HRP920518A2 - Antiproliferative substituted naphthalene compounds - Google Patents

Description

The field of technology

The invention is from the field of pharmaceutical chemistry, that is, the synthesis of certain naphthalene compounds and their effect on the enzyme thymidylate synthase.

Technical problem

The invention relates to certain substituted naphthalene compounds that inhibit the enzyme thymidylate synthase ("TS"), to pharmaceutical compositions containing these naphthalene compounds and to the use of these compounds to inhibit TS, including all effects resulting from inhibition of TS. The effects resulting from inhibiting TS include inhibiting the growth and proliferation of cells of higher organisms and microorganisms, such as yeast and fungi. Such effects include antitumor activity. The procedure for obtaining substituted naphthalene compounds of the invention is also presented.

State of the art

A large class of antiproliferative agents includes antimetabolic compounds. A special subclass of antimetabolites, known as antifolates or "antifolis" are antagonists of the vitamin folic acid. Typically, antifolates have a structure close to folic acid, including the characteristic p-benzoyl-glutamic moiety of folic acid. TS has long been considered an important target enzyme in the construction and synthesis of antitumor agents, and a number of folate analogs have been synthesized and studied for their ability to inhibit TS. See, for example, Brixner et al., Folate Analogs as Thymidylate Synthase Inhibitors, J. Med. Chem. 30, 675 (1987); Jones et al., Quinazoline antifolates that inhibit thymidylate synthase: benzoyl ring modifications, J. Med. Chem. 29, 468 (1986); Jones et al., Quinazoline antifolates that inhibit thymidylate synthase: Amino acid variations, J. Med. Chem., 29, 1114(1986); and Jones et al., Quinazoline Antifolates Inhibiting Thymidylate Synthase: Variation of the N10 Substituent, 28, 1468(1985); and summary review of US patent application Ser. no. 07/432,338 filed Nov. 6, 1989.

This invention introduces a new class of substituted naphthalene compounds, which are not particularly structurally similar to folic acid, yet unexpectedly inhibit the TS enzyme. The invention also relates to pharmaceutical preparations containing these substituted naphthalene compounds, as well as to the use of these compounds for inhibiting TS, which includes all the effects resulting from inhibition of TS. Effects resulting from inhibition of TS include inhibition of cell growth and proliferation of higher organisms and microorganisms, such as yeast and fungi. Such effects include antitumor activity. Processes for obtaining substituted naphthalene compounds are also presented.

Technical problem solution with implementation examples

This invention relates to antiproliferative naphthalene compounds capable of inhibiting thymidylate synthase having the formula:

[image]

where:

Z and W are independently nitrogen, sulfur, or substituted or unsubstituted alkylene groups with the proviso that if either Z or W is nitrogen or sulfur, the other is a substituted or unsubstituted alkylene group;

Ar is a group containing one or more rings selected from the group consisting of (1) substituted or unsubstituted aryl rings and (2) substituted or unsubstituted heterocyclic rings;

R is hydrogen or a substituted or unsubstituted alkyl group;

R1 is hydrogen, a substituted or unsubstituted lower alkyl group or a substituted or unsubstituted amino group;

A is hydrogen, halogen, carbon, nitrogen or sulfur with the proviso that, if A is carbon, nitrogen or sulfur, A may be substituted with a substituted or unsubstituted alkyl group; and

X and Y together form a five- or six-membered nitrogen-containing heterocyclic ring which may itself be substituted or unsubstituted.

As used herein, the term "compound capable of inhibiting thymidylate synthase" means a compound with a TS inhibitory constant K that is less than or equal to about 10-4 M. The compounds of the invention preferably have a Ki value in the range of less than 10-5 M, preferably less than about 10-6 M, especially less than about 10-9 M, and most often in the range from about 10-12 to about 10-14 M.

Z in the above formula may be nitrogen, sulfur, or a substituted or unsubstituted alkylene group provided that, if nitrogen or sulfur, Z is a substituted or unsubstituted alkylene group. Primarily, Z is a nitrogen atom, and most often nitrogen, which, when found with R and W, forms a tertiary amino group.

W in the above formula may be nitrogen, sulfur, or a substituted or unsubstituted alkylene group provided that, if Z is nitrogen or sulfur, W is a substituted or unsubstituted alkylene group, such as methylene, ethylene, hydroxyethylene, n-propylene, isopropylene, chloropropylene and similar. Primarily, W is an unsubstituted alkylene group, and most often it is a methylene group.

As mentioned above, Ar can be any of a large number of cyclic compounds selected from the group consisting of (1) substituted or unsubstituted aryl rings and (2) substituted or unsubstituted heterocyclic rings. Examples of useful aryl cyclic groups include phenyl, 1,2,3,4-tetrahydronaphthyl, naphthyl, phenanthryl, anthryl, etc. Examples of typical heterocyclic rings include 5-membered monocyclic cyclic groups, such as thienyl, pyrrolyl, 2H- pyrrolyl, imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl, isoxazolyl and the like; 6-membered monocyclic groups, such as pyridyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl and the like; and polycyclic heterocyclic groups such as benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxaniinyl, indolizinyl, 3H-indonyl, indolyl, indazolyl, pyrinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinolinyl, pteridinyl, 4H-carbazolyl, beta-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazyl, isothiazilyl, phenothiazinyl, phenoxazinyl, etc.

Preferably, Ar is a monocyclic or bicyclic, substituted or unsubstituted aryl or heterocyclic or heteroaryl ring. More commonly, Ar is a phenyl, naphthyl, or heteroaryl ring, most commonly phenyl. Ar may be unsubstituted or Ar may be substituted with one or more electron-donating or electron-withdrawing substituents of various types. Typical substituents include halogen, hydroxy, alkoxy, alkyl, hydroxyalkyl, fluoroalkyl, amino, -CN, -NO2, carbalkoxy, carbamyl, carbonyl, carboxyldioxy, carboxy, amino acid carbonyl, amino acid sulfonyl, sulfamyl, sulfanylyl, sulfhydryl, sulfino, sulfinyl, sulfo , sulfonamido, sulfonyl, substituted or unsubstituted phenylsulfonyl, phenylmercapto, phosphazo, phosphinico, phosphino, phospho, phosphono, phosphoro, phosphorose.

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In one preferred embodiment, Ar is substituted with at least one electron-withdrawing group, such as -NO2, -CN, sulfonyl, carboxy, halogen, mercaptoaryl, or the like. More preferably, Ar is substituted with a >C=O or >SO2 group, such as a sulfonyl group directly attached to a substituted or unsubstituted phenyl or heterocyclic ring. Most preferably, Ar is substituted with a sulfonylphenyl group in the para position (ie, position 4).

It should be noted that if the Ar phenyl group is substituted with a sulfonylphenyl group, the phenyl ring of the sulfophenyl group may itself be substituted with such substituents as hydroxy, alkoxy, amino, carboxy, halogen, and the like.

Particularly preferred structures for Ar include:

[image]

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R in the substituted naphthalene compounds of the invention can be hydrogen or any of a large number of substituted or unsubstituted alkyl groups, such as methyl, ethyl, hydroxyethyl, n-propyl, isopropyl, hydroxypropyl, -CH2-S-CH3, n-butyl, tert-butyl, pentyl, hexyl and the like. Preferably, R is lower alkyl, such as a methyl group.

R1 in the above formula can be hydrogen; a substituted or unsubstituted lower alkyl group, such as methyl, ethyl, hydroxyethyl, n-propyl, isopropyl, hydroxypropyl and the like; or a substituted or unsubstituted amino group, such as -NH2, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, n-propylamine, di-n-propylamine, tri-n-propylamine, isopropylamine, n-butylamine, tert-butylamine , benzylamine and the like. Preferably, R is a hydrogen atom.

And in the above formula there can be a hydrogen atom; a halogen atom such as chlorine, bromine or iodine; a carbon atom which can, for example, be part of an alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, pentyl or hexyl or can be part of a substituted alkyl group, such as alkoxymethyl, hydroxyethyl or similar; or a nitrogen atom which can, for example, be part of a substituted or unsubstituted amino or nitro group; or a sulfur atom, for example, -SH, alkyl sulfides, such as methyl sulfide, ethyl sulfide, and the like. It should be noted, however, that if A is carbon, nitrogen, or sulfur, A may itself be substituted with a substituted or unsubstituted alkyl group.

Primarily, A is a hydrogen, halogen or carbon atom, more commonly a hydrogen atom, a chlorine atom or a carbon atom, which taken together with a suitable number of hydrogen atoms give a lower alkyl group, such as a methyl group. More commonly, A is a carbon atom, which taken together with three hydrogen atoms gives a methyl group.

X with Y in the above formula forms a five- or six-membered heterocyclic ring, which contains nitrogen and may itself be substituted or unsubstituted. Primarily, X was a carbon atom or a nitrogen atom, for example, as part of the =C(NHQ)-group, where Q is a hydrogen atom, a substituted or unsubstituted alkyl group, an amino or a hydroxy group; as part of the >C=O group; as part of the >NH group; or part of the =N- group.

X with Y in the above structural formula forms a nitrogen five-membered or six-membered heterocyclic ring which may itself be substituted or unsubstituted. Primarily, Y is a carbon atom or a nitrogen atom, for example, as part of -CH2-; >C=O; >C=S; =C(NHQ)- where Q is a hydrogen atom, substituted or unsubstituted alkyl group, amino or hydroxy group; =C(CH3)-; -N= or =NH. More preferably, Y is part of a -CH2-, >C=O, >C=S, =C(NH2)- or =C(CH3)- group. The most preferred for Y is the =C(NH2)- group.

Together, X and Y form a 5- or 6-membered nitrogen-containing heterocyclic ring, which may be substituted or unsubstituted. Examples of such heterocyclic rings include, for example, a pyrrole, 2H-pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, isothiazole, isoxazole or furazan ring. Primarily, heterocycles which are constructed from X and Y taken together are selected from the group consisting of

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in which P is a hydrogen atom, a substituted or unsubstituted alkyl group or an amino group;

[image]

and

[image]

where Q is a hydrogen atom, a substituted or unsubstituted alkyl group, or an amino or hydroxy group;

[image]

and

[image]

In a particularly preferred form, according to the present invention, Z is a nitrogen atom; W is an unsubstituted alkylene group; Ar is a monocyclic or bicyclic, substituted or unsubstituted aryl or heteroaryl ring; R 1 is a hydrogen atom; A is hydrogen, carbon or halogen; X is a nitrogen atom. More preferred are those substituted naphthalene compounds in which there is a methylene group; A is a hydrogen atom; X is a carbon atom, which together with hydrogen creates -NH= group; Y is a carbon atom. The most preferred substituted naphthalene cyclic compounds in this first form are those that fall within the above parameters and in which, in addition, R is methyl, Ar is a 4-phenylsulfone group, and Y is a carbon atom that is substituted with an amino group, resulting in =C(NH2 )- group.

In another embodiment of the invention, preferred are those substituted naphthalene compounds according to the present invention, where Z is a nitrogen atom; W is a substituted alkylene group; Ar is a phenyl group substituted with an electron-withdrawing moiety; R 1 is a hydrogen atom; A is hydrogen, halogen or carbon; R is selected from the group consisting of methyl, ethyl, hydroxyethyl, n-propyl, isopropyl, hydroxypropyl and -CH2S-CH3; and X and Y are independently carbon and nitrogen. In this second embodiment, those compounds in which W is a methylene group are preferred; the electron-withdrawing moiety is a >C=O or >SO2 group directly attached to an amino acid group, substituted or unsubstituted aryl group; a substituted or unsubstituted alkyl group or a substituted or unsubstituted heterocyclic group; A is a hydrogen or carbon atom.

In another embodiment, X and Y together form a substituted or unsubstituted heterocyclic ring containing two nitrogen atoms. Primarily, Ar is a phenyl group substituted in the para position with a >SO2 group directly attached to another phenyl group; A is a hydrogen atom; X is a nitrogen atom; Y is a nitrogen atom; and X and Y together form a heterocyclic ring having the formula:

[image]

in which P is a hydrogen atom, a substituted or unsubstituted alkyl group or an amino group. The most priority is the methyl group for P.

Alternatively, in the above preferred group of compounds, A is a carbon atom forming part of a substituted or unsubstituted alkyl group. In addition, primarily, A is a carbon atom that forms a methyl group together with three hydrogen atoms.

Another group of compounds in this second embodiment includes those substituted naphthalene cyclic compounds in which X and Y together form a substituted or unsubstituted heterocyclic ring containing one nitrogen atom. Primarily, Ar is a phenyl group substituted in the para position with a >SO2 group directly attached to another phenyl group; A is a hydrogen, halogen or carbon atom, which together with other atoms form a substituted or unsubstituted alkyl group; X is a nitrogen atom; Y is a carbon atom, and X and Y together form a heterocyclic ring whose formula is

[image]

and

wherein Q is a hydrogen atom, a substituted or unsubstituted alkyl group; or an amino or hydroxy group. Most often, A is a hydrogen, chloride or carbon atom that forms a methyl group together with three hydrogen atoms; Q is a hydrogen atom or a methyl or hydroxyl group.

Alternatively, X is a carbon atom; Y is a nitrogen atom; X and Y together form a heterocyclic ring having the formula

[image]

wherein Q is a hydrogen atom, a substituted or unsubstituted alkyl group, or an amino or hydroxy group. In addition, most often A is a hydrogen atom and Q is a hydrogen atom.

Furthermore, X and Y together can form a heterocyclic ring having the formula

[image]

In addition, most often, A is a hydrogen atom or a carbon atom, which together with three hydrogen atoms form a methyl group.

In a third embodiment of this invention, Ar is substituted with an electron-withdrawing group >C=O or >SO2 and directly attached to a substituted or unsubstituted heterocyclic ring. The heterocyclic ring is preferably selected from the group consisting of pyrimidine, pyrrolidone, pyrrole and indole.

Even more preferably, with this group of preferred compounds, A is a hydrogen atom, halogen or carbon atom, which together with other atoms forms a substituted or unsubstituted alkyl group; X is a nitrogen atom; Y is a carbon atom, and X and Y together form a heterocyclic ring having the formula

[image]

wherein Q is a hydrogen atom, a substituted or unsubstituted alkyl group, or an amino or hydroxy group. Most often, A is hydrogen, chlorine, or carbon which, together with three hydrogen atoms, forms a methyl group; Q is a methyl or hydroxy group.

Examples of useful compounds of the invention include those found in Table I relating to the working examples provided herein, which deals with specific examples:

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The invention also relates to a process for obtaining the compounds of this invention, where Z is a nitrogen atom from the successive alkylation of aniline having the formula

[image]

in which A, X and Y are defined as above. Successive alkylation is carried out by reacting aniline with an activated group R-Act, wherein R is as defined above and Act is one activated group preferably selected from the group containing halogen, such as bromine, chlorine or iodine, sulfonate, aromatic or alkyl aldehyde and the like. Alkylation is primarily carried out in a suitable organic solvent, such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane dimethylformamide, dimethylacetamide and the like. Solvents including dimethylformamide and dimethylacetamide are particularly preferred.

The first stage of alkylation takes place primarily in the presence of an organic or weak inorganic base, for example, a substituted amine, such as trimethylamine, diisopropyl-ethyl-amine, dimethyl-sec-butylamine, N-methyl-N-ethylaniline, N,N-dimethylaniline, diazobicyclicundecine, tributylamine or the like; or an inorganic carbonate, such as sodium, potassium or calcium carbonate; and the like.

The temperature of the first alkylation stage varies widely, but typically ranges from about 65°C to about 130°C. The time required for the reaction will depend on the large temperature range used and the relative reactivity of the starting material, but typically varies from about 1 to 20 hours.

The product of the first stage alkylation is then typically reacted under similar conditions with the compound Act-W-Ar where Act, W and Ar are defined above to form a secondary alkylated compound.

It should be noted that one or more of -R and -Ar may contain a chemical group or groups either before, after or during either the first stage of alkylation (1) or the secondary stage of alkylation (2):

(a) may be protected by a protective group or

(b) may have one or more, whichever of the present, removable protecting groups.

A suitable protecting group for the ring nitrogen, such as may be included in Ar, is, for example, a pivaloyloxymethyl group, which can be removed by hydrolysis with a base such as sodium hydroxide; a tert-butyloxycarbonyl group, which can be removed by hydrolysis with an acid such as hydrochloric acid or trifluoroacetic acid or a base such as tetra-n-butylammonium fluoride ("TBAF") or lithium hydroxide; or a 2-(tri-methylsilyl)-ethoxymethyl group, which can be removed with TBAF or with an acid, such as hydrochloric acid.

A suitable protecting group for the hydroxyl group is, for example, an ester group such as an acetyl or benzoyl group, which can be removed by hydrolysis with a base such as sodium hydroxide. Alternatively, if other groups present in the starting material contain an alkenyl or alkynyl group, the protecting group can be, for example, an alpha-arylalkyl group such as a benzyl group, which can be removed by hydrogenation with a catalyst such as palladium on carbon or Raney nickel. An additional protecting group for the hydroxyl group is a group such as t-butyldiphenyl-silyl (-Si-t-Bu-Ph2), which can be removed by treatment with TBAF.

A suitable protecting group for the mercapto group is, for example, an ester group such as an acetyl group, which can be removed by hydrolysis with a base such as sodium hydroxide.

A suitable protecting group for the amino group can be, for example, an alkylcarbonyl group, such as an acetyl group (CH3CO-), which can be removed by treatment with hydrogen with a reduction catalyst or by treatment with an inorganic acid, such as nitric, sulfuric or hydrochloric acid . Another protecting group for the amino group is an alkoxycarbonyl group or a tert-butyloxycarbonyl group. These groups can be removed by the action of an organic acid such as trifluoroacetic acid.

A suitable protecting group for the primary amino group is, for example, an acetyl group, which can be removed by treatment with an inorganic acid such as nitric, sulfuric or hydrochloric acid, or a phthaloid group, which can be removed with an alkylamine such as dimethylaminopropylamine. , or hydrazine.

A suitable protecting group for the carboxy group may be an ester group, for example a methyl or ethyl group, which can be removed by hydrolysis with a base such as sodium hydroxide. Another protecting group is the tert-butyl group, which can be removed by treatment with an organic acid, such as trifluoroacetic acid.

Preferred protecting groups include an esterifying group: an alpha-arylalkyl group, an alkylcarboxyl group, a substituted or unsubstituted alkoxycarbonyl group, a phthaloid group, a pivaloyloxymethyl group, a methyloxyether type of group such as methoxymethyl or 2-(trimethylsilyl)ethoxymethyl, or a silicon group such as which is a tert-butyldiphenylsilyl group.

A particular aspect of the invention relates to a process for obtaining a naphthalene ring compound capable of inhibiting thymidylate synthase having the formula:

[image]

where Z, W, Ar, R, R1, A are as defined above for the compounds of the invention, and where X and Y together form a heterocyclic ring having one of the following formulas:

[image]

It should also be noted that if X and Y form a ring of formula (A), the substituent A is not an electron-withdrawing group. In each case, A is primarily a carbon atom which, when combined with other atoms, forms a substituted or unsubstituted alkyl group. Most preferably, A is a carbon atom that is bonded to three hydrogen atoms, forming a methyl group.

The procedure for obtaining this group of substituted naphthalene compounds may include the following stages:

(1) treating a compound of formula (Ia) or (IIa):

[image]

[image]

wherein R 1 and A are as defined above, with a lower alkyl haloformate and a base in the first solvent to form an activated acid derivative;

(2) treating the activated acid derivative with sodium azide at a temperature lower than room temperature to form naphthyl acyl azide;

(3) heating the naphthyl acyl azide in another solvent to form the isocyanate; and

(4) treating the isocyanate with a Lewis acid to form a compound having formula (I) or (II):

[image]

(5) reacting a compound obtained from a compound obtained from a compound of formula (I) or a compound of formula (II) with a compound R-Act wherein R-Act is defined as above, to form a first alkylated compound; and

(6) reaction of the first alkylated compound with the compound Act-W-Ar where Act, W and Ar are defined as above, to form the second alkylated compound.

The term "activated acid derivatives" refers to derivatives of acid compounds, such as acid chlorides, carbonates, imidazoles, mixed phosphates and carbonic anhydrides and other known acid derivatives.

In the first stage, by treating the compound of formula (Ia) or (IIa) with a lower alkyl haloformate and a base in the first solvent, the lower alkyl haloformate can be ethyl chloroformate, benzyl chloroformate, methyl chloroformate or the like, but primarily ethyl chloroformate . The first solvent can be any suitable organic solvent, such as tetrahydrofuran, dioxane, dichloromethane, benzene, acetone, toluene or the like, but preferably acetone. The temperature at which the first phase proceeds can vary widely from room temperature to about -78 °C, but primarily proceeds at temperatures well below room temperature, such as about -5 °C. The activated acid derivative obtained during this step is directly used in the next step without isolating the product or otherwise separating the first solvent.

The second stage of treating the activated acid derivative, obtained in the first stage with sodium azide at a temperature below room temperature, can be carried out at a temperature ranging from about -78°C to about 25°C, preferably carried out at a temperature ranging from around -20°C to around 10°C, most often around -5°C. If the activated acid derivative obtained in the first step is used directly without isolating the acid product, the solvent used in the second step will, of course, be whatever solvent was used in the first step. If the activated acid derivative obtained as a result of the first stage is isolated or if the first solvent is removed in another way, further amounts of the first solvent or another similar solvent, such as tetrahydrofuran, dioxane, dichloromethane, benzene, acetone, are used in the second stage , toluene and the like.

The third stage, heating the naphthyl acyl azide (which is obtained as a result of the second stage) to give the isocyanate, can be carried out at any temperature up to 240°C. The temperature, however, varies typically from about 50 to about 160°C, preferably from about 80 to about 140°C, and most commonly from about 115 to about 135°C. Primarily, the temperature is maintained at the boiling point of the second solvent in which the reaction takes place. The second solvent should also be completely anhydrous (ie contain less than 0.1% water) and should not react either with naphthylazide as a starting material or with isocyanate as a reaction product. Preferred solvents include such solvents as nitrobenzene, methylene chloride, chlorobenzene, dichloroethane and mixtures thereof. The most preferred second solvent is chlorobenzene, nitrobenzene or a mixture thereof. Primarily, the third stage is performed in a dry, inert atmosphere, such as a nitrogen, argon or helium atmosphere. The third phase is preferably carried out in a nitrogen or argon atmosphere.

The fourth step involves treating the isocyanate resulting from the third step with a Lewis acid to form a compound of formula (I) or (II). The Lewis acid used in the fourth step is one selected from the group consisting of boron trichloride, aluminum chloride, boron trifluoride etherate, titanium tetrachloride and stannous tetrachloride. Primarily, the Lewis acid is boron trichloride. The fourth stage can be carried out in the presence of an organic solvent, such as chlorobenzene, dichlorobenzene, nitrobenzene, dichloroethane or a mixture thereof.

Phase (5), the first stage of alkylation, includes the reaction of the compound obtained from the compound of formula (I) or formula (II) with the compound R-Act, and stage (6), the second stage of alkylation with Ar-W-Act to form the second alkylated product, as described in detail above. Phases (5) and (6) can also be given in reverse order.

In one preferred embodiment, the resulting second alkylated compound is treated with either P2S5 or Lawssen's reagent (2,4-bis(4-methoxyphenyl)-2,3-dithia-2,4-diphosphetane-2,4-disulfide) to form corresponding thione compound as follows:

[image]

The resulting thione compound can then be treated with an alkyl halide to form the corresponding alkylated thiolactam, for example, using the following reaction:

[image]

The corresponding alkylated thiolactam can then itself be treated with any of a number of nucleophiles, such as ammonia, alkylamines, alkoxyamines, hydroxylamines, and hydrazines, to form the corresponding amidine, alkylated amidine, hydroxylated amidine, and aminated amidine rings.

Another aspect of the invention relates to processes for creating naphthalene compounds of the following formula,

[image]

wherein W, Ar, R, R1, A and P are as defined above for the compounds of the invention, and where X and Y have a pyrimidine ring formed. The preferred procedure for the formation of this group of naphthalene compounds includes the following steps:

(1) reaction of the compound R-Z-W-Ar with the starting naphthalene compound of the formula

[image]

where L is a leaving group, for example, a halogen atom, such as F or Cl, to form the following intermediate having two nitro groups:

[image]

(2) reduction of the two nitro groups of the intermediate to form the corresponding amino group; and

(3) cyclization of the resulting amino groups to form the desired substituted naphthalene compound of the invention, where X and Y form a pyrimidine ring.

The first stage reaction of the R-Z-W-Ar compound with the starting naphthalene compound can be carried out under highly variable conditions, but is typically carried out in the presence of an organic solvent such as dimethylsulfoxide, dioxane or dimethoxyethane, in the presence of a neutralizing agent such as calcium -carbonate, potassium carbonate, cesium carbonate or trisubstituted amine, and at a temperature that varies greatly from room temperature to about 180°C, preferably from about 100 to about 150°C, most preferably at about 130°C.

The second phase, the reduction phase, can be carried out under very wide conditions, but is primarily carried out in water or in an organic solvent such as ethanol, ethyl acetate, tetrahydrofuran or acetic acid, in the presence of a reducing agent such as hydrazine, hydrogen under a pressure of one atmosphere or more. Primarily, Raney nickel, palladium on carbon, palladium on barium sulfate and the like are used as reduction catalysts.

In the third step, the cyclization step, the reagent used to induce the cyclization determines the nature of the substituent P on the pyrimidine ring, resulting from the substituted naphthalene compound of the invention. The cyclization reagent can be, for example, very different compounds, such as acetic anhydride, trimethylorthoformate, triethylorthoformate or cyanobromide, but is typically an organic anhydride compound, such as acetic anhydride. When, for example, acetic anhydride is used for cyclization, P on the resulting pyrimidine ring is a methyl group. If, on the other hand, the cyclization reagent is cyanobromide, P would be an amino group.

Another aspect of the invention relates to pharmaceutical compositions containing a pharmaceutically acceptable diluent or carrier in admixture with at least one compound according to the present invention in an amount effective in inhibiting thymidylate synthase. The preparation primarily contains the compound of the invention in an amount that is suitable for therapeutic purposes.

Substituted naphthalene compounds from this invention that can be used in pharmaceutical preparations from the invention include all those compounds that are described above, as well as salts of these compounds that are pharmaceutically acceptable. Pharmaceutically acceptable acid addition salts of the compounds of the invention containing a basic group are formed when they react with strong or less strong organic or inorganic acids in the presence of basic amines according to methods known in the art. Acid addition salts exemplified in this invention include maleates, fumarates, lactates, oxalates, methanesulfonates, ethanesulfonates, benzenesulfonates, citrates, chlorides, bromides, sulfates, phosphates, and nitrates. Pharmaceutically acceptable basic addition salts of compounds from the invention containing an acidic group are obtained by known methods from organic and inorganic bases, including non-toxic bases of alkali and alkaline earth metals, for example, calcium, sodium and potassium hydroxide; ammonium hydroxide and non-toxic organic bases such as triethylamine, butylamine, piperazine and tri(hydroxymethyl)-methylamine.

As stated above, the compounds of the invention have antiproliferative activity, a property that can be expressed in the form of antitumor activity. The compound of the invention may be active by itself or may be converted in vivo into an active compound by means of a drug. Preferred compounds of the invention are active in inhibiting the growth of the L1210 cell strain, a murine leukemia cell strain, which can grow in tissue culture. Such compounds of the invention are also active in inhibiting the growth of bacteria, such as E. coli, gram-negative bacteria that can grow in culture.

The substituted naphthalene compounds according to the present invention, as well as their pharmaceutically acceptable salts, can be incorporated into suitable dosage forms, such as capsules, tablets or injectable preparations. A solid or liquid pharmaceutically acceptable carrier may be used. Solid carriers include starch, lactose, calcium sulfate dihydrate, "tera alba," sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Liquid carriers include syrup, peanut oil, olive oil, saline, and water. Similarly, the carrier or diluent may include any sustained release agent, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. When a liquid carrier is used, the preparation may be in the form of a syrup, elixir, emulsion, soft gelatin capsules, a sterile injectable liquid (eg, a solution), such as an ampoule, or an aqueous or non-aqueous liquid suspension.

Pharmaceutical preparations are prepared according to conventional pharmaceutical techniques that include stages such as mixing, granulation and pressing, if necessary for tablet forms; or mixing, filling, and dissolving the ingredients as appropriate to obtain the desired product for oral, parenteral, topical, intravaginal, intranasal, intrabronchial, intraocular, intraaural, or rectal administration.

The compositions of the invention may further contain one or more compounds that are antitumor agents, such as mitotic inhibitors (e.g. vinblastine), alkylating agents (e.g. cisplatin carboplatin or cyclophosphamide), DHFR inhibitors (e.g. methotrexate, pyritrexate or trimetrexate), antimetabolites ( eg 5-fluorouracil and cytosine arabinoside), intercalating antibiotics (eg adriamycin and bleomycin), enzymes (eg asparaginase), topoisomer inhibitors (eg etoposide) or biological response modifiers) (eg interferon).

The composition of the invention may also contain one or more compounds including antibacterial, antifungal, antiparasitic, antiviral, antipsoriatic and anticoccal agents. Exemplary antibacterial agents include, for example, sulfonamides, such as sulfamethaxazole, sulfadiazine, sulfameter, or sulfadoxine; DHFR inhibitors such as trimethoprim, bromdiaprim or trimethotroxate; penicillins; cephalosporins; amino-glycosides; bacteriostatic protein synthase inhibitors; quinolocarboxylic acids and their fused isothiazolo analogs.

Another aspect of the invention relates to a therapeutic method of inhibiting thymidylate synthase, a method comprising administering to a vertebrate host, such as a bird or mammal, an effective amount of a naphthalene compound according to the present invention to inhibit thymidylate synthase. The compounds of the invention are particularly useful in the treatment of mammalian hosts, such as the human host and in the treatment of avian hosts.

Any of the substituted naphthalene compounds described above, or pharmaceutically acceptable salts thereof, may be used in the therapeutic process of the invention. The compounds of the invention may be administered in the therapeutic method of the invention in the form of a pharmaceutically acceptable formulation containing a diluent or carrier, as described above. Dosages of the compounds include primarily pharmaceutical dosages comprising an effective amount of the active compound. By an effective amount is meant an amount sufficient to inhibit TS and produce beneficial effects therefrom by administration of one or more pharmaceutical dosage units. An exemplary daily dose for vertebrates implies an amount of about 5000 mg of active substance per square meter of the surface of the host-vertebrate.

The selected dose is administered to a warm-blooded animal or mammal, e.g., a human patient, when necessary for treatment by inhibiting thymidylate synthase by any known method of administration, including topical (e.g., ointment or ointment), oral, rectal (e.g., suppository), parenteral, injection , or by continuous infusion, intravaginally, intranasally, intrabronchially, intraaurally or intraocularly.

The substituted naphthalene compounds of the present invention may further be indicated as agents for producing any of one or more antiproliferative effects, antibacterial, antiviral, antipsoriatic, antiprotozoal, anticoccadial or antifungal effects. The compounds are particularly useful in producing an antitumor effect in tumor-affected vertebrate hosts.

The compounds of the invention are folate cofactor antagonists and therefore may affect one or more other folate-dependent enzyme systems. Examples of other folate-dependent enzyme systems that may be affected include 5,10-methylenetetrahydrofolate reductase, serine hydroxymethyltransferase, and glycine-aminoribotide transformylase.

The following examples illustrate the invention, although they do not limit the scope and spirit of the invention.

The structures of all compounds of the invention were confirmed by proton magnetic resonance spectroscopy, IR spectroscopy, elemental analysis and, in some cases, mass spectroscopy.

Proton magnetic resonance spectra were determined on a General Electric QE-300 spectrometer in a voltage field of 300 MHz. Chemical shifts are shown in parts per million (8) and by calibrating references so that in CDCl3, the CHCl peak is at 7.26 ppm, and in D6DMSO, the DMSO peak is at 2.49 ppm. Standards and peaks are labeled as follows: s, singlet; d, doublet; dd, double doublet; t, triplet; brs, wide singlet; hill; wide doublet; number; wide signal; m, multiplet.

Mass spectra were determined on a high resolution mass spectrometer VG 7070 E-HF using the insertive method, ionizing electric voltage of 70eV and ion source temperature of 200°C. Infrared spectra were recorded on a Perkin-Elmer 457 spectrometer. Elemental microanalysis gives results for elements that are determined with ±0.4% of the theoretical value.

The general procedure was as follows:

N,N-Dimethylformamide ("DMF") was dried over activated (250°C) 3-A molecular sieves; N,N-Dimethylacetamide ("DMA") (Aldrich Gold Label Grade) was similarly dried. Tetrahydrofuran ("THF") was distilled from sodium-benzophenone-ketyl under nitrogen. The term "ether" refers to diethyl ether.

"Flash" chromatography is performed using silica gel 60 (Merck type 9385). When the crude solid is insoluble in the solvent of choice, it is dissolved in a more polar solvent and silica gel Merck type 7734 is added. The suspension is evaporated to dryness in a rotary evaporator supplied with a crude glass melt to prevent dispersion of the silica gel. The coated silica gel is then placed in the column. Thin layer chromatography ("TLC") was performed on a precoated layer of silica gel 60 F254 (Merck type 5719). Extracts were dried over anhydrous Na2SO4 or MgSO4. Melting points were determined in a melting point apparatus and were not corrected.

Example 1: Preparation of compounds 1 to 6

Compounds 1 to 6 are obtained according to the following reaction scheme:

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Obtaining the compound 1 - 6-nitrobenz[cd]indol-2(1H)-one

16.5 ml (0.260 mol) of 70% nitric acid is added dropwise to a mixture of 33.9 g (0.200 mol) of benz[cd]indol-2(1H)-one in 150 ml of glacial acetic acid. In the beginning, the reaction is slightly exothermic, and then, during one hour, the reaction temperature rises to 50°C. The reaction mixture is gradually cooled to room temperature using a water cooler. A thick dark green paste is obtained. The mixture is filtered, washed with 50% aqueous acetic acid and extracted as much as possible. The resulting moist filter cake is heated in 600 ml of methanol under reflux and then cooled to 0°C. The mixture is filtered, washed with cold methanol and dried under vacuum, yielding 22.2 g (51% of theory) of 6-nitrobenz[cd]indol-2(1H)-one. TLC (CHCl3:MeOH 95:5) shows that the product is essentially a single-peak substance.

An analytically pure sample is obtained by refluxing 10.52 g of 6-nitrobenz[cd]indol-2(1H)-one in 350 ml of THF. After refluxing for 30 minutes, the mixture is filtered and the filtrate is evaporated almost to dryness. The obtained wet substance is mixed with 200 ml of methanol and then evaporated almost to dryness. Finally, the wet cake is placed in 200 ml of methanol, heated to reflux and cooled to -4°C overnight. The mixture is filtered and then the filter cake is washed with cold methanol and dried under vacuum, which gives 8.97 g (85% of theory) of a solid orange substance: m.p. 298-300°C (lit. 297-298°C); 1H NMR (d6-DMSO TMS) δ (ppm): 7.10 (d,1H,J=9Hz), 8.05 (dd,1H,J=6Hz), 8.16 (d,1H,J=6Hz), 8.61 (d, 1H, J=6Hz), and 8.85 (d, 1H, J=9Hz).

Obtaining the compound 2 - 6-aminobenz[cd]indol-2(1H)-one hydrochloride

A solution of 4.00 g (18.7 mmol) of 6-nitrobenz[cd]indol-2(1H)-one (1) in 300 ml of THF was filtered into a Parr hydrogenation flask. Undissolved substances are discarded. 0.44 g of 5% Pd/C (ie palladium on carbon) is added to the solution in the Parr flask. This mixture is hydrogenated at 40 psi H2 in a Parr hydrogenator overnight with stirring. The next morning, the H2 pressure dropped to 37 psi. The Parr flask is opened, the reaction mixture is filtered through diatomaceous earth commercially available under the name "Celite" and the filtrate is evaporated. The residue is placed in hot ethanol, filtered, and then acidified with ethanol saturated with HCl(g). A precipitate forms. 500 ml of diethyl ether is added dropwise to the mixture. The mixture is filtered and the resulting filter cake is washed with diethyl ether and dried under vacuum, which gives 3.44 g of a solid red substance. This material is refluxed in 150 ml of ethanol and cooled, and then 500 ml of diethyl ether is added dropwise. The precipitate obtained is collected, washed with diethyl ether and dried in vacuo, which gives 3.16 g (77% of theory) of 6-aminobenz[cd]indol-2(1H)-one hydrochloride. TLC (CHCl3:MeOH:HOAc 19:5:1) shows that the substance is pure.

A sample of the free base is obtained by dissolving 1.51 g of chloride salt in 200 ml of water and leaching the solution with a saturated bicarbonate solution. The resulting precipitate is collected, washed with water and dried in vacuo to give 1.21 g of 6-aminobenz[cd]indol-2(1H)-one: m.p. 240-242°C (lit. 244°C); 1H NMR (d6-acetone/TMS) δ (ppm): 2.85 (bs,2H), 5.21 (bs,1H), 6.64 (d,1H,J=9Hz), 6.76 (d,1H,J=9Hz), 7.71 (dd,1H,J=6Hz), 7.78 (d,1H,J=6Hz), and 8.22 (d,1H,J=6Hz).

Preparation of compound 3 - N6-ethyl-aminobenz[cd]indol-2(1H)-one hydrochloride

To a mixture of 3.26 g (0.014 mol) of 6-aminobenz[cd]-indol-2(1H)-one hydrochloride (3), 4.18 g (0.0393 mol) of anhydrous potassium carbonate and 60 ml of DMF, 1.77 ml (0.0222 mol) of ethyl - iodide. This mixture is heated to 70-100°C for eight hours, then cooled to room temperature, diluted with ethyl acetate, filtered and evaporated to dryness. The obtained residue is placed in a solution of chloroform:methanol 9:1 and chromatographed on flash grade silica gel using chloroform:methanol 9:1 as eluent. Fractions containing only the pure product are collected, evaporated, which gives 2.63 g of crude product. This material was placed in ethyl acetate/methanol and acidified with ethyl acetate saturated with HCl(g). Enough ethyl ether is added dropwise to this mixture to precipitate the product. Thus, it is collected, washed with diethyl ether and dried under vacuum, which gives 2.25 g (61% of theory) of N6-ethyl-6-aminobenz[cd]-indol-2(1H)-one-hydrochloride. tt. 261.5-253°C.

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1H NMR (d6-DMSO/TMS) δ (ppm): 1.30 (t,3H,J=6Hz), 3.36 (q,2H,J=6Hz), 4.0 (bs,2H), 6.98 (d,1H,J =9Hz), 7.35 (bs,1H), 7.87 (t,1H,J=6.9Hz), 8.08 (d,1H,J=6Hz), 8.51 (d,1H,J=9Hz), and 10.86 (s, 1H).

Obtaining the compound 4-N6-ethyl-N6-[4-(N,N-1-t-butoxycarbonyl)piperazinyl)sulfamoyl] benzyl-6-aminobenz[cd]indol-2-(1H)one

A mixture of 0.371 g of 4-bromomethyl-[N-(t-butoxycarbonyl)-piperazinyl]benzenesulfonamide (12) (70% purity, 0.619 mmol), 0.171 g (1.24 mmol) of anhydrous potassium carbonate, 0.154 (0.619 mol) of N6-ethyl of -6-aminobenz[cd]indol-2(1H)-one hydrochloride and 20 ml of DMF were heated to 100°C until TLC (ethyl acetate) of one aliquot showed no further consumption of the starting material. The reaction mixture is cooled to room temperature and 100 ml of water is added. A small amount of saturated sodium chloride solution is added to coagulate the solid. The precipitate is collected by filtration, washed with water and dried in a vacuum. The yield is 0.37 g of impure product. This material was dissolved in chloroform and purified by silica gel flash chromatography using ethyl acetate:hexane 1:1 as eluent. Fractions containing the pure product were collected and evaporated, yielding 0.16 g (47% of theory) of the pure product: 1H NMR (CDCl3/TMS) δ (ppm): 1.12 (t,3H,J=9Hz), 1.40 (s ,9H), 2.95 (m,4H), 3.25 (q,2H,J=9Hz), 3.50 (m,4H), 4.43 (s,2H), 6.84 (d,1H,J=9Hz), 6.92 (d ,1H,J=9Hz), 7.54 (d,2H,J=9Hz), 7.67 (d,2H,J=9Hz), 7.75 (dd,1H,J=9Hz), 8.09 (d,1H,J=9Hz ), and 8.30 (m, 2H).

Preparation of compound 5 - N6-[4-(N,N-pioperazinyl)sulfamoyl]benzyl-6-aminobenz[cd]indol-2(1H)-one

A solution of 0.161 g (0.292 mmol) of N6-ethyl-N6-[4-(N,N-(1-t-butoxycarbonyl)piperazinyl)sulfamoyl]benzyl-6-aminobenz [cd]indol-2-(1H)one in 10 ml of MeOH is acidified with methanol which is saturated with HCl(g). This solution is stirred at room temperature until TLC (ethyl acetate) shows that all the starting material has been consumed. The solution is evaporated and the residue partitioned between saturated aqueous bicarbonate and chloroform. The solution of the product in chloroform is evaporated, and the residue is taken up in fresh chloroform and purified by flash silica chromatography using chloroform:methanol 95:5 as eluent. Fractions containing the pure product were pooled and evaporated to give 0.124 g of a yellow solid (94% theoretical yield).

1H NMR (CDCl3/TMS) δ (ppm): 1.11 (t,3H,J=9Hz), 2.93 (m,8H), 3.24 (q,2H, J=9Hz), 4.42 (s,2H), 6.86 ( d,1H,J=9Hz), 6.94 (d,1H,J=9Hz), 7.55 (d,2H,J=9Hz), 7.67 (d,2H,J=9Hz), 7.73 (dd,1H,J= 6Hz), 8.09 (d,1H,J=6Hz), 8.29 (d,1H,J=6Hz), and 8.56 (s,1H).

For analytical purposes, 102 mg of the free base is placed in 5 ml of ethyl acetate and acidified with ethyl acetate saturated with HCl(g). The product is precipitated by the addition of diethyl ether. The yellow solid was collected by filtration, washed with diethyl ether and dried in vacuo to give 92 mg of the chloride salt.

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Preparation of compound 6 - N6-ethyl-N6[(4-N,N-piperazinyl)sulfamoyl]-benzyl-6-aminobenz[cd]indole-2(1H)-thione

A mixture of 0.124 g (0.275 mmol) of N6-ethyl-N6-[4-(N,N-piperazinyl)-sulfamoyl]benzyl-6-aminobenz[cd]indol-2(1H)-one (5), 0.061 g (0.151 mmol) of Lawssen's reagent (i.e. 2,4-bis(methoxyphenyl)-1,3-dithia-2,4-diphosphothane-2,4-disulfide) and 10 ml of toluene are refluxed for one hour. The solvent evaporates. The residue was dissolved in chloroform and purified by flash chromatography on silica using chloroform:methanol 95:5 as eluent. Fractions containing pure product were pooled and evaporated to give 0.100 g (78% of theory) of a purple solid. High-resolution mass spectroscopy searches 466.1498. Found: 466.1518

1H NMR (CDCl3/TMS) δ (ppm): 1.15 (t,3H,J=6Hz), 2.96 (m,8H), 3.29 (q,2H, J=6Hz), 4.48 (s,2H), 6.88 ( d,1H,J=9Hz), 6.97 (d,1H,J=9Hz), 7.53 (d,2H,J=9Hz), 7.70 (m,3H), 8.27 (d,1H,J=9Hz), and 8.31 (d, 1H, J=9Hz).

Example 2: Preparation of compounds 7 and 8

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Obtaining the compound 7-4-bromomethyldiphenylsulfone

11.5 g (64.6 mmol) of N-bromosuccinimide was added to a solution of 15 g (64.6 mmol) of phenyl-p-tolylsulfone in 300 ml of CCl4 at 85°C, with rapid stirring. The mixture is heated with a 200 W IR lamp for 30 minutes. After cooling, the mixture is filtered and the solvent is removed under reduced pressure. The crude product is chromatographed on flash grade silica (500 g) ethyl acetate/petroleum ether (15:85). In this way, 17.4 g (86%) of the desired bromide is obtained, as a white solid product contaminated with about 10% of the corresponding bromide. Repeated chromatography and recrystallization fails to remove the impurity, and the material is used as such in the next stage.

IR (KBr) 1290, 1140, 1100, 720 cm-1; 1H NMR (CDCl3) δ 4.45 (s,2H,-CH2Ar), 7.51-7.62 (m,5H), and 7.90-8.00 (m,4H). High resolution mass spectrum. Calculated for C13H11O2SBr: 309.9663. Found: 309.9648.

Preparation of compound 8 - N-4-(phenylsulfonyl)benzyl-N-ethyl-6-aminobenz[cd]indol-2(1H)-one

With vigorous stirring, 3.2 ml (18.2 mmol) of diisopropylethylamine and 2.85 g (9.10 mmol) of 4-bromoethylphenylsulfone (7). The mixture is heated for 3 hours at 90°C and poured into water (500 ml). The aqueous layer is extracted with ethyl acetate (3x400 ml), and the collected layers are dried over anhydrous Na2SO4. After removal of the solvent under reduced pressure, the crude residue is chromatographed on "flash" silica gel (200 g) with a gradient of 0-20% ethyl acetate in CH 2 Cl 2 . In this way, 2.7 g (81%) of the desired product is obtained as an orange solid: m.p. 213-216°C; IR (KBr) 3140, 1300, 1140, 725 cm-1, 1H NMR (CDCl3) δ 1.08 (t,3H,J=7Hz,-CH3), 3.20 (q,2H,J=7Hz,-CH2-), 4.38 (s,2H,-CH2Ar), 6.81 (d,1H,J=7.5Hz), 6.90 (d,1H,J=7.5Hz), 7.45-7.60 (m,5H), 7.70 (t,1H,J =7Hz), 7.81 (brs,1H,N-H), 7.87 (d,2H,J=8.4Hz), 7.93 (dd,2H,J=6.8,1.9Hz), 8.07 (d,1H,J=7Hz), and 8.25 (d, 1H, J=8.07Hz). Anal. calcd for C26H22N2O3S 0.5H2O: C, 69.16; H, 5.13; N, 6.20; S, 7.10. Found: C, 68.88; H, 5.13; N, 5.96; S, 7.07. High resolution mass spectrum. Calculated for C26H22N2O3S: 442.1351. Found: 442.1331.

Example 3: Preparation of compounds 9 to 16

Compounds 9 to 16 are obtained by the following reaction scheme:

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Getting a connection 9

N,N-(t-butyl-1-piperazinecarboxylate)-4-carboxybenzenesulfonamide

With vigorous stirring, to a solution of 40 g (215 mmol) of t-butyl-1-piperazinecarboxylate and 18.5 ml (128 mmol) of diisopropylethylamine in 300 ml of dry THF, a solution of 23.7 g (107 mmol) of 4- of (chlorosulfonyl)benzoic acid in 200 ml of dry THF. The resulting mixture is stirred for an additional hour and then poured into water (1000 ml). After extraction with ethyl acetate (300 ml which is discarded), the aqueous solution is acidified to pH 1 with concentrated HCl and then extracted with ethyl acetate (3x1000 ml). The combined organic layers are dried over anhydrous Na2SO4 and the solvent is removed under reduced pressure. In this way, 21 g (53%) of the desired acid is obtained as a whitish solid: 1H NMR (D6DMSO) δ 1.33 (s,9H), 2.89 (brs,4H), 3.40 (BRM,4H), 7.86 (d,2H ,J=9Hz), and 8.17 (d,2H, J=9Hz). This material is fully identified in the next step as the methyl ester.

Getting a connection 10

N,N-(t-butyl-1-piperazinecarboxylate)-4-methoxycarbonyl-benzenesulfonamide

With vigorous stirring, 5.3 ml (85.1 mmol) of methyl iodide is added to a solution of 21 g (56.7 mmol) of acid (9) and 23.5 g (170 mmol) of K2CO3 in 300 ml of DMF at 25°C. After 20 minutes, the mixture was poured into H2O (1000 ml) and the aqueous solution was extracted with ethyl acetate (3x1000 ml). The combined organic layers are dried over anhydrous Na2SO4 and the solvent is removed under reduced pressure. The crude residue is chromatographed on flash silica gel (600 g) with EtOAc/CH 2 Cl 2 (5:95). In this way, 19.8 g (91%) of the desired ester is obtained as a white solid: m.p. 173.5-174.5°C (EtOAc/CH2Cl2 3:1); IR (KBr) 2980, 2870, 1688, 1270, 1160, 1110, 940, 750 cm-1; 1H NMR (CDCl3) δ 1.40 (s,9H), 2.99 (brt,4H,J=5.3Hz), 3.50 (brt,4H,J=5.3Hz), 3.96 (s,3H), 7.82 (d, 2H,J=7.4Hz), and 8.20 (d,2H,J=7.4Hz). Anal. calcd for C17H24N2O6S: C, 53.11; H, 6.29; N, 7.29; S, 8.34. Found: C, 53.21; H, 6.34; N, 7.14; With 8.11.

Getting a connection 11

N,N-(t-butyl-1-piperazinecarboxylate)-4-hydroxymethyl-benzenesulfonamide

With vigorous stirring, to a solution of 18.2 g (51.8 mmol) of methyl ester (10) in 475 ml of THF at 0°C under argon, 116.7 g (116.7 mmol) of a 1M solution of diisobutylaluminum hydride in hexane was added over a period of 5 minutes. After 30 minutes, 25 ml of a saturated aqueous solution of potassium-sodium-tartrate is added, and the resulting mixture is left for another 10 minutes. The mixture is then poured into 500 ml of 1:1 saturated potassium-sodium-tartrate and the aqueous layer is extracted with CH2Cl2 (4x400 ml). The combined organic layers are dried over anhydrous Na2SO4 and the solvent is removed under reduced pressure. The crude product was flash chromatographed on silica gel (500 g) with EtOAc/CH 2 Cl 2 (1:4) to give 17.0 g (93%) of the desired alcohol as a white solid: m.p. 170-171.5°C (EtOAc/CH2Cl2, 1:1); IR (KBr) 3450, 2980, 1660, 1430, 1345, 1270, 1160, 930, 720 cm-1; 1H NMR (CDCl3) δ 1.39 (s,9H), 2.10 (t,1H,J=5.1Hz,-OH), 2.95 (t,4H,J=4.94Hz), 3.49 (t,4H,J=4.94Hz ), 4.80 (d,2H,J=5.1Hz), 7.53 (d,2H,J=8.2Hz), 7.72 (d,2H,J=8.2Hz). Anal. calcd for C16H24N2O5S: C, 53.91; H, 6.79; N, 7.86; S, 9.00. Found: C, 54.10; H, 6.70; N, 7.63; S, 8.72.

Getting a connection 12

N,N-(t-butyl-1-piperazinecarboxylate)-4-bromomethyl-benzenesulfonamide

With vigorous stirring, to a solution of 4.4 g (16.8 mmol) of triphenylphosphine and 5.6 g (16.8 mmol) of CNBr in 80 ml of CH2Cl2, 4.0 g (11.2 mmol) of solid alcohol (11) is added at 25°C. After 20 minutes, the mixture was poured into water (400 ml), and the aqueous layer was extracted with CH2Cl2 (2x400 ml). The combined organic layers are dried over anhydrous Na2SO4 and the solvent is removed under reduced pressure. The crude residue is chromatographed on "flash" silica (200 g) with Et2O/CH2Cl2 (1.5"98.5). In this way, 4.53 g (96%) of the desired bromide is obtained as a white solid: mp 155-156° C ( decay); IR (KBr) 2980, 2860, 1680, 1410, 1350, 1240, 1160, 930, 845, 740, 730 cm-1; 1H NMR (CDCl3) δ 1.40 (s,9H), 2.98 (t,4H ,J=4.9Hz), 3.50 (t,4H, J=4.9Hz), 4.49 (s,2H,-CH2Br), 7.56 (d,2H,J=8.3Hz), and 7.72 (d,2H,J= 8.3Hz). Anal. calcd for C16H23N2O4SBr: C, 45.83; H, 5.53; N, 6.68; Br, 19.06. Found: C, 45.66; H, 5.59; N, 6.44; Br, 19.04.

Getting a connection 13

2-tert-butyldiphenylsilylether-1-iodoethane

2-Hydroxy-1-iodoethane (2.26 mol, 29.1 mmol) was added to a 100 mL round-bottom flask containing tert-butylchlorodiphenylsilane (8.79 g, 32.0 mmol), triethylamine (5.26 mL, 37 mmol), and a catalytic amount of 4- of dimethylaminopyridine (0.183 g, 1.5 mmol) in methylene chloride at 0°C. Addition of 2-hydroxy-1-iodoethane results in a precipitate. The solution is stirred at 0°C for 1.5 hours. The reaction is then stopped and the solid filtered off. Distilled water (30 ml) is added to the bottle containing the filtrate, and the organic layer is separated. The aqueous layer is then extracted with methylene chloride (3x20 ml). The organic layers are collected and dried with anhydrous Na2SO4. Removal of the solvent on a rotary evaporator gives 11.9 g of oil. 1H NMR: δ 1.07 (9H,s), 3.19-3.24 (2H,t,J=6.7Hz), 3.84-3.88 (2H,t,J=6.7Hz), 7.36-7.44 (6H,m), and 7.65-7.69 (4H,m). IR (cm-1), 3500 (w), 3060-3080 (w), 2960 (m), 2940 (m), 2888 (m), 2860 (m), 1700-1950 (w), 1460-1470 ( m), 1270 (m), 1190 (m), 1170 (m), 1080-1100 (s), 700 (s), 500 (s).

Getting a connection 14

N-(2-tert-butyldiphenylsiloxyethyl)-6-aminobenz[cd]indol-2(1H)-one

With vigorous stirring, 1.86 g (4.5 mmol) of 2- of tert-butyldiphenylsiloxy-1-iodoethane at 120°C. After 3 hours, the reaction mixture was poured into water (150 ml) and the aqueous layer was extracted with ethyl acetate (3x90 ml). The collected organic layers are dried with anhydrous Na2SO4, and the solvent is removed under reduced pressure. The crude residue was chromatographed on flash silica gel (150 g) with EtOAc/CH 2 Cl 2 (15:85). In this way, 581 mg (38%) of the desired product is obtained as a red-orange foam: IR (KBr) 3200, 2930, 2860, 1630, 1450, 1260, 1080, 700 cm-1; 1H NMR (CDCl3) δ 1.58 (s,9H), 3.38 (m,2H,-NCH2-); 4.02 (t,2H,J=5Hz,-OCH2-), 4.85 (brs,1H,-NH-), 6.31 (d,1H,J=7.7Hz), 6.78 (d,1H,J=7.7Hz), 7.30-7.48 (m,6H), 7.63-7.71 (m,5H), 7.91 (d,1H,J=8.2Hz), 8.10 (d,1H,J=7.0Hz). High resolution mass spectrum. Calculated for C29H30N2O2Si: 466.2077. Found: 466.2076.

Getting a connection 15

N-[4-(N,N-t-butoxycarbonylpiperazinylsulfamoyl)-benzyl]-N-(2-t-butyldiphenylsiloxyethyl)-6-amino-benz[cd]indol-2(1H)-one

With vigorous stirring, 557 mg (1.33 mmol) of N,N-(t-butyl-1-piperazinecarboxylate)-4- is added to a solution of 575 mg (1.2 mmol) of amine (14) and 0.27 ml (1.56 mmol) of diisopropylethylamine in 5 ml of DMF. bromoethyl-benzenesulfonamide. After two hours, the mixture is poured into water (120 ml) and the aqueous layer is extracted with ethyl acetate (3x100 ml). The combined organic layers are dried over anhydrous Na2SO4 and the solvent is removed under reduced pressure. The crude residue is chromatographed on "flash" silica gel (50 g with Et2O/CH2Cl2 (1:4)). This gives 878 mg (90%) of the desired product as an orange foam: IR (KBr). 2930, 2860, 1680, 1640, 1240, 920, 700 cm-1; 1H NMR (CDCl3) δ 1.02 (s,9H), 1.40 (s,9H), 2.93 (t,4H,J=5.0Hz), 3.41 (t,2H, J=5.4Hz), 3.49 (t,4H, J=4.8Hz), 3.81 (t,2H,J=5.6Hz), 4.51 (s,2H), 6.70 (d,1H, J=7.5Hz), 6.81 (d,1H,J=7.5Hz), 7.20 -7.30 (m,4H), 7.34-8.02 (m,2H), 7.55 (d,4H, J=6.6Hz), 7.60-7.73 (m,3H), 7.80(brs,1H,-NH-), 8.08 (d,1H,J=6.9Hz), 8.38 (d,1H,J=8.1Hz). High resolution mass spectrum. Calculated for C45H52N4O6SSi: 804.3377. Found: 804.3375.

Getting a connection 16

N-[4-(N,N-piperazinylsilphamoyl)benzyl]-N-hydroxyethyl-6-aminobenz[cd]-indol-2(1H)-one

With vigorous stirring, 1.5 ml of trifluoroacetic acid was added to a solution of 870 mg (1.08 mmol) of lactam (15) in 15 ml of CH2CI2 at 25°C. After 6 hours, the solvent is removed under reduced pressure. The crude residue is dissolved in 15 ml of THF and 6.6 ml (6.48 mmol) of a 1M solution of tetrabutylammonium fluoride in THF is added to this mixture. The mixture is then heated to reflux. After 24 hours, the mixture was poured into H2O (200 mL) and NaCl was added to saturation. A saturated solution of NaHCO3 (30 ml) was added to the aqueous layer and the mixture was extracted with ethyl acetate (6x200 ml). The collected organic layers are dried over anhydrous Na2SO4 and the solvent is removed under reduced pressure. The crude residue is chromatographed on "flash" silica gel (50 g) using a gradient of 0-12% MeOH in CH 2 Cl 2 . This gives 425 mg (84%) of the desired material as a light orange solid: m.p. 98°C (decomposition); IR (KBr) 3190, 2940, 2840, 1670, 1320, 1240, 1160, 730 cm-1; 1H NMR (D6DMSO) δ 2.68 (m,8H), 3.26 (m,2H), 3.58 (m,2H), 4.53 (S,2H,-NCH2Ar), 4.66 (t,1H,J=5Hz,-OH) , 6.80 (d,1H,J=7.5Hz), 7.05 (d,1H,J=7.5Hz), 7.61 (m,4H), 7.77 (t,1H,J=7.1Hz), 7.97 (d,1H, J=6.9Hz), 8.42 (d,1H,J=8.2Hz), and 10.59 (s,1H,-NH). High resolution mass spectrum. Calculated for C24H26N4O4S: 466.1675. Found: 466.1700.

Example 4: Preparation of compounds 17 to 19

Compounds 17 to 19 are obtained using the following reaction scheme:

[image]

Getting a connection 17

N-propyl-6-aminobenz[cd]indol-2(1H)-one

With vigorous stirring, to a solution of 500 mg (2.27 mmol) of 6-aminobenz[cd]indol-2(1H)-one-hydrochloride (2) and 1.0 ml (7.04 mmol) of diisopropylethylamine in 8 ml of DMF, 0.26 ml (2.72 mmol) of propyl iodide was added. at 120°C. After 2 hours, the mixture was poured into H2O (120 mL) and the aqueous layer was extracted with ethyl acetate (3x100 mL). The combined organic layers are dried over anhydrous Na2SO4 and the solvent is removed under reduced pressure. The crude residue was chromatographed on flash silica gel (50 g) with EtOAc/CH 2 Cl 2 (15:85). This gives 320 mg (68%) of the desired material as a red solid: m.p. 166-167°C (EtOAc); IR (KBr) 3140, 1660, 1630, 1450, 1260, 760 cm-1; 1H NMR (CDCl3) δ 1.08 (t,3H,J=7.4Hz), 1.79 (tq,2H,J=7.4, 7.0Hz), 3.22 (t,2H,J=7.70Hz), 4.31 (brs,1H, HNAr), 6.38 (d,1H,J=7.7Hz), 6.84 (d,1H,J=7.7Hz), 7.68 (dd,1H,J=7.1,7.1Hz), 8.03 (d,1H,J=7.1 Hz), 8.05 (brs,1H,NH), and 8.10 (d,1H,J=7.03). Anal. calculated for C14H14N2O: C 74.31; H, 6.24; N, 12.38. Found: C, 74.14; H, 6.40; N, 12.19.

Getting a connection 18

N-[4-(N,N-t-butoxypiperazinylsulfamoyl)benzyl]-N-propyl-6-aminobenz[cd]indol-2(1H)-one

With vigorous stirring, 667 mg (1.60 mmol) of N,N-(t-butyl-1-piperazinylcarboxylate)-4- bromomethyl-benzenesulfonamide (12). After 14 hours, the mixture was poured into water (40 ml) and the aqueous layer was extracted with ethyl acetate (2x80 ml). The combined organic layers were dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The crude residue is chromatographed on "flash" silica gel (30 g) with EtOAc/CH2Cl2 (1:9). This afforded 610 mg (81%) of the desired material as orange needles: m.p. 115°C (dec) (EtOAc/petroleum ether 3:1); IR (KBr) 2970, 2930, 2870, 1680, 1410, 1345, 1250, 1160, 930, 730 cm-1; 1H NMR (CDCl3) δ 0.86 (t,3H,J=7.3Hz), 1.40 (s,9H), 1.59 (m,2H), 2.94 (t,4H,J=5.1Hz), 3.12 (t,2H, J=5.9Hz), 3.49 (t,4H,J=5.1Hz), 4.42 (s,2H,-NCH2-), 6.81 (d,1H,J=7.6Hz), 6.91 (d,1H,J=7.6 Hz), 7.51 (d,2H,J=8.3Hz), 7.66 (d,2H,J=8.3Hz), 7.73 (t,1H,J=7.1Hz), 8.07 (brs,1H,-NH), 8.09 (d,1H,J=7.1Hz), and 8.31 (d,1H,J=7.1Hz). Anal. calcd for C30H36N4O5S: C, 63.81; H, 6.43; N, 9.92; S, 5.68. Found: C, 63.72; H, 6.50; N, 9.73; S, 5.52.

Getting a connection 19

N-[4-(N,N-piperazinylsulfamoyl)benzyl]-N-propyl-6-benz[cd]indol-2(1H)-one

With vigorous stirring of a solution of 545 mg (0.96 mmol) of amine (18) in 15 ml of CH2Cl2, 1.5 ml of trifluoroacetic acid was added at 25°C. After two hours, the mixture was poured into saturated NaHCO3 solution (100 ml) and the aqueous layer was extracted with ethyl acetate (3x140 ml). The combined organic solutions are dried over anhydrous Na2SO4, and the solvent is removed under reduced pressure. The crude residue is recrystallized from ethyl acetate/petroleum ether (3:1). In this way, 375 mg (84%) of the desired material was obtained as an orange solid: m.p. 187-189°C; IR (KBr) 3180, 2940, 2835, 1640, 1445, 1410, 1315, 1160, 1090, 935, 730 cm-1; 1H NMR (CDCl3) δ 0.87 (t,3H,J=7.3Hz), 1.60 (m,2H), 288-3.02 (M,8H), 3.11 (t,2H,J=5.8Hz), 4.42 (s, 2H), 6.83 (d,1H,J=7.5Hz), 6.93 (d,1H,J=7.5Hz), 7.52 (d,2H,J=8.3Hz), 7.67 (d,2H,J=8.3Hz) , 7.73 (t, 1H,J=7.1Hz), 7.80 (brs,1H), 8.09 (d,1H,J=7.0Hz), and 8.31 (d,1H,J=7.8Hz). Anal. calcd for C25H28N4O3S: C, 64.63; H, 6.07; N, 12.6; S, 6.90. Found: C, 67.44; H, 6.27; N, 11.82; S, 6.71.

Example 5: Preparation of compounds 20 to 22

Compounds 20 to 22 can be obtained according to the following reaction scheme:

[image]

Getting a connection 20

N-isopropyl-6-aminobenz[cd]indol-2(1H)-one

Amine (20) was prepared in a similar manner to compound 38 using 2-iodopropane. After the completed reaction, the crude product is chromatographed on "flash" silica gel, eluting with hexane:ethyl acetate (1:1). In this way, (20) is obtained in a yield of 38% as a red solid: 1H NMR (CDCl3) δ 1.32 (s,3H), 1.34 (s,3H), 3.77 (m,1H), 4.14 (bs,1H ), 6.40 (d,1H,J=7.8Hz), 6.86 (d,1H,J=7.7Hz), 7.67 (t,1H,J=7.1Hz), 8.01 (d,1H,J=8.3Hz), 8.10 (d, 1H, J=7.0Hz), 8.38 (bs, 1H). Anal. calculated for C14H14N2O (exact mass): 226.1106. Found: 226.1105.

Getting a date 21

N-isopropylamino-4-methylphenylsulfonyl-t-butyl-1-piperazine-carboxylate-6-aminobenz [cd]indol-2(1H)-one

Amine (21) is obtained in a similar way as (38). The crude residue is chromatographed on "flash" silica gel eluting with methylene chloride:ethyl acetate (9:1). In this way, a yield of 62% of an orange solid substance in the form of a foam is obtained: IR (KBr) 3200, 2930, 1650, 1250 cm-1; 1H NMR (CDCl3) δ 1.27 (s,3H), 1.30 (s,3H), 1.38 (s,9H), 2.85 (m,4H), 3.44 (m,4H), 3.82 (m,1H), 4.43 ( s,2H), 6.72 (d,1H,J=7.6Hz), 6.89 (d,1H,J=7.6Hz), 7.50 (m,4H), 7.75 (t,1H,J=7.1Hz), 8.02 ( bs,1H), 8.07 (d,2H, J=7.0Hz), and 8.30 (d,1H,J=8.2Hz). Anal. calculated C30H36N4O5S (exact mass): 564.2406. Found: 564.2446.

Getting a date 22

N- [4-(N,N-piperazinylsulfamoyl)benzyl]-N-isopropyl-6-amino-benz [cd]indol-2(1H)-one

With vigorous stirring, 1 ml of trifluoroacetic acid is added to a solution of 295 mg (0.52 mmol) of amine (21) in 8 ml of CH2Cl2 at 25°C. After three hours, the mixture was poured into saturated NaHCO3 solution (60 ml) and the aqueous layer was extracted with ethyl acetate (3x100 ml). The combined organic layers are dried over anhydrous Na2SO4, and the solvent is removed under reduced pressure. The crude residue is chromatographed on "flash" silica gel (30 g) with MeOH/CH2Cl2 (5:95). This gives 177 mg (73%) of the desired material as an orange foam: IR (KBr) 2960, 1665, 1640, 1440, 1340, 1320, 1250, 1155, 1090, 940, 730 cm-1; 1H NMR (CDCl3) δ 1.28 (d,6H,J=6.5Hz), 2.85 (brs, 8H,-NCH2CH2N-), 3.80 (sep,1H,J=6.5Hz), 4.41 (s,2H,-NCH2Ar) , 6.75 (d,1H, J=7.6Hz), 6.93 (d,1H,J=7.6Hz), 7.48-7.56 (m,4H), 7.75 (t,1H,J=7.1Hz), 7.91 (brs, 1H), 8.06 (d,1H,J=7.1Hz), and 8.31 (d,1H,J=7.1Hz). High resolution mass spectrum. Calculated for C25H28N4OS: 464.1882. Found: 464.1860.

Example 6: Preparation of compounds 23 and 24

Compounds 23 and 24 are obtained according to the following reaction scheme:

[image]

Getting a date 23

N-[4-(phenylsulfonyl)benzyl]-6-aminobenz[cd]indol-2(1H)-one

With vigorous stirring, 507 mg (1.6 mmol) of 4-bromomethyldiphenylsulfone was added to a mixture of 300 mg (1.36 mmol) of diisopropylethylamine in 5 ml of DMF at 75°C. After three hours, the mixture was poured into H2O and the aqueous layer was extracted with ethyl acetate (3x100 ml). The combined organic compounds are dried over anhydrous Na2SO4 and the solvent is removed under reduced pressure. The crude residue was crystallized from EtOH to give 403 mg of the desired product as an orange solid: m.p. 196-212°C (decomposition); IR (KBr) 1630, 1450, 1265, 1150, 1100, 725 cm-1; 1H NMR (D6DMSO) δ 4.51 (brs, 2H,-NCH2Ar), 6.05 (d,1H,J=7.7Hz), 6.63 (d,1H,J=7.7Hz), 7.15 (brs,1H,-NH -R), 7.55-7.75 (m,6H), 7.88-7.98 (m,5H), 8.47 (d,1H,J=8.1Hz), and 10.35 (s,1H,-NH-C=O). High resolution mass spectrum. Calculated for C24H18N2O2S: 414.1038. Found: 414.1032.

Getting a date 24

N-[4-(phenylsulfonyl)benzyl]-N-methylthiomethyl--6-aminobenz[cd]indol-2(1H)-one

With vigorous stirring, to a solution of 260 mg (0.62 mmol) of amine (23) and 0.26 ml (1.49 mmol) of diisopropylethylamine in 6 ml of DMF, 0.10 ml (1.25 mmol) of chloromethyl sulfide was added dropwise at 120°C. After 1.5 hours, the mixture was poured into 1:1 saturated NaHCO 3 /H 2 O (100 ml) and the aqueous layer was extracted with ethyl acetate (3x100 ml). Each ethyl acetate layer was washed again with H2O (2x50 ml). The combined layers are dried over anhydrous Na2SO4 and the solvent is removed under reduced pressure. The crude residue is chromatographed on "flash" silica gel (30 g) with a gradient of 0-10% EtOH/CH2Cl2. This afforded 59 mg (20%) of the desired product as an orange solid: m.p. 170-180°C (dec) (EtOAc/CH2Cl2 3:1); IR (KBr) 3190, 1630-1690, 1445, 1300, 1145, 1100, 725 cm-1; 1H NMR (CDCl3) δ 178(s,3H,-SH3), 4.48 (s,2H), 4.57 (s,2H), 6.83 (d,1H,J=7.5 Hz), 7.08 (d, 1H,J=7.5Hz), 7.48-760 (m,5H), 7.71 (brs, 1H,-NH-C=O), 7.76 (t,1H,J=7.2 Hz), 7.88 (d,2H,J =8.3Hz), 8.09 (d,1H,J=7.0Hz), and 8.26 (d,1H,J=8.3Hz). High resolution mass spectrum. Calculated for C26H22N2O3S2: 474.1072. Found: 474.1077.

Example 7: Preparation of compounds 25 to 27

Compounds 25 to 27 are obtained according to the following reaction scheme:

[image]

Getting a connection 25

N-4-(N,N-t-butoxycarbonylpiperazinylsulfamoyl)-benzyl-6-aminobenz[cd]indol-2(1H)-one

With vigorous stirring, 1.04 g (2.49 mmol) of N was added to a solution of 500 mg (2.26 mmol) of 6-aminobenz[cd]indol-1(1H)-one hydrochloride (2) and 0.9 ml (5.20 mmol) of diisopropylethylamine in 6 ml of DMF. ,N-(t-butyl-1-piperazinecarboxylate)-4-bromomethylbenzsulfonamide (12) at 75°C. After 3 hours, the mixture was poured into H2O (150 mL) and the aqueous layer was extracted with ethyl acetate (3x90 mL). The combined organic layers were dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The crude residue is chromatographed on "flash" silica gel (50 g with EtOAc/CH2Cl2) (3:7). This gives 513 mg (43%) of the desired material as an orange solid: m.p. 174-180°C decomposition) (EtOAc/CH2Cl 2:1); IR(KBr) 2980, 1650, 1400, 1325, 1250, 1160, 925, 730 cm-1; 1H NMR (D6DMSO) δ 1.31 (s,9,H), 2.80 (m,4H), 3.36 (m,4H), 4.56 (d,2H, J=5,8Hz,-NCH2Ar), 6.10 (d,1H ,J=7.7Hz), 6.65 (d,1H,J=7.7Hz), 7.15 (brd,1H,-NH-), 7.65-7.80 (m,5H), 7.96 (d,1H,J=7.40 Hz), 8.49 (d,1H,J=8.2Hz), and 10.37 (s,1H, -NHC=O). Anal. calcd for C27H30N4O5S: C, 61.05; H, 5.79; N, 10.72; S, 6.14. Found: C, 62.02, H, 5.80; N, 10.64; S, 5.95.

Getting a connection 26

N-[4-(N,N-t-butoxycarbonylpiperazinylsulfamoyl)benzyl-N-methyl-6-aminobenz [cd]indol-2(1H)-one

With vigorous stirring, 20 μl (0.32 mmol) of methyl iodide was added to a solution of 150 mg (0.29 mmol) of amine (25) and 65 μl (0.37 mmol) of diisopropylethylamine in 2 ml of DMF at 90°C. After 2 hours, another 20 μl (0.32 mmol) of methyl iodide was added. The mixture is stirred for another 2 hours, and then another 20 μl (0.32 mmol) of methyl iodide is added. After an additional two hours, the mixture was poured into H2O/saturated NaHCO3 1:1 (50 mL) and the aqueous layer was extracted with ethyl acetate (3x60 mL). Each organic layer is washed with H2O (2x50 ml). The combined organic layers are then dried over anhydrous Na2SO4 and the solvent is removed under reduced pressure. The crude residue is chromatographed on "flash" silica gel (20 g) with EtOAc/CH2Cl2 (1:4). This gives 80 mg (52%) of the desired product as an orange solid: IR (KBr) 2980, 2860, 1670, 1400, 1350, 1250, 1160, 930, 730 cm-1; 1H NMR (CDCl3) δ 1.40 (s,9H), 2182 (s,3H,-NCH3), 2.99 (brt,4H,J=5.0Hz) 3.51 (brt,4H,J=5.1Hz), 4.41 (s, 2H,-NCH2Ar), 6.89 (s,2H), 7.61 (d,2H,J=8.3Hz), 7.66-7.75 (m,3H), 8.09 (d,1H,J=7.0Hz), 8.23 (d, 1H, J=8.2Hz), and 9.06 (s, 1H, -NCH=O). High resolution mass spectrum. Calculated for C28H32N4O5S: 536.2093. Found: 536.2084.

Getting a date 27

N-[4-(N,N-piperazinylsulfamoir)benzyl]-N-methyl-6-aminobenz[cd]-indol-2(1H)-one

With vigorous stirring, 0.2 ml of hydrofluoroacetic acid is added to a solution of 75 mg (0.14 mmol) of amine (26) in 2 ml of CH2Cl2 at 25°C. After 3 hours, the mixture was poured into saturated NaHCO 3 (50 ml) and the aqueous layer was extracted with ethyl acetate (4x60 ml). The combined organic layers are then dried over anhydrous Na2SO4 and the solvent is removed under reduced pressure. The crude residue is chromatographed on "flash" silica gel (20 g) with MeOH/CH2Cl2 (5:95). This afforded 48 mg (79%) of the desired product as an orange solid: m.p. 176-178°C; IR(KBr) 3280, 1680, 1340, 1260, 1160, 900, 720 cm-1; 1H NMR (D6DMSO) δ 2.68 (m,4H), 276 (m,7H), 4.42 (s,2H,-NCH2Ar), 6.34 (d,1H,J=7.3Hz), 8.25 (d,1H,J= 8.2Hz), and 10.63 (s,1H,-NHC=O). High resolution mass spectrum. Calculated for C23H24N4O3S: 436.1569. Found: 436.1557.

Example 8: Preparation of compounds 28 and 29

Compounds 28 and 29 are obtained according to the following reaction scheme:

[image]

Getting a connection 28

N-methyl-6-aminobenz[cd]indol-2-(1H)-one

With vigorous stirring, to a solution of 690 mg (3.13 mmol) of 6-aminobenz[cd]-indol-2(1H)-one-hydrochloride (2) and 1.25 ml (7.20 mmol) of diisopropylethylamine in 5 ml of DMF, 0.2 ml (3.44 mmol) was added. of methyl iodide at 70°C. After 2 hours, the mixture was poured into H2O/saturated NaHCO3 (1:1) and the aqueous layer was extracted with ethyl acetate (3x100 mL). The combined organic layers are then dried over anhydrous Na2SO4 and the solvent is removed under reduced pressure. The crude residue is chromatographed on "flash" silica gel (50 g) with MeOH/CH2Cl2 (2:98). This afforded 232 mg (37%) of the desired product as an orange solid: m.p. 237-240°C (EtOAc/MeOH 2:1); IR (KBr) 3180, 1610, 1520, 1450, 1380, 1270, 770, 745 cm-1; 1H NMR (D6DMSO) δ 2.81 (brs,3H), 6.19 (d,1H,J=7.7Hz), 6.44 (m,1H-NH-), 6.78 (d,1H,J=7.7Hz), 7.67 (t ,1H,J=7.2Hz), 7.93 (d,1H,J=7.0Hz), 8.35 (d,1H,J=8.2Hz), and 10.38 (s,1H,-NHC=O). Anal. calcd for C12H10N2O: C, 72.71; H, 5.09; N, 14.13. Found: C, 72.72; H, 5.30; N, 14.29.

Getting a date 29

N-[4-(phenylsulfonyl)benzyl]-N-methyl-6-aminobenz[cd]-indol-2(1H)-one

With vigorous stirring, 120 mg (0.39 mmol) of 4-bromomethyldiphenylsulfone (7) was added to a solution of 60 mg (0.32 mmol) of amine (28) and 78 μl (0.45 mmol) of diisopropylethylamine in 2 ml of DMF at 90°C. After 2 hours, another 24 mg (0.08 mmol) of bromide is added together with 17 μl (0.08 mmol) of base. After two hours, the mixture was poured into 1:1 H 2 O/saturated NaHCO 3 (40 mL) and the aqueous layer was extracted with EtOAc (3x60 mL). Each organic layer is washed with water (2x20 ml). The combined organic layers are then dried over anhydrous Na2SO4 and the solvent is removed under reduced pressure. The crude residue was chromatographed on "flash" silica gel (20 g) with EtOAc/CH 2 Cl 2 (15:85). This gives 130 mg (95%) of the desired product as an orange solid: m.p. 228-230°C (EtOAc); IR (KBr) 1670, 1470, 1450, 1310, 1150, 725 cm-1; 1H NMR (CDCl3), δ 2.80 (s,3H,-NCH3), 4.39 (s,2H-NCH2Ar), 6.85 (d,1H, J=7.6Hz), 6.88 (d,1H,J=7.6Hz), 7.50-7.61 (m,5H), 7.68 (t,1H,J=7.33Hz), 7.75 (brs,1H,-NHC=O), 7.94 (d,2H,J=8.5Hz), 7.97 (d,2H ,J=7.3Hz), 8.08 (d,1H,J=7.0Hz), and 8.19 (d,1H,J=8.3Hz). Anal. calcd for C25H20O3N2S: C, 70.07; H, 4.70; N, 6.54; S, 7.48. Found C, 70.32; H, 4.72; N, 6.37; S, 7.22. High resolution mass spectrum. Calculated for C25H20O3N2S: 428.1195. Found 428.1181.

Example 9: Preparation of compounds 30 and 31

Compounds 30 and 32 are obtained according to the following reaction scheme:

[image]

Getting a connection 30

N-[4-tert-butylphenylsilyl)oxymethyl-1-naphthobenzyl]-N-methyl-6-aminobenz[cd]indol-2(1H)-one

With vigorous stirring, to a solution of 165 mg (0.83 mmol) of N-methyl-6-aminobenz[cd]indol-2-(1H)-one (28) and 194 µl (1.10 mmol) of diisopropylethylamine in 5 ml of DMF, 400 mg (1.10 mmol) of 1-bromoethyl-4-[(tert-butyldiphenylsilyl)oxy]methylnaphthalene at 100 °C. After three hours, the mixture was poured into 1:1 H2O/saturated NaHCO3 (100 ml) and the aqueous layer was extracted with ethyl acetate (2x100 ml). Each organic compound is washed with H2O (2x50 ml) and the combined organic layers are dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the crude product was chromatographed on flash silica gel (20 g) with EtOAc/CH 2 Cl 2 (15:85). This afforded 417 mg (83%) of the desired material as an orange foam: IR (KBr) 3180, 3040, 2930, 2850, 1620, 1350, 1220, 1070, 1030, 735 cm-1; 1H NMR (CDCl3), δ 112(s,9H), 2.92 (s,3H,-N-CH3), 4.81 (s,2H,-NCH2Ar), 5.26 (s,2H,-OCH2Ar), 6.92 (d, 1H,J=7.5Hz), 7.05 (d, 1H,J=7.5Hz), 7.35-7.5 (m,8H), 7.60 (t,1H,J=7.1Hz), 7.68-7.82 (m,6H), 7.95 (m,2H), 8.06 (m,2H), and 8.19 (d,1H,J=8.3Hz). High resolution mass spectrum. Calculated for C40H38N2O2Si: 606.2703. Found: 606.2720.

Getting a connection 31

N-[4-hydroxymethyl-1-naphthobenzyl]-N-methyl-6-aminobenz[cd]indol-2(1H)-one

With vigorous stirring, 1.2 ml (1.36 mmol) of 1.1 M tetra-n-butylammonium fluoride in THF at 25°C is added to a solution of 412 mg (0.68 mmol) of silyl ether (30) in 6 ml of THF. After 10 min, the mixture was poured into H2O (50 mL) and the aqueous layer was extracted with ethyl acetate (3x100 mL). Each aqueous layer was washed with H2O (40 mL) and the combined organic layers were dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. This gives 212 mg (85%) of the desired product as an orange solid: m.p. 230-232°C; IR (KBr) 3380, 3160, 2820, 1620, 1435, 1395, 1340, 1225, 1195, 1070, 920, 815, 740 cm-1; 1H NMR (D6DMSO) δ 2.85 (s,3H,-NCH3), 4.76 (s,2h,-NCH2Ar), 4.94 (d,2H,J=5.2Hz,ArCH2O-), 5.28 (t,1H,J=5.2 Hz,-OH), 6.87 (d,1H,J=7Hz), 7.11 (d,1H,J=7.5Hz), 7.42-7.57 (m,3H), 7.62-7.75 (m,2H), 7.94 (d , 1H,J=7.0Hz), 8.05-8.18 (m,3H), 10.61 (s,1H,-NHC=O). Anal. calcd for (C24H20N2)2: C, 78.24; H, 5.47; N, 7.60. Found: C, 77.97; H, 5.53, N, 7.51.

Example 10: Preparation of compounds 32 to 34

Compounds 32 to 34 are obtained according to the following reaction scheme:

[image]

Getting a connection 32

N-[4[(phenylsulfonyl)benzyl]-N-ethyl-6-aminobenz[cd]indol-2(1H)-one

With vigorous stirring, a solution of 200 mg (0.45 mmol) lactam N-[4-phenyl-sulfonyl)benzyl]-N-ethyl-aminobenz[cd]indol-1(1H)-one (8) in 10 ml of toluene at 110°C 200 mg (0.49 mmol) of Lawssen's reagent is added. After one hour, the solvent was removed under reduced pressure and the crude product was chromatographed on flash silica gel (30 g) with Et2O/CH2Cl2 (3:97). Thus, 198 mg (96%) of the desired thiolactam is obtained in the form of a red glassy substance: IR (KBr) 3300, 3060, 1420, 1290, 1140, 810, 720 cm-1; 1H NMR (CDCl3), δ 1.12 (t,3H,J=7Hz), 4.37 (q,2H,J=7Hz), 4.45 (s,2H,-NCH2Ar), 6.85 (d,1H,J=7.7Hz) , 6.94 (d,1H,J=7.7Hz), 7.46-7.60 (m,5H), 7.68 (t,1H,J=7.4Hz), 7.88 (d,2HJ=8.3Hz), 7.95 (d,2H, J=6.3Hz), 8.26 (m,2H), and 9.27 (brs,1H,-NCH=S). High resolution mass spectrum. Calculated for C26H22N2O2S2: 458.1123. Found: 458.1130.

Getting a connection 33

N-[4-(phenylsulfonyl)benzyl]-N-ethyl-6-aminobenz[cd]-indole-2-thiomethyl

With vigorous stirring of a solution of 190 mg (0.41 mmol) of thiolactam (32) and 0.91 (0.91 mmol) of aqueous 1N NaOH solution in 4 ml of EtOH/THF (3:1) mixture, 28 μl (0.46 mmol) of methyl iodide is added at 25° C. After 2 hours, the mixture was poured into H2O (50 ml) and the aqueous layer was extracted with ethyl acetate (3x100 ml). The combined organic layers are then dried over anhydrous Na2SO4 and the solvent is removed under reduced pressure. The crude residue was chromatographed on flash silica gel (20 g) with EtOAc/CH 2 Cl 2 (5:95). This gives 172 mg (88%) of the desired product as a red solid: m.p. 228-230°C (EtOAc); IR (KBr) 2920, 1435, 1300, 1225, 1150, 725 cm-1; 1H NMR (CDCl3), δ 1.15 (t,3H,J=7.1Hz), 2.83 (s,3H,-SCH3), 3.33 (q,2H,J=7.1Hz), 4.52 (s,2H,-NCH2Ar) , 6.84 (d,1H,J=7.6Hz), 7.45 (d,1H,J=7.6Hz), 7.50-7.60 (m,6H), 7.82-7.95 (m,5H), and 8.11 (d,1H, J=8.1Hz). Anal. calcd for C27H24N2O2S2: C, 68.61; H, 5.12; N, 5.93; S, 13.57. Found: C, 68.83; H, 5.12; N, 5.80; S, 13.32.

Getting a compound 34

N-[4-phenylsulfonyl)benzyl]-N-ethyl-6-aminobenz[cd]indol-2-amine

A mixture of 20 mg (0.04 mmol) of thiomethyl ether (33) in 1 ml of MeOH saturated with ammonia was heated in a sealed tube at 160°C for 4 hours. After cooling, the solvent is removed under reduced pressure and the crude product is chromatographed on "flash" silica gel (15 g) with a gradient of 10% MeOH/CH2Cl2. In this way, 18 mg (96%) of the desired amidine is obtained as a red foam: IR (KBr) 2690, 1620, 1430, 1300, 1140, 1100, 720 cm-1; 1H NMR (CDCl3), δ 1.07 (t,3H,J=7.0Hz), 3.21 (q,2H,J=7.0Hz), 4.40 (s,2H,-NCH2Ar), 6.84 (d,1H,J=7.7 Hz), 7.10 (d,1H,J=7.7Hz), 7.45-7.55 (m,5H), 7.61 (t,1H,J=7.8Hz), 7.82-7.95 (m,4H), 8.21 (d,1H ,J=8.2Hz), 8.25 (brs,2H,-NH2), and 8.54 (d,1H,J=7.1Hz). High resolution mass spectrum. Calculated for C26H23N3O2S: 441.1511. Found: 441.1515.

Example 11: Preparation of compounds 35 to 37

Compounds 35 to 37 are obtained according to the following reaction scheme:

[image]

Getting a compound 35

N-[4-phenylsulfonyl)benzyl]-N-methyl-6-aminobenz[cd]-indole-2(1H)-thione

With vigorous stirring, to a solution of 547 mg (1.28 mmol) of N-[4-(phenylsulfonyl)benzyl]-N-methyl-6-aminobenz[cd]indol-2(1H)one (29) in 30 ml of toluene, 568 mg ( 1.40 mmol) of Lawssen's reagent at 120°C. After 1 hour, the solvent is removed under reduced pressure and the crude residue is chromatographed on "flash" silica gel (50 g) with Et2O/CH2Cl2 (4:96). This gave 268 mg (47%) of the desired product as a red solid: m.p. 196-199°C; IR (KBr) 3160, 1430, 1415, 1300, 1180, 1145, 1100, 925, 805, 725 cm-1; 1H NMR (CDCl3), δ 2.84 (s,3H,-NCH3), 4.47 (S,2H,-NCH2Ar), 6.85 (d,1H,J=7.7Hz), 6.98 (d,1H,J=7.7Hz) , 7.49-7.61 (m,5H), 7.66 (t,1H,J=7.3Hz), 7.93-8.01 (m,4H), 8.19 (d,1H,J=8.1Hz), 8.25 (d,1H,J =7.3Hz), and 9.32 (brs,1H,-NCH=S). High resolution mass spectrum. Calculated for C25H20N2O2S2: 444.0966. Found: 444.0963.

Getting compound 36

N-[4-(phenylsulfonyl)benzyl]-N-methyl-6-aminobenz[cd]indole-2-thiomethyl

With vigorous stirring, to a solution of 265 mg (0.60 mmol) of thiolactam (35) and 1.3 ml (1.31 mmol) of 1N aqueous NaOH solution in 10 ml of 1:1 EtOH/THF, 41 μl (0.66 mmol) of methyl iodide n1 at 25°C was added. After 30 min, the mixture was poured into H2O (50 ml) and the aqueous layer was extracted with ethyl acetate (3x60 ml). The combined organic layers are then dried over anhydrous Na2SO4 and the solvent is removed under reduced pressure. The crude residue is chromatographed on "flash" silica gel (30 g) with EtOAc/CH2Cl2 (1:9). This gives 259 mg (95%) of the desired product as a red solid: m.p. 209°C; IR (KBr) 2800, 1410, 1300, 1200, 1145, 1100, 920, 810, 770, 720 cm-1; 1H NMR (CDCl3), δ 2.84(s,3H), 2.89 (s,3H), 4.57 (s,2H,-NCH2Ar), 6.84 (d,1H, J=7.6Hz), 7.48-7.62 (m,7H ), 7.85 (d,1H,J=7.0Hz), 7.93-8.00 (m,4H), and 8.03 (d,1H,J=8.1Hz). High resolution mass spectrum. Calculated for C26H22N2O2S2: 458.1123. Found: 458.1107.

Getting a compound 37

N-[4-(phenylsulfonyl)benzyl]N-methyl-6-aminobenz[cd]-indol-2-amine

A mixture of 255 mg (0.56 mmol) of thiomethyl ether (36) in 10 ml of MeOH saturated with ammonia was heated in a sealed tube at 145°C for 5 hours. After cooling, the solvent was removed under reduced pressure and the crude residue was chromatographed on flash silica gel (30 g) with MeOH/CH 2 Cl 2 (1:9). In this way, 207 mg (87%) of the desired amidine was obtained as a red foam: IR (KBr) 2840, 1610, 1410, 1295, 1215, 1140, 1090, 1050, 805, 720 cm-1; 1H NMR (D3DMSO), δ 2.83 (s,3H,-N-CH3), 4.46 (s,2H,-NCH2Ar), 6.86 (d,1H,J=7.6Hz), 7.16 (d,1H,J=7.6 Hz), 7.49-7.61 (m,5H), 7.66 (t,1H,J=8.1Hz), 7.92-8.02 (m,Hz), 820 (d,1H,J=8.2Hz), and 8.55 (d, 1H, J=7.2Hz). High resolution mass spectrum. Calculated for C25H21N3O2S: 427.1354. Found: 427.1370.

Example 12: Preparation of compounds 38 to 40

Compounds 38 to 40 were obtained according to the following reaction scheme:

[image]

Getting a connection 38

N-[3(1-t-butylmethylsiloxypropyl]-6-aminobenz[cd]indol-2(1H)-one

A solution of 0.613 g (2.76 mmol) of 6-aminobenz[cd]indol-2(1H)-one hydrochloride (2) in 10 ml of DMF, which is stirred, is added to 1.1 ml (6.31 mmol) of N,N-diisopropyl-ethylamine (DIEA) and 0.778 g (3.07 mmol) of 3-bromopropyl-1-t-butyl-dimethylsilyl-ether. The obtained mixture is heated for 4 hours at 120°C, after which 0.15 g (0.59 mmol) of bromide and 0.10 ml (0.57 mmol) of DIEA are added. After heating for 24 hours, the reaction mixture was cooled and poured into 100 ml of H2O and extracted with CH2Cl2 (2x200 ml). The organic layers are combined, dried with anhydrous MgSO4 and after removal of the solvent under reduced pressure, the crude residue is chromatographed on "flash" silica gel with hexane:ethyl acetate (1:1). This gives 0.45 g (46%) of the desired product (38) as a red solid: m.p. 126-129°C; IR (KBr) 3400, 3200, 2920, 2880, 1680, 1630 cm-1; 1H NMR (CDCl3), δ 0.10 (s,6H), 0.93 (s,9H), 2.00 (m,2H), 3.38 (m,2H), 3.86 (t,2H,J=5.5Hz), 4.93 (bs ,1H), 6.37 (d,1H,J=7.7Hz), 6.48 (d,1H,J=7.7Hz), 7.67 (t,1H,J=7.2Hz), 8.00 (bs,1H). Calculated for C20H28N2O2Si (exact mass): 356.1921. Found: 356.1920.

Getting a connection 39

N-[3(1-t-butylmethyl-siloxypropyl]amino-4-methylphenylsulfonyl-t-butyl-1-piperazinecarboxylate-6-aminobenz[cd]-indol-2(1H)-one

A solution of 0.242 g (0.68 mmol) of aniline (38), 0.300 g (0.72 mmol) of bromide (12) and 0.13 ml (0.72 mmol) of DIEA was heated for 4 hours at 100°C. Then another 0.09 g (0.67 mmol) of bromide and 0.012 mol (0.07 mmol) of DIEA are added. After 1.5 hours, the reaction mixture was cooled and poured into 50 ml of saturated aqueous NaCl solution. It is thus collected, dried in a vacuum and "flash" chromatographed on silica with hexane:ethyl acetate (1:1). In this way, 0.430 g (91%) of the desired product (39) was obtained as a brittle foam: IR (KBr) 2920, 2860, 1675, 1160 cm-1; 1H NMR (CDCl3), δ 1.40 (s,9H), 1.78 (m,2H), 2.94 (t,4H,J=5.0Hz), 3.28 (t,2H,J=7.3Hz), 3.49 (t,4H , J=5.0Hz), 3.60 (t,2H,J=5.9Hz), 4.43 (s,2H), 6.80 (d,1H,J=7.6Hz), 6.90 (d,1H, J=7.6Hz), 7.49 (d,2H,J=8.3Hz), 7.65 (d,2H,J=8.3Hz), 7.72 (t,1H,J=7.1Hz), 8.01 (bs,1H), 8.08 (d,1H,J =7.0Hz), and 8.29 (d,1H,J=8.2Hz). Anal. calculated for C36H50N4O6SiS (exact mass): 694.3223. Found: 694.3244.

Getting compound 40

N-[4-(N,N-piperazinylsulfamoyl)benzyl]-N-hydroxypropyl-6-aminobenz[cd]indol-2-(1H)-one

0.6 ml of trifluoroacetic acid (TFA) was added with stirring to a solution of 0.343 g (0.49 mmol) (39) in 5 ml of CH2Cl2. After 2.5 hours, the volatiles were removed under reduced pressure and the orange oily residue was dissolved in 5 ml of THF. 0.5 ml of a 1M solution of tetrabutylammonium fluoride in THF (0.50 mmol) was added. After two hours at room temperature, the reaction mixture is poured into 50 ml of H2O and extracted again with ethyl acetate until the aqueous layer becomes colorless. The combined organic layers were dried with anhydrous MgSO4 and after removal of the solvent, the crude residue was "flash" chromatographed on silica eluting first with EtOAc:MeOH (0-15%) and then with EtOAc-MeOH-CH3OH (8:1:1 ). Favorable fractions were collected, concentrated, dissolved in 300 ml of ethyl acetate and washed with 4 x 150 ml of H2O to remove the tetrabutylammonium salts that eluted with the product (3). The ethyl acetate layer was dried with anhydrous MgSO4 and after removal of the solvent, the solid was recrystallized from CH3CN. In this way, 0.13 g (55%) of substance (40) was obtained as a yellow product: m.p. 178-179°C; IR (KBr) broad 3300, 1680, 1450, 1350, 1160 cm-1; 1H NMR (CDCl3), δ 1.81(m,2H), 2.92 (m,8H), 3.28 (t,2H,J=6.8Hz), 3.69 (t,2H,J=6.0Hz), 4.42 (s,2H ), 6.84 (d,1H,J=7.5Hz), 6.95 (d,1H,J=7.6Hz), 7.47 (d,2H,J=8.3Hz), 7.67 (d,2H,J=8.3Hz), 7.75 (t,2H,J=7.1Hz), 7.83 (bs,1H), 8.09 (d,1H,J=6.9Hz), and 8.29 (d,1H,J=8.3Hz). Anal. calculated for C25H28N4O4S (exact mass): 480.1833. Found: 480.1850.

Example 13: Preparation of compound 41

Compound 41 was obtained according to the following reaction scheme:

[image]

Getting a connection 41

N-[4-(phenylsulfonyl)benzyl]-N-ethyl-6-amino-dihydrobenz[cd]indole

152 mg (0.34 mmol) of N-]4-(phenylsulfonyl)benzyl]-N-ethyl-6-aminobenz[cd]indol-2(1H)-one (8) in 5 ml of dry THF was added via syringe to a suspension of 28 mg (0.74 mmol) of LAH (ie lithium aluminum hydride) in 5 ml of THF. The reaction mixture is left to stir in an argon atmosphere at room temperature for 1.5 hours, after which the reaction is "quenched" with a saturated solution of NaHCO3 in water (15 ml) and extracted with 2x25 ml of ethyl acetate. The organic compounds were dried with anhydrous MgSO4 and concentrated under reduced pressure. The obtained dark-colored film was chromatographed on silica gel eluting with degassed CH2CI2 under nitrogen pressure. In this way, 46 mg (31%) of substance (41) was obtained as a light colored brittle foam, which decomposes if exposed to air: 1H NMR (CDCl3), δ 1.00 (t,2H,J=7.0Hz), 3.05 ( t,2H, J=7.0Hz), 4.25 (s,2H), 6.32 (d,1H,J=7.6Hz), 6.86 (d,1H,J=7.6Hz), 7.18 (d,1H, J=6.8 Hz), 7.40-7.54 (m,6H), 7.76 (d,1H,J=8.4Hz), 7.83 (d,2H,J=8.3Hz), and 7.92 (dd, 1H,J=8.3Hz, 1.5Hz ).

Example 14:

Compounds 42 to 45 were obtained according to the reaction scheme:

Compounds 42 to 47 were obtained according to the reaction scheme:

[image]

Obtaining compound 42

2,6-hydroxynaphthalene

102 ml (102 mmol) of a 1M solution of BH3THF in THF was placed in a dropping funnel and slowly added to a suspension of 10.0 g (46.25 mmol) of 2,6-naphthalenedicarboxylic acid in 130 ml of THF, and cooled to 0°C. When the addition is complete, the reaction mixture is warmed to room temperature and stirred for 18 hours and then the reaction is "quenched" with water. The aqueous layer is saturated with K2CO3 and the layers are separated. The aqueous layer is extracted again with ethyl acetate. The combined organic layers are washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. In this way, 7.37 g (85%) of substance (42) was obtained. An analytical sample was crystallized from THF: m.p. 172-173°C; IR (KBr) 3200 (broad), 1020, 890, 820 cm-1; 1H NMR (dms-d6) δ 4.63 (d,4H,J=5.6Hz), 5.30 (t,2H,J=5.6Hz), 7.43 (dd,2H,J=8.5,1.0Hz), 7.77 (s, 2H), and 7.82 (d, 2H, J=8.4Hz). Anal. calcd for: C12H12O2: C, 76.57; H, 6.43. Found C, 76.77; H, 6.48.

Getting compound 43

2-hydroxymethyl-6-tert-butylphenylsiloxymethyl-naphthalene

7.37 g (39.16 mmol) of diol was dissolved in 40 ml of DMF. 2.66 g (39.20 mmol) of imidazole and 10.2 ml (39.16 mmol) of tert-butyldiphenyl-chlorosilane were added and allowed to stir overnight. Volatile substances are removed under reduced pressure and the residue is dissolved in 250 ml of ethyl acetate and washed with 0.5 N HCl. The organic layer is dried over anhydrous MgSO4 and concentrated. The crude oil was chromatographed on "flash" silica eluting with CH2Cl2. Thus, 9.8 g (59%) of the mono-protected diol (43) were obtained in the form of a colorless oil: 1H NMR (CDCl3) δ 1.12 (s,9H), 1.77 (t,1H,J=6.0Hz), 4.85 (d, 2H,J=6.0Hz), 4.92 (s,2H), 7.34-7.48 (m,8H), and 7.70-7.83 (m,8H).

Getting compound 44

2-bromoethyl-6-tert-butyldiphenylsiloxymethylnaphthalene

4.31 g (16.40 mmol) of triphenylphosphine was dissolved in 20 ml of CH2Cl2 and cooled to 0 °C. 2.72 g (8.2 mmol) of carbon tetrabromide is added. After 5 minutes, 3.50 g (8.20 mmol) of alcohol (43) dissolved in 10 ml of CH2Cl2 were added. The reaction ends after 10 minutes, after which the volatile substances are evaporated under reduced pressure. The crude oily residue was filtered through a short column of silica, which was eluted with CH 2 Cl 2 to remove triphenylphosphine oxide. In this way, 2.80 g (68%) of the bromine product was obtained in the form of an oil, which was used in further reactions without purification: 1H NMR (CDCl3) δ 1.12 (s,9H), 4.64 (s,2H), 4.91 (s, 2H), 7.37-7.43 (m,8H), and 7.70-7.81 (m,8H). Anal. calculated for C28H29BrOS (exact mass): 488.1171. Found 488.1157.

Getting compound 45

N-[2-methyl-6-tert-butylphenylsiloxymethylnaphthalene]-6-aminobenz[cd]indol-2(1H)-one

Amine (45) was obtained in a similar manner to (38) above, using 2-bromomethyl-6-tert-butyldiphenyl-siloxymethylnaphthalene. After the work was completed, the crude material of the residue was chromatographed by elution with CH2Cl2:ETOAc (5:1). In this way, compound (45) was obtained in 49% yield as an orange solid: m.p. 182-184°C; IR (KBr) 2915, 2830, 1700, 1450, 1100 cm-1; 1H NMR (CDCl3) δ 1.12 (s,9H), 4.64 (s,2H), 4.80 (bs,1H), 4.92 (s,2H), 6.45 (d,1H,J=7.7Hz), 6.79 (d, 1H,J=7.6Hz), 7.36-7.87 (m,18H), 8.08 (d,1H,J=8.1Hz), and 8.11 (d,1H,J=7.1Hz). Anal. calculated for C39H36N6O2Si (exact mass): 592.2548. Found: 592.2562.

Getting compound 46

N-[2-methyl-6-tert-butyldiphenylsiloxymethylnaphthalene]-N-methyl-6-aminobenz[cd] indol-2(1H)-one

A solution of 823 mg (1.39 mmol) of amine (45), 0.25 ml (1.44 mmol) of DIEA and 0.091 ml (1.46 mmol) of iodomethane in 15 ml of DMF was heated at 75°C for 3 hours. After that, 0.086 ml (1.39 mmol) of CH3I and 0.24 ml (1.39 mmol) of DIEA were added. Heating continues for another 12 hours. The precipitate is filtered, dried in vacuo and chromatographed on silica gel eluting with CH2Cl2-EtOAc (10:1). This gave 300 mg (36%) of compound 46 as an orange solid: IR (KBr) 2925, 1680, 1460, 1000, 810 cm-1; 1H NMR (CDCl3) 1.12 (s,9H), 2.87 (s,3H), 4.54 (s,2H), 4.93 (s,2H), 6.86 (d,1H,J=7.6Hz), 6.92 (d,1H ,J=7.6Hz), 7.36-7.84 m,17H), 7.90 (bs,1H), 8.09 (d,1H,J=7.0Hz), and 8.37 (d,1H,J=8.2Hz). Anal. calculated for: C40H38N2O2Si (exact mass): 606.2704. Found: 606.2707.

Getting compound 47

N-(6-hydroxymethyl-2-naphthobenzyl)-N-methyl-6-aminobenz[cd]-indol-2(1H)-one

With stirring, 0.65 ml (0.71 mmol) of a 1.1M solution of tetra-n-butyl-ammonium-fluoride in THF was added to a solution of 288 mg (0.47 mmol) of amine (46) in 5 ml of THF. After 10 min, the reaction mixture was diluted with 10 ml H 2 O and extracted with ethyl acetate until the orange precipitate dissolved. The organic layers are combined and washed with 20 ml of saturated aqueous NaCl solution and dried. The solvent was removed under reduced pressure. The remaining orange solid product is refluxed with 10 ml of ethyl acetate, cooled and filtered. This last process is then repeated. In this way, 125 mg (69%) of compound (47) was obtained as an orange solid: m.p. 205-206°C (decomposition); IR (KBr) 3350, 3160, 1710, 1450, 1200 cm-1: 1H NMR (DMSO-D6), δ 2.78 (s,3H), 4.47 (s,2H), 4.64 (s,2H), 6.84 (d ,1H,J=7.5Hz), 6.97 (d,1H,J=7.6Hz), 7.44 (dd,1H,J=8.5, 1.3Hz), 7.51 (dd,1H,J=8.5, 1.3Hz), 7.75 -7.89 (m,5H), 7.98 (d,1H,J=6.9Hz), 8.33 (d,1H,J=8.2Hz), and 10.62 (s,1H). Anal. calculated for: C24H20N2O2 (exact mass): 368.1526. Found: 368.1525.

Example 15: Preparation of compounds 48 and 49

Compounds 48 and 49 were obtained using the reaction scheme:

[image]

Getting compound 48

5-methylnaphthyl acyl azide

A solution of 1.00 g (5.37 mmol) of 5-methylnaphthoic acid and 1.50 ml (10.7 mmol) of triethylamine in 15 ml of acetone is added dropwise to a solution of 1.023 ml (10.7 mmol) of ethyl chloroformate in 10 ml of acetone at -5°C with vigorous stirring. 10 minutes. After stirring at -5°C for 30 minutes, a solution of 0.696 g (10.7 mmol) of sodium azide in 10 ml of water was added dropwise to the mixture. After mixing at -5°C for 30 minutes, the obtained suspension is poured into 100 ml of water. The product was collected by filtration as a white solid (0.934 g, 82%) and used without further purification: m.p. 69-70°C (decomposition); 1H NMR (CDCl3) δ 2.73 (s,3H), 7.40 (d,1H, J=7.0Hz), 7.50-7.57 (m,2H), 8.23-8.31 (m,2H), and 8.92 (d,1H, J=8.6Hz).

Getting a connection 49

5-Methylnaphthostyryl

A solution of 100 mg (0.54 mmol) of 5-methyl-naphthyl acylazide (dried azeotropically with benzene) in 2 ml of dry chlorobenzene is added dropwise to a container of 25 ml of dry distilled chlorobenzene under argon. The solvent is distilled over a period of one hour to a volume of approximately 1 ml.

The resulting isocyanate solution is added to a test tube containing approximately 4 ml of condensed boron trichloride at 78°C. The test tube is sealed and heated to 110-120°C with stirring for 85 hours. After cooling to ambient temperature, the test tube is opened and boron trichloride is allowed to come out. The dark solution is poured into 50 ml of 0.5N HCl. The test tube is washed with ethyl acetate (2x5 ml) and THF (2x5 ml). The aqueous solution is extracted with ethyl acetate (2x20 ml) and CH2Cl2 (2x20 ml). The combined extracts are washed with saline (20 ml) and dried over anhydrous Na2SO4, and the solvent is removed under reduced pressure. The residue was chromatographed on flash silica gel (10 g) using THF/CH 2 Cl 2 (5:95) as eluent. In this way, 25 mg (25%) of the desired product was obtained as a yellow substance: m.p. 215-217°C; 1H NMR (CDCl3) δ 6.96 (d,1H, J=7.03Hz), 7.46 (m,dd,1H,Jl=7.13Hz,J2=8.55Hz), 7.53 (d,1H,J=7.06Hz), 7.64 (d, 1H,J=8.5Hz), 7.83 (broad s,1H); IR (KBr) 1685, 1640, 1495, 765 cm-1. Anal. calcd for C12H9NO: c, 78.67; H, 4.95; N, 7.65. Found: C,78.40; H, 4.99; N, 7.57.

Example 16: Compounds 50 to 53

Compounds 50 to 53 were obtained according to the following reaction scheme:

[image]

Getting compound 50

4-[methylaminoethyl]diphenylsulfone

A solution of 5.02 g (16.14 mmol) of 4-bromomethyldiphenylsulfone in 100 ml of THF was slowly added over one hour to a vigorously stirred mixture of 14.0 ml (162.63 mmol) of 40% (w/w) aqueous methylamine in 50 ml of THF. The mixture is then concentrated under reduced pressure to 30 ml, diluted with 100 ml of CH2Cl2 and extracted with 2x120 ml of 0.5N HCl. The combined aqueous solutions are made alkaline with 6N NaOH and extracted with 2x150 ml of CH2Cl2. The combined organic layers are dried with anhydrous MgSO4, and the solvent is removed under reduced pressure. In this way, 2.30 g (55%) of the desired product is obtained in the form of a white solid: mp 107-110°C; IR (KBr) 3340, 2840, 1450, 1400, 1300, 1150, 1100 cm-1; m NMR (CDCl 3 ) δ 2.42 (s,3H), 3.79 (s,2H), 7.45-7.60 (m,5H), and 7.88-7.95 (m,4H).

Getting a connection 51

N-[4-(phenylsulfonyl)benzyl]-N-methyl-1-amino-4,5-dinitronaphthalene

A solution of 1,597 g (6.32 mmol) of 1-chloro-4,5-dinitronaphthalene, 1,650 g (6.32 mmol) of 4-[N-methylaminomethyl]-diphenylsulfone and 0.82 g (8.19 mmol) of anhydrous calcium carbonate was stirred for 20 hours at 130°. C. A further 0.150 g (0.57 mmol) of amine was added and left to react for two hours. The reaction mixture is cooled, poured into H2O (200 ml) and extracted with ethyl acetate (2x250 ml). The combined organic layers are dried with anhydrous MgSO4 and the solvent is removed under reduced pressure. The crude residue was "flash" chromatographed on silica, eluting with CH2CI2. Thus, 2.02 g (67%) of the desired product was obtained as an orange foam: IR (KBr) broad 3420, 1560, 1520, 1340, 1310, 1150 cm-1; 1H NMR (CDCl3) δ 2.91 (s,3H), 4.46 (s,2H), 7.15 (d,1H, J=8.5Hz), 7.50-7.66 (m,7H), 7.97 (d,4H,J=8.0 Hz), 8.21-8.26 (m,2H), and 8.49 (d,1H, J=8.6Hz). High resolution mass spectrum. Calculated for C24H19N3O6S: 477.0996. Found: 477.1009.

Getting compound 52

N-[4-(phenylsulfonyl)benzyl]-4-methyl-4,5-diaminonaphthalene

With stirring, a solution of 0.40 g (0.84 mmol) of N-[4-(phenylsulfonyl)benzyl]-N-methyl-1-amino-4,5-dinitronaphthalene and 0.40 ml (8.25 mmol) of hydrazine monohydrate in 3 ml of THF solution: MeOH 2:1 heat to reflux. Add one drop of 50% Raney nickel in water. The color of the reaction mixture changes from dark red to green. TLC shows that the reaction is complete. The reaction mixture is filtered through diatomaceous earth sold under the trade name "Celite", and the solvent is removed under reduced pressure. The wet (H2O) residue is dissolved in CH2CI2 and dried over anhydrous MgSO4. The solvent is removed under reduced pressure, and the crude residue is "flash" chromatographed by elution with CH2Cl2:EtOAc (20:1). in this way, 137 mg (40%) of diaminonaphthalene were obtained as a dark colored foam that quickly decomposes. 1H NMR (CDCl3) δ 2.63 (s,3H), 4.15 (s,2H), 4.52 (bs,4H), 6.51 (d,1H,J=7.9Hz), 6.62 (d,1H,J=6.85Hz) , 6.87 (d,1H,J=7.9Hz), 7.21 (d,1H,J=7.9Hz), 7.47-7.55 (m,5H), 7.87 (d,1H,J=8.2Hz), 7.88 (d, 1H,J=8.3Hz), and 7.93-7.96 (m,2H). This material was used without retention in the crystallization step to obtain compound 53.

Getting compound 53

N-[4-(phenylsulfonyl)benzyl]-N-methyl-4-amino-2-methylpyrimidine

A solution of 130 mg (0.31 mmol) of N-[4-(phenylsulfonyl)-benzyl]-N-methyl-4,5-diaminonaphthalene in 3 ml of acetic anhydride was left to react for 10 minutes. The acetic anhydride is removed in vacuo. The obtained residue was dissolved in 25 ml of ethyl acetate and washed with a saturated aqueous solution of NaHCO3 (2x20 ml). The organic layer was dried with anhydrous MgSO4, and the solvent was removed under reduced pressure. The residue was "flash" chromatographed on silica gel eluting with CH2Cl2:CH3OH (14:1). To remove impurities in the eluate, a second flash column was used and eluted with EtOAc:MeOH (19:1). This gives a light oil which, when recrystallized from MeOH, gives 75 mg (20%) of a tan solid: m.p. 141 (dissolution); IR (KBr) broad 3500-2740, 1610, 1405, 1365, 1305, 1150, 1100 cm-1; 1H NMR (CDCl3) δ 2.14 (s,3H), 2.62 (s,3H), 4.13 (s,2H), 6.5 (bs,2H), 6.86 (d,1H,J=7.8Hz), 7.18 (d, 1H, J=8.0Hz), 7.37 (d,1H,J=8.6Hz), 7.48-7.60 (m,5H), 7.89 (d,2H,J=8.3Hz), and 7.95 (m,2H). High resolution mass spectrum. Calculated for C26H23N3O2S: 441.1511. Found: 441.1528.

Example 17: Determination of inhibition constants according to 5,10-methylene-tetrahydrofolate

The inhibition constant Ki of thymidylate synthase was determined by the following method. All tests were performed at 25°C and injected with the addition of three different types of thymidlate synthase ("TS"): (1) Escherichia Coli TS ("ETS"); (2) Candida TS ("CTS"), one fungus; and (3) human TS ("HTS").

TS exhibits ordered two-reactant kinetics (Daron, H.H. and Auli, J.L., J. Biol. Chem. 253, 940-951 (1978), and DUMP (2'-deoxyuridine-5'-monophosphate). The concentration used for these reactions was near the saturation level so that the experiments were pseudo-first order.All reaction mixtures contained 50 mM Tris at pH 7.8 (the final pH of the reaction was 7.6), 10 mM DTT (dithiothreitol), 1 mM EDTA (ethylenediaminetetraacetic acid), 25 mM MgCl2, 15 mM formaldehyde and 25 µM dUMP. When human TS was tested, 100 μg/ml BSA (bull serum albumin) was 5 to 150 (J.M (eight concentrations: 5, 6.6, 10, 13, 16, 25 and 150 μM). A standard curve in the absence of inhibitor was made in each experiment. Three curves were then made with inhibitor at three different concentrations with a minimum range, where possible, of 1/2 to 2 times K; (Cleland, W.W., Biochem . Biophys. Acta 67, 173-187 (1963). Three experiments were made with a spectrometer at 340 nm (Wahba, A.3. and Friedkin, M., J. Biol. Chem. 236, PC11-PC 12 (1961), by monitoring the formation of DHF (dihydrofolate) (mM absorption coefficient of 6.4) or by monitoring the release of tritium (Lomax, M.I.S. and Greenberg, G.R., J. Biol. Chem. 242, 109-113 (1967) from the 5-position of DUMP (experiments for liberated tritium contained 0.5 μcI dUMP). Carbon was used to remove unreacted dUMP from the tritium released by the reaction mixture, and the resulting water was determined. Inhibition constants are determined graphically, by plotting Km or the reciprocal of Vmax versus inhibitor concentration (Cleland, W.W., The Enzymes 2, 1-65 (1970)).

Testing in vitro

Cell growth in the presence of the subject compounds was observed using three cell lines: (1) murine leukemia L1210 (ATCC CCL 219); (2) CCRF-CEM, human lymphoplastic leukemia lines of T-cell origin (ATCC CCL 119); and (3) kinase-deficient human adenocarcinoma (GC3/M TK) lines. Both lines were maintained in RPMI 1640 medium containing 5% heat-inactivated fetal saline in antibiotic-free saline.

IC50 values were determined in 150 μl microcultures each containing 1500 (L1210), 4000 (CCRF-CEM) or 10000 (GC3/M TK) cells established in 96-well plates in growth medium containing 50 Ul/ml penicillin and 50 mcg/ml streptomycin. Growth was measured during 3 days (L1210) or 5 days (CCRF-CEM GC3/M TH) of continuous exposure to various concentrations of each test compound added 4 hours after initial cell application with an MTT-tetrazolium reduction experiment according to Mosmann, T.J. , Immunol. Meth. 65, 55-63 (1983), modified from Alley et al., Cancer Res. 48, 589-601 (1988). The water-insoluble derivatives were dissolved in DMSO and diluted to a final concentration of 0.3% solvent in cell cultures.

The results obtained from these procedures are shown below in Table 2, in which the tested compounds have the following formula:

[image]

[image]

[image]

Although the invention has been described in detail with reference to its specific embodiments, it will be clear to a person skilled in the art that various changes and modifications can be made within the invention without departing from its spirit and scope. Thus, it was intended to cover modifications and variations of this invention if they come within the scope of the appended claims and their equivalents.

The best way to apply the invention known to the applicant

This invention can best be used if it is realized in the following way:

16.5 ml (0.260 mol) of 70% nitric acid was added to a mixture of 33.9 g (0.200 mol) of benz[cd]indol-2(1H)-one in 150 ml of glacial acetic acid. In the beginning, the reaction is weakly exothermic, and then during one hour the reaction temperature rises to 50°C. The reaction mixture is gradually cooled to room temperature in a water bath. A thick dark green paste is obtained. The mixture is filtered, washed with 50% aqueous acetic acid and extracted as much as possible. The resulting moist filter cake is heated in 600 ml of ethanol under reflux and cooled to 0°C. The mixture is filtered, washed with cold methanol and dried in vacuo to give 22.6 g (51% of theory) of 6-nitrobenz[cd]indol-1(1H)-one. TLC (CHCl3MeOH 95:5) shows that the product is practically a single spot substance.

An analytically pure sample is obtained by refluxing 10.52 g of 6-nitrobenz[cd]indol-2(1H)-one in 350 ml of THF. After refluxing for 30 minutes, the mixture is filtered and the filtrate is evaporated almost to dryness. The wet solid obtained was mixed with 200 ml of methanol and then evaporated to dryness. Finally, the wet cake is placed in 200 ml of methanol, heated to reflux and cooled to -4°C overnight. The mixture is filtered and then the filter cake is washed with cold methanol and dried in vacuo to give 8.97 g (85% of theory) of an orange solid: m.p. 298-300°C; 1H NMR (dg DMSO TMS) δ (ppm): 7.10 (d,1H,J=9Hz, 8.05 (dd,1H,J=6Hz), 8.16 (d,1H,J=6Hz), 8.61 (d,1H,J=6Hz) and 8.85 (d,1H,J=9Hz).

Claims (99)

1. A compound with a naphthalene ring that inhibits thymidylate synthase, formulas: [image] indicated by, in which: Z and W are independently nitrogen, sulfur, or substituted or unsubstituted alkylene groups with the limitation that when one of Z or W is nitrogen or sulfur, the other is a substituted or unsubstituted alkylene group; Ar is a group comprising one or more rings selected from the group consisting of (1) substituted or unsubstituted aryl rings and (2) substituted or unsubstituted heterocyclic rings; R is hydrogen or a substituted or unsubstituted alkyl group; R 1 is hydrogen, a substituted or unsubstituted lower alkyl group or a substituted or unsubstituted amino group; A is hydrogen, halogen, carbon, nitrogen or sulfur with the proviso that if A is carbon, nitrogen or sulphur, A may itself be substituted with a substituted or unsubstituted alkyl group; and X and Y together form a five- or six-membered nitrogen-containing heterocyclic ring which may be substituted or unsubstituted. 2. A compound with a naphthalene ring according to claim 1, wherein said compound has a thymidylate synthase inhibition constant Kj less than or equal to about 10-4 M. 3. A compound with a naphthalene ring according to claim 2, wherein said compound has a thymidylate synthase inhibition constant Kj less than or equal to about 10-6 M. 4. A compound with a naphthalene ring according to claim 3, wherein said compound has a thymidylate synthase inhibition constant Kj less than or equal to about 10-9 M. 5. A compound with a naphthalene ring according to claim 1, wherein: Z is a nitrogen atom; W is an unsubstituted alkylene group; Ar is a monocyclic or bicyclic, substituted or unsubstituted aryl or heteroaryl ring; R1 is a hydrogen atom; A is a hydrogen, halogen or carbon atom; and X is a nitrogen atom. 6. A compound with a naphthalene ring according to claim 5, characterized in that: W is a methylene group; A is a hydrogen atom; X is a nitrogen atom which, together with a hydrogen atom, forms the -NH= group; and Y is a carbon atom. 7. A compound with a naphthalene ring according to claim 6, characterized in that: R is selected from the group consisting of methyl, ethyl, hydroxyethyl, n-propyl, isopropyl, hydroxypropyl and CH2-S-CH3; Ar is a phenyl, naphthyl or heteroaryl ring unsubstituted or substituted with an agent selected from the group consisting of a halogen atom, hydroxy, alkoxy, alkyl, hydroxyalkyl, fluoroalkyl, amino, -CN, -NO2, carbalkoxy, carbamyl, carbonyl, carboxyldioxy, carboxy, amino acid carbonyl, amino acid sulfonyl, sulfamyl, sulfanylyl, sulfahydryl, sulfino, sulfinyl, sulfo, sulfonamido, sulfonyl, substituted or unsubstituted phenylsulfonyl, phenylmercapto, phosphazo, phosphinico, phosphino, phospho, phosphono, phosphoro, phosphorose, [image] Y is unsubstituted or substituted carbon forming a carbon-containing group and may be -CH2-, >C=O, >C=S, =C(NH2)- and =C(CH3)-. 8. A compound with a naphthalene ring according to claim 7, wherein R is methyl, Ar is 4-phenylsulfonyl, and Y is a carbon atom substituted with an amino group so as to form a =C(NH2) group. 9. A compound with a naphthalene ring according to claim 1, characterized in that: Z is a nitrogen atom; W is an unsubstituted alkylene group; Ar is a phenyl group substituted with an electron-withdrawing group; R1 is a hydrogen atom; A is a hydrogen, halogen or carbon atom; R is selected from the group consisting of methyl, ethyl, hydroxyethyl, n-propyl, isopropyl, hydroxypropyl and -CH2--S-CH3; and X and Y are independently a carbon or nitrogen atom. 10. A compound with a naphthalene ring according to claim 9, wherein: W is methyl; said electron-withdrawing group is a >C=O or >SO2 group directly attached to an amino acid group, a substituted or unsubstituted aryl group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted cathocyclic group; and A is a hydrogen or carbon atom. 11. A compound with a naphthalene ring according to claim 10, wherein X and Y together form a substituted or unsubstituted heterocyclic ring containing two nitrogen atoms. 12. A compound with a naphthalene ring according to claim 11, wherein: Ar is a phenyl group substituted in the para position with a >SO2 group directly attached to another phenyl group; A is a hydrogen atom; X is a nitrogen atom; Y is a nitrogen atom; and X and Y together form a heterocyclic ring that has the formula: [image] where P is a hydrogen atom, an unsubstituted or substituted alkyl group or an amino group. 13. A compound with a naphthalene ring according to claim 12, wherein P is a methyl group. 14. A compound with a naphthalene ring according to claim 11, characterized in that: Ar is a phenyl group substituted in the para position with a >SO2 group directly attached to another phenyl group; A is a carbon atom forming part of a substituted or unsubstituted alkyl group; X is a nitrogen atom; Y is a nitrogen atom; and X and Y together form a heterocyclic ring that has the formula: [image] where P is a hydrogen atom, a substituted or unsubstituted alkyl group or an amino group. 15. A compound with a naphthalene ring according to claim 14, characterized in that A is a carbon atom which together with three hydrogen atoms forms a methyl group, and P is a methyl group. 16. A compound with a naphthalene ring according to claim 9, wherein X and Y together form a substituted or unsubstituted heterocyclic ring containing one nitrogen atom. 17. A compound with a naphthalene ring according to claim 16, wherein: Ar is a phenyl group substituted in the para position with a >SO2 group directly attached to another phenyl group; A is a hydrogen, halogen or carbon atom which, together with other atoms, forms a substituted or unsubstituted alkyl group; X is a nitrogen atom; Y is a carbon atom; and X and Y together form a heterocyclic ring that has the formula: [image] where Q is a hydrogen atom, a substituted or unsubstituted alkyl group or an amino or hydroxy group. 18. A compound with a naphthalene ring according to claim 17, wherein: A is a hydrogen, chlorine or carbon atom which taken together with three hydrogen atoms forms a methyl group; and Q is a hydrogen atom, or a methyl or hydroxy group. 19. A compound with a naphthalene ring according to claim 16, wherein: Ar is a phenyl group substituted in the para position with a >SO2 group directly attached to another phenyl group; A is a hydrogen, halogen or carbon atom which, together with other atoms, forms a substituted or unsubstituted alkyl group; X is a carbon atom; Y is a nitrogen atom; and X and Y together form a heterocyclic ring that has the formula: [image] where Q is a hydrogen atom, a substituted or unsubstituted alkyl group, or an amino or hydroxy group. 20. A compound with a naphthalene ring according to claim 19, wherein A is a hydrogen atom and Q is a hydrogen atom. 21. A compound with a naphthalene ring according to claim 16, wherein: Ar is a phenyl group substituted in the para position with a >SO2 group directly attached to another phenyl group; A is a hydrogen, halogen or carbon atom which, together with other atoms, forms a substituted or unsubstituted alkyl group; X is a nitrogen atom; Y is a carbon atom; and X and Y together form a heterocyclic ring that has the formula: [image] 22. A compound with a naphthalene ring according to claim 21, characterized in that A is a hydrogen, chlorine or carbon atom, which together with three hydrogen atoms forms a methyl group. 23. A compound with a naphthalene ring according to claim 16, wherein: Ar is a phenyl group substituted in the para position with a >SO2 group directly attached to another phenyl group; A is a hydrogen, halogen or carbon atom which, together with other atoms, forms a substituted or unsubstituted alkyl group; X is a nitrogen atom; Y is a carbon atom; and X and Y together form a heterocyclic ring that has the formula: [image] 24. A compound with a naphthalene ring according to claim 23, characterized in that A is a hydrogen atom or a carbon atom which together with three hydrogen atoms forms a methyl group. 25. A compound with a naphthalene ring according to claim 9, characterized in that the electron-attracting agent >C=O or >SO2 group is directly attached to a substituted or unsubstituted heterocyclic ring. 26. A compound with a naphthalene ring according to claim 25, characterized in that the heterocyclic ring is selected from the group consisting of pyrimidines, pyrrolidines, pyrroles and indoles. 27. A compound with a naphthalene ring according to claim 26, wherein: Ar is a phenyl group substituted in the para position with a >SO2 group directly attached to the heterocyclic ring; A is a hydrogen, halogen or carbon atom which, together with other atoms, forms a substituted or unsubstituted alkyl group; X is a nitrogen atom; Y is a carbon atom; and X and Y together form a heterocyclic ring that has the formula: [image] 28. A compound with a naphthalene ring according to claim 27, characterized in that A is a hydrogen, chlorine or carbon atom which, together with three other hydrogen atoms, forms a methyl group. 29. A compound with a naphthalene ring according to claim 26, wherein: Ar is a phenyl group substituted in the para position with a >SO2 group directly attached to the heterocyclic ring; A is a hydrogen, halogen or carbon atom which, together with other atoms, forms a substituted or unsubstituted alkyl group; X is a nitrogen atom; Y is a carbon atom; and X and Y together form a heterocyclic ring that has the formula: [image] where Q is hydrogen, substituted or unsubstituted alkyl, amino or hydroxy group. 30. A compound with a naphthalene ring according to claim 29, wherein: A is a hydrogen, chlorine or carbon atom which, together with three other hydrogen atoms, forms a methyl group; and Q is a methyl or hydroxy group. 31. A pharmaceutical composition containing a pharmaceutically acceptable diluent or carrier combined with an effective amount to inhibit thymidylate synthase of the naphthalene ring compound of the following formula: [image] indicated by, in which: Z and W are independently nitrogen, sulfur, or substituted or unsubstituted alkylene groups with the limitation that when one of Z or W is nitrogen or sulfur, the other is a substituted or unsubstituted alkylene group; Ar is a group comprising one or more rings selected from the group consisting of (1) substituted or unsubstituted aryl rings and (2) substituted or unsubstituted heterocyclic rings; R is hydrogen or a substituted or unsubstituted alkyl group; R 1 is hydrogen, a substituted or unsubstituted lower alkyl group or a substituted or unsubstituted amino group; A is hydrogen, halogen, carbon, nitrogen or sulfur with the proviso that if A is carbon, nitrogen or sulfur, A may itself be substituted with a substituted or unsubstituted alkyl group; and X and Y together form a five- or six-membered nitrogen-containing heterocyclic ring which may be substituted or unsubstituted. 32. Pharmaceutical composition according to claim 31, characterized in that said compound has a thymidylate synthase inhibition constant Kj less than or equal to about 10-6 M. 33. Pharmaceutical preparation according to claim 31, characterized in that: Z is a nitrogen atom; W is an unsubstituted alkylene group; Ar is a monocyclic or bicyclic, substituted or unsubstituted aryl or heteroaryl ring; R1 is a hydrogen atom; A is a hydrogen, halogen or carbon atom; and X or Y is a nitrogen atom. 34. Pharmaceutical preparation according to claim 33, characterized in that: R is selected from the group consisting of methyl, ethyl, hydroxyethyl, n-propyl, isopropyl, hydroxypropyl and -CH2-S-CH3; Ar is a phenyl, naphthyl or heteroaryl ring unsubstituted or substituted with a means selected from the group consisting of a halogen atom, hydroxy, alkoxy, alkyl, hydroxyalkyl, fluoroalkyl, amino, -CN, -NO2, carbalkoxy, carbamyl, carbonyl, carboxyldioxy, carboxy, amino acid carbonyl, amino acid sulfonyl, sulfamyl, sulfanylyl, sulfahydryl, sulfino, sulfinyl, sulfo, sulfonamido, sulfonyl, substituted or unsubstituted phenylsulfonyl, phenylmercapto, phosphazo, phosphinico, phosphino, phospho, phosphono, phosphoro, phosphorose, [image] A is a hydrogen, chlorine or carbon atom, which forms a methyl group with three hydrogen atoms; and X and Y form a heterocyclic ring selected from the group consisting of: [image] where P is a hydrogen atom, a substituted or unsubstituted alkyl group or an amino group [image] where Q is a hydrogen atom, a substituted or unsubstituted alkyl group or an amino or hydroxy group; [image] 35. Pharmaceutical preparation according to claim 34, characterized in that: R is a methyl group; Ar is a 4'-phenylsulfonyl group; A is a hydrogen atom; X is a nitrogen atom which, together with a hydrogen atom, forms the -NH= group; and Y is a hydrogen atom substituted with an amino group to form a =C(NH2) group. 36. Pharmaceutical preparation according to claim 33, characterized in that: Ar is a phenyl group substituted in the para position with a >SO2 group directly attached to another phenyl group or heterocyclic group: [image] A is a hydrogen or carbon atom forming part of a substituted or unsubstituted alkyl group; X and Y are nitrogen atoms; and X and Y together form a heterocyclic ring that has the formula: [image] where P is a hydrogen atom, a substituted or unsubstituted alkyl group or an amino group. 37. Pharmaceutical preparation according to claim 33, characterized in that: Ar is a phenyl group substituted in the para position with a >SO2 group directly attached to another phenyl group or heterocyclic group: [image] A is a hydrogen, halogen or carbon atom which, together with other atoms, forms a substituted or unsubstituted alkyl group; X is a nitrogen atom; Y is a carbon atom; and X and Y together form a heterocyclic ring that has the formula: [image] wherein Q is a hydrogen atom, a substituted or unsubstituted alkyl group, or an amino or hydroxyl group. 38. Pharmaceutical preparation according to claim 33, characterized in that: Ar is a phenyl group substituted in the para position with an SO2 group that is directly attached to another phenyl group or to a heterocyclic group: [image] 39. A pharmaceutical preparation according to claim 31, characterized in that, in a form selected from the group consisting of forms suitable for oral, parenteral, topical, intravaginal, intra-nasal, intrabronchial, intraocular, intraaural and rectal administration. 40. Pharmaceutical preparation according to claim 31, characterized in that it contains at least one other compound, which is an antitumor agent. 41. Pharmaceutical preparation according to claim 34, characterized in that at least one of said compounds is selected from the group consisting of mitotic inhibitors, alkylating agents, DHFR inhibitors, antimetabolites, interchelate antibiotics, enzymes, topoisomerase inhibitors or biological response modifiers. 42. Pharmaceutical preparation according to claim 31, characterized in that it further contains at least one compound that is an antibacterial agent, an anti-fungal agent, an anti-parasitic agent, an antiviral agent, an anti-psoriatic agent, an anti-protozoal agent or an anti-coccidial agent. 43. A therapeutic method of inhibiting thymidylate synthase, characterized in that it comprises administering to a vertebrate host an effective amount, for inhibiting thymidylate synthase, of a compound of the formula: [image] where: Z and W are independently nitrogen, sulfur, or substituted or unsubstituted alkylene groups with the limitation that when one of Z or W is nitrogen or sulfur, the other is a substituted or unsubstituted alkylene group; Ar is a group comprising one or more rings selected from the group consisting of (1) substituted or unsubstituted aryl rings and (2) substituted or unsubstituted heterocyclic rings; R is hydrogen or a substituted or unsubstituted alkyl group; R 1 is hydrogen, a substituted or unsubstituted amino group; A is hydrogen, halogen, carbon, nitrogen or sulfur with the restrictions that when A is carbon, nitrogen or sulphur, A may itself be substituted with a substituted or unsubstituted alkyl group; and X and Y together form a five- or six-membered nitrogen-containing ring which may be substituted or unsubstituted. 44. The method according to claim 43, characterized in that the compound has a thymidylate synthase inhibition constant less than or equal to about 10-6 M. 45. The procedure according to claim 43, characterized in that: Z is a nitrogen atom; W is an unsubstituted alkylene group; Ar is a monocyclic or bicyclic, substituted or unsubstituted aryl or heteroaryl ring; R1 is a hydrogen atom; A is a hydrogen, halogen or carbon atom; and X or Y is a nitrogen atom. 46. The procedure according to claim 45, characterized in that: W is a methylene group; R is selected from the group consisting of methyl, ethyl, hydroxyethyl, n-propyl, isopropyl, hydroxypropyl and CH2-S-CH3, Ar is a phenyl, naphthyl or heteroaryl ring unsubstituted or substituted with a means selected from the group consisting of a halogen atom, hydroxy, alkoxy, alkyl, hydroxyalkyl, fluoroalkyl, amino, -CN, -NO2, carbalkoxy, carbamyl, carbonyl, carboxyldioxy, carboxy, amino acid carbonyl, amino acid sulfonyl, sulfamyl, sulfanylyl, sulfahydryl, sulfino, sulfinyl, sulfo, sulfonamido, sulfonyl, substituted or unsubstituted phenylsulfonyl, phenylmercapto, phosphazo, phosphinico, phosphino, phospho, phosphono, phosphoro, phosphorose, [image] A is a hydrogen, chlorine or carbon atom, which forms a methyl group with three hydrogen atoms; and X and Y form a heterocyclic ring selected from the group consisting of: [image] where P is a hydrogen atom, a substituted or unsubstituted alkyl group or an amino group [image] where Q is a hydrogen atom, a substituted or unsubstituted alkyl group or an amino or hydroxy group; [image] 47. The procedure according to claim 46, characterized in that: R is a methyl group; Ar is a 4-phenylsulfonyl group; A is a hydrogen atom; X is a nitrogen atom which, together with a hydrogen atom, forms the -NH= group; and Y is a hydrogen atom substituted with an amino group to form a =C(NH2) group. 48. The procedure according to claim 45, characterized in that: Ar is a phenyl group substituted in the para position with a >SO2 group directly attached to another phenyl group or heterocyclic group [image] A is a hydrogen or aryl carbon atom forming part of a substituted or unsubstituted alkyl group; X and Y are nitrogen atoms; X and Y together form a heterocyclic ring that has the formula: [image] in which P is a hydrogen atom, a substituted or unsubstituted alkyl group or an amino group. 49. 49. The procedure according to claim 45, characterized in that: Ar is a phenyl group substituted in the para position with a >SO2 group directly attached to another phenyl group or heterocyclic group [image] A is a hydrogen, halogen or carbon atom which, together with other atoms, forms a substituted or unsubstituted alkyl group; X is a nitrogen atom; Y is a carbon atom; and X and Y together form a heterocyclic ring that has the formula: [image] where Q is a hydrogen atom, a substituted or unsubstituted alkyl group, or an amino or hydroxyl group. 50. The procedure according to claim 45, characterized in that: Ar is a phenyl group substituted in the para position with a >SO2 group directly attached to another phenyl group or heterocyclic group [image] A is a hydrogen, halogen or carbon atom which, together with other atoms, forms a substituted or unsubstituted alkyl group; X is a nitrogen atom; Y is a carbon atom; and X and Y together form a heterocyclic ring that has the formula: [image] wherein Q is a hydrogen atom, a substituted or unsubstituted alkyl group, or an amino or hydroxyl group. 51. The procedure according to claim 45, characterized in that: Ar is a phenyl group substituted in the para position with a >SO2 group directly attached to another phenyl group or heterocyclic group: [image] A is a hydrogen, halogen or carbon atom which, together with other atoms, forms a substituted or unsubstituted alkyl group; X is a nitrogen atom; Y is a carbon atom; and X and Y together form a heterocyclic ring that has the formula: [image] 52. The procedure according to claim 33, characterized in that: Ar is a phenyl group substituted in the para position with a >SO2 group directly attached to another phenyl group or a heterocyclic group of the formula: [image] A is a hydrogen, halogen or carbon atom which, together with other atoms, forms a substituted or unsubstituted alkyl group; X is a carbon atom; Y is a nitrogen atom; and X and Y together form a heterocyclic ring that has the formula: [image] 53. The method according to claim 43, characterized in that the compound in the pharmaceutical preparation is present in a pharmaceutical form suitable for oral, parenteral, topical, intravaginal, intranasal, intrabronchial, intraocular, intraaural and rectal administration. 54. The method according to claim 43, characterized in that the dose of the compound is about 5000 mg per square meter of the body surface of the vertebrate host. 55. The method according to claim 43, characterized in that the host vertebrate is a mammal. 56. The method according to claim 55, characterized in that the host vertebrate is a human. 57. The method according to claim 43, characterized in that the host vertebrate is a bird. 58. The method according to claim 43, characterized in that the compound further has an antiproliferative effect. 59. The method according to claim 43, characterized in that the vertebrate host has tumor cells and the compound has an inherent antitumor effect. 60. The method according to claim 43, characterized in that the compound has at least one of the following effects: antibacterial, antifungal, antiparasitic, antiviral, antipsoriatic, antiprotozoal or anticoccidial. 61. Process for obtaining compounds with a naphthalene ring of formula I or II: [image] where: R 1 is a hydrogen atom, a substituted or unsubstituted alkyl group or a substituted or unsubstituted group; And A is a hydrogen, halogen, carbon, nitrogen or sulfur atom, with the restriction that (1) when A is carbon or nitrogen, A itself may be substituted with a substituted or unsubstituted alkyl group and (2) in formula (I), A is not an electron-attracting group, indicated by including degrees: (1) treatment of compounds of formula Ia or IIa [image] where R1 and A are as defined above, with a lower alkyl haloformate and a base in the first solvent to form an activated acid derivative; (2) treating the activated acid with sodium azide at a temperature below room temperature to form naphthyl acyl azide, (3) heating the naphthyl acyl azide in another solvent to form the isocyanate, i (4) treating the isocyanate with a Lewis acid to form a compound of formula I or II. 62. The process according to claim 61, characterized in that R1 is hydrogen. 63. The method according to claim 61, characterized in that A is a hydrogen, halogen or carbon atom which, together with other atoms, forms a substituted or unsubstituted alkyl group. 64. The method according to claim 63, characterized in that A is a hydrogen, chlorine or carbon atom which together with three hydrogen atoms forms a methyl group. 65. The method according to claim 64, characterized in that A is a hydrogen or carbon atom which together with three carbon atoms forms a methyl group. 66. The process according to claim 61, characterized in that the chloroformate is a lower alkyl haloformate. 67. The process according to claim 61, characterized in that the first solvent is acetone. 68. The method according to claim 61, characterized in that the Lewis acid is selected from the group consisting of boron trichloride, aluminum chloride, boron trifluoride etherate, titanium tetrachloride and tin tetrachloride. 69. The method according to claim 61, characterized in that the second solvent is selected from the group consisting of nitrobenzene, methylene chloride, chlorobenzene, dichloroethane and their mixture. 70. The method according to claim 61, characterized in that the Lewis acid is boron trichloride and the second solvent is chlorobenzene, nitrobenzene or a mixture thereof. 71. Process for obtaining a compound with a naphthalene ring that can inhibit thymidylate synthase, formulas: [image] where: Z and W are independently nitrogen, sulfur, or substituted or unsubstituted alkylene groups with the limitation that when one of Z or W is nitrogen or sulfur, the other is a substituted or unsubstituted alkylene group; Ar is a group comprising one or more rings selected from the group consisting of (1) substituted or unsubstituted aryl rings and (2) substituted or unsubstituted heterocyclic rings; R is hydrogen or a substituted or unsubstituted alkyl group; R 1 is hydrogen, a substituted or unsubstituted amino group; A is hydrogen, halogen, carbon, nitrogen or sulfur with the restrictions that when A is carbon, nitrogen or sulfur. A may itself be substituted with a substituted or unsubstituted alkyl group; and X and Y together form a five- or six-membered ring containing nitrogen and which may be substituted or unsubstituted, characterized by including degrees of: (1) treating a compound of formula Ia or IIa [image] wherein R 1 and A are as defined above, with a lower alkyl haloformate and a base in the first solvent to form an activated acid derivative; (2) treating the activated acid derivative with sodium azide at a temperature lower than room temperature to form naphthyl acyl azide; (3) heating naphthyl acylazide in another solvent to form the isocyanate: (4) treating the isocyanate with a Lewis acid to form a compound of formula I or II: [image] (5) reacting a derivative of a compound of formula I or formula II with a compound R-Act, where R is as defined above and Act is an activating group selected from the group consisting of halogen, sulfonate or aldehyde to form the first alkylated compound; and (6) reaction of the first alkylated compound with the compound Act-W-Ar, where Act, W and Ar are as defined above to form the second alkylated compound, with the restriction that steps (5) and (6) can be performed in reverse order. 72. The method according to claim 71, characterized in that the lower alkyl haloformate is ethyl chloroformate. 73. The process according to claim 71, characterized in that the first solvent is acetone. 74. The method according to claim 71, characterized in that the Lewis acid is selected from the group consisting of boron trichloride, aluminum chloride, boron trifluoride etherate, titanium tetrachloride and tin tetrachloride. 75. The method according to claim 71, characterized in that the second solvent is selected from the group consisting of nitrobenzene, methylene chloride, chlorobenzene and dichloroethane. 76. The method according to claim 71, characterized in that the Lewis acid is boron trichloride, and the second solvent is chlorobenzene, nitrobenzene or a mixture thereof. 77. A process for obtaining a compound with a naphthalene ring that inhibits thymidylate synthase according to claim 71, characterized in that step (5) is performed in the presence of a base and a third solvent. 78. A process for obtaining a compound with a naphthalene ring that inhibits thymidylate sythase according to claim 77, characterized in that the base is selected from the group consisting of unsubstituted and inorganic carbonates. 79. A process for obtaining a compound with a naphthalene ring that inhibits thymidylate synthase according to claim 77, characterized in that the third solvent is dimethylformamide or dimethylacetamide. 80. A process for obtaining a compound with a naphthalene ring that inhibits thymidylate synthase according to claim 71, characterized in that the second alkylated compound is treated with Lawssen's reagent to obtain the corresponding thione compound. 81. A process for obtaining a compound with a naphthalene ring that inhibits thymidylate synthase according to claim 80, characterized in that the thione compound reacts with an alkyl halide to form the corresponding alkylated thiolactam. 82. A process for obtaining a compound with a naphthalene ring that inhibits thymidylate synthase according to claim 81, wherein the alkylated thiolactam is treated with a nucleophile. 83. A process for obtaining a compound with a naphthalene ring that inhibits thymidylate synthase according to claim 82, characterized in that the nucleophile is selected from the group consisting of ammonia, alkyl amine, alkoxyamine and hydrazine. 84. A process for obtaining a compound with a naphthalene ring that inhibits thymidylate synthase according to claim 83, characterized in that the nucleophile is ammonia, and the product obtained is an amine. 85. Process for obtaining a compound with a naphthalene ring that inhibits thymidylate synthase, formula I: [image] where: Z and W are independently nitrogen, sulfur, or substituted or unsubstituted alkylene groups with the limitation that when one of Z or W is nitrogen or sulfur, the other is a substituted or unsubstituted alkylene group; Ar is a group comprising one or more rings selected from the group consisting of (1) substituted or unsubstituted aryl rings and (2) substituted or unsubstituted heterocyclic rings; R is hydrogen or a substituted or unsubstituted alkyl group; R 1 is hydrogen, a substituted or unsubstituted amino group; A is a hydrogen, halogen, carbon, nitrogen or sulfur atom with the restriction that when A is carbon or nitrogen and A itself may be substituted with a substituted or unsubstituted group; and P is a hydrogen atom, a substituted or unsubstituted alkyl group, indicated by including (1) the reaction of the compound Ar-Z-W-Ar with the initial naphthalene compound of the formula: [image] where L is a leaving group for the formation of an intermediate compound that has two nitro groups: [image] (2) reduction of intermediate nitro groups to form corresponding amino groups; and (3) cyclization of the resulting amino groups using a cyclization agent to form a substituted naphthalene compound of formula I. 86. A process for obtaining a compound with a naphthalene ring according to claim 85, characterized in that reaction step (1) is performed in the presence of an organic solvent selected from the group consisting of diphnetyl sulfoxide, dioxane and dimethoxyethane. 87. A process for obtaining a compound with a naphthalene ring according to claim 85, characterized in that reaction step (1) is performed in the presence of a neutralizing agent selected from the group consisting of calcium carbonate, sodium carbonate, potassium carbonate and trisubstituted amines. 88. A process for obtaining a compound with a naphthalene ring according to claim 85, characterized in that the reduction step (2) is performed in water or an organic solvent selected from the group consisting of ethanol, methanol, ethyl acetate, tetrahydrofuran and acetic acid. 89. A process for obtaining a compound with a naphthalene ring according to claim 85, characterized in that the reduction step (2) is performed in the presence of a reducing agent selected from the group consisting of a hydrazine compound and hydrogen gas under a pressure of 1 atmosphere or more. 90. A process for obtaining a compound with a naphthalene ring according to claim 85, characterized in that the reduction step (2) is performed with a catalyst selected from the group consisting of Raney nickel, palladium on carbon, palladium on barium sulfate. 91. A process for obtaining a compound with a naphthalene ring according to claim 85, characterized in that the cyclizing agent in step (3) is selected from the group consisting of acetic anhydride, trimethylorthoformate, triethylorthoformate and cyanogen bromide. 92. A process for obtaining a compound with a naphthalene ring according to claim 85, characterized in that the leaving group L is a halogen atom selected from the group consisting of fluorine and chlorine. 93. Process for obtaining a compound with a naphthalene ring that inhibits thymidylate synthase of formula I: [image] where: Z and W are independently nitrogen or sulfur or substituted or unsubstituted alkylene groups with the limitation that when one of Z or W is nitrogen or sulfur, the other is a substituted or unsubstituted alkylene group; Ar is a group comprising one or more rings selected from the group consisting of (1) substituted or unsubstituted aryl rings and (2) substituted or unsubstituted heterocyclic rings; R is hydrogen or a substituted or unsubstituted alkyl group; R1 is hydrogen, a substituted or unsubstituted alkyl group or a substituted or unsubstituted amino group; A is a hydrogen, halogen, carbon, nitrogen or sulfur atom with the limitation that when A is carbon or nitrogen, A itself may be substituted with a substituted or unsubstituted alkyl group; and X and Y together form a five- or six-membered heterocyclic ring containing a nitrogen which may itself be substituted or unsubstituted; characterized in that it comprises successive alkylation of the aniline of formula II: [image] by the reaction of aniline with an activated group R-Act, where R is as previously defined and Act is an activating group to obtain the first alkylated compound. 94. A process for obtaining a compound with a naphthalene ring according to claim 93, characterized in that the activating group is a halogen, sulfonate or aldehyde group. 95. A process for obtaining a compound with a naphthalene ring according to claim 93, characterized in that the reaction with R-Act is performed in an organic solvent selected from the group consisting of tetrahydrofuran, dioxane, 1,2-dioxyethane, dimethylformamide and dimethylacetamide. 96. A process for obtaining a compound with a naphthalene ring according to claim 93, characterized in that the reaction with R-Act is performed in the presence of an organic or inorganic weak base. 97. A process for obtaining a compound with a naphthalene ring according to claim 96, characterized in that the base is a substituted amine or an inorganic carbonate. 98. A process for obtaining a compound with a naphthalene ring according to claim 93, characterized in that it comprises the further reaction of the first alkylated compound with Act-W-Ar to obtain the second alkylated compound. 99. A process for obtaining a compound with a naphthalene ring according to claim 93, wherein Z is a nitrogen atom.