KR810000494B1 - Method for preparing oxazolidine dione derivatives of vinca alkaloids - Google Patents

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Description

Method for preparing oxazolidine dione derivatives of vinca alkaloids

The present invention relates to a method for preparing spirooxa zolidinedione, the following structural formula (I) effective as an anticancer agent.

In the above structure,

R ² is H, CH ₃ or CHO

Each of R ³ and R ⁴ , independently, is H or OH, the other is C ₂ H ₅ and R ⁵ is H, or

R ⁴ and R ⁵ join together to form an epoxide ring and R ³ is C ₂ H ₅

이다.R ⁶ is OH or

to be.

The compound of formula (I) is prepared by reacting indole dihydroindole dione dimer of the following formula (II) with dimethyl carbonate in the presence of sodium hydride.

In the above structural formula,

R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as described above.

＂C ₁ -C ₄ alkyl＂ contains alkyl groups such as methyl, ethyl, n-propyl, isobutyl, n-butyl, isopropyl, sec-butyl and t-butyl, and ＂C ₃ -C ₄ alkenyl ＂Contains allyl, metalyl and crotyl. Several naturally occurring alkaloids from Vinca rosea have been found to be effective in the treatment of malignant tumors in animals. Among these, lyo rosin (US Patent No. 3,370,057), vinca rioblastine (Vinblastin, US Patent No. 3,097,137) to be referred to as VLB, uripomin (Belgium Patent 811,110), and urirogine (bin) Rojidine), and Riuro Christine (Vin Christine) (all in US Patent Nos. 3,205,220), Deoxy VLB VIIA and VIIB, Tetraheadone Letters, 783 (1958), 4-desacetoxy vinblastine (US Pat. No. 3,954,773), 4-Desacetoxy-3 -'- hydroxyvinblastine (US Pat. No. 3,944,554), Riocolombin (US Pat. No. 3,890,325), and Vincardioline (US Pat. 3,887,565). Of these alkaloids, VLB and vincristine are currently marketed as therapeutic agents for malignancies, particularly leukemia and related diseases in the human body. Vincristine is more active and effective in the treatment of leukemia, but also lacks the antitumor alkaloids of Vinca Rosea. Such alkaloids are usually administered intravenously.

The chemical alteration of vinca alkaloids is limited.

First, its molecular structure is so complex that it is difficult to carry out chemical reactions that affect special functional groups in a molecule without altering other groups.

Second, alkaloids without the desired characteristics of the desired chemotherapy were recovered or produced in vinca rosea ash or alkaloids. Therefore, we have concluded that this compound is closely related to active hakaloids. Antitumor activity seems to be limited to very specific structures and there is a rare chance of altering the structure to obtain more active agents. Among the alkaloids, the group was successfully modified to obtain a physiologically active compound by dihydro VLB preparation (US Pat. Or unsubstituted acyl groups (US Pat. No. 3,392,173), some derivatives of which can sustain long life for mice inoculated with P 1534 leukemia.

Derivatives in which the C-4 acetyl group of the VLB is substituted with the chloroacetyl group are useful as derivatives of the VLB compound preparation in which the C-4 acetyl group of the VLB is also structurally changed to the N, N-dialkylglycyl group.

(US Pat. No. 3,387,001), C-3 carboxamide derivatives of VLB, vincristine, empty cardioline, and the like, were also prepared and found to be active as anticancer agents (Belgium Patent No. 813,168). This compound is a very interesting compound. This is because the activity of Ridgeway osteosarcoma and Gardner lympharcoma is greater than that of VBL induced by 3-carboxamide of VLB. Some amide derivatives actually have activity similar to that of vincristine against cancer. One such amide, 4-desacetyl VLB C-3 carboxamide or bindecine, has recently been clinically tested in humans and found to be active in some leukemias. In the human body, bindesin is less neurotoxic than vinklestin.

One of the most important medical problems is the treatment of new tissue diseases in the human body. This includes a variety of diseases and has considerable specificity for compounds that are active against other diseases. Small modifications to the structure of the present compounds can simultaneously affect specificity and activity. These novel vinca derivatives are very welcome for chemotherapy researchers looking for new ways to treat neoplastic diseases.

The compound of formula (I) is a VLB derivative wherein R ⁶ is acetoxy, R ² is methyl, R ³ is hydroxy, R ⁴ is ethyl, R ⁵ is H, R ⁶ is acetoxy, R ² is formyl, R ³ is hydroxyl, R ⁴ is ethyl, R ⁵ is H, vincristine derivative, R ⁶ is acetoxy, R ² is hydrogen, R ³ and R ⁴ are hydroxy and ethyl, R ⁵ is H Desmethyl VLB derivatives (also known as desportylvin kristin), R ⁶ is acetoxy, R ² is methyl, R ³ is ethyl, R ⁴ is hydroxyl, R ⁵ is H, urirogidine derivative, R ⁶ is acetoxy, R ² is, but with the case of methyl, R ³ and R ⁵ is H and R ⁴ is ethyl-deoxy VLB "a" derivative, R ^6, R ² and R ⁵ is-deoxy VLB "B" R ³ A deoxy VLB ＂A＂ derivative in which is ethyl and R ⁴ is hydrogen, R ⁶ is acetoxy, R ² is methyl, R ³ is ethyl and R ⁴ and R ⁵ are linked together to form an α-epoxide ring Rosin derivatives or It may be described as a riboformin derivative which is the corresponding compound of R ² = CHO.

The compounds of the present invention are named 3-spiro-5'-oxazolidine dione derivatives which are the special alkaloids mentioned above. For example, oxazolidine dione derived from VLB is named 3-descabomethoxy-3-deshydroxy VLB 3-spiro-5′-oxazolidine-2 ′, 4′-dione. According to the nomenclature, a spiro compound is formed of a vinca alkaloid ring having 3 carbon atoms and a oxazolidinedione ring having 5 carbon atoms. When systematically naming the compound of the present invention, ＂3-descabomethoxy-3-deshydroxyxane is a carbomethoxy group having 3 carbon atoms and a hydroxy group substituted (or bound) with oxazolidine ring. Say. However, in order to simplify the nomenclature of the compounds of the present invention, " 3-descabomethoxy-3-deshydroxy " is subtracted. This is because the oxazolidine ring in each compound means the substitution of hydroxy and carbomethoxy groups having 3 carbon atoms in the vinca alkaloid. Thus each name of oxazolidine dione includes ＂3-descabomethoxy-3-deshydroxy＂.

Non-toxic acids used to form pharmaceutically toxic acid addition salts with the compounds of the present invention include salts derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrochloric acid, hydroiodic acid, nitrous acid, phosphorous acid, and aliphatic mono and dicarboxylic acids. Non-toxic organic acid salts containing carboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanedionates, aromatic acids, aliphatic and aromatic sulfonic acids, and the like. Such pharmaceutical non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, hydrochloride, bromide, iodide, acetate, Propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, hentainoate, propiolate, oxalate, malonate, succinate, suverate, sebacate, fumarate, Malate, butyne-1, 4-dioate, hexyn-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, tere Phthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropio Salts such as yates, phenylbutyrate, citrate, lactate, 2-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2 sulfonate This includes.

In preparing the compounds of the present invention, sodium hydride is suspended in an inert organic solvent such as tetrahydrofuran, vinca alkaloid of formula (II) is added to the suspension, followed by addition of dimethyl carbonate. The reaction mixture is stirred at room temperature until oxazolidine dione formation is substantially completed. The solvent is removed to give oxazolidine dione as a residue, which is further purified by chromatography. Other inert solvents that may be used in the reaction include methylene dichloride, chloroform and the like.

It is preferable that the compound of formula (I) wherein R is H is reacted according to the following production methods.

For example, bindecine is reacted with dimethyl carbonate in the presence of sodium hydride. Such reaction products have an unsubstituted spiroxazolidine dione ring and a hydroxyl group at the position of the acetoxy group having 4 carbon atoms. The first compound of acetic anhydride is reacted under mild reaction conditions to obtain a compound of formula (I) wherein R ⁶ is acetoxy.

Pharmaceutically nontoxic acid addition salts of 3-spiro-5′-oxazolidine-2 ′ and 4′-dione derivatives of vinca alkaloids represented by the formula (I) are prepared by adding 1 mol of an alkaloid free base solution in an inert solvent. Prepared by mixing with desired non-toxic acid. If the salt is dissolved, the solvent is recovered by evaporation in vacuo. If the salt is inert in the reaction solvent, it is precipitated and filtered.

Some inorganic salts are prepared by other preparation methods. For example, sulphates are prepared by dissolving the free base of formula (I) in a small amount of an organic solvent of the same polarity as ethanol and then dropping 2% aqueous sulfuric acid in ethanol to bring the pH of this solution to about 4.0. Sulfate is recovered by evaporation of the solvent to dryness. Hydrochloride can be prepared according to a similar method by adding an alcoholic hydrochloric acid solution to an alcoholic solution of free base. The acid addition salts prepared above may be purified according to known methods such as chromatography or recrystallization.

The C-3 carboxamide starting material of formula (II) is composed of VLB, vincristine, urirogine, leuurozin, uripomin, deoxy VLB ＂A＂ and ＂B＂ isolated from vinca rosea plant leaves or In the formula (II), R ⁶ is derived from an alkaloid OH. (Belgium Patent No. 813,018)

인 상응하는 화합물을 산성가수분해하여 제조한다. 4-데스아세틸 화합물은 원한다면 다음 참조의 제조방법 또는 완화한 조건하에서 1롤의 초산 무수물을 사용하여 아세틸화함으로써 탄소수 4위치를 다시 아세틸화시킬 수 있다. (참조 : Hargrove, Lloydia 27,340(1964)), 빈크리스틴, N-데스포밀 리우로크리스틴, N-데스포밀리우로포민 및 리우로포민, 빈카로제아잎에서 얻은 모든 것을 제의하고 R²가 H 또는 포밀인 구조식(II)로 표시되는 출발물질은 데옥시 VLB ＂A＂ 또는 ＂B＂의 1-메틸그룹을 무수총산중에서 크로뮴옥사이드로 산화시켜(-60℃에서)R²가 H 또는 포밀인 화합물의 혼합물을 얻는다(미합중국특허 제3,899,493호의 제조방법에 따름). R²가 H인 화합물을 포름화하거나 또는 R²가 포밀인 화합물을 탈포름화 할 수 있다.The starting material is R ⁶

Phosphorus corresponding compounds are prepared by acidic hydrolysis. The 4-desacetyl compound can be acetylated again at the C4 position by acetylation, if desired, using one roll of acetic anhydride under the following procedure or under relaxed conditions. (Refer to Hargrove, Lloydia 27,340 (1964)), Vincristine, N-Desformilurocristine, N-Desformyuropomin and Riuropomin, all obtained from Vincaroa leaves and R ² is H or a starting material represented by the formula formyl (II) are deoxy VLB "a" or "B" by oxidizing the 1-methyl group with chromium oxide in anhydrous total Yamanaka (from -60 ℃) R ² is H or formyl A mixture of phosphorus compounds is obtained (according to the preparation method of US Pat. No. 3,899,493). Compounds in which R ² is H can be formed or compounds in which R ² is formyl can be deformed.

The invention is further elucidated with the following specific examples.

Example 1

Preparation of VLB 3-Spiro-5'-oxazolidine-2 ', 4'-dione

A suspension of 208.0 mg (50% oil dispersion) of sodium hydride is prepared in 20 ml of tetrahydrofuran. 200.9 mg of vindesine (VLB C-3 carboxamide) is added thereto. The solution is stirred at room temperature for 25 minutes, after which 4.0 ml of dimethyl carbonate is added. The reaction solution is then stirred for 4.5 hours at room temperature and the volatile composition is evaporated to dryness. Water is added and the aqueous solution is acidified with dilute hydrochloric acid. The acidic layer is extracted with methylene chloride 3 and the methylene dichloride extract is removed. Aqueous 10% sodium hydroxide solution is then added to the aqueous layer to make it basic. VLB 3-spiro-5'-oxazolidine-2 ', 4'-dione, which is insoluble in the basic layer, is separated and methylene dichloride is extracted four times. The methylene dichloride extract is collected and the solvent is evaporated off. 98.4 mg of the residue is subjected to preparative thin layer chromatography on silica gel using a 1: 1 ethyl acetate-methanol solvent system.

Four bands appear and the fourth band is 4-desacetyl 3-spiro-5'-oxazolidine-2 ', 4'-dione. This band is mechanically separated and eluted from the silica. The elution solvent was evaporated to yield 10.9 mg of the residue having the following physical properties.

nmr (heavy chloroform): δ 990, 2.87, 3.57, 3.65, 3.84, 3.95, 5.5-6.0, 6.08, 8.5

ir: maximum value at 3680, 3470, 1810, 1735, 1620, 1505, 1460, 1435, 1335, 1010, 910 cm ^-1 .

Molecular Spectrum: 807, 793, 763, 749, 718, 706, 692, 690, 634, 434, 422, 408, 355, 351, 325, 323, 297, 295, 269, 268, 187, 167, 154, 149 , 135.

Field desorption molecular ions: 779, 753, 735.

Oxazolidine diones without substituents on the nitrogen atoms of the ring may be present in the form of tautomers by hydrogenation of the ring nitrogen atoms with any of the carbonyl groups present in the ring to form hydroxy oxazolinones. In particular oxazolidine-2,4-dione is tautomerized with 2-hydroxy-2-oxazolin-4-one or 4-hydroxy-3-oxazolin-2-one. The reaction product comprises at least two tautomer forms, if not all three.

Example 2

Preparation of Salt

Salts of oxazolidinediones of formula (I) are prepared as follows:

Dissolve the free base in the minimum amount of ethanol and drop the pH to 4.0 ± 0.2 by adding dropwise 2% ethanol sulfuric acid.

The pH is diluted by adding 1 ml of water to 2 drops of the solution and measured with a pH meter.

Ethanol acid solution is evaporated to dryness. If desired, the residue containing sulfate can be recrystallized from methanol or ethanol.

The compound of the present invention is active against the cancer transplanted in vivo in the mouse and it can be seen that in the tissue culture Chinese hamster ovary cells cause chromosomes in a row in the middle of the equator in the equator plate. To determine the activity of the compounds of the present invention on cancer cells transplanted into mice, a routine transcript is made by usually intranasal administration at a given dose for 7 to 10 days after inoculation of cancer cells.

Table 1 shows the experimental results of successively treating cancers transplanted into mice with the compounds of the present invention. In the table, column 1 is the name of the compound, column 2 is the transplanted cell (B ¹⁶ is melanoma), column 3 is the dose level or range of doses and the date of the dose administered, and column 4 is the route of administration. (1P) is intraperitoneal), and row 5 is the percentage of cancer cell growth arrest or percentage of survival duration.

TABLE 1

Survived 60 days until the end of the experiment.

The novel oxazolidine diones of the present invention effective as mammalian anticancer agents may be administered parenterally or orally. An appropriate amount of a compound made of a salt with a non-toxic acid, the base according to formula (I) formed at the dose by oral administration, is mixed with starch or other excipients, and the mixture is filled into gelatin capsules containing 7.5 to 50 mg of the active ingredient, respectively. Let's do it. According to a similar method, pharmaceutically harmless salts are mixed with starch, binder and activating agent and the mixture is inhibited by tableting each to mix 7.5-50 mg. If you are taking smaller doses or divided doses, you can add gold to the tablets. In the case of parenteral administration, intravenous administration is preferred, although intraperitoneal administration to small mammals such as mice. For parenteral administration, an isotonic solution containing 1 to 10 ml / ml of the oxazolidinedione salt of formula (I) is used. The compound is administered at 0.01 to 1 mg / kg mammalian weight depending on the activity or toxicity of the drug, and preferably at 0.1 to 1 mg / kg mammalian weight once or twice every week or two weeks. Another method of reaching a therapeutic dose is a dose of 0.1 to 10 mg / m 2 stray animal surface area every 7 or 14 days based on body surface area:

Claims (1)

A process for preparing spiroxazolidine dione of the following structural formula (I), wherein the indoledihydroindione dimer of the following formula (II) and dimethyl carbonate are reacted in the presence of sodium hydride.

In the above structural formula R ² is H, CH ₃ or CHO, R ³ and R ⁴ are one if H or OH the other is C ₂ H ₅ and R ⁵ is H, or R ⁴ and R ⁵ combine to form an epoxide ring, R ³ is C ₂ H ₅ R ⁶ is OH or

to be.