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Aromatic heterocyclic compounds as antiinflammatory agents

a heterocyclic compound and antiinflammatory agent technology, applied in the field of aromatic heterocyclic compounds as antiinflammatory agents, can solve the problems of bioavailability and stability, high cost of protein therapeutics, etc., and achieve the effects of improving stability of inhibitors, facilitating the administration of pharmaceutical compositions, and increasing dissolution or dispersion

Inactive Publication Date: 2002-05-16
CIRILLO PIER F +4
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0284] The compounds of this invention may be administered alone or in combination with adjuvants that enhance stability of the inhibitors, facilitate administration of pharmaceutic compositions containing them in certain embodiments, provide increased dissolution or dispersion, increase inhibitory activity, provide adjunct therapy, and the like, including other active ingredients. Advantageously, such combination therapies utilize lower dosages of the conventional therapeutics, thus avoiding possible toxicity and adverse side effects incurred when those agents are used as monotherapies. Compounds of the invention may be physically combined with the conventional therapeutics or other adjuvants into a single pharmaceutical composition. Advantageously, the compounds may then be administered together in a single dosage form. In some embodiments, the pharmaceutical compositions comprising such combinations of compounds contain at least about 5%, but more preferably at least about 20%, of a compound of formula (I) (w / w) or a combination thereof. The optimum percentage (w / w) of a compound of formula(I) may vary and is within the purview of those skilled in the art. Alternatively, the compounds may be administered separately (either serially or in parallel). Separate dosing allows for greater flexibility in the dosing regime.

Problems solved by technology

Protein therapeutics are costly to produce and have bioavailability and stability problems.

Method used

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  • Aromatic heterocyclic compounds as antiinflammatory agents
  • Aromatic heterocyclic compounds as antiinflammatory agents
  • Aromatic heterocyclic compounds as antiinflammatory agents

Examples

Experimental program
Comparison scheme
Effect test

example 1

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)n-aphthalen-1-yl]-urea:

[0286] 36

[0287] A mixture of 4-methylphenyl hydrazine hydrochloride (10.0 g) and 4,4-dimethyl-3-oxopentanenitrile (8.67 g) in 150 mL ethanol and 7 mL concentrated HCl was heated at reflux overnight, cooled to room temperature, basified to pH 12 with alkali and extracted with diethyl ether. The combined organic extracts were washed with brine and dried (MgSO.sub.4). Removal of the volatiles in vacuo left a residue which was triturated with hot petroleum ether (100 mL) and provided 12.5 g of LXVII.

[0288] To a mixture of 4-amino-1-naphthol hydrochloride (LXIII) (172.1 g) in 750 mL anhydrous THF at -78.degree. C. was added dropwise over 60 min n-butyl lithium (490 mL of a 1.60 M solution in hexanes). After the addition was complete the mixture was allowed to warm to room temperature and then cooled to -78.degree. C. and di-tert-butyl dicarbonate ((BOC).sub.2O, 192 g) in 200 mL THF was added o...

example 2

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(tetrahydropyran-2-yl-o-xy)propyn-1-yl)naphthalen-1-yl]-urea:

[0291] 37

[0292] Tetrahydro-2-(2-propynyloxy)-2H-pyran (LXVIII) (2.50 mL; 17.8 mmol) in 100 mL anhydrous THF at -78.degree. C. under inert atmosphere was treated with n-butyllithium (7.1 mL of a 2.5 M solution in hexanes), added via syringe. The reaction was warmed to -20.degree. C. and after 1 h stirring, tributyltin chloride (4.8 mL, 17.8 mmol) was added. After stirring at -20.degree. C. for 1 h the reaction mixture was quenched with dilute NaHCO.sub.3 solution (75 mL) and extracted with ethyl ether (3.times.50 mL). The combined ethereal extracts were washed with brine and dried (MgSO.sub.4). After filtration all volatiles were removed in vacuo to produce LXIX as a yellow oil (4.7 g; 11.0 mmol or 62% yield).

[0293] A mixture LXVII (Example 1) (1.00 g; 3.76 mmol) and phosgene (5.6 mL of a 2 M solution in toluene) and 4-bromonaphthylamine were reacted according to Method B (...

example 3

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-pyridin-4-yl-propoxy)na-phthalen-1-yl]-urea (3):

[0295] 38

[0296] To a mixture of LXIV (Example 1) (0.51 g), 4-pyridinyl-1-propanol (0.76 mL), and triphenylphosphine (1.5 g) in 10 mL anhydrous THF was added dropwise diethyl azodicarboxylate (DEADC, 0.90 mL). After stirring overnight, the volatiles were removed in vacuo. Purification of the residue by flash chromatography using 25% hexanes in ethyl acetate as the eluent and concentration of the product-rich fractions in vacuo provided ether LXXI. A mixture of LXXI (0.74 g) and HCl (5 mL, 4.0 M in dioxane) in 10 mL anhydrous dioxane was stirred overnight. Collection of the precipitate by vacuum filtration provided LXXII. LXXVII (Example 1) (0.23 g), saturated NaHCO.sub.3 (15 mL), dichloromethane (15 mL), phosgene (2.1 mL, 1.93M in toluene) and LXXII (0.32 g) were reacted according to Method B (Scheme I and Example 1). Purification of the residue by flash chromatography using 25% hexanes...

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Abstract

Disclosed are novel aromatic heterocyclic compounds of the formula(I) wherein Ar1, Ar2, L, Q and X are described herein. The compounds are useful in pharmaceutic compositions for treating diseases or pathological conditions involving inflammation such as chronic inflammatory diseases. Also disclosed are processes of making such compounds.

Description

RELATED APPLICATION DATA[0001] This application is a divisional of U.S. application Ser. No. 09 / 484,638 filed Jan. 18, 2000.[0002] This invention relates to novel aromatic heterocyclic compounds of formula (I): 2[0003] wherein Ar.sub.1, Ar.sub.2, X, L and Q are defined below, which inhibit production of cytokines involved in inflammatory processes and are thus usefuil for treating diseases and pathological conditions involving inflammation such as chronic inflammatory disease. This invention also relates to processes for preparing these compounds and to pharmaceutical compositions comprising these compounds.[0004] Tumor necrosis factor (TNF) and interleukin-1 (IL-1) are important biological entities collectively referred to as proinflammatory cytokines. These, along with several other related molecules, mediate the inflammatory response associated with the immunological recognition of infectious agents. The inflammatory response plays an important role in limiting and controlling pa...

Claims

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Application Information

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IPC IPC(8): A61K31/415A61K31/435A61K31/4439A61K31/5377C07D231/38A61K31/541A61P1/04A61P3/10A61P17/06A61P19/02A61P19/10A61P25/28A61P29/00A61P37/00A61P37/06C07D231/40C07D401/04C07D401/12C07D401/14C07D403/12C07D405/12C07D413/12C07D417/12
CPCC07D231/38C07D231/40C07D401/04C07D401/12C07D417/12C07D403/12C07D405/12C07D413/12C07D401/14A61P1/04A61P17/06A61P19/02A61P19/10A61P25/28A61P29/00A61P37/00A61P37/06A61P3/10
Inventor CIRILLO, PIER F.GILMORE, THOMAS A.HICKEY, EUGENE R.REGAN, JOHN R.ZHANG, LIN-HUA
Owner CIRILLO PIER F
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