The fractions were washed with EtOAc (EtOAc) elute A methanol is recrystallized to obtain VR - 3 0 1 6 (0.23 3 3 mg). The mother liquor was purified by HPLC (dichloromethane), followed by recrystallization in the same solvent to obtain a further V 1 - 3 0 16 g of 0 1 1 0 3 g. These compounds have been identified and identified as novel and altered "Mosquito derivatives, based on spectral data and single crystal X-ray diffraction analysis, which was named Soutopesone (Sootepenseone) 1 ° Ministry of Economics The property bureau employee consumption cooperative printed the materialized data of sootepenseone (1): m . p . 1 9 2 - 1 9 3 °C [a] 28D- 8·00, 〇 = 0·075 ( In CHC 1 3) Elemental analysis: measured 値: C, 7 2 · 3 2 ; Η, 6 · 8 9 C28H32 〇 6 Theory 値: C, 72 · 39 ; Η, 6.94 IR ^ λ max CHClscm-1: 3560 ^ This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1278455 A7 B7 V. Invention description (13) 3033, 3011, 2980, 2932' 1740' 1638, 159 0, 1470, 1428 ' 1382 UV ^ λ ma XE t Ο Η nm ( 1 0 ge): 2 13 (3.06), 263 (2.18) J 3 2 6 ( sh ) (2.66), 355 (2.74) Mass Spectrum: m/z (7〇eV ) 464 (2%) '436 (10 0), 421 (45) >367 (17) '339 (60), 297 (40), 28l (8) '241 (7), 215 (28), 69 (9 0)° NMR assignments : 1 H and 1 c NMR ( 300 400MHz, CDC13): See Table 1° Sootepenseone (1) Junction j scoop^丨Biochemical _ Analysis of spectral data by Sootepenseone', ie IR spectrum, UV spectrum , mass spectrometry, and especially 1 Η NMR spectroscopy and 1 3 C NMR spectroscopy, reveal which compound it is. I----------·装--------Book--------Line· (Please read the notes on the back and fill out this page) Ministry of Economic Affairs Intellectual Property Bureau The employee consumption cooperative printed this paper scale applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1278455 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (14) Table 1 1 H — η · m · r · data of ketone (sootepenseone) ( 1 ) (5 units, multiplicity) Proton and 値 値 片 片 片 (1) Long-range correlation (related C-atoms) C2-H 6.05(s) Cl,C4,C9a C7-H 3.42(dd) C6, C8a,C5*,C2” C8-H 7.50(d) C4b,C6, C7 CT-H 1.40(d) C2,,C3, C2 , -H 4.40(q) C4,-H 1.18(s) C2,,C3,,C4' C5,-H 1.60(s) C2,,C3,,C4' C1,,-CH2 2.27(dd) ci, , -ch2 1.37(dd) C2,,-H 2.45(d) C4b,C8a, Cl",C3" C4,,-H 1.28(s) C2",C3" C5,,-H 1.73(s) C2" , C3" cr, -CH2 2.58(bd) C4b, C5, C3"', C4", ci,,, -ch2 2.50(dd) C4b C2,,,-H 4.40(m) C4",-H 1.37( Dd) C2", , C3,,, C5,,,-H 1.10(dd) C2,",C3,,,C1-0H 13.10(s) Cl,C2, C9a : Suggested connection (please read the notes on the back and fill in again) This page applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). -17- Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 1274845 A7 _B7____ V. Invention Description (15) Table 2 Suter Films 13C — η · m .r . of sootepenseone ( 1 ) data (5 units, multiplicity) C-atom and sulphate (1) C1 166.2(s) C2 92.6(s) C3 168.5(s) C4 113.6(d) C4a 156.0(s) C4b 90.9(s) C5 84.6(s) C6 203.6(s) C7 47.1(d) C8 134.1(d) C8a 133.7(s) C9 178.9(s) C9a 101.4(s) cr 13.5(q) C2' 91.0(d) C3, 43.2(s) C4' 21.0 (4) C5, 23.9(d) Cl" 26.0(t) C2" 49.6(d) C3" 82.9(s) C4 28.9(d) C5" 30.7(q) Cl," 29.0(t) C2,,, 117.8(d) C3," 135.3(s) C4,,, 25.5(q) C5,,,, 16.9( a) (Please read the notes on the back and fill out this page) — II I Book - III II II . Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) -18- 1278455 A7 B7 V. Description of invention (16) Related stereochemistry Sotepenseone (1) has been borrowed 4 It is determined by single crystal X-ray diffraction analysis. Therefore, its absolute configuration is the stereochemistry shown below.

〇 0H

Or its corresponding image isomerized form. The relative stereochemistry of the aforementioned sootepenseone (1) is also applicable to sootepenseone derivatives conforming to formula (I), but not included in the selected reaction repairs, in C - 5, C - 7, C - 1 〇 a, C - 1 2 and C - 2 2 One or more derivatives that are inverted or racemized at the center of the palm. Preparation of derivatives of sootepenseone (please read the notes on the back and fill out this page) Ministry of Economic Affairs Intellectual Property Office Staff Cooperatives Printed on this paper scale Applicable to China National Standard (CNS) A4 Specification (210 X 297 mm) -19- 1278455 A7 B7 V. Description of invention (Table 3

Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives Printed Compound No. R1 R2 R3 1 (Suite Testosterone) Η R2 and R3 form part of the C17-C18 double bond 6 Acetyl group Same as above 7 Pharmaceutically acceptable counterion * Same as above 8 C2-C2. The base of the orthopedic group is the same as that of the above 9 methyl group and the above 10 C2-C20 alkyl group. The same as the above 11 benzhydryl group. The same as above, the benzyl group substituted by hydrazine or -OCH3 is the same as the above 13 Η Η Η * For the phenol anion, Suitable equilibrium cations are 'for example, N a + , K+, l/2Mg++, l/2Ca++, HN(Ci-6 alkyl)3+. This paper size applies to the Chinese National Standard (CNS) A4 specification (210 297 297 mm) -20 - (Please read the notes on the back and fill in this page) ▼ Install! I!定-!! · 1278455 A7 _B7__ V. INSTRUCTIONS (18) Preparation of compounds 6 to 13 can be used as a starting material for sootepenseone (1). Know the organic chemical standard derivative program (please read the precautions on the back and fill out this page). Example 2 Preparation of 1 - oxime acetophenone (sootepenseone ) ( 6 ) 1 mg of sootepenseone (1 ) at 1 m «water at room temperature The solution formed by acetic anhydride was stirred for 1 hour. The solvent was evaporated in a water bath under reduced pressure. Yield: 1 m g of crude residue (6.). For example, the salt of sootepenseone (7) can be obtained according to Houben-Weyl, Methoden der Organischen Chemie (methods in organic chemistry), 4th edition, 1963, volume 6 /2, "Sauerstoffverbindungen I (oxygen compounds I), part 2", pages 3 5 ff methods and reagents, prepared. Thus, for example, one equivalent of the appropriate base can be reacted with one equivalent of sootepenseone in a suitable solvent, and then the solvent is distilled off or the precipitated salt (7) is filtered off. Suitable bases, for example, may be selected from alkali metal or alkaline earth metal hydroxides or organic amines. 0H - methylation of the group (compound 9) by means of Mustafa;

Hishmat; JOCEAH; J.〇rg. Chem·; 22; 1 957; 1 644, 1646 A similar method, starting with sootepenseone (1) and double gas hospital Come in. -21 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1274845 A7 ____B7___ V. Invention Description (19) 〇Η —Base Group (Compounds 6, 8, 11 and 12) can be used as a starting material by Sootepenseone (1), by using Houben-Weyl, Methoden der Organischen Chemie (methods in organic chemistry), 4th Edition, 1 985, volume E5, "Carbonsauren und Carbons aure-Derivate (carboxylic acids and their derivatives), pages 691 ff, which are similar methods and reagents. The alkyl group of the Η-group at the C-1 position (Compound 1 可以) can be used as a starting material by sootepenseone (1), by a procedure similar to standard procedures and using, for example, Houben- Weyl, Methoden der Organischen Chemie (methods in organic chemistry), 4th edition, volume VI/3, "Sauerstoffverbindungen (oxygen compounds), part 3", Gerog Thieme Verlag Stuttgart, 1965, pages 49 ff standard reagents, for . Hydrogenation of an isopentenyl C 1 7 -C 1 8 double bond bonded to a C 1 7 -C 1 7 single bond (wherein R 2 and R 3 in formula (I) are each a hydrogen atom; 3) According to, for example, Houben-Weyl, Methoden der Organischen Chemie (methods in organic chemistry), 4th edition, volume IV/lc, "Reduktion (reduction), part I", Georg Thieme Verlag Stuttgart, 1981, pages 15 ff The standard procedure described is carried out. Biological activity: The compounds of the invention are less toxic than standard compounds (see Table 1). The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -22 - I--------- --•装--------Book·-------Line· (Please read the notes on the back and fill out this page) 1278455 A7 B7 V. Invention Description (20). On the other hand, in the hollow fiber test, compared with the standard compound, Sotepenseone ( 1 ; D — 2 5 6 3 7 ) (please read the notes on the back and fill out this page) The activity is higher (see Table 3). Table 1: Sootepenseone (D - 2 5 6 3 7 ) Compound LD50 (mg/kg ip·mouse) Sutertzone (1; D-25637) >100 Actinomycin D ( Actinomycin D) about 1 vinblastine about 6 adriamycin (Adriamycin) about 40 bleomycin (B1 e 〇myci η) about 80 i · P · through the intraperitoneal results to discuss the toxicity of sootepenseone (sootepenseone) Actinomycin D is at least 100 times lower, and longer spring alkali is about 16 times lower, and 60% and 20% lower than doxorubicin and bleomycin, respectively. Printed by the Consumer Intellectual Property Office of the Ministry of Economic Affairs. 2 · In vitro anti-tumor activity (XTT proliferation/cytotoxicity test) This XTT analysis is based on DA·Scudiero et al., Cancer Res. 48 (September 1, 1988), ρρ· 4827-4833 The above is done. The results of this test were doses which inhibited 5 〇 % growth (growth relative to the control group) 45 hours after administration of the test substance. The dose nucleus thus obtained is referred to as ED 5 0, and ED 5 0 値 < 3 0 # g / mT is regarded as -23- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 gong) PCT) 1278455 A7 B7 V. Description of invention (21) Active. The smaller the E D 5 0 値 of the test substance, the higher the activity. The activity of sootepenseone (1) obtained in Example 1 is shown in Table 2 below. (Please read the notes on the back and fill out this page.) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed -24- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1278455 A7 B7 V. Illustrative Note (22) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives Printed Table 2 Compound Cell Line ED 50 β g/ml Sutt-Bothone (1; D-25637) KB 1.74 L1210 1.74 SK-OV-3 1.74 LNCAP 1.74 Actinomycin D KB 0.17 L1210 0.17 SK-OV-3 1.74 LNCAP 0.17 Doxorubicin KB 0.17 L1210 0.017 SK-OV-3 0.17 LNCAP 0.17 Bleomycin KB 0.17 L1210 0.017 SK-OV-3 0.17 LNCAP 0.17 Vinblastine KB 0.17 L1210 0.017 SK-OV-3 0.17 LNCAP 0.17 KB : Epidermal cancer of the oral cavity I----------•装--------订---------Line· (Please read the notes on the back and fill out this page.) This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). 1278455 A7 B7 V. Invention Description (Μ) L 1 2 1 0 : Mouse Lymph Leukemia LNCA Ρ : Lymphoma metastasis of prostate cancer SK — 0V — 3 : Human ovarian cancer MCF - 7: Human Breast Cancer Results Discussion = D - 2 5 6 3 7 has significant anticancer activity for all tested swollen cell lines. 3 · In vivo antitumor activity of sootepenseone (D - 2 5 6 3 7 ) (hollow fiber analysis) This hollow fiber analysis is based on 1\^1丨11 (1&0.11〇11丨1125 }^3 (16131· was carried out as described in Life Sciences, Vol. 57, No. 2, ρρ·131-141, 1995. The results are shown in Table 3. (Please read the notes on the back and fill out this page) | Installation -------- Order --------- Line. Ministry of Economic Affairs Intellectual Property Bureau employees consumption cooperatives printed this paper scale applies China National Standard (CNS) A4 specifications (210 X 297 mm) 1278455 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Description of invention (2f) Table 3 Compound dose (mg/kg) Site inhibition rate (cell line) KB MCF-7 Sutertzone (l; D -25637) 4 X 10 ipsc 49 41 actinomycin D 4x0.1 ipsc 40 -150 doxorubicin 4x4 ipsc 52 41 bleomycin 4x8 ipsc 53 -67 berberine 4 x 0.65 ipsc 13 -165 KB : oral Epidermal carcinoma MCF-7: human breast cancer s · c·: subcutaneous 1.ρ.: intraperitoneal results discussion: compared to vinblastine (13%) and actinomycin D (4 0 % ), D - 2 5 6 3 7 has a higher activity against Κ Β tumors (49% inhibition rate), and is almost equivalent to the activity of bleomycin (53%). In addition, it is against MCF-7. In terms of cell line function, D - 2 5 6 3 7 showed as strong anticancer activity as doxorubicin (41%), however, actinomycin D, bleomycin and vinblastine increased tumors. Growth (negative inhibition rate 値 indicates increased cell growth (control against untreated control)). This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) ------- ---- 参装·-------Book---------Line· (Please read the notes on the back and fill out this page) 1278455 A7 B7 \—/ 2jr ✓IV I ® 嫔 发 经济 经济 智慧 智慧 员工 员工 员工 员工 员工 ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I ...................1.............................. ................... n-butanol extract 388.7g 丨松1 thief _ | 1............... ................................. Ethyl acetate extract 103.6g丨[13 o)9z inch ε·0ω*5ε-ο:Λ . ^—-----"^装--------订- -------- line (please first Read the notes on the back and fill out this page.) This paper size applies to the Chinese National Standard (CNS) A4 specification (210 297 297 mm).

Claims (1)

Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Printed 1278455 A8 Patent Application No. 89 1 1 2905 Replacement of Chinese Patent Application Range December 26, 1992 Correction of Compounds of Formula I R1, 0 Wherein R 1 is a hydrogen atom; R 2 and R 3 form a part of a C 1 7 di C 1 8 double bond, or a tautomer, a mirror image isomer, a stereoisomer or a physiologically acceptable salt or Solvates or mixtures of them. 2. A method of preparing a compound of formula I as claimed in claim 1 which comprises the steps of: a) continuously extracting Dasymaschalon sootepenseone Craib, an Annonaceae (an allergen) according to an increasing order of polarity The leaves of the genus Annona sinensis, b) the most polar organic extract is dissolved in a mixture of water and a slightly miscible polar organic solvent, c) chromatographically extracted organically with a suitable solvent For the pure image paper scale, apply the Chinese National Standard (CNS) A4 specification (210 X 29<7 mm) (please read the notes on the back and fill out this page) 1278455 A8 B8 C8 D8 VI. Scope of application for patents, d) Optionally, step c) is repeated for fractions containing souteresone (so〇tepenseone), and e) optionally, using crystallization Purification, f) optionally, with at least one equivalent of a suitable inorganic or organic test, is carried out by a method known per se to give the corresponding salt. 3. A compound of the formula I as claimed in claim 1 for use as a medicament. 4. A compound of the formula I as claimed in claim 1 which is used as an anticancer agent. A medicament for treating cancer in humans or animals # a ′′ which contains at least one compound of the formula I as in claim 1 of the patent application, a physiologically acceptable carrier, diluent and _ necessary or shaped 6 • A compound of formula I, in claim 1 of the patent application, for the manufacture of a medicament for the treatment of a human or animal disease. 7 · If you do not combine the formula 1 of the patent application, make a drug for the treatment of cancer. Agent. It is used in the department of the Ministry of Economic Affairs, the Intellectual Property Bureau, the employee consumption cooperative, the printing standard, the country, the country I, the I, the rule, the I, the paper, the I, the public, the 7 9 2 (please read the notes on the back first) Fill in this page)