CN1219933A - Novel oxazolidine derivatives, process for their production and medicaments containing them - Google Patents

Novel oxazolidine derivatives, process for their production and medicaments containing them Download PDF

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CN1219933A
CN1219933A CN97195072A CN97195072A CN1219933A CN 1219933 A CN1219933 A CN 1219933A CN 97195072 A CN97195072 A CN 97195072A CN 97195072 A CN97195072 A CN 97195072A CN 1219933 A CN1219933 A CN 1219933A
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hydrogen atom
oxo
octahydro
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benzoxazole
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C·特萨克拉基迪斯
L·多尔格
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Roche Diagnostics GmbH
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Priority claimed from DE1996154479 external-priority patent/DE19654479A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

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Abstract

The present invention relates to novel oxazolidine derivatives, a process for their production and medicaments containing said substances. The object of the present invention are compounds of the general formula (I) in which the symbols have the meanings given in the claims.

Description

Xin De oxazolidine derivative, its preparation method and contain the pharmaceutical preparation of these compounds
Known when have between alkalescence and the acidic-group very specific apart from the time, the compound of band alkalescence and acidic-group can suppress platelet aggregation (Drugs of the Future 19 (2): 135-159 (1994)).The compound that thrombocyte is had anticoagulation is described in following patent: WO 93/14077, EP-A-0537980, and EP-A-0542363, WO 94/22834, WO94/22835 and EP 0623615A1.
The present invention relates to Xin De oxazolidine derivative, its preparation method and close the pharmaceutical preparation of these materials.
Have now found that ， oxazolidine derivative suppresses hematoblastic aggegation effectively and therefore can be used to treat the disease that thromboembolism causes, for example shock, myocardial infarction or obliterative arteriopathy and inflammation, osteoporosis or tumor disease.
The present invention relates to the compound and the pharmaceutical salts thereof of formula I: Wherein E expression (a) or residue (b):
Figure A9719507200042
(a)
Figure A9719507200043
(b) M represents Sauerstoffatom, sulphur atom or NR 00,
X represents hydrogen atom or NR 1R 2,
W represents nitrogen-atoms or NH or CH or CH 2,
Q represents nitrogen-atoms or CH,
Y represents nitrogen-atoms or CH,
Z represents nitrogen-atoms, CH or C-OH,
A represents alkylidene chain-(CH 2) p-, it is optional substituted,
D expression-(CHR 3) m-COO-R 8Or=CR 3-COO-R 8Side chain,
N represents 1-3,
M represents 0 or 1,
P represents 0-3,
R 1, R 2Represent hydrogen atom, low alkyl group, aryl, arylalkyl, heteroaryl independently of one another; acyl group or optional substituted carbocyclic ring or heterocycle; perhaps form optional substituted five yuan or six-ring with the nitrogen-atoms that they connected; this ring also closes 1 to 3 heteroatoms in addition, perhaps represents group (c)
Figure A9719507200051
R 3Expression hydrogen atom or group-OR 5Or-NR 6R 7,
R 4Expression hydrogen atom, low alkyl group, aryl, aralkyl, heteroaryl or group-OR 5,
R 5Expression hydrogen atom, low alkyl group, aryl or aralkyl,
R 6Expression hydrogen atom, low alkyl group or aralkyl,
R 7Expression hydrogen atom, low alkyl group, aralkyl, acyl group, alkyl sulphonyl or aryl sulfonyl,
R 8Expression hydrogen atom, methyl, ethyl, sec.-propyl, the tertiary butyl, phenyl or benzyl, particularly hydrogen atom, ethyl, phenyl or sec.-propyl,
R 10Expression hydrogen atom, low alkyl group, aralkyl, acyl group, alkyl sulphonyl, aryl sulfonyl or group (c),
R 0Expression hydrogen atom, low alkyl group, aralkyl or group-NHR 00,
R 00Expression hydrogen atom, low alkyl group, aralkyl, acyl group, alkyl sulphonyl or aryl sulfonyl.
In all situations, low alkyl group is represented straight or branched C 1-C 6Alkyl is as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, amyl group or hexyl, particularly methyl, ethyl, propyl group, isobutyl-and amyl group.
The aryl ordinary representation is optional to be substituted once or phenyl residues several times.
Heteroaryl is often referred to and do not have replaces or be substituted once or pyridyl several times, pyrimidyl, piperazinyl, imidazolyl, pyrryl, furyl or thienyl preferred pyridyl, pyrimidyl, indyl or imidazolyl.
Aralkyl is often referred to and do not have replaces or be substituted once or benzyl several times, styroyl, phenyl propyl, phenyl butyl or phenylpentyl.C 1-C 6Alkyl; preferable methyl, ethyl or sec.-propyl, and chlorine atom, bromine atoms, fluorine atom or hydroxyl, methoxyl group, benzyloxy, acetoxyl group, carboxyl, ethoxycarbonyl, aminocarboxyl, methylamino carbonyl, dimethylamino carbonyl, cyano group, amino, methylamino, dimethylamino, benzylamino, acetylamino, benzoyl-amido and amidino groups are considered as substituting group.
Acyl group is often referred to formyl radical, ethanoyl, propionyl, butyryl radicals or benzoyl, particularly the acetyl or benzoyl base.
Alkyl sulphonyl is often referred to methylsulfonyl, ethylsulfonyl, third alkylsulfonyl or fourth alkylsulfonyl, particularly fourth alkylsulfonyl.
Aryl sulfonyl is often referred to benzenesulfonyl or tosyl group.
Carbocyclic ring is often referred to the first ring of saturated or unsaturated 5-6 as cyclopentyl, cyclohexyl, cyclopentenyl or tetrahydrobenzene basic ring, and this ring is optional to be replaced once or twice by low alkyl group.
Heterocycle is often referred to the first ring of saturated or unsaturated 5-6 as tetramethyleneimine, piperidines, piperazine, morpholine, tetrahydropyrimidine, dihydro piperidines or glyoxalidine ring, preferred piperidines or tetrahydropyrimidine ring, and this ring is optional by the low alkyl group replacement once or twice.
At R 1And R 2With the nitrogen-atoms that they connected form five or the situation of six-ring under, this ring is that the first ring of saturated or unsaturated 5-6 is as tetramethyleneimine, piperidines, piperazine, morpholine, tetrahydropyrimidine, dihydropyridine or glyoxalidine ring, preferred piperidines, tetramethyleneimine or tetrahydropyrimidine ring, this ring is optional to be replaced once or twice by low alkyl group.
Heterocycle ordinary representation pyridine, pyridazine or pyrimidine ring, particularly pyridine or the pyrimidine ring of formula (a).
The heterocycle ordinary representation piperidines of formula (b) or hexahydropyrimidine ring, particularly piperidine ring.
The compound of formula I contains at least one unsymmetrical carbon, so the optically active compound of formula I also is the application's a theme.The conformational isomer of issuable formula I is another theme of the application.
Preferred formula I compound is n=1-2, p=0-1 and E, D, Y, Z and R 4Definition compound as above.
The preferred especially D of the compound of formula I represents-COOR 5Group, n=2, p=0 and Y=CH, Z represent that nitrogen-atoms, M represent that Sauerstoffatom and E represent the compound of the pyridine, pyrimidine or the piperidine ring that replace or do not have replacement.
R 8The compound of the formula I of expression hydrogen atom can be by currently known methods by R 8The ester hydrolysis that is not the formula I of H makes.
R 8The compound that is not the formula I of H can prepare according to the reaction scheme that scheme 1 provides.Scheme 1
Figure A9719507200081
In scheme 1, R 4, A, D, E, M, Y, Z and n definition as above.In general; ring-closure reaction synthon " M=C-" expression phosgene, trichloromethylchloroformate, triphosgene, carbonyl dimidazoles, carbonic acid dimethyl diethyl or diphenyl; methyl-chloroformate or ethyl ester; thiophosgene, thio-carbonyldiimidazole, dithiocarbonic anhydride, alkyl isonitrile, N; dinethylformamide, bromo cyanogen or chloro cyanogen, (N-acyl group or N-alkylsulfonyl)-dithiocarbamic acid dimethyl ester, dialkyl group carbonyl diurethane imide, 1-amidino groups-3; 5-pyrazoles-nitric ether, particularly carbonyl dimidazoles, diethyl carbonate, chloro ethyl formate, thio-carbonyldiimidazole or bromo cyanogen.MN 3Expression metal azide such as lithium, sodium, potassium, tributyl tin or azide magnesium, particularly Lithium Azide or sodium.TMSN 3Be the trimethyl silyl trinitride.
The compound of the general formula IV of E expression (a) can be according to the reaction path preparation of scheme 2.
Figure A9719507200091
C) hydrolysis of phthalimide; D) hydrogenation of benzyl; E) nitroso reduction
Scheme 2
In scheme 2, X, Q, W and Y definition are as above; In general, L refers to leavings group such as chlorine atom, bromine atoms, iodine atom, methylsulfonyl, trifluoromethyl sulfonyl or tosyl group, particularly chlorine atom or tosyl group.
E expression (b) but general formula IV compound through type X VI or the hydrogenated preparation of compound of X VIII.The compound of general formula V can prepare by the reaction path that scheme 3 provides.
Figure A9719507200101
A) epoxidation; B) organometallic reaction; C) dehydroxylation
Scheme 3
In scheme 3, R 4, A, D, L and n definition as above.
Some compounds of general formula VI commercially available and can be under specific circumstances pure oxidation by the general formula XI obtain,
Figure A9719507200102
Wherein D and R 4Definition as above.
The compound of general formula VII can be by the general formula VI compound and the organometallic compound prepared in reaction of formula XX, this organometallic compound is by the compound of general formula VIII,
Wherein A and n define as above, and M represents metal such as lithium, magnesium or titanium.
The compound of general formula XX V (scheme 1), wherein R 8Not hydrogen, p=0 and Z=N, also the reaction path preparation that can provide by scheme 4.Scheme 4
Figure A9719507200121
A) phthalimide potassium; B) hydrolysis; C) acidylate; D) peroxy acid; E) deacylation effect
Scheme 4
In scheme 4, R 4, D, MN 3, TMSN 3Define as above with n.In general, L 1Refer to hydroxyl or acetoxyl group or have one of definition of L.In general, R 11Nail base, ethyl, the tertiary butyl, phenyl or benzyl, the particularly tertiary butyl or benzyl.
For the compound of general formula VIII, if p=0, then they are commercially available cycloalkyl halogenide.If p＞0, then the compound of general formula VIII is known or can be according to the preparation of the method described in the following document (Brinker U.H., Tetrahedron Lett., 1991,4461-4464 in the document; Atkinson P.H., J.Chem.Soc.Perkin Trans 1,1977,230-238; M ü ller E., Chem.Ber.108,1401-1412 (1975); WaltonJ.C., J.Chem.Soc.Perkin Trans 2,1986,1641-1646; BalmeG., Tetrahedron 48,3891-3902 (1992); Fieser etc., J.Amer.Chem.Soc., 70,3174-3196 (1948); Lee G.M., J.Org.Chem .55,1281-1285 (1990)).
The compound of general formula XII generally is commercially available pipecolinic acid derivative; Under specific situation, the compound of general formula XII can be by the 3-piperidone or the 4-piperidone of the formula X XI that is purchased With the acetic ester prepared in reaction of commercially available general formula X XII, R 8OOC-CH 2-R 3(X XII)
R wherein 3And R 8Definition as above; Perhaps the Wittig reagent react with general formula XX III prepares,
Figure A9719507200141
R wherein 3, R 8Define as above R with m 9Represent butyl, phenyl or p-methylphenyl and Hal -Expression chlorine, bromine or iodine.
Some compounds of general formula XI are commercially available, and can pass through the hydrogenated preparation of the aryl carboxylic acid of general formula XX IV under specific circumstances according to currently known methods,
R wherein 4Define as above with D.
The compound of general formula XX can be synthetic on the spot according to the general method of preparation organometallic compound.
Some Wittig reagent of formula XX III commercially available and can by be purchased accordingly halogen compound and triphosphine the preparation.
The ester of formula I is hydrolyzed to the corresponding carboxylic acid of formula I generally to carry out according to standard method, wherein with the carboxylicesters of formula I in water or water, tetrahydrofuran (THF), diox, methyl alcohol or alcoholic acid mixture, in the mixture of preferably water/tetrahydrofuran (THF), in temperature is room temperature to 80 ℃, use the oxyhydroxide of oxyhydroxide such as sodium, potassium or lithium under the preferred room temperature, preferably handle, perhaps handle with sour example hydrochloric acid, sulfuric acid or trifluoroacetic acid, preferred trifluoroacetic acid with sodium hydroxide or lithium hydroxide.
In general, the reaction of the compound of general formula X III and 1-benzyl diethylenediamine or 4-hydroxy piperidine or 4-oxo-piperidine (scheme 2), the perhaps reaction of the compound of the compound of formula IX and formula XII (scheme 3), in aprotic solvent such as toluene, tetrahydrofuran (THF), ether, dimethyl formamide or diamino methane, preferred dimethyl formamide or tetrahydrofuran (THF), use alkali such as potassium hydride KH, sodium hydride, salt of wormwood or sodium bicarbonate, preferred sodium hydride or salt of wormwood, and be room temperature to 180 ℃, preferably under 120 ℃ or room temperature, carry out in temperature.
Reaction between the ester of the 3-piperidone of formula X XI or 4-piperidone and formula X XII generally under the condition of aldol reaction in solvent such as methyl alcohol, ethanol, toluene, tetrahydrofuran (THF), ether or dimethyl formamide, in preferred tetrahydrofuran (THF) or the dimethyl formamide, use alkali such as sodium methylate or potassium methylate or potassium ethylate, sodium hydride, potassium hydride KH, lithium diisopropylamine, hexamethyldisilane base potassium azide, preferred sodium hydride or lithium diisopropylamine, in temperature is-78 ℃ to 90 ℃, but preferably carries out with room temperature at-78 ℃.
If desired,, for example use palladium/carbon/hydrogen, benzyl protecting group is removed by catalytic hydrogenation.
Mitsunobu reaction between formula X VIII compound and the phthalimide is carried out according to the method for putting down in writing in the document (Mitsunobu O., Synthesis, page 1 (1981)).
With the amine of dibenzyl amine or formula XX V to the ketone of formula X VI carry out the reduction amination effect according to the currently known methods in the document by ketone and amine component in solvent such as methyl alcohol or ethanol in the presence of reductive agent such as sodium cyanoborohydride or sodium borohydride nitrilotriacetic thing, add Br nsted or Lewis acid example hydrochloric acid, acetate, titanium tetrachloride or titanium tetraisopropylate, and under 0 ℃ to 100 ℃, preferred room temperature, or in the presence of hydrogenation catalyst such as platinum dioxide, in hydrogen, carry out (Borch R.F., Org.Synth.Coll.Vol.6,499 (1988); HeinzelmanR.V.Z.Chem.8,270 (1968); Mattson R.J., J.Org.Chem.55,2552 (1990); Barney C.L.Tetr.Letters 31,5547 (1990); Hutchins R.O., J.Org.Chem.46,3571 (1981)).
The nitrosification of the compound of the compound formation formula X V of general formula XI V usually with Sodium Nitrite or Isopentyl nitrite in water or ethanol, add sour example hydrochloric acid or acetate, and-20 ℃ to 80 ℃, preferably at room temperature carry out.
The nitroso compound of general formula X V reduces according to currently known methods, the compound that is through type X V is in solvent such as water, acetate, ethanol, tetrahydrofuran (THF) or ether, preferred acetate or tetrahydrofuran (THF), with reductive agent such as element zinc, lithium aluminium hydride or sodium aluminum hydride, preferred elements zinc or lithium aluminium hydride, in room temperature to 120 ℃ but react under preferred 70 ℃.Use catalyzer such as palladium/carbon also the compound of general formula X V can be converted into compound (Hatt, H.H., Org.Synth.Coll.Vol.2,211 (1943) of formula IV V by the hydrogenolysis method; Sch ü ler F.W., J.Amer.Chem.Soc.73,4996 (1951)).
The oxidizing reaction of the ketone of the alcohol formation general formula VI of general formula XI is according to currently known methods such as Jones oxidizing reaction (Jones E.R.H., J.Chem.Soc.36 (1946)), Swern oxidizing reaction (Swern D.Tetrahedron 34,1651 (1978)), Dess-Martin oxidizing reaction (Dess D.B., Martin J.C., J.Org.Chem.48,4155 (1983)) or with bromo-urotropine mixture carry out as oxygenant (Yavari I., J.Chem.Res. (S) 274 (1994)).
Used Witrig reagent is arbitrarily according to the currently known methods (Buddras J., " Angew.Chem. " 80,535 (1968) that are similar in the document; Bestmann H.J. " Angew.Chem. " 77,620,651 (1965); Wittig G.Ber.Deutsch.Chem.Ges.88,1654 (1955)) preparation.
Wittig reaction according to currently known methods by reactant reflux in aprotic solvent such as benzene, toluene or dimethylbenzene, preferred toluene is carried out.
The hydrolysis of phthalimide is generally according to currently known methods, by with hydrazine hydrate or half dense mineral acid example hydrochloric acid or sulfuric acid, preferably with hydrazine hydrate or hydrochloric acid, carries out in room temperature.
The acylation reaction of amine being carried out with acylating reagent is generally in solvent such as methylene dichloride, dimethyl formamide or pyridine, preferred methylene dichloride and pyridine; add a kind of auxiliary alkali such as triethylamine or 4-dimethylaminopyridine and at-10 ℃ to 50 ℃, but carry out under the preferred room temperature.Etheride such as Acetyl Chloride 98Min., propionyl bromide or Carbobenzoxy Chloride or acid anhydrides such as diacetyl oxide or di-tert-butyl dicarbonic acid ester can be used as acylating reagent, but preferred diacetyl oxide, Carbobenzoxy Chloride or di-tert-butyl dicarbonic acid ester.
The epoxidation Reaction of Alkenes of formula VII or formula X or formula VIII or formula XX VIII is according to known method in the document, by with itself and peracid such as metachloroperbenzoic acid, peracetic acid or trifluoroperacetic acid, preferred metachloroperbenzoic acid, at aprotic solvent such as methylene dichloride, and under-30 ℃ to 50 ℃, preferred room temperature, carry out; In addition, the above-mentioned alkene of listing can pass through Sharpless epoxidation reaction (Sharpless K.B., Org.Syntheses, Vol.63,66 (1985)) and is converted into corresponding epoxide.
In the scheme 3, organometallic reaction generally is a kind of Grignard reaction, and it carries out according to currently known methods in the document.But the azoviolet of formula XX can randomly be converted into lithium or tiron (Reetz M.T., Chem.Ber.118,1421 (1985)) before the carbonyl compound with the formula VI reacts.
The amino alcohol of formula III is converted into the reaction (scheme 1) of formula I compound to carry out according to known method in the document, the amino alcohol of through type III and diethyl carbonate (Evans D.A., Org.Syntheses, Vol.68,77 (1989)), or carbonyl dimidazoles (Chadwick D.I., J.Chem.Soc.Perkin Trans 481 (1984); Geffken D.Arch.Pharm.313,817 (1980)), or phosgene (Newman W.S., J.Am.Chem.Soc.73,4199 (1951)) or trichloromethylchloroformate or triphosgene (Hassner A., Synth.Commun.23,2839 (1993)) or albendazole, ethyl ester or benzyl ester (Kanoshinzo, J.Org.Chem.53,3865 (1988)) or thiophosgene (Dubey S.K., Can.J.Chem., 61565, (1983)) or thio-carbonyldiimidazole (Goering B.K., Tetrahedron Lett.35 (38), 6997, or dithiocarbonic anhydride (Zinner H., J.Prakt.Chem., 15 (1994)), 72 (1962)) or bromo cyanogen (Mousseron, Bull.Soc.Chim.Fr., 737 (1953)) or alkyl isonitrile (Ito Y., J.Organomet.Chem.131121 (1977)) or (N-acyl group or N-alkylsulfonyl)-dithiocarbamic acid dimethyl ester (Bretschneider H., Monatsh.Chem.103,1377 (1972); Evers R., J.Prakt.Chem., 333,699 (1991)) or 1-amidino groups-3,5-pyrazoles-nitrate (Fotsch C.H., Tetrahedron Lett., 35,2481 (1994)) reaction, be reflected at solvent such as methylene dichloride, dimethyl formamide, toluene, dimethylbenzene, ethanol, diox, tetrahydrofuran (THF), water or ether, carry out in preferred dimethyl formamide, methylene dichloride, ethanol or the tetrahydrofuran (THF), and optional a kind of auxiliary alkali such as triethylamine or the pyridine of adding, temperature of reaction is-50 ℃ to 80 ℃, preferred room temperature.
The catalytic hydrogenation of the compound of formula XX IV adds catalyzer such as ruthenium oxide, rhodium oxide or carbonate palladium/strontium, preferred rhodium oxide in solvent such as methyl alcohol or ethanol be that 1-200 crust, preferred 200 crust, temperature are to carry out (Rastin R.H., I.Chem.Soc.1855 (1949)) under room temperature to the 200 ℃ condition at pressure in nitrogen atmosphere.
The epoxy bond of the epoxide of formula V is opened (scheme 1) or the epoxy bond of the epoxide of formula IX is opened with the amine of formula IV, in solvent such as methyl alcohol, ethanol, dimethyl formamide or toluene, preferred alcohol or toluene and 0 ℃ of temperature, carry out usually to 120, under preferred 80 ℃ with the amine of formula XII.
According to the currently known methods in the document with open (scheme 1) of metal azide with the epoxy bond of the epoxide of formula V, the epoxide of through type V and metal azide such as lithium, sodium, potassium, the trinitride of tributyl tin or magnesium, preferred sodiumazide, at solvent such as methyl alcohol, ethanol, 1, the 4-diox, water, dimethyl formamide, tetrahydrofuran (THF), in the mixture of acetonitrile or hexamethyl phosphoric triamide or described solvent, but preferably at methyl alcohol, dimethyl formamide or 1, in 4-diox-water mixture, in temperature of reaction is-10 ℃ to 120 ℃, carry out (Vanderverf C.A. under preferred 80 ℃, J.Am.Chem.Soc.76,1231 (1954); Saito S., Tetrahedron Lett.30,4153 (1989); Hudlichy T., J.Chem.Soc.Perkin Trans.I, 2907 (1991)).General and the trimethyl silyl trinitride reaction of the epoxide of formula V, this is reflected at solvent such as methyl alcohol, tetrahydrofuran (THF), methylene dichloride, chloroform, ethylene dichloride or benzene, in preferred tetrahydrofuran (THF) or the methylene dichloride, without other additive or use additive such as titanium tetraisopropylate, aluminum isopropylate, diisopropanol titanium dichloride or diethyl aluminum fluoride, optional titanium tetraisopropylate or aluminum isopropylate, and at 0 to 100 ℃, carry out (Emziane M. under the preferred room temperature, Synthesis, p.541 (1988); Saito S., Tetrahedron Lett.26,5309 (1985); Blandy C., Tetrahedron Lett.24,4189 (1983); Jung M.E., J.Org.Chem., 56,2614 (1991)).
The reaction (scheme 4) that formula XX XI compound and metal azide form formula XX VI compound is a nucleophilic substitution reaction, the same L of the implication of L1 wherein, and this reaction is carried out according to the standard method of organic synthesis.
Carry out the deacylation reaction of formula XXX compound formation formula XX V compound according to standard method; its Chinese style XXX compound is in water or water, tetrahydrofuran (THF), diox, methyl alcohol or alcoholic acid mixture; preferably in water/tetrahydrofuran compound; with oxyhydroxide such as sodium hydroxide, potassium or lithium; preferred sodium hydroxide or lithium hydroxide; perhaps use sour example hydrochloric acid, sulfuric acid or trifluoroacetic acid, preferred trifluoroacetic acid is perhaps with palladium/carbon/hydrogen and in room temperature to 80 ℃, preferably handle under the room temperature.
The trinitride of formula XX VI carries out according to currently known methods to the conversion of the amine of formula XX V: Suami T., Bull.Chem.Soc.Jpn., 51,855 (1978); Boullanger P., Bull.Soc.Chim.Fr., P.2149 (1973); Ackerman K., Can.J.Chem., 50,3886 (1972); Hanessian S., Chem.Ind., P.1296 (1965); Horner L., Liebigs Ann.Chem., 591,117 (1955); Koziara A.Synthesis, p.487 (1987); Vogel E., Ang.Chem.Int.Ed.Engl., 18,962 (1979); Purwono B., Synlett, 3,231 (1992).
The compound of formula I contains one or several chiral centre and therefore exists with racemic modification or optical activity form.Can be enantiomorph with racemic mixture by known machinery or chemical process.Preferably by forming diastereomer by racemic mixture with sour tartrate, diacetyl tartrate, dibenzoyl tartaric acid, amygdalic acid, oxysuccinic acid, lactic acid or various optically active camphorsulfonic acid such as the reaction of beta camphor sulfonic acid of optical activity as D and L shaped formula.
Certainly, can be that optically active initiator (suc as formula the compound of V or formula VIII) obtains optically active formula I compound by using also with aforesaid method.
According to spirit of the present invention, the prodrug forms of all generalformulas also is protected, but especially protects the carboxylicesters of formula I, wherein R 8Nail base, ethyl, n-propyl, sec.-propyl, butyl, phenyl or benzyl, particularly methyl, ethyl or benzyl.
An alkali metal salt, ammonium salt, trifluoroacetate or hydrochloride at first use as pharmacologically acceptable salt, they prepare in a usual manner, for example, by with inorganic or organic bases or acidometric titration, as use sodium bicarbonate or saleratus, sodium hydroxide solution, potassium hydroxide solution, ammoniacal liquor or amine such as Trimethylamine 99 or triethylamine, trifluoroacetic acid or hydrochloric acid.General by this salt of deposition and purification from water/acetone.
The novel substance of formula I of the present invention and salt thereof can through gi tract or non-through the gi tract approach with the liquid or solid form administration.Can consider all the conventional formulations used such as tablet, capsule, lozenge, syrup, solution, suspension agent etc.Water is preferably used as injectable media, wherein contains additive such as stablizer, solubilizing agent and the buffer reagent of injection liquid routine.
Such additive is, for example, tartrate and tangerine same regimen acid salt damping fluid, ethanol, sequestrant (as ethylenediamine tetraacetic acid (EDTA) and non-toxic salt thereof), regulates the high molecular polymer (as the liquid polyethylene oxide) that viscosity is used.Injection liquid should sterilize with liquid carrier material and the ampoule of preferably packing in.The solid carrier material is, for example, starch, lactose, seminose, methylcellulose gum, talcum, high dispersive silicic acid, polymer fatty acid (as stearic acid), gelatin, agar, calcium phosphate, Magnesium Stearate, animal or plant fat, solid high molecular polymer (as polyoxyethylene glycol); Be suitable for oral preparation and can randomly contain correctives and sweeting agent.
Using dosage depends on multiple factor such as use-pattern, species, age and/or individual healthy state.The per daily dose that uses is about 1-1000mg/ people, preferred 100-500mg/ people, and can once or divide administration several times.
According to spirit of the present invention, the compound of in embodiment, mentioning and by with substituent all implications combination in the claim and the derived compounds, Xia Lie oxazolidone derivative is preferred:
1) 1-[2-oxo-3-(1-pyrimidine-4-base-piperidin-4-yl]-octahydro benzoxazole-7-yl]-piperidines-4-formic acid
2) 1-{2-oxo-3-[1-(2-tetramethyleneimine-1-base-pyrimidine-4-yl)-piperidin-4-yl]-octahydro benzoxazole-7-yl }-piperidines-4-formic acid
3) 1-[2-oxo-3-(1-pyrimidine-4-base-piperidin-4-yl]-octahydro benzoxazole-7-yl]-piperidin-4-yl }-acetate
4) (1-{3-[1-(2-amino-pyrimidine-4-yl)-piperidin-4-yl]-2-oxo-octahydro benzoxazole-7-yl }-piperidin-4-yl)-acetate
5) (1-{3-[1-(2-methylamino-pyrimidine-4-yl)-piperidin-4-yl]-2-oxo-octahydro benzoxazole-7-yl }-piperidin-4-yl)-acetate
6) (1-{2-oxo-3-[1-(2-phenyl amino-pyrimidine-4-yl)-piperidin-4-yl]-octahydro benzoxazole-7-yl }-piperidin-4-yl)-acetate
7) 2-methylsulfonyl amino-3-{1-[2-oxo-3-(1-pyrimidine-4-base-piperidin-4-yl)-octahydro benzoxazole-7-yl }-piperidin-4-yl)-propionic acid
8) 1-[2-oxo-3-(1-pyrimidine-4-base-piperidin-4-yl)-octahydro benzoxazole-7-ylmethyl]-piperidines-4-formic acid
9) 1-[2-oxo-3-(3,4,5,6-tetrahydrochysene-2H-[1,4 '] two pyridin-4-yls)-octahydro benzoxazole-7-ylmethyl]-piperidines-4-formic acid
10) 1-{3-[1-(2-amino-pyrimidine-4-yl)-piperidin-4-yl]-2-oxo-octahydro benzoxazole-7-ylmethyl }-piperidines-4-formic acid
11) 1-{2-oxo-3-[1-(2-piperidines-1-base-pyrimidine-4-yl)-piperidin-4-yl]-octahydro benzoxazole-7-ylmethyl }-piperidines-4-formic acid
12) 1-{3-[1-(2-amino-pyrimidine-4-yl)-piperidin-4-yl]-2-oxo-octahydro benzoxazole-7-yl }-piperidines-4-formic acid
13) 1-{3-[1-(2-benzylamino-pyrimidine-4-yl)-piperidin-4-yl]-2-oxo-octahydro benzoxazole-7-ylmethyl }-piperidines-4-formic acid
14) 4-{3-[1-(2-benzylamino-pyrimidine-4-yl)-piperidin-4-yl]-2-oxo-octahydro benzoxazole-7-ylmethyl }-hexahydrobenzoic acid
15) 4-{3-[1-(2-benzylamino-pyrimidine-4-yl)-piperidin-4-yl]-2-oxo-octahydro benzoxazole-7-ylmethyl }-4-hydroxyl-hexahydrobenzoic acid
16) 4-[2-oxo-3-(3,4,5,6-tetrahydrochysene-2H-[1,4 '] two pyridin-4-yls)-octahydro benzoxazole-7-yl]-hexahydrobenzoic acid
17) 4-{3-[1-(2-amino-pyrimidine-4-yl)-piperidin-4-yl]-2-oxo-octahydro benzoxazole-7-yl }-hexahydrobenzoic acid
18) 4-hydroxyl-4-[2-oxo-3-(3,4,5,6-tetrahydrochysene-2H-[1,4 '] two pyridin-4-yls)-octahydro benzoxazole-7-yl]-hexahydrobenzoic acid
19) 4-hydroxyl-4-{2-oxo-3-[1-(2-tetramethyleneimine-1-base-pyrimidine-4-yl)-piperidin-4-yl]-octahydro benzoxazole-7-yl]-hexahydrobenzoic acid
20) 1-[2-oxo-3-(3,4,5,6-tetrahydrochysene-2H-[1,4 '] two pyridin-4-yls)-octahydro benzoxazole-7-yl]-piperidin-4-yl }-acetate
21) 2-(butane-1-sulfuryl amino)-3-{1-[2-oxo-3-(3,4,5,6-tetrahydrochysene-2H-[1,4 '] two pyridin-4-yls)-octahydro benzoxazole-7-yl]-piperidin-4-yl }-propionic acid
22) 1-{2-[2-oxo-3-(3,4,5,6-tetrahydrochysene-2H-[1,4 '] two pyridin-4-yls)-octahydro benzoxazole-7-yl] ethyl }-piperidines-4-formic acid
23) 1-{3-[1-(2-methylamino-pyrimidine-4-yl)-piperidin-4-yl]-2-oxo-octahydro benzoxazole-7-ylmethyl }-piperidines-4-formic acid
24) 1-{3-[2-oxo-3-(3,4,5,6-tetrahydrochysene-2H-[1,4 '] two pyridin-4-yls)-octahydro benzoxazole-7-yl] propyl group }-piperidines-4-formic acid
25) 1-{3-[2-oxo-3-(1-pyrimidine-4-base-piperidin-4-yl)-octahydro benzoxazole-7-yl] propyl group }-piperidines-4-formic acid
26) 1-(3-{3-[1-(2-amino-pyrimidine-4-yl)-piperidin-4-yl]-2-oxo-octahydro benzoxazole-7-yl propyl group)-piperidines-4-formic acid
27) 1-[2-oxo-3-(1-piperazine-4-base-piperidin-4-yl)-octahydro benzoxazole-7-yl]-piperidines-4-formic acid
28) 1-[2-oxo-3-(1-piperazine-4-base-piperidin-4-yl]-octahydro benzoxazole-7-yl]-piperidin-4-yl }-acetate
29) 1-[2-oxo-3-(1-piperazine-4-base-piperidin-4-yl)-octahydro benzoxazole-7-ylmethyl]-piperidines-4-formic acid
30) 4-[2-oxo-3-(1-piperazine-4-base-piperidin-4-yl)-octahydro benzoxazole-7-yl]-hexahydrobenzoic acid
31) 1-{3-[2-oxo-3-(1-piperazine-4-base-piperidin-4-yl)-octahydro benzoxazole-7-yl] propyl group }-piperidines-4-formic acid
32) 1-[2-oxo-3-(4-pyrimidine-4-base-piperazine-1-yl)-octahydro benzoxazole-7-yl]-piperidines-4-formic acid
33) 4-[2-oxo-3-(4-pyrimidine-4-base-piperazine-1-yl)-octahydro benzoxazole-7-yl]-naphthenic acid
34) (±)-(3 ' α, 7 ' β, 7 α)-1-{3-[1-(2-benzylamino-pyrimidine-4-yl]-piperidin-4-yl)-2-oxo-octahydro benzoxazole-7-yl }-piperidines-4-formic acid
35) 1-{2-[2-oxo-3-(4-piperidin-4-yl-piperazine-1-yl)-octahydro benzoxazole-7-yl] ethyl }-piperidines-4-formic acid
36) 1-[2-oxo-3-(1-pyrimidine-4-base-piperidin-4-yl)-six hydrogen ring Wu Bing oxazole-6-yls]-piperidines-4-formic acid
37) 1-[2-oxo-3-(3,4,5,6-tetrahydrochysene-2H-[1,4 '] two pyridin-4-yls)-six hydrogen ring Wu Bing oxazole-6-yls]-piperidines-4-formic acid
38) 1-{3-[1-(2-amino-pyrimidine-4-yl)-piperidin-4-yl]-2-oxo-six hydrogen ring Wu Bing oxazole-6-yl }-piperidines-4-formic acid
39) (1-{2-oxo-3-[1-(2-phenyl amino-pyrimidine-4-yl)-piperidin-4-yl]-six hydrogen ring Wu Bing oxazole-6-yls }-piperidin-4-yl)-acetate
40) 1-{2-[2-oxo-3-(3,4,5,6-tetrahydrochysene-2H-[1,4 '] two pyridin-4-yls)-six hydrogen ring Wu Bing oxazole-6-yls] ethyl }-piperidines-4-formic acid
41) 1-[2-oxo-3-(1-piperazine-4-base-piperidin-4-yl)-six hydrogen ring Wu Bing oxazole-6-yls]-piperidines-4-formic acid
42) 1-[2-oxo-3-(4-pyridin-4-yl-piperidines-1-yl)-six hydrogen ring Wu Bing oxazole-6-yls]-piperidines-4-formic acid
43) 4-hydroxyl-4-[2-oxo-3-(3,4,5,6-tetrahydrochysene-2H-[1,4 '] two pyridin-4-yls)-six hydrogen ring Wu Bing oxazole-6-yls]-naphthenic acid
44) 1-[2-oxo-3-(1-pyrimidine-4-base-piperidin-4-yl)-octahydro Huan Geng Bing oxazole-8-yl]-piperidines-4-formic acid
45) 1-{2-oxo-3-[1-(2-phenyl amino-pyrimidine-4-yl)-piperidin-4-yl]-octahydro benzoxazole-7-yl }-piperidines-4-formic acid
46) 1-[2-oxo-3-(3,4,5,6-tetrahydrochysene-2H-[1,4 '] two pyridin-4-yls)-octahydro Huan Geng Bing oxazole-8-yl]-piperidines-4-formic acid
47) 1-{3-[1-[2-amino-pyrimidine-4-yl)-piperidin-4-yl]-2-oxo-octahydro Huan Geng Bing oxazole-8-yl }-piperidines-4-formic acid
48) (1-{3-[1-(2-amino-pyrimidine-4-yl)-piperidin-4-yl]-2-octahydro Huan Geng Bing oxazole-8-yl }-piperidin-4-yl)-acetate
49) 1-{2-oxo-3-[(1-2-piperidines-1-base-pyrimidine-4-yl)-piperidin-4-yl]-octahydro Huan Geng Bing oxazole-8-ylmethyl }-piperidines-4-formic acid
50) 1-(2-oxo-3-{1-[2-(pyridin-4-yl amino)-pyrimidine-4-yl]-piperidin-4-yl-octahydro benzoxazole-7-yl)-piperidines-4-formic acid
51) 1-(2-oxo-3-{1-[2-(pyrimidine-2--amino)-pyrimidine-4-yl]-piperidin-4-yl-octahydro benzoxazole-7-yl)-piperidines-4-formic acid
52) 1-(2-oxo-3-{1-[2-(1,4,5,6-tetrahydrochysene-pyrimidine-2--amino)-pyrimidine-4-yl]-piperidin-4-yl-octahydro benzoxazole-7-yl)-piperidines-4-formic acid
53) 1-{3-[1-(2-cyclohexyl amino-pyrimidine-4-yl)-piperidin-4-yl]-2-oxo-octahydro benzoxazole-7-yl }-piperidines-4-formic acid
54) 1-{3-[1-(2-tetramethyleneimine-1-base-pyrimidine-4-yl)-piperidin-4-yl]-2-sulfo--octahydro benzoxazole-7-yl }-piperidines-4-formic acid
55) 1-{2-oxo-3-[1-(2-tetramethyleneimine-1-base-six hydrogen-pyrimidine-4-yl)-piperidin-4-yl]-octahydro benzoxazole-7-yl }-piperidines-4-formic acid
56) 1-{2-oxo-3-[1-(2-tetramethyleneimine-1-base-1,4,5,6-tetrahydrochysene-pyrimidine-4-yl)-piperidin-4-yl]-octahydro benzoxazole-7-yl }-piperidines-4-formic acid
57) 1-[3-(1 '-benzyl-[1,4 '] two piperidin-4-yls)-2-sulfo--octahydro benzoxazole-7-yl]-piperidines-4-formic acid
58) 1-[2-acetylimino--3-(3,4,5,6-tetrahydrochysene-2H-[1,4 '] two pyridin-4-yls)-octahydro benzoxazole-7-yl]-piperidines-4-formic acid
59) 1-[2-imino--3-(3,4,5,6-tetrahydrochysene-2H-[1,4 '] two pyridin-4-yls)-octahydro benzoxazole-7-yl]-piperidines-4-formic acid
60) 4-(1H-indol-3-yl methyl)-1-[2-oxo-3-(3,4,5,6-tetrahydrochysene-2H-[1,4 '] two pyridin-4-yls)-octahydro benzoxazole-7-yl]-piperidines-4-formic acid
61) 4-butyl-1-[2-oxo-3-(3,4,5,6-tetrahydrochysene-2H-[1,4 '] two pyridin-4-yls)-octahydro benzoxazole-7-yl]-piperidines-4-formic acid
62) 1-[2-oxo-3-(3,4,5,6-tetrahydrochysene-2H-[1,4 '] two pyridin-4-yls)-octahydro benzoxazole-7-yl]-4-styroyl-piperidines-4-formic acid
63) (-)-(3 ' S, 7 ' S, 7R)-1-[2-oxo-3-(3,4,5,6-tetrahydrochysene-2H-[1,4 '] two pyridin-4-yls)-octahydro benzoxazole-7-yl]-piperidines-4-formic acid [α] 20 D=-17.4 ° of (c=1.18; CHCl 3)
64) (+)-(3 ' R, 7 ' R, 7S)-1-[2-oxo-3-(3,4,5,6-tetrahydrochysene-2H-[1,4 '] two pyridin-4-yls)-octahydro benzoxazole-7-yl]-piperidines-4-formic acid [α] 20 D+ 18.7 ° of (c=1.2; CHCl 3)
The following example has illustrated some different methods that can be used to synthetic The compounds of this invention.But they do not represent the restriction to theme of the present invention.The structure of these compounds is passed through 1H and selectivity are passed through 13C-NMR chromatogram and mass spectrum are determined.Determine the purity of material by C, H, N and thin-layer chromatography.
Embodiment 1
(±)-(3 ' α, 7 ' β, 7 α)-1-[2-oxo-3-(3,4,5,6-tetrahydrochysene-2H-[1,4 '] two pyridin-4-yls)-octahydro benzoxazole-7-yl]-piperidines-4-formic acid
Figure A9719507200241
A) in the 400ml p-Xylol with 46g (0.4mol) 4-chloropyridine and 123.5g (0.86mol) 4-piperidone-ethylene ketal reflux 48 hours.With this reaction mixture cooling, filter and shift out precipitation subsequently, filtrate is concentrated into dry doubling by composing (ethyl acetate/saturated ammonia alkaline methanol solution 9/1) with this residue purified in the enterprising circumstances in which people get things ready for a trip of silica gel.Obtain 79.7g (90%) 8-pyridin-4-yl-1 like this, 4-two oxa-s-8-azepine-spiral shell-[4,5] decane are white powder.m/e=220；F p=65℃。
B) with 79.7g a) in 2 liters of tetrahydrofuran solutions of ketal of preparation and 1 liter of 6N mixed in hydrochloric acid and with this reaction mixture stirring at room 2 hours.Vacuum is removed tetrahydrofuran (THF) in rotatory evaporator subsequently, with half dense solution of ammonium hydroxide 100ml dichloromethane extraction four times is also used in the hydrochloric acid soln alkalization at every turn.With sodium sulfate that the organic extract that merges is dry also except that after desolvating, this resistates is passed through the column chromatography purifying on silica gel.Obtain 64.2g (productive rate 100%) 2,3,5 like this, 6-tetrahydrochysene [1,4 '] two pyridines-4-ketone are the grey powder.m/e=176；F p=102℃。
C) at 0 ℃, 41.6g is suitable-2, and 650ml dimethyl formamide (DMF) solution of 3-oxirane ring hexanol (Svante T., J.Org.Chem., 38,1380 (1973)) and 54g imidazoles mixes with the 67.7g TERT-BUTYL DIMETHYL CHLORO SILANE.After this with this reaction mixture 0 ℃ of restir 4 hours, mix with 600ml water then and with the 100ml ethyl acetate with aqueous solution extraction four times.After the organic phase and removal of solvent under reduced pressure with the dried over sodium sulfate merging, with this resistates vacuum distilling.Obtain 50g suitable-the 1-tertiary butyl-dimethyl-siloxy--2, the 3-epoxy cyclohexane.
Bp0.05=74 ℃. 1H-NMR (CDCl 3): δ=3.90ppm (m, 1H); 3.10 (wide s, 1H); 3.0 (wide s, 1H); 1.65 (m, 2H); 1.40 (m, 3H); 1.15 (m, 1H); 1.82 (s, 9H); 0.01 (s, 6H).
D) with 1c) epoxide 20g and the mixture heating up of 34ml 4-piperidine ethyl formate in 160ml ethanol refluxed 48 hours.Subsequently, this reaction mixture is evaporated to dry doubling by column chromatography on silica gel with this residue purified (ethyl acetate/isohexane=1/2).Obtain 22.2g (±)-(1 α, 2 β, 3 β)-1-[3-(t-butyldimethylsilyl oxygen base)-2-hydroxyl-cyclohexyl] piperidine-4-ethyl formate, be white powder.m/e=385。
E) be 5-10 ℃ at internal temperature, with the 1d of 18.7g) alcohol solution and the solution of 12ml triethylamine in the 200ml methylene dichloride mix with the 5.4ml methylsulfonyl chloride.Under the room temperature this reaction mixture was stirred 1 hour, subsequently, heating 50ml saturated sodium bicarbonate solution will be separated, with 100ml water washing organic phase and use dried over sodium sulfate.Except that after desolvating, this resistates is passed through column chromatography purifying (ethyl acetate/isohexane=1/3) with rotatory evaporator on silica gel.Obtain 21g (±)-(1 α, 2 β, 3 β)-1-[3-(t-butyldimethylsilyl oxygen base)-2-mesyloxy-cyclohexyl] piperidine-4-ethyl formate, be light yellow oil.
1H-NMR (d 6-DMSO): δ=4.45ppm (d, 1H); 4.20 (wide s, 1H); 3.95 (q, 2H); 3.10 (s, 3H); 2.88-263 (m, 2H); 2.50 (m, 1H); 2.20-2.00 (m, 2H); 1.75-1.62 (m, 1H); 1.58-1.18 (m, 7H); 1.10 (t, 3H); 0.80 (s, 9H); 0.01 (s, 6H).
F) with 1e) the solution of silyl derivative 21g in the 200ml tetrahydrofuran (THF) mix with the tetrahydrofuran solution of 1.1 moles of tetrabutylammonium chlorides of 63ml.With this reaction mixture stirring at room 30 hours, be concentrated into then dry doubling with this resistates on silica gel by chromatogram purification (ethyl acetate/isohexane=95/5).Obtain 6.3g (±)-(1 α, 2 β, 3 β)-1-(3-hydroxyl-2-mesyloxy-cyclohexyl) piperidine-4-ethyl formate, be white powder.m/e=349。
G) with 5.48g 1f) the hydroxyl methanesulfonates and the mixture of 550mg sodium hydride stirred 1 hour in 200ml tetrahydrofuran (THF) (THF) at 5 ℃, add 50ml water after, stirred 15 hours at 50 ℃.After this in rotatory evaporator, remove THF and the each 30ml of using methylene dichloride with this aqueous mixture extraction three times.With the organic phase that merges with dried over sodium sulfate and solvent removed in vacuo after, obtain 3.9g (±)-anti-form-1-(2,3-epoxy-cyclohexyl) piperidine-4-ethyl formate, be yellow oil, directly carry out the next step without purifying.
H) with 1g) in epoxide 3.4g, 5.3g sodiumazide and the 4.3g ammonium chloride of preparation 70 ℃ of solution heating in 50ml ethanol/water mixture (80/20) 24 hours.Subsequently, vacuum is removed ethanol, and with 10ml water dilute this resistates and each with the 15ml methylene dichloride with this solution washing three times.After the organic phase that merges with dried over sodium sulfate and removing in rotatory evaporator is desolvated, with crude product at the enterprising circumstances in which people get things ready for a trip spectrum of silica gel purifying (ethyl acetate/isohexane: 4/1).Obtain 2.74g (±)-(1 α, 2 β, 3 α)-1-(3-azido--2-hydroxyl-cyclohexyl) piperidine-4-ethyl formate like this, be orange oily matter, it slowly solidifies.
1H-NMR (d 6-DMSO): δ=4.53ppm (wide s, 1H, OH); 4.05 (q, 2H); 3.30 (broad d, 2H); 2.80 (quasi d, 1H); 2.65 (quasi d, 1H); 2.50 (m, 1H); 2.25 (m, 3H); 1.90-1.40 (m, 7H); 1.30-1.02 (m+t, 6H).
I) with 1h) solution and the 0.8g 10% palladium/carbon of trinitride 2.7g in 20ml ethanol of preparation is mixed was incorporated under 40 millibars of pressure and the room temperature hydrogenation 6 hours.Subsequent filtration remove catalyzer and with rotatory evaporator with this solution concentration.Obtain 2.4g (±)-(1 α, 2 β, 3 α)-1-(3-amino-2-hydroxyl-cyclohexyl) piperidines-4-manthanoate like this.FAB?271。
J) with 2.4g 1i) in amine, 1.6g 1b) in ketone and the solution stirring at room of 3.75g nitrilotriacetic sodium borohydride in the 40ml methylene dichloride 48 hours.Then, this reaction mixture is mixed with 10ml water and use the 1N hcl acidifying.After being separated, use 10ml dichloromethane extraction tart water again, then with the alkalization of 1N sodium hydroxide solution.After using the 15ml methylene dichloride with this alkaline mixt extraction 3 times and organic phase, in rotatory evaporator, solvent is removed with the dried over sodium sulfate merging at every turn.Then, by preparing HPLC (RP 18, methyl alcohol/damping fluid (pH=7.5) 70/30) with this purifying crude.Obtain 2.5g (±)-(1 α, 2 β, 3 α)-1-[2-hydroxyl-3-(3,4,5,6-tetrahydrochysene-2H-[1,4 '] two pyridin-4-yl amino)-cyclohexyl like this) piperidine-4-ethyl formate.
1H-NMR(d 6-DMSO):δ=8.20ppm(d,2H)；
6.85(d,2H)；4.15(m,1H)；4.12(q,2H)；3.85
(wide d, 2H); 3.10 (t, 1H); 3.0-2.8 (m, 4H); 2.70
(d, 1H); 2.55 (m, 2H); 2.30 (wide t, 3H); 2.0 (d,
1H)；1.88(m,4H)；1.80-1.50(m,5H)；1.38-0.88(m,
5H)；1.25(t,3H).
K) with 2.5g 1j) in amino alcohol and the solution of 1.9g carbonyl dimidazoles in the 20ml dimethyl formamide stirring at room 15 hours.Subsequently, this reaction soln is evaporated to dry doubling by preparing HPLC (Merck, Select B, methyl alcohol/damping fluid (pH=7.5) 65/35) with this residue purified.Obtain 2.78g (±)-(3 ' α, 7 ' β, 7 α)-1-[2-oxo generation-3-(3,4,5,6-tetrahydrochysene-2H-[1,4 '] two pyridin-4-yls)-octahydro benzoxazole-7-yl like this]-piperidine-4-ethyl formate, be yellow oil.m/e=456。
1) with 1.85g 1k) in ethyl ester and the solution of 4.60ml 1N sodium hydroxide solution in 30ml methyl alcohol, stirring at room 1 hour.Then, vacuum is removed methyl alcohol and is passed through ion-exchanger (Dowex 50, the H type) purified product.Obtain the 0.95g title compound like this, be white powder.Fp＞200℃。M/e (EI spectrum)=500 (measuring) with trimethyl silyl derivative.
Embodiment 1a
(-)-(3 ' S, 7 ' S, 7R)-1-[2-oxo-3-(3,4,5,6-tetrahydrochysene-2H-[1,4 '] two pyridin-4-yls)-octahydro benzoxazole-7-yl]-piperidines-4-formic acid
Figure A9719507200271
Carry out reactions steps 2a)-2c) after, with (1R, 2R, 3S)-1-hydroxyl-2, the 3-epoxy cyclohexane replaces embodiment 2a) in racemic suitable-2,3-oxirane ring hexanol, obtain optically active compound (1S, 2S, 3R)-1-azido--2-hydroxyl-cyclohexyl)-piperidine-4-ethyl formate ([α] D 20=-41.4 ° of (C1.2; CHCl 3)), be similar to embodiment 1i by it)-1l) obtain title compound ([α] D=-17.4 ° of (C1.18; CHCl 3)).
(1R, 2R, 3S)-1-hydroxyl-2, the 3-epoxy cyclohexane is according to Svante T. (J.Org.Chem.38,1380 (1973)) method by (R)-hexamethylene-2-enol according to known method (Fukazawa etc. in the document, Tetrahydron Asymmetry 4,2323 (1993)) prepare with metachloroperbenzoic acid.
Embodiment 2
(±)-(1 α, 2 β, 3 α)-1-(3-azido--2-hydroxyl-cyclohexyl) piperidine-4-ethyl formate 1h) another kind of preparation method
Figure A9719507200281
A) 119.65g is suitable-2,3-oxirane ring hexanol (seeing embodiment 1c) and the solution of 188ml triethylamine in the 400ml methylene dichloride mix with the solution of 240g Tosyl chloride in the 500ml methylene dichloride at 0 ℃.Then, room temperature stirs this reaction mixture 15 hours, leaches sedimentary salt then and uses 100ml sodium hydrogen carbonate solution wash filtrate.Mutually also except that after desolvating, this crude product is passed through column chromatography purifying (ethyl acetate/isohexane=1/1) with the dried over sodium sulfate methylene dichloride on silica gel.It is suitable-2 to obtain 211g (75%) like this, and 3-epoxycyclohexyl tosylate is yellow oil, and it slowly solidifies.
1H-NMR (CDCl 3): δ=7.85ppm (d, 2H); 7.35 (d, 2H); 4.90 (m, 1H); 3.27 (wide s, 1H); 3.17 (wide s, 1H); 2.45 (5,3H); 1.80 (m, 2H); 1.65 (m, 3H); 1.22 (m, 1H).
B) with 112g 2a) epoxide and the mixture of 110ml 4-piperidine-1-carboxylic acid ethyl ester in 250ml ethanol in the 500W microwave oven, shone 2.75 hours, making temperature of reaction is 65 ℃.Then, reaction soln is cooled to 0 ℃, with the product suction filtration, at every turn with twice of the cold washing with alcohol of 50ml and each, and 30 ℃ of vacuum-dryings with 50ml ether washing 3 times.Obtain 96g (54%) (1 α, 2 β, 3 β)-1-(3-tolysulfonyl oxygen base-2-hydroxyl-cyclohexyl) piperidine-4-ethyl formate like this.
Fp=135-137 ℃ of .m/e=425. 1H-NMR (CDCl 3): δ=7.75ppm (d, 2H); 7.22 (d, 2H); 4.85 (wide s, 1H); 4.05 (q, 2H); 3.28 (d has good resolving power, 1H); 2.62 (m, 2H); 2.50 (t, 1H); 2.35 (s, 3H); 2.18 (m, 1H); 2.05 (t, 2H); 1.75 (m, 3H); 1.55 (m, 4H); 1.32 (m, 1H); 1.15 (t, 3H); 1.10 (m, 1H).
C) with 37g 2b) tosylate and the mixture of 34.3g sodiumazide in the 250ml dimethyl formamide in the 500W microwave oven, shone 20 minutes, making temperature of reaction is 90 ℃.Then, reaction soln is cooled to room temperature, suction filtration goes out this salt, at 50 ℃ filtrate vacuum-evaporation is extremely done, and reclaims this resistates and uses the 50ml ether that aqueous mixture is extracted 3 times at every turn with 50ml water.With the organic phase of dried over sodium sulfate merging and except that after desolvating, on silica gel, pass through this crude product of column chromatography purifying (ethyl acetate/isohexane=6/4).Obtain 21.8g (84%) title compound like this, be light grey powder.Fp.:61-63℃。The title compound ratio method 1h that this method obtains) productive rate is good and purity is high.
Embodiment 2a
(+)-(3 ' R, 7 ' R, 7S)-1-[2-oxo-3-(3,4,5,6-tetrahydrochysene-2H-[1,4 '] two pyridin-4-yls)-octahydro benzoxazole-7-yl]-piperidines-4-formic acid
Carry out reactions steps 2a)-2c) after, with (1S, 2S, 3R)-1-hydroxyl-2, the 3-epoxy cyclohexane replaces embodiment 2a) in racemic suitable-2,3-oxirane ring hexanol, obtain optically active compound (1R, 2R, 3S)-1-azido--2-hydroxyl-cyclohexyl)-piperidine-4-ethyl formate ([α] D 20=+42 ° of (C1.23; CHCl 3)), be similar to embodiment 1i by it)-1l) obtain title compound ([α] D=+18.7 ° of (C1.2; CHC1 3)).
(1S, 2S, 3R)-1-hydroxyl-2, the 3-epoxy cyclohexane is according to Svante T. (J.Org.Chem.38,1380 (1973)) method by (S)-hexamethylene-2-enol according to known method (Singh V.K. etc. in the document, Synth.Commun.24,375 (1994)) prepare with metachloroperbenzoic acid.
Embodiment 3
(±)-(3 ' α, 7 ' β, 7 α)-1-{3-[1-(2-benzylamino-pyrimidine-4-yl)-piperidin-4-yl]-2-oxo-octahydro benzoxazole-7-yl }-piperidines-4-formic acid
Figure A9719507200301
A) the 100ml ethanolic soln with 16ml (0.12mol) 4-piperidone-ethylene ketal is added drop-wise to 18.5g (0.12mol) 2, in the 150ml ethanolic soln of 4-dichloro pyrimidine and 17.5ml triethylamine, uses ice-cooled simultaneously.With this reaction mixture stirring at room 2.5 hours, be evaporated to dried then then.In 50ml water, reclaim this resistates and the each 20ml of using dichloromethane extraction 3 times.With the organic phase of dried over sodium sulfate merging and except that after desolvating, use ethyl acetate/isohexane with this resistates recrystallization.Obtain 21.8g 8-(2-chloro-pyrimidine-4-yl)-1 like this, 4-two oxa-s-8-azepine-spiral shell-[4.5] decane are white powder.m/e=256。 1H-NMR (CDCl 3): δ=7.92ppm (d, 1H; Ar-H); 6.35 (d, 1H; Ar-H); 3.91 (s, 4H; Ketal-CH 2); 3.65 (wide s, 4H); 1.68 (t, 4H).
B) with 8g3a) the 2-Aminometradine and the mixture of 7.2ml benzylamine 150 ℃ of heating 2 hours.Then this reaction mixture is cooled to room temperature, adds 30ml water, use the 20ml methylene dichloride at every turn, merge extract and use dried over sodium sulfate this aqueous solution extraction 3 times, with rotatory evaporator except that desolvate and with ethyl acetate with this residue crystallized.Obtain 7g 8-(2-benzylamino-pyrimidine-4-yl)-1 like this, 4-two oxa-s-8-azepine-spiral shell-[4.5] decane.
M/e=326. 1H-NMR (d 6-DMSO): δ=7.88ppm (d, 1H; Ar-H); 7.32 (m, 5H; Ar-H); 7.25 (wide s, 1H; NH); 6.12 (d, 1H; Ar-H); 4.45 (d, 2H; PH-CH 2-) 3.98 (s, 4H; Ketal-CH 2); 3.65 (wide s, 4H); 1.72 (wide s, 4H).
C) be similar to embodiment 1b) by 7g 3b) ketal and 80ml 6N hydrochloric acid obtain 6.3g1-(2-benzylamino-pyrimidine-4-yl)-piperidin-4-one-, be brown oil.It is directly used with the crude product form.
D) be similar to embodiment 1j) by 1i) amine 0.42g, 0.44g 3c) ketone, 0.66g nitrilotriacetic sodium borohydride and 0.3ml 100% acetate obtain 0.77g (±)-(1 α, 2 β, 3 α)-1-{2-hydroxyl-3-[1-(2-benzylamino-pyrimidine-4-yl)-piperidin-4-yl amino] cyclohexyl } piperidine-4-ethyl formate.m/e=537。
E) be similar to embodiment 1k) by 0.77g 3d) amino alcohol and 0.28g carbonyl dimidazoles obtain 0.54g (±)-(3 ' α, 7 ' β, 7 α)-1-{3-[1-(2-benzylamino-pyrimidine-4-yl)-piperidin-4-yl]-2-oxo-octahydro benzoxazole-7-yl }-piperidine-4-ethyl formate.
Pos.FAB=562. 1H-NMR (d 6-DMSO): δ=7.75ppm (d, 1H); 7.20 (m, 5H); 7.12 (wide s, 1H; NH); 6.03 (d, 1H); 4.43 (d, 2H); 4.39 (wide s, 1H); 4.05 (q, 2H); 3.80 (t, 1H); 3.69 (m, 1H); 3.25 (wide t, 1H); (2.76 m, 55); 2.48 (m, 2H); 2.25 (m, 2H); 1.95-1.20 (m, 14H); 1.18 (t, 2H).
F) be similar to embodiment 11) by 0.1g 3e) ethyl ester and 0.4ml 1N sodium hydroxide solution obtain the 0.065g title compound.m/e=534。Fp=180℃。
Embodiment 4
(±)-(3 ' α, 7 ' β, 7 α)-1-{3-[1-(2-tetramethyleneimine-1-base-pyrimidine-4-yl)-piperidin-4-yl]-2-oxo-octahydro benzoxazole-7-yl }-piperidines-4-formic acid
Figure A9719507200321
A) with 7.7g chloropyrimide derivative 3a) and the 25ml tetramethyleneimine in the 500W microwave oven, shone 15 minutes, making temperature of reaction is 50 ℃.Then reaction soln is evaporated to dried, in 20ml water, reclaim this resistates and each with the 20ml methylene dichloride with this aqueous solution extraction 4 times.With sodium sulfate that the extract that merges is dry also except that after desolvating, by preparing HPLC (Merck, Select B, methyl alcohol/damping fluid (pH=7.5) 75/25) with this residue purified.Obtain 7.8g 8-(2-tetramethyleneimine-1-base-pyrimidine-4-yl)-1 like this, 4-two oxa-s-8-azepine-spiral shell-[4.5] decane, m/e=290.
B) be similar to embodiment 1b) by 7.8g ketal 4a) and 72ml 6N hydrochloric acid obtain 5.9g1-(2-tetramethyleneimine-1-base-pyrimidine-4-yl)-piperidin-4-one-, it is directly used with the crude product form.
C) be similar to embodiment 1j) by 2.46g ketone 4b), 2.7g amine li), 3.2g nitrilotriacetic sodium borohydride and 6ml 100% acetate obtains 3.4g (±)-(1 α, 2 β, 3 α)-and 1-{2-hydroxyl-3-[1-(2-tetramethyleneimine-1-base-pyrimidine-4-yl)-piperidin-4-yl amino] cyclohexyl } piperidine-4-ethyl formate, be yellow oil.
1H-NMR (d 6-DMSO+AcOH): δ=7.92ppm (d, 1H); 6.29 (d, 1H); 4.52 (wide d, 2H); 4.15 (q, 2H); 3.79 (t, 1H); 3.53 (m, 4H); 3.20 (m, 3H); 3.00 (m, 3H); 2.55 (m, 2M); 2.20-1.70 (m, 13H); 1.62-1.35 (m, SM); 1.25 (t, 3H).
D) be similar to embodiment 1k) by 3.3g amino alcohol 4c) and the 1.6g carbonyl dimidazoles obtain 2.5g (±)-(3 ' α, 7 ' β, 7 α)-1-{3-[1-(2-tetramethyleneimine-1-base-pyrimidine-4-yl)-piperidin-4-yl]-2-oxo-octahydro benzoxazole-7-yl }-piperidine-4-ethyl formate, be light grey powder.Fp=140℃。M/e=526. 1H-NMR (d 6-DMSO): δ=8.01ppm (d, 1H); 6.21 (d, 1H); 4.62 (wide t, 2H); 4.20 (q, 2H); 3.99 (t, 1H); 3.88 (m, 1H); 3.55 (m, 5H); 2.98 (m, 5H); 2.65 (m, 1H); 2.45 (m, 2H); 2.13 (m, 1H); 2.08-1.40 (m, 18H); 1.33 (t, 3H).
E) be similar to embodiment 1l) by 0.4g ethyl ester 4d) and 0.9ml 1N sodium hydroxide solution obtain the 0.16g title compound.M/e=498. 1H-NMR (d 6-DMSO+AcOH): δ=7.60ppm (d, 1H); 6.25 (d, 1H); 4.35 (wide s, 2H); 3.78 (t, 1H); 3.59 (wide t, 1H); 3.25 (m, 5H); 3.05-2.70 (m, 5H); 2.60 (wide t, 1H); 2.42 (wide t, 1H); 2.15 (m, 1H); 1.80-1.38 (m, 14H); 1.20 (m, 4H).
Embodiment 5
(±)-(3 ' α, 7 ' β, 7 α)-1-{3-[1-(2-amino-pyrimidine-4-yl)-piperidin-4-yl]-2-oxo-octahydro benzoxazole-7-yl }-piperidines-4-formic acid
Figure A9719507200331
A) with 26g chloropyrimide derivative 3a) and the maintenance 60 hours under 5 crust and 90 ℃ of conditions in 1 liter of autoclave of the solution of 120ml liquefied ammonia in 500ml ethanol.Then reaction soln is evaporated to dried, in 20ml water, reclaim this resistates and each with the 20ml methylene dichloride with this aqueous solution extraction 5 times.With sodium sulfate that the organic phase that merges is dry also except that after desolvating, this solid residue is stirred with the 40ml ethyl acetate.Obtain 5.7g 8-(2-amino-pyrimidine-4-yl)-1 like this, 4-two oxa-s-8-azepine-spiral shell-[4.5] decane are yellow powder.m/e=236。
B) be similar to embodiment 1b) by 6g ketal 5a) and 65ml 6N hydrochloric acid obtain 5.5g (2-amino-pyrimidine-4-yl)-piperidin-4-one-.m/e=192。
C) be similar to embodiment 1j) by 1g amine 1i), 0.7g ketone 5b), 1.6g nitrilotriacetic sodium borohydride and 0.8ml 100% acetate obtains 1.5g (±)-(1 α, 2 β, 3 α)-and 1-{2-hydroxyl-3-[1-(2-amino-pyrimidine-4-yl)-piperidin-4-yl amino] cyclohexyl } piperidine-4-ethyl formate, be yellow oil.
M/e=446. 1H-NMR (d 6-DMSO): δ=7.80ppm (d, 1H); 6.08 (d, 1H); 6.00 (s, 1H; NH); 4.24 (d, 2H); 4.15 (m, 4H); 3.12 (t, 1H); 2.90 (m, 4H); 2.72 (wide d, 1H); 2.60 (m, 3H); 2.30 (wide t, 3H); 1.88 (m, 5H); 1.70 (m, 5H); 1.25 (t, 3H); 1.15 (m, 3H).
D) be similar to embodiment 1k) by 1.1g amino alcohol 5c) and the 0.5g carbonyl dimidazoles obtain 0.3g (±)-(3 ' α, 7 ' β, 7 α)-1-{3-[1-(2-amino-pyrimidine-4-yl)-piperidin-4-yl]-2-oxo-octahydro benzoxazole-7-yl }-piperidine-4-ethyl formate, be light grey powder.m/e=472。Fp=120-122℃。
E) be similar to embodiment 11) by 0.11g ethyl ester 5d) and 0.25ml 1N sodium hydroxide solution obtain the 0.07g title compound.m/e=444。Fp＞200℃。
Embodiment 6
(±)-(3 ' α, 7 ' β, 7 α)-(1-[2-oxo-3-(3,4,5,6-tetrahydrochysene-2H-[1,4 '] two pyridin-4-yls)-octahydro benzoxazole-7-yl]-piperidin-4-yl }-acetate
Figure A9719507200341
Be similar to embodiment 2b), 2c) and 1i) to 1l), replace embodiment 2b with the 4-ethyl piperidine) in 4-piperidine-1-carboxylic acid ethyl ester obtain title compound.Fp=135 ℃ (decomposition).M/e=(EI spectrum)=514 (detecting) with trimethyl silyl derivative.
Embodiment 7
(±)-(3 ' α, 7 ' β, 7 α)-1-[2-oxo-3-(3,4,5,6-tetrahydrochysene-2H-[1,4 '] two pyridin-4-yls)-octahydro benzoxazole-7-yl]-the 4-2-styroyl }-piperidine-4-ethyl formate
Be similar to embodiment 2b), 2c) and 1i) to 1k), with 4-[4-(2-styroyl)] the piperidine-1-carboxylic acid ethyl ester replaces embodiment 2b) in 4-piperidine-1-carboxylic acid ethyl ester obtain title compound (Gilligan etc., J.Med.Chem.37,364 (1994)).
m/e=560. 1H-NMR(d 6-DMSO):δ=8.13ppm(d,2H)；7.25(m,2H)；7.15(m,3H)；6.80(d,2H)；4.12(q,2H)；4.01(m,2H)；3.80(t,1H)；3.70(m,1H)；3.60(m,4H)；3.28(m,1H)；2.80(m,5H)；2.45(m,2H)；2.32(t,3H)；2.05(m,2H)；1.95(m,2H)；1.70(m,9H)；1.35(m,5H)；1.20(t,3H).
Embodiment 8
(±)-(3 ' α, 7 ' β, 7 α)-1-[2-sulfo--3-(3,4,5,6-tetrahydrochysene-2H-[1,4 '] two pyridin-4-yls)-octahydro benzoxazole-7-yl]-piperidines-4-formic acid
Figure A9719507200352
A) be similar to embodiment 1k) by 0.3g amino alcohol 1j) and the 0.21g thio-carbonyldiimidazole obtain 0.2g (±)-(3 ' α, 7 ' β, 7 α)-1-[2-sulfo--3-(3,4,5,6-tetrahydrochysene-2H-[1,4 '] two pyridin-4-yls)-octahydro benzoxazole-7-yl]-piperidine-4-ethyl formate.Pos.FAB=472。
B) be similar to embodiment 11) by 0.14g ethyl ester 8a) and 0.35ml 1N sodium hydroxide solution obtain the 0.1g product, add 0.6ml 1N hydrochloric acid after, therefrom isolate the hydrochloride form of 143mg title compound.Pos.FAB=472。Fp=180℃。
Embodiment 9
(±)-(3 ' α, 7 ' β, 7 α)-1-[3-(1 '-benzyl-[1,4 '] two pyridin-4-yls)-2-oxo-octahydro benzoxazole-7-yl]-piperidines-4-formic acid
A) with 15g pyridine derivate 1a) and the mixture of 4g rhodium oxide be hydrogenated to absorption of hydrogen and finish (30 hours).Leach catalyzer then, vacuum concentrated filtrate, at 120ml 1, the solution that this resistates of recovery also will obtain like this in the 4-diox mixes with 18ml benzyl chloride and 15g salt of wormwood.With this reaction mixture reflux 5 hours, cooling then leached precipitation and filtrate is evaporated to dried.This crude product is passed through column chromatography purifying (methyl alcohol that ethyl acetate+10% ammonia is saturated) on silica gel.Obtain 3.4g 8-(1-benzyl-piperidin-4-yl)-1 like this, 4-two oxa-s-8-azepine-spiral shell [4.5] decane.
1H-NMR (d 6-DMSO): δ=7.30ppm (m, 5H); 3.85 (s, 4H); 3.45 (s, 2H); 2.84 (d, 2H); 2.52 (m, 4H); 2.25 (m, 1H); 1.88 (t, 2H); 1.63 (m, 6H); 1.42 (q has good resolving power, 2H) .b) is similar to embodiment 1b) by 1.5g ketal 9a) and 10ml 6N hydrochloric acid obtain 1.2g1 '-benzyl-[1,4 '] two piperidin-4-one-s.m/e=272。 1H-NMR(d 6-DMSO):δ=7.35ppm(m,5H)；4.01(s,2H)；3.22(d,2H)；3.01(m,1H)；2.84(d,3H)；2.65(q,3H)；2.33(t,3H)；1.80(m,5H).
C) be similar to embodiment 1j) by 1.2g amine 1i), 1.2g ketone 9b) and 1.9g nitrilotriacetic sodium borohydride obtain 1.4g1-[3-(piperidin-4-yl amino 1 '-benzyl-[1,4 '] two)-2-hydroxyl-cyclohexyl] piperidine-4-ethyl formate, be light gray solid.Fp=92℃。
D) be similar to embodiment 1k) by 0.99g amino alcohol 9c) and the 0.45g carbonyl dimidazoles obtain 0.51g (±)-(3 ' α, 7 ' β, 7 α)-1-[3-(1 '-benzyl-[1,4 '] two piperidin-4-yls)-2-oxo-octahydro benzoxazole-7-yl]-piperidine-4-ethyl formate, be white powder.Fp=148-150℃。
E) be similar to embodiment 11) by 0.25g ethyl ester 9d) and 0.5ml 1N sodium hydroxide solution obtain the 0.12g title compound.m/e=524. 1H-NMR(D 2O):δ=7.25ppm(m,5H)；3.92(t,1H)；3.60(s,2H)；3.45(m,2H)；3.01(d,4H)；2.82(m,3H)；2.48(t,2H)；2.38-2.00(m,7H)；1.95-1.60(m,10H)；1.35(m,7H).
Embodiment 10
(±)-(3 ' α, 7 ' β, 7 α)-1-(3-[1,4 '] two pyridin-4-yls-2-oxo-octahydro benzoxazole-7-yl)-piperidines-4-formic acid
Figure A9719507200371
A) with 0.74gN-benzyl derivative 9d) and the mixture of 0.3g 10% palladium/carbon in 20ml ethanol under 50 ℃/4 crust conditions, be hydrogenated to absorption of hydrogen and finish (2 hours).After leaching catalyzer, filtrate is evaporated to dried.Obtain 0.355g (±)-(3 ' α, 7 ' β, 7 α)-1-(3-[1,4 '] two pyridin-4-yls-2-oxo generation-octahydro benzoxazole-7-yl)-piperidine-4-ethyl formate like this.Pos.FAB=524。Fp＞200℃。
B) be similar to embodiment 11) by 0.2g ethyl ester 10a) and 0.7ml 1N sodium hydroxide solution obtain the 0.13g title compound.Pos.FAB(MH +)=435。Fp＞200℃。
Embodiment 11
(±)-(3 ' β, 7 ' α, 7 α)-1-[2-oxo-3-(3,4,5,6-tetrahydrochysene-2H-[1,4 '] two pyridin-4-yls)-octahydro benzoxazole-7-yl]-piperidines-4-formic acid
Figure A9719507200381
A) with 1.77g trans-3-bromo-1,2-epoxy cyclohexane (Lier E. etc., Helv.Chim.Acta, 62,932 (1979)), 1.7ml 4-piperidine ethyl formate and the mixture stirring at room of 1.8g salt of wormwood in the 30ml dimethyl formamide 24 hours.Then this reaction mixture is mixed with 400ml water and each with the 40ml ether with this aqueous solution extraction 3 times.With the organic phase of dried over sodium sulfate merging and except that after desolvating, on silica gel, pass through this crude product of column chromatography purifying (the saturated methanol solution of ethyl acetate+1% ammonia).Obtain 0.6g (±)-cis-1-(2,3-epoxy-cyclohexyl) piperidines-4-formic acid like this.
1H-NMR (CDCl 3): δ=4.05ppm (q, 2H); 3.20 (d, 1H); 3.05 (t, 1H); 2.98 (m, 1H); 2.82 (m, 2H); 2.40 (m, 12 lines, 2H); 2.18 (m, 1H); 1.85 (m, 2H); 1.70 (m, 6H); 1.50 (m, 1H); 1.36 (m, 1H); 1.19 (t, 3H).
B) be similar to embodiment 2c) by 0.6g epoxide 11a) and the 0.23g sodiumazide obtain 0.6g (±)-(1 α, 2 α, 3 β)-1-(3-azido--2-hydroxyl-cyclohexyl)-piperidine-4-ethyl formate, be gray solid.m/e=296。Fp=90℃。
C) be similar to embodiment 1i) by 0.44g trinitride 11b) obtain 0.2g (±)-(1 α, 2 α, 3 β)-1-(3-amino-2-hydroxyl-cyclohexyl)-piperidine-4-ethyl formate.
Pos.FAB=270. 1H-NMR(CDCl 3):δ=4.05ppm(q,2H)；3.60(t,1H)；3.15(q,1H)；3.00(m,2H)；2.50(m,1H)；2.28-2.00(m,5H)；1.90-1.40(m,11H)；1.25(m,1H)；1.18(t,3H).
D) be similar to embodiment 1j) by 0.2g amine 11c), 0.13g ketone 1b) and 0.31g nitrilotriacetic sodium borohydride obtain 0.12g (±)-(1 α, 2 α, 3 β)-1-(2-hydroxyl-3-(3,4,5,6-tetrahydrochysene-2H-[1,4 '] two pyridin-4-yl amino)-cyclohexyl]-piperidine-4-ethyl formate.Pos.FAB=430。
E) be similar to embodiment 1k) by 0.42g amino alcohol 11d) and the 0.24g carbonyl dimidazoles obtain 0.35g (±)-(3 ' β, 7 ' α, 7 α)-1-[2-oxo-3-(3,4,5,6-tetrahydrochysene-2H-[1,4 '] two pyridin-4-yls)-octahydro benzoxazole-7-yl]-piperidine-4-ethyl formate.
M/e=456, 1H-NMR d 6-DMSO): δ=8.20ppm (d, 2H); 6.85 (d, 2H); 4.05 (q+m, 5H); 3.75 (m, 1H); 3.20 (wide d, 1H); 2.90 (m, 3H); 2.30 (m, 1H); 2.04 (m, 4H); 1.80 (m, 5H); 1.65-1.35 (m, 9H); 1.20 (t, 3H).
F) be similar to embodiment 11) by 0.3g ethyl ester 11e) and 1ml 1N sodium hydroxide solution obtain the 0.26g title compound.Pos.FAB=428。
Embodiment 12
(±)-(3 ' β, 7 ' β, 7 α)-1-[2-oxo-3-(3,4,5,6-tetrahydrochysene-2H-[1,4 '] two pyridin-4-yls)-octahydro benzoxazole-7-yl]-piperidines-4-formic acid
Figure A9719507200401
A) be similar to embodiment 1d) by 0.65g cis-3-benzyloxycarbonyl amino-1,2-epoxy cyclohexane (Brouillette W.J. etc., J.Org.Chem., 59,4297 (1994)) and 0.6ml 4-piperidine ethyl formate obtain 0.9g (±)-(1 α, 2 β, 3 β)-1-(3-benzyloxycarbonyl amino-2-hydroxyl-cyclohexyl)-piperidine-4-ethyl formate, be thickness oily matter.It is further processed with the crude product form.
B) with embodiment 12a) solution of 0.9g N-carbobenzoxy-(Cbz) amine in 15ml ethanol of preparation mixes with 0.8g 10% palladium/carbon and with the hydrogenation under atmospheric pressure at room of this mixture, finishes (12 hours) to absorption of hydrogen.Then, leach catalyzer and with rotatory evaporator with this solution concentration.Obtain 0.5g (±)-(1 α, 2 β, 3 β)-1-(3-amino-2-hydroxyl-cyclohexyl)-piperidine-4-ethyl formate like this.
M/e=270. 1H-NMR (d 6-DMSO): δ=4.05ppm (q, 2H); 3.48 (dd, 1H); 3.20 (q, 1H); 2.80 (dt, 1H); 2.68 (dt, 1H); 2.58 (t has good resolving power, 1H); 2.42 (t has good resolving power, 1H); 2.25 (m, 1H); 2.13 (t has good resolving power, 1H); 1.78 (m, 2H); 1.63 (m, 2H); 1.55 (m, 4H); 1.38 (m, 2H); 1.19 (t, 3H); 1.15 (m, 2H).
C) be similar to embodiment 1j) by 0.4g amine 12b), 0.26g ketone 1b) and 0.42g nitrilotriacetic sodium borohydride obtain 0.33g (±)-(1 α, 2 β, 3 β)-1-[2-hydroxyl-(3,4,5,6-tetrahydrochysene-2H-[1,4 '] two pyridin-4-yl amino)-cyclohexyl]-piperidine-4-ethyl formate.Then, with amino alcohol and the 0.17g carbonyl dimidazoles of preparation like this according to embodiment 1k) similarly method react and obtain 0.22g (±)-(3 ' β, 7 ' β, 7 α)-1-[2-oxo-3-(3,4,5,6-tetrahydrochysene-2H-[1,4 '] two pyridin-4-yls)-octahydro benzoxazole-7-yl]-piperidine-4-ethyl formate, be similar to embodiment 11) with 0.6ml 1N sodium hydroxide this saponification is obtained the 0.11g title compound.
Fp=150 ℃ of (decomposition) .m/e=428. 1H-NMR (d 6-DMSO+AcOH): δ=4.05ppm 8.15 (d, 2H); 7.10 (d, 2H); 4.65 (t, 1H); 4.25 (wide d, 2H); 3.98 (wide d, 1H); 3.61 (m, 1H); 3.05 (m, 4H); 2.70 (m, 2H); 2.35 (m, 1H); 2.10 (m, 1H); (2.0-1.10 m, 16).
Buy and execute example 13
Detect:
With the isolating activation of 2 μ g/ml Gp II b/ III a acceptor droplet plate bag is spent the night.After washing step is washed unconjugated acceptor off several times, wash off once again with the surface sealing of this plate and with it with 1% casein.Concentration with needs adds tested material, then this plate is hatched 10 minutes, shakes on the line style shaking table simultaneously.The native ligand that adds Gp II b/ III a acceptor, fibrinogen.After hatching 1 hour, unconjugated fibrinogen is removed, and determined the bonded fibrinogen with the ELISA reader by the variation that detection peroxidase bonded monoclonal antibody causes in 405nm place optical density(OD) by several washing steps.Fibrinogen and the interactional inhibition of Gp II b/ III a reduce optical density(OD).Determine IC according to the concentration effect curve 50Value.
Document:
Gp II b/ III a fibrinogen ELISA is the improved detection method that is described in the following document:
Nachman, R.L.﹠amp; Leung, L.L.K. (1982): platelet membrane glycoprotein II b and III a and fibrinogen form mixture, J.Clin.Invest.69:263-269.
Wrignt, P.S. etc., (1993): echiststin C-terminal peptide activatory Gp II b III a combines Biochem.J.293:263-267 with fibrinogen, fibronectin, vitronectin and collagen I and IV.
Pharmacology data:
Embodiment IC 50(nMol/l) Title
1 25 (±)-(3 ' α, 7 ' β, 7 α)-1-[2-oxo-3-(3,4,5,6-tetrahydrochysene-2H-[1,4 '] two pyridin-4-yls)-octahydro benzoxazole-7-yl]-piperidines-4-formic acid

Claims (5)

1. the compound of formula I and its configuration and conformational isomer and pharmacologically acceptable salt thereof:
Figure A9719507200021
Wherein E expression (a) or residue (b):
Figure A9719507200022
(a)
Figure A9719507200023
(b)
M represents Sauerstoffatom, sulphur atom or NR 00,
X represents hydrogen atom or NR 1R 2,
W represents nitrogen-atoms or NH or CH or CH 2,
Q represents nitrogen-atoms or CH,
Y represents nitrogen-atoms or CH,
Z represents nitrogen-atoms, CH or C-OH,
A represents alkylidene chain-(CH 2) p-, it is optionally substituted,
D expression-(CHR 3) m-COO-R 8Or=CR 3-COO-R 8Side chain,
N represents 1-3,
M represents 0 or 1,
P represents 0-3,
R 1, R 2Represent hydrogen atom, low alkyl group, aryl, arylalkyl, heteroaryl independently of one another; acyl group or optional substituted carbocyclic ring or heterocycle; perhaps form optional substituted five yuan or six-ring with the nitrogen-atoms that they connected; this ring also can contain other 1 to 3 heteroatoms, perhaps represents group (c)
Figure A9719507200031
(c)
R 3Expression hydrogen atom or group-OR 5Or-NR 6R 7,
R 4Expression hydrogen atom, low alkyl group, aryl, aralkyl, heteroaryl or group-OR 5,
R 5Expression hydrogen atom, low alkyl group, aryl or aralkyl,
R 6Expression hydrogen atom, low alkyl group or aralkyl,
R 7Expression hydrogen atom, low alkyl group, aralkyl, acyl group, alkyl sulphonyl or aryl sulfonyl,
R 8Expression hydrogen atom, methyl, ethyl, sec.-propyl, the tertiary butyl, phenyl or benzyl, particularly hydrogen atom, ethyl, phenyl or sec.-propyl,
R 10Expression hydrogen atom, low alkyl group, aralkyl, acyl group, alkyl sulphonyl, aryl sulfonyl or group (c),
R 0Expression hydrogen atom, low alkyl group, aralkyl or group-NHR 00,
R 00Expression hydrogen atom, low alkyl group, aralkyl, acyl group, alkyl sulphonyl or aryl sulfonyl.
2. the compound of the described formula I of claim 1, wherein n is 1,2 or 3 and p is 0,1 or 3.
3. compound:
(±)-(3 ' α, 7 ' β, 7 α)-1-[2-oxo-3-(3,4,5,6-tetrahydrochysene-2H-[1,4 '] two pyridin-4-yls)-octahydro benzoxazole-7-yl]-piperidines-4-formic acid,
(±)-(3 ' α, 7 ' β, 7 α)-1-[2-oxo-3-(3,4,5,6-tetrahydrochysene-2H-[1,4 '] two pyridin-4-yls)-octahydro benzoxazole-7-yl]-piperidine-4-ethyl formate,
And configuration and conformational isomer with and pharmacologically acceptable salt.
4. pharmaceutical composition wherein contains one of at least a claim 1 to 3 described formula I compound and common carrier and assistant agent.
5. the described material of one of claim 1-3 is used to prepare the purposes of the medicine of the disease that the treatment platelet aggregation causes.
CN97195072A 1996-03-30 1997-03-26 Novel oxazolidine derivatives, process for their production and medicaments containing them Pending CN1219933A (en)

Applications Claiming Priority (4)

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DE19612827A DE19612827A1 (en) 1996-03-30 1996-03-30 New (pyridyl-piperidinyl)-(carboxy-cycloalkyl)cycloalkano:oxazolidinone
DE19612827.7 1996-03-30
DE19654479.3 1996-12-27
DE1996154479 DE19654479A1 (en) 1996-12-27 1996-12-27 Oxazolidine derivs. to inhibit blood platelet aggregation,

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