Synthesis and properties of 1,3-disubstituted ureas and their isosteric analogues containing polycyclic fragments: XX. 1-[(3,5-difluoroadamantan-1-yl)]-3-R-ureas and symmetric diureas

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Abstract

A method has been developed for the production of (3,5-difluoroadamantan-1-yl) isocyanate from 3,5-difluoroadamantan-1 carboxylic acid and diphenyphosphoryl azide, using a new fluorinating agent, the Ishikawa reagent, at one of the synthesis stages. Reaction of (3,5- difluoroadamantane-1-yl)isocyanate with aliphatic diamines and trans-4-amino(cyclohexyloxy)A series of 1,3-disubstituted urea and dimourea with yields of 43-96% was synthesized with benzoic acid. By hydrolysis of (3,5-difluoroadamantan-1-yl)isocyanate in the presence of catalytic amounts of DBU, a symmetrical 1,3-bis(3,5-difluoroadamantan-1-yl) was obtainedurea with a yield of 47%.The influence of the number of fluorine atoms in the adamantile substituent on the melting temperatures and lipophilicity of urea has been established, which makes it possible to purposefully regulate these important properties of urea as potential enzyme inhibitors.

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B. P. Gladkikh

Volgograd State Technical University

Email: butov@post.volpi.ru
ORCID iD: 0000-0001-6271-0479
Russian Federation, prosp. Lenina 28, Volgograd, 400005

D. V. Danilov

Volgograd State Technical University

Email: butov@post.volpi.ru
ORCID iD: 0000-0001-8734-2617
Russian Federation, prosp. Lenina 28, Volgograd, 400005

V. S. Dyachenko

Volgograd State Technical University; VSTU

Email: butov@post.volpi.ru
ORCID iD: 0000-0002-6209-7106

Volzhsky polytechnic institute (branch) VSTU

Russian Federation, prosp. Lenina 28, Volgograd, 400005; ul. Engelsa 42a, Volzhsky, 404121

V. V. Burmistrov

Volgograd State Technical University

Email: butov@post.volpi.ru
ORCID iD: 0000-0002-8547-9166
Russian Federation, prosp. Lenina 28, Volgograd, 400005

G. M. Butov

Volgograd State Technical University; VSTU

Author for correspondence.
Email: butov@post.volpi.ru
ORCID iD: 0000-0002-0839-4513

Volzhsky polytechnic institute (branch) VSTU

Russian Federation, prosp. Lenina 28, Volgograd, 400005; ul. Engelsa 42a, Volzhsky, 404121

I. A. Novakov

Volgograd State Technical University

Email: butov@post.volpi.ru
ORCID iD: 0000-0002-0980-6591
Russian Federation, prosp. Lenina 28, Volgograd, 400005

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Supplementary files

Supplementary Files
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2. Fig. 1. 1-(1-Acetylpiperidin-4-yl)-3-adamantan-1-yl urea (A) and its fluorinated analogs (B, C) are candidate compounds for clinical trials

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3. Fig. 2. Structures of P2X7 receptor antagonists containing an adamantyl substituent

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4. Scheme 1

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5. Scheme 2

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6. Scheme 3

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7. Scheme 4

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8. Scheme 5

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9. Fig. 3. Dependence of logP (Y axis) on the number of methylene bridges n (X axis) in diureas with different contents of fluorine atoms in the adamantyl substituent

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10. Fig. 4. Dependence of the melting temperature on the number of methylene bridges n in diureas with different contents of fluorine atoms in the adamantyl substituent F–Ad [11]

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Note

Сообщение XIX см. [1].


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