Ten analogs of luteinizing hormone-releasing hormone (LH-RH) substituted in position 2 with D-amino acids and at 6 with either a D-amino acid or a nonasymmetric amino acid were synthesized by solid-phase methodology and assayed for antiovulatory activity. [D-Phe2]-LH-RH substituted in the 6 position with D-Ala, D-Leu, D-Arg, D-(Ph)Gly, D-Phe, or 2-Me-Ala possessed varying degrees of antiovulatory activity. [D-p-F-Phe2-D-Ala6]-LH-RH was one of the most active antiovulatory compounds, while the [D-p-Cl-Phe2-D-Ala6]-LH-RH analog was devoid of activity at a comparable dose.
Triamcinolone and triamcinolone 16a,2 1-diacetate have been characterized by ultraviolet absorption spectra, infrared absorption spectra, absorption spectra in sulfuric acid, polarogra hy, reduction of tetrazolium blue, and by Porter-Silber chromogens. The use of agsorption spectra, polarography, and colorimetry for quantitative determination of bulk triamcinolone and of triamcinolone in tablets is discussed.Some new chemistry of 16a-hydroxylated steroids is reviewed. RIAMCINOLONE (9a -fluoro -11/3,16a,lia,21tetrahydroxy-l,4-pregnadiene-3,20-dione) is a new potent corticosteroid of clinical importance (1-3). Triamcinolone is currently marketed in this country as the alcohol, although the IGa,21diacetate has been tested clinically (4). Characterization of the hormone has been limited to brief accounts in the chemical journals (5-i) and in the patent literature (8). A more detailed characterization of both triamcinolone and triamcinolone diacetate is the subject of this report. in the preparation of triamcinolone and triamcinolone diacetate standards. Ultraviolet absorption spectra were obtained under the direction of Mr. Walter Muller, infrared spectra were kindly supplied by Mr. William Fulmor.
By using procedures previously developed for (*)-cestrone,l a variety of ( &)-13p-alkylgona-l,3,5( 10)-trienes and cognate compounds has been synthesised and converted into various ( & ) -1 3p-alkylgon-4-enes. Biological activities are given for several compounds and in some cases compared with those of the corresponding (+)and (-)-enantiomers.A series of related (&)-cestranes has been totally synthesised for comparison in biological activities with these gonanes and the corresponding cestranes prepared from (+)-oestrone. Preliminary accounts of some of this work have been given. R1 = Et, R2 = Me, R3 = H, n = 2), made by a sequence involving interaction of the ketone (8; R1 = Et, R2 = Me, n = 2) with methylmagnesium bromide. This alcohol may be a 17ap-01 from its appreciable androgenic-anabolic activity (below) and the reported 22 lack of such activity in 17a-hydroxy-19-norandrost4en-3-one, but the evidence is inconclusive. Ananchenko et aZ.l% observed the formation of both possible epimers in a similar Grignard reaction with the cestratetraene (8; R1 = R2 = Me, n = 2).
An analogue of synthetic hypothalamic LRH, D-[ALA]6-DES-[GLY]10-PRO9-ethylamide-LRH (Wy-18,481) was evaluated for agonistic (in vivo LH-releasing and ovulation-inducing), post-coital contraceptive and reproductive target organ effects. Both LRH and the analogue terminated pregnancy; there appeared to be a direct relationship between agonistic and post-coital contraceptive potency and activity. The analogue proved to be a potent agonist and both a pre-and post-implantational post-coital anti-fertility agent. In contrast to LRH, the congener did not produce a uterotrophic effect in the hypophysectomized rat. The data suggest that agonist analogue(s) of LRH can terminate pregnancy via hyperstimulation of the pituitary-ovarian-reproductive complex and the use of members of this neurohormonal class as potential clinical pro-fertility agents should be weighted with caution.
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