text:
|Publication number
|Publication type
|Application number
|Publication date
|Jul 21, 1981
|Filing date
|Oct 13, 1978
|Priority date
|Aug 4, 1976
|Also published as
|Publication number
|Barry J. Price, John W. Clitherow, John Bradshaw
|Original Assignee
|Allen & Hanburys Ltd.
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (2), Non-Patent Citations (2), Referenced by (39), Classifications (33)
|External Links: USPTO, USPTO Assignment, Espacenet
This is a division of application Ser. No. 818,762, filed July 25, 1977, now U.S. Pat. No. 4,128,658.
This invention relates to new aminoalkyl furan derivatives having a selective action on histamine receptors, to processes for the preparation thereof and pharmaceutical compositions containing them, as well as their use in therapeutics.
A subdivision of histamine receptors (H-receptors) into two groups designated H1 - and H2 -receptors has been proposed by Ash and Schild (Brit. J. Pharmacol. Chemother, 1966, 27, 427) and Black et al (Nature 1972, 236, 385). Stimulation of bronchial and gastrointestinal smooth muscle is mediated through H1 -receptors and these effects can be prevented by conventional histamine antagonists such as mepyramine. Stimulation of gastric acid secretion and heart rate is mediated through H2 -receptors; these effects are not modified by mepyramine but are prevented or abolished by H2 -antagonists such as metiamide. Histamine stimulates H1 - and H2 -receptors.
We have found that certain novel aminoalkyl furan derivatives are selective H2 -antagonists, that is they show inhibition of the secretion of gastric acid when this is stimulated via histamine H2 -receptors (Ash and Schild loc. cit.). Their ability to prevent the secretion of gastric juice when it is stimulated via histamine H2 -receptors can be demonstrated in the perfused rat stomach, using the method described by Ghosh and Schild (Brit. J. Pharmacol. 1958 13 54), modified as hereinafter described and in conscious dogs equipped with Heidenhain pouches using the same method as Black et al (Nature 1972 236 385). The compounds according to the invention do not modify histamine induced contractions of isolated gastrointestinal smooth muscle.
Compounds with histamine H2 -blocking activity may be used in the treatment of conditions where there is a hypersecretion of gastric acid e.g. in gastric and peptic ulceration, and in the treatment of allergic conditions where histamine is a known mediator. They may be used, either alone, or in combination with other active ingredients in the treatment of allergic and inflammatory conditions such as urticaria.
The invention therefore provides compounds of general formula (I): ##STR4## and physiologically acceptable salts and N-oxides and hydrates thereof, in which R1 and R2 which may be the same or different represent hydrogen, lower alkyl, cycloalkyl, lower alkenyl, aralkyl or lower alkyl interrupted by an oxygen atom or a group ##STR5## in which R4 represents hydrogen or lower alkyl or R1 and R2 may, together with the nitrogen atom to which they are attached, form a heterocyclic ring which may contain other heteroatoms selected from 0 and ##STR6## R3 is hydrogen, lower alkyl, lower alkenyl or alkoxyalkyl; X is --CH2 --, O or S;
Y represents ═S, ═O, ═NR5 or ═CHR6 ;
Alk denotes a straight or branched alkylene chain of 1 to 6 carbon atoms;
R5 is H, nitro, cyano, lower alkyl, aryl, alkylsulphonyl, or arylsulphonyl;
R6 represents nitro, arylsulphonyl or alkylsulphonyl;
m is an integer from 2 to 4; and
n is 1 or 2; or when X═S, or --CH2 --, n is zero, 1 or 2.
The term `lower` when applied to alkyl groups means that the group has preferably from 1 to 8 carbon atoms and when applied to alkenyl groups means that the group has preferably 3 to 6 carbon atoms. The term `aryl` as a group or part of a group preferably means phenyl or phenyl substituted, for example, with alkyl, alkoxy or halogen.
The compounds according to the invention have the advantage that they are readily preparable from readily accessible starting materials.
All the compounds of formula (I) can exhibit tautomerism and the formula is intended to cover all tautomers. Where Alk denotes a branched chain alkylene group, optical isomers may exist, and the formula is intended to cover all diastereoisomers and optical enantiomers.
In a preferred class of compounds according to the invention the following groups have the meanings indicated:
R1 and R2 independently represent hydrogen, alkyl, phenylalkyl, dialkylaminoalkyl or together with the nitrogen atom form a 5- or 6-membered saturated heterocyclic ring e.g. morpholino, piperidino, pyrrolidino, and N-alkylpiperazino.
Alk represents a straight alkylene chain of 1 to 4 carbon atoms.
Y is ═S, ═O, ═CHNO2 or ═NR5 where R5 is hydrogen, nitro, cyano, lower alkyl, alkylsulphonyl or benzenesulphonyl.
X, m, n, and R3 have the meanings given above.
In a particularly preferred class of compounds according to the invention the following groups have the meanings indicated:
R1 and R2 independently represent hydrogen, alkyl of 1 to 3 carbon atoms or phenethyl or together with the nitrogen atom form a pyrrolidine ring.
Alk represents an alkylene chain of 1 to 3 carbon atoms.
Y is ═S, ═CHNO2, or ═NR5, where R5 is nitro, cyano, methylsulphonyl or benzenesulphonyl.
R3 represents hydrogen, alkyl of 1 to 3 carbon atoms, propenyl or alkoxyalkyl of 3 carbon atoms.
n+m is 3 or 4, and X is as defined above.
In another preferred class of compounds according to the invention the following groups have the meanings indicated:
R1 and R2 independently represent H, alkyl of 1 to 3 carbon atoms, phenethyl or together with the nitrogen atom form a pyrrolidine ring.
Alk represents an alkylene group of 1 to 3 carbon atoms.
Y is ═S, ═CHNO2, or ═NR5, where R5 is nitro, cyano, methylsulphonyl or benzenesulphonyl.
X is S or --CH2 --.
R3 is hydrogen, methyl or methoxyethyl.
n is 1 and m is 2 or 3.
In another particularly preferred class of compounds according to the invention the following groups have the meanings indicated:
R1 is hydrogen, methyl or ethyl.
R2 is methyl or ethyl.
Alk represents a methylene group.
Y is ═NCN, ═NNO2, or ═CHNO2.
R3 is hydrogen or methyl.
X is S or --CH2 --.
n is 1 and m is 2.
Particularly preferred specific compounds are:
N-Cyano-N'-[5-[5-(dimethylamino)methyl-2-furanyl]pentyl]-N'-methyl guanidine
The compounds according to the invention readily form physiologically acceptable salts. Such salts include salts with inorganic and organic acids such as hydrochlorides, hydrobromides and sulphates. Particularly useful salts of organic acids are formed with aliphatic mono- or di-carboxylic acids. Examples of such salts are acetates, maleates and fumarates. The compounds may also form hydrates. As indicated the compounds to the invention also include N-oxides, where R1 and R2 are both other than hydrogen.
The compounds according to the invention can be administered orally, topically or parenterally or by suppository, of which the preferred route is the oral route. They may be used in the form of the base or as a physiologically acceptable salt. They will in general be associated with a pharmaceutically acceptable carrier or diluent, to provide a pharmaceutical composition.
The compounds according to the invention can be administered in combination with other active ingredients, e.g. conventional antihistamines if required. For oral administration the pharmaceutical composition can most conveniently be in the form of capsules or tablets, which may be slow release tablets. The composition may also take the form of a dragee or may be in syrup form. Suitable topical preparations include ointments, lotions, creams, powders and sprays.
A convenient daily dose by the oral route would be of the order of 100 mg to 1.2 g per day, in the form of dosage units containing from 20 to 200 mg per dosage unit. A convenient regimen in the case of a slow release tablet would be twice or three times a day.
Parenteral administration may be by injections at intervals or as a continuous infusion. Injection solutions may contain from 10 to 100 mg/ml of active ingredient.
For topical application a spray, ointment, cream or lotion may be used. These compositions may contain an effective amount of the active ingredient, for example of the order of 11/2 to 2% by weight of the total composition.
The compounds of the present invention may be made from a primary amine of the formula: ##STR7## in which R1, R2, n, X and m have the meanings given herein with a compound capable of introducing the group ##STR8## in which R3 and Y have the meanings given herein. The amine may be used as the free base or in the form of a salt with a weak acid e.g. acetic acid. Compounds which are capable of introducing the group ##STR9## are, isocyanates R3 NCO, isothiocyanates R3 NCS, or compounds of the formula ##STR10## or ##STR11## where P is a leaving group. The reaction with the isocyanate or isothiocyanate may be carried out by allowing the amine and isocyanate or isothiocyanate to stand in a solvent such as acetonitrile. The reaction with ##STR12## or ##STR13## can be carried out by fusing the reactants at an elevated temperature e.g. 100�-120� C. Alternatively the reaction between the amine (II) and ##STR14## may be carried out in a solvent e.g. acetonitrile at elevated temperatures in the presence of silver nitrate. Alternatively again the amine (II) and the compound ##STR15## may be stirred in aqueous solution at room temperature. Where R3 represents hydrogen alkali metal cyanates and thiocyanates are used. Examples of leaving groups are halogen, thiomethyl, 3,5-dimethylpyrazolyl or alkoxy, preferably thiomethyl. The introduction of the group ##STR16## may also be effected by first reacting the amine (II) with a compound of the formula: ##STR17## in which P is a leaving group as defined above. This reaction may be effected in a solvent, e.g. ether or acetonitrile at a temperature from ambient to reflux. Treatment of the resulting compound of formula (III): ##STR18## where Q represents ═NR5 or ═CHR6 with a primary amine R3 NH2 at a temperature from ambient to reflux gives the desired end product.
In an alternative procedure for the production of products in which Y is sulphur, the amine (II) can be heated with carbon disulphide and then reacted with a chloroformate ester, e.g. ethyl chloroformate to form an isothiocyanate (IV) which is then reacted with an amine R3 NH2 preferably in an alkanol as solvent e.g. ethanol. ##STR19##
In another process, compounds wherein X is sulphur and n is 1, and when R1 and R2 are both hydrogen Y is other than ═CHNO2, can be prepared from a starting material of formulae (V) or (VI): ##STR20## (R7 may be hydrogen or an acyl group such as acetyl or p-nitrobenzoyl).
If R1 and R2 in the products are both hydrogen, there may be protected in a compound of formula (V) as, for example a phthalimido group. The above compounds may be reacted with a thiol of formula (VII): ##STR21## with subsequent deprotection where appropriate. When the compound of formula (V) is used the reaction is preferably carried out at 0� C. in concentrated hydrochloric acid. When a compound of formula (VI) is used the reaction may be carried out at room temperature in an organic solvent e.g. dimethylformamide. The chloromethyl compound (VI) may be prepared from the corresponding alcohol using for example, thionyl chloride or concentrated hydrochloric acid.
Products in which Y is a group NCN may be prepared from compounds of formula I where Y is sulphur by heating the latter compounds with a heavy metal cyanamide, such as that of silver, lead, cadmium or mercury preferably in aqueous solution.
Compounds according to the invention in which Y is ═NR5 and Alk is a methylene group or branched alkylene chain can also be prepared from compounds of the formula (VIII): ##STR22## by a Mannich reaction using an appropriate aldehyde and secondary amine or a salt of a primary amine or a secondary amine. For example, the (CH3)2 NCH2 -- group can be introduced using dimethylamine and formaldehyde. The process may be carried out by reacting the amine salt with aqueous formaldehyde and the compound of formula (VIII) or by refluxing the amine salt with paraformaldehyde and the compound of formula (VIII).
In the above discussion of the processes available for the production of the compounds according to the invention reference has been made to primary amines of formula II. These amines are novel compounds and the invention includes such compounds. These intermediates may be made by a number of processes which are described below.
Amines of formula (II) wherein X is S and n is 1 may be prepared from the furfurylthiol of formula (IX): ##STR23## by reaction with an ω-bromoalkylphthalimide (X): ##STR24## The group ##STR25## may be introduced into the resulting compound of formula (XI): ##STR26## by for example a Mannich reaction.
Removal of the protecting group by reaction with, for example, hydrazine hydrate gives an amino of formula (II).
In an alternative process to amines of formula (II) wherein X is S and n is 1, 2-furfuryl chloride may be used as starting material. The reaction between furfuryl chloride and an ω-aminoalkylthiol in which the amine group is protected, for example as a phthalimide (XII): ##STR27## gives an intermediate of formula (XI). This is treated as described above to give an amine of formula (II).
A further process to the amines (II) wherein X is S and n is 1 uses a starting material of formula (XIII): ##STR28##
This compound may be treated under acid conditions, with an ω-aminoalkylthiol, in which the amine group may be protected if desired. Alternatively, the compound of formula (XIII) may be converted into the corresponding acetate prior to reaction, under basic conditions with the ω-aminoalkylthiol.
Primary amines of formula II (except those in which X=S and n=zero) may be prepared by reacting furan with butyl lithium, to produce a lithio derivative (XIV): ##STR29## which is then reacted sequentially with (i) an α,ω-dihalo-compound Hal(CH2)n X(CH2)m Hal (where Hal is chlorine, bromine or iodine), and (ii) potassium phthalimide. The product of the reaction of formula (XV): ##STR30## is then subjected to, for example, a Mannich reaction and deprotected by reaction with, for example, hydrazine hydrate.
Intermediates where X is S and n is zero can be made from a furan of formula (XVI): ##STR31## in which neither R1 nor R2 are hydrogen by reacting it with lithium and elemental sulphur followed by reaction with an ω-bromoalkylphthalimide (X). The resulting product of formula (XVII): ##STR32## may then be reacted with hydrazine hydrate to remove the protecting group.
The production of an intermediate in which X is an oxygen atom and n is 1 involves reacting an alcohol of the formula (XIII) in a solvent such as dimethylformamide with a compound Hal(CH2)m NH2 where Hal represents a halogen atom, preferably chlorine, in the presence of a base, particularly potassium tertiary butoxide.
Intermediates of formula II where m is 2 and X is S or O may also be prepared by using ethylene imine. The compound is reacted with a compound of formula XIII or the isosteric thiol.
Amines of formula II may also be prepared by starting with a compound of formula (XVIII): ##STR33## in which n, m and X have the above stated meanings. A Mannich reaction is carried out on this nitrile compound followed by reduction with lithium aluminium hydride, to give a compound of formula II.
When a Mannich reaction is used, the group ##STR34## may be introduced at any convenient stage but the reaction is preferably carried out on compounds of formula (XIX) or (XX): ##STR35## The Mannich reaction, using an appropriate aldehyde and amine, is used to prepare compounds in which Alk represents a methylene group or a branched chain alkylene group. Where Alk represents methylene, formaldehyde is used.
An alternative process to compounds wherein Alk is methylene uses furan-2-carboxylic acid as starting material. This is reacted with an amine of formula R1 R2 NH to give an amide of formula (XXI) which is then reduced with, for example, lithium aluminium hydride to give a compound of formula (XXII): ##STR36##
In order to convert a compound of formula XXII into a compound of formula XIII the hydroxymethyl group may be introduced using formaldehyde and acetic acid. If R1 and R2 are both hydrogen, the amino group is protected during hydroxymethylation as a phthalimide. Deprotection is subsequently effected using hydrazine hydrate.
Alternatively, where neither R1 nor R2 are hydrogen, hydroxymethylation may be effected using butyl lithium, followed by formaldehyde.
Where Alk is a straight chain alkylene group containing 2 or more carbon atoms, the following two methods are applicable.
A convenient method used for ethylene derivatives analogous to that above for methylene derivatives using the carboxylic acid (XXIII): ##STR37## in place of furan-2-carboxylic acid.
Where the alkylene chain, Alk, is longer than 2 carbon atoms the lithio derivative of formula (XIV) may be treated sequentially with (i) a dihalo alkane of formula Hal Alk Hal where Hal is chlorine, bromine or iodine and (ii) and amine R1 R2 NH to give a compound of formula (XVI) wherein Alk contains 3 to 6 carbon atoms.
Where R1 and R2 are hydrogen, potassium phthalimide replaces the amine R1 R2 NH in both the above reactions. The product of both reactions is hydroxymethylated as described above, followed by deprotection where appropriate to give a compound of formula (XIII).
If compounds where R1 and R2 are other than hydrogen are required, the free amino compounds can be converted into suitable substituted amino groups, for example, by the use of formaldehyde and formic acid by the Eschweiler-Clarke procedure to give the dimethylamino compounds but it is preferable to use the substituted amine at the appropriate stage in the reaction.
Amines of formula II where n is 2 may be made by utilizing as starting material a compound of the formula XXIV: ##STR38## in which Z is a leaving group, e.g. tosyloxy, mesyloxy or bromine. This compound is reacted with an ω-phthalimidoalkylthiol of the formula (XII). The resultant compound is then subjected to a Mannich reaction and subsequently deprotected to produce the desired amine of formula II.
In producing the compounds of the invention one may react a compound of formula V with a thiol of formula VII in which Y may inter alia be ═CHNO2. Compounds of formula VII in which Y is ═CHNO2 and m is 2 may be made from a thiazolidine intermediate of the formula: ##STR39## by reaction with an amine R3 NH2. The thiazolidine XXV may be made from cysteamine and a bis methylthio compound XXVI: ##STR40##
The thiols of formula VII wherein Y is ═CHNO2 and m is 2 are novel compounds and the invention extends also therefore to such compounds and to the above process of making them.
In order that the invention may be more fully understood, the following Examples are given by way of illustration only. Preceding the Examples are Preparations 1 to 4 which describe the production of starting materials. Examples A to L exemplify the preparation of amines of formula II and related intermediates, and Examples 1-32 of compounds of formula I. Example 33 exemplifies pharmaceutical compositions.
(a) 5-(Methylamino)methyl-2-furanmethanol
A mixture of 2-furanmethanol (49 g), methylamine hydrochloride (51.5 g) and 36% formaldehyde solution (50 ml) was stirred at 0�-3� for 3 hr and allowed to stand for 16 hr. Excess sodium carbonate was added and the slurry extracted with ethyl acetate. After removal of solvent the residue was distilled to give 5-(methylamino)methyl-2-furanmethanol (36.2 g) b.p. 111�-113� (0.2 mm).
Similarly prepared from 2-furanmethanol and the corresponding amine hydrochloride were:
(b) 5-[(2-Phenylethyl)amino]methyl-2-furanmethanol. Oil Rf 0.45 (silica/acetone). NMR (CCl4) 7.29, br.s (4H); 6.8 s (2H); 6.40 s (2H); 4.0 br 2H); 2.87 s (5H).
(c) 5-[(1-Methylethyl)amino]methyl-2-furanmethanol. Oil Rf 0.55 (silica/methanol). Analysis Found C, 63.35; H, 8.78; N, 8.09. C9 H15 NO2 requires C, 63.88; H, 8.94; N, 8.28%.
(d) 5-(Ethylmethylamino)methyl-2-furanmethanol. Rf 0.32 (silica/acetone). NMR (CDCl3) 8.93 t (3H); 7.80 s (3H); 7.55 q (2H); 6.50 s (2H); 6.33 br.s (1H); 5.47 s (2H); 3.80 m (2H).
(e) 5-[[2-(Dimethylamino)ethyl]amino]methyl-2-furanmethanol bis maleate salt m.p. 119�-121�.
N,N-Dimethyl-2-furanethanamine (9.8 g), 30% aqueous formaldehyde (17.5 g) and glacial acetic acid (18 ml) were heated at 70� for 5 hr. The reaction was cooled, basified with sodium hydroxide and extracted with ether. The organic extracts were distilled to give an oil b.p. 90�-100� (0.5 mm). Found: C, 64.0; H, 8.9; N, 8.0. C9 H15 NO2 requires: C, 63.9; H, 8.9; N, 8.2%.
n-Butyl lithium (1.6 M in hexane, 375 ml) was added to a solution of furan (40.8 g) in dry tetrahydrofuran (375 ml) and the mixture was stirred at 40� for 3 hr. 1,4-Dibromobutane (129.6 g) was then added at -30� and the reaction stirred at room temperature for 4 hr. Water was added and the mixture was extracted with ethyl acetate. Distillation of the extract gave a clear colourless liquid b.p. 60�-62�, 0.5 mm Hg.
Dimethylamine (56 g) was added to a solution of 2-[1-(4-bromobutyl)]furan (82 g) in toluene (500 ml). The resultant solution was stirred at room temperature for 2 days, and then acidified with hydrochloric acid. The acid layer was separated, washed with ether, basified with sodium hydroxide and extracted with ether. The ethereal extract was distilled to give a clear colourless oil b.p. 55�-58�, 0.8 mm Hg. Hydrochloride salt m.p. 133�-136�. Found: C, 59.01; H, 9.02; H, 6.87. Calc. for C10 H17 NO.HCl: C, 58.96; H, 8.91; N, 6.88%.
(a) n-Butyl lithium (1.6 M in n-hexane, 125 ml) was added to an ice-cooled solution of N,N-dimethyl-4-(2-furanyl)butanamine (33.4 g) in dry tetrahydrofuran (125 ml). The mixture was stirred at room temperature for 4 hr. Paraformaldehyde (6.0 g) was then added and the mixture stirred for a further 1 hr. The reaction was quenched with water and extracted with chloroform. The organic extracts were distilled to give a clear colourless oil b.p. 100�-105�, 0.1 mm Hg, m.p. 26�-28.5 �. Found: C, 67.09; H, 10.01; N, 7.06. Calc. for C11 H19 NO2 : C, 66.97; H, 9.71; N, 7.10%.
Similarly prepared was:
(b) 5-[-3-(Dimethylamino)propyl]-2-furanmethanol, b.p. 160�/0.08 mm Hg, m.p. ca. 24�. Found: C, 64.66; H, 9.36; N, 7.39. Calc. for C10 H17 NO2.1/5H2 O: C, 64.28; H, 9.39; N, 7.50%.
A mixture of 5-[4 -(dimethylamino)butyl]-2-furanmethanol (4.9 g), acetic anhydride (25 g) and fused and powdered sodium acetate (10 g) in benzene (25 ml) was stirred at room temperature for 24 hr. The reaction was diluted with water (100 ml) and extracted with ethyl acetate. The combined extracts were distilled to afford a clear colourless oil b.p. 100�, 0.5 mm Hg. Found: C, 65.62; H, 9.03; N, 5.95. Calc. for C13 H21 NO3 ; C, 65.24; H, 8.85; N, 5.85%.
(a) 2-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine
5-(Dimethylamino)methyl-2-furanmethanol (15.5 g) was added dropwise to a stirred, ice-cold solution of cysteamine hydrochloride (11.36 g) in concentrated hydrochloric acid (40 ml). After standing at 0� for 18 hr, excess anhydrous sodium carbonate was added and the resultant solid extracted with diethyl ether. Removal of solvent followed by distillation of the residue gave 2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine (11.6 g) b.p. 104�-106� (0.1 mm). Picrate salt m.p. 142�-144�.
Similarly prepared from the corresponding furanmethanols and cysteamine hydrochloride were:
(b) 2-[[[5-(Methylamino)methyl-2-furanyl]methyl]thio]ethanamine. Monopicrate salt m.p. 116�-118�.
(c) 2-[[[5-[(1-Methylethyl)amino]methyl-2-furanyl]methyl]thio]ethanamine. Oil Rf. 0.4 (silica/methanol:0.880 ammonia 79:1).
(d) 2-[[[5-(Diethylaminomethyl)-2-furanyl]methyl]thio]ethanamine b.p. 134�-135� (1 mm).
(e) 2-[[[5-(1-Piperidinyl)methyl-2-furanyl]methyl]thio]ethanamine. Oil Rf 0.37 (silica/methanol:0.880 ammonia 79:1).
(f) 2-[[[5-(Aminomethyl)-2-furanyl]methyl]thio]ethanamine, dihydrochloride m.p. 222�-224� (dec.).
(g) N-[5-[[[(2-Aminoethyl)thio]methyl]-2-furanyl]methyl]benzene ethanamine. Oil Rf 0.33 (silica/methanol:0.880 ammonia 79:1).
(h) 2-[[[5-(2-(Dimethylamino)ethyl]-2-furanyl]methyl]thio]ethanamine b.p. 150�-155� (0.04 mm).
(i) 2-[[[5-[3-(Dimethylamino)propyl]-2-furanyl]methyl]thio]ethanamine b.p. 150� (0.05 mm).
(j) 2-[[[5-(Ethylmethylamino)methyl-2-furanyl]methyl]thio]ethanamine Rf 0.34 (silica/methanol:0.880 ammonia 79:1).
(k) 2-[[[5-[(2-Dimethylaminoethyl)amino]methyl-2-furanyl]methyl]thio]ethanamine. Tris maleate salt m.p. 132�-135�.
(l) 2-[[[5-(1-Pyrrolidino)methyl-2-furanyl]methyl]thio]ethanamine. Bis oxalate salt m.p. 136.5�-138.5�.
Crysteamine hydrochloride (4.5 g) was added to a cooled solution of potassium-t-butoxide (8.98 g) in a dry dimethylformamide (125 ml). The mixture was stirred for 20 min and [5-[4-(dimethylamino)butyl]-2-furanyl]methyl ethanoate (9.6 g) was added. The reaction was heated at 90� for 4 hr, poured onto an ice-water mixture and extracted with chloroform. Distillation of the organic extract gave a yellow oil which after column chromatography on silica, using methanol/0.880 ammonia (9:1) as eluent, and a further distillation afforded a colourless oil b.p. 140�/0.05 mm Hg. Found: C, 60.81; H, 9.86; N, 10.44. Calc. for C13 H24 N2 OS: C, 60.91; H, 9.44; N, 10.93%.
80% Sodium hydride (0.155 g) was added portionwise to a solution of 2-phthalimido-ethanethiol (1.03 g) in dry dimethylformamide at 0�. After 20 mins a solution of 2-furanethanol, 4-methylbenzenesulphonate (1.33 g) in dry dimethylformamide was added dropwise and the solution stirred overnight at room temperature. The mixture was poured into ice-water and 2-[[2-(2-furanyl)ethyl]thio]ethyl-1H-isoindole-1,3(2H)-dione isolated as a white solid (1.3 g) m.p. 53�-55�.
(a) 2-[2-[[)2-Furanyl)methyl]thio]ethyl]-1H-isoindole-1,3(2H)-dione
80% Sodium hydride (1.58 g) was added in portions to a solution of furfuryl mercaptan (6 g) in dry dimethylformamide (50 ml). After 30 mins a solution of 2-bromoethylphthalimide (16.71 g) was added in dry dimethylformamide (65 ml) and the solution heated at 110� for 2 days. After removal of solvents the residue was washed with water and extracted with ethyl acetate. The ethyl acetate extracts were combined, the solvent removed and the residue recrystallised from cyclohexane to give 2-[2-[[(2-furanyl)methyl]thio]ethyl]-1H-isoindole-1,3(2H)-dione m.p. 62�-63� (7.8 g).
Similarly prepared from the ω-bromoalkylphthalimide and furfuryl mercaptan were:
(b) 2-[3-[[(2-Furanyl)methyl]thio]propyl]-1H-isoindole-1,3(2H)-dione, NMR (CDCl3) 7.7-8.3 m (2H); 7.2-7.7 m (2H); 6.29 s (2H); 6.23 t (2H); 3.7 m (2H); 2.7 m (1H); 2.4 m (4H);
(c) 2-[4-[[(2-Furanyl)methyl]thio]butyl]-1H-isoindole-1,3(2H)-dione, NMR (CDCl3) 8-8.5 m (4H); 7.49 t (2H); 6.33 m (4H); 3.7 n (2H); 2.7 m (1H); 2.3 m (4H).
(a) 2-[2-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-1H-isoindole-1,3(2H)-dione
A mixture of 2-[2-[[(2-furanyl)methyl]thio]ethyl]-1H-isoindole-1,3(2H)-dione (10 g), dimethylammonium chloride (3.1 g) and 36% formaldehyde solution (3 ml) in acetic acid (50 ml) was heated on a steam bath for 9 hr. The solution was cooled and solvent removed in vacuo. The residue was basified with 5 N sodium hydroxide and extracted with ethyl acetate. The organic phase was treated with charcoal, dried and evaporated to give an oil which was purified by column chromatography (silica/ethanol:ethyl acetate 1:1) (5.7 g) Rf 0.4. NMR (CDCl3 /DMSO) 7.71 s (6H); 7.22 t (2H); 6.52 s (2H); 6.2 s (2H); 6.1 t (2H); 3.8 m (2H); 2.2 m (4H).
Similarly prepared from 2-[ω-[[(2-furanyl)methyl]thio]alkyl]-1H-isoindole-1,3(2H)-dione, the corresponding amine and formaldehyde were:
(b) 2-[2-[[[5[(1-Pyrrolidinyl)methyl]-2-furanyl]methyl]thio]ethyl]-1H-isoindole-1,3(2H)-dione. NMR (CDCl3) 8-8.4 m (4H); 7-7.6 m (6H); 6-6.5 m (6H); 3.7-4.0 m (2H); 2-2.4 m (4H).
(c) 2-[3-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]propyl]-1H-isoindole-1,3(2H)-dione. Rf 0.45 (silica/methanol).
(d) 2-[4-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]butyl]-1H-isoindole-1,3(2H)-dione. Rf 0.26 (silica/methanol). NMR (CDCl3) 8.85 m (4H); 7.7 s (6H); 7.42 t (2H); 6.52 s (2H); 6.29 m (4H); 3.9 m (2H); 2-2.4 m (4H).
(e) 2-[2-[[[5-[(4-Methyl-1-piperazinyl)methyl]-2-furanyl]methyl]thio]ethyl]-1H-isoindole-1,3(2H)-dione. NMR (CDCl3) 7.75 s (3H); 7.52 s (8H); 7-7.5 m (2H); 6.5 s (2H); 6-6.3 m (4H); 3.85 m (2H); 2-2.4 m (4H).
(f) 2-[2-[[[5-[(4-Morpholinyl)methyl]-2-furanyl]methyl]thio]ethyl]-1H-isoindole-1,3(2H)-dione. NMR (CDCl3) 7.54 m (4H); 7.24 m (2H); 6.50 s (2H); 6.22 m (8H); 3.8 m (2H); 2.0-2.4 m (4H).
2-[[2-(2-Furanyl)ethyl]thio]ethyl-1H-isoindole-1,3(2H)-dione (0.5 g), dimethylamine hydrochloride (0.27 g) and paraformaldehyde (0.102 g) were heated together under reflux in ethanol. After 5 hr further dimethylamine hydrochloride (0.27 g) and paraformaldehyde (0.102 g) were added and the heating continued for a further 16 hr. Solvent was removed, the residue basified and extracted with ethyl acetate to give an oil which after column chromatography (silica/methanol) gave 2-[2-[[2-[5-(dimethylamino)methyl-2-furanyl]ethyl]thio]ethyl]-1H-isoindole-1,3(2H)dione as a pale oil (0.43 g). Analysis Found: C, 61.48; H, 6.13; N, 7.63; C19 H22 N2 O3 S.3/4H2 O requires: C, 61.35; H, 6.37; N, 7.53%.
To a solution of 5-(dimethylamino)methyl-2-furanmethanol (6.2 g) and ethylene imine (2.82 g) in dry tetrahydrofuran was added a solution of methanesulphonic acid (11.6 g) in tetrahydrofuran (40 ml). The solution was evaporated and the oily residue heated at 98�-100� for 10 mins. After 18 hr, 5 N sodium hydroxide (60 ml) was added and the solution evaporated to dryness. Anhydrous sodium sulphate and ethyl acetate (150 ml) were added and after 2 hr the suspension was filtered, treated with decolourising charcoal and evaporated. The resulting oil was chromatographed on silica, firstly with methanol-ammonia 0.88 79:1, and the eluate discarded, and secondly with methanol-ammonia 0.88 19:1. This eluate was evaporated to give an oil from which the bisoxalate salt of 2-[[5-(dimethylamino)methyl-2-furanyl]methoxy]ethanamine (from ethanol) 0.2 g, m.p. 125�-128�, was obtained. Route (ii)
A solution of 2-chloroethylamine hydrochloride (6.25 g) in dry dimethylformamide was added dropwise to a stirred, cooled solution of potassium tert-butoxide (8.96 g) and 5-(dimethylamino)methyl-2-furanmethanol (12.4 g) in the same solvent. After 2 hr solvent was removed, the residue basified and extracted with ethyl acetate. The residue after removal of solvent was treated in ethanol with ethanolic oxalic acid. The crystalline salt was recrystallised from ethanol to give 2-[[5-(dimethylamino)methyl-2-furanyl]methoxy]ethanamine, bis oxalate, m.p. 130�-133� (3.05 g).
Similarly prepared by route (ii) was:
(b) 2-[[5-(Methylamino)methyl-2-furan]methoxy]ethanamine, bis oxalate m.p. 162�-164�.
(a) 2-[4-(2-Furanyl)butyl]-1H-isoindole-1,3-(2H)-dione
2[1-(4-bromobutyl)]furan (406 mg) and potassium phthalimide (370 mg) were stirred together at room temperature in dry dimethylformamide overnight. The solution was poured into ice-water and the resulting white solid filtered, dried and recrystallised from chloroform/petroleum ether (b.p. 60�-80�) to give 2-[4-(2-Furanyl)butyl]-1H-isoindole-1,3-(2H)-dione as white microcrystals (430 mg) m.p. 61�-63�.
In a similar manner was prepared:
(b) 2-[5-(2-Furanyl)pentyl]-1H-isoindole-1,3-(2H)-dione, m.p. 54�-56�.
(a) 2-[4-[5-(Dimethylamino)methyl-2-furanyl]butyl]-1H-isoindole-1,3-(2H)-dione
2-[4-(2-Furanyl)butyl]-1H-isoindole-1,3(2H)-dione (5.38 g), paraformaldehyde (1.2 g) and dimethylamine hydrochloride (3.26 g) were refluxed in absolute ethanol (100 ml). After 6 hr further paraformaldehyde (0.6 g) and dimethylamine hydrochloride (1.6 g) were added and heating continued for a further 20 hr. The solvent was removed, the residue made strongly basic with 5 N sodium hydroxide, extracted with ethyl acetate and the organic layer evaporated. The crude product was purified by column chromatography to give an amber oil (3.25 g) Rf 0.4 silica/methanol. NMR (CDCl3) 8-8.6 m (4H); 7.75 s (6H); 7.3 m (2H); 6.55 s (2H); 6.3 m (2H); 4.0 m (2H); 1.9-2.4 m (4H).
In a similar manner was prepared:
(b) 2-[5-[5-(Dimethylamino)methyl-2-furanyl]pentyl]-1H-isoindole-1,3(2H)-dione. TLC Rf 0.4 silica/methanol. NMR 8.0-8.8 m (6H); 7.70 m (6H); 7.37 t (2H); 6.52 s (2H); 6.30 t (2H); 4.0 m (2H); 2.2 m (4H).
Furanpropionitrile (1.21 g), dimethylamine hydrochloride (1.62 g) and paraformaldehyde (0.7 g) in ethanol (20 ml) were heated under reflux for 24 hr. Solvents were removed, the residue basified to pH 12 and extracted with ethyl acetate. After removal of solvents the residual oil was purified by column chromatography (silica/methanol) and 5-(dimethylamino)methyl-2-furanpropionitrile isolated (0.6 g) Rf 0.55 (silica/methanol).
The nitrile (6.0 g) in dry ether (40 ml) was added dropwise with stirring to lithium aluminium hydride (2.0 g) in ether at 0�. Addition of water, followed by removal of solvents, gave, after column chromatography, 5-(dimethylamino)methyl-2-furanpropanamine as a pale oil (3.33 g). NMR (CDCl3) 8.2 m (2H); 7.6 br (2H); 7.75 s (6H); 7.30 m (4H); 6.60 s (2H); 4.0 m (2H).
Sulphur (1.9 g) was added in portions to a solution of the lithio derivative of N,N-dimethylfuranmethanamine (7.5 g) at -40�. The mixture was stirred at -10� for 20 mins and 2-(3-bromopropyl)1H-isoindole-1,3(2H)-dione (16 g) added. The mixture was left at 0� overnight, solvent removed in vacuo and the residue in ethyl acetate filtered and extracted with 2 N sulphuric acid. The aqueous layer was basified, re-extracted with ethyl acetate and the organic phase dried. Removal of the solvent gave a crystalline solid, which recrystallised from ethanol (charcoal) to give 2-[3-[[[5-(dimethylamino)methyl-2-furanyl]thio]propyl]]-1H-isoindole-1,3(2H)-dione (7.59 g) m.p. 64�-65�.
(a) 4-[5-(Dimethylamino)methyl-2-furanyl]butanamine
2-[[4-(5-Dimethylamino)methyl-2-furanyl]butyl]-1H-isoindole-1,3(2H)-dione (2.9 g) and hydrazine hydrate (0.55 ml) were refluxed in ethanol for 6 hr. Solvent was removed and the crystalline residue dissolved in 5 N sodium hydroxide solution. This was extracted with ethyl acetate which on removal of solvent gave the product as a mobile yellow oil (1.68 g). TLC silica/methanol single spot Rf 0.15. NMR (CDCl3) 8.0-8.8 m (4H); 7.7 s (6H); 7.6 br (2H); 7.3 m (4H); 6.58 s (2H); 4.0 m (2H).
In a similar manner were prepared from the corresponding phthalimide:
(b) 5-[5-(Dimethylamino)methyl-2-furanyl]pentanamine. NMR (CDCl3) 8.0-8.8 m (6H); 7.75 s (6H); 7.0-7.6 m (4H); 6.60 s (2H); 4.0 m (2H).
(c) 5-[[(3-Aminopropyl)thio]methyl]-N,N-dimethylfuran-2-methanamine. NMR (CDCl3) 8-8.5 m (2H); 7.75 s (6H); 7.42 t (2H); 7.25 m (2H); 6.58 s (2H); 6.3 s (2H); 3.88 s (2H).
(a) N-[2-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-methylthiourea
2-[2-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-1H-isoindole-1,3(2H)-dione (5.3 g) and hydrazine hydrate (0.85 g) were refluxed in ethanol for 30 hr. Evaporation of the solvent gave the phthalhydrazide salt of 2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine.
This salt (1 g) was suspended in acetonitrile and methylisothiocyanate (0.21 g) added. The suspension was stirred at room temperature for 5 hr and at 60� for 2 hr, filtered and evaporated to give an oil which was purified by column chromatography (silica/methanol). N-[2-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-methylthiourea was isolated as a pale oil (0.3 g). Analysis Found: C, 49.68; H, 7.52; 14.22; C12 H21 N3 OS2 requires: C, 50.14; H, 7.37; N, 14.62%.
Similarly prepared were:
(b) N-Methyl-N'-[2-[[[5-(1-pyrrolidinyl)methyl-2-furanyl]methyl]thio]ethyl]thiourea. Analysis Found: C, 52.33; H, 7.12; N, 13.17. C14 H23 N3 OS2.1/2H2 O requires: C, 52.14; H, 7.50; N, 13.03%.
(c) N-[4-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]butyl]-N'-methylthiourea. Analysis Found: C, 51.69; H, 8.53; N, 12.83; C14 H25 N3 OS2 requires: C, 51.82; H, 8.08; N, 12.95%.
(d) N-[3-[[5-(Dimethylamino)methyl-2-furanyl]thio]propyl]-N'-methylthiourea. Analysis Found: C, 49.71; H, 7.33; N, 14.35. C12 N21 N3 OS2 requires: C, 50.10; H, 7.30; N, 14.62%.
(e) N-Methyl-N'-[2-[[[5-[(4-morpholinyl)methyl]-2-furanyl]methyl]thio]ethyl]thiourea. Analysis Found: C, 51.26; H, 7.08; N, 12.51. C14 H23 N3 O2 S2 requires: C, 51.03; H, 7.04; N, 12.75%.
(f) N-Methyl-N'-[2-[[[5-[(4-methyl-piperazinyl)methyl]-2-furanyl]methyl]thio]ethyl]thiourea. Analysis Found: C, 50.93; H, 7.74; N, 15.82. C15 H26 N4 OS2 requires: C, 51.25; H, 8.03; N, 15.94%.
(g) N-[2-[[2-[5-(Dimethylamino)methyl-2-furanyl]ethyl]thio]ethyl]-N'-methylthiourea. Analysis Found: C, 50.19; H, 7.20; N, 13.18. C13 H23 N3 O2 O.1/2H2 O requires: C, 50.32; H, 7.74; N, 13.54%.
(a) N-[5-[5-(Dimethylamino)methyl-2-furanyl]pentyl]-N'-methylthiourea
5-[5-(Dimethylamino)methyl-2-furanyl]pentanamine (0.5 g) and methylisothiocyanate (0.25 g) were stirred in acetonitrile at room temperature for 24 hr. Solvent was removed and the product purified by column chromatography (silica/methanol) to give after trituration with ether N-[5-[5-(dimethylamino)methyl-2-furanyl]pentyl]-N'-methylthiourea as off-white crystals m.p. 66�-69�.
Similarly prepared from the corresponding amine and methylisothiocyanate were:
(b) N-[3-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]propyl]-N'-methylthiourea. Analysis Found: C, 51.38; H, 7.93; N, 13.41. C13 H23 N2 OS2 requires: C, 51.79; H, 7.69; N, 13.94%.
(c) N-[4-[5-(Dimethylamino)methyl-2-furanyl]butyl]-N'-methylthiourea. NMR τ(CDCl3) 8-8.6 m (4H); 7.72 s (6H); 7.35 t (2H); 6.98 d (3H); 6.2-6.8 m (4H); 4.0 d (2H); 3-3.8 m (2H).
(d) N-[2-[[5-(Dimethylamino)methyl-2-furanyl]methoxy]ethyl]-N'-methylthiourea. Analysis Found: C, 51.91; H, 8.14; N, 14.98. C12 H21 N3 O2 S.1/2H2 O requires: C, 51.40; H, 7.91; N, 14.99%.
(a) N-[2-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-(2-methoxyethyl)thiourea
1-(Isothiocyanato)-2-methoxyethane (1.17 g) and 2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine (2.14 g) in acetonitrile were stood overnight. Solvent was removed and the residual oil chromatographed (silica/methanol) to give N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-(2-methoxyethyl)thiourea as a pale oil Rf 0.45. Analysis Found: C, 50.64; H, 7.51; N, 12.58. C14 H25 N3 O2 S2 requires: C, 50.75; H, 7.55; N, 12.69%.
Similarly prepared from the corresponding isothiocyanate and 2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine were:
(b) N-[2-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-(2-propenyl)thiourea. Found: C, 52.68; H, 7.58; N, 13.16. C14 H23 N3 OS2.1/2H2 O requires: C, 52.14; H, 7.50; N, 13.03%.
(c) N-[2-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N-(1-methylethyl)thiourea. Analysis Found: C, 51.84; H, 7.88; N, 13.00. C14 H25 N3 OS2.1/2H2 O requires: C, 51.90; H, 8.09; N, 12.97%.
To a stirred solution of 2-[[[5-(methylamino)methyl-2-furanyl]methyl]thio]ethanamine (1.5 g) in acetonitrile (24 ml) was added dropwise a solution of methylisocyanate (0.45 g) in acetonitrile (15 ml). After 30 mins the solution was evaporated to dryness to give an oil which was column chromatographed firstly on silica/methanol: 0.88 ammonia 79:1 then alumina/methanol to give an oil consisting of N-[2-[[[5-(methylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-methylurea (0.25 g). Analysis Found: C, 51.00; H, 7.38; N, 15.91. C11 N19 N3 O2 S requires: C, 51.33; H, 7.44; N, 16.33%.
(a) N-[2-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-methylurea
Methylisocyanate (0.33 g) was added to a suspension of 2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine, phthalhydrazide complex (2 g) in acetonitrile (50 ml). After 2 hr the solution was filtered and the filtrate evaporated to give an oil which was purified by column chromatography (silica/methanol) to give N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-methylurea. Analysis Found: C, 52.38; H, 7.61; N, 15.25. C12 H21 N3 O2 S.1/4H2 O requires: C, 52.24; H, 7.76; N, 15.32%.
Similarly prepared was:
(b) N-Methyl-N'-[2-[[[5-(1-pyrrolidinyl)methyl-2-furanyl]methyl]thio]ethyl]urea. Analysis Found: C, 54.70; H, 7.33; N, 14.07. C14 H23 N3 O2 S.1/2H2 O requires: C, 54.87; H, 7.89; N, 13.71%.
(a) N-[2-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-(1-methylethyl)urea
2-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine (2.14 g) and isopropylisocyanate (0.89 g) were dissolved in acetonitrile and allowed to stand overnight. Solvents were removed and the residue recrystallised from methanol:ether to give N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-(1-methylethyl)urea as crystals m.p. 65�-67� (2.8 g).
Similarly prepared were:
(b) N-[3-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]propyl]-N'-methylurea m.p. 69�-69.5�.
A solution of 2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine dihydrochloride (2.8 g) and potassium cyanate (3.75 g) in water (50 ml) was heated on a steam bath for 8 hr. Excess solid sodium carbonate was added and organic material continually extracted with diethyl ether. The extracts were evaporated and the residue after column chromatography yielded N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]urea as a waxy solid (1.28 g). Analysis Found: C, 48.22; H, 7.50; N, 15.61. C11 H19 N3 O2 S.H2 O requires: C, 48.00; H, 7.63; N, 15.27%.
A solution of 2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine (2.14 g) and S-methyl-N-nitroisothiourea (1.5 g) in ethanol (10 ml) was heated to 40� for 5 mins. The resulting precipitate was filtered and recrystallised from ethyl acetate and petroleum ether b.p. 80�-100� to give N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-nitroguanidine m.p. 103�-104�.
(a) N-Cyano-N'-[2-[[[5-(methylamino)methyl-2-furanyl]methyl]thio]ethyl]-N"-methylguanidine
A mixture of 2-[[[5-(methylamino)methyl-2-furanyl]methyl]thio]ethanamine (2.0 g) and N-cyano-N'-methylcarbamimido-thioic acid, methyl ester (1.25 g) was heated on a steam bath for 6.5 hr. Vacuum was applied at regular intervals to remove methanethiol. The crude product was purified by column chromatography Rf 0.65 (silica/methanol:ammonia 79:1) to give N-cyano-N'-[2-[[[5-(methylamino)methyl-2-furanyl]methyl]thio]ethyl]-N"-methylguanidine (1.05 g) m.p. 81�-85�.
In a similar manner were prepared from the corresponding amine and N-cyano-N'-methylcarbamimidothioic acid, methyl ester:
(b) N-Cyano-N'-[2-[[[5-(1-methylethyl)amino]methyl-2-furanyl]methyl]thio]ethyl]-N"-methylguanidine. Analysis Found: C, 54.73; H, 7.82; N, 22.31. C14 H23 N5 OS requires: C, 54.34; H, 7.49; N, 22.64%.
(c) N-Cyano-N'-[2-[[[5-(diethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N"-methylguanidine. Analysis Found: C, 53.54; H, 7.82, N, 20.65. C15 H25 N5 OS.3/4H2 O requires: C, 53.46; H, 7.70; N, 20.78%.
(d) N-Cyano-N'-[2-[[[5-(1-pyrrolidinyl)methyl-2-furanyl]methyl]thio]ethyl]-N"-methylguanidine. Analysis Found: C, 53.97; H, 6.87; N, 21.06. C15 H23 N5 OS.3/4H2 O requires: C, 53.79; H, 7.37; N, 20.91%.
(e) N-Cyano-N'-[3-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]propyl]-N"-methylguanidine. Analysis Found: C, 52.86; H, 7.49; N, 20.64; C14 H23 N5 OS.1/2H2 O requires: C, 52.80; H, 7.59; N, 21.20%.
To a stirred suspension of potassium carbonate (20.7 g) in a solution of 2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine (10.7 g) and N-cyano-N'-methylcarbamimidothioic acid methyl ester (7.1 g) in acetonitrile (107 ml) at 70� was added a solution of silver nitrate (9.35 g) in acetonitrile (20 ml) during 1 hr. The mixture was stirred for 16 hr, the solid filtered and the filtrate evaporated to dryness. The residue was dissolved in ethyl acetate (250 ml). A portion of this (10.5 ml) was washed with water (6 ml), the ethyl acetate layer evaporated to give a solid which was crystallised from isopropylacetate (1.75 ml) giving N"-cyano-N-[2-[[[5-(dimethylaminomethyl)-2-furanyl]methyl]thio]ethyl]-N'-methylguanidine (0.35 g) m.p. 79�-81.5�.
To a further portion (225 ml) was added a solution of sebacic acid (9.09 g) in ethanol (30 ml), the filtered solution giving the sebacate salt (13.74 g) m.p. 92.5�-94�. Analysis Found: C, 54.91; H, 7.94; N, 14.02. C13 H21 N5 OS. C10 H18 O4 requires: C, 55.51; H, 7.90; N, 14.07%.
Powdered cyanamide (4.2 g) was added to a stirred solution of sodium (2.3 g) in absolute ethanol. After 30 mins a solution of methoxyethylisothiocyanate (11.7 g) in absolute ethanol was added to the cooled solution. After a further hour at room temperature dimethyl sulphate (12.66 g) was added over 30 mins and the mixture stirred overnight. The solvent was removed and remaining solid washed well with water to give N-cyano-N'-2(methoxyethyl)carbamimidothioic acid, methyl ester as a white crystalline solid (12.37 g) m.p. 94.5�-95.5�.
Similarly prepared was:
N-Cyano-N'-(2-propenyl)carbamimidothioic acid, methyl ester, m.p. 109�-110�.
(a) N-Cyano-N'-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N"-(2-methoxyethyl)guanidine
A mixture of 2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine (2.14 g) and N-cyano-N'-(2-methoxyethyl)carbamimidothioic acid, methyl ester (1.73 g) was heated on a steam bath for 6.5 hr. Vacuum was applied occasionally to remove methanethiol. The crude product was purified by chromatography (silica gel/methanol) to give N-cyano-N'-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N"-(2-methoxyethyl)guanidine (1.4 g). Analysis Found: C, 50.51; H, 7.20; N, 19.41, C15 H25 N5 O2 S.H2 O requires: C, 50.42; H, 7.50; N, 19.60%.
In a similar manner were prepared from 2-[[[5-(dimethylamino)-methyl-2-furanyl]methyl]thio]ethanamine and the corresponding N-alkyl-N'-cyanocarbamimidothioic acid, methyl ester:
(b) N-Cyano-N'-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N"-(2-propenyl)guanidine. Analysis Found: C, 53.33; H, 7.01; N, 20.70. C15 H23 N5 OS.H2 O requires: C, 53.09; H, 7.37; N, 20.64%.
(c) N-Cyano-N'-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N"-(1-methylethyl)guanidine. Analysis Found: C, 52.97; H, 7.70; N, 20.57. C15 H25 N5 OS.H2 O requires: C, 52.78; H, 7.91; N, 20.52%.
(a) N-[2-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-methylguanidine
A mixture of 2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine (2.14 g) and N,S-dimethylisothiouronium iodide was heated on a steam bath for 3 hr. The residue in methanol was eluted from an Amberlyst A26 ion exchange resin to give N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-methylguanidine as an amber oil (1.5 g). Analysis Found: C, 50.92; H, 8.23; N, 19.90. C12 H22 N4 OS.3/4H2 O requires: C, 50.76; H, 8.34; N, 19.74%.
Similarly prepared were:
(b) N-[2-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N',N"-dimethylguanidine. NMR (CDCl3) 7.75 s (6H); 6.8-7.3 m (8H); 6.5 m (4H); 6.22 s (2H); 3.80 m (2H); 2.0-3.5 br (2H).
A solution of methylamine in ethanol/ethylenedichloride (112.5 ml of 33% ethanolic methylamine in 0.8 liters of ethylene dichloride; 0.9 4 mole) was added over 51/2 hr at 70� to a stirred solution of 1,1-bismethylthio-2-nitroethene (99.0 g, 0.6 mole) in ethylene dichloride (1.5 liters). The solution was heated to boiling and 0.7 liters of solvent were distilled off. The cooled solution was washed with 2 N hydrochloric acid (0.25 liters), then with brine (0.25 liters). The solvent was removed and the residue crystallised from isopropyl acetate (0.5 liters), treating the hot solution with charcoal (10.0 g). The product (35.0 g) formed yellow prisms, m.p. 114�.
A solution of 2-[[[5-(methylamino)methyl-2-furanyl]methyl]thio]ethanamine (10 g, 0.05 mole) and N-methyl-1-methylthio-2-nitroetheneamine (7.4 g) in water (25 ml) was stirred at 50� for 2 hr. Acetone (350 ml) was added and the solvent was removed by distillation at atmospheric pressure until 275 ml of distillate had been collected. Ethanolic hydrogen chloride (2 M; 27.5 ml) was added to the residue and the solution was stirred overnight at room temperature. The product (11.0 g) m.p. 161�, was collected and recrystallised from ethanol as a colourless microcrystalline solid (10.1 g) m.p. 162�. Analysis Found: C, 42.6; H, 6.3; N, 16.4. C12 H20 N4 O3 S.HCl requires: C, 42.8; H, 6.2; N, 16.6%.
(a) N-[2-[[[5-(Methylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine
A mixture of 2-[[[5-(methylamino)methyl-2-furanyl]methyl]thio]ethanamine (0.9 g) and N-methyl-1-methylthio-2-nitro-etheneamine was heated at 100�-120� for 30 mins under water pump pressure. The residue was purified by column chromatography (silica/methanol:0.88 ammonia) to give N-[2-[[[5-(methylamino )methyl-2-furanyl]methyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine which was crystallised from acetonitrile m.p. 106�-108� (0.65 g).
In a similar manner were prepared:
(b) N-[2-[[[5-[(1-Methylethyl)amino]methyl-2-furanyl]methyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine. Analysis Found: C, 49.75; H, 7.21; N, 16.36. C14 H24 N4 O3 S.1/2H2 O requires: C, 49.83; H, 7.47; N, 16.60%.
(c) N-Methyl-2-nitro-N'-[2-[[[5-[(2-phenylethyl)amino]- methyl]-2-furanyl]methyl]thio]ethyl]-1,1-ethenediamine. Anaylsis Found: C, 57.19; H, 6.53; N, 13.83. C19 H26 N4 O3 S.1/2H2 O requires: C, 57.12; H, 6.81; N, 14.02%.
(d) N-Methyl-2-nitro-N'-[2-[[[5-[(1-piperidinyl)methyl]-2-furanyl]methyl]thio]ethyl]-1,1-ethenediamine. Analysis Found: C, 53.36; H, 7.51; N, 14.23. C16 H26 N4 O3 S.1/4H2 O requires: C, 53.33; H, 7.44; N, 15.61%.
(e) N-8 2-[[[5-[2-[Dimethylamino]ethyl]-2-furanyl]methyl]thio]-ethyl]-N'-methyl-2-nitro-1,1-ethenediamine, m.p. 95.5�-96�.
(f) N-[2-[[[5-[3-[Dimethylamino]propyl]-2-furanyl]methyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine. NMR τ (CDCl3), 8.1-7.1 m (6H); 7.65 s (6H); 7.1 s (3H); 6.5 m (2H); 6.28s (2H); 4.0 m (2H); 3.38 s (1H).
(g) N-[2-[[[5-[4-[Dimethylamino]butyl]-2-furanyl]methyl]thio]ethyl]-N-methyl-2-nitro-1,1-ethenediamine. Waxy solid analysis found: C, 53.90; H, 7.95; N, 15.64. C16 H28 N4 O3 S requires: C, 53.91; H, 7.92; N, 15.72%.
(h) N-[2-[[[5-(Ethylmethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine. NMR τ (CDCL3) 8.90 t (3H); 7.76 s (3H); 6.8-7.5 m (7H); 6.5 br (2H); 6.42 s (2H); 6.25 s (2H); 3.77 s (2H); 3.35 s (1H).
(i) N-[2-[[[5-[[2-(dimethylamino)ethyl]amino]methyl-2-furanyl]methyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine. NMRτ(CDCl3) 7.79 s (6H); 7-7.6 m (10H); 6.6 m (2H); 6.26 s (2H); 6.22 s (2H); 3.85 m (2H); 3.37 s (1H); 2-3.2 br (1H); 0.8-0.2 br (1H).
(j) N-[2-[5-(Dimethylamino)methyl-2-furanylmethoxy]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine, m.p. 110�-112�.
N-Methyl-1-(methylthio)-2-nitroetheneamine (230 g) in water (400 ml) was stirred and heated at 45�-50�. 2-[[[5-(Dimethylamino) methyl-2-furanyl]methyl]thio]ethanamine (321 g) was added dropwise over 4 hr and the resultant solution stirred for a further 31/2 hr. The solution was then heated at reflux for 1/2 hr., cooled to 70� and 4-methylpentan-2-one (2 liters) added. The water was removed by azeotropic distillation under reduced pressure (260 torr) and the resultant solution treated with charcoal (10 g) at 50�. The solution was filtered and cooled to 10�. N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine (380 g) was filtered off and dried m.p. 69�-70�.
A mixture of 2-[[[5-(1-pyrrolidino)methyl-2-furanyl]methyl]thio]ethanamine bis oxalate salt (2.1 g), potassium hydroxide (1.12 g) and N-methyl-(1-methylthio)-2-nitroethenamine (0.9 g) in water (9 ml) was stirred at room temperature for 18 hours. The water was removed by evaporation under reduced pressure and the residue extracted with ethyl acetate in the presence of excess anhydrous sodium carbonate. Evaporaton of the solvent gave a residue which was crystallised from isopropyl acetate as a white crystalline solid (0.9 g) m.p. 79�-82�. Analysis Found: C, 52.78; H, 7.05; N, 16.57. C15 H24 N4 O3 S requires: C, 52.92; H, 7.11; N, 16.46%.
To a stirred solution of N-[2-mercaptoethyl]-N'-methylurea (2.0 g) in concentrated hydrochloric acid at 0� was added dropwise a solution of 5-(methylamino)methyl-2-furanmethanol (2.0 g) in water (3 ml). After 24 hr, ethyl acetate (100 ml) and excess anhydrous sodium carbonate were added. The suspension was filtered, the filtrate evaporated to dryness and the oily residue column chromatographed (silica/methanol:0.88 ammonia 79:1). The relevant eluate was evaporated to dryness to give an oil identical to product of Example 4 (0.42 g).
To a stirred solution of N-cyano-N'-(2-mercaptoethyl)- N"-methylguanidine (1 g) in concentrated hydrochloric acid at 0� was added 5-(dimethylamino)-2-furanmethanol (0.98 g) dropwise during 10 mins. After 3 hr, at room temperature, the solution was neutralized with excess anhydrous sodium carbonate and the resultant solid extracted with ethyl acetate. Evaporation of the solvent gave an oil, which after column chromatography yielded a product identical with the compound of Example 10.
2-(5-Hydroxymethyl-2-furanylmethyl)-1H-isoindole-1,3(2H)- dione (10 g) was dissolved in thionyl chloride (15 ml) with the aid of gentle heat. The solution was evaporated to dryness and the solid residue re-evaporated with cyclohexanebenzene (1:1). The residue was suspended in ether, the suspension filtered, washed with ether and dried to give 2-(5-chloromethyl-2-furanylmethyl)-1H-isoindole-1,3(2H)- dione (10.1 g) m.p. 119�-122� (dec.). Analysis Found: C, 61.32; H, 3.71; N, 5.00. C14 H10 ClNO4 requires: C, 60.99; H, 3.66; N, 5.08%.
To a stirred solution of N"-cyano-N-(2-mercaptoethyl)- N'-methylguanidine (1.0 g) and sodium hydride (0.152 g ) in dry dimethylformamide (4 ml) at room temperature was added slowly a solution of 2-(5-chloromethyl-2-furanylmethyl)-1H- isoindole-1,3(2H)-dione (1.74 g) in dry dimethylformamide (8 ml). After stirring for 2 hr in the solution was evaporated to dryness and the oily residue suspended in an ethyl acetate (25 ml)-water (20 ml) mixture. The solid residue was filtered and crystallised from methanol to give the title compound (1.4 g) m.p. 179�-182�.
A suspension of N"-cyano-N-[2-[[5-[(1,3-dioxo-2H-isoindol-2-yl)methyl]-2-furanylmethyl]thio]ethyl]-N'-methylguanidine (4.45 g) and hydrazine hydrate (0.6 g) in methanol (35 ml) was heated under reflux for 4 hr. The suspension was evaporated to dryness, the residue dissolved in water (15 ml) at 0� and neutralised with 5 N hydrochloric acid. The suspension was filtered, excess anhydrous sodium carbonate added and the solution evaporated to dryness. The residue was mixed with anhydrous sodium sulphate and the solid mass extracted with ethanol. Evaporation of the extract gave a semi-solid which was mixed with anhydrous sodium sulphate and extracted with ethyl acetate to give an oil (2.12 g) which was column chromatographed (silica/methanol:0.88 ammonia 79:1). Evaporation of the relevant eluate yielded an oil which slowly solidified consisting of the title compound (1.88 g) m.p. 80�-82�. Analysis Found: C, 49.57; H, 6.66; N, 25.93. C11 H17 N5 OS requires: C, 49.41; H, 6.41; N, 26.20%.
A mixture of cysteamine hydrochloride (11.36 g), potassium hydroxide (5.61 g) and 1,1-bis(methylthio)-2-nitroethene (16.52 g) in water (30 ml) and ethanol (100 ml) was heated under reflux for 1 hr. The suspension was evaporated to dryness, the residue suspended in water, filtered and the residue crystallised from methanol to give 2-nitroethylene thiazolidine (9.2 g) m.p. 141�-142�. Analysis Found: C, 32.91; H, 4.13; N, 19.10. C4 H6 N2 O2 S requires: C, 32.87; H, 4.14; N, 19.17%.
A solution of 2-nitroethylene thiazolidine (5 g) in a solution of methylamine 33% in ethanol (40 ml) was kept at room temperature for 65 hr. The solid which separated was filtered, washed with ethanol and dried to give n-(2-mercaptoethyl)-N'-methyl-2-nitro-1,1'-ethenediamine (4.98 g), m.p. 174�-175�, decomp. 209�-211�.
Analysis Found: C, 34.05; H, 5.87; N, 23.85. C5 H11 N3 O2 S requires C, 33.88; H, 6.26; N, 23.71%.
N-(2-Mercaptoethyl)-N'-methyl-2-nitro-1,1-ethenediamine (354 mg) in concentrated hydrochloric acid (2 ml) was added dropwise to 5-(dimethylamino)methyl-2-furanmethanol (428 mg) at 0�. After standing at 0� for 7 days the reaction was diluted with water (3 ml), excess potassium carbonate was added and the solid extracted with ethyl acetate (50 ml).
The solvent was evaporated and the residue purified by preparative layer chromatography to give the title compound (100 mg) as Example 15.
N,N-Dimethyl-2-furanmethanamine (125 mg) was dissolved in glacial acetic acid (1 ml) and paraformaldehyde (30 mg) added. A solution of N-(2-mercaptoethyl)-N'-methyl-2-nitro-1,1-ethenediamine (354 mg) in concentrated hydrochloric acid (1 ml) and glacial acetic acid (1 ml) was added dropwise and the mixture left to stand at room temperature for 5 days. The solution was diluted with water (30 ml), saturated with potassium carbonate and extracted with ethyl acetate. The combined extracts were purified by preparative layer chromatography to give the title compound as Example 15 (89 mg).
N-Cyao-N'-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]carbadmimidothioic acid, methyl ester
2-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine (1.07 g) was added to a solution of N-cyanoimidocarbamodithioic acid, dimethyl ester (0.73 g) in ether, and stirred overnight. The crystalline solid which formed was filtered, washed with ether and dried to give N-cyano-N'-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]carbamimidothioic acid, methyl ester (1.14 g) m.p. 78�-79�.
A solution of N'-cyano-N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]carbamimidothioic acid, methyl ester (1.06 g) in ethanolic methylamine 33% (10 ml) was stirred at room temperature for 4 hr. The solution was evaporated to dryness and the oily residue crystallised from ethyl acetatelight petroleum (b.p. 80�-100�) to give the title compound m.p. 77�-80�.
A mixture of heptylamine (1.15 g) and N-cyano-N'-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]carbamimidothioic acid (3.12 g) was heated on an oil bath for 12 hr at 100�. The product was chromatographed (silica/methanol) to give N-cyano-N'[2-[[[5-dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]N"-heptylguanidine hydrate (2.31 g) Rf 0.49. Analysis Found: C, 56.99; H, 8.32; N, 17.53. C19 H33 N5 OS.H2 O requires: C, 57.43; H, 8.81; N, 17.63%.
2-[[[5-(Dimethylamimo)methyl-2-furanyl]methyl]thio]ethanamine (4.25 g) and 1,1-bis(methylthio)-2-nitroethene (3.3 g) were refluxed in acetonitrile (50 ml) for 14 hr. Solvent was removed and the residue dissolved in 36% methanolic methylamine (50 ml) and the solution refluxed for 8 hr. Solvents were removed and the residue in methanol treated with charcoal. Filtration and evaporation of the solvent give the title compound as Example 15 (5.0 g).
(a) N-[2-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-(2-methoxyethyl)-2-nitro-1,1-ethenediamine
2-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine (2.14 g) and 1,1-bis(methylthio)-2-nitroethene (1.65 g) were refluxed in acetonitrile for 8 hr. Solvents were removed and an ethanolic solution of 2-methoxyethylamine (0.75 g) added. After refluxing for a further 8 hr, removal of solvents gave an oil. This was purified by column chromatography to give N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-(2-methoxyethyl)-2-nitro-1,1-ethenediamine (1.0 g). NMR τ (CDCl3) 7.73 s (6H); 7-7.5 m (2H); 6.2-7 m (11H); 6.23 s (2H); 3.81 s (2H); 3.42 s (1H).
Similarly prepared was:
(b) N-[2-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-2-nitro-1,1-ethenediamine, m.p. 100�-101�.
(a) N-[4-[5-(Dimethylamino)methyl-2-furanyl]butyl]-N'-methyl-2-nitro-1,1-ethenediamine
4-[5-(Dimethylamino)methyl-2-furanyl]butanamine (0.7 g) and 1,1-bis(thiomethyl)-2-nitroethene (0.6 g) in acetonitrile (12 ml) were refluxed for 22 hr. Solvent was removed and the residue in 33% ethanolic methylamine refluxed for 2 hr. Solvents were removed and the residue purified by column chromatography (silica/methanol) to give N-[4-[5-(dimethylamino)methyl-2-furanyl]butyl]-N'-methyl-2-nitro-1,1-ethenediamine (310 mg). Analysis Found: C, 55.54; H, 8.23; N, 17.75. C14 H24 N4 O3.1/2H2 O requires: C, 55.26; H, 8.22; N, 18.42%.
Similarly prepared were:
(b) N-[5-[5-(Dimethylamino)methyl-2-furanyl]pentyl]-N'-methyl-2-nitro-1,1-ethenediamine. Analysis Found: C, 56.76; H, 8.36; N, 17.37. C15 H26 N4 O3.1/2H2 O requires: C, 56.43; H, 8.46; N, 17.55%.
(c) N-[3-[[5-(Dimethylamino)methyl-2-furanyl]thio]propyl]-N'-methyl-2-nitro-1,1-ethenediamine. Analysis Found: C, 49.36; H, 7.19; N, 17.45. C13 H22 N4 O3 S requires: C, 49.66; H, 7.05; N, 17.84%.
(d) N-[3-[5-(Dimethylamino)methyl-2-furanyl]propyl]-N'-methyl-2-nitro-1,1-ethenediamine. Analysis Found: C, 55.09; H, 7.84; C13 H22 N4 O3 requires: C, 55.31; H, 7.72%.
(e) N-[2-[[[5-(Diethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine. Analysis Found: C, 51.38; H, 7.44; N, 15.66. C15 H26 N4 O3 S.1/2H2 O requires: C, 51.26; H, 7.74; N, 15.94%.
(f) N-[3-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]propyl]-N'-methyl-2-nitro-1,1-ethenediamine. Analysis Found: C, 49.57; H, 7.20; N, 15.59. C14 H24 N4 O3 S.1/2H2 O requires: C, 49.86; H, 7.47; N, 16.61%.
(a) N-Cyano-N'-[4-[5-(dimethylamino)methyl-2-furanyl]butyl]-N"-methylguanidine
4-[5-(Dimethylamino)methyl-2-furanyl]butanamine (0.4 g) and N-cyanoimidocarbamodithioic acid, dimethyl ester (0.3 g) were stirred in ethanol at room temperature for 3 hr. A solution of 33% methylamine in ethanol was then added and the mixture heated under reflux for 2 hr. Solvent was removed under reduced pressure and the product purified by column chromatography (silica/methanol) to give the product as a pale yellow oil. MNR τ (CDCl3) 8-8.5 br (4H); 7.77 s (6H); 6.61-7.5 m (9H); 4.0 m (2H); 2.8-3.7 m (2H).
In a similar manner were prepared:
(b) N-Cyano-N'-[5-[5-(dimethylamino)methyl-2-furanyl]pentyl]-N'-methyl guanidine. NMR τ (CDCl3) 8.0-8.7 br (6H); 7.68 s (6H); 7.32 t (2H); 7.10 d (3H); 6.7 q (2H); 6.48 s (2H); 3.8-4.3 m (4H).
(a) N-[2-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-methanesulphonyl-N"-methylguanidine
Methanesulphonylimiodithiocarbamic acid, dimethyl ester (1.9 g) and a 2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine (2.14 g) were stirred in ethanol at room temperature for 3 hr. 33% Ethanolic methylamine (20 ml) was added and the whole heated under reflux for 16 hr. The product was purified by column chromatography (silica/methanol) to give N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-methanesulphonyl-N"-methylguanidine as a pale oil (2.7 g). Found: C, 43.54; H, 7.05; N, 15.48. C13 H24 N4 O3 S2.1/2H2 O requires: C, 43.70; H, 7.00; N, 15.69%.
Similarly prepared was:
(b) N-Benzenesulphonyl-N'-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N"-methylguanidine. Analysis Found: C, 50.30; H, 6.25; N, 12.93. C18 H26 N4 O3 S.H2 O requires: C, 50.47; H, 6.54; N, 13.08%.
A solution of silver nitrate (8.25 g) in dimethylformamide (50 ml) was added dropwise to a solution of N-cyano-N'-methylcarbamimidothioic acid, methyl ester (6.1 g), triethylamine (4.8 g) and 2-[[[2-furanyl]methyl]thio]ethanamine (7.8 g) in methanol (150 ml). After 42 hr at 50� the mixture was filtered and the filtrate evaporated. The residue was partitioned between ethyl acetate and water. The organic layers were dried and evaporated to give an oil which yielded crystalline N-cyano-N'-[2-[[[2-furanyl]methyl]thio]ethyl]-N"-methylguanidine (3.9 g) m.p. 78�-82�.
A solution of this amine (4.5 g), dimethylamine hydrochloride (3.1 g) and 36% aqueous formaldehyde (3.16 g) in ethanol (20 ml) was heated at 50� for 60 hr. The residue was partitioned between ethyl acetate and aqueous base. The organic extracts were combined, dried and evaporated to give an oil which on treatment with sebacic acid in isopropanol gave the sebacic acid salt of the title compound (2 g) m.p. 93�-94�.
Carbon disulphide (1.52 g) was added with stirring to a cooled solution of sodium hydroxide (0.8 g) in water (1.7 ml). 2-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine (4.28 g) was added slowly and when addition was complete the mixture heated at 100� for 2 hr. After cooling to below 40� ethyl chloroformate (1.94 ml) was added and stirring continued for a further 30 mins. The lower thick yellow oil was extracted with chloroform, dried and evaporated to give N,N-dimethyl-5-[[[2-(isothiocyanato)ethyl]thio]methyl]furanmethanamine as an oil RF 0.43 (silica/methanol).
The crude isothiocyanate (0.46 g) was dissolved in 33% ethanolic methylamine (25 ml), left to stand overnight and N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-methylthiourea isolated as a pale oil (0.16 g) identical to material prepared from 2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine and methyl isothiocyanate.
A solution of N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-methylthiourea (1.3 g) was heated at reflux with lead cyanamide (1.5 g). The solution was filtered and the filtrate evaporated. Treatment of the residue with a solution of sebacic acid in isopropanol gave the title compound as its monosebacate salt (0.7 g) m.p. 90�-92�.
N-[2-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine (50 g, 0.16 mole) was dissolved in industrial methylated spirit 74� o.p. (200 ml) containing 0.16 of an equivalent of hydrogen chloride. Ethyl acetate (200 ml) was added slowly to the solution. The hydrochloride crystallised and was filtered off, washed with a mixture of industrial methylated spirit 74� o.p. (50 ml) and ethyl acetate (50 ml) and was dried at 50�. The product (50 g) was obtained as an off-white solid m.p. 133�-134�.
______________________________________(a) Oral Tablets 50 mg for 10,000 tablets______________________________________Active ingredient 500 gAnhydrous lactose U.S.P. 2.17 kgSta-Rx 1500 Starch* 300 gMagnesium Stearate B.P. 30 g______________________________________ *A form of directly compressible starch, supplied by A.E. Staley Mfg. Co. (London) Limited, Orpington, Kent.
The drug is sieved through a 250 μm sieve and then the four powders are intimately mixed in a blender and compressed between 8.5 mm diameter punches in a tabletting machine.
______________________________________(b) Injection for Intravenous administration (200 mg in 2 ml) % w/w______________________________________Active ingredient 10.0Water for Injections BP to 100.0Dilute hydrochloric acid BP to pH 5.0______________________________________
The active ingredient is dissolved with mixing in the Water for Injections, adding the acid slowly until the pH is 5.0. The solution is sparged with nitrogen and is then clarified by filtration through a membrane filter of pore size 1.35 μm. It is packed into 2 ml glass ampoules (2.2 ml in each) and each ampoule sealed under an atmosphere of nitrogen. The ampoules are sterilised in an autoclave at 121� for thirty minutes.
______________________________________(c) Oral Sustained Release Tablets 150 mg for 10,000 tablets______________________________________Active ingredient 1.50 kgCutina HR** 0.40 kgAnhydrous lactose U.S.P. 2.060 kgMagnesium Stearate BP 40g______________________________________ **Cutina HR is a grade of microfine hydrogenated castor oil supplied by Sipon Products Limited, London.
The active ingredient, Anhydrous lactose and most of the Cutina HR are intimately mixed and then the mixture is moistened by mixing with a 10% solution of the remainder of the Cutina HR in Industrial Methylated Spirit OP 74. The moistened mass is granulated through a 1.2 mm aperture sieve and dried at 50� C. in a fluidised bed dryer. The granules are then passed through a 0.85 mm aperture sieve, blended with the magnesium stearate and compressed to a hardness of at least 10 kg (Schleuniger tester) on a tabletting machine with 12.5 mm diameter punches.
______________________________________(d) Oral Syrup % w/v______________________________________Active ingredient 2.0Dilute hydrochloric acid BP, as requiredSorbitol Solution BPC 60 v/vFlavour as requiredDistilled water to 100______________________________________
The drug is dissolved in some of the water with stirring by adding gradually hydrochloric acid until the pH has fallen to 5.0. The Sorbitol Solution, flavour and the rest of the water are added and the pH re-adjusted to 5.0. The syrup is clarified by filtration through suitable cellulosic filter pads.
______________________________________(e) Oral Capsules 50 mg for 10,000 capsules______________________________________Active ingredient 500 gSta-Rx 1500* 1700 gMagnesium Stearate BP 20 mg______________________________________
The drug is sieved through a 250 μm mesh sieve and is then blended with the other powders. The powder is filled into No. 3 size hard gelatin capsules on a suitable filling machine.
______________________________________(f) Ointment % by weight______________________________________Active ingredient 2.0White Soft Paraffin BP to, 100______________________________________
The drug is sieved through a 150 μm aperture sieve and is then uniformly blended with the White Soft Paraffin in a high shear mixer.
______________________________________(g) Cream % by weight______________________________________Active ingredient 2.0Cetomacrogol Emulsifying Ointment BP 30.0Chlorocresol 0.1Distilled water to 100______________________________________
The drug is passed through a 150 μm aperture sieve and is then blended intimately with the Cetomacrogol Emulsifying Ointment at 65� C. The chlorocresol is dissolved in the water at 65� C. and this solution is then mixed with the oily drug mixture and the resulting emulsion is stirred continuously during cooling to give a cream.
The active ingredient is a compound according to the invention. Particular examples are the compounds of Example 10 and Example 15. Other compounds according to the invention may also be used.
The compounds of the formula (I) have been found to be inhibitors of gastric acid secretion induced by histamine. This has been shown in rats using a modification of the procedure described by M. N. Ghosh and H. O. Schild in the British Journal of Pharmacology 1958, Vol. 13, page 54.
Female rats weighing about 150 g are starved overnight and provided with 8% sucrose in normal saline instead of drinking water.
The rats are anaesthetized by a single intraperitoneal injection of 25% w/v urethane solution (0.5 ml/100 g) and the trachea and jugular veins cannulated.
A mid-line incision in the abdomen well is made to expose the stomach which is separated from the liver and spleen by cutting the connective tissue. A small opening is made in the fundic region of the stomach and the stomach washed with a 5% dextrose solution. The oesophagus is cannulated with rubber tubing and the oesophagus and vagi are then cut above the cannula.
A small opening is then made in the pyloric region of the stomach. A large perspex cannula is then placed in the stomach via the opening in the fundic region in such a manner that the inlet end of the cannula passes out of the stomach through the opening in the pyloric region. The cannula is of such a shape so as to reduce the effective volume of the stomach and to provide a turbulent flow of the perfusion fluid over the mucosal surface. A drainage cannula is then inserted through the opening in the fundic region of the stomach. Both cannulae are tied in place by ligatures around the stomach, positioned to avoid the main blood vessels. Stab wounds are made in the body wall and the cannulae passed through. The stomach is perfused through the oesophageal and pyloric cannulae with 5% dextrose solution at 39� C. at a rate of 1.5 ml/min. for each cannula. The effluent is passed over a micro-flow pH electrode and recorded via a pH meter and flat bed recorder.
The basal output of acid secretion from the stomach is monitored by measurement of the pH of the perfusion effluent and then increased acid secretion is induced by a continuous intravenous infusion of a sub-maximal dose of histamine; this produces a stable plateau of acid secretion and the pH of the perfusion effluent is determined when this condition is obtained.
The test compound is then administered to the rat by an intravenous injection and the change in `gastric` acid secretion is monitored by measuring the change in the pH of the perfusion effluent.
From the change in pH of the perfusion effluent, the difference in acid secretion between basal output and the histamine stimulated plateau level is calculated as hydrogen ion concentration in mole/L. The reduction of acid secretion caused by the administration of the test compound is also calculated as the change in hydrogen ion concentration in mole/L from the difference in the pH of t perfusion effluent. The percentage reduction in acid secretion caused by the administration of the test compound may then be calculated from the two figures obtained.
ED50 values for inhibition of acid secretion are determined by administering one dose of the test compound to one rat and repeating this in at least four rats for each of three or more dose levels. The results obtained are then used to calculate the ED50 value by the standard method of least squares, as used for any dose response line.
Using the above procedure the following ED50 s were obtained:
______________________________________Compound of Example No. ED.sub.50 mg/kg______________________________________ 2(c) 1.5 8 0.65 9(a) 2.30 10 1.39 14(a) 0.23 14(f) 0.8 14(h) 0.48 15 0.18 25(a) 1.82 26(a) 0.55______________________________________
|Cited Patent
|Filing date
|Publication date
|Dec 30, 1958
|Jun 20, 1961
|Synthesis of furans
|Sep 26, 1963
|Mar 18, 1969
|Merck & Co Inc
|Aminopropoxymethylfurans and intermediates therefor
|Kizu et al., Chemical Abstracts, vol. 71 (1969) 125,886r.
|Webb et al., Chemical Abstracts, vol. 45 (1951) 5676e.
|Citing Patent
|Filing date
|Publication date
|Mar 23, 1983
|May 7, 1985
|Inke, S.A.
|Furan derivatives and addition salts thereof pharmaceutical compositions and the therapeutical applications thereof
|Aug 9, 1982
|Jun 4, 1985
|Glaxo Group Limited
|Aminoalkyl furan derivative
|Jun 10, 1983
|Sep 3, 1985
|The Dow Chemical Company
|Processes for making thioalkyl carboxamides and amines
|May 28, 1985
|Jan 6, 1987
|Ausonia Farmaceutici S.R.L.
|Furan derivatives having anti-ulcer activity
|Jan 11, 1984
|May 12, 1987
|Ube Industries, Ltd.
|Process for producing heterocyclic compound having nitromethylene group as the side chain group
|Mar 18, 1985
|Jun 9, 1987
|Glaxo Group Limited
|Process for forming Form 2 ranitidine hydrochloride
|Jan 14, 1987
|Nov 10, 1987
|Medosan Industrie Biochimiche Riunite S.P.A.
|Derivatives of 2-amino-thiazole having an acid secretion inhibiting activity
|Nov 10, 1987
|Nov 15, 1988
|Nippon Shokubai Kagaku Kogyo Co. Ltd.
|Method for production of amine compound
|Jun 23, 1987
|Mar 21, 1989
|Biomeasure, Incorporated
|Antiviral compounds
|Aug 26, 1988
|Oct 3, 1989
|Toyama Chemical Co., Ltd.
|Amine derivative and its salt and anti-ulcer agent containing the same
|May 22, 1990
|Jul 9, 1991
|Janus Farmaceutici S.R.L.
|Synthesis of antiulcer compounds
|Feb 21, 1990
|Aug 20, 1991
|Laboratorios Vinas S.A.
|Furan derivatives
|Aug 14, 1990
|Dec 24, 1991
|Kyowa Hakko Kogyo, Co., Ltd.
|Furan derivatives useful for the treatment of gastro-intestinal disorders
|Nov 15, 1991
|Dec 8, 1992
|Baxter International Inc.
|Unbuffered premixed ranitidine formulation
|Jul 8, 1992
|Apr 19, 1994
|Baxter International Inc.
|Unbuffered premixed ranitidine formulation
|Nov 30, 1994
|Jul 23, 1996
|Applied Analytical Industries, Inc.
|Oral compositions of H2 -antagonists
|May 10, 1993
|Nov 12, 1996
|Zeria Pharmaceutical Co., Ltd.
|Quaternary ammonium salts and use thereof as medicine
|Nov 16, 1995
|Sep 30, 1997
|Hoechst Marion Roussel, Inc.
|Processes for preparing ranitidine
|Mar 7, 2000
|Jul 17, 2001
|Robert R. Whittle
|Alkoxy substituted Benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same
|Jul 31, 2000
|Jul 17, 2001
|Robert R. Whittle
|Pharmaceutical unit dosage form
|Aug 24, 2000
|Jul 31, 2001
|Robert R. Whittle
|Dry blend pharmaceutical formulations
|Jul 31, 2000
|Nov 6, 2001
|Robert R. Whittle
|Method of improving bioavailability
|Jul 31, 2000
|Nov 6, 2001
|Robert R. Whittle
|Pharmaceutical unit dosage form
|Jul 31, 2000
|Nov 13, 2001
|Robert R. Whittle
|Pharmaceutical formulations
|Aug 24, 2000
|Dec 4, 2001
|Robert R. Whittle
|Dry blend pharmaceutical unit dosage form
|Aug 24, 2000
|Apr 9, 2002
|Robert R. Whittle
|Alkoxy substituted benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same
|Jan 25, 2002
|Sep 3, 2002
|Robert R. Whittle
|Alkoxy substituted benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same
|May 16, 2003
|Nov 25, 2003
|Robert R. Whittle
|Granulated pharmaceutical formulations and methods for making the same
|Jul 3, 2002
|Dec 23, 2003
|Robert R. Whittle
|Alkoxy substituted benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same
|May 7, 2003
|Dec 23, 2003
|Robert R. Whittle
|Dry-blend pharmaceutical formulations
|May 16, 2003
|Dec 23, 2003
|Robert R. Whittle
|Dry blend pharmaceutical formulations
|May 8, 2003
|Mar 16, 2004
|Robert R. Whittle
|Alkoxy substituted benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same
|Aug 25, 2000
|Aug 24, 2004
|Robert R. Whittle
|FT-Raman spectroscopic measurement
|Feb 2, 2004
|Aug 12, 2004
|Whittle Robert R.
|Alkoxy substituted benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same
|Dec 3, 1982
|Jun 29, 1983
|Merck & Co., Inc.
|Substituted derivatives of amino alkane diols as gastric secretion inhibitors
|Dec 3, 1982
|Aug 22, 1984
|Merck & Co., Inc.
|Substituted derivatives of amino alkane diols as gastric secretion inhibitors
|May 24, 1985
|Feb 26, 1986
|Biomeasure Inc.
|Novel triazine derivative, process for preparing same and pharmaceutical preparations containing same
|Aug 16, 1990
|Feb 20, 1991
|Kyowa Hakko Kogyo Co., Ltd.
|Furan derivatives
|Aug 16, 1990
|Apr 22, 1992
|Kyowa Hakko Kogyo Co., Ltd.
|Furan derivatives
|U.S. Classification
|548/517, 546/214, 544/379, 544/152
|International Classification
|Cooperative Classification
|European Classification


text:
Each And Every Investor Really Should Have The Proper App To Aid Them With Stock Trading
Trading stocks implies monitoring the stocks nearly as much as possible in order to make sure the individual doesn't overlook an opportunity to sell or buy stocks. Nonetheless, this might not be simple to achieve because an individual might have a full time job as well as a family in order to take care of. Yet, it does not have to be out of the question for an individual to accomplish. With today's technology, it really is increasingly simple for a person to successfully monitor the stocks and make certain they are able to make far more funds from the stocks.
A person who will be serious about making nearly as much as is possible from the stocks may desire to search for an app they can make use of on their mobile phone to make sure they are able to keep an eye on the stocks all of the time. These apps offer help to watch certain stocks and to be able to know the minute anything alters. An individual could want to proceed to Read What He Said in order to discover far more regarding precisely why it's very crucial to have apps that will help a person keep close track of the stock market whenever they are trying to get started or perhaps whenever they will already know what they are doing.
Anyone who is serious about using apps to aid them with trading stocks might desire to have a peek at this web-site. They can discover a lot more facts about the apps which are now available and also ensure they are able to discover the right one for their requirements. Many of these apps will assist them to keep on top of the stocks by telling them whenever a stock they're paying attention to shifts or helping them connect to the most recent information whenever they'll want. This can be priceless for novices and also people who happen to be more familiar with the stocks because it lets them observe the information they'll need to have regardless of where they are or exactly what they're doing.
In case you would like to begin trading stocks or even you currently have some experience as well as desire to bring in more cash, be sure you have a peek here. You are able to Check This Out to understand a lot more about the apps that are available right now and also determine just how they'll assist you to make more money with the stocks beginning now.

subset: commoncrawl


text:
Maruti Ertiga facelift starts testing ahead of 2015 launch – Spied
Anjan Ravi, I'm a true-blooded petrolhead. Hope you enjoy our news stories, launch coverages, motorshow coverages and test drive reports.
Likely to get an AMT variant.
Launched in April 2012, the Maruti Ertiga will get its facelift by the middle of next year, and has already started testing in India. Just like with the Swift, Maruti doesn't want to comprehensively change the looks of the car, as the Ertiga is a well accepted design among buyers.
Thus, minor changes to the grille and bumper are expected upfront, while new alloy wheel patterns and body colors will more-or-less complete the exterior round of changes. Inside, the Ertiga is expected to gain similar features as that seen on the 2015 Swift. Electrically retractable wing mirrors, a Bluetooth-enabled music system, keyless entry and go should be seen on the top-end variant.
More significantly though, the engines are expected to be optimized for better fuel efficiency. Currently, the 1.4-liter K-Series petrol engine delivers 16.02 km/l while the 1.3-liter diesel returns 20.77 km/l. Taking the Swift as reference, expect a 10 percent increase of these figures.
This report points out that Maruti will introduce its AMT (automated manual transmission) technology on the Ertiga, most probably in the petrol version. A 4-speed automatic gearbox is already available on the Ertiga petrol in international markets, but to keep costs in check and pitch the idea of low running cost with a clutch-free drive to self-driven customers, the company could indeed use the 5-speed AMT unit.
Also see: Maruti YBA compact SUV rendered
Despite new competitors like the Honda Mobilio and Chevrolet Enjoy, the Ertiga continues to post healthy sales numbers, with November 2014 witnessing sales of 5,003 units.
Competitors: Honda Mobilio, Chevrolet Enjoy, Mahindra Xylo
Expected Price: INR 6-10 lakhs, ex-Showroom
Launch date: Mid-2015
Maruti Ertiga Limited Edition – Image Gallery
[Spyshots from GaadiWaadi]


text:
"Excellent, professional and swift treatment, very..."
About: Royal Derby Hospital Royal Derby Hospital Derby DE22 3NE
Posted via NHS Choices
Anything else?
I would like to thoroughly and sincerely thank everyone who helped and treated me today at the Derby Royal Hospital. Arriving at A & E, I felt I was having a heart attack. The treatment was very prompt and professional, whilst maintaining a comforting friendliness. The whole process from my first ECG, Blood tests, CT scan, Clinical Measurements, including the Nurses, Doctors and Porters really exceeded any expectations I could have had. Waiting times were minimal, I was kept informed of my progress and possible diagnosis throughout the time I spent in the hospital, so therefore was reassured and confident in the care provided. The hospital has a friendly, helpful feel, I was made comfortable and felt reassured during the time I was there. There is certainly a feel of efficiency and organisation and although we all would prefer not to end up in Hospital, I could not recommend a better place to ask for treatment and help. Thankfully I left without any serious problems Once again, I would like to thank everyone who treated and helped me, what a wonderful, professional and pleasant team.
Response from Royal Derby Hospital 3 years ago
Many thanks for your kind comments regarding your recent stay here at the Royal Derby Hospital. The staff work very hard to ensure that all patients receive a high standard of care and I was very pleased to hear that you felt this was the case on this occasion. I will certainly ensure that this important feedback is shared with all the appropriate staff as I am sure they will also be very appreciative. Many thanks once again for taking the time to provide us with this feedback on your recent experience here. Kind regards Beth Maher Assistant Director Communications
- {{helpful}} {{helpful == 1 ? "person thinks" : "people think"}} this response is helpful
- Was this response helpful? Yes | No
Thank you for your feedback.
See more responses from Royal Derby Hospital


text:
Strike Witches 2 Episode 3 English Subbed
You are watching Strike Witches 2 Episode 3 English Subbed from the Strike Witches 2 Anime Show. Watch or Download Strike Witches 2 Episode 3 MP4 English Sub and other episodes of Strike Witches 2 Streamed for Free.
"Things we can Accomplish Together"
Stream Strike Witches 2 Episode 3
Episode Summary: Mio meets up with Junko Takei of the 504th Joint Fighter Wing to learn about the new breed of Neuroi. Having gotten out of shape following inactivity during the past six months, Yoshika, Lynne and Perrine are sent to an old lady named Anna Ferrara, who teaches them the basics, namely how to ride old fashioned brooms. They struggle at first, but they soon start to get the hang of it. During their training, a Neuroi ship threatens to come into contact with Anna's home, but the girls team up to defeat it.


text:
Support » Fixing WordPress » Multiauthors site fail to store to when add in Tag
5 years, 1 month ago
Recently, I have a site which fails to stores data into the database as soon as the users add in Tags into the post. When the user hit save/publish, the browser freeze, the user have to force to close the browser and when they open it up, the post will be published but not all the content are saved.
This problem never occur in the beginning, but as soon as the site grows (after 6 month time), this problem started to happen. I cannot find any problem related on the web, is there anyone that can help me out?
This only happen when the user add in TAG in the beginning of the post.
5 years ago
Anyone. Any direction will be great.


text:
(Adds futures prices, company news items)
LONDON, March 24 (Reuters) - European equity index futures fell on Monday, with new signs of a possible economic slowdown in China - the world's second largest economy - expected to weigh on the region's stock markets.
The euro zone's blue-chip Euro STOXX 50 futures contract fell 0.8 percent, Germany's DAX futures weakened by 0.5 percent while France's CAC futures fell 0.6 percent.
Asian shares gave up earlier gains on Monday after the China HSBC flash manufacturing purchasing managers index (PMI) fell to an eight-month low in March.
The preliminary reading of 48.1 fell from February's final reading of 48.5, while the "flash" March index also showed that new orders slid for a fourth consecutive month to 46.9 - its lowest point since July 2013, while output fell to 47.3, the lowest since September 2012.
Some traders cited speculation that the Chinese central bank could undertake stimulus measures in order to prop up the country's economy, but they added that for now, the weak nature of the PMI numbers was overriding any prospect of a Chinese central bank cash injection.
"It seems the markets are reacting more to the negativity of numbers rather than the potential cash injection," said Alpari UK chief market analyst James Hughes.
The pan-European FTSEurofirst 300 index rose 0.1 percent to 1,307.24 points on Friday, enabling it to notch up a gain of 1.8 percent last week, which was its best weekly gain in a month.
Euro zone PMI economic data is due out on Monday, and a Reuters poll last week predicted that European stocks will extend their rally this year, fuelled by a long-awaited rebound in corporate profits as the region's economy picks up and global investors shift from emerging markets to Europe.
Europe bourses in 2014: link.reuters.com/pad95v
Asset performance in 2014: link.reuters.com/rav46v ------------------------------------------------------------------------------ > GLOBAL MARKETS-Asia shares up; China, Ukraine fears limit gains > US STOCKS-Wall St ends lower as biotechs fall; indexes up for week > Nikkei bounces off 6-week low, economic uncertainty casts shadow > TREASURIES-Prices rise, curve flattens on rate hike speculation > FOREX-U.S. dollar rally needs fresh catalyst, Aussie dips on China survey
> PRECIOUS-Gold ticks lower on dollar, palladium holds near 2-1/2-yr high
> METALS-Copper slips as China factory growth ebbs for fifth month > Brent holds above $106 on weak China data, seasonal slump
Singapore's Tiger Airways Holdings Ltd has placed an order for 37 Airbus A320neo aircraft valued at $3.8 billion at list prices, taking delivery of the planes from 2018 to 2025, the carrier said in a statement on Monday.
Britain's healthcare cost agency has recommended against using Bayer's new prostate cancer drug Xofigo on the state health service because the German firm did not provide evidence on how well it worked compared to other therapies.
Credit Suisse could cut up to 500 jobs at its private bank as part of a cost-saving drive, a Swiss newspaper reported on Sunday.
Finland's Nokia said on Monday it expected the 5.4 billion euro ($7.5 billion) sale of most of its Devices and Services business to Microsoft will close in April this year.
Orange boss Stephane Richard has said he should be given a second term as chief executive of the state-backed telecom group despite an ongoing investigation of his role as a government aide in a 2008 arbitration case in which the state awarded a large payout to businessman Bernard Tapie.
British life insurance and pensions group Standard Life has announced it is in "exclusive and advanced" talks to buy rival Phoenix Group Holdings' Ignis Asset Management.
Telecoms group Swisscom has 1.6-1.7 billion Swiss francs ($1.8-$1.9 billion) available for acquisitions in Switzerland and Italy, the company's chief financial officer said in an interview published on Saturday.
German insurer Talanx AG raised its dividend and confirmed its 2014 outlook after comfortably beating analyst expectations and its own net profit target for 2013, helped by lower taxes. (Reporting by Sudip Kar-Gupta, editing by Tricia Wright)


text:
sort by best latest
Well the only advice I can give you is try having them apply at movie theaters. It seems like a thing of the past, but my teenager secured a job with one and she can watch movies for free and also family members are allowed to go to for free at selected times. A Win Win especially with the price of movie tickets. Also college kids go back to school and there is usually many time slots to fill with part timers.She enrolled in college and her position is still there but someone had to fill her spot while she away at college. Jobs of this nature where students are employed. Ask around and find out where some of the older teens have worked or are working and these are the hot spots. Helpful?
Now they have to be willing to sacrifice some weekends but once the money starts rolling they will see why its so important to work during their free time. Ensure them that the first job is always the hardest to get and always find another job before quiting the present one. It easier to get a job when you have one.
You can help the HubPages community highlight top quality content by ranking this answer up or down.
Three ideas:
1. Many teens apply to work at chain stores and chain restaurants, but forget to apply at the little "mom &pop" businesses in their neighbourhood. Small businesses can't always afford to advertise job openings in the paper, but might still need someone. Walk in looking clean-cut and friendly and offer your resume. You might just get an impromptu interview or even a job right away! If not, keep trying different places.
2. Be open minded about the type of work you'll accept. You never know what you'll like until you try.
3. Apply to work somewhere where that already knows you... somewhere where you are a customer. You already know what they sell, and a lot about the business, from a customer's point of view.
4. Be positive and friendly. Never go handing out resumes when you're in a bad mood. Give yourself a little pep talk first then go in smiling!
You can help the HubPages community highlight top quality content by ranking this answer up or down.
I've found internships to be really helpful. I'm not sure if you mean just for money, and just to pay the bills, but if you want a specific profession, it's good to look for those internships. I've had a few internships, and even though one of them didn't pay that well, it helps you get your foot in the door and build your resume. Eventually, you may get recommendations and the like to other opportunities. I know that some internships may be a little hesitant, and might get you a 1099 contract job. IF you can, try getting payroll, it can help pay your tax, and I hear it may help your credit. I'm not sure about the credit though. Hope that helps.
You can help the HubPages community highlight top quality content by ranking this answer up or down.
Hi There,
A teen will first need to explore options and decide what type of job they are interested in. The next step is to get working papers, if necessary, and to learn how to fill out a job application or write a resume. Then it will be time to start a job search.
Before they start looking for a job, it is important to take some time to decide what they want to do. Even though they may not have experience, there are a variety of positions available for teens.
For example, if they love animals, check with local veterinarians to see if they are hiring. If they prefer working with children, check with your local pre schools (many have after-school child care programs and summer camps) or child care centers. Fast food restaurants and retail establishments rely on workers without experience and are willing to train new employees. Local libraries often hire teens to help put away books. During the summer, amusement parks and summer camps offer a variety of summer jobs for teens.
Take some time to explore their options. Keep in mind that their first few jobs will provide a good opportunity to find out what they want to do - and what they don't.
Cheers :)
You can help the HubPages community highlight top quality content by ranking this answer up or down.
There's no shame in McDonald's. The place has made an art out of sculpting tomorrow's work force.
You can help the HubPages community highlight top quality content by ranking this answer up or down.