WO2000000474A1 - Pyridine building blocks as intermediates in the synthesis of pharmaceutically active compounds - Google Patents

Pyridine building blocks as intermediates in the synthesis of pharmaceutically active compounds Download PDF

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WO2000000474A1
WO2000000474A1 PCT/IE1999/000055 IE9900055W WO0000474A1 WO 2000000474 A1 WO2000000474 A1 WO 2000000474A1 IE 9900055 W IE9900055 W IE 9900055W WO 0000474 A1 WO0000474 A1 WO 0000474A1
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alkoxy
compound
formula
alkyl
anion
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PCT/IE1999/000055
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French (fr)
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Angelo Nikolopoulos
Helmut Schickaneder
Christian Kocher
Trevor Murphy
Gesine Hermann
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Russinsky Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/68—One oxygen atom attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
    • C07F3/003—Compounds containing elements of Groups 2 or 12 of the Periodic Table without C-Metal linkages

Definitions

  • the invention relates to pyridine building blocks and in particular to the use of such products in the manufacture of pyridine benzimidazole compounds.
  • These compounds are useful intermediates in the synthesis of pharmaceutically active compounds, in particular for the preparation of various H + /K + -ATPase inhibitors.
  • R 1 hydrogen, d-C 4 -alkyl, CF 3 , CHF 2) CH 2 F, C C 4 -alkoxy, C C 4 -alkoxy-CrC 4 alkoxy, OCH 2 CF 3 .
  • R 2 hydrogen, C C 4 -alkyl, CF 3 , CHF 2 , CH 2 F, C,-C 4 -alkoxy, d-Q-alkoxy-d- - alkoxy, OCH 2 CF 3 .
  • R 3 hydrogen, C,-C 4 -alkyl, CF 3 , CHF 2 , CH 2 F, C r C 4 -alkoxy, d-C 4 -alkoxy-C,-C 4 - alkoxy, OCH 2 CF 3 .
  • R 4 hydrogen, d-d-alkyl, benzyl, acetoxy, benzoxy, trialkylsilyl.
  • X halogen, N0 2 , S0 3) OH.
  • pyridine derivatives can be activated for nucleophilic substitution in the 4-position via N-oxide formation (Scheme 1).
  • a compound of type (a) may be readily converted into a compound of formula (b) by reaction with a nucleophilic reagent (R. A. Abramovitch, Heterocylic Compounds: Pyridine and its Deriviatives, Vol.2 [1979], Angew. Chem. 70(24) 719-746 [1958], EP - A - 0 103 553, US - A -5 708 013).
  • R 1 , R 2 , R 3 and R 4 may be represented as described above.
  • X is preferably a nitro group or a halide.
  • Y may be chosen from one of the following groups: C r C 4 -alkoxy, aryloxy, OCH 2 CF 3 , d-C 4 -alkoxy-d-C 4 -alkoxy, d-d-alkylthio, d-d-alkylthio-d-d- alkylthio.
  • the present invention provides a novel method for the preparation of compounds of the formula (IV) using starting materials of the general formula (I) (Scheme 2).
  • the substituents may be selected from one or more of the following:
  • R 1 hydrogen, C r C 4 -alkyl, CF 3 , CHF 2 , CH 2 F, d-C 4 -alkoxy, C r C 4 -alkoxy-C,-C 4 - alkoxy, OCH 2 CF 3 .
  • R 2 hydrogen, d-C 4 -alkyl, CF 3 , CHF 2 , CH 2 F, d-C 4 -alkoxy, C,-C 4 -alkoxy-C r C 4 - alkoxy, OCH 2 CF 3 .
  • R J hydrogen, d-d-alkyl, CF 3 , CHF 2 , CH 2 F, d-C 4 -alkoxy, d-d-alkoxy-d-d- alkoxy, OCH 2 CF 3 .
  • R 4 hydrogen, d-d-alkyl, benzyl, acetoxy, benzoxy, trialkylsilyl.
  • Y d-d-alkoxy, aryloxy, OCH 2 CF 3 , d-d-alkoxy-d-d-alkoxy, C r C 4 -alkylthio,
  • the invention further provides complexes of the general formula (II) which are used as intermediates for the preparation of compounds of the formula (IV):
  • R , R and R are as described above;
  • R 4 hydrogen, d-d-alkyl, benzyl, acetoxy, benzoxy, trialkylsilyl, (-) (negative charge);
  • R 5 d-d-alkyl, CF 3 , CHF 2) CH 2 F, OCH 2 CF 3 , d-C 4 -alkyl, d-C 4 -alkoxy;
  • X halogen, N0 2 , S0 3 or OH
  • M earth alkali metal, third main group element, transition metal
  • Solv may be any suitable solvent, especially an alcohol or ketone, typically methanol or acetone.
  • the invention also provides complexes of the general formula (III) which are used as intermediates for making compounds of the formula (IV):
  • R , R , R , R , R , M, k, m n, and z are as herein described above.
  • Y may be represented by C C 4 -alkoxy, aryloxy, OCH 2 CF 3 , d-d-alkoxy-Ci-d- alkoxy, d-d-alkylthio, d-d-alkylthio-d-d-alkylthio.
  • a preferred embodiment of the invention is the use of magnesium halides and zinc halides as complex forming metal components.
  • the invention also provides a process for the preparation of complexes of the formulae (II) and (III).
  • a complex of formula (II) is converted into a complex of formula (III) which in turn is converted into the desired compound of formula (IV).
  • the process may be a single pot process.
  • a compound of formula (I) is converted into a complex of formula (II) and/or formula (III) by the addition of a metal salt.
  • the metal salt may be added in a molar proportion relative to the compound of formula (I) of from 1:1 to 1:4.
  • the complex is converted into a compound of formula (IV) by the addition of a substitution reagent.
  • the substitution reagent is preferably an alkali C C 4 alkoxide, especially sodium methoxide.
  • a further preferred embodiment of the invention is the use of alkali d-d- alkoxides as a co-ligand (OR 5 ) for the complex formation and as a substitution reagent.
  • a compound of formula (IV) is converted using known processing technology into a pyridine benzimidazole.
  • the pyridine benzimidazole is selected from omeprazole, pantoprazole, lansoprazole, rabeprazole or the compound TU-199 which have the following formulae:
  • R , R , R , R ,X and Y are as described above.
  • a pyridine derivative of general formula (I) can be reacted with various metal salts or boron compounds to form different complexes of type (II) and (III).
  • the complex formed depends on the ratio of pyridine ligand, metal salt or boron compound and co-ligand.
  • the obtained complexes are generally very useful intermediates for performing substitution reactions in the 4-position at the pyridine unit affording products of formula (IV).
  • Scheme 4 gives an example of numerous possibilities of how complex formation can be achieved prior to the final substitution reaction.
  • the starting material (I) containing substituents R 1 , R 2 , R 3 , R 4 , and X as herein described above is dissolved in a suitable solvent, e.g. C ⁇ -C 4 -alcohol, acetone, THF or acetonitrile.
  • a metal salt is added, preferably a metal halide such as MgCl 2 or ZnCl 2 to form an intermediate of type (II).
  • This can then be converted stepwise into intermediates (VI) and (III 1 ) by adding one or two equivalents of alkali alkoxides as co-ligands; the alkali alkoxide can be e.g. sodium methoxide. With more than two equivalents of alkali alkoxide substitution of X takes place to form product (IV).
  • Related complexes can be formed by reacting two equivalents of ligand with one equivalent of metal salt, e.g. MgCl 2 or ZnCl 2 generating a complex of type (II 1 ) This can be converted into (III) by addition of alkali alkoxide acting first as a co- ligand. After saturation of free co-ordination sites with alkoxide excess is used for performing the substitution reaction affording the 4-alkoxy substituted pyridine complex which liberates product (IV).
  • metal salt e.g. MgCl 2 or ZnCl 2
  • the crude material (507 g) is dissolved in 750 ml of ethanol. 260 ml of 30% sodium hydroxide solution are added and the reaction mixture is stirred at 0-60°C, preferably 10-30°C for approximately one hour. The solvent is distilled off and the product extracted with a suitable solvent such as toluene, ethyl acetate, dichloromethane or chloroform.
  • FT-IR(KBr): v[cm] 3440, 3171, 3020, 1542, 1392, 1371, 1343, 1296, 1260, 1240, 1224, 1100, 1029, 983, 942, 796, 761, 736, 558.5, 520.
  • Example 8 The complex obtained according to the procedure given in example 4 is suspended in methanol. 3 equivalents of a 25-30% sodium methoxide solution in methanol are added. The mixture is heated to reflux for 1.5-2 hours. Work up is undertaken as described in example 9.
  • Example 8 The complex obtained according to the procedure given in example 4 is suspended in methanol. 3 equivalents of a 25-30% sodium methoxide solution in methanol are added. The mixture is heated to reflux for 1.5-2 hours. Work up is undertaken as described in example 9.
  • Example 8 Example 8
  • the mixture is refluxed for 1.5-2 hours and 250-300 ml of the solvent is distilled off. 100-150 ml of water are added and the mixture is acidified to approximately pH 5 with acetic acid. After re-basification with ammonia the product is extracted with toluene. The volume is reduced under vacuum to crystallise the title compound. Yield 20.7 g (approximately 75%).
  • the product can be converted into the hydrochloride.
  • 2-Hydroxy- methyl-3,5-dimethyl-4-methoxypyridine is dissolved in acetone.
  • the solution is treated with HC1 gas to precipitate the hydrochloride as a white to off-white solid. Mp. 130°C.
  • the product can be converted into the hydrochloride salt as described in example 9.
  • the product may also be isolated as the hydrochloride salt by treating the crude oil with HC1 in a suitable solvent such as an isopropanol - ethyl acetate mixture.
  • a suitable solvent such as an isopropanol - ethyl acetate mixture.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Complexes of formulae (II or III) are useful intermediates for preparing compounds of formula (IV) which in turn may be converted into a pyridine benzimidazole.

Description

PYRIDINE BUILDING BLOCKS AS INTERMEDIATES IN THE SYNTHESIS OF PHARMACEUTICALLY ACTIVE COMPOUNDS
Introduction
The invention relates to pyridine building blocks and in particular to the use of such products in the manufacture of pyridine benzimidazole compounds.
Pyridine building blocks of the general formula (I) are well known compounds with well established syntheses as described in Chem. Pharm. Bull. 38 (9), 2446- 2458 [1990], J. Med. Chem. 26(2), 218-222 [1983], J. Med. Chem. 40 (18), 2866- 2875 [1997], EP - A - 0 103553.
Figure imgf000003_0001
These compounds are useful intermediates in the synthesis of pharmaceutically active compounds, in particular for the preparation of various H+/K+-ATPase inhibitors.
The substituents in (I) may be represented by the following groups:
R1: hydrogen, d-C4-alkyl, CF3, CHF2) CH2F, C C4-alkoxy, C C4-alkoxy-CrC4 alkoxy, OCH2CF3.
R2: hydrogen, C C4-alkyl, CF3, CHF2, CH2F, C,-C4-alkoxy, d-Q-alkoxy-d- - alkoxy, OCH2CF3. R3: hydrogen, C,-C4-alkyl, CF3, CHF2, CH2F, CrC4-alkoxy, d-C4-alkoxy-C,-C4- alkoxy, OCH2CF3.
R4: hydrogen, d-d-alkyl, benzyl, acetoxy, benzoxy, trialkylsilyl. X: halogen, N02, S03) OH.
It is known that pyridine derivatives can be activated for nucleophilic substitution in the 4-position via N-oxide formation (Scheme 1). A compound of type (a) may be readily converted into a compound of formula (b) by reaction with a nucleophilic reagent (R. A. Abramovitch, Heterocylic Compounds: Pyridine and its Deriviatives, Vol.2 [1979], Angew. Chem. 70(24) 719-746 [1958], EP - A - 0 103 553, US - A -5 708 013).
Figure imgf000004_0001
Scheme 1
R1, R2, R3 and R4 may be represented as described above. X is preferably a nitro group or a halide.
Y may be chosen from one of the following groups: CrC4-alkoxy, aryloxy, OCH2CF3, d-C4-alkoxy-d-C4-alkoxy, d-d-alkylthio, d-d-alkylthio-d-d- alkylthio. There is however a need for a process for preparing HVK+-ATPase inhibitors on a large scale with high yields and efficiency generally using relatively mild reaction conditions and optimum usage of reagents.
Statements of Invention
Surprisingly, it has been found that a complexation of compounds of formula (I) with various metal centres prior to the actual substitution reaction is synthetically extremely useful. The reaction can be undertaken under mild conditions affording the required product of type (IV) in good yield and high quality. Virtually no side products are observed.
The present invention provides a novel method for the preparation of compounds of the formula (IV) using starting materials of the general formula (I) (Scheme 2).
[Complex]
Figure imgf000005_0002
Figure imgf000005_0001
IY
Scheme 2
The substituents may be selected from one or more of the following:
R1: hydrogen, CrC4-alkyl, CF3, CHF2, CH2F, d-C4-alkoxy, CrC4-alkoxy-C,-C4- alkoxy, OCH2CF3. R2: hydrogen, d-C4-alkyl, CF3, CHF2, CH2F, d-C4-alkoxy, C,-C4-alkoxy-CrC4- alkoxy, OCH2CF3.
RJ: hydrogen, d-d-alkyl, CF3, CHF2, CH2F, d-C4-alkoxy, d-d-alkoxy-d-d- alkoxy, OCH2CF3.
R4: hydrogen, d-d-alkyl, benzyl, acetoxy, benzoxy, trialkylsilyl.
X: halogen, N02, S03) OH.
Y: d-d-alkoxy, aryloxy, OCH2CF3, d-d-alkoxy-d-d-alkoxy, CrC4-alkylthio,
C i -C4-alkylthio-C r C4-alkylthio .
The invention further provides complexes of the general formula (II) which are used as intermediates for the preparation of compounds of the formula (IV):
Mz(anion) , (OR5) m [Solv]n
Figure imgf000006_0001
II
R , R and R are as described above;
R4: hydrogen, d-d-alkyl, benzyl, acetoxy, benzoxy, trialkylsilyl, (-) (negative charge);
R5: d-d-alkyl, CF3, CHF2) CH2F, OCH2CF3, d-C4-alkyl, d-C4-alkoxy;
X: halogen, N02, S03 or OH;
M: earth alkali metal, third main group element, transition metal;
Anion: e.g. halide, sulphate; k: 1, 2, 3, 4;
1: 1, 2, 3; m: 0, 1,2, 3; n: >_0; z: 1 + m, (if R4 = (-), then z = k + 1 + m).
In all cases Solv may or may not be present. When not present n=0. Solv may be any suitable solvent, especially an alcohol or ketone, typically methanol or acetone.
The invention also provides complexes of the general formula (III) which are used as intermediates for making compounds of the formula (IV):
Figure imgf000007_0001
JIL
R , R , R , R , R , M, k, m n, and z are as herein described above.
Y may be represented by C C4-alkoxy, aryloxy, OCH2CF3, d-d-alkoxy-Ci-d- alkoxy, d-d-alkylthio, d-d-alkylthio-d-d-alkylthio.
A preferred embodiment of the invention is the use of magnesium halides and zinc halides as complex forming metal components. The invention also provides a process for the preparation of complexes of the formulae (II) and (III).
In one embodiment of the invention a complex of formula (II) is converted into a complex of formula (III) which in turn is converted into the desired compound of formula (IV). The process may be a single pot process.
In one embodiment of the invention a compound of formula (I) is converted into a complex of formula (II) and/or formula (III) by the addition of a metal salt. The metal salt may be added in a molar proportion relative to the compound of formula (I) of from 1:1 to 1:4.
In a preferred embodiment of the of the invention the complex is converted into a compound of formula (IV) by the addition of a substitution reagent. The substitution reagent is preferably an alkali C C4 alkoxide, especially sodium methoxide.
A further preferred embodiment of the invention is the use of alkali d-d- alkoxides as a co-ligand (OR5) for the complex formation and as a substitution reagent.
In an especially preferred aspect a compound of formula (IV) is converted using known processing technology into a pyridine benzimidazole. Most preferably the pyridine benzimidazole is selected from omeprazole, pantoprazole, lansoprazole, rabeprazole or the compound TU-199 which have the following formulae:
Figure imgf000009_0001
Omeprazole
Figure imgf000009_0002
Lansoprazole
Figure imgf000009_0003
Figure imgf000010_0001
Detailed Description of the Invention
We have attempted to carry out a substitution reaction as outlined in Scheme 3. However reaction of compound (I) with a sodium alkoxide solution requires harsh reaction conditions and a long reaction time. Product (IV) is formed, though in a very low yield (5-20%) and various side products are generally obtained. The reaction appears to be particularly difficult if substituent R4 is a hydrogen atom, in this case decomposition effects are frequently observed. For these reasons this method is not practical for large scale production.
Figure imgf000010_0002
IV
Scheme 3
R , R , R , R ,X and Y are as described above. We have however unexpectedly found that a pyridine derivative of general formula (I) can be reacted with various metal salts or boron compounds to form different complexes of type (II) and (III). The complex formed depends on the ratio of pyridine ligand, metal salt or boron compound and co-ligand. The obtained complexes are generally very useful intermediates for performing substitution reactions in the 4-position at the pyridine unit affording products of formula (IV).
Figure imgf000011_0001
IV
Alkali-Y
Figure imgf000011_0002
(I)MHal2 (I)2MHal (I)2MY2 (I)MY2
II ri' Alkali-Y Tii m1
Alkali-Y (I)MHalY
Alkali-Y
Scheme 4
Scheme 4 gives an example of numerous possibilities of how complex formation can be achieved prior to the final substitution reaction.
The starting material (I) containing substituents R1, R2, R3, R4, and X as herein described above is dissolved in a suitable solvent, e.g. Cι-C4-alcohol, acetone, THF or acetonitrile. One equivalent of a metal salt is added, preferably a metal halide such as MgCl2 or ZnCl2 to form an intermediate of type (II). This can then be converted stepwise into intermediates (VI) and (III1) by adding one or two equivalents of alkali alkoxides as co-ligands; the alkali alkoxide can be e.g. sodium methoxide. With more than two equivalents of alkali alkoxide substitution of X takes place to form product (IV).
Related complexes can be formed by reacting two equivalents of ligand with one equivalent of metal salt, e.g. MgCl2 or ZnCl2 generating a complex of type (II1) This can be converted into (III) by addition of alkali alkoxide acting first as a co- ligand. After saturation of free co-ordination sites with alkoxide excess is used for performing the substitution reaction affording the 4-alkoxy substituted pyridine complex which liberates product (IV).
Alternatively (I) can be reacted directly in a one pot process to (IV) with alkali alkoxide in the presence of suitable metal centres such as magnesium or zinc without the isolation of complex intermediates.
The invention will be more clearly understood from the following examples.
Example 1
Preparation of 3,5-dimethyl-2-hydroxymethyl-4-nitropyridine from 4-nitro-2.3,5- trimethylpyridine N-oxide
467 g (2.56 mol) of 4-nitro-2,3,5-trimethylpyridine N-oxide are dissolved in 600- 700 ml of glacial acetic acid. The obtained solution is added to 1000-1100 ml of acetic anhydride. The resulting red mixture is stirred is at 20-100°C for approximately one hour. The solvent is evaporated under reduced pressure to dryness. The residue is neutralised with diluted NaOH solution keeping the temperature between 20°C and 50°C. The product is extracted with toluene affbrding 507 g (approximately 88%) of crude product which does not require any further purification and is used as such for further reaction step.
Η-NMR of crude material (60 MHz, TMS, CDCI3): δ = 8.3 (s, 1H, ar-H); 5.2 (s,
2H, CH2); 2.3 (6H, CH3); 2.2 (s, 3H, CH3).
The crude material (507 g) is dissolved in 750 ml of ethanol. 260 ml of 30% sodium hydroxide solution are added and the reaction mixture is stirred at 0-60°C, preferably 10-30°C for approximately one hour. The solvent is distilled off and the product extracted with a suitable solvent such as toluene, ethyl acetate, dichloromethane or chloroform.
Further purification can be obtained by re-crystallisation from petroleum ether /MTBE. A yield of 346 g (approximately 84%) is obtained.
Mp.: 66.4-69.5°C. Η-NMR (270 MHz, CDCI3): δ = 8.43 (s, 1H, aryl-H), 4.73 (s, 2H, CH2), 4.14
(sbr, 1H, OH), 2.31 (s, 3H, CH3); 2.16 (s, 3H, CH3).
^C-NMR (67.5 MHz): δ = 157.46, 156.94, 147.94, 122.16, 119.74 (C-2, C-3, C-4, C-5, C-6); 61.78 (CH2); 13.87, 11.05 (CH3).
FT-IR (KBr): v [cm1] = 3228, 2889, 1540, 1457, 1386, 1366, 1268, 1238, 1208, 1172, 1051, 1025, 995, 954, 906, 883, 812, 773, 746, 708, 652, 553, 500.
Microanalysis: C8H,0N2O3 (182.18) calc: C: 52.74 H: 5.53 N: 15.38 found: C: 52.59 H: 5.54 N: 15.38
Example 2
Preparation of 4-Chloro-3,5-dimethyl-2-hydroxymethylpyridine from 4-Chloro- 2,3,5-trimethylpyridine N-oxide 41.6 g (0.24 mol) of 4-Chloro-2,3,5-trimethylpyridine N-oxide are reacted with 66.9 (0.66 mol) of acetic anhydride in 25 ml of glacial acetic acid according to the procedure given in example 1. After work up the crude material of 2- acetoxymethyl-4-chloro-3,5-dimethylpyridine is dissolved 100-150 ml of methanol. 25 ml of 30% sodium hydroxide solution are added and the mixture is stirred at room temperature for approximately one hour. The solvent is removed under vacuum affording a brown oil. After addition of 20-40 ml of water the product is extracted with a suitable solvent such as chloroform, THF or ethyl acetate. The organic phase is dried over sodium sulphate. After evaporation of the solvent the product crystallises from the obtained oil in a yield of approximately
80% (33.3 g).
Mp.: 57.1-60.7°C.
Η-NMR (270 MHz, CDC13): δ = 8.21 (s, 1H, ar-H); 4.66 (s, 2H, CH2); 4.37 (sbr, 1H, OH); 2.34 (s, 3H, CH3); 2.24 (s, 3H, CH3).
13C-NMR (67.5 MHz, CDC13): δ = 155.14, 146.05, 144.89, 130.48, 127.78 (C-2,
C-3, C-4, C-5, C-6); 17.31 (CH3), 13.67 (CH3).
FT-IR (KBr): v [cm 1] = 3154, 2879, 1581, 1552, 1441, 1386, 1357, 1323, 1266,
1235, 1205, 1156, 1028, 923, 829, 782, 741. Microanalysis: C8HI0NC10 [171.63]: calc: C: 55.99 H: 5.87 N: 8.16 Cl: 20.66 found: C: 55.80 H: 5.99 N: 8.18 Cl: 20.41
Example 3
Preparation of complex [Zn(I)ClQCHj from ZnCl?. 2-hydroxymethyl-3,5- dimethyl-4-nitropyridine (I) and sodium methoxide
41.0 g (0.22 mol) of 2-hydroxymethyl-3,5-dimethyl-4-nitropyridine are dissolved in 600-800 ml of methanol. 30.8 g (0.22 mol) of zinc chloride are added. The mixture is stirred at room temperature and one equivalent of sodium methoxide (25-30% solution in methanol) is added. After complete addition the temperature is raised to 30-50°C for 20-30 minutes. The solvent is then removed under vacuum affording a white to off-white solid. 300-500 ml of chloroform are added and the mixture is filtered to remove inorganics. The product can be precipitated in quantitative yield.
Η-NMR (60 MHz, CDC13): δ = 8.30 (s, 1H, H-6); 5.08 (s, 2H, CH2); 3.57 (s, 1H, OH); 3.23 (s, 3H, OCH3); 2.18 (s, 3H, CH3); 2.15 (s, 3H, CH3).
FT-IR (KBr): v [cm1] = 3420, 2926, 2848, 1606, 1576, 1538, 1442, 1389, 1367, 1257, 1229, 1183, 1097, 1031, 922, 802, 761, 658, 623, 568.
Example 4
Preparation of complex [Mg(I ClQCHj] from MgCl2. 2-hydroxymethyl-3,5- dimethyl-4-nitropyridine (I) and sodium methoxide
20.4 g (0.11 mol) of 2-hydroxymethyl-3,5-dimethyl-4-nitropyridine are dissolved in 150-200 ml of methanol. 10.7 g (0.11 mol) of magnesium chloride are added. The mixture is heated to 30-50°C and 0.11 mol of sodium methoxide is added as a
25-30% solution in methanol. Stirring is continued at room temperature for 20-40 minutes. The product precipitates from the solution and is filtered off. It is taken up in 50-100 ml of chloroform, filtered to remove inorganics and re-precipitated again in quantitative yield.
Η-NMR (270 MHz, CDC13): δ = 8.18 (s, 1H, aryl-H); 6.60 (d, 1H, CH2); 4.85 (d, 1H, CH2); 3.30 (s, OCH3, MeOH), 2.18 (s, 6H, CH3).
13C-NMR (67.5 MHz, CDC13): δ = 162.49, 157.43 (C-2, C-4); 147.16 (C-6); 122.47, 120.39 (C-3, C-5); 62.54 (CH2); 50.30 (OCH3); 13.62, 11.44 (CH3). FT-IR (KBr): v [cm1] = 3396, 3235, 2923, 1636, 1604, 1570, 1535, 1447, 1390, 1369, 1253, 1228, 1184, 1146, 1120, 1100, 1034, 913, 884, 800, 757, 626, 563, 480.
Example 5
Preparation of complex fZnfDCkfacetone)] from ZnCl?. 2-hydroxymethyl-3,5- dimethyl-4-nitropyridine (I)
20.5 g (0.11 mol) of 2-hydroxymethyl-3,5-dimethyl-4-nitropyridine are dissolved in 120-150 ml of acetone. 15.4 g (0.11 mol) of zinc chloride are added and the mixture is stirred at room temperature for 20-40 minutes. The solvent is removed under vacuum affording the title compound in quantitative yield.
Η-NMR (270 MHz, do-DMSO): δ = 8.52 (s, 1H, aryl-H); 6.01 (sbr, 1H, OH); 4.71
(s, 2H, CH2); 2.33 (s, 3H, CH3); 2.24 (s, 3H, CH3); 2.10 (s, 6H, CH3). 13C-NMR (67.5 MHz, de-DMSO): δ = 206 (C = O); 158.61, 157.23 (C-2, C-4);
148.28 (C-6), 121.99, 121.27 (C-3, C-5); 62.65 (CH2); 30.60 (CH3C=0);
13.27, 11.63 (CH3).
FT-IR(KBr): v[cm'] = 3481, 3214, 2923, 2837, 1616, 1540, 1438, 1387, 1369,
1259, 1230, 1082, 1029, 915, 894.5, 798, 766.
Example 6
Preparation of [Znfl^Cl?] from ZnCl? and 2-hvdroxymethyl-3,5-dimethyl-4- nitropyridine
20.4 g (0.11 mol) of 2-hydroxymethyl-3,5-dimethyl-4-nitropyridine are dissolved in 120-150 ml of acetone. 7.77 g (0.056 mol) of zinc chloride are added. The mixture is stirred for 60-80 minutes at room temperature to form a white to off- white precipitate. The solvent is removed affording the title compound in quantitative yield. 'H-NMR (60 MHz, de-DMSO): δ =8.32 (s, 1H, aryl-H); 5.43 (sbr, 1H, OH); 4.57 (s, 2H, CH2); 2.20 (s, 6H, CH3).
FT-IR(KBr): v[cm] = 3440, 3171, 3020, 1542, 1392, 1371, 1343, 1296, 1260, 1240, 1224, 1100, 1029, 983, 942, 796, 761, 736, 558.5, 520.
Example 7
Preparation of2-hydroxymethyl-3,5-dimethyl-4-methoxypyridine from [MgfDClOCHj and sodium methoxide
The complex obtained according to the procedure given in example 4 is suspended in methanol. 3 equivalents of a 25-30% sodium methoxide solution in methanol are added. The mixture is heated to reflux for 1.5-2 hours. Work up is undertaken as described in example 9. Example 8
Preparation of [Zn(I)2] from ZnCl2 and 2-hydroxymethyl-3,5-dimethyl-4- nitropyridine
20.5 g (0.11 mol) of 2-hydroxymethyl-3,5-dimethyl-4-nitropyridine are dissolved in 120-150 ml of acetone. A solution of 15.4 g (0.11 mol) of zinc chloride in 80- 120 ml of acetone is added. The mixture is stirred for 30-60 minutes at room temperature. After evaporation of the solvent the title complex is isolated in quantitative yield.
Η-NMR (270 MHz, c^-DMSO): δ = 8.52 (s, 1H, aryl-H); 5.75 (Sbr, 1H, OH); 4.69 (s, 2H, CH2); 2.25 (s, 6H, CH3).
13C-NMR (67.5 MHz, de-DMSO): δ = 158.84, 157.23 (C-2, C-4); 148.37 (C-6); 121.88, 121.26 (C-3, C-5); 62.95 (CH2); 13.28, 11.68 (CH3). FT-IR (KBr): v[cm-l] = 3170, 1542, 1392, 1371, 1240, 1223, 1100, 1028, 796, 761. The following examples show that a one pot process can also be performed. There is no need to isolate the active complex in-between. However complex formation and isolation can be used as a purification method where the complex forming pyridine units were not purified before.
Example 9
Preparation of 2-hydroxymethyl-3,5-dimethyl-4-methoxypyridine from, MgCl2. 2- hydroxymethyl-3.5-dimethyl-4-nitropyridine and sodium methoxide (one pot process)
30.0 g (0.16 mol) of 2-hydroxymethyl-3,5-dimethyl-4-nitropyridine are dissolved in 300-350 ml of methanol and 15.7 g (0.16 mol) of magnesium chloride are added. The mixture is stirred at room temperature for 20-30 minutes. Then 4 equivalents of sodium methoxide as a 25-30% solution in methanol are added.
The mixture is refluxed for 1.5-2 hours and 250-300 ml of the solvent is distilled off. 100-150 ml of water are added and the mixture is acidified to approximately pH 5 with acetic acid. After re-basification with ammonia the product is extracted with toluene. The volume is reduced under vacuum to crystallise the title compound. Yield 20.7 g (approximately 75%).
Mp.: 57-60°C.
Η-NMR (60 MHz, CDC13): δ = 8.14 (s, 1H, aryl-H);4.80 (s, 1H, OH); 4.60 (s, 2H, CH2); 3.79 (s, 3H, OCH3); 2.25 (s, 3H, CH3); 2.13 (s, 3H, CH3). FT-IR (KBr): v [cm 1] = 3168, 2942, 1820, 1683, 1592, 1570, 1538, 1476, 1395,
1379, 1361, 1287, 1255, 1233, 1094, 1021, 1000, 950, 911, 872, 802, 763, 723, 692, 646, 559, 533, 504.
Optionally the product can be converted into the hydrochloride. 2-Hydroxy- methyl-3,5-dimethyl-4-methoxypyridine is dissolved in acetone. The solution is treated with HC1 gas to precipitate the hydrochloride as a white to off-white solid. Mp. 130°C.
1H-NMR (270 MHz, CDC13): δ = 9.70 (sbr, 2H, NH, OH); 8.71 (s, 1H, aryl-H),
4.99 (s, 2H, CH2); 4.02 (s, 3H, OCH3); 2.41 (s, 3H, CH3); 2.27 (s, 3H, CH3).
13C-NMR (67.5 MHz, CDC13): δ = 170.06, 154.61, 140.71, 128.02, 126.32 (C-2,
C-3, C-4, C-5, C-6); 61.06, 58.90 (CH2, OCH3); 14.25, 10.56 (CH3).
FT-IR (KBr): v[cm''] = 3359, 3241, 3185, 3031, 2969, 2923, 2867, 2805, 1717.5,
1820, 1596, 1514, 1470, 1446, 1401, 1386, 1294, 1252, 1230, 1210,1140, 1111,
1062, 1048, 1004, 982, 957, 901, 851, 770, 670, 627, 584, 502.
Microanalysis: C9H14C1N02 [203.07] calα: C: 53.08 H: 6.93 N: 6.88 Cl: 17.41 found: C: 53.07 H: 6.60 N: 6.93 Cl: 17.55
Example 10
Alternative preparation of 2-hydroxymethyl-3,5-dimethyl-4-methoxypyridine- from ZnCl2 and 2-hydroxymethyl-3,5-dimethyl-4-nitropyridine
20.4 g (0.11 mol) of 2-hydroxymethyl-3,5-dimethyl-4-nitropyridine are dissolved in 220-250 ml of methanol. 7.63 g (0.056 mol) of zinc chloride and 50-55 ml of a 25-30% solution of sodium methoxide in methanol are added. The mixture is stirred at reflux for 5-7 hours. Then the solvent is evaporated and the residue acidified with glacial acetic acid to pH 5 and re-basified with ammonia to pH 10. The product is extracted with toluene or any other suitable solvent affording the title compound in approximately 65-70% yield. Optionally the product can be converted into the hydrochloride salt as described in example 9.
Example 11 Further alternative preparation of 2-hvdroxymethyl-3,5-dimethyl-4- methoxypyridine - from ZnCl2 and 2-acetoxymethyl-3.5-dimethyl-4-nitropyridine
25.4 g (0.11 mol) of 2-acetoxymethyl-3,5-dimethyl-4-nitropyridine are dissolved in 200-250 ml of methanol. 7.63 g (0.056 mol) of zinc chloride and 50-55 ml of a 25-
30% solution of sodium methoxide in methanol are added. The reaction mixture is heated for 5-6 hours to reflux. The solvent is evaporated and the residue acidified with glacial acetic acid to pH 5. After re-basification with ammonia to pH 10 the title compound is extracted with toluene or any other suitable solvent furnishing the product in 60-65 % yield. Optionally the product can be converted into the hydrochloride salt as described in example 9.
Example 12
Preparation of 2-hydroxymethyl-3-methyl-4-nitropyridine from 2,3-dimethyl-4- nitropyridine N-oxide
30.0 g (0.18 mol) of 2,3-dimethyl-4-nitropyridine N-oxide are dissolved in 40-60 ml of acetic acid. The obtained solution is added to 250 ml of acetic anhydride. The mixture is stirred at elevated temperature for approximately one hour. The solution is then cooled to room temperature and quenched with 700-800 ml of water. The crude intermediate is extracted with a suitable solvent such as methylene chloride. The organic phase is washed with water and potassium hydrogencarbonate affording 24.2 g (approximately 81%) of crude intermediate which does not require any further purification and can be used as such for the following hydrolysis step.
Η-NMR of crude material (60 MHz, TMS, CDC13): δ = 8.4 (d, 1H, ar-H); 7.4 (d, 1H, ar-H); 5.3 (s, 2H, CH2); 2.5 (s, 3H, CH3); 2.2 (s, 3H, CH3). The crude intermediate is dissolved in 200-300 ml of methanol. The mixture is treated with sodium hydroxide keeping the temperature preferably in a range of 0- 60°C. After completion of the reaction the solvent is removed and the crude product is taken up in a suitable solvent such as methylene chloride. The organic phase is washed with water and dried over magnesium sulfate. The solvent is evaporated and the product crystallises from the obtained oil. The product may be re-crystallised from ethyl acetate / petroleum ether. A yield of > 60% is typically obtained for the hydrolysis step.
Mp.: 64.6-65.3°C.
Η-NMR (60 MHz, TMS, CDC13): δ = 8.4 (d, 1H, ar-H); 7.4 (d, 1H, ar-H); 4.7 (s, 2H, CH2); 4.6 (sbr, 1H, OH); 2.3 (s, 3H, CH3).
FT-IR (KBr): v [cm 1] = 3471, 1545, 1531, 1432, 1355, 1288, 1232, 1194, 1096, 1070, 1022, 844, 781.
Example 13
Preparation of 2-hydroxymethyl-3-methyl-4-(2,2,2-trifluoroethoxy)-pyridine from ZnCl2 and 2-hydroxymethyl-3-methyl-4-nitropyridine
20.0 g (0.11 mol) of 2-hydroxymethyl-3-methyl-4-nitropyridine and 7.80 g (0.055 mol) of zinc chloride are suspended in a suitable solvent such as THF. The mixture is stirred at room temperature until a clear solution is obtained. 50 ml of 2,2,2-trifluoroethanol and 26 g of potassium tert.-butylate are added. The mixture is heated to reflux for 1-3 h. The solvent is removed and the crude product acidified with acetic acid, re-basified with ammonia and extracted with a suitable solvent such as methylene chloride. The solvent is removed and the product crystallised from the crude oil with a yield typically >65%.
The product may also be isolated as the hydrochloride salt by treating the crude oil with HC1 in a suitable solvent such as an isopropanol - ethyl acetate mixture. Analytical data for hydrochloride salt:
Mp.: 201.8-206°C.
Η-NMR (60 MHz, TMS, d4-MeOH): δ = 8.3 (d, 1H, ar-H); 7.4 (d, 1H, ar-H); 4.7-
5.1 (m, 6H, CH2, OH, HC1); 2.2 (s, 3H, CH3).
FT-IR (KBr): v [cm 1] = 3159, 2960, 1630, 1523, 1487, 1462, 1329, 1303, 1279,
1200, 1165, 1107, 1067, 977, 859, 805, 674.
Example 14
Preparation of 2-hydroxymethyl-3-methyl-4-methoxypyridine from 2-hydroxy- methyl-3-methyl-4-nitropyridine, ZnCl2 and sodium methoxide
15.0 g (0.08 mol) of zinc chloride are added to a solution of 20 g (0.08 mol) of 2- hydroxy-methyl-3-methyl-4-nitropyridine in 200-250 ml of methanol. The solution is stirred at room temperature and 72 ml of a 25% sodium methoxide solution in methanol are added. The mixture is heated to reflux for 5-6 hours and most of the solvent is distilled off. 300-400 ml of water are added and the mixture is acidified with acetic acid to approximately pH 5. After re-basification with aqueous ammonia solution the product is extracted with a suitable solvent such as toluene or chloroform. The organic solvent is removed and the product crystallised from the residue affording the title compound in 75% yield (10.3 g). The crude material may be converted into the hydrochloride salt as described in example 9.
The invention is not limited to the embodiments hereinbefore described which may be varied in detail.

Claims

Claims
1. A compound of the formula (II):
M z (anion) , (OR5) m Solv
Figure imgf000023_0001
Figure imgf000023_0002
Jl
wherein the substituents are independently selected from one or more of the following:
R1: hydrogen, d-C4-alkyl, CF3, CHF2, CH2F, d-d-alkoxy, C C4-alkoxy- d-C4-alkoxy, or OCH2CF3; R2: hydrogen, CrC4-alkyl, CF3, CHF2, CH2F, d-d-alkoxy, d-d-alkoxy- d-d-alkoxy, or OCH2CF3; R3: hydrogen, CrC4-alkyl, CF3, CHF2, CH2F, C,-C4-alkoxy, C,-C4-alkoxy- d-C4-alkoxy, or OCH2CF3; R4: hydrogen, C╬╣-C4-alkyl, benzyl, acetoxy, benzoxy, trialkylsilyl, or ╬╕
(negative charge); R5: d-d-alkyl, aryl, CH2CF3, CF3, CHF2, CH2F, or d-d-alkyl-d-d- alkoxy; X: halogen, N02, S03, or OH;
M: earth alkali metal, third main group element or transition metal; k: 1, 2, 3 or 4. 1: 1, 2 or 3. m: 0, 1, 2 or 3. n: > 0 z: 1 + m, with the proviso that if R4 = ╬╕ (negative charge), then z= k + 1 + m.
2. A compound as claimed in claim 1 wherein R1 = H, R2 = CH3, R3 = CH3, R4 = H, X = N02, anion = Cl╬╕, R5 = CH3,
M = Mg2╬╕,k = l = m= l,n>0.
3. A compound as claimed in claim 1 wherein
R1 = H, R2 = CH3, R3 = CH3, R4 = H, X = N02, anion = Cl╬╕, R5 = CH3, M = Zn2╬╕, k = l = m= l,n>0.
4. A compound as claimed in claim 1 wherein
R1 = H, R2 = CH3, R3 = CH3, R4 = H, X = Cl, anion = Cl╬╕, R5 = CH3, M = Mg2╬╕,k = l = m=l,n>0.
5. A compound as claimed in claim 1 wherein
R1 = H, R2 = CH3, R3 = CH3, R4 = H, X = Cl, anion = Cl╬╕, R5 = CH3, M = Zn2@,k = l = m = l,n>0.
6. A compound as claimed in claim 1 wherein
R1 = H, R2 = H, R3 = CH3, R4 = H, X = N02, anion = Cl╬╕, R5 = CH3, M = Mg2@,k = l = m=l,n>0.
7. A compound as claimed in claim 1 wherein R1 = H, R2 = H, R3 - CH3, R4 = H, X - N02, anion = Cl╬╕, R5 = CH3, M =
Zn2╬╕,k = l = m=l,n>0.
8. A compound as claimed in claim 1 wherein
R1 = H, R2 = H, R3 = CH3, R4 = H, X = Cl, anion = Clθ, R5 = CH3, M = Mg2φ,k = l = m=l,n>0.
9. A compound as claimed in claim 1 wherein
R1 = H, R2 = H, R3 = CH3, R4 = H, X = Cl, anion = Clθ, R5 = CH3, M = Zn2®, k = l = m = l, n > 0.
10. A compound as claimed in any preceding claim wherein Solv is selected from one or more of the same or different of: an alcohol or a ketone.
11. A compound as claimed in claim 10 wherein Solv is selected from methanol and acetone.
12. A compound as claimed in any preceding claim wherein n = 0.
13. A compound as claimed in any preceding claim wherein anion is selected from: halide; sulphate and phosphate.
14. A compound of the formula (III):
Figure imgf000025_0001
wherein R1, R2, R3, R4, R5, M, Solv, k, m and n are as defined in claim 1, z = m, with the proviso that if R4 =╬╕ (negative charge) then z = k + m; and Y is selected from: d-d-alkoxy, aryloxy, OCH2CF3, d-d-alkoxy-d-d- alkoxy, C,-C4-alkylthio, d-C4-alkylthio-CrC4-alkylthio.
15. A compound of the formula (II) substantially as hereinbefore described with reference to the examples.
16. A compound of the formula (III) substantially as hereinbefore described with reference to the examples.
17. Process for the preparation of compounds of the general formula (IV):
Figure imgf000026_0001
IV
by forming a complex as claimed in any of claims 1 to 16 and converting the complex into the desired compound of formula (IV) according to the reaction scheme:
[Complex]
Figure imgf000026_0003
Figure imgf000026_0002
IV
the substituents independently selected from one or more of the following: R1: hydrogen, d-d-alkyl, CF3, CHF2, CH2F, C,-C4-alkoxy, d-d-alkoxy- d-d-alkoxy, OCH2CF3; R2: hydrogen, C,-C4-alkyl, CF3, CHF2, CH2F, -d-alkoxy, d-C4-alkoxy- d-d-alkoxy, OCH2CF3; R3: hydrogen, d-C4-alkyl, CF3, CHF2, CH2F, d-C4-alkoxy, d-d-alkoxy- d-d-alkoxy, OCH2CF3; R4: hydrogen, d-C -alkyl, benzyl, acetoxy, benzoxy, trialkylsilyl; Y: d-d-alkoxy, aryloxy, OCH2CF3, d-C4-alkoxy-CrC4-alkoxy, d-C4- alkylthio, d-d alkylthio-CrC4-alkylthio;
18. A process as claimed in claim 17 wherein the complex is a compound of the formula (II) as defined in claims 1 to 13 or 15 and/or a compound of the formula (III) as defined in claim 14 or 16.
19. A process as claimed in claim 17 or 18 wherein a complex of formula (II) is converted into a complex of formula (III) as defined in claim 14 or 16 which in turn converted into the desired compound of formula (IV) as defined in claim 17.
20. A process as claimed in any of claims 17 to 19 in which the process is a single pot process.
21. A process as claimed in any of claims 17 to 20 wherein the compound of formula (I) is converted into a complex of formula (II) and/or formula (III) by the addition of a metal salt.
22. A process as claimed in claim 21 wherein the metal salt is added in a molar proportion relative to the compound of formula (I) of from 1:1 to 1:4.
23. A process as claimed in any of claims 17 to 22 wherein the complex is converted into a compound of formula (IV) by the addition of a substitution reagent.
24. A process as claimed in claim 23 wherein the substitution reagent is an alkali Ci to C4 alkoxide, especially sodium methoxide.
25. A process as claimed in any of claims 17 to 24 wherein the compound of formula (IV) is converted into a corresponding pyridine benzimidazole.
26. A process as claimed in claim 25 wherein the pyridine benzimidazole is selected from omeprazole, pantoprazole, lansoprazole, rabeprazole, and the compound TU-199.
27. A process substantially as hereinbefore described with reference to the examples.
28. A compound of formula (IV) as defined in claim 17 whenever prepared by a process as claimed in any of claims 17 to 24 or 27.
29. A pyridine benzimidazole whenever prepared by a process as claimed in any of claims 25 to 27.
30. Omeprazole whenever prepared by the process and/or using the intermediate(s) of the invention.
31. Pantoprazole whenever prepared by the process and/ or using the intermediate(s) of the invention.
32. Lansoprazole whenever prepared by the process and/ or using the intermediate(s) of the invention.
33. Rabeprazole whenever prepared by the process and/or using the intermediate(s) of the invention.
34. The compound TU-199 whenever prepared by the process and/or using the intermediate(s) of the invention.
PCT/IE1999/000055 1998-06-26 1999-06-18 Pyridine building blocks as intermediates in the synthesis of pharmaceutically active compounds WO2000000474A1 (en)

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