Progress toward the development of a safe and effective agent for treating reentrant cardiac arrhythmias: synthesis and evaluation of ibutilide analogues with enhanced metabolic stability and diminished proarrhythmic potential.

A series of ibutilide analogues with fluorine substituents on the heptyl side chain was prepared and evaluated for class III antiarrhythmic activity, metabolic stability, and proarrhythmic potential. It was found that fluorine substituents stabilized the side chain to metabolic oxidation. Many of the compounds also retained the ability to increase the refractoriness of cardiac tissue at both slow and fast pacing rates. The potential for producing polymorphic ventricular tachycardia in the rabbit model was dependent on the chirality of the benzylic carbon. The S-enantiomers generally had less proarrhythmic activity than the corresponding racemates. One compound from this series (45E, trecetilide fumarate) had excellent antiarrhythmic activity and metabolic stability and was devoid of proarrhythmic activity in the rabbit model. It was chosen for further development.

Substituent effects on the antibacterial activity of nitrogen-carbon-linked (azolylphenyl)oxazolidinones with expanded activity against the fastidious gram-negative organisms Haemophilus influenzae and Moraxella catarrhalis.

A series of new nitrogen-carbon-linked (azolylphenyl)oxazolidinone antibacterial agents has been prepared in an effort to expand the spectrum of activity of this class of antibiotics to include Gram-negative organisms. Pyrrole, pyrazole, imidazole, triazole, and tetrazole moieties have been used to replace the morpholine ring of linezolid (2). These changes resulted in the preparation of compounds with good activity against the fastidious Gram-negative organisms Haemophilus influenzae and Moraxella catarrhalis. The unsubstituted pyrrolyl analogue 3 and the 1H-1,2,3-triazolyl analogue 6 have MICs against H. influenzae = 4 microgram/mL and M. catarrhalis = 2 microgram/mL. Various substituents were also placed on the azole moieties in order to study their effects on antibacterial activity in vitro and in vivo. Interesting differences in activity were observed for many analogues that cannot be rationalized solely on the basis of sterics and position/number of nitrogen atoms in the azole ring. Differences in activity rely strongly on subtle changes in the electronic character of the overall azole systems. Aldehyde, aldoxime, and cyano azoles generally led to dramatic improvements in activity against both Gram-positive and Gram-negative bacteria relative to unsubstituted counterparts. However, amide, ester, amino, hydroxy, alkoxy, and alkyl substituents resulted in no improvement or a loss in antibacterial activity. The placement of a cyano moiety on the azole often generates analogues with interesting antibacterial activity in vitro and in vivo. In particular, the 3-cyanopyrrole, 4-cyanopyrazole, and 4-cyano-1H-1,2,3-triazole congeners 28, 50, and 90 had S. aureus MICs

N-[(omega-amino-1-hydroxyalkyl)phenyl]methanesulfonamide derivatives with class III antiarrhythmic activity.

N-[4-[4-(Ethylheptylamino)-1-hydroxybutyl]phenyl]methanesulfonamid e, (E)-2-butenedioate (2:1) salt (ibutilide fumarate, 2E), has been found to have Class III antiarrhythmic activity. In an in vitro rabbit heart tissue preparation designed to evaluate the cardiac electrophysiology of potential antiarrhythmic agents, it selectively prolongs the effective refractory period of papillary muscle. In vivo it increases the ventricular refractory period of the canine heart and prevents the ventricular arrhythmias induced by programmed electrical stimulation 3-9 days after a myocardial infarction. This paper describes the synthesis of 2E and a series of related compounds. The in vitro evaluation of the cardiac electrophysiology of these compounds has allowed us to determine the structural requirements for Class III antiarrhythmic activity in this series. Evaluation of the antiarrhythmic activity of 2E and one of the more potent analogues on the late postinfarction ventricular arrhythmias induced by programmed electrical stimulation of the canine myocardium is also described. This activity is compared with that of the Class III antiarrhythmic agent sotalol. Compound 2E appears to be as effective and 10-30 times more potent than sotalol in this model.

1-(2-aminoethyl)-6-aryl-4H- [1,2,4]triazolo[4,3-a][1,4]benzodiazepines with diuretic and natriuretic activity.

A series of 1-(2-amino-1-phenylethyl)-6-phenyl-4H- [1,2,4]triazolo[4,3-a][1,4]benzodiazepines was prepared and evaluated for diuretic activity. These compounds have diuretic and natriuretic activity but no kaliuretic activity when evaluated by oral administration to the conscious rat. The structure requirements for this activity are discussed. In particular it was found that the 2-aminoethyl side chain at C-1 with hydrogen or methyl substituents on the amino group was required for diuretic activity. A substituent at C-8 was also required; soft substituents such as methylthio and iodo at this position favored activity. Compounds with both phenyl and 2-pyridyl substituents at C-6 were active; substituents on the C-6 phenyl, however, reduced or eliminated the activity. Substituents other than phenyl at the 1-position of the 2-aminoethyl side chain were detrimental to activity; phenyl substitution at this position was required for activity when the substituent at C-8 was chloro but not when it was bromo.

4-amino-4-arylcyclohexanones and their derivatives: a novel class of analgesics. 2. Modification of the carbonyl function.

The effect on potency of modification of the carbonyl function of analgesics derived from 4-(dimethylamino)-4-arylcyclohexan-1-one was studied by reduction and by addition of nucleophiles. The resulting amino alcohols were separated and assigned structures on the basis of X-ray crystallography, NMR, and TLC mobility. The trans (OH and N) isomers were invariably more potent than the cis. Inclusion of flat lipophilic moieties (phenyl, cyclohexenyl) at a distance of at least two carbon atoms from the carbon bearing hydroxyl led to increases in potency by orders of magnitude. The possible significance of this on receptor interaction is discussed.

4-aryl-4-aminocyclohexanones and their derivatives, a novel class of analgesics. 3. m-Hydroxyphenyl derivates.

Derivatives of 4-aryl-4-(dimethylamino)cyclohexan-1-ones substituted by m-hydroxy groups were obtained by using as a key reaction the displacement of cyanide from the alpha-aminonitrile of 1,4-cyclohexanedione ketal, with the THP ether of m-hydroxyphenylmagnesium bromide. A number of the products show narcotic antagonist activity. Amino alcohols obtained on reaction of the free ketones with phenethyl Grignard reagents are potent analgetics, though devoid of antagonist activity. Systematic variation of the substituent on nitrogen revealed nonclassical structure-activity relationships; the dimethylamino group gives the most potent antagonist.

4-Amino-4-arylcyclohexanones and their derivatives, a novel class of analgesics. 1. Modification of the aryl ring.

Investigation of central nervous system activity of phenylcyclohexylamines was continued by preparation of "reversed" analogues. Following the unexpected finding of analgesic activity with 1-(dimethylamino)-1-phenylcyclohexylamine, the SAR of the series was investigated. Synthesis starts by double Michael reaction of acrylate on arylacetonitriles. Following cyclization, decarboxylation, ketalization, and saponification, the geminally substituted acid is rearranged to the isocyanate by means of (C6H5O)2PON3. Isocyanates were then converted to the title compounds. Analgesic activity is very sensitive to the nature and position of the substitutent on the aromatic ring. The most potent compounds in this series (p-CH3, p-Br) showed 50% the potency of morphine. Deletion of the ring oxygen abolishes activity.

Hypobetalipoproteinemic agents. 2. Compounds related to 4-(1-adamantyloxy)aniline.

While the previously used displacement reaction of sodim 1-adamantyl oxide on 4-fluoronitrobenzene was applicable to the preparation of 4-(1-adamantyloxy)aniline and several related compounds, certain derivatives were not easily accessible by this route. Thus the recently reported ortho alkylation of anilines and the dicyclohexylcarbodiimide-promoted coupling of 1-adamantanol with phenols were useful in the preparation of aromatic-substituted derivatives. Furthermore, addition of phenylmagnesium bromide to 1-cyanoadamantane provided entry to the 4-(1-adamantylmethyl)aniline series. 4-(1-Adamantyloxy)aniline (3) is herein reported to be a more potent hypobetalipoproteinemic agent than the previously reported bicyclooctyloxy analogue. Replacement of the oxygen atom of 3 with sulfur (74) or methylene (62), but not nitrogen (71), results in active compounds. In the oxygen series derived from 3, the widest scope of substitution on nitrogen resulting in activity is found. The N-ethoxycarbonyl (5), acetyl (6), methyl (12), ethyl (13), N-methyl-N-(2-hydroxyethyl) (19), N-methyl-N-formyl (22), N,N-dimethyl (26), pyrrolidine (14), and piperidine (15) derivatives are active. Aromatic ring substitution also provided the active 3-chloro (44b), 2-fluoro (41b, 42, and 43), and 2-methylthiomethyl (48) compounds. Thus these active compounds are identified for further development as hypobetalipoproteinemic agents.

Hypo-beta-lipoproteinemic agents. 1. Bicyclo[2.2.2]octyloxyaniline and its derivatives.

A new assay for agents which normalize beta-lipoproteins in cholesterol-cholic acid fed rats is described. Both lowering of serum cholesterol and of serum heparin precipitable lipoproteins (HPL) were measured at the end of the treatment period. Compounds which shifted the ratio of the decrease in favor of HPL are considered hypo-beta-lipoproteinemic. p-(1-Bicyclo[2.2.2]octyloxy)aniline and several of its derivatives proved active in this assay. The synthesis of these compounds is described.