CN101747287B - 2-oxo-1,3-O-aza-cyclopentane-4-carboxamide derivative and application thereof in preparation of immunosuppressant - Google Patents
2-oxo-1,3-O-aza-cyclopentane-4-carboxamide derivative and application thereof in preparation of immunosuppressant Download PDFInfo
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Abstract
The invention relates to a 2-oxo-1,3-O-aza-cyclopentane-4-carboxamide derivative, a geometric isomer thereof, or medicinal salts thereof or a hydras thereof, and the preparation thereof which contains medical compounds. The invention relates to the application of the compound in the preparation of medicines for resisting organ transplantation rejection and preventing and/or treating some autoimmune diseases, such as rheumatism, psoriasis, multiple sclerosis, systemic lupus erythematosus, and the like.
Description
Technical field
The present invention relates to 2-oxo-1,3-oxazolidine-4-carboxamides derivatives, its geometrical isomer or pharmacy acceptable salt or hydrate, their preparation method contains the pharmaceutical composition of said compound.The invention still further relates to said compound is used to prepare anti-organ transplant rejection and prevents and/or treats some autoimmune disease such as the purposes of the medicine of disease such as similar rheumatism, psoriasis, multiple sclerosis, systemic lupus erythematous.
Background technology
The present invention relates to one type of compound with immunoregulation effect with and as the purposes of medicine and/or pharmaceutical composition.
Immune disorder can cause a series of autoimmune diseases and chronic inflammatory diseases; As; Systemic lupus erythematous, chronic rheumatic arthritis, I type and type ii diabetes, some enteritis, courage sclerosis, multiple sclerosis and other disease are like Crohn disease, ulcerative colitis, big pemphigoid, sarcoidosis and asthma etc.
Though pathogenesis and process that these are sick there are differences, they produce with aspect such as lymphocyte autoactivation at autoantibody is identical.Possibly be because due to normally the immunity system balance is broken.Likewise, after marrow or organ transplantation, host's lymphocyte identification external organization's antigen also begins to produce cell and humoral response, comprises antibody, cytokine, cellulotoxic lymphocyte, causes graft-rejection.Due to this is likely that also normal immunity system balance broken.
A net result of autoimmune disease and graft-rejection is exactly that inflammatory cell causes tissue injury with the attemperator that they discharge.Although clinical had many immunosuppressor using, there is different shortcomings separately in they.As, the early immune suppressor factor is representative with glucocorticosteroid and azathioprine.Uniting of the two makes organ transplantation obtain for the first time breakthrough progress, and still, up to the end of the seventies in last century, the combined utilization of the two has only about 50% as 1 annual survival rate of keeping the renal transplantation of immunosuppressant therapy.Simultaneously, the prolonged application glucocorticosteroid can produce serious adverse reaction, as brings out and increase the weight of and infect, and causes adrenal cortex function disorder etc.; The immunological reagent of cell toxicant classes such as prolonged application azathioprine then causes the inhibition and the gastrointestinal tract mucous infringement of medulla hematopoietic system.Subsequently, the application of ciclosporin A (CsA) makes and various organ transplantations comprises that the transplanting of organs such as liver, heart, heart lung, pancreas, marrow has obtained significant progress.Up to the mid-80, most of immunosuppressant therapy scheme still is the basis with the ciclosporin A, but ciclosporin A has tangible toxicity, like renal toxicity, liver toxicity, initiation hyperglycemia, nervous lesion, bring out and infect and cause tumour etc.Mycophenlate mofetil is the ester derivative of mycophenolic acid, has stronger immunosuppressive action.1996, clinical trial showed, mycophenlate mofetil, retrocortine and ciclosporin A drug combination group relatively, it is nearly 50% that the mycophenlate mofetil group reduces the renal transplantation acute rejection incidence, and significantly reduce the mortality of kidney transplantation treatment.Mycophenlate mofetil can reverse the invalid vascular repulsion of routine immunization suppression therapy simultaneously, thereby avoids the graft loss merit.Mycophenlate mofetil has low liver toxicity, renal toxicity and bone marrow inhibition, side reactions such as no hypertension, mellitus, pancreatitis, osteoporosis, and still, its some toxic reactions still make us and can't stand in clinical application.The discovery of FK506 makes organ transplantation get into another New Times.Carry out historical control with ciclosporin A treatment group, patient's survival rate of FK506 treatment group obviously increases, and rejection takes place less; Consumption that simultaneously can also type of minimizing SUV; Also have document to show, use the rejection that occurs behind the ciclosporin A, have 65%-80% to be reversed by FK506.In addition, FK506 is also advantageous in that it makes it more favourable to liver transplantation to hepatocellular proliferative effect, and can not produce the spinoff like some hamartoplasiaes due to the ciclosporin A.Comparatively speaking; Use that FK506 has transplant patient's survival rate and the graft survival rate is high, incidence of acute rejection is low, to the relative no dependence of class SUV, hang down advantage such as infection rate, but FK506 still has spinoffs such as renal toxicity, neurotoxicity, tumour, infection, anaphylaxis, hypertension and hyperglycemia.This shows that existing immunosuppressor can't satisfy the needs of clinical treatment, the immunosuppressor of seeking new high-efficiency low-toxicity is still very necessary.
Therefore, the object of the present invention is to provide a kind of safer, more effective immunosuppressive activity compound.
Summary of the invention
The inventor has been found that through research the represented compound of general formula I has immunosuppressive action.It can be used for but be not limited in the organ transplantation anti-immunological rejection, prevent and/or treat some autoimmune disease such as similar rheumatism, psoriasis, multiple sclerosis, systemic lupus erythematous, Crohn disease, ulcerative colitis, big pemphigoid, sarcoidosis and asthma etc.
Therefore, the formula I compound that relates in one aspect to of the present invention, its geometrical isomer or its pharmacologically acceptable salt or hydrate:
Wherein,
Ar is a phenyl, and it is selected from following substituting group replacement: the C of straight or branched
1-C
20Alkoxyl group, phenyl-C
1-C
4Alkoxyl group, this phenyl is optional by straight or branched C
1-C
4Alkyl or halogen replace, perhaps
Ar is an oxazolyl, and it is optional by C
1-C
4Alkyl or C
6-C
10Aryl one or two replaces;
N is 1,2 or 3.
Another aspect of the present invention relates to pharmaceutical composition, and it comprises at least a compound of Formula I or its geometrical isomer or its pharmacologically acceptable salt or hydrate and one or more pharmaceutical carriers or vehicle.
The preparation method who relates in one aspect to formula I compound or its geometrical isomer or its pharmaceutical salts or hydrate more of the present invention.
Further aspect of the present invention relates to said compound and is used to prepare anti-organ transplant rejection and prevents and/or treats some autoimmune disease such as the purposes of the medicine of disease such as similar rheumatism, psoriasis, multiple sclerosis, systemic lupus erythematous.
According to an embodiment of the invention, the present invention relates to formula I compound, its geometrical isomer or its pharmacologically acceptable salt or hydrate:
Wherein:
Ar is a phenyl, and it is selected from following substituting group replacement: the C of straight or branched
1-C
20Alkoxyl group, phenyl-C
1-C
4Alkoxyl group, this phenyl is optional by straight or branched C
1-C
4Alkyl or halogen replace, perhaps
Ar is an oxazolyl, and it is optional by C
1-C
4Alkyl or C
6-C
10Aryl one or two replaces;
N is 1,2 or 3.
According to a preferred implementation of the present invention,
Ar is a phenyl, and it is selected from following substituting group replacement: the C of straight or branched
1-C
10Alkoxyl group, phenyl-C
1-C
4Alkoxyl group, this phenyl is optional by straight or branched C
1-C
4Alkyl or chlorine replace, perhaps
Ar is an oxazolyl, and it is optional by C
1-C
4Alkyl or phenyl one or two replaces;
N is 2.
The compound that the present invention is more preferably following:
Can prepare formula I compound or pharmaceutically acceptable salt thereof of the present invention or hydrate according to following synthetic route:
Synthetic logical method
The compound method of The compounds of this invention comprises with next step:
1) Sodium Nitrite with 2.77M mixes stirring with the 2.3M ethyl cyanacetate; Drip phosphoric acid, keeping the pH of reaction system is 3-3.5, and the reaction times is 2 hours; Reaction finishes to add concentrated hydrochloric acid 150ml and is warming up to 50 ℃, is cooled to 5-0 ℃ then naturally and obtains midbody compound I;
2) the midbody compound I with 1.17M mixes by the volume ratio of 2:1 with saturated sodium bicarbonate aqueous solution, and the mol ratio that adds Sulfothiorine and compound I is 1:3, keeps room temperature reaction 30min, and extraction, drying obtain compound I I;
3) with compound I I with (Boc)
2O joins in the toluene according to the ratio of mol ratio 1:2, adds an amount of triethylamine, back flow reaction 8 hours, and cooling adds isopyknic ETHYLE ACETATE and water extraction, and column chromatography obtains compound III;
4) add triethylamine in the dichloromethane solution with 0.25M raw material A (wherein the definition of Ar and n as stated); Be cooled to 0 ℃; Drip the dichloromethane solution of 12.9M methylsulfonyl chloride; Raw material A: triethylamine: the mol ratio of methylsulfonyl chloride is 10:11:11, insulation reaction 3 hours, separatory, extraction, the dry compound IV that gets;
5) with the anhydrous tetrahydrofuran solution of 0.125M compound IV under nitrogen protection, add anhydrous lithium iodide (2.01g, 15mmol), the mol ratio of compound IV and anhydrous lithium iodide is 1:3 room temperature reaction 24 hours; Stir and add sherwood oil down; Filter, remove solid, removal of solvent under reduced pressure; Drying obtains V;
6) sodium hydride is joined in the dry DMF, stir, drip N-tertbutyloxycarbonyl-2-urea anhydride ETHYLE ACETATE 3, room temperature reaction 30min; Be warming up to 50 ℃, add compound V, sodium hydride: N-tertbutyloxycarbonyl-2-urea anhydride ETHYLE ACETATE 3: the mol ratio of compound V is 10.5:1:1; Insulation reaction 2 hours, 2N hydrochloric acid conditioning solution are neutral, and DMF is removed in decompression; Resistates is dissolved in 60ml ETHYLE ACETATE, anhydrous sodium sulfate drying, and column chromatography obtains compound VI;
7) with the anhydrous tetrahydrofuran solution that adds the 0.27M compound VI in the anhydrous tetrahydrofuran solution of 0.54M tetrahydro boron lithium; The tetrahydro boron lithium: the mol ratio of compound VI is 1:1, and insulation reaction 30 hours adds saturated aqueous ammonium chloride to separating out loose white solid; Filter; Merging filtrate, anhydrous slufuric acid is dry, and column chromatography obtains compound VI I;
8) the methyl chloride solution with 0.24M compound VI I adds trifluoracetic acid, and both volume ratios are 5:1, and stirring at room reaction 24 hours adds closely neutrality of 2N aqueous sodium hydroxide solution regulator solution, extracts, and drying obtains compound VIII.
The concrete operations of synthetic logical method
The compound method of compound I
(50g 0.72mol) is dissolved in 260ml water, and (68g 0.6mol), stirs to add ethyl cyanacetate again with Sodium Nitrite; Drip phosphoric acid, keeping the pH of reaction system is 3-3.5, and about 2 hours, reaction finished; Add concentrated hydrochloric acid 150ml, be warming up to 50 ℃, be cooled to 5-0 ℃ then naturally, separate out white crystal; Filter drying, the 69g that weighs, yield 81%.
The compound method of compound I I
(60g 0.422mol) is added in the 360ml water, adds saturated sodium bicarbonate aqueous solution 180ml, adds Sulfothiorine (204g in batches with I; 1.2mol), finish, keep room temperature reaction 30min; Add dichloromethane extraction 400ml * 3, anhydrous sodium sulfate drying, removing desolvates obtains II; It is orange-yellow oily thing, the 45g that weighs, yield 83.3%.(directly being used for next step reaction).
The compound method of compound III
With II (6.44g, 50mmol) with (Boc)
2(218g 100mmol) joins in the 150ml toluene O, adds an amount of triethylamine, back flow reaction 8 hours; Cooling adds ETHYLE ACETATE 50ml, water 50ml, jolting; Separatory, organic phase with water washing once, salt solution washs once; Anhydrous sodium sulfate drying, (eluent is a sherwood oil: ETHYLE ACETATE=4:1) obtains product 5.6g, yield 49.1% to column chromatography.
The synthetic logical method of compound IV
Raw material A (wherein the definition of Ar and n as stated) (10mmol) is dissolved in the 40ml methylene dichloride, adds triethylamine (1.53ml, 11mmol, ρ=0.725g/ml), be cooled to 0 ℃; (the dichloromethane solution 10ml of ρ=1.47g/ml) finishes insulation reaction 3 hours for 0.85ml, 11mmol to drip methylsulfonyl chloride; Add saturated sodium bicarbonate solution 20ml, stir 10min, separatory, organic layer are again with adding saturated sodium bicarbonate solution 20ml washing once, saturated common salt water washing secondary; Anhydrous sodium sulfate drying, removal of solvent under reduced pressure obtains 2-(4-oxygen in heptan base phenyl) ethanol methanesulfonates, just is oily matter; Place and solidify, drying obtains IV, yield: 90-98.73%.
The synthetic logical method of compound V
IV (5mmol) is dissolved in the 40ml anhydrous tetrahydro furan, nitrogen protection, the adding anhydrous lithium iodide (2.01g, 15mmol); Room temperature reaction 24 hours stirs adding sherwood oil 120ml down, filters, and removes solid; Removal of solvent under reduced pressure, drying obtains V, yield: 95.0-99.0%.
The synthetic logical method of compound VI
(0.15g 63mmol) joins in the dry DMF, stirs, and drips N-tertbutyloxycarbonyl-2-urea anhydride ETHYLE ACETATE III (1.4g with sodium hydride; 6.0mmol), finishing, room temperature reaction 30min is warming up to 50 ℃; Add 5 (6mmol), insulation reaction 2 hours adds a small amount of 2N hydrochloric acid conditioning solution for neutral, and DMF is removed in decompression; Resistates is dissolved in 60ml ETHYLE ACETATE, water 20ml * 2 washing then, saturated common salt water washing once, anhydrous sodium sulfate drying; Column chromatography obtains VI, and it is an oily matter, yield 70-90%.
The synthetic logical method of compound VI I
(0.12g 5.4mmol) joins in the 10ml anhydrous tetrahydro furan, adds the anhydrous tetrahydrofuran solution 20ml of 6 (5.4mmol), insulation reaction 30 hours with the tetrahydro boron lithium; It is a small amount of to add saturated aqueous ammonium chloride, separates out loose white solid, filters, and filter cake is with 20ml THF making beating washing; Filter, merging filtrate, anhydrous slufuric acid is dry, column chromatography (eluent is a sherwood oil: ETHYLE ACETATE=4:1); Obtain VII, it is a white solid, yield 85.40 ± 5%.
The synthetic logical method of compound VIII
VII (4.78mmol) is joined adding trifluoracetic acid 4ml in the 20ml methyl chloride, and stirring at room reaction 24 hours adds closely neutrality of 2N aqueous sodium hydroxide solution regulator solution, adds entry 10ml; Jolting, separatory, water with the 20ml dichloromethane extraction once merge organic phase; Use the saturated aqueous common salt washed twice, anhydrous sodium sulfate drying, removal of solvent under reduced pressure obtains white solid; Re-crystallizing in ethyl acetate, drying obtains VIII, yield 60.02 ± 10%.
Through experiment confirm, general formula of the present invention (I) compound can be used for preventing and/or treating autoimmune disease or anti-organ transplant rejection.Wherein said autoimmune disease is similar rheumatism, psoriasis, multiple sclerosis, systemic lupus erythematous etc.
The compound of general formula I of the present invention or its pharmaceutically useful salt can use separately; Or use with the form of pharmaceutical composition with pharmaceutically useful carrier or vehicle; When using with the form of pharmaceutical composition; Usually the compound of Formula I of the present invention of effective dose or its pharmacologically acceptable salt or hydrate and one or more pharmaceutically acceptable carrier or thinner are combined to process suitable administration form or dosage form, this program comprises through suitable manner component mixing, granulation, compression or dissolving.Therefore, the invention provides pharmaceutical composition, it comprises compound, its geometrical isomer or pharmacy acceptable salt or the hydrate and at least a pharmaceutically useful carrier of general formula I.
According to the present invention, the pharmaceutical composition of The compounds of this invention can be used with following any-mode: oral, spraying sucks; Rectal application, nasal cavity applied medicine, cheek medication; Vagina medicinal; Local application, in non-enterally administer such as subcutaneous, vein, intramuscular, intraperitoneal, the sheath, in the ventricle, in the breastbone and intracranial injection or input, or by the medication of a kind of outer planting reservoir.Wherein preferred oral, intraperitoneal or intravenously medication and local application method.
When medicine for oral use, The compounds of this invention can be made into oral acceptable dosage form arbitrarily, includes but not limited to tablet, capsule, the aqueous solution or aqeous suspension.Wherein, the general carrier that uses of tablet comprises lactose and W-Gum, also can add lubricant such as Magnesium Stearate in addition.The general thinner that uses of capsule preparations comprises lactose and dried corn starch.Aqueous suspension preparation then normally mixes use with activeconstituents with examples of suitable emulsifiers and suspension agent.If desired, also can add some sweeting agents in the above oral prepns form, perfume compound or tinting material.
When rectal application, The compounds of this invention generally can be made into the form of suppository, and it makes through medicine is mixed with a kind of suitable non-irritating excipient.This vehicle at room temperature presents solid state, and fusing disengages medicine under rectal temperature.This type vehicle comprises theobroma oil, beeswax and polyoxyethylene glycol.
During the Where topical medication; Particularly treat local external application easy to reach and suffer from face or organ; During like eyes, skin or lower intestinal tract nervous system disease, The compounds of this invention can be processed different local application's dosage forms according to different trouble faces or organ, specifies as follows:
When the eye topical application, The compounds of this invention can be mixed with the dosage form of a kind of micronization suspension-s or solution, and the carrier that uses is the Sterile Saline of isoosmotic certain pH, wherein can add also not adding preservative agent such as zephiran chloride alkoxide.For eye usefulness, also can compound be processed paste form such as vaseline paste in addition.
When topical application, The compounds of this invention can be made into suitable ointment, lotion or creme dosage form, and wherein activeconstituents suspends or is dissolved in one or more carriers.Here the spendable carrier of ointment formulation includes but not limited to: MO, Albolene, white vaseline, Ucar 35, polyoxyethylene, polyoxytrimethylene, emulsifying wax and water; The spendable carrier of lotion or creme includes but not limited to: MO, and sorbitan monostearate, polysorbate60, the n-Hexadecane ester type waxes, cetene is fragrant and mellow, 2-Standamul G, benzyl alcohol and water.
When the lower intestinal tract topical application, The compounds of this invention can be made into aforesaid rectal suppository preparation or suitable enema agent form, also can use the topical transdermal patch in addition.
The all right aseptic injection preparation form medication of The compounds of this invention comprises aseptic injection water or oil suspension, or aseptic injectable solution.Wherein, spendable carrier and solvent comprise water, Ringer's solution and isotonic sodium chlorrde solution.In addition, the fixed oil of sterilization also can be used as solvent or suspension medium, like direactive glyceride or two glyceryl ester.
In addition, The compounds of this invention also can be used with other immunosuppressive drug, and these materials include but not limited to: cyclosporin A, steroid hormone, FK506, RPM, Leflunomide, DSG, SKF105685MZ, RS61443BQR etc.
It may be noted that in addition; The compounds of this invention is decided by many factors to different patients' specific using dosage and method of use, comprises activity intensity, Time of Administration, metabolic rate, the severity of illness and diagnosis and treatment doctor's the subjective judgement of patient's age, body weight, sex, natural health situation, nutritional status, compound.Preferred using dosage is between 0.01～300mg/kg body weight/day.
Embodiment
Following embodiment is with further explain the present invention, but the present invention is not constituted any limitation.
Melting point compound is measured by RY-1 type fusing point appearance, and TM is without calibration.
1H-NMR is measured by the ARX-400NMR appearance.Mass spectrum is measured by Micromass-ZabSpec MS appearance.Respond is unreceipted all through the stdn pre-treatment with solvent.
Embodiment 1 4-[2-(4-octyloxyphenyl)-ethyl]-2-oxo-1,3-oxazolidine-4-methane amide
1.1 cyanic acid glyoxylic acid oxime ethyl ester I
(50g 0.72mol) is dissolved in 260ml water, and (68g 0.6mol), stirs to add ethyl cyanacetate again with Sodium Nitrite; Drip phosphoric acid, keeping the pH of reaction system is 3-3.5, and about 2 hours, reaction finished; Add concentrated hydrochloric acid 150ml, be warming up to 50 ℃, be cooled to 5-0 ℃ then naturally, separate out white crystal; Filter drying, the 69g that weighs, yield 81%.
1.2 N-tertbutyloxycarbonyl-2-urea anhydride ETHYLE ACETATE III
(60g 0.422mol) is added in the 360ml water, adds saturated sodium bicarbonate aqueous solution 180ml with cyanic acid glyoxylic acid oxime ethyl ester (14); Add Sulfothiorine (204g 1.2mol), finishes in batches; Keep room temperature reaction 30min, add dichloromethane extraction 400ml * 3, anhydrous sodium sulfate drying; Removing desolvates obtains orange-yellow oily thing 45g, yield 83.3%.(directly being used for next step reaction)
To go up one the step oily matter (6.44g, 50mmol) with (Boc)
2(218g 100mmol) joins in the 150ml toluene O, adds an amount of triethylamine, back flow reaction 8 hours; Cooling adds ETHYLE ACETATE 50ml, water 50ml, jolting; Separatory, organic phase with water washing once, salt solution washs once; Anhydrous sodium sulfate drying, (eluent is a sherwood oil: ETHYLE ACETATE=4:1) obtains product 5.6g, yield 49.1% to column chromatography.
1H-NMR(400MHz，CDCl
3)δ(ppm)：7.35-7.37(m，5H)，5.60-5.62(d，1H)，5.29-5.31(d，1H)，4.34-4.39(q，2H)，1.34-1.38(t，3H).
1.3 2-(4-octyloxyphenyl) ethanol
With p-hydroxyphenylethanol (1.38g, 10mmol) and Anhydrous potassium carbonate (2.07g 15mmol) add to arrive among the DMF (50ml), stirs to add the 1-bromooctane down; Be warming up to 65-70 ℃ of reaction and spend the night, filter, filtrate decompression is removed most of DMF; Add 30ml ETHYLE ACETATE and 15ml water, jolting, separatory; Water merges organic phase, with saturated common salt water washing secondary with 15ml ethyl acetate extraction secondary; Anhydrous sodium sulfate drying, (the eluent sherwood oil: ETHYLE ACETATE=6:1) obtain 2-(4-octyloxyphenyl) ethanol, it is a white solid to column chromatography.The 1.80g that weighs, yield 71.89%.
1H-NMR(400MHz，CDCl
3)δ(ppm)：7.12-7.14(d，2H)6.82-6.84(d，2H)，3.91-3.94(t，2H)，3.80-3.83(t，2H)，2.79-2.82(t，2H)，1.73-1.78(m，2H)，1.29-1.46(m，11H)，0.86-0.89(t，3H).
1.4 2-(4-octyloxyphenyl) ethanol methanesulfonates
(2.50g 10mmol) is dissolved in the 40ml methylene dichloride, adds triethylamine (1.53ml, 11mmol, ρ=0.725g/ml) with 2-(4-octyloxyphenyl) ethanol; Be cooled to 0 ℃, (the dichloromethane solution 10ml of ρ=1.47g/ml) finishes for 0.85ml, 11mmol to drip methylsulfonyl chloride; Insulation reaction 3 hours adds saturated sodium bicarbonate solution 20ml, stirs 10min, and separatory, organic layer are again with adding saturated sodium bicarbonate solution 20ml washing once; Saturated common salt water washing secondary, anhydrous sodium sulfate drying, removal of solvent under reduced pressure obtains 2-(4-oxygen in heptan base phenyl) ethanol methanesulfonates; Be oily matter just, place and solidify drying, the 3.10g yield of weighing: 94.40%.Directly be used for next step reaction.
1H-NMR(400MHz，CDCl
3)δ(ppm)：7.80-7.82(m，2H)，7.60-7.64(m，1H)，7.48-7.52(t，2H)6.99-6.02(d，2H)，6.67-6.79(m，2H)，4.16-4.20(t，3H)，3.90-3.93(t，2H)，2.88-2.91(t，2H)，1.73-1.79(m，2H)，1.31-1.46(m，10H)，0.87-0.91(t，3H).
1.5 1-octyloxy-4-(2-iodine ethyl) benzene
(1.64g 5mmol) is dissolved in the 40ml anhydrous tetrahydro furan, and nitrogen protection adds anhydrous lithium iodide (2.01g with 2-(4-octyloxyphenyl) ethanol methanesulfonates; 15mmol), room temperature reaction 24 hours stirs adding sherwood oil 120ml down; Filter, remove solid, removal of solvent under reduced pressure obtains 1-oxygen in heptan base-4-(2-iodine ethyl) benzene; Drying, the 1.64g that weighs, yield: 91.11%.
1H-NMR(400MHz，CDCl
3)δ(ppm)：7.12-7.14(d，2H)6.82-6.84(d，2H)，3.91-3.94(t，2H)，3.29-3.33(t，2H)，3.10-3.13(t，2H)，1.73-1.78(m，2H)，1.29-1.46(m，11H)，0.86-0.89(t，3H).
1.6 uncle's 2-fourth oxygen amido-2-cyanic acid-4-(4-octyloxyphenyl) ethyl n-butyrate
(0.15g 63mmol) joins in the dry DMF, stirs, and drips N-tertbutyloxycarbonyl-2-urea anhydride ETHYLE ACETATE (28) (1.4g with sodium hydride; 6.0mmol), finishing, room temperature reaction 30min is warming up to 50 ℃; Adding 1-(2-iodine ethyl)-4-octyloxy benzene (2.2g, 6mmol), insulation reaction 2 hours adds a small amount of 2N hydrochloric acid conditioning solution for neutral; DMF is removed in decompression, and resistates is dissolved in 60ml ETHYLE ACETATE, water 20ml * 2 washings then, and the saturated common salt water washing is once; Anhydrous sodium sulfate drying, column chromatography obtains oily matter, the 2.5g that weighs, yield 90.0%.
1H-NMR(400MHz，CDCl
3)δ(ppm)：7.10-7.12(d，2H)，6.70-6.75(d，2H)，5.25(s，1H)，4.29-4.34(q，2H)，3.91-3.94(t，2H)，2.75-2.79(t，2H)，1.72-1.79(m，2H)，1.28-1.47(m，24H)，0.87-0.90(t，3H).
[1.7 1-cyanic acid-1-methylol-3-(4-octyloxyphenyl) propyl group] t-butyl carbamate
(0.12g 5.4mmol) joins in the 10ml anhydrous tetrahydro furan, adds uncle's 2-fourth oxygen amido-2-cyanic acid-4-(4-octyloxyphenyl) ethyl n-butyrate (2.5g with the tetrahydro boron lithium; 5.4mmol) anhydrous tetrahydrofuran solution 20ml, insulation reaction 30 hours, it is a small amount of to add saturated aqueous ammonium chloride; Separate out loose white solid, filter, filter cake is with 20ml THF making beating washing; Filter, merging filtrate, anhydrous slufuric acid is dry; (eluent is a sherwood oil to column chromatography: ETHYLE ACETATE=4:1), obtain white solid 1.93g, yield 85.40%.
1H-NMR(400MHz，CDCl
3)δ(ppm)：7.08-7.10(d，2H)，6.78-6.80(d，2H)，4.95(brs，1H)，3.92-3.95(m，4H)，2.79-2.82(m，2H)，2.22-2.26(m，2H)，1.73-1.78(m，2H)，1.28-1.47(m，20H)，0.87-0.90(t，3H).
1.8 4-[2-(4-octyloxyphenyl)-ethyl]-2-oxo-1,3-oxazolidine-4-methane amide
(2.0g 4.78mmol) joins adding trifluoracetic acid 4ml in the 20ml methyl chloride, and stirring at room reaction 24 hours adds closely neutrality of 2N aqueous sodium hydroxide solution regulator solution with [1-cyanic acid-1-methylol-3-(4-octyloxyphenyl) propyl group] t-butyl carbamate (embodiment 1); Add entry 10ml, jolting, separatory, water are with the 20ml dichloromethane extraction once; Merge organic phase, use the saturated aqueous common salt washed twice, anhydrous sodium sulfate drying; Removal of solvent under reduced pressure obtains white solid, re-crystallizing in ethyl acetate; Drying obtains 1.04g, yield 60.02%.EI-MS(m/e)：[M+]＝362；
1H-NMR(400MHz，DMSO-d
6)δ(ppm)：8.24(s，1H)，7.47(s，2H)，7.06-7.08(d，2H)，6.81-6.83(d，2H)，4.33-4.35(d，1H)，4.17-4.19(d，1H)，2.54-2.60(m，1H)，2.30-2.38(m，1H)，1.98-2.06(m，1H)，1.82-1.90(m，1H)，1.64-1.71(m，2H)，1.25-1.40(m，10H)，0.84-0.87(t，3H).
Embodiment 2 4-{2-[4-(4-methyl benzyloxy)-phenyl]-ethyl }-2-oxo-1,3-oxazolidine-4-methane amide
The preparation method is with embodiment 1, and raw material A wherein is 3-[4-(4-methyl benzyloxy) phenyl] propyl alcohol
{ 1-cyanic acid-1-methylol-3-[4-(4-methyl benzyloxy) phenyl] propyl group } t-butyl carbamate and trifluoracetic acid, yield 78.67%, EI-MS (m/e): [M+]=355;
1H-NMR (400MHz, DMSO-d
6) δ (ppm): 8.24 (s, 1H), 7.44-7.47 (d, 2H), 7.30-7.32 (d, 2H), 7.17-7.19 (d; 2H), 7.07-7.09 (d, 2H), 6.89-6.91 (d, 2H), 5.00 (s, 2H); 4.33-4.35 (d, 1H), 4.17-4.19 (d, 1H), 2.54-2.60 (m, 1H), 2.30-2.38 (m; 1H), 2.29 (s, 3H), 1.98-2.06 (m, 1H), 1.82-1.90 (m, 1H).
Embodiment 3 4-[2-(4-oxygen in last of the ten Heavenly stems base phenyl)-ethyl]-2-oxo-1,3-oxazolidine-4-methane amide
The preparation method is with embodiment 1, and raw material A wherein is 2-(4-oxygen in last of the ten Heavenly stems base phenyl)-ethanol
[1-cyanic acid-3-(4-oxygen in last of the ten Heavenly stems base phenyl)-1-methylol propyl group] t-butyl carbamate and trifluoracetic acid, yield 68.52%.EI-MS (m/e): [M+]=390;
1H-NMR (400MHz, DMSO-d6) δ (ppm): 8.19 (s, 1H), 7.45-7.47 (d, 2H), 7.06-7.08 (d, 2H), 6.81-6.83 (d; 2H), and 4.33-4.36 (d, 1H), 4.17-4.19 (d, 1H), 3.88-3.90 (t, 2H); 2.56-2.62 (m, 1H), 2.30-2.38 (m, 1H), 1.98-2.06 (m, 1H), 1.83-1.90 (m; 1H), 1.63-1.70 (m, 2H), 1.28-1.42 (m, 14H), 0.87-0.90 (t, 3H).
13C-NMR (100MHz, DMSO-d
6) δ (ppm): 173.9 (1C), 157.7 (1C), 156.9 (1C), 132.7 (1C), 129.0 (2C), 114.3 (2C); 71.6 (1C), 67.2 (1C), 63.7 (1C), 31.2 (1C), 28.9 (2C); 28.6 (3C), 28.4 (2C), 25.4 (1C), 22.0 (1C), 13.9 (1C).
Embodiment 4 4-[2-(3-oxygen in last of the ten Heavenly stems base phenyl)-ethyl]-2-oxo-1,3-oxazolidine-4-methane amide
The preparation method is with embodiment 1, and raw material A wherein is 2-(3-oxygen in last of the ten Heavenly stems base phenyl)-ethanol
[1-cyanic acid-3-(3-oxygen in last of the ten Heavenly stems base phenyl)-1-methylol propyl group] t-butyl carbamate and trifluoracetic acid, yield 71.64%.EI-MS (m/e): [M+]=390;
1H-NMR (400MHz, DMSO-d
6) δ (ppm): 8.14 (s, 1H), 7.42-7.45 (d, 2H), 7.14-7.17 (t, 1H), 6.72-6.74 (m; 3H), and 4.34-4.36 (d, 1H), 3.90-3.92 (d, 1H), 2.58-2.64 (m, 1H); 2.34-2.41 (m, 1H), 2.01-2.08 (m, 1H), 1.88-1.95 (m, 1H); 1.64-1.71 (m, 2H), 1.25-1.40 (m, 14H), 0.84-0.87 (t, 3H).
Embodiment 5 4-{2-[4-(4-chlorine benzyloxy)-phenyl]-ethyl }-2-oxo-1,3-oxazolidine-4-methane amide
The preparation method is with embodiment 1, and raw material A wherein is 2-[4-(4-chlorine benzyloxy)-phenyl]-ethanol
3-[4-(4-chlorine benzyloxy) phenyl]-1-cyanic acid-1-methylol propyl group } t-butyl carbamate and trifluoracetic acid, yield 69.76%.EI-MS (m/e): [M+]=374;
1H-NMR (400MHz, DMSO-d
6) δ (ppm): 8.14 (s, 1H), 7.41-7.45 (m, 6H), 7.08-7.10 (d, 2H), 6.90-6.92 (d, 2H); 5.00 (s, 2H), 4.33-4.35 (d, 1H), 4.17-4.19 (d, 1H), 2.54-2.60 (m; 1H), 2.30-2.38 (m, 1H), 1.98-2.06 (m, 1H), 1.82-1.90 (m, 1H).
Embodiment 6 4-{2-[4-(3-phenyl propoxy-)-phenyl]-ethyl }-2-oxo-1,3-oxazolidine-4-methane amide
The preparation method is with embodiment 1, and raw material A wherein is 2-[4-(3-phenyl propoxy-)-phenyl]-ethanol
{ 1-cyanic acid-1-methylol-3-[4-(3-phenyl propoxy-) phenyl] propyl group } t-butyl carbamate and trifluoracetic acid, yield 68.71%.EI-MS (m/e): [M+]=368;
1H-NMR (400MHz, DMSO-d
6) δ (ppm): 8.17 (s, 1H), 7.44-7.47 (d, 2H), 7.16-7.30 (m, 5H), 7.07-7.9 (d; 2H), and 6.83-6.85 (d, 2H), 4.33-4.35 (d, 1H), 4.17-4.19 (d, 1H); 3.89-3.91 (t, 2H), 2.71-2.73 (t, 2H), 2.54-2.60 (m, 1H); 2.30-2.38 (m, 1H), 1.98-2.06 (m, 1H), 1.82-1.90 (m, 1H).
Embodiment 7 4-{2-[4-(2-methyl benzyloxy)-phenyl]-ethyl }-2-oxo-1,3-oxazolidine-4-methane amide
The preparation method is with embodiment 1, and raw material A wherein is 2-[4-(2-methyl benzyloxy)-phenyl]-ethanol
{ 1-cyanic acid-1-methylol-3-[4-(2-methyl benzyloxy) phenyl] propyl group } t-butyl carbamate and trifluoracetic acid, yield 71.82%.EI-MS(m/e)：[M+]＝355；
1H-NMR(400MHz，DMSO-d
6)δ(ppm)：8.14(s，1H)，7.37-7.45(m，3H)，7.16-7.26(d，3H)，7.10-7.12(d，2H)，6.90-6.92(d，2H)，5.03(s，2H)，4.34-4.36(d，1H)，4.17-4.19(d，1H)，2.54-2.60(m，1H)，2.32-2.40(m，1H)，2.31(s，3H)，1.98-2.06(m，1H)，1.82-1.90(m，1H).
Embodiment 8 4-{2-[4-(2-chlorine benzyloxy)-phenyl]-ethyl }-2-oxo-1,3-oxazolidine-4-methane amide
The preparation method is with embodiment 1, and raw material A wherein is 2-[4-(2-chlorine benzyloxy)-phenyl]-ethanol
{ 3-[4-(2-chlorine benzyloxy) phenyl]-1-cyanic acid-1-methylol propyl group } t-butyl carbamate and trifluoracetic acid, yield 52.21%EI-MS (m/e): [M+]=375;
1H-NMR (400MHz, CDCl
3) δ (ppm): 7.53-7.55 (m, 1H), 7.38-7.41 (m, 1H), 7.27-7.32 (m, 2H), 7.10-7.14 (d; 2H), 6.92-6.94 (d, 2H), 6.57 (brs, 1H), 5.96 (brs, 1H); 5.67 (brs, 1H), 5.14 (s, 2H), 4.55-4.58 (d, 1H), 4.23-4.26 (d; 1H), 2.59-2.72 (m, 2H), 2.40-2.46 (m, 1H), 2.05-2.07 (m, 1H).
Embodiment 9 4-{2-[3-(3-phenyl propoxy-)-phenyl]-ethyl }-2-oxo-1,3-oxazolidine-4-methane amide
The preparation method is with embodiment 1, and raw material A wherein is 2-[3-(3-phenyl propoxy-)-phenyl]-ethanol
{ 1-cyanic acid-1-methylol-3-[3-(3-phenyl propoxy-) phenyl] propyl group } t-butyl carbamate and trifluoracetic acid, yield 57.58%.EI-MS (m/e): [M+]=374;
1H-NMR (400MHz, CDCl
3) δ (ppm): 7.19-7.27 (m, 6H), 6.72-6.75 (m, 3H), 6.64 (brs1H), 5.87 (brs, 1H); 5.67 (brs, 1H), 4.59-4.61 (d, 1H), 3.91-3.94 (d, 1H), 2.78-2.82 (t; 4H), and 2.61-2.67 (m, 2H), 2.40-2.46 (m, 2H), 2.07-2.11 (m, 2H)
Embodiment 10 4-{2-[4-(3-methyl butoxy)-phenyl]-ethyl }-2-oxo-1,3-oxazolidine-4-methane amide
The preparation method is with embodiment 1, and raw material A wherein is 2-[4-(3-methyl butoxy)-phenyl]-ethanol
{ 1-cyanic acid-1-methylol-3-[4-(3-methyl butoxy) phenyl] propyl group } t-butyl carbamate and trifluoracetic acid, yield 66.53%.EI-MS(m/e)：[M+]＝320；
1H-NMR(400MHz，DMSO-d
6)δ(ppm)：8.14(s，1H)，7.46-7.48(d，2H)，7.16-7.18(d，1H)，6.73-6.75(d，3H)，4.34-4.36(d，1H)，4.17-4.19(d，1H)，3.94-3.96(t，2H)，2.58-2.65(m，1H)，2.33-2.40(m，1H)，2.02-2.06(m，1H)，1.91-1.95(m，1H)，1.74-1.79(m，1H)，1.56-1.61(q，2H)，0.90-0.935(d，6H).
Embodiment 11 4-[2-(3-oxygen in ninth of the ten Heavenly Stems base phenyl)-ethyl]-2-oxo-1,3-oxazolidine-4-methane amide
The preparation method is with embodiment 1, and raw material A wherein is 2-(3-oxygen in ninth of the ten Heavenly Stems base phenyl)-ethanol
[1-cyanic acid-1-methylol-3-(3-oxygen in ninth of the ten Heavenly Stems base phenyl) propyl group] t-butyl carbamate and trifluoracetic acid, yield 47.48%.EI-MS (m/e): [M+]=376;
1H-NMR (400MHz, DMSO-d
6) δ (ppm): 8.14 (s, 1H), 7.45-7.48 (d, 2H), 7.15-7.17 (t, 1H), 6.72-6.74 (m; 3H), and 4.34-4.36 (d, 1H), 4.19-4.21 (d, 1H), 3.90-3.92 (t, 2H); 2.58-2.64 (m, 1H), 2.34-2.41 (m, 1H), 2.01-2.08 (m, 1H), 1.88-1.95 (m; 1H), 1.64-1.71 (m, 2H), 1.25-1.40 (m, 12H), 0.84-0.87 (t, 3H).
Embodiment 12 4-{2-[4-(4-tertiary butyl benzyloxy)-phenyl]-ethyl }-2-oxo-1,3-oxazolidine-4-methane amide
The preparation method is with embodiment 1, and raw material A wherein is 2-[4-(4-tertiary butyl benzyloxy)-phenyl]-ethanol
{ 1-cyanic acid-1-methylol-3-[4-(4-tertiary butyl benzyloxy) phenyl] propyl group } t-butyl carbamate and trifluoracetic acid, yield 79.70%, EI-MS (m/e): [M+]=396;
1H-NMR (400MHz, DMSO-d
6) δ (ppm): 8.14 (s, 1H), 7.33-7.44 (m, 6H), 7.08-7.10 (d, 2H); 6.90-6.92 (d, 2H), 5.00 (s, 2H), 4.33-4.35 (d, 1H); 4.17-4.19 (d, 1H), 2.54-2.60 (m, 1H), 2.30-2.38 (m, 1H); 1.98-2.06 (m, 1H), 1.82-1.90 (m, 1H), 1.27 (s, 9H).
Embodiment 13 4-[2-(3-octyloxyphenyl)-ethyl]-2-oxo-1,3-oxazolidine-4-methane amide
The preparation method is with embodiment 1, and raw material A wherein is 2-(3-octyloxyphenyl)-ethanol
[1-cyanic acid-1-methylol-3-(3-octyloxyphenyl) propyl group] t-butyl carbamate and trifluoracetic acid, yield 65.14%, EI-MS (m/e): [M+]=352;
1H-NMR (400MHz, CDCl
3) δ (ppm): 7.19-7.23 (t, 1H), 6.72-6.77 (m, 3H), 6.63 (brs, 1H), 6.10 (brs, 1H); 5.74 (brs, 1H), 4.57-4.59 (d, 1H), 4.24-4.26 (d, 1H), 3.90-3.94 (t, 2H); 2.68-2.78 (m, 1H), 2.57-2.65 (m, 1H), 2.43-2.49 (m, 1H), 2.07-2.12 (m; 1H), 1.73-1.80 (m, 2H), 1.25-1.44 (m, 10H), 0.87-0.90 (t, 3H).
Embodiment 14 4-[2-(4-methyl-2-phenyl-oxazoles-5-yl)-ethyl]-2-oxo-1,3-oxazolidine-4-methane amide
The preparation method is with embodiment 1, and raw material A wherein is 2-(4-methyl-2-phenyl-oxazoles-5-yl)-ethanol
[1-cyanic acid-1-methylol-3-(4-methyl-2-Ben Ji oxazole-5-yl) propyl group] t-butyl carbamate and trifluoracetic acid, yield 68.30%, EI-MS (m/e): [M+]=315;
1H-NMR (400MHz, DMSO-d
6) δ (ppm): 8.24 (s, 1H), 7.89-7.91 (m, 2H), 7.48-7.50 (m, 5H), 4.43-4.46 (d, 1H), 4.19-4.22 (d, 1H), 2.51-2.62 (m, 1H), 2.27-2.35 (m, 3H), 2.12-2.19 (m, 1H), 1.88-1.96 (m, 1H).
The activity rating of embodiment 15 compounds
Evaluation method
EGFP-S1P1_U2OS cell 0.8 * 10
4/ hole kind 96 hole fluorescent plates, 37 ℃ of 5% CO
2Cultivate 18-24h, wash once, add the analysis nutrient solution that 150 μ l/ holes contain degreasing BSA with analyzing nutrient solution 100 μ l/ holes; Cultivate 2h for 37 ℃, add 50 μ l/ holes, 4 * compound, establish solvent control; Cultivate 1h for 37 ℃, last machine testing, every hole is according to 3-4 the visual field; Analysing particulates forms, the exciting multiple of computerized compound.
The activity rating result
The result shows, compound of the present invention all has and is better than or near the immunosuppressive activity of positive drug FTY720, can be developed as one type of new immunosuppressor.
Claims (3)
1. following compound, or its geometrical isomer, or its pharmacologically acceptable salt:
4-[2-(4-octyloxyphenyl)-ethyl]-2-oxo-1,3-oxazolidine-4-methane amide
4-{2-[4-(4-methyl benzyloxy)-phenyl]-ethyl }-2-oxo-1,3-oxazolidine-4-methane amide
4-[2-(4-oxygen in last of the ten Heavenly stems base phenyl)-ethyl]-2-oxo-1,3-oxazolidine-4-methane amide
4-[2-(3-oxygen in last of the ten Heavenly stems base phenyl)-ethyl]-2-oxo-1,3-oxazolidine-4-methane amide;
4-{2-[4-(4-chlorine benzyloxy)-phenyl]-ethyl }-2-oxo-1,3-oxazolidine-4-methane amide;
4-{2-[4-(3-phenyl propoxy-)-phenyl]-ethyl }-2-oxo-1,3-oxazolidine-4-methane amide;
4-{2-[4-(2-methyl benzyloxy)-phenyl]-ethyl }-2-oxo-1,3-oxazolidine-4-methane amide;
4-{2-[4-(2-chlorine benzyloxy)-phenyl]-ethyl }-2-oxo-1,3-oxazolidine-4-methane amide;
4-{2-[3-(3-phenyl propoxy-)-phenyl]-ethyl }-2-oxo-1,3-oxazolidine-4-methane amide;
4-{2-[4-(3-methyl butoxy)-phenyl]-ethyl }-2-oxo-1,3-oxazolidine-4-methane amide;
4-[2-(3-oxygen in ninth of the ten Heavenly Stems base phenyl)-ethyl]-2-oxo-1,3-oxazolidine-4-methane amide;
4-{2-[4-(4-tertiary butyl benzyloxy)-phenyl]-ethyl }-2-oxo-1,3-oxazolidine-4-methane amide;
4-[2-(3-octyloxyphenyl)-ethyl]-2-oxo-1,3-oxazolidine-4-methane amide; With
4-[2-(4-methyl-2-phenyl-oxazoles-5-yl)-ethyl]-2-oxo-1,3-oxazolidine-4-methane amide.
2. the described compound of claim 1 is used to prepare the purposes of the medicine that prevents and/or treats autoimmune disease or anti-organ transplant rejection.
3. the purposes of claim 2, wherein said autoimmune disease is similar rheumatism, psoriasis, multiple sclerosis, systemic lupus erythematous.
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| PCT/CN2009/001391 WO2010066100A1 (en) | 2008-12-08 | 2009-12-08 | The 2-oxo-1,3-oxaazocyclopentane-4-formamide derivatives and their uses as the immunosuppressant. |
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| DE1158075B (en) * | 1961-04-07 | 1963-11-28 | Basf Ag | Process for the preparation of 4, 5, 5-trisubstituted oxazolidone- (2) -carboxamides- (4) |
| WO2007092638A1 (en) * | 2006-02-09 | 2007-08-16 | University Of Virginia Patent Foundation | Bicyclic sphingosine 1-phosphate analogs |
| CN101184739A (en) * | 2005-06-08 | 2008-05-21 | 诺瓦提斯公司 | Polycyclic oxadiazoles or isoxazoles and their use as S1P receptor ligands |
| CN101291908A (en) * | 2005-08-23 | 2008-10-22 | Irm责任有限公司 | Immunosuppressant compounds and compositions |
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|---|---|---|---|---|
| DE1158075B (en) * | 1961-04-07 | 1963-11-28 | Basf Ag | Process for the preparation of 4, 5, 5-trisubstituted oxazolidone- (2) -carboxamides- (4) |
| CN101184739A (en) * | 2005-06-08 | 2008-05-21 | 诺瓦提斯公司 | Polycyclic oxadiazoles or isoxazoles and their use as S1P receptor ligands |
| CN101291908A (en) * | 2005-08-23 | 2008-10-22 | Irm责任有限公司 | Immunosuppressant compounds and compositions |
| WO2007092638A1 (en) * | 2006-02-09 | 2007-08-16 | University Of Virginia Patent Foundation | Bicyclic sphingosine 1-phosphate analogs |
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