NZ241408A - Strong acid salt of 3-butyryl-4-(2-methylphenylamino)-8-(2-hydroxy-ethoxy)quinoline and pharmaceutical compositions thereof - Google Patents
Strong acid salt of 3-butyryl-4-(2-methylphenylamino)-8-(2-hydroxy-ethoxy)quinoline and pharmaceutical compositions thereofInfo
- Publication number
- NZ241408A NZ241408A NZ241408A NZ24140892A NZ241408A NZ 241408 A NZ241408 A NZ 241408A NZ 241408 A NZ241408 A NZ 241408A NZ 24140892 A NZ24140892 A NZ 24140892A NZ 241408 A NZ241408 A NZ 241408A
- Authority
- NZ
- New Zealand
- Prior art keywords
- methylphenylamino
- quinoline
- butyryl
- salt
- hydroxyethoxy
- Prior art date
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
Description
New Zealand Paient Spedficaiion for Paient Number £41408
241408
Priority Datc(s): !*.*?'.
Complete Specification Filed:
Class: CpMMriwZf.. )v»n
Publication Date: MAY ]9?4 P.O. Journal, No: .. tsso
NO DRAWINGS
NEW ZEALAND PATENTS ACT, 1953
No.:
Date:
COMPLETE SPECIFICATION COMPOUNDS
We, SMITHKLINE BEECHAM INTERCREDIT B.V. 28-34 Blaak, P.O. Box 2, 3000 DG Rotterdam, Netherlands, a Dutch Company, hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:-
- 1 -(followed by page la)
N.Z. PATENT OFFICE
27 JAN 1992
RECEIVED
- la -
0 k 1 l>t ® ^
COMPOUNDS
The present invention relates to certain salts of a quinoline compound, pharmaceutical compositions 5 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, New 10 Zealand Patent Specification No. 228098 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 New Zealand Patent Specification No. 228098 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 of 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
Specification No. 228098 when produced in the 30 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.
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The present invention therefore provides in a first aspect a compound of structure (I):
(ch2)2ch3
(I)
0(ch2)20h 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 4.0. The nature of such acids will be apparent to those skilled in the art and include, for example, mineral acids such as 20 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 25 acid or methane sulphonic acid, that is to say,
3-butyryl-4-(2-methylphenylamino)-8-(2-hydroxyethoxy)-quinoline hydrochloride, and 3-butyryl-4-(2-methylphenylamino) -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 Specification No. 228098. Thus,
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2 THAR 1994
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ir-
4m
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8i
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 15 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 20 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 25 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 New Zealand Patent Specification No.228098.
Suitable daily dosage regimens for an adult patient may be, for example, an oral dose of between 1 and 35 1000 mg, preferably between 1 and 500 mg, or an ^
f* •' *' *
£ 22 KAS SS">i fa . - 'aiHMiiWr
24 1 408
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).
P30004/5
Claims (9)
- EXAMPLE 1 3-Butyryl-4-(2-methylphenylamino)-8-(2-hydroxyethoxy)-quinoline can be prepared according to the procedures described in New Zealand Patent Specification No.2280 98.
- Preparation of 3-butvrvl-4-(2-methvlphenvlamino)-8-(2-hvdroxvethoxv^ cruinoline hydrochloride
- 3-Butyry1-
- 4-(2-methylphenylamino)-8-(2-hydroxy-ethoxy)quinoline (10 g) was suspended in methanol (100 ml) at room temperature, conc. 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•0•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-butvrvl-4-(2-methvlphenvlaminol-8-f2-hvdroxvethoxv) cruinoline mesylate;3-Butyryl-4-(2-methylphenylamino)-8-(2-hydroxyethoxy) quinoline (60 g) was suspended in ethyl acetate (400 ml), warmed to 50°C, and methanesulphonic 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,H20 Found C 57.78, H 6.28, N 5.84 Requires C 57.73, H 6.32, N 5.85 4 P30004/5 24140 8 -6- W8ft¥!j^S CLAIM B: Claims 10 15 1. A compound of structure (I): CKL (CH2)2CH3 (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. 20 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-butyryl-4-(2-methylphenylamino)-8-(2-hydroxyethoxy ) quinoline mesylate. 25 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. 30
- 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 suitable for use in therapy. 8. 3-Butyryl-4-(2-methylphenylamino)-
- 8-(2-hydroxyethoxy) quinoline hydrochloride suitable for use in therapy.
- 9. A process for preparing a salt according to claim 1, substantially as hereinbefore described with particular reference to either of Examples 1 and 2.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB919101918A GB9101918D0 (en) | 1991-01-29 | 1991-01-29 | Compound |
| GB919101919A GB9101919D0 (en) | 1991-01-29 | 1991-01-29 | Compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NZ241408A true NZ241408A (en) | 1994-05-26 |
Family
ID=26298350
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NZ241408A NZ241408A (en) | 1991-01-29 | 1992-01-27 | Strong acid salt of 3-butyryl-4-(2-methylphenylamino)-8-(2-hydroxy-ethoxy)quinoline and pharmaceutical compositions thereof |
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
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 |
| 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 |
| EP0569396A1 (en) | 1993-11-18 |
| 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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