JP2001247573A - Fr900482 analog and method of synthesizing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an analog of FR900482 for which the new development of an antitumor antibiotic substance and application thereof are expected and to provide a method of synthesizing the analog. SOLUTION: This FR900482 analog is represented by the following formula (A) or (B) (wherein R1 and R2 denote each mutually the same or different hydrocarbon group; R3, R4 and R5 denote each hydrogen atom or mutually the same or different hydrocarbon group) or its enantiomer or diastereomer.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The invention of this application relates to FR90
0482 analogs and a method for synthesizing the same. More specifically, the invention of this application relates to Mytomycin
FR, an antitumor substance with a mechanism of action similar to C
The present invention relates to an analog of 900482, a method for synthesizing the same, and a synthetic intermediate.

[0002]

2. Description of the Related Art Conventionally,

[0003]

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[0004] FR900482 represented by
It is known as an antitumor active substance having a mechanism of action similar to that of omycin C, and the inventors of this application have established a total synthesis method of its racemic form.

[0005] However, with regard to FR900482, its analogs and methods for synthesizing them have not been studied much.

[0006] Therefore, the search and establishment of analogs of FR900482 and methods for synthesizing them, which are expected to have novel development and application of antitumor antibiotics, have become extremely important issues.

[0007]

In order to solve the above-mentioned problems, the invention of the present application firstly solves the following problem by the following formula (A).

[0008]

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(Wherein R ¹ and R ² each represent the same or different hydrocarbon groups, and R ³ , R ⁴ and R
⁵ each represents a hydrogen atom or an identical or different hydrocarbon group), and FR900482 analogs or enantiomers or diastereomers thereof;

[0010]

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An FR900482 analog represented by the following formula (B):

[0012]

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(R ¹ and R ² in the formula each represent the same or different hydrocarbon groups, and R ³ , R ⁴ and R
⁵ each represents a hydrogen atom or an identical or different hydrocarbon group), and FR900482 analogs or enantiomers or diastereomers thereof;

[0014]

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There is provided an FR900482 analog represented by the formula:

The invention of this application is a method for synthesizing the analog (A) according to claims 5 and 6, wherein

[0017]

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The epoxide compound of the formula

[0019]

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A method for synthesizing a FR900482 analog, which comprises subjecting the compound to a carbonate compound of the following, followed by ammonia or amine decomposition, and, if necessary, introducing a hydrocarbon group to a carbamoyl group and a hydroxyl group;
A method for synthesizing the analog (B), comprising the following formula:

[0021]

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After converting the epoxide compound of formula 1 into an azide compound,

[0023]

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The azide group is reduced to give a carbonate compound of the following formula:

[0025]

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The present invention provides a method for synthesizing an FR900482 analog, which comprises subjecting to an aziridine compound of the above, followed by ammonia or amine decomposition, and introducing a hydrocarbon group into a carbamoyl group or a hydroxyl group as required. The method for producing a synthetic intermediate according to claims 7 to 12 is as follows:

[0027]

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(Wherein R ¹ and R ² are the same or different and each represents a hydrocarbon group).

[0029]

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Is converted into a 1,2-diol compound of the formula

[0031]

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A synthesis method characterized by deriving an epoxide compound of the following formula:

[0033]

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(Wherein R ¹ and R ² each independently represent the same or different hydrocarbon groups), the amino group of the secondary amine compound is converted to a protected hydroxyamine compound, and a ring transfer reaction is carried out. Next formula

[0035]

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A synthesis method characterized by deriving a tetracyclic compound of the following formula:

[0037]

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(Wherein R ¹ and R ² in the formula each represent the same or different hydrocarbon groups) by a glycol cleavage reaction, a reduction reaction and a TBS protection reaction according to the following formula:

[0039]

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A synthesis method characterized by deriving a secondary amine compound of the following formula:

[0041]

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(Wherein R ¹ and R ² are the same or different and each represents a hydrocarbon group), and after protecting the amino group of the secondary amine compound, the N—O bond is reductively cleaved. ,
Next formula

[0043]

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And then via a reduction reaction and a deprotection reaction, the following formula

[0045]

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A synthesis method characterized by deriving a triol compound of the following formula:

[0047]

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(Wherein R ¹ and R ² each represent the same or different hydrocarbon groups) to reduce the ethoxycarbonyl group of the secondary amine compound

[0049]

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A synthesis method characterized by deriving a secondary amine compound of the following formula:

[0051]

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(Wherein R ¹ and R ² each represent the same or different hydrocarbon groups, and R represents a protecting group) from the cinnamic acid derivative via the reaction with the tartaric acid derivative.

[0053]

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An oxime compound of the formula:

[0055]

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The present invention provides a synthesis method characterized by deriving the secondary amine compound.

Further, the invention of this application is based on claims 13 to 1
As in 7, a synthetic intermediate is also provided.

[0058]

BEST MODE FOR CARRYING OUT THE INVENTION The invention of this application has the features as described above, and embodiments thereof will be described below.

The chloroplast (A) of the invention of this application
The compound (B), particularly a specific example of the compound, exhibits remarkable antitumor activity. Will greatly contribute to

FR9004 of the present invention as described above
In the chemical formulas described for the 82 analogs (A) and (B) and their synthetic intermediates, R ¹ and R ² are the same or different hydrocarbon groups, and these hydrocarbon groups are appropriately substituted. And various kinds of aliphatic, aromatic and cycloaliphatic hydrocarbons. For example, a methyl group,
Lower alkyl groups such as an ethyl group and a butyl group are shown as examples. The same applies to the case where R ³ , R ⁴ and R ⁵ are hydrocarbon groups.

R ¹ O— and R ² bonded to the benzene ring may be bonded at various positions, and the benzene ring may be further substituted with another allowable substituent which does not inhibit the synthesis method of the present invention. A group may be attached.

In the synthesis method, it is possible in the present invention to selectively synthesize stereoisomers and enantiomers. For example, in the above-mentioned synthesis method, as shown in the examples below, the same synthetic route can be obtained by using the L-form or the D-form tartaric acid derivative in the reaction between the cinnamic acid derivative [Formula 22] and the tartaric acid derivative. In the above-mentioned conversion of the compound of the formula [11] into the compound of the formula [12], the hydroxyl group of the compound of the formula [11] can be easily distinguished, so that the compound of the formula [12] Synthesis of the stereoisomer of is also easy.

Therefore, in the invention of this application, the enantiomers and stereoisomers of the above-mentioned analog compounds (A) and (B) and the various compounds of the embodiment are easily synthesized. Become.

Hereinafter, synthetic examples and physiological activity tests will be described as examples.

[0065]

EXAMPLES <Example 1> The following reaction formula

[0066]

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According to the above, Compound 116 was synthesized as Invention Compound (A) of this application.

That is, the epoxide 114 (5.5 m
g, 0.017 mmol) by acid treatment (15 μl) to remove the acetonide, and triphosgene (2.3 mg,
0.079 mmol) and carbonate 115 (1.5 m
g, yield 62%).
R-900482 chloroplast 116 (1.3 mg, yield 79)
%) Was successfully synthesized.

The physical properties identified for Compound 115 and Compound 116 are shown in Tables 1 and 2 below.

[0070]

[Table 1]

[0071]

[Table 2]

Example 2 The following reaction formula

[0073]

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According to this invention compound (B),
Compound 121 was synthesized.

That is, the epoxide 114 (12.0 m
g, 0.037 mmol) with LiN ₃ (36.8 mg,
0.75 mmol) to introduce an azide group, and free hydroxyl group to be mesylated to give 118 (9.8 mg, yield 79).
%). 118 was treated with TFA to remove acetonide and carbonate 1 with triphosgene (6.1 mg).
19 (5.8 mg, 75%). Next, the azide was reduced with triphenylphosphine (14 mg) to give azirine 1
20 (2.8 mg, 70%). Finally, the carbonate was bubbled with ammonia gas for 2 minutes and ammonolyzed to form a carbamoyl group by FR900482.
The synthesis of chloroplast 121 (1.9 mg, 75%) was successful.

The fixed physical properties of the compounds 118, 119, 120 and 121 were as shown in Tables 3 to 6 below.

[0077]

[Table 3]

[0078]

[Table 4]

[0079]

[Table 5]

[0080]

[Table 6]

Example 3 A compound 114 as a starting material in Examples 1 and 2 was synthesized. (1) First, the following reaction formula

[0082]

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According to this, compound 98 to compound 10
3 was synthesized.

That is, the secondary amine of compound 98 (58
0 mg, 1.33 mmol) was oxidized with m-chloroperbenzoic acid (495 mg, 1.72 mmol) to give hydroxylamine, and then treated with acetic anhydride (12.0 ml) to selectively only hydroxylamine with an acetyl group. To 101 (423 mg). The hydroxyl group of 101 was subjected to Dess-Martin oxidation (1.03 mg, 1.
70 mmol) to obtain ketone 102 (410 mg), and then removing the acetyl group with hydrazine, the transannular reaction proceeds quickly to obtain a tetracyclic compound 103 (0.29 mg) having a hemiketal structure as a single compound. Succeeded.

Then, 103 was treated with an equivalent amount of acetic acid to TBAF (1MTHF solution, 0.77 ml) to remove TBS.
Body 105 (4.21 mg) was obtained.

The identified physical properties of Compounds 101, 102 and 105 were as follows.

[0087]

[Table 7]

[0088]

[Table 8]

[0089]

[Table 9]

(2) Next, the reaction formula

[0091]

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Compound 105 (100 mg)
The acetonide was removed using Amberlyst 15E, and the resulting tetraol was treated with 2,2-dimethoxypropane, 2-methoxypropene, and PPTS without isolation to produce the acetonide. 2-diol 110 (77.2 mg) was successfully obtained as a single compound. In order to obtain an epoxide having the desired stereochemistry, the vacant hydroxyl group of the diol 110 was selectively protected with a TES group, the remaining hydroxyl group was mesylated to form a leaving group, and the TES group was removed with TBAF. . Next, treatment with sodium hydride and epoxide 1
14 (14 mg) could be obtained.

The identified physical properties of Compounds 110, 112 and 114 are as follows.

[0094]

[Table 10]

[0095]

[Table 11]

[0096]

[Table 12]

<Example 4> The following reaction formula

[0098]

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According to the above procedure, compound 98 as a starting material of Example 3 was synthesized.

First, the secondary amine of compound 88 (8.20
mmol) obtained by protecting the compound with a trifluoroacetyl group.
A portion of (2) (228 mg) was treated with freshly adjusted Raney Ni in a hydrogen atmosphere to reductively cleave the NO bond, and the desired β, γ-dihydroxyketone 93 (114 mg, 62%) I got β, γ-dihydroxyketone 93 (3.3 mmol) undergoes stereoselective reduction using sodium triacetoxyborohydride (3.5 g, 17 mmol) to give a single triol form, without purification. Treatment with aqueous sodium hydroxide in methanol to remove the trifluoroacetyl group gave compound 96 (85%).

Thus, the obtained triol 96 is treated with sodium periodate to carry out a glycol cleavage reaction, and the resulting aldehyde is post-treated, then reduced with sodium borohydride without isolation and purification, and the diol 97
Was converted to Next, only the primary alcohol was protected with a TBS group to give 98.

Compounds 92, 93, 96, 97 and 9
The identification physical properties of No. 8 are as follows.

[0103]

[Table 13]

[0104]

[Table 14]

[0105]

[Table 15]

[0106]

[Table 16]

[0107]

[Table 17]

<Example 5> Compound 88, which is a starting material of Example 4, was prepared by the following reaction formula.

[0109]

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According to the compound 84 (8.20 mmol)
To a solution of ethanol l) (20ml) -THF (20ml ) was obtained by reduction by adding NaBH ₄ to (465 mg) (99% yield).

The identified physical properties of Compound 88 are as follows.

[0112]

[Table 18]

Example 6 The following reaction formula

[0114]

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According to the above, the compound 84 was synthesized.

That is, the benzaldehyde compound 53
Carboethoxymethylenetriphenylphosphorane (64 mmol) was added to an ethanol solution of (58 mmol) and reacted at room temperature to obtain cinnamic azide compound 78 (14.6 g, 96%). This compound 78
(44.0 mmol) in acetic acid-dichloromethane solution was added with zinc powder and reacted. Thereafter, 4-nitrobenzenesulfonyl chloride: p-NsCl (53.0 mmol) was added.
l) is added with pyridine to give the sulfonamide compound 79 (87%).

The following equation

[0118]

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A benzene solution of the resulting sulfonamide compound 79 (28.6 mmol), triphenylphosphine (7.50 g, 28.0 mmol),
And an alcohol solution of the L-tartaric acid derivative 46
AD (40% toluene solution, 12.4 ml, 28.6 m
mol), and reacted at a temperature of 50 ° C for 30 minutes.

Compound 80 (13.9 g, 93%) was obtained.

Thereafter, the compound 80 (20.5 mmol)
1) with TBAF (1.0 M THF in THF)
Solution, 22.5 ml).
(11.0 g, 95%).

Compound 81 (11.0 g, 19.5 mmol
l) in dichloromethane is treated with oxalyl chloride (3
(5.1 mmol) in a dichloromethane solution and a mixed solution of DMSO were stirred and mixed, and Swern-oxidized.

After the reaction, sodium acetate (39.0 mmo)
l) and hydroxylamine (29.2 mmol) were added to give compound 82.

Further, a sodium perchlorate solution was added to a dichloromethane solution of the compound 82 to obtain an isoxazoline compound 83 (6.43 g, 57%). Then
This compound 83 (6.43 g, 11.1 mmol) and cesium carbonate (10.8 g, 33.3 mmol)
Thiophenol (1.70 m
1, 16.7 mmol) and reacted at 50 ° C. for 30 minutes.

Compound 84 (3.23 g, 74%) was obtained.

The identified physical properties of compounds 78, 79, 80, 81, 83 and 84 are as follows.

[0127]

[Table 19]

[0128]

[Table 20]

[0129]

[Table 21]

[0130]

[Table 22]

[0131]

[Table 23]

[0132]

[Table 24]

Example 7 Regarding FR-900482 analogs 116 and 121 synthesized in Examples 1 and 2, in vitro using human leukemia cell U937
o A cytotoxicity test was attempted. For comparison, (+)
-Cytotoxicity tests were similarly performed on FR-900482 and FK317. The measured IC ₅₀ is shown in the table.

[0134]

[Table 25]

In the cytotoxicity test, the strength of the cell killing effect was highest for FK317, followed by FR-9004.
82 and 121 were confirmed to have the same activity as FR-900482.

[0136]

According to the invention of this application, novel development of antitumor antibiotics and application of FR9004 are expected.
82 analogs and methods for their synthesis are provided.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification FI FI Theme Court ゛ (Reference) C07D 498/18 C07D 498/18 498/22 498/22

Claims (17)

[Claims] (1) The following formula (A): (R ¹ and R ² in the formula each represent the same or different hydrocarbon group, and R ³ , R ⁴ and R ⁵ each represent a hydrogen atom or the same or different hydrocarbon group.) Or an enantiomer or diastereomer thereof. 2. The following formula: 2. The FR900482 analog of claim 1 represented by: 3. The following formula (B): (R ¹ and R ² in the formula each represent the same or different hydrocarbon group, and R ³ , R ⁴ and R ⁵ each represent a hydrogen atom or the same or different hydrocarbon group.) Or an enantiomer or diastereomer thereof. 4. The following formula: The FR900482 analog of claim 2 represented by: 5. A method for synthesizing an analog according to claim 1 or 2, comprising the following formula: An epoxide compound of the following formula: A method for synthesizing an FR900482 analog, comprising subjecting the compound to a carbonate compound of the following formula, followed by ammonia or amine decomposition, and introducing a hydrocarbon group into a carbamoyl group and a hydroxyl group as required. 6. A method for synthesizing an analog according to claim 3 or 4, comprising the following formula: After converting the epoxide compound of formula 1 into an azide compound, the following formula: The azide group is reduced to give a carbonate compound of the following formula: A process for synthesizing an FR900482 analog, comprising subjecting an aziridine compound to the above, followed by ammonia or amine decomposition to introduce a hydrocarbon group into a carbamoyl group or a hydroxyl group as required. 7. The following formula: (Wherein R ¹ and R ² in the formula each represent the same or different hydrocarbon group) by the following formula: To a 1,2-diol compound of the formula
The following formula: A synthesis method characterized by deriving an epoxide compound of the formula: 8. The following formula: (Wherein R ¹ and R ² in the formula each represent the same or different hydrocarbon group) wherein the amino group of the secondary amine compound is converted to a protected hydroxyamine compound, and a ring transfer reaction is carried out. Formula 14 A synthesis method characterized by deriving a tetracyclic compound of the formula: 9. The following formula: (Wherein R ¹ and R ² in the formula each represent the same or different hydrocarbon group) from a triol compound by glycol cleavage, reduction and TBS protection by the following formula: A synthesis method characterized in that a secondary amine compound is derived. 10. The following formula: (Wherein R ¹ and R ² each independently represent the same or different hydrocarbon group), after protecting the amino group of the secondary amine compound, reductively cleave the N—O bond, Embedded image Then, via a reduction reaction and a deprotection reaction, the following formula: A synthesis method characterized in that a triol compound of formula (I) is derived. 11. The following formula: (Wherein R ¹ and R ² each represent the same or different hydrocarbon groups) to reduce the ethoxycarbonyl group of the secondary amine compound to give the following formula: A synthesis method characterized in that a secondary amine compound is derived. 12. The following formula: (Wherein R ¹ and R ² each represent the same or different hydrocarbon groups, and R represents a protecting group) from a cinnamic acid derivative via a reaction with a tartaric acid derivative. ] An oxime compound represented by the formula: A synthesis method characterized in that a secondary amine compound is derived. 13. The following formula: An epoxide compound represented by 14. The following formula: A secondary amine compound represented by the formula: 15. The following formula: A triol compound represented by the formula: 16. The following formula: A secondary amine compound represented by the formula: 17. The following formula: A secondary amine compound represented by the formula: