5-(2,5-bis(4-chloro-2-isopropylphenyl)thiophen-3-yl)-1h-tetrazole for the topical treatment of bacterial infections

A technology of cumene and thiophene, which can be used as a dermatologically acceptable carrier to eliminate pathogenic bacteria in diabetic ulcers, in the field of cellulitis drugs, and can solve problems such as multidrug resistance

Pending Publication Date: 2020-08-11
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Unfortunately, currently available topical antibiotics are often ineffective due to their own physicochemical properties that prevent them from penetrat

Method used

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  • 5-(2,5-bis(4-chloro-2-isopropylphenyl)thiophen-3-yl)-1h-tetrazole for the topical treatment of bacterial infections
  • 5-(2,5-bis(4-chloro-2-isopropylphenyl)thiophen-3-yl)-1h-tetrazole for the topical treatment of bacterial infections
  • 5-(2,5-bis(4-chloro-2-isopropylphenyl)thiophen-3-yl)-1h-tetrazole for the topical treatment of bacterial infections

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] Example 1 - Synthesis of 5-(2,5-bis(4-chloro-2-isopropylphenyl)thiophen-3-yl)-1H-tetrazole

[0067] Refer to the following chemical schemes:

[0068]

[0069] Bromonitrile 2 (1.0 g, 3.7 mmol), isopropylphenyl borate 1 (2.31 g, 8.2 mmol, 2.2 equivalents) and Pd (PPh 3 ) 4 (0.22 g, 0.19 mmol, 0.05 equiv) was added to a round bottom flask and vacuum was applied for 3 seconds and flushed with argon 3 times. To this mixture was added 2M aqueous sodium carbonate solution (9.4ml, 18.8mmol, 5eq) and 20ml of dioxane. The reaction was stirred overnight at 95 °C, then quenched with water. The dark mixture was extracted with ethyl acetate (2 x 20ml), dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation. Thiobenzonitrile 3 (1.4 g, 90%) was obtained by flash column chromatography (25% DCM in hexane).

[0070] Thiobenzonitrile 3 (1.0g, 2.4mmol), sodium azide (0.39g, 6.0mmol, 2.5eq) and zinc bromide (1.36g, 6.0mmol, 2.5eq) were mixed with 20ml of...

Embodiment 2

[0072] Example 2 (prophetic)

[0073] Azide-free Synthesis of 5-(2,5-bis(4-chloro-2-isopropylphenyl)thiophen-3-yl)-1H-tetrazole

[0074] 5-(2,5-Bis(4-chloro-2-isopropylphenyl)thiophen-3-yl)-1H-tetrazole can also be prepared by protecting the tetrazole to give a mixture of N-protected tetrazoles . This step is followed by bromination to give the N-protected 5-bromotetrazole mixture, followed by palladium cross-coupling using thiophen-3-ylboronic acid. The resulting product was then brominated at the 2- and 5-positions of thiophene, followed by palladium cross-coupling using (4-chloro-2-isopropylphenyl)boronic acid. Deprotection of the N-protected tetrazole moiety decomposes the mixture into single products. Deprotection may be combined with or subsequently introduced into a pharmaceutically acceptable salt moiety using methods known in the art. A possible synthesis is given in the following scheme, where the nitrogen protecting group is benzyl:

[0075]

[0076]

Embodiment 3-

[0078] Preparation of a pharmaceutical composition comprising 5-(2,5-bis(4-chloro-2-isopropylphenyl)thiophen-3-yl)-1H-tetrazole and a dermatologically acceptable carrier

[0079] Compounds were formulated by dissolving 50 mg of compound in 50 μl of 100% DMSO, then gradually added and mixed into 5 ml of Glaxal matrix (WellSpring Pharmaceutical Canada Corp., Oakville, Canada) at a final concentration of 1% (w / v) compound and 1% (v / v) DMSO.

[0080] biological data

[0081] Minimum Inhibitory Concentration (MIC)

[0082] Using a broth microdilution assay according to Clinical Laboratory Standards Institute (CSLI) guidelines, we tested 5-(2,5-bis(4-chloro-2-isopropylphenyl)thiophen-3-yl)- 1H-tetrazole ("test sample" in the table below), established MICs against a variety of MDR bacteria and indicated associations with methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci ( VRE) and substantial activity of Streptococcus species. Antimicrobial susc...

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Abstract

A compound 5-(2,5-bis(4-chloro-2-isopropylphenyl)thiophen-3-yl)-1H-tetrazole, methods for the manufacture of said compound, topical compositions comprising said compound and methods of use thereof inthe topical treatment of infections caused by pathogenic bacteria as a wound site.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Provisional Patent Application No. 62 / 597,159, entitled "Topical Treatment of Infections," filed December 11, 2017, the contents of which are incorporated herein by reference. Background technique [0003] Diabetes is a serious disease that affects more than 415 million people worldwide and the incidence of the disease is projected to rise to more than 642 million by 2035 (International Diabetes Federation, 2016). People with diabetes can experience a number of serious complications, including decreased peripheral blood flow. Reduced blood flow to the extremities can cause episodes of peripheral neuropathy, the degeneration of peripheral nerves. Affecting up to 50% of people with diabetes, peripheral neuropathy is typically characterized by tingling, numbness and inability to feel pain in extremities, which can lead to infection developing into a diabetic ulcer (so-called "diabe...

Claims

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Application Information

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IPC IPC(8): C07D409/04A61K31/40A61K8/49A61P31/04A61Q19/06
CPCA61K8/49A61Q19/06C07D409/04A61P31/04A61Q17/005A61K31/41A61P17/02
Inventor 吴帆克里斯多夫·R·麦克马斯特唐纳德·F·韦弗
Owner DENOVAMED
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