Compound containing adamantane structure as well as preparation method and application thereof

Abstract

The invention relates to a compound containing an adamantane structure as well as a preparation method and application of the compound. The compound has a structure as shown in a general formula (I): # imgabs0 #, an amide-containing fragment is introduced into a system on the basis of an adamantane structure, a series of adamantane-containing amide or sulfonamide compounds are synthesized, and the compound has a good inhibition effect on plant pathogenic bacteria.

Description

Technical Field

[0001] The present invention relates to the technical field of medicinal chemistry, and in particular to an amide compound containing adamantane, a preparation method thereof and an application thereof. Background Art

[0002] In recent years, plant bacterial diseases caused by pathogenic bacteria have seriously affected agricultural production. For example, Pseudomonas syringae pv. actinidiae (Psa) is a Gram-negative bacterium that can easily cause kiwifruit canker. Due to its concealment, fast transmission speed and great difficulty in prevention and control, it has long been regarded as an "incurable disease" of kiwifruit and a "bottleneck problem" restricting the development of the global kiwifruit industry. In addition, Xanthomonas oryzae pv. Oryzae is a rod-shaped Gram-negative bacterium that can cause the leaves of rice to wither and turn white, and it causes a reduction in rice yield every year. In the process of agricultural production, due to the long-term use of traditional pesticides, plant pathogenic bacteria have developed certain resistance to them. Therefore, it is of great significance to develop new, highly efficient, low-toxic and safe green pesticides.

[0003] According to literature reports, adamantane derivatives exhibit significant biological properties, some of which have been commercialized for antiviral, antidiabetic, anti-neurodegenerative drugs and other drugs, and are being vigorously developed for other fields. In order to find highly antibacterial active compounds, the present invention is based on the adamantane structure, uses isopropanol as a linking chain, introduces an amide or sulfonamide structure into this system, synthesizes a series of novel adamantane amide compounds, and examines their antibacterial activity and its mechanism of action, providing an important scientific basis for the research and development of new pesticides.

[0004] The research progress of the biological activity of adamantane compounds is as follows:

[0005] In 2021, Zhu et al. [Zhu, J., Teng, G., Li, D., Hou, R., & Xia, Y. (2021). Synthesis and Antibacterial Activity of Novel Schiff Bases of Thiosemicarbazone Derivatives With Adamantane Moiety. 1-13.] designed and synthesized a series of Schiff base thiosemicarbazone derivatives containing adamantane structure, through 1 1H NMR, 13Its structure was characterized by \(^{13}\)C NMR and HRMS. The in vitro antibacterial activity test showed that the antibacterial activity of compound 7e against Escherichia coli (Gram-negative bacteria) was comparable to that of ampicillin (MIC = 1.0 ± 0.2 μg / mL), while 7g had good antibacterial activity against Bacillus subtilis (Gram-positive bacteria) (MIC = 1.0 ± 0.01 μg / mL).

[0006] In 2017, Kuznetsov et al. [Kuznetsov, N.Y., Tikhov, R.M., Godovikov, I.A., Medvedev, M.G., Lyssenko, K.A., et al. (2017). Stereoselective synthesis of novel adamantane derivatives with high potency against rimantadine-resistant influenza A virus strains. Org Biomol Chem, 15(15), 3152 - 3157.] synthesized a series of R and S isomers of novel adamantane-substituted heterocycles. Through 1 \(^1\)H NMR, 13 \(^{13}\)C NMR and HRMS, they were characterized, and a biological assay was performed on the rimantadine-resistant S31N mutant strains of influenza A-A / California / 7 / 2009 (H1N1)pdm09 and the contemporary epidemic strain A / IIV-Orenburg / 29-L / 2016 (H1N1)pdm09. Among them, the most effective compounds were the two enantiomers of enol ester 10, with an IC\(_50\) = 7.7 μM against the 2016 Orenburg strain.

[0007] In 2019, Niu et al. [Niu, T., Zhao, X., Jiang, J., Yan, H., Li, Y., et al. (2019). Evolution and Biological Evaluation of Matrinic Derivatives with Amantadine Fragments As New Anti-Influenza Virus Agents. Molecules, 24(5).] designed and synthesized a series of adamantyl-substituted tricyclic matrine derivatives. Through 1 \(^1\)H NMR, 13 \(^{13}\)C NMR and HRMS, their structures were verified, and their anti-influenza A H3N2 virus activity was evaluated. Among them, compounds 9f and 9j showed good anti-H3N2 activity, with an IC 50The values are 7.2 μM and 10.2 μM respectively.

[0008] In 2019, Stankova et al. [Stankova, I., Chuchkov, K., Chayrov, R., Mukova, L., Galabov, A., et al. (2019). Adamantane Derivatives Containing Thiazole Moiety: Synthesis, Antiviral and Antibacterial Activity. International Journal of Peptide Research and Therapeutics, 26(4), 1781 - 1787.] reported the design and synthesis of a series of adamantane derivatives containing thiazole - modified peptides. These compounds were characterized by 1 1H NMR, 13 13C NMR and HRMS, and their antiviral and antibacterial activities were tested. The results showed that the rimantadine analogue with a thiazole ring (Gly - Thz - rimantadine) had good antiviral activity against influenza virus A / Hongkong / 68, and its MIC 50 was 0.11 μg / mL, and CC 50 was 50 μg / mL. In addition, Gly - Thz - rimantadine showed very good antifungal activity against Gram - positive (Bacillus cereus) and Gram - negative (Escherichia coli) at two test concentrations (10 mM and 60 mM).

[0009] In 2022, Ji et al. [Ji, Q.T., Mu, X.F., Hu, D.K., Fan, L J., Xiang, S.Z., et al. (2022). Fabrication of Host - Guest Complexes between Adamantane - Functionalized 1,3,4 - Oxadiazoles and beta - Cyclodextrin with Improved Control Efficiency against Intractable Plant Bacterial Diseases. ACS Appl Mater Interfaces, 14(2), 2564 - 2577.] synthesized a class of adamantane - functionalized 1,3,4 - oxadiazoles and by 1 1H NMR, 13The compounds were characterized by 13C NMR and HRMS. Preliminary antibacterial activity screening showed that compound III-18 had good antibacterial activity against plant pathogenic bacteria Xoo (EC 50 = 0.936 μg / mL), Xac (EC 50 = 0.889 μg / mL) and Psa (EC 50 = 3.29 μg / mL). SUMMARY OF THE INVENTION

[0010] One object of the present invention is to provide an adamantane amide compound or its stereoisomer, or its salt or its solvate.

[0011] Another object of the present invention is to provide an intermediate compound for preparing the above compound or its stereoisomer, or its salt or its solvate and a preparation method thereof.

[0012] Another object of the present invention is to provide a composition containing the above compound or its stereoisomer, or its salt or its solvate.

[0013] Another object of the present invention is to provide the use of the above compound or its stereoisomer, or its salt or its solvate, or the composition.

[0014] Another object of the present invention is to provide a method for controlling agricultural pests and diseases by using the above compound or its stereoisomer, or its salt or its solvate, or the composition.

[0015] To achieve the above object, the present invention adopts the following technical solutions:

[0016] An adamantane amide or sulfonamide compound or its stereoisomer, or its salt or its solvate, the compound has the structures shown in general formulas (II) and (III):

[0017]

[0018] Preferably, it has the following structure:

[0019]

[0020] Wherein

[0021] Wherein R 1 is selected from unsubstituted hydrogen, optionally substituted or unsubstituted alkyl;

[0022] R 2 is selected from optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted aryl, optionally substituted or unsubstituted heterocycle;

[0023] Preferably, R 1Selected from unsubstituted hydrogen, alkyl;

[0024] Preferably, R 2 is selected from optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted aryl, optionally substituted or unsubstituted heterocycle. More preferably, R 2 is selected from one or more of C 1 -C 6 alkyl, C 6 -C 15 aryl, C 6 -C 15 heteroaryl; Most preferably, R 2 is selected from optionally substituted or unsubstituted phenyl, optionally substituted or unsubstituted naphthyl, and the substituents are selected from one or more of hydrogen, F, Cl, Br, I, CN, -CF 3 , -NO 2 , -CH 3 .

[0025] By adopting the above technical solutions, the present invention uses adamantane as the starting material to synthesize a series of amide compounds containing adamantane, and it is found that the compounds have good inhibitory effects on pathogenic plant pathogenic bacteria, and have good inhibitory effects on pathogenic bacteria [such as Xanthomonas oryzae pv. oryzae (Xoo), Pseudomonas syringae pv. actinidiae (Psa), etc.], providing an important scientific basis for the research and development of new pesticides. Examples

[0026] The present invention will be further described below by way of examples. It should be understood that the methods described in the embodiments of the present invention are only used to illustrate the present invention, rather than limiting the present invention. Any simple improvement of the preparation method of the present invention under the premise of the concept of the present invention belongs to the scope of protection of the present invention. All raw materials and solvents used in the examples are commercially available products.

[0027] Example 1: Preparation of tert-Butyl (4-Hydroxyphenyl) Carbamate

[0028] p-Aminophenol (400 mg, 3.67 mmol), di-tert-butyl dicarbonate (1.20 g, 5.50 mmol) and triethylamine (370.9 mg, 3.67 mmol) were mixed in a 100 mL round-bottom flask. The mixture was reacted at room temperature for 2 hours until the reaction was completed. Then saturated salt solution (150 mL) was added, and the mixture was extracted with ethyl acetate (60 mL). The organic phase was collected, and anhydrous Na 2 SO 4Dry the organic layer under reduced pressure and concentrate it. Purify it by column chromatography using ethyl acetate / petroleum ether (gradient from 30 / 1 to 10 / 1, v / v) to obtain Intermediate 1 (white solid, 644.7 mg, 3.08 mmol, yield 84.53%). Its NMR data are as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.06 (s, 1H, -NH), 9.01 (s, 1H, -OH), 7.22 (d, J = 7.3 Hz, 2H, phenyl-H), 6.64 (d, J = 8.9 Hz, 2H, phenyl-H), 1.45 (s, 9H, -C(CH 3 ) 3 ).

[0029] Example 2: Preparation of tert-Butyl (4-(oxiran-2-ylmethoxy)phenyl)carbamate

[0030] Mix tert-Butyl (4-hydroxyphenyl)carbamate (330 mg, 1.58 mmol), epibromohydrin (259.23 mg, 1.89 mmol) and KOH (115.03 mg, 2.05 mmol) in a 100 mL round-bottom flask and react at room temperature for 6 hours until the reaction is complete. Dissolve the reaction mixture in ethyl acetate (60 mL) and wash it with saturated ammonium chloride (3 × 80 mL). Collect the organic phase, dry it over anhydrous Na 2 SO 4 Dry the organic layer under reduced pressure and concentrate it. Purify it by column chromatography using petroleum ether / ethyl acetate (10 / 1, v / v) to obtain Intermediate 2 (white solid, 339.70 mg, 1.28 mmol, 81.18%). Its NMR data are as follows: 1 H NMR (500 MHz, CDCl 3 ) δ 7.26 (d, J = 6.7 Hz, 2H, phenyl-H), 6.89 - 6.80 (m, 2H, phenyl-H), 4.18 (dd, J = 11.0, 3.1 Hz, 1H, -phenyl-O-CH 2 ), 3.91 (dd, J = 11.0, 5.7 Hz, 1H, -phenyl-O-CH 2 ), 3.34 (ddd, J = 7.0, 5.8, 3.0 Hz, 1H, -O-CH), 2.94 - 2.84 (m, 1H, -0-CH 2 ), 2.75 (dd, J = 4.9, 2.7 Hz, 1H, -O-CH 2 ), 1.50 (s, 9H, -C(CH 3 ) 3 ).

[0031] Example 3: Preparation of tert-butyl (4-(3-(((3s,5s,7s)-adamantan-1-yl)amino)-2-hydroxypropoxy)phenyl)carbamate

[0032] Mix 4-(oxiran-2-ylmethoxy)phenyl)carbamate (200 mg, 0.75 mmol), adamantylamine (169.89 mg, 1.13 mmol) and potassium carbonate (135.44 mg, 0.98 mmol) in a 100 mL round-bottom flask and reflux at 60 °C for 6 h until the reaction is complete. Dissolve the reaction mixture in dichloromethane (60 mL) and wash with saturated ammonium chloride (3 × 80 mL). Collect the organic phase and dry it over anhydrous Na 2 SO 4 Dry, concentrate the organic layer under reduced pressure, and purify by column chromatography with dichloromethane / methanol (30 / 1 - 10 / 1 v / v) to obtain Intermediate 3 (transparent oil, 227.6 mg, 0.54 mmol, 72.47%). Its NMR data are as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.10 (s, 1H, -CO-NH), 7.33 (d, J = 8.4 Hz, 2H, phenyl-H), 6.85 - 6.79 (m, 2H, phenyl-H), 3.89 (dd, J = 9.5, 4.6 Hz, 1H, OH-CH), 3.83 - 3.74 (m, 2H, -O-CH 2 ), 2.68 (dd, J = 11.3, 4.4 Hz, 1H, NH-CH 2 ), 2.59 (dd, J = 11.4, 6.8 Hz, 1H, NH-CH 2 ), 2.01 (s, 3H, adamantane), 1.58 (t, J = 14.7 Hz, 12H, adamantane), 1.46 (s, 9H, -C(CH 3 ) 3 ).

[0033] Example 4: Preparation of 1-(((3s,5s,7s)-adamantan-1-yl)amino)-3-(4-aminophenoxy)propan-2-ol

[0034] Mix tert-butyl (4-(3-(((3s,5s,7s)-adamantan-1-yl)amino)-2-hydroxypropoxy)phenyl)carbamate (200 mg, 0.48 mmol) and concentrated hydrochloric acid (17.50 mg, 0.48 mmol) in a 100 mL round-bottom flask and react at room temperature for 6 h until the reaction is complete. Use NaHCO 3The solution adjusted the pH value of the system to 8 - 9, and then it was washed with dichloromethane (60 mL) and saturated ammonium chloride (3×80 mL). The organic phase was collected, and anhydrous Na 2 SO 4 dried. The organic layer was concentrated under reduced pressure to obtain Intermediate 4 (white solid, 97.87 mg, 0.31 mmol, 64.42%). Its NMR data were as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 6.66 - 6.61 (m, 2H, phenyl), 6.52 - 6.47 (m, 2H, phenyl), 4.60 (s, 2H, phenyl-NH 2 ), 3.79 (q, J = 7.3 Hz, 1H, OH-CH), 3.74 - 3.66 (m, 2H, -O-CH 2 ), 2.62 (dd, J = 11.2, 4.3 Hz, 1H, NH-CH 2 ), 2.53 (dd, J = 11.2, 6.3 Hz, 1H, NH-CH 2 ), 2.00 (s, 3H, adamantane), 1.62 - 1.51 (m, 12H, adamantane).

[0035] Example 5: Preparation of N-(4-(3-(((3s,5s,7s)-adamantan-1-yl)amino)-2-hydroxypropoxy)phenyl)-4-methylbenzenesulfonamide

[0036] 1-(((3s,5s,7s)-adamantan-1-yl)amino)-3-(4-aminophenoxy)propan-2-ol (1.26 mmol), p-toluenesulfonyl chloride (1.26 mmol), triethylamine (1.26 mmol), and 8 mL of anhydrous acetonitrile were added to a 100 mL round-bottom flask and reacted at low temperature for 24 hours. The mixture was washed with dichloromethane (100 mL×4) and water (20 mL×4). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. It was purified by column chromatography using a dichloromethane / methanol gradient (50 / 1 - 10 / 1, V / v) as the eluent to obtain the target compound. (Pale yellow oil, yield 63.2%)

[0037] Example 6: Preparation of N-(4-(3-(((3s,5s,7s)-adamantan-1-yl)amino)-2-hydroxypropoxy)phenyl)-2-chlorobenzenesulfonamide

[0038] 1-(((3S,5S,7S)-Adamantan-1-yl)amino)-3-(4-aminophenoxy)propan-2-ol (1.26 mmol), 2-chlorobenzenesulfonyl chloride (1.26 mmol), triethylamine (1.26 mmol), and 8 mL of anhydrous acetonitrile were added to a 100 mL round-bottom flask and reacted at low temperature for 24 hours. The mixture was washed with dichloromethane (100 mL × 4) and water (20 mL × 4). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. Purification by column chromatography using a dichloromethane / methanol gradient (50 / 1 - 10 / 1, v / v) as the eluent gave the target compound. (Pale yellow oil, yield 56.7%)

[0039] Example 7: Preparation of N-(4-(3-(((3S,5S,7S)-adamantan-1-yl)amino)-2-hydroxypropoxy)phenyl)-3-chlorobenzamide

[0040] 1-(((3S,5S,7S)-Adamantan-1-yl)amino)-3-(4-aminophenoxy)propan-2-ol (1.26 mmol), 3-chlorobenzoyl chloride (1.26 mmol), triethylamine (1.26 mmol), and 8 mL of anhydrous acetonitrile were added to a 100 mL round-bottom flask and reacted at low temperature for 24 hours. The mixture was washed with dichloromethane (100 mL × 4) and water (20 mL × 4). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. Purification by column chromatography using a dichloromethane / methanol gradient (50 / 1 - 10 / 1, v / v) as the eluent gave the target compound. (Pale yellow oil, yield 62.0%)

[0041] Other compounds were prepared in a similar manner to Examples 1 - 7 by replacing the corresponding starting materials.

[0042] The structures of the synthesized adamantane amide compounds, as well as the 1H NMR and 13C NMR data, are shown in Table 1, and the physical and chemical properties are shown in Table 2.

[0043] Table 1 1H NMR and 13C NMR Data of Compounds

[0044]

[0045]

[0046]

[0047]

[0048] Table 2 Physical and Chemical Properties of Target Compounds

[0049]

[0050]

[0051] Pharmacological Example 1:

[0052] EC 50 (median effective concentration) is an important indicator for evaluating the sensitivity of plant pathogens to compounds, and is also an important parameter for setting the compound concentration when studying the mechanism of action of target compounds. In the concentration gradient experiment, five appropriate concentrations were set by the two-fold dilution method. Finally, the inhibition rate of the medicament against plant pathogens and the logarithm of the medicament concentration were converted, and the toxicity curve was obtained by regression analysis using SPSS software, and EC 50 .

[0053] The turbidimetric method was used to test the median effective concentration EC of the target compound against plant pathogens 50 , and the test objects were Xanthomonas oryzae pv. oryzae (Xoo) and Pseudomonas syringae pv. actinidiae (Psa). DMSO was dissolved in the medium as a blank control. Xanthomonas oryzae pv. oryzae (plant pathogenic bacteria of rice bacterial blight on M210 solid medium) was placed in NB medium and cultured in a constant temperature shaker at 28 °C and 180 rpm until the logarithmic growth phase for standby; Pseudomonas syringae pv. actinidiae (on M210 solid medium) was placed in NB medium and cultured in a constant temperature shaker at 28 °C and 180 rpm until the logarithmic growth phase for standby. The medicament (compound) was prepared into 5 mL of toxic NB liquid medium with different concentrations (e.g., 100, 50, 25, 12.5, 6.25 μg / mL) and added to test tubes. 40 μL of NB liquid medium containing phytopathogenic bacteria was added respectively, and the mixture was shaken in a constant temperature shaker at 28 - 30 °C and 180 rpm. The Xanthomonas oryzae pv. oryzae was cultured for 48 h, and the Pseudomonas syringae pv. actinidiae was cultured for 36 h. The OD 595 value of the bacterial liquid at each concentration was measured on a spectrophotometer, and the OD 595 value of the toxic sterile NB liquid medium at the corresponding concentration was measured separately. The experimental results of the target compound are shown in Table 3 and Table 4.

[0054] Corrected OD value = OD value of medium containing bacteria - OD value of sterile medium

[0055] Inhibition rate % = [(OD value of bacterial liquid in corrected control medium - OD value of bacterial liquid in corrected toxic medium) / OD value of bacterial liquid in corrected control medium] × 100

[0056] Table 3 Primary screening of the activity of amide compounds containing adamantane against plant pathogenic bacteria

[0057]

[0058] Table 4 EC of amide compounds containing adamantane against plant pathogenic bacteria50

[0059]

[0060] "NT" indicates not tested

[0061] As can be seen from Table 3 and Table 4, in in vitro tests, the target compounds showed good inhibitory activity against phytopathogenic bacteria (such as Xanthomonas oryzae pv. oryzae and Pseudomonas syringae pv. actinidiae). The compounds showed excellent inhibitory activity against Pseudomonas syringae pv. actinidiae (Psa), with an EC 50 of 1.48 - 17.3 μg / mL; for Compounds 1, 5, 8, and 15, their EC 50 were 2.62, 2.02, 1.84, and 1.48 μg / mL respectively. At the same time, they also showed excellent inhibitory activity against Xanthomonas oryzae pv. oryzae (Xoo), with an EC 50 of 4.24 - 14.5 μg / mL; for Compounds 5, 10, 11, and 16, their EC 50 were 5.40, 4.24, 5.51, and 5.47 μg / mL respectively, and can be used to prepare pesticides against phytopathogenic bacteria.

Claims

1. An adamantyl-containing compound or a stereoisomer thereof, or a salt thereof or a solvate thereof, characterized in that The compound has a structure as shown in the general formula (I): Wherein R1 is selected from hydrogen, alkyl; A represents or -C(S)R2; R2 is selected from one or more of hydrogen, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted aryl, and optionally substituted or unsubstituted heteroaryl.

2. The adamantyl-containing compound according to claim 1, or its stereoisomer, or its salt or solvate thereof, characterized in that: Wherein R1 is selected from hydrogen, methyl, ethyl, and propyl; R2 is selected from methyl, ethyl, fluorophenyl, chlorophenyl, dichlorophenyl, cyanophenyl, nitrophenyl, trifluorophenyl, -CH2-O-CH3, and -N(CH3)2.

3. The adamantyl-containing compound according to claim 1, or its stereoisomer, or its salt or solvate thereof, characterized in that Selected from the following specific compounds:

4. An intermediate compound for preparing the adamantyl-containing compound or its stereoisomer, or its salt or solvate according to claim 1, characterized in that As shown below:

5. The method for preparing the adamantyl-containing compound or its stereoisomer, or its salt or solvate according to any one of claims 1 to 3, characterized in that The steps include: Wherein R1 is as described in any one of claims 1-3.

6. A composition characterized in that Contains a compound or a stereoisomer thereof, or a salt or a solvate thereof according to any one of claims 1 to 3, and an agriculturally usable adjuvant or fungicide, insecticide or herbicide; preferably, the composition is in the form of emulsifiable concentrate (EC), dust (DP), wettable powder (WP), granule (GR), aqueous solution (AS), suspension (SC), ultra low volume spray (ULV), soluble powder (SP), microcapsule (MC), smoke agent (FU), emulsion in water (EW), water dispersible granule (WG).

7. Use of the compound or its stereoisomer, or its salt or solvate according to any one of claims 1 to 3, or the composition according to claim 6 for preventing and controlling agricultural pests and diseases, preferably, the agricultural pests and diseases are bacterial or fungal diseases of plants; more preferably, the agricultural pests and diseases are plant leaf blight and plant canker; most preferably, the agricultural pests and diseases are rice bacterial leaf blight, cucumber bacterial leaf blight, konjac bacterial leaf blight, citrus canker, grape canker, tomato canker, kiwi canker, apple canker, cucumber gray mold, pepper wilt pathogen, rapeseed sclerotinia, wheat fusarium rust, potato late blight, and blueberry root rot.

8. A method for preventing and controlling agricultural pests and diseases, characterized in that: The compound or stereoisomer thereof, or salt or solvate thereof according to any one of claims 1 to 3, or the composition according to claim 6 is allowed to act on a pest or its living environment; preferably, the pest is a plant bacterial or fungal disease; more preferably, the agricultural pests and diseases are rice bacterial blight, tobacco bacterial wilt, cucumber bacterial blight, konjac bacterial blight, citrus canker, grape canker, tomato canker, kiwi canker, apple canker, cucumber gray mold, pepper wilt pathogen, rapeseed sclerotinia, wheat fusarium head blight, potato late blight, and blueberry root rot.

9. A method for protecting plants from agricultural pests and diseases, comprising a method step in which the plant is contacted with a compound or a stereoisomer thereof, or a salt or a solvate thereof as claimed in any one of claims 1 to 3, or a composition as claimed in claim 6.

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