[go: up one dir, main page]

CN1240701C - 2,3,4,4-tetrahydro-1H-pyrazino (1,2-a) quinoxalin-5(6H) one deivatives being 5HT2C agonists - Google Patents

2,3,4,4-tetrahydro-1H-pyrazino (1,2-a) quinoxalin-5(6H) one deivatives being 5HT2C agonists Download PDF

Info

Publication number
CN1240701C
CN1240701C CNB998144169A CN99814416A CN1240701C CN 1240701 C CN1240701 C CN 1240701C CN B998144169 A CNB998144169 A CN B998144169A CN 99814416 A CN99814416 A CN 99814416A CN 1240701 C CN1240701 C CN 1240701C
Authority
CN
China
Prior art keywords
hydrogen
compound
pyrazine
quinoxaline
chloro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CNB998144169A
Other languages
Chinese (zh)
Other versions
CN1330652A (en
Inventor
A·L·萨布
G·S·维尔马克
J·A·纳尔逊
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wyeth LLC
Original Assignee
Wyeth LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Wyeth LLC filed Critical Wyeth LLC
Publication of CN1330652A publication Critical patent/CN1330652A/en
Application granted granted Critical
Publication of CN1240701C publication Critical patent/CN1240701C/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Diabetes (AREA)
  • Pain & Pain Management (AREA)
  • Hematology (AREA)
  • Psychiatry (AREA)
  • Obesity (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Anesthesiology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

This invention provides compounds of formula (I), and enantiomers thereof, wherein R is hydrogen or alkyl of 1-6 carbon atoms; R' is hydrogen, alkyl of 1-6 carbon atoms, acyl of 2-7 carbon atoms, or aroyl; R1, R2, R3, and R4 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, trifluoroalkyl, -CN, alkyl sulfonamide of 1-6 carbon atoms, alkyl amide of 1-6 carbon atoms, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, trifluoroalkoxy of 1-6 carbon atoms, acyl of 2-7 carbon atoms, or aroyl; X is CR5R6 or a carbonyl group; R5 and R6 are each, independently, hydrogen or alkyl of 1-6 carbon atoms; or a pharmaceutically acceptable salt thereof, with the proviso that at least one of R1, R2, R3, or R4 are not hydrogen; which are 5HT2C receptor agonists useful for the treatment of disorders involving the central nervous system such as obsessive-compulsive disorder, depression, anxiety, schizophrenia, migraine, sleep disorders, eating disorders, obesity, type II diabetes, and epilepsy.

Description

As the 5HT2C agonist 2,3,4,4a-tetrahydrochysene-1H-pyrazine also (1,2-a) quinoxaline-5 (6H) ketone derivatives
Background of invention
The present invention relates to 2,3,4,4a-tetrahydrochysene-1H-pyrazine also (1,2-a) quinoxaline-5 (6H) ketone derivatives, they are thrombotonin serotonin 2 C(5HT 2C) receptor stimulant, can be used for treatment illness such as obsessional idea and behavior disorder, dysthymia disorders, anxiety, schizophrenia, migraine, somnopathy, eating disorder, obesity, type ii diabetes and epilepsy.
Obesity is a kind of medical conditions that mostly is feature of crossing with body fat or adipose tissue.The association disease relevant with obesity has I type i diabetes, cardiovascular diseases, hypertension, hyperlipoidemia disease, apoplexy, osteoarthritis, sleep apnea.Cholecystopathy, gout, some cancer, some infertility and early stage dead.Along with the U.S. and the hundreds of proportions by subtraction of overseas obese people continue increase, estimate that obesity will become the main Health hazard of 21 century.Thrombotonin serotonin (5-HT) acceptor is to be expressed in the G-protein linked receptor .[Wilkinson on the neurone in the many zones of people's central nervous system, L.O. and Dourish, C.T.5-seretonine receptor 5 hypotype: basis and clinical application aspect (Peroutka, S.J. edit) 147-210 (Wiley-Liss, NewYork, 1991) .].5HT 2CAcceptor [is called 5HT previously 1CAcceptor] be the important hypotype that sees the 5-hydroxytryptamine receptor of rat and people's central nervous system.Wide expression is in cortex and cortex lower area .[Julius, D.MacDermott, A.B., Axel, R.Jessell, T.M.Science 241:558-564 (1988)].To studies show that of several animal and humans, nonselective 5HT 2CReceptor stimulant 1-(3-chloro-phenyl)-piperazine (MCPP) can reduce ingestion of food .[Cowen, P.J., Clifford, E.M., Williams, C., Walsh, A.E.S., Fairburn, C.G.Nature 376:557 (1995)].Tecott etc. are verified, lack 5HT 2CThe transgenic rat of acceptor is bigger than the appetite of wild-type rat, weight increase .[Tecott, L.H., Sun, L.M., Akana, S.F., Strack, A.M., Lowenstein, D.H., Dallman, M.F., Jullus, D.Nature 374:542-546 (1995)].The compounds of this invention is 5HT 2CThe receptor subtype selective agonist, they have selectivity to other monoamine receptor, can reduce ingestion of food, increase thereby reduce weight.5HT 2COther treatment indication of agonist comprises obsessional idea and behavior disorder, dysthymia disorders, Phobias, schizophrenia, somnopathy, eating disorder and epilepsy.
United States Patent (USP) 4,032,639; 4,089,958; With 4,203,987 have described as 2,3,4 of antihypertensive drug, and 4a-tetrahydrochysene-1H-pyrazine is [1,2-a] quinoxaline-5 (6)-ketone and derivative thereof also.And in contrast, The compounds of this invention in conjunction with and activate 5HT among the CNS 2CAcceptor, and be used for the treatment of the CNS disease.
Indian J.Chem.17B, 244-245 (1979) disclose 2,3,4 of 3-replacement, 4a, and 5,6-six hydrogen-1 (H)-pyrazine is [1,2-a] quinoxaline compounds also, and they do not show under 60mg/kg i.p. dosage reduces appetite or stimulating activity.In anesthetized animal, show the weak CNS sedative activity and the activity that brings high blood pressure down significantly.Observe the tachysynthesis effect.
Summary of the invention
The invention provides formula I compound or pharmaceutically acceptable salt thereof with following structure:
Figure C9981441600091
Wherein
R is the alkyl of hydrogen or 1-6 carbon atom;
R ' is a hydrogen, the alkyl of 1-6 carbon atom, the acyl group of 2-7 carbon atom, or aroyl;
R 1, R 2, R 3And R 4Be hydrogen independently of one another, the alkyl of 1-6 carbon atom, the alkoxyl group of 1-6 carbon atom, halogen, trifluoroalkyl ,-CN, the alkyl amino sulfonyl of 1-6 carbon atom, the alkyl-carbamoyl of 1-6 carbon atom (alkyl amide), amino, the alkylamino of 1-6 carbon atom, each moieties contains the dialkyl amido of 1-6 carbon atom, the thrihalothaneoxy of 1-6 carbon atom, the acyl group of 2-7 carbon atom, or aroyl;
X is CR 5R 6Or carbonyl;
R 5And R 6Be the alkyl of hydrogen or 1-6 carbon atom independently of one another;
Condition is R 1, R 2, R 3, or R 4In at least one can not be hydrogen;
These compounds are 5HT 2CReceptor stimulant can be used for treating central nervous system disease, as obsessional idea and behavior disorder, dysthymia disorders, anxiety, Phobias, schizophrenia, migraine, somnopathy, eating disorder, obesity, type ii diabetes and epilepsy.
Compound of the present invention can comprise unsymmetrical carbon, and compounds more of the present invention can contain one or more asymmetric centers, therefore can produce optically active isomer, enantiomorph and diastereomer.When the stereochemistry of formula I does not add when indicating, The compounds of this invention then comprises this optically active isomer and diastereomer; And the enantiomer-pure R of racemize and fractionation and S steric isomer; And other mixture of R and S steric isomer and their pharmacologically acceptable salt.
Term " alkyl " comprises straight chain and side chain radical of saturated aliphatic alkyl.Preferred alkyl group is methyl, ethyl, propyl group or butyl, most preferable.Term " aroyl " is meant aryl ethers, and wherein the definition of aryl is meant the aroma system of 6-14 carbon atom, and it can be for monocycle or many rings aromatic nucleus of condensing each other or connecting, and this condense or shack at least a portion constitute the conjugation aroma system.Preferred aryl groups comprises phenyl, naphthyl, xenyl, anthryl, tetralyl, phenanthryl.Halogen is meant Cl, Br, F and I, preferred chlorine or fluorine.
Pharmacologically acceptable salt can form for example following acid by organic and mineral acid: acetate, propionic acid, lactic acid, citric acid, tartrate, succsinic acid, fumaric acid, toxilic acid, propanedioic acid, amygdalic acid, oxysuccinic acid, phthalic acid, hydrochloric acid, Hydrogen bromide, phosphoric acid, nitric acid, sulfuric acid, methylsulfonic acid, naphthene sulfonic acid, Phenylsulfonic acid, toluenesulphonic acids, camphorsulfonic acid and the similar known acid of accepting.
Preferred The compounds of this invention is these, wherein R 1, R 2, R 3Or R 4In at least one can not be hydrogen, and R 1, R 2, R 3And R 4In non-hydrogen substituting group be halogen or trifluoromethyl.
Enantiomer-pure general formula I A that is preferably as follows and IB compound:
R wherein 1, R 2, R 3And R 4As mentioned above.
The compounds of this invention can be according to the feedstock production of following reaction process by marketable material or the preparation of available literature method.These process descriptions the preparation of representative compounds of the present invention.
Flow process 1
Figure C9981441600111
In the flow process 1, symbol Cbz represents benzyloxycarbonyl, and Y represents chlorine, fluorine or bromine.4-benzyloxycarbonyl piperazine-2-carboxylic acid's (I) the solution and the neighbour of replacement-nitro halogeno-benzene (II) reaction generates 4-benzyloxycarbonyl-1-(neighbour-nitro-substituted-phenyl)-piperazine-2-carboxylic acid (III).Be reflected in inert organic solvents such as the methyl-sulphoxide and carry out under alkali such as triethylamine existence, temperature of reaction is higher than room temperature, for example 50-150 ℃.
It is amino that the method for cyclisation intermediate (III) comprises nitroreduction, preferably in acid (as acetate), react and carry out by metal (as iron), and then in high temperature such as 50-100 ℃ of heating down, thus cyclisation formation (IV).Utilize boron tribromide, catalytic reduction or alkali such as potassium hydroxide to remove the Cbz protecting group, generate product of the present invention (IVa).Perhaps handle (IV),, generate intermediate (V) then with alkylogen such as iodomethane reaction with alkali such as sodium hydride.Remove the Cbz group with boron tribromide or potassium hydroxide and get The compounds of this invention (VI), wherein R ' is a low alkyl group.
Compound (VI) also can utilize alkali (as sodium hydride) and alkylogen (as methyl iodide) alkylation once more, generates The compounds of this invention (VIII).On the other hand, use reductive agent such as borine/THF and compound (VI) can be reduced into The compounds of this invention (VII).Compound (VIII) also can reduce in THF with borine and generate The compounds of this invention (IX).
Amide compound (V) also can utilize reductive agent such as borine to be reduced to amine (VII) in tetrahydrofuran (THF) under 0-50 ℃.Compound (VII) is similarly The compounds of this invention.
Similarly, amide compound (VI) also can be reduced into The compounds of this invention amine (VIII).R ' is in the acylated compound (VI) therein, and the introducing of this carboxyl groups is to be undertaken by the above afterwards reducing the acid amides (VI) for hydrogen of R ' wherein.
Flow process 2
Figure C9981441600131
In flow process 2, intermediate (IV) carboxylic acid transforms corresponding N-methoxyl group-N-methyl nitrosourea (IX) by following reaction: in the presence of alkali (as pyridine) and coupling agent (as dicyclohexylcarbodiimide (DCC)), make corresponding acid (IV) and N in organic solvent such as methylene dichloride, the O-dimethyl hydroxylamine hydrochloride is in 0-50 ℃ of reaction down.Handle intermediate (IX) with Grignard reagent or organolithium reagent such as lithium methide then, generate ketone (X).In acetate, reduce nitro in the intermediate (X) with reductive agent such as iron, generate corresponding amine (XI).The latter is carrying out cyclisation in the presence of acid as the right-toluenesulphonic acids under high temperature such as 50-150 ℃ in inert organic solvents such as benzene, generation The compounds of this invention (XII).With alkylogen such as methyl iodide or carboxylic acid halides such as Acetyl Chloride 98Min. alkylation (XII), generate The compounds of this invention (XIII).Handle intermediate (X) with Grignard reagent such as methylmagnesium-chloride, produce the tertiary alcohol (XIV).Reduce the nitro of intermediate (XIV) with metal such as iron in as acetate in acid, under 50-150 ℃ temperature, heat then, obtain The compounds of this invention (XV).Compound (XV) and alkylogen such as methyl iodide or carboxylic acid halides (as Acetyl Chloride 98Min.) react The compounds of this invention (XVI).
Enantiopure compound of the present invention can be prepared according to the raw material of flow process 3 by marketable material or the preparation of available literature method.This process description the preparation of the representativeness of formula IA of the present invention (R)-compound, it is raw material (reference in vide infra) with known 2-(R)-piperazine carboxylic acid.With known 2-(S)-piperazine carboxylic acid is (S)-compound that raw material then generates formula IB of the present invention.
Flow process III
In flow process 3, (R)-2-piperazine carboxylic acid (reference in vide infra) is converted into the amino acid (XVII) that N-is protected with standard method; Symbol Cbz represents benzyloxycarbonyl.(R)-and 4-benzyloxycarbonyl piperazine-2-carboxylic acid's (XVII) solution and the neighbour of replacement-nitro fluorobenzene reaction, generate 4-benzyloxycarbonyl-1-(phenyl of neighbour-nitro-replacement)-(R)-piperazine-2-carboxylic acid (XVIII).Reaction is to carry out under the temperature that is higher than room temperature such as 50-70 ℃ in inert organic solvents (as dimethyl formamide) in the presence of alkali such as the triethylamine.
According to following method cyclisation intermediate (XVIII): with nitroreduction is amino, preferably react in as acetate in acid by metal such as iron and carries out, and descends to heat high temperature such as 50-70 ℃ then, thereby is cyclized into (XIX).Utilize 30%HBr/ acetate, boron tribromide or catalytic reduction to remove the Cbz protecting group, generate chiral product of the present invention (IA).
The preparation method of formula I, IA and IB compound has constituted another aspect of the present invention.
The compounds of this invention is as 5HT 2CThe ability of agonist can be confirmed with several standard pharmacological test methods; Using method and gained result are as follows.
Test method
5HT 2CThe receptor binding assays method
In order to estimate to 5HT 2CThe high-affinity of acceptor will be used the expressing human serotonin 2C(h5HT 2C) CHO (the Chinese grey mouse ovary) clone of cDNA transfection of acceptor is kept in the DMEM (the improved Eagle substratum of Dulbecco) that adds following ingredients: foetal calf serum, glutamine and marker: urine purine phosphoribosyltransferase (GTP) and xanthoglobulin thymidine (HT).Make cell grow to converging state in big culture dish, middle replacing substratum is also cut cell.In case reach converging state, at once by the scraping harvested cell.Harvested cell is suspended in fresh physiology phosphate-buffered saline (PBS) solution of half volume, and (900 * g) is centrifugal for low speed.Repeat this operation again.Then at 10 volume 50mM Tris.HCl, among pH7.4 and the 0.5mM EDTA with polytron (being set at 7 grades) homogenate collected 15 seconds of cell.With the centrifugal homogenate of 900 * g 15 minutes to remove karyon particle and other cell debris.Discard throw out, with 40,000 * g centrifuged supernatant 30 minutes again.Gained throw out resuspending in a small amount of Tris.HCl damping fluid, is measured the content of tissue protein in 10-25 microlitre (μ l) the volume aliquots containig.In the protein determination that carries out according to people's such as Lowry method (J.Biol.Chem., 193:265 (1951)), use bovine serum albumin (BSA) as standard.With containing 0.1% xitix, 10mM eutonyl and 4mM CaCl 250mM Tris.HCl damping fluid regulate the volume of suspension cell film, the concentration that reaches tissue protein in every ml suspension is 1-2mg.Membrane product suspension (concentrate repeatedly) is divided into the 1ml volume ,-70 ℃ of storages be ready for use on subsequently in conjunction with test.
In 96 hole microtiter plates, carry out cumulative volume 200 μ l in conjunction with measuring.Add in each hole: 60 μ l are by containing 4mM CaCl 2The cultivation damping fluid made of 50mM Tris.HCl damping fluid (pH7.4); 20 μ l[ 125I] DOI (S.A., 2200Ci/mmol, NEN LifeScience).
By constantly increase [ 125I] concentration of DOI, utilize saturated in conjunction with test try to achieve [ 125I] DOI is at the plain 5HT of human serum 2CDissociation constant KD value on the acceptor is 0.4nM.Add the tissue suspension that 100.0 μ l contain 50 μ g receptor proteins at last and start the non-specific combination of reaction mensuration in the presence of the unlabelled DOI of 1 μ M (adding) with 20.0 μ l volumes.Add the 20.0ml test compound.Room temperature incubation mixture 60 minutes.Stop incubation by quick filtration.Utilize Packard _Filtremate 196 harvesting devices are filled into bonded ligand-receptor mixture on the even filter in 96 holes.On vacuum drying oven internal heating to 60 ℃ dry filter disc, caught in conjunction with mixture, utilize 40 μ l Microscint-20 scintillation solutions, measure radioactivity with the Packard TopCount_ that is furnished with six times of (6) photomultiplier detectors.
Specificity is in conjunction with equaling gross activity in conjunction with the binding capacity that deducts under the unmarked DOI existence of 1 μ M.Specificity bonded per-cent when the combination under the variable concentrations trial drug exists exists with no medicine is represented.Then these results are mapped to log trial drug concentration with the log% combination.Each data point of nonlinear regression analysis is tried to achieve the IC50 and the Ki value (95% fiducial limit) of test compound.Perhaps, draw the linear regression straight line that successively decreases of each data point, read the IC50 value, measure the Ki value by finding the solution following equation then from curve:
Ki = I C 50 1 + L / KD
Wherein L is the concentration of used radioligand, and KD is the dissociation constant of part to acceptor, and they are all represented with nM.
Provide following Ki value respectively for different reference compounds:
Ki value and 95% credible limit.
Ritanserin 2.0(1.3-3.1)nM
Sufrexal 94.8 (70.7-127.0) nM
Mianserin 2.7 (1.9-3.8) nM
Leoponex 23.2 (16.0-34.0) nM
U.S. plug Xiping 4.6 (4.0-6.0) nM
Desernil 6.3 (4.6-8.6) nM
Loxapine 33.0 (24.0-47.0) nM
mCPP 6.5(4.8-9.0)nM
DOI 6.2(4.9-8.0)nM
5HT 2CAgonist to [ 3 H] hormesis that produces of inositol monophosphate
In the improved Eagle substratum of the Dulbecco that adds 10% foetal calf serum and non-essential amino acid (DMEM), cultivate and use the expressing human serotonin 2C(h5HT 2C) CHO (the Chinese grey mouse ovary) cell of cDNA transfection of acceptor.In case reach converging state, to use the PBS/EDTA harvested cell at once, and be tiled in 24 orifice plates, initial density is every hole 2.5 * 10 5Cell.In each hole, add and contain 1 μ Ci/ml myo-[ 3H] inositol keep substratum.Behind the mark 48 hours, cell washs once with the DMEM that 0.5ml contains 25mM HEPES and 10mM LiCl, uses substratum preincubation then 30 minutes (if test, comprising antagonist during this period).After preincubation finishes, remove substratum, then with cell and test compound (if desired in the presence of antagonist) incubation 30 minutes together.By remove incubation solution and add the ice-cold 5%PCA of 0.5ml successively, then in incubation 15-30 minute termination reaction on ice.In each hole, add 200 μ l 0.5M Tes/1.5M K 2CO 3In and pH to 7, culture plate is placed 15-30 minute again in the hope of being settled out all salt on ice.The centrifugation liquid-solid phase.
To go up aqueous portion (350 μ l) and go up Dowex AG-1X8 post (formate form, 100-200 order).Then post is washed step by step with 10ml water and 10ml 25mM ammonium formiate, remove respectively flesh-[ 3H] inositol and deacylated tRNA phosphoinositide.At last 10ml 0.2M ammonium formate solution is added in the post, and will [ 3H] inositol monophosphate ([ 3H IP 1]) directly be eluted in the flicker bottle.Get this elutriant of 1ml and measure radioactivity by scintillation counting.
The agonist stimulation [ 3H] inositol monophosphate ([ 3H IP 1]) per-cent of the reaction that observes during with the maximum effective concentration of 5-HT (10 μ M) of level represents.Use three parameter logical functions to obtain EC 50/ IC 50Value.Antagonist is tested in the presence of 10 μ M 5-HT.
Provide time column data respectively for different reference compounds:
5-HT 15.1nM EC 50
mCPP 46.8nM EC 50
60% E MAX(with respect to 5-HT)
SB200646 286nM IC 50(10 μ M 5-HT are as agonist)
Compound is to the influence of rat feeding behavior
The male Sprague-Dawley rat of 8 body weight 150-180g is separately put in each cage, adapted to powdery 2 weeks of food.During this period and in the entire test, weigh every day food bucket and animal weight.After the adaptive phase, fasting animal 24 hours, injection of vehicle or 1 dosetest compound (consumption of test compound is 4 dosage altogether) then.To the 2nd and the 24th hour evaluation food intake behind the drug compound.Inject 1-2x compound to be assessed weekly, all accepted all dosetest compounds until all animals and adopted improved LatinSquare Scheme Choice dosage order.Other research can adopt the rat of being satiated with food to carry out when dark cycle begins.Intraperitoneal, subcutaneous injection or oral administration of compound.When finishing, research adopts of the effect of replicate measurement analysis of variance (ANOVA) evaluation test compound to ingestion of food.Collected data are 2 hours food intakes (g).Data have single factor (one-way) variance analysis of posthoct-test and organize otherness with evaluation.If suitable calculating ED50 value.The ED50 value is meant the dosage when the duration of test food intake produces 50% minimizing.
The result
The result of in vitro tests method
Compound 5HT 2CThe combination of affinity DOI/ agonist (Ki, nM) 5HT 2C ％Emax (5HT.100％) The hormesis of IP3 (EC50, nM)
Embodiment 1 4.33 107.50 12.00
Embodiment 2 4.18 112.50 7.92
Embodiment 3 66.40 89.00 289.50
Embodiment 4 1.00 99.00 7.32
Embodiment 5 7.00 100.00 33.80
Embodiment 6 8.00 77.00 23.20
Embodiment 7 8.00 100.00 97.30
Embodiment 8 516.00 85.00 2607.00
Embodiment 9 25.00 100.00 18.80
Embodiment 10 1036.00 ND * ND
Embodiment 11 19.79 73％@1μM ND
Embodiment 12 9.00 95.00 30.00
Embodiment 13 91.00 ND ND
*The ND=undetermined
The 5HT of rat 2CIngestion of food in vivo test result (fasting 24 hours)
Compound Route of administration ED50(mg/kg)
Embodiment 1 Intraperitoneal is oral 1.91 9.73
Embodiment 2 Intraperitoneal 1.99
Embodiment 3 Intraperitoneal 9.99
The result of these standard pharmacology test methods proves that The compounds of this invention is 5HT 2CReceptor stimulant, they can be used for treating central nervous system disease, as obsessional idea and behavior disorder, dysthymia disorders, anxiety, Phobias, schizophrenia, migraine, somnopathy (as sleep apnea), eating disorder (as hyperphagia), obesity, type ii diabetes and epilepsy.The compounds of this invention is used for the treatment of Mammals (preferred people's) disease.
The compounds of this invention can together be prepared administration with its original form administration or with pharmaceutically acceptable carrier, and wherein the ratio of activeconstituents and carrier is decided according to solvability and chemical property, selected route of administration and the conventional pharmacy practice of compound.Pharmaceutically acceptable carrier can be solid or liquid.
Solid carrier can comprise one or more materials, and they also can be used as seasonings, lubricant, solubilizing agent, suspension agent, weighting agent, glidant, compression aid, tackiness agent or tablet disintegrant; And can be used as encapsulating material.With regard to pulvis, carrier is and activeconstituents blended subdivided solids in small, broken bits.And in tablet, activeconstituents then mixes with suitable proportion with the carrier with required suppression performance, and is pressed into the tablet with desired shape and size.Pulvis and tablet all preferably contain the activeconstituents up to 99%.Suitable solid carrier comprises for example calcium phosphate, Magnesium Stearate, talcum, sucrose, lactose, dextrin, starch, gelatin, Mierocrystalline cellulose, methylcellulose gum, Xylo-Mucine, polyvinylpyrrolidine, low melt wax and ion exchange resin.
Liquid vehicle is used to prepare solution, suspension, emulsion, syrup, elixir and pressurized compositions.Active ingredient can be dissolved in or be suspended in the pharmaceutically acceptable liquid vehicle, for example water, organic solvent, the two mixture or pharmaceutically useful oil or fat.Liquid vehicle can contain other suitable medicinal additive, as solubilizing agent, emulsifying agent, buffer reagent, sanitas, sweeting agent, correctives, suspension agent, thickening material, tinting material, viscosity modifier, stablizer or Osmolyte regulator.The suitable example that is used for the liquid vehicle of oral and parenterai administration comprises that (part contains above-mentioned additive to water, as derivatived cellulose, the preferably carboxymethyl cellulose sodium solution), alcohol (comprises monohydroxy-alcohol and polyvalent alcohol, as ethylene glycol) and derivative, Yelkin TTS, and oil (as cochin oil and peanut oil).For parenterai administration, carrier can also be an oily ester, for example ethyl oleate and Isopropyl myristate.Sterile liquid carrier is applicable to the sterile liquid form composition that parenterai administration is used.The liquid vehicle that is used for pressurized compositions can be halohydrocarbon or other pharmaceutically useful propelling agent.
The liquid medicine composition of sterile solution or form of suspension can use by for example intramuscular, intraperitoneal or subcutaneous injection approach.Sterile solution also can intravenously administrable.The compounds of this invention can also be with liquid or solid composition forms oral administration.
The compounds of this invention can be with conventional suppository form rectum or vagina administration.For sucking or be blown into administration in the nose or in the segmental bronchus, The compounds of this invention can be mixed with can be with the aqueous solution or the partially aqueous solution of aerosol form use.The compounds of this invention can also contain the transdermal patch percutaneous dosing of active compound and carrier by use, and wherein said carrier is inertia to active compound, and is nontoxic and can be sent in the blood flow being fit to the transdermal agent skin that general absorbs to skin.Carrier can present various ways, for example creme and ointment, paste, gelifying agent and tightness system.Creme and ointment can be viscous liquid or oil-in-water or the semi-solid emulsion of water-in-oil-type.Also be suitable for by being dispersed in the paste that the Vaseline that contains activeconstituents or the absorbed pulvis in the wetting ability Vaseline form.Can use various tightness systems that activeconstituents is discharged in the blood flow, as be covered with and contain activeconstituents and contain or carrier-free medicine storage device or be covered with the semipermeable partition of the matrix that contains activeconstituents.Other tightness system is known in the document.
Dosage requires to become with the severity and the different of subject concrete individuality of used concrete composition, route of administration, existing symptom.According to the result who obtains in the standard pharmacology test method, the expectation per daily dose of active compound is 0.02 μ g/kg-750 μ g/kg.Usually, treatment begins with the low dose less than the compound optimal dose.Increase dosage subsequently gradually until the best effect that reaches under the condition of living in; In oral, the non-enteron aisle, nose or the definite dosage of administration in the segmental bronchus by the attending doctor according to the individual diagnosis situation of concrete treatment is decided.Preferred pharmaceutical compositions is a unit dosage form, for example tablet or capsule.With regard to this class dosage form, composition can be subdivided into the unitary dose that contains the appropriate amount activeconstituents; Unit dosage form can be the packaged composition form, for example Bao Zhuan pulvis, bottle, ampoule, prepackage syringe or contain the anther sac of liquid.Unit dosage form can be for example capsule or tablet itself, perhaps can be the packaged form of this based composition of proper amt.
The preparation of representative compounds of the present invention has hereinafter been described.
Embodiment 1
8,9-two chloro-2,3,4,4a-tetrahydrochysene-1H-pyrazine is [1,2-a] quinoxaline-5 (6H)-ketone also
A.4-benzyloxycarbonyl piperazine-2-carboxylic acid, copper chelate
In 10g piperazine-2-carboxylic acid's the 40mL aqueous solution, add 39mL 2.5N NaOH.And then adding 6.5g CuSO 45H 2The solution of O in 80mL water cools off formed dark blue solution to 0 ℃.Disposable adding 5g solid NaHCO in this cooling solution 3, then in 10 minutes, dropwise add the 40mL dioxane solution of 7.7mL chloroformic acid benzyl ester.Monitoring pH value adds NaHCO when needing 3To keep solution to be alkalescence.Remove ice bath subsequently, the stirring at room reaction mixture spends the night.Filter blue throw out, the gained solid washs with cold water (20mL), EtOH (20mL) and EtOAc (20mL), thereby obtains 10.4g sapphirine solid.
B.4-benzyloxycarbonyl-1-(4,5-two chloro-2-nitrophenyls) piperazine-2-carboxylic acid
The mixture to 80 ℃ that heating contains 10.4g 4-benzyloxycarbonyl piperazine-2-carboxylic acid's copper chelate and 7.9g disodium EDTA and 800mL water kept 3 hours.After being cooled to room temperature, enriched mixture is to doing.Then with this solid, 7.3g 1,2-two chloro-4-fluoro-5-oil of mirbane and the mixture heating up to 60 of 20mL triethylamine in the 100mL methyl-sulphoxide ℃ continue 12 hours.After being cooled to room temperature, handle the gained mixture to pH3 with HCl.Thin up gained mixture then, and then use ethyl acetate extraction.The extract that merges is with dried over mgso, and then concentrates, thereby obtains the 16g crude product.
C.3-benzyloxycarbonyl-8,9-two chloro-2,3,4,4a-tetrahydrochysene-1H-pyrazine is [1,2-a] quinoxaline-5 (6H)-ketone also
Heating 16g 4-benzyloxycarbonyl-1-(4, the 5-two chloro-2-nitrophenyls) solution to 60 of piperazine-2-carboxylic acid in 200mL acetate ℃ under stirring fast adds the 16g iron powder then in batches.60 ℃ of stirred reaction mixtures 3 hours are cooled to room temperature thereafter.Mixture is used 1N HCl dilution, and collect the throw out that is produced.Solids water and ether washing get the 11g product.Crude product 1H-NMR is consistent with described structure.(1g) the above-mentioned product that takes a morsel must be analyzed the pure sample product by flash column chromatography purifying (with 25% ethyl acetate-hexane-100% ethyl acetate gradient elution).
1H NMR(400MHz，d 6-DMSO)δ10.8(s，1H)；7.39-7.31(m，5H)；7.04(s，1H)；6.96(s，1H)；5.12(s，2H)；4.38(d，1H，J＝13.0Hz)；4.06(d，1H，J＝13.1Hz)；371(d，1H，J＝11.5Hz)；3.63(dd，1H，J＝11.2，3.7Hz)；2.99(brs，2H)；2.68(d1，1H，J＝12.1.3.6Hz).
IR(KBr)3400，3250，2800，1690，1500，1370，1240，1130，860，770，730cm -1.MS(ESI，m/e(％))406(100，[M+H] +)，408(65，[M+H] +).
Ultimate analysis C 19H 17Cl 2N 3O 3:
Calculated value: C, 56.17; H, 4.22; N, 10.34.
Measured value: C, 55.95; H, 3.88; N, 10.29.
D.8,9-two chloro-2,3,4,4a-tetrahydrochysene-1H-pyrazine is [1,2-a] quinoxaline-5 (6H)-ketone also
To 4.2g 3-benzyloxycarbonyl-8,9-two chloro-2,3,4,4a-tetrahydrochysene-1H-pyrazine are the interior solution of 20g KOH in 50mL water that adds of 50mL methanol solution of [1,2-a] quinoxaline-5 (6H)-ketone also.The formed reaction mixture of reflux 3 hours is cooled to room temperature then.Concentrated solution is fitted on rough solids constituent within water and the ethyl acetate.Separate each phase, water is further used ethyl acetate extraction.Concentrate the organic phase that merges.The gained solid crude product is dissolved in small amount of thermal ethanol again, and the ethanolic soln that adds HCl then is to pH3.Collect solids, 80 ℃ of dryings in vacuum chamber get the 2.4g product, are its hydrochloride form.
1H NMR(400MHz，d 6-DMSO)δ11.0(s，1H)；9.51(br s，2H)；7.12(s，1H)；7.02(s，1H)；4.02(dd，1H，J＝11.5，34Hz)；3.88(d，1H，J＝11.0Hz)；3.61(m，1H)；3.41(d，1H，J＝9.8Hz)；3.15-2.98(m，3H).
IR(KBr)3420，3200，3020，2970，2800，1695，1500，1460，1430，1395，1375，1290，1140cm -1.
MS(APCI，m/e(％))272(100，[M+H] +)，274(65，[M+H] +).
Ultimate analysis C 11H 12Cl 3N 3O:
Calculated value: C, 42.81; H, 3.92; N, 13.62.
Measured value: C, 42.66; H, 3.75; N, 13.33.
Embodiment 2
(R)-8,9-two chloro-2,3,4,4a-tetrahydrochysene-1H-pyrazine is [1,2-a] quinoxaline-5 (6H)-ketone also
Method A (separation method)
Enantiomorph with HPLC method separation embodiment 1 compound uses Chiracel AD post, with 100% ethanol elution, and flow velocity 0.5mL/min, thereby the compound of acquisition embodiment 2 and 3.First enantiomorph (embodiment 2) was located wash-out at 10.4 minutes and is obtained ([α] 25 D+ 27.8), second enantiomorph (embodiment 3) then located wash-out at 13.7 minutes and obtained ([α] 25 D-25.5).
Method B (chirality is synthetic)
A. (R)-4-benzyloxycarbonyl piperazine-2-carboxylic acid
To 5.0g (R)-piperazine-2-carboxylic acid 1The 30mL aqueous solution in add 5.0gCuSO 45H 2The 60mL aqueous solution of O.Cooling gained solution adds 10.0gNaHCO to 0-5 ℃ 3, then in 90 minutes, add 5.3g chloroformic acid benzyl ester/40mL acetone.Warm mixture stirred 24 hours to room temperature.Filter blue throw out, the solid cold water washing.With the gained solid at 1: 1 methyl alcohol of 100mL: pulp in the water mixed liquid adds 2.5N HCl and regulates pH＜4.Gained solution is added to uses 1: 16: 16 pyridine in advance: methyl alcohol: on the washed 400g AG of the water mixed liquid 50W-8X resin column.Product is with identical solvent liquid wash-out, and decompression (＜50 ℃) concentrates the product cut that merges, and gets semi-solid residue.With this material of 50mL ethanol pulp, get crystalline solid.Collect solids, get 6.0g (59.5%) white solid, mp 246-8 ℃ (decomposition) after the drying.
H 1NMR(400Hz，d 6-DMSO)δ7.37-7.30(m，5H)；5.08(s，2H)；4.19(d，1H，J＝12.1Hz)；3.89(d，1H，J＝13.8)；3.27(dd，1H，J＝11.0，4.0Hz)；3.08(m，3H)；2.82(dt，1H，J＝12.2，3.6Hz).
IR(KBr)3050，1700，1620，1430，1400，1235，1150cm -1.
MS(ESI(+)，m/e(％))265(100，[M+H] +).
Ultimate analysis C 13H 16N 2O 4:
Calculated value: C, 59.08; H, 6.10; N, 10.60.
Measured value: C, 59.04; H, 6.09; N, 10.40.
Chiral purity=99.99% (HPLC:Chiralcel WH, 4.6 * 25mm).
[α] D＝-38.77°(c＝1，H 2O).
B. (R)-4-benzyloxycarbonyl-1-(4,5-two chloro-2-nitrophenyls)-piperazine-2-carboxylic acid
To containing 5.0g (R)-4-benzyloxycarbonyl piperazine-2-carboxylic acid, 4.2g 1, slowly add the 5.3mL triethylamine in the slurries of 2-two chloro-fluoro-5-oil of mirbane, 85mL water and 170mL dimethyl formamide.Heated solution to 50 ℃ maintenance 5 hours, room temperature is placed and is spent the night then.Decompression (1-2mm,＜50 ℃) concentrates the darkorange solution that forms, and gets an orange oily residue.This oily matter is dissolved in the 400mL ethyl acetate, uses 100mL 1N HCl (2X), 150mL water (2X) and the water washing of 100mL salt successively.The organic layer dried over mgso is filtered and is concentrated, and gets 8.1g (94.2%) title compound, is the orange solids foam.
MS (ESI (+), m/e (%)) 454 (40, [M+H] +), 456 (35, [M+H] +), 471 (100, [M+NH 4] +) and 473 (100, [M+NH 4] +).
Chiral purity=99.99% (HPLC:Whelk-0,4.6 * 250mm).
C. (R)-benzyloxycarbonyl-8,9-two chloro-2,3,4,4a-tetrahydrochysene-1H-pyrazine is [1,2a]-quinoxaline-5 (6H)-ketone also
To 8.0g (R)-4-benzyloxycarbonyl-1-(4,5-two chloro-2-nitrophenyls)-and add the 6.0g iron powder in piperazine-2-carboxylic acid's the 200mL acetic acid solution. under fully stirring, 60 ℃ of heated mixt 2 hours, concentrating under reduced pressure (1-2mm then,＜40 ℃), get a grey black residue.With the 400mL ethyl acetate pulp of this material, and then filter.Repeat this process.The ethyl acetate filtrate that merges is used 150mL 1M HCl, 200mL water (2X), the water washing of 200mL salt, dried over mgso.Filter and concentrated solvent, get semi-solid material, and then, get 5.44g (76.1%) white solid title compound, mp 136-138 ℃ with ethyl acetate-hexane crystallization.
H 1 NMR(400Hz，d 6-DMSO)δ10.81(s，1H)；7.38-7.31(m，5H)；7.04(s，1H)；6.95(s，1H)；5.11(s，2H)；4.37(d，1H，J＝12.5Hz)；4.05(d，1H，J＝13.4Hz)；3.70(d，1H，J＝11.2Hz)；3.63(dd，1H，J＝3.6，10.8Hz)；3.00(bs，2H)；2.66(dt，1H，J＝3.6，12.2Hz).
IR(KBr)3240，1710，1675，1500，1300，1245，1130cm -1.
MS(APCI，m/e(％))406(100，[M+H] +)and 408(90，[M+H] +).
Ultimate analysis C 19H 17Cl 2N 3O 3:
Calculated value: C, 56.17; H, 4.27; N, 10.34.
Measured value: C, 55.97; H, 4.33; N, 9.90.
Chiral purity=99.99% (HPLC:Chiralcel AD, 4.6 * 250mm).
[α] D＝+23.89°(c＝1，CHCl 3).
1E.Felder，S.Maffei，S.Pietra.D.Pitrc，Helv.Chim.Acta.1960，888-896.
D. (R)-8,9-two chloro-2,3,4,4a-tetrahydrochysene-1H-pyrazine is [1,2a] quinoxaline-5 (6H)-ketone also
To 5.0g (R)-benzyloxycarbonyl-8,9-two chloro-2,3,4,4a-tetrahydrochysene-1H-pyrazine also dropwise add the acetic acid solution of 15mL30%Hbr in [1,2a]-quinoxaline-5 (the 6H)-solution of ketone in 100mL acetate.The described solution of stirring at room 5 hours, concentrating under reduced pressure (1mm,＜40 ℃) gets solid residue then.Residue is dissolved in the 300mL ethyl acetate again, washs successively with 100mL 1NNaOH, 200mL water (2X) and 300mL salt solution, and through dried over mgso.Filter the back concentrated solvent and get 3.59g (99%) free alkali crude product.Column chromatography (265g silica gel, 9: 1 ethyl acetate: 2M NH 3/ methyl alcohol) purifying gets 1.8g (54.9%) faint yellow solid product, 203 ℃ of mp (decomposition). get solid (1.6g) and be dissolved in 50mL methyl alcohol, handle with excessive 1M Hcl/ ether, 1.6g (88.2%) hydrochloride, be pale solid, mp＞290 ℃.
H 1 NMR(400Hz，d 6-DMSO)δ11.00(s，1H)；9.58(s，2H)；7.12(s，1H)；7.02(s，1H)；4.03(dd，1H，J＝11.6，3.6Hz)；3.87(d，1H，J＝10.7Hz)；3.61(dd，1H，J＝12.9，2.0Hz)；3.41(d，1H，J＝9.5Hz)；3.42-2.99(m，3H).
IR(KBr)2950，2700，1700，1590，1500cm -1.
MS (APCI, m/e (%)) 272 (100, [M+H] +) and 274 (65, [M+H] +).
Ultimate analysis C 11H 11Cl 2N 3OHCl:
Calculated value: C, 42.81; H, 3.92; N, 13.62.
Measured value: C, 42.45; H, 3.78; N, 13.43.
Chiral purity=99.99% (HPLC:Chiralcel AD, 4.6 * 250mm).
[α] D＝+27.72°(c＝1，DMSO).
Embodiment 3
(S)-8,9-two chloro-2,3,4,4a-tetrahydrochysene-1H-pyrazine is [1,2-a] quinoxaline-5 (6H)-ketone also
Method A (separation method)
The enantiomorph that separates embodiment 1 compound with the HPLC method: use Chiracel AD post to pass through, with 100% ethanol elution, flow velocity 0.5mL/ branch, thereby the compound of acquisition embodiment 2 and 3.First enantiomorph (embodiment 2) was located wash-out at 10.4 minutes and is obtained ([α] 25 D+ 27.8), second enantiomorph (embodiment 3) then located wash-out at 13.7 minutes and obtained ([α] 25 D-25.5).
Method B (chirality is synthetic)
A. (S)-4-benzyloxycarbonyl piperazine-2-carboxylic acid
To 4.0g (S)-piperazine-2-carboxylic acid 1The 70mL aqueous solution in add 4.2g CuCl 2By adding the pH to 10 that 2.5N NaOH regulates formed blue look solution, add 70mL acetone then.Cool off gained solution to 0-5 ℃, add 5.3g chloroformic acid benzyl ester/40mL acetone in 90 minutes.Monitor pH and keep above-mentioned pH value by adding 1N NaOH.Warm mixture is to room temperature, and stirring is spent the night.Filter blue throw out, the solid cold water washing.With the gained solid at 100mL1: 1 methyl alcohol: pulp in the water mixed liquid adds 2.5N HCl and regulates pH＜4.Then gained solution is added to and uses 1: 16: 16 pyridine in advance: methyl alcohol: on the washed 400g AG50W-8X of the water mixed liquid resin column.Product is with identical solvent liquid wash-out, and decompression (＜50 ℃) concentrates the product cut that merges, and gets semi-solid residue.Use this material of 50mL ethanol pulp again, get crystalline solid.Collect solids, get 4.0g (50%) white solid, 247 ℃ of mp (decomposition) after the drying.
H 1 NMR(400Hz，d 6-DMSO)δ7.37-7.30(m，5H)；5.08(s，1H)；4.19(d，1H，J＝12.1Hz)；3.89(d，1H，J＝13.8)；3.27(dd，1H，J＝11.0，40Hz)；3.08(m，3H)；2.82(dt，1H，J＝122，3.6Hz).
IR(KBr)3200，1700，1620，1430，1400，1235，1150cm -1.
MS(APCI，m/e(％))263(100，[M-H] -).
Ultimate analysis C 13H 16N 2O 4
Calculated value: C, 59.08; H, 6.10; N, 10.60.
Measured value: C, 58.90; H, 6.20; N, 10.58.
Chiral purity=99.88% (HPLC:Chiralcel WH, 4.6 * 25mm).
B. (S)-4-benzyloxycarbonyl-1-(4,5-two chloro-2-nitrophenyls)-piperazine-2-carboxylic acid
To containing 1.5g (S)-4-benzyloxycarbonyl piperazine-2-carboxylic acid, 1.25g 1, slowly add the 1.6mL triethylamine in the slurries of 2-two chloro-fluoro-5-oil of mirbane, 25mL water and 50mL dimethyl formamide.Heated solution to 50 ℃ maintenance 5 hours, room temperature is placed and is spent the night then.Decompression (1-2mm,＜50 ℃) concentrates the darkorange solution that forms, and gets an orange oily residue.This oily matter is dissolved in the 100mL ethyl acetate, uses 20mL 1N HCl (2X), 100mL water (2X) and the water washing of 100mL salt successively.The organic layer dried over mgso is filtered and is concentrated, and gets 2.5g (99%) orange solids foam.
MS (APCI, m/e (%)) 452 (100, [M-H] -) and 454 (75, [M-H] -).
Ultimate analysis C 19H 17Cl 2N 3O 60.5H 2O:
Calculated value: C, 49.26; H, 3.92; N, 9.07.
Measured value: C, 48.90; H, 3.80; N, 8.74.
Chiral purity=99.99% (HPLC:Whelk-0,4.6 * 250mm).
[α] D＝-64.2°(c＝1，MeOH).
C. (S)-benzyloxycarbonyl-8,9-two chloro-2,3,4,4a-tetrahydrochysene-1H-pyrazine is [1,2a]-quinoxaline-5 (6H)-ketone also
In 1.5g (S)-4-benzyloxycarbonyl-1-(4,5-two chloro-2-nitrophenyls)-piperazine-2-carboxylic acid's 40mL acetic acid solution, add the 1.2g iron powder.Under fully stirring, 60 ℃ of heated mixt 2 hours, concentrating under reduced pressure (1-2mm,＜40 ℃) then, a grey black residue.With the 100mL ethyl acetate pulp (2X) of this material.The ethyl acetate filtrate that merges is used 100mL1N HCl, 200mL water (2X), the water washing of 100mL salt, dried over mgso.Filter and concentrated solvent, get semi-solid material, and then, get 1.08g (80.6%) white solid title compound, mp 174-6 ℃ with the hexane crystallization.
H 1 NMR(400Hz，d 6-DMSO)δ10.93(s，1H)；7.41-7.31(m，5H)；7.04(s，1H)；6.95(s，1H)；5.11(s，1H)；4.37(d，1H，J＝12.5Hz)；4.05(d，1H，J＝13.4Hz)；3.70(d，1H，J＝11.2Hz)；3.63(dd，1H，J＝3.6，10.8Hz)；3.00(bs，2H)；2.66(dt，1H，J＝3.6，12.2Hz).
IR(KBr)3240，1710，1675，1500，1300，1245，1130cm -1.
MS (APCI, m/e (%)) 406 (70, [M+H] +) and 408 (45, [M+H] +).
Ultimate analysis C 19H 17Cl 2N 3O 3:
Calculated value: C, 56.17; H, 4.27; N, 10.34.
Measured value: C, 56.26; H, 4.18; N, 10.37.
Chiral purity=99.9% (HPLC:Chiralcel AD, 4.6 * 250mm).
D. (S)-8,9-two chloro-2,3,4,4a-tetrahydrochysene-1H-pyrazine is [1,2a] quinoxaline-5 (6H)-ketone also
To 0.155g (S)-benzyloxycarbonyl-8,9-two chloro-2,3,4,4a-tetrahydrochysene-1H-pyrazine also dropwise add the acetic acid solution of 1.5mL30%HBr in [1,2a]-quinoxaline-5 (the 6H)-solution of ketone in 8mL acetate.The described solution of stirring at room 2.5 hours, concentrating under reduced pressure (1mm,＜40 ℃) gets the 0.18g brown solid then.This solid is dissolved in the 50mL ethyl acetate, washs successively with 10mL 1N NaOH, 20mL water (2X) and 30mL salt solution, and through dried over mgso.Filter the back concentrated solvent and get 0.056g (53.8%) white solid title compound.
H 1 NMR(400Hz，d 6-DMSO)δ10.63(s.1H)；6.96(s，1H)；6.92(s，1H)；3.49(bd，1H，J＝10.0Hz)；3.41(dd，1H，J＝10.5，3.5Hz)；3.29(m，1H)；2.94(bd，1H，J＝9.9Hz)2.67-2.53(m，4H).
MS (APCI, m/e (%)) 272 (100, [M+H] +) and 274 (55, [M+H] +).
Chiral purity=99.99% (HPLC:Chiralcel AD, 4.6 * 250mm).
[α] D＝-25.5°(c＝1，DMSO).
Embodiment 4
8,9-two chloro-2,3,4,4a, 5,6-six hydrogen-1H-pyrazine is [1,2-a] quinoxaline dihydrochloride also
To 0.43g 8,9-two chloro-2,3,4,4a-tetrahydrochysene-1H-pyrazine also add 5mL 1M BH in [1,2-a] quinoxaline-5 (6H)-ketone ice-cold (0 ℃) solution in 20mL THF 3The THF solution of THF.Warm gradually gained mixture is to ambient temperature overnight.Add the methyl alcohol termination reaction, concentrate then.Crude product is dissolved in methyl alcohol, concentrates once more.Product gets 0.30g (73%) with quick silica gel chromatography (with 40% ethyl acetate-hexane wash-out).Gains are dissolved in ethanol, add HCl/ ethanolic soln to solution and be acid.Add diethyl ether then until there being throw out to generate.Collecting solids, get the 68mg product after the vacuum-drying, is dihydrochloride.
1H NMR(400MHz，d 6-DMSO)δ9.44-9.35(m，2H)；6.86(s，1H)；6.59(s，1H)；3.78(d，1H，J＝11.8Hz)；3.37-3.24(m，4H)；3.07-2.89(m，3H)；2.69(m，1H).IR(KBr)3380，3190，2970，2810，2750，2400，1600，1500，1450，1380，1270，1140，1110cm -1.
MS(APCI，m/e(％))258(100，[M+H] +)，260(65，[M+H] +).
Embodiment 5
(R)-8,9-two chloro-2,3,4,4a, 5,6-six hydrogen-1H-pyrazine is [1,2-a] quinoxaline disalt also Hydrochlorate
According to embodiment 4 described same procedure, reduction 1.8g (R)-8,9-two chloro-2,3,4,4a-tetrahydrochysene-1H-pyrazine is [1,2-a] quinoxaline-5 (6H)-ketone also, gets the 0.77g product.
With HPLC method enantiomer separation: use Chirapak AD post, with 100% methanol-eluted fractions, flow velocity is the 0.8mL/ branch.Obtain first enantiomorph at 7.2 office wash-outs, second enantiomorph then obtains at 8.9 office wash-outs.
Its ee of HPLC analysis revealed＞99% (7.2 minutes retention time).
1H NMR(400MHz，d 6-DMSO)δ9.44-9.35(m，2H)；6.86(s.1H)；6.59(s，1H)；3.78(d，1H，J＝11.8Hz)；3.37-3.24(m，4H)；3.07-2.89(m，3H)；2.69(m，1H).
IR(KBr)3380，3190，2970，2810，2750，2400，1600，1500，1450，1380，1270，1140，1110cm -1.
Ms(APCI，m/e(％))258(100，[M+H] +)，260(65，[M+H] +).
Embodiment 6
(S)-8,9-two chloro-2,3,4,4a, 5,6-six hydrogen-1H-pyrazine is [1,2-a] quinoxaline disalt also Hydrochlorate
According to embodiment 4 described same procedure, reduction 0.80g (R)-8,9-two chloro-2,3,4,4a-tetrahydrochysene-1H-pyrazine also [1,2-a] quinoxaline-5 (6H)-ketone get the 0.31g product.
With HPLC method enantiomer separation: use Chirapak AD post, with 100% methanol-eluted fractions, flow velocity is the 0.8mL/ branch.Go out first enantiomorph (embodiment 5) at 7.2 office wash-outs, second enantiomorph then obtains (embodiment 6) at 8.9 office wash-outs.
Its ee of HPLC analysis revealed＞99% (8.9 minutes retention time).
[α] 25 D+4.35
1H NMR(400MHz，d 6-DMSO)δ9.44-9.35(m，2H)；6.86(s，1H)；6.59(s.1H)；3.78(d.1H，J＝11.8Hz)；3.37-3.24(m，4H)；3.07-2.89(m，3H)；269(m，1H).
IR(KBr)3380，3190，2970，2810，2750，2400，1600，1500，1450，1380，1270，1140，1110cm -1.
MS(APCI，m/e(％))258(100，[M+H] +)，260(65，[M+H] +).
Ultimate analysis C 11H 14Cl 3N 3:
Calculated value: C, 44.85; H, 4.79; N, 14.26.
Measured value: C, 44.48; H, 4.84; N, 13.71.
Embodiment 7
9-chloro-8-trifluoromethyl-2.3.4.4a-tetrahydrochysene-1H-pyrazine also [1.2-a] quinoxaline- 5 (6H)-keto hydrochlorides
A.4-benzyloxycarbonyl-1-(5-chloro-2-nitrophenyl-4-trifluoromethyl) piperazine-2-carboxylic acid
60 ℃ are heated 0.98g 4-benzyloxycarbonyl piperazine-2-carboxylic acid, 1.0g 2,4-two chloro-5-nitro fluorobenzene and the mixture of 0.99mL diisopropylethylamine in the 35mL methyl-sulphoxide 72 hours.After being cooled to room temperature, handle the gained mixture to pH3 with HCl.Mixture thin up and use ethyl acetate extraction then.The extract that merges concentrates and obtains crude product with dried over mgso.
B.3-benzyloxycarbonyl-9-chloro-8-trifluoromethyl-2,3,4,4a-tetrahydrochysene-1H-pyrazine is [1,2-a] quinoxaline-5 (6H)-ketone also
50 ℃, the quick stirring down add the 0.64g iron powder in batches in 1.8g 4-benzyloxycarbonyl-1-(5-chloro-2-nitrophenyl-4-trifluoromethyl) piperazine-2-carboxylic acid's 35mL glacial acetic acid solution.50 ℃ of stirrings of gained mixture are spent the night.After being cooled to room temperature, reaction mixture is poured in the 20mL water, filtered.Solids washs with 1N HCl and ether, thereby gets the required product of 0.59g, is brown solid.
C.9-chloro-8-trifluoromethyl-2,3,4,4a-tetrahydrochysene-1H-pyrazine is [1,2-a] quinoxaline-5 (6H)-ketone also, hydrochloride
Reflux 0.58g 3-benzyloxycarbonyl-9-chloro-8-trifluoromethyl-2,3,4,4a-tetrahydrochysene-1H-pyrazine be the mixture of [1,2-a] quinoxaline-5 (6H)-ketone 2.3g potassium hydroxide in 12ml 50% hydration methyl alcohol 2 hours also.Half of extremely about its initial volume of concentrating under reduced pressure reaction mixture.Add the thick material of 100mL ethyl acetate and 100mL saturated aqueous solution of sodium bicarbonate dilution gained.Separate each phase, and with the water ethyl acetate extraction.The organic phase that merges is with dried over mgso, filtration, also concentrated.Crude product is dissolved in ethanol, and the ethanolic soln that adds HCl is to acid.
Filter the gained mixture, solids washs with ether.At the vacuum oven solids, get the required product of 0.21g (48%), i.e. its hydrochloride then.
1H NMR(400MHz，d 6-DMSO)δ11.0(s，1H)；9.47(br s，2H)；7.22(s，1H)；7.18(s，1H)；4.19(dd，1H，J＝11.6，3.2Hz)；4.01(d，1H，J＝11.8Hz)；3.62(d，1H，J＝11.7Hz)；3.41(d，1H，J＝10.1Hz)；3.14-3.01(m，3H).
IR(KBr)3460，3170，3020，2970，2800，1700，1620，1505，1450，1400，1370，1300，1230，1160，1110cm -1.
MS(APCI，m/e 306(100，[M+H] +)，308(33，[M+H] +).
Ultimate analysis C 12H 12ClF 3N 3O:
Calculated value: C, 42.13; H, 3.54; N, 12.28.
Measured value: C, 41.88; H, 3.71; N, 11.81.
Separation of Enantiomers is carried out with HPLC: use Chirapak AD post, wash with 85: 15 methyl alcohol: water (+0.1% diethylamine) wash-out, flow velocity is the 0.5mL/ branch.First enantiomorph (embodiment 9) obtains ([α] at 17.5 office wash-outs 25 D+ 43), second enantiomorph (embodiment 8) then located wash-out at 22.0 minutes and obtained ([α] 25 D-40).
Embodiment 8
(S)-9-chloro-8-trifluoromethyl-2,3,4,4a-tetrahydrochysene-1H-pyrazine also [1,2-a] quinoxaline- 5 (6H)-keto hydrochlorides
Separation of Enantiomers utilizes HPLC to carry out, and wherein uses Chirapak AD post, washes with 85: 15 methyl alcohol: water (+0.1% diethylamine) wash-out, flow velocity is the 0.5mL/ branch.First enantiomorph (embodiment 9) obtains ([α] at 17.5 office wash-outs 25 D+ 43), second enantiomorph (embodiment 8) then located wash-out at 22.0 minutes and obtained ([α] 25 D-40).
1H NMR(400MHz，d 6-DMSO)δ11.0(s，1H)；9.47(br s，2H)；7.22(s，1H)；7.18(s，1H)；4.19(dd，1H，J＝11.6，3.2Hz)；4.01(d，1H，J＝11.8Hz)；3.62(d，1H，J＝11.7Hz)；341(d，1H，J＝10.1Hz)；3.14-3.01(m，3H).
IR(KBr)3460，3170，3020，2970，2800，1700，1620，1505，1450，1400，1370，1300，1230，1160，1110cm -1.
MS(APCI，m/c 306(100，[M+H] +)，308(33，[M+H] +).
[α] 25 D-40
Ultimate analysis C 12H 12ClF 3N 3O:
Calculated value: C, 42.13; H, 3.54; N, 12.28.
Measured value: C, 41.59; H, 3.61; N, 12.07.
Embodiment 9
(R)-9-chloro-8-trifluoromethyl-2,3,4,4a-tetrahydrochysene-1H-pyrazine also [1,2-a] quinoxaline- 5 (6H)-keto hydrochlorides
Separation of Enantiomers is carried out with the HPLC method, wherein uses Chirapak AD post, washes with 85: 15 methyl alcohol: water (+0.1% diethylamine) wash-out, flow velocity is the 0.5mL/ branch.First enantiomorph (embodiment 9) obtains ([α] at 17.5 office wash-outs 25 D+ 43), second enantiomorph (embodiment 8) then located wash-out at 22.0 minutes and obtained ([α] 25 D-40).
HPLC analysis revealed ee is 9696 (retention time 17.5 minutes)
[α] 25 D+43
1H NMR(400MHz，d 6-DMSO)δ11.0(s，1H)；9.47(br s，2H)；7.22(s，1H)；7.18(s，1H)；4.19(dd，1H，J＝11.6，3.2Hz)；4.01(d，1H，J＝11.8Hz)；3.62(d，1H，J＝11.7Hz)；3.41(d，1H，J＝10.1Hz)；3.14-3.01(m，3H).
IR(KBr)3460，3170，3020，2970，2800，1700，1620，1505，1450，1400，1370，1300，1230，1160，1110cm -1.
MS(APCI，m/e 306(100，[M+H] +)，308(33，[M+H] +).
Ultimate analysis C 12H 12ClF 3N 3O:
Calculated value: C, 42.13; H, 3.54; N, 12.28.
Measured value: C, 41.83; H, 3.49; N, 12.01.
Embodiment 10
9,10-two chloro-2,3,4,4a-tetrahydrochysene-1H-pyrazine is [1,2-a] quinoxaline-5 (6H)-ketone also, salt Hydrochlorate
A.4-benzyloxycarbonyl-1-(5,6-two chloro-2-nitrophenyls) piperazine-2-carboxylic acid
According to the described same procedure of embodiment 7A, use 0.86g 2,3,4-trichlorine nitro-benzene and 1.0g 4-benzyloxycarbonyl piperazine-2-carboxylic acid, thus make the required product of 0.75g, be brown oil.
B.3-benzyloxycarbonyl-9,10-two chloro-2,3,4,4a-tetrahydrochysene-1H-pyrazine is [1,2-a] quinoxaline-5 (6H)-ketone also
According to the described same procedure of embodiment 7B, use 0.75g 4-benzyloxycarbonyl-1-(5,6-two chloro-2-nitrophenyls) piperazine-2-carboxylic acid and 0.28g iron powder, thereby make the required product of 0.34g (49%), be brown solid.
C.9,10-two chloro-2,3,4,4a-tetrahydrochysene-1H-pyrazine is [1,2-a]-quinoxaline-5 (6H)-ketone also, hydrochloride
According to embodiment 7 described same procedure, make the 18mg product by 0.34g 4-benzyloxycarbonyl-1-(5,6-two chloro-2-nitrophenyls) piperazine-2-carboxylic acid and 1.5g potassium hydroxide, separate obtaining with its hydrochloride form.
1H NMR(400MHz，d 6-DMSO)δ11.1(s，1H)；9.05(br s，2H)；7.45(d，1H，J＝8.8Hz)；6.97(d，1H，J＝8.8Hz)；4.06(d，1H，J＝3.7Hz)；3.84(d，1H，J＝13.2Hz)；3.29-3.12(m，4H)；2.77(m，1H).
IR(KBr)3440，3160，3020，2970，1695，1570，1470，1390，1280cm -1.
MS(EI，m/e(％)271(55，M +)，273(35，M +).
Ultimate analysis C 11H 2Cl 3N 3O:
Calculated value: C, 42.81; H, 3.92; N, 13.62.
Measured value: C, 42.40; H, 3.98; N, 12.82.
Embodiment 11
7,9-two chloro-2,3,4,4a-tetrahydrochysene-1H-pyrazine is [1,2-a] quinoxaline-5 (6H)-ketone also, salt Hydrochlorate
According to the method for embodiment 1, with 2,4-two chloro-6-fluoronitrobenzene [Clark, J.H.; Nightengale, D.J., J.Fluorine Chem. (1996) 78 (1), 91-93.] substitute 1,2-two chloro-4-fluoro-5-oil of mirbane synthesising title compounds.The fusing point of title compound is 308-311 ℃.
Embodiment 12
(R)-and 9-chloro-2,3,4a-tetrahydrochysene-1H-pyrazine is [1,2-a] quinoxaline-5 (6H)-ketone also
A. (R)-4-benzyloxycarbonyl-1-(5-chloro-2-nitrophenyl)-piperazine-2-carboxylic acid.
According to the described same procedure of embodiment 2 method 2B, use 0.95g (R)-4-benzyloxycarbonyl piperazine-2-carboxylic acid, thereby make 1.2g (85.7%) title compound, be orange solids, mp 145-155 ℃.
MS (ESI, m/e (%)) 420 (100, [M+H] +) and 422 (40, [M+H] +).
[α] D＝+196.0°(c＝1，MeOH).
B. (R)-benzyloxycarbonyl-9-chloro-2,3,4,4a-tetrahydrochysene-1H-pyrazine is [1,2a] quinoxaline-5 (6H)-ketone also
According to the described same procedure of embodiment method 2C, use 1.12g (R)-4-benzyloxycarbonyl-1-(5-chloro-2-nitrophenyl)-piperazine-2-carboxylic acid, thereby make 0.80g (80.8%) white solid title compound, mp 139-141 ℃.
H 1(NMR(400Hz，d 6-DMSO)δ10.73(s，1H)；7.38-7.30(m，5H)；6.87-6.78(m，3H)；5.11(s，2H)；4.38(d，1H，J＝13.0Hz)；4.06(d，1H，J＝13.0Hz)；3.70(d，1H，J＝11.4Hz)；3.57(dd，1H，J＝11.0，3.7Hz)；2.97(bs，2H)；2.65(dt，1H，J＝11.3，3.5Hz).
MS (APCI, m/e (%)) 372 (100, [M+H] +) and 374 (40, [M+H] +).
Ultimate analysis C 19H 18ClN 3O 3:
Calculated value: C, 61.38; H, 4.88; N, 11.30.
Measured value: C, 61.46; H, 4.76; N, 11.27.
C. (R)-9-chloro-2,3,4, and 4a-tetrahydrochysene-1H-pyrazine is [1,2-a]-quinoxaline-5 (6H)-ketone also
According to the described same procedure of embodiment 2 method 2D, use 0.50g (R)-benzyloxycarbonyl-9-chloro-2,3,4,4a-tetrahydrochysene-1H-pyrazine is [1,2a] quinoxaline-5 (6H)-ketone also, thereby make 0.27g (87.1%) white solid title compound, mp 146-149 ℃.
MS((+)ESI，m/e(％))238(85，[M+H] +).
Ultimate analysis C 11H 12ClN 3O:
Calculated value: C, 55.59; H, 5.09; N, 17.68.
Measured value: C, 55.59; H, 4.98; N, 17.40.
[α] D＝+28.9°(c＝1，MeOH).
Chiral purity=99.9% (Chiralpak AD, 4.6 * 250mm).
Its hydrochloride is the bright green solid with HCl and MeOH preparation, mp 270-280 ℃ (decomposition).
H 1 NMR(400Hz，d 6-DMSO)δ10.90(s，1H)；9.53(s，2H)；6.94(bs，1H)；6.90-6.84(m，2H)；3.96(dd，1H，J＝13.1，3.4Hz)；3.86(d，1H，J＝11.0Hz)；3.62(bd，1H，J＝12.0Hz)；3.42(d，1H，J＝10.6Hz)；3.10-2.97(m，3H).
MS (APCI, m/e (%)) 238 (100, [M+H] +) and 240 (40, [M+H] +).
Ultimate analysis C 11H 12ClN 3OHCl:
Calculated value: C, 48.19; H, 4.78; N, 15.33.
Measured value: C, 48.38; H, 5.06; N, 14.91.
Chiral purity=99.9% (Chiralpak AD, 4.6 * 250mm).
[α] D＝+7.0°(c＝1，MeOH).
Embodiment 13
8,9-two fluoro-2,3,4,4a-tetrahydrochysene-1H-pyrazine is [1,2-a] quinoxaline-5 (6H)-ketone also
A.4-benzyloxycarbonyl-1-(4,5-two fluoro-2-nitrophenyls)-piperazine-2-carboxylic acid
According to the described same procedure of embodiment 2 method 2B, use 1.5g racemize 4-benzyloxycarbonyl piperazine-2-carboxylic acid and 1,2,4-three fluoro-5-oil of mirbane, thus make 0.4g (16.7%) title compound, be the reddish orange residue.
MS(APCI，m/e(％))422(45，[M+H] +).
B.3-benzyloxycarbonyl-8,9-two fluoro-2,3,4,4a-tetrahydrochysene-1H-pyrazine is [1,2-a] quinoxaline-5 (6H)-ketone also
According to the described same procedure of embodiment 2 method 2C, use 0.29g 4-benzyloxycarbonyl-1-(4,5-two fluoro-2-nitrophenyls)-piperazine-2-carboxylic acid, thereby make 0.17g (66.0%) white solid title compound, mp 226-8 ℃.
H 1 NMR(400MHz，d 6-DMSO)δ10.70(s，1H)；7.39-7.30(m，5H)；6.98-6.92(m，1H)；6.82-677(m，1H)；5.11(s，2H)；4.38(d，1H，J＝13.0Hz)；4.(06(d，1H.J＝13.0Hz)；3.62(d，1H，J＝11.0Hz)；3.52(dd，1H，J＝11.0，4.0Hz)；2.98(bs，2H)；2.65(dt，1H，J＝11.0，4.0Hz).
MS(APCI，m/e(％))374(100，[M+H] +).
Ultimate analysis C 19H 17F 2N 3O 3:
Calculated value: C, 61.12; H, 4.59; N, 11.25.
Measured value: C, 60.79; H, 4.54; N, 10.95.
C.8,9-two fluoro-2,3,4,4a-tetrahydrochysene-1H-pyrazine is [1,2-a] quinoxaline-5 (6H)-ketone also
According to the described same procedure of embodiment 2 method 2D, use 0.28g 3-benzyloxycarbonyl-8,9-two fluoro-2,3,4,4a-tetrahydrochysene-1H-pyrazine is [1,2-a] quinoxaline-5 (6H)-ketone also, thereby make 0.14g (78.1%) white solid title compound.By its hydrochloride of excessive hydrogenchloride/ethanol preparation, thereby obtain white solid, mp＞280 ℃.
H 1 NMR(400MHz，d 6-DMSO)δ10.89(s，1H)；9.57(s，2H)；7.07-7.02(m，1H)；6.90-6.86(m，1H)；3.93(dd，1H，J＝11.0，3.0Hz)；3.77(d，1H，J＝11.0Hz)；3.62(m，1H)；3.62(m，1H)；3.42(d，1H，J＝10.0Hz)；3.10-2.95(m，3H).
MS((+)APCI，m/e(％))240(75，[M+H] +).
Ultimate analysis C 11H 11F 2N 3O:
Calculated value: C, 47.92; H, 4.39; N, 15.24.
Measured value: C, 47.96; H, 4.37; N, 14.86.

Claims (18)

1. the formula I compound or pharmaceutically acceptable salt thereof that has following structure:
Wherein
R is a hydrogen;
R ' is a hydrogen;
R 1, R 2, R 3And R 4Be the trifluoroalkyl of hydrogen, a halogen or 1-6 carbon atom independently of one another;
X is CR 5R 6Or carbonyl;
R 5And R 6Be hydrogen;
Condition is R 1, R 2, R 3And R 4In at least two can not be hydrogen, and when X is carbonyl, R 2And R 3It not all is halogen.
2. according to the compound or pharmaceutically acceptable salt thereof of claim 1, R wherein 1, R 2, R 3And R 4In be not that the substituting group of hydrogen is halogen or trifluoromethyl.
3. according to the compound or pharmaceutically acceptable salt thereof of claim 1, it has following structure:
Figure C998144160002C2
Wherein R, R 1, R 2, R 3And R 4Has the implication that provides in the claim 1.
4. the compound or pharmaceutically acceptable salt thereof of claim 1, described compound is:
A) 8,9-two chloro-2,3,4,4a, 5,6-six hydrogen-1H-pyrazine is [1,2-a] quinoxaline or its pharmacologically acceptable salt also;
B) (R)-8,9-two chloro-2,3,4,4a, 5,6-six hydrogen-1H-pyrazine is [1,2-a] quinoxaline or its pharmacologically acceptable salt also;
C) (S)-8,9-two chloro-2,3,4,4a, 5,6-six hydrogen-1H-pyrazine is [1,2-a] quinoxaline or its pharmacologically acceptable salt also;
D) 9-chloro-8-trifluoromethyl-2,3,4,4a-tetrahydrochysene-1H-pyrazine is [1,2-a] quinoxaline-5 (6H)-ketone or its pharmacologically acceptable salt also;
E) (S)-and 9-chloro-8-trifluoromethyl-2,3,4,4a-tetrahydrochysene-1H-pyrazine is [1,2-a] quinoxaline-5 (6H)-ketone or its pharmacologically acceptable salt also;
F) (R)-and 9-chloro-8-trifluoromethyl-2,3,4,4a-tetrahydrochysene-1H-pyrazine is [1,2-a] quinoxaline-5 (6H)-ketone or its pharmacologically acceptable salt also;
G) 9,10-two chloro-2,3,4,4a-tetrahydrochysene-1H-pyrazine is [1,2-a] quinoxaline-5 (6H)-ketone or its pharmacologically acceptable salt also;
H) 7,9-two chloro-2,3,4,4a-tetrahydrochysene-1H-pyrazine is [1,2-a] quinoxaline-5 (6H)-ketone or its pharmacologically acceptable salt also.
5. the compound or pharmaceutically acceptable salt thereof of claim 1, described compound is:
A) 8,9-two chloro-2,3,4,4a, 5,6-six hydrogen-1H-pyrazine is [1,2-a] quinoxaline dihydrochloride also;
B) (R)-8,9-two chloro-2,3,4,4a, 5,6-six hydrogen-1H-pyrazine is [1,2-a] quinoxaline dihydrochloride also;
C) (S)-8,9-two chloro-2,3,4,4a, 5,6-six hydrogen-1H-pyrazine is [1,2-a] quinoxaline dihydrochloride also;
D) 9-chloro-8-trifluoromethyl-2,3,4,4a-tetrahydrochysene-1H-pyrazine is [1,2-a] quinoxaline-5 (6H)-keto hydrochloride also;
E) (S)-and 9-chloro-8-trifluoromethyl-2,3,4,4a-tetrahydrochysene-1H-pyrazine is [1,2-a] quinoxaline-5 (6H)-keto hydrochloride also;
F) (R)-and 9-chloro-8-trifluoromethyl-2,3,4,4a-tetrahydrochysene-1H-pyrazine is [1,2-a] quinoxaline-5 (6H)-keto hydrochloride also;
G) 9,10-two chloro-2,3,4,4a-tetrahydrochysene-1H-pyrazine is [1,2-a] quinoxaline-5 (6H)-keto hydrochloride also; Or
H) 7,9-two chloro-2,3,4,4a-tetrahydrochysene-1H-pyrazine is [1,2-a] quinoxaline-5 (6H)-keto hydrochloride also.
6. the formula I compound or pharmaceutically acceptable salt thereof of following structure is used for the preparation treatment by 5-HT 2cThe purposes of the medicine of the disease of mediation:
Wherein
R is a hydrogen;
R ' is a hydrogen;
R 1, R 2, R 3And R 4Be the trifluoroalkyl of hydrogen, a halogen or 1-6 carbon atom independently of one another;
X is CR 5R 6Or carbonyl;
R 5And R 6Be hydrogen;
Condition is R 1, R 2, R 3And R 4In at least one can not be hydrogen.
7. the purposes of claim 6, wherein said disease is obsessional idea and behavior disorder, dysthymia disorders, anxiety, Phobias or schizophrenia.
8. the purposes of claim 6, wherein said disease is a migraine.
9. the purposes of claim 6, wherein said disease is a somnopathy.
10. the purposes of claim 6, wherein said disease is an eating disorder.
11. the purposes of claim 6, wherein said disease are obesity.
12. the purposes of claim 6, wherein said disease are type ii diabetes.
13. the purposes of claim 6, wherein said disease are epilepsy.
14. a pharmaceutical composition, it comprises formula I compound or pharmaceutically acceptable salt thereof and the pharmaceutically acceptable carrier with following structure:
Figure C998144160004C2
Wherein
R is a hydrogen;
R ' is a hydrogen;
R 1, R 2, R 3And R 4Be the trifluoroalkyl of hydrogen, halogen or 1-6 carbon atom independently of one another;
X is CR 5R 6Or carbonyl;
R 5And R 6Be hydrogen;
Condition is R 1, R 2, R 3And R 4In at least two can not be hydrogen, when X is carbonyl, R 2And R 3It not all is halogen.
15. preparation has the method for the formula I compound or pharmaceutically acceptable salt thereof of following structure:
Wherein
R is a hydrogen;
R ' is a hydrogen;
R 1, R 2, R 3And R 4Be the trifluoroalkyl of hydrogen, a halogen or 1-6 carbon atom independently of one another;
X is CR 5R 6Or carbonyl;
R 5And R 6Be hydrogen;
Condition is R 1, R 2, R 3And R 4In at least two can not be hydrogen, and when X is carbonyl, R 2And R 3Not all be halogen,
This method is included in alkali and exists down, makes following formula: compound:
Wherein Cbz represents benzyloxycarbonyl,
React being higher than under the temperature of room temperature with following formula: compound:
R wherein 1, R 2, R 3And R 4Chlorine, fluorine or bromine are represented in as above definition, and Y, generate following formula: compound:
And then pass through at high temperature with NO 2Group is reduced to amino and heating ring changes into following formula: compound:
Figure C998144160006C2
Remove the Cbz group then and obtain the formula I compound of R ' wherein, and then randomly handle and generate wherein that X is CR with reductive agent for H 5R 6Formula I compound.
16. the method for preparation formula IA or IB compound or pharmaceutically acceptable salt thereof:
Wherein R is a hydrogen,
R 1, R 2, R 3And R 4Be the trifluoroalkyl of hydrogen, a halogen or 1-6 carbon atom independently of one another;
Condition is R 1, R 2, R 3And R 4In at least two can not be hydrogen,
This method comprises with relevant (S) or (R)-piperazine carboxylic acid is a raw material, and change into the protected compound of corresponding following formula N:
Wherein Cbz represents benzyloxycarbonyl,
Then with the neighbour who replaces-nitro fluorobenzene reaction, generate corresponding following formula (S) or (R) compound:
And then, then remove the Cbz blocking group, thereby generate corresponding IA or IB compound, and randomly form its pharmacologically acceptable salt by at high temperature nitro group being reduced to amino and cyclisation is carried out in heating.
17. a compound is selected from:
A) (R)-8,9-two chloro-2,3,4,4a-tetrahydrochysene-1H-pyrazine is [1,2-a] quinoxaline-5 (6H)-ketone or its pharmacologically acceptable salt also; Or
B) 8,9-two fluoro-2,3,4,4a-tetrahydrochysene-1H-pyrazine is [1,2-a] quinoxaline-5 (6H)-ketone or its pharmacologically acceptable salt also.
18. claim 17 compound is selected from:
A) (R)-8,9-two chloro-2,3,4,4a-tetrahydrochysene-1H-pyrazine is [1,2-a] quinoxaline-5 (6H)-keto hydrochloride also; Or
B) 8,9-two fluoro-2,3,4,4a-tetrahydrochysene-1H-pyrazine is [1,2-a] quinoxaline-5 (6H)-keto hydrochloride also.
CNB998144169A 1998-12-17 1999-12-16 2,3,4,4-tetrahydro-1H-pyrazino (1,2-a) quinoxalin-5(6H) one deivatives being 5HT2C agonists Expired - Fee Related CN1240701C (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US21347198A 1998-12-17 1998-12-17
US09/213,471 1998-12-17

Publications (2)

Publication Number Publication Date
CN1330652A CN1330652A (en) 2002-01-09
CN1240701C true CN1240701C (en) 2006-02-08

Family

ID=22795247

Family Applications (1)

Application Number Title Priority Date Filing Date
CNB998144169A Expired - Fee Related CN1240701C (en) 1998-12-17 1999-12-16 2,3,4,4-tetrahydro-1H-pyrazino (1,2-a) quinoxalin-5(6H) one deivatives being 5HT2C agonists

Country Status (18)

Country Link
EP (1) EP1140940A1 (en)
JP (1) JP2002532504A (en)
KR (1) KR20010108025A (en)
CN (1) CN1240701C (en)
AR (1) AR022687A1 (en)
AU (1) AU3123400A (en)
BR (1) BR9916326A (en)
CA (1) CA2351385A1 (en)
CZ (1) CZ20012193A3 (en)
EA (1) EA200100671A1 (en)
HU (1) HUP0104773A3 (en)
IL (1) IL143323A0 (en)
NO (1) NO20013001L (en)
NZ (1) NZ512765A (en)
PL (1) PL348815A1 (en)
SK (1) SK8192001A3 (en)
WO (1) WO2000035922A1 (en)
ZA (1) ZA200104598B (en)

Families Citing this family (52)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6960579B1 (en) 1998-05-19 2005-11-01 Alcon Manufacturing, Ltd. Serotonergic 5HT7 receptor compounds for treating ocular and CNS disorders
US6956036B1 (en) 2000-03-17 2005-10-18 Alcon, Inc. 6-hydroxy-indazole derivatives for treating glaucoma
US7012090B1 (en) 2000-03-17 2006-03-14 Alcon, Inc. Pyranoindoles for treating glaucoma
US6806285B1 (en) 2000-03-17 2004-10-19 Alcon, Inc. 5-Hydroxyl indole derivatives for treating glaucoma
DK1325008T3 (en) * 2000-07-31 2006-02-13 Hoffmann La Roche piperazine
AR031196A1 (en) 2000-11-03 2003-09-10 Wyeth Corp PROCEDURE FOR THE PREPARATION OF CYCLOPENTA (B) (1,4) -DIAZEPINO (6,7,1-HI) INDOLES AND DERIVATIVES
US6777407B2 (en) 2000-11-03 2004-08-17 Wyeth Cyclopenta[b][1,4]diazepino[6,7,1-hi]indoles and derivatives
AR031195A1 (en) 2000-11-03 2003-09-10 Wyeth Corp PROCEDURE FOR THE PREPARATION OF DERIVATIVES OF 1,2,3,4,8,9,10,10A-OCTAHIDRO-7BH-CICLOPENTA (B) (1,4) DIAZEPINO (6,7,1) DIAZEPINO (6,7, 1-HI) INDOL
US7141563B2 (en) 2000-11-03 2006-11-28 Wyeth Process for the preparation of 1, 2, 3, 4, 8, 9, 10, 10a-octahydro-7bH-cyclopenta[b] [1, 4]diazepino[6, 7, 1-hi] indole derivatives
US6858604B2 (en) 2000-11-03 2005-02-22 Wyeth Cyclohepta[b][1,4]diazepino[6,7,1-hi]indoles and derivatives
ES2230382T3 (en) * 2000-11-03 2005-05-01 Wyeth CYCLOPENTAL (B) (1,4) DIAZPINO (6,7,1-HI) INDOLES AS 5HT2C ANTAGONISTS.
US6759405B2 (en) 2000-11-03 2004-07-06 Wyeth Cycloocta[b][1,4]diazepino[6,7,1-hi]indoles and derivatives
SE0004245D0 (en) 2000-11-20 2000-11-20 Pharmacia Ab Novel compounds and their use
EP1337518B1 (en) 2000-11-20 2009-06-17 Biovitrum AB (publ) Piperazinylpyrazines compounds as antagonists of serotonin 5-ht2 receptor
GB0030710D0 (en) 2000-12-15 2001-01-31 Hoffmann La Roche Piperazine derivatives
ES2260335T3 (en) * 2000-12-20 2006-11-01 Bristol-Myers Squibb Pharma Company DERIVATIVES OF PIRAZINOQUINOXALINA AS AGONISTS AND ANTAGONISTS OF SEROTONINE.
ES2291374T3 (en) * 2000-12-27 2008-03-01 F. Hoffmann-La Roche Ag DERIVATIVES OF INDOL AND ITS EMPLOYMENT AS RECEIVING LINKS OF 5-HT2B AND 5-HT2C.
JPWO2002074746A1 (en) * 2001-03-16 2004-07-08 山之内製薬株式会社 Benzoazepine derivatives
JP2004534781A (en) 2001-06-01 2004-11-18 アルコン，インコーポレイテッド Novel arylaminopropane analogs and their use in treating glaucoma
JP2004532887A (en) 2001-06-01 2004-10-28 アルコン，インコーポレイテッド Novel fused indazoles and their use in treating indole and glaucoma
RU2273641C2 (en) 2001-06-01 2006-04-10 Алькон, Инк. Pyranoindazoles, pharmaceutical composition based on thereof and their using in glaucoma treatment
TW593302B (en) 2001-12-20 2004-06-21 Alcon Inc Novel benzodifuranimidazoline and benzofuranimidazoline derivatives and their use for the treatment of glaucoma
TW200307682A (en) 2002-04-25 2003-12-16 Wyeth Corp 1,2,3,4,7,8-Hexahydro-6H-[1,4]diazepino[6,7,1-ij]quinoline derivatives as antipsychotic and antiobesity agents
TW200307540A (en) 2002-04-25 2003-12-16 Wyeth Corp [1, 4]Diazocino[7, 8, 1-hi] indole derivatives as antipsychotic and antiobesity agents
TWI312781B (en) 2002-04-25 2009-08-01 [1,4]diazepino[6,7,1-ij]quinoline derivatives as antipsychotic and antiobesity agents
CA2485537A1 (en) 2002-06-19 2003-12-31 Biovitrum Ab Novel compounds, their use and preparation
JP2006511556A (en) 2002-12-13 2006-04-06 アルコン，インコーポレイテッド Novel benzopyran analogs and their use for the treatment of glaucoma
PL377426A1 (en) 2002-12-19 2006-02-06 Bristol-Myers Squibb Company Substituted tricyclic gamma-carbolines as serotonin receptor agonists and antagonists
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
CN1809545A (en) * 2003-06-20 2006-07-26 艾尼纳制药公司 N-phenyl-piperazine derivatives and methods of prophylaxis or treatment of 5HT2c
GB0314967D0 (en) 2003-06-26 2003-07-30 Hoffmann La Roche Piperazine derivatives
WO2005053688A1 (en) 2003-11-26 2005-06-16 Alcon, Inc. Substituted furo[2,3-g] indazoles for the treatment of glaucoma
US7338972B1 (en) 2003-12-15 2008-03-04 Alcon, Inc. Substituted 1-alkylamino-1H-indazoles for the treatment of glaucoma
US7129257B1 (en) 2003-12-15 2006-10-31 Alcon, Inc. Pyrazolo[3,4- e]benzoxazoles for the treatment of glaucoma
TW200520760A (en) 2003-12-15 2005-07-01 Alcon Inc Substituted [1,4] oxazino [2,3-g] indazoles for the treatment of glaucoma
US8685924B2 (en) 2004-08-25 2014-04-01 Takeda Pharmaceutical Company Limited Preventives/remedies for stress urinary incontinence and method of screening the same
KR100875041B1 (en) * 2004-09-30 2008-12-19 에프. 호프만-라 로슈 아게 Benzoxazine and quinoxaline derivatives and uses
GT200500317A (en) 2004-11-05 2006-10-27 PROCESS TO PREPARE QUINOLINE COMPOUNDS AND PRODUCTS OBTAINED FROM THEM
US7425572B2 (en) 2004-12-08 2008-09-16 Alcon, Inc. Use of dioxindoindazoles and dioxoloindazoles for treating glaucoma
AR054849A1 (en) 2005-07-26 2007-07-18 Wyeth Corp DIAZEPINOQUINOLINAS, SYNTHESIS OF THE SAME, AND INTERMEDIARIES TO OBTAIN THEM
WO2007132841A1 (en) 2006-05-16 2007-11-22 Takeda Pharmaceutical Company Limited Fused heterocyclic compound and use thereof
WO2009063992A1 (en) 2007-11-15 2009-05-22 Takeda Pharmaceutical Company Limited Condensed pyridine derivative and use thereof
KR101062376B1 (en) 2008-04-10 2011-09-06 한국화학연구원 Novel indole carboxylic acid bispyridyl carboxamide derivatives, preparation method thereof and composition containing the same as an active ingredient
KR101110199B1 (en) 2009-05-18 2012-03-14 한국화학연구원 Piperazine-quinoline derivatives, pharmaceutically acceptable salts thereof, preparation method thereof and pharmaceutical composition for prevention or treatment of central nervous system diseases containing the same as an active ingredient
WO2011044134A1 (en) 2009-10-05 2011-04-14 Albany Molecular Research, Inc. Epiminocycloalkyl(b)indole derivatives as serotonin sub-type 6 (5-ht6) modulators and uses thereof
EP2510949A4 (en) 2009-12-11 2013-11-13 Astellas Pharma Inc Therapeutic agent for fibromyalgia
AU2011212930B2 (en) 2010-02-04 2016-02-11 The Board Of Trustees Of The University Of Illinois Highly selective 5-HT(2C) receptor agonists having antagonist activity at the 5-HT(2B) receptor
WO2012030953A1 (en) 2010-09-01 2012-03-08 Arena Pharmaceuticals, Inc. 5-ht2c receptor agonists in the treatment of disorders ameliorated by reduction of norepinephrine level
US9067949B2 (en) 2011-01-19 2015-06-30 Albany Molecular Research, Inc. Benzofuro[3,2-c] pyridines and related analogs as serotonin sub-type 6 (5-HT6) modulators for the treatment of obesity, metabolic syndrome, cognition and schizophrenia
WO2015066344A1 (en) 2013-11-01 2015-05-07 Arena Pharmaceuticals, Inc. 5-ht2c receptor agonists and compositions and methods of use
WO2016123164A1 (en) 2015-01-29 2016-08-04 The Board Of Trustees Of The University Of Illinois Cyclopropylmethanamines as selective 5-ht(2c) receptor agonists
US20210052600A1 (en) 2017-12-27 2021-02-25 Takeda Pharmaceutical Company Limited Therapeutic agents for stress urinary incontinence and incotinence of feces

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4032639A (en) * 1976-03-22 1977-06-28 American Home Products Corporation 2,3,4,4A-Tetrahydro-1H-pyrazino[1,2-a,]quinoxalin-5(6H)-ones and derivatives thereof for relieving hypertension
US4089958A (en) * 1976-12-20 1978-05-16 American Home Products Corporation 2,3,4,4A-Tetrahydro-1H-pyrazino[1,2]quinoxalin-5(6)-ones and derivatives thereof
US4203987A (en) * 1979-05-21 1980-05-20 American Home Products Corporation 3-[Pyridinylalkyl and piperidinylalkyl]-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-ones
GB8917333D0 (en) * 1989-07-28 1989-09-13 Merck Sharp & Dohme Therapeutic agents
EP0539209A1 (en) * 1991-10-24 1993-04-28 The Upjohn Company Benzo-isoquinoline derivatives and analogs and their use in therapeutics
AU4547796A (en) * 1995-02-03 1996-08-21 Sankyo Company Limited Hexahydropyrazinoquinoline derivatives

Also Published As

Publication number Publication date
HUP0104773A2 (en) 2002-04-29
IL143323A0 (en) 2002-04-21
KR20010108025A (en) 2001-12-07
ZA200104598B (en) 2002-09-05
CN1330652A (en) 2002-01-09
AR022687A1 (en) 2002-09-04
NO20013001D0 (en) 2001-06-15
NO20013001L (en) 2001-06-15
CA2351385A1 (en) 2000-06-22
JP2002532504A (en) 2002-10-02
PL348815A1 (en) 2002-06-17
HUP0104773A3 (en) 2004-10-28
EP1140940A1 (en) 2001-10-10
WO2000035922A1 (en) 2000-06-22
EA200100671A1 (en) 2001-12-24
SK8192001A3 (en) 2001-12-03
AU3123400A (en) 2000-07-03
BR9916326A (en) 2001-10-02
NZ512765A (en) 2003-10-31
CZ20012193A3 (en) 2001-12-12

Similar Documents

Publication Publication Date Title
CN1240701C (en) 2,3,4,4-tetrahydro-1H-pyrazino (1,2-a) quinoxalin-5(6H) one deivatives being 5HT2C agonists
CN1036920C (en) Heterocyclic carbonic acid derivatives
CN1084748C (en) Aminomethyl-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]-indol-8-ones and derivatives
CN100351236C (en) 1-heterocyclylalkyl-3-sulfonyl-indole or -indazole derivatives as 5-hydroxytryptamine-6 ligands
CN1036652C (en) Quaternary basic amides, method of preparing them and pharmaceutical compositions in which they are present
CN1234738A (en) Olanzapine dihydrate D
CN1202107A (en) Selective 'beta'3 adrenergic agonists
CN1551881A (en) Novel dihydropteridones, processes for their preparation and use as pharmaceutical compositions
CN1133043A (en) Bicyclic aromatic compounds as therapeutic agents
CN1291095A (en) Chemical compounds
CN1270585A (en) Substituted 1,2,3, 4-tetrahydronaphthalene derivatives
CN86106428A (en) Anti-tumor method and compound thereof
CN1867552A (en) Probe for disease with amyloid deposit, amyloid-staining agent, remedy and preventive for disease with amyloid deposit and diagnostic probe and staining agent for neurofibril change
CN1093859C (en) Novel indole-2,3-done-3-oxime derivatives
CN1620290A (en) Indolylalkylamine derivatives as 5-hydroxytryptamine-6 ligands
CN1069309C (en) N-(3-aminopropyl)-N-phenyl-5,6,7,8-tetrahydronaphtalene-2-carboxamide derivative, preparation and application of same
CN1468224A (en) Derivatives of quinoline as alpha-2 antagonists
CN1278727A (en) A combination of a monomine oxidase inhibitor and a hs-ht antagonist or partial agonist
CN1111986A (en) Isoxazole derivatives for the treatment of irritable bowels syndrome
CN1798744A (en) 3-fluoro-piperidines as NMDA/NR2B antagonists.
CN1041943A (en) Pyrrolo-[3,2-e] pyrazolo [1,5-a] pyrimidine derivatives and contain the medicine of above-mentioned composition
CN1234801A (en) 3-methylamide derivatives of 5H-pyrrolo [2,1,-C] [1,4]-benzodiazepines
CN1030586A (en) (8 β)-1-alkyl-6-(replacement) ergoline cycloalkyl amides
CN1487831A (en) Tetrahydro-(benzo or thieno)-aza-pyrazine and triazine derivatives used as mGluR1 antagonists
CN1234024A (en) 4-aminoethoxy indolone derivatives

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
C17 Cessation of patent right
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20060208

Termination date: 20100118