Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/72—Nitrogen atoms
  • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D213/79—Acids; Esters
  • C07D213/80—Acids; Esters in position 3
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D213/84—Nitriles
  • C07D213/85—Nitriles in position 3

Definitions

• 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 antilipb lytic activity.
• 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.
• the present invention provides a pharmaceutical composition which comprises a pharmaceutically acceptable carrier together with at least one compound of formula (I): wherein R 3 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 C 1-6 alkylcarbonyl group; and R is hydrogen or C 1-6 alkyl and R 4 and R 5 are hydrogen, C 1-6 alkyl or halogen.
• Suitable ester groups for R 3 include groups of formula CO 2 R°, wherein R° is:
• aryl includes phenyl and naphthyl optionally substituted with up to five halogen, C 1-6 alkyl, C 1-6 alkox y , halo (C 1-6 ) alkyl, hydroxy, amino, carboxy, C 1-6 alkoxycarbonyl, or C 1-6 alkoxycarbonyl-(C 1-6 )-alkyl groups.
• 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, C 1-6 alkyl, C 1-6 alkoxy, halo-(C 1-6 )-alkyl, hydroxy, amino, carboxy, C l-6 alkoxycarbonyl, C 1-6 alkoxycarbonyl (C 1-6 ) alkyl, aryl or oxo groups.
• the group R° may be for example C 1-6 alkyl, in particular, methyl, ethyl n- or iso-propyl, n-, sec-, iso- or tert-butyl; halo-(C 1-6 )-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
• 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.
• acyloxyalkyl groups such as acetoxymethyl, pivaloyloxymethyl, a-acetoxyethyl, a-acetoxybenzyl and a-pivaloyloxyethyl groups
• alkoxycarbonyloxyalkyl groups such as
• 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.
• the alkyl group within the definition of R 3 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.
• Suitable alkylcarbonyl groups for R 3 include acetyl, propionyl and butyryl.
• the group R 3 is other than hydrogen.
• Advanta- geeusly, R 3 is carboxylic acid or a salt or ester thereof or alkyl.
• Suitable alkyl groups for R 2 , R 4 and R and also for Z include methyl, ethyl and straight or branched chain propyl and butyl.
• Suitable halogen groups for R 4 and R 5 are chlorine, fluorine, bromine.
• R 4 and R 5 are methyl, hydrogen or halogen. If halogen is present it is suitably at posi- ti o n R 5 .
• Z is hydrogen or C 1-6 alkyl.
• Alk may suitably be a C 1-10 alkylene chain, more suitably C 1-6 alkylene such as methylene, ethylene, propylene, butylene, optionally substituted by methyl or ethyl
• Alk represents straight chain alkylene such as methylene or ethylene.
• Suitable substituents for the group R 1 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.
• 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.
• inorganic salts such as the sulphate, nitrate, phosphate and borate, hydrohalides e.g. hydrochloride, hydrobromide and hydroiodide
• organic acid addition salts such as acetate, oxalate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methane- sulphate and p-toluenesulphonate.
• Another sub-class of compounds are those of formula (I) wherein R 5 is halogen. Particular such compounds include:
• R represents hydrogen, a pharmaceutically acceptable salting ion, a C l-6 alkyl group or a readily hydrolysable ester
• R 7 and R 8 represent hydrogen, halogen, C 1-6 alkyl, C l-6 alkox y , nitro, carboxy or C l-6 alkoxycarbonyl.
• R 7 and R 8 represent hydrogen, halogen, C 1-6 alkyl or C 1-6 al k ox y .
• Particular compounds of formula (III) include:
• 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), R 2 , R 3 , R 4 and R 5 are hydrogen, or C 1-6 alkyl arid R 9 is.hydrogen, halogen, C 1-6 alkyl , C 1-6 alkoxy, carboxy or trifluoromethyl.
• At least one of R 2 , R 3 , R 4 and R 5 is C 1-6 alkyl, especially methyl.
• Another sub-class of compounds of the present invention comprises compounds of formula (I) in which R 3 is a nitrile or tetrazole group.
• R 3 is a nitrile or tetrazole group. Examples of such compounds include:
• 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 R 1 9 R 2 , R 3 , R 4 , R 5 , Z, Alk and x are as defined above and Hal represents halogen.
• 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.
• 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.
• 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.
• the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing.
• adjuvants such as a local anesthetic, preservative and buffering agents can be dissolved in the vehicle.
• 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.
• a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
• 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.
• 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 R 2 , R3, R 4 and R 5 are as defined with respect to formula (VII)]; one group A, B or D represents a group of formula (XI): [wherein Alk, x and R 1 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 R 3 to a different such group.
• 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.
• a solvent for example a high boiling, inert organic solvent such as diethylene glycol, xylene, toluene, dimethylformamide, dimethylsulphoxide, dioxan, or water.
• a solvent for example a high boiling, inert organic solvent such as diethylene glycol, xylene, toluene, dimethylformamide, dimethylsulphoxide, dioxan, or water.
• a solvent for example a high boiling, inert organic solvent such as diethylene glycol, xylene, toluene, dimethylformamide, dimethylsulphoxide, dioxan, or water.
• the two reagents (VIII) and (IX) may be heated together in the absence of solvent.
• Alternative methods of preparing compounds (VII) wherein R 3 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.
• a catalyst such as a strong acid, dry hydrogen chloride, or p-toluenesulphonic acid.
• R 3 is an ester
• the formation of compounds (VII) wherein R 3 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.
• a catalyst such as the sodium salt of the alcohol, or dry hydrogen chloride, p-toluenesulphonic acid, or potassium cyanide.
• R 3 is a carboxylic acid group
• R 3 is selected from:
• 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.
• esterified carboxylic acid groups R 3 may be, for example lower alkoxycarbonyl groups such as methoxycarbonyl'or tertiary butoxycarbonyl groups.
• R 3 is a tetrazolyl group
• R 3 is a cyano group
• 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.
• a base e.g. sodium or potassium hydroxide
• Suitable reagents for this reduction include metallic hydrides, in particular sodium borohydride in an alcohol such as ethanol.
• 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.
• Compounds of formula (VII) with a CH 2 group adjacent the amino nitrogen atom may be prepared by reducing a ketone of formula (XVIIA) or (XVIIB): wherein R 11 represents a C 1 -C 5 alkyl group optionally substituted with phenyl and Y represents a bond or a C 1 -C 11 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 BH 3 .S(CH 3 ) 2 .
• Compounds of formula (VII) wherein R 3 is a hydroxymethyl group may be prepared by reduction of a compound (VII) wherein R 3 is a formyl or carboxylic ester group.
• One reagent suitable for this reduction is lithium aluminium hydride.
• 6-(2-Naphthylmethvlamino)-3-picoline was prepared by the method of Example 33, m.p. 161-3°.
• Boiling Range 143-145 0 C (0.3 mm. Hg.)
• 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/CHCl 3 ). 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°.
• 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.
• 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.
• 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.
• Boiling Point 198° (0.6 mm Hg).
• 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.
• the system is as follows:
• hypocholesterolaemic and/or hypotriglyceridaemic effects of several compounds of the present invention were demonstrated in the following experiment;

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Citations (14)

• 1978
  • 1978-07-25 EP EP78300190A patent/EP0000816A1/de not_active Withdrawn
  • 1978-07-28 IL IL55242A patent/IL55242A0/xx unknown
  • 1978-08-03 AU AU38620/78A patent/AU3862078A/en active Pending
  • 1978-08-04 IT IT50601/78A patent/IT1106623B/it active
  • 1978-08-04 ES ES472384A patent/ES472384A1/es not_active Expired
  • 1978-08-04 DK DK346278A patent/DK346278A/da unknown
  • 1978-08-07 JP JP9604778A patent/JPS5441881A/ja active Pending
• 1979
  • 1979-04-25 ES ES479932A patent/ES479932A1/es not_active Expired
  • 1979-04-25 ES ES479931A patent/ES479931A1/es not_active Expired
  • 1979-04-25 ES ES479933A patent/ES479933A1/es not_active Expired

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