Organic carbamates in drug design and medicinal chemistry

Abstract

The carbamate group is a key structural motif in many approved drugs and prodrugs. There is an increasing use of carbamates in medicinal chemistry and many derivatives are specifically designed to make drug-target interactions through their carbamate moiety. In this Perspective, we present properties and stabilities of carbamates, reagents and chemical methodologies for the synthesis of carbamates, and recent applications of carbamates in drug design and medicinal chemistry.

Figure 1

Possible resonance structures for the carbamate moiety.

Figure 2

Syn and anti conformations of carbamates.

Figure 3

Possible dimer between a syn-carbamate and an acid group.

Figure 4

(A) Syn-carbamate of 1 is stabilized by hydrogen bonding with acetic acid; (B) acetic acid is associated with the anti rotamer of 2; (C) association of 3 with anti-rotamer of 2; (D) association of 3 with the syn-rotamer (preferred); (E) association of 3 with the syn rotamer of 1 is disfavored.

Figure 5

Example of carbamate drugs displaying different metabolic stability.

Scheme 1. Traditional Synthetic Methodologies Adopted for the Synthesis of Carbamates

Figure 6

Most commonly employed carbonate reagents for carbamate synthesis.

Scheme 2. Carbamate Synthesis via Activated Mixed Carbonates (Highlighted in the Red Box)

Scheme 3. Solid-Phase Synthesis of Carbamates Using Aromatic Amines and Merrifield Resin

Scheme 4. Synthesis of N-Alkyl Carbamates by a Three-Component Coupling of Primary Amines, CO₂, and an Alkyl Halide in the Presence of Cesium Carbonate and TBAI

Scheme 5. Halogen-Free Carbamate Synthesis Employing Dense Carbon Dioxide in the Presence of Amines and Alcohols

Scheme 6. Ni-Based Catalytic Systems for Dehydrative Urethane Formation from Carbon Dioxide, Amine, and Alcohol

Scheme 7. DBU-Catalyzed Carbamate Formation in the Presence of Gaseous Carbon Dioxide

Scheme 8. Carbamate Formation by a PdCl₂-Catalyzed Efficient Assembly of Organic Azides, Carbon Monoxide, and Alcohols

Scheme 9. Carbamate Synthesis by the Use of Carbamoylimidazolium Salts

Scheme 10. Synthesis of Methyl Carbamates by a Modified Hofmann Rearrangement

Scheme 11. Synthesis of Carbamates by Modified Curtius Rearrangement

Scheme 12. Indium-Catalyzed Carbamate Formation

Scheme 13. Coupling of Organoindium Reagents with Imines via Copper Catalysis

Scheme 14. Carbamate Synthesis Employing 1-Alkoxycarbonyl-3-nitro-1,2,4-triazole Reagents

Scheme 15. Carbamate Preparation by Reductive Carbonylation of Aromatic Nitro Compounds

Scheme 16. Carbamate Synthesis via Transfunctionalization of Substituted Ureas and Carbonates in the Presence of DBTO

Scheme 17. Zr(IV)-Catalyzed Carbonate–Carbamate Exchange

Scheme 18. Carbamates Synthesis in Aqueous Media by the Use of CDI

Scheme 19. CDI-Mediated Lossen Rearrangement for Carbamate Synthesis

Scheme 20. TCT-Mediated Lossen Rearrangement for Carbamate Synthesis

Figure 7

Carbamates with clinical potential.

Figure 8

Representative carbamate-containing therapeutic HIV protease inhibitors.

Figure 9

Examples of phenol carbamate prodrugs and their metabolic activation.

Scheme 21. Plasmin Hydrolysis and Subsequent Spontaneous Cyclization of the N,N′-Dimethyl Ethylenediamine Spacer and Release of Paclitaxel

Figure 10

Examples of amine and amidine prodrugs and their metabolic activation.

Figure 11

Evolution of 3-tetrahydrofuranyl carbamate as an HIV-1 protease inhibitor.

Figure 12

Cyclic sulfolane and bicyclic ligand-derived carbamates as HIV-1 protease inhibitors.

Figure 13

Design of bicyclic carbamate and inhibitor 239-bound HIV-1 protease X-ray structure.

Figure 14

Darunavir and highlight of the X-ray structure of darunavir-bound HIV-1 protease showing the main interactions.

Scheme 22. Assembly of Carbamate Functionality of Darunavir

Figure 15

Bis-THF-derived protease inhibitors for preclinical and clinical development.

Figure 16

Cyclic ether carbamate-derived novel protease inhibitors.

Figure 17

Design of pseudopeptide BACE1 inhibitors.

Figure 18

Carbamate-based macrocyclic BACE1 inhibitors.

Figure 19

Carbamate-derived selective BACE1 inhibitors.

Scheme 23. Synthesis of BACE1 Inhibitors 258 and 259

Figure 20

Butyl sulfone carbamate-derived selective BACE1 inhibitors.

Figure 21

Carbamate-derived potent γ-secretase inhibitors.

Figure 22

Tetrahydroquinoline and piperidine sulfonamide carbamate-derived γ-secretase inhibitors.

Figure 23

Carbamate-appended sulfonamides as γ-secretase inhibitors.

Figure 24

Structures of representative carbamate-containing kallikrein, thrombin, and elastase inhibitors.

Figure 25

Structural evolution of carbamate-containing HCV NS3/4A protease inhibitors from ciluprevir to the discovery of boceprevir.

Figure 26

Structure of carbamate-containing HCV NS3/4A protease inhibitors.

Figure 27

Carbamate-containing α-ketoamide inhibitors of HCV NS3/4A protease and α-ketoheterocycle inhibitors of HNE.

Figure 28

Carbamate-containing HCV NS5A inhibitors daclatasvir and ledipasvir.

Figure 29

Representative carbamate-containing cysteine protease inhibitors.

Figure 30

Representative carbamate-containing inhibitors of MAGL, ABHD6, and FAAH.