DE102011116373A1 - Preparing substituted amino-phenylamino-phenyl-pyrazolo(3,4-d)pyrimidine derivatives useful e.g. for treating picornavirus infection, comprises reacting substituted amino-phenylamino-pyrazole-carbonitrile compounds and benzamidine compounds - Google Patents

Abstract

Preparing substituted 4-amino-3-phenylamino-6-phenyl-pyrazolo[3,4-d]pyrimidine derivatives (I), comprises reacting substituted 5-amino-3-phenylamino-1H-pyrazole-4-carbonitrile compounds (II) with substituted benzamidine compounds (III) in a polar organic solvent. Preparing substituted 4-amino-3-phenylamino-6-phenyl-pyrazolo[3,4-d]pyrimidine derivatives of formula (I), comprises reacting substituted 5-amino-3-phenylamino-1H-pyrazole-4-carbonitrile compounds of formula (II) with substituted benzamidine compounds of formula (III) in a polar organic solvent. R 1, R 2aliphatic group with 1-6 atoms or alkanol with 1-6 atoms (both optionally saturated and optionally branched), NO 2, CN, CON(R 3) 2, COOR 3, CHO, CONH 2, halo, OR 3, SR 3, N(R 3) 2, SO 2N(R 3) 2or di- or trifluoromethyl, where R 1and R 2are optionally present; and R 3H, CH 3, ethyl, propyl or butyl. An independent claim is also included for purifying (I), comprising recrystallizing (I) using tetrahydrofuran or a mixture of tetrahydrofuran and water or other organic solvent, preferably toluene. [Image] [Image] ACTIVITY : Virucide. No biological data given. MECHANISM OF ACTION : None given.

Description

Technical area

The present invention relates to a novel process for the preparation of 4-amino-3-arylamino-6-arylpyrazolo [3,4d] pyrimidine derivatives

Background of the invention

Arylpyrazolo [3,4d] pyrimidine derivatives, especially 4-amino-3-phenylamino-6-phenylpyrazolo [3,4-d] pyrimidines, can be used as medicaments for the treatment of diseases, e.g. B. for the treatment of virus-related diseases in mammals (humans and animals), which are caused in particular by enteroviruses including rhinoviruses such. B. Mengitis, Enzepahilitis, myocarditis, common cold, asthma and COPD relapses ( WO 2007/147401 and literature cited therein). Arylpyrazolo [3,4d] pyrimidine derivatives have also been described as CRF antagonists ( EP 574642 ).

A method for the synthesis of 4-amino-3-arylamino-6-arylpyrazolo [3,4d] pyrimidine derivatives has already been described. This process involves the reaction of fusing 5-amino-4-cyano-3- (phenylamino) -pyrazoles with optionally substituted benzamidines as the hydrochloride hydrate and sodium acetate (see DE10 2006 029 074 . US20100010018 . EP2049540 ). However, this synthesis process leads to the formation of a highly contaminated target product with several by-products. The purification processes also described for obtaining the target compounds are very complicated and characterized by a very low yield. The purified final compounds also always contain traces of DMF, which is unacceptable for pharmaceutical use. In addition, this complicates the synthesis of large amounts of substance, as they are essential for drug development.

In this context, there is an urgent need to obtain a scalable, simple method of synthesis and purification which allows to obtain high purity 4-amino-3-arylamino-6-arylpyrazolo [3,4d] pyrimidine derivatives in any amount.

It has surprisingly been found that the substituted 3-arylamino-6-arylpyrazolo [3,4-d] pyrimidines described in the present invention can be synthesized in good yield and without readily separable by-products, if the benzamidine component is used as the free base and the reaction in polar solvents is carried out.

wobei:

• – die Reste R¹ und R² voneinander unabhängig NO₂, CN, CONR³ ₂, COOR³, CHO, CONH_2, ein Halogen, ein gesättigtes oder ungesättigtes, lineares oder verzweigtes aliphatisches Radikal (auch Alkylgruppe genannt) mit 1–6 Kettengliedern, ein gesättigtes oder ungesättigtes, lineares oder verzweigtes alkanoles Radikal (auch Alkoxygruppe genannt) mit 1–6 Kettengliedern, OR³, SR³, NR³ ₂, SO₂NR³ ₂, Di- oder Trifluoromethyl sein können, und
• – der Rest R³ aus H, Methyl, Ethyl, Propyl oder Butyl-Gruppen bestehen kann.

According to the invention, this object is achieved by the reaction of optionally substituted 5-amino-4-cyano-3-phenylamino-pyrazoles (I) with optionally substituted benzamidines as the free base (II) to give 4-amino-3- (phenylamina) -6-phenylpyrazole [3,4-d] pyrimidines (III) dissolved in polar solvents, including the following reaction:

in which:

• - The radicals R ¹ and R ² are independently NO ₂ , CN, CONR ³ ₂ , COOR ³ , CHO, CONH _2, a halogen, a saturated or unsaturated, linear or branched aliphatic radical (also called alkyl group) with 1-6 chain members , a saturated or unsaturated, linear or branched alkanoles radical (also called alkoxy group) with 1-6 chain members, OR ³ , SR ³ , NR ³ ₂ , SO ₂ NR ³ ₂ , di- or trifluoromethyl, and
• - The radical R ^{3 may} consist of H, methyl, ethyl, propyl or butyl groups.

If the compounds according to the invention can occur in tautomeric forms, the present invention encompasses all tautomeric forms.

Compounds according to the invention are the compounds of the formula (III) and the salts, solvates and solvates of the salts prepared therefrom. Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, eg. Salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.

In the context of the present invention, unless specified otherwise, the substituents have the following meanings: Alkyl and the alkyl moieties in alkoxy represent straight-chain or branched alkyl and, unless stated otherwise, include (C 1 -C 6) -alkyl, in particular (C 1 -C 4) -alkyl. C4) alkyl, such as. For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl.

In the context of the invention, alkoxy preferably represents a straight-chain or branched alkoxy radical, in particular having 1 to 6, 1 to 4 or 1 to 3 carbon atoms. Preference is given to a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy, n-pentoxy and n-hexoxy.

Aryl is a mono- to tricyclic aromatic, carbocyclic radical of usually 6 to 14 carbon atoms; by way of example and preferably phenyl, naphthyl and phenanthrenyl, particularly preferably phenyl. Halogen is fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.

The reaction is carried out in inert, polar organic solvents. Examples of inert polar organic solvents are ethers, such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, glycol diethyl ether or diethylene glycol dimethyl ether, cyclic ethers, such as dioxane, tetrahydrofuran, hydrocarbons, such as ethylbenzene, xylene, toluene or alcohols, such as ethanol, propanol, butanol. Isobutanol, isopropanol. Especially pure products are obtained by using n-butanol as a solvent.

The volume of n-butanol is best used in a molar ratio of 1-10, preferably 1.5 to 3, based on the initial value of the pyrazole derivative.

The benzamidines (II) in their basic form (as free bases) should be used freshly prepared. The synthesis is carried out by conventional methods from the corresponding available salt. It is best to use benzamidines (II) in a molar ratio of 1-1.5 starting from the pyrazole derivatives (I).

The reaction is carried out at a temperature of 60-110 ° C, preferably at 85-95 ° C, over the course of 10-30 hours, preferably 18-20 hours.

The purification of the resulting 4-amino-3- (phenylamino) -6-phenylpyrazolo [3,4-d] pyrimidines (III) by recrystallization. For this example, tetrahydrofuran or a mixture of tetrahydrofuran / toluene is used.

4-Amino-3- (phenyl) amino-6-phenylpyrazolo [3,4-d] pyrimidines (III) can be further converted to suitable pharmaceutical compositions, for example by mixing with suitable excipients.

If pharmaceutically required, the 4-amino-3- (phenylamino) -6-phenylpyrazolo [3,4-d] pyrirnidines (III) prepared in this way can be converted into pharmaceutically acceptable salt forms by customary methods in order to influence the solubility and other pharmaceutical parameters ,

The compounds of general formula (III) and their pharmaceutically acceptable salts can be used because of their special properties for the preparation of medicaments which are suitable for the prophylaxis and / or treatment of diseases, in particular viral infections.

This invention will be further described below in the following examples. However, the selection of examples is not intended to limit the invention to the examples listed here.

Examples

Chemicals and solvents were purchased from Alfa-Aesar (UK) or Aldrich Co. (Sigma-Aldrich Company, St Louis, USA). They were used without post-purification.

Other starting materials may, for example, according to the in WO 2007/14701 can be obtained.

Melting points were determined in accordance with the method of the British Pharmacopoeia and were not corrected (Elektrothermal 9001, UK).

If the analysis only instructs the symbols of the elements, the analytical results are within ± 0.3% of the theoretical value (Carlo Erba-5500, Italy).

NMR spectra were determined on a Varian Unity Plus-400 spectrometer (US). Shifts for ¹ H NMR are in ppm relative to the signal TMS (δ).

The mass spectrum was obtained using a Finnigan SSQ-700 mass spectrometer (USA) with direct injection.

The course of the reaction and the purity of the compounds were monitored by TLC (thin layer chromatography) using aluminum plates with Kieselgel 60 F ₂₅₄ (Merck Co, Germany).

example 1

4-Amino-3- (phenylamino) -6-phenylpyrazolo [3,4-d] pyrimidine (Compound 1)

5.22 g of benzamidine hydrochloride, which had been previously dried for 2.5 hours at 115 ° C, is slowly added to a solution of 1.74 g of sodium methylate in 100 ml of methanol and stirred for 30 min at room temperature. After filtering off the inorganic white precipitate, add 3.5 ml of n-butanol and reduce the volume in vacuo to 3 ml. The residue is a whitish D1, and corresponds to 4.0 g of benzamidine, which is used immediately in the next step of the reaction.

5-Amino-4-cyano-3- (phenylamino) -pyrazole (6.0 g, powder) is dissolved in 10 ml of n-butanol and 4.0 g of benzamidine in 3 ml of n-butanol are added at room temperature. The reaction takes place over 20 hours at 85 ° C. Then the solution is cooled, the yellow precipitate filtered and rinsed with 5 ml of n-butanol and 5 ml of toluene.
Yield: 68%
Melting point: 265-267 ° C (tetrahydrofuran)
MS (m / z): 302 (M ⁺ )
¹ H NMR (DMSO-d ₆ ): δ 12.38 (1H, s, NH), 8.30-8.36 (2H, q, 2CH), 8.23 (1H, br, s, NH), 7.67 (2H, d, 2CH ), 7.48 (2H, br, s, NH ₂ ), 7.42 (3H, m, 3CH), 7.12 (2H, d, 2CH) and 6.98 (1H, m, CH) ppm
Elemental Analysis C ₁₇ H ₁₄ N ₆ :
Calculated%: C, 67.54; H, 4.67; N, 27.80
Found%: C, 67.49; H, 4.53; N, 27.74

Example 2

4-Amino-3 - [(4-fluorophenyl) amino] -6-phenylpyrazolo [3,4-d] pyrimidine (Compound 2)

Compound 2 is prepared in the same manner as in Example 1, but as the starting material pyrazole (I), 5-amino-4-cyano-3 - [(4-fluorophenyl) amino] pyrazole is used. This forms a pale yellow crystalline precipitate.
Yield: 70%
Melting point: 262-263 ° C (THF / toluene)
MS (m / z): 320 (M ^+)
1 H NMR (DMSO-d ₆ ): δ 12.69 (1H, s, NH), 8.33-8.41 (4H, m, 4CH), 8.18 (1H, br, s, NH), 7.58-7.65 (5H, m , NH ₂ , 3CH), 7.27-7.31 (2H, m, 2CH) ppm
Elemental Analysis C ₁₇ H ₁₄ FN ₆ :
Calculated%: C, 63.74; H, 4.09; N, 26,24
Found%: C, 63.81; H, 4:11; N, 26,27

Example 3

4-Amino-6-phenyl-3 - [(4-trifluoromethyl) -phenyl] -amino-pyrazolo [3,4-d] pyrimidine (Compound 3)

Compound 3 is prepared in the same manner as in Example 1, but as pyrazole (I), 5-amino-4-cyano-3 - [(4-trifluoromethyl) phenyl] aminopyrazal is used. This forms a pale yellow crystalline precipitate.
Yield: 58%
Melting point: 313-314 ° C (THF / toluene)
MS (m / z): 370 (M ^+)
1 H NMR (DMSO-d ₆ ): δ 12.77 (1H, s, NH), 8.91 (1H, s, NH), 8.47 (2H, s, NH ₂ ), 7.81, 7.79, 7.63, 7.58 and 7.47 (9H , m, C ₆ H ₄ and C ₆ H ₅₎ ppm
Elemental Analysis C ₁₈ H ₁₃ F ₃ N ₆ :
Calculated%: C, 58.38; H, 3.54; N, 22.69
Found%: C, 58.41; H, 3.58; N, 22.74
HPLC: 99.30% (column Luna C18 (2), acetonitrile / water - 90:10, flow rate of 0.6 ml / min, UV 254 nm, t _R = 5.3 min)

Example 4

4-Amino-3 - [(3-fluorophenyl) amino] -6-phenylpyrazolo [3,4-d] pyrimidine (Compound 4)

Compound 4 is obtained in the same manner as in Example 1, but as the pyrazole component (I), 5-amino-4-cyano-3 - [(3-fluorophenyl) amino] pyrazole is used. This forms a salubrious crystalline precipitate.
Yield: 76%
Melting point: 278-279 ° C (THF / toluene)
MS (m / z): 320 (M ^+)
1 H NMR (DMSO-d ₆ ): δ 12.61 (1H, s, NH), 8.34-8.42 (2H, q, 2CH), 8.14 (1H, br, s, NH), 7.48 (2H, br , NH ₂ ), 7.3-7.43 (6H, m, 6CH), 6.60 (1H, s, CH) ppm
Elemental analysis for C ₁₇ H ₁₄ FN ₆ :
Calculated%: C, 63.74; H, 4.09; N, 26,24
Found%: C, 63.81; H, 4:11; N, 26,27

Example 5

4-Amino-6-phenyl-3 - [(4-trifluoromethoxy) phenylamino] -pyrarolo [3,4-d] pyrimidine (Compound 5)

Compound 5 is obtained in the same manner as in Example 1, but as the pyrazole component (I), 5-amino-4-cyano-3 - [(4-trifluoromethoxyphenyl) amino] pyrazole is used. This forms a white crystalline precipitate.
Yield: 68%
Melting point: 260-262 ° C (tetrahydrofuran / DMF)
MS (m / z): 386 (M ^+)
1 H NMR (DMSO-d ₆ ): δ 12.56 (1H, s, NH), 8.82 (2H, q, 2CH), 8.16 (1H, br, s, NH), 7.48 (2H, br, s., NH ₂ ), 7.3-7.43 (4H, m, C ₆ H 5), 7.05-7.11 (2H, 2 s, 2CH), 6.98 (1H, m, CH) ppm
Elemental Analysis C ₁₈ H ₁₃ F ₃ N ₆ O
Calculated%: C, 55.96; H, 3.39; N, 21.75
Found%: C, 56.07; H, 3.36; N, 21.61

Example 6

Purification of 4-amino-6-phenyl-3 - [(4-trifluoromethyl) phenyl] amino-pyrazolo [3,4-d] pyrimidine (Compound 3)

50 g of dry 4-amino-6-phenyl-3 - [(4-trifluoromethyl) phenyl] amino-pyrazolo [3,4-d] pyrimidine, synthesized by the method described in Example 3, are added with heating in 300 ml of THF solved. This solution is treated with 300 ml of cold toluene. The resulting solution is kept at a temperature below 0 ° C for 6 hours in a freezer. 36 g of 4-amino-3- (4-trifluorophenyl) amino-6-phenylpyrazolo [3,4-d] pyrimidine in yellow crystals are obtained by filtration.
Melting point: 313-314 ° C (THF / DMF)
HPLC: 99.16% (column Luna C18 (2), acetonitrile / water - 90:10, flow rate of 0.6 ml / min, UV 254 nm, t _R = 5.3 min)

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

• WO 2007/147401 [0002]
• EP 574642 [0002]
• DE 102006029074 [0003]
• US 20100010018 [0003]
• EP 2049540 [0003]
• WO 2007/14701 [0022]

Claims (10)

A process for the preparation of 4-amino-3-arylamino-6-arylpyrazolo [3,4d] pyrimidine derivatives of the formula (III) comprising the reaction of a pyrazole of the formula (I) with a benzamidine derivative of the formula (II) in a polar organic solvent, according to the following scheme,

where R ¹ and R ² are each independently NO ₂ , CN, CONR ³ ₂ , COOR ₃ , CHO, CONH ₂ , a halogen, a saturated or unsaturated, linear or branched aliphatic radical (also called alkyl group), with 1- 6 chain members, a saturated or unsaturated, linear or branched alkanoles radical (also called alkoxy group), with 1-6 chain members, OR ³ , SR ³ , NR ³ ₂ , SO ₂ NR ³ ₂ , di- or trifluoromethyl, and the radical R ^{3 may} consist of H, methyl, ethyl, propyl or butyl groups. A method according to claim 1, characterized in that the aryl moiety is a substituted or unsubstituted phenyl ring, for the preparation of 4-amino-3-phenylamino-6-phenylpyrazolo [3,4d] pyrimidine derivatives of the formula (III), comprising the reaction of a pyrazole of the formula (I) with a benzamidine derivative of the formula (II) in a polar organic solvent, according to the following scheme,

where R ¹ and R ² are each independently NO _2, CN, CONR ³ ₂ , COOR ₃ , CHO, CONH ₂ , a halogen, a saturated or unsaturated, linear or branched aliphatic radical (also called alkyl group), with 1- 6 chain members, a saturated or unsaturated, linear or branched alkanoles radical (also called alkoxy group), with 1-6 chain members, OR ³ , SR ³ , NR ³ ₂ , SO ₂ NR ³ ₂ , di- or trifluoromethyl, and the radical R ^{3 may} consist of H, methyl, ethyl, propyl or butyl groups. A method according to claim 1 or 2, characterized in that the reaction proceeds in n-butanol. 4-Amino-3-arylamino-6-arylpyrazolo [3,4-d] pyrimidine derivatives according to claim 2 or 3, characterized in that they are selected from the group of 6-phenylaminopyrazolo [3,4-d] pyrimidines, full: 4-amino-3- (3-fluorophenyl) amino-o-phenylpyrazolo [3,4-d] pyrimidine, 4-amino-3- (3-fluorophenyl) amino-o- (4-chlorophenyl) -pyrazolo [3,4-d] pyrimidine, 4-amino-3- (3-chloro) amino-6-phenylpyrazolo [3,4-d] pyrimidine, 4-amino-3- (3-methoxy) amino-6-phenylpyrazolo [3,4-d] pyrimidine, 4-Amino-3- (4-fluorophenyl) amino-6-phenylpyrazolo [3,4-d] pyrimidine, 4-Amino-3- (4-fluorophenyl) amino-6- (4-chlorophenyl) pyrazolo [3,4-d] pyrimidine, 4-Amino-3- (4-chlorophenyl) amino-6-phenylpyrazolo pyrimidine (3,4-d], 4-amino-3- (3-fluorophenyl) amino-1-methyl-6-phenylpyrazolo [3,4-d] pyrimidine, 4-amino-1-benzyl-3- (3-fluorophenyl) amino-6-phenylpyrazolo [3,4-d] pyrimidine. Purification of 4-amino-3- (phenyl) amino-6-phenylpyrazolo [3,4-d] pyrimidines obtained according to one of claims 1 to 4 by recrystallization from tetrahydrofuran or from a mixture of tetrahydrofuran and water or other organic solvent, preferably toluene. Purification of 4-amino-3- (phenyl) amino-6-phenylpyrazolo [3,4d] pyrimidines obtained according to one of claims 1 to 4 by precipitation from a hot solution of tetrahydrofuran with water or an organic solvent, preferably toluene. Use of the prepared according to claims 1-6 4-amino-3- (phenyl) amino-6-phenylpyrazolo [3,4d] pyrimidines for the treatment and / or prophylaxis of diseases. Use of the compounds prepared according to claims 2-6 for the manufacture of a medicament for the treatment and / or prophylaxis of viral infections. Use of 4-amino-3-arylamino-6-arylpyrazolo [3,4-d] pyrimidine derivatives according to claim 8, characterized in that they are used for prophylactic and therapeutic use against viral infections, in particular for the treatment of picornavirus infections. Medicament according to claim 8 or 9 for the treatment and / or prophylaxis of viral infections.