CN101594868B - A pharmaceutical composition having antipsychotic, antidepressant or antiepiieptic activity with reduced side effect - Google Patents
A pharmaceutical composition having antipsychotic, antidepressant or antiepiieptic activity with reduced side effect Download PDFInfo
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- CN101594868B CN101594868B CN200780040548.7A CN200780040548A CN101594868B CN 101594868 B CN101594868 B CN 101594868B CN 200780040548 A CN200780040548 A CN 200780040548A CN 101594868 B CN101594868 B CN 101594868B
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- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000016097 disease of metabolism Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
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- 125000004494 ethyl ester group Chemical group 0.000 description 1
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- 235000012631 food intake Nutrition 0.000 description 1
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- 235000001727 glucose Nutrition 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
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- 230000000147 hypnotic effect Effects 0.000 description 1
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- 208000017169 kidney disease Diseases 0.000 description 1
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- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
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- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
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- PISQNYYKVIWAKE-UHFFFAOYSA-N n-carbamoyl-n-phenylacetamide Chemical compound CC(=O)N(C(N)=O)C1=CC=CC=C1 PISQNYYKVIWAKE-UHFFFAOYSA-N 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
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- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 1
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- 230000000474 nursing effect Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 229960001057 paliperidone Drugs 0.000 description 1
- 230000007918 pathogenicity Effects 0.000 description 1
- 208000000689 peptic esophagitis Diseases 0.000 description 1
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- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229960004526 piracetam Drugs 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 1
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- 150000003230 pyrimidines Chemical class 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
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- 230000001235 sensitizing effect Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 description 1
- 229940084026 sodium valproate Drugs 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
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- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
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- GXPHKUHSUJUWKP-UHFFFAOYSA-N troglitazone Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)COC(C=C1)=CC=C1CC1SC(=O)NC1=O GXPHKUHSUJUWKP-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
已知的抗精神病、抗抑郁或抗癫痫的药物治疗引发超重或肥胖的副作用，通过施用O-(3-哌啶子基-2-羟基-1-丙基)-烟碱偕胺肟或其药学上可接受的酸加成盐，减轻了这些副作用。Known antipsychotic, antidepressant, or antiepileptic drug treatment that induces side effects of overweight or obesity, by administering O-(3-piperidino-2-hydroxy-1-propyl)-nicotine amidoxime or its A pharmaceutically acceptable acid addition salt alleviates these side effects.
Description
Invention field
The present invention relates to a kind ofly have the pharmaceutical composition that psychosis, antidepressant or antiepileptic activity and side effect reduce, and O-(3-piperidino-2-hydroxyl-1-propyl group)-nicotine amidoxim or its pharmaceutically-acceptable acid addition are applicable to prevention or alleviate the purposes in the medicine of the overweight or fat side effect that is caused by known antipsychotic drug, antidepressant drug or antiepileptic treatment in preparation.
Background of invention
Antipsychotic drug is used for mental sickness, particularly schizoid treatment, and antidepressant drug then is used to alleviate depressive symptom.Antiepileptic can prevent or alleviate the order of severity and the occurrence frequency of epilepsy in all kinds of epilepsies.Many use antipsychotic drug, for example the patient of olanzapine or clozapine always has voracious sensation, and this is that therefore, the treatment regular meeting of mental sickness causes weight increase because medicine has disturbed the regulation and control function of food intake.Have the scholar to be directed against this type of treatment patient and launched research, report this type of overweight with in addition fat 3-6 month of generally occurring in behind the begin treatment in (Blin O.:A comparative review ofnew antipsychotics.Can.J.Psychiatry,
44, 235-44 (1999)).Similarly, many antidepressants, for example amitriptyline, imipramine etc. and antuepileptic (anticonvulsant), for example Drug therapy such as valproic acid, sodium valproate also can cause weight increase, and then cause fat [Ruetsch O.et al., L ' Enc é phale,
31, 507-16 (2005)].For the adult, the overweight Body Mass Index that is meant is at 25-30kg/m
2Situation, and surpass 30kg/m
2Then belong to fat.
Overweight and obesity often are accompanied by hypertension and metabolic ANOMALOUS VARIATIONS, for example insulin resistant and dyslipidemia, and the two all is the risk factor that causes diabetes.Fat (particularly abdominal obesity), insulin resistant and dyslipidemia are the principal characters of " accurate diabetes " (metabolism syndrome), and " accurate diabetes " are easy to develop into type ii diabetes subsequently.Diabetes often are accompanied by severe complications, such as retinopathy, nephropathy and neuropathy.In addition, owing to suffer from the more excessive risk of cardiovascular disease, diabetes patient's mortality rate is also higher.
Along with antipsychotic drug, antidepressant drug and antiepileptic obtain application more and more widely in the U.S. and other developed countries, the problem that fatality rate that above-mentioned undesired side effect brings and pathogenicity rate increase begins to cause people's attention.In addition, need the patient of psychosis or antidepressant or antiepileptic treatment also possibly to send out weight increase and determine to stop treatment by predisposition.
Therefore, this invention is intended to provide a kind of pharmaceutical composition, it has psychosis, antidepressant or antiepileptic activity, has less side effect, said side effect to be meant again simultaneously and can cause overweight or fat body weight gain.
1976; A patent has given noval chemical compound O-(3-piperidino-2-hydroxyl-1-propyl group)-nicotine amidoxim (being called for short BGP-15), and---diabetes cause the complication of blood vessel injury---this basic patent is US4187220 to be used to treat the vascular lesion that is caused by diabetes.
U.S. Patent number US6306878 discloses a kind of protection mitochondrial genome and/or the method for mitochondrion injury-free---this damage can cause myopathy and neurodegenerative diseases---; Comprise that the susceptible patient to this type of damage uses the amidoxime acid salt derivant of effective nontoxic amount, wherein just comprises BGP-15.Preferred myopathy is a cardiomyopathy.Neurodegenerative diseases comprises Parkinson's disease, Huntington Chorea and amyotrophic lateral sclerosis.
U.S. Patent number US6458371 discloses a kind of compositions, comprises the active component of 0.1-30%---hydroxamic acid derivatives that comprises BGP-15---and pharmaceutical carrier can be made into cream, lotion, foam and spray.Said composition can reduce the influence of the photic damage that is caused by uv b radiation.
U.S. Patent number US6884424 discloses a kind of method of preventing actinic keratosis, promptly on affected epidermis, uses the hydroxamic acid derivatives that comprises BGP-15.
U.S. Patent number US6451851 discloses a kind of method of treating viral infection, promptly uses the known antiviral drugs and the hydroxamic acid derivatives that comprises BGP-15 of pharmacy effective dose to the patient.
U.S. Patent number 6440998 relates to a kind of pharmaceutical composition with anti-tumor activity and less side effect, and it comprises cisplatin (or carboplatin) and hydroxamic acid derivatives (comprising BGP-15).U.S. Patent number 6656955 relates to a kind of pharmaceutical composition with anti-tumor activity and less side effect, and it comprises paclitaxel or docetaxel and hydroxamic acid derivatives (comprising BGP-15).U.S. Patent number 6720337 relates to a kind of pharmaceutical composition with anti-tumor activity and less side effect, and it comprises oxaliplatin and hydroxamic acid derivatives (comprising BGP-15).U.S. Patent number 6838469 relates to a kind of pharmaceutical composition with anti-tumor activity and less side effect, and it comprises pyrimidine derivatives and BGP-15.
The anti-diabetic effect experimental data that BGP-15 is used to treat type i diabetes is disclosed among the PCT patent application WO00/07580 that announces.It should be noted that type i diabetes is an autoimmune disease, be mainly in youngster, and type ii diabetes is a metabolic disease, be mainly in middle-aged and elderly people.
A kind of pharmaceutical composition is disclosed among the PCT patent application WO03/007951 that announces; It comprises hydroxamic acid derivatives and antidiabetic medicine or the antihyperlipidemic drug thing that comprises BGP-15; Be used for prevention or treat accurate diabetes, metabolism X syndrome and diabetes; Also can be used for simultaneously dysfunction, i.e. endogenous metabolism imbalance, insulin resistant, dyslipidemia, alopecia, dispersivity alopecia and/or the female incretion imbalance that causes by the androgen surplus by aforementioned disease initiation.Experimental data in its description shows that BGP-15 can strengthen the pharmacological action of known antidiabetic medicine metformin and troglitazone through synergism respectively.Simultaneously, experimental data also shows, compare with matched group, and no matter be healthy animal group or hypercholesterolemia animal groups, under the effect of BGP-15 itself, improved the sensitivity (promptly having reduced insulin resistant) of insulin.
Disclose the pharmaceutical composition of a kind of BGP-15 of comprising among the PCT patent application WO2005/122678 that announces, had prokinetic effect (promptly causing gastrointestinal motility).Prokinetic effect comprises can treat reflux esophagitis, gastroparesis, influences bile and flows out or the like from gallbladder.
Disclose BGP-15 among the PCT patent application WO2005/123049 that announces in the purposes that promotes in the mitochondrion breeding, promptly increased intracellular plastochondria quantity, thereby strengthen the cell vitality.
The purposes of BGP-15 in treatment oral injury, particularly periodontal disease disclosed among the PCT patent application WO2006/079910 that announces.
Summary of the invention
O-(3-piperidino-2-hydroxypropyl)-nicotine amidoxim or its pharmaceutically-acceptable acid addition have come to light and can be used in prevention or alleviate the overweight and fat of the patient that takes antipsychotic drug or antidepressant drug or antiepileptic.
Thus; The present invention provides O-(3-piperidino-2-hydroxyl-1-propyl group)-nicotine amidoxim or the application of its pharmaceutically-acceptable acid addition in pharmaceutical compositions, and said pharmaceutical composition is applicable to prevention or alleviates the overweight and fat side effect that known antipsychotic drug, antidepressant drug or antiepileptic treatment cause.
In addition; The present invention also provides a kind of littler pharmaceutical composition of psychosis, antidepressant or antiepileptic activity side effect simultaneously that has, and comprises known psychosis, antidepressant or antiepileptic and O-(3-piperidino-2-hydroxyl-1-propyl group)-nicotine amidoxim or its pharmaceutically-acceptable acid addition and one or more conventional carriers.
Preferred embodiment
Term " psychotolytic " or " psychotolytic medicine " are meant the medicine that is used to treat the serious abalienation (being psychosis) that comprises schizophrenia and mania.Some antipsychotic drug low dose is administered for the alleviation anxiety.
Preferred antipsychotic drug comprises phenothiazine derivative and the pharmaceutically-acceptable acid addition thereof that formula I A representes,
R wherein
1Expression two (C
1-4Alkyl) amino, 1-(C
1-4Alkyl) piperidyl, 4-(C
1-4Alkyl) piperazinyl or 4-[2-hydroxyl (C
1-4Alkyl)]-the 1-piperazinyl,
R
2And R
3Represent hydrogen atom or C respectively
1-4Alkyl,
R
4Expression hydrogen atom or halogen atom, carboxyl, C
1-4Alkoxyl, C
1-4Alkanoyl, trifluoromethyl, first sulfydryl or methyl sulfinyl; And
N gets 0 or 1.
Preferably, among the formula IA,
R
1Expression dimethylamino, 1-methyl piperidine base, 4-methyl piperazine base or 4-(2-ethoxy)-1-piperazinyl,
R
2And R
3Represent hydrogen atom or methyl respectively,
R
4Expression hydrogen atom, chlorine atom, carboxyl, methoxyl group, acetyl group, trifluoromethyl, first sulfydryl or methyl sulfinyl, and
N gets 0 or 1.
Preferred especially phenothiazine derivative is as follows:
Chlorpromazine, i.e. 2-chloro-N, N-dimethyl-10H-phenothiazine-10-propylamine,
Promazine, i.e. N, N-dimethyl-10H-phenothiazine-10-propylamine,
Mesoridazine, i.e. 10-[2-(1-methyl-2-piperidines) ethyl]-2-(methyl-sulfinyl)-10H-phenothiazine,
Fluphenazine, promptly 4-[3-[2-(trifluoromethyl)-10H-phenothiazine-10-yl] propyl group]-1-piperazine ethanol and
Trifluoperazine, i.e. 10-[3-(4-methyl isophthalic acid-piperazine) propyl group]-2-(trifluoromethyl)-10H-phenothiazine,
And above-claimed cpd pharmaceutically-acceptable acid addition.
Another organizes thioxanthene analog derivative and pharmaceutically-acceptable acid addition thereof that preferred antipsychotic drug comprises that formula IB representes,
Wherein, R wherein
1Expression two (C
1-4Alkyl) amido, 4-(C
1-4Alkyl)-and the 1-piperazinyl, 4-[2-hydroxyl (C
1-4Alkyl)]-and the 1-piperazinyl, 4-[2-(C
1-4Alkanoyloxy)-(C
1-4Alkyl)]-1-piperazinyl or 4-(2-acyloxy in last of the ten Heavenly stems ethyl)-1-piperazinyl,
R
2The expression halogen atom, trifluoromethyl or N, N-dimethyl-sulfoamido.
Preferably, among the formula IB,
R
1The expression dimethylamino, 4-methyl isophthalic acid-piperazinyl, 4-(2-ethoxy)-1-piperazinyl, 4-(2-acetoxyl group ethyl)-1-piperazinyl or 4-(2-acyloxy in last of the ten Heavenly stems ethyl)-1-piperazinyl,
R
2Expression chlorine atom, trifluoromethyl or N, N-dimethyl-sulfoamido.
Preferred especially thioxanthene analog derivative is as follows:
Chlorprothixene, i.e. 3-(2-chloro-9H-thioxanthene-9-subunit)-N, N-dimethyl-1-propylamine (propanamine),
Clopenthixol, i.e. 4-[3-(2-chloro-9H-thioxanthene-9-subunit]-propyl group-1-piperazine-ethanol,
Tiotixene, i.e. N, N-dimethyl-9-[3-(4-methyl isophthalic acid-piperazinyl)-propylidene]-thioxanthene-2-sulfonamide and
Flupentixol, i.e. 4-[3-(2-(trifluoromethyl)-9H-thioxanthene-9-subunit) propyl group]-1-piperazine-ethanol,
And above-claimed cpd pharmaceutically-acceptable acid addition.
Another organizes the chemical compound that preferred antipsychotic drug comprises that formula IC representes,
Wherein, X representes nitrogen-atoms or group " C=" or " CH-",
Y representes group " NH-", oxygen atom or nitrogen-atoms,
R
1Expression 4-(2-hydroxyethoxy ethyl)-1-piperazinyl, 4-(C
1-4Alkyl)-1-piperazinyl or 4-(3-hydroxypropyl)-1-piperazinyl,
R
2Expression hydrogen atom or halogen atom,
Ring C represents a benzene ring, optionally substituted by a halogen atom or N, N-dimethyl-substituted sulfonamide group; C is a heterocyclic ring group can be, with benzodiazepines
some form thieno [2,3-b] [1,5] benzodiazepines
structure, in which five yuan thiophene ring is optionally substituted at the 2 substituted by methyl,
Dotted line between X and adjacent carbon atom is meaningless when saturated rings, then representes valence link during the unsaturation ring,
And if chemically if possible, the pharmaceutically-acceptable acid addition of above-claimed cpd.
Preferably, in formula IC,
R
1Expression 4-(2-hydroxyethoxy ethyl)-1-piperazinyl, 4-(methyl)-1-piperazinyl or 4-(3-hydroxypropyl)-1-piperazinyl,
R
2Be hydrogen atom or chlorine atom,
X, Y, C ring and dotted line such as preceding text define.
Preferred especially formula IC derivant is as follows:
Clozapine; Be 8-chloro-11-(4-methyl isophthalic acid-piperazinyl)-5H-dibenzo-[b; E] [1,4] diaza
Olanzapine; It is 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno-[2; 3-b] [1,5]-benzene diaza
Quetiapine; Be 2-[2-(4-dibenzo [b; F] [1; 4] ethyoxyl sulfur azepine
-11-base-1-piperazinyl)]-ethanol
Zotepine; Be that [(the 8-chlorodiphenyl is [b also for 2-; F] sulfur
-10-yl) the oxygen base]-N; The N-dimethyl amine
Different clozapine; Be chloro-11-(4-methyl isophthalic acid-piperazinyl)-5H-dibenzo-[b; E] [1,4] diaza
Clotiapine; Be 2-chloro-11-(4-methyl isophthalic acid-piperazinyl) dibenzo [b; F] [1; 4] sulfur
western Horizon difficult to understand (oxithepine); Be 10-[4-(3-hydroxypropyl) piperazinyl]-10; 11-dihydro-dibenzo [b, f]-sulfur
And chemically possibly form the above-claimed cpd pharmaceutically-acceptable acid addition.
Another organizes heterocyclic carbamate derivatives and pharmaceutically-acceptable acid addition thereof that preferred antipsychotic drug comprises that formula ID representes,
Wherein, R
1Expression N-[1-(C
1-4Alkyl)-the 2-pyrrolidinyl]-(C
1-4Alkyl), 2-[two (C
1-4Alkyl)-amino]-(C
1-4Alkyl) or 1-benzyl-3-pyrrolidinyl,
R
2Expression hydrogen atom or halogen atom, amino-sulfonyl or (C
1-4Alkyl) sulfonyl,
R
3Expression hydrogen atom or halogen atom, amino or (C
1-4Alkyl) amino,
R
4Expression hydrogen atom or halogen atom or methoxyl group,
R
5Expression C
1-4Alkoxyl or allyloxy.
Preferably, among the Formula I D
R
1Expression N-(1-ethyl-2-pyrrolidinyl) methyl, 2-(lignocaine) ethyl or 1-phenyl-3-pyrrolidinyl,
R
2Expression hydrogen atom or chlorine atom, amino-sulfonyl or ethylsulfonyl,
R
3Expression hydrogen atom or chlorine atom, amino or methylamino,
R
4Expression hydrogen atom or bromine atoms or methoxyl group,
R
5Expression methoxyl group or allyloxy.
The derivant of preferred especially formula ID is as follows:
Sulpiride, i.e. 5-(amino-sulfonyl)-N-[(1-ethyl-2-pyrrolidinyl)-methyl]-2-methoxyl group-Benzoylamide,
Amisulpride, promptly 4-amino-N-[(1-ethyl-2-pyrrolidinyl) methyl]-5-(ethylsulfonyl)-2-methoxy benzamide with
Remoxipride, i.e. (S)-3-bromo-N-[(1-ethyl-2-pyrrolidinyl)-methyl]-2,6-dimethoxy Benzoylamide,
And above-claimed cpd pharmaceutically-acceptable acid addition.
Another is organized preferred antipsychotic drug and comprises the Ben isoxazole derivatives shown in the formula IF
Wherein
R
1Expression hydrogen atom or hydroxyl.
The Ben isoxazole derivatives of preferred especially Formula I F is as follows:
Risperidone, i.e. 3-[2-[4-(6-fluoro-1,2-Ben isoxazole-3-base)-piperidino]-ethyl]-6,7,8,9-tetrahydrochysene-2-methyl-4H-pyrido [1,2-a]-pyrimidin-4-one with
Paliperidone, i.e. 3-[2-[4-(6-fluoro-1,2-Ben isoxazole-3-base)-1-piperidines ethyl]-6,7,8,9-tetrahydrochysene-9-hydroxy-2-methyl-4H-pyrido [1,2-α]-pyrimidin-4-one.
Another is organized preferred antipsychotic drug and comprises the diphenylbutylpiperidine derivant shown in the formula IG
Wherein
R
1Expression 2-benzimidazolone-1-base.
The chemical compound of preferred especially Formula I G is
Pimozide, i.e. 1-[1-[4,4-two (4-fluoro phenyl) butyl]-4-piperidyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone.
Another is organized preferred antipsychotic drug and comprises butyrophenone derivatives and pharmaceutically-acceptable acid addition thereof, for example:
Haloperidol, i.e. 4-[4-(4-chlorophenyl)-4-hydroxyl-piperidino]-1-(4-fluoro phenyl)-1-butanone,
Bromine piperidines alcohol, i.e. 4-[4-(4-bromo phenyl)-4-hydroxyl-piperidino]-1-(4-fluoro phenyl)-1-butanone,
Psychoperidol, i.e. 1-(4-fluoro phenyl)-4-[4-hydroxyl-4-[3-(trifluoromethyl) phenyl]-piperidino]-1-butanone.
Another is organized preferred antipsychotic drug and comprises indole derivatives and pharmaceutically-acceptable acid addition thereof, for example:
Molindone, like 3-ethyl-1,5,6,7-tetrahydrochysene-2-methyl-5-(4-morpholine methyl)-4H-indole-4-ketone,
Ziprasidone, like 5-[2-[4-(1,2-benzisothiazole-3-yl)-1-piperazinyl]-ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one,
Sertindole, as 1-[2-[4-[5-chloro-1-(4-fluoro phenyl)-1H-indol-3-yl]-piperidino]-ethyl]-2-imidazolone or
Oxypertine, promptly 5,6-dimethoxy-2-methyl-3-[2-(4-phenyl-peiperazinyl) ethyl]-1H-indole.
Term " antidepressant " or " antidepressant drug " are meant the medicine that alleviates depressive symptom.Preferred antidepressant drug comprises bicyclic compound, for example
Paroxetine, i.e. (3S-is trans)-3-[(1,3-benzodioxole-5-base oxygen base) methyl]-4-(4-fluoro phenyl)-piperidines,
Citalopram, i.e. 1-[3-(dimethylamino) propyl group]-1-(4-fluoro phenyl)-1,3-dihydro-5-isobenzofuran nitrile,
Sertraline, i.e. (1S-cis)-4-(3, the 4-Dichlorobenzene base)-1,2,3,4-tetrahydrochysene-N-methyl isophthalic acid-naphthylamines
And above-claimed cpd pharmaceutically-acceptable acid addition.
Another is organized preferred antidepressant drug and comprises tricyclic compound, for example:
Amitriptyline, i.e. 3-(10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5-subunit)-N, N-dimethyl-1-propylamine,
Doxepin; Be 3-dibenzo [b; E] oxa-
-11 (6H) alkenylene-N; N-dimethyl-propylamine
Imipramine; Promptly 10; 11-dihydro-N; N-dimethyl-5H-dibenzo [b, f] azepine
-5-propylamine
Clomipramine; It is 3-chloro-10; 11-dihydro-N; N-dimethyl-5H-dibenzo [b, f] azepine
-5-propylamine
Nortriptyline, i.e. 3-(10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5-subunit)-N-methyl isophthalic acid-propylamine,
Trimeprimine; Promptly 10; 11-dihydro-N, N, β-trimethyl-5H-dibenzo [b; F] azepine
-5-propylamine, or
Desipramine; Promptly 10; 11-dihydro-N-methyl-5H-dibenzo [b; F]-azepine
-5-propylamine
And above-claimed cpd pharmaceutically-acceptable acid addition.
Another is organized preferred antidepressant drug and comprises tetracyclic compound, for example:
Maprotiline, like N-methyl-9,10-ethano-anthracene-9 (10H)-propylamine and pharmaceutically-acceptable acid addition thereof.
Preferred antidepressant drug also for example comprises
Fluoxetine, i.e. (±)-N-methyl-γ-[4-(trifluoromethyl) phenoxy group]-amfetamine,
Fluvoxamine, i.e. (E)-5-methoxyl group-1-[4-(trifluoromethyl) phenoxy group]-1-pentanone-O-(2-amino-ethyl) oxime
And above-claimed cpd pharmaceutically-acceptable acid addition.
Term " antiepileptic " or " anticonvulsant " or " antiepileptic " are meant the medicine that in all kinds of epilepsies, can prevent or alleviate the order of severity and the frequency of epilepsy.Preferably use a technical term " antiepileptic " be because all there is the situation of convulsions in not all outbreak.Preferred antiepileptic comprises some phenothiazine derivatives shown in the formula IA, for example, and triflupromazine; Be N; N-dimethyl-2-(trifluoromethyl)-10H-phenothiazine-10-propylamine and methophenazine, promptly 3,4; 5-trimethoxybenzoic acid 2-[4-[3-(2-chloro-10H-phenothiazine-10-yl) propyl group]-1-piperazinyl] ethyl ester, the latter generally is the mode administration with difumarate.Said phenothiazine derivative not only has antipsychotic activity, also has antiepileptic activity.
Another is organized preferred antiepileptic and comprises benzodiazepine
derivant, clonazepam for example, i.e. 5-(2-chloro-phenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepine
-2-ketone; Clobazam, i.e. 7-chloro-1-methyl-5-phenyl-1H-1,5-benzodiazepine
-2,4 (3H, 5H)-diketone or the like; Dibenzo nitrogen
derivant, carbamazepine for example, i.e. 5H-dibenzo [b, f] nitrogen
-5-Methanamide, it also has analgesic activities simultaneously; Oxcarbazepine, promptly 10,11-dihydro-10-oxygen-5H-dibenzo [b, f] nitrogen
-5-Methanamide or the like also has the barbituric acid derivatives of hypnosis sedation simultaneously; Phenobarbital for example, i.e. 5-ethyl-5-phenyl-2,4,6 (1H, 3H; 5H)-and pyrimidine-triketone and pharmaceutically acceptable slaine thereof, eterobarb, i.e. 5-ethyl-1,3-two (methoxyl group-methyl)-5-phenyl-2; 4,6 (1H, 3H, 5H)-pyrimidine-triketone; Proxibarbal, i.e. 5-(2-hydroxyl-propyl group)-5-(2-acrylic)-2,4,6 (1H; 3H, 5H)-pyrimidine trione, primidone, i.e. 5-ethyl-dihydro-5-phenyl-4; 6 (1H, 5H)-hybar X or the like, hydantoin derivatives, for example phenytoin; Promptly 5,5-diphenyl-2,4-imidazolidimedione, Mephenetoin; Be 5-ethyl-3-methyl-5-phenyl-2,4-imidazolidimedione, fosphenytoin, promptly 5; 5-diphenyl-3-phosphorus acyloxy-methyl-2,4-imidazolidimedione or the like, and pharmaceutically acceptable slaine, oxazolidine derivant; Ethadione for example, i.e. 3-ethyl-5,5-dimethyl-2,4-oxazolidinedione or the like; Succinimide derivatives, for example, ethosuximide, i.e. 3-ethyl-3-methyl-2; The 5-pyrrolidine-diones, phensuximide, i.e. 1-methyl-3-phenyl-2,5-pyrrolidine-diones or the like; Carboxylic acid derivates, for example, valproic acid, i.e. 2-Propylpentanoic and pharmaceutically acceptable slaine thereof; Valpromide, i.e. dipramide, valnoctamide, i.e. 2-ethyl-3-methyl-pentanamide or the like.
Also have one type of available antiepileptic to comprise GABA (GABA) derivant, gabapentin for example, i.e. 1-(amino methyl) Cyclohexaneacetic acid, progabide, i.e. 4-[[(4-chlorophenyl) (5-fluoro-2-hydroxy phenyl)-methylene] amino] butyramide; Vigabatrin, i.e. 4-amino-5-hexenoic acid, piracetam, i.e. 2-OXo-1-pyrrolidine yl acetamide, oxiracetam; Be 4-hydroxyl-2-OXo-1-pyrrolidine yl acetamide, nefiracetam, the i.e. pharmaceutically acceptable salt that N-(2,6-dimethyl-phenyl) 2-OXo-1-pyrrolidine yl acetamide etc., and sour form and metal form; The carbamic acid salt derivative, meprobamate for example, i.e. 2-methyl-2-propyl group-1, the ammediol diurethane, this chemical compound also has angst resistance effect; Felbamate, i.e. 2-phenyl-1, ammediol diurethane or the like, some sulfa drugs; For example acetazolamide, i.e. N-[5-(amino-sulfonyl)-1,3,4-thiadiazoles-2 base] acetamide; Zonisamide, promptly 1,2-benzoisoxazole-3-NSC-249992, thiazine relaxes; Be 4-(tetrahydrochysene-2H-1,2-thiazine-2-yl)-benzsulfamide S, S-dioxide or the like, N-acyl urea derivatives; Phenacal for example, i.e. N-(amino-carbonyl) phenyl acetamide, ethylphenacemide, i.e. N-(amino-carbonyl)-α-ethylo benzene acetamide or the like.
Other available antiepileptic comprises lamotrigine, i.e. 6-(2, the 3-Dichlorobenzene base)-1,2; 4-triazine-3,5-diamidogen, topiramate; Promptly 2,3:4,5-is two-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate; And tiagabine, i.e. (R)-1-[4,4-two (3-methyl-2-thienyl)-3-cyclobutenyl]-nipecotic acid and pharmaceutically acceptable slaine thereof.
Preferred especially one group of antiepileptic comprises valproic acid and pharmaceutically acceptable alkali metal valproate.
Pharmaceutically-acceptable acid addition is meant the salt that forms with pharmaceutically acceptable mineral acid example hydrochloric acid, sulphuric acid etc. or pharmaceutically acceptable organic acid such as acetic acid, lactic acid, tartaric acid etc.Preferred acid-addition salts comprises hydrochlorate, acetate, maleate or the like.(3-piperidino-2-hydroxyl-1-propyl group)-the preferred acid-addition salts of nicotine amidoxim is its dihydrochloride to O-.
Pharmaceutically acceptable slaine is meant the salt that forms with pharmaceutically acceptable inorganic base.Preferred slaine comprises alkali metal salt such as sodium salt or potassium salt.
If chemically possibly form, the active component used according to the present invention also can be processed pharmaceutically-acceptable acid addition or metallic salt form.
BGP-15 can be by the process preparation of describing in the files such as for example U.S. Patent number US4187220.
In one embodiment; Known psychosis or antidepressant or the antiepileptic of using convention amount for the patient that psychosis or antidepressant or antiepileptic treatment needs are arranged give BGP-15 or its pharmaceutically-acceptable acid addition of its doses simultaneously.The BGP-15 of this non-toxic prevents effectively or alleviates by using the overweight even fat body weight gain that psychosis or antidepressant or antiepileptic cause.
In general, the psychosis of the per day for adults of the about 70kg of body weight, antidepressant or antiepileptic consumption are 1-1000mg.Similarly, the consumption per day of BGP-15 (in dihydrochloride) is generally 5-1000mg, preferred 50-500mg.
According to some embodiment, the adult uses 10-20mg olanzapine or 100-800mg clozapine and 50-500mg BGP-15 dihydrochloride every day.
In further embodiment; O-(3-piperidino-2-hydroxyl-1-propyl group)-nicotine amidoxim or its pharmaceutically-acceptable acid addition are used for pharmaceutical compositions, and said pharmaceutical composition is applicable to and prevents or alleviate the overweight or fat side effect that in known psychosis, antidepressant or antiepileptic treatment, causes.Said pharmaceutical composition is applied to the patient of psychosis, antidepressant or antiepileptic treatment, with the overweight or fat side effect that prevents that these Drug therapys from causing.Comprise given similar of consumption per day and the preceding text of pharmaceutical composition of BGP-15 or its pharmaceutically-acceptable acid addition.
Another embodiment is to have psychosis, antidepressant or antiepileptic activity to have the pharmaceutical composition that reduces side effect, said pharmaceutical composition to comprise known psychosis or antidepressant or antiepileptic medicine and O-(3-piperidino-2-hydroxyl-1-propyl group)-nicotine amidoxim or its pharmaceutically-acceptable acid addition and one or more common carrier again simultaneously.
Process have psychosis, antidepressant or antiepileptic activity have again in the pharmaceutical composition situation of less side effect simultaneously; Two kinds of active component (being known psychosis or antidepressant or antiepileptic medicine and BGP-15) can use one or more conventional carriers; According to any manufacture method of medicine commonly used, process separate pharmaceutical composition one by one, in this case; Two kinds of pharmaceutical compositions that make can be applied to patient, also administration successively simultaneously;
Or two kinds of active component also can be processed and can give the same pharmaceutical composition that has the patient that needs to use.In this case, two kinds of active component both can form of mixtures be present in the pharmaceutical composition, can be present in the different piece of pharmaceutical composition again, and for example, one of them active component is in the label position, and another is in label coating composition.Certainly, can use one or more conventional carriers and any manufacture method of medicine commonly used to prepare this single pharmaceutical composition.
Described have psychosis, antidepressant or antiepileptic activity and have the pharmaceutical composition of less side effect to comprise psychosis or antidepressant or antiepileptic or its simultaneously again; If chemically can form, pharmaceutically-acceptable acid addition or slaine and BGP-15 or its pharmaceutically-acceptable acid addition and one or more pharmaceutically acceptable carriers.Said pharmaceutical composition can comprise be suitable for arbitrarily that oral, intestinal is outer, the dosage form of rectum or topical, can be solid or liquid.In general, the weight ratio of known psychosis or antidepressant or antiepileptic and BGP-15 or its pharmaceutically-acceptable acid addition is (1-1000): (1000: 1).
In principle, pharmaceutical composition of the present invention can comprise more than a kind of psychosis and/or antidepressant and/or antiepileptic medicine.
The solid composite medicament that is suitable for oral administration can be made into powder, capsule, tablet, film coating tablet, microcapsule etc., can comprise binding agent, like gelatin, sorbitol, and polyvidone etc.; Filler is like lactose, glucose, starch, calcium phosphate etc.; Tabletting is used adjuvant, like magnesium stearate, Talcum, Polyethylene Glycol, silicon dioxide etc.; Wetting agent is like sodium lauryl sulphate etc., as carrier.
The composition of liquid medicine that is suitable for oral administration can be made into solution, suspensoid or Emulsion, can comprise suspending agent, like gelatin, carboxymethyl cellulose etc.; Emulsifying agent, single oleic acid Pyrusussuriensis ester etc.; Solvent, Ru Shui, oil, glycerol, propylene glycol, ethanol etc.; Antiseptic is like methyl hydroxybenzoate etc., as carrier.
The pharmaceutical composition that is suitable for the gastrointestinal tract external administration generally comprises the sterile solution of active component.
Above-mentioned dosage form and other dosage form itself are known, can with reference to such as Remington ' sPharmaceutical Sciences (the 18th edition, Mack publishing company nineteen ninety publishes, Easton, USA).
Described pharmaceutical composition generally comprises dosage unit.Dosage can be divided into one or many and took every day.Actual amount depends on many factors, needs to be determined by the doctor.
Active component is mixed with one or more carriers, by the known method of prior art the gained mixture is prepared into pharmaceutical composition again.Available method can be known by document, Remington ' s Pharmaceutical Sciences for example above-mentioned.
The present invention preferably have antipsychotic activity simultaneously the less pharmaceutical composition of side effect comprise and be selected from chlorpromazine, promazine, mesoridazine, fluphenazine, trifluoperazine; Chlorprothixene, clopenthixol, tiotixene, flupentixol, clozapine; Olanzapine, Quetiapine, zotepine, different clozapine, clotiapine; Western Horizon difficult to understand, sulpiride, amisulpride, remoxipride, risperidone; Pa Panli ketone, pimozide, haloperidol, bromine piperidines alcohol; Psychoperidol, molindone, Ziprasidone, the antipsychotic drug of Sertindole and Equipertine or above-claimed cpd pharmaceutically-acceptable acid addition and BGP-15 or its pharmaceutically-acceptable acid addition and one or more conventional carriers.
The present invention is preferred to have the less pharmaceutical composition of antipsychotic activity side effect simultaneously to comprise antipsychotic drug and BGP-15 or its pharmaceutically-acceptable acid addition and one or more the conventional carriers that is selected from olanzapine, clozapine, risperidone, Quetiapine and sulpiride or above-claimed cpd pharmaceutically-acceptable acid addition.
The present invention especially preferably has the less pharmaceutical composition of antipsychotic activity side effect simultaneously to comprise antipsychotic drug and BGP-15 or its pharmaceutically-acceptable acid addition and one or more the conventional carriers that is selected from olanzapine and clozapine.
The present invention preferably have antidepressant activity simultaneously the less pharmaceutical composition of side effect comprise and be selected from paroxetine, citalopram, fluoxetine; Fluvoxamine, Sertraline, amitriptyline; Doxepin, imipramine, Clomipramine; Nortriptyline, trimeprimine, the antidepressant drug of desipramine, maprotiline or above-claimed cpd pharmaceutically-acceptable acid addition and BGP-15 or its pharmaceutically-acceptable acid addition and one or more conventional carriers.
The present invention is preferred to have the less pharmaceutical composition of antidepressant activity side effect simultaneously to comprise antidepressant drug and BGP-15 or its pharmaceutically-acceptable acid addition and one or more the conventional carriers that is selected from Clomipramine, citalopram, fluoxetine, fluvoxamine, paroxetine and Sertraline or above-claimed cpd pharmaceutically-acceptable acid addition.
The present invention especially preferably has the less pharmaceutical composition of antidepressant activity side effect simultaneously to comprise antidepressant drug and BGP-15 or its pharmaceutically-acceptable acid addition and one or more the conventional carriers that is selected from Clomipramine, citalopram, fluvoxamine and paroxetine or above-claimed cpd pharmaceutically-acceptable acid addition.
The present invention preferably have antiepileptic activity simultaneously the less pharmaceutical composition of side effect comprise and be selected from triflupromazine, methophenazine, clonazepam, clobazam, carbamazepine, oxcarbazepine; Phenobarbital, eterobarb, proxibarbal, primidone, phenytoin, Mephenetoin; Fosphenytoin, ethadione, ethosuximide, phensuximide, valproic acid, valpromide; Valnoctamide, gabapentin, progabide, lyrica, vigabatrin, oxiracetam; Nefiracetam, meprobamate, felbamate, acetazolamide, zonisamide; Easypro thiazine, phenacal, ethylphenacemide, lamotrigine, the antiepileptic of topiramate and tiagabine and BGP-15 or its pharmaceutically-acceptable acid addition and one or more conventional carriers.
The present invention is preferred to have the less pharmaceutical composition of antiepileptic activity side effect simultaneously to comprise antiepileptic and BGP-15 or its pharmaceutically-acceptable acid addition and one or more the conventional carriers that is selected from carbamazepine, gabapentin, lyrica and valproic acid or above-claimed cpd pharmaceutically-acceptable acid addition or slaine.
The present invention especially preferably has the less pharmaceutical composition of antiepileptic activity side effect simultaneously to comprise antiepileptic and BGP-15 or its pharmaceutically-acceptable acid addition and one or more conventional carriers of valproic acid or pharmaceutically acceptable valproic acid alkali metal salt.
In following examples, tested known antipsychotic drug and BGP-15 effect to body weight gain.
Embodiment 1
The effect that BGP-15 increases the rat body weight that is brought out by olanzapine
Each group female Wistar rats was treated 28 days with vehicle (matched group) and test compounds.Every group of 6 animals are freely fed with normal laboratory feedstuff and tap water.Test compounds early 8 with twice of oral administration, 6 every days of evening.Wherein, psychosis olanzapine dosage 1mg/kg is to bring out body weight gain.BGP-15 dosage 10mg/kg, one group individually dosed, another group and olanzapine co-administered.Oral antidiabetic thing metformin (100mg/kg) and rosiglitazone (3mg/kg) be as control compound, be equally one group individually dosed, another group and olanzapine co-administered.The average initial body weight of experimental rat is 171g.The body weight of each treated animal was as shown in table 1 when experiment finished in the 28th day.
Table 1
| The treatment group | Body weight (meansigma methods in the group)/g |
| Contrast | 255 |
| Olanzapine, 1mg/kg | 330 |
| The BGP-15 dihydrochloride, 10mg/kg | 242 |
| Metformin, 100mg/kg | 266 |
| Rosiglitazone, 3mg/kg | 284 |
| Olanzapine 1mg/kg+BGP-15 dihydrochloride 10mg/kg | 262 |
| Olanzapine 1mg/kg+ metformin 100mg/kg | 331 |
| Olanzapine 1mg/kg+ rosiglitazone 3mg/kg | 359 |
Animals of control group in 28 days of experimental period with respect to when beginning weight body weight gain can think the normal condition of rat.Compare with matched group, the average weight of olanzapine treatment group is obviously higher.This is with fat consistent in observed on one's body its initiation of the patient who uses the olanzapine treatment.Compare with matched group, reduced average weight a little with the BGP-15 treatment separately; And produce higher slightly average weight respectively with metformin group and the treatment of rosiglitazone group.Fail to reduce the body weight gain that brings out by olanzapine with the metformin treatment; And with rosiglitazone treatment even strengthened the body weight gain that brings out by olanzapine.Yet BGP-15 dihydrochloride administration group has suppressed the body weight gain that olanzapine brings out.
Embodiment 2
BGP-15 is to the effect of the weight of mice that caused by olanzapine or clozapine
Each is organized female NMRI mice with vehicle (matched group) and test compounds oral medication 15 days.Every group of 10 animals are freely fed with Routine Test Lab feedstuff and tap water.Between 5 o'clock to 6 o'clock every afternoon, slightly early than treating at dark, this also is the main nursing time of every day.For bringing out body weight gain, the dosage of anti-neuropathy medicine olanzapine is 0.5mg/kg, and the dosage of antipsychotic drug clozapine is 1mg/kg.The BGP-15 dosage is 10mg/kg, and one group is individually dosed, in addition two groups respectively with olanzapine and clozapine co-administered.Write down the body weight situation of twice laboratory animal weekly.The body weight change of animal is as shown in table 2 between the 1st day and the 15th day.
Table 2
| The treatment group | Body weight gain (meansigma methods in the group)/g |
| Contrast | 2.98 |
| Olanzapine, 0.5mg/kg | 3.5 |
| Clozapine, 1mg/kg | 4.11 |
| The BGP-15 dihydrochloride, 10mg/kg | 2.85 |
| Olanzapine, 0.5mg/kg+BGP-15 dihydrochloride, 10mg/kg | 2.33 |
| Clozapine, 1mg/kg+BGP-15 dihydrochloride, 10mg/kg | 2.19 |
Compare with matched group, two antipsychotic drug groups have all caused body weight gain.Give BGP-15 separately and can reduce body weight gain to a certain extent.When share with antipsychotic drug, BGP-15 has prevented the side effect of its body weight gain, compares even also reduced the variation of body weight with matched group.
So more than experiment shows that BGP-15 can effectively reduce the body weight gain that is caused by antipsychotic drug, and is used as the known oral antidiabetic thing metformin that the insulin sensitizing agent effect is arranged equally and the not onset of rosiglitazone of placebo.Therefore, BGP-15 can be used for effectively preventing or reducing body weight gain, and is overweight or fat.
Embodiment 3
BGP-15 is to the effect of rat by the body weight gain of risperidone initiation
Experiment employing female Wistar rats in eight ages in week.Each experimental group has 10 animals, freely gives Routine Test Lab feedstuff and drop bottle water.Give animal vector thing (matched group) and test compounds respectively, treated 21 days.The antipsychotic drug risperidone is through subcutaneous injection administration once a day, and dosage is respectively 0.005mg/kg and 0.05mg/kg, to bring out body weight gain.The administration of BGP-15 dihydrochloride administered through oral, once a day, dosage is 20mg/kg, one group is individually dosed, in addition two groups respectively with the risperidone co-administered of two dosage.
The average initial body weight of animal is 195g.The body weight of each treated animal was as shown in table 3 when experiment finished in the 21st day.
Table 3
| The treatment group | Body weight gain/g |
| Contrast | 27 |
| The BGP-15 dihydrochloride, 20mg/kg, oral | 22.7 |
| Risperidone, 0.005mg/kg, subcutaneous injection | 39.7 |
| Risperidone, 0.05mg/kg, subcutaneous injection | 41 |
| Risperidone, 0.005mg/kg, subcutaneous injection+BGP-15 dihydrochloride, 20mg/kg, oral | 25.8 |
| Risperidone, 0.05mg/kg, subcutaneous injection+BGP-15 dihydrochloride, 20mg/kg, oral | 28.7 |
Compare with matched group, the psychosis risperidone of two dosage has all caused body weight gain; Give BGP-15 separately and can reduce body weight gain to a certain extent.When share with antipsychotic drug, BGP-15 all prevents effect to the side effect of the body weight gain that its two dosage cause.
Claims (3)
1.0-(3-piperidino-2-hydroxyl-1-propyl group)-nicotine amidoxim or its pharmaceutically-acceptable acid addition are applicable to prevention or alleviate the purposes in the pharmaceutical composition of the overweight or fat side effect that is caused by olanzapine, clozapine or risperidone treatment in preparation.
2. purposes as claimed in claim 1, wherein administration 0-(3-piperidino-2-hydroxyl-1-propyl group)-nicotine amidoxim dihydrochloride.
3. one kind has the overweight or fat pharmaceutical composition that causes because of administration olanzapine, clozapine or risperidone that psychosis, antidepressant or antiepileptic activity have reduction simultaneously, comprises known overweight or fat olanzapine, clozapine or the risperidone and 0-(3-piperidino-2-hydroxyl-1-propyl group)-nicotine amidoxim or its pharmaceutically-acceptable acid addition of causing and mixes one or more conventional carriers.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US85617706P | 2006-11-02 | 2006-11-02 | |
| US60/856,177 | 2006-11-02 | ||
| US11/687,954 | 2007-03-19 | ||
| US11/687,954 US20080108602A1 (en) | 2006-11-02 | 2007-03-19 | Prevention of obesity in antipsychotic, antidepressant and antiepileptic medication |
| PCT/HU2007/000067 WO2008053257A1 (en) | 2006-11-02 | 2007-07-23 | A pharmaceutical composition having antipsychotic, antidepressant or antiepiieptic activity with reduced side effect |
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Non-Patent Citations (3)
| Title |
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| 周建英，等.药物相关性肥胖的研究进展.《国际内分泌代谢杂志》.2006,第26卷(第1期),32-34. * |
| 宋敬卉,等.托吡酯对癫痫病人胰岛素及瘦素水平的影响.《中国新药与临床杂志》.2006,第25卷(第1期),14-16. * |
| 王祖承，等.精神药物与肥胖.《新药与临床》.1989,第8卷(第4期),213-215. * |
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| CN101594868A (en) | 2009-12-02 |
| ZA200902761B (en) | 2010-07-28 |
| UA96311C2 (en) | 2011-10-25 |
| ES2357983T3 (en) | 2011-05-04 |
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