- Process development of (2-nitrophenylcarbamoyl)-(S)-prolyl-(S)-3-(2-naphthyl)alanyl-n-benzyl-n- methylamide (SDZ NKT343)
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(2-Nitrophenylcarbamoyl)-(S)-prolyl-(S)-3-(2-naphthyl)alanyl-N-benzyl-N- methylamide (1; SDZ NKT343) is a human NK-1 tachykinin receptor antagonist. The development of a robust process for a multikilogram scale, chromatography-free preparation of this compound is described. The new four-step synthesis was based on a convergent approach, which utilized a peptide coupling of 1-[(2-nitrophenylamino)carbonyl]-L-proline (11) with free base of (S)-3-(2-naphthyl)alanyI-N-benzyl-N-methylamide hydrochloride (4) as the key step in the presence of 1,3-dicyclohexylcarbodiimide and 1-hydroxybenzotriazole as coupling agents. A scale-up of the well-known mixed anhydride coupling method, using isobutyl chloroformate, to produce 4 was found to be problematic due to coupling of the amine at the undesired carbonyl group of the mixed anhydride. This problem was overcome. The drug substance, initially an amorphous powder, was obtained with the desired purity without any chromatography. A process for crystallization of 1 was also developed.
- Prashad, Mahavir,Prasad, Kapa,Repic, Oljan,Blacklock, Thomas J.,Prikoszovich, Walter
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p. 409 - 415
(2013/09/08)
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- 2-Nitrophenylcarbamoyl-(S)-prolyl-(S)-3-(2-naphthyl)alanyl-N-benzyl-N- methylamide (SDZ NKT 343), a potent human NK1 tachykinin receptor antagonist with good oral analgesic activity in chronic pain models
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A lead compound which had sub-micromolar affinity for the rabbit NK1 receptor but negligible affinity for rat NK1 receptors, 3a, was discovered by directed screening. 2-Substitution in the ring of the benzylthiourea substituent in the initial lead was found to be important, and halogens (Cl, Br) in this position were found to improve affinity for the human receptor. The activity of a series of 2-halo-substituted benzylthioureas was then optimized by modification of the proline diphenylmethyl amide, guided by a simple conceptual model based on structural overlay between these early antagonists and NK1 selective peptides. In this way, aromatic amino acid amides were identified which had improved affinity with respect to the starting diphenylmethyl (DPM) amides. The first sub-nanomolar ligand for the human NK1 receptor which arose from this series, 4af, combined a 2- chlorobenzylthiourea unit with a 2-naphthylalanine amide. Contemporaneously it was discovered that the benzylthiourea unit could be simplified to a phenylthiourea providing that an appropriate 2-substituent was also incorporated. Combination of these two series gave 2-NO2 phenylthiourea analogues which led directly to the analogous urea, 5f (2- nitrophenylcarbamoyl-(S)-prolyl-(S)-3-(2-naphthyl)alanyl-N-benzy-N- methylamide, SDZ NKT 343), a highly potent ligand for the human NK1 receptor (K(i) = 0.16 nM). In addition to its high in vitro potency, 5f proved to be a potent orally active analgesic in guinea pig models of chronic inflammatory and neuropathic pain. The nature of the 2-aryl substituent was found to be critical for oral activity in this series. Clinical evaluation of 5f as a novel analgesic agent is currently underway.
- Walpole,Ko,Brown,Beattie,Campbell,Dickenson,Ewan,Hughes,Lemaire,Lerpiniere,Patel,Urban
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p. 3159 - 3173
(2007/10/03)
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