EP1877410A1

EP1877410A1 - Mutual prodrug compounds for use as antiinflammatory agents with gastrointestinal protective activity

Info

Publication number: EP1877410A1
Application number: EP06763060A
Authority: EP
Inventors: Christof Brehm; Thomas Klein; Wilm Buhr; Maria Vittoria Chiesa; Andreas Palmer; Peter Jan Zimmermann; Wolfgang-Alexander Simon; Stefan Postius; Wolfgang Kromer; Gerhard Grundler
Original assignee: Nycomed GmbH
Current assignee: Takeda GmbH
Priority date: 2005-04-29
Filing date: 2006-04-26
Publication date: 2008-01-16
Also published as: AU2006243255A1; WO2006117316A1; CA2605900A1

Abstract

The invention relates compounds of the formula I in which the substituents and symbols have the meanings as indicated in the description. The compounds are prodrugs and exhibit in the human and/or animal body antipyretic, analgesic, antiphlogistic and/or anti-inflammatory activity as well as gastric acid secretion inhibiting and therefore gastro and intestinal protective activity.

Description

MUTUAL PRODRUG COMPOUNDS FOR USE AS ANTIINFLAMMATORY AGENTS WITH GASTROINTESTINAL PROTECTIVE ACTIVITY

Field of application of the invention

The invention relates to novel compounds, which are used in the pharmaceutical industry as active compounds for the production of medicaments, to medicaments comprising these compounds and to the use of these compounds for the treatment and/or prophylaxis of diseases.

Known technical background

Non-steroidal anti-inflammatory drugs (NSAID^'s) are a class of compounds which are widely used inter alia for the treatment of inflammation, pain and fever. However, it is known that NSAID^'s can cause unwanted side effects, inter alia on the gastrointestinal system, such as for example gastrointestinal ulcers, which is a major limitation to the use of NSAID^'s.

Reversible proton pump inhibitors, also named as potassium competitive acid blockers (P-CABs) or acid pump antagonists (APA^'s), are known to bind reversibly to the H+/K+-ATPase and thus inhibit gastric acid secretion. Compounds of different chemical classes, such as for example imidazopyridine, benzimidazole, quinazoline or pyrrolopyridazine derivatives are known in the art to act as P-CAB^'s.

P-CABs which can be used inter alia in the prevention or treatment of gastrointestinal disorders are known from a variety of prior art documents such as, for example, from the international applications WO 91/17164, WO 93/08190, WO 92/06979, WO 98/42707, WO 98/54188, WO 00/17200, WO 00/26217, WO 00/63211 , WO 01/72754, WO 01/72756, WO 01/72755, WO 01/72757, WO 02/34749, WO 03/014120, WO 03/016310, WO 03/014123, WO 03/068774, WO 03/091253, WO 04/046144, WO 04/074289, WO 04/054984, WO 04/087701 , WO 99/55705, WO 99/55706, WO 00/11000, WO 02/20523, WO 02/069968, WO 03/018582, WO 04/113338, WO 04/113339 and WO 04/113340, WO 96/05177, WO 98/43968, WO 95/019980, WO 00/77033 and WO 01/58901.

The compounds mentioned in the patent applications cited above are said to have advantageous gas- tro-protective action against certain medicaments (such as, for example, those medicaments mentioned below in the description of this invention, especially antiinflammatoriies and antirheumatics, and/or, in particular, those medicaments which cause erosive changes and/or lesions in the gastrointestinal system) and/or are well useful and effective in the prevention or treatment of gastrointestinal disorders associated with certain medicaments indicated below and/or are particularly useful and effective in prevention or treatment of gastrointestinal diseases caused by certain medicaments selected from the group consisting of NSAIDs (non-steroidal antiinflammatory drugs), COX-2 (cyclooxygenase 2) inhibitors, NO-NSAIDs (nitric oxide releasing NSAID), bisphosphonates and corticosteroids.

In the International Patent Application WO 02/069968 the use of certain pharmaceutically active compounds for the treatment and/or prevention of NSAID induced gastric ulcer as well as a pharmaceutical composition in the unit dosage form comprising an NSAID together with a 6-carboxamido-imidazo[1 ,2- a]-pyridine compound are described. Other pharmaceutically active compounds described in that patent application include COX-2-inhibitors, NO-NSAIDs and bisphosphonates.

In the International Patent Application WO 04/071391 pharmaceutical compositions are described comprising as a first active ingredient an acid pump antagonist which is a tricyclic imidazo[1 ,2-a]- pyridine compound and a second active ingredient which is selected from the group consisting of NSAIDs, COX-2-inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids.

Christians and Timmerman described in the European Journal of Pharmaceutical Sciences, 4, 1996, 1 hybride drugs as the combination of more than one pharmacological property in one single molecule. Inter alia a classification of hybide drugs and various examples of different classes of hybride drugs are described.

Because of the side effects, especially in the gastrointestinal system, of the medicaments mentioned below in the description of the invention (see for example "The gastrointestinal effects of non-selective NSAIDs and COX-2-selective inhibitors", Seminars in Arthritis and Rheumatism, 2002, 32, 3, Suppl. 1 , 43-50), there is still a severe need in the art of having novel compounds from the class of NSAID^'s, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids with outstanding antipyretic, analgesic, antiphlogistic and/or anti-inflammatory properties, and simultaneously, excellent tolerance on the gastrointestinal system.

Description of the invention

It has now been found, unexpectedly, that the compounds according to the present invention exhibit antipyretic, analgesic, antiphlogistic and/or anti-inflammatory properties as well as gastric acid secretion inhibiting and therefore gastro and intestinal protective properties.

The invention relates to compounds of the formula I

in which

A is the residue derived from a corresponding carboxylic acid of the formula Na

Ha which carboxylic acid of the formula Ma is a compound with antipyretic, analgesic, antiphlogistic and/or anti-inflammatory properties, is the residue derived from a corresponding hydroxy compound of the formula III

which hydroxy compound of the formula III is a compound from the class of potassium competitive acid blockers and is selected from one of the following compounds (7R,8R,9R)-2,3-dimethyl-7,8-dihydroxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2- h][1 ,7]naphthyridine,

(7S,8R,9R)-7,8-dihydroxy-3-hydroxymethyl-2-methyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2- h][1 ,7]naphthyridine,

(7R,8R,9R)-7,8-dihydroxy-2,3-dimethyl-9-phenyl-7H-8,9-dihydropyrano[2,3-c]imidazo[1 ,2- a]pyridine,

(7R,8R,9R)-2,3-dimethyl-8-hydroxy-7-methoxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2- h][1 ,7]naphthyridine,

(7S,8S,9S)-2,3-dimethyl-8-hydroxy-7-methoxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2- h][1 ,7]naphthyridine,

(7S,8R,9R)-2,3-dimethyl-8-hydroxy-7-methoxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2- h][1 ,7]naphthyridine,

(7R,8S,9S)-2,3-dimethyl-8-hydroxy-7-methoxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2- h][1 ,7]naphthyridine,

(7R,8R,9R)-2,3-dimethyl-7-ethoxy-8-hydroxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2- h][1 ,7]naphthyridine,

(7S,8R,9R)-2,3-dimethyl-7-ethoxy-8-hydroxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2- h][1 ,7]naphthyridine,

(7R,8R,9R)-2,3-dimethyl-8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10- tetrahydroimidazo[1 ,2-h][1 ,7]naphthyridine (SORAPRAZAN), (7S,8S,9S)-2,3-dimethyl-8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10- tetrahydroimidazo[1 ,2-h][1 ,7]naphthyridine,

(7S,8R,9R)-2,3-dimethyl-8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10- tetrahydroimidazo[1 ,2-h][1 ,7]naphthyridine,

(7R,8S,9S)-2,3-dimethyl-8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10- tetrahydroimidazo[1 ,2-h][1 ,7]naphthyridine,

(7S,8R,9R)-2,3-dimethyl-8-hydroxy-9-phenyl-7-(2-propoxy)-7,8,9,10-tetrahydroimidazo[1 ,2- h][1 ,7]naphthyridine,

(7R,8R,9R)-2,3-dimethyl-8-hydroxy-7-(2-methylthioethyloxy)-9-phenyl-7,8,9,10- tetrahydroimidazo[1 ,2-h][1 ,7]naphthyridine,

(7S,8R,9R)-2,3-dimethyl-8-hydroxy-7-(2-methylthioethyloxy)-9-phenyl-7,8,9,10- tetrahydroimidazo[1 ,2-h][1 ,7]naphthyridine,

(7R,8R,9R)-2,3-dimethyl-8-hydroxy-7-(2-methylsulphinylethoxy)-9-phenyl-7,8,9,10-tetrahydro- imidazo[1 ,2-h][1 ,7]naphthyridine, ^■ (7S,8R,9R)-2,3-dimethyl-8-hydroxy-7-(2-methylsulphinylethoxy)-9-phenyl-7,8,9,10-tetrahydro- imidazo[1 ,2-h][1 ,7]naphthyridine,

■ (7R,8R,9R)-2,3-dimethyl-7-(ethylthio)-8-hydroxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2- h][1 ,7]naphthyridine,

^■ (7S,8R,9R)-2,3-dimethyl-7-(ethylthio)-8-hydroxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2- h][1 ,7]naphthyridine,

■ (7R,8R,9R)-2,3-dimethyl-8-hydroxy-9-phenyl-7-(2,2,2-trifluoroethoxy)-7,8,9,10-tetrahydroimi- dazo[1 ,2-h][1 ,7]naphthyridine,

■ (7S,8R,9R)-2,3-dimethyl-8-hydroxy-9-phenyl-7-(2,2,2-trifluoroethoxy)-7,8,9,10-tetrahydroimi- dazo[1 ,2-h][1 ,7]naphthyridine,

^■ (7R,8S,9R)-7,8-dihydroxy-9-phenyl-2,3,8-trimethyl-7,8,9,10-tetrahydroimidazo[1 ,2-h][1 ,7]naph- thyridine,

^■ (7S,8S,9R)-8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-2,3,8-trimethyl-7,8,9,10-tetrahydro- imidazo[1 ,2-h][1 ,7]naphthyridine,

^■ (7S,8S,9R)-8-hydroxy-7-methoxy-9-phenyl-2,3,8-trimethyl-7,8,9,10-tetrahydroimidazo[1 ,2-h]- [1 ,7]naphthyridine,

■ (7R,8R,9R)-7,8-dihydroxy-9-phenyl-2,3,7-trimethyl-7,8,9,10-tetrahydroimidazo[1 ,2-h][1 ,7]naph- thyridine,

^■ (7S,8R,9R)-7,8-dihydroxy-9-phenyl-2,3,7-trimethyl-7H-8,9-dihydropyrano[2,3-c]imidazo[1 ,2-a]- pyridine,

^■ (7R,8R,9R)-7,8-dihydroxy-9-phenyl-2,3,7-trimethyl-7H-8,9-dihydropyrano[2,3-c]imidazo[1 ,2-a]- pyridine,

^■ (7R,8R,9R)-2,3-dimethyl-8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7H-8,9-dihydropyrano[2,3- c]imidazo[1 ,2-a]pyridine,

^■ (7S,8R,9R)-2,3-dimethyl-8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7H-8,9-dihydropyrano[2,3- c]imidazo[1 ,2-a]pyridine,

^■ (7S,8R,9R)-2,3-dimethyl-8-hydroxy-9-phenyl-7-(2,2,2-trifluoroethoxy)-7H-8,9-dihydropyrano- [2,3-c]imidazo[1 ,2-a]pyridine,

^■ (7R,8R,9R)-2,3-dimethyl-7-ethoxy-8-hydroxy-9-phenyl-7H-8,9-dihydropyrano[2,3-c]imidazo- [1 ,2-a]pyridine,

^■ (7S,8R,9R)-2,3-dimethyl-7-ethoxy-8-hydroxy-9-phenyl-7H-8,9-dihydropyrano[2,3-c]imidazo- [1 ,2-a]pyridine,

^■ (7R,8R,9R)-2,3-dimethyl-8-hydroxy-7-(2-methoxypropoxy)-9-phenyl-7H-8,9-dihydropyrano[2,3- c]imidazo[1 ,2-a]pyridine,

^■ (7S,8R,9R)-2,3-dimethyl-8-hydroxy-7-(2-methoxypropoxy)-9-phenyl-7H-8,9-dihydropyrano[2,3- c]imidazo[1 ,2-a]pyridine,

^■ (7R,8R,9R)-2,3-dimethyl-8-hydroxy-7-(2-propoxy)-9-phenyl-7H-8,9-dihydropyrano[2,3- c]imidazo[1 ,2-a]pyridine,

^■ (7S,8R,9R)-2,3-dimethyl-8-hydroxy-7-(2-propoxy)-9-phenyl-7H-8,9-dihydropyrano[2,3- c]imidazo[1 ,2-a]pyridine, ^■ (y^SR^^-y-butoxy^^-dimethyl-S-hydroxy-θ-phenyl-yH-S^-dihydropyrano^^- c]imidazo[1 ,2-a]pyridine,

^■ (7S,8R,9R)-7-butoxy-2,3-dimethyl-8-hydroxy-9-phenyl-7H-8,9-dihydropyrano[2,3- c]imidazo[1 ,2-a]pyridine,

^■ (7S,8R,9R)-7,8-dihydroxy-6-methoxymethyl-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydro- imidazo[1 ,2-h][1 ,7]naphthyridine,

^■ (7R,8R,9R)-7,8-dihydroxy-6-methoxymethyl-2,3-dimethyl-9-phenyl-7,8,9,10- tetrahydroimidazo[1 ,2-h][1 ,7]naphthyridine,

^■ (7S,8R,9R)-2,3-dimethyl-8-hydroxy-7-methoxy-6-methoxymethyl-9-phenyl-7,8,9,10-tetra- hydroimidazo[1 ,2-h][1 ,7]naphthyridine,

^■ (7R,8R,9R)-2,3-dimethyl-8-hydroxy-7-methoxy-6-methoxymethyl-9-phenyl-7,8,9,10-tetra- hydroimidazo[1 ,2-h][1 ,7]naphthyridine,

^■ (7R,8R,9R)-2,3-dimethyl-8-hydroxy-7-(2-methoxyethoxy)-6-methoxymethyl-9-phenyl-7,8,9,10- tetrahydroimidazo[1 ,2-h][1 ,7]naphthyridine,

^■ (7S,8R,9R)-2,3-dimethyl-8-hydroxy-7-(2-methoxyethoxy)-6-methoxymethyl-9-phenyl-7,8,9,10- tetrahydroimidazo[1 ,2-h][1 ,7]naphthyridine,

^■ (7R,8R,9R)-2,3-dimethyl-7-ethoxy-8-hydroxy-6-methoxymethyl-9-phenyl-7,8,9,10-tetrahydro- imidazo[1 ,2-h][1 ,7]naphthyridine,

^■ (7S,8R,9R)-2,3-dimethyl-7-ethoxy-8-hydroxy-6-methoxymethyl-9-phenyl-7,8,9,10-tetrahydro- imidazo[1 ,2-h][1 ,7]naphthyridine,

■ (7R,8R,9R)-7,8-dihydroxy-2-methyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2-h][1 ,7]naph- thyridine,

^■ (7S,8R,9R)-8-hydroxy-2-methyl-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2- h][1 ,7]naphthyridine,

■ (7R,8R,9R)-8-hydroxy-2-methyl-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2- h][1 ,7]naphthyridine,

^■ (7R,8R,9R)-3-chloro-8-hydroxy-7-(2-methoxyethoxy)-2-methyl-9-phenyl-7,8,9,10-tetrahydro- imidazo[1 .2-h][1.7]naphthyridine,

^■ (7R,8R,9R)-3-chloro-8-hydroxy-7-(2-methoxyethoxy)-2-methyl-9-phenyl-7H-8,9-dihydro- pyrano[2,3-c]imidazo[1 ,2-a]pyridine,

^■ (7R,8R,9R)-8-hydroxy-7-(2-methoxyethoxy)-2-methyl-9-phenyl-7H-8,9-dihydro-pyrano[2,3- c]imidazo[1 ,2-a]pyridine,

■ (7R,8R,9R)-7,8-dihydroxy-2-methyl-9-phenyl-7H-8,9-dihydropyrano[2,3-c]imidazo[1 ,2- a]pyridine,

■ (7S,8R,9R)-7,8-dihydroxy-2-methyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2-h][1 ,7]naph- thyridine,

^■ (7R,8R,9R)-8-hydroxy-7-methoxy-2-methyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2- h][1 ,7]naphthyridine,

■ (7S,8R,9R)-8-hydroxy-7-methoxy-2-methyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2- h][1 ,7]naphthyridine, ^■ (7R,8R,9R)-8-hydroxy-3-hydroxymethyl-7-(2-methoxyethoxy)-2-methyl-9-phenyl-7,8,9,10- tetrahydroimidazo[1 ,2-h][1 ,7]naphthyridine,

^■ (7R,8R,9R)-8-hydroxy-3-hydroxymethyl-7-(2-hydroxyethoxy)-2-methyl-9-phenyl-7,8,9,10- tetrahydroimidazo[1 ,2-h][1 ,7]naphthyridine,

^■ (7R,8R,9R)-2,3-dimethyl-8-hydroxy-7-(2-hydroxyethoxy)-9-phenyl-7,8,9,10- tetrahydroimidazo[1 ,2-h][1 ,7]naphthyridine,

■ (7R,8R,9R)-8-hydroxy-7-(2-methoxyethoxy)-2-methyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2- h][1 ,7]naphthyridine,

^■ (7fl,8fl,9fl)-3-chloro-8-hydroxy-7-(2-methoxyethoxy)-2-methyl-9-phenyl-7H-8,9- dihydropyrano-[2,3-c]-imidazo-[1 ,2-a]pyridine

■ 1 ,2-dimethyl-4-(2-ethyl-6-methyl-benzylamino)-6-[Λ/-(2-hydroxyethyl)aminocarbonyl]- 1 H- benzimidazole

■ 4-(2,6-Dimethyl-benzylamino)-6-(2-hydroxyethyl-aminocarbonyl)-2-methoxymethyl-1 -methyl- 1 H-benzimidazole

■ 4-(2,6-Dimethyl-benzylamino)-6-hydroxymethyl-1 ,2-dimethyl-1 /-/-benzimidazole

■ 6-(N,N-Dimethylaminocarbonyl)-4-(2,6-dimethyl-benzylamino)-2-hydroxymethyl-1 -methyl-1 H- benzimidazole

■ 6-(N, N-Dimethylaminocarbonyl)-4-(2-ethyl-6-methyl-benzylamino)-2-hydroxymethyl-1 -methyl- 1 /-/-benzimidazole

■ 1 ,2-dimethyl-4-(2,6-dimethyl-benzylamino)-6-[Λ/-(2-hydroxyethyl)aminocarbonyl]- 1 H- benzimidazole

■ 1 ,2-dimethyl-4-(2,6-dimethyl-benzylamino)-6-[Λ/-(2-hydroxyethyl)-Λ/-methyl-aminocarbonyl]- 1 /-/-benzimidazole

^■ 2,3-dimethyl-8-phenyl-3,4,5,6-tetrahydro-chromeno[7,8]imidazole-5-carboxylic acid Λ/-(2- hydroxyethyl)amide

^■ 2,3-dimethyl-8-phenyl-6,7,8,9-tetrahydro-3/-/-imidazo[4,5-h]quinoline-5-carboxylic acid Λ/-(2- hydroxyethyl)amide,

^■ 5-Hydroxymethyl-2,3-dimethyl-8-phenyl-6,7,8,9-tetrahydro-3/-/-imidazo[4,5-/7]quinoline

^■ Methyl 8-(frans-2,3-dihydro-2-hydroxy-1 -indenylamino)-2,3-dimethyl-imidazo[1 ,2-a]pyridine-6- carboxylate

^■ 8-(frans-2,3-Dihydro-2-hydroxy-1 -indenylamino)-2,3-dimethyl-imidazo[1 ,2-a]pyridine-6- carboxylic acid

^■ 8-(frans-2,3-Dihydro-2-hydroxy-1 -indenylamino)-6-[N-(2-methoxyethyl)-amino-carbonyl]-2,3- dimethyl-imidazo[1 ,2-a]pyridine

■ 8-(frans-2,3-Dihydro-2-hydroxy-1 -indenylamino)-6-(N,N-dimethylamino-carbonyl)-2,3-dimethyl- imidazo[1 ,2-a]pyridine

■ 8-(frans-2,3-Dihydro-2-hydroxy-1 -indenylamino)-6-(N-methylamino-carbonyl)-2,3-dimethyl- imidazo[1 ,2-a]pyridine

^■ 8-(frans-2,3-Dihydro-2-hydroxy-1 -indenylamino)-2,3-dimethyl-imidazo[1 ,2-a]pyridine-6- carboxamide ^■ 8-(frans-2,3-Dihydro-2-hydroxy-1 -indenyloxy)-2,3-dimethyl-imidazo[1 ,2-a]pyridine-6-carboxylic acid

■ 8-(frans-2,3-Dihydro-2-hydroxy-1 -indenyloxy)-6-(N,N-dimethylamino-carbonyl)-2,3-dimethyl- imidazo[1 ,2-a]pyridine

^■ 8-(frans-2,3-Dihydro-2-hydroxy-1 -indenyloxy)-6-methoxymethyl-2,3-dimethyl-imidazo[1 ,2- a]pyridine

■ 8-[(1 S,2S)-2,3-Dihydro-2-hydroxy-1 -indenyloxy)-6-(N,N-dimethylamino-carbonyl)-2,3-dimethyl- imidazo[1 ,2-a]pyridine

^■ 6-(N,N-Dimethylamino-carbonyl)-2,3-dimethyl-8-(frans-1 ,2,3,4-tetrahydro-2-hydroxy-1 - naphthalenyloxy)-imidazo[1 ,2-a]pyridine

^■ 8-(trans-2,3-Dihydro-2-hydroxy-7-methoxy-1 -indenyloxy)-6-(N,N-dimethylamino-carbonyl)-2,3- dimethyl-imidazo[1 ,2-a]pyridine

^■ 8-(frans-2,3-Dihydro-2-hydroxy-7-methyl-1 -indenyloxy)-6-(N,N-dimethylamino-carbonyl)-2,3- dimethyl-imidazo[1 ,2-a]pyridine

■ 4-(frans-2,3-Dihydro-2-hydroxy-1 -indenyloxy)-6-(N,N-dimethylaminocarbonyl)-1 ,2-dimethyl-1 H- benzimidazole

■ 4-[(1 S,2S)-2,3-Dihydro-2-hydroxy-1 -indenyloxy]-6-(N,N-dimethylaminocarbonyl)-1 ,2-dimethyl- 1 /-/-benzimidazole

■ 4-(frans-2,3-Dihydro-2-hydroxy-1 -indenyloxy)-6-methoxymethyl-1 ,2-dimethyl-1 H-benz- imidazole

^■ Ethyl 4-(frans-2,3-dihydro-2-hydroxy-1 -indenyloxy)-1 ,2-dimethyl-1 /-/-benzimidazole-6- carboxylate

^■ 4-(frans-2,3-Dihydro-2-hydroxy-1 -indenyloxy)-1 ,2-dimethyl-1 /-/-benzimidazole-θ-carboxylic Acid

^■ Ethyl 4-(frans-5-chloro-2,3-dihydro-2-hydroxy-1 -indenyloxy)-1 ,2-dimethyl-1 /-/-benzimidazole-6- carboxylate

^■ 4-(frans-5-Chloro-2,3-dihydro-2-hydroxy-1 -indenyloxy)-1 ,2-dimethyl-1 /-/-benzimidazole-6- carboxylic Acid

■ 4-(frans-5-Chloro-2,3-dihydro-2-hydroxy-1 -indenyloxy)-6-(N,N-dimethylaminocarbonyl)-1 ,2- dimethyl-1 /-/-benzimidazole

■ Ethyl 4-(frans-2,3-dihydro-2-hydroxy-4,7-dimethyl-1 -indenyloxy)-1 ,2-dimethyl-1 /-/-benzimi- dazole-6-carboxylate

■ 4-(frans-2,3-Dihydro-2-hydroxy-4,7-dimethyl-1 -indenyloxy)-1 ,2-dimethyl-1 /-/-benzimidazole-6- carboxylic Acid

■ 4-(frans-2,3-Dihydro-2-hydroxy-4,7-dimethyl-1 -indenyloxy)-6-(N,N-dimethylaminocarbonyl)- 1 ,2-dimethyl-1 /-/-benzimidazole

^■ 4-(frans-2,3-Dihydro-2-hydroxy-1 -indenyloxy)-1 ,2-dimethyl-6-[(1 -pyrrolidino)carbonyl]-1 H- benzimidazole

■ 4-(frans-2,3-Dihydro-2-hydroxy-1 -indenyloxy)-6-[N-(2-methoxyethyl)-N-methyl-aminocarbonyl]- 1 ,2-dimethyl-1 /-/-benzimidazole ^■ 4-(frans-2,3-Dihydro-2-hydroxy-1 -indenyloxy)-1 ,2-dimethyl-6-[(1 -piperidino)carbonyl]-1 H- benzimidazole

^■ Θ^Cyclopropylaminocarbonyl^-^rans^S-dihydro^-hydroxy-i -indenyloxy)-1 ,2-dimethyl-1 H- benzimidazole

■ 4-(frans-2,3-Dihydro-2-hydroxy-1 -indenylamino)-6-(N,N-dimethylaminocarbonyl)-1 ,2-dimethyl- 1 /-/-benzimidazole

^■ 2-Cyclopropyl-4-(frans-2,3-dihydro-2-hydroxy-1 -indenyloxy)-1 -methyl-1 /-/-benzimidazole-6- carboxylic acid

■ 2-Cyclopropyl-4-(frans-2,3-dihydro-2-hydroxy-1 -indenyloxy)-6-(N,N-dimethylaminocarbonyl)-1 - methyl-1 /-/-benzimidazole

■ 1 -Benzyl-7-(4-fluorbenzyloxy)-3-hydroxymethyl-2-methyl-pyrrolo[2,3-d]pyridazin

■ 1 -Benzyl-2,3-dimethyl-7-(2-hydroxymethylbenzyloxy)-pyrrolo[2,3-d]pyridazin

■ 1 -Benzyl-2,3-dimethyl-7-(2-hydroxyethylbenzyloxy)-pyrrolo[2,3-d]pyridazin

■ 2,3-Dimethyl-1 -furfuryl-7-(2-hydroxymethylbenzyloxy)-pyrrolo[2,3-d]pyridazin X is either a bond or a linker,

Y is a radical

O A ^■ o^' whereby the carbonyl group is attached to A, z is a bond, -0-, -CHR1 - or -NR1 -, wherein

R1 is hydrogen or 1 -4C-alkyl, or X, Y and z together form a bond, and the salts of these compounds.

Some combinations of X, Y and z may be unfavourable as yielding one or more very labile bonds which are cleaved easily or spontaneously and therefore rendering the resulting compounds of the formula I less useful for application in medicaments. Especially, some combinations wherein X is a bond, may be unfavourable, for example if a bond is formed between two heteroatoms. The person skilled in the art is able to identify such unfavourable combinations due to his expert knowledge. Such an unfavourable combination is, for instance, when

X is a bond,

Y is the radical

and z is -O- or NR1 , yielding for example one of the following, presumably unstable fragments:

Possible salts of compounds of the formula I - depending on substitution - are especially all acid addition salts. Particular mention may be made of the pharmacologically tolerable salts of the inorganic and organic acids customarily used in pharmacy. Those suitable are water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)- benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, where the acids are used in salt preparation - depending on whether a mono- or polybasic acid is concerned and on which salt is desired - in an equimolar quantitative ratio or one differing therefrom.

Pharmacologically intolerable salts, which can initially be obtained, for example, as process products in the production of the compounds according to the invention on the industrial scale, are converted into the pharmacologically tolerable salts by processes known to the person skilled in the art.

The compounds of the formula I may have, depending on the residues A and B, and depending on the nature of X, Y and z, one or more centers of chirality in the skeleton. The invention thus provides all feasible stereoisomers in any mixing ratio, including the pure stereoisomers, which are a preferred subject matter of the invention.

It is known to the person skilled in the art that the compounds according to invention and their salts, if, for example, they are isolated in crystalline form, can contain various amounts of solvents. The invention therefore also comprises all solvates and in particular all hydrates of the compounds of the formula I, and also all solvates and in particular all hydrates of the salts of the compounds of the formula I.

Preferred are those compounds of the formula I, in which the compound of the formula Ma and/or the compound of the formula III are released under physiological conditions in the human or animal body.

Particularly preferred are those compounds of the formula I, in which the compound of the formula Na and the compound of the formula III are released under physiological conditions in the human or animal body.

The compounds of the formula I according to the invention are prodrugs and become pharmaceutically active if, under physiological conditions in the human or animal body, cleavage of these compounds of the formula I with concomitant release of the compounds of the formula Ma and/or the compounds of the formula III occurs. The cleavage can occur hydrolytically, for example under the influence of certain pH conditions, for example in an acidic environment, or under the influence of suitable enzymes present in the human or animal body, such as for example esterases.

The complete hydrolytical cleavage of the compounds of the formula I can lead, besides the pharmaceutically active compounds of the formula Na and/or III, to the release of a compound which comprises the linker X and, if present, further components of the compound of the formula I. Examplary compounds which can be released from the compounds of the formula I are those of the following formula IV:

Exemplary structure of compounds of the formula IV

As the compound of the formula IV, or related compounds, are released after complete hydrolytical cleavage in an equimolar ratio when compared to the compound of the formula Il and the compound of the formula III, this compound of the formula IV has to be a non-toxic compound when applied in doses according to the present invention.

Suitable linkers X which can be used for the present invention are known to the person skilled in the art or can be identified by a person skilled in the art due to his expert knowledge. If a linker is to be used according to the present invention, the person skilled in the art will take several considerations into account, such as for example the following: the linker should form two stable covalent bonds to both residues A and B in compounds of the formula I, which are resistant to cleavage under normal physiological conditions in the human and animal body encountered by the administered compound on its way to the target site, the linker should not confer such a steric hindrance on cleavage, that the pharmaceutically active compounds can not be released from the compounds of the formula I, different linkers may be required for different combinations of compounds of the formula Il and of the formula III, different linkers may be required if different diseases or conditions are to be treated with compounds of the formula I, different linkers will regulate the release of the compounds of the formula Il and of the formula III by facilitating or delaying the cleavage from compounds of the formula I, the compound of the formula IV which is released after hydrolytical cleavage of the compounds of the formula I should be a non-toxic compound when applied in doses according to the invention.

According to the present invention, the linker X is a divalent radical.

Preferably, the linker X is a linear or branched, saturated or unsaturated hydrocarbon chain, optionally forming one or more (e.g. 1 , 2 or 3) hydrocarbon cycles of 3 to 7 ring members, whereby the hydrocar- bon chain has 1 to 21 carbon atoms, wherein one or more (e.g. 1 , 2, 3 or 4) of the carbon atoms with its two substituents is optionally replaced by oxygen (-0-), and wherein the chain is optionally substituted on carbon with one or more (e.g. 1 , 2, 3 or 4) substituents selected from 1 -4C-alkoxy, 1 -4C-alkoxy-1 -4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkylalkyl, 1 -4C-alkylcarbonyl, 1 -4C- alkylcarbonyloxy, 1 -4C-alkoxycarbonyl, 1 -4C-alkylthio, azido, amino, cyano, nitro, halogen, hydroxy, oxo (=0), carboxy, aryl, aryloxy, heteroaryl and heteroaryloxy.

In a special embodiment (embodiment Oa) of the invention, which is to be mentioned, X is a linker of the formula -(CH₂)_n-(O)_m-(CH₂)_p-(O)_q-(CH₂)_r, wherein n is an integer from 1 to 7, m is either 0 or 1 , p is an integer from 0 to 7, q is either 0 or 1 and r is an integer from 0 to 7, wherein, optionally, one or more of the hydrogen atoms in the -CH₂- radicals is substituted by a fluoro, 1 -4C-alkyl or fluoro-1 -4C-alkyl radical, with the proviso that p is not 0 if m is 1 , and r is not 0 if q is 1.

In another special embodiment (embodiment Ob) of the invention which is to be particularly emphasized, X is a linker of the formula -(CH₂)_n-, wherein n is an integer from 1 to 7.

In another special embodiment (embodiment Oc) of the invention which is to be particularly emphasized, X is a linker of the formula -(CH₂)₂-O-(CH₂)₂-O-CH₂- or -(CH₂)₂-O-CH₂-.

1 -4C-Alkyl represents straight-chain or branched alkyl radicals having 1 to 4 carbon atoms. Examples which may be mentioned are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and the methyl radical.

Fluoro-1 -4C-alkyl represents one of the aforementioned 1 -4C-alkyl radicals, which is substituted by one or more fluorine atoms. An example which may be mentioned is the trifluoromethyl radical.

1 -4C-Alkoxy represents radicals, which in addition to the oxygen atom contain a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy and preferably the ethoxy and methoxy radical.

1 -4C-Alkoxy-1 -4C-alkyl represents one of the aforementioned 1 -4C-alkyl radicals, which is substituted by one of the aforementioned 1 -4C-alkoxy radicals. Examples which may be mentioned are the meth- oxymethyl, the methoxyethyl radical and the butoxyethyl radical. 3-7C-Cycloalkyl represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, of which cyclopropyl, cyclobutyl and cyclopentyl are preferred.

3-7C-Cycloalkyl-1 -4C-alkyl represents one of the aforementioned 1 -4C-alkyl radicals, which is substituted by one of the aforementioned 3-7C-cycloalkyl radicals. Examples which may be mentioned are the cyclopropylmethyl, the cyclohexylmethyl and the cyclohexylethyl radical.

1 -4C-Alkylcarbonyl represents a radical, which in addition to the carbonyl group contains one of the aforementioned 1 -4C-alkyl radicals. An example which may be mentioned is the acetyl radical.

1 -4C-Alkylcarbonyloxy represents a 1 -4C-alkylcarbonyl group which is bonded to an oxygen atom. An example which may be mentioned is the acetoxy radical (CH₃CO-O-).

1 -4C-Alkoxycarbonyl represents a carbonyl group, to which one of the aforementioned 1 -4C-alkoxy radicals is bonded. Examples which may be mentioned are the methoxycarbonyl (CH₃O-C(O)-) and the ethoxycarbonyl radical (CH₃CH₂O-C(O)-) .

Halogen within the meaning of the invention is bromo, chloro and fluoro.

Aryl is is a mono- or bicyclic aromatic residue, which is selected from phenyl or naphthyl optionally substituted by one, two or three identical or different substituents from the group consisting of 1 -4C- alkyl, 1 -4C-alkoxy, carboxyl, 1 -4C-alkoxycarbonyl, halogen, fluoro-1 -4C-alkyl, nitro, trifluoromethoxy, hydroxyl and cyano.

Heteroaryl is a mono- or bicyclic aromatic residue, which is selected from pyrrolyl, pyrazolyl, imidazolyl, 1 ,2,3-triazolyl, indolyl, benzimidazolyl, furanyl (furyl), benzofuranyl (benzofuryl), thiophenyl (thienyl), benzothiophenyl (benzothienyl), thiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, quinolinyl and isoquinolinyl optionally substituted by one, two or three identical or different substituents from the group consisting of 1 -4C-alkyl, 1 -4C-alkoxy, carboxyl, 1 -4C-alkoxycarbonyl, halogen, fluoro-1 -4C-alkyl, nitro, trifluoromethoxy, hydroxyl and cyano.

The compound of the formula Na with antipyretic, analgesic, antiphlogistic and/or anti-inflammatory properties preferably is a compound belonging to the class of NSAID's (non-steroidal antiinflammatory drugs).

The term NSAID according to the present invention is to be understood to comprise compounds which inhibit one or more of the cyclooxygenase isomers C0X1 (cyclooxygenase 1 ), C0X2 (cyclooxygenase 2) or COX 3 (cyclooxygenase 3).

The residue A in compounds of the formula I is derived from carboxylic acids of the formula Na with antipyretic, analgesic, antiphlogistic and/or anti-inflammatory properties, which compounds of the for- mula Na can belong to different chemical classes of NSAID^'s. These different chemical classes of NSAID^'s are known to a person skilled in the art. Therefore any compound of formula Na with antipyretic, analgesic, antiphlogistic and/or anti-inflammatory properties can be used according to the present invention.

The currently preferred embodiments according to the invention are outlined in more detail below. However, any compound with NSAID activity which is presently known or those that will be available in the future and which can be incorporated into the compounds of the formula I are included within the scope and concept of the present invention.

Classes of NSAID^'s which can be used according to the present invention include, but are not limited to, inter alia aryl or heteroaryl acetic acid derivatives, aryl or heteroaryl propionic acid derivatives, aryl or heteroaryl butyric acid derivatives, aryl or heteroaryl carboxylic acid derivatives, aminoaryl or ami- noheteroaryl carboxylic acid derivatives, anthranilic acid derivatives and salicylic acid derivatives. These classes of NSAID^'s are known to a person skilled in the art.

Exemplary NSAID^'s of the formula Na within the meaning of the present invention are for example those NAIDS^'s listed in the following List A1 a: glycolic acid [o-(2,6-dichloroanilino)phenyl]acetate(ester) [INN: ACECLOFENAC]; i -^-chlorobenzoyO-δ-methoxy^-methyl-I H-indole-S-acetic acid carboxymethyl ester [INN:

ACEMETACIN];

2-(acetyloxy)benzoic acid [AC ETYLSALI CYLI C ACID],

2-(4-acetamidophenyl)acetic acid [INN: ACTARIT], butanedioic acid, mono[4-[[1 -[[3,5-bis(1 ,1 -dimethylethyl)-4-hydroxyphenyl]thio]-1 -methylethyl]thio]-

2,6-bis(1 ,1 -dimethylethyl)phenyl] ester [Research Code: AGI-1067]

(6aR,10aR)-3-(1 ,1 -dimethylheptyl)-1 -hydroxy-6,6-dimethyl-6a,7,10,10a-tetrahydro-6H- benzo[c]chromene-9-carboxylic acid [INN: AJULEMIC ACID], (4-allyloxy-3-chlorophenyl)acetic acid [INN: ALCLOFENAC],

2-amino-3-benzoylphenylacetic acid [INN: AMFENAC],

2-[(1 -benzyl-1 H-indazol-3-yl)methoxy]-2-methylpropionic acid [INN: BINDARIT],

[2-amino-3-(p-bromobenzoyl)phenyl]acetic acid [INN: BROMFENAC],

2-mercapto-2-methylpropanoyl-L-cysteine [INN: BUCILLAMINE],

3-(3-chloro-4-cyclohexylbenzoyl)propionic acid [INN: BUCLOXIC ACID], butylmalonic acid mono(1 ,2-diphenylhydrazide) [INN: BUMADIZONE], alpha-ethyl-4-(2-methylpropyl)benzeneacetic acid [INN: BUTIBUFEN],

2-(4-biphenylyl)butyric acid, trans-4-phenylcyclohexylamine salt (1 :1 ) [INN: BUTIXIRATE],

2-amino-3-[(carboxymethyl)thio]propionic acid [INN: CARBOCISTEINE]

(plus/minus)-6-chloro-alpha-methylcarbazole-2-acetic acid [INN: CARPROFEN], i -cinnamoyl-δ-methoxy^-methylindole-S-acetic acid [INN: CINMETACIN],

6-chloro-5-cyclohexyl-1 -indancarboxylic acid [INN: CLIDANAC],

2-[4-(p-chlorophenyl)benzyloxy]-2-methylpropionic acid [INN: CLOBUZARIT], (S)-(+)-p-isobutylhydratropic acid [INN: DEXIBUPROFEN], (+)-(S)-m-benzoylhydratropic acid [INN: DEXKETOPROFEN], i ^-diacetoxyanthraquinone-S-carboxylic acid [INN: DIACEREIN], 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC], 2',4'-Difluoro-4-hydroxy-3-biphenylcarboxylic acid [INN: DIFLUNISAL], 4-(2,6-dichloroanilino)-3-thiopheneacetic acid [INN: ELTENAC], N-beta-phenethyl-anthranilic acid [INN: ENFENAMIC ACID] 1 ,8-diethyl-1 ,3,4,9-tetrahydropyrano[3,4-b]indole-1 -acetic acid [INN: ETODOLAC], 4-biphenylacetic acid [INN: FELBINAC], 3-(4-biphenylylcarbonyl)propionic acid [INN: FENBUFEN], [o-(2,4-dichlorophenoxy)phenyl]acetic acid [INN: FENCLOFENAC], 5-(4,5-dihydro-2-phenyl-3H-benz[e]indol-3-yl)salicylic acid [INN: FENDOSAL] (plus/minus)-m-phenoxyhydratropic acid [INN: FENOPROFEN], 4-(p-chlorophenyl)-2-phenyl-5-thiazoleacetic acid [INN: FENTIAZAC], 4-(2',4'-difluorobiphenylyl)-4-oxo-2-methylbutanoic acid [INN: FLOBUFEN], N-(alpha,alpha,alpha-trifluoro-m-tolyl)anthranilic acid [INN: FLUFENAMIC ACID], (plus)-2-(p-fluorophenyl)-alpha-methyl-5-benzoxazoleacetic acid [INN: FLUNOXAPROFEN], 2-(2-fluoro-1 ,1 '-biphenyl-4-yl)propanoic acid [INN: FLURBIPROFEN], (2S)-2-(2-fluoro-1 ,1 '-biphenyl-4-yl)propanoic acid [INN: ESFLURBIPROFEN] 2-[4-(2'-furoyl)phenyl]propionic acid [INN: FURPROFEN], (p-isobutylphenyl)acetic acid [INN: IBUFENAC], alpha-p-isobutylphenylpropionic acid [INN: IBUPROFEN], (plus/minus)-2-[p-(1 -oxo-2-isoindolinyl)phenyl]butyric acid [INN: INDOBUFEN], 1 -(4-chlorobenzoyl)-5-methoxy-2-methyl-1 H-indole-3-acetic acid [INN: INDOMETACIN], p-(1 -oxo-2-isoindolinyl)hydratropic acid [INN: INDOPROFEN],

2-[8-chloro-2-(trifluoromethyl)-1 ,2,3,4-tetrahydroquinolin 6-yl]acetic acid [Research Code: IRA- 378],

2-(10-methoxy-4H-benzo[4,5]cyclohepta[1 ,2-b]thiophen-4-ylidene)-acetic acid [Research Code: IX- 207-887], m-benzoylhydratropic acid [INN: KETOPROFEN],

(DL)-5-benzoyl-3H-1 ,2-dihydropyrrolo[1 ,2-a]pyrrole-1 -carboxylic acid [INN: KETOROLAC], (2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1 H-pyrrolizin-5-yl)-acetic acid [INN : Ll- COFELONE]],

N-(2-carboxyphenyl)-4-chloroanthranilic acid [INN: LOBENZARIT], 3-(p-chlorophenyl)-1 -phenylpyrazole-4-acetic acid [INN: LONAZOLAC], 2-[4-(2-oxocyclopentan-1 -ylmethyl)phenyl]-propionate [INN: LOXOPROFEN], 2-[2-(2-chloro-6-fluorophenylamino)-5-methylphenyl]acetic acid [INN: LUMIRACOXIB], N-(2,6-dichloro-m-tolyl)anthranilic acid [INN: MECLOFENAMIC ACID] N-(2,3-xylyl)anthranilic acid [INN: MEFENAMIC ACID], 5-aminosalicylic acid [INN: MESALAZINE], 3,4-bis(4-methoxyphenyl)-5-isoxazoleacetic acid [INN: MOFEZOLAC], (plus)-6-methoxy-alpha-methyl-2-naphthalineacetic acid [INN: NAPROXEN],

2-[3-(trifluoromethyl)anilino]nicotinic acid [INN: NIFLUMIC ACID],

5,5'-azodisalicylic acid [INN: OLSALAZINE],

4,5-diphenyl-2-oxazolepropionic acid [INN: OXAPROZIN],

4-aminosalicylic acid [INN: PAS],

3-chloro-4-(3-pyrrolin-1 -yl)hydratropic acid [INN: PIRPROFEN],

2-[5H-(1 )benzopyrano]2,3-b]pyridin-7-yl]propionic acid [INN: PRANOPROFEN],

7-methoxy-alpha,10-dimethylphenothiazine-2-acetic acid [INN: PROTIZINIC] ACID],

2-[[2-(p-chlorophenyl)-4-methyl-5-oxazolyl]methoxy]-2-methylpropionic acid [INN: ROMAZARIT],

2-hydroxybenzoic acid [SALICYLIC ACID],

2-hydroxybenzoic acid 2-carboxyphenyl ester [INN: SALSALATE],

(Z)-5-fluoro-2-methyl-1 -[p-(methylsulfinyl)benzylidene]indene-3-acetic acid [INN: SULINDAC], p-2-thenoylhydratropic acid [INN: SUPROFEN], butanedioic acid mono[(4-butyl-3,5-dioxo-1 ,2-diphenyl-4-pyrazolidinyl)-methyl]ester [INN: SUXIBU-

ZONE],

2-thiophenecarboxylic acid, ester with salicylic acid [INN: TENOSAL], alpha-(5-benzoyl-2-thienyl)propionic acid [INN: TIAPROFENIC ACID],

N-(3-chloro-o-tolyl)anthranilic acid [INN: TOLFENAMIC ACID],

1 -methyl-5-(4-methylbenzoyl)-1 H-pyrrole-2-acetic acid [INN: TOLMETIN],

2-carboxy-2-phenylethylester(plus/minus)-2-carboxy-2-phenylethyl 1 -(4-chloro benzoyl)-5- methoxy-2-methyl-1 H-indole-3-acetate [INN: TROPESIN],

2-(10,11 -dihydro-10-oxo-dibenz[b,f]thiepin-2-yl-propionic acid [INN: ZALTOPROFEN].

Exemplary NSAIDs according to the present invention which are to be emphasized are: ACETYL- SALICYLIC ACID, DICLOFENAC, DIFLUNISAL, ELTENAC, ETODOLAC, FENOPROFEN, FLURBIPROFEN, ESFLURBIPROFEN, IBUPROFEN, INDOMETHACIN, KETOPROFEN, LUMIRACOXIB, MEFENAMIC ACID, NAPROXEN, OXAPROZIN, SALICYLIC ACID, SULINDAC, TIAPROFENIC ACID and TOLMETIN, as well as the pharmaceutically acceptable derivatives of these compounds.

In an alternative embodiment, exemplary NSAIDs according to the present invention which are to be emphasized are: ACETYLSALICYLIC ACID, DICLOFENAC, DIFLUNISAL, ELTENAC, ETODOLAC, FENOPROFEN, FLURBIPROFEN, ESFLURBIPROFEN, IBUPROFEN, INDOMETHACIN, KETOPROFEN, LUMIRACOXIB, MEFENAMIC ACID, NAPROXEN, OXAPROZIN, SALICYLIC ACID, SULINDAC, TIAPROFENIC ACID and TOLMETIN, as well as the pharmaceutically acceptable derivatives of these compounds.

Preferred exemplary NSAIDs according to the present invention which are selected from the above- defined group of exemplary NSAIDs, are, DICLOFENAC, ELTENAC, FLURBIPROFEN, ESFLURBIPROFEN, IBUPROFEN, INDOMETACIN, LUMIRACOXIB and NAPROXEN, SALICYLIC ACID as well as the pharmaceutically acceptable derivatives of these compounds. In an alternative embodiment, preferred exemplary NSAIDs according to the present invention, which are selected from the above-defined group of exemplary NSAIDs, are DICLOFENAC, ELTENAC, FLURBIPROFEN, ESFLURBIPROFEN, IBUPROFEN, I N DOM ETACI N, LUMIRACOXIB and NAPROXEN, SALICYLIC ACID as well as the pharmaceutically acceptable derivatives of these compounds.

In an alternative embodiment, preferred exemplary NSAIDs according to the present invention, are DICLOFENAC, ELTENAC, FLURBIPROFEN, ESFLURBIPROFEN ,SALICYLIC ACID, NAPROXEN and INDOMETACIN, as well as the pharmaceutically acceptable derivatives of these compounds.

In an alternative embodiment, preferred exemplary NSAIDs according to the present invention, are those NSAIDs which were used in the examples of the present invention, as well as the pharmaceutically acceptable derivatives of these compounds.

The residue A, which is derived from a compound of the formula Ma according to the present invention is to be understood as to be the residue A which is attached to the carboxylic acid functionality of the compound of the formula Ma. For illustration by way of example, the residue A and the resulting compound of the formula I which are derived from DICLOFENAC, are shown in scheme A1. If the carboxylic acid of the formula Ma comprises more than one carboxylic acid functionality and if the residues A which are attached to functional groups are of a different chemical structure, all the different residues A can be used according to the present invention. This case is shown by way of example in scheme A for CARBOCISTEINE.

Scheme A1 :

Residue A derived Compound of the Formula I wherein from Diclofenac A is derived from Diclofenac

I wherein

Second residue A derived Second Compound of the Formula I from Carbocisteine wherein A is derived from Carbocisteine

The hydroxy compound of the formula III is a compound from the class of potassium competitive acid blockers (P-CAB^'s) which binds reversibly to the H+/K+-ATPase and thus inhibits gastric acid secretion. Compounds of different chemical classes, such as for example imidazopyridine, benzimidazole, quinazoline or pyrrolopyridazine derivatives are known in the art to act as P-CAB^'s, for example from those patent applications mentioned in the known technical background, without being limited to these patent applications or to the chemical classes mentioned in these patent applications.

The residue B in compounds of the formula I is derived from hydroxyl compounds of the formula III which is a compound from the class of potassium competitive acid blockers, which compounds of the formula III can belong to different chemical classes of P-CAB^'s. These different chemical classes of P- CAB^'s are known to a person skilled in the art.

The currently preferred embodiments according to the invention are outlined in more detail below.

Exemplary P-CAB^'s of the formula III within the meaning of the present invention are, in a further embodiment (embodiment 2) according to the present invention, all those P-CAB^'s listed in the following lists B1 , B2 or B3.

Another special embodiment of the invention (embodiment 2) relates to compounds of the formula I, wherein B is the residue derived from a hydroxy compound of the formula III which are disclosed in the International Patent Applications WO 98/42707, WO 98/54188, WO 00/17200, WO 00/26217, WO 00/63211 , WO 01/72754, WO 01/72756, WO 0172755, WO 0172757, WO 0234749, WO 03014120, WO 03014123, WO 03016310, WO 03/068774, WO 03091253, WO 04/054984, WO 04/087701 , WO 04/046144, WO 04/054984, WO 91/17164, WO 93/08190 and WO 92/06979. The exemplary compounds described in these patent applications are a preferred embodiment of embodiment 2.

Compounds of the formula I according to embodiment 2 are those compounds of the formula I, wherein B is the residue derived from one of the following exemplary hydroxy compounds of the formula III (List B1 ):

■ (7R,8R,9R)-2,3-dimethyl-7,8-dihydroxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2- h][1 ,7]naphthyridine,

■ (7S,8R,9R)-7,8-dihydroxy-3-hydroxymethyl-2-methyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2- h][1 ,7]naphthyridine,

■ (7R,8R,9R)-7,8-dihydroxy-2,3-dimethyl-9-phenyl-7H-8,9-dihydropyrano[2,3-c]imidazo[1 ,2- a]pyridine,

^■ (7R,8R,9R)-2,3-dimethyl-8-hydroxy-7-methoxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2- h][1 ,7]naphthyridine,

■ (7S,8S,9S)-2,3-dimethyl-8-hydroxy-7-methoxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2- h][1 ,7]naphthyridine,

■ (7S,8R,9R)-2,3-dimethyl-8-hydroxy-7-methoxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2- h][1 ,7]naphthyridine,

^■ (7R,8S,9S)-2,3-dimethyl-8-hydroxy-7-methoxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2- h][1 ,7]naphthyridine,

■ (7R,8R,9R)-2,3-dimethyl-7-ethoxy-8-hydroxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2- h][1 ,7]naphthyridine,

■ (7S,8R,9R)-2,3-dimethyl-7-ethoxy-8-hydroxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2- h][1 ,7]naphthyridine,

^■ (7R,8R,9R)-2,3-dimethyl-8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10- tetrahydroimidazo[1 ,2-h][1 ,7]naphthyridine (SORAPRAZAN),

^■ (7S,8S,9S)-2,3-dimethyl-8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10- tetrahydroimidazo[1 ,2-h][1 ,7]naphthyridine,

^■ (7S,8R,9R)-2,3-dimethyl-8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10- tetrahydroimidazo[1 ,2-h][1 ,7]naphthyridine,

^■ (7R,8S,9S)-2,3-dimethyl-8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10- tetrahydroimidazo[1 ,2-h][1 ,7]naphthyridine,

^■ (7S,8R,9R)-2,3-dimethyl-8-hydroxy-9-phenyl-7-(2-propoxy)-7,8,9,10-tetrahydroimidazo[1 ,2- h][1 ,7]naphthyridine,

^■ (7R,8R,9R)-2,3-dimethyl-8-hydroxy-7-(2-methylthioethyloxy)-9-phenyl-7,8,9,10- tetrahydroimidazo[1 ,2-h][1 ,7]naphthyridine,

^■ (7S,8R,9R)-2,3-dimethyl-8-hydroxy-7-(2-methylthioethyloxy)-9-phenyl-7,8,9,10- tetrahydroimidazo[1 ,2-h][1 ,7]naphthyridine, ^■ (7R,8R,9R)-2,3-dimethyl-8-hydroxy-7-(2-methylsulphinylethoxy)-9-phenyl-7,8,9,10-tetrahydro- imidazo[1 ,2-h][1 ,7]naphthyridine,

^■ (7S,8R,9R)-2,3-dimethyl-8-hydroxy-7-(2-methylsulphinylethoxy)-9-phenyl-7,8,9,10-tetrahydro- imidazo[1 ,2-h][1 ,7]naphthyridine,

^■ (7R,8R,9R)-2,3-dimethyl-8-hydroxy-7-(2-propoxy)-9-phenyl-7H-8,9-dihydropyrano[2,3- c]imidazo[1 ,2-a]pyridine, ^■ (7S,8R,9R)-2,3-dimethyl-8-hydroxy-7-(2-propoxy)-9-phenyl-7H-8,9-dihydropyrano[2,3- c]imidazo[1 ,2-a]pyridine,

^■ (7R,8R,9R)-7-butoxy-2,3-dimethyl-8-hydroxy-9-phenyl-7H-8,9-dihydropyrano[2,3- c]imidazo[1 ,2-a]pyridine,

^■ (7R,8R,9R)-8-hydroxy-7-methoxy-2-methyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2- h][1 ,7]naphthyridine, ■ (7S,8R,9R)-8-hydroxy-7-methoxy-2-methyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2- h][1 ,7]naphthyridine,

^■ (7R,8R,9R)-8-hydroxy-3-hydroxymethyl-7-(2-methoxyethoxy)-2-methyl-9-phenyl-7,8,9,10- tetrahydroimidazo[1 ,2-h][1 ,7]naphthyridine,

■ 8-(frans-2,3-Dihydro-2-hydroxy-1 -indenylamino)-6-(N-methylamino-carbonyl)-2,3-dimethyl- imidazo[1 ,2-a]pyridine ^■ 8-(frans-2,3-Dihydro-2-hydroxy-1 -indenylamino)-2,3-dimethyl-imidazo[1 ,2-a]pyridine-6- carboxamide

^■ 8-(frans-2,3-Dihydro-2-hydroxy-1 -indenyloxy)-2,3-dimethyl-imidazo[1 ,2-a]pyridine-6-carboxylic acid

^■ 4-(frans-2,3-Dihydro-2-hydroxy-1 -indenyloxy)-1 ,2-dimethyl-6-[(1 -pyrrolidino)carbonyl]-1 H- benzimidazole ■ 4-(frans-2,3-Dihydro-2-hydroxy-1 -indenyloxy)-6-[N-(2-methoxyethyl)-N-methyl-aminocarbonyl]- 1 ,2-dimethyl-1 /-/-benzimidazole

^■ 4-(frans-2,3-Dihydro-2-hydroxy-1 -indenyloxy)-1 ,2-dimethyl-6-[(1 -piperidino)carbonyl]-1 H- benzimidazole

■ 1 -Benzyl-2,3-dimethyl-7-(2-hydroxymethylbenzyloxy)-pyrrolo[2,3-d]pyridazin

■ 1 -Benzyl-2,3-dimethyl-7-(2-hydroxyethylbenzyloxy)-pyrrolo[2,3-d]pyridazin

■ 2,3-Dimethyl-1 -furfuryl-7-(2-hydroxymethylbenzyloxy)-pyrrolo[2,3-d]pyridazin as well as the pharmaceutically acceptable derivatives of these compounds.

An embodiment of the invention which is to be emphasized relates to those compounds of the formula I, wherein B is the residue derived from one of the following exemplary hydroxy compounds of the formula III (List B2):

■ (7R,8R,9R)-2,3-dimethyl-7-ethoxy-8-hydroxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2- h][1 ,7]naphthyridine, (7S,8R,9R)-2,3-dimethyl-8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10- tetrahydroimidazo[1 ,2-h][1 ,7]naphthyridine,

^■ (7S,8R,9R)-2,3-dimethyl-8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7H-8,9-dihydropyrano[2,3- c]imidazo[1 ,2-a]pyridine, ^■ (7R,8R,9R)-2,3-dimethyl-8-hydroxy-9-phenyl-7-(2,2,2-trifluoroethoxy)-7H-8,9-dihydropyrano- [2,3-c]imidazo[1 ,2-a]pyridine,

(7R,8R,9R)-2,3-dimethyl-7-ethoxy-8-hydroxy-9-phenyl-7H-8,9-dihydropyrano[2,3-c]imidazo- [1 ,2-a]pyridine,

^■ (7R,8R,9R)-3-chloro-8-hydroxy-7-(2-methoxyethoxy)-2-methyl-9-phenyl-7H-8,9- dihydropyrano-[2,3-c]-imidazo-[1 ,2-a]pyridine

■ 1 ,2-dimethyl-4-(2,6-dimethyl-benzylamino)-6-[N-(2-hydroxyethyl)aminocarbonyl]- 1 H- benzimidazole

■ 1 ,2-dimethyl-4-(2,6-dimethyl-benzylamino)-6-[N-(2-hydroxyethyl)-N-methyl-aminocarbonyl]- 1 H-benzimidazole

■ 8-(trans-2,3-Dihydro-2-hydroxy-1 -indenylamino)-6-(N,N-dimethylamino-carbonyl)-2,3-dimethyl- imidazo[1 ,2-a]pyridine

■ 8-(trans-2,3-Dihydro-2-hydroxy-1 -indenyloxy)-6-(N,N-dimethylamino-carbonyl)-2,3-dimethyl- imidazo[1 ,2-a]pyridine

■ 8-[(1 S,2S)-2,3-Dihydro-2-hydroxy-1 -indenyloxy)-6-(N,N-dimethylamino-carbonyl)-2,3-dimethyl- imidazo[1 ,2-a]pyridine.

■ 1 -Benzyl-2,3-dimethyl-7-(2-hydroxymethylbenzyloxy)-pyrrolo[2,3-d]pyridazin

■ 1 -Benzyl-2,3-dimethyl-7-(2-hydroxyethylbenzyloxy)-pyrrolo[2,3-d]pyridazin

An embodiment of the invention which is to be particularly emphasized, relates to those compounds of the formula I, wherein B is the residue derived from one of the following exemplary hydroxy compounds of the formula III (List B3):

(7R,8R,9R)-2,3-dimethyl-8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2- h][1 ,7]naphthyridine (SORAPRAZAN),

(7S,8R,9R)-2,3-dimethyl-8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2- h][1 ,7]naphthyridine, (7R,8R,9R)-8-hydroxy-7-(2-methoxyethoxy)-2-methyl-9-phenyl-7,8,9,10-tetrahydroιmιdazo[1 ,2- h][1 ,7]naphthyπdιne,

(7R,8R,9R)-3-chloro-8-hydroxy-7-(2-methoxyethoxy)-2-methyl-9-phenyl-7H-8,9-dιhydropyrano-[2,3- c]-ιmιdazo-[1 ,2-a]pyrιdιne,

(7R,8R,9R)-2,3-dιmethyl-8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7H-8,9-dιhydropyrano[2,3-c]- ιmιdazo[1 ,2-a]pyrιdιne,

1 -Benzyl-7-(4-fluorbenzyloxy)-3-hydroxymethyl-2-methyl-pyrrolo[2,3-d]pyrιdazιn, 1 -Benzyl-2,3-dιmethyl-7-(2-hydroxymethylbenzyloxy)-pyrrolo[2,3-d]pyrιdazιn, as well as the pharmaceutically acceptable derivatives of these compounds.

In an alternative embodiment, preferred exemplary P-CABs according to embodiment 2, are those P- CABs which were used in the examples of the present invention, as well as the pharmaceutically acceptable derivatives of these compounds.

The residue B, which is derived from a corresponding hydroxy compound of the formula III according to the present invention is to be understood as to be the residue B which is attached to the hydroxyl functionality of the compound of the formula III. For illustration by way of example, the residue B and the resulting compound of the formula I which are derived from SORAPRAZAN, are shown in scheme B. If the hydroxy compound of the formula III comprises more than one hydroxyl functionality, and if the residues B which are attached to these hydroxyl functionalities are of a different chemical structure, all the different residues B can be used according to the present invention. This case is shown by way of example in scheme B for (7R, 8R, 9R)-8-hydroxy-3-hydroxymethyl-7-(2-methoxyethoxy)-2-methyl- 9phenyl-7,8,9,10-tetrahydroιmιdazo[1 ,2-h][1 ,7]naphthyrιdιne. Scheme B:

Soraprazan Residue B derived Compound of the Formula I wherein from Soraprazan B is derived from Soraprazan

Second residue B Second compound of the Formula I

Particularly preferred are the compounds given as final products of formula I in the examples, and the salts of these compounds

The invention particularly relates to compounds of the formula I

A-^Y-X-^z

O in which

A is the residue derived from a corresponding carboxylic acid of the formula Ma,

O

Ha which carboxylic acid of the formula Ma is a compound with antipyretic, analgesic, antiphlogistic and/or anti-inflammatory properties,

B is the residue derived from an exemplary hydroxy compound listed in list B1 ,

X is either a bond or a linker,

Y is a radical

whereby the carbonyl group is attached to A, is a bond, -0-, -CHR1 - or -NR1 -, wherein R1 is hydrogen or 1 -4C-alkyl, or X, Y and z together form a bond, and the salts of these compounds.

The invention particularly also relates to compounds of the formula I

in which

A^^O^{^H} Ha which carboxylic acid of the formula Ma is a compound with antipyretic, analgesic, antiphlogistic and/or anti-inflammatory properties,

B is the residue derived from a exemplary hydroxy compound listed in list B2,

X is either a bond or a linker,

Y is a radical

whereby the carbonyl group is attached to A, z is a bond, -O-, -CHR1 - or -NR1 -, wherein

The invention particularly also relates to compounds of the formula I

I ° in which

B is the residue derived from a exemplary hydroxy compound listed in list B3,

X is either a bond or a linker,

Y is a radical

whereby the carbonyl group is attached to A, z is a bond, -0-, -CHR1 - or -NR1 -, wherein

A further aspect of the invention relates to compounds of the formula 1 , wherein

A is the residue derived from an exemplary carboxylic acid listed in list A1 a,

B is the residue derived from an exemplary hydroxy compound listed in list B1 ,

X is either a bond or a linker,

Y and z are as defined in the outset, and the salts of these compounds.

A is the residue derived from an exemplary carboxylic acid listed in list A1 a,

B is the residue derived from an exemplary hydroxy compound listed in list B1 ,

X is as defined in embodiment Oa,

Y and z are as defined in the outset, and the salts of these compounds.

A is the residue derived from an exemplary carboxylic acid listed in list A1 a,

B is the residue derived from an exemplary hydroxy compound listed in list B1 ,

X is as defined in embodiment Ob,

Y and z are as defined in in the outset, and the salts of these compounds.

A is the residue derived from an exemplary carboxylic acid listed in list A1 a, B is the residue derived from an exemplary hydroxy compound listed in list B1 , X is as defined in embodiment Oc,

Y and z are as defined in in the outset, and the salts of these compounds.

A is the residue derived from an exemplary carboxylic acid listed in list A1 a,

B is the residue derived from an exemplary hydroxy compound listed in list B2,

X is a bond or a linker,

Y and z are as defined in the outset, and the salts of these compounds.

A is the residue derived from an exemplary carboxylic acid listed in list A1 a,

B is the residue derived from an exemplary hydroxy compound listed in list B2,

X is as defined in embodiment Oa,

Y and z are as defined in the outset, and the salts of these compounds.

A is the residue derived from an exemplary carboxylic acid listed in list A1 a,

B is the residue derived from an exemplary hydroxy compound listed in list B2,

X is as defined in embodiment Ob,

Y and z are as defined in the outset, and the salts of these compounds.

A is the residue derived from an exemplary carboxylic acid listed in list A1 a,

B is the residue derived from an exemplary hydroxy compound listed in list B2,

X is as defined in embodiment Oc,

Y and z are as defined in in the outset, and the salts of these compounds.

A further aspect of the invention relates to compounds of the formula 1 , wherein A is the residue derived from an exemplary carboxylic acid listed in list A1 a, B is the residue derived from an exemplary hydroxy compound listed in list B3, X is a bond or a linker,

Y and z are as defined in the outset, and the salts of these compounds.

A is the residue derived from an exemplary carboxylic acid listed in list A1 a,

B is the residue derived from an exemplary hydroxy compound listed in list B3,

X is as defined in embodiment Oa,

Y and z are as defined in the outset, and the salts of these compounds.

A is the residue derived from a exemplary carboxylic acid listed in list A1 a,

B is the residue derived from an exemplary hydroxy compound listed in list B3,

X is as defined in embodiment Ob,

Y and z are as defined in the outset, and the salts of these compounds.

A is the residue derived from an exemplary carboxylic acid listed in list A1 a,

B is the residue derived from an exemplary hydroxy compound listed in list B3,

X is as defined in embodiment Oc,

Y and z are as defined in in the outset, and the salts of these compounds.

Particular emphasis is given to compounds of the formula 1 , wherein

A is the residue derived from one of the following carboxylic acids:

DICLOFENAC,

ELTENAC,

FLURBIPROFEN,

ESFLURBIPROFEN

SALICYLIC ACID,

NAPROXEN or

INDOMETACIN, B is the residue derived from one of the following hydroxy compounds: (7R,8R,9R)-2,3-dimethyl-8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10- tetrahydroimidazo[1 ,2-h][1 ,7]naphthyridine (SORAPRAZAN),

(7S,8R,9R)-2,3-dimethyl-8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2- h][1 ,7]naphthyridine,

(7R,8R,9R)-8-hydroxy-7-(2-methoxyethoxy)-2-methyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2- h][1 ,7]naphthyridine,

(7R,8R,9R)-3-chloro-8-hydroxy-7-(2-methoxyethoxy)-2-methyl-9-phenyl-7H-8,9- dihydropyrano-[2,3-c]-imidazo-[1 ,2-a]pyridine or

(7R,8R,9R)-2,3-dimethyl-8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7H-8,9-dihydropyrano[2,3-c]- imidazo[1 ,2-a]pyridine,

1 -Benzyl-7-(4-fluorbenzyloxy)-3-hydroxymethyl-2-methyl-pyrrolo[2,3-d]pyridazin, 1 -Benzyl-2,3-dimethyl-7-(2-hydroxymethylbenzyloxy)-pyrrolo[2,3-d]pyridazin, X is a linker of the formula -(CH₂)_n-(O)_m-(CH₂)_p-(O)_q-(CH₂)_r, wherein n is an integer from 1 to 7, m is either 0 or 1 , p is an integer from 0 to 7, q is either 0 or 1 and r is an integer from 0 to 7, wherein, optionally, one or more of the hydrogen atoms in the -CH₂- radicals is substituted by a fluoro, 1 -4C-alkyl or fluoro-1 -4C-alkyl radical, with the proviso that p is not 0 if m is 1 , and r is not 0 if q is 1. Y is a radical

whereby the carbonyl group is attached to A, z is a bond, or X, Y and z together form a bond, and the salts of these compounds.

Particular emphasis is also given to compounds of the formula 1 , wherein

A is the residue derived from one of the following carboxylic acids:

DICLOFENAC,

ELTENAC,

FLURBIPROFEN,

ESFLURBIPROFEN

SALICYLIC ACID,

NAPROXEN or INDOMETACIN, B is the residue derived from one of the following hydroxy compounds:

(7R,8R,9R)-2,3-dimethyl-8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10- tetrahydroimidazo[1 ,2-h][1 ,7]naphthyridine (SORAPRAZAN),

1 -Benzyl-7-(4-fluorbenzyloxy)-3-hydroxymethyl-2-methyl-pyrrolo[2,3-d]pyridazin,

1 -Benzyl-2,3-dimethyl-7-(2-hydroxymethylbenzyloxy)-pyrrolo[2,3-d]pyridazin, X is a linker of the formula -(CH₂)_n-, wherein n is an integer from 1 to 7, or a linker of the formula

-(CH₂)₂-O-(CH₂)₂-O-CH₂- or a linker of the formula -(CH₂)₂-O-CH₂- Y is a radical

Particular emphasis is also given to compounds of the formula 1 , wherein

A is the residue derived from one of the following carboxylic acids:

DICLOFENAC,

ELTENAC,

SALICYLIC ACID,

NAPROXEN or

INDOMETACIN, B is the residue derived from one of the following hydroxy compounds:

(7R,8R,9R)-8-hydroxy-7-(2-methoxyethoxy)-2-methyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2- h][1 ,7]naphthyridine, (7R,8R,9R)-3-chloro-8-hydroxy-7-(2-methoxyethoxy)-2-methyl-9-phenyl-7H-8,9- dihydropyrano-[2,3-c]-imidazo-[1 ,2-a]pyridine or

X is a linker of the formula -(CH₂)_n-, wherein n is an integer from 1 to 7

Y is a radical

whereby the carbonyl group is attached to A, z is a bond or X, Y and z together form a bond, and the salts of these compounds.

The compounds according to the invention can be synthesized from corresponding starting compounds, for example according to the reaction schemes given below. The synthesis is carried out in a manner known to the expert, for example as described in more detail in the following examples. The starting compounds are known (for example from the patents or patent applications mentioned above) or they can be prepared in an analogous manner to the known compounds.

The compounds according to the invention can be prepared, for example, according to the following reaction schemes. The compounds of the general formula I, wherein X, Y and z together form a bond, can be obtained for example by reacting a carboxylic acid of the formula Ma with a hydroxyl compound of the formula III (as shown in scheme 1 ). The esterification can be performed using coupling technologies known per se (for example using acid activating agents like N,N-carbonyldiimidazole or dicyclohexylcarbodiimide in the presence of a base like, for example, 4-(N,N-dimethylamino)pyridine). Scheme 1 :

O O

A^^O^{^H} + ^{H^}o^{^B} *- A^^O^{^B}

"^a '" wherein X, Y and z together form a bond

Alternatively, in the case when X, Y and Z together do not form a bond, the linker -Y-X-Z-C(O)-O- can be coupled in a first step either with the compound of the formula Na or with the hydroxyl compound of the formula III by reaction with a linker precursor. In the next reaction step, the intermediate where either the compound of the formula Ma or the compound of the formula III is attached to the linker -Y-X- Z-C(O)-O-, can be coupled by methods known to the expert to the final compounds of the formula I.

The linker precursor is a compound of the general formula Lp1

L_P1 in which G1 a is a group which reacts with the carboxylic acid functionality in compounds of the formula Ma or an activated carboxylic acid analogue thereof, for example a carboxylic acid chloride, and G2 is a group which reacts with the hydroxyl functionality in compounds of the formula III. Each of these reactions leads to a covalent bond between the linker and its reaction partner.

Suitable groups G1 a and G2 are, depending on the coupling partner, radicals like for example halogen radicals or hydroxyl groups.

The coupling reactions of the linker precursor with the compounds of the formula Na and III again can be performed using coupling technologies known per se to a person skilled in the art, for example those mentioned above for esterification reactions when X, Y and z together form a bond.

Possible reaction schemes are shown by way of example in the following scheme 2, where the linker precursor is in an exemplary manner first reacted with the P-CAB of the formula III and the resulting intermediate is then coupled with the NSAID of the formula Ma, respectively. Alternative reaction sequences may be necessary to obtain certain compounds of the formula I. As an example, it may be necessary and/or advantageous that the linker precursor is first reacted with the NSAID of the formula Ma and the resulting intermediate is then reacted with the P-CAB of the formula III. The person skilled in the art is able to identify with his expert knowledge the most favourable scheme of synthesis for each individual compound according to the invention.

O ₊ ^Gla^γ^G2 "-x-ys, ^A "a^0H *VH,-~VS

O ~ o O O

III ■

If the synthesis of compounds of the formula I is performed, it may be necessary to temporarily protect one or more of the functional groups present in one or more of the reactants. Suitable protecting groups for these purposes are known to a person skilled in the art, for example from T.W. Greene, P. G. M. Wuts "Protective groups in organic Synthesis", 3^rd edition, J. Wiley & Sons, New York, 1999. The person skilled in the art is able to identify suitable protecting groups for the purposes according to the invention.

The isolation and purification of the substances according to the invention are carried out in a manner known per se, for example by distilling off the solvent in vacuo and recrystallizing the residue obtained from a suitable solvent or subjecting it to one of the customary purification methods, such as column chromatography on suitable support material. Salts are obtained by dissolving the free compounds of the formula I in suitable solvent, e.g. in a chlorinated hydrocarbon, such as dichloromethane or chloroform, or a low-molecular weight aliphatic alcohol (ethanol, isopropanol) which contains the desired acid, or to which the desired acid is then added. The salts are obtained by filtering, reprecipitating, precipitating with a non-solvent for the addition salt or by evaporating the solvent. Salts obtained can be converted by alkalization or by acidification into the free compounds of the formula I, from which salts can in turn be prepared. In this manner, pharmacologically non-tolerable salts can be converted into pharmacologically tolerable salts.

The examples below serve to illustrate the invention in more detail without limiting it. Further compounds of the formula 1 whose preparation is not described explicitly can likewise be prepared in an analogous manner or in a manner known per se to the person skilled in the art, using customary process techniques. The compounds named expressly as examples, and the salts of these compounds, are preferred subject matter of the invention. The abbreviation min stands for minute(s), h stands for hour(s), m.p. stands for melting point and ee for enantiomeric excess.

Examples Final products:

1. [2-(2,6-Dichlorophenylamino)-phenyl] acetic acid (7S,8R,9R)-2,3-dimethyl-7-(2- methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2-h][1 ,7]naphthyridine-8-yl ester

N,N-Carbonyldiimidazole (0.66 g, 4.08 mmol) is added in portions to the solution of [2-(2,6- dichlorophenylamino)-phenyl] acetic acid (1.20 g, 4.08 mmol) in dichloromethane (15 ml) at room temperature. After stirring at reflux for one hour (7S,8fl,9fl)-8-hydroxy-2,3-dimethyl-7-(2-methoxyethoxy)- 9-phenyl-7,8,9,10-tetrahydro-imidazo-[1 ,2-h][1 ,7]naphthyridin (1.00 g, 2.73 mmol) is added. The reaction mixture is refluxed for 5 h, poured onto water, and extracted three times with dichloromethane. The collected organic phases are washed with water, dried (MgSO₄), and the solvent is removed in vacuo. The oily residue is purified by column chromatography using silica gel (eluent: toluene/dioxane 4:1 ). 0.16 g of the title compound are obtained.

¹H-NMR (200 MHz, d₆-DMSO): δ =7.56-7.41 (m, 3H), 7.40-6.94 (m, 6H), 6.83-6.72 (m, 3H), 6.46 (d, 1 H), 6.25 (d, 1 H), 5.38 (dd, 1 H), 4.80 (dd, 1 H), 4.44 (d, 1 H), 4.32 (d, 1 H), 4.71 -4.48 (m, 2H), 4.42-3.30 (m, 2H), 3.16 (s, 3H), 2.36 (s, 3H), 2.29 (s, 3H).

2. [2-(2,6-Dichlorophenylamino)-phenyl] acetic acid (7ff,8ff,9ff)-2,3-dimethyl-7-(2- methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2-h][1 ,7]naphthyridine-8-yl ester

N,N,N',N'-Tetramethyl-O-(benzotriazol-1 -yl)uranium tetrafluoroborate (TBTU) (1.05 g, 3.26 mmol) is added in portions to the suspension of [2-(2,6-dichlorophenylamino)-phenyl] acetic acid (0.89 g, 2.99 mmol) in tetrahydrofuran (10 ml) at room temperature. After stirring at reflux for 30 min (7R,8R,9R)-8- hydroxy-2,3-dimethyl-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydro-imidazo-[1 ,2- h][1 ,7]naphthyridin (1.00 g, 2.72 mmol) is added. The reaction mixture is refluxed for 6 h, poured onto water, neutralized by adding a saturated NaHCO₃ solution (pH 8), and extracted three times with dichloromethane. The collected organic phases are washed with water, dried (MgSO₄), and the solvent is removed in vacuo. The oily residue is purified by column chromatography using silica gel (eluent: toluene/dioxane 9:1 ) and crystallized from isopropanol. 0.21 g of the title compound of melting point 100-123 °C are obtained.

3. [4-(2,6-Dichlorophenylamino)-thiophen-3-yl] acetic acid (7/?,8/?,9fi)-2,3-dimethyl-7-(2- methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2-h][1 ,7]naphthyridine-8-yl ester; salt with oxalic acid

N,N,N',N'-Tetramethyl-O-(benzotriazol-1 -yl)uranium tetrafluoroborate (TBTU) (0.53 g, 1.64 mmol) is added in portions to the solution of [4-(2,6-dichlorophenylamino)-thiophen-3-yl] acetic acid (0.45 g, 1.49 mmol) in dichloromethan (10 ml) at room temperature. After stirring at room temperature for 18 h (7R,8R,9R)-8-hydroxy-2,3-dimethyl-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydro-imidazo-[1 ,2- h][1 ,7]naphthyridin (0.50 g, 1.36 mmol) is added. The reaction mixture is refluxed for 3 h, poured onto water, neutralized by adding a saturated NaHCO₃ solution (pH 8), and extracted three times with di- chloromethane. The collected organic phases are washed with water, dried (MgSO₄), and the solvent is removed in vacuo. The oily residue is purified by column chromatography using silica gel (eluent: toluene/dioxane 4:1 ) and precipitated as salt of oxalic acid from isopropanol. 0.18 g of the title compound of melting point 177-179 °C (isopropanol) are obtained.

4. 2-Hydroxy-benzoic acid (7/?,8/?,9fl)-2,3-dimethyl-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10- tetrahydroimidazo[1 ,2-h][1 ,7]naphthyridine-8-yl ester

N,N-Carbonyldiimidazole (0.88 g, 5.44 mmol) is added in portions to the solution of 2-acetoxy benzoic acid (0.98 g, 5.44 mmol) in dichloromethane (15 ml) at room temperature. After stirring at reflux for one hour (7R,8R,9R)-8-hydroxy-2,3-dimethyl-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydro-imidazo- [1 ,2-h][1 ,7]naphthyridin (1 .00 g, 2.73 mmol) is added. The reaction mixture is refluxed for 6 h, poured onto water, neutralized by adding a saturated NaHCO₃ solution (pH 8), and extracted three times with dichloromethane. The collected organic phases are washed with water, dried (MgSO₄), and the solvent is removed in vacuo. The oily residue is purified by column chromatography using silica gel (eluent: toluene/dioxane 20:1 ) and crystallized from isopropanol. 0.33 g of the title compound are obtained. ¹H-NMR (200 MHz, d₆-DMSO): δ = 7.62 (dd, 1 H), 7.53-7.09 (m, 7H), 6.97-6.78 (m, 2H), 6.73 (d, 1 H), 6.59 (d, 1 H), 5.72 (t, 1 H), 4.95 (t, 1 H), 4.74 (d, 1 H), 3.65-3.48 (m, 1 H), 3.45-3.29 (m, 1 H), 3.15-2.94 (m, 5H), 2.37 (s, 3H), 2.31 (s, 3H).

5. [2-(2,6-Dichlorophenylamino)-phenyl] acetic acid (7/?,8/?,9fl)-7-(2-methoxyethoxy)-2-methyl-9- phenyl-7,8,9,10-tetrahydroimidazo[1 ,2-h][1 ,7]naphthyridine-8-yl ester; salt of oxalic acid

N,N,N',N'-Tetramethyl-O-(benzotriazol-1 -yl)uranium tetrafluoroborate (TBTU) (1.09 g, 3.40 mmol) is added in portions to the suspension of [2-(2,6-dichlorophenylamino)-phenyl] acetic acid (0.92 g, 3.11 mmol) in tetrahydrofuran (10 ml) at room temperature. After stirring at reflux for 30 min (7R,8R,9R)-8- hydroxy-7-(2-methoxyethoxy)-2-methyl-9-phenyl-7,8,9,10-tetrahydro-imidazo-[1 ,2-h][1 ,7]naphthyridin (1.00 g, 2.83 mmol) is added. The reaction mixture is refluxed for 6 h, stirred at room temperature for 18 h, poured onto water, neutralized by adding a saturated NaHCO₃ solution (pH 8), and extracted three times with dichloromethane. The collected organic phases are washed with water, dried (MgSO₄), and the solvent is removed in vacuo. The oily residue is purified by column chromatography using silica gel (eluent: toluene/dioxane 9:1 ) and precipitated as salt of oxalic acid from isopropanol. 0.18 g of the title compound of melting point 139-149 °C are obtained.

6. [4-(2,6-Dichlorophenylamino)-thiophen-3-yl] acetic acid (7/?,8/?,9fl)-7-(2-methoxyethoxy)-2- methyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2-h][1 ,7]naphthyridine-8-yl ester N,N,N',N'-Tetramethyl-O-(benzotriazol-1 -yl)uranium tetrafluoroborate (TBTU) (1.09 g, 3.40 mmol) is added in portions to the suspension of [4-(2,6-dichlorophenylamino)-thiophen-3-yl] acetic acid (0.94 g, 3.11 mmol) in tetrahydrofuran (10 ml) at room temperature. After stirring at reflux for one hour (7R,8R,9R)-8-hydroxy-7-(2-methoxyethoxy)-2-methyl-9-phenyl-7,8,9,10-tetrahydro-imidazo-[1 ,2- h][1 ,7]naphthyridin (1.00 g, 2.83 mmol) is added. The reaction mixture is refluxed for 5 h, stirred at room temperature for 18 h, poured onto water, neutralized by adding a saturated NaHCO₃ solution (pH 8), and extracted three times with dichloromethane. The collected organic phases are washed with water, dried (MgSO₄), and the solvent is removed in vacuo. The oily residue is purified by column chromatography using silica gel (eluent: toluene/dioxane 9:1 ) and crystallized from isopropanol. 0.84 g of the title compound of melting point 73-81 °C (isopropanol) are obtained.

7. 2-Hydroxy-benzoic acid (7/?,8/?,9fl)-7-(2-methoxyethoxy)-2-methyl-9-phenyl-7,8,9,10- tetrahydroimidazo[1 ,2-h][1 ,7]naphthyridine-8-yl ester

N,N-Carbonyldiimidazole (0.92 g, 5.66 mmol) is added in portions to the solution of 2-acetoxy benzoic acid (1.02 g, 5.66 mmol) in dichloromethane (15 ml) at room temperature. After stirring at reflux for one hour (7R,8R,9R)-8-hydroxy-7-(2-methoxyethoxy)-2-methyl-9-phenyl-7,8,9,10-tetrahydro-imidazo-[1 ,2- h][1 ,7]naphthyridin (1.00 g, 2.83 mmol) is added. The reaction mixture is refluxed for 6 h, poured onto water, and extracted three times with dichloromethane. The collected organic phases are washed with water, dried (MgSO₄), and the solvent is removed in vacuo. The oily residue is purified by column chromatography using silica gel (eluent: toluene/dioxane 9:1 ). 0.23 g of the title compound are obtained.

¹H-NMR (200 MHz, d₆-DMSO): δ = 10.24 (s, 1 H), 7.79 (d, 1 H), 7.65-7.12 (m, 8H), 6.98-6.81 (m, 2H), 6.66 (d, 1 H), 6.60 (d, 1 H), 5.72 (t, 1 H), 5.00-4.91 (m, 1 H), 7.73 (d, 1 H), 3.65-3.51 (m, 1 H), 3.45-3.31 (m, 1 H), 3.19-3.01 (m, 5H), 2.33 (s, 3H).

8. (R)-2-(6-Methoxynaphthalen-2-yl)propionic acid (7/?,8/?,9ff)-2,3-dimethyl-7-(2-methoxyethoxy)- 9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2-h][1 ,7]naphthyridine-8-yl ester hydrochloride

4-(N,N-Dimethylamino)pyridin (DMAP) (1.50 g, 12.24 mmol) is added in portions to the solution of (S)- 2-(6-methoxynaphthalen-2-yl) propionic acid (1.04 g, 4.49 mmol) and (7R,8R,9R)-2,3-dimethyl-8- hydroxy-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2-h][1 ,7]naphthyridine (1.50 g, 4.40 mmol) in tetrahydrofuran (25 ml) at room temperature. The solution of toluene sulfonyl chloride (1.01 g, 5.30 mmol) in tetrahydrofuran (5 ml) is added. The resulting suspension is stirred at room temperature for 60 min, poured onto water, neutralized by adding a saturated NaHCO₃ solution (pH 8), and extracted three times with dichloromethane. The collected organic phases are washed with water, dried (MgSO₄), and the solvent is removed in vacuo. The oily residue is purified by column chromatography using silica gel (eluent: toluene/dioxane 4:1 ) and precipitated as hydrochloride from diethylether. 2.28 g of the title compound are obtained. ¹H-NMR (200 MHz, O₆-DMSO): δ =7.92 (d, 1 H), 7.66 (t, 2H), 7.49 (s, 1 H), 7.40-7.03 (m, 9H), 5.44 (t, 1 H), 4.81 (dd, 2H), 3.96-3.72 (m, 4H), 4.67-3.52 (m, 1 H), 3.49-3.34 (m, 1 H), 3.25-3.11 (m, 5H), 2.42 (s, 6H), 1 .37 (d, 3H).

9. {1-[1-(4-Chloro-phenyl)-methanoyl]-5-methoxy-2-methyl-1 H-indol-3-yl}-acetic acid (7R,8R,9R)- 2,3-dimethyl-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2-h][1 ,7]naphthyridine- 8-yl ester

4-(N,N-Dimethylamino)pyridin (DMAP) (1.50 g, 12.24 mmol) is added in portions to the solution of 1 -[1 - (4-chlorobenzoyl)-5-methoxy-2-methyl-1 H-indol-3-yl] acetic acid (1.60 g, 4.49 mmol) and (7R,8R,9R)- 2,3-dimethyl-8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2- h][1 ,7]naphthyridine (1.50 g, 4.40 mmol) in tetrahydrofuran (25 ml) at room temperature. The solution of toluene sulfonyl chloride (1 .01 g, 5.30 mmol) in tetrahydrofuran (5 ml) is added. The resulting suspension is stirred at room temperature for 60 min, poured onto water, neutralized by adding a saturated NaHCO₃ solution (pH 8), and extracted three times with dichloromethane. The collected organic phases are washed with water, dried (MgSO₄), and the solvent is removed in vacuo. The residue is purified by column chromatography using silica gel (eluent: toluene/dioxane 4:1 ) and and crystallized from diisopropylether. 2.37 g of the title compound of melting point 164-168⁹C (diisopropylether) are obtained.

10. [2-(2,6-Dichlorophenylamino)-phenyl] acetic acid (7/?,8/?,9ff)-2,3-dimethyl-7-(2- methoxyethoxy)-9-phenyl-7H-8,9-dihydropyrano[2,3-c]imidazo[1 ,2-a]pyridine-8-yl ester

N,N,N',N'-Tetramethyl-O-(benzotriazol-1 -yl)uranium tetrafluoroborate (TBTU) (1.78 g, 5.50 mmol) is added in portions to the suspension of [2-(2,6-dichlorophenylamino)-phenyl] acetic acid (1.50 g, 5.00 mmol) in tetrahydrofuran (30 ml) at room temperature. After stirring at room temperature for 2 h (7R,8R,9R)-2,3-dimethyl-8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7H-8,9-dihydropyrano[2,3-c]- imidazo[1 ,2-a]pyridine (0.61 g, 1.66 mmol) is added. The reaction mixture is refluxed for 3 h, poured onto water, neutralized by adding a saturated NaHCO₃ solution (pH 8), and extracted three times with dichloromethane. The collected organic phases are washed with water, dried (MgSO₄), and the solvent is removed in vacuo. The oily residue is purified by column chromatography using alumina (eluent: toluene) and crystallized from diisopropylether. 0.10 g of the title compound are obtained. ¹H-NMR (200 MHz, d₆-DMSO): δ =7.56-7.41 (m, 3H), 7.40-6.94 (m, 6H), 6.83-6.72 (m, 3H), 6.46 (d, 1 H), 6.25 (d, 1 H), 5.38 (dd, 1 H), 4.80 (dd, 1 H), 4.44 (d, 1 H), 4.32 (d, 1 H), 4.71 -4.48 (m, 2H), 4.42-3.30 (m, 2H), 3.16 (s, 3H), 2.36 (s, 3H), 2.29 (s, 3H).

11. 2-Hydroxybenzoic acid (7/?,8/?,9fl)-2,3-dimethyl-7-(2-methoxyethoxy)-9-phenyl-7H-8,9- dihydropyrano[2,3-c]imidazo[1 ,2-a]pyridine-8-yl ester N,N-Carbonyldiimidazole (0.99 g, 6.10 mmol) is added in portions to the suspension of 2-acetoxy benzoic acid (1.00 g, 5.50 mmol) in dichloromethane (15 ml) at room temperature. After stirring at room temperature for 2 h (7fl,8fl,9fl)-2,3-dimethyl-8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7H-8,9- dihydropyrano[2,3-c]imidazo[1 ,2-a]pyridine (1 .00 g, 2.75 mmol) is added. The reaction mixture is stirred at room temperature for 18 h, poured onto water, neutralized by adding a saturated NaHCO₃ solution (pH 8), and extracted three times with dichloromethane. The collected organic phases are washed with water, dried (MgSO₄), and the solvent is removed in vacuo. The oily residue is filtered through a pad of alumina (eluent: toluene/dioxane 6:1 ) and purified by HPLC (reversed phase C18, eluent: water/acetonitril). 0.05 g of the title compound of melting point 57-63 °C are obtained.

12. [4-(2,6-Dichlorophenylamino)-thiophen-3-yl] acetic acid (7/?,8/?,9fl)-3-chloro-7-(2- methoxyethoxy)-2-methyl-9-phenyl-7H-8,9-dihydropyrano[2,3-c]imidazo[1 ,2-a]pyridine-8-yl ester; salt with oxalic acid

N,N,N',N'-Tetramethyl-O-(benzotriazol-1 -yl)uranium tetrafluoroborate (TBTU) (0.37 g, 1.15 mmol) is added in portions to the solution of [4-(2,6-dichlorophenylamino)-thiophen-3-yl] acetic acid (0.29 g, 0.96 mmol) in dichloromethane (10 ml) at room temperature. After stirring at reflux for one hour (7R,8R,9R)-3-chloro-8-hydroxy-7-(2-methoxyethoxy)-2-methyl-9-phenyl-7H-8,9-dihydropyrano[2,3-c]- imidazo[1 ,2-a]pyridine (0.37 g, 0.95 mmol) is added. The reaction mixture is refluxed for 4 h, stirred at room temperature for 60 h, poured onto water, neutralized by adding a saturated NaHCO₃ solution (pH 8), and extracted three times with dichloromethane. The collected organic phases are washed with water, dried (MgSO₄), and the solvent is removed in vacuo. The oily residue is purified by column chromatography using silica gel (eluent: toluene/dioxane 9:1 ) and precipitated as salt of oxalic acid from isopropanol. 0.1 O g of the title compound of melting point 158-160 °C (isopropanol) are obtained.

13. (S)-2-(6-Methoxynaphthalen-2-yl) propionic acid 3-[(7/?,8/?,9ff)-2,3-dimethyl-7-(2- methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2-h][1 ,7]naphthyridine-8-yloxycarbonyl] propyl ester

4-(N,N-Dimethylamino)pyridin (DMAP) (0.81 g, 6.60 mmol) is added in portions to the solution of (S)-2- (6-methoxynaphthalen-2-yl) propionic acid (0.66 g, 2.80 mmol) and 4-hydroxybutyric acid (7R,8R,9R)- 2,3-dimethyl-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2-h][1 ,7]naphthyridine-8-yl ester (1.00 g, 2.20 mmol) in tetrahydrofuran (20 ml) at room temperature. The solution is cooled to 0 °C and the solution of toluene sulfonyl chloride (0.63 g, 3.30 mmol) in tetrahydrofuran (8 ml) is added. The resulting suspension is stirred at room temperature for 3 h, the precipitate is filtered off and the filtrate is concentrated. The resulting residue is dissolved in ethyl acetate, the organic layer is washed with an aqueous solution of citric acid (10 ml, 10%) and brine (10 ml), dried (MgSO₄), and the solvent is removed in vacuo. The oily residue is crystallized from ethyl acetate/n-heptane/diisopropylether. 1.00 g of the title compound are obtained. ¹H-NMR (200 MHz, CDCI₃): δ = 8.33 (s, 1 H), 7.76-7.58 (m, 3H), 7.44-7.05 (m, 10H), 5.56 (t, 1 H), 4.82 (d, 1 H), 4.56 (d, 1 H), 4.40-3.70 (m, 6H), 3.63-3.48 (m, 1 H), 3.42-3.28 (m, 1 H), 3.25-3.04 (2H), 2.54 /s, 3H), 2.41 (s, 3H), 2.17 (t, 2H), 1.74 (q, 2H), 1.55 (d, 3H).

14. [1-(4-Chlorobenzoyl)-5-methoxy-2-methyl-1 H-indol-3-yl] acetic acid 3-[(7/?,8/?,9fl)-2,3- dimethyl-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2-h][1 ,7]naphthyridine-8- yloxycarbonyl] propyl ester

4-(N,N-Dimethylamino)pyridin (DMAP) (0.81 g, 6.60 mmol) is added in portions to the solution of [1 -(4- chlorobenzoyl)-5-methoxy-2-methyl-1 /-/-indol-3-yl] acetic acid (0.95 g, 2.60 mmol) and 4-hydroxybutyric acid (7fl,8fl,9fl)-2,3-dimethyl-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2- h][1 ,7]naphthyridine-8-yl ester (1.00 g, 2.20 mmol) in tetrahydrofuran (20 ml) at room temperature. The solution is cooled to 0 °C and the solution of toluene sulfonyl chloride (0.63 g, 3.30 mmol) in tetrahydrofuran (8 ml) is added. The resulting suspension is stirred at room temperature for 3 h, the precipitate is filtered off, and the filtrate is concentrated. The resulting residue is dissolved in a mixture of ethyl acetate and citric acid (10% aqueous solution), the layers are separated, and the aqueous phase is extracted twice with ethyl acetate. The organic layer is washed with brine, dried (MgSO₄), and the solvent is removed in vacuo. The oily residue is crystallized from ethyl acetate/diisopropylether. 1.20 g of the title compound are obtained.

¹H-NMR (200 MHz, CDCI₃): δ = 8.40 (s, 1 H), 7.72-7.57 (m, 2H), 7.52-7.13 (m, 9H), 6.95 (d, 1 H), 6.88 (d, 1 H), 7.65 (dd, 1 H), 6.62 (t, 1 H), 4.89 (d, 1 H), 4.60 (d, 1 H), 4.01 (td, 2H), 3.82 (s, 3H), 3.72-3.53 (m, 3H), 3.46-3.33 (m, 1 H), 3.28-3.09 (m, 5H), 2.55 (s, 3H), 2.42 (s, 3H), 2.36 (s, 3H), 2.24 (t, 2H), 1.81 (quintet, 2H).

15. [2-(2,6-Dichlorophenylamino)-phenyl] acetic acid 3-[(7/?,8/?,9ff)-2,3-dimethyl-7-(2- methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2-h][1 ,7]naphthyridine-8-yloxycarbonyl] propyl ester

4-(N,N-Dimethylamino)pyridin (DMAP) (0.40 g, 3.30 mmol) is added in portions to the solution of [2- (2,6-dichlorophenylamino)-phenyl] acetic acid (0.95 g, 1.30 mmol) and 4-hydroxybutyric acid (7R,8R,9R)-2,3-dimethyl-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2- h][1 ,7]naphthyridine-8-yl ester (0.50 g, 1.10 mmol) in tetrahydrofuran (10 ml) at room temperature. The solution is cooled to 0 °C and the solution of toluene sulfonyl chloride (0.31 g, 1 .65 mmol) in tetrahydrofuran (4 ml) is added. The resulting suspension is stirred at room temperature for 3 h, the precipitate is filtered off, and the filtrate is concentrated. The resulting residue is dissolved in a mixture of ethyl acetate and citric acid (10% aqueous solution), the layers are separated, and the aqueous phase is extracted twice with ethyl acetate. The organic layer is washed with brine, dried (MgSO₄), and the sol- vent is removed in vacuo. The oily residue is crystallized from ethyl acetate/diisopropylether. 0.32 g of the title compound are obtained.

¹H-NMR (200 MHz, CDCI₃): δ = 8.37 (s, 1 H), 7.55-6.78 (m, UH), 6.54 (d, 1 H), 5.63 (t, 1 H), 4.90 (d, 1 H), 4.63 (d, 1 H), 4.05 (td, 2H), 3.78 (s, 2H), 3.71 -3.52 (m, 1 H), 3.47-3.33 (m, 1 H), 3.30-3.07 (m, 5H), 2.55 (s, 3H), 2.42 (s, 3H), 2.28 (t, 2H), 1.85 (quintet, 2H).

16. [4-(2,6-Dichlorophenylamino)-thiophen-3-yl] acetic acid 3-[(7R,8R,9R)-2,3-dimethyl-7-(2- methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2-h][1 ,7]naphthyridine-8-yloxycarbonyl] propyl ester

4-(N,N-Dimethylamino)pyridin (DMAP) (0.81 g, 6.60 mmol) is added in portions to the solution of [4- (2,6-dichlorophenylamino)-thiophen-3-yl] acetic acid (0.73 g, 2.40 mmol) and 4-hydroxybutyric acid (7R,8R,9R)-2,3-dimethyl-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2- h][1 ,7]naphthyridine-8-yl ester (1.00 g, 2.20 mmol) in tetrahydrofuran (20 ml) at room temperature. The solution is cooled to 0 °C and the solution of toluene sulfonyl chloride (0.63 g, 3.30 mmol) in tetrahydrofuran (8 ml) is added. The resulting suspension is stirred at room temperature for 2 h, the precipitate is filtered off, and the filtrate is concentrated. The resulting residue is dissolved in a mixture of ethyl acetate and citric acid (10% aqueous solution), the layers are separated, and the aqueous phase is extracted twice with ethyl acetate. The organic layer is washed with brine, dried (MgSO₄), and the solvent is removed in vacuo. The oily residue is crystallized from ethyl acetate/diisopropylether. 0.60 g of the title compound are obtained.

¹H-NMR (200 MHz, CDCI₃): δ = 7.95 (s, 1 H), 7.47-6.82 (m, 11 H), 6.46 (s, 1 H), 6.15 (d, 1 H), 5.64 (t, 1 H), 4.86 (d, 1 H), 4.67 (d, 1 H), 4.04 (td, 2H), 3.74-3.52 (m, 3H), 3.50-3.33 (m, 1 H), 3.31 -3.10 (m, 5H), 2.51 (s, 3H), 2.41 (s, 3H), 2.27 (t, 2H), 1.84 (quintet, 2H).

17. [2-(2,6-Dichlorophenylamino)phenyl]acetic acid 2-[2-(2-{[(7R,8R,9R)-2,3-dimethyl-7-(2- methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2-h]-1 ,7-naphthyridin-8-yl]oxy}-2- oxoethoxy)ethoxy]ethyl ester

4-(N,N-Dimethylamino)pyridin (DMAP) (1.06 g, 8.70 mmol) is added in portions to the solution of [2- (2,6-dichlorophenylamino)-phenyl] acetic acid (1.12 g, 3.80 mmol) and [2-(2- hydroxyethoxy)ethoxy]acetic acid (7fl,8fl,9fl)-2,3-dimethyl-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10- tetrahydroimidazo[1 ,2-h]-[1 ,7]naphthyridin-8-yl ester (1.50 g, 2.90 mmol) in tetrahydrofuran (45 ml) at room temperature. The solution is cooled to 0 °C and the solution of toluene sulfonyl chloride (0.83 g, 4.30 mmol) in tetrahydrofuran (15 ml) is added slowly over a period of 1 h via a syringe pump. Simultaneously to the addition of the toluene sulfonyl chloride solution a further portion of a solution of [2-(2,6- dichlorophenylamino)-phenyl] acetic acid (0.70 g, 2.38 mmol) in tetrahydrofuran (10 ml) is added slowly. The resulting suspension is stirred at room temperature for 1 h, the precipitate is filtered off, and the filtrate is concentrated. The resulting residue is dissolved in a mixture of ethyl acetate and water, the layers are separated, and the aqueous phase is extracted three times with ethyl acetate. The organic layer is washed with brine, dried (MgSO₄), and the solvent is removed in vacuo. The oily residue is purified twice by column chromatography using silica gel (eluent: toluene/dioxane 4:1 and 9:1 , respectively) and lyophilized from dioxane/water. 0.44 g of the title compound are obtained. ¹H-NMR (200 MHz, CD₂CI₂): δ = 7.56-6.76 (m, 14H), 6.50 (d, 1 H), 6.40 (d, 1 H), 5.62 (t, 1 H), 4.75 (d, 1 H), 4.71 (d, 1 H), 4.25 (t, 2H), 3.94 (dd, 2H), 3.82 (s, 2H), 3.74-3.18 (m, 13H), 2.36 (s, 6H).

18. [4-(2,6-Dichlorophenylamino)-3-thienyl]acetic acid 2-(2-{[(7R,8R,9R)-2,3-dimethyl-7-(2- methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2-h]-1 ,7-naphthyridin-8-yl]oxy}-2- oxoethoxy)ethyl ester

4-(N,N-Dimethylamino)pyridin (DMAP) (0.62 g, 5.10 mmol) is added in portions to the solution of [4- (2,6-dichlorophenylamino)-thiophen-3-yl] acetic acid (0.62 g, 2.00 mmol) and (2-hydroxyethoxy)acetic acid (7R,8R,9R)-2,3-dimethyl-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2-h]-

[1 ,7]naphthyridin-8-yl ester (0.80 g, 1.70 mmol) in tetrahydrofuran (20 ml) at room temperature. The solution is cooled to 0 °C and the solution of toluene sulfonyl chloride (0.49 g, 2.50 mmol) in tetrahydrofuran (7 ml) is added slowly over a period of 1 h via a syringe pump. The resulting suspension is stirred at 0 °C for 10 min, the precipitate is filtered off, and the filtrate is concentrated. The resulting residue is dissolved in a mixture of ethyl acetate and water, the layers are separated, and the aqueous phase is extracted twice with ethyl acetate. The combined organic layers are dried (MgSO₄) and the solvent is removed in vacuo. The oily residue is purified by column chromatography using silica gel (eluent: toluene/dioxane 5:1 ) and lyophilized from dioxane/water. 0.90 g of the title compound are obtained.

¹H-NMR (200 MHz, CDCI₃): δ = 7.50-7.38 (m, 2H), 7.35-7.22 (m, 6H), 7.08 (d, 1 H), 6.96 (d, 1 H), 6.89- 6.81 (m, 1 H), 6.47 (s, 1 H), 6.15 (d, 1 H), 5.73 (t, 1 H), 5.47 (bs, 1 H), 4.92 (d, 1 H), 4.64 (d, 1 H), 4.22 (t, 1 H), 3.91 (dd, 2H), 3.80-3.33 (m, 8H), 3.31 (s, 3H), 2.38 (s, 3H), 2.37 (s, 3H).

19. [2-(2,6-dichlorophenylamino)phenyl]acetic acid 2-(2-{[(7R,8R,9R)-2,3-dimethyl-7-(2- methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2-h]-1 ,7-naphthyridin-8-yl]oxy}-2- oxoethoxy)ethyl ester

4-(N,N-Dimethylamino)pyridin (DMAP) (0.62 g, 5.10 mmol) is added in portions to the solution of [2- (2,6-dichlorophenylamino)-phenyl] acetic acid (0.61 g, 2.00 mmol) and (2-hydroxyethoxy)acetic acid (7R,8R,9R)-2,3-dimethyl-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2-h]- [1 ,7]naphthyridin-8-yl ester (0.80 g, 1.70 mmol) in tetrahydrofuran (20 ml) at room temperature. The solution is cooled to 0 °C and the solution of toluene sulfonyl chloride (0.49 g, 2.50 mmol) in tetrahydrofuran (7 ml) is added slowly over a period of 25 min via a syringe pump. The resulting suspension is stirred at 0 °C for 10 min, the precipitate is filtered off, and the filtrate is concentrated. The resulting residue is dissolved in a mixture of ethyl acetate and water, the layers are separated, and the aqueous phase is extracted twice with ethyl acetate. The combined organic layers are dried (MgSO₄) and the solvent is removed in vacuo. The oily residue is purified twice by column chromatography using silica gel (eluent: toluene/dioxane 20:1 ) and lyophilized from dioxane/water. 0.3g of the title compound are obtained.

¹H-NMR (400 MHz, CD₂CI₂): δ = 7.45 (d, 2H), 7.39-7.25 (m, 6H), 7.23 (d, 1 H), 7.1 1 (t, 1 H), 7.01 (t, 1 H), 6.95 (t, 1 H), 6.83 (s, 1 H), 6.79 (d, 1 H), 6.51 (d, 1 H), 5.63 (t, 1 H), 5.39 (s, 1 H), 4.81 (d, 1 H), 4.65 (d, 1 H), 4.21 (t, 2H), 3.99 (d, 1 H), 3.88-3.76 (m, 3H), 3.70-3.63 (m, 1 H), 3.59-3.43 (m, 3H), 3.36-3.29 (m, 2H), 3.27 (s, 3H), 2.36 (s, 3H), 2.32 (s, 3H).

20. (2-R/S)-2-(2-fluoro-1 ,1 '-biphenyl-4-yl)propionic acid 2-(2-{[(7R,8R,9R)-2,3-dimethyl-7-(2- methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2-h]-1 ,7-naphthyridin-8-yl]oxy}-2- oxoethoxy)ethyl ester

4-(N,N-Dimethylamino)pyridin (DMAP) (0.47 g, 3.84 mmol) is added in portions to the solution of (2rac)-2-(2-fluoro-1 ,1 '-biphenyl-4-yl)propanoic acid (0.31 g, 1.28 mmol) and (2-hydroxyethoxy)acetic acid (7R,8R,9R)-2,3-dimethyl-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2-h]-

[1 ,7]naphthyridin-8-yl ester (0.60 g, 1.28 mmol) in tetrahydrofuran (15 ml) at room temperature. The solution is cooled to 0 °C and the solution of toluene sulfonyl chloride (0.37 g, 1 .90 mmol) in tetrahydrofuran (6 ml) is added slowly over a period of 15 min. The resulting suspension is stirred at 0 °C for 30 min, the precipitate is filtered off, and the filtrate is concentrated. The resulting residue is dissolved in a mixture of dichloromethane and water, the layers are separated, and the aqueous phase is extracted twice with dichloromethane. The combined organic layers are dried (MgSO₄) and the solvent is removed in vacuo. The oily residue is purified by column chromatography using silica gel (eluent: tolu- ene/dioxane/methanol 20:2:1 ) and lyophilized from dioxane/water. 0.50 g of the title compound are obtained.

¹H-NMR (400 MHz, CDCI₃): δ = 7.55-7.49 (m, 2H), 7.47-7.21 (m, 9H), 7.18-7.10 (m, 3H), 6.84 (d, 1 H), 5.73 (dd, 1 H), 5.30 (s, 1 H), 4.94 (dd, 1 H), 4.60 (dd, 1 H), 4.23-4.07 (m, 2H), 3.97 (dd, 1 H), 3.83-3.72 (m, 2H), 3.97 (dd, 1 H), 3.83-3.72 (m, 2H), 3.69-3.61 (m, 1 H), 3.55-3.34 (m, 5H), 3.31 (s, 3H), 2.37 (s, 6H), 1 .53 (d, 3H). [α]_D ²⁰ = - 59.0° (c = 1 in CHCI₃).

21. (2S)-2-(2-fluorobiphenyl-4-yl)propionic acid 2-(2-{[(7R,8R,9R)-2,3-dimethyl-7-(2- methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2-h]-1 ,7-naphthyridin-8-yl]oxy}-2- oxoethoxy)ethyl ester

4-(N,N-Dimethylamino)pyridin (DMAP) (0.47 g, 3.84 mmol) is added in portions to the solution of (2S)-2-(2-fluoro-1 ,1 '-biphenyl-4-yl)propanoic acid (0.31 g, 1 .28 mmol) and (2-hydroxyethoxy)acetic acid (7R,8R,9R)-2,3-dimethyl-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2-h]- [1 ,7]naphthyridin-8-yl ester (0.60 g, 1.28 mmol) in tetrahydrofuran (15 ml) at room temperature. The solution is cooled to 0 °C and the solution of toluene sulfonyl chloride (0.37 g, 1 .90 mmol) in tetrahy- drofuran (6 ml) is added slowly over a period of 15 min. The resulting suspension is stirred at 0 °C for 30 min, the precipitate is filtered off, and the filtrate is concentrated. The resulting residue is dissolved in a mixture of dichloromethane and water, the layers are separated, and the aqueous phase is extracted twice with dichloromethane. The combined organic layers are dried (MgSO₄) and the solvent is removed in vacuo. The oily residue is purified by column chromatography using silica gel (eluent: tolu- ene/dioxane/methanol 20:2:1 ) and lyophilized from dioxane/water. 0.56 g of the title compound are obtained.

¹H-NMR (400 MHz, CDCI₃): δ = 7.55-7.49 (m, 2H), 7.47-7.21 (m, 9H), 7.18-7.10 (m, 3H), 6.84 (d, 1 H), 5.73 (dd, 1 H), 5.30 (s, 1 H), 4.94 (d, 1 H), 4.60 (d, 1 H), 4.23-4.07 (m, 2H), 3.97 (d, 1 H), 3.83-3.72 (m, 2H), 3.97 (dd, 1 H), 3.83-3.72 (m, 2H), 3.69-3.61 (m, 1 H), 3.55-3.34 (m, 5H), 3.31 (s, 3H), 2.37 (s, 6H), 1.53 (d, 3H). [α]_D ²⁰ = - 54.7° (c = 1 in CHCI₃).

22. (2R/S)-2-(2-f luorobiphenyl-4-yl)propionic acid {1 -benzyl-7-[(4-f luorobenzyl)oxy]-2-methyl-1 H- pyrrolo[2,3-d]pyridazin-3-yl}methyl ester

4-(N,N-Dimethylamino)pyridin (DMAP) (0.48 g, 3.90 mmol) is added in portions to the solution of (2rac)-2-(2-fluoro-1 ,1 '-biphenyl-4-yl)propanoic acid (0.32 g, 1.30 mmol) and 1 -benzyl-7-(4- fluorbenzyloxy)-3-hydroxymethyl-2-methyl-pyrrolo[2,3-α(|pyridazin (0.50 g, 1.30 mmol) in tetrahydrofuran (15 ml) at room temperature. The solution is cooled to 0 °C and the solution of toluene sulfonyl chloride (0.37 g, 1.90 mmol) in tetrahydrofuran (6 ml) is added slowly over a period of 20 min. The resulting suspension is stirred at 0 °C for 30 min, the precipitate is filtered off, and the filtrate is concentrated. The resulting residue is dissolved in a mixture of dichloromethane and water, the layers are separated, and the aqueous phase is extracted twice with dichloromethane. The combined organic layers are dried (MgSO₄) and the solvent is removed in vacuo. The oily residue is purified by column chromatography using silica gel (eluent: toluene/dioxane/methanol 40:4:1 ) and and crystallized from ethyl acetate/diisopropylether. 0.30 g of the title compound are obtained.

¹H-NMR (200 MHz, CDCI₃): δ = 9.10 (s, 1 H), 7.54-6.68 (m, 17H), 5.55 (s, 4H), 5.30 (s, 2H), 3.74 (q, 1 H), 2.32 (s, 3H), 1 .50 (d, 3H).

23. [2-(2,6-dichlorophenylamino)phenyl]acetic acid 2-{[(1-benzyl-2,3-dimethyl-1 H-pyrrolo[2,3- d]pyridazin-7-yl)oxy]methyl}benzyl ester

4-(N,N-Dimethylamino)pyridin (DMAP) (0.95 g, 7.80 mmol) is added in portions to the solution of [2- (2,6-dichlorophenylamino)-phenyl] acetic acid (0.84 g, 3.20 mmol) and 1 -benzyl-2,3-dimethyl-7-(2- hydroxymethylbenzyloxy)-pyrrolo[2,3-φyridazin (1.00 g, 2.60 mmol) in tetrahydrofuran (75 ml) at room temperature. The solution is cooled to 0 °C and the solution of toluene sulfonyl chloride (0.75 g, 3.90 mmol) in tetrahydrofuran (10 ml) is added slowly over a period of 60 min via a syringe pump. The resulting suspension is stirred at 0 °C for 30 min, the precipitate is filtered off, and the filtrate is concen- trated. The resulting residue is dissolved in a mixture of dichloromethane and water, the layers are separated, and the aqueous phase is extracted twice with dichloromethane. The combined organic layers are dried (MgSO₄) and the solvent is removed in vacuo. The oily residue is purified by column chromatography using silica gel (eluent: toluene/dioxane/methanol 40:4:1 ) and crystallized from ethyl acetate/diisopropylether. 0.31 g of the title compound are obtained.

¹H-NMR (200 MHz, CDCI₃): δ = 9.00 (s, 1 H), 7.38-6.82 (m, 13 H), 6.78-6.63 (m, 3H), 6.51 (d, 1 H), 5.68 (S, 2H), 5.51 (S, 2H), 3.76 (s, 2H), 2.27 (s, 3H), 2.24 (s, 3H).

Starting materials:

A. 4-(tert-Butyldimethylsilanyloxy) butyric acid (7/?,8/?,9ff)-2,3-dimethyl-7-(2-methoxyethoxy)-9- phenyl-7,8,9,10-tetrahydroimidazo[1 ,2-h][1 ,7]naphthyridine-8-yl ester (BYK 395702)

4-(N,N-Dimethylamino)pyridin (DMAP) (10.0 g, 81 .6 mmol) is added in portions to the solution of (7R,8R,9R)-8-hydroxy-2,3-dimethyl-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydro-imidazo-[1 ,2- h][1 ,7]naphthyridin (10.0 g, 27.2 mmol) and 4-(tert-butyldimethylsilanyloxy) butyric acid (7.70 g, 35.4 mmol) in tetrahydrofuran (200 ml) at room temperature. The solution is cooled to 0 °C and the solution of toluene sulfonyl chloride (7.80 g, 40.8 mmol) in tetrahydrofuran (100 ml) is added. The resulting suspension is stirred at room temperature for one hour, the precipitate is filtered off and the filtrate is concentrated. The resulting residue is dissolved in ethyl acetate (250 ml), the organic layer is washed with an aqueous solution of citric acid (100 ml, 10%) and brine (10 ml), dried (MgSO₄), and the solvent is removed in vacuo. 18.0 g of the title compound are obtained which can be used without further purification in the next step.

B. 4-Hydroxybutyric acid (7/?,8/?,9fl)-2,3-dimethyl-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10- tetrahydroimidazo[1 ,2-h][1 ,7]naphthyridine-8-yl ester (BYK 395716)

The solution of 4-(tert-butyldimethylsilanyloxy) butyric acid (7R,8/^:?,9/^:?)-2,3-dimethyl-7-(2- methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2-h][1 ,7]naphthyridine-8-yl ester (18.0 g, 27.2 mmol) in methanol (100 ml) is cooled to 0 °C. Concentrated aqueous hydrochloric acid (2 ml) is slowly added. The mixture is stirred for 20 min at 0 °C, poured onto water (300 ml), neutralized by adding a saturated NaHCO₃ solution (pH 8), and extracted three times with dichloromethane. The collected organic phases are dried (MgSO₄), and the solvent is removed in vacuo. The residue is purified by column chromatography using silica gel (eluent: toluene/dioxane 2:1 ) and crystallized from diisopro- pylether. 9.50 g of the title compound are obtained.

¹H-NMR (200 MHz, CDCI₃): δ =7.52-7.40 (m, 2H), 7.38-7.21 (m, 4H), 6.84 (d, 1 H), 5.70 (t, 1 H), 5.31 (s, 1 H), 4.94 (d, 1 H), 4.63 (d, 1 H), 3.76-3.59 (m, 1 H), 3.50-3.36 (m, 5H), 3.32 (s, 3H), 2.37 (s, 6H), 2.35- 2.08 (m, 2H), 1.97-1.50 (m, 3H).

C. {2-[2-(fert.-Butyldimethylsiloxy)ethoxy]ethoxy}acetic acid The suspension of sodium hydride (4.00 g, 0.10 mol; 60 % in mineral oil) in benzene (60 ml) is stirred for 10 min, benzene is decanted, and the washed sodium hydride is suspended again in benzene (60 ml). The solution of of 2-[2-(te/t-butyldimethylsiloxy)ethoxy]ethanol (11.0 g, 0.05 mol) (prepared as described in M. Lautens et al. J. Org. Chem. 2002, 67, 11, 3972-3974) in benzene (60 ml) is added dropwise, and the suspension is stirred for 2 h at room temperature. The solution of chloroacetic acid (4.73 g, 0.05 mol) in benzene (30 ml) is added carefully. The reaction mixture is stirred for 2 h at reflux and 18 h at room temperature, quenched by adding water (10 ml), poured onto water, and extracted with diethylether (the extract is discarded). The aqueous solution is neutralized by adding hydrochloric acid (2N) (pH 6) and extracted three times with ethyl acetate. The collected organic phases are dried (MgSO₄), and the solvent is removed in vacuo. 5.40 g of the title compound are obtained as yellow oil which can be used without further purification in the next step. MS (API-ES) = 279.1 (MH⁺), 296.1 (MNH₄ ⁺).

D. [2-(2-Hydroxyethoxy)ethoxy]acetic acid (7R,8R,9R)-2,3-dimethyl-7-(2-methoxyethoxy)-9- phenyl-7,8,9,10-tetrahydroimidazo[1 ,2-h]-[1 ,7]naphthyridin-8-yl ester

4-(N,N-Dimethylamino)pyridin (DMAP) (3.00 g, 24.5 mmol) is added in portions to the solution of (7R,8R,9R)-8-hydroxy-2,3-dimethyl-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydro-imidazo-[1 ,2- h][1 ,7]naphthyridin (3.00 g, 8.16 mmol) and {2-[2-(te/t-butyldimethylsiloxy)ethoxy]ethoxy}acetic acid (2.95 g, 10.6 mmol) in tetrahydrofuran (60 ml) at room temperature. The solution is cooled to 0 °C and the solution of toluene sulfonyl chloride (2.33 g, 12.2 mmol) in tetrahydrofuran (30 ml) is added. The resulting suspension is stirred at room temperature for 1.5 h, the precipitate is filtered off, and the filtrate is concentrated. The resulting residue is dissolved in a mixture of ethyl acetate and an aqueous solution of ammonium chloride. The phases are separated, the aqueous solution is extracted three times with ethyl acetate, the combined organic layers are dried (MgSO₄), and the solvent is removed in vacuo.

5.2 g of a high-viscous oil are obtained which is dissolved in methanol (50 ml). The solution is cooled to 0°C and concentrated hydrochloric acid (0.85 ml) is added. The solution is stirred for 18 h at 0°C, poured onto water (250 ml), and the ph value is adjusted to 10 by adding aqueous sodium bicarbonate. The aqueous mixture is extracted three times with ethyl acetate, the combined organic phases are dried (MgSO₄), and the solvent is removed in vacuo. The oily residue is purified by column chromatography using silica gel (eluent: toluene/dioxane 2:1 ) and precipitated from diisopropylether. 2.6 g of the title compound are obtained.

¹H-NMR (400 MHz, CD₂CI₂): δ = 7.45 (d, 2H), 7.37-7.24 (m, 4H), 6.78 (d, 1 H), 5.66 (t, 1 H), 5.54 (s, 1 H), 4.78 (d, 1 H), 4.71 (d, 1 H), 3.97 (dd, 2H), 3.75-3.61 (m, 3H), 3.56-3.38 (m, 7H), 3.35-3.27 (m, 2H), 3.26 (S, 3H), 3.01 (bs, 1 H), 2.36 (s, 3H), 2.33 (s, 3H).

E. [2-(ferf.-Butyldimethylsiloxy)ethoxy]acetic acid The suspension of sodium hydride (4.54 g, 113 mmol; 60 % in mineral oil) in benzene (60 ml) is stirred for 15 min, benzene is decanted, and the washed sodium hydride is suspended again in benzene (60 ml). The solution of of 2-(te/t-butyldimethylsiloxy)ethanol (10.0 g, 56.7 mmol) (prepared as described in I. Azumaya et al. Angew. Chem. 2004, 116, 11, 1384-1387) in benzene (55 ml) is added dropwise, and the suspension is stirred for 1 h at room temperature. The solution of chloroacetic acid (5.30 g, 56.7 mmol) in benzene (50 ml) is added carefully. The reaction mixture is stirred for 2 h at reflux and 18 h at room temperature, quenched by adding water (10 ml), poured onto water, and extracted with ethyl acetate (the extract is discarded). The aqueous solution is neutralized by adding hydrochloric acid (1 N) (pH 6) and extracted twice with ethyl acetate. The collected organic phases are dried (Na₂SCVMgSO₄), and the solvent is removed in vacuo. 7.30 g of the title compound are obtained as yellow oil which can be used without further purification in the next step. MS (ESI) = 235.1 (MH⁺), 252.0 (MNH₄ ⁺).

F. (2-Hydroxyethoxy)acetic acid (7R,8R,9R)-2,3-dimethyl-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10- tetrahydroimidazo[1 ,2-h]-[1 ,7]naphthyridin-8-yl ester

4-(N,N-Dimethylamino)pyridin (DMAP) (3.00 g, 24.5 mmol) is added in portions to the solution of (7R,8R,9R)-8-hydroxy-2,3-dimethyl-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydro-imidazo-[1 ,2- h][1 ,7]naphthyridin (3.00 g, 8.16 mmol) and [2-(te/t-butyldimethylsiloxy)ethoxy]acetic acid (2.50 g, 10.6 mmol) in tetrahydrofuran (60 ml) at room temperature. The solution is cooled to 0°C and the solution of toluene sulfonyl chloride (2.33 g, 12.2 mmol) in tetrahydrofuran (30 ml) is added. The resulting suspension is stirred at room temperature for 18 h, the precipitate is filtered off, and the filtrate is concentrated. The resulting residue is dissolved ethyl acetate (100 ml), the organic layer is washed with an aqueous solution of citric acid (50 ml, 10 %) and brine (10 ml). The mixture is filtered through a plug of celite, the phases are separated, the organic phase is dried (MgSO₄), and the solvent is removed in vacuo.

5.0 g of a high-viscous oil are obtained which are dissolved in methanol (50 ml). The solution is cooled to 0°C and concentrated hydrochloric acid (1.00 ml) is added. The solution is stirred for 30 min at O⁹C, poured onto water, and the ph value is adjusted to 9 by adding aqueous sodium bicarbonate. The aqueous mixture is extracted twice with ethyl acetate, the combined organic phases are dried (MgSO₄), and the solvent is removed in vacuo. The oily residue can be crystallized from diisopro- pylether. 3.00 g of the title compound are obtained.

¹H-NMR (400 MHz, CDCI₃): δ = 7.48-7.42 (m, 2H), 7.38-7.25 (m, 4H), 6.83 (d, 1 H), 5.76 (t, 1 H), 5.34 (s, 1 H), 4.99 (d, 1 H), 4.64 (d, 1 H), 4.12 (d, 1 H), 3.82 (d, 1 H), 3.72-3.35 (m, 8H), 3.33 (s, 3H), 2.61 (t, 1 H), 2.37 (s, 6H). Advantageous effects

The excellent gastric protective action and the gastric acid secretion-inhibiting action of the compounds according to the invention can be demonstrated in investigations on animal experimental models. On the other hand, the compounds according to the invention show an excellent profile concerning especially antiinflammatorical, antiphlogistic and analgetic effects, what can be demonstrated in investigations on in vitro models.

The compounds of the formula 1 according to the invention investigated in the models mentioned below have been provided with numbers which correspond to the numbers of these compounds in the examples.

Testing of the secretion-inhibiting action on the perfused rat stomach

In Table A which follows, the influence of the compounds of the formula 1 according to the invention on the pentagastrin-stimulated acid secretion of the perfused rat stomach after intraduodenal administration in vivo is shown. Table A

Methodology

The abdomen of anesthetized rats (CD rat, female, 200-25O g; 1.5 g/kg i.m. urethane) was opened after tracheotomy by a median upper abdominal incision and a PVC catheter was fixed transorally in the esophagus and another via the pylorus such that the ends of the tubes just projected into the gastric lumen. The catheter leading from the pylorus led outward into the right abdominal wall through a side opening.

After thorough rinsing (about 50-100 ml), warm (37°C) physiological NaCI solution was continuously passed through the stomach (0.5 ml/min, pH 6.8-6.9; Braun-Unita I). The pH (pH meter 632, glass electrode EA 147; φ = 5 mm, Metrohm) and, by titration with a freshly prepared 0.01 N NaOH solution to pH 7 (Dosimat 665 Metrohm), the secreted HCI were determined in the effluent in each case collected at an interval of 15 minutes.

The gastric secretion was stimulated by continuous infusion of 1 μg/kg (= 1.65 ml/h) of i.v. pentagastrin (left femoral vein) about 30 min after the end of the operation (i.e. after determination of 2 preliminary fractions). The substances to be tested were administered intraduodenally in a 2.5 ml/kg liquid volume 60 min after the start of the continuous pentagastrin infusion. The body temperature of the animals was kept at a constant 37.8-38°C by infrared irradiation and heat pads (automatic, stepless control by means of a rectal temperature sensor).

Testing of the inhibiting of COX-1/2 activity in vitro

In Table B which follows, the inhibition of the compounds of the formula 1 according to the invention of COX-1/2 activity in vitro is shown. Table B

Methodology

In vitro human whole blood COX-1/2 assay

Fresh blood was collected in heparinized (8U/ml, Roche, Switzerland) tubes by venipuncture from female volunteers with consent. The subjects had no apparent inflammatory conditions and had not taken any NSAIDs for the last 7 days prior to blood collection. 450 μl aliquots of blood were incubated in deep wells with either 1 μl vehicle (DMSO) or 1 μl of test compound at a final concentration varying from 100 μM-10 nM for 15 min at 37 °C. This was followed by incubation of the blood with 50 μl lipopolysaccharide (LPS , Sigma, Germany) 10 μg / ml in 0.1% Hydroxylamine/PBS (Sigma) for 24 h. At the end of incubation the blood was centrifuged at 2000 g for 5 min and 100-150 ml supernatant was assayed for PGE2 using a immunoassay kit (RD Systems, Germany). Calculation

The data were analysed from 2-3 independent dose response curves with a nonlinear estimation program using GRAPHPAD/Prism and given as IC₅₀. Commercial applicability

The compounds according to the invention have miscellaneous valuable pharmacological properties which make them commercially utilizable. Thus, for example, their excellent properties as non-steroidal anti-inflammatory drugs (NSAID^'s) and as potassium competitive acid blockers (P-CAB^'s) allow them to be used in veterinary and/or, particularly, in human medicine as active principles for preventing and/or treating of, for example, inflammation, pain (both chronic and acute), fever, cancer and other cyclooxygenase mediated disorders, for facilitating wound healing and for gastro and intestinal protection, for decreasing or reversing renal or other toxicity (e.g. kidney toxicity) and for providing of medicaments of improved tolerance at the renal level, the cardiovascular level, the level of the central nervous or autonomous system or, in particular, at the gastrointestinal or respiratory level.

Special isoforms of the abovementioned cyclooxygenase, which are preferred to be mentioned in this connection, include in particular cyclooxygenase-1 (COX-1 ) and cyclooxygenase-2 (COX-2) but also cyclooxygenase-3 (COX-3). Each of these cyclooxygenase isoforms (COX-1 , COX-2 and COX-3) can be regarded as a valuable pharmacological target of the compounds according to this invention.

With respect to the compounds according to the present invention, a target for inhibition, which is to be emphasized with regard to favourable antiinflammatory effects, represents the cyclooxygenase-1 and the cyclooxygenase-2. The compounds according to the invention demonstrate potent inhibition of the cyclooxygenase 1 and/or cyclooxygenase-2 and in parallel demonstrate potent and reversible inhibition of the H/K-ATPase. Therefore the commonly observed side effects of NSAIDs mainly on the gastrointestinal levels are minimized and the compounds are superior to conventional unselective or selective NSAID^'s. Inter alia due to their excellent gastric acid secretion inhibiting and gastro and intestinal protective properties, the compounds according to the invention show also beneficial tolerance and/or an advantageous and desired therapeutic profile.

Furthermore, the compounds according to the present invention are characterized by a particularly advantageous kinetic profile, such as for example prolonged half life, associated with the release of the compounds of the formula Na or Mb and III from the compounds of the formula I.

A further advantage of the compounds of the formula I is associated with a better compliance of the patients because no co-medication has to take place as compared to standard combination therapies.

Moreover, the compounds according to the present invention can be used to provide agents, which feature, as a whole, inhibition of cyclooxygenase-1 and cyclooxygenase-2 with little selectivity for either isoform but without or with reduced adverse effects commonly associated with the inhibition of the cyclooxygenase-1.

Still further, the compounds according to the invention can be used as agents, which show - in comparison to the NSAID^'s from which they are derived - further improved properties. Thus, the compounds according to the invention can be used, for example as analgesics in the treatment of pain, including but not limited to headaches, migraines, postoperative pain, dental pain, muscular pain and pain resulting from cancer, as antipyretics in the treatment of fever, including but not limited to rheumatic fever, symptoms associated with influenza or other viral infections, common cold, low back and neck pain, dysmenorrhea, headache, toothache, sprains, strains, myositis, neuralgia and synovitis, or as an anti-inflammatory in the treatment of arthritis, including but not limited to rheumatoid arthritis, degenerative joint disease (osteoarthritis), spondylarthritis, gouty arthritis, systemic lupus erythematosus and juvenile arthritis.

Furthermore, inter alia due to the release of a potassium competitive acid blocker under physiological conditions, the compounds according to the invention exhibit a marked inhibition of gastric acid secretion and an excellent gastric and intestinal protective action in warm-blooded animals, in particular humans.

"Gastric and intestinal protection" in this connection is understood as meaning the prevention and treatment of gastrointestinal diseases, in particular of gastrointestinal inflammatory diseases and lesions (such as, for example, gastric ulcer, peptic ulcer, including peptic ulcer bleeding, duodenal ulcer, gastritis, hyperacidic or medicament-related functional dyspepsia), which can be caused, for example, by microorganisms (e.g. Helicobacter pylori), bacterial toxins, chemicals (e.g. ethanol), gastric acid or stress situations or in particular by the NSAID which are released from the compounds of the formula I under physiological conditions. "Gastric and intestinal protection" is understood to include, according to general knowledge, gastroesophageal reflux disease (GERD), the symptoms of which include, but are not limited to, heartburn and/or acid regurgitation.

A further subject of the invention are therefore the compounds according to the invention for use in the treatment and/or prophylaxis of the abovementioned diseases.

The invention likewise includes the use of the compounds according to the invention for the production of medicaments which are employed for the treatment and/or prophylaxis of the abovementioned diseases.

The invention furthermore includes the use of the compounds according to the invention for the treatment and/or prophylaxis of the abovementioned diseases.

A further subject of the invention are medicaments which comprise one or more compounds of the formula I and/or their pharmacologically acceptable salts.

The medicaments are prepared by processes which are known per se and familiar to the person skilled in the art. As medicaments, the pharmacologically active compounds according to the invention (= active compounds) are either employed as such, or preferably in combination with suitable pharmaceu- tical auxiliaries or excipients in the form of tablets, coated tablets, capsules, suppositories, patches (e.g. as TTS), emulsions, suspensions or solutions, the active compound content advantageously being between 0.1 and 95% and it being possible to obtain a pharmaceutical administration form exactly adapted to the active compound and/or to the desired onset and/or duration of action (e.g. a sustained- release form or an enteric form) by means of the appropriate selection of the auxiliaries and excipients.

The auxiliaries and excipients which are suitable for the desired pharmaceutical formulations are known to the person skilled in the art on the basis of his/her expert knowledge. In addition to solvents, gel-forming agents, suppository bases, tablet auxiliaries and other active compound excipients, it is possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, flavor corrigents, preservatives, solubilizers, colorants or, in particular, permeation promoters and complexing agents (e.g. cyclodextrins).

The active compounds can be administered orally, parenterally or percutaneously.

The dosage of the compound of the formula I largely depends on the specific combination of the compound of the formula Ma and of the compound of the formula III. In general, it is desired to use a dose of the compound of the formula I, which results in a release in the human or animal body of an effective doses of both the compound of the formula Na and the compound of the formula III. However it should be noted that the compounds of the formula I according to the present invention can be administered in doses of up to 10-times more or less than the optimal dose of a the compound of the formula Na or the compound of the formula III if administered alone.

The daily dose of the compounds of the formula I can be administered, in the form of several, preferably 1 to 4, individual doses to achieve the desired results. In the case of a parenteral treatment, similar or (in particular in the case of the intravenous administration of the active compounds), as a rule, lower doses as compared to oral administration can be used. The establishment of the optimal dose and manner of administration of the active compounds necessary in each case and for each combination of compounds of the formula Ma and compounds of the formula III can easily be carried out by any person skilled in the art on the basis of his/her expert knowledge.

The compounds and compositions of the present invention may also be used in a fixed or free combination together with other suitable substances for co-therapies and/or prophylaxis of the abovemen- tioned illnesses. Said suitable substances comprise for example - without being restricted to - opioids and other analgesics, inducible nitric oxide synthase inhibitors, steroids, nonsteroidal antiinflamma-tory drugs (NSAID), cyclooxygenase-2 (COX-2) inhibitors, 5-lipoxygenase (5-LO) inhibitors, leukotriene B4 (LTB4) receptor antagonists, leukotriene A4 (LT A4) hydrolase inhibitors, 5-HT agonists, 3-hydroxy-3- methylglutaryl coenzyme A (HMG-CoA) inhibitors, H2 antagonists, antineoplastic agents, antiplatelet agents, antitussives, decongestants, diuretics, sedating or non-sedating anti-histamins, Helicobacter pylori inhibitors, reversible and irreversible proton pump inhibitors (such as those described in litera- ture, for example in Goodman and Gilman, The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill, 1995, p. 901 -915 or in the Merck Index on CD-ROM, 12th Edition, Version 12:1 , 1996, whereby omeprazole, lansoprazole, rabeprazole and pantoprazole are particularly mentioned), iso- prostane inhibitors, and, optionally, at least one compound that donates, transfers or releases nitric oxide, or elevates levels of endogenous endothelium-derived relaxing factor (EDRF) or nitric oxide, or is a substrate for nitric oxide synthase. The compounds can be administered separately, sequentially or simultaneously.

Claims

1. A compound of the formula I

in which

A is the residue derived from a corresponding carboxylic acid of the formula Na

O

Ha which carboxylic acid of the formula Ma is a compound with antipyretic, analgesic, antiphlogistic and/or anti-inflammatory properties, B is the residue derived from a corresponding hydroxy compound of the formula III III which hydroxy compound of the formula III is a compound from the class of potassium competitive acid blockers and is selected from one of the following compounds

^■ (7S,8R,9R)-2,3-dimethyl-7-ethoxy-8-hydroxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2- h][1 ,7]naphthyridine,

^■ (7S,8S,9S)-2,3-dimethyl-8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10- tetrahydroimidazo[1 ,2-h][1 ,7]naphthyridine, ^■ (7S,8R,9R)-2,3-dimethyl-8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10- tetrahydroimidazo[1 ,2-h][1 ,7]naphthyridine,

^■ (7S,8R,9R)-2,3-dimethyl-8-hydroxy-7-(2-methylthioethyloxy)-9-phenyl-7,8,9,10- tetrahydroimidazo[1 ,2-h][1 ,7]naphthyridine,

^■ (7R,8R,9R)-2,3-dimethyl-8-hydroxy-7-(2-methylsulphinylethoxy)-9-phenyl-7,8,9,10-tetrahydro- imidazo[1 ,2-h][1 ,7]naphthyridine,

^■ (7S,8R,9R)-2,3-dimethyl-8-hydroxy-9-phenyl-7-(2,2,2-trifluoroethoxy)-7H-8,9-dihydropyrano- [2,3-c]imidazo[1 ,2-a]pyridine, ^■ (y^SR^^^^-dimethyl-y-ethoxy-S-hydroxy-θ-phenyl-yH-S^-dihydropyrano^^-climidazo- [1 ,2-a]pyridine,

^■ (yS^R^^^^-dimethyl-y-ethoxy-S-hydroxy-θ-phenyl-yH-S^-dihydropyrano^^-climidazo- [1 ,2-a]pyridine,

^■ (7S,8R,9R)-2,3-dimethyl-8-hydroxy-7-(2-propoxy)-9-phenyl-7H-8,9-dihydropyrano[2,3- c]imidazo[1 ,2-a]pyridine,

^■ (7R,8R,9R)-3-chloro-8-hydroxy-7-(2-methoxyethoxy)-2-methyl-9-phenyl-7,8,9,10-tetrahydro- imidazo[1 .2-h][1.7]naphthyridine, ^■ (7R,8R,9R)-3-chloro-8-hydroxy-7-(2-methoxyethoxy)-2-methyl-9-phenyl-7H-8,9-dihydro- pyrano[2,3-c]imidazo[1 ,2-a]pyridine,

■ (7S,8R,9R)-8-hydroxy-7-methoxy-2-methyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2- h][1 ,7]naphthyridine,

^■ 5-Hydroxymethyl-2,3-dimethyl-8-phenyl-6,7,8,9-tetrahydro-3/-/-imidazo[4,5-/7]quinoline ^■ Methyl 8-(frans-2,3-dihydro-2-hydroxy-1 -indenylamino)-2,3-dimethyl-imidazo[1 ,2-a]pyridine-6- carboxylate

^■ 8-(frans-2,3-Dihydro-2-hydroxy-1 -indenylamino)-2,3-dimethyl-imidazo[1 ,2-a]pyridine-6- carboxamide

^■ 4-(frans-2,3-Dihydro-2-hydroxy-1 -indenyloxy)-1 ,2-dimethyl-1 /-/-benzimidazole-6-carboxylic Acid

^■ 4-(frans-5-Chloro-2,3-dihydro-2-hydroxy-1 -indenyloxy)-1 ,2-dimethyl-1 /-/-benzimidazole-6- carboxylic Acid ■ 4-(frans-5-Chloro-2,3-dihydro-2-hydroxy-1 -indenyloxy)-6-(N,N-dimethylaminocarbonyl)-1 ,2- dimethyl-1 /-/-benzimidazole

■ 4-(frans-2,3-Dihydro-2-hydroxy-1 -indenyloxy)-6-[N-(2-methoxyethyl)-N-methyl-aminocarbonyl]- 1 ,2-dimethyl-1 /-/-benzimidazole

^■ 6-(Cyclopropylaminocarbonyl)-4-(frans-2,3-dihydro-2-hydroxy-1 -indenyloxy)-1 ,2-dimethyl-1 H- benzimidazole

■ 1 -Benzyl-2,3-dimethyl-7-(2-hydroxymethylbenzyloxy)-pyrrolo[2,3-d]pyridazin

■ 1 -Benzyl-2,3-dimethyl-7-(2-hydroxyethylbenzyloxy)-pyrrolo[2,3-d]pyridazin

Y is a radical

R1 is hydrogen or 1 -4C-alkyl, or X, Y and z together form a bond, and its salts.

2. A compound of the formula I as claimed in claim 1 , in which

A is the residue derived from a corresponding carboxylic acid of the formula Na

Ha which carboxylic acid of the formula Ma is a compound with antipyretic, analgesic, antiphlogistic and/or anti-inflammatory properties, is the residue derived from a corresponding hydroxy compound of the formula III III which hydroxy compound of the formula III is a compound from the class of potassium competitive acid blockers and is selected from one of the following compounds

^■ (7R,8R,9R)-2,3-dimethyl-8-hydroxy-9-phenyl-7-(2,2,2-trifluoroethoxy)-7H-8,9-dihydropyrano- [2,3-c]imidazo[1 ,2-a]pyridine,

■ (7R,8R,9R)-8-hydroxy-7-(2-methoxyethoxy)-2-methyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2- h][1 ,7]naphthyridine, ^■ (7R,8R,9R)-3-chloro-8-hydroxy-7-(2-methoxyethoxy)-2-methyl-9-phenyl-7H-8,9- dihydropyrano-[2,3-c]-imidazo-[1 ,2-a]pyridine

■ 1 -Benzyl-2,3-dimethyl-7-(2-hydroxymethylbenzyloxy)-pyrrolo[2,3-d]pyridazin

■ 1 -Benzyl-2,3-dimethyl-7-(2-hydroxyethylbenzyloxy)-pyrrolo[2,3-d]pyridazin

Y is a radical

O A ^■ o^Λ whereby the carbonyl group is attached to A, z is a bond, -O-, -CHR1 - or -NR1 -, wherein

3. A compound of the formula I as claimed in claim 1 , in which

A is the residue derived from a corresponding carboxylic acid of the formula Na

(7R,8R,9R)-3-chloro-8-hydroxy-7-(2-methoxyethoxy)-2-methyl-9-phenyl-7H-8,9-dihydropyrano-[2,3- c]-imidazo-[1 ,2-a]pyridine,

1 -Benzyl-7-(4-fluorbenzyloxy)-3-hydroxymethyl-2-methyl-pyrrolo[2,3-d]pyridazin, 1 -Benzyl-2,3-dimethyl-7-(2-hydroxymethylbenzyloxy)-pyrrolo[2,3-d]pyridazin, X is either a bond or a linker,

Y is a radical

4. A compound of the formula I as claimed in claim 1 , in which

A is the residue derived from a corresponding carboxylic acid of the formula Na

O

_A^U_Q-H

Ua which carboxylic acid of the formula Ma is a compound with antipyretic, analgesic, antiphlogistic and/or anti-inflammatory properties, B is the residue derived from a corresponding hydroxy compound of the formula III

which hydroxy compound of the formula III is a compound from the class of potassium competitive acid blockers and is the following compound

(7R,8R,9R)-2,3-dimethyl-8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2- h][1 ,7]naphthyridine (SORAPRAZAN), X is either a bond or a linker,

Y is a radical

5. A compound of the formula I as claimed in claim 1 ,2,3 or 4, in which

A is the residue derived from one of the following exemplary carboxylic acid compounds glycolic acid [o-(2,6-dichloroanilino)phenyl]acetate(ester) [INN: ACECLOFENAC];

1 -(4-chlorobenzoyl)-5-methoxy-2-methyl-1 H-indole-3-acetic acid carboxymethyl ester [INN:

ACEMETACIN];

2-(acetyloxy)benzoic acid [AC ETYLSALI CYLI C ACID],

2,6-bis(1 ,1 -dimethylethyl)phenyl] ester [Research Code: AGI-1067]

2-amino-3-benzoylphenylacetic acid [INN: AMFENAC],

2-[(1 -benzyl-1 H-indazol-3-yl)methoxy]-2-methylpropionic acid [INN: BINDARIT],

[2-amino-3-(p-bromobenzoyl)phenyl]acetic acid [INN: BROMFENAC],

2-mercapto-2-methylpropanoyl-L-cysteine [INN: BUCILLAMINE],

3-(3-chloro-4-cyclohexylbenzoyl)propionic acid [INN: BUCLOXIC ACID], butylmalonic acid mono(1 ,2-diphenylhydrazide) [INN: BUMADIZONE], alpha-ethyl-4-(2-methylpropyl)benzeneacetic acid [INN: BUTIBUFEN], 2-(4-biphenylyl)butyric acid, trans-4-phenylcyclohexylamine salt (1 :1 ) [INN: BUTIXIRATE], 2-amino-3-[(carboxymethyl)thio]propionic acid [INN: CARBOCISTEINE] (plus/minus)-6-chloro-alpha-methylcarbazole-2-acetic acid [INN: CARPROFEN], i -cinnamoyl-δ-methoxy^-methylindole-S-acetic acid [INN: Cl NMETACIN], 6-chloro-5-cyclohexyl-1 -indancarboxylic acid [INN: CLIDANAC], 2-[4-(p-chlorophenyl)benzyloxy]-2-methylpropionic acid [INN: CLOBUZARIT], (S)-(+)-p-isobutylhydratropic acid [INN: DEXIBUPROFEN], (+)-(S)-m-benzoylhydratropic acid [INN: DEXKETOPROFEN], 1 ,8-diacetoxyanthraquinone-3-carboxylic acid [INN: DIACEREIN], 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC], 2',4'-Difluoro-4-hydroxy-3-biphenylcarboxylic acid [INN: DIFLUNISAL], 4-(2,6-dichloroanilino)-3-thiopheneacetic acid [INN: ELTENAC], N-beta-phenethyl-anthranilic acid [INN: ENFENAMIC ACID] 1 ,8-diethyl-1 ,3,4,9-tetrahydropyrano[3,4-b]indole-1 -acetic acid [INN: ETODOLAC], 4-biphenylacetic acid [INN: FELBINAC], 3-(4-biphenylylcarbonyl)propionic acid [INN: FENBUFEN], [o-(2,4-dichlorophenoxy)phenyl]acetic acid [INN: FENCLOFENAC], 5-(4,5-dihydro-2-phenyl-3H-benz[e]indol-3-yl)salicylic acid [INN: FENDOSAL] (plus/minus)-m-phenoxyhydratropic acid [INN: FENOPROFEN], 4-(p-chlorophenyl)-2-phenyl-5-thiazoleacetic acid [INN: FENTIAZAC], 4-(2',4'-difluorobiphenylyl)-4-oxo-2-methylbutanoic acid [INN: FLOBUFEN], N-(alpha,alpha,alpha-trifluoro-m-tolyl)anthranilic acid [INN: FLUFENAMIC ACID], (plus)-2-(p-fluorophenyl)-alpha-methyl-5-benzoxazoleacetic acid [INN: FLUNOXAPROFEN], 2-(2-fluoro-1 ,1 '-biphenyl-4-yl)propanoic acid [INN: FLURBIPROFEN], (2S)-2-(2-fluoro-1 ,1 '-biphenyl-4-yl)propanoic acid [INN: ESFLURBIPROFEN] 2-[4-(2'-furoyl)phenyl]propionic acid [INN: FURPROFEN], (p-isobutylphenyl)acetic acid [INN: IBUFENAC], alpha-p-isobutylphenylpropionic acid [INN: IBUPROFEN], (plus/minus)-2-[p-(1 -oxo-2-isoindolinyl)phenyl]butyric acid [INN: INDOBUFEN], 1 -(4-chlorobenzoyl)-5-methoxy-2-methyl-1 H-indole-3-acetic acid [INN: INDOMETACIN], p-(1 -oxo-2-isoindolinyl)hydratropic acid [INN: INDOPROFEN],

(DL)-5-benzoyl-3H-1 ,2-dihydropyrrolo[1 ,2-a]pyrrole-1 -carboxylic acid [INN: KETOROLAC], (2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1 H-pyrrolizin-5-yl)-acetic acid [INN : Ll- COFELONE]], N-(2-carboxyphenyl)-4-chloroanthranilic acid [INN: LOBENZARIT], 3-(p-chlorophenyl)-1 -phenylpyrazole-4-acetic acid [INN: LONAZOLAC], 2-[4-(2-oxocyclopentan-1 -ylmethyl)phenyl]-propionate [INN: LOXOPROFEN], 2-[2-(2-chloro-6-fluorophenylamino)-5-methylphenyl]acetic acid [INN: LUMIRACOXIB], N-(2,6-dichloro-m-tolyl)anthranilic acid [INN: MECLOFENAMIC ACID] N-(2,3-xylyl)anthranilic acid [INN: MEFENAMIC ACID], 5-aminosalicylic acid [INN: MESALAZINE],

3,4-bis(4-methoxyphenyl)-5-isoxazoleacetic acid [INN: MOFEZOLAC], (plus)-6-methoxy-alpha-methyl-2-naphthalineacetic acid [INN: NAPROXEN], 2-[3-(trifluoromethyl)anilino]nicotinic acid [INN: NIFLUMIC ACID], 5,5'-azodisalicylic acid [INN: OLSALAZINE], 4,5-diphenyl-2-oxazolepropionic acid [INN: OXAPROZIN], 4-aminosalicylic acid [INN: PAS],

3-chloro-4-(3-pyrrolin-1 -yl)hydratropic acid [INN: PIRPROFEN], 2-[5H-(1 )benzopyrano]2,3-b]pyridin-7-yl]propionic acid [INN: PRANOPROFEN], 7-methoxy-alpha,10-dimethylphenothiazine-2-acetic acid [INN: PROTIZINIC] ACID], 2-[[2-(p-chlorophenyl)-4-methyl-5-oxazolyl]methoxy]-2-methylpropionic acid [INN: ROMAZARIT], 2-hydroxybenzoic acid [SALICYLIC ACID], 2-hydroxybenzoic acid 2-carboxyphenyl ester [INN: SALSALATE],

(Z)-5-fluoro-2-methyl-1 -[p-(methylsulfinyl)benzylidene]indene-3-acetic acid [INN: SULINDAC], p-2-thenoylhydratropic acid [INN: SUPROFEN], butanedioic acid mono[(4-butyl-3,5-dioxo-1 ,2-diphenyl-4-pyrazolidinyl)-methyl]ester [INN: SUXIBU- ZONE],

2-thiophenecarboxylic acid, ester with salicylic acid [INN: TENOSAL], alpha-(5-benzoyl-2-thienyl)propionic acid [INN: TIAPROFENIC ACID], N-(3-chloro-o-tolyl)anthranilic acid [INN: TOLFENAMIC ACID], 1 -methyl-5-(4-methylbenzoyl)-1 H-pyrrole-2-acetic acid [INN: TOLMETIN],

2-(10,11 -dihydro-10-oxo-dibenz[b,f]thiepin-2-yl-propionic acid [INN: ZALTOPROFEN]. and its salts.

6. A compound of the formula I as claimed in claim 1 , 2, 3, 4, or 5, in which

X is a linker of the formula -(CH₂)_n-(O)_m-(CH₂)_p-(O)_q-(CH₂)_r, wherein n is an integer from 1 to 7, m is either O or 1 , p is an integer from O to 7, q is either O or 1 and r is an integer from O to 7, wherein, optionally, one or more of the hydrogen atoms in the -CH₂- radicals is substituted by a fluoro, 1 -4C-alkyl or fluoro-1 -4C-alkyl radical, with the proviso that p is not O if m is 1 , and r is not O if q is 1 or X, Y and z together form a bond, and its salts.

7. A compound of the formula I as claimed in claim 1 , 2, 3, 4, or 5, in which

X is a linker of the formula -(CH₂)_n-, wherein n is an integer from 1 to 7 or a linker of the formula

-(CH₂)₂-O-(CH₂)₂-O-CH₂- or a linker of the formula -(CH₂)₂-O-CH₂- and its salts.

8. A compound of the formula I as claimed in claim 1 , in which A is the residue derived from one of the following carboxylic acids:

DICLOFENAC, ELTENAC, FLURBIPROFEN, ESFLURBIPROFEN, SALICYLIC ACID, NAPROXEN or INDOMETACIN, B is the residue derived from one of the following hydroxy compounds:

1 -Benzyl-7-(4-fluorbenzyloxy)-3-hydroxymethyl-2-methyl-pyrrolo[2,3-d]pyridazin, 1 -Benzyl-2,3-dimethyl-7-(2-hydroxymethylbenzyloxy)-pyrrolo[2,3-d]pyridazin X is a linker of the formula -(CH₂)_n-(O)_m-(CH₂)_p-(O)_q-(CH₂)_r, wherein n is an integer from 1 to 7, m is either O or 1 , p is an integer from O to 7, q is either zero or 1 and r is an integer from O to 7, wherein, optionally, one or more of the hydrogen atoms in the -CH₂- radicals is substituted by a fluoro, 1 -4C-alkyl or fluoro-1 -4C-alkyl radical, with the proviso that p is not O if m is 1 , and r is not O if q is 1. is a radical O A ^■ o^' whereby the carbonyl group is attached to A, z is a bond, or X, Y and z together form a bond, and its salts.

9. A compound of the formula I as claimed in claim 1 , in which A is the residue derived from one of the following carboxylic acids:

DICLOFENAC,

ELTENAC,

FLURBIPROFEN,

ESFLURBIPROFEN,

SALICYLIC ACID,

NAPROXEN or

1 -Benzyl-7-(4-fluorbenzyloxy)-3-hydroxymethyl-2-methyl-pyrrolo[2,3-d]pyridazin

1 -Benzyl-2,3-dimethyl-7-(2-hydroxymethylbenzyloxy)-pyrrolo[2,3-d]pyridazin X is a linker of the formula -(CH₂)_n-, wherein n is an integer from 1 to 7, or a linker of the formula

-(CH₂)2-O-(CH₂)2-O-CH2- or a linker of the formula -(CH₂)₂-O-CH₂- Y is a radical

whereby the carbonyl group is attached to A, z is a bond, or X, Y and z together form a bond, and its salts.

10. A medicament comprising a compound as claimed in claim 1 and/or a pharmacologically acceptable salt thereof together with customary pharmaceutical auxiliaries and/or excipients.

11. The use of a compound as claimed in claim 1 and its pharmacologically acceptable salts for the prevention and treatment of inflammation, pain (both chronic and acute), fever, cancer and other cyclooxygenase mediated disorders, for facilitating wound healing and for gastro and intestinal protection.