CN1284074A - Novel compounds - Google Patents
Novel compounds Download PDFInfo
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- CN1284074A CN1284074A CN98813490A CN98813490A CN1284074A CN 1284074 A CN1284074 A CN 1284074A CN 98813490 A CN98813490 A CN 98813490A CN 98813490 A CN98813490 A CN 98813490A CN 1284074 A CN1284074 A CN 1284074A
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- Prior art keywords
- pyridyl
- butyl
- oxygen base
- diketone
- base
- Prior art date
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- 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
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
The invention provides novel compounds, a process for their preparation, pharmaceutical compositions containing them, a process for preparing the pharmaceutical compositions, and their use in therapy.
Description
The present invention relates to new compound, their preparation method, the pharmaceutical composition that comprises them, the method for preparing this class pharmaceutical composition and their application in treatment.
P2X
7Acceptor (being called the P2Z acceptor previously) is a kind of ligand-gated ion channel, is present in multiplely all to participate on the cell type of inflammation/immunologic process mostly, particularly scavenger cell, mastocyte and lymphocyte (T and B).P2X
7After being activated by the outer Nucleotide (particularly Triphosaden) of born of the same parents, acceptor can cause interleukin-1 ' beta ' (IL-1) to discharge and giant cells forms (scavenger cell/microgliacyte), threshing (mastocyte) and L-selection albumen come off (lymphocyte).P2X
7Acceptor also is positioned on antigen presenting cell (APC), keratinocyte, sialisterium cystencyte (parotid gland cell) and the liver cell.
The compound that can be effective as the P2X7 receptor antagonist and be used for the treatment of inflammation, immunity or cardiovascular disorder, P2X with regard to the nosetiology of these diseases are prepared in people's expectation
7Acceptor is played a role therein.
The invention provides following general formula compound or its pharmaceutically useful salt and solvate:
Wherein X represents oxygen or sulphur atom, or represents group NH, CH
2, CH
2CH
2Or OCH
2Y represents group CH
2Or C=O; R
1Represent pyridyl (especially 3-pyridyl or 4-pyridyl) or pyrimidyl; R
2Represent phenyl, pyridyl or pyrimidyl, they separately can be randomly independently be selected from following substituting group and replace by one or more: halogen atom or amino, cyano group, hydroxyl, nitro, C
1-C
6-alkyl, halo-C
1-C
6-alkyl, C
1-C
6-alkoxyl group, C
1-C
6-alkylthio, (two) C
1-C
6-alkylamino C
1-C
6-alkyl-carbonyl, C
1-C
6-alkoxy carbonyl, C
1-C
6-alkyl sulfinyl, C
1-C
6-alkyl sulphonyl ,-NR
3SO
2R
4Or-SO
2NR
5R
6Group, or group-Z-(CH
2)
p-Z-(CH
2)
q-H, wherein Z represents nitrogen or Sauerstoffatom separately, and p is integer 2-5, and q is 0 or integer 1-5; R
3And R
4Represent hydrogen atom or C independently of one another
1-C
6-alkyl; And R
5And R
6Represent hydrogen atom or C independently of one another
1-C
6-alkyl, perhaps the nitrogen-atoms that connects with their institute's keys forms pyrrolidyl or piperidyl.
In this specification sheets, except as otherwise noted, the moieties in alkyl substituent or the substituting group group can be a straight or branched, and each moieties in the dialkyl amido substituting group can be identical or different.In addition, represent group OCH as X
2The time, Sauerstoffatom is arranged in the ortho position of ring carbonyl group.
Radicals R
2Preferred phenyl, pyridyl or the pyrimidyl represented, they can randomly independently be selected from following substituting group by one, two, three or four separately and replace: halogen atom (as fluorine, chlorine, bromine or iodine) or amino, cyano group, hydroxyl, nitro, C
1-C
6-alkyl (as methyl, ethyl, propyl group, butyl, amyl group or hexyl), halo-C
1-C
6-alkyl (as trifluoromethyl), C
1-C
6-alkoxyl group (as methoxyl group, oxyethyl group, propoxy-, butoxy, pentyloxy or hexyloxy), C
1-C
6-alkylthio (as methylthio group, ethylmercapto group, rosickyite base, butylthio, penta sulfenyl or own sulfenyl), (two) C
1-C
6-alkylamino (as methylamino-, dimethylamino, ethylamino or diethylamino), C
1-C
6-alkyl-carbonyl (as methyl-, ethyl-, propyl group-, butyl-, amyl group-or the hexyl carbonyl), C
1-C
6-alkoxy carbonyl (as methoxyl group-, oxyethyl group-, propoxy--, butoxy-, pentyloxy-or hexyloxy carbonyl), C
1-C
6-alkyl sulfinyl (as methyl-, ethyl-, propyl group-, butyl-, amyl group-or the hexyl sulfinyl), C
1-C
6-alkyl sulphonyl (as methyl-, ethyl-, propyl group-, butyl-, amyl group-or the hexyl alkylsulfonyl) ,-NR
3SO
2R
4Or-SO
2NR
5R
6Group, or group-Z-(CH
2)
p-Z-(CH
2)
q-H, wherein Z represents nitrogen or Sauerstoffatom independently of one another, and p is that 2-5 integer and q are 0 or integer 1-5.
R more preferably
2Represent phenyl, pyridyl or pyrimidyl, they separately can be randomly by one, two or three independently are selected from following substituting group and replace: halogen atom or amino, cyano group, hydroxyl, nitro, C
1-C
4-alkyl, halo-C
1-C
4-alkyl, C
1-C
4-alkoxyl group, C
1-C
4-alkylthio (two) C
1-C
4-alkylamino, C
1-C
4-alkyl-carbonyl, C
1-C
4-alkoxy carbonyl, C
1-C
4-alkyl sulfinyl, C
1-C
4-alkyl sulphonyl ,-NR
3SO
2R
4Or-SO
2NR
5R
6Group.
More preferably R
2Represent phenyl, pyridyl or pyrimidyl, they can randomly independently be selected from following substituting group by one or two separately and replace: halogen atom or amino, cyano group, nitro, C
1-C
4-alkyl, halo-C
1-C
4-alkyl, C
1-C
4-alkoxyl group or-SO
2NR
5R
6Group.
R most preferably
2Representative independently is selected from optional phenyl or the pyridyl group that replaces of following substituting group by one or two: fluorine or chlorine atom or amino, cyano group, nitro, trifluoromethyl, methoxyl group or-SO
2NR
5R
6Group.
Preferred R
3And R
4Represent hydrogen atom or C independently of one another
1-C
4-alkyl (as methyl or ethyl).
Preferred R
5And R
6Represent hydrogen atom or C independently of one another
1-C
4-alkyl (as methyl or ethyl), perhaps the nitrogen-atoms that connects with their institute's keys forms pyrrolidyl or piperidyl, especially pyrrolidyl.
Preferred The compounds of this invention comprises:
(+/-)-(N-[1-(biphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl] tetramethyleneimine-2, the 5-diketone,
(+/-)-N-[1-(3 '-methoxyl biphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl] tetramethyleneimine-2, the 5-diketone,
(+/-)-N-[1-(biphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl] thiazolidine-2, the 4-diketone,
(+/-)-N-[1-(3 '-chlordiphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl] tetramethyleneimine-2, the 5-diketone,
(+/-)-N-[1-(3 '-fluorine biphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl] tetramethyleneimine-2, the 5-diketone,
(+/-)-N-[1-(3 '-methoxyl biphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl] tetramethyleneimine-2, the 5-diketone,
(+/-)-N-[1-(3 '-methoxyl biphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl] thiazolidine-2, the 4-diketone,
(2R)-N-[1-(3 '-cyanobiphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl] thiazolidine-2, the 4-diketone,
(2R)-N-[1-(3 '-nitrobiphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl] tetramethyleneimine-2, the 5-diketone,
(2R)-N-[1-(3 '-cyanobiphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl] tetramethyleneimine-2, the 5-diketone,
(+/-)-N-[1-(3 '-nitrobiphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl] thiazolidine-2, the 4-diketone,
(+/-)-N-[1-(3 '-nitrobiphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl] tetramethyleneimine-2, the 5-diketone,
(+/-)-N-[1-(4 '-fluorine biphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl] tetramethyleneimine-2, the 5-diketone,
(+/-)-N-[1-(4 '-fluorine biphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl] thiazolidine-2, the 4-diketone,
Id=" tilte4 " font-size=" 5 "〉(+/-)-N-[1-(biphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl] oxazolidine-2-ketone, (2R)-N-[1-(3 '-chloro-4 '-fluorine biphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl] thiazolidine-2, the 4-diketone
(2R)-N-[1-(3 '-chloro-4 '-fluorine biphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl] tetramethyleneimine-2, the 5-diketone,
(2R)-N-[1-(3 ', 5 '-dicyanobiphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl] thiazolidine-2, the 4-diketone,
(+/-)-N-[1-(3 '-nitrobiphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl] oxazolidine-2-diketone,
(2R)-N-[1-(3 '-fluorine biphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl] thiazolidine-2, the 4-diketone,
(+/-)-N-[1-(3 '-(trifluoromethyl) biphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl] thiazolidine-2, the 4-diketone,
(+/-)-N-[1-(2 '-methoxyl biphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl] thiazolidine-2, the 4-diketone,
(+/-)-N-[1-(3 '-nitrobiphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl] piperidines-2, the 6-diketone,
(+/-)-N-[1-(3 '-phenylaniline-4-base oxygen base)-4-(4-pyridyl)-2-butyl] thiazolidine-2, the 4-diketone,
(+/-)-N-[1-(3 '-nitrobiphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl]-[1,3] oxazine alkane-2-ketone,
(2S)-N-[1-(3 '-cyanobiphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl] thiazolidine-2, the 4-diketone,
(2S)-N-[1-(3 '-phenylaniline-4-base oxygen base)-4-(4-pyridyl)-2-butyl] thiazolidine-2, the 4-diketone,
(2S)-N-[1-(3 '-methanesulfonamido biphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl] thiazolidine-2, the 4-diketone,
(2S, 3S)-N-[1-(3 '-(tetramethyleneimine-1-alkylsulfonyl) biphenyl-4-base oxygen base)-4-(3-pyridyl)-3-amyl group] tetramethyleneimine-2, the 5-diketone,
(2S, 3S)-N-[1-(3 '-cyano group-4 '-fluorine biphenyl-4-base oxygen base)-4-(3-pyridyl)-3-amyl group] tetramethyleneimine-2, the 5-diketone,
(2S)-N-[1-(3 '-cyano group-4 '-fluorine biphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl] thiazolidine-2, the 4-diketone,
(+/-)-N-[1-(4 '-fluoro-3 '-sulfamyl biphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl] oxazolidine-2-ketone,
(+/-)-N-[1-(4-(6-methoxypyridine-2-yl)-phenoxy group)-4-(4-pyridyl)-2-butyl] oxazolidine-2-ketone,
(+/-)-N-[1-(biphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl] oxazolidine-2-ketone,
(+/-)-N-[1-(4 '-chlordiphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl] oxazolidine-2-ketone,
(+/-)-N-[1-(4 '-methyl diphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl] oxazolidine-2-ketone,
(+/-)-N-[1-(4 '-methoxyl biphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl] oxazolidine-2-ketone,
(+/-)-N-[1-(3 ', 4 '-DCBP-4-base oxygen base)-4-(4-pyridyl)-2-butyl] oxazolidine-2-ketone,
(+/-)-N-[1-(4-(6-methoxypyridine-2-yl)-phenoxy group)-4-(4-pyridyl)-2-butyl] piperidines-2, the 6-diketone,
(+/-)-N-[1-(3 '-nitrobiphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl] imidazolidine-2, the 4-diketone,
(+/-)-N-[1-(3 '-nitrobiphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl] piperidines-2-ketone and
(+/-)-N-[1-(3 '-nitrobiphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl] pyrrolidin-2-one.
The present invention further provides the preparation method of above-mentioned formula I compound, this method comprises:
(a) make logical formula II compound:
Wherein L represents leavings group (as hydroxyl), and R
1And R
2As above definition, react with logical formula III compound:
Wherein X and Y as above define, and are Sauerstoffatom or OCH but work as X
2The time, then Y can not be CH
2Group; Perhaps
(b) when X be that Sauerstoffatom and Y are CH
2During group, make logical formula IV compound:
R wherein
1And R
2As above definition is reacted with chloroformic acid 2-chloroethene ester; Perhaps
(c) when X be OCH
2Group and Y are CH
2During group, the formula IV compound described in (b) reacts with the 3-propylene chlorohydrin in the presence of phosgene above making; Perhaps
(d) when X be CH
2Group and Y are CH
2During group, formula IV compound described in (b) and 4-chlorobutanoylchloride reaction above making; Perhaps
(e) when X be CH
2CH
2Group and Y are CH
2During group, formula IV compound described in (b) and 5-valeryl chloride reaction above making; Perhaps
(f) when X be Sauerstoffatom or OCH
2During group, make general formula (V) compound:
Wherein X represention oxygen atom or OCH
2Group, and Y and R
1Then as above definition is with logical formula VI R
2-B (OH)
2Compound reaction, R wherein
2As above definition; Perhaps (g) when X be Sauerstoffatom or OCH
2During group, make general formula (VII) compound:
Wherein X represention oxygen atom or OCH
2Group, and Y and R
1As above definition is with general formula (VIII), R
2The compound reaction of-Br, wherein R
2As above definition; And, (b), (c), (d), (e), (f) or (g) afterwards, the formula I compound is converted into other formula I compound and/or forms the pharmacologically acceptable salt or the solvate of formula I compound randomly at (a).
Method (a) and (b), (c), (d), (e), (f) and (g) can in solvent (as methylene dichloride, chloroform, acetonitrile, dioxane or tetrahydrofuran (THF)), under 0-100 ℃ temperature range, carry out easily, preferred temperature is 10-80 ℃, especially envrionment temperature (20 ℃).
The formula II compound can be learnt by WO97/20815 and WO98/42670, perhaps can prepare according to WO97/20815 and the described similar approach of WO98/42670.
Formula III, (VI) and (VIII) compound are known or the commercial compound, perhaps can prepare according to means known in the art.
The formula IV compound can be made by the formula II compound according to approach well known.
Formula (V) and (VII) compound can use formula II or (IV) compound of brominated accordingly or boracic according to top (a) and (b) or similar approach (c).
It will be apparent to those skilled in the art that in the methods of the invention some functional group in the midbody compound such as hydroxyl or amino may need to be protected with protecting group.Like this, the terminal stage of preparation formula I compound may comprise and removes one or more protecting group steps.
[J.W.F.McOmie edits referring to " protecting group in the organic chemistry " about the protection of functional group and the introduction of deprotection; Plenum Press (1973)] and " protecting group in the organic synthesis " [second edition; T.W.Greene and P.G.M.Wuts, Wiley-Interscience (1991)].
The application standard method can be converted into the formula I compound other formula I compound.For example, R wherein
2For the formula I compound of nitrophenyl can be pressed the described R in the formula I that is converted into
2Compound for aminophenyl: under the reflux conditions, in ethanol or ethanol/water mixture, use iron powder and ammonium chloride to reduce.
Above-mentioned formula I compound can be converted into pharmaceutically useful salt or its solvate, preferred acid additive salt example hydrochloric acid salt, hydrobromate, phosphoric acid salt, acetate, fumarate, maleate, tartrate, Citrate trianion, oxalate, mesylate or right-tosylate, perhaps be an alkali metal salt, as sodium salt or sylvite.
Some formula I compounds can exist with stereoisomer form.Therefore, should be appreciated that all geometry and optical isomer that the present invention includes the formula I compound and the mixture that comprises racemic modification thereof.Their tautomer and composition thereof has also constituted one aspect of the present invention.
The superior part of The compounds of this invention is that they have pharmacologically active.Illustrate that thus they can be used as medicine and are used for the treatment of or prevent following disease: rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, air flue overreaction, septic shock, glomerulonephritis, supersensitivity enteropathy, the Crohn disease, ulcerative conjunctivitis, atherosclerosis, the growth of malignant cell and transfer, myocardial ischemia, heart reperfusion injury, cerebral ischemia, apoplexy, sarcoplast property leukemia, diabetes, Alzheimer disease, osteoporosis, burn, apoplexy, varix and meningitis.
Therefore, the invention provides the above-mentioned formula I compound that is used for the treatment of, or its pharmaceutically useful salt and solvate.
On the other hand, the invention provides the application of above-mentioned formula I compound or its pharmaceutically useful salt or solvate at preparation medicine for treatment object space face.
The present invention further provides and produced immunosuppressant method (for example in the treatment rheumatoid arthritis, the supersensitivity enteropathy, in atherosclerosis or the psoriasic process), this method comprises the above-mentioned formula I compound of patient's administering therapeutic significant quantity or its pharmaceutically useful salt or solvate.
Use for above-mentioned treatment, dosage is certainly with compound used therefor, administering mode, desired result of treatment and the disease variation of curing the disease.
Formula I compound and pharmaceutically useful salt thereof and solvate can use with its original form, but use with pharmaceutical compositions usually, wherein formula I compound/salt/solvate (activeconstituents) combines with pharmaceutically useful auxiliary, diluent or carrier.According to administering mode, pharmaceutical composition preferably includes 0.05-99%w (weight percentage), the pharmaceutically useful auxiliary of more preferably 0.10-70%w activeconstituents, and 1-99.95%w (more preferably 30-99.90%w), diluent or carrier, all wt percentage number average is based on composition total weight.
For this reason, the present invention also provides pharmaceutical composition, comprising above-mentioned formula I compound, or its pharmaceutically useful salt or solvate and pharmaceutically useful auxiliary, diluent or carrier.
The present invention further provides preparation of drug combination method of the present invention, it comprises above-mentioned formula I compound, or its pharmaceutically useful salt or solvate mix with pharmaceutically useful auxiliary, diluent or carrier.
Pharmaceutical composition of the present invention can be with solution, suspension, Sevoflurane hydrocarbon aerosol and the topical application of dry powder formulations form (as impose on lungs and/or air flue or impose on skin); Or general uses, as by tablet, capsule, syrup, pulvis or granule form oral administration, and perhaps by solution or suspension form parenterai administration, or by subcutaneous administration or with suppository form rectal administration or transdermal administration.
With reference to the following example the present invention is done further understanding.Term MS, NMR and DMSO in each example represent mass spectrum, nucleus magnetic resonance and methyl-sulphoxide respectively.
Embodiment 1 (+/-)-(N-[1-(biphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl]-tetramethyleneimine-2, the 5-diketone
In tetrahydrofuran (THF) (2ml) solution of triphenyl phosphine (0.16g), add diethylazodicarboxylate's (O.1ml); Observe the reaction slight exotherm.Stir the gained orange solution 5 minutes, and added succinimide (0.062g) then, continue to stir 5 minutes, add (±)-1-(biphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butanols (0.10g) of pressing embodiment 25 described preparations among the WO97/20815 again.Stir after 1.5 hours, the concentrating under reduced pressure reaction mixture, and,, thereby obtain colorless solid form title compound (0.09g) with eluent ethyl acetate with gained residue silica gel chromatography purifying.Fusing point: 150-151 ℃ MS (APCI+ve) 401 (M+H)
+ 1H NMR (DMSO-d
6) δ 8.42-8.40 (2H, m), 7.64-7.55 (5H, m), 7.43 (2H, t), 7.33-7.28 (2H, m), 6.97 (2H, d), 4.45-4.33 (2H, m), 4.27-4.23 (1H, m), 2.62-2.57 (6H, m), 2.32-2.24 (1H, m), 2.11-2.02 (1H, m)
Embodiment 2 (+/-)-N-[1-(3 '-methoxyl biphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl]-tetramethyleneimine-2, the 5-diketone
Method according to top embodiment 1, use succinimide (0.30g) and (±)-1-(3 '-the basic oxygen base of methoxyl biphenyl-4-)-4-(3-pyridyl)-2-butanols (0.25g) [according to 42 described the making of embodiment among the WO97/20815] to be prepared, thereby to obtain white solid form title compound (0.17g).Fusing point: 92-94 ℃ MS (EI) 430 (M+H)
+ 1H NMR (DMSO-d
6) δ 8.42-8.40 (2H, m), 7.61 (1H, m), 7.59 (2H, t), 7.33-7.28 (2H, m), 7.16 (1H, d), 7.12 (1H, t), 6.97 (2H, d), 6.88 (1H, dd), and 4.44-4.33 (2H, m), 4.26-4.24 (1H, m), 3.81 (3H, s), 2.62-2.57 (6H, m), 2.32-2.24 (1H, m), 2.11-2.02 (1H, m)
Embodiment 3 (+/-)-N-[1-(biphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl]-thiazolidine-2, the 4-diketone
Method according to top embodiment 1, use is according to (±)-1-(biphenyl-4-base oxygen base)-4-(3-the pyridyl)-2-butanols (0.32g) and 2 of the 25 described preparations of embodiment among the WO97/20815,4-thiazolidinedione (0.23g) is prepared, and obtains white solid form title compound (0.08g).Fusing point: 125-126 ℃ MS (FAB) 419 (M+H)
+ 1H NMR (DMSO-d
6) δ 8.42-8.40 (2H, m), 7.55-7.49 (5H, m), 7.41 (2H, t), 7.33-7.28 (2H, m), 6.97 (2H, d), 4.76 (1H, m), 4.52 (1H, t), 4.16 (1H, dd), 3.83 (2H, s), 2.73-2.60 (2H, m), 2.55-2.49 (1H, m), 2.15-2.06 (1H, m)
Embodiment 4 (+/-)-N-[1-(3 '-chlordiphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl]-tetramethyleneimine-2, the 5-diketone
Method according to top embodiment 1, use (±)-1-by the 33 described preparations of embodiment among the WO97/20815 (3 '-the basic oxygen base of chlordiphenyl-4-)-4-(3-pyridyl)-2-butanols (0.42g) and succinimide (0.24g) to be prepared, obtain white solid form title compound (0.21g).Fusing point: 154 ℃ of MS (APCI+ve) 436/438 (M+H)
+ 1H NMR (DMSO-d
6) δ 8.47-8.45 (2H, m), 7.53-7.23 (8H, m), 6.92 (2H, d), 4.63 (1H, m), 4.50 (1H, t), 4.16 (1H, dd), 2.73 (1H, m), 2.62-2.57 (6H, m), 2.11-2.02 (1H, m)
Embodiment 5 (+/-)-N-[1-(3 '-fluorine biphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl]-tetramethyleneimine-2, the 5-diketone
Method according to top embodiment 1, use is prepared according to (±)-1-of the 43 described preparations of embodiment among the WO97/20815 (3 '-fluorine biphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butanols (0.05g) and succinimide (0.03g), obtains white solid form title compound (0.06g).Fusing point: 148 ℃ of MS (APCI+ve) 419 (M+H)
+ 1H NMR (DMSO-d
6) δ 8.42-8.40 (2H, m), 7.54-7.45 (3H, m), 7.38-7.20 (4H, m), 7.01 (1H, m), 6.91 (2H, d), 4.62 (1H, m), 4.50 (1H, t), 4.16 (1H, dd), 2.75-2.47 (2H, m), 2.56 (4H, s), 2.53 (1H, m), 2.11-2.02 (1H, m)
Embodiment 6 (+/-)-N-[1-(3 '-methoxyl biphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl]-tetramethyleneimine-2, the 5-diketone
A) (+/-)-4-bromine phenoxymethyl oxirane
In the solution of acetonitrile (50ml), add cesium carbonate (24g) to 4-bromophenol (17g) and epichlorohydrine (25ml), and heated gained suspension 4 hours.The concentrating under reduced pressure reaction mixture is assigned to the gained residue within ether and the water then.Separate organic phase, the salt water washing is with sal epsom (MgSO
4) drying, obtain another residue behind the concentrating under reduced pressure.This residue of distillation under vacuum, thus colorless oil subhead compound (13g) obtained.Boiling point: 140 ℃ of (oil pump) MS (gcms) 228/230M
+.b) (+/-)-1-(4-bromine phenoxy group)-4-(4-pyridyl)-2-butanols
Be cooled to hexane solution (5.8 ml that add n-Butyl Lithium in 4-picoline (1.2g)/tetrahydrofuran (THF) (10ml) solution of-78 ℃, 2.5M solution), warm reaction mixture to 0 ℃, and slowly be added in tetrahydrofuran (THF) (5ml) solution that has been cooled to the made 4-bromine phenoxymethyl oxirane (3.0g) of 0 ℃, top step a) by sleeve pipe.After the stirring at room 1.5 hours,, use ethyl acetate extraction then earlier by adding chlorination ammonium solution quenching reaction mixture.Separate organic phase, the salt water washing is with sal epsom (MgSO
4) drying, get a residue behind the concentrating under reduced pressure.With this residue of silica gel chromatography purifying (with 5% ethanol/methylene wash-out), obtain the subhead compound, be a yellow solid (1.8g).MS (APCI+ve) 322/324 (M+H)
+.c) (+/-)-1-(3 '-methoxyl biphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butanols
Heating by 1-(4-bromine phenoxy group)-4-(4-pyridyl)-2-butanols (1.8g) [as preparation as described in the top step b)], 3-anisole ylboronic acid (0.90g), four (triphenyl phosphine) palladium (0) (0.16g), mixture to the reflux temperature that forms of aqueous sodium carbonate (3.5ml, 2M solution), ethanol (2ml) and toluene (7.5ml) kept 1.5 hours.Reaction mixture is assigned within ethyl acetate and the water, separates organic phase, the salt water washing is with sal epsom (MgSO
4) drying, get a residue behind the concentrating under reduced pressure.With this residue of silica gel chromatography purifying (with 5% ethanol/methylene wash-out), obtain white solid form subhead compound (1.0g).Fusing point: 74-76 ℃ MS (APCI+ve) 350 (M+H)
+.d) (+/-)-(N-[1-(3 '-methoxyl biphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl]-tetramethyleneimine-2, the 5-diketone
Method according to embodiment 1, use (±)-1-by the described preparation of top step c) (3 '-the basic oxygen base of methoxyl biphenyl-4-)-4-(4-pyridyl)-2-butanols (0.42g) and succinimide (0.30g) to be prepared, obtain white solid form title compound (0.15g).Fusing point: 111-113 ℃ MS (EI) 431 (M+H)
+ 1H NMR (DMSO-d
6) δ 8.42 (2H, s), 7.48 (2H, d), 7.34 (1H, t), 7.15 (3H, m), 7.06 (1H, m), 6.88 (2H, d), 6.84 (1H, m), 4.61 (1H, m), 4.47 (1H, t), 4.16 (1H, dd), 3.83 (3H, s), 2.78 (1H, m), 2.61-2.50 (2H, m), 2.46 (4H, s), 2.11-2.02 (1H, m)
Embodiment 7 (+/-)-N-[1-(3 '-methoxyl biphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl]-thiazolidine-2, the 4-diketone
Method according to top embodiment 1, use (±)-1-(3 '-methoxyl biphenyl-4-base oxygen base)-4-(4-the pyridyl)-2-butanols (0.10g) and 2 of the described preparation of embodiment 6c as mentioned, 4-thiazolidinedione (0.067g) is prepared, thereby obtaining title compound, is a colorless solid (0.07g).Fusing point: 111-112 ℃ MS (EI) 449 (M+H)
+ 1H NMR (DMSO-d
6) δ 8.46 (2H, d), 7.58 (2H, d), 7.34 (1H, t), 7.23 (2H, d), 7.17 (2H, d), 7.12 (1H, d), 6.88 (2H, d), 4.53 (1H, m), 4.44 (1H, t), 4.28 (1H, dd), 4.18 (2H, s), 3.81 (3H, s), 2.62 (2H, t), and 2.37-2.24 (1H, m), 2.16-2.06 (1H, m)
Embodiment 8 (2R)-N-[1-(3 '-cyanobiphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl]-thiazolidine-2, the 4-diketone
Method according to top embodiment 1, use is according to (the 2S)-1-of the 38 described preparations of embodiment among the WO97/20815 (3 '-cyanobiphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butanols (0.20g) and 2,4-thiazolidinedione (0.13g) is prepared, thereby obtains white solid title compound (0.14g).Fusing point: 110-112 ℃ MS (EI) 444 (M+H)
+ 1H NMR (DMSO-d
6) δ 8.43 (2H, m), 8.10 (1H, s), 7.97 (1H, d), 7.76 (1H, d), 7.70-7.60 (4H, m), 7.32 (1H, dd), 7.01 (2H, d), 4.56 (1H, m), 4.46 (1H, t), 4.30 (1H, dd), 4.19 (2H, s), 2.65 (2H, t), 2.30 (1H, m), 2.09 (1H, m)
Embodiment 9 (2R)-N-[1-(3 '-nitrobiphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl]-tetramethyleneimine-2, the 5-diketone
Method according to top embodiment 1, use is prepared as (the 2S)-1-of preparation as described in the embodiment among the WO97/20815 41 (3 '-nitrobiphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butanols (0.10g) and succinimide (0.054g), thereby obtains white solid title compound (0.03g).Fusing point: 115-117 ℃ MS (EI) 446 (M+H)
+ 1H NMR (DMSO-d
6) δ 8.40 (3H, m), 8.14 (2H, s), 7.72 (3H, m), 7.63 (1H, d), 7.32 (1H, ddd), 7.03 (2H, d), 4.42 (2H, m), 4.28 (1H, dd), 2.61 (6H, m), 2.28 (1H, m), 2.07 (1H, m)
Embodiment 10 (2R)-N-[1-(3 '-cyanobiphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl]-tetramethyleneimine-2, the 5-diketone
Method according to top embodiment 1, use is prepared as (the 2S)-1-of preparation as described in the embodiment among the WO97/20815 38 (3 '-cyanobiphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butanols (0.15g) and succinimide (0.09g), obtains white solid form title compound (0.09g).Fusing point: 136-137 ℃ MS (EI) 426 (M+H)
+ 1H NMR (DMSO-d
6) δ 8.41 (2H, m), 8.11 (1H, s), 7.97 (1H, d), 7.77 (1H, d), 7.69-7.60 (4H, m), 7.32 (1H, dd), 6.99 (2H, d), 4.39 (2H, m), 4.28 (1H, dd), 2.60 (6H, m), 2.27 (1H, m), 2.02 (1H, m)
Embodiment 11 (+/-)-N-[1-(3 '-nitrobiphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl]-thiazolidine-2, the 4-diketone
A) (+/-)-1-(3 '-nitrobiphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butanols
According to top embodiment 6c) method, use embodiment 6b) 1-(4-bromine phenoxy group)-4-(4-the pyridyl)-2-butanols (3.12g) and the 3-nitrophenyl boric acid (2.59g) of preparation are prepared, thereby obtain the subhead compound, for-orange (2.20g).MS (APCI+ve) 365 (M+H)
+.b) (+/-)-N-[1-(3 '-nitrobiphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl]-thiazolidine-2, the 4-diketone
Method according to top embodiment 1, use (+/-)-1-(3 ' nitrobiphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butanols (0.14g) and 2 of the described preparation of step a) as mentioned, 4-thiazolidinedione (0.09g) is prepared, thereby obtains light yellow solid form title compound (0.11g).Fusing point: 145-150 ℃ MS (EI) 446 (M+H)
+ 1H NMR (DMSO-d
6) δ 8.47 (2H, d), 8.38 (1H, s), 8.17 (1H, d), 8.11 (1H, d), 7.75-7.70 (3H, m), 7.23 (2H, dd), 7.04 (2H, d), 4.60-4.44 (2H, m), 4.31 (1H, dd), 4.19 (2H, s), 2.65 (2H, t), 2.32 (1H, m), 2.09 (1H, m)
Embodiment 12 (+/-)-N-[1-(3 '-nitrobiphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl]-tetramethyleneimine-2, the 5-diketone
Method according to top embodiment 1, use as embodiment 11a) as described in (+/-)-1-(3 '-the basic oxygen base of nitrobiphenyl-4-)-4-(4-the pyridyl)-2-butanols (0.09g) and the succinimide (0.05g) of preparation be prepared, thereby obtain yellow solid form title compound (0.03g).Fusing point: 116-118 ℃ MS (EI) 426 (M+H)
+ 1H NMR (DMSO-d
6) δ 8.46 (2H, m), 8.38 (1H, s), 8.16 (1H, d), 8.11 (1H, d), 7.75-7.70 (3H, m), 7.22 (2H, d), 7.03 (2H, d), 4.76-4.34 (2H, m), 4.28 (1H, dd), 2.65-2.60 (6H, m), 2.29 (1H, m), 2.08 (1H, m)
Embodiment 13 (+/-)-N-[1-(4 '-fluorine biphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl]-tetramethyleneimine-2, the 5-diketone
A) (+/-)-1-(4 '-fluorine biphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butanols
According to embodiment 6c) method, use as embodiment 6b) as described in 1-(4-bromine phenoxy group)-4-(4-the pyridyl)-2-butanols (0.40g) and the 4-fluorophenyl boric acid (0.28g) of preparation be prepared, thereby obtain colorless solid form subhead compound (0.23g).MS (APCI+ve) 338 (M+H)
+.b) (+/-)-N-[1-(4 '-fluorine biphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl]-tetramethyleneimine-2, the 5-diketone
Method according to top embodiment 1, use (+/-)-1-of preparing in the step a) (4 '-fluorine biphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butanols (0.10g) and succinimide (0.06g) to be prepared, thereby obtain light yellow solid form title compound (0.06g).Fusing point: 113-114 ℃ MS (EI) 419 (M+H)
+ 1H NMR (DMSO-d
6) δ 8.46 (2H, d), 7.63 (2H, dd), 7.55 (2H, d), 7.28-7.21 (4H, m), 6.87 (2H, d), 4.45-4.33 (2H, m), 4.26 (1H, m), 2.59 (6H, m), 2.28 (1H, m), 2.08 (1H, m)
Embodiment 14 (+/-)-N-[1-(4 '-fluorine biphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl]-thiazolidine-2, the 4-diketone
Method according to top embodiment 1, use as embodiment 13a) as described in (+/-)-1-(4 '-the basic oxygen base of fluorine biphenyl-4-)-4-(4-the pyridyl)-2-butanols (0.12g) and 2 of preparation, 4-thiazolidinedione (0.08g) is prepared, thereby obtains light gray solid title compound (0.06g).Fusing point: 88-90 ℃ MS (EI) 437 (M+H)
+ 1H NMR (DMSO-d
6) δ 8.46 (2H, d), 7.63 (2H, dd), 7.56 (2H, d), 7.23 (4H, m), 6.97 (2H, d), 4.50 (lH, m), 4.44 (1H, t), 4.28 (1H, dd), 4.18 (2H, s), 2.65 (2H, t), 2.30 (1H, m), 2.12 (1H, m)
Embodiment 15 (+/-)-N-[1-(biphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl]-oxazolidines-2-ketone
A) (+/-)-N-[1-(biphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl-isoindole-1, the 3-diketone
According to embodiment 1 described method, in tetrahydrofuran (THF), be prepared by (±)-1-(biphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butanols (2.55g) (by the 25 described preparations of embodiment among the WO97/20815), triphenyl phosphine (3.62g), diethylazodicarboxylate (2.52ml) and phthalic imidine (2.36g).The gained residue uses hexane by the flash column chromatography purifying: ethyl acetate (3: 2) wash-out, thus obtain the subhead compound, be colorless solid thing (3.9g).Fusing point: 132-133 ℃ MS (EI) 448 (M+H)
+ 1H NMR (DMSO-d
6) δ 8.40 (1H, d), 8.25 (1H, d), 7.85 (4H, m), 7.62-7.51 (5H, m), 7.41 (2H, t), 7.29 (1H, t), 7.23 (1H, dd); 6.93 (2H, d), 4.52 (2H, m), 4.38 (1H, dd), 2.70 (2H, t), 2.40 (1H, n), 2.20 (1H, m) .b) (±)-1-(biphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butylamine
Will (+/-)-N-[1-(biphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl]-isoindole-1,3-diketone (3.41g) is dissolved in 30% methylamine/methanol solution (100ml).Heated solution to reflux temperature kept 3 hours.Removal of solvent under reduced pressure, residue is dissolved in ethyl acetate, and washing with dried over mgso, is filtered and is concentrated.(eluent: 10% ethanol/methylene), obtaining the subhead compound, is a paste solid (1.08g) to adopt the neutral alumina chromatogram purification.Fusing point: 52-53 ℃ MS (EI) 318 (M+H)
+ 1H NMR (CDCl
3) δ 8.51 (1H, d); 8.45 (1H, d); 7.56-7.51 (5H, m); 7.42 (2H, t); 7.32-7.31 (1H, m); 7.24-7.22 (1H, m); 6.96 (2H, d); 4.00-3.96 (1H, m); 3.82 (1H, t); 3.25-3.15 (1H, m); 2.89-2.82 (1H, m); 2.78-2.72 (1H, m); 1.92-1.88 (1H, m); (1.80-1.72 3H, m) .c) (+/-)-N-[1-(biphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl]-oxazolidines-2-ketone
Chloroformic acid 2-chloroethene ester (0.516ml) dropwise is added in acetonitrile (30ml) solution of (±)-1-(biphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butylamine (0.318g).Stirring at room gained solution 3 hours.Removal of solvent under reduced pressure, residue are dissolved in tetrahydrofuran (THF) (5ml) and the dimethyl formamide (1ml).In solution, add sodium hydride (60% oil content loose thing) (0.12g).Continue under the room temperature to stir 1 hour, in reaction mixture, add 20ml water then, the product ethyl acetate extraction, and with organic extraction dried over mgso, concentrating under reduced pressure subsequently.With 3% ethanol/methylene is that eluent carries out the silica gel chromatography purifying, and then uses the ether recrystallization, thereby obtains white solid form title compound (0.093g).Fusing point: 58-59 ℃ MS (FAB) 389 (M+H)
+ 1H NMR (CDCl
3) δ 8.50-8.49 (2H, m); 7.58-7.52 (5H, m); 7.42 (2H, 0; 7.31 (1H, t); 7.29-7.23 (1H, m); 6.95 (2H, d); 4.43-4.26 (3H, m); 4.15 (2H, d); 3.73-3.60 (2H, m); 2.74 (2H, t); 2.16-2.03 (2H, m).
Embodiment 16 (2R)-N-[1-(3 '-chloro-4 '-fluorine biphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl]-thiazolidine-2, the 4-diketone
A) (2S)-1-(3 '-chloro-4 '-fluorine biphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butanols
Method according to embodiment 1, use as embodiment 40a among the WO97/20815) as described in (2R)-1-(4-bromine phenoxy group)-4-(3-the pyridyl)-2-butanols (0.214g) and the 3-chloro-4-fluorophenyl boric acid (0.18g) of preparation be prepared, obtain yellow gluey subhead compound (0.24g).MS (APCI+ve) 372/374 (M+H)
+.b) (2R)-N-[1-(3 '-chloro-4 '-fluorine biphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl]-thiazolidine-2, the 4-diketone
According to the method for embodiment 1, (the 2S)-1-of use step a) preparation (3 '-chloro-4 '-fluorine biphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butanols (0.14g) and 2,4-thiazolidinedione (0.088g) is prepared.(with 80% ethyl acetate/isohexane wash-out) obtains colourless gluey title compound (0.077g) behind the silica gel chromatography purifying.MS(APCI+ve)471/473(M+H)
+ 1H?NMR(DMSO-d
6)δ8.43-8.40(2H,m)，7.81(1H,dd)，7.65-7.60(4H,m)，7.46(1H,t)，7.32(1H,dd)，6.97(2H,d)，4.50(1H,m)，4.45(1H,t)，4.28(1H,dd)，4.19(2H,d)，2.64(2H,t)，2.39-2.26(1H,m)，2.18-2.03(1H,m)
Embodiment 17 (2R)-N-[1-(3 '-chloro-4 '-fluorine biphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl]-tetramethyleneimine-2, the 5-diketone
According to the method for top embodiment 7, use embodiment 16a) (the 2S)-1-of preparation (3 '-chloro-4 '-fluorine biphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butanols (0.10g) and succinimide (0.053g) be prepared.(with 50% acetone/isohexane wash-out) obtains title compound behind the silica gel chromatography purifying, is light brown foam thing (0.05g).MS(APCl+ve)453/455(M+H)
+ 1H?NMR(DMSO-d
6)δ8.41(1H,s)，8.39(1H,m)，7.81(1H,dd)，7.65-7.59(4H,m)，7.56(1H,t)，7.32(1H,dd)，6.97(2H,d)，4.45-4.32(2H,m)，4.26?(1H,m)，2.51(6H,m)，2.25(1H,m)，2.07(1H,m)
Embodiment 18 (2R)-N-[1-(3 ', 5 '-dicyanobiphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl]-thiazolidine-2, the 4-diketone
A) (2S)-1-(4-bromine phenoxy group)-4-(3-pyridyl)-2-(t-butyldimethylsilyloxy base) butane
With (2S)-4-(3-pyridyl)-1,2-butyleneglycol (10g) [according to embodiment 26c among the WO97/20815) described method preparation] and 1, the solution stirred overnight at room temperature of 1-carbonyl dimidazoles (12g) in chloroform (250ml).Second concentrated gained mixture that reduces pressure filters by the silicon-dioxide pad then.Evaporated filtrate obtains a residue, and then it is dissolved in dimethyl formamide (100ml).Add 4-bromophenol (11.6g) and cesium carbonate (16.6g) then, heated mixt is 18 hours under reflux temperature.Cooled reaction mixture 2M hcl acidifying is then with ether extraction (x3).Divide water-yielding stratum, add 2M sodium hydroxide, reach 9, use ethyl acetate (x3) to extract then until the pH of mixture value.The organic extraction anhydrous magnesium sulfate drying that merges filters and concentrating under reduced pressure, obtains a residue.In this residue, add dimethyl formamide (10ml), then add imidazoles (6g) and tert-butyldimethylsilyl chloride (8.4g), stirring at room gained mixture overnight again.Then reaction mixture is added in the water, extracts twice with 1: 1 ether/hexane.Merge organic extracting solution,, filter and concentrating under reduced pressure, obtain a residue with anhydrous magnesium sulfate drying.With 1: 1 ether/hexane was that eluent carries out the silica gel chromatography purifying, thereby obtained oily subhead compound (13.27g).MS (APCI+ve) 436/438 (M+H) b) (2S)-and 4-[4-(3-pyridyl)-2-(t-butyldimethylsilyloxy base) butoxy] phenylo boric acid
-78 ℃ and stir down, in (the 2S)-1-of preparation as described in step a) (4-bromine phenoxy group)-4-(3-pyridyl)-2-(t-butyldimethylsilyloxy base) butane (5.0g) and the solution of triisopropyl borate ester (4.3ml) in tetrahydrofuran (THF) (200ml), dropwise add tert-butyl lithium solution (1.7m hexane solution, 15.0ml, note: the meeting spontaneous combustion].Finish, in-70 ℃ of stirred reaction mixtures 1 hour.Add entry (200ml) and ethyl acetate (200ml) then.Separate organic phase,, filter with anhydrous magnesium sulfate drying, behind the concentrating under reduced pressure an oily matter, and then be that eluent carries out the silica gel chromatography purifying, thereby obtain spumescence subhead compound (4.06g) .MS (APCI+ve) 402 (M+H) with 5: 1 ethyl acetate/methanol
+.c) (2S)-1-(3 ', 5 '-dicyanobiphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butanols
With (2S)-4-[4-(3-pyridyl)-2-(t-butyldimethylsilyloxy base) butoxy] phenylo boric acid (0.479g) [as preparation as described in the step b)], 5-bromo-1,3-benzene dicarbonitrile (0.371g, referring to J.Het.Chem. (1994), 31 (6), p1417-1420, registration number 160892-07-9), four (triphenyl phosphines) close palladium (0) (0.035g), the mixture of aqueous sodium carbonate (0.9ml, 2M solution), toluene (10ml) and ethanol (4ml) is 100 ℃ of heating 2 hours down.Reaction mixture is assigned within ether and the 2N hydrochloric acid, and separates each layer.Water is then used ethyl acetate extraction with the neutralization of 2N sodium hydroxide.Separate organic phase,, filter and concentrating under reduced pressure, obtain a residue with anhydrous magnesium sulfate drying.This residue is dissolved in tetrahydrofuran (THF) (25ml) and tetrabutyl ammonium fluoride (0.163g).After the stirred overnight at room temperature, the concentrating under reduced pressure mixture, and be assigned within ether and the 2N hydrochloric acid, separate each layer.Water is with the neutralization of 2N sodium hydroxide and use ethyl acetate extraction.Separate organic phase,, filter and concentrating under reduced pressure, obtain a residue again with anhydrous magnesium sulfate drying.With 2: 1 methylene dichloride/acetone was that eluent carries out the silica gel chromatography purifying, and then by ethyl acetate/isohexane recrystallization, obtained white solid form subhead compound.MS (APCI+ve) 370 (M+H)
+.d) (2R)-N-[1-(3 ', 5 '-dicyanobiphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl]-thiazolidine-2, the 4-diketone
According to the method for embodiment 1, (the 2S)-1-of use step c) preparation (3 ', 5 '-dicyanobiphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butanols (0.05g) and 2,4-thiazolidinedione (0.032g) is prepared.(with 0%-45% methyl alcohol/Liquid carbon dioxide wash-out) obtains glassy title compound (0.015g) behind overcritical liquid chromatography purifying.MS(APCI+ve)469(M+H)
+ 1H?NMR(DMSO-d
6)δ8.49(2H,m)，8.41(2H,m)，8.36(1H,s)，7.80(2H,6)，7.63(1H,d)，7.32(1H,dd)，7.03(2H,m)，4.47(2H,m)，4.31(1H,dd)，4.19(2H,s)，2.65(2H,t)，2.30(1H,m)，2.20(1H,m)
Embodiment 19 (+/-)-N-[1-(3 '-nitrobiphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl]-oxazolidines-2-ketone
A) (+/-)-N-2-[1-(4-bromine phenoxy group)-4-(4-pyridyl)-2-butyl]-isoindole-1, the 3-diketone
According to embodiment 15a) method, use preparation as described in 1-(4-bromine phenoxy group)-4-(4-pyridyl)-2-butanols (6.02g) (as embodiment 6b)) and phthalic imidine (5.49g) be prepared.Obtain the subhead compound, be golden yellow oily matter (10.13g).MS (APCI) 451/453 (M+H)
+.b) (+/-)-N-2-(4-bromine phenoxy group)-4-(4-pyridyl)-butylamine
According to embodiment 15b) method, use (+/-)-N-2-[1-(4-bromine phenoxy group)-4-(4-pyridyl)-2-butyl]-isoindole-1,3-diketone (9.78g) is prepared, and obtains yellow solid form subhead compound (3.04g).Fusing point: 168-169 ℃ MS (APCI) 321/323 (M+H)
+.c) (+/-)-N-2-(3 '-nitrobiphenyl-4-base oxygen base)-4-(4-pyridyl)-butylamine
To close as (+/-)-N-2-(4-bromine phenoxy group)-4-(4-pyridyl)-butylamine (0.5g), 3-nitrophenyl boric acid (0.31g), four (triphenyl phosphines) of preparation as described in the top step b) palladium (0) (0.03g), aqueous sodium carbonate (2M solution, 0.93ml) and the mixture heating up of ethanol (2ml) refluxed 4 hours.After the room temperature cooling, solvent removed in vacuo.Add dilute hydrochloric acid then, and with the mixture ether extraction.Aqueous mixture alkalizes with some solid sodium bicarbonates, and uses ethyl acetate extraction.The extracting solution anhydrous magnesium sulfate drying that merges filters and concentrating under reduced pressure.Residue neutral alumina gel column chromatography purifying, earlier with methylene dichloride: ethanol (98: 2) is eluent, and then uses ethanol elution, thereby obtains yellow oily subhead compound (0.28g).MS (APCI) 364 (M+H)
+.d) (+/-)-N-[1-(3 '-nitrobiphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl]-oxazolidines-2-ketone
According to embodiment 15c) method use chloroformic acid 2-chloroethene ester (0.030ml) to be prepared.End product uses 0-10% ethanol/dichloromethane gradient elution, thereby obtains yellow form of foam title compound (0.025g) by the NPHPLC purifying.Fusing point: 67-69 ℃ MS (APCI) 434 (M+H)
+ 1H NMR (DMSO-d
6) δ 8.46 (2H, dd), 8.39 (1H, t), 8.18-8.09 (2H, m), 7.76-7.70 (3H, m), 7.30 (2H, d), 7.09 (2H, d), 4.32-4.20 (2H, m), 4.16 (2H, d), 4.14 (1H, m), 3.63-3.47 (2H, m), 2.72-2.58 (2H, m), 1.95 (2H, q)
Embodiment 20 (2R)-N-[1-(3 '-fluorine biphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl]-thiazolidine-2, the 4-diketone
A) (2S)-1-(3 '-fluorine biphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butanols
According to top embodiment 18c) method, use embodiment 18b as mentioned) (2S)-4-[4-(3-pyridyl)-2-(t-butyldimethylsilyloxy base) butoxy of described preparation] phenylo boric acid (0.30g) and 1-bromo-3-fluorobenzene (0.15ml) be prepared, thereby obtain colorless oil subhead compound (0.21g).MS (APCI+ve) 338 (M+H)
+.b) (2R)-N-[1-(3 '-fluorine biphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl]-thiazolidine-2, the 4-diketone
According to the method for embodiment 1, (2S)-1-that the use step a) obtains (3 '-fluorine biphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butanols (0.205g) and 2,4-thiazolidinedione (0.14g) is prepared.After positive HPLC (using 0%-10% ethanol/dichloromethane wash-out) and ethyl alcohol recrystallization purifying, obtain title compound, be colorless solid (0.032g).Fusing point: 117-118 ℃ MS (APCI+ve) 437 (M+H)
+ 1H NMR (DMSO-d
6) δ 8.42 (2H, m), 7.63 (3H, m), 7.44 (3H, m), 7.33 (1H, dd), 7.13 (1H, m), 6.98 (2H, d), 4.54 (1H, m), 4.45 (1H, t), 4.27 (1H, dd), 4.19 (2H, s), 2.62 (2H, t), 2.30 (1H, m), 2.10 (1H, m)
Embodiment 21 (+/-)-N-[1-(3 '-(trifluoromethyl) biphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl]-thiazolidine-2, the 4-diketone
A) (+/-)-1-(3 '-(trifluoromethyl) biphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butanols
According to embodiment 6c) method, use as embodiment 6b) as described in 1-(4-bromine phenoxy group)-4-(4-the pyridyl)-2-butanols (0.20g) and the 3-trifluoromethyl phenyl boronic acid (0.13g) of preparation be prepared, thereby obtain yellow oily subhead compound (0.18g).MS (APCI+ve) 388 (M+H)
+.b) (+/-)-N-[1-(3 '-(trifluoromethyl) biphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl]-thiazolidine-2, the 4-diketone
According to the method for embodiment 1, use that step a) obtains (+/-)-1-(3 '-trifluoromethyl-biphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butanols (0.175g) and 2,4-thiazolidinedione (0.106g) is prepared.The gained residue is by silica gel chromatography (using 2% ethanol/methylene wash-out) and overcritical liquid chromatography (with 0%-45% methyl alcohol/Liquid carbon dioxide wash-out) purifying, then use ethanol/ethyl acetate/isohexane mixed solution crystallization again, thereby obtain colorless solid form title compound (0.10g).Fusing point: 95-96 ℃ MS (APCI+ve) 487 (M+H)
+ 1H NMR (DMSO-d
6) δ 8.46 (2H, m), 7.92 (2H, m), 7.67 (4H, m), 7.23 (2H, d), 7.01 (2H, m), 4.56 (1H, m), 4.46 (1H, t), 4.30 (1H, dd), 4.18 (2H, s), 2.65 (2H, t), 2.32 (1H, m), 2.10 (1H, m)
Embodiment 22 (+/-)-N-[1-(2 '-methoxyl biphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl]-thiazolidine-2, the 4-diketone
A) (+/-)-1-(2 '-methoxyl biphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butanols
According to embodiment 6c) method, use as embodiment 6b) as described in 1-(4-bromine phenoxy group)-4-(4-the pyridyl)-2-butanols (0.20g) and the 2-anisole ylboronic acid (0.104g) of preparation be prepared, thereby obtain the subhead compound, be colorless solid (0.18g).MS (APCI+ve) 350 (M+H)
+.b) (+/-)-N-[1-(2 '-methoxyl biphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl]-thiazolidine-2, the 4-diketone
According to the method for top embodiment 1, step a) prepares above using (+/-)-1-(3 '-methoxyl biphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butanols (0.17g) and 2,4-thiazolidinedione (0.114g) is prepared.The gained residue is by silica gel chromatography (using 2% ethanol/methylene wash-out) and overcritical liquid chromatography (with 0%-45% methyl alcohol/Liquid carbon dioxide wash-out) purifying, then use ethanol/ethyl acetate/isohexane mixed solution crystallization again, thereby obtain title compound, be colorless solid (0.055g).Fusing point: 128-130 ℃ MS (APCI+ve) 487 (M+H)
+ 1H NMR (DMSO-d
6) δ 8.46 (2H, d), 7.38 (2H, d), 7.33-7.22 (4H, m), 7.08 (1H, d), 6.99 (1H, m), 6.91 (2H, d), 4.55 (1H, m), 4.44 (1H, t), 4.26 (1H, dd), 4.18 (2H, s), 3.75 (3H, s), 2.65 (2H, t), 2.31 (1H, m), 2.10 (1H, m)
Embodiment 23 (+/-)-N-[1-(3 '-nitrobiphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl]-piperidines-2, the 6-diketone
Method according to top embodiment 1, use as embodiment 11a) as described in (+/-)-1-(3 '-the basic oxygen base of nitrobiphenyl-4-)-4-(4-the pyridyl)-2-butanols (0.25g) and the glutarimide (0.16g) of preparation be prepared, obtain light yellow spumescence title compound (0.11g).Fusing point: 53-55 ℃ MS (APCI) 460 (M+H)
+ 1H NMR (DMSO-d
6) δ 8.45 (2H, d), 8.38 (1H, s), 8.17-8.09 (2H, m), 7.75-7.70 (3H, m), 7.21 (2H, d), 7.02 (2H, d), 5.10-5.00 (1H, m), 4.43-4.29 (2H, m), 2.57 (6H, t), 2.36-2.21 (1H, m), 2.16-2.01 (1H, m), 1.74 (2H, t)
Embodiment 24 (+/-)-N-[1-(3 '-phenylaniline-4-base oxygen base)-4-(4-pyridyl)-2-butyl]-thiazolidine-2, the 4-diketone
With top embodiment 11b) (+/-)-N-[1-of preparation (3 '-nitrobiphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl]-thiazolidine-2,4-diketone (0.377g), ammonium chloride (0.17g) and iron powder (0.18g) the yellow suspension reflux in 1: 1 ethanol/water mixed solution 1.5 hours.Filter chilled reaction mixture.Colourless filtrate is poured in the saturated solution of sodium bicarbonate, uses ethyl acetate extraction.Separate organic phase, water and salt water washing are with sodium sulfate (Na
2SO
4) drying, obtain a residue behind the concentrating under reduced pressure.And then precipitate purifying in addition by positive HPLC (0%-10% ethanol/dichloromethane wash-out) with ethanol/ethyl acetate/isohexane mixed solution, thus obtain title compound, be a colorless solid (0.34g).Fusing point: 147-148 ℃ MS (APCI+ve) 434 (M+H)
+ 1H NMR (DMSO-d
6) δ 8.46 (2H, d), 7.46 (2H, d), 7.23 (2H, d), 7.05 (1H, t), 6.94 (2H, d), 6.77 (1H, s), 6.71 (1H, d), 6.50 (1H, d), 5.10 (2H, s), 4.54 (1H, m), 4.43 (1H, t), 4.26 (1H, dd), 4.17 (2H, s), 2.62 (2H, t), 2.31 (1H, m), 2.12 (1H, m)
Embodiment 25 (+/-)-N-[1-(3 '-nitrobiphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl]-[1,3]-oxazines alkane-2-ketone
To phosgene (1.93M toluene solution, 0.31ml) add step 19c in the solution in toluene (10ml)) (+/-)-N-2-of obtaining (3 '-nitrobiphenyl-4-base oxygen base)-4-(4-pyridyl)-butylamine (0.20g), and stirred reaction mixture 2 hours at room temperature.In mixture, add 3-propylene chlorohydrin (0.09ml), stirred overnight at room temperature then.Removal of solvent under reduced pressure, residue are dissolved in dimethyl formamide (10ml) again.This solution slowly is added to sodium hydride, and (the 60% oil content thing that looses is in dimethyl formamide 0.09g) (1ml) suspension.Mixture was in 70 ℃ of heating 9 hours.After being cooled to room temperature, removal of solvent under reduced pressure.Residue is regulated with sodium hydroxide (2M) and is alkalescence, then with ethyl acetate extraction.The extracting solution anhydrous magnesium sulfate drying that merges filters and concentrating under reduced pressure.Residue uses 0-10% ethanol/dichloromethane gradient elution, thereby obtains yellow oily title compound (0.009g) by the NPHPLC purifying.MS(APCI)448(M+H)
+ 1H?NMR(DMSO-d
6)δ8.46(2H,dd)，8.39(1H,t)，8.18-8.09(2H,m),7.75-7.70(3H，m)；7.29(2H,dd)，7.09(2H,dd)，4.48-4.33(1H,m)，4.20-4.12(4H,m)，3.31-3.21(2H,m)，2.65(2H,t)，2.07-1.86(4H,m)
Embodiment 26 (2S)-N-[1-(3 '-cyanobiphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl]-thiazolidine-2, the 4-diketone
In (2R)-1-(3 '-cyanobiphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butanols (5 μ mol) [embodiment 37 described methods preparations in according to WO97/20815], add triphenyl phosphine (50 μ l, 0.2M tetrahydrofuran solution), then add 2 again, 4-thiazolidinedione (50 μ l, 0.2M tetrahydrofuran solution).Add diethylazodicarboxylate (2 μ l) subsequently, the sealed reaction mixture at room temperature stirs and spends the night.Obtain a residue behind the concentrating under reduced pressure mixture.Then the gained residue is dissolved in methyl-sulphoxide, obtains 10mM dimethyl sulfoxide solution form title compound,, carry out HPLC on the 5 μ m particle diameter Waters Symmetry C8 posts and analyze, with 0.1% ammonium acetate solution wash-out at 50mm x 3.9mm.MS(APCI+ve)444(M+H)
+.
Embodiment 27 (2S)-N-[1-(3 '-phenylaniline-4-base oxygen base)-4-(4-pyridyl)-2-butyl]-thiazolidine-2, the 4-diketone
According to top embodiment 26) method, (2R)-1-that use prepares according to the 50 described methods of embodiment among the WO97/20815 (3 '-phenylaniline-4-base oxygen base)-4-(3-pyridyl)-2-butanols (5 μ mol), triphenyl phosphine (50 μ l, 0.2M tetrahydrofuran solution), 2,4-thiazolidinedione (50 μ l, 0.2M tetrahydrofuran solution) and diethylazodicarboxylate (2 μ l) be prepared, thereby obtain the title compound of 10mM DMSO solution form, and at 50mm x 3.9mm, carry out HPLC on the 5 μ m particle diameter Waters Symmetry C8 posts and analyze, with 0.1% ammonium acetate solution wash-out.MS(APCI+ve)434(M+H)
+
Embodiment 28 (2S)-N-[1-(3 '-methanesulfonamido biphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl]-thiazolidine-2, the 4-diketone
According to top embodiment 26) described, by (2R)-1-(3 '-methanesulfonamido biphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butanols (5 μ mol) [according to the 98 described methods preparations of embodiment among the WO97/20815], triphenyl phosphine (50 μ l, 0.2M tetrahydrofuran solution), 2,4-thiazolidinedione (50 μ l, 0.2M tetrahydrofuran solution) and diethylazodicarboxylate (2 μ l) be prepared, obtain the solution form title compound of 10mM in DMSO, and at 50mmx3.9mm, carry out HPLC on the 5 μ m particle diameter Waters Symmetry C8 posts and analyze, with 0.1% ammonium acetate solution wash-out.MS(APCI+ve)512(M+H)
+
Embodiment 29 (2S, 3S)-N-[1-(3 '-(tetramethyleneimine-1-alkylsulfonyl) biphenyl-4-base oxygen base)-4-(3-pyridyl)-3-amyl group]-tetramethyleneimine-2, the 5-diketone
According to top embodiment 26) method; use is according to (the 3R of the 72 described method preparations of embodiment among the WO98/42670; 4S)-and 1-pyridin-3-yl-4-[3 '-(tetramethyleneimine-1-alkylsulfonyl) biphenyl-4-base oxygen base] pentane-3-alcohol (6.67 μ mol); triphenyl phosphine (50 μ l; 0.27M tetrahydrofuran solution); succinimide (50 μ l; 0.27M tetrahydrofuran solution) and diethylazodicarboxylate (3 μ l) be prepared; thereby obtain the title compound of 10mM dimethyl sulfoxide solution form; and at 50mmx3.9mm; carry out HPLC on the 5 μ m particle diameter Waters Symmetry C8 posts and analyze, with 0.1% ammonium acetate solution wash-out.MS (APCI+ve) 548 (M+H)
+Embodiment 30 (2S, 3S)-N-[1-(3 '-cyano group-4 '-fluorine biphenyl-4-base oxygen base)-4-(3-pyridyl)-3-amyl group]-tetramethyleneimine-2, the 5-diketone
According to embodiment 26) method, use is according to (the 1S of the 36 described method preparations of embodiment among the WO98/42670,2R)-4-fluoro-4 '-(2-hydroxyl-1-methyl-4-pyridin-3-yl butoxy) biphenyl-3-formonitrile HCN (6.67 μ mol), triphenyl phosphine (50 μ l, 0.27M tetrahydrofuran solution), succinimide (50 μ l, 0.27M tetrahydrofuran solution) and diethylazodicarboxylate (3 μ l) be prepared, thereby obtain the title compound of 10mM DMS0 solution form, and at 50mmx3.9mm, carry out HPLC on the 5 μ m particle diameter Waters Symmetry C8 posts and analyze, with 5%-95% acetonitrile/ammonium acetate wash-out.MS(APCI+ve)458(M+H)
+
Embodiment 31 (2S)-N-[1-(3 '-cyano group-4 '-fluorine biphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl]-thiazolidine-2, the 4-diketone
According to embodiment 26) method, use (2R)-1-(3 '-cyano group-4 '-fluorine biphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butanols (6.67 μ mol), triphenyl phosphine (50 μ l, 0.27M tetrahydrofuran solution), 2,4-thiazolidinedione (50 μ l, 0.27M tetrahydrofuran solution) and diethylazodicarboxylate (3 μ l) be prepared, thereby obtain the solution form title compound of 10mM in DMSO, and at 50mmx3.9mm, carry out HPLC on the 5 μ m particle diameter WatersSymmetry C8 posts and analyze, with 5%-95% acetonitrile/ammonium acetate wash-out.MS(APCI+ve)462(M+H)
+
Embodiment 32 (+/-)-N-[1-(4 '-fluoro-3 '-sulfamyl biphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl] oxazolidine-2-ketone
A) (+/-)-N-[1-(4-bromine phenoxy group)-4-(4-pyridyl)-2-butyl]-oxazolidine-2-ketone
According to embodiment 15c) described method, use (+/-)-N-2-(4-bromine phenoxy group)-4-(4-pyridyl)-butylamine (embodiment 19b), 1.08g), chloroformic acid 2-chloroethene ester (0.521ml) and sodium hydride (60% mineral oil dispersion thing) (0.408g) be prepared.70 ℃ of reactions added entry (100ml), the product ethyl acetate extraction after 10 hours.The organic extracting solution that merges filters and concentrating under reduced pressure with dried over mgso.The gained residue is by silica gel chromatography, and with methylene dichloride: ethanol (95: 5) is eluent, thereby obtains oily subhead compound (0.651g).MS (APCI+ve) 391/393 (M+H)
+ 1H NMR (DMSO-d
6) δ 8.46 (2H, dd), 7.44 (2H, dd), 7.28 (2H, dd), 6.92 (2H, dd), 4.29-4.19 (2H, m), 4.07 (2H, d), and 4.04-3.96 (1H, m), 3.59-3.41 (2H, m), 2.70-2.56 (2H, m), 1.90 (2H, q) .b) (+/-)-[4-(4-pyridyl)-2-(oxazolidine-2-ketone-1-yl) butoxy] phenylo boric acid
According to embodiment 18b) described method, (+/-) that uses that step a) makes-N-[1-(4-bromine phenoxy group)-4-(4-pyridyl)-2-butyl]-oxazolidine-2-ketone (0.20g), tert-butyl lithium (1.7M hexane solution, 0.60ml) and triisopropyl borate ester (0.17ml) be prepared, obtain spumescence subhead compound (0.09g).MS (APCI+ve) 313 (M-B (OH)
2)
+.
1H NMR (DMSO-d
6) δ 8.56 (2H, d), 7.82 (2H, d); 7.39 (2H, d), 6.91 (2H, d); 4.25-4.15 (2H, m), 4.07 (2H; d), and 4.05-3.94 (1H, m); 3.60-3.46 (2H, m), 2.74-2.62 (2H; m), 1.92 (2H, q) .c) (+/-)-N-[1-(4 '-fluoro-3 '-sulfamyl biphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl] oxazolidine-2-ketone
According to embodiment 6c) described method, (+/-) that adopts that step b) obtains-[4-(4-pyridyl)-2-(oxazolidine-2-ketone-1-yl) butoxy] phenylo boric acid (0.090g), 5-bromo-2-fluorophenyl sulphonamide (0.097g) [according to the described preparation of embodiment 35a among the WO98/42760], ethanol (1ml), sodium bicarbonate aqueous solution (2M, 0.2ml) and four (triphenyl phosphines) close palladium (0) and (0.010g) be prepared.
After the aftertreatment, by silica gel chromatography, use methylene dichloride successively: ethanol (95: 5) and methylene dichloride: ethanol (90: 10) wash-out obtains solid form title compound (0.034g) with residue.Fusing point: 89-91 ℃ MS (APCI+ve) 486 (M+H)
+ 1H NMR (DMSO-d
6) δ 8.46 (2H, d), 7.95 (1H, dd), 7.91-7.86 (1H, m), 7.72 (2H, s), 7.60 (2H, d), 7.48 (1H, t), 7.29 (2H, d), 7.07 (2H, d), 4.29-4.19 (2H, m), 4.14 (2H, d), 4.08-4.00 (1H, m), 3.63-3.47 (2H, m), 2.72-2.60 (2H, m), 1.99-1.90 (2H, m).
Embodiment 33 (+/-)-N-[1-(4-(6-methoxypyridine-2-yl)-phenoxy group)-4-(4-pyridyl)-2-butyl] oxazolidine-2-ketone
According to embodiment 6c) described method, adopt (+/-)-[4-(4-pyridyl)-2-(oxazolidine-2-ketone-1-yl) butoxy] phenylo boric acid (embodiment 32b, 0.100g), 2-bromo-6-methoxypyridine (J.0rg.Chem_55, (1990), 69-73,0.079g), ethanol (3ml), sodium bicarbonate aqueous solution (2M, 0.2ml) and four (triphenyl phosphines) close palladium (0) and (0.010g) be prepared.
After the aftertreatment, residue NPHPLC purifying with 0-10% ethanol/dichloromethane gradient elution, obtains oily title compound (0.082g).MS(APCI+ve)420(M+H)
+ 1H?NMR(DMSO-d
6)δ8.46(2H,dd)，8.04(2H,d)，7.73(1H,t)，7.48(1H,d)，7.30(2H,dd)，7.04(2H,d)，6.70(1H,d)，4.29-4.22(2H,m)，4.15(2H,d)，4.09-4.02(1H,m)，3.94(3H,s)，3.60-3.50(2H,m)，2.73-2.59(2H,m)，1.94(2H,q).
Embodiment 34 (+/-)-N-[1-(biphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl] oxazolidine-2-ketone
According to embodiment 6c) described method, adopt (+/-)-N-[1-(4-bromine phenoxy group)-4-(4-pyridyl)-2-butyl] oxazolidine-2-ketone (embodiment 32a), 0.100g), phenylo boric acid (0.047g), ethanol (3ml), sodium bicarbonate aqueous solution (2M, 0.2ml) and four (triphenyl phosphines) close palladium (0) and (0.010g) be prepared.
After the aftertreatment, residue by the NPHPLC purifying, with 0-10% ethanol/dichloromethane gradient elution, thereby is obtained solid form title compound (0.012g).Fusing point: 116-117 ℃ MS (APCI+ve) 389 (M+H)
+ 1H NMR (DMSO-d
6) δ 8.46 (2H, d), 7.60 (4H, t), 7.43 (2H, t), 7.30 (3H, d), 7.03 (2H, d), 4.31-4.20 (2H, m), 4.13 (2H, d), 4.07-4.00 (1H, m), 3.62-3.48 (2H, m), 2.72-2.59 (2H, m), 1.94 (2H, q)
Embodiment 35 (+/-)-N-[1-(4 '-chlordiphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl] oxazolidine-2-ketone
According to embodiment 6c) described method, adopt (+/-)-N-[1-(4-bromine phenoxy group)-4-(4-pyridyl)-2-butyl] oxazolidine-2-ketone (embodiment 32a), 0.100g), 4-chlorobenzene boric acid (0.060g), ethanol (3ml), sodium bicarbonate aqueous solution (2M, 0.2ml) and four (triphenyl phosphines) close palladium (0) and (0.010g) be prepared.
After aftertreatment, residue by the NPHPLC purifying, with 0-10% ethanol/dichloromethane gradient elution, thereby is obtained solid form title compound (0.038g).Fusing point: 103-105 ℃ MS (APCI+ve) 423 (M+H)
+ 1H NMR (DMSO-d
6) δ 8.46 (2H, d), 7.62 (4H, q), 7.47 (2H, d), 7.29 (2H, d), 7.03 (2H, d), 4.30-4.20 (2H, m), 4.13 (2H, d), 4.07-4.00 (1H, m), 3.62-3.48 (2H, m), 2.70-2.58 (2H, m), 1.94 (2H, q).
Embodiment 36 (+/-)-N-[1-(4 '-methyl diphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl] oxazolidine-2-ketone
According to embodiment 6c) described method, adopt (+/-)-N-[1-(4-bromine phenoxy group)-4-(4-pyridyl)-2-butyl] oxazolidine-2-ketone (embodiment 32a), 0.100g), 4-methylphenylboronic acid (0.052g), ethanol (3ml), sodium bicarbonate aqueous solution (2M, 0.2ml) and four (triphenyl phosphines) close palladium (0) and (0.010g) be prepared.
After the aftertreatment, residue with 0-10% ethanol/dichloromethane gradient elution, thereby obtains solid form title compound (0.033g) by the NPHPLC purifying.Fusing point: 109-110 ℃ MS (APCI+ve) 403 (M+H)
+ 1H NMR (DMSO-d
6) δ 8.46 (2H, d), 7.56 (2H, d), 7.50 (2H, d), 7.29 (2H, d), 7.23 (2H, d), 7.01 (2H, d), 4.30-4.20 (2H, m), 4.12 (2H, d), 4.07-4.01 (1H, m), 3.62-3.48 (2H, m), 2.72-2.59 (2H, m), 1.94 (2H, q).
Embodiment 37 (+/-)-N-[1-(4 '-methoxyl biphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl] oxazolidine-2-ketone
According to embodiment 6c) described method, adopt (+/-)-N-[1-(4-bromine phenoxy group)-4-(4-pyridyl)-2-butyl] oxazolidine-2-ketone (embodiment 32a), 0.100g), 4-methoxyphenylboronic acid (0.059g), ethanol (3ml), sodium bicarbonate aqueous solution (2M, 0.2ml) and four (triphenyl phosphines) close palladium (0) and (0.010g) be prepared.
After the aftertreatment, residue by the NPHPLC purifying, with 0-10% ethanol/dichloromethane gradient elution, thereby is obtained solid form title compound (0.026g).Fusing point: 114-115 ℃ MS (APCI+ve) 419 (M+H)
+ 1H NMR (DMSO-d
6) δ 8.46 (2H, d), 7.53 (4H, dd), 7.29 (2H, d), 6.99 (4H, dd), 4.30-4.20 (2H, m), 4.11 (2H, d), 4.06-4.01 (1H, m), 3.32 (3H, s), 3.61-3.48 (2H, m), 2.70-2.59 (2H, m), 1.94 (2H, q).
Embodiment 38 (+/-)-N-[1-(3 ', 4 '-DCBP-4-base oxygen base)-4-(4-pyridyl)-2-butyl] oxazolidine-2-ketone
According to embodiment 6c) described method, adopt (+/-)-[4-(4-pyridyl)-2-(oxazolidine-2-ketone-1-yl) butoxy] phenylo boric acid (embodiment 32b), 0.050g), 1-bromo-3, (2M 0.1ml) closes palladium (0) with four (triphenyl phosphines) and (0.006g) is prepared for 4-dichlorobenzene (0.048g), ethanol (2ml), sodium bicarbonate aqueous solution.
After the aftertreatment, residue by the NPHPLC purifying, with 0-10% ethanol/dichloromethane gradient elution, thereby is obtained solid form title compound (0.010g).Fusing point: 92-93 ℃ MS (APCI+ve) 4.57/459/461 (M+H)
+ 1H NMR (DMSO-d
6) δ 8.46 (2H, d), 7.89 (1H, d), 7.68-7.62 (4H, m), 7.29 (2H, d), 7.04 (2H, d), 4.30-4.20 (2H, m), 4.13 (2H, d), 4.07-4.01 (1H, m), 3.62-3.48 (2H, m), 2.72-2.59 (2H, m), 1.94 (2H, q).
Embodiment 39 (+/-)-N-[1-(4-(6-methoxypyridine-2-yl)-phenoxy group)-4-(4-pyridyl)-2-butyl] piperidines-2, the 6-diketone
A) (+/-)-1-(4-bromine phenoxy group)-4-(4-pyridyl)-2-(t-butyldimethylsilyloxy base) butane
(+/-)-1-(4-bromine phenoxy group)-4-(4-pyridyl)-2-butanols (embodiment 6b), add tert-butyldimethylsilyl chloride (20.53g) and imidazoles (9.25g) in anhydrous methylene chloride 14.60g) (500ml) solution.Stirred solution spends the night under the room temperature.Filtering solid and concentrating under reduced pressure filtrate.
Residue silica gel chromatography purifying, with methylene dichloride: ethyl acetate (5: 1) wash-out, thus solid form subhead compound (19.34g) obtained.Fusing point: 73-75 ℃ MS (APCI+ve) 436/438 (M+H)
+ 1H NMR (DMSO-d
6) δ 8.50 (2H, dd), 7.49 (2H, dd), 7.27 (2H, d), 6.94 (2H, dd), 4.13-4.02 (2H, m), 3.93-3.86 (1H, m), 2.82-2.68 (2H, m), 1.97-1.79 (2H, m), 0.91 (9H, s), 0.12 (3H, s), 0.09 (3H, s) .b) (+/-)-4-[4-(4-pyridyl)-2-(t-butyldimethylsilyloxy base) butoxy] phenylo boric acid
According to embodiment 18b) described method, (+/-) that uses that step a) obtains-1-(4-bromine phenoxy group)-4-(4-pyridyl)-2-(t-butyldimethylsilyloxy base) butane (10.0g), tert-butyl lithium (the 1.7M hexane solution, 27ml) and triisopropyl borate ester (6ml) in anhydrous tetrahydro furan (200ml), be prepared.
After the aftertreatment, residue is used ethyl acetate successively by silica gel chromatography: hexane (2: 1) and eluent ethyl acetate, thus obtain the subhead compound, for-foams (4.38g).MS (APCI+ve) 402 (M+H)
+ 1H NMR (DMSO-d
6+ D
2O) δ 8.45 (2H, dd), 7.71 (2H, d), 7.24 (2H, q), 6.87 (2H, d), 4.04-3.82 (3H, m), 2.79-2.66 (2H, m), and 1.97-1.75 (2H, m), 0.87 (9H, s), 0.14 (3H, s), 0.08 (3H, s) .c) (+/-)-4-[4-(4-pyridyl)-2-butoxy] phenylo boric acid
In methyl alcohol (200ml) solution of (+/-)-1-(4-bromine phenoxy group)-4-(4-pyridyl)-2-(t-butyldimethylsilyloxy base) butane (4.38g) that step b) makes, add dilute hydrochloric acid (2M, 65ml).Stirring at room mixture 2 hours, concentrating under reduced pressure then.Residue is assigned within ether and the water.Water layer alkalizes with sodium bicarbonate aqueous solution, uses ethyl acetate extraction then.The organic extracting solution that merges filters and concentrating under reduced pressure, thereby obtains powdery subhead compound with anhydrous magnesium sulfate drying.MS (APCI+ve) 288 (M+H)
+ 1H NMR (DMSO-d
6+ D
2O) δ 8.43 (2H, d), 7.71 (2H, d), 7.31 (2H, d), 6.92 (2H, d), 3.92 (2H, d), 3.84-3.78 (1H, m), 2.87-2.64 (2H, m), 1.89-1.74 (2H, m) .d) (+/-)-1-[4-(6-methoxypyridine-2-yl) phenoxy group]-4-(4-pyridyl)-2-butanols
According to embodiment 6c) described method, (+/-) that uses that step c) makes-4-[4-(4-pyridyl)-2-butoxy] phenylo boric acid (0.20g), 2-bromo-6-methoxypyridine (J.Org.Chem_55, (1990), 69-73,0.26g), ethanol (3ml), sodium bicarbonate aqueous solution (2M, 0.7ml) and four (triphenyl phosphines) close palladium (O) and (0.020g) be prepared.
After the aftertreatment, residue by the NPHPLC purifying, with 0-10% ethanol/dichloromethane gradient elution, is obtained oily subhead compound (0.15g).MS (APCI+ve) 351 (M+H)
+ 1H NMR (DMSO-d
6) δ 8.45 (2H, d), 8.03 (2H, dd), 7.73 (1H, t), 7.47 (1H, d), 7.26 (2H, dd), 7.03 (2H, dd), 6.70 (1H, d), 5.08 (1H, d), 3.95 (2H, d), 3.83-3.78 (1H, m), 3.32 (3H, s), and 2.85-2.77 (1H, m), 2.72-2.64 (1H, m), 1.91-1.83 (1H, m), 1.78-1.70 (1H, m) e) (+/-)-N-[1-(4-(6-methoxypyridine-2-yl)-phenoxy group)-4-(4-pyridyl)-2-butyl] piperidines-2, the 6-diketone
According to the method for embodiment 1, (+/-) that uses that step d) obtains-1-[4-(6-methoxypyridine-2-yl) phenoxy group]-4-(4-pyridyl)-2-butanols (0.15g), glutarimide (0.1g), triphenyl phosphine (0.22g) and diethylazodicarboxylate (0.14ml) be prepared.
After the aftertreatment, residue by the NPHPLC purifying, with 0-10% ethanol/dichloromethane gradient elution, is obtained oily title compound (0.10g).MS(APCI+ve)446(M+H)
+ 1H?NMR(DMSO-d
6)δ8.44(2H,dd)，8.01(2H,dd)，7.73(1H,t)，7.47(1H,d)，7.21(2H,dd)，6.97(2H,d)，6.70(1H,d)，5，07-5.02(1H,m)，4.42-4.28(2H,m)，3.94(3H,s)，2.62-2.51(6H,m)，2.35-2.24(1H,m)，2.12-2.01(1H,m)，1.78-1.70(2H,m).
Embodiment 40 (+/-)-N-[1-(3 '-nitrobiphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl] imidazolidine-2, the 4-diketone
Method according to embodiment 1, use (+/-)-N-1-(3 '-nitrobiphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butanols (embodiment 15a), 0.20g), glycolylurea (0.11g), triphenyl phosphine (0.29g) and diethylazodicarboxylate (0.17ml) be prepared in anhydrous tetrahydro furan (10ml) and dimethyl formamide (2ml).
After the aftertreatment, residue by the NPHPLC purifying, with 0-10% ethanol/dichloromethane gradient elution, is obtained solid form title compound (0.03g).Fusing point: 143-145 ℃ MS (APCI+ve) 447 (M+H)
+ 1H NMR (DMSO-d
6) δ 8.45 (2H, d), 8.38 (1H, s), 8.17-8.07 (3H, m), 7.74-7.70 (3H, m), 7.24 (2H, d), 7.03 (2H, d), 4.51-4.45 (1H, m), 4.38-4.23 (2H, m), 3.87 (2H, s), 2.69-2.60 (2H, m), 2.38-2.22 (1H, m), 2.16-2.00 (1H, m).
Embodiment 41 (+/-)-N-[1-(3 '-nitrobiphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl] piperidines-2-ketone
In the presence of triethylamine (1ml), to (+/-)-N-2-(3 '-nitrobiphenyl-4-base oxygen base)-4-(4-pyridyl)-butylamine (embodiment 19c), slowly add 5-chlorine valeryl chloride (0.07ml) in anhydrous methylene chloride 0.20g) (10ml) solution.Stirred the mixture under the room temperature 15 minutes, then concentrating under reduced pressure.
Adding potassium tert.-butoxide in the residue solution that is dissolved in anhydrous tetrahydro furan (10ml) again (the 1M tetrahydrofuran solution, 1.5ml).React after 30 minutes the concentrating under reduced pressure mixture under the room temperature.Add entry and with the mixture ethyl acetate extraction.The organic extracting solution anhydrous magnesium sulfate drying that merges filters and concentrating under reduced pressure.
Residue with 0-10% ethanol/dichloromethane gradient elution, obtains oily title compound (0.03g) by the NPHPLC purifying.MS(APCI+ve)446(M+H)
+ 1H?NMR(DMSO-d
6)δ8.45(2H,d)，8.38(1H,t)，8.18-8.09(2H,m)，7.75-7.69(3H,m)，7.26(2H,d)，7.07(2H,d)，4.86-4.76(1H,m)，4.19-4.07(2H,m)，3.25-3.14(2H,m)，2.73(2H,t)，2.28-2.22(2H,m)，2.00-1.87(2H,m)，1.64(4H,bd).
Embodiment 42 (+/-)-N-[1-(3 '-nitrobiphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl]-pyrrolidin-2-one
Method according to top embodiment 41, use (+/-)-N-2-(3 '-nitrobiphenyl-4-base oxygen base)-4-(4-pyridyl)-butylamine (embodiment 19c), 0.20g), (the 1M tetrahydrofuran solution 1.5ml) is prepared for triethylamine (1ml), 4-chlorobutanoylchloride (0.06ml) and potassium tert.-butoxide solution.
After the aftertreatment, residue by the NPHPLC purifying, with 0-10% ethanol/dichloromethane gradient elution, thereby is obtained oily title compound (0.035g).MS(APCI+ve)432(M+H)
+ 1H?NMR(DMSO-d
6)δ8.45(2H,dd)，8.38(1H,t)，8.18-8.09(2H,m)，7.75-7.69(3H,m)，7.28(2H,dd)，7.07(2H,dd)，4.34-4.27(1H,m)，4.11(2H,d)，3.38-3.26(2H,m)，2.61-2.55(2H,m)，2.24(2H,t)，1.97-1.85(4H,m).
Embodiment 43 pharmacological researches
Known some compound such as benzoyl benzoyl adenosine triphosphate (bbATP) are the agonists of P2X7 acceptor, they can be in plasma membrane pore-forming (Drug Development Research (1996), 37 (3), p.126).Therefore, when acceptor in bromination 3,8-diamino-5-ethyl-6-phenylphenanthridineand (a kind of fluorescent DNA probe) exists when activating with bbATP down, can observe DNA in the born of the same parents and strengthen in conjunction with the fluorescence of bromination second pyridine.This fluorescence enhancing can be used as measuring of P2X7 receptor activation, and therefore is used to prove the effect of compound to the P2X7 acceptor.
Each title compound of test implementation example 1-42 is at P2X in this way
7Antagonistic activity on the acceptor.For example, test is carried out in 96 hole flat-bottom microtiter plates, and each hole adds and contains 10 by 200 μ l
-4M bromination 3, the THP-1 cell suspension (2.5x10 of 8-diamino-5-ethyl-6-phenylphenanthridineand
6Cell/ml), 25 μ l contain 10
-5High potassium damping fluid and the 25 μ l of M bbATP contain 3x10
-5The 250 μ l solution that the high potassium damping fluid of M test-compound is formed.Titer plate covers with plastic plate, 37 ℃ of incubations 1 hour.With titer plate reading on Perkin-Elmer fluorescent plate reader, excite 520nm then, emission 595nm, slit width: Ex15nm, Em20nm.For relatively, use in test bbATP (a kind of P2X respectively
7Agonist) and pyridoxal 5-phosphoric acid (a kind of P2X
7Antagonist) thing in contrast.According to the gained reading, calculate the IC of each compound
50Value, this value is for reducing the negative logarithm concentration of the required test-compound of 50%bbATP agonist activity.Each compound of embodiment 1-42 all proves to have antagonistic activity, they have＞and 4.50 IC
50Value.
Claims (13)
1. logical formula I compound or its pharmaceutically useful salt or solvate:
Wherein X represents oxygen or sulphur atom, or represents group NH, CH
2, CH
2CH
2Or OCH
2
Y represents group CH
2Or C=O;
R
1Represent pyridyl or pyrimidyl;
R
2Represent phenyl, pyridyl or pyrimidyl, they separately can be randomly independently be selected from following substituting group and replace by one or more: halogen atom or amino, cyano group, hydroxyl, nitro, C
1-C
6-alkyl, halo-C
1-C
6-alkyl, C
1-C
6-alkoxyl group, C
1-C
6-alkylthio, (two) C
1-C
6-alkylamino, C
1-C
6-alkyl-carbonyl, C
1-C
6-alkoxy carbonyl, C
1-C
6-alkyl sulfinyl, C
1-C
6-alkyl sulphonyl ,-NR
3SO
2R
4Or-SO
2NR
5R
6Group, or group-Z-(CH
2)
p-Z-(CH
2)
q-H, wherein Z represents nitrogen or Sauerstoffatom separately, and p is integer 2-5, and q is 0 or integer 1-5;
R
3And R
4Represent hydrogen atom or C independently of one another
1-C
6-alkyl; With
R
5And R
6Represent hydrogen atom or C independently of one another
1-C
6-alkyl or the nitrogen-atoms that connects with their institute's keys form pyrrolidyl or piperidyl.
2. according to the compound of claim 1, wherein X represents sulphur atom or group CH
2
3. according to the compound of claim 1 or 2, wherein Y represents group C=O.
4. according to each compound among the claim 1-3, wherein R
1Represent pyridyl.
5. according to each compound among the claim 1-4, wherein R
2Represent phenyl, pyridyl or pyrimidyl, they separately can be randomly by one, two or three independently are selected from following substituting group and replace: halogen atom or amino, cyano group, hydroxyl, nitro, C
1-C
4-alkyl, halo-C
1-C
4-alkyl, C
1-C
4-alkoxyl group, C
1-C
4-alkylthio, (two) C
1-C
4-alkylamino, C
1-C
4-alkyl-carbonyl, C
1-C
4-alkoxy carbonyl, C
1-C
4-alkyl sulfinyl, C
1-C
4-alkyl sulphonyl ,-NR
3SO
2R
4Or-SO
2NR
5R
6Group.
6. according to each compound among the claim 1-5, wherein R
2Represent phenyl, pyridyl or pyrimidyl, they can randomly independently be selected from following substituting group by one or two separately and replace: halogen atom or amino, cyano group, nitro, C
1-C
4-alkyl, halo-C
1-C
4-alkyl, C
1-C
4-alkoxyl group or-SO
2NR
5R
6Group.
7. according to the compound of claim 1, described compound is:
(+/-)-(N-[1-(biphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl] tetramethyleneimine-2, the 5-diketone,
(+/-)-N-[1-(3 '-methoxyl biphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl] tetramethyleneimine-2, the 5-diketone,
(+/-)-N-[1-(biphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl] thiazolidine-2, the 4-diketone,
(+/-)-N-[1-(3 '-chlordiphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl] tetramethyleneimine-2, the 5-diketone,
(+/-)-N-[1-(3 '-fluorine biphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl] tetramethyleneimine-2, the 5-diketone,
(+/-)-N-[1-(3 '-methoxyl biphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl] tetramethyleneimine-2, the 5-diketone,
(+/-)-N-[1-(3 '-methoxyl biphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl] thiazolidine-2, the 4-diketone,
(2R)-N-[1-(3 '-cyanobiphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl] thiazolidine-2, the 4-diketone,
(2R)-N-[1-(3 '-nitrobiphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl] tetramethyleneimine-2, the 5-diketone,
(2R)-N-[1-(3 '-cyanobiphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl] tetramethyleneimine-2, the 5-diketone,
(+/-)-N-[1-(3 '-nitrobiphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl] thiazolidine-2, the 4-diketone,
(+/-)-N-[1-(3 '-nitrobiphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl] tetramethyleneimine-2, the 5-diketone,
(+/-)-N-[1-(4 '-fluorine biphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl] tetramethyleneimine-2, the 5-diketone,
(+/-)-N-[1-(4 '-fluorine biphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl] thiazolidine-2, the 4-diketone,
(+/-)-N-[1-(biphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl] oxazolidine-2-ketone,
(2R)-N-[1-(3 '-chloro-4 '-fluorine biphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl] thiazolidine-2, the 4-diketone,
(2R)-N-[1-(3 '-chloro-4 '-fluorine biphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl] tetramethyleneimine-2, the 5-diketone,
(2R)-N-[1-(3 ', 5 '-dicyanobiphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl] thiazolidine-2, the 4-diketone,
(+/-)-N-[1-(3 '-nitrobiphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl] oxazolidine-2-ketone,
(2R)-N-[1-(3 '-fluorine biphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl] thiazolidine-2, the 4-diketone,
(+/-)-N-[1-(3 '-(trifluoromethyl) biphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl] thiazolidine-2, the 4-diketone,
(+/-)-N-[1-(2 '-methoxyl biphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl] thiazolidine-2, the 4-diketone,
(+/-)-N-[1-(3 '-nitrobiphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl] piperidines-2, the 6-diketone,
(+/-)-N-[1-(3 '-phenylaniline-4-base oxygen base)-4-(4-pyridyl)-2-butyl] thiazolidine-2, the 4-diketone,
(+/-)-N-[1-(3 '-nitrobiphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl]-[1,3] oxazine alkane-2-ketone,
(2S)-N-[1-(3 '-cyanobiphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl] thiazolidine-2, the 4-diketone,
(2S)-N-[1-(3 '-phenylaniline-4-base oxygen base)-4-(4-pyridyl)-2-butyl] thiazolidine-2, the 4-diketone,
(2S)-N-[1-(3 '-methanesulfonamido biphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl] thiazolidine-2, the 4-diketone,
(2S, 3S)-N-[1-(3 '-(tetramethyleneimine-1-alkylsulfonyl) biphenyl-4-base oxygen base)-4-(3-pyridyl)-3-amyl group] tetramethyleneimine-2, the 5-diketone,
(2S, 3S)-N-[1-(3 '-cyano group-4 '-fluorine biphenyl-4-base oxygen base)-4-(3-pyridyl)-3-amyl group] tetramethyleneimine-2, the 5-diketone,
(2S)-N-[1-(3 '-cyano group-4 '-fluorine biphenyl-4-base oxygen base)-4-(3-pyridyl)-2-butyl] thiazolidine-2, the 4-diketone,
(+/-)-N-[1-(4 '-fluoro-3 '-sulfamyl biphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl] oxazolidine-2-ketone,
(+/-)-N-[1-(4-(6-methoxypyridine-2-yl)-phenoxy group)-4-(4-pyridyl)-2-butyl] oxazolidine-2-ketone,
(+/-)-N-[1-(biphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl] oxazolidine-2-ketone,
(+/-)-N-[1-(4 '-chlordiphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl] oxazolidine-2-ketone,
(+/-)-N-[1-(4 '-methyl diphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl] oxazolidine-2-ketone,
(+/-)-N-[1-(4 '-methoxyl biphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl] oxazolidine-2-ketone,
(+/-)-N-[1-(3 ', 4 '-DCBP-4-base oxygen base)-4-(4-pyridyl)-2-butyl] oxazolidine-2-ketone,
(+/-)-N-[1-(4-(6-methoxypyridine-2-yl)-phenoxy group)-4-(4-pyridyl)-2-butyl] piperidines-2, the 6-diketone,
(+/-)-N-[1-(3 '-nitrobiphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl] imidazolidine-2, the 4-diketone,
(+/-)-N-[1-(3 '-nitrobiphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl] piperidines-2-ketone, or
(+/-)-N-[1-(3 '-nitrobiphenyl-4-base oxygen base)-4-(4-pyridyl)-2-butyl] pyrrolidin-2-one.
8. the method for preparing the described formula I compound of claim 1, this method comprises:
(a) make logical formula II compound:
Wherein L represents leavings group, and R
1And R
2Define as formula I, react with logical formula III compound:
Wherein define in X and Y such as the formula I, just working as X is Sauerstoffatom or OCH
2The time, then Y can not be CH
2Group; Perhaps
(b) when X be that Sauerstoffatom and Y are CH
2During group, make logical formula IV compound:
R wherein
1And R
2As defining in the formula I,
React with chloroformic acid 2-chloroethene ester; Perhaps
(c) when X be OCH
2Group and Y are CH
2During group, above making in (b) defined formula IV compound in the presence of phosgene, react with the 3-propylene chlorohydrin; Perhaps
(d) when X be CH
2Group and Y are CH
2During group, defined formula IV compound and the reaction of 4-chlorobutanoylchloride in (b) above making; Perhaps
(e) when X be CH
2CH
2Group and Y are CH
2During group, defined formula IV compound and the reaction of 5-valeryl chloride in (b) above making; Perhaps
(f) when X be Sauerstoffatom or OCH
2During group, make general formula (V) compound:
Wherein X represention oxygen atom or OCH
2Group, and Y and R
1As the formula I definition,
With logical formula VI R
2-B (OH)
2Compound reaction, R wherein
2Define as formula I; Perhaps (g) when X be Sauerstoffatom or OCH
2During group, make general formula (VII) compound:
Wherein X represention oxygen atom or OCH
2Group, and Y and R
1As the formula I definition,
With general formula (VIII), R
2The compound reaction of-Br, wherein R
2Define as formula I;
And, (b), (c), (d), (e), (f) or (g) afterwards, the formula I compound is converted into other formula I compound and/or forms the pharmacologically acceptable salt or the solvate of formula I compound randomly at (a).
9. pharmaceutical composition, it comprises among the claim 1-7 each described formula I compound or its pharmaceutically useful salt or solvate and pharmaceutically useful auxiliary, diluent or carrier.
10. the described preparation of drug combination method of claim 9, this method comprise each described formula I compound among the claim 1-7, or its pharmaceutically useful salt or solvate mix with pharmaceutically useful auxiliary, diluent or carrier.
11. each described formula I compound or its pharmaceutically useful salt or solvate among the claim 1-7 of treatment usefulness.
12. each described formula I compound or its pharmaceutically useful salt or the solvate application in the medicine of preparation treatment usefulness among the claim 1-7.
13. produce immunosuppressant method, this method comprises each described formula I compound or its pharmaceutically useful salt or solvate among the claim 1-7 of patient's administering therapeutic significant quantity.
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| WO (1) | WO1999029686A1 (en) |
Cited By (1)
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| CN101511787B (en) * | 2006-07-06 | 2011-11-30 | 葛兰素集团有限公司 | Substituted N-phenylmethyl -5-oxo-proline-2-amides as P2X7-receptor antagonists and their methods of use |
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| SE9901875D0 (en) | 1999-05-25 | 1999-05-25 | Astra Pharma Prod | Novel compounds |
| SE9904505D0 (en) | 1999-12-09 | 1999-12-09 | Astra Pharma Prod | Novel compounds |
| TWI258462B (en) | 1999-12-17 | 2006-07-21 | Astrazeneca Ab | Adamantane derivative compounds, process for preparing the same and pharmaceutical composition comprising the same |
| SE9904652D0 (en) * | 1999-12-17 | 1999-12-17 | Astra Pharma Prod | Novel Compounds |
| JP2002330787A (en) * | 2000-10-21 | 2002-11-19 | Astrazeneca Ab | Chemical substance |
| PA8557501A1 (en) | 2001-11-12 | 2003-06-30 | Pfizer Prod Inc | BENZAMIDA, HETEROARILAMIDA AND INVESTED AMIDAS |
| WO2003042190A1 (en) | 2001-11-12 | 2003-05-22 | Pfizer Products Inc. | N-alkyl-adamantyl derivatives as p2x7-receptor antagonists |
| US7071223B1 (en) | 2002-12-31 | 2006-07-04 | Pfizer, Inc. | Benzamide inhibitors of the P2X7 receptor |
| PA8591801A1 (en) | 2002-12-31 | 2004-07-26 | Pfizer Prod Inc | BENZAMID INHIBITORS OF THE P2X7 RECEIVER. |
| CA2525437C (en) | 2003-05-12 | 2009-04-28 | Pfizer Products Inc. | Benzamide inhibitors of the p2x7 receptor |
| GB0324498D0 (en) | 2003-07-21 | 2003-11-26 | Aventis Pharma Inc | Heterocyclic compounds as P2X7 ion channel blockers |
| RU2006146675A (en) | 2004-06-29 | 2008-07-10 | Пфайзер Продактс Инк. (Us) | METHOD FOR PRODUCING 5- [4- (2-HYDROXYPROPYL) -3,5-DIOXO-4,5-DIHYDRO-3H- [1,2,4] TRIAZIN-2-IL] BENZAMIDE DERIVATIVES BY REMOVING PROTECTION FROM INTERMEDIATE PRODUCTS, SODA HYDROXYL |
| EP1937643B1 (en) | 2006-03-16 | 2016-07-13 | Second Genome, Inc. | Bicycloheteroaryl compounds as p2x7 modulators and uses thereof |
| TWI464148B (en) | 2006-03-16 | 2014-12-11 | Evotec Us Inc | Bicycloheteroaryl compounds as p2x7 modulators and uses thereof |
| DK2001474T3 (en) | 2006-03-16 | 2016-05-09 | Second Genome Inc | BICYCLOHETEROARYL COMPOUNDS AS P2X7 MODULATORS AND APPLICATIONS THEREOF |
| TW200813018A (en) | 2006-06-09 | 2008-03-16 | Astrazeneca Ab | Novel compounds |
| AU2007271182B2 (en) | 2006-07-06 | 2012-03-15 | Glaxo Group Limited | Substituted N-phenylmethyl -5-oxo-proline-2-amides as P2X7-receptor antagonists and their methods of use |
| CA2680275C (en) | 2007-03-09 | 2016-08-23 | Renovis, Inc. | Bicycloheteroaryl compounds as p2x7 modulators and uses thereof |
| US20100168171A1 (en) * | 2007-03-28 | 2010-07-01 | Paul John Beswick | Piperidinone Carboxamide Derivatives as P2X7 Modulators |
| JP2010522710A (en) * | 2007-03-29 | 2010-07-08 | グラクソ グループ リミテッド | Oxazolidine and morpholinecarboxamide derivatives as P2X7 modulators |
| KR20090127435A (en) | 2007-04-03 | 2009-12-11 | 글락소 그룹 리미티드 | Imidazolidine carboxamide derivatives as p2x7 modulators |
| US8119661B2 (en) | 2007-09-11 | 2012-02-21 | Astrazeneca Ab | Piperidine derivatives and their use as muscarinic receptor modulators |
| GB0803729D0 (en) * | 2008-02-29 | 2008-04-09 | Ge Healthcare Ltd | Imaging the central nervous system |
| JP5506776B2 (en) | 2008-03-25 | 2014-05-28 | アフェクティス ファーマシューティカルズ アーゲー | Novel P2X7R antagonist and use thereof |
| MX2011010810A (en) | 2009-04-14 | 2012-01-12 | Affectis Pharmaceuticals Ag | Novel p2x7r antagonists and their use. |
| EP2322149A1 (en) | 2009-11-03 | 2011-05-18 | Universidad del Pais Vasco | Methods and compositions for the treatment of ischemia |
| CN102858741A (en) | 2010-05-14 | 2013-01-02 | 阿费克蒂斯制药股份公司 | Novel methods for the preparation of P2X7R antagonists |
| WO2012110190A1 (en) | 2011-02-17 | 2012-08-23 | Affectis Pharmaceuticals Ag | Novel p2x7r antagonists and their use |
| WO2012163456A1 (en) | 2011-05-27 | 2012-12-06 | Affectis Pharmaceuticals Ag | Novel p2x7r antagonists and their use |
| WO2012163792A1 (en) | 2011-05-27 | 2012-12-06 | Affectis Pharmaceuticals Ag | Novel p2x7r antagonists and their use |
| EP3713540A1 (en) | 2017-11-21 | 2020-09-30 | 3M Innovative Properties Company | Oral plant-based-oil-in-water emulsions and methods of use |
| WO2019123171A1 (en) | 2017-12-20 | 2019-06-27 | 3M Innovative Properties Company | Oral compositions and methods of use |
| CN111511348A (en) | 2017-12-20 | 2020-08-07 | 3M创新有限公司 | Oral compositions and methods of use |
-
1997
- 1997-12-05 SE SE9704546A patent/SE9704546D0/en unknown
-
1998
- 1998-12-01 EE EEP200000321A patent/EE200000321A/en unknown
- 1998-12-01 TR TR2000/01544T patent/TR200001544T2/en unknown
- 1998-12-01 JP JP2000524280A patent/JP2001525406A/en not_active Withdrawn
- 1998-12-01 WO PCT/SE1998/002190 patent/WO1999029686A1/en not_active Application Discontinuation
- 1998-12-01 PL PL98340837A patent/PL340837A1/en unknown
- 1998-12-01 HU HU0100731A patent/HUP0100731A3/en unknown
- 1998-12-01 BR BR9813378-0A patent/BR9813378A/en not_active Application Discontinuation
- 1998-12-01 SK SK844-2000A patent/SK8442000A3/en unknown
- 1998-12-01 CN CN98813490A patent/CN1284074A/en active Pending
- 1998-12-01 EP EP98962753A patent/EP1037889A1/en not_active Withdrawn
- 1998-12-01 AU AU17915/99A patent/AU1791599A/en not_active Abandoned
- 1998-12-01 CA CA002312357A patent/CA2312357A1/en not_active Abandoned
- 1998-12-01 IL IL13636898A patent/IL136368A0/en unknown
- 1998-12-01 KR KR1020007006117A patent/KR20010032800A/en not_active Application Discontinuation
-
2000
- 2000-05-31 NO NO20002787A patent/NO20002787L/en not_active Application Discontinuation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101511787B (en) * | 2006-07-06 | 2011-11-30 | 葛兰素集团有限公司 | Substituted N-phenylmethyl -5-oxo-proline-2-amides as P2X7-receptor antagonists and their methods of use |
Also Published As
| Publication number | Publication date |
|---|---|
| EE200000321A (en) | 2001-08-15 |
| HUP0100731A3 (en) | 2002-08-28 |
| JP2001525406A (en) | 2001-12-11 |
| IL136368A0 (en) | 2001-06-14 |
| EP1037889A1 (en) | 2000-09-27 |
| CA2312357A1 (en) | 1999-06-17 |
| BR9813378A (en) | 2000-10-10 |
| HUP0100731A2 (en) | 2002-05-29 |
| WO1999029686A1 (en) | 1999-06-17 |
| TR200001544T2 (en) | 2000-11-21 |
| AU1791599A (en) | 1999-06-28 |
| NO20002787L (en) | 2000-08-01 |
| PL340837A1 (en) | 2001-02-26 |
| KR20010032800A (en) | 2001-04-25 |
| SK8442000A3 (en) | 2001-01-18 |
| NO20002787D0 (en) | 2000-05-31 |
| SE9704546D0 (en) | 1997-12-05 |
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