ES2352927B1 - DEUTERATED COMPOUNDS OF 5-TRIDEUTEROMETIL-6-METHYL-2-THIOXO-2,3-DIHYDROPIRIDIN-4 (1H) -ONA AND PREPARATION PROCEDURE OF THE SAME. - Google Patents

Abstract

Deuterated compounds of 5-trideuterometil-6-methyl-2-thioxo-2,3-dihydropyridin-4 (1H) -one and preparation process thereof. # The invention defines deuterated compounds of formula (I) # ** FIGURE ** # in which: #R {sub, 1}, R {sub, 2} independently represent a hydrogen atom or a C {sub, 1} -C {sub, 4} alkyl group, substituted with #a group? OR {sub, 4}, where R {sub, 4} is a hydrogen atom or a C {sub, 1} -C {sub, 3} alkyl group substituted with phenyl; #a group? NR {sub , 5} R {sub, 6}, where R {sub, 5} and R {sub, 6} are independently a hydrogen atom, or a C {sub, 1} -C {sub, 3} alkyl group, tosyl or mesyl; #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} is a C {sub, 1} -C {sub, 3} or phenyl alkyl group: # or 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 compounds of 5-trideuterometil-6-methyl-2-thioxo-2,3-dihydropyridin-4 (1H) -one and preparation process thereof.

Introduction

The invention is framed in the field of synthesis of deuterated derivatives of chemical compounds. Specifically, in the synthesis of deuterated derivatives of 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).

In addition, 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 5,6-dimethyl-2-thioxo-2,3-dihydropyridin-4 (1H) -one. However, no deuterated derivative thereof is known in the state of the art.

Object of the invention

The object of the invention is the design and chemical preparation of a trideuterated isotopomer of the compound 5,6-dimethyl-2-thioxo-2,3-dihydropyridin-4 (1H) -one, specifically the deuterated compound of formula (I).

Wherein: R1 and R2 independently represent a hydrogen atom or a C1-C4 alkyl group 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, tosyl or mesyl group; 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; and 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 thyrostatic drug.

Detailed description of the invention

The present invention provides a deuterated compound of formula (I).

In a particular embodiment of the deuterated compound of the invention, R1 and R2 independently represent hydrogen, either a methyl or ethyl group that is optionally substituted with a hydroxy (-OH), methoxy (-OMe), ethoxy (-OEt) group , 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 and R2 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 5-trideuterometyl-6-methyl-2-thioxo-2,3-dihydropyridin-4 (1H) -one.

In general, the process for the preparation of the compounds of general formula (I) comprises the following steps:

(a) reacting a compound of formula (1)

with a deuterated methyl halide in the presence of a base at low temperature.

(b) reacting the deuterated methyl derivative 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 methylation of the corresponding compound is carried out using a suitable base and a deuterated methylation reagent.

As deuterated methylation reagent, any deuterated methyl halide, preferably deuterated methyl chloride (CD3Cl) or deuterated methyl bromide (CD3Br) and, more preferably, deuterated methyl iodide (CD3I) can be used.

The base used in step (a) is selected from a metal hydride, a metal hydroxide, a metal alkoxide, a metal amide, a nitrogenous organic base, a metal acetylide, a metal hexamethyldisilazide and an alkyl metal. Preferably, metal hydrides such as sodium hydride or potassium hydride will be employed; metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide; metal alkoxides such as lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide or potassium ethoxide; metal amides such as lithium amide, sodium amide, potassium amide or lithium diisopropyl amide (LDA); organic nitrogen bases such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU); metal hexamethyldisilazides such as lithium hexamethyldisilazide, sodium hexamethyldisilazide or potassium hexamethyldisilazide; or alkyl metals such as tert-butyl lithium or butyl lithium.

In the preferred embodiment of the process of the invention, the base employed in step (a) is a metal hydride selected from sodium hydride (NaH) and potassium hydride (KH).

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

Also, this reaction is carried out at 0 ° C and for a time of 10 minutes to 1 hour, preferably 0.5 hours.

After the methylation reaction of step (a), the reaction product is treated with a strong base at high 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, a metal hydroxide, a metal alkoxide, a metal amide, a nitrogen organic base, a metal acetylide, a metal hexamethyldisilazide and an alkyl metal.

More particularly, said strong base can be 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. Preferably, the strong base to be used in the reaction of step (b) is an alkyl metal such as tert-butyl lithium (t-BuLi), butyl lithium (BuLi) or phenyl lithium (PhLi); or a metal amide such as diisopropyl lithium amide (LDA).

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

In another particular embodiment of the process of the invention, the reaction with the strong base of step (b) is carried out at reflux.

In another particular embodiment of the process of the invention, the reaction with the strong base of step (b) is carried out for a time of between 30 minutes to 24 hours, preferably for a time of between 1 and 24 hours and, more preferably, for a time. 20 hours

Finally, the methyldeuterated product and treated with the strong base at high temperature is reacted with an acid until acidic pH.

The acid reagent will preferably be, by way of example, sulfuric acid (H2SO4), nitric acid (HNO3) or phosphoric acid (H3PO4) and, more preferably hydrochloric acid (HCl).

In another particular embodiment of the process of the invention, 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 18ºC.

In another particular embodiment of the process of the invention, the reaction with the strong acid of step (c) is carried out for a time of between 30 to 30 minutes, preferably for a time of between 1 and 15 minutes and, 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, hereinafter "pharmaceutical composition of the invention (I)" comprising the compound of the invention previously defined and, at least, a pharmaceutically acceptable excipient.

The pharmaceutically acceptable excipients will be those excipients of the art that allow the proper formulation of the pharmaceutical composition of the invention. Said composition may be formulated for oral, intravenous, topical, rectal, subdermal, etc. administration. That is, it can be presented in the form of solutions, tablets, capsules, implants, etc. Also, said formulation may be immediate release or controlled release.

In addition, the compounds of general formula (I) are especially advantageous in the pharmaceutical field, as an active ingredient, so they can be used for the manufacture of medicaments for the treatment of hyperthyroidism.

On the other hand, the compounds of general formula (I) can be used as a standard in the detection of tyrostatic compounds. In particular, as a standard for the detection of compounds of formula (II).

in which R1 and R2 have the meanings given previously,

using high resolution chromatographic techniques combined with mass spectrometry such as high performance liquid chromatography (HPLC) and gas chromatography (GC).

The following example illustrates the invention and should not be considered as limiting its scope.

Preferred embodiment

Preparation of 5-trideuterometyl-6-methyl-2-thioxo-2,3-dihydropyridin-4 (1H) -one

To a solution of 500 mg of commercial ethyl acetoacetate in tetrahydrofuran (THF) (25 ml) was added 169 mg of sodium hydride (NaH) and 835 mg of commercial deuterated methyl iodide and the solution was stirred at room temperature.

Water was added to the reaction crude to remove excess sodium hydride (NaH), extracted with diethyl ether (Et2O) and the organic phase dried with Na2SO4, filtered and evaporated the solvent to give a methyldeuterated compound with a yield 100%

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 (17)

1. Deuterated compound of formula (I) in which: R1 and R2 independently represent a hydrogen atom or a C1-C4 alkyl group, 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 and R2 independently represent hydrogen, or a methyl or ethyl group optionally substituted with a hydroxy, methoxy, ethoxy, benzyloxy, amine, methylamine, ethylamine, tosylamine, mesylamine, thiol, thiomethoxy, thioethoxy group , acetoxy or benzoyloxy; or with a fluorine, chlorine, bromine or iodine atom.

3.

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

4. Compounds according to claim 3, characterized in that they are selected from: [1] 5-Trideuterometyl-6-methyl-2-thioxo-2,3-dihydropyridin-4 (1H) -one. [2] 6-pentadeuterophenyl-2-thioxo-2,3-dihydropyridin-4 (1H) -one. 5. Process for the preparation of the compounds of formula (I) comprising the following steps: (a) reacting a compound of formula (1) with a deuterated methyl halide in the presence of a base at low temperature. (b) reacting the deuterated methyl derivative 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.

6.

Process according to claim 5, characterized in that the deuterated methyl halide used in step (a) is deuterated methyl iodide.

7.

Method according to any one of claims 5 or 6, characterized in that the base used in step (a) is selected from a metal hydride, a metal hydroxide, a metal alkoxide, a metal amide, a nitrogenous organic base, a metal acetylide, a metal hexamethyldisilazide and an alkyl metal.

8.

Method according to claim 7, characterized in that the base used in step (a) is a metal hydride selected from sodium hydride and potassium hydride.

9.

Method according to any of claims 5, 6, 7 or 8, characterized in that the strong base used in step (b) is selected from a metal hydride, a metal hydroxide, a metal alkoxide, a metal amide, a nitrogen 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.

eleven.

Method according to any of claims n 5 to 10, characterized in that the reaction with the strong base of step (b) is carried out at reflux.

12.

Method according to any of claims 5 to 11 5, characterized in that the reaction with the strong base of step (b) is carried out for a period of between 30 minutes to 24 hours.

13.

Process according to any one of claims 5 to 12, 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).

14.

Pharmaceutical composition comprising a deuterated compound of formula (I) defined in claims 1-4 and at least one pharmaceutically acceptable excipient.

fifteen.

Use of the deuterated compound of formula (I) defined in claims 1-4 for the manufacture of a medicament for the treatment of hyperthyroidism.

16.

Use of the deuterated compound of formula (I) defined in claims 1-4 as a standard for the detection of a compound of formula (III)

wherein R1 and R2 have the meanings given in claim 1. 8 SPANISH OFFICE OF THE PATENTS AND BRAND Application no .: 201001573 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., Analytica 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. 1-16

TO

S ABUÍN et al., Journal of Chromatography a 2008, vol 1207, pages 17-23. " Analysis of thyreostatic drugs in thyroid samples by liquid chromatography tandem mass spectrometry: comparison of two sample treatment strategies " 1-16

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: 201001573 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: 201001573 Date of Completion of Written Opinion: 01.21.2011 Statement

Novelty (Art. 6.1 LP 11/1986)

Claims Claims 1-16 IF NOT

Inventive activity (Art. 8.1 LP11 / 1986)

Claims Claims 1-16 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: 201001573 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, Analytica 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 the deuterated compounds of formula (I) (claim 1), process for their preparation from the deuterated builder of formula (1) (claim 5) and their pharmaceutical use and as a standard for detecting the compound of formula ( III) (5,6-dimethyl-2-thiouracil, DMTU) claims 14-16. Document D1 discloses a method for the detection of thyrostatic drugs, including DMTU (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 DMTU in biological samples using the deuterated compound as a standard to improve the resolution of the mass spectrum has not been found. Consequently, claims 1-16 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