Design and Synthesis of Novel Opiate Antagonists with LH‐Stimulating Properties

Abstract

Opiate antagonists stimulate the release of LH and might, therefore, contribute to an innovative therapy for the treatment of numerous clinical syndromes characterized by hypofnnction of the HHG axis. The purpose of this work was to design and synthesize pure opiate antagonists useful for this therapy. Me, Et, Pr, and PhCH, groups were introduced at the crucial 14D-position of morphines and morphinans via a hetero-Diels-Alder key step starting from thebaine derivative 1 and tested for opiate antagonism and LH-stimulating activity. Me-, Et-, and Pr-substituted compounds 1la-C were stronger antagonists than naltrexone, whereas Pr and PhCH, substituents in l l c , l l d , 9d, 9d3, 9d4, and 9d5 led to orally active LH stimulators. Based on our finding that the y-antagonists 12 and lib5 showed no LH stimulation, we conclude that a Combination of both p -and x-antagonism is necessary for potent LH stimulation.Introduction. -Endogenous opiate peptides (EOP's) of the CNS participate in the regulation of the hypothalamo-hypophyseal-gonadal (HHG) axis. In rodents as well as in primates, the administration of opiate agonists leads to suppression of the secretion of luteinizing hormone (LH), while on the other hand, increased release of LH follows the application of opiate antagonists [ 11. Hypofunction of the HHG axis underlies numerous clinical syndromes such as the hypothalamic syndrome, idiopathic hypogonadotrophic hypogonadism, secondary hypothalamic hypogonadism, Kullmun's syndrome, delayed puberty, adolescent menstrual disorders, anorexia nervosa, and stress-related disorders. The presently available therapeutic approaches -human gonadotrophin, anti-estrogens, and pulsatile LHRH -all have inherent drawbacks and limitations associated with them. Opiate antagonists as LH secretion stimulators, therefore, represent a potential novel approach to their treatment.With the above background in mind, we have attempted to synthesize potent, longacting, and orally active opiate antagonists as LH-secretion stimulators. In the present article, we describe the design, synthesis, and LH-stimulating activities of a series of novel 14P-alkylated N-(cyclopropylmethy1)morphinans and -4,5a -epoxymorphinans.

Diels–Alder Adducts of Morphinan-6,8-Dienes and Their Transformations

“…Hydrolysis of the acetal (213) with methanolic hydrochloric acid led to 14-aminocodeinone (214). Aiming to synthesize potent and orally active opioid antagonists with luteinizing hormone (LH)-stimulating properties (in the context of opioid regulation of sex steroid production), Révész et al [201] prepared a series of N 17 -cyclopropylmethyl-14-alkylatedmorphinans and their 4,5α-epoxy analogues (Figure 58). For the introduction of a 14-alkyl substituent into the morphinan skeleton, they established a new method.…”

“…Desulfurization with Raney-Ni (MeOH, reflux 23 h) was only possible for the hetero Diels-Alder adduct 215d (R = Ph), which resulted in 14-benzyl-N 17 -cyclopropylmethyl-dihydrothebainone (217) in low isolated (25%) yield. Pharmacological screening in mice showed [201] that the synthesized ligands were primarily µ-OR antagonists with low κ-OR affinity but lacked the desired LH-stimulating properties. The authors concluded that µ-OR and κ-OR antagonistic properties are both necessary for potent LH stimulation.…”

β-Phenylethylamines and the isoquinoline alkaloids

“…229 Diels-Alder reaction of thebaine with hexafluorobut-2-yne gave a mixture of the bases ( 161) and ( 162) in benzene, but only (163) in methanol.z3o Reaction of thebaine with fluoroacrolein gave products of addition to the carbon-carbon double bond (164) and to the carbonyl group (165).231 Reaction of Ncyclopropylmethylnorthebaine with thioaldehydes (generated in situ from thiosulfinates) gave a series of adducts of general structure (166) which were rearranged by acids to (167) and these were reduced to (1 68, R' = SH) and (1 68, R1 = H), which were in turn cyclized, by conventional methods, to the related dihydrocodeinones and dihydromorphinones. 232 The adduct of N-cyclopropylmethylnorthebaine and acrolein, on treatment with methyl bromomethacrylate in a Reformatsky reaction, followed by demethylation, yielded the lactone ( 169). 233 The azide (1 70), prepared from the adduct of thebaine and acrolein, has been arranged by heat to the aziridine (1 7…”

“…The acetate (230, R = Ac) was hydrolysed at the ketal grouping to give the diol, which was then oxidized to the diketone (23 1). Methylation of this diketone with dimethoxypropane and toluenesulfonic acid gave the methoxy-enone (232). Reduction of (232) gave 10-acetoxycephalotaxine.…”