CN103800339A - Compounds for treatment of schizophrenia and their use - Google Patents

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

One class is treated schizoid compound and uses thereof

Technical field

The present invention relates to a class and treat schizoid compound and officinal salt and its analog, the pharmaceutical composition of being prepared by above-claimed cpd and officinal salt thereof and its analog, and described compound or pharmaceutically acceptable salt thereof and the purposes of analog in the schizoid medicine of preparation treatment thereof.

Background technology

Schizophrenia is a kind of common mental sickness, and the collapse of degree varies appears in the form of thinking that symptom is sufferer and emotional response.Common symptom comprises auditory hallucination, 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 the poverty of thought, apathy, aboulia.Patient there will be serious disturbance in thinking, contamination without chapter, and the situation of hurting sb.'s feelings also may appear in this class patient.Delusion of persecution is the modal performance of schizophrenic, 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, galvanic shock and cerebral surgery operation, wherein electric shock treatment remains first-selected therapeutic modality to some cases, and other two kinds of therapeutic modalities seldom use.Mostly adopt antipsychotic medications for general schizophrenic.The types of drugs that mental sickness uses is at present more, reach hundreds of so treat clinically the drug use scheme of mental sickness, wherein clozapine, risperidone, Kui sulfur is flat, and Aripiprazole and some mood stabilizers (comprising sodium valproate, slow-releasing magnesium propylvalerate tablet and lithium carbonate etc.) are main flow medications.Due to the difference of therapeutic effect, the clinical use amount that current risperidone or risperidone are combined clozapine reaches more than 60%, is far longer than the use amount of other drug.These medicines are selectivity monoaminergic antagonist mostly, very easily produce 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 psychotic's state of an illness of today, the adaptability of medicine and therapeutic effect 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 officinal 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 officinal 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 analog, the structure of described compound is as follows:

Compound (A);

Compound (B);

Compound (C);

Compound (D);

Compound (E);

Above formula compound and analog thereof or its officinal 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 injectable powder of head administration, aqueous injection, microball preparation, nanometer formulation, Liposomal formulation, dendrimer preparation, polyethyleneglycol modified preparation, aqueogel etc.Described parenteral administration preparation is the dosage form 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 practice.Be significant for the misery of removing sufferer and its family.

The specific 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 mannitol, phospholipid, glycerol, cyclodextrin derivative, dimethyl sulfoxide and poloxamer;

2. after mixing dissolving, after stable, first use 0.45um microporous filter membrane coarse filtration, then use 0.2um filtering with microporous membrane;

3. be distributed into little cillin bottle, add other lyophilizing therapeutic agent and adjuvants;

4. carry out procedural lyophilizing;

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 mannitol, phospholipid, glycerol, cyclodextrin derivative, dimethyl sulfoxide and poloxamer;

2. after mixing dissolving, after stable, first use 0.45um microporous filter membrane coarse filtration, then use 0.2um filtering with microporous membrane;

3. be distributed into little cillin bottle, add other lyophilizing therapeutic agent and adjuvants;

4. carry out procedural lyophilizing;

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 mannitol, phospholipid, glycerol, cyclodextrin derivative, dimethyl sulfoxide and poloxamer;

2. after mixing dissolving, after stable, first use 0.45um microporous filter membrane coarse filtration, then use 0.2um filtering with microporous membrane;

3. be distributed into little cillin bottle, add other lyophilizing therapeutic agent and adjuvants;

4. carry out procedural lyophilizing; 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 mannitol, phospholipid, glycerol, cyclodextrin derivative, dimethyl sulfoxide and poloxamer;

2. after mixing dissolving, after stable, first use 0.45um microporous filter membrane coarse filtration, then use 0.2um filtering with microporous membrane;

3. be distributed into little cillin bottle, add other lyophilizing therapeutic agent and adjuvants;

4. carry out procedural lyophilizing; 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 mannitol, phospholipid, glycerol, cyclodextrin derivative, dimethyl sulfoxide and poloxamer;

2. after mixing dissolving, after stable, first use 0.45um microporous filter membrane coarse filtration, then use 0.2um filtering with microporous membrane;

3. be distributed into little cillin bottle, add other lyophilizing therapeutic agent and adjuvants;

4. carry out procedural lyophilizing;

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 therapeutical effect of Mus

Prepare: 160 of male Wistar rats, body weight 200-220 gram, animal feeding is in the circadian rhythm Animal House of 12/12 hour, and ambient 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, matched group (normal rat only gives normal saline); Model group (modeling of administration ketamine, but do not treat); Risperidone medication group (existing clinical application, injectable powder), administering mode intramuscular injection, dosage 2mg/kg; Medicine (A-E) group.Medicine (A-E) group is by muscle injection mode administration, dosage 1mg/kg.

Modeling: raise by the mouse cage of 25 × 45 × 15cm size (10, every cage).Except matched group, other respectively organizes rat and gives ketamine 30mg/kg pretreatment every day, according to the volume of 1ml/100g, and intraperitoneal injection ketamine 5 days, control rats was according to the continuous normal saline injection of same route of administration 5 days.

Treatment: from testing the 6th day, divide cage list only to feed ketamine processed group rat and control rats, ketamine processed group is given respectively to the pharmaceutical intervention of different embodiment compounds (A-E), matched group gives normal saline, risperidone group gives risperidone, successive administration 7 days.Intervene the 6th day and the 7th day in administration, every rat adapts to social communication's 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 communication's test, test box is 100 × 100 × 40cm (length × wide × height) wooden case.This wooden case is placed in an airtight test room, and observer, by by the photographic head that is placed in room roof, observes and record the behavior of animal in next door room with photographic head on the computer being connected.Illumination level between test room is that (luminous flux 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 luminous flux is 1 lumen (lm).Stopping after the pharmaceutical intervention same day and drug withdrawal the 7th day, record respectively the social communication behavior of each assembly to rat, test period is 7 minutes.The behavior of rat social communication is divided into non-attacking behavior (smell news with companion, trail, manage hair, sociability plays) 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

Group	Before administration	Drug withdrawal same day	After drug withdrawal 7 days
				Matched group	55.6±7.9	53.6±9.8	56.8±1.5
Model group	14.2±3.5	13.3±2.1	13.9±3.7
				Risperidone medication group	13.9±2.9	23.2±6.1*	18.2±6.3
Compound (A) group	14.0±3.2	40.1±3.7**	50.0±6.2**
				Compound (B) group	14.1±3.0	40.2±4.8**	47.9±4.0**
Compound (C) group	13.8±3.8	40.6±3.3**	42.2±3.6**
				Compound (D) group	14.6±4.0	38.0±4.0**	43.8±4.3**
Compound (E) group	14.7±3.2	40.2±5.3**	50.2±5.2**

With relatively * P < 0.05**P < 0.01 of model group

Each group rat is observed the data obtained with mean ± standard deviation (x ± s) represent.Statistical disposition is with variance analysis.

The impact (n=20) of table 2 embodiment compound on the behavior of rat Split disease ketamine rat model social communication

Group	Aggression number of times	Non-attacking behavior number of times
			Matched group	1.1±0.9	10.7±3.8
Model group	5.2±1.5	3.8±1.6
			Risperidone medication group	3.1±1.5	6.3±3.9**
Compound (A) group	1.7±0.3**	9.3±4.1**
			Compound (B) group	1.7±0.5**	9.4±3.2**
Compound (C) group	1.7±0.3**	9.6±3.5**
			Compound (D) group	1.8±0.4**	9.2±4.2**
Compound (E) group	1.7±0.4**	9.0±3.4**

Note: table 2 is the drug withdrawal result on the same day, with relatively * P < 0.05**P < 0.01 of model group

Result demonstration, the overall activity time, medicine group A-E approaches normal group very much, shows that therapeutic effect is better than risperidone group and model group.The minimizing that ketamine Split disease model causes rat social behavior is after the Drug therapy 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 percentage ratio 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 therapeutical effect, its therapeutic effect is significantly better than clinical application risperidone.

Claims (8)

1. a compounds or its officinal salt, and analog, 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 officinal salt and its analog.

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 officinal salt thereof and its analog 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 officinal salt thereof and its analog 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 paranoid 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.