Showing papers in "Journal of Medicinal Chemistry in 1975"

Calculation of hydrophobic constant (log P) from pi and f constants.

Abstract: The highest level of confidence can be placed in calculated log P values when (1) the log P of a parent solute is known, (2) pi constants for the required substituent(s) are available, and (3) the substituents either do not have an effect on groups already present in the parent or else this effect has been previously determined. In some instances there are no values available for any related structures which could serve as a parent; then, rather than substitute groups for hydrogen, it is easier to begin "from scratch", as suggested by Nys and Rekker, and assemble the structure from fragments, each of which has been assigned a hydrophobic value. In the present paper some new log P values for the lower alkanes and the inert gases are analyzed with the view of separating hydrophobic effects according to volume (including branching and flexibility) and polarity. Modified fragment values appear to enable reliable calculations to be made for a wider range of structures than was possible with the originally proposed constants.

Chemical differentiation of histamine H1- and H2-receptor agonists.

Abstract: Histamine exists predominantly as the NT-H tautomer of the monocation (IIa) at a physiological pH of 7.4 and structure-activity studies indicate that this tautomer is likely to be the pharmacologically active species for both H1 and H2 receptors. Effective H2-receptor agonists appear to require a prototropic tautomeric system whereas H1-receptor agonists do not need to be tautomeric. This identifies a chemical difference in the receptor requirements which provides the basis for obtaining selective histamine H1-receptor agonists. Thus 2-(2-aminoethyl)thiazole and 2-(2-aminoethyl)pyridine are nontautomeric and are highly selective agonists for histamine H1 receptors (H1:H2 ca. 90:1 and 30:1, respectively). In conjunction with the selective H2-receptor agonist, 4-methylhistamine, they are of great value for studying the pharmacology of histamine receptors.

Liquid-lipquid partition coefficients by high-pressure liquid chromatography.

Abstract: Lipid-water partition values can be rapidly and reliably measured by high-pressure liquid chromatography (HPLC) on bonded octadecylsialne supports This method has been developed and applied to a family of hypotensive triaminopyrimidine 3-oxides The measured column retention values for this class of compounds correlate well with the values calculated by the Hansch method We believe that this technique is an important addition to the methodology of Hansch analysis

Microelectrometric titration measurement of the pKa's and partition and drug distribution coefficients of narcotics and narcotic antagonists and their pH and temperature dependence.

Abstract: The pKa's, partition coefficients, and drug distribution coefficients (apparent partition coefficients) have been investigated for a number of narcotics and, where possible, for their congener narcotic antagonists. These studies were carried out by a microelectrometric titration technique as a function of temperature and pH. This method enables one to determine not only the dissociation constants to deconvolute overlapping pKa's, but also to determine the solubilities of oil-water distribution of these various drugs. The drug distribution coefficients displayed marked sensitivity to pH at values which span the range of attainable human physiological pH values. This has significant pharmacological implications for proper choice and scaling of drug dosages under various clinical situations. The partition coefficients and drug distribution coefficients were noticeably different at 20 degrees (where such measurements are customarily made) than at 37 degrees (body temperature). Furthermore, various drugs exhibit very nonequivalent increases in drug distribution coefficients with increasing temperature, ranginf from 21% for morephine to 200% for naltrexone. This nonregularity indicates that it will not be valid to extrapolate by any constant factor the measurements made at lower temperatures. Even the true partition coefficients increase with temperature from 20 degrees to 37 degrees. There is more of a difference in the drug distribution coefficients for naloxone and naltrexone than might have been expected from the similarities in their structures with naltrexone being significantly less lipophilic than naloxone. This would imply that this would lead to naloxone having a more rapid onset for antagonist activity and likewise a shorter duration of action than naltrexone.

Synthesis and antitumor properties of new glycosides of daunomycinone and adriamycinone.

Abstract: The synthesis of 4'-epi-daunorubicin and of 4'-epi-adriamycin was performed by condensation of 2,3,6-trideoxy-3-trifluoroacetamido-4-O-trifluoroacetyl-alpha-L-arabino-hexopyranosyl chloride with daunomycinone or the protected adriamycinone derivative 17, respectively. Both the alpha and beta anomers were obtained and characterized. All new compounds are biologically active in cultured cells and the alpha anomers display noticeable activity in experimental tumors in mice. Interestingly, 4'-epi-adriamycin (4) appears nontoxic to cultured heart cells up to a concentration of 5 mug/ml.

Synthesis and pharmacology of some 2-aminotetralins. Dopamine receptor agonists.

Abstract: A series of 2-amino-1,2,3,4-tetrahydronaphthalene compounds bearing substituents on the nitrogen and in the aromatic ring was synthesized from beta-tetralone intermediates. Compounds were screened in vivo for dopaminergic activity using tests in which apomorphine was especially active. It was found that apparent dopaminergic activity is inherent in 2-dialkylaminotetralins, the dipropylamine substitution being the most consistently productive amine group studies. Activity was greatly enhanced by proper substitution in the aromatic ring. The 5,6-dihydroxy group was the best potentiating group found. These data support the idea that the extended conformation for the phenylethylamine moiety of ampmorphine and dopamine is favorable for dopaminergic agonist activity. They also suggest that an unetherified catechol group may not be essential for such activity.

Pyrido(2,3-d)pyrimidine antibacterial agents. 3. 8-Alkyl- and 8-vinyl-5,8-dihydro-5-oxo-2-(1-piperazinyl)pyrido(2,3-d)pyrimidine-6-carboxylic acids and their derivatives.

Abstract: The preparation and antibacterial activity of a series of the title compounds (21-73) are described. These compounds were prepared from the 2-methylthio derivatives 2 and 3 via the 2-methylthio-8-substituted compounds 4-20; compounds 4-20 easily underwent displacement reactions with a variety of piperazines to afford 2-(4-substituted or unsubstituted 1-piperazinyl) derivatives 21-56, of which 21, 22, 27 and 51 with unsubstituted piperazinyl group at position 2 are converted subsequently into 57-73 by alkylation, acylation, sulfonylation, or addition of isocyanates to the piperazine nitrogen. The hexahydro-1H-1,4-diazepinyl analog 74 was also prepared. The most active members in this series of compounds were found to be 8-ethyl- and 8-vinyl-5,8-dihydro-5-oxo-2-(1-piperazinyl)pyrido(2,3-d)pyrimidine-6-carboxylic acids (22 and 51), both of which are more active in vitro and in vivo against gram-negative bacteria, including Pseudomonas aeruginosa, than piromidic acid (1). Structure-activity relationships are discussed.

Synthesis and antischistosomal activity of certain pyrazolo[1,5-a]pyrimidines.

Abstract: Several bridgehead nitrogen heterocycles were synthesized to be screened as antimicrobial agents, modeled after nalidixic acid. The activity of these new compounds, all derivatives of 3-nitro-4,6-disubstituted pyrazolo (1,5-a)pyrimidin-7-ones (3,7,8, and 9), however, was found to be highly specific for Trichomonas foetus and completely lacking in activity against bacteria, fungi, and parasites other than Trichomonas. Of the nine componds synthesized, including the intermediate 4,6-disubstituted pyrazolo (1,5-a) pyrimidin-7-ones (2-6) and the 6-substituted or unsubstituted pyrazolo (1,5-a) pyrimidin-7-ones (1 and 4), only 6-carbethoxy-4-ethyl-3-nitropyrazolo(1,5-a)pyrimidin-7-one (7) was found to be a potent antitrichomal agent, being comparable or perhaps better than metronidazole. From a tentative structure-activity relationship study, it was apparent that the combination of the 3-mitro, 4-ethyl, and 6-carbethoxy groups imparted specific activity, wheras other substitutions imparted little or no antitrichomonal activity.

Physiochemical-activity relations in practice. 1. A rational and self-consistent data bank.

Abstract: A data bank of substituent constants of 26 ortho and 34 meta and para benzenoid substituents is presented for use in physicochemical-activity relations (PAR) studies. The distributive parameters pri and pri-, a bulk parameter based on molar refraction, and positionally weighted electronic parameters F and R are listed for the three substituent positions. There are no gaps in the table caused by missing values and the interparameter correlation are low.

Inhibitors of nucleoside transport. Structure-activity study using human erythrocytes

Abstract: The passage of nucleosides across the plasma membrane of erythrocytes is a membrane-mediated process which is strongly inhibited by derivatives of 9-beta-D-ribofuranosylpurine (1) with S, O, or N atoms at the purine 6 position bearing variously substituted arylalkyl groups. In this structure-activity study, nucleoside derivatives were compared in respect to their ability to inhibit a transport-dependent aspect of nucleoside metabolism in erythrocytes, the synthesis of inosine from external guanosine and hypoxanthine. 6-Benzylthio, 6-benzylamino, and 6-benzyloxy derivatives of 1 were inhibitory at 10(-5)-10(-6) M and the similarity of their activities suggested that alkylation of the transporter as the mechanism of transport inhibition was unlikely. The hydrophobicity of the 6-position substituents appeared to contribute importantly to inhibitory activity. Although replacement of the ribofuranose moiety by other sugars reduced inhibitory activity, compounds with 9-butyl groups were inhibitory. 6-[(2-Hydroxy-5-nitrobenzyl)thio] derivatives of 1 were the most potent of the inhibitors tested, being active at about 10(-7) M.

Potential antitumor agents. 16.4'-(Acridin-9-ylamino)methanesulfonanilides.

Abstract: The structure-antileukemic activity (L1210) relationships for sulfonanilide ring-substituted variants of 4'-(acridin-9-ylamino)methanesulfonanilides have been investigated. Electron-donor substituents are necessary for antileukemic activity and it is suggested that high electron density at the 6' position is associated with high activity. A 3'-OCH3 function markedly increases (2-8-fold) potency with a variety of acceptable acridine ring substituents. Further variants with hydrophobic acridine 3-substituents have been shown to be more active than expected on the basis of overall molecular hydrophilic-lipophilic balance. There is a size limit to 3-substituents which may acceptably be as large as an iodine atom but should be smaller than an isoporpyl function.

Amidines and related compounds. 6. Studies on structure-activity relationships of antihypertensive and antisecretory agents related to clonidine.

Abstract: Correlations of antihypertensive and antisecretory activities with various structural modifications of the antihypertensive agent clonidine (2-(2,6-dichlorophenylimino)imidazolidine) are described. Eleven chemical classes of compounds containing an "amidine" moiety were prepared in this study. The antihypertensive activity of these compounds was evaluated in metacorticoid hypertensive rats and unanesthetized neurogenic hypertensive dogs following oral administration. Antisecretory activity was evaluated in fistula rats by measuring pH and volume of gastric secretion. Two compounds, 2-(2,6-dimethylphenylimino)imidazolidine and 2-(2,6-dichlorophenylimino)pyrrolidine, are particularly effective antisecretory agents with minimal antihypertensive activity.

Analgesic properties of the tetrahydrocannabinols, their metabolites, and analogs.

Abstract: The tetrahydrocannabinols from marihuana were found to have moderate analgesic activity in mice by the hot-plate test (sc administration). Of the several metabolites of these two compounds tested, only the 11-hydroxy derivatives were more potent than the parent compounds. Analogs 1 and 2 (9-demethyl relatives which cannot be metabolized to 11-hydroxy compounds), both of which produce a pharmacological profile generally similar to that of delta8- and delta9-THC, were analgesically inert. This suggests that metabolism to 11-hydroxy congeners may be necessary for the mediation of analgesic activity in the mouse hot-plate test but not for other pharmacologic effects produced by these substances which we have examined.

Alkylating derivatives of amino acids and peptides. Synthesis of N-maleoylamino acids, [1-(N-maleoylglycyl)cysteinyl]oxytocin. Effects on vasopressin-stimulated water loss from isolated toad bladder.

Abstract: A method for the preparation of N-maleoylamino acids and esters is reported. These compounds were shown to inhibit both the oxytocin-induced smooth muscle contraction in the isolated rat uterus and the vasopressin-induced water loss from the isolated toad bladder. The inhibitory ability of the maleimides in the toad bladder assay was found to be related to their corresponding partition coefficients by the equation: log 1/C = -0.055 (log P) 2 + 0.227 log P + 3.96. N-Maleoylamino acids can be coupled to peptides to form alkylating reagents which react rapidly with sulfhydryl groups. The synthesis of [1-(N-maleoylglycyl)cysteinyl]oxytocin (3) and [1=(N-maleoyl-11-aminoundecanoyl)cysteinyl]oxytocin (4) as potential affinity labeling reagents is described. These oxytocin analogs were shown to readily react with sulfhydryl-containing compounds; however, neither 3 nor 4 was seen to inhibit in the rat uterus assay at concentrations up to 3 times 10(-5)M. When tested on the mucosal and serosal surfaces of the toad bladder, assay inhibition was seen only on the mucosal surface. These results are discussed with respect to the possible existence of sulfhydryl groups at neurohypophyseal receptors.

4-hydroxy-3-nitro-2-quinolones and related compounds as inhibitors of allergic reactions.

Abstract: The synthesis and biological activity of a number of 4-hydroxy-3-nitro-2-quinolones are discussed and compared with their related hydroaromatic analogs. Antiallergic activity has been assessed by their ability to inhibit the homocytotropic antibody-antigen induced passive cutaneous anaphylaxis reaction in the rat.

Synthesis and biological activity of some antitumor benzophenanthridinium salts.

Abstract: A facil synthesis of benzophenanthridinium salts has been developed and used for preparing a number of these compounds. The antitumor activities in mouse leukemia L1210 (LE) and P388 (PS) were determined as well as some selected antimicrobial activities. Although antitumor activity was exhibited by several of the derivatives, none was as active as the naturally occurring alkaloid fagaronine. Fagaronine was made available as a synthetic by an improved procedure. Some structure-activity relationships among antitumor benzophenanthridinium salts are discussed.

Narcotic antagonists. 4. Carbon-6 derivatives of N-substituted noroxymorphones as narcotic antagonists.

Abstract: A series of new narcotic antagonists has been synthesized by modifying the C-6 carbonyl group in naloxone (Ia) and naltrexone (Ib). New functional units were introduced by reaction with various phosphorus and sulfur ylides and alkyllithium reagents. The activity of the new compounds were measured by the hot-plate and tail-clip tests after oral administration to mice. The majority of the new narcotic antagonists exhibited oral potencies considerably superior to the parent compounds, with 6-methylene derivatives IIa and IIb showing the most impressive increases.

Methyl 5(6)-phenylsulfinyl-2-benzimidazolecarbamate, a new, potent anthelmintic.

Abstract: 1. Human hepatic "acid" beta-galactosidase preparations, which had been purified approximately 250-fold, were examined for activities toward 4-methylumbelliferyl beta-galactosylceramide, lactosylceramide, galactosyl-N-acetylgalactosaminyl-[N-acetylneuraminyl]-galactosyl-glucosylceramide(GM1-ganglioside) and galactosyl-N-acetylgalactosaminyl-galactosyl-glucosylceramide (asialo GM1-ganglioside). 2. The enzyme was active toward the synthetic substrate, GM1-ganglioside and asialo GM1-ganglioside but was inactive toward galactosylceramide. Under our assay conditions, optimized for lactosylceramidase II, the preparations were as active toward lactosylceramide as toward GM1-ganglioside or its asialo derivative. The apparent Km values for the three natural substrates were similar. When determined by the assay system of Wehger, D.A., Sattler, M., Clark, C. and McKelvey, H. (1974) Clin. Chim Acta 56, 199-206, lactosylceramide-cleaving activity was 0.2% of that determined by our assay system. This confirmed our previous suggestion that the Wenger assay system determines exclusively the activity of lactosylceramidase I, which is probably identical with galactosylceramide beta-galactosidase. 3. Crude sodium taurocholate was far more effective than pure taurocholate in stimulating hydrolysis of the three glycosphingolipids by the beta-galactosidase. However, crude taurocholate could largely be replaced by smaller amounts of sodium taurodeoxycholate, suggesting that the unique activating capacity of the crude taurocholate might be due to taurodeoxycholate present as the major impurity. 4. Cl- was generally stimulatory for hydrolysis of the natural glycosphingolipids by our enzyme preparation. Effects of additional oleic acid and Triton X-100 were generally minor in either direction. 5. When the enzyme preparation was diluted with water, activity toward the synthetic substrate declined rapidly while those toward the natural substrates were essentially stable. Activity toward the synthetic substrate remained much more stable when the enzyme was diluted with 0.1 M sodium citrate/phosphate buffer, pH 5.0. 6. These observations provide insight into the complex relationship among the human hepatic beta-galactosidases.

A hydrophobic binding site in acetylcholinesterase.

Abstract: The dissociation constants have been determined and compared for a series of reversible, noncovalent inhibitors of eel acetylcholinesterase that are structurally related to the very potent inhibitor, 1,2,3,4-tetrahydro-9-aminoacridine (THA). It is concluded that there exists on the enzyme protein, closely adjacent to the anionic subsite, a conformationally flexible, hydrophobic area which tends readily to assume a near planar form. The dimensions of this area are unknown, but it is adequate in size to fully accomodate THA. It is this area, acting conjointly with the adjacent anionic subsite, which provides the attraction for THA and related inhibitors. Uv absorbance maxima and pKa vlaues are reported for many of the compounds.

Biologically active polycycloalkanes. 1. Antiviral adamantane derivatives.

Abstract: Convenient methods for the synthesis of 1-substituted 3-adamantyl chlorides and bromides (2), 1-adamantylphenols and -cresols (3), and 1-adamantylacetic (6) as well as 1,3-adamantanediacetic (11) acids are described. Several novel derivatives were synthesized from these key intermediates: adamantylcyclohexanols (4) and -cyclohexanones (5) from adamantylphenols (3), and esters (7,12, and 22), amides (13 and 18), thioamides (9 and 16), amidine (10), nitrile (15), and amines (14 and 17) from 1-adamantanecarboxylic (19) and -acetic (6) acids and 1,3-adamantanediacetic acid (11). Some adamantylpyrimidines (24) and -purines (25 and 26) were also prepared. Antiviral activities of the compounds obtained in this work and a series of new 1-adamantyl alkyl ketones synthesized before, together with those of some known adamantane derivatives, were tested in vitro on monolayer culture of chick ambryo fibroblasts against Newcastle disease virus.

A lapachol derivative active against mouse lymphocytic leukemia P-388.

Abstract: Lapachol [2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone] and its analogs [2-(3,7-dimethyl-2,6-octadienyl)-3-hydroxy-1,4-naphthoquinone and 2-(3,3-dibromo-2-propenyl)-3-hydroxy-1,4-naphthoquinone] have been described, among almost a hundred synthesized analogs, as active against rat tumor Walker 256 carcinosarcoma. The acetylglucosylation of lapachol results in a compound which extends lapachol activity becoming effective against mouse lymphocytic leukemia P-388. When mice inoculated with 10(6) leukemic cells were treated with the drug during 9 days, their life span increased 80% over the control animals. Identification spectral data (uv, ir, 1H NMR, and MS) of the compound obtained by synthesis are given.

4-Trifluoromethylimidazoles and 5-(4-pyridyl)-1,2,4-triazoles, new classes of xanthine oxidase inhibitors.

Abstract: The syntheses of a number of 2-substituted 4-trifluoromethylimidazoles and 3-substituted 5-(4-pyridyl)-1,2,4-triazoles are described. The trifluoromethylimidazoles were prepared from 3,3-dibromo-1,1,1-trifluoroacetone after hydrolysis with aqueous sodium acetate solution and condensation with an aldehyde in the presence of ammonia. Basic hydrolysis of the trifluoromethyl group was found to provide a facile method for the synthesis of imidazole-4-carboxylic acids. In the imidazole series a 2-aryl substituent and a free imino group were required for xanthine oxidase inhibitory activity. The triazoles were obtained through the reaction of an aroylhydrazine and an imino ether followed by thermal ring closure of the intermediate acylamidrazone. As in the imidazole series, a free imino group is an absolute requirement for in vitro activity. Additional structure-activity relationships of these compounds are presented.

Stereospecific synthesis of the 6beta-hydroxy metabolites of naltrexone and naloxone.

Abstract: The narcotic antagonists naltrexone (1a) and naloxone (2a) were stereospecifically reduced to the corresponding 6beta-hydroxy epimers 1b and 2b, respectively, with formamidinesulfinic acid in an aqueous alkaline medium. The reaction products were obtained with no detectable quantity of the 6alpha epimers 1c and 2c. The products 1b and 2b were formed in yields of 88.5 and 40%, respectively, and characterized by spectral methods. Compared to 1a and 2a, the stereospecific reduction products 1b and 2b and their 6alpha epimers 1c and 2c are all significantly less potent as narcotic antagonists in mice. Only 1c and 2c also possess antinociceptive activity.

Synthesis and biological activity of 5-fluoro-4'-thiouridine and some related nucleosides

Abstract: The synthesis of a series of 4'-thio-5-halogenopyrimidine nucleosides, including the 5-fluoro, chloro, bromo and iodo derivatives, has been carried out by condensation of the 2,4-bis-O-trimethylsilyl derivatives of the corresponding pyrimidine bases with the protected 4-thio-D-ribofuranosyl chloride. Among these, the alpha and beta anomers of 4'-thio-5-fluorouridine inhibited the growth of leukemia L1210 cells at concentrations of 4 x 10(-7) and 2 x 10(-7) M, respectively, and that of S. faecium at 4 x 10(-9) and 6 x 10(-10) M, respectively. These compounds retained marked activity against strains of S. faecium resistant to 10(-3) M 5-fluorouracil or 5-fluorouridine. As determined in S. faecium cultures, 4'-thio-5-fluorouridine decreased the total protein content of the cells more markedly than it did their RNA or DNA content. X-Ray crystallography showed that substitution of sulfur for the oxygen in the carbohydrate ring markedly changes the conformation of that moiety.

Partition coefficients and the structure-activity relation of the anesthetic gases

Abstract: Partition coefficients of 32 gaseous anesthetics in the octanol-water system have been determined. It is shown that relative anesthetic potency depends on hydrophobicity of the anesthetic (as defined by log P) and on a polar factor. The presence of a polar hydrogen in the anesthetic greatly increases potency. A quantitative structure-activity relationship is formulated based on these two factors.

Rm values of phenols. Their relationship with log P values and activity.

Abstract: The experimental Rm values for a series of phenols were obtained by a reversed-phase TLC system. The extrapolation from a range of linear relationship between experimental Rm values and acetone concentration provided a set of extrapolated Rm values. This were used for studying the relationship between structure and activity in vitro and in vivo. The possibility to obtain by means of the extrapolation technique the Rm values in a standard system for serveral series of chemotherapeutic agents is pointed out.

Potential bioreductive alkylating agents. 5. Antineoplastic activity of quinoline-5,8-diones, naphthazarins, and naphthoquinones.

Abstract: A number of 2-chloromethyl and 2-bromomethyl derivatives of naphthoquinones, quinolinediones, and naphthazarins were designed and synthesized as potential bioreductive alkylating agents, and the antitumor activity of these compounds was assessed in mice bearing Sarcoma 180 ascites cells. The results indicated that, with the exception of 3-benzamido-2-chloromethyl-1,4-naphthoquinone, which was inactive, all newly synthesized naphthoquinones possessed strong antitumor activity against this neoplasm. 6,7-Bis(bromomethyl)quinoline-5,8-dione had moderate inhibitory activity against Sarcoma 180 at its optimal daily dosage level of 15 mg/kg. 3-Bromo-2-bromomethyl- and 3-bromo-2-chloromethylnaphthazarin produced a moderate extension of the life span of tumor-bearing mice; whereas, in contrast, 6,7-dimethyl analogs of these agents were inactive when employed in daily doses up to 40 mg/kg body weight.

Potential central nervous system antitumor agents. Hydantoin derivatives.

Abstract: Hydantoin derivatives of varying lipophilic character were prepared as nitrogen mustard carriers for CNS antitumor evaluation. Activity was studied in the murine ependymoblastoma brain tumor system. Multiple cures were observed for three of the four analogs examined. The compounds were also active in the intraperitoneal leukemia L1210 and P388 systems as well as in B16 melanoma and Lewis lung carcinoma.