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A novel series of quinolizidine salicylamides was synthesized as specific inhibitors of the H1 subtype of influenza A viruses. These inhibitors inhibit the pH-induced fusion process, thereby blocking viral entry into host cells. Compound 16 was the most active inhibitor in this series with an EC50 of 0.25 microg/mL in plaque reduction assay. The synthesis and the SAR of these compounds are discussed.

The resolution of N-t-Boc-piperazine carboxamide 5 proceeded smoothly in the presence of leucine aminopeptidase to produce acid (S)-1 and amide (R)-5 with good optical purity. Sequential alkylation and functional group manipulation of carboxamide (S)-5 provided the known nucleoside transport blocker draflazine (-) 2.

A number of N-aryl and N-alkyl substituted piperazines 1 were prepared from variously substituted 2-oxazolidinone derivatives 3. The method involved treatment of 3 with HBr in glacial acetic acid followed by heating the resulting ring-opened salts 5 in alcoholic solvent. The piperazines 1a–1q were isolated by crystallization in yields ranging from 23–91%.

New N-substituted hydrazine linkers were synthesized and their hydrazone derivatives of adriamycin were prepared. These functionalized adriamycin derivatives were conjugated with a monoclonal antibody, 5E9. The release rate of adriamycin from the hydrazones and from some of the conjugates was studied, and their relationship to the IC50's of the conjugate against 5E9-positive Daudi cells was investigated.

Dihydropyridine 5a was found to be an inhibitor of neuropeptide Y(1) binding in a high throughput (125)I-PYY screening assay. Structure-activity studies around certain portions of the dihydropyridine chemotype identified BMS-193885 (6e) as a potent and selective Y(1) receptor antagonist. In a forskolin-stimulated c-AMP production assay using CHO cells expressing the human Y(1) receptor, 6e demonstrated full functional antagonism (K(b)=4.5 nM). Compound 6e inhibited NPY-induced feeding in satiated rats when dosed at 3.0 and 10.0 mg/kg (ip), and also decreased spontaneous overnight food consumption in rats at doses of 10 and 20 mg/kg (ip).

A series of new substituted benzamides has been synthesized and evaluated for dopamine antagonist activity and for antagonism of cisplatin-induced emesis in the dog and in the ferret. It was found that modification of the 2-methoxy substituent of metoclopramide was detrimental to dopaminergic D2 antagonism but not necessarily to antagonism of cisplatin-induced emesis. A number of analogues having a beta-keto, beta-hydroxy, beta-methoxy, beta-imino, or beta-unsaturated alkyloxy substituent instead of methoxy have shown equal or superior protection from emesis to that of metoclopramide. At the same time these compounds were found to be free of dopaminergic D2 antagonism in both in vitro ([3H]spiperone binding) and in vivo tests (rat catalepsy, antagonism of apomorphine-induced stereotypy in the rat, and apomorphine-induced emesis in the dog).

A series of 2-substituted-4-amino-5-chloro-N-[2-diethylaminoethyl]benzamides was synthesized and evaluated for gastrointestinal motility enhancing activity in vitro (enhancement of field stimulated guinea pig ileum test) and in vivo (enhancement of rat stomach emptying). A number of compounds were shown to be potent gastrointestinal prokinetic agents yet were devoid of dopaminergic D2-receptor antagonism as shown by their inability to displace [3H]spiperone from brain membranes. The model compound 6b would be expected to have clinical use in a spectrum of upper gastroinstestinal motility disorders but without the central nervous system side effects characteristic of dopaminergic D2-receptor blockade in the brain.

A new total synthesis of racemic 3-hydroxyisomorphinans (3), 3-hydroxyhasubanans (9), 3,9α-dihydroxyhasubanans (5), and 3,9β-dihydroxyhasubanans (7), via 4a-(2-aminoethyl)-1,2,3,4,4a,9-hexahydro-6-methoxyphenanthrene (1a) is described.

La desalkylation d'amines tertiaires se fait par une reaction «one pot»: oxydation d'amines tertiaires par l'acide m-chloroperbenzoique dans le dichloromethane suivie d'addition de FeCl 2 ; application a la synthese de (−)-methoxy-3 morphinanol-14, d'octahydroisoquinoleines, de derives de pyridine, etc

A series of 3,14-dihydroxymorphinans 8 was synthesized via a method of (a) acylation of 3-methoxy-Δ8,14-morphinan 4a (b) stereospecific epoxidation of the resultant amides to β-epoxides 5 (c) simultaneous reduction of amide and epoxide functions and (d) demethylation of the resultant 3-methoxy-14-hydroxymorphinans 7. Alternatively deblocking of the amine function in 5b by hydrolysis followed by reduction of the resultant amino epoxide 5e afforded 14-hydroxy-3-methoxymorphinan 7e, which is readily alklyated and demethylated to give various 8. On a basis of interesting pharmacological profiles compounds l-8c (oxilorphan) and l-8d (butorphanol) were selected for clinical studies.

The synthesis of 5-allyl-2'-methoxy-9-oxo-6,7-benzomorphan (5b) is described. The 10-hydroxy-2-methyl-1,11-propano-9H-indeno-1,2,10,11-tetrahydro[2,1-c]pyridine (7a) and the corresponding 6-methoxy derivative (7b) are unexpected products of pyrolysis of 5-allyl-2-methyl-9-oxobenzomorphan methobromide (4a) and 5-allyl-2′-methoxy-2-methyl-9-oxobenzomorphan methobromide (4b) respectively. The molecular structure of 7a (C16H19NO) has been determined from spectral and microanalytical data, and confirmed by X-ray single crystal analysis on its hydrobromide salt using the heavy atom technique. The crystals of [C16H20NO]+Br− are monoclinic, P21/a, with a = 13.724(2), b = 14.022(3), c = 7.495(2) Å, β = 97.33(5)°, and Z = 4. The crystal structure has been refined by block-diagonal least-squares calculations to R and Rw = 0.036 for the 2197 observed reflections. The N atom has planar trigonal coordination, and forms one double and two single C—N bonds of lengths 1.273(4), 1.465(4), and 1.474(4) Å, respectively. The Br is hydrogen-bonded to O. The N and O atoms are trans.

A series of 3-hydroxy-8-oxyisomorphinans (11, 16) has been synthesized from the corresponding 5-allyl-9β-hydroxy-6,7-benzomorphans (7, 12) via a hydroboration, oxidation, mesylation, and cyclization sequence of reactions. Selective reduction of and methylmagnesium iodide addition to 5-allyl-2′-methoxy-2-methyl-9-oxo-6,7-benzomorphan (1) gave the respective 9α-hydroxy-6,7-benzomorphans (17). These were transformed to a number of 2-substituted-5-allyl-2′,9β-dihydroxy-6,7-benzomorphans (22) and corresponding methyltetrahydrofurano analogs (24).

The acid-catalyzed rearrangement of 3-methoxy-17-(N-phenylthioamido)-Δ8,14-morphinan (1) to 3-methoxy-17-(N-phenylthioamido)- Δ9,10-hasubanan (2), and acid-catalyzed cyclization of 2 to thiazinohasubanan (3) are described. Both transformations are discussed in terms of intramolecular vs. intermolecular hydride (proton) transfers. The reduction of 3 afforded 3-methoxy-10β-thiohasubanan (4), which was further hydrogenolized to 3-methoxy-hasubanan (5).

The synthesis of a versatile intermediate 4a-(2-aminoethyl)-l,2,3,4,4a,9-hexahydro-6-methoxyphenanthrene (3a) and its utilization in the synthesis of 9α-hydroxy-3-methoxy-17-methylhasubanan (10), 3,14-dimethoxy-17-methylisomorphinan (9l), various 14-hydroxyisomorphinans (9), and 3-methoxy-Δ8,14-morphinan (11b) is described. A number of 17-alkyl-3,14-dihydroxyisomorphinans were prepared and tested for narcotic antagonist and analgesic activities in laboratory animals. Some of these new compounds have exhibited significant activities.

The preparation of (4-tritylthio-2-azetidinon-l-yl)triphenylphosphoranylideneacetates from 4-acetoxyazetidin-2-one is described. They are easily converted to mercuric or silver mercaptides. These mercaptides are acylated with a wide variety of acylating agents and cyclized to 2-substituted penem-3-carboxylates.

The preparation of (4-tritylthio-2-azetidinon-l-yl)triphenylphosphoranylideneacetates from 4-acetoxyazetidin-2-one is described. They are easily converted to mercuric or silver mercaptides. These mercaptides are acylated with a wide variety of acylating agents and cyclized to 2-substituted penem-3-carboxylates.

A series of 2-substituted-4-amino-5-chloro-N-[2-diethylaminoethyl]benzamides was synthesized and evaluated for gastrointestinal motility enhancing activity in vitro (enhancement of field stimulated guinea pig ileum test) and in vivo (enhancement of rat stomach emptying). A number of compounds were shown to be potent gastrointestinal prokinetic agents yet were devoid of dopaminergic D2-receptor antagonism as shown by their inability to displace [3H]spiperone from brain membranes. The model compound 6b would be expected to have clinical use in a spectrum of upper gastroinstestinal motility disorders but without the central nervous system side effects characteristic of dopaminergic D2-receptor blockade in the brain.

3-Methoxy-8-oxamorphinans 9 have been prepared from the corresponding 5-allyl-9alpha-hydroxy-2'-methoxy-2-methyl-6,7-benzomorphans 7. The former compounds were transformed to the 3-hydroxy-8-oxamorphinans 6, a class of potent analgesics and analgesic-antagonists. In ring C of the morphinan nucleus substitution of 8-CH2 with oxygen enhanced both analgesic and antagonist activities, while replacement of hydrogen with a methyl group at C-14 in these compounds enhanced antagonist activity and decreased analgesic activity. Tetrahydrofuranobenzomorphans 3 and 3-hydroxy-8-oxaisomorphinans 4 displayed lower levels of activity. Structural requirements for antagonist activity are discussed.

2-Tetralone has been converted to 5-allyl-2-methyl-9-oxo-benzomorphan methobromide (4). Thermal dequaternization of 4 afforded tertiary base 5. Alternatively, 4 was reduced with sodium borohydride to give 7a or reacted with methylmagnesium iodide to give 7b. Dequaternization of these to tertiary bases (8a and 8b) followed by acid-catalyzed cyclization afforded tetrahydrofurano compounds 9a and 9b, respectively. Bromocyclization of 8b afforded bromomethyltetrahydrofurano compound 9c, which was further converted to dimethylamino compound 9d.

A series of 3-hydroxy-8-oxyisomorphinans (11, 16) has been synthesized from the corresponding 5-allyl-9β-hydroxy-6,7-benzomorphans (7, 12) via a hydroboration, oxidation, mesylation, and cyclization sequence of reactions. Selective reduction of and methylmagnesium iodide addition to 5-allyl-2′-methoxy-2-methyl-9-oxo-6,7-benzomorphan (1) gave the respective 9α-hydroxy-6,7-benzomorphans (17). These were transformed to a number of 2-substituted-5-allyl-2′,9β-dihydroxy-6,7-benzomorphans (22) and corresponding methyltetrahydrofurano analogs (24).

A new total synthesis of racemic 3-hydroxyisomorphinans (3), 3-hydroxyhasubanans (9), 3,9α-dihydroxyhasubanans (5), and 3,9β-dihydroxyhasubanans (7), via 4a-(2-aminoethyl)-1,2,3,4,4a,9-hexahydro-6-...

Publisher Summary This chapter discusses the therapeutic use of the prokinetic compounds in treating some gastrointestinal motor disorders. A brief outline on the neuroanatomical organization of the gastrointestinal tract and on the methods employed to study motility and its disorders is also discussed in this chapter. Motility is a dynamic term and consists of two distinct components, the movement of the gut wall and the movement of ingesta through the gastrointestinal tract. Different parts of the gastrointestinal tract have diverse functions, and hence the motility of each organ is different. Acetylcholine is an excitatory neurotransmitter and in the gastrointestinal tract evokes contractions. Other muscarinic agonists, such as bethanechol, methacholine, or carbachol also increase intestinal motility. Drugs that are cholinesterase inhibitors act as muscarinic agonists, enhancing the effect of released acetylcholine by inhibiting its degradation. Since its introduction, metoclopramide has been used therapeutically to accelerate bowel transit in fluoroscopic examinations to facilitate tube placement into the small bowel, to relieve diabetic gastroparesis, and to treat gastroesophageal reflux. In clinical studies, it has been demonstrated that bromopride increases esophageal motility and accelerates small bowel transit. The role of peptides in gastrointestinal motility is becoming very important because various peptides have been localized immunocytochemically and their role as neurotransmitters or neuromodulators is becoming apparent. The influence of a particular peptide on gut motility may be different in vivo and in vitro . Several peptides, such as vasoactive intestinal peptide, secretin, and glucagon influence gastrointestinal motility by inhibiting or relaxing smooth muscle. However, there is a need to synthesize and identify prokinetic compounds that will enhance gastrointestinal motility and be devoid of the side effects. This goal can be achieved only when further advances are made in the understanding of the physiology and pharmacology of gastrointestinal motility.

Total synthesis of 3,14-dihydroxyisomorphinans and 9α-hydroxy-3-methoxyhasubanans via 4a-(2-aminoethyl)-1,2,3,4,4a,9-hexahydro-6-methoxyphenanthrene (Ia) is described.

2-Tetralone has been converted to 5-allyl-2-methyl-9-oxo-benzomorphan methobromide (4). Thermal dequaternization of 4 afforded tertiary base 5. Alternatively, 4 was reduced with sodium borohydride to give 7a or reacted with methylmagnesium iodide to give 7b. Dequaternization of these to tertiary bases (8a and 8b) followed by acid-catalyzed cyclization afforded tetrahydrofurano compounds 9a and 9b, respectively. Bromocyclization of 8b afforded bromomethyltetrahydrofurano compound 9c, which was further converted to dimethylamino compound 9d.