ES2352926B1 - FENUCIL DEUTERADO AND DERIVATIVES, PROCEDURE FOR THEIR PREPARATION AND USES OF THE SAME. - Google Patents

Abstract

Deuterated fenucil and derivatives, process for its preparation and uses thereof # The invention defines deuterated compounds of formula (I) # ** FIGURE ** # in which: #R {sub, 1}, R {sub, 2 } and R {sub, 3} independently represent a hydrogen atom or a C {sub, 1} -C {sub, 4} alkyl group, optionally substituted with # a? OR {sub, 4} group, being R {sub, 4} a hydrogen atom or a C {sub, 1} -C {sub, 3} alkyl group optionally substituted with phenyl; # a group? NR {sub, 5} R {sub, 6}, being R {sub, 5} and R {sub, 6} independently a hydrogen atom, or a C {sub, 1} -C {sub, 3}, tosyl or mesyl alkyl group; #a group? SR {sub , 7}, where R {sub, 7} is a hydrogen atom or a C {sub, 1} -C {sub, 3} alkyl group; # a group? OCOR {sub, 8}, where R {sub, 8 } a C {sub, 1} -C {sub, 3} or phenyl alkyl group, #o a halogen atom; and # D represents deuterium. # The invention also defines a process for preparing said deuterated compounds, a pharmaceutical composition comprising them, and the use thereof in the pharmaceutical and analytical field.

Description

Deuterated fenucil and derivatives, procedure for their preparation and uses thereof.

Introduction

The invention relates to the design, synthesis and applications of deuterated derivatives of certain tyrostatic compounds.

State of the art

As is well known in the state of the art, tyrostatic compounds are orally active drugs that can be used in the fraudulent fattening of cattle prior to slaughter. The main consequences of the abuse of these compounds are not only obtaining lower quality meat, but the potential risk they constitute for human health. For these reasons, the use of these compounds has been banned within the framework of the European Union since 1981 (directive 81/602 / EC).

The detection of these compounds in samples of diverse origin (urine, milk, meat, blood, thyroid samples) is problematic due to the existence of tautomeric forms thereof, in addition to presenting a high polarity, which greatly complicates their detection using reverse phase high resolution liquid chromatography (RP-HPLC).

Additionally, the study by mass spectrometry of these low molecular weight compounds is not satisfactory in terms of sensitivity (signal to background noise ratio), since the signals due to these molecules frequently overlap with background noise.

However, high performance liquid chromatography (HPLC) and gas chromatography (GC) techniques coupled to mass spectrometry are the most commonly used in the detection of such compounds. A recent European Union directive (96/23 / EC), indicates that the use of deuterated derivatives of the tyrostatic compounds to be analyzed constitutes a high precision analytical method for the detection of these compounds [E.C. Council directive 96/23 / CE, Off. J. Eur. Commun. 2002 L221 / 8].

There remains, therefore, the need to provide new deuterated derivatives of the tyrostatic compounds for reliable and accurate detection thereof by means of high resolution chromatographic techniques combined with mass spectrometry.

One of these tyrostatic compounds is 6-phenyl-2-thioxo-2,3-dihydropyridin-4 (1H) -one, also known as Fenucil. However, no deuterated derivatives thereof are known in the state of the art.

Object of the invention

The object of the present invention is the chemical preparation of a deuterated isotopomer of the compound 6-phenyl-2-thioxo-2,3-dihydropyridin-4 (1H) -one, also known as Fenucil, as well as other derivatives thereof, specifically, the deuterated compound of formula (I)

in which:

R1, R2 and R3 independently represent a hydrogen atom or a C1-C4 alkyl group substituted with:

a -OR4 group, where R4 is a hydrogen atom or a C1-C3 alkyl group optionally substituted with phenyl;

a group -NR5R6, R5 and R6 being independently a hydrogen atom, or a C1-C3 alkyl group,

tosyl or mesyl;

a group -SR7, where R7 is a hydrogen atom or a C1-C3 alkyl group;

a -OCOR8 group, R8 being a C1-C3 alkyl or phenyl group; or

a halogen atom; Y

D represents deuterium.

Another object of the invention is the deuterated compound itself (I).

Also, another object of the invention is to provide a pharmaceutical composition comprising said deuterated compound.

Finally, another object of the invention is to provide the use of said deuterated compound to manufacture medicaments intended for the treatment of hyperthyroidism or to use as a standard in the detection of the corresponding tyrostatic compound.

Detailed description of the invention

The present invention provides the deuterated compound of general formula (I)

In a particular embodiment of the deuterated compound of the invention, R1, R2 and R3 independently represent hydrogen, either a methyl or ethyl group that is substituted with a hydroxy group (-OH), methoxy (-OMe), ethoxy (-OEt ), benzyloxy (-OBn), amine (-NH2), methylamine (-NHMe), ethylamine (-NHEt), tosylamine (-NHTs), mesylamine (-NHMs), thiol (-SH), thiomethoxy (-SMe), thioethoxy (-SEt), acetoxy (-OCOCH3) or benzoyloxy (-OBz); or with a fluorine, chlorine, bromine or iodine atom.

In a preferred embodiment, R1, R2 and R3 independently represent hydrogen or methyl. In an even more preferred embodiment, R1, R2 and R3 represent hydrogen.

Thus, the preferred deuterated compound of formula (I) of the invention is 6-pentadeuterophenyl-2-thioxo-2,3-dihydropyridin-4 (1H) -one.

In another aspect of the invention there is provided a process for preparing the deuterated compound of the invention previously described, which comprises the following steps:

(a) reacting a compound of formula (1),

wherein R3 has the meanings given previously, with deuterated benzene (C6D6) in the presence of a Lewis acid at elevated temperature, according to a Friedel-Crafts acylation reaction.

(b) reacting the deuterated derivative acyl obtained in step (a) with the compound (2) in the presence of a strong base at elevated temperature;

in which R1 and R2 have the meanings given previously.

(c) treating the reaction product of step (b) with an acid until acidic pH.

In the first stage of the process, the acylation of the corresponding compound is carried out using a suitable Lewis acid, preferably at reflux.

As Lewis acid, in particular, aluminum bromide (AlBr3) or, preferably, aluminum chloride (AlCl3) can be used.

The solvent used in this step (a) will be any suitable solvent of the state of the art, such as tetrahydrofuran (THF), diethyl ether (Et2O) or without solvent, the deuterated benzene itself (C6H6) acting as such, for example, although it is preferred without solvent, with deuterated benzene itself (C6H6) acting as such. Also, this reaction is carried out between 20 and 150 ° C, with an optimum yield at 90 ° C and for a time of 5 minutes to 1 hour, preferably 20 minutes.

After the reaction of step (a), the reaction product is treated with a strong base at elevated temperature.

Thus, in another particular embodiment of the process of the invention, the strong base employed in step (b) is selected from a metal hydride such as sodium hydride or potassium hydride; a metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide; a metal alkoxide such as lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide or potassium ethoxide; a metal amide such as lithium amide, sodium amide, potassium amide or lithium diisopropyl amide (LDA); a nitrogenous organic base such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU); a metal hexamethyldisilazide such as lithium hexamethyldisilazide, sodium hexamethyldisilazide or potassium hexamethyldisilazide; or an alkyl metal such as tert-butyl lithium or butyl lithium.

Thus, in a preferred embodiment of the process of the invention, the strong base employed in step (b) is sodium ethoxide.

The reaction with the strong base of step (b) is carried out at a temperature between 40 ° C and 130 ° C, preferably at a temperature between 60 to 120 ° C and, more preferably, at a temperature of 90 ° C. The time necessary for the reaction to be effective is between 5 and 48 hours, preferably for a time between 10 and 24 hours and, more preferably, for a time of 20 hours.

Finally, the product accildeuterated and treated with the strong base at high temperature is reacted, step (c), with an acid until acidic pH.

As the acid reagent, sulfuric acid (H2SO4), nitric acid (HNO3), phosphoric acid (H3PO4), or, preferably, hydrochloric acid (HCl) can be used.

The reaction with the strong acid of step (c) is carried out at a temperature between 5 ° C and 30 ° C, preferably at a temperature between 10 to 25 ° C and, more preferably, at a temperature of 18 ° C. This reaction with the strong acid of step (c) is carried out for a time of between 1 and 15 minutes, more preferably for a time of 5 minutes.

The solvent used in this step (c) will be any suitable solvent of the state of the art, such as absolute ethanol (EtOH), tetrahydrofuran (THF) or diethyl ether (Et2O), for example, although absolute ethanol is preferred.

In another aspect of the invention there is provided a pharmaceutical composition, which comprises the compound of the invention previously defined and, at least, a pharmaceutically acceptable excipient.

In another aspect of the invention the use of the compounds previously defined for the manufacture of medicaments for the treatment of hyperthyroidism is provided.

On the other hand, the deuterated compound of the invention can be used as a standard in the detection of the corresponding tyrostatic compound.

Thus, in another aspect of the invention there is provided the use of the deuterated compounds of the invention (I), and their derivatives previously defined, as standards for the detection of tyrostatic compounds of formula (II).

in which R1, R2 and R3 have the meanings given previously, by means of high resolution chromatographic techniques combined with mass spectrometry.

Among these chromatographic techniques that can be used are high performance liquid chromatography (HPLC) and gas chromatography (GC).

Embodiment

Preparation of 6-pentadeuterophenyl-2-thioxo-2,3-dihydropyridin-4 (1H) -one (Deuterated Fenucil)

A solution of 897 mg of commercial methyl malonyl chloride in deuterated benzene (C6D6) (0.37 ml) was refluxed for 20 minutes. After this time, it was allowed to cool and the reaction crude was poured onto ice by adding 10% sodium hydroxide solution (NaOH) to basic pH. It was extracted with diethyl ether (Et2O) and the organic phase was dried with anhydrous Na2SO4, filtered and evaporated to give a deuterated compound with a yield of 90%.

Subsequently, the compound obtained was treated with sodium ethoxide and thiourea (SC (NH2) 2) in absolute ethanol (EtOH) and the mixture was heated at reflux for 18 h. 10% HCl solution was added until acidic pH, ethanol (EtOH) was removed under reduced pressure. The precipitate appeared was collected and washed with hexane giving a yield of 80%.

Claims (16)

1. Deuterated compound of formula (I) wherein: R1, R2 and R3 independently represent a hydrogen atom or a C1-C4 alkyl group, optionally substituted with a -OR4 group, R4 being a hydrogen atom or a C1-C3 alkyl group optionally substituted with phenyl; a group -NR5R6, R5 and R6 being independently a hydrogen atom, or a C1-C3 alkyl group, tosyl or mesyl; a group -SR7, where R7 is a hydrogen atom or a C1-C3 alkyl group; a -OCOR8 group, R8 being a C1-C3 alkyl or phenyl group; or a halogen atom; Y D represents deuterium.

2.

Compounds according to claim 1, characterized in that R1, R2 and R3 independently represent hydrogen, or a methyl or ethyl group optionally substituted with a hydroxy, methoxy, ethoxy, benzyloxy, amine, methylamine, ethylamine, tosylamine, mesylamine, thiol, thiomethoxy group , thioethoxy, acetoxy or benzoyloxy; or with a fluorine, chlorine, bromine or iodine atom.

3.

Compounds according to claim 2, characterized in that R1, R2 and R3 independently represent hydrogen or methyl.

4. Process for the preparation of the compound of formula (I) comprising the following steps: (a) reacting a compound of formula (1) wherein R3 has the meanings given previously, with deuterated benzene (C6D6) in the presence of a Lewis acid at elevated temperature, according to a Friedel-Crafts acylation reaction. (b) reacting the deuterated derivative acyl obtained in step (a) with the compound (2) in the presence of a strong base at elevated temperature; in which R1 and R2 have the meanings given previously. (c) treating the reaction product of step (b) with an acid until acidic pH.

5.

Method according to claim 4, characterized in that the deuterated reagent used in step (a) is deuterated benzene (C6D6).

6.

Method according to claims 4 or 5, characterized in that the acid Lewis used in step (a) is selected from aluminum chloride (AlCl3) or aluminum bromide (AlBr3).

7.

Process according to claim 6, characterized in that the Lewis acid used in step (a) is aluminum chloride (AlCl3).

8.

Process according to claims 4, 5, 6 or 7, characterized in that the Friedel-Crafts acylation reaction with Lewis acid step (a) is carried out at reflux.

9.

Method according to any of claims 4 to 8, characterized in that the strong base employed in step (b) is selected from a metal hydride, a metal hydroxide, a metal alkoxide, a metal amide, a nitrogen-based organic base, a metal acetylide, a metal hexamethyldisilazide and an alkyl metal.

10.

Method according to claim 9, characterized in that the strong base used in step (b) is sodium ethoxide.

11. Method according to claims 9 or 10, characterized in that the reaction with the strong base of the stage (b) is carried out at fl ow.

12.

Process according to any of claims 4 to 11, characterized in that the acid used in step (c) is selected from hydrochloric acid (HCl), sulfuric acid (H2SO4), nitric acid (HNO3) or phosphoric acid (H3PO4), preferably, hydrochloric acid (HCl).

13.

Pharmaceutical composition comprising a deuterated compound of formula (I) and at least one pharmaceutically acceptable excipient.

14.

Use of the deuterated compound of formula (I) for the manufacture of a medicament for the treatment of hyperthyroidism.

fifteen.

Use of the deuterated compound of formula (I) defined in claims 1-3 as a standard for the detection of a compound of formula (II)

wherein R1, R2 and R3 have the meanings given in claim 1. SPANISH OFFICE OF THE PATENTS AND BRAND Application no .: 201001572 SPAIN Date of submission of the application: 07.12.2010 Priority Date: REPORT ON THE STATE OF THE TECHNIQUE 51 Int. Cl.: C07D239 / 56 (01.01.2006) A61K31 / 513 (01.01.2006) RELEVANT DOCUMENTS

Category

Documents cited Claims Affected

TO

S ABUÍN et al., Analytical Chimica Acta 2008, vol 617, pages 184-191. "Analysis of thyreostatic drugs in thyroid samples by ultra-performance liquid chromatography tandem mass spectrometry detection", the entire document. 1-15

TO

S ABUÍN et al., Journal of Chromatography A 2008, vol 1207, pages 17-23. " Analysis of thyreostatic drugs in thyroid samples by liquid chromatographt tandem mass spectrometry: comparison of two sample treatment strategies ", the entire document. 1-15

Category of the documents cited X: of particular relevance Y: of particular relevance combined with other / s of the same category A: reflects the state of the art O: refers to unwritten disclosure P: published between the priority date and the date of priority submission of the application E: previous document, but published after the date of submission of the application

This report has been prepared • for all claims • for claims no:

Date of realization of the report 26.01.2011

Examiner P. Fernández Fernández Page 1/4

REPORT OF THE STATE OF THE TECHNIQUE Application number: 201001572 Minimum documentation sought (classification system followed by classification symbols) C07D, A61K Electronic databases consulted during the search (name of the database and, if possible, terms of search used) INVENES, EPODOC, WPI, CAS, BIOSIS State of the Art Report Page 2/4  WRITTEN OPINION Application number: 201001572 Date of Completion of Written Opinion: 01.21.2011 Statement

Novelty (Art. 6.1 LP 11/1986)

Claims Claims 1-15 IF NOT

Inventive activity (Art. 8.1 LP11 / 1986)

Claims Claims 1-15 IF NOT

The application is considered to comply with the industrial application requirement. This requirement was evaluated during the formal and technical examination phase of the application (Article 31.2 Law 11/1986).  Opinion Base.- This opinion has been made on the basis of the patent application as published. State of the Art Report Page 3/4  WRITTEN OPINION Application number: 201001572 1. Documents considered.- The documents belonging to the state of the art taken into consideration for the realization of this opinion are listed below.

Document

Publication or Identification Number publication date

D01

S ABUÍN et al., Analytical Chimica Acta 2008, vol 617, pages 184-191. "Analysis of thyreostatic drugs in thyroid samples by ultra-performance liquid chromatography tandem mass spectrometry detection", the entire document.

2. Statement motivated according to articles 29.6 and 29.7 of the Regulations for the execution of Law 11/1986, of March 20, on Patents on novelty and inventive activity; quotes and explanations in support of this statement The application refers to deuterated compounds of formula (I) (claim 1), a process for their preparation from deuterated builder of formula (1) (claim 4) and their pharmaceutical use and as a standard for detecting the compound of formula ( II) (fenucil, 6-phenyl-2-thiouracil, PhTU) in claims 13-15. Document D1 discloses a method for the detection of thyrostatic drugs, including PhTU (Figure 1), by high performance liquid chromatography-mass spectrometry. The compound of formula (I) of the application or its obtaining has not been disclosed in the prior art; The procedure for detecting fenucil in biological samples using the deuterated compound as a standard to improve the resolution of the mass spectrum has not been found. Consequently, claims 1-15 of the application are considered to meet the criteria of novelty and inventive activity established in Art. 6.1 and 8.1 of Patent Law 11/1986. State of the Art Report Page 4/4