CN1064268A - Preparation contains the method for the pharmaceutical composition of quinolinium - Google Patents
Preparation contains the method for the pharmaceutical composition of quinolinium Download PDFInfo
- Publication number
- CN1064268A CN1064268A CN92101029A CN92101029A CN1064268A CN 1064268 A CN1064268 A CN 1064268A CN 92101029 A CN92101029 A CN 92101029A CN 92101029 A CN92101029 A CN 92101029A CN 1064268 A CN1064268 A CN 1064268A
- Authority
- CN
- China
- Prior art keywords
- salt
- quinolinium
- oxethyl
- hydroxyl
- 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.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
- C07D215/44—Nitrogen atoms attached in position 4 with aryl radicals attached to said nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The salt of substd quinolines compound and as the application of gastric acid secretion inhibitor.
Description
The present invention relates to some quinoline compound salt, contain they pharmaceutical composition and they in treatment as the application of gastric acid secretion inhibitor.
Quinoline compound known in the state of the art has the activity of gastric acid secretion inhibitor, and for example, EP-330485-A discloses a series of 4-amino-3-acyl group quinoline, is wherein replaced such as hydroxyalkyl and hydroxy alkoxy base group on the 8-position of quinoline.
The dissolution rate of compound in water that has been found that EP-330485-A is very poor, and the possibility of result can show as very poor in vivo bioavailability and therefore may show as very low and very poor therapeutic activity reproduction level.Find now that the salt that these compounds are made particular category can solve the problem of solvency action difference.And, during the compound that in selecting treatment, uses, except considering physicals, as good solvency action (therefore good bioavailability is arranged) in addition, importantly to consider the thing of some or principle, for example, require the effectiveness that selected compounds itself has and the time of effect must reach the ideal level.Found when a kind of particular compound of EP-330485-A is generated the form of salt described herein, it is except having the ideal physicals, beyond high dissolution rate, its effect is renderd a service and is also reached desirable level action time, and these have constituted technical theme of the present invention.
Therefore, primary aspect of the present invention has provided the compound of the structure formula I of salt form:
It is characterized in that this salt is generated by described structure formula I compound and strong acid reaction.
Here used term strong acid is meant that PKa is less than about 4.0 acid.Concerning those skilled in the art, these sour character are conspicuous, and they comprise for example mineral acid, example hydrochloric acid, and sulfonic acid, and as alkylsulphonic acid, methylsulfonic acid particularly.
The particularly preferred salt of the present invention is the salt that generates with hydrochloric acid or methylsulfonic acid reaction; promptly be; 3-butyryl radicals-4-(2-aminomethyl phenyl amino)-and the 8-(2-hydroxyl-oxethyl) the quinolinium acidulants, and 3-butyryl radicals-4-(2-aminomethyl phenyl amino)-the 8-(2-hydroxyl-oxethyl) the quinoline mesylate.
Salt of the present invention, hydrochloride particularly above-mentioned are compared with the free alkali compound of disclosed structure formula I among the EP-330485-A with mesylate and are demonstrated express intrinsic dissolution rate.Therefore, because the dissolution rate of free alkali is low, can estimate its reproducibility bioavailability in vivo also poor (so having only bad result of treatment), but estimate that salt of the present invention can demonstrate much better conforming bioavailability (because their dissolution rate much better), and proof for every given dose of patient's administration more effectively and more reliable.
Salt described herein can be used for treating mammiferous gastrointestinal illness, particularly treats the gastrointestinal illness of human body.These diseases comprise, for example, and gastric duodenal ulcer, aspiration pneumonitis and Zollinger-Ellison syndromes.In addition, these salts can be used for the treatment of other deficiency disorder that requirement has the secretion inhibitor effect, as are used to have patient chronic and excessive alcohol consumption history, and the patient who is used to have gastroesophageal reflux disease (GERD).
In treatment was used, these salts can saliferous and the standard drug composition administration of pharmaceutically acceptable carrier.Therefore, on the other hand, the present invention also provides pharmaceutical composition, and this pharmaceutical composition contains the above-mentioned salt that combines with pharmaceutically acceptable carrier.
Suitable pharmaceutical composition is as described in the EP-330485-A.
The every day dosage standard suitable to adult patients can be, for example oral dosage is between 1 to 1000mg, between preferred 1 to 500mg, or intravenously, subcutaneous or intramuscular administration dosage are between 0.1 to 100mg, above-mentioned salt between preferred 0.1 to 25mg, above-mentioned salt administration are unitary dose 1 to 4 time every day.
In addition, these salt can be with other activeconstituents administration, these activeconstituentss for example the medicine of antacid (as magnesiumcarbonate or magnesium hydroxide, and aluminium hydroxide), on-steroidal anti-infective, steroid or nitrite clean-out system or other treatment stomach ulcer (as prostaglandin(PG) or H
2-antagonist is as Cimitidine Type A/AB).
Embodiment 1
3-butyryl radicals-4-(2-aminomethyl phenyl amino-8-(2-hydroxyl-oxethyl) quinoline can prepare with method described in the EP-330485-A.
3-butyryl radicals-4-(2-aminomethyl phenyl amino)-and the 8-(2-hydroxyl-oxethyl) preparation of quinolinium acidulants
Under the room temperature with 3-butyryl radicals-4-(2-aminomethyl phenyl amino)-the 8-(2-hydroxyl-oxethyl) quinoline (10g) is suspended in the methyl alcohol (100ml), slowly adds concentrated hydrochloric acid and obtains settled solution, steams solvent then.Then the resistates secondary is dissolved in the 2-propyl alcohol and repeats to steam, obtain required salt (9.7g), m.p.214-215 ℃ with 2-propyl alcohol/ether recrystallization then.
C
22H
24N
2O
3·HCl·0.2H
2O
Measured value C65.50, H6.21, N6.88
Calculated value C65.32, H6.33, N6.93
Embodiment 2
3-butyryl radicals-4-(2-aminomethyl phenyl amino)-and the 8-(2-hydroxyl-oxethyl) preparation of quinoline mesylate
With 3-butyryl radicals-4-(2-aminomethyl phenyl amino)-the 8-(2-hydroxyl-oxethyl) quinoline (60g) is suspended in the ethyl acetate (400ml), is heated to 50 ℃, adds methylsulfonic acid (16.3g) under vigorous stirring.Crystallisation by cooling goes out required salt, it is leached and with ethyl acetate washing, productive rate 50.1g, m.p.83-85 ℃.
C
22H
24N
2O
3·CH
4O
3S·H
2O
Measured value C57.78, H6.28, N5.84
Calculated value C57.73, H6.32, N5.85.
Claims (7)
1, the method for the salt of preparation structure formula I compound and strong acid,
Comprising compound that makes the structure formula I and strong acid reaction.
2, be hydrochloric acid according to the strong acid that the process of claim 1 wherein.
3, be methylsulfonic acid according to the strong acid that the process of claim 1 wherein.
4, according to the process of claim 1 wherein that prepared salt is 3-butyryl radicals-4-(2-aminomethyl phenyl amino)-the 8-(2-hydroxyl-oxethyl) the quinolinium acidulants.
5, according to the process of claim 1 wherein that prepared salt is 3-butyryl radicals-4-(2-aminomethyl phenyl amino)-the 8-(2-hydroxyl-oxethyl) the quinoline mesylate.
6, the method for pharmaceutical compositions combines with its pharmaceutically acceptable carrier comprising the salt that the structure formula I compound reaction described in strong acid and the claim 1 is generated.
7, according to the method for claim 6, salt wherein is 3-butyryl radicals-4-(2-aminomethyl phenyl amino)-the 8-(2-hydroxyl-oxethyl) the quinolinium acidulants.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9101919.0 | 1991-01-29 | ||
| GB919101918A GB9101918D0 (en) | 1991-01-29 | 1991-01-29 | Compound |
| GB919101919A GB9101919D0 (en) | 1991-01-29 | 1991-01-29 | Compound |
| GB9101918.2 | 1991-01-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1064268A true CN1064268A (en) | 1992-09-09 |
Family
ID=26298350
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN92101029A Pending CN1064268A (en) | 1991-01-29 | 1992-01-28 | Preparation contains the method for the pharmaceutical composition of quinolinium |
Country Status (18)
| Country | Link |
|---|---|
| EP (1) | EP0569396A1 (en) |
| JP (1) | JPH06504541A (en) |
| CN (1) | CN1064268A (en) |
| AP (1) | AP337A (en) |
| AU (1) | AU652028B2 (en) |
| CA (1) | CA2099117A1 (en) |
| CZ (1) | CZ153293A3 (en) |
| FI (1) | FI933376A0 (en) |
| HU (1) | HUT67609A (en) |
| IE (1) | IE920267A1 (en) |
| IL (1) | IL100791A0 (en) |
| MA (1) | MA22401A1 (en) |
| MX (1) | MX9200338A (en) |
| NO (1) | NO932722L (en) |
| NZ (1) | NZ241408A (en) |
| PT (1) | PT100056A (en) |
| SK (1) | SK70993A3 (en) |
| WO (1) | WO1992012969A1 (en) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9126438D0 (en) * | 1991-12-12 | 1992-02-12 | Smithkline Beecham Intercredit | New quinoline derivatives |
| US5556863A (en) * | 1993-06-11 | 1996-09-17 | Astra Aktiebolag | Compound for gastric acid secretion inhibition |
| IS4164A (en) * | 1993-06-11 | 1994-12-12 | Ab Astra | Compounds that inhibit gastric acid flow |
| USRE43932E1 (en) | 1997-07-18 | 2013-01-15 | Novartis Ag | Crystal modification of a N-phenyl-2-pyrimidineamine derivative, processes for its manufacture and its use |
| US6852739B1 (en) | 1999-02-26 | 2005-02-08 | Nitromed Inc. | Methods using proton pump inhibitors and nitric oxide donors |
| UA80393C2 (en) | 2000-12-07 | 2007-09-25 | Алтана Фарма Аг | Pharmaceutical preparation comprising an pde inhibitor dispersed on a matrix |
| EP1453493A2 (en) * | 2001-11-19 | 2004-09-08 | ALTANA Pharma AG | Reversible proton pump inhibitors for the treatment of airway disorders |
| MY140561A (en) | 2002-02-20 | 2009-12-31 | Nycomed Gmbh | Dosage form containing pde 4 inhibitor as active ingredient |
| AU2003254282A1 (en) | 2002-08-01 | 2004-02-23 | Nitromed, Inc. | Nitrosated proton pump inhibitors, compositions and methods of use |
| EP1682133A1 (en) | 2003-11-03 | 2006-07-26 | AstraZeneca AB | Imidazo 1,2-a pyridine derivatives for the treatment of silent gastro-esophageal reflux |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8804444D0 (en) * | 1988-02-25 | 1988-03-23 | Smithkline Beckman Intercredit | Compounds |
-
1992
- 1992-01-27 MX MX9200338A patent/MX9200338A/en unknown
- 1992-01-27 EP EP92903019A patent/EP0569396A1/en not_active Withdrawn
- 1992-01-27 AU AU11799/92A patent/AU652028B2/en not_active Ceased
- 1992-01-27 HU HU9302201A patent/HUT67609A/en unknown
- 1992-01-27 CA CA002099117A patent/CA2099117A1/en not_active Abandoned
- 1992-01-27 SK SK709-93A patent/SK70993A3/en unknown
- 1992-01-27 JP JP4503051A patent/JPH06504541A/en active Pending
- 1992-01-27 CZ CZ931532A patent/CZ153293A3/en unknown
- 1992-01-27 AP APAP/P/1992/000352A patent/AP337A/en active
- 1992-01-27 MA MA22687A patent/MA22401A1/en unknown
- 1992-01-27 NZ NZ241408A patent/NZ241408A/en unknown
- 1992-01-27 WO PCT/EP1992/000200 patent/WO1992012969A1/en not_active Application Discontinuation
- 1992-01-28 IL IL100791A patent/IL100791A0/en unknown
- 1992-01-28 CN CN92101029A patent/CN1064268A/en active Pending
- 1992-01-28 PT PT100056A patent/PT100056A/en not_active Application Discontinuation
- 1992-01-28 IE IE026792A patent/IE920267A1/en unknown
-
1993
- 1993-07-28 FI FI933376A patent/FI933376A0/en unknown
- 1993-07-28 NO NO93932722A patent/NO932722L/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU1179992A (en) | 1992-08-27 |
| NO932722D0 (en) | 1993-07-28 |
| EP0569396A1 (en) | 1993-11-18 |
| HU9302201D0 (en) | 1993-10-28 |
| PT100056A (en) | 1993-03-31 |
| JPH06504541A (en) | 1994-05-26 |
| WO1992012969A1 (en) | 1992-08-06 |
| IE920267A1 (en) | 1992-07-29 |
| NZ241408A (en) | 1994-05-26 |
| MA22401A1 (en) | 1992-10-01 |
| FI933376A (en) | 1993-07-28 |
| AP9200352A0 (en) | 1992-01-31 |
| MX9200338A (en) | 1992-12-01 |
| HUT67609A (en) | 1995-04-28 |
| SK70993A3 (en) | 1994-01-12 |
| CA2099117A1 (en) | 1992-07-30 |
| FI933376A0 (en) | 1993-07-28 |
| NO932722L (en) | 1993-07-28 |
| IL100791A0 (en) | 1992-09-06 |
| AU652028B2 (en) | 1994-08-11 |
| CZ153293A3 (en) | 1993-12-15 |
| AP337A (en) | 1994-04-08 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C01 | Deemed withdrawal of patent application (patent law 1993) | ||
| WD01 | Invention patent application deemed withdrawn after publication |