CN1221254C - New combination of serotonin agonist (5HT2) and antagonist (5HT6) as pharmaceutical formulation - Google Patents
New combination of serotonin agonist (5HT2) and antagonist (5HT6) as pharmaceutical formulation Download PDFInfo
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- CN1221254C CN1221254C CNB018131549A CN01813154A CN1221254C CN 1221254 C CN1221254 C CN 1221254C CN B018131549 A CNB018131549 A CN B018131549A CN 01813154 A CN01813154 A CN 01813154A CN 1221254 C CN1221254 C CN 1221254C
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- receptor
- stimulating agent
- antagonist
- receptor antagonist
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Abstract
The invention relates to a method of preventing or treating a disease related to the 5-HT2C receptor and the 5-HT6 receptor, comprising administering to a human or animal subject in need thereof a 5-HT2C receptor agonist and a 5-HT6 receptor antagonist in sufficient amounts to provide a therapeutic affect. The invention also relates to a pharmaceutical composition comprising an effective amount of a combination of a 5-HT2C receptor agonist and a 5-HT6 receptor antagonist, and optionally a pharmaceutically acceptable carrier.
Description
Technical field
The present invention relates to and 5-HT
2CAnd 5-HT
6The prevention and treatment of diseases that receptor is relevant.In addition, the invention provides a kind of Pharmaceutical composition, contain the 5-HT that is used for the treatment of purposes
2CReceptor stimulating agent and 5-HT
6Receptor antagonist.
Background technology
Serotonin (5-hydroxy tryptamine or 5-HT) is periphery and central nervous system's (PNS and CNS) a crucial neurotransmitter, has related to polyesthesia, motion and behavior official energy, such as regulating feed, sleep, body temperature, blood pressure, emotion and understanding.At least 14 kinds of different serotonin receptor hypotypes are expressed in mammal PNS and CNS also by Official Classification; Referring to people such as Glennon, Neurosci.Biobehav.Rev.1990,14,35-37; With people such as D.Hoyer, Pharmacol.Rev.1994,46,157-203.Advised combination of serotonin agonist and antagonist are used for the treatment of multiple disease, comprised the vomiting that anxiety, depression, hypertension, migraine, obesity, drug dependence and addiction, obsessive-compulsive disorder, schizophrenia, autism, neurodegenerative disorders (for example alzheimer's disease, Parkinson's disease and Huntington) and chemotherapy cause.
The 5-HT of receptor
2Subfamily is made up of three kinds of subtype acceptors: 5-HT
2A, 5-TH
2BAnd 5-HT
2CSerotonin 5-HT
2CReceptor is expressed in many brains district, and relates to feed adjusting (Dourish, C.T.Obes.Res.1995,3, Suppl.4,449S-462S; Bickerdike, M.J. waits the people, Diabetes, Obes.Metab.1999,1,207-214).Verified non-special 5-HT
2CReceptor stimulating agent m-chlorphenyl piperazine (m-CPP) is to 5-HT
2CSome preference of receptor has reduced and has expressed normal 5-HT
2CThe feed of the mice of receptor, and it is to expressing abnormal inactivation form 5-HT
2CThe mice of receptor lacks activity, and (Tecott.L.H. waits the people, and Nature 1995,374,542-546).
In addition, reported that m-CPP and bifurcation have alleviated people's body weight because of diindyl U-22394A heptan after carrying out 2 weeks and the treatment of 9 weeks respectively, the latter is confirmed as 5-HT recently
2C(Psychopharmacology 1994,116,120-122 for Walsh, A.E.S. for the agonist of receptor (not seeing open); Sargent, P.A. waits people Psychopharmacology 1997,133,309-312 and Gallant, D.M. waits the people, Curr.Ther.Res.1967,9,579-581).
Recently, a series of pyrrolo-[3,2,1-ij] quinoline is confirmed as 5-HT
2AReceptor has optionally 5-HT
2CReceptor stimulating agent (Isaac M. waits the people, Bioorg.Med.Chem.Lett.2000, and 10,919-921).It is reported that these chemical compounds provide the new trial of treatment obesity and epilepsy.
5-HT is also proposed
2CReceptor has related to the CNS disease, and (Jenck, F. wait the people, Expert Opin.Invest.Drugs 1998,7,1587-1599 such as depressed and anxiety; Leysen, D.C.M.IDrugs 1999,2,109-120).5-HT has also been proposed
2CReceptor subtype has related to urinary disorders, and (Leysen, D.C.M.IDrugs 1999,2,109-120) such as urinary incontinence.
Also has 5-HT
6Receptor (be determined at 1993, people such as Monsma, Mol.Pharmacol.1993,43,320-327 and Ruat, people such as M., Biochem.Biophys.Res.Commun.1993,193,269-276) related to feed and regulated and the CNS disease.
Therefore, Bentley for example, people such as J.C., Br.J.Pharmacol.1999,126,66P has described by imposing 5-HT
6Antagonist has reduced the feed of rat.Also have, some antidepressant and atypical anti-psychataxia promptly show 5-HT
6The high affinity of receptor, this points out that schizophrenia has related to 5-HT
6Receptor (people such as Roth, J.Pharmacol.Exp.Ther.1994,268,1403-1410; People such as Sleight, Expert Opin.Ther.Patents 1998,8,1217-1224; People such as Bourson, Br.J.Pharm.1998,125,1562-1566; People such as Boess, Mol.Pharmacol.1988,54,577-583; People such as Sleight, Br.J.Pharmacol.1998,124,556-562).In addition, 5-HT
6Receptor related with general stress and anxiety state (people such as Yoshioka, LifeSci.1998,17/18,1473-1477).
Summary of the invention
According to the present invention, now find 5-HT unexpectedly
2CReceptor stimulating agent and 5-HT
6The receptor antagonist administering drug combinations has reduced feed, and effect is more obvious than using agonist or antagonist separately.Compare this 5-HT with independent use agonist or antagonist
2CReceptor stimulating agent and 5-HT
6The receptor antagonist administering drug combinations can provide the benefit on the therapeutics.
Therefore one aspect of the present invention provides a kind of pharmaceutical composition, comprises the 5-HT of effective dose
2CReceptor stimulating agent and 5-HT
6The combination of receptor antagonist, and optional pharmaceutically acceptable carrier.
Another aspect of the present invention provides a kind of prevention or treatment and 5-HT
2CReceptor and 5-HT
6The method of the disease that receptor is relevant, particularly fat, comprise to the people of needs or mammal (simultaneously or continuously) and use the 5-HT that is enough to provide the therapeutic effect amount
2CReceptor stimulating agent and 5-HT
6Receptor antagonist.
Of the present invention in addition-individual aspect provides 5-HT
2CReceptor stimulating agent and 5-HT
6Receptor antagonist relates to 5-HT at production for treating
2CReceptor and 5-HT
6Application in the medicine of the disease of receptor.
Another aspect of the present invention provides a kind of method of pharmaceutical compositions, the 5-HT of wherein therapeutic alliance amount
2CReceptor stimulating agent and 5-HT
6Receptor antagonist mixes fully with pharmaceutically acceptable carrier.
Another aspect of the present invention provides a kind of 5-HT of containing
2CReceptor stimulating agent and 5-HT
6The product of receptor antagonist, it is used for being used for the treatment of simultaneously, respectively or one after the other and 5-HT as the co-formulated product
2CReceptor and 5-HT
6The disease that receptor is relevant, particularly fat.
Description of drawings
Accompanying drawing 1 has been represented to use 5-HT the ob/ob mice
2CReceptor stimulating agent (PNU-183933F; 50mg/kg po) and 5-HT
6Receptor antagonist (PNU-186053A; 50mg/kg sc) effect of aspect on the feed behind the administering drug combinations, and the effect of using agonist and antagonist separately.
Accompanying drawing 2 has been represented to use 5-HT the ob/ob mice
2CReceptor stimulating agent (BVT.2938F; 5mg/kg sc) and 5-HT
6Receptor antagonist (BVT.5182C; 3mg/kg sc) effect of aspect on the feed behind the administering drug combinations, and the effect of using agonist and antagonist separately.
Detailed Description Of The Invention
As mentioned above, the present invention is based on a unexpected discovery, that is, and 5-HT2CReceptor stimulating agent and 5-HT6The administering drug combinations of receptor antagonist is than using separately activator or antagonist more can Reduce feed. Compare this 5-HT with independent use activator or antagonist2CReceptor stimulating agent and 5-HT6The administering drug combinations of receptor antagonist also can provide several benefits, for example controlling in obesity In the treatment.
At first, administering drug combinations is lower for the dosage that every kind of compound needs, and has but obtained similar Or than the better minimizing of single therapy feed effect.
Next, the lower danger that reduces the rough sledding generation of the dosage that administering drug combinations needs.
The 3rd, the lower danger that reduces tolerance and abuse liability generation of the dosage that administering drug combinations needs The danger.
The 4th, with respect to the treatment based on a target, can increase individuality based on the treatment of two targets Curative effect. Also reduced simultaneously the risk of no response effect (no responsor).
The beneficial effect of administering drug combinations of the present invention is not only to can be used for regulating the feed behavior, is used for controlling Treat overweight and obesity, and can be used for treating the CNS imbalance, such as depression, mania, Schizophreniform diseases, anxiety, memory disorders (such as Alzheimer's disease), inclined to one side head Bitterly, stress reaction syndrome and sleep-disorder after the drug habit, convulsions, personality disease, wound, And be used for the treatment of the urinary incontinence (or more generally hyperactive bladder), property kakergasia, Gastrointestinal disease and glaucoma.
Term " 5-HT as used herein
2CReceptor stimulating agent " be to cause serotonin 5-HT
2CThe chemical compound of receptor activation.5-HT
2CReceptor stimulating agent preferably has the affinity costant K less than 50nM
i, preferably less than 20nM, with Ca in the cell
2+The metric external intrinsic activity of level greater than 20%, is preferably greater than 50% with respect to 5-HT (1 μ M).
Term " 5-HT as used herein
6Receptor antagonist " be blocking-up serotonin 5-HT
6The chemical compound of receptor conditioned reaction.5-HT
6Receptor antagonist preferably has the affinity costant K less than 50nM
i, preferably less than 20nM, with the metric external intrinsic activity of cAMP level in the cell with respect to 5-HT (1 μ M) less than 50%, preferably less than 20%.
Can be used for determining respectively 5-HT
2CReceptor stimulating agent and 5-HT
6The in vitro tests of receptor antagonist affinity and intrinsic activity is known in the art, and experimental section has below also been described them, as determining 5-HT
2AAnd 5-HT
2BThe test of the affinity of receptor.
Usually, 5-HT
2CReceptor stimulating agent and 5-HT
6Receptor antagonist should have enough selectivitys, can not cause any substantial unfavorable side reaction.But in context, term " selectivity " and " in fact " can explain broadly that its implication is that those skilled in the art are conspicuous.
Respectively with respect to 5-HT
2A, 5-HT
2BAnd 5-HT
6Receptor, 5-HT
2CReceptor stimulating agent is to 5-HT
2CThe selectivity of receptor preferably is at least 5, preferably is at least 10, and more preferably at least 20 (as 5-HT
2A/ 5-HT
2C, 5-HT
2B/ 5-HT
2CAnd 5-HT
6/ 5-HT
2CAffine than measuring).
Respectively with respect to 5-HT
2A, 5-HT
2BAnd 5-HT
2CReceptor, 5-HT
6Receptor antagonist is to 5-HT
6The selectivity of receptor preferably is at least 5, preferably is at least 10, and more preferably at least 20 (as 5-HT
2A/ 5-HT
6, 5-HT
2B/ 5-HT
6And 5-HT
2C/ 5-HT
6Affine than measuring).
Be used for determining that chemical compound is 5-HT optionally
2CReceptor stimulating agent is 5-HT optionally still
6The correlation test of receptor antagonist is known in the art, and as mentioned above, also experimental section is hereinafter roughly described.
Known is 5-HT
2CThe chemical compound of receptor stimulating agent is the azetidine and the pyrrolidin derivatives of for example type described in the EP-A-0863136; The tricyclic azole derivatives of type described in the EP-A-0657426; The 1-amino-ethylindole of type described in the EP-A-0655440; The Pyrazinoindoles of type described in the EP-A-0572863; The piperazinyl pyrazines of type described in the US 4081542; The indolin derivatives of type described in the WO 00/12475; The pyrrolo-indole of type described in the WO 00/12510, pyrido indole and bifurcation heptan are because of diindyl; Indazole derivative described in the WO00/12482; The pyrroloquinoline of type described in the WO 00/12502; 2,3,4 of type described in the WO00/35922,4a-tetrahydrochysene-1H-pyrazine be [1,2-a] quinoxaline-5 (6H) ketone also; The indazolyl propyl group amine of type described in the WO00/12481; The indazole of type described in the WO00/17170; The piperazinyl pyrazines of type described in WO 00/76984 and Swedish patent application No.0004244-0 that submitted in 2000 11 about 20 days and the 0004245-7; Heterocyclic fused γ-the carboline of type described in WO 00/77001, WO 00/77002 and the WO 00/77010; The benzofuranyl piperazine of type described in WO 01/09111 and the WO 01/09123; The benzofuran of type described in the WO 01/09122; The benzothiophene of type described in the WO 01/09126; The pyridine radicals piperazine of type described in the EP 370560; Bioorg.Med.Chem.Lett.2000,10, the pyrroloquinoline of type described in the 919-921; The aminoalkyl indazole of type described in the WO98/30548; The indoline of type described in the WO 01/12602; The indole of type described in the WO01/12603; The pyrazine of type described in the WO 00/44753 is (azepine) indole also; The tricyclic azole of type or pyrazoles described in the WO 98/56768.
At present preferred 5-HT
2CReceptor stimulating agent is the chemical compound of type described in aryl piperazines and piperazinyl pyrazines chemical compound, particularly WO 00/76984 and Swedish patent application No.0004244-0 that submitted in 2000 11 about 20 days and the 0004245-7.
Known is 5-HT
6The chemical compound of receptor antagonist is the piperazinyl phenyl sulfonamide of type described in the WO 99/37623 for example; The sulfonyl benzene derivative of type described in the EP-A-0930302; The sulfamide derivative of type described in the WO 99/02502; The sulfamide derivative of type described in the WO 99/42465; The sulfamide derivative of type described in the WO 98/27081; The carboxamide derivatives of type described in the WO98/27058; The sulfamide derivative of type described in the EP-A-0815861; The ketopyrrolidine methyl indole derivatives of type described in the WO 99/47516; The bicyclic piperidine of type and bridged piperazine derivatives described in the WO 99/65906; The pyrazolopyrimidine of type described in the EP-A-0941994 and method for preparation of pyrazolotriazine derivant; Six hydrogen bifurcation heptan that the aryl sulfone of type described in the WO 01/05793 replaces are because of diindyl; Type De oxazine and carbazole described in the WO 01/09142; The aminoalkoxy carbazoles of type described in the WO 01/17963; The diphenyl sulfoxide of type described in the PCT/USOO/30177 international patent application of submitting on June 20th, 2000; Aryl sulfonyl indole with type described in the Swedish patent application No.0003810-9 that submitted on October 20th, 2000.
At present preferred 5-HT
6Receptor antagonist be bifurcation heptan because of the diindyl chemical compound, the aryl sulfone of type replaced described in WO01/05793 six hydrogen bifurcation heptan are because of diindyl.Other preferred 5-HT
6Receptor antagonist comprises the aryl sulfonyl benzazolyl compounds, the chemical compound described in Swedish patent application No.0003810-9.
5-HT
2CReceptor stimulating agent and 5-HT
6Receptor antagonist can be a chemical compound itself, or is the acceptable salt of its pharmacy (acid or base addition salts) or its stereoisomer form (comprising optical isomer, such as enantiomer and racemic modification) in due course.
Above-mentioned pharmacy acceptable addition salt comprises the non-toxicity bronsted lowry acids and bases bronsted lowry addition salts form of the therapeutic activity that chemical compound can form.The chemical compound of alkalescence can change into their the acceptable acid-addition salts of pharmacy by the form with suitable acid treatment alkali.The example of acid comprises mineral acid, all example hydrochloric acids, hydrobromic acid, hydroiodic acid, sulphuric acid, phosphoric acid; Organic acid is such as acetic acid, propanoic acid, glycolic, lactic acid, acetone acid, glycolic, maleic acid, malonic acid, oxalic acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, fumaric acid, succinic acid, malic acid, tartaric acid, citric acid, salicylic acid, para-aminosalicylic acid, pounce on acid, benzoic acid, ascorbic acid etc.The example of base addition salts form is sodium, potassium, calcium salt, and the salt that forms with the acceptable amine of pharmacy, and described amine is such as ammonia, alkylamine, aniline and aminoacid, such as arginine and lysine.Term " addition salts " also comprises solvate as used herein, chemical compound with and salt can form such as hydrate, alcohol adduct etc.
5-HT
2CReceptor stimulating agent and 5-HT
6Receptor antagonist can also be prodrug or the form that discharges described active component in vivo after the metabolic alterations.At " Design of Prodrugs " ed.H.Bundgaard, Elsevier has described in 1985 and has selected and the conventional method of the prodrug derivant that preparation is fit to.
5-HT
2CReceptor stimulating agent and 5-HT
6Receptor antagonist can be mixed with various medicine type administrations, and they can be in the form of identical drug dose, such as with a kind of tablet, or in medicine type independently.But, in the latter case, advantageously with 5-HT
2CThe unit dosage form of receptor stimulating agent and 5-HT
6The unit dosage form of receptor antagonist is contained in the same packing, for example is packaged in the same vacuolar membrane.
The 5-HT of free alkali or salt form
2CReceptor stimulating agent and 5-HT
6Receptor antagonist can be made appropriate pharmaceutical dosage forms according to known pharmaceutical methods, the compositions of purposes such as, injection oral such as being used for, intranasal spray delivery.This class pharmaceutical composition according to the present invention comprises the 5-HT of effective dose
2CReceptor stimulating agent and 5-HT
6Receptor antagonist and suitable acceptable carrier material well known in the art of pharmacy or diluent.Carrier can be any inert material, organic or inorganic, be applicable to per os, intestinal, rectum, skin, subcutaneous or parenterai administration, such as: water, gelatin, arabic gum, lactose, microcrystalline Cellulose, starch, primojel, calcium hydrogen phosphate, magnesium stearate, Talcum, colloidal silica etc.These compositionss also can contain other forms of pharmacologically active agents and conventional additives, such as stabilizing agent, wetting agent, emulsifying agent, flavouring agent, buffer agent etc.
Compositions according to the present invention can be made into and is used for oral solid or liquid form, but such as tablet, pill, capsule, powder, syrup, elixir discrete particles, cachet, suppository etc., be used for parenterai administration can sterile solution, suspending agent or Emulsion, spray, nose spray for example, eye is used preparation, for example paster etc.
5-HT
2CReceptor stimulating agent and 5-HT
6The administration frequency of the dosage level of receptor antagonist and the dosage of particular combination changes according to multiple factor, comprise usefulness, metabolic stability and the compound effects of every kind of particular compound of use length, patient's age, body weight, general health situation, sex, diet, form of medication and time, drainage rate, drug regimen, to treat the order of severity of symptom.For example, 5-HT
2CReceptor stimulating agent and 5-HT
6Dosage dosage every day of receptor antagonist can be respectively the about 0.001-150mg of every kg body weight, the about 0.01-100mg of preferred every kg body weight, and the about 0.1-50mg of particularly every kg body weight, they can single agent or multi-agent administration, and for example every dose month 0.01mg is to about 1g.Usually, this merging dosage is used for oral, but also can select for example non-intestinal or rectally.The example that tablet is united prescription can be the form of (A) two individual sheets, and 1 contains 10mg, 20mg or 50mg 5-HT
2CReceptor stimulating agent, 1 contains 10mg, 20mg or 50mg 5-HT
6Receptor antagonist; Or (B) composite sheet, contain 10mg, 20mg or 50mg 5-HT
2CReceptor stimulating agent and 10mg, 20mg or 50mg 5-HT
6Receptor antagonist.
Now further specify the present invention by following nonrestrictive experimental section.
Experimental section
A. the preparation of test compound
As described in WO 00/76984, prepare 5-HT
2CReceptor stimulating agent free alkali (2R)-methyl isophthalic acid-3-[2-(3-pyridine radicals oxygen base) ethyoxyl]-the 2-pyrazinyl } piperazine fumarate (" PNU-183933F ").Free alkali is converted into the form of its fumarate, m.p.126-129 ℃.MS?m/z?315(M)
+。Anal.(C
16H
21N
5O
2·C
4H
4O
4)C，H，N。
As described in WO 01/05793, prepare 5-HT
6Receptor antagonist 6-methyl-9-(phenyl sulfonyl)-1,2,3,4,5, six hydrogen bifurcation heptan of 6-are because of [4,5-b] indole also, hydrochlorate (" PUN-186053A ").
As described in WO 00/76984, prepare 5-HT
2CReceptor stimulating agent.(2R)-and 1-(3-{2-[(2-ethyoxyl-3-pyridine radicals) oxygen base] ethyoxyl }-the 2-pyrazinyl)-the 2-methyl piperazine, fumarate (" BVT.2938F ").
Described in the Swedish patent application No.0003810-9 that submitted on October 20th, 2000, prepare 5-HT
6Receptor antagonist 1-(phenyl sulfonyl)-4-(1-piperazinyl)-1H-indole, hydrochlorate (" BVT.5182C ").In brief; BVT.5182C is according to the preparation of the general process shown in the following reaction equation 1, and the 4-piperazinyl indole (chemical compound 1) from buying from market carries out step (a) to (C); obtain 1-(phenyl sulfonyl)-4-(1-piperazinyl)-1H-indole, hydrochlorate (productive rate 80%).HPLC purity (P10 frame 1).
1H?NMR(DMSO-d
6)δ9.64(br?s，2H)，8.00-7.85(m，3H)，7.79(d，J＝3.77Hz，1H)，7.70-7.65(m，1H)，7.63-7.60(m，3H)，7.27-7.22(m，1H)，6.95(d，J＝3.76Hz，1H)，6.81-6.77(m，1H)，3.30-3.20(m，4H)；
13C?NMR(DMSO-d6)δ144.79，137.02，135.22，134.62，129.82，126.85，125.63，125.54，123.49，111.15，107.87，107.76，47.81，42.86；MS(posES-FLA)m/z?342(M+H).
Reaction equation 1
Step (a): the BOC protection of piperazine N4 nitrogen
4-piperazinyl indole (1eq), DMAP (0.1eq) and Et
3N (4eq) is dissolved in DMF.Add (BOC)
20 (1.1eq), reactant mixture is in stirring at room (12 hours).Steam DMF, residue is purified on silica gel by chromatograph, and the mixture that uses chloroform, methanol and ammonia is as eluent.HPLC:100% purity.MS?m/z?302.2(M+H)。
Step (b): the preparation of intermediate 3
Intermediate 2 (1.0eq) is dissolved among the DMF, adds NaH (1.3eq), and suspension stirred 0.5 hour under nitrogen atmosphere.Add benzene sulfonyl chloride (1.2eq), reactant is in stirred overnight at room temperature.Steam volatile material.Residue is dissolved in DCM, uses saturated NaHCO
3Solution washing, dry (MgSO
4), filter, concentrate, obtain the oily residue, purify on silica gel by chromatograph, the mixture of using hexane and ethyl acetate (7: 3) obtains 4-[1-(benzenesulfonyl)-1H-indole-4-yl as eluent]-1-piperazine carboxylic acid butyl ester (3).HPLC?100％。NMR (
1H and
13C) and the MS analysis confirmation described structure.
Step (c): remove the BOC protecting group
BOC group on the intermediate 3 adds the saturated ether of HCl gas then by chemical compound is dissolved in methanol.Filter and dry HCl salt (4).
B. preparation of drug combination
Tablet
Ingredient m g/ sheet
1 5-HT
2CReceptor stimulating agent 10.0
2 5-HT
6Receptor antagonist 10.0
3 microcrystalline Cellulose 57.0
4 calcium hydrogen phosphate 15.0
5 primojels 5.0
6 colloidal silicas 0.25
7 magnesium stearate 0.75
Active component 1 and 2 mixed about 10 minutes with composition 3,4,5 and 6.Add magnesium stearate (7) then, the mixture of generation mixed about 5 minutes, was pressed into to be with or without the sheet that film coats.
C. receptor affinity and effectiveness analysis
5-HT
2CReceptor affinity is analyzed
5-HT
2CReceptor affinity is measured in competition experiments, wherein replaces being combined in the 5-HT by the stably express people by the active technical monitoring serial dilution degree chemical compound of measuring the film homogenize thing of crossing in scintillation counter on glass fiber filter
2COn the film of the transfection HEK293 cell line preparation of receptor protein
3The ability of the 5-HT of H-labelling.Determine non-specific binding with 5 μ M mianserins.
5-HT
2AReceptor affinity is analyzed
5-HT
2AReceptor affinity is measured in competition experiments, wherein replaces being combined in the 5-HT by the stably express people by the active technical monitoring serial dilution degree chemical compound of measuring the film homogenize thing of crossing in scintillation counter on glass fiber filter
2AOn the film of the transfection CHO cell system preparation of receptor protein
3The ability of the ketanserin of H-labelling or lysergic acid diethylamide (LSD).Determine non-specific binding with 5 μ M mianserins.
5-HT
2BReceptor affinity is analyzed
5-HT
2BReceptor affinity is measured in competition experiments, wherein replaces being combined in the 5-HT by the stably express people with flicker near analyzing (SPA) technical monitoring serial dilution degree chemical compound
2BOn the film of the transfection CHO cell system preparation of receptor protein
3The ability of the 5-HT of H-labelling.Determine non-specific binding with 5 μ M mianserins.
5-HT
2CThe receptor effectiveness analysis
At 5-HT
2CThe agonist usefulness of receptor is by (MO U.S.A) measures chemical compound at stably express people 5-HT for Sigma, St.Louis with calcium chelating fluorescent dye FLUO-3
2CThe ability of loosening intracellular Ca2+ is determined in the transfection HEK293 cell of receptor protein.With respect to 1 μ M serotonin, measure relative efficiency (%).
5-HT
6Receptor affinity is analyzed
The radioligand-binding assay use [
3H]-LSD (lysergicaciddiethylamide) (LSD).Analysis is carried out on the sample panel of 96-hole, add the suitable dilution test compound of 11 μ l (analyzing the sample that uses double 11 series concentration), 11 μ l radioligands, and the SPA pearl of the 178 μ l WGA-coating of washing, the film in the binding buffer agent is with containing the 5-HT that clones people
6The HEK293-cell preparation of receptor.With about 5 minutes of panel vibration, then incubated at room temperature 1 hour.Then plate is loaded in the counting magazine, in scintillation counter, counts.The particular combination cpm that obtains adjusts to one-site combination model with GraphPad Prism ver.2.0.With the IC of Cheng Prusoff equation with evaluation
50Value is converted into K
iValue (affinity costant) (Cheng, people such as Y.C., Biochem.Pharmacol.1973,22,3099-3108).
5-HT
6The receptor effectiveness analysis
At 5-HT
6(Uppsala Sweden) measures chemical compound at stably express people 5-HT to the antagonist usefulness of receptor for RPA559, Amersham Pharmacia Biotech with the direct florescence analysis of cAMP SPA system
6The antagonistic ability that in the transfection HEK293 cell of receptor protein the cAMP that is caused by 5-HT is increased is determined.
D. feed experiment
Test compound
5-HT
2CReceptor stimulating agent (2R)-methyl isophthalic acid-{ 3-[2-(3-pyridine radicals oxygen base) ethyoxyl]-2-pyrazinyl } piperazine fumarate (" PNU-183933F ") and (2R)-1-(3-{2-[(2-ethyoxyl-3-pyridine radicals) oxygen base] ethyoxyl }-the 2-pyrazinyl)-the 2-methyl piperazine, fumarate (" BVT.2938F ") is dissolved in saline (0.9% NaCl), is diluted to suitable concentration in identical carrier.
5-HT
6Receptor antagonist 6-methyl-9-(phenyl sulfonyl)-1,2,3,4,5, six hydrogen bifurcation heptan of 6-are because of also [4,5-b] indole hydrochloride (" PNU-186053A ") and 1-(phenyl sulfonyl)-4-(1-piperazinyl)-1H-indole hydrochloride (5-HT
6Receptor antagonist (" BVT.5182C ") dissolves in 25% cyclodextrin and dilutes.
The fresh solution of handling of preparation on the same day.
Animal
Use the male mice (C57BL/6JBom-Lep of 8-9 average weight 45g in age in week
Ob(ob/ob), Bomholtsgaard, Denmark).Animal encages separately, 23 ± 1 ℃ of temperature, and humidity 40-60% can freely drink water and the food sanitation standard laboratory diet.Establish 12/12h bright/dark circulation, turn off the light at 5p.m..Before beginning one's study, animal was accustomed to for 1 week at least.At duration of test, animal obtains special food (BioServ, Frenchtown, NJ, the dustless smart granule of USA, every heavy 20mg).
Experimental section
In the beginning of research, animal is transferred to (Habitest Modular Animal Behavior Test System in the special cage " operant tests cage "; Colbourn Instr, Allentown, PA, USA).These cages comprise a feeding groove, and it has the pick off that is used to measure food intake; An optics lickometer who is used to write down the water intake amount; And one based on ultrared monitor, is used to write down all general motor activities.Monitor links to each other with computer, and computer is controlled and the monitoring situation continuously.Weigh the food particle that is used for whole institute requirement, water bottle is filled with fresh tap water and is weighed.Animal adapts to 3 days to set up reference value in their new environment.Animal is weighed at 3p.m. when beginning and end research.Before dark begins, 4.20 and the 5.00p.m. chemical compound of throwing something and feeding.Three treated animals are accepted (i) 5-HT in 25% cyclodextrin respectively
6Receptor antagonist; The (ii) 5-HT in saline
2CReceptor stimulating agent; (iii) Lian He 5-HT
2CReceptor stimulating agent/5-HT
6Receptor antagonist.When uniting use, 5-HT
6Receptor antagonist or saline are at 5-HT
2CReceptor stimulating agent or 25% cyclodextrin administration were thrown something and fed in preceding 30 minutes.The 4th group with the identical method carrier of throwing something and feeding respectively.Research finished at the 5th day.Weigh with area of computer aided Mettler-Toledo PR5002/PR802.
Result's evaluation
Each dosage group comprises 12-16 animal.During 22 hours, proofread and correct food leakage rate data, and suppose that it is according to time-based ratio based on the leakage rate of weighing.Calculating data before handling and afterwards.The difference between the food intake is with the % numerical value (meansigma methods ± SEM) expression of basic food ration before processing and between 3 hours (5pm-8pm), 6 hours (5pm-11pm), 12 hours (5pm-5am), 21 hours (5pm-2pm).
Result shown in the accompanying drawing 1 points out, uses 5-HT
6Receptor antagonist " PNU-186053A " (50mg/kg is subcutaneous) and 5-HT
2CReceptor stimulating agent " PNU-183933F " (50mg/kg the is oral) food consumption that Combined Treatment reduced is apparently higher than using the unification compound.Correspondingly, the result shown in the accompanying drawing 2 points out, uses 5-HT
2CReceptor stimulating agent " BVT.2938F " (5mg/kg is subcutaneous) and 5-HT
6The food consumption that receptor antagonist " BVT.5182C " (3mg/kg is subcutaneous) Combined Treatment was reduced after administration in 12 and 21 hours is apparently higher than using the unification compound.Therefore, obviously use 5-HT
2CReceptor stimulating agent and 5-HT
6The receptor antagonist therapeutic alliance is obviously more effective than using agonist or antagonist for treating separately to the reduction of food intake.
Claims (24)
1. pharmaceutical composition comprises the 5-HT of effective dose
2CReceptor stimulating agent aryl piperazines chemical compound and 5-HT
6Receptor antagonist bifurcation heptan is because of the combination of officinal salt, enantiomer or the prodrug forms of diindyl or aryl sulfonyl indole or described agonist and/or antagonist, and optional pharmaceutically acceptable carrier.
2. the pharmaceutical composition of claim 1, wherein 5-HT
2CReceptor stimulating agent is (2R)-methyl isophthalic acid-{ 3-[2-(3-pyridine radicals oxygen base) ethyoxyl]-2-pyrazinyl } piperazine fumarate.
3. the pharmaceutical composition of claim 1, wherein 5-HT
2CReceptor stimulating agent is (2R)-1-(3-{2-[(2-ethyoxyl-3-pyridine radicals) oxygen base] ethyoxyl }-the 2-pyrazinyl)-2-methyl piperazine fumarate.
4. the pharmaceutical composition of claim 1, wherein 5-HT
6Receptor antagonist is 6-methyl-9-(phenyl sulfonyl)-1,2,3,4,5, and six hydrogen bifurcation heptan of 6-are because of [4,5-b] indole hydrochloride also.
5. the pharmaceutical composition of claim 1, wherein 5-HT
6Receptor antagonist is 1-(phenyl sulfonyl)-4-(1-piperazinyl)-1H-indole hydrochloride.
6. according to each pharmaceutical composition among the claim 1-5, wherein respectively with respect to 5-HT
2A, 5-HT
2BAnd 5-HT
6Receptor, 5-HT
2CReceptor stimulating agent is to 5-HT
2CThe selectivity of receptor is at least 10.
7. according to each pharmaceutical composition among the claim 1-5, wherein respectively with respect to 5-HT
2A, 5-HT
2BAnd 5-HT
2CReceptor, 5-HT
6Receptor antagonist is to 5-HT
6The selectivity of receptor is at least 10.
8. according to the pharmaceutical composition of claim 1,5-HT wherein
2CReceptor stimulating agent is the piperazinyl pyrazines chemical compound.
9. according to the pharmaceutical composition of claim 1,5-HT wherein
6Receptor antagonist is that aryl sulfone six hydrogen bifurcation heptan of replacing are because of diindyl.
10. according to each pharmaceutical composition of claim 1-9, wherein 5-HT
2CReceptor stimulating agent and 5-HT
6Receptor antagonist is with the therapeutic dose combination, with the pharmaceutically acceptable carrier uniform mixing.
11. one kind contains 5-HT
2CReceptor stimulating agent aryl piperazines chemical compound and 5-HT
6Receptor antagonist bifurcation heptan is because of the product of diindyl or aryl sulfonyl indole, its as combination formulations with 5-HT
2CReceptor and 5-HT
6Use simultaneously, respectively or in succession in the treatment of diseases that receptor is correlated with.
12. the product of claim 11, wherein 5-HT
2CReceptor stimulating agent is (2R)-methyl isophthalic acid-{ 3-[2-(3-pyridine radicals oxygen base) ethyoxyl]-2-pyrazinyl } piperazine fumarate.
13. the product of claim 11, wherein 5-HT
2CReceptor stimulating agent is (2R)-1-(3-{2-[(2-ethyoxyl-3-pyridine radicals) oxygen base] ethyoxyl }-the 2-pyrazinyl)-2-methyl piperazine fumarate.
14. the product of claim 11, wherein 5-HT
6Receptor antagonist is 6-methyl-9-(phenyl sulfonyl)-1,2,3,4,5, and six hydrogen bifurcation heptan of 6-are because of [4,5-b] indole hydrochloride also.
15. the product of claim 11, wherein 5-HT
6Receptor antagonist is 1-(phenyl sulfonyl)-4-(1-piperazinyl)-1H-indole hydrochloride.
16. according to each product among the claim 11-15, wherein disease is selected from drinking and eating irregularly, CNS imbalance, urinary incontinence and glaucoma.
17. according to the product of claim 16, wherein disease is overweight or obesity.
18.5-HT
2CReceptor stimulating agent aryl piperazines chemical compound and 5-HT
6Receptor antagonist bifurcation heptan is the purposes in the preparation medicine because of diindyl or aryl sulfonyl indole, and described medicine is used for the treatment of and 5-HT
2CReceptor and 5-HT
6The disease that receptor is relevant.
19. the purposes of claim 18, wherein 5-HT
2CReceptor stimulating agent is (2R)-methyl isophthalic acid-{ 3-[2-(3-pyridine radicals oxygen base) ethyoxyl]-2-pyrazinyl } piperazine fumarate.
20. the purposes of claim 18, wherein 5-HT
2CReceptor stimulating agent is (2R)-1-(3-{2-[(2-ethyoxyl-3-pyridine radicals) oxygen base] ethyoxyl }-the 2-pyrazinyl)-2-methyl piperazine fumarate.
21. the purposes of claim 18, wherein 5-HT
6Receptor antagonist is 6-methyl-9-(phenyl sulfonyl)-1,2,3,4,5, and six hydrogen bifurcation heptan of 6-are because of [4,5-b] indole hydrochloride also.
22. the purposes of claim 18, wherein 5-HT
6Receptor antagonist is 1-(phenyl sulfonyl)-4-(1-piperazinyl)-1H-indole hydrochloride.
23. according to each purposes among the claim 18-22, wherein disease is selected from drinking and eating irregularly, CNS imbalance, urinary incontinence and glaucoma.
24. according to the purposes of claim 23, wherein disease is overweight or obesity.
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| CN107628981A (en) * | 2017-10-31 | 2018-01-26 | 威海市妇女儿童医院 | A kind of cinnamoyl sulfonylindoline compounds and its application for preparing glaucoma medicine |
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| JP4184077B2 (en) * | 2000-11-02 | 2008-11-19 | ワイス | 1-aryl or 1-alkylsulfonyl-heterocyclylbenzazole as 5-hydroxytryptamine-6 ligand |
| US7034029B2 (en) | 2000-11-02 | 2006-04-25 | Wyeth | 1-aryl- or 1-alkylsulfonyl-heterocyclylbenzazoles as 5-hydroxytryptamine-6 ligands |
| CN1321110C (en) * | 2001-06-15 | 2007-06-13 | 弗·哈夫曼-拉罗切有限公司 | 4-piperazinylindole derivatives with 5-HT6 receptor affinity |
| ES2268113T3 (en) * | 2001-06-15 | 2007-03-16 | F. Hoffmann-La Roche Ag | DERIVATIVES OF 4-PIPERAZINYLINDOL WITH AFFECTION TO THE RECEIVER 5-HT6. |
| US6825198B2 (en) | 2001-06-21 | 2004-11-30 | Pfizer Inc | 5-HT receptor ligands and uses thereof |
| GB0202679D0 (en) * | 2002-02-05 | 2002-03-20 | Glaxo Group Ltd | Novel compounds |
| NZ535239A (en) | 2002-03-27 | 2008-03-28 | Glaxo Group Ltd | Quinoline derivatives and their use as 5-HT6 ligands |
| CL2004000826A1 (en) * | 2003-04-25 | 2005-03-04 | Pfizer | USE OF AN AGONIST FOR THE 5-HT2C RECEPTOR TO PREPARE A USEFUL MEDICINAL PRODUCT IN THE TREATMENT OF URINARY INCONTINENCE CAUSED BY STRESS, WITH THE CONDITION THAT THE AGONIST IS NOT 1- [6-CHLORINE-5- (TRIFLUOROMETIL) -2- PIRIDINIL] PIPERAZINA (ORG-129 |
| MY141862A (en) | 2003-07-22 | 2010-07-16 | Arena Pharm Inc | Diaryl and arylheteroaryl urea derivatives as modulators of the 5-ht2a serotonin receptor useful for the prophylaxis and treatment of disorders related thereto |
| EP2248524A3 (en) | 2004-08-25 | 2011-03-09 | Takeda Pharmaceutical Company Limited | Preventives/remedies for stress urinary incontinence and method of screening the same |
| US7713954B2 (en) | 2004-09-30 | 2010-05-11 | Roche Palo Alto Llc | Compositions and methods for treating cognitive disorders |
| US20100048713A1 (en) * | 2006-01-06 | 2010-02-25 | Aarhus Universitet | Compounds acting on the serotonin transporter |
| EP2742936A1 (en) | 2006-05-16 | 2014-06-18 | Takeda Pharmaceutical Company Limited | Fused heterocyclic compound and use thereof |
| WO2007149728A2 (en) * | 2006-06-20 | 2007-12-27 | Alcon Research, Ltd. | Aryl and heteroaryl tetrahydrobenzazepine derivatives and their use for treating glaucoma |
| ATE495737T1 (en) * | 2007-08-01 | 2011-02-15 | Esteve Labor Dr | COMBINATION OF AT LEAST TWO 5-HT6 LIGANDS |
| EP2789338A3 (en) | 2007-11-15 | 2015-01-14 | Takeda Pharmaceutical Company Limited | Condensed pyridine derivate and use thereof |
| EP2254564A1 (en) | 2007-12-12 | 2010-12-01 | Glaxo Group Limited | Combinations comprising 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline |
| WO2009123714A2 (en) | 2008-04-02 | 2009-10-08 | Arena Pharmaceuticals, Inc. | Processes for the preparation of pyrazole derivatives useful as modulators of the 5-ht2a serotonin receptor |
| WO2010062321A1 (en) | 2008-10-28 | 2010-06-03 | Arena Pharmaceuticals, Inc. | Processes useful for the preparation of 1-[3-(4-bromo-2-methyl-2h-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea and crystalline forms related thereto |
| UA100192C2 (en) | 2008-11-11 | 2012-11-26 | УАЙТ ЭлЭлСи | 1-(arylsulfonyl)-4-(piperazin-1-yl)-1h-benzimidazoles as 5-hydroxytryptamine-6 ligands |
| TW201529584A (en) | 2009-06-15 | 2015-08-01 | Takeda Pharmaceutical | Pyrazinooxazepine derivatives |
| JPWO2011071136A1 (en) | 2009-12-11 | 2013-04-22 | アステラス製薬株式会社 | Fibromyalgia treatment |
| US10022355B2 (en) | 2015-06-12 | 2018-07-17 | Axovant Sciences Gmbh | Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of REM sleep behavior disorder |
| BR112018000728A2 (en) | 2015-07-15 | 2018-09-04 | Axovant Sciences Gmbh | method for the prophylaxis and / or treatment of visual hallucinations in a subject in need |
| EP3733204A4 (en) | 2017-12-27 | 2021-09-15 | Takeda Pharmaceutical Company Limited | Therapeutic agent for stress urinary incontinence and fecal incontinence |
| CN111269165A (en) * | 2018-12-05 | 2020-06-12 | 中国科学院大连化学物理研究所 | Synthetic method of 3-arylsulfonyl indole derivative |
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| DZ2376A1 (en) * | 1996-12-19 | 2002-12-28 | Smithkline Beecham Plc | New sulfonamide derivatives process for their preparation and pharmaceutical compositions containing them. |
| GB9803411D0 (en) * | 1998-02-18 | 1998-04-15 | Smithkline Beecham Plc | Novel compounds |
| US6100291A (en) * | 1998-03-16 | 2000-08-08 | Allelix Biopharmaceuticals Inc. | Pyrrolidine-indole compounds having 5-HT6 affinity |
| US6251893B1 (en) * | 1998-06-15 | 2001-06-26 | Nps Allelix Corp. | Bicyclic piperidine and piperazine compounds having 5-HT6 receptor affinity |
| GB9819035D0 (en) * | 1998-09-01 | 1998-10-28 | Cerebrus Res Ltd | Chemical compounds VII |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107628981A (en) * | 2017-10-31 | 2018-01-26 | 威海市妇女儿童医院 | A kind of cinnamoyl sulfonylindoline compounds and its application for preparing glaucoma medicine |
| CN107628981B (en) * | 2017-10-31 | 2019-07-30 | 威海市妇女儿童医院 | A kind of cinnamoyl sulfonylindoline compounds and its application for preparing glaucoma medicine |
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| AU2001282734B2 (en) | 2006-10-12 |
| ZA200210234B (en) | 2004-03-18 |
| IL154057A0 (en) | 2003-07-31 |
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| NO20030304L (en) | 2003-03-12 |
| AU8273401A (en) | 2002-02-05 |
| HUP0301346A3 (en) | 2005-05-30 |
| EA200300183A1 (en) | 2003-08-28 |
| NO20030304D0 (en) | 2003-01-20 |
| MXPA03000548A (en) | 2004-04-05 |
| WO2002008178A1 (en) | 2002-01-31 |
| JP2004504376A (en) | 2004-02-12 |
| HUP0301346A2 (en) | 2003-08-28 |
| BR0112661A (en) | 2003-06-24 |
| HK1057536A1 (en) | 2004-04-08 |
| EA006604B1 (en) | 2006-02-24 |
| KR20030036599A (en) | 2003-05-09 |
| KR100845450B1 (en) | 2008-07-10 |
| YU2603A (en) | 2006-05-25 |
| CA2411192A1 (en) | 2002-01-31 |
| NZ523216A (en) | 2005-05-27 |
| EP1301476A1 (en) | 2003-04-16 |
| CN1443162A (en) | 2003-09-17 |
| PL360309A1 (en) | 2004-09-06 |
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