TECHNICAL FIELD

The present disclosure relates to the fields of medicine and chemistry, and more particularly, to benfotiamine derivatives, a method for preparing the same and a pharmaceutical composition comprising the same.

BACKGROUND

Alzheimers disease (AD, commonly known as senile dementia) is a progressive neurodegenerative disorder characterized by cognitive and behavioral disorders. It is one of the most common form of elderly dementia primarily with recognition disorder and rapid decay in memory function. The main pathological features of Alzheimer's disease are senile plaques caused by the deposition of β-amyloid (Aβ) in the brain, neurofibrillary tangles caused by the hyperphosphorylation of tau protein, the glucose dysmetabolism in the brain and the loss of neuronal/synaptic junction. Due to long courses of illness and the poor self-care ability of patients, AD brings serious mental and economic burdens to families and the society. However, currently, few medicines in the worldwide can prevent or slow down the progression of this disease. Medicines on the market now for the treatment of AD are symptomatic, which can only control or improve cognitive and functional symptoms for a period of time, but cannot prevent or delay the deterioration of the disease.

Benfotiamine, chemical name: S-[2-[[(4-amino-2-methyl-5-pyrimidinyl) methyl] formylamino]-1-[2-(phosphonooxy)ethyl]-1-propenyl]ester, the molecular formula: C₉H₂₃N₄O₆PS, which can greatly improve low-bioavailability of water-soluble vitamin B₁and can elevate the thiamine level in the blood and tissues, thereby increasing the curative effect. The present researches on benfotiamine mainly focus on the synthesis method, the crystal form and the application in medicine. Although recent studies have shown that benfotiamine can be used to the preparation of the prevention and treatment of Alzheimer's disease, for example, the patent application CN200710041571.X discloses a pharmaceutical composition containing benfotiamine for the treatment of Alzheimer's disease, no studies have been found on the use of benfotiamine derivatives and medicine uses thereof, particularly the derivatives used in Alzheimer's disease.

SUMMARY

Embodiments of the present disclosure provide benfotiamine derivatives, a method for preparation of the same and a pharmaceutical composition comprising the same.

In an embodiment, benfotiamine derivatives are provided, wherein the benfotiamine derivatives are as shown in formula (1):

[Image Omitted]

wherein, R₁is selected from a group consisting of hydrogen atom, halogen atom, nitro group, cyano group, sulfo group, amino group, carboxyl group, hydroxyl group, sulfydryl group, hydrocarbyl group, substituted hydrocarbyl group, alkoxy group, substituted alkoxy group and acyl group;

R₂is selected from a group consisting of hydrogen atom, halogen atom, nitro group, cyano group, sulfo group, amino group, carboxyl group, hydroxyl group, sulfydryl group, hydrocarbyl group, substituted hydrocarbyl group, alkoxy group, substituted alkoxy group and acyl group;

R₃is selected from a group consisting of hydrogen atom, halogen atom, nitro group, cyano group, sulfo group, amino group, carboxyl group, hydroxyl group, sulfydryl group, hydrocarbyl group, substituted hydrocarbyl group, alkoxy group, substituted alkoxy group and acyl group;

R₄is selected from a group consisting of hydrogen atom, halogen atom, nitro group, cyano group, sulfo group, amino group, carboxyl group, hydroxyl group, sulfydryl group, hydrocarbyl group, substituted hydrocarbyl group, alkoxy group, substituted alkoxy group and acyl group;

R₅is selected from a group consisting of hydrogen atom, halogen atom, nitro group, cyano group, sulfo group, amino group, carboxyl group, hydroxyl group, sulfydryl group, hydrocarbyl group, substituted hydrocarbyl group, alkoxy group, substituted alkoxy group and acyl group; and

wherein at least one of R₁, R₂, R₃, R₄and R₅is not hydrogen atom.

Optionally, only one of R₁, R₂, R₃, R₄and R₅is not hydrogen atom, and any one of the others is hydrogen atom.

Optionally, each one of R₂, R₃, R₄and R₅is hydrogen atom, and R₁is halogen atom or ethoxy group.

Optionally, each one of R₂, R₃, R₄and R₅is hydrogen atom, and R₁is fluorine atom or bromine atom.

Optionally, each one of R₁, R₃, R₄and R₅is hydrogen atom, and R₂is bromine atom, chlorine atom, fluorine atom or nitro group.

Optionally, each one of R₁, R₂, R₄and R₅is hydrogen atom, and R₃is chlorine atom, methoxy group or nitro group.

In an embodiment, a method for preparing the above benfotiamine derivatives is provided, wherein a compound of monophosphothiamine the formula (1a) shows reacts with a compound of benzoyl chloride the formula (1b) shows so as to prepare and obtain the benfotiamine derivatives of the formula (1).