CN1178524A - Di-substituted 1, 4 -piperidine esters and amides having 5-HT4 antagonistic activity - Google Patents

Di-substituted 1, 4 -piperidine esters and amides having 5-HT4 antagonistic activity Download PDF

Info

Publication number
CN1178524A
CN1178524A CN 96192500 CN96192500A CN1178524A CN 1178524 A CN1178524 A CN 1178524A CN 96192500 CN96192500 CN 96192500 CN 96192500 A CN96192500 A CN 96192500A CN 1178524 A CN1178524 A CN 1178524A
Authority
CN
China
Prior art keywords
compound
amino
formula
piperidin
acid
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.)
Pending
Application number
CN 96192500
Other languages
Chinese (zh)
Inventor
恩佐·西里达
莫拉·比格诺堤
文森佐·马堤诺
吉瓦尼·B·夏维
安杰洛·萨格拉达
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.)
Boehringer Ingelheim Italia SpA
Original Assignee
Boehringer Ingelheim Italia SpA
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 Boehringer Ingelheim Italia SpA filed Critical Boehringer Ingelheim Italia SpA
Priority to CN 96192500 priority Critical patent/CN1178524A/en
Publication of CN1178524A publication Critical patent/CN1178524A/en
Pending legal-status Critical Current

Links

Landscapes

  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

The invention relates to pharmacologically active novel esters and amides of di-substituted 1,4-piperidine as 5-HT4 antagonists of general formula (I), wherein A, X, Y and R have the meanings specified in the description, processes for their preparation and pharmaceutical compositions containing them.

Description

Has 5-HT 4The two of antagonistic activity replace 1, the ester class and the amides of 4-piperidines
The invention relates to novel the two of pharmacologically active that have and replace 1, the derivative of 4-piperidines, its preparation method and the pharmaceutical composition that contains this compound.
Compounds of the present invention is to 5-HT 4Seretonine receptor 5 has high-affinity and specificity.They can suppress because of the caused effect of the activation of this receptor hypotype in central authorities or peripheral position.Therefore, compound of the present invention may be defined as 5-HT 4" in the body " of acceptor and the novel antagonist of " external ".
5-HT 4Acceptor belongs to one of numerous groups of seretonine receptor 5, and it is just to be found recently, and pharmacology is qualitative and the clone.Identify in the individual regions of guinea pig [people such as Dumuis for the first time; Mol.Pharmacol. (1988), 34,880; People such as Bockaert; Trends, Pharmacol.Sci. (1992) 13, and 141] after, these 5-HT 4Seretonine receptor 5 also has been positioned in other zones of different plant species (comprising the mankind), promptly in central authorities or peripheral position (ileum, anterior chamber, esophagus, colon, bladder and the suprarenal gland), and [people such as Criaig; Britain medicine, (Brit.J.Pharmacol.) (1989) 96,246P; People such as Craig; Drug study treatment (J.Pharmacol.Exp.Ther) (1990) 352,1378; People such as Kauman; Britain medicine (Brit.J.Pharmacol.) (1989), 98,664P; People such as Hoyer; Medicine comment (Pharmacological Reviews) (1994), 46,157].These acceptors are present in Different Organs and the tissue, make compound can block its overstimulation effect, are used for the treatment of and prevent different pathological conditions.
Therefore, for example, because 5-HT 4The stimulation of atrium acceptor influences convergent force and influencing the positive interaction of speed except causing, also can cause [the people such as Kauman of viewed arrhythmia phenomenon in some experiment situation; The pharmacology of the arcs of Naunyn-Schmiedeberg (Naunyn-Schmiedeberg ' s Arch Pharmacol,) (1994) 349,331], so the antagonist of these acceptors can be used for the particular treatment of cardiac rhythm illness, such as the arrhythmia phenomenon of auricular fibrillation and other types.In gi tract, because 5-HT 4Acceptor is facilitated the prime mover and the secretion [people such as Kilbinger of hydroxy-tryptamine; Naunyn-Schmiedeberg ' s Arch Pharmacol. (1992) 345,270; Burleigh; Europe pharmacology (Eur.J.Pharmacol.) (1991), 202,277], so suggestion 5-HT 4Antagonist can be used for treating with the motility of the intestines that change or secretes relevant illness, such as I.B.S. (irritable bowel syndromes), the I.B.S. situation of especially concurrent diarrhoea.Be present in the 5-HT in mouse or the human central nervous system 4Acceptor is not to spread all over all sites but be confined to specific zone [people such as Waeber; Neuroscience report (Neuro Report) (1993), 4,1239; People such as Monferini; Life science (Life Sci.) (1993), 52,61] such as hippocampus, face amount cortex, basal ganglion and marginal texture.Therefore can control 5-HT in the central nervous system 4The compound of the change hormesis of acceptor just can be used in psychosis and the neuropathic field, such as following treatment of conditions: anxiety, depression, psychosis, cognition disease, dynamic disease and migraine.In addition, because found 5-HT 4Known from experience and facilitate 5-HT partly the effect of control on the alcohol panning [people such as Panocka; The biochemical performance of pharmacology, (Pharmacol.Biochem.Behav.) (1995) 52,255], so 5-HT 4Antagonist can be used for the treatment excessive drinking.5-HT 4Acceptor also relates to the control of other functions of urogenital system and adrenal system, as if they can facilitate the release [people such as Lefebre of quasi-ester alcohol hormone in this respect; Neuroscience (Neuroscience), (1992), 47,999].Therefore, be the illness of feature with the secretion change or the urinary incontinence of hormone, also can use and can block 5-HT 4The compound of acceptor is treated.
Find now, the compound of (purpose just of the present invention) novel kind, it has 5-HT 4Therefore the high-affinity of acceptor and specificity can be used for treating illnesss such as cardiac rhythm illness, intestines motility illness such as I.B.S. anxiety, depression, psychosis, cognition disease, motility disease, excessive drinking and migraine.
The invention relates to general formula (I) compound and with the formed acid salt of the acceptable acids of pharmacology
Figure A9619250000071
Wherein
A is selected from following group:
Below shown in the phenyl that is substituted of structural formula
Figure A9619250000081
R wherein 1Be C 1-3Alkoxyl group and R 2Be halogen; Be selected from two following rings or the close cyclic group of three rings
R wherein 3Be hydrogen or halogen, R 4Be hydrogen or C 1-3Alkyl, R 5Be hydrogen or C 1-3Alkoxyl group, R 6C for hydrogen or straight or branched 1-6Alkyl;
X is oxygen or NH;
Y is-OR 7Or NHR 7, R wherein 7Be C 1-3Alkyl, aryl or aralkyl;
R is hydrogen, phenyl, hydroxyl, benzyloxy, methylthiomethyl, 3-indyl, methoxycarbonyl or formamyl.
In this manual, C 1-3Alkyl is meant straight or branched such as methyl, ethyl, n-propyl or sec.-propyl.Halogen is meant fluorine, chlorine, bromine and iodine.Preferred halogen is fluorine, chlorine, bromine, especially fluorine, chlorine.C 1-3Alkoxyl group is meant methoxyl group, oxyethyl group or propoxy-.R in formula (I) compound 6C for straight or branched 1-6During alkyl, then it can be for example methyl, ethyl, n-propyl, sec.-propyl, butyl, amyl group, hexyl, 2-methyl amyl etc.Work as R 7During for aryl, then it can be a phenyl for example.Work as R 7During for aralkyl, then it can be a phenmethyl for example.
General formula (I) compound has a unsymmetrical carbon, therefore can be the optical activity enantiomeric form with R or S configuration, or the racemic mixture form.Even these compounds are to describe and differentiate with independent R or S enantiomeric form in an embodiment, will be appreciated that to the present invention includes whole optical isomeric compounds and racemic mixture thereof.
Compound of Formula I can be passed through, and for example following method is prepared, and these methods are another characteristics of the present invention.
Wherein X is oxygen and A, R and Y definition formula (I) compound as above, can be prepared by following reaction process 1.
Reaction process 1
Wherein A definition as above and R be formula (VI) intermediate amine of hydrogen, phenyl, first thiomethyl and indyl, be and R 7The isocyanic ester of NCO or and R 7The chloro-formic ester of OCOCl (R wherein 7Definition is as above) reaction.The preparation feedback of this ureas is in being selected from toluene, tetrahydrofuran (THF), ethanol, methanol solvent, preferably in ethanol, in 0 ℃ to the reflux temperature of solvent, preferably at room temperature carry out.
In the preparation of carbamate, reaction is such as tetrahydrofuran (THF), diethyl ether or chloroform in inert solvent, be preferably in the tetrahydrofuran (THF), have acid acceptor (such as pyridine or triethylamine) in the presence of, in 0 ℃ to the reflux temperature of solvent (preferably at room temperature) carry out.
At R is in the particular case of hydroxyl, formula (I) compound can by the same precursor of formula (VI) (wherein A as defined above and R be that the precursor of hydroxyl functional is such as benzyloxy) be prepared.In this case, be after changing the effect of urea groups or amido methanoyl derivative into according to said procedure and method, that then carries out hydroxyl protecting group again goes to protect step.The de-protected effect of an adjacent phenylcarbinol there is multiple known method (asking for an interview " protecting group in the organic synthesis, (Protective Groups in OrganicSynthesis) ", T.W.Green P.G.M.Wutz John Wiley, 1991,10-142 page or leaf).It is desirable to is especially having in the presence of the suitable catalyzer (preferably Pd/C), with hydrogen or with its precursor such as method of reducing that tetrahydrobenzene or ammonium formiate were carried out.At R is under another particular case of carbamyl group, formula (I) compound can by same precursor (VI) (wherein A as defined above and R be the carbamyl precursor group, such as carbalkoxy, be preferably methoxycarbonyl) and be prepared.In this case, change the effect of urea and carbamate derivatives into according to said procedure after, then under 0 ℃ to 30 ℃ temperature, gaseous ammonia introduced again in the reaction mixture that contains protic or non-proton polar solvent (being preferably methyl alcohol or acetonitrile), carry out ammonolysis and carry out.
The intermediate of formula (VI) can be easily according to protecting group itself and be present in that other functional groups select in the matrix commonly use guard method (" protecting group in organic synthesis (Protective Group inOrganic Synthesis) " T.W.Green and P.G.M Wuts for example, Ed.John Wiley, 1991; The 309-405 page or leaf), make by the precursor of formula V (wherein A and R as defined above, and Z is suitable amino protecting group, such as tert-butoxycarbonyl or benzyloxycarbonyl).For example, tert-butoxycarbonyl can be by in the presence of having such as nonpolar inert solvents such as ether or ethyl acetate, in-10 ℃ to room temperature, under preferred about 0 ℃, react with anhydrous gaseous hydrochloric acid and remove.
The compound of formula V then can be by being selected from following known process for selective reduction by the precursor of formula (IV) (A wherein, R and Z are all as defined above) and make, promptly to wanting the reductive amido to have hyperergy, and other are present in functional group in these intermediates (IV), especially carboxylicesters and carbamate have the inert method.Special ideal method is in tetrahydrofuran (THF), in room temperature to the solvent refluxing temperature, preferably under 50 ℃, the method for carrying out with borane coordination thing.
The compound of formula (IV) can react with the acid intermediate (wherein R and Z are as defined above) of formula (III) by the ester (wherein A as defined above) with formula (II) and make.Formula (III) compound is the protected amino acid of nitrogen-atoms, and can be obtained by commercially available D or L absolute configuration.This method is after the activation of amino acid carboxyl, in polarity or non-polar solvent, preferably in tetrahydrofuran (THF), for example utilizes 1, and the 1-carbonyl dimidazoles carries out.
Wherein X is an oxygen, and A is benzimidazolone (d) (R wherein 6As defined above) or indoles (c) (R wherein 3, R 4, R 5As defined above) and Y definition preferably suc as formula (Id) and (Ie) middle defined, and can make by following reaction process 2.
Reaction process 2
Figure A9619250000141
Figure A9619250000161
Wherein R is formula (XIII) intermediate amine of hydrogen, phenyl, methylthiomethyl and indyl, is by said procedure and R 7The isocyanic ester of NCO or R 7The chloro-formic ester of OCOCl reacts and the urea or the carbamate of a conversion accepted way of doing sth (Id).At R 6Be not under the particular case under the situation of hydrogen, be at activator such as NaH, NaNH 2, under the existence of KOH or NaOH (being preferably NaH), use alkylating agent R 6Q (wherein Q is a halogen atom, is preferably chlorine or bromine) is with prepared alkylation.Used solvent is generally nonpolar or polar aprotic solvent, is preferably tetrahydrofuran (THF) or dimethyl formamide.Temperature of reaction is between 10 ℃ to 80 ℃, preferably in room temperature.The intermediate of formula (XIII) can be according to being customarily used in the de-protected method of amino functional, and made by the precursor (wherein R and Z are as defined above) of formula (XII).
Formula (XII) compound can be by in inert solvent (such as tetrahydrofuran (THF), ether, methylene dichloride, be preferably tetrahydrofuran (THF)), with phosgene or its safe derivative such as trichloromethylchloroformate or triphosgene, or carbonyl dimidazoles, with formula (XI) compound (wherein R and Z person) as defined above cyclisation and make.Temperature of reaction can be preferably 40 ℃ between 0 ℃ to 60 ℃.
Formula (XI) compound then can be by using suitable reagent and method (promptly do not influence be present in this compound and with the reagent and the method for other represented functionalities of Z and R), nitro-derivative (X) (wherein R and as defined above) is reduced and makes.It is desirable to especially in alcoholic solvent (such as methyl alcohol or ethanol, can contain water in case of necessity, preferable), with SnCl with EtOH95 ° 22H 2O carries out as reductive agent.Temperature of reaction be 40 ℃ between the solvent refluxing temperature, be preferably 70 ℃.
Formula (X) compound can pass through at inert solvent (such as tetrahydrofuran (THF), diox and toluene, be preferably tetrahydrofuran (THF)) in, under (being preferably 60 ℃) in room temperature to the solvent refluxing temperature, the amino alcohol (wherein R and Z are as defined above) that makes formula (IX) is with isocyanic acid neighbour-nitro phenyl ester reaction and make.
Formula (IX) compound can have high narrow spectrum process for selective reduction to amido according to above-mentioned, and is made by the precursor alcohols of formula (VIII), for example utilizes the above-mentioned borane coordination thing in tetrahydrofuran (THF).
Formula (VIII) compound can be by making the amino acid reaction of 4-hydroxymethyl piperidine (VII) with above-mentioned protected D of nitrogen-atoms or L configuration.This step is in nonpolar or polar solvent, preferably in tetrahydrofuran (THF), behind this amino acid whose carboxyl functionality of activation suitably, utilizes 1,1-carbonyl dimidazoles and carrying out.Select by another kind to be, can to prepare wherein X be that oxygen and A are indoles (c) (R wherein by reaction process 2 is described 3, R 4And R 5Formula as defined above) (I) compound, their detailed being shown in the formula (Ic).The intermediate of formula (XIV) (wherein R, R 3, R 4And R 5Be by previous described method as defined above), utilize R 7NCO isocyanic ester or R 7OCOCl chloro-formic ester (R wherein 7Definition is as above), and change into compound (Ic).
Intermediate amine (XIV) then by above-mentioned with the de-protected method of amino functionality, and by precursor (XV) (R wherein 3, R 4, R 5, R and Z definition as) and make.
Intermediate (XV) can be by the alkoxide method by the precursor of formula (XVI) (R wherein 3, R 4, R and Z all as defined above) and make.At first, with the oxygenant in inertia halogenated solvent (such as methylene dichloride or chloroform), such as N-chloro-succinimide, the activation indole ring; Utilize suitable alkyl alcohol R then 5OH such as methyl alcohol or ethanol are finished this program.This two program phases all 0 ℃ under 50 ℃, preferably at room temperature carry out.
Compound (XVI) can be by with the indole-carboxylic acid of formula (XVII) (R wherein 3And R 4Make as defined above) with amino alcohol (wherein R and Z the are as defined above) reaction of formula (IX).This esterification is under subambient temperature, preferably under 0 ℃ to-5 ℃, with acid anhydrides (for example trifluoroacetic anhydride) and methylsulfonic acid activated carboxyl official can and carry out.This program is finished after adding pure composition and being warming up to 50 ℃ to 60 ℃.Used solvent is halogenated solvent normally, can be selected from chloroform and methylene dichloride.
Wherein X be nitrogen-atoms and A, R and Y all as defined above formula (I) compound can be prepared by the synthesis step described in the following reaction process 3.
Figure A9619250000191
Wherein A as defined above and R be the intermediate amine of the formula (XVIII) of hydrogen, phenyl, methylthiomethyl and indyl, be and isocyanic ester R 7NCO or chloro-formic ester R 7OCOCl (R wherein 7React as defined above).Used program is similar to noted earlier.
At R is in the particular case of hydroxyl, formula (I) compound can by identical formula (XVIII) precursor (wherein A as defined above and R be that the hydroxyl precursor is such as benzyloxy) make.In this case, be after having carried out the above-mentioned effect that is converted into urea or carbamate derivatives, carry out the de-protected program of above-mentioned hydroxy functionality again.At R is under another particular case of formamyl, formula (I) compound can by identical formula (XVIII) precursor (wherein A as defined above and R be the precursor of formamyl such as carbalkoxy, be preferably methoxycarbonyl) and make.After this is converted into the effect of urea or carbamate derivatives, carry out the ammonolysis program more as described above.
The intermediate of formula (XVIII) can be by the above-mentioned guard method of going, and by the precursor of formula (XIX) (wherein A and R as defined above and Z be suitable amino-functional protecting group, such as tertbutyloxycarbonyl or carbobenzoxy-(Cbz)) make.
Formula (XIX) compound can make with formula (XXI) compound (wherein W is suitable leaving group such as chlorine or imidazoles) reaction by the amine (wherein R and Z are as defined above) with formula (XX).This program is in the presence of organic bases, such as triethylamine and 1,8 diazabicylos [5.4.0]-7-undecylene (DBU) exists down, in inert solvent, such as ether, tetrahydrofuran (THF), methylene dichloride, chloroform, toluene, preferably in tetrahydrofuran (THF), and in 10 ℃ to the solvent refluxing temperature, preferably under 40 ℃, carry out.
Formula (XXI) compound can be obtained or be made by known method in the document by commercially available intermediate, promptly by in inert solvent (such as toluene or tetrahydrofuran (THF)), in 0 ℃ under 70 ℃, with phosgene or preferred react with its derivative such as superpalite or carbonic acid two (three chloromethyl esters) and make.
Formula (XX) compound can for example utilize the borane coordination thing in tetrahydrofuran (THF), and be made by the intermediate (wherein R and Z are as defined above) of formula (XXII) by above-mentioned process for selective reduction.R is under formamyl and the Z particular case as defined above in formula (XX) compound, it can by identical formula (XXII) compound (wherein Z as defined above and R be that carbalkoxy is such as methoxycarbonyl) make.Behind this reducing program, use mentioned reagent and step to carry out ammonolysis reaction again.
The intermediate of formula (XXII) can be by making intermediate (wherein Z and the R as defined above) reaction of different 3-piperidines acid amides (XXIII) with formula (III).These compounds (III) are for to have by the amino acid of the amino-functional of Z radical protection, and can be obtained by commercially available D or L configuration.This program is in nonpolar or polar aprotic solvent (being preferably tetrahydrofuran (THF)), carries out under the suitable activator (such as 1, the 1-carbonyl dimidazoles) of amino acid carboxyl-functional exists.Another kind method is that the formula shown in the reaction process 3 (I) compound can make with intermediate (XXI) (wherein A and W have above-mentioned definition) reaction by the amine (wherein R and Y are as defined above) with formula (XXIV).This reaction is in inert solvent, such as ether, tetrahydrofuran (THF), methylene dichloride, chloroform, toluene, be preferably in the tetrahydrofuran (THF), in the presence of organic bases such as triethylamine or DBU, and 10 ℃ to the solvent refluxing temperature, preferably under 40 ℃, carry out.Intermediate (XXIV) is by above-mentioned process for selective reduction, and is made by the acid amides (wherein R and Y have aforesaid definition) of formula (XXV), for example can utilize the borane coordination thing in tetrahydrofuran (THF).Formula (XXV) compound can be by aforesaid reaction, and by amine (XXVI) (wherein R has aforesaid definition) and isocyanic ester R 7NCO or chloro-formic ester R 7The reaction of OCOCl and making.At last, intermediate (XXVI) can by above-mentioned amino-functional suitably remove defence program, and make by the precursor (wherein Z and R are as defined above) of formula (XXII).
Formula of the present invention (I) compound such as the above-mentioned mentioned asymmetric carbon atoms that has.Therefore there are with relative configuration two kinds independently optical activity enantiomers in its.The enantiomerism form of these two kinds of final compounds (I) can be begun by the intermediate predecessor of the formula (III) that has predetermined absolute R or S configuration, and presses described in reaction process 1,2 and 3, can keep the program of palm of the hand configuration is reacted and made.Another kind method is, identical enantiotopic final form (I) can be according to the isolating habitual of prediction enantiomeric form and the method for knowing, and is directly obtaining on final compound, or obtains in having the synthetic intermediate that is suitable for of alkaline functionality.These are separated into racemic mixture the method for independent enantiomorph, be to carry out the single or multiple recrystallization by the salt of final compound or alkaline intermediate and optical activity acid (such as d-camphorsulfonic acid, d-or 1-tartrate and d-or 1-neighbour, ortho-xylene acyl tartrate) gained.Used solvent is generally the alcoholic solvent that water content does not wait.
The compound of Zhi Bei general formula (I) as stated above, can change into corresponding nontoxicity in case of necessity and be physiologically acceptable inorganic or organic acid addition salt, for example by habitual method for transformation, such as reacting as these compounds (dissolving in the appropriate solvent in case of necessity) of alkali and the respective acids solution in appropriate solvent.The example of nontoxicity and physiologically acceptable acid salt is that those and following acid are formed: Hydrogen bromide, hydrochloric acid, nitric acid, sulfuric acid, toxilic acid, fumaric acid, citric acid, tartrate, methylsulfonic acid, tosic acid, acetate, phenylformic acid, Succinic Acid, glyconic acid, lactic acid, glycine, oxysuccinic acid, muconic acid, L-glutamic acid, hydroxyethylsulfonic acid, phosphoric acid, xitix or thionamic acid.Special ideal acid is hydrochloric acid, Hydrogen bromide, toxilic acid, fumaric acid and methylsulfonic acid.
The preferred compound of the present invention is promptly as 5-HT 4Have during receptor antagonist preferable active, be those general formulas (I) compound wherein A be group (c) or (d), R 3Be halogen, R 4Be hydrogen or C 1-3Alkyl, R 5Be C 1-3Alkoxyl group, R 6C for straight or branched 1-6Alkyl, X are oxygen or NH, and Y is OR 7R wherein 7Be C 1-3Alkyl, aryl or aralkyl, R are hydrogen, hydroxyl, benzyloxy or formamyl.Pharmacology
By at porcine striatal (a kind of 5-HT that is rich in 4The tissue of acceptor) the receptors bind research in, and carry out test compound (I) to 5-HT in the mode of " in vitro " 4The affinity of seretonine receptor 5.Receptors bind research
Carry out 5-HT 4The receptors bind research of acceptor is carried out with the affinity of determination test compound.The preparation of tissue
Porcine striatal is taken out and cleans, with the Ultra-Turrax (W/V1: 70) 30 seconds that homogenizes under the most at a high speed, then in 50mM Hepes buffer reagent (pH7.4), homogenize (30 times) with the Potter-Elvehjem homogenizer again, and filter with two-layer cheese cloth.In conjunction with experiment
The binding curve of different compounds is by to 0.1nM[ 3H]-competitive assay of GR113808 derives indirectly.
In the presence of the cold dentate of mark dentate and different concns, and under 37 ℃, the homogenate of cultivation 1ml part 30 minutes.
With the quick filtration of automatic gear (1H-110 Inotech) to stop this cultivation.Then filter (glass fibre filter of Inotech, G7 type) is transferred in the scintillation vial that contains 4m Filter Count (Packard), and counted existing radioactivity with liquid scintillation spectrometry (Kontron Betamat V).Replication three times, non-specificity (when 3-ethyl-2, the developing medium of 3-dihydro-2-oxygen-benzoglyoxaline-1-(3 α-tropyl methane amide), is combined in or is caught to cut radioactivity in filter in conjunction with being defined as at the BIMU 0001 that contains 10 μ M.Non-specificity is in conjunction with being about 10-15%.After proofreading and correct the shared displacement of radioactivity dentate according to Cheng and Prusoff equation (biochemical pharmacology is learned (Biochem.Pharmaco.) 22,3099,1973), calculate and suppress constant (ki).
The experimental result of drawing the receptor binding affinity of lifting some compound in the table 1.
Table 1-is to 5-HT 4The affinity of acceptor
(porcine striatal) compound K i x 10 9H21 1.323 0.8630 4.312 2.813 4.310 2.1 1 4.6 9 4.311 1.135 1.636 3.037 0.3726 1.034 3.216 2.917 0.1619 0.25
The compounds of this invention blocking-up 5-HT 4The ability of acceptor is to test in the following manner, tests it loosens effect to the mouse esophagus flesh layer mucous membrane (being that Samoryl is shunk) that hydroxy-tryptamine was brought out in advance antagonistic activity in " in vitro " mode.This experiment is according to [the people such as Baxter of program described in the document; Naunyn-Schmiedeberg's Arch.Pharmacol. (1991), 343,439] carry out.
All compounds of the present invention can both be with good to high ability antagonism 5-HT 4Acceptor, they represent higher pA 2Value, and in some cases far above 7.
Another characteristics of the present invention are to provide pharmaceutical composition of the present invention, and it comprises as the general formula of the significant quantity of active ingredient (I) compound or its physiologically acceptable acid salt, and one or more pharmaceutical carriers, thinner or vehicle.
These compositions can be modulated into by habitual mode be used for oral, parenteral, the form of rectum or subcutaneous administration, or be suitable for sucking or being blown into the form of (per os or intranasal) administration.
Be used for for example, can making tablet (comprising slow releasing tablet) or capsule when oral by ways customary with these pharmaceutical compositions and pharmaceutically acceptable vehicle.Described vehicle has: W-Gum, polyvinylpyrrolidone, lactose, Microcrystalline Cellulose, Magnesium Stearate, talcum, yam starch, Sodium Lauryl Sulphate BP/USP.Be used for oral liquid preparation and can for example make solution, the form of syrup or suspension, they can utilize pharmaceutically acceptable additive such as Sorbitol Powder syrup, derivatived cellulose, Yelkin TTS, Prunus amygdalus oil, methyl p-hydroxybenzoate by ways customary, and the buffering salt, seasonings, tinting material and the sweeting agent that add in case of necessity and make.Formula (I) compound also can be modulated into the parenteral form of medication that is used for injection (as bolus injection or injection continuously).The composition unit of the can be consumption form that is used to inject is as with ampoule form or multi-dose container form.Said composition also can be suspension, solution or the emulsion form in oiliness or aqueous carrier.Perhaps, this active ingredient can powder type, forms and modulate as the unlikely hot water of sterilizing with appropriate carriers before use.
When being used for rectal administration, this pharmaceutical composition can, for example, contain the suppository of habitual suppository base such as Oleum Cocois or other glyceryl ester.
Except above-mentioned composition, formula (I) compound also can be mixed with storage composition.The composition of this type of long term can be by implanting the mode administration of (for example subcutaneous, implant through skin or intramuscular) or intramuscularly.Therefore, for example, their available suitable polymkeric substance or lyophobic dust or ion exchange resin and be mixed with this preparation.
In order to increase the solubleness of general formula (I) compound or its physiologically acceptable salt, can mix tensio-active agent, nonionic surfactant such as PEG400, cyclodextrin, metastability polymorphic form, inertia absorption agent such as bentonite.In addition, can use also that for example mannitol, Sorbitol Powder, sucrose, Succinic Acid prepare eutectic mixture and/or solid dispersion, or utilize water-soluble polymers, PVP, PEG4000-20000 to prepare some used technology in the form preparation of physical property upgrading.
These compositions are preferably prepared with the consumption unit form: each consumption unit is all in order to provide the active ingredient of a dosage.0.1mg-100mg can be contained in each consumption unit, is preferably the active ingredient of 1mg to 20mg.
The following example also comprises the explanation of intermediate preparation, and some compounds of the present invention has been described; These embodiment are not the scope that is used for limiting in any form the present invention itself. Illustrative examples 1
4-amino-5-chloro-2-methoxyl group-phenylformic acid (piperidin-4-yl) methyl esters
A) with 1, (0.8g, (1g in THF 5mmol) (20ml) solution, and stirred this reaction mixture about 30 minutes to the 1-carbonyl dimidazoles under room temperature 0.005mol) to join 4-amino-5-chloro-2-methoxyl group-phenylformic acid.Follow evaporating solvent, and residue is placed H 2O also is extracted into ethyl acetate (in 3 * 20ml) with it.Collect organic phase, with its dehydration and be evaporated to dried.The solid residue of gained is dissolved among the THF (10ml), and will remains on 1-benzyl piepridine-4-base-methyl alcohol [Drug thing chemistry, (J.Med.Chem.) (1992) under 0 ℃, 35,4344] (1g, and (10ml) solution of THF 5mmol) and butyllithium (in the hexane, 1.6M; 3ml) be added dropwise to wherein.Then under room temperature, stirred this reaction mixture 1 hour.Evaporating solvent then, and with H 2The O dissolution residual substance also is extracted into it in ethyl acetate.Should be organic extract dehydration and evaporation, and the required product (1.63g) of faint yellow oily.
B) with chloroformic acid α-chloroethene ester (0.3ml, 2.8mmol) be added dropwise to 4-amino-5-chloro-2-methoxyl group-phenylformic acid (1-benzyl-piperidin-4-yl) methyl esters (1g that remains under 0 ℃, 2.6mmol) and proton sponge (proton sponge) (0.27g, 1.3mmol) 1, in the 2-ethylene dichloride (20ml) in the formed mixture.Follow this mixture overnight of restir under room temperature.Then this reaction mixture is poured in the aqueous solution of 5%HCl, and with H 2O cleans separated organic layer, dewaters and is evaporated to dried.With CH 3OH (20ml) dissolution residual substance also heated 30 minutes under reflux temperature.Follow evaporating solvent, and get the compound that requires (0.36g) of the solid state that is white in color of hydrochloride form, fusing point 250-251 ℃.
Prepare following product according to said procedure:
1-methyl-indoles-carboxylic acid (piperidin-4-yl) ester, fusing point 227-239 ℃ (hydrochloride). Illustrative examples 2
Carbazole-9-carboxylic acid (piperidin-4-yl) methyl esters
A) will contain the pyridine (7.2ml of activated carbon (1.5g); 0.090mol) (10g is in anhydrous toluene solution 0.060mol) to add carbazole.At 100 ℃ down after the heating, splash into trichloromethylchloroformate (5.6ml, 0.046mol).In 100 ℃ of following stirred reaction mixtures 18 hours.The pyridinium salt of gained leached and with remaining solution evaporation to dry.Make 13g reddish-brown solid, fusing point 95-96 ℃.
B) (26g 0.108mol) adds in batches that (22.2g 0.108mol) is dissolved in anhydrous CH by 1-benzyl piepridine-4-base-methyl alcohol with carbazole-9-carbonyl chlorine 2Cl 2(700ml) in the formed solution, and under room temperature, stirred 48 hours.Then, with this solution evaporation to dry doubling with chromatography (silica gel; Eluant: CH 2Cl 2/ CH 3OH=96/4) the thick solid of purifying gained.Make the pink solid of 30g, fusing point 196-199 ℃ (hydrochloride).
C) (10.8g 0.175mol) joins simultaneously that (15g 0.035mol) is dissolved in CH by carbazole-9-carboxylic acid (1-benzyl-piperidin-4-yl) methyl esters with 10%Pd/C (15g) and ammonium formiate 3Among the OH (450ml) in the formed solution.This reaction mixture of reflux 40 minutes; After ending heating, when being cooled to room temperature, stir this reaction mixture.Leach catalyzer and will clarify colourless solution evaporation to doing.Make the white solid of 9g, decompose during 240 ℃ of fusing points (hydrochloride). Illustrative examples 3
S (-)-4-amino-5-chloro-2-methoxyl group-phenylformic acid [1-(2-t-butoxycarbonyl amino-3-benzyloxy propionyl)-piperidin-4-yl] methyl esters
With 1, (5.3g 0.033mol) adds L-O-B to the 1-carbonyl dimidazoles 2(9.7g in THF 0.033mol) (100ml) solution, and stirred this mixture 40 minutes to Serine N-t-Boc under room temperature.Then splash into 4-amino-5-chloro-2-methoxyl group-phenylformic acid (piperidin-4-yl) methyl esters (9.7g, THF 0.033mol) (50ml) solution, and under room temperature, stir this reaction mixture and spend the night.Solvent evaporation is extremely done, and with H 2The O dissolution residual substance also is extracted to it in ethyl acetate.Collect organic extract then, drying also is evaporated to dried.With the residue of gained with chromatography (silica gel; Eluant: n-hexane/ethyl acetate=4/6) purifying, and must be the product that requires (10.47g) of faint yellow solid shape.[α] 20 D＝-0.97°(c＝1％CH 3OH)。
Can prepare following product according to above-mentioned program:
S (+)-4-amino-5-chloro-2-methoxyl group-phenylformic acid [1-(2-carbobenzoxy-(Cbz)-amino-3-phenyl-propionyl)-piperidin-4-yl] methyl esters [α] 20 D=+8.48 ° of (c=1%CH 3OH)
S (+)-4-amino-5-chloro-2-methoxyl group-phenylformic acid [1-[2-tertbutyloxycarbonyl-amino-3-(1H-indol-3-yl)-propionyl] piperidin-4-yl] methyl esters [α] 20 D=+21.28 ° of (c=1%CH 3OH)
S (-)-4-amino-5-chloro-2-methoxyl group-phenylformic acid [1-(2-tertbutyloxycarbonyl-amino-4-methylthio group-butyryl) piperidin-4-yl] methyl esters [α] 20 D=14.13 ° of (c=1%CH 3OH)
S (+)-1-Methyl-1H-indole-3-base-carboxylic acid [1-(2-carbobenzoxy-(Cbz)-amino-3-phenyl-propionyl) piperidin-4-yl] methyl esters [α] 20 D=+8.16 ° of (c=1%CH 3OH)
S (+)-carbazole-9-carboxylic acid [1-(2-carbobenzoxy-(Cbz)-amino-propionyl) piperidin-4-yl] methyl esters [α] 20 D=+12.16 ° of (c=1%CH 3OH) fusing point: decompose in the time of 70 ℃
S (+)-carbazole-9-carboxylic acid [1-(2-carbobenzoxy-(Cbz)-amino-3-phenyl-propionyl)-piperidin-4-yl] methyl esters [α] 20 D=+15.45 ° of (c=1%CH 3OH) fusing point: 75 ℃
S (-)-carbazole-9-carboxylic acid [1-(2-tertbutyloxycarbonyl-amino-3-benzyloxy-propionyl)-piperidin-4-yl] methyl esters [α] 20 D=-2.13 ° of (c=1%CH 3OH) fusing point: 67-69 ℃
S (-)-carbazole-9-carboxylic acid [1-(2-tertbutyloxycarbonyl-amino-3-methoxycarbonyl-propionyl)-piperidin-4-yl] methyl esters [α] 20 D=-23.28 ° of (c=1%CH 3OH) solid 76-78 ℃
S (+)-1-methyl isophthalic acid-indol-3-yl-carboxylic acid [1-(2-carbobenzoxy-(Cbz)-amino-3-phenyl-propionyl)-piperidin-4-yl] methyl esters [α] 20 D=+8.16 ° of (c=1%CH 3OH) Illustrative examples 4
S (-)-carbazole-9-carboxylic acid [1-(2-carbobenzoxy-(Cbz)-amino-3-phenyl-propyl group)-piperidin-4-yl] methyl esters
To be dissolved in S (+)-carbazole-9-carboxylic acid [1-(2-carbobenzoxy-(Cbz)-amino-3-phenyl-propionyl)-piperidin-4-yl] methyl esters (4g among the anhydrous THF (60ml), 7mmol), (33ml is in anhydrous THF (60ml) solution 0.033mol) to be added dropwise to 1M borane coordination thing under gentle reflux.This solution of reflux is 8 hours under stirring, and cools off under room temperature then.Evaporating solvent and with chromatography (silica gel; Eluant: CH 2Cl 2/ CH 3OH=95/5) purification of crude residue, and get white solid (1.5g).[α] 20 D=-3.36 ° of (c=1%CH 3COOH) fusing point: decompose in the time of 200 ℃.
Following compounds can make in a similar fashion:
S (+)-carbazole-9-carboxylic acid [1-(2-carbobenzoxy-(Cbz)-amino-propyl group)-piperidin-4-yl] methyl esters [α] 20 D=+13.16 ° of (c=1%CH 3COOH)
S (+)-carbazole-9-carboxylic acid [1-(2-tertbutyloxycarbonyl-amino-3-benzyloxy-propyl group)-piperidin-4-yl] methyl esters [α] 20 D=+9.58 ° of (c=1%CH 3COOH) fusing point: 170-172 ℃ (hydrochloride)
S (-)-carbazole-9-carboxylic acid [1-(2-tertbutyloxycarbonyl-amino-3-methoxycarbonyl-propyl group)-piperidin-4-yl] the dense oily of methyl esters; [α] 20 D=-2.8 ° of (c=1%CH 3OH)
S-4-amino-5-chloro-O-Anisic Acid [1-(2-tertbutyloxycarbonyl-amino-3-phenoxy group-propyl group)-piperidin-4-yl] methyl esters [α] 20 D=-4.5 ° of (c=1%CH 3OH)
S (-)-4-amino-5-chloro-2-methoxyl group-phenylformic acid [[1-(2-tertbutyloxycarbonyl-amino-3-(1H-indol-3-yl)-propyl group]-piperidin-4-yl]] methyl esters [α] 20 D=-2.67 ° of (c=1%CH 3OH)
S (+)-4-amino-5-chloro-2-methoxyl group-phenylformic acid [1-(2-tertbutyloxycarbonyl-amino-4-methylthio group-butyl)-piperidin-4-yl] methyl esters [α] 20 D=+9.94 ° of (c=1%CH 3OH, hydrochloride)
S (+)-1-Methyl-1H-indole-3-base-carboxylic acid [1-(2-carbobenzoxy-(Cbz)-amino-3-phenyl-propyl group)-piperidin-4-yl] methyl esters [α] 20 D=+0.25 ° of (c=1%CH 3OH)
S-4-amino-5-chloro-2-methoxyl group-phenylformic acid [1-(2-tertbutyloxycarbonyl-amino-3-phenyl-propyl group)-piperidin-4-yl] methyl esters [α] 20 D=+6.2 ° of (c=1%CH 3OH) Illustrative examples 5
S (+)-4-amino-5-chloro-2-methoxyl group-phenylformic acid [1-(2-amino-3-(1H-indol-3-yl) propyl group)-piperidin-4-yl] methyl esters
Anhydrous gaseous state HCl bubbling is blown into 0 ℃ of refrigerative S (-)-4-amino-5-chloro-2-methoxyl group-phenylformic acid [1-(2-tertbutyloxycarbonyl-amino-3-(1H-indol-3-yl) propyl group]-piperidin-4-yl] methyl esters (2g, in ethyl acetate 3.5mmol) (30ml) solution 30 minutes.Evaporating solvent and with the solid residue of gained, with the ether crystallization, and the product that requires (1.8g) of white solid of hydrochloride form.[α] 20 D=+7.4 ° of (c=1%CH 3OH, hydrochloride).
Can prepare following product according to above-mentioned mode:
S-4-amino-5-chloro-2-methoxyl group-phenylformic acid [1-(2-amino-3-benzyloxy-propyl group)-piperidin-4-yl] methyl esters [α] 20 D=+7.3 ° of (c=1%CH 3OH)
S-4-amino-5-chloro-2-methoxyl group-phenylformic acid [1-(2-amino-3-phenyl-propyl group)-piperidin-4-yl] methyl esters [α] 20 D=-5.5 ° of (c=1%CH 3OH)
S (+)-carbazole-9-carboxylic acid [1-(2-amino-3-benzyloxy-propyl group)-piperidin-4-yl] methyl esters [α] 20 D=+1.64 ° of (c=1%CH 3OH)
S (+)-carbazole-9-carboxylic acid [1-(2-amino-3-methoxycarbonyl-propyl group)-piperidin-4-yl] methyl esters [α] 20 D=+2.63 ° of (c=0.5%CH 3OH)
S (+)-5-fluoro-1H-Indole-3-Carboxylic Acid [1-(2-amino-3-benzyloxy-propyl group)-piperidin-4-yl] methyl esters [α] 20 D=+3.4 ° of (c=1%CH 3OH) fusing point: 150 (getting) by ethyl acetate
S (+)-5-fluoro-2-methoxyl group-1H-3-carboxylic acid [1-(2-amino-3-benzyloxy-propyl group)-piperidin-4-yl] methyl esters [α] 20 D=+1.55 ° of (c=1%CH 3OH, hydrochloride) fusing point: decompose during 125-130 (hydrochloride is got by ether) Illustrative examples 6
S (+)-carbazole-9-carboxylic acid [1-(2-amino-propyl group)-piperidin-4-yl] methyl esters
(0.48g 7.65mmol) adds simultaneously that (0.82g 1.53mmol) is dissolved in CH to methyl esters by S (+)-carbazole-9-carboxylic acid [1-(2-carbobenzoxy amino-propyl group)-piperidin-4-yl] with 10%Pd/C (0.82g) and ammonium formiate 3In the solution of the middle gained of OH (35ml).This reaction mixture of reflux 40 minutes; After ending heating, when being cooled to room temperature, stir again.Leach catalyzer and will clarify colourless solution evaporation to dry.Make the white solid of 9.45g.[α] 20 D=+26 ° of (c=1%CH 3OH, hydrochloride) decomposes (hydrochloride) fusing point: 188-190 ℃ the time.
Following compound is to make in a similar fashion:
S (+)-carbazole-9-carboxylic acid [1-(2-amino-3-phenyl-propyl group)-piperidin-4-yl] methyl esters [α] 20 D=+2.08 ° of (c=1%CH 3COOH) Illustrative examples 7
S (+)-1-Methyl-1H-indole-3-carboxylic acid [1-(2-amino-3-phenyl-propyl group)-piperidin-4-yl] methyl esters
At room temperature normal pressure and H 2Exist down, with S (+)-1-Methyl-1H-indole-3-carboxylic acid [1-(2-CBZ-amino-3-phenyl-3-propyl group)-piperidin-4-yl] methyl esters (3.3g, 6.11mmol) and 10%Pc/C (0.33g) at anhydrous CH 3CH 2OH (35ml) and contain in the ether of 20%HCl (1.1ml) formed suspension and stir and spend the night.Leach catalyzer and solution evaporation is extremely dried.With the acetone crystalline residue, and the product of 2.5g hydrochloride form, [α] 20 D=+30.1 ° of (c=1%CH 3OH) decompose in the time of fusing point: 212-215 ℃. Embodiment 1
S (+)-4-amino-5-chloro-2-methoxyl group-phenylformic acid [1-[3-benzyloxy-2-(3-phenyl-urea groups) propyl group]-piperidin-4-yl } methyl esters
With phenylcarbimide (0.35g, 3.2mmol) be added dropwise at 0 ℃ of refrigerative S-4-amino-5-chloro-2-methoxyl group-phenylformic acid [1-(2-amino-3-benzyloxy-propyl group)-piperidin-4-yl] methyl esters (1.5g, 3.2mmol) THF (20ml) solution in, and down stirred this reaction mixture 30 minutes in 0 ℃.Evaporating solvent gets crude product to doing, then with chromatography (silica gel; Eluant: EtAc/CH 3OH=98.2) purifying, and the blister product that solid requires (1.6g) that must be white in color.[α] 20 D＝+5.59°(c＝1％CH 3OH)。
Can prepare following product according to said procedure:
S (+)-4-amino-5-chloro-2-methoxyl group-phenylformic acid [1-[3-benzyloxy-2-(3-ethyl-urea groups) propyl group)-piperidin-4-yl] methyl esters [α] 20 D=+5.08 ° of (c=1%CH 3OH)
S (+)-5-fluoro-1H-Indole-3-Carboxylic Acid [1-(2-(3-phenyl-urea groups)-3-benzyloxy-propyl group)-piperidin-4-yl] methyl esters [α] 20 D=+14.7 ° of (c=1%CH 3OH)
S (+)-carbazole-9-carboxylic acid [1-(3-benzyloxy-2-(3-ethyl-urea groups) propyl group)-piperidin-4-yl] methyl esters [α] 20 D=+11.88 ° of (c=1%CH 3OH)
S (+)-carbazole-9-carboxylic acid [1-(3-methoxycarbonyl-2-(3-phenyl-urea groups)-propyl group)-piperidin-4-yl] methyl esters [α] 20 D=+10.9 ° of (c=1%CH 3OH)
S (+)-4-amino-5-chloro-2-methoxyl group-phenylformic acid [1-[2-(3-ethyl-urea groups)-3-(1H-indol-3-yl-propyl group)-piperidin-4-yl] methyl esters (compound 1)[α] 20 D=+13.25 ° of (c=1%CH 3OH) fusing point: 143-145 ℃ of (hydrochloride is got by diethyl ether) M.S. (C.I.)=543m/e (M+H) analyzes: C 28H 37Cl 2N 5O 4
C H N measured value % 57.19 6.46 12.00 calculated value % 58.13 6.45 12.11S (-)-4-amino-5-chloro-2-methoxyl group-phenylformic acid 1-[4-methylthio group-2-(3-phenyl-urea groups)-butyl) and piperidin-4-yl } methyl esters (compound 2)[α] 20 D=-0.8 ° of (c=1%CH 3OH) fusing point=121-123 ℃ (hydrochloride is got by ether) M.S.=536m/e[M+H] analyze: C 26H 36Cl 2N 4O 4S
C H N measured value % 53.97 6.34 9.50 calculated value % 54.64 6.35 9.80S (+)-carbazole-9-carboxylic acid 1-[2-(3-phenyl-urea groups)-propyl group)-piperidin-4-yl } methyl esters (compound 3)[α] 20 D=+8.74 ° of (c=1%CH 3COOH) fusing point=188-190 ℃ (hydrochloride is got by ether) M.S. (C.I.)=485m/e[M+H] analyze: C 29H 33ClN 4O 3
C H N measured value % 66.18 6.20 10.38 calculated value % 66.85 6.38 10.75S (+)-carbazole-9-carboxylic acid 1-[2-(3-ethyl-urea groups)-phenyl propyl)-piperidin-4-yl } methyl esters (compound 4)[α] 20 D=+0.76 ° of (c=1%CH 3COOH) fusing point=95 ℃ (hydrochloride is got by ether) M.S. (C.I.)=513m/e[M+H] analyze: C 31H 37ClN 4O 4
C H N measured value % 68.00 6.82 10.40 calculated value % 67.81 6.79 10.20S (+)-1-Methyl-1H-indole-carboxylic acid 1-[2-(3-ethyl-urea groups)-propyl group)-piperidin-4-yl] methyl esters (compound 5)[α] 20 D=+11.02 ° of (c=1%CH 3OH, hydrochloride) decompose (hydrochloride get by ether) M.S. (C.I.)=477m/e[M+H fusing point=200-205 ℃ the time] analysis: C 28H 37ClN 4O 3
C H N measured value % 65.50 7.32 10.95 calculated value % 65.55 7.27 10.92 Embodiment 2
S (+)-carbazole-9-carboxylic acid [1-(2-ethoxycarbonyl-amino-3-benzyloxy-propyl group)-piperidin-4-yl] methyl esters
(1g 1.84mmol) is dissolved in CH to methyl esters with S (+)-carbazole-9-carboxylic acid [1-(2-amino-3-benzyloxy-propyl group)-piperidin-4-yl] 2Cl 2The solution of gained is 0 ℃ of down cooling (30ml), and be added dropwise to subsequently Vinyl chloroformate (0.350ml, 3.69mmol).Under cooling, stirred this reaction mixture 15 minutes, under room temperature, stirred 6 hours then.This solution evaporation is extremely done, and with chromatography (silica gel: eluant: CHCl 3/ CH 3OH=98/2) purifying crude product.Make the semi-solid product of 400mg.Gaseous state HCl bubbling is gone in the AcOEt solution of this free alkali and corresponding hydrochloride.[α] 20 D＝+9.20°(c＝1％CH 3OH)。
Following product can make by similar mode:
S (+)-5-fluoro-2-methoxyl group-1H-Indole-3-Carboxylic Acid [1-[2-benzyloxy-carbonyl amino-3-benzyloxy propyl group)-piperidin-4-yl] methyl esters.[α] 20 D＝+1.20°(c＝1％CH 3OH)
S (-)-carbazole-9-carboxylic acid [1-[2-ethoxycarbonyl-amino-3-methoxycarbonyl-propyl group)-piperidin-4-yl] methyl esters.Fusing point: 85 ℃ [α] 20 D=-0.55 ° of (c=1%CH 3OH)
S (+)-5-fluoro-1H-Indole-3-Carboxylic Acid [1-[2-ethoxycarbonyl-amino-3-benzyloxy propyl group)-piperidin-4-yl]-methyl esters.[α] 20 D＝+6.90°(c＝1％CH 3OH)
R (-)-5-fluoro-1H-Indole-3-Carboxylic Acid [1-[2-ethoxycarbonyl-amino-3-benzyloxy propyl group)-piperidin-4-yl]-methyl esters.[α] 20 D＝-7.02°(c＝1％CH 3OH)
S (+)-carbazole-9-carboxylic acid [1-[2-ethoxycarbonyl-amino-3-phenyl-propyl group)-piperidin-4-yl]-methyl esters. (compound 6)[α] 20 D=+9.31 ° of (c=1%CH 3COOH) decompose (tartrate is got by ethyl acetate) during fusing point=118 ℃; M.S. (C.I.)=514m/e[M+H] analyze: C 35H 41N 3O 10
C H N measured value % 62.92 6.33 6.13 calculated value % 63.34 6.23 6.33S (+)-carbazole-9-carboxylic acid [1-[2-ethoxycarbonyl-amino-propyl group)-piperidin-4-yl]-methyl esters (compound 7)[α] 20 D=+13.68 ° of (c=1%CH 3COOH) decompose (hydrochloride is got by ethyl acetate) fusing point=196-198 ℃ the time; M.S. (C.I.)=438m/e[M+H] analyze: C 25H 32ClN 3O 4
C H N measured value % 63.30 6.81 8.81 calculated value % 63.35 6.81 8.87S (+)-1-Methyl-1H-indole-carboxylic acid 1-[2-(3-ethoxycarbonyl-amino)-propyl group]-piperidin-4-yl }-methyl esters (compound 8)[α] 20 D=+8.21 ° of (c=1%CH 3OH, hydrochloride) decomposes (hydrochloride is got by ethyl acetate) fusing point=200-204 ℃ the time; M.S. (C.I.)=478m/e[M+H] analyze: C 28H 38ClN 3O 4
C H N measured value % 65.34 7.08 8.12 calculated value % 65.42 7.06 8.17S (+)-4-amino-5-chloro-2-methoxyl group-phenylformic acid [1-(2-ethoxycarbonyl-amino-4-methylthio group-butyl)-piperidin-4-yl] methyl esters (compound 9)[α] 20 D=+3.98 ° of (c=1%CH 3OH, hydrochloride) decomposes (hydrochloride is got by ether) fusing point=151-153 ℃ the time; M.S. (C.I.)=489m/e[M+H] analyze: C 22H 35Cl 2N 3O 5S
C H N measured value % 49.81 6.79 7.85 calculated value % 50.38 6.73 8.01S (+)-4-amino-5-chloro-O-Anisic Acid [1-(2-carbobenzoxy-(Cbz)-amino-3-(1H-indol-3-yl)-propyl group)-piperidin-4-yl] methyl esters (compound 10)[α] 20 D=+0.58 ° of (c=1%CH 3OH, hydrochloride) decomposes (hydrochloride is got by ether) fusing point=191-193 ℃ the time; M.S. (C.I.)=606m/e[M+H] analyze: C 33H 38Cl 2N 4O 5
C H N measured value % 61.03 5.80 8.62 calculated value % 61.78 5.97 8.73S (+)-4-amino-5-chloro-O-Anisic Acid [1-[2-carbobenzoxy-(Cbz)-amino-3-phenyl-propyl group)-piperidin-4-yl] methyl esters (compound 11)[α] 20 D=+1.57 ° of (c=1%CH 3OH, hydrochloride) decomposes (hydrochloride is got by ether) fusing point=165-167 ℃ the time; M.S. (C.I.)=567m/e[M+H] analyze: C 31H 37Cl 2N 3O 5
C H N measured value % 60.85 6.14 6.86 calculated value % 61.79 6.19 6.97S (-)-5-fluoro-2-methoxyl group-1H-Indole-3-Carboxylic Acid [1-[(2-carbobenzoxy-(Cbz)-amino-3-phenyl)-propyl group)-piperidin-4-yl] methyl esters (compound 40)[α] 20 D=-1.2 ° of (c=1%CH 3OH).Decompose fumarate in the time of fusing point=155-160 ℃.M.S. (C.I.)=574m/e[M+H] analyze: C 33H 36FN 3O 5
C H N measured value % 63.90 5.86 6.12 calculated value % 64.43 5.85 6.09R (+)-5-fluoro-2-methoxyl group-1H-Indole-3-Carboxylic Acid 1-[(2-carbobenzoxy-(Cbz)-amino-3-phenyl)-propyl group)-piperidin-4-yl } methyl esters (compound 41)[α] 20 D=+1.16 ° of (c=1%CH 3OH).Decompose fumarate in the time of fusing point=154-158 ℃.M.S. (C.I.)=574m/e[M+H] analyze: C 33H 36FN 3O 5
C H N measured value % 64.30 5.90 6.05 calculated value % 64.43 5.85 6.09 Embodiment 3
S (+)-carbazole-9-carboxylic acid [1-(2-ethoxycarbonyl-amino-3-hydroxyl-propyl group)-piperidin-4-yl] methyl esters (compound 12)
(400mg 6.5mmol) joins simultaneously that (0.76g 1.3mmol) is dissolved in CH to methyl esters by S (+)-carbazole-9-carboxylic acid [1-(2-ethoxycarbonyl-amino-3-benzyloxy-propyl group)-piperidin-4-yl] with 10Pd/C (0.76g) and ammonium formiate 3In the solution of the middle gained of OH (30ml).This reaction mixture of reflux 40 minutes; After ending heating, when being cooled to room temperature, stir.Leach catalyzer and will clarify colourless solution evaporation to doing.Make the white solid of 330mg.[α] 20 D=+8.04 ° of (c=1%CH 3OH) decompose (hydrochloride is got by ether) during fusing point=190 ℃; M.S. (C.I.)=454m/e[M+H] analyze: C 25H 32ClN 3O 5
C H N measured value % 60.70 6.52 8.41 calculated value % 60.28 6.58 8.58
Make following compounds: S (+)-carbazole-9-carboxylic acid (1-[2-ethyl-urea groups)-3-hydroxyl-propyl group in a similar manner]-piperidin-4-yl } methyl esters Compound 13[α] 20 D=+10.27 ° of (c=1%CH 3OH, hydrochloride) decomposes (hydrochloride is got by ether) during fusing point=200 ℃; M.S. (C.I.)=453m/e[M+H] analyze: C 25H 33ClN 4O 4
C H N measured value % 61.05 6.75 11.16 calculated value % 61.40 6.8 11.46 Embodiment 4S (+)-4-amino-5-chloro-3-methoxybenzoic acid 1-[3-hydroxyl-2-(3-phenyl-urea groups)-propyl group]-piperidin-4-yl } methyl esters (compound 14)
Will be at CH 3CH 2Gaseous state HCl introducing S (+)-4-amino-5-chloro-O-Anisic Acid among the OH 1-[3-benzyloxy-2-(3-phenyl-urea groups)-propyl group]-piperidin-4-yl } methyl esters (1.5g, CH 2.5mmol) 3In OH (20ml) solution, up to obtaining tart pH value, and at the room temperature normal pressure and have in the presence of the 5%Pd/C (0.1g) the reaction mixture hydrogenation of gained 20 hours.Leach catalyzer and evaporating solvent to doing, get crude product, with chromatography (silica gel; Eluant: CH 2Cl 2/ CH 3OH/NH 4OH=93/7/0.7) purifying, and get white blister compound that solid requires (0.83g).Its corresponding hydrochloride can get by the diethyl ether solution of handling this compound with gaseous state HCl.[α] 20 D=+5.64 ° of (c=1%CH 3OH, hydrochloride) decomposes (hydrochloride is got by ether) fusing point=138-140 ℃ the time; M.S. (C.I.)=492m/e[M+H] analyze: C 24H 32Cl 2N 4O 5
C H N measured value % 53.31 6.37 10.42 calculated value % 54.65 6.12 10.62
Make following compounds according to said procedure: S (+)-4-amino-5-chloro-O-Anisic Acid 1-[2-(3-ethyl-urea groups)-3-hydroxyl-propyl group]-piperidin-4-yl } methyl esters (compound 15)[α] 20 D=+11.19 ° of (c=1%CH 3OH, hydrochloride) decompose (hydrochloride of lipophilization) M.S. (C.I.)=443m/e[M+H fusing point=60-70 ℃ the time] analyze: C 20H 32Cl 2N 4O 5
C H N measured value % 50.00 6.93 11.50 calculated value % 50.11 6.73 11.69S (+)-5-fluoro-1H-Indole-3-Carboxylic Acid 1-[2-(3-phenyl-urea groups)-3-hydroxyl-propyl group]-piperidin-4-yl } methyl esters (compound 16)[α] 20 D=+6.24 ° of (c=1%CH 3OH, hydrochloride) decomposes (hydrochloride is got by ether) during fusing point=210 ℃; M.S. (C.I.)=469m/e[M+H] analyze: C 25H 30FClN 4O 4
C H N measured value % 59.89 6.28 10.60 calculated value % 59.46 5.99 11.09S (+)-5-fluoro-2-methoxyl group-1H-Indole-3-Carboxylic Acid [1-[2-carbobenzoxy-(Cbz)-amino-3-hydroxyl-propyl group]-piperidin-4-yl } methyl esters (compound 17)[α] 20 D=+3.80 ° of (c=1%CH 3OH, hydrochloride) decomposes (hydrochloride is got by ether) fusing point=120-130 ℃ the time; M.S. (C.I.)=514m/e[M+H] analyze: C 27H 33FClN 3O 6
C H N measured value % 59.12 6.10 7.58 calculated value % 58.96 6.05 7.64R (-)-5-fluoro-2-methoxyl group-1H-Indole-3-Carboxylic Acid [1-(2-carbobenzoxy-(Cbz)-amino-3-hydroxyl-propyl group]-piperidin-4-yl } methyl esters (compound 18)[α] 20 D=-3.95 ° of (c=1%CH 3OH, hydrochloride).Decompose in the time of fusing point=124-132 ℃ (hydrochloride is got by ether); M.S. (C.I.)=514m/e[M+H] analyze: C 27H 33FClN 3O 6
C H N measured value % 58.70 6.11 7.60 calculated value % 58.96 6.05 7.64S (+)-5-fluoro-2-methoxyl group-1H-Indole-3-Carboxylic Acid [1-(2-ethoxycarbonyl-amino-3-hydroxyl-propyl group]-piperidin-4-yl } methyl esters (compound 19)[α] 20 D=+6.60 ° of (c=1%CH 3OH, hydrochloride) decomposes (hydrochloride is got by ether) fusing point=110-120 ℃ the time.M.S. (C.I.)=452m/e[M+H] analyze: C 22H 31FClN 3O 6
C H N measured value % 54.10 6.43 8.58 calculated value % 54.15 6.40 8.61R (-)-5-fluoro-2-methoxyl group-1H-Indole-3-Carboxylic Acid [1-(2-ethoxycarbonyl-amino-3-hydroxyl-propyl group]-piperidin-4-yl] methyl esters (compound 20)[α] 20 D=-6.43 ° of (c=1%CH 3OH, hydrochloride) decomposes (hydrochloride is got by ether) fusing point=109-114 ℃ the time.M.S. (C.I.)=452m/e[M+H] analyze: C 22H 31FClN 3O 6
C H N measured value % 53.99 6.45 8.55 calculated value % 54.15 6.40 8.61 Illustrative examples 8S (-)-1-(4-methylol-piperidines-1-yl)-2-benzyloxycarbonyl amino-propane-1-ketone
With 4-piperidine carbinols (14.2g, 0.123mol) [pharmaceutical chemistry (J.Med Chem.) (1991) 34,1073] anhydrous THF (140ml) solution joins the CBZ-L-L-Ala (25g that cools off under 5 ℃, 0.112mol) and 1, (18.2g is in anhydrous THF (250ml) solution 0.112mol) for the 1-carbonyl dimidazoles.At room temperature stir this reaction mixture after 4 hours, it is evaporated to dry doubling residue is dissolved in the ethyl acetate.With 5% aqueous hydrochloric acid, water and 17%Na 2CO 3The aqueous solution cleans this organic solution, and it is evaporated to drying.With chromatography (silica gel; Eluant: CH 2Cl 2/ CH 3OH=98/2) purifying residue is clarification product that dense buttery requires and get 24.8g.[α] 20 D＝-9.2°(c＝1％CH 3OH)。
Make following product: R (+)-1-(4-methylol-piperidines-1-yl)-2-benzyloxycarbonyl amino-propane-1-ketone [α] in a similar manner 20 D=+9.32 ° of (c=1%CH 3OH) S (-)-1-(4-methylol-piperidines-1-yl)-2-t-butoxycarbonyl amino-3-benzyloxy-propyl group-1-ketone [α] 20 D=-11.99 ° of (c=1%CH 3OH); Fusing point: 75 ℃ (decomposition) Illustrative examples 9S (-)-1-[4-(2-nitre phenyl-amino-carbonyl oxygen methyl)-piperidines-1-yl]-2-carbobenzoxy-(Cbz)-amino-propane-1-ketone
With isocyanic acid-2-nitro phenyl ester (9.2g, 56.1mmol) and S (-)-(4-methylol-1-yl)-2-carbobenzoxy-(Cbz)-propane-1-ketone (18g, THF 56.1mmol) (200ml) solution stirred under room temperature 24 hours.This reaction mixture is evaporated to dried, at purification by chromatography (silica gel; Eluant: cyclohexane/ethyl acetate=50/50), obtain low fusibleness solid and require product 17.5g.[α] 20 D＝-2.47°(c＝1％CH 3OH)。
Make in a similar manner: R (+)-1-[4-(2-nitre phenyl amino-carbonyl oxygen methyl)-piperidines-1-yl]-2-carbobenzoxy-(Cbz)-propane-1-ketone [α] 20 D=+2.41 ° of (c=1%CH 3OH) Illustrative examples 10S (+)-3-[4-(2-nitre phenyl-amino-carbonyl oxygen methyl)-piperidines-1-yl]-2-carbobenzoxy-(Cbz)-amino-propane
With S (-)-1-[4-(2-nitre phenyl-amino-carbonyl oxygen methyl)-piperidines-1-yl]-2-benzyloxycarbonyl amino-propane-1-ketone (16.5g, 34.1mmol) and the solution reflux of THF (102ml) solution gained in tetrahydrofuran (THF) of 1M borane coordination thing 4 hours.This reaction mixture is evaporated to dry doubling to be allocated between the ether and the 5%HCl aqueous solution.With ethyl acetate once more wash water solution once, with 17%Na 2CO 3The aqueous solution makes it become alkalescence, and institute's precipitated solid is extracted in the ethyl acetate.With this organic solution crystallization, dry and evaporate to dryness.With the isopropyl ether crystalline residue, and get desired compound (12.3g).[α] 20 D＝9.47°(c＝1％CH 3OH)。
Make in a similar manner: R (-)-3-[4-(2-nitre phenyl-amino-carbonyl oxygen methyl)-piperidines-1-yl]-2-carbobenzoxy-(Cbz)-propane [α] 20 D=-9.51 ° of (c=1%CH 3OH). Illustrative examples 11S (+)-3-[4-(2-aminophenyl-amino-carbonyl oxygen methyl)-piperidines-1-yl]-2-benzyloxycarbonyl amino-propane
With S (+)-3-[4-(2-nitre phenyl amino-carbonyl oxygen methyl)-piperidines-1-yl]-2-carbobenzoxy-(Cbz)-amino-propane (10g, 21.2mmol) and SnCl 22H 2(24g, 106.4mmol) the solution reflux in 95%EtOH is 30 minutes, cools off then and is evaporated to dried for O.To have the water dissolution residue of ether.With ethyl acetate washing water, again with 17%Na 2CO 3The aqueous solution makes it become alkalescence, and is extracted in the ethyl acetate.After this solution is dry and evaporation, make the product that requires of white solid, its purity is enough to be used in next step (7.7g).[α] 20 D＝-10.41°(c＝1％CH 3OH)。
Make in a similar manner: R (-)-3-[4-(2-amino-phenyl amino-carbonyl oxygen methyl)-piperidines-1-yl]-2-carbobenzoxy-(Cbz)-amino-propane [α] 20 D=-10.32 ° of (c=1%CH 3OH). Embodiment 5S (+)-2-oxygen-2,3-dihydro-benzoglyoxaline-1-carboxylic acid-[1-(2-carbobenzoxy-(Cbz)-amino)-propyl group-piperidin-4-yl] methyl esters (compound 21)
With S (-)-3-[4-(2-aminophenyl-amino-carbonyl oxygen methyl)-piperidines-1-yl]-2-benzyloxycarbonyl amino-propane (6.7g, 15.2mmol) and trichloromethylchloroformate (3.6g is 18.24mmol) at CH 2Cl 2Solution (100ml) at room temperature stirred 20 hours.This solution evaporation to dry doubling is distributed in residue between the ethyl acetate and the 5%HCl aqueous solution.Handle this acid solution with ethyl acetate, with 17%Na 2CO 3The aqueous solution makes it become alkalescence, and is extracted into CH 2Cl 2In.With these solution dehydrates and evaporate to dryness, and get the rough product that requires.Then with it by changing into corresponding hydrochloride and purifying (3.4g) with the acetone recrystallize.[α] 20 D=+17.14 ° of (c=1%CH 3OH), decompose (hydrochloride) M.S. (C.I.)=467m/e[M+H in the time of fusing point: 187-188 ℃] analyze: C 25H 31ClN 4O 5
C H N measured value % 59.07 6.21 10.99 calculated value % 59.70 6.25 11.14
Make in a similar manner: R (-)-2-oxygen-2,3-dihydro-benzoglyoxaline-1-carboxylic acid [1-(2-benzyloxycarbonyl amino)-propyl group-piperidin-4-yl] methyl esters (compound 22)[α] 20 D=-17.20 ° of (c=1%CH 3OH).Decompose (hydrochloride) M.S. (C.I.)=467m/e[M+H in the time of fusing point: 185-188 ℃] analyze: C 25H 31ClN 4O 5
C H N measured value % 59.19 6.20 11.12 calculated value % 59.70 6.25 11.14 Embodiment 6S (+)-3-ethyl-2-oxygen-2,3-dihydro-benzoglyoxaline-1-carboxylic acid [1-(2-carbobenzoxy-(Cbz)-amino)-propyl group-piperidin-4-yl] methyl esters (compound 23)
With iodoethane (1.44g, 9.2mmol) under room temperature, join S (+)-2-oxygen-2,3-dihydro-benzoglyoxaline-1-carboxylic acid [1-(2-benzene methoxycarbonyl amino)-propyl group-piperidin-4-yl] methyl esters (4.3g, 9.2mmol) and 80%NaH (0.28g is in dry DMF 9.2mmol) (40ml) solution.Under room temperature, stirred this solution 8 hours, be poured into then in the water (200ml).Throw out is extracted in the ethyl acetate also again with this organic solution of 5%HCl aqueous solution extraction.Wash this solution once with ethyl acetate again, with 17%Na 2CO 3The aqueous solution makes it become alkalescence also again with CH 2Cl 2Extraction.With this solution dehydrates and evaporate to dryness, and get desired compound.With chromatography (silica gel; Eluant: CH 2Cl 2/ CH 3OH=95/5) purifying (2g).[α] 20 D＝+17.33°(c＝1％CH 3OH)。Decompose (hydrochloride) M.S. (C.I.)=495m/e[M+H during 185 ℃ of fusing points] analyze: C 27H 35ClN 4O 5
C H N measured value % 60.59 6.68 10.45 calculated value % 61.07 6.64 10.55
Make in a similar manner: R (-)-3-ethyl-2-oxygen-2,3-dihydro-benzoglyoxaline-1-carboxylic acid [1-(2-carbobenzoxy-(Cbz)-amino)-propyl group-piperidin-4-yl] methyl esters (compound 24)[α] 20 D=-17.45 ° of (c=1%CH 3OH).Decompose (hydrochloride) M.S. (C.I.)=495m/e[M+H in the time of fusing point=184-187 ℃] analyze: C 27H 35ClN 4O 5
C H N measured value % 61.18 6.70 10.48 calculated value % 61.07 6.64 10.33 Illustrative examples 12S (+)-[1-(2-t-butoxycarbonyl amino-3-benzyloxy-propyl group)-piperidin-4-yl]-methyl alcohol
(16.5g, 42mmol) and the anhydrous THF solution of the 1M borane coordination thing in THF (126ml), reflux also stirred 16 hours with S (-)-t-butoxycarbonyl amino-3-benzyloxy-1-(4-methylol-piperidines-1-yl)-propane-1-ketone.With this reaction mixture evaporate to dryness, with ether dissolution and with twice of this solution of 5%HCl aqueous solution extraction.Each extraction liquid is closed in collection, with the ether washing and with 17%Na 2CO 3The aqueous solution makes it become alkalescence.The oily product is separated and be extracted in the ethyl acetate; Then that this solution washing is extremely neutral, dehydration and evaporate to dryness.With chromatography (silica gel; Eluant: CH 2Cl 2/ CH 3Behind the OH=95/5 purifying crude product, make the product that requires (11.2g) that is colorless oil.[α] 20 D＝+12.02°(c＝1％CH 3OH)
Can make in a similar manner: R (-)-[1-(2-t-butoxycarbonyl amino-3-benzyloxy-propyl group)-piperidin-4-yl] methyl alcohol [α] 20 D=-12.02 ° of (c=1%CH 3OH) Illustrative examples 13S (+)-5-fluoro-1H-Indole-3-Carboxylic Acid [1-(2-t-butoxycarbonyl amino-3-benzyloxy-propyl group)-piperidin-4-yl] methyl alcohol
(5.2g, (4g is 22.3mmol) at CH 24.5mmol) to be added in 5 ℃ of refrigerative 5-fluoro-1H-Indole-3-Carboxylic Acids [pharmaceutical chemistry (J.Med.Chem.) (1991), 34,140] with trifluoroacetic anhydride down in stirring 2Cl 2In the suspension of middle gained.After 90 minutes, under the stirring of uniform temp, with methylsulfonic acid (2.2g, 22.3mmol) and S (+) subsequently-[1-(2-t-butoxycarbonyl amino-3-benzyloxy-propyl group)-piperidin-4-yl]-methyl alcohol (8.5g, CH 22.32mmol) 2Cl 2(5ml) solution adds wherein apace.Under room temperature, stirred this reaction mixture 24 hours, then evaporate to dryness.With chromatography (silica gel; Eluant: CH 3OH/CH 2Cl 2/ NH 4OH=95/5/0.5) behind the purifying crude product, make low fusibleness product that solid requires (1.9g).[α] 20 D=+8.59 ° of (c=1%CH 3OH) Illustrative examples 14S (+)-5-fluoro-2-methoxyl group-1H-Indole-3-Carboxylic Acid [1-(2-t-butoxycarbonyl amino-3-benzyloxy-propyl group)-piperidin-4-yl] methyl alcohol
With S (+)-5-fluoro-1H-Indole-3-Carboxylic Acid [1-(2-t-butoxycarbonyl amino-3-benzyloxy-propyl group)-piperidin-4-yl] methyl esters (0.5g, 0.92mmol) and N-chloro-succinimide (0.19g is 1.38mmol) at CHCl 3In solution, under room temperature, stir and spend the night.With its evaporate to dryness and with CH 3OH (20ml) dissolution residual substance, and with gained solution stirring 24 hours.Behind evaporate to dryness, residue is dissolved in CH 2Cl 2In; With 17%Na 2CO 3This solution of solution washing once, then with water washing.Behind dehydration and evaporate to dryness, with chromatography (silica gel; Eluant: CH 2Cl 2/ CH 3OH=97/3) purifying residue, and must be the product that requires (0.18g) of colorless oil.[α] 20 D＝+5.70°(c＝1％CH 3OH)
Make following product: S (+)-5-fluoro-2-methoxyl group-1H-Indole-3-Carboxylic Acid [1-(2-ethoxycarbonyl amino-3-benzyloxy-propyl group)-piperidin-4-yl] methyl esters [α] in a similar manner 20 D=+3.99 ° of (c=1%CH 3OH) R (-)-5-fluoro-2-methoxyl group-1H-Indole-3-Carboxylic Acid [1-(2-ethoxycarbonyl amino-3-benzyloxy-propyl group)-piperidin-4-yl] methyl esters [α] 20 D=-4.06 ° of (c=1%CH 3OH) R (-)-5-fluoro-2-methoxyl group-1H-Indole-3-Carboxylic Acid [1-(uncle's 2-fourth carbonylamino-3-benzyloxy-propyl group)-piperidin-4-yl] methyl esters [α] 20 D=-5.46 ° of (c=1%CH 3OH) Illustrative examples 15S (-)-1-(2-t-butoxycarbonyl amino-3-benzyloxy-propionyl)-4-carbamyl-piperidines
With 1, (5.5g, 33.8mmol) add the N-t-Boc-O-Bz-L-Serine (10g is in anhydrous THF (58ml) solution 33.8mmol) in batches for the 1-carbonyl dimidazoles under stirring.After 30 minutes, (4.34g, the suspension that stirs gained 33.8mmol) and under room temperature spends the night, and gives evaporate to dryness then to add different piperidyl urea.With the acetic acid ethyl dissolution residue, and subsequently in regular turn with the 5%HCl aqueous solution, H 2O and 8%Na 2CO 3This organic solution of solution washing.Behind dehydration and evaporate to dryness, make low fusibleness platinum sponge shape product that solid requires (11.9g).[α] 20 D＝-10.28°(c＝1％CH 3OH)
Can make following product: R (+)-1-(t-butoxycarbonyl amino-3-benzyloxy propyl group)-4-carbamyl-piperidines [α] in a similar manner 20 D=+10.41 ° of (c=1%CH 3OH) S (-)-1-(t-butoxycarbonyl amino-4-methylthio group-butyryl radicals)-4-carbamyl-piperidines [α] 20 D=-24.19 ° of (c=1%CH 3OH) fusing point: 132-134 ℃ is decomposed R (+)-1-(t-butoxycarbonyl amino-4-methylthio group butyryl radicals)-4-carbamyl-piperidines [α] 20 D=+23.98 ° of (c=1%CH 3OH) fusing point: 130-132 ℃ is decomposed S (-)-3-(t-butoxycarbonyl amino-4-(4-carbamyl-piperidines-1-yl)-4-oxygen-methyl-butyrate [α] 20 D=-65.03 ° of (c=1%CH 3OH) fusing point: 121-123 ℃ is decomposed S (-)-3-benzyloxycarbonyl amino-4-(4-formamyl-piperidines-1-yl)-4-oxygen-methyl-butyrate [α] 20 D=-43.3 ° of (c=1%CH 3OH) fusing point: 160 ℃ are decomposed S (-)-1-(2-benzyloxycarbonyl amino)-propionyl-4-methane amide-piperidines [α] 20 D=-10.96 ° of (c=1%CH 3OH) R (+)-1-(2-benzyloxycarbonyl amino)-propionyl-4-methane amide-piperidines [α] 20 D=+11.05 ° of (c=1%CH 3OH) S (-)-4-methane amide-1-(3-phenyl-2-t-butoxycarbonyl amino)-propionyl-piperidines [α] 20 D=-1.2 ° of (c=1%CH 3OH) R (+)-4-methane amide-1-(3-phenyl-2-t-butoxycarbonyl amino)-propionyl-piperidines [α] 20 D=+1.35 ° of (c=1%CH 3OH) Illustrative examples 16S (+)-1-benzyloxymethyl-2-(4-aminomethyl-piperidines-1-yl)-N-tertbutyloxycarbonyl-ethamine
In 3 hours and under reflux; tetrahydrofuran (THF) (148ml) solution of 1M borane coordination thing is added S (-)-1-(2-t-butoxycarbonyl amino-3-benzyloxy propionyl)-4-carbamyl-piperidines in batches, and (15g is in anhydrous THF (100ml) solution 37mmol).Behind cooling and evaporate to dryness, residue is dissolved in the ethyl acetate.With the aqueous citric acid solution extraction, with the ethyl acetate washing, with the 8%Na of dilution 2CO 3The aqueous solution makes it become alkalescence, and with ethyl acetate extraction.After with this organic solution dehydration and evaporate to dryness, with chromatography (silica gel; Eluant: CH 2Cl 2/ CH 3OH/NH 4OH=90/10/1) purifying residue, and must be clarification product that dense buttery requires (5.6g).[α] 20 D＝+7.21°(c＝1％CH 3OH)
Make following product: R (-)-1-benzyloxymethyl-2-(4-aminomethyl-piperidines-1-yl)-N-tertbutyloxycarbonyl-ethamine [α] in a similar manner 20 D=-8.01 ° of (c=1%CH 3OH) R (+)-1-(4-aminomethyl-piperidines-1-base-methyl)-3-methylthio group-N-tertbutyloxycarbonyl-propylamine [α] 20 D=+14.48 ° of (c=1%CH 3OH) S (-)-1-(4-aminomethyl-piperidines-1-base-methyl)-3-methylthio group-N-tertbutyloxycarbonyl-propylamine [α] 20 D=-14.61 ° of (c=1%CH 3OH) S (-)-3-benzyloxycarbonyl amino-4-(4-aminomethyl-piperidines-1-yl) methyl-butyrate [α] 20 D=-1.90 ° of (c=1%CH 3OH) S (+)-2-(4-aminomethyl-piperidines-1-yl)-benzene methoxycarbonyl amino-1-methyl-ethamine [α] 20 D=+9.05 ° of (c=1%CH 3OH) R (-)-2-(4-aminomethyl-piperidines-1-yl)-benzyloxycarbonyl amino-1-methyl-ethamine [α] 20 D=-9.28 ° of (c=1%CH 3OH) S (+)-4-aminomethyl-1-[(3-phenyl-2-t-butoxycarbonyl amino)-and propyl group] piperidines [α] 20 D=+1.43 ° of (c=1%CH 3OH) R (-)-4-aminomethyl-1-[(3-phenyl-2-t-butoxycarbonyl amino)-and propyl group] piperidines [α] 20 D=-1.53 ° of (c=1%CH 3OH) Illustrative examples 173-ethyl-2-oxygen-2,3-dihydro-benzoglyoxaline-1-is chloroformyl
60 ℃ and stir under and have in the presence of a small amount of charcoal, heat 1-ethyl-2-oxygen-2,3-dihydro-benzoglyoxaline (5g, 0.025ml) and trichloromethylchloroformate (5.6g, 3.5ml) solution in THF.This solution is remained on 60 ℃ and stirred following 5 hours.After filtering and cooling off, its evaporate to dryness is got residue, behind this residue of ether crystallization, get the product that requires (4.4g) of white solid.Decompose in the time of fusing point: 99-105 ℃.
Make in a similar manner: 3-sec.-propyl-2-oxygen-2, the chloroformyl fusing point of 3-dihydro-benzoglyoxaline-1-: decompose in the time of 110-112 ℃ Illustrative examples 18S (+)-3-ethyl-2-oxygen-2,3-dihydro-benzoglyoxaline-1-methane amide [1-(2-t-butoxycarbonyl amino-3-benzyloxy-propyl group)-piperidin-4-yl-methyl]
With 3-ethyl-2-oxygen-2,3-dihydro-benzoglyoxaline-1-is chloroformyl, and (2.14g 10.8mmol) adds S (+)-1-benzyloxymethyl-2-(4-aminomethyl-piperidines-1-yl)-N-tertbutyloxycarbonyl ethamine (3.4g, CH 9mmol) in batches under stirring 2Cl 2(50ml) in the solution.After at room temperature stirring 4 hours, with this reaction mixture evaporate to dryness.Residue is dissolved in the ethyl acetate, then 8%Na to dilute 2CO 3Solution washing once.Behind dehydration and evaporate to dryness, with chromatography (silica gel; Eluant: cyclohexane/ethyl acetate=1/1) the desired product of purifying (3.6g): gray solid.[α] 20 D＝+5.19°(c＝1％CH 3OH)
Make following product: R (+)-3-ethyl-2-oxygen-2 in a similar manner, 3-dihydro-benzoglyoxaline-1-methane amide-[1-(2-t-butoxycarbonyl amino-4-methylthio group-butyl)-piperidin-4-yl-methyl] [α] 20 D=+9.95 ° of (c=1%CH 3OH) S (-)-3-ethyl-2-oxygen-2,3-dihydro-benzoglyoxaline-1-methane amide-[1-(2-t-butoxycarbonyl amino-4-methylthio group-butyl)-piperidin-4-yl-methyl] [α] 20 D=+10.01 ° of (c=1%CH 3OH) S (-)-2-oxygen-2,3-dihydro-benzoglyoxaline-1-methane amide-[1-(2-t-butoxycarbonyl amino-4-methylthio group-butyl)-piperidin-4-yl-methyl] [α] 20 D=-10.06 ° of (c=1%CH 3OH) fusing point: 65-68 ℃ of R (-)-3-ethyl-2-oxygen-2,3-dihydro-benzoglyoxaline-1-methane amide-[1-(2-t-butoxycarbonyl amino-3-benzyloxy-propyl group)-piperidin-4-yl-methyl] [α] 20 D=-4.38 ° of (c=1%CH 3OH) S (-)-3-sec.-propyl-2-oxygen-2,3-dihydro-benzoglyoxaline-1-methane amide-[1-(2-t-butoxycarbonyl amino-4-methylthio group-butyl)-piperidin-4-yl-methyl] [α] 20 D=-9.91 ° of (c=1%CH 3OH) fusing point: decompose S (+)-3-ethyl-2-oxygen-2,3-dihydro-benzoglyoxaline-1-methane amide-N-{1-[(2-tertbutyloxycarbonyl-amino-3-phenyl in the time of 55 ℃)-propyl group]-piperidin-4-yl-methyl } [α] 20 D=+1.63 ° of R (-)-3-ethyl-2-oxygen-2,3-dihydro-benzoglyoxaline-1-methane amide-N-{1-[(2-t-butoxycarbonyl amino-3-phenyl)-propyl group]-piperidin-4-yl-methyl } [α] 20 D=-1.70 ° Illustrative examples 19S (+)-3-benzyloxycarbonyl amino-4-(4-aminomethyl-piperidines-1-yl)-butyramide
With the anhydrous NH of gaseous state 3Slowly bubbling is gone into S (-)-3-benzyloxycarbonyl amino-4-(4-aminomethyl-piperidines-1-yl)-methyl-butyrate (0.7g, CH 1.9mmol) 3In OH (20ml) solution 8 hours.Under stirring, this solution was kept at room temperature two days, then evaporate to dryness.With residue with chromatography (silica gel; Eluant: CH 2Cl 2/ CH 3OH/NH 4OH=80/20/2) behind the purifying, make desired product (320mg).The light brown solid.[α] 20 D=+3.89 ° of (c=1%CH 3OH) Embodiment 7S (+)-3-ethyl-2-oxygen-2,3-dihydro-benzoglyoxaline-1-methane amide-[1-(2-benzyloxycarbonyl amino-3-carbamyl-propyl group)-piperidin-4-yl-methyl] (compound 25)
In room temperature and triethylamine (0.083g is arranged, 0.70mmol) exist down, (0.19g is 0.54mmol) with 3-ethyl-2-oxygen-2 with S (+)-3-benzyloxycarbonyl amino-4-(4-aminomethyl-piperidines-1-yl)-butyramide, 3-dihydro-benzoglyoxaline-1-is chloroformyl, and (0.13g is 0.65mmol) at CH 2Cl 2Solution stirring (20ml) 4 hours.This reaction mixture of 5%HCl aqueous solution extraction with dilution; Wash this acid solution with ethyl acetate again, and the 8%Na to dilute 2CO 3Aqueous solution neutralization.Isolated oily product is extracted in the ethyl acetate; With this solution of water washing, dehydration and evaporate to dryness, and get the rough product that requires.With chromatography (silica gel; Eluant: CH 2Cl 2/ CH 3OH/NH 4OH=95/5/0.5) purifying.(0.15g) [α] 20 D=+3.21 ° (c=1% is at CH 3Among the OH) fusing point: decompose (getting) M.S. (C.I.)=537m/e (M+H) in the time of 120 ℃ and analyze: C by ether 28H 36N 6O 5
C H N measured value % 61.98 6.79 15.60 calculated value % 62.67 6.76 15.67R (-)-3-ethyl-2-oxygen-2,3-dihydro-benzoglyoxaline-1-methane amide-N-{1-[(2-benzyloxycarbonyl amino)-propyl group]-piperidin-4-yl-methyl } (compound 42)[α] 20 D=-18.41 ° (c=1% is at CH 3OH).Decomposing (hydrochloride) M.S. (C.I.)=494m/e (M+H) in the time of fusing point: 177-178 ℃ analyzes: C 27H 36ClN 5O 4
C H N measured value % 60.53 6.83 13.02 calculated value % 61.18 6.85 13.21S (+)-3-ethyl-2-oxygen-2,3-dihydro-benzoglyoxaline-1-methane amide-N-{1-[(2-benzyloxycarbonyl amino)-propyl group]-piperidin-4-yl-methyl] (compound 43)[α] 20 D=+17.97 ° (c=1% is at CH 3Among the OH).Decomposing (hydrochloride) M.S. (C.I.)=494m/e (M+H) in the time of fusing point: 178-180 ℃ analyzes: C 27H 36N 5O 4
C H N measured value % 60.85 6.81 13.04 calculated value % 61.18 6.85 13.21R (-)-3-ethyl-2-oxygen-2,3-dihydro-benzoglyoxaline-1-methane amide-N-{1-[(2-benzyloxycarbonyl amino)-3-phenyl-propyl group]-piperidin-4-yl-methyl } (compound 44)[α] 20 D=-3.35 ° (c=1% is at CH 3OH (80)-CHCl 3(20) in) decompose M.S. (C.I.)=570m/e (M+H) during fusing point: 136-138 ℃ and analyze: C 33H 39N 5O 4
C H N measured value % 69.26 6.94 12.16 calculated value % 69.57 6.90 12.29S (+)-3-ethyl-2-oxygen-2,3-dihydro-benzoglyoxaline-1-methane amide-N-{1-{ (2-benzene methoxycarbonyl amino)-3-phenyl-propyl group]-piperidin-4-yl-methyl } (compound 45)[α] 20 D=+3.24 ° (c=1% is at CH 3OH (80)-CHCl 3(20) in).Decomposing M.S. (C.I.)=570m/e (M+H) in the time of fusing point: 136-138 ℃ analyzes: C 33H 39N 5O 4
C H N measured value % 69.02 6.88 12.15 calculated value % 69.57 6.90 12.29S (-)-3-ethyl-2-oxygen-2,3-dihydro-benzoglyoxaline-1-methane amide-N-{1-[(2-ethoxycarbonyl amino-3-carbamyl)-propyl group]-piperidin-4-yl-methyl } (compound 31)[α] 20 D=-1.1 ° (c=1% is at CH 3Among the OH).Decomposing M.S. (C.I.)=475m/e (M+H) in the time of fusing point: 128-130 ℃ analyzes: C 29H 34N 6O 5
C H N measured value % 57.90 7.18 17.58 calculated value % 58.21 7.22 17.71 Illustrative examples 20S (+)-3-ethyl-2-oxygen-2,3-dihydro-benzoglyoxaline-1-methane amide-[1-(2-amino-3-benzyloxy propyl group]-piperidin-4-yl-methyl]
Dry gaseous state HCl bubbling is blown at 5 ℃ of following refrigerative S (+)-3-ethyl-2-oxygen-2,3-dihydro-benzoglyoxaline-1-methane amide-[1-(2-t-butoxycarbonyl amino-3-benzyloxy propyl group]-piperidin-4-yl-methyl] (2.5g, in ethyl acetate 4.41mmol) (25ml) solution 20 minutes.With its evaporate to dryness and with the ether crystalline residue, and the product that requires of hydrochloride form.[α] 20 D=+1.97 ° (c=1% is at CH 3OH is at CH 3Among the OH), decompose in the time of fusing point: 85-90 ℃
Make following product: S (+)-3-ethyl-2-oxygen-2 in a similar manner, 3-dihydro-benzoglyoxaline-1-methane amide-[1-(2-amino-4-methylthio group-butyl]-piperidin-4-yl-methyl] [α] 20 D=+12.88 ° of (c=1%CH 3OH, hydrochloride) decompose (hydrochloride) R (-)-3-ethyl-2-oxygen-2 fusing point: 118-120 ℃ the time, 3-dihydro-benzoglyoxaline-1-methane amide-[1-(2-amino-4-methylthio group-butyl]-piperidin-4-yl-methyl] [α] 20 D=-12.52 ° of (c=1%CH 3OH, hydrochloride) decompose (hydrochloride) S (+)-3-sec.-propyl-2-oxygen-2 fusing point: 112-115 ℃ the time, 3-dihydro-benzoglyoxaline-1-methane amide-[1-(2-amino-4-methylthio group-butyl]-piperidin-4-yl-methyl] [α] 20 D=+14.19 ° of (c=1%CH 3OH, hydrochloride) decompose (hydrochloride) S (+)-2-oxygen-2 fusing point: 160-165 ℃ the time, 3-dihydro-benzoglyoxaline-1-methane amide-[1-(2-amino-4-methylthio group-butyl]-piperidin-4-yl-methyl] [α] 20 D=+15.61 ° (c=1% is at CH 3OH, hydrochloride) decompose (hydrochloride) S (+)-3-ethyl-2-oxygen-2,3-dihydro-benzoglyoxaline-1-methane amide-N-{1-[(2-amino-3-phenyl fusing point: 220-225 ℃ the time)-propyl group]-piperidin-4-yl-methyl] [α] 20 D=+6.12 ° of R (-)-3-ethyl-2-oxygen-2,3-dihydro-benzoglyoxaline-1-methane amide-N-{1-[(2-amino-3-phenyl)-propyl group]-piperidin-4-yl-methyl] [α] 20 D=-6.01 ° Embodiment 8S (-)-3-ethyl-2-oxygen-2,3-dihydro-benzoglyoxaline-1-methane amide-1-[2-(3-phenyl-urea groups)-4-methylthio group-butyl]-piperidin-4-yl-methyl] (compound 26)
With S (+)-3-ethyl-2-oxygen-2,3-dihydro-benzoglyoxaline-1-methane amide-[1-(2-amino-4-methylthio group butyl]-piperidin-4-yl-methyl] (0.8g, 1.90mmol) and phenylcarbimide (0.227g, THF 1.9mmol) (15ml) solution, under room temperature, stirred 30 minutes, then evaporate to dryness.With chromatography (silica gel; Eluant: CH 2Cl 2/ CH 3OH=95/5) behind the purifying, make the product that requires (0.65g) of shaping.[α] 20 D=5.80 ° of (c=1%CH 3OH) decompose in the time of fusing point: 195-198 ℃ (hydrochloride).M.S. (C.I.)=539m/e (M+H) analyzes: C 28H 30ClN 6O 5S
C H N measured value % 59.00 6.80 14.66 calculated value % 58.47 6.83 14.61
Can make following product: R (+)-3-ethyl-2-oxygen-2 in a similar manner, 3-dihydro-benzoglyoxaline-1-methane amide-1-[2-(3-phenyl-urea groups)-4-methylthio group-butyl]-piperidin-4-yl-methyl } (compound 27)[α] 20 D=-5.49 ° of (c=1%CH 3OH).Decomposition (hydrochloride) M.S. (C.I.) in the time of fusing point: 195-200 ℃=+ 539m/e (M+H) analysis: C 28H 29ClN 6O 3S
C H N measured value % 58.20 6.90 14.50 calculated value % 58.47 6.83 14.61S (+)-3-ethyl-2-oxygen-2,3-dihydro-benzoglyoxaline-1-methane amide-1-[2-(3-ethyl-urea groups)-4-methylthio group-butyl]-piperidin-4-yl-methyl } (compound 28)[α] 20D=+3.85 ° of (c=1%CH 3OH, hydrochloride).Decomposing (hydrochloride) M.S. (C.I.)=491m/e (M+H) in the time of fusing point: 189-194 ℃ analyzes: C 24H 39ClN 6O 3S
C H N measured value % 54.60 7.53 15.56 calculated value % 54.69 7.46 15.94S (-)-2-oxygen-2,3-dihydro-benzoglyoxaline-1-methane amide-1-[2-(3-phenyl-urea groups)-4-methylthio group-butyl]-piperidin-4-yl-methyl } (compound 29)[α] 20 D=-5.08 ° of (c=1%CH 3OH).Decomposing M.S. (C.I.)=511m/e (M+H) in the time of fusing point: 174-176 ℃ analyzes: C 26H 34N 6O 3S
C H N measured value % 61.02 6.80 16.38 calculated value % 61.15 6.71 16.46S (+)-3-ethyl-2-oxygen-2,3-dihydro-benzoglyoxaline-1-methane amide-1-[3-benzyloxy-2-(3-phenyl-urea groups)-propyl group]-piperidin-4-yl-methyl } [α] 20 D=+7.6 ° of (c=1%CH 3OH, hydrochloride) decompose (hydrochloride) S (+)-3-ethyl-2-oxygen-2 fusing point: 170-180 ℃ the time, 3-dihydro-benzoglyoxaline-1-methane amide-1-[3-benzyloxy-2-(3-ethyl-urea groups)-propyl group]-piperidin-4-yl-methyl } [α] 20 D=+8.69 ° of (c=1%CH 3OH) S (+)-3-ethyl-2-oxygen-2,3-dihydro-benzoglyoxaline-1-methane amide-1-[2-(3-phenyl-urea groups)-3-carbamyl-propyl group]-piperidin-4-yl-methyl } (compound 30)[α] 20 D=+0.65 ° of (c=1%CH 3OH, hydrochloride).Decompose (hydrochloride) M.S. (C.I.)=522m/e[M+H in the time of fusing point: 126-130 ℃] analyze: C 27H 35N 7O 4
C H N measured value % 62.03 6.80 18.71 calculated value % 62.17 6.57 18.80 Embodiment 9S (+)-2-oxygen-2,3-dihydro-benzoglyoxaline-1-methane amide-[1-(2-ethoxycarbonyl amino-4-methylthio group-butyl]-piperidin-4-yl-methyl] (compound 32)
In stir down with Vinyl chloroformate (0.2g 1.83mmol) joins S (+)-2-oxygen-2,3-dihydro-benzoglyoxaline-1-methane amide-[1-(2-amino-4-methylthio group-butyl]-piperidin-4-yl-methyl] (80.6g, CH 1.53mmol) 2Cl 2In the suspension (10ml).This reaction mixture sat is spent the night, then evaporate to dryness.With H 2O (10ml) and the 17%HCl aqueous solution (0.5ml) dissolution residual substance.The throw out of gained is filtered and drying.Behind the acetone recrystallize, make the product that requires of hydrochloric acid form, 0.53g.[α] 20 D=+4.98 ° of (c=1%CH 3OH, hydrochloride) fusing point: decompose (hydrochloride) M.S. (C.I.)=464m/e (M+H) in the time of 240 ℃ and analyze: C 22H 34ClN 5O 4S
C H N measured value % 52.70 6.91 13.90 calculated value % 52.84 6.85 14.01
Make following product: S (+)-3-sec.-propyl-2-oxygen-2 in a similar manner, 3-dihydro-benzoglyoxaline-1-methane amide-[1-(2-ethoxycarbonyl amino-4-methylthio group-butyl)-piperidin-4-yl-methyl] (compound 33)[α] 20 D=+4.72 ° of (c=1%CH 3OH, hydrochloride) decomposes (hydrochloride get by acetone-ether) M.S. (C.I.)=506m/e (M+H) analysis: C fusing point: 172-175 ℃ the time 26H 40ClN 5O 4S
C H N measured value % 55.21 7.51 12.85 calculated value % 55.39 7.44 12.92S (+)-3-ethyl-2-oxygen-2,3-dihydro-benzoglyoxaline-1-methane amide-[1-(2-ethoxycarbonyl amino-4-methylthio group-butyl)-piperidin-4-yl-methyl] (compound 34)[α] 20 D=+6.60 ° of (c=1%CH 3OH, hydrochloride) decomposes (hydrochloride, ether and get) M.S. (C.I.)=492m/e (M+H) analysis: C fusing point: 180-185 ℃ the time 24H 38ClN 5O 4S
C H N measured value % 54.08 7.30 13.20 calculated value % 54.54 7.25 13.26 Illustrative examples 21R (-)-3-ethyl-2-oxygen-2,3-dihydro-benzoglyoxaline-1-methane amide-[1-(2-amino-3-hydroxypropyl)-piperidin-4-yl-methyl]
At normal pressure and H 2Under the atmosphere and the CH that 25%HCl is arranged 3CH 2OH (1.5ml) solution exists down, continue to rock R (-)-3-ethyl-2-oxygen-2,3-dihydro-benzoglyoxaline-1-methane amide-[1-(2-butoxy carbonyl amino-3-benzyloxy propyl group)-piperidin-4-yl-methyl] (1.5g, 2.65mmol) and 10%Pd/C (150mg) at CH 3CH 2Suspension among the OH (20ml).After 48 hours, leach catalyzer and with the solution evaporate to dryness; Residue is dissolved in H 2Among the O and with rare 8%K 2CO 3Aqueous solution neutralization.Semi-solid throw out is extracted in the ethyl acetate, behind evaporate to dryness, makes the low fusibleness product that solid requires of white.[α] 20 D＝-3.30°(c＝1％CH 3OH)
Make in a similar manner: S (+)-3-ethyl-2-oxygen-2,3-dihydro-benzoglyoxaline-1-methane amide-[1-(2-amino-3-hydroxyl-propyl group)-piperidin-4-yl-methyl] [α] 20 D=+3.5 ° of (c=1%CH 3OH) Embodiment 10S (+)-3-ethyl-2-oxygen-2,3-dihydro-benzoglyoxaline-1-methane amide-1-[2-(3-phenyl-urea groups)-3-hydroxyl-propyl group]-piperidin-4-yl-methyl } (compound 35)
In room temperature normal pressure and H 2Under the atmosphere, with S (+)-3-ethyl-2-oxygen-2,3-dihydro-benzoglyoxaline-1-methane amide-{ 1-[3-benzyloxy-2-(3-phenyl-urea groups)-propyl group]-piperidin-4-yl-methyl } (0.53g, 0.85mmol) and 10%Pd/C (100mg) at anhydrous CH 3CH 2Suspension among the OH (10ml) shook 48 hours.Leach catalyzer and evaporate to dryness solution.After the ether crystallization, make the desired product of Off-white solid, 0.36g.[α] 20 D=+5.30 ° of (c=1%CH 3OH) fusing point: 98-101 ℃ M.S. (C.I.)=495m/e (M+H) analyzes: C 26H 34N 6O 4
C H N measured value % 63.05 7.00 16.87 calculated value % 63.14 6.93 16.99
Can make following compounds: S (+)-3-ethyl-2-oxygen-2 in a similar manner, 3-dihydro-benzoglyoxaline-1-methane amide-1-[2-(3-ethyl urea groups-3-hydroxyl-propyl group]-piperidin-4-yl-methyl } (compound 36)[α] 20 D=+20.50 ° of (c=1%CH 3OH, hydrochloride).Decomposing (hydrochloride) M.S. (C.I.)=447m/e (M+H) in the time of fusing point: 170-175 ℃ analyzes: C 22H 35ClN 6O 4
C H N measured value % 54.61 7.39 17.22 calculated value % 54.71 7.30 17.40S (+)-3-ethyl-2-oxygen-2,3-dihydro-benzoglyoxaline-1-methane amide-[1-(2-benzyloxycarbonyl amino-3-hydroxyl-propyl group)-piperidin-4-yl-methyl] (compound 37)[α] 20 D=+15..7 ° (c=1%CH 3OH, hydrochloride).Decomposing (hydrochloride is got by ether) M.S. (C.I.)=510m/e (M+H) in the time of fusing point: 192-198 ℃ analyzes: C 27H 36ClN 5O 5
C H N measured value % 59.17 6.70 11.99 calculated value % 59.39 6.65 12.03R (-)-3-ethyl-2-oxygen-2,3-dihydro-benzoglyoxaline-1-methane amide-[1-(2-benzyloxycarbonyl amino-3-hydroxyl-propyl group)-piperidin-4-yl-methyl] (compound 38)[α] 20 D=-15.9 ° of (c=1%CH 3OH, hydrochloride).Decomposing (hydrochloride is got by ether) M.S. (C.I.)=510m/e (M+H) in the time of fusing point: 194-197 ℃ analyzes: C 27H 36ClN 5O 5
C H N measured value % 59.20 6.70 12.00 calculated value % 59.39 6.65 12.03 Illustrative examples 22S (+)-1-(2-amino-3-phenyl-propionyl)-piperidin-4-yl-methane amide
In the room temperature normal pressure down and 10%Pd/C (1.2g) and gaseous state HCl are being arranged at Et 2O (3.4ml, 0.03mol) under the existence in, with S (+)-1-(2-benzyloxycarbonyl amino-3-phenyl-propionyl]-(12.5g is 0.03mol) at CH for piperidin-4-yl-methane amide 3Solution hydrogenation among the OH (200ml) 20 hours.After leaching catalyzer, with this solution evaporate to dryness, with Et 2After the O crystallization, make the product that requires (9g) of hydrochloride form.[α] 20 D=+33.83 ° of (c=1%CH 3OH) Illustrative examples 23S (+)-1-(2-ethoxycarbonyl amino-3-phenyl-propionyl]-piperidin-4-yl-methane amide
With Vinyl chloroformate (2.67ml, 0.027ml) be added dropwise to S (+)-1-of cooling under 0 ℃ (2-amino-3-phenyl-propionyl]-piperidin-4-yl-methane amide (7g, 0.025mol) and triethylamine (3.5ml, CH 0.025mol) 2Cl 2(70ml) in the solution.Continue down to stir this reaction mixture 30 minutes in 0 ℃; With the solvent evaporate to dryness, with the 5%HCl dissolution residual substance and be extracted in the ethyl acetate.With this organic phase dehydration and evaporation, and get white foam shape product that solid requires (5.3g).[α] 20 D=+8.89 ° of (c=1%CH 3OH) Illustrative examples 24S-2-(4-ethoxycarbonyl aminomethyl-piperidines-1-yl)-1-benzyl ethamine
Will (5g, 0.015mol), (57.5ml be 0.058mol) in the solution to be added dropwise to the THF of borane coordination thing at S (+)-1-among the THF (60ml) (2-ethoxycarbonyl amino-3-phenyl-propyl group)-piperidin-4-yl-methane amide.Heated this reaction mixture 6 hours down in 60 ℃; Then add CH 3OH (10ml) and with the solvent evaporate to dryness.With 5%HCl aqueous solution dissolution residual substance, with 5%NaHCO 3The aqueous solution makes it become alkalescence and with CH 2Cl 2Extraction.Collect each organic phase and dewater and evaporate to dryness.With chromatography (silica gel; Eluant: CH 2Cl 2/ CH 3OH/NH 4OH=90/10/1) product that requires of acquisition yellow solid behind the purifying residue, this purifying is enough to be used in next step (1.73g). Embodiment 11S (+)-4-amino-N-[1-(2-ethoxycarbonyl amino-3-phenyl-propyl group)-piperidin-4-yl-methyl]-5-chloro-2-methoxyl group-benzamide (compound 39)
With 1, (0.81g, (1.01g 5mmol) in the mixture in THF (20ml), and stirred 30 minutes under room temperature the 1-carbonyl dimidazoles 5mmol) to join 4-amino-5-chloro-2-methoxyl group-phenylformic acid.((1.6g 5mmol), and stirs under room temperature and spends the night 2-(4-ethoxycarbonyl aminomethyl-piperidines-1-yl)-1-benzyl-ethamine to be added dropwise to S-in THF (10ml) then.With the solvent evaporate to dryness, with the water dissolution residue and with ethyl acetate extraction.Collect each organic phase, and dehydration and evaporate to dryness.With chromatography (silica gel; Eluant: CH 2Cl 2/ CH 3OH=96/4) behind the purifying residue, obtain white foam shape product that solid requires (0.52g).Dry gaseous state HCl is imported in the diethyl ether solution of this alkali, and get corresponding hydrochloride.[α] 20 D=+12.78 ° of (c=1%CH 3OH, hydrochloride).Decomposing (hydrochloride is got by ether) M.S. (C.I.)=504.05m/e (M+H) in the time of fusing point: 167-169 ℃ analyzes: C 26H 36Cl 2N 4O 4
C H N measured value % 56.55 6.79 10.29 calculated value % 57.88 6.73 10.39
To be explanation mix the active ingredient of formula I in the habitual pharmaceutical composition and use by the present invention the following example, but non-ly be used to limit the present invention. Embodiment 12The heavy 200mg preparation method of the active ingredient 5mg lactose 158mg Microcrystalline Cellulose 35mg Magnesium Stearate BP 2mg tablet of tablet formula I: active ingredient is sieved by 24 purposes, with lactose, Microcrystalline Cellulose and Magnesium Stearate are admixed again.The mixture of gained is pressed into the heavy tablet of every 200mg.Each tablet contains the active ingredient of 5mg. Embodiment 13The active ingredient 5mg lactose 158mg Magnesium Stearate BP 2mg filling weight 200mg preparation method of capsule-type I, sieving active ingredient and with the blending of it and vehicle.Utilize proper device that this mixture is filled in the hard gel capsule. Embodiment 14The active ingredient 5mg Vltra tears USP 45mg buffer reagent seasonings tinting material of syrup formula I optionally sanitas sweetener pure water BP makes total amount reach the 10ml preparation method: Vltra tears is dispersed in the hot water, cooling then, and with contain the aqueous solution that active ingredient and other are mixed with part.Adjust the volume of gained solution and give mixing again.Filter this syrup of clarification. Embodiment 15The active ingredient 1 sodium-chlor BP of medicine administered by injection %W/V formula I optionally water for injection BP makes total amount reach 100 can to add sodium-chlor adjusting the tension force of solution, and usable acid or alkali are adjusted pH to the best stabilized sexual state and/or facilitate the dissolving of active ingredient.Also can use suitable buffer reagent salt in addition.
The preparation method: preparation and settled solution are filled to it then in the ampoule of appropriate size and by glass melting and seal.Heat with this injection of sterilizing through in autoclave, using acceptable circulation.Perhaps can be by the mode of filtering and under aseptic condition, be filled to the sterilization ampoule this solution of sterilizing.This solution can be packed under inert nitrogen or other suitable gas atmospheres. Embodiment 16The semisynthetic glycerin fatty acid ester 193mg of the active ingredient 15mg preparation method of suppository formula I: the suspension of preparation active ingredient in the semi-synthetic fatty acid glycerine of fused, use proper device that it is filled in the suppository mold then.

Claims (15)

  1. The compound of general formula (I) and with the formed acid salt of the acceptable acids of pharmacology
    Figure A9619250000021
    Wherein
    A is selected from following group:
    Structure is following is substituted phenyl R wherein 1Be C 1-3Alkoxyl group and R 2Be halogen; Be selected from two following ring or tricyclic heterocyclic bases
    Figure A9619250000023
    R wherein 3Be hydrogen or halogen, R 4Be hydrogen or C 1-3Alkyl, R 5Be hydrogen or C 1-3Alkoxyl group, R 6C for hydrogen or straight or branched 1-6Alkyl;
    X is oxygen or NH;
    Y is-OR 7Or NHR 7, R wherein 7Be C 1-3Alkyl, aryl or aralkyl;
    R is hydrogen, phenyl, hydroxyl, benzyloxy, methylthiomethyl, 3-indyl, methoxycarbonyl or formamyl.
  2. 2. compound as claimed in claim 1 and with pharmacology on the formed acid salt of acceptable acids, wherein A is a group (c) or (d), R 3Be halogen, R 4Be hydrogen or C 1-3Alkyl, R 5Be C 1-3Alkoxyl group, R 6C for straight or branched 1-6Alkyl, X are oxygen or NH, and Y is OR 7R wherein 7Be C 1-3Alkyl, aryl or aralkyl, R are hydrogen, hydroxyl, benzyloxy or formamyl.
  3. 3. as the physiologically acceptable hydrochlorate of general formula (I) compound of claim 1-2.
  4. 4. salt as claimed in claim 3 is characterized in that, physiologically acceptable acid is hydrochloric acid, Hydrogen bromide, toxilic acid, fumaric acid, methylsulfonic acid.
  5. 5. the preparation method of general formula as claimed in claim 1 (I) compound is characterized in that, when X be oxygen and Y as defined in claim 1, then in polarity or non-polar solvent, at 0 ℃ to the solvent refluxing temperature, with the compound of following formula (VI)
    Figure A9619250000031
    With isocyanic ester R 7NCO reaction, the A among its Chinese style VI as defined in claim 1, and R is hydrogen, phenyl, methylthiomethyl, indyl and R in the isocyanic ester 7As defined in claim 1.
  6. 6. preparation method as claimed in claim 5 is characterized in that, in inert solvent and have acid acceptor in the presence of, in 0 ℃ to the solvent refluxing temperature, with formula (VI) compound and chloro-formic ester R 7OCOCl reaction, wherein R 7Such as claim 1 definition.
  7. 7. as the preparation method of claim 5 and 6, it is characterized in that, when the R in formula (VI) compound is hydroxyl, it be by its precursor benzyloxy as claim 5 and 6 with the reaction of isocyanic ester or chloro-formic ester after, make by the reducing program that in the presence of Pd/C, carries out with hydrogen.
  8. 8. as the preparation method of claim 5 and 6, it is characterized in that, when the R in formula (VI) compound is carbamyl, then it is as described in claim 5 and 6 by its precursor carbalkoxy, after isocyanic ester or chloro-formic ester reaction, by in protic or non-protonic solvent, under 0-30 ℃, carry out ammonolysis and make with gaseous ammonia.
  9. 9. the preparation method of general formula as claimed in claim 1 (I) compound is characterized in that, when X be nitrogen and Y as defined in claim 1, then in polarity or non-polar solvent, in 0 ℃ to the solvent refluxing temperature, with formula (XVIII) compound and isocyanic ester R 7NCO reacts wherein A as defined in claim 1, and R is hydrogen, phenyl, methylthiomethyl and indyl, the R in the isocyanic ester 7As defined in claim 1.
  10. 10. preparation method as claimed in claim 9 is characterized in that, in inert solvent and have in the presence of the acid acceptor, in 0 ℃ to the solvent refluxing temperature, with formula XVIIII compound and chloro-formic ester R 7OCOCl reacts wherein R 7As defined in claim 1.
  11. 11. preparation method as claim 9 and 10, it is characterized in that, when the R in formula (XVIII) compound is hydroxyl, it be by its precursor benzyloxy as claim 9 and 10 with the reaction of isocyanic ester or chloro-formic ester after, make by in the presence of Pd/C, carrying out the reductive program with hydrogen.
  12. 12. preparation method as claim 9 and 10, it is characterized in that, when the R in the formula XVIII compound is carbamyl, it be by its precursor carbalkoxy as claim 9 and 10 with the reaction of isocyanic ester or chloro-formic ester after, by in protic or non-protonic solvent, under 0-30 ℃, carry out ammonolysis and make with gaseous ammonia.
  13. 13. the preparation method of general formula as claimed in claim 1 (I) compound is characterized in that, when X be nitrogen and Y as defined in claim 1, then in inert solvent, in the presence of organic bases, and at 10 ℃ to the solvent refluxing temperature, with the compound of formula (XXIV) and the compound reaction of formula (XXI)
    Figure A9619250000041
    Figure A9619250000042
    Among the formula XXIV R and Y as defined in claim 1,
    A-CO-W (XXI)
    Among the formula XXI W be suitable leaving group and A as defined in claim 1.
  14. 14. pharmaceutical composition, it comprises the compound of defined general formula 1 in the claim 1 of significant quantity, or its single enantiomorph or relevant racemic mixture, or its biological acceptable salt, as active constituent, and combine with pharmaceutically acceptable carrier or vehicle.
  15. 15. the application of the compound of claim 1 and 2 in medication preparation, it is uneven that this medicine is used for the treatment of cardiac rhythm, intestinal motility imbalance, anxiety, depression, psychosis, cognition disease, motility disease, excessive drinking and migraine.
CN 96192500 1995-03-14 1996-03-04 Di-substituted 1, 4 -piperidine esters and amides having 5-HT4 antagonistic activity Pending CN1178524A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN 96192500 CN1178524A (en) 1995-03-14 1996-03-04 Di-substituted 1, 4 -piperidine esters and amides having 5-HT4 antagonistic activity

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI95A000491 1995-03-14
CN 96192500 CN1178524A (en) 1995-03-14 1996-03-04 Di-substituted 1, 4 -piperidine esters and amides having 5-HT4 antagonistic activity

Publications (1)

Publication Number Publication Date
CN1178524A true CN1178524A (en) 1998-04-08

Family

ID=5128311

Family Applications (1)

Application Number Title Priority Date Filing Date
CN 96192500 Pending CN1178524A (en) 1995-03-14 1996-03-04 Di-substituted 1, 4 -piperidine esters and amides having 5-HT4 antagonistic activity

Country Status (1)

Country Link
CN (1) CN1178524A (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1968946B (en) * 2004-06-15 2011-12-21 辉瑞大药厂 benzimidazolone carboxylic acid derivatives

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1968946B (en) * 2004-06-15 2011-12-21 辉瑞大药厂 benzimidazolone carboxylic acid derivatives

Similar Documents

Publication Publication Date Title
JP4559230B2 (en) Novel N-arylsulfonyl-3-substituted indoles having affinity for serotonin receptors, methods for their preparation, and pharmaceutical compositions containing them
JP4021477B2 (en) Di-substituted 1,4-piperidine esters and amides having 5-HT4 antagonistic action
CN1037439C (en) Neuroprotective indolone and related derivatives
CN1273451C (en) Piperidine MCH antagonists and their use in treatment of obesity
CN1072664C (en) Novel aryl glycinamide derivatives, method of producing said derivatives and pharmaceutical compositions containing these compounds
CN1162409C (en) Depsipeptide deriv., its intermediate and method for preparing said intermediate
CN1129449A (en) Heterocycles useful as neurokinin antagonists
CN1141043A (en) Non-peptide tachykinin receptor antagonists
CN1882541A (en) derivatives of n-[phenyl(alkylpiperidine-2-yl)methyl]benzamide, preparation method thereof and application of same in therapeutics
CN1649845A (en) Muscarinic antagonists
CN1079964A (en) The  (oxazolidinon-5-yl-methyl)-2-thiophene-carboxamides antiseptic-germicide that contains the substituted diazine moieties base
CN1287487A (en) Aminophenoxyacetic acid derivatives as neuroprotectants and pharmaceutical composition containing the same
CN1378539A (en) Thiocarbamic acid derivatives
CN1882534A (en) Derivatives of n-[phenyl(pyrrolidine-2-yl)methyl]benzamide and n-[(azepan-2-yl)phenylmethyl]benzamide, preparation method thereof and application of same in therapeutics
CN1261887A (en) Azetidinyl propylpiperidine derivatives, intermediates and use as tachykinin antagonists
JP2005529866A (en) Benzoxazinone derivative compounds, their preparation and use as pharmaceuticals
CN1119328C (en) Acylaminoalkenylene-amide derivatives as NK1 and NK2 antagonists
CN1105360A (en) 1-[2H-1-benzopyran-2-one-8yl]-piperazin derivative
CN1113059C (en) Piperazino derivatives as neurokinin antagonists
CN1125575A (en) Adhesion receptor antagonists
CN1266433A (en) Benzpyrido cycloheptane compounds useful for inhibition of franesyl protein transferase
CN1144788C (en) Bicycle vasporession agonists
CN1134149A (en) Phenylindole compounds
CN1121390C (en) Novel substituted pyridino arylpiperazines useful in the treatment of benign prostatic hyperplasia
CN1167682C (en) Muscarinic antagonists

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C01 Deemed withdrawal of patent application (patent law 1993)
WD01 Invention patent application deemed withdrawn after publication