3-dimethylaminopropyl Chloride Research Articles

Synthesis, spectroscopic, and cellular properties of α-pegylated cis-A2B2- and A3B-types ZnPcs.

A series of pegylated cis-A2B2- or A3B-type ZnPcs, substituted on the α-positions with tri(ethylene glycol) and hydroxyl groups, were synthesized from a new bis-phthalonitrile. A clamshell-type bis-phthalocyanine was also obtained as a byproduct. The hydroxyl group of one ZnPc was alkylated with 3-dimethylaminopropyl chloride to afford a pegylated ZnPc functionalized with an amine group. All mononuclear ZnPcs were soluble in polar organic solvents, showed intense Q absorptions in DMF, and had fluorescence quantum yields in the range 0.10-0.23. The clamshell-type bis-phthalocyanine adopts mainly open shell conformations in DMF, and closed clamshell conformations in chloroform. All ZnPcs were highly phototoxic to human carcinoma HEp2 cells, particularly the amino-ZnPc mainly protonated under physiological conditions, which showed the highest phototoxicity (IC50 = 0.5 μM at 1.5 J/cm2) and dark cytotoxicity (IC50 = 22 μM), in part due to its high cellular uptake. The ZnPcs localized in multiple organelles, including mitochondria, lysosomes, Golgi and ER.

Synthesis and characterization of a novel well-defined comb-like ionomer

A novel well-defined comb-like ionomer with cations was synthesized by the combination of living anionic polymerization and atom transfer radical polymerization (ATRP). The synthetic approach involves the coupling reaction of polystyrene (PS) backbone bearing 1,1-diphenylethene (DPE) pendant groups with living polystyryllithium (PSLi), subsequent amine functionalization of the resulting 1,1-diphenylmethyl anions with 3-dimethylaminopropyl chloride (DMAPC), and quaternization of tertiary amino groups with hydrochloric acid. The comb-like ionomer was characterized by 1H NMR, IR, GPC measurements and end-group titrition.

Synthesis of Surfactants Based on Pentaerythritol. I. Cationic and Zwitterionic Gemini Surfactants

Simple strategies for the synthesis of five series of cationic gemini surfactants and one series of zwitterionic gemini surfactants from pentaerythritol have been developed. Two lipophilic groups were introduced onto pentaerythritol by alkylation of the known compound, O-benzylidenepentaerythritol, with 1-bromooctane, 1-bromodecane, 1-bromododecane, and 1-bromotetradecane. Hydrogenolysis of the benzylidene acetals gave diols which were converted into three different series of trimethylammonium derivatives. The diiodides derived from the diols could be displaced by dimethylamine, even though they are adjacent to a quaternary carbon atom. Alkylation with methyl iodide gave the first series. The iodides were easily displaced by cyanide ion and the resulting dinitriles were hydrolyzed, converted to N,N-dimethylamides, and reduced to give a second series. Oxidation of the diols to dialdehydes under Swern conditions followed by Horner-Wadsworth-Emmons reactions with diethyl N,N-dimethylcarbamoylmethylphosphonate followed by two-stage reduction gave a third series. The dialkoxides derived from the four di-O-alkylpentaerthritol diols were reacted with 2-dimethylaminoethyl chloride and 3-dimethylaminopropyl chloride in neighboring-group assisted double Williamson ether syntheses to give precursors to two more series. As expected because the neighboring group participation occurs through a four-membered-ring intermediate, considerably more vigorous conditions were required for the reactions with 3-dimethylaminopropyl chloride. 2-Diethylaminoethyl bromide was found to be less reactive than 2-dimethylaminoethyl chloride. The products were alkylated with methyl iodide and, in some cases, other alkyl halides to give cationic gemini surfactants. Alkylation of one series with ethyl bromoacetate followed by anion exchange resin catalyzed ester hydrolysis gave zwitterionic gemini surfactants. The members of all series have superior surfactant properties.

Novel derivatives of benzo[b]thieno[2,3-c]quinolones: synthesis, photochemical synthesis, and antitumor evaluation.

Novel derivatives of benzo[b]thieno[2,3-c]quinolones 3a-j were synthesized in a multistep synthesis starting from substituted benzo[b]thiophene-2-carbonyl chlorides, to their corresponding benzo[b]thiophene-2-carboxamides, which were photochemically dehydrohalogenated to their corresponding substituted benzo[b]thieno[2,3-c]quinolones. Compound 4 was prepared from 3i by alkylation with 3-dimethylaminopropyl chloride in the presence of NaH. Compounds 7a,b were prepared from 3g in the multistep synthesis from compounds 5 and 6. Compounds 3b, 3c-f, 3h, 7a, and 7b were found to exert cytostatic activity against malignant cell lines: pancreatic carcinoma (MiaPaCa2), breast carcinoma (MCF7), cervical carcinoma (HeLa), laryngeal carcinoma (Hep2), colon carcinoma (CaCo-2), melanoma (HBL), human fibroblast cell lines (WI-38). The compounds that bear a 3-dimethylaminopropyl substituent on the quinolone nitrogen (3b, 3c-f, 3h) showed higher antitumor activity than compounds bearing the same substituent on the amidic nitrogen (7a and 7b). The compound 3h, which has a 3-dimethylaminopropyl substituent on the quinolone nitrogen and a methoxycarbonyl substituent at position 9, had marked antitumor activity. Because of strong cytotoxic effect of compound 4 on melanoma cells (HBL, ME 67.3, and ME 67.1), a potential mechanism of action was examined. Analysis of DNA and Annexin-V-FLUOS staining indicated that compound 4 causes cell death by apoptosis.

Anionic synthesis of well-defined polymers with amine end groups

The results for efficient tertiary and primary amine functionalization of polymeric organolithium compounds in hydrocarbon solution at room temperature are described for termination reactions with N-trimethylsilylbenzophenone imine, 3-dimethylaminopropyl chloride and 2,2,5,5-tetramethyl-1-(3-chloropropyl)-1-aza-2,5-disilacyclopentane. Functionalizations with the functionalized initiator, 2,2,5,5-tetramethyl-1-(3-lithiopropyl)-1-aza-2,5-disilacyclopentane are presented. Conditions for quantitative amine functionalization were observed for all of these reactions and reagents.

Quantitative amine functionalization of polymeric organolithium compounds with 3-dimethylaminopropyl chloride in the presence of lithium chloride

The addition of lithium chloride promoted the coupling reaction of hydrocarbon solutions of poly(styryl)lithium (PSLi) and poly(isoprenyl)lithium (PILi) with 3-dimethylaminopropyl chloride to form the corresponding w-dimethylamino-functionalized polymers. Quantitative amine functionalization was achieved for PSLi and PILi in the presence of 1 and 10 equivalents, respectively, of LiCl in benzene; the functionalization efficiency was only 67% for PSLi and 85% for PILi in the absence of LiCl. The polymer products were characterized by size exclusion chromatography, thin-layer chromatography, and amine end-group titration. The pure amine-functionalized polymers were isolated by silica gel column chromatography.

Quantitative amine functionalization of polymeric organolithium compounds with 3‐dimethylaminopropyl chloride in the presence of lithium chloride

The addition of lithium chloride promoted the coupling reaction of hydrocarbon solutions of poly(styryl)lithium (PSLi) and poly(isoprenyl)lithium (PILi) with 3-dimethylaminopropyl chloride to form the corresponding ω-dimethylamino-functionalized polymers. Quantitative amine functionalization was achieved for PSLi and PILi in the presence of 1 and 10 equivalents, respectively, of LiCl in benzene; the functionalization efficiency was only 67% for PSLi and 85% for PILi in the absence of LiCl. The polymer products were characterized by size exclusion chromatography, thin-layer chromatography, and amine end-group titration. The pure amine-functionalized polymers were isolated by silica gel column chromatography. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 38: 145–151, 2000

Anionic synthesis of ω-dimethylamino-functionalized polymers by functionalization of polymeric organolithiums with 3-dimethylaminopropyl chloride

The functionalization reactions of polystyryllithium, polyisoprenyllithium and polybutadienyllithium in benzene with 3-dimethylaminopropyl chloride have been investigated in detail. The effects of addition mode (normal and inverse addition), added Lewis bases (THF and TMEDA), temperature and concentration have been investigated. The polymer products were analysed by SEC, 1 H and 13 C NMR spectroscopy and end-group titration. The pure ω-dimethylamino-functionalized polymers were quantitatively isolated by silica gel column chromatography. The functionalizations of polystyryllithium, polyisoprenyllithium and polybutadienyllithium by normal addition in benzene produce the corresponding w-dimethylamino-functionalized polymers in isolated yields of 67%, 85% and 90%, respectively. Functionalization efficiencies were improved by using the inverse addition procedure and by post-polymerization addition of Lewis bases before functionalization.

14C-Labeling of a New Cerebral Metabolic Enhancer SM-3163.

Both enantiomers of 1- [3- (dimethylamino) propoxy] -1, 5-diphenylpentane citrate (SM-3163), a new cerebral metabolic enhancer, were labeled with 14C at the 1-position of pentyl chain for use in comparative metabolic studies. The synthesis was achieved according to the scheme illustrated in Fig. 2. 14C-Cyanation of 4-phenylbutylbromide (3) with potassium [14C] cyanide (2) followed by the reaction of the resulting nitrile (4) with phenylmagnesium bromide gave the ketone (5) . Reduction of 5 with lithium aluminum hydride produced the racemic alcohol (6) . Optical resolution of 6 by chiral-phase HPLC afforded two optically active alcohols (6a and 6b) . Condensation of 6a and 6b with 3-dimethylaminopropyl chloride and subsequent treatment of the aminoethers (7a and 7b) with citric acid gave (R) -and (S) -SM-3163 (1a and 1b) in the overall yields of 12.5% and 8.2%, respectively.

Potential antidepressants and tranquillizers: Synthesis of some 9-(aminoalkoxy)-2,3,6,7-tetrahydro-1H,5H-benzo[ij] quinolizines and 1-(substituted amino)-3-(1-naphthoxy)-2-propanols

The hydrobromide of 9-hydroxyjulolidine was reacted with hydrochloride of 2-dimethylaminoethyl chloride, 2-(1-pyrrolidinyl)ethyl chloride, 2-(1-piperidinyl)ethyl chloride, and 3-dimethylaminopropyl chloride in ethanol in the presence of sodium ethoxide to give the title bases II-V which were transformed to dihydrochlorides. Heating of 1,2-epoxy-3-(1-naphthoxy)propane with 2,3,3-trimethyl-2-butylamine, 1-methylcyclopentylamine, 1-methylcyclohexylamine, 1-methylcycloheptylamine, and 10,11-dihydroxydibenzo[a,d]cycloheptene-5-amine in ethanol afforded the second part of the title compounds (VII-XI), prepared also in the form of hydrochlorides. Only the ethers II and V showed indications of possible antidepressant activity.

Potential antidepressant and anti-inflammatory agents: 4-(2-Propylthio)acetophenone oximes and 4-(2-propylthio)phenylalkanoic acids

4-(2-Propylthio)acetophenone oxime (IV) was reacted with 2-aminoethyl chloride and 3-dimethylaminopropyl chloride to give the O-(aminoalkyl)oximes V and VI which are analogues of the antidepressant agent fluvoxamine (I). Kindler-Willgerodt reaction of 4-(2-propylthio)acetophenone (III) gave the thiomorpholide VII which was hydrolyzed to the acid IX. Friedel-Crafts reaction of (2-propylthio)benzene with ethoxalyl chloride afforded ethyl 4-(2-propylthio)benzoylformate (X) which was transformed by reaction with methylmagnesium iodide, by the following hydrolysis and reduction with hydroiodic acid to 2-(4-(2-propylthio)phenyl)propionic acid (XII), a thia isostere of the anti-inflammatory and analgesic agent ibuprofen (II); acid XII was also obtained by reaction of 2-(4-mercaptophenyl)propionic acid (XVII) with 2-bromopropane and by the following hydrolysis. The acids IX and XII were converted to the amides XIII-XV. The fluvoxamine analogue V (V⁄FB-16 650) showed some pharmacological properties of potential antidepressants. The acids IX and XII (V⁄FB-16 603) have comparable anti-inflammatory activity with that of ibuprofen (II); in addition, XII has lower acute toxicity and higher analgetic activity than ibuprofen.

Potential antidepressants: 6-(Aminoalkoxy)dibenzo[b,f]thiepin-10(11H)-ones and 6-(aminoalkoxy)-10,11-dihydrodibenzo[b,f]thiepin-10-ols

Sodium salts of 6-hydroxydibenzo[b,f]thiepin-10(11H)-one and its 2-chloro derivative were reacted with hydrochlorides of 2-dimethylaminoethyl chloride, 2-(piperidino)ethyl chloride, 3-dimethylaminopropyl chloride, and 3-(piperidino)propyl chloride in ethanol in the presence of sodium ethoxide which resulted in the title compounds IIa, IIb, IVa, Va, Vb, and VIIa. The tertiary amines IIa, IIb, and Va were partially demethylated via the carbamates VIIIa, VIIIb, and IXa to the secondary amines IIIa, IIIb, and VIa. The amino ketones IIa and Va were reduced to the amino alcohols XII and XIII. With the exception of compound Va (hydrochloride VÚFB-15 515), the products lacked completely the expected pharmacological profile of potential antidepressants.

Potential antidepressants: Synthesis of two 4-(aminoalkoxy)dibenzo[b,e]thiepin-11(6H)-ones

Heating of 4-methoxydibenzo[b,e]thiepin-11(6H)-one with pyridine hydrochloride to 225 to 235 °C effected demethylation and gave IV. Its sodium salt reacted with 3-dimethylaminopropyl chloride in ethanol and afforded the 4-(3-dimethylaminopropoxy) compound II. The isomeric ether III was prepared via the 4-(4-bromobutoxy) compound V. Hydrochloride of II (VÚFB-17 033) inhibited mildly the binding of [3H]desipramine in rat hypothalamus, had antireserpine activity in rats, mild anticonvulsant effect, and antihypoxic effect in the test of nitrogen anoxia in mice.

Potential antidepressants: Saturated side chain amines derived from 6,11-dihydrodibenzo[b,e]thiepin and 4,9-dihydrothieno[2,3-c]-2-benzothiepin

Reduction of IV with hydroiodic acid afforded almost quantitatively the spirocyclic amino sulfide VII, evidently via V and VI. The carbamate II was chlorinated with N-chlorosuccinimide, the product (XII) was reacted with phenylmagnesium bromide and then reduced with LiAlH4 to give the 6-phenyl derivative X of the antidepressant agent hydrothiadene (I). Treatment of 11-methyl-6,11-dihydrodibenzo[b,e]thiepin (XIII) with butyllithium followed by alkylation with 3-dimethylaminopropyl chloride resulted in 6-(3-dimethylaminopropyl) derivative XIV. Reaction of XIV with ethyl chloroformate and the following alkaline hydrolysis gave the 6-(3-methylaminopropyl) derivative XV (mixture of stereoisomers). Reduction of the corresponding olefinic amine and the tertiary alcohol with hydroiodic acid gave the saturated side chain amines derived from 4,9-dihydrothieno[2,3-c]-2-benzothiepin XVIII and XIX. The dihydro derivative of dithiadene XVIII (VÚFB-17 031) proved very effective in a series of tests predictive of antidepressant activity.

5-Substituted and 5,7-disubstituted 5,7-dihydrodibenzo[c,e]thiepins and the corresponding S-oxygenated compounds: Alkylamines, carboxylic acids, and carboxamides; synthesis and pharmacological screening

Reaction of 5,7-dihydrodibenzo[c,e]thiepin (I) with n-butyllithium resulted in the partial sulfur extrusion and in the formation of the 9,10-dihydrophenanthrene-9-thiolate anion (B). Its further transformations (by hydrolysis, aminoalkylation and spontaneous dehydrogenation) led to phenanthrene-9-thiol (IX), the corresponding disulfide X, and the S-(2-dimethylaminoethyl) derivatives XI and XIV. Reactions of 5-chloro-5,7-dihydrodibenzo[c,e]thiepin (II) with the corresponding Grignard reagents were only a poor source of the amines III and IV. Reaction of the sulfoxide XVIII with n-butyllithium or with sodium hydride and the following treatment with 2-dimethylaminoethyl chloride gave the amine XIX in a low yield. Only the sulfone X was found more useful for preparing the 5- and 5,7-substituted derivatives. Treatment with n-butyllithium and following carbonation afforded mixtures of the monocarboxylic acid XXI and dicarboxylic acid XXVIII. Via acid chlorides they were transformed to the methylamides XXII and XXIX, and to the dimethylamides XXIII and XXX. The amide XXIII was reduced to the 5-(dimethylaminomethyl) compound XXV. Lithiation of the sulfone XX or treatment with sodium hydride, and the following action of 2-dimethylaminoethyl chloride and 3-dimethylaminopropyl chloride gave the amines XXVI, XXVII, and XXXI. Only the phenanthrene derivatives XI and XIV, and the amino sulfone XXVII showed clear indications of thymoleptic activity as potential antidepressants.

Cyclic amidines derived from benz[c,d]indole and 4,5-dihydro-3H-1-benzazepine including some related compounds: Synthesis and pharmacological screening

Reactions of naphthostyril (I) with primary and secondary amines and titanium tetrachloride afforded cyclic amidines III-IX. Hydrogenation of I on Pd-C resulted in the 6,7,8,8a-tetrahydro derivative X which gave by treatment with sodium amide and 3-dimethylaminopropyl chloride the N-(aminoalkyl) compound XI. Reduction of I and its N-methyl derivative II with sodium amalgam in aqueous sodium hydroxide gave the 2a,3,4,5-tetrahydro derivatives XII and XIII. Reaction of XIII with sodium amide and 3-dimethylaminopropyl chloride afforded the 2a-(aminoalkyl) compound XIV. 1,3,4,5-Tetrahydro-1-benzazepin-2-one (XV) treated with primary amines and titanium tetrachloride gave the amidines XVI-XVIII. 3-Methyl-7,8,9,9a-tetrahydro-1H-benz[d,e]isoquinoline (XIX) was reduced with sodium borohydride to compound XX which was alkylated with propargyl bromide to 1-methyl-2-propargyl-2,3,3a,4,5,6-hexahydro-1H-benz[d,e]isoquinoline (XXI). An attempt to prepare the 2-(2-phenylethyl) analogue by treatment of compound XX with phenylacetyl chloride and by the following reduction with lithium aluminium hydride resulted in the open-chain amine XXII. The lactams I, II, X, and XIII showed some discoordinating, hypothermic, peripheral vasodilating, hyperglycaemic, diuretic and antiinflammatory effects. The amidines III-IX and XVI-XVIII had local anaesthetic, slight hypotensive, antiarrhythmic, peripheral myorelaxant, papaverine-like spasmolytic and thiopental potentiating effects.

11-(Dimethylaminoalkyl)-6,11-dihydrodibenzo[b,e]thiepin-11-carbonitriles and some related compounds

The title compounds II and III were obtained by alkylations of 6,11-dihydrodibenzo[b,e]thiepin-11-carbonitrile (I) with 2-dimethylaminoethyl chloride and 3-dimethylaminopropyl chloride in the presence of sodium hydride or sodium amide. Hydrolysis of the nitrile II with potassium hydroxide in ethanol resulted in a small amount of the amino acid X and in the amine XI as the main product. Alkylations of I with 1,2-dibromoethane and 1,3-dibromopropane in the presence of sodium hydride gave the bromoalkylnitriles IV and V and the alkylenebisnitriles XIII and XIV. The preparation of the methylpiperazinopropyl derivative VI proved the usefulness of compounds IV and V in the synthesis of further aminonitriles of this series. Alkylation of the nitrile I with 1,2-dibromoethane in the presence of sodium hydroxide or potassium carbonate and benzyltriethylammonium chloride afforded three isomeric nitriles C17H13NS: the vinyl derivative IX, the 6,11-ethano-6H, 11H-dibenzo[b,e]thiepin derivative XV and finally the 1a,11b-dihydro-1H,7H-dibenzo[b,f]cyclopropa[d]thiocin derivative XVI. Compounds II, III, VI and XII showed some spasmolytic effects but their central neurotropic activity is insignificant.

Dibenzo[b,f]thiepin-10-carbonitrile, its 10,11-dihydro derivative, some transformation products and related compounds

Reactions of 10-bromodibenzo[b,f]thiepin (IIIa), its 2-chloro derivative IIIb and 2,8-dichloro derivative IIIc with cuprous cyanide in boiling dimethylformamide gave the carbonitriles Iabc out of which the first two were reduced with sodium borohydride to the 10,11-dihydro derivatives IVab; the amides VIIab were obtained as by-products. Alkaline hydrolysis of the nitriles IVab or their mixtures with the amides VIIab afforded the acids VIIIab. By the addition of 3-dimethylaminopropylmagnesium chloride to the nitrile Ia cis and trans-11-(3-dimethylaminopropyl)-10,11-dihydrodibenzo[b,f]thiepin-10-carbonitriles (XVIII) were obtained. Alkylation of the nitrile IVa with 2-dimethylaminoethyl chloride and 3-dimethylaminopropyl chloride resulted in the 10-(dimethylaminoalkyl) derivatives XX and XXI. A reaction of the crude cyano alcohol XXIII with phosphorus tribromide afforded the 2-bromoethyl derivative XXIV as a by-product only. The main product was the hydrobromide of the spirocyclic imidate XXX which affords by acid hydrolysis the spirocyclic lactone XXXI. An analogous sequence proceeding via the ether XXVI and the alcohol XXVII leads to the 10-(3-bromopropyl) derivative XXVIII as the main product. An attempt at preparing the same substance by alkylation of the nitrile IVa with 1,3-dibromopropane gave stereoisomeric dinitriles XXXII. At high doses the amides VIIab reveal an anticonvulsant effect, the acids VIIIab antiinflammatory actions, the basic nitrile cis-XVIII antireserpine activity and the basic nitriles XX and XXI a central depressant and pseudo-analgesic activity in addition to further peripheral and cardiovascular effects.

6,11-Dihydrodibenzo[b,e]thiepin-11-thiol and 11-acetic acid derivatives; Some 2-methyl-6,11-dihydrodibenzo[b,e]thiepins; Synthesis and pharmacological screening

11-Chloro-6,11-dihydrodibenzo[b,e]thiepin was transformed via the isothiourea V to the thiol IV which was used for the synthesis of aminoalkyl sulfides VII and VIII and of the methylpiperazide X. The same starting compound was used for alkylating diethyl malonate and via the intermediates XIV and XV, 6,11-dihydrodibenzo[b,e]thiepin-11-acetic acid (XVI) was obtained, which was converted to the methylpiperazide XVIII. Oxime XIX and 2-diethylaminoethylimine XX were prepared from 2-methyldibenzo[b,e]thiepin-11(6H)-one (II). Reduction of the ketone II afforded 2-methyl-6,11-dihydrodibenzo[b,e]thiepin (XII) giving by treatment with sodium amide and 3-dimethylaminopropyl chloride the amine XXIII. In the reaction of 6,11-dihydrodibenzo[b,e]thiepin-11-ol with sodium amide and 3-dimethylaminopropyl chloride, C-alkylation took place in addition to the expected etherification resulting in the diamine XXII. Reaction of phthalide with 4-aminothiophenol gave the acid XXIV which was transformed to the 3-dimethylaminopropyl ester XXV and N-acetyl derivative XXVI. Compound XXVI was cyclized with zinc chloride to the ketone III. Some of the compounds prepared exhibit structurally less specific peripheral and vegetative neurotropic effects (local anaesthetic, spasmolytic) and cardiovascular activity (antiarrhytmic).