Sodium cyanoborohydride in the presence of zinc iodide is found to exhibit unique and selective reducing properties. The reagents reduce aryl aldehydes and ketones as well as benzylic, allylic, and tertiary alcohols to the corresponding hydrocarbons.

Tanezumab, a humanized monoclonal antibody against nerve growth factor is in development for treatment of chronic pain. Three nonclinical studies assessed effects of clinically relevant and supratherapeutic doses of tanezumab on the sympathetic nervous system (SNS) of adult nonhuman primates. Study 1 evaluated potential effects of subcutaneous (SC) tanezumab (1.2 mg/kg every 8 weeks [Q8W]) on SNS in cynomolgus monkeys for 3 or 6 months and reversibility or persistence of any effects through a nondosing/recovery period. Study 2 evaluated whether neuronal cell death occurs shortly after a single SC tanezumab injection (1.2 mg/kg). Assessments for these two studies included evaluations of superior cervical and cervicothoracic ganglia for neuronal cell death and morphology. Study 3 evaluated effects of SC tanezumab (1.2 mg/kg Q8W and 30 mg/kg/week) over 6 months on sympathetic control of cardiovascular function. Tanezumab exposure was associated with stereologic changes in sympathetic ganglia, including smaller ganglion volume, and smaller average neuron size/area beginning at 2 weeks and reaching maximal levels by 1 month with no further progression through 6 months. These changes were not associated with clinical signs, completely reversed upon tanezumab withdrawal, and were not considered adverse. Tanezumab had no adverse effects on sympathetic control of cardiovascular function. These data support the conclusion that tanezumab administration for up to 6 months has no adverse effects on SNS morphology or function and does not cause neuronal cell death in adult nonhuman primates.

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A series of 6,ll-dihydro-5R-pyrrolo [2,l-b][3]benzazepin-ll-ones, 4, has been prepared as intermediates for potential CNS drugs. Substituents in the pyrrole ring of 4 were introduced by Friedel-Crafts cyclization of pyrrole-substituted l-(2-phenethyl)pyrrole-2-carboxylic acid derivatives (6) and by electrophilic substitution on the parent ketone 4a. Substituents in the benzene ring of 4 were introduced by Friedel-Crafts cyclization of substituted 2-(2-pyrrol-l-ylethyl)benzoic acids (12). Novel and efficient photochemical reactions were discovered for the direct introduction of the cyano and trifluoromethyl groups into the pyrrole ring of 4a. The latter reaction was extended to yield a series of trifluoromethylated heterocycles. Pyrrolo[2,l-6][3]benzazepin-ll-ones Scheme I r4 *-fFX jsr' SOCl2 or CI2CHOMeI, total synthesis of the ring system; II, introduction of substituents into the parent ketone 4; and III, modification of substituents introduced in I or II. The major successes and difficulties encountered in these approaches are detailed below.1.1 Total Synthesis of Pyrrole-Substituted Ketones (4, X , Y = H). The synthesis of the requisite acid derivatives 6 was carried out by three methods as summarized in Scheme I. Method A has already been de-scribed7 and is quite satisfactory as long as the group X is resistant to catalytic hydrogenation. Method B, the alkylation of a substituted pyrrole-2-carboxylic ester with 2-phenethyl bromide, was also found to be a very satisfactory route to the esters 6.1, particularly when X was a strong electron-withdrawing group. When X was less electron withdrawing, it was advantageous to use phenethyl tosylate to minimize competitive elimination to form styrene.Method C was used to prepare ester 6.1h and, although quite satisfactory, was not used extensively. The preparation of the 4-substituted pyrrole-2-carboxylates was generally carried out by the recent method of Belanger8

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