CN101594868A - Pharmaceutical composition having antipsychotic, antidepressant or antiepileptic activity and minor side effects - Google Patents
Pharmaceutical composition having antipsychotic, antidepressant or antiepileptic activity and minor side effects Download PDFInfo
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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 therapy 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 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 launch research at this type of treatment patient, report this type of overweight and even 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 is 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 more and more widely application 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 may 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, described 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 for the treatment of 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 uses the hydroxamic acid derivatives that comprises BGP-15 on affected epidermis.
U.S. Patent number US6451851 discloses a kind of method for the treatment of 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 for the treatment of 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 by 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 been found and have 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 invention provides O-(3-piperidino-2-hydroxyl-1-propyl group)-nicotine amidoxim or the application of its pharmaceutically-acceptable acid addition in pharmaceutical compositions, described 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 for the treatment of 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 IA represents,
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.
Particularly preferred 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, i.e. 4-[3-[2-(trifluoromethyl)-10H-phenothiazine-10-yl] propyl group]-the 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 I B represents,
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-caprinoyl oxygen oxygen base ethyl)-1-piperazinyl,
R
2Expression chlorine atom, trifluoromethyl or N, N-dimethyl-sulfoamido.
Particularly preferred thioxanthene analog derivative is as follows:
Chlorprothixene, i.e. 3-(2-chloro-9H-thioxanthene-9-subunit)-N, N-dimethyl-1-propylamine (propanamine),
Clopenthixol, promptly 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 represents,
Wherein, X represents nitrogen-atoms or group " C=" or " CH-",
Y represents 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,
C ring expression phenyl ring, optional by halogen atom or N, N-dimethyl methyl amide groups replaces; C ring also can be heterocyclic group, itself and benzene diaza
Part forms thiophene [2,3-b] [1,5] benzene diaza
Structure, wherein five yuan of thiphene ring are chosen wantonly No. 2 positions by methyl substituted,
Dotted line between X and adjacent carbon atom is meaningless when saturated rings, then represents 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 define as mentioned.
Particularly preferred formula IC derivant is as follows:
Clozapine, i.e. 8-chloro-11-(4-methyl isophthalic acid-piperazinyl)-5H-dibenzo-[b, e] [1,4] diaza
Olanzapine, i.e. 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno-[2,3-b] [1,5]-benzene diaza
Quetiapine, i.e. 2-[2-(4-dibenzo [b, f] [1,4] sulfur azepine
-11-base-1-piperazinyl) ethyoxyl]-ethanol,
Zotepine, i.e. 2-[(8-chlorodiphenyl [b, f] sulfur also
-10-yl) oxygen base]-N, the N-dimethyl amine,
Different clozapine, i.e. chloro-11-(4-methyl isophthalic acid-piperazinyl)-5H-dibenzo-[b, e] [1,4] diaza
Clotiapine, i.e. 2-chloro-11-(4-methyl isophthalic acid-piperazinyl) dibenzo [b, f] [1,4] magnetic
Western Horizon (oxithepine), i.e. 10-[4-(3-hydroxypropyl) piperazinyl difficult to understand]-10,11-dihydro-dibenzo [b, f]-sulfur
And chemically may 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 represents,
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 particularly preferred formula ID is as follows:
Sulpiride, i.e. 5-(amino-sulfonyl)-N-[(1-ethyl-2-pyrrolidinyl)-methyl]-2-methoxyl group-Benzoylamide,
Amisulpride, i.e. 4-amino-N-[(1-ethyl-2-pyrrolidinyl) methyl]-5-(ethylsulfonyl)-2-methoxy benzamide and
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 particularly preferred 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 and
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 particularly preferred Formula I G is
Pimozide, i.e. 1-[1-[4,4-two (4-fluoro phenyl) butyl]-the 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, promptly 4-[4-(4-chlorophenyl)-4-hydroxyl is at-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]-the 1-butanone.
Another is organized preferred antipsychotic drug and comprises indole derivatives and pharmaceutically-acceptable acid addition thereof, for example:
Molindone, as 3-ethyl-1,5,6,7-tetrahydrochysene-2-methyl-5-(4-morpholine methyl)-4H-indole-4-ketone,
Ziprasidone is as 5-[2-[4-(1,2-benzisothiazole-3-yl)-1-piperazinyl]-ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one,
The house draw diindyl, as 1-[2-[4-[5-chloro-1-(4-fluoro phenyl)-1H-indol-3-yl]-piperidino]-ethyl]-the 2-imidazolone or
Oxypertine, promptly 5,6-dimethoxy-2-methyl-3-[2-(4-phenyl-peiperazinyl) ethyl]-the 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, i.e. 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, promptly the 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, as 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 can prevent or alleviate the order of severity and the frequency of epilepsy in all kinds of epilepsies.The preferred term " antiepileptic " that uses is the situation that all has convulsions owing to not all outbreak.Preferred antiepileptic comprises some phenothiazine derivatives shown in the formula IA, for example, 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]-the 1-piperazinyl] ethyl ester, the latter generally is the mode administration with difumarate.Described 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, for example carbamazepine, 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, for example phenobarbital simultaneously, be 5-ethyl-5-phenyl-2,4,6 (1H, 3H, 5H)-pyrimidine-triketone and pharmaceutically acceptable slaine thereof, eterobarb, be 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, i.e. 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, for example ethadione, i.e. 3-ethyl-5,5-dimethyl-2,4-oxazolidinedione or the like, succinimide derivatives, for example, ethosuximide, be 3-ethyl-3-methyl-2,5-pyrrolidine-diones, phensuximide, it is 1-methyl-3-phenyl-2,5-pyrrolidine-diones or the like, carboxylic acid derivates, for example, valproic acid, be 2-Propylpentanoic and pharmaceutically acceptable slaine thereof, valpromide, i.e. dipramide, valnoctamide, i.e. 2-ethyl-3-methyl-pentanamide or the like.
Also have the available antiepileptic of a class to comprise γ-An Jidingsuan (GABA) derivant; gabapentin for example; it is 1-(amino methyl) Cyclohexaneacetic acid; progabide; be the 4-[[(4-chlorophenyl) (5-fluoro-2-hydroxy phenyl)-methylene] amino] butyramide; vigabatrin; it is 4-amino-5-hexenoic acid; piracetam; it is 2-OXo-1-pyrrolidine yl acetamide; oxiracetam, i.e. 4-hydroxyl-2-OXo-1-pyrrolidine yl acetamide, nefiracetam; be N-(2; 6-dimethyl-phenyl) 2-OXo-1-pyrrolidine yl acetamide etc., and the pharmaceutically acceptable salt that forms of sour form and metal, the carbamic acid salt derivative; meprobamate for example; be 2-methyl-2-propyl group-1, the ammediol diurethane, this chemical compound also has angst resistance effect; felbamate; be 2-phenyl-1, ammediol diurethane or the like, some sulfa drugs; acetazolamide for example; be N-[5-(amino-sulfonyl)-1,3,4-thiadiazoles-2 base] acetamide; zonisamide; promptly 1,2-benzoisoxazole-3-amsacrine, thiazine relaxes; be 4-(tetrahydrochysene-2H-1; 2-thiazine-2-yl)-and benzsulfamide S, S-dioxide or the like, N-acyl urea derivatives; phenacal for example; be 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-pair-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.
Particularly preferred 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 may form, the active component used according to the present invention also can be made 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, giving has psychosis or antidepressant or antiepileptic to treat known psychosis or antidepressant or the antiepileptic that the patient who needs uses convention amount, gives 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 described pharmaceutical composition is applicable to and prevents or alleviate the overweight or fat side effect that causes in known psychosis, antidepressant or antiepileptic treatment.Described 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.The consumption per day of pharmaceutical composition that comprises BGP-15 or its pharmaceutically-acceptable acid addition is with above given similar.
Another embodiment is to have psychosis, antidepressant or antiepileptic activity to have the pharmaceutical composition that reduces side effect, described 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.
Make 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, make 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 made 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.Described 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, as gelatin, sorbitol, and polyvidone etc.; Filler is as lactose, glucose, starch, calcium phosphate etc.; The tabletting adjuvant is as magnesium stearate, Talcum, Polyethylene Glycol, silicon dioxide etc.; Wetting agent is as 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, as gelatin, carboxymethyl cellulose etc.; Emulsifying agent, single oleic acid Pyrusussuriensis ester etc.; Solvent, Ru Shui, oil, glycerol, propylene glycol, ethanol etc.; Antiseptic is as 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, chlorine piperazine plug ton, Thiothixene, 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, Sertindole, antipsychotic drug and BGP-15 or its pharmaceutically-acceptable acid addition and one or more conventional carriers with Equipertine or above-claimed cpd pharmaceutically-acceptable acid addition.
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 is particularly 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 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 is particularly 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, 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, U.S.A draws together and puts forth energy is ester, 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, thiazine relaxes, 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.
Particularly preferred antiepileptic and BGP-15 or its pharmaceutically-acceptable acid addition and one or more the conventional carriers that has the less pharmaceutical composition of antiepileptic activity side effect simultaneously to comprise valproic acid or pharmaceutically acceptable valproic acid alkali metal salt of the present invention.
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 and 6 every days of evening twice of oral administration.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 chemical compound in contrast, be equally one group individually dosed, another the group with 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 by subcutaneous injection administration once a day, and dosage is respectively 0.005mg/kg and 0.05mg/kg, to bring out body weight gain.The BGP-15 dihydrochloride is by oral administration, and once a day, dosage is 20mg/kg, and 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 two dosage causes.
Claims (10)
1.O-(3-piperidino-2-hydroxyl-1-propyl group)-nicotine amidoxim or its pharmaceutically-acceptable acid addition are applicable to prevention or alleviate purposes in the pharmaceutical composition of the overweight or fat side effect that is caused by known antipsychotic drug, antidepressant drug or antiepileptic treatment in preparation.
2. purposes as claimed in claim 1, wherein administration O-(3-piperidino-2-hydroxyl-1-propyl group)-nicotine amidoxim dihydrochloride.
3. purposes as claimed in claim 1, antipsychotic drug wherein are selected from olanzapine, clozapine, risperidone, Quetiapine and sulpiride or their pharmaceutically-acceptable acid addition.
4. one kind has the littler pharmaceutical composition of psychosis, antidepressant or antiepileptic activity side effect simultaneously, comprises 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 conventional carriers.
5. pharmaceutical composition as claimed in claim 4, wherein antipsychotic drug is selected from olanzapine, clozapine, risperidone, Quetiapine and sulpiride or their pharmaceutically-acceptable acid addition.
6. as claim 4 or 5 described pharmaceutical compositions, comprise olanzapine and O-(3-piperidino-2-hydroxyl-1-propyl group)-nicotine amidoxim or its pharmaceutically-acceptable acid addition.
7. as claim 4 or 5 described pharmaceutical compositions, comprise clozapine and O-(3-piperidino-2-hydroxyl-1-propyl group)-nicotine amidoxim or its pharmaceutically-acceptable acid addition.
8. as claim 4 or 5 described pharmaceutical compositions, comprise risperidone and O-(3-piperidino-2-hydroxyl-1-propyl group)-nicotine amidoxim or its pharmaceutically-acceptable acid addition.
9. pharmaceutical composition as claimed in claim 4, antidepressant drug wherein are selected from Clomipramine, citalopram, fluoxetine, fluvoxamine, paroxetine and Sertraline or their pharmaceutically-acceptable acid addition.
10. pharmaceutical composition as claimed in claim 4, antuepileptic wherein are selected from valproic acid or its pharmaceutically acceptable alkali metal salt.
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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| CN101594868A true CN101594868A (en) | 2009-12-02 |
| CN101594868B CN101594868B (en) | 2012-12-12 |
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| CN (1) | CN101594868B (en) |
| ES (1) | ES2357983T3 (en) |
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| ES2357983T3 (en) | 2011-05-04 |
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