Guanidinylamino heterocycle compunds useful as alpha-2 adrenoceptor agonists

a technology of guanidinylamino heterocycle and alpha-2 adrenoceptor, which is applied in the field of guanidinylamino heterocycle compunds useful as alpha-2 adrenoceptor agonists, can solve the problems of high specificity, many compounds found to be effective nasal decongestants are often found to have undesirable side effects, and achieve good activity

Inactive Publication Date: 2002-03-07
PROCTER & GAMBLE CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0007] It is an object of this invention to provide novel compounds having substantial activity in preventing or treating nasal congestion, otitis media, and sinusitis, without undesired side effects.
[0014] It is a still further object of this invention to provide such compounds which have good activity from peroral, parenteral, intranasal and / or topical dosing.

Problems solved by technology

However, many compounds related in structure to those of this invention do not provide the activity and specificity desirable when treating disorders modulated by alpha-2 adrenoceptors.
For example, many compounds found to be effective nasal decongestants are frequently found to have undesirable side effects, such as causing hypertension and insomnia at systemically effective doses.

Method used

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  • Guanidinylamino heterocycle compunds useful as alpha-2 adrenoceptor agonists
  • Guanidinylamino heterocycle compunds useful as alpha-2 adrenoceptor agonists
  • Guanidinylamino heterocycle compunds useful as alpha-2 adrenoceptor agonists

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0062] [(8-Methylquinolin-7-yl)amino]guanidine

[0063] A. 8-Methyl-7-nitroquinoline.

[0064] To a suspension of 2 g of 2-methyl-3-nitroaniline and 1.02 g of arsenic(V) oxide hydrate are added 2.88 mL of glycerin followed by 1.09 mL of concentrated sulfuric acid. The resulting black slurry is stirred at about 150.degree. C. for 4 hours. The black oil is cooled to room temperature, diluted with water and poured into a mixture of 25% aqueous ammonium hydroxide in ethyl acetate. The organic layer is washed with water followed by brine. The aqueous layers are extracted with ethyl acetate; the combined organic layers are dried over magnesium sulfate, filtered and rotary evaporated. The residue is purified by flash column chromatography on silica gel, eluting with 50% ethyl acetate / hexanes followed by recrystallization from hexanes / methylene chloride to provide 1.45 g of 8-methyl-7-nitroquinoline as a pale brown solid.

[0065] B. 7-Amino-8-methylquinoline.

[0066] To a solution of 1.45 g of 8-meth...

example 2

[0070] [(4-Methylbenzimidazol-5-yl)amino]guanidine

[0071] A. 2,3-Diamino-6-nitrotoluene.

[0072] To a solution of 30 g of 3-methyl-2,4-dinitroaniline in 750 mL of boiling ethanol is added dropwise over 90 minutes a solution of 109.6 g of sodium sulfide nonahydrate in 750 mL of water. At the end of the addition, the mixture is heated to reflux for 30 minutes, then poured into ice (2000 g) and allowed to stand until all the ice has melted. The mixture is then extracted with methylene chloride and the organic layer is dried over magnesium sulfate and rotary evaporated. The residue is purified by flash column chromatography on silica gel, eluting with methylene chloride to provide 2,3-diamino-6-nitrotoluene as an orange solid.

[0073] B. 4-Methyl-5-nitrobenzimidazole.

[0074] A mixture of 11.8 g of 2,3-diamino-6-nitrotoluene, 390 mL of 88% formic acid and 38 mL of 12N hydrochloric acid is heated to reflux for 1 hour. The resulting mixture is cooled to room temperature and rotary evaporated. Th...

example a

[0158]

2 Oral Tablet Composition Ingredient Amount per tablet (mg) Subject Compound 2 20.0 Microcrystalline cellulose (Avicel PH 102 .RTM.) 80.0 Dicalcium phosphate 96.0 Pyrogenic silica (Cab-O-Sil .RTM.) 1.0 Magnesium stearate 3.0 Total = 200.0 mg

[0159] One tablet is swallowed by a patient with nasal congestion. The congestion is substantially diminished.

[0160] Other compounds having a structure according to Formula I are used with substantially similar results.

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Abstract

This invention involves compounds having the following structure: as described in the claims; and enantiomers, optical isomers, stereoisomers, diastereomers, tautomers, addition salts, biohydrolyzable amides and esters thereof, as well as pharmaceutical compositions comprising such novel compounds. The invention also relates to the use of such compounds for preventing or treating disorders modulated by alpha-2 adrenoceptors.

Description

CROSS REFERENCE[0001] This application claims priority under Title 35, United States Code 119(e) from Provisional Application Ser. No. 60 / 031,833, filed Nov. 25, 1996.[0002] This invention relates to certain substituted guanidinylamino heterocycle compounds. The compounds have been found to be alpha-2 adrenoceptor agonists and are useful for treatment of disorders modulated by alpha-2 adrenoceptors.[0003] Therapeutic indications of alpha-2 adrenoceptor agonists have been discussed in the literature: Ruffolo, R. R., A. J. Nichols, J. M. Stadel, & J. P. Hieble, "Pharmacologic and Therapeutic Applications of Alpha-2 Adrenoceptor Subtypes", Annual Review of Pharmacology & Toxicology, Vol. 32 (1993) pp. 243-279.[0004] Information regarding alpha adrenergic receptors, agonists and antagonists, in general, and regarding compounds related in structure to those of this invention are disclosed in the following references: Timmermans, P. B. M. W. M., A. T. Chiu & M. J. M. C. Thoolen, "12.1 .al...

Claims

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Application Information

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Patent Type & AuthorityApplications(United States)
IPC IPC(8): A61K31/47C07D215/06C07D215/16C07D215/38C07D215/40C07D235/06C07D277/62C07D417/12
CPCA61K31/47C07D215/06C07D215/16C07D215/38C07D215/40C07D235/06C07D277/62C07D417/12
InventorCUPPS, THOMAS LEEBOGDAN, SOPHIE EVAHENRY, RAYMOND TODDSHELDON, RUSSELL JAMESSEIBEL, WILLIAM LEEARES, JEFFREY JOSEPH
OwnerPROCTER & GAMBLE CO