DE102007022094B4 - Use of oxime compounds - Google Patents

Abstract

wobei:
X¹ und X² unabhängig ausgewählt werden aus F, Cl, Br und I;
X³ ein bis drei Substituenten bedeutet, die unabhängig ausgewählt werden aus F, Cl, Br und I, wobei mindestens eins von X¹, X² oder X³ Br ist;
R¹ ausgewählt wird aus H, substituiertem oder unsubstituiertem C₁-C₁₀ Alkyl, substituiertem oder unsubstituiertem C₁-C₁₀ Alkenyl, substituiertem oder unsubstituiertem C₁-C₁₀ Alkinyl, substituiertem oder unsubstituiertem C₃-C₈ Cycloalkyl, substituiertem oder unsubstituiertem C₆-C₁₄ Aryl, einem substituierten oder unsubstituierten 5- bis 10-gliedrigen Heteroarylring in dem 1 bis 4 Ringatome unabhängig Stickstoff, Sauerstoff oder Schwefel sind, einem unsubstituierten oder substituierten 5- bis 10-gliedrigen heteroalicyclischen Ring in dem 1 bis 3 Ringatome unabhängig Stickstoff, Sauerstoff oder Schwefel sind, -C(O)R, -C(O)NRR', -NRR', -S(O)₂R und -S(O)₂NRR';
R² ein oder zwei Substituenten bedeutet und ausgewählt wird aus H, substituiertem oder unsubstituiertem C₁-C₄ Alkyl, substituiertem oder unsubstituiertem C₁-C₄ Alkenyl, substituiertem oder unsubstituiertem C₁-C₄ Alkinyl, substituiertem oder unsubstituiertem C₁-C₄ Alkoxy, -CN, -NO₂, -OR, -C(O)R, -C(O)OR, -C(O)NRR', -NRR', -S(O)₂R, -S(O)₂OR, und -S(O)₂NRR',
R⁵ ein bis vier Substituenten bedeutet und ausgewählt wird aus H, substituiertem oder unsubstituiertem C₁-C₄ Alkyl, substituiertem oder unsubstituiertem C₁-C₄ Alkenyl, substituiertem oder unsubstituiertem C₁-C₄ Alkinyl, substituiertem oder unsubstituiertem C₁-C₄ Alkoxy, Halogen, -CN, -NO₂, -OR, -C(O)R, -C(O)OR, -C(O)NRR', -NRR', ...Use of a compound of formula V as antifouling agent

in which:
X ¹ and X ^{2 are} independently selected from F, Cl, Br and I;
X ^{3 represents} one to three substituents independently selected from F, Cl, Br and I, wherein at least one of X ¹ , X ² or X ^{3 is} Br;
R ^{1 is} selected from H, substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₁ -C ₁₀ alkenyl, substituted or unsubstituted C ₁ -C ₁₀ alkynyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted C ₆ -C ₁₄ aryl, a substituted or unsubstituted 5- to 10-membered heteroaryl ring in which 1 to 4 ring atoms are independently nitrogen, oxygen or sulfur, an unsubstituted or substituted 5- to 10-membered heteroalicyclic ring in the 1 to 3 ring atoms independently are nitrogen, oxygen or sulfur, -C (O) R, -C (O) NRR ', -NRR', -S (O) ₂ R and -S (O) ₂ NRR ';
R ^{2 represents} one or two substituents and is selected from H, substituted or unsubstituted C ₁ -C ₄ alkyl, substituted or unsubstituted C ₁ -C ₄ alkenyl, substituted or unsubstituted C ₁ -C ₄ alkynyl, substituted or unsubstituted C ₁ -C ₄ alkoxy, -CN, -NO ₂ , -OR, -C (O) R, -C (O) OR, -C (O) NRR ', -NRR', -S (O) ₂ R, -S ( O) ₂ OR, and -S (O) ₂ NRR ',
R ^{5 is} one to four substituents and is selected from H, substituted or unsubstituted C ₁ -C ₄ alkyl, substituted or unsubstituted C ₁ -C ₄ alkenyl, substituted or unsubstituted C ₁ -C ₄ alkynyl, substituted or unsubstituted C ₁ -C ₄ alkoxy, halogen, -CN, -NO ₂ , -OR, -C (O) R, -C (O) OR, -C (O) NRR ', -NRR', ...

Description

Field of the invention

The present invention is directed to the use of halogenated aromatic oxime compounds as anti-fouling agents.

Background of the invention

As early as 1952, the Woods Hole Oceanographic Institute coined the term "biofouling" for the growth of animal and plant organisms on artificial underwater surfaces. Biofouling includes microfouling, d. H. by bacteria and diatoms, and macrofouling, d. H. by macroalgae and invertebrates, causing significant economic losses and environmental damage worldwide due to reduced vessel speeds and increased fuel consumption (Clare (1996) Natural product antifoulants: Status and Potential.) Biofouling 9: 211-229 (1989) Marine epibiosis Fouling and antifouling - some basic aspects Mar. Ecol. Prog. Ser. 58: 175-189).

To prevent growth, organzine (tri-n-butyltin oxide, TBTO), copper oxide and herbicide coatings have been used commercially to date. However, these coatings are toxic to aquatic life (Alzieu et al., (1986) Tin contamination in Arcachon bay - effects on oyster shell anomalies Mar. Pollut. Bull. 17: 494-498; Alzieu et al. (1989) Monitoring and assessment of Butyltins in Atlantic coastal waters, Mar. Pollut., Bull. 20: 22-26) and were recently approved by the International Maritime Organization (IMO) in a resolution calling for a gradual reduction in the use of organotin compounds by 2003 and a full ban by 2008 , banned (IMO (2001) Resolution on early and effective application of the International Convention on the Control of Anti-Fouling Systems on Ships, resolution A928 (22) IMO).

Barnacles are an example of macro-fouling organisms of economic importance as they colonize and grow on hulls, cooling systems and similar man-made substrates. Attempts are currently being made to understand the physiology of barnacle larvae, their colonization behavior and their ability to undergo metamorphosis (Fusetani (2004) Biofouling and Antifouling, Nat. Prod. Rep. 21: 94-104; Sjogren et al. (2004) Recruitment in the biofouling 20: 291-297; Dahlstrom et al. (2005) Evidence for different pharmacological targets for imidazoline compounds inhibiting Settlement of the barnacle Balanus improvisus, J. Exp. Zool, Part A 303A: 551-562). These studies are not only important for understanding ecological processes, such as the competition and the order of sedentary marine invertebrates, but also for the development of environmentally sound, non-toxic antifouling agents. In the colonization process, the barnacle larvae (Cypris larvae) look for a surface that they colonize in several and on which they undergo the metamorphosis to young barnacles. The organisms that are commonly used for Cyprislarventests are either Balanus amphitrite Darwin 1854 or Balanus improvisus Darwin 1854.

Sponges (phylum Porifera) are sedentary molluscs with no backbone and shell (Armstrong and Quigley (1999) alpha (2) macroglobulin: an evolutionarily conserved arm of the innate immune system. Dev. Corp. Immunol. 23: 375-390). To defend against fouling organisms, predators and neighbors with whom they compete for space, sponges rely on bioactive natural products (Proksch et al (2002) Drugs from the seas - current status and microbiological implications.) Appl. Microbiol. 59: 125-134). Since sponges are filter feeders, overgrowth with fouling organisms would be devastating to their survival prospects as the inflow pores would be clogged. Among the thousands of natural products previously isolated from sponges (Blunt et al., 2006 Marine natural products 23: 26-78), halogenated compounds are commonly found. In the past, numerous brominated compounds from sponges have been shown to possess antifouling activity against the barnacle B. amphitrite. Among these active compounds, for example, heterocyclic substances such as pseudoceratidine (Tsukamoto et al., (1996) Pseudoceratidines: A novel antifouling spermidine derivative from the marine sponge Pseudoceratina purpurea, Tetrahedron Lett., 37: 1439-1440), bromotyrosine derivatives including ceratinamines (Tsukamoto et al (1996) Ceratinamine: An unprecedented antifouling cyanoformamide from the marine sponge Pseudoceratina purpurea J.Org.Chem. 61: 2936-2937) and Ceratinamides (Tsukamoto et al. (1996) Ceratinamides A and B: New antifouling dibromotyrosine derivatives from the marine sponge Pseudoceratina purpurea, Tetrahedron 52: 8181-8186) and brominated peptides against B. improvisus (Sjögren et al., 2004) Antifouling activity of brominated cyclopeptides from the marine sponge Geodia barretti J. Nat., Prod. 67: 368- 372).

Much of the research has focused on compounds from tropical aquatic organisms, but it has recently been reported that cold-water invertebrates also produce brominated metabolites with antifouling activity (Sjögren et al., 2004) Antifouling activity of brominated cyclopeptides from the marine sponge Geodia barretti J. Nat. Prod. 67: 368-372). Although halogenation is a frequently observed phenomenon in antifouling substances, non-halogenated antifouling compounds such as sesquiterpene axinyssimide, steroid halistonol sulfate, triterpene glycoside famoside, and phakellin-derived alkaloid styoluanidine are also known (Fusetani, supra).

The extent of research activity in this area shows that there is still a high demand for environmentally safe, non-toxic compounds with antifouling activity that can replace the long-term toxic compounds currently used.

The synthesis of bastadin 6 as well as the medical use of bastadines are known, for example, from Kotoku et al. (Tetrahedron (2005), 61 (39), 7211-7218) and US 2004/0229800 A1 known. However, the suitability of these compounds as anti-fouling agent is not described.

Antifouling alkaloids from Pseudoceratina sp. are for example from Thirionet et al. (Natural Product Letters (1998), 12 (3), 209-214).

The aim of the present invention was therefore the use of other compounds which show antifouling activity as antifouling agents.

Summary of the invention

The present invention is directed to the use of compounds containing a halogenated aromatic group and an oxime group as antifouling agents.

wobei:
X¹ und X² unabhängig ausgewählt werden aus F, Cl, Br und I;
X³ ein bis drei Substituenten bedeutet, die unabhängig ausgewählt werden aus F, Cl, Br und I;
Wobei mindestens eins von X¹, X² oder X³ Br ist;
R¹ ausgewählt wird aus H, substituiertem oder unsubstituiertem C₁-C₁₀ Alkyl, substituiertem oder unsubstituiertem C₁-C₁₀ Alkenyl, substituiertem oder unsubstituiertem C₁-C₁₀ Alkinyl, substituiertem oder unsubstituiertem C₃-C₈ Cycloalkyl, substituiertem oder unsubstituiertem C₆-C₁₄ Aryl, einem substituierten oder unsubstituierten 5- bis 10-gliedrigen Heteroarylring in dem 1 bis 4 Ringatome unabhängig Stickstoff, Sauerstoff oder Schwefel sind, einem unsubstituierten oder substituierten 5- bis 10-gliedrigen heteroalicyclischen Ring in dem 1 bis 3 Ringatome unabhängig Stickstoff, Sauerstoff oder Schwefel sind, -C(O)R, -C(O)NRR', -NRR', – S(O)₂R und -S(O)₂NRR';
R² ein oder zwei Substituenten bedeutet und ausgewählt wird aus H, substituiertem oder unsubstituiertem C₁-C₄ Alkyl, substituiertem oder unsubstituiertem C₁-C₄ Alkenyl, substituiertem oder unsubstituiertem C₁-C₄ Alkinyl, substituiertem oder unsubstituiertem C₁-C₄ Alkoxy, -CN, -NO₂, -OR, -C(O)R, -C(O)OR, -C(O)NRR', -NRR', -S(O)₂R, -S(O)₂OR, und -S(O)₂NRR',
R⁵ ein bis vier Substituenten bedeutet und ausgewählt wird aus H, substituiertem oder unsubstituiertem C₁-C₄ Alkyl, substituiertem oder unsubstituiertem C₁-C₄ Alkenyl, substituiertem oder unsubstituiertem C₁-C₄ Alkinyl, substituiertem oder unsubstituiertem C₁-C₄ Alkoxy, Halogen, -CN, -NO₂, -OR, -C(O)R, -C(O)OR, -C(O)NRR', -NRR', -S(O)₂R, -S(O)₂OR, und -S(O)₂NRR', und
R und R' unabhängig ausgewählt werden aus H und unsubstituiertem C₁-C₄ Alkyl.In a first aspect, therefore, the invention is directed to the use of a compound of formula V as antifouling agent:

in which:
X ¹ and X ^{2 are} independently selected from F, Cl, Br and I;
X ^{3 represents} one to three substituents independently selected from F, Cl, Br and I;
Wherein at least one of X ¹ , X ² or X ^{3 is} Br;
R ^{1 is} selected from H, substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₁ -C ₁₀ alkenyl, substituted or unsubstituted C ₁ -C ₁₀ alkynyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted C ₆ -C ₁₄ aryl, a substituted or unsubstituted 5- to 10-membered heteroaryl ring in which 1 to 4 ring atoms are independently nitrogen, oxygen or sulfur, an unsubstituted or substituted 5- to 10-membered heteroalicyclic ring in which 1 to 3 ring atoms are independently nitrogen, oxygen or sulfur , -C (O) R, -C (O) NRR ', -NRR', - S (O) ₂ R, and -S (O) ₂ NRR ';
R ^{2 represents} one or two substituents and is selected from H, substituted or unsubstituted C ₁ -C ₄ alkyl, substituted or unsubstituted C ₁ -C ₄ alkenyl, substituted or unsubstituted C ₁ -C ₄ alkynyl, substituted or unsubstituted C ₁ -C ₄ alkoxy, -CN, -NO ₂ , -OR, -C (O) R, -C (O) OR, -C (O) NRR ', -NRR', -S (O) ₂ R, -S ( O) ₂ OR, and -S (O) ₂ NRR ',
R ^{5 is} one to four substituents and is selected from H, substituted or unsubstituted C ₁ -C ₄ alkyl, substituted or unsubstituted C ₁ -C ₄ alkenyl, substituted or unsubstituted C ₁ -C ₄ alkynyl, substituted or unsubstituted C ₁ -C ₄ alkoxy, halogen, -CN, -NO ₂ , -OR, -C (O) R, -C (O) OR, -C (O) NRR ', -NRR', -S (O) ₂ R, - S (O) ₂ OR, and -S (O) ₂ NRR ', and
R and R 'are independently selected from H and unsubstituted C ₁ -C ₄ alkyl.

In a particular embodiment, R ¹ in one of the compounds of the formula V is H, C (O) R or C ₁ -C ₄ alkyl, for example H.

Exemplary compounds of the formula V are:

In a further aspect, the present invention comprises the use of the salts of the above-mentioned compounds.

In another aspect, the invention also encompasses the use of a composition containing one of the compounds of the invention as an antifouling agent. Such a composition may be a paint or color composition and in addition to the compounds of the invention also auxiliaries, excipients and additives such as solvents, wetting agents, defoamers, flow additives, surfactants, pigments, dyes, (synthetic) resins , Plasticizers and / or polymers or combinations thereof. Alternatively, the compounds may also be contained in a solution suitable for painting a surface of metal, wood, ceramic, plastic, glass, etc.

Brief description of the drawings

1A and 1B show the structures of the tested compounds.

2 shows the effect of active natural products on the settlement of B. improvisus. The results are given in percent (+ - SE) of the settlement, percent (+ - SE) of living cypris larvae and percent (+ - SE) of dead cypris larvae. C stands for a control experiment.

3 shows the effect of synthesized oxime compounds on the colonization of B. improvisus. The results are given in percent (+ - SE) of the settlement, percent (+ - SE) of living cypris larvae and percent (+ - SE) of dead cypris larvae. C stands for a control experiment.

Detailed description of the invention

Unless otherwise stated, the terms used in the claims and the description have the meanings given below.

"Alkyl" refers to a saturated aliphatic hydrocarbon including straight and branched chain groups. Preferably, the alkyl group has 1 to 10 carbon atoms (when a numerical range of, for example, "1-10" is given herein, it is meant that this group, in this case the alkyl group, 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. to including 10 carbon atoms inclusive). In particular, the alkyl may be a middle alkyl having 1 to 6 carbon atoms or a lower alkyl having 1 to 4 carbon atoms, e.g. Methyl, ethyl, n-propyl, Isopropyl, butyl, iso-butyl, tert-butyl, etc., act. The alkyl group may be substituted or unsubstituted. When substituted, the substituent is one or more groups, for example, one or two groups independently selected from C ₃ -C ₈ cycloalkyl, C ₆ -C ₁₄ aryl, a 5-10 membered heteroaryl ring in the 1 to 4 ring atoms independently Nitrogen, oxygen or sulfur, a 5-10 membered heteroalicyclic ring in which 1 to 3 ring atoms are independently nitrogen, oxygen or sulfur, hydroxy, C ₁ -C ₁₀ alkoxy, C ₃ -C ₈ cycloalkoxy, aryloxy, mercapto, alkylthio, Arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amide, N-amide, C-carboxy, O-carboxy, nitro, silyl, sulfinyl, sulfonyl, Amino and -NR ¹⁰ R ¹¹ wherein R ¹⁰ and R ^{11 are} independently hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₈ cycloalkyl, C ₆ -C ₁₄ aryl, carbonyl, acetyl, sulfonyl or amino, or R ¹⁰ and R ¹¹ , together with the nitrogen atom to which they are attached, form a five- or six-membered heteroalicyclic ring.

A "cycloalkyl" group refers to monocyclic or polycyclic (multiple rings having common carbon atoms) groups of 3-8 carbon atoms in which the ring does not have a complete conjugated pi-electron system, e.g. Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, etc. Examples of cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, adamantane, cyclohexadiene, cycloheptane and cycloheptatriene. A cycloalkyl group may be substituted or unsubstituted. When substituted, the substituent group is one or more, for example one or two, independently selected from C ₁ -C ₁₀ alkyl, C ₃ -C ₈ cycloalkyl, C ₆ -C ₁₄ aryl, a 5-10 membered heteroaryl ring wherein 1 to 4 ring atoms are independently nitrogen, oxygen or sulfur, a 5-10 membered heteroalicyclic ring in which 1 to 3 ring atoms are independently nitrogen, oxygen or sulfur, hydroxy, C ₁ -C ₁₀ alkoxy, C ₃ -C ₈ cycloalkoxy , Aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amide, N-amide, C-carboxy, O-carboxy, nitro , Silyl, sulfinyl, sulfonyl, amino and -NR ¹⁰ R ¹¹ wherein R ¹⁰ and R ^{11 are} as defined above.

"Alkenyl" refers to an alkyl group, as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon double bond, e.g. Ethenyl, propenyl, butenyl or pentenyl and their structural isomers such as 1- or 2-propenyl, 1-, 2-, or 3-butenyl, etc.

"Alkynyl" refers to an alkyl group as defined herein which consists of at least two carbon atoms and at least one carbon-carbon triple bond, e.g. Ethynyl (acetylene), propynyl, butynyl or petinyl and their structural isomers as described above.

"Aryl" refers to monocyclic or polycyclic (ie, rings that share adjacent carbon atoms) groups of 6 to 14 carbon ring atoms that possess a complete conjugated pi-electron system. Examples of aryl groups are phenyl, naphthalenyl and anthracenyl. The aryl group may be substituted or unsubstituted. When substituted, the substituent group is one or more, for example one or two, independently selected from C ₁ -C ₁₀ alkyl, C ₃ -C ₈ cycloalkyl, C ₆ -C ₁₄ aryl, a 5-10 membered heteroaryl ring wherein 1 to 4 ring atoms are independently nitrogen, oxygen or sulfur, a 5-10 membered heteroalicyclic ring in the 1 to 3 ring atoms are independently nitrogen, oxygen or sulfur, hydroxy, C ₁ -C ₁₀ alkoxy, C ₃ -C ₈ cycloalkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, trihalomethyl, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amide, N-amide, C-carboxy, O-carboxy, nitro, silyl, sulfinyl, sulfonyl, amino and -NR ¹⁰ R ¹¹ where R ¹⁰ and R ^{11 are} as shown are defined above. In a particular embodiment, the substituent (s) is / are selected from chlorine, fluorine, bromine, iodine, methyl, ethyl, hydroxy, methoxy, carboxy or amino.

A "heteroaryl" group refers to a monocyclic or fused aromatic ring (ie, rings sharing an adjacent ring atom pair) of 5 to 10 ring atoms, where one, two, three, or four ring atoms are nitrogen, oxygen, or sulfur and the balance Carbon is. Examples of heteroaryl groups are pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1, 2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, Isoindolyl, 3H-indolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolizinyl, quinazolinyl, pthalazinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolyl, Purinyl, pteridinyl, pyridinyl, pyrimidinyl, carbazolyl, xanthenyl or benzoquinolyl. The heteroaryl group may be substituted or unsubstituted. When substituted, the substituent group is one or more, for example one or two, independently selected from C ₁ -C ₁₀ alkyl, C ₃ -C ₈ cycloalkyl, C ₆ -C ₁₄ aryl, a 5-10 membered heteroaryl ring wherein 1 to 4 ring atoms are independently nitrogen, oxygen or sulfur, a 5-10 membered heteroalicyclic ring in which 1 to 3 ring atoms are independently nitrogen, oxygen or sulfur, hydroxy, C ₁ -C ₁₀ alkoxy, C ₃ -C ₈ cycloalkoxy , Aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, trihalomethyl, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amide, N-amide, C-carboxy, O-carboxy , Nitro, silyl, sulfinyl, sulfonyl, amino and -NR ¹⁰ R ¹¹ , wherein R ¹⁰ and R ^{11 are} as defined above. In a particular embodiment, the substituent (s) is / are selected from chlorine, fluorine, bromine, iodine, methyl, ethyl, hydroxy, methoxy, carboxy or amino.

A "heteroalicyclic" group refers to a monocyclic or fused ring of 5 to 10 ring atoms which contains neat, two or three heteroatoms selected from nitrogen, oxygen and -S (O) _n wherein n is 0-2 and the rest of the ring atoms is carbon. The ring may also have one or more double bonds. However, the ring does not have a complete conjugated pi-electron system. Examples of heteroalicyclic groups include pyrrolidine, piperidine, piperazine, morpholine, imidazolidine, tetrahydropyridazine, tetrahydrofuran, thiomorpholine, tetrahydropyridine, and the like. The heteroalicyclic ring may be substituted or unsubstituted. When substituted, the substituent group is one or more, for example one or two, independently selected from C ₁ -C ₁₀ alkyl, C ₃ -C ₈ cycloalkyl, C ₆ -C ₁₄ aryl, a 5-10 membered heteroaryl ring wherein 1 to 4 ring atoms are independently nitrogen, oxygen or sulfur, a 5-10 membered heteroalicyclic ring in which 1 to 3 ring atoms are independently nitrogen, oxygen or sulfur, hydroxy, C ₁ -C ₁₀ alkoxy, C ₃ -C ₈ cycloalkoxy , Aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, trihalomethyl, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amide, N-amide, C-carboxy, O-carboxy , Nitro, silyl, sulfinyl, sulfonyl, amino and -NR ¹⁰ R ¹¹ , wherein R ¹⁰ and R ^{11 are} as defined above. In a particular embodiment, the substituent (s) is / are selected from chlorine, fluorine, bromine, iodine, methyl, ethyl, hydroxy, methoxy, carboxy or amino.

A "hydroxy" group refers to an -OH group.

An "alkoxy" group refers to an -O-unsubstituted and -O-substituted alkyl group, wherein alkyl is as defined herein. Examples include methoxy, ethoxy, propoxy, butoxy, etc.

A "cycloalkoxy" group refers to an -O-cycloalkyl group, wherein cycloalkyl is as defined herein. An example is cyclopropyloxy.

An "aryloxy" group refers to an -O-aryl or -O-heteroaryl group, wherein aryl and heteroaryl are as defined herein. Examples include phenoxy, napthyloxy, pyridyloxy, furanyloxy, etc.

A "mercapto" group refers to a -SH group.

An "alkylthio" group refers to both an -S-alkyl and an -S-cycloalkyl group, wherein alkyl and cycloalkyl are as defined herein. Examples include methylthio, ethylthio, etc.

An "arylthio" group refers to both an -S-aryl and an -S-heteroaryl group, with aryl and heteroaryl as defined herein. Examples include phenylthio, naphthylthio, pyridylthio, furanylthio, etc.

A "sulfinyl" group refers to an -S (O) -R "group wherein R" is selected from hydrogen, hydroxy, alkyl, cycloalkyl, aryl, heteroaryl (attached via a ring carbon atom) and a heteroalicyclic ring (attached via a ring carbon atom) as defined herein.

A "sulfonyl" group refers to a -S (O) ₂ -R "group wherein R" is hydrogen, hydroxy, alkyl, cycloalkyl, aryl, heteroaryl (attached via a ring carbon atom) and a heteroalicyclic ring (attached via a ring carbon atom) as defined herein.

A "trihalomethyl" group refers to a -CX ₃ group wherein X is a halogen as defined herein, for example, trifluoromethyl, trichloromethyl, tribromomethyl, dichlorofluoromethyl, etc.

"Carbonyl" refers to a -C (= O) -R "group wherein R" is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (attached via a ring carbon atom) and a heteroalicyclic ring (attached via a ring carbon atom), as defined herein. Exemplary groups are acetyl, propionyl, benzoyl, formyl, cyclopropylcarbonyl, pyridinylcarbonyl, pyrrolidin-1-ylcarbonyl, etc.

A "thiocarbonyl" group refers to a -C (= S) -R "group, where R" is as defined above.

The terms "C-carboxy" and "carboxy" used interchangeably herein refer to a -C (= O) O-R "group wherein R" is as defined above, e.g. For example, -COOH, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, etc.

An "O-carboxy" group refers to an -OC (= O) R "group, where R" is as defined above, e.g. Methylcarbonyloxy, phenylcarbonyloxy, benzylcarbonyloxy, etc.

An "acetyl" group refers to a -C (= O) CH ₃ group.

A "carboxylic acid" group refers to a C-carboxy group in which R "is hydrogen.

A "halo" or "halo" group refers to fluorine, chlorine, bromine or iodine.

A "cyano" group refers to a -CN group.

A "nitro" group refers to a -NO ₂ group.

An "O-carbamyl" group refers to an -OC (= O) NR ¹⁰ R ¹¹ group, wherein R ¹⁰ and R ^{11 are} as defined above.

An "N-carbamyl" group refers to an R ¹¹ OC (= O) NR ¹⁰ group wherein R ¹⁰ and R ^{11 are} as defined above.

An "O-thiocarbamyl" group refers to an -OC (= S) NR ¹⁰ R ¹¹ group, wherein R ¹⁰ and R ^{11 are} as defined above.

An "N-thiocarbamyl" group refers to an R ¹¹ OC (= S) NR ¹⁰ group, wherein R ¹⁰ and R ^{11 are} as defined above.

An "amino" group refers to an -NR ¹⁰ R ¹¹ group, wherein R ¹⁰ and R ^{11 are} independently hydrogen or unsubstituted lower alkyl, such as e.g. B. -NH ₂ , dimethylamino, diethylamino, ethylamino, methylamino, etc.

A "C-amide" group refers to a -C (= O) NR ¹⁰ R ¹¹ group, wherein R ¹⁰ and R ^{11 are} as defined above. For example, R ^{10 is} hydrogen or unsubstituted C ₁ -C ₄ alkyl and R ¹¹ is hydrogen, C ₁ -C ₄ alkyl optionally substituted with a heteroalicyclic ring, hydroxy or amino. C (= O) NR ¹⁰ R ¹¹ may be, for example, aminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, diethylaminoethylaminocarbonyl, ethylaminoethylaminocarbonyl, etc.

An "N-amide" group refers to an R ¹¹ C (= O) NR ¹⁰ group wherein R ¹⁰ and R ^{11 are} as defined above, e.g. Acetylamino, etc.

A "composition" or "formulation" refers to a mixture of one or more of the compounds described herein or their salts with other chemical compounds, such as solvents, carriers, excipients, pigments, etc. The purpose of such a composition is, for example, U.S. Patent Nos. 5,434,674 To allow application to a surface (as antifouling agent).

In the context of the compounds disclosed herein, "salt" refers to one (1) acid addition salt formed by reacting a free base of the parent compound with an inorganic acid such as hydrochloric, hydrobromic, nitric, sulfuric, phosphoric and perchloric acid or the like or with an organic acid such as acetic acid, oxalic acid, malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid and malonic acid or the like; or (2) salts obtained by reacting an acidic proton in the parent compound with either a metal ion, e.g. For example, an alkali metal ion such as sodium or potassium, an alkaline earth metal ion such as calcium or magnesium, or an aluminum ion is replaced, or with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethanine, N-methylglucamine and the like coordinated.

The present invention is directed to the use of halogenated aromatic compounds containing an oxime function as antifouling agents. The uses according to the invention are based on the surprising finding of the inventors that certain brominated tyrosine derivatives from sponges, especially compounds derived from bastadines, can serve as inhibitors for the settlement of cypris larvae.

Bastadines are derived from the amino acid tyrosine, brominated, oximgruppen-bearing depsipeptides, which may be either cyclic or linear. Bastadines have been reported to be cytotoxic in earlier studies (Miao et al., (1990) Cytotoxic metabolites from the sponge Ianthella basta collected in Papua New Guinea, J. Nat. Prod. 53: 1441-1446, Pordesimo and Schmitz (1990) New Oral Chems 55: 4704-4709; Jaspars et al. (1994) The search for inosine 5'-phosphate dehydrogenase (IMPDH) inhibitors from marine sponges - evaluation of the bastadin alkaloids Tetrahedron 50: 7367-7374; Park et al. (1994) 2 more bastadins, 16 and 17, from Indonesian sponge Ianthella basta, J. Nat., Prod. 57: 407-410; Pettit et al. (1996) Isolation and structure of hemibastadinols 1-3 from the Papua New Guinea marine sponge Ianthella basta, J. Nat., Prod. 59: 927-934), which inhibit inosine 5'-phosphate dehydrogenase (Jaspars et al., 1994) The search for inosine 5'-phosphate dehydrogenase (IMPDH) inhibitors from marine sponges - evaluation of the bastadin alkaloids Tetrahedron 50: 7367-7374) d modulate sarcoplasmic reticulum ryanodine-sensitive calcium channels (Mack et al. (1994) Novel modulators of skeletal muscle Fkbp12 calcium-channel complex from Ianthella basta - role of Fkbp12 in channel gating. J. Biol. Chem. 269: 23236-23249). However, bastadins have not yet been tested for antifouling activity.

The inventors of the present invention have surprisingly found that not only certain bastadins, but also their precursors, the hemibastadines can inhibit the colonization of barnacle larvae. In further experiments, the inventors were able to show that synthetic derivatives of the hemibastadines also have the desired antifouling activity, but in some cases surprisingly show reduced toxicity. Furthermore, important structural determinants for the observed antifouling activity of the investigated compounds could be determined. It was found that in particular the oxime function is essential for the action of the compounds according to the invention. Furthermore, it was found that the halogen substituents, i. H. the bromo substituents on the aromatic ring make an important contribution to the antifouling activity of the compounds investigated.

Based on these findings of the inventors, a new class of compounds having anti-fouling activity could be identified. The compounds identified are halogenated aromatic compounds bearing an oxime group.

The compounds of the present invention therefore comprise the above-described compounds of the formula V.

Specific examples of compounds of formula V are those wherein R ^{1 is} H, C ₁ -C ₄ alkyl or (C = O) R where R is C ₁ -C ₄ alkyl, X ¹ and X ^{2 are} independently Cl, Br or I X ^{3 represents} one or two substituents in meta position to the rest of the compound selected from Cl, Br or I, all R ^{2 are} H, and R ^{5 represents} two or three substituents selected from H, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy and hydroxy.

In further examples of compounds of formula V, R ^{1 is} H or C ₁ -C ₄ alkyl, X ¹ and X ² are Br, X ³ means two substituents in meta position to the rest of the compound selected from Cl, Br or I are selected, all R ^{2 are} H, and R ⁵ is C ₁ -C ₄ alkoxy or hydroxy in the para position relative to the remainder of the compound.

The present invention also relates to the use of the salts of the compounds of formula V, which can be obtained by reacting a compound of formula V with an acid or a base.

The invention also relates to the corresponding use of compositions containing one or more of the compounds of the invention. Such compositions can be used as antifouling agents and, for example, applied in liquid form to surfaces which are to be used under water and protected from growth. For such a purpose, the composition is advantageously liquid and may, for example, be in the form of a paint solution, a varnish or a paint which, in addition to the compounds of the invention, may also contain auxiliaries, vehicles and additives. Depending on the mode of use, such auxiliaries, carriers and additives may be, for example, solvents, wetting agents, defoamers, flow control additives, surfactants, pigments, dyes, (synthetic) resins, plasticizers and / or polymers or combinations thereof.

The compounds or compositions described herein are used as anti-fouling agents and may be applied, for example, to submerged surfaces, for example in the form of a protective paint. For this use, the compounds or compositions are preferably in liquid form and are applied, for example, as a drying or otherwise curing coating on a surface of a material such as metal, metal alloys, ceramic materials, wood, glass, plastic, etc. By presenting the compounds described on the surface and / or slow release so colonization by barnacles and other fouling organisms can be prevented or reduced.

Alternatively, the compounds described can also be coupled chemically to a surface, for example by means of a linker molecule. Suitable linker molecules are known in the art and include, for example, silanes.

Further embodiments can be found in the following claims and non-limiting examples.

Examples

The present invention will be explained in more detail in the following examples. However, the examples are for the purpose of illustration only, and it is not intended that the scope of the invention be limited thereto.

material and methods

All sponge-derived natural products analyzed in the following examples (1-5 and 10-18) were structurally characterized by mass spectrometry and one- and two-dimensional NMR spectroscopy ( ¹ H, ¹³ C, COZY, HMBC). The bastadins (1-4) were isolated from Ianthella basta, and aplysamine-2 (5) and the oxazolidinone derivative (16) were isolated from Pseudoceratina purpurea. Isofistulin-3 (12) was from Aplysina aerophoba, the Psammapline (10, 11) from Aplysinella rhax, Ageliferin (13) from Agelas confiera and Sceptrin (14) and Debromsceptrin (15) from Agelas nakamurai. Hymenidine (17) was from Stylissa carteri and 2-bromaldisin (18) was isolated from Axinella damicornis.

Example 1: Chemical Synthesis of Hemibastadin-1 Derivatives and Tyrosine Tyramide

Schema 1. Synthese von Hemibastadin-1 Analoga. a) NH₂OH/NaOH/60°C/3 h; b) CH₃I/DBU/DMF/0°C/3 h; c) Tyramin/130°C/15 min; d) Br₂/Ether/CH₂Cl₂/25°C/24 h.

Scheme 1. Synthesis of hemibastadine-1 analogues. a) NH ₂ OH / NaOH / 60 ° C / 3 h; b) _CH3 I / DBU / DMF / 0 ° C / 3 h; c) tyramine / 130 ° C / 15 min; d) Br ₂ / ether / CH ₂ Cl _2/25 ° C / 24 h.

Norbrom-hemibastadine-1 (8) was synthesized in a three-step synthesis from the phenylpyruvic acid (I), which was converted to the oxime (II) and converted to the ester (III). After mixing III with a threefold excess of tyramine, the powder mixture was heated in an open flask with stirring in an oil bath for 15 minutes without solvent. After dissolving the mixture in a 2-phase system of 0.1 N HCl, ether and EtOAc, the organic phase was separated and the water phase extracted 3 times with EtOAc. The entire organic extract was washed with NaCl and dried (MgSO ₄ ) and evaporated in vacuo to dryness. After chromatography on silica gel with toluene: ethyl acetate (1: 1), the product (8) was obtained as colorless crystals having a melting point of 179 ° C.

The subsequent reaction of (8) with various amounts of bromine (two and four equivalents respectively) in ether / methylene chloride at room temperature resulted in a mixture of brominated products (6 and 7), which were purified by flash chromatography (silica gel, methylene chloride / ether 100 + 5 ) could be separated (see Scheme 1)

L-tyrosine tyramide (9) was synthesized starting from L-tyrosine methyl ester, which was triturated gently with a double excess of tyramine in an open flask and melted at 150 ° C without solvent for three hours. After cooling, the residue was dissolved in dilute HCl, adjusted to pH 8-9 with sodium carbonate and extracted with ethyl acetate. After concentrating and cooling, colorless crystals of 9 (87%) were separated and dried in vacuo. The melting point was 161 ° C.

Compounds 6-9 were characterized by MS, IR and ¹ H NMR.

Analytical data:

• 6: ¹ H-NMR (500 MHz, DMSO-d ₆ ) 2.62 (2H, t, J = 7.3 Hz, H-7), 3.28 (2H, m, H-8), 3.67 (2H, s, H- 7 '), 6.82 (1H, d, J = 8.2 Hz, H-6), 6.83 (1H, d, J = 8.2 Hz, H-6'), 6.95 (1H, dd, J = 1.9, 8.2 Hz, H-5), 6.98 (1H, dd, J = 1.9, 8.2 Hz, H-5 '), 7.72, (2H, s, H-3, H-3'), 7.91 (1H, t, 5.8, NH -9), 9.97 (1H, s, OH), 10.01 (1H, s, OH), 11.77 (1H, s, NOH). ESIMS m / z (%): 470 (16), [M + HH] ^- 472 (100), 473 (33), 517 (18), 519 (14), 939 (4), 941 (15), [ 2M-H] 943 (23), 945 (16).
• 7: ¹ H-NMR (500 MHz, DMSO-d ₆ ) 2.66 (2H, t, J = 6.9 Hz, H-7), 3.31 (2H, m, H-8), 3.68 (2H, s, H- 7 '), 7.33 (2H, s, H-6, H-6') 7.32 (2H, s, H-2, H-2 '), 8.00 (1H, t, J = 5.8 Hz, NH-9) , 9.73 (1H, s, OH) 9.65 (1H, s, OH), 11.90 (1H, s, NOH). ESIMS m / z (%): [M + H] ⁺ 630 (100), 627 (18), 629 (75), 632 (80), 635 (30), [2M + H] ⁺ 1259 (100), 1252 (2), 1253 (9), 1255 (34), 1257 (83), 1261 (78), 1263 (43), 1265 (12), 1266 (2).
• 8: ¹ H-NMR (500 MHz, DMSO-d ₆ ) 2.61 (2H, t, J = 6.9 Hz, H-7), 3.28 (2H, m, H-8), 3.67 (2H, s, H- 7 '), 6.59-6.69 (4H, m, H-2, H-6, H-2', H-6 '), 6.91-7.01 (4H, m, H-3, H-3', H- 5, H-5 '), 7.82 (1H, t, J = 5.6Hz, NH-9), 9.17 (2H, s, OH) 11.67 (1H, s, NOH). MS 70 eV, m / z (%): M ⁺ 314 (2), 163 (16), 134 (10), 133 (40), 132 (17), 107 (100), 78 (31), 77 ( 38), 51 (25).
• 9: ¹ H-NMR (200 MHz, pyridines-d ₅ ) 2.2 (2H, s, NH ₂ -8 '), 2.85 (2H, t, J = 7.0, H-7), 3.00 (1H, dd J = 8.2, 13.5 Hz, H-7'A), 3.39 (1H, dd, J = 4.7, 13.5 Hz, H-7'B), 3.70 (2H, m, H-8), 3.84 (2H, dd, J = 4.7, 8.2Hz, H-8 '), 7.2 (8H, m, H-Ar), 8.4 (1H, t, J = 5.6Hz, NH-9), 11.5 (2H, s, OH). MS 70 eV, m / z (%): [M-2H] 298 (2), [MH ₂ O] 283 (5), 194 (18), [MC ₇ H ₇ O] 193 (36), 164 ( 13), [MC ₈ H ₁₀ NO] 136 (100), 121 (33), 120 (23), [MC ₁₀ H ₁₃ N ₂ O ₂ ] 107 (41), 91 (20), 77 (19), 51 (19).

Example 2: Antifouling Assay.

Cypris larvae of Barnacle improvisus Darwin in laboratory culture as previously described (Berntsson et al., 2000) Analysis of behavioral rejection of micro-textured surfaces and implications for recruitment by the barnacle Balanus improvisus J. Exp. Mar. Biol. Ecol. 251: 59 -83). The experiments to evaluate the effect of the respective substance on larval colonization and the mortality of B. improvisus were carried out using polystyrene Petri dishes (48 mm diameter, Nunc AS, Denmark, No 2440045). To each Petri dish was added 10 ml of filtered (filter pore size 0.2 μm) of seawater. The seawater for the controls contained 0.1% DMSO, whereas the treated samples contained 0.1% DMSO in which a certain amount of a specified natural product or synthetic analog had been dissolved. Cypris larvae (n = 16) were added to each dish and each experiment performed in quadruplicate (n = 4). The dishes were kept for 3-4 days at room temperature (about 20 ° C) under normal lighting conditions (day / night), followed by examination of the cypris larvae under a stereomicroscope on settled and transformed, floating and dead individuals. All substances were tested at concentrations of 0.1, 1, and 10 μM, and in some cases even 100 μM.

Example 3: Saline cancer assay

The assay was performed using nauplii from Artemia salina. The brine used corresponded to previously described brine (Meyer et al., (1982) Brine shrimp - a convenient general bioassay for active-plant constituents., Planta Med 45: 31-34). The compounds were dissolved in 40 μl DMSO and added to 10 ml tubes. After addition of artificial seawater to the tubes, the final concentration of the test samples was 1, 10 or 100 μM, with the DMSO concentration being 0.8%. Saline crab eggs (Dohse Aquaristik KG) were hatched in a small tank filled with artificial seawater prepared with 33 g / L sea salt (Wiegandt GmbH) and tap water. After two days, 20 nauplii were removed with a pipette and transferred to each test tube. The tubes were kept under light and after 24 hours the surviving saline cancer larvae counted. Solvent controls with 0.8% DMSO in seawater were performed in parallel to the samples. The Saline Cancer Assay is an established model for evaluating the cytotoxicity of compounds (Carballo et al., 2002) Comparison between two brine shrimp assays to detect in vitro cytotoxicity in marine natural products. BMC Biotech 2: 17-21

Statistical analysis of the data

The mean ± standard deviation (SE) is given. The effect of various substances on Cypris larvae colonization was calculated using the 1-factor analysis of variance (ANOVA) with the fixed factor dosages. The minimal dose resulting in a significant difference compared to the control was determined using the Student-Newman-Keuls (SNK) assay. All data were submitted to Cochran's homoscedasticity test. In cases where the data showed significant heterogeneity, logarithmic transformations were successfully performed. The degree of significance was set to p <0.05.

Results

There were a total of 18 different halogenated compounds that either naturally occur in different marine sponges ( 1 : 1-6 and 10-18) or synthetic products ( 1 : 7 [8-9 lacks bromine]) for antifouling activity using B. improvisus larvae. The effects of the substances on larval colonization and mortality, including F values, P values and degrees of freedom are summarized in Tables 1 and 2. The inhibitory minimum concentrations for Cypris larvae colonization and toxicity are given in the tables.

Four of the natural products analyzed in the examples, namely bastadine-3 (4), -4 (1) and -9 (2), and aplysamin-2 (5), significantly inhibited the colonization at concentrations of 1 or 10 μM of the larvae without increasing the mortality of the larvae ( 2 ). Bastadin-16 (3), hemibastadine-1 (6) and psammapline A (10) similarly inhibited the colonization of larvae at a concentration of 10 μM, but additionally caused a significant increase in cypris larvae mortality ( 2 and 3 ). It was found that all other natural products analyzed except for isofistulin-3 (16), which was toxic to the cypris larvae at only 1 μM but did not inhibit the colonization of the surviving B. improvisus larvae (data not shown), in this bioassay were inactive. Interestingly, it was found that psammapline A sulphate (11) did not hinder the colonization but was slightly toxic to the cypris larvae at 10 μM.

Hemibastadine-1 (6) was chosen because of its simple structure compared to bastadins -3, -4, -9, or -16 [1-4] for the preparation of synthetic analogues and structure-activity relationship studies. Three synthetic congeners, namely norbrom-hemibastadine-1 (8), 2,2'-dibromo-hemibastadine-1 (7) and tyrosine-tyramide (9), were prepared and investigated for their effect on larval colonization and mortality ( 3 ). Hemibastadine-1 (6) and its 2,2'-dibromo derivative (7) were substantially comparable with respect to larval colonization ( 3 ).

k.A. = keine Aktivität, ¹Data log-transformiert Tabelle 2. Die inhibierende Wirkung synthetisierter Hemibastadin-1 Analoga auf die Siedlung von Balanus improvisus.

k.A. = keine AktivitätHowever, only the natural product hemibastadine-1 (6) caused significant larval mortality at this concentration, whereas no toxicity was observed for the synthetic analogue (7). 3 ). Compared to compounds 6 and 7, the second synthetic analogue norbromemibastadine-1 (8) was considerably less active and caused larval colonization only at a dose of 100 μM ( 3 ). At this concentration, the norbromo derivative (8) was also toxic to the cypris larvae, thus resembling the activity profile of the parent compound, hemibastadine-1 (6), albeit at higher concentrations. Tyrosine tyramide (9), which lacks the bromine atom and oxime function, but instead has an amino substituent, was completely inactive even at a dose of 100 μM and had no effect on larval colonization or survival ( 3 ). None of the synthesized compounds caused an increased mortality of saline cancer nauplii compared to controls. Table 1. The inhibitory effect of brominated secondary metabolites derived from sponges on the settlement of Balanus improvisus

kA = no activity, ¹ data log transformed Table 2. The inhibitory effect of synthesized hemibastadine-1 analogues on the settlement of Balanus improvisus.

kA = no activity

Claims (4)

Use of a compound of formula V as antifouling agent

wherein: X ¹ and X ^{2 are} independently selected from F, Cl, Br and I; X ^{3 represents} one to three substituents independently selected from F, Cl, Br and I, wherein at least one of X ¹ , X ² or X ^{3 is} Br; R ^{1 is} selected from H, substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₁ -C ₁₀ alkenyl, substituted or unsubstituted C ₁ -C ₁₀ alkynyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted C ₆ -C ₁₄ aryl, a substituted or unsubstituted 5- to 10-membered heteroaryl ring in which 1 to 4 ring atoms are independently nitrogen, oxygen or sulfur, an unsubstituted or substituted 5- to 10-membered heteroalicyclic ring in the 1 to 3 ring atoms independently are nitrogen, oxygen or sulfur, -C (O) R, -C (O) NRR ', -NRR', -S (O) ₂ R and -S (O) ₂ NRR '; R ^{2 represents} one or two substituents and is selected from H, substituted or unsubstituted C ₁ -C ₄ alkyl, substituted or unsubstituted C ₁ -C ₄ alkenyl, substituted or unsubstituted C ₁ -C ₄ alkynyl, substituted or unsubstituted C ₁ -C ₄ alkoxy, -CN, -NO ₂ , -OR, -C (O) R, -C (O) OR, -C (O) NRR ', -NRR', -S (O) ₂ R, -S ( O) ₂ OR, and -S (O) ₂ NRR ', R ^{5 is} one to four substituents and is selected from H, substituted or unsubstituted C ₁ -C ₄ alkyl, substituted or unsubstituted C ₁ -C ₄ alkenyl, substituted or unsubstituted C ₁ -C ₄ alkynyl, substituted or unsubstituted C ₁ -C ₄ alkoxy, halogen, -CN, -NO ₂ , -OR, -C (O) R, -C (O) OR, -C (O) NRR ', -NRR', -S (O) ₂ R, -S (O) ₂ OR, and -S (O) ₂ NRR ', and R and R' are independently selected from H and unsubstituted C ₁ -C ₄ alkyl ; or a salt of it. Use of a compound according to claim 1, wherein R ^{1 is} H, C (O) R or C ₁ -C ₄ alkyl. Use of a compound according to claim 1 or 2, wherein R ^{1 is} H. Use of a compound according to any one of claims 1-3, wherein the compound is selected from:

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