ES2378927B1 - PROCEDURE FOR PREPARATION OF LAPACHOL AND DERIVATIVES. - Google Patents

Abstract

Preparation procedure for lapachol and derivatives # Synthesis procedure for lapachol and its derivatives of formula I where the meanings for the different substituents are those indicated in the description.

Description

Preparation procedure for lapachol and derivatives.

The present invention relates to a method of synthesizing lapachol and its derivatives, and the present invention also relates to obtaining 1-lapachone and a-lapachone.

STATE OF THE TECHNIQUE

Lapachol is a naphthoquinone that was first isolated by E. Paterno from Tabebuia avellanedae in 1882. The interest of lapachol lies in the wide variety of therapeutic applications in which its activity has been demonstrated, such as, antiulcer, anticancer , anti-anemic, anti-inflammatory, antimalarial, antiseptic, anticancer, antiviral, bactericidal, fungicidal and virucidal.

Numerous syntheses of lapachol have been described as well as two derivatives thereof, 1-lapachone and alapachona. Not only lapachol, but also its derivatives, a- and 1-lapachone possess an important pharmacological activity. In particular, 1-lapachone has anti-angiogenic, anti-inflammatory and, especially, anti-tumor activity, having achieved phase II clinical trials for prostate cancer, being active on its own or in combination with other antitumor drugs (genistein, taxol).

None of the described synthesis of lapachol exceeds 45% overall yield (see for example pages 154 to 156 of the article by Hidayat Hussain et al., ARKIVOC 2007 (ii) 145-171 and the references cited therein).

Therefore, it would be desirable to provide a more efficient process for preparing lapachol, 1-lapachone and a-lapachona with a performance superior to that described to date and with less environmental impact.

DESCRIPTION OF THE INVENTION

One aspect of the invention relates to a process of synthesis of the compounds of formula I comprising a reaction step between a compound of formula II and a compound of formula III:

each R1, R2, R3 and R4 independently represent hydrogen, C1-8alkyl, hydroxyC1-8alkyl, haloC1-8alkyl, C18alkoxyC1-8alkyl, cyanoC1-8alkyl, Cy1C1-8alkyl, C2-8alkenyl, C2-8alkynyl, halogen, -CN NR10R10 -OR10 or Cy1, where each Cy1 is optionally substituted independently by one or more R11;

each R5, R6, R7, R8 and R9 independently represent hydrogen, C1-8alkyl, hydroxyC1-8alkyl, haloC1-8alkyl, C1-8alkoxyC1-8alkyl, cyanoC1-8alkyl, Cy1C1-8alkyl, halogen, -CN, -NR10R10, –OR10 or Cy1, where Cy1 is optionally substituted by one or more R11;

each R10 independently represents hydrogen or C1-8alkyl;

each R11 independently represents C1-8alkyl, hydroxyC1-8alkyl, haloC1-8alkyl, C1-8alkoxyC1-8alkyl, cyanoC18alkyl, halogen, -CN, -NR10R10 or -OR10; Y

each Cy1 independently represents a monocyclic ring of 3 to 7 members or bicyclic ring of 6 to 11 members which can be carbocyclic or heterocyclic in which case it can contain 1 to 4 heteroatoms selected from N, S and O, where said ring can be saturated, partially unsaturated or aromatic, and may be attached to the rest of the molecule through any available C or N atom, and where one or more C or S atoms of the ring are optionally oxidized to form CO, SO or SO2 groups.

The present invention also relates to the process of synthesis of salts and solvates of the compounds of formula I as defined above.

Some compounds of formula I may have chiral centers, which may give rise to various stereoisomers. The present invention relates to each of the individual stereoisomers as well as their mixtures.

Another aspect of the present invention relates to a method of synthesis of a compound of formula IV comprising:

i) .- the synthesis step of a compound of formula I as defined above; Y

ii) .- the synthesis step of a compound of formula IV from a compound of formula I and an acid

heating at a temperature between 20 and 50 ° C, preferably between 25 and 45 ° C, and even more preferably at 30

ºC:

understands:

i) .- the synthesis step of a compound of formula I as defined above; Y

ii) .- the synthesis step of a compound of formula V from a compound of formula I and an acid

15 heated to a temperature between 50 and 90 ° C, preferably at about 70 ° C:

R1O R1O

R9

OH R2

OR

R2

R7

R8

H

R8

R3

R3

R7

R4 O R5R6R9 R4 O R5R6

I V

where R1, R2, R3, R4, R5, R6, R7, R8, and R9 have the meaning described above.

In the above definitions, the term C1-8alkyl, as a group or part of a group, means an alkyl group of

The straight or branched chain containing 1 to 8 C atoms and includes the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl and octyl groups.

A C2-8alkenyl group means a linear or branched alkyl chain containing from 2 to 8 C atoms, and which also contains one or two double bonds. Examples include ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, pentenyl, hexenyl, heptenyl and octenyl groups.

A C2-8alkynyl group means a linear or branched alkyl chain containing from 2 to 8 C atoms, and which also contains one or two triple bonds. Examples include the ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1,3-butadiinyl, pentinyl, hexinyl, heptinyl and octinyl groups.

A C1-8alkoxy group, as a group or part of a group, means a -OC1-8alkyl group, where the C1-8alkyl part has the same meaning described above. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, hexyloxy, heptyloxy and octyloxy.

A halogen radical or its abbreviation halo means fluoro, chloro, bromo or iodo.

A hydroxyC 1-8 alkyl group means a group resulting from the substitution of one or more hydrogen atoms of a C 1-8 alkyl group by one or more hydroxy groups. Examples include, but are not limited to, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, 3-hydroxybutyl, 2-hydroxybutyl and 1-hydroxybutyl.

A haloC1-8alkyl group means a group resulting from the substitution of one or more hydrogen atoms of a C1-8alkyl group by one or more halogen atoms (i.e. fluoro, chloro, bromo or iodo), which can be the same

or different. Examples include, among others, the groups trifluoromethyl, fluoromethyl, 1-chloroethyl, 2-chloroethyl, 1fluoroethyl, 2-fluoroethyl, 2-bromoethyl, 2-iodoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3- chloropropyl, 2,2,3,3-tetrafluoropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, 4-fluorobutyl and nonafluorobutyl.

A C1-8alkoxyC1-8alkyl group means a group resulting from the substitution of one or more hydrogen atoms of a C1-8alkyl group by one or more C1-8alkoxy groups as defined above, which may be the same or different. Examples include, among others, the methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, isobutoxymethyl, sec-butoxymethyl, tert-butoxymethyl, dimethoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 2-ethoxymethyl, 1,2-diethoxyethyl, 1-butoxyethyl, 1 3-methoxypropyl, 2-butoxypropyl, 1-methoxy-2-ethoxypropyl, 2-sec-butoxyethyl, 3-tert-butoxypropyl and 4-methoxybutyl.

A cyanoC1-8alkyl group means a group resulting from the substitution of one or more hydrogen atoms of a C1-8alkyl group by one or more cyano groups. Examples include, among others, the cyanomethyl, dicyanomethyl, 1-cyanoethyl, 2-cyanoethyl, 3-cyanopropyl, 2,3-dicyanopropyl and 4-cyanobutyl groups.

A group Cy1 refers to a monocyclic ring of 3 to 7 members or bicyclic of 6 to 11 members which can be carbocyclic or heterocyclic. When it is heterocyclic it can contain 1 to 4 heteroatoms selected from N, S and

O. When Cy1 is a bicyclic ring, it may be formed by two fused rings through two adjacent C or N atoms, or through two non-adjacent C or N atoms forming a bridge ring, or it may be formed by two rings joined through a single C atom forming a ring of the Spieran type. A Cy1 group can be saturated, partially unsaturated or aromatic. In Cy1 one or more C or S atoms of any saturated or partially unsaturated ring are optionally oxidized forming CO, SO or SO2 groups. Cy1 is optionally substituted as indicated in the definition of formula I; if substituted, the substituents may be the same or different and may be located in any available position. Cy1 can be attached to the rest of the molecule through any available C or N atom. Examples of Cy1 groups include, among others, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, aziridinyl, oxiranyl, oxetanyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, oxazolidinyl, pyrazolidinyl, pyrrolidinyl, thiazolidinyl, dioxanyl, morpholinyl, thiomorpholinyl, 1,1 -dioxotiomorfolinilo, piperazinyl, homopiperazinyl, piperidinyl, pyranyl, tetrahydropyranyl homopiperidinyl, oxazinyl, oxazolinyl, pyrrolinyl, thiazolinyl, pyrazolinyl, imidazolinyl, isoxazolinyl, isothiazolinyl, 2-oxo pyrrolidinyl-, piperidinyl 2-oxo-4-oxo-piperidinyl, 2oxo -piperazinyl, 2-oxo-1,2-dihydropyridyl, 2-oxo-1,2-dihydropyrazinyl, 2-oxo-1,2-dihydropyrimidinyl, 3-oxo-2,3-dihydropyridazyl, phenyl, naphthyl, thienyl, furyl, pyrrolyl , thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2 , 4oxadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyre zinilo, pyrimidinyl, pyridazinyl, benzimidazolyl, benzooxazolyl, benzofuranyl, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, benzothiazolyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, indazolyl, imidazopyridinyl, pyrrolopyridinyl, thienopyridinyl, imidazopyrimidinyl, imidazopirazinilo, imidazopyridazinyl, pyrazolopyrazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, benzo [1,3] dioxolyl, phthalimidyl, 1-oxo-1,3-dihydroisobenzofuranyl, 1,3-dioxo-1,3-dihydroisobenzofuranyl, 2-oxo-2,3-dihydro-1H-indolyl, 1-oxo-2,3-dihydro-1H-isoindolyl, perhydroquinolinyl, 1-oxoperhydroisoquinolinyl, 1-oxo-1,2-dihydroisoquinolinyl, 4-oxo-3,4-dihydroquinazolinyl, 2-aza-bicyclo [2.2.1] heptanyl, 5aza-bicyclo [2.1.1] hexanyl, 2H-spiro [benzofuran-3,4'-piperidinyl], 3H-spiro [isobenzofuran-1,4'-piperidinyl], 2,8diazapiro [4.5] decan-1- onyl and 2,7-diazaspiro [4.5] decan-1-onyl.

A Cy1C1-8alkyl group means a group resulting from the substitution of a hydrogen of a C1-8alkyl group by a Cy1 group.

In the previous definitions of Cy1, when the specified examples refer to a bicyclic ring in general terms, all possible arrangements of atoms are included. Thus, for example, the term "pyrazolopyridinyl" may include groups such as 1 H -pyrazolo [3,4-b] pyridinyl, pyrazolo [1,5-a] pyridinyl, 1 H -pyrazolo [3,4-c] pyridinyl, 1 Hpyrazolo [4,3 -c] pyridinyl and 1H-pyrazolo [4,3-b] pyridinyl, the term imidazopyrazine may include groups such as 1Himidazo [4,5-b] pyrazinyl, imidazo [1,2-a] pyrazinyl and imidazo [1,5- a] pyrazinyl and the term pyrazolopyrimidinyl may include groups such as 1 H -pyrazolo [3,4-d] pyrimidinyl, 1 H -pyrazolo [4,3-d] pyrimidinyl, pyrazolo [1,5-a] pyrimidinyl and pyrazolo [1,5 -c] pyrimidinyl.

When in the definitions used throughout the present description for cyclic groups the specified examples refer to a ring radical in general terms, for example pyridyl, thienyl or indolyl, all possible binding positions are included, except that in the definition of the corresponding group indicates some limitation in this regard, for example that the ring is attached via a C atom, in which case said limitation applies. Thus, for example, in the definitions of Cy1, which do not include any limitation regarding the binding position, the term pyridyl includes 2-pyridyl, 3-pyridyl and 4-pyridyl; thienyl includes 2-thienyl and 3-thienyl; and indolyl includes 1 indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl and 7-indolyl.

The term "optionally substituted by one or more" means the possibility of a group being substituted by one or more, preferably by 1, 2, 3 or 4 substituents, more preferably by 1, 2 or 3 substituents and even more preferably by 1 or 2 substituents, provided that said group has sufficient available positions that can be substituted. If present, said substituents may be the same or different and may be located over any available position.

When a non-aromatic cycle is as a substituent of a non-aromatic cycle, it may be replacing a hydrogen atom, or it may replace two hydrogen atoms on the same C atom thus forming a ring of the Spiranus type. Similarly, when a non-aromatic cycle is as a substituent of an alkyl, alkenyl or alkynyl group, it may be replacing a hydrogen atom, or it may replace two hydrogen atoms on the same C atom.

In another embodiment, the invention relates to the process of synthesis of the compounds of formula I, IV or V where each R1, R2, R3 and R4 independently represent hydrogen, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, halogen, - CN, -NR10R10 -OR10 or Cy1, where each Cy1 is optionally substituted independently by one or more R11.

In another embodiment, the invention relates to the process of synthesis of the compounds of formula I, IV or V where each R1, R2, R3 and R4 independently represent hydrogen, C1-8alkyl, halogen, -CN, -NR10R10 -OR10 or Cy1 , where each Cy1 is optionally substituted independently by one or more R11.

In another embodiment, the invention relates to the process of synthesis of the compounds of formula I, IV or V where each R1, R2, R3 and R4 independently represent hydrogen, C1-8alkyl, halogen, -CN, -NR10R10 or -OR10.

In another embodiment, the invention relates to the process of synthesis of the compounds of formula I, IV or V where each R1, R2, R3 and R4 independently represent hydrogen or C1-8alkyl, preferably hydrogen or methyl, and even more preferably hydrogen.

In another embodiment, the invention relates to the process of synthesis of the compounds of formula I, IV or V where each R5, R6, R7, R8 and R9 independently represent hydrogen, C1-8alkyl, halogen, -CN, -NR10R10, - OR10 or Cy1, where Cy1 is optionally substituted by one or more R11.

In another embodiment, the invention relates to the process of synthesis of the compounds of formula I, IV or V where each R5, R6, R7, R8 and R9 independently represent hydrogen, C1-8alkyl, halogen, -CN, -NR10R10 or - OR10.

In another embodiment, the invention relates to the process of synthesis of the compounds of formula I, IV or V where each R5, R6, R7, R8 and R9 independently represent hydrogen or C1-8alkyl, preferably hydrogen or methyl.

In another embodiment, the invention relates to the method of synthesis of the compounds of formula I, IV or V where:

each R5, R6 and R7, independently represent hydrogen; Y

each R8 and R9 independently represent C1-8alkyl, preferably methyl.

In another embodiment, the invention relates to the method of synthesis of the compounds of formula I, IV or V where:

each R1, R2, R3 and R4 independently represent hydrogen, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, halogen, -CN, -NR10R10 -OR10 or Cy1, where each Cy1 is optionally substituted independently by one or more R11; Y

each R5, R6, R7, R8 and R9 independently represent hydrogen, C1-8alkyl, halogen, -CN, -NR10R10, -OR10 or Cy1, where Cy1 is optionally substituted by one or more R11.

In another embodiment, the invention relates to the method of synthesis of the compounds of formula I, IV or V where:

each R1, R2, R3 and R4 independently represent hydrogen, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, halogen, -CN, -NR10R10 -OR10 or Cy1, where each Cy1 is optionally substituted independently by one or more R11; Y

each R5, R6, R7, R8 and R9 independently represent hydrogen or C1-8alkyl, preferably hydrogen or methyl.

In another embodiment, the invention relates to the method of synthesis of the compounds of formula I, IV or V where:

each R1, R2, R3 and R4 independently represent hydrogen, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, halogen, -CN, -NR10R10 -OR10 or Cy1, where each Cy1 is optionally substituted independently by one or more R11;

each R5, R6 and R7, independently represent hydrogen; Y

each R8 and R9 independently represent C1-8alkyl, preferably methyl. In another embodiment, the invention relates to the method of synthesis of the compounds of formula I, IV or V where:

each R1, R2, R3 and R4 independently represent hydrogen, C1-8alkyl, halogen, -CN, -NR10R10 or -OR10; Y

each R5, R6, R7, R8 and R9 independently represent hydrogen, C1-8alkyl, halogen, -CN, -NR10R10, -OR10 or Cy1, where Cy1 is optionally substituted by one or more R11.

In another embodiment, the invention relates to the method of synthesis of the compounds of formula I, IV or V where:

each R1, R2, R3 and R4 independently represent hydrogen, C1-8alkyl, halogen, -CN, -NR10R10 or -OR10; Y

each R5, R6, R7, R8 and R9 independently represent hydrogen or C1-8alkyl, preferably

hydrogen or methyl In another embodiment, the invention relates to the method of synthesis of the compounds of formula I, IV or V where:

each R1, R2, R3 and R4 independently represent hydrogen, C1-8alkyl, halogen, -CN, -NR10R10 or -OR10;

each R5, R6 and R7, independently represent hydrogen; Y

each R8 and R9 independently represent C1-8alkyl, preferably methyl. In another embodiment, the invention relates to the method of synthesis of the compounds of formula I, IV or V where:

each R1, R2, R3 and R4 independently represent hydrogen or C1-8alkyl, preferably hydrogen or methyl, and even more preferably hydrogen; Y

each R5, R6, R7, R8 and R9 independently represent hydrogen, C1-8alkyl, halogen, -CN, -NR10R10,

–OR10 or Cy1, where Cy1 is optionally substituted by one or more R11. In another embodiment, the invention relates to the method of synthesis of the compounds of formula I, IV or V where:

each R1, R2, R3 and R4 independently represent hydrogen or C1-8alkyl, preferably hydrogen or methyl, and even more preferably hydrogen; Y

each R5, R6, R7, R8 and R9 independently represent hydrogen or C1-8alkyl, preferably

hydrogen or methyl In another embodiment, the invention relates to the method of synthesis of the compounds of formula I, IV or V where:

each R1, R2, R3 and R4 independently represent hydrogen or C1-8alkyl, preferably hydrogen or methyl, and even more preferably hydrogen;

each R5, R6 and R7, independently represent hydrogen; Y

each R8 and R9 independently represent C1-8alkyl, preferably methyl. Also, the present invention covers all possible combinations of the particular and preferred embodiments described above.

In another embodiment, the invention relates to a compound of formula I selected from the list of compounds described in examples 1 to 3.

The compounds of the present invention that contain one or more basic nitrogen and could therefore form salts with acids, both organic and inorganic. Examples of such salts include: salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid; and salts with organic acids, such as methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, fumaric acid, oxalic acid, acetic acid, maleic acid, ascorbic acid, citric acid, lactic acid, tartaric acid, malonic acid , glycolic acid, succinic acid and propionic acid, among others. Some compounds of the present invention may contain one or more acidic protons and therefore may also form salts with bases. Examples of such salts include: salts with inorganic cations such as sodium, potassium, calcium, magnesium, lithium, aluminum, zinc, etc .; and salts formed with pharmaceutically acceptable amines such as ammonia, alkylamines, hydroxyalkylamines, lysine, arginine, N-methylglucamine, procaine and the like.

There is no limitation on the type of salt that can be used, provided that when used for therapeutic purposes they are pharmaceutically acceptable. Pharmaceutically acceptable salts are understood to be those salts that, in medical judgment, are suitable for use in contact with the tissues of humans or other mammals without causing undue toxicity, irritation, allergic response or the like. Pharmaceutically acceptable salts are widely known to any person skilled in the art.

The salts of a compound of formula I, IV or V can be obtained during the final isolation and purification of the compounds of the invention or they can be prepared by treating a compound of formula I, IV or V with a sufficient amount of the acid or desired base to give the salt in a conventional manner. The salts of the compounds of formula I, IV or V can in turn be transformed into other salts of compounds of formula I, IV or V by ion exchange by means of an ion exchange resin.

The compounds of formula I, IV or V and their salts may differ in certain physical properties, but are equivalent for the purposes of the invention. All salts of the compounds of formula I, IV or V are included within the scope of the invention.

The compounds of the present invention can form complexes with solvents in which they are reacted

or from those that are precipitated or crystallized. These complexes are known as solvates. As used herein, the term "solvate" refers to a complex of variable stoichiometry formed by a solute (a compound of formula I, IV or V or a salt thereof) and a solvent. Examples of solvents include pharmaceutically acceptable solvents such as water, ethanol and the like. A complex with water is known as hydrate. Solvates of the compounds of the invention (or their salts), including hydrates, are included within the scope of the invention.

The compounds of formula I, IV or V may exist in different physical forms, that is, in amorphous form and crystalline forms. Also, the compounds of the present invention may have the ability to crystallize in more than one way, a characteristic known as polymorphism. Polymorphs can be distinguished by several physical properties well known to those skilled in the art such as their x-ray diffractograms, melting points or solubility. All physical forms of the compounds of formula I, IV or V, including all their polymorphic forms ("polymorphs"), are included within the scope of the present invention.

Some compounds of the present invention could exist in the form of several diastereoisomers and / or several optical isomers. The diastereoisomers can be separated by conventional techniques such as chromatography or fractional crystallization. Optical isomers can be resolved by using conventional optical resolution techniques, to give optically pure isomers. This resolution can be performed on synthesis intermediates that are chiral or on products of formula I, IV or V. Optically pure isomers can also be obtained individually using enantiospecific synthesis. The present invention covers both the individual isomers and their mixtures (for example racemic mixtures or mixtures of diastereoisomers), whether they are obtained by synthesis or by physically mixing them.

The compounds of formula I, IV and V can be obtained following the procedures described below. As will be apparent to one skilled in the art, the precise method used for the preparation of a given compound may vary depending on its chemical structure. Also, in some of the procedures detailed below, it may be necessary or convenient to protect reactive or labile groups by conventional protecting groups. Both the nature of such protecting groups and the procedures for their introduction and removal are well known and form part of the prior art (see for example Greene TW and Wuts PGM, "Protective Groups in Organic Synthesis", John Wiley & Sons, 3rd edition, 1999). By way of example, the tetrahydropyranyl group (THP) can be used as the protecting group for a hydroxyl function. Whenever a protective group is present, a subsequent deprotection stage will be necessary, which is carried out under the usual conditions in organic synthesis, such as those described in the reference mentioned above.

Unless otherwise indicated, in the methods described below the meanings of the different substituents are the meanings described above in relation to a compound of formula I, IV and V.

In general, the compounds of formula I can be obtained following the conditions described in the method of De Kimpe et al. (S. Claessens, B. Kesteleyn, T. Nguyen Van, N. De Kimpe, Tetrahedron, 2006, 62, 84198424, whose content is incorporated here by reference). Thus, the one-step synthesis of the compounds of formula I has been developed. It is a quick method, since in about 6 hours the final product can be obtained and also the treatment for the isolation and purification of the products is very simple (scheme 1).

Scheme 1

where R1, R2, R3, R4, R5, R6, R7, R8 and R9  they have the meaning described above for a compound of formula I.

A suspension of the derivative of formula II and the acid of formula III is prepared in the presence of a salt such as silver nitrate in a solvent such as acetonitrile and water. The reaction is heated between 50 and 90 ° C, preferably at about 70 ° C; and stir. A solution of ammonium persulfate in a solvent such as water is slowly added for about 20 and 50 minutes, preferably for about 30 minutes. Continue heating for about 30 more minutes. Then another acid equivalent of formula III is added and another

15 equivalent of ammonium persulfate. The reaction mixture is continued to heat for 1 to 4 hours, preferably for about 2 hours.

In general, the compounds of formula IV can be obtained from a compound of formula I in a reaction step (scheme 2)

R1 O R1 O

R2R2 OH

R7

R3 R6

R8

R3

R7R4 OR R6R5R9 R9 R8

I IV

20 Scheme 2

wherein R1, R2, R3, R4, R5, R6, R7, R8 and R9 have the meaning described above for a compound of formula I and for a compound of formula IV. A compound of formula I is treated with acidic medium, such as sulfuric acid or hydrochloric acid and heating at a temperature between 20 and 50 ° C, preferably between 25 and 45 ° C, and even more preferably at 30 ° C for about 20 and 50 minutes , preferably for 30 minutes to obtain a

25 compound of formula IV.

In general, the compounds of formula V can be obtained from a compound of formula I in a reaction step (scheme 3)

Scheme 3 where R1, R2, R3, R4, R5, R6, R7, R8 and R9 have the meaning described above for a compound of formula I

and for a compound of formula V. A compound of formula I is treated with an acid such as hydrochloric acid or sulfuric acid, heated between 50 and 90 ° C, preferably at about 70 ° C; and for between 1 and 4 hours, preferably for about 3 hours to obtain a compound of formula V.

Also, some compounds of the present invention can be obtained from other compounds of formula I, IV or V by transformation reactions of suitable functional groups, in one or more stages, using reactions widely known in organic chemistry under the usual experimental conditions .

Such interconversions can be carried out on the groups R1, R2, R3, R4, R5, R6, R7, R8, or R9 and include, for example:

the replacement of a primary or secondary amine by treatment with an alkylating agent under standard conditions; or by reductive amination, that is, by treatment with an aldehyde or ketone in the presence of a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride;

the transformation of an amine into a sulfonamide by reaction with a sulfonyl halide, such as sulfonyl chloride, optionally in the presence of catalytic amounts of a base such as 4-dimethylaminopyridine, in a suitable solvent such as dioxane, chloroform, dichloromethane or pyridine, optionally in the presence of a base such as triethylamine or pyridine;

the transformation of an amine into an amide, carbamate or urea under standard conditions;

alkylation of an amide by treatment with an alkylating agent under basic conditions;

the conversion of an alcohol into an ether, ester or carbamate under standard conditions;

partial or total oxidation of an alcohol to obtain ketones, aldehydes or carboxylic acids under standard oxidation conditions;

the reduction of an aldehyde or ketone to alcohol, by treatment with a reducing agent such as sodium borohydride;

the reduction of a carboxylic acid or a carboxylic acid derivative to alcohol by treatment with a reducing agent such as diisobutylaluminum hydride or LiAlH4;

the transformation of an alcohol into a halogen by treatment with SOCl2, PBr3, tetrabutylammonium bromide in the presence of P2O5, or PI3;

the transformation of a halogen atom into an amine by reaction with an amine, optionally in the presence of a suitable solvent, and preferably heating;

the transformation of a primary amide into a -CN group or vice versa, of a -CN group into an amide using standard conditions.

Likewise, any of the aromatic rings of the compounds of the present invention may undergo aromatic electrophilic substitution or aromatic nucleophilic substitution reactions, widely described in the literature.

Some of these interconversion reactions are explained in more detail in the examples.

As will be apparent to those skilled in the art, these interconversion reactions can be carried out both on the compounds of formula I, IV or V and on any suitable synthesis intermediate thereof.

The compounds of formula II and III are commercial or can be prepared by methods widely described in the literature, and can be conveniently protected.

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

Reference Example 1

Synthesis 4-methyl-3-pentenoic acid

To carry out this reaction, the corresponding acid had to be synthesized. The 3 routes that have been used to obtain it are detailed below.

A) Using pyridinium acetate as catalyst

This method has been carried out following the procedure described by V. Ragoussis (V. Ragoussis, M. Panopoulou, N. Ragoussis, J. Agric. Food. Chem., 2004, 52, 5047-5051, the content of which is incorporated herein by reference). It consists of the condensation of isobutyraldehyde with malonic acid in dimethylsulfoxide and in the presence of piperidinium acetate. Under these conditions a yellow oil is obtained, which by TLC reacts quickly to contact with permanganate (presence of the double bond). In the MS electronic impact analysis, the peak corresponding to the mass of the compound of interest does not appear (m / z 114); and also the 1H-NMR spectrum has many impurities. The procedure that has been carried out is described below: 0.05 mL of piperidine, 0.03 mL of acetic acid and 2 mL of DMSO are added in a round bottom flask. Stir vigorously under argon atmosphere and at room temperature. Then 3.6 g of isobutyraldehyde, 10.4 g of malonic acid and 25 mL of DMSO are added. The solution begins to heat at 85 ° C at reflux. The reaction was continued heating until the CO2 bubbling ceased (6 hours). Allow to cool to room temperature and pour over 50 mL of ice. It is extracted with CHCl3 (3x20 mL) and washed with distilled water and saturated NaCl solution. It is dried with Na2SO4 and evaporated in the rotary evaporator.

B) Using pyridine

With the above method, an acid was obtained that had many impurities, so another method was used consisting of the condensation of isobutyraldehyde with malonic acid and subsequent decarboxylation to form an α-unsaturated acid. Once this acid is obtained, it is isomerized in the presence of a base and the product is obtained. In the MS-IE analysis, the signal corresponding to m / z 114 appears corresponding to the mass of the desired compound. The infrared analysis confirms the presence of the carbonyl group, as an intense band appears at 1709 cm-1. Analyzing the NMR spectrum it is concluded that the acid is in a proportion of 80%, since it is not completely isomerized. Malonic acid (30 g, 0.288 mmol) is dissolved in a mixture of 26 mL of isobutyraldehyde (0.288 mmol) previously distilled and 23.2 mL of pyridine (0.288 mmol) bubbling argon, following a described procedure (S. Claessens, B. Kesteleyn , T. Nguyen Van, N. De Kimpe, Tetrahedron, 2006, 62, 8419-8424; K. Mikolajczak and C. Smith, J. Org. Chem., 1978, 43, 4762-4765 and E. Caspi and K. Varma, J. Org. Chem., 1968, 33, 2181-2186, whose content is incorporated herein by reference). Once dissolved, they were added

0.2 mL of piperidine The reaction begins to proceed at room temperature, observing the bubbling of CO2. As the reaction progresses, the solution changes from a whitish to yellow color. The solution is progressively heated to reflux and with vigorous stirring. By TLC (CHCl3 1: AcOEt 1) it is verified that a compound appears that reacts rapidly upon contact with permanganate. Once the CO2 bubbling has stopped, the solution is allowed to cool and poured onto 200 mL of ice. It is extracted with CHCl3 (3 x 60 mL) and washed with a solution of 2N HCl to remove excess pyridine and then with saturated sodium chloride solution. It is dried with Na2SO4 and the solvent is evaporated in the rotary evaporator. 24.77 g of product are obtained, the yield being 76%. The acid obtained is refluxed with a solution of KOH (146.3 g in 250 mL of water). It is heated to 120 ° C and with vigorous stirring. After 24 hours it is allowed to cool and acidified with 37% HCl (200 mL). It is extracted with chloroform and washed with saturated NaCl solution. Dry with Na2SO4 and evaporate the solvent. A yellow oil is obtained which is distilled under vacuum (120 ° C and 40 mmHg), obtaining 17.5 g of a transparent liquid (71%).

C) Using commercial acid

Because the 4-methyl-2-pentenoic acid is commercial, the direct isomerization reaction was carried out. The reaction time has been increased to achieve a higher proportion of the desired acid, although it is not possible to isomerize more than 85%. A solution of the commercial acid (25 g) in 148 g of KOH (12 equivalents) dissolved in 250 mL of water is prepared. It is heated at reflux and with vigorous stirring for 96 hours. Allow to cool and acidify with 37% HCl (200 mL). It is extracted with chloroform and washed with saturated NaCl solution. Dry with Na2SO4 and evaporate the solvent. A yellow oil is obtained which is distilled under vacuum (120 ° C and 40 mmHg), obtaining 18.2 g of a transparent liquid (73%). The 1 H-NMR spectrum is analyzed and it is concluded that 85% isomerized.

Example 1

2-hydroxy-3- (3-methylbut-2-enyl) naphthalene-1,4-dione (lapachol)

A suspension of 2-hydroxynaphthalene-1,4-dione (lawsona) (3.48 g, 20 mmol), 85% purity pentenoic acid (2.68 g, 20 mmol) and silver nitrate (680 mg, 4 mmol) is prepared ) in 20 mL of acetonitrile and 40 mL of deionized water bubbling argon. The reaction is heated to approximately 70 ° C and stirred vigorously. A solution of ammonium persulfate (4.66 g, 20 mmol) in 10 mL of deionized water is slowly added (for half an hour). Continue heating for half an hour. Then another acid equivalent (20 mmol) and again another persulfate equivalent (20 mmol in 10 mL of water) are added. The reaction mixture is continued heating for 2 hours. It is then allowed to cool and extracted with chloroform (3 x 40 mL) and washed with distilled water (4 x 30 mL). Dry over anhydrous sodium sulfate and filter through a silica gel filter plate. The solvent is evaporated and 3.16 g of the title compound is obtained as a yellow solid (65%) which by HPLC has a purity of 94%. This reaction has been repeated starting from 2 g of product and the title compound has been obtained with a yield of 73%.

Example 2

5 4,4-dimethyl-3,4-dihydro-2H-benzo [h] chromene-5,6-dione (j-lapachone)

The compound obtained in Example 1 is treated with 25 mL of sulfuric acid and stirred at room temperature for 30 minutes. It is poured onto 50 mL of ice and extracted with chloroform (3 x 20 mL). It is washed with distilled water and dried with anhydrous sodium sulfate. Purify with silica gel filter plate using CHCl3: AcOEt

12: 1 as eluent, and evaporates to dryness, obtaining 2.06 g of an orange solid which by HPLC has a purity of 89%, obtaining the title compound with a yield of 71%.

Example 3

2,2-dimethyl-3,4-dihydro-2H-benzo [g] chromene-5,10-dione (a-lapachone)

200 mL of 37% HCl are added to the product obtained in Example 1. It is heated at 70 ° C for 3 hours. It is poured onto 150 mL of ice and extracted with chloroform (3 x 50 mL). Wash with distilled water and with solution

15 saturated with sodium chloride and dried with anhydrous sodium sulfate. It is evaporated to dryness, obtaining 1,545 g of 3 with a purity of 89%, obtaining the title compound with a yield of 53%.

Claims (7)

1. Method of synthesis of the compounds of formula I comprising a reaction step between a compound of formula II and a compound of formula III: each R5, R6, R7, R8 and R9 independently represent hydrogen, C1-8alkyl, hydroxyC1-8 alkyl, haloC18alkyl, C1-8alkoxyC1-8alkyl, cyanoC1-8alkyl, Cy1C1-8alkyl, halogen, -CN, -NR10R10, -OR10 or Cy1, where Cy1 is optionally substituted by one or more R11; each R10 independently represents hydrogen or C1-8alkyl; each R11 independently represents C1-8alkyl, hydroxyC1-8alkyl, haloC1-8alkyl, C1-8alkoxyC1-8alkyl, cyanoC1-8alkyl, halogen, -CN, -NR10R10 or -OR10; Y each Cy1 independently represents a monocyclic ring of 3 to 7 members or bicyclic ring of 6 to 11 members which can be carbocyclic or heterocyclic in which case it can contain 1 to 4 heteroatoms selected from N, S and O, where said ring can be saturated, partially unsaturated or aromatic, and can be attached to the rest of the molecule through any available C or N atom, and where one or more C atoms or S of the ring are optionally oxidized forming groups CO, SO or SO2. 2. Process according to claim 1, wherein each R1, R2, R3 and R4 independently represent hydrogen, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, halogen, -CN, -NR10R10 -OR10 or Cy1, where each Cy1 is optionally independently substituted by one or more R11. 3. Process according to claim 2, wherein each R1, R2, R3 and R4 independently represent hydrogen, C1-8alkyl, halogen, -CN, -NR10R10 -OR10 or Cy1, where each Cy1 is optionally substituted independently for one or more R11. 4. Method according to any of claims 2 or 3 wherein each R1, R2, R3 and R4 independently represent hydrogen, C1-8alkyl, halogen, -CN, -NR10R10 or -OR10. 5. Method according to any of claims 2 to 4 wherein each R1, R2, R3 and R4 independently they represent hydrogen or C1-8alkyl, preferably hydrogen or methyl, and even more preferably hydrogen. 6. Method according to any of claims 1 to 5, wherein each R5, R6, R7, R8 and R9 independently represent hydrogen, C1-8alkyl, halogen, -CN, -NR10R10, -OR10 or Cy1, where Cy1 is optionally substituted for one or more R11. 7. Method according to claim 6, wherein each R5, R6, R7, R8 and R9 independently represent hydrogen, C1-8alkyl, halogen, -CN, -NR10R10 or -OR10. 8. Method according to any of claims 6 or 7, wherein each R5, R6, R7, R8 and R9 independently represent hydrogen or C1-8alkyl, preferably hydrogen or methyl. 9. Method according to any of claims 6 to 8, wherein: each R5, R6 and R7, independently represent hydrogen; Y each R8 and R9 independently represent C1-8alkyl, preferably methyl. 10. Method of synthesis of a compound of formula IV comprising: i) .- the step of synthesis of a compound of formula I obtained by the process of any of claims 1 to 9; Y ii) .- the synthesis step of a compound of formula IV from a compound of formula I and an acid heating at a temperature between 20 and 50 ° C, preferably between 25 and 45 ° C, and even more preferably at 30 ° C : where R 1, R2, R3, R4, R5, R6, R7, R8, and R9 I. 11.- Synthesis process of a compound of formula V comprising: i) .- the synthesis step of a compound of formula I obtained by the process of any of claims 1 to 9; and 10 ii) .- the synthesis step of a compound of formula V from a compound of formula I and an acid heated at a temperature between 50 and 90 ° C, preferably at about 70 ° C: R1 O R1 O R9 Or R8 R2 R2 R5 R6 H R3 R3 R7 R4 O R9 R4 OR5R6 R8 IV wherein R1, R2, R3, R4, R5, R6, R7, R8, and R9 have the meaning described for a compound of formula I. 12. Process according to any of claims 10 or 11 wherein the acid is selected from acid sulfuric acid 15 or hydrochloric acid. SPANISH OFFICE OF THE PATENTS AND BRAND Application no .: 201031447 SPAIN Date of submission of the application: 29.09.2010 Priority Date: REPORT ON THE STATE OF THE TECHNIQUE 51 Int. Cl.: See Additional Sheet RELEVANT DOCUMENTS

Category

56 Documents cited Claims Affected

X

HOOKER, S. C. “The Constitution of Lapachol and its derivatives. Part V. The Structure of Paterno’s Isaopachone ’’. Journal of the American Chemical Society, 1936, Vol. 58, page 1190. See page 1191, column 1, paragraph 2, Scheme, note 11. 10-12

X

BONIFAZI, E. L. et al. “Antiproliferative activity of synthetic naphtoquinones related to lapachol. First synthesis of 5-hydroxylapachol ". Bioorganic & Medicinal Chemistry, 2010, Vol. 18, pages 2621-2630. See page 2622, column 2, paragraph 3; page 2623, Schemes 3 and 5. 10.12

X

SALAS, C. et al. "Trypanosoma cruzi: Activities of lapachol and aand 1-lapachone derivatives against epimastigote and trypomastigote forms". Bioorganic & Medicinal Chemistry, 2008, Vol. 16, pages 668-674. See page 672, section 4.1.4. 11.12

TO

CLAESSENS, S. et al. "Synthesis of mollugin". Tetrahedron, 2006, Vol. 62, pages 8419-8424. See Scheme 2. 1-12

TO

WO 9621355 A1 (BRITISH TECHNOLOGY GROUP LIMITED) 18.07.1996, claims 1.34.38; Table 9, compound 31; Examples 24-29,30-31. 1-9

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

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

Date of realization of the report 02.04.2012

Examiner N. Martín Laso Page 1/4

REPORT OF THE STATE OF THE TECHNIQUE Application number: 201031447 CLASSIFICATION OBJECT OF THE APPLICATION C07C46 / 00 (2006.01) C07C50 / 32 (2006.01) C07D311 / 92 (2006.01) Minimum documentation sought (classification system followed by classification symbols) C07C, C07D Electronic databases consulted during the search (name of the database and, if possible, terms of search used) INVENES, EPODOC, WPI, TXT, BIOSIS, NPL, XPESP, CAS. State of the Art Report Page 2/4  WRITTEN OPINION Application number: 201031447 Date of Completion of Written Opinion: 02.04.2012 Statement

Novelty (Art. 6.1 LP 11/1986)

Claims Claims 1-9 10-12 IF NOT

Inventive activity (Art. 8.1 LP11 / 1986)

Claims Claims 1-9 10-12 IF NOT

The application is considered to comply with the industrial application requirement. This requirement was evaluated during the formal and technical examination phase of the application (Article 31.2 Law 11/1986).  Opinion Base.- This opinion has been made on the basis of the patent application as published. State of the Art Report Page 3/4  WRITTEN OPINION Application number: 201031447  1. Documents considered.- The documents belonging to the state of the art taken into consideration for the realization of this opinion are listed below.

Document

Publication or Identification Number publication date

D01

HOOKER, S. C. “The Constitution of Lapachol and its derivatives. Part V. The structure of Paterno’s Isaopachone ’’. Journal of the American Chemical Society, 1936, Vol. 58, page 1190. 1936

D02

BONIFAZI, E. L. et al. “Antiproliferative activity of synthetic naphtoquinones related to lapachol. First synthesis of 5hydroxylapachol ". Bioorganic & Medicinal Chemistry, 2010, Vol. 18, pages 2621-2630. 02.23.2010

D03

SALAS, C. et al. "Trypanosoma cruzi: Activities of lapachol and alfa-and beta-lapachone derivatives against epimastigote and trypomastigote forms". Bioorganic & Medicinal Chemistry, 2008, Vol. 16, pages 668-674. 18.10.2007

D04

CLAESSENS, S. et al. "Synthesis of mollugin", Tetrahedron, 2006, Vol. 62, pages 8419-8424. 07.07.2006

D05

WO 9621355 A1 (BRITISH TECHNOLOGY GROUP LIMITED) 18.07.1996

 2. Statement motivated according to articles 29.6 and 29.7 of the Regulations for the execution of Law 11/1986, of March 20, on Patents on novelty and inventive activity; quotes and explanations in support of this statement The application refers to the method of synthesis of naphthoquinones of general formula I from hydroxynaphthalenediones of general formula II by alkylation with 1, and unsaturated acids and to the process of preparation of naphthoquinones of general formula IV and V from naphthoquinones of general formula I. Document D01 discloses the preparation of naphthoquionones a-Lapachona and 1-Lapachona from napathoquinone Lapachol. A-Lapachona is obtained by heating Lapachol with hydrochloric acid at 55-60 ° C and 1-Lapachona can be obtained by heating Lapachol with sulfuric acid either at 25 ° C or 100 ° C (page 1191, column 1, paragraph 2, Scheme , note 11). Since the process for obtaining the starting naphthoquinone (Lapachol) does not give said product technical characteristics that differ from the same compound disclosed in the state of the art, the invention defined in claims 10-12 of the application is collected in document D01, therefore lacking novelty (Art. 6.1 LP 11/1986). Document D02 discloses the preparation of naphthoquinone 1-Lapachone by treating naphthoquinone Lapachol with dilute sulfuric acid at room temperature (page 2622, column 2, paragraph 3; page 2623, Schemes 3 and 5). The invention defined in claims 10 and 12 of the application is known from document D02, therefore it is new (Art. 6.1 LP 11/1986). Document D03 discloses the synthesis of naphthoquinone a-Lapachona from Lapachol by heating with hydrochloric acid at 70 ° C for 3 hours (page 672, section 4.1.4). Since the invention defined in claims 11 and 12 of the application is disclosed in document D03, said invention is not new (Art. 6.1 LP 11/1986). However, in relation to claims 1-9 of the application, although different methods of obtaining naphthoquinones from hydroxynaphthalenediones by radical alkylation are collected in the state of the art (see for example documents D02: Scheme 3; D04: Scheme 2; D05: claims 1, 34 and 38, Table 9, compound 31, examples 24-29, 30-31) none of said documents disclose or direct the person skilled in the art towards the development of a method of preparing naphthoquinones of formula general I from hydroxynaphthalenediones of general formula II in which the alkylation is carried out with acids that are 1, and unsaturated, without carrying out the necessary experimentation. Therefore, the invention defined in claims 1-9 of the application is new and has inventive activity (Art. 6.1 and 8.1 LP 11/1986). State of the Art Report Page 4/4