CN103804353A - Compounds for treatment of schizophrenia and their use - Google Patents
Compounds for treatment of schizophrenia and their use Download PDFInfo
- Publication number
- CN103804353A CN103804353A CN201210442387.7A CN201210442387A CN103804353A CN 103804353 A CN103804353 A CN 103804353A CN 201210442387 A CN201210442387 A CN 201210442387A CN 103804353 A CN103804353 A CN 103804353A
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- compound
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- acceptable salt
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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
- C07D401/12—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 linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
-
- 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
-
- 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
- C07D401/06—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 linked by a carbon chain containing only aliphatic carbon atoms
Abstract
The invention discloses compounds, their pharmaceutical compositions and their new use, the new use is the use in drugs for the treatment of schizophrenia, and the compounds have very obvious effects on the treatment of the schizophrenia.
Description
Technical field
The present invention relates to a class and treat schizoid compound and pharmacologically acceptable salt and its analogue, 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 the purposes of analogue in the schizoid medicine of preparation treatment thereof.
Background technology
Schizophrenia is a kind of common mental disorder, and the collapse of degree varies appears in the form of thinking that symptom is sufferer and emotional reactions.Common symptom comprises phonism, photis, bigoted, vain hope and mixed and disorderly speech and thinking, can not adapt to the requirement of society and occupation.Patient shows initial stage symptom in the young and the middle aged conventionally, and wherein approximately 2% patient is all the life with this disease.If schizophrenia can not be cured for a long time, or state of an illness multiple relapse, patient just there will be the persistence symptoms such as poverty of thought, apathy, aboulia.Patient there will be serious disturbance in thinking, incoherence of speech without chapter, and the situation of hurting sb.'s feelings also may appear in this class patient.Persecutory delusion is the modal performance of schizophreniac, and patient usually thinks that someone will do harm to him, and watches out for others everywhere, also therefore lives in for a long time in fear.Most patient is taked the attitude of restraining oneself, escaping, and a few patients also can be to his " skeleton enemy " active attack, to the very large threat of stable formation of own residing family and society.
Conventionally for serious schizophrenia sufferer, adopt the treatment meanss such as insulin induced coma, electroshock and cerebral surgery operation, wherein electro-shock therapy remains first-selected therapeutic modality to some cases, and other two kinds of therapeutic modalities seldom use.Mostly adopt antipsychotic medications for general schizophreniac.The types of drugs that mental disorder uses is at present more, reach hundreds of so treat clinically the drug use scheme of mental disorder, wherein leoponex, risperidone, Kui sulphur is flat, and Aripiprazole and some mood stabilizers (comprising Sodium Valproate, slow-releasing magnesium propylvalerate tablet and Quilonum Retard etc.) are main flow medications.Due to the difference of result for the treatment of, the clinical usage quantity that current risperidone or risperidone are combined leoponex reaches more than 60%, is far longer than the usage quantity of other drug.These medicines are selectivity monoaminergic antagonist mostly, there is very high avidity with the 5-HT2 acceptor of serotonin energy and the D2 acceptor of Dopamine HCL, also can be combined with adrenergic receptor, and be combined with H1-histaminergic acceptor and α 2-adrenoceptor with lower avidity, but said medicine all very easily produces cone vitro reactions, again or cause the damage of liver function, renal function and sexuality, and along with social high speed development, the diversification of mental patient's state of an illness of today, the adaptability of medicine and result for the treatment of are all not so good as in the past.Therefore be badly in need of releasing a kind of novel medicine.The inventor is surprised to find that some compounds and similar compound or its pharmacologically acceptable salt thereof have an unexpected effect on the schizoid medicine of preparation treatment, there is no report for this compounds for treating schizophrenia at present.
Summary of the invention
The invention provides one group of compound and similar compound thereof or its pharmacologically acceptable salt new purposes in the schizoid medicine of preparation treatment.
Technical scheme of the present invention is as follows:
The invention provides the one group of compound or pharmaceutically acceptable salt thereof that can treat schizophrenia disease, and analogue, the structure of described compound is as follows:
Compound (A);
Compound (B);
Compound (C);
Compound (D);
Compound (E);
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 head 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 the symptoms of schizophrenia, and from the result of pharmacodynamic experiment, the effect of this compounds exceeds the medicine of current clinical application.Be significant for the misery of removing sufferer and its family.
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 therapeutic domain of the present invention.
Medicine Preparation Example
Compound (A);
Compound (B);
Compound (C);
Compound (D);
Compound (E);
Preparation containing compd A lyophilized injection:
1. altogether 50mg and 950mg 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 freeze-drying therapeutical agent and auxiliary materials;
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 950mg 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 freeze-drying therapeutical agent and auxiliary materials;
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 Compound C lyophilized injection:
1. altogether 50mg and 950mg 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 freeze-drying therapeutical agent and auxiliary materials;
4. carry out procedural freeze-drying; Carry out the corresponding inspections such as pyrogen, aseptic, visible foreign matters, particulate matter, stand-by after all meeting the requirements.
Preparation containing Compound D lyophilized injection:
1. altogether 50mg and 950mg formula (D) 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 freeze-drying therapeutical agent and auxiliary materials;
4. carry out procedural freeze-drying; And carry out the corresponding inspections such as pyrogen, aseptic, visible foreign matters, particulate matter, stand-by after all meeting the requirements.
Preparation containing compd E lyophilized injection:
1. altogether 50mg and 950mg formula (E) 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 freeze-drying therapeutical agent and auxiliary materials;
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:
Medicine A-E is to the schizoid therapeutic action of mouse
Prepare: 160 of male Wistar rats, body weight 200-220 gram, animal rearing is in the diel rhythm Animal House of 12/12 hour, and envrionment temperature is controlled at 22 ± 2 ℃, humidity 55-60%, rat ad lib and drinking-water.Adapt to after 3 days at Animal House, rat is divided into 8 groups at random, control group (normal rat, only give physiological saline), model group (administration ketamine modeling, but do not treat), risperidone medication group (existing clinical application, powder injection), medicine (A-E) group.Medicine (A-E) group is by muscle injection mode administration.
Modeling: raise by the mouse cage of 25 × 45 × 15cm size (10, every cage).Except control group, other respectively organizes rat and gives ketamine 30mg/kg pre-treatment every day, according to the volume of 1ml/100g, and intraperitoneal injection ketamine 5 days, control rats was according to the continuous physiological saline injection of same route of administration 5 days.
Treatment: from testing the 6th day, divide cage list only to feed ketamine treatment group rat and control rats, ketamine treatment group is given respectively to the drug intervention of different embodiment compounds (A-E), control group gives physiological saline, risperidone group gives risperidone, successive administration 7 days.Intervene the 6th day and the 7th day in administration, every rat adapts to social interaction test box 7 minutes every day.Within the 7th day last adapts to, behind place, each group of rat be matched between two in group, allow on the same group, every pair of rat is familiar with mutually, poor being controlled in 20g of body weight of every pair of rat.
Test and inspection: then carry out social interaction test, test box is 100 × 100 × 40cm (length × wide × height) wooden case.This wooden case is placed in an airtight test room, and viewer, by by the camera that is placed in room roof, observes and record the behavior of animal in next door room with camera on the computer being connected.Illumination level between test room is that (optical throughput of the ordinary incandescent lamp of a 40W is 350lm-470lm to 30lx for lux, illumination when lux (lx) is equivalent on every square metre of face to be illuminated that optical throughput is 1 lumen (lm).Stopping after the drug intervention same day and drug withdrawal the 7th day, record respectively the social interaction behavior of each assembly to rat, test period is 7 minutes.Rat social interaction behavior is divided into non-attacking behavior (smell news with companion, trail, manage hair, sociability is played) and Aggression (with companion's savate, boxing, tumbles, and stings).Record the overall activity time of every rat at test period simultaneously.
The result (n=20) of table 1 embodiment compound to the rat Split disease ketamine overall activity time of rat model
With model group comparison
*p < 0.05
*p < 0.01
Each group rat is observed the data obtained with mean ± standard deviation (x ± s) represent.Statistical treatment is with variance analysis.
The impact (n=20) of table 2 embodiment compound on rat Split disease ketamine rat model social interaction behavior
Note: table 2 is for the drug withdrawal result on the same day, with model group comparison
*p < 0.05
*p < 0.01
Result demonstration, the overall activity time, medicine group A-E approaches normal group very much, shows that result for the treatment of is better than risperidone group and model group.The minimizing that ketamine Split disease model causes rat social behavior is after the pharmacological agent by giving compound (A)-(E) prepare, this phenomenon is obviously improved, and the effect of the more current clinical main drug application risperidone of effect will be got well, and after medication, rat Aggression obviously reduces.After treatment, the result on drug withdrawal same day shows, compound (A)-medicine group of (E) preparing can obviously increase the non-attacking behavior per-cent of rat, makes it approach the non-attacking behavior number of times of Normal group.
Comprehensive above-mentioned experimental result is reached a conclusion: compound (A), (B), (C), (D), (E) medicine of preparing all can obviously improve the symptom of schizophrenia, play extraordinary therapeutic action, its result for the treatment of is significantly better than clinical application risperidone.
Claims (8)
1. a class can be treated schizoid compound or pharmaceutically acceptable salt thereof, and analogue, and the structure of described compound is as follows:
Compound (A);
Compound (B);
Compound (C);
Compound (D);
Compound (E).
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 is the various preparations of head administration.
6. compound and pharmacologically acceptable salt thereof and its analogue purposes in the schizoid medicine of preparation treatment described in claim 2.
7. the purposes of claim 6, described schizoid treatment contains the treatment to delusional type, chaotic type, a stiff type, residual flow type spirit classification disease.
8. the purposes of claim 6, described schizoid treatment refers to the treatment of spirit classification disease and associated conditions thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210442387.7A CN103804353A (en) | 2012-11-01 | 2012-11-01 | Compounds for treatment of schizophrenia and their use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210442387.7A CN103804353A (en) | 2012-11-01 | 2012-11-01 | Compounds for treatment of schizophrenia and their use |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103804353A true CN103804353A (en) | 2014-05-21 |
Family
ID=50701788
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210442387.7A Pending CN103804353A (en) | 2012-11-01 | 2012-11-01 | Compounds for treatment of schizophrenia and their use |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103804353A (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1483028A (en) * | 2000-09-11 | 2004-03-17 | ϣ | Quinolinone derivatives as tyrosine kinase inhibitors |
| CN1665787A (en) * | 2002-04-30 | 2005-09-07 | 惠氏控股公司 | Process for the preparation of 7-substituted-3-quinoline and 3-quinol-4-one carbonitriles |
| CN101115485A (en) * | 2005-02-04 | 2008-01-30 | 贝林格尔·英格海姆国际有限公司 | Use of EGFR tyrosine kinase inhibitors for the treatment of chronic rhinosinusitis |
| WO2012071321A1 (en) * | 2010-11-22 | 2012-05-31 | Glaxosmithkline Llc | Method of treating cancer |
-
2012
- 2012-11-01 CN CN201210442387.7A patent/CN103804353A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1483028A (en) * | 2000-09-11 | 2004-03-17 | ϣ | Quinolinone derivatives as tyrosine kinase inhibitors |
| CN1665787A (en) * | 2002-04-30 | 2005-09-07 | 惠氏控股公司 | Process for the preparation of 7-substituted-3-quinoline and 3-quinol-4-one carbonitriles |
| CN101115485A (en) * | 2005-02-04 | 2008-01-30 | 贝林格尔·英格海姆国际有限公司 | Use of EGFR tyrosine kinase inhibitors for the treatment of chronic rhinosinusitis |
| WO2012071321A1 (en) * | 2010-11-22 | 2012-05-31 | Glaxosmithkline Llc | Method of treating cancer |
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| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20140521 |
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| WD01 | Invention patent application deemed withdrawn after publication |