CN1205637A - Method for treating depression - Google Patents
Method for treating depression Download PDFInfo
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- CN1205637A CN1205637A CN 96199221 CN96199221A CN1205637A CN 1205637 A CN1205637 A CN 1205637A CN 96199221 CN96199221 CN 96199221 CN 96199221 A CN96199221 A CN 96199221A CN 1205637 A CN1205637 A CN 1205637A
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- methyl
- thieno
- piperazinyl
- benzodiazepine
- isophthalic acid
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention provides a method for treating depressive signs and symptoms comprising administering an effective amount of 2-Methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine to a patient in need thereof.
Description
The invention relates to method with 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine treatment depression.
Strong depression (Major Depressive Disorder) has high mortality.Suffer from serious strong depression patient's committed suicide up to 15%.The epidemiology evidence shows that also the patient death rate of suffering from strong depression more than 55 years old increases by four times.Enter the patient who suffers from strong depression of nursing specialized hospital, significant increase is arranged 1 year dead probability.
Depression is a kind of epidemic disease.The life-span risk of strong depression in the community sampling, the women becomes 25% from 10%, and the man becomes 12% from 5%.The popularity of strong depression seems and the race, education, and income, or marriage condition shape is irrelevant.
Chemical compound 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine has described in 382 (' 382) in U.S. Patent No. 5,229, and the document all is incorporated herein by reference at this.
The application's invention provides a kind of method for the treatment of depressed disease and symptom, comprises that the patient to the needs treatment gives 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] the benzodiazepine chemical compound of effective dose.
In addition, the present invention also provides a kind of method for the treatment of strong depression, comprises that the patient to the needs treatment gives 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] the benzodiazepine chemical compound of effective dose.
2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine is a kind of chemical compound as the structure formula I:
This chemical compound is described in above-mentioned patent ' 382.Patent ' 382 have been told about 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine and can be used for treating psychotic symptoms and LA symptom attitude.
Astoundingly, according to the present invention, the applicant finds that 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine can be used for treating depressed disease and symptom.
2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine treats the effect of depressed disease and symptom, can prove by clinical trial.
In following clinical trial, shown this treatment, improvement and/or preventive effect to depressed disease and symptom:
This research is international double blinding, a parallel test that 1996 experimenters are carried out.The experimenter gives 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine or haloperidol (5-20mg every day) continuous 6 weeks by 2: 1 random packet.With MADRS standardization Evaluation Method, weekly the experimenter is estimated.Suicidal tendency is relevant with depressed disease and symptom.
In baseline terminal point MADRS always keeps the score the change assessment, be better than haloperidol significantly on 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine statistics.In haloperidol treatment group, the experimenter of the remarkable quantity of statistics shows the deterioration of depressed disease and symptom.
2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine has the effective dosage ranges of broad, and actual dosage depends on the situation of treatment.For example, for adult treatment, available about 1-40mg/ days dosage, most preferred dosage is 5-30mg/ days.Though also can the gradation administration, be administered once every day, generally is enough.Be used for the treatment of depressed disease of people and symptom, approximately 2.5-30mg/ days dosage range is fit to preferably 5-25mg/ days.Radiolabeled 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine can be detected in saliva, therefore, might monitor this chemical compound, so that evaluating patient is to its adaptability.
When being used for the treatment of depressed disease and symptom, 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine chemical compound oral administration normally perhaps can also drug administration by injection, and, for this purpose, normally use with the form of pharmaceutical composition.In patent ' 382, also enumerated other dosage form that is fit to.
Term " mammal " refers to high vertebrates mammal as used herein.Term " mammal " comprises the people, but is not limited to the people.Term " treatment " comprises the prevention to the indication disease as used herein, perhaps works as this disease and forms, then comprises improvement or elimination to disease.
When being used for the treatment of depressed disease and symptom, suffering from the patient can be the non-human mammal.In this case, 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine chemical compound can be used as the food additive administration, can also tablet or transdermal administration.
Patent ' 382 provide the method for preparation 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine , and still, the following examples may have directive significance too.
Embodiment 1
Technical grade 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine
Intermediate 1
In a suitable three-neck flask, add following reagent:
Dimethyl sulfoxide (analytical pure): 6 times of volumes
Intermediate 1:75g
N methyl piperazine (reagent is pure): 6 equivalent intermediate 1 can prepare with the method that those skilled in the art is known.For example, in patent ' 382, told about preparation process to intermediate 1.
Under liquid level, put into the nitrogen spray conduit, so that remove the ammonia that forms in the course of reaction.Reactant is heated to 120 ℃, and during entire reaction, keeps this temperature.By means of the HPLC tracking reaction process, till the unreacted intermediate of leaving over 1≤5%.Reaction makes mixture be cooled to 20 ℃ (about 2 hours) lentamente after finishing.Then each reactant mixture is transferred in another suitable three-necked round bottom flask, and places water-bath.Under agitation this solution is added 10 times of volume reagent-grade methanols, and this reactant was stirred 30 minutes at 20 ℃.Again lentamente, last about 30 minutes, add 3 times of volume water.Make reacting slurry be cooled to 0-5 ℃, restir 30 minutes.Filter out product, and wash this wet filtrate with cold methanol.This wet filtering residue is spent the night at 45 ℃ of vacuum dryings.This product is accredited as technical grade 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine .
Productive rate: 76.7%, render a service: 98.1% repeats the program of the foregoing description 1 basically, has obtained 81% productive rate, and effectiveness is 101.1%.
Embodiment 2
Technical grade 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine
Intermediate 1 (same as above) is suspended in DMSO (3.2 times of volumes) and the toluene (4.5 times of volumes).A part (0.65 times of volume of ≈) solvent is removed in distillation under 120-125 ℃.This mixture is cooled to 110 ℃, adds N methyl piperazine (NMP, 4.2 equivalents), (120-125 ℃) again refluxes this mixture heated.Remove another part (1 times of volume of ≈) solvent by distillation, make the reactant mixture drying.Require violent reflux, so that, promote reaction to finish (about 7 hours) by from reaction, removing deammoniation.Can isolate product by refrigerative (10 ℃) reactant liquor is added entry (12.75 times of volumes) lentamente.Collect product by means of filtering, and wash with cold water (2 times of volumes).At 60 ℃ this rough 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine is carried out vacuum drying.This product with hot toluene (5 times of volumes) recrystallization, is obtained technical grade 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine .After 50 ℃ of vacuum dryings, again with this technical grade 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine ethyl acetate (10 times of volumes)/toluene (0.62 times of volume)/methanol (3.1 times of volumes) recrystallization, obtain 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] the methanol solvate thing of [1,5] benzodiazepine .By dry under＞50 ℃, this methanol solvate thing is converted to anhydrous technical grade 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine .
Embodiment 3
Tablet formulation
Get a hydroxypropyl cellulose and be dissolved in the pure water, be formed for granuloplastic solution.With all the other very highly purified hydroxypropyl celluloses (being total up to the 4.0%w/w of last tablet weight); in high shearforce system granulation machine; with 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2; 3-b] [1; 5] benzodiazepine chemical compound (1.18%w/w); lactose (79.32%w/w), and a crospovidone (5%w/w) mixes.All compositions all need sieve carry out dry blending in adding the system granulation machine before meticulously.Make this mixture in high shearforce system granulation machine, form granule then by means of hydroxylated cellulose solution.Method with standard is made wet sub-sieve to this granule.Then that this wet granular is dry in the suspension bed exsiccator, and sub-sieve once more.These raw materials are added in the rolling groove blender.
This granule through sub-sieve is added surperficial dusting, and this dusting is by microcrystalline Cellulose (granule) (10%w/w), magnesium stearate (0.5%w/w), and the crospovidone of remainder forms.Behind this mixture mixing, on tablet machine, carry out tabletting with suitable mold.The bottom coating:
Be in harmonious proportion hydroxypropyl emthylcellulose (1.5%w/w) with pure water, form solution.Earlier label is divided into several parts of quantity about equally, sprays coating with this Gonak then.This operation is to be coated with in the container at porous bag to carry out.The label coating:
White mixture (Color Mixture White) (hydroxypropyl emthylcellulose, Polyethylene Glycol, Tween 80, and titanium dioxide) is in harmonious proportion with pure water, constitutes bag and be coated with suspension.The tablet of sub-coating layer is divided into several parts of quantity about equally, is coated with suspension spraying coating with above-mentioned bag then.This operation is to be coated with in the container at porous bag to carry out.
The tablet of coating spread be coated with some Brazil waxs, and engrave mark with suitable sign.
Claims (18)
1. a method for the treatment of depressed disease and symptom comprises that the patient to this treatment of needs gives the 2-methyl-4-of effective dose (4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine .
2. the process of claim 1 wherein that the effective dose to human patients is about 2.5-30mg/ days.
3. the method for claim 2, effective dose wherein are about 15mg/ days-20mg/ days.
4. the method for claim 3, wherein 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine is the form administration with tablet.
5. the patient who the process of claim 1 wherein is a mammal.
6. the method for claim 5, wherein 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine is the form administration with food additive.
7. the method for claim 5, patient wherein is the people.
8. a method for the treatment of people's depression comprises that the patient to this treatment of needs gives the 2-methyl-4-of effective dose (4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine .
9. the method for claim 8, effective dose wherein is about 2.5-25mg/ days.
10. a method for the treatment of the strong depression of mammal comprises that the patient to the needs treatment gives 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine , the perhaps acceptable salt on its pharmaceutics of effective dose.
11. the method for claim 10, mammal wherein is the people.
12. the method for claim 11, wherein said people does not have psychotic symptoms after diagnosing.
13. the method for claim 8, effective dose wherein are about 2.5-30mg/ days.
14.2-acceptable salt or solvate are used for the treatment of application in depressed disease and the symptom medicine in manufacturing on methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine or its pharmaceutics.
15. the application of claim 14, effective dose wherein are about 2.5-30mg/ days.
16. the application of claim 14, patient wherein is a mammal.
17. the application of claim 16, patient does not wherein have psychotic symptoms after diagnosing.
18. the diaza olanzapine that the process of claim 1 wherein is acceptable salt of pharmaceutics or solvate forms.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 96199221 CN1205637A (en) | 1995-12-22 | 1996-12-04 | Method for treating depression |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US60/009,173 | 1995-12-22 | ||
| CN 96199221 CN1205637A (en) | 1995-12-22 | 1996-12-04 | Method for treating depression |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1205637A true CN1205637A (en) | 1999-01-20 |
Family
ID=5129375
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 96199221 Pending CN1205637A (en) | 1995-12-22 | 1996-12-04 | Method for treating depression |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1205637A (en) |
-
1996
- 1996-12-04 CN CN 96199221 patent/CN1205637A/en active Pending
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