CN103724281A - Novel derivative of N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-propyl and application of novel derivative - Google Patents
Novel derivative of N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-propyl and application of novel derivative Download PDFInfo
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- CN103724281A CN103724281A CN201310643198.0A CN201310643198A CN103724281A CN 103724281 A CN103724281 A CN 103724281A CN 201310643198 A CN201310643198 A CN 201310643198A CN 103724281 A CN103724281 A CN 103724281A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
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Abstract
The invention discloses a novel derivative of N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-propyl and application of the novel derivative. The novel derivative has good medicine activity, can greatly prolong the half-life period of a medicine, prolongs the retention time of the medicine in a human body, and meanwhile, improves the concentration of the medicine in blood; therefore, a better curative effect is achieved. As the half-life period of the medicine is greatly prolonged, activity concentration of the medicine in the blood can be maintained for a longer period of time; under the cure condition of dose constrain, the curative effect is maintained and the dosage of the medicine is reduced, so that the problem of bad metabolism of the medicine is eliminated, the medicine toxicity is reduced, and the toxic and side effects in the medicine use process are reduced.
Description
Technical field
The present invention relates to a kind of derivative and application thereof of compound, belong to technical field of pharmaceuticals.
Background technology
Pulmonary hypertension (PAH) is a chronic disease, and what this disease was gradual can debilitating disease, and severe patient can cause death or need lung transplantation.Pulmonary hypertension is to connect heart to the Arterial Hypertention of lung, and it causes that the work when normal of the right heart is more difficult, can cause the ability of constrained motion and breathe hard.The feature of this disease is the abnormal hypertension of artery between the heart of diseased individuals and lung, and symptom scope can be from slight expiratory dyspnea and tired to serious constrained motion ability until finally reduce the life-span.On October 13rd, 2013, U.S. food Drug Administration (FDA) has ratified a kind of medicine and has been used for the treatment of pulmonary hypertension patient, and the chemical name of this medicine is: N-[5-(4-bromophenyl) the bromo-2-pyrimidyl of-6-[2-[(5-) oxygen base] oxyethyl group]-4-pyrimidyl]-N'-sulfonyl propyl amine.Trade name: Macitentan.Macitentan is as a dual endothelin-receptor antagonists, and it act as lax pulmonary artery, lowers blood pressure in lung, delays progression of disease.Progression of disease comprises: death, vein or the beginning of subcutaneous prostaglandin(PG) or the clinical deterioration rates of pulmonary hypertension, also can reduce pulmonary hypertension and be in hospital.Due to when using Macitentan to treat, conventionally in order to reach result for the treatment of, strengthen dosage, cause producing a lot of poor metabolism problems, the active metabolite producing by bad metabolic reaction due to medicine normally medicine produces the important factor of toxicity and other side effects, thereby can produce more side effect to human body in therapeutic process, use the untoward reaction that can make patient produce in Macitentan therapeutic process to have: anaemia, rhinopharyngitis/pharyngitis, bronchitis, headache, influenza and urinary tract infection.
Summary of the invention
The object of the invention is to overcome defect of the prior art, N-[5-(4-bromophenyl is provided) the bromo-2-pyrimidyl of-6-[2-[(5-) oxygen base] oxyethyl group]-4-pyrimidyl] new derivatives and the application thereof of-N'-sulfonyl propyl amine, the pharmaceutical activity of described derivative is good, the bad metabolic problems that can solve medicine simultaneously, the toxic side effect in medication process is little.
The present invention is achieved by the following technical programs.
N-[5-(4-bromophenyl) the bromo-2-pyrimidyl of-6-[2-[(5-) oxygen base] oxyethyl group]-4-pyrimidyl] new derivatives of-N'-sulfonyl propyl amine, there is the following chemical structure general formula:
R in formula
1, R
2, R
3, R
4, R
5, R
6, R
7be hydrogen or fluorine independently, wherein have one at least for fluorine.
Above-mentioned N-[5-(4-bromophenyl) the bromo-2-pyrimidyl of-6-[2-[(5-) oxygen base] oxyethyl group]-4-pyrimidyl] new derivatives of-N'-sulfonyl propyl amine, wherein, R
1, R
2, R
3, R
4, R
5, R
6, R
7in one or several is fluorine.
Above-mentioned N-[5-(4-bromophenyl) the bromo-2-pyrimidyl of-6-[2-[(5-) oxygen base] oxyethyl group]-4-pyrimidyl] new derivatives of-N'-sulfonyl propyl amine, wherein, R
1, R
2, R
3, R
4, R
5, R
6, R
7be fluorine.
Above-mentioned N-[5-(4-bromophenyl) the bromo-2-pyrimidyl of-6-[2-[(5-) oxygen base] oxyethyl group]-4-pyrimidyl] application of new derivatives of-N'-sulfonyl propyl amine, the application of described derivative in the medicine of preparation treatment pulmonary hypertension disease.
N-[5-(4-bromophenyl of the present invention) the bromo-2-pyrimidyl of-6-[2-[(5-) oxygen base] oxyethyl group]-4-pyrimidyl] new derivatives of-N'-sulfonyl propyl amine can be used as the activeconstituents of the medicine for the treatment of pulmonary hypertension disease, in this medicine, also can contain described derivative and pharmaceutically acceptable carrier or the figuration body of significant quantity, make the formulation that is applicable to use.Drug delivery system can be albumin bound type injection liquid, liposome, powder pin, nanoparticle and cyclodextrin inclusion compound etc., form of administration can be injection liquid, also can be solid dosage or semisolid dosage form, as being injection, tablet, wafer, pill, powder or granule etc.
N-[5-(4-bromophenyl of the present invention) the bromo-2-pyrimidyl of-6-[2-[(5-) oxygen base] oxyethyl group]-4-pyrimidyl] new derivatives of-N'-sulfonyl propyl amine can be made into the pharmaceutically acceptable salt that is suitable as medicine, the pharmaceutically acceptable salt that is suitable as medicine refers to the salt that is suitable as medicine that derivative of the present invention and acid or alkali form, and comprises inorganic salt and organic salt.The preferred salt of one class is derivative of the present invention and the sour salt forming.The acid that is applicable to formation salt includes, but are not limited to: the mineral acids such as hydrochloric acid, Hydrogen bromide, hydrofluoric acid, sulfuric acid, nitric acid and phosphoric acid, the organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, picric acid, methylsulfonic acid, benzene methanesulfonic acid and Phenylsulfonic acid; And the acidic amino acid such as aspartic acid, L-glutamic acid.
N-[5-(4-bromophenyl of the present invention) the bromo-2-pyrimidyl of-6-[2-[(5-) oxygen base] oxyethyl group]-4-pyrimidyl] new derivatives of-N'-sulfonyl propyl amine is compared with Macitentan of the prior art, and tool has the following advantages:
(1) better efficacy of derivative of the present invention, it can increase the transformation period of medicine greatly, the time that prolong drug is detained at human body Inner, improves the concentration of blood Chinese traditional medicine simultaneously, thereby reaches better curative effect.
(2) the drug use dosage of derivative of the present invention is less, thereby can eliminate the bad metabolic problems of medicine, because the transformation period of medicine greatly increases and makes medicine can keep for more time active concentration in blood, make under the treatment condition that has dose limitation, the using dosage that can reduce medicine when keeping curative effect, reduces drug toxicity.
(3) toxicity of derivative of the present invention, side effect are still less, the active metabolite producing by bad metabolic reaction due to medicine normally medicine produces the important factor of toxicity and other side effects, eliminate the bad metabolic problems of medicine, greatly reduced toxicity and other side effects of medicine.
Embodiment
By specific embodiment, the specific embodiment of the present invention is described in further detail below.
Embodiment 1
Preparation N-[5-(4-bromophenyl) the bromo-2-pyrimidyl of-6-[2-[(5-) oxygen base] oxyethyl group]-4-pyrimidyl]-N'-seven fluoropropyl sulphonamide.
The preparation of derivative of the present invention comprises sulfuryl amine and 2 steps of etherificate.
Preparation process is as follows:
(1) sulfuryl amine is prepared N-[5-(4-bromophenyl)-6-[2 – hydroxyl-oxethyl]-4-pyrimidyl]-N'-seven fluoropropyl sulphonamide:
Under anhydrous and oxygen-free argon shield; in dry flask, add 4-chloro-[5-(4-bromophenyl)-6-[2 – hydroxyl-oxethyl] pyrimidine and DMSO; under stirring at room, add seven fluoropropyl sulphonamide sodium salts; stirring reaction 48h under stirring at room; then add saturated aqueous common salt cancellation reaction, then add trichloromethane.Organic phase is used respectively saturated common salt water washing, and anhydrous sodium sulfate drying filters, concentrated.Thick product obtains N-[5-(4-bromophenyl through purification by silica gel column chromatography)-6-[2 – hydroxyl-oxethyl]-4-pyrimidyl]-N'-seven fluoropropyl sulphonamide.The mole ratio of 4-chloro-[5-(4-bromophenyl)-6-[2 – hydroxyl-oxethyl] pyrimidine and seven fluoropropyl sulphonamide sodium is 1 ︰ 1-1.2.1 molar 4-chloro-[5-(4-bromophenyl)-6-[2 – hydroxyl-oxethyl] pyrimidine is used the trichloromethane of DMSO, 5-10L and the saturated aqueous common salt of 10-40L of 2-5L.(2) etherification step is prepared target product N-[5-(4-bromophenyl) the bromo-2-pyrimidyl of-6-[2-[(5-) oxygen base] oxyethyl group]-4-pyrimidyl]-N'-seven fluoropropyl sulphonamide.
Under anhydrous and oxygen-free argon shield; in dry flask by N-[5-(4-bromophenyl)-6-[2 – hydroxyl-oxethyl]-4-pyrimidyl]-N'-(seven fluorine) sulfonyl propyl amine is dissolved in trichloromethane; under stirring at room, add the bromo-2-chloropyrimide of sodium hydride and 5-; stirring reaction 1-3h; with the hydrochloric acid soln cancellation reaction of 1 volumetric molar concentration, then add trichloromethane.Organic phase is used respectively saturated common salt water washing, and anhydrous sodium sulfate drying filters, concentrated.Thick product obtains target product N-[5-(4-bromophenyl through purification by silica gel column chromatography) the bromo-2-pyrimidyl of-6-[2-[(5-) oxygen base] oxyethyl group]-4-pyrimidyl]-N'-seven fluoropropyl sulphonamide.N-[5-(4-bromophenyl)-6-[2 – hydroxyl-oxethyl]-4-pyrimidyl]-N'-(seven fluorine) mole ratio of sulfonyl propyl amine and sodium hydride and the bromo-2-chloropyrimide of 5-is 1 ︰ 1-1.2 ︰ 1.2-1.5.1 molar N-[5-(4-bromophenyl)-6-[2 – hydroxyl-oxethyl]-4-pyrimidyl]-N'-seven fluoropropyl sulphonamide use hydrochloric acid, the trichloromethane of 5-10L and the saturated aqueous common salt of 10-40L of 1 volumetric molar concentration of 2-5L.
Embodiment 2
Preparation N-[5-(4-bromophenyl) the bromo-2-pyrimidyl of-6-[2-[(5-) oxygen base] oxyethyl group]-4-pyrimidyl]-N'-(1,1-, bis-fluoropropyls) sulphonamide.
Preparation method, with embodiment 1, replaces with N-(1,1-, bis-fluoropropyls) sulphonamide sodium salt by seven fluoropropyl sulphonamide sodium salts in embodiment 1.
Embodiment 3
Preparation N-[5-(4-bromophenyl) the bromo-2-pyrimidyl of-6-[2-[(5-) oxygen base] oxyethyl group]-4-pyrimidyl]-N'-(3,3,3-trifluoro propyl) sulphonamide.
Preparation method, with embodiment 1, replaces with N-(3,3,3-trifluoro propyl) sulphonamide sodium salt by seven fluoropropyl sulphonamide sodium salts in embodiment 1.
Here description of the invention and application is illustrative, not wants scope of the present invention to limit in the above-described embodiments, and therefore, the present invention is not subject to the restriction of the present embodiment, and the technical scheme that any employing equivalence replacement obtains is all in the scope of protection of the invention.
Claims (4)
1.N-[5-(4-bromophenyl) the bromo-2-pyrimidyl of-6-[2-[(5-) oxygen base] oxyethyl group]-4-pyrimidyl] new derivatives of-N'-sulfonyl propyl amine, it is characterized in that thering is the following chemical structure general formula:
R in formula
1, R
2, R
3, R
4, R
5, R
6, R
7be hydrogen or fluorine independently, wherein have one at least for fluorine.
2. N-[5-(4-bromophenyl as claimed in claim 1) the bromo-2-pyrimidyl of-6-[2-[(5-) oxygen base] oxyethyl group]-4-pyrimidyl] new derivatives of-N'-sulfonyl propyl amine, it is characterized in that R
1, R
2, R
3, R
4, R
5, R
6, R
7in one or several is fluorine.
3. N-[5-(4-bromophenyl as claimed in claim 2) the bromo-2-pyrimidyl of-6-[2-[(5-) oxygen base] oxyethyl group]-4-pyrimidyl] new derivatives of-N'-sulfonyl propyl amine, it is characterized in that R
1, R
2, R
3, R
4, R
5, R
6, R
7be fluorine.
4. the N-[5-(4-bromophenyl as described in any one in claim 1-3) the bromo-2-pyrimidyl of-6-[2-[(5-) oxygen base] oxyethyl group]-4-pyrimidyl] application of new derivatives of-N'-sulfonyl propyl amine, it is characterized in that the application of described derivative in the medicine of preparation treatment pulmonary hypertension disease.
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| CN201310643198.0A CN103724281A (en) | 2013-12-03 | 2013-12-03 | Novel derivative of N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-propyl and application of novel derivative |
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| CN201310643198.0A CN103724281A (en) | 2013-12-03 | 2013-12-03 | Novel derivative of N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-propyl and application of novel derivative |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2017125055A (en) * | 2014-02-14 | 2017-07-20 | アクテリオン ファーマシューティカルズ リミテッドＡｃｔｅｌｉｏｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｌｔｄ | Process for manufacturing pyrimidine sulfamide derivatives |
| TWI643848B (en) * | 2013-07-12 | 2018-12-11 | 艾克泰聯製藥有限公司 | Process for preparing a pyrimidine intermediate |
| CN109232546A (en) * | 2018-09-25 | 2019-01-18 | 中国人民解放军总医院 | A kind of medical usage of pyrimidine sulfonyl amine derivant |
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| CN1524079A (en) * | 2000-12-18 | 2004-08-25 | ������˹ҩƷ��˾ | Novel sulfamides and their use as endothelin receptor antagonists |
| CN101056872A (en) * | 2004-11-11 | 2007-10-17 | 埃科特莱茵药品有限公司 | Sulfamides as endothelin receptor antagonists for the treatment of cardiovascular diseases |
| CN100379730C (en) * | 2002-12-02 | 2008-04-09 | 埃科特莱茵药品有限公司 | Pyrimidine-sulfamides and their use as endothelian receptor antagonist |
| WO2010144477A2 (en) * | 2009-06-12 | 2010-12-16 | Auspex Pharmaceuticals, Inc. | Sulfonylurea modulators of endothelin receptor |
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2013
- 2013-12-03 CN CN201310643198.0A patent/CN103724281A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1524079A (en) * | 2000-12-18 | 2004-08-25 | ������˹ҩƷ��˾ | Novel sulfamides and their use as endothelin receptor antagonists |
| CN100379730C (en) * | 2002-12-02 | 2008-04-09 | 埃科特莱茵药品有限公司 | Pyrimidine-sulfamides and their use as endothelian receptor antagonist |
| CN101056872A (en) * | 2004-11-11 | 2007-10-17 | 埃科特莱茵药品有限公司 | Sulfamides as endothelin receptor antagonists for the treatment of cardiovascular diseases |
| WO2010144477A2 (en) * | 2009-06-12 | 2010-12-16 | Auspex Pharmaceuticals, Inc. | Sulfonylurea modulators of endothelin receptor |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI643848B (en) * | 2013-07-12 | 2018-12-11 | 艾克泰聯製藥有限公司 | Process for preparing a pyrimidine intermediate |
| JP2017125055A (en) * | 2014-02-14 | 2017-07-20 | アクテリオン ファーマシューティカルズ リミテッドＡｃｔｅｌｉｏｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｌｔｄ | Process for manufacturing pyrimidine sulfamide derivatives |
| CN109232546A (en) * | 2018-09-25 | 2019-01-18 | 中国人民解放军总医院 | A kind of medical usage of pyrimidine sulfonyl amine derivant |
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Application publication date: 20140416 |