Accordingly, the present invention comprises the use as a biocide of a compound of formula I, optionally in the form of an acid addition salt I:

(B) _b CONH(CH ₂ ) _c N(D)(CH ₂ ) _d N(E)(CH ₂ ) _f [N(F)(CH ₂ ) _h 3.-NGJ

in which formula:

A represents a substituent which is: hydroxyl, 0-alkyl, O-cycloalkyl , 0-alkenyl, 0-aryl , 0-aralkyl, O-carbamate, O-carbonate, 0-acyl or halogen a is 0-5; the substituents A are identical or different when a is more than

1;

B represents a C- _| -C ₆ aliphatic hydrocarbon group optionally carrying one or more of the substituents: hydroxyl, amino, halogen, C1-C alkoxy, C- _| -C alkyl, aryloxy or carboalkoxy and optionally comprising one or more sites of unsaturation and/or one or more carbonyl groups or ketal derivatives thereof; b is 0 or 1; c, d, f and h, which may be identical or different, are 2, 3, 4,

5 or 6; and i is 0 or 1

D, E and F, which may be identical or. different, represent hydrogen or C1-C4 alkyl or cycloalkyl, and

G and 0 which may be identical or different represent hydrogen, alkyl or cycloalkyl or G and J together with the nitrogen atom to

which they are attached represent a saturated heterocyclic ring system.

Typically: when A represents 0-alkyl, the alkyl group is C ^* ]-C_] alkyl; when A represents O-cycloalkyl the group is cyclohexyl; when A represents. 0-alkenyl the alkenyl group is a C-j-C4 alkenyl group such as ethenyl, propenyl or butenyl ; when A represents 0-aryl, the aryl group is a phenyl group; when A represents 0-aralkyl, the aralkyl group is a 07-0 ^* 10 phenalkyl group; when A represents O-carbamate, the O-carbamate group is of formula -0-C0-NR---R ¹ *- wherein R-- and R ^* --!, which may be identical or different, represent Cη-C4 alkyl groups; when A represents O-carbonate, the O-carbonate is of formula -0-C0-0R ¹¹¹ wherein RIII represents a C-1-C alkyl group; when A represents O-acyl , the O-acyl group is of formula -0-C0-R-* ^v wherein R ^IV represents a C1-C4 alkyl group e.g. methyl and when A represents halogen, the halogen is typically Cl, Br or F.

It will be appreciated that the compounds in which A represents a substituent other than hydroxyl or halogen may act through conversion i_n vivo to the corresponding compound in which the group or groups A are hydroxy groups. Indeed the present invention extends in general to compounds of formula (I) as defined above in which A is hydroxyl when in a pro-form which delivers the hydroxyl group - containing compound in use.

Although a may be 0-5, it is typically at least 1 and normally no more than 3, mono or di substitution of the aromatic ring being preferred and disposition of a mono substituent e.g. a hydroxyl group, at the 2, 3 or 4 position in the ring being especially so.

The aliphatic hydrocarbon group B is typically unbranched and generally contains no more than two carbon atoms intermediate between the aromatic ring and the carbpnyl group of the C0NH(CH2) _C - function. It will be appreciated that, when present, substituents may be identical or different. Sites of unsaturation may be present as double bonds (typically configurationally trans) or triple bonds or both. Groups of the

following formula are of particular interest, R* _| R ₂ and R ₃ representing hydrogen or one or more of the substituents hereinbefore described as carried on the C- _j -C aliphatic hydrocarbon group: -CHR _1r , -CHR- _| CHR ₂ -, -CR ₁ =CR ₂ -, -CH ^^C^-, -CR^CR^HRg- and -CHR- _| -CR ₂ =CR ₃ -. , ^"

Although R- _j , R ₂ and R3 may represent one or more of the hereinbefore identified substituents it is most usual for all to be hydrogen.

Usually no more than one carbonyl group or a ketal derivative thereof is present in the group B (i.e. one carbon atom of the C- _| _ _β aliphatic hydocarobon group is substituted by an oxo group or such a group in ketal form) and there is generally at least one other carbon atom present in the carbon chain between the aromatic ring and the C0NH(CH ₂ ) _c - function as in the phenylpyruvic and hydroxyphenylpyruvic moieties wherein B represents -CH ₂ C0-, which are of particular interest. When a carbonyl group is derivatised as a ketal group, of formula -( OR _g XORtø)-, R _a and R^, which may be identical or different, represent C- _j -Cg alkyl groups e.g. methyl or ethyl groups or groups which are linked together to form a ring incorporating the carbon and two oxygen atoms as for example in the ethylene ketal wherein R _a and R^ each represent -CH ₂ -.

D, E anf F may be C- _j _ ₄ alkyl or, for example, C3-C5 cycloalkyl but it is generally preferred for D, E and F to each represent hydrogen and for i to be zero. In compounds of particular interest the values for c, d and f are each 3 (as in bis (3-aminopropyl)-l ,3-propanediamine> or, respectively 3, 4 and 3 (as in sper ine).

Although generally the substituents G and J each represent hydrogen, G and J may represent certain organic groups as indicated and particularly each of G and 3 may independently represent C1-C4 alkyl or C ₃ -Cg cycloalkyl or together may represent a C ₂ -Cg alkylene group, for example a tetra ethylene, pentamethylene or hexamethylene group or a group -CH ₂ CH ₂ -0-CH ₂ CH ₂ - (to form a morpholine ring system).

Compounds of formula I which are of particular interest include those with the following formulae:

₃ NH(CH ₂ ) NH(CH ₂ ) ₃ NH ₂

Acid addition salts of compounds of formula (I) in accordance with the invention are preferably acceptable to mammals although other acid addition salts are within the scope of the invention. Suitable salts are those derived from, for example, the following acids: hydrochloric, hydrobromic, sulphuric, nitric, isethionic, phosphoric, aleic, salicylic, p-toluenesulphonic, tartaric, citric, lactobionic, formic, malonic, pantothenic, succinic, naphthalene-2-sulphonic, benzenesulphonic, methanesulphonic and ethanesulphonic. The preferred salts in terms of pharmaceutical acceptability are the ethanesulphonic acid salts.

Such salts may be prepared from the free-base by treatment with the acid suitably in a polar solvent such as water and if necessary with the application of heat.

The compounds of the present invention may be readily produced by reaction between an acid and an amine moiety.

Accordingly to a further aspect of the present invention a

process for the production of a compound of formula I comprises reacting an acid of formula II or esterifiable derivative thereof, e.g. an acid halide,

with an a ine or of formula III or acid addition salt thereof: III NH ₂ (CH ₂ ) _c N(D)(CH ₂ ) _d N(E)(CH ₂ )f[N(F)(CH ₂ )hJiNGJ, in which formulae the symbols have the hereinbefore given meanings.

In general the reaction ^" is conducted in an organic solvent such as ,2-dimethoxyethane or tetrahydrofuran or dioxan in the presence of a coupling reagent such as a carbodiimide e.g. dicyclohexylcarbodiimide or another carbodiimide e.g. l-cyclohexyl-3-(2-morpholinoethyl)carbodiimide-metho-p- toluenesulphonate (morpho CDI, Aldrich), or l-(3-dimethyl- aminopropyl)-3- ethylcarbodiimide hydrochloride or ethiodide (water soluble reagents, EDC, Aldrich), or 1 ,3-diisopropyl- carbodii ide. The product may be readily purified by chromatography and/or lyophilisation.

The acid (or esterifiable derivative) thereof may, for example, be benzoic, phenylacetic, phenylpropanoic, or cinna ic or substituted derivatives e.g. hydroxyphenylglycine, dopa, tyrosine, hydroxyphenylpyruvic-, hydroxyphenylacetic- and hydroxymandelic acid.

Compounds of formula I are of particular interest for application to pests such as arthropods including insect species and especially those species which are prey to spiders such as locusts, grasshoppers, blowfly larvae and also Lepidoptera larvae and arachnids e.g. mites. Application inter alia as a fungicide, nematocide or molluscide is also envisaged.

The present invention further includes within its scope a composition for use as a biocide, for example as an arthropod

biocide e.g. an insecticide or acaricide or for use as a herbicide, ne atocide, fungicide or molluscicide which composition comprises a compound of formula I together with a diluent or carrier therefor. Compositions may be in the form of dusts and granular solids, wettable powders, mosquito coils and other solid preparations or as emulsions, emulsifiable concentrates, sprays and aerosols and other liquid preparations after the addition of appropriate solvents, diluents and surface-active agents. The present compositions of the invention normally contain from 0.001 to 257. by weight of the compound of formula I but the compositions can contain higher concentrations of active ingredient of formula I e.g. up to 95% in compositions to be sold as concentrates for dilution before use by the ultimate user. The compositions can, depending on the intended application, Include diluents such as hydrocarbon oils, e.g. xylene or other petroleum fractions, water, anionic, cationic or non-ionic surface-active agents, anti-oxidants and other stabilisers as well as perfumes and colouring matters. These inert ingredients may be of the type and in proportions such as are conventionally used in pesticidal compositions.

In addition to these Inactive ingredients, the compositions of the present invention may contain one or more further active ingredients which may be other pesticidal compounds and the composition may also include synergists.

Compounds of formula I may be applied in such a manner that pest infestation is diminished or prevented or both.

In accordance with a further aspect of the present invention, a method of pest control comprises treating a pest or a surface or environment susceptible to pest infestation with an effective amount of a compound of formula I.

The compounds or compositions of the invention can be used as, for example, insecticides or acaricides in a domestic environment by spraying ^' rooms to combat infestation with houseflies or other insects, they can be used for treatment of

stored crops or cereals to combat infestation by Insects or other pests, they can be used to spray growing crops, e.g. cotton to combat infestation by common pests and they can be used in the medical or veterinary field, e.g. as a cattle spray to prevent or treat infestation by insects or other pests.

It will be appreciated, of course, that in order to be acceptable for application particularly in agriculture and horticulture, compounds of formula I hereinbefore described should exhibit a low level of mammalian toxicity combined with a high degree of pesticidal effectiveness.

The invention is illustrated by the following Examples: General procedure for the preparation of monoacyl spermines. To a solution of the required carboxylic acid in an organic solvent such as 1 ,2-dimethoxyethane or dichloromethane an activating agent e.g. dicyclohexyl carbodiimide was added. The polyamine was introduced in slight excess (two-four fold) in order to increase the yield of the desired monoacylated product. The product was isolated by chromatography over Kieselgel 60 (230-400 mesh). The final product was always soluble in water and was therefore purified by lyophi11sation as a final step. Loucst Test Method and rationale

The compounds were assayed for biological activity on the isolated, retractor unguis nerve-muscle preparation of the locust Schistocerca qregaria (Usherwood, P.N.R and Machili, P. (1968) J. Exp. Biol., 42: 341.). Isolated muscle preparations were bathed continuously in standard locust saline in a bath of volume 250μl . Twitch tension recordings of the muscle were made to electrical stimulation of its motor innervation supramaxi al voltage, frequency 0.1Hz). The locust isolated retractor unguis nerve-muscle is a preparation with well characterised muscle receptors belonging to the qulsqualate-sensitive class (Boden, P. et il- , ⁽ 1986 ⁾ Brain Res., 3_£5: 205.). This preparation has previously been employed to Identify antogonists of excitatory amino add receptors, ⁽ e.g. Bateman, A. el aU , (1985) Brain Res., 3J2: 237 and Budd, T. et

Al. , (1988) Brain Res., 44£: 30.). Example 1

N-(2-Hvdroxyphenv1acetyl)-spermin : ^" To a solution of 2-hydroxyphenylacetic acid (50mg, 0.33mMol) 1n 1,2-dimethoxy- ethane (DME) (1ml) was added a solution of dicyclohexyl carbodiimide (71mg, 0.34mMol, 1.05 equivalents) in DME (1ml) in one portion of 25 ^β C. The colourless mixture was allowed to stand at 25°C for 3h during which time a voluminous white precipitate of the urea was formed. This precipitate was then removed by filtration and the residue washed with DME (2 X 1ml). The filtrate and the washings were combined and a solution of spermine (351mg, 1.73mMol, 5.3 equivalents) in DME/dimethylformamide (2ml, 1:1) was added in one portion. The colourless, homogeneous solution was sealed under an atmosphere of nitrogen and allowed to stand at 25°C for 48h. The solution was concentrated in vacuo (water aspirator) and then the residue was applied to a column of silica gel (Kieselgel 60, 230-400 mesh). The product was eluted with dichloromethane/ ethanol/- 0.880 ammonia solution (4:2:1). The desired amide was eluted in fractions 9-14 (10ml fractions) and was homogeneous when monitored by tic on silica (CH ₂ Cl ₂ /Me0H/NH ₄ 0H, 4:2:1), R _f =0.25, chromatogram visualised by inspection under UV light (254nm) and by the production of a pink-purple stain with 0.3% ninhydrin in solution in acidic alcohol. The fractions containing the product were combined and concentrated in vacuo to yield a colourless oil. This oil was dissolved in ethanol (2ml), filtered and the solution was then concentrated in vacuo (51mg, 46%). The residue was dissolved In distilled water (2ml) and lyophilised which gave the amide as a colourless, viscous oil (48mg) whose spectroscopic data include: UV _max 271 (e _maχ l 000) and 289sh n ; pmr (90 MHz, ² H ₂ 0) 1.5-1.9 (m, 8H, 4 X CH ₂ -CH ₂ ), 2.6-2.9 ( , 10H, 5 X CH ₂ -N), 3.25 (t, J _. = 7, 2H, C0N ² H-CH ₂ -CH ₂ , 3.55 (s, 2H, Ar-CH ₂ -C0), 6.55-6.85 (m, 2H, 2 X ArH 3,5), and 7.1-7.3 (m, 2H, 2X ArH 4,6)ppm; M+l 337 (FAB matrix m-nitrobenzyl alcohol) -*gH ₃₂ N4θ ₂ requires M ⁺ 336).

The potency of this monoacylated spermine as an antagonist of the complex formed by the invertebrate L-quisqualate sub-type L-glutamate receptor and its ion channel was assayed using the electrically stimulated retractor ungu ^' is muscle of the locust (Schistocerca gregaria). Twitch amplitude was reduced (1% inhibition) from control (100%) levels at the following

dicyclohexyl carbodiimide (75mg, 0.36mMol, 1.1 equivalents) in DME (1ml) in one portion of 25°C. The colourless mixture was allowed to stand at 25 ^β C for 3h during which time a voluminous white precipitate of the urea was formed. This precipitate was then removed by filtration and the residue washed with DME (2 X 1ml). The filtrate and the washings were combined and a solution of spermine (167mg,; 0.83mMol, 2.5 equivalents) in DME/dimethylformamide (2ml, 1:1) was added in one portion. The colourless, homogeneous solution was sealed under an atmosphere of nitrogen and allowed to stand at 25°C for 24h. The solution was concentrated in vacuo (water aspirator) and then the residue was applied to a column of silica gel (Kieselgel 60, 230-400 mesh). The product was eluted with dichloro ethane/methanol/- 0.880 ammonia solution (4:2:1). The desired amide was eluted in fractions 12-18 (10ml fractions) and was homogeneous when monitored by tic on silica (CH ₂ Cl ₂ /MeOH/NH ₄ OH, 4:2:1), R _f =0.18,

chro atogram visualised by Inspection under UV light (254nm) and by the production of a pink-purple stain with 0.3% ninhydrin in solution in acidic alcohol. The fractions containing the product were combined and concentrated in vacuo to yield a colourless oil. This oil was dissolved In ethanol (2ml), filtered and the solution was then concentrated in vacuo (36mg, 33%). The residue was dissolved 1n distilled water (2ml) and lyophilised which gave the amide as a colourless, viscous oil (30mg) whose spectroscopic data include:- UV _maχ 274sh, 278 (e _maχ 950), and 290sh nm; pmr (90 MHz, ² H ₂ 0) 1.2-2.0 ( , 8H, 4 X CH ₂ -CH ₂ ), 2.5-2.9 (m, 10H, 5 x CH ₂ -N), 3.3 (t, 0=7, 2H, CON ² H-CH ₂ -CH ₂ ) , 3.5 (s, 2H, Ar-CH ₂ -C0) , 6.45-6.75 (m, 3H, 3 X ArH 2,4,6), and 7.0-7.3 (m, 1H, ArH 5)ppm: M+l 337 (FAB matrix m-nitrobenzyl alcohol) (C*jgH ₃₂ 4θ ₂ requires M ⁺ 336). The potency of this monoacylated spermine as an antagonist of the complex formed by the invertebrate L-quisqualate sub-type L-glutamate receptor and its 1on channel was assayed using the electrically stimulated retractor unguis muscle of the locust (Schistocerca gregarla). Twitch amplitude was reduced from control (100%) levels at the following concentrations: 3 x 10 ^"8 M 30% 3 x 10 ^"7 M 35% Example 3

N-(4-Hydroxyphenylacetyl)-spermine. To a solution of 4-hydroxyphenylacetic acid (80mg, 0.53mMol) in 1 ,2-dimethoxyethane (DME) (1ml) was added a solution of dicyclohexyl carbodiimide (120mg, 0.58mMol, 1.1 equivalents) in DME (1ml) in one portion at 25°C. The colourless mixture was allowed to stand at 25 ^β C for 3 h during which time a voluminous white precipitate of the urea was formed. This precipitate was then removed by filtration and the residue washed with DME (2 X 1ml). The filtrate and the washings were combined and a solution of spermine (600mg, 2.97mMol, 5.6 equivalents ⁾ in DME/dimethylformamide (2ml, 1:1) was added in one portion. The colourless, homogeneous solution was sealed under an atmosphere

of nitrogen and allowed to stand at 25°C for 48h. The solution was concentrated in vacuo (water spirator) and then the residue was applied to a column of silica gel (Kieselgel 60, 230-400 mesh ⁾ . The product was eluted with dichloromethane/methanol/- 0.880 ammonia solution (4:2:1). The desired amide was eluted in fractions 8-13 (10ml fractions) and was homogeneous when monitored by tic on silica (CH ₂ Cl ₂ /MeOH/NH ₄ OH, 4:2:1), R _f =0.17, chro atogram visualised by Inspection under UV light (254nm) and by the production of a- pink-purple stain with 0.3% ninhydrin in solution in acidic alcohol. The fractions containing the product were combined and concentrated in vacuo to yield a colourless oil. This oil was dissolved in methanol (2ml), filtered and the solution was then concentrated in vacuo (65mg, 37%). The residue was dissolved in distilled water (2ml) and lyophilised which gave the amide as a colourless, viscous oil (57mg) whose spectroscopic data include:- UV _mκ 220 (e _max 6 000) and 270 <e _max 1 300) nm: pmr (90 MHz, ² H ₂ 0) 1.2-2.0 (m, 8H, 4 X CH ₂ -CH ₂ -CH ₂ ) , 2.5-2.9 ( , 10H, 5 X CH ₂ -N), 3.2 (t, , 2H, CON ² H-CH ₂ -CH ₂ ) , 3.4 (s, 2H, Ar-CH ₂ -C0), 6.7 (d, J=8, 2H, 2 X ArH 3,5), and 7.1 (d, J-8, 2H, 2 X ArH 2,6)ppm: M+l 337 (FAB matrix m-n1trobenzyl alcohol) ^C 18 ^H 32 ^N 4°2 ^r eQ ^uires M+ 336 ⁾ .

The potency of this onoacylated spermine as an antagonist of the complex formed by the invertebrate L-qu1squalate sub-type L-glutamate receptor and its ion channel was assayed using the electrically stimulated retractor unguis muscle of the locust (Schistocerca gregaria). Twitch amplitude was reduced from control (100%) levels at the following concentrations: 5.9 x 10 ^"7 M 9% 5.9 X 10 ^"6 M 25% 2.95X 10 ^"5 M 74%

4.43x 10~ ⁵ M 91% 5.9 x 10~ ⁵ M 96% The IC ₅₀ = 8.7 x 10 ^"6 M Example 4 N-(2-Hvdroxyphenylpropanov1)-spermine.-To a solution of

2-hydroxyphenylpropanoic acid (61 mg, 0.37 mMol) in 1,2- dimethoxyethane (DME) (1 ml) was added a solution of dicyclohexylcarbodiimide (76 mg, 0.37 mMol) in DME (1 ml) in one portion at 25°C. The colourless mixture was allowed to stand at 25°C for 3 h during which time a voluminous white precipitate of the urea was formed. This precipitate was then removed by filtration and the residue washed with DME (2 x 1 ml). The filtrate and the washings were combined and a solution of spermine (300 mg, 1.48 mMol, 4.0 equivalents) in DME/dimethylformamide (2 ml, 1:1) was added in one portion. The colourless, homogeneous solution was sealed under an atmosphere of nitrogen and allowed to stand at 25°C for 48 h. The solution was concentrated in vacuo (water aspirator) and the residue was then applied to a column of silica gel (Kieselgel 60, 230-400 mesh). The product was eluted with dichloromethane/methanol/- 0.880 ammonia solution (4:2:1). The desired amide was eluted in fractions 7-11 (10 ml fractions) and was homogeneous when monitored by tic on silica (CH ₂ Cl ₂ /MeOH/NH ₄ OH, 4:2:1), R _f = 0.33, chromatogram visualised by inspection under UV light (254 nm) and by the production of a pink-purple stain with 0.3% ninhydrin in solution in acidic alcohol. The fractions containing the product were combined and concentrated in vacuo to yield a colourless oil.

This oil was dissolved in ethanol (2 ml), filtered and the solution was then concentrated in vacuo (112 mg, 87%). The residue was dissolved in distilled water (2 ml) and lyophilised which gave the amide as a colourless, viscous oil (82 mg ⁾ whose spectroscopic data include: pmr (90 MHz, ² H ₂ 0) 1.3-2.1 (m, 8H, 4 X CH ₂ -CH ₂ ), 2.5-3.1 (m, 14H, 5 x CH ₂ -N and Ar-CH ₂ -CH ₂ ) , 3.3 (t, 3 •*= 7, 2H, CON ² H-CH ₂ -CH ₂ ), 6.7-7.0 (m, 2H, 2 x ArH 3,5), and 7.1-7.4 (m, 2H, 2 x ArH 4,6)ppm.

The potency of this monoacylated spermine as an antagonist of the complex formed by the invertebrate L-quisqual te sub-type L-glutamate receptor and its ion channel was assayed using the electrcically stimulated retractor unguis muscle of the locust (Schistocerca gregaria). Twitch amplitude was reduced from

control levels between the following concentrations: 1 x 10~ ⁵ M and 9 x 10~ ^* - ^* M, such that an approximately 50% reduction was obtained at 5 x 10 ^-5 M. Example 5 N-(3-Hvdroxyphenylpropanoyl)-sperm1ne.-To a solution of 3-hydroxyphenylpropanoic acid (167 mg, 1.01 mMol) in dichloromethane (5 ml) was added dicyclohexylcarbodiimide (226 mg, 1.10 mMol, 1.1 equivalents) in one portion at 25 ^C C. The colourless mixture was allowed to stand at 25°C for 2 h during which time a voluminous white precipitate of the urea was formed. This precipitate was then removed by filtration and the residue washed with dichloromethane (1 ml). The filtrate and the washings were combined and spermine (400 mg, 1.98 mMol, 1.96 equivalents) was added in one portion. The colourless, homogeneous solution was sealed under an atmosphere of nitrogen and allowed to stand at 25°C for 4 h. The solution was concentrated in vacuo (water aspirator) and the residue was then applied to a column of silica gel (Kieselgel 60, 230-400 mesh). The product was eluted with dichloromethane/methanol/0.880 ammonia solution (4:2:1). The desired amide was eluted in fractions 13-19 (10 ml fractions) and was homogeneous when monitored by tic on silica (CH ₂ Cl ₂ /MeOH/NH ₄ OH, 4:2:1), R _f = 0.11, chromatogram visualised by inspection under UV light (254 nm) and by the production of a pink-purple stain with 0.3% ninhydrin in solution in acidic alcohol. The fractions containing the product were combined and concentrated in vacuo to yield a colourless oil. This oil was dissolved in methanol (2 ml), filtered and the solution was then concentrated in vacuo (105 mg, 30% ⁾ . The residue was dissolved in distilled water (2 ml) and lyophilised which gave the amide as a colourless glass (80 mg) whose spectroscopic data include: UV _maχ 217 (e _max 2 500) and 272 ⁽ e _maχ 1 200)nm; p r (90 MHz, ² H ₂ 0) 1.5-2.0 (m, 8H, 4 x CH ₂ -CH ₂ ), 2.4-3.0 (m, 14H, 5 x CH ₂ -N and Ar-CH ₂ -CH ₂ ), 3.2 (t, J = 7, 2H, CON ² H-CH ₂ -CH ₂ ), 6.55-6.75 (m, 3H, 3 x ArH 2,4,6), and 7.05-7.3 (m, H, ArH 5)ppm; M+l 351 (FAB matrix m-nitrobenzyl alcohol ⁾

^C 19 ^H 34 ^N 4°2 requires M ⁺ 350).

The potency of this monoacylated spermine as an antagonist of the complex formed by the invertebrate L-quisqualate sub-type L-glutamate receptor and Its ion channel was assayed using the electrically stimulated retractor unguis muscle of the locust (Schistocerca gregaria). Twitch amplitude was reduced from control (100%) levels at the following concentrations: 1.08 x 10 ^"7 M 10% inhibition of twitch l.Oβ ^' x 10 ^"6 M 15%. Example 6 N-(4-Hvdroxycinnamoyl)-spermine.-To a solution of 4-hydroxycinnamic acid (82 mg, 0.50 mMol) in 1 ,2-dimethoxyethane (DME) (1 ml) was added a solution of dicyclohexylcarbodii ide (106 mg, 0.51 mMol, 1.03 equivalents) in DME (1 ml) in one portion at 25 ^β C. The colourless mixture was allowed to stand at 25°C for 3 h during which time a voluminous white precipitate of the urea was formed. This precipitate was then removed by filtration and the residue washed with DME (2 x 1 ml). The filtrate and the washings were combined and a solution of spermine (336 mg, 1.66 mMol, 3.3 equivalents) in DME/dimethyl- formamide (2 ml , 1:1) was added in one portion. The yellow, homogeneous solution was sealed under an atmosphere of nitrogen and allowed to stand at 25°C for 48 h. The solution was concentrated in vacuo (water aspirator) and the residue was then applied to a column of silica gel (Kieselgel 60, 230-400 mesh). The product was eluted with dichloromethane/methanol/0.880 ammonia solution (4:2:1). The desired amide was eluted in fractions 11-16 (10 ml fractions) and was homogeneous when monitored by tic on silica (CH ₂ Cl ₂ /Me0H/NH ₄ 0H, 4:2:1), R _f = 0.21, chromatogram visualised by inspection under UV light (254 n ) and by the production of a pink purple stain with 0.3% ninhydrin in solution in acidic alcohol. The fractions containing the product were combined and concentrated in vacuo to yield a pale yellow oil.

This oil was dissolved in ethanol (2 ml), filtered and the solution was then concentrated in vacuo (30 mg, 17% ⁾ . The

residue was dissolved in distilled water (2 ml) and lyophilised which gave the amide as a colourless, viscous oil (30 mg) whose spectroscopic data include: UV _maχ 224 293 and 312sh nm; pmr (90 MHz, ² H ₂ 0) 1.4-2.0 (m, 8H, 4 x CH ₂ -CH ₂ ) , 2.6-3.0 (m, 10H, 5 x CH ₂ -N), 3.35 (t, 0 = 7, 2H, C0N ² H _r CH ₂ -CH ₂ ) , 6.36 (d, J = 16, 1H, CH=CH-C0) 6.6-6.9 (m, 2H, 2 x ArH 3,5), and 7.2-7.6 (m, 3H, 2 x ArH 2,6 and Ar-CH=CH)ppm; M+l 349 (FAB matrix m-nitrobenzyl alcohol) C- _| gH ₃₂ N 0 ₂ requires M+ 348).

The potency of this monoacylated spermine as an antagonist of the complex formed by the invertebrate L-quisqualate sub-type L-glutamate receptor and its ion channel was assayed using the electrically stimulated retractor unguis muscle of the locust (Schistocerca gregaria). Twitch amplitude was reduced from control (100%) levels at the following concentrations: 10- ^* °M 4%

10 ^"9 M 18% 10 ^"8 M 24% 10 ^"7 M 33% 10- ⁶ M 56% 10 ^"5 M 70%

The IC ₅₀ = 6 x 10~ ⁵ M Example 7

N-(2.4-Dihvdroxyphenylacetv1)-spermine.-To a solution of

2,4-dibenzyloxyphenylacetic acid N-hydroxysuccinimide ester (93 mg, 0.22 mMol) in dichloromethane (3 ml) was added spermine (112 mg, 0.55 mMol, 2.5 equiva-lents)) in one portion. The colourless, homogeneous solution was sealed under an atmosphere of nitrogen and allowed to stand at 25 ^β C for 24 h. The solution was concentrated in vacuo (water aspirator) and the residue was then applied to a column of silica gel (Kieselgel 60, 230-400 mesh).

The product was eluted with dichloro ethane/methanol/- 0.880 ammonia solution (8:4:1). The desired amide was eluted in fractions 10-15 (10 ml fractions) and was homogeneous when monitored by tic on silica (CH ₂ Cl ₂ /MeOH/NH ₄ OH, 4:2:1), R _f = 0.22, chromatogram visualised by inspection under UV light ⁽ 254 nm ⁾ and

by the production of a pink-purple stain with 0.3% ninhydrin in solution in acidic alcohol. The fractions containing the product were combined and concentrated in vacuo to yield a pale yellow gum. This gum was dissolved in ethanol (2 ml), filtered and the solution was then concentrated in vacuo (50 mg, 45%). The residue was dissolved in distilled water (2 ml) and lyophilised which gave the amide as a white solid (43 mg) . The amide was dissolved in water ⁽ 2 ml) and aqueous hydrochloric acid (2M, 0.5 ml) and palladium on carbon (10%, 11 mg) were then added. The mixture was stirred and hydrogenated at 1 atm and 25°C for 24 h. The catalyst was removed by filtration through a pad of ieselguhr, eluted with water. The clear solution was then lyophilised which gave the desired amide trihydrochloride (34 mg) as a colourless glass whose spectroscopic data include : UV _maχ 293 (e _max 1 500)nm at ^' pH = 11; M+l 353 (FAB matrix m-nitrobenzyl alcohol) 1gH5.--.N4O3 requires M ⁺ 352).

The potency of this onoacylated spermine as an antagonist of the complex formed by the invertebrate L-quisqualate sub-type L-glutamate receptor and its ion channel was assayed using electrically stimulated the retractor unguis muscle of the locust (Schistocerca gregaria). Twitch amplitude was reduced from control levels between the following concentrations: 1 x 10 ^~*** M and 9 x 10 ^-5 M, such that an approximately 50% reduction was obtained at 5 x 10 ^_5 M. Example 8

N-(3.4-Dihydro yphenylacety1)-sperm1ne.-To a solution of 3,4-dibenzyloxyphenylacetic acid N-hydroxysuccinimide ester (115 mg, 0.26 mMol) in dichloromethane (5 ml) was added spermine (128 mg, 0.63 mMol, 2.45 equivalents) in one portion. The colourless, homogeneous solution was sealed under an atmosphere of nitrogen and allowed to stand at 25°C for 22 h. The solution was concentrated in vacuo (water aspirator) and the residue was then applied to a column of silica gel (Kieselgel 60, 230-400 mesh). The product was eluted with dichloromethane/methanol/0.880

ammonia solution (8:4:1). The desired amide was eluted in fractions 18-26 (10 ml fractions) and was homogeneous when monitored by tic on silica (CH ₂ Cl ₂ /MeOH/NH ₄ OH, 8:4:1), R _f = 0.16, chromatogram visualised by inspection under UV light (254 nm) and by the production of a pink-purple stain with 0.3% ninhydrin in solution 1n acidic alcohol. The fractions containing the product were combined and concentrated in vacuo to yield a pale yellow gum.

This gum was dissolved in methanol (2 ml), filtered and the solution was then concentrated in vacuo (48 mg, 35%). The residue was dissolved in distilled water (2 ml) and lyophilised which gave the amide as a colourless, viscous oil (46 mg). The amide was dissolved in water (2 ml) and aqueous hydrochloric acid

(2M, 0.5 ml) and palladium on carbon (10%, 12 mg) were then added. The mixture was stirred and hydrogenated at 1 at and

25°'C for 24 h. The catalyst was removed by filtration through a pad of Kieselguhr, eluted with water. The clear solution was then lyophilised which gave the desired amide trihydrochloride as a colourless glass (32 mg) whose spectroscopic data include: UV _maχ 2700) and 291 (e _maχ 2 500)nm at pH = 11.

The potency of this monoacylated spermine as a non-competitive antagonist of the complex formed by the invertebrate L-quisqualate sub-type L-glutamate receptor and its ion channel was assayed using the electrically stimulated retractor unguis muscle of the locust (Schistocerca gregarla). Twitch amplitude was reduced from control levels between the following concentrations: 1 x 10 ^"4 M and 9 x 10 ^_4 M, such that an approximately 50% reduction was obtained at 5 x 10~ ⁴ M. Example 9 N-(3.5-Dihvdroxyphenylacetyl)-spermine.-To a solution of 3,5-dibenzyloxyphenylacetic acid (86 mg, 0.247 mMol) in dichloromethane (1 ml) was added a solution of dicyclohexylcarbo¬ diimide (55 mg, 0.27 mMol 1.08 equivalents) in dichloromethane (1 ml) in one portion at 25°C. The colourless mixture was allowed to stand at 25°C for 1.5h during which time a voluminous white

precipitate of the urea was formed. This precipitate was then removed by filtration and the residue washed with dichloromethane (2 x 1 ml ⁾ . The filtrate and the washings were combined and a solution of spermine (150 mg, 0.74 mMol, 3.0 equivalents) in dichloromethane (1 ml) was added in one portion. The colourless, homogeneous solution was sealed under an atmosphere of nitrogen and allowed to stand at 25°C for 4 h. The solution was concentrated in vacuo (water aspirator) and the residue was then applied to a column ,of silica gel (Kieselgel 60, 230-400 mesh). The product was eluted with dichloromethane/methanol/0.800 ammonia solution (8:4:1). The desired amide was eluted in fractions 15-18 (10 ml fractions) and was homogeneous when monitored by tic on silica (CH ₂ Cl ₂ /MeOH/NH ₄ OH, 4:2:1) R _f = 0.11, chromatogram visualised by Inspection under UV light (254 nm) and by the production of a pink-purple stain with 0.3% ninhydrin in solution in acidic alcohol. The fractions containing the product were combined and concentrated in vacuo to yield a pale yellow gum.

This gum was dissolved in ethanol (2 ml), filtered and the solution was then concentrated in vacuo (29 mg, 22%). The residue was dissolved in distilled water (2 ml) and lyophilised which gave the amide as a pale yellow solid (29 mg) . The amide was dissolved in water (2 ml) and aqueous hydrochloric acid (2M, 0.5 ml) and palladium on carbon (10%, 11 mg) were then added. The mixture was stirred and hydrogenated at 1 atm and 25°C for 22 h. The catalyst was removed by filtration through a pad of Kieselguhr, eluted with water. The clear solution was then lyophilised which gave the desired amide trihydrochloride (24 mg) as a colourless glass whose spectroscopic data include: UV _maχ 290 ^(e max ¹ 300)nm at pH = 11; M+l 353 ⁽ FAB matrix m-nitrobenzyl alcohol) Cι H ₃₂ N θ3 requires M ⁺ 352).

The potency of this monoacylated spermine as an antagonist of the complex formed by the invertebrate L-quisqualate sub-type L-glutamate receptor and its ion channel was assayed using the

electrically stimulated retractor unguis muscle of the locust (Schistocerca gregarla). Twitch amplitude was reduced from control levels between the following concentrations: 1 07 x 10" ⁶ M 25% 1.07 x 10 ^"5 M 45%

Examples 10-22

In the present Examples, compounds of formula I were prepared by following the above General Procedure and adapting the methods described in Examples 1 to 7. The compounds prepared together with an indication of their potency as L-glutamate antagonists when tested in the locust leg retractor tr. ^• •-■e pharmacological screen fol low: Example 10

N-2-Hvdroxybenzoyl )-spermine.-According to the General Procedure using 2-hydroxybenzoic acid (138 mg, 1.00 mMol), dicyclohexylcarbodiimide (226 mg, 1.10 mMol), and spermine (400 mg, 1.98 mMol) in dichloromethane (6 ml), activation during 3 h and coupling over 4 h. The product was eluted over silica gel with dichloromethane/methanol/0.880 ammonia solution (4:2:1). The desired amide was in fractions 8-15 and was homogeneous when monitored by tic on silica (CH ₂ Cl ₂ /MeOH/NH ₄ OH, 4:2:1), R _f = 0.23, (98 mg, 29%), lyophi lisation gave 64 mg of a colourless, viscous oil whose spectroscopic data include: pmr (90 MHz, ² H ₂ 0) 1.5-1.9 (m, 8H, 4 x CH ₂ -CH ₂ , 2.6-2.9 (m, 10H, 5 x CH ₂ -N), 3.25 (t, 0 = 7, 2H, CON ² H-CH ₂ -CH ₂ ), 6.55-6.85 (m, 2H, 2 x ArH 3,5), and 7.1-7.3 (m, 2H, 2 x ArM 4,6)ppm; M+l 323 (FAB matrix m-nitrobenzyl alcohol and sodium chloride) C17H3 _Q N4O2 requires M ⁺ 322).

The potency of this onoacylated spermine as an antagonist of the invertebrate L-quisqualate sub-type L-glutamate receptor and its ion channel was assayed using the electrically stimulated retractor unguis muscle of the locust (Schistocerca gregaria). Twitch amplitude was reduced from control level at 1.09 x lO^M by approximately 25%.

Example 11

N-(3-Hvdroxybenzoyl)-spermine.-According to the General Procedure using 3-hydroxybenzoic acid (138 mg, 1.00 mMol), dicyclohexylcarbodiimide (226 mg, 1.10 mMol), and spermine (400 mg, 1.98 mMol) in dichloromethane (6 ml), activation during 3 h and coupling over 17 h. The product was eluted over silica gel with dichloromethane/methanol/0.880 ammonia solution (4:2:1). The desired amide was in fractions 8-13 and was homogeneous when monitored by tic on silica (CH ₂ Cl ₂ /Me0H/NH ₄ 0H, 4:2:1), R _f = 0.29, (76 g, 24%), lyophilisation gave 52 mg of a colourless, viscous oil whose spectroscoplc data include: pmr (90 MHz, ² H ₂ 0) 1.4-1.9 (m, 8H, 4 x CH ₂ -CH ₂ ), 2.5-2.9 (m, 10H, 5 x CH ₂ -N), 3.25 (t, 0 = 7, 2H, CON ² H-CH ₂ -CH ₂ ) , 6.5-6.8 On, 3H, 3 x ArH 2,4,6), and 7.0-7.3 ( , 1H, ArH 5)ppm; M+l 323 (FAB matrix m-nitrobenzyl alcohol and sodium chloride) 1 H304O2 requires M ⁺ 322).

The potency of this monoacylated spermine as an antagonist invertebrate L-quisqualate sub-type L-glutamate receptor and its 1on channel was assayed using the electrically stimulated retractor unguis muscle of the locust (Schistocerca gregaria). Twitch amplitude was reduced from control levels at 1.02 x lO^M by approximately 40%. Example 12

N-(4-Hydroxybenzov1)-spermine.-Accordinq to the General Procedure using 4-hydroxybenzoic acid (80 mg, 0.58 mMol), dicyclohexylcarbodiimide (125 mg, 0.61 mMol), and spermine (430 mg, 2.13 mMol) in DME/DMF (4 ml, 3:1), activation during 3 h and coupling over 48 h. The product was eluted over silica gel with dichloromethane/methanol/0.880 ammonia solution (2:2:1). The desired amide was in fractions 8-12 and was homogeneous when monitored by tic on silica (CH ₂ Cl ₂ /Me0H/NH ₄ 0H, 2:2 1), R _f = 0.29, (23 mg, 12%), lyophilisation gave 7 mg of a colourless, viscous oil whose spectroscoplc data include: pmr (90 MHz, ² H ₂ 0) 1.4-1.9 (m, 8H, 4 x CH ₂ -CH ₂ ), 2.5-2.9 (m, 10H, 5 x CH ₂ -N), 3.25 (t, 1 = 7, 2H, CON ² H-CH ₂ -CH ₂ ), 6.6-6.9 (m, 2H, 2 x ArH 3,5), and 7.0-7.3

( , 2H, 2 x ArH 2,6)ppm; M+l 323 (FAB matrix m-nitrobenzyl alcohol) C- _j H ₃₀ N ₄ 0 ₂ requires M ⁺ 322).

The potency of this monoacylated spermine as an antagonist of the invertebrate L-quisqual te sub-type -L-glutamate receptor and Its 1on channel was assayed using the electrically stimulated retractor unguis muscle of the locust (Schistocerca gregaria). Twitch amplitude was reduced from control levels: between 10~ ⁵ M and 10~ ⁴ M such that an approximately 50% reduction was obtained at 5 x 10-- ^** M. Example 13

N-(3-Hydroxycinnamov1)-spermine.-According to the General Procedure using 3-hydroxycinnamic acid (160 mg, 0.97 mMol), dicyclohexylcarbodiimide (226 mg, 1.10 mMol), and spermine (400 mg, 1.98 mMol) in dichloromethane (6 ml), activation during 2 h and coupling over 21 h. The product was eluted over silica gel with dichloromethane/methanol/0.880 ammonia solution (4:2:1). The desired amide was in fractions 15-22 and was homogeneous when monitored by tic on silica (CH ₂ Cl ₂ /MeOH/NH ₄ OH, 4:2:1), R _f = 0.22, (108 mg, 32%), lyophilisation gave 90 mg of a yellow viscous gum whose spectroscopic data include: UV _maχ 213 (e _max 3 500), 230sh and 375 (e _maχ 3 800) nm; pmr (90 MHz, ² H ₂ 0) 1.4-2.0 (m, 8H, 4 x CH ₂ -CH ₂ ), 2.6-3.0 (m, 10H, 5 x CH ₂ -N), 3.35 (t, 0 = 7, 2H, CON ² H-CH ₂ -CH ₂ ), 6.4 (d, 0_ = 16, 1H, CH=CH-C)), 3.55 (s, 2H, Ar-CH ₂ -C0), 6.6-6.9 (m, 3H, 3 x ArH 2,4,6), and 7.2-7.6 ( , 2H, ArH 5 and ArCH=CH)ppm; M+l 349 (FAB matrix -nitrobenzyl alcohol)

^C 19 ^H 32 ^N 4°2 ^{re u} i ^r s M ⁺ 348 ⁾ .

The potency of this monoacylated spermine as an antagonist of the invertebrate L-quisqualate sub-type L-glutamate receptor and

Its ion channel was assayed using the electrically stimulated retractor unguis muscle of the locust (Schistocerca gregaria).

Twitch amplitude was reduced from control levels at 9.2 x 10 ^-7 M by approximately 25%.

Example 14

N-(3-F1uoro-4-hvdroxyphenylacetyl)-spermine.-According to the General Procedure using 3-fluoro-4-hydroxyphenylacetic acid (85

mg, 0.50 mMol), dicyclohexylcarbodiimide (106 mg, 0.31 mMol), and spermine (512 mg, 2.53 mMol) in DME/DMF (4 ml, 3:1), activation during 2 h and coupling over 48 h. The product was eluted over silica gel with dichloromethane/methanol/0.880 ammonia solution (4:2:1). The desired amide was in fractions 12-19 and was homogeneous when monitored by ti on silica (CH ₂ Cl ₂ /Me0H/NH ₄ 0H, 4:2:1), Rf - 0.19, (39 mg, 22%), lyophilisation gave 30 mg of a colourless, viscous oil whose spectroscopic data include: pmr (90 MHz, ² H ₂ 0) 1.6-2.2 ( , 8H, 4 x CH ₂ -CH ₂ ), 2.85-3.2 (m, 10H, 5 x CH ₂ -N), 3.4 (t, 0 = 7, 2H, C0N ² H-CH ₂ -CH ₂ ), 3.6 (s, 2H, Ar-CH ₂ -C0), 6.8-7.1 (m, 2H, 2 x ArH 5,6), and 7.1 (d, 3 0 H-F-ll, H, ArH 2)ppm.

The potency of this monoacylated spermine as an antagonist of the invertebrate L-quisqualate sub-type L-glutamate receptor and its ion channel was assayed using the electrically stimulated retractor unguis muscle of the locust (Schistocerca gregaria). Twitch amplitude was reduced from control levels between 10~ ⁴ M and 10 ^~3 M, such that an approximately 50% reduction was obtained at 5 x 10 ^"4 M. Example 15

N-(2-Methoxyphenylacetyl)-spermine,-According to the General Procedure using 2-methoxyphenylacetic acid (81 mg. 0.49 mMol), dicyclohexylcarbodiimide (53 mg, 0.26 mMol), and spermine (201 mg, 0.99 mMol) in DME (4 ml), activation during 2.5 h and coupling over 48 h. The produce was eluted over silica gel with the lower layer of dichloromethane/methanol/0.880 ammonia solution (2:1:1). The desired amide was in fractions 6-10 and was homogeneous when monitored by tic on silica (CH ₂ Cl ₂ /Me0H/NH ₄ 0H lower layer, 2:1:1), R _f = 0.25, (28 mg, 31%), lyophilisation gave 16 mg of a colourless, viscous oil whose spectroscopic data include: pmr (90 MHz, ² H ₂ 0) 1.35-1.85 ( , 8H, 4 x CH ₂ -CH ₂ ), 2.4-2.9 (m, 10H, 5 x CH ₂ -N), 3.25 (t, J = 7, 2H, CON ² H-CH ₂ -CH ₂ ), 3.5 (s, 2H, Ar-Cfl ₂ -C0) , 3.83(s, 3H, 0CH ₃ ), 6.75-7.05 (m, 2H, 2 x ArH 3,5), and 7.15-7.35(m, 2H, 2 x ArH 4,6>ppm.

The potency of this monoacylated spermine as a non- competitive antagonist of the invertebrate L-quisqualate sub-type L-glutamate receptor and its ion channel was assayed using the electrically stimulated retractor unguis muscle of the locust (Schistocerca gregaria). Twitch amplitude was reduced from control (100%) levels between 1 x 10~ ⁴ M and 1 x 10 ^_3 M, such that an approximately 50% reduction was obtained at 5 x 10 ^_4 M. Example 16

N-(4-Methoxyphenylacetyl)-spermine.-According to the General Procedure using 4-methoxyphenylacetic acid (83 mg, 0.50 mMol), dicyclohexylcarbodiimide (56 mg, 0.27 mMol), and spermine (201 mg, 0.99 mMol) in DME (4 ml), activation during 2.5 h and coupling over 48 h. The product was eluted over silica gel with the lower layer of dichloromethane/methanol/0.880 ammonia solution (4:1:1). The desired amide was in fractions 16-25 and was homogeneous when monitored by tic on silica (CH ₂ Cl ₂ /Me0H/NH ₄ 0H lower layer, 4:1:1), R _f = 0.07, (30 mg, 32%), lyophilisation gave 21 mg of a colourless, viscous oil whose spectroscopic data include: pmr (90 MHz, ² H ₂ 0) 1.4-1.9 (m, 8H, 4 x CH ₂ -CH ₂ ), 2.4-2.9 (m, 10H, 5 x CH ₂ -N), 3.23 (t, -2 = 7, 2H, CON ² H-CH ₂ -CH ₂ ), 3.5 (s, 2H, Ar-CH ₂ -C0) , 3.83(s, 3H, 0CH ₃ ), 6.8-6.95 (m, 2H, 2 x ArH 3,5), and 7.1-7.3 (m, 2H, 2 x ArH 2,6)ppm.

The potency of this monoacylated spermine as an antagonist of the invertebrate L-quisqualate sub-type L-glutamate receptor and its ion channel was assayed using the electrically stimulated retractor unguis muscle of the _, locust (Schistocerca gregaria ⁾ . Twitch amplitude was reduced from control (100%) levels between 1 x 10~ ⁴ M and 1 x 10 ^_3 M, such that an approximately 50% reduction was obtained at 5 x 10 ^_4 M. Example 17

N-(2-Methoxyphenv1acetyl)-N' ,N' '-bis(3-aminopropyl)-l ,3- propanediamine.-Accordinα to the General Procedure using 2-methoxyphenylacetic acid (80 mg, 0.48 mMol ⁾ , dicyclohexyl¬ carbodiimide (106 mg, 0.51 mMol), and b1s(3-aminopropyl )-l ,3-

propanediamine (452 mg, 2.40 mMol) in DME (4 ml, activation during 2 h and coupling over 48 h. The product was eluted over silica gel with the lower layer of dichloromethane/methanol/0.880 ammonia solution (2:1:1). The desired amide was in fractions 4-7 and was homogeneous when monitored by tic on silica (CH ₂ Cl ₂ /Me0H/NH ₄ 0H lower layer, 2:1:1), R _f = 0.23, (55 mg, 34%) lyophilisation gave 54 mg of a colourless, viscous oil whose spectroscopic data include: pmr (90 MHz, C ² HC1 ₃ ) 0.9-1.4 (m, 4H, 4 x NH), 1.3-2.0 Cm., 6H, 3 x CH ₂ -CH ₂ ), 2.3-2.9 (m, 10H, 5 x CH ₂ -N), 3.22 (app. q, J = 7, 2H, C0NH-CH ₂ -CH ₂ ), 3.5 (s, 2H, Ar-CH ₂ -C0), 3.8(s, 3H, 0CH ₃ ) , 6.35(br t, 0 = 7, C0NH-CH ₂ ), 6.7-7.0 ( , 2H, 2 x ArH 3,5), and 7.1-7.35 (m, 2H, 2 x ArH 4,6)ppm.

The potency of this compound as an antagonist of the invertebrate. L-quisqualate sub-type L-glutamate receptor and its ion channel was assayed using the electrically stimulated retractor unguis muscle of the locust (Schistocerca gregaria). Twitch amplitude was reduced from control levels between 10 ^_4 M and 9 x 10~ ³ M, such that an approximately 50% reduction was obtained at 9 x 10 ^_4 M. Example 18

N-(4-Methoxyphenylacetyl)-N' ,N' '-bis(3-aminopropyl)-l.3- propanediamine.-Accordino to the General Procedure using 4- methoxyphenylacetic acid (80 mg, 0.48 mMol), dicyclohexyl- carbodiimide (106 mg, 0.51 mMol), and bis(3- aminopropyl)-l ,3- propanediamine (464 mg, 2.46 mMol) in DME (6 ml), activation during 2 h and coupling over 48 h. The product, was eluted over silica gel with the lower layer of dichloromethane/methanol/0.880 ammonia solution (2:1:1). The desired amide was in fractions 4-8 and was homogeneous when monitored by tic on silica (CH ₂ Cl ₂ /MeOH/NH ₄ OH lower layer, 2:1:1), R _f = 0.30, (35 mg, 22%) lyophilisation gave 26 mg of a colourless, viscous oil whose spectroscopic data include: pmr (90 MHz, C ² HC1 ₃ ) 1.0-1.4 (m, 4H, 4 x NH), 1.3-2.0 (m, 6H, ^' 3 x CH ₂ -CH ₂ ), 2.2-2.9 (m, 10H, 5 x CH ₂ -N), 3.25 (app. q, J _. = 7, 2H, C0NH-CH ₂ -CH ₂ ) , 3.42 (s, 2H,

Ar-CH ₂ -C0), 3.76 (s, 3H, 0CH ₃ ), 6.63 (br t, J = 7, C0NH-CH ₂ ), 6.8 (d, J = 8, 2H, 2 x ArH 3,5), and 7.15 (d, 0. -= 8, 2H, 2 x ArH 2,6)ppm.

The potency of this compound as an antagonist of the complex formed by the invertebrate L-quisqualate sub-type L-glutamate receptor and its 1on channel was assayed using the electrically stimulated retractor unguis muscle of the locust (Schistocerca gregaria). Twitch amplitude was reduced from control (100%) levels between 1 x 10 ^"4 M and 9 x 10 ^_3 M, such that an approximately 50% reduction was obtained at 9 x 10" ⁴ M. Example 19

N-(2-HvdroxyDhenylacetyl)-N' ,N' '-bis(3-aminopropyl)-l ,3- propanediamine.-According to the General Procedure using

2-hydroxyphenylacetic acid (160 mg, 1.05 mMol), dicyclohexyl- carbodiimide (230 mg, 1.11 mMol), and bis(3-aminopropy1)-l ,3- propanediamine (806 mg, 4.28 mMol) in DME (6 ml), activation during 4.5 h and coupling over 24 h. The product was eluted over silica gel with dichloromethane/- methanol/0.880 ammonia solution

(4:2:1). The desired amide was 1n fractions 8-20 and was homogeneous when monitored by ti on silica (CH ₂ Cl ₂ /MeOH/NH ₄ OH,

4:2:1), R _f = 0.11, (235 mg, 69%), lyophilisation gave 188 mg of a colourless, viscous oil whose spectroscopic data include: pmr (90

MHz, C ² HC1 ₃ ) 1.4-1.8 (m, 6H, 3 x CH ₂ -CH ₂ ), 2.3-2.85 (m, 10H, 5 x

CH ₂ -N), 3.2 (t, J = 7, 2H, CON ² H-CH ₂ -CH ₂ ), 3.5 (s, 2H, Ar-CH ₂ -C0), 3.9 (br s, 6H, 5 x NH and OH), 6.65-6.9 ( , 2H, 2 x

ArH 3,5), and 6.95-7.2 (m, 2H, 2 x ArH 4,6)ppm.

The potency of this compound as an antagonist of the complex formed by the invertebrate L-quisqualate sub-type L-glutamate receptor and its ion channel was assayed using the electrically stimulated retractor unguis muscle of the locust (Schistocerca gregaria). Twitch amplitude was reduced from control (100%) levels between 1 x 10 ^_4 M and 9 x 10 ^-3 M, such that an approximately 50% reduction was obtained at 9 x 10 ^_4 M. Example 20 N-(3-Hvdroxyphenylacetv1)-N' .N' '-bis(3-aminopropy1 )-l .3-

propanediamine.-Accord1no to the General Procedure using 3-hydroxyphenylacetic acid (150 mg, 0.98 mMol), dicyclohexyl¬ carbodiimide (226 mg, 1.10 mMol),.- and bis(3-aminopropyl)-l ,3- propanediamine (370 mg, 1.97 mMol) 1n dichloromethane (6 ml), activation during 2 h and coupling over 3 h. The product was eluted over silica gel . with dichloromethane/methanol/0.880 ammonia solution (4:2:1). The desired amide was in fractions 13-21 and was homogeneous when monitored by tic on silica (CH ₂ Cl ₂ /MeOH/NH ₄ OH, 4:2:1), R _f = 0.27, (97 mg, 31%), lyophilisation gave 79 mg of a colourless, viscous oil whose spectroscopic data include: pmr (90 MHz, ² H ₂ 0) 1.4-2.0 (m, 6H, 3 x CH ₂ -CH ₂ ), 2.3-2.9 (m, 10H, 5 x CH ₂ -N), 3.25 (t, 3_ = 7, 2H, CON ² H-CH ₂ -CH ₂ ), 3.5 (s, 2H, Ar-CH ₂ -C0) , 6.55-6.75 (m, 3H, 3 x ArH 2,4,6), and 7.05-7.3 ( , H, ArH)ppm. The potency of this compound as an antagonist of the complex formed by the invertebrate L-quisqualate sub-type L-glutamate receptor and its ion channel was assayed using the electrically stimulated retractor unguis muscle of the locust (Schistocerca gregaria). Twitch amplitude was reduced from control (100% ⁾ levels at 1.04 x 10 ^-4 M by approximately 60%. Example 21

N-(4-Hvdroxyphenylacetyl )-N' ,N" '-bis(3-aminopropyl )-l ,3- propanediamine,-Accordinα to the General Procedure using 4-hydroxyphenylacetic acid (160 mg, 1.05 mMol), dicyclohexyl- carbodiimide (231 mg, 1.12 mMol), and bi s(3-aminopropyl)-l ,3- propanediamine (806 mg, 4.28 mMol) 1n DME (6 ml), activation during 4.5 h and coupling over 48 h. The product was eluted over silica gel with dichloromethane/methanol/0.880 ammonia solution (4:2:1). The desired amide was in fractions 11-20 and was homogeneous when monitored by tic on silica (CH ₂ Cl ₂ /MeOH/NH. ₄ OH, 4:2:1), R _f = 0.13, (88 mg 26%), lyophilisation gave 74 mg of a colourless gum whose spectroscopic data include: pmr (90 MHz, ² H ₂ 0) (1.4-2.0 (m, 6H, 3 x CH ₂ -CH ₂ >, 2.4-2.9 (m, 10H, 5 x CH ₂ -N), 3.18 (t, 0_ = 7, 2H, C0N ² H-CH ₂ -CH ₂ ), 3.4 (s, 2H, Ar-CH ₂ -C0) , 6.68 (d, i •*-* 8, 2H x ArH 3,5), and 7.05 (d, 0 = 8, 2H, 2 x ArH 2,6)ppm.

The potency of this compound as an antagonist of the complex formed by the invertebrate L-quisqualate sub-type L-glutamate receptor and its ion channel was assayed using the electrically stimulated retractor unguis muscle of ^' the locust (Schistocerca gregaria). Twitch amplitude- was ^" reduced from control (100%) levels between 1 x 10 ^"4 M and 9 x 10 ^_3 M, such that an approximately 50% reduction was obtained at 9 x 10 ^"4 M, and an approximately 30% reduction at 10 ^_4 M. Example 22 N-(4-Hvdroxyphenylpropanoyl)-spermine.-To a solution of 4-hydroxyphenylpropanoic acid (83 mg, 0.50 mMol) in 1,2- dimethoxyethane (DME) (1 ml) was added a solution of dicyclohexylcarbodiimide (107 mg, 0.52 mMol, 1.04 equivalents) in DME (1 ml) in one portion at 25°C. The colourless mixture was allowed to stand at 25°C for 5 h during which time a voluminous white precipitate of the urea was formed. This precipitate was then removed by filtration and the residue washed with DME (2 x 1 ml). The filtrate and the washings were combined and a solution of spermine (401 mg, 1.98 mMol, 4.0 equivalents) in DME/dimethylformamide (2 ml, 1:1) was added in one portion. The colourless, homogeneous solution was sealed under an atmosphere of nitrogen and allowed to stand at 25 ^C C for 48 h. The solution was concentrated in vacuo (water aspirator) and the residue was then applied to a column of silica gel (Kieselgel 60, 230-400 mesh). The product was eluted with dichloromethane/methanol/0.880 ammonia solution (4:2:1). The desired amide was eluted 1n fractions 10-16 (10 ml fractions) and was homogeneous when monitored by tic on silica (CH ₂ CH ₂ /MeOH/NH ₄ OH, 4:2:1), R _f = 0.16, chromatogram visualised by inspection under UV light (254 nm) and by the production of a pink-purple stain with 0.3% ninhydrin in solution in acidic alcohol. The fractions containing the product were combined and concentrated in vacuo to yield a colourless oil.

This oil was dissolved in methanol (2 ml), filtered and the solution was then concentrated in vacuo (66 mg, 50%). The residue was dissolved in distilled water (2 ml) and lyophilised which gave the amide as a colourless, viscous oil (44 mg) whose spectroscopic data include: UV _maχ 224 (e _max 4 900) and 278 (e _max 1 600) nm; pmr (90 MHz, ² H ₂ 0) 1.2-2.1 (m, 8H, 4 x CH ₂ -CH ₂ ), 2.3-3.0 (m, 14H, 5 x CH ₂ -N and Ar-CH ₂ -CH ₂ ), 3.18 (t. 1 = 7, 2H, CON ² H-CH ₂ OCH ₂ ), 6.75 (d, 0 = 9, 2H, 2 x ArH 3,5), and 7.1 (d, 0_ = 9, 2H, 2 x ArH 4,6)ppm. The potency of this monoacylated spermine as an antogonist of the complex formed by the invertebrate L-quisqualate sub-type L-glutamate receptor and its ion channel was assayed using the electrically stimulated retractor unquis muscle of the locust (Schistorcerca gregaria). Twitch amplitude was reduced from control levels at the following concentrations:

The IC ₅₀ = 6 x 10~ ⁶ M