WO2007073301A1

WO2007073301A1 - Benzoimidazole derivatives as prodrugs of proton pump inhibitors

Info

Publication number: WO2007073301A1
Application number: PCT/SE2006/001465
Authority: WO
Inventors: Rolf Bergman; Per Lindberg
Original assignee: Astrazeneca Ab
Priority date: 2005-12-23
Filing date: 2006-12-21
Publication date: 2007-06-28

Abstract

The present invention relates to new compounds, which are prodrugs of proton pump inhibitors and to pharmaceutical formulations and the use thereof. The present application is also related to a process for preparing said prodrugs.

Description

Benzoimidazole derivatives as prodrugs of proton pump inhibitors .

FIELD OFINVENTION

BACKGROUND OF THE INVENTION

Benzimidazole derivatives intended for inhibiting gastric acid secretion are for instance disclosed in U.S. Pat. Nos. 4,045, 563; 4,255,431; 4,628,098; 4,686,230; 4,758,579;

4,965,269; 5,021,433; 5,045,5525, 430,042 and 5,708,017. Compounds which inhibit the gastric H,K-ATPase enzyme are generally known in the field as "proton pump inhibitors" (PPI).

Some of the benzimidazole compounds capable of inhibiting the gastric H₅K- ATPase enzyme have found substantial use as drugs in human medicine and are known under such names as lansoprazole (U.S. Pat. No. 4,628,098), omeprazole (U.S. Pat. Nos. 4,255,431), esomeprazole (U.S. Pat No. 6,369,085, US 5,714,504, US 6,875,872) pantoprazole (U.S. Pat. No. 4,758,579), and rabeprazole (U.S. Pat. No. 5,045,552). Some of the diseases treated by proton pump inhibitors and specifically by the five above-mentioned drugs include peptic ulcer, heartburn, reflex esophagitis, erosive esophagitis, non- ulcer dyspepsia, infection by Helicobacter pylori, laryngitis and asthma.

The published applications WO 95/32957, US 2005/0182101, US 2005/0038076, US 2005/0075351, WO 2005/82338 and WO 2005/001297 disclose prodrugs of PPI. OUTLINE OF THE PRESENT INVENTION

The present invention relates to new compounds, which are prodrugs of proton pump inhibitor and to pharmaceutical formulations and the use thereof. The present application is also related to a process for preparing said prodrugs. More specifically the prodrugs of the present invention are prodrugs of esomeprazole. The term "prodrug" as used herein is intended to include a derivate of the esomeprazole, which after administration undergo conversion to esomeprazole. The conversion may be spontaneous, or enzyme catalyzed.

Thus, the present invention relates to a compound of formula (I)

*

wherein the methoxygroup (*) on the benzimidazole moiety is situated either in 5- or 6- position; and

R₁ is selected from COOH, (CH₂)₂COOH, OCH₂COOH, OCH₂COOCH₃ or

OCH₂C(CH₃)₂COOH; R₂ is selected from H, OCH₃, CH₃, CH(CH₃)_2; COOH, or

OCH₂COOH; and R₃ is selected from H, OCH₃, CH₃, or CH(CH₃)₂; or isomers thereof or mixtures of such isomers or pharmaceutically acceptable salts of such compounds, isomers or mixtures of such isomers, or esters of such compounds or isomers or mixtures of such isomers.

Within the scope of the invention are also pharmaceutically acceptable salts of the compound of the formula (I). A pharmaceutically acceptable salt is any salt that retains the activity of the parent compound and does not impart any deleterious or unwanted effect on the subject to which it is administered and in the context in which is it administered. The pharmaceutically acceptable salt may be derived from organic or inorganic basis. The inorganic salt may be a mono or polyvalent ion such as an alkali metal ion (such as sodium, potassium, or lithium), or an alkali earth metal ion (such as calcium or magnesium), or a metal ion (such as zinc). The organic salt may be selected from ammonium salt such as primary, secondary, tertiary or quaternary ammonium salts, such as triethyl ammonium salt, tert-butyl ammonium salt. Other examples are mono-, di- or trialkyl amines or ethanolamine. Generally, pharmaceutically acceptable salts of the compounds of the present invention may be obtained using standard procedures well known in the art.

According to one embodiment of the present invention the esters are methyl esters.

According to yet another embodiment of the present invention Ri is in the 3-position of the phenyl ring. According to yet another embodiment of the present invention R₁ is in the 4- position of the phenyl ring. According to a further embodiment of the present invention Rj is in the 5-position of the phenyl ring

According to another embodiment of the present invention R₁ is OCH₂COOCH₃.

According to a further embodiment of the present invention Rj is OCH₂COOH or an ammonium salt thereof According to a further embodiment of the present invention the ammonium salt is triethyl ammonium salt.

One embodiment of the present invention relates to compounds selected from: Methyl {4-[(5-methoxy-2-{(S)-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfrnyl} - 1 H-benzimidazolr 1 -yl)sulfonyl]phenoxy } acetate or

Methyl {4-[(6-methoxy-2-{(S)-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl} - lH-benzimidazol-l-yl)sulfonyl]phenoxy}acetate or mixture thereof.

Another embodiment of the present invention relates to compounds selected from 4-[(5- methoxy-2-{(S)-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-lH-benzimidazol- l-yl)sulfonyl]phenoxyacetic acid, triethylammonium salt or 4-[(6-methoxy-2-{(S)-[(4- methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfmyl} - lH-benzimidazol- 1 - yl)sulfonyl]phenoxyacetic acid, triethylammonium salt or mixtures thereof.

The present invention also relates to a pharmaceutical formulation comprising a s pharmaceutically acceptable excipient and one of the compounds disclosed above. Another aspect of the present invention relates to an oral dosage form comprising a compound as disclosed above.

The term "oral dosage form" as used herein is intended to include any form of solid or o liquid to be administered orally to a person. In the preparation of pharmaceutical formulations in form of dosage units for oral administration the optically pure compound may be mixed with a solid, powdered carrier, such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivates, gelatine or another suitable carrier, stabilizing substances such as alkaline compounds e.g. carbonates, hydroxides and oxides s of sodium, potassium, calcium, magnesium and the like as well as with lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. The mixture is then processed into granules or compressed into tablets. Granules and tablets may be coated with an enteric coating which protects the active compound from acid catalysed degradation as long as the dosage form remains in the 0 stomach.

Those skilled in the art will readily understand that for oral administration the compounds of the invention are admixed with pharmaceutically acceptable excipients, which per se are well known in the art. The oral dosage form may be designed as a powder, pill or a tablet. S The oral dosage form may also be a capsule. The compounds of the present invention are included in the oral dosage form according to methods familiar to the man skilled in the art.

Another embodiment of the present invention relates to liquid preparation for oral 0 administration. These may be prepared in the form of syrups or suspensions. If desired, such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose or other thickening agents. These liquid preparations for oral administration may also be prepared in the form of dry powder to be reconstituted with a suitable solvent prior to use.

The compounds of the present invention can also be used in intravenous solution. Solutions for parenteral administrations may be prepared as solutions of the optically pure compounds of the invention in pharmaceutically acceptable solvents, preferably in a concentration from 0.1 to 10% by weight (% compound per total solution). These solutions may also contain stabilizing agents and/or buffering agents and may be manufactured in different unit dose ampoules or vials. Solutions for parenteral administration may also be prepared as dry preparations to be reconstituted with a suitable solvent extemporaneously before use.

Usually the amount of active compound is between 0.1 —95 wt% of the preparation and between 1-50% by weight in preparations for oral administration. The typical daily dose of the active compound will depend on various factors such as for example the individual requirement of each patient, the route of administration and the disease. In general, oral and parenteral dosages will be in the range of 5 to 500 mg per day of active substance.

Another embodiment of the present invention relates to that the compounds of the present invention can be combined with certain amounts of known proton pump inhibitor, e.g. omeprazole, esomeprazole, lansoprazole, pantoprazole or rabeprazole, thus providing a drug-prodrug combination.

The present invention relates to the use of a compound as disclosed above for the reduction and/or prevention of gastrointestinal complications and/or gastric acid secretion. The term "gastrointestinal complications" as used herein is intended to include ulcer in the stomach or duodenum, some complications to said ulcers, such as bleeding, perforation and/or obstruction, and dyspeptic symptoms such as epigastric pain and/or discomfort. The term "prevention" as used herein, also includes the inhibition of "gastrointestinal complications". The term "reduction" as used herein is intended to also include the "risk reduction" of "gastrointestinal complications". Another aspect of the present invention relates to a method for the reduction and/or prevention of gastrointestinal complications and/or acid gastric secretion by administering to a man or mammal in need thereof a pharmaceutical formulation as disclosed above or an oral dosage form as disclosed above. Yet another aspect of the present invention relates to a method for the reduction and/or prevention of gastrointestinal complications and/or acid gastric secretion by administering to a man or mammal in need thereof a therapeutically effective dose of the compounds of the present invention.

Yet another aspect of the present invention relates to a process for preparing the compounds disclosed above comprising the steps of:

(i) reacting an arylsulphonyl chloride of formula (II),

with esomeprazole in a solvent; whereby a compound of formula (IV)

(IV)

is obtained and wherein R₁, R₂ and R₃ are as disclosed above; and the methoxygroup (*) on the benzimidazole moiety is situated either in 5- or 6- position; and

(ii) performing selective base catalyzed hydrolysis, in a solvent, on the compound of formula (IV),

*

(JV)

wherein R₁, R₂ and R₃ are as disclosed above, the methoxygroup (*) on the benzimidazole moiety is situated either in 5- or 6- position;

obtained from step (i), whereby a compound of formula (V),

(V) wherein Ri, R₂ and R₃ are as disclosed above and X⁺ is a monovalent or polyvalent cation, and the methoxygroup (*) on the benzimidazole moiety is situated either in 5- or 6- position, is obtained.

Step (i) and step (ii) are performed in room temperature. The solvent used for step (i) may be ethanol, methanol, methylene chloride, a mixture of tetrahydrofuran and water or a mixture of dimethoxyethane and water. The solvent used for step (ii) may be tetrahydrofuran or dimethoxyethane. The base used in step (ii) may be sodium hydroxide or triethyl amine. The obtained compounds are separated from the solvent by conventional methods, such as chromatography. However, one of ordinary skill in the art will recognize that there are other solvent and bases, which can be used for the claimed process without departing from the spirit and scope of the present invention. The mono or polyvalent cation (X) may be selected from cation such as Li⁺, Na⁺, K⁺ Mg²⁺ Ca²⁺, Zn²⁺ or Et₃NH⁺. NaHCO₃ can be used in step (i) for protection of the composition of esomeprazole. The compounds obtained from step (i) may be purified before step (ii). The purification methods used are conventional methods, such as chromatography.

Thus, the process can be generalized:

Reaction scheme 1

(V)

Y⁺ is selected from H*^", Na⁺ or K⁺. The reaction can be performed with little or no racemization. The methoxygroup (*) on the benzimidazole moiety is situated either in 5- or 6- position.

Another embodiment of the present invention related to a process of preparing a compound of formula (V-A) wherein R₁ is OCH₂COOCH₃ and R₂ is H and R₃ is H comprising the steps of

(i) reacting an arylsulphonyl chloride of formula (II- A), in a solvent whereby a compound of formula (IV-A) is obtained. The reaction can be performed in the precence NaHCO₃

(ii) performing selective base catalyzed hydrolysis, in a solvent, on the compound of formula (FV-A) whereby a compound of formula (V-A) is obtained. The reaction performed in step (ii) is a selective base catalyzed hydrolysis of phenoxyacetic acid esters coupled as the sulfonamide of esomeprazole. The process is shown in the reaction scheme 2. Y^1" is selected from H⁺, Na⁺ or K⁺ and X^1" is a monovalent or polyvalent cation such as Li⁺, Na⁺, K⁺, Mg²⁺, Ca²⁺ Zn²⁺ or Et₃NH⁺. Reaction scheme 2

(IV-A) (V-A)

The methoxygroup (*) on the benzimidazole moiety is situated either in 5- or 6- position.

Examples

The invention is described in more detail by the following examples. The examples should not in any way be limiting to the scope of the present invention..

Example 1: Methyl {4-[(5-methoxy-2-{(S)-[(4-methoxy-3,5-dimethylpyridin-2- yl) methyl] sulfinyl} -lH-benzimidazol-1 -yl)sulfonyl]phenoxy} acetate and Methyl {4-[(6- methoxy-2-{(S)-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-lH-benzimidazol-l- yl)sulfonyl]phenoxy} acetate.

Methyl {4-[(5-methoxy-2-{(S)-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}- 1H-benzimidazol-1-yl)sulfbnyl]phenoxy}acetate.

Methyl {4-[(6-methoxy-2-{(S)-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}- 1 H-benzimidazol-1 -yl)sulfonyl]phenoxy}acetate. Esomeprazole sodium salt (370 mg, 1 mmol), triethylamine (200 mg, 2 mmol) and sodium hydrogen carbonate (420 mg, 5 mmol) was dissolved/suspended in abs ethanol (20 ml). Methyl [4-(chlorosulfonyl)phenoxy]acetate (300 mg, 1.13 mmol) was added and the mixture was stirred at ambient temperature for 20 h. The reaction mixture was 5 concentrated at reduced pressure and the residue was taken up in ethyl acetate (50 ml) and water (25 ml). After separation the organic phase was washed with brine (cone), dried over sodium soleplate, filtered and concentrated at reduced pressure. The residue was purified by flash chromatography (SiO₂, EtOAc/Hexan+10 % Et₃N) to give 460 mg (0.8 mmol) of the title compound.

I₀ ¹H-NMR (400 MHzjCDCi): δ 8.13 (s, IH), 8.04 (m, 2H), 7.84 (d, 0.6H), 7.66 (d, 0.4H), 7.44 (d, 0.4H), 7.05 (dd, 0.6H), 6.98 (dd, 0.4H), 6.94 (m, 2.6H), 4.85 (dd, 2H), 4.63 (s, 2H), 3.89 (s, 1.2H), 3.81 (s,1.8H), 3.76 (s, 3H), 3.72 (s, 3H)₅ 2.29 (s, 3H), 2.20 (s, 3H).

Example 2: 4-[(5-methoxy-2-{(S)-[(4-methoxy-3, 5-dimethylpyridin-2-yl)methyl]sulfinyl} - lH-henzimidazol-l-yl)sulfonyl]phenoxyacetic acid, triethylammonium salt and 4-[(6- methoxy-2-{(S)-[(4-methoxy-3,5-dimethylpyridm-2-yl)methyl]sulflnyl}-lH-benzύnidazol-l- yl)sulfonyl]phenoxy acetic acid, triethylammonium salt

4-[(5-methoxy-2-{(S)-[(4-methoxy-3,5-dimethylpyridin-2-yI)methyl]sulfinyl}-

1 H-benzimidazol-1-yl)sulfonyl]phenoxyacetic acid, triethylammonium salt.

4-[(6-methoxy-2-{(S)-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-

1 H-benzimidazol-1-yl)sulfonyl]phenoxyacetic acid, triethylammonium salt.

Methyl {4-[(5-methoxy-2-{(5)-[(4-me1hoxy-3,5-dime1iiylpyridin-2-yl)methyl]sulfinyl} - lH-benzimidazoM-yl)sulfonyl]phenoxy} acetate and methyl {4-[(6-methoxy-2-{(iS)-[(4- methoxy- 3,5- dimethylpyridin- 2- yl)methyl] sulfinyl } - 1 H-benzimidazol- 1 - yl)sulfonyl]phenoxy} acetate (460 mg, 0.8 mmol) was dissolved and stirred in Tetrahydroruran (30 ml) at room temperature. A 0.1 M NaOH solution (9 ml) was added and after 10 min stirring at room temperature the reaction was quenched by the addition of methyl format (0.5 ml). After 20 min the reaction mixture was concentrated to near drieness at reduced pressure and the residue was taken up in ethyl acetate (20 ml) and brine (40 ml, 10 % NaCl). After separation citric acid (200 mg) was added to water containing phase whereupon the mixture was extracted with ethyl acetate (40 ml). The extract was diluted with diethyl ether (40 ml), triethyl amine (200 mg) was added and the mixture was extracted with brine (80 ml, 10 % NaCl). Finally the brine extract was extracted with methylene chloride (2x40 ml). The organic phase was dried over sodium sulphate, filtered and concentrated at reduced pressure to give 300 mg (0.46 mmol) of the title compound as a foam.

■ ¹H-NMR (400 MHz;CDC|): δ 8.15 (s, IH), 7.96 (m, 2H), 7.83 (d, 0.4H), 7.65 (d, 0.6H), 7.43 (d, 0.6H), 7.05 (dd, 0.4H), 6.97 (m, 3H), 4.84 (dd, 2H), 4.50 (s, 2H), 3.89 (s, 1.8H), 3.81 (s, 1.2H), 3.72 (s, 3H), 2.98 (q, 6H), 2.28 (s, 3H), 2.20 (s, 3H), 1.18 (s, 9H).

Claims

1. A compound of formula (I)

wherein the methoxygroup (*) on the benzimidazole moiety is situated either in 5- or 6- position; and R₁ is selected from COOH, (CH₂)₂COOH, OCH₂COOH, OCH₂COOCH₃ or OCH₂C(CH₃)ZCOOH;

R₂ is selected from H, OCH₃, CH₃, CH(CH₃)_2; COOH, or OCH₂COOH; and R₃ is selected from H, OCH₃, CH₃, or CH(CH₃ )₂; or isomers thereof or mixtures of such isomers or pharmaceutically acceptable salts of such compounds, isomers or mixtures of such isomers, or esters of such compounds or isomers or mixtures of such isomers.

2. A compound according to claim 1 wherein Ri is in the 3 -position of the phenyl ring.

3. A compound according to claim 1 wherein R₁ is in the 4-position of the phenyl ring.

4. A compound according to claim 1 wherein Ri is in the 5-position of the phenyl ring.

5. A compound according to claim 3 wherein R₁ is OCH₂COOCH₃.

6. A compound according to claim 3 wherein R₁ is OCH₂COOH or an ammonium salt thereof

7. A compound according to claim 1 selected from:

Methyl {4-[(5-methoxy-2- {(S)-[(4-memoxy-3,5-dimethylpyridin-2- yl)methyl]sulfinyl} - 1 H-benzimidazot 1 -yl)sulfonyl]phenoxy } acetate or Methyl {4-[(6-methoxy-2-{(S)-[(4-methoxy-3,5-dimethylpyridin-2- yl)methyl]sulfinyl}-lH-benzimidazoH-yl)sulfonyl]phenoxy}acetate or mixture thereof.

8. A compound according to claim 1 selected from: 4-[(5-methoxy-2-{(S)-[(4- methoxy-3,5-dimethylpyridin-2- yl)methyl]sulfinyl} - 1 H-benzimidazot 1 - yl)sulfonyl]phenoxyacetic acid, triethylammonium salt or 4-[(6-methoxy-2-{(S)-

[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-lH-benzimidazo]-l- yl)sulfonyl]phenoxyacetic acid, triethylammonium salt or mixtures thereof.

9. A pharmaceutical formulation comprising a pharmaceutically acceptable excipient and a compound according to any one of claims 1-8.

10. An oral dosage form comprising a compound according to any one of claims 1-8.

11. The use of a compound according to any one of claims 1-8 for the reduction and/or prevention of gastrointestinal complications and/or gastric acid secretion.

12. A method for the reduction and/or prevention of gastrointestinal complications and/or acid gastric secretion by administering to a man or mammal in need thereof a pharmaceutical formulation according to claim 9 above or an oral dosage form according to claim 10.

13. A process for preparing a compound according to any one of claims 1-8 comprising the steps of: (i) reacting an arylsulphonyl chloride of formula (H)₅

(H) wherein R₁, R₂ and R₃ are as defined according to anyone of claims 1-8, with esomeprazole in a solvent; whereby a compound of formula (IV)

(IV)

is obtained wherein R₁, R₂ and R₃ are as defined according to anyone of claims 1-8, and wherein the methoxygroup (*) on the benzimidazole moiety is situated either in 5- or 6- position; and

(ii) performing selective base catalyzed hydrolysis, in a solvent, on the compound of formula (IV)

(W)

wherein R₁, R₂ and R₃ are as defined according to anyone of claims 1-8, and wherein the methoxygroup (*) on the benzimidazole moiety is situated either in 5- or 6- position, obtained from step (i) whereby a compound of formula (V),

is obtained; wherein R₁, R₂ and R₃ are as defined according to anyone of claims 1-8, and wherein the methoxygroup (*) on the benzimidazole moiety is situated either in 5- or 6- position, and X is a monovalent or polyvalent cation.