IE50012B1 - Heterocyclic compounds having fungicidal herbicidal and plant-growth regulating properties - Google Patents

Description

Tbe present invention relates to heterocyclic compounds, to a process for their preparation, ana to biologically-active compositions containing them.

An article hy Carelli et al it "aruaco (Pavia) Ed. Sci. vol.

It pages 375—Si (1961) discloses that certain H-aeyl derivatives of N-pyridylmettylariline have pharmaceutical properties. US Patent 4,082,851 relates to compounds again having pharmaceutical properties, in this case to certain'benzyiaminoheterocyclic compound substituted hy an SOgHEg group.

It has nov been found that certain novel K-acyl derivatives of heterocyclic compounds have useful fungicidal, herbicidal and plant-growth regulating properties.

The present invention provides a compound of the general H - CE - R |3 *4 (I) . . in which one of R and R represents an optionally-substituted S-menbered heteroarcmatic ring containing 1 or 2 nitrogen atoms, 2 and the other of R and R also represents such a ring or represents an optionally-substituted phenyl group; R^ represents an acyl group derived from a carboxylic acid; and K represents a hydrogen atom or an alkyl group having from 1 to fe carbon atoms; or an acid addition' salt, N-oxide or metal salt complex thereof; provided that if γΛ represents an optionally substituted pyridyl group, must represent an optionally subs' ed heteroaromatie ring; if ΐ.~ represents an optionally substituted phenj’l group, must represent an aeyl group derived from ar. acid other then an optionally substituted benzoic acid; if R^ represents an 2 unsubstituted phenyl group, R represents an unsubstituted 2- or 5 3-pyridyl group and R^ represents a group of formula CB^CO-, CpH^CO-, (phenyl)?CH.CO- or phenyl.CB"CE.CO-, then R*1 must represent an alkyl group; if R2 represents a phenyl group substituted by an SO^Jic, group, R must represent an alkyl group; . 1 2 2 and if both of R and F. represent optionally-substituted pyridyl groups, neither of these groups is substituted by an amino, acylamino, alkylamino, or dialkylamino group.

Unless otherwise stated, any aliphatic moiety present in R1, 3 E or R preferably has up to 6, more preferably up to 4, carbon atoms.

The acyl group represented by R^ may for example be a formyl group, an alioxycarbonylcarbonyl group or an optionally substituted alkanoyl, alkenoyl, cycloalkancyl cr aroyl group.

Most preferably ? is derived from an aliphatic or cycloaliphatic acid.

Suitable substituents which may be present in an alkanoyl or alkenoyl group which is substituted include halogen atoms and alkoxy, phenyl, phenoxy, carboxy and alkoxycarbonyl groups. Preferably the group is unsubstituted or substituted by up to 3 halogen atoms or by a phenyl, phenoxy, C(l-4) alkoxy, especially methoxy, methoxycarbonyl or ethoxyearbonyl group. Especially preferred alkanoyl and alkenoyl groups are unsubstituted groups having up to 6 carbon atoms in the alkyl or alkenyl moiety.

Alkanoyl groups are preferred, and a tertiary butylcarbocyl group is especially preferred. jo Suitable optionally substituted cycloalkanoyl groups include those having 3 to 6 carbon atoms in the ring, especially cyclopr opylcarbonyl and cyclohexylcarbonyl groups. Suitable substituents include halogen atoms and alkyl groups, especially methyl groups. Thus en optionally substituted cycloalkanoyl group may for example be a cyclopropylcarbonyl, l-methylcyclopropyicarbonyl, 2,2diehlcrc-3,3-dimethyieyclopropylcarbcryi or cyclohexylcarbonyl group. 500 12 An optionally substituted aroyl group is preferably an optionally substituted benzoyl group. Preferred substituents which may be present in the phenyl ring are the same preferred 1 2 substituents described below for a phenyl ring R or R .

An alkoxycarbonylcarbonyl group suitably has free 1 tc £ carbon atoms in tbe alkoxy moiety, for example, a CgE^.O.CO.COgroup or a CH-.O.CO.CO- group. a 3 Thus typical groups R uill include formyl, alkanoyl, for example t-butylcarbonyl or 2,2-dimethylpropylcarbonyl, alkoxyalkanoyl, for example metboxymethylcarbonyl, cycloalkanoyl, for exanple cyclopropylearbonyl, alkyl cycloalkanoyl, for example 1methylcyclopropylcarbonyl, and optionally substituted aroyl, for example benxoyl optionally substituted by an elkyl group having 1 to 4 carbon atoms or by a halogen atom.

Preferably R represents a methyl group or, especially, a hydrogen atom. 2 A heteroaromatic ring represented by R or R may be an optionally substituted pyrimidinyl, pyridazinyl or, preferably pyridyl or pyrazinyl ring, end a heteroaromatic or phenyl ring 12 represented by R or R nay be unsubstituted cr substituted. A heteroaronatic ring is preferably unsubstituted and a phenyl ring is preferably mono- or di- substituted. A ring may for example be substituted by one or more of the same or different substituents selected from halogen atoms and nitro, alkyl, haloalkyl, hydroxyallyl, alkoxy, halo alkoxy, hydroxyalkoxy and hydroxy groups, as well es cyano, alkylsulphonyl, alkylcarbonyl, alkoxycarbonyl, carboxy and alkylthio groups. Preferably it is unsubstituted or substituted by one or two of the same or different substituents selected from halogen atoms and alkyl, alkoxy and nitro groups.

Most preferably, it is unsubstituted or substituted hy a halogen atom, especially a fluorine or chlorine atom, or an elkyl group, for example a methyl group, or disuhstituted hy halogen, especially fluorine or chlorine, atoms, and/or alkyl, especially methyl, groups. 2 If one or both of R and R represent a pyridyl ring, this 3 4 ring is preferably bound to the MB .CER moiety of the molecule in a 3-position relative to the ring nitrogen atom. One preferred group of compounds for use in the process of the invention is that in which R^ represents an optionally substituted phenyl group aac R^ represents an optionally substituted pyridyl group, especially a 3-pyridyl group. Such compounds have especially useful fungicidal activity.

A second preferred group of compounds is that in which R^ Λ represents an optionally substituted pyrazinyl group and R represents an optionally substituted phenyl group. Such compounds have especially useful plant growth regulating effects. In such a compound, the pyrazinyl group is preferably unsubstituted and the phenyl group is preferably unsubstituted or substituted by one or more, preferably one or two, of the preferred substituents listed above. Especially preferred is the compound of the general · 2 formula I xn which R represents a pyrazinyl group, R represents a 1-ehlorophenyl group, R^ represents a t-butylearbonyl group and It ....

R represents a hydrogen atom; or an acid addition salt, K-oxide or metal salt complex thereof.

Compounds of the general formula I form H-oxides; acid addition salts with ecids, for exanple mineral acids such as sulphuric or hydrochloric acid or organic acids such as citric or tartaric acid; and complexes with metal salts, for example complexes of the compound of the general formula I with a salt, for example a halide, of calcium, copper or iron, in the ratio of 2:1, 1:1 or 1:2. Such derivatives form part of the present invention, and the derivatives may he prepared from compounds of the general formula I hy methods analogous to known methods.

The compounds of the invention may he used to combat fungus, especially barley powdery mildew. Further, they may be used to combat and/or regulate the growth of plants as a result of their herbicidal and plant growth regulating properties. A method of combating fungus and/or combating or regulating plant growth hy means of these compounds is claimed in Patent Specification No. 50011 , out of which this present application has been divided.

The invention also provides a process for the preparation of a novel compound according to the invention, which comprises acylating a compound of the general formula R - HE - CH - Rc (II) S 0 0 1 2 - 7 1 2 A in vbich R , R and R have the meanings given for the novel compounds of the general fonnula I, using a suitable acylating agent.

Any suitable acylating agent, for example a carboxylic acid or an acid anhydride or, preferably, acid halide, derived from a carboxylic acid, may be used. Acid chlorides are especially suitable, and the reaction is then preferably carried out in the presence of an acid binding agent, which may be an organic or inorganic base. Organic amines, for example triethylamine, are especially suitable acid-binding agents. The reaction is preferably carried out in the presence of an inert solvent, for example a hydrocarbon such as benzene, at a temperature in the range of from 50 to 150°C, preferably 60 to 100°C. The reaction is conveniently carried out under reflux.

The compound of the general foraula II may for example be prepared by reduction of a compound of the general formula r - κ = c - ?, (iii) . 12k . . in which R , R and R have the meanings given for the novel compounds of the general formula I. The reduction may for example be carried out using gaseous hydrogen and a catalyst, or using formic acid. When formic acid is used the reaction conditions may be chosen such that at least some of the compound of the general fonnula II produced is formylated in situ, thus directly producing a compound of the general formula I in which RJ represents a formyl group starting from a compound of the general formula III.

The compound of the general formula III may be prepared hy methods analogous to methods known in the art, for example by npnpl i ng a compound of the general formula R4jH_ with a compound k 4 oT the general formula R COR .

The method of comhating or regulating plant growth claimed in Patent Specification No. 5Ooil is suitably carried out using a 012 - 8 composition which comprises the active compound together vith a suitable carrier. The invention therefore also provides a biologically active composition vhich comprises a novel conpound according to the invention together vith a suitable carrier. Preferably the amount of active ingredient in tbe composition is in the range of from 0.03 to 95% by veight of the composition.

A carrier in a composition according to the invention is eny material vith vhich the active ingredient is formulated to facilitate application to the locus to be treated, vhich may for example be a plant, seed or soil, or to facilitate storage, transport or handling. A carrier may be a solid or a liquid, including a material vhich is normal ly gaseous but vhich has been compressed to form a liquid, and any of the carriers normally used in formulating agricultural compositions may be used.

Suitable solid carriers include natural and synthetic clays end silicates, for example natural silicas such as diatomaceous earths; magnesium silicates, for example talcs; magnesium aluminium silicates, for example attapulgites and vermiculites; aluminium silicates, for example kaolinites, montmorillonites and micas; calcium carbonate; calcium sulphate; synthetic hydrated silicon oxides and synthetic calcium or aluminium silicates; elements, for example carbon and sulphur; natural and synthetic resins, for example coumarone resins, polyvinyl chloride, and styrene polymers and copolymers; solid polychloropheDOls; bitumen; vaxes, for example beesvax, paraffin wax, and chlorinated mineral vsxes; and solid fertilisers, for example superphosphates.

Suitable liquid carriers include vater; alcohols, for example isopropanol and glycols; ketones, for exanple acetone, methyl ethyl ketone, methyl isobutyl ketone and cyclohexanone; ethers; aromatic or araliphatic hydrocarbons, for exanple benzene, toluene and xylene; petroleum fractions, for exanple kerosine and light mineral oils; chlorinated hydrocarbons, for example carbon tetrachloride, perchloroethylene and tri chloroethane. Mixtures of different liquids are often suitable.

Agricultural compositions are often formulated and transported in a concentrated form vhich is subsequently diluted by the user before application. Tbe presence of small amounts cf a carrier which is a surface-active agent facilitates this process of dilution.

A surface-active agent may be an emulsifying agent, a dispersing agent or a vetting agent; it may be nonionic or ionic. Examples of suitable surface-active agents include the sodium or calcium salts of polyacrylic acids aDd lignin sulpKonic acids; the condensation products of fatty acids or aliphatic amines or amides containing at least 12 carbon atoms‘in the molecule with ethylene oxide and/or propylene oxide; fatty ecid esters of glycerol, sorbitan, sucrose or pentaerythritol; condensates of these with ethylene oxide and/or propylene oxide; condensation products of fatty alcohol or alkyl phenols, for example poctylphenol or p-octylcresol, with ethylene oxide and/or propylene oxide; sulphates or sulphonates of these condensation products; alkali or alkaline earth metal salts, preferably sodium salts, of sulphuric or sulphonic acid esters containing at leest 10 carbon atoms in the molecule, for example sodium lauryl sulphate, sodium secondary alkyl sulphates, sodium salts of sulphonated castor oil, and sodium alkylaryl sulphonates such as sodium dodecylbenzene sulphonate; and polymers of ethylene oxide and copolymers of ethylene oxide and propylene oxide.

The compositions of the invention may for example be formulated as wettable powders, dusts, granules, solutions,· emulsifiable concentrates, emulsions, suspension concentrates and aerosols. Wettable powders usually contain 25, 50 and 75? w of active ingredient and usually contain, in addition to solid inert carrier, 3-10? w of a dispersing agent and, where necessary, 010? w of stabiliser(s) and/or other additives such as penetrants or stickers. Dusts are usually formulated as a aust concentrate having a similar compositions to that of a wettable powder but without a dispersant, and are diluted in the field with further solid carrier to give a composition usually containing 2-10? w of active ingredient. Granules are usually prepared to have a size between 10 and.100 335 mesh {1.676 - 0.152 mm), and may be manufactured by agglomeration or impregnation techniques. Generally, - 10 granules will contain j-25? w active ingredient and 0-10? w of additives such as stabilisers, slow release modifiers and binding agents. Emulsifiable concentrates usually contain, in addition to a solvent and, when necessary, co-solvent, 10-50? w/v active ingredient, 2-20' w/v emulsifiers and 0-20' w/v of other additives such as stabilisers, penetrants and corrosion inhibitors. Suspension concentrates are usually compounded so as to obtain a stable, non-sedimenting flowable product and usually contain 1075? v active ingredient, 0.5-15? w of dispersing agents, 0.1-10? v of suspending agents such as protective colloids and thixotropic agents, 0-10? w of other additives such as defoamers, corrosion inhibitors, stabilisers, penetrants and stickers, and water or an organic liquid in which the active ingredient is substantially insoluble; certain organic solids or inorganic salts may be present dissolved in the formulation to assist in preventing sedimentation or as anti-freeze agents for water.

Aqueous dispersions and emulsions, for example compositions obtained by diluting a wettable powder or a concentrate according to the invention with water, also lie within the scope of the present invention. The said emulsions may be of the water-in—oil or of the oil-in-vater type, and may have a thick 'mayonnaise’like consistency.

The compositions of the invention may also contain other ingredients, for example, other compounds possessing insecticidal herbicidal, plant growth regulating or fungicidal properties.

The following Examples illustrate the invention.

Example 1 H-t-butylcarbonyl-3-( 3' -pyTidylmethyl)aw'nopyridine (a) To a solution of 3-(3'-pyridylimincmethyl)pyridine (18.3 g, 0.1 mole) in dry toluene (50 ml) was added formic acid (98?, .8 g), .and the mixture was stirred and heated under reflux for 16 hours. Toluene and formic acid were removed in vacuo, and to the residue was added 10? HCl (100 ml) and toluene (100 ml).

After shaking, the aqueous layer was separated and made alkaline by tbe addition of a concentrated aqueous solution of KDE. The product was extracted into methylene chloride, and the extracts - 11 dried (KgSO^). After removal of solvent the product vas purified ty column chromatography (neutral alumina/5% methanol in diethyl ether) and distillation. The pure 3-(3'-pyridylmethyl)aminopyridine was obtained in 27% yield as a colourless material, boiling point 176-170°C at pressure 1 mm Hg, melting point 6669°t.

Analysis C Η H Calculated for »3^!!^ 71.35 5-95 22.7% Found 71.7- 6.3 23.0% (7>) To * stirred solution of 3-(3*-pyridylaethyl)aminopyridine (3-7 6> 0.02 mole) in dry benzene (50 ml) was added a solution of trimethylacetylchloride (2.8 g, 0.02b mole) in dry benzene (15 ml) followed by a solution of dry triethylamine (2.6 g, 0.02b mole) in dry benzene (10 ml). The mixture vas stirred and heated under reflux for 7 hours. After cooling, the reaction mixture was washed 3 times with water and dried (MgSO^). Solvent was removed in vacuo and the residue was chromatographed on neutral alumina, eluting with 5% methanol in diethyl ether. K-t-butylcarbonyl-3(3'-pyridylmethyl)-aminopyridine was thus obtained in 65% yield as a colourless solid, melting point 69-70°C.

Analysis C Η N Calculated for HgOC^H^ 71.38 7.06 15.61% Found 71.1 7.5 15.6% Examcle 2 y-henzoyl-b-fluoro-H-( 3 '-pyridylmetbyl )aniline (a) To a solution of 3-(b'-fluorophenyiiminomethyl)pyridiae (67.Ο g, 0.335 mole) in dry toluene (200 ml) was added formic acid (96%, 36.18 g), and the mixture was stirred and heated under reflux for 20 hours. Toluene and formic acid were removed in vacuo, and to the residue was added 10% HCl (120 ml). After extracting with toluene, the aqueous layer was separated and made alkaline by the addition of a concentrated aqueous solution of potassium hydroxide. The product was extracted into diethyl ether, and +he extracts dried (MgSO^). After removal of solvent, tjie residue was subjected to column chromatography (neutral 500 12 - 12 alumir.a/diethyl ether). The pure 4_fiuoro-N-(3'-pyridylmethyl)aniline was obtained in 10? yield as a colourless solid, melting point 85-87°C.

Analysis Calculated for N-FC.-R.. 12 xl C 71.29 71.2 H .45 -8 H 13.86? 14.0? Found (b) To a stirred solution of 4-fiuoro-N-{3'-pyridylmethyl)aniline (3-03 g, 0.015 mole) in dry benzene (50 ml) was added a solution of benzoyl chloride (2.4 g, 0.017 mole) in dry benzene (15 ml) followed by a solution of dry triethylamine (1.8 g, 0.018 mole) in dry benzene (10 ml). The mixture was stirred and heated under reflux for 16 hours. After cooling, the reaction mixture was vashed with water (X3) and dried (MgSO^). Solvent was removed in vacuo, and the residue triturated vith a little ether. The solid product was filtered off, washed with a little ether and dried.

Tne yield of pure K-benzoyl-4-fluoro-N-(3'-pyridylEethyl)aniliae thus obtained was 89?. Melting poiDt l62-l63°C.

Analysis C Η H Calculated for l^OFC^H,^ 74.51 4.90 9.15% Found 74.4 4.8 9.1% Example 3 K-t-butylcarbonyl-K- (4 ’ -chloronhenylmethyl)aainonyrazine (a) To a suspension of 4-chloro-(pyrazineiminamethyl)beczene (21.75 g, 0.1 mole) in dry toluene (50 ml) was added formic acid (98%, 10.8 g), and the mixture was stirred and heated under reflux for 16 hours. Toluene and formic acid were removed in vacuo, and to the residue was added 10? HCI (100 ml). After extracting vith 100 ml toluene, the aqueous layer was separated and made alkaline hy the addition of a concentrated aqueous solution of KOH. The product was extracted into diethyl ether, and the extracts dried (MgSO^). After removal of solvent, the produot was purified by column chromatography (neutral alumina/ diethyl ether). The pure H-(4'-chlorophenylaethylJaminopyrazine was obtained in 27? yield as a colourless material, melting point 86-87°C.

Analysis Calculated for N^CIC^H.^ Fouad C 60.l4 60.4 H 4.56 4.8 li Cl 19.13 16.17? 19.2 16.0? (h) To a stirred solution of K-(4'-chlorophenylmethyl)eminopyrazine (2.2 g, 0.01 sole) in dry benzene (30 ml) vas added a solution of trimethylacetylchloride (1.4 g, 0.012 mole) in dry benzene (10 ml) followed by a solution of dry triethylamine (1.3 g, 0.013 mole) in dry benzene (10 ml). The mixture was stirred end heated under reflux for 22 hours. After cooling, the reaction mixture was washed three times with water and dried (MgSO^).

Solvent vas removed in vacuo and the residue was subjected to column chromatography on neutral alumina, eluting with diethyl etber/hexane (3:1), N-t-butylcorbonyl-K-(4 *-chlorophenylmethyl) aminopyrazine was thus obtained in 58? yield as a colourless solid, melting point 65-8°C.

Analysis Calculated for S OCIC^E.^ Found ExeHDle 4 K 13.84? 13.9? E -93 -9 C 63.26 63.3 K-fonnyl-K-( 41 -chloronheny lmethyl)-3-aEinonyridine To a solution of 4-chloro-(3'-pyridyliminoaethyl)benzene (21.65 g, 0.1 mole) in dry toluene (50 ml) was added formic acid (98?, 10.8 g), and the mixture was stirred and heated under reflux for 16 hours. Toluene and formic acid vere removed in vacuo, and to the residue vas added 10? HCI (100 ml). After extracting with toluene (100 ml), the aqueous layer vas separated and made alkaline by the addition of a concentrated aqueous solution of KOE. The products vere extracted into diethyl ether, and the extracts dried (MgSO^). After removal of solvent, the residue vas subjected to column chromatography (neutral alumina/ diethyl ether). The faster eluting material vas H-{4'-chlorophenylmethyl)-3-aminopyridine while the desired product N-formylE-(4*-chloropheuylmethyl)-3-eminopyridine vas obtained, as the slower eluting material, in 13.5? yield, as an oil.

SO Ο 1 2 C Η Ν (total 3Η), ppm Example 5 H-t-tutyIcarbonyl-N-(4' -chi orophenylmethyll-S-aainopyri dine To a stirred solution of H-(4'-phenylmethyl)-3-aminopyridine (4.5 g, 0.0206 mole) in dry benzene (50 ml) was added a solution Pq of trimethylacetylchloride (2-9 g, 0.024 mole) in dry benzene (15 al) folloved by a solution of dry triethylamine (2.6. g, 0.026 mole) in dry benzene (10 ml). The mixture was stirred and heated under reflux for 6J hours. After cooling, the reaction mixture was washed three times with water and dried (MgSO^). Solvent was removed in vacuo, and the residue triturated vith a little diethy ether. The solid material was filtered off, washed with a little diethyl ether and dried. Recrystallisation from hexane gave the pure N-t-butylcarbonyl-K-( 4 ' -chi nrophenyl methyl )-3-etni rwljyri dine in 4l$ yield as a colourless solid, melting point 100-102°C.

Analysis C B li Calculated for N^OCIC. Found 67-44 67.6 6.28 6.4 9-26$ 9.2$ Examples 6 to 24 Using methods analogous to those described in Examples 1 to 25 5, the following compounds were prepared. - 15 oc. c Example Ho. In the general formula I: Elemental Analysis Meltii ι Point o t- Ch oj I I I Uh CO CD lA Ch CU cK eo VO 00 co vo vo cv co vo ® VD fr— co co Ov OV CD ® CO CO fr— fr— to m t— cc t—vo = a a Ό VO a a a a a to t- to t— to © © t— t— © rl o o © t~ t— \o vo t— r- t— c— 0 0 0 0 tf tf tf tf +J +5 4» a! tf tf tf r-l i-l M P 0 0 0 0 0 0 *2 tf fi tf C tf C tf c i-l 0 tf o r-l 0 tf O 3 g 3 g © © fc © fc © fc ro CO I e\j co OJ CV Ch VO ( I w O'» vo CO \O t- VO cv a © o r— co t— co CO CD Ch Ov to to H »-l Ch P\ Ch O\ t— to tox fOeS- VO CO VO Ov a ua VO vo a a VO VO vo* vo t- O a ia t— IA (O fr- to r-l a Uh t— VO VO r-i © r-l rl t— t— VO vo vo vo t— fr— t—,t" 0 0 0 0 0 tf tf tf tf tf 43 -p -P mJ +5 tf tf tf tf tf rH r—1 rH ri p 0 0 0 0 0 0 *2 SJ 0 tf c tf C u c υ c tf fi p r-l P rl 0 h 3 i-t 0 tf O tf O tf 0 «9 0 ej O © fc © fc © fc © fc © fc - X X X X X X X rl fc C tf r-4 fc a ί rH fc c V r1 c V 1—I fc V rl I? 5 rl fc tf 0 i? j? rl fc a s js X fc i JS ft fc fc 1 a 1 a a O © i 8 0 'f 8 1 8 1 0 © 1 8 d © 1 © © I υ js fc $ •rl fc I CJ I £ X fi tf tf a fc & Ο r-l rH fc X c tf tf I X a fc r4 •S’ •rl u & I co I co fc •rl L rl fc a fi ο tf J- *fc ι § > ϋ v rH fc ι—I fc 0 •rl £ CJ »—I •ri 0 r-i fc s fc a fc tf fc u tf X 1 1 JS fc to a fc fc •rl I I to §£ rt fi C-l tf I JS -a fc x fe .—( CJ a: o\ ca CA Π» — _r in as 0 3 C «Η 3 d O O fe 0 § d o © fe - 16 VO Ό CA CA to σ\ co co ΓΊ-J ro ro 4» c o o m © ft I I I as O ·—( fc fe I o c O t—ι 3 G fi fi I 3 fe JZ 4» o fc o w 3 fe <—I fe 0 ί \Ο CA I o cu © co ro so σν so t— a: as as r-l CA © ro f— O fH «—ι cn CM t- . m ITS LT\ mas ro ro UA UA at aS roro ro O' © co w CM UA ΠΊ_3· CA r-l CA CA . m I cu m as m CO rH ι-1 ro t- ro c— ro ro ro ro ro ro ro c- c— ro ro ro ro 0 0 0 0 0 3 3 0) ω 3 3 ρ p o 4> P «Ρ 3 3 3 3 3 3 i-l H rH 0 3 0 3 0 3 0 3 0 3 0 3 0 c ύ c u c o c 3 C o s « s : 3 r-l 3 r-l 3 rH 3 r-l 3 <—1 3 rH 3 Q aj o 3 O 3 O 3 O 3 O 3 O ' (fc © fe © fe © fe © fe © fe © fe cn © o w sz © o © I H fe O fe fe I fe fe I cn ω ι a as O *->> fc I 0 O W © fi I ο cn az CU ri © r—1 *·—> fe fe 1 C o P o 3 © 3 © fi 1 fi 1 fe fe c fi I fe CM Q fc I O O 3 © jH I fe fe «Ρ ·? 4» o © I I «—1 t—1 1 fe fe fe 0 0 0 0 fc , • H •r| -rl 0 r-l L fc fc 3 fe & £> fe H S fe fe fe fci 3 1 fi cn cn cn as fe o o O O fe fc fc fc fc 3 rd O r-l O r-i 0 K OH •rl fe C 2 & 2 & 2 = 2& N 3 3 3 3 3 3 3 3 3 3 fc A 1 fi 1 JZ 1 fi 1 fi fe fe as fe as fe as fe as fe fe pyrazinyl h-fluoro- -CO.phenyl H Calcu: phenyl Found - 17 Table 1 (Cont.) Example In the general formula I I Elemental Analysis Melting point ts IA ao ia 1 c- la © rt 1 co vo rt cn 1 O' co IA LA cn LA CM O' 1 o O' rt •H © rt *rH o fM © VO *T f— rt •rJ o m vc 1 rt VO Cs m rt® cn CM rt a co co O' O' a a cm rt a ia rt LA f" vo O o m m a vo cn O' o rt rt cn cn m cn cn cn CM CM a m rt © •VQ VD co © rt rt rt® rt ·"· rt rt rt rt rt rt rt rt rt rt rt rt rt rt (A rt CM CO O m VO CD cnvo cn O' rt cnvo a trt © © cp cn t— a αθ O' IA © vo O rt CM CM -=T LA cn cn vo vo IAVO ia m a ia a ia OJ OJ a ia LA LA IA rt o Ch O lA ru IA CM CO VO CM rt fc— a Ό la cn cn vo © a t— IA VO VO O' cn a os VO rt -3" Of CD CO VO VO O CM VO vc a a VD VO cn m VD Ό cn cn vo vo CO vo vo t—co LA LA CM rt O' © IAVO rt © t-O P u c rt P tf c © fc. Ό X ti •0 c p o fc. 4. *> ti ti •P tf Ό ti 4^ tf s? rt P tf O © fc0 Ό « s rt P tf p © fc. ρ ό u c -as © fcΌ ti rt tf rt P o rt Ό s P £ Ό ti rt tf rt P c Ό c P o fc. Ό ti rt tf rt P ·£ s p -e U fl rt P tf o © fc. p ·£ ϋ c rt P tf 0 © fc.

X X X X X X X 1 o P rt —fci rt 1 >» CM C '—r 9) ό 1 OJ X rt © s 1 o rt X*-a rt 1 H a £ s->* ti 1 X P i CM X o rt rt >» rt 4 rt 1 X rt ti*—· ε h 7 x CM C irt ti 1 X cn X © o JcM © cn rt © © 1 o 1 m oj X X rt © u S · . c 1 X O Pl © O 1 fc 1 £ Ο ti © X t P« t X © p. © O t fc t rt 8i? 1 P 1 © © 1 8 1 O Pl © rt 1 >* o © 1 6 © t o O ti © ϋ X 1 I P< rt >> *o • I-i £ t cn •ti •ri £ cn I 0 fc 0 rt ί c υ v J’S. O fc Ο H H b X c a o 1 X -ΣΓ Pt n s c •H N tf fc Pf 1 CM O 0 rt 3 C V £ a Pi 1 0 fc 0 *2 rt x c ο o 1 X a P< X p. 0 fc o 3 rt ti s f c -3· ti 1 o O rt rt X c ti ti i X a P 1 o fc O rt rt X £ ti ti I X -3 Pi rt >> •0 rt fc Cm > m 1 o Sh 1 o Ο rt rt X G tf rt & •H M tf ί o >» £ •fl tf ι—1 >> £ •H tf 3, c .fl N tf rt s c • H M tf rt >» c •fl H tf 1 o fc C rt P £ & o ti 2 & ν ti & £ rt (c & L> ti fc fc P< fc X P< 1 £ t rt C fcl ti ί X 1 X a Pi I X a P< CM 1 CM 1 X a P· 1 cu CM CM CM OJ a P« ia vo CM CV rt Cd O CM CV O rt cu m m CM m cn a ia rt) m rn r- O rH CM m m o r^ LA CM r-i O' vo r- © o D 1 © o I & O CD 1 m Γ- Ι © 1 © © rH O' CM VO r-i C— Ch e— r-l • rl ό rH ι—1 co t- l—i O' r"( CM cn cn O' \O © © m la CM CM VO m © © t- cn J3 © © m -3 cn X co co t— t— c- t- CD CO co co r-i r-l f—1 r-t CM CM <—I r-i -3 -3 r4 r-l CM CM r-i r-i CM © CD LA O -3 LA C— CO m r-l r-i r-i vo © m m LA t— m 0-3 CM -3 © m © -3 X -- LA LA CM CM ~ - .3 LA LA -3 -3 (A LA t- t- LA LA O' o m CM CO O' LA r-i cn CM m la VO O' © cn -S’ -3 o LA O o © t- © © r-i O © r-l © CD tΌ Ό f—( «-Η t- f- VO vo -3 -3 vo VO LA LA VO © vo vo r-l cn t— t— .3 IA vo VO vpvo LA LA CM CM t- fc- VO t— LA LA -c o c r-i 3 0 O © fc *0 u c r-l 0 0 O © fc Ό +3 Ό o c 1-( 0 0 O © fc r^ *0 ϋ C o © fc «Ρ Ό 0 C r-i 0 O © fc Ό O 0 r-i 0 0 0 © fc Ό ϋ C rM 0 0 O © fc Ό υ c •Ή 0 0 O © fc Ό ϋ E r-i 0 0 O © fc «0 •P r-I *0 0 C «Η 0 0 O © fc e o fc , k O 0 © X I fc CM r-i Ύ & O 0 © X I fc r-i fc I i-t Ο r-i H fe X C ϋ V k fc I m t fc o fc O fH ί c ϋ 0 I X -3 fc ©= X K X r-1 r4 <—{ | 1 fe fe fe O I o ι •P 0 P 3 43 3 r-i CM CM X X X fe X r-i 53 r-l • C © fe © fe -p -P X Φ 1 c i C t 1 l J= © 0 O 0 O o o fc © 3= ϋ X © © © 0 1 fc 1 fc I 1 1 1 o O 3 >!, 1 r-i ife k fc u c fe u s rM 0 r-i O I-i •rl 0 X r-t -Η α fe 0 fe I-i fe •0 X -P fe *0 X β r-i C X c I fc 0 C 1 fc 0 fc 0 U 0 -3 0 S 0 -3 O C 1 X I X - Jm 1 XΛ Jm fc -3 fc -3 fc m o -3 fc CM 0 fe *0 •rl k fc m f o Ο H a & U 0 I X -3 fc r-i fe Ό •H & I i—i fe C r-! fe C I OJ 1 k fe fc k ε I 1 CM CM CM 2-pyrazinyl phenyl -CO-t.butyl tl Calcutnted 71.30 7.06 15.61 53-55 Found 71.9 7.5 15.7 - 19 Oj Ov I VO co ι 2-pyrazinyl 4-chloro- -CO-eyelo- H Calculated 65.55 6.07 12.75 Oil phenyl hexyl Found 65.0 6.5 12.5 iavo fi fi rH H CO O cnnr ao O on fi o (A I ov cu cu VO I σ vo cu σ σι no m vo VO vo co co pa m M r-l rH OV m cu VO Ό cu cu 4AVO fi fi Ov cn irv so Ov-=r IAV0 co — σ\ σ> co rH vq co rH rH VO tzvaO cn Ov vo cu © IA CU fi vo ~ cu © coco vq O H vo vo CU VO cu vo cu vo CU vo fc- fcVO VO en vo en Ό mfi vo vo fi fi vo VO f*l Cl VO VO VOVO IA IA tA Ό ti P ti r-H *3 a c rH 3 ti O o fr +5 ti 3 S § ti o © fr *3 ti P ti rH 3 81 P © fr *0 ti P ti *3 3 ti 3 rH 3 ti O © fr ti P ti rH *2 a 3 rH 3 ti 0 O fr P ti *3 -3 t, e rH 3 ti 0 V fr ti ti rH 3 ti C rH 3 ti O © fr *3 ti P ti rH 3 ti O © fr p 3 a c r-t 3 ti O υ fr m x © cu X .© o CJ I cu m rH I cn x © cu o cu cu o © u rH O p cu x cu © *-* SB © X © 8 · © & ti fi 6 © ι © o © 6 © * o © Pi 1 1 ' t 1 1 o O rH 2 & O ti Ji I 0 0 H a & 3 ti fi Pt 0 fc Ο H a & ο ν 1 fi fi fr 1 2 O rH a & V 5 fi Pt 1 o fc O r-i 2 & ti ti 1 «5 fi fr 1 O O rH 3 & ti ti 1 fi fi Pt o fc O rH 3 & ti ti 1 fi fi fr o Ο H rH fc fi s ti ti -4 fr o fc 0 rH rH fc fi c ti ti I fi fi fr o Sn 3 & ti ti 1 fi fi ft . rH fc C •rl P ti & rH & •rt H ti fc fe rH fc C •rt »3 ti % fe s •rt P ti fe & 1 3 •rt s •rt h % • rl H ti £ rH fc C • rt P ti fc s t fe 3 •rt P ti £ rH & •rt P ti & rH & •rt P ti fc fe 1 1 cu 1 CU 1 cu cu cu ·η cu CU w cu cu - 20 \0 m rt ι Ο ι—I 1 J3 ο ο c co ο co co m rn m cu co o CM © Os Os fr- free co t— KD r-l r-l r-l ι—ί CO frΓΠ cn CO r-l kA SO m ja LA IT\ o co IA kA (Π ΓΠ kA kA (**i kA IA kA Ό m cn cn ·3 u c rt 3 0 0 a fe r-ι 3 tf O O fe tf P tf rd Ό tf tf rt 3 tf O υ fe tf - Ό 4) P tf r-l Ό tf C r-l 3 tf O O fe r-l 3 tf p © fe Ό tf C rt 3 tf p O fe -7 C z © K X X K = OJ cn x r-l irt r—( rt fe fe © fe fe fe fe c p P P P P p tf 3 'o 3 3 3 3 cn 1 P P u 42 P P P - PC -7 ft rt P © P P P P Irt 1 o fe P 1 © o O t o i σ o tf © 3 © © © © © © •rt 1 P 1 1 < * fe P I ^7 rt ·— fe t c © tf O 42 1 ft fe P P P I o © I 1 1 rt o 0 fe fc fc tf irt rt 0 irt 0 rt •rt fe fe rt fe d fe b c tf 42 C 4= C fe tf tf tf tf tf tf ft £ p 1 JZ 1 P 1 ft ft — ft -3 ft k ft I irt fe tf •rt I o fc O rt r-l fe 42 C O tf I 42 ^7 ft I O fc O irt C tf V I P -7 ft irt fe C •rt ¢3 rt fe fi •rt fr} irt fe c •rl N 1 tf *o 1 rt rt P fe tf fi u s I · 3 rt rt fe 1 JT ( o fc fe c tf ft 1 tf •tf r tf •σ tf tf tf •rt •rl tf •rl tf •rt tf o o •rt •rt 4_ L, fc rt tf P *3 P tf P rt fc t* d h d k fe ft fe ft fe fe ft C 1 -rt 1 ft -7 O - fc J ft «7 O • fc ( ft «7 O • fc 42 tf 1 o 3 rt fe fri ft C 1 -rl fe >» ft c l -rt cu ci OJ cn n Ol o cn o OJ o fc< -7 N JT « οι r-I ft o AJ - 21 Table I (Cont.) Example In the general formula I : Elemental Analysis Melting point o CM (A O *7 © o rt rt <*s Os •H O rt vo ό d rt Ox ss t— t— © rt fr—. tA IA r-l CJ rt rt © OS CSI CM •ϋ V -P tf rt s rt o rt rt ι o o I rt >> C tf Ό o c *3 § o &, Ό O C a § Q B fti rt tf rt tf Ό § tf o © ft cn >» rt tf rt o υ I ‘S rt rt I I rt | rt s 0 *tf fa Ό •rf o rt fa rt >» b £ rt C ft 0 tf ft T 1 rt 1 cn rt ft cn 1 •H O o H fa ε rt tf o rt o μ k a Λ c rt tf ft o tf 7 rt 1 1 rt rt ft CM rt ft «· 5 0 012 - 22 Examples 72-77 5y methods analogues to known methods, the following derivative were prepared from compounds of the general formula I. - 23 Example Ho. Compound Elemental Analyeie Melting Point OV fo co © cu co Ί1 7 VO rl VO © © CU co O rl ·"* 0 Ov b- vo I Uh a vo to rd rd C— IA rl CJ Ov CJ CO Ov CD CO co-a· rd CO CO CJ CJ VO VO rd rd rd H rd rd rd rl rd O Φ a CO Uh r| VO O VO GO VD vo cj a CO co IA Uh VA uh vrv a a a a CJ X tA tf P tf Ov © a Ov rl © a rl rd a co t— t— d o b- b— Ov co rl rd IA vo vo Uh Uh Uh Uh Uh uh 0 0 0 0 tf tf tf tf P P P P tf tf tf « ri rd rl d 0 P 0 0 0 0 *3 3 0 c tf C tf S tf C tf c 0 o rd P tf O 3 g 3 § rd P tf O fc © fc © fc o a. © fc tf X CO p a U tf 0 d fc c O a § ο tf JR — p co rl © VO VO CJ OJ LA Uh ΙΑ CO IA a Uh Uh V tf rd 3 tf -° © fc •rt X X W o I fc β o X I o I ' X fc la tf 6 tf tf tf fc O (3 O 6fc ° O fc o C tf fc P rd OOO fc B tf X fi 0 « Q la ·η rd tf V la ft fc O B tf H o X vo X © P -sr tf cj co a b- t— b" LD O rd fc tf H O rd fc tf w 0 rd fc c fc la tf B tf V 3 fc rl X ft o fc o Ε O tf fi la tf 3 tf rd X ft 0 fc ft E 0 •2 0 P c •Η P 0 O 0 fc tf B fc g 0 o •Μ u g % 0 0 tf •vd 1 P 0 M § ° ag« KB _·Ο fc 5 tf OOH ft O tf X Β B 0 tf tf tf * P tf •rd fc la O rd tf tf la Η ϋ k Ja η. ίί Λ CI P P fc fc O β tf rd M« W V fi tf fc rl Λ r r la rd tf tf © P cu tf o a «— © P CO tf E-« a o Cd

Claims (21)

1.CLAIMS 1, A compound of che general formula 1 2 R - N - CH - R (I) 1 ’ in which one of E and R represents an optionally-substituted 6-membered beteroaromstic ring containing 1 or 2 nitrogen atoms, and the other of R^ and R^ also represents such a ring or represents an optionally-substituted phenyl group; R ή represents an acyl group derived from a carboxylic acid; and R represents a hydrogen atom or so alkyl group having from 1 to 4 carbon atoms; or an acid addition salt, N-oxide or metal salt complex thereof; provided that if R^ represents an optionally 2 substituted pyridyl group, R must represent an optionally substituted beteroaromatic ring; if R^ represents an optionally substituted phenyl group, R^ must represent an acyl group derived from an acid other than an optionally substituted 1 benzoic acid; if R* represents an unsubstituted phenyl group,

2. 3 R represents an unsubstituted 2- or 3-pyridyl group and R represents a group of formula CH^CO-, phenyl.CH=CH. CO-, C.E.CO-, or (phenyI)„CH.CO-, then R 4 must represent an alkyl L 5 '2 L group; if R represents a phenyl group substituted by an SO.NH. 4 1 * z group, R must represent an alkyl groun; and if both of R and R represent optionally substituted pyridyl groups, neither of these groups is substituted by an amino, acylamino, alkylamino or dialkylamino group. - 25 2. A compound as claimed in claim 1, characterised in that R^ represents a formyl group, an alkoxycarbonyl group or an optionally substituted alkanoyl, alkenoyl, cycloalkanoyl, or •aroyl group.

3. -A compound as claimed in claim 2, characterised in that R represents a formyl group; an alkoxycarbonylcarbonyl group; an alkanoyl or alkenoyl group optionally substituted by one or more of the same or different eubstituents selected from halogen atoms and alkoxy, phenyl, phenoxy, carboxy and alkoxycarbonyl groups; a cycloalkanoyl group having from 3 to 6 carhon atoms in the ring optionally substituted by one or more of the same or different substituents selected from halogen atoms and methyl groups; or a benzoyl group optionally substituted by one or more of the same or different substituents selected free halogen atoms and nitro, alkyl, haloalkyl, hydroxyaikyl, alkoxy, haloalkoxy, hydroxvalkoxy, hydroxy, cyano, alkylsulphonyl, alkylcarbonyl, alkoxvcarbonyl, carboxy and alkylthio groups.

4. A compound as claimed in claim 3, characterised in that R represents a formyl group; an ethoxy- or methoxycarhonylcarbonyl group; an alkanoyl or alkenoyl group optionally substituted by up to 3 halogen atoms or hy a phenyl, phenoxy, C(l-4)alkoxy, methoxycarbonyl or hetoxycarbonyl group; a eyclopropylearbonyl, cyclobexylcarhonyl, 1-methylcyclopropylcarbonyl or a 2,2-dichloro-3,3-dimethylcyclopropylcarbonyl group; or a benzoyl group optionally substituted hy one or two halogen atoms and/or alkyl groups.

5. A compound as claimed in claim 4, characterised in that R represents an unsubstituted alkanoyl group having up to 6 carbon atoms in the alkyl moiety.

6. A compound as claimed in any one of claims 1 to 5, t characterised in that R represents a hydrogen atom or a methyl group.

7. A compound as claimed in any one of claims 1 to 6, characterised in that each of the rings represented by R^ and 2 R is unsubstituted or substituted by one or more of the same - 26 or different substituents selected from halogen atoms and nitro, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, hydroxy, cyano, alkylsulphonyl, alkylcarbonyl, alkoxycarbonyl, carboxy and alkylthio groups.

8. A compound as claimed in claim 7, characterised in that 1 2 each of the rings represented by R and R is unsubstituted or substituted by one or two halogen atoms and/or alkyl groups.

9. A compound as claimed in any one of claims 1 to 8, charac1 2 terised in that any phenyl group represented by R or R is mono- or disubstituted, and any heteroaromatic ring represented 1 2 by R or R is unsubstituted.

10. A compound as claimed in any one of claims 1 to 9, 1 2 characterised in that any pyridyl group represented by R or R is a 3-pyridyl group.

11. A compound as claimed in any one of claims 1 to 10, characterised in that R^ represents an optionally substituted phenyl group and R represents an optionally substituted pyridyl group.

12. A compound as claimed in any one of claims 1 to 11, characterised in that R^ represents an optionally substituted 2 pyrazinyl group and R represents an optionally substituted phenyl group.

13. A compound as claimed in claim 12, characterised in that 2 1 R represents a 4-chlorophenyl group·, R represents an unsub3 stituted pyrazinyl group; R represents a t.butylcarbonyl 4 group; and R represents a hydrogen atom.

14. A compound as claimed in claim 1 and named in any one of Examples 1, 3, 10 to 12, 14, 16, 18, 20, 23-35, and 42 to 74, 76 and 77 herein.

15. A process for the preparation of a compound as claimed in any one of claims 1 to 14, which comprises acylating a compound of the general formula R 1 - KH - CH - R 2 R4 (II) 12 4 in which R , R and R have the weanings given in claim 1, using a suitable acylating agent.

16. A process as claimed in claim 15. in which the acylating agent is an acid chloride derived iron the appropriate 5 carboxylic acid, and the reaction is carried out in the presence.of an acid-binding agent.

17. A process as claimed in either claim 15 or claim 16, in which the compound of the general formula II has been prepared by reduction of a compound of the general formula ’ (HI) R 4 12 A in which R , R and R have the meanings given in claim 1.

18. A process as claimed in claim 15, carried out substantially as described in either of Examples 1 and 3 herein.

19. A compound as claimed in claim 1, whenever prepared by a 15 process as claimed in either of claims 15 and 16.

20. A biologically active composition which comprises a compound as claimed in any one of claims 1 to 14 and 19, together vith one or more carriers.

21. A composition as claimed in claim 20, which comprises at 20 least two carriers, at least one of which is a surface- active agent.