CN102406646B - Arylurea derivatives is for the preparation of the purposes for the treatment of transplant rejection medicine - Google Patents

Abstract

The invention discloses the purposes of a kind of Arylurea derivatives for the preparation for the treatment of transplant rejection medicine, described Arylurea derivatives is 1-(4-(trifluoromethyl)-phenyl)-3-(3-(6-(1-methyl-4-pyrazolyl)-4-2-pyrimidinyl oxy) the fluoro-phenyl of-6-) urea.The compounds of this invention obviously can alleviate the rejection of body to transplant organ, improve transplant organ function, may be used for the medicine preparing control organ transplantation immunological rejection, especially for the medicine of immunological rejection after preparation control renal transplantation, liver transplantation or heart transplant operation.

Description

Arylurea derivatives is for the preparation of the purposes for the treatment of transplant rejection medicine

Technical field

The present invention relates to Arylurea derivatives and preparing the application in immunosuppressive drug, the application particularly in the immunosuppressive drug for the preparation of control organ transplant rejection.

Background technology

Over nearly 30 years, along with the immunobiologic progress of transplant organ rejection, particularly anti-immunological rejection medicine use clinically, makes the quantity of organ transplantation, kind and success rate all be significantly improved.At present, rhzomorph (CsA) encircled by the most frequently used anti-immunological rejection medicine, and CsA is actually a kind of immunosuppressant, and it is the immunological rejection by suppressing in body, improves the function of transplant organ and extend the time-to-live.But the toxic and side effects of the hepatotoxicity of the dependent dose that CsA causes and nephrotoxicity etc., and the price of costliness, make the use of CsA be restricted.

At present, have been found that 30 kinds of immunosuppressant nearly, wherein part is used for the treatment of Organ Transplantation Patients immunological rejection clinically.Test finds, the medicine of these new developments, also has the problem similar with CsA.Therefore, finding effective, that toxic and side effects is little and drug cost the is lower novel drugs that can be used for anti-immunological rejection, is when previous important subject.

Summary of the invention

The object of this invention is to provide formula I and prepare the application in immunosuppressive drug; Application particularly in the immunosuppressive drug for the preparation of control organ transplant rejection.

WO2007076473 disclosed formula I in 2007:

And refer to the purposes that this compound is used as raf kinase inhibitor.The Chinese named of formula I is:

1-(4-(trifluoromethyl)-phenyl)-3-(3-(6-(1-methyl-4-pyrazolyl)-4-2-pyrimidinyl oxy) the fluoro-phenyl of-6-) urea.

The present inventor is surprised to find, and formula I has unexpected outstanding effect in treatment transplant rejection.

Experiment of the present invention proves, formula I has significant immunosuppressive action.Animal model test proves further, and formula I obviously can alleviate the rejection of body to transplant organ, improves transplant organ function, extends the grafting device wife's term of address for husband or other mammiferous survival period.

Examination face of the present invention shows, the compounds of this invention may be used for the immunosuppressive drug preparing control organ transplantation immunological rejection, especially for the medicine of immunological rejection after preparation control renal transplantation, liver transplantation or heart transplant operation.

For renal transplantation, acute rejection occurred in renal transplantation after one week, showed as patient's heating, hypourocrinia, hypertension, transplanted kidney tenderness, serum creatinine rising.Chronic rejection: after generally occurring in six months of renal transplantation, after can occurring in three months the earliest.Show as transplanted kidney function little by little to reduce, have albuminuria or hematuria, hypertension etc., the state of an illness is slowly in progress, and finally causes the forfeiture of transplanted kidney function.

The compounds of this invention can be used for the acute and chronic allograft rejection after organ transplantation, is particularly useful for the acute and chronic allograft rejection after liver transplantation or renal transplantation.

The compounds of this invention can also have the Drug combination treating organs graft-rejection of immune suppression function with other.

Formula I preferably with venoclysis and oral administration, preferably administration in the form of tablets or capsules.Other administration route is also feasible, such as, by implant, parenteral (except intravenously administrable, as intraperitoneal and subcutaneous injection), rectally, intranasal administration, intravaginal administration and percutaneous dosing.

Can adjust dosage according to route of administration.Such as, qf oral administration dosage usually exceeds intravenously administrable dosage 10 times.

Formula I can be used as unique active therapeutic agent administration or carries out administration as the part in the therapeutic scheme containing more than one resisting transplant rejection agent.Utilize synergistic therapeutic agent usually to require to reduce often kind of certain drug dosage, thus add the safety range of particular agent.

Oral formulations containing reactive compound of the present invention can comprise any traditional oral form, comprises tablet, capsule, cheek form, buccal tablet, lozenge and liquid oral, suspension or solution.Capsule can contain reactive compound and inert filler and/or diluent knows that the acceptable starch of pharmacy is (as Semen Maydis, Rhizoma Solani tuber osi or tapioca), saccharide, artificial sweetener, powdery cellulose is as crystallization and microcrystalline Cellulose, flour, gelatin, the mixture of natural gum etc. useful tablet is by traditional compacting, the thick method of wet system or drying traction therapy also utilize the acceptable diluent of pharmacy, binding agent, lubricant, disintegrating agent, surface modifier (comprising surfactant), suspending agent or stabilizing agent, include but are not limited to: magnesium stearate, stearic acid, Talcum, sodium lauryl sulphate, microcrystalline Cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidone, gelatin, alginic acid, arabic gum, xanthan gum, sodium citrate, composition silicate, calcium carbonate, glycine, dextrin, sucrose, sorbitol, calcium hydrogen phosphate, calcium sulfate, lactose, Kaolin, mannitol, sodium chloride, Talcum, dried starch and Powdered saccharide.Preferred surface modifier comprises nonionic and anionic surface modifier.The representative illustration of surface modifier includes but are not limited to: PLURONICS F87, geramine, calcium stearate, cetostearyl alcohol, Isosorbide Dinitrate, silica sol, phosphate, sodium lauryl sulphate, Magnesiumaluminumsilicate and triethanolamine. and the delay of usable criterion oral processed herein or Co ntrolled release preparation are to change the absorption of reactive compound.Oral formulations also comprises the active component in the water or fruit juice be included in containing required suitable solubilizing agent or emulsifying agent.

Compound of the present invention is also by parenteral or Intraperitoneal medication.Can at the solution being suitable for preparing in the water mixed as hydroxypropyl cellulose with surfactant as these compounds of free alkali or pharmaceutically acceptable salt or suspension.Also can glycerol, liquid macrogol and with the mixture of oil in prepare dispersion.Under normal storage and application conditions, these preparations contain antiseptic to prevent growth of microorganism.

The medicament forms being suitable for injecting application comprises aseptic aqueous solution or dispersion and the sterilized powder for extemporaneous preparation of sterile injection and dispersion.In all cases, these forms are necessarily aseptic thus preserve the ability being easy to inject.It is necessarily stable under preparation and storage requirement, and is stored in microorganism can be prevented as under the condition of antibacterial and fungal contamination.Carrier can be the molten other or disperse medium containing, for example water, ethanol, polyhydric alcohol (as glycerol, propylene glycol and liquid macrogol), their suitable mixture and vegetable oil.For the object of content disclosed by the invention, percutaneous dosing is interpreted as all administrations carried out with the body passage comprising epithelium and mucosal tissue by body surface.Such administration is carried out with lotion, cream, foam, patch, suspension, solution and suppository (rectum and vagina) form by utilizing compound of the present invention or the acceptable salt of its pharmacy.

The effect of the compounds of this invention resisting transplant rejection is proved further by following examples.

Detailed description of the invention

Embodiment 1: the effect that the In vitro culture of dendritic cell and formula I are expressed its surface molecular

Venous puncture health adult peripheral blood 50ml/ people, EDTA-K3 anticoagulant, is separated PBMC with Ficoll-Hypaque, and with RPMI1640 suspension cell completely, adjustment cell concentration is 2 × 10 ⁶/ ml, add in 24 well culture plates, every hole 0.5ml, 37 DEG C, 5%CO2 incubator cultivates 2h, make adherent mononuclear cells wherein, wash culture plate gently to remove non-adherent cell with the RPMI1640 liquid of warm serum-free, namely obtain adherent mononuclear cell, in culture plate, add the AIM-V culture medium containing rhGM-CSF 1000IU/ml, rh-IL-4800IU/ml, be placed in 37 DEG C of 5%CO2 incubators, half amount changes culture fluid every other day.At the 3rd and the 5th day that cultivates, every hole added LPS (1 μ g/ml), is divided into two groups, be respectively formula I effect group and do not act on group, at the 7th day that cultivates, in formula I effect group, add the formula I of 100 μ g/ml, Dual culture 10 days.

Collect the cell suspended, this suspension cell is dendritic cell, the expression of flow cytometer detection HLA-DR, CD80, CD83, CD86, CD11c, CD3, CD14.Found that, after using formula I, the positive rate of CD80, CD86, CD83 of Healthy People 1 expressed by dendritic cells is all obviously lowered, and difference all has significance (P < 0.01) compared with before and after stimulation, and concrete comparative result is in table 1.

The comparison that before and after the meridional I effect of table 1. Healthy People dendritic cell, DC surface molecular is expressed

* statistical significance (P < 0.01) is indicated

Dendritic cell (dendritic cell, DC) be unique antigen presenting cell that can activate Naive T cells known at present, T lymphocyte can be regulated, the function of bone-marrow-derived lymphocyte, be in startup, regulate and control and maintain the key link of specific immune response.

By to the separation of healthy human peripheral blood dendritic cell (DC) and cultivation, and inquire into the effect of DC conversion process compounds of formula I in vitro, discoverable type I can participate in adjustment that is ripe to DC and immunostimulatory potency, the stimulation of formula I can suppress differentiation and the maturation of people DC, thus Immunosuppression response, reach immunologic tolerance.

The DC phenotype of formula I stimulating group is compared with non-stimulating group, and the expression of CD80, CD83, CD86 significantly reduces, and the expression of CD14 significantly raises.CD83 is the important symbol of DC maturation, in DC functionating, have important function, and viral infection can lower the expression of CD83, thus the antiviral immunity reaction suppressing body to produce; CD14 is then monocytic specific molecular marker, and its expression height prompting DC transforms not good enough; CD80/CD86 is the co-stimulators on DC surface, and its reduction expressed can affect the function of the antigen presentation of DC.Result shows, under the effect of formula I, healthy human peripheral blood mononuclear cell to DC phenotype in DC conversion process and maturation all lower than non-stimulating group.

Embodiment 2:

The healthy male Wistar rat of cleaning grade is as donor, body weight 180-230g, the healthy male SD rat of cleaning grade is as receptor, body weight 220-260g, according to forefathers' research (happy and carefree. liver transplantation animal model // Zheng Shusen. liver transplantation. Beijing: People's Health Publisher .2001:140-143), utilize improvement double-jacket tube method to set up orthotopic liver transplantation model.

Liver transplantation rat model is divided into 5 groups at random, often organize 9, wherein 3 groups of respectively giving construction I 2.0,10.0 and 50.0mg/kg/d, other 2 groups give CsA (10.0mg/kg/d) and normal saline (0.5ml/d) respectively in contrast, are abdominal channels administration.Observe the time-to-live of each group of rat, the results are shown in Table 2.

The table 2 liver transplantation survival of rats time compares

Relatively find, the time-to-live of formula I 10.0 and 50.0mg/kg/d group is obviously longer than saline control group (P < 0.01), formula I has the effect of obvious resisting transplant rejection reaction, and, the time-to-live of formula I 50.0mg/kg/d group, formula I 50.0mg/kg/d group was slightly better than CsA matched group compared with CsA matched group.

Claims (6)

1. formula I is for the preparation of the purposes of the medicine for the treatment of transplant rejection,

。

2. purposes according to claim 1, wherein, described transplant rejection is acute transplantation rejection.

3. purposes according to claim 1, wherein, described transplant rejection is chronic transplanting rejection.

4. purposes according to claim 1, wherein, described transplant rejection is that liver transplantation is repelled.

5. purposes according to claim 1, wherein, described transplant rejection is renal transplant rejection.

6. purposes according to claim 1, wherein, described transplant rejection is cardiac transplant rejection episode.