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(11) | EP 0 000 816 A1 |
| (12) | EUROPEAN PATENT APPLICATION |
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| (54) | Substituted amino-pyridine derivatives, processes for their preparation and pharmaceutical compositions containing them |
| (57) A class of substituted amino pyridine derivatives are of value in the treatment of
diabetes. Some of the compounds also possess hypolipidaemic activity. The compounds are represented by the formula (I): wherein R3 is hydrogen, alkyl or an acidic function; R2 is hydrogen or alkyl; R4 and R' are hydrogen, alkyl or halogen; Z is hydrogen, phenyl, alkyl or aralkyl; Alk is alkylene and x is 0 or 1; R1 is optionally substituted phenyl or naphthyl. Most of the compounds of formula (I) are novel. |
[0001] This invention relates to pharmaceutical compositions which are of value in the treatment of diabetes. The active ingredients in the compositions comprise a class of substituted amino pyridine derivatives, many of which are novel compounds and also form part of the invention. The active ingredients have hypoglycaemic activity. Some also possess hypolipidaemic and/or antilipblytic activity.
[0002] A number of substituted amino pyridine derivatives are known but no biological activity has been described for them. For example, U.S. patent no. 3,604,096 discloses compounds of formula:
in which R represents inter alia an aryl group, and Rb represents hydrogen, an alkyl group, a carboxy group, an ester group or a halogen atom. The only utility described for those compounds are either as chemical intermediates or as oxidation inhibitors.
[0003] In addition, 6-benzylamino-3-methylpyridine, and 6-benzylamino-4-methylpyridine are known from Chem. Tech. (Berlin) 10,093-9 (1958), but again no biological activity is disclosed therefor.
[0004] The present invention provides a pharmaceutical composition which comprises a pharmaceutically acceptable carrier together with at least one compound of formula (I):
wherein R3 is hydrogen or a carboxylic acid group or a pharmaceutically acceptable salt or ester of a carboxylic acid group; an alkyl group optionally substituted with one or more hydroxyl groups; or nitrile, formyl, tetrazolyl, or C1-6 alkylcarbonyl group; and R is hydrogen or C1-6 alkyl and R4 and R5 are hydrogen, C1-6 alkyl or halogen.
Z represents hydrogen, phenyl or C1-6 alkyl optionally substituted with phenyl;
Alk represents a straight or branched chain alkylene group having up to 12 carbon atoms;
xis zero or 1; and
R1 represents phenyl or naphthyl,optionally substituted with up to three groups selected from C1-6 alkyl, phenyl, halogen, C1-6 alkoxy, amino, nitro, hydroxy, C1-6 alkylamido, Cl-6 alkyl- carbonyloxy, carboxy, Cl-6 alkoxycarbonyl, halo(C1-6)alkyl, oxo (C1-6)alkyl, or a pharmaceutically acceptable acid addition salt thereof.
[0005] Suitable ester groups for R3 include groups of formula CO2R°, wherein R° is:
(a) C1-20 alkyl, C2-8 alkenyl or C2-8 alkynyl each of which may be optionally substituted by C3-7 cycloalkyl, halogen, carboxy, C1-6 alkoxycarbonyl, carbamoyl, aryl, heterocyclyl, hydroxy, Cl-6 alkanoyloxy, amino mono- and di- (C1-6) alkylamino;
(b) C3-7 cycloalkyl optionally substituted with C1-6 alkyl;
(c) aryl;
(d) heterocyclyl;
(e) a group known to readily hydrolyse in the human body to produce the parent acid.
[0006] The term "aryl" includes phenyl and naphthyl optionally substituted with up to five halogen, C1-6 alkyl, C1-6 alkoxy, halo (C1-6) alkyl, hydroxy, amino, carboxy, C1-6 alkoxycarbonyl, or C1-6 alkoxycarbonyl-(C1-6)-alkyl groups.
[0007] The term "heterocyclyl" includes single or fused rings comprising up to four hetero atoms in the ring selected from oxygen, nitrogen and sulphur and optionally substituted with up to three halogen, C1-6 alkyl, C1-6 alkoxy, halo-(C1-6)-alkyl, hydroxy, amino, carboxy, Cl-6 alkoxycarbonyl, C1-6 alkoxycarbonyl (C1-6) alkyl, aryl or oxo groups.
[0008] Thus the group R° may be for example C1-6 alkyl, in particular, methyl, ethyl n- or iso-propyl, n-, sec-, iso- or tert-butyl; halo-(C1-6)-alkyl such as trifluoromethyl, 2-chloroethyl, 2,2,2-trichloroethyl; aminoalkyl groups such as aminoethyl, 2-aminoethyl; hydroxymethyl, 2-hydroxyethyl; phenyl; substituted phenyl; or a benzyl group
[0009] Examples of groups which hydrolyse readily in the body to produce the parent acid include acyloxyalkyl groups such as acetoxymethyl, pivaloyloxymethyl, a-acetoxyethyl, a-acetoxybenzyl and a-pivaloyloxyethyl groups; alkoxycarbonyloxyalkyl groups, such as ethoxycarbonyloxymethyl and a-ethoxycarbonyloxyethyl; dialkylaminoalkyl groups such as dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl or diethylaminoethyl; and lactone groups such as phthalidyl.
[0010] Suitable carboxylic acid salts include alkali metal salts such as lithium, sodium and potassium, other metal salts such as barium, calcium, aluminium or ammonium or substituted ammonium.salts.
[0011] The alkyl group within the definition of R3 may suitably have from 1 to 10 carbon atoms, such as methyl, ethyl, straight ox branched chain propyl, butyl, pentyl, hexyl; and may be substituted at any position with one or more hydroxy groups.
[0013] Suitably, the group R3 is other than hydrogen. Advanta- geeusly, R3 is carboxylic acid or a salt or ester thereof or alkyl.
[0014] Suitable alkyl groups for R2, R4 and R and also for Z include methyl, ethyl and straight or branched chain propyl and butyl. Suitable halogen groups for R4 and R5 are chlorine, fluorine, bromine. Preferably, R4 and R5 are methyl, hydrogen or halogen. If halogen is present it is suitably at posi- tion R5. Preferably Z is hydrogen or C1-6 alkyl.
[0015] The group "Alk" may suitably be a C1-10 alkylene chain, more suitably C1-6 alkylene such as methylene, ethylene, propylene, butylene, optionally substituted by methyl or ethyl Preferably "Alk" represents straight chain alkylene such as methylene or ethylene.
[0016] Suitable substituents for the group R1 include methyl, ethyl, n- and iso- propyl, n-, iso-, sec- and t- butyl, phenyl, chlorine, bromine, fluorine, iodine, methoxy, ethoxy, n- and iso- propoxy, n-, sec- and t- butoxy, carboxy, methoxy-carbonyl, ethoxycarbonyl, trifluoromethyl, 2,2,2-trichloroethyl, amino, nitro,hydroxy, acetamido (-NHCOCH3),propionamido, acetoxy, formyl, formylmethyl, acetyl, acetylmethyl.
[0017] Suitable acid addition salts of compound (I) include inorganic salts such as the sulphate, nitrate, phosphate and borate, hydrohalides e.g. hydrochloride, hydrobromide and hydroiodide and organic acid addition salts such as acetate, oxalate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methane- sulphate and p-toluenesulphonate.
[0018] One sub-class of compounds for use in the compositions of this invention has formula (II):
wherein Z and Alk are as defined above with respect to formula (I);
R represents hydrogen, a pharmaceutically acceptable salting ion, a C1-68alkyl group or a readily hydrolysable ester; and R and R represent hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, carboxy, C1-6 alkoxycarbonyl, or nitro. preferably R7 is hydrogen, and R is hydrogen, halogen, C1-6 alkyl or C1-6 alkoxy. Particular compounds within formula (II) in which Alk represents CH2 include the following:
6-benzylaminonicotinic acid;
6-(N-benzyl-N-methylamino)-nicotinic acid;
6-(N-benzyl-N-ethylamino)-nicotinic acid;
6-(4-chlorobenzylamino)-nicotinic acid;
ethyl 6-(benzylamino) nicotinate;
6-(2-chlorobenzylamino)-nicotinic acid;
6-(4-nitrobenzylamino)-nicotinic acid;
6-(3-methylbenzylamino)-nicotinic acid;
6-(N,N-dibenzylamino)-nicotinic acid;
6-(3-chlorobenzylamino)-nicotinic acid;
6-(3,4-dichlorobenzylamino)-nicotinic acid;
6-(2-methylbenzylamino)-nicotinic acid;
6-(4-methylbenzylamino)-nicotinic acid;
6-(4-methoxybenzylamino)-nicotinic acid;
6-(3-methoxybenzylamino)-nicotinic acid;
6-(2-methoxybenzylamino)-nicotinic acid;
6-[N-methyl-N-(4-methylbenzyl)amino]-nicotinic acid;
ethyl 6-(4-methylbenzylamino)nicotinate;
6-[N-methyl-N-(3,4-dimethylbenzol) amino]nicotinec acid;
6-[N-methyl-N-(4-carboxybenzyl)amino]nicotinic acid;
6-(4-carboxybenzylamino)-nicotinic acid;
ethyl-6-N-methyl-N-(4-ethoxycarbonyl)amino]-nicotinate;
ethyl-6-(4-ethoxycarbonylbenzylamino)-nicotinate;
methyl 6-[N-methyl-N-(4-methylbenzyl)amino]nicotinate 6-(3,4-dimethylbenzylamino)-nicotinic acid;
methyl 6-(4-methylbenzylamino)-nicotinate.
[0019] Compoundsof formula (II) in which "Alk" represents an alkylene chain having from 2 to 6 carbon atoms, include the following:
l-(-)-6-(l-phenylethylamino)-nicotinic acid;
d-(+)-6-(1-phenylethylamino)-nicotinic acid;
6-(2-phenylethylamino)-nicotinic acid;
6-(3-phenylpropylamino)-nicotinic acid;
6-[N-methyl-N-(2-phenylethyl)amino]-nicotinic acid;
6-(4-phenyl-n-butylamino)-nicotinic acid;
6-[2-(4-methylphenyl)-ethylamino]-nicotinic acid
6-(5-phenyl-n-pentylamino)-nicotinic acid;
6-[N-methyl-N-(4-phenyl-n-butyl)amino]-nicotinic acid;
6-[N-methyl-N-(3-phenyl-n-propyl)amino]nicotinic acid;
6-[N-methyl-N-(4-methylphenethyl)amino]nicotinic acid;
6-[N-methyl-N-(5-phenyl-n-pentyl)amino]nicotinic acid;
6-(4-methoxyphenylethylamino)-nicotinic acid;
6-(4-bromophenylethylamino)-nicotinic acid;
6- N-methyl-N-4-bromophenethyl)amino]nicotinic acid;
6-[N-methyl-N-(4-methoxyphenylethyl)amino]nicotinic acid;
ethyl 6-(3-phenyl-n-propylamino)-nicotinate.
[0020] Another sub-class of compounds are those of formula (I) wherein R5 is halogen. Particular such compounds include:
6-benzylamino-5-chloro-3-picoline
6-(4-methylbenzylamino)-5-chloro-3-picoline
6-(N-methyl-N-(4-methylbenzyl)amino)-5-chloro-3-picoline
[0021] Another group of compounds useful in the composition of this invention is represented by formula (III):
wherein Z is as defined above with respect to formula (I), R represents hydrogen, a pharmaceutically acceptable salting ion, a Cl-6 alkyl group or a readily hydrolysable ester; and R7 and R8 represent hydrogen, halogen, C1-6 alkyl, Cl-6 alkoxy, nitro, carboxy or Cl-6 alkoxycarbonyl. Preferably R7 and R8 represent hydrogen, halogen, C1-6 alkyl or C1-6 alkoxy.
[0022] Particular compounds of formula (III) include:
6-(phenylamino)-nicotinic acid;
6-(4-methylphenylamino)-nicotinic acid;
6-(N-ethyl-N-phenylamino)-nicotinic acid;
6-(N-methyl-N-phenylamino)-nicotinic acid;
6-(N,N-diphenylamino)-nicotinic acid;
6-(3-methylphenylamino)-nicotinic acid;
6-(4-chlorophenylamino)-nicotinic acid;
6-(4-ethylphenylamino)-nicotinic acid;
6-(4-bromophenylamino)-nicotinic acid;
6-(4-methQxyphenylamino)-nicotinic acid;
6-(3-chlorophenylamino)-nicotinic acid;
6-(4-fluorophenylamino)-nicotinic acid;
6-(4-iodophenylamino)-nicotinic acid;
6-(2,4-dichlorophenylamino)-nicotinic acid;
6-(2-chlorophenylamino)-nicotinic acid;
ethyl 6-(phenylamino)-nicotinate;
6-(3,4-dichlorophenylamino)-nicotinic acid;
6-(3,4-dimethylphenylamino)-nicotinic acid;
6-(3-methoxyphenylamino)-nicotinic acid;
6-(2-methylphenylamino)-nicotinic acid;
6-(2-methoxyphenylamino)-nicotinic acid;
6-(n-phenyl-N-n-propylnmino)-nicotinic acid;
6-(4-ethoxycarbonylphenylamino)-nicotinic acid;
6-(4-nitrophenylamino)-nicotinic acid;
6-(4-carboxyphenylamino)-nicotinic acid;
6-(3,5-dichlorophenylamino)-nicotinic acid;
6-[N-methyl-N-(4-Chlorophenyl)amino]nicotinic acid;
6-[N-methyl-N-(4-methylphenyl)amino]nicotinic acid.
[0023] A further sub-group of compounds within formula (I) above comprises compounds of formula (IV):
wherein Z, Alk and x are as defined above with respect to formula (I), R2, R3 , R4 and R5 are hydrogen, or C1-6 alkyl arid R9 is.hydrogen, halogen, C1-6 alkyl , C1-6 alkoxy, carboxy or trifluoromethyl.
[0025] Saitably Z is alkyl, benzyl or phenyl. Particular compounds of formula (IV) include:
6-[N-methyl-N-(2-phenylethyl)amino]-3-picoline;
6-(N-methyl-N-benzylamino)-3-picoline;
6-benzylamino-3-picoline;
6-benzylamino-2-picoline;
6-benzylamino-5-picoline;
6-(4-methylbenzylamino)-3-picoline;
6-benzylamino-4-picoline;
6-phenylamino-3-picoline;
6-(4-chlorophenylamino)-3-picoline;
6-(4-chlorobenzylamino)-3-picoline;
6-(4-methylphenylamino)-3-picoline;
phenylamino -2-pyridine;
benzylamino-2-pyridine;
6-phenylamino-2-picoline;
6-[N-(4-methylbenzyl)-N-methylamino]-3-picoline;
6-(4-phenyl-n-butylamino)-3-picoline;
6-(2-phenylethylamino)-3-picoline;
6-(4-ethoxycarbonylbenzylamino)-3-pivolline;
6-[4-methyl-N-(4-ethoxycarbonylhenzyl)amino]-3-picoline;
6- N-methyl-N-(4-ethoxycarbonylhenzyl)amio]-3-picoline;
6-(4-carboxybenzylamino)-3-picoline;
6-[N-methyl-N-(4-carboxybenzyl)amino]-3-picoline;
6-(3-trifluoromethylbenzylamine)-3-picolinel;
6-(4-bromobenzylamino)-3-picoline;
6-(4-methoxybenzylamino)-3-picoline;
6-[N-methyl-N-(4-methoxybenzyl)amino]-3-picoline;
6-(4-methylphenylethylamino)-3-picoline;
6-[N-methyl-N-(4-phenyl-n-butyl)amino]-3-picoline;
6-[N-methyl-N-(4-methylphenylethyl)amino]-3-picoline;
6-[N-methyl-N-(4-chlorobenzyl)amino]-3-picoline;
6-(5-phenyl-n-pentylamino)-3-picoline;
6-[N-methyl-N-(5-phenyl-n-pentyl)amino]-3-picoline;
6-(3-phenyl-n-propylamino)-3-picoline;
6-[N-methyl-N-(4-chlorophenyl)amino]-3-picoline;
6-[N-methyl-N-(3-phenyl-n-propyl)amino]-3-picoline;
6-[N-methyl-N-(3,4-dimethylbenzyl)amino]-3-picoline;
6-(3,4-dimethylbenzylamino)-3-picoline;
(N-ethyl-N-benzyl)amino-2-pyridine;
6-[N-ethyl-N-(4-chlorobenzyl)amino]-3-picoline;
6-[N-ethyl-N-(4-methylbenzyl)amino]-3-picoline;
6-[N-(n-propyl)-N-(4-methylbenzyl)amino]-3-picoline;
6-[N-(n-butyl)-N-(4-methylbenzyl)amino]-3-picoline;
6-[N-(iso-butyl)-N-(4-methylbenzyl)amino]-3-picoline.
[0026] Another sub-class of compounds of the present invention comprises compounds of formula (I) in which R3 is a nitrile or tetrazole group. Examples of such compounds include:
6-benzylamino nicotinonitrile
5-[4-(benzylamino)-3-pyridyl]-tetrazole
3-hydroxymethyl-6-[N-methyl-N-(4-methylbenzyl)amino]-pyridine
[0027] The compounds for use in the compositions of this invention may be prepared by known methods, for example by the reaction of a compound (V) with a compound (VI):
wherein R19 R2, R3, R4, R5, Z, Alk and x are as defined above and Hal represents halogen.
[0028] The compositions may be formulated for administration by any route, although an oral administration is preferred. The compositions may be in the form of tablets, capsules, powders, granules, lozenges, or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
[0029] Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrollidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol, or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oilv suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup gelatin, hydroxyethylcelluslose, carboxy-methyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan nonooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl.p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents. The compound may also if desired be incorporated in a foodstuff, for example in the form of a biscuit.
[0030] For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
[0031] The compositions may contain from 0.1% to 99% by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration. The dosage employed for adult treatment will of course depend on the dose-response characteristics of the particular active ingredient but will normally be in the range O.5 to 300 mg/kg/day.
[0032] Many of the compounds of formula (I) are novel compounds and, in a further aspect, this invention provides a compound of formula (VII):
wherein R1, R2, R3, R4, R5, Alk, x, and Z are defined above with respect to formula (I), provided that:
(a) When x represents zero, then Z represents C1-6 alkyl or phenyl; and
(b) When x represents 1, Z is hydrogen, Alk is -CH2- and either R3 or R4 is methyl, then R1 is other than phenyl.
[0034] The novel compounds of this invention may be prepared by a process which comprises reacting an amine of formula (VIII) with a halide of formula (IX):
wherein "Hal" represents halogen; one group A,B or D represents a group of formula (X):
[wherein R2, R3, R4 and R5 are as defined with respect to formula (VII)]; one group A, B or D represents a group of formula (XI):
[wherein Alk, x and R1 are as defined with respect to formula (VII)] and the third group A, B or D represents the group Z as defined with respect to formula (VII) and optionally converting one group R1 or R3 to a different such group.
[0035] This reaction may be carried out in a solvent, for example a high boiling, inert organic solvent such as diethylene glycol, xylene, toluene, dimethylformamide, dimethylsulphoxide, dioxan, or water. Alternatively, the two reagents (VIII) and (IX) may be heated together in the absence of solvent. In either case, a high temperature is usually required, preferably at least 100°C. In some cases, especially when the group D is of formula (XI), more vigorous conditions are required and the reaction can be carried out in a sealed tube and/or in the presence of a catalyst such as copper, potassium iodide, sodium iodide, potassium carbonate, or sodamide.
[0036] Alternative methods of preparing compounds (VII) wherein R3 is an ester group include the esterification of the free acid or its salt or other reactive derivative of the acid. or transesterification of a compound having a different ester group. Esterification may be performed by any conventional method, for example by reaction of the free acid with the appropriate alcohol in the presence of a catalyst such as a strong acid, dry hydrogen chloride, or p-toluenesulphonic acid.
[0037] The formation of compounds (VII) wherein R3 is an ester may also be carried out by conventional transesterification methods, for example reaction of an ester with the appropriate second alcohol in the presence of a catalyst such as the sodium salt of the alcohol, or dry hydrogen chloride, p-toluenesulphonic acid, or potassium cyanide.
[0038] Compounds of formula (VII) wherein R3 is an ester may also be prepared by alkanolysis of the corresponding cyano compound (R3 is C≡N); or by hydrolysis of an iminoether compound having formula (VII) wherein R3 is a group of formula:
wherein RX is the hydrocarbon residue of an alcohol on phenol.
[0039] Compounds wherein R3 is a carboxylic acid group can also be prepared by the acid or base catalysed hydrolysis of the corresponding compound of formula (1) wherein R3 is selected from:
(a) carboxylic acid amide group:
(b) cyano group (-C≡N);
(c) esterified carboxylic acid group. Hydrolysis of amides may be carried out using a mineral acid as catalyst, suitably hydrochloric acid or sulphuric acid. Base catalysed hydrolysis may be carried out using an alkali metal or alkaline earth metal hydroxide, e.g. sodium or potassium hydroxide. Suitably the hydrolysis reaction is carried out in aqueous solution e.g. refluxing for several hours. The desired compound can be isolated as the free acid by neutralisation of the resultant reaction mixture or as the appropriate base addition salt (e.g. sodium salt if sodium hydroxide was employed) or acid addition salt (e.g. the hydrochloride if HC1 was employed.) Alternatively the free acid can be converted to any desired salt by standard procedures.
[0040] For the hydrolysis of a compound wherein R3 is a cyano group, ammonia is liberated and thus the preferred catalyst is an acid which will bind the ammonia e.g. hydrogen halide such as HC1 or HBr. If base catalysed hydrolysis is used, ammonia is liberated and the acid will be obtained as an alkali salt, or after neutralisation, as the free acid.
[0041] For the hydrolysis of an esterified carboxylic acid group, preferably the process involves hydrolysis with a strong base such as sodium hydroxide. The esterified carboxylic acid groups R3 may be, for example lower alkoxycarbonyl groups such as methoxycarbonyl'or tertiary butoxycarbonyl groups. The remarks made earlier about salts of the resultant free acid also apply in this case.
[0042] Compounds wherein R3 is a tetrazolyl group may.be prepared from a compound in which R3 is a cyano group, for example by treatment with sodium azide, ammonium chloride and lithium bromide.
[0043] Compounds of formula (VII) may also be prepared by reacting an amine of formula (XII) with a compound of formula (XIII):
[0044] This reaction is generally carried out in the presence of a base, e.g. sodium or potassium hydroxide, preferably without additional solvent at elevated temperature.
[0045] Compounds of formula (VII) wherein x is 1 and Alk represents methylene may be prepared by reducing a compound of formula (XIV):
[0046] Suitable reagents for this reduction include metallic hydrides, in particular sodium borohydride in an alcohol such as ethanol.
[0047] Compounds of formula (XIV) may be prepared by condensing together compounds of formula (XV) and (XVI):
[0048] Compounds of formula (VII) wherein Z is methyl may be prepared by reacting a compound of formula (VII) wherein Z is hydrogen with a mixture of formic acid and formaldehyde.
[0049] Compounds of formula (VII) with a CH2 group adjacent the amino nitrogen atom may be prepared by reducing a ketone of formula (XVIIA) or (XVIIB):
wherein R11 represents a C1-C5 alkyl group optionally substituted with phenyl and Y represents a bond or a C1-C11 alkylene group. Suitable reagents for this reduction are those capable of reducing amides, for example, lithium aluminium hydride, diborane or preferably the reagent of formula BH3.S(CH3)2.
[0050] It may be preferable to modify the substituents R1 and/or R3 after the condensation reaction rather than before. Thus, it is preferable, when preparing compounds of formula (VII) wherein R3 is a carboxylic acid group, first to prepare the corresponding compound with a carboxylic acid ester group and then to convert such group to carboxylic acid group by conventional means.
[0051] Compounds of formula (VII) wherein R3 is a hydroxymethyl group may be prepared by reduction of a compound (VII) wherein R3 is a formyl or carboxylic ester group. One reagent suitable for this reduction is lithium aluminium hydride.
[0052] The following examples illustrate the preparation of some of the novel compounds of this invention:
EXAMPLE 1
6-Benzvlaminonicotinic Acid
[0053]
Two stoichiometric equivalents of benzylamine (6.8 g) wtre added to 6-chloro-nicotinic acid (5 g). The mixture was heated at 150°, with stirring, for 4 hours, The cooled reaction mixture was diluted with water, The resulting solid-liquid mixture was filtered. The solid was taken up in sodium hydroxide solution, heated, with stirring, for 15 minutes and filtered. The basic filtrate was brought to pH 6 by addition of dilute hydrochloric acid. A white precipitate was deposited. The precipitate was filtered off, washed with water, and dried, m.p. 228-230°C.
EXAMPLES 2-32
EXAMPLE 33
Preparation of 6-benzylamino-2-picoline
Methods
[0056] 2-amino-6-picoline (10.8 g, 0.01M), benzyl alcohol (15 g) and 85% KOH (0.9 g) were placed in a'100 ml flask set up for distillation. A thermometer was placed such that its bulb was in the reaction mixture. The flask was heated on an electric mantle such that water distilled over slowly accompanied by as little benzyl alcohol as possible. The temperature of the boiling mixture rose gradually from 180° to 250° over a period of about 30 minutes. The mixture was maintained at 250° for 3 minutes and then allowed to cool. The contents of the flask were cooled to 100° and then poured into water (50 ml). The solid which immediately formed was crushed and collected on a Buchner funnel. The dried product was recrystallised from an ethanol/Pet. Ether (40-60) mixture. The product was a white crystalline material, m.p. 58-60°C.
EXAMPLES 34-44
EXAMPLE 45
6-(2-Naphthylmethvlamino)-3-picoline was prepared by the method of Example 33, m.p. 161-3°.
EXAMPLE 46
Preparation of 6-(4-ethoxvcarbonylbenzyl)-amino-3-picoline
[0058]
2-amino-5-picoline (5.4 g) was dissolved in dry benzene (100 ml). A slight excess of ethyl-4-carboxybenzaldehyde (9 g) was added and the mixture was heated under reflux for 30 hours using a Dean and Stark separator. The solvent was removed by rotary evaporation and the solid residue was taken up in ethanol (100 ml). Sodium borohydride (3.78 g) was added with caution, a vigorous reaction taking place. The resulting solution was refluxed for 2 hours. The solvent was removed and the residue dissolved in chloroform and washed with water. The chloroform phase was dried over MgSO4 and evaporated to dryness. A pale yellow solid was obtained which was purified by column chromatography. (Silice Gel/Ether.) The product was isolated as a white crystalline solid; mass of product 6 g; 0 m.p. 123-125°C.
EXAMPLES 47-48
EXAMPLE 49
Preparation of 6-(4-methylphenylethyl)amino-3-picoline
[0060]
2-bromo-5-picoline (6.36 g) and p-tolyl ethylamine (10 g) were heated together at 150°C, with stirring, for 6 hours. The cooled reaction mixture was diluted with water, made basic with sodium hydroxide solution and extracted with ether. The ether extract was dried and concentrated to give a yellow oil. The oil was purified by distillation.
EXAMPLES 50-51
EXAMPLE 52
Ethyl 6-benzylaminonicotinate
[0063]
6-benzylaminonicotinic acid (4 g) was added to ethanol (100 ml) acidified with sulphuric acid. The mixture was refluxed for 6 hours. The cooled reaction mixture was poured into water and extracted with chloroform. The chloroform extract was dried over magnesium sulphate and evaporated to dryness. A pale-yellow, semi-solid residue remained. Infrared spectroscopy and thin layer chromatography showed that the residue was a mixture of the starting acid and the required ester. The mixture was passed through a chromatography column (alumina/CHCl3). The ester was eluted first and was isolated as a white solid. The product was recrystallised from Ethanol/ Pet. ether (60-80), m.p. 95-97°.
ExAMPLES 53-54
EXAMPLE 55
Preparation of 6-(4-carboxybenzyl)amino-nicotinic acid
[0065]
The di-ester (1.5 g) was heated under reflux in sodium hydroxide solution (50 ml, 1N soln.) for 6 hours. The reaction mixture was cooled and brought to pH5 with dilute HC1. A white precipitate was formed and filtered off. The solid was recrystallised from ethanol.
EXAMPLES 56-60
EXAMPLE 61
6-[N-methyl-N-(4-methylbenzyl)]-amino-3-picoline
[0068]
6-(4-methylbenzyl)-amino-3-picoline (5.25 g, 0.025M) was added to a mixture of formic acid (6.25 ml) and formaldehyde solution (3 ml 40% HCHO). The mixture was heated at 100° for eight hours. The cooled reaction mixture was poured into dilute sodium sulphite solution and made basic with NaOH solution. The product was extracted into ether and isolated as a yellow oil which was distilled under vacuum.
EXAMPLES 62-83
EXAMPLES 84-85
[0071] The following compounds were also prepared by a method substantially as described in Example 61.
EXAMPLE 86
5-[4-(benzylamino)-3-pyridyl]-tetrazole
[0072]
6-Benzylamino nicotinonitrile (2.34 g, 0.011 M) was added to a mixture of sodium azide (0.975 g), ammonium chloride (0.81 g) and lithium bromide (0.015 g) in dimethylformamide (7.5 ml). The mixture was heated at 125°C for twelve hours. When cool, the insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure to give an orange gum. A yellow solid formed on addition of water. The solid was reprecipitated from basic solution with HC1. The product was recrystallised from ethanol as the hydrate.
EXAMPLE 87
2-(N-benzyl-N-ethyl]amino pyridine
[0074]
Borane - methyl sulphide complex (3.8 ml) in dry tetrahydrafuran (25 ml) was added dropwise, at room temperature, to 2-[N-acetyl-N-benzyl]amino pyridine (4.7 g) in dry tetrahydrofuran under nitrogen with stirring over 40 minutes. After a further 20 minutes, the mixture was reflux/stirred under nitrogen for 5 hours and cooled to room temperature. Methanol (7 ml) in dry tetrahydrofuran (10 ml) was added over one hour, allowed to stand overnight, cooled to 0°C, hydrogen chloride passed through for 25 minutes then heated under reflux for one hour, cooled and evaporated to dryness. The residual oil was dissolved in 5N HC1, washed with ether (x2) and the aqueous layer basified with aq. NaOH. Extraction with chloroform gave, on evaporation, an oil. Purification by column chromatography on silica using diethyl ether as eluent gave the analytically pure product (3.75 g) as an oil.
EXAMPLES 88-93
EXAMPLE 94
Preparation of 6-[N-methyl-N-(4-methylbenzyl)amino]-3-hydroxy methyl pyridine
[0076]
Excess lithium aluminium hydride (0.2 g) was placed in a 3-necked, 500 ml round-bottomed flask fitted with a mechanical stirrer, dropping funnel and condenser. The apparatus was thoroughly dry and flushed with nitrogen. Sodium-dried ether (50 ml) was added to the flask and the stirrer was started. The flask was cooled in ice and methyl-6-[N-methyl-N-(4-methyl benzyl)amino]nicotinate (2.5 g) dissolved in Na-dried ether (50 ml) was added dropwise. The reaction mixture was stirred at room temperature for one hour. Excess LiAlH4 was decomposed by careful addition of ethyl acetate. The resulting solution was poured into dil. H2S04. The organic layer was removed and the aqueous phase was basified with NaOH. The basic solution was extracted with ether. The ether extract was dried over MgSO4 and concentrated to give a pale-yellow oil. The product was purified by column chromatography and distillation.
BIOLOGICAL DATA:
Hypoglycaemic assay in alloxan-diabetic mouse
[0078] For this assay, mice were made diabetic with alloxan five days before the experiments, drugs were dosed orally in 1% aq, carboxymethyl cellulose. Eleven animals were used for each treatment.
[0079] The table below shows the percentage lowering of compounds described in the present specification after 1 hour and 3 hours, compared with data for the known hypoglycaemic agent, Phenformin.
N.B.:
[0080] A standard system for indicating the significance of results with respect to control is used in the table.
Hypolipidaemic assay
[0082] The hypocholesterolaemic and/or hypotriglyceridaemic effects of several compounds of the present invention were demonstrated in the following experiment;
[0083] Groups of 8 male albino rats (C.F.Y. strain), weighing approximately 150 g., were given a powdered commercially available diet (oxoid) to which compounds were added at level of of 0.1%. These diets were fed for seven days. The rats were then killed and their serum total cholesterol and triglyceride were measured by the Technicon Autoanalyser. The following table shows the results expressed in terms of percentage cholesterol lowering and percentage triglyceride lowering compared with controls.
Triglyceride and Cholesterol Lowering Results
wherein R3 is hydrogen or a carboxylic acid group or a pharmaceutically acceptable salt or ester of a carboxylic acid group; an alkyl group optionally substituted with one or more hydroxyl groups; or nitrile, formyl, tetrazolyl, or C1-6 alkylcarbonyl group; and R is hydrogen or C1-6 alkyl and R and R5 are hydrogen, C1-6 alkyl or halogen.
Z represents hydrogen, phenyl or C1-6 alkyl optionally substituted with phenyl ;
Alk represents a straight or branched chain alkylene group having up to 12 carbon atoms;
x is zero or 1; and
R represents phenyl or naphthyl, optionally substituted with up to three groups selected from C1-6 alkyl, phenyl, halogen, C1-6 alkoxy. amino, nitro, hydroxy, C1-6 alkylamido, C1-6 alkylcarbonyloxy, carboxy, C1-6 alkoxycarbonyl, halo ( C1-6 ) alkyl, oxo ( C1-6) alkyl; or a pharmaceutically acid addition salt thereof.
wherein Z and Alk are as defined in claim 1; R represents hydrogen, a pharmaceutically acceptable salting ion, a C1-6 alkyl group or a readily hydrolysable ester; and R7 and R represent hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, or nitro.
wherein Z is as defined in claim 1, R represents hydrogen, a pharmaceutically acceptable salting ion, a C1-6 alkyl group or a readily hydrolysable ester; and R7 and R8 represent hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, nitro, carboxy or C1-6 alkoxycarbonyl.
wherein Z, Alk and x are as defined in claim 1, R2, R3, R4 and R5 are hydrogen, or C1-6 alkyl and R9 is hydrogen, halogen, C1-6 alkyl or C1-6 alkoxy.
wherein R3 is hydrogen or a carboxylic acid group or a pharmaceutically acceptable salt or ester of a carboxylic acid group; an alkyl group optionally substituted with one or more hydroxyl groups; or nitrile, formyl, tetrazolyl, or C1-6 alkylcarbonyl group; and R is hydrogen or C1-6 alkyl and R4 and R5 are hydrogen, C1-6 alkyl or halogen.
Z represents hydrogen, phenyl or C1-6 alkyl optionally substituted with phenyl;
Alk represents a straight or branched chain alkylene group having up to 12 carbon atoms;
x is zero or 1; and
R1 represents phenyl or naphthyl, optionally substituted with up to three groups selected from C1-6 alkyl, phenyl, halogen, C1-6 alkoxy, amino, nitro, hydroxy, C1-6 alkylamido, C1-6 alkylcarbonyloxy, carboxy, C1-6 alkoxycarbonyl, halo-( C1-6 )-alkyl, oxo-( C1-6 )-alkyl; or a pharmaceutically acceptable acid addition salt thereof; provided that :
(a) When x represent zero, then Z represents C1-6 alkyl, phenyl or phenylalkyi;
(b) When x represents 1, Z is hydrogen, Alk is -CH2- and either R3 or R is methyl, then R1 is other than phenyl.
wherein Z and Alk are as defined in claim 11, R represents hydrogen, a pharmaceutically acceptable salting ion, a C1-6 alkyl group or a readily hydrolysable ester; and R and R represent hydrogen, halogen, C1-6alkyl, C1-6alkoxy or nitro.
wherein Z1 is phenyl or C1-6 alkyl optionally substituted with phenyl, R represents hydrogen, a pharmaceutically acceptable salting ion, a C1-6 alkyl group or a readily hydrolysable ester; and R7 and R8 represent hydrogen, halogen, C1-6alkyl, C1-6 alkoxy, nitro, carboxy or C1-6 alkoxycarbonyl.
wherein R2, R3, R4 and R5 are hydrogen, or C1-6 alkyl;
R9 is hydrogen, halogen, C1-6 alkyl or C1-6 alkoxy;
Alk represents a C2-6 straight or branched alkylene chain; and
either x is zero and Z is C1-6 alkyl, phenyl or benzyl;
or x is 1 and Z is hydrogen, C1-6 alkyl, phenyl or benzyl.
a) reacting an amine of formula (VIII) with a halide of formula (IX):
wherein " Hal " represents halogen; one group A, B or D represents a group of formula
(X):
[ wherein R2, R3,R4 and R5 are as defined in claim 11 ] one group A, B or D represents a group of formula (XI);
- (Alk)x - R1 (XI) [ wherein Alk, x and R1 are as defined in claim 11 ]; and the third group A, B, or D represents the group
Z as defined in claim 11;
b) reacting an amine of formula (XII) with a compound of formula (XIII):
wherein R1, R2, R3, R4, R5, Z, Alk and x are as defined in claim 11;
c) when x is 1 and Alk represents methylene reducing a compound of formula (XIV):
wherein R1, R2, R3, R4 and R5 are as defined in claim 11;
d) for compounds of formula (VII) with a CH2 group adjacent the amino nitrogen, reducing a ketone of formula (XVII A) or (XVII
B):
wherein R11 represents a C1-5 alkyl group optionally substituted with phenyl, Y represents a bond or a C1-11 alkylene group, and R1, R2, R3, R4, R5, Alk, x and Z are as defined in claim 11;
and after step a), b), c) or d), optionally converting one group R3 or R1 to a different such group.
6- [N-methyl-N-(4-methylbenzyl)amino]-3-picoline
6- [N-methyl-N-(4-chlorophenyl) amino]nicotinic acid
6- [N-methyl-N-(4 chlorophenyl ) amino]-3-picoline
6- [N-methyl-N-( 3,4 dimethylphenyl ) amino]-3-picoline
6- [N-methyl-N-(4-methylbenzyl ) amino ]nicotinic acid and it's methyl ester
6- [N-methyl-N-( 4-chlorobenzyl ) amino ] -3-picoline
6- [ N-methyl-N-( 4-carboxybenzyl ) amino ] -3-picoline