AU652028B2 - Salts of a 4-amino-3-acyl quinoline derivatives - Google Patents

Description

t a ist OPI DATE 27/OR/97 AOJP DATE 01/10/92 APPLN. TD 117qq 92 J-- PCT NUMBER PCT/EP9?/00200

INTERN,.

;TREATY (PCT) (51) International Patent Classification 5 (11) International Publication Number: WO 92/12969 C07D 215/44, A61K 31/47 Al (43) International Publication Date: 6 August 1992 (06.08.92) (21) International Application Number: PCT/EP92/00200 (74) Agent: GIDDINGS, Peter, Corporate Patents, Smith- Kline Beecham, Mundells, Welwyn Garden City, Hert- (22) International Filing Date: 27 January 1992 (27.01.92) fordshire AL7 1EY (GB).

Priority data: (81) Designated States: AT, AT (European patent), AU, BB, BE 9101918.2 29 January 1991 (29.01.91) GB (European patent), BF (OAPI patent), BG, BJ (OAPI 9101919.0 29 January 1991 (29.01.91) GB patent), BR, CA, CF (OAPI patent), CG (OAPI patent), CH, CH (European patent), Cl (OAPI patent), CM (71) Applicant (for all designated States except US): SMITH- (OAPI patent), CS, DE, DE (Et .opean patent). DK, KLINE BEECHAM INTERCREDIT B.V. [NL/NL]; DK (European patent), ES, ES (European patent), FI, Jaagpad 1, P.O. Box 3120, NL-2280 GC Rijswijk FR (European patent), GA (OAPI patent), GB, GB (European patent), GN (OAPI patent), GR (European pa- (72) Inventors; and tent), HU, IT (European patent), JP, KP, KR, LK, LU, Inventors/Applicants (for US only): IFE, Robert, John [GB/ LU (European patent), MC (European patent), MG, ML GB]; LEACH, Colin, Andrew [GB/GB]; Smithkline (OAPI patent), MR (OAPI patent), MW, NL, NL (Euro- Beecham Pharmaceuticals, The Frythe, Welwyn, Hert- pean patent), NO, PL, RO, RU, SD, SE, SE (European fordshire AL6 9AR patent), SN (OAPI patent), TD (OAPI patent), TG (OA- PI patent), US.

Published With international search report.

652 28 (54) Title: SALTS OF A 4-AMINO-3-ACYL QUINOLINE DERIVATIVE AND THEIR USE AS INHIBITORS OF GAS- TRIC ACID SECRETION

(CH

2 2 CH3 O(CH2)2OH 22 f (57) Abstract A compound of structure in the form of a salt, a process for its preparation and pharmaceutical compositions comprising such a salt and its use in therapy.

.il C WO 92/12969 PCT/EP92/00200 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-3acylquinoline 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.

L I II I| I- I WO 92/12969 PCT/EP92/00200 -2- The present invention therefore provides in a first aspect a compound of structure

CH

3 3 NH 0

(CH

2 2

CH

3 (I)

N

O(CH2)2OH 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-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 disclosed in EP-330485-A. Thus, 1.

WO 92/12969 PCT/EP92/00200 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 j 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 WO 92/12969 PCT/EP92/00200 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 H 2 -antagonists such as cimetidine).

%WO 92/12969 PCT/ EP92/00200 EXkMPLE 1 3-Butyryl-4-(2-methylphenylaino)-8-(2-hydroxyethoxy)quinoline can be prepared according to the procedures described in EP-330485-A.

Preparation of 3-butvrvl-4-(2-methylphenylamino)-8-(2hydroxvethoxv)guinoline hydrochloride 3-Butyryl-4-(2-ethylphenylamino)-8-(2-hydroxyethoxy)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 0

C.

C

22

H

24

N

2 0 3 HC1.0.2H 2 0 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-butyrvl-4-(2-meth lhenvlamino) 2hvdroxvethoxvyluinoline mesylate 3-Butyryl-4 (2-methyIphenylamino)-8-(2-hydroxyethoxy)quinoline (60 g) was suspended in ethyl acetate (400 ml), warmed to 50 0 C, and methanesuiphonic 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 0

C.

C

22

H

24

N

2 0 3 1CH 4 0 3

S.H.,O

Found C 57.78, H 6.28, N 5.84 Requires C 57.73, H 6.32, N 5.85.

I

-~L~IIII-

5a Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

t,

J'

9L4 5.p:\opcr-\&b, 1799-971

Claims (9)

1. A compound of structure CH, -NH 0 (CH 2 2 CH (I) (CH 2 2 0H 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-butyryl-4-(2-methylphenylamino)-8-(2-hydro;cy- ethoxy)quinoline mesylate.

4. A process for preparing a salt according to claim 1 which comprises reacting a compound of structure as described in claim 1 with a strong acid. A pharmaceutical composition comprising a salt according to claim 1 in association with a pharmaceutically acceptable carrier. c ts, a -s Y-t I -7

6. A-harmaceutical composition comprising 3-butyryl-4- (2-methylphenylamino)-8-(2-hydroxyethoxy)-quinoline hydrochloride in association with a pharmaceutically acceptable carrier.

7. A method for the treatment of gastrointestinal diseases which comprises administering a therapeutically effective amount of a salt according to claim 1.

8. A method for the treatment of gastrointestinal diseases which comprises administering a therapeutically effective amount of 3-butyryl-4-(2-methylphenylamino)-8-(2- hydroxyethoxy)quinoline hydrochloride.

9. A method according to claim 7 or claim 8 wherein the gastrointestinal disease is gastric and duodenal ulcers, aspiration pneumonitis or Zollinger-Ellison syndrome. Compounds of structure or processes for their preparation, substantially as hereinbefore described with reference to the Examples. DATED this 17th day of June, 1994. SMITHKLINE BEECHAM INTERCREDIT B.V. By its Patent Attorneys DAVIES COLLISON CAVE oCr dab, 11799-92.145.7

16- I- INTERNATIONAL SEARCH REPORT International Application No PCT/EP 92/00200 I. CLASSIF;ICATION OPSUBJECT MATrER (if sVeralclassification symbols apply, indlcate all)6 According to intenariona.l Patent Classification (IMC or to both Nationl Or-fication and IPC Int.C1. 5 C070215/44; A61K31/47 11. FIEUDS SEARCHED Minimum Documentation Smjdcd 7 Cla~ssification Systers Classification Symbols Int.Cl. 5 iC070 Documentation Searched other than Minimum Documentation to the Extent that such Documents are Included in the Fields Searcheds M. DOCUMENT'S CONSIDERED TO BE RELEVANT9 Category 0 Citation of Document, 1 1 with indication, wisa-, appropriate, of the relevant passages 1e2 ".vunt to Claim No.- 1 X EP,A,0 330 485 (SMITHKLINE BECKMAN INTERCREDIT 30 August 1989 cited in the application see page 3, line 19 line 23 see page 6, line 31 line 34; claims 1,6-9; example Specal categories of cited documents 10 later document published after the international filing date document defining the general state of the art which is not or prioritydate and not in sonflict with the application bt asn~l~td o f c te to unerstand the principle or theory underlying th e consderd t beof artiula retvaiceinvention earlier documoent but published on or after the international document of particular relevance; the claimed invention filing date cannot be considered novel or nnot be considered to document which may throw doubts on priority csLaim(s) or involve an inventive step which is cited to establish the publication date of another docamant oprtclrrlaneheclaimed invention Citation or other special reason (as specified) cannot be con ",dr tivoeannventive step when the document referring to an oral1 disclosure use, exhibition or document is combined with ooe or more other such docu- other meas ments, such combination being obvious to a pawsn skilled 'P document published prior to the internationaJ1 filing dite but in the art. later than the priority date claimed W, document member of the same patent family IV. CERTIFICATION Date of the Actual Completion of the International Sawch Date of Mail~ng of this International Search Report 03 APRIL 1992 1 2. 05. 92 rInternational Searching Authortty Signature of Authorized Officer EUROPEAN PATENT OFFICE I P. B 0SSMA Fu PCTILSA/21 (o m &big J t. 193IW1 ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION No. EP 9200200 SA 55460 This annex fists the patent family members relating to the patent documents cited in the above-mentioned international search report. The members are as contained in the European Patent Office EDP fle on The European Patent Office is in no way liable for thes particulars which are merely given for the purpose of infornustion. 03/04/92 Patent document Publication Patent family Publication cited in search report 7date member(fi) date EP-A-0330485 30-08-89 AU-B- 606508 07-02-91 AU-A- 3181989 22-09-89 WO-A- 8908104 08-09-89 JP-T- 2503318 11-10-90 0 0 w For more details about ths annex :see Official Journal of the European Patent Office, No. 12/82 nh I- I IT_