JP2010275229A - Hydantoin derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a novel thalidomide analog expected to have pharmacological activity such as an antitumor effect. <P>SOLUTION: L-glutamic acid or L-aspartic acid is converted into a dimethyl ester, and then the amino group therein is protected. Next, the dimethyl ester in which the amino group is protected is converted into an imide, and then a protecting group is removed, thereby obtaining a hydrochloride of 3-aminoglutarimide or a hydrochloride of 3-aminosuccinimide. Next, the hydrochloride of the imide obtained by the procedures is condensed with a desired natural amino acid, the protecting group is removed from the resultant amino acid condensation compound, and then 4-nitrophenyl chloroformate is reacted therewith. A thalidomide analog having a hydantoin moiety is thus obtained. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to hydantoin derivatives, and more particularly to novel thalidomide analogs having a hydantoin moiety.

  Recently, it has been reported that thalidomide (N-α-phthalimidoglutarimide) has an anti-angiogenic effect. Based on this report, various syntheses of novel compounds using thalidomide as a lead compound have been studied in order to be applied to the treatment of malignant tumors such as myeloma, which are less effective for chemotherapy. JP-T-2007-505922 (Patent Document 1) discloses a thalidomide analog that regulates tumor necrosis factor α (TNF-α) activity and angiogenesis.

Special Table 2007-505922

  This invention is made | formed in view of the said prior art, and this invention aims at providing the novel thalidomide analog by which pharmacological activities, such as an antitumor effect, are anticipated.

  As a result of diligent studies from the viewpoint of mimetics, the present inventors have sought to synthesize a novel compound that can be expected to have a physiological activity similar to that of thalidomide. The present inventors succeeded in synthesizing thalidomide analogs and arrived at the present invention.

That is, according to the present invention, novel hydantoin derivatives as thalidomide analogs represented by the following general formulas (1) to (4) are provided. However, in the following general formulas (1) to (4), R ₁ represents a side chain of a natural amino acid, R ₂ and R ₃ may be the same or different, and each represents a hydrogen atom or a carbon atom number of 1 to A substituent selected from the group consisting of 10 branched or straight chain alkyl groups, alkoxy groups, thioalkoxy groups, or halogen atoms is shown.

  Further, according to the present invention, after converting L-glutamic acid to dimethyl ester, a step of introducing a protective group into the amino group, a step of converting glutamic acid dimethyl ester having the protective group introduced into imide, A step of obtaining a hydrochloride of 3-aminoglutarimide by removing the protecting group, and a step of obtaining an amino acid condensed compound by condensing the hydrochloride of 3-aminoglutarimide and a natural amino acid having a protecting group introduced into the amino group And a method for producing a novel hydantoin derivative represented by the above general formulas (1) and (2), which comprises removing a protecting group from the amino acid condensation compound and then allowing 4-nitrophenyl chloroformate to act on the compound. Provided.

  Further, according to the present invention, after converting L-aspartic acid to dimethyl ester, a step of introducing a protecting group into the amino group, and a step of converting dimethyl ester of aspartic acid having the protecting group introduced into imide, Removing the protecting group to obtain 3-aminosuccinimide hydrochloride; and condensing the 3-aminosuccinimide hydrochloride with a natural amino acid having a protecting group introduced into the amino group to obtain an amino acid condensed compound. And a method for producing a novel hydantoin derivative represented by the above general formulas (3) and (4), comprising removing a protecting group from the amino acid condensation compound and then allowing 4-nitrophenyl chloroformate to act on the compound. Provided.

  As described above, according to the present invention, a novel thalidomide analog expected to have a pharmacological activity such as an antitumor effect is provided.

The figure which shows the synthetic | combination process of the glutarimide yl hydantoin derivative of this invention, and a glutarsuccinimidoyl hydantoin derivative. The figure which shows the NMR data of the compound which condensed 3-aminoglutarimide derived from the phenylalanine which the amino group protected by the Boc group, and L, D-glutamic acid. The figure which shows the structural formula of the glutarimide yl hydantoin derivative of a present Example. The figure which shows the NMR data of a derivative (1). The figure which shows the NMR data of a derivative (2). The figure which shows the NMR data of a derivative | guide_body (3). The figure which shows the NMR data of a derivative (4). The figure which shows the NMR data of a derivative (5). The figure which shows the NMR data of the compound which condensed 3-amino succinimide derived from the phenylalanine in which the amino group was protected by the Boc group, and L, D-aspartic acid. The figure which shows the structural formula of the succinimidyl hydantoin derivative of a present Example. The figure which shows the NMR data of a derivative (6). The figure which shows the NMR data of a derivative (7). The figure which shows the NMR data of a derivative (8). The figure which shows the NMR data of a derivative | guide_body (9).

  Hereinafter, the present invention will be described with reference to embodiments shown in the drawings, but the present invention is not limited to the embodiments shown in the drawings.

  FIG. 1 is a diagram showing a synthesis process of a novel thalidomide analog of the present invention. Hereinafter, the method for synthesizing a thalidomide analog of the present invention will be described with reference to FIG.

  In the present invention, first, commercially available L-glutamic acid or L-aspartic acid is prepared as a starting material. When L-glutamic acid is used as the starting material (n = 2 in FIG. 1 (1)), the glutarimide ylhydantoin derivative of the present invention is synthesized as the final material, and when L-aspartic acid is used as the starting material. (N = 1 in FIG. 1 (1)), the succinimidoylhydantoin derivative of the present invention is synthesized as the final substance. That is, the method for synthesizing each derivative is different only in the starting material, and all other steps are common. Hereinafter, the common process will be described.

  After converting L-glutamic acid or L-aspartic acid (hereinafter referred to as a starting amino acid) to a dimethyl ester (step a), the amino group is protected by introducing a tert-butoxycarbonyl group (Boc group) (step b). ). A benzyloxycarbonyl group (Z group) may be introduced as a protective group.

  Next, the amino acid-protected starting amino acid dimethyl ester (2) is converted to an imide under Birch reduction conditions (step c) and then the protecting group is removed to remove aminoglutarimide hydrochloride or amino The succinimide hydrochloride (3) is obtained (step d).

  Next, the hydrochloride of the imide obtained by the above procedure is condensed with the desired amino acid. Specifically, after protecting the amino group of the amino acid to be condensed with a Boc group or the like, the amino acid and the imide are condensed in a solution to which an appropriate condensing agent is added (step e), and then protected from the amino acid condensed compound. By removing the group, an amino acid-imide condensation compound (5) is obtained. In the present invention, the amino acid to be condensed is not particularly limited, and alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine Natural α-amino acids such as valine and the like can be used. The amino acid-imide condensation compound is obtained as a mixture of stereoisomers in which the configuration of the imide portion is reversed, as shown in (5).

  Finally, the desired hydantoin derivative (6) is obtained by allowing the amino acid-imide condensation compound (5) to react with 4-nitrophenyl chloroformate in dry acetonitrile in the presence of excess sodium bicarbonate (step g). Obtainable. The hydantoin derivative of the present invention is obtained as a mixture of diastereomers in which the configuration of the imide moiety is reversed as shown in (6).

  Hereinafter, although the novel thalidomide analog of this invention is demonstrated more concretely using an Example, this invention is not limited to the Example mentioned later.

(Synthesis of glutarimide ylhydantoin derivatives)
Distilled thionyl chloride was added to a solution in which L-glutamic acid was dissolved in methanol at 0 ° C. over 30 minutes using a dropping funnel, and then the reaction mixture was vigorously stirred at room temperature for 12 hours. The solvent was then evaporated under reduced pressure, diluted with aqueous sodium bicarbonate and extracted with dichloromethane. The organic layer was washed with saturated brine and dried over sodium sulfate to obtain glutamic acid dimethyl ester (L-1,5-dimethyl-2-aminopentanedioate).

  Di-tert-butyl dicarbonate was stirred in the chloroform solution of glutamic acid dimethyl ester obtained by the above procedure in the presence of triethylamine at room temperature for 12 hours. After washing with 10% -citric acid aqueous solution and drying with sodium sulfate, a tert-butoxycarbonyl group (Boc group) was introduced as a protecting group into the amino group of the glutamic acid dimethyl ester.

  To a stirred solution of sodium amide, an anhydrous THF solution of glutamic acid dimethyl ester in which the amino group was Boc protected was added and stirred for 2 hours. Then, ammonium chloride was added, and ammonia was evaporated at room temperature. Water was added to the residue and the mixture was extracted with chloroform and then dried over sodium sulfate. Thereafter, a 4M hydrochloric acid / dioxane solution corresponding to 20 to 30 equivalents of the Boc group was added, stirred at room temperature for 0.5 to 1 hour, concentrated under reduced pressure as it was to remove the Boc group, and the hydrochloride of 3-aminoglutarimide was obtained. Obtained.

  Next, a DMF solution of five kinds of natural amino acids (valine, leucine, isoleucine, phenylalanine, tryptophan) in which the amino group was protected with a Boc group was prepared. To each DMF solution is added the aminoglutarimide hydrochloride obtained by the procedure described above, and 1-hydroxybenzotriazole (HOBt) monohydrate as a racemization inhibitor and 1- (3-dimethyl) as a condensing agent. Aminopropyl) -3-ethylcarbodiimide hydrochloride (WSC · HCl) was added and stirred overnight at room temperature. After distilling off DMF under reduced pressure, the organic matter was extracted with ethyl acetate, the organic layer was washed with a 10% citric acid solution and then with saturated brine, dried over sodium sulfate, and the organic layer was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (with an appropriate chloroform / methanol mixed solvent as an eluent).

  Here, the NMR spectrum of the proton of the compound (LG) obtained by condensing 3-aminoglutarimide derived from phenylalanine whose amino group is protected with a Boc group and L-glutamic acid is shown in FIG. FIG. 2 (b) shows the NMR spectra of protons of the compound (DG) obtained by condensing 3-aminoglutarimide derived from phenylalanine protected with a Boc group and D-glutamic acid. As a result of comparing the spectral data of both, 1) a signal of a double line and a double line observed around 3.0 ppm, 2) a signal of a methine proton observed around 4.6 ppm, 3) 6.9 and 8.3 ppm As shown by the NH proton signal observed in the vicinity, it was shown that the spectrum data of LG includes the signal observed in DG. From the above observation results, it was found that the spectrum of the compound derived from L-glutamic acid includes the compound derived from the D-form, and the amino group of the glutarimide part is racemized. The following compounds proceeded as diastereomeric mixtures.

  A 4M hydrochloric acid / dioxane solution corresponding to 20 to 30 equivalents of the Boc group was added to the purified product, and the mixture was stirred at room temperature for 0.5 to 1 hour to remove the Boc group. Or its hydrochloride) was obtained.

  Each of the condensed compounds was suspended in dry acetonitrile, and then an equivalent amount of 4-nitrophenyl chloroformate was allowed to act at room temperature for 3 hours in the presence of 3-5 equivalents of sodium bicarbonate. After confirming disappearance of the raw materials, an appropriate amount of water was added, and the mixture was further stirred at room temperature for 3 hours. When acetonitrile was distilled off under reduced pressure and a precipitate was formed, the precipitate was collected by suction filtration. If no precipitation occurred, the aqueous solution was saturated with sodium chloride and extracted several times with ethyl acetate. The collected product or extract was dried over sodium sulfate and concentrated under reduced pressure to obtain a glutarimide ylhydantoin derivative. The structural formulas of the five types of glutarimide ylhydantoin derivatives obtained are shown in FIG. FIG. 3 shows, in order from the top, derivatives obtained when valine (1), leucine (2), isoleucine (3), phenylalanine (4), and tryptophan (5) are used as natural amino acids. Further, FIG. 4 shows NMR data of the derivative (1), FIG. 5 shows NMR data of the derivative (2), FIG. 6 shows NMR data of the derivative (3), FIG. 7 shows NMR data of the derivative (4), and FIG. The NMR data of the derivative (5) are shown in FIG.

(Synthesis of succinimidylhydantoin derivatives)
Distilled thionyl chloride was added to a solution of L-aspartic acid in methanol at 0 ° C. over 30 minutes using a dropping funnel, and the reaction mixture was stirred vigorously at room temperature for 12 hours. The solvent was then evaporated under reduced pressure, diluted with aqueous sodium bicarbonate and extracted with dichloromethane. The organic layer was washed with saturated brine and dried over sodium sulfate to obtain aspartic acid dimethyl ester (L-1,5-dimethyl-2-aminobutanedioate).

  Di-tert-butyl dicarbonate was stirred continuously in the presence of triethylamine at room temperature for 12 hours in the aspartic acid dimethyl ester chloroform solution obtained by the above procedure. After washing with a 10% aqueous citric acid solution and drying with sodium sulfate, a tert-butoxycarbonyl group (Boc group) was introduced as a protective group into the amino group of the aspartic acid dimethyl ester.

  To a stirred solution of sodium amide, an anhydrous THF solution of aspartic acid dimethyl ester in which the amino group was Boc protected was added and stirred for 2 hours, and then ammonium chloride was added to evaporate the ammonia. Water was added to the residue and the mixture was extracted with chloroform and then dried over sodium sulfate. Then, 4M hydrochloric acid / dioxane solution corresponding to 20-30 equivalents of Boc group was added, stirred at room temperature for 0.5-1 hour, concentrated under reduced pressure as it was to remove Boc group, and hydrochloride of 3-aminosuccinimide was obtained. It was.

  Next, a DMF solution of four kinds of natural amino acids (valine, leucine, phenylalanine, tryptophan) in which the amino group was protected with a Boc group was prepared. To each DMF solution was added 3-aminosuccinimide hydrochloride obtained by the procedure described above, and 1-hydroxybenzotriazole (HOBt) monohydrate as a racemization inhibitor and 1- (3- Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (WSC · HCl) was added and stirred overnight at room temperature. After distilling off DMF under reduced pressure, the organic matter was extracted with ethyl acetate, the organic layer was washed with a 10% citric acid solution and then with saturated brine, dried over sodium sulfate, and the organic layer was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (with an appropriate chloroform / methanol mixed solvent as an eluent).

  Here, FIG. 9A shows the proton NMR spectrum of a compound (LS) obtained by condensing 3-aminosuccinimide derived from L-aspartic acid and phenylalanine whose amino group is protected with a Boc group. The NMR spectra of protons of the compound (DS) obtained by condensing 3-aminosuccinimide derived from phenylalanine protected with a Boc group and D-aspartic acid are shown in FIG. As a result of comparing the spectral data of both, 1) a signal of a double line and a double line observed around 3.0 ppm, 2) a signal of a methine proton observed around 4.6 ppm, 3) 6.9 and 8.3 ppm As shown by the NH proton signal observed in the vicinity, the spectrum of the compound derived from L-aspartic acid was shown to contain the signal observed in DS. From the above observation results, it was found that the spectrum of the compound derived from L-aspartic acid included the compound derived from the D-form, and the amino group of the succinimide part was racemized. The following compounds proceeded as a mixture of diastereomers.

  A 4M hydrochloric acid / dioxane solution corresponding to 20 to 30 equivalents of the Boc group was added to the purified product, and the Boc group was removed by stirring at room temperature for 0.5 to 1 hour to remove four types of amino acid-succinimide condensation compounds (or Its hydrochloride).

  Each of the above condensed compounds was suspended in dry acetonitrile, and then an equivalent amount of 4-nitrophenyl chloroformate was allowed to act at room temperature for 3 hours in the presence of 3-5 equivalents of sodium bicarbonate. After confirming disappearance of the raw materials, an appropriate amount of water was added, and the mixture was further stirred at room temperature for 3 hours. When acetonitrile was distilled off under reduced pressure and a precipitate was formed, the precipitate was collected by suction filtration. If no precipitation occurred, the aqueous solution was saturated with sodium chloride and extracted several times with ethyl acetate. The collected product or extract was dried over sodium sulfate and concentrated under reduced pressure to obtain a succinimidylhydantoin derivative. The structural formulas of the obtained four types of succinimidoylhydantoin derivatives are shown in FIG. FIG. 10 shows the derivatives obtained when valine (6), leucine (7), phenylalanine (8), and tryptophan (9) are used as natural amino acids in order from the top. FIG. 11 shows NMR data of the derivative (6), FIG. 12 shows NMR data of the derivative (7), FIG. 13 shows NMR data of the derivative (8), and FIG. 14 shows NMR data of the derivative (9). Each is shown.

Claims (6)

General formula (1)

(In the general formula (1), R ₁ represents a side chain of a natural amino acid, and R ₂ and R ₃ may be the same or different, and each represents a hydrogen atom, a branched chain having 1 to 10 carbon atoms, or And a substituent selected from the group consisting of a linear alkyl group, an alkoxy group, a thioalkoxy group, or a halogen atom.). General formula (2)

(In the above general formula (2), R ₁ represents a side chain of a natural amino acid, and R ₂ and R ₃ may be the same or different, and each represents a hydrogen atom, a C 1-10 branched or And a substituent selected from the group consisting of a linear alkyl group, an alkoxy group, a thioalkoxy group, or a halogen atom.). General formula (3)

(In the above general formula (3), R ₁ represents a side chain of a natural amino acid, and R ₂ and R ₃ may be the same or different, and each represents a hydrogen atom, a branch having 1 to 10 carbon atoms, or And a substituent selected from the group consisting of a linear alkyl group, an alkoxy group, a thioalkoxy group, or a halogen atom.). General formula (4)

(In the general formula (4), R ₁ represents a side chain of a natural amino acid, and R ₂ and R ₃ may be the same or different, and each represents a hydrogen atom, a branched chain having 1 to 10 carbon atoms, or And a substituent selected from the group consisting of a linear alkyl group, an alkoxy group, a thioalkoxy group, or a halogen atom.). Converting L-glutamic acid to dimethyl ester and then introducing a protecting group to the amino group;
Converting glutamic acid dimethyl ester introduced with the protecting group into imide;
Removing the protecting group to obtain hydrochloride of 3-aminoglutarimide;
A step of condensing the hydrochloride of 3-aminoglutarimide with a natural amino acid having a protective group introduced into an amino group to obtain an amino acid condensation compound;
Removing a protecting group from the amino acid condensation compound and then reacting 4-nitrophenyl chloroformate;
The manufacturing method of the hydantoin derivative of Claim 1 or 2 containing this. Converting L-aspartic acid to dimethyl ester and then introducing a protecting group to the amino group;
Converting aspartic acid dimethyl ester introduced with the protecting group into imide;
Removing the protecting group to obtain hydrochloride of 3-aminosuccinimide;
A step of condensing the hydrochloride of 3-aminosuccinimide with a natural amino acid having a protective group introduced into the amino group to obtain an amino acid condensation compound;
Removing a protecting group from the amino acid condensation compound and then reacting with 4-nitrophenyl chloroformate;
The manufacturing method of the hydantoin derivative of Claim 3 or 4 containing this.

Images