Two ortho-rhom-bic polymorphs of hydro-morphone.

Conditions to obtain two polymorphic forms by crystallization from solution were determined for the analgesic drug hydro-morphone [C17H19NO3; systematic name: (4R,4aR,7aR,12bS)-9-hy-droxy-3-methyl-1,2,4,4a,5,6,7a,13-octa-hydro-4,12-methano-benzofuro[3,2-e]iso-quinolin-7-one]. These two crystalline forms, designated as I and II, belong to the P212121 ortho-rhom-bic space group. In both polymorphs, the hydro-morphone mol-ecules adopt very similar conformations with some small differences observed only in the N-methyl amine part of the mol-ecule. The crystal structures of both polymorphs feature chains of mol-ecules connected by hydrogen bonds; however, in form I this inter-action occurs between the hydroxyl group and the tertiary amine N atom whereas in form II the hydroxyl group acts as a donor of a hydrogen bond to the O atom from the cyclic ether part.

Buprenorphine.

In the crystal structure of a semi-synthetic opioid drug buprenorphine, C29H41NO4 {systematic name: (2S)-2-[(5R,6R,7R,14S)-9α-cyclo-propyl-methyl-3-hy-droxy-6-meth-oxy-4,5-ep-oxy-6,14-ethano-morphinan-7-yl]-3,3-di-methyl-butan-2-ol}, the cyclo-propyl-methyl group is disordered over two sites with an occupancy factor of 0.611 (3) for the major component. One of the hy-droxy groups is involved in intra-molecular O-H⋯O hydrogen bond. The other hy-droxy group acts as a proton donor in an inter-molecular O-H⋯O inter-action that connects mol-ecules into a zigzag chain along the b axis.

An efficient synthetic strategy for obtaining 4-methoxy carbon isotope labeled combretastatin A-4 phosphate and other Z-combretastatins.

Human cancer and other clinical trials under development employing combretastatin A-4 phosphate (1b, CA4P) should benefit from the availability of a [(11)C]-labeled derivative for positron emission tomography (PET). In order to obtain a suitable precursor for addition of a [(11)C]methyl group at the penultimate step, several new synthetic pathways to CA4P were evaluated. Geometrical isomerization (Z to E) proved to be a challenge, but it was overcome by development of a new CA4P synthesis suitable for 4-methoxy isotope labeling.

Antineoplastic agents. 509: synthesis of fluorcombstatin phosphate and related 3-halostilbenes(1).

The present SAR study of combretastatin A-3 (3a) focused on replacement of the 3-hydroxyl group by a series of halogens. That approach with Z-stilbenes resulted in greatly enhanced (>10-100-fold) cancer cell growth inhibition against a panel of human cancer cell lines and the murine P388 lymphocytic leukemia cell line. Synthesis of the 3-fluoro-Z-stilbene designated fluorcombstatin (11a) and its potassium 3'-O-phosphate derivative (16c) by the route 7 --> 8a --> 11a --> 14 --> 16c illustrates the general synthetic pathway. The 3'-O-phosphoric acid ester (15) of 3-bromo-Z-stilbene 13a was also converted to representative cation salts to evaluate the potential for improved aqueous solubility, and the potassium salt (16 mg/mL in water) proved most useful. The fluoro (11a), chloro (12a), and bromo (13a) halocombstatins were nearly equivalent to combretastatin A-4 (1a) as inhibitors of tubulin polymerization and of the binding of colchicine to tubulin. The tubulin binding in cell-free systems was also retained in human umbilical vein endothelial cells. All three halocombstatins retained the powerful human cancer cell line inhibitory activity of combretastatin A-4 (1a) and proved superior to combretastatin A-3 (3a). In addition, the halocombstatins targeted Gram-positive bacteria and Cryptococcus neoformans.