Process for the manufacture of fused piperazin-2-one derivatives

Disclosed are processes for the preparation of fused piperazin-2-one derivatives of general formula (I) wherein the groups R1 to R5, A1 and A2 have the meanings given in the claims and in the description, particularly the preparation of 7,8-dihydro-5H-pteridin-6-one derivatives and intermediates thereof.

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Description
APPLICATION DATA

This application claims priority to German application DE 10 2004 058 337.4 filed Dec. 2, 2004.

The invention relates to a process for preparing fused piperazin-2-one derivatives of general formula (I)


wherein the groups R1 to R5 have the meanings given in the claims and specification, particularly a process for preparing 7,8-dihydro-5H-pteridin-6-one derivatives.

BACKGROUND TO THE INVENTION

Pteridinone derivatives are known from the prior art as active substances with an antiproliferative activity. WO 03/020722 describes the use of dihydropteridinone derivatives for the treatment of tumoral diseases and processes for preparing them.

7,8-Dihydro-5H-pteridin-6-one derivatives of formula (I) are important intermediate products in the synthesis of these active substances. Up till now they have been prepared using methods involving reduction of nitro compounds of formula (II) below, which led to strongly coloured product mixtures and required laborious working up and purification processes.

WO 96/36597 describes the catalytic hydrogenation of nitro compounds using noble metal catalysts with the addition of a vanadium compound, while disclosing as end products free amines, but no lactams.

The aim of the present invention is to provide an improved process for preparing compounds of formula (I), particularly 7,8-dihydro-5H-pteridin-6-one derivatives.

DETAILED DESCRIPTION OF THE INVENTION

The present invention solves the problem outlined above by the method of synthesising compounds of formula (I) described hereinafter.

The invention thus relates to a process for preparing compounds of general formula I

  • wherein
  • R1 denotes a group selected from the group consisting of chlorine, fluorine, bromine, methanesulphonyl, ethanesulphonyl, trifluoromethanesulphonyl, paratoluenesulphonyl, CH3S(═O)— and phenylS(═O)—
  • R2 denotes hydrogen or C1-C3-alkyl,
  • R3 denotes hydrogen or a group selected from the group consisting of optionally substituted C1-C12-alkyl, C2-C12-alkenyl, C2-C12-alkynyl and C6-C14-aryl, or a group selected from the group consisting of optionally substituted and/or bridged C3-C12-Cycloalkyl, C3-C12-cycloalkenyl, C7-C12-polycycloalkyl, C7-C12-polycycloalkenyl, C5-C12-spirocycloalkyl and saturated or unsaturated C3-C12-heterocycloalkyl, which contains 1 to 2 heteroatoms,
  • R4, R5 which may be identical or different denote hydrogen or optionally substituted C1-C6-alkyl, or
  • R4 and R5 together denote a 2- to 5-membered alkyl bridge which may contain 1 to 2 heteroatoms, or
  • R4 and R3 or R5 and R3 together denote a saturated or unsaturated C3-C4-alkyl bridge, which may optionally contain 1 heteroatom,
    and

A1 and A2 which may be identical or different represent —CH═ or —N═, preferably —N═, in which a compound of formula II


wherein

  • R1-R5 and A1, A2 have the stated meaning and
  • R6 denotes C1-C4-alkyl,
  • a) is hydrogenated with hydrogen in the presence of a hydrogenation catalyst and
  • b) a copper, iron or vanadium compound is added,
    in which steps a) and b) may take place simultaneously or successively.

In a preferred process, the hydrogenation of the compound of formula II is carried out directly in the presence of the hydrogenation catalyst and the copper, iron or vanadium compound to form the compound of formula I.

In a particularly preferred process, after the first hydrogenation step a), first of all the intermediate product of formula III is obtained, which may optionally be isolated,


and is then further reduced in the presence of a hydrogenation catalyst and a copper, iron or vanadium compound to form a compound of formula I

Also preferred is a process in which the hydrogenation catalyst is selected from the group consisting of rhodium, ruthenium, iridium, platinum, palladium and nickel, preferably platinum, palladium and Raney nickel. Platinum is particularly preferred. Platinum may be used in metallic form or oxidised form as platinum oxide on carriers such as e.g. activated charcoal, silicon dioxide, aluminium oxide, calcium carbonate, calcium phosphate, calcium sulphate, barium sulphate, titanium dioxide, magnesium oxide, iron oxide, lead oxide, lead sulphate or lead carbonate and optionally additionally doped with sulphur or lead. The preferred carrier material is activated charcoal, silicon dioxide or aluminium oxide.

Preferred copper compounds are compounds in which copper assumes oxidation states I or II, for example the halides of copper such as e.g. CuCl, CuCl2, CuBr, CuBr2, CuI or CuSO4. Preferred iron compounds are compounds wherein iron assumes oxidation states II or III, for example the halides of iron such as e.g. FeCl2, FeCl3, FeBr2, FeBr3, FeF2 or other iron compounds such as e.g. FeSO4, FePO4 or Fe(acac)2.

Preferred vanadium compounds are compounds wherein vanadium assumes the oxidation states 0, II, III, IV or V, for example inorganic or organic compounds or complexes such as e.g. V2O3, V2O5, V2O4, Na4VO4, NaVO3, NH4VO3, VOCl2, VOCl3, VOSO4, VCl2, VCl3, vanadium oxobis(1-phenyl-1,3-butanedionate), vanadium oxotriisopropoxide, vanadium(III)acetylacetonate [V(acac)3] or vanadium(IV)oxyacetylacetonate [VO(acac)2]. Vanadium(IV)oxyacetylacetonate [VO(acac)2] is particularly preferred.

The copper, iron or vanadium compound may be used either directly at the start of the hydrogenation or after the formation of the intermediate of formula (III), as preferred.

Also preferred is a process wherein the amount of added hydrogenation catalyst is between 0.1 and 10 wt.-% based on the compound of formula (II) used.

Also preferred is a process wherein the amount of copper, iron or vanadium compound used is between 0.01 and 10 wt.-% based on the compound of formula (II) used.

Also preferred is a process wherein the reaction is carried out in a solvent selected from the group consisting of dipolar, aprotic solvents, for example dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, dimethylsulphoxide or sulpholane; alcohols, for example methanol, ethanol, 1-propanol, 2-propanol, the various isomeric alcohols of butane and pentane; ethers, for example diethyl ether, methyl-tert.-butylether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane or dimethoxyethane; esters, for example ethyl acetate, 2-propylacetate or 1-butylacetate; ketones, for example acetone, methylethylketone or methylisobutylketone; carboxylic acids, for example acetic acid; apolar solvents, for example toluene, xylene, cyclohexane or methylcyclohexane, as well as acetonitrile, methylene chloride and water. The solvents may also be used as mixtures.

Also preferred is a process wherein the reaction temperature is between 0° C. and 150° C., preferably between 20° C. and 100° C.

Also preferred is a process wherein the hydrogen pressure is 1 bar to 100 bar.

The invention further relates to a compound of formula (III)

wherein R1 to R5 may have the stated meaning.

Preferred compounds of formula (III) are those wherein A1 and A2 are identical and denote —N═.

The reactions are worked up by conventional methods e.g. by extractive purification steps or precipitation and crystallisation methods.

The compounds according to the invention may be present in the form of the individual optical isomers, mixtures of the individual enantiomers, diastereomers or racemates, in the form of the tautomers as well as in the form of the free bases or the corresponding acid addition salts with acids—such as for example acid addition salts with hydrohalic acids, for example hydrochloric or hydrobromic acid, or organic acids, such as for example oxalic, fumaric, diglycolic or methanesulphonic acid.

Examples of alkyl groups, including those which are part of other groups, are branched and unbranched alkyl groups with 1 to 12 carbon atoms, preferably 1-6, particularly preferably 1-4 carbon atoms, such as for example: methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and dodecyl. Unless otherwise stated, the above-mentioned designations propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and dodecyl include all the possible isomeric forms. For example the term propyl includes the two isomeric groups n-propyl and iso-propyl, the term butyl includes n-butyl, isobutyl, sec. butyl and tert.-butyl, the term pentyl includes isopentyl, neopentyl etc.

In the above-mentioned alkyl groups one or more hydrogen atoms may optionally be replaced by other groups. For example these alkyl groups may be substituted by fluorine. It is also possible for all the hydrogen atoms of the alkyl group to be replaced.

Examples of alkyl bridges, unless otherwise stated, are branched and unbranched alkyl groups with 2 to 5 carbon atoms, for example ethylene, propylene, isopropylene, n-butylene, iso-butyl, sec. butyl and tert.-butyl etc. bridges. Particularly preferred are ethylene, propylene and butylene bridges. In the above-mentioned alkyl bridges 1 to 2 C atoms may optionally be replaced by one or more heteroatoms selected from among oxygen, nitrogen or sulpr.

Examples of alkenyl groups (including those which are part of other groups) are branched and unbranched alkylene groups with 2 to 12 carbon atoms, preferably 2-6 carbon atoms, particularly preferably 2-3 carbon atoms, provided that they have at least one double bond. The following are mentioned by way of example: ethenyl, propenyl, butenyl, pentenyl etc. Unless otherwise stated, the above-mentioned designations propenyl, butenyl etc. include all the possible isomeric forms. For example the term butenyl includes 1-butenyl, 2-butenyl, 3-butenyl, 1 -methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl and 1-ethyl-1-ethenyl.

In the above-mentioned alkenyl groups, unless otherwise described, one or more hydrogen atoms may optionally be replaced by other groups. For example these alkyl groups may be substituted by the halogen atom fluorine. It is also possible for all the hydrogen atoms of the alkenyl group to be replaced.

Examples of alkynyl groups (including those which are part of other groups) are branched and unbranched alkynyl groups with 2 to 12 carbon atoms, provided that they have at least one triple bond, for example ethynyl, propargyl, butynyl, pentynyl, hexynyl etc., preferably ethynyl or propynyl.

In the above-mentioned alkynyl groups, unless otherwise described, one or more hydrogen atoms may optionally be replaced by other groups. For example these alkyl groups may be fluorosubstituted. It is also possible for all the hydrogen atoms of the alkynyl group to be replaced.

The term aryl denotes an aromatic ring system with 6 to 14 carbon atoms, preferably 6 or 10 carbon atoms, preferably phenyl, which, unless otherwise described, may for example carry one or more of the following substituents: OH, NO2, CN, OMe, —OCHF2, —OCF3, halogen, preferably fluorine or chlorine, C1-C10-alkyl, preferably C1-C5-alkyl, preferably C1-C3-alkyl, particularly preferably methyl or ethyl, —O—C1-C3-alkyl, preferably —O-methyl or —O-ethyl, —COOH, —COO—C1-C4-alkyl, preferably —O-methyl or —O-ethyl, —CONH2.

Examples of cycloalkyl groups are cycloalkyl groups with 3-12 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, preferably cyclopropyl, cyclopentyl or cyclohexyl, while each of the above-mentioned cycloalkyl groups may optionally also carry one or more substituents, for example: OH, NO2, CN, OMe, —OCHF2, —OCF3 or halogen, preferably fluorine or chlorine, C1-C10-alkyl, preferably C1-C5-alkyl, preferably C1-C3-alkyl, particularly preferably methyl or ethyl, —O—C1-C3-alkyl, preferably —O-methyl or —O-ethyl, —COOH, —COO—C1-C4-alkyl, preferably —COO-methyl or —COO-ethyl or —CONH2. Particularly preferred substituents of the cycloalkyl groups are ═O, OH, methyl or F.

Examples of cycloalkenyl groups are cycloalkyl groups with 3-12 carbon atoms, which have at least one double bond, for example cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl, preferably cyclopropenyl, cyclopentenyl or cyclohexenyl, while each of the above-mentioned cycloalkenyl groups may optionally also carry one or more substituents.

“═O” denotes an oxygen atom linked by a double bond.

Examples of heterocycloalkyl groups are, unless otherwise described in the definitions, 3- to 12-membered, preferably 5-, 6- or 7-membered, saturated or unsaturated heterocycles, which may contain nitrogen, oxygen or sulphur as heteroatoms, for example tetrahydrofuran, tetrahydrofuranone, γ-butyrolactone, α-pyran, γ-pyran, dioxolane, tetrahydropyran, dioxane, dihydrothiophene, thiolane, dithiolane, pyrroline, pyrrolidine, pyrazoline, pyrazolidine, imidazoline, imidazolidine, tetrazole, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, tetrazine, morpholine, thiomorpholine, diazepan, oxazine, tetrahydro-oxazinyl, isothiazole and pyrazolidine, preferably morpholine, pyrrolidine, piperidine or piperazine, while the heterocycle may optionally carry substituents, for example C1-C4-alkyl, preferably methyl, ethyl or propyl.

Examples of polycycloalkyl groups are optionally substituted, bi-, tri-, tetra- or pentacyclic cycloalkyl groups, for example pinane, 2,2,2-octane, 2,2,1-heptane or adamantane. Examples of polycycloalkenyl groups are optionally bridged and/or substituted, 8- membered bi-, tri-, tetra- or pentacyclic cycloalkenyl groups, preferably bicycloalkenyl or tricycloalkenyl groups, if they contain at least one double bond, for example norbornene.

Examples of spiroalkyl groups are optionally substituted spirocyclic C5-C12 alkyl groups.

Halogen generally denotes fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, particularly preferably chlorine.

The substituent R1 may represent a group selected from the group consisting of chlorine, fluorine, bromine, methanesulphonyl, ethanesulphonyl, trifluoromethanesulphonyl and para-toluenesulphonyl, preferably chlorine.

The substituent R2 may represent hydrogen or C1-C3-alkyl, preferably hydrogen.

The substituent R3 may represent hydrogen,

    • or a group selected from the group consisting of optionally substituted C1-C12-alkyl, C2-C12-alkenyl, C2-C12-alkynyl, and C6-C14-aryl, preferably phenyl,
    • or a group selected from the group consisting of optionally substituted and/or bridged C3-C12-Cycloalkyl, preferably cyclopentyl, C3-C12-cycloalkenyl, C7-C12-polycycloalkyl, C7-C12-polycycloalkenyl, C5-C12-spirocycloalkyl and saturated or unsaturated C3-C12-heterocycloalkyl, which contains 1 to 2 heteroatoms.

The substituents R4, R5 may be identical or different and may represent hydrogen,

    • or optionally substituted C1-C6-alkyl,
    • or R4 and R5 together represent a 2- to 5-membered alkyl bridge which may contain 1 to 2 heteroatoms,
    • or R4 and R3 or R5 and R3 together represent a saturated or unsaturated C3-C4-alkyl bridge, which may optionally contain 1 heteroatom.

A1 and A2 which may be identical or different represent —CH═ or —N═, preferably —N═.

R6 may represent a C1-C4-alkyl, preferably methyl or ethyl.

The compound of formula (II) may be prepared according to methods known from the literature, for example analogously to the syntheses described in WO 03/020722.

The compounds of general formula (I) may be prepared inter alia analogously to the following examples of synthesis. These Examples are, however, intended only as examples of procedures to illustrate the invention, without restricting it to their content. The general synthesis is shown in Scheme (1).

Synthesis of (7R)-2-chloro-8-cyclopentyl-7-ethyl-5-hydroxy-7,8-dihydro-5H-pteridin-6-one

30 g (84.2 mmol) of 1 are dissolved in 300 ml tetrahydrofuran and 3 g Pt/C (5%) are added. The reaction mixture is hydrogenated for 5 h at 35° C. and a hydrogen pressure of 4 bar. The catalyst is filtered off and washed with approx. 30 ml of tetrahydrofuran. The filtrate is concentrated by evaporation under reduced pressure. 25.6 g of product 2 are obtained as a yellow solid.

1H-NMR (400 MHZ) (DMSOd6): δ 11.05 (bs 1H); 7.85 (s 1H); 4.47-4.45 (dd 1H); 4.16-4.08 (t 1H); 1.95-1.67 (m 10H); 0.80-0.73 (t 3H)

Synthesis of (7R)-2-chloro-8-cyclopentyl-7-ethyl-7,8-dihydro-5H-pteridin-6-one

5.22 g (17.6 mmol) of 2 are dissolved in 55 ml of tetrahydrofuran. 520 mg Pt-C (5%) and 250 mg vanadium(IV)oxyacetylacetonate are added. The reaction mixture is hydrogenated for 6 hours at 20° C. and a hydrogen pressure of 4 bar. The catalyst is filtered off and washed with approx. 15 ml of tetrahydrofuran. The filtrate is concentrated by evaporation under reduced pressure.

5.0 g of product 3 are obtained as a yellow powder.

1H-NMR (400 MHz) (DMSOd6): δ 11.82 (bs 1H); 7.57 (s 1H); 4.24-4.21 (dd 1H); 4.17-4.08 (m 1H); 1.97-1.48 (m 10H); 0.80-0.77 (t 3H).

Synthesis of: (7R)-2-chloro-8-cyclopentyl-7-ethyl-7,8-dihydro-5H-pteridin-6-one

70 g Pt/C (5%)are added to a solution of 700 g (1.96 mol) of 1 in 700 ml of tetrahydrofuran. The reaction mixture is hydrogenated for 2.5 hours at 35° C. and a hydrogen pressure of 4 bar until the hydrogen uptake has stopped. The autoclave is opened and 35 g vanadium(IV)oxyacetylacetonate are added. The mixture is hydrogenated for a further 2.5 hours at 35° C. and a hydrogen pressure of 4 bar. It is filtered and the residue is washed with tetrahydrofuran. The filtrate is concentrated by evaporation under reduced pressure. The residue is dissolved in 2.75 L acetone and precipitated by the addition of an equal amount of demineralised water. The solid is suction filtered and washed with an acetone/water mixture (1:1), then with tert.-butylmethylether. After drying 551 g of product 3 are obtained.

Synthesis of: (7R)-2-chloro-8-cyclopentyl-7-ethyl-7,8-dihydro-5H-pteridin-6-one

30 g (84 mmol) of 1 are dissolved in 300 ml of tetrahydrofuran. 3 g Pt/C (5%) and 1.5 g vanadium(IV)oxyacetylacetonate are added. The reaction mixture is hydrogenated for 24 hours at 35° C. and a hydrogen pressure of 4 bar until the reaction is complete. It is filtered, the residue is washed with tetrahydrofuran and the filtrate is concentrated by evaporation under reduced pressure. The residue is dissolved in 118 ml acetone and precipitated by the addition of an equal amount of demineralised water. The solid is suction filtered and washed with an acetone/water mixture (1:1) and then with tert.-butylmethylether. After drying 18 g of product 3 are obtained.

Synthesis of: (7R)-2-chloro-7-ethyl-8-isopropyl-7,8-dihydro-5H-pteridin-6-one

10 g (316 mmol) of 4 are dissolved in 800 ml of tetrahydrofuran and 200 ml isopropanol. 10 g Pt/C (5%) and 5 g vanadium(IV)oxyacetylacetonate are added. The reaction mixture is hydrogenated for 24 hours at 35° C. and a hydrogen pressure of 4 bar until the reaction is complete. It is filtered and the filtrate is evaporated down until crystallisation sets in. 150 ml isopropanol are added and the suspension is heated to 70-80° C. until fully dissolved. After the addition of 600 ml demineralised water the product is brought to crystallisation. It is suction filtered and washed with demineralised water. After drying 68 g of product 5 are obtained.

1H NMR (400 MHz) (DMSOd6): δ 10.81 (bs 1H); 7.56 (s 1H); 4.37-4.24 (m 2H); 1.89-1.65 (m 2H); 1.34-1.31 (m 6H); 0.80-0.73 (t 3H)

Claims

1. A Process for preparing compounds of the formula I wherein R4 and R5 together denote a 2- to 5-membered alkyl bridge, which may contain 1 to 2 heteroatoms, or “A1 and A2 denote —N═”, comprising a) hydrogenating with hydrogen in the presence of a hydrogenation catalyst and a compound of formula II wherein b) adding a copper, iron or vanadium compound,

R1 denotes a group selected from the group consisting of chlorine, fluorine, bromine, methanesulphonyl, ethanesulphonyl, trifluoromethanesulphonyl, para-toluenesulphonyl, CH3S(═O)— and phenylS(═O)—,
R2 denotes hydrogen or C1-C3-alkyl,
R3 denotes hydrogen or a group selected from the group consisting of optionally substituted C1-C12-alkyl, C2-C12-alkenyl, C2-C12-alkynyl and C6-C14-aryl, or a group selected from the group consisting of optionally substituted and/or bridged C3-C12-cycloalkyl, C3-C12-cycloalkenyl, C7-C12-polycycloalkyl, C7-C12-polycycloalkenyl, C5-C12-spirocycloalkyl and saturated or unsaturated C3-C12-heterocycloalkyl, which contains 1 to 2 heteroatoms,
R4, R5 which may be identical or different denote hydrogen or optionally substituted C1-C6-alkyl, or
R4 and R3 or R5 and R3 together denote a saturated or unsaturated C3-C4-alkyl bridge, which may optionally contain 1 heteroatom, and
R1 to R5, A1 and A2 have the meanings given above and
R6 denotes C1-C4-alkyl, and
wherein in which steps a) and b) may take place simultaneously or successively wherein step b) followed by follows step a).

2. The Process according to claim 1, wherein in step b) a copper compound is added.

3. The Process according to claim 1, wherein in step b) an iron compound is added.

4. The Process according to claim 1, wherein in step b) a vanadium compound is added.

5. The Process according to claim 1 wherein steps a) and b) are carried out successively wherein step b) follows step a).

6. The Process according to claim 5, wherein that after the first step a) the intermediate product of formula III is first obtained, which may optionally be isolated, and after the subsequent step b) a compound of formula I is obtained.

7. The Process according to claim 1, wherein steps a) and b) are carried out simultaneously.

8. The Process according to claim 1, wherein the hydrogenation catalyst is selected from the group consisting of rhodium, ruthenium, iridium, platinum, palladium and nickel.

9. The Process according to claim 1, wherein the amount of hydrogenation catalyst added is between 0.1 and 10 wt.-%, based on the compound of formula (II) used.

10. The Process according to claim 1, wherein the amount of copper, iron or vanadium compound added is between 0.01 and 10 wt-%, based on the compound of formula (II) used.

11. The Process according to claim 1, wherein the reaction is carried out in a solvent or mixture of solvents selected from the group consisting of dipolar, aprotic solvents, alcohols, ethers, esters, carboxylic acids, apolar solvents, acetonitrile, methylene chloride and water.

12. The Process according to claim 1, wherein the reaction temperature is between 0° C. and 150° C.

13. The Process according to claim 1, wherein the hydrogen pressure is from 1 bar to 100 bar.

14. A Process for preparing compounds of the formula I wherein hydrogenating a compound of formula III with hydrogen in the presence of a hydrogenation catalyst and a copper, iron or vanadium compound wherein

R1 denotes a group selected from the group consisting of chlorine, fluorine, bromine, methanesulphonyl, ethanesulphonyl, trifluoromethanesulphonyl, para-toluenesulphonyl, CH3S(═O)— and phenylS(═O)—,
R2 denotes hydrogen or C1-C3-alkyl,
R3 denotes hydrogen or a group selected from the group consisting of optionally substituted C1-C12-alkyl, C2-C12-alkenyl, C2-C12-alkynyl C1-C12-alkyl, C2-C12-alkenyl, C2-C12-alkynyl and C6-C14-aryl, or a group selected from the group consisting of optionally substituted and/or bridged C3-C12-cycloalkyl, C3-C12-cycloalkenyl, C7-C12-polycycloalkyl, C7-C12-polycycloalkenyl, C5-C12-spirocycloalkyl and saturated or unsaturated C3-C12-heterocycloalkyl, which contains 1 to 2 heteroatoms,
R4, R5 which may be identical or different denote hydrogen or optionally substituted C1-C6-alkyl, or
R4, R5 together denote a 2- to 5-membered alkyl bridge, which may contain 1 to 2 heteroatoms, or
R4 and R3 or R5 and R3 together denote a saturated or unsaturated C3-C4-alkyl bridge, which may optionally contain 1 heteroatom, and
A1 and A2 denote —N═, comprising
R1 to R5 and A1, A2 have the meanings given above in this claim.

15. The Process according to claim 11, wherein the solvent or mixture of solvents is:

alcohols selected from ethanol, 1-propanol and 2-propanol,
ethers selected from diethyl ether, methyl-tert.-butylether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane and dimethoxyethane,
esters selected from ethyl acetate, 2-propylacetate or 1-butylacetate,
acetic acid, acetonitrile, methylene chloride or water.

16. The Process according to claim 15, wherein the solvent is 2-propanol or tetrahydrofuran or mixtures thereof.

Referenced Cited
U.S. Patent Documents
4957922 September 18, 1990 Lammens et al.
5043270 August 27, 1991 Abrams et al.
5167949 December 1, 1992 Ferrand et al.
5198547 March 30, 1993 Bailey et al.
5424311 June 13, 1995 Billhardt-Troughton et al.
5698556 December 16, 1997 Chan
6096924 August 1, 2000 Studer et al.
6156766 December 5, 2000 Arita et al.
6174895 January 16, 2001 Kleinman
6605255 August 12, 2003 Kroll et al.
6806272 October 19, 2004 Bauer et al.
6861422 March 1, 2005 Hoffmann et al.
6875868 April 5, 2005 Bonnert et al.
7238807 July 3, 2007 Duran et al.
7241889 July 10, 2007 Hoffmann et al.
7332491 February 19, 2008 Grauert et al.
7371753 May 13, 2008 Stadtmueller et al.
7414053 August 19, 2008 Grauert et al.
7439358 October 21, 2008 Linz et al.
7547780 June 16, 2009 Grauert et al.
7625899 December 1, 2009 Hoffmann et al.
7626019 December 1, 2009 Duran et al.
7629460 December 8, 2009 Grauert et al.
7700769 April 20, 2010 Grauert et al.
7723517 May 25, 2010 Grauert et al.
7728134 June 1, 2010 Linz et al.
7750152 July 6, 2010 Hoffman et al.
7759347 July 20, 2010 Hoffmann
7759485 July 20, 2010 Linz et al.
7807831 October 5, 2010 Grauert et al.
7816530 October 19, 2010 Grauert
20020183292 December 5, 2002 Pairet et al.
20020183293 December 5, 2002 Banerjee et al.
20030130286 July 10, 2003 Denny et al.
20040029885 February 12, 2004 Bauer et al.
20040147524 July 29, 2004 Bauer et al.
20040176380 September 9, 2004 Hoffmann et al.
20050014760 January 20, 2005 Hoffmann et al.
20050014761 January 20, 2005 Hoffmann et al.
20050148501 July 7, 2005 Palmer et al.
20050159414 July 21, 2005 Nickolaus et al.
20050165010 July 28, 2005 Nickolaus et al.
20060004014 January 5, 2006 Hoffmann et al.
20060009457 January 12, 2006 Hoffmann et al.
20060025411 February 2, 2006 Hoffmann et al.
20060035902 February 16, 2006 Linz et al.
20060035903 February 16, 2006 Mohr et al.
20060046989 March 2, 2006 Grauert et al.
20060047118 March 2, 2006 Stadtmueller et al.
20060052383 March 9, 2006 Grauert et al.
20060058311 March 16, 2006 Munzert et al.
20060074088 April 6, 2006 Munzert et al.
20060079503 April 13, 2006 Schwede et al.
20070043055 February 22, 2007 Maier et al.
20070208027 September 6, 2007 Duran et al.
20070213528 September 13, 2007 Duran et al.
20070213529 September 13, 2007 Duran et al.
20070213530 September 13, 2007 Duran et al.
20070213531 September 13, 2007 Duran et al.
20070213534 September 13, 2007 Duran et al.
20070219369 September 20, 2007 Duran et al.
20080108812 May 8, 2008 Grauert et al.
20080113992 May 15, 2008 Grauert et al.
20080171747 July 17, 2008 Hoffman et al.
20080177066 July 24, 2008 Linz et al.
20080194818 August 14, 2008 Grauert et al.
20080221099 September 11, 2008 Munzert et al.
20080293944 November 27, 2008 Hoffmann et al.
20080319190 December 25, 2008 Grauert et al.
20080319192 December 25, 2008 Grauert et al.
20080319193 December 25, 2008 Grauert et al.
20090018333 January 15, 2009 Grauert et al.
20090023733 January 22, 2009 Cage et al.
20090029990 January 29, 2009 Maier et al.
20090030004 January 29, 2009 Linz et al.
20090124628 May 14, 2009 Hoffmann et al.
20090143379 June 4, 2009 Mohr et al.
20090238828 September 24, 2009 Munzert et al.
20090280115 November 12, 2009 Maier et al.
20090298840 December 3, 2009 Linz et al.
20100029642 February 4, 2010 Hoffmann et al.
20100249412 September 30, 2010 Linz et al.
20100249458 September 30, 2010 Linz et al.
20100280037 November 4, 2010 Linz et al.
20100324288 December 23, 2010 Hoffmann et al.
Foreign Patent Documents
2458699 March 2003 CA
2517020 September 2004 CA
2517010 November 2004 CA
2576290 February 2006 CA
143478 June 1985 EP
347146 December 1989 EP
399856 November 1990 EP
429149 May 1991 EP
2287583 December 2007 ES
2002125451 January 2004 RU
9609045 March 1996 WO
9634867 November 1996 WO
9636597 November 1996 WO
WO 96/36597 November 1996 WO
9811893 March 1998 WO
0119825 March 2001 WO
0170741 September 2001 WO
0178732 October 2001 WO
02057261 July 2002 WO
02076954 October 2002 WO
02076985 October 2002 WO
03020722 March 2003 WO
WO 03/020722 March 2003 WO
03093249 November 2003 WO
04014899 February 2004 WO
04076454 September 2004 WO
04093848 November 2004 WO
05067935 July 2005 WO
06018182 February 2006 WO
06018185 February 2006 WO
06018220 February 2006 WO
06018221 February 2006 WO
06021378 March 2006 WO
07014838 February 2007 WO
07090844 August 2007 WO
09019205 February 2009 WO
Other references
  • Snyder, J. S. et al., “Common bacteria whose susceptibility to antimicrobials is no longer predictable”. NCBI, PubMed, 2000, Le Journal Medical Libanais (The Lebanse Medical Journal), 48, pp. 208-214.
  • Souillac, P. et al., “Characterization of delivery systems, differential scanning calorimetry”. (In Encyclopedia of Controlled Drug Delivery), 1999, John Wiley & Sons, pp. 212-227.
  • Sugar, A. M. et al., “Comparison of three methods of antifungal susceptibility testing with the proposed NCCLS standard broth macrodilution assay: lack of effect of phenol red”. Mycology, Diagn Microbiol. Infect. Dis. 1995, 21—pp. 129-133.
  • Takai, N. et al., “Polo-like kinases (PLKs) and cancer”. Oncogene , 2005, 24, pp. 287-291.
  • Tenbrink, R. E. et al., “Antagonist, partial agonist, and full agonist imidazo[1,5-a]quinoxaline amides and carbamates acting through the BABA/Benzodiazepine receptor”. J. Med. Chem. 1994, 37, pp. 758-768.
  • Turner, S., “The Design of Organic Syntheses”. Elsevier, 1976, pp. 10 and 149.
  • Turner, W.W.et al., “Recent advances in the medicinal chemistry of antifungal agents”. Current Pharmacutical Design, 1996, 2, pp. 209-224.
  • Verschuren, E.W. et al., “The cell cycle and how it is steered by Kaposi's sarcoma-associated herpesvirus cyclin”. Journal of General Virology, 2004, 85, pp. 1347-1361.
  • Vippagunta, S. R. et al., “Crystalline solids”. Advanced Drug Delivery Reviews, 48, 2001, pp. 3-26.
  • Visiting Nurse Association of America. www.vnaa.org/gen/Germ—Protection—Center—Cold—and—Flu—Resources,html, 2009.
  • Voskoglou-Nomikos, T. et al., “Clinical predictive value of the in vitro cell line, human xenograft, and mouse allograft preclinical cancer models”. Clinical Cancer Research vol. 9, 2003, pp. 4227-4239.
  • Wagner, B. et al, “7-Benzylamino-6-chloro-2-piperazino-4-pyrrolidino-pteridine, a potent inhibitor of cAMP-specific phosphodiesterase, enhancing nuclear protein binding to the CRE consensus sequence in human tumour cells”, Biochemical Pharmacology, Pergamon, Oxford, GB, 2002, pp. 659-668.
  • Wagner, G. et al., “Synthesis of new phrido[3′,2′:4,5] thieno ′3,2-d] 1,2,3-triazine derivatives as antianaphylactics”. Biosciences Dept of the University of Leipzig, Pharmazie (Pharmacy), 48, vol. 7,1993, pp. 514-518.
  • Webster's Comprehensive Dictionary, 1996, pp. 1013-1014.
  • Wikipedia. “Melting Point”, Jan 17, 2007. http://en.wikipedia.org/wiki/Melting—point.
  • Wolf, D. E.et al., “The structure of rhizopterin”. Contribution from the Research Labs of Merck and Co. Inc. Nov. 1947, Journal of American Chem. Soc., vol. 69, pp. 2753-2759. XP002352205.
  • ACPS Meeting, Background Information. “Scientific considerations of plymorphism in pharmaceutical solids: abbreviated new drug applications”. Oct. 2002.
  • Ahlenius, T. List of cardiovascular disorder/diseases. Ahlenius, Karolinska Institutet. Stockholm, Sweden. Cardiovascular Diseases, p. 1-34, Apr. 2007.
  • Ahmad, N. “Polo-like kinase (Plk) 1: a novel target for the treatment of prostate cancer”. The FASEB Journal. 2004, 18:5-7. Dept of Dermatology, Univ. Wisconsin, pp. 5-7.
  • Arnold, K. “Collaboration to play key role in NCI's future, director says”. Journal of the National Cancer Institute, Jun. 5, 2002, pp. 790-792, vol. 94, No. 11.
  • BBC News/Health, Killer Breast Cancern Therapy Hope, www.newsvote.bbc/co./uk, Published Jan. 21, 2006.
  • Bennett, J.C., et al., “Textbook of Medicine”, Part XIV, Oncology, 1997.
  • Blain, S. W. et al., “Differential interaction of the cyclin-dependent kinase (Cdk) Inhibitor p27KIP with cyclin A-Cdk2 and cyclin D2-Cdk4”. The Journal of Biological Chemistry, vol. 272, No. 41, Issue Oct. 10, 1997, pp. 25862-25872.
  • Chen, J.X. et al., “Parallel differentiated recognition of ketones and acetals”. Angewandte Chemie Int. Ed, vol. 37, Issue 1/2, p. 91-93, 1998.
  • Dipolar aprotic solvent. Exhibit A, IUPAC Compendium of Chemical Terminology, 2nd Edition, 1997.
  • Doerwald, F.Z. Book Wiley-VCH Verlag GmbH & Co. KGaA, “Side reactions in organice synthesis: A Guide to Successful Synthesis Design”. 2005.
  • Dyson, G, et al. “The Chemistry of Synthetic Drugs”. Mir 1964, p. 12-19.
  • Eurasian Opinion, Appln No. 2007/00389/28, Maly Slatoustinsky per., d.10, kv.15, 101000 Moscow, Russia, “EVROMARKPAT”, 2007.
  • Ferrand, G., et al., “Synthesis and potential antiallergic activity of new pteridinones and related compounds”. Eur. J. Med. Chem, 31, 1996, pp. 273-280. XP--2246920.
  • Ghandi, L., et al., “An Open-Label Phase II Trial of the PLK Inhibitor BI 2536 in Patients with Sensitive Relapse Small Cell Lung Cancer”. ASCO Meeting 2009.
  • Giron, G. “Thernal analysis and calorimetric methods in the characterization of plymorphs and solvates”. Thermochimica Acta 248, 1995, pp. 1-59.
  • Goodman-Gilman's “The Pharmacological Basis of Therapeutics”. Ninth edition, 1996, pp. 1225-1271.
  • International Search Report for PCT/EP2005/056291 mailed Mar. 21, 2006.
  • Ito, Y., et al., “Polo-like kinase 1 (PLK) expression is associated with cell proliferative activity and cdc2 expression in malignant-lymphoma of the thyroid”. Anticancer Research, 2004, vol. 24, No. 1, pp. 259-263.
  • Jamieson, C. et al., “Application of ReactArray Robotics and Design of Experiments Techniques in Optimisation of Supported Reagent Chemistry”. Org. Proc. Res. & Dev., 2002, 6, p. 823-825.
  • Jaworska, J., et al., “Review of methods for assessing the applicability domains of SARS and QSARS”. Sponsor: The European Commission—Joint Research Ctr., Institute for Health and Consumer Protection—ECVAM, Italy, 2004.
  • Kashima, M. K. et al., “Expression of polo-like kinase (PLK1) in non-Hodgkin's lymphomas”. NCBI, PubMed, 2005.
  • Kimball, S. D. et al., “Cell cycle kinases and checkpoint regulation in cancer”. Annual Reports in Medicinal Chemistry, 36, Chapter 14, 2001, pp. 139-148.
  • Leukemia & Lymphoma Society—Disease Information—Lymphoma. www.leukemia-lymphoma.org/all—page?item—id-7030, 2008.
  • Leukemia & Lymphoma Society—Disease Information. www.leukemia-lymphoma.org/all—page?item—id-7026, 2008.
  • Marko, D. et al., “Intracellular localization of 7-benzylamino-6-chloro-2-piperazino-4-pyrrolidino-pteridine in membrane structures impeding the inhibition of cytosolic cyclic AMP-specific phosphodiesterase”. Biochemical Pharmacology, 63, 2002, pp. 669-676.
  • Mashkovkii, M.D., “Medicaments”. Moscow, Novaja Volna, 2001, vol. 1, p. 11.
  • Mashkovskii, M.D. “Drugs”, Handbook for Doctors, 1993, Part I, Ch.1, p. 8.
  • Masuda, Y. et al., “B-Hydroxyisovalerylshikonin induces apoptosis in human leukemia cells by inhibiting the activity of a polo-like kinase 1 (PLK)”. 2003, Oncogene, 22, pp. 1012-1023.
  • Mayer, SF, et al., “Enzyme-initiated domino (cascase) reactions”. Chem. Soc. Rev, 2001, p. 332-339.
  • MedlinePlus: Bacterial Infections. www.nim.nih.gov/medlineplus/print/bacterialinfections.htm, date last updated Mar. 25, 2009.
  • MedlinePlus: Viral Infections. www.nim.nih.gov/medlineplus/print/viralinfections.htm, date last updated Feb. 11, 2009.
  • Merck Manual of Medical Information—Home Edition, Section 17. “Parasitic Infections”. Chapter 184, 2003.
  • Mikhailov, I.B., Principles of Rational Pharmacotherapy. Handbook for clinical pharmacology for students of pediatric and medical faculties of medical high schools, St. Petersburg, Russia, “Foliant”, 1999, p. 25.
  • Mito, K., et al., “Expression of polo-like kinase (PLK1) in non-Hodgkin's lymphomas”. NCBI, PubMed, 2005, Leuk. Lymphoma, 46(2), pp. 251-231.
  • Nagao, K. et al., “Effect of MX-68 on airway inflammation and hyperresponsiveness in mice and guinea-pigs”. Journal of Pharmacy and Pharmacology, JPP 2004, 56, pp. 187-196.
  • National Institute of Neurological Disorders, Index Stroke, 2006.
  • Norman, P. “PDE4 inhibitors”. Ashley Publications Ltd., Expert Opinions Ther. Patents, 1999, pp. 1101-1118.
  • Office Action mailed Dec. 10, 2003 for U.S. Appl. No. 10/226,710, filed Aug. 23, 2002. Inventor: Eckhart Bauer.
  • Office Action mailed Apr. 28, 2004 for U.S. Appl. No. 10/374,876, filed Feb. 26, 2003. Inventor: Matthias Hoffmann.
  • Ohio Dept of Health, “Brain and Other Central Nervous System Cancer in Ohio, 1997-2001”. Sep. 2004, pp. 1-4.
  • Organic Chemistry, Grupo Editorial Iberoamerica, Section 13, 3, pp. 301-302, 1983 (best copy available in Spanish).
  • Rocha Lima, C.M. et al. “Randomized phase II trial of gemcitabine plus irinotecan or docetaxel uin stage IIIB or stage IV NSCLC” Annals of Oncology, 15(3), p. 410-418, 2004.
  • Rylander, P.N. “Hydrgenation Methods”. 1985, Chapter 13.
  • Rylander, P.N. “Hydrgenation Methods”. 1985, Chapters 3, 4.
  • Rylander, P.N. “Hydrgenation Methods”. 1985, Chapters 8, 9, 10, 11.
  • Rylander, P.N. “Hydrgenation Methods”. 1985, Chapter 5, 6, 7.
  • Rylander, P.N., “Hydrogenation Methods”. 1985, Chapters 1, 2.
  • Santing, R. E. et al., “Brochodilatory and anti-inflammatory properties of inhaled selective phosphodiesterase inhibitors in a guinea pig model of allergic asthma”. European Journal of Pharmacology, 429, 2001, pp. 335-344.
  • Savelli, F. et al., “Heterotricyclic system Part II—synthesis of new pyrido[1′2′:4,5]pyrazino[3,2-d] pyrimidines”. Bollettino Chimico Farmaceutico, 131(8), Sep. 1992, pp. 309-312.
  • Science, vol. 310, Oct. 21, 2005, p. 409, Chemistry: One After Another.
  • Kummer B, et al., “Combination of Radiation and Polo-like Kinase 1 Inhibition with BI6727 in tumour model A431”. Vortrag. 20. Symposium •Experimentelle Strahlentherapie und klinische Strahlenbiologie, Exp. Strahlenther. Klin. Strahlenbiol. 20: 93-96 (2011) (Lecture 20, Symposium Experimental Radiation Therapy and Clinical Radiation Biology.).
  • Kummer, B. et al., Presentation: “Combination of irradiation and polo-like kinase 1 inhibition with BI 6727 in tumour model A 431”. OncoRay—National Centre for Radiation Research in Oncology, Dresden 2011, Experimental Radiotherapy and Clinical Radiobiology.
  • Tenbrink, R. E. et al., “Antagonist, Partial Agonist, and Full Agonist Imi8daxo[1,5-a]quinoxaline Amides and Carbamates Acting through the GABA a/Benzodiazepine Receptor”, J. Med. Chem, 1994, 37, 758-768.
Patent History
Patent number: RE43115
Type: Grant
Filed: Aug 5, 2010
Date of Patent: Jan 17, 2012
Assignee: Boehringer Ingelheim International GmbH (Ingelheim am Rhein)
Inventors: Adil Duran (Biberach an der Riss), Guenter Linz (Mittelbiberach)
Primary Examiner: Susanna Moore
Attorney: Michael P. Morris
Application Number: 12/850,993
Classifications
Current U.S. Class: Pteridines (including Hydrogenated) (544/257); Spiro Diazine (544/231)
International Classification: C07D 475/00 (20060101); C07D 239/30 (20060101);