HRP20030141A2 - Phenoxybenzylamine derivatives as selective serotonin re-uptake inhibitors - Google Patents

Description

This invention relates to novel diphenyl ether compounds that inhibit monoamine reuptake. In more detail, the compounds of the present invention exhibit selective serotonin reuptake inhibitor (SSRI) activity and as such are useful in a variety of therapeutic areas. The significance of the compounds of this invention is their utility in the treatment or prevention of various disorders, including those involving the regulation of monoamine transport function, such as depression, attention deficit hyperactivity disorder, obsessive-compulsive disorder, post-traumatic stress disorder, drug abuse disorders and sexual dysfunction. including premature ejaculation, as well as in pharmaceutical forms containing such compounds.

According to the first aspect, the invention describes the compound represented by the general formula (1), its pharmaceutically acceptable salts, solvates or polymorphs;

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where;

R1 and R2, which may be the same or different, are H, C1-C6alkyl or (CH2)d(C3-C6cycloalkyl) where d=0, 1, 2 or 3; or R1 and R2 together with the nitrogen to which they are attached form an azetidine ring;

Z or Y is -SR3 and the other Z or Y is halogen or -R3; wherein R 3 is an independent C 1 -C 4 alkyl optionally substituted with fluorine; with the exception that R 3 is not CF 3 ;

or Z and Y are linked so that, together with the connecting atoms, Z and Y form a fused 5- to 7-membered carbocyclic or heterocyclic ring which may be saturated, unsaturated or aromatic, and when Z and Y form a heterocyclic ring, in addition to carbon atoms, the linker contains one or two heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen; with the proviso that when R5 is fluorine and R2 is methyl then the fused ring is not 1,3-dioxolane and Z and Y together do not form a fused phenyl ring;

R4 and R5, which can be the same or different, are:

A-X, where A=-CH=CH- or -(CH2)p- where p is 0, 1 or 2; X is hydrogen, F, Cl, Br, I, CONR6R7, SO2NR6R7, SO2NHC(=O)R6, OH, C1-4Alkoxy, NR8SO2R9, NO2, NR6R11, CN, CO2R10, CHO, SR10, S(O)R9 or SO2R10 ; R 6 , R 7 , R 8 and R 10 , which may be the same or different, are hydrogen or C 1-6 alkyl optionally substituted independently by one or more R 12 ; R 9 is C 1-6 alkyl optionally substituted independently by one or more R 12 ; R 11 is hydrogen, C 1-6 alkyl optionally substituted independently by one or more R 12 , C(O)R 6 , CO 2 R 9 , C(O)NHR 6 or SO 2 NR 6 R 7 ; R 12 is F (up to 3 atoms are preferred), OH, CO 2 H, C 3-6 cycloalkyl, NH 2 , CONH 2 , C 1-6 alkoxy, C 1-6 alkoxycarbonyl or a 5- or 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from the group consisting of N, S and O optionally substituted independently by one or more R 13 ; or R 6 and R 7 , together with the nitrogen to which they are attached, form a 4-, 5- or 6-membered heterocyclic ring optionally substituted independently by one or more R 13 ; or

5- or 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from the group consisting of N, S and O, optionally substituted independently by one or more R 13 ; wherein R 13 is hydroxy, C 1 -C 4 alkoxy, F, C 1 -C 6 alkyl, haloalkyl, haloalkyl, -NH 2 , -NH(C 1 -C 6 alkyl) or -N(C 1 -C 6 alkyl) 2 .

Unless otherwise indicated, each alkyl group may be straight or branched and contain 1 to 6 carbon atoms, preferably 1 to 4, and especially 1 to 3 carbon atoms.

Unless otherwise indicated, each carbocyclyl group contains 3 to 8 ring atoms and may be saturated, unsaturated or aromatic. Suitable saturated carbocyclyl groups are cyclopropyl, cyclopentyl or cyclohexyl. Suitable unsaturated carbocyclyl groups contain up to 3 double bonds. A suitable aromatic carbocyclyl group is phenyl. The term carbocyclic should be interpreted similarly. Furthermore, the term carbocyclyl includes any fused combination of carbocyclyl groups, for example naphthyl, phenanthryl, indanyl and indenyl.

Unless otherwise indicated, each heterocyclyl group contains 5 to 7 ring atoms, with up to 4 atoms being heteroatoms such as nitrogen, oxygen, and sulfur, and each group can be saturated, unsaturated, or aromatic. Examples of heterocyclyl groups are furyl, thienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, dioxolanyl, oxazolyl, thiazolyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyranyl, pyridyl, piperidinyl, dioxanyl, morpholino, dithianyl, thiomorpholino, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, sulfolanyl, tetrazolyl, triazinyl, azepinyl, oxazepinyl, thiazepinyl, diazepinyl and thiazolinyl. Further, the term heterocyclyl includes fused heterocyclyl groups, e.g., benzimidazolyl, benzoxazolyl, imidazopyridinyl, benzoxazinyl, benzothiazinyl, oxazolopyridinyl, benzofuranyl, quinolinyl, quinazolinyl, quinoxalinyl, dihydroquinazolinyl, benzothiazolyl, phthalimido, benzofuranyl, benzodiazepine, indolyl, and isoindolyl. The term heterocyclic should be interpreted similarly.

Halo means fluoro, chloro, bromo or iodo.

Suitable R 1 and R 2 , which may be the same or different, are hydrogen or C 1 -C 6 alkyl.

Preferably hydrogen or methyl.

When Z or Y is -SR 3 , it is preferred that R 3 is methyl or ethyl.

When Z and Y form a fused ring, a suitable ring is heterocyclic. It is even more convenient for the linker to contain one or two sulfur atoms.

It is preferred that R4 and R5 are not both hydrogen.

Suitable R4 and R5, which may be the same or different, are

-(CH2)p-X, where p is 0, 1 or 2 (0 or 1 is preferred); X is hydrogen, hydroxy, CONR6R7, SO2NR6R7, NR8SO2R9, SR10, SOR9 or SO2R10 wherein R6, R7, R8, R9 and R10 are as described in the first aspect, or

A 5- or 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from the group consisting of N, S and O (oxadiazolyl, triazolyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl or pyrimidinyl are preferred).

More suitable R4 and R5, which can be the same or different, are:

-(CH2)p-X, where p is 0 or 1; X is hydrogen, hydroxy, CONR6R7, SO2NR6R7 or NR8SO2R9; wherein R 6 and R 7 , which may be the same or different, are hydrogen or C 1 -C 3 alkyl optionally substituted with hydroxy, -CONH 2 or C 1 -C 3 alkoxy (methoxy is preferred); R 8 is hydrogen, hydroxyethyl or methyl; or R 9 is methyl, ethyl, isopropyl, trifluoromethyl or methoxyethyl; or

triazolyl, imidazolyl or pyrazolyl.

An even more suitable R4 is hydrogen.

Suitable R 6 and R 7 , which may be the same or different, are hydrogen, C 1 -C 3 alkyl optionally substituted with hydroxy, -CONH 2 or C 1 -C 3 alkoxy (methoxy is preferred). More suitable R6 and R7, which can be the same or different, are hydrogen or methyl, and even more suitable is hydrogen.

When present, suitable R 12 is oxadiazolyl, triazolyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl or pyrimidinyl. More suitable triazolyl, imidazolyl or pyrazolyl.

In the case where R 6 and R 7 , together with the nitrogen to which they are attached, form a heterocyclic ring, the preferred rings are pyrrolidine or piperidine rings, each of which may be substituted with OH or CONH 2 , or a morpholine ring which may be substituted with CONH 2 .

Suitable R 11 is hydrogen or C 1-6 alkyl.

Suitable R8 is hydrogen, hydroxyethyl or methyl. Better hydrogen.

Suitable R9 is methyl, ethyl, isopropyl, trifluoromethyl or methoxyethyl. Preferably methyl or ethyl (most preferably methyl).

Suitable R 10 is methyl or ethyl.

A suitable p is 1 or 0, more preferably 0.

Fit

R1 and R2, which may be the same or different, are hydrogen or methyl;

when present, R 3 is methyl or ethyl; or Z and Y are linked so that, together with the connecting atoms, Z and Y form a fused 5- to 7-membered carbocyclic or heterocyclic ring which may be saturated, unsaturated or aromatic, and when Z and Y form a heterocyclic ring, next to the carbon atom , the linker contains one or two heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen; and

R4 and R5, which may be the same or different, are

(CH2)p-X, where p is 0 or 1; X is hydrogen, hydroxy, CONR6R7, SO2NR6R7, NR8SO2R9, SR10, SOR9 or SO2R10 and wherein R6 and R7, which may be the same or different, are hydrogen, C1-C3alkyl optionally substituted with hydroxy, -CONH2 or C1-C3 alkoxy (preferred is methoxy); or R 6 and R 7 , together with the nitrogen to which they are attached, may form a morpholine, pyrrolidine or piperidine ring, each of which may be substituted with OH or CONH 2 ; R 8 is hydrogen, hydroxyethyl or methyl (hydrogen is preferred); R 9 is methyl, ethyl, isopropyl, trifluoromethyl or methoxyethyl; and R 10 is methyl or ethyl; or

an oxadiazolyl, triazolyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl or pyrimidinyl group.

More convenient

R1 and R2, which may be the same or different, are hydrogen or methyl;

when present, R 3 is methyl or ethyl; or Z and Y are linked such that, together with the linking atoms, Z and Y form a fused 5- to 7-membered heterocyclic ring containing 1 or 2 sulfur atoms; and

R4 and R5, which may be the same or different, are

-(CH2)p-X, where p is 0 or 1; X is hydrogen, hydroxy, CONR6R7, SO2NR6R7 or NR8SO2R9; wherein R 6 and R 7 , which may be the same or different, are hydrogen, C 1 -C 3 alkyl optionally substituted with hydroxy, -CONH 2 or C 1 -C 3 alkoxy (methoxy is preferred); R 8 is hydrogen, hydroxyethyl or methyl; R 9 is methyl, ethyl, isopropyl, trifluoromethyl or methoxyethyl; or

triazolyl, imidazolyl or pyrazolyl.

Even more convenient

R1 and R2, which may be the same or different, are hydrogen or methyl;

when present, R 3 is methyl or ethyl; or Z and Y are linked such that, together with the linking atoms, Z and Y form a fused saturated 5- to 7-membered heterocyclic ring containing 1 or 2 sulfur atoms;

R 4 is hydrogen, and

It's an R5

-(CH2)p-X, where p is 0 or 1; X is hydrogen, hydroxy, CONR6R7, SO2NR6R7 or NR8SO2R9; wherein R 6 and R 7 , which may be the same or different, are hydrogen, C 1 -C 3 alkyl optionally substituted with hydroxy, -CONH 2 or C 1 -C 3 alkoxy (methoxy is preferred); R 8 is hydrogen, hydroxyethyl or methyl; R 9 is methyl, ethyl, isopropyl, trifluoromethyl or methoxyethyl; or

triazolyl, imidazolyl or pyrazolyl.

More preferably, R4 and R5 are not both hydrogen.

Suitable compounds are:

4-(2,3-dihydro-1-benzothien-5-yloxy)-3-[(methylamino)methyl]-benzenesulfonamide (Example 2);

3-[(dimethylamino)methyl]-4-[3-methyl-4-(methylsulfanyl)phenoxy]-benzenesulfonamide (Example 12);

4-(2,3-dihydro-1-benzothien-5-yloxy)-3-[(dimethylamino)methyl]-benzenesulfonamide (Example 16);

4-[3-chloro-4-(methylsulfanyl)phenoxy]-3-[(dimethylamino)methyl]-benzenesulfonamide (Example 17);

3-[(dimethylamino)methyl]-4-[3-fluoro-4-(methylsulfanyl)phenoxy]-benzenesulfonamide (Example 18);

N,N-dimethyl-N-[2-(6-quinolinyloxy)benzyl]-amine (Example 29);

3-[(methylamino)methyl]-4-(6-quinolinyloxy)-benzenesulfonamide (Example 35);

4-(2,3-dihydro-1-benzothien-5-yloxy)-3-[(methylamino)methyl]-benzamide (Example 60);

4-(2,3-dihydro-1-benzothien-5-yloxy)-N-methyl-3-[(methylamino)methyl]-benzamide (Example 62);

N-{3-[(methylamino)methyl]-4-[3-methyl-4-(methylsulfanyl)phenoxy]benzyl}-methanesulfonamide (Example 75);

3-[(methylamino)methyl]-4-[3-methyl-4-(methylsulfanyl)phenoxy]-benzamide (Example 79);

4-(2,3-dihydro-1,4-benzoxathin-7-yloxy)-3-[(dimethylamino)methyl]-benzamide (Example 88);

{3-[(dimethylamino)methyl]-4-[3-fluoro-4-(methylsulfanyl)phenoxy]phenyl}-methanol (Example 90);

3-[(dimethylamino)methyl]-4-(6-quinolinyloxy)-benzamide (Example 100);

3-[(methylamino)methyl]-4-(6-quinolinyloxy)-benzamide (Example 102);

N-methyl-N-{3-[(methylamino)methyl]-4-[3-methyl-4-(methylsulfanyl)phenoxy]phenyl}-methanesulfonamide (Example 116) and

N-{4-(2,3-dihydro-1,4-benzoxathin-7-yloxy)-3-[(dimethylamino)methyl]phenyl}-methanesulfonamide (Example 124).

According to another aspect, the invention describes a compound represented by formula (I) or (XIX)

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and pharmaceutically acceptable salts or solvates thereof wherein (in this aspect): R1 and R2 independently represent H, C1-C6alkyl or (CH2)d(C3-C6cycloalkyl) where d=0, 1, 2 or 3, or where NR1R2 when are joined to represent a 4-membered ring where R1 and R2 together represent C3 alkyl; Z and Y both independently represent -SR3 wherein, when Z=-SR3 then Y=halogen, -ORa, -Ra or -SRa; or when Y=-SR3 then Z=halogen, -ORa, Ra or -SRa; and R3 and Ra independently represent: C1-C4alkyl (optionally substituted with fluorine atoms, e.g. -CF3); or Z and Y when taken together may represent a fused 5 to 7 membered ring as shown by the general formula XIX, wherein said 5 to 7 membered ring may be saturated, unsaturated or aromatic and wherein said 5 to 7 membered ring may optionally contain one or more heteroatoms P and Q, where P and Q = may independently be O, S or N, and wherein E, F, or G independently represent CH or CH2, and where k and p may independently be = 0, 1, 2 or 3, and m=1, 2 or 3; and

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R4 and R5 independently represent A-X wherein A=-(CH2)n-, where n represents 0, 1 or 2 and where X represents: H, F, Cl, Br, I, CONR6R7 or SO2NR6R7, OH, NR8SO2R9, NO2, NR6R11, CN, CO2R10, CHO, S(O)mR10 where m=0, 1 or 2 and where R6, R7, R8 and R10 independently represent H or C1-6 alkyl, wherein R9 represents C1-6 alkyl, R11 represents H , C1-6 alkyl, C(O)R6, CO2R9, C(O)NHR6 or SO2NR6R6 and wherein said C1-6 alkyl group is optionally substituted with one or more groups selected from the group consisting of OH, CO2H, C3-6 cycloalkyl, NH 2 , CONH 2 , C 1-6 alkoxy, C 1-6 alkoxycarbonyl and a 5- or 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, S and O; or with the condition that when P=Q=oxygen then both k and p are not zero; provided that Z and Y together do not form a fused phenyl ring; R 4 or R 5 may represent a 5- or 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, S and O; and furthermore, R6 and R7 can, together with the N atom to which they are attached, represent a 5- or 6-membered heterocyclic ring that can be optionally substituted; and pharmaceutically acceptable salts or solvates thereof with the proviso that both R 4 and R 5 are not H.

For the avoidance of doubt, unless otherwise indicated, the term substituted means substituted with one or more of the groups described. In the case where the groups may be selected from a number of alternative groups, the selected groups may be the same or different.

For the avoidance of doubt, the term "independently" means that where more than one substituent is selected from a range of possible substituents, those substituents may be the same or different.

According to a third aspect, the invention describes a compound represented by the general formula I and its pharmaceutically acceptable salts, wherein R 1 , R 2 , R 3 , Z and Y are as described in the first aspect; and R4 and R5, which may be the same or different, are -(CH2)p-A', where p is 0, 1 or 2 and A' is a polar group. In this aspect, polar groups can be described as having a negative π-value (see C Hansch and A Leo, 'Substitute Constants for Correlation Analysis in Chemistry and Biology', Wiley, New York, 1979). In that system, for example, H has a π-value of 0.00, -OCH3 has a π-value of –0.02, and -SO2NH2 has a π-value of -1.82, [see Tables VI-I, 'Well- Characterized Aromatic Substituents', p 49, ibid]. More favorable polar groups have a more negative π-value: therefore, favorable groups have π-values more negative than –0.1, more favorable more negative values than -0.5, and most favorable more negative values than –1.0. Even when p is something other than zero in the above definition, the definition of A' is based on the above references as if p were zero.

Unless otherwise described, the compounds of the first, second and third aspects are described below as compounds of the invention.

The compounds of the invention have the advantage that they are selective serotonin reuptake inhibitors (SRIs) (and as such are likely to have reduced side effects), they have a rapid onset of action (making them suitable for administration just before action is required), they have the desired potency and side effects properties. Compounds that selectively inhibit the reuptake of serotonin, but not noradrenaline or dopamine, are preferred.

It was established that the compounds represented by formula I possessing such properties have a relatively polar group at the R4/R5 position.

Pharmaceutically or veterinary acceptable salts of the compounds shown by formula I containing basic centers are, for example, non-toxic acid addition salts obtained from inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acids, with carboxylic acids or with organo-sulfonic acids. Examples include HCI, HBr, HI, sulfate or bisulfate, nitrate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, saccharate, fumarate, maleate, lactate, citrate, tartrate, gluconate, camsylate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate salts. The compounds of the present invention can also provide pharmaceutically or veterinary acceptable metal salts, specifically non-toxic salts of alkali and alkaline earth metals with bases. Examples include sodium, potassium, aluminum, calcium, magnesium, zinc, diolamine, olamine, ethylenediamine, tromethamine, chloin, megulamine and diethanolamine salts. For a review of suitable pharmaceutical salts, see Berge et al., J. Pharm, Sci., 66, 1-19, 1977; P L Gould, International Journal of Pharmaceutics, 33 (1986), 201-217; and Bighley et al., Encyclopedia of Pharmaceutical Technology, Marcel Dekker Inc, New York 1996, volume 13, pages 453-497.

Below, the compounds, their pharmaceutically acceptable salts, solvates and polymorphs thereof, described in each aspect of the invention (except intermediate compounds in chemical processes) refer to "compounds of this invention".

Pharmaceutically acceptable solvates of the compounds of this invention include their hydrate forms.

The compounds of the invention may have one or more chiral centers and thus exist in a series of stereoisomeric forms. All stereoisomers and mixtures thereof are included within the scope of this invention. Racemic compounds can either be separated using preparative HPLC and a column with a chiral stationary phase or resolved to give individual enantiomers using procedures known to those of ordinary skill in the art. Furthermore, the chiral intermediates can be dissolved and used to prepare the chiral compounds of this invention.

In cases where the compounds of this invention exist as E and Z isomers, the invention includes the individual isomers as well as mixtures thereof.

In cases where the compounds of this invention exist as tautomeric isomers, the invention includes individual tautomers as well as mixtures thereof.

In cases where the compounds of this invention exist as optical isomers, the invention includes individual isomers as well as mixtures thereof.

In cases where the compounds of this invention exist as diastereomers, the invention includes individual diastereomers as well as mixtures thereof.

Separation of diastereoisomers or E and Z isomers can be achieved by conventional techniques, eg fractional crystallization, chromatography or H.P.L.C. A single enantiomer of a compound of the present invention can be obtained from the corresponding optically pure intermediate or by resolution, such as H.P.L.C. of the appropriate racemate using a suitable chiral carrier or by fractional crystallization of diastereoisomeric salts obtained by the reaction of the appropriate racemate with a suitable optically active acid or base as needed.

The compounds of this invention may exist as one or more tautomeric forms. All tautomers and mixtures thereof are included within the scope of this invention. For example, the claim for 2-hydroxypyridinyl also covers its tautomeric form, α-pyridonyl.

Those of ordinary skill in the art will appreciate that certain protected derivatives of the compounds of this invention, which may be made prior to the final stage of deprotection, may not possess pharmacological activity as such, but may, in certain cases, after oral or parenteral administration, be metabolized in the body to yield compounds of this invention. inventions that are pharmacologically active. Such derivatives may therefore be described as "prodrugs". Furthermore, certain compounds of the present invention may act as prodrugs of other compounds of the present invention.

All proprietary derivatives and prodrugs of the compounds of this invention are included within the scope of this invention. Examples of suitable prodrugs for the compounds of this invention are described in Drugs of Today, Volume 19, Number 9, 1983, p. 499-538, in Topics in Chemistry, Chapter 31, p. 306-316 and in "Design of Prodrugs" by H. Bundgaard, Elsevier, 1985, Chapter 1 (communications from which documents are incorporated herein by reference).

Those of ordinary skill in the art will further appreciate that certain units, known to those of ordinary skill in the art as "pro-units", e.g., as described by H. Bundgaard in "Design of Prodrugs" (a communication from which document is incorporated herein by reference), can be located at appropriate functional sites when such functional sites are present in the compounds of this invention.

Suitable prodrugs for the compounds of this invention include: esters, carbonate esters, hemi-esters, phosphate esters, nitro esters, sulfate esters, sulfoxides, amides, carbamates, azo compounds, phosphamides, glycosides, ethers, acetals and ketals.

The invention also includes all suitable isotopic variations of the compounds of this invention. An isotopic variation is described as a variation in which at least one atom is replaced by an atom that has the same atomic number but a different atomic mass than the atomic mass usually found in nature. Examples of isotopes that can be incorporated into the compounds of this invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, respectively, such as 2H, 3H, 13C, 14C, 15N, 17O, 18O, 31P, 32P, 35S. , 13F and 36Cl. Certain isotopic variations of the present invention, eg, those in which a radioactive isotope such as 3H or 14C is included, are useful in assays of drug and/or substrate distribution in tissues. The isotopes of tritium, i.e. 3H, and carbon-14, i.e. 14C, are particularly suitable due to their simple acquisition and detection. In addition, substitution with isotopes such as deuterium, i.e. 2H, may provide certain therapeutic advantages as a result of greater metabolic stability, eg, increased in vivo half-life or reduction of required dose, and may therefore be preferred in certain circumstances. Isotopic variations of the compounds of this invention can generally be obtained by conventional procedures such as the procedures or preparations described in the Examples and Preparations below using appropriate isotopic variations of suitable reagents.

The compounds of this invention can be obtained, by a known process, in various ways. In the following reaction schemes and hereafter, unless otherwise indicated, R1 to R13, Z and Y are as described in the first aspect. These procedures provide the following aspects of the invention.

Throughout the patent description, the general formulas are designated by Roman numerals I, II, III, IV, etc. The subunits of these general formulas are described as Ia, Ib, Ic, etc.,... IVa, IVb, IVc, etc.

Compounds represented by general formula (I) can be obtained from compounds represented by formula (II) by reaction with an amine of general formula HNR1R2, or with a suitable salt thereof, together with a hydride reducing agent in a suitable solvent (see scheme 1). When either R 1 or R 2 is hydrogen, a suitable solvent includes a protic solvent such as ethanol, and sodium borohydride is a suitable reducing agent as described by Example 36 herein. When neither R1 nor R2 is hydrogen, tetrahydrofuran/dichloromethane is a suitable solvent system and sodium triacetoxyborohydride is a suitable reducing agent. In such reactions, it is preferred to use HNR1R2 in salt form, such as the hydrochloride, and an auxiliary base, to improve the solubility of the HNR1R2 salt, such as triethylamine may optionally be added in addition to acetic acid, as described in Example 25 herein.

SCHEME 1

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Compounds represented by formula (II) can be obtained below by coupling compounds represented by general formula (IV) with aldehyde compounds represented by general formula (III), wherein L is a suitable releasing group such as halogens (F, Cl, Br or I) or a sulfonate ester such as trifluoromethanesulfonate or methanesulfonate, and a suitable L is F or Cl. Such coupling reactions can be carried out by known art procedures, such as reaction with potassium carbonate in a suitable solvent such as dimethylformamide under suitable reaction conditions such as at elevated temperature and in an inert atmosphere.

Thus, according to the following aspect, the invention describes a process for obtaining compounds represented by general formula (I) from compounds represented by general formula (II).

Alternatively, R 4 and/or R 5 may be introduced into the reaction after coupling the ether (see Scheme 2). The compounds represented by the general formula (I) can be obtained from the compounds represented by the general formula (Ia), i.e. the compounds represented by the general formula (I) where R 4 and R 5 are hydrogen. The compounds represented by the general formula (Ia) can be obtained from (IIa) by an analogous procedure as when obtaining (I) from (II) (see scheme 1), while the compounds represented by the general formula (IIa) can be obtained from (IV) and (IIIa) ) by an analogous procedure as in obtaining (II) (see scheme 1).

SCHEME 2

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As follows from the following aspect, the invention describes a process for obtaining the compounds represented by the general formula (I) from the compounds represented by the general formula (Ia).

Procedures for introducing R4 and/or R5 into compounds of formula (Ia) include:

where R 4 /R 5 are halogen, react (Ia) with a suitable halogenating agent in an inert solvent which does not adversely affect the reaction. Suitable halogenating agents include trifluoromethanesulfonic acid and N-iodosuccinimide, and suitable inert solvents include dichloromethane.

wherein R 4 /R 5 are -NO 2 , reacting (Ia) with a suitable nitrating agent, such as an alkali metal nitrate, in a solvent which does not adversely affect the reaction at, or below, room temperature. Suitable nitrating agents include trifluoromethanesulfonic acid/potassium nitrate and suitable solvents include trifluoroacetic acid.

where R4/R5 is -SO2NR6R7, reaction of the sulfonyl chloride intermediate with the required amine represented by the formula HNR6R7 in a suitable solvent. Suitable solvents include a mixture of water and dichloromethane, and the reactions are generally carried out at or below room temperature. The sulfonyl chloride intermediate can be obtained from compounds of formula (Ia) by reaction with chlorosulfonic acid at low temperature in the presence of a solvent that does not adversely affect the reaction, either with or without subsequent procedures with a chlorinating agent such as phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride or thionyl chloride in a solvent that does not adversely affect the reaction. Suitable solvents for reaction with chlorosulfonic acid include trifluoroacetic acid and a common reaction temperature is 0 °C. Suitable solvents for reaction with the chlorinating agent include acetonitrile, and suitable conditions include reflux, as described in Example 12 herein.

For example, compounds of formula (Iq), where R5 is -SO2NR6R7, can be obtained via the sulfonyl chloride intermediate (XVIII) from compounds of formula (Ia) by reaction of (Ia) with chlorosulfonic acid, either with or without the following procedures with a chlorinating agent as which are phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride or thionyl chloride, followed by reaction with HNR6R7 (see Scheme 2a). Reaction conditions usually involve low temperature. The reaction can be carried out either undiluted, i.e. in the absence of solvent, or in the presence of an inert solvent that does not adversely affect the reaction. The sulfonyl chloride intermediate (XVII) can be isolated, purified and then reacted with HNR6R7, alternatively it can be obtained in situ, without isolation, and then reacted with HNR6R7.

SCHEME 2a

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Thus, according to the following aspect, the invention describes a process for obtaining compounds represented by general formula (I) from compounds represented by general formula (II). In a suitable embodiment, procedures are described for obtaining compounds shown by formula (Iq) by reacting compounds shown by formula (la) in a suitable solvent, with chlorosulfonic acid, either with or without subsequent procedures with a chlorinating agent such as phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride or thionyl chloride to give compounds of formula (XVIII) followed by reaction with HNR 6 R 7 to give compounds of formula (Iq). Suitable compounds represented by formula (XVIII) are obtained in situ and react with HNR 6 R 7 without isolation.

Alternatively, compounds of general formula (I) having a particular R 4 /R 5 substituent can be converted into other compounds of formula (I) using known methods. For example:

when R4/R5 is a halogen such as chloro, bromo or iodo, it can be converted to cyano by reaction with a cyanide salt in the presence of a Pd(0) or (II) catalyst in a high boiling solvent at elevated temperatures. Suitable Pd catalysts include palladium tetrakis(triphenylphosphine), suitable cyanide salts include Zn(CN) 2 , and suitable high boiling solvents that do not adversely affect the reaction include dimethylformamide as described in Example 78 in the text;

when R4/R5 is a halogen such as chloro, bromo or iodo, it can be converted to the corresponding ester -CO2R by a high pressure carbon monoxide process with a Pd(0) or (II) catalyst, in an alcoholic solvent (ROH where R is C1-C4 alkyl), in the presence of a base at elevated temperatures. As an example, the reaction can be carried out at an ambient pressure of about 100 psi, while suitable Pd catalysts include dichlorobis(triphenylphosphine)palladium(II), suitable bases include triethylamine, and suitable alcoholic solvents include methanol as described in the preparation of 50 herein;

when R 4 /R 5 is nitro, it can be reduced to give the corresponding -NH 2 group by a reducing agent procedure in a flowing solvent at or above room temperature. Suitable reducing agents include iron powder/calcium chloride, suitable protic solvents include aqueous ethanol, and a typical reaction temperature is from about 70°C to about 100°C, preferably about 90°C, as described herein in Example 103;

when R4/R5 is -NH2, it can be converted to the corresponding -NHSO2R9 group by reaction with a sulfonating agent in the presence of a base in an inert solvent that does not adversely affect the reaction at, or below, room temperature. Suitable sulfonating agents include methanesulfonyl chloride, suitable bases include triethylamine, and suitable inert solvents include dichloromethane as described herein in Example 128;

when R 4 /R 5 is a -NHSO 2 R 9 group, it can be converted to the corresponding NR 8 SO 2 R 9 group by a procedure with an alkylating agent and a base in a suitable inert solvent. Examples of suitable alkylating agents include methyl iodide, suitable bases include potassium carbonate, and suitable inert solvents include acetonitrile, as described herein in the preparation of 88;

when R4/R5 is a nitrile -CN, it can be converted to the corresponding -C(O)NH2 group by hydrolysis under basic, oxidative or acidic conditions. A convenient basic hydrolysis is performed with a hydroxide salt such as potassium hydroxide in a protic solvent such as t-butanol at elevated temperatures, as described herein in Example 79.

when R4/R5 is an ester -CO2R, it can be reduced to the corresponding alcohol group -CH2OH by a procedure with a hydride reducing agent, such as lithium aluminum hydride, according to the preparation of 69 described herein;

when R4/R5 is an ester -CO2R, it can be converted to the corresponding acid -CO2H by a suitable hydroxide salt in the presence of water and a suitable co-solvent. Suitable hydroxide salts include lithium hydroxide and suitable co-solvents include tetrahydrofuran, as described herein in the preparation of 55;

when R 4 /R 5 is an acid -CO 2 H, it can be converted to the corresponding amide -CONR 6 R 7 by a coupling agent, base and amine HNR 6 R 7 in a suitable inert solvent which does not adversely affect the reaction. Suitable coupling agents include 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in the presence of 1-hydroxybenzotriazole, suitable bases include triethylamine, and suitable solvents include dichloromethane, as described herein in the preparation of 59;

when R4/R5 is a halogen such as chloro, bromo or iodo, it can be converted to an α,β-unsaturated amide by treatment with acrylamide, a Pd(0) or (II) catalyst and a suitable base, in an inert solvent that does not adversely affect to the reaction, at elevated temperatures. Suitable Pd catalysts include palladium(II) acetate in the presence of tri(o-tolyl)phosphine, suitable bases include triethylamine, and suitable inert solvents include acetonitrile as described herein by Example 50;

when R4/R5 is an α,β-unsaturated amide, it can be converted to CH2CH2CO2NH2, by a process with a suitable reducing agent at a suitable temperature, in a suitable solvent which does not adversely affect the reaction. Suitable reducing agents include samarium diiodide at room temperature, and suitable solvents include tetrahydrofuran containing a small amount of water, as described herein in Example 51;

when R 4 /R 5 is -CH 2 OH, it can be converted to -CH 2 NR 8 SO 2 R 9 according to the method described in Mitsunoba's reaction at a suitable temperature, in a suitable solvent which does not adversely affect the reaction. Suitable reagents include diethyl azodicarboxylate, triphenylphosphine and tert-butyl methylsulfonylcarbamate, 0 °C is a suitable reaction temperature and tetrahydrofuran is a suitable solvent as described herein in the preparation of 72;

Alternatively, compounds represented by the general formula (I) having a certain NR 1 R 2 group can be converted into other compounds represented by the general formula (I) having a different NR 1 R 2 group.

For example:

Compounds of formula (Ib) wherein either R1 or R2 is hydrogen can be converted into compounds of formula (Ic) wherein neither R1 nor R2 is hydrogen by reacting the compound of formula (Ib) with an aldehyde and a hydride reducing agent. Suitable aldehydes include formaldehyde, suitable reducing agents include sodium tri(acetoxy)borohydride, and it is preferred that the reaction be carried out in a solvent that does not interfere with the reaction, such as dichloromethane at or below room temperature, as exemplified herein 12.

Compounds of formula (Ib) where R1 or R2 is hydrogen can be converted into compounds of formula (Ic) where R1 or R2 is methyl by reacting the compound of formula (Ib) with a formylating agent in a suitable solvent, followed by reduction of intermediate N -formyl using a hydride reducing agent in an inert solvent, preferably at an elevated temperature. Suitable formylation agents include pentafluorophenyl formate (derived from formic acid, pentafluorophenol and dicyclohexylcarbodiimide) and suitable formylation solvents include dichloromethane. Suitable reducing agents include a borane-tetrahydrofuran complex, and suitable inert reducing solvents include tetrahydrofuran as described herein in Example 110.

Alternatively, compounds of general formula (I) can be obtained from compounds of formula V (see Scheme 3) where L is as described in Scheme 1 and T is a group convertible into CH 2 NR 1 R 2 . Examples of suitable T substituents include: -CO 2 R 10 , -CN and -C(O)NR 1 R 2 .

SCHEME 3

[image]

Procedures for converting compounds of formula (V) into compounds of formula (I) include:

where T is -CO2R10 and R10=methyl or ethyl, reaction with an amine represented by the general formula NHR1R2 to form an amide, followed by reduction to give an amine.

where T = -CN, reduction resulting in the corresponding amine represented by the formula -CH2NH2.

where T = -C(O)NR1R2, reduction resulting in amine.

The compounds represented by the general formula (V) can be obtained below by combining the compounds represented by the general formula (VI) and the compounds represented by the general formula (IV). The reagents and conditions for such coupling reactions are as previously described for the coupling of compounds represented by general formula (IV) and (III) in Scheme 1.

The compounds represented by the general formula (VI) can be obtained below from the compounds represented by the general formula (VII) (see Scheme 4).

SCHEME 4

[image]

Compounds represented by formula (VI) can be obtained by aromatic electrophilic substitution of compounds represented by formula (VII), thereby directly obtaining compounds represented by formula (VI). Alternatively, the compounds shown by formula (VI) can be obtained in two or more steps; by aromatic electrophilic substitution of the compounds represented by formula (VII), whereby intermediate compounds are obtained which are then subjected to the following reaction giving compounds represented by formula (VI). Interconnects can be insulated or obtained in situ without insulation. A suitable sequence is shown in Scheme 5.

SCHEME 5

[image]

Compounds of formula (VII) react with sulfonyl chloride to give compounds of formula (VIII) followed by reaction with NHR 6 R 7 to give compounds of formula (VIa).

According to the following aspects, the invention describes compounds represented by formula (II), (IIa) and (V) as described above.

Compounds of formula (III), (IIIa), (IV), (VI) or (VII) are either known and available from commercial sources or are available from commercially available materials using known procedures (see examples in the text below).

It will be apparent to those of ordinary skill in the art that sensitive functional groups may require protection and deprotection during the synthesis of a compound of formula I. This can be accomplished by conventional procedures, eg as described in 'Protective Groups in Organic Synthesis', 3rd Edition, T W Greene and P G M Wuts, John Wiley and sons Inc, 1999. Example 35 provides an example in which a protecting group is used (as a synthetic procedure strategy) in the synthesis of a compound of the present invention.

A skilled chemist will appreciate that diaryl ethers can be prepared using a variety of synthetic procedures. For a list of procedures, see J S Sawyer, Tetrahedron, 56 (2000) 5045-5065, referenced below.

The compounds of the invention are useful because they are pharmacologically active in mammals, including humans. In more detail, they are useful in the treatment or prevention of disorders in which the regulation of monoamine transport function is involved. Disease states that may be mentioned include hypertension, depression (eg depression in tumor patients, depression in Parkinson's disease patients, post-myocardial infarction depression, subsyndromal symptomatic depression, infertile depression, pediatric depression, major depression, single depression, recurrent depression, abused child depression, postpartum depression and irritable elderly syndrome), generalized anxiety disorder, phobias (e.g. agoraphobia, social phobia and simple phobias), post-traumatic stress syndrome, personality disorder, premature ejaculation, eating disorders (e.g. . anorexia and bulimia), obesity, addiction to chemical compounds (e.g. addiction to alcohol, cocaine, heroin, phenobarbital, nicotine and benzodiazepines), Cluster headache, migraine, pain, Alzheimer's disease, obsessive-compulsive disorder, panic disorder, memory disorders (e.g. dementia, memory loss disorders and age-related cognitive decline (ARCD)), Parkinson's disease (e.g. dementia in patients suffering from Parkinson's disease, neuroleptic-induced parkinsonism and tardive dyskinesia), endocrine disorders (eg hyperprolactinemia), vasospasm (especially in cerebral blood vessels), cerebellar ataxia, gastrointestinal tract disorders (including changes in motility and secretion), negative symptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress incontinence, Tourette's syndrome, trichotillomania, kleptomania, impotence, attention deficit hyperactivity disorder (ADHD), chronic paroxysmal hemicrania, headache (associated with blood vessel disorders), emotional instability, pathological crying, cataplexy and shock.

Disorders of particular interest include depression, attention deficit hyperactivity disorder, obsessive-compulsive disorder, post-traumatic stress disorder, substance abuse disorders, and sexual dysfunction including (especially) premature ejaculation.

Premature ejaculation can be described as continuous or repeated ejaculation before, during or shortly after penetration of the sexual organ of the sexual partner. It can also be described as ejaculation that occurs before the person wants it [see 'The Merck Manual', 16th edition, p. 1576, published by Merck Research Laboratories, 1992].

From there, according to the following aspects, the invention describes:

a compound of the present invention for use as a pharmaceutical agent;

use of a compound of the present invention for the manufacture of a medicament for the treatment or prevention of disorders involving the regulation of monoamine transport function, eg depression, attention deficit hyperactivity disorder, obsessive-compulsive disorder, post-traumatic stress disorder, drug abuse disorders or sexual dysfunction involving premature ejaculation;

the use of a compound of this invention for the production of a medicament for the treatment or prevention of premature ejaculation;

a method of treating or preventing depression, attention deficit hyperactivity disorder, obsessive-compulsive disorder, post-traumatic stress disorder, substance abuse disorder or sexual dysfunction including premature ejaculation, the method comprising administering a therapeutically effective amount of a compound of the present invention to a patient in need of such treatment or prevention;

a method of increasing ejaculatory latency comprising administering an effective amount of a compound of the present invention to a male patient desiring to increase ejaculatory latency; and

a compound of this invention for the treatment or prevention of disorders in which the regulation of monoamine transport function is involved, eg, depression, attention deficit hyperactivity disorder, obsessive-compulsive disorder, post-traumatic stress disorder, substance abuse disorders, or sexual dysfunction including premature ejaculation.

compound of the present invention for the treatment of premature ejaculation.

It will be appreciated that all references to treatment herein include curative, palliative and prophylactic procedures.

The compounds of this invention may be administered alone or as part of combination therapy. If a combination of active agents is applied, then they can be applied simultaneously, separately or sequentially. In more detail, the compounds of the present invention can be combined with the following compounds suitable for the treatment of PE:

Alpha-blockers (e.g. phentolamine, doxazazim, tamsulosin, terazasin, prazasin and the compound obtained in example 19 of the invention WO9830560. The possible principle of action of alpha-blockers in the treatment of premature ejaculation is as follows. Muscle activity of the smooth muscles involved in ejaculation (vasus, seminal vesicles and urethra) are under the control of the sympathetic nervous system through the release of noradrenaline. Noradrenaline acts on alpha 1 adrenoreceptors, stimulating muscle contractions, which leads to the release of semen and then ejaculation. Blocking these receptors will therefore inhibit ejaculation.

Apomorphine - A report on the use of apomorphine as a pharmaceutical agent can be found in US-A-5945117.

Dopamine D2 antagonists (eg Premiprixal, Pharmacia Upjohn compound number PNU95666).

Melanocortin receptor antagonists (eg Melanotan II).

PGE1 receptor antagonists (eg alprostadil).

Monoamine transport inhibitors, especially noradrenaline reuptake inhibitors (NRIs) (eg Reboxetine), other serotonin reuptake inhibitors (SRIs) (eg paroxetine) or dopamine reuptake inhibitors (DRIs).

5-HT3 antagonists (eg ondansetron and granisetron). A possible principle for the treatment of premature ejaculation with 5-HT3 antagonists is as follows. 5-HT3 receptors, located in the lumen of the posterior part of the urethra, are stimulated by 5-HT from the seminal fluid during ejaculation, and this leads to spinal parasympathetic stimulation leading to ejaculation. Therefore, the antagonist will prevent this sensitivity and therefore delay ejaculation.

PDE inhibitors such as PDE2 (e.g. erythro-9-(2-hydroxyl-3-nonyl)-adenine) and the compound in Example 100 of EP 0771799-incorporated herein by reference), and in particular a PDE5 inhibitor (e.g. sildenafil, 1 -{[3-(3,4-dihydro-5-methyl-4-oxo-7-propylimidazo[5,1-f]-as-trazin-2-yl)-4-ethoxyphenyl]sulfonyl}-4-ethylpiperazine ie, vardenafil/Bayer BA 38-9456 or IC351 (see structure below, Icos Lilly)). The possible principle of action of PDE inhibitors in the treatment of premature ejaculation is as follows. The levels of CAMP and CGMP in the smooth muscles involved in ejaculation regulate the muscle tone of these ejaculatory muscles and thus delay ejaculation.

[image]

potassium channel openers.

Antagonists of P2X purinergic receptors.

Endothelial receptor antagonists

The compounds of this invention for human use may be administered alone, but in human treatment will generally be administered as admixture with a suitable pharmaceutical excipient, diluent or carrier selected with respect to the intended route of administration and standard pharmaceutical procedures.

For example, the compounds of this invention can be administered orally, buccally or sublingually in the form of tablets, capsules (including soft gel capsules), ovules, elixirs, solutions or suspensions, which may contain agents that provide flavor or color, agents for immediate-, delayed- , modified-, continuous-, dual-, controlled-release or pulse application. The compounds of the present invention may also be administered by intracavernosal injection. The compounds of the present invention may also be provided in rapidly dispersible or rapidly dissolving dosage forms.

Such tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine and starch (corn, potato or tapioca starch is preferred), disintegrants such as sodium starch glycolate, croscarmellose sodium and certain silicate complexes, and granulating binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin, and acacia. Lubricants such as magnesium stearate, stearic acid, glyceryl behenate and talc may additionally be included.

Solid preparations of similar shapes may also be included as fillers in gelatin capsules. In this regard, suitable excipients include lactose, starch, cellulose, milk sugar or high molecular weight polyethylene glycols. For aqueous suspensions and/or elixirs, the compounds of this invention and their pharmaceutically acceptable salts can be combined with various sweeteners or flavoring agents, with coloring agents, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and their combinations.

Modified-release and pulse-release dosage forms may contain excipients such as those described for immediate-release dosage forms along with additional excipients that act as release rate modifiers, with which the dosage forms are coated and/or incorporated into the dosage contents. Release rate modifiers include, but are not limited to, hydroxypropylmethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, polyethylene oxide, xanthan gum, carbomer, ammonium methacrylate copolymer, hydrogenated castor oil, palm wax, paraffin wax, cellulose acetate phthalate. , hydroxypropylmethyl cellulose phthalate, methacrylic acid copolymers and their mixtures. Modified and pulsed release dosage forms may contain one or a combination of excipients as release rate modifiers. Excipients as modifiers of the release rate can be present both inside the dose, i.e. inside the matrix, and/or on the dose, i.e. on the surface or as an envelope

.

Fast Dispersing or Dissolving Dose Formulation (FDDFs) may contain the following ingredients: aspartame, acesulfame potassium, citric acid, croscarmellose sodium, crospovidone, diascorbic acid, ethyl acrylate, ethyl cellulose, gelatin, hydroxypropylmethyl cellulose, magnesium stearate, mannitol, methyl methacrylate , agent that gives a mint flavor, polyethylene glycol, dried silica gel, silicon dioxide, starch sodium glycolate, sodium stearyl fumarate, sorbitol, xylitol. The terms disperse or dissolve as used here in the text to describe FDDFs depend on the solubility of the medicinal substance used, i.e. when the medicinal substance is insoluble it can be prepared in a dosage form that disperses quickly, and when the medicinal substance is soluble it can be prepared in a dosage form that dissolves quickly.

The compounds of this invention may also be administered parenterally, eg, intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracranially, intramuscularly, or subcutaneously, or may be administered by infusion procedures. For such parenteral administration, they are best used in the form of a sterile aqueous solution that may contain medicinal substances, eg, enough salt or glucose to make the solution isotonic with respect to blood. Aqueous solutions should be suitably buffered if necessary (pH 3 to 9 is preferred). Obtaining suitable parenteral formulations under sterile conditions has already been achieved by standard pharmaceutical procedures well known to those of ordinary skill in the art.

The following dose levels and other dose levels herein are for the average human being weighing in the range of about 65 to 70 kg. A skilled person will be able to quickly determine the dose levels required for a patient whose weight is outside this range, such as children and the elderly.

For oral and parenteral administration to human patients, the daily dose level of the compounds of this invention or their salts or solutions is usually from 10 to 500 mg (in one or several divided doses).

Therefore, for example, tablets or capsules of the compounds of the present invention may contain from 5 mg to 250 mg of the active compound for administration as needed at once or in two or more doses. In each case, the doctor will determine the right dose that will be most suitable for each individual patient and it will differ with regard to the age, weight and reaction to the medicine of a particular patient. The above doses are examples of an average case. Of course, there may be individual cases where higher or lower dose ranges are required, and these are also within the scope of this invention. The skilled person will also appreciate that, in the treatment of certain conditions (including PE), the compounds of this invention may be taken as a single dose on an "as needed" (ie, as needed or desired) basis.

Example of Tablet Formulation

In general, a tablet formulation may typically contain between about 0.01 mg and 500 mg of a compound of the present invention while the tablet fill weight may range from 50 mg to 1000 mg. An example formulation for a 10 mg tablet is shown:

Ingredient mass fraction

Compound of this invention 10,000* ;Lactose 64,125 ;Starch 21,375 ;Croscarmellose sodium 3,000 ;Magnesium stearate 1,500 ;* This amount is symbolically adjusted according to the activity of the drug.

The compounds of this invention may also be administered intranasally or by inhalation and are usually available as a dry powder inhaler or as an aerosol spray delivered by means of a pressurized container, pump, spray, or nebulizer using a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoro- ethane, hydrofluoroalkanes such as 1,1,1,2-tetrafluoroethane (HFA 134A [proprietary name]) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA [proprietary name]), carbon dioxide or other suitable gas. In the case of pressurized aerosols, the unit dose can be determined by means of a valve to deliver a specific metered amount. A pressure vessel, pump, spray or atomizer may contain a solution or suspension of the active compound, eg using a mixture of ethanol and propellant as a solvent, which may additionally contain a lubricant, eg sorbitan trioleate. Capsules and fillers (made, eg, of gelatin) for use in inhalers or insufflators may be formulated to contain a mixture of a powder of a compound of this invention and a suitable powder base such as lactose or starch.

Aerosol or dry powder forms are preferably designed such that each metered dose or "actuation" contains from 1 to 50 mg of a compound of the present invention for administration to a patient. The total daily dose of the aerosol will range from 1 to 50 mg, and can be given as a single dose or, as is more common, in divided doses throughout the day.

The compounds of the present invention may also be formulated for administration by an electronic pump. The electronic pump may contain the following ingredients as solubilizers, emulsifiers or suspending agents: water, ethanol, glycerol, propylene glycol, low molecular weight polyethylene glycols, sodium chloride, fluorocarbons, polyethylene glycol ethers, sorbitan trioleate, oleic acid.

Alternatively, the compounds of the present invention may be administered in the form of a suppository or vaginal insert, or may be administered topically in the form of a gel, hydrogel, lotion, solution, cream, ointment, or powder. The compounds of the present invention may also be administered dermally or transdermally, eg, using a patch. They can also be administered by the ocular, pulmonary or rectal routes.

For ophthalmic use, the compounds may be formulated as a microsuspension in isotonic, pH-adjusted, sterile saline, or, as preferred, as a solution in isotonic, pH-adjusted, sterile saline, possibly in combination with preservatives such as benzylalkonium chloride. Alternatively, they can be formulated into an ointment such as white petrolatum.

For topical application to the skin, the compounds of this invention are formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture of one or more of the following ingredients: mineral oil, liquid petroleum, white kerosene, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, they may be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following ingredients: mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters, wax, cetearyl alcohol, 2- octyldodecanol, benzyl alcohol and water.

The compounds of this invention may also be used in combination with cyclodextrin. Cyclodextrins are known to form inclusion and non-inclusion complexes with drug molecules. The formation of the drug-cyclodextrin complex can change the solubility, degree of dissolution, bioavailability and/or stability properties of the drug molecules. Drug-cyclodextrin complexes are generally usable for most dosage forms and routes of administration. As an alternative to direct complexation with the drug, cyclodextrin can be used as an additional auxiliary agent, eg as a carrier, diluent or agent to increase solubility. Alpha-, beta- and gamma-cyclodextrins are most commonly used, and suitable examples are described in WO-A-91/11172, WO-A-94/02518 and WO-A-98/55148.

For oral or parenteral administration to human patients, daily dose levels of the compounds of this invention range from 0.01 to 30 mg/kg (in single or divided doses), and are preferably in the range of 0.01 to 5 mg/kg. Accordingly, the tablets will contain 1mg to 0.4g of compound for administration at once or in two or more doses, as appropriate. In any case, the doctor will determine the right dose that will be most suitable for each particular patient, and the dose will vary with the age, weight and reaction of the particular patient. The doses mentioned above are, of course, only examples of an average condition, and there are conditions where higher or lower doses are required, and such conditions are also within the scope of this invention.

Oral administration is preferred. It is convenient to administer the medicine shortly before the action is needed.

For veterinary use, the compound of this invention is administered in an acceptable form in accordance with normal veterinary practice, and the veterinarian will determine the dosage method and route of administration most appropriate for a particular animal.

Thus according to the following aspect, the invention describes a pharmaceutical form comprising a compound of the present invention and a pharmaceutically acceptable excipient, diluent or carrier.

The invention is explained by the following non-limiting examples in which the following abbreviations and definitions are used:

Arbocel® filtering agent

No. wide

Boc tert-butoxycarbonyl

CDI carbonyldiimidazole

δ chemical shift

d doublet

Δ heat

DCCl dicyclohexylcarbodiimide

DCM dichloromethane

DMF N,N-dimethylformamide

DMSO dimethylsulfoxide

ES+ positive ionization by electrospray

ES - negative ionization by electrospray

Ex example

h hours

HOBt 1-Hydroxybenzotriazole

High performance HPLC liquid chromatography

m/s mass spectrum peak

min minutes

MS mass spectrum

NMR nuclear magnetic resonance

Precursor

Age gaining

q quartet

with a singlet

t triplet

Tf trifluoromethanesulfonyl

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography

TS+ positive ionization by thermospray

WSCDI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

The 1H nuclear magnetic resonance (NMR) spectrum is consistent with the proposed structures in all cases. Characteristic chemical shifts (δ) are given in parts per million down from tetramethylsilane using the usual abbreviations to indicate the main peaks: eg s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; no, wide.

The following abbreviations are used for common solvents: CDCl3, deuterium chloroform; DMSO, dimethylsulfoxide. The abbreviation psi stands for pounds per square inch (1 pound=453.59 g, 1 inch=2.54 cm) and LRMS stands for low resolution mass spectrometry. When thin layer chromatography (TLC) is used it means TLC on silica gel using silica gel 60 F254 plates, Rf is the distance traveled by the compound divided by the distance traveled by the solvent front on the TLC plate. The melting temperature is determined using a Perkin Elmer DSC7 at a heating rate of 20 °C/minute).

Where indicated, the compounds are described as their hydrochloride salts. A typical procedure for obtaining hydrochloride salts is given in example 12. The procedure can be carried out with other solvents, for example diethyl ether or DCM.

Commercially available starting materials were obtained from Aldrich Chemical Co, Lancaster Synthesis Ltd or from Acros Organics.

EXAMPLE 1

3-[(Methylamino)methyl]-4-[3-methyl-4-methylsulfanyl)phenoxy]-benzenesulfonamide

[image]

The amide formed in the preparation of 8 (760 mg, 2.07 mmol) was dissolved in THF (10 mL) to give a thick suspension, and the resulting suspension was treated with borane tetrahydrofuran complex (1M solution in THF, 6.22 mL, 6.22 mmol) at room temperature. The resulting solution is heated at reflux for 5 hours in an atmosphere of dry nitrogen. The reaction mixture was cooled to room temperature and treated carefully with 6M HCl solution (6 mL). The resulting mixture is heated under reflux for 30 min. After cooling to room temperature, the mixture is diluted with water (10 mL) and made alkaline by careful addition of solid potassium carbonate. The aqueous layer is extracted with EtOAc (20 mL) to form a precipitate in the organic layer, and the aqueous layer is further extracted with DCM (2 x 20 mL). The EtOAc fraction was washed with 2M NaOH (20 mL) to give separate clear two phases, and the base layer was extracted with DCM (4 x 25 mL). All organic fractions were combined and washed with brine (20 mL), dried (MgSO4) and evaporated to give a colorless oil. Purification by flash chromatography [SiO2; 95:5:0.5 to 90:10:1 (EtOAc/MeOH/880 NH3)] to give a white powder of the desired amine (646 mg, 89%). δH (300 MHz, d6-DMSO) 2.26 (3H, d), 2.32 (3H, d), 2.45 (3H, d), 3.75 (2H, d), 6.90 (3H , m), 7.25 (3H, br), 7.67 (1H, t) 7.98 (1H, d); MS m/z (TS+) 353 (MH+).

The compounds shown by the formula Id, i.e. the compounds shown by the general formula I where R1 is methyl, R2 is hydrogen and R5 is -SO2NH2, shown in table 1 are obtained in an analogous way as in example 1 from the indicated precursors.

[image]

Table 1

[image] [image]

EXAMPLES 12 and 13

3-[(Dimethylamino)methyl]-4-[3-methyl-4-(methylsulfanyl)phenoxy]-benzenesulfonamide (Example 12) and 3-[(dimethylamino)methyl]-N-methyl-4-[3-methyl- 4(methylsulfanyl)phenoxy]benzenesulfonamide (Example 13)

[image]

Formaldehyde (37% aqueous solution, 282 L, 3.76 mmol) was added to a suspension of the secondary amine from Example 1 (409 mg, 1.16 mmol) in DCM (20 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 15 min before sodium triacetoxyborohydride (984 mg, 4.64 mmol) was added. The resulting reaction mixture was stirred for 5 h before being basified with saturated NaHCO 3 (10 mL) and extracted with DCM (3 x 20 mL). The organic layers were washed with brine (10 mL), dried (MgSO4) and evaporated to give a yellow oil. The oil was purified by HPLC (Phenomonex Luna C18 75 x 4.6 mm column, CH3CN, H2O, TFA). Fractions containing the major product were evaporated, and the residue was treated with saturated NaHCO3 solution (5 mL) and extracted with DCM (3x30 mL). The combined organic fractions were washed with brine (30 mL), dried (MgSO 4 ) and evaporated to give a white foam (155 mg, 36%) from Example 12; δH (300 MHz, CDCl3) 2.30 (6H, s), 2.35 (3H, s), 2.48 (3H, s), 3.60 (2H, s), 6.83 (3H, m ), 7.20 (1H, m), 7.28 (2H, s), 7.74 (1H, d), 8.08 (1H, s); MS m/z (TS+) 367 (MH+).

A side product is also obtained after HPLC purification. The relevant fractions were evaporated, and the residue was treated with saturated NaHCO3 solution (5 mL) and extracted with DCM (2x30 mL). The combined organic fractions were washed with brine (30 mL), dried (MgSO 4 ) and evaporated to give a gum. The gum was taken up in DCM (5 mL), treated with 1M HCl in ether (2 mL) and evaporated to give a white powder (39 mg, 9%) from Example 13; HCl salt : δH (CDCl3, 300 MHz) 2.30 (6H, s), 2.35 (3H, s), 2.48 (3H, s), 3.60 (2H, s), 6.83 ( 3H, m), 7.20 (1H, m), 7.28 (2H, s), 7.74 (1H, d), 8.08 (1H, s); MS m/z (TS+) 381 (MH+).

In a repeated reaction, by the action of 1 equivalent of formaldehyde with the amine from example 1, the compound from example 12 is obtained with 78% yield after chromatography on a column [SiO2; 95:5:0.5 to 90:10:1 (EtOAc/MeOH/880 NH3)]. The compound was taken up in EtOAc and converted to the HCl salt by addition of 1M HCl in ether. The resulting precipitate is filtered and dried in a vacuum to give the HCl salt from example 12; d.p. 188 °C.

Alternatively, the compound of Example 12 can also be obtained from the amine of Example 1 according to the procedure of Example 110.

The compound of Example 12 is also obtained as follows.

A solution of the hydrochloride salt of Example 94 (20 g) in trifluoroacetic acid (100 mL) was added slowly to a solution of chlorosulfonic acid (72 g) maintaining the temperature between 0 and 5 °C. After 1 hour, the reaction in the mixture is stopped slowly in water (200 mL), at 0-20 °C. The mixture was then extracted with dichloromethane (200 mL) and separated. The aqueous layer was then extracted with dichloromethane (60 mL) and separated. The combined organic layers are washed with water (200 mL). The layers were separated and the dichloromethane was removed in vacuo to give a solid. Acetonitrile (240 mL) was added and phosphorus oxychloride (28.8 mL) was added to the resulting thick mixture. The solution is then heated overnight at reflux. The reaction mixture was cooled to room temperature and quenched in a stirred mixture of ammonium (90 mL), dichloromethane (240 mL) and water (100 mL), maintaining the temperature between 0 °C and 10 °C. The pH of the mixture is adjusted using ammonia (if necessary) to more than 8. After 15 minutes, the reaction mixture is allowed to warm to room temperature and the layers are separated. The organic layer was concentrated in vacuo to give a thick brown oil. It is dissolved in acetone (100 mL) and concentrated with charcoal (Norit SX plus, 50% by weight), filtered and treated with another addition of charcoal (Norit SX plus, 50% by weight). This mixture is filtered again and the solution is concentrated by squeezing out water (200 mL). The thick solution was granulated, filtered and vacuum dried overnight to give the title product as a creamy white solid (40% yield).

EXAMPLES 14 and 15

4-(2,3-Dihydro-1,4-benzoxathiin-7-yloxy)-3-[(dimethylamino)methyl]-benzenesulfonamide and 4-(2,3-dihydro-1,4-benzoxathiin-7-yloxy) -3-[(dimethylamino)methyl]-N-methylbenzenesulfonamide

[image]

These compounds are obtained according to the analogous method from examples 12 and 13 starting from the secondary amine from example 5.

EXAMPLE 14. HCl salt: δH (CD3OD, 400 MHz) 2.97 (6H, s), 3.18 (2H, m), 4.42 (2H, m), 4.52 (2H, s), 6 .68 (2H, d), 6.99 (1H, d), 7.14 (1H, d), 7.94 (1H, d), 8.07 (1H, s); MS m/z (ES+) 381 (MH+).

EXAMPLE 15. HCl salt: δH (CD3OD, 400 MHz) 2.56 (3H, s), 2.80 (6H, s), 3.17 (2H, m), 4.35 (2H, s), 4 .41 (2H, m), 6.68 (2H, m), 6.98 (1H, d), 7.13 (1H, d), 7.81 (1H, d), 8.00 (1H, with); MS m/z (ES+) 395 (MH+).

The compounds shown by the formula Ie, i.e. the compounds shown by the general formula I where R1 and R2 are methyl and R5 is -SO2NH2, shown in table 2, are obtained according to the procedure from example 12 from the indicated precursor. The N-methyl sulfonamide analogs of Example 13 are not isolated in these reactions and do not require HPLC purification.

[image]

Table 2

[image] [image]

EXAMPLE 24

3-[(Dimethylamino)methyl]-4-[4-methyl-3-(methylsulfanyl)phenoxy]-benzenesulfonamide

[image]

The title compound is obtained from the secondary amine of Example 9 according to the procedure of Example 110; δH (CD3OD, 400 MHz) 2.27 (3H, s), 2.41 (3H, s), 2.61 (6H, s), 4.19 (2H, s), 6.76 (1H, d ), 6.88-6.93 (2H, m), 7.20 (1H, d), 7.82 (1H, d), 8.03 (1H, d); MS m/z (TS+) 367 (MH+).

EXAMPLE 25

N-{5-Methoxy-2-[3-methyl-4-(methylsulfanyl)phenoxy]benzyl}-N,N-dimethylamine

[image]

Add dimethylamine hydrochloride (424 mg, 5.2 mmol), Et3N (725 μL, 5.2 mmol), AcOH (298 μL, 5.2 mmol), and sodium triacetoxyborohydride (1.0 g, 5.2 mmol) in a solution of the aldehyde from procedure 24 (1.00 g, 3.47 mmol) in THF (15 mL) and DCM (15 mL) and the mixture was stirred at room temperature for 16 h. After removing the solvent in vacuo, the precipitate was transferred to 2M HCl (20 mL) and washed with ether (2x15 mL). The aqueous layer was basified with NaOH granules and washed with DCM (4x20 mL). The combined DCM extracts were washed with brine, dried (MgSO4) and evaporated. The precipitate was taken up in a small amount of DCM and treated with 1M HCl in ether to precipitate the HCl salt. The mixture was filtered, washed with ether and dried to give a white solid (936 mg) contaminated with triethylamine hydrochloride. The solid was dissolved in 1 M NaOH (10 mL) and extracted with EtOAc (3x15 mL). The organic extracts were washed with brine (10 mL), dried (MgSO 4 ) and evaporated before being redissolved in EtOAc and evaporated once more. The residue was taken up in DCM and treated with 1M HCl in ether to precipitate the HCl salt, which was filtered, washed with ether and dried to give a white solid (635 mg, 52%); δH (CDCl3, 300 MHz) 2.35 (3H, s), 2.45 (3H, s), 2.79 (6H, s), 3.90 (3H, s), 4.21 (2H, s ), 6.70 (1H, d), 6.73 (1H, s), 6.90 (2H, m), 7.18 (1H, d), 7.65 (1H, s), 12.83 (1H, brs); MS m/z (TS+) 318 (MH+).

The compounds shown by the formula If, i.e. the compounds shown by the general formula I where R1 and R2 are methyl, shown in table 3 are obtained according to the procedure from example 25 from the indicated precursors.

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Table 3

[image] [image]

EXAMPLE 34

3-[(Dimethylamino)methyl]-N-methyl-4-(6-quinolinyloxy)benzenesulfonamide

[image]

To a solution of Example 29 (50 mg, 0.16 mmol) in DCM (2 mL) was added chlorosulfonic acid (106 μL, 1.6 mmol) and the mixture was stirred for 3 hours at room temperature. Water (2 mL) was added, the pH of the mixture was adjusted with saturated aqueous NaHCO3 and the mixture was extracted with DCM (2x5 mL). The organic extracts were dried (MgSO4) and filtered, and 8M methylamine in EtOH (0.3 mL) was added. After standing for 1 hour, the solvent is removed in vacuo and the precipitate is purified by column chromatography [SiO2; 95:5:0.5 (DCM/MeOH/880 NH3)]. The product is taken up in EtOAc and converted to the HCl salt by addition of HCl in ether. This gives the desired product in the form of a hygroscopic solid (3 mg, 5%); δH (CD3OD, 300 MHz) 2.60 (3H, s), 2.99 (6H, s), 4.60 (2H, s), 7.21 (1H, d), 7.96 (1H, d ), 8.04 (3H, m), 8.19 (1H, s), 8.38 (1H, d), 9.03 (1H, d), 9.18 (1H, d); MS m/z (TS+) 371 (MH+).

EXAMPLE 35

3-[(Methylamino)methyl]-4-(6-quinolinyloxy)benzenesulfonamide

[image]

Trifluoroacetic anhydride (0.96 mL, 6.8 mmol) was added to a solution of the amine from example 48 (900 mg, 3.4 mmol) and triethylamine (1.9 mL, 13.6 mmol) in CH2Cl2 (15 mL) (15 mL) at 0 °C and the mixture was stirred for 5 min. The solvent was removed in vacuo and the precipitate was partitioned between CH2Cl2 and water. The organic layer was washed with brine, dried (MgSO4) and evaporated to give a yellow oil, which was used without further purification. The resulting crude oil was taken up in CH2Cl2 (20 mL), cooled to 0 °C and ClSO3H (2.4 mL, 36.1 mmol) was added in portions. The mixture is allowed to warm to room temperature and stirred for 4 hours before being poured into ice water. The mixture was extracted with CH2Cl2 (50 mL) and the organic layer was treated with a saturated solution of NH3 in MeOH (10 mL). After stirring for 4 hours, 1M LiOH (20 mL) was added and stirring was continued overnight. Tlc analysis shows that the reaction is incomplete and an additional amount of 1M LiOH (50 mL) is added and the mixture is stirred for 2 hours. The mixture was acidified to pH 8 with 2M HCl and extracted with CH 2 Cl 2 (3X200 mL). The combined organic extracts were dried (MgSO 4 ) and evaporated, and the residue was triturated with ether to give the title compound (500 mg, 43%) as a yellow solid; δH (CDCl3, 400 MHz) 2.46 (3H, s), 3.87 (2H, s), 6.93 (1H, d), 7.25 (1H, s), 7.39 (1H, t ), 7.42 (1H, d), 7.78 (1H, d), 8.00-8.08 (2H, m), 8.12 (1H, d), 8.86 (1H, s) ; MS m/z (ES+) 344 (MH+).

EXAMPLE 36

N-[5-Bromo-2-(2,3-dihydro-1-benzothien-5-yloxy)benzyl]-N-methylamine

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The aldehyde formed to give 19 (1.10 g, 3.28 mmol) was dissolved in 8M methylamine in EtOH (4.1 mL, 32.8 mmol) and stirred for 5 h before the portionwise addition of NaBH4 (372 mg, 9, 83 mmol) for 30 minutes. EtOH (100 mL) was added and the reaction mixture was stirred for 16 h before being concentrated in vacuo. The precipitate was cooled with 6M HCl to pH 1 and the precipitated HCl salt was collected by filtration, washed with water (100 mL) and dried in vacuo to give a crystalline solid (1.04 g, 82%); δH (CDCl3, 400 MHz) 2.62 (3H, s), 3.26 (2H, t), 3.41 (2H, t), 4.18 (2H, s), 6.66 (1H, d ), 6.90 (1H, d), 7.03 (1H, s), 7.19 (1H, d), 7.39 (1H, d), 7.80 (1H, s); MS m/z (ES+) 350, 352 (MH+).

The compounds shown by the formula Ig, i.e. the compounds shown by the general formula I where R1 and R4 are hydrogen and R2 is methyl, shown in table 4 are obtained according to the procedure from example 36 from the indicated precursors. For those compounds that are isolated as free bases, the reaction mixture is partitioned between 2M HCl and ether after removal of the reaction solvent in vacuo. The aqueous layer is then basified and extracted with DCM, the DCM layer is dried (MgSO4) and evaporated to give the desired secondary amine.

[image]

Table 4

[image] [image] a-2M methylamine in MeOH (2 equiv.) and Ti(OiPr)4 (2 equiv.) in EtOH (~0.1M aldehyde solution) are used instead of methylamine in EtOH. After isolation of the free base, the base is converted to the maleate salt by standard procedures.

EXAMPLE 50

(2E)-3-{4-(2,3-dihydro-1-benzothien-6-yloxy)-3-[(dimethylamino)methyl]phenyl}-2-propenamide

[image]

A mixture of bromide from Example 32 (400 mg, 1.10 mmol), acrylamide (156 mg, 2.19 mmol), triethylamine (0.38 mL, 2.74 mmol), palladium II acetate (12.5 mg, 0.06 mmol) ) and tri-o-tolylphosphine (33.4 mg, 0.11 mmol) in acetonitrile (15 mL) was heated at reflux for 72 h. After cooling to room temperature, the solvent was removed in vacuo and the precipitate was partitioned between EtOAc (50 mL) and 2M HCl (50 mL). The aqueous phase was basified with 2M NaOH and extracted with EtOAc (3x50 mL). The combined base extracts are dried (MgSO4) and evaporated. The precipitate is purified by column chromatography [SiO2; 96 4:0.5 (DCM/MeOH/880 NH3) increasing the polarity to 90:10:1] to give the title compound (196 mg, 50%) as a beige foam; δH (CDCl3, 400 MHz) 2.28 (6H, s), 3.24 (2H, t), 3.38 (2H, t), 3.51 (2H, s), 5.73 (2H, no ), 6.42 (1H, d), 6.59 (1H, dd), 6.82 (2H, m), 7.10 (1H, d), 7.32 (1H, d), 7.60 (1H, d), 7.69 (1H, s); MS m/z (ES+) 355 (MH+).

EXAMPLE 51

3-{4-(2,3-dihydro-1-benzothien-6-yloxy)-3-[(dimethylamino)methyl]phenyl}propanamide

[image]

A solution of SmI2 in THF (0.1 M, 21.9 mL, 2.19 mmol) was added to a solution of the alkene from Example 50 (194 mg, 0.55 mmol) in THF (5 mL) under nitrogen, followed by water (1 mL) is added. After stirring at room temperature for 10 minutes, the reaction in the mixture was stopped with 6M NaOH (10 mL) and stirred under water for 30 minutes. The organic phase was separated and the aqueous phase was extracted with EtOAc (2x20 mL). The combined organic layers are dried (MgSO4) and evaporated to give an oil, which is purified by column chromatography [SiO2; 93:7:1 (DCM/MeOH/880 NH3) increasing the polarity to 90:10:1] to give the title compound (90 mg, 46%); δH (CDCl3, 400 MHz) 2.25 (6H, s), 2.54 (2H, t), 2.97 (2H, t), 3.22 (2H, t), 3.36 (2H, t ), 3.42 (2H, s), 5.20-5.46 (2H, br), 6.54 (1H, d), 6.73 (1H, s), 6.81 (1H, d) , 7.05 (2H, m), 7.31 (1H, s); MS m/z (TS+) 357 (MH+).

The compounds shown by the formula If, i.e. the compounds shown by the general formula I where R1 and R2 are methyl, shown in table 5 are obtained according to the procedure for obtaining 50 from the indicated precursors.

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Table 5

[image]

The compounds shown by the formula If, i.e. the compounds shown by the general formula I where R1 and R2 are methyl, shown in table 6 are obtained according to the procedure for obtaining 55 from the indicated precursors.

Table 6

[image]

The compounds shown by the formula If, i.e. the compounds shown by the general formula I where R1 and R2 are methyl, shown in table 7, are obtained according to the procedure for obtaining 59 from the indicated precursors.

Table 7

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The compounds shown by the formula If, i.e. the compounds shown by the general formula I where R1 and R2 are methyl, shown in table 8, are obtained according to the procedure for obtaining 69 from the indicated precursors.

Table 8

[image]

EXAMPLE 60

4-(2,3-dihydro-1-benzothien-5-yloxy)-3-[(methylamino)methyl]benzamide

[image]

The protected amine formed in the preparation of 59 (317 mg, 0.76 mmol) was dissolved in a saturated solution of HCl in DCM (25 mL) at 0 °C and left for 1 hour before neutralization by addition of 10% aqueous K2CO3 (25 mL). Water (50 mL) was added and the layers were separated. The aqueous layer was extracted with DCM (25 mL) and the combined organic layers were dried (MgSO 4 ) and evaporated. The resulting oil was dissolved in EtOAc (10 mL) and treated with 1 M HCl in ether (1 mL). The white precipitate was collected by filtration and dried in vacuo to give the desired product (211 mg, 77%); δH (CD3OD, 400 MHz) 2.77 (3H, s), 3.35 (2H, obs), 3.39 (2H, t), 4.34 (2H, s), 6.79 (1H, d ), 6.90 (1H, dd), 7.02 (1H, s), 7.21 (1H, d), 7.83 (1H, d), 8.00 (1H, s); MS m/z (TS+) 315 (MH+).

The compounds shown by the formula Ig, i.e. the compounds shown by the general formula I where R1 and R4 are hydrogen and R2 is methyl, shown in table 9, are obtained according to the procedure from example 60 from the indicated precursors.

[image]

Table 9

[image] [image] [image]

EXAMPLE 77

N-{4-[(dimethylamino)methyl]-3-[3-methyl-4(methylsulfanyl)phenoxy]benzyl}methanesulfonamide

[image]

The compound from example 77 is obtained from the Boc-protected sulfonamide formed in the preparation of 74 by the procedure from example 60; HCl salt: δH(CD3OD, 400 MHz) 2.29 (3H, s), 2.42 (3H, s), 2.82 (3H, s), 2.89 (6H, s), 4.17 ( 2H, s), 4.39 (2H, s), 6.39 (3H, m), 7.19 (1H, d), 7.24 (1H, d), 7.48 (1H, d); MS m/z (TS+) 395 (MH+).

EXAMPLE 78

3-[(methylamino)methyl]-4-[3-methyl-4-(methylsulfanyl)phenoxy]benzonitrile

[image]

Zn(CN)2 (700 mg, 5.96 mmol) and Pd(PPh3)4 (1.97 g, 1.7 mmol) and the mixture is heated at 100 °C for 17 hours. The reaction mixture is cooled to room temperature, diluted with water (100 mL) and extracted with ether (2x100 mL then 3x50 mL). The combined organic layers were washed with water (3x50 mL), dried (MgSO4) and evaporated to give a yellow oil. Initial purification by column chromatography [SiO2; 95:5:0.5 (DCM/MeOH/880 NH3)] was unsuccessful so the material was rechromatographed [SiO2; 50% pentane in 95:5:0.5 (DCM/MeOH/880 NH3) increasing the polarity to 0% pentane) to give the product (1.275 g, 50%) as a pale yellow oil. The sample was taken up in DCM (5 mL) and treated with 1M HCl in ether to give the HCl salt as a white powder which was collected by filtration; δH (CDCl3, 300 MHz) 2.35 (3H, s), 2.47 (6H, s), 3.88 (2H, s), 6.79 (1H, d), 6.87 (2H, m ), 7.20 (1H, d), 7.46 (1H, d), 7.72 (1H, s); MS m/z (TS+) 299 (MH+)

EXAMPLE 79

3-[(Methylamino)methyl]-4-[3-methyl-4-(methylsulfanyl)phenoxy]benzamide

[image]

A mixture of the nitrile from Example 78 (404 mg, 1.35 mmol) and KOH (304 mg, 5.42 mmol) in tert-butanol (10 mL) was heated at reflux for 1 hour under N 2 . After cooling to room temperature, the solvent was removed in vacuo, and the precipitate was partitioned between water (10 mL) and DCM (10 mL). The aqueous layer was extracted with DCM (4 x 20 mL) and the combined organic layers were washed with brine, dried (MgSO 4 ) and evaporated. The precipitate is purified by column chromatography [SiO2; 93:7:1 (DCM/MeOH/880 NH3)] to give the desired product (376 mg, 88%) as a white foam; δH (CDCl3, 300 MHz) 2.35 (3H, s), 2.47 (3H, s), 2.49 (3H, s), 3.88 (2H, s), 5.90-6.30 (2H, brs), 6.82 (3H, m), 7.19 (1H, d), 7.70 (1H, d), 7.90 (1H, s); MS m/z (TS+) 317 (MH+).

The compounds shown by the formula Ih, i.e. the compounds shown by the general formula I where R1 and R2 are methyl and R4 is hydrogen, shown in table 10 are obtained according to the procedure in example 12 from the indicated precursors.

[image]

Table 10

[image] [image] [image]

The compound of Example 94 can also be obtained according to the following procedure.

A solution of the product formed in the preparation of 30 (200 g, 0.78 mol) in DCM (1.4 L) was added to THF (1.4 L). Dimethylamine hydrochloride (69.5 g, 0.85 mol) and triethylamine (235 g, 2.33 mol) are added to this mixture one after the other. The temperature is adjusted to 20 °C and after 3 hours sodium triacetoxyborohydride (246 g, 1.16 mol) is added (after 20 hours, if the reaction is complete, continue with the procedure; if not, see note below). Dichloromethane (2 L) is added, and a solution of 8% sodium bicarbonate (0.9 L) is added over a period of 0.5 hours. The layers were separated and the organic layer was washed with water (1 L). The layers are separated once more, and the organic layer is concentrated. Ethyl acetate (0.27 L) was added and the solvent was removed by squeezing with fresh ethyl acetate (800 mL). The solution was then cooled to below 5 °C and 7.02 M HCl/IPA (0.117 L, 0.82 mol) was added maintaining the temperature below 10 °C. After stirring for 1 hour at below 5 °C, the thick solution was filtered, washed with ethyl acetate (3 x 0.2 L) and dried in a vacuum oven at 50 °C overnight to give the desired product as a powdery solid (141.5 g, 56%). [Note: If the reaction is not complete after 20 hours, another portion of dimethylamine hydrochloride (13 g, 0.16 mol) and triethylamine (43.4 g, 0.43 mol) are added one after the other. After 2 hours at room temperature, sodium triacetoxyborohydride (46 g, 0.22 mol) was added. The mixture is left for the next 20 hours and then the procedure described above is continued].

The compounds shown by the formula Ii, i.e. the compounds shown by the general formula I where R2 is methyl, R4 is hydrogen and R5 is -C (=O)NH2, shown in table 11, are obtained according to the procedure of example 79 from the indicated precursors.

[image]

Table 11

[image]

EXAMPLE 103

N-{5-amino-2-[3-methyl-4-(methylsulfanyl)phenoxy]benzyl}-N,N-dimethylamine

[image]

A mixture of the nitro compound from Example 27 (2.0 g, 6 mmol), iron powder (2.51 g, 44.9 mmol) and CaCl2 (300 mg, 2.7 mmol) in EtOH (20 mL) and water (4 mL) is heated under reflux for 20 hours. After cooling to room temperature, the solvent was removed in vacuo, and the precipitate was partitioned between salt solution (100 mL) and ether (100 mL). The aqueous layer was extracted with ether (50 mL) and the combined organic layers were dried (MgSO 4 ) and evaporated to give the product (1.47 g, 81%) as an orange oil; δH (CDCl3, 300 MHz) 2.22 (6H, s), 2.32 (3H, s), 2.40 (3H, s), 3.33 (2H, s), 6.59 (1H, dd ), 6.60-6.75 (2H, m), 6.78 (1H, dd), 6.94 (1H, s), 7.10-7.20 (3H, m); MS m/z (ES+) 303 (MH+).

EXAMPLE 104

N-[5-amino-2-(2,3-dihydro-1-benzothien-5-yloxy)benzyl]-N,N-dimethylamine

[image]

The title compound is obtained from the nitro compound from Example 28 according to the procedure described in Example 103; δH (CDCl3, 400 MHz) 2.20 (6H, s), 3.16 (2H, t), 3.30 (4H, m), 3.54 (2H, br), 6.53 (1H, dd ), 6.60 (1H, d), 6.71 (2H, m), 6.79 (1H, d), 7.01 (1H, d); MS m/z (ES+) 301 (MH+).

EXAMPLE 105

N-[3-(aminomethyl)-4-(2,3-dihydro-1,4-benzoxathin-6-yloxy)phenyl]-methanesulfonamide

[image]

The nitrile formed to give 95 (720 mg, 1.99 mmol) was dissolved in a 1 M solution of BH3.THF in THF (10 mL, 10 mmol) and the mixture was heated at reflux for 3 hours. After cooling to room temperature, the reaction in the mixture was stopped by careful addition of MeOH (10 mL). The solvent is evaporated, the residue is treated with 6M HCl (10 mL) and heated at reflux for 1 hour. After cooling, the mixture is basified with 2M NaOH, and the pH is adjusted to 7 using a saturated aqueous solution of NH4Cl. The mixture was extracted with EtOAc (3x50 mL) and DCM (2x50 mL), and the combined organic layers were dried (MgSO4) and evaporated to give a beige foam (685 mg, 94%) which was used without further purification; δH (CDCl3, 400 MHz) 3.00 (3H, s), 3.13 (2H, m), 3.87 (2H, s), 4.40 (2H, m), 6.62 (1H, d ), 6.67 (1H, s), 6.79 (2H, d), 7.08 1H, d), 7.25 (1H, d); MS m/z (TS+) 367 (MH+).

Compounds shown by formula Ij, i.e. compounds shown by general formula I where R1, R2 and R4 are hydrogen, and R5 is –NR8-SO2Me, shown in table 12, are obtained according to the procedure from example 105 from the indicated precursors.

[image]

Table 12

[image]

EXAMPLE 110

N-{4-(2,3-dihydro-1,4-benzoxathin-6-yloxy)-3-[(methylamino)methyl]phenyl}-methanesulfonamide

[image]

Dicyclohexylcarbodiimide (460 mg, 2.23 mmol) was added to a solution of pentafluorophenol (413 mg, 2.24 mmol) in ether (10 mL), followed by formic acid (95 μL, 2.5 mmol). The mixture is stirred for 2 hours and then filtered, washing the precipitate with ether. The filtrate was concentrated to ~5 mL and a solution of the primary amine from Example 105 (411 mg, 1.1 mmol) in DCM (10 mL) was added. The mixture is stirred for 16 hours and then concentrated into an oily residue. The resulting oil was transferred to a solution of BH3.THF in THF (1 M, 20 mL, 20 mmol) and heated at reflux for 1.5 hours under N2 atmosphere. After cooling to room temperature, the reaction in the mixture was stopped by the careful addition of MeOH (10 mL) and then the mixture was concentrated in vacuo. The oily residue is treated with 6M HCl and heated at reflux for 30 minutes. After cooling to room temperature, the mixture is basified with aqueous K2CO3 and extracted with DCM (3x). The combined organic extracts are dried (MgSO4) and evaporated. The precipitate is purified by column chromatography [SiO2; 90:10:1 (DCM/MeOH/880 NH3)] to give a colorless oil which was taken up in EtOAc (20 mL) and treated with 1 M HCl in ether (2 mL). After stirring for 1.5 hours, the solid was collected by filtration to give the title product (282 mg, 60%); δH (CD3OD, 400 MHz) 2.78 (3H, s), 2.98 (3H, s), 3.18 (2H, m), 4.29 (2H, s), 4.39 (2H, m ), 6.74 (1H, d), 6.80-6.90 (3H, m), 7.22 (1H, d), 7.44 (1H, s); MS m/z (TS+) 381 (MH+).

Compounds shown by formula Ik, i.e. compounds shown by general formula I where R1 and R4 are hydrogen, R2 is methyl, and R5 is -NHSO2Me, shown in table 13, are obtained according to the procedure from example 110 from the indicated precursors.

[image]

Table 13

[image]

The compounds shown by the formula Im, i.e. the compounds shown by the general formula I where R1 and R4 are hydrogen, R2 is methyl, and R5 is -NR8SO2Me, shown in table 14, are obtained according to the procedure from example 110 from the indicated precursors.

[image]

Table 14

[image] a-also obtained from the compound from example 108 according to the procedure of example 110.

The compounds shown by the formula In, i.e. the compounds shown by the general formula I where R1 and R2 are methyl, R4 is hydrogen, and R5 is -NR8SO2Me, shown in table 15, are obtained according to the procedure of example 12 from the indicated precursors.

[image]

Table 15

[image] [image]

EXAMPLE 128

N-{3-[(dimethylamino)methyl}-4-[3-methyl-4-(methylsulfanyl)phenoxy]-phenyl}-methanesulfonamide

[image]

To a solution of aniline from Example 103 (725 mg, 2.4 mmol) and Et3N (1 mL, 7.17 mmol) in DCM (10 mL) was added methanesulfonyl chloride (371 μL, 4.79 mmol) at 0 °C. After stirring at 0 °C for 1 hour, the reaction mixture was allowed to warm to room temperature before the solvent was removed in vacuo. 2M NaOH (10 mL) was added to the precipitate and the mixture was stirred overnight. The resulting clear solution is neutralized by the addition of a saturated aqueous solution of NH4Cl and extracted with DCM (2x30 mL). The combined organic layers were dried (MgSO4) and evaporated to give an oil. The oil was taken up in EtOAc (10 mL), and the HCl salt was precipitated by adding 1M HCl in ether, and the product (669 mg, 67%) was collected by filtration; δH (d6-DMSO, 400 MHz) 2.23 (3H, s), 2.42 (3H, s), 2.75 (6H, s), 3.04 (3H, s), 4.38 (2H , s), 6.84 (1H, d), 6.93 (1H, d), 6.98 (1H, s), 7.17-7.25 (2H, m), 7.50 (1H, with); MS m/z (ES+) 381 (MH+).

Compounds shown by formula Ip, i.e. compounds shown by general formula I where R1 and R2 are methyl, R4 is hydrogen, and R5 is -NHSO2R9, shown in table 16, are obtained according to the procedure from example 128 from the indicated precursors.

[image]

Table 16

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RECEIVING

OBTAINING 1

5-(aminosulfonyl)-2-fluoro-N-methylbenzamide

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In a solution of 5-(aminosulfonyl)-2-fluorobenzoic acid [obtained according to Chem. Pharm. Bull. 1995, 43, 582-7] (22.98 g, 105 mmol) in THF (500 mL) at room temperature under a nitrogen atmosphere was added carbonyldiimidazole (17 g, 105 mmol). After stirring for 2.25 hours, a solution of methylamine in THF (2M, 70 mL, 140 mmol) was added in portions, and the reaction mixture was stirred for 18 hours. The crude reaction mixture was concentrated to a small volume and EtOAc ( 150 mL). The resulting mixture is mixed and a granular precipitate is formed, which is collected by filtration. The resulting crude product, contaminated with imidazole, was suspended in DCM (300 mL) and heated at reflux for 5 hours. After cooling to room temperature, the mixture was filtered to give the desired product (19.8 g, 81%) containing <2% by weight of imidazole; 1H NMR δH (300 MHz, d4-MeOH) 2.97 (3H, s), 7.40 (1H, t), 8.05 (1H, m), 8.29 (1H, d); MS m/z (TS+) 250 (MNH4+).

GETTING 2

3-chloro-4-(methylsulfanyl)phenol

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Preparation of 2-chloro-1-(methylsulfanyl)-4-nitrobenzene

5-tert-butyl-4-hydroxy-2-methylphenyl sulfide (100 mg) is added to a solution of 4-fluoro-3-chloronitrobenzene (27 g, 156 mmol) in DMF (150 mL) at room temperature, followed by sodium thiomethoxide (NaSMe) (10 g, 143 mmol) and the reaction mixture was stirred for 6 h. The DMF was removed in vacuo and the precipitate was partitioned between ether (1 L) and water (1 L). The ether layer was washed with water (1 L) and brine (1 L), dried (MgSO4), and the solvent was removed under reduced pressure. The residue was purified by column chromatography (SiO2; DCM:pentane 1:5 increasing polarity to 3:7) to give the title compound (15.22 g, 49%) as a yellow solid; δH (400 MHz, CDCl 3 ) 2.53 (3H, s), 7.20 (1H, d), 8.09 (1H, dd), 8.20 (1H, d).

Preparation of 3-chloro-4-(methylsulfanyl)aniline

Iron powder (23 g, 412 mmol) was added to a mixture of the above compound (14.08 g, 69 mmol) in acetic acid (300 mL) and water (60 mL) and the reaction mixture was stirred until all the starting material was dissolved. . The mixture is left to stand for 1.5 hours and then the acetic acid is removed under reduced pressure. The precipitate was taken up in a saturated aqueous solution of NaHCO3 (500 mL) and EtOAc (500 mL) and filtered through Arbocel®. The layers were separated, the aqueous phase was extracted with EtOAc (300 mL), and the combined organic phases were washed with brine, dried (MgSO 4 ), the solvent removed in vacuo to give the title compound (11.52 g, 96%) in the form of a beige solid; δH (400 MHz, CDCl3) 2.38 (3H, s), 3.66 (2H, br), 6.53 (1H, dd), 6.70 (1H, d), 7.12 (1H, d ); MS m/z (ES+) 174 (MH+).

Preparation of 3-chloro-4-(methylsulfanyl)phenol

The above aniline (11.5 g, 66.2 mmol) was dissolved in a minimal amount of THF (~15 mL) and water (500 mL) was added with vigorous stirring, followed by concentrated H2SO4 (25 mL). The mixture was cooled in an ice-water bath and a solution of NaNO2 (5.0 g, 72.5 mmol) in ice water (10 mL) was added below the surface of the reaction mixture using a pipette. The reaction mixture was stirred at 0 °C for 1.5 h, and the resulting yellow/brown solution was poured from the remaining solid into a separatory funnel containing ice (~200 g). This solution was added at a uniform rate over a period of 7 minutes to a mixture of Cu(NO3)2 (230 g, 0.99 mol) and Cu2O (8.52 g, 67.4 mmol) in water (1 L) at room temperature with vigorous mixing. After the addition was complete, the mixture was stirred for a further 15 minutes before extraction with ether (500 mL). The red/brown solid remaining in the reaction flask was taken up in MeOH (100 mL) and diluted with ether (300 mL) before being poured into the above aqueous layer. The ether layer was separated and the combined organic layers were extracted with 1M NaOH (3 x 100 mL). The aqueous extracts were acidified with concentrated HCl and then extracted with ether (2 x 150 mL). The ether layers were then washed with brine, dried (MgSO 4 ) and the solvent removed in vacuo to give phenol (5.465 g, 47%) as a brown crystalline solid; δH (400 MHz, CDCl3) 2.44 (3H, s), 5.08 (1H, br), 6.77 (1H, d), 6.93 (1H, d), 7.18 (1H, d ); MS m/z (ES-) 173 (M-H+).

OBTAINING 3

3-fluoro-4-(methylsuphanyl)phenol

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This compound is obtained using a similar procedure to that described above in the preparation of 2 starting from commercially available 3,4-difluoronitrobenzene; δH (CDCl 3 , 300 MHz) 2.40 (3H, s), 5.03 (1H, br), 6.60 (2H, m), 7.27 (1H, m obscured); MS m/z (ES-) 157 (M-H+).

OBTAINING 4

2,3-dihydro-1,4-benzoxathiin-6-ol

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1,2-Dibromoethane (2.3 mL, 26.7 mmol) and K2CO3 (8.21 g, 59.4 mmol) were dissolved in acetone (250 mL) and a solution of 2-sulfanyl-1,4-benzenediol was added. (obtained according to J. Org. Chem. 1990, 55, 2736) (4.22 g, 29.7 mmol) in acetone (50 mL) for 4 hours while stirring the mixture. When the addition is complete, stirring is continued for another 10 hours before the solvent is removed in vacuo. The residue was partitioned between water (50 mL) and EtOAc (50 mL), the aqueous layer was extracted with EtOAc (50 mL), and the combined organic layers were dried (MgSO 4 ) and evaporated. Purification of the precipitate by column chromatography [SiO2; 9:1 (pentane/EtOAc)] afforded the title compound (2.48 g, 55%) as a pale orange oil; δH (CDCl3, 400 MHz) 3.08 (2H, m), 4.31 (2H, m), 4.44 (1H, s), 6.42 (1H, d), 6.49 (1H, s ), 6.66 (1H, d); MS m/z (ES-) 167 (M-H+).

OBTAINING 5

2,3-dihydro-1,4-benzoxathiin-7-ol

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The title compound is obtained according to a similar procedure as the compound from the preparation of 4 starting from 4-sulfanyl-1,3-benzenediol (obtained according to J. Org. Chem. 1979, 26, 4971-4973); δH (CDCl3, 400 MHz) 3.05 (2H, t), 4.37 (2H, t), 6.32 (1H, s), 6.35 (1H, d), 6.84 (1H, d ); MS m/z (TS+) 169 (MH+).

OBTAINING 6

1,3-dihydro-2-benzofuran-5-ol

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1,3-dihydro-2-benzofuran-5-amine (obtained according to US4000286) (2.7 g, 20 mmol) was dissolved in a mixture of water (300 mL) and concentrated H2SO4 (21 mL), cooled to 0 °C and NaNO2 (1.43 g, 20.7 mmol) in water (10 mL) was added over 15 minutes. After stirring at 0 °C for 1 hour, the mixture is continued to stir at 10 °C for 30 minutes, and urea is added until a negative starch/KI paper test result is obtained. The solution was then poured over 2 minutes into a mixture of water (180 mL) and concentrated H2SO4 (12.6 mL) at 90 °C and stirred at that temperature for 1.5 hours. The hot mixture is then filtered and allowed to cool to room temperature. The aqueous mixture was extracted with EtOAc (2 x 100 mL) and the combined organic layers were dried (MgSO 4 ) and evaporated to give the title phenol (974 mg, 36%) as a cream solid; δH (CDCl 3 , 400 MHz) 5.03 (4H, s), 6.71 (2H, m), 7.08 (1H, d).

OBTAINING 7

2,3-dihydro-1-benzothiophen-6-ol

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obtaining 2,3-dihydro-1-benzothiophen-6-ol 1,1-dioxide

A suspension of 2,3-dihydro-1-benzothiophene-6-amine 1,1-dioxide [obtained according to J. Am. Chem. Soc. 1955, 77, 5939] (15.73 g, 85.8 mmol) in water (500 mL) and concentrated H2SO4 (35 mL) was heated until a solution was obtained. The mixture was cooled to 0 °C and then a solution of NaNO2 (6.22 g, 90 mmol) in water (15 mL) was added over 5 min. The reaction mixture was stirred at 0 °C for 1 hour and then urea was added to remove excess nitrite until a negative starch/KI paper test result was obtained. The mixture was allowed to warm to room temperature and then added with stirring to a mixture of concentrated H2SO4 (55 mL) and water (750 mL) at 90 °C. The reaction mixture was reheated to 90 °C and stirred at that temperature for 30 minute. The hot reaction mixture is filtered through Arbocel® and then stirred at room temperature overnight. The aqueous mixture was extracted with ether (2.5 L), then with EtOAc (5 x 500 mL), and the combined organic layers were dried (MgSO 4 ) and evaporated to give the desired phenol (12.7 g, 80%) which was used without further purification; δH (CDCl3, 400 MHz) 3.30 (2H, m), 3.50 (2H, m), 7.05 (1H, m), 7.14 (1H, s), 7.23 (1H, m ); MS m/z (ES-) 183 (M-H+).

obtaining 2,3-dihydro-1-benzothiophen-6-ol

A solution of the sulfone from step (i) (4.84 g, 26.3 mmol) in toluene (100 mL) and THF (70 mL) was added to a solution of DIBAL in toluene (1M, 100 mL, 100 mmol) and the mixture was then heats with return for 16 hours. After cooling to room temperature, carefully add EtOH (75 mL), followed by water (100 mL) with stirring. 6M HCl is added to the resulting thick suspension and the organic layer is separated. The aqueous layer was extracted with EtOAc (3 x 150 mL) and the combined organic layers were dried (MgSO4) and evaporated to give a beige solid. Purification by column chromatography [SiO2; DCM/MeOH/880 NH3 (97:3:0.25) increasing the polarity to (95:5:0.5)] to give the desired title phenol as a beige solid (1.85 g, 53%); δH (CD3OD, 400 MHz) 3.13 (2H, t), 3.30 (2H, m), 6.41 (1H, d), 6.60 (1H, s), 6.98 (1H, d ); MS m/z (ES-) 151 (M-H+).

OBTAINING 8

5-(aminosulfonyl)-2-[3-methyl-4-(methylsulfanyl)phenoxy]-N-methylbenzamide

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The fluoroamide formed in preparation 1 (732 mg, 3.15 mmol) was treated with 4-(methylthio)-m-cresol (commercially available) (535 mg, 3.47 mmol) and potassium carbonate (457 mg, 3.31 mmol) ) in DMF (10 mL). The mixture is heated to 100 °C for 5 hours. The solvent was removed by evaporation under reduced pressure, and the residue was treated with 2M HCl (10 mL). The resulting suspension is extracted several times with dichloromethane. The combined dichloromethane layers containing the suspension were evaporated to give a solid residue. The residue was triturated with ether (5 mL) and the remaining solid was washed with ether (3x10 mL) to give an off-white solid (765 mg, 66%). δH (300 MHz, d6-DMSO) 2.28 (3H, s), 2.48 (3H, s), 2.70 (3H, d), 6.90 (1H, d), 7.02 (1H , d), 7.03 (1H, s), 7.30 (1H, d), 7.35 (2H, s), 7.79 (1H, d), 8.10 (1H, d), 8 .30 (1H, m); MS m/z (TS+) 367 (MH+), 385 (MNH4+).

GETTING 9-18

The compounds shown by the formula Va, i.e. the compounds shown by the general formula V where T is -C(=O)NHMe, R4 is hydrogen, and R5 is -SO2NH2, shown in table 17, are obtained according to the procedure for obtaining 8 using sulfonamides from obtaining 1 and indicated phenol.

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Table 17

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GETTING THE 19

5-bromo-2-(2,3-dihydro-1-benzothien-5-yloxy)benzaldehyde

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A mixture of 5-bromo-2-fluorobenzaldehyde (1.08 g, 5.32 mmol), 5-hydroxy-2,3-dihydrobenzothiophene (prepared as described in Synth. Commun. 1991, 21, 959-964) (808 mg, 5.31 mmol) and K2CO3 (1.47 g, 10.6 mmol) in DMF (5 mL) was heated at 90 °C for 16 h. After cooling to room temperature, the mixture was partitioned between water (50 mL) and ether (50 mL), the aqueous layer was extracted with ether (50 mL). The combined organic extracts were washed with water (50 mL), dried (MgSO4) and evaporated. The precipitate is purified by column chromatography [SiO2; 9:1 (pentane/EtOAc)], then triturated with ether to give the product (1.1 g, 62%) as a pale yellow solid; δH (CDCl3, 400 MHz) 3.28 (2H, t), 3.41 (2H, t), 6.78 (1H, d), 6.84 (1H, d), 6.92 (1H, s ), 7.20 (1H, d), 7.58 (1H, d), 8.00 (1H, s), 10.43 (1H, s).

The compounds represented by the general formula II, listed in table 18, are obtained according to the procedure for obtaining 19 by reacting the indicated phenol with the required 2-fluorobenzaldehyde. In most cases, the crude product of the reaction after mixing with water is used directly in the following stages without further purification.

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Table 18

[image] [image] [image] a-4-fluoro-3-formylbenzonitrile is synthesized according to the procedure described in Synth. Commun. 1997, 27(7), 1199 and J. Org. Chem. 1961, 26, 2522.

The product formed in the preparation of 30 is also obtained according to the following procedure.

Potassium carbonate (334.1 g, 2.42 mol) and 4-(methylthio)-m-cresol (273.4 g, 1.77 mol) were added dropwise to DMF (2 L). 2-Then fluorobenzaldehyde (200 g, 1.61 mol) is added to the thick solution and the mixture is heated in the range 100-110 °C. After 48 hours, the reaction mixture was allowed to cool to room temperature and water (1.2 L) was added. The solution was cooled to below 10 °C and the pH was adjusted to 5 using concentrated HCl (0.37 L), maintaining the temperature below 10 °C. Water (0.15 L) and dichloromethane (0.9 L) were added, and the mixture was stirred. The layers were separated and the organic layer was washed with water (4 x 0.75 L). The solvent is distilled to remove water azeotropically. If necessary, fresh dichloromethane is added. The dry dichloromethane solution was then concentrated in vacuo to give the crude product as an oil (422 g, 100%).

The compounds represented by formula IX shown in Table 19 are obtained according to the procedure in the preparation of 19, using either 2-chloro-5-nitrobenzaldehyde or 2-chloro-5-nitrobenzonitrile with the indicated phenol. For these reactions, a shorter reaction time (about 2-3 hours) is usually sufficient to achieve a satisfactory conversion. In most cases, the raw product of the reaction after mixing with water is used directly in subsequent stages without further purification.

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Table 19

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GETTING 44

tert-butyl 5-bromo-2-(2,3-dihydro-1-benzothien-5-yloxy)benzyl(methyl)carbamate

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The hydrochloride salt from Example 36 (1.04 g, 2.7 mmol) was dissolved in a thick solution with DCM (12 mL) and Et 3 N (750 μL, 5.38 mmol) was added, followed by di-tert-butyl dicarbonate (766 mg, 3.51 mmol). After stirring at room temperature for 20 minutes, the reaction was stopped by adding 0.2M HCl (20 mL). The well-stirred mixture was separated and the aqueous layer was extracted with DCM (10 mL). The combined organic layers were dried (MgSO4) and evaporated to give the product (the yield is assumed to be quantitative) as a colorless oil which was used without further purification; δH (CDCl3, 400 MHz) 1.56 (9H, s), 2.82-2.98 (3H, brd), 3.23 (2H, t), 3.40 (2H, t), 4.44 (2H, brd), 6.71 (2H, d), 6.79 (1H, s), 7.12 (1H, d), 7.29 (1H, d), 7.39 (1H, s) .

The compounds represented by formula X shown in table 20 are obtained according to the preparation procedure 44 starting from the indicated precursors.

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Table 20

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GETTING 49

tert-butyl 5-cyano-2-[3-fluoro-4-(methylsulfanyl)phenoxy]benzyl-(methyl)carbamate

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The title compound is obtained from the bromide formed in the preparation of 47 by the procedure of Example 78; δH (CDCl3, 300 MHz) 1.48 (9H, brs), 2.50 (3H, s), 2.93 (3H, brs), 4.55 (2H, brs), 6.79 (2H, m ), 6.88 (1H, d), 7.35 (1H, t), 7.53 (1H, d), 7.59 (1H, s); MS m/z (TS+) 403 (MH+).

GETTING 50

methyl 3-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-4-(2,3-dihydro-1-benzothien-5-yloxy)benzoate

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A mixture of the bromide formed according to the preparation of 44 (1.22 g, 2.7 mmol), Et3N (1.13 mL, 8.11 mmol) and dichlorobis(triphenylphosphine)palladium(II) (190 mg, 0.27 mmol) in MeOH (14 mL) was heated to 80 °C under 100 psi CO for 18 h. Tlc analysis indicated that the reaction was incomplete so another portion of catalyst (190 mg, 0.27 mmol) was added and the mixture was heated to 100 °C under 100 psi CO for 24 hours. The mixture was diluted with EtOAc (20 mL) and filtered through a pad of silica gel, eluting with excess EtOAc. The solvent was removed in vacuo and the precipitate was partitioned between EtOAc (50 mL) and a 2:1 mixture of water:880 NH 3 (50 mL). The aqueous layer was extracted with EtOAc (25 mL) and the combined organic layers were dried (MgSO 4 ) and evaporated. Purification by column chromatography [SiO2; 4:1 (pentane/EtOAc)] gave the product (970 mg, 84%) as an oil; δH (CDCl3, 400 MHz) 1.42 (9H, s), 2.90 (3H, brs), 3.22 (2H, t), 3.38 (2H, t), 3.84 (3H, s ), 4.50 (2H, brd), 6.74 (2H, d), 6.82 (1H, s), 7.13 (1H, d), 7.82 (1H, d), 7.93 (1H, hill); MS m/z (ES+) 430 (MH+).

The compounds represented by formula XI shown in table 21 are obtained according to the preparation procedure 50 starting from the indicated precursors.

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Table 21

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GETTING THE 55

3-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-4-(2,3-dihydro-1-benzothien-5-yloxy)benzoic acid

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A solution of the ester from preparation 50 (970 mg, 2.26 mmol) in THF (20 mL) and 1M LiOH (20 mL) was heated at reflux for 16 h. After cooling to room temperature, THF was removed in vacuo, the precipitate was neutralized with saturated aqueous NH 4 Cl and the mixture was extracted with DCM (100 mL) and then with ether (100 mL). The combined organic layers were dried (MgSO4) and evaporated to give a white foam (960 mg) which was used without further purification; δH (CDCl3, 400 MHz) 1.30 (9H, s), 2.78 (3H, brs), 3.20 (2H, brs), 3.38 (2H, t), 4.41 (2H, m ), 6.62 (2H, m), 6.78 (1H, m), 7.10 (1H, m), 7.84 (1H, m), 7.99 (1H, m); MS m/z (ES-) 414 (M-H).

Compounds represented by formula XII shown in table 22 are obtained according to the procedure for obtaining 55 from the indicated precursors.

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Table 22

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GETTING 59

tert-butyl 5-(aminocarbonyl)-2-(2,3-dihydro-1-benzothien-5-yloxy)benzyl-(methyl)carbamate

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To a solution of the acid from preparation 55 (318 mg, 0.77 mmol) in DCM (10 mL) was added Et3N (267 μL, 1.92 mmol), HOBt.H2O (129 mg, 0.84 mmol) and WSCDI (191 mg, 1.0 mmol) and the mixture was stirred for 1 h before a saturated solution of NH 3 in THF (2 mL) was added. After stirring for the next 16 hours, the reaction mixture is diluted with water (50 mL), 0.2M HCl (20 mL) and DCM (25 mL). The organic layer was separated and the aqueous layer was extracted with DCM (25 mL). The combined organic layers were dried (MgSO4) and evaporated to give a white foam (the yield is assumed to be quantitative) which was used without further purification; δH (CDCl3, 400 MHz) 1.44 (9H, s), 2.91 (3H, br), 3.27 (2H, t), 3.40 (2H, t), 4.54 (2H, br ), 6.75-6.88 (3H, m), 7.18 (1H, d), 7.68 (1H, d), 7.74 (1H, s).

The compounds represented by formula XIII shown in table 23 are obtained according to the procedure for obtaining 59 from the indicated precursors.

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Table 23

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GETTING 69

tert-butyl 2-[3-chloro-4-(methylsulfanyl)phenoxy]-5-(hydroxymethyl)benzyl-(methyl)carbamate

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A solution of LiAlH 4 in THF (1 M, 2 mL, 2 mmol) was added portionwise to a solution of the ester from preparation 52 (452 mg, 1 mmol) in THF (10 mL) under N 2 . When tlc analysis concluded that the reaction was completed, ether (10 mL) was added and excess LiAlH4 was removed by carefully adding 2M NaOH. The organic layer is separated, washed with brine, dried (MgSO4) and evaporated. Purification of the precipitate by column chromatography [SiO2; 39:1 (DCM/MeOH)] afforded the desired alcohol (200 mg, 47%) as a gummy white solid; δH (CDCl3, 400 MHz) 1.41 (9H, brs), 1.80 (1H, brs), 2.43 (3H, s), 2.81 (3H, brd), 4.42 (2H, brd ), 4.66 (2H, s), 6.82 (1H, d), 6.88 (1H, d), 6.96 (1H, s), 7.16 (1H, d), 7.27 (2H, obs); MS m/z (ES + ) 446 (MNa + ).

The compounds represented by the formula XIV shown in table 24 are obtained according to the preparation procedure 69 starting from the indicated precursors.

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Table 24

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GETTING 72

tert-butyl 3-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-4-[3-methyl-4-(methylsulfanyl)phenoxy]benzyl(methylsulfonyl)

carbamate

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A solution of diethyl azodicarboxylate (505 μL, 3.21 mmol) in THF (5 mL) was added portionwise to a solution of tert-butyl methylsulfonylcarbamate (synthesized according to Tetrahedron Lett. 1994, 35, 379-380) (655 mg, 3.36 mmol). ), allochol from the preparation of 71 (1.226 g, 3.04 mmol) and triphenylphosphine (880 mg, 3.36 mmol) in THF (15 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h and then diluted with EtOAc (80 mL) and washed with 10% aqueous K 2 CO 3 (100 mL). The organic layer is washed with brine, dried (MgSO4) and evaporated. The precipitate is purified by column chromatography [SiO2; 1:4 EtOAc:pentane] to give the title compound (1.406 g, 80%) as a colorless oil; δH (CDCl3, 300 MHz) 1.45 (9H, s), 1.52 (9H, s), 2.38 (3H, s), 2.44 (3H, s), 2.83 (3H, s ), 3.22 (3H, s), 4.49 (2H, s), 4.85 (2H, s), 6.74-6.83 (3H, m), 7.18-7.29 ( 3H, observed); MS m/z (TS+) 481 (MH+-BOC).

GETTING 73

tert-butyl 3-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-4-[3-fluoro-4(methylsulfanyl)phenoxy]benzyl(methylsulfonyl)

carbamate

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The title compound is obtained from the alcohol from preparation 70 according to the procedure from preparation 72; δH (CDCl3, 300 MHz) 1.44 (9H, s), 1.52 (9H, s), 2.44 (3H, s), 2.82 (3H, s), 3.23 (3H, s ), 4.45 (2H, s), 4.87 (2H, s), 6.61-6.70 (2H, m), 6.90 (1H, d), 7.25-7.33 ( 3H, m); MS m/z (ES+) 607 (MNa+).

GETTING 74

tert-butyl 4-[(dimethylamino)methyl]-3-[3-methyl-4(methylsulfanyl)phenoxylbenzyl(methylsulfonyl)carbamate

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The title compound is obtained from the alcohol from example 59 according to the preparation procedure 72. The crude product is not purified by column chromatography but is transferred directly to the next step; δH (CDCl3, 400 MHz) 1.39 (9H, s), 2.22 (6H, s), 2.28 (3H, s), 2.38 (3H, s), 3.07 (3H, s ), 3.42 (2H, s), 4.76 (2H, s), 6.72 (2H, m), 6.79 1H, s), 7.07 (1H, d), 7.12 ( 1H, d), 7.40 (1H, obs).

GETTING THE 75

tert-butyl methyl [2-[3-methyl-4-(methylsulfanyl)phenoxy]-5-({[(trifluoromethyl)sulfonyl]amino}methyl)benzyl]carbamate

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The title compound is obtained from the alcohol from preparation 71 according to the procedure for preparation 72 using trifluoromethanesulfonamide instead of tert-butyl methylsulfonylcarbamate. The desired product is contaminated with tert-butyl 5-({{3-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-4-[3-methyl-4-methylsulfanyl)phenoxy]benzyl}[(trifluoromethyl)sulfonyl ] amino}methyl)-2-[3-methyl-4-(methylsulfanyl)phenoxy]benzyl(methyl)carbamate and taken as a mixture; MS m/z (ES-) 533 (M-H+).

The compounds represented by the formula XV shown in Table 25 are obtained according to the procedure for obtaining 44 using the indicated precursors.

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Table 25

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GETTING 79

tert-butyl methyl {2-[3-methyl-4-(methylsulfanyl)phenoxy]-5-nitrobenzyl}carbamate

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N-methyl-N-{2-[3-methyl-4-(methylsulfanyl)phenoxy]-5-nitrobenzyl}amine and {2-[3-methyl-4-(methylsulfanyl)phenoxy]-5-nitrophenyl}methanol.

To a suspension of the aldehyde from Preparation 39 (21.0 g, 69.2 mmol) in EtOH (100 mL) was added 8M methylamine in EtOH (86.5 mL, 692 mmol). A solution is formed and after short-term mixing, a precipitate is observed. The precipitate was redissolved by the addition of THF (100 mL), the solution was cooled to 0 °C and then NaBH 4 (7.85 g, 208 mmol) was added. The reaction mixture was allowed to slowly warm to room temperature and stirred overnight before the solvent was removed in vacuo. The precipitate was taken up in water (150 mL) and ether (150 mL), and 2M HCl was carefully added to pH 1. The layers were separated and the aqueous layer was washed with ether (2X100 mL). The combined organic extracts were dried and evaporated to give {2-[3-methyl-4(methylsulfanyl)phenoxy]-5-nitrophenyl}methanol (18.9 g, 89%) as a yellow solid; δH (CDCl3, 400 MHz) 2.35 (3H, s), 2.48 (3H, s), 4.90 (2H, s), 6.79 (1H, d), 6.89 (1H, s ), 6.91 (1H, d), 7.22 (1H, d), 8.07 (1H, dd), 8.41 (1H, d).

The aqueous layer obtained above is neutralized by pouring on the solid K2CO3 in excess. The base solution was extracted with ether (2x100 mL), and the resulting ether extracts were dried (MgSO4) and evaporated to give N-methyl-N-{2-[3-methyl-4-(methylsulfanyl)phenoxy]-5-nitrobenzyl}amine (1.65 g, 7.5%) as an orange oil; MS m/z (ES+) 319 (MH+).

N-methyl-N-{2-[3-methyl-4-(methylsulfanyl)phenoxy]-5-nitrobenzyl}amine from {2-[3-methyl-4-(methylsulfanyl)phenoxyl-5-nitrophenyl}methanol.

Methanesulfonyl chloride (4.81 mL, 61.9 mmol) was slowly added to a solution of {2-[3-methyl-4-(methylsulfanyl)phenoxy]-5-nitrophenyl}methanol (18.9 g, 61.9 mmol) and Et 3 N (9.5 mL, 68.2 mmol) in DCM (60 mL). The mixture was stirred at room temperature for 3 hours, then poured into water and extracted with DCM (3 times). The combined organic extracts were dried (MgSO4) and evaporated to give a dark, viscous oil. This oil was taken up in DCM (50 mL) and 8M methylamine in EtOH (200 mL, 1.6 mol) was added followed by Et 3 N (10 mL, 71.7 mmol). After stirring for 18 h, the mixture was concentrated in vacuo to give the crude amine which was used without further purification.

tert-butyl methyl {2-[3-methyl-4-(methylsulfanyl)phenoxy]-5-nitrobenzyl}carbamate

The crude amine obtained above was dissolved in DCM (100 mL) at 0 °C, Et 3 N (11.4 mL, 81.8 mmol) was added followed by di-tert-butyl dicarbonate (15.0 g, 68.7 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 16 hours before being concentrated in vacuo. The precipitate was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc (2x). The combined organic layers are dried (MgSO4) and evaporated. The residue was purified by column chromatography (SiO2; 1st column - 3% MeOH in DCM; 2nd column EtOAc:pentane 1:3) to give the title compound (14.2 g, 54%) as a yellow oil; δH (CDCl3, 400 MHz) 1.44 (9H, s), 2.32 (3H, s), 2.44 (3H, s), 2.95 (3H, s), 4.56 (2H, no ), 6.75 (1H, d), 6.84 (2H, m), 7.17 (1H, d), 8.00 (1H, d), 8.18 (1H, br); MS m/z (TS+) 419 (MH+).

The compounds of formula XVI shown in Table 26 are obtained according to the procedure of Example 103 from the indicated precursors.

[image]

Table 26

[image]

GETTING 84

tert-butyl methyl {2-[3-methyl-4-(methylsulfanyl)phenoxy]-5-[(methylsulfonyl)amino]benzyl}carbamate

[image]

Methanesulfonyl chloride (4.16 mL, 53 .7 mmol) at 0 °C. After stirring for 30 min at 0 °C, the reaction mixture was allowed to warm to room temperature before the solvent was removed in vacuo. 2M NaOH (50 mL) was added to the precipitate and the mixture was stirred for 30 minutes. The mixture was extracted with EtOAc and the organic layer was washed with brine, dried (MgSO4) and evaporated to give an oil. Purification by column chromatography [SiO2; 97.5:2.5:0.25 (DCM/MeOH/880 NH3)] gave the product (9.0 g, 79%) as a brown foam; δH (CDCl3, 300MHz) 1.43 (9H, brs), 2.35 (3H, s), 2.42 (3H, s), 2.88 (3H, brs), 3.01 (3H, s) , 4.46 (2H, brs), 6.76 (2H, d+s), 6.83 (1H, d), 7.16 (1H, s), 7.20 (2H, brs); MS m/z (ES+) 467 (MH+).

The compounds represented by formula XVII shown in table 27 are obtained according to the procedure for obtaining 84 from the indicated precursors.

[image]

Table 27

[image]

GETTING THE 88

tert-butyl methyl {2-[3-methyl-4-(methylsulfanyl)phenoxy]-5-[methyl(methylsulfonyl)amino]benzyl}carbamate

[image]

Mel (1.07 mL, 17.2 mmol) was added portionwise to a mixture of sulfonamide from the preparation of 84 (2.0 g, 4.3 mmol) and K 2 CO 3 (592 mg, 4.3 mmol) in CH 3 CN (10 mL) under N 2 . The mixture was stirred for 16 h and then partitioned between EtOAc (50 mL) and 2M NaOH (50 mL). The organic layer is washed with brine, dried (MgSO4) and evaporated. Purification of the precipitate by column chromatography [SiO2; 590:10:1 (DCM/MeOH/880 NH3)] gave the product (1.23 g, 60%) as a yellow oil; δH (CDCl3, 300 MHz) 1.45 (9H, s), 2.34 (3H, s), 2.42 (3H, s), 2.86 (3H, s), 2.90 (3H, s ), 3.28 (3H, s), 4.49 (2H, s), 6.80 (3H, br), 7.18 (3H, m); MS m/z (TS+) 498 (MNH4+).

GETTING 89

tert-butyl 5-[(2-hydroxyethyl)(methylsulfonyl)amino]-2-[3-methyl-4(methylsulfanyl)phenoxy]benzyl(methyl)carbamate

[image]

2-Bromoethanol (1.34 mL, 18.9 mmol) was added to a mixture of sulfonamide from preparation 84 (2.0 g, 4.3 mmol) and K2CO3 (2.605 g, 18.8 mmol) in CH3CN (10 mL) in an N2 atmosphere. The mixture was heated at reflux for 16 h, cooled and then partitioned between EtOAc (50 mL) and 2M NaOH (50 mL). The organic layer is washed with brine, dried (MgSO4) and evaporated. Purification of the precipitate by column chromatography [SiO2; 390:10:1 (DCM/MeOH/880 NH3)] gave the product (524 mg, 24%) as a pink foam; δH (CDCl3, 300 MHz) 1.42 (9H, s), 2.37 (3H, s), 2.43 (3H, s), 2.91 (3H, s), 2.98 (3H, s ), 3.68 (2H, brs), 3.79 (2H, d), 4.49 (2H, s), 6.81 (3H, m), 7.19 (3H, m); MS m/z (TS+) 528 (MNH4+).

GETTING THE 90

5-amino-2-(2,3-dihydro-1,4-benzoxathin-6-yloxy)benzonitrile

[image]

To the nitro compound from preparation 41 (740 mg, 2.38 mmol) in AcOH (5 mL) and water (1 mL) was added iron powder (930 mg, 16.7 mmol) and the mixture was stirred at room temperature for 16 h . The solvent was removed in vacuo, the precipitate was taken up in EtOAc (50 mL) and 10% aqueous K 2 CO 3 (50 mL) and filtered through Arbocel®. The organic layer was separated and the aqueous layer was extracted with EtOAc (50 mL). The combined organic extracts were dried (MgSO4) and evaporated to give a brown foam (670 mg, 99%) which was used without further purification; δH (CDCl3, 400 MHz) 3.18 (2H, m), 4.36 (2H, m), 6.60-6.70 (2H, m), 6.70-6.80 (3H, m) , 6.85 (1H, s); MS m/z (TS+) 302 (MNH4+).

The compounds shown by the formula Vb, i.e. the compounds shown by the formula V where T is cyano, R4 is hydrogen, and R5 is amino, shown in table 28 are obtained according to the procedure for obtaining 90 from the indicated precursors.

[image]

Table 28

[image]

GETTING 94

5-amino-2-[4-methyl-3-(methylsulfanyl)phenoxy]benzonitrile

[image]

The title compound is obtained from the nitro compound from the preparation of 43 according to the procedure of example 103; δH (CDCl3, 400 MHz) 2.27 (3H, s), 2.41 (3H, s), 3.66 (2H, br), 6.62 (1H, d), 6.79 (2H, s ), 6.82 (1H, s), 6.89 (1H, s), 7.08 (1H, d); MS m/z (ES+) 293 (MNa+), (ES-) 269 (M-H+).

Compounds shown by formula Vc, i.e. compounds shown by formula V where T is cyano, R4 is hydrogen, and R5 is -NHSO2Me, shown in table 29 are obtained according to the procedure for obtaining 84 from the indicated precursors.

[image]

Table 29

[image]

GETTING 100

N-{3-cyano-4-[3-methyl-4-(methylsulfanyl)phenoxyl]phenyl}-N-methylmethanesulfonamide

[image]

The title compound is obtained from sulfonamides from the preparation of 98 according to the procedure for the preparation of 88; δH (CDCl3, 400 MHz) 2.31 (3H, s), 2.44 (3H, s), 2.83 (3H, s), 3.27 (3H, s), 6.79 (1H, d ), 6.88 (2H, m), 7.17 (1H, d), 7.44 (1H, dd), 7.58 (1H, d); MS m/z (ES+) 385 (MNa+).

GETTING IT 101

1,3-dihydro-2-benzothiophen-5-ol

[image]

Preparation of [4-(allyloxy)-2-(hydroxymethyl)phenyl]methanol

Dimethyl 4-(allyloxy) phthalate [obtained according to Inouye, M.; Suchiya, K.; Kitao, T. Angew. Chem. 1992, 104, 198-200 (see also Angew. Chem., Int. Ed. Engl., 1992, 204-205)] (9.9 g, 38 mmol) was dissolved in THF (40 mL) and cooled to 0 °C before adding lithium aluminum hydride (1M in THF, 77 mL, 77 mmol) in portions over 10 minutes. The mixture was then stirred at room temperature for 3 hours before the reaction was carefully quenched by the addition of water (1.4 mL) followed by 2M NaOH (1.4 mL). After that, MgSO4 is added in excess, followed by water until a granular precipitate forms (about 5 mL). The mixture is then filtered and evaporated to give a brown oil (7.1 g, about 95%). 1H

NMR analysis shows that the oil is 85% pure. It is used directly in the next step without further purification; δH (CDCl3, 400 MHz) 2.63 (1H, brs), 2.91 (1H, brs), 4.52 (2H, m), 4.67 (4H, m), 5.26 (1H, dd ), 5.38 (1H, dd), 5.97-6.09 (1H, m), 6.80 (1H, dd), 6.92 (1H, d), 7.22 (1H, d) .

Preparation of 5-(allyloxy)-1,3-dihydro-2-benzothiophene

The crude diol from step (i) (3.5 g, 18 mmol) was dissolved in DCM (60 mL) and treated with Et 3 N (10 mL, 72 mmol), and the solution was cooled to 0 °C. Ethansulfonyl chloride (4.2 mL, 54 mmol) was added portionwise and the solution was stirred for 1 hour to warm to room temperature. The reaction in the mixture is then stopped by the addition of water, followed by 2M HCl (50 mL). The DCM layer was separated and the aqueous layer was re-extracted with DCM (50 mL). The combined organic fractions were washed with water (50 mL), dried (MgSO4) and concentrated to a volume of about 30 mL. After the addition of benzyltriethylammonium chloride (1 g), a solution of sodium sulfide (5 g, 91 mmol) in water (50 mL) was added. The mixture is vigorously stirred under nitrogen for 15 hours. The organic layer was separated and the aqueous layer was re-extracted with DCM (50 mL). The combined organic layers were dried (MgSO4) and evaporated to give a yellow oil. Flash chromatography produces two fractions; the first is the pure product, and the second is the product contaminated with dimer material. Trituration of the second fraction causes crystallization of the dimeric material, which is removed by filtration. The filtrate was combined with the first chromatographic fraction to give the desired product (800 mg, 23%); δH (CDCl3, 400 MHz) 4.16 (2H, s), 4.19 (2H, s), 4.48 (2H, m), 5.26 (1H, d), 5.37 (1H, d ), 5.95-6.06 (1H, m), 6.74 (2H, m), 7.09 (1H, d).

Preparation of 1,3-dihydro-2-benzothiophen-5-ol

The allyl ether from step (ii) (800 mg, 4.16 mmol) was dissolved in THF (10 mL) and treated with palladium tetrakis(triphenylphosphine) (481 mg, 0.42 mmol) followed by sodium borohydride (944 mg, 25 mmol). The mixture is then heated to 45 °C and stirred at that temperature for 15 hours. After cooling to room temperature, the THF was evaporated, and the precipitate was partitioned between 2M NaOH solution (25 mL) and diethyl ether (25 mL). The aqueous layer was separated and the organic layer was re-extracted with 2M NaOH solution (25 mL). The combined aqueous layers were neutralized to pH 7-8 with concentrated hydrochloric acid and extracted with EtOAc (2 x 25 mL). The combined organic extracts were dried (MgSO4) and evaporated to give a clear oil of the title phenol which solidified on standing (540 mg, 85%); 4.14 (2H, s), 4.17 (2H, s), 6.63-6.68 (2H, m), 7.04 (1H, d).

Biological activity

A series of compounds were tested for biological activity according to their ability to inhibit the reuptake of serotonin by the human serotonin transporter by the following procedure.

Cell culture

Human embryonic kidney (HEK-293) cells persistently infected with either human serotonin transporter (hSERT), noradrenaline transporter (hNET) or dopamine transporter (hDAT) were grown under standard cell culture procedures (cells grow at 37 °C and 5% CO2 in DMEM-medium in culture (supplemented with 10% dialyzed fetal calf serum (FCS), 2 mM l-glutamine and 250 μg/ml geneticin)). Test cells are cultured to obtain a cell suspension of 750,000 cells/ml.

determination of inhibition potential

All test compounds were dissolved in 100% DMSO and diluted in assay buffer to obtain appropriate assay concentrations. Assays are performed in 96-well plates with a bottom filter. Cells (7500 cells/test well) are preincubated in standard assay buffer containing either test compound, standard inhibitor, or vehicle compound (1% DMSO) for 5 minutes. The reactions start with the addition of either the substrate 3H-serotonin, 3H-noradrenaline or 3H-dopamine. All reactions are performed at room temperature in a shaking incubator. Incubation times are 5 minutes for the hSERT and hDAT tests and 15 minutes for the hNET test. Reactions were stopped by removing the reaction mixture using a multiport vacuum pump followed by rapid washing with ice-cold assay buffer. Then the quantity of 3H-substrate incorporated into the cells is determined.

The test plates are dried in a microwave oven, scintillation liquid is added, and the radioactivity is measured. The potential of the tested compounds is determined quantitatively as IC50 values (the concentration of the tested compound required for 50% inhibition of the specific reuptake of the radiolabeled substrate into the cells).

Content of the standard test buffer:

Trizma hydrochloride (26mM)

NaCl (124mM)

KCl (4.5mM)

KH2PO4 (1.2mM)

MgCl2.6H2O (1.3mM)

Ascorbic acid (1.136mM)

Glucose (5.55mM)

pH 7.40

CaCl2 (2.8mM)

Pargyline (100M)

Note: pH of the buffer is adjusted to 7m40 using 1M NaOH before adding CaCl2 and pargyline.

Summary of parameters used in the experiments

[image]

Compounds having an IC50 serotonin reuptake inhibition (SRI) value of less than or equal to 100nM include the title compound of Examples 1-6, 8-23, 25, 26, 29-32, 34-36, 43, 45-49, 51, 56-102, 109-130.

Compounds having an IC50 serotonin reuptake inhibition (SRI) value of less than or equal to 100nM and which are more than 10-fold more potent in inhibiting serotonin reuptake than in inhibiting dopamine reuptake or noradrenaline reuptake include the title compound of Examples 1-6, 9-13, 16-19, 21, 22, 25, 26, 29-32, 34-36, 43, 45, 47-49, 51, 57-88, 90-102, 109-121, 123, 124, 127, 129.

Compounds having an IC50 serotonin reuptake inhibition (SRI) value of less than or equal to 100 nM and which are more than 100-fold more potent in inhibiting serotonin reuptake than in inhibiting dopamine reuptake or noradrenaline reuptake include the title compound of Examples 1, 2, 4, 5, 9, 12, 13, 16-19, 21, 22, 25, 26, 29-32, 34-36, 43, 45, 48, 49, 58-80, 83-88, 90, 92- 97, 99-102, 111-113, 115-118, 120, 123, 124, 127.

Compounds that have an IC50 serotonin reuptake inhibition (SRI) value of less than or equal to 50nM and that are more than 100-fold more potent in inhibiting serotonin reuptake than in inhibiting dopamine reuptake and noradrenaline reuptake include the title compound of Examples 1, 2, 4, 9, 12, 17, 18, 26, 29, 30, 36, 43, 45, 48, 49, 60-66, 68-75, 78, 79, 90, 92-94, 100, 102, 116, 118, 124.

In detail, the title compound of Example 16 has a serotonin reuptake inhibition (SRI) IC50 value of 4.7 nM; the title compound of Example 29 has an IC50 value of serotonin reuptake inhibition (SRI) of 2.0 nM; and the title compound of Example 62 has a serotonin reuptake inhibition IC50 value of 3.7 nM.

Claims (32)

1. The compound represented by the general formula (I), its pharmaceutically acceptable salts, solvates or polymorphs; [image] indicated that: R1 and R2, which may be identical or different, are H, C1-C6alkyl or (CH2)d(C3-C6cycloalkyl) wherein d=0, 1, 2 or 3; or R1 and R2 together with the nitrogen to which they are attached form an azetidine ring; Z or Y is -SR 3 and the second Z or Y is halogen or -R 3 ; wherein R 3 is an independent C 1 -C 4 alkyl optionally substituted with fluorine; with the exception that R 3 is not CF 3 ; or Z and Y are linked so that, together with intermediate atoms, Z and Y form a fused 5- to 7-membered carbocyclic or heterocyclic ring which may be saturated, unsaturated or aromatic, and in which when Z and Y form a heterocyclic ring, in addition to the carbon atom , the linker contains one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; with the proviso that when R5 is fluorine and R2 is methyl then the fused ring is not 1,3-dioxalane and Z and Y together do not form a fused phenyl ring; R4 and R5, which can be identical or different, are: A-X, where A =-CH=CH- or -(CH2)p- where p is 0, 1 or 2; X is hydrogen, F, Cl, Br, I, CONR6R7, SO2NR6R7, SO2NHC(=O)R6, OH, C1-4Alkoxy, NR8SO2R9, NO2, NR6R11, CN, CO2R10, CHO, SR10, S(O)R9 or SO2R10 ; R 6 , R 7 , R 8 and R 10 , which may be identical or different, are hydrogen or C 1-6 alkyl optionally independently substituted by one or more R 12 ; R 9 is C 1-6 alkyl optionally independently substituted with one or more R 12 ; R 11 is hydrogen, C 1-6 alkyl optionally independently substituted with one or more R 12 , C(O)R 6 , CO 2 R 9 , C(O)NHR 6 or SO 2 NR 6 R 7 ; R 12 is F, OH, CO 2 H, C 3-6 cycloalkyl, NH 2 , CONH 2 , C 1-6 alkoxy, C 1-6 alkoxycarbonyl or a 5- or 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, S and O optionally independently substituted with one or more R13; or R6 and R7, together with the nitrogen to which they are attached, form a 4-, 5- or 6-membered heterocyclic ring optionally independently substituted with one or more R13; or 5- or 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, S and O, optionally independently substituted with one or more R 13 ; wherein R 13 is hydroxy, C 1 -C 4 alkoxy, F, C 1 -C 6 alkyl, haloalkyl, haloalkyl, -NH 2 , -NH(C 1 -C 6 alkyl) or -N(C 1 -C 6 alkyl) 2 . 2. The compound according to claim 1, its pharmaceutically acceptable salts, solvates or polymorphs, characterized in that R1 and R2, which may be identical or different, are hydrogen or C1-C6 alkyl. 3. A compound according to claims 1 or 2, its pharmaceutically acceptable salts, solvates or polymorphs, characterized in that when Z or Y is -SR3, R3 is methyl or ethyl. 4. A compound according to claim 1 or 2, its pharmaceutically acceptable salts, solvates or polymorphs, characterized in that when Z and Y are linked to form a fused ring, the ring is heterocyclic. 5. The compound according to claim 4, its pharmaceutically acceptable salts, solvates or polymorphs, characterized in that in addition to the carbon atom, the compound contains one or two sulfur atoms. 6. A compound according to any preceding claim, its pharmaceutically acceptable salts, solvates or polymorphs, characterized in that R6 and R7, which may be identical or different, are hydrogen, C1-C3alkyl optionally substituted with a hydroxy, -CONH2 or C1-C3alkoxy group . 7. A compound according to any preceding claim, its pharmaceutically acceptable salts, solvates or polymorphs, characterized in that R8 is hydrogen, hydroxyethyl or methyl. 8. A compound according to any preceding claim, its pharmaceutically acceptable salts, solvates or polymorphs, characterized in that R9 is methyl, ethyl, isopropyl, trifluoromethyl or methoxyethyl. 9. A compound according to any preceding claim, its pharmaceutically acceptable salts, solvates or polymorphs, characterized in that p is 1 or 0. 10. A compound according to any preceding claim, its pharmaceutically acceptable salts, solvates or polymorphs, characterized in that R4 and R5, which may be identical or different, are: -(CH2)p-X, where p is 0, 1 or 2; X is hydrogen, hydroxy, CONR6R7, SO2NR6R7, NR8SO2R9, SR10, SOR9 or SO2R10 wherein R6, R7, R8, R9 and R10 are as described in claim 1, or A 5- or 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, S and O. 11. A compound according to any preceding claim, its pharmaceutically acceptable salts, solvates or polymorphs, characterized in that R4 and R5, which may be identical or different, are: -(CH2)P-X, where p is 0 or 1; X is hydrogen, hydroxy, CONR6R7, SO2NR6R7 or NR8SO2R9; wherein R 6 and R 7 , which may be identical or different, are hydrogen or C 1 -C 3 alkyl optionally substituted with hydroxy, -CONH 2 or C 1 -C 3 alkoxy (methoxy is preferred); R 8 is hydrogen, hydroxyethyl or methyl; or R 9 is methyl, ethyl, isopropyl, trifluoromethyl or methoxyethyl; or triazolyl, imidazolyl or pyrazolyl. 12. A compound according to any preceding claim, its pharmaceutically acceptable salts, solvates or polymorphs, characterized in that R4 and R5 are not both hydrogen. 13. A compound according to any preceding claim, its pharmaceutically acceptable salts, solvates or polymorphs, characterized in that R4 is hydrogen. 14. The compound according to claim 1, its pharmaceutically acceptable salts, solvates or polymorphs, characterized in that they are selected from the group consisting of: 4-(2,3-dihydro-1-benzothien-5-yloxy)-3-[(methylamino)methyl]-benzenesulfonamide (Example 2); 3-[(dimethylamino)methyl]-4-[3-methyl-4-(methylsulfanyl)phenoxy]-benzenesulfonamide (Example 12); 4-(2,3-dihydro-1-benzothien-5-yloxy)-3-[(dimethylamino)methyl]-benzenesulfonamide (Example 16); 4-[3-chloro-4-(methylsulfanyl)phenoxy]-3-[(dimethylamino)methyl]-benzenesulfonamide (Example 17); 3-[(dimethylamino)methyl]-4-[3-fluoro-4-(methylsulfanyl)phenoxy]-benzenesulfonamide (Example 18); N,N-dimethyl-N-[2-(6-quinolinyloxy)benzyl]-amine (Example 29); 3-[(methylamino)methyl]-4-(6-quinolinyloxy)-benzenesulfonamide (Example 35); 4-(2,3-dihydro-1-benzothien-5-yloxy)-3-[(methylamino)methyl]-benzamide (Example 60); 4-(2,3-dihydro-1-benzothien-5-yloxy)-N-methyl-3-[(methylamino)methyl]-benzamide (Example 62); N-{3-[(methylamino)methyl]-4-[3-methyl-4-(methylsulfanyl)phenoxy]benzyl}-methanesulfonamide (Example 75); 3-[(methylamino)methyl]-4-[3-methyl-4-(methylsulfanyl)phenoxy]-benzamide (Example 79); 4-(2,3-dihydro-1,4-benzoxathiin-7-yloxy)-3-[(dimethylamino)methyl]-benzamide (Example 88); {3-[(dimethylamino)methyl]-4-[3-fluoro-4-(methylsulfanyl)phenoxy]phenyl}-methanol (Example 90); 3-[(dimethylamino)methyl]-4-(6-quinolinyloxy)benzamide (Example 100); 3-[(methylamino)methyl]-4-(6-quinolinyloxy)benzamide (Example 102); N-methyl-N-{3-[(methylamino)methyl]-4-[3-methyl-4-(methylsulfanyl)phenoxy]phenyl}-methanesulfonamide (Example 116) and N-{4-(2,3-dihydro-1,4-benzoxathiin-7-yloxy)-3-[(dimethylamino)methyl]phenyl}-methanesulfonamide (Example 124). 15. A compound as described in any preceding claim, its pharmaceutically acceptable salts, solvates or polymorphs, indicated to be used as a medicine. 16. A pharmaceutical formulation, characterized in that it contains the compound described in any one of claims 1 to 14, or its pharmaceutically acceptable salts, solvates or polymorphs, and a pharmaceutically acceptable excipient, diluent or carrier. 17. The use of the compound defined in any of claims 1 to 14, its pharmaceutically acceptable salts, solvates or polymorphs, indicated in the production of drugs for the treatment or prevention of disorders involving the regulation of monoamine transport function. 18. Use according to claim 17, characterized in that the disorder is depression, attention deficit hyperactivity disorder, obsessive-compulsive disorder, post-traumatic stress disorder, drug abuse disorder or sexual dysfunction. 19. Use according to claim 18, characterized in that the disorder is premature ejaculation. 20. A method of treatment or prevention of a disorder in which the regulation of monoamine transport function is involved, characterized in that it consists in the administration of an effective amount of the compound described in any of claims 1 to 14, its pharmaceutically acceptable salts, solvates or polymorphs, to the patient who is in need of such treatment or prevention. 21. A method of treatment or prevention of premature ejaculation, characterized by the fact that it consists of applying an effective amount of the compound described in any of claims 1 to 14, its pharmaceutically acceptable salt, solvate or polymorph, to a patient in need of such treatment or prevention. 22. A method of increasing ejaculation latency characterized by the fact that it contains the application of an effective amount of the compound described in any of claims 1 to 14, its pharmaceutically acceptable salt, solvate or polymorph, to men who wish to increase ejaculation latency. 23. Procedure for obtaining the compound represented by the general formula (I); [image] wherein R 1 , R 2 , R 4 , R 5 , X and Z are as described in any one of claims 1 to 14, characterized in that it involves the reaction of a compound represented by the general formula Ia [image] under suitable reaction conditions giving the compound shown by formula 1, wherein the suitable reaction conditions are: i) where R4/R5 are halogen, by reacting compound (Ia) with a suitable halogenating agent in an inert solvent that does not adversely affect the reaction mixture; ii) where R4/R5 are -NO2, by reacting compound (Ia) with a suitable nitrating agent in an inert solvent that does not adversely affect the reaction mixture at or below room temperature; or iii) where R4/R5 is -SO2NR6R7 by reacting the sulfonyl chloride intermediate with the required amine shown by the formula HNR6R7 in a suitable solvent. 24. Process according to claim 23 for obtaining the compound represented by formula (Iq), i.e. the compound represented by formula I where R5 is -SO2NR6R7 and R4 is hydrogen, [image] characterized by the fact that it contains: a) reaction of the compound represented by formula Ia, possibly in a suitable solvent, with chlorosulfonic acid to give the compound represented by formula XVIII [image] after which follows b) reaction with HNR6R7 giving the compound shown by formula (Iq). 25. The process according to claim 24, characterized in that the compound represented by formula XVIII is obtained in situ and reacts with HNR6R7 without isolation. 26. The method according to any one of claims 23 to 25, characterized in that it further includes the step of obtaining compounds represented by formula (Ia), by reaction of compounds represented by formula (IIa) [image] with the compound represented by the formula HNR1R2, or with a suitable salt thereof, together with a hydride reducing agent in a suitable solvent, thereby obtaining the compound represented by the formula (Ia). 27. An intermediate represented by formula (IIa) or (XVIII) as described in claims 23 to 26, characterized in that the condition that (IIa) cannot be 2-((31,41-methylenedioxy)phenoxy)benzaldehyde. 28. Procedure for obtaining the compound represented by formula I [image] wherein R 1 , R 2 , R 4 , R 5 , X and Z are as described in any one of claims 1 to 14, characterized in that it contains the reaction of the compounds shown by formula II [image] with a compound of the formula HNR1R2 or a suitable salt thereof, together with a hydride reducing agent in a suitable solvent. 29. The method according to claim 28, characterized in that it further contains the coupling under suitable reaction conditions of the compound represented by formula III, [image] wherein L is a suitable leaving group such as halogen or a sulfonate ester such as trifluoromethanesulfonate or methanesulfonate, with a compound of formula IV [image] thereby obtaining the compound shown by formula II. 30. Intermediate compound represented by formula II as described in claim 28, characterized in that the condition is that the compound represented by formula (II) cannot be 2-((31,41-methylenedioxy)phenoxy)benzaldehyde or 2-((31, 41-methylenedioxy)phenoxy)-5-fluorobenzaldehyde. 31. The compound represented by the general formula (I), or its pharmaceutically acceptable salts, solvates or polymorphs, characterized in that R1, R2, Y and Z are as described in claim 1; and R 4 and R 5 , which may be identical or different, are -(CH 2 ) p -A', wherein p is 0, 1 or 2 and A' is a polar group. 32. A compound according to claim 23, characterized in that the polar group has [image] 32. -value more negative than -0.1.