WO1995027714A1 - Active compounds - Google Patents

Abstract

The present invention relates to substituted tricyclic imidazo[1,2-a]pyridines of formula (I) which reversibly inhibit exogenously or endogenously stimulated gastric acid secretion and thus can be used in the prevention and treatment of gastrointestinal inflammatory diseases.

Description

ACTIVE COMPOUNDS

TECHNICAL HELD

The present invention relates to novel compounds, and therapeutically acceptable salts thereof, which reversibly inhibit exogenously or endogenously stimulated gastric acid secretion and thus can be used in the prevention and treatment of gastrointestinal inflammatory diseases. In further aspects, the invention relates to compoimds of the invention for use in therapy; to processes for preparation of such new compoimds; to pharmaceutical compositions containing at least one compound of the invention, or a therapeutically acceptable salt thereof, as active ingredient; and to the use of the active compounds in the manufacture of medicaments for the medical use indicated above.

BACKGROUND ART

Substituted imidazo[l,2-a]pyridines, useful in the treatment of peptic ulcer diseases, are known from publications, hereinafter referred to as "Dl" to

"D5", by J. J. Kaminski et al. in the Journal of Medical Chemistry:

Dl J. Med. Chem. vol. 28, 876-892, 1985

D2 J. Med. Chem. vol. 30, 2031-2046, 1987 D3 J. Med. Chem. vol. 30, 2047-2051, 1987

D4 J. Med. Chem. vol. 32, 1686-1700, 1989

D5 J. Med. Chem. vol. 34, 533-541, 1991

In Dl, the representative compound 3-(cyanomethyl)-2-methyl-8- (phenylmethoxy)imidazo[l,2-a]pyridine (compound 27 of Dl; subsequently designated "Sch 28080") was prepared. When tested for inhibition of Wstamine-stimulated gastric acid secretion in dogs, this compound had an ED5ø-value of 4.4 mg/kg, equivalent to 15.9 μmol/kg (oral administration).

In comparison, the compound 3-(hydroxymethyl)-2-methyl-8- (phenylmethoxy)imidazo[l,2-a]pyridine (compound 80 of Dl) gave only 43% inhibition when 8 mg/kg (29.8 μmol/kg) was administered. From these and other experiments, the conclusion was drawn that the 3-cyanomethyl substituent is almost uniquely effective in imparting inhibition of gastric acid

H⁺K⁺-ATPase and it is also a substituent that gives orally active compounds. Replacing the 3-cyanomethyl with 3-hydroxymethyl decreased the antisecretory activity.

8,9-diiιydro-2-me yl-9-phenyl-7H-imidazo[l,2-a]pyrano[2,3-c]-pvridine-3- acetonitrile, i.e. a tricyclic imidazo[l,2-a]pyridine, is known from D4, D5 and US 4,468,400 (Schering Corporation). This compound had an antisecretory activity comparable to that of the compound "Sch 28080".

However, compounds having the cyanomethyl substituent have the disadvantage that cyanide is produced when the compound is metabolized, and such compounds is likely to be of limited clinical use. There is consequently a need for compounds which avoid a cyanomethyl substituent while retaining the antisecretory activity at an acceptable level.

BRIEF DESCRIPTION OF THE DRAWING

Figure 1 is a scheme over Process A for preparation of compounds with the general Formula I. DISCLOSURE OF THE INVENTION

Compounds of the Formula I, which are substituted tricyclic imidazo[l,2- alpyridines, having a hydroxymethyl substituent in 3-position, are effective as inhibitors of gastric acid secretion, by reversibly inhibiting the gastrointestinal H⁺,K⁺-ATPase. It has surprisingly been found that the compounds according to the invention has improved properties concerning the f armacokinetics and metabolism. These properties together lead to an improved therapeutic profile.

In one aspect, the invention thus relates to compounds of the general Formula I:

or a pharmaceutically acceptable salt thereof, wherein

R- s

(a) CH₃, or

(b) CH₂CH₃;

R² is (a) H,

(b) halogen,

(c) lower alkyl,

(d) lower alkoxy, or (e) OH; R3, which is in position 3, 4 ,5 or 6 of the phenyl ring, is (a) H,

(b) halogen, or

(c) lower alkyl.

As used herein, the term "lower alkyl" denotes a straight or branched alkyl group having from 1 to 6 carbon atoms. Examples of said lower alkyl indude methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl and straight- and branched-chain pentyl and hexyl.

The term "lower alkoxy" denotes a straight or branched alkoxy group having from 1 to 6 carbon atoms. Examples of said lower alkoxy indude methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, t-butoxy and straight- and branched-diain pentoxy and hexoxy.

The term "halogen" indudes fluoro, chloro, bromo and iodo.

Both the pure enantiomers, racemic mixtures and unequal mixtures of two enantiomers are within the scope of the present invention. Also included in the invention are derivatives of the compounds of the Formula I which have the biological function of the compounds of the Formula I.

Depending on the process conditions the end products of the Formula I are obtained either in neutral or salt form. Both the free base and the salts of these end products are within the scope of the invention.

Add addition salts of the new compounds may in a manner known per se be transformed into the free base using basic agents such as alkali or by ion exchange. The free base obtained may also form salts with organic or inorganic adds. In the preparation of add addition salts, preferably such adds are used which form suitably therapeutically acceptable salts. Examples of such adds are hydrohalogen adds, sulfuric acid, phosphoric acid, nitric add, aliphatic, alicydic, aromatic or heterocyclic carboxyl or sulfonic adds, such as formic add, acetic acid, propionic add, sucdnic acid, glycolic add, lactic acid, malic add, tartaric add, dtric acid, ascorbic add, maleic add, hydroxymaleic acid, pyruvic add, p-hydroxybensoic add, embonic add, methanesulfonic add, ethanesulf onic acid, hydroxyethanesulfonic add, halogenbensenesulfonic add, toluenesulfonic add or naphthalenesulfonic add.

Preferred compounds of the formula I are those wherein R¹ is CH3 or

CH₂ ^CH3. R² is H, CH3, OH, OCH3, OCH₂CH₃, F or Cl; and R3 is H, 4-CH₃, 4-F or 4-C1.

The most preferred compound of the invention is the compound wherein Rl is CH3; R² is H; and R^ is H; i.e. the compound 3-hydroxymethyl-2-methyl- 9-phenyl-7H-8,9-dihydropyrano [2,3-c]-imidazo [1 ,2-a]pyridine:

Preparation

The present invention also provides processes for the manufacture of compounds with the general Formula I. Process A

Process A for the manufacture of compounds with the general Formula I, with reference to the roman numbers in Fig. 1, comprises the following steps:

(a) Compounds of the general Formula VII can be prepared according to known methods described e.g. in Kaminski et al. (1985) J. Med. Chem.28, 876-892.

Compounds of the general Formula VII, wherein R^ is as defined for Formula I, can be debenzylated with e.g. cydohexene in the presence of a catalyst (e.g. Pd(OH)₂) to the compound of the Formula VI wherein R is as defined for Formula I. The reaction can be carried out under standard conditions e.g. by heating the reactants in an inert solvent, preferably ethanol.

VI (b) Compounds of the Formula V, wherein R is as defined for Formula I, can be prepared by reacting compounds of the general Formula VI to a Mannich base with e.g. N,N-dimethylmethyleneammonium iodide in an inert solvent, e.g. methylene chloride, at ambient temperature.

(c) Compounds of Formula V can be reacted with enamines of the general

Formula VIII, wherein R² and R³ are as defined for Formula I, to the compounds of the Formula IV, wherein Rl, R² and R³ are as defined for Formula I. The reactions can be carried out according to methods described by von Standtmann, et al, J. Heterocyclic Chem. 7, 1311 (1970).

IV (d) Compounds of Formula IV can be reduced (e.g. with NaBHj) to the corresponding hydroxy compounds of Formula IH, wherein R¹, R² and R³ are as defined for Formula I. The solvent used for the reactions can e.g. be alcohols such as methanol and ethanol.

(e) The cyclizised compounds of Formula π, wherein R**-, R² and R³ are as defined for Formula I, can be prepared by treating the compounds of

Formula III with a Lewis add (e.g. borontrifluoride etherate) under standard conditions in an inert solvent, e.g. methylene chloride.

(f) Reduction of compounds of the general Formula π, e.g. by using lithium aluminium hydride in tetrahydrofuran or ether, yields the compounds of the general Formula I.

Process B

The phenolic hydroxy group in Formula Dl (see Process A) can be converted to a leaving group as for Formula IX, wherein R¹, R², and R³ are as defined in Formula I and X is a leaving group e.g. mesylate, tosylate or triflate, by reacting the hydroxy group with such reagents as mesyl chloride, tosyl chloride or N-phenyltrifluoromethylsulf onimide. The reactions can be carried out under standard conditons with a base in an inert solvent, e.g methylene chloride or acetonitrile.

The cyclizised compounds of Formula H (see Process A), wherein R¹, R², and R³ are as defined for Formula I, can be prepared by treating the compounds of the Formula IX with a base e.g sodium hydride or potassium tert-butoxide in an inert solvent e.g. dimethylformamide or acetonitrile.

The alternative process B for the preparation of a compound according to the invention thus comprises: (a) converting the phenolic hydroxygroup of a compound of the Formula III, wherein R-*-, R², and R³ are as defined for Formula I, to a leaving group X resulting in a compound of the general Formula IX;

(b) ringclosure of a compound of the Formula IX, wherein Rl, R², and R³ are as defined for Formula I and X is a leaving group, with a base in an inert solvent, to a compound of the general Formula D; and

(c) reducing a compound of the Formula II, wherein R¹, R², and R³ are as defined for Formula I, to a compound of the Formula I.

Process C

The phenolic hydroxy group in Formula IV can be converted to a leaving group as for Formula X, wherein R*, R², and R³ are as defined in Formula I and X is a leaving group e.g. mesylate, tosylate or triflate, by reacting the hydroxy group with such reagents as mesyl chloride, tosyl chloride or N- phenyltrϋluoromethylsulfonimide. The reactions can be carried out under standard conditons with a base in an inert solvent, e.g methylene chloride or acetonitrile.

Compounds of the general Formula X can be reduced (e.g. with NaBH4) to the corresponding hydroxy compounds of Formula IX, wherein Rl, R², and

R³ are as defined for Formula I and X is a leaving group. The solvent used for the reactions are espedally alcohols, e.g. methanol or ethanol.

The cyclizised compounds of Formula II (see Process A), wherein Rl, R², and R³ are as defined for Formula I, can be prepared by treating the compounds of the Formula IX with a base e.g sodium hydride or potassium tert-butoxide in an inert solvent e.g. dimethyl formamide or acetonitrile.

The further alternative process C for the preparation of a compound according to the invention thus comprises:

(a) converting the phenolic hydroxygroup of a compound of the Formula IV, wherein Rl, R², and R³ are as defined for Formula I, to a leaving group X resulting in a compound of the general Formula X;

(b) redudng a compound of the Formula X, wherein Rl, R², and R³ are as defined for Formula I, to the corresponding hydroxy compound of the Formula IX;

(c) ring dosure of a compound of the Formula IX, wherein Rl, R², and R³ are as defined for Formula I and X is a leaving group, with a base in an inert solvent, to a compound of the general Formula II; and

(d) reducing a compound of the Formula ϋ, wherein Rl, R², and R³ are as de ined for Formula I, to a compound of the Formula I.

Preparation of enantiomers

The present invention also provides processes for the manufacture of the pure enantiomers of the compounds with the general Formula I. Processes for the manufacture the pure enantiomers of compounds with the general Formula I, comprises the following steps:

Path A

Compounds of the general formula IV can be reduced with an enantio- selective reduction with e.g. (+ or -)-DIP-chlorideTM (Diisopinocampheyl chloroborane) to the corresponding hydroxy compounds of Formula D (R or

S), wherein Rl, R², and R³ are as defined for Formula I. The solvent used for the reactions can e.g. be tetrahydrofuran or ether.

Using Process B gives the pure enantiomers of compounds with the general Formula I.

A process for the preparation of the pure enantiomers of a compound according to the invention thus comprises:

(a) enantioselective reduction of a compound of the Formula IV, wherein Rl, R², and R³ are as defined for Formula I, to the corresponding hydroxygroup of a compound of the general Formula III (R or S); (b) converting the phenolic hydroxygroup of a compound of the Formula m

(R or S) wherein Rl, R², and R³ are as defined for Formula I, to a leaving group X resulting in a compound of the general Formula IX (R or S);

(c) ringdosure of a compound of the Formula IX (R or S), wherein Rl, R², and R³ are as defined for Formula I and X is a leaving group, with a base in an inert solvent, to a compound of the general Formula II (R or S); and

(d) reducing a compound of the Formula II (R or S), wherein Rl, R², and R³ are as defined for Formula I, to a compound of the Formula I (R or S). Path B

Compounds of the general Formula X (see Process C) can be reduced with an enantio-selective reduction with e.g. (+ or -)-DIP-chlorideTM (Diisopinocampheyl chloroborane) to the corresponding hydroxy compounds of Formula IX (R or S), wherein Rl, R², and R³ are as defined for Formula I and X is a leaving group. The solvent used for the reactions are especially tetrahydrofuran or ether.

Using Process C gives the pure enantiomers of compounds with the general Formula I.

An alternative process for the preparation of the pure enantiomers of a compound according to the invention thus comprises:

(a) enantioselective reduction of a compound of the Formula X, wherein Rl,

R², and R³ are as defined for Formula I, to the corresponding hydroxy compound of the Formula IX (R or S);

(b) ringclosure of a compound of the Formula IX (R or S), wherein Rl, R², and R³ are as defined for Formula I and X is a leaving group, with a base in an inert solvent, to a compound of the general Formula II (R or S); and

(c) reducing a compound of the Formula D (R or S), wherein Rl, R², and R³ are as defined for Formula I, to a compound of the Formula I (R or S).

Use

In a further aspect, the invention relates to the use of a compound as defined above for the manufacture of a medicament for the inhibition of gastric add secretion, or for the treatment of gastrointestinal inflammatory diseases.

In a more general sense, the compounds of the invention may be used for prevention and treatment of gastrointestinal inflammatory diseases, and gastric acid-related diseases in mammals induding man, such as gastritis, gastric ulcer, duodenal ulcer, reflux esophagitis and Zollinger-Ellison syndrom.

Furthermore, the compounds may be used for treatment of other gastrointestinal disorders where gastric antisecretory effect is desirable, e.g. in patients with gastrinomas, and in patients with acute upper gastrointestinal bleeding. They may also be used in patients in intensive care situations, and pre-and postoperatively to prevent acid aspiration and stress ulceration. Pharmaceutical formulations

In yet a further aspect, the invention relates to pharmaceutical compositions containing at least one compound of the invention, or a therapeutically acceptable salt thereof, as active ingredient.

The compounds of the invention can also be used in formulations together with other active ingredients, e.g. antibiotics such as amoxicillin.

For clinical use, the compounds of the invention are formulated into pharmaceutical formulations for oral, rectal, parenteral or other mode of administration. The pharmaceutical formulation contains a compound of the invention in combination with one or more pharmaceutically acceptable ingredients. The carrier may be in the form of a solid, semi-solid or liquid diluent, or a capsule. These pharmaceutical preparations are a further object of the invention. Usually the amount of active compounds is between 0.1- 95% by weight of the preparation, preferably between 0.2-20% by weight in preparations for parenteral use and preferably between 1 and 50% by weight in preparations for oral administration.

In the preparation of pharmaceutical formulations containing a compound of the present invention in the form of dosage units for oral administration the compound selected may be mixed with solid, powdered ingredients, such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, caldum stearate, sodium stearyl fumarate and polyethylene glycol waxes. The mixture is then processed into granules or pressed into tablets.

Soft gelatine capsules may be prepared with capsules containing a mixture of the active compound or compounds of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatine capsules. Hard gelatine capsules may contain granules of the active compound. Hard gelatine capsules may also contain the active compound in combination with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatine.

Dosage units for rectal administration may be prepared (i) in the form of suppositories which contain the active substance mixed with a neutral fat base; (ii) in the form of a gelatine rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for gelatine rectal capsules; (iii) in the form of a ready-made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.

Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, e.g. solutions or suspensions containing from 0.2% to 20% by weight of the active ingredient and the remainder consisting of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose or other thickening agent. Liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.

Solutions for parenteral administration may be prepared as a solution of a compound of the invention in a pharmaceutically acceptable solvent, preferably in a concentration from 0.1% to 10% by weight. These solutions may also contain stabilizing ingredients and/or buffering ingredients and are dispensed into unit doses in the form of ampoules or vials. Solutions for parenteral administration may also be prepared as a dry preparation to by reconstituted with a suitable solvent extemporaneously before use. The typical daily dose of the active substance varies within a wide range and 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 1000 mg per day of active substance.

EXAMPLES

1. PREPARATION OF COMPOUNDS OF THE INVENTION

Example 1.1

3-Hydroxymethyl-2-methyl-9-phenyl-7H-8.9-dihydro-pyranor23-cl- imidazo.1 ,2-alpyridine

To a solution of 4.2 g (12.4 mmol) of 8,9-dihydro-2-methyl-9-phenyl-7H- i_αύdazo[l,2-a]pyrano[2,3-c]pyridine-3-carboxylic add ethyl ester in 150 ml tetrahydrofuran there was added 1.8 g (47.5 mmol) lithium aluminium hydride in portions at ambient temperature under 3 h. To the reaction mixture was 1.8 ml water added dropwise followed by 1.8 ml 15% aqueous sodium hydroxide and then 5.4 ml water. The mixture was filtered in a sintered glass funnel and the filtrate was evaporated under reduced pressure. The residue was dissolved in methylene chloride and washed with 2 M hydrochloric add, and then basified to pH 8 with a bicarbonate solution. The methylene chloride layer was separated dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residual oil was chromatographed on silica gel, eluting with methylene chloride containing 10% methanol, crystallized from acetonitrile to obtain 2.5 g (68%) of the title compound. (iH-NMR, 300 MHz, CDC1₃): 2.20-2.35 (m, 2H), 2.40 (s, 3H), 2.70-2.90 (m, 2H), 4.90 (s,2H), 5.20-5.30 (m,lH), 6.5 (d, IH), 7.30-7.50 (m, 5H), 7.75 (d, IH)

Example 1.2.

3-Hydroxymethyl-2-methyl-9-(4-fluorophenyl)-7H-8,9-dihydro-pyrano- f23-climidazo.l.2-a.pyridine

8,9-D_-hydro-2-methyl-9-(4-fluorophenyl)-7H-imidazo [l,2-a]pyrano[2,3-c]- pyridine-3-carboxylic add ethyl ester (1.0 g, 2.82 mmol) was dissolved in toluene (15 ml). The solution was cooled to 0 °C. 1.6 ml (5.9 mmol) of a 70% solution of sodium bis (2-methoxyethoxy) aluminum hydride in toluene was added. The mixture was stirred for 20 h at ambient temperature. An additional amount of 1 ml sodium bis (2-meΛoxyethoxy)alι__m__num was added and stirring was continued for 2 h at 50 °C Water (3ml) was added carefully to the reaction mixture. The predpitate formed was filtered and washed with methylene chloride, acetone and methanol. The filtrate was evaporated to dryness. The residue was purified by column chromatography on silica gel, using methylene chloride containing 10 % methanol as eluent. 0.55 g (62 %) of the title compound was obtained.

(iH-NMR, 300 MHz, CDCI3): 2.05-2.25 (m, 2H), 2.28 (s, 3H), 2.60-2.70 (m,

IH), 2.85-3.0 (m, IH), 4.70 (s, 2H), 5,08 (broad s, IH), 5.24 (dd, IH), 6.63 (d, IH), 7.22-7.29 (m, 2H), 7.49-7.55 (m, 2H), 7.85 (d, IH). 2. PREPARATION OF INTERMEDIATES

Example 2.1

8-Hydroxy-2-methylimidazori,2-a1pyridme-3-carboxylic add ethyl ester

8-Ber_zyloxy-2-methyUmid-_zo[l,2-a]pyridine-3-carboxylic acid ethyl ester (π) (95 g, 0.3 mol), ethanol (1000 ml), cyclohexan (600 ml), cydohexene (200 ml)and palladium hydroxide (8 g) were mixed together and refluxed for 2 h. The catalyst was removed by filtration and the volatiles were removed under reduced pressure. Recrystallization from acetonitrile gave 45.5 g (69%) of the desired product.

(iH-NMR, 300 MHz, CDC1₃): 1.45 (t, 3H), 2.75 (s, 3H), 4.50 (q, 2H), 6.9-7.0 (m, 2H), 8.95 (dd, IH)

Example 2.2

7-r(Dimethylamino)methyll-8-hydroxy-2-methylimidazo-ri.2-a1pyridine-3- carboxylic add ethyl ester

A mixture of 55 g (0.25 mol) of 8-hydroxy-2-methylimidazo- [l,2-a]pyridine- 3-carboxylic add ethyl ester and 50 g (0.26 mol) of N,N-dimethylmethylene- ammonium iodide in 1.751 of methylene chloride was stirred at ambient temperature for 6 h. The reaction mixture was made basic by the addition of a sodium bicarbonate solution. The organic layer was separated and dried over anhydrous sodium sulfate. Drying agent was removed by filtration and the filtrate was evaporated under reduced pressure. The residual material was crystallized from ethyl acetate to obtain 40.7 g (59%) of the title compound. (iH-NMR, 500MHz, CDC1₃): 1.45 (t, 3H), 2.40 (s, 6H), 2.75 (s, 3H), 3.75 (s,

2H), 4.45 (q, 2H), 6.55 (d, IH), 8.80 (d, IH)

Example 2.3

7-(2-Benzoylethyl)-8-hydroxy-2-methylimidazo-ri.2-a1pyridine-3-carboxyhc add ethyl ester

7-[(d__methylammo)methyl]-8-hydroxy-2-methyliιnidazo[l,2-a] pyridine-3- carboxylic add ethyl ester (1.0 g 3.61 mmol) was added to a stirred hot solution of l-dimethylaminophenylethylene (1.2 g 8.18 mmol) in dry toluene (18 ml) under nitrogen. The reaction mixture was refluxed for 50 min. Vacuum evaporation of solvent gave an oily residue wich was subjected to flash chromatography on silica gel, methylene chloride : methanol (100:3), to give 1.45 g (85%) of the product as colorless crystals.

(iH-NMR, 300 MHz, CDCI3): 1.45 (t, 3H), 2.70 (s, 3H), 3.25 (t, 2H), 3.45 (t,

2H), 4.45(q, 2H), 6.95 (d, IH), 7.40-7.50 (m, 2H), 7.50-7.60 (m, IH), 8.0 (d, 2H), 8.80 (d, IH)

Example 2.4

8-Hydroxy-2-methyl-7-(3-phenyl-3-hydroxypropyl)-imidazori.2-a1pyridine- 3-carboxylic add ethyl ester

A suspension of 5 g (12.9 mmol) of 7-(2-be_r_zoylethyl)-8-hydroxy-2-methyl- imidazo[l,2-a]pyridine-3-carboxylic add ethyl ester hydrochloride in 150 ml ethanol and 50 ml of methylene chloride was treated with 1.6 g (42.3 mmol) of sodium borohydride added portionwise over 2 h. The volatiles were removed under reduced pressure and the residue was dissolved in methylene chloride, washed with 2 M hydrochloric add was brought to pH 8 with a bicarbonate solution. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure to obtain 4.4 g (96%) of the title compound as an oil.

(iH-NMR, 500 MHz, DMSO-d₆): 1.40 (t, 3H), 1.80-1.90 (m, 2H), 2.6 (s, 3H),

2.60-2.75 (m, 2H), 4.40 (q, 2H), 4.50-4.60 (m, IH), 6.9 (d, IH), 7.20-7.40 (m, 5H), 8.70 (d, IH)

Example 2.5

8.9-Dmydro-2-methyl-9-phenyl-7H-imidazori.2-a1-pyranof2_>3-c1pyridine-3- carboxylic add ethyl ester

To a solution of 4.4 g (12.4 mmol) of 8-hydroxy-2-methyl-7-(3-phenyl-3- hydroxypropyl)imidazo[l,2-a]pyridine in 150 ml of methylene diloride were added 4.4 ml (5 g, 35.6 mmol) of boron trifluoride etherate. After the mixture was stirred for 3 h at ambient temperature, another 1.5 ml (1.7 g, 12.1 mmol) of boron trifluoride etherate was added, and the mixture was stirred 3 h at ambient temperature. The reaction mixture was basified to pH 8 with a bicarbonate solution. The organic layer was separated dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain 4.1 g (99%) of the desired compound.

(iH-NMR, 500 MHz, DMSO-d₆): 1.45 (t, 3H), 1.25-1.35 (m, 2H), 1.70 (s, 3H), 1.70-3.0 (m, 2H), 4.40 (q, 2H) 5.25-5.35 (m, IH), 6.65 (d,lH), 7.30-7.50 (m,

5H),8.85 (d,lH)

Example 2.6.

7-(2-(4-Huorobenzoyl) ethyl)-8-hydroxy-2-methylimidazori,2-a1pyridine-3- carboxylic add ethyl ester 7-[(Dimethylamino)methyl]-8-hydroxy-2-methylimidazo[l,2-a]pyridine-3- carboxylic add ethyl ester (5.7 g, 20.6 mmol) was added to a stirred hot solution (100 °C) of l-dimethylamino(4-fluorophenyl)ethylene (4.1 g, 25 mmol) in toluene (30 ml). The mixture was refluxed for 2 h and then cooled to room temperature. Water (5 ml) was added and the mixture was stirred for 16 h at ambient temperature. The mixture was then evaporated to dryness and the residue was triturated with methylene chloride (100 ml). Solid material was filtered off and the filtrate evaporated. The residue was refluxed in isopropanol (40 ml). After cooling the product was filtered and washed with isopropanol and aceton.3.0 g (39%) of the title compound was obtained.

(iH-NMR, 300 MHz, CDC1₃): 1.39 (t, 3H), 2.61 (s, 3H), 3.21 (t, 2H), 3.40 (t, 2H), 4.36 (q, 2H), 6.94 (d, IH), 7.09 (t, 2H), 7.98-8.04 (m, 2H), 8.80 (d, IH).

Example 2.7.

8-Hydroxy-2-methyl-7-(3-(4-fluorophenyl)-3-hydroxypropyl)-imidazofl.2- a.-pyridine-3-carboxylic acid ethyl ester

7-(2-(4-Huorober_zoyl) ethyl)-8-hydroxy-2-memylimidazo[l,2-a]pyridine-3- carboxylic add ethyl ester (3.0 g, 8.1 mmol) was dissolved in 25 ml ethanol. 370 mg (9.8 mmol) NaBH4 was added portionwise over 1 h. The mixture was stirred at ambient temperature for 18 h. An additional amount of 350 mg NaBHj was added and the reaction was continued for 1 h at ambient temperature. Acetic add (0.5 ml) was added. The reaction mixture was evaporated to dryness. The residue was extracted with methylene chloride and water. The organic layer was separated and evaporated. The residue was purified by column chromatography on silica gel. The product was eluted with metylene chloride containing 8% methanol.2.0 g (66% ) of the title compound was obtained.

(iH-NMR, 300 MHz, CDC1₃): 1.39 (t, 3H), 1.95-2.05 (m, 2H), 2.56 (s, 3H), 2.80-

3.10 (m, 2H), 4.38 (q, 2H), 4.65-4.69 (m, IH), 6.83 (d, IH), 6.93-7.00 (m, 2H), 6.97 (t, 2H), 7.25-7.32 (m, 2H), 8.79 (d, IH).

Example 2.8.

8.9-Dihydro-2-methyl-9-(4-fluorophenyl)-7H-imidazofl.2-alpyranor2.3-c1- pyridine-3-carboxylic acid ethyl ester

8-Hydroxy-2-methyl-7-(3-(4-fluorophenyl)-3-hydroxypropyl)-imid__zo[l,2- a]-pyridine-3-carboxylic add ethyl ester (2.0 g, 5.37 mmol) was dissolved in methylene chloride (30 ml) and the solution cooled to -5 °C. 2 ml (2.26g, 15.9 mmol) boron trifluoride etherate was added and the reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was washed with sodium carbonate solution and the organic layer separated and evaporated to dryness. The residue was purified by column chromatography on silica gel. The product was eluted with a 70:30 mixture of methylene chloride and ethyl acetate. 1.0 g (53%) of the title compound was obtained.

(iH-NMR, 300 MHz, CDCI3): 1.40 (t, 3H), 2.15-2.30 (m, 2H), 2.68 (s, 3H), 2.68-

2.80 (m, IH), 2.90-3.0 (m, IH), 4.38 (q, 2H), 5.25 (dd, IH), 6.63 (d, IH), 7.01 (t, 2H), 7.36-7.42 (m, 2H), 8.81 (d, IH).

Preparation of racemate by process C

Example 2.9 7-(2-Benzoyledιyl)-8-mesyl-2-methylimidazo-π.2-a1pyridine-3-carboxylic add ethyl ester

To a solution of 7-(2-Benzoylethyl)-8-hydroxy-2-methylimidazo-[l,2- a]pyridine-3-carboxylic acid ethyl ester (1.0 g 2.8 mmol) in methylene chloride (50 ml) was added 0.84 g (8.4 mmol) of triethyl amin and 0.93g (8.4 mmol) of mesyl chloride. After stirring the reaction mixture for 20 h water was added. The organic layer was separated dried over anhydrous sodium sulfate and was evaporated under reduced pressure. The residue was triturated with diethyl ether, filtered and dried to give a powder of the tided product (0.9g, 83%).

(iH-NMR, 300 MHz, DMSO-d₆ ) : 1.40 (t, 3H), 2.65 (s, 3H), 3.25 (t, 2H), 3.40 (t, 2H), 3.80 (s, 3H), 4.40 (q, 2H), 7.00 (d, IH), 7.25 (t, 2H), 7.55 (t, IH), 7.95 (d,

2H), 9.15 (d, IH).

Example 2.10

8-Mesyl-2-methyl-7-(3-phenyl-3-hydroxypropyl)rimidazofl.2-a1pyridine-3- carboxylic add ethyl ester

To a solution of 7-(2-Benzoylethyl)-8-mesyl-2-methylimidazo-[l,2- a]pyridine-3-carboxylic acid ethyl ester (0.5g 1.2 mmol) in ethanol (20 ml) at 70 °C was added sodium hydride (0.05g 1.3 mmol) (55% in oil) and die mixture was stirred for 3 h at rom temperature. The mixture was concentrated under reduced pressure and die residue was dissolved in methylene chloride and washed with aqueous bicarbonate. The organic layer was separated dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was triturated with diethyl etiier to give a powder of the title product (0.25 g, 48%). (iH-NMR, 400 MHz, DMSO-d₆ ) : 1.40 (t, 3H), 2.10-2.20 (m, 2H), 2.65 (s, 3H),

2.90-3.00 (m, 2H), 3.80 (s, 3H), 4.40 (q, 2H), 4.47 (dd, IH), 6.90 (d, IH), 7.15- 7.40 (m, 5H), 9.15 (d, IH).

3. PREPARATION OF THE PURE ENANTIOMERS

3.1. Preparation by process B. patii A

3.1.1. (-)Enantiomers

Example 3.1.1.1.

8-Hydroxy-2-methyl-7-(3-phenyl-3-hydroxypropyl)-imidazori.2-a1pyridine- 3-carboxylic add ethyl ester

A solution of 1.0 g (2.8 mmol) 7-(2-benzoylethyl)-8-hydroxy-2-methyl- imidazo[l,2-a]pyridine-3-carboxylic add ethyl ester in tetrahydrofuran (10 ml) was cooled to -25 °C (argon atmosphere). (+)-Diisopinocampheyl- chloroborane (1.8 g, 5.6 mmol) was added and the mixture was stirred for 24 h. (temperature between -25°C and 0°C). Additional (+)- Diisopinocampheyl-chloroborane (1.1 g, 3.4 mmol) was added during a period of 7 h and the mixture was stirred for 15 h. The reaction mixture was allowed to reach R.T and methylene chloride 20 ml and aqueous sodium bicarbonate was added. The organic layer was separated dried over anhydrous sodium sulfate and evaporated under reduced pressure to give an oily residue. The residue was twice subjected to flash chromatography on silica ge metylene chloride : methanol a) 10:1 b) 100:5 , to give 0.55 g (55%) of the desired product as pure enatiomer. ( H-NMR, 300 MHz, CDCI3): 1.4 (t, 3H), 2.0-2.25 ( , 2H), 2.65 (s, 3H), 2.75-

2.85 (m, IH), 2.95-3.10 (m, IH), 4.0 (bs, 2H), 4.45 (q, 2H), 4.70 (dd, IH), 6.85 (d, IH), 7.20-7.40 (m, 5H), 8.85 (d, IH).

Example 3.1.1.2

8-Mesyl-2-methyl-7-(3-phenyl-3-hydroxypropyl)-i_midazori,2-alpyridine-3- carboxylic add ethyl ester

To a solution of 8-hydroxy-2-methyl-7-(3-phenyl-3-hydroxypropyl)- imidazo[l,2-a]pyridine-3-carboxylic add ethyl ester (0.5 g 1.4 mmol) in acetonitril (25 ml) was added 0.32 g (2.0 mmol) of potassium carbonate and 0.16 ml (2.0 mmol) of mesyl chloride. The reaction mixture was stirred for 16 h, filtred and the filtrate was evaporated under reduced pressure. The residue was subjected to flash chromatography on silica gel, methylene chloride : methanol (100:5), to give die pure enantiomer of the tide compound 0.4 g (66%).

(iH-NMR, 300 MHz, CDCI3): 1.45 (t, 3H), 2.05-2.15 (m, 2H), 2.65 (s, 3H), 2.95-3.05 (m, 2H), 3.80 (s, 3H), 4.45 (q, 2H), 4.70-4.80 (m, IH), 6.90 (d, IH),

7.20-7.40 (m, 5H), 9.10 (d, IH).

Example 3.1.1.3

8,9-Dihydro-2-memyl-9-phenyl-7H-imidazofl.2-al-pyranor23-clpyridine-3- carboxylic add ethyl ester

Sodium hydride (0.04 g 0.93 mmol)(55% in oil) was added to a solution of 8- mesyl-2-methyl-7-(3-phenyl-3-hydroxypropyl)-imidazo[l,2-a]pyridine-3- carboxylic acid ethyl ester (0.4 g 0.93 mmol) in dimethylformamide (15 ml) at 5 °C. The reaction mixture was stirred for 3 h. at 5 °C and 30 min. at ambient temperature and was tiien concentrated under reduced pressure. The residue was dissolved in mediylene chloride washed with aqueous bicarbonate. The organic layer was separated dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified twice by column chromatography on silica gel with a mixture of dichloromethane and methanol (100:1 and 100:5) as eluent to give die pure enantiomer (96.6 % ee) of the title product as an oil. (0.18 g 58%)

(iH-NMR, 300 MHz, CDC1₃): 1.40 (t, 3H), 2.10-2.35 (m, 2H), 2.60-2.75 (m, 4H), 2.80-2.95 (m, IH), 4.40 (q, 2H), 5.25 (dd, IH), 6.60 (d, IH), 7.20-7.40 (m, 5H), 8.80 (d, IH).

Example 3.1.1.4

(-)-3-Hydroxymethyl-2-methyl-9-phenyl-7H-8.9-dihydro-pyranof2.3-c1- imidazon ,2-a lpyridine

To a solution of 0.17g (0.51 mmol) of the pure enantiomer 8,9-dihydro-2- methyl-9-phenyl-7H-imidazo [l,2-a]-pyrano [2,3-c]pyridine-3-carboxylic add ethyl ester in toluen (10 ml) was added 0.6 ml (2.1 mmol) of sodium bis (2- methoxyedioxy) aluminium hydride and the reaction mixture was stirred for 3 h at ambient temperature. The reaction was stopped by adding 0.3 ml water and the reaction mixture was filtered. The filtrate was evaporated under reduced pressure. The residue was dissolved in methylene chloride, washed with water and dried over sodium sulfate. The solvent was evaporated under reduced pressure and was triturated witii a mixture of acetonitril and ether (50:50) affording powder of the pure enantiomer (96% ee) of the tide product. (0.05g 33%) (iH-NMR, 300 MHz, CDC1₃): 2.05-2.40 (m, 5H), 2.65-2.75 (m, IH), 2.85-3.00 (m, IH), 4.85 (s, 2H), 5.25 (dd, IH), 6.50 (d, IH), 7.25-7.50 (m, 5H), 7.80 (d, IH).

3.1.2. (- )-Enantiomers

Example 3.1.2.1

8-Hydroxy-2-me yl-7-(3-phenyl-3-hydroxypropyl)-imidazofl.2-a1pyridine- 3 carboxylic add ethyl ester

A solution of 14.0 g (40.0 mmol) 7-(2-benzoyletiιyl)-8-hydroxy-2-methyl- __midazo[l,2-a]pyridine-3-carboxylic add ethyl ester in tetrahydrofuran (400 ml) was cooled to -50 °C (argon atmosphere). (-)-Dϋsopinocampheyl- chloroborane (50 g, 155 mmol) and the mixture was stirred for 24 h.

(temperature between -25°C and -5°C). To the reaction mixture was added acetaldehyd (12.3g 280 mmol) and the mixture was allowed to reach R.T and was stirred for 1.5 h. To the mixture (after cooling to 5 °C) was added etiier (200 ml) and 2M NaOH (200 ml) and was stirred for 20 min. at the same temperature. The organic layer was separated dried over anhydrous sodium sulfate and evaporated under reduced pressure. The oily product was dissolved in ether and was converted to hydrochloride salt by adding a HCL-ether solution and the resultant predpitate was filtered off. The salt was dissolved in methylene chloride and was basified with 2M NaOH. The organic layer was separated, dried over anhydrous sodium sulfate and die solvent was evaporated under reduced pressure to give a residue, which was triturated in petrol ether to give a powder of die pure enantiomer of die tide comρound.(10.7g 76%) ( H-NMR, 300 MHz, CDC1₃): 1.45 (t, 3H), 2.00-2.25 (m, 2H), 2.65 (s, 3H),

2.80-2.90 (m, IH), 3.00-3.15 (m, IH), 4.40 (q, 2H), 4.70 (m, IH), 6.90 (d, IH), 7.20-7.40 (m, 5H), 8.85 (d, IH).

Example 3.1.2.2

8-Mesyl-2-methyl-7-⁽3-phenyl-3-hydroxypropyl)-imidazofl.2-alpyridine-3- carboxylic add ethyl ester

To a solution of 8-Hydroxy-2-methyl-7-(3-phenyl-3-hydroxypropyl)- imidazo[l,2-a]pyridine-3-carboxylic add ethyl ester (lO.Og 28 mmol) in acetonitril (200 ml) was added 7.7g (55 mmol) of potassium carbonate and 4.8g (38 mmol) of mesyl chloride. The reaction mixture was stirred for 24 h, filtred and thesolvent was evaporated under reduced pressure. The residue was subjected to flash chromatography on silica gel, methylene chloride : methanol (100:5), to give the pure enantiomer of die tide compound 8.0g (66%).

(iH-NMR, 400 MHz, CDCI3): 1.40 (t, 3H), 2.05-2.10 (m, 2H), 2.70 (s, 3H), 2.95-3.00 (m, 2H), 3.75 (s, 3H), 4.40 (q, 2H), 4.85-4.90 (m, IH), 6.85 (d, IH), 7.15-7.40 (m, 5H), 9.10 (d, IH).

Example 3.1.2.3

8.9-Dihydro-2-methyl-9-phenyl-7H-imidazori.2-a1-pyranor23-c1pyridine-3- carboxylic add ethyl ester

Sodium hydride (1.0 g 22.5 mmol) (55% in oil) was added to a solution of 8- mesyl-2-memyl-7-(3-phenyl-3-hydroxypropyl)-imidazo[l,2-a]pyridine-3- carboxylic add ethyl ester (7.8 g 18.0 mmol) in dimethylformamide 100 ml at 5 °C. The reaction mixture was stirred for 6 h. at ambient temperature and was tiien concentrated under reduced pressure. The residue was dissolved in methylene chloride washed with aqueous bicarbonate. The organic layer was separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel with etiiyl acetate:petroleum ether (50:50) as eluent to give the pure enantiomer ( 90% ee) of the title product as an oil. (3.37g 62%)

(iH-NMR, 300 MHz, CDC1₃): 1.45 (t, 3H), 2.20-2.40 (m, 2H), 2.70-2.85 (m,

4H), 2.90-3.00 (m, IH), 4.40 (q, 2H), 5.35 (dd, IH), 6.70 (d, IH), 7.30-7.50 (m, 5H), 8.80 (d, IH).

Example 3.1.2.4

(+)-3-Hydroxymethyl-2-methyl-9-phenyl-7H-8.9-dihydro-pyranor23-c1- imidazoπ ,2-alpyridine

To a solution of 3.7 g (O.llmmol) of the pure enantiomer 8,9-dihydro-2- methyl-9-phenyl-7H-i_midazo[l,2-a]-pyrano[2^-c]pyridine-3-carboxylic add ethyl ester in 40 ml toluen was added slowly 9.0 ml (33.0 mmol) of sodium bis (2-methoxyethoxy) alummium hydride in 15 ml toluen for 2 h at 5 °C and the reaction mixture was stirred for 5 h. at ambient temperature. The reaction was cooled to 5 °C and was stopped by adding 7.0 ml water slowly and the reaction mixture was filtered. The filtrate was evaporated under reduced pressure. The residue was purified by column chromathography on silica gel with a mixture of dichloromethane and methanol (10:1) as an eluent to give a powder of the pure enantiomer (90.2% ee) of the tide product. (2.7g 90%)

(iH-NMR, 300 MHz, CDCI3): 2.15-2.35 (m, 2H), 2.40 (s, 3H), 2.65-2.75 (m, IH), 2.85-2.95 (m, IH) 4.90 (s, 2H), 5.30 (dd, IH), 6.55 (d, IH), 7.25-7.50 (m,

5H), 7.80 (d, IH). Example 3.3.

Resolution of die compound according to Example 1.1

(a) A hot solution of 0.52 g (1.7mmol) [(lR)-(endo,anti)]-(+)-3- bromocamphor-8-sulfonic acid and 0.5 g (1.7mmol) of racemic 3- hydroxymethyl-2-medιyl-9-phenyl-7H-8,9-dihydropyrano[2^-c]imidazo- [l,2-a]pyridine in 11 ml ethanol was allowed to cool to room temperature and was stirred for 24 h. The crystalline salt filtered off (the filtrate was used in (b)). The recrystallization was repeated four times, finally yielding 9 mg of the salt. The salt was solved in methylene chloride and basified with a sodium bicarbonate solution. The organic layer was separated dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 3.9 mg of die enantiomer as an oil.

(b) The filtrate from the first crystallisation in (a) was evaporated under reduced pressure. The residue was solved in methylene chloride and was made basic by the addition of a sodium bicarbonate solution.The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure, yielding 150 mg of an oil. This oil (150 mg, 0.5 mmol) was solved in 2.5 ml hot ethanol and to the solution was added 0.16 g (0.5 mmol) of [(lS)-(endo,anti)]-(-)-3-bromocamphor-8-sulfonic add. The solution was allowed to cool to room temperature and was stirred for 24 h. The crystalline material was filtered off. This recrystallization was repeated twice. Working up as in (a) gave 6.9 mg of die enantiomer as an oil.

The enantiomers was separated on a 250 X 4.6 mm i.d. Chiralpak AD column (Dadel apan) using die following parameters: mobilphase: n-hexane : 2- propanol : acetonitrile : diethyl amin (84:16:2.5:0.1 ml); temperature: 35°C; flow rate: 0.8 ml/min.

Enantiomer according to (a): retention time 12.0 min Enantiomer according to (b): retention time 13.6 min

4. PREPARATION OF SALTS

Example 4.1.

Preparation of the hydrochloride salt of 3-hydroxymethyl-2-methyl-9- phenyl-7H-8.9-d-hydro-pyranof23-c1-imidazofl.2-a1pyridine

3-hydroxymethyl-2-medιyl-9-phenyl-7H-8,9-dihydro-pyrano[2 -c]- imidazo[l,2-a]pyridine (0.5g, 1.7 mmol) was dissolved in hot ethanol (10 ml) and was cooled to room temperature. A solution of hydrogen chloride in diethyl ether (4 ml) was added and the reaction mixture was stirred for 10 min. The resulting white solid was filtered off and dried to give. die tide salt. (0.35g, 62%)

(iH-NMR, 300 MHz, DMSO-d₆ ) : 2.15-2.25 (m, IH), 2.30-2.40 (m, IH) 2.50

(s, 3H), 2.85-2.95 (m, IH), 3.05-3.15 (m, 1H),4.85 (s,2H), 5.45-5.55 (m,lH),5.75 (bs, IH), 7.35 (d, IH), 7.40-7.60 (m, 5H), 8.35 (d, IH) .

Example 4.2.

Preparation of d e methanesulfonic acid salt of 3-hydroxymethyl-2-methyl-9- phenyl-7H-8,9-dihydro-pyranor23-cl-imidazofl^-a1pyridine 3-hydroxymethyl-2-medιyl-9-phenyl-7H-8,9-dihydro-pyrano[2,3-c]- imidazo[l,2-a]pyridine (0.5g, 1.7 mmol) was dissolved in hot ethanol (5 ml).

To die solution was added methanesulfonic add (0.11 ml, 1.7 mmol) and the mixture was stirred for 15 min at room temperature. The resulting white solid was filtered off and dried to give the tide salt (0.5g, 75%).

(iH-NMR, 300 MHz, DMSO-d₆ ) : 2.10-2.20 (m, IH), 2.30 (s, 3H) 2.35-2.2.55

(m, 4H), 2.85-2.95 (m, IH), 3.05-3.15 (m,lH), 4.85 (s,2H), 5.40-5.50 (m,lH), 7.30 (d, IH), 7.35-7.65 (m, 5H), 8.30 (d, IH) .

Example 4.3.

Preparation of the hydrogen sulfate salt of 3-hydroxymethyl-2-methyl-9- phenyl-7H-8 ,9-dihydro-pyrano \23-cl-imidazo f 1 ,2-a Ipyridine

3-hydroxymethyl-2-methyl-9-phenyl-7H-8,9-dihydro-pyrano[2,3-c]- imidazo[l,2-a]pyridine (0.5g, 1.7 mmol) was dissolved in hot ethanol (5 ml). To the solution was added sulfuric acid (95ml, 1.7 mmol) and the mixture was stirred for 15 min at room temperature. The resulting white solid was filtered off and dried to give the tide salt (0.5g, 75%).

(iH-NMR, 300 MHz, DMSO-d₆ ) : 2.15-2.25 (m, IH), 2.30-2.40 (m, IH) 2.45

(s, 3H), 2.85-2.95 (m, IH), 3.10-3.20 (m, 1H),4.85 (s,2H), 5.45-5.55 (m,lH), 7.35 (d, IH), 7.40-7.60 (m, 5H), 8.30 (d, IH) .

Example 4.4.

Preparation of di-[3-hydroxymethyl-2-methyl-9-phenyl-7H-8.9-dihydro- pyranof23-c1-imidazo.l.2-a.pyridine1 tartaric add salt 3-hydroxymethyl-2-medιyl-9-phenyl-7H-8,9-dihydro-pyrano[2,3-c]- imidazo[l,2-a]pyridine (1.0 g, 3.4 mmol) was dissolved in a mixture of diethyl ether (4 ml) and ethanol (5 ml). To the solution was added tartaric add (0.5g, 3.4 mmol) dissolved in hot ethanol (3 ml). The mixture was stirred at room temperature over night. The resulting white solid was filtered off and dried to give the tide salt (0.8g, 64%).

(iH-NMR, 300 MHz, DMSO-d₆ ) : 2.05-2.15 (m, 2H), 2.20-2.40 (m, 8H) 2.60-

2.75 (m, 2H), 2.90-3.00 (m, 2H), 4.25 (s, 2H),4.70 (s,4H), 5.20-5.30 (m,2H), 6.7 (d, 2H), 7.30-7.55 (m, 10H), 7.90 (d, 2H) .

Example 4.5.

Preparation of the metiianesulfonic add salt of (+)-3-hydroxymethyl-2- methyl-9-phenyl-7H-8.9-d- ydro-pyranor23-c1-imidazori.2-a1pyridine

(+) 3-hydroxymethyl-2-medιyl-9-phenyl-7H-8,9-dihydro-pyrano[23-c]- imidazo[l,2-a]pyridine (4.7 g, 16.0 mmol) was dissolved in a hot mixture of etiiyl acetate (60 ml) and ethanol (22 ml). To the solution was added methanesulfonic add (1.6 g , 16.7 mmol) solved in 3 ml ethyl acetate and die mixture was stirred for 15 min at room temperature. An additional amount of ethyl acetate was added (15 ml) and the resulting white solid was filtered off and dried to give the tide salt (5.7 g, 91%) (91.2% ee).

(iH-NMR, 300 MHz, DMSO-d₆ ) : 2.10-2.25 (m, 1 H), 2.30 (s, 3H), 2.35-2.45

(m, 4H), 2.85-2.95 (m, IH), 3.05-3.20 (m, IH), 4.85 (s, 2H), 5.50 (dd, IH), 5.60 (bs, IH), 7.35 (d, IH), 7.40-7.65 (m, 5H), 8.35 (d, IH). Example 4.6.

Preparation of the meti anesulfonic add salt of (-)-3-hydroxymethyl-2- methyl-9-phenyl-7H-8.9-dihydro-pyranof23-c1-imidazo[l,2-a1pyridine

(-)-3-hydroxymethyl-2-methyl-9-phenyl-7H-8,9-dihydro-pyrano[2,3-c]- imidazo[l,2-a]pyridine (4.0 g, 13.6 mmol) was dissolved in a hot mixture of etiiyl acetate (30 ml) and ethanol (12 ml). To the solution was added methanesulfonic add (1.4 g, 15.0 mmol) solved in 2 ml ethyl acetate and die mixture was stirred for 15 min at room temperature. An additional amount of etiiyl acetate was added (15 ml) and the resulting white solid was filtered off and dried to give the tide salt (5.0 g, 94%) (92% ee).

(iH-NMR, 300 MHz, DMSO-d₆ ) : 2.10-2.25 (m, 1 H), 2.30 (s, 3H), 2.35-2.45 (m, 4H), 2.85-2.95 (m, IH), 3.05-3.20 (m, IH), 4.85 (s, 2H), 5.50 (dd, IH), 5.60

(bs, IH), 7.35 (d, IH), 7.40-7.65 (m, 5H), 8.35 (d, IH).

5. PREPARATION OF PHARMACEUTICAL FORMULATIONS

Pharmaceutical formulations containing a compound of the invention as active ingredient are illustrated in the following examples:

Example 5.1: Syrup

A syrup containing 1 % (weight per volume) of active substance is prepared from die following ingredients:

Add addition salt of die compound according to Example 1.1 1.0 g Sugar, powder 30.0 g

Saccharine 0.6 g 38

Glycerol 5.0 g

Flavouring agent 0.05 g

Ethanol 96% 5.0 g

Distilled water q.s. to a final volume of 100 ml

Sugar and saccharine are dissolved in 60 g of warm water. After cooling the add addition salt is dissolved in the sugar solution and glycerol and a solution of flavouring agents dissolved in ethanol are added. The mixture is diluted witii water to a final volume of 100 ml.

Example 5.2: Tablets

A tablet containing 50 mg of active compound is prepared from the following ingredients:

I Compound according to Example 1.1 500 g Lactose 700 g Methyl cellulose 6 g Polyvinylpyrrolidone cross-linked 50 g Magnesium stearate 15 g

Sodium carbonate 6 g

Distilled water q.s.

II Hydroxypropyl methylcellulose 36 g Polyethylene glycol 9 g Colour Titanium dioxide 4 g

Purified water 313 g

I. Compovmd according to Example 1.1, powder, is mixed with lactose and granulated witii a water solution of mediyl cellulose and sodium carbonate. The wet is forced dirough a sieve and the granulate dried in an oven. After drying, the granulate is mixed with polyvinylpyrrolidone and magnesium stearate. The dry mixture is pressed into tablet cores (10,000 tablets), each tablet containing 50 mg of active substance, in a tabletting machine using 7 mm diameter punches.

II. A solution of hydroxypropyl methylcellulose and polyethylene glycol in purified water is prepared. After dispersion of titanium dioxide the solution is sprayed onto die tablets I in an Accela Cota®, Manesty coating equipment. A final tablet weight of 130 mg is obtained.

Example 5.3: Solution for intravenous administration

A parenteral formulation for intravenous use, containing 4 mg of active compound per ml, is prepared from the following ingredients:

Compound according to Example 1.1 4 g

Polyethylene glycol 400 for injection 400 g

Disodium hydrogen phosphate q.s.

Sterile water to a final colume of 1.000 ml

Compound according to Example 1.1 is dissolved in polyethylene glycol 400 and 550 ml of water is added. The pH of the solution is brought to pH 7.4 by adding a water solution of disodium hydrogen phosphate and water is added to a final volume of 1000 ml. The solution is filtered dirough a 0.22 μm filter and immediately despensed into 10 ml sterile ampoules. The ampoules are sealed.

6. BIOLOGICAL TESTS

6.1. Acid secretion inhibition in isolated rabbit gastric glands Inhibiting effect on add secretion in vitro in isolated rabbit gastric glands was measured as described by Berglindh et al. (1976) Acta Physiol. Scand.

97, 401-414. The compound according to Example 1.1 of the invention had an

IC50 value of 0.25 μM.

Bioavailability

Bioavailability is assessed by calculating the quotient between the area under blood/plasma concentration (AUC) curve following (i) intraduodenal (i.d.) or oral (p.o.) administration and (ii) intravenous (i.v.) administration from me rat or die dog, respectively.

Potency for inhibition of acid secretion

The potency for inhibition of add secretion is measured in the rat intraduodenally and intravenously, and orally in the dog.

6.2. Inhibiting effect on acid secretion in female rats

Female rats of the Sprague-Dawly strain were used. They were equipped with cannulated fistulae in the stomach (lumen) and the upper part of die duodenum, for collection of gastric secretions and administration of test substances, respectively. A fourteen days recovery period after surgery was allowed before testing commenced.

Before secretory tests, the animals were deprived of food but not water for 20 h. The stomach was repeatedly washed through the gastric cannula with tap water (37°C), and 6 ml of Ringer-Glucose given subcutaneously. Add secretion was stimulated witii infusion during 3 h (1.2 ml/h, subcutaneously) of pentagastrin and carbachol (20 and 110 nmol/kg h, respectively), during which time gastric secretions were collected in 30-min fractions. Test substances or vehides were given intravenously or intraduodenally at 60 min after starting the stimulation, in a volume of 1.2 ml/h. Gastric juice samples were titrated to pH 7.0 witii NaOH, 0.1 mol/1, and acid output calculated as die product of titrant volume and concentration.

Furdier calculations were based on group mean responses from 4-5 rats. The add output during the periods after administration of test substances or vehicle were expressed as fractional responses, setting the add output in the 30-min period preceding administration to 1.0. Percentage inhibition was calculated from die fractional responses elidted by test compound and vehicle. ED50 values were obtained from graphical interpolation on log dose-response curves, or estimated form single-dose experiments assuming a similar slope for all dose-response curves.

The compound according to Example 1.1 of the invention had after id administration an ED50 value of 1.8 μmol/kg. The result are based on gastric add secretion during die period from 30 to 60 minutes after drug/vehide administration.

63. Bioavailability in rat

Adult rats of the Sprague-Dawley strain were used. One to three days prior to the experiments all rats were prepared by cannulation of the left carotid artery under anaestiiesia. The rats used for intravenous experiments were also cannulated in the jugular vein (Popovic (1960) J. Appl. Physiol. 15, 727- 728). The cannulas were exteriorized at the nape of die neck. The compound according to Example 1.1 was given intraduodenally (10 μmol/kg) or intravenously (5 μmol/kg) as a bolus for about 0.5 min (2 ml/kg). 12 μmol/kg of the compound according to Example 1.1 was given orally by gavage and the dose 4 μmol/kg was given intravenously as a bolus for about 0.5 min (2 ml/kg). For compound A for comparison, the dose 40 μmol/kg was given orally by gavage and the dose 45 μmol/kg was given intravenously as a bolus.

Blood samples (0.1 - 0.4 g) were drawn repeatedly from die carotid artery at intervals up to 4 hours after given dose. The samples were frozen until analysis o f the test compound.

The area under die blood concentration vs time curve, AUC, was determined by the linear trapezoidal rule and extrapolated to infinity by dividing the last determined blood concentration by the elirnination rate constant in the terminal phase. The systemic bioavailability (F%) following intraduodenal administration was calculated as F(%) = ( AUC (p.o. or i.d.) / AUC (i.v.) ) x 100.

6.4. Inhibition of gastric acid secretion and bioavailability in the concious dog.

Labrador retreiver or Harrier dogs of either sex were used. They were equipped witii a duodenal fistula for the administration of test compounds or vehide and a cannulated gastric fistula or a Heidenhain-pouch for the collection of gastric secretion.

Before secretory tests die animals were fasted for about 18 h but water was freely allowed. Gastric add secretion was stimulated for up to 4 h infusion of histamine dihydrochloride (12 ml/h) at a dose producing about 80% of the individual maximal secretory response, and gastric juice collected in consecutive 30-min fractions, test substance or vehide was given orally, i.d. or i.v., 1 or 1.5 h after starting die histamine infusion, in a volume of 0.5 ml/kg body weight. In the case of oral administration, it should be pointed out that die test compound is adminstered to the add secreting main stomach of the Heidenham-pouch dog. The addity of the gastric juice samples were determined by titration to pH 7.0, and the add output calculated. The add output in the collection periods after administration of test substance or vehide were expressed as fractional responses, setting die add output in die fraction preceding administration to 1.0. Percentage inhibition was calculated from fractional responses elidted by test compound and vehide. ED5ø-values were obtained by graphical interpolation on log dose - response curves, or estimated under the assumption of the same slope of die dose-response curve for all test compounds. All results are based on add output during the period from 1.5 to 2 hours after dosing.

Blood samples for the analysis of test compound concentration in plasma were taken at intervals up to 4 h after dosing. Plasma was separated and frozen witiiin 30 min after collection and later analyzed. The systemic bioavailability (F%) after oral i.d. administration was calculated as described above in the rat model.

6.5. Determination of cyanide

The cyanide in whole blood was determinated as described by Lundquist et al. (1985) Clin. Chem. vol 31. No. 4., p. 591-595. Administration of 8 μmol/kg i.d. of compound B for comparison repeated once daily for 8 days was done in four dogs. Cyanide concentration was determinated in whole blood day 1, day 4 and day 8. The result is given as medium cyanide peak concentration in whole blood 5-15 minutes (Tmax) after the dose and the min and max value of die cyanide peak concentration determined in whole blood from four dogs.

The compounds for comparison in Table 1 are:

A: (3-(hydroxymethyl)-2-me yl-8-(pheny]_methoxy)iιnidazo[l,2-a]pyridine); B: (8,9-cUhydro-2-methyl-9-phenyl-7H-imidazo[l,2-a]pyrano[2,3-c]-pyridine-

3-acetonitrile); and

C : (3-(cyanomemyl)-2-memyl-8-(phenylmethoxy)imidazo[l,2-a]pyridine).

TABLE 1

Summary of die biological tests.

Examples for comparison

Compound ~ according to Example 1.1

6.1. Gastric glands 0.25 0.43 0.064 0.065 IC50 .UM) Value from D5 Value from D5

6.2.(a) Rat i.v. EU50 (μmol/kg)

6.2. (b) Rati.d. 1.8 6.4 ED50 (μmol/kg)

6.3. Rat - bioavailability 54 (i.d.) (%) 23 (p.o.) 12 (p.o.)

6.4.(a) Dog p.o. 16 29.8 12.2 15.9 EDso (μmol/kg) Value from Value from D4 Value from Dl Dl

6.4.(b) Dog - 18 2.3 bioavailability i.d. (Beagles)

(%)

65.(a) CN- peak 3.3 concentration in dog, whole blood

(μM)

6.5.(b) CN- in dog 20.2 measured as SCN- in Value from D2 urine

(%)

Claims

1. A compound of die Formula I

or a pharmaceutically acceptable salt thereof, wherein

R is

(a)CH₃,or (b)CH₂CH₃;

R is

(a)H,

(b) halogen,

(c) lower alkyl, (d) lower alkoxy, or

(e)OH;

R³, which is in position 3, 4 ,5 or 6 of die phenyl ring, is (a)H,

(b) halogen, or (c) lower alkyl.

2. A compound according to daim 1 wherein R is CH3 or CH₂CH3; R² is H,

CH3, OH, OCH3, OCH₂CH₃, F or Cl; and R³ is H, 4-CH₃, 4-F or 4-C1, or a pharmaceutically acceptable salt thereof.

3. A compound according to daim 2 wherein Rl is CH3, R² is H and R³ is H, i.e. the compound 3-hydroxymethyl-2-methyl-9-phenyl-7H-8,9-dihydropyrano[2,3-c]- imidazo[l,2-a]pyridine, or a pharmaceutically acceptable salt tiiereof.

4. A compound according to daim 2 wherein Rl is CH3, R² is H and R³ is 4-F, i.e. the compound 3-hydroxymethyl-2-methyl-9-(4-fluorophenyl)-7H-8,9- dihydropyrano[2,3-c]imidazo[l,2-a]pyridine or a pharmaceutically acceptable salt thereof.

5. A compound according to daim 3 which is the compound (+)-3-hydroxymethyl- 2-metiιyl-9-phenyl-7H-8,9-d__hydropyrano[2,3-c]-imidazo[l,2-a]pyridine or a pharmaceutically acceptable salt thereof.

6. A compound according to claim 3 which is the compound (-)-3-hydroxymethyl- 2-methyl-9-phenyl-7H-8,9-dihydropyrano[2,3-c]-__αιidazo[l,2-a]pyridine or a pharmaceutically acceptable salt thereof.

7. A compound which is a hydrochloride salt of a compound according to any one of daims 1 to 6.

8. A compound which is a methanesulfonic add salt of a compound according to any one of daims 1 to 6.

9. A process for the preparation of a compound according to any one of daims 1 to 8 comprising (a) debenzylating a compound of the Formula VII

wherein Rl is as defined for Formula I, in the presence of a catalyst, to die compound of the Formula VI;

(b) reacting a compound of die general Formula VI, wherein Rl is as defined for Formula I, in a Mannich reaction in an inert solvent, to prepare a compound of die Formula V;

(c) reacting a compound of Formula V, wherein Rl is as defined for Formula I, with an enamine of the general Formula VDI

vm wherein R² and R³ are as defined for Formula I, to a compound of die Formula IV;

(d) reducing a compound of Formula IV, wherein Rl, R² and R³ are as defined for Formula I, to the corresponding hydroxy compound of Formula HI;

(e) treating a compound of Formula HI, wherein Rl, R² and R³ are as defined for Formula I, with a Lewis acid under standard conditions in an inert solvent, thereby forming a compound of Formula II; and

(f) reducing a compound of the Formula π, wherein Rl, R² and R³ are as defined for Formula I, to a compound of the general Formula I.

10. A process for die preparation of a compound according to any one of daims 1 to 8 comprising

(a) converting the phenolic hydroxygroup of a compound of die Formula HI, wherein Rl, R², and R³ are as defined for Formula I, to a leaving group X resulting in a compound of the general Formula IX;

(b) ringdosure of a compound of die Formula IX, wherein Rl, R², and R³ are as defined for Formula I and X is a leaving group, witii a base in an inert solvent, to a compound of die general Formula II; and

(c) reducing a compound of the Formula II, wherein R , R², and R³ are as defined for Formula I, to a compound of die Formula I.

11. A process for die preparation of a compound according to any one of daims 1 to 8 comprising

(a) converting the phenolic hydroxygroup of a compound of die Formula IV, wherein Rl, R², and R³ are as defined for Formula I, to a leaving group X resulting in a compound of die general Formula X;

(b) redudng a compound of the Formula X, wherein Rl, R², and R³ are as defined for Formula I, to die corresponding hydroxy compound of the Formula IX;

(c) ringdosure of a compound of die Formula IX, wherein Rl, R², and R³ are as defined for Formula I and X is a leaving group, witii a base in an inert solvent, to a compound of die general Formula II; and

(d) reducing a compound of die Formula π, wherein Rl, R², and R³ are as defined for Formula I, to a compound of die Formula I.

12. A process for the preparation of die pure enantiomers of a compound according to any one of daims 1 to 8 comprising (a) enantioselective reduction of a compound of die Formula IV, wherein , R², and R³ are as defined for Formula I, to die corresponding hydoxygroup of a compound of die general Formula m (R or S);

(b) converting the phenolic hydroxygroup of a compound of the Formula Dl (R or

S) wherein R , R², and R³ are as defined for Formula I, to a leaving group X resulting in a compound of the general Formula IX (R or S);

IX (R or S) (c) ringdosure of a compound of the Formula IX (R or S), wherein R , R², and R³ are as defined for Formula I and X is a leaving group, with a base in an inert solvent, to a compound of the general Formula II (R or S); and

(d) reducing a compound of the Formula II (R or S), wherein Rl, R², and R³ are as defined for Formula I, to a compound of die Formula I (R or S).

13. A process for die preparation of the pure enantiomers of a compound according to any one of daims 1 to 8 comprising

(a) enantioselective reduction of a compound of die Formula X, wherein Rl, R², and R³ are as defined for Formula I, to the corresponding hydroxy compound of die Formula IX (R or S);

(b) ringclosure of a compound of die Formula IX (R or S), wherein Rl, R², and R³ are as defined for Formula I and X is a leaving group, with a base in an inert solvent, to a compound of die general Formula II (R or S); and

(c) reducing a compound of the Formula II (R or S), wherein Rl, R², and R³ are as defined for Formula I, to a compound of die Formula I (R or S).

14. A compound according to any one of claims 1 to 8 for use in therapy.

15. A pharmaceutical formulation containing a compound according to any one of daims 1 to 8 as active ingredient and comprising a pharmaceutically acceptable carrier.

16. Use of a compound according to any one of daims 1 to 8 for the manufacture of a medicament for the inhibition of gastric add secretion.

17. Use of a compound according to any one of daims 1 to 8 for the manufacture of a medicament for the treatment of gastrointestinal inflammatory diseases.

18. Amediod for inhibiting gastric add secretion which comprises administering to a mammal, including man, in need of such inhibition an effective amount of a compound according to any one of daims 1 to 8.

19. A method for die treatment of gastrointestinal inflammatory diseases which comprises administering to a mammal, induding man, in need of such treatment an effective amount of a compound according to any one of daims 1 to 8.

20. A pharmaceutical formulation for use in the inhibition of gastric add secretion wherein the active ingredient is a compound according to any one of daims 1 to 8.

21. A pharmaceutical formulation for use in the treatment of gastrointestinal inflammatory diseases wherein the active ingredient is a compound according to any one of daims 1 to 8.