Preparation method of cholic acid derivative

Abstract

The present invention relates to a process for the preparation of cholic acid derivatives, in particular compounds of formula (V). The invention also relates to compounds useful for the preparation of such derivatives. # imgabs0 #

Description

[0001] manual

[0002] The present invention relates to a method for preparing bile acid derivatives, in particular compounds of formula (V):

[0003]

[0004] The present invention also relates to compounds used for the preparation of such derivatives.

[0005] Bile acids are the main bile acids synthesized in the liver from cholesterol through multiple complementary enzymatic processes. Bile acids comprise a group of molecular species with similar chemical structures that are secreted in bile and transported into the small intestinal lumen, where they act as emulsifiers to aid fat digestion and absorption, and as endocrine molecules that can control different signaling pathways.

[0006] Bile acids (BAs) are not only digestive surfactants but also important cell signaling molecules that can stimulate different signaling pathways to regulate a number of important biological processes. The nuclear bile acid-activated receptor, the farnesoid X receptor (FXR), plays a key role in regulating bile acid, lipid, and glucose homeostasis as well as modulating inflammatory responses, barrier function, and preventing intestinal bacterial translocation. As expected, FXR has been implicated in the pathophysiology of multiple gastrointestinal diseases, including inflammatory bowel disease, colorectal cancer, and type 2 diabetes.

[0007] The identification of new steroid molecules capable of binding and modulating the FXR receptor has proven to be of great importance for the discovery of new potential therapeutics.

[0008] Of particular interest in this sense are steroid derivatives with one less carbon atom in the side chain, such as BAR502 and 24-norursodeoxycholic acid (nor-UDCA).

[0009] Therefore, most synthetic protocols involving BAs include side-chain modifications, and for this purpose, the carboxyl functionality located at C-24 plays a crucial role.

[0010] Dehomologation of carboxylic acids allows tailoring of the carbon chain to the desired length and can be obtained by different methods.

[0011] Several general protocols for the dehomologation of carboxyl functions to the corresponding alcohols are known in the literature, with specific reference to the example of steroid derivatives.

[0012] MF Saraiva et al. in Tetrahedron, 2009, 65, 3563-3572 describe the following method for converting bile acid derivatives into the corresponding bromides having one less carbon atom by the Barton-McCombie reaction using 2-mercaptopyridine N-oxide sodium salt and bromotrichloromethane:

[0013]

[0014] Hernández-Huerta E. et al., "A Straightforward One-Pot Two-Step Conversion of Bile Acids into Dehomologated Alcohols", Steroids, 2021, 176, 108917, describe a one-pot method that allows the synthesis of dehomologated alcohols from carboxylic acids using hypervalent iodine, MCPBA and photochemical radiation:

[0015]

[0016] The above examples are not industrially convenient because they involve complicated techniques and separation and purification procedures.

[0017] Another example of a method reported in the literature, with reference to cholic acid derivatives, involves rearrangement of the carboxylic acid to the corresponding dehomologated amine.

[0018] Pellicciari R. et al. describe a method using the Schmidt reaction in J. Med. Chem, 2004, 47, 4559-4569. After the corresponding acid chloride is prepared, it is reacted with sodium azide to obtain the corresponding acyl azide. The latter is then rearranged to the corresponding isocyanate, which reacts with an alcohol to obtain the corresponding carbamate, which is then hydrolyzed to the final dehomologated amine.

[0019]

[0020] Likewise, the multistep procedure is complicated because it requires protection of hydroxyl groups that are incompatible with the formation of acyl chlorides using thionyl chloride. Furthermore, the process results in mixed products, making it unsuitable for industrial scale-up.

[0021] Therefore, there is a need to find a new synthetic method to dehomologate the side chains of derivatized cholic acids that uses simple and reproducible reactions on an industrial scale.

[0022] The object of the present invention is therefore a process for preparing a compound of formula (V),

[0023]

[0024] The method includes:

[0025] a) reacting a compound of formula (I) with an organic azide of formula R-N3 in an aprotic solvent in the presence of a base to obtain the corresponding isocyanate of formula (II); wherein R is selected from diphenylphosphoryl, trimethylsilyl, trifluoromethanesulfonyl, preferably diphenylphosphoryl;

[0026]

[0027] in

[0028] R1 represents a -C=O group or an OH group in α or β configuration;

[0029] R2 represents a hydrogen atom or an OH group;

[0030] b) reacting the obtained isocyanate of formula (II) with an alcohol of formula R3-OH to obtain a carbamate of formula (III);

[0031]

[0032] in

[0033] R1 and R2 have the meanings given above;

[0034] R3 represents a straight or branched chain C 1-10 Alkyl, aryl or alkaryl.

[0035] c) hydrolyzing the carbamate of formula (III) in the presence of an acid or a base to obtain an amine of formula (IV);

[0036]

[0037] wherein R1 and R2 have the above-mentioned meanings.

[0038] d) subjecting the compound of formula (IV) to a diazotization reaction in the presence of a suitable reagent to provide the corresponding desired alcohol of formula (V).

[0039] The process of the present invention is a dehomologation process for preparing alcohol derivatives of cholic acid starting from the corresponding carboxylic acid, wherein the alcohol derivative has one less carbon atom than the starting carboxylic acid.

[0040] According to the present invention, the term "dehomologation" refers to one or more reactions which allow the side chain of the starting cholic acid derivative to be shortened by a -CH2 group.

[0041] Step a) of the process object of the present invention consists of a Curtius reaction, which, as is well known to the skilled person, is carried out by reacting a carboxylic acid of formula (I) dissolved in an aprotic solvent with an organic azide of formula R-N3, wherein R is selected from diphenylphosphoryl, trimethylsilyl, trifluoromethanesulfonyl, preferably diphenylphosphoryl.

[0042] Examples of aprotic solvents which can be used in step a) are N-methylpyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, tetrahydrofuran, methyltetrahydrofuran, toluene, dichloromethane and mixtures thereof, preferably tetrahydrofuran.

[0043] To the reaction mixture containing the acid of formula (I) and azide dissolved in the above aprotic solvent is added a tertiary amine selected from the group consisting of triethylamine, tri-n-butylamine, N,N-diisopropylethylamine, N,N-dimethylaminopyridine.

[0044] Preferably, the tertiary amine is triethylamine.

[0045] According to the present invention, the reaction is carried out at a temperature ranging from room temperature to the reflux temperature of the solvent for 2 hours to 6 hours, preferably for about 4 hours.

[0046] Once the reaction is complete, the isocyanate of formula (II) can be isolated by techniques well known to those skilled in the art (eg, filtration, extraction, precipitation, crystallization).

[0047] Subsequently, in step b) of the process, the obtained isocyanate of formula (II) is reacted with an alcohol of formula R3-OH, wherein R3 is a linear or branched C1-C4 alkyl, aryl or alkaryl group.

[0048] The alcohol is preferably selected from methanol, ethanol, isopropanol, tert-butanol, more preferably tert-butanol.

[0049] As is clear to the person skilled in the art, steps a) and b) can be carried out as described above, ie by isolating the isocyanate of formula (II) formed at the end of step a).

[0050] Alternatively, steps a) and b) can be performed in a "one-pot process", ie without isolation of intermediate compounds.

[0051] Preferably, steps a) and b) are carried out in a "one-pot process", ie, R3-OH is directly used as the reaction solvent.

[0052] According to the present invention, in step c) of the method, the carbamate of formula (III) is hydrolyzed in the presence of an acid (preferably selected from hydrochloric acid, sulfuric acid) or a base (preferably selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, more preferably potassium hydroxide).

[0053] Preferably, the acid or the base is used in a molar amount of 0.8 to 5 equivalents, more preferably 1 to 2.5 equivalents, relative to the molar amount of the carbamate of formula (III).

[0054] The hydrolysis reaction is carried out in a polar protic solvent selected from the group consisting of methanol, ethanol, isopropanol, 1-methoxy-2-propanol, butanol, preferably 1-methoxy-2-propanol.

[0055] In contrast to previous synthesis processes described in the prior art, thanks to the process of the invention it is possible to isolate the amine of formula (IV) in a yield of 87% and a conversion of 95%.

[0056] Once the amine of formula (IV) has been isolated by techniques well known to the skilled person, said amine is, according to the invention, subjected to a diazotization reaction in step d).

[0057] The reaction is carried out in the presence of an appropriate reagent capable of releasing nitroso ions (eg sodium nitrite) (in acetic acid alone or in a mixture with water, preferably in acetic acid alone, or in an organic nitrous acid R-NO2), wherein R is a linear or branched alkyl group.

[0058] Preferably, sodium nitrite is used in a molar amount of 1 to 3 equivalents, more preferably about 2 equivalents, relative to the molar amount of the amine of formula (IV).

[0059] According to a particularly preferred embodiment, the method of the present invention allows the side chain of a cholic acid derivative such as 7K-LCA (compound of formula (Ia)) to be dehomologated for the preparation of a key intermediate of BAR502 or a compound of formula (Va) or a corresponding acetyl derivative of formula (Vb), followed by hydrolysis to obtain a compound of formula (Va);

[0060]

[0061] Therefore, the present invention preferably relates to a process for preparing a compound of formula (Va),

[0062]

[0063] The method includes:

[0064] a) reacting a compound of formula (Ia) with an organic azide of formula R-N3 in an aprotic solvent in the presence of a base to obtain the corresponding isocyanate of formula (IIa); wherein R is selected from diphenylphosphoryl, trimethylsilyl, trifluoromethanesulfonyl;

[0065]

[0066] b) reacting the obtained isocyanate of formula (IIa) with R3-OH to obtain a carbamate of formula (III);

[0067]

[0068] Wherein R3 is selected from methyl and tert-butyl;

[0069] c) hydrolyzing the carbamate of formula (IIIa) or (IIIb) in the presence of a base to give an amine of formula (IVa);

[0070]

[0071] wherein R1 and R2 have the above-mentioned meanings.

[0072] d) subjecting the compound of formula (IVa) to diazotization in acetic acid in the presence of sodium nitrite to obtain the corresponding desired alcohol of formula (Va).

[0073] It can be seen that the compounds of formula (Ia), (IIa), (IIIa), (IIIb), (IVa) and (Va) correspond to the compounds of formula (I), (II), (III), (IV) and (V), respectively, wherein R1, R2 and R3 have the following meanings:

[0074] -R1 represents a -C=O group;

[0075] -R2 represents a hydrogen atom;

[0076] -R3 represents a methyl group or a tert-butyl group.

[0077] The compounds of the formulae (IIa), (IIIa), (IIIb) and (IVa) are novel compounds and constitute a further object of the present invention.

[0078] Furthermore, these compounds are useful intermediates for the synthesis of cholic acid derivatives, in particular, key intermediates for the synthesis of BAR502 (ie, the compound of formula (Va)).

[0079] Therefore, another object is the use of compounds of formula (IIa), (IIIa), (IIIb), (IVa) as intermediates in the synthesis of cholic acid derivatives and preferably in the synthesis of compounds of formula (Va).

[0080] While characteristic aspects of the invention have been described, modifications and equivalents apparent to those skilled in the art are encompassed by the following invention.

[0081] The present invention will now be illustrated by some examples, which should not be construed as limiting the scope of the present invention. Example

[0082] Example 1. Methyl ((3R)-3-((3R,10S,13R,17R)-3-hydroxy-10,13-dimethyl-7-oxohexadeca Synthesis of 1H-cyclopenta[a]phenanthrene-17-yl)butyl)carbamate

[0083] 7-Ketolithocholic acid (20.0 g, 1 eq (equivalent)) and tetrahydrofuran (100.0 mL, 5 vol (volume)) were charged into a reaction flask, the temperature was controlled at about 25°C, triethylamine (8.5 mL, 1.2 eq) and diphenylphosphoryl azide (DPPA, 15.5 g, 1.1 eq) were added. The reaction was heated to reflux and maintained under this condition for about 2 hours. The temperature was controlled at room temperature, and the resulting solution was dripped into a 30% methanol solution of sodium methoxide (48.3 mL, 5 eq) for about 4 hours. The reaction mixture was maintained under this condition for about two hours, and methyltetrahydrofuran (200.0 mL, 10 vol) and water (100.0 mL, 5 vol) were added after the reaction was completed. The organic phase was washed with 1M sodium hydroxide (2×200.0 mL), dried over magnesium sulfate, and the residue was distilled under reduced pressure to obtain 20.5 g of methyl ((3R)-3-((3R,10S,13R,17R)-3-hydroxy-10,13-dimethyl-7-oxohexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)butyl)carbamate (96%).

[0084] 1 H-NMR (d6-DMSO, 400MHz): δ6.98(t,1H), δ4.5(s,1H), δ3.5(s,3H), δ3.35(m,1H), δ3.03(m,1H), δ2.9(m,2H), δ2.46( t,1H), δ2.07(m,1H), δ1.8(d,1H), δ1.7(m,5H), δ1.5(m,3H), δ1.4(m,4H), δ1.13(m,10H), δ0.9(d,4H), δ0.62(s,3H).

[0085] 13 C-NMR (d6-DMSO, 400MHz): δ211.6, δ157.03, δ69.6, δ55.02, δ51.5, δ49.3, δ49.05, δ42.65, δ39.1, δ38.26, δ37.85, δ36.16, δ35.2, δ34.36, δ33.48, δ30.27, δ28.41, δ24.89, δ23.23, δ21.71, δ21.32, δ19.01, δ12.28.

[0086] Example 2. (3R,10S,13R,17R)-17-((R)-4-aminobutan-2-yl)-3-hydroxy-10,13-dimethyldeca Synthesis of Hexahydro-7H-Cyclopenta[a]phenanthrene-7-one

[0087] In a reaction flask, methyl-((3R)-3-((3R,10S,13R,17R)-3-hydroxy-10,13-dimethyl-7-oxohexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)butyl)carbamate (10.0 g, 1 eq), 1-methoxy-2-propanol (50.0 mL, 5 vol) and potassium hydroxide (3.0 g, 2 eq) were added and the temperature was controlled at about 25°C. The resulting suspension was heated to reflux and maintained at this condition for about 16 hours. After the reaction was completed, the mixture was controlled at room temperature and filtered on paper. The residual solid was washed with 1-methoxy-2-propanol (2×25.0 mL) and concentrated by distillation under reduced pressure to obtain 7.5 g of (3R,10S,13R,17R)-17-((R)-4-aminobutan-2-yl)-3-hydroxy-10,13-dimethylhexahydro-7H-cyclopenta[a]phenanthrene-7-one (87%).

[0088] 1 H-NMR (d6-DMSO, 400MHz): δ3.35(m,1H), δ2.89(m,1H), δ2.5(s,2H), δ2.44(m,2H), δ2.05(m,1H), δ1.93( d,1H), δ1.8(m,3H), δ1.4(m,5H), δ1.09(s,3H), δ1.07(m,4H), δ1.02(d,2H), δ0.88(d,4H), δ0.62(s,3H).

[0089] 13 C-NMR (d6-DMSO, 400MHz): δ211.85, δ129.2, δ69.6, δ55.36, δ49.3, δ49.05, δ42.65, δ37. 9, δ35.2, δ34.36, δ33.6, δ30.3, δ28.55, δ24.89, δ23.26, δ21.69, δ20.75, δ19.3, δ12.3.

[0090] Example 3. Tert-butyl ((3R)-3-((3R,10S,13R,17R)-3-hydroxy-10,13-dimethyl-7-oxodecaproyl) Synthesis of Hexahydro-1H-cyclopenta[a]phenanthrene-17-yl)butyl)carbamate

[0091] 7-Ketolithocholic acid (10.0 g, 1 eq), tert-butyl alcohol (50.0 mL, 5 vol) and tetrahydrofuran (10.0 mL, 1 vol) were charged into a reaction flask to obtain a colorless solution. Triethylamine (4.3 mL, 1.2 eq) and diphenylphosphoryl azide (DPPA, 7.75 g, 1.1 eq) were added to the solution, and the mixture was heated to reflux and maintained under this condition for about 4 hours. After the reaction was completed, the temperature was controlled at about 20°C, and methyltetrahydrofuran (100.0 mL, 10 vol) and 2M sodium hydroxide solution (30.0 mL, 3 vol) were added. The organic phase was washed with 2M sodium hydroxide (2×50.0 mL) and brine (50.0 mL), dried over magnesium sulfate, and the residue was distilled under reduced pressure to give 16.0 g of tert-butyl ((3R)-3-((3R,10S,13R,17R)-3-hydroxy-10,13-dimethyl-7-oxohexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)butyl)carbamate (100%).

[0092] 1 H-NMR (d6-DMSO, 400MHz): δ5.7(t,1H), δ4.5(s,1H), δ3.5(s,3H), δ3.03(m,1H), δ2.9(m,2H), δ2.44(t,1H), δ2.07(m,1H), δ1.9(d,1H), δ1.7(m,3H), δ1.5(m,3H), δ1.4(m,7H), δ1.13(m,8H), δ0.9(d,4H), δ0.62(s,3H).

[0093] 13 C-NMR (d6-DMSO, 400MHz): δ211.6, δ158.6, δ139.6, δ69.6, δ55.4, δ55.2, δ49.3, δ49.05, δ45.85, δ45.53, δ42.65, δ42.64, δ39.1, δ37.9, δ37.21, δ36.7, δ35.2, δ34.85, δ34.36, δ33.48, δ30.89, δ30.27, δ28.7, δ28.41, δ24.89, δ23.23, δ21.71, δ19.11, δ12.37.

[0094] Example 4. (3R,10S,13R,17R)-17-((R)-4-aminobutan-2-yl)-3-hydroxy-10,13-dimethyldeca Synthesis of Hexahydro-7H-Cyclopenta[a]phenanthrene-7-one

[0095] Tert-butyl ((3R)-3-((3R,10S,13R,17R)-3-hydroxy-10,13-dimethyl-7-oxohexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)butyl)carbamate (14.0 g, 1 eq), acetonitrile (70.0 mL, 5 vol) and methanol (70.0 mL, 5 vol) were charged into a reaction flask and the temperature was controlled at about 25°C. 37% hydrochloric acid solution (4.0 mL, 1.5 eq) was added dropwise to the reaction over 10 minutes. The reaction was maintained under this condition for about 6 hours. After the reaction was completed, the solvent was removed and methyltetrahydrofuran (210.0 mL, 15 vol) and tetrahydrofuran (70.0 mL, 5 vol) were added. The mixture was washed with hydrochloric acid (280.0 mL), washed with methyltetrahydrofuran (70.0 mL, 5 vol) and tetrahydrofuran (28.0 mL, 2 vol) and filtered through celite. The aqueous phase was basified with sodium carbonate at pH = 10. Methyltetrahydrofuran (140.0 mL, 15 vol) and tetrahydrofuran (52.0 mL, 5 vol) were added. The organic phase was then dried over magnesium sulfate, filtered and the residue was obtained by distillation under reduced pressure to obtain 9.3 g of (3R, 10S, 13R, 17R)-17-((R)-4-aminobutan-2-yl)-3-hydroxy-10,13-dimethylhexahydro-7H-cyclopenta[a]phenanthrene-7-one (80%).

[0096] 1 H-NMR (d6-DMSO, 400MHz): δ3.35(m,1H), δ2.89(m,1H), δ2.5(s,2H), δ2.44(m,2H), δ2.05(m,1H), δ1.93( d,1H), δ1.8(m,3H), δ1.4(m,5H), δ1.09(s,3H), δ1.07(m,4H), δ1.02(d,2H), δ0.88(d,4H), δ0.62(s,3H).

[0097] 13 C-NMR (d6-DMSO, 400MHz): δ211.85, δ129.2, δ69.6, δ55.36, δ49.3, δ49.05, δ42.65, δ37. 9, δ35.2, δ34.36, δ33.6, δ30.3, δ28.55, δ24.89, δ23.26, δ21.69, δ20.75, δ19.3, δ12.3.

[0098] Example 5. (3R, 10S, 13R, 17R)-3-hydroxy-17-((R)-4-hydroxybutan-2-yl)-10,13-dimethyldecamethoxy-1-((R)-4-hydroxybutan-2-yl) ... Synthesis of Hexahydro-7H-Cyclopenta[a]phenanthrene-7-one

[0099] (3R,10S,13R,17R)-17-((R)-4-aminobutan-2-yl)-3-hydroxy-10,13-dimethylhexahydro-7H-cyclopenta[a]phenanthrene-7-one (1.0 g, 1 eq) and acetic acid (5.0 mL, 5 vol) were charged into a reaction flask, the reaction temperature was controlled at about 25°C and a small amount of sodium nitrite (0.38 g, 2 eq) was added. The mixture was stirred under this condition for about 16 hours. After the reaction was completed, the pH of the mixture was controlled to 9 by adding sodium bicarbonate. The product was extracted with ethyl acetate (10.0 mL, 10 vol), and the organic phase was washed with sodium bicarbonate aqueous solution (55.0 mL, 5 vol) and brine (5.0 mL, 5 vol). The solvent was removed by vacuum distillation to obtain an oily mixture containing the acetylated derivative. The mixture was then treated at reflux with 30% sodium hydroxide (5 eq) in methanol (10 vol) until complete conversion after 16 hours to afford (3R,10S,13R,17R)-3-hydroxy-17-((R)-4-hydroxybutan-2-yl)-10,13-dimethylhexadecanehydro-7H-cyclopenta[a]phenanthrene-7-one (80%), which was purified by column chromatography (eluent: dichloromethane:methanol 98:2) for analytical purity.

[0100] 1 H-NMR (d6-DMSO, 400MHz): δ4.49(m,1H), δ4.25(m,1H), δ3.45(s,1H), δ3.35(s4H), δ2.9(m,1H), δ2.44(t,1H) , δ2.1(m,1H), δ1.9(m,1H), δ1.8(m,2H), δ1.7(m,3H), δ1.14(s,3H), δ1.08(m,5H), δ0.9(d,4H), δ0.62(s,3H).

[0101] 13 C-NMR (d6-DMSO, 400MHz): δ211.85, δ69.6, δ58.9, δ55.4, δ49.3, δ49.05, δ45.85, δ45.5, δ4 2.7, δ42.65, δ37.9, δ35.2, δ34.36, δ30.3, δ28.55, δ24.89, δ23.26, δ21.69, δ19.3, δ12.3.

Claims

1. A method for preparing a compound of formula (V), The method comprises: a) reacting a compound of formula (I) with an organic azide of formula R-N3 in an aprotic solvent in the presence of a base to obtain the corresponding isocyanate of formula (II); wherein R is selected from diphenylphosphoryl, trimethylsilyl, trifluoromethanesulfonyl; in R1 represents a -C=O group or an OH group in α or β configuration; R2 represents a hydrogen atom or an OH group; b) reacting the obtained isocyanate of formula (II) with an alcohol of formula R3-OH to obtain a carbamate of formula (III); in R1 and R2 have the meanings given above; R3 represents C 1-10 Straight-chain or branched alkyl, aryl or alkaryl; c) hydrolyzing the carbamate of formula (III) in the presence of an acid or a base to obtain an amine of formula (IV), wherein R1 and R2 have the above meanings; d) subjecting the compound of formula (IV) to a diazotization reaction in the presence of a suitable reagent to obtain the desired alcohol of formula (V).

2. The method according to claim 1, wherein the azide of formula R-N3 in step a) is diphenylphosphoryl azide.

3. The process according to any one of the preceding claims, wherein the base in step a) is a tertiary amine, preferably selected from triethylamine, tri-n-butylamine, N,N-diisopropylethylamine, N,N-dimethylaminopyridine.

4. The process according to any one of the preceding claims, wherein the alcohol of formula R3-OH in step b) is selected from methanol, ethanol, isopropanol, tert-butanol, preferably tert-butanol.

5. The process according to any one of the preceding claims, wherein steps a) and b) are performed in a "one-pot process".

6. The process according to any one of the preceding claims, wherein the acid or the base in step c) is used in a molar amount of 0.8 to 5 equivalents, preferably 1 to 2.5 equivalents, relative to the molar amount of the carbamate of formula (III).

7. A method according to any one of the preceding claims, wherein the suitable reagent in step d) is sodium nitrite.

8. The method according to claim 7, wherein the sodium nitrite is used in a molar amount of 1 to 3 equivalents, preferably about 2 equivalents, relative to the molar amount of the amine of formula (IV).

9. A method according to any one of the preceding claims, wherein: -R1 represents a -C=O group; -R2 represents a hydrogen atom; -R3 represents a methyl group or a tert-butyl group.

10. Use of a compound of the following formula as an intermediate in the method according to any one of claims 1 to 9:

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