AU2003268866A1 - New compounds - Google Patents

Description

P/00/011 Regulation 3.2

AUSTRALIA

Patents Act 1990 COMPLETE SPECIFICATION STANDARD PATENT Invention Title: New compounds The following statement is a full description of this invention, including the best method of performing it known to us: WO 00/11000 PCT/SE99/01402 NEW COMPOUNDS TECHNICAL FIELD The present invention relates to novel compounds, and therapeutically acceptable salts thereof, which 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 compounds of the invention for use in therapy; to processes for preparation of such new compounds; 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.

is' BACKGROUND ART Substituted imidazo[1,2-a]pyridines, useful in the treatment of peptic ulcer diseases, are known in the art, e.g. from EP-B-0033094 and US 4,450,164 (Schering Corporation); from EP-B-0204285 and US 4,725,601 (Fujisawa Pharmaceutical from WO 9418199 and WO 9510518 (Byk Gulden Lomberg Chem.) and from publications by J. J. Kaminski et al.

in the Journal of Medical Chemistry (vol. 28, 876-892, 1985; vol. 30, 2031-2046, 1987; vol. 30, 2047-2051, 1987; vol. 32, 1686-1700, 1989; and vol. 34, 533-541, 1991).

For a review of the pharmacology of the gastric acid pump (the K+-ATPase), see Sachs et al. (1995) Annu. Rev. Pharmacol. Toxicol. 35: 277-305.

DISCLOSURE OF THE INVENTION It has surprisingly been found that compounds of the Formula I, which are substituted imidazopyridine derivatives, are effective as inhibitors of the gastrointestinal H K ATPase and thereby as inhibitors of gastric acid secretion.

WO 00/11000 PCT/SE99/01402 2 In one aspect, the invention thus relates to compounds of the general Formula 1: R k

_R

2 "N N Ar or a pharmaceutically acceptable salt thereof, wherein R' is

H,

C I -C 6 alkyl,

C

1

-C

6 alkenyl,

CH

2

OH,

halogen, or thiocyano

R

2 is

C,-C

6 alkyl, hydroxyalkyl.

C I-C 6 alkoxy C I-C 6 alkyl, hydroxy C,-C 6 alkoxy CI-C 6 alkyl,

CI-C

6 alkylthio C,-C 6 alkyl, cyano C,-C 6 alkyl, ()aoentdC-C 6 alkyl, or aminocarbonyl C I-C 6 alkyl

R

3 is wo 00/ 11 Goo PCT/SE99/01402 3

H,

CI-C6 alkoxy, C I-C 6 alkyl, halogen, hydroxy CI-C 6 alkyl, hydroxy C 1

-C

6 alkoxy, (cc) CI-C6 alkoxy Cl-C(, alkyl, C I-C 6 alkoxy C I-C 6 alkoxy,

CI-C

6 alkoxycarbonyl, C I-C 6 alkanoyl, halogenated CI-C 6 alkyl, N0 2 (in) CN,

CI-C

6 sulfonyl,

CI-C

6 sulfinyl,

C

1

-C

6 alkylthio,

CI-C

6 alkylaminosulfonyl,

CI-C

6 (alkyl) 2 aminosulfonyl, aminosulfonyl, Mt CI-C 6 alkylsulfonylamino.

C

1

-C

6 (alkylsulfonyl 2 amfino, trifluoroinethylsulfonylaino,

C

1

-C

6 alkylcarbonylamino,

C

1

-C

6 alkoxycarbonylamiflo, or

C

1

-C

6 aminocarbonylamino, optionally substituted by one Or IWO CI-C 6 alkyl.

groups, R' is

H,

C I-C6, alkyl.

wo 00/11000 PCT/SE99/01402 4 halogenated Ci-C 6 alkyl, (di) C 1

-C

6 alkoxy, or halogen, Ar is a with R 5

,R

6 and/or R' substituted phenyl. thieny1. furanyl, naphcyL or pyridyl group.

RK~O RK&H.N ,NH,,CH 2 R8 !zCH ,CH, orRk-, I.GH 2 C cC 0 Nj R

H,

C

1

-C

6 alkyl, C I-C 6 alkoxy, hydroxy, hydroxy C 1

-C

6 alkyl, hydroxy Cg-C 6 alkoxy, halogenated Ci-C6 alkyl, halogenated C I-C 6 alkoxy,

C

1

-C

6 alkoxy C 1

-C

6 alkyl, 0) halog en, hydroxy C i-C 6 alkoxy C 1

-C

6 alkyl,

CN,

(in) C I-C 6 alkoxycarbonyl,

CI-C

6 alkoxycarbolyloxy, (o)C i-C 6 alkylsulfonyloxy, trifluoromethylsulfolloxy,

CI-C

6 acyloxy C 1

-C

6 alkyl,

CI-C

6 alkylsuffonyl

C

1

-C

6 alkyl, wo 00/11000 WO 0011000PCT/SE99/01 402

C

1

-C

6 aikylsulfinyl

CI-C

6 alkyl.

C

1

-C

6 alkyithia Cr-C6 alkyl, Ct-C 6 alkoxycarboflyl aminlo CI-C 6 alkyl, aryl, amino CI-C 6 alkyl, NHC=R 1 2 N 0 H or C I-Cj alkyl substituted r group N o (aa) Hl or C alkyl substituted -,group. or (ab) CI-C 6 alkyl sulfonyl amino to R 6is

H,

CI-C

6 alkyl, halogen, hydroxy CI-C 6 alky!, halogenated CI-C 6 alkyl, halogenated CI-C 6 alkoxy.

CI-C

6 alkoxy C 1

-C

6 alkyl, or

CN

R, is

H,

C

1

-C

6 alkyl,

CI-C

6 aikoxy, halogen,

NO,,

halosgenatedl C 1

-C

6 alkyl.

wo 00/11000 PCT/SE99/01402 6 halogenated CI-C 6 alkoxy, aryloxy, or

CN

R' is H or C I-C 6 alkyl

R'

2 is (a)W CI-C 6 alkoxy,

C

1

-C

6 alkoxy C-C.

4 alkoxy,

NH,.

hydroxy C 2

-C

4 alkoxy,

C

1

-C

6 alkyl carbonyloxy C 2

-C

4 j alkoxy, (f halogenated C 2 -CL alkoxy, halogenated Cg-C 4 alkyl, hydroxy C 1

-C

4 alkyl, Gi) CI-C 6 alkyl carbonyloxy C 1 -Cs alkyl, j) aryt, aryl CI-C 4 alkyl,

C

1

-C

4 sulfanyl C,-C 4 alkoxy, (in) CI-C., sulfinyl C,-C 4 alkoxy, or

CIC

4 sulfonyl C 2

C

4 alkoxy, R 5 and R 6 are in the ortho positions relative to X R 7 is in the meta or para position relative to X

R

5 and R8 may together form a hydroxy- or alkoxy- substituted 5- or 6- membered ring, provided that one of R 3 and R 4 H or halogen WO 00/11000 PCT/SE99/01402 7 provided also that at least one of R 5

R

6 and R 7

H

provided also that when R or at least one of R 3 and R 4

H

provided also that when H or Cl, XAr OCH:Ar provided also that when R H, halogen or CHOH, at least one of R' and R 6 is CI-C 6 alkyl provided also that when R 2 is CH 2 OH or CH 2 CN. at least one of R 5 and R 6 is CI-C 6 alkyl The term "aryl" includes phenyl, naphtyl, thienyl, furyl, pyridyl or imidazolyl, optionally substituted by 1-3 substituentents selected from H, CI-C 6 alkyl, CI-C 6 alkoxy, halogen or so CF 3 As used herein, the term "Ci-C 6 alkyl" denotes a straight or branched alkyl group having from I to 6 carbon atoms. Examples of Ci-C 6 alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, t-butyl and straight- and branched-chain pentyl and is hcxyl.

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

The term "pyridyl" includes the and 4-isomers and the terms thienyl and furanyl include the and 3-isomers.

Both the pure enantiomers, racemic mixtures and unequal mixtures of the two enantiomers are within the scope of the invention. It should be understood that all the possible diastereomeric forms (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 present invention.

WO 00/11000 PCT/SE99/0140.2 8 Acid 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 acids.

1n the preparation of acid addition salts, preferably s uch acids are used which form suitable therapeutically acceptable salts. Examples of such acids are hydrohalogen acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid. aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic acid, acetic acid, propionic in acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, pyruvic acid, p-hydroxybensoic acid, embonic acid.

methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, halogenbcnsenesulfonic acid, toluenesulfonic acid or naphthalenesulfonic acid.

Preferred compounds according to the invention are those of the formula I wherein R' is H. CR 1

CH

2

OH;

R 2 is CR 1 CI-1CH3, CH 2

CH

2 OH,, CHCHSCH 3

CHCH.

2 OCH3 or CH 2

CH

2

CN;

R

3 is H, CR 1

CH

1

CH

3 F, C1, Br, OCH3,OCHCH3, CH 1 ,OH, CH 2

CH

2 OH, OCHCHOH,

CHCH

2 00H3. OCH.,CH,OCH3, C=OOCH3, C=OOCH-1CH3 C=OCH 3 C=OCHCH3,

C=OCH(CH

3 2 or C=OCH 2 CHiCH3, R 4 Is H4, CR 1

CH

2 CH-. F, Cl, Br, OCR 1 or OCH 2 CH4 3 Ar is phenyl. thienyl, furyl or naphtyl: I I I R8 is RKH R R&,,H,,CH 2 or C H R~is H CHCH, OCR 1 OH. CH 2 OH, CHOCH, CHCHOH, CH 2

CH

2

OCH

3

OCR

2 CHOH. OC=OOCHi, OC=OCH-1CH3, OCHF,, OCF3, F, Cl, Br, CN, phenyl,

CH

2

CH

2 OC=OCH-,, CHNHC=OOCH.

1 or CH,NHC=OOCHCFI, R' is H, CHR 1

CH

2

CR

3

CE

1

OCF

3

OCF

2 F, Cl. Br, or CH 2 00H 1 3; R 7 is H, F, Cl Br, OCFR, or OCF 3

R

8 is H or CH,, or CH 2 CH3.

Wo 00/11000 PCT/SE99/01402 9.

More preferred compounds according to the invention are those Of the formula I wherein R' is H, CR.; or CH 2

OH;

R2 is CH3, CH 2

CH

3

CH

2 OH. CH 2

SCH

3 CH-1 2 CHi or CH 2

CN;

R' is H, CH-, CH 2

CH

3

OCH

3

OCH

3 CHOH, C=OOCH,, C=OOCHCH3,

C=OCH

3

C=OCH

2

CH

3 or C=OCH 2

CH

2

CH

3 R' is H, or CH.); Ar is phenyl. thienyl or fury] I I I R8 RK..~H,.NH

,H,,CH

2 r o0 X is C C2or

T

R

5 is H, CR;. CHf 2

CH

3 1, OCH 3 0OH, CH 2 OH, CH 2 OCH. CHCH 2 OH. CHCH 1

,OCH

3 OCH,CH,O-,

OC=OOCH

3

OC=OCH'CH

3 ,'OCHF,, OCF. F, Cl, Br, CN,

CH

2 CHOC=OCH3,

CH

2

NHC=OOCH

3 or CH,NHC=OOCHCH3 6 ~is H, CH 2

CH

3

CF

3 OCF, 0C-l1 F.C.B rC 2 3

R

7 is H, F, Cl, Br, OCF 2 H, OCF3; Rs is Hor CR 3 Preparation The present invention also provides the following processes A, B, C, D, E or for the manufacture of compounds with the general Formula I.

Process A Process A for manufacture of compounds with the general Formula I comprises the following steps: Compounds of the general Formula BI WO 00/11000 PCT/SE99/01402

R'

R N R 2

II

N

Xl wherein X 1 is NH 2 or OH, and R

I

R

2

R

3 and R 4 are as defined for Formula I, can be reacted with compounds of the general Formula M

Y

r III Ar wherein "Ar" is as defined for Formula I and Y is a leaving group, such as a halide, tosyloxy or mesyloxy to the compounds of the Formula I.

It is convenient to conduct this reaction in an inert solvent, e.g. acetone, acetonitrile, dimethoxyethane, methanol, ethanol or dimethylformamide with or without a base. The base is e.g. an alkali metal hydroxide, such as sodium hydroxide and potassium hydroxide; an alkali metal carbonate, such as potassium carbonate and sodium carbonate; or an organic amine. such as triethylamin.

Process B Process B for manufacture of compounds with the general Formula I, wherein X is NH, comprises the following steps: Compounds of the general Formula IV WO 00/11000 PCT/SE99/01402

*R

2

(IV)

wherein R

I

R

2 R and R' are as defined.for Formula I, can be reacted with compounds of the general Formula V O H Ar wherein "Ar" are as defined for Formula I, in the presence of a Lewis acid e.g. zinc chloride to the compounds of the Formula VI wherein R 1

R

2

R

3

R

4 and Ar are as defined for Formula I, whereupon the compounds of the general Formula VI are reduced e.g. by using sodium borohydride or sodiumcyano borohydride to compounds of the general Formula I. wherein X is NH. The reactions can be carried out under standard conditions in an inert solvent e.g. methanol or ethanol.

Process C Process C for manufacture of compounds with the general Formula I, wherein R I is CHI+OH or H comprises the following steps: PCT/SE99/01402 WO 00/11000 Compounds of the general Formula VII

(VII)

wherein X 1 is NH 2 or OH, R 2

R

3 and R 4 are as defined for Formula I. can be reacted with compounds of the general Formula EI wherein Ar is as defined for Formula I and Y is a leaving group, such as a halide, tosyloxy or mesyloxy to the compounds of the Formula Vm 0 R ll R2 "N

(VIII)

wherein R 2

R

3

R

4 Ar and X is as defined for Formula I.

It is convenient to conduct this reaction in an inert solvent, e.g. acetone. acetonitrile, dimethoxyethane, methanol. ethanol or N,N-dimethylformamide with or without a base.

The base is e.g. an alkali metal hydroxide, such as sodium hydroxide and potassium WO 00/11000 PCT/SE99/01402 13 hydroxide: an alkali metal carbonate, such as potassium carbonate and sodium carbonate; or an organic amine. such as triethylamin.

Reduction of compounds of the general Formula VIII, e.g. by using lithium aluminium hydride in tetrahydrofuran or ether yields the compounds of the general Formula I wherein RI is CH 2

OH.

Hydrolysis of compounds of formula VIII, e.g. by using a base such as sodium hydroxide or an acid such as hydrochloric acid. After hydrolysis, decarboxylation in an inert solvent such as diphenylether gives the compounds of formula I wherein R' is H.

Process D Process D for manufacture of compounds with the general Formula I. wherein R I is CH-OH and X is NH comprises the following steps: Compounds of the Formula IX

O

R A 4 R2

(IX)

N

NH

2

R

2

R

3 and R 4 is as defined for Formula I, can be reacted with compounds of the general Formula V O H

(V)

Ar WO 00/11000 PCT/SE99/01402 14 wherein Ar is as defined for Formula I, in the presence of a Lewis acid, e.g. zinc chloride to the compounds of the Formula X 0 R3 0\0 3 2

R(N\)R

wherein R 2

R

3

R

4 and Ar are as defined for Formula 1. whereupon the compounds of the general Formula X are reduced, e.g. by using sodium borohydride or sodium cyano borohydride to compounds of the general Formula XI

NH

wherein R 2

R

3

R

4 and Ar are as defined for Formula I. The reactions can be carried out under standard conditions in an inert solvent e.g. methanol or ethanol.

Reduction of compounds of the general Formula XI e.g. by using lithium aluminium hydride in tetrahydrofuran or ether yields the compounds of the general Formula I wherein

R

I is CH 2 OH and X is NH.

Hydrolysis of compounds of formula XI, e.g. by using a base such as sodium hydroxide or an acid such as hydrochloric acid. After hydrolysis, decarboxylation in an inert solvent such as diphenylether gives the compounds of formula I wherein R' is H.

PCT/SE99/01402 WO 00/11000 Process E Condensation of compounds of the general Formula XII

(XII)

wherein R 3

R

4 and Ar are as defined for Formula I, with a-halocarbonyl intermediates of the general formula R 2 COCH(Z)R' wherein Z is a leaving groupBr or Cl, in an inert a solvent e.g. acetonitrile or ethanol results in formation of compounds of the general Formula XII wherein R 2

R

3

R

4 and Ar are as defined for Formulaj,

R

t R R 2

(XIII)

'N

r0 Ar Medical use In a further aspect, the invention relates to compounds of the formula I for use in therapy, in particular for use against gastrointestinal inflammatory diseases. The invention also provides the use of a compound of the formula I in the manufacture of a medicament for the inhibition of gastric acid secretion, or for the treatment of gastrointestinal inflammatory diseases.

WO 00/11000 PCT/SE99/01402 16 The compounds according to the invention may thus be used for prevention and treatment of gastrointestinal inflammatory diseases, and gastric acid-related diseases in mammals including man, such as gastritis, gastric ulcer, duodenal ulcer, reflux esophagitis and Zollinger-Ellison syndrome. 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.

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.

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 0 object of the invention. Usually the amount of active compounds is between 0.1-95% by weight of the preparation, preferably between 0.1-20% by weight in preparations for WO 00/11000 PCT/SE99/01402 17 parenteral use and preferably between 0.1 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, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. The mixture is then to processed into granules or pressed into tablets.

Soft gelatin 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 gelatin capsules. Hard gelatin capsules may contain granules of the active compound.

1s Hard gelatin 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 gelatin.

Dosage units for rectal administration may be prepared in the form of suppositories which contain the active substance mixed with a neutral fat base: (ii) in the form of a gelatin rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for gelatin rectal capsules; (iii) in the form of a readymade 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 0.1 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 3u preparations may contain coloring agents. flavoring agents, saccharine and carboxymethyl cellulose or other thickening agent. Liquid preparations for oral administration may also be WO 00/11000 PCT/SE99/01402 18 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 compounds according to the invention can also be used in formulations together with other active ingredients, e.g. for the treatment or prophylaxis of conditions involving infection by Helicobacter pylori of human gastric mucosa. Such other active ingredients may be antimicrobial agents, in particular: P-lactam antibiotics such as amoxicillin, ampicillin, cephalothin, cefaclor or cefixime; macrolides such as erythromycin, or clarithromycin: tetracyclines such as tetracycline or doxycycline; aminoglycosides such as gentamycin, kanamycin or amikacin; quinolones such as norfloxacin, ciprofloxacin or enoxacin; others such as metronidazole, nitrofurantoin or chloramphenicol: or preparations containing bismuth salts such as bismuth subcitrate, bismuth subsalicylate, bismuth subcarbonate, bismuth subnitrate or bismuth subgallate.

Examples

EXAMPLES

1. PREPARATION OF COMPOUNDS OF THE INVENTION Example 1. I1 WO 00/11000 PCTISE99/01402 19 Synhesis qf 2, 3-dimethyl-8-('2, 6-dim ethyvlbenz-l amino)- 6-,maehox~viinidazo[1, 2-alpyridine A mixture of 8-amino-6-methoxy-2,-imidazo[ 1,2-a)pyridifle (0.4 g, 2.09 mmol), 2,6dimethylbenzylchloride (0.32 g, 2.07 mmol), sodium carbonate (0.4 potassium iodide (0.2 gy) and acetonitrile (5 ml) was refluxed for 5 hours. The solvent was evaporated and the residue was purified by chromatography (methylene chloride:ethyl acetate, 70:30) yielding 250 ma (39 of the desired product.

Example 1.2-1.6, 1.9-1.16, 1.18-1.28, 1.30-1.40, 1.48-1.50 and 1.73-1.79 were prepared according to example 1.

Example 1.2 Synthesis of 2, 3-dimethyl-8-j2, 6-dimethyliben::vaminoJ-6-n itroimidazofi, 2-alpyridine Yield: 86 IH-NMR (300 MHz, CDCI 3 8 2.3 3H), 2.35 6H), 2.45 3H), 4.4 2H), 5.05 (bs, 6.9 IH), 7.05-7-15 (in, 3H), 8.4 1IH) Example 1.3 Synthesis of 2, 3-dimet hyl-3-(2 ,6-dimethylbenzylalmino)-6-rifluorom'thYlimiclU-o[l. 2-ajlpyridine Yield: 9 1 IH-NMR (300 MHz, CDCI 3 5 2.35 3H), 2.38 6H), 2.4 3H), 4.3 2H), 4.95 (bs. IH), 6.25 LR), 6.75 2H), 7.6 I H) Example 1. 4 Synthesis of 6-dimethylbenzylamnino)-2. -frimethyvlim idazofi. 2-al~pyridine WO 00/ 11000 PCT/SE99101402 Yield: 52 IH-NMIR (300 MI-z, CDC] 3 8 2.3 3H), 2.4 2.65 3H). 2.75 3H), 4.3 2H), 4.65 (bs, 1H). 6.05 6.3 IH) 6.95-7.15 (in, 3H-) Example 1. Synthesis of 8- (2-methylbenz-ylamilo)- 2 ,.S.6-trimethyvlimidazofi. 2-alpyridine Yield: 60 I NMR (300 MJ-z, CDCI 3 582.25 3H), 3.32 3H). 2.36 3H), 2.38 3H), 4.38 2H), 5.20 I1H), 5.9 3 IlH), 7.02 I 7.17-7.3 3 (in, 4H) Example 1. 6 Synthesis of ethyl 6-dimethylbenzylamino) 3-dimethylimidazo[,2-apyridile-6-carboxylate Yieid:37% I H-NMR (300 MHz, CDC1 3 5 1.45 3H), 2.35 3H), 2.4 6H), 2.45 3H), 4.4-4.5 (in, 4H), 4.85 Cbs, lH), 6.75 1H), 7.05-7.15 (in, 3H), 8.05 I H) Example 1. 7 Synthesis of 8- (4-met hoxy-2 ,6-dime thylbenzylamino) 2,3 -dime thyvlim idazo[1. 2-a.Ipyidine 8-amino-2,3-dimethylimidazo[1.2-alpyridine (0.5 g, 3.1 mmol), 4-methoxy-2.6dimethylbenzaldehyd (0.51 3.11 mmol) were dissolved in methanol (10 ml) whereupon zinc chloride (0.5 1 g,3.82 inrol) dissolved in methanol (5 ml) was added. Sodium cyanoborohydride was added in portions and the mixture was refluxed for 3 h under under nitrogen. The mixture Was stirred at 0-5 0 C and I M sodium hydroxide (20ml) was added. After extraction with 2x 50 ml of methylene chloride the combined organic layer was washed with water and dried over sodium sulfate. The solvent was removed under reduced pressure. The residue was chromatographed on WO 00/11000 PCT/SE99/01402 21 s ilica (dichloromethane: ethyl acetate. 1: 1) yielding 0.58 g60 of the title compound.

1 H-NMR (300 MHz, CDCI 3 582.35 12H), 3.79 3H), 4.27 2H), 4.75 IH), 6.19 (d, LH), 6.59 2H), 6.69-6.75 (in, lH), 7.24 IH) Example 1.8. 1.17 and 1.41- 1.45 were prepared according to Example 7.

Example 1. 8 Synthesis of 8-f(2. 6-bismet hoxvmet hyl) ben-ylam ino)]- 2,3. 6-n-ineihvlimidazofl. 2-alpyridine Yield: 54 I H-NMR (300 M4Hz, CDC1 3 8 2.25 3H), 2.3 6H), 3.35 6H), 4.45 2H), 4.5 4H), 4.95 (bs, IH), 6.15 1H), 7.0 7.2-7.35(m, 3H) Example 1.9-1.28 were prepared according to Example 1. 1 Example 1. 9 Synthesis of 8- 6-dimekhvlben ylamino) -3-f htoro-2-mei'hvlim idarofi, 2-alpyridine Yield: 33 I H-NMIR (300 MHz, CDC1 3 582.3 2.35 6H). 4.3 2H), 4.8 (bs, IRH), 6.15 I H), 6.7 1H), 6.95-7.15 (in, 3H), 7.25 1H) Example 1.10 Synthesis of 3-chloro-8-(2. 6-dlimeihylben:vlamino) -2-mezhylimidctz7o[l 2-cilpyridine, Yield: 0.6 WO 00/11000 PCT/SE99/0 1402 22 1 H-NMR (300 MHz, CDCI 3 ):852.4 6H), 2.45 3H), 4.35 2H), 4.8 (bs, 1H), 6.3 1H), 6.8 IH), 7.05-7.15 (in. 3H). 7.5 1H) Example 1.11 Synthesis of 2,3 -dime thyl-8- (2-phenylb'mlim io) -im idaZof [12-alpyridine Yield: 15 IH-NN4R (300 M1-z, CDCI 3 562.35 3H), 2.4 3H), 4.35 2H), 5.35 IH), 5.85 lH) 5 I 7.20 IRH). 7.25 7.4 (mn. 8 7.5 5 I1H) Example 1. 12 Synthesis of 2, 3-dinethyl-8-[('2.4-dimethyl-3 -fwtyl,)methylaminol- imidazTofi, 2-alpyridine Yield: 4 I H-NMR (300 MHz, CDCI 3 6 1.95 3H), 2.25 3H), 2.35 3H). 2.4 3H). 4.1 2H), 4.9 (bs, I 6.15 I 6.7 I 7.05 I 7.25 I1H) Example 1. 13 Synthesis of 2, 3-dim ethyl-8-f('2-methyl-I -nap h-y )met hylamino]-imidazo[I. 2-a Ipyridine hydrochloride Yield: 24 %7 1 H-NMR (300 MHz. DMSO): 5 2.35 3H), 2.45 3H), 2.6 3H), 4.8 2H), 6.6 (bs, I 7.15 I 7.35-7.55 (in, 4H), 7.8-8.1 t m, 4H) In Example 1. 14 Synthesis of 8-f(l -bromo-2 -ncp hty4'meihvlamino]- 2. 3-climeihylviinidazi-o[1. 2-alpyridine WO 00i I 1000 PCT/SE99/01402 23 Yield: 21 I H-NMR (300 MI-z, CDCI 3 5 2.3 3H), 2.4 3H), 4.8 2H), 5.8 1H), 5.95 (d, 6.55 IH), 7.2 IH), 7.45-7.6 (in, 3H), 7.68 1H), 7.77 IH), 8.33 lH) Example 1. Synthesis of 8- (2-ethoxycarbonyl-6-methylbflz~lamilo.)-2,3-dirnethylimnida7ofi, 2alpyridine Yield: 5 [H-NMR (300 MHz, CDCI 3 5 1.25 3H), 2.35 6H), 2.45 3H), 4.25 2H), 4.55 2H), 5.1 (bs, IH). 6.2 IR), 6.7 1H), 7.2-7.35 (in, 3H), 7.65 IH) Example 1. 16 Synthesis of 8-(2-rneihoxfy-6-methylbenylamilo,)- 2 ,3-dimethylimidazo[1 2-alpyridine Yield: 39 'H-NMR (300 MHz, CDC1 3 5 2.35 6H), 2.4 3H), 3.8 3H), 4.4 2H), 4.9 (bs, I 6.25 I 6.7-6.85 (in, 7.15 I 7.2 IlH) Example 1. 17 was prepared according to example 1.7 Example 1. 17 Synthesis of 8- (2 m elho xymet hyl-6-met hylbenzylamino)-2,3-dimethylimidazofl, 2cajpyridine Yield: 52 wo 00/11000 PCTISE99/01402 24 1 H-NMR (500 MHz, CDC1 3 852.34 3H), 2.35 3H), 2.40 3H), 3.36 3H), 4.40 2H), 4.50 2H), 4.86 IH), 6.24 1H), 6.71-6.74 (in, 1H), 7.15-7.21 (in, 3H), 7.25 I H) Example 1. 18 Synthesis of 6-dichlorobenzyvlamino) -2,3 3-dim e!hylimida:ofi, 2-u./pyridine Yield: 49 1 H-NMR (300 MHz, CDCI 3 5 2.35 3H), 2.4 3H), 4.7 2H), 5.2 (bs. IH). 6.3 (d, I 6.7 I 7.1-7.4 (in, 4 H) Example 1. 19 IS Synhesis of 6-dibromobenzylamino)-2 3-dimethylimidaz7ofl, 2-a }vyridine Yield: 70 I H-NMR (500 MHz, CDC1 3 5 2.45 3H), 2.48 3H), 4.7 2H), 5.15 (bs. I1H), 6.3 IH), 6.7 IR), 7.0 IH), 7.25 7.55 2H) Example 1.20 Synthesis of/2.3-dim ethyl-8-(2-trifiuorometho~ybelylamilo.) -imidazof!. 2-alpyridine hydrochloride Yield: 51 I H-NMR (300 MHz, CDC1 3 5 2.3 6H), 2.4 6H), 4.55 2H), 5.7 5.95 (d, I 6.5 7.1-7.3 (mn, 4H), 7.45 I H) wo 00/11000 PCT/SE99/01402 Example 1.21 Synthesis of 2, 3-dimethyvl-8-(2-flutoro-6-trfluorometh~vlbenfl.lCmino)-imida o [1,2alpyridine hydrochloride Yield: 36 1 H-NMR (300 MHz.DL\/ISO-d6): 5 2.4 3H), 2.45 3H), 4.55 2H), 6.85 (bs, ILH), 7.05 I 7.35 IRH), 7.7 (bs, 3H), 8.0 I H) Example 1.22 Synthesis of 3-dimethylimiduzofl. 2-a]pyridin-8-yl)amilo~m'hyO)PhenflI ace'tate met hanesulfonate Yield: 58% 1 H-NMR (600 MHz, CDCI 3 8 2.04 2.43 3H), 2.57 3H), 2..68 3H), 3.08 2H), 4.31 2H), 4.60 6.47 I 7.03-7.06 (m 1lH), 7.18-7.40 (in, 2H), 7.23- 7.24 (in. 2H), 7.38-7.40 2H), 7.45 (bs, IlH), 14.64 I H) Example 1.23 Synthesis of 8- (2-ethylben-7ylcimino)-2 3-diimethylimidazofl, 2-a]pyridine Yield: 36 1 H-NMR (300 MHz, CDCI 3 5 1.27 3H),'-2.35 3H), 2.39 3H), 2.74 2H), 4.44 2H), 5.30 IH), 6.06 6.60-6.66 IR), 7.10-7.30 (in. 5H), 7.37 IlH) Example 1.24 Synthesis of 8-fl 6-dimet h.vlphenyl) ethylim ino]-2, 3-dimethylimidazt-o[l, 2-alp yridine WO 00/110 00 PCT/SE99/0 1402 26 Yield: 16 1 H-NMR (300 MI-z, CDCI 3 8 1.65 3H), 2.3 3H), 2.4 3H), 2.45 6H), 5.0 (in, 1H), 5.4 IH), 5.55 IH), 6.45 1H), 6.9-7.05 (mn, 3H), 7.1 1H) Example 1.25 Synthesis of 8-fl 6-dimet hyiphenyl) ethoxy]-2, 3-dim ethylimidazofi. 2-alpyridine Yield: 24 1 H-NMR (300 MHz. CDCI 3 8 1.8 3H), 2.35 3H), 2.45 3H), 2.5 6H), 5.8 (q, I 5.95 IH), 6.45 IRH), 6.9-7.0 (in, 3H), 7.30 I H) Example 1.26 Synthesis of 2.3 -dm thl8 2[-et hylsuilfonyl) et hyl]- ben ylainino) -iinidazofl, 2alpyridine Yield: 34 IH-N.MR (000 MHz, CDC1 3 562.34 6H), 2.67 3H). 3.18-3.33 (mn, 4H), 4.43 2H), 5.15 ILH), 6.14 I 6.62-6.68 (mn, ILH), 7.15-7.30 (in, 4H), 7.37 I1H) Example 1.27 Synthesis of 8-2[-rehlabnl~yehl--lir--ntvbnimn)3dimethyl-imidaz-o[], 2-alpyridine Yield: 33 WO 00/11000 PCTISE99/01402 27 1 H-NMR (300 MHz. CDC1 3 562.01 3H), 2.33 3H), 2.35 3H). 2.37 3H). 3.00 2H), 4.25 2H), 4.31 2H), 4.78 (bs, I 6.22 I 6.73 1 6.80 2H), 7.26 ILH) Example 1.28 Synthesis of 8- (3-phenoxyvbenL-ylaimino)-. 3-dimcthkvimi~idaz-:ofl.2-ajpyridine Yield: 20 IH-NMR (300 MHz, CDC13): 562.3 3H), 2.4 3H), 4.4 2H), 5.5 (in. IH), 6.55(tIH).6.35-7.35 Example 1.29 Syvnthesis of 8-(2.6-dimethvlhenzylamifl& 2. 3-dirnethyl- 7-nitr-oimidazo[1, 2-alpyridine 2,3-dimethyl-8-(2,6-dimcthylbflzyamilo)-irnidzazo[ I.2-alpyridine (2.0 g, 7.16 mmol) was dissolved in acetic acid (30 ml) and nitric acid (0.53 g. 7.57 minol) was added.The mixture was heated to 80-85 'C and stirred for 3 h at this temperature. After evaporation of the 21) major part of the acetic acid. the residue was partitioned between methylene chloride and water. The orcanic layer was washed with a solution of sodium carbonate and the solvent was removed under reduced pressure. The residue was dissolved in methylene chloride (100 ml) and filtered throuah silica gel (10 g) whereupon the methylene chloride was removed under reduced pressure. Chromatography with methylene chloride (100%7) gave 0.4 g(17%) of the title compound.

Example 1.30-1.40 werc prepared according to Example 1. 1 PCT/SE99/01402 wo 00/ 11000 28 Example 1.30 and I .31 are prepared from a Mixture of 2-chioro-6-methylbenzybromide and 3-chloro-2-methylbenzylbromide. The yields are referred to 8-amino-2,3-dirnethyvl-6met hvlimidazo[]. 2-alp yridine.

Example 1.30 Synthesis of 8-42clloro-6-etlivlbelzylamiflo)- 2 3, 6-tnimet hylimidazof 2-ajpyridine Yield: 34 In IH-NMR (300 MHz, CDC1 3 5 2.35 9H), 2.55 3H). 4.5 2H), 4.85 (bs, I 6.1 I 7.05 7.1-7.3 (in, 3 H) Example 1. 31 Sivnthesis of-8-(3-chloro-2-methlbflZvlamil0, 3, 6methylimnidazofl 2-aipyridine Yield:- 27 lH-NMR (300 MvHz, CDCI 3 5 2.25 3H), 2.35 3H). 2.4 3H), 2.45 3H), 4.4 (d, 2H). 5.25 1H), 5.85 lH), 7.0-7.1 (in, 2H), 7.25-7.35 (mn. 2H) Example 1.32 and 1.33 are prepared from a mixture of 2-broino-6-nethylbenzylbromidC and 3-broino-2-inethyl benzyl bromnide. The yields are refer-red to S-ainino-2,3dimethyliinidazo[ l,2-a]pyridine.

Example 1.32 Synthesis of 8- t2-bromno-6-methzylbenzylomilo,)- 2 3-climethylimidaz-o (TI,2-alpyridine Yield: 25 %a wo 00/11000 PCT/SE99/01402 29 1H-NMR (300 MHz, CDCI 3 8 2.35 6H), 2.45 3H). 4.55 2H), 4.85 (bs. t1H). 6.25 I 6.75 I 7.05-7.2 (in, 2H), 7.25 IRH), 7.4 I H) Example 1.33 of 8- (3-bromo- ?I-methvlhen -ylamino)-2, 3-dimethy/imidao 2-alpyridine Yield: 16%Ol I HNMR (300 MHz. CDCl 3 5 2.35 3H), 2.4 3H), 2.45 3H). 4.45 2H), 5.35 (bs, 1K), 6.0 1K), 6.65 1H), 7.0 LH), 7.2-7.35 (in. 3H). 7.5 1H) Example 1.34 and L.35 are prepared from a mixture of 2.chloro-6-methylbelzylbromide and 3-chloro-2-methylbenzylbromdc. The yields are refer-red to 8-amino-2.3dimethylimidazo[ 1 ,2-alpyridine.

Example 1.34 Synthesis of 8- (2-chloro'-6-rietvlbenZylamilo)-2. 3-dimethiylimida~zofl, 2-a./pyridine Yield: 24 r% tH-NMR (300 MHz. CDCI 3 5 2.35 6H), 2.45 3H), 4.5 2H), 4.85 (bs. 1KH), 6.25 I1H), 6.7 I H),.7.1-7.35 (in. 4H) Example 1.35 Synthesis oj'8- (3 -chlro-2-,nethylbenzylamino)-2,3-dimethylimidazofl. 2-alpyridine Yield: 19 07 IH-NMR (300 MHz, CDClj) 6 2.35 3H). 2.4 3H). 2.45 3H). 4.45 2HW. 5.3 (t, 114), 6.0 1KH), 6.6 Ct. 1KH), 7.05 I 7.25-7.35 (in, 3H) wo 00/11000 PCT/SE99/01402 Example 1.36 Synthesis of 8- (2-c hlor-o-4. 6-dimL'rhylbenz'ylam mo) 3-dimneihylim ida~ofi, 2-alpyr-idine Yield: 7 1 H-NMR (300 MHz. CDCI 3 5 2.28 3H), 2.34 6H), 2.38 3H), 4.46 2H), 4.36 1H), 6.22 LH), 6.28-6.74 (in, IH), 6.90 1H), 7.07 IH), 7.25 1H) Example 1.37 Synthesis of 84(2, 4-dichloro-6-methlenzylamfilo)- 2 3-dimethylimidaz-ofi.2-alp vridine Yield: 28 I1--NMR (500 MHz, CDC1 3 562.34 3H), 2.35 3H), 2.41 3H), 4.46 2H), 4.86 is t, IH), 6.21 1H) 6.69-6.72 (in, I1-1). 7. 10 1I-1), 7.24-7.28 (in, 2H) Example 1.38 Synthesis of 8- i2-cyaino-6-niethylenylamino) -2,3'-dime thylimnidazofi, 2-alpyridine Yield: 49 I H-NMR (300 MI-z, CDC1 3 562.35 6H), 2.45 3H), 4.6 2H), 4.95 (bs. IlH), 6.25 t 6.7 111), 7.25 -7.3 5 (mn, 2 7.4 I1H), 7.5 5 IRH) Example 1.3 9 Synthesis of 84(3 cyainc-2-methylbenzylciunino)- 2 .3-cditneihylimidazafl.2-aipyricline Yield: 26 WO 00/11000 PCT/SE99/01402 31 1 H-NMR (300 MvHz, CDC0j): 2.35 3H), 2.4 3H), 2.6 3H), 4.45 2H), 5.35 (t, I 5.95 I 6.65 IlH). 7.2-7.3 (in, 2H), 7.55 2H) Example 1. Syvnthesis of 3- (3 -diflioromethoxvbenzylamino)-2, 3 -dim ethylinidazo [I.2-alpyridine hydrochloride 1a Yield: 45 IH-NMR (300 MHz. CDC1 3 5$2.25 3H), 2.35 3H), 4.5 2H), 5.65 1H), 5.95 I 6.5 I 6.5 5 I 7.0- 7.2 5 (in, 4 7.4 I H) Example 7 41- 45 were prepared accordingc to Exam ple 7.

Example 1. 41 Synthesis of 8 -e' 2 ,nethoxymethyl-6-methvlben:7vflmino) 6-rimethylimidaZofl. 2alpyridine Yield: 60 I H-NMR (300 MHz. CDC13): 5 2.25 3H), 2.3 6H), 2.4 3H), 3.35 3H), 4.4 (d, I 4.5 3H), 4.85 (bs, I 6.1 (7.0 s. 7.05-7.2 (mn, 3H) Exam pie 1. 42 Synthesis of 6-dlimethyl -3-nitr-ohenzylatmino)-2 3-dlimediylimidazo[1 .2 -cipyridine Yield: 1517c WO 00/11000 PCT/SE99/01402 32 1 H-NMR (300 MHz. CDCI 3 5 2.32 3H), 2.35 3H), 2.45 3H). 2.5 3H), 4.4 (d, 2H), 4.75 1H). 6.22 IH), 6.75 7.17 IH). 7.3 7.7 (d.I H) Example 1.43 Synthesis of 2.3- dimethy/-8-p-(2-nethoxythyl)-6-methylbenrylamino-6methylimidazo[l 2-a]pyridine hydrochloride Yield: 11 1 H-NMR (300 MHz. CDC] 3 6 2.35 3H), 2.38 3H), 2.44 3H), 2.46(s, 3H), 3.02 2H), 3.30 3H), 3.59 2H), 4.41 2H), 6.46 1H), 7.10-7.35 4H) Example 1.44 Synthesis of 8-2, 6-dimethylhenzylamino]-2,3,7-trimethy/imidazo[l, 2-alpyridine is hvdrochloride Yield: 11 IH-NMR (300 MHz. CDC1 3 6 2.35 9H), 2.4 3H). 2.6 3H). 4.65 2H). 6.95- 7.15 4H), 7.5 (bs, I (neutral form) Example 1.45 Synthesis of 2,3-dimethv/-8-[2,4-dim ethyl-3 -th ienyl)methylamino]-im idazofi. 2-a]pyridine Yield: 44 1 H-NMR (300 MHz, CDCI 3 6 2.2 3H), 2.35 3H), 2.36 3H). 2.45 3H), 4.2 (d.

2H), 4.8 (bs, IH), 6.2 6.65-6.75 2H), 7.25 IH) Y) Example 1.46 wo 00/11000 PCT/SE99/01402 33 Synthesis of 2. 6-dimethyl-3-hydr-oxyvmeth~yl-8-(2-m ethox-ynlL'lhyIl-6-miethyI lbci? .ylail.)imidaZoll. 2-ajpyridine Litium aluminium hydride (0.29 g,7.7 mmol) was added to tetrahydrofuran (30 in]) and 3- 5carbethox.S-(2-methoxymethyl-6-methlbel7ylamilo)-2-methyliinidazo[ 1,2- a]pyridine (1.4 g,3.8 minol) dissolved in tetrahydrofuran (30 ml) was added dropwise during S0 min.

at room temperature and stirred for 4 h. Water (0.29 ml) was added droppAise, follewed by sodium hydroxide 15%, 0.29 ml) and finally 0.93 Ml Of water. After stirring 30 min. the solids were filtered off and washed thoroughly with tetrahydrofuiran. The solvent was rcmoved under reduced pressure and chromatography on silica gel (methylene chloride:methanol, 9: 1) gave (0.97 g 75 of the title compound as a white solid.

I H-NMR (300 MHz, CDC1 3 5 2.0 3H), 2.3 3H), 2.4 3H), 3.35 3H). 3.6 (bs I H) 4.4 2H), 4.5 2H), 4.6 2H), 4.9 (bs, IRH), 6.15 3H), .7.l-7.25 3 H), Is 7.3 5 I-I) Example 1.47 was prepared according to Example 1.46 Example 1. 47 Syvnthesis ojf8- 1 2-chloro-6-methiylbenzylatmilo) 2. 6-dimethyl-S -hydriioxvimethy limidoz7o[I.2a~pyridinL' Yield: 46 %7, H-NMVR (300 MI-z, CDCI 3 5 2.25 3H), 2.3 3H), 2.45 4.5 2H). 4.8 (s, 2H), 4.85 (bs, IH), 6.2 7.1-7.25 (mn, 3H), 7.4 I) Example 1 .48- 1.49 were prcpared according to Example 1. 1 3U Example 1.48 WO 00/11000 PCTISE99/01402 34 Synthesis of 6-dimethv lbenL-ylam~ino)-2-mei'hylimidaz:of 2-aipyr-idine Yield: 70 IH--NMR (300 M'Hz, CDCI 3 582.35 9H), 4.3 4.8 (bs, IH). 6.2 l 6.65 (t, LH), 7.0-7.15 (in, 7.25 IH), 7.45 I) Example 1. 49 Synthesis of 8-"4-fliuoro-2. 6-dimethylhenz-ylamino)-2-met hylimidio[f. 2-a jZvridine Yield: 71 IH-NMR (300 MHz, CDC1 3 582.35 6H), 2.4 3H), 4.3 2H), 4.75 (bs, IH), 6.2 (d, I 6.65 IlH), 6.75 2 7.25 IRH), 7.5 (di, I H) Example 1.51 Synthesis oJ'2.6-dimethvl-8-(4 -fl ioro-2 ,6-dlimet'hylbenz-ylamino)- imidaz7ofi, 2-a Ipyridine A mixture of 8-(4-fluoro-2,6-dimethylbenzylamino)-2-lethy-6-mehyliridazo[ 1,2alpyridine 3-carboxylic acid (0.35 g.1.03 mmol) and diphenyl ether and refluxed for min. Petroleum ether 40-60 was added at room temperature followed by hydrogene chloride in diethyl ether. The petroleum ether diphenlether layer was removed from the formed precipitate. The precipitate was washed with petroleum ether thereafter dissolved in methylene chloride and basified with sodium hydroxide The layers were separated and the organic layer was washed with water. The solvent was evaporated and the residue was chromnatographed (hexane:ethyl acetate, 2: 1) giving 0. 17 a (50 of the title compound.

I H-NMR (300 MHz, CDC1 3 582.25 2.35 9H). 4.25 2H), 4.75 (bs. 6.05 I 6.75 (di, 2H), 7.1 IRH). 7.25 I H) WO 00/11000 PCT/SE99/01402 Example 1.52 were prepared according to example 1.51 Example 1.52 Synthesis of?2, 6-dimethyl-8- 6-dimnethvlben-7ylalio)-imidazo[l, 2-alpyridine Yield: 40 17 1 H-NM-,R (300 MHz, CDCI 3 5 2.25 I 2.35 3H). 2.4 6H), 4.3 2H), 4.75 (bs, IRH). 6.05 6.95-7.15, (in. 4H), 7.2 I H) In) Example 1.53 Synthesis of 6-dimethy.lbenzylamino)-3-ethyl-2-rnethyliunida7o 2-a]pyridine hydrochlorid'e To a stirred mixture of 1-8(,-iehlezimn)2-Chlmdz(,-~yiie3 yl]-l-ethanol (0.3 g, 0.98 mmol), boron trifluoride diethyl ethcrate (0.14 ml. 3.2 rnmol) in tetrahydrofuran (10 ml) was added sodium cyanoborohydride 13 g, 2.0 mmol). The reaction mixture was stirred for 2.5 h and the solvent was evaporated under reduced pressure. Thc residue was solved in methylene chloride and was washed twice with a saturated sodium bicarbonate solution. The organic layer was separated, dried and evaporated undcr reduced pressure. Purification twice by column chromatography on silica gel using 1) mnethylene chloride: ethyl acetate (100:7) 2) methylene chloride:inethanol (100:3) as eluent and treating with HCI/diethyl ether gave 0. 1 g, (3 1%7) of the title compound.

IH-NMR (300 MHz, CDC1 3 5 1.2 IH), 2.35 3H), 2.4 6H), 2.85 2H), 4.35 (d.

2H), 4.8 (bs, IH), 6.2 IH), 6.7 7.05-7.15 (mn, 3H). 7.35 [H) Exacmple 1. 54 301 Synfhesis of 8- 6-dlimediv lbenzyltmino) -2-methl%,-3- vinyiiiaof. 2-ai]pyridine WO 00/11000 PCT/SE99/01402 36 A mixture of I -(8-(2,3-dimcthylbenzylamino)-2-methyimidazo[ 1.2-a~pyridine-3-yl]- I ethanol (0.2 g,0.65 mmol) and p-toluenesulfonic acid (0.029 g, 0.15 mmol) in benzene mrl) was refluxed for 20 h with Dean-Stark water separation. The solvent was evaporated under reduced pressure, the residue was solved in methylene chloride and washed with saturated sodium bicarbonate solution. The organic layer was separated, dried and evaporated under reduced pressure. Purification of the residue by column chromatography on Silica gel uIsing methylene chloride: ethyl acetate (10: 1) gave 0.062g of the title compound.

I H-NNIR (300 MHz, CDCI 3 2.4 6H), 2.5 3H), 4.35 2H), 4.S5 (bs, I1H), 5.35 5.55 I 6.25 1K), 6.75-6.85 (in. 2H), 7.05-7.15 (in, 3H), 7.6 I H) Example 1.55 Syvnthesis of 2-cyanomethiyl-8-(?. 6-dirnethylbenzylavnino)-3-methylimidaZ-o[]. 2-a] pyridine 2-c hlorometh y methylbe nzylamtino)-3 -me thyl iiidazo I .2-a]pyridine (2.4 mmol) and potassium cyanide (2.4 minol) were added to dimethyl sulfoxide (25 ml) and stirred for 2 h. at room temperature. Methylene chloride and water were added to the reaction mixture and the organic layer was separated dried (Na 2 SO,) and evaporated under reduced pressure. The residue was purified by by column chromatography on silica gel using methylene chl oridc:mcthanol (10: 1) as eluent. Crystallization from acetonitrile gave 0.25 g (34 of the title compound.

1 H..NMR (500 MHz, CDCI 3 6 2.4 6H), 2.45 3H), 3.8 2H), 4.35 2K). 4.8 (bs.

I 6.3 I1-H), 6.8 I1H), 7.1 2H), 7.15 1H), 7.3 I H) Example 1.56 Synthesis oj'8-42. 6-dimethylbenz:ylatmino)3 -mCehyl- 2-ne thlsufaly~m ethyl- imidazo[1 2a]pyridine 2-hormt 1--26dm lezlmn)3-ehlmdz(,2-ai]pyridine (0.2 g, 0.64 minol) and sodium methanethiolate 1 g,1.3 inol) were added to acetonitrile(lO0 ml) WO 00/11000 PCT/SE99/01402 37 and stirred for 4 h. at room temperature. The solvent was evaporated under reduced pressure and to the residue were added methylene chloride and water. The organic layer was separated, dried (NaSO.1) and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel using diethyl ether:petroleum ether (1:2) as eluent and crystallization from diethyl ether:petroleum ether gave 0.05 g of the desired product.

1 H-NMR (400 MHz, CDC1 3 5 2.1 3H), 2.4 6H), 2.45 3H), 3.85 2H), 4.4 (s, 2H), 4.9 (bs, lH), 6.25 IH), 6.75 IH), 7.1 2H), 7.15 1H), 7.3 1H) Example 1.57 Synthesis of 8-(2,6-dimethylbenzylamino)-2-methoxymethyl-3-methyl-imidazo[l.

2 a]pyridine 2-chloromethyl-8-(2.6-dimethylbenzylamino)-3-methylimidazo[ 1,.2-a]pyridine (0.3 g, 0.96 mmol) was solved in methanol (20 ml) and stirred for 20 h. at room temperature and refluxed for 20 min. The solvent was evaporated under reduced pressure and the residue was dissolved in methylene chloride and washed with a bicarbonate solution. The organic layer was separated, dried (NaSOa) and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel using diethyl ether:petroleum ether as eluent and crystallization from diethyl ether:petroleum ether gave 0.13 g of the desired product.

IH-NMR (500 MHz, CDC1 3 5 2.4 6H), 2.45 3H), 3.4 3H), 4.35 2H), 4.55 (s, 2H). 4.95 (bs, IH), 6.25 IH), 6.8 1H). 7.05 2H), 7.15 1H), 7.3 IH) Example 1.58 Synthesis of2-ainocarbonylmethyl-3-methyl-8-(2.6-dimethylbenzylamino)- 7-imidazo[l,2a]pyridine A mixture of Example 55 (40 mg, 0.13 mmol). potassium hydroxide (30 mg) in t-butanol ml was refluxed for 10 minutes. The mixture was filtered and methylene chloride (2 ml) was added to the filtrate and washed with water. The organic layer was dried over sodium sulfate and evaporated giving 26 mg (64 of the title compound.

WO 00/ 11000 PCT/SE99/01402 38 IH.NMR (300 IMI-z. CDCI 3 5 2.35 3H), 2.4 6H), 3.6 2H), 4.35 2H). 4.8 (bs, IH), 5.5 5 (bs, I 6.3 I1H). 6. 8 I 7.0- 7.3 5 (in, 5 H) Exrample 1.59 Synthesis of 8-2-hydroymethyl-6-methvlbe7lmino,)-2, 3-dimethylimidazo[1,2ajpyridine hydrochloride To an icecooled mixture of 2 -dime thyl imidazo( I ,2-alpyridin-8-yl)amino)methyl)-3methylbenzoic acid 18 g, 0.59 mmol) in toluene (30 ml) was added dropwise Red-Al ml) in toluene (7 ml) and was stirre at room temperature for 20 h.The Mixture was cooled with ice and water (10 ml) and methylene chloride were added. After filtration the Filtrate was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using methylene chloride:methanol (100:5) as eluent. The product was solved in methylene chloride/ether and treated with HCI/diethyl ether to give 0.024 g(12 of thc title compound.

IH-NMR (300 MHz, CDCI 3 5 2.25 3H), 2.3 3H), 2.4 3H), 4.4 IH), 4.65 (s, 2H), 5.05 (bs, 6.25 1H), 6.75 IH), 7.1-7.25 (Ii, 4H) Example 1. Synthesis of 8-(2-hydroxy-6-methylbenzylamino)-2. S-dimethylimnidazo[1, 2-a]pyridine 8-(2-methoxy-6-methylbenzylamino)-2,3-dimethylimidazo[ 1 ,2-a]pyridine 14 a, 0.48 inmol) was solved in methylene chloride (9 ml) and the mixture was cooled to -73 'C.

Boron tribromide in methylene chloride (IM) (2.37 ml, 2.37 mmol) was added dropwise and the mixture was stirred for 20 h. in a nitrogen atmosphere and the temperature was allowed to raise to room temperature. The reaction mixture was cooled on ice and ice,water and methylene chloride were added. The organic layer was separated, washed with saturated sodium bicarbonate, dried and evaporated under reduced pressure to give 0.077 (57 of the title compound WO 00/11000 PCT/SE99/01402 39 I H-NIVIR (500 MHz, CDCl 3 5 2.25 3H), 2.35 3H), 2.4 3H), 4.4 2H), 4.95 (t, lH), 6.3 1H), 6.55 1K), 6.7 IH), 6.8 1K), 6.9 LH) 7.25 1K) Example 1.61 Synthesis of 8-(2-aminomethyl-6-methylbenzylamino)-2, 3-dimet hylimidazof 2-alpyridine To a solution of 8-(2-cyano-6-methylbenzylamino)-2,3-dimethylimidazo(1 ,2-a]pyridine (0.42 g, 1.44 m-mol) in ammonia saturated ethanollmethanol (10/2.5)(30 ml) was added Raney nickel (50 in water)(0.45 g) The mixture was hydrogenated at room temperature o0 and atmospheric pressure until the uptake of hydrogen ceased. Following filtration through celite, the solvents were evaporated under reduced pressure and the residue was purified by by column chromatography on silica gel using methylene chloride:tnethanol (10:2) as eluent. Recrystallization from methylene chloride! diethyl ether gave 0.052 g of the desired product.

is I HNMR (300 MHz, CDCI 3 5 2.35 6H), 2.4 3H), 3195 2H), 4.4 2K), 6.25 (d, 6.75 lH), 7.1-7.25 (in, 4H) Example 1. 62 Synthesis of methyl 3-dimethylimidazofi .2-a~pyridine-8y)aminoJmethyl)-3met hylbenzyl) carbamate To an ice cooled solution of 8-(2-aminomethyl-6-methylbenzylamino)-2,3dimethylimidazo[ 1,2-a]pyridine 17 g, 0.58 mmol), pyridine (0.046 g, 0.58 inmol) in 23 methylene chloride (9 ml) was added methyl chloroformate (0.05 5 g, 0.58 inmol) and the reacton mixture was stirred for 1.5 h. and the temperature was allowed to raise tol12 'C.Methylene chloride was added and the solution was washed twice with water. The organic layer was separated, washed with saturated sodium bicarbonate, dried and evaporated under reduced pressure. The residue was purified by by column WO 00/11000 PCT/SE99/01402 chromatography on silica gel using methylene chloride: methanol (100:5) as eluent.

Recrystallization from diethyl ether gave 0.052 g(25 of the title compound.

IH-NMR (300 MHz, CDCI 3 5 2.35 6H), 2.45 3H), 3.55 3H), 4.4 2H), 4.45 2H), 4.75 (bs, IH), 5.25 (bs, 114), 6-25 IR), 6.75 1H), 7.1-7.3 (in, 4H Example 1. 63 Syvnthesis of' 2- -dimethyvlimida--o[l. 2-a~pyridine-8-vl) amino,)methyl)-3)-methylphenyI methYl carbonate hycdrochlorid A mixture of 8-(2-hydroxy-6-methylbenzylamino)-2,3-dimethvlimidazo[1I,2-a]pyridine (0.068 _0.2)4 mmol) sodium carbonate 12 g,1. 1 mmol). and potassium hydroxide (0.0 19 g,0.34 mmol) In acetone (12 ml) was stirred for 15 min in room temperature in a nitrogen atmosphere. Mvethyl chloroformate (0.023 g,0.24 mmol) was added and the reaction mixture was stirred for 70 min. Methylene chloride was added and the mixture was filtred and the filtrate was evaporated under reduced pressure. The residue was solved in methylene chloride, washed with saturated sodium bicarbonate and water and the organic layer was separated, dried and evaporated under reduced pressure. The residue was purified by by column chromatography on silica gel using methylene chloride: methanol (100:5) as eluent and treated with HCI/diethyl ether to give 0.025 g (28 of the title compound.

I H-NMR (300 Nl~z, CDCI 3 8 2.35 3H1), 2.5 3H), 2.6 3H), 3.9 3H), 4.5 (d, 2H), 6.75 I 6.95-7.3 (in. 5 8.0 I 15.6 (bs, I H) Example 1. 64 Synthesis of 2- S-dimethyvlim idaz-of1-i. rdn8-lcmn~mty)3 met hyphenoxy)- I -ethanol WO 00/11000 PCT/SE99/01402 41 To a solution of 8-(2-hydroxy-6-methylbenzylamino)-2,3-dimethylimidazo[ 1.2-a]pyridine (0.14 g, 0.5 mmol) in N,N-dimethylformamide (3 ml) was added lithium hydride (0.004 g, 0.51 mmol) and the mixture was stirred for 10 min at 100 Ethylene carbonate (0.055 g, 0.63 mmol) was added and the mixture was stirred for 10 min at 130 °C.

Tetramethylammonium iodide (0.054 g, 0.63 mmol) was added and the mixture was stirred for 12 h. at 140-145 oC. The solvent was evaporated under reduced pressure and the residue was solved in methylene chloride, washed twice with saturated sodium bicarbonate.

The organic layer was separated, dried and evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using methylene 1o chloride:methanol (100:6) as eluent to give 0.067 g (41 of the title compound.

1 H-NMR (500 MHz, CDC1 3 5 2.3 3H), 2.35 3H). 2.45 3H), 4.0 2H), 4.15 (t, 2H). 4.5 2H), 6.25 1H), 6.35 1H), 6.7 1H), 6.75 IH), 6.8 IH), 7.1 (t, IH), 7.2 IH) Example 1.65 Synthesis of 2-(((2.3-dimethylimidazo[l. 2-a]pyridin-8-yl)amino)methyl)-3-methylphenyl trifluoromethanesulfonate To a solution of 8-(2-hydroxy-6-methylbenzylamino)-2,3-dimethylimidazo[ 1,2-ajpyridine (0.1 g, 0.32 mmol) in methylene chloride (7 ml) was added triethyl amine (0.07 g, 0.69 mmol) and the reaction mixture was cooled on ice. N.N-dimethylamino pyridine (0.077 g.

mmol) and trifluoromecthanesulfonic anhydride (0.12 g, 0.41 mmol) in methylene chloride (0.5 ml) and N-phenylcrifuoromethanesulfonimide (0.28 g, 0.78 mmol) and potassium carbonate (0.38 g, 2.7 mmol) were added and the reaction mixture was stirred for 135 min. at 18 Methylene chloride was added and the solution was washed with water/NH 4 CI, saturated sodium bicarbonate and water. The organic layer was separated, dried, and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel using methylene chloride: ethyl acetate (10:2) as eluent and WO 00/1 WOO PCT/SE99/01402 42 crystal lization from diethyl ether/petroleum ether gave 0.053 (40 of the title compound.

I H-NiVR (500 MHz. CDC[ 3 562.33 3H), 3.35 3H), 2.45 3 4.45 2H), (bs, IH), 6.25 IH), 6.75 IH), 7.15 IFI), 7.2-7.35 (in, 3H4) Example 1. 66 Synthesis of 8-f212-hydroxvethylbeni:ylaizo-2. 3-dimnethylimnidaz-o [I.2-aijpyridine 1o A mixture of Example 22 (xCH3SO3H) (0.8 g,1.85 mnmol) and sodium hydroxide (0.2 g were refluxeci in ethyl alcohol for 3 hours. The solvent was evaporated and methylene chloride water were added to the residue. The organic layer was dried over sodium sulfate and the solvent removed under reduced pressure. Trituration of the solid residue with diethyl ether grave 0.48 g 88 of the title compound.

I H-NN4R (300 MHz, CDCI-): 5 2.33 3H), 2.34 3H), 2.91 2H), 3.50 (bs, IH), 3.87 2H), 4.40 2H), 5.63 (bs, 1H), 6.12 1H). 6.62-6.68 (in, IH), 7.14-7.27 (mn, 4H), 7.3 6(d, I H) Example 1.6 7 Synthesis ojI2. 3-dimeth~yl-8- 6-dimet'hylbet7izylamino)-6-hydrox~vmethvl-iiflida00[I, 2q~pyridine To a stirred solution of ethyl 2.3-dimethyl-8-(2.6-dimethylbenzlaino)-inidazo[ I ,2alpyridine-6-carboxylate (1.2 g,3.4 mmol) in tetrahydrofuran (30 ml) was added LiALH 4 (0.7 g, 18.5 minol) during 20 min. at 5 0.7 ml of water was added dropwise. followed by 0.7 ml of 15%7 sodium hydroxide and then 2.1 ml of water. The solids were removed by filtration and washed thoroughly with methylene chloride: methanol The filtrate and washings were combined and the solvents were removed under reduced pressure. The residue was purified by column chromatography on silica gel using methylene chloride: methanol (10: 1) aIS elUent. Treating the residue with diethyI ether and filtration gave 0.7g of the title compound.

WO 00/11000 PCT/SE99/01402 43 IH-NMR (400 MHz, CDCI 3 ):8~2.35 6H), 2.4 6H), 4.35 2H). 4.65 2H), 4.9 (bs, 6.2 IlH), 7.05-7. [5 (in. 3H), 7.25 H) Exrample 1. 68 Synthesis of 2, 3-dimethyvl-8- 6-dlimet hvlbenzylamino)-6-m ethoxyymethyl-imidazo[I, 2alpyridine hydrochloride To a stirred solution of 2,3-dimethyl-8-(2-.6-dimethylbenzyamino)-6-hydroxymethylmidazofl,2-ajpyridine (0.08 a, 0.26 mmol) in methylene chloride (5 ml) was added thionyt chloride (0.038 ml, 0.52 mmol) and the mixture was stirred for 2 h. A saturated bicarbonate solution was added and the organic layer was separated. dricd (iNa 2

SO

4 and evaporated under reduced pressure. To the residue was added methanol (5 mrl) the mixture was stirred overnight. The solvent was evaporated under reduced pressure and the residue was purified by coIlumn chromatography on silica gel using methylene chloride: methanol 100:5) as eluent. Treating the residue with 1ICI/diethyl ether and filtration gave 0.0 1 g(11 of the title compound.

1 H--NMR (300 MHz. CDCI 3 8 2.35 3H), 2.4 3H). 2.45 3.55 3H), 4.35 2H), 4.45 2H), 4.85 (bs, IH), 6.2 7.05-7.15 (in. 3H), 7.3 I H) Exaomple 1. 69 Syvnthesis of N-("8-('(2.6-diamcihyvlben:yl.amino) -2.3 -dim7ethviidacit-o[l. 2-ajpyridin- 7vl)acetamicde 7-amino-2,3-dimethyl.8-(2,6-dimethylbenzylamino)-imidazoE 1,2-a]pyridine (example 77) 16 g, 0.53 rnmol) was dissolved in methylene chloride (5 ml) and acetic anhydride mg) was addded. The Mixture was stirred over night at ambient temperature. A small amount of triethylamine was added and the solvent was removed under reduced pressure.

Chromatography first with methylenie chloride methanol, 95-:5 and secondly with mcthylene chloride:ethyl acetate. 50:50 gave after trituration with diethyl ether 87 ma (47 as white solid.

WO 00111000 PCT/SE99/01402 44 H-NN4R (300 MHz, CDC]I 3 ):562.00 3H), 2.35 6H), 2.39 6H), 4.0 (bs I H),4.36 2H), 7.0-7.15 (in, 3 7.44 I 7.55 IRH), 7.65 (bs, IlH) Example 1. Synthesis of 6-dimet hyl benzyl) arnino) 3-dimethylimidaz-ofl 2-alpyridin- 7-y)-NVmethvlsulfonylmet hanesutlfoncamide 7 -amino- 2,3 -djmethyl-8-(2,6-d imethylbenfl~yamilo)- imidazof I .2-al pyridine (example 77) 1 g.0.34 mmol) was dissolved in methylene chloride (2 ml) followed by sodium carbonate (0.2g 1.9 mmol) and methanesultbnyl chloride 1g 0.87 mmol). The mixture was stirred at ambient temperature for 30 min. and after addition of 2 ml of water the mixture was stirred for I h. The organic layer was dried over sodium sulfate and the solvent evaporated in vacuo. Chromatography of the residue with methylene chloride: ethyl acetate 50:50, gave 4 mg (2.6 of the desired compound.

1 HNMR (300 MHz, CDC1 3 6 2.35 3H), 2.36 3H), 2.40 6H), 3.34 6H), 4.7 (t, IRH), 5.09 6.54 I1-H), 7.05-7.15 (in, 3 7.24 IlH) Example 1. 71 Synthesis of NV-(8-62, 6-dimethylbenzyl) azmino)-2, 3-dimethylimidazo 2-alpyridin- 7yl.) (trij/loro)methainesulfonamide A mixture of 7-amino-2 ,3-dimethyl-8-(2,6-dimethylbenzylamino)-imidazo[1I 2-alpyridine (example 77) (0.1 g,0.34 mmol). N- phenyl-bis(rrifluoromethanesulfon)-amide (125 mg,0.35 inmol) and 3 ml of acetonitrilc was refluxed for 20 h. The solvent was evaporated in vacuc and the residue was chromatographed with methylene c hlIoride: methanol, 97:3 as the eluent. The isolated product was treated with ethyl acetate and diethyl ether and 23 mg (16 was obtained.

WO 00/11000 PCT/SE99/01402 IH-NMR (300 MHz, CDCI 3 6 2.16 6H), 2.22 3H), 2.23 3H), 3.85 (bs, 2H). 4.12 2H), 6.70 1H), 6.85-7.0 3H), 7.56 1H) Example 1. 72 Synthesis of 8-(2,6-dimethyl-4-fluorobenzyloxy)-3-chloro-2-methylimidazo[l, 2-a]pyridine To a solution of 8-(2,6-dimethyl-4-fluorobenzyloxy)-2-methylimidazo[1,2-a]pyridine (0.6 g, 2.1 mmol) in acetic acid (13 mi) was added dropwise 1.1 M Cl_ in acetic acid (2.2 ml, 2.43 mmol). The reaction mixture was stirred for 2 h. at room temperature and the solvent was evaporated under reduced pressure. The residue weas solved in methylene chloride and was washed with water. The organic layer was separated, dried and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using methylene chloride: ethyl acetate (100:4) as eluent. Treating the residue with diethyl ether and filtration gave 0.3 g (45 of the title compound.

IH-NMR (300 MHz, CDC1 3 S 2.4 6H), 2.45 3H), 5.2 2H), 6.65 1H), 6.75 2H), 6.8 IH), 7.7 1H) Example 1.73 Synthesis of 8-(2-(2.6-dimethylphenyl)ethenyl)-2,3-dimethylimidazo[1,2-a]pyridine To an icecooled suspension of sodium hydride (0.2 g, 5 mmol) (50 in oil) in 1,2dimethoxyethane (2 ml) was added diethyl (2,3-dimethylimidazo[1,2-a]pyridin-8-yl) methyl phosphonate and 2,6-dimethylbcnzaldehyd. The reaction mixture was stirred in a nitrogen atmosphere for I h. at 0 °C and for 80 min at room temperature.The solvent was decanted and evaporated under reduced pressure. The residue was solved in methylene chloride and was washed with saturated sodium bicarbonate. The organic layer was separated, dried and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel using petroleum ether:ethyl acetate (30:8) as eluent gave 0.4 g (69 of the title compound.

WO 00/11000 PCT/SE99/01402 46 1 H-NMR (300 MHz, CDCI 3 5 2.45 2.5 3H), 6.85 I1H), 7.05 7.1 (d.

IH), 7.25 7.7 5 7.95 H) Example 1. 74 of 8- 6-dimethylpheryl)-2. 3-dimerhylimidaz o[l. 2-aj/pyridine 8-(2-(2,6dimethyphenyl)etheflyl)2,3-dimethylimidazo[1, 2-a~pyridine was solved in methanol (3 ml) and ethanol (2 ml) and Pd/C (40 mg) was added. The mixture was hydrogenated at room temperature and atmospheric pressure until the uptake of hydrogen o0 ceased. Following filtration through celite, the solvents were evaporated undcr rcduced pressure to give the title compound. (0.069 g, 100%) H.NMR (300 MHz, CDCI 3 5 2.35 6H), 2.4 3H), 2.45 31-1), 3.05-3.2 (in, 4H), 6.7 6.8 5 I 7. 0 3 7.7 IlH) Is Example 1. Synhesis of.N-a(2, 3-dimethyvlimidaz7of!.2-a]pyridin-8-ylmehyl)- 2 6-dimethylaniline hydrochloride 8-chloromcthyl-2,3-dimethylimidazo[ I ,2-a]pyridine (0.06 g,0.3 1 mmol), 2,6dimethylaniline (0.039 g,0.32 inmol), sodium carbonate 15 1.4 mmol) and sodium iodide (0.06 g, 0.4 mmol) in acetone (3 ml) was stirred for 20 h. at room temperature.

Methylene chloride was added and the solids were isolated by filtration and the solvents were evaporated under reduced pressure. The residue was purified by column chromatography on silica gel usinga methylene chloride: methanol The oily product was solved in methylene chloride and treated with HCI/diethyl ether to give the title compound. 0.02 g. (18%) I HNMR (300 MHz, CDC] 3 5 2.25 6H), 2.4 3H), 2.45 3K), 4.5 2H), 6.7 (t, 1 6.8 6.95 2H). 7.05 7.75 1KH) (base) WO 00/11000 PCT/SE99/01402 47 Example 1. 76 Synthesis of 6-dimethylphenoxy,)methyl)-2 3-dimethyvlimida7ofl. 2-alpyridine.

To a suspension of potassium hydroxide (0.035 g,0.62 mmol). 2.6-dimethyiphenol (0.075 0.62 mmol) and IlS-crown-6 (0.035 g) in l,2-dimethoxyethane was added 8chloromethyl-2,3-dimethylinidazo( I 2-a]pyridine 1 g,0.51 mmol) in 1,2dimcthyxyethane (3 ml). The reaction mixture was stirred for 1.5 h. at room temperature and sodium iodide (0.035 g, 0.23 mmol) was added. The mixture was stirred for 3.5 h. and o0 N,N-dimethylformamide (I ml) and methanol were added and the solids were isolated by filtration. The Filtrate was evaporated under reduced pressure. the residue was solved in methylene chloride and washed with saturated sodium bicarbonate. The organic layer was separated, dried and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using methylene chloride: methanol (100:3.5) as eluent to give 0. 11 of the title compound.

IH-NMR (400 MlHz, CDCI 3 8 2.3 6H), 2.4 3H), 2.45 3H), 5.3 2H), 6.9 (t, IH), 6.95 IFI), 7.05 2H), 7.55 IH), 7.75 IH) Example 1. 77 Synthesis of' 7-am ino-2, 3-dim et hyl-8-(2. 6-dime,vlhenzylaminio) -im idaoi, l2-ajpyridine A mixture of 2.3-dimethyl-8-(2,6-dimethytbenzyiamino)-7-niromidazo[ I,2-alpyridine ma, 0. 139 mmol) Raney-Ni 1 a) and ethyl alcohol 4 ml was hydrogenated I bar) at 40 'C for 3 h. The mixture was filtrated using a small amount of silica gel and the solvent was removed uinder reduced pressure. 40 mg (97 of the title compound was obtained.

I H-NMR (300 M4Hz, CDCI 3 5 2.30 3H), 2.34 3H), 2.49 6H), 3.85 (bs, 2B), 4.24 2H), 6.35 I 7.05-7.15 (in, 3H), 7.35 I H) Wo 00111000 PCT/SE99/01402 48 Example 1.78-1.79 wee prepared according to Example 1. 1 Example 1. 78 Synthesis of 8-(2-methoycarbofl.ylafllino-6-methylbenz-ylam ino)J-2,3.6trimethylmethylimidazof] 2-ajpyridine Yield: 37 1 H-NMR (300 M1-z, CDC1 3 5 2.35 9H), 2.4 3H), 3.7 3H), 4.35 2H), 4.75 (bs, I 6.2 I 6.95 IlH), 7. 1 1 7.2 (in, I 7.5 (bs, I 7.7 (bs, I H) Example 1. 79 Synthesis of 2, 3-dimet hyl-8 -(4-trrijluoromethoxybenz:ylamiflo)-imidazofl. 2-alpyridine, hydrogen chloride Yield: 35 2.3 3H), 2.4 3 4.4 2H), 5.65 I 5.95 I 6.55 I 7.05-7.2 (in, 3H), 7.35 2H) PREPARATION OF INTERMEDIATES Example 2.1 Synthesis of 2, 6-dimethyl-4-jhiorobenzylbromide- A mixture of 3,5-dimethyl-fluorobenzene (5 g,0.04 mol), paraformaldehyde (15 g), hydrobromic acid (70 ml) (30% in acetic acid) and acetic acid (25 ml) was stirred at ambient temperature for 4.5 h. To the mixture, water and petroleum ether were added and the organic layer was separated dried over anhydrous sodium sulfate and evaporated WO 00/11000 PCT/SE99/01402 49 carefully under reduced pressure. The residue was purified by column chromatography on silica gel with petroleum ether as eluent to give the desired product. (3.7 g, 43%).

I H-NMR (300 MHz, CDCI 3 8 2.5 6H), 4.55 2H), 6.75 2H) Example 2.2 Synthesis of 2-chloro-4,6-dimethylbenzylbromide.

2-Chloro-3,5-dimethylbenzene (1.42 g, 0.01 mol) and paraformaldehyde (0.31 g, 0.01 mol) in were added to 2 ml of hydrogenbromide in acetic acid. The mixture was stirred over night at +70 0 C. The reaction mixture was poured on 25 ml water and the product was extracted with diethyl ether. The organic layer was washed with water. The organic layer was dried (Na 2

SO

4 and evaporated. 1.1 g product (oil) was obtained. The 'H-NMR spectrum shows that the substance was a mixture of the title compound and 4-chloro-2,6is dimethylbenzylbromide. The product was used as such without any further purification in the next synthetic step (Example 1.15).

SH-NMR (300 MHz, CDC13): 8 2.28 6H), 4.51 2H), 7.04 2H).

Example 2.3-2.4 were prepared according to example 2.1 Example 2.3 Synthesis of 2, 4-dichloro-6-methylbenzylbromide Yield: 0.7 IH-NMR (300 MHz, CDC1 3 8 2.43 3H), 4.61 2H), 7.11 1H), 7.27 1H) Example 2.4 Synthesis of 4-fluoro-6-methyl-2-[2-(methylccrhonyloxy)ethyl]-benzylbromide WO 00/11000 PCT/SE99/01402 Yield: 31 1 H-NMR (300 MHz, CDC1 3 5 2.12 3H), 2.32 3H), 2.88 2H), 4.26 2H)I 4.66 2H), 6.65-6.8 2H) Example Synthesis of8-amino-2,3,6-trimethylimidazo[l.2-ajpyridine To a solution of 2,3-diamino-5-methylpyridine (2.0 g, 16 mmol) in ethanol (100 ml) was added 3-bromo-2-butanon (2.4 g, 16 mmol). The reaction mixture was refluxed for 16 h.

An additional amount of 3-bromo-2-butanon (1.0 g 6.7 mmol) and triethylamine (1.0 g, 9.9 mmol) were added and the mixture was refluxed for 2 h. The ethanol was evaporated under reduced pressure and the residue was treated with methylene chloride and a solution of bicarbonate. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure. The oily residue was purified by column chromatography on silica gel, using methanol methylene chloride 20) as eluent to give the desired product (1.05 g, 37%).

'H-NMR (300 MHz, DMSO-d 6 5 2.15 3H), 2.25 3H), 2.3 3H), 5.45 (bs, 2H), 6.05 IH), 7.20 IH).

Example 2.6 Synthesis of8-amino-3-carboethoxy-2,6-dimethylimidazo[ l, 2-a]pyridine A stirred mixture of 2,3-diamino-5-methyl-pyridine (4.0 g, 32.5 mmol) and (5.9 g, 36.0 mmol) of ethyl chloroacetoacetate in 75 ml abs. ethanol was refluxed over night. The ethanol was evaporated under reduced pressure. The residue was dissolved in 2 M HCI and washed 3 times with diethyl ether, pH was adjusted to 9 and extracted 3 times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel with dichloromethane methanol 95 5 as eluent to give the title product 2.0 g WO 00/11000 PCT/SE99/01402 51 I H-NMR (300 MHz, CDCl 3 :61.42 3H), 2.28 3H), 2.65 3H), 4.40 2H), 4.47 2H), 6.40 I1-H), 8.55 H).

Example 2.7 Synthesis of -3)-carboethoxy-2, 6-dimethyl-8-(2 ,6-dimethylbenzylamino) imidazo[1. 2ajpyridine A stirred mixture of 8-amino-2,6 dimethylimidazol [l1,2-alpyridine (1.2 g,5.1 mmol), zinc(fl)chloride (0.84 g, 6.2 mmol) and 2,6 dime thylIbenzaldehyde (0.84 g.6.2 inmol) in 50 ml methanol was treated with sodium cyanoboro hyd ride (0.39 0-, 6.2 mmol) and was refluxed for 5 h. The methanol was evaporated under reduced pressure and the residue was dissolved in dichloromethane and 40 ml 2 M sodium hydroxide. The organic layer was separated, dried over sodium sulfate and evaporated under reduced Is pressure. The residue was purified by column chromatography on silica gel, eluent petroleum ether (40 60) isopropyl ether 8:2, in yield of 0.8 g, of the title compound.

'H-NMR (300 MI-z, CDCI 3 6 1.44 3H), 2.35 9H), 2.60 3H), 4.33 2H), 4.40 4.6 I 6.60 t 7. 10 2H), 7.25 IlH), 8.50 I H).

Example 2.8 Synthesis of 3-carboethoxy-2, 6-dime thyl-8-(2 ,6-dimethyl--flutoroben-ylamilo)imidazo[], 2-ajpyridine A stirred mixture of g 4.7 mrnol) 8-amino-3-carboethoxy-2,6-dimethylimidazo( l, 2 ajpyridine 5.7 mmol) 2,6-di1me th yl-4- fluorobe nzylbromide, (1.0g 7.5 mmol) potassium carbonate and 1 g) sodium iodide in 15 ml acetonitrile was refluxed over night. After evaporation of the solvent under reduced pressure the residue was dissolved in dichloromethane and washed with water, the organic layer was separatled dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column WO 00/11000 PCT/SE99/01402 52 chromatography on silica gel, eluent petroleum ether (40-60) :isopropyl ether 7:3 to give 0.8 of the title compound.

'H-NMR (300 MHz, CDC1 3 5 1.42 3H), 2.36 9H), 2.62 3H), 4.45 2H), 4.48 2H), 4.54 IH), 6.30, IH), 6.75 2H), 8.55 I H).

Example 2.9 Synthesis of 2, 6-dime thyl-8-(2, 6-dimeihyl-4-fluioroben-ylamino.) imidazo 2- a~lpyridine-3carboxylic acid A mixture of 3-carboethoxy-2,6-dimethyl-8-(2,6-dimethylbenzylamiflo) imidazo[ 1.2a]pyridine (0.4 g. 1. 1 mrnol), sodium hydroxide (2M, 6 ml) and dioxane (6 ml) was refluxud for 20 min. The dioxane was removed under reduced pressure. pH was adjusted to pH=7 with 2M HCI and the formed precipitate was filtered off. 0.23 g (75 of the title compound was obtained.

Example 2. 10 was prepared according to example 2.9.

Example 2. 2o Synthesis of 2, 6-dime! hyl-8-(2. 6-dimethylbenzylamino) imidazo 2- alpyridine-3carboxylic acid Yield: 100 Example 2. 11 Synthesis of ethyl 8-am ino-3 -met hylimidazo~l, 2-ajpyridine-2- curboxylate A solution of 2,3-diaminopyridine (6.8 g, 62 mmol) and 3-bromo-2-oxo-butyric acid ethyl ester (13 g, 62 mmol) in I ,2-dimethoxyethane (150 ml) was refluxed for 2 h. Sodium carbonate (6.5 g' 62 mmol) was added and the mixture was refluxed for 2 h. The solids were isolated by Filtration and washed with dichloromcthane:mcthanol (10: The filtrate and washings were combined the solvents were removed under reduced pressure. The oily WO 00/11000 PCT/SE99/01402 53 residue was washed with petroleum ether and was purified twice by column chromatography on silica gel using 1) dichloromethane:methanol (10:1) 2) ethyl acetate as eluent to give 4.6 g of the title compound.

H-NMR (300 MHz, CDC1 3 5 1.45 3H), 2.75 4.5 2H), 4.65 (bs, 2H), 6.35 IH), 6.7 1H), 7.35 IH) Example 2.12 Synthesis of ethyl 8-(2,6-dimethylben:ylamino)-3-methylimidazol, 2-a]pyridine-2carboxylate Ethyl 8-amino-3-methylimidazo[ t,2-a]pyridine-2-carboxylate (4.6 g, 21 mmol), 2,6dimethylbenzyl chloride (3.2 g, 21 mmol), sodium carbonate (4.4 g, 42 mmol) and a cat.

amount of potassium iodide were added to acetonitrile (50 ml) and refluxed for 3 h., stirred for 20 h. at room temperature and refluxed for I h. The solids were removed by filtration and the solvents were evaporated under reduced pressure. The residue was dissolved in methylene chloride and washed with water. The organic layer was separated, dried (NaSO 4 and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel using methylene chloride:methanol (10:1) as eluent and crystallization from ethyl acetate gave 4.0 g of the desired product.

IH-NMR (300 MHz, CDC1 3 5 1.4 3H), 2.4 6H), 2.75 3H), 4.35 2H), 4.45 (q, 2H), 5.15 1H), 6.25 1H), 6.85 IH). 7.05-7.2 3H), 7.35 IH) Example 2.13 Synthesis of 8-(2,6-dimethylhbenzylamino)-2-hydroxymethyl-3-methylimidazo[1, 2a]pyridine Ethyl 8-(2.6-dimethylbenzylamino)-3-methylimidazo[ .2-a]pyridine-2-carboxylate (5.2 g, 0.015 mol) was solved in tetrahydrofuran (100 ml) and LiAlH4 (1.15 g 0.03 mol) was added. After stirring the mixture at room temperature. for 45 min, 1.15 ml of water was added dropwise, followed by 1.15 ml of 15% sodium hydroxide and then 3.45 ml of water.

The solids were removed by filtration and washed thoroughly with methylene chloride. The filtrate and washings were combined and dried and the solvents were removed under reduced pressure. Purification of the residue by column chromatography on silica gel using methylene chloride methanol (10:2) as eluent gave 3.2 g of the title compound.

WO 00/11000 PCT/SE99/01402 54 1 1--NMR (300 MHz, DMSO-d6): 5 2.35 6H), 2.4 3H), 4.35 2H), 4.5 2H), 4.85 IH), 4.9 IH), 6.3 IH), 6.S IH), 7.05-7.2 (in, 3H), 7.55 lH) Example 2.14 Synthesis of 6-dimetihylbenzylamino)-2-chloromethyl-3-methylimidazo[1 2-aipyridine To a solution of 8-(2,6-di methylbenzylamino)-2-hydroxymethyl-3-methylinhidazo[ 1,2alpyridine (1.0 g, 3.4 mrnol) in methylene chloride (50 ml) was added dropwise thionyl chloride (0.5 g, 3.4 mmol) solved in methylene chloride (10 mld) at 5 The reaction mixture was stirred 2 h. at 5 To the mixture was washed with a saturated bicarbonate solution, the organic layer was separated, dried (Na-,SO 4 and evaporated under reduced pressure to givc 1.0 g(93%) of the title compound.

1 H-NMR (300 MHz, CDCI 3 5 2.4 6H), 2.5 3H), 4.35 2H), 4.75 2H), 4.9 bs, I1H), 6.25 I 6.8 I 7.05-7.15 (in, 3H), 7.25 IlH) Example 2.15 Synthesis of 2,3S-dimethyl-8-(2 ,6-dimethylbenzylornino)imidazofi. 2-ajpyridine A mixture of 8-amino-2,3-dimethylimidazot1,2-ajpyridine (0.7 g,4.34 mrnol), sodium carbonate (2.0 sodium iodide (0.3 g,2,6-dimethylbenzylchloridc (0.67 1 g, 4.34 inmol) and acetone (30 ml) was stirred overnight. The reaction mixture was filtered and the solvent was removed in vacuo. The residue was dissolved in methylene chloride and washed with aqueous NaHCO 3 The organic layer was separated and the solvent was evaporated. The crude product was purified by flash chromatography eluting with CH,)C1 2 /MeOH to give 0.7 g of the title compound.

HI- NMR (300 M/Hz, CDCI 3 5 7.25 J=7.7 Hz, I 7.14-7.09 (in, I 7.03 J=7.7 Hz, 2H), 6.73 3=7.7 Hz, I 6.21 J=7.7 Hz. I 4.79 (br IH), 4.34 Hz, 2H), 2.38 6H), 2.34 6H).

Example 2.16 WO 00/ 11000 PCTISE99/01402 Synthesis of 8-amino-3-acetyl-2-methyvlimidazo[1. 2-a] pyridine A mixture of 2,3-diaminopyridine (7 a, 64.1 rnrol), 3-chloroacetylacetone (8.6 g,64.1I mmol) in ethyl alcohol (80 ml) was refluxed for 9 hours. The solvent was removed under reduced pressure and the residue dissolved in methylene chloride. A sodium bicarbonate solution was added and the organic layer was separated. The aqueous layer was extracted twice with methylene chloride. The combined orgranic layer was dried and evaporated under reduced pressure. Chromatography of the residue on silica gel (methylene chloride: methanol, 100:5) gave a product which after recrystallisation from ethyl acetate w0 gave 1.9 g (15 of the title compound.

IH NMR (300 MHz. CDCI 3 5 2.6 3H), 2.75 3H), 4.5 (bs, 2H), 6.6 IH), 6.8 (t, I 9.15 IH) Example 2.17 was prepared according to example 1. 1 Example 2.17 Synthesis of 3-acetyl-8-(2, 6-dimethylben -ylamino)-2-methylimidazo[l, 2-a] pyridine Yield: 72 I1-H NMR (300 MHz, CDC1 3 5 2.4 6H), 2.6 3 2,7 3H), 4.35 2H), 4.85 (bs, 1 6.5 5 1 7.9 I 7.0-7.2 (in, 3 9. 1 I H) Example 2. 18 Synthesis of I -[8-(2,3-dimethylbenzylamino)-2-nethylinidazo(1I,2-alpyridine-3-yl)- I ethanol To a mixture of 3-acetyI-8-(2,6-dimethylbenzylainino)-2-methylim'idazo[ 1,2-a~pyridine .(500 mg, 1.63 minol) and methanol (20 ml) was sodium borohydride (62 mng, 1.63 minol) added in portions. Tctrahydrofurane was added and the mixture stirred for 1 hour. TLC showed starting material and sodium borohydride (62 mng, 1.63 inmol) was added.and the mixture stirred for 1.5 hour. The solvent was removed under reduced pressure and to the WO 00/11000 PCT/SE99/01402 56 residue, methylene chloride and water was added. pH was adjusted to pH=3 with hydrogen chloride (conc.) and thereafter alkaline with sodium bicarbonate. The methylene choride layer was separated washed with water, dried over sodium sulfate and evaporated in vacuo.

The residue was treated with ethanol/ ethyl acetate and after filtration (410 mg, 81 'H NMR (300 MHz, CDCI 3 5 1.6 3H), 2.15 3H), 2.4 4.35 2H), 4.8 (bs, IH), 5.2 IH), 6.25 IH), 6.7 7.0-7.2 3H), 6.8 1H) Example 2.19 and 2.20 Synthesis of 2-chloro-6-methylben:ylbromide and 3 chloro-2-methylbenzylbromide A mixture of 3-chloro-o-xylene (20g, 142.2 mmol), N-bromo succinimid (26.57 g, 149.3 mmol), dibenzoylperoxid (0.67 g) and tetrachloromethane (200 ml) was refluxed for hours. After filtration the filtrate was washed with sodium hydrogensulfite and water.The organic layer was dried over sodium sulfate and evaporated in vacuo. Chromatography (SiO2) (petroleum ether: ethyl acetate, 100:4) gave a 10 g fraction containing a mixture of the two title compounds 2-chloro-6-methylbenzylbromide 3-chloro-2methylbenzylbromide 1:0.7. This mixture was used without further purification.

Example 2.21 was prepared according to example 2.8 Example 2.21 Synthesis of ethyl 8-(2,6-dimethylbenzylamino)-2-methylimidazo[l, 2-ajpyridine-3carboxylate Yield: 34% IH NMR (300 MHz, CDCI 3 5 1.4 2.35 3H), 2.45 3H), 2.6 3H), 4.4 (q, 2H), 4.5 2H), 4.9 (bs, 1H), 6.35 1H). 7.05- 7.35 3H), 8.5 IH) Example 2.22, 2.23 (mixture), 2.24, 2.25 and 2.26 were prepared according to example 2.19 and 2.20.

Example 2.22 and 2. 23 WOOO/11000 PCT/SE99/01402 57 Synthesis of 2 -bromo-6-methylbenzylbromid' (2.22) and S-bromno-2-methylhenzylbromide (2.23) Yield: 78 (16.8 gof a fraction containing- a mixture of the two title compounds 1:0.7) Example 2.24 Synthesis of ethyl 2-bromomethyl-3-methylbenflzote Yield: 26 1H NMR (300 MVI-.z, CDCI 3 3 1.4 3H), 2.45 3H), 4.4 2H), 5.0 2H), 7.2-7.4 (in. 2 H) 7.7 5 I H) Example 2.2.5 and 2.26 Synthesis of 2-bromomethyl-3-methylbenzo nitrite (2.25) and 3-broinomethyl-2methylbenzonitrile (2.26) Yield: 5.6 (2.25) 18 of fraction containing a mixture of the two compounds (2.25:2.26), 1.8: 1) 1 H NMR (300 MI-z, CDC1 3 Example 2.25: 3 2.45 4.70 2H), 7.2-7.6 (in. 3H) Example 2.27 Synthesis of 3-dimethylirnidaz ofi.2-ajpyridin-8-y.)-4-methkvl-l -isoindoline The title compound was obtained in the synthesis of example 1. 15 (8-(2-ethoxycarbonyl-6rnethylbenzylamino)-2,3-di methylimidazo[ 1.2-a] pyridine).

Yield: 24 I H NMR (300 MHz, CDCI 3 8 2.91 3H), 2.92 3H), 2.94 3H). 5.4 2H), 6.9 (t, IH), 7.35-7.45 (in, 2H), 7.65 IH), 7.7-7.85 2H) WO 00/11000 PCT/SE99/01402 58 Example 2.28 Synthesis of 2-(((2,3-dimethylimidazo[I, 2-a]pyridin-8-yl)amino)methyl)-3-methylbenzoic acid A mixture of Example 2.27 (700 mg. 2.4 mmol), sodiumhydroxide (15 ml, 10M) and ethyl alcohol (30 ml) and water (7.5 ml) was refluxed for 4 days.The organic solvent was evaporated in vacuo. The reidue was partitioned between methylene chloride and water.

The aqueous layer was cooled and hydrogen chloride (conc.) was added. After extraction with methylene chloride, a mixture of the title compound and Example 2.27 (150 mg) was to obtained. The product crystallize from ethyl alcohol and after filtration the precipitate was washed with ethyl alcohol and methylene chloride. 60 mg (8 of the title compound was obtained.

'H NMR (300 MHz, CD 3 OD): 8 2.35 3H), 2.45 3H), 2.47 3H), 4.65 2H), 6.95 1H), 7.2-7.45 3H), 7.6 IH), 7.8 IH) Example 2.29 Synthesis of 2-bromo-l-methoxymethyl-3-methylbenzene To a stirred solution of 2-bromo-3-methylbenzylbromide (5.2 g, 0.0197 mol) in methanol ml) was added saturated sodiumbicarbonate (5 ml) and the mixture was refluxed overnight.The mixture was neutralised with acetic acid and the solvent was evaporated under reduced pressure. Chromatography of the residue on silica gel using hexane: methylene chloride as eluent gave 4.2 g (99 of the title compound.

H-NVIR (300 MHz, CDC1 3 5 2.43 3H), 3.47 3H), 4.55 2H), 7.18-7.30 3H) Example 2.30 was prepared according to Example 2.29 Example. 2.30 WO 00/11000 PCT/SE99/01402 59 Synthesis of 2-bromo-1, 3-bis(methoxymethyl)benzene Yield: 94 IH-NMR (500 MHz, CDC1 3 5 3.5 6H), 4.6 4H), 7.35-7.45 3H) Example 2.31 Synthesis of 2-bromo-3-methylbenzylcyanid A mixture of 2-brom-3-methylbenzylbromide (25 g, 0.095 mol) and potassium cyanide (16 g, 0.25 mol) in dimethylformamide (100 ml) was stirred at 90 °C for 20 h. The solvent was evaporated under reduced pressure and to the residue were added toluene and water. The organic layer was separated washed with water, separated and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel using is methylene chloride as eluent gave 8.8 g (44 of the title compound.

IH-NMR (300 MHz, CDC1 3 5 2.42 3H), 3.83 2H), 7.21-7.35 3H) Example 2.32 Synthesis of2-bromo-3-methylphenyl acetic acid 2-bromo-3-methylbenzylcyanid (8.8 g, 42 mmol) was added to a mixture of conc sulfuric acid (50 ml) and water (60 ml) and was refluxed overnight. Water (150 ml) and diethyl ether were added and the organic layer was separated. To the organic layer was added a saturated sodium bicarbonate solution and the aqueous layer was separated. The aqueous layer was made acidic by additon of conc sulfuric acid. The acidic water solution was extracted with diethyl ether and the organic layer was washed with water, dried (Na 2

SO

4 and evaporated under reduced pressure to give 6.5 g of the title compound.

1 H-NMR (300 MHz, CDC1 3 5 2.43 3H), 3.87 3H), 7.1-7.2 3H) WO 00/11000 PCT/SE99/01402 Example 2.33 Synthesis of ethyl 2-bromo-methylphenyl acetate To a stirred mixture of 2-bromo-3-methylphenyl acetic acid (4.8 g, 21 mmol) in ethanol (50 ml) was added a small amount of conc. sulfuric acid and the mixture was refluxed overnight. Sodium carbonate (1 g) was added and the solvent was evaporated under reduced pressure. To the residue were added methylene chloride and water. The organic layer was separated and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel using methylene chloride as eluent gave 2.0 g (37 of the desired product as an oil.

IH-NMR (300 MHz, CDC1 3 5 1.27 3H), 2.43 3H), 3.81 2H), 4.18 2H), 7.2- 7.4 3H) is Example 2.34 Synthesis of 2-(2-bromo-3-methylphenyl)ethanol To a stirred solution of 2-bromo-methylphenyl acetate (2 g, 7.9 mmol) in tetrahydrofuran ml) was added LiAIHd (0.8 g, 21 mmol) at 0-5 After stirring the mixture at 0-5 °C for 2 0.8 ml of water was added dropwise, followed by 0.8 ml of 15% sodium hydroxide and then 2.4 ml of water. The solids were removed by filtration and washed with tetrahydrofuran and tetrahydrofuran/methanol The filtrate and washings were combined and the solvents were removed under reduced pressure. The residue was solved in methylene chloride/methanol and was filtrated through silica gel (0.5 The solvent was evaporated under reduced pressure to give 1.6 g (95 of the title compound.

IH-NMR (300 MHz, CDC1 3 5 2.43 3H), 3.07 2H), 3.89 2H), 7.1-7.3 (rn, 3H) Example 2.35 Synthesis of2-(2-bromo-3-methylphenyl)ethyl methylether WO 00/11000 PCT/SE99/01402 61 To a stirred solution of 2-(2-bromo-3-methylphenyl)ethanol 1.6 g, 7.4 mmol) in tetrahydrofuran (20 ml) was added sodium hydride (50 in oil) (0.46 g, 9.6 mmol). After stirring the mixture for 15 min methyl iodide (1.6 g, 11.3 mmol) was added and the reaction mixture was stirred for 3 h. at room temperature. Water (0.2 g) was added and then acetic acid (0.2 The solvents were evaporated under reduced pressure and purification of the residue by column chromatography on silica gel using methylene chloride as eluent gave 1.5 g (89 of the desired product as an oil.

1H-NMR (300 MHz. CDCI 3 5 2.42 3H), 3.07 2H), 3.38 3H), 3.62 2H), 7.1- 7.25 3H) Example 2.36 Synthesis of2-(2-methoxyethyl)-6-methylbenzaldehyd To a stirred solution of 2-(2-bromo-3-methylphenyl)ethyl methylether (1.5 g, 6.5 mmol) in anhydrous tetrahydrofuran (10 ml) was added magnesium (turnings) (0.16 g, 6.6 mmol).

The mixture was refluxed in a nitrogen atmosphere until the reaction started and then stirred without heating for 15 min. The mixture was stirred at 50 °C overnight. The mixture was cooled to room temperature and N,N-dimethylformamide (0.7 g) was added and the mixture was stirred for 30 min. A saturated ammonium chloride solution (10 ml) was added and the mixture was stirred for 1 h. at room temperature. Toluene (20 ml) was added and the organic layer was separated, dried (NaSO 4 and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using methylene chloride as eluent to separate the lipophilic biproducts and methylene chloride/diethyl ether(7:3) as eluent to isolate (0.17 g, (15 of the title compound as an oil.

1 H-NMR (300 MHz, CDC1 3 5 2.61 3H), 3.25 2H), 3.36 3H), 3.61 2H), 7.1- Iu 7.4 3H) WO 00/ 11000 PCTISE99O 1402 62 Example 2.37, 2.38 and 2.39 were prepared accordingI to Example 2.36 Example 2.3 7 Synthesis of 2-methoxymethyl-6-methylbeflzaldehYd Yield: 90 'H-NMR (300 MHz, CDCI 3 5 2.64 3H), 3.43 3H), 4.78 2H), 7.2-7.45 (in, 3H), 10.55 Ks. I H) Example 2.38 Synthesis of 2. 6-biv(methoxymethyl)-belzT2ldehYd is Yield: 79 1 H-NMR (500 MHz, CDCI 3 8 3.5 6H), 4.85 4H), 7.6 3H), 10.55 I1H) Example 2.39 Synthesis of 2, 5-dime thylthiophene-3-carbaldehyde Yield: 57 I HNMR (300 MI-z, CDC] 3 8 2.41 3H), 2.74 3H), 6.62 10. 11 IH) BIOLOGICAL TESTS 1. In vitro experiments Acid secretion inhibition in isolated rabbit gastric glands Inhibiting, effect on acid secretion in vitro in isolated rabbit gastric glands was measured as described by Berglindh et (1976) Acta Physiol. Scand. 97, 401-414.

Determination of'H+.K+-ATPase activity WO 00/11000 PCT/SE99/01402 63 Membrane vesicles (2.5 to 5 pg) were incubated for 15 min at +37 0 C in 18 mM Pipes/Tris buffer pH 7.4 containing 2 mM MgCI 2 10 mM KCl and 2 mM ATP. The ATPase activity was estimated as release of inorganic phosphate from ATP, as described by LeBel et al.

(1978) Anal. Biochem. 85, 86-89.

2. In vivo experiments Inhibiting effect on acid secretion in female rats Female rats of the Sprague-Dawly strain are used. They are equipped with cannulated fistulae in the stomach (lumen) and the upper part of the duodenum. for collection of gastric secretions and administration of test substances, respectively. A recovery period of 14 days after surgery is allowed before testing commenced.

Before secretory tests, the animals are deprived of food but not water for 20 h. The stomach is repeatedly washed through the gastric cannula with tap water (+37 0 and 6 ml Ringer- Glucose given subcutaneously. Acid secretion is stimulated with infusion during 2.5-4 h (1.2 ml/h, subcutaneously) of pentagastrin and carbachol (20 and 110 nmol/kg.h, respectively), during which time gastric secretions are collected in 30-min fractions. Test substances or vehicle are given either at 60 min after starting the stimulation (intravenous and intraduodenal dosing, t ml/kg), or 2 h before starting the stimulation (oral dosing, ml/kg, gastric cannula closed). The time interval between dosing and stimulation may be increased in order to study the duration of action. Gastric juice samples are titrated to pH 7.0 with NaOH, 0.1 M, and acid output calculated as the product of titrant volume and concentration.

Further calculations are based on group mean responses from 4-6 rats. In the case of administration during stimulation; the acid output during the periods after administration of test substance or vehicle are expressed as fractional responses, setting the acid output in the period preceding administration to 1.0. Percentage inhibition is calculated from the WO 00/11000 PCT/SE99/01402 64 fractional responses elicited by test compound and vehicle. In the case of administration before stimulation: percentage inhibition is calculated directly from acid output recorded after test compound and vehicle.

Bioavailabiliry in rat Adult rats of the Sprague-Dawley strain are used. One to three days prior to the experiments all rats arc prepared by cannulation of the left carotid artery under anaesthesia.

The rats used for intravenous experiments are also cannulated in the jugular vein (Popovic (1960) J. Appl. Physiol. 15, 727-728). The cannulas are exteriorized at the nape of the neck.

Blood samples 1 0.4 g) are drawn repeatedly from the carotid artery at intervals up to hours after given dose. The samples are frozen until analysis of the test compound.

Bioavailability is assessed by calculating the quotient between the area under blood/plasrma concentration (AUC) curve following intraduodenal or oral administration and (ii) intravenous administration from the rat or the dog, respectively.

The area under the blood concentration vs. time curve. AUC. is determined by the log/linear trapezoidal rule and extrapolated to infinity by dividing the last determined blood concentration by the elimination rate constant in the terminal phase. The systemic bioavailability following intraduodenal or oral administration is calculated as AUC or AUC x 100.

Inhibition ofgastric acid secretion and bioavailability in the conscious dog.

Labrador retriever or Harrier dogs of either sex are used. They arc equipped with a duodenal fistula for the administration of test compounds or vehicle and a cannulated Po gastric fistula or a Heidenhaim-pouch for the collection of gastric secretion.

Before secretory tests.the animals are fasted for about 18 h but water is freely allowed.

Gastric acid secretion is stimulated for up to 6.5 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 vehicle is given orally, i.d. or 1 or 1.5 h after starting the histamine infusion, in a volume of ml/kg body weight. In the case of oral administration, it should be pointed out that the test compound is administered to the acid secreting main stomach of the Heidenham-pouch dog, The acidity of the gastric juice samples are determined by titration to pH 7.0, and the acid output calculated. The acid output in the collection periods after administration of test substance or vehicle are expressed as fractional responses, setting the acid output in the fraction preceding administration to 1.0. Percentage inhibition is calculated from fractional responses elicited by test compound and vehicle.

Blood samples for the analysis of test compound concentration in plasma are taken at intervals up to 4 h after dosing. Plasma is separated and frozen within 30 min after collection and later analyzed. The systematic bioavailability after oral or i.d.

administration is calculated as described above in the rat model.

It will be understood that the term "comprises" or its grammatical variants as used herein is equivalent to the term "includes" and is not to be taken as excluding the presence of other elements or features.

Claims (16)

1. A compound of the formula I R_ N R 2 (I N Arx or a pharmaceutically acceptable salt thereof, wherein R' is H, CI-C 6 alkyl. C -C 6 alkenyl, CH 2 )OH, halogen, or thiocyano R 2 is Ci-C 6 alkyl, hydroxyalkyl C 1 -C 6 alkoxy C,-C 6 alkyl, hydroxy C 1 -C 6 alkoxy C 1 -C 6 alkyl, CI-C 6 alkylthio C 1 -C 6 alkyl, cyano Cj-C 6 alkyl or halogenuted C I-C( 6 alkyl, or aminocarbonyl C 1 -C 6 alkyl, PCT/SE99/0 1402 Wo 00/11000 PCT/SE99/01402 67 R~ is H, CI-C 6 alkoxy, CI-C 6 alkyl, halogen, hydroxy CI-C 6 alkyl. ()hydroxy CI-C 6 alkoxy. g)CI-C 6 alkoxy CI-C 6 alkyl, C 1 -C 6 alkoxy C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, CI-C 6 alkanoyl, halogenated C 1 -C 6 alkyl. NO,, CN, C 1 -C 6 sulfonyl, C 1 -C 6 suffinyt, Ci-C 6 alkyichia, CI-C 6 alkylaminosulfony[. CI-C 6 (alkyl)2aminosulfonyl. aminosulfonyl. (W CI-C 6 alkylsulfonylamino, C 1 -C 6 (alkylsulfonylD 2 amino or trifIloromethylsuifonylamino CI-C 6 alkylcarboniylamino CI-C 6 alkoxycarbonylamino, or CI-C6 aminocarbonylam Lno. optionally substituted by one or two CI-C 6 alkyl groups. R i S H, WO 00/11000 PCT/SE99/01402 68 halot-enated C 1 -C6 alkyl. C 1 -C 6 alkoxy, or halogen, Ar Is a with R3, R 6 and/or R 7 substituted phenyl. thienvi, furanyl. naphtyl or pyridyl group. X represents R~HO RK.,H~H, R H _C H 2 ,R 'H or Rk CH 2 c r H-, CI-C 6 alkyl, C I-C 6 alkoxy, hydroxy, hydroxy C 1 -C 6 alkyl, hydroxy CI-C6 alkoxy, (gr) halogenated CI-C 6 alkyl, halogenated C 1 -C 6 aikoxy, CI-C 6 alkoxy C 1 -C 6 alkyt. 0j) halogen, hydroxy C I-C 6 alkoxy C I-C 6 alkyl, CN, (in) CI-C6 alkoxycarbonyl, C 1 -C 6 alkoxycarbonyloxy, alkyISuLtbonyloxy. trinLuoromethyisulfonvioxy. wo 00/i 1000 69 CI-C 6 acyloxy CI-C 6 alkyl, CI-C 6 alkylsulfonvi CI-C. 6 alkyl, CI-C 6 alkylsuifinyl C 1 -C 6 alkyl, CI-C 6 aikyithia C 1 -C 6 alkyl, CI-C 6 alkoxycarbonyl amino CI-C 6 alkyl or aryl. amino CI-C 6 alkYl NHC=0R 1 2 H- or C 1 -C. 4 alkyl Substituted -group 0 N (aa) H or C alkyl substituted -gro up, or (ab) C I-C 6 alkyl sulfonyl amino R 6 is H, CI-C6 alkyl, halogen, hydroxy CI-C 6 alkyl, halogenated C 1 -C 6 alkyl, halogenated C I-C 6 alkoxy, CI-C 6 alkoxy CI-C 6 alkyl, or CN R 7is H, C 1 -C 6 alkoxy, (di) halogen. PCT/SE99/O 1402 WO 00/11000 NO,, halogenated C 1 -C6 alkyl, halogenated CI-C 6 alkoxy. aryloxy. or CN R, is H or C 1 -C 6 alkyl R 'is C 1 -C6 alkoxy. C 1 -C 6 alkoxy C 2 -C. 4 alkoxy, NH,, hydroxy C 2 alkoxy. CI-C 6 alkyl carbonyloxy C 2 -C 4 alkoxy, halogenated C 2 -C 4 alkoxy, halogenated C 1 alkyl, hvclroxy C 1 alkyl. CI-C 6 alkyl carbonyloxy C 1 -C 4 alkyl, j) aryl, aryl CI-Cj alkyl, CI-C.j sulfanyl C 2 C 4 alkoxy, (in) C 1 -C 4 sulfinyl C,-C 4 alkoxy, C 1 -C 4 sulfonyl C 2 -Cl alkoxy, R 5 and R 6 are in the ortho positions relative to X R 7 is in the meta or para position relative to X PCT/S E9910 1402 WO 00/11000 PCT/SE99/01402 7' R~ and R8 may together form a hvdroxy- or alkoxy- substituted 5- or 6- membered ring,. provided that one of and R-1 H or halogen provided also that at least one of R R 6 and R 7 H 3 provided also that when R 5 or then one of R3 and R' H provided also that when RK=H. then R 7 CH 3 provide also that when R 2 CH ,OH or CH 2 CN, then one of R. and R 6 H

2. A compound according to claim 1. or a pharmaceutically acceptable salt thereof, wherein 1o R is H, CRH. or CH 2 OH, R 2is CHI, CHCH~, CHCHOH, CHCH 2 SCH3, CH 2 CH 2 OCH.,, or CH 2 CHCN-. Ris H. CH 2 CH 3 F. CI, Br, OCH3,OCH 2 ,CH 3 CHOH. CHCHOH. OCH, 2 CHOH, CH 2 CH 2 OCHI. OCHCH 2 OCH 3 C=OOCH 3 i, C=OOCH 2 CH 3 C=OCH,, C=OCH 2 CH3, C=OCH(CH 3 2 ,or C=OCH'CH 2 CH 3 isR 4 is H. CHI, CH 2 CH 3 1, F. Cl, Br OCH 3 or OCH 2 CH 3 Ar is phenyl, thienyl, furyl or naphtyl Xis RH Rkr-H NH iHH or R' G-H C C C R 5 is H, CH 3 CHCH 3 OCH.,, OH, CH,OH. CHOCH.-, CH 2 CH,0OH. CH 1 CHOCH3, OCHCHOH, OC=OOCH-t. OC=OCH, 2 CH. OCHF 2 OCF. F. Cl. Br. CN, phenyl, CH 2 CHOC=OCH. CHNHC=OOCH. 3 or CH 2 NHC=OOCHCH~i R 6 is H. CH 3 CHCI. CF. OCF 3 OCFH, F. Cl, Br or CH 2 OCH3 R 7 is H, F, Cl, Br, OCF 2 H, or OCF 3 R 8 is H. ClF 3 or CHCH 3 2; 3. A compound accordingT to claim t, or a pharmaceutically acceptable salt thereof, whcrein R' is H. CH 3 or CFIOH, R 2 is CHCI-i. CHOFH, CH-,SCH 3 CH 2 ,OCH, or CH 2 ,CN WO 00/11000 PCT/SE99/O1 402 72 R 3 is H, CH 1 CHit.OCH 3 ,OCH 1 ,,CH 2 ,OH,C=OOCH-, C=OOCHCEH3, C=OCH3, C=OCH 2 CH 3 or C=OCHCH 2 CH3. Ris H, or CH 3 Ar is phenyl, thienyl or furyl RK.,H, 0. Rk.,'NH R H -CH 2 or R8 C(H X is c R 5 is H, CH. CHCH., OCH. OH, CHIOH. CH 2 OCH3, CHCHOH, CH 1 CH 2 OCH.-> OCHCH 2 OH, OC=OOCH3, OC=OCH 2 CH 3 OCHF 2 OCF 3 F, Cl, Br. CN, CHCHOC=OCH 3 CHNHC=OOCH3 or CHNHC=OOCH 2 CH.- o R' is H, CH 2 CH3, CF 3 OCF3, OCF 2 H, F, CI, Br or CH,OCH 3 R 7 is H, F. Cl Br. OCF 2 H. or OCF 3 R 8 is Hor CH 3

4. A process for the preparation of a compound according. to any of claims 1 to 3 comprising: reacting a compound of the general formula Ul R_ N- _R 2 N X I is NH-, or OH, and R. R 2 R3, and R" are as defined for Formula L. with a compound of the general Formula fI Ar WO 00/11000 PCT/SE99/01402 73 wherein "Ar" is as defined for Formula I and Y is a leaving group, such as a halide, tosyloxy or mesyloxy in an inert solvent, such as acetone, acetonitrile, dimethoxyethane, methanol, ethanol or N,N-dimethylformamide, and optionally in the presence of a base, such as an alkali metal hydroxide, an alkali metal carbonate, or an organic amine, to give a compound of the general Formula I. A process for the preparation of a compound according to any of claims I to 3 wherein X is NH comprising; a) reacting a compound of the general formula IV R' RN N R 2 (IV) N NH 2 wherein R 1 R 2 R 3 and R" are as defined for Formula I, with a compound of the general Formula V Y H (V) Ar wherein Ar are as defined for Formula I. in an inert solvent in the presence of a Lewis acid, such as zinc chloride, under standard conditions to give a compound of the general formula VI WO 00/11000 PCT/SE99/01402 74 R' R 3 RN (Vl) I N Ar wherein R 2 R 3 R 4 and Ar are as defined for Formula I; b) treating the compound of the general formula VI. wherein R 2 R 3 R 4 and Ar are as defined for Formula I, with sodium borohydride or sodium cyanoborohydride under standard condition in an solvent, such as methanol or ethanol, to give a compound of the general formula I, wherein X in NH.

6. A process for the preparation of a compound according to any of claims I to 3, wherein R i is CH2OH or H, comprising; a) reacting a compound of the general formula VII O R3 0 R N R 2 (Vll) "N X' wherein X 1 is NH 2 or OH, R 2 R' and R 4 are as defined for Formula I, with a compound i. of the general formula I S (Ill) Ar .wherein Ar is as defined for Formula I and Y is a leaving group, such as a halide, tosyloxy or mesyloxy to give a compound of the general Formula VfII WO 00/11000 PCT/SE99/01402 0 0 R-l R2 N (VIll) rX Ar wherein R 2 R 3 R 4 Ar and X is as defined for Formula I, in an inert solvent, such as acetone, acetonitrile, dimethoxyethane, methanol, ethanol or N,N-dimethylformamide. and optionally in the presence of a base, such as an alkali metal hydroxide, an alkali metal carbonate, or an organic amine, under standard conditions, b) treating a compound of the general formula VIII. wherein R 2 R 3 R 4 Ar and X is as defined for Formula I, with lithium aluminium hydride under standard conditions in an solvent, such as tetrahydrofuran or ether, to give a compound of the general Formula I, wherein RI is CH-OH, or b) treating a compound of the general formula VITI, wherein R 2 R 3 R 4 Ar and X is as defined for Formula 1, with aqueous base or acid, in an inert solvent, such as diphenylether, under standard conditions, to give a compound of the general formula I. wherein R I is H.

7. A process for the preparation of a compound according to any of claims 1 to 3, wherein R I is CH-OH and X is NH, comprising; a) reacting a compound of the general formula IX WO 00/11000 PCT/SE99/01402 0 N R N 1 R 2 N (IX) with a compound of the general formula V 0 H wherein Ar is as defined for Formula I, in an inert solvent under standard conditions, in the presence of a Lewis acid, such as zinc chloride to give a compound of the general formula the compounds of the Formula X N wherein R 2 R 3 R 4 and Ar are as defined for Formula I; b) reacting a compound of the general formula X. wherein R 2 R 3 R 4 and Ar are as defined for Formula I with sodium borohydride or sodium cyanoborohydride under standard condition in an solvent, such as methanol or ethanol, to give a compound of the general formula XI WO 00/11000 PCT/SE99/01402 77 0 N (XI) NH Ar wherein R 2 R 3 R 4 and Ar are as defined for Formula I; c) reacting a compound of the general formula XI, wherein R 2 R 3 R 4 and Ar are as defined for Formula I. with lithium aluminium hydride under standard conditions in an solvent, such as tetrahydrofuran or ether, to give a compound of the general Formula I., wherein R I is CHOH and X is NH, or; c) or treating a compound of the general formula XI, wherein R 2 R 3 R 4 and Ar is as defined for Formula 1, with aqueous base or acid. in an inert solvent, such as diphenylether, under standard conditions, to give a compound of the general formula I, wherein RI is H.

8. A process for the preparation of a compound according to any of claims I to 3, wherein X is CHO, comprising; a) reacting a compound of the general formula XII 3 N R' NH, (XII) WO 00/11000 PCTISE99/01402 78 with an cx-halocarbonyl compound of the general formula R 2 COCH(Z)R' wherein R' and R' are as defined for Formula I and Z is a leaving group, such as Br or Cl. in an inert solvent, such as acetonitrile or ethanol, under standard conditions to give s compounds of the general formula XIII R 3 R 4 N 2 (XIII) N r° Ar wherein R 2 R 1 R 4 ,.and Ar is as defined for Formula I.

9. A pharmaceutical formulation containing a compound according to any one of claims I to 3 as active ingredient in combination with a pharmaceutically acceptable diluent or carrier.

10. Use of a compound according to any one of claims I to 3 for the manufacture of a medicament for the inhibition of gastric acid secretion.

11. Use of a compound according to any one of claims 1 to 3 for the manufacture of a medicament for the treatment of gastrointestinal inflammatory diseases.

12. Use of a compound according to any one of claims 1 to 3 the manufacture of a medicament for the treatment or prophylaxis of conditions involving infection by Helicobacter pylori of human gastric mucosa, wherein the said salt is adapted to be administered in combination with at least one antimicrobial agent.

13. A method for inhibiting gastric acid 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 claims 1 to 3.

14. A method for the treatment of gastrointestinal inflammatory diseases which comprises administering to a mammal, including man, in need of such treatment an effective amount of a compound according to any one of claims 1 to 3. A method for the treatment or prophylaxis of conditions involving infection by Helicobacter pylori of human gastric mucosa, which comprises administering to a mammal, including humans, in need of such treatment an effective amount of a compound as claimed in any one of claims 1 to 3, wherein the said salt is administered in combination with at least one antimicrobial agent.

16. A pharmaceutical formulation for use in the. inhibition of gastric acid secretion wherein the active ingredient is a compound according to any one of claims 1 to 3.

17. A pharmaceutical formulation for use in the treatment of gastrointestinal inflammatory diseases wherein the active ingredient is a compound according to any one of claims 1 to 3.

18. A pharmaceutical formulation for use in the treatment or prophylaxis of conditions involving infection by Helicobacter pylori of human gastric mucosa, wherein the active ingredient is a compound according to any one of claims 1 to 3 in combination with at least one antimicrobial agent.

19. A compound according to Claim 1 substantially as hereinbefore described with reference to any one of the examples.