CN109988089B - Prostaglandin compound, preparation method and application thereof - Google Patents

Prostaglandin compound, preparation method and application thereof Download PDF

Info

Publication number
CN109988089B
CN109988089B CN201810535451.3A CN201810535451A CN109988089B CN 109988089 B CN109988089 B CN 109988089B CN 201810535451 A CN201810535451 A CN 201810535451A CN 109988089 B CN109988089 B CN 109988089B
Authority
CN
China
Prior art keywords
compound
prostaglandin
mmol
preparation
prostaglandin compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201810535451.3A
Other languages
Chinese (zh)
Other versions
CN109988089A (en
Inventor
唐志军
侯伟
孙福虎
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Fanqin Pharmaceutical Technology Co ltd
Original Assignee
Shanghai Fanqin Pharmaceutical Technology Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Fanqin Pharmaceutical Technology Co ltd filed Critical Shanghai Fanqin Pharmaceutical Technology Co ltd
Priority to CN201810535451.3A priority Critical patent/CN109988089B/en
Publication of CN109988089A publication Critical patent/CN109988089A/en
Application granted granted Critical
Publication of CN109988089B publication Critical patent/CN109988089B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • C07C405/0008—Analogues having the carboxyl group in the side-chains replaced by other functional groups
    • C07C405/0041—Analogues having the carboxyl group in the side-chains replaced by other functional groups containing nitrogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Abstract

The invention discloses a prostaglandin compound, a preparation method and application thereof, wherein the structural general formula of the prostaglandin compound is as shown in formula (I):
Figure DDA0001677707500000011
wherein n is 0-3, m is 1-3,

Description

Prostaglandin compound, preparation method and application thereof
Technical Field
The invention relates to the field of development of new prostanoids, in particular to a prostaglandin compound, a preparation method and application thereof.
Background
Prostaglandins (PGs) are active substances with various physiological effects, composed of a class of unsaturated fatty acids present in animals and humans. It was first found to be present in human semen, when it was assumed that this substance was released from the prostate, and was thus named. It has been demonstrated that prostaglandins in seminal fluid are mainly derived from seminal vesicles and are produced by many tissue cells throughout the body.
Prostaglandin (PG) is synthesized in vivo from arachidonic acid and has the structure of a 20-carbon unsaturated fatty acid consisting of a pentacyclic ring and two side chains. Prostaglandins are classified into A, B, C, D, E, F, G, H, I types, etc. according to their structure, and different types of prostaglandins have different functions. Prostaglandins have effects on endocrine, reproductive, digestive, blood respiratory, cardiovascular, urinary and nervous systems.
Prostaglandin E1 (PGE 1) is an important cell growth and regulatory factor, a metabolite of arachidonic acid cyclooxygenase, an eicosanoid unsaturated fatty acid, a form of Prostaglandin (PG).
Prostaglandin E1 is a drug for treating myocardial infarction, thromboangiitis obliterans and other diseases, and is also the only prostaglandin drug on the market for the application. The early prostaglandin E1 was extracted from sheep seminal vesicles. The chemical name of prostaglandin E1 is: 11a, 15 (S) -dihydroxy-9-carbonyl-13-trans-prostanoic acid. Prostaglandin E1 has the following structural formula:
Figure 655667DEST_PATH_IMAGE001
。
prostaglandin E1 is unstable, and is easily degraded during the use, and the degradation product is easy to generate toxic and side effects, and the common toxic and side effects are as follows: shock, vascular pain, vasculitis, redness, occasional hardness and itching at the injection site; aggravate heart failure, pulmonary edema, tightness in chest, occasionally flush face and palpitation. Diarrhea, abdominal distension, unpleasant feeling, occasional abdominal pain, inappetence, vomiting, constipation, elevated transaminase, dizziness, headache, fever, etc.
Clinically, the appearance of a medicament with stable medicament, small toxic and side effect and stronger pharmacological action is urgently needed.
Disclosure of Invention
In order to solve the problems that the existing prostaglandin E1 medicine is unstable and is easy to degrade to generate toxic and side effects, the invention aims to provide a prostaglandin compound which has a stable structure, is difficult to degrade and has small toxic and side effects. For this reason, the present invention also provides a method for preparing the prostaglandin compound.
In order to achieve the purpose, the invention adopts the following technical scheme:
in a first aspect of the present invention, there is provided a prostaglandin compound having the general structural formula (I):
Figure 713752DEST_PATH_IMAGE002
（Ⅰ）
wherein n is 0-3, m is 1-3,
Figure 24648DEST_PATH_IMAGE003
presentation sheetA bond or a double bond.
Preferably, where n is 1 to 3, m is 1 to 2,
Figure 872387DEST_PATH_IMAGE003
represents a single bond.
In a second aspect of the present invention, there is provided a method for producing the above prostaglandin compound, comprising the step of condensing a compound of formula (I) with a nitro compound in an alkaline environment,
Figure 93284DEST_PATH_IMAGE004
（Ⅱ）
the structural general formula of the nitro compound is as follows:
Figure 446905DEST_PATH_IMAGE005
（Ⅲ）
wherein X is Cl, Br or I; n is 0 to 3; m is 1 to 3;
Figure 871195DEST_PATH_IMAGE003
represents a single bond or a double bond.
Preferably, the alkaline environment is a sodium carbonate environment or a potassium carbonate environment.
In a third aspect of the present invention, there is provided a pharmaceutical composition comprising the prostaglandin compound described above.
Wherein, the pharmaceutical composition is a freeze-dried powder injection, an injection or a solid oral preparation.
Wherein, the medicine composition also comprises a cosolvent, a stabilizing agent or a disintegrating agent.
In a fourth aspect of the present invention, there is provided use of the prostaglandin compound described above for the preparation of a medicament for the treatment of vascular occlusion or a blood circulation disorder.
Compared with the prior art, the invention has the following beneficial effects: the prostaglandin compound has the advantages of stable structure, difficult degradation, strong activity, small toxic and side effects and good treatment effect, wherein the remission rate of the compound D in the treatment of arterial occlusion is as high as 93.75%.
Detailed Description
A prostaglandin compound having the following general structural formula:
Figure 601254DEST_PATH_IMAGE006
（Ⅰ）
wherein n is 0-3, m is 1-3,
Figure 676657DEST_PATH_IMAGE003
represents a single bond or a double bond.
When n is 1-3, m is 1-2,
Figure 201180DEST_PATH_IMAGE003
when a single bond is represented, the corresponding prostaglandin compound shows high activity and has a structural formula shown as A-G.
Figure 611301DEST_PATH_IMAGE007
A
Figure 879472DEST_PATH_IMAGE008
B
Figure 809381DEST_PATH_IMAGE009
C
Figure 504805DEST_PATH_IMAGE010
D
Figure 697496DEST_PATH_IMAGE011
E
Figure 379144DEST_PATH_IMAGE012
F
Figure 553773DEST_PATH_IMAGE013
G
Wherein, the above
Figure 544732DEST_PATH_IMAGE003
Represents a single bond.
The compounds of formula (I) are prepared as follows:
Figure 804812DEST_PATH_IMAGE015
wherein, X is Cl, Br or I.
Example 1: the preparation of the compound of formula (B) is as follows:
Figure 290151DEST_PATH_IMAGE017
prostaglandin E1(191mg, 0.54 mmol) was dissolved in 5.0 ml anhydrous DMF and K was added2CO3(207 mg, 1.5 mmol), KI (77 mg, 0.46 mmol) and a solution of 2-bromoethyl nitrate (93.6mg, 1.02 mmol) in 5ml of dichloromethane were added to the mixture, heated to 40-50 ℃ and the reaction stirred for 2 hours and TLC indicated completion. The reaction mixture was diluted with 50 ml of dichloromethane, washed with brine (3 × 50 ml), dried over anhydrous sodium sulfate, concentrated, and subjected to silica gel column chromatography to give product B (196 mg, yield 82%). The nuclear magnetic characterization data are as follows:1H-NMR (CDCl3) δ: δ0.96(t, 3H), 1.29-1.33 (m, 10H),1.53（dd，2H）1.68(m，2H),2.08-2.09 (m, 2H), 2.25(t，2H)，2.34 (m, 1H), 2.77(m，1H)，3.78-3.81(m, 3H),3.90(m，1H)，4.27(m，2H)，5.67-5.69(m，2H)。
example 2: preparation of Compounds of formula (A)
Compound a was prepared in the same manner as in example 1, using bromomethyl nitrate as a starting material.
Prostaglandin E1(191mg, 0.54 mmol) was dissolved in 5.0 ml anhydrous DMF and K was added2CO3(207 mg, 1.5 mmol), KI (77 mg, 0.46 mmol), and bromomethyl nitrate (156mg,1.03 mmol) of dichloromethane 5ml are added to the mixture, heated to 40-50 ℃ and the reaction stirred for 2 hours, TLC showed completion of the reaction. The reaction mixture was diluted with 50 ml of dichloromethane, washed with brine (3X 50 ml), dried over anhydrous sodium sulfate, concentrated and chromatographed on silica gel.
The nuclear magnetic characterization data of compound a were obtained as follows: 1H-NMR (CDCl 3). delta.0.96 (t, 3H), 1.29-1.33 (m, 10H),1.53 (dd, 2H) 1.68(m, 2H),2.08-2.09 (m, 2H), 2.25(t, 2H), 2.34 (m, 1H), 2.77(m, 1H), 3.78-3.83(m, 3H),3.90(m, 1H), 5.67-5.69(m, 2H).
Example 3: preparation of the Compound of formula (C)
Compound C was prepared in the same manner as in example 1, using 3-bromopropylnitrate as a starting material.
Prostaglandin E1(191mg, 0.54 mmol) was dissolved in 5.0 ml anhydrous DMF and K was added2CO3(207 mg, 1.5 mmol), KI (77 mg, 0.46 mmol) and 3-bromopropylnitrate (187mg, 1.01 mmol) in 5ml dichloromethane were added to the mixture, heated to 40-50 ℃ and the reaction stirred for 2h, TLC indicated completion of the reaction. The reaction mixture was diluted with 50 ml of dichloromethane, washed with brine (3X 50 ml), dried over anhydrous sodium sulfate, concentrated and chromatographed on silica gel.
Nuclear magnetic characterization data for compound C were obtained as follows: 1H-NMR (CDCl 3). delta.0.96 (t, 3H), 1.29-1.35 (m, 10H), 1.49-1.56 (m, 4H) 1.68(m, 2H),2.06-2.09 (m, 2H), 2.25(t, 2H), 2.34 (m, 1H), 2.77(m, 1H), 3.78-3.83(m, 3H),3.90(m, 1H), 4.25(t, 2H), 5.67-5.69(m, 2H).
Example 4: preparation of the Compound of formula (D)
Compound D was prepared in the same manner as in example 1, using 4-bromobutyl nitrate as the starting material.
Prostaglandin E1(191mg, 0.54 mmol) was dissolved in 5.0 ml anhydrous DMF and K was added2CO3(207 mg, 1.5 mmol), KI (77 mg, 0.46 mmol) and 4-bromobutyl nitrate (201mg, 1.02 mmol) in dichloromethane (5 ml) were added to the mixture, heated to 40-50 ℃ and the reaction stirred for 2 hours, TLC indicated completion of the reaction. Subjecting the reaction mixture toDiluting with 50 ml dichloromethane, washing with brine (3X 50 ml), drying over anhydrous sodium sulfate, concentrating, and subjecting to silica gel column chromatography
Nuclear magnetic characterization data for compound D were obtained as follows: 1H-NMR (CDCl 3). delta.0.96 (t, 3H), 1.29-1.35 (m, 10H), 1.49-1.56 (m, 6H) 1.68(m, 2H),2.06-2.09 (m, 2H), 2.25(t, 2H), 2.34 (m, 1H), 2.77(m, 1H), 3.78-3.83(m, 3H),3.90(m, 1H), 4.25(t, 2H), 5.65-5.69(m, 2H).
Example 5: preparation of the Compound of formula (E)
Compound E was prepared using 2-bromo-1, 3-dinitrate-based propylene glycol as the starting material in the same manner as in example 1.
Prostaglandin E1(191mg, 0.54 mmol) was dissolved in 5.0 ml anhydrous DMF and K was added2CO3(207 mg, 1.5 mmol), KI (77 mg, 0.46 mmol) and a solution of 2-bromo-1, 3-dinitrato-propanediol (248mg, 1.02 mmol) in 5ml of dichloromethane were added to the mixture, heated to 40-50 ℃ and the reaction stirred for 2 hours, TLC indicated completion of the reaction. The reaction mixture was diluted with 50 ml of dichloromethane, washed with brine (3X 50 ml), dried over anhydrous sodium sulfate, concentrated and chromatographed on silica gel.
Nuclear magnetic characterization data for compound E were obtained as follows: 1H-NMR (CDCl 3). delta.0.96 (t, 3H), 1.29-1.35 (m, 10H), 1.49-1.56 (m, 6H) 1.68(m, 2H),2.06-2.09 (m, 2H), 2.25(t, 2H), 2.34 (m, 1H), 2.77(m, 1H), 3.78-3.85(m, 8H), 4.25(t, 2H), 5.65-5.69(m, 2H).
Example 6: preparation of Compounds of formula (F)
Compound F was prepared in the same manner as in example 1, using 3-bromo-1, 2-dinitrate-based propylene glycol as a starting material.
Prostaglandin E1(191mg, 0.54 mmol) was dissolved in 5.0 ml anhydrous DMF and K was added2CO3(207 mg, 1.5 mmol), KI (77 mg, 0.46 mmol) and 3-bromo-1, 3-dinitrato propanediol (248mg, 1.02 mmol) in 5ml dichloromethane were added to the mixture, heated to 40-50 ℃ and the reaction stirred for 2 hours, TLC indicated completion. The reaction mixture was diluted with 50 ml of dichloromethane, washed with brine (3X 50 ml), dried over anhydrous sodium sulfate,concentrating, and performing silica gel column chromatography.
The nuclear magnetic characterization data of compound F were obtained as follows: 1H-NMR (CDCl 3). delta.0.96 (t, 3H), 1.29-1.35 (m, 10H), 1.49-1.56 (m, 6H) 1.68(m, 2H),2.06-2.09 (m, 2H), 2.25(t, 2H), 2.34 (m, 1H), 2.77(m, 1H), 3.73-3.85(m, 8H), 4.24(t, 2H), 5.67-5.68(m, 2H).
The compounds of formula (F) may also be prepared by the following process:
prostaglandin E1(191mg, 0.54 mmol) was dissolved in 5.0 ml anhydrous DMF and K was added2CO3(207 mg, 1.5 mmol), KI (77 mg, 0.46 mmol), and then a solution of 3-chloro-1, 3-dinitrato-propanediol (205mg, 1.02 mmol) in 5ml of dichloromethane was added to the mixture, heated to 40-50 ℃ and the reaction stirred for 2 hours, TLC indicated completion of the reaction. The reaction mixture was diluted with 50 ml of dichloromethane, washed with brine (3X 50 ml), dried over anhydrous sodium sulfate, concentrated and chromatographed on silica gel.
Example 7: preparation of the Compound of formula (G)
Compound G was prepared in the same manner as in example 1, using 3-bromo-1, 5-dinitratopentanediol as the starting material.
Prostaglandin E1(191mg, 0.54 mmol) was dissolved in 5.0 ml anhydrous DMF and K was added2CO3(207 mg, 1.5 mmol), KI (77 mg, 0.46 mmol) and a solution of 3-bromo-1, 5-dinitratopentanediol (262mg, 1.02 mmol) in 5ml of dichloromethane were added to the mixture, heated to 40-50 ℃ and the reaction stirred for 2 hours, TLC indicated completion of the reaction. The reaction mixture was diluted with 50 ml of dichloromethane, washed with brine (3X 50 ml), dried over anhydrous sodium sulfate, concentrated and chromatographed on silica gel.
The nuclear magnetic characterization data of compound G were obtained as follows: 1H-NMR (CDCl 3). delta.0.97 (t, 3H), 1.29-1.35 (m, 14H), 1.49-1.56 (m, 6H) 1.68(m, 2H),2.06-2.09 (m, 2H), 2.25(t, 2H), 2.34 (m, 1H), 2.77(m, 1H), 3.73-3.82(m, 8H), 4.26(t, 2H), 5.67-5.69(m, 2H).
The compounds of formula (G) may also be prepared by the following process:
prostaglandin E1(191mg, 0.54 mmol) was dissolved in 5.0 ml anhydrous DMFAdding K2CO3(207 mg, 1.5 mmol), KI (77 mg, 0.46 mmol), and a solution of 3-iodo-1, 5-dinitratopentanediol (309mg, 1.02 mmol) in 5ml of dichloromethane were added to the mixture, heated to 40-50 ℃ and stirred for 2 hours, and TLC indicated completion of the reaction. The reaction mixture was diluted with 50 ml of dichloromethane, washed with brine (3X 50 ml), dried over anhydrous sodium sulfate, concentrated and chromatographed on silica gel.
Prostaglandin E1 is a carboxyl group-containing compound that is readily degraded by dehydration under acidic conditions; the prostaglandin compound of the invention changes carboxyl into ester group, which can not degrade under acidic condition, thus enhancing stability.
Example 8
Taking 48 rat models with artery occlusion, randomly dividing the rat models into 8 groups of 6 rats each, namely a, b, c, d, e, f, g and h,
the compounds A-G are respectively administered to a group a-G and the prostaglandin E1 is administered to a group h of white rats at a dose of 1 mg/kg; after 2h administration, the arterial occlusions were compared for remission, which was comparable to or even higher than prostaglandin E1, as shown in the table below.
Figure 319287DEST_PATH_IMAGE019
The foregoing detailed description is given by way of example only, to better enable one of ordinary skill in the art to understand the patent, and is not to be construed as limiting the scope of what is encompassed by the patent; any equivalent alterations or modifications made according to the spirit of the disclosure of this patent are intended to be included in the scope of this patent.

Claims (3)

1. A pharmaceutical composition comprising a prostaglandin compound:
Figure FDF0000015996000000011
the prostaglandin compound is prepared by condensing a compound shown in a formula (II) and 4-bromobutyl nitrate in a sodium carbonate environment or a potassium carbonate environment;
Figure FDF0000015996000000012
2. the pharmaceutical composition of claim 1, wherein the pharmaceutical composition is a lyophilized powder for injection, an injection or a solid oral preparation; the pharmaceutical composition also comprises a cosolvent, a stabilizer or a disintegrant.
3. Use of the pharmaceutical composition of claim 1 or 2 for the manufacture of a medicament for the treatment of vascular occlusion, blood circulation disorders.
CN201810535451.3A 2018-05-29 2018-05-29 Prostaglandin compound, preparation method and application thereof Active CN109988089B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201810535451.3A CN109988089B (en) 2018-05-29 2018-05-29 Prostaglandin compound, preparation method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201810535451.3A CN109988089B (en) 2018-05-29 2018-05-29 Prostaglandin compound, preparation method and application thereof

Publications (2)

Publication Number Publication Date
CN109988089A CN109988089A (en) 2019-07-09
CN109988089B true CN109988089B (en) 2022-04-26

Family

ID=67129072

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201810535451.3A Active CN109988089B (en) 2018-05-29 2018-05-29 Prostaglandin compound, preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN109988089B (en)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5625083A (en) * 1995-06-02 1997-04-29 Bezuglov; Vladimir V. Dinitroglycerol esters of unsaturated fatty acids and prostaglandins
WO2000051978A1 (en) * 1999-03-01 2000-09-08 Nitromed, Inc. Nitrosated and nitrosylated prostaglandins, compositions and metods of use
CN1906159A (en) * 2004-01-05 2007-01-31 尼考斯股份公司 Prostaglandin nitrooxyderivatives
CN101318948A (en) * 2008-04-01 2008-12-10 上海天伟生物制药有限公司 Lubiprostone1 crystal, preparation method and uses thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5625083A (en) * 1995-06-02 1997-04-29 Bezuglov; Vladimir V. Dinitroglycerol esters of unsaturated fatty acids and prostaglandins
WO2000051978A1 (en) * 1999-03-01 2000-09-08 Nitromed, Inc. Nitrosated and nitrosylated prostaglandins, compositions and metods of use
CN1906159A (en) * 2004-01-05 2007-01-31 尼考斯股份公司 Prostaglandin nitrooxyderivatives
CN101318948A (en) * 2008-04-01 2008-12-10 上海天伟生物制药有限公司 Lubiprostone1 crystal, preparation method and uses thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
1,3-Dinitrates of Cyclooxygenase Metabolites of Endocannabinoid 2-Arachidonoylglycerol. Synthesis and Properties;I. V. Serkov等;《Russian Journal of Bioorganic Chemistry》;20091231;第35卷(第2期);第226页Scheme1 *

Also Published As

Publication number Publication date
CN109988089A (en) 2019-07-09

Similar Documents

Publication Publication Date Title
US5591887A (en) Prostaglandins of the F series
US7459583B2 (en) Method for providing a cathartic effect
US8202909B2 (en) Method for treating central nervous system disorders
BE834794A (en) 3-TRIHYDROXYGERMANO-PROPIONIC ACID
DE2734678A1 (en) EPININESTERS AND METHOD OF MANUFACTURING THEM
CN109988089B (en) Prostaglandin compound, preparation method and application thereof
EA020303B1 (en) Use of 4-[ethyl(dimethyl)ammonio]butanoate in the treatment of cardiovascular disease
CH635072A5 (en) PROSTAGLANDIN ANALOGS.
RU2593203C2 (en) Panthenol docosahexaenoate and use thereof for treating and preventing cardiovascular diseases
JPS58213716A (en) Carcisnostatic agent
CH638510A5 (en) PROSTACYCLINANALOGA.
JP2014528460A (en) Derivatives of butylphthalide and methods for producing and using the same
DE2809452A1 (en) PROSTAGLANDIN DERIVATIVES AND PROCESS FOR THEIR PRODUCTION
US4851448A (en) Gem-dihalo-1,8-diamino-4-aza-octanes
JPS6054933B2 (en) Method for stabilizing prostaglandin and prostaglandin-like compound preparations
JP2022537518A (en) Use of aminothiol compounds as cranial nerve or cardioprotective agents
US3137621A (en) Method of treating colic with trihydroxyacetophenones
KR102275045B1 (en) Methods for preparing mosapride citrate hydrate and pharmaceutical composition comprising the same
US4914240A (en) Gem-dihalo-1, 8-diamino-4-aza-octanes
CH639378A5 (en) PROSTAGLANDIN DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF.
CN108558869B (en) For treating the compound and its preparation of liver cancer
JPS6026121B2 (en) New dextran derivatives and their production method
RU2021114870A (en) METHODS FOR OBTAINING NITROSYLATED PROPANEDIOLS, COMPOSITIONS CONTAINING SUCH COMPOUNDS, AND THEIR CLINICAL APPLICATION
DE2632950A1 (en) Purine (1)-deoxy ribofuranuronic acid bis-amides - with cardiovascular and metabolic activity
DE2638676A1 (en) NEW CYCLOPENTANOL DERIVATIVES, PROCEDURES FOR THEIR MANUFACTURING AND PHARMACEUTICAL COMPOSITIONS

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant