Functionalised antifouling compounds and use thereof

Abstract

The present invention relates to derivatives of , -disubstituted amide compounds which comprise a substituted aryl at the carbon such that the substituent provides a means for attachment or incorporation of the compound to or in a polymer. The provision of such a substituent on the aryl has surprisingly been found not only to permit attachment to or incorporation n a polymer but also retention of useful antifouling activity. In embodiments, the substituent is selected from hydroxyl, ethers, esters, carboxyls, alkylsilyls and alkenyls. Experiments demonstrate that antifouling activity can be as good or better as the corresponding unsubstituted compound and that polymers functionalized so as to include or be formed from the substituted compound can be used to reduce settlement.

Claims

1. A compound of formula (I) or a salt thereof: ##STR00049## wherein R.sup.1 is saturated C.sub.3 to C.sub.12 alkyl or C.sub.3 to C.sub.12 alkenyl; R.sup.2 is ##STR00050## wherein each of R.sup.A1, R.sup.A2, R.sup.A3, R.sup.A4 and R.sup.A5 is independently selected from OH, R.sup.S1OH, OR.sup.S2, R.sup.S1OR.sup.S2, OC(O)H, OC(O)R.sup.S2, R.sup.S1OC(O)H, R.sup.S1OC(O)R.sup.S2, C(O)OH, C(O)OR.sup.S2, R.sup.S1C(O)OH, R.sup.S1C(O)OR.sup.S2, OR.sup.S1OH, OR.sup.S1OR.sup.S2, OR.sup.S1OC(O)H, OR.sup.S1OC(O)R.sup.S2, OR.sup.S1C(O)OH, OR.sup.S1C(O)OR.sup.2, H and R.sup.S2, wherein, if present, each R.sup.S1 is independently optionally substituted C.sub.1 to C.sub.5 alkylene, and wherein, if present, each R.sup.S2 is independently selected from optionally substituted C.sub.1 to C.sub.5 alkyl, C.sub.2 to C.sub.5 alkenyl and C.sub.1 to C.sub.5 alkylsilyl-C.sub.1 to C.sub.5 alkylene, with the proviso that at least one of R.sup.A1, R.sup.A2, R.sup.A3, R.sup.A4 and R.sup.A5 is not H or R.sup.S2, and each of R.sup.3 and R.sup.4 is Me.

2. The compound according to claim 1 wherein R.sup.1 is C.sub.4 alkyl or C.sub.6 alkyl.

3. The compound according to claim 1, wherein, if present, each R.sup.S1 is independently optionally substituted C.sub.1 to C.sub.3 alkylene, and wherein, if present, each R.sup.S2 is independently selected from optionally substituted C.sub.1 to C.sub.3 alkyl and C.sub.2 to C.sub.3 alkenyl and C.sub.1 to C.sub.3 alkylsilyl-C.sub.1 to C.sub.3 alkylene.

4. The compound according to claim 1, wherein R.sup.2 is ##STR00051## wherein each of R.sup.A1, R.sup.A2, R.sup.A3, R.sup.A4 and R.sup.A5 is independently selected from OH, OMe, C(O)OH, CH.sub.2OH, CH.sub.2OAc, OC(O)CH.sub.3, OCH.sub.2C(O)OH, OCH.sub.2C(O)OCH.sub.3, OCH.sub.2CH.sub.2OH, OCH.sub.2CH.sub.2OC(O)CH.sub.3, OCH.sub.2CH.sub.2Si(Me).sub.3 and OC(O)CHCH.sub.2, and H, with the proviso that at least one of R.sup.A1, R.sup.A2, R.sup.A3, R.sup.A4 and R.sup.A5 is not H.

5. The compound according to claim 4, wherein at least two of R.sup.A1, R.sup.A2, R.sup.A3, R.sup.A4 and R.sup.A5 are H.

6. A compound according to claim 5, wherein at least three of R.sup.A1, R.sup.A2, R.sup.A3, R.sup.A4 and R.sup.A5 are H.

7. The compound according to claim 1, wherein the compound is selected from compounds ##STR00052##

8. A method of reducing or preventing fouling of a substrate comprising the step of applying to the substrate a compound according to claim 1.

9. The method according to claim 8, wherein R.sup.1 is C.sub.4 alkyl or C.sub.6 alkyl.

10. The method according to claim 8, wherein, if present, each R.sup.S1 is independently optionally substituted C.sub.1 to C.sub.3 alkylene, and wherein, if present, each R.sup.S2 is independently selected from optionally substituted C.sub.1 to C.sub.3 alkyl and C.sub.2 to C.sub.3 alkenyl and C.sub.1 to C.sub.3 alkylsilyl-C.sub.1 to C.sub.3 alkylene.

11. The method according to claim 8, wherein the compound is selected from ##STR00053##

12. A polymer comprising at least one repeating unit formed from a compound of formula (I) as defined in claim 1.

13. The polymer according to claim 12, wherein the polymer is selected from a (meth)acrylate polymer and a silicone polymer.

14. The polymer according to claim 13, wherein the polymer is a (meth)acrylate polymer and comprises repeating units derived from one or more of methylmethacrylate (MMA), hydroxyethyl acrylate (HEA) and vinyl pyrrolidinone (VP).

15. The polymer according to claim 12 comprising a pendant group according to formula X ##STR00054## wherein R.sup.1 is saturated C.sub.3 to C.sub.12 alkyl or C.sub.3 to C.sub.12 alkenyl; each of R.sup.3 and R.sup.4 is Me, each R.sup.AX is independently selected from OH, R.sup.S1OH, OR.sup.S2, R.sup.S1OR.sup.S2, OC(O)H, OC(O)R.sup.S2, R.sup.S1OC(O)H, R.sup.S1OC(O)R.sup.S2, C(O)OH, C(O)OR.sup.S2, R.sup.S1C(O)OH, R.sup.S1C(O)OR.sup.S2, OR.sup.S1OH, OR.sup.S1OR.sup.S2, OR.sup.S1OC(O)H, OR.sup.S1OC(O)R.sup.S2, OR.sup.S1C(O)OH, OR.sup.S1C(O)OR.sup.S2, H and R.sup.S2, n is an integer in the range 0 to 4, and wherein R.sup.L is a linker group selected from O, R.sup.L1O, OR.sup.L2, R.sup.L1OR.sup.L2, OC(O), OC(O)R.sup.L2, R.sup.L1OC(O), R.sup.L1OC(O)R.sup.L2, C(O)O, C(O)OR.sup.L2, R.sup.L1C(O)O, R.sup.L1C(O)OR.sup.L2, OR.sup.L1O, OR.sup.L1OR.sup.L2, OR.sup.L1OC(O), OR.sup.L1OC(O)R.sup.L2, OR.sup.L1C(O)O and OR.sup.L1C(O)OR.sup.L2; wherein, if present, each R.sup.L1 is independently optionally substituted C.sub.1 to C.sub.5 alkylene, and wherein, if present, each R.sup.L2 is independently optionally substituted C.sub.1 to C.sub.5 alkylene.

16. An antifouling coating composition comprising a compound of formula (I) as defined in claim 1 or a polymer according to claim 12.

17. A method of reducing or preventing fouling of a substrate, which method comprises the step of applying to the substrate a polymer according to claim 12 or coating composition according to claim 16.

18. The method according to claim 17, wherein the method of reducing or preventing fouling is a method of reducing or preventing biofilm formation by one or more of bacteria, fungi, algae and protozoans.

19. The method according to claim 8, wherein the method reduces or prevents biofilm formation by one or more of bacteria, fungi, algae and protozoans.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 shows average percentage settlement of barnacles in wells coated with polymers containing repeating units derived from a compound (16.11) of the present invention. Settlement on the control coating was similar to that for uncoated polystyrene. Whereas when increased amounts of P(MMA-co-16.11-co-VP) resulted in decline in barnacle settlement, with no settlement for test treatments >40 l.

DETAILED DESCRIPTION OF THE INVENTION

(2) Chemical Terms

(3) The term saturated, as used herein, pertains to compounds and/or groups which do not have any carbon-carbon double bonds or carbon-carbon triple bonds.

(4) The term unsaturated, as used herein, pertains to compounds and/or groups which have at least one carbon-carbon double bond or carbon-carbon triple bond. Compounds and/or groups may be partially unsaturated or fully unsaturated.

(5) The term carbo, carbyl, hydrocarbo, and hydrocarbyl, as used herein, pertain to compounds and/or groups which have only carbon and hydrogen atoms.

(6) The term hetero, as used herein, pertains to compounds and/or groups which have at least one heteroatom, for example, multivalent heteroatoms (which are also suitable as ring heteroatoms) such as boron, silicon, nitrogen, phosphorus, oxygen, sulfur, and selenium (more commonly nitrogen, oxygen, and sulfur) and monovalent heteroatoms, such as fluorine, chlorine, bromine, and iodine.

(7) The phrase optionally substituted, as used herein, pertains to a parent group which may be unsubstituted or which may be substituted.

(8) Unless otherwise specified, the term substituted, as used herein, pertains to a parent group which bears one or more substitutents. The term substituent is used herein in the conventional sense and refers to a chemical moiety which is covalently attached to, or if appropriate, fused to, a parent group. A wide variety of substituents are well known, and methods for their formation and introduction into a variety of parent groups are also well known.

(9) Alkyl: The term alkyl, as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a hydrocarbon compound having from 1 to 20 carbon atoms (unless otherwise specified), which may be aliphatic or alicyclic, and which may be saturated or unsaturated (e.g., partially unsaturated, fully unsaturated). Thus, the term alkyl includes the sub-classes alkenyl, alkynyl, cycloalkyl, cycloalkyenyl, cylcoalkynyl, etc., discussed below.

(10) In the context of alkyl groups, the prefixes (e.g., C.sub.1 to C.sub.4, C.sub.1 to C.sub.6, etc.) denote the number of carbon atoms, or range of number of carbon atoms. For example, the term C.sub.1 to C.sub.4alkyl, as used herein, pertains to an alkyl group having from 1 to 4 carbon atoms. Examples of groups of alkyl groups include C.sub.1 to C.sub.4alkyl (lower alkyl), and C.sub.2 to C.sub.6 alkyl. Note that the first prefix may vary according to other limitations; for example, for unsaturated alkyl groups, the first prefix must be at least 2; for cyclic and branched alkyl groups, the first prefix must be at least 3; etc.

(11) Examples of (unsubstituted) saturated alkyl groups include, but are not limited to, methyl (C.sub.1), ethyl (C.sub.2), propyl (C.sub.3), butyl (C.sub.4), pentyl (C.sub.5) and hexyl (C.sub.6).

(12) Examples of (unsubstituted) saturated linear alkyl groups include, but are not limited to, methyl (C.sub.1), ethyl (C.sub.2), n-propyl (C.sub.3), n-butyl (C.sub.4), n-pentyl (amyl) (C.sub.5) and n-hexyl (C.sub.6).

(13) Examples of (unsubstituted) saturated branched alkyl groups include iso-propyl (C.sub.3), iso-butyl (C.sub.4), sec-butyl (C.sub.4), tert-butyl (C.sub.4), iso-pentyl (C.sub.5), and neo-pentyl (C.sub.5).

(14) Alkenyl: The term alkenyl, as used herein, pertains to an alkyl group having one or more carbon-carbon double bonds. Examples of groups of alkenyl groups include C.sub.2-4alkenyl, C.sub.2-7alkenyl, C.sub.2-20alkenyl.

(15) Examples of (unsubstituted) unsaturated alkenyl groups include, but are not limited to, ethenyl (vinyl, CHCH.sub.2), 1-propenyl (CHCHCH.sub.3), 2-propenyl (allyl, CHCHCH.sub.2), isopropenyl (1-methylvinyl, C(CH.sub.3)CH.sub.2), butenyl (C.sub.4), pentenyl (C.sub.5), and hexenyl (C.sub.6).

(16) Hydroxy-C.sub.1-C.sub.6 alkyl: The term hydroxy-C.sub.1-C.sub.6 alkyl, as used herein, pertains to a C.sub.1-C.sub.6 alkyl group in which at least one hydrogen atom (e.g., 1, 2, 3) has been replaced with a hydroxy group. Examples of such groups include, but are not limited to, CH.sub.2OH, CH.sub.2CH.sub.2OH, and CH(OH)CH.sub.2OH.

(17) Hydrogen: H. Note that if the substituent at a particular position is hydrogen, it may be convenient to refer to the compound or group as being unsubstituted at that position.

(18) Aryl: The term aryl, as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound, which moiety has from 3 to 20 ring atoms (unless otherwise specified). Preferably, each ring has from 5 to 7 ring atoms.

(19) In this context, the prefixes (e.g., C.sub.3-20, C.sub.5-7, C.sub.5-6, etc.) denote the number of ring atoms, or range of number of ring atoms, whether carbon atoms or heteroatoms. For example, the term C.sub.5-6aryl, as used herein, pertains to an aryl group having 5 or 6 ring atoms. Examples of groups of aryl groups include C.sub.3-29aryl, C.sub.5-20aryl, C.sub.5-15aryl, C.sub.5-12aryl, C.sub.5-10aryl, C.sub.5-7aryl, C.sub.5-6aryl, C.sub.5aryl, and C.sub.6aryl.

(20) The ring atoms may be all carbon atoms, as in carboaryl groups. Examples of carboaryl groups include C.sub.3-20carboaryl, C.sub.5-20carboaryl, C.sub.5-15carboaryl, C.sub.5-12carboaryl, C.sub.5-10carboaryl, C.sub.5-7carboaryl, C.sub.5-6carboaryl, C.sub.5carboaryl, and C.sub.6carboaryl.

(21) Examples of carboaryl groups include, but are not limited to, those derived from benzene (i.e., phenyl) (C.sub.6), naphthalene (C.sub.10), azulene (C.sub.10), anthracene (C.sub.14), phenanthrene (C.sub.14), naphthacene (C.sub.18), and pyrene (C.sub.16).

(22) Examples of aryl groups which comprise fused rings, at least one of which is an aromatic ring, include, but are not limited to, groups derived from indane (e.g., 2,3-dihydro-1H-indene) (C.sub.9), indene (C.sub.9), isoindene (C.sub.9), tetraline (1,2,3,4-tetrahydronaphthalene (C.sub.10), acenaphthene (C.sub.12), fluorene (C.sub.13), phenalene (C.sub.13), acephenanthrene (C.sub.15), and aceanthrene (C.sub.16).

(23) Alternatively, the ring atoms may include one or more heteroatoms, as in heteroaryl groups. Examples of heteroaryl groups include C.sub.3-20heteroaryl, C.sub.5-20heteroaryl, C.sub.5-15heteroaryl, C.sub.5-12neteroaryl, C.sub.5-10heteroaryl, C.sub.5-7heteroaryl, C.sub.5-6heteroaryl, C.sub.5heteroaryl, and C.sub.6heteroaryl.

(24) Halo (or halogen): F, Cl, Br, and I.

(25) Hydroxy: OH.

(26) Silyl: SiR.sub.3, where R is a silyl substituent, for example, H, a C.sub.1-7alkyl group, a C.sub.3-20heterocyclylgroup, or a C.sub.5-20aryl group, preferably H, a C.sub.1-7alkyl group, or a C.sub.5-20aryl group. Examples of silyl groups include, but are not limited to, SiH.sub.3, SiH.sub.2(CH.sub.3), SiH(CH.sub.3).sub.2, Si(CH.sub.3).sub.3, Si(Et).sub.3, Si(iPr).sub.3, Si(tBu)(CH.sub.3).sub.2, and Si(tBu).sub.3.

(27) Oxysilyl: Si(OR).sub.3, where R is an oxysilyl substituent, for example, H, a C.sub.1-7alkyl group, a C.sub.3-20heterocyclylgroup, or a C.sub.5-20aryl group, preferably H, a C.sub.1-7alkyl group, or a C.sub.5-20aryl group. Examples of oxysilyl groups include, but are not limited to, Si(OH).sub.3, Si(OMe).sub.3, Si(OEt).sub.3, and Si(OtBu).sub.3.

(28) Siloxy (silyl ether): OSiR.sub.3, where SiR.sub.3 is a silyl group, as discussed above. Oxysiloxy: OSi(OR).sub.3, wherein OSi(OR).sub.3 is an oxysilyl group, as discussed above.

(29) Silyl-alkylene: -alkylene-SiR.sub.3, where R is a silyl substituent as discussed above. For example, CH.sub.2CH.sub.2Si(Me).sub.3.

(30) Includes Other Forms

(31) Unless otherwise specified, included in the above are the well known ionic, salt, solvate, and protected forms of these substituents. For example, a reference to carboxylic acid (COOH) also includes the anionic (carboxylate) form (COO.sup.), a salt or solvate thereof, as well as conventional protected forms. Similarly, a reference to an amino group includes the protonated form (N.sup.+HR.sup.1R.sup.2), a salt or solvate of the amino group, for example, a hydrochloride salt, as well as conventional protected forms of an amino group. Similarly, a reference to a hydroxyl group also includes the anionic form (O.sup.), a salt or solvate thereof, as well as conventional protected forms.

(32) Salts

(33) It may be convenient or desirable to prepare, purify, and/or handle a corresponding salt of the active compound, for example, an environmentally-acceptable salt.

(34) Examples of suitable salts are discussed in Berge et al., 1977, Pharmaceutically Acceptable Salts, J. Pharm. Sci., Vol. 66, pp. 1-19.

(35) For example, if the compound is anionic, or has a functional group which may be anionic (e.g., COOH may be COO.sup.), then a salt may be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na.sup.+ and K.sup.+, alkaline earth cations such as Ca.sup.2+ and Mg.sup.2+, and other cations such as Al.sup.+3. Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NH.sub.4.sup.+) and substituted ammonium ions (e.g., NH.sub.3R.sup.+, NH.sub.2R.sub.2.sup.+, NHR.sub.3+, NR.sub.4.sup.+). Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylannine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH.sub.3).sub.4.sup.+.

(36) If the compound is cationic, or has a functional group which may be cationic (e.g., NH.sub.2 may be NH.sub.3.sup.+), then a salt may be formed with a suitable anion. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.

(37) Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.

(38) Unless otherwise specified, a reference to a particular compound also includes salt forms thereof.

(39) Solvates

(40) It may be convenient or desirable to prepare, purify, and/or handle a corresponding solvate of the active compound. The term solvate is used herein in the conventional sense to refer to a complex of solute (e.g., active compound, salt of active compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc.

(41) Unless otherwise specified, a reference to a particular compound also include solvated forms thereof.

(42) Certain Preferred Substituents

(43) In one preferred embodiment, the substituent(s), often referred to herein as R, are independently selected from: halo; hydroxy; ether (e.g., C.sub.1-7alkoxy); formyl; acyl (e.g., C.sub.1-7alkylacyl, C.sub.5-20arylacyl); acylhalide; carboxy; ester; acyloxy; amido; acylamido; thioamido; tetrazolyl; amino; nitro; nitroso; azido; cyano; isocyano; cyanato; isocyanato; thiocyano; isothiocyano; sulfhydryl; thioether (e.g., C.sub.1-7alkylthio); sulfonic acid; sulfonate; sulfone; sulfonyloxy; sulfinyloxy; sulfamino; sulfonamino; sulfinamino; sulfamyl; sulfonamido; C.sub.1-7alkyl (including, e.g., unsubstituted C.sub.1-7hydroxyalkyl, C.sub.1-7carboxyalkyl, C.sub.1-7aminoalkyl, C.sub.5-20aryl-C.sub.1-7alkyl); C.sub.3-20heterocyclyl; or C.sub.5-20aryl (including, e.g., C.sub.5-20carboaryl, C.sub.5-20heteroaryl, C.sub.1-7alkyl-C.sub.5-20aryl and C.sub.5-20haloaryl)).

(44) In one preferred embodiment, the substituent(s), often referred to herein as R, are independently selected from:

(45) F, Cl, Br, and I;

(46) OH;

(47) OMe, OEt, O(tBu), and OCH.sub.2Ph;

(48) SH;

(49) SMe, SEt, S(tBu), and SCH.sub.2Ph;

(50) C(O)H;

(51) C(O)Me, C(O)Et, C(O)(tBu), and C(O)Ph;

(52) C(O)OH;

(53) C(O)OMe, C(O)OEt, and C(O)O(tBu);

(54) C(O)NH.sub.2, C(O)NHMe, C(O)NMe.sub.2, and C(O)NHEt;

(55) NHC(O)Me, NHC(O)Et, NHC(O)Ph, succinimidyl, and maleimidyl;

(56) NH.sub.2, NHMe, NHEt, NH(iPr), NH(nPr), NMe.sub.2, NEt.sub.2, N(iPr).sub.2, N(nPr).sub.2, .sup.N(nBu).sub.2, and N(tBu).sub.2;

(57) CN;

(58) NO.sub.2;

(59) -Me, -Et, -nPr, -iPr, -nBu, -tBu;

(60) CF.sub.3, CHF.sub.2, CH.sub.2F, CCl.sub.3, CBr.sub.3, CH.sub.2CH.sub.2F, CH.sub.2CH F.sub.2, and CH.sub.2CF.sub.3;

(61) OCF.sub.3, OCHF.sub.2, OCH.sub.2F, OCCl.sub.3, OCBr.sub.3, OCH.sub.2CH.sub.2F, OCH.sub.2CHF.sub.2, and OCH.sub.2CF.sub.3;

(62) CH.sub.2OH, CH.sub.2CH.sub.2OH, and CH(OH)CH.sub.2OH;

(63) CH.sub.2NH.sub.2, CH.sub.2CH.sub.2NH.sub.2, and CH.sub.2CH.sub.2NMe.sub.2; and, optionally substituted phenyl.

(64) In one preferred embodiment, the substituent(s), often referred to herein as R, are independently selected from: F, Cl, Br, I, OH, OMe, OEt, SH, SMe, SEt, C(O)Me, C(O)OH, C(O)OMe, CONH.sub.2, CONHMe, NH.sub.2, NMe.sub.2, NEt.sub.2, N(nPr).sub.2, N(iPr).sub.2, CN, NO.sub.2, -Me, -Et, CF.sub.3, OCF.sub.3, CH.sub.2OH, CH.sub.2CH.sub.2OH, CH.sub.2NH.sub.2, CH.sub.2CH.sub.2NH.sub.2, and -Ph.

(65) In one preferred embodiment, the substituent(s), often referred to herein as R, are independently selected from: hydroxy; ether (e.g., C.sub.1-7alkoxy); ester; amido; amino; and, C.sub.1-7alkyl (including, e.g., unsubstituted C.sub.1-7haloalkyl, C.sub.1-7hydroxyalkyl, C.sub.1-7carboxyalkyl, C.sub.1-7aminoalkyl, C.sub.5-20aryl-C.sub.1-7alkyl).

(66) In one preferred embodiment, the substituent(s), often referred to herein as R, are independently selected from:

(67) OH;

(68) OMe, OEt, O(tBu), and OCH.sub.2Ph;

(69) C(O)OMe, C(O)OEt, and C(O)O(tBu);

(70) C(O)NH.sub.2, C(O)NHMe, C(O)NMe.sub.2, and C(O)NHEt;

(71) NH.sub.2, NHMe, NHEt, NH(iPr), NH(nPr), NMe.sub.2, NEt.sub.2, N(iPr).sub.2, N(nPr).sub.2, N(nBu).sub.2, and N(tBu).sub.2;

(72) -Me, -Et, -nPr, -iPr, -nBu, -tBu;

(73) CF.sub.3, CHF.sub.2, CH.sub.2F, CCl.sub.3, CBr.sub.3, CH.sub.2CH.sub.2F, CH.sub.2CHF.sub.2, and CH.sub.2CF.sub.3;

(74) CH.sub.2OH, CH.sub.2CH.sub.2OH, and CH(OH)CH.sub.2OH; and,

(75) CH.sub.2NH.sub.2, CH.sub.2CH.sub.2NH.sub.2, and CH.sub.2CH.sub.2NMe.sub.2.

(76) Other Terms

(77) As used herein, the term fouling refers to the attachment and growth of microorganisms and small organisms to a substrate exposed to, or immersed in, a liquid medium, for example an aqueous medium, as well as to an increase in number of the microorganisms and/or small organisms in a container of the liquid medium.

(78) Accordingly foulers or microfoulers are used interchangeably and refer to the organisms that foul a substrate. Fouling may occur in structures exposed to or immersed in fresh water as well as in sea water. In particular, the term may be used to refer to a solid medium or substrate exposed to, or immersed in sea water.

(79) Accordingly, the term antifouling refers to the effect of preventing, reducing and/or eliminating fouling. Antifouling agents or compounds are also called antifoulants.

(80) An antifoulant compound is usually applied at a standard concentration which is the concentration that is effective for its purpose. Accordingly, a concentration less than or below the standard concentration is one where the antifoulant is not effective when it is used alone.

(81) The term substrate as used herein refers to a solid medium such as surfaces of structures or vessels exposed to, or immersed in a liquid medium. The liquid medium may be fresh water or seawater and may be a body of water in a manmade container such as a bottle, pool or tank, or the liquid may be uncontained by any manmade container such as seawater in the open sea.

(82) A structure as used herein refers to natural geological or manmade structures such as piers or oil rigs and the term vessel refers to manmade vehicles used in water such as boats and ships.

(83) The microorganisms referred to herein include viruses, bacteria, fungi, algae and protozoans. Small organisms referred to herein can include organisms that commonly foul substrates exposed to, or immersed in, fresh water or seawater such as crustaceans, bryozoans and molluscs, particularly those that adhere to a substrate. Examples of such small organisms include barnacles and mussels and their larvae. Small organisms can also be called small animals. The term organism referred to herein is to be understood accordingly and includes microorganisms and small organisms.

(84) The term marine organism as used herein refers to organisms whose natural habitat is sea water. The terms marine microorganism and marine small organism are to be understood accordingly.

(85) Further, the term microfouling refers to fouling by microorganisms and the term macrofouling refers to fouling by organisms larger than microorganisms such as small organisms defined above.

(86) The terms biocide or biocidal compound refer to compounds that inhibit the growth of microorganisms and small organisms by killing them. The terms biostatic or biostatic compound refer to compounds that inhibit the growth of microorganisms or small organisms by preventing them from reproducing and not necessarily by killing them.

(87) The term degradation as used herein refers to the chemical breakdown or modification of a compound in water, preferably sea water.

(88) The term growth as used herein refers to both the increase in number of microorganisms and small organisms, as well to the development of a small organism from juvenile to adult stages. Accordingly, biocides and biostatics can be applied as a treatment to a body of liquid or to a substrate surface to inhibit the growth of microorganisms and small organisms. As such, biocides and biostatics can be antifoulants and can prevent, reduce or eliminate biofilm formation.

(89) Accordingly, the terms bacteriocidal and bacteriostatic refer to effects of compounds on bacteria.

(90) The term bioactivity as used herein refers to the effect of a given agent or compound, such as a biocidal or biostatic compound, on a living organism, particularly on microorganisms or small organisms.

(91) A biofilm is a complex aggregation of microorganisms, usually bacteria or fungi, marked by the excretion of a protective and adhesive matrix. Biofilms are also often characterized by surface attachment, structural heterogeneity, genetic diversity, complex community interactions, and an extracellular matrix of polymeric substances. Biofilms may also be more resistant to antibiotics compared to unaggregated bacteria due to the presence of the matrix.

(92) The term pharmaceutical as it relates to a use, agent, compound or composition, refers to the medical treatment of a disease or disorder in humans or animals. Accordingly, a pharmaceutical compound is a compound used for the medical treatment of a disease or disorder in humans or animals.

(93) As used herein, the term standard concentration as it pertains to an anti-fouling agent or compound, refers to the concentration at which the agent or compound is effective against microorganisms or small organisms at which it are directed when that agent or compound is used alone. Accordingly, the term effective means having a desired effect and the term below standard concentration refers to the level at which the agent or compound is not effective when used alone.

Examples Part 1Compounds

Synthesis of Compounds

(94) Several methods for the chemical synthesis of compounds of the present invention are described herein. These and/or other well known methods may be modified and/or adapted in known ways in order to facilitate the synthesis of additional compounds within the scope of the present invention.

(95) The amides may be prepared according to the following general methodologies

(96) Method A

(97) The synthesis of alkoxylated substituted compounds such as the 15-series compounds is based on a two step protocol in which commercially available phenylacetic acid derivatives undergo DCC mediated amide formation with piperidine (Scheme 1). Subsequent alkylation of the resultant 2-arylacetamides then proceeds upon treatment with LDA and bromobutane under standard conditions.

(98) ##STR00009##

(99) The same methodology was also adopted for the dialkyl amides. Thus, the synthesis of the methoxy- and hydroxyaryl congeners of the unsubstituted parent compound is based on a three or four step protocol in which commercially available phenylacetic acid derivatives are first converted to either the piperdine or dimethyl amides via the corresponding acid chlorides or benzotriazolyl esters. Subsequent LDA promoted alkylation with either 1-bromobutane or 6-bromo-1-hexene affords the desired methoxyaryl compounds in low to good yields as shown in Scheme 1.1.

(100) ##STR00010##

(101) Demethylation of selected methoxyaryl targets was performed using boron tribromide in dichloromethane as outlined in Scheme 1.2. Treatment of 15.1, 15.2, 15.3 and 17.2 under these conditions all proceeded smoothly to afford the corresponding hydroxyaryl derivatives in good yield and in high purity.

(102) ##STR00011##
Method B

(103) The synthesis of hydroxymethylated compounds and acetylated analogues were accessed from the readily synthesized amides following standard protection and alkylation protocols (Scheme 2). Acetylation of the p-derivative afforded compounds in good isolated yield.

(104) ##STR00012##

(105) More specifically, in order to gain access the hydroxymethylated congeners of 12.1 and their acetate derivatives, it was necessary to use different synthetic routes based on the commercial availability of the phenylacetic acid derivatives. Whilst p-hydroxymethylphenylacetic acid is commercially available and was able to be used directly in a coupling reaction with piperidine, the corresponding o-hydroxymethylphenylacetic acid was not commercially available. Hence the requisite amide was accessed by nucleophilic ring opening of commercially available isochromanone with piperidine in moderate isolated yield (Scheme 2.1 below). With the o- and p-hydroxymethylamides in hand, treatment with tert-butyldimethylsilyl (TBS) chloride in the presence of imidazole afforded the corresponding TBS ethers in moderate yield and these underwent alkylation to furnish 16.1 and 16.2 in their protected form. Treatment of the TBS ethers with TBAF in THF resulted in removal of the TBS protecting group to afford 16.1 and 16.2 in near quantitative yields. Compound 16.3 was then isolated following treatment of 16.2 with acetic anhydride in pyridine. This is shown in Scheme 2.1 below, being a modified version of Scheme 2.

(106) ##STR00013##

(107) The procedure to convert 16.2 directly to 17.9 was a two step process whereby Swern oxidation to the corresponding aldehyde was performed prior to treatment with Oxone. The desired acid was obtained in moderate overall yield (Scheme 3).

(108) ##STR00014##

(109) The remaining targeted congeners of 12.1 could all be accessed by modification of 16.5 by treatment with an appropriate electrophile. In all cases the target compounds were obtained in moderate to excellent yield. A summary of these reactions are shown in Scheme 4.

(110) ##STR00015##

(111) Using the above methodologies, the compounds based on the following structure were synthesised, and are preferred embodiments (reference compound excluded):

(112) TABLE-US-00001 (III) R.sup.A1 R.sup.A2 R.sup.A3 R.sup.A4 R.sup.A5 Compound H H H H H 12.1 (reference) H H OMe H H 15.1 H OMe H H H 15.2 OMe H H H H 15.3 H OMe H OMe H 15.4 H OMe H H OMe 15.5 H OMe OMe H H 15.6 OMe H OMe H H 15.7 CH.sub.2OH H H H H 16.1 H H CH.sub.2OH H H 16.2 H H CH.sub.2OAc H H 16.3 H H OH H H 16.5 H OH H H H 17.5 OH H H H H 17.4

(113) Additionally, the following compounds were synthesised, and are preferred embodiments.

(114) TABLE-US-00002 Compound R.sup.A1 R.sup.A2 R.sup.A3 R.sup.A4 R.sup.A5 No. H H HOC(O) H H 17.9 CH.sub.2OH H H H H 16.1 H H CH.sub.2OH H H 16.2 H H CH.sub.2OAc H H 16.3 H H CH.sub.3C(O)O H H 16.4 H H HOC(O)CH.sub.2O H H 16.9 H H CH.sub.3OC(O)CH.sub.2O H H 16.7 H H HOCH.sub.2CH.sub.2O H H 16.6 H H CH.sub.3C(O)OCH.sub.2CH.sub.2O H H 16.8 H H (CH.sub.3).sub.3SiCH.sub.2CH.sub.2O H H 16.10 H H CH.sub.2CHC(O)O H H 16.11

(115) Additionally, the compounds of the following structure were synthesised, and are preferred embodiments

(116) TABLE-US-00003 (IV) Compound R.sup.A1 R.sup.A2 R.sup.A3 R.sup.A4 R.sup.A5 No. H H OCH.sub.3 H H 17.1 H H OH H H 17.6

(117) Additionally, the compounds of the following structure were synthesised, and are preferred embodiments

(118) TABLE-US-00004 (V) Compound R.sup.A1 R.sup.A2 R.sup.A3 R.sup.A4 R.sup.A5 No. H H OCH.sub.3 H H 17.2 H H OH H H 17.7

(119) Additionally, the compounds of the following structure were synthesised, and are preferred embodiments

(120) TABLE-US-00005 (VI) Compound R.sup.A1 R.sup.A2 R.sup.A3 R.sup.A4 R.sup.A5 No. H H OCH.sub.3 H H 17.3 H H OH H H 17.8

(121) These compounds were tested for bioactivity against barnacles.

(122) Synthesis Methods and Data for Selected Amide Derivatives

(123) Characterisation

(124) Proton (.sup.1H) and carbon (.sup.13C) NMR spectra were recorded on a Bruker NMR spectrometer operating at 400 MHz for .sup.1H and 75.4 MHz for .sup.13C. Deuterochloroform (CDCl.sub.3) was used as the solvent unless otherwise indicated. Chemical shifts (d) are reported as the shift in parts per million (ppm) from tetramethylsilane (TMS, 0.00 ppm). NMR spectra recorded in CDCl.sub.3 were referenced to the residual chloroform singlet (7.26 ppm) for .sup.1H, and the central peak of the CDCl.sub.3 triplet (77.00 ppm) for .sup.13C. .sup.1H NMR spectroscopic data are reported as follows: chemical shift (), multiplicity (s: singlet, d: doublet, t: triplet, q: quartet, qt: quintet, m: multiplet, dd: doublet of doublets, etc., br: broad), coupling constant (J Hz) and relative integral (number of protons). .sup.13C spectroscopic data are reported as chemical shift () and assignment where possible. Infrared spectra were recorded on a Bio-rad Excalibur Series TFS 3000MX FTIR. Samples were run as thin liquid films on NaCl plates. IR spectral data is reported as follows: frequency (.sub.max cm.sup.1), strength (vs: very strong, s: strong, m: medium, w: weak). High resolution EI mass spectra were recorded on a Thermo Finnigan MAT XP95 mass spectrometer. Analytical thin layer chromatography (tlc) was conducted on aluminium sheets coated with silica gel F.sub.254 (Merck). The chromatograms were analysed at a wavelength of 254 nm (where appropriate) and/or developed using an acidic solution (5% H.sub.2SO.sub.4) of potassium permanganate in water followed by heating. All solvents used were of AR grade and purified by literature procedures where appropriate (Armarego, 2003).

(125) General ProcedureDCC Mediated Amide Bond Formation

(126) To a cooled (0 C.) stirred solution of phenylacetic acid deriVative (1 equiv.) in DMF (1.2 mL/mmol) was added DCC (1.1 equiv.) and HOBt (1.1 equiv.). The resulting mixture was allowed to stir for 1 hour, by which time a heavy colourless precipitate was evident. Piperidine (1.1 equiv.) was added to the reaction mixture and stirring was continued for a further two hours, after which time the reaction mixture was filtered. The mother liquor was taken up in EtOAc and washed successively with saturated NaHCO.sub.3 and water (3, 2.4 mL/mmol). The organic layer was dried (MgSO.sub.4) and concentrated in vacuo to afford the crude amides, which were purified by flash column chromatography using the solvent systems specified.

(127) General ProcedureAmide Bond Formation Via Acid Chlorides

(128) To a cooled (0 C.) stirred solution of methoxyphenylacetic acid in DCM (0.4 mL mmol.sup.1) was added thionyl chloride (0.4 mL mmol.sup.1). The resulting mixture was allowed to warm to room temperature and was heated at 50 C. for 2 hours after which time the reaction mixture was cooled to room temperature and carefully poured onto ice. The organic layer was dried (MgSO.sub.4) and concentrated in vacuo to afford the desired acid chloride which was used without further purification.

(129) For piperidine amides, the appropriate amount of acid chloride (1 mol. equiv.) was dissolved in an equal amount of dry CH.sub.2Cl.sub.2 and added slowly to a cooled (0 C.) solution of piperidine (2 mol. equiv.) in CH.sub.2Cl.sub.2 (1 mL mmol.sup.1). The resulting mixture was allowed to warm to room temperature and stirred for a further two hours. The crude reaction mixture was washed with water and the organic layer dried (MgSO.sub.4) and concentrated in vacuo to afford the desired amide. No further purification was necessary.

(130) For dimethyl amides, the appropriate amount of acid chloride was slowly added to cooled (0 C.) 40% solution of dimethylamine in water (10 mol. equiv.) and stirred for 2 hours after warming to room temperature. CH.sub.2Cl.sub.2 was added to the reaction mixture and the organic layer was washed with water, dried (MgSO.sub.4) and concentrated in vacuo to afford the desired amide.

(131) General Procedure-Alkylation

(132) To a cooled (78 C.) stirred solution of freshly distilled diisopropylamide (1 equiv.) in dry THF (2 mL/mmol) was added n-butyllithium in hexanes (1 equiv). The resulting reaction mixture became pale yellow and was stirred for 10-15 minutes at 78 C. prior to the careful addition of the desired amide (0.95 equiv.). The resulting mixture was stirred for 1 hour at which point bromobutane (1 equiv.) was'added. The resulting mixture was allowed to warm to room temperature over a number of hours (at least 3) and continued stirring for a further 13 hours (16 hours in total). The reaction was quenched by the careful dropwise addition of water to the reaction mixture. Following this, water was added to the reaction mixture and the aqueous phase removed. The organic layer was washed with water followed by brine, dried (MgSO.sub.4) and concentrated under reduced pressure. Purification was carried out by flash column chromatography using the solvent systems specified.

Compound 15.1

2-(4-methoxy)phenyl-1-(piperidin-1-yl)ethanone

(133) ##STR00020##

(134) The title compound was prepared from 4-methoxyphenylacetic acid (1.0 g, 6.1 mmol) following the general procedure for amide bond formation. The product was isolated as a colourless oil (1.0 g, 65%) following purification by flash column chromatography (EtOAc, Rf=0.5). .sup.1H NMR (400 MHz, CDCl.sub.3) 1.35 (m, 2H); 1.49 (m, 2H); 1.57 (m, 2H); 3.35 (m, 2H); 3.55 (m, 2H); 3.64 (s, 2H); 3.77 (s, 3H); 6.85 (d, J=8.4 Hz, 2H); 7.16 (d, .sup.2J=8.4 Hz 2H). .sup.13C NMR (75 MHz, CDCl.sub.3) 24.47, 25.52, 26.25, 40.26, 42.90, 47.25, 55.28, 114.08, 127.47, 129.61, 158.27, 169.60. HRMS (ESI+1 ion) m/z calcd for C.sub.14H.sub.20NO.sub.2 234.1489, found 234.1496.

2-(4-methoxy)phenyl-(1-piperidin-1-yl)hexanone

(135) ##STR00021##

(136) The title compound was prepared following the general procedure outline for n-alkylation from 2-(4-methyoxy)phenyl-1-(piperidin-1-ypethanone (740 mg, 3.41 mmol). The title compound was isolated as a pale yellow oil (160 mg, 16%) following purification by flash column chromatography (20% EtOAc in hexane, Rf=0.6). .sup.1H NMR (400 MHz, CDCl.sub.3) 0.83 (t, J=7 Hz, 3H); 1.03 (m, 1H); 1.14 (m, 1H); 1.2-1.6 (multiple signals, 8H); 1.68 (m, 1H); 2.05 (m, 1H); 3.31-3.45 (2m, 3H); 3.64 (m, 2H); 3.78 (s, 3H); 6.83 (d, J=8.9 Hz, 2H); 7.18 (d, J=8.9 Hz 2H). .sup.13C NMR (75 MHz, CDCl.sub.3) 14.05, 22.74, 24.60, 25.60, 26.16, 30.07, 34.81, 43.15, 46.64, 47.78, 55.24, 113.98, 128.29, 133.03, 158.34, 171.67. HRMS (ESI+ 1 ion) m/z calcd for C.sub.18H.sub.29NO.sub.2 290.2115, found 290.2130.

Compound 15.7

2-(2,4-dimethoxy)phenyl-1-(piperidin-1-yl)ethanone

(137) ##STR00022##

(138) The title compound was prepared from 2,4-dimethoxyphenylacetic acid (1.0 g, 4.7 mmol) following the general procedure outline for amide bond formation. The product was isolated as a yellow oil (690 mg, 56%) following purification by flash column chromatography (EtOAc, Rf=0.6). .sup.1H NMR (400 MHz, CDCl.sub.3) 1.38 (m, 2H); 1.52 (m, 2H); 1.58 (m, 2H); 3.36 (m, 2H); 3.56 (m, 2H); 3.20 (s, 2H); 3.29 (s, 3H); 3.81 (s, 3H); 6.45 (m, 3H); 7.13 (d, J=8.6 Hz). .sup.13C NMR (75 MHz, CDCl.sub.3) 24.46, 25.56, 26.26, 40.72, 40.77, 42.94, 47.27, 111.24, 111.70, 120.66, 127.97, 147.80, 149.07, 169.45. HRMS (ESI+1 ion) m/z calcd for C.sub.15H.sub.22NO.sub.3 264.1594, found 264.1605.

2-butyl-2-(2,4-dimethoxy)phenyl-1-(piperidin-1-yl)hexanone

(139) The title compound was prepared following the general procedure outline for -alkylation from 2-(21,41-dimethyoxy)phenyl-1-(piperidin-1-yl) ethanone (688 mg, 2.61 mmol). The product was isolated as a pale yellow oil (380 mg, 45%) following purification by flash column chromatography (50% EtOAc in hexane, Rf=0.7). .sup.1H NMR (400 MHz, CDCl.sub.3) 0.87 (t, J=7 Hz, 3H); 0.973 (m, 1H); 1.13 (m, 1H), 1.23-1.65 (multiple signals, 9H); 2.01 (m, 1H); 3.33 (m, 3H); 3.7 (m, 1H); 3.79 (s, 3H); 3.82 (s, 3H); 4.12 (t, J=7 Hz, 1H); 6.42 (m, 3H); 7.20 (d, J=8 Hz). .sup.13C NMR (75 MHz, CDCl.sub.3) 14.06, 22.79, 24.73, 25.67, 26.16, 29.92, 34.04, 39.21, 43.11, 46.19, 55.32, 55.50, 98.26, 104.66, 121.93, 128.56, 156.79, 159.38, 172.45. HRMS (ESI+1 ion) m/z calcd for C.sub.19H.sub.30NO.sub.3 320.2220, found 320.2229.

Compound 15.6

2-butyl-2-(2,4-dimethyoxy)phenyl-1-(piperidin-1-yl)hexanone

(140) ##STR00023##

(141) The title compound was prepared following the general procedure outline for -alkylation from 2-(21,41-dimethyoxy)phenyl-1-(piperidin-1-yl)ethanone (688 mg, 2.61 mmol). The product was isolated as a pale yellow oil (380 mg, 45%) following purification by flash column chromatography (50% EtOAc in hexane, Rf=0.7). .sup.1H NMR (400 MHz, CDCl.sub.3) 0.87 (t, J=7 Hz, 3H); 0.97 (m, 1H); 1.13 (m, 1H), 1.23-1.65 (multiple signals, 9H); 2.01 (m, 1H); 3.33 (m, 3H); 3.7 (m, 1H); 3.79 (s, 3H); 3.82 (s, 3H); 4.12 (t, J=7 Hz, 1H); 6.42 (m, 3H); 7.20 (d, J=8 Hz). .sup.13C NMR (75 MHz, CDCl.sub.3) 14.06, 22.79, 24.73, 25.67, 26.16, 29.92, 34.04, 39.21, 43.11, 46.19, 55.32, 55.50, 98.26, 104.66, 121.93, 128.56, 156.79, 159.38, 172.45. HRMS (ESI+1 ion) m/z calcd for C.sub.19H.sub.30NO.sub.3 320.2220, found 320.2229.

Compound 16.2

2-(4-hydroxymethyl)phenyl-1-(piperidin-1-yl)ethanone

(142) The title compound was prepared from 4-hydroxymethylphenylacetic acid (1.0 g, 6.0 mmol) following the general procedure outlined for amide coupling. The product was isolated as a viscous, colourless oil (540 mg, 39%) following purification by flash column chromatography (EtOAc, Rf=0.5). .sup.1H NMR (400 MHz, CDCl.sub.3) 1.37 (m, 2H); 1.52 (m, 2H); 1.58 (m, 2H); 3.36 (m, 2H); 3.56 (m, 2H); 3.71 (s, 2H); 4.66 (s, 2H); 7.23 (d, J=8 Hz, 2H); 7.31 (d, J=8 Hz, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3) 524.39, 25.44, 25.47, 26.21, 34.91, 40.77, 42.92, 47.25, 55.77, 64.92, 127.33, 128.76, 134.65, 139.48, 169.30. HRMS (ESI+1 ion) m/z calcd for C.sub.14H.sub.20NO.sub.2 234.1489, found 234.1489.

2-(4-tert-butyldimethylsilyloxymethyl)phenyl-1-(piperidin-1-yl)ethanone

(143) To a cooled (0 C.) solution of 2-(4-hydroxymethyl)phenyl-1-(piperidin-1-ypethanone (540 mg, 2.32 mmol) and imidazole (97 mg, 1.4 mmol) in dry DCM was added a solution of TBSCI (214 mg, 1.42 mmol) in DCM (5 mL). The resulting reaction mixture was allowed to stir for 2 hours. After this time, the reaction mixture was washed successively with water (2) and brine and the organic layer was dried (MgSO.sub.4) and concentrated in vacuo. The title compound was obtained as a colourless oil (420 mg, 53%) following purification by flash column chromatography (20% EtOAc, Rf=0.6). .sup.1H NMR (400 MHz, CDCl.sub.3) 0.084 (s, 6H); 0.929 (s, 9H); 1.34 (m, 2H); 1.52 (m, 2H); 1.59 (m, 2H); 3.43 (m, 2H); 3.57 (m, 2H); 3.71 (s, 2H); 4.71 (s, 2H); 7.20 (d, J=8 Hz, 2H); 7.25 (d, J=8 Hz, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3) 5-5.21, 24.45, 25.59, 25.97, 26.20, 40.94, 42.89, 47.27, 64.77, 126.41, 128.40, 133.96, 139.81, 169.36. HRMS (ESI+1 ion) m/z calcd for C.sub.20H.sub.34NO.sub.2Si, 348.2353, found 348.2354.

2-(4-tert-butyldimethylsilyloxymethyl)phenyl-1-(piperidin-1-yl)hexanone

(144) The title compound was prepared from 2-(4-tert-butyldimethylsilyloxymethyl)phenyl-1-(piperidin-1-yl) ethanone (420 mg, 1.21 mmol) following the general procedure outlined for -alkylation. The product was obtained as a colourless oil (260 mg, 53%) following purification by flash column chromatography (20% EtOAc in hexane, Rf=0.6). .sup.1H NMR (400 MHz, CDCl.sub.3) 0.010 (s, 6H); 0.087 (t, J=7 Hz, 314); 0.94 (s, 9H); 1.01 (m, 1H); 1.14 (m, 1H); 1.2-1.6 (multiple signals, 8H); 1.68 (m, 1H); 2.10 (m, 1H); 3.3-3.5 (m, 3H); 3.68 (m, 2H); 4.72 (s, 2H); 7.15 (m, 4H). .sup.13C NMR (75 MHz, CDCl.sub.3) 5.20, 14.03, 22.75, 24.75, 25.68, 26.12, 30.40, 34.78, 43.16, 46.62, 48.47, 64.79, 126.38, 127.66, 139.52, 139.73, 171.42. HRMS (ESI+1 ion) m/z calcd for C.sub.24H.sub.42NO.sub.2Si, 404.2979, found 404.2983.

2-(4-hydroxymethyl)phenyl-1-(piperidin-1-yl)hexanone

(145) A solution of 2-(4-tert-butyldimethylsilyloxymethyl)phenyl-1-(piperidin-1-yl)hexanone (260 mg, 0.64 mmol) in dry THF (5 mL) was added to a flask containing a solution of TBAF in THF (1.29 mmol). The resulting reaction mixture was allowed to stir for 1 hour, by which time analysis by tlc revealed that no starting material remained. The reaction mixture was washed with water (2) followed by brine and the organic layer was dried (MgSO.sub.4) and concentrated in vacuo to afford the crude product. The title compound was isolated as a colourless oil (142 mg, 76%) following purification by flash column chromatography (50% EtOAc in hexane, Rf=0.4). .sup.1H NMR (400 MHz, CDCl.sub.3) 0.87 (t, J=7 Hz, 3H); 1.04 (m, 1H); 1.14 (m, 1H); 1.9-1.7 (m, 8H); 1.71 (m, 1H); 1.91 (m, 1H); 3.34 (m, 2H); 3.47 (m, 1H); 3.63 (m, 1H); 3.69 (t, J=7 Hz, 1H); 4.66 (s, 2H); 7.25 (d, J=8 Hz, 2H); 7.30 (d, J=8 Hz, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3) 14.02, 22.72, 24.56, 25.57, 26.12, 30.07, 34.76, 43.19, 46.64, 48.41, 65.07, 127.06, 127.99, 139.28, 140.32, 171.32. HRMS (ESI+1 ion) m/z calcd for C.sub.18H.sub.28NO.sub.2 290.2114, found 289.2117.

Compound 16.3

2-(4-acetoxymethyl)phenyl-1-(piperidin-1-yl)hexanone

(146) To a round bottomed flask containing DMAP (2 mg) was added a solution of 2-(4-hydroxymethyl) phenyl-1-(piperidin-1-yl)hexanone (30 mg, 0.10 mmol) in dry dichloromethane (2 mL). To the resulting mixture was added dry NEt.sub.3 (208 L, 1.5 mmol) followed by acetic anhydride (100 L, 1.0 mmol). The resulting mixture was allowed to stir for 3 hours. After this time, the reaction mixture was washed with saturated NaHCO.sub.3, water and then brine and the organic phase was dried (Na.sub.2SO.sub.4) and concentrated under reduced pressure. The title compound was obtained as a colourless oil (20 mg, 60%) following purification by flash column chromatography (50% EtOAc in hexane, Rf=0.7). .sup.1H NMR (400 MHz, CDCl.sub.3) 0.86 (t, J=7 Hz, 3H); 1.0-1.2 (2m, 2H); 1.2-1.5 (multiple signals, 8H); 1.68 (m, 1H); 4.53 (m+s, 4H); 3.33 (m, 1H), 3.39 (m, 1H); 3.49 (m, 1H); 3.60 (m, 1H); 3.70 (t, J=7 Hz, 1H); 5.07 (s, 2H); 7.72 (m, 4H). .sup.13C NMR (75 MHz, CDCl.sub.3) 14.01, 21.08, 22.72, 24.57, 25.60, 26.20, 30.09, 34.77, 43.20, 46.66, 48.38, 66.07, 128.03, 128.58, 134.24, 141.02, 171.09, 171.17. Note: Compound hydrolyses on standing, HRMS consistent with that of free alcohol.

Compound 17.1

2-(4-methoxyoxyphenyl)-1-(piperidin-1-yl)oct-7-en-1-one

(147) ##STR00024##

(148) The title compound was prepared following the general procedure for alkylation from 2-(4-hydroxyphenyl)-1-(piperidin-1-yl)ethanone (100 mg, 0.43 mmol) and 6-bromo-1-hexene (70 L, 0.47 mmol). The purified compound was isolated as a pale yellow oil (26 mg, 26%) following purification by flash column chromatography (20% EtOAc in hexane, Rf=0.5). .sup.1H NMR (400 MHz, CDCl.sub.3) 1.1-1.5 (multiple signals, 10H); 1.65 (m, 1H); 2.01 (m, 3H); 3.35, (m, 3H); 3.63 (t, J=7 Hz, 1H); 3.65 (m, 1H); 3.78 (s, 3H); 4.89 (dm, J=10 Hz, 1H); 4.95 (dm, J=17 Hz, 1H); 5.77 (ddd, J=17, 10, 6.5 Hz, 1H); 6.83 (d, J=8.5 Hz, 2H); 7.17 (d, J=8.5 Hz, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3) 24.69, 25.70, 26.25, 27.46, 29.07, 33.79, 35.02, 43.27, 46.75, 47.88, 55.35, 114.13, 114.34, 278.08, 128.89, 133.05, 139.19, 158.38, 171.69. HRMS (ESI+1 ion) m/z calcd for C.sub.20H.sub.30NO.sub.2 316.2271, found 316.2265.

Compound 17.2

2-(4-methoxyphenyl)-N,N-dimethylhexanamide

(149) ##STR00025##

(150) The title compound was prepared following the general procedure for alkylation from 2-(4-hydroxyphenyl)-N,N-dimethylacetamide (100 mg, 0.52 mmol) and 1-bromobutane (70 L, 0.57 mmol). The purified compound was isolated as a pale yellow oil (120 mg, 60%) following purification by flash column chromatography (EtOAc, Rf=0.7). .sup.1H NMR (400 MHz, CDCl.sub.3) 0.85 (t, J=7 Hz, 3H); 1.14 (m, 1H); 1.28 (m, 3H); 1.68 (m, 1H); 2.05 (m, 1H); 2.93 (s, 3H); 2.94 (s, 3H); 3.63 (t, J=7 Hz, 1H); 3.78 (s, 3H); 6.84 (d, J=8.8 Hz, 2H); 7.20 (d, J=8.8 Hz, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3) 14.16, 22.84, 35.03, 36.02, 37.30, 48.09, 55.37, 114.14, 129.04, 132.64, 158.50, 173.75. HRMS (ESI+1 ion) m/z calcd for C.sub.16H.sub.24NO.sub.2 262.1802, found 262.1795.

Compound 17.3

2-(4-methoxyphenyl)-N,N-dimethyloct-7-enamide

(151) ##STR00026##

(152) The title compound was prepared following the general procedure for alkylation from 2-(4-hydroxyphenyl)-N,N-dimethylacetamide (100 mg, 0.52 mmol) and 6-bromo-1-hexene (84 L, 0.57 mmol). The purified compound was isolated as a pale yellow oil (120 mg, 60%) following purification by flash column chromatography (EtOAc, Rf=0.6). .sup.1H NMR (400 MHz, CDCl.sub.3) 1.1-1.5 (multiple signals, 4H); 1.66 (m, 1H); 2.02 (m, 3H); 2.93 (2s, 6H); 3.63 (t, J=7 Hz, 1H); 3.78 (s, 3H); 4.90 (dm, J=10 Hz, 1H); 4.96 (dm, J=17 Hz, 1H); 5.77 (ddd, J=17, 10, 6.5 Hz, 1H); 6.85 (d, J=8.8 Hz, 2H); 7.19 (d, J=8.8 Hz, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3) 27.41, 29.02, 33.75, 35.10, 36.00, 37.27, 48.05, 55.34, 114.13, 114.35, 128.98, 132.49, 139.12, 158.49, 173.62. HRMS (ESI+1 ion) m/z calcd for C.sub.17H.sub.26NO.sub.2 276.1958, found 276.1958.

Compound 16.5

2-(4-hydroxyphenyl)-1-(piperidin-1-yl)hexan-1-one

(153) ##STR00027##

(154) To a cooled (78 C.) solution of 15.1 (1 g, 3.46 mmol) in dry DCM was added a solution of boron tribromide in DCM (10 mL, 10 mmol). The resulting mixture was allowed to warm to room temperature over a number of hours (at least 3) and continued stirring for a further 14 hours (17 hours in total). The reaction was quenched by the careful dropwise addition of ammonium hydroxide to the reaction mixture (caution: slow addition to reaction mixture at 0 C.). Following this, water was added to the reaction mixture and the aqueous phase removed. The organic layer was dried (MgSO.sub.4) and concentrated in vacuo. The title compound was obtained as a pale brown solid (0.93 g, 97%). .sup.1H NMR (400 MHz, CDCl.sub.3) 0.85 (t, 3H); 1.29 (m, 10H); 1.70 (m, 2H); 2.04 (m, 1H); 3.39 (m, 2H); 3.63 (t, 1H); 3.67 (m, 1H); 6.77 (d, J=8.5 Hz, 2H); 7.12 (d, J=8.5 Hz, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3) 13.99, 22.67, 24.51, 25.55, 26.11, 29.98, 34.59, 43.32, 46.75, 47.73, 115.63, 128.83, 132.28, 154.95, 172.09. HRMS (ESI+1 ion) m/z calcd for C.sub.17H.sub.26NO.sub.2 276.1958, found 276.1954.

Compound 17.7

2-(4-hydroxyphenyl)-N,N-dimethylhexanamide

(155) ##STR00028##

(156) The title compound was obtained as a pale yellow solid (6 mg, 53%) in a similar manner to that described for 16.5 from 17.2 (12 mg, 0.048 mmol). 0.85 (t, J=7 Hz, 3H); 1.1-1.5 (multiple signals, 4H); 1.65 (m, 1H); 2.03 (m, 1H); 2.94 (s, 3H); 3.63 (t, J=7 Hz, 1H); 6.76 (d, J=8.5 Hz, 2H); 7.16 (d, J=8.5 Hz, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3) 14.15, 22.82, 30.14, 31.10, 34.96, 48.05, 115.61, 129.22, 132.53, 154.65, 173.87. HRMS (ESI+1 ion) m/z calcd for C.sub.14H.sub.23NO.sub.2 236.1645, found 236.1644.

Compound 17.8

2-(4-hydroxyphenyl)-N,N-dimethyloct-7-enamide

(157) ##STR00029##

(158) To a cooled (78 C.) solution of 17.3 (25 mg, 0.09 mmol) in dry CH.sub.2Cl.sub.2 (1 mL) was added BBr.sub.3 (1 M solution in CH.sub.2Cl.sub.2, 0.27 mL, 0.27 mmol). The resulting mixture was allowed to warm to room temperature and was stirred for an additional 30 minutes. After this time, the reaction mixture was cooled to 78 C. and MeOH (2 mL) was added to the reaction mixture. After 5 minutes the resulting mixture was poured onto water and an additional 10 mL of CH.sub.2Cl.sub.2 was added. The organic layer was washed dried and concentrated in vacuo to afford the crude product as a pale yellow solid. Purification of the crude product by flash column chromatography (50% EtOAc/hexane, Rf=0.2) afforded the title compound as a pale yellow oil which solidified upon standing (4 mg, 15%). .sup.1H NMR (400 MHz, CDCl.sub.3) 1.1-1.5 (multiple signals, 4H); 1.67 (m, 1H); 1.98 (m, 3H); 2.93 (s, 3H); 2.94 (s, 3H); 3.62 (t, J=7 Hz, 1H); 4.84 (s, 1H ArOH); 4.90 (dm, J=10 Hz, 1H); 4.95 (dm, J=17 Hz, 1H); 5.77 (ddd, J=17, 10, 6.5 Hz, 1H); 6.76 (d, J=8.8 Hz, 2H); 7.14 (d, J=8.8 Hz, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3) 27.29, 28.90, 33.64, 34.97, 35.94, 37.19, 47.92, 114.26, 115.51, 129.10, 132.48, 139.01, 173.55. HRMS (ESI+1 ion) m/z calcd for C.sub.16H.sub.24NO.sub.2 262.1802, found 262.1086.

Compound 17.6

2-(4-hydroxyphenyl)-1-(piperidin-1-yl)oct-7-en-1-one

(159) ##STR00030##

(160) The title compound was prepared in a similar manner to that described for 17.8 from 2-(4-methoxyoxyphenyl)-1-(piperidin-1-yl)oct-7-en-1-one (50 mg, 0.18 mmol). The title compound was obtained as a colourless, low melting point solid (6 mg, 11%) following purification by flash column chromatography (50% EtOAc/hexane, Rf=0.5). .sup.1H NMR (400 MHz, CDCl.sub.3) 1.0-1.5 (multiple signals, 10H); 1.66 (m, 1H); 2.02 (m, 3H); 3.38, (m, 3H); 3.62 (t, J=7 Hz, 1H); 3.65 (m, 1H); 4.88 (dm, J=10 Hz, 1H); 4.95 (dm, J=17 Hz, 1H); 5.76 (ddd, J=17, 10, 6.5 Hz, 1H); 6.76 (d, J=8.5 Hz, 2H); 7.11 (d, J=8.5 Hz, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3) 24.54, 25.58, 26.12, 27.31, 28.91, 33.66, 34.79, 43.27, 46.72, 47.72, 114.24, 115.59, 128.92, 132.59, 139.04, 154.64, 171.80. HRMS (ESI+1 ion) m/z calcd for C.sub.19H.sub.28NO.sub.2 302.2115, found 302.2120.

2-(4-hydroxymethyl)phenyl-1-(piperidin-1-yl)ethanone

(161) ##STR00031##

(162) The title compound was prepared from 4-hydroxymethylphenylacetic acid (1.0 g, 6.0 mmol) following the general procedure outlined for DCC mediated amide formation. The product was isolated as a viscous, colourless oil (0.54 g, 39%) following purification by flash column chromatography (EtOAc, Rf=0.5). .sup.1H NMR (400 MHz, CDCl.sub.3) 1.37 (m, 2H); 1.52 (m, 2H); 1.58 (m, 2H); 3.36 (m, 2H); 3.56 (m, 2H); 3.71 (s, 2H); 4.66 (s, 2H); 7.23 (d, J=8 Hz, 2H); 7.31 (d, J=8 Hz, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3) 24.39, 25.44, 25.47, 26.21, 34.91, 40.77, 42.92, 47.25, 55.77, 64.92, 127.33, 128.76, 134.65, 139.48, 169.30. HRMS (ESI+1 ion) m/z calcd for C.sub.14H.sub.20NO.sub.2 234.1489, found 234.1489.

2-(4-tert-butyldimethylsilyloxymethyl)phenyl-1-(piperidin-1-yl)ethanone

(163) ##STR00032##

(164) To a cooled (0 C.) solution of 2-(4-hydroxyrnethyl)phenyl-1-(piperidin-1-yl)ethanone (540 mg, 2.32 mmol) and imidazole (97 mg, 1.4 mmol) in dry DCM was added a solution of TBSCI (214 mg, 1.42 mmol) in DCM (5 mL). The resulting reaction mixture was allowed to stir for 2 hours. After this time, the reaction mixture was washed successively with water (2) and brine and the organic layer was dried (MgSO.sub.4) and concentrated in vacuo. The title compound was obtained as a colourless oil (420 mg, 53%) following purification by flash column chromatography (20% EtOAc, Rf=0.6). .sup.1H NMR (400 MHz, CDCl.sub.3) 0.084 (s, 6H); 0.929 (s, 9H); 1.34 (m, 2H); 1.52 (m, 2H); 1.59 (m, 2H); 3.43 (m, 2H); 3.57 (m, 2H); 3.71 (s, 2H); 4.71 (s, 2H); 7.20 (d, J=8 Hz, 2H); 7.25 (d, J=8 Hz, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3) -5.21, 24.45, 25.59, 25.97, 26.20, 40.94, 42.89, 47.27, 64.77, 126.41, 128.40, 133.96, 139.81, 169.36. HRMS (ESI+1 ion) m/z calcd for C.sub.20H.sub.34NO.sub.2Si, 348.2353, found 348.2354.

2-(4-tert-butyldimethylsilyloxymethyl)phenyl-1-(piperidin-1-yl)hexanone

(165) ##STR00033##

(166) The title compound was prepared from 2-(4-tert-butyldimethylsilyloxymethyl)phenyl-1-(piperidin-1-yl) ethanone (420 mg, 1.21 mmol) following the general procedure outlined for -alkylation. The product was obtained as a colourless oil (260 mg, 53%) following purification by flash column chromatography (20% EtOAc in hexane, Rf=0.6). .sup.1H NMR (400 MHz, CDCl.sub.3) 0.010 (s, 6H); 0.087 (t, J=7 Hz, 3H); 0.94 (s, 9H); 1.01 (m, 1H); 1.14 (m, 1H); 1.2-1.6 (multiple signals, 8H); 1.68 (m, 1H); 2.10 (m, 1H); 3.3-3.5 (m, 3H); 3.68 (m, 2H); 4.72 (s, 2H); 7.15 (m, 4H). .sup.13C NMR (75 MHz, CDCl.sub.3) -5.20, 14.03, 22.75, 24.75, 25.68, 26.12, 30.40, 34.78, 43.16, 46.62, 48.47, 64.79, 126.38, 127.66, 139.52, 139.73, 171.42. HRMS (ESI+1 ion) m/z calcd for C.sub.24H.sub.42NO.sub.2Si, 404.2979, found 404.2983.

Compound 16.1

2-(4-hydroxymethyl)phenyl-1-(piperidin-1-yl)hexanone

(167) ##STR00034##

(168) A solution of 2-(4-tert-butyldimethylsilyloxymethyl)phenyl-1-(piperidin-1-yl)hexanone (260 mg, 0.64 mmol) in dry THF (5 mL) was added to a flask containing a solution of TBAF in THF (1.29 mmol). The resulting reaction mixture was allowed to stir for 1 hour, by which time analysis by tlc revealed that no starting material remained. The reaction mixture was washed with water (2) followed by brine and the organic layer was dried (MgSO.sub.4) and concentrated in vacuo to afford the crude product. The title compound was isolated as a colourless oil (142 mg, 76%) following purification by flash column chromatography (50% EtOAc in hexane, Rf=0.4). .sup.1H NMR (400 MHz, CDCl.sub.3) 0.87 (t, J=7 Hz, 3H); 1.04 (m, 1H); 1.14 (m, 1H); 1.9-1.7 (m, 8H); 1.71 (m, 1H); 1.91 (m, 1H); 3.34 (m, 2H); 3.47 (m, 1H); 3.63 (m, 1H); 3.69 (t, J=7 Hz, 1H); 4.66 (s, 2H); 7.25 (d, J=8 Hz, 2H); 7.30 (d, J=8 Hz, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3) 14.02, 22.72, 24.56, 25.57, 26.12, 30.07, 34.76, 43.19, 46.64, 48.41, 65.07, 127.06, 127.99, 139.28, 140.32, 171.32. HRMS (ESI+1 ion) m/z calcd for C.sub.18H.sub.28NO.sub.2 290.2114, found 289.2117.

Compound 16.3

2-(4-acetoxymethyl)phenyl-1-(piperidin-1-yl)hexanone

(169) ##STR00035##

(170) To a round bottomed flask containing DMAP (2 mg) was added a solution of 2-(4-hydroxymethyl) phenyl-1-(piperidin-1-yl)hexanone (30 mg, 0.10 mmol) in dry CH.sub.2Cl.sub.2 (2 mL). To the resulting mixture was added dry NEt.sub.3 (208 L, 1.5 mmol) followed by acetic anhydride (100 L, 1.0 mmol). The resulting mixture was allowed to stir for 3 hours. After this time, the reaction mixture was washed with saturated NaHCO.sub.3, water and then brine and the organic phase was dried (Na.sub.2SO.sub.4) and concentrated under reduced pressure. The title compound was obtained as a colourless oil (20 mg, 60%) following purification by flash column chromatography (50% EtOAc in hexane, Rf=0.7). .sup.1H NMR (400 MHz, CDCl.sub.3) 0.86 (t, J=7 Hz, 3H); 1.0-1.2 (2m, 2H); 1.2-1.5 (multiple signals, 8H); 1.68 (m, 1H); 4.53 (m+s, 4H); 3.33 (m, 1H), 3.39 (m, 1H); 3.49 (m, 1H); 3.60 (m, 1H); 3.70 (t, J=7 Hz, 1H); 5.07 (s, 2H); 7.72 (m, 4H). .sup.13C NMR (75 MHz, CDCl.sub.3) 14.01, 21.08, 22.72, 24.57, 25.60, 26.20, 30.09, 34.77, 43.20, 46.66, 48.38, 66.07, 128.03, 128.58, 134.24, 141.02, 171.09, 171.17. Note: Compound hydrolyses on standing, HRMS consistent with that of free alcohol.

Compound 16.11

4-(1-oxo-1-(piperidin-1-yl)hexan-2-yl)phenyl acrylate

(171) ##STR00036##

(172) To a cooled (0 C.) stirred solution of 16.5 (100 mg, 0.36 mmol) and triethylamine (56 L, 0.40 mmol) in dry CH.sub.2Cl.sub.2 (10 mL) was added acryloyl chloride (33 L, 0.40 mmol). The resulting mixture was allowed to warm to room temperature and was stirred for a further 1 hour, by which time analysis by tlc (50% EtOAc/hexane) revealed complete consumption of starting material. After this time, the reaction mixture was concentrated in vacuo and purified by flash column chromatography (50% EtOAc/hexane, Rf=0.5) to afford the title compound as a colourless oil (120 mg, >95%). .sup.1H NMR (400 MHz, CDCl.sub.3) (0.85 (t, J=7 Hz, 3H); 1.0-1.6 (multiple signals, 10H); 1.70 (m, 1H); 2.05 (m, 1H); 3.3-3.5 (2m, 3H); 3.68 (m, 1H); 3.70 (t, J=7 Hz, 1H); 5.99, (d, J=10 Hz, 1H); 6.29 (dd, J=17, 10 Hz, 1H); 6.57 (d, J=17 Hz, 1H); 7.06 (d, J=8.4 Hz, 2H); 7.28 (d, J=8.4 Hz, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3) 13.93, 22.63, 24.49, 25.51, 26.10, 30.00, 34.77, 43.12, 46.61, 47.96, 121.53, 127.88, 128.69, 132.42, 138.42, 149.15, 164.43, 171.06. HRMS (ESI+1 ion) m/z calcd for C.sub.20H.sub.28NO.sub.3 330.1989, found 330.2056.

Compound 16.4

4-(1-oxo-1-(piperidin-1-yl)hexan-2-yl)phenyl acetate

(173) ##STR00037##

(174) Acetic anhydride (38 L, 0.40 mmol) as added to a cooled (0 C.) stirred solution of 16.5 (100 mg, 0.36 mmol) and pyridine (32 L, 0.40 mmol) in dry CH.sub.2Cl.sub.2 (20 mL). The reaction was allowed to warm to room temperature and stirring was continued for a further 18 hours, by which time analysis by tlc (50% EtOAc/hexane) showed consumption of starting material. The crude reaction mixture was washed with dilute (0.1 M) HCl followed by water. The organic layer was dried (MgSO.sub.4) and concentrated in vacuo and the resulting oily residue was purified by flash column chromatography (50% EtOAc/hexane, Rf=0.26) to afford the title compound as a colourless oil (110 mg, >95%). .sup.1H NMR (400 MHz, CDCl.sub.3) 0.86 (t, J=7 Hz, 3H); 1.0-1.7 (multiple signals, 11H); 2.1 (m, 1H); 2.28 (s, 3H); 3.37 (m, 2H); 3.48 (m, 1H); 3.59 (m, 1H); 3.72 (t, J=7 Hz, 1H); 7.04 (d, J=8.4 Hz, 2H); 7.28 (d, J=8.4 Hz, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3) 13.96, 21.14, 22.67, 24.53, 25.55, 26.15, 30.04, 34.80, 43.15, 46.64, 47.97, 121.59, 128.72, 138.38, 149.29, 169.39, 171.11. HRMS (ESI+1 ion) m/z calcd for C.sub.19H.sub.28NO.sub.3 318.2064, found 318.2060.

Compound 16.6

2-(4-(2-hydroxyethoxy)phenyl)-1-(piperidin-1-yl)hexan-1-one

(175) ##STR00038##

(176) A solution of 16.5 (0.50 g, 1.8 mmol) ethylene carbonate (176 mg, 2.00 mmol) and tetraethylammonium bromide (20 mg, 0.09 mmol) in dry DMF (10 mL) was heated at an oil bath temperature of 180 C. for 16 hours. After this time cold water (50 mL) was added and the resulting mixture was extracted with EtOAc (320 ml). The combined organic layers were washed with water, dried (MgSO.sub.4) and concentrated in vacuo. The crude product was purified was purified by flash column chromatography (10% MeOH in CH.sub.2Cl.sub.2, Rf=0.4) to afford the title compound as a colourless oil (200 mg, 34%). .sup.1H NMR (400 MHz, CDCl.sub.3) 0.84 (t, J=7 Hz, 3H); 1.05 (m, 1H); 1.17 (m, 1H); 1.2-1.6 (multiple signals, 8H); 1.7 (m, 1H); 2.08 (m, 1H); 2.39 (t, J=6 Hz, 1H (OH)); 3.35 (m, 3H); 3.62 (t, J=7 Hz, 1H); 3.64 (m, 1H); 3.92 (m, 2H); 4.05 (m, 1H); 6.83 (d, J=8.4 Hz, 2H); 7.16 (d, J=8.4 Hz, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3) 13.96, 22.64, 24.50, 25.51, 26.09, 29.96, 34.70, 43.10, 46.58, 47.70, 61.36, 69.10, 114.59, 128.78, 133.38, 157.28, 171.55. HRMS (ESI+1 ion) m/z calcd for C.sub.19H.sub.30NO.sub.3 320.2220, found 320.2205.

Compound 16.8

2-(4-(1-oxo-1-(piperidin-1-yl)hexan-2-yl)phenoxy)ethyl acetate

(177) ##STR00039##

(178) To a cooled (0 C.) stirred solution of 16.6 (100 mg, 0.31 mmol) and DMAP (85 mg, 0.34 mmol) in dry CH.sub.2Cl.sub.2 (20 mL) was added acetyl chloride (50 L, 0.34 mmol). The resulting reaction mixture was stirred at reflux for 16 hours by which time analysis by tlc (50% EtOAc/hexane) showed complete consumption of starting material. The reaction mixture was washed with HCl (0.1 M) and water and the organic layer was dried (MgSO.sub.4) and concentrated in vacuo. The title compound was obtained as a colourless oil (110 mg, >95% yield) following purification by flash column chromatography (50% EtOAc/hexane, Rf=0.4). .sup.1H NMR (400 MHz, CDCl.sub.3) 0.85 (t, J=7 Hz, 3H); 1.05-1.60 (multiple signals, 10H); 1.7 (m, 1H); 2.08 (m, 1H); 2.10 (s, 3H); 3.35-3.45 (m, 3H); 3.6-3.7 (m, 2H); 4.15 (app t, J=5 Hz, 2H); 4.40 (app t, J=5 Hz, 2H); 6.84 (d, J=8.4 Hz, 2H); 7.17 (d, J=8.4 Hz, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3) 13.99, 20.89, 22.69, 24.55, 25.56, 26.15, 30.11, 34.77, 43.11, 46.61, 47.74, 62.86, 65.88, 114.68, 128.85, 133.61, 157.13, 171.00, 171.55. HRMS (ESI+1 ion) m/z calcd for C.sub.21H.sub.32N C.sub.4 362.2326, found 362.2320.

Compound 16.7

Methyl 2-(4-(1-oxo-1-(piperidin-1-yl)hexan-2-yl)phenoxy)acetate

(179) ##STR00040##

(180) To a stirred solution of 16.5 (300 mg, 1.15 mmol) and K.sub.2CO.sub.3 (400 mg, 2.87 mmol) in dry acetonitrile (20 mL) was added methylbromoacetate (0.18 g, 1.2 mmol). The resulting mixture was refluxed for 16 hours by which time analysis by tlc (5% MeOH in CH.sub.2Cl.sub.2) showed that no starting material remained. Acetonitrile was removed in vacuo and the residue was taken up in EtOAc and washed with water. The organic layer was dried (MgSO.sub.4) and concentrated in vacuo and the title compounds was obtained as a colourless oil (300 mg, 72%) following purification by flash column chromatography (5% MeOH in CH.sub.2Cl.sub.2, Rf=0.7). .sup.1H NMR (400 MHz, CDCl.sub.3) 0.86 (t, J=7 Hz, 3H); 1.05-1.60 (multiple signals, 10H); 1.7 (m, 1H); 2.05 (m, 1H); 3.38 (m, 2H); 3.42 (m, 1H), 3.6-3.7 (m, 2H); 3.80 (s, 3H); 4.61 (s, 2H); 6.83 (d, J=8.4 Hz, 2H); 7.19 (d, J=8.4 Hz, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3) 14.02, 22.72, 24.59, 25.60, 26.18, 30.06, 34.78, 43.15, 46.65, 47.73, 52.26, 65.45, 114.80, 128.94, 134.29, 156.51, 169.44, 171.48. HRMS (ESI+1 ion) m/z calcd for C.sub.20H.sub.30NO.sub.4 348.2169, found 348.2157.

Compound 16.9

2-(4-(1-oxo-1-(piperidin-1-yl)hexan-2-yl)phenoxy)acetic acid

(181) ##STR00041##

(182) Powdered LiOH (72 mg, 3.0 mmol) was added to a solution of 16.7 (100 mg, 0.30 mmol) in THF (10 mL) and the mixture was allowed to stir at room temperature for 16 hours. After this time the reaction mixture was acidified with HCl (0.1 M) and washed with EtOAc (320 mL). The organic phase was dried (MgSO.sub.4) and concentrated in vacuo. The title compound was obtained as a colourless oil (59 mg, 60%) following purification by flash column chromatography (10% MeOH in CH.sub.2Cl.sub.2, Rf=0.5). .sup.1H NMR (400 MHz, CDCl.sub.3) 0.84 (t, J=7 Hz, 3H); 1.05-1.60 (multiple signals, 10H); 1.68 (m, 1H); 2.05 (m, 1H); 3.37 (m, 2H); 3.42 (m, 1H), 3.66 (m, 2H); 4.63 (s, 2H); 6.85 (d, J=8.4 Hz, 2H); 7.18 (d, J=8.4 Hz, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3) 13.96, 22.61, 24.41, 25.52, 26.10, 29.92, 34.52, 43.49, 46.82, 47.71, 65.10, 114.87, 128.89, 133.87, 156.46, 171.92, 172.03. HRMS (ESI+1 ion) m/z calcd for C.sub.19H.sub.28NC.sub.4 334.2013, found 334.2001.

Compound 16.10

1-(piperidin-1-yl)-2-(4-(2-(trimethylsilyi)ethoxy)phenyl)hexan-1-one

(183) ##STR00042##

(184) To cooled (0 C.) solution of 16.5 (100 mg, 0.36 mmol), triphenylphosphine (140 mg, 0.54 mmol) and trimethylsilylethanol (80 L, 0.54 mmol) in dry THF (10 mL) was added DIAD (110 L) over a period of 10 minutes. The resulting reaction mixture was allowed to warm to room temperature and was stirred for a further 16 hours. After this time, the solvent was removed in vacuo and the residue was taken up in EtOAc and washed with water. The organic layer was dried (MgSO.sub.4) and concentrated in vacuo and the resulting residue was purified by flash column chromatography (50% EtOActhexane, Rf=0.7) to afford the title compound as a pale yellow oil (40 mg, 30%). .sup.1H NMR (400 MHz, CDCl.sub.3) 0.07 (s, 9H); 0.84 (t, J=7 Hz, 3H); 1.05 (m, 1H); 1.17 (m, 1H); 1.2-1.6 (multiple signals, 10H; app t, J=6 Hz, 2H); 1.7 (m, 1H); 2.05 (m, 1H); 3.25-3.35 (m, 3H); 3.62 (t, J=7 Hz, 1H); 3.65 (m, 1H); 4.03 (app t, J=6 Hz, 2H); 4.05 (m, 1H); 6.80 (d, J=8.4 Hz, 2H); 7.15 (d, J=8.4 Hz, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3) -1.33, 14.01, 17.75, 22.71, 24.58, 25.57, 26.11, 30.03, 34.77, 43.11, 46.60, 47.80, 65.31, 114.59, 128.70, 132.75, 157.59, 171.67. HRMS (ESI+1 ion) m/z calcd for C.sub.22H.sub.38NO.sub.2 376.2672, found 376.2666.

4-(1-oxo-1-(piperidin-1-yl)hexan-2-yl)benzaldehyde

(185) ##STR00043##

(186) DMSO (0.20 mL, 2.8 mmol) was added to a cooled (78 C.) stirred solution of oxaloyl chloride (122 L, 1.42 mmol) in dry CH.sub.2Cl.sub.2 (5 mL). After 5 minutes 16.2 (300 mg, 1.29 mmol) was added and stirring was continued for 15 minutes after which time triethylamine (0.90 mL, 6.5 mmol) was added dropwise. After a further 5 minutes, the mixture was allowed to warm to room temperature. The reaction mixture was washed with HCl (0.1 M) and the organic layer was further extracted with water, dried (MgSO.sub.4) and concentrated in vacuo. The title compound was obtained as a colourless oil (222 mg, 59%). No purification was necessary. .sup.1H NMR (400 MHz, CDCl.sub.3) 0.80 (t, J=7 Hz, 3H); 1.05 (m, 1H); 1.15 (m, 1H); 1.2-1.6 (multiple signals, 8H); 1.7 (m, 1H); 2.05 (m, 1H); 3.29 (m, 2H); 3.36 (m, 1H), 3.61 (m, 1H); 3.71 (t, J=7 Hz, 1H); 7.39 (d, J=8.4 Hz, 2H); 7.76 (d, J=8.4 Hz, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3) 13.97, 22.67, 24.49, 25.55, 26.21, 30.05, 34.64, 43.33, 46.69, 48.88, 128.57, 130.21, 135.08, 148.03, 170.36, 191.91. HRMS (ESI+1 ion) miz calcd for C.sub.18H.sub.26NO.sub.2 288.1958, found 288.1963.

Compound 17.9

4-(1-oxo-1-(piperidin-1-yl)hexan-2-yl)benzoic acid

(187) ##STR00044##

(188) Oxone (257 mg, 0.42 mmol) was added to a stirred solution of 4-(1-oxo-1-(piperidin-1-yl) hexan-2-yl)benzaldehyde (100 mg, 0.35 mmol) in DMF (5 mL) and the resulting mixture was stirred at room temperature for 16 hours. The DMF was removed in vacuo and the resulting residue was purified by flash column chromatography (50% EtOAc/hexane, Rf=0.4) to afford the desired compound as a pale yellow solid (68 mg. 64%). MP=142 C. .sup.1H NMR (400 MHz, CDCl.sub.3) 0.86 (t, J=7 Hz, 3H); 1.05 (m, 1H); 1.15 (m, 1H); 1.2-1.6 (multiple signals, 8H); 1.71 (m, 1H); 2.10 (m, 1H); 3.33-3.43 (m, 3H); 3.69 (m, 1H); 3.77 (t, J=7 Hz, 1H); 7.38 (d, J=8.4 Hz, 2H); 8.02 (d, J=8.4 Hz, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3) 13.98, 22.68, 24.50, 25.55, 26.16, 30.04, 34.60, 43.32, 46.68, 48.82, 128.04, 130.50, 153.75, 170.59. HRMS (ESI+1 ion) m/z calcd for C.sub.18H.sub.26NO.sub.3 304.1907, found 304.1917.

(189) The remaining compounds were made by methods corresponding to those given above, with appropriate variation of starting materials.

Examples Part 2Polymer Systems

(190) A number of polymers were synthesised, which polymers included a pendant group corresponding to antifouling compound 16.5.

(191) Specifically, compound 16.5 was incorporated into acrylate based polymers via the use of monomer 16.11.

(192) ##STR00045##

(193) The polymers were evaluated with respect to their ability to release (active) compound 16.5 in an aqueous environment in a sustained fashion. In particular, the antifouling efficacy of polymeric materials was studied in laboratory and field assays to identify anti-fouling performance and toxicity.

(194) Synthesis of Polymers

(195) The same polymers were designed and synthesized as the embodiments to illustrate the potential applications of our invention in marine coatings. But no limitations should be drawn from those embodiments.

(196) Polymers containing compound 16.5 as a releasable functional unit were designed with moderately hydrophilic (to ensure hydration in water) and to possess suitable strength, solubility and compatibility with commercial marine paints. To fulfil these requirements, the Tg of the polymer should preferably be higher than room temperature and the molecular weight is targeted to be approximately 10 KDaltons.

(197) Such polymers were synthesized by the polymerization of vinyl-containing compound 16.11 with the appropriate vinyl monomers under free radical conditions using AIBN, ABCN or benzoyl peroxide as initiators.

(198) Polymer A

(199) P(16.11-co-MMA-co-HEA) The copolymer of compound 16.11 with methyl methacrylate (MMA) and hydroxyethyl acrylate (HEA) was designed to obtain the functional polymer. Thus 16.11, methyl methacrylate (MMA) and (HEA) were mixed and polymerized under standard free radical conditions.

(200) ##STR00046##

(201) The mass ratio was designed so that MMA would form the majority of the backbone of the polymer, imparting mechanical strength and ensuring a Tg higher than room temperature, whilst HEA would provide hydrogen bonding capabilities which can improve the hydrophilicity of the polymer.

(202) 0.54 g of the functional monomer (16.11) (heavy viscose oil-like yellow liquid) was mixed with 2.0 g of MMA, 1.0 g of 2-hydroxylehtyl acrylate (HEA) and 40 mg of ABCN in 3 ml of DMF. The mixture was degassed by purging with nitrogen for 10 min. and then placed into an oil bath thermosetted at 70 C. for 16 hours. Following this, the reaction mixture was poured into 50 mL of ether. The precipitate was collected by filtration and dried under vacuum at room temperature to afford the title compounds as a colourless solid (2.5 g, 74%).

(203) Analysis of the polymeric material by IR spectroscopy revealed the expected ester CO stretching absorbances at 1730 cm.sup.1 along with a key absorbance detected at 1621 cm.sup.1. Such low frequency CO vibrations are characteristic of tertiary amides, and therefore this band is assigned to the piperidine amide linkage of the polymerized 16.11.

(204) Polymer B

(205) P(16.11-co-MMA-co-VP)

(206) Polymer B was of a similar design to polymer A but vinyl pyrrolidinone (VP) was used in the place of HEA in order to increase the hydrophilicity of the polymer. Polymer B was synthesized under free radical conditions using the same monomer ratios as that described for polymer A. The structure of polymer B is shown below.

(207) ##STR00047##

(208) 0.5 g of the functional monomer was mixed with 2.0 g of MMA, 1.0 g of vinyl pyrrolidone (VP) and 40 mg of ABCN in 3 ml of DMF and the mixture was degassed by purging with nitrogen for 10 min. Then the mixture was placed into an oil bath thermosetted at 70 C. for 16 hours. Then to the product was added 5 ml of DCM to form a clear solution. The solution was poured into hexane with stirring. The purified product was collected as a white precipitate. The pure product was collected and dried in air at room temperature to afford the title compound as a colourless solid (1.9 g, 54%).

(209) Analysis of the polymer by IR spectroscopy revealed the expected ester carbonyl stretching absorbances at 1724 cm.sup.1 along with the previously assigned piperidine amide carbonyl vibration at 1640 cm.sup.1. The incorporation of VP is evident by IR spectroscopy with a clear absorbance appearing at 1660 cm.sup.1, consistent with the presence of the -lactam.

(210) GPC revealed a MW of 5300 Daltons. Finally, the soluble nature of the polymer allowed further analysis by .sup.1H NMR spectroscopy. Signals at 6.9-7.2 ppm are assigned to the phenyl moiety of the 16.11 units, whilst the broad peak at 4.0 ppm to 4.3 ppm was assigned to ring methylene adjacent to the N-atom of the pyrrolidinone unit. Large broad signals in the 3.5-3.8 ppm are assigned to the methyl ester of the MMA units (Brar and Kumar, 2002). The signals at 0.9 ppm-2.5 ppm are ascribed to the methylene and methine groups of the polymer backbone and the methylene and methyl groups of side chain of 16.11.

(211) Polymer C

(212) P(TBA-co-MMA-co-VP)

(213) A standard co-polymer (polymer C) was also synthesized where 16.11 was replaced with t-butyl acrylate (TBA). Such a polymer was synthesised in order to ascertain if any background toxicity or anti-settlement activity existed as a function of the copolymer itself.

(214) ##STR00048##

(215) The free radical polymerization was carried out using the same mass ratios as for polymers A and B.

(216) 0.6 g of tert-butyl acrylate was mixed with 2.0 g of MMA, 1.0 g of vinyl pyrrolidone (VP) and 40 mg of ABCN in 3 ml of DMF and the mixture was degassed by purging with nitrogen for 10 min. Then the mixture was placed into an oil bath thermosetted at 70 C. for 16 hours. Then to the product was added 5 ml of DCM to form a clear solution. The solution was poured into hexane with stirring. The purified product was collected as a white precipitate. The pure product was collected and dried in air at room temperature to afford the desired compound as a colourless solid (3.2 g, 89%)

(217) Analysis of the polymer by IR spectroscopy revealed the presence of key vibrational modes ester and lactam carbonyl groups at 1728 cm.sup.1 and 1664 cm.sup.1. GPC indicated the desired MW of 67000 Daltons had been achieved and this was much higher than that obtained for polymer B.

(218) .sup.1H NMR analysis of the polymer confirmed the presence of the t-butyl moiety in the polymer, appearing at 1.4 ppm.

Examples Part 3Biological Investigation of Compounds

(219) Methodology

(220) Biological assays were conducted with larval barnacles. Barnacles are dominant and tenacious members of marine fouling communities, and often serve as a substrate for less resistant organisms. Therefore, historically they have been used as a model organism for antifouling studies. To determine the biological response of larvae to test compounds, two bioassays were performed: settlement (using settlement stage cyprids), and toxicity (using nauplii). Procedures followed methods standard in the field, which were first described by Rittschof et al. (1992).

(221) Preparation of Stock Solution for Bioassays

(222) Stock solutions of each compound were made at 50 mg/ml. Pure compounds were diluted in DMSO and sonicated. Stock solutions were stored at 20 C. in 4 ml amber screw cap vials until use. For bioassays, a small amount of stock solution was diluted in 1 m filtered seawater (in a glass scintillation vial). The solution was then sonicated for 10 minutes. To obtain the desired concentration range, serial dilutions of the test solution were made. As control, a serial dilution of the equivalent amounts of DMSO in seawater was used.

(223) Toxicity Assays

(224) Toxicity assays employed stage II naupliar larvae of the barnacle Amphibalanus amphitrite (previously Balanus amphitrite: Pitombo, 2004). Assay procedures were modified from Rittschof et al. (1992). Adult A. amphitrite were collected from inter-tidal areas near the Kranji mangrove, Singapore. Larval culture was based on Rittschof et al. (1984). Following collection, nauplii were concentrated for use in bioassays by placing a fiber optic light source at one side of the container, and pipetting from the resulting dense cloud of nauplii.

(225) In order to determine LD50 values for each compound, compounds were tested over a range of concentrations between 0-50 g/ml. For each assay, each compound at each concentration was tested in triplicate with a single batch of nauplii. The overall assay was conducted twice, using two different batches of nauplii. Two controls were run along with each assay (in triplicate): filtered seawater only, and DMSO at 1 g/ml (since DMSO was used as a solvent for test compounds, this concentration is equivalent to the concentration of DMSO in the highest test compound concentration).

(226) For assays, approximately 20 nauplii (in 50 l filtered seawater) were added to 1 ml test solution or control, in a 2 ml glass vial (La Pha Pack PN 11-14-0544). Assays were run for 22-24 hours at 25-27 C. After this time, living and dead nauplii were counted using a Bogorov tray. Nauplii that were approaching death were scored as dead. Data for all assays was combined and LD50 was calculated (where possible) using a probit analysis (Libermann, 1983). If LD50 could not be calculated using probit analysis, values were extrapolated based on plotted data.

(227) Settlement Assays

(228) Settlement assays (using barnacle cyprids) were based on methodology described in Rittschof et al. (1992). Nauplii were cultured as described above, and then reared at 25 C. on an algal mixture of 1:1 v/v of Tetraselmis suecica and Chaetoceros muelleri (approximately density 5105 cells per ml). Under these conditions, nauplii typically metamorphose to cyprids in 5 days. Cyprids were aged at 4 C. for 2 days. Settlement in filtered seawater controls after aging is generally 45-70%.

(229) Settlement assays were conducted in 7 ml neutral glass vials (Samco T103/V1; 3423 mm diameter). For assays, each solution was made at twice the desired final concentration; 0.5 ml of this solution was transferred to vials. To each vial, cyprids were added by transferring 0.5 ml filtered seawater containing 20-40 aged cyprids. As in toxicity assays: each compound at each concentration was run in triplicate with cyprids from a single batch; two controls (filtered seawater and DMSO) were run along with each assays; and the overall assay was conducted twice, using two different batches of cyprids.

(230) Assays were conducted for 24 hours, after which time the number of settled cyprids, the number of free swimming (unsettled) cyprids, and the number of dead cyprids were counted for each vial. Both metamorphosed, juvenile barnacles and cyprids that had committed to settlement (glued themselves to the vial), but had not yet metamorphosed, were counted as settled. Data was expressed as percent settlement. Data for all assays was combined and ED50 (the concentration that caused a 50% reduction in settlement as compared to controls) was calculated (where possible) using a probit analysis (Libermann, 1983). If ED50 could not be calculated using probit analysis, values were extrapolated based on plotted data.

(231) Results

(232) Biological activity for the compounds is shown in Tables 1 and 2. Data is from assays with batches of larvae, and three replicates of each compound per batch. Where LD.sub.50 or ED.sub.50 could not be calculated using probit analysis, values were estimated from plotted data. Compounds with a high LD.sub.50 value (low toxicity), but low ED.sub.50 (highly potency) are most desirable for anti-fouling purposes. A number of the tested compounds show a therapeutic ratio equal to, or greater than previously identified non-functionalised compounds (12.1 and 12.2; PCT/SG2009/000175)

(233) TABLE-US-00006 TABLE 1 Biological activity. ED.sub.50 values are anti-settlement (tested with barnacle cyprids); LD.sub.50 values are toxicity (tested with barnacle nauplii). Compound LD.sub.50 (g/ml) ED.sub.50 (g/ml) TR (LD.sub.50/ED.sub.50) 12.1 9.11 1.50 6.07 (reference) 12.2 9.83 2.00 4.92 (reference) 15.1 22.95 0.19 120.79 15.2 >25 1.46 >17.12 15.3 3.67 2.85 1.29 15.4 8.22 3.29 2.5 15.5 8.66 2.16 4.01 15.6 33.21 9.12 3.64 15.7 >25 1.75 14.29 16.1 >50 4.11 >12.17 16.2 >50 13.4 >3.73 16.3 >50 6.35 >7.87 16.4 27.2 0.23 118.26 16.5 17.15 0.19 90.26 16.6 >50 9.25 >5.41 16.7 24.58 26.88 0.91 16.8 >50 29.05 1.72 16.9 >50 >50 NA 16.10 >50 3.49 >14.33 16.11 6.57 1.53 4.29

(234) TABLE-US-00007 TABLE 2 Biological activity. ED.sub.50 values are anti-settlement (tested with barnacle cyprids); LD.sub.50 values are toxicity (tested with barnacle nauplii). Compound LD.sub.50 (g/ml) ED.sub.50 (g/ml) TR (LD.sub.50/ED.sub.50) 17.1 9.27 2.37 3.91 17.2 >50 8.69 >5.75 17.3 18.61 2.85 6.53 17.4 14.62 0.65 22.49 17.5 25.14 3.44 7.31 17.6 9.82 2.14 4.59 17.7 >50 34.12 >1.46 17.8 12.46 4.29 2.90 17.9 >50 >50 1

(235) Biological screening therefore indicates that functionalized molecules retained or improve upon desirable biological activity (high potency against barnacle cyprid settlement, yet low toxicity).

(236) Compounds with a high LD.sub.50 value (low toxicity), but low ED.sub.50 (highly potency) are most desirable for anti-fouling purposes. All the compounds gave therapeutic ratios greater than 1.

(237) The above results demonstrate that these new small organic molecules can be used as environmentally benign antifouling additives. These molecules retain effective anti-settlement activity despite differing substituents and substitution patterns on the aromatic ring. Indeed, a number of the compounds display bioactivity comparable to, or better than that of the unsubstituted parent structure. These new molecules improve upon the parent structure in that they can support functionality which can be used to tether or anchor the antifouling compounds to a marine coating system.

(238) The compounds can be blended into existing acrylate paints and are therefore practical alternatives to the current coating options. Furthermore, due to their simple structure the compounds are attractive candidates for degradation via bacterial means in the marine environment and are less likely to accumulate and pose a health risk in the future. In addition, given that existing organic biocides such as Diuroh and Sea-Nine have been shown to bioaccumulate and cause detrimental effects in the marine environment, the compounds of the present invention represent a valuable alternative to traditional metal-based additives.

Examples Part 4Polymeric Systems

(239) Release Studies

(240) Preparation of Multiwell Plates for Laboratory Assays

(241) Two batches of polystyrene 46 multiwell plates (base of the well 2 cm.sup.2) were prepared for laboratory assays. A stock solution of polymer was made by dissolving 50 mg of P(MMA-co-16.11-co-VP) in 1.0 ml of ethanol. The plates were coated with the desired amount of the stock solution (10 l, 20 l, 30 l, 40 l, 50 l, and 70 l) and placed in air at 27 C. for 6 hours. Then deionised water was added into those wells. After 24 hours the water was removed completely from the wells and stored for further analysis. The polystyrene plates were then dried under a stream of dry air. Meanwhile, the control specimens were prepared in the same way without water soaking.

(242) Settlement Assay

(243) The coatings were tested for antifouling effects using barnacle cyprid settlement assays. Cyprids were cultured as described above. After 5 days, cyprids were obtained and they were aged at 4 C. for 2 days before the settlement experiment. For experiment, cyprids were added by transferring 1 ml filtered seawater containing 20-40 aged cyprids into each well. The multi-well plates were incubated for 24 hours, after which time the number of settled cyprids, the number of free swimming (unsettled) cyprids, and the number of dead cyprids were counted for each well.

(244) The result of the assay is given in FIG. 1. For all treatments, cyprid mortality was less than 10%. Settlement on the control coating, P(MMA-co-tBA-co-VP), was similar to that for uncoated polystyrene. Wells coated with P(MMA-co-16.11-co-VP) showed reduction in cyprid settlement, with no settlement observed for treatments >40 l.

(245) Quantification by HPLC

(246) Aliquots of solutions obtained after soaking for 24 hours were mixed with a known volume of the internal standard and directly injected into a HPLC system and monitored at 226 nm. The amount of 16.5 released into the solutions obtained after soaking are shown below in Table 3 along with the calculated release rate. In each case, the amount of 16.5 released falls in a very narrow range (0.15-0.45 g), representing the similar surface area exposed to the aqueous environment in each case, regardless of the quantity of polymer.

(247) TABLE-US-00008 TABLE 3 Mass released and calculated release rates of 16.5 released from coated wells after 24 hours. Volume of P(MMA-co- Mass of 16.11-co-VP) P(MMA-co- Released Release Rate stock solution 16.11-co-VP) 16.5 (g) (g cm.sup.2 day.sup.1) 10 L 500 g 0.247 0.124 20 L 1000 g 0.136 0.0677 30 L 1500 g 0.212 0.106 40 L 2000 g 0.400 0.200 50 L 2500 g 0.242 0.121 70 L 3500 g 0.430 0.215

(248) FIG. 1 shows average percentage settlement of barnacles in the coated wells. P(MMA-co-tBA-co-VP) was applied as the control coating. Settlement on this coating was similar to that for uncoated polystyrene. Increased amounts of P(MMA-co-16.11-co-VP resulted in decline in barnacle settlement, with no settlement for test treatments >40 l. In all treatments, cyprid mortality was less than 10%.

(249) Following successful release of active compound 16.5 from the polymer, analysis was carried out into the hydrolysis of compound 16.11 from the polymer to release compound 16.5 into solution.

(250) Preparation of Coated Vials for Laboratory Analysis

(251) The inner base of glass vials with an internal diameter of 12 mm was matted with coarse sandpaper and then inoculated with a stock solution of P(MMA-co-16.11-co-VP) in ethanol such that the quantity of copolymer present is 500 g and 2500 g of P(MMA-co-16.11-co-VP) respectively, covering a surface area of 1.13 cm.sup.2. The vials were allowed to cure overnight prior to the addition of 2 mL of deionised water was added to each well. After 24 hours, the water was removed and replaced by 2 mL of fresh deionised water. The process was repeated after a further 24 hours and again for a further 48 hours giving a time course of 1, 2 and 4 days. Aliquots of the collected solutions were run against an internal standard (phenol), monitoring the response ratio at 226 nm. The resulting mass of 16.5 released at the specified time points are shown in Table 4.

(252) In each case the presence of 16.5 in the water was confirmed by analysis of the aliquots by analytical HPLC-ESI.

(253) TABLE-US-00009 TABLE 4 Mass of 16.5 released from polymer coated vials after 24 hours Mass of P(MMA-co- 16.11-co-VP) Mass of 16.5 released (g) coating Day 1 Day 2 Day 3-4 Day 5-7 500 g 0.482 0.0064 0.046 0.0054 0.572 0.0022 0.039 0.0086 0.534 0.0018 0.083 0.0096 2500 g 0.067 0.0042 0.0031 0.0263 0.034 0.0051 0.0013 0.0233 0.050 0.0091 0.0053 0.0350

(254) The average release rates for the first four days are shown in Table 5. The strikingly different release rates of the 500 g and 2500 g coated vials on day 1 (0.468 g cm.sup.2 day.sup.1 and 0.045 g cm.sup.2 day.sup.1 respectively) reflect the different surface roughness of the coatings at the start of the release studies. After day 1 it can be seen that the release rates converge and this level of release is sustained at similar levels over the next 6 days.

(255) TABLE-US-00010 TABLE 5 Release rate of 16.5 from P(MMA-co-16.11- co-VP) coated vials as a function of time. Mass of P(MMA-co- 16.11-co-VP) Average release rate of 16.5 (g cm.sup.2 day.sup.1) Coating Day 1 Day 2 Day 4 Day 7 500 g 0.482 0.0031 0.0089 0.0049 2500 g 0.0448 0.0054 0.0031 0.0083

REFERENCES

(256) A number of patents and publications are cited above in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Full citations for these references are provided below. Each of these references is incorporated herein by reference in its entirety into the present disclosure, to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference. Armarego, W. L. F.; C. L. L. Chai. 2003. Purification of Laboratory Chemicals; 5th ed.; Butterwortth-Heinemann: Sydney. Brar, A. S. and R. Kumar. Investigation of Microstructure of the N-Vinyl-2-pyrrolidone/Methyl Methacrylate Copolymers by NMR Spectroscopy Inc. J Appl Polym Sci 85: 1328-1336, 2002. Libermann H. R. Estimating LD.sub.50 using the probit technique: a basic computer program Drug Chem. Toxicol 1983, 6, 111-116. Pitombo F. B. 2004. Phylogenetic analysis of the Balanidae (Cirripedia, Balanomorpha). Zool. Scr. 33: 261-276. Rittschof D.; Clare, A. S.; Gerhart, D. J.; Avelin, M. Sr.; Bonaventura, J. Barnacle in-vitro assays for biologically active substances: toxicity and settlement inhibition assays using mass cultured Balanus amphitrite amphitrite Darwin Biofouling 1992, 6, 115-122.

(257) Rittschof D.; Branscomb, E.; Costlow, J. Settlement and behavior in relation to flow and surface in larval barnacles, Balanus amphitrite Darwin J. Exp. Mar. Biol. Ecol. 1984, 82, 131-146.

(258) Teo, L. M. S., D. Rittschof, F. Jameson, C. Chai, C. L. Chen, S. C. Lee. Antifouling compounds for use in marine environment. PCT Int. Appl. (2009), WO2009139729 A1.

(259) Voulvoulis, N. Antifouling paint booster biocides: occurrence and partitioning in water and sediments In: Konstantinou, I. K. (ed). Antifouling Paint Biocides. The Handbook of Environmental Chemistry, 2006, Volume 5, Part O, pp. 155-170. Springer-Verlag Berlin-Heidelberg.