CN1871243A - Oral neurotherapeutic cefazolin compositions - Google Patents
Oral neurotherapeutic cefazolin compositions Download PDFInfo
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- CN1871243A CN1871243A CN 200480031510 CN200480031510A CN1871243A CN 1871243 A CN1871243 A CN 1871243A CN 200480031510 CN200480031510 CN 200480031510 CN 200480031510 A CN200480031510 A CN 200480031510A CN 1871243 A CN1871243 A CN 1871243A
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Abstract
The treatment of neurological disorders using cefazolin compositions and pharmaceutical compositions including oral dosage forms that include cefazolin compositions are described.
Description
Technical field
The present invention relates to be used for the Compounds and methods for that neuropsychiatry is intervened.More specifically, the present invention relates to use pharmaceutical formulations and the method that is used for the treatment of multiple neurological disorder state with cynnematin sulfoxide, cephalosporin sulphone, its pharmacologically acceptable salt and the active ester thereof of oral dosage form explanation.
Background technology and summary of the invention
Extensive studies has been carried out in pharmaceutical industry, is intended to find to be used for the treatment of the medicine of neuroscience illness and with its commercialization.This illness typically comes from the unbalanced of chemical substance in the brain.The excessive generation of relevant neurochemical or generation deficiency and/or receptor function controlling obstacle are considered to relevant with the known numerous disease state of other practitioner in neuropathist, psychiatrist, psychologist and the mental disease diagnosis and treatment field.Be intended to find that the great majority effort of new neuroscience active medicine is based on the Study of Interaction to one or more and/or its receptors ligand separately in many acceptors in agonist/antagonist medicine and the brain.
The oral dosage form that the invention provides Cephazolin compound and derivative thereof is as the application of psychotherapeutic agent in the multiple neuroscience illness of treatment.
Description of drawings
Fig. 1 a-b represents Δ
3(Fig. 1 a) and Δ for-Cephazolin-1-sulfoxide
2Result in the dosage-response studies of-Cephazolin-1-sulfoxide (Fig. 1 b) in the seed discovery model of anxiety.
Fig. 2 a-b represents to use Δ
2The result of-Cephazolin-1-sulfoxide in the labyrinth model research of overhead cross.Fig. 2 a represents to enter the waiting time of closure arm, and Fig. 2 b is illustrated in the time of open arms.
Fig. 3 a-d is illustrated in occupant/invader's model system and uses Δ
2The active test-results of calmness (serenic) of-Cephazolin-1-sulfoxide.Fig. 3 a represents waiting time of baiting, and Fig. 3 b represents duration of contact, and Fig. 3 c represents to bait number of times and Fig. 3 d represents to coerce gland mark (flankmarking) number of times.
Fig. 4 a-b is illustrated in the locomotor activity after occupant/invader's test of summing up among Fig. 3 a-d, and Fig. 4 a represents spacious (open field) activity, and Fig. 4 b property represented is actuated.
Fig. 5 is illustrated in the wrong number of the learning and memory in the system of radiation arm labyrinth.
Fig. 6 a-c is illustrated in the use Δ
3(Fig. 6 is to show with the pg numerical table among per 15 μ l a) and the level of HVA (Fig. 6 b) and thrombotonin metabolite (Fig. 6 c) to the Dopamine HCL metabolite DOPAC that measures by Electrochemical Detection after-Cephazolin-1-sulfoxide is handled.
Detailed Description Of The Invention
The present invention and describe herein and the different embodiments advocated partly originates from some carboxypeptidase E inhibitor is effectively shown the active discovery of strong Neurotherapeutic in administration during threshold value enzyme inhibition concentration so that it to be provided in brain.This inhibitor shows significant neural activity clinically, and this active part ground is proved by behavior change and cognitive enhancing.According to existing testing data and molecular simulation research, hint is intensive now can be by target/be suppressed, so that the basis of multiple Neurotherapeutic effect to be provided through originality carboxypeptidase E.Carboxypeptidase E combining site model has been discerned some cynnematin sulfoxide and sulfone, with Δ
2-and Δ
3-Cephazolin sulfoxide is an example, as the potential inhibitor of carboxypeptidase E.Though Cephazolin itself has some sedative activity, Δ
2-and Δ
3-Cephazolin sulfoxide all shows not only has calmness but also have the anxiety activity.In addition, though known Cephazolin has some anti-microbial activity when parenteral admin,, cynnematin sulfoxide of the present invention and sulfone not only have sedative activity but also have the anxiety activity in hamster even when oral administration, also showing.Therefore, one embodiment of the invention are Δ
2-and Δ
3-Cephazolin sulfoxide and sulfone and derivative thereof (referring to Formula Il) are as the application of the psychotherapeutic agent in the treatment of aggressive behaviour, obsession, anxiety, cognitive disorder etc.In a specific embodiment, Δ
2-and Δ
3-Cephazolin sulfoxide and derivative thereof provide with oral dosage form.
The responsive behavior of treatment of the present invention and the example of cognitive disorder are comprised: attack illness, obsession, anxiety, dysthymia disorders, schizophrenia, ADHD and show as the disease of memory/learning disorder.Preliminary animal data shows, it is in the Neurotherapeutic treatment of conditions of example that method and composition of the present invention can be used for autism, Tourette's syndrome, mental retardation, psychosis, mania, senile dementia as the anti-attack medicine of control impulsion and violence, and is used to suffer from the treatment of the individuality of personality disorder and improper aggressive behaviour medical history.Its clinical application for example also extends to the treatment that is used to suffer from the children of ADHD and behavior disorder as anxiolytic, is used to improve learning and memory and improves the direction unconsciousness as the elderly population cognitive enhancer.According to the present invention, with Δ
2-and Δ
3The oral dosage form of-Cephazolin sulfoxide and derivative thereof is that the cynnematin sulfoxide and the sulfone of example explanation can be used for multiple psychotherapy application.
The Neurotherapeutic that is used to prepare oral dosage form of the present invention is generally the compound of following formula with cephalosporin compound
Formula Ia formula Ib
Wherein n is 1 or 2;
R is hydrogen, group or the pharmaceutically acceptable positively charged ion that forms active ester;
R
1Be hydrogen; Optional substituted alkyl comprises low alkyl group and C
1-C
4Alkyl is as methyl, ethyl, propyl group or the like; Optional substituted alkoxyl group comprises lower alkoxy and group (C
1-C
4Alkyl)-O-; Or optional substituted alkylthio, as lower alkylthio and group (C
1-C
4Alkyl)-and S-, comprise methylthio group and ethylmercapto group;
Acyl group is carboxylic acid such as R
2-CO
2The residue of H, wherein R
2Be alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, it can be chosen wantonly separately and be substituted; With
X is that hydrogen, alkyl (comprise low alkyl group and C
1-C
6Alkyl), halo, haloalkyl, hydroxyl, alkoxyalkyl, halogenated alkoxy alkyl, alkoxyl group alkoxyl group, alkylthio, optional substituted arylthio, optional substituted heteroarylthio, acyloxy (wherein acyl group as mentioned above) are as optional substituted alkyl-carbonyl oxygen base, optional substituted aryl carbonyl oxygen base and optional substituted heteroaryl ketonic oxygen base; Perhaps X is-CH
2B, wherein B is the residue of nucleophilic reagent B-H.
Illustrative ground, acyl group are to have residue following structure, that connect at (*) atom place:
Wherein R is being independently selected from hydrogen, optional substituted alkyl and pharmaceutically acceptable positively charged ion in the situation separately; And form each aryl of the part of described acyl group herein or heteroaryl is optional is substituted.
Nucleophilic reagent B-H be can permutations as shown in the formula any nucleophilic reagent of the leavings group on the molecule of compound or its protected derivative (L):
Formula Ic
Wherein n is 1 or 2;
R is hydrogen, group or the pharmaceutically acceptable positively charged ion that forms active ester;
R1 is hydrogen, alkyl, alkoxyl group or alkylthio;
The definition of acyl group is suc as formula the definition in Ia and the Ib compound; With
L is a leavings group, as halo, alkoxyl group, aryloxy, alkyl-carbonyl oxygen base, halogenated alkyl carbonyl oxygen base, aryl carbonyl oxygen base, alkyl sulphonyl oxygen base, halogenated alkyl sulfonyl oxygen base etc., and substituted derivative.
Illustrative ground, X is-CH
2B, wherein B has residue one of following structure, that connect at (*) atom place:
Wherein R is being independently selected from hydrogen in the situation separately, optional substituted alkyl and pharmaceutically acceptable positively charged ion; And form optional being substituted of each heteroaryl of the part of described X herein.
Illustrative ground, the Neurotherapeutic cephalosporin compound is the Cephazolin derivative, and has the structure of following formula:
Formula II
Wherein:
N is 1 or 2;
One of key a and key b are two keys; With
R is hydrogen, group or the pharmaceutically acceptable positively charged ion that forms active ester.
Have more illustrative ground, Neurotherapeutic has following structure with compound, and wherein formula III is a Δ
2-Cephazolin sulfoxide (or Δ-2-Cephazolin-1-sulfoxide) and formula IV are Δ-3-Cephazolin sulfoxide (or Cephazolin-1-sulfoxide).
Formula III formula IV
Wherein n is 1 or 2, and R is hydrogen or pharmaceutically acceptable positively charged ion.
The invention still further relates to pharmaceutical compositions, it comprises and is selected from above-mentioned compound and pharmaceutically acceptable sanction body, thinner or vehicle.
The universalization technics that is used for following formula has its implication commonly used.For example, term " alkyl " comprises group such as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, 2-amyl group, 3-amyl group, neo-pentyl, hexyl, heptyl, octyl group or the like.
Term " aryl " is meant aromatic nucleus or assorted aromatic nucleus, and comprise group such as furyl, pyrryl, thienyl, thiazolyl, azoles base, different azoles base, isothiazolyl, imidazolyl, pyrazolyl, tetrazyl, phenyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, thiadiazolyl group, di azoly, naphthyl, 2,3-indanyl, fluorenyl, quinolyl, isoquinolyl, benzo dioxane base, benzofuryl, benzothienyl or the like.
Term " optional being substituted " is meant with one or more, preferred one to three hydrogen atom of one or more substituting group displacements.This substituting group comprises following group such as C
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
4Alkylthio, hydroxyl, nitro, halo, carboxyl, cyano group, C
1-C
4Haloalkyl, C
1-C
4Halogenated alkoxy, C
1-C
4Alkoxyalkyl, C
1-C
4Halogenated alkoxy alkyl, amino, carboxamide groups (carboxamido), amino, single (C
1-C
4Alkyl) amino, two (C
1-C
4Alkyl) amino, C
1-C
4Alkyl sulphonyl, C
1-C
4Alkyl sulfonyl-amino or the like.
Term " acyl group " and " alkyloyl " comprise group such as formyl radical, ethanoyl, propionyl, butyryl radicals, pentanoyl or the like.
Term " halo " is meant fluoro, chloro, bromo and iodo.
Should be appreciated that the mode that described term can chemically be correlated with makes up herein.For example, term " arylalkyl " is meant optional substituted aromatic nucleus or the hetero-aromatic ring that is connected with alkyl chain, and it includes but not limited to benzyl, tolyl, 2-, 3-and 4-picolinyl, pyrimidinylethyl, 2-(thiophene-2-yl) propyl group or the like.
Term " pharmaceutically acceptable positively charged ion " is meant and can be under suitable reaction, solvent, pH or buffer condition combines the cationic residues of any pharmacologically acceptable salt that forms corresponding carboxylic acid salt with compound with described Neurotherapeutic herein.These positively charged ions also can prepare by the mode of cationic exchange with routine.Should be appreciated that described Neurotherapeutic is with the salt derivative of compound herein, remove the form that conduct exists in solution owing to reaction, solvent, pH or buffer condition, also comprise the form after the separation.
Exemplary pharmaceutically acceptable positively charged ion includes but not limited to inorganic cation, comprises aluminium, silver; An alkali metal salt such as lithium, sodium or potassium; Alkaline earth salt such as calcium or magnesium; With ammonium salt of ammonium salt and replacement or the like.Exemplary pharmaceutically acceptable positively charged ion includes but not limited to that organic cation comprises alkylammonium such as triethyl ammonium, hydroxyalkyl ammonium such as 2-hydroxyethyl ammonium, two-(2-hydroxyethyl) ammonium and three-(2-hydroxyethyl) ammonium, cycloalkyl ammonium such as tetramethyleneimine , piperidines , dicyclohexyl ammonium, the dibenzyl ammonium, N, N-dibenzyl ethylene ammonium, 1-ephenammonium, N-methylmorpholine , ethyl piperidine , N-benzyl-β-styroyl ammonium, the westvaco rosin ammonium, N, N '-two westvaco rosin ammoniums, the ethylene ammonium, pyridine class such as pyridine , 4-ethyl-2-picoline , quinoline , cetyl pyridinium and tetradecyl ethylpyridine ; With biguanides or the like.Exemplary pharmaceutically acceptable positively charged ion include but not limited to blended inorganic/organic cation, comprise glycocoll-copper or the like.
Term " forms the group of active ester " and is meant the group that forms carboxylates derivatives, and described carboxylicesters is hydrolyzed to parent carboxylic in vivo under suitably selected state.This group comprises prodrug.The group of exemplary formation active ester includes but not limited to 1-indanyl, N-oxygen base succinimide; Acyloxy alkyl such as acetoxy-methyl, oxy acid methyl neopentyl, β-acetoxyl group ethyl, β-new pentane acyloxy ethyl, 1-(cyclohexyl-carbonyl oxygen base) third-1-base, (1-amino-ethyl) ketonic oxygen ylmethyl or the like; Alkoxy-carbonyl oxy alkyl such as ethoxy carbonyl oxygen ylmethyl, (α-ethoxy carbonyl oxygen base ethyl or the like; Dialkyl aminoalkyl such as ethoxy carbonyl oxygen ylmethyl, β-ethoxy carbonyl oxygen base ethyl or the like; Dialkyl aminoalkyl, comprise two (low alkyl group) aminoalkyl groups such as dimethylaminomethyl, dimethyl aminoethyl, diethylamino methyl, diethylamino ethyl or the like; 2-(alkoxy carbonyl)-2-thiazolinyl such as 2-(isobutoxy carbonyl) penta-2-thiazolinyl, 2-(ethoxy carbonyl) but-2-ene base or the like; With lactone groups such as phthalidyl, dimethoxy-phthalidyl or the like.
Be used to prepare the cynnematin sulfoxide of exemplary oral dosage form typically by using peracid such as Peracetic Acid, the metachloroperbenzoic acid corresponding 2-cephalos well known in the art of oxidation such as (mCPBA) or the preparation of 3-cephalosporin compound.Also peracid, hydrogen peroxide etc. directly carry out from 2-cephalo, 3-cephalo analogue as described herein with excessive oxygenant by oxidation sulfoxide analogue or in the presence of for example ruthenium tetroxide similarly in the preparation of sulfone.
According to present animal experiment, it is believed that according to the present invention cynnematin sulfoxide by effective dosage and sulfone, exemplarily be Δ
2-and Δ
3The general classes of the behavior disorder that the oral dosage form of-Cephazolin sulfoxide and derivative thereof can be treated comprises: aggressive obstacle (aggressivedisorder), obsession, anxiety, dysthymia disorders and attention deficit Attention Deficit Hyperactivity Disorder (ADHD).Therefore, in one embodiment of the invention, Δ
2-or Δ
3-Cephazolin sulfoxide or Δ
2-and Δ
3The combination of-Cephazolin sulfoxide, as the anti-drug administration of attacking, be used for controlling suffer from autism, Tourette's syndrome, mental retardation, psychosis, mania, senile dementia the patient's or impulsion and violence among the patient of personality disorder and improper aggressive behaviour medical history arranged.
Other sacred disease state that can treat according to the present invention comprises dysthymia disorders, comprise heavy dysthymia disorders (single outbreak type, recurrent, inhibitable type (melancholic)), atypia dysthymia disorders, evil mood dysthymia disorders, inferior syndrome (subsyndromal) dysthymia disorders, anxious depression, retardance depression, with the dysthymia disorders of cancer, the common morbidity of diabetes or myocardial infarction retarded depression disease, involutional depression; Manic-depressed illness, psychotic depression, endogenous and reactive depression, obsession or exessive appetite.In addition, peptidase inhibitors can be used for treating the patient that suffers from following disease (individually dosed or and morphine, morphine monomethyl ether or Dextropoxypheene (dextroproposyphene) combination medicine-feeding): anancastic personality disorder, posttraumatic stress disorder, hypertension, atherosclerosis, anxiety, anorexia nervosa, panic, social phobia, stutter, somnopathy, confirmed fatigue, the cognition relevant with Alzheimer lacks, excessive drinking, limited appetite, lose weight, agoraphobia, improve memory, amnesia, smoking cessation, nicotine withdrawal syndrome symptom, mood relevant and/or appetite imbalance with premenstrual syndrome, depressed and/or the carbohydrate relevant with premenstrual syndrome thirsted for, emotional maladjustment, appetite imbalance or help the imbalance of the recurrence relevant with nicotine withdrawal, the diel rhythm obstacle, borderline personality's obstacle, hypochondriasis, premenstrual syndrome (PMS), the disease of having the fidgets luteal phase in evening, through preceding dysphoria disease, trichotillomania, symptom behind inactive other thymoleptic, aggressiveness/intermittent violent disease, compulsive gambling, mandatory consumption, mandatory sexual behaviour, the application illness of peychoactive material, sexual dysfunction, schizophrenia, premature ejaculation or be selected from stress, worried, indignation, refusal sensitivity and the psychiatric symptom that lacks spirit or muscle power.
The pathology that can treat according to the present invention, other example of psychology situation include but not limited to: moderate mental retardation (318.00); Severe mental retardation (318.10); Extreme mental retardation (318.20); Ming Xi mental retardation (319.00) not; Autism (299.00); Popularity development obstacle NOS (299.80); Attention deficit Attention Deficit Hyperactivity Disorder (314.01); Behavior disorder, tissue-type (group type) (312.20); Behavior disorder, individual (solitary) attack (312.00); Behavior disorder, not differentiation type (312.90); Tourette's syndrome disease (307.23); Chronic exercise or sound tic (307.22); Of short duration tic (307.21); Tic NOS (307.20); Senium Alzheimer type PDD, no complication (290.00); Senium Alzheimer type PDD (290.30) with delirium; Senile Alzheimer type PDD (390.20) with paranoea; Senile Alzheimer type PDD (290.21) with depression; Senile Alzheimer type PDD early, no complication (290.10); With the senile Alzheimer type PDD morning of delirium (290.11); With the senile Alzheimer type PDD morning of paranoea (290.12); With the senile Alzheimer type PDD morning of depression (290.13); Multi-infarct dementia, no complication (290.40); Multi-infarct dementia is with delirium (290.41); Multi-infarct dementia is with paranoea (290.42); Multi-infarct dementia is with depressed (290.43); Senile dementia NOS (290.10); Old dementia NOS (290.10) early; The alcohol property given up delirium (291.00); Alcohol hallucinosis (291.30); The alcoholic dementia relevant (291.20) with alcoholism; Amphetamine or similar effect sympathomimetic cause poisoning (305.70); Amphetamine or similar effect sympathomimetic cause paranoea (292.11); Hemp causes paranoea (292.11); Cocaine causes poisoning (305.60); Cocaine delirium (292.81); Cocaine causes paranoea (292.11); Fantasy causes hallucinosis (305.30); Fantasy causes paranoea (292.11); Fantasy causes emotional handicap (292.84); Fantasy causes hazy and illusionary back (Posthallucinogen) consciousness illness (292.89); The aryl rings hexyl amine of phencyclidine (PCP) or similar effect causes poisoning (305.90); The aryl rings hexyl amine of phencyclidine (PCP) or similar effect causes delirium (292.81); The aryl rings hexyl amine of phencyclidine (PCP) or similar effect causes paranoea (292.11); The aryl rings hexyl amine of phencyclidine (PCP) or similar effect causes emotional handicap (292.84); The aryl rings hexyl amine of phencyclidine (PCP) or similar effect causes organic mental disorders NOS (292.90); Other or not detailed neuroactive substance cause poisoning (305.90); Other or not detailed neuroactive substance cause delirium (292.81); Other or not detailed neuroactive substance cause dementia (292.82); Other or not detailed neuroactive substance cause paranoea (292.11); Other or not detailed neuroactive substance cause hallucinosis (292.12); Other or not detailed neuroactive substance cause emotional handicap (292.84); Other or not detailed neuroactive substance cause anxiety disorder (292.89); Other or not detailed neuroactive substance cause personality disorder (292.89); Other or not detailed neuroactive substance cause organic mental disorders NOS (292.90); Delirium (293.00); Dull-witted (294.10); Organic paranoea (293.81); Organic hallucinosis (293.81); Organic emotional handicap (293.83); Organic anxiety disease (294.80); Organic personality disorder (310.10); Organic mental disorders (29.80); Obsession (300.30); Posttraumatic stress disorder (309.89); Generalized anxiety disorder (300.02); Anxiety disorder NOS (300.00); " body image disturbance (300.70); Hypochondriasis (or hypochondriasis sexual neurosis) (300.70); Somatization disorder (300.81); Not differentiation type body sample obstacle (300.70); Body sample obstacle NOS (300.70); Intermittent irascible disease (312.34); Kleptomania (312.32); Pathological Gambling disease (312.31); Empresmomania (312.33); Trichotillomania (312.39); With impulsion control illness NOS (312.39).
The other example of other pathology described in medicable the present invention, psychology situation comprises: schizophrenia, catatonic type, inferior chronic (295.21); Schizophrenia, catatonic type, chronic (295.22); Schizophrenia, catatonic type, inferior chronic with acute attack (295.23); Schizophrenia, catatonic type, chronic with acute attack (295.24), schizophrenia, catatonic type is in the alleviation (295.55); Schizophrenia, catatonic type, not Ming Xi (295.20); Schizophrenia, chaotic type, chronic (295.12); Schizophrenia, chaotic type, inferior chronic with acute attack (295.13); Schizophrenia, chaotic type, chronic with acute attack (295.14); Schizophrenia, chaotic type is in the alleviation (295.15); Schizophrenia, chaotic type, not Ming Xi (295.10); Schizophrenia, delusional type, inferior chronic (295.31); Schizophrenia, delusional type, chronic (295.32), schizophrenia, delusional type, inferior chronic with acute attack (295.33); Schizophrenia, delusional type, chronic with acute attack (295.34); Schizophrenia, delusional type is in the alleviation (295.35); Schizophrenia, delusional type, not Ming Xi (295.30); Schizophrenia, not differentiation type, inferior chronic (295.91); Schizophrenia, not differentiation type, chronic (295.92); Schizophrenia, not differentiation type, inferior chronic with acute attack (295.93); Schizophrenia, not differentiation type, chronic with acute attack (295.94); Schizophrenia, not differentiation type is in the alleviation (295.95); Schizophrenia, not differentiation type, not Ming Xi (295.90); Schizophrenia, remaining type, inferior chronic (295.61); Schizophrenia, remaining type, chronic (295.62); Schizophrenia, remaining type, inferior chronic with acute attack (295.63); Schizophrenia, remaining type, chronic with acute attack (295.94); Schizophrenia, remaining type is in the alleviation (295.65); Schizophrenia, remaining type, not Ming Xi (295.60); Vain hope (delusional type) illness (297.10); Of short duration reactive psychosis (298.80); Schizophreniform illness (295.40); Emotionality schizophrenia illness (295.70); Induced insanity illness (297.30); Psychosis illness NOS (atypical psychosis) (298.90); Manic-depressed illness, mixed type, severe does not have psychosis characteristics (296.63); Manic-depressed illness, manic type, mixed type, severe does not have psychosis characteristics (296.43); Manic-depressed illness, depressive type, severe does not have psychosis characteristics (296.53); Manic-depressed illness, mixed type is with psychosis characteristics (296.64); Manic-depressed illness, manic type is with psychosis characteristics (296.44); Manic-depressed illness, depressive type is with psychosis characteristics (296.54); Manic-depressed illness NOS (296.70); Heavy dysthymia disorders, single outbreak type is with psychosis characteristics (296.24); Heavy dysthymia disorders, the recurrence type, with psychosis characteristics (296.34), personality disorder, delusional type (301.00); Personality disorder, schizophrenia type (301.20); Personality disorder, Schizoid (301.22); Personality disorder, conflict koinotropic type (301.70); And personality disorder, peripheral type (301.83).
The anxiety illness that can treat according to the present invention comprises: anxiety disorder (235); Phobias (235); Phobias (300.21) with agoraphobia; The Phobias (300.01) that does not have agoraphobia; The agoraphobia (300.22) that does not have the Phobias medical history; Social phobia (300.23); Simple phobia (300.29); Organic anxiety disease (294.80); Neuroactive substance anxiety disorder (292.89); Separation anxiety disorder (309.21); Young or hebetic avoidance illness (313.21); And overanxious disorder (313.00).
The carboxypeptidase of described significant quantity suppresses the treatment that compound can be used for following pathology, psychology situation herein: moderate mental retardation; Severe mental retardation; The extreme mental retardation; Autism; The attention deficit Attention Deficit Hyperactivity Disorder; Popularity development obstacle NOS; Behavior disorder, tissue-type; Behavior disorder, individual attack; Tourette's syndrome disease; Senile Alzheimer type PDD with delirium; Senile Alzheimer type PDD with paranoea; Senile Alzheimer type PDD early; Schizophrenia, catatonic type, inferior chronic; Schizophrenia, catatonic type, chronic; Schizophrenia, catatonic type, inferior chronic with acute attack; Schizophrenia, catatonic type, chronic with acute attack; Schizophrenia, catatonic type is in the alleviation; Schizophrenia, catatonic type, not detailed; Schizophrenia, chaotic type, inferior chronic; Schizophrenia, chaotic type, chronic; Schizophrenia, chaotic type, inferior chronic with acute attack; Schizophrenia, chaotic type, chronic with acute attack; Schizophrenia, chaotic type is in the alleviation; Schizophrenia, chaotic type, not detailed; Schizophrenia, delusional type, inferior chronic; Schizophrenia, delusional type, chronic; Schizophrenia, delusional type, inferior chronic with acute attack; Schizophrenia, delusional type, chronic with acute attack; Schizophrenia, delusional type is in the alleviation; Schizophrenia, delusional type, not detailed; Schizophrenia, not differentiation type, inferior chronic; Schizophrenia, not differentiation type, chronic; Schizophrenia, not differentiation type, inferior chronic with acute attack; Schizophrenia, not differentiation type, chronic with acute attack; Schizophrenia, not differentiation type is in the alleviation; Schizophrenia, not differentiation type, not detailed; Schizophrenia, remaining type, inferior chronic; Schizophrenia, remaining type, chronic; Schizophrenia, remaining type, inferior chronic with acute attack; Schizophrenia, remaining type, chronic with acute attack; Schizophrenia, remaining type is in the alleviation; Schizophrenia, remaining type, not detailed; Vain hope (delusional type) illness; The temporary response psychosis; Schizophreniform illness; Emotionality schizophrenia illness; Induction type psychosis illness; Psychosis illness NOS (atypical psychosis); Manic-depressed illness, mixed type is with the psychosis characteristics; Manic-depressed illness, manic type is with the psychosis characteristics; Manic-depressed illness, depressive type is with the psychosis characteristics; Manic-depressed illness NOS; Heavy dysthymia disorders, single outbreak type, or recurrence type are with the psychosis characteristics; Personality disorder, delusional type; Personality disorder, the schizophrenia type; Personality disorder, Schizoid; Personality disorder, conflict koinotropic type; Personality disorder, peripheral type, anxiety disorder; Phobias; Phobias is with agoraphobia; Phobias does not have agoraphobia; Agoraphobia does not have the Phobias medical history; Social phobia; Simple phobia; Obsession; Posttraumatic stress disorder; Generalized anxiety disorder; Anxiety disorder NOS; Organic anxiety disease; The neuroactive substance anxiety disorder; Separation anxiety disorder; Young or hebetic avoidance illness; And overanxious disorder.
One or more compound of the present invention can use separately or make up with the P-glycoprotein inhibitors, is used for the treatment of following psychosis situation: schizophrenia, and catatonic type, inferior chronic; Schizophrenia, catatonic type, chronic; Schizophrenia, catatonic type, inferior chronic with acute attack; Schizophrenia, catatonic type, chronic with acute attack; Schizophrenia, catatonic type is in the alleviation; Schizophrenia, catatonic type, not detailed; Schizophrenia, chaotic type, inferior chronic; Schizophrenia, chaotic type, chronic; Schizophrenia, chaotic type, inferior chronic with acute attack; Schizophrenia, chaotic type, chronic with acute attack; Schizophrenia, chaotic type is in the alleviation; Schizophrenia, chaotic type, not detailed; Schizophrenia, delusional type, inferior chronic; Schizophrenia, delusional type, chronic; Schizophrenia, delusional type, inferior chronic with acute attack; Schizophrenia, delusional type, chronic with acute attack; Schizophrenia, delusional type is in the alleviation; Schizophrenia, delusional type, not detailed; Schizophrenia, not differentiation type, inferior chronic; Schizophrenia, not differentiation type, chronic; Schizophrenia, not differentiation type, inferior chronic with acute attack; Schizophrenia, not differentiation type, chronic with acute attack; Schizophrenia, not differentiation type is in the alleviation; Schizophrenia, not differentiation type, not detailed; Schizophrenia, remaining type, inferior chronic; Schizophrenia, remaining type, chronic; Schizophrenia, remaining type, inferior chronic with acute attack; Schizophrenia, remaining type, chronic with acute attack; Schizophrenia, remaining type is in the alleviation; Schizophrenia, remaining type, not detailed; Vain hope (delusional type) illness; The temporary response psychosis; Schizophreniform illness; Emotionality schizophrenia illness; The induced insanity illness; Psychosis illness NOS (atypical psychosis); Manic-depressed illness, mixed type is with the psychosis characteristics; Manic-depressed illness, manic type is with the psychosis characteristics; Manic-depressed illness, depressive type is with the psychosis characteristics; Manic-depressed illness NOS; Personality disorder, delusional type; Personality disorder, the schizophrenia type; Personality disorder, Schizoid; Personality disorder, conflict koinotropic type; And personality disorder, peripheral type.
Most preferably the example of the psychosis situation of the method according to this invention treatment comprises: schizophrenia, and catatonic type, inferior chronic; Schizophrenia, catatonic type, chronic; Schizophrenia, catatonic type, inferior chronic with acute attack; Schizophrenia, catatonic type, chronic with acute attack; Schizophrenia, catatonic type is in the alleviation; Schizophrenia, catatonic type, not detailed; Schizophrenia, chaotic type, inferior chronic; Schizophrenia, chaotic type, chronic; Schizophrenia, chaotic type, inferior chronic with acute attack; Schizophrenia, chaotic type, chronic with acute attack; Schizophrenia, chaotic type is in the alleviation; Schizophrenia, chaotic type, not detailed; Schizophrenia, delusional type, inferior chronic; Schizophrenia, delusional type, chronic; Schizophrenia, delusional type, inferior chronic with acute attack; Schizophrenia, delusional type, chronic with acute attack; Schizophrenia, delusional type is in the alleviation; Schizophrenia, delusional type, not detailed; Schizophrenia, not differentiation type, inferior chronic; Schizophrenia, not differentiation type, chronic; Schizophrenia, not differentiation type, inferior chronic with acute attack; Schizophrenia, not differentiation type, chronic with acute attack; Schizophrenia, not differentiation type is in the alleviation; Schizophrenia, not differentiation type, not detailed; Schizophrenia, remaining type, inferior chronic; Schizophrenia, remaining type, chronic; Schizophrenia, remaining type, inferior chronic with acute attack; Schizophrenia, remaining type, chronic with acute attack; Schizophrenia, remaining type is in the alleviation; Schizophrenia, remaining type, not detailed; Vain hope (delusional type) illness; The temporary response psychosis; Schizophreniform illness; Emotionality schizophrenic illness; Personality disorder, the schizophrenia type; And personality disorder, Schizoid.
Of the present invention one preferred aspect in, the treatment to anxiety is provided.Can use the example of the anxiety disorder of method of the present invention and pharmaceutical formulations of the present invention treatment to comprise anxiety disorder, Phobias, the Phobias that has agoraphobia, the Phobias that does not have agoraphobia, the agoraphobia that does not have the Phobias medical history, social phobia, simple phobia, obsession, posttraumatic stress disorder, generalized anxiety disorder, anxiety disorder NOS, organic anxiety disease, the neuroactive substance anxiety disorder, separation anxiety disorder, young or hebetic avoidance illness and overanxious disorder.
Most preferably the example of Zhi Liao anxiety disorder comprises Phobias; Social phobia; Simple phobia; Organic anxiety disease; Obsession; Posttraumatic stress disorder; Generalized anxiety disorder; With anxiety disorder NOS.
Should be appreciated that, above-mentioned listed be not whole illnesss, other illness also can use described composition to treat herein.
When used according to the invention, the effective dose of cynnematin sulfoxide and sulfone and derivative thereof is along with multiple factor is different and different, and described factor includes but not limited to that they are to the route of administration of the inherent avidity of target peptase, selection, weight in patients, hemato encephalic barrier transport efficacy or the like.The effective dose of cynnematin sulfoxide of the present invention and sulfone and derivative thereof can use animal model easily to determine by rule of thumb in conjunction with art-recognized analytical technology.Illustrative ground, oral dosage can be about 2.5ng/kg body weight to about 30mg/kg body weight, represent that every dose is the dosage of about 100ng to about 1g.When the attending doctor judged the higher or lower dosage of needs according to status of patient, higher or lower dosage also was suitable.
The present invention is provided for some pharmaceutical formulations of treatment behavior or cognitive disorder in addition.Usually, said preparation comprises cynnematin sulfoxide or the sulfone of one or more formulas I, more specifically is the Δ of one or more formulas II
2-or Δ
3-Cephazolin sulfoxide, and be used for its pharmaceutically acceptable carrier.The amount of compound for the symptom that provides effective treatment in the tissue brain that when sending, is needing compound effectively and reduce goal behavior or cognitive disorder by predetermined route of administration maybe may be by suppressing carboxypeptidase E active treatment the amount of compound concentration of symptom of other obstacle.The compound that the present invention uses can make up with one or more pharmaceutically acceptable carrier, but and can be used as tablet, capsule, capsule sheet dispersion powder, particle, lozenge, mucous membrane paster, pouch (sachets) or the like oral administration.Compound can make up with pharmaceutically acceptable carrier such as starch, maltose, lactose or trehalose, makes up and be pressed into tablet or lozenge separately or with one or more tablet excipients.Optionally, this tablet, capsule sheet or capsule can be carried out enteric coating so that hydrolysis/minimum degradation under one's belt.Oral dosage form comprises about 0.00001 to about 99 weight % active ingredient and about 1 to one or more pharmaceutically acceptable carrier and/or the formulation excipients that surpass 99 weight %.Optionally, can pass through with compound and for example P-glycoprotein inhibitors formulated in combination formulation, so that enhanced drug half-life and the active ingredient concentration in brain to be provided.Perhaps, can be simply with compound and P-glycoprotein inhibitors co-administered.
In another embodiment of the invention, pharmaceutical preparation can comprise the active ingredient to about 100mg with for example about 4 μ g that cut out the body combination, represents the dosage of about 100ng/kg body weight to about 30mg/kg body weight.The dosage of having considered similar about 300mg/kg body weight also may be effectively.The pharmaceutical formulations of one embodiment of the invention is formulated as and is used for oral (po) administration, that is, and and oral absorption administration or per os cheek or sublingual administration (with the form of pouch, lozenge and/or mucous membrane paster).In another embodiment, formulation is formulated as the prolongation release dosage form that is used for oral administration, is used for discharging active ingredient in the preset time section.
Though exemplary embodiment comprises oral dosage form, other formulation also is possible.For example, topical formulations, comprise percutaneous plaster, nose dosage unit formulation interior and suppository, also within the scope of the invention, described dosage unit formulation contains nontoxic pharmaceutically acceptable carrier, the auxiliary agent of cynnematin sulfoxide of the present invention and sulfone and routine and is suitable for the medium of this route of administration.
Pharmaceutical formulations of the present invention or can send by the parenteral admin approach comprises subcutaneous administration, intraperitoneal administration, intramuscular administration and intravenous administration.This parenteral dosage form typically is pharmaceutically acceptable carrier such as the aqueous solution of isotonic saline solution, 5% glucose or other known pharmaceutically acceptable liquid carrier composition or the form of dispersion used.
Be applicable to that the pharmaceutical formulation that injectable uses comprises the aseptic aqueous solution or dispersion and the sterilized powder or the lyophilized powder (lyophilizates) that are used for preparing sterile injectable solution or dispersion temporarily.Formulation produce and storage condition under for example be aseptic with stable, and under the condition of combating microorganisms contamination, preserve.The carrier that is used for injectable formulation can be and comprises for example solvent or the dispersion medium of water, ethanol or polyvalent alcohol (as glycerine, propylene glycol, liquid macrogol etc.), its mixture, and vegetables oil.
Be used for the treatment of the cynnematin sulfoxide of other morbid state that behavior and cognitive disorder and response neurogenicity peptase suppress and the parenteral dosage form of sulfone and also can be formulated as injectable time-delay delivery formulations, wherein with active substance and one or more natural or the biodegradable or biological dispersible polymers of synthetic such as carbohydrate make up, described carbohydrate comprises derivatived cellulose, polyethers, polyester (being specially polylactide, poly-glycollide or polylactide-glycollide), polyvinyl alcohol, gelatin or the alginates of starch, natural gum and etherificate or esterification.This dosage particles can be prepared as the form of the polymeric matrix implant (it is known in the industry as provides biologically active ingredient " warehouse-style (depot-type) " drug delivery system that time-delay discharges) of microsphere suspension, (wetting ability or hydrophobicity constitute) gelifying agent or moulding.This composition can use preparation technique preparation recognized in the art and be designed for multiple drug release curve.
The administration that is used for pharmaceutical compositions of the present invention can be intermittent, or with gradually or successive, constant or in check speed to patient's administration of needs treatment.In addition, when day of administration pharmaceutical formulations is different and different with every day, number of times can be along with status of patient and environment.The effectiveness of any given composition that uses within the scope of the present invention and optimal dose and formulation are dependent and can adjust in the reasonable scope according to attending doctor's judgement as the patient.The typical administration time of preparation is the time period that is enough to treat or prevent the patient disease state, is used for behavior or cognitive performance as the patient who changes the experience treatment.Dosage regimen that is can using dosage identical or that the reduce preparation that continues medication is used for the prophylactic treatment of target disease state.
The embodiment of the invention described above partly comes from the mechanism of action of collecting that data hinted from animal behavior cognition as described below and technical ability model.Analysis by data that following nonrestrictive experimental example is obtained, other embodiment of the present invention is conspicuous, and described experimental example is just to the exemplary illustration of the available behavior correction of the method and formulation of the application of the invention and cognitive performance and improvement.
Embodiment
Example I
Δ
2-and Δ
3Synthesizing of-Cephazolin sulfoxide sodium salt
Cephazolin-with the Cephazolin sodium salt (998mg, 2.095mmol is available from ChemifarmaS.A., Madrid, Spain, Fujian Fukang Pharmaceutical Co., Ltd., Fuzhou, China) solution in water (100mL) is handled (to pH2.90) with the 1N HCl aqueous solution.The throw out that obtains is carried out suction filtration and washes with water.By handle alkalization (to pH3.50) with the 1N NaOH aqueous solution, (2 * 20mL) extract to use ethyl acetate then with filtrate.With acetic acid ethyl acetate extract Na
2SO
4Drying is filtered, evaporation, and merge and dry with material after filtering, obtain the title compound of 751mg (79%).
Δ
2-and Δ
3-Cephazolin diphenyl methyl ester. in order to generate diphenyl diazomethane, at N
2Descend under-78 ℃ Pb (OAc)
4(986mg, (3.84g, (437mg is 2.22mmol) in the solution in methylene dichloride (40mL) for benzophenone hydrazone 33.4mmol) 2.22mmol) to join the tetramethyl guanidine that comprises under stirring.After the reaction seventy points clock, will react cancellation by the KOH aqueous solution (100mL) that adds cold (20 ℃) 30%.Be poured into mixture in the separating funnel and usefulness hexane (30mL) processing, shake and separatory.Organic layer is washed with other cold (20 ℃) 30%KOH (100mL), extracted with the merging of KOH washing lotion and with hexane (20mL) is anti-then.Hexane extraction liquid merged and with cold (10 ℃) 2%KOH aqueous solution wash (5 * 150mL), K
2CO
3Drying is used for following reaction then.In order to carry out esterification, at room temperature with Cephazolin (674mg, 1.48mmol) and the mixture of methylene dichloride (250mL) handle with the hexane solution of whole diphenyl diazomethanes.1.5 after hour, add DMF (15mL), and at room temperature under reduced pressure slowly remove methylene dichloride.After Cephazolin dissolves 30 minutes, add acetate (2mL).Remove DMF under the high vacuum, and resistates is dissolved in the methylene dichloride (5mL), and join the sherwood oil of vigorous stirring: hexane (1: 1,100mL) in the solution.Separate the jelly that produces, wash, be dissolved in and also use saturated NaHCO in the methylene dichloride (30mL) with sherwood oil
3(10mL) wash Na
2SO
4Drying is filtered, and evaporation, obtains the title compound of 875mg (95%), is respectively 1: 1.7 mixture.
Δ
2-and Δ
3-Cephazolin sulfoxide diphenyl methyl ester. with Δ
2-and Δ
3-Cephazolin diphenyl methyl ester (875mg, methylene dichloride 1.41mmol) (20mL) solution 30%H
2O
2(196mg, 1.83mmol) and acetate (339mg 5.64mmol) handles.The biphase mixture that obtains was stirred 18 hours, carry out aftertreatment then.With the K of mixture at methylene dichloride (20mL) and 20%
2CO
3Distribute between the aqueous solution (30mL).Organic extracting solution Na
2SO
4Drying is filtered, evaporation, and by column chromatography (SiO
2, Merck 70-230 order, the oily matter that the purifying of 12cm * 5cm) produces is with gradient moving phase 50: 1-40: 1-30: 1-25: 1 CH
2Cl
2: MeOH wash-out first product, use 20 then: 1-10: 1-15: 1-8: 1 CH
2Cl
2: MeOH wash-out second product: the Δ that is respectively 284mg (32%)
2The Δ of-isomer and 511mg (57%)
3-isomer.Δ
2-isomer:
1H-NMR (CDCl
3, 300MHz) δ 8.92 (s, 1H), 8.33 (d, J=8.5Hz, 1H), 7.50-7.21 (m, 10H), 6.89 (s, 1H), 6.29 (s, 1H), 5.57 (dd, J=8.5,4.0Hz, 1H), and 5.47-5.29 (m, 3H), 4.25 (d, J=4.0Hz, 1H), 3.93 (ABq, J=14.3Hz, 2H), 2.67 (s, 3H).Δ
3-isomer:
1H-NMR (CDCl
3, 300MHz) δ 8.84 (s, 1H), 7.63 (d, J=9.6Hz, 1H), and 7.40-7.25 (m, 8H), 7.13-7.02 (m, 1H), 6.93 (s, 1H), 5.94 (dd, J=9.6,4.4Hz, 1H), 5.01 (ABq, J=17.5Hz, 2H), 4.50 (d, J=4.4Hz, 1H), 4.33 (ABq, J=13.7Hz, 2H), 3.77 (ABq, J=18.8Hz, 2H), 2.58 (s, 3H).
Δ
3-Cephazolin sulfoxide. under 0 ℃ with Δ
3Methylene dichloride (0.5mL) solution of-sulfoxide diphenyl methyl ester (505mg, 793 μ mol) and methyl-phenoxide (52mg, 480 μ mol) was handled 90 minutes with trifluoroacetic acid (13mL).Removal of solvent under reduced pressure, and the oily matter that produces is dissolved in the methylene dichloride (1mL).Begin to occur precipitation.Add methyl alcohol, and collect the white depositions that produces, obtain the title compound of 299mg (80%) by suction filtration.
1H-NMR(DMSO-d
6，300MHz)δ13.90(bs，1H)，9.37(s，1H)，8.99(d，J＝8.5Hz，1H)，5.85(dd，J＝8.5，4.3Hz，1H)，5.44(ABq，J＝17.2Hz，2H)，4.90(d，J＝4.3Hz，1H)，4.44(ABq，J＝13.7Hz，2H)，3.89(ABq，J＝18.3Hz，2H)，2.68(s，3H)。
Δ
2-Cephazolin sulfoxide. from Δ
2Δ is produced in-Cephazolin sulfoxide diphenyl methyl ester (284mg, 402 μ mol) beginning in a similar fashion
2-Cephazolin sulfoxide obtains the title compound of 190mg (80%).
1H-NMR(DMSO-d
6，300MHz)δ13.77(bs，1H)，9.57(d，J＝7.9Hz，1H)，9.36(s，1H)，6.71(s，1H)，5.51(dd，J＝7.9，3.9Hz，1H)，5.36(ABq，J＝16.8Hz，2H)，5.18(d，J＝3.9Hz，1H)，5.08(s，1H)，4.21(ABq，J＝14.0Hz，2H)，2.70(s，3H)。
Δ
3-Cephazolin sulfoxide sodium salt. with NaHCO
3Water (6mL) solution of (53mg, 631 μ mol) joins in DMSO (3mL) solution of Cephazolin sulfoxide (297mg, 631 μ mol).With the solution vortex that obtains, freezing and freeze-drying obtains oil/solid mixture, and it is ground with ethanol/methylene.Wash with the solid suction filtration that obtains and with sherwood oil, obtain the title compound of 283mg (91%).
1H-NMR(DMSO-d
6，300MHz)δ9.37(s，1H)，8.84(d，J＝8.2Hz，1H)，5.62(dd，J＝8.2，4.4Hz，1H)，5.43(ABq，J＝16.9Hz，2H)，4.73(d，J＝4.4Hz，1H)，4.28(ABq，J＝12.6Hz，2H)，3.59(ABq，J＝18.1Hz，2H)，2.65(s，3H)。
Δ
2-Cephazolin sulfoxide sodium salt. from Δ
2-Cephazolin sulfoxide (189mg, 402 μ mol) beginning prepares Δ in a similar fashion
2-Cephazolin sulfoxide sodium salt obtains the title compound of 160mg (81%).
1H-NMR(DMSO-d
6，300MHz)δ9.56-9.46(m，1H)，9.36(s，1H)，6.31(s，lH)，5.50-5.10(m，5H)，4.35(ABq，J＝13.5Hz，2H)，2.69(s，3H)。
Example II
Anxiety behavioral study: the dosage in the seed discovery model of anxiety-reply
Ultimate principle: the golden hamster seed of anxiety finds that model is to be used to screen the practical simple bioassay method with the active beta-lactam of CNS.In brief, with the hamster overnight fasting.Subsequently several days, make they stand other stress: they are taken out and place new environment several minutes from its cage of living., sunflower seed is ensconced under the straw mattress in a corner of cage not in the inhabitation cage time at them.Sent when returning to the cage of living when hamster, hamster habitually creeped 1-2 minute along wall, quieted down subsequently to find out seed and it is eaten up.Yet the animal of handling with conventional anxiolytic such as zeisin, fluoxetine or buspirone is found seed (people such as King JA, (2001) in less than 20 seconds time
Neuropsychobiology45:150-155).The time of finding seed from several minutes to several seconds this shortening also occur in handle with some beta-lactam antibiotics after.
Experiment flow: male golden hamster is housed in the Plexiglas cage respectively (among 24cm * 24cm * 20cm), remains on the illumination of putting upside down: dark cycle (14:10; Begin illumination at 19:00) and quantity-unlimiting supply food and water.With Cephazolin-1-sulfoxide (Δ
3-Cephazolin sulfoxide) and Δ-2-Cephazolin-1-sulfoxide (Δ
2-Cephazolin sulfoxide) each comfortable a series of dosage is tested (100ng/kg, 10 μ g/kg, 1mg/kg and brine media are in contrast) (Fig. 1 a-b) in four every group four treated animals.All tests were carried out under dim red illumination in the dark period of diel rhythm round-robin.Before test, all animal fasting 20-24 hour.After oral tube feed administration 90 minutes, animal taken out and place from the cage of its inhabitation kept cage (holding cage) 2 minutes.At them not in the inhabitation cage time, six sunflower seeds are embedded under the straw mattress in a corner of the cage that their live.Animal is put back in the cage of their inhabitations towards any one empty corner randomly, and write down they find seed in five minutes observation period waiting time.Use two-way ANOVA method to analyze the waiting time, carry out Bonferroni subsequently and examine and determine afterwards.
The result: as illustrating among Fig. 1 a-b, dosage be 100ng/kg to two kinds of medicines of 1mg/kg significantly (p＜0.01) shorten the waiting time of finding seed, compare with the average latency that the brine media winding is nearly five minutes.
Sum up: these data show, the Cephazolin class of hamster oral administration is found test effectively at the seed that is used for anxiety, and seed finds that test is the highly sensitive animal model that is used for screening rapidly the anxiolytic active medicine (people such as King JA, (2001)
Neuropsychobiology45:150-155).This model validity (McKinney that sees service, W.T. (1989) Basisof development of animal models in psychiatry:An overview.In:ANIMAL MODELS OF DEPRESSION, Eds.G.G.Koob, C.L.Ehlers, E.J.Kupfer Birkanser, Boston) promptly, anxiolytic such as zeisin, fluoxetine and buspirone are at 1 μ g/kg and more shorten the seed discovery time significantly under the high dosage, and medicine such as Desipramine, Yohimbine and leoponex are invalid.
EXAMPLE III
Anxiety behavioral study: the anxiety activity in overhead cross labyrinth (elevated plus-maze)
Having developed overhead cross labyrinth is used for evaluating anxiety and causes the anxiety medicine at the effect of rat people such as (, (1985) Journal of Neuroscience Methods14:149-167) Pellow.Be proved on this method subordinate act science, physiology and the pharmacology effectively.The cross labyrinth has two open arms and two closure arm.Rat can lessly naturally enter open arms (illumination), enters closure arm (dark) morely, and spends remarkable less time in open arms.Compare with being limited to closure arm, be limited to the stress hormone level that open arms relates to significantly more anxiety related behavior and Geng Gao.Clinical effective anxiolytic such as zeisin or diazepam are increased in the percentage of time that spends in the open arms significantly and enter the number of times of open arms.On the contrary, cause the minimizing of anxiety compound such as Yohimbine or Amphetamine and enter the number of times of open arms and the time that in open arms, spends.
Method: the male Wistar rat grouping that will be weighed as 250-300g is housed in the normal 12:12 illumination-dark cycle, in the 08:00 illumination, and quantity-unlimiting supply food and water.The cross labyrinth is made up of two open arms 50 * 10cm and two closure arm 50 * 10 * 40cm, and open-top is arranged so that two open arms toward each other.The labyrinth is elevated to the height of 50cm.Δ-2-Cephazolin-1-sulfoxide (Δ at oral tube feed medium or 100ng/kg, 10 μ g/kg or 1mg/kg
2-Cephazolin sulfoxide) afterwards, four groups to every group of five animals are carried out 90 minutes test in the cross labyrinth.When on-test, place the centerplane in cross labyrinth to closure arm animal.In 3 minutes observation period, the record animal enters the waiting time of closure arm, time that spends in closure arm and enter the number of times of open arms after for the first time entering closure arm.
Result: with Δ-2-Cephazolin-1-sulfoxide (Δ
2-Cephazolin sulfoxide) processing is compared with medium, and (Fig. 2 a) simultaneously, compares with medium, has increased the time (p＜0.01) (Fig. 2 b) that spends in open arms significantly to have increased the waiting time (p＜0.05) that enters closure arm.
Sum up: to rat oral administration Δ
2-Cephazolin sulfoxide shows the anxiety activity of dose-dependently in overhead cross labyrinth.
EXAMPLE IV
The test of sedative activity
The agonistic behavior of animal can be divided into offensiveness and attack or defensive aggression (Blanchard, R.J., Blanchard, D.C. (1977) Physiology and Behavior, 1,197-224; Adams, D.B. (1979) The Behavioral Brain Sciences, 2,201-241; Albert, D.J. and Walsh, M.L. (1984) Neufoscience andBehavioral Reviews, 8,5-24).Offensiveness is attacked and is characterised in that the invader initiates the attack to the adversary, and defensive aggression does not have initiatively approaching.Two kinds of aggressive behaviours all have its unique separately neurobehavioral system.It is different with the stimulation of defensive aggression to cause offensiveness, different as the behavior order of following each reaction of competing for first place, though supporting many rule of thumb data of the idea of different separately attack and defense neural networks collects from animal model, but the similarity (Blanchard that in showing the similar neural human aggressive behaviour that constitutes, attracting people's attention is also arranged and convince, D.C. (1984) Applicability of animal models tohuman aggression In:Biological Perspectives on Aggression, Alan R.Liss, Inc.pgs 49-74).The male golden hamster that use is tested in occupant/invader's example (fixed offensive attack model) is easily studied offensiveness and attacks (Ferris, C.F., Potegal, M. (1988) Physiology and Behavior, 44,235-239).The cage that places the male hamster of another to live a unfamiliar male hamster causes the clear and definite animal agonistic behavior order that comprises the offensiveness attack that the occupant initiates.
The care of animal: will derive from Harlan Sprague-DawleyLaboratories (Indianapolis, IN) male Syrian golden hamster (Mesocricetus auratus) (140-150g) is housed in the Plexiglas cage respectively and (among 24cm * 24cm * 20cm), keeps the illumination of putting upside down: dark cycle (14L:10D; In the 19:00 illumination) and quantity-unlimiting supply food and water.Before test, make animal adapt to the illumination of putting upside down: at least two weeks of dark cycle.All behavior tests carried out in the dark period of diel rhythm round-robin.
Behavior measure and analysis: hamster is a Nocturnal Animals, and therefore, first of the dark period of behavior test under dim red illumination carried out in four hours.Record occupant offensiveness is attacked in 10 minute trial period, as, bait the invader waiting time, total time that contact with the invader, bait sum and coerce gland mark (Ferris, C.F., Potegal, M. (1988) Physiology and Behavior, 44,235-239).Side of body gland be labeled as hamster wherein arch upward its with the back towards the object friction in the environment produce the sense of smell communication way (Johnston of the flank gland of pheromone, R.E. (1985) Communication, In:THE HAMSTERREPRODUCTION AND BEHAVIOR.Ed Siegel, H.I.Plenum Press, NewYork, pp 121-154).In the process of meet with attacking, side of body gland mark frequency increase greatly and initiate and win in the fight dominant animal and be reinforced especially (Ferris, C.F. wait the people, (1987) Physiology and Behavior, 40,661-664).
Supplemental characteristic: promptly, analyze waiting time and duration of contact, carry out Newman-Keuls subsequently and examine and determine afterwards with unidirectional ANOVA method.Distribution free data: promptly, bait number of times and side of body gland mark number of times, use Crewe Si Kai-Wo Lisi (Kruskal-Wallis) check analysis, check to determine the difference between group with Mann-Whitney U subsequently.
Method: four treated animals that use five every group are at a series of dosage (100ng/kg, 10 μ g/kg, 1mg/kg and brine media are in contrast) check Δ-2-Cephazolin-1-sulfoxide (Δ
2-Cephazolin sulfoxide) (Fig. 3 a-d).After the oral tube feed 90 minutes, the invader is placed the cage of inhabitation, and record occupant's offensiveness is attacked.After aggressive behaviour test, at the locomotor activity screening animal (Fig. 4 a-b) in spacious field model and property are actuated.
Result: by Δ-2-Cephazolin-1-sulfoxide (Δ
2-Cephazolin sulfoxide) handle, the waiting time of baiting significantly increases and baits number of times and reduce (p＜0.01).Though shorten duration of contact significantly when maximum dose level, coercing the gland mark significantly increases.
Sum up: these data show Δ-2-Cephazolin-1-sulfoxide (Δ
2-Cephazolin sulfoxide) is very effective tranquilizer, suppresses offensiveness and attack.The behavior that side of body gland mark, sense of smell drive does not reduce.As shown in Fig. 4 a-b, do not change aspect actuating in locomotor activity or property, the minimizing that shows aggressive behaviour is not because activity or appetitive behavior reduce.
EXAMPLE V
Learning and memory test in the radiation arm labyrinth
The radiation arm labyrinth is one of method of the most normal use of the check space learning of rodent and memory.By Olton and colleague exploitation thereof (Olton, D.S., Samuelson, R.J. (1976) J.Experimental Psychology, 2:97-115), this labyrinth provides the selection of several alternative paths simultaneously for the test experimenter.Animal must use the visual space clue to remember which position supply food (position study).
The care of animal: the male BALBc mouse that will be weighed as 21-23gm is housed in normal 12:12 illumination respectively: in the dark cycle (in the 06:00 illumination), and quantity-unlimiting supply food and water.The following stated method is by people such as Crusio (1987) Brain Research, the 425:182-185 report.The radiation arm labyrinth comprises central platform and eight arms of being made by transparent Plexiglas.The centre portions diameter is 22cm.Closure arm is that 25cm is long, and 6cm is high and 6cm is wide.End at each arm is placed several fresh food pellets with the back of external porose wall.This layout is used to prevent that from there is or do not exist the arm of selecting bait in animal by smelling food.All arms all pass through to place food pellets (about 10mg) in low barrier back bait are set.Place the labyrinth on the floor and (extramaze) is provided near the labyrinth and between the arm outside several labyrinths hint.Before each on-test, mouse is placed the center in labyrinth and allow it freely to select eight arms.Between twice selection, block the center 5 seconds that the goalkeeper mouse is limited in the labyrinth by each arm ingress transparent.In training preceding 24 hours, mouse was accepted freely to enter habituation in 10 minutes of all arms and tests.Subsequently, mouse is broken off provand the water supply is still arranged.In training process, keep body weight to be 85% of the preceding body weight of test.
Method: use six every group or seven s' four treated animals to carry out Cephazolin-1-sulfoxide (Δ of a series of concentration (brine media, 2.5ng, 250ng, 25 μ g/kg)
3-Cephazolin sulfoxide) test (Fig. 5).Δ at peritoneal injection 0.05ml
3Trained in 60 to 90 minutes after the-Cephazolin sulfoxide, test was carried out five days continuously once a day.Termination test when animal eats up all food or after 15 minutes.When mouse arrives perforated wall, count and enter arm once.Misregistration once if animal enters the former arm that went.The wrong number of record training every day.Only the last three days data that will train are used for analysis subsequently.By the two-way ANOVA method of repeated measurement, carry out Bonferroni subsequently and examine and determine afterwards, determine dose response effect.
Result: compare with the medium contrast, use Δ
3-Cephazolin sulfoxide is handled the wrong number (Fig. 5) that significantly reduces (* p＜0.05, * * p＜0.01) test the 3rd day and the 4th day.Compared with the 4th day with the 3rd day, showed wrong significantly reduce (p＜0.05) at the 5th day with the mouse of media processes.At the 5th day, there is not significant difference between the wrong number of what treatment group in office and media pack.
Sum up: in the radiation arm labyrinth, compare Δ with the medium contrast
3The intraperitoneal administration of-Cephazolin sulfoxide reduces the incorrect number of times that enters arm, has shown the raising of space memory in this cognition test.Performance with the mouse of media processes strengthens in time, makes when five day trial period finished their performance be comparable to the performance of the animal that Cephazolin handles basically.
Example VI
Micro-dialysis research
Cephazolin-1-sulfoxide (Δ
3-Cephazolin sulfoxide) biological study as anxiety, minimizing aggressive behaviour and enhancing study, has hinted that the mechanism of action relates to the serotonergic neurotransmission and catecholamine can neurotransmission.In order to verify this hypothesis, at Δ
3After-Cephazolin sulfoxide is handled, use the extracellular neurotransmitter levels in micro-dialysis method evaluation volt nuclear (nucleus accumbens) district.Volt nuclear is the part of limbic forebrain, known itself and schizophrenia, conditionality strengthen and drug habit is related, and think that it participates in the sensitization of wound in one's early years, cause anxiety disorder PTSD or posttraumatic stress disorder (Charney and Bremner (1999) Theneurobiology of anxiety disorder.In:Neurobiology of MentalIllness (Cahrney, DS, et al eds.), Oxford University Press, NewYork, pgs 494-517).
Method: the one-sided micro-dialysis guide thimble of 24 male Sprague Dawley rats being aimed at volt nuclear with vetanarcol (50mg/kg) anesthesia and implantation.Animal is divided into six groups of every group of four animals and with a series of Cephazolin dosage processing (brine media, 10ng, 100ng, 1 μ g, 10 μ g, 100 μ g/kg) (Fig. 6 a-c).After surgery recovery two days, micro-dialysis probe (2mm) is reduced to this zone and is connected with infusion pump by Tygon pipe.Dialyzate is the artificial CSF of the pH 7.4 that sends with 1.8 μ 1/min flow velocitys.Discard first dialyzate of 30 minutes.Thereafter, at Δ
3The administration of-Cephazolin sulfoxide intraperitoneal was collected sample with 15 minutes interval afterwards with 75 minutes before 45 minutes.With sample collection in the miniature centrifuge tube of the 0.16N perchloric acid that comprises 5 μ l to stablize catecholamine.When research finishes, prepare to be used for microanatomy to confirm the position of micro-dialysis probe with sacrifice of animal and with brain.
(Fig. 6 a) and the level of HVA (Fig. 6 b) and thrombotonin metabolite HIAA (Fig. 6 c) by Electrochemical Detection evaluation Dopamine HCL metabolite DOPAC.First sample of 15 minutes is got rid of from analyze after the peritoneal injection, because there is the variability that causes when animal is used for drug administration by handling.All the other four samples measuring result separately of collecting between 15-75 after the processing minute is analyzed.For every kind of metabolite, sample (amounting to 16 samples) equalization of each animal in each group will be derived from.Analyze mean value with unidirectional ANOVA method, carry out Bonferroni subsequently and examine and determine afterwards.
Result: at Δ
3DOPAC, HVA and HIAA level had (* p＜0.05 significantly after-Cephazolin sulfoxide was handled; * p＜0.01) increase of dose-dependently.
Sum up: these micro-dialysis studies show that, Δ
3-Cephazolin sulfoxide increases thrombotonin and the Dopamine HCL neurotransmission in the volt nuclear.New progress in the treatment of anxiety disorder, impulsion and violence concentrates on (Feighner JP. (1999) in the activation of thrombotonin neurotransmission
J.Clinical Psychiatry, 60:18-22; Ferris, people such as C.F. (1997)
J.Neuroscience, 17: 4331-4340; People such as Coccaro (1998)
Archives of General Psychiatry,
55: 708-714.).Consider the research in this field, the Δ in the animal model
3It is just not astonishing that the thrombotonin release of-Cephazolin sulfoxide is attended by the anxiety and the calm behavior that are reinforced yet.
The activation of thrombotonin and Dopamine HCL neurotransmission has increased the Cephazolin sulfoxide and has been used for the treatment of drug habit, obesity and schizoid possibility in the volt nuclear.The scientist of the U.S. state-run drug abuse Study on Problems institute (the National Institute of Drug Abuse) and the state-run diabetes of the U.S., digestion, kidney disease research institute (the National Institute of Diabetes andDigestive and Kidney Diseases) studies show that, the combination medicine-feeding (PHEN/FEN) of similar thing phentermine of Amphetamine and Phenfluoramine increases extracellular Dopamine HCL in the rat volt nuclear and thrombotonin level (people such as Baumann, (2000)
Synapse, 36:102-113).PHEN/FEN is for effectively being used for pharmacologic Therapy for Obesity (people such as Weintraub, (1984)
Archive of Internal Medicine, reduce Cocaine 144:1143-1148) and in clinical open trial and thirst for, alleviate Withrawal symptom and prolong drug and guard against addiction (people (1994) such as Rothman
J.Subs tance Abuse Treatment, 11:273-275).The scientist of U.S.'s National Institutes of Health infers, has to PHEN/FEN to cause that the medicine of the similar mechanism that thrombotonin and Dopamine HCL neurotransmission increase in the volt nuclear may be useful in therapeutant abuse and obesity.
Eli Lilly and Company (Indianapolis, IN) micro-dialysis and the in vitro tissue analysis of prefrontal cortex and volt nuclear used in scientist's research, be developed the mechanism of action (people such as Cartmell of short metabolism (metabotropic) glutamate receptor agonists that is used for psychiatric treatment with evaluation, (2000) Brain Research, 887:378-384; People such as Cartmell (2000)
J.Neurochemistry, 75:1147-1154).Atypical antipsychotic drug such as risperidone increase the neurotransmission (people (2000) such as Cartmell of Dopamine HCL and thrombotonin in prefrontal cortex and the volt nuclear
J.Neurochemistry, 75:1147-1154; People such as Hertel (1996)
Psychopharmacology, 124:74-86).The scientist of Lilly finds that the activation of metabotropic glutamate receptor has the similar mechanism to raise DOPAC, HIAA and HVA in these brain zones.
Example VII A
With Δ
2-Cephazolin sulfoxide and Δ
3Each of-Cephazolin sulfoxide or its combination merge with pharmaceutically acceptable tabletting mixture, so that the composition of film-making separately to be provided, with its tablet forming or be filled in the gelatine capsule, make every/capsule comprise the Δ of 100ng, 1 μ g, 10 μ g, 100 μ g, 1mg, 10mg, 50mg, 100mg, 200mg, 350mg and 500mg
2-or Δ
3-Cephazolin sulfoxide or its combination.
Example VII A I
To the preparation of patient's administration the foregoing description VII of suffering from ADHD to improve the symptom of this disease.
Example I X
Suffer from the aggressive behaviour patient of the neuroscience illness that is feature with the preparation for treating of above-mentioned example VII A, every day two to three times is to reduce patient's Aggression.
Embodiment X
Suffer from dull-witted patient with the preparation for treating of above-mentioned example VII A, every day three times is with the patient's cognition that improves.
Embodiment XI
To the preparation of patient's administration the foregoing description VII of suffering from anxiety disorder, every day two to three times is to reduce patient's anxiety.
Though describe the present invention in detail, have changes and improvements in the scope of the invention of describing in the claims and defining and the spirit scope with reference to some preferred embodiment.
Claims (21)
1. the Neurotherapeutic pharmaceutical formulations of oral dosage form form comprises:
Be effective to treat and reduce the Neurotherapeutic compound of amount of the symptom of nervous system disorders, wherein this compound is selected from cynnematin sulfoxide, cephalosporin sulphone, its pharmacologically acceptable salt and active ester thereof; With
The pharmaceutically acceptable carrier that is used for above-claimed cpd.
2. the Neurotherapeutic pharmaceutical formulations of claim 1, wherein compound is a 2-cephalo sulfoxide.
3. the Neurotherapeutic pharmaceutical formulations of claim 1, wherein compound is a 3-cephalo sulfoxide.
4. the Neurotherapeutic pharmaceutical formulations of claim 1, wherein compound is a 2-cephalo sulfone.
5. the Neurotherapeutic pharmaceutical formulations of claim 1, wherein compound is a 3-cephalo sulfone.
6. the Neurotherapeutic pharmaceutical formulations of claim 1, wherein this compound is selected from Δ
2-Cephazolin sulfoxide, Δ
3-Cephazolin sulfoxide, and Δ
2-Cephazolin sulfoxide and Δ
3The mixture of-Cephazolin sulfoxide.
7. the compound of following formula:
Wherein
N is 1 or 2;
One of key a or key b are two keys; With
R is hydrogen, group or the pharmaceutically acceptable positively charged ion that forms active ester.
8. the compound of claim 7, wherein key a is two keys, key b is a singly-bound.
9. preparation, it comprises compound and pharmaceutically acceptable carrier, thinner or the vehicle of following formula:
Wherein
N is 1 or 2;
One of key a or key b are two keys; With
R is hydrogen, group or the pharmaceutically acceptable positively charged ion that forms active ester.
10. the preparation of claim 9, wherein preparation provides with oral dosage form.
11. the preparation of claim 10, but wherein oral dosage form is the unit dosage form that is selected from tablet, capsule, capsule sheet dispersion powder, particle, lozenge, mucous membrane paster and pouch.
12. each preparation among the claim 9-11 further comprises the P-glycoprotein inhibitors.
13. the Neurotherapeutic pharmaceutical formulations of oral dosage form form, described preparation comprises:
The Neurotherapeutic compound of the amount of the symptom of effective treatment and minimizing behavior disorder or cognitive disorder, wherein this compound is selected from penicillin sulfoxide, benzylpenicillin sulfoxide, cynnematin sulfoxide, cephalosporin sulphone and pharmacologically acceptable salt thereof; With
The pharmaceutically acceptable carrier that is used for above-claimed cpd.
14. the Neurotherapeutic pharmaceutical formulations of claim 13, but wherein oral dosage form is the unit dosage form that is selected from tablet, capsule, capsule sheet dispersion powder, particle, lozenge, mucous membrane paster and pouch.
15. the Neurotherapeutic pharmaceutical formulations of claim 13, wherein the Neurotherapeutic compound is cynnematin sulfoxide or the cephalosporin sulphone that following formula is represented:
Wherein
N is 1 or 2;
R is hydrogen, group or the pharmaceutically acceptable positively charged ion that forms active ester;
R
1Be hydrogen, alkyl, alkoxyl group or alkylthio;
Acyl group is R
2-C (O), R wherein
2Be optional substituted alkyl, optional substituted aryl, optional substituted arylalkyl, optional substituted heteroaryl or optional substituted heteroarylalkyl; With
X be hydrogen, alkyl, halo, haloalkyl, hydroxyl, alkoxyalkyl, halogenated alkoxy alkyl, alkoxyl group alkoxyl group, alkylthio, optional substituted arylthio, optional substituted heteroarylthio, optional substituted alkyl-carbonyl oxygen base, optional substituted aryl carbonyl oxygen base, optional substituted heteroaryl ketonic oxygen base or-CH
2B, wherein B is the residue of nucleophilic reagent B-H.
16. the method for treatment behavior obstacle or cognitive disorder comprises: each the Neurotherapeutic step of pharmaceutical formulations among the claim 1-6 of oral administration effective dose and the claim 9-15.
17. the method for treatment behavior obstacle or cognitive disorder comprises:
The Neurotherapeutic of the oral administration effective dose step of pharmaceutical formulations, described pharmaceutical formulations comprises:
The Neurotherapeutic compound of the amount of the symptom of effective treatment and minimizing behavior disorder or cognitive disorder, wherein this compound is selected from Δ
2-Cephazolin sulfoxide, Δ
3-Cephazolin sulfoxide and Δ
2-Cephazolin sulfoxide and Δ
3The mixture of-Cephazolin sulfoxide and pharmacologically acceptable salt thereof and
The pharmaceutically acceptable carrier that is used for above-claimed cpd.
18. the method for treatment behavior obstacle or cognitive disorder comprises:
The Neurotherapeutic of the oral administration effective dose step of pharmaceutical formulations, described pharmaceutical formulations comprises:
The Neurotherapeutic compound of the amount of the symptom of effective treatment and minimizing behavior disorder or cognitive disorder, wherein compound is selected from Δ
2-Cephazolin sulfoxide, Δ
3-Cephazolin sulfoxide and Δ
2-Cephazolin sulfoxide and Δ
3The mixture of-Cephazolin sulfoxide and pharmacologically acceptable salt thereof and
The pharmaceutically acceptable carrier that is used for above-claimed cpd,
Wherein effective dose arrives about 30mg/Kg body weight for about 1.2ng/Kg body weight.
19. the Neurotherapeutic pharmaceutical formulations of unit dosage form form, described preparation comprises:
About 4 μ g are to the Neurotherapeutic compound of the amount of about 100mg, and wherein this compound is selected from Δ
2-Cephazolin sulfoxide, Δ
3-Cephazolin sulfoxide and Δ
2-Cephazolin sulfoxide and Δ
3The mixture of-Cephazolin sulfoxide and pharmacologically acceptable salt thereof; With
The pharmaceutically acceptable carrier that is used for above-claimed cpd.
20. the method for treatment behavior obstacle or cognitive disorder comprises:
Claim 19 Neurotherapeutic of the administration effective dose step of pharmaceutical formulations, wherein effective dose arrives about 1mg/Kg body weight for about 100ng/Kg body weight.
21. the method for treatment behavior obstacle or cognitive disorder comprises:
The Neurotherapeutic of the claim 19 of the administration effective dose step of pharmaceutical formulations, wherein effective dose is about 30mg/Kg body weight to the maximum.
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| US60/533,132 | 2003-12-30 |
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| CN114767690A (en) * | 2022-06-22 | 2022-07-22 | 中国中医科学院中药研究所 | Application of cephalothin acid in preparation of antidepressant drug |
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| CN114767690A (en) * | 2022-06-22 | 2022-07-22 | 中国中医科学院中药研究所 | Application of cephalothin acid in preparation of antidepressant drug |
| CN114767690B (en) * | 2022-06-22 | 2022-08-23 | 中国中医科学院中药研究所 | Application of cephalothin acid in preparation of antidepressant drug |
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