JPS626552B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel 3-ethylidenephthalide derivatives useful as modifiers for prodrugs of pharmaceuticals or protecting group reagents in chemical reactions.

Some pharmaceuticals have high pharmacological activity, but
There are some drugs that cannot fully demonstrate their usefulness as pharmaceuticals due to chemical instability or low bioavailability, and one way to improve these drawbacks is to develop prodrugs. There is a method. This method involves, for example, chemically partially modifying a drug with a low rate of intestinal absorption to increase its rate of intestinal absorption, and restoring it to the original drug in the body through chemical and biological effects, thereby enhancing the drug's original pharmacological activity. This is the way to make it manifest. Various modifying groups have been proposed for this purpose, but prodrugs using these groups are still insufficient in terms of their chemical stability and ability to revert back to the original drug in vivo. Hard to say.

The present invention is particularly useful as a modifier for the above-mentioned prodrugs, and also useful as a protecting group reagent in chemical reactions. (In the formula, X represents a halogen atom.) A novel 3-ethylidenephthalide derivative represented by the following is provided.

3-ethylidenephthalide derivative of the present invention ()
are all new compounds that have not been described in literature, and specific examples include 3-(2-bromoethylidene) phthalide, 3-(2-chloroethylidene) phthalide, and 3-(2-iodoethylidene) phthalide. .

3-ethylidenephthalide derivative of the present invention ()
easily reacts with alcohols, thiols, phenols, carboxylic acids, etc. to produce ether and ester compounds, respectively, but these ether and ester compounds are stable in neutral and acidic media. Although it is easily hydrolyzed under alkaline hydrolysis conditions in normal chemical reactions, it is relatively stable in an alkaline medium equivalent to intestinal fluid, and is easily hydrated in the presence of enzymes in vivo. It is broken down and restored to its original compound.

For example, when a penicillin having a carboxyl group is reacted with a 3-ethylidenephthalide derivative (3-ethylidenephthalide), a corresponding ester is produced. Easily hydrolyzed in the presence of enzymes to restore the original penicillins.

Thus, the 3-ethylidenephthalide derivative () of the present invention is particularly useful as a modifier for pharmaceutical prodrugs.

Furthermore, as mentioned above, the ether type and ester type compounds derived from the 3-ethylidenephthalide derivative () of the present invention are stable in neutral and acidic media, but are easily hydrated under normal alkaline hydrolysis conditions. Since it undergoes decomposition, the 3-ethylidenephthalide derivative () of the present invention is also useful as a protecting group reagent in chemical reactions.

Next, specific examples showing the usefulness of the 3-ethylidenephthalide derivative () of the present invention will be given.

When ampicillin is reacted with a 3-ethylidenephthalide derivative (), ampicillin phthalidylidene ethyl ester hydrochloride represented by the following formula is obtained.

When the above penicillin ester was orally administered to mice and the blood ampicillin concentration was measured 10 minutes later, the blood ampicillin concentration was approximately 4 times higher than when the same potency of ampicillin trihydrate was orally administered. Ta. Moreover, the above penicillin ester was superior in terms of non-enzymatic stability compared to conventional similar esters, such as ampicillin phthalidyl ester hydrochloride (talampicillin hydrochloride), which is ampicillin modified with a phthalidyl group. . That is, when the stability of ampicillin phthalidylidene ethyl ester hydrochloride and talampicillin hydrochloride in a phosphate buffer [PH8.0 (37°C)] was investigated,
The hydrolytic half-life of ampicillin phthalidylidene ethyl ester hydrochloride was approximately 100 minutes, whereas that of talampicillin hydrochloride was less than 10 minutes.

3-ethylidenephthalide derivative of the present invention ()
is 3-ethylidenephthalide (), On the other hand, it is usually obtained by reacting equimolar or excess halogenating agents under radical generation conditions in an inert solvent under heating conditions or at room temperature.

Examples of the halogenating agent include chlorine, bromine, N-bromophthalimide, N-bromosuccinimide, and the like.

In order to generate radicals, ultraviolet rays may be irradiated during the reaction, or a radical generator such as α·α'-azobisisobutyronitrile or benzoyl peroxide may be used, or both may be used in combination.

Examples of the inert solvent include methylene chloride, chloroform, carbon tetrachloride, ethylene tetrachloride, ethylene dichloride, benzene, and a mixed solvent thereof.

In addition, 3-(2-iodoethylidene) phthalide can be obtained by adding sodium iodide or iodine to 3-(2-bromoethylidene) phthalide or 3-(2-chloroethylidene) phthalide obtained by the above method. It can be obtained by the action of potassium chloride.

Next, the present invention will be explained in more detail with reference to Examples and Reference Examples.

Example 3 - Preparation of (2-bromoethylidene) phthalide: 3-ethylidene phthalide [Chem.Ber., 32 ,
958 (1899). ] 52.5 g was dissolved in 1500 ml of carbon tetrachloride, 67.0 g of N-bromosuccinimide and a catalytic amount of α,α'-azobisisobutyronitrile were added thereto, and the mixture was heated under reflux for 40 hours under ultraviolet irradiation. The generated succinimide was filtered off, the filtrate was concentrated under reduced pressure, and the precipitated crystals were collected by filtration to obtain 53 g of 3-(2-bromoethylidene) phthalide as pale yellow needle-like crystals.

Melting point: 106-108°C IR (KBr): 1780 (C = 0), 1685 (exo-olefin) cm ^-1 NMR (CDCl ₃ ) δ: 4.3 (2H, d, J = 8.0Hz, -
CH ₂ Br), 5.7 (1H, t, J=8.0Hz, =CH−),
7.5 (4H, m, benzene ring) Elemental analysis value (as C ₁₀ H ₇ BrO ₂ ): Calculated value (%) C, 50.24; H, 2.95;
Br, 33.42 Actual value (%) C, 50.23; H, 3.09;
Br, 33.13 Reference example Production of ampicillin phthalididene ethyl ester hydrochloride: After suspending 510 mg of ampicillin trihydrate in 5 ml of dimethylformamide, 125 mg of potassium hydrogen carbonate was added.
was added and cooled to 0°C. In this, benzaldehyde
0.25 ml was added dropwise and stirred at 0 to 5°C for 3.5 hours. Next, 145 mg of potassium hydrogen carbonate and 350 mg of 3-(2-bromoethylidene) phthalide were added, and the mixture was further heated at 0 to 5°C.
The mixture was stirred for 3 hours. The reaction solution was added to ice water, and the precipitated solid was extracted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 520 mg of oily N-benzylidene ampicillin phthalidylidene ethyl ester.

Next, 520 mg of the obtained N-benzylidene ampicillin phthalidylidene ethyl ester was dissolved in 3 ml of acetonitrile, and 2 ml of 1N-hydrochloric acid was added thereto.
Stirred at ℃ for 30 minutes. After the reaction mixture was concentrated under reduced pressure, 6 ml of water was added, washed with ethyl acetate, added with common salt, and extracted with methylene chloride. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate.
The solvent was concentrated under reduced pressure, and the precipitated crystals were collected by filtration to obtain 230 mg of ampicillin phthalidylidene ethyl ester hydrochloride as white amorphous crystals.

Melting point 145-155℃ (decomposition)

Claims (1)

[Claims] 1 General formula () (In the formula, X represents a halogen atom.) A 3-ethylidenephthalide derivative represented by the following.