ZA200109497B

ZA200109497B - New use of compounds as antibacterial agents.

Info

Publication number: ZA200109497B
Application number: ZA200109497A
Authority: ZA
Inventors: Arne Eek; Johan Raud
Original assignee: Astrazeneca Ab
Priority date: 1999-06-01
Filing date: 2001-11-16
Publication date: 2003-02-17
Also published as: SE9902027D0

Description

& . NEW USE OF COMPOUNDS AS ANTIBACTERIAL AGENTS

Field of the invention

The present invention is directed to a new use of nitric oxide-releasing Non Steriodal ~ Antinflammatory Drugs (NO-releasing NSAIDs). More particularly the invention is directed to the use of NO-releasing NSAIDs for the manufacture of a medicament for the treatment of bacterial infections, paticularly caused or mediated by Helicobacter pylori as well as a combination with acid susceptible proton pump inhibitors for the treatment of bacterial infections.

Background of the invention and prior art } Win&

NSAIDs, are among the most commonly prescribed and used drugs worl d{g Despite the therapeutic benefits of NSAIDs, their use is limited. The use of NSAIDs may lead to } gastric mucosal damage due to inhibited production of prostaglandins which increases the risk of gastrointestinal side-effects. : ]

A recent proposal for reducing the side-effects associated with NSAIDs treatment is to use nitric oxide-releasing NSAID derivatives (NO-releasing NSAIDs) (del Soldato P et al. ———— ——MNOreleasing NSAIDs Ancvel class cf safer and effective antiinflammarcryagonts—————————

Inflammopharmacology, 1996; 4, 181-188). NO-releasing NSAIDs reduce the gastrointestinal side-effects but still have the pharmacological activity characteristic of the frequently used NSAIDs.

NO-releasing NSAIDs and pharmaceutically acceptable salts thereof are for instance described in WO 94/04484, WO 94/12463, WO 95/09831 and WO 95/30641.

Helicobacter pylori is a gram-negative spirilliform bacteria which colonises in the gastric mucosa. The relationship between gastrointestinal disorders and infections with

SUBSTITUTE SHEET (RULE 26)

0 2

Helicobacter pylori proposed in 1983 by Warren (Warren JR Lancer 1983:1.1273) is well . established today.

A number of different therapies have been proposed for the treatment of Helicobacter pylori infections. Combination therapies are commonly used. The most commonly used comprise a proton pump inhibitor in combination with one or more antibacterial compounds such as claritromycin and amoxicillin. For instance W093/00327 discloses the combination of a substance with inhibiting effect on the gastric acid secretion which increases the intragastric pH, and an acid degradable antibacterial compound. Some of these therapies also comprise a bismuth compound, se for instance WO 98/03219 and

W098/22117, which latter application discloses a composition containing bismuth. an antimicrobial agent and a non-steriodal antiinflammatory agent for the treatment of gastrointestinal disorders caused or mediated by Helicobacter pylori.

In view of the vast number of the population suffering from gastrointestinal disorders : caused or mediated by bacterial infections, such as Helicobacter pylori infections, and also in view of the fact that many bacterial strains develop a resistance to commonly used . antibiotics, a continuing need exists for a safe and effective medicament having an antibacterial effect, especially for the treatment of Helicobacter pylori infections.

Qutline of the invention

It has now surprisingly been found that NO-releasing NSAIDs have an antibacterial effect. which makes them useful for the treatment of bacterial infections. : 25

The present invention is related to the use of a NO-releasing NSAID as well as pharmaceutically acceptable salts or enantiomers thereof, for the manufacture ofa : medicament for the treatment of bacterial infections.

Preferably the NO-releasing NSAID is defined by the formula I

3 nN i

M—C—0—X—ONO, I wherein M is selected from anyone of cl CH,— 0 \ s \_/

S ci CH,

CH, 0 o CH, a ~~

N Q cH, $ :

AND .

CH, a. _

CH

F

0]

Or \_/ |_| CH,O bH 4

Cl 0] ll

CH, N._-CH, _CH-CH; CH—

CH CHO CH,—

Cc "en,

CH,0 ©]

EN

I and X is a spacer, i.e. a compound forming a bridge between the nitrogen oxide donating group and the NSAID moiety, or a pharmaceutically acceptable salt or enantiomer thereof;

X is preferably selected from linear, branched or cyclic -(CHz)-y wherein n is an integer of from 2 to 10; -(CH3);m-0-(CHy)p- wherein m and p are integers of from 2 to 10; and -CH»- pCeH4-CHa-.

M is not limited by the above definition but may be any other compound giving the is corresponding NSAID by hydrolysis of the compound according to formula I.

In a preferred embodiment of the invention M is selected from :

: ol CH— z

CLO oo ci CH,0

CH, 0}

OH o-! ¢ and X is selected from linear -(CH,)p- wherein n is an integer of from 2 to 6; -(CHjy)2-0-(CHj);- and -CH3-pCgH4-CHy-.

In an even more preferred embodiment of the invention the NO-releasing NSAID is a compound according to any one of the formulas go

SCT

CH,0 (1a) 0 CH, 0)

Oo 0 CH,

OC

ONO, (1d) :

Vv 6 ; lo) CH,

OL ~-ONO, (lc) .

SRSA fo) CH,

Og -ONC; (le) .

J lo} a lo]

NH (1g) : , ONO,

CO

NH a

OAC

EE a - oo oo 0

Co N @] \ S08 GENE 0]

CH,

CH,O 2 ( ) '

7 ~ pe

NHC a

T°

CH, 0 ONO

MOTT em 0)

CH,0 0._~_-ONO,

CY

NH (ln)

T°

CH, lo :

CH,O © (lo) . CH, 0) ONO ~~ N 2 (Ip) ; and 0

CH,0

> 8

NH

~~ (la)

In a particularly preferred embodiment of the invention the NO-releasing NSAID is a compound according to formula Ia. to A further aspect of the invention is the use of a NO-releasing NSAID, preferably a compound of the formula I above, in the manufacture of a medicament for use in the treatment of Helicobacter pylori infections, especially in the treatment of gastrointestinal disorders caused or mediated by Helicobacter pylori. 1s Still a further aspect of the invention is a method for the treatment of bacterial infections, : in particular Helicobacter pylori infections, whereby an effective amount of a medicament comprising a NO-releasing NSAID, preferably a compound of the formula I. as active agent is administered to a subject suffering from said bacterial infection. ) 20 Also a pharmaceutical formulation suitable for use in the treatment of bacterial infections, which formulation comprising a NO-releasing NSAID, preferably a compound of the © formulal is within the scope of the invention. EE - Furthermore, the invention is related to the use of a NO-releasing NSAID, preferably a ; 25 compound of the formula I, in combination with an acid susceptible proton pump inhibitor or a salt thereof or an enantiomer or a salt of the enantiomer in the manufacture of pharmaceutical formulations intended for simultanous, separate or sequential : administration in the treatment of bacterial infections, especially Helicobacter pylori infections.

9 “~/

The invention may be applied in combination with other agents generally associated with treatment of bacterial infections, such as for instance antibacterial agents.

An acid susceptible proton pump inhibitor is, for instance, a compound of the general s formula II 0

Het, — X -S —Het, I wherein 10 Het is

R, oN

NJ ps '

N or Rg

Het, is ’

Rg N

R : 2

N ’ N— S ¢ : / R or A = or 8 N x y

H Re H R's _

X= —CH— Ri 1 or wherein

N in the benzimidazole moiety means that one of the carbon atoms substituted by Re-Ro optionally may be exchanged for a nitrogen atom without any substituents;

(DP 10

R,, R; and Rj are the same or different and selected from hydrogen, alkyl, alkoxy : optionally substituted by fluorine, alkylthio, alkoxyalkoxy, dialkylamino, piperidino. morpholino, halogen, phenyl and phenylalkoxy; 5s Ry and R; are the same or different and selected from hydrogen. alkyl and aralkyl:

Re’ is hydrogen, halogen, trifluoromethyl, alkyl and alkoxy;

Rs-Ry are the same or different and selected from hydrogen, alkyl, alkoxy, halogen, halo- alkoxy, alkylcarbonyl, alkoxycarbonyl, oxazolyl, trifluoroalkyl, or adjacent groups Rs-Ro form ring structures which may be further substituted;

Ryo is hydrogen or forms an alkylene chain together with R; and

Ry and Ry; are the same or different and selected from hydrogen, halogen or alkyl, alky! : groups, alkoxy groups and moities thereof . The substituents may be branched or straight

C, - Cy -chains or comprise cyclic alkyl groups, such as cycloalkyl-alkyl.

Examples of proton pump inhibitors according to formula II are

I OCH,

CH, CH,

O 0 N OCH,

N “cH, S ( Omeprazole

N

H

Claims

er TT ee— ~~ PCYSECCI/Ot1O0O71 The Swedish Pat t Offi -14- PCT Interation: | Appia er 1 4 08 2001

) 2.0 Claims

1. Use of a NO-releasing NSAID as well as a pharmaceutically acceptable salt or an enantiomer thereof, for the manufacture of a medicament for the treatment of disorders s caused or mediated by Helicobacter pylori.

2. Use of a NO-releasing NSAID and an acid susceptible proton pump inhibitor either of them in the form of a salt or an enantiomer or a salt of the enantiomer in the manufacture of pharmaceutical formulations intended for simultaneous, separate, or sequential administration in the treatment of bacterial infections.

3. Use according to claim 1 or 2 wherein the NO-releasing NSAID is a compound of the formula I i M—C—0O—X—0ONO, I wherein M is selected from anyone of Cl H— ®) So SAGES OOH cl CH, CH, 0 . CH, =O ~~ AMENDED SHEET

. - CC . ~H2000 The Swedish Paemo—— PCT/SE 00/0 1 } ] PO t Offi N 2 S ad OY Or CH, (, nO CH, F

0 C Cl 0) I J ' N CH, CH__ [| CH, : CH30 CH;— CH,0O 0] NN THs a cant CR - HN —— ee ———— Fs orcn— —CH—— Z CHy” = CH— 3 and X is selected from linear, branched or cyclic -(CH,)p- wherein n is an integer of from 2 to 10; ~(CH2)-O-(CH3)p- wherein m and p are integers of from 2 to10; and -CH»-pC¢Hy-CHa-, 5 or a pharmaceutically acceptable salt or enantiomer thereof.

AMENDED SHEET

EE a PCT/SE 0-0 0-10 71 . H 2101 The Swecijen Form Sm 1 4 1 : : = [224 ice ol PCT In raisticn = Application 03- 2001 v 23

4. Use according to claim 3 wherein M in formula 1 is selected from 0 one / Cc SG en cl CH,0 CH, O Or" O- c C

5. Use according to claim 3 or 4 wherein X in formula I is selected from linear -(CH»),,- wherein n is an integer of from 2 to 6, -(CH»)2-O-(CH3);- and -CH,-pCeHy4-CH>-.

’ 6. Use according to any one of claims 1 - 3 wherein the NO-releasing NSAID is a compound according to any one of the formulas la - Iq gio [SCNT Hs one: CH,0 (la) I — a oo 0 CH, Oo ~"""ono, (Ib) 0] 0 CH, OL ~~ ONG, (1d) ; AMENDED SHEET

— ~~ PCUSECOIO01071 ooHne [Fe See rons Swedizh Patent Office 14 -09%- 2001 : PCT Ini rmction =i Application u N 0) CH, O_~_-ONO, (i) JU 0 CH, Oo ONO; (le) : (JJ " 0 CH, Cy ee ° an JU oo NH lg) r° ONO, 0 } CS wy Cl< g Cl 0 N Na , (i 0 CH, CITC ow, (1K) : : CH,0 AMENDED SHEET

Ee ~~ PCE O4OT O71 oT The Swos : 14 -03- 2001 Cop ; NHC (Ly T° CH, 0 ONO ~~ 2 (Im) : 0 CH,0 O~~_-ONO;,

CY . NH (In) : Cr CH, I 0 Ga FS — IJ 5 (0) : CHO” ~F CH, Oo ONO: (Ip) ;and o) CH,0 ; 5 : NH : Cin g Cl (lq) : AMENDED SHEET

Ce me — I oo a. E - - Hao EE eon PETSEC0 T0107 [ienadonal Application 14 -0%- 2001 ) Ww 26

7. Use according to claim 6, wherein the NO-releasing NSAID is a compound of formula Ia CR [ ~C—0-(CH,),-ONO, (Ia) CH, . CH,O

8. Use according to claim 2 wherein the acid susceptible proton pump inhibitor is a compound of the formula II 9 Het, — X -S — Het, H ) wherein Het, is R, R,

N. EE SN RAN N or 6 Het, is Re N R J \ ’ N— S ( ] N ) R or A — or 8 N x A | ; H o H R's yp X= AMENDED SHEET

TT gz0 BE Swedish Patent Offi | PPATISE NN na FCT Intzrnational Application PCT St 0 0 Io 0 7 1 14 -09- 2001 Ay 27% —CH— Ri 1 R or wherein N in the benzimidazole moiety means that one of the carbon atoms substituted by Re Rg s optionally may be exchanged for a nitrogen atom without any substituents; Ri, R; and Rj are the same or different and selected from hydrogen, alkyl, alkoxy optionally substituted by fluorine, alkylthio, alkoxyalkoxy, dialkylamino, piperidino, morpholino, halogen, phenyl and phenylalkoxy;

R, and Rs are the same or different and selected from hydrogen, alkyl and aralkyl; Re’ is hydrogen, halogen. trifluoromethyl, alkyl and alkoxy: 1s Re-Ry are the same or different and selected from hydrogen, alkyl, alkoxy, halogen, halo- alkoxy, alkylcarbonyl, alkoxycarbonyl, oxazolyl, trifluoroalkyl, or adjacent groups Re-Rg form ring structures which may be further substituted; Ryo is hydrogen or forms an alkylene chain together with R; and

R,; and R), are the same or different and selected from hydrogen, halogen or alkyl, alkyl groups, alkoxy groups and moities thereof , they may be branched or straight C; - Cy - chains or comprise cyclic alkyl groups, such as cycloalkyl-alkyl. is 9. Use according to claim 8 wherein the acid susceptible proton pump inhibitoris selected from omeprazole, an alkaline salt thereof, (S)-omeprazole and an alkaline salt 3 thereof . AMENDED SHEET

PCT/SE00/01071

10. Use according to claim 8 wherein the acid susceptible proton pump inhibitor is lansoprazole or a pharmaceutically acceptable salt thereof or an enantiomer or a salt of the enantiomer.

11. Use according to claim 8 wherein the acid susceptible proton pump inhibitor is pantoprazole or a pharmaceutically acceptable salt thereof or an enantiomer or a salt of the enantiomer.

12. Use according to claim 2 wherein the NO-releasing NSAID is a compound of formula Ia and the acid susceptible proton pump inhibitor is omeprazole, an alkaline salt thereof, (S)-omeprazole or an alkaline salt thereof.

13. Use according to claim 1, wherein the amount of NO-releasing NSAID in each dosage form is 0.5 - 5000 mg.

14. Use according to claim 13, wherein the amount of NO-releasing NSAID is 5 - 1000 mg.

15. Use according to claim 2 and claim 12, wherein the amount of NO-releasing NSAID is 0.5 - 5000 mg and the amount of proton pump inhibitor is 0.1 - 200 mg together in one dosage form or in two separate dosage forms.

16. Use according to claim 2 and claim 12, wherein the amount of NO-releasing NSAID is 5 - 1000 mg and the amount of proton pump inhibitor is 10 - 80 mg.

17. A substance or composition for the use in a method for the treatment of a bacterial infection, said substance or composition comprising a NO-releasing NSAID or a pharmaceutically acceptable salt or an enantiomer thereof, and said method comprising administering an effective amount of said substance or composition to a patient suffering from said bacterial infection. AMENDED SHEET

29 PCT/SE00/01071

18. A substance or composition for the use in a method for the treatment of a bacterial infection, said substance or composition comprising a NO-releasing NSAID, and an acid susceptible proton pump inhibitor or a salt thereof or an enantiomer or a salt of the enantiomer, and said method comprising administering to a patient suffering from said bacterial infection an effective amount of said substance or composition.

19. A substance or composition for the use in a method for the treatment of a bacterial infection, said substance or composition comprising a NO-releasing NSAID, and said method comprising simultaneously, separately or sequentially administering to a patient suffering from said bacterial infection, said substance or composition and an acid susceptible proton pump inhibitor or a salt thereof or an enantiomer or a salt of the enantiomer.

20. A substance or composition for the use in a method for the treatment of a bacterial infection, said substance or composition comprising an acid susceptible proton pump inhibitor or a salt thereof or an enantiomer or a salt of the enantiomer, and said method comprising simultaneously, separately or sequentially administering to a patient suffering from said bacterial infection, an effective amount of said substance or composition and an effective amount of a NO-releasing NSAID.

21. A substance or composition for use in a method of treatment according to any one of claims 17 to 20 wherein the NO-releasing NSAID is a compound of the formula

I. i M—C—0—X—0NO, I : AMENDED SHEET

30 PCT/SE00/01071 wherein M is selected from Tow I 7 / ~ C SA = NZ Cl CH, CH, 0 CH Q CT 5 = N i CH, S Sd | \ J — CH, Os ow (OY CH; =

22. A substance or composition for use in a method of treatment according to claim 21 wherein M in formula I is selected from eee —__ cr, CHT / C cl CH,0 : CH, ®) : OH

23. A substance or composition for use in a method of treatment according to claim 5 21 or 22 wherein X in formula I is selected from linear -(CH,),- wherein n is an integer of from 2 to 6, -(CH,),-0-(CH,),- and -CH,-pCgH4-CH,-. AMENDED SHEET

31 PCT/SE00/01071

24. A substance or composition for use in a method of treatment according to any one of claims 17 - 21, wherein the NO-releasing NSAID is a compound according to - any one of the formulas Ia - Iq g 2 RR NGF N rs ONO, (12) CH,0 10 : 0 CH, ESS On "ong, (1b) : 0) CH, = | ONO, (Id) , = C 2 CH, NO Th Ih Th 1h itn CE I ) J J o) 0 CH, Og ONC: (le) : ® Q CH, Lye y 0 Im 0 AMENDED SHEET

3) PCT/SE00/01071 NHC Co (Ig) : Or AY one: ve CY Au (Ii) : ” T° 0 N ON" 2 (1 0

) Tr ’ COTO ee ® CH,O ES Na WPS NG- Ie ue LF » CC] ay “Cr CH, ONO NS 2 (im) ; Q CH,0 AMENDED SHEET

33 PCT/SE00/01071 X Oa ONO, (ny; Cin ~ of NS CH, CH,O INE Q (ley CH, I (lp) and CH,O ©) ~~ T ~~ _. 0 NH er A 5

25. A substance or composition for use in a method of treatment according to claim 24, wherein the NO-releasing NSAID is a compound of formula Ia H O Cl 5 : CHO" ~ AMENDED SHEET

34 PCT/SE00/01071

26. A substance or composition for use in a method of treatment according to any one of claims 18 to 20, wherein the acid susceptible proton pump inhibitor is a compound of the formula II Q Het, — X =S — Het, I wherein Het, is R, R, ? Ng R, or iL R;

~~ . N or Rs 0) Het is Rs / of 7 c A / or / R of PS — 8 N AS L Rq H R's X= R —C H— 11 Rig > | Riz F N in the benzimidazole moiety means that one of the carbon atoms substituted by Rg-Rg optionally may be exchanged for a nitrogen atom without any substituents; R;, R, and Rj are the same or different and selected from hydrogen, alkyl, alkoxy optionally substituted by fluorine, alkylthio, alkoxyalkoxy, dialkylamino, piperidino, morpholino, halogen, phenyl and phenylalkoxy; AMENDED SHEET

35 PCT/SE00/01071 R, and Rs are the same or different and selected from hydrogen, alkyl and aralkyl; Rg is hydrogen, halogen, trifluoromethyl, alkyl and alkoxy; R¢-Rg are the same or different and selected from hydrogen, alkyl, alkoxy, halogen, haloalkoxy, alkylcarbonyl, alkoxycarbonyl, oxazolyl, trifluoroalkyl, or adjacent groups R¢-Rg form ring structures which may be substituted; Rg is hydrogen or forms an alkylene chain together with Ry and R,; and R,, are the same or different and selected from hydrogen, halogen or alkyl, alkyl groups, alkoxy groups and moities thereof, they may be branched or straight C, - Cg - chains or comprise cyclic alkyl groups, such as cycloalkyl-alkyl.

27. A substance or composition for use in a method of treatment according to claim 26 wherein the acid susceptible proton pump inhibitor is selected from omeprazole, an alkaline salt thereof, (S)-omeprazole and an alkaline salt thereof. _

28. A substance or composition for use in a method of treatment according to claim 26 wherein the acid susceptible proton pump inhibitor is lansoprazole or a pharmaceutically acceptable salt thereof of an enantiomer or a salt of the enantiomer. a

29. A substance or composition for use in a method of treatment according to claim 26 wherein the acid susceptible proton pump inhibitor is pantoprazole or pharmaceutically acceptable salt thereof or an enantiomer or a salt of the enantiomer.

30. A substance or composition for use in a method of treatment according to any one of the preceeding claims 17 to 29, wherein the bacterial infection is caused or mediated by Helicobacter pylori.

31. A substance or composition for use in a method of treatment according to claim 17, wherein the amount of NO-releasing NSAID in each dosage form is 0.5 - 5000 mg. AMENDED SHEET

36 PCT/SE00/01071

32. A substance or composition for use in a method of treatment according to claim 31, wherein the amount of NO-releasing NSAID is 5 - 1000 mg.

33. A substance or composition for use in a method of treatment according to any one of claims 18 to 20, wherein the amount of NO-releasing NSAID is 0.5 - 5000 mg and the amount of proton pump inhibitor is 0.1 - 200 mg together in one dosage form or in two separate dosage forms.

34. A substance or composition for use in a method of treatment according to claim 33, wherein the amount of NO-releasing NSAID is 5 - 1000 mg and the amount of proton pump inhibitor is 10 - 80 mg.

35. A pharmaceutical formulation suitable for use in the treatment of bacterial infections, comprising a NO-releasing NSAID or a pharmaceutically acceptable salt or an enantiomer thereof as active agent.

36. A pharmaceutical formulation suitable for use in the treatment of bacterial infections, comprising a NO-releasing NSAID and an acid susceptible proton pump inhibitor or a salt thereof or an enantiomer or a salt of the enantiomer as active agent. ~~ 37. A pharmaceutical formulation according to claim 27 or 28 wherein the NU- To releasing NSAID is a compound of the formula I Q M—C—O—X—0ONQ,- I wherein M is selected from AMENDED SHEET :

37 PCT/SE00/01071 of CH, 0 ~ N ° \_/ a CH, CH, Q gy To-0-" I N — N Q CH, 4g 7) LJ CH,

a. ne OP CH, = o) Il N O-ters " CH,0O Cl o) I

/

N._ CH c Xx 3 FY ANG (CX | cH, ANF TN NNF CH,0 CH— CH,0 CH, : CHa __LCH-CH; CH— CH; 13 AMENDED SHEET CLEAN COPY

38 PCT/SE00/01071 and X is selected from linear, branched or cyclic -(CH,),- wherein n is an integer of from 2 to 10; (CH) p-O-(CHy),- wherein m and p are integers of from 2 to 10; and -CH,-pCgHy- CH,-; or a pharmaceutically acceptable salt or enantiomer thereof.

38. Use as claimed in claim 1 or claim 2, substantially as herein described and illustrated.

39. A substance or composition for use in a method of treatment as claimed in any of claims 17 to 20, substantially as herein described and illustrated.

40. Formulation as claimed in claim 35 or claim 36, substantially as herein described and illustrated.

41. A new use of a NO-releasing NSAID, a new use of a NO-releasing NSAID and an acid susceptible proton pump inhibitor, a new use of an acid susceptible proton pump inhibitor, a substance or composition for a new use in a method of treatment, or a new formulation, substantially as herein described. AMENDED SHEET