EP0569396A1 - Salts of a 4-amino-3-acyl quinoline derivative and their use as inhibitors of gastric acid secretion - Google Patents
Salts of a 4-amino-3-acyl quinoline derivative and their use as inhibitors of gastric acid secretionInfo
- Publication number
- EP0569396A1 EP0569396A1 EP92903019A EP92903019A EP0569396A1 EP 0569396 A1 EP0569396 A1 EP 0569396A1 EP 92903019 A EP92903019 A EP 92903019A EP 92903019 A EP92903019 A EP 92903019A EP 0569396 A1 EP0569396 A1 EP 0569396A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- salts
- inhibitors
- amino
- salt
- methylphenylamino
- 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.)
- Withdrawn
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
Definitions
- the present invention relates to certain salts of a quinoline compound, pharmaceutical compositions containing them and their use in therapy as inhibitors of gastric acid secretion.
- EP-330485-A discloses a series of 4-amino-3- acylquinoline derivatives in which the quinoline is substituted in the 8-position by, for example, hydroxyalkyl and hydroxyalkoxy groups.
- the compounds of EP 330485-A have been found to have poor dissolution rates in water and, as a consequence, could potentially exhibit poor bioavailability in vivo and hence low and poorly reproducible levels of therapeutic activity. It has now been found that the problem of poor dissolution can be overcome by producing the compounds in the form of a particular class of salts. Furthermore, in selecting compounds for use in therapy it is important to take a number or criteria into account, for example, in addition to physical qualities such as good dissolution (and hence good bioavailability) , the desired level of intrinsic potency and duration of action of the chosen compounds has to be at the desired level.
- strong acid shall be taken to mean an acid with a pka of less than about 4.0.
- the nature of such acids will be apparent to those skilled in the art and include, for example, mineral acids such as hydrochloric acid, and sulphonic acids such as alkyl sulphonic acids, in particular methane sulphonic acid.
- Particularly preferred salts of the present invention are those formed by reaction with hydrochloric acid or methane sulphonic acid, that is to say,
- the salts of the present invention have been found to exhibit exceptionally fast intrinsic dissolution rates when compared to the free base compound of structure (I) disclosed in EP-330485-A.
- the free base has a poor dissolution rate and, as such, may be expected in vivo to exhibit poorly reproducible bioavailability (and so be less effective therapeutically)
- the salts of the present invention are expected to exhibit a much more consistent bioavailability (since their dissolution rates are far more favourable) and to prove more effective per given dose and more reliably effective per given dose on administration to patients.
- the salts described herein can be used in therapy in the treatment of gastrointestinal diseases in mammals, in particular humans. Such diseases include, for example, gastric and duodenal ulcers, aspiration pneumonitis and Zollinger-Ellison syndrome. Further, the salts can be used in the treatment of other disorders where an anti-secretory effect is desirable, for example in patients with a history of chronic and excessive alcohol consumption, and in patients with gastrooesophageal reflux disease (GERD) .
- GSD gastrooesophageal reflux disease
- the salts can be administered in a standard pharmaceutical composition comprising the salt and a pharmaceutically acceptable carrier.
- the present invention provides in a further aspect therefore a pharmaceutical composition comprising a salt as described herein in association with a pharmaceutically acceptable carrier.
- Suitable pharmaceutical compositions are as described in EP-330485-A.
- Suitable daily dosage regimens for an adult patient may be, for example, an oral dose of between 1 and 1000 mg, preferably between 1 and 500 mg, or an intravenous, subcutaneous or intramuscular dose of between 0.1 and 100 mg, preferably between 0.1 and 25 mg of the salts described herein, the salt being administered in a unit dosage 1 to 4 times a day.
- the salts can be co-administered with further active ingredients such as antacids (for example, magnesium carbonate or hydroxide and aluminium hydroxide) , non-steroidal anti-inflammatory drugs, steroids or nitrite scavengers or other drugs used for treating gastric ulcers (for example, prostanoids or H 2 -antagonists such as cimetidine) .
- antacids for example, magnesium carbonate or hydroxide and aluminium hydroxide
- non-steroidal anti-inflammatory drugs for example, steroids or nitrite scavengers or other drugs used for treating gastric ulcers (for example, prostanoids or H 2 -antagonists such as cimetidine) .
- active ingredients such as antacids (for example, magnesium carbonate or hydroxide and aluminium hydroxide) , non-steroidal anti-inflammatory drugs, steroids or nitrite scavengers or other drugs used for treating gastric ulcers (for example, prostanoids or H 2
Abstract
Composé de structure (I) sous la forme d'un sel, procédé de préparation de ce composé et compositions pharmaceutiques comprenant ce sel et son utilisation en thérapie.Compound of structure (I) in the form of a salt, process for the preparation of this compound and pharmaceutical compositions comprising this salt and its use in therapy.
Description
Salts of a 4-amino-3-acyl quinoline derivative and their use as inhibitors of gastric acid secretion.
The present invention relates to certain salts of a quinoline compound, pharmaceutical compositions containing them and their use in therapy as inhibitors of gastric acid secretion.
Quinoline compounds which have activity as gastric acid secretion inhibitors are known in the art, for example, EP-330485-A discloses a series of 4-amino-3- acylquinoline derivatives in which the quinoline is substituted in the 8-position by, for example, hydroxyalkyl and hydroxyalkoxy groups.
The compounds of EP 330485-A have been found to have poor dissolution rates in water and, as a consequence, could potentially exhibit poor bioavailability in vivo and hence low and poorly reproducible levels of therapeutic activity. It has now been found that the problem of poor dissolution can be overcome by producing the compounds in the form of a particular class of salts. Furthermore, in selecting compounds for use in therapy it is important to take a number or criteria into account, for example, in addition to physical qualities such as good dissolution (and hence good bioavailability) , the desired level of intrinsic potency and duration of action of the chosen compounds has to be at the desired level. It has been found that a particular compound of EP-330485-A when produced in the form of a salt as described herein, in addition to having the desired physical qualities such as a high dissolution rate, also has the desired levels of potency and duration of action and, as such, form the subject matter of the present invention.
The present invention therefore provides in a first aspect a compound of structure (I) :
in the form of a salt characterised in that the salt is that formed by reaction of said compound of structure (I) with a strong acid.
As used herein, the term strong acid shall be taken to mean an acid with a pka of less than about 4.0. The nature of such acids will be apparent to those skilled in the art and include, for example, mineral acids such as hydrochloric acid, and sulphonic acids such as alkyl sulphonic acids, in particular methane sulphonic acid.
Particularly preferred salts of the present invention are those formed by reaction with hydrochloric acid or methane sulphonic acid, that is to say,
3-butyryl-4-(2-methylphenylamino)-8-(2-hydroxyethoxy)- quinoline hydrochloride, and 3-butyryl-4-(2-methylphenyl¬ amino)-8-(2-hydroxyethoxy)quinoline mesylate.
The salts of the present invention, in particular the hydrochloride and mesylate salts referred to above, have been found to exhibit exceptionally fast intrinsic dissolution rates when compared to the free base compound of structure (I) disclosed in EP-330485-A. Thus,
whereas the free base has a poor dissolution rate and, as such, may be expected in vivo to exhibit poorly reproducible bioavailability (and so be less effective therapeutically) , the salts of the present invention are expected to exhibit a much more consistent bioavailability (since their dissolution rates are far more favourable) and to prove more effective per given dose and more reliably effective per given dose on administration to patients.
The salts described herein can be used in therapy in the treatment of gastrointestinal diseases in mammals, in particular humans. Such diseases include, for example, gastric and duodenal ulcers, aspiration pneumonitis and Zollinger-Ellison syndrome. Further, the salts can be used in the treatment of other disorders where an anti-secretory effect is desirable, for example in patients with a history of chronic and excessive alcohol consumption, and in patients with gastrooesophageal reflux disease (GERD) .
In therapeutic use, the salts can be administered in a standard pharmaceutical composition comprising the salt and a pharmaceutically acceptable carrier. The present invention provides in a further aspect therefore a pharmaceutical composition comprising a salt as described herein in association with a pharmaceutically acceptable carrier.
Suitable pharmaceutical compositions are as described in EP-330485-A.
Suitable daily dosage regimens for an adult patient may be, for example, an oral dose of between 1 and 1000 mg, preferably between 1 and 500 mg, or an
intravenous, subcutaneous or intramuscular dose of between 0.1 and 100 mg, preferably between 0.1 and 25 mg of the salts described herein, the salt being administered in a unit dosage 1 to 4 times a day.
In addition, the salts can be co-administered with further active ingredients such as antacids (for example, magnesium carbonate or hydroxide and aluminium hydroxide) , non-steroidal anti-inflammatory drugs, steroids or nitrite scavengers or other drugs used for treating gastric ulcers (for example, prostanoids or H2-antagonists such as cimetidine) .
-D-
EXAMPLE 1
3-Butyry1-4-(2-methylphenylamino)-8-(2-hydroxyethoxy)- quinoline can be prepared according to the procedures described in EP-330485-A.
Preparation of 3-butyryl-4-(2-methylphenylamino)-8-C2- hvdroxyethoxy)quinoline hydrochloride
3-Butyry1-4-(2-methylphenylamino)-8-(2-hydroxy- ethoxy)quinoline (10 g) was suspended in methanol (100 ml) at room temperature, cone, hydrochloric acid added slowly to give a clear solution, then the solvent evaporated. The residue was twice taken up in 2-propanol and re-evaporated, and was then recrystallised from
2-propanol/ether to obtain the desired salt (9.7 g) , m.p. 214-215°C.
C22H24N2°3*HC1'°•2H2°
Found C 65.50, H 6.21, N 6.88 Requires C 65.32, H 6.33, N 6.93.
EXAMPLE 2
Preparation of 3-butyryl-4-(2-methylphenylamino)-8-(2- hvdroxyethoxy)quinoline mesylate
3-Butyryl-4-(2-methylphenylamino)-8-(2-hydroxy- ethoxy)quinoline (60 g) was suspended in ethyl acetate (400 ml) , warmed to 50°C, and ethanesulphonic acid (16.3 g) added with vigorous stirring. The desired salt crystallised on cooling, and was filtered off and washed with ethyl acetate; yield 50.1 g, m.p. 83-85°C.
C22H24N2°3-CH4°3S-H2°
Found C 57.78, H 6.28, N 5.84 Requires C 57.73, H 6.32, N 5.85.
Claims
A compound of structure (I)
in the form of a salt, characterised in that the salt is that formed by reaction of the compound of structure (I) with a strong acid.
2. A salt according to claim 1 which is 3-butyryl-4-(2-methylphenylamino)-8-(2-hydroxy- ethoxy)quinoline hydrochloride.
3. A salt according to claim 1 which is 3-butyry1-4-(2-methylphenylamino)-8-(2-hydroxy- ethoxy)quinoline mesylate.
4. A process for preparing a salt according to claim 1 which comprises reacting a compound of structure (I) as described in claim 1 with a strong acid.
5. A pharmaceutical composition comprising a salt according to claim 1 in association with a pharmaceutically acceptable carrier.
6. A pharmaceutical composition comprising
3-butyryl-4-(2-methylphenylamino)-8-(2-hydroxyethoxy)- quinoline hydrochloride in association with a pharmaceutically acceptable carrier.
7. A salt according to claim 1 for use in therapy.
8. 3-Butyryl-4-(2-methylphenylamino)-8-(2-hydroxy- ethoxy)quinoline hydrochloride for use in therapy.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB91019182 | 1991-01-29 | ||
| GB919101918A GB9101918D0 (en) | 1991-01-29 | 1991-01-29 | Compound |
| GB919101919A GB9101919D0 (en) | 1991-01-29 | 1991-01-29 | Compound |
| GB91019190 | 1991-01-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0569396A1 true EP0569396A1 (en) | 1993-11-18 |
Family
ID=26298350
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP92903019A Withdrawn EP0569396A1 (en) | 1991-01-29 | 1992-01-27 | Salts of a 4-amino-3-acyl quinoline derivative and their use as inhibitors of gastric acid secretion |
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) | FI933376A (en) |
| HU (1) | HUT67609A (en) |
| IE (1) | IE920267A1 (en) |
| IL (1) | IL100791A0 (en) |
| MA (1) | MA22401A1 (en) |
| MX (1) | MX9200338A (en) |
| NO (1) | NO932722D0 (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 |
| IS4164A (en) * | 1993-06-11 | 1994-12-12 | Ab Astra | Compounds that inhibit gastric acid flow |
| US5556863A (en) * | 1993-06-11 | 1996-09-17 | Astra Aktiebolag | Compound for gastric acid secretion inhibition |
| 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 |
| WO2003043614A2 (en) * | 2001-11-19 | 2003-05-30 | 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 |
| CA2493618A1 (en) | 2002-08-01 | 2004-02-12 | Nitromed, Inc. | Nitrosated proton pump inhibitors, compositions and methods of use |
| CN1874772A (en) | 2003-11-03 | 2006-12-06 | 阿斯利康(瑞典)有限公司 | 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 CA CA002099117A patent/CA2099117A1/en not_active Abandoned
- 1992-01-27 AU AU11799/92A patent/AU652028B2/en not_active Ceased
- 1992-01-27 CZ CZ931532A patent/CZ153293A3/en unknown
- 1992-01-27 WO PCT/EP1992/000200 patent/WO1992012969A1/en not_active Application Discontinuation
- 1992-01-27 JP JP4503051A patent/JPH06504541A/en active Pending
- 1992-01-27 NZ NZ241408A patent/NZ241408A/en unknown
- 1992-01-27 EP EP92903019A patent/EP0569396A1/en not_active Withdrawn
- 1992-01-27 MA MA22687A patent/MA22401A1/en unknown
- 1992-01-27 MX MX9200338A patent/MX9200338A/en unknown
- 1992-01-27 AP APAP/P/1992/000352A patent/AP337A/en active
- 1992-01-27 SK SK709-93A patent/SK70993A3/en unknown
- 1992-01-27 HU HU9302201A patent/HUT67609A/en unknown
- 1992-01-28 PT PT100056A patent/PT100056A/en not_active Application Discontinuation
- 1992-01-28 IL IL100791A patent/IL100791A0/en unknown
- 1992-01-28 IE IE026792A patent/IE920267A1/en unknown
- 1992-01-28 CN CN92101029A patent/CN1064268A/en active Pending
-
1993
- 1993-07-28 NO NO932722A patent/NO932722D0/en unknown
- 1993-07-28 FI FI933376A patent/FI933376A/en unknown
Non-Patent Citations (1)
| Title |
|---|
| See references of WO9212969A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1992012969A1 (en) | 1992-08-06 |
| FI933376A0 (en) | 1993-07-28 |
| AU652028B2 (en) | 1994-08-11 |
| CA2099117A1 (en) | 1992-07-30 |
| NZ241408A (en) | 1994-05-26 |
| AP9200352A0 (en) | 1992-01-31 |
| MX9200338A (en) | 1992-12-01 |
| JPH06504541A (en) | 1994-05-26 |
| AP337A (en) | 1994-04-08 |
| NO932722L (en) | 1993-07-28 |
| CN1064268A (en) | 1992-09-09 |
| FI933376A (en) | 1993-07-28 |
| CZ153293A3 (en) | 1993-12-15 |
| HU9302201D0 (en) | 1993-10-28 |
| MA22401A1 (en) | 1992-10-01 |
| IE920267A1 (en) | 1992-07-29 |
| NO932722D0 (en) | 1993-07-28 |
| IL100791A0 (en) | 1992-09-06 |
| HUT67609A (en) | 1995-04-28 |
| PT100056A (en) | 1993-03-31 |
| SK70993A3 (en) | 1994-01-12 |
| AU1179992A (en) | 1992-08-27 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
| 17P | Request for examination filed |
Effective date: 19930709 |
|
| AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU MC NL SE |
|
| 17Q | First examination report despatched |
Effective date: 19931209 |
|
| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN |
|
| 18W | Application withdrawn |
Withdrawal date: 19960124 |