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New compounds

a new type of compound technology, applied in the field of compounds, can solve the problems of adverse biological effects, gastrointestinal side effects, and reduced formation of all metabolites, and achieve the effects of affecting platelet and renal function, and reducing the formation of all metabolites

Inactive Publication Date: 2012-08-02
BOEHRINGER INGELHEIM INT GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0303]Compounds of the invention may also have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and / or have a better pharmacokinetic profile (e.g. higher oral bioavailability and / or lower clearance) than, and / or have other useful pharmacological, physical, or chemical properties over, compounds known in the prior art, whether for use in the above-stated indications or otherwise.

Problems solved by technology

However, the inhibition of COXs has the disadvantage that it results in the reduction of the formation of all metabolites downstream of PGH2, some of which are known to have beneficial properties.
In view of this, drugs which act by inhibition of COXs are therefore known / suspected to cause adverse biological effects.
For example, the non-selective inhibition of COXs by NSAIDs may give rise to gastrointestinal side-effects and affect platelet and renal function.
Even the selective inhibition of COX-2 by coxibs, whilst reducing such gastrointestinal side-effects, is believed to give rise to cardiovascular problems.
These drugs may be given orally, but do not control inflammation satisfactorily.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

2-[5-(1-Acetamidoethyl)-2-chlorophenylamino]-N-(4-bromophenyl)-1-methylbenz-imidazole-5-carboxamide

[0413]

(a) 4-Chloro-α-methyl-3-nitrobenzylamine

[0414]Ammonium acetate (3.86 g, 50 mmol), NaBH3CN (0.22 g, 3.5 mmol), and 3 Å molecular sieves (25 g) were added to a mixture of 4-chloro-3-nitroacetophenone (1.00 g, 5 mmol) in MeOH (15 mL) at rt. The mixture was stirred at rt for 20 h and NaHCO3 (aq, sat) and EtOAc were added. The mixture was filtered and the aq layer washed with EtOAc. The combined organic phases were dried over Na2SO4 and concentrated to give the sub-title compound. Yield: 0.27 g (27%).

(b) N-[1-(4-Chloro-3-nitrophenyl)ethyl]acetamide

[0415]TEA (0.28 mL, 2.0 mmol) followed by acetylchloride (96 μL, 1.3 mmol) were added to 4-chloro-α-methyl-3-nitrobenzylamine (0.27 g, 1.3 mmol) in THF (5 mL) at rt. The mixture was stirred at rt for 3.5 h and additional acetylchloride (20 μL, 0.27 mmol) was added. After 1 h at rt, NaHCO3 (aq, 5%) was added and the mixture extracted with EtO...

example 2

2-[5-(tert. Butylcarbonylaminomethyl)-2-chlorophenylamino]-6-chloro-N-(2,2,2-trifluorethyl)-benzimidazole-5-carboxamide

[0425]

(a) tert-Butyl 4-chloro-3-nitrobenzylcarbamate

[0426]Di-tert-butyl dicarbonate (21.05 g, 96.5 mmol) in DCM (30 mL) was added to an ice-cooled mixture of 4-chloro-3-nitrobenzylamine (15 g, 80.4 mmol), DMAP (0.49 g, 4 mmol) and DCM (100 mL). The mixture was stirred at rt for 12 h, poured into ammonia and extracted with DCM. The combined extracts were washed with brine and concentrated.

[0427]The residue was washed with Et2O to give the sub-title compound which was used directly in the next step without any further purification.

(b) tert-Butyl 3-amino-4-chlorobenzylcarbamate

[0428]A mixture of tert-butyl 4-chloro-3-nitrobenzylcarbamate (crude material from step (b)), Fe powder (17.65 g, 316 mmol), NH4Cl (aq, sat, 100 mL) and EtOH (100 mL) was heated at 90° C. for 4 h and allowed to cool. The pH was adjusted to ˜10 and the mixture was filtered through Celite. The soli...

example 3

6-Chloro-2-{2-chloro-5-[(1-methylcyclohexylamido)methyl]phenylamino}-N-cyclopentyl-1-methylbenzimidazole-5-carboxamide

[0437]

(a) 2-Chloro-N-cyclopentyl-4-fluoro-5-nitrobenzamide and 2-Chloro-N-cyclopentyl-4-cyclopentylamino-5-nitrobenzamide

[0438]2-Chloro-4-fluoro-5-nitrobenzoyl chloride (1.5 g, 6.30 mmol) was added to a mixture of cyclopentylamine (430 μL, 12.6 mmol), TEA (1.76 mL, 12.6 mmol) and DCM (30 mL) at −20° C. After 12 h at rt, the mixture was diluted with DCM and washed with NH4OH (aq sat). The organic layer was washed with H2O and brine, dried over Na2SO4, concentrated and purified by HPLC to afford 510 mg (28%) of 2-chloro-N-cyclopentyl-4-fluoro-5-nitrobenzamide and 300 mg (14%) of 2-chloro-N-cyclopentyl-4-cyclopentylamino-5-nitro-benzamide.

(b) 2-Chloro-N-cyclopentyl-4-methylamino-5-nitrobenzamide

[0439]N-Methylamine in MeOH (2 M, 2.0 mL, 4.0 mmol) was added to 2-chloro-N-cyclopentyl-4-fluoro-5-nitrobenzamide (230 mg, 0.79 mmol) in EtOH. The mixture was heated at 50° C. fo...

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Abstract

The present invention relates to compounds of general formula Iin which A, L, M, Q2, Q3, Q4, R1, R5, Ra, Rb, Rc, W, X, Y, Z1, Z2, Z3 are defined in the description, the salts thereof, particularly the physiologically acceptable salts thereof.The compounds are of potential utility in the treatment and / or prevention of inflammatory diseases and associated conditions, in particular, in the treatment and / or prevention of pain.The invention also relates to the use of such compounds as medicaments, to pharmaceutical compositions containing them, and to their preparation.

Description

FIELD OF THE INVENTION[0001]This invention relates to novel compounds, which are inhibitors of the microsomal prostaglandin E2 synthase-1 (mPGES-1), pharmaceutical compositions containing them, and their use as medicaments for the treatment and / or prevention of inflammatory diseases and associated conditions.BACKGROUND OF THE INVENTION[0002]There are many acute and chronic diseases / disorders that are inflammatory in their nature including but not limited to rheumatoid diseases e.g. rheumatoid arthritis, osteoarthritis, diseases of the visceral system e.g. inflammatory bowel syndrome, autoimmune diseases, e.g. lupus erythematodes, lung diseases like asthma and COPD. Current treatment with non-steroidal anti-inflammatory drugs (NSAIDs) and Cyclooxygenase (COX)-2 inhibitors are efficacious, but show a prevalence for gastrointestinal and cardiovascular side effects. There is a high need for new treatment options showing equivalent efficacy with an improved side effect profile.[0003]NSAI...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/454A61K31/4184C07D403/10C07D409/12A61K31/4439C07D405/10C07D405/12C07D403/12A61P29/00C07D235/30C07D401/12
CPCC07D235/30C07D401/12C07D403/12C07D409/12C07D405/12A61P11/00A61P25/04A61P29/00
Inventor PFAU, ROLANDARNDT, KIRSTENDOODS, HENRIKLINDER, KLAUSKUELZER, RAIMUNDLUBRIKS, DIMITRIJSMACK, JUERGENPELCMAN, BENJAMINPRIEPKE, HENNINGROENN, ROBERTSTENKAMP, DIRKSUNA, EDGARS
Owner BOEHRINGER INGELHEIM INT GMBH
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