WO2012007619A1 - Method for producing water-soluble derivatives of 20(s)-camptothecin as antitumor agents - Google Patents

Abstract

The present invention relates to a novel method for synthesizing a series of water-soluble derivatives of camptothecin that act as antitumor agents, which can be used within the field of the pharmaceuticals industry as drugs for curing, halting or palliating tumours or cancer, such as cancer of the uterus.

Description

 Process for obtaining water soluble derivatives of

 20 (S) Camptothecin as antitumor agents

The present invention relates to a new method of synthesis of a series of water soluble derivatives of camptothecin, which act as antitumor agents, with application within the scope of the pharmaceutical industry as drugs for curing, stopping or alleviating tumors or cancer, such Like uterine cancer

STATE OF THE PREVIOUS TECHNIQUE

Despite being one of the most potent antitumor agents known, 20- (S) -Camptothecin (CPT), has a great limitation at the level of clinical development since it has a minimum water solubility (2.5 ig / mL) .

The CPT is a pentacyclic alkaloid isolated for the first time by Wall et al. (J. Am. Chem. Soc, vol. 88 (16), pp. 3888-90, 1966) from a tree of Chinese origin (Campoteca acuminatá) in 1966. Due to the presence of a hydroxylated lactone ring in the alkaloid structure, under physiological pH conditions, a balance is established between the form of "lactone-closed" and "carboxylate-open" in the CPT. The first invitro trials demonstrated extraordinary cytotoxic activity in a wide spectrum of tumor lines, however the clinical trials, carried out with the soluble form of the carboxylate in the form of sodium salt, were interrupted due to the high and unpredictable toxicity that the drug presented next to a substantial loss of antitumor activity.

The conclusion obtained confirmed the need to keep the lactone form unchanged and to solubilize the compound by chemical substitutions capable of not altering the cytotoxic activity of the CPT. In recent years, different strategies focused on the development of soluble CPT analogues have been developed, however, only Topotecan and Irínotecan have been approved for clinical use in ovarian, colon and certain types of lung cancer.

Topotecan (Hycamtin ^® ), [20- (S) -9-dimethylaminomethyl-10-hydroxycamptothecin] is a semi-synthetic derivative that incorporates a basic chain at position 9 of the quinolinic ring of 10-Hydroxycamptothecin which allows the drug to be solubilized in hydrochloride form. The obtaining of Topotecan is widely studied and has different variants, although all of them imply a Manních reaction between 10-hydroxycoatotecine, dimethylamine and formalin in an acidic medium, obtaining the final product in a clearly viable yield. However, neutropenia, thrombocytopenia and hemorrhagic cystitis are some of the side effects of the compound.

The Mannich reaction has allowed to obtain numerous soluble analogs of CPT based on the reactivity of primary or secondary amines of different size, nature and polarity. However, there are no publications or studies that present synthetic routes alternative to the Mannich reaction, simple and with acceptable yields, when obtaining water-soluble aminomethyl Camptothecin derivatives substituted at position 9.

For the synthesis of said 9-aminomethyl derivatives of the CPT, different synthetic routes have been developed as shown in US5004758 A, EP0321122 A2 or in US5734056 (A), J. Med, Chem, 1991, 34, 98-107, through which these derivatives are obtained in procedures with at least 4 stages and also the yields are quite low and economically unprofitable.

Therefore it is necessary to develop new routes of synthesis of this type of compounds with such high anti-tumor activity, but in which the number of stages of synthesis is significantly reduced and obtain with at least reasonable yields so that they can be used for the development of new anti-tumor drugs.

DESCRIPTION OF THE INVENTION

The present invention relates to a new and surprising method of synthesis of 9-aminomethyl camptotecine derivatives that act as antitumor agents, with application within the scope of the pharmaceutical industry, as drugs to cure, stop or alleviate tumors or cancer, such as cancer of the epithelial type, for example and without limitation, uterine cancer.

By means of the present synthesis procedure, the stages of said synthesis are significantly reduced, passing from 4 to 2 stages and considerably increasing the yields of obtaining the derivatives, reaching yields of 80%, which makes said synthesis to be feasible and economically viable for the development of new drugs or pharmaceutical compositions comprising said CPT derivatives.

While the Mannich reaction allows the direct obtaining of CPT derivatives with secondary and tertiary amines in its structure, the methodology described in the present invention allows the introduction of the methyl amino unit, at position 9 of the CPT, in the form of a primary amine, obtaining in this way one of the structurally most similar derivatives to Topotecan.

Therefore the present invention relates to a method of synthesis of 9-aminomethyl camptothecin of general formula (I)

o cualquiera de sus sales, isómeros o solvatos. que comprenden las siguientes etapas: a) reaccionar un compuesto de fórmula general (II) con un compuesto de fórmula general (III):

or any of its salts, isomers or solvates. comprising the following steps: a) reacting a compound of general formula (II) with a compound of general formula (III):

b) reacting the compound of formula (IV) obtained in the previous stage with a compound of general formula (V) in the presence of an alcohol or reacting the compound of formula (IV) obtained in the previous stage under acidic conditions, aqueous acidic or aqueous acid solutions, to obtain the 9-aminomethyl compounds derived from the CPT:

where

R ¹ and R ⁴ are the same or different and are independently selected from hydrogen or a C C alkyl group,

R ² is selected from the list comprising hydrogen, a Crdo alkyl, C ₂ -Ci ₀ alkenyl, C ₂ -C ₁₀ alkynyl, -COR ¹¹ , -COOR ¹² , aryl or heterocyclic group,

^R3 is selected from the list comprising an alkyl group C1-C10 alkyl , C ₂ -C ₁₀ alkynyl, C ₂ -C _10, -NR ⁹ R ^10, -COR ^11, -COOR ^12, aryl, heterocycloalkyl or joined R ² formed a heterocycloalkyl,

R ⁵ , R ⁶ , R ⁷ and R ⁸ are the same or different, and are independently selected from hydrogen or a C ₁ -C ₁₀ alkyl group,

R ⁹ , R ¹⁰ and R ¹² , are the same or different, and are independently selected from hydrogen or a C ₁ -C- ₁₀ alkyl group, and R ^{1 1} is selected from the list comprising hydrogen, C1-C10 alkyl or aryl.

The term "alkyl" refers, in the present invention, to radicals of hydrocarbon chains, linear or branched, having 1 to 10 carbon atoms, preferably 1 to 4, and which are attached to the rest of the molecule by a single bond, for example, methyl, ethyl, n-propyl, / -propyl, n-butyl, tere-butyl, sec-butyl, n-pentyl, n-hexyl, etc. The alkyl groups may be optionally substituted by one or more substituents such as halogen, hydroxyl, alkoxy, carboxyl, carbonyl, cyano, acyl, alkoxycarbonyl, amino, nitro, mercapto and alkylthio.

The term "alkenyl" refers to radicals of hydrocarbon chains, linear or branched, having 2 to 10 carbon atoms, preferably 2 to 4, and containing one or more double carbon-carbon bonds, for example, vinyl, 1-Propenyl, allyl, isoprenyl, 2-butenyl, 1, 3- butadiene, etc. Alkenyl radicals may be optionally substituted by one or more substituents such as halo, hydroxy, alkoxy, carboxyl, cyano, carbonyl, acyl, alkoxycarbonyl, amino, nitro, mercapto and alkylthio.

The term "alkynyl" refers to radicals of hydrocarbon chains, linear or branched, having 2 to 10 carbon atoms, preferably 2 to 4, and containing one or more triple carbon-carbon bonds, for example 1 - propynyl, 2-butynyl, 1,3-butadiinyl, etc.

The term "aryl" refers in the present invention to an aromatic carbocyclic chain, having from 6 to 12 carbon atoms, which may be single or multiple ring, for example a phenyl, naphthyl, indenyl, phenanthryl or anthracil radical. The aryl radical may be optionally substituted by one or more substituents such as alkyl, haloalkyl, aminomethyl, dialkylamino, hydroxyl, alkoxy, phenyl, mercapto, halogen, nitro, cyano and alkoxycarbonyl. The term "heterocycloalkyl" refers, in the present invention, to a stable monocyclic or bicyclic radical of 3 to 15 members, which is unsaturated, saturated or partially saturated, and consisting of carbon atoms and at least one heteroatom selected from the group consisting of nitrogen, oxygen or sulfur. Preferably it has 4 to 8 members with one or more heteroatoms and more preferably 5 to 6 members with one or more heteroatoms. For the purpose of this invention the heterocycle may be a monocyclic, bicyclic or tricyclic system, which may include fused rings. The nitrogen, carbon and sulfur atoms of the heterocyclic radical may optionally be oxidized; The nitrogen atoms may optionally be quaternized and the heterocyclic radical may be partially or fully saturated or aromatic. Examples of heterocycles may be, but are not limited to: azepines, indols, imidazoles, isothiazoles, thiaadiazoles, furan, tetrahydrofuran, benzimidazole, benzothiazole, piperidine, piperazine, purine, quinoline.

In a preferred embodiment, R ¹ and R ⁴ are the same or different and are independently selected from H or C 1 -C 4 alkyl.

In another preferred embodiment, R ¹ and R ⁴ are independently selected from H or C1-C2 alkyl.

In another preferred embodiment R ¹ is hydrogen. According to another preferred embodiment R ⁴ is hydrogen. According to another preferred embodiment R ⁴ is an ethyl group. According to another preferred embodiment R ⁴ is a methyl group. In another preferred embodiment, R ² is hydrogen. In another embodiment, R ³ is a C1-C10 alkyl chain. According to a preferred embodiment R ³ is a methyl group.

According to another preferred embodiment, R ³ is attached to R ² forming a heterocycloalkyl group of general formula (VI):

 (VI) where X is selected from a C3-C5 alkyl group or a carbonyl group (-CO).

In another preferred embodiment the heterocycloalkyl group of the general formula (VI) is selected from the list comprising pyrrolidinone, maleimide, succinimide, hydantoin, glutaridime, urazole and N- (hydroxymethyl) phthalimide, preferably pyrrolidinone, maleimide, or phthalimide and more preferably N - (hydroxymethyl) phthalimide.

In another preferred embodiment R ⁵ , R ⁶ , R ⁷ and R ⁸ are hydrogen.

In another preferred embodiment, the compound of general formula (I) is selected from:

 -20 (S) -10-Hydroxy-9-aminomethylcamptothecin

 -20 {S) -7-Ethyl-10-Hydroxy-9-aminomethylcamptothecin; or

 -20 (S) -7-Methyl-10-Hydroxy-9-aminomethylcamptothecin.

In another preferred embodiment, the compound of general formula (I) is selected from: -20 {S) -10-Hydroxy-9-aminomethylcamptothecin

 -20 {S) -7-Ethyl-10-Hydroxy-9-aminomethylcamptothecin.

In another preferred embodiment, the compound of general formula (II) is selected from:

 -20 (S) -10-Hydroxycamptothecin;

 -20 (S) -7-Ethyl-10-Hydroxycamptothecin; or

 -20 (S) -7-Methyl-10-Hydroxycamptothecin.

Preferably the compound of general formula (II) is selected from:

-20 (S) -10-Hydroxycamptothecin; or

 -20 (S) -7-Ethyl-10-Hydroxycocysteine.

In another preferred embodiment, the compound of general formula (IV) is selected from:

- 20 (S) -10-Hydroxy-9-Phthalamidomethylcamptothecin;

 - 20 (S) -7-Ethyl-10-Hydroxy-9-Phthalamidomethylcamptothecin; or

 - 20 (S) -7-Methyl-10-Hydroxy-9-Phthalamidomethylcamptothecin.

Preferably the compound of general formula (V) is hydrazine.

In another preferred embodiment step (a) is carried out under standard conditions of the Tscherniac-Einhorn reaction.

In the present invention, in the second stage, in which the compound of general formula (IV) reacts with the compound of general formula (V), alcohol is understood as any hydroxyalkyl chain of 1 to 6 carbon atoms, as per example and without limitation methanol or ethanol.

Alternatively, the second stage can be carried out in acidic medium without the compound of general formula (V), by standard conditions, for example of HCI or dilutions thereof with alcohols or water.

The compounds of the present invention represented by formula (I) may include isomers, depending on the presence of multiple bonds (eg, Z, E), including optical isomers or enantiomers, depending on the presence of chiral centers. The individual isomers, enantiomers or diastereoisomers and mixtures thereof fall within the scope of the present invention, that is, the term isomer also refers to any mixture of isomers, such as diastereomers, racemic, etc., even their optically isomers. assets or mixtures in different proportions thereof. The individual enantiomers or diastereoisomers, as well as mixtures thereof, can be separated by conventional techniques.

The compounds of the invention may be in crystalline form as free compounds or as solvates. In this sense, the term "solvate", as used herein, includes both pharmaceutically acceptable solvates, that is, solvates of the compound of formula (I) that can be used in the manufacture of a medicament, as pharmaceutically acceptable solvates, which may be useful in the preparation of pharmaceutically acceptable solvates or salts. The nature of the pharmaceutically acceptable solvate is not critical as long as it is pharmaceutically acceptable. In a particular embodiment, the solvate is a hydrate. Solvates can be obtained by conventional solvation methods known to those skilled in the art.

Finally, according to another preferred embodiment, the compound of general formula (I) is in the form of a pharmaceutically acceptable salt selected from the group consisting of acetates, methane sulphonates, mono or dihydrochlorides, or alkali metal salts such as sodium, potassium. For application in therapy, the compounds of formula (I), their salts, isomers or solvates, will preferably be found in a pharmaceutically acceptable or substantially pure form, that is, having a pharmaceutically acceptable level of purity excluding pharmaceutical additives. normal such as diluents and carriers, and not including material considered toxic at normal dosage levels. The purity levels for the active ingredient are preferably greater than 50%, more preferably greater than 70%, and still more preferably greater than 90%. In a preferred embodiment, they are greater than 95% of the compound of formula (I), or of its salts, isomers or solvates.

The synthesis process presented in the present invention shows optimal yields for industrial development and possible scaling processes.

Throughout the description and the claims the word "comprises" and its variants are not intended to exclude other technical characteristics, additives, components or steps. For those skilled in the art, other objects, advantages and features of the invention will be derived partly from the description and partly from the practice of the invention. The following examples are provided by way of illustration, and are not intended to be limiting of the present invention.

EXAMPLES

The invention will now be illustrated by tests carried out by the inventors, which shows the specificity and effectiveness in obtaining the compounds of formula (I) of the present invention.

The examples described below represent some of the derivatives included in the present invention as well as their preparation methodology. 1) Synthesis of (20S) -10-Hydroxy-9-aminomethylcamptothecin hydrochloride in acidic conditions.

a) Obtaining 20 (S) -10-Hydroxy-9-phthalamidomethylcamptothecin

N- (Hydroxymethyl) phthalamide (00mgrs, 0.56mmol) was gradually added to a continuously stirred solution of 10-Hydroxycamptothecin (204mgrs, 1 eq) in concentrated sufuric acid at 0 ° C, the reaction was followed by TLC and added water and ice when considered finished. The precipitated reaction crude was kept in a refrigerator for 12 hours, then filtered and dried in vacuo.

The solid obtained can be considered pure enough to be used later, obtaining 261 mgrs (0.498 mmol)

Yield: 89%. H-NMR (300 MHz; DMSO-d ₆ ) δ: 0.87 (t, 3H, -CH ₃ , J = 7.4 Hz); 1 .82-1 .90 (m, 2H, -CH ₂ ); 5.23 (s, 2H, -CH ₂ -N); 5.26 (s, 2H, CH ₂ -17); 5.41 (s, 2H, -CH ₂ -5); 6.48 (s, 1 H, -OH); 7.26 (s, 1 H, H-14); 7.45 (d, 1 H, 1 Ar, J = 9.2Hz, H-1 1); 7.82 (s, 4H, -Ftal-4); 8.01 (d, 2H, 1 Ar, J = 9.1 Hz, H-12); 8.87 (s, 1 H, 1 Ar, H-7); 10.48 (s, 1 H, -OH). ³ C NMR (300 MHz, DMSO) δ- 8.12, 30.61, 33.51, 50.68, 65.622, 72.75, 1 13.64, 1 18.60, 122.65, 123.36, 126.55, 129.06, 130.19, 130.99, 131 .90, 134.77, 143.64, 146.13 , 149.34, 150.40, 155.65, 157.20, 167.94, 172.87.

20 (S) -10-Hydroxy-9-phthalimidomethylcamptothecin (75mgrs, 0.14mmol), in 8mL of EtOH, 4ml_ of water and 5ml_ of concentrated HCI was refluxed for 4 hours and subsequently concentrated to dryness. After the addition of water and filtration, the solution was concentrated. A 5% HCI / MeOH solution is added, the product precipitating in the form of hydrochloride after precipitation with ether. The product is collected by filtration and dried until a constant weight of 49mgrs (0.1 1 immoles) of an intense yellow solid is obtained.

Yield: 78%. ¹ H-NMR (300 MHz; D ₂ O) δ: 0.90 (t, 3H, -CH ₃ , J = 7.3 Hz); 1.88 (q, 2H, -CH ₂ , J _{1 =} = 7.4 Hz, J ₂ = 15 Hz); 4.50 (s, 2H, -CH ₂ N); 4.89 (s, 2H, -CH ₂ - 5), 5.26 (d, 1 H, -CH _2> J = 16 Hz, H-22a); 5.34 (d, 1 H, -CH _2> J = 16 Hz, H-22b); 7.21 (s, 1 H, H-14), 7.30 (d, 1 H, 1 Ar, J = 9.3 Hz, H-1 1); 7.71 (d, 1 H, 1 Ar, J = 9.3, H-12); 8.52 (s, 1 H, 1 Ar, H-7). ¹³ C NMR (300 MHz; D ₂ 0) δ: 7.34, 31 .03, 34.02, 50.82, 66.10, 73.92, 98.72, 1 10.97, 1 18.46, 122.70, 126.20, 128.14, 129.88, 131 .12, 142.80, 145.09 , 148.33, 150.95, 156.03, 157.86, 175.01.

2) Synthesis of (20S) -10-Hydroxy-9-aminomethylcamptothecin hydrochloride with hydrazine.

20 {S) -10-Hydroxy-9-phthalimidomethylcamptothecin 53mgrs (0.1 mmol), obtained according to example 1 a), was maintained for 4 hours at reflux of ethanol with 0.5ml of 65% hydrazine. After cooling the solution is concentrated to dryness and chromatographed (eluent: CH ₂ Cl ₂ : MeOH: TEA 100: 5: 2). The product obtained is concentrated to dryness and dissolved in 5% methanolic hydrochloric acid, the desired product (31 mgrs, 0.07mmol, R = 72%) being precipitated as a salt described in example 1)

3) Synthesis of (20S) -7-Ethyl-10-Hydroxy-9-aminomethylcamptothecin hydrochloride.

b) Obtaining 20 (S) -7-Ethyl-10-Hydrox¡-9-phthalimidomethylcamptothecin.

N- (Hydroxymethyl) phthalamide (60 mgrs, 0.34mmol) was added gradually over a stirring solution of 20 (S) -7-Ethyl-10-Hydroxycamptothecin (133mgrs, 1 eq) in sulfuric acid concentrated at 0 ° C , the reaction was followed by TLC and water and ice was added when it was considered finished. The precipitated reaction crude was kept in a refrigerator for 12 hours, then filtered and dried in vacuo.

The resulting solid was separated and purified by flash elution chromatography (eluent: CH ₂ CI ₂ : CH ₃ OH 100: 5) to obtain 180 mgrs. (0.33mmol).

Yield: 97% ¹ H-NMR (300 MHz; DMSO-d ₆ ) δ: 0.88 (t, 3H, -CH ₃ , J = 7.3 Hz); 1.41 (t, 3H, -CH ₃ , J = 7.5 Hz); 1 .82-1 .91 (m, 2H, -CH ₂ -); 5,031 (s, 2H, -CH ₂ -N- ); 5.36 (s, 2H, CH ₂ -17); 5.43 (s, 2H, -CH ₂ -5); 6.52 (s, 1 H, -OH); 7.25 (s, 1H, H-14); 7.40 (d, 1H, 1Ar, J = 9.2Hz, H-11); 7.80 (s, 4H, -Ftal-4); 8.01 (d, 2H, 1Ar, J = 9.2Hz, H-12); 10.46 (s, 1 H, -OH). ¹³ C NMR (300 MHz, DMSO) δ- 7.72, 13.71, 25.81, 30.19, 36.46, 65.24, 72.38, 95.70, 113.83, 118.04, 121.15, 122.80, 128.71, 130.71, 131.50, 132.21, 134.31, 144.18, 145.07, 146.31 , 148.12, 150.07, 156.14, 156.81, 167.54, 172.53.

20 (S) -7-Ethyl-10-Hydroxy-9-phthalamidomethylcamptothecin (92mgrs, 0.16mmols), in EtL of EtOH, 4mL of water and 5mL of concentrated HCI was refluxed for 5 hours and subsequently concentrated to dryness. After the addition of water and filtration, the solution was concentrated. A 5% HCI / MeOH solution is added, the product precipitating in the form of hydrochloride after precipitation with ether. The product is collected by filtration and dried until a constant weight of 61 mgrs (0.13 mmol) of an intense yellow solid is obtained.

Yield: 81%. H-NMR (300 MHz; D ₂ 0) δ: 0.95 (t, 3H, -CH ₃ , J = 7.3 Hz); 1.55 (t, 3H, -CH ₃ , J = 7.3 Hz); 1.89-1.98 (m, 2H, -CH ₂ -); 3.1-3.19 (m, 2H, -CH ₂ -); 4.65 (wide s, 2H, -CH ₂ N); 4.96 (s, 2H, -CH ₂ -5.); 5.35 (d, 1H, -CH ₂ , J = 16Hz, H-22a); 5.49 (d, 1H, -CH ₂ , J = 16Hz, H-22b); 7.19 (s, 1H, H-14); 7.32 (d, 1H, 1Ar, J = 9.2 Hz, H-11); 7.69 (d, 1H, 1Ar, J = 9.2Hz, H-12). ¹³ C NMR (300 MHz; D ₂ 0) δ: 7.44, 13.66, 26.38, 31.09, 36.81, 50.57, 66.19, 73.97, 98.36, 111.380, 118.53, 121.39, 127.72, 130.78, 132.51, 144.47, 144.92, 146.00, 147.62 , 151.22, 157.06, 158.10, 175.00.

Claims

one . Synthesis procedure of the compound of general formula (I)

 or any of its salts, isomers or solvates. comprising the following steps: a) reacting a compound of general formula (II) with a compound of general formula (III):

b) reacting the compound of formula (IV) obtained in the previous stage, with a compound of general formula (V) in the presence of an alcohol or reacting the compound of formula (IV) obtained in the previous stage under acidic conditions, acid solutions alcoholic or aqueous acids, to obtain the 9-aminomethyl compounds derived from the CPT:

where R ¹ and R ⁴ are the same or different and are independently selected from hydrogen or a C _r Ci ₀ alkyl group; R ² is selected from the list comprising hydrogen, a d-C10 alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -Ci ₀ alkynyl, -COR ¹¹ , -COOR ² , aryl or heterocyclic group; R ³ is selected from the list comprising a C ₁ -C ₁₀ alkyl, C ₂ -Ci ₀ alkenyl, C ₂ -C ₁₀ alkynyl, -NR ⁹ R ¹⁰ , -COR ¹¹ , -COOR ¹² , aryl, heterocycloalkyl or bonded to R ² formed a heterocycloalkyl; R ⁵ , R ⁶ , R ⁷ and R ⁸ are the same or different, and are independently selected from hydrogen or a C- _1- C ₁₀ alkyl group; R ⁹ , R ¹⁰ and R ¹² , are the same or different, and are independently selected from hydrogen or a C1-C10 alkyl group, and R ¹¹ is selected from the list comprising hydrogen, C ₁ -C- ₁₀ alkyl or aryl. 2. The process according to claim 1, wherein R ¹ is selected from H or CrC ₄ alkyl. 3. The process according to claim 2, wherein R ¹ is selected from H or C-C ₂ alkyl. 4. The process according to claim 3, wherein R ¹ is hydrogen. 5. The process according to any of claims 1 to 4, wherein R ² is hydrogen. 6. The process according to any of claims 1 to 4, wherein R ³ is a Ci-C ₁₀ alkyl group. 7. The process according to claim 6, wherein R ³ is a methyl group. 8. The process according to any one of claims 1 to 5, wherein R ³ is attached to R ² forming a heterocycloalkyl group of general formula (VI):

 (VI) where: X is selected from a C3-C5 alkyl group or a carbonyl group (-CO). 9. The method according to claim 8, wherein the heterocycloalkyl group of the general formula (VI) is selected from the list comprising pyrrolidinone, maleimide, succinimide, hydantoin, glutaridime, urazole, or N- (hydroxymethyl) phthalamide. 10. The process according to claim 9, wherein the heterocycloalkyl group of general formula (VI) is selected from pyrrolidinone, maleimide, or N- (hydroxymethyl) phthalamide. 11. The process according to claim 10, wherein the heterocycloalkyl group of general formula (VI) is N- (hydroxymethyl) phthalamide. 12. The process according to any of claims 1 to 11, wherein R ⁴ is selected from H or C _r C ₄ alkyl. 13. The process according to claim 12, wherein R ⁴ is selected from H or C1-C2 alkyl. 14. The process according to claim 13, wherein R ⁴ is hydrogen. 15. The process according to claim 13, wherein R ⁴ is an ethyl group. 16. The process according to claim 13, wherein R ⁴ is a methyl group. 17. The process according to any one of claims 1 to 16, wherein R ⁵ , R ⁶ , R ⁷ and R ⁸ are hydrogen. 18. The process according to any one of claims 1 to 17, wherein the compound of general formula (I) is selected from:  -20 {S) -10-Hydroxy-9-aminomethylcamptothecin;  -20 (S) -7-Ethyl-10-Hydroxy-9-aminoomethylcamptothecin; or  -20 (S) -7-Methyl-10-Hydroxy-9-aminomethylcamptothecin. 19. The process according to claim 18, wherein the compound of general formula (I) is selected from:  -20 (S) -10-Hydroxy-9-aminomethylcamptothecin; or  -20 (S) -7-Ethyl-10-Hydroxy-9-aminomethylcamptothecin. 20. The process according to any of claims 1 to 19, wherein the compound of general formula (II) is selected from:  -20 (S) -10-Hydroxycamptothecin;  -20 (S) -7-Ethyl-10-Hydroxycamptothecin; or  -20 {S) -7-Methyl-10-Hydroxycamptothecin. 21. The process according to claim 20, wherein the compound of general formula (II) is selected from:  -20 {S) -10-Hydroxycamptothecin; or  -20 (S) -7-Ethyl-10-Hydroxycanthothecin. 22. The process according to any of claims 1 to 21, wherein the compound of general formula (IV) is selected from:  - 20 (S) -10-Hydroxy-9-Phthalamidomethylcamptothecin;  - 20 (S) -7-Ethyl-10-Hydroxy-9-Phthalamidomethylcamptothecin; or - 20 (S) -7-Methyl-10-Hydroxy-9-Phthalamidomethylcamptothecin. 23. The process according to any one of claims 1 to 22, wherein the compound of general formula (V) is hydrazine. 24. The method according to any of claims 1 to 23, wherein step (a) is carried out under standard conditions of the Tscherniac-Einhorn reaction. 25. The process according to any one of claims 1 to 24, wherein step (b) of the process is carried out only with the compound of general formula (V) in acidic medium. 26. The process according to any one of claims 1 to 25 wherein the compound of general formula (I) is in the form of a pharmaceutically acceptable salt selected from the group consisting of acetates, methane sulphonates, mono or dihydrochlorides, or alkali metal salts like sodium, potassium.