WO2008098329A2

WO2008098329A2 - Pharmaceutical composition, pharmaceutical product, obtaining processes of pharmaceutical compounds and use of such compounds for treating erectile dysfunction

Info

Publication number: WO2008098329A2
Application number: PCT/BR2008/000041
Authority: WO
Inventors: Emerson Ferreira Queiroz
Original assignee: Aché Laboratórios Farmacêuticos S/A
Priority date: 2007-02-13
Filing date: 2008-02-13
Publication date: 2008-08-21
Also published as: AR065339A1; WO2008098329A4; BRPI0705772A; WO2008098329A3; WO2008098329A8

Abstract

The present invention generally relates to a process to obtain a compound and a standardized pharmaceutical product from parts of plants of genre Erythroxylum (Erythroxylum vacciniifolium Mart), in the form of isolated extracts, or enriched moieties, or pure compounds, or obtained by synthesis, used isolatedly or in mixture with other natural or synthetic products, in different ratios, comprising pharmaceutical compositions to be used by suitable routes (topic or oral) particularly presented in the form of tablets, capsules, dies, emulsions, W/O and 0/0 (creams and gels), liposomes, microcapsules, nanoparticles, sprays, slurries and the like, used for treating the erectile dysfunction.

Description

"PHARMACEUTICAL COMPOSITION, PHARMACEUTICAL PRODUCT, OBTAINING PROCESSES OF PHARMACEUTICAL COMPOUNDS AND USE OF SUCH COMPOUNDS FOR TREATING ERECTILE DYSFUNCTION"

The present invention generally relates to the obtention of a compound and a standardized pharmaceutical product from roots, stems, skins and leaves of plants of genre Erythroxylum (family Erythroxylaceae) , like species Erythroxylum vacclniifolium Mart (= Erythroxylum catuaba) , popularly known as catuaba. This product is obtained in the form of enriched moieties or extracts or isolated pure compounds, or obtained by synthesis or semi-synthesis. It can be used isolatedly (pure extracts) or mixed to other natural or synthetic products, in different ratios, to comprise pharmaceutical compositions to be used by suitable routes (topic or oral) particularly in presentations like tablets, capsules, dies, emulsions, W/O and 0/0 (creams and gels), liposomes, microcapsules, nanoparticles, sprays, slurries and the like, used for treating erectile dysfunction. Background of the Invention

Sexual impotency (in nomenclature modern the term erectile dysfunction is used) and defined as the inability to achieve or sustain proper erection to satisfactory allow intercourse. The erectile dysfunction is a problem with global dimensions affecting in several degrees more than 150 million men in the world. In some men, there are clinical manifestations mostly related to hormonal dysfunctions generally related to the process of aging, although the range of manifestations may include a great variability of other diseases. Such changes are responsible for a decrease in the production of some hormones, including the growth hormone, dehydroepiandrosterone (DHEA, adrenopause) , and of particular interest, testosterone (adrenopause or partial androgen which decreases at man aging) . These hormonal changes are closely related to sexual dysfunctions, as libido, erection, and sometimes to ejaculation problems, particularly the decrease of volume and intensity of the ejaculated.

The sexual stimulation by visual imagination, auditive, tactile, olfactory, or any other erotic stimulation, leading to the release of nitric oxide (NO) by noradrenergic and norcolinergic neurons (NANC) . Originally named endothelial derived relaxing factor, currently NO is the most important physiologically vasoactive molecule in all cardiovascular system. Also acting in the cavernous body function, wherein it locally causes the muscle relaxation, it consequently causes erection. Oxide nitric activates guanylate cyclase, which induces cleavage of guanosine triphosphate^' to 3', 5' -cyclic guanosine monophosphate (3',5'~ cGMP) . The muscle relaxing effect of NO is mediated by this second messenger (cGMP) . Cyclic GMP which activates protein kinase G (PKG) , with phosphorilated proteins also called "maximus" potassium channels. Which results in an increase of intracellular flow of potassium ions (K⁺) and consequently a hyperpolarization, leading to the inhibition or blocking dependent of the voltage of the channels of calcium (Ca++), decreasing thus the calcium intracellular. Intracellular decrease of the calcium ions suppresses the activity of the "myosin light chain (MLC) kinase" and consequently decreases the intracellular contents of the MLC dephosphorylated, allowing cell relaxation of the smooth muscle. It is therefore established that the nitric oxide and the cyclic guanosine monophosphate are important transmitters in the process of erection. In terms physiological, the levels of 3',5'-cGMP are permanently directed to inactive form 5'-GMP by enzyme phosphodiesterase (PDE5) .

The adenosine cyclic monophosphataded (cAMP) , is considered the second messenger in the mechanism of erection, having a role inferior when compared the cGMP. When erection occurs, a vasoactive intestinal polypeptide

(VIP) is released in the parasympathetic nervous terminals

(NANC), similarly to the case of nitric oxide release. Both,

NO and VIP, are collocated in the respective nervous terminals NANC and are simultaneously released with sexual stimulation. The vasoactive intestinal polypeptide (VIP) activates the binding membrane of the cyclic adenine promoting the cleavage of adenosine triphosphate to 3',5'- cAMP . The cAMP activates the protein kinase A, with phosphorylation of adjacent proteins, resulting in an increase of the flow of potassium ions (K+) and hyperpolarization. In return, the same biochemical chain is activated as presented by 3',5'-cGMP.

In addition to the mentioned mechanisms, other important biological routes may induce or inhibit the erection. Particularly, the activation of the system nervous sympathetic, which occur, for example, with the action of the anxiety, results in the inhibition of the erection. As the sympathetic tone increases, norepinephrine is released in adrenergic alpha-1 receptors located in the cell of the smooth muscle tissue of the cavernous body. The norepinephrine activates the binding membrane of phospholipase C, which induces cleavage between phosphoinositol diphosphate and inositol triphosphate and diacetylglycerol . Either inositol triphosphate or diacetylglycerol cause an increase of intracellular Ca++, leading to the activation of the MLC kinase leading to activation of MLC phospholipase. This leads to contraction of the cell of the smooth muscle preventing the erection. Furthermore, the compounds with vasoactive action, as the endothelin 1, angiotensin II and tromboxane A2, which have the property of contracting the cell of the smooth muscle, also may interfere in the relaxation of the muscle and prevent the erection.

There is a great variety of options for treating the erectile dysfunction, including inhibitors oral of the type 5 phosphodiesterase (PDE5) , dopamine agonists, blocking agents of the alpha receptors, in addition to intraurethral and intracavernous vasodilator, as prostaglandins El (PGEl) , and aprostadil or papaverin and phentolamine for intracavernous injections, instruments for vacuum erection and penis prosthesis, as shown in Table 1 below.

Table 1

The performed studies verified the extracts obtained from plants of genre Erythroxylum, as species Erythroxylum vacciniifolium, and their isolated compounds and moieties presented dilatating effect of the human cavernous body in performed in vitro tests. Thus, the development of suitable processes for the industrial production and which result in a standardized pharmaceutical product for use as medicament in the treatment of erectile dysfunction is desired.

Still, from state of the art, documents JP2003095860. JP2001322941 and JP2004292368, JP2003192605 mention the use of the extract of species Erythroxylum vacciniifolium but in cosmetic anti-aging compositions and as agent against obesity, respectively.

Description of the Invention

The researches were initially performed from data obtained by etnopharmacological surveys about plants used in Brazilian popular medicine, empirically said to present properties for fighting erectile dysfunction. Then phytochemical and pharmacological studies were performed with alkaloidic extracts of the upper parts of more than 30 plants, among which, a number of species of genre Erythroxylum. By means of these screenings it has been observed that the extract of roots, stems and leaves of species Erythroxylum vacciniifolium present pharmacological activity. These data corroborate with the use of catuaba in traditional medicine as aphrodisiac and stimulant. For developing chemical and pharmacological studies of alkaloidic extracts of upper parts of species Erythroxylum vacciniifolium, the extracts were obtained the following way: The species Erythroxylum vacciniifolium, used for obtaining the alcoholic, hydroalcoholic and aqueous extracts, were collected from 1995 to 2002 in the States of the Paraiba, Pernambuco and Ceara. The flowered exsicates of the specimens, separately, were deposited in the collections of the New York Botanical Garden and identified by Dr. Douglas C. Daly.

The extracts of the roots, leaves and of the upper parts of the plants, separately, were performed by means of protocol described below. A certain amount, 840 g, of the collected material, was dried is cooled in liquid nitrogen and then powdered. The powder obtained by the process was wetted with NH₄OH, concentrated exhaustively and extracted three times with 3L of CHCI₃ during the period of 24 h in stirring constant at room temperature. After the filtration the extracts of CHC13 were removed by vacuum evaporation at maximum temperature of 35⁰C and freeze-dried. The yields of the alkaloidic extracts are shown in Table 2. Table 2

Material Extracts Solvent Time Temperature Yield

Stem 84Og CHCl₃ (3 X 3L) 24 h RT 15.74 g

Roots 50Og CHCl₃ (3 X 3L) 24 h RT 10 g

Leaves 50Og CHCl₃ (3 X 3L) 24 h RT 5 g

Purification of the alkaloidic extracts of the leaves and of the upper parts of the plants, separately, was performed with 10 g of the extract by MPLC using in the eluent system a mixture of MeCN and H₂O with 2 mM of triethylamine (Et3N) in gradient way (5% to 100% in 3 days) . The products were detected by UV at 254 nm. The moieties obtained were subjected to numerous chromatographic techniques as MPLC, HPLC leading to the compound isolation of alkaloid 24 as shown below.

' Alkaloidic extract

Structures of the studied compounds were elucidated by electroscopic means including ultraviolet (UV) , nuclear magnetic resonance (NMR ID and 2D) , low and high resolution mass spectrometry (MS and HRMS) , as well as, reactions of chemical derivatization. Therefore, 19 new tropanic alkaloids were isolated from the alkaloidic extract of the plant, including catuabines D and I, and their vacinines derivatives A and B. The structures of the tropanic alkaloids identified from the species E. vacciniifolium were entirely identified and may be verified below:

MpC

=

Compound R¹ R^z R^J R" Other

2 3- H OH H

3 H Mpc OH (α) H N O

4 Hdmb Mpc OH H

5 - H H OMpc N 0

6 Mpc H OH H

7 H Mpc OH H

8 H Mpc OH (α) H

9 Hdmb Mpc H H

11 OH (β) Mpc H H

12 Mpc H H H

13 H Mpc H H

14 - H H OMpC

15 H - H OMpc

18 Mpc Mpc H H N 0

20 Mpc Pc H

21 Mpc Mpc H

22 Mpc Pc H H

23 Mpc Mpc H 42 Mpc Mp c H H -

All compounds have a tropane nucleus tropanic mono-, di- or tri-esterifled by a pyrrol group, N- methylpyrrol, COCH2Ph-3' -OH, COPh-3'-OH. Some tropanic alkaloids have an N-oxide group. Extracts, moieties and isolated compounds were subjected to biological essay on the relaxation of the human cavernous body. The test consists of the recovery of the human cavernous body (HCB) during change-of-sex surgeries. The tissue is immediately placed in cool Krebs solution with heparinized Krebs solution. Followed by washing, the HCB is placed in Krebs solution at 4⁰C, in the presence of ice. The In vitro test is performed in dissected laminae of about 2 cm diameter. The laminae are suspended in 2 mL of Krebs solution heated at 37⁰C and oxygenated. Each lamina is connected to a power isometric transductor, wherein tension is continuously obtained using a polygraph. Sildenafil was used as positive control. Four compounds were identified as being actives, among which two compounds 22 and 24, presented 100% of relaxation of the HCB at concentrations similar to Sildenafil (12.5 μg/mL) . Whereas compounds 21 and 23 presented the same activity at concentrations of 50 μm/mL. The activity of the compounds isolated from the extracts of E. vacciniifolium are shown in the Table 3 below: Table 3

^concentration responsible for 100 of dilatation.

Their respective molecular structures are:

In a first aspect, the present invention relates to a production process of a pharmaceutical product from standardized extracts, moieties or molecules isolated from plants of genre Erythroxylum, as species Erythroxylum vacciniifolium, for using as medicament in the treatment of erectile dysfunction. The production process according to the present invention comprises the steps of: (a) The biomass which comprises one or more parts of plants of genre Erythroxylum, as well as roots, stems, skins, and leaves; green or dried, and powdered, or ground, or in pieces or branny; the starting material can comprise, without any limitation, the species Erythroxylum vacciniifolium;

(b) The biomass obtained by process (a) is extracted by percolation, or maceration, or Soxlet or using gases in supercritical state, or extraction using basic or acid media; the extraction can be achieved with aqueous, or acidic or basic media or using organic solvents; the organic solvents are, for example, and without any limitation, halogenated solvents, alcohols, aldehydes, ketones, cycloalkane or alkane, ethers, phenols, esters, benzenes and derivatives, alone or mixtures thereof; and in the case of an acid/base extraction, the extraction can be achieved with strong or weak acids, diluted or concentrated, alone or in mixtures, such as acetic acid, hydrochloric acid, formic acid, and the base used in the extraction process comprises concentrated or diluted bases, alone or in mixtures as, for example, the ammonium hydroxide (NH₄OH) and sodium carbonate (Na₂CO₃) ;

(c) The extract obtained can be dried with spray dryer, with inlet temperature between 150-190⁰C, and outlet temperature between 60-90⁰C, or the reduced pressure, with temperature between 25-75⁰C, or room temperature;

(d) The extract is purified by chromatographic techniques giving as result, at least one of the alkaloids in free form or in the form of salts, such as, chlorates, sulphates, borates, of chemical structure (I),

wherein R¹, R², R³, R⁴, are the same or different and each one is independently selected from the group consisting of H, OH, CH3, COCH3, metals alkaline, halogens, monosaccharides, disaccharides or polysaccharides, CO(CH₂)_nCH₃, (CH₂) _I1CH₃ (wherein n varies from 2 to 16) and also N-pyrrol (Pc), N-methylpyrrol (Mpc) , COCH₂Ph-₃-OH and Hdmb, according to the structures shown as follows.

During the separation process of the semisynthetic compounds chromatographic techniques shall be used with or without pressure, such as chromatography at atmospheric pressure, chromatography at low, medium or high pressure, using normal stationary phase as silica gel or reverse phase as C-8 or C-18, or liquid/liquid partition as upstream chromatography, or centrifugal partition, or using ion exchange resins or filtration membranes. Using as mobile phase, in aqueous media or using organic solvents as, for example, and without any limitation, alcohols, aldehydes, ketones, cycloalkane or alkane, phenols, alone or mixtures thereof .

The process according to the present invention allows the production in industrial scale, once it reduces the time of process, presents suitable yield and results in a pharmaceutical product with standardized amount in tropanic alkaloids.

The medicament according to the present invention contains about 0.001 to 99 % of at least one of the alkaloids in free form or in the form of salts, such as, chlorates, sulphates and borates, of chemical structure (I) .

The pharmaceutical product obtained in accordance with the present invention is useful either to be administered directly to a patient or to be used in preparing pharmaceutical compositions, in dosages ranging from about 0.001 to about 5000 mg/kg/day, particularly about 200 to about 400 mg/kg/day, divided in one or more times a day. In another aspect, the present invention relates to pharmaceutical compositions containing about 0.001 mg to about 5000 mg of the extract, as well as pharmaceutically accepted excipients. Pharmaceutically accepted excipients suitable for the invention are, for example, and without any limitation, those mentioned in the following literature: Remington's Pharmaceutical Sciences, Mack Publishing, European Pharmacopoeia, Brazilian Pharmacopoeia, and new excipients to be developed.

The pharmaceutical compounds and the pharmaceutical compositions according to the present invention are efficient in the treatment of erectile dysfunction.

The present invention also relates to a production process of a pharmaceutical product obtained by semi- synthesis from the extracts of plant species of genre Erythroxylum, as Erythroxylum vacclniifollum, for use as medicament in the treatment of erectile dysfunction. The chemical reactions and products of said process may be verified below:

-Extracts

(a) The biomass which comprises one or more parts of plants of genre Erythroxylum, as well as roots, stems, skins, and leaves; green or dried, and powdered, or ground, or in pieces or branny; the starting material can comprise, without any limitation, the species Erythroxylum vacclniifolium;

(b) The biomass obtained by process' (a) is extracted by percolation, or maceration, or Soxlet or using gases in supercritical state, or extraction using basic or acid media; the extraction can be achieved with aqueous, or acidic or basic media or using organic solvents; the organic solvents are, for example, and without any limitation, halogenated solvents, alcohols, aldehydes, ketones, cycloalkane or alkane, ethers, phenols, esters, benzenes and derivatives, alone or mixtures thereof; and in the case of an acid/base extraction, the extraction can be achieved with strong or weak acids, diluted or concentrated, alone or in mixtures, such as acetic acid, hydrochloric acid, formic acid, and the base used in the extraction process comprises concentrated or diluted bases, alone or in mixtures as, for example, the ammonium hydroxide (NH₄OH) and sodium carbonate (Na₂CO₃) ;

(c) The extract obtained can be dried with spray dryer, with inlet temperature between 150-190⁰C, and outlet temperature between 60-90⁰C, or the reduced pressure, with temperature between 25-75 °C, or room temperature;

(d) The extract obtained is subjected to a Hydrolysis using an acid solution under reflux (50-100⁰C); (e) The solution is then cooled;

(f) The solution comprising the tropanic alkaloids is added from basic to neuter pH using a concentrated or diluted basic solution; (g) The recovery of the tropanic alkaloids is achieved with a liquid/liquid extraction using aqueous, or acidic or basic media or organic solvents, alone or mixtures thereof; (h) The solution containing the tropanic alkaloids is dried under reduced pressure between 20-95⁰C;

(i) The organic partition containing the tropanic alkaloids is subjected to an esterification reaction with N- methylpyrrol acid or methylpyrrol acid chlorides. The organic partition containing alkaloids is dried and weighted, and then, transferred to a flask, wherein in suitable conditions pyridine and N-methylpyrrol acid chloride are added under stirring and inert atmosphere gas as, for example, nitrogen, argon or helium; (j) The reaction is purified by chromatographic techniques resulting in at least one of the alkaloids in free form or in the form of salts such as chlorates, sulphates, borates, of chemical structure (Ia) , wherein R¹, R², R³, R⁴, are the same or different and each one is independently selected from H, OH, N-pyrrol, N-methylpyrrol.

(Ia)

During the separation process of the semisynthetic compounds chromatographic techniques shall be used with or without pressure, such as chromatography at atmospheric pressure, chromatography at low, medium or high pressure, using normal stationary phase as silica gel or reverse phase as C-8 or C-18, or liquid/liquid partition as upstream chromatography, or the centrifugal partition, or using ion exchange resins or filtration membranes. Using as mobile phase, in aqueous media or organic solvents as, for example, and without any limitation, alcohols, aldehydes, ketones, cycloalkane or alkane, phenols, alone or mixtures thereof.

The present invention also relates to a production process of a pharmaceutical product by semi-synthesis from scopolamine, for using as medicament in the treatment of erectile dysfunction. The chemical reactions and products of such process may be verified below:

(I) Hydrolysis, specific extraction, purification. (I ⁽a ) Esterification with N-methyl pyrrolic acid

(Ua) Esterification with pyrrolic acid

The present invention comprises the following steps : (a) Scopolamine is solved in an acid aqueous solution with pH from 2.5-3.5; comprising, without any limitation, scopolamine in its free form or in the form of salts, as, for example, hydrochloride, borate and sulphate salts . (b) The solution is subjected to hydrolysis under reflux at temperature between 60-100⁰C;

(c) After 2-4 h the acid solution is cooled until room temperature, and the recovery of the tropanic alkaloids can be achieved with organic solvents as, for example, alcohols, aldehydes, ketones, cycloalkane or alkane, phenols, ethers, esters, alone or mixtures thereof;

(d) The organic solution containing the alkaloids of the free tropanic nucleus is dried under reduced pressure, with temperatures of 25-75°C or by spray-drier, with inlet temperature of 150-190⁰C and outlet temperature of 80-90⁰C;

(e) The organic partition containing the tropanic alkaloids is subjected to a reaction of esterification with N-methylpyrrol acid or methylpyrrol acid chlorides. The organic partition containing alkaloids is dried and weighted, and then, transferred to a flask, wherein in suitable conditions pyridine and N-methylpyrrol acid chloride are added under stirring and atmosphere of inert gas as, for example, nitrogen, argon or helium ; (f) The reaction is purified by chromatographic techniques giving as result, at least one of the alkaloids in free form or in the form of salts (as chlorates, sulphates, borates) of chemical structure (Ib) , wherein Ri, R₂, R₃ are the same or different and each one is independently selected from H, OH, N-pyrrol, N-methylpyrrol, wherein n varies from 2 to 16.

During the separation process of the semi- synthetic compounds chromatographic techniques shall be used with or without pressure, such as chromatography at atmospheric pressure, chromatography at low, medium or high pressure, using normal stationary phase as silica gel or reverse phase as C-8 or C-18, or liquid/liquid partition as upstream chromatography, or the centrifugal partition, or using ion exchange resins or filtration membranes. Using as mobile phase, in aqueous media or organic solvents as, for example, and without any limitation, alcohols, aldehydes, ketones, cycloalkane or alkane, phenols, alone or mixtures thereof.

The present invention also relates to a production process of a pharmaceutical product obtained by semi- synthesis from the 6β-hydroxy-hiosciamine, for using as medicament in the treatment of erectile dysfunction. The chemical reactions and products of such process may be verified below: (I) Hydrolysis, specific extraction, purification.

do Esterification with N-methyl pyrrolic acid or pyrrolic acid

This process comprises the following steps:

(a) The 6β-hydroxy-hiosciamine is solved in an aqueous acid solution with pH between 1.0 and 3.5; the starting material may comprise without any limitation, the 6β-hydroxy-hiosciamine, in its free form or in the form of salt, as, for example, the salts of hydrochloride, borate and sulphate;

(b) The solution is subjected to hydrolysis under reflux at temperature from 60° to 100⁰C; (c) The solution is cooled;

(d) The solution which contains the tropanic alkaloids is added from basic until neuter pH using a basic concentrated or diluted solution;

(e) The recovery of the tropanic alkaloids among which the 3, 6-dihydroxy-tropanol and achieved with a liquid/liquid extraction using aqueous media or organic solvents as, for example, and without any limitation, alcohols, aldehydes, ketones, cycloalkane or alkane, phenols, alone or mixtures thereof; (f) The solution is dried by media of a system at reduced pressure, with temperatures comprised between 25- 75⁰C, or by spray-dryer, the inlet temperature between 150- 190⁰C and outlet temperature between 80-900C, or at room temperature;

(g) The organic partition containing the tropanic alkaloids is subjected to the reaction of esterification with N-methylpyrrol acid or methylpyrrol acid chlorides. The organic partition containing alkaloids is dried and weighted, and then, transferred to a flask, wherein in suitable conditions pyridine and N-methylpyrrol acid chloride are added under stirring and atmosphere of inert gas as, for example, as the nitrogen, argon or helium; h) The solution is purified by chromatographic techniques giving as result, at least one of the alkaloids of chemical structure (Ic) : wherein R¹, R² are the same or different and each one is independently selected from H, OH, N-pyrrol, N methylpyrrol.

The present invention also relates to a production process of a pharmaceutical product obtained by synthesis from the 3-hydroxy-tropanol, or 3, 6-dihydroxytropanol, or 3, 7-dihydroxytropanol, or 3, 6, 7-trihydroxy-tropanol, to obtain derivatives used as medicament in the treatment of erectile dysfunction. The chemical reactions of such process and products of such process may be verified below:

{1} Esterificatioπ with N-methyl pyrrolio acid or pyrrolio acid

This process comprises the following steps:

(a) The 3-hydroxy-tropanol, or 3,6- dihydroxytropanol, or 3, 7-dihydroxytropanol, or 3,6,7- trihydroxy-tropanol is weighted and solved in a organic solvent anhydrous; the starting material can comprise without any limitation scopolamine in its free form or in the form of salt as, for example, the salts of hydrochloride, borate and sulphate;

(b) The organic partition containing the tropanic alkaloids is subjected to a reaction of esterification with N-methylpyrrol acid or methylpyrrol acid chlorides. The organic partition containing alkaloids is dried and weighted, and then, transferred to a flask, wherein in suitable conditions pyridine and N-methylpyrrol acid chloride are added under stirring and atmosphere of inert gas as, for example, as the nitrogen, argon or helium;

(c) The solution is dried by means of a system at reduced pressure, with temperatures comprised between 25-

100⁰C, or spray-dryer, with inlet temperature between 150- 190⁰C and outlet temperature between 80-900C, or the room temperature;

(d) The reaction is purified by chromatographic techniques giving as result, at least one of the alkaloids of chemical structure (Id) : wherein R¹, R², R³ are the same or different and each one is independently selected between H, OH, N-pyrrol, N-methylpyrrol.

It is presented, as follows, merely expositive examples of particular realizations of the present invention, without creating any limitations to its scope.

Example 1: Methodology employed to obtain the alkaloidic extract.

In an extractor sink with a mechanical stirring, add 1.5 kg of leaves or upper parts of plants of genre Erythroxylum, as Erythroxylum vacciniifolium, dried in drying oven with controlled temperature at 60⁰C and ground in electric grinder. Then, add 50 mL of NH₄OH. After this process, add 9 L of CHCI₃, with frequent stirring, for a period of 70 to 150 hours, vacuum filter the extract by means of a lOOμm filter. After evaporation of the solvent in rotatory evaporator with reduced pressure, it is obtained concentrated alkaloidic extract, in average, 20 g of extract. Example 2: Methodology employed to obtain tropanic alkaloids by semi-synthesis from the alkaloidic extract of Erythroxylum vacciniifolium.

In a IL flask add 15g of alkaloidic extract obtained from plants of genre Erythroxylum, as Erythroxylum vacciniifolium. Then add 500 mL of a solution of 2N HCL, increase the solution to reflux during 4 h at a temperature of 70°C. After cooling the solution is basified to a basic pH using a concentrated NH₄OH solution. The aqueous solution will then be extracted with 2 x 3L of CH₂CI₂. The organic solution containing the tropanic alkaloids is dried under reduced pressure between 20-95⁰C. After this process, free tropanic alkaloids (8g) are esterified with a solution of pyridine/ N-methylpyrrol acid chloride (4OmL: 4OmL) under stirring and atmosphere of inert gas during 8 h. After the indicated period of time the reaction mixture is evaporated at reduced pressure at 80 °C, 3.6 g of the dried mixture obtained by the reaction of esterification is purified by chromatography at medium pressure (MPLC) using as eluent system a mixture of MeCN and H₂O with 2 mM of triethylamine

(Et3N) in gradient way (5% to 100% in 3 days) , and a stationary phase to reverse phase (Lichroprep C18, 15-25 μm,

Merck) in a column of 460 mm width to 70 mm diameter. The compounds were detected by ultraviolet at 254 nm. The moieties obtained were subjected to numerous chromatographic techniques as MPLC, HPLC, leading to the isolation of 3 major alkaloids, identified by classical techniques of structural elucidation including ultraviolet, nuclear magnetic resonance (NMR) and mass spectrometry (MS) as desired; 3α (l-methyl-lH-pyrrol-2-yl-carbonyloxy) tropane referred to as compound 1; 3α, 6β-di (1-methyl-lH pyrrol-2-yl- carbonyloxy) tropane referred to as compound 2, 3 α, 6 β,7 β -tri (l-methyl-lH-pyrrol-2-yl-carbonyloxy) tropane referred to as compound 3.

Example 3: Methodology employed to obtain tropanic alkaloids by semi-synthesis from scopolamine.

In a IL flask, add 1Og of scopolamine (98%) Then add 500 mL of a solution of 2N HCL, increase the solution to reflux during 4 h at a temperature of 7O⁰C. After cooling the solution it is basifies until a basic pH using a concentrated NH₄OH solution. The aqueous solution will be then extracted with 2 x 3L of CH₂CI₂. The organic solution containing the tropanic alkaloids is dried under reduced pressure between 20-95⁰C. After this process, the free tropanic alkaloids are esterified with a solution of pyridine/N-methylpyrrol acid chloride (5OmL: 5OmL) under stirring and atmosphere of inert gas during 8 h. After the indicated period of time the reaction mixture is evaporated at reduced pressure at 8O⁰C, 4,5 g of the mixture dried obtained by reaction of esterification is purified by chromatography at medium pressure (MPLC) using as eluent system a mixture of MeCN et H₂O with 2 Mn of triethylamine

(Et3N) in gradient way (5% to 100% in 3 days), and a stationary phase to reverse phase (Lichroprep C18, 15-25 a,

Merck) in a column of 460 mm of width by 70 mm of diameter.

The compounds were detected by ultraviolet at 254 nm. The obtained moieties were subjected to numerous techniques chromatography as MPLC, HPLC, leading to the isolation of 2 major alkaloids, identified by classical techniques of structural elucidation including ultraviolet, nuclear magnetic resonance (NMR) and mass spectrometry (MS) as desired; 3α, ββ, 7β-tri (l-methyl-lH-pyrrol-2-yl-carbonyloxy) tropane referred to as compound 1, 3α, 6β, 7βtri (1-methyl-lH- pyrrol-2-yl-carbonyloxy) tropane referred to as compound 26 Example 4 : Methodology employed to obtain tropanic alkaloids by semi-synthesis from the 6β-hydroxy hiosciamine .

In a IL flask add 1Og of 6β-hydroxy hiosciamine

(90%) Then add 500 mL of a solution of 2N HCL, increase the solution to reflux during 4 h at a temperature of 70⁰C. After cooling the solution is basified to a basic pH using a concentrated NH₄OH solution. The aqueous solution will be then extracted with 2 x 3L of CH₂CI₂. The organic solution containing the tropanic alkaloids (3, 6-dihydroxy-tropanol) is dried under reduced pressure between 20-95⁰C. After this process, the free tropanic alkaloids are esterified with a solution of pyridine/N-methylpyrrol acid chloride (50 mL:50 mL) under stirring and atmosphere of inert gas during 8 h. After the indicated period of time the reaction mixture is evaporated at reduced pressure at 8O⁰C, 5 g of the dried mixture obtained by reaction of esterification is purified by chromatography at medium pressure (MPLC) using as eluent system a mixture of MeCN and H₂O with 2 Mn of triethylamine (Et3N) in gradient way (5% to 100% in 3 days) , and a stationary phase to reverse phase (Lichroprep C18, 15-25 μm, Merck) in a column of 460 mm of width by 70 mm of diameter detection by ultraviolet at 254 nm. The moiety was evaporated leading to the isolation of a major alkaloid, identified by classical techniques of structural elucidation including ultraviolet, nuclear magnetic resonance (NMR) and mass spectrometry (MS) as being the 3α, 6β-di (1-methyl-lH- pyrrol-2-ylcarbonyloxy) tropane.

Example 5 : Methodology employed to obtain tropanic alkaloids by synthesis from the 3, 6-di-hydroxytropanol . In a flask of IL add 5g of 3, 6-di-hydroxytropanol (90%), add a solution of pyridine/N-methylpyrrol acid chloride (50 mL: 5OmL) under stirring and atmosphere of inert gas during 8 h. After the indicated period of time the reaction mixture is evaporated at reduced pressure at 80⁰C, 5 g of the dried mixture obtained by reaction of esterification is purified by chromatography at medium pressure (MPLC) using as eluent system a mixture of MeCN et H2O with 2 Mn of triethylamine (Et3N) in gradient way (5% to 100% in 3 days) , and a stationary phase to reverse phase

(Lichroprep C18, 15-25 a, Merck) in a column of 460 mm of width by 70 mm of diameter detection by ultraviolet at 254 nm. The moiety was evaporated leading to the isolation of a major alkaloid, identified by classical techniques of structural elucidation including ultraviolet, nuclear magnetic resonance (NMR) and mass spectrometry (MS) as being 3α, ββ-di (l-methyl-lH-pyrrol-2-yl-carbonyloxy) tropane.

Claims

1. Pharmaceutical composition comprising alkaloid compounds, in their free form or as salts pharmaceutically accepted, obtained by synthesis, semi-synthesis or isolated from the alcoholic, hydroalcoholic, aqueous or organic extracts of one or more parts of plants of genre Erythroxylum.

2. Pharmaceutical composition, according to claim 1, wherein such alkaloids are of the tropanic group.

3. Pharmaceutical composition, according to claim 1, wherein such compound has following the general chemical structure:

, which may contain one or more radicals R, wherein R¹, R², R³, R⁴, are the same or different, and each one is independently selected between H, OH, CH₃, COCH3, metals alkaline, halogens, sugars, CO(CH₂)_I1CH₃, (C^)_nCH₃ , which may also be: N-pyrrol (Pc)

N-methylpyrrol (Mpc) Hdmb,

in the free form or a pharmaceutically acceptable salt, wherein n varies from 2 to 16.

4. Pharmaceutical composition, according to claims 1 and 3, wherein the compounds are in the form of pharmaceutically acceptable salts as, for example, chlorates, sulphate or borates.

5. Pharmaceutical composition, according to claim 1, wherein the starting material comprises the species Erythroxylum vacciniifolium (= E. catuaba) .

6. Pharmaceutical composition, according to claim 1, comprising 0.001 to 99% of the extract in weight of composition total weight .

7. Pharmaceutical composition, according to claim 1, comprising about 0.001 to about 5000 mg of the alkaloidic extract.

8. pharmaceutical composition, according to claim 1, wherein the compounds are used isolatedly or in mixtures thereof or combined with the extracts, fixed oils, essential oils, fragrances, powders or excipients from other natural or synthetic sources, or used under combined form with drug(s), vitamin (s), salt(s), sugar (s) or other pharmaceutically accepted excipients, suitable for oral, topic, injectable or inhalable application.

9. Pharmaceutical composition, according to claim 8, comprising.001% to 99.% of one or more compounds.

10. Pharmaceutical composition, according to claim 1, wherein said composition is encapsulated in hard gelatin capsule or in soft gelatin capsule.

11. Pharmaceutical product wherein said product is presented in the form of pure extract or combined, in the form of tablets, capsules, dies, syrups and the like or in the form of emulsions W/O and 0/0 (creams and gels) , liposomes, microcapsules, nanoparticles, aerosols, spray, slurries and the like, injectable liquids, powders, freeze- dried, patches, as well as formulations for controlled release implants, or the like used as adjuvants and other synthetic or natural pharmaceutically accepted carriers.

12. Pharmaceutical product, comprising a pharmaceutical composition, according to claim 1, which is a phytodrug, a phytotherapic, or synthetic medicament.

13. Process for obtaining a phytotherapic pharmaceutical compound wherein said compound may be obtained by the following ways: (a) from standardized extracts, moieties or molecules of plants of species E. vacciniifolium; (b) by semi-synthesis from the extracts of plants of species E. vacciniifolium; (c) by semi-synthesis from scopolamine, (d) by synthesis from 3-hydroxy-tropanol, or 3, β-dihydroxy-tropanol, 3, 7-dihydroxy-tropanol, or 3,6,7- trihydroxytropanol and (and) by semi-synthesis from 6β- hydroxy-hiosciamine .

14. Process for obtaining the pharmaceutical compound, according to claim 13, comprising in items (a) and (b) the following steps:

(a) Spraying, or grinding, or slicing or branning one or more parts of plants of genre Erythroxylum, as well as, roots, stems, skins, and leaves; green or dried;

(b) Extraction of the compounds by percolation, or maceration, or Soxlet, or using gases in supercritical state, using basic or acid media, or in aqueous media, or using organic solvents, alone or mixtures thereof.

15. Process for obtaining the pharmaceutical compound, according to claim 14, wherein the extraction in step (b) is achieved with strong or weak, diluted or concentrated acids, as in mixtures, as, for example, the acetic acid, the hydrochloridic acid, the formic acid and the base used in the extraction process comprises concentrated or diluted bases, alone or in mixtures as for example, the ammonium hydroxide (NH₄OH) and sodium carbonate (Na₂CO₃) .

16. Process for obtaining the pharmaceutical compound, according to claim 14, wherein the extraction in step (b) uses an organic solvent comprising halogenated compounds, alcohols, aldehydes, ethers, esters, ketones, alkane, cycloalkane, phenolic compounds, benzenes and derivatives, alone or mixtures thereof.

17. Process for obtaining the pharmaceutical compound, according to claim 13 wherein the concentration of the organic solution is performed by means of a system at reduced pressure, or spray-dryer, or at room temperature.

18. Process for obtaining the pharmaceutical compound, according to claim 17, wherein inlet and outlet temperatures, of the process of concentration by spray- dryer, is between 150-190⁰C and 80-90°C respectively.

19. Process for obtaining the pharmaceutical compound, according to claim 17, wherein the temperature of the system at reduced pressure is from 25-100⁰C.

20. process for obtaining the pharmaceutical compound, according to claim 13, wherein organic partition containing the tropanic alkaloids, in processes (b) , (c ), (d) , and (e) , is subjected to the a reaction of esterification with N-methylpyrrol acid or methylpyrrol acid chlorides and then pyridine and N-methylpyrrol acid chloride are added under stirring in inert atmosphere.

21. Process for obtaining the pharmaceutical compound, according to claim 13, wherein scopolamine and 6β- hydroxy-hiosciamine, in processes (c) and (e) respectively, are solved in an acid solution at pH 1.0-3.5.

22. Process for obtaining the pharmaceutical compound, according to claim 13, wherein 3-hydroxytropanol, or 3, 6-dihydroxy-tropanol, 3, 7-dihydroxy-tropanol or 3,6,7- trihydroxytropanol, in item (d) , are solved in an anhydrous organic solvent.

23. Process for obtaining the pharmaceutical composition, according to claim 13, comprising in processes (b) , (c) and (and) , a step of hydrolysis under reflux.

24. Process for obtaining the composition pharmaceutical, according to claim 23 wherein reflux temperature is between 50° and 100⁰C.

25. Process for obtaining the pharmaceutical compound, according to claim 13, wherein the solution which contains the tropanic alkaloids, in processes (b) and (e) , is basified to neuter pH using a concentrated or diluted basic solution.

26. Process for obtaining the pharmaceutical compound, according to claim 13, wherein separation and purification of the compounds are performed by chromatographic techniques with or without pressure, as for example, chromatography at atmospheric pressure, chromatography at low, medium or high pressure, using normal stationary phase as silica gel or reverse phase as C-8 or C- 18, or liquid/liquid partition as upstream chromatography, or the centrifugal partition, or using ion exchange resins or filtration membranes.

27. Process for obtaining the pharmaceutical compound, according to claim 26, wherein said process results in at least one of the alkaloids in free form or in the form of salts, of chemical structure I, containing one or more radicals R¹, R², R³, R⁴, being the same or different and each one being independently selected from H, OH, CH3, C0CH3, alkaline metals, halogens, monosaccharides, disaccharides or polysaccharides, CO (CH₂) _nCH₃, (CHa)_nCH₃ and also N-pyrrol (Pc), N~methylpyrrol (Mpc) , COCH₂Ph-3-OH and Hdrαfa.

28. Process for obtaining the pharmaceutical compound, according to claim 13, wherein starting compounds, in processes (c) , (d) and (e) , are in their free form or in the form of salts.

29. Pharmaceutical composition used in the treatment of erectile dysfunction comprising one or more compounds obtained by one or more of the processes of claim 13, in their free form or salts pharmaceutically accepted.

30. Use of a pharmaceutical composition isolatedly or in mixture thereof at different ratios or in mixture with other natural or synthetic products, in different ratios, wherein said composition integrates pharmaceutical compositions to be used by suitable routes (topic, oral, injectable) particularly presented in the form of tablets, capsules, dies, emulsions, The/The and The/The (creams and gels), liposomes, microcapsules, nanocapsules, sprays, slurries and the like, used for treating the erectile dysfunction.