WO1992012969A1 - 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 secretion Download PDF

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Publication number
WO1992012969A1
WO1992012969A1 PCT/EP1992/000200 EP9200200W WO9212969A1 WO 1992012969 A1 WO1992012969 A1 WO 1992012969A1 EP 9200200 W EP9200200 W EP 9200200W WO 9212969 A1 WO9212969 A1 WO 9212969A1
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WIPO (PCT)
Prior art keywords
salts
inhibitors
amino
salt
methylphenylamino
Prior art date
Application number
PCT/EP1992/000200
Other languages
French (fr)
Inventor
Robert John Ife
Colin Andrew Leach
Original Assignee
Smithkline Beecham Intercredit B.V.
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
Priority claimed from GB919101918A external-priority patent/GB9101918D0/en
Priority claimed from GB919101919A external-priority patent/GB9101919D0/en
Application filed by Smithkline Beecham Intercredit B.V. filed Critical Smithkline Beecham Intercredit B.V.
Priority to SK709-93A priority Critical patent/SK70993A3/en
Priority to CZ931532A priority patent/CZ153293A3/en
Priority to AU11799/92A priority patent/AU652028B2/en
Priority to JP4503051A priority patent/JPH06504541A/en
Publication of WO1992012969A1 publication Critical patent/WO1992012969A1/en
Priority to FI933376A priority patent/FI933376A0/en
Priority to NO93932722A priority patent/NO932722L/en

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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

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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

A compound of structure (I) in the form of a salt, a process for its preparation and pharmaceutical compositions comprising such a 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) :
Figure imgf000004_0001
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

-t>-Claims
A compound of structure (I)
Figure imgf000008_0001
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.
PCT/EP1992/000200 1991-01-29 1992-01-27 Salts of a 4-amino-3-acyl quinoline derivative and their use as inhibitors of gastric acid secretion WO1992012969A1 (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
SK709-93A SK70993A3 (en) 1991-01-29 1992-01-27 Salts of 4-amino-3-acylquionoline derivative and their use as inhibitors of gastric acid secretion
CZ931532A CZ153293A3 (en) 1991-01-29 1992-01-27 Salts of 4-amino-acylquinoline derivative
AU11799/92A AU652028B2 (en) 1991-01-29 1992-01-27 Salts of a 4-amino-3-acyl quinoline derivatives
JP4503051A JPH06504541A (en) 1991-01-29 1992-01-27 Salts of 4-amino-3-acylquinoline derivatives and their use as gastric acid secretion inhibitors
FI933376A FI933376A0 (en) 1991-01-29 1993-07-28 4-AMINO-3-ACYLKINOLINDERIVATER AND DERASE ANVAENDNING SOM INHIBITORER AVMAGSYRASEKRETION
NO93932722A NO932722L (en) 1991-01-29 1993-07-28 SALTS OF A 4-AMINO-3ACYL-QUINOLINE DERIVATIVE AND THEIR USE AS INHIBATORS FOR GASTRIC ACID SECRETION

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB919101918A GB9101918D0 (en) 1991-01-29 1991-01-29 Compound
GB9101918.2 1991-01-29
GB919101919A GB9101919D0 (en) 1991-01-29 1991-01-29 Compound
GB9101919.0 1991-01-29

Publications (1)

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WO1992012969A1 true WO1992012969A1 (en) 1992-08-06

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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)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993012090A1 (en) * 1991-12-12 1993-06-24 Smithkline Beecham Intercredit B.V. 4-amino-3-acyl quinoline derivatives and their use as inhibitors of gastric acid secretion
WO1994029274A1 (en) * 1993-06-11 1994-12-22 Astra Aktiebolag New active compounds
WO1996017830A1 (en) * 1994-12-08 1996-06-13 Astra Aktiebolag Compounds for inhibition of gastric acid secretion
WO2003043614A2 (en) * 2001-11-19 2003-05-30 Altana Pharma Ag Reversible proton pump inhibitors for the treatment of airway disorders
US6852739B1 (en) 1999-02-26 2005-02-08 Nitromed Inc. Methods using proton pump inhibitors and nitric oxide donors
US7175854B2 (en) 2000-12-07 2007-02-13 Altana Pharma Ag Pharmaceutical preparation comprising an active dispersed on a matrix
US7211590B2 (en) 2002-08-01 2007-05-01 Nitromed, Inc. Nitrosated proton pump inhibitors, compositions and methods of use
EP1974730A1 (en) 2003-11-03 2008-10-01 AstraZeneca AB Imidazo[1,2-a]pyridine derivatives for use in the treatment of sleep disturbance due to silent gastro-esophageal reflux
US7951397B2 (en) 2002-02-20 2011-05-31 Nycomed Gmbh Oral dosage form containing a PDE 4 inhibitor as an active ingredient and polyvinylpyrrolidon as excipient
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

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0330485A1 (en) * 1988-02-25 1989-08-30 SmithKline Beecham Intercredit B.V. 4-Amino-3-acyl quinoline derivatives and their use as inhibitors of gastric acid secretion

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0330485A1 (en) * 1988-02-25 1989-08-30 SmithKline Beecham Intercredit B.V. 4-Amino-3-acyl quinoline derivatives and their use as inhibitors of gastric acid secretion

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993012090A1 (en) * 1991-12-12 1993-06-24 Smithkline Beecham Intercredit B.V. 4-amino-3-acyl quinoline derivatives and their use as inhibitors of gastric acid secretion
WO1994029274A1 (en) * 1993-06-11 1994-12-22 Astra Aktiebolag New active compounds
US5556863A (en) * 1993-06-11 1996-09-17 Astra Aktiebolag Compound for gastric acid secretion inhibition
AU680516B2 (en) * 1993-06-11 1997-07-31 Astra Aktiebolag New active compounds
US5889021A (en) * 1993-06-11 1999-03-30 Astra Aktiebolag Active Compounds
CN1045955C (en) * 1993-06-11 1999-10-27 阿斯特拉公司 New active compounds
WO1996017830A1 (en) * 1994-12-08 1996-06-13 Astra Aktiebolag Compounds for inhibition of gastric acid secretion
AU697006B2 (en) * 1994-12-08 1998-09-24 Astra Aktiebolag Compounds for inhibition of gastric acid secretion
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
US7332505B2 (en) 1999-02-26 2008-02-19 Nitromed, Inc. Nitrosated and nitrosylated proton pump inhibitors, compositions and methods of use
US7175854B2 (en) 2000-12-07 2007-02-13 Altana Pharma Ag Pharmaceutical preparation comprising an active dispersed on a matrix
US7951398B2 (en) 2000-12-07 2011-05-31 Nycomed Gmbh Pharmaceutical preparation comprising an active dispersed on a matrix
WO2003043614A3 (en) * 2001-11-19 2004-03-11 Altana Pharma Ag Reversible proton pump inhibitors for the treatment of airway disorders
WO2003043614A2 (en) * 2001-11-19 2003-05-30 Altana Pharma Ag Reversible proton pump inhibitors for the treatment of airway disorders
US7951397B2 (en) 2002-02-20 2011-05-31 Nycomed Gmbh Oral dosage form containing a PDE 4 inhibitor as an active ingredient and polyvinylpyrrolidon as excipient
US8431154B2 (en) 2002-02-20 2013-04-30 Takeda Gmbh Oral dosage form containing a PDE 4 inhibitor as an active ingredient and polyvinylpyrrolidone as excipient
US9468598B2 (en) 2002-02-20 2016-10-18 Astrazeneca Ab Oral dosage form containing a PDE 4 inhibitor as an active ingredient and polyvinylpyrrolidon as excipient
US7211590B2 (en) 2002-08-01 2007-05-01 Nitromed, Inc. Nitrosated proton pump inhibitors, compositions and methods of use
EP1974730A1 (en) 2003-11-03 2008-10-01 AstraZeneca AB Imidazo[1,2-a]pyridine derivatives for use in the treatment of sleep disturbance due to silent gastro-esophageal reflux

Also Published As

Publication number Publication date
CN1064268A (en) 1992-09-09
NO932722D0 (en) 1993-07-28
IE920267A1 (en) 1992-07-29
AU1179992A (en) 1992-08-27
EP0569396A1 (en) 1993-11-18
MA22401A1 (en) 1992-10-01
CA2099117A1 (en) 1992-07-30
AU652028B2 (en) 1994-08-11
HUT67609A (en) 1995-04-28
AP337A (en) 1994-04-08
NZ241408A (en) 1994-05-26
IL100791A0 (en) 1992-09-06
CZ153293A3 (en) 1993-12-15
FI933376A (en) 1993-07-28
AP9200352A0 (en) 1992-01-31
PT100056A (en) 1993-03-31
FI933376A0 (en) 1993-07-28
MX9200338A (en) 1992-12-01
NO932722L (en) 1993-07-28
JPH06504541A (en) 1994-05-26
SK70993A3 (en) 1994-01-12
HU9302201D0 (en) 1993-10-28

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