BR102012026555B1 - PROCESS FOR OBTAINING AND COMPOSING A DRUG FROM CHENODEOXYCOLATE BOUND TO A NATURAL SULFAMATE MONOSACCHARIDE DERIVATIVE D-FRUCTOSE (TOPIRAMATE) AND TO A PHENYLKETONE (BUPROPRION) FOR THE TREATMENT OF OBESITY AND PLURIMETABOLIC SYNDROMES - Google Patents

Abstract

PROCESS FOR OBTAINING AND COMPOSITION OF A DRUG FROM CHENODEOXICOLATE LINKED TO A NATURAL D-FRUCTOSE MONOSACCHARIDE SULFAMATE DERIVATIVE (TOPYRAMATE) AND A PHENYLKETONE (BUPROPRION) FOR THE TREATMENT OF OBESITY AND PLURIMETABOLIC SYNDROMES essentially consists of a new chemical entity, which has a specific receptor in the biological membrane, allowing better absorption due to its active transport, and after being hydrolyzed, this molecule releases bupropyn and topiramate, which have already demonstrated efficacy in the treatment of obesity and plurimetabolic syndromes. Bupropion is an aminoketone, which has a mild inhibition of norepinephrine, serotonin and dopamine reuptake as a mechanism of action, which has been shown to promote weight loss in several studies, with a low incidence of adverse events. Topiramate is a substituted sulfamate fructose 1,6-diphosphate analogue that induces weight loss, with human studies suggesting that it plays a role in decreasing calorie intake, hormonal involvement in obesity, and glucose and glucose metabolism. lipids. A new chemical entity with the association of the molecules of these two drugs allows a synergistic effect, since each part will act on a certain physiological system to reduce body weight in patients with (...).

Description

SHORT PRESENTATION

This patent application deals with a “PROCESS FOR OBTAINING AND COMPOSITION OF A DRUG FROM CHENODEOXICOLATE ATTACHED TO A NATURAL MONOSACCHARIDE SULFAMATE DERIVATIVE D-FRUCTOSE (TOPYRAMATE) AND A PHENYLKETONE (BUPROPRION) FOR THE TREATMENT OF OBESITY AND PLURIMETABOLIC SYNDROMES ”, whose composition was idealized through a new pharmaceutical entity derived from chenodeoxycholate linked to a monosubstituted sulfamate derivative of the natural monosaccharide d-fructose (topiramate) and a phenylketone (bupropion) for the treatment of obesity and plurimetabolic syndromes, with the advantage the body has a specific membrane receptor for this fatty acid, increasing the absorption of this compound.

Body weight is homeostatically regulated to preserve an individual's current weight. When body weight deviates from this level, several regulatory mechanisms are activated to restore weight to previous levels. Therefore, targeting a particular molecular pathway may lead to weight loss, but compensatory homeostatic responses will be activated, minimizing the effectiveness of the drug. The treatments of some diseases, such as systemic arterial hypertension and type II diabetes, have associated drugs, in which a single drug would be used. Therefore, we have a new therapeutic proposal that would act through two different mechanisms, in an attempt to maximize the desired effect and, simultaneously, reduce the incidence of adverse events.

APPLICATION FIELD

The invention is particularly suited to the human need, it is specifically a drug aimed at the treatment of obesity and plurimetabolic diseases.

STATE OF THE TECHNIQUE

It is known that obesity in the world has been something alarming and worrying, due to the considerable increase in adults and children who fall into the obese group in recent decades. Faced with this situation, the exponential increase in cases of patients undergoing bariatric surgery has been reflecting a greater effort by physicians in an attempt to reverse potential complications associated with obesity diseases and, at the same time, exposing the small range of pharmacological options available for clinical treatment.

Today, in Brazil, we have two drug options approved by ANVISA for the treatment of obesity, Sibutramine and Orlistat, where the second is a drug with little effectiveness in weight reduction, but has the advantage of being free of adverse events in the cardiovascular system, and can be used safely in the obese population and even prevent diabetes, according to the Xendos study, while the first drug mentioned, sibutramine, with a greater number of studies carried out, is one of the most prescribed drugs, because in addition to the good result , offers a favorable security profile to its users. But recently studies reporting data from the SCOUT Study, aimed to assess whether the medication was able to reduce cardiovascular events in a high-risk obese population such as patients with type 2 diabetes, patients with a history of previous cardiovascular event and patients with another risk factor, in which it was concluded that there was a slight but significant increase in these outcomes in the group of patients receiving sibutramine (11.4% vs. 10%), which led to the suspension of the sale of this drug in Europe and the USA. Here in Brazil, ANVISA chose not to suspend it, but issued an opinion restricting its use and prohibiting the use of amfepramone, fenproporex and mazindol, for bringing a high cardiovascular risk arising from the noradrenergic effects of these drugs.

The State of the Art is known from document WO 01/00205 A1 priority of 24/06/1999, which consists of a method for treating comorbid conditions associated with obesity in a human being in need of such treatment which comprises administering to the being human dose of a therapeutically effective amount of a compound of formula, including enantiomers and their pharmaceutically acceptable salts, wherein R1 and R2 are independently H or methyl, and a therapeutically effective amount of a compound of formula (II) are administered simultaneously, separately or sequentially.

Another known product from the state of the art is the priority document EP 1 964 555 A1 of 20/12/2005, the invention relates to the pharmaceutical industry, in general, involved in the production of drugs to control obesity and overweight. More specifically, the invention relates to a composition that contains a substance that inhibits the reuptake of dopamine, noradrenaline and serotonin and an amino acid. The composition is characterized by the fact that the aforementioned combination or association is constituted by a selected substance that inhibits the reuptake of dopamine, noradrenaline and serotonin, known as sibutramine, and an amino acid known as carnitine, in order to produce a product that has an effect synergistic for the treatment of obesity and overweight, with fewer side effects.

The use of the above drugs for weight loss is effective in the long term, but after one year of treatment, such drugs approved by regulatory bodies lead to an average weight loss of 3 to 5 kg due to the physiological effects of the patient's belief that that is being treated. Therefore, if we compare the discreet effectiveness of these drugs with the weight loss of patients undergoing bariatric surgery, which ranges from 20% to 25% depending on the procedure adopted, resulting in a significant reduction in diseases associated with obesity and an increase in expectation of life, it is necessary and extremely important to develop new medications that are more effective, associated with a favorable safety profile, with a minimum of adverse events.

With the prohibition of amfepramone, fenproporex and mazindol, which had been the pillars of the pharmacological treatment of obesity for decades, but without admissible safety, leaving thousands of people all over the world, mainly in Brazil, without a therapeutic option, leading the field of pharmacological treatment of obesity is going through a turbulent time, which makes it imperative that research on new drugs and drug combinations with different proposals and mechanisms of action be intensified, aiming at adequate treatment for the growing population of obese people.

INVENTION

THE “PROCESS FOR OBTAINING AND COMPOSITION OF A DRUG FROM CHENODEOXICOLATE ATTACHED TO A NATURAL D-FRUCTOSE MONOSACCHARIDE SULFAMATE DERIVATIVE (TOPYRAMATE) AND A PHENYLKETONE (BUPROPRION) FOR THE TREATMENT OF OBESITY AND PLURIMETABOLIC SYNDROMES”, object of this request for Patent of Invention , has its own characteristics in its composition, contemplating a new chemical entity called 3a, 7a-bis(4-(tert-butyl(1-(4-chlorophenyl)-1-oxopropan-2-yl)amido)bis(oxomethylene)bis (oxy)diacetic acid)-chenodeoxycholate-β-alanyl-((3aS, 5aR, 8aR, 8bS)-2,2,7,7-tetramethyltetrahydro-3aHbis[ 1,3]dioxolo[4,5- b:4' ,5'-d]pyran-3a-yl) methyl sulfamate which comes from chenodeoxycholate linked to a monosubstituted sulfate derivative of the natural monosaccharide d-fructose (topiramate) and to a phenylketone (bupropion) for the treatment of obesity and plurimetabolic syndromes , with the advantage that the organism has a specific membrane receptor for this fatty acid, increasing the abs sorption of this compound.

Body weight is homeostatically regulated to preserve an individual's current weight. When body weight deviates from this level, several regulatory mechanisms are activated to restore weight to previous levels. Therefore, targeting a particular molecular pathway may lead to weight loss, but compensatory homeostatic responses will be activated, minimizing the drug's effectiveness. In analogy with the treatment of other diseases, such as systemic arterial hypertension (which uses the combination of an ACE inhibitor and a thiazide) and type 2 diabetes (which uses the combination of metformin and sulfonylurea), a single drug would be used ( new chemical entity) that would act through two different mechanisms, in an attempt to maximize the desired effect and, simultaneously, reduce the incidence of adverse events.

ADVANTAGES OF THE INVENTION

The present invention has, in addition to all of the above, a new chemical entity, which has a specific receptor on the biological membrane, allowing better absorption due to its active transport, and after being hydrolyzed, this molecule releases bupropion and topiramate, which have already demonstrated efficacy in the treatment of obesity and plurimetabolic syndromes.

Bupropion is an aminoketone, which has as a mechanism of action a slight inhibition of the reuptake of norepinephrine, serotonin and dopamine, which has been shown to promote weight loss in several studies, with a low incidence of adverse events.

Topiramate is a substituted sulfamate analogue of fructose 1,6-diphosphate that induces weight loss, with human studies suggesting that it plays a role in decreased calorie intake, hormonal involvement in obesity, and in glucose metabolism and lipids.

A new chemical entity with the association of the molecules of these two drugs allows a synergistic effect, since each part will act on a certain physiological system to reduce body weight in overweight or obese patients.

DETAILED DESCRIPTION OF THE INVENTION THE “PROCESS OF OBTAINING AND COMPOSITION OF DRUG

Para síntese do fármaco são necessários os compostos a seguir, definidos qualitativamente e quantitativamente, conforme demonstrado abaixo, podendo ocorrer alteração das quantidades, de acordo com a necessidade de produção do fármaco, sendo os componentes apresentados em gramas, mmoles e equivalente-grama, segundo os parâmetros elencados na composição:FROM KENODEOXYCHOLATE ATTACHED TO A NATURAL D-FRUCTOSE MONOSACCHARIDE SULFAMATE DERIVATIVE (TOPYRAMATE) AND TO A PHENYLKETONE (BUPROPRION) FOR THE TREATMENT OF OBESITY AND 10 OF THE PLURIMETABOLIC SYNDROMES", object of this patent application, consists of a drug derived from chenodeoxycholate linked to a phenylketone (bupropion) and a derivative of the natural monosaccharide d-fructose (topiramate) which results in a new chemical entity called 3a, 7a-bis(4-(tert-butyl(1-(4-chlorophenyl)-1 -oxopropan-2-yl)amido)bis(oxomethylene)bis(oxy)diacdic acid)-chenodeoxycholate-β-alanyl-((3aS, 5aR, 8aR, 8bS)-2,2,7,7-tetramethyltetrahydro-3aHbis [1,3]dioxolo[4,5-b:45'-d]pyran-3a-yl) methyl sulfamate. Molecular Formula: C71H99N4CI2O20S.

For the synthesis of the drug, the following compounds are required, defined qualitatively and quantitatively, as shown below, with the possibility of changing the amounts, according to the need for drug production, with the components presented in grams, mmoles and gram-equivalent, according to the parameters listed in the composition:

Quantity Substance g Chenodeoxycholic acid 1.05 eq 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate (HBTU) 1.05 eq β-alanine benzyl ester hydrochloride 2, 1 eq diisopropylethylamine (DIPEA) 100 mL anhydrous dimethyl formamide (DMF) 90 mL ether 180 mL sodium bicarbonate solution (2.5% weight/volume) 90 mL 0.1N hydrochloric acid (HCI) 90 mL brine (salt-saturated water) 50 mL anhydrous THF 7.3 eq 2-(chlorocarbonyloxy)-acetic acid 8 mL dry pyridine 50 mL chloroform 150 mL sodium hydroxide (NaOH) 37% hydrochloric acid 140 mL ethyl acetate (EtOAc) 20 mL anhydrous dichloromethane (DCM) 10 eq oxalyl chloride solution (OxCl) Qsp* Tetrahydrofuran (THF) anhydrous 2.1 eq (BUP) 50 mL ethyl acetate Qsp* Acetone Qsp* Toluene 25 mL methanol 0.3% acid acetic acid 30 mL anhydrous DMF 1.05 eq HBTU 1.05 eq DIPEA 1.05 eq ((3aS,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[ 4,5-b:4',5'-d]pyran-3a-yl) methyl sulfamate (TOP) *qsp = amount sufficient to standardize r (complete) the volume of the formula.

PRODUCT OBTAINING PROCESS

The process for obtaining compound 3 a, 7 a-bis(4-tert-butyl(1-(4-chlorophenyl)-1-oxopropan-2-yl)amido)bis(oxomethylene)bis(oxy)diacetic acid)- chenodeoxycholate-β-alanyl-((3aS,5aR,8aR,8bS)-2,2,7,7-tramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4',5'-d ]pyran-3a-yl)methyl sulfamate is as follows: 10 g (grams) (25.5 mmol) chenodeoxycholic acid, 1.05 eq (gram equivalent) 2-(1H-benzotriazol-1-yl)- 1,1,3,3-tetramethyl uronium hexafluorophosphate (HBTU), 1.05 eq (gram equivalent) of β-alanine benzyl ester hydrochloride together with 2.1 eq (gram equivalent) of diisopropylethylamine (DIPEA ) were dissolved in 100 mL (mmoles) of anhydrous dimethyl formamide (DMF) under stirring, in a nitrogen atmosphere, and the solution was left at room temperature for 24 hours for the reaction to occur. After this period, 3 volumes of ice-cold distilled water were added to block the reaction. The resulting suspension was extracted with 3 x 30 mL (mmoles) of ether and the combined organic extracts were washed with 3 x 30 mL (mmoles) of sodium bicarbonate solution (2.5% weight/volume), 3 x 30 mL (mmoles) 0.1 N hydrochloric acid (HCI), 1 x 30 mL (mmoles) water and 1 x 30 mL (mmoles) brine (water saturated with salt). The ethereal solution was dried over anhydrous sodium sulfate (Na2SO4), filtered and concentrated under vacuum until obtaining chenodeoxycholate-β-alanine amide benzyl ester (92% yield), which was used without further purification. 9 g (grams) (16.3 mmoles) of chenodeoxycholate-β-alanine amide benzyl ester were added in small proportions in 50 ml_ (mmoles) of anhydrous THF containing 7.3 eq (gram equivalent) of 2-(chlorocarbonyl oxy) - acetic acid and 8 mL (mmoles) of dry pyridine. The resulting suspension was left to react for 18 hours at room temperature and then dried under reduced pressure. The yellowish oil obtained was dissolved in 50 mL (mmoles) of chloroform, extracted with 3 x 20 mL (mmoles) of distilled water and with 3 x 20 mL (mmoles) of 1N sodium hydroxide (NaOH). The combined aqueous extracts were placed in an ice bath and acidified to pH 3 with the slow addition of 37% hydrochloric acid under vigorous stirring. The resulting white precipitate, after filtering the solution, was dissolved in 50 mL (mmol) of ethyl acetate (EtOAc), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum until obtaining the pure compound 3a, 7a-bis ( oxomethylene) bis(oxy)diacetic acid - chenodeoxycholate-β-alanine amide benzyl ester (yield 72%), and the purity assessment was performed by thin layer chromatography (TLC). 8 g (grams) (10.6 mmoles) of 3α, 7a-bis (oxomethylene) bis (oxy) diacetic acid-chenodeoxycholate-β-alanine amide benzyl ester were dissolved in 20 mL (mmoles) of anhydrous dichloromethane (DCM), the solution was placed in an ice bath and 10 eq (gram equivalents) of a solution of oxalyl chloride (OxCl) was added dropwise over a period of 20 minutes. The mixture was left for 18 hours at room temperature for the reaction to occur. The obtained solution was concentrated under vacuum until resulting in a brownish oil, which was triturated with a mixture of ether and hexane in a bath of dry ice and acetone, decanting the supernatant until solidification occurred (precipitation). The yellowish solid was dissolved in anhydrous tetrahydrofuran (THF) and added dropwise (typically over 30 minutes) to an ice-cold solution (in an ice bath) containing 2.1 eq (gram equivalent) of (BUP) in THF, in the presence of the DMF catalyst. After this step, the reaction was left under stirring at 55°C for 24 hours or until complete (assessment by TLC). The obtained solution was concentrated under vacuum, dissolved in 50 mL (mmoles) of ethyl acetate and extracted with 3 x 30 mL (mmoles) of 1N sodium hydroxide, 1 x 30 mL (mmoles) of distilled water and 1 x 30 mL (mmoles) of brine (water saturated with salt). The organic solution was left over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The product obtained was purified by silica gel column chromatography using a mixture of chloroform / acetone / toluene as mobile phase, obtaining 3a-7a-bis(4-tert-butyl(1-(4-chlorophenyl)-1-oxopropan- 2-yl)amido)bis(oxy)diacetic acid)-chenodeoxycholate-β-alanine amide benzyl ester (25% yield) as an off-white powder. 5 g (grams) (4.2 mmoles) of 3α-7α-bis(4-tert-butyl(1-(4-chlorophenyl)-1-oxopropan-2-yl)amido)bis(oxy)diacetic acid)- chenodeoxycholate-β-alanine amide benzyl ester were dissolved in 25 mL (mmoles) of methanol, in the presence of a catalyst moistened with 10% Pd/C (palladium/carbon), and this mixture was left in a hydrogen atmosphere at 52 psig at room temperature for 16 hours for the reaction to occur. The suspension was filtered through a pad of Celite® to remove the catalyst and the resulting solution was evaporated under vacuum. The product obtained was purified by column chromatography containing silica gel, using a mixture of chloroform / acetone / toluene with 0.3% acetic acid as mobile phase. The combined pure fractions were evaporated under vacuum in the presence of carbon tetrachloride to azeotropically remove excess acetic acid (HAc), until obtaining the pure compound 3α, 7a-bis(4-tert-butyl(1-(4-chlorophenyl)1- oxopropan-2-yl)amido)bis(oxomethylene)bis(oxy)diacetic acid)-chenodeoxycholate-β-alanine amide, as a white amorphous solid, in almost quantitative yield. 2g (grams) (1.8 mmoles) of 3α,7a-bis(4-tert-butyl(1-(4-chlorophenyl)1-oxopropan-2-yl)amido)bis(oxomethylene) bis(oxy)diacetic acid )- chenodeoxycholate-β-alanine amide were dissolved in 30 mL (mmoles) of anhydrous DMF, together with 1.05 eq (gram equivalent) of HBTU and with 1.05 eq (gram equivalent) of DIPEA. After 1 hour of stirring at room temperature, 1.05 eq (gram equivalent) of ((3aS, 5aR, 8aR, 8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis[ 1,3]dioxolo[ 4,5-b:45 d]pyran-3a-yl)methyl sulfamate (TOP) were added and the resulting solution was left to react at room temperature for 24 hours. After this period, the reaction was “blocked” by adding 3 volumes of water and the product was extracted with 3 x 30 mL (mmoles) of EtOAc. The combined organic extracts were washed with 3 x 30 mL (mmoles) sodium bicarbonate solution (2.5% weight/volume), 1 x 30 mL (mmoles) water and 1 x 30 mL (mmoles) brine. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to obtain 3o,7o-bis(4-tertbutyl(1-(4-chlorophenyl)-1-oxopropan-2-yl)amido)bis(oxomethylene ) bis(oxy)diacotic acid)-chenodeoxycholate-β-alanyl-((3aS, 5aR, 8aR, 8 b S)-2,2,7,7-tetramethyltetrahydro-3aH-bis[ 1,3]dioxolo[4, 5-b:45'd]pyran-3a-yl)methyl sulfamate (68% yield).

Claims (8)

1. Process for obtaining 3α, 7α-bis(4-(tert-butyl(1-(4-chlorophenyl)-1-oxopropan-2-yl)amido)bis(oxomethylene)bis(oxy)diacetic acid)-chenodeoxycholate -e—alanyl- ((3aS, 5aR, 8aR, 8bS)-2, 2, 7, 7-tetramethyltetrahydro-3aHbis[1, 3]dioxolo[4, 5- b:4', 5'-d] pyran- 3a-yl) methyl sulfamate characterized by the fact that chenodeoxycholic acid is reacted with Beta-alanine-benzyl ester hydrochloride in the presence of diisopropylamine, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate and anhydrous dimethylformamide to generate chenodeoxycholate-B-alanine amide benzyl ester, this ester obtained is then reacted with 2-(chlorocarbonyloxy)-acetic acid in the presence of anhydrous tetrahydrofuran and sodium hydroxide to generate the compound 3α, 7α-bis ( oxomethylene) bis(oxy)diacetic acid - chenodeoxycholate-Beta-alanine amide benzyl ester, which is reacted with oxalyl chloride in anhydrous dichloromethane followed by reaction with bupropion in the presence of tetrahydrofuran and DMF to generate compound 3α, 7α- bis(4-tert-butyl(1-(4-chlorophenyl)-1-oxopropan-2-yl)amido)bis(oxy)diacetic acid)-chenodeoxycholate-beta-alanine amide benzyl ester, and, treating the latter product with a palladium/carbon catalyst in the presence of methanol to generate the compound 3α, 7α-bis(4-tert-butyl(1-(4-chlorophenyl)-1-oxopropan-2-yl-amido)bis(oxymethylene) bis( oxy)diacetic acid)-chenodeoxycholate-beta-alanine amide, the latter compound being reacted with ((3aS, 5aR, 8aR, 8b S)-2, 2, 7, 7-tetramethyltetrahydro-3aH-bis[1,3]dioxol [4,5-b:4',5'-dipyran-3a-yl)methyl sulfamate (topiramate) in the presence of DIPEA, HBTU in anhydrous DMF to generate 3α,7α-bis(4-(tert-butyl(1- (4-chlorophenyl)-1-oxopropan-2-yl)amido)bis(oxomethylene)bis(oxy)diacetic acid)-chenodeoxycholate-β-alanyl- ((3aS, 5aR, 8aR, 8bS)-2, 2, 7 , 7-tetramethyltetrahydro-3aHbis[1,3]dioxolo[4,5-b:4',5'-d]pyran-3a-yl)methylsulfamate. 2. Process for obtaining 3α,7α-bis(4-(tert-butyl(1-(4-chlorophenyl)-1-oxopropan-2-yl)amido)bis(oxomethylene)bis(oxy)diacetic acid)-chenodeoxycholate -e—alanyl- ((3aS, 5aR, 8aR, 8bS)-2, 2, 7, 7-tetramethyltetrahydro-3aHbis[1,3]dioxolo[4, 5- b:4', 5'-d] pyran- 3a-yl) methyl sulfamate, according to claim 1, characterized in that the compounds necessary for the synthesis of the drug are defined as follows, between amount and substance, being: 10 g of chenodeoxycholic acid; 1.05 eq of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate (HBTU); 1.05 eq of β alanine benzyl ester hydrochloride; 2.1 eq diisopropylethylamine (DIPEA); 100 ml anhydrous dimethyl formamide (DMF); 90 ml of ether; 180 ml sodium bicarbonate solution (2.5% weight/volume); 90 ml of 0.1N hydrochloric acid (HCI); 90 ml brine (water saturated with salt); 50 ml anhydrous THF; 7.3 eq of 2-(chlorocarbonyloxy)acetic acid; 8 ml dry pyridine; 50 ml of chloroform; 150 ml of sodium hydroxide (NaOH); 37% hydrochloric acid; 140 ml ethyl acetate (EtOAc); 20 L anhydrous dichloromethane (DCM); 10 eq of oxalyl chloride (OxCl) solution Qsp* anhydrous Tetrahydrofuran (THF); 2.1 eq of (BUP) 50 ml of ethyl acetate; Qsp* of Acetone; Toluene Qsp*; 25 ml of methanol; 0.3% acetic acid; 30 ml anhydrous DMF; 1.05 eq HBTU; 1.05 eq of DIPEA; and 1.05 eq of ((3aS,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-3aHbis[1,3]dioxolo[4,5-b:4',5'-d]pyran -3a-yl)methyl sulfamate (TOP). 3. Process for obtaining 3α,7α-bis(4-(tert-butyl(1-(4-chlorophenyl)-1-oxopropan-2-yl)amido)bis(oxomethylene)bis(oxy)diacetic acid)-chenodeoxycholate -e—alanyl- ((3aS, 5aR, 8aR, 8bS)-2, 2, 7, 7-tetramethyltetrahydro-3aHbis[1, 3]dioxolo[4, 5- b:4', 5'-d] pyran- 3a-yl) methyl sulfamate, according to claims 1 and 2, characterized by the association of chenodeoxycholic acid to 2-(1 H-benzotriazol-1-yl)-1, 1,3, 3-tetramethyluronium hexafluorophosphate (H BTU ) and β-alanine-benzyl ester hydrochloride, processed until obtaining chenodeoxycholate - β-alanine amide benzyl ester, with anhydrous THF containing 2-(chlorocarbonyl oxy)-acetic acid and dry pyridine being added, processed until obtaining the pure compound 3 α, 7 α-bis (oxomethylene) bis (oxy) diacetic acid- chenodeoxycholate- β -alanine amide benzyl ester (72% yield), which was dissolved in anhydrous dichloromethane (DCM) until 3α -7α- was obtained bis(4-tert-butyl(1-(4-chlorophenyl)-1-oxopropan-2-yl)amido)bis(oxy)diacetic acid ico) chenodeoxycholate-β-alanine amide benzyl ester (25% yield), dissolved in methanol and processed to obtain the pure compound 3α, 7α-bis (4-tert-butyl( 1-( 4-chlorophenyl) 1-oxopropan-2 -il)amido)bis(oxomethylene)bis(oxy)diacetic acid)-chenodeoxycholate-β-alanine amide which was dissolved in anhydrous DMF together with HBTU and DIPEA and processed to obtain 3α, 7α-bis 4-tertbutyl (1-(4-chlorophenyl)-1-oxopropan-2-yl)amide )bis(oxomethylene)bis(oxy)diacetic acid)-chenodeoxycholate-β-alanyl-((3aS,5aR,8aR,8bS)-2 ,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4',5(d]pyran-3a-yl)methyl sulfamate. 4. Process for obtaining 3α,7α-bis(4-(tert-butyl(1-(4-chlorophenyl)-1-oxopropan-2-yl)amido)bis(oxomethylene)bis(oxy)diacetic acid)-chenodeoxycholate -e—alanyl- ((3aS, 5aR, 8aR, 8bS)-2, 2, 7, 7-tetramethyltetrahydro-3aHbis[1, 3]dioxolo[4, 5- b:4', 5'-d] pyran- 3a-yl) methyl sulfamate, according to claims 1, 2 and 3, characterized by the association of chenodeoxycholic acid with 2-(1H-benzotriazol-1-ylj-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) and to the hydrochloride of {β-alanine-benzyl ester together with diisopropylethylamine DIPEA) that after dissolving and stirring the solution, this is left at room temperature for 24 hours; after this period, the reaction is blocked; the resulting suspension is extracted and the combined organic extracts are washed; the ethereal solution is dried, filtered and concentrated until obtaining chenodeoxycholate-{ β -alanine amide benzyl ester (92% yield). 5. Process for obtaining 3α,7α-bis(4-(tert-butyl(1-(4-chlorophenyl)-1-oxopropan-2-yl)amido)bis(oxomethylene)bis(oxy)diacetic acid)-chenodeoxycholate -e—alanyl- ((3aS, 5aR, 8aR, 8bS)-2, 2, 7, 7-tetramethyltetrahydro-3aHbis[1, 3]dioxolo[4, 5- b:4', 5'-d] pyran- 3a-yl) methyl sulfamate, according to claim 4, characterized by the addition of anhydrous THF containing 2-(chlorocarbonyloxy)-acetic acid and dry pyridine, the resulting suspension is left in reaction for 18 hours at room temperature and then dried ; the yellowish oil obtained is dissolved in chloroform, extracted with distilled water and 1 N sodium hydroxide (NaOH); the combined aqueous extracts were placed in an ice bath and acidified with 37% hydrochloric acid with vigorous stirring; the resulting white precipitate, after filtration of the solution, is dissolved in ethyl acetate (EtOAc), dried over anhydrous sodium sulfate, filtered and concentrated until obtaining the pure compound 3α, 7α-bis (oxomethylene) bis (oxy) diacetic acid - chenodeoxycholate-β-alanine amide benzyl ester (72% yield). 6. Process for obtaining 3α,7α-bis(4-(tert-butyl(1-(4-chlorophenyl)-1-oxopropan-2-yl)amido)bis(oxomethylene)bis(oxy)diacetic acid)-chenodeoxycholate -e—alanyl- ((3aS, 5aR, 8aR, 8bS)-2, 2, 7, 7-tetramethyltetrahydro-3aHbis[1, 3]dioxolo[4, 5- b:4', 5'-d] pyran- 3a-yl) methyl sulfamate, according to claims 3 to 5, characterized by dissolution in anhydrous dichloromethane (DCM) and to this solution is added a solution of oxalyl chloride (OxCl), the mixture was left for 18 hours at temperature environment and the obtained solution is concentrated until resulting in a brownish oil, which was triturated with a mixture of ether and hexane in a bath of dry ice and acetone, decanting the supernatant until the occurrence of olidification (precipitation); the yellowish solid is dissolved in anhydrous tetrahydrofuran (THF) and added to an ice-cold solution containing (BUP) in THF, in the presence of the DMF catalyst; after this step, the obtained solution is concentrated, dissolved in ethyl acetate and extracted with 1N sodium hydroxide, distilled water and brine; the organic solution is left on anhydrous sodium sulfate, filtered and evaporated under reduced pressure and the product obtained is purified using a mixture of chloroform, acetone, toluene as mobile phase, obtaining 3α, 7α-bis(4-tert-buty/ (1-(4-chlorophenyl)-1-oxopropan-2-yljamido)bis(oxy)diacetic acid)-10 chenodeoxycholate-β-alanine amide benzyl ester (25% yield) as an off-white powder. 7. Process for obtaining 3α,7α-bis(4-(tert-butyl(1-(4-chlorophenyl)-1-oxopropan-2-yl)amido)bis(oxomethylene)bis(oxy)diacetic acid)-chenodeoxycholate -e—alanyl- ((3aS, 5aR, 8aR, 8bS)-2, 2, 7, 7-tetramethyltetrahydro-3aHbis[1, 3]dioxolo[4, 5- b:4', 5'-d] pyran- 3a-yl) methyl sulfamate, according to claims 3 and 6, characterized by dissolution in methanol, and this mixture is left in a hydrogen atmosphere at 52 psig at room temperature for 16 hours; the suspension is filtered and the resulting solution is evaporated; the product obtained is purified using a mixture of chloroform, acetone, toluene with acetic acid; the combined pure fractions are evaporated in the presence of carbon tetrachloride to remove excess acetic acid (HAc), until obtaining the pure compound 3α, 7α -bis(4-tert-butyl(1-(4-chlorophenyl)-1-oxopropan- 2 -yl)amido)bis(oxomethylene)bis(oxy)diacetic acid)-chenodeoxycholate-β-alanine amide, as a white amorphous solid. 8. Process for obtaining 3α,7α-bis(4-(tert-butyl(1-(4-chlorophenyl)-1-oxopropan-2-yl)amido)bis(oxomethylene)bis(oxy)diacetic acid)-chenodeoxycholate -e—alanyl- ((3aS, 5aR, 8aR, 8bS)-2, 2, 7, 7-tetramethyltetrahydro-3aHbis[1, 3]dioxolo[4, 5- b:4', 5'-d] pyran- 3a-yl) methyl sulfamate, according to claims 3 and 7, characterized by the dissolution of anhydrous DMF, together with HBTU and with DIPEA; after stirring at room temperature, ((3aS,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxo/o[4,5-b:4',5' -d]pyran-3a-yl)methyl sulfamate (TOP) is added and the resulting solution is left to react at room temperature for 24 hours; after this period, the reaction is "blocked" by adding water and the product is extracted with EtOAc; the combined organic extracts are washed with sodium bicarbonate solution (2.5% weight/volume), water and brine; the organic solution is dried over anhydrous sodium sulfate, filtered and concentrated to obtain 3a, 7a-bis(4-tertbutyl/(1-(4-chlorophenyl)-1-oxopropan-2-yl)amido)bis(oxomethylene) bis(oxy)diacetic acid)-chenodeoxycholate-{ β-alanyl((3aS, 5aR, BaR, BbS)-2, 2, 7, 7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b :4', 5'd]pyra n-3a-yl) methyl/sulfamate.