Aporphines. 31. Synthesis and antitumor activity of aporphine nitrogen mustards.

A series of aporphine nitrogen mustards and their congeners (1b-g) has been prepared. N-[[Bis(2-chloroethyl)-amino]-2,11-dihyroxy-10-methoxynoraporphine (1b) and its mono- and diacetyl ester derivatives (1c-d) were prepared from N-(chloroacetyl)-2,11-diacetoxy-10-methoxynoraporphine (2). Reaction of 2 with diethanolamine under various conditions and different solvents resulted in the corresponding N-[[bis(2-hydroxyethyl)amino]acetyl] precursors, which were subsequently treated with SOCl2 to yield the target compounds. N-(2-Choroethyl)norapocodeine (1e) was obtained from the chlorination of N-(2-hydroxyethyl)norapocodeine (9) with SOCl2. Prolonging such treatment was found to result in the formation of N-[2-(chloroethoxy)ethyl]norapocodeine (1f) at the expense of 1e. N-[[[N'-(2-Chloroethyl)carbamyl]oxy]ethyl]norapocodeine (1g) and its 11-(2-chloroethyl)carbamyl derivative (1h) were also prepared. All the double-armed aporphine amide nitrogen mustards (ab-d) were found to have antitumor activity. The single-armed aporphine nitrogen mustard (1e) was also active in P388 but the activity was less than that observed with 1b-d. The lead compound 1a was inactive in the LE1210 and P388 systems at the doses tested. Similarly, the two aporphine mustard congeners (1f,g) were also inactive in the P388 system. All the activity was observed in the intraperitoneally innoculated tumor systems.

Isoquinolines. 6. Potential central nervous system antitumor agents. Nitrogen mustards of 3-amino-4-(p-aminophenyl)isoquinoline.

A series of 3-amino-4-(p-aminophenyl)isoquinolines bearing the bis(2-chloroethyl)amino group was synthesized as potential CNS antitumor agents. Diol precursors 1e and 1f were prepared by the treatment of 1b and 1c with ethylene oxide. Diol precursors 5a-c and 9 were prepared by the treatment of 4a-c and 8 with diethanolamine. The reaction of these diols with SOCl2 yielded target mustards 10-15 which were evaluated in the intraperitoneal murine L1210 tumor. No intermediates or target mustards were active in this tumor system.

Drugs derived from cannabinoids. 1. Nitrogen analogs, benzopyranopyridines and benzopyranopyrroles.

Various nitrogen analogs of delta6a,10a-tetrahydrocannabinol were synthesized by a general procedure described in an earlier communication. Minimum effective doses (MED50's) and lethal doses (LD50's) were determined by a modified Irwin mouse screen after iv administration of compounds in PEG 200. The most potent compounds were the propargyl (5t), allyl (5m), and chloroallyl (5o-q) derivatives. Overt behavioral effects (CNS depression, static ataxia, and hypersensitivity) of 5t and Roger Adams' carbocyclic analog (III) were found to be similar in the mouse, cat, dog, and monkey. Dichloroisoproterenol prevented and reversed many of the depressant effects of both III and 5t but had no effect on the ataxia produced by these compounds. In antinociceptive tests, 5t was active in the phenylquinone and Eddy hot-plate tests but was inactive in the tail-flick test.

Antimalarials V: aminobenzothiazoles.

Four mono- and dialkylated 4-aminobenzothiazoles (VII-X) were prepared as analogs of potent causal prophylactic drugs in the 8-aminoquinoline series. Compounds VII and VIII were toxic at 80 mg/kg in the chick; IX was inactive at 640 mg/kg. In a sporozoite-induced mouse test system, X was inactive at 30 mg/kg and toxic at 480 mg/kg. None of the compounds was active as a suppressive drug.

Use of synthetic polypeptides in the preparation of biodegradable delivery vehicles for narcotic antagonists.

Synthetic polypeptides consisting of copolymers of glutamic acid and leucine have been shown to be useful materials for the fabrication of practical, biodegradable delivery vehicles for narcotic antagonists. Model delivery vehicles in film form were prepared from copolymers containing 10 mole percent to 40 mole percent glutamic acid, and loaded with 10% to 40% naltrexone by weight. The naltrexone was found to be released by diffusion, exhibiting diffusion coefficients that varied as a function of the glutamic acid content and the initial naltrexone loading. A wide range in diffusion coefficients were achieved (0.31 x 10-7 cm2/hr to 120 x 10-7 cm2/hr), leading to release rates within practical ranges of interest for meeting the program goals. We have demonstrated that the polypeptides can be fabricated into dosage forms that are amenable to administration by trochar. For example, rods 0.4 mm to 0.8 mm in diameter containing as much as 40% naltrexone by weight were extruded using a simple compression mold and die arrangement. An in vitro evaluation of the rods showed that antagonist is released by diffusion at a continuously decreasing rate, a behavior similar to that observed with the film devices that were, nonetheless, capable of blocking an AD80 challenge of morphene sulfate in mice for more than 30 days. One of the most promising delivery vehicles that we have developed to date consists of a polypeptide tube filled with a naltrexone/polypeptide core. Preliminary experiments have shown that these devices may be capable of administering high, constant rates of release for prolonged periods of time. Additional work, however, is required to develop techniques for the preparation of reproducible delivery vehicles.

Emetic activity of N-substituted norapomorphines.

Norapomorphine and ten of its N-substituted derivatives were prepared by modifications of procedures described earlier. In a dog emesis test the N-ethyl and N-n-propyl compounds had minimum effective doses of 0.00025 and 0.0005 mg/kg, respectively, when administered iv, sc, or im. In a modified Irwin mouse profile screen the minimum effective iv dose was 0.013 mg/kg for the N-ethyl and 0.0024 mg/kg for the N-n-propyl compound; percutaneous absorption was also observed in mice. All compounds examined caused the stereotyped apomorphine behavior syndrome but hypotensive effects were not serious.

Use of synthetic polypeptides in the preparation of biodegradable delivery vehicles for narcotic antagonists.

Synthetic polypeptides consisting of copolymers of glutamic acid and leucine have been shown to be useful materials for the fabrication of practical, biodegradable delivery vehicles for narcotic antagonists. Model delivery vehicles in film form were prepared from copolymers containing 10 mole percent to 40 mole percent glutamic acid, and loaded with 10% to 40% naltrexone by weight. The naltrexone was found to be released by diffusion, exhibiting diffusion coefficients that varied as a function of the glutamic acid content and the initial naltrexone loading. A wide range in diffusion coefficients were achieved (0.31 x 10(-7) cm2/hr to 120 x 10(-7) cm2/hr), leading to release rates within practical ranges of interest for meeting the program goals. We have demonstrated that the polypeptides can be fabricated into dosage forms that are amenable to administration by trochar. For example, rods 0.4 mm to 0.8 mm in diameter containing as much as 40% naltrexone by weight were extruded using a simple compression mold and die arrangement. An in vitro evaluation of the rods showed that antagonist is released by diffusion at a continuously decreasing rate, a behavior similar to that observed with the film devices that were, nonetheless, capable of blocking an AD80 challenge of morphine sulfate in mice for more than 30 days. One of the most promising delivery vehicles that we have developed to date consists of a polypeptide tube filled with a naltrexone/polypeptide core. Preliminary experiments have shown that these devices may be capable of administering high, constant rates of release for prolonged periods of time. Additional work, however, is required to develop techniques for the preparation of reproducible delivery vehicles.