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PubMed1986

Adriamycin analogues. Preparation and biological evaluation of some N-(trifluoroacetyl)-14-O-[(N-acetylamino)acyl]adriamycin derivatives.

In connection with structure-activity studies related to the novel DNA-nonbinding adriamycin analogues N-(trifluoroacetyl)adriamycin 14-valerate (AD 32) and N-(trifluoroacetyl)adriamycin 14-O-hemiadipate (AD 143), we have now prepared a series of N-(trifluoroacetyl)adriamycin derivatives with N-acylamino acid esters at the 14-carbinol position. Target compounds were made by reaction of N-(trifluoroacetyl)-14-iododaunorubicin with the sodium salts of N-acylamino acids generally in dimethylformamide-ethylene glycol solvent. Products were evaluated for in vitro growth-inhibitory activity and, to a limited extent, in vivo antitumor activity in the murine P388 leukemia system. ID50 values for the target compounds vs. cultured CCRF-CEM cells were generally in the same range as those for the above-mentioned DNA nonbinding adriamycin analogues. Of the four compounds tested for in vivo activity, although none was as effective as N-(trifluoroacetyl)adriamycin 14-valerate, all showed significant activity in the P388 assay system, with three of the compounds, at the doses used, being essentially equiactive with an optimal dose of adriamycin. Studies on the rate of esterase-mediated deacylation of the products, in a defined system containing unfractionated mouse serum as the source of enzyme, showed no relationship between the in vitro and in vivo activities of these compounds and the relative ease at which the side-chain ester substituents were hydrolyzed.

Animals↗
PubMed1986

Synthetic 1,4-disubstituted-1,4-dihydro-5H-tetrazol-5-one derivatives of fentanyl: alfentanil (R 39209), a potent, extremely short-acting narcotic analgesic.

The synthesis of a series of N-1,4-disubstituted-1,4-dihydro-5H-tetrazol-5-one piperidinyl derivatives of fentanyl, carfentanil, and sufentanil is described. The 1-substituted tetrazolinones 2 were essentially prepared via the addition reaction of aluminium azide to isocyanates or acid chlorides in tetrahydrofuran. Alkylation of 2 under neutral or weakly basic conditions afforded almost exclusively the 1,4-disubstituted tetrazolinone isomer 3. N-Alkylation of the piperidine derivatives 4 with 3 in dimethylformamide yielded 9a-v. The morphinomimetic activity in rats, after intravenous injection of the compounds, was evaluated in the tail withdrawal reflex test. The fentanyl analogues 9a-c (R4 = H) are inactive at the measured dose of 2.5 or 10 mg/kg (iv). For the carfentanil analogues (R4 = COOCH3) maximal narcotic activity is found when R1 represents a lower alkyl group (9d-f) or a thienylethyl group (9n). The sufentanil analogues (R4 = CH2OCH3) show the same structure-activity relationship (SAR) profile as the carfentanil derivatives (R4 = COOCH3). The structural requirements for optimal activity are in good agreement with earlier observations in the series of 10-12. From the series the ethyl tetrazolinone derivative 9r, alfentanil (R 39209), was selected for clinical investigation. As an analgesic in rats, 9r is 140 times more potent than pethidine 15 and 72 times more potent than morphine 14. Alftentanil reaches its peak effect within 1 min after injection, and its duration of action is very short; at 2 times its MED50, 9r has a duration of action of 11 min. This duration is 30 min for 10 and 90 min for 14. Compared to 10, alfentanil 9r is about 4 times faster but 3 times shorter acting. Structurally, 9r shows most resemblance to sufentanil 12, since it differs only by substitution of a 4-ethyltetrazolinone ring for the thiophene ring. The considerable differences in their pharmacological profiles were explained in terms of marked variations in physicochemical and, hence, pharmacokinetic properties.

Alfentanil↗
PubMed1990

(Pyrimidinyloxy)acetic acids and pyrimidineacetic acids as a novel class of aldose reductase inhibitors.

Pyrimidineacetic acids and (pyrimidinyloxy)acetic acids were synthesized by alkylation, with methyl bromoacetate or tert-butyl bromoacetate as alkylating agents. Alkylation reaction at the nitrogen or oxygen atom for different substrates was found to be solvent dependent. N-Alkylation was favored in ethereal solvent, e.g., tetrahydrofuran and dimethoxyethane, whereas O-alkylation was predominant in dimethylformamide. These compounds were tested in vitro to determine their ability to inhibit bovine lens aldose reductase. Selected compounds were assayed in vivo, in a 4-day galactose-fed rat model. The decrease in galactitol from the control was determined in lens, nerve, and diaphragm. Several of the 6-oxopyrimidine-1-acetic acids and (pyrimidinyl-4-oxy)acetic acids were found to be potent inhibitors of bovine lens aldose reductase. A study was also undertaken to determine in vitro the transport behavior of selected compounds in the isolated rat sciatic nerve. A discussion of the structure-activity relationship of this class of compounds with reference to their intrinsic biochemical activity is reported. It is concluded, in general, that ability of a compound to penetrate the tissue membrane plays an important role in the genesis of in vivo lens aldose reductase (LAR) inhibitory activity.

Acetates↗
PubMed1980

Synthesis and antitumor activity of 2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidine.

The synthesis of 2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidine (BW301U, 7) by a route that has general applicability to the preparation of many 6-(substituted benzyl)-5-methylpyrido[2,3-d]pyrimidines is described. The key intermediate, 2,4-diamino-7,8-dihydro-6-(2,5-dimethoxybenzyl)-5-methyl-7-oxopyrido[2,3-d]pyrimidine (4), is converted to the 7-chloro compound 5 by treatment with a 1:1 complex of N,N-dimethylformamide--thionyl chloride, and 5 is hydrogenolyzed with palladium on charcoal in the presence of potassium hydroxide to yield 7. BW301U is a potent lipid-soluble inhibitor of mammalian dihydrofolate reductase and has significant activity against the Walker 256 carcinosarcoma in rats.

Animals↗
PubMed1978

Cyclic analogues of luteinizing hormone-releasing hormone with significant biological activities.

There is evidence that, in its receptor-binding conformation, the N and C terminus of LH-RH may be in close proximity and two cyclic analogues of the hormone were synthesized to test the hypothesis. Cyclic [beta-Ala1,D-Ala6,Gly10]- and [6-aminohexanoic acid1,D-Ala6,Gly10]-LH-RH were prepared by treatment of their linear precursor peptides with dicyclohexylcarbodiimide in the presence of 1-hydroxybenzotriazole in dilute dimethylformamide solution. Although the linear peptides possessed no detectable LH-releasing activity in ovariectomized rats, the cyclic beta-Ala analogue had 1.2% the activity of LH-RH, whereas the longer chain cyclic 6-aminohexanoic acid analogue had 0.65% activity. These results support the concept of an important interaction between the ends of the LH-RH molecule possibly involving hydrogen-bond formation between the pyrrolidone carbonyl group of pyroglutamic acid and the glycinamide group.

Animals↗
PubMed1977

Synthesis of 5-azacytidine-6-13C and -6-14C.

5-Azacytidine (1) labeled with 13C or 14C at the chemically labile C-6 position was synthesized. A method utilizing hydrolytic opening of the triazine ring followed by recyclization with dimethylformamide dimethyl acetal was used. Urinary and biliary excretion was measured in rabbits following intravenous doses of 1-4-14C and 1-6-14C. Differences in recoveries of the dose from 4-14C and 6-14C demonstrate that ring cleavage of 1 with loss of the C-6 carbon represents a major metabolite route.

Animals↗
PubMed1977

Antimycotic imidazoles. 2. Synthesis and antimycotic properties of 1-[2-(arylalkyl)-2-phenylethyl]-1H-imidazoles.

Synthesis of 1-[2-(arylalkyl)-2-phenylethyl]-1H-imidazoles was accomplished starting from the corresponding phenylacetonitriles. Via successive alkylation, conversion to the corresponding ester, and sodium borohydride-lithium iodide reduction, beta-phenylalcanols were obtained. These alcohols were mesylated and then refluxed with imidazole in dimethylformamide to yield the title compounds, which were active in vitro against dermatophytes, yeasts, other fungi, and gram-positive bacteria. Some were also active in vivo against Candida albicans.

Animals↗
PubMed1976

Synthesis of the antileukemic compound N,N(11)-[5-[bis(2-chloroethyl)amino]-1, 3-phenylene]bisurea.

Conversion of 5-nitro-1, 3-benzenedicarboxylic acid (1) to the diamide 2 followed by hypochlorite rearrangement to the idamine 3 and subsequent reaction with acetic anhydride gave the bisacetamide 4. Reduction to the amine 5 followed by treatment with ethylene oxide formed the diol 6. The latter was converted to the bistosylate 7, which undrewent facile displacement with lithium chloride in acetone to give the mustard 8. Removal of the acetyl groups with hydrochloric acid gave 9, which reacted with potassium cyanate to provide the bisurea 10. In an alternative, but less satisfactory synthesis of 10, the compound (5-nitro-1, 3-phenylene) biscarbamic acid diphenyl ester (11), or the corresponding diethyl ester 12, was converted by ammonolysis to 13. The nitrodiurea 13 was next reduced to the amine 14, the hydrochloride of which reacted with ethylene oxide to give the diol 15. Treatment of the latter in dimethylformamide with N-chlorosuccinimide in the presence of triphenylphosphine gave 10 in low yield. The nitrogen mustards 8, 9 and 10 showed significant antitumor activities against P388 lymphocytic leukemia in mice.

Animals↗
PubMed1976

Synthesis and biological activities of 5-trifluoromethyl-5'-azido-2',5'-dideoxyuridine and 5-trifluoromethyl-5'-amino-2',5'-dideoxyuridine.

5-Trifluoromethyl-2'-deoxyuridine (1) was tosylated with p-toluenesulfonyl chloride in dry pyridine at 3 degrees to give 5-trifluoromethyl-5'-O-(p-tolylsulfonyl)-2'-deoxyuridine (2), which was converted to 5-trifluoromethyl-5'-azido-2',5'-dideoxyuridine (3) by reacting with lithium azide in N,N-dimethylformamide at 85-90 degrees for 2 h. Compound 3 was then hydrogenated in ethanol-water (1:1, v/v) at room temperature and 35 psi of hydrogen pressure, using 10% palladium on charcoal as cstalyst, to yield 5-trifluoromethyl-5'-amino-2',5'-dideoxyuridine (4). Compound 4 is about fourfold less potent than compound 1 as an antiviral agent but is about 40-fold less toxic to the host Vero cells. Thus the therapeutic index of compound 1 has been improved by a factor of 10 by replacement of the 5'-hydroxyl with an amino group. Compound 1, however, is more than 100-fold more inhibitory to Sarcoma 180 cells in culture relative to compound 4. Compound 3 is markedly less potent than compound 1 or 4 as either an antiviral or an antineoplastic compound.

Animals↗
PubMed1976

Synthesis and antimyoctic properties of 1-(2-alkyl-2-phenylethyl)-1H-imidazoles.

The synthesis of 1-(2-alkyl-2-phenylethyl)-1H-imidazoles was accomplished starting from the corresponding phenylacetonitriles. Via alkylation, esterification, and sodium borohydride reduction-in the presence of lithium iodide-beta-phenylalconols were obtained. Mesylation of these alcohols and refluxing with imidazole in dimethylformamide furnished title compounds, which were active in vitro against dermatophytes, yeasts, other fungi, and gram-positive bacteria and in vivo as well as in vitro against Candida albicans.

Animals↗
PubMed1975

(1-Beta-mercaptopropionic acid, 2-(3,5-dibromo-L-tyrosine))oxytocin, a potent inhibitor of oxytocin.

[1-Beta-Mercaptopropionic acid,2-(3,5-dibromo-L-tyrosine)]oxytocin was synthesized from a protected polypeptide intermediate that had been prepared by the condensation of S-ethylcarbamoyl-beta-mercaptopropionyl-3,5-dibromotyrosine with H-Ile-Gln-Asn-Cys(Ec)-Pro-Leu-Gly-NH2, using dicyclohexylcarbodiimide in dimethylformamide. The ethylcarbamoyl (Ec) protecting groups were removed by refluxing NH3, and the resulting disulfhydryl peptide was oxidatively cyclized to the corresponding disulfide by ICH2CH2I. Purification of the analog was effected by partition chromatography and gel filtration. The analog possesses antioxytocic (pA2 = 7.05) and antiavian vasodepressor (pA2 = 7.44) activities but has neither agonist nor antagonist activity in the rat pressor assay.

Animals↗
PubMed1982

Synthesis and pharmacology of metabolically stable tert-butyl ethers of morphine and levorphanol.

3-O-tert-Butylmorphine (5) was prepared from 6-O-acetylmorphine (3) via alkylation with N,N-dimethylformamide di-tert-butyl acetal, followed by hydrolytic removal of the 3-(dimethylamino)-2-propenoate group. The same process was used to prepare the tert-butyl ether of levorphanol (6), (-)-3-tert-butoxy-N-methylmorphinan (8). Both 5 and 8 exhibited in vitro affinity for the opiate receptor comparable to codeine and had analgesic properties in the writhing test. Only 5 exhibited activity in the tail-flick procedure and neither compound showed significant antitussive activity.

Analgesics↗
PubMed1999

Structure-antiviral activity relationship in the series of pyrimidine and purine N-[2-(2-phosphonomethoxy)ethyl] nucleotide analogues. 1. Derivatives substituted at the carbon atoms of the base.

A series of dialkyl esters of purine and pyrimidine N-[2-(phosphonomethoxy)ethyl] derivatives substituted at position 2, 6, or 8 of the purine base or position 2, 4, or 5 of the pyrimidine base were prepared by alkylation of the appropriate heterocyclic base with 2-chloroethoxymethylphosphonate diester in the presence of sodium hydride, cesium carbonate, or 1,8-diazabicyclo[5,4, 0]undec-7-ene (DBU) in dimethylformamide. Additional derivatives were obtained by the transformations of the bases in the suitably modified intermediates bearing reactive functions at the base moiety. The diesters were converted to the corresponding monoesters by sodium azide treatment, while the free acids were obtained from the diester by successive treatment with bromotrimethylsilane and hydrolysis. None of the PME derivatives in the pyrimidine series, their 6-aza or 3-deaza analogues, exhibited any activity against DNA viruses or retroviruses tested, except for the 5-bromocytosine derivative. Substitution of the adenine ring in PMEA at position 2 by Cl, F, or OH group decreased the activity against all DNA viruses tested. PMEDAP was highly active against HSV-1, HSV-2, and VZV in the concentration range (EC50) of 0.07-2 microg/mL. Also the 2-amino-6-chloropurine derivative was strongly active (EC50 = 0.1-0. 4 microg/mL) against herpes simplex viruses and (EC50 = 0.006-0.3 microg/mL) against CMV and VZV. PMEG was the most active compound of the whole series against DNA viruses (EC50 approximately 0.01-0.02 microg/mL), though it exhibited significant toxicity against the host cells. The base-modified compounds did not show any appreciable activity against DNA viruses except for 7-deazaPMEA (IC50 approximately 7.5 microg/mL) against HIV-1 and MSV. The neutral (diisopropyl, diisooctyl) diesters of PMEA were active against CMV and VZV, while the corresponding monoesters were inactive. The diisopropyl ester of the 2-chloroadenine analogue of PMEA showed substantially (10-100x) higher activity against CMV and VZV than the parent phosphonate. Also, the diisopropyl and diisooctyl ester of PMEDAP inhibited CMV and VZV, but esterification of the phosphonate residue did not improve the activity against either MSV or HIV.

Animals↗
PubMed2000

Stereoelectronic effect on one-electron reductive release of 5-fluorouracil from 5-fluoro-1-(2-oxocycloalkyl)uracils as a new class of radiation-activated antitumor prodrugs.

A series of 5-fluoro-1-(2'-oxocycloalkyl)uracils (3-11) that are potentially novel radiation-activated prodrugs for the radiotherapy of hypoxic tumor cells have been synthesized to evaluate a relationship between the molecular structure and the reactivity of one-electron reductive release of antitumor 5-fluorouracil (1) in anoxic aqueous solution. All the compounds 3-11 bearing the 2'-oxo group were one-electron reduced by hydrated electrons (eaq-) and thereby underwent C(1')-N(1) bond dissociation to release 5-fluorouracil 1 in 47-96% yields upon radiolysis of anoxic aqueous solution, while control compounds (12, 13) without the 2'-oxo substituent had no reactivity toward such a reductive C(1')-N(1) bond dissociation. The decomposition of 2-oxo compounds in the radiolytic one-electron reduction was more enhanced, as the one-electron reduction potential measured by cyclic voltammetry in N,N-dimethylformamide became more positive. The efficiency of 5-fluorouracil release was strongly dependent on the structural flexibility of 2-oxo compounds. X-ray crystallographic studies of representative compounds revealed that the C(1')-N(1) bond possesses normal geometry and bond length in the ground state. MO calculations by the AM1 method demonstrated that the LUMO is primarily localized at the pi* orbital of C(5)-C(6) double bond of the 5-fluorouracil moiety, and that the LUMO + 1 is delocalized between the pi* orbital of 2'-oxo substituent and the sigma* orbital of adjacent C(1')-N(1) bond. The one-electron reductive release of 5-fluorouracil 1 in anoxic aqueous solution was presumed to occur from the LUMO + 1 of radical anion intermediates possessing a partial mixing of the antibonding C(2')=O pi* and C(1')-N(1) sigma* MO's, that may be facilitated by a dynamic conformational change to achieve higher degree of (pi* + sigma*) MO mixing.

Antineoplastic Agents↗
PubMed2001

Evaluation of the extent of conjugation in symmetrical and asymmetrical aryl-substituted acetophenone azines using electrochemical methods.

The electrochemical behavior of a series of symmetrical and unsymmetrical aryl-substituted acetophenone azines (1-X/Y, where X and Y are 4-NO2, 4-CN, H, 3-OCH3, 4-OCH3, 4-CH3, and 4-N(CH3)2) was studied in acetonitrile and N,N-dimethylformamide (DMF) solution using cyclic voltammetry (CV). Compounds 1-X/Y, where neither X or Y are nitro substituents, undergo successive reduction to their radical anion (1-X/Y.-) and then dianion (1-X/Y2-), respectively. In all cases, the formation of the radical anion is completely reversible and the standard reduction potentials, Eo1-X/Y/1-X/Y.- could be determined. The reversibility of the second electron transfer is substituent dependent with certain dianions sufficiently basic to be protonated under our conditions. Standard reduction potentials (Eo1-X/Y/1-X/Y.-) for the formation of radical anions exhibit a large substituent effect with values differing by more than 0.66 V throughout the series going from 1-4-CN/4-CN to 1-4-OCH3/4-OCH3; similar substituent effects were determined for the formation of the dianion. The nitro-containing azines deviate from the above-mentioned behavior. With the exception of 1-4-NO2/4-NO2, they exhibit single electron waves that have values of Eo1-X/Y/1-X/Y.- within 40 mV of each other and thus the reduction is not subject to the same substituent effect as the other azines. 1-4-NO2/4-NO2 exhibits an Eo at a similar potential, but is a two-electron reversible wave with features indicative of a reduction system containing two localized, nonconjugated redox centers. The reduction potentials of all the aryl azines were correlated with Hammett sigma parameters to look at variations in Eo1-X/Y/1-X/Y.- vs SCE as a function of substituent. The small rho values in combination with the other electrochemical data provide support for single bond character of the N-N bond and evidence for a lack of strong electronic communication between the two aryl centers through the azomethine bonds, especially for those systems with electron-withdrawing groups.

Journal Article↗
PubMed2001

Synthesis of primary aromatic amides by aminocarbonylation of aryl halides using formamide as an ammonia synthon.

Primary aromatic amides were prepared by a palladium-catalyzed aminocarbonylation reaction of aryl halides in high yields (70-90%) using formamide as the amine source. The reactions require a palladium catalyst in combination with a nucleophilic Lewis base such as imidazole or 4-(dimethylamino)pyridine (DMAP). Aryl, heteroaryl, and vinyl bromides and chlorides were converted to the primary amides under mild conditions (5 bar, 120 degrees C) using 1 mol % of a palladium-phosphine complex. Best results were obtained in dioxane using triphenylphosphine as the ligand and DMAP as the base. For activated aryl bromides, a phosphine-to-palladium ratio of 2:1 was sufficient, but less reactive aryl bromides or aryl chlorides required ligand-to-palladium ratios up to 8:1 in order to stabilize the catalyst and achieve full conversion. The influence of catalyst, base, solvent, pressure, and temperature was studied in detail. The mechanism of the reaction could be clarified by isolating and identifying the reaction intermediates. In addition, methylamides and dimethylamides were prepared by the same method using N-methylformamide and N,N-dimethylformamide as the amine source.

Journal Article↗
PubMed2002

A new, facile synthesis of 1,4,7,10-tetraazacyclododecane: cyclen.

This report outlines a new and efficient synthesis of cyclen (1,4,7,10-tetraazacyclododecane, 1) utilizing bis-imidazoline, 6 (1,1'-ethylenedi-2-imidazoline), with 1,2-dibromoethane. General conditions were developed, allowing for the simple, three-step synthesis of 1 at the multigram scale with an isolated overall yield approaching 65%. The cyclization of 6 produced by the condensation of triethylene tetraamine (TETA) with N,N-dimethylformamide dimethyl acetal, gave the twelve-membered, imidazolinium, cyclized intermediate bromide salt, 7 (2,3,4,5,6,7,8,8c-octahydro-1H-4a,6a,8a-triaza-2a-azoniacyclopent[fg]acenaphthylene), which hydrolyzed to 1 with the use of hot, aqueous caustic. Hydrolysis of 7 under milder conditions formed the 1,4,7,10-tetraazabicyclo[8.2.1]tridecan-13-one (20). Mechanistically, the formation of 7 may be rationalized as involving a diaminocarbene that undergoes an intramolecular carbon-hydrogen insertion.

Journal Article↗