CN1362949A - 1,5-benzodiazepine derivatives as cck-A receptor agonists - Google Patents
1,5-benzodiazepine derivatives as cck-A receptor agonists Download PDFInfo
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- CN1362949A CN1362949A CN00809932A CN00809932A CN1362949A CN 1362949 A CN1362949 A CN 1362949A CN 00809932 A CN00809932 A CN 00809932A CN 00809932 A CN00809932 A CN 00809932A CN 1362949 A CN1362949 A CN 1362949A
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Abstract
An enantiomerically enriched compound of Formula (I) is disclosed, processes for its preparation, pharmaceutical compositions containing it and the use therefore, for the treatment of CCK-A mediated diseases or conditions, such as obesity.
Description
The present invention relates to newly 1,5-benzodiazepine derivative, its preparation method, contain their medicinal compositions and the application in medical science thereof.More particularly, the present invention relates to the CCK-A acceptor is shown the compound of agonist activity.
Cholecystokinin (CCK) is the peptide of finding in gi tract and central nervous system.See A.J.Prange etc., Ann.Reports Med.Chem.17,31,33 (1982), J.A.Williams, Biomed Res, 3,107 (1982) and V.Mutt, Gastrointestinal Hormones, G.B.J.Green, Ed., Raven Press, N.Y., 169.Found that CCK especially can be used as the full sense of physiological (satiety) hormone that participates in appetite stimulator, see Della-Ferra etc., Science.206,471 (1979), Satio etc., Nature, 289,599 (1981), G.P.Smith, Eating and ItsDisorders, A.J.Stunkard and E.Stellar, Eds., Raven Press, New York, 67 (1984), as the conditioning agent of gall-bladder contraction and pancreas enzyme secretion, stomach emptying inhibitor and as neurotransmitter, see A.J.Prange, the same, J.A.Williams, Biomed Res, 3,107 (1982); J.E.Morley, Life Sci, 30,479, (1982).Gastrin relates to the peptide of hydrochloric acid in gastric juice and pepsinia in the stomach, sees L.Sandvik etc., American J.Physiology, 260, G925 (1991), C.W.Lin etc., American J.Physiology, 262, G1113 (1992).CCK and gastrin are at the terminal tetrapeptide of their C-: have same structure among the Trp-Met-Asp-Phe.
Identify two kinds of hypotypes of cck receptor, be called CCK-A and CCK-B, in periphery and central nervous system, all found two kinds of hypotypes.Report CCK-B acceptor and gastrin acceptor are similar recently, see Pisegna, J.R., de Weerth, A, Huppi, K.Wank, S.A., Biochem.Biophys.Res.Commun.189,296-303 (1992).The CCK-A acceptor mainly is arranged in peripheral tissues, comprises that pancreas, gall-bladder, ileum, pyloric sphincter and fan walk afferent neurofibers; Find that the CCK-A acceptor seldom is present in the brain, sees T.H.Moran etc., Brain Res., 362,175-179 (1986), D.R.Hill etc., Brain Res., 4545,101 (1988), D.R.Hill etc., Neurosci Lett., 89,133 (1988), R.W.Barret etc., Mol.Pharmacol., 36,285, (1989), D.R.Hill etc., J.Neurosci., 10,1070 (1990), V.Dauge etc., Pharmacol Biochem Behac, 33,637 (1989), and the CCK-B acceptor mainly is found in the brain, see V.J.Lotti and R.S.L Chang, Proc.Natl.Acad.Sci.U.S.A., 83,4923 (1986), J.N.Crawley etc., Trends Pharm.Sci., 88,232 (1991).
The CCK agonist activity is relevant with the picked-up of inhibition animal foodstuff, therefore can reduce body weight, sees Della-Fera etc., and is the same, K.E.Asin etc., Intl.Conference on Obesity, summary pp.40 (1990).Think that CCK walks fibre-effects in periphery by the fan, do not directly act on brain and produce full sense, see Smith G.P. and Cushin, B.J., Neuroscience Abstr., 4,180 (1978), Smith G.P., Jerome, C., Cushin, B.J., Eterno, R. and Simansky, K.J., Science, 212,687-689 (1981).
U.S. Patent No. 5,646,140 (Sugg etc.) disclose some 3-amino-1,5-benzodiazepine compound, these compounds present agonist activity to mammiferous CCK-A acceptor, therefore can make it regulate hormone gastrin and cholecystokinin (CCK).See the compound of embodiment 7 for details.Some this compounds also presents antagonistic activity to the CCK-B acceptor.
In brief, on the one hand, the invention provides formula (I) compound or its pharmacy acceptable salt or the solvate that are rich in enantiomorph.
Formula (I) compound is 3-{3-[1-(sec.-propyl-phenyl-carbamyl ylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydrochysene-1H-benzo [b] [1,4] diaza -3-yl]-urea groups } phenylformic acid.This compound has chiral carbon on benzodiazepine ring.The applicant finds preferably have the enantiomorph of forward opticity under the condition of following explanation.According to Cahn Ingold Prelog rule, this enantiomorph that below is referred to as (+) enantiomorph has (S) configuration.The applicant finds that this ratios of the isomers racemic mixture has better character, therefore is more suitable for the disease and the illness of treatment of obesity and other CCK-A mediation than racemic mixture.The present invention's used " being rich in enantiomorph " is meant the raceme mixture with respect to each isomer with equivalent, and (+) enantiomorph is more than (-) enantiomorph.The present invention's used " The compounds of this invention " or " compound of enantiomorph is rich in the present invention " and contain these or the expression of similar phrase all comprise its pharmacy acceptable salt or solvate." (+) enantiomorph " refers to the optics rotation of enantiomorph, rather than refers to its salt and solvate thereof.Preferred salt and solvate are the salt and the solvate of this formula (I) compound (+) enantiomorph, and no matter the rotation of the optics of this salt or solvate.
Preferably (+) enantiomorph accounts for this and is rich at least 90% of enantiomeric compounds total amount.More preferably (+) enantiomorph accounts at least 96% of this total amount of compound.Most preferably (+) enantiomorph accounts at least 99% of this total amount of compound.
(+) of the present invention enantiomorph presents the CCK-A agonist activity, and can be identified as be a kind of agonist of cholecystokinin completely, its can with the CCK-A receptors bind, in animal test model (paradigms), can stimulate gall-bladder to shrink comprehensively and reduce diet.For example, (+) of the present invention mapping physical efficiency is indirectly by reducing body weight or directly induce the delay stomach emptying by CCK-A, and is used for treatment of obesity and associated conditions, as hypertension, stasis gallbladder disease and diabetes.In addition, (+) disclosed by the invention enantiomorph is Mammals (especially people) modulation of appetite, treatment is fat and keep loss of weight, and the new approach that brings out the satiety sense, appetite stimulator and change food absorption are provided is provided.
Therefore, the present invention provides the disease of the CCK-A mediation for the treatment of Mammals (comprising the people) or the method for symptom on the other hand, and it comprises (+) the of the present invention enantiomorph that gives the patient treatment significant quantity.
On the other hand, the invention provides the present invention is rich in the compound of enantiomorph or its pharmacy acceptable salt or solvate and is used for the treatment of purposes in the medicine of the disease of CCK-A mediation or illness in preparation.
Those skilled in the art are clear: treatment comprises the definite disease or the prevention and the treatment of symptom referred in this.In addition, need be clear that: the amount that is used for the treatment of needed preferred enantiomorph of the present invention will be decided according to the character of treatment disease and patient's age and the state of an illness, finally by doctor in charge or animal doctor's decision.But the general used dosage of adult treatment is generally 0.02-5 every day, and the scope of 000mg is as 1-1500mg.Ideal dosage is generally with single dose or with the divided dose of appropriate intervals administration, as every day two, three, four or sub-doses form repeatedly existing more favourable.
Though in treatment, can give the compound that enantiomorph is rich in the present invention, preferably give this active ingredient with the medicinal compositions form with the chemical feedstocks form.Therefore, the present invention also provides medicinal compositions, and it comprises that the present invention is rich in the compound of enantiomorph and one or more pharmaceutically acceptable carrier and/or vehicle, and other optional component that treats and/or prevents.Therefore said carrier and/or vehicle must be " acceptable ", and its meaning is and other component compatibility of preparation and harmless to its acceptor.
Preparation of the present invention comprises that those make in oral, the oral cavity specially, the preparation of non-enteron aisle, implantation, part or rectal administration, but the preferred oral administration.For oral administration, composition can be mixed with tablet or lozenge form according to common method.Oral tablet or capsule can comprise vehicle commonly used, as tackiness agent (as syrup, gum arabic, gelatin, sorbyl alcohol, tragacanth gum, starch mucus or polyvinylpyrrolidone), weighting agent (as lactose, sugar, Microcrystalline Cellulose, W-Gum, calcium phosphate or sorbyl alcohol), lubricant (as Magnesium Stearate, stearic acid, talcum powder, polyoxyethylene glycol or silica gel), disintegrating agent (as yam starch or sodium starch glycollate) or wetting agent, as sodium lauryl sulphate.Can with tablet coating, comprise enteric coating according to method well known in the art.
In addition, the preferred enantiomorph of the present invention can be made oral liquid, as water-based or oiliness suspensoid, solution, emulsion, syrup or elixir.In addition, the preparation that contains these preferred enantiomorphs can be the drying products form, and water or other suitable solvent are made solution again before use for they.These liquid preparations can contain additive commonly used, as suspension agent, and for example sorbitol syrups, methylcellulose gum, glucose/sucrose syrup, gelatin, Natvosol, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible oil; Emulsifying agent, for example Yelkin TTS, sorbitol monooleate or gum arabic; Water-insoluble solvent (it can comprise edible oil) is as Prunus amygdalus oil, rectifying peanut oil, grease class, polyoxyethylene glycol or ethanol; And sanitas, as the methyl or the propyl diester of P-hydroxybenzoic acid or Sorbic Acid.Also these preparations can be mixed with suppository, as, suppository base commonly used contained, for example the suppository of theobroma oil or other glyceryl ester.
In addition, the present composition can be mixed with formulation by the injection or the parenterai administration of continuous infusion.Injection can adopt in the suspensoid of water-based or oiliness solvent, solution or emulsion form, and can contain formulation excipients, as suspension agent, stablizer and/or dispersion agent.In addition, this active ingredient can adopt and face the powder type that is mixed with liquid with the suitable solvent of preceding usefulness (as aseptic, apirogen water) again.
Also the present composition can be mixed with and store agent (depot).These prolonged action preparations can be by implanting (as subcutaneous or intramuscular) or giving by intramuscular injection.Therefore, preferred enantiomorph of the present invention and suitable polymer or the derivative (as the salt of indissoluble) of hydrophobic materials (for example, at the emulsion that can accept in the oil), ion exchange resin or poorly water-soluble can be mixed with preparation.
The present composition can contain the active ingredient of 0.1-99%, and general tablet and capsule contain the active ingredient of 30-95%, and liquid dosage form contains the active ingredient of 3-50%.
(+) of the present invention enantiomorph can at first be made racemic mixture by the method for 7 explanations of embodiment in the United States Patent (USP) 5,646,140, then by the preparation of chiral chromatography enantiomer separation.
Perhaps, described (+) enantiomorph can pass through suitable enantiomorph, i.e. (the S)-enantiomorph of formula (II) amine:
With the isocyanic ester (wherein R is a carboxyl-protecting group, as the tertiary butyl) of formula (III), formula (IV) imidazoles (wherein R is a carboxyl-protecting group, as the tertiary butyl) or the optional formula V carbonic acid phenyl ester that replaces (wherein R is a carboxyl-protecting group, as the tertiary butyl, R
1Be hydrogen or conventional phenyl substituent, as NO
2) reaction, remove carboxyl-protecting group R then and prepare.
This reaction in the presence of appropriate solvent such as ether (as tetrahydrofuran (THF)) or halohydrocarbon (as methylene dichloride) or nitrile (as acetonitrile), is carried out in 0-80 ℃ of temperature range expediently.
The enantiomorph of required amine (II) can use the form of its salt, as the R-camsilate, in this embodiment, can exist down at alkali (as tertiary amine, as triethylamine), carries out this reaction.
The hydrolysis of carboxyl-protecting group can adopt ordinary method to carry out.(Protecting?groups?inOrganic?Synthesis?T.Greene，Ed，Wiley?Interscience，New?York，p168，1981)。Therefore, for example when R is the tertiary butyl, can adopt definite method, by with suitable acid, this protecting group is removed in example hydrochloric acid, trifluoroacetic acid or formic acid hydrolysis.For example in solvent (as 1, the 4-dioxane) with hydrochloric acid reaction, perhaps heating is down removed protecting group with the formic acid reaction in solvent such as acetone or aqueous acetone solution.
(the S)-enantiomorph of required formula (II) amine:
Can split corresponding racemic amine preparation by chirality HPLC chromatography, perhaps bring out asymmetric fractionation preparation by the R camsilate.
Racemic amines (II) can be by the method preparation of explanation in the intermediate 11 of United States Patent (USP) 5,646,140.
In addition, the reduction when racemic amines (II) can pass through oxime (VI) and hydrogenolysis preparation, wherein R
2It is the optional benzyl that replaces.
This reaction in ethanol, Virahol or industrial methylated spirit or tetrahydrofuran (THF), in the presence of the hydrogen or the ammonium formiate aqueous solution, is adopted suitable palladium catalyst expediently at solvent such as alkanol, carries out as palladium on carbon (on the 5%Pd/ gac).This is reflected at heating down, and is as 40-80 ℃, more favourable as carrying out under 60 ℃.
The suitable R that uses in the reaction
2Example comprise the benzyl of benzyl or replacement, as to methoxy-benzyl or diphenyl-methyl.
Oxime (VI) can pass through adjacent phenylenediamine derivative (VII):
With the activity derivatives reaction preparation of diacid (VIII), wherein R
2It is the optional benzyl that replaces.
The reactive derivative of diacid (VIII) generally is two corresponding carboxylic acid halides, and as muriate, it can be by this diacid (VIII) and oxalyl halogen (as oxalyl chloride) prepared in reaction.This reaction in aprotic solvent such as ester (as ethyl acetate), toluene, methylene dichloride, dimethoxy ether and composition thereof, is carried out in the presence of dimethyl formamide easily.
This diacid (VIII) in the presence of alkali (as pyridine), makes ketone group dialkyl malonate (as the ketone group diethyl malonate) and corresponding azanol R easily by in solvent such as alkanol (as ethanol or industrial methylated spirit)
2ONH
2React, adopt aqueous sodium hydroxide solution that corresponding oximido dialkyl malonate hydrolysis is prepared then.
On the other hand, the invention provides method with (the S)-enantiomorph of formula (I) compound of above-mentioned racemic amines (II) preparation essentially no (R) enantiomorph, wherein this racemic amines (II) is prepared by oxime (VI) as mentioned above, more particularly, wherein oxime (VI) prepares by compound (VII) with (VIII).
Formula (III) isocyanic ester can be buied, perhaps can be in appropriate solvent such as methylene dichloride, and the amine (VI) by correspondence is in phosgene or triphosgene prepared in reaction.Can be under the temperature of 0-80 ℃ of scope (easily at room temperature), in appropriate solvent (methylene dichloride, ether, tetrahydrofuran (THF)), by handling corresponding amine (VI) with carbonyl dimidazoles, but preparation formula (IV) imidazoles.Can under 0-50 ℃ temperature, in appropriate solvent (methylene dichloride), in the presence of alkali (pyridine, triethylamine),, can prepare the carboxylamine phenylester of the optional formula V that replaces by making corresponding amine (VI) and the optional chloroformic acid phenylester reaction that replaces.Formula (VI) amine is compound known, can be by those used similar method preparations of preparation known compound.
Adopt the following example explanation the present invention, the present invention is not done any qualification.
In an embodiment, abbreviation EtOAc=ethyl acetate; MeOH=methyl alcohol; DMF=N, dinethylformamide; The IPA=Virahol; The IMS=industrial methylated spirit.Intermediate 1 (+)-2-(3-amino-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro benzo-[b] [1,4] diaza -1-yl)-N-sec.-propyl-phenyl acetanilide,Phenacetylaniline camsilate
In tetrahydrofuran (THF) (35ml) and toluene (65ml), will (+/-)-2-(3-amino-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro benzo-[b] [1,4] diaza -1-yl)-and N-sec.-propyl-phenyl acetanilide,Phenacetylaniline (10g) and R-camphorsulfonic acid (4.98g) stirring, obtain solution.This solution is heated to 70 ℃, forms suspension.Toluene (5ml) solution that adds entry (0.4ml), 2-pyridylaldehyde (0.24g) in turn.This mixed solution was heated 3 hours down at 70 ℃, be cooled to 25 ℃ with 5 hours then, stirred 16 hours down at 25 ℃.With suspension be cooled to 0-5 ℃ following 1.5 hours.Solid collected by filtration (10ml) is washed with toluene/tetrahydrofuran (THF) (2: 1).Obtain title compound 50 ℃ of following vacuum-dryings, be white solid (12.6g).Chromatographic analysis: eluent: 30% Virahol, 70% heptane+0.05% diethylamine; Post: 25cm * 4.6mm internal diameter, Chiralpak AD; Flow velocity: 1ml/ minute; Temperature: 40 ℃; Detect: UV 230nm; Volume injected: 10 μ L; Sample solution: 0.1mg/ml; Sample is dissolved in 30% Virahol, 70% heptane.Injection immediately after the sample solution preparation.Retention time: (+) enantiomorph, 8.2 minutes.Unwanted (-) enantiomorph (12.7 minutes) is lower than detectability.Intermediate 23-nitrobenzoic acid tertiary butyl ester
Potassium tert.-butoxide (3.82g) is joined in anhydrous tetrahydro furan (70ml) solution of 3-nitrobenzoyl chloride (5.00g), under nitrogen, stirred 2 hours.The vacuum concentration reaction mixture distributes between methylene dichloride and water then.Separate each phase, water layer is returned with ethyl acetate again carry then.Merge organic layer,, filter, then vacuum concentration through anhydrous magnesium sulfate drying.Crude product is through quick level silica gel purification, with the normal hexane liquid gradient elution of 0-5% ethyl acetate.Merge the part that contains product, vacuum concentration, dry under the high vacuum then, obtain title compound, be oily matter (3.82g).
1H?NMR(300MHz，CDCl
3)。δ＝1.63(s，9H)；7.62(t，J＝7.9Hz，1H)；8.29-8.41(m，2H)；8.78-8.80(m，1H)。MS(Cl)：[M+H]
+＝224。Intermediate 33-amino-phenylformic acid tertiary butyl ester
(10wt%, 0.30g), stir about is 3 hours under hydrogen with dehydrated alcohol (50ml) solution of 3-nitrobenzoic acid tertiary butyl ester (3.77g) and palladium on carbon.By diatomite layer filtering reaction mixed solution, vacuum concentration obtains oily matter then, and crystallization when dry obtains title compound under high vacuum, is brown solid (3.28g).
1H?NMR(300MHz，CDCl
3)δ＝1.58(s，9H)；6.79-6.87(m，1H)；7.19(t，J＝8.5Hz，1H)；7.24-7.34(m，1H)；7.38(d，J＝8.0Hz，1H)。MS(Cl)：[M+H]
+＝194。Intermediate 43-isocyano--phenylformic acid tertiary butyl ester
Under 0-5 ℃, triphosgene (13.428g) is joined in anhydrous tetrahydro furan (600ml) solution of 3-benzaminic acid tertiary butyl ester (26.50g) and triethylamine (38.23ml).Under 0-5 ℃, reaction mixture was stirred 2 hours, vacuum concentration obtains white solid then.Crude product is stirred slurry in hexane (500ml), filter, vacuum concentrated filtrate obtains title compound, is oily matter (21.54g, 71.6%).This crude product isocyanic ester need not be further purified and can directly use.
1H?NMR(300MHz，CDCl
3)δ＝1.59(s，9H)；7.23(bd，J＝7.8Hz，1H)；7.36(t，J＝7.8Hz，1H)；7.69(bs，1H)；7.81(d，J＝7.8Hz，1H)。Intermediate 5 (+)-3-{3-[1-(sec.-propyl-phenyl-carbamyl ylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydrochysene-1H-benzo [b] [1,4] diaza -3-yl]-urea groups } phenylformic acid tertiary butyl ester method A
With intermediate (1; 66.30g) slowly join in anhydrous tetrahydro furan (750ml) solution of 3-isocyano--phenylformic acid tertiary butyl ester (21.54g).In reaction mixture, drip triethylamine (13.70ml).Under the room temperature, the reaction mixture stirring that obtains is spent the night.Reaction mixture is poured in the water (3000ml), obtained white solid.Solid collected by filtration, water (3 * 500ml) washings.The vacuum filtration drying obtains title compound, is white solid (65.01g).This crude product title compound need not be further purified and can directly use.Chromatography feature: eluent: 30% Virahol, 70% heptane+0.05% diethylamine; Post: 25cm * 4.6mm internal diameter, ChiralpakAD; Flow velocity: 1ml/ minute; Temperature: 40 ℃; Detect: UV 230nm; Volume injected: 10 μ L; Sample solution: the 0.1mg/ml sample in 30% Virahol, 70% heptane.Injection immediately after the sample solution preparation.Retention time: (+) enantiomorph, 15.6 minutes.Unwanted (-) enantiomorph (13.3 minutes) is lower than detectability.Method B
In 20 ℃ of carbonyl dimidazoles (13.2g) suspensions in methylene dichloride (55ml) that stir down, with methylene dichloride (40ml) solution that dripped 3-benzaminic acid tertiary butyl ester (15.8g) in 30 minutes.Under 20 ℃, with the solution stirring that obtains 1 hour.With methylene dichloride (130ml) solution that adds intermediate 1 (50g) in 5 fens this solution of clockwise.Add entry (200ml) quencher reaction solution, stirred 10 minutes.Separate each phase, organic phase is washed with water.Under atmospheric pressure concentrate organic phase, the 100ml methylene dichloride is removed in distillation.Add t-butyl methyl ether (700ml), under 20 ℃, the mixture stirring is spent the night.Solid collected by filtration, with t-butyl methyl ether (100ml) washing, 45 ℃ of following vacuum-dryings, obtain title compound, for white solid (42g, 63mmol).Intermediate 62-[(benzyloxy) imino-] diethyl malonate
Under 20 ℃, ketone group diethyl malonate (60g) is joined in the suspension of O-benzyl hydroxylamine (57.8g) in the IMS that contains pyridine (30ml) (500ml) of stirring.Under 75 ℃, with reaction solution heating 4 hours.With reaction solution cooling, removal of solvent under reduced pressure.Residue is distributed between EtOAc (500ml) and water (300ml), separate organic layer, water (250ml) washing is through MgSO
4Dry.Evaporating solvent obtains title compound 95.3g, for colorless oil (yield 99%, the residual EtOAc of about 3%w/w), need not be further purified and can directly use.
1H?NMR(300MHz，CDCl
3)7.4(m，5H)，5.35(s，2H)，4.35(m，4H)，1.3(m，6H)。Intermediate 72-[(benzyloxy) imino-] propanedioic acid
With 20 minutes, in the MeOH of intermediate 6 (40g) (80ml) solution, add 2M NaOH (200ml).Under the room temperature, reaction solution was stirred 2 hours.MeOH is removed in decompression, drips dense HCl (about 30ml), and residual solution is acidified to pH2.Cool off during this time to keep temperature to be lower than 35 ℃.Form dense white soup compound, water (50ml) dilution is flowed helping.Solid collected by filtration with cold water (25ml) washing, 55 ℃ of following vacuum-dryings, obtains title compound (17g), is white solid, finds to contain the residual inorganic salt of the 10%w/w that has an appointment in the product.Yield corrected is about 45%, need not be further purified and can directly use.
1H?NMR(300MHz，D
2O)7.4(m，5H)，5.2(s，2H)。Intermediate 82-[3-[(benzyloxy) imino-]-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydrochysene-1H-1,5-benzodiazepine yl)-N-sec.-propyl-phenyl acetanilide,Phenacetylaniline
Oxalyl chloride (38.3g) is dripped (about 1 hour), and (0.5ml is in the suspension among EtOAc 5mol%) (200ml) containing DMF to the intermediate 7 that stirs (40g proofreaies and correct salts contg to 31.4g).Under 25 ℃, mixed solution was stirred 0.5 hour, filter by the Dicalite layer then, with EtOAc (40ml) washing, obtain clarifying yellow solution.Under 25 ℃, this solution is joined in N-sec.-propyl-N-phenyl-2-(2-phenyl amino the phenyl amino)-pulpous state liquid of ethanamide (50g) in EtOAc (120ml) of stirring.Mixture is warmed to 60 ℃, forms deep purple solution.After 1 hour, remove EtOAc (200ml) by the normal atmosphere distillation.Add IPA (120ml) and water (40ml), more more solvent (80ml) is further removed in the mixed solution distillation and added IPA (40ml) and water (40ml), the solvent (80ml) of other amount is removed in redistillation.With 1.5 hours, reaction mixture is cooled to 25 ℃, solid collected by filtration.With this solid with IPA (2 * 120ml), water (1 * 120ml) and use again at last IPA (1 * 40ml) washing, 55 ℃ of following vacuum-dryings, obtain title compound then, be orange red powder (56.6g).
1H NMR (300MHz, CDCl
3) 2: 1 isomer mixture 7.6-6.95 of this oxime (m, 18H), 6.9 (t, 1H), 5.3 (m, 2H), 4.95 (m, H), 4.65 (d, 0.33H), 4.4 (d, 0.67H), 4.1 (d, 0.67H), 4.0 (d, 0.33H), 0.95 (m, 6H).Intermediate 9 (±)-2-(3-amino-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro benzo-[b] [1,4] diaza -1-yl)-N-sec.-propyl-phenyl acetanilide,Phenacetylaniline
In the suspension of the IMS (30ml) of intermediate 8 (3g) that stirs and ammonium formiate (2.08g) and water (3ml), adding 5%Pd/C (50%w/w water) (0.25g).Under nitrogen, with mixture 60 ℃ of following heated overnight.Filter this hot reaction mixture to remove catalyzer by Dicalite.Catalyzer with hot IMS (60ml) washing, is filtered.Concentrating under reduced pressure filtrate obtains title compound, is white solid (2.34g).
The chromatography of embodiment 1 enantiomorph splits (+) and (-)-3-{3-[1-(sec.-propyl-phenyl-carbamyl ylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydrochysene-1H-benzo [b] [1,4] diaza -3-yl]-urea groups } phenylformic acid
Press United States Patent (USP) 5, the method of embodiment 7 explanations prepares racemic 3-{3-[1-(sec.-propyl-phenyl-carbamyl ylmethyl)-2 in 646,140,4-dioxo-5-phenyl-2,3,4,5-tetrahydrochysene-1H-benzo [b] [1,4] diaza -3-yl]-urea groups } phenylformic acid, under the following conditions, split: 250 * 4.0 μ m (internal diameter) posts, 5 μ m Diacel Chiracel OD-R by chirality HPLC; Eluent is 80: 20: 0.1: 1,80 part of acetonitrile, 20 parts of water, 0.1 part of triethylamine and 1 part of acetate; It is 230nm that UV detects wavelength; Temperature is that room temperature flow rate is 1ml/min; Volume injected is 20 μ L.Under these conditions, (+) enantiomorph retention time is 6.50 minutes, and (-) isomer retention time is 3.89 minutes.
Embodiment 2 (+)-3-{3-[1-(sec.-propyl-phenyl-carbamyl ylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydrochysene-1H-benzo [b] [1,4] diaza -3-yl]-urea groups } phenylformic acid method A
Under the room temperature; with (+)-3-{3-[1-(sec.-propyl-phenyl-carbamyl ylmethyl)-2; 4-dioxo-5-phenyl-2; 3; 4; 5-tetrahydrochysene-1H-benzo [b] [1,4] diaza -3-yl]-urea groups } phenylformic acid tertiary butyl ester (intermediate 5:65.01g) stirred 6 hours in the dioxane (280ml) of 4N hydrochloric acid.With the reaction mixture vacuum concentration, the solid/oily matter that obtains is ground in water, obtain white solid.Filter and collect white solid, water (2 * 500ml) washings.Crude product is dissolved in the hot acetone (250ml), adds entry (275ml) until the solution becomes muddiness.Add acetone (40ml) again, this solution is heated to obtains settled solution.This solution is placed cooling.Filter and collect the white solid that obtains, and water (3 * 100ml) washings, dry in vacuum (20-25Hg) chamber under 40-50 ℃, obtain title compound, be white solid (40.496g).Through chirality chromatography (seeing that chromatogram splits scheme) purity analysis.Specific rotation (0.712g is in the 100mL acetone soln) [α]
D=+84.3.
1H?NMR(300MHz，DMSO)δ＝0.95(d，J＝7.5Hz，3H)；0.97(d，J＝7.2Hz，3H)；4.18(d，J＝16.7Hz，1H)；4.48(d，J＝16.7Hz，1H)；4.78(m，1H)；5.02(d，J＝7.8Hz，1H)；6.91(d，J＝7.8Hz，1H)；6.95(bd，J＝8.1Hz，1H)；7.22-7.57(m，19H)；8.00(s，1H)；9.34(s，1H)；12.78(s，1H)。MS(ES)：[M+1]＝606.1；[M+Na]＝628.1；[M-1]＝604.1。Method B
Under the room temperature, intermediate 5 (5g) is joined in the mixed solution of acetone (15ml) and formic acid (25ml), the suspension that obtains is heated to 50 ℃ and stirred 5 hours.In this solution, drip entry (30ml), and keep the content temperature more than 50 ℃.Under 55 ℃, the soup compound that obtains was stirred 1 hour, be cooled to room temperature, stirring is spent the night.This soup compound is filtered water (3 * 25ml) washings.Residue is joined among the IMS (50ml), this soup compound is heated to 45 ℃, stirring is spent the night.Soup compound is cooled to room temperature, filters, under 55 ℃,, obtain title compound, be white solid (3.40g) this wet cake vacuum drying.
The required product of this reaction of chiral chromatography analysis revealed contains unwanted (-)-enantiomorph of 0.7%.Medicine embodiment oral liquid
Active ingredient 0.5-800mg
Poly(oxyethylene glycol) 400 NF is in right amount to 50ml
Active ingredient is suspended in the poly(oxyethylene glycol) 400, and ultrasonic dissolution is made oral liquid then.Oral administration mixed suspension
Active ingredient 0.5-80mg
Polysorbate80 NF (tween 80) 0.02ml
The aseptically filling water is in right amount to 20ml
Active ingredient is joined in 0.1% (v/v) the tween 80 solution (20ml), and oral administration mixed suspension is made in the ultrasonic or jolting with mixed solution then.Tablet a.
Active ingredient 6mg
Lactose hydrous USP 136.2mg
Sodium starch glycollate USP/NF 6mg
Stearic acid USP/NF 1.5mg
Colloid silica USP/NF 0.3mg
Compressed tablet weight 150mg
Active ingredient, lactose and sodium starch glycollate are sieved by 590 tm screen, suitably mixing in the mixing tank.Add stearic acid (sieving) and hand over body silicon-dioxide, mix with activated mixture by 250 tm screen.Use suitable stamping machine, in flakes with this mixture compacting.b.
Active ingredient 6mg
Microcrystalline Cellulose USP/NF 136.5mg
Cross-linked polyvinylpyrrolidone USP/NF 6mg
Magnesium Stearate USP/NF 1.5mg
Compressed tablet weight 150mg
Active ingredient, Microcrystalline Cellulose and cross-linked polyvinylpyrrolidone are sieved by 590 tm screen, suitably mixing in the mixing tank.Screening Magnesium Stearate (by 250 tm screen) mixes with activated mixture.With suitable tablet stamping machine, that the mixture compacting that obtains is in blocks.Capsule a.
Active ingredient 6mg
Microcrystalline Cellulose USP/NF 128.25mg
Sodium starch glycollate USP/NF 15mg
Magnesium Stearate USP 0.75mg
Filling weight 150mg
Active ingredient, Microcrystalline Cellulose and sodium starch glycollate are sieved by 590 tm screen, be mixed together, lubricate with the Magnesium Stearate that sieves by 250 tm screen then.Mixture is filled in the capsule of proper volume.b.
Active ingredient 6mg
Lactose monohydrate USP 130.5mg
Polyvinylpyrrolidone USP 6mg
Cross-linked polyvinylpyrrolidone NF 6mg
Magnesium Stearate 1.5mg
Filling weight 150mg
Active ingredient and lactose are mixed together, granulate with polyvinylpyrrolidonesolution solution.The material drying that this is wetting is ground.Magnesium Stearate and cross-linked polyvinylpyrrolidone are screened by 250 tm screen, mix with this particle.The mixture that obtains is filled in the hard gelatin capsule of proper volume.Physiological Experiment
By following experimental identification (+) and (-) enantiomorph and racemic modification.Summarize these test-results in the following table.The preparation of cavy gallbladder tissue is from using CO
2Take out gall-bladder in the male Hartley cavy that gas is put to death.Adherent reticular tissue in the isolating gall-bladder of flush away is cut into two rings (2-4mm is long) from each animal gall-bladder.Ring is suspended in contains normal saline solution (118.4mM NaCl, 4.7mM KCl, 1.2mM MgSO
4, 2.5mM CaCl
2, 1.2mM KH
2PO
3, 25mMNaHCO
3, 11.1mM glucose) have in the cabinet, this body lotion is remained under 37 ℃, charge into 95%O
2/ 5%CO
2To keep pH=7.4.By gold chain and stainless steel metal wire, on power such as tissue is connected to displacement transmitter (Grass, Model FT03D).Then with response record on polygraph (Grass, Model 7E).The portion tissue of getting each animal is as time/solvent control, and this tissue is handled without test compound.To encircle gradually the basic rest tension that elongation (through 120 fens clock times) keeps 1gm to the whole test.Regulating between basic tension period, ring is exposed to vagusstoff (10
-6M) four shrinkabilitys to confirm to organize.Then this tissue is exposed to CCK-8 vitriol (Sigma, 3 * 10 of inferior maximal dose
-9M) in.After obtaining stable response, in 1 hour every 5-10 minute, will organize washing fast 3 times with the reconstruction of stability baseline.Agonist EC
50Value is dissolved in compound in the methyl-sulphoxide (DMSO), dilute with water then, by accumulative total concentration-response curve to test compound (10
-11To 3 * 10
-5M) measure, then in the presence of the maximum concentration test compound, by the concentration-response curve to CCK-8 vitriol (10
-10-10
-6M) measure.At last, add vagusstoff (1mM) and bring out maximum collapse.Each test compound is minimum to carry out three determinations of activity.The foundation of the stable clone that has cck receptor is with human body CCK-A
18Or CCK-B
19CDNA clone be connected in the pcDNA1-novel vector (derive from Invitrogen Corp, San Diego carry out direct transfection in CA).Prepare DNA by the molten born of the same parents' method of alkalescence, adopt then lipofection reagent (Gibco BRL, Gaithersberg, MD) transfection to the CHO-K1 cell (ATCC, Rockville, MD) on.Adopt Geneticin (Gibco BRL) to select stable transfection at first, by with fluorescein-Gly-[(Nle28,31)]-and CCK-8 is combined into the fluorescence activity cell of basic sorting, and enrichment has the resistant cell of acceptor.Then, establish clone system by the limit dilution process.The cytolemma preparation is at 37 ℃, humid atmosphere (95%O
2/ 5%CO
2) under, in the HamShi F12 substratum that is supplemented with 5% heat inactivation ox tire serum, make CHO-K1 cell growth through people CCK-A or CCK-B receptor cdna stable transfection.With passage 2 times, grow to 2-4 * 10 weekly
6The density of cell/mL.Centrifugal (600xg, 15 minutes, 4 ℃) collecting cell, be resuspended to then the damping fluid that contains TrisHCl (25mM), EDTA (5mM), EGTA (5mM), benzene sulfonyl fluorine (0.1mM) and soybean insulin inhibitor (100 μ g/mL) (20mL, pH7.4) in.With motorize glass teflon refiner (25 amplitude) ruptured cell, that homogenate low speed (600xg, 10 minutes, 4 ℃) is centrifugal.Collect supernatant liquor, high speed centrifugation (500,000xg, 15 minutes, 4 ℃) precipitation specific part.The low speed precipitation is carried out 3 times again.Merge ultracentrifugal specific part, it is (in the 1-5mg protein/mL), freezing down at-80 ℃ to be resuspended to damping fluid.Adopting BioRad reagent and bovine serum albumin is standard substance, measures protein concn according to manufacturer's specification sheets.
Receptor binding assays will
125(Amersham 2000Ci/mmol) is dissolved in and contains HEPES (20mM), NaCl (118mM), KCl (5mM), MgCl I-Bolton Hunter CCK-8
2(5mM) and in the binding buffer liquid of EGTA (1mM) (pH7.4,100,000cpm/25 μ L).Use MK-329
20(10 μ M, CCK-A) and L-365,260
21(10 μ M CCK-B), measure non-specific binding.Deposit concentration with 100 times of whole experimental concentration is dissolved in test compound among the DMSO, is diluted to suitable concentration with binding buffer liquid then in titer plate.With 96-hole titer plate, carry out combination test in triplicate, in titer plate, add in turn then test compound (25 μ L),
125I-Bolton Hunter CCK-8 (25 μ L), damping fluid (pH7.4,150 μ L) and acceptor prepare liquid (50 μ L).In all test holess, the final concentration of DMSO is 1%.30 ℃ after following 3 hours, by mixture being filtered to fast on the glass filter (Whatman GF/B), stop hatching, continuous washing is removed unconjugated part.By gamma counter, the bonded radioactivity is carried out quantitatively.
Being determined on the glass cover slide of cellular calcium makes the CHO-K1 cell through hCCK-A or hCCK-B acceptor stable transfection grow to the 75-90% fusion.With 50 minutes, this cell is filled in the serum free medium that contains 5mM FURA2-AM and 2.5mM probenecid.By standard ratio meter technology, adopt the excitation wavelength of 340nm and 380nm, use the variation of JASCO CAF-102 calcium analysis-e/or determining cellular calcium concentration.With CCK-8 (n=2) that increases concentration or compound (n=2) perfusion cell, until the ratio platform that reaches 340/380.Between continued stimulus, allow flushing/time of recovery of at least 10 minutes.Peak response is normalized to CCK-8 inductive peak response.The EC at half desired concn place of peak response is induced in calculating
50Value.Except that agonist concentration-response curve, with the compound (10 of three concentration
-8, 10
-7, 10
-6M, n=2) the CHO-K1 cell of perfusion expressing human CCK-B acceptor is 1 hour, obtains CCK-8 (10 then
-12To 10
-6M) concentration-response curve.The apocleisis test: with male Long-Evans rat (225-300g) fasting 2 hours, (Bio-Serve F1657, Frenchtown NJ), made it adapt to for two weeks to the good to eat liquid food of feeding then.In the day of pre-treatment, with rat fasting (100 minutes), IP injectable drug solvent (propylene glycol, PG, 1mL/kg) and oral give load (preload) salt solution (0.9%NaCl, 8mL/kg).Provide liquid food after 20 minutes, located to measure consumption at 30,90 and 180 minutes.For qualitative to drug treating research, within 30 minutes of day of pre-treatment, rat must consume 8mL liquid food at least.Next day, after the fasting 100 minutes, through IP or PO give rat (each dosage 8-10 animal) solvent (PG, 1mL/kg) or various dosage (0.01-10 μ mol/kg) be dissolved in test compound among the PG (1mL/kg), oral immediately then preload salt solution.After 20 minutes, provide food again, located to measure food intake at 30,90 and 180 minutes.From pre-treatment, the data normalization of every rat food intake is worth to each.Potential when measuring 30 minutes and 30 minutes, the usefulness under the 1 μ mol/kg dosage.N mouse gall-bladder round test: Makovec, F.; Bani, M.; Cereda, R.; Chiste, R.; Pacini, MA.; Revel, L.; Rovati, L.C. is to the antispastic activity (Lorglumide) of CR1409 mouse gall-bladder, effective antagonistic action of periphery cholecystokinin, Pharmacol.Res.Commun.1987,19,41-51.The pharmacology contrast of enantiomorph and racemic modification
1. select ratio=IC
50(hCCK-A)/K
i(hCCK-B) 2. non-activity is the highest can not observe diet and obviously reduce when 10 μ mol/kg3. dosage be up to 10 μ mol/kg.PApp value: adopt Artursson P. and Karlson J.1991, Biochem.Biophys Res.Common.175, the intestines infiltration is measured in the in vitro tests of 880-885 (relation in absorption of human body oral pharmaceutical and human gut epithelial (CACO-2) cell between the apparent drug osmotic coefficient).
| Test | (+) enantiomorph | (-) enantiomorph | Racemic modification |
| External | |||
| GPGB?EC 50(nM) | 9.3 | 63 | 40 |
| HCCK-A?IC 50(nM) | 148 | 191 | 123 |
| HCCK-A?EC 50(nM) | 150 | 298 | 252 |
| HCCK-B?K i(nM) | 3.2 | 22.3 | 10 |
| HCCK-B?EC 50(nM) | Antagonist | Antagonist | Antagonist |
| Select ratio 1 | 46 | 8.6 | 12.3 |
| PApp(x10 -7cm/sec) | 1.6 | 0.7 | |
| In the body | |||
| The rat apocleisis | |||
| ED 50IP(μmol/kg) | 0.034 | 0.48 | 0.06 |
| ED 50PO(μmol/kg) | 1.1 | Non-activity 3 | 2.0 |
| The test of mouse gall bladder emptying | |||
| ED 50IP(μmol/kg) | 0.002 | 0.012 | 0.007 |
| ED 50PO(μmol/kg) | 0.007 | Non-activity 2 | 0.055 |
Three kinds of unexpected physiologically actives will make a distinction between (+) enantiomorph and (-) enantiomorph and the racemic modification.Wherein two kinds of activity relate to the effectiveness that strengthens CCK-A, and this effectiveness should be improved the useful activity of this enantiomorph.The third is active relevant with the CCK-B antagonistic activity of (+) enantiomorph, and it can improve helpfulness by reducing toxicity.
In the cavy gall-bladder test (" GPGB ") of in-vitro separation, the effect of (+) enantiomorph is than 4 times of racemize heights.In mouse gall bladder emptying test (oral administration), the effect of (+) enantiomorph is than 8 times of racemize heights.The increase of predicting this usefulness is useful to the treatment of stasis gallbladder and obesity, because stasis gallbladder is the key issue that body weight reduces fast.
Anoretic plans therefore must have extremely low toxicity risk for life-time service.Using relevant main toxicity with cholecystokinin is the CCK-B receptor agonist activity of following.The activity of CCK-B acceptor is main relevant with the increase of anxiety and gastric acid secretion.Explored and utilized CCK-B antagonist exploitation antianxiety agent and anti ulcer agent.See, for example, Lowe, J, " cholecystokinin-B receptor antagonist (Cholecystokinin-B Receptor Antagonists) " in Exp.Opin.Ther.Patents, 5 (3), pp 231-237 (1995).
Topmost cck receptor hypotype is the CCK-A hypotype in the rodent pancreas, and the intensity of activation of this hypotype is brought out the high pungency and the hypertrophy of pancreas in the rodent.Think that now these two kinds of activity all are undesirable.Reported the tissue distribution of cck receptor in the tissue recently.Be that topmost receptor subtype is the CCK-B receptor subtype in people's pancreas astoundingly.See, for example, Wank, S.A, " cholecystokinin receptor " in American Journal ofPhysiology-Gastrointestinal ﹠amp; Liver Physiology, 32 (5):, pp G628-G646 (1995).Therefore, in human body, the activation of CCK-B acceptor (CCK-B agonist activity) can be brought out the increase of anxiety and gastric acid secretion, and life-time service also can bring out the high pungency and the hypertrophy of pancreas.
For reducing the danger of unwanted CCK-B agonist activity in the body, preferred compound reply CCK-B acceptor has affinity, and has the CCK-B antagonistic activity that can measure in vitro tests.Two kinds of enantiomorphs and racemic modification all are the CCK-B antagonists.Though these three kinds of compositions all have similar human body CCK-A receptor affinity (IC
50) and validity (EC
50), but (+) enantiomorph has the highest CCK-B receptor affinity (IC
50) and selectivity (46 times).Therefore, with regard to the minimum potentiality of the toxic side effects of bringing out with regard to CCK-A potential and validity and CCK-B, preferred (+) enantiomorph.
Under the useful dosage of treatment, (+) of the present invention enantiomorph is avirulent basically.For example, in single oral dose research, the maximum non-lethal dose of finding rat is greater than 2000mg/kg, and male mice is greater than 1000mg/kg, and female mice is greater than 500mg/kg.
Claims (12)
1. be rich in the 3-{3-[1-(sec.-propyl-phenyl-carbamyl ylmethyl)-2 of enantiomorph, 4-dioxo-5-phenyl-2,3,4,5-tetrahydrochysene-1H-benzo [b] [1,4] diaza -3-yl]-urea groups } phenylformic acid, or its pharmacy acceptable salt or solvate.
2. the compound that is rich in enantiomorph of claim 1, wherein (+) enantiomorph or its pharmacy acceptable salt or solvate account at least 90% of described compound.
3. claim 1 or 2 the compound that is rich in enantiomorph, wherein (+) enantiomorph or its pharmacy acceptable salt or solvate account at least 99% of described compound.
4. medicinal compositions, it comprise with one or more pharmaceutically acceptable carrier and or the claim 1-3 of mixed with excipients in each the compound that is rich in enantiomorph.
5. treat the disease of CCK-A mediation or the method for illness for one kind, it comprises among the claim 1-3 that gives significant quantity each compound.
6. treat the disease of CCK-A mediation or the method for illness for one kind, it comprises the medicinal compositions that gives claim 4.
7. claim 5 or 6 method, wherein said disease or illness are obesity, stasis gallbladder disease or diabetes.
8. claim 5 or 6 method, wherein said disease or illness are obesity.
9. each compound is used for the treatment of purposes in the medicine of the disease of CCK-A mediation or illness in preparation among the claim 1-3.
10. method for preparing the compound of claim 1, this method comprises:
(a) 3-[3-[1-(sec.-propyl-phenyl-carbamyl ylmethyl)-2 by chirality HPLC resolution of racemic, 4-dioxo-5-phenyl-2,3,4,5-tetrahydrochysene-1H-benzo [b] [1,4] diaza -3-yl] phenylformic acid;
(b) make the enantiomorph of suitable formula (II) amine:
With the isocyanic ester of formula (III), the imidazoles of formula (IV) or the phenyl carbamate reaction of the optional formula V that replaces,
Remove carboxy protective group R preparation then.
11. the method for claim 10, the compound of wherein required claim 1 can be by racemic amine (II) preparation, reduction and hydrogenolysis preparation when described racemic amine can pass through oxime (VI),
R wherein
2It is the optional benzyl that replaces.
12. the method for claim 11, wherein oxime (VI) can be prepared by the activated derivatives of adjacent phenylenediamine (VII) and diacid (VIII),
R wherein
2It is the optional benzyl that replaces.
Applications Claiming Priority (4)
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|---|---|---|---|
| GB9910366.5 | 1999-05-06 | ||
| GBGB9910366.5A GB9910366D0 (en) | 1999-05-06 | 1999-05-06 | 1,5-Benzodiazepine Derivatives |
| GB0008179.4 | 2000-04-05 | ||
| GBGB0008179.4A GB0008179D0 (en) | 2000-04-05 | 2000-04-05 | Chemical process |
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| CN1161345C CN1161345C (en) | 2004-08-11 |
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| BR (1) | BR0010338A (en) |
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| CO (1) | CO5170461A1 (en) |
| CZ (1) | CZ20013988A3 (en) |
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| TR200103169T2 (en) | 2002-04-22 |
| PE20010110A1 (en) | 2001-03-05 |
| BR0010338A (en) | 2002-02-13 |
| IL146124A0 (en) | 2002-07-25 |
| EP1212305A2 (en) | 2002-06-12 |
| NO20015397L (en) | 2001-11-05 |
| HUP0201181A2 (en) | 2002-12-28 |
| CZ20013988A3 (en) | 2002-02-13 |
| AR022044A1 (en) | 2002-09-04 |
| HUP0201181A3 (en) | 2003-10-28 |
| PL351546A1 (en) | 2003-05-05 |
| NO20015397D0 (en) | 2001-11-05 |
| MXPA01011267A (en) | 2002-05-06 |
| MY138319A (en) | 2009-05-29 |
| AU4754800A (en) | 2000-11-21 |
| NZ515048A (en) | 2004-01-30 |
| HK1046138A1 (en) | 2002-12-27 |
| CO5170461A1 (en) | 2002-06-27 |
| WO2000068209A2 (en) | 2000-11-16 |
| CA2370801A1 (en) | 2000-11-16 |
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