Solid-Phase Synthesis of 6-Sulfonylamino Morphinan Libraries

Abstract

A solid-phase synthesis of 6-sulfonylamino morphinan has been developed. The morphinan derivatives were designed as selective opioid ligands. The sulfonamide moiety was introduced by reductive amination of a ketone on solid phase, followed by sulfonylation of the resulting amine. Using this methodology, the synthesis of three combinatorial libraries was accomplished to prepare 339 morphinan derivatives with over 70% purity.Combinatorial chemistry has been shown to be an important tool that aids in the discovery of new drug leads as well as in the optimization of lead compounds. 1 For a rapid assembly of a huge number of compounds, solid-phase technology is very useful because it can simplify work up and purification. This is especially essential for the synthesis of a library whose compounds are difficult to extract with organic solvent or purify by column chromatography owing to their high polarity. For example, we have previously reported an efficient solid-phase synthesis of oligosaccharide conjugated enediynes by solid-supported coupling of hydroxyl free tri-to monosaccharides to a 9-membered enediyne. 2 Opioids receptors are generally classified to three types (m, d, and k) not only by pharmacological studies but also by molecular biological studies. Previously, there have been numerous studies for the synthesis of selective opioid ligands. 3 Recently we have been developed TRK-820(1) as a new type of k-agonist 4 on the basis of the "message-address concept" 5 and "accessory site hypothesis" 6 ( Figure 1). The message part is a morphinan skeleton having a phenol group, which is an essential moiety for elicitation of intrinsic activity on opioid receptors. The address part is an amide side-chain, which generates selectivity for subtypes of the opioid receptor. In order to discover new novel selective ligands for other subtypes, morphinan derivatives having a different side chain could be a promising candidate. Herein we describe the design of novel morphinan opioid ligands 2 having a sulfonamide side chain and the efficient library synthesis on solid-phase based on sequential diversification by reductive amination followed by sulfonylation.Our new morphinan derivatives 2 have a sulfonamide side chain. The sulfonamide derivatives 2 are expected to show different selectivity toward the opioid receptors because of a difference in conformation between the side chains. However, handling of the morphinan derivatives 2 should be relatively difficult owing to their high polarity derived from their phenol and tert-amine. In order to simplify the handling, we would apply the solid-phase technology to the library synthesis. Our strategy for the solidphase synthesis of the sulfonamide 2 is illustrated in Figure 1. Introduction of the sulfonamide chain to morphinan skeleton is based on two sequential modifications of naltrexone 4 immobilized at the phenol on Wang resin. 1) Reductive amination of ketone 4 with amine 6 would provide the bound amine. 2) The resulting amine would be converted to the sulfonamide 3 by treatment...

Synthesis of 6‐Amino Acid Substituted Derivatives of the Highly Potent Analgesic 14‐O‐Methyloxymorphone

“…Ionizable compounds with an amide function (except for the 6-glycine derivative of naltrexone) at C(6) of the morphinan skeleton were synthesized from b-oxymorphamine (1) and b-naltrexamine (2) [19], or from b-funaltrexamine (b-FNA; 3) [22]. A recent study describes the synthesis of zwitterionic 6-sulfonamide compounds synthesized from naltrexone (NTX; 4) [25].…”

“…These differ from the earlier published compounds, since the substituents at C(6) are amines instead of amides [19] [22] or sulfonamides [25]. 14-O-Methyloxymorphone (5), a compound that is 40 times more potent in the hot-plate assay in mice than its 14-hydroxy analogue oxymorphone (6) [26], has been used as a starting material for the synthesis of the zwitterionic derivatives as outlined in the Scheme.…”

N-Alkylation Reactions and Indirect Formation of Amino Functionalities in Solid-Phase Synthesis

“…Furthermore, reductive amination procedures have proved to be efficient for N-alkylation in SPS sequences leading to complex small molecules such as 30-37 ( Figure 3). [111][112][113][114][115][116][117][118][119]…”

“…[107][108][109][110] As shown in Figure 3, structurally diverse heterocyclic and/or polycyclic as well as macrocyclic small molecules were prepared by SPS using reductive amination as one of the steps in the synthetic sequence. [111][112][113][114][115][116][117][118][119] Ley et al (30, 36-86% yields) 111 and Ohno et al (33, 75-94% yields) 115 treated keto groups in relatively complex, resin-bound substrates with primary amines in the presence of borohydride species. Other examples involve the coupling of amines with immobilized aldehydes 112,116 or aldehydes with immobilized amines, 118,119 and in one example, a resin-bound aldehyde was converted into a secondary amine, which was further alkylated with another aldehyde to give the tertiary amino functionality in 35 (58-91% yields).…”

“…Structures of compound libraries 30-37. The arrows indicate bonds that arise from an aldehyde/ketone in the reductive amination [111][112][113][114][115][116][117][118][119]. …”