CN103787949A - Compound for protecting transplanted organs and application thereof - Google Patents
Compound for protecting transplanted organs and application thereof Download PDFInfo
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- CN103787949A CN103787949A CN201310524006.4A CN201310524006A CN103787949A CN 103787949 A CN103787949 A CN 103787949A CN 201310524006 A CN201310524006 A CN 201310524006A CN 103787949 A CN103787949 A CN 103787949A
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- compound
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- acceptable salt
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention discloses a compound as well as a drug composition and new application thereof. The compound is applied to drugs for protecting transplanted organs. The compound can relieve symptoms of rejection reaction and can effectively inhibit rejection reaction after organ transplantation. Animal experiments prove that the compound disclosed by the invention has a very obvious effect on protecting the transplanted organs and can effectively improve the living conditions of animals receiving organ transplantation.
Description
Technical field
The present invention relates to compound and pharmacologically acceptable salt and its analogue of a class protection transplant organ; the pharmaceutical composition of being prepared by above-claimed cpd and pharmacologically acceptable salt thereof and its analogue, and described compound or pharmaceutically acceptable salt thereof and analogue thereof suppress the purposes in the medicine of organ transplant rejection in preparation.
Background technology
Organ transplantation is a kind of very important treatment means,, being described as the great life science progress that changes human lives 20th century, China has totally successfully carried out organ transplantation 110,000 examples at present, be the second largest organ transplantation state that is only second to the U.S., transplant number and maintain the leading position.Legal and illegal organ transplantation conservative estimation in worldwide, totally carries out examples up to a million.And after organ transplantation, sixty-four dollar question is exactly the acute or long-standing immunological rejection of short-term.
At present in the treatment of the rejection for inhibition organ transplantation, main employing pharmacological agent, main drug application is Ciclosporin A clinically, this effect of drugs is single, the immunologic rejection reaction that is mainly used in kidney, liver, the heart, lung, bone marrow transplantation is upper, but obtains exactissima diligentia using dosage when its untoward reaction in cardiovascular, kidney and central nervous system makes it in application; Tacrolimus and sirolimus are macrolide immunosuppressants, its immunosuppressive effect is 10-100 times of ciclosporin, but macrolide immunosuppressants can cause the illnesss such as renal dysfunction, hypertension, hyperglycemia, leukocytosis and high potassium hypomagnesemia; DNA synthetic inhibitor, as azathioprine, mycophenlate mofetil texts, and can cause the side effects such as gastrointestinal reaction, blood system obstacle, oligoleukocythemia, dysfunction of liver; Report that in addition trypterygine, Schuttgelb etc. are at the report of the provide protection of organ transplantation, but in general, many medicines of the whole provide protection for organ transplantation, effect all can not be satisfactory.
The inventor is surprised to find that one group of compound and similar compound or its pharmacologically acceptable salt thereof have an unexpected effect on the medicine of preparation inhibition organ transplant rejection, suppress organ transplant rejection for this compounds at present and there is no report.
Summary of the invention
The invention provides one group of compound and similar compound thereof or its pharmacologically acceptable salt new purposes in the medicine of preparation inhibition organ transplant rejection.
Technical scheme of the present invention is as follows:
The invention provides one group of compound or pharmaceutically acceptable salt thereof that can suppress organ transplant rejection disease, and analogue, the structure of described compound is as follows:
compound (B);
Above formula compound and analogue thereof or its pharmacologically acceptable salt can be prepared into through topical, the various preparations of gastrointestinal administration or parenteral administration.Described preparation comprises ordinary preparation, controlled release preparation, targeting preparation etc.Described local administration preparation is through the powder injection of organ administration, aqueous injection, microball preparation, nanometer formulation, Liposomal formulation, dendrimer preparation, polyethyleneglycol modified preparation, aqueogel etc.Described parenteral administration preparation is the formulation of suitable intravenous injection, intramuscular injection, subcutaneous injection, bone marrow injection, transdermal administration, mucosa delivery and inhalation.
The inventor studies discovery: this compounds can greatly be alleviated inhibition organ transplant rejection symptom, and from the result of pharmacodynamic experiment, the effect of the inhibition rejection of this compounds exceeds the medicine of current clinical application.The exploitation of this new compound is by for to play very large effect to the recovery of following Organ Transplantation Patients.For removing sufferer misery, the quality of life that improves patient is significant.
Accompanying drawing explanation
fig. 1mouse liver transplantation Histopathological Studies result, is followed successively by Ciclosporin A, medicine A, medicine B, medicine C
Embodiment
The present invention's compound used can be purchased, and also can be prepared according to disclosed preparation method, and it does not limit the scope of the invention.
medicine Preparation Example
compound (B);
compound (C).
Preparation containing compd A lyophilized injection:
1. altogether 50mg and 900mg formula (A) compound mix and make it dissolving in water for injection to get N.F,USP MANNITOL, phosphatide, glycerine, cyclodextrin derivative, dimethyl sulfoxide (DMSO) and poloxamer;
2. after mixing dissolving, after stable, first use 0.45um millipore filtration coarse filtration, then use 0.2um filtering with microporous membrane;
3. be distributed into little cillin bottle, add other lyophilized vaccines and auxiliary material;
4. carry out procedural freeze-drying;
5. carry out the corresponding inspections such as pyrogen, aseptic, visible foreign matters, particulate matter, stand-by after all meeting the requirements.
Preparation containing compd B lyophilized injection:
1. altogether 50mg and 900mg formula (B) compound mix and make it dissolving in water for injection to get N.F,USP MANNITOL, phosphatide, glycerine, cyclodextrin derivative, dimethyl sulfoxide (DMSO) and poloxamer;
2. after mixing dissolving, after stable, first use 0.45um millipore filtration coarse filtration, then use 0.2um filtering with microporous membrane;
3. be distributed into little cillin bottle, add other lyophilized vaccines and auxiliary material;
4. carry out procedural freeze-drying;
5. carry out the corresponding inspections such as pyrogen, aseptic, visible foreign matters, particulate matter, stand-by after all meeting the requirements.
Preparation containing the dry injection of Compound C:
1. altogether 50mg and 900mg formula (C) compound mix and make it dissolving in water for injection to get N.F,USP MANNITOL, phosphatide, glycerine, cyclodextrin derivative, dimethyl sulfoxide (DMSO) and poloxamer;
2. after mixing dissolving, after stable, first use 0.45um millipore filtration coarse filtration, then use 0.2um filtering with microporous membrane;
3. be distributed into little cillin bottle, add other lyophilized vaccines and auxiliary material;
4. carry out procedural freeze-drying;
5. carry out the corresponding inspections such as pyrogen, aseptic, visible foreign matters, particulate matter, stand-by after all meeting the requirements.
effect embodiment:
1 provide protection of medicine A-C to mouse transplant organ
1.1 laboratory animal and grouping
Adopt the clean level of healthy adult rat, male, body weight 200-300g.Raising condition meets SPF standard.Acceptor body weight is slightly larger than donor.Preoperative fasting, adopts chlorine peace ketone 75mg/kg intraperitoneal injection of anesthesia, under operating microscope, operates.According to Meng Kewei, the method that the mad expert of grade of Lee ancestor successively reports is carried out rat orthotopic liver transplantation.Method referring to the foundation of the orthotopic liver transplantation model of the 18th the 1st phase of volume in 2004 of Chinese Reconstructive surgery magazine and art formula is improved and the Schuttgelb of the 13rd the 5th phase of volume in 2009 of Chinese Tissue Engineering Study and clinical rehabilitation on Rat Liver Transplantation after the impact of hepatocellular apoptosis in acute rejection.Establish after model, 100 animal models that delivery type is successfully prepared are by being divided at random 5 groups, 20 every group.After transplanting, within the 1st day, start to carry out intraperitoneal injection by echelon design, model control group only gives physiological saline, medicine A group gives medicine A 0.5mg/(kgd), medicine B group gives medicine B 0.5mg/(kgd), medicine C group gives medicine C 0.5mg/(kgd), contrast medicine Ciclosporin A group gives Ciclosporin A 3 mg/(kgd).After transplanting, within the 7th day, get blood, and put to death at random 8 rats in each group, get the micro-Microscopic observation pathologic condition of liver specimens, remaining rat continues the breeding observing survival time.
1.2 testing index
Observe and record each group of mouse operation survival rate, survival time.Get and transplant latter the 7th day each group execution rat liver sample, carry out hematoxylin-eosin staining, under mirror, observe, detect the situation of transaminase in blood (ALT) simultaneously.
1.3 statistical analysis
Each group rat is observed the data obtained with mean ± standard deviation (x ± s) represent.Between group, carry out t check.
1.4 experimental result
1.4.1 medicine is on suppressing the impact of organ transplant rejection
Model group is due to organ transplant rejection, and liver is affected, and function reduces, so ALT level significantly raises; With model group comparison, medicine A-C all can significantly reduce ALT level (P<0.01), and action effect be far better than contrast ciclosporin group (P<0.01), refer to table 1.
Table 1 different dosing group is on suppressing the impact of ALT in organ transplant rejection rat serum
| Group | ALT ( IU /L ) |
| Model group | 1050.5±170.4 |
| Medicine A group | 200.1±33.5** |
| Medicine B group | 202.5±23.8** |
| Medicine C group | 190.7±51.2** |
| Ciclosporin A | 488.66±90.2* |
With relatively * P<0.05**P<0.01 of model group
1.4.2 the comparison of survival time after mouse organ transplantation
The survival time of medicine A-C group is obviously longer than model group and positive drug ciclosporin control group, and effect significantly.Refer to table 2.
The contrast of table 2 survival of rats time
| Group | Survival time (my god) |
| Model group | 7.1±1.3 |
| Medicine A group | 30.6±5.0** |
| Medicine B group | 34.1±3.6** |
| Medicine C group | 31.1±2.7** |
| Ciclosporin A | 10.4±2.9* |
With relatively * P<0.05**P<0.01 of model group
1.4.3 histological observation result:
The histological observation result of liver, medicine A, B, C group is significantly better than model group and positive drug ciclosporin control group, and effect is significantly.Refer to Fig. 1.
Comprehensive above-mentioned experimental result is reached a conclusion: compound (A), and (B), the medicine of (C) preparing all can obviously improve the rejection symptom of organ transplantation, plays the provide protection to transplant organ preferably, and its action effect is significantly better than current clinical application.
Claims (8)
1. a class can be protected the compound or pharmaceutically acceptable salt thereof of transplant organ, and analogue, and the structure of described compound is as follows:
Compound (A);
compound (B);
Compound (C).
2. a pharmaceutical composition, it comprises compound claimed in claim 1 and pharmacologically acceptable salt and its analogue.
3. the pharmaceutical composition of claim 2, it can be ordinary preparation, controlled release preparation, targeting preparation etc.
4. the pharmaceutical composition of claim 2, described compound and pharmacologically acceptable salt thereof and its analogue are prepared into through topical, the various preparations of gastrointestinal administration or parenteral administration.
5. topical described in claim 4, for being directly administered into the various preparations of organ.
6. compound and pharmacologically acceptable salt thereof and its analogue purposes in the medicine of preparation protection transplant organ described in claim 2.
7. compound and pharmacologically acceptable salt thereof and its analogue purposes in the medicine of preparation inhibition organ transplant rejection described in claim 2.
8. the purposes of claim 7, the inhibition organ transplant rejection described in it comprises rejection or the relative disease that the various organ transplantations except head produce.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310524006.4A CN103787949A (en) | 2012-10-31 | 2013-10-30 | Compound for protecting transplanted organs and application thereof |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210437672.X | 2012-10-31 | ||
| CN201210437672 | 2012-10-31 | ||
| CN201310524006.4A CN103787949A (en) | 2012-10-31 | 2013-10-30 | Compound for protecting transplanted organs and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103787949A true CN103787949A (en) | 2014-05-14 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310524006.4A Pending CN103787949A (en) | 2012-10-31 | 2013-10-30 | Compound for protecting transplanted organs and application thereof |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090286789A1 (en) * | 2005-11-01 | 2009-11-19 | Targegen, Inc. | Bi-Aryl Meta-Pyrimidine Inhibitors of Kinases |
| US20100311985A1 (en) * | 2007-12-03 | 2010-12-09 | Boehringer Ingelheim International Gmbh | Indolinone derivatives and process for their manufacture |
-
2013
- 2013-10-30 CN CN201310524006.4A patent/CN103787949A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090286789A1 (en) * | 2005-11-01 | 2009-11-19 | Targegen, Inc. | Bi-Aryl Meta-Pyrimidine Inhibitors of Kinases |
| US20100311985A1 (en) * | 2007-12-03 | 2010-12-09 | Boehringer Ingelheim International Gmbh | Indolinone derivatives and process for their manufacture |
Non-Patent Citations (1)
| Title |
|---|
| WILLIAM R. ANTONIOS-MCCREA等: "LHMDS mediated tandem acylation–cyclization of 2-aminobenzenecarbonitriles with 2-benzymidazol-2-yl acetates: a short and efficient route to the synthesis of 4-amino-3-benzimidazol-2-ylhydroquinolin-2-ones", 《TETRAHEDRON LETTERS》 * |
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| PB01 | Publication | ||
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| RJ01 | Rejection of invention patent application after publication | ||
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Application publication date: 20140514 |