IL41825A - Pyridine derivatives their preparation and pharmaceutical compositions containing them - Google Patents

Pyridine derivatives their preparation and pharmaceutical compositions containing them

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Publication number
IL41825A
IL41825A IL41825A IL4182573A IL41825A IL 41825 A IL41825 A IL 41825A IL 41825 A IL41825 A IL 41825A IL 4182573 A IL4182573 A IL 4182573A IL 41825 A IL41825 A IL 41825A
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alk
formula
compound
salt
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IL41825A
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Beecham Group Ltd
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    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

1437781 Pyridine derivatives BEECHAM GROUP Ltd 18 May 1973 [4 April 1972] 15280/72 Heading C2C [Also in Division A5] Compounds (mostly novel) of Formulµ I and II in which formulµ "Py" represents a substituted or unsubstituted 2-, 3- or 4-pyridyl group, or an N-oxidized or quaternized pyridyl group; "A" represents a group of Formula (IIIa), (IIIb) or (IIIc) wherein "ALK" represents a straight or branched chain alkylene group having from 1 to 6 carbon atoms; R 1 represents a carboxylic acid group or a group which is converted in the human body to a carboxylic acid group R 2 , R 3 and R 4 each separately represent hydrogen, a carboxylic acid group, a group which is converted in the human body to a carboxylic acid group, a hydroxy group, an alkoxy group, an aralkoxy group, an aryloxy group, an esterified hydroxy group, a nitro group, a halogen group or an amine group, are prepared by reacting a compound of formula B-(ALK) n OH with a compound of formula HO-(ALK) m -Py in which m and n are 0 or 1, provided n + m#0, and B is a group of Formula Ia or IIa The known compounds are those in which Py is 2-pyridyl or 5-ethylpyrid-2-yl, A is R 1 is methyl or methoxycarbonyl and R 2 , R 3 and R 4 are H or halogen. 2-Chloromethylpyridine is prepared by reacting 2-hydroxymethylpyridine with phosphorus oxychloride. p - Ethoxycarbonylbenzyl bromide is prepared by reacting ethyl p-toluate with N-bromosuccinimide. Pharmaceutical composition having hypoglycaemic activity, for oral administration, comprise a compound I or II together with a pharmaceutical carrier. [GB1437781A]

Description

jn: n , ηΐΐ?*τπ I'T S nnVm ?ηικ D' ' H ninpn 'r ni Novel pyridine derivatives, their preparation and pharmaceutical compositions containing them BEECHAM GROUP LIMITED, hynoglycaemic activity and which are therefore of value in th treatment of hyperglycaemic conditions sue!) as diabetes mellitus. Many of the compounds also have h olipidaernri c ac ivity . The invention also relates to pharmaceutical compositions comprising such compounds and to a method for the preparation of the compounds .
Present oral antidiabetic therapy involves the administration of either- sulphonyl ureas or biguanides.
The former class of compound exert their effect by re-] easing insulin from the pancreas while the latter class of compound inhibit glucose uptake from' the small intestine, inhibit hepatic gluconeogenesis and under certain conditions increase peripheral glucose utilisation.
In our search for new agents for the treatment of diabetes mellitus which have advantages over the previously available sulphonylureas and biguanides, we have noted a class of basic ethers. Preliminary tests showed that hypoglycaemio activity in alloxanised mice was a characteristic of the class as a v;hole and subsequent tests in normal mice and other species including rats, guinea pigs and squirrel monkeys, confirmed these preliminary findings.
The compounds which -we found to have hypoglycae ic activity were those of formula (I) or formula (II) and acid add i tion_ salts the of: - 41825/ substituted 2 -, 3- or 4- pyridyl group; tl tl A represents a group of formula (ΙΙΙΛ), (IIIB) or (IIIC) -4- ALK-04- -f- O-ALK - ALK-O-ALK - (ΙΙΙΛ) (IIIB) (IIIC) wherein " ALK" represents a straight or branched chain alkylene group, haying from 1 to 6 carbon atoms; represents a carboxylic acid group or salt, ester, or amide of a carboxylic acid group, a carboxylic acyl, alkyl, alkenyl, alkynyl group or an alkyl, alkenyl or alkynyl group which carries a hydroxy, esterified hydroxy or carboxylic acid substituent, or salt, ester, or amide of a carboxylic acid substituent; R2 , and each separately represent hydrogen, lower alkyl, lower alkoxy or halogen.
However, a search of the chemical literature ha£ shown that not all compounds of formula (I) or (II) are novel. The known compounds are those of formula (I) or (II) wherein "Py" is 2-pyridyl or 5-ethylpyrid-2-yl, A is -f-O-CHg}, activity of this known clatS of .compounds is insecticidal or fungicidal activity.
Further, New Zealand specification number 156,509 discloses a generic class of substituted aryloxy pyridylmethanes as intermediate compounds, but does not disclose the specific class of hypoglycaemic compounds of the present invention.
It will therefore be clear that the discovery that compounds of formulae (I) and (II) above have hypoglycaemic activity is a new and unexpected one, and that pharmaceutical compositions Thus, in its broadest aspect, the present invention provides a pharmaceutical composition, useful in the treatment of hyperglycaemia, comprising a compound of formula (I) or (II) as defined above, or an acid addition salt therof and one or more pharmaceutically acceptable carriers.
As is common practice, such compositions will usually be accompanied by or associated with written or printed directions, for use in the medical treatment concerned, in this case as an agent for reducing serum sugar levels.
In preparing the pharmaceutical compositions of this invention, the compound is incorporated in a suitable carrier such as a pharmaceutical carrier, a beverage or a foodstuff. The compositions may be in the form of tablets, linguets, powders, capsules, slurries, troches or lozenges. The choice of carrier will be governed by the desired properties of the composition and normal pharmaceutical practice may be followed. Thus, in formulating solid compositions carriers such as magnesium salts, starch, lactose, talc and chalk may be used. The composition may also be in the form of an ingestible capsule (e.g. of gelatin) to contain the compound; or in the form of a syrup, a liquid solution or a suspension. Suitable liquid pharmaceutical carriers include ethyl alcohol, glycerine, saline, and water, and if desired conventional flavouring or colouring agents may be present. The compound may also, if desired, be incorporated in a foodstuff, e.g. in the form of a biscuit .
Since the majority of compounds of formula (I) and (II) above are new compounds, this invention includes, in another of its aspects, these new compounds, i.e. compounds of formula (I) or formula (II) and acid addition salts there¬ in which formula "Py" represents an unsubstituted or (lower alkyl) -substituted 2-, 3- or 4-pyridyl group; "A" represents a group of formula (IIIA) , (IIIB) or (IIIC) . -f-ALK-0-3- - O-ALK - --ALK-O-ALK -}- (IIIA) (IIIB) ( IIIC) wherein "ALK" represents a straight or branched chain alkylene group having from 1 to 6 carbon atoms; represents a carboxylic acid group or salt, ester, or amide of a carboxylic acid group, a carboxylic acyl, alkyl, alkenyl, alkynyl group or an alkyl, alkenyl or alkynyl group which carries a hydroxy, esterified hydroxy or carboxylic acid substituent, or salt, ester, or amide of a carboxylic acid substituent; R2, R3 and each separately represent hydrogen, lower alkyl, lower alkoxy or halogen, provided that R-^ is not methyl, cyano or rr.e hoxycarbonyl when "Py" is 2-pyridyl or 5-ethylpyrid-2-yl and A is - O-CH2- and R2, and are hvdrnrren or haloeren.
In the above definition the divalent radical A which links the phenyl and pyridyl rings has been defined as a group of formula (IIIA), (IIIB) or (IIIC). The symbol "ALK" preferably represents a methylene, ethylene, or n-propylene group, but straight or branched chain alkylene groups having from 1 to 6 carbon atoms are in general suitable.
Also in the definition of the compounds of this invention, the symbol "Py" has been defined as a (lower alkyl) -substituted or unsubstituted 2-, 3- or 4-pyridyl group.
Of these, 2- and 3- pyridyl groups are preferred. Preferably, if the pyridyl ring contains lower alkyl substituents these should be in the meta- or para- positions relative to the bond joining the ring to the group A. Examples of groups R-^ which are converted in the human body to carboxylic acid groups include salt, ester or amide derivatives of carboxylic acid groups, alkyl, alkenyl or alkynyl groups, (especially those having an odd number of carbon atoms), alkyl, alkenyl 41825/2 or alkynyl groups which carry hydroxy, esterified hydroxy or carboxylic acid substituent, or a salt, ester or amide derivative of a carboxylic acid substituent . x \ V/e have noted a tendency for substituents in the 2-position of the phenyl ring to reduce the hypoglycaemic activity of the compounds of this invention. Thus, preferably, the groups R'^ and R^ in compounds of formula (I) or (II) above are hydrogen.
To summarise what' has been said above, of the compounds tested, we have noted that the majority of those having high acitivity fall within a fairly well defined sub-class.
This preferred sub-class of compounds according to the invention consists of compounds of formula (VI) and acid addition salts thereof:- wherein Py represents a 2-, 3- or -pyridyl group which is unsubstituted or is substituted in the me ta-or-para-position (relative to the Py - A bond) by an alkyl group having an odd number of carbon atoms; A prepresents a group of formula (IIIA) , (IIIB) or (IIIC) . --0-ALK-f- -f-ALK-O-}- —£- ALK-O-ALK (IIIA) (MB) (IIIC) wherein ALK represents a straight chain alkyl group of from 1 to 6 carbon atoms (especially 1 to 5 carbon atoms) and Ra and R^ separately represent hydrogen or carboxylic acid groups or salt, ester or amide derivatives of carboxylic .acid groups or alkyl groups having an odd number of carbon atoms or alkyl groups having an even number of carbon atoms and carrying carboxylic acid substituents or salt, ester or amide sub-stituents, at least one of R and R not being hydrogen, a ¾ provided that when Py is 2-pyridyl or 5-ethypyrid-2-yl and A is [0-CH ], neither R nor R is methyl or methoxycarbonyl .
^ B b Examples of compounds falling within the scope of the present invention which are particularly preferred for their high level of hypoglycaemic activity are the following, and their pharmaceutically acceptable acid addition salts :- 4-Metb.ylphenoxy-3l -pyridylmethane 4-n-Propylphenoxy-21 -pyridylmethane 4-Methylbenzyloxy-2 ' -pyridylethane 1-( -Methylbenzyloxy)-3-(2' -pyridyl )nrpropane 4-Hydroxymethylphenoxy-2 ' -pyridylme thane 4-Carboxyphenoxy-2' -pyridylmethane 4-Carboxymethylphenoxy-2' -pyridylmethane 4-Carboxyethylphenoxy-2 ' -pyridylmethane 4-Carboxyethylethylenephenoxy-2 ' -pyridylme thane 4- -Carboxyethylethylphenoxy-2 ' -pyridylmethane 4-Carbatnylphenoxy-2 ' -pyridylmethane 4-Carbamylphenoxy-3' -pyridylmethane 4-Carbamylphenoxy- ' -pyridylmethane 4-Carboxyethyiphencxy~3' pyridylme thane 3- (6-Methyl )pyridoxy- ' -me thylphenylme thane 2-(6-Methyl)pyridoxy- ' -carboxyethylphenyl- The acids which can be used to prepare acid addition salts of the compounds of this invention are suitably those which produce, when combined with the free base, salts whose anions are pharmaceutically acceptable. Examples of such acid addition salts are those derived from inorganic acids such as hydrochloric, hydrobromic, nitrq phosphoric, and sulphuric acids and from organic acids such as acetic, citric, malic, tartaric and lactic acids. V/hen used in the form of its salt, the basic ether itself is the active portion of the molecule which produces the therapeutic effect, but by suitable choice of salt, the solubility, absorbtion or other properties of the compound may be varied .
The compounds of the present invention may be prepared by condensing a compound of formula (IV) with a compound of formula (V): (IV) B - (ALK)nOH HO - ( ALK ) m -Py (V) wherein n and m are either 0 or 1, provided n-m ^ 0 and wherein the symbols "ALK" and "By" are as defined with respect to formula (I) or (II), and the symbol B represents a group of formula (IA) or (IIA) (IA) (IIA) wherein R-^, Rg* R-j and ^ are as defined with reference to formula ( I) or ( II) .
The above condensation reaction may be effected with the aid of a condensing agent such as a carbodiimide (e.g. dicyclohexylcarbodiimide ) or a carbonyldiimidazole . Alternatively a halide (e.g. chloride or bromide) of the compound of formula (IV) or (V) may be reacted with a salt (e.g. the sodium or potassium salt) of the appropriate compound of formula (V) or (IV) respectively. Naturally it will be appreciated that it may be preferable to modify the sub-stituents in the phenyl or pyridyl rings after the coupling reaction rather than before. Thus, it is preferable, when preparing compounds of formula (I) or (II) wherein R-^ or any of the other substituents is an amide or carboxylic acid group, first to prepare the corresponding compound wherein R^ or the other substituents are carboxylic acid ester groups and then to convert such groups to carboxylic acid groups or amides or by conventional means. Further details of the overall preparation procedures used to prepare the compounds of this invention will become clear from the specific examples given below.
It has previously been mentioned that the compounds of this invention are hypoglycaemic agents and are thus useful in the preparation of pharmaceutical compositions for the treatment of diabetes mellitus. An added advantage of many- of the compounds of this invention is that they are also hypolipidaemic agents. Since raised serum cholesterol and triglyceride levels are often found in diabetic patients this hypolipidaemic action is desirable.
The dose-response characteristics of the compounds of this invention vary from compound to compound. The more active of the compounds which we have tested cause a lowering of blood-sugar levels in alloxanised mice and normal mice when administered at dosages ranging from >0 to 500 mg/kg. In mice, rats, guinea pigs and squirrel monkeys, the hypoglycaemic activity of the compounds generally lasts over a period of from 2 to 6 hours. In the case of the compound which we have investigated most fully (4-carbeth-oxyethylphenoxy-2 ' -pyridylmethane ) a suitable dosage range for a human being is from 0.5 to J>0 mg/kg/day, preferably about 5 mg/kg/day.
The compounds of this invention, especially 4-carboxyethylphenoxy-2 ' -pyridylmethane, have a different mode of action from the sulphonyl ureas since they do not cause insulin release. In common with the biguanides they inhibit glucose uptake from the small intestine but their effects on peripheral glucose utilisation are therapeutically more satisfactory. The preferred compounds are less likely to produce lactic acidosis than biguanides and are less likely to produce gastrointestinal irritation.
The following Examples illustrate the present invention: -4 EXAMPLE I The following Table gives details of the structure and hypoglycaemic activity of a representative number of compounds. The hypoglycaemic activity was measured in alloxanised mice and scored by measuring the fall in blood -sugar caused by a dose of 500 mg/kg administered intraperit-oneaily in carboxytnethyle llulose .
Score Key 2 = 15-2 ^ Details of the preparation of the compounds given in the table will be found in EXAMPLE 2 below.
- COMPOUND A ½-Carboxyeth-ylphenoxy-3' - -OCEL- ■oyridylmethane; ^ Hydrochloride 41825/2 EXAMPLE 2 a) . Preparation of 4-Carbethoxyphenoxyphenoxy-21 -pyridylmethane Phosphorus oxychloride (I5g) was added with stirring to 2-hydroxymethylpyridine (I7«5g) in ethyl acetate (80ml) at 0°C. The mixture was heated on a water bath for 1 hour and allowed to stand at room temperature for 5 hours. The solvent was distilled off under reduced pressure to give a residue which was dissolved in water and the solution made alkaline with aqueous sodium carbonate. The resulting oil was extracted into ether; the ether extracts were washed twice with water, dried over MgSO^, the solvent was removed by distillation and the residue fractionated to give 2-chloromethylpyridine (l4.5g; 71°/0)· Ethyl-4-hydroxybenzoate (19.6 g) in ethanol (100ml) followed by 2-chloromethylpyridine (15· g) was added to a solution of sodium (2.8g) in ethanol (100ml) and the mixture re-fluxed for 4 hours. On cooling, the NaC.l was filtered off and the solvent distilled off under reduced pressure to give a solid product which was recrystallised from ethanol. This was 4-carboxyethylphenoxy-2' -pyridylmethane (l6.7g; 55$)· .p 78°C.
I.R. Vmax (KBr) 2991, 1710, 1270, 768 cm"1.
N.M.R. 1.37 d. (J. 4 Hz., 1 aromatic proton); 1.9-3. M. ( 7 x aromatic proton); 4.75 8. (_¾); 5.65 q (J. 8 Hz., -OCH^CH^); 8.64 t (J. 8HZ. , 0-CH2CH3) in CDCl-j.
Following the above procedure (i.e. reaction of the sodium salt of the appropriate pyridine derivative with the chloride of the appropriate hydroxybenzoate, compounds 1, 2, 3, 41825/2 4, 5, 6, 7, 8, 9, 10, 11, 15, β, 18, 20, 22, 25, 26, 28, 3 and 42 were prepared. Elemental analyses, infra-red spectra, proton magnetic resonance spectra confirmed the structures. b ) . Preparation of 4-Carboxyphenoxy-2' -pyrldylme thane 4-Carboxyethylphenoxy-2' -pyridylme thane (2g) was refluxed with 20% aqueous sodium hydroxide (50ml) for 4 hours. The solution was cooled, acidified with glacial acetic acid and the precipitated solid filtered off. It was then dried and recrystallised from ethanol to give 1.6g (90$) of 4-carboxy-phenoxy-2' -pyridylmethane . .pt 2l4°C.
I..R. Vmax (KBr) 1690, 1600, 1260, 768 cm"1.
N. .R. T :- 1.4 d. (J. 4 Hz., 1 aromatic proton) . 2-3 M.- (7 * aromatic proton). 4.75 S (CH?) in (CD,)?S0.
Following the above procedure (i.e. alkaline hydrolysi of the appropriate ethyl ester), the following compounds were prepared:- 19, 24, 2 , and 27· Again elemental analysis, infra-red spectra and proton magnetic resonance spectra confirmed the structures. c). Preparation of ?-(6-Methyl )pyridoxy-4-tolylmethane . 3-Hydroxy-6-methylpyridine (5«5g) in ethanol (150ml) followed by p-ethylbenzyl chloride (7.1g) was added to a solution of sodium (1.2g) in ethanol and the mixture refluxed for 5 hours.. After cooling the sodium chloride was filtered off and the solvent distilled off under reduced pressure to give g-ive 4.6g (42$) of ^-(e-methylJpyridoxy-^-tolylmethane, ra.pt 71°C." I.R. Vmax (KBr) 2920, 1255, 1010, 810 cm"1.
N.M.R. T :- 1.75 d. (J. 3 Hz. , 1 aromatic proton); 2.58-2.97 . (6 x aromatic proton); 4.88 S. '(CHg); 5.60 q. (J. 8 HZ., -0CH2CH3); 7.50 3. (CHj) 8.62 t. (J. 8 Hz. , O-CHg-CH..) in CDCl^.
Following the above procedure compounds $ ~ 6 and 37 were prepared. Infra-red spectra, proton magnetic resonance spectra and elemental analyses confirmed the structures. ) . 4-Carbamylphenoxy-2t -pyridylmethane hydrochloride 4-Hydroxybenzamide (Ι3·7δ) were dissolved in 150 mis of isopropyl alcohol containing 2.3g sodium at 60°C. l4g of 2-picolyl chloride was added to the solution and the mixture left for 5 hours at 100°C. The solvent was then distilled off and the residue dissolved in ethanol., The insoluble material was filtered off and the alcohol evaporated. The residue was then dissolved in 2N HC1 and the solution decolourised with charcoal. The solution was evaporated to dryness and the residue recrystallised twice from ethanol.
This gave 17.8g (67.5$) of required compound, m.pt 208°-210°C.
Following the above procedure, compounds 30 and 31 were prepared. Elemental analysis, infra-red spectra and proton magnetic resonance spectra confirmed the structures. ■ 41825/2 e ) . -Carbonylhydrazinophenoxy-2 ' -joyridylmethane 4-Carboxyethylphenoxy-2' -pyridylmethane (.3 g) and hydrazine hydrate (10 ml) were refluxed together in ethanol (20 ml). The hot solution was filtered, allowed to cool and the solid which crystallised out was filtered off, dried and recrystallised from ethanol. This gave 2.00 g (71#) 4-Carbonylhydrazinophenoxy-2' -pyridylmethane.
M.P.T. 185-186°C.
I.R ■ (KBr) 3360, 1620, 1600, 760 cm"1.
N.M.R. T:- 0.4 S.(NH), 1.37 d. (J. 4 Hz., 1 aromatic proton). 2.1-3 M. (7 x aromatic proton); 4.75 S (CH2); 5.55 S.
(NH2) in (CD5)230. f). 4-(l- [ 3, 5-Dimethylpyrazole] ) carbonylphenoxy-2 ' - pyrldylmethane · -Carbonylhydrazinophenoxy-2 ' -pyridylmethane (3.58 g) and acetylacetone (1.5 ml) were refluxed together in ethanol (100 ml) for 3 hours. The solvent was evaporated to dryness and the product recrystallised from petroleum ether (βθ-8θ) . This gave 1.26 g (28$) 4-( 1-[ 3, 5-Dimethylpyrazole ] ) carbonylphenoxy-21 -pyridylmethane .
M.P.T. 106°C.
I.R. (KBr) 1700, 1345, 926, 758 cm"1.
N.M.R. T 1.4-3.07 M. (8 x aromatic proton); 3.98 S. (CH); . 4.74 S. (CH2); 7.4 S. (CH-j); 7.80 S. (CH5) in CDCl-j.
S ) · 4- (Ethoxyhippuryloxy )- ' -pyrldylmethane Glycine hylester hydrochloride (2-50 g) was suspended in dichloromethane (75 ml)* trlethylamine (3· ml) added and the mixture stirred for 5 minutes. The reaction mixture was filtered and 4-carboxyphenoxy-2' -pyridylmethan (5· 70 g) and dicyclohexylcarbodiimide (5-10 g) added to the filtrate. The reaction mixture was stirred at room temperature for 16 hours. The insoluble material was filtered off, the solvent evaporated to dryness and the product recrystallised from ethanol. This gave 3·5 g ( 9$) 4-(Ethoxyhippuryloxy)-2* -pyridylmethane .
M.P.T. 107-108°C.
I.R. Vmax (KBr) 3275 » 2900, 1740, 1500, 855, 772 cm"1.
N.M.R. T:- 1.35-3 M. (8 x aromatic proton); 4.75 S. (CH2); 5.87 ¾. (J. 8 Hz., 0-CH2-CH5); NH overlapped in q a 5.87 T; 6.72 S (CHg); 8.8 t. (J. 8 Hz., 0-QH2CH5) in (CD.'5)2S0. h) . 3-(6-Methyl)-pyridoxy-4 ' -carboxyeth l phenylme hane Ethyl-p-toluate (23.68 g), N-bromosuccinimide and -azobutyronitrile (0.05 g) were refluxed together in carbon-tetrachloride for 2 hours. The reaction mixture was cooled, the solid filtered off and the solvent evaporated to give p-carboxyethylbenzylbromide (36.05 g). p-Carboxyethylbenzylbromid (13·7 g) was added to a solution of 3-hydroxy-6-methylpyridine (6.2 g) in ethanol. (130 ml) containing sodium (1.3 g). The solution was refluxed for 3 hours, cooled, the sodium chloride filtered off, the solvent evaporated to dryness and the product recrystallised from petroleum ether (60-80). This gave 8.4 g 1 ) · 1- ( -Meth lbenzyloxy) -2- (2"-pyridyl)ethane 2- ( 2-Hydroxy thyl ) pyridine (13 g) were dissolved in methane (50 mis) containing sodium (2.3 g) and the solution evaporated to dryness under vacuum. The resulting sodium salt was suspended in toluene 50 mis and -bromo-p- (24 g) was added, and the mixture leveled at 100°C. for 5 hours. The solution was cooled, the which filtered off and the solvent removed under vacuum. The residue was dissolved in 2N HCl and extracted with ethyl acetate. The aqueous layer was made alkaline with potassium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried so the solvent removed and the residue distilled under vacuum.
This gave 3 g (l .8$) of title compound.
BPT. 115-ll8°C /0.15mins. 41825/2 I.R.- Vmax (KBrj 2860, 1595, 1095, 805, 755 cm"1.
JS.M.R. T :- 1.52 d. (J. 4 Hz., 1 aromatic proton) 2.4-3.1 M (7 x aromatic proton); 5.55 S ((¾); 6.15 (J. 7 Hz - CH2-CH 6.9 t. (J. 7 Hz - CH2CH2-); 7.75 S. (CH^) in CDC1.
Elemental analysis.
Theoretical ■ 79.29$ C 7.48$ H 6.17$ N Found 78.62$ C · 7.40$ H 5.60$ N Found 78.46$ C 7.59$ H 5.97$ N Following the above procedure, compounds 12 and 14 were prepared. Elemental analysis, infra-red spectra and proton magnetic resonance spectra confirmed the structures.
J ) . 4-Methylphenoxy-2' -pyridylmethane N-Oxide Hydrochloride 4-Methylphenoxy-2'-pyridylme han (5 g) was suspended in acetic acid (10 mis) and 30 hydrogen peroxide (3·8 mis).
The solution was heated at 70°C for 24 hours. After cooling the solid was filtered off, washed with acetic acid and re-crystallised from ethanol by addition of ether. This gave 5.5 g (87$) of the title compound m.pt 126-127. k). -Methylphenoxy-l ' -methylenecarbethoxy pyridinium-21 - ylmethane bromide.
-Methylphenoxy-2 ' -pyridyl e thane (1.9 g) and ethyl bromoacetate (1.7 g) were heated at 80°C for hours in nitropropane (20 mis). The solution was then cooled and filtered, the solid washed with ether and dried in vacuu to give 2.3 g (655Q of title compound, m.pt l87-192°C.
From the list of compounds in the Table in Example 1 a number were selected for examination of hypoglycaemic activity in normal mice, the compound being administered by the oral and intraperitoneal routes, and toxicity studies. The compounds examined in this way were nos. 2, > , 6, 8, 11, 16, 19, 20, 21, 32, 38 and 42.
After examination of the results achieved with these compounds, compound no. 21 (4-carboxyethylphenoxy-2 ' -pyridyl-methane) was chosen for further evaluation. The compound is notable for its low order of oral toxicity, but useful hypoglycaemic activity at low doses, i.e. the compound has a very good therapeutic ratio. Further biological data for the compound is given in the Table below.
Key 0 = Oral IP - Intraperitoneal

Claims (1)

1. ¾ ■ , ' 41825/5 Claims: · l). Λ pharmaceutical composition for the treatment of hypetglycaemia comprising a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers: (I) (ID in which formulae "Py" represents an unsubstit ted or (lower plkyl) -subst itut e i 2- , ';- or 4- yrid l gro up ; "A" represent s a gro ur> of for inula ( IIIA ) (IIIB) or (IIIC) ALK-0 · O-AL - -{- ALK-O-ALK}— • (IIIA) ' (IIIB) . (IIIC) wherein "ALK" represents a straight or branched chain alkylene group having from 1 to 6 carbon atoms; represents a carboxylic acid group or salt, ester, or amide of a carboxylic acid group, a carboxylic acyl, alkyl, alkenyl, alkynyl group or an alkyl, alkenyl or alkynyl group which carries a hydroxy, esterified hydroxy or carboxylic acid substituent, or salt, ester, or amide of a carboxylic acid substituent; R , ' and R^ each separately represent hydrogen, lower alkyl, lower alkoxy group or halogen. •5 41825/2 2), Λ pharmaceutical composition as claimed in claim 1 comprising a compound of formula (VI) or a pharmaceutically acceptable acid addition salt thereof and one or more pharmaceutically acceptable carriers: wherein Py represents a 2-, 3- or ^i-pyridyl group which is unsubstituted or is substituted n the meta-or-para-position (relative to the Py - A bond) by . *an alkyl group having an odd number of carbon atoms, • ;—— - A represents a group of formula (IIIA), (IIIB) or (IIIC). 4.0-ALK - -ΑΙ. -0 · - ALK-.0-ALK ~j- (IIIA) (IIIB) (Ilia) wherein ALK represents a straight chain alkyl group of from 1 to 6 oarbon atoms (especially 1 to 3 carbon atoms) and Ra (and B0 separatel represent hydrogen or carboxyl1 groups , or salt, ester or amide derivatives of carboxyl groups i or alkyl groups having an odd number of carbon atoms or alkyl groups having an even number of carbon atoms and carrying carboxyl . substituents or salt, ester or amide substit-. uents, at least one of R^ and not being hydrogen. 3). A pharmaceutical composition as claimed In claim 1 comprising as active ingredient one of the following compounds or a pharmaceutically acceptable acid addition salt thereofs- 41825/2 -Meth Iphenox -51 -pyrid lmethane . 4-n-Propylphenoxy-2 ' -pyridylme hane 4-Methylbenzyloxy- 1 -pyridylethane , l-(4-Methy.lbenzyloxy -(2' ~pyridyl)n-propane ■ 4-Hydroxymethyl-phenoxy-2' -pyi-idylmethane 4) < compr pyrid or a pharmaceutically acceptable acid ' addition salt thereof.. 5) . A pharmaceutical composition as claimed in any one of the preceding claims which is in unit dosage form. 6) . A pharmaceutical composition as claimed in olalm 4 which is in unit dosage form, each dosage unit containing from 0.1 to 20 mg of 4¾thoxyc:aiixnyliphenoxy-2 ' -pyridylmethane, or, if an acid addition salt of said compound is present, the equivalent 0f from o.l to 20 mg of said compound. ' 7) . A oompound of formul (I) or formula (II) or an acid addition sal thereof: 41825/5 in which formula "py" represents an unsubstituted or (lower alkyl) -substituted 2-, 3- or 4-pyridyl group; "A" represents a group of formula (IIIA) , (IIIB) or (IIIC) . 4- ALK-0 - -f- O-ALK - - -ALK-O-ALK (IIIA) (IIIB) (IIIC) wherein "ALK" represents a straight or branched chain alkylene group having from 1 to 6 carbon atoms; represents a carboxylic acid group or salt, ester, or amide of a carboxylic acid group, a carboxylic acyl, alkyl, alkenyl, alkynyl group or an alkyl, alkenyl or alkynyl group which carries a hydroxy, esterified hydroxy or carboxylic acid substituent, or salt, ester, or amide of a carboxylic acid substituent; R2, and R^ each separately represent hydrogen, lower alkyl, lower alkoxy or halogen, provided that is not methyl, cyano or methoxycarbonyl when "Py" is 2-pyridyl or 5-ethylpyrid-2-yl and A is -fO-Ciy- and R^, and are hydrogen or halogen. 8. A compound of formula (VI) or an acid addition salt thereof :- 41825/2 wherein Py. represents a 2-, 5- or -pyridyl group which Is unsubstituted or is substituted in the meta-or-para-position (relative to the Pjr - A bond) by an alkyl group having an off number of carbon atoms ; A represents a group of formula (IIIA), (IIIB) or (IIIC). _f. Ο-Al-K-l·- -{-ALK-O-}- -ξ- ALK-O-ALK (IIIA) (IIIB) (IIIC) wherein ALK represents a straight cfrain alkyl group of from 1 to 6 carbon atoms (especially 1 to 3 carbon atoms) and R a and R^ separately represent hydrogen or carboxyl groups or salt, ester or amide derivatives of carboxyl groups or alkyl groups having an odd number of carbon atoms or alkyl groups having an even number of carbon atoms and carrying carboxyl isubstituents or salt, ester or amide substituents , at least one of R and R, not being hydrogen, provided that when Py is 2-pyridyl or 5-ethylpyrid-2-yl and A is [0-CHp], neither R nor R, is methyl or methoxyqarbonyl. 9). Λ compound selected from the group consisting of ^- ethylphenoxy-J' -pyridylmethane 4-n-Propylphenoxy-2 ' -pyridylm hane 4-Methylbenzyloxy~21 -pyridylethane l-^-MethylbenzyloxyJ-jS-^'-pyridylJn-propane 4-IIydroxymethylphenoxy-21 -pyridylmethane 4-Carboxyphenoxy-2 ' -pyridylme hane 4-Carboxymethylphenoxy-21 -pyridylmethane 4-Carboxyethylethylenephenoxy-2 ' -pyridylmethane 4-P-Carboxyethylethylphenoxy-2 ' -pyridylmethane 4-Carbamylphenoxy- 1 -pyridylmethane -Carbamylphenoxy-5' -pyridylmethane 4-Carbamylpiienoxy-4 ' -pyridylme hane 4-Carboxyethylphenoxy-j5' -pyridylmethane 3- ( 6-Methyl)pyridoxy-4 ' -methylphenylmethane 3-(6-Methyl )pyridoxy-4 ' -carboxye hylphenylrnethane and acid addition salts thereof. 10). The compound 4-ethoxycarbonylphenoxy-2 ' -pyridylmethane formula: and acid addition salts thereof. 11). A process for the preparation of a compound of formula (I) or (II) (lower alkyl)-substitut ed 2-, 3- or 4-pyridyl group "A" represents a group of formula (IIIA), (IIIB) or (IIIC). 4- ALK-0 - -f- 0-ALK 4- -f-ALK-O-ALK- - 41825/4^ wherein "ALK" represents a straight or branched chain -,^. alkylene group having from 1 to 6 carbon atoms; R^ represents a carboxylic acid group or salt, ester, or amide of a carboxylic acid group, a carboxylic acyl, alkyl, alkenyl, alkynyl group or an alkyl, alkenyl or alkynyl group which carries a hydroxy, esterified hydroxy or carboxylic acid substituent, or salt, ester, or amide of a carboxylic acid substituent; , R3 and R4 each separately represent hydrogen, lower alkyl, lower alkoxy or halogen, provided that R-^ is not methyl, cyano or rr.ethoxycarbonyl when "Py" Is 2-pyrIdyl or 5-ethylpyrid-2-yl and A is -fO-CHg^- and R^, R^ and R^ are hydrnren or halogen; which process comprises condensing a compound of formula (IV) with a compound of formula (V) B - (ALK) - OH HO - (ALK) - Py n m (IV) (v) wherein n and m are either 0 or 1 provided n + m 0 and wherein "ALK" and "Py" are as defined with respect to formula (I) or (II) and the symbol B represents a group of formula (LA) or (IIA) 41825/2 wherein R^, R2, R and are as defined with reference to formula (I) or (II). 12) . A process as claimed in claim 11 wherein the condensing step is effected by the use of a carbodiimide or carbonyldiimidazole . 13) . A process as claimed in claim 1-1 wherein a halide of a compound of formula (IV) or (V) is reacted with a 'salt of the appropriate compound of formula (V) or (IV) respectively. 1* . A process as claimed in claim 1 wherein a chXoride or bromide of a compound of formula (IV) or (V) is reacted wi.th a sodium or potassium salt of a compound of formula (V) o (IV) respectively. D/rb
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