Prostoglandine derivative possessing blood hypotensive effect and bronchodilatior effect

专利摘要:
The invention relates to prostaglandin derivatives, in particular 5- - {(E), 5S, 6K, 7K t-7-hydroxy-6- (E) - -Zr-hydroxy-1-octane 1} -bicyclo 3.3. 0 - octane-3-ylidene-pentanoic acid. affecting blood pressure reduction and bronchial dilatation. Among the prostaglandins, compounds with a better prostaglandin PG-1 than the known natural prostaglandin PG-1 activity obtained a new acid (PG-H). It is prepared from solutions in dimethyl sulfoxide (DMSO) of 4-carboxybutyltriphenylphosphonium and methylsulfinylmethyl sodium bromide at room temperature in an inert gas atmosphere (argon). A solution in DMSO lR, 5S, 5R, 7K -7-Stetrahydropyran-2-yloxy - -6- (E) - (Zy) - (tetrahydropyran-2-yl-hydroxy) -bicyclo 3.3 was added dropwise to the red ilen solution. About octan-3-one at 45 C. Then the reaction mixture was poured into ice-cold water, acidified with citric acid to pH 4-5 and extracted with CH Cl,. The organic phase is evaporated and chromatographed. The target acid PG-H has so pl. 95 ° C, its LDjo toxicity is 201-204 mg / kg body weight (intravenous). with s (l with:: o 00 o
公开号:SU1310390A1
申请号:SU813242701
申请日:1981-02-12
公开日:1987-05-15
发明作者:Скубалла Вернер；Радюхель Бернд；Форбрюгген Хельмут；Маннесманн Герда；Лазерт Вольфганг；Казальс Хорхе
申请人:Шеринг Аг (Фирма)；
IPC主号:

专利说明:

This invention relates to a novel prostagland derivative of formula I
(JHil3-6t) OH W
L
n
CHj
, W / CH-ClVC C-CH: i
sn sn
he
he
which has a lowering blood pressure and a bronchodilatory effect.
The purpose of the invention is to obtain a new synthetic derivative of prostaglandin, which is superior in its pharmacological activity to a natural analogue, prostagladin PG 12.
Example 1. 5 - {(E), 5S, BK 7K -7-hydroxy-6- (E) -Zob-hydroxy-1-hydroxy-bicyclo 3.3.0 octane-3-ylidene -pentanoic acid,
To a solution of 3.04 bromide 4-carboxybutyltriphenylphosphonium in 6 ml of dried dimethyl sulfoxide (DMSO) was added dropwise under an atmosphere of argon 12 ml of a 1.04 M solution of methyl sulfinylmethyl sodium in DMSO and stirred for 30 minutes at room temperature. A solution of 495 mg of (1R, 58, 6R, 7K) - (tetrahydropyran-2-yloxy) - -6- (E) - (38) -3- (tetrahydropyran-2- -yl-hydroxy) is added dropwise to the red ilen-solution -1-octenyl-bicyclo 3.3.Oj octane-3-one in 3 ml of absolute DMSO and stirred for 2 hours at 45 ° C. The reaction mixture was poured into ice-cold water, acidified with 10% citric acid solution to pH 4-5 and Trinods are extracted with methylene chloride. The organic phase is shaken with brine, dried over magnesium sulphate and evaporated under vacuum. After chromatography of the residue on silica gel, a mixture of ether-pentane (3: 2) and 462 mg of olefinated product is obtained, which is mixed with 15 ml of a mixture of acetic acid and water and tetrahydrofuran (63:35:10) to separate the protective groups. h at 25 ° C. The mixture is evaporated in vacuo and the residue is chromatographed on silica gel. With a mixture of methylene chloride, - isopropanol (95: 5), first of all, 65 mg of 5 - {(Z) - - (1S, 5S, 6R, 7K) - (7-hydroxy-6- (E) - - (35) - 3-hydroxy-1-octenyl-bicyclo-3.3. Octane-3-ylidene-pentanoic acid, melting point equal to 95 ° C, and also as floor p10
-

3103902
103 mg of the major compound as a colorless oil.
IR: 3600, 3450 (width), 2940, 2865, 1712, 1604, 975 .. 5 Starting material for the title. the main compound is prepared as follows.
Ha) (1R, 5S, 6R, 7K) -3.3 ethylenedioxy-7-benzoyloxy-6-G (E) -3-oxo--1-octenyl-bicyclo 3, 3.0 j octane.
To a suspension of 126 mg of sodium hydride (55% suspension in oil) in 11 ml of absolute dimethoxyethane (DME), a solution of 664 mg of 2-oxo-heptylphosphonic acid dimethyl ether in 5.5 ml abs. DME, stirred for 10 minutes, added 121 ml of lithium chloride and stirred for 2 hours at room temperature under argon atmosphere. Then, at -20 ° C, it is mixed with a solution of 755 mg of the aldehyde prepared according to a reference example in 11 ml abs. DME and stirred for 2.5 hours at room temperature under argon atmosphere. Then - the reaction mixture is poured into 120 ml of a saturated solution of ammonium chloride.
25
thirty
ether, wash the organic extract with water until neutral, dry over magnesium sulphate and evaporate in vacuo. The residue is chromatographed on silica gel. With a mixture of ether ether (1 + 1).
35 yields 795 mg of the major compound as a colorless oil.
IR spectrum: 2940, 2862, 1715.1670, 1628, 1275, 979, 948. Mb) - (1K, 5S, 6R, 7R) -3,3-ethylen40 Dioxy-7-benzoyloxy-6- (E) -Zo (, - hydroxy-1-octenyl-bicyclo 3.3.0 octane.
To a solution of 790 mg of the ketone prepared in Example 1 in 24 ml of methanol was added at portions of 420 m
45 sodium borohydride and stirred for 1 h at -40 ° C under argon atmosphere. It is then diluted with ether, washed with water until neutral. SCRUBNY, dried over magnesium sulfate and evaporated under
50 vacuum. With the aid of column chromatography on silica gel with a mixture
ether (7 + 3), first of all, produces 245 mg of the main compound in the form of a colorless oil. As the polar component, 152 mg of (1R, 5 s, 6R, 7R) -3,3-α-ethy. Pendioxy-7-benzoyloxy-b- (E) - - (ZR) -3-oxy-1 is obtained. -octylJ bicyclo Z.Z.o1 octane,
31
IR spectrum: 3160, 3400 (width), 2940, 1715, 1604, 1588, 1279, 971, 948. ,
IB) (1R, 5S, 6R, 7K) -3,3-ethylenedia OXI-7-OXI-6- (E) -Zo6-hydroxy-1-octenyl-bicyclo; 3 0 octane.
A mixture of 500 mg of the o6 alcohol obtained in Example 16 and 333 mg of anhydrous potassium carbonate in 35 ml of methanol was stirred for 16 hours at room temperature under argon atmosphere. It is then concentrated under vacuum, diluted with ether and washed with brine until neutral. Dry over magnesium sulfate and evaporate in vacuo. 495 mg of the title compound are obtained as a colorless oil (raw material).
IR spectrum: 3600, 3450 (width), 2940, 975, 948.
1g) (1R, 5S., 6R, 7R) -7-oxy-6- - (E) -3 (-oxy-1-octyl-bicyclo. 3, OZ octan-3-one.
495 mg of the diol prepared according to Example 1 f are stirred for 22 hours with 18 ml of a mixture of acetic acid-tetrahydrofuran-water (65:10:35). It is then evaporated by adding toluene under vacuum, the residue is dissolved in methyl chloride, shaken twice with brine, dried over magnesium sulphate and evaporated under vacuum. The residue is chromatographed on silica gel with ethyl acetate-pentane (9: 1). 1 mg of the title compound is obtained as a colorless oil.
IR spectrum: 3660, 3610, 2940.2870, 1739, 973 cm.
1d) (1R, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6- (E) -Zy1- (tetrahydropyran-2-yloxy) -1-octenyl bicyclo 3.3. OZ Octane-3-one.
Plant solution 260 mg of the ketone prepared in accordance with Example 1g, 0.36 ml of dihydropyran and 2.5 mg of p-toluenesulfonic acid in 11 ml of methylene chloride are stirred at 5 ° C for 20 minutes. Then diluted with ether, shaken with 4 The% sodium bicarbonate solution is washed with water until neutral, dried over magnesium sulphate and evaporated in vacuo. 490 mg of bis-tetrahydropyranyl ether are obtained, which is used in the Wittig reaction without further purification.
IR spectrum: 2955, 2862, 1739, 970 cm.
904
Example 2. 5 - {(E) - (1S, 5S, 6R, 7R) -7-oxy-6- (E) - () - Zog.-hydroxy-4-methyl-oct-1-ene-6 - vinyl 3 bicyclo., 3.3.dj octan-3-ylidene-pentanova
acid.
To a solution of 5.3 g of 4-carboxybutylphenylphosphonium bromide in 12 ml of absolute dimethyl sulfoxide (DMSO) is added dropwise at 15 ° C under argon atmosphere 21.3 ml of a 1.04 M solution of methylsulfinylmethyl sodium in DMSO and stirred for 30 minutes at room temperature . The solution is added dropwise to the red solution.
870 mg 41R, 5S, 6R, 7R) -7- (terapagidopiran-2-yloxy) -6- (E) - (4RS) -4- methyl-Zo6- (tetrahydropyran-2-yloxy) -oct -1-en-6-inyl-bicyclo 3.3. tan-3-she in 6 ml of absolute DMSO
and stirred at 45 ° C for 2 hours. The reaction mixture was poured into ice-cold water, acidified with 10% citric acid solution to pH 5 and extracted three times with methylene chloride. The organic phase is shaken with brine, dried over magnesium sulphate and evaporated in vacuo. After chromatography of the residue on silica gel, 340 mg of ether-pentane (3: 2) are obtained.
the olefinated product, which is cleaved with 30 ml of an acetic acid-water-tetrahydrofuran mixture (65:35:10) for 20 hours at 25 s, for the cleavage of the zash of the resulting groups.
It is evaporated in vacuo and the residue is chromatographed on silica gel with a mixture of methylene chloride - isopropanol (95: 5). 165 mg of 5 - ((Z) - (1S, 5S, 6R, 7R) - -7-OXI-6- (E) - (4RS) -3 () - hydroxy-4-methyl- are obtained
oct-1-en-b-ynyl bicyclo 3.3.0 octane-3-ylidene-pentanoic acid, and also as a polar component, 263 mg of the main compound as a colorless oil.
IR spectrum: 3600, 3400 (width), 2940, 2860, 1712, 975. The starting material for the title compound is prepared as follows.
Na) (1R, 5S, 6R, 7R) -3,3-ethylene-dioxy-7-benzoyloxy-6- (E) - (4RS) -4-methyl-3-oxo-oct-1-en-6 - vinyl) - bicyclo 3.3.Ozoktan.
By analogy with the example, Ha is obtained from 1.3 g prepared in Comparative Example 1; aldehyde and 1 g of di-, methyl ester of Z-methyl-2-oxo-hept-5-in phosphonic acid 1.45 g of the main compound as an oil.
51
IR spectrum: 2940, 2860, 1714, 1670. 1629, 1275, 978, 948 cm.
116) (1R, 5S, 6R, 7K) -3,3-ethylenedioxy-7-benzoyloxy-6- (E) - (4RS) - -3-6 oxy-4-methyl-oct-1-en-6- inil - bicyclor.3.0 octane.
By analogy with Example iS, from 810 mg of the ketone produced according to the Example and 450 mg of sodium borohydride, 380 mg of the main compound are obtained in the form of a colorless oil.
IR spectrum: 3600, 3400 (width), 2945, 2860, 1715, 1602, 1589, 1278, 973, 948.
Yves) (1R, 5S, 6R, 7R) -3,3-ethylene-DIOXI-7-OXI-6- (E) - (4RS) -Zo // - oxy-4-methyl oct-1-E- 6-ynyl-bicyclo 3.3.Oj octan-3-one.
By analogy with Example I, & from 500 mg of the IlSoi alcohol prepared according to the example and 340 mg of potassium carbonate 465 mg of the main compound in the form of an oil (raw material).
IR spectrum: 3600, 3400 (width), 2940, 2860, 976, 948 cm.
Ig) (1R, 5S, 6R, 7R) -7-oxy-6- - (E) - (4RS) -o-6-oxy-4-methyl-oct-1-en-6-ynyl-bicyclo 3.3.OJ Octane-3-en.
By analogy with Example 1g, 295 mg of the main compound in the form of a colorless oil is obtained from 455 mg of the diol prepared according to Example IIS.
 IR spectrum: 3600, 2945, 2860.1740, 974 cm.
Id) (1R, 5S, 6R, 7R) -7- (TeTpa-hydropyran-2-yloxy) -6- (E) - (4RS) -4-metsh1-Zo6- (tetrahydropyran-2-yl-oxy) -oct-1-en-6-ynyl | -bicyclo-.3.o3okTaH-3-OH.
Compiled by R1. Fedoseyev Editor I. Segl nick Tehred N. Glushchenko Proofreader I, Erdei
Order 1865/24 Circulation 372 Subscription VNIIPI USSR State Committee
for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., 4/5
Production and printing plant, Uzhgorod, st. Project, 4
06
By analogy with example 1d, 270 mg of 460 mg of bis-tetrahydropyranyl ether, prepared according to the example of Ig ketone and 0.38 ml of dihydropyran, are obtained, which is used in the Wittig reaction without further purification.
IR spectrum: 2960, 2865, 1738, 975 cm. Pharmacological data.
The LD jj of the compound from Example 2 (ilostrost) 201-204 mg / kg intravenously in mice.
The inhibition of aggregation of ADR-induced plaque by iloprost was measured in comparison with PGI (i with 50 nmol / l):
PGI Iloprost Man 0.81 0.72 Pig 19.4 13.9
In contrast to PGIg, ilostrost is also pharmacologically active after oral administration.
Iloprost: EDy, hypotensive activity of 0.5 mg / kg. (Bp) in rats.
PGI,

权利要求:
Claims (1)
[1]
Claims of the Invention Prostaglandin Form 30 Derivative
mules
1cNg s-COOH CH
BUT.
cx
I nn
he
Shee
QI Ш-СН-С С-СНо, 01
HE
having a blood pressure lowering 0 and bronchodilatory effect.

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引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

US4097489A|1977-06-17|1978-06-27|The Upjohn Company|9-Deoxy-9α,6-nitrilo or 6,9α-imino-PGF compounds|

---

JPS6121216B2|1978-01-06|1986-05-26|Sankyo Kk|

---

GB2040928B|1978-01-26|1982-12-08|Erba Farmitalia|Bicycloalkane derivatives useful as intermediates in preparing pg1 isosteres|

---

US4238414A|1978-02-13|1980-12-09|The Upjohn Company|2-Decarboxy-2-aminomethyl-6a-carba-PGI2 compounds|

---

JPS54119441A|1978-03-09|1979-09-17|Sumitomo Chem Co Ltd|Novel bicyclooctane derivative|

---

JPS6125010B2|1978-03-31|1986-06-13|Ono Pharmaceutical Co|

---

JPS6223737B2|1978-08-22|1987-05-25|Sankyo Kk|JPS6121216B2|1978-01-06|1986-05-26|Sankyo Kk|

---

GB2040928B|1978-01-26|1982-12-08|Erba Farmitalia|Bicycloalkane derivatives useful as intermediates in preparing pg1 isosteres|

---

DE3021895A1|1980-06-06|1981-12-24|Schering Ag Berlin Und Bergkamen, 1000 Berlin|NEW METHOD FOR PRODUCING CARBACYCLIN INTERMEDIATE PRODUCTS|

---

DE3048906A1|1980-12-19|1982-07-15|Schering Ag, 1000 Berlin Und 4619 Bergkamen|NEW CARBACYCLINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS|

---

DE3104044A1|1981-02-02|1982-08-26|Schering Ag, 1000 Berlin Und 4619 Bergkamen|NEW PROSTACYCLIN DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS|

---

DE3121155A1|1981-05-22|1982-12-09|Schering Ag, 1000 Berlin Und 4619 Bergkamen|NEW CARBACYCLINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS|

---

DE3204443A1|1982-02-08|1983-08-18|Schering Ag, 1000 Berlin Und 4619 Bergkamen|NEW CARBACYCLINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS|

---

US4533749A|1982-02-16|1985-08-06|The Upjohn Company|9-Substituted carbacyclin analogs|

---

US4486598A|1982-02-22|1984-12-04|The Upjohn Company|Carbacyclin analogs|

---

DE3225287A1|1982-07-02|1984-01-05|Schering AG, 1000 Berlin und 4709 Bergkamen|NEW CARBACYCLINAMIDES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS|

---

GB2129427B|1982-10-01|1986-01-08|Erba Farmitalia|15-cycloaliphatic derivatives of 13,14-didehydrocarboprostacyclins and process for their preparation|

---

HU191110B|1982-10-01|1987-01-28|Farmitala Carlo Erba Spa,It|Process for the production of the 15-cycloaliphatic derivatives 13,14-didehydro-carbaprostacyclines|

---

DE3306125A1|1983-02-18|1984-08-23|Schering AG, 1000 Berlin und 4709 Bergkamen|Novel carbacyclins, process for their preparation and their use as medicaments|

---

EP0136779B1|1983-07-26|1988-09-14|Sankyo Company Limited|New carbacyclin derivatives, processes for their preparation and compositions containing them|

---

DE3408699A1|1984-03-08|1985-09-12|Schering AG, 1000 Berlin und 4709 Bergkamen|NEW CARBACYCLINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS|

---

GB2156343B|1984-03-26|1988-01-13|Erbo Spa Farmitalia Carlo|13,14,19,19,20,20-hexadehydro derivatives of carboprostacyclins and process for their preparation|

---

GB2156341B|1984-03-26|1987-10-21|Erba Farmitalia|Furyl and imidazolyl derivatives of carboprostacyclins and process for their preparation|

---

DE3448256C2|1984-07-25|1988-08-18|Schering Ag, 1000 Berlin Und 4709 Bergkamen, De|Cytoprotective action of prostacyclin derivatives on the pancreas|

---

DE3427797C2|1984-07-25|1988-08-11|Schering Ag, 1000 Berlin Und 4709 Bergkamen, De|

---

DE3428266A1|1984-07-27|1986-01-30|Schering AG, 1000 Berlin und 4709 Bergkamen|NEW CARBACYCLINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS|

---

EP0195379B1|1985-03-18|1991-04-03|G.D. Searle & Co.|Allenic prostacyclins|

---

US4757087A|1985-03-19|1988-07-12|Sankyo Company Limited|Carbacyclin derivatives|

---

DE3608088C2|1986-03-07|1995-11-16|Schering Ag|Pharmaceutical preparations containing cyclodextrin clathrates of carbacyclin derivatives|

---

US5663203A|1986-09-11|1997-09-02|Schering Aktiengesellschaft|Agents containing prostacyclin derivatives for topical application|

---

DE3631169A1|1986-09-11|1988-03-24|Schering Ag|PROSTACYCLINE DERIVATIVES CONTAINING AGENTS FOR TOPICAL APPLICATION|

---

US5221763A|1987-04-30|1993-06-22|R-Tech Ueno, Ltd.|Prostaglandins of the F series|

---

HU206084B|1987-07-17|1992-08-28|Schering Ag|Process for producing 9-halogen-/z/-prostaglandin derivatives and pharmaceutical compositions comprising such active ingredient|

---

US5891910A|1987-07-17|1999-04-06|Schering Aktiengesellschaft|9-halogen- prostaglandin derivatives, process for their production and their use as pharmaceutical agents|

---

DE3839155A1|1988-11-17|1990-05-23|Schering Ag|PROCESS FOR THE PREPARATION OF CARBACYCLINE DERIVATIVES BY STEREOSELECTIVE INTRODUCTION OF 5,6-DUAL BINDING|

---

DE4010355A1|1990-03-28|1991-10-02|Schering Ag|BICYCLOOCTANE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR PHARMACEUTICAL USE|

---

DE4104607A1|1991-02-12|1992-08-13|Schering Ag|PROSTACYCLIN AND CARBACYCLINE DERIVATIVES AS A MEDIUM FOR TREATING FEVERED DISEASES|

---

DE4104606C1|1991-02-12|1992-10-15|Schering Ag Berlin Und Bergkamen, 1000 Berlin, De|

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DE4135193C1|1991-10-22|1993-03-11|Schering Ag Berlin Und Bergkamen, 1000 Berlin, De|

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US5654339A|1992-08-07|1997-08-05|Schering Aktiengesellschaft|Use of prostane derivatives of formulate I and II for treatment of chronic polyarthritis|

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DE19530884C2|1995-08-11|1997-07-31|Schering Ag|Use of prostane derivatives and their combination with antibiotics for the treatment of bacterial meningitis|

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DE19828881A1|1998-06-22|1999-12-23|Schering Ag|Industrial preparation of prostane derivatives, especially iloprost, having reduced content of decomposition products|

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WO2000002450A1|1998-07-08|2000-01-20|Fibrogen, Inc.|Method for treatment of fibrosis related diseases by the administration of prostacyclin derivatives|

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EP1661580B1|2003-07-25|2014-01-08|Ono Pharmaceutical Co., Ltd.|Remedy for cartilage-related diseases|

---

CN1917866B|2003-12-16|2010-12-15|联合治疗公司|Use of treprostinil, its derivant or pharmaceutically acceptable salt, in preparing medicine to treat and prevent ischemic lesions|

---

US20090124697A1|2003-12-16|2009-05-14|United Therapeutics Corporation|Inhalation formulations of treprostinil|

---

KR20070054644A|2004-07-26|2007-05-29|액테리온 파마슈티칼 리미티드|Treatment of pulmonary hypertension by inhaled iloprost with a microparticle formulation|

---

US7741317B2|2005-10-21|2010-06-22|Bristol-Myers Squibb Company|LXR modulators|

---

US7893050B2|2005-10-26|2011-02-22|Asahi Kasei Pharma Corporation|Fasudil in combination therapies for the treatment of pulmonary arterial hypertension|

---

EP2351569B1|2005-10-26|2012-08-22|Asahi Kasei Pharma Corporation|Fasudil in combination therapies for the treatment of pulmonary arterial hypertension|

---

US7888376B2|2005-11-23|2011-02-15|Bristol-Myers Squibb Company|Heterocyclic CETP inhibitors|

---

US7919506B2|2006-03-10|2011-04-05|Pfizer Inc.|Dibenzyl amine compounds and derivatives|

---

CA2654492C|2006-05-15|2017-06-27|United Therapeutics Corporation|Treprostinil administration using a metered dose inhaler|

---

DE102006026786A1|2006-06-07|2007-12-13|Joachim Kern|metered dose inhaler|

---

CA2669763C|2006-11-16|2015-02-17|Bayer Schering Pharma Aktiengesellschaft|Ep2 and ep4 agonists as agents for the treatment of influenza a viral infection|

---

WO2008070496A2|2006-12-01|2008-06-12|Bristol-Myers Squibb Company|N--2, 2--propan-1-amine derivatives as cetp inhibitors for the treatment of atherosclerosis and cardiovascular diseases|

---

EP2065054A1|2007-11-29|2009-06-03|Bayer Schering Pharma Aktiengesellschaft|Combinations comprising a prostaglandin and uses thereof|

---

PT3300729T|2008-08-13|2020-01-20|Actelion Pharmaceuticals Ltd|Therapeutic compositions containing macitentan|

---

JP2013508282A|2009-10-14|2013-03-07|ジェンムスファーマインコーポレイティド|Combination therapy treatment for viral infection|

---

ES2525748T3|2009-11-13|2014-12-29|Toray Industries, Inc.|Therapeutic or prophylactic agent for diabetes|

---

CA2909442A1|2013-04-17|2014-10-23|Pfizer Inc.|N-piperidin-3-ylbenzamide derivatives for treating cardiovascular diseases|

---

KR20160042039A|2013-08-09|2016-04-18|알데릭스, 인코포레이티드|Compounds and methods for inhibiting phosphate transport|

---

WO2016055901A1|2014-10-08|2016-04-14|Pfizer Inc.|Substituted amide compounds|

---

US10799653B2|2017-01-09|2020-10-13|United Therapeutics Corporation|Aerosol delivery device and method for manufacturing and operating the same|

---

US20200368223A1|2019-05-21|2020-11-26|Ardelyx, Inc.|Methods for inhibiting phosphate transport|

法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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DE19782845770|DE2845770A1|1978-10-19|1978-10-19|NEW PROSTACYCLINE DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF|

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