KR20030029889A - Phenoxybenzylamine Derivatives as Selective Serotonin Re-Uptake Inhibitors - Google Patents

Abstract

R ¹ and R ² may be the same or different and H, C ₁ -C ₆ alkyl or (CH ₂ ) _d (C ₃ -C ₆ cycloalkyl), where d is 0, 1, 2 or 3 Or; R ¹ and R ² together with the nitrogen atom to which they are attached form an azetidine ring;

Z or Y is -SR ³ and the remaining Z or Y is halogen or -R ³ ; Wherein R ³ is, independently, C ₁ -C ₄ alkyl optionally substituted with fluorine except when R ³ is CF ₃ ;

When Z and Y are joined together with a linking atom to form a 5 to 7 membered carbocyclic or heterocyclic ring, wherein when Z and Y form a heterocyclic ring, the linking group, in addition to carbon atoms, Contains 1 or 2 heteroatoms independently selected from sulfur and nitrogen;

R ⁴ and R ⁵ may be the same or different and AX wherein A is —CH═CH— or — (CH ₂ ) _p — where p is 0, 1 or 2; X is hydrogen, F, Cl, Br, I, CONR ⁶ R ⁷ , SO ₂ NR ⁶ R ⁷ , SO ₂ NHC (= O) R ⁶ , OH, C _1-4 alkoxy, NR ⁸ SO ₂ R ⁹ , NO ₂ , NR ⁶ R ¹¹ , CN, CO ₂ R ¹⁰ , CHO, SR ¹⁰ , S (O) R ⁹ or SO ₂ R ¹⁰ ; 5 or 6 membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, S and O, independently optionally substituted by one or more R ¹³ , wherein R ¹³ is hydroxy, C ₁ − C ₄ alkoxy, F, C ₁ -C ₆ alkyl, haloalkyl, haloalkoxy, —NH ₂ , —NH (C ₁ -C ₆ alkyl) or —N (C ₁ -C ₆ alkyl) ₂ ) Of compounds. Compounds of formula (I) inhibit nomoamine reuptake and show activity, in particular as selective serotonin reuptake inhibitors.

Description

Phenoxybenzylamine Derivatives as Selective Serotonin Re-Uptake Inhibitors

The present invention relates to novel diphenyl ether compounds that inhibit monoamine reuptake. In particular, the compounds of the present invention exhibit activity as selective serotonin reuptake inhibitors (SSRIs) and therefore have utility in a variety of therapeutic areas. In particular, the compounds of the present invention include those involved in the regulation of monoamine transporter function, such as depression, attention deficit hyperactivity disorder, obsessive compulsive disorder, post-traumatic stress disorder, drug abuse disorders and sexual dysfunction, including premature ejaculation Useful for the treatment or prevention of various disorders, the present invention relates to a medicament containing the compounds.

According to a first aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, solvate or polymorph thereof:

In the formula,

R ¹ and R ² may be the same or different and H, C ₁ -C ₆ alkyl or (CH ₂ ) _d (C ₃ -C ₆ cycloalkyl), where d is 0, 1, 2 or 3 Or; R ¹ and R ² together with the nitrogen atom to which they are attached form an azetidine ring;

Z or Y is -SR ³ and the remaining Z or Y is halogen or -R ³ ; Wherein R ³ is, independently, C ₁ -C ₄ alkyl optionally substituted with fluorine except when R ³ is CF ₃ ;

Z and Y are joined together with a linking atom to form one conjugated 5 to 7 membered carbocyclic or heterocyclic ring which may be saturated, unsaturated or aromatic, wherein Z and Y form a heterocyclic ring When formed, the linking group contains, in addition to carbon atoms, one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; When R ⁵ is fluorine and R ² is methyl, the conjugate ring is not 1,3-dioxolane and Z and Y together do not form a conjugated phenyl ring;

R⁴And R⁵May be the same or different, and A-X [where A is -CH = CH- or-(CH₂)_p-Wherein p is 0, 1 or 2; X is hydrogen, F, Cl, Br, I, CONR⁶R⁷, SO₂NR⁶R⁷, SO₂NHC (= O) R⁶, OH, C_1-4Alkoxy, NR⁸SO₂R⁹, NO₂, NR⁶R¹¹, CN, CO₂R¹⁰, CHO, SR¹⁰, S (O) R⁹Or SO₂R¹⁰ego; R⁶, R⁷, R⁸And R¹⁰May be the same or different and are hydrogen or one or more R¹²Independently substituted by C_1-6Alkyl; R⁹Is one or more R¹²Independently substituted by C_1-6Alkyl; R¹¹Is hydrogen or at least one R¹²Independently substituted by C_1-6Alkyl, C (O) R⁶, CO₂R⁹, C (O) NHR⁶Or SO₂NR⁶R⁷ego; R¹²Is F (preferably 3 or less), OH, CO₂H, C_3-6Cycloalkyl, NH₂, CONH₂, C_1-6Alkoxy, C_1-6Alkoxycarbonyl or contain 1, 2 or 3 heteroatoms selected from N, S and O and at least one R¹³Is a 5 or 6 membered heterocyclic ring optionally substituted by independently; R⁶And R⁷One or more with the nitrogen atoms to which they are attached R¹³Independently forms an optionally substituted 4, 5 or 6 membered heterocyclic ring; or at least one R¹³Is a 5 or 6 membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, S and O independently substituted by¹³Silver hydroxy, C_One-C₄Alkoxy, F, C_One-C₆Alkyl, haloalkyl, haloalkoxy, -NH₂, -NH (C_One-C₆Alkyl) or -N (C_One-C₆Alkyl)₂being).

Unless otherwise indicated, any alkyl group may be straight or branched and consists of 1 to 6, preferably 1 to 4, in particular 1 to 3 carbon atoms.

Unless otherwise indicated, any carbocyclyl group contains 3 to 8 ring atoms and may be saturated, unsaturated or aromatic. Preferred saturated carbocyclyl groups are cyclopropyl, cyclopentyl or cyclohexyl. Preferred unsaturated carbocyclyl groups contain up to three double bonds. Preferred aromatic carbocyclyl groups are phenyl. The term carbocyclic should be interpreted in a similar sense. The term carbocyclyl also includes conjugated combinations of any carbocyclyl groups, for example naphthyl, phenanthryl, indanyl and indenyl.

Unless otherwise indicated, any heterocyclyl group includes five to seven membered ring atoms having up to four atoms which may be heteroatoms such as nitrogen, oxygen and sulfur, and may be saturated, unsaturated or aromatic. Examples of heterocyclyl groups include furyl, thienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, dioxolanyl, oxazolyl, thiazolyl, imidazolyl, imidazolinyl, imidazolidinyl, Pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, oxdiazolyl, triazolyl, thiadiazolyl, pyranyl, pyridyl, piperidinyl, dioxanyl, morpholino, ditianyl , Thiomorpholino, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, sulfolanil, tetrazolyl, triazolyl, azepinyl, oxazinyl, thiazinyl, diazepinyl and thiazolinyl There is this. The term heterocyclyl also refers to conjugated heterocyclyl groups, such as benzimidazolyl, benzoxazolyl, imidazopyridinyl, benzoxazinyl, benzothiazinyl, oxazolopyridinyl, benzofuranyl, quinolinyl Nil, quinazolinyl, quinoxalinyl, dihydroquinazolinyl, benzothiazolyl, phthalimido, benzofuranyl, benzodiazepynyl, indolyl and isoindoleyl. The term heterocyclic should be interpreted in a similar sense.

Halo means fluoro, chloro, bromo or iodo.

Preferably, R ¹ and R ² may be the same or different and are hydrogen or C ₁ -C ₆ alkyl. More preferred are hydrogen or methyl.

When Z or Y is -SR ³ , R ³ is preferably methyl or ethyl.

When Z and Y form a conjugated ring, this ring is preferably a heterocyclic ring. More preferably, this linker contains 1 or 2 sulfur atoms.

It is preferred that both R ⁴ and R ⁵ are not hydrogen.

Preferably, R ⁴ and R ⁵ may be the same or different, and-(CH ₂ ) _p -X, where p is 0, 1 or 2 (preferably 0 or 1); X is hydrogen, hydroxy, CONR ⁶ R ⁷ , SO ₂ NR ⁶ R ⁷ , NR ⁸ SO ₂ R ⁹ , SR ¹⁰ , SOR ⁹ or SO ₂ R ¹⁰ , wherein R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are as defined in the first embodiment], or a 5 or 6 membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, S and O (preferably oxadiazolyl, tria Zolyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl or pyrimidinyl).

More preferably, R ⁴ and R ⁵ may be the same or different, and-(CH ₂ ) _p -X, wherein p is 0 or 1; X is hydrogen, hydroxy, CONR ⁶ R ⁷ , SO ₂ NR ⁶ R ⁷ or NR ⁸ SO ₂ R ⁹ , wherein R ⁶ and R ⁷ may be the same or different and are hydrogen, hydroxy, -CONH ₂ or C ₁ -C ₃ alkoxy optionally substituted with C ₁ -C ₃ alkyl, by (preferably methoxy); R ⁸ is hydrogen, hydroxyethyl or methyl; R ⁹ is methyl, ethyl, isopropyl, trifluoromethyl or methoxyethyl; or is triazolyl, imidazolyl or pyrazolyl.

More preferably R ⁴ is hydrogen.

Preferably, R ⁶ and R ⁷ may be the same or different, are hydrogen, hydroxy, -CONH ₂ or C ₁ -C ₃ alkoxy by (preferably methoxy) optionally substituted C ₁ -C ₃ Alkyl. More preferably, R ⁶ and R ⁷ may be the same or different and are hydrogen or methyl, with hydrogen being more preferred.

If present, R ¹² is preferably oxadiazolyl, triazolyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl or pyrimidinyl. More preferably triazolyl, imidazolyl or pyrazolyl.

When R ⁶ and R ⁷ together with the nitrogen atom to which they are attached form a heterocyclic ring, the preferred ring is pyrrolidine or piperidine, each of which may be substituted by OH or CONH ₂ , or Morpholine ring which may be substituted by CONH ₂ .

Preferably, R ¹¹ is hydrogen or C _1-6 alkyl.

Preferably, R ⁸ is hydrogen, hydroxyethyl or methyl, more preferably hydrogen.

Preferably, R ⁹ is methyl, ethyl, isopropyl, trifluoromethyl or methoxyethyl, with methyl or ethyl (preferably methyl) being more preferred.

Preferably, R ¹⁰ is methyl or ethyl.

p is preferably 1 or 0, more preferably 0.

R ¹ and R ² may be the same or different, with hydrogen or methyl being preferred;

If present, R ³ is methyl or ethyl; Z or Y is joined together with the linking atoms to form a conjugated 5 to 7 membered carbocyclic or heterocyclic ring which may be saturated, unsaturated or aromatic, wherein Z and Y form a heterocyclic ring In addition to a carbon atom, the linking group includes one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;

R ⁴ and R ⁵ may be the same or different and — (CH ₂ ) _p -X wherein p is 0 or 1; X is hydrogen, hydroxy, CONR ⁶ R ⁷ , SO ₂ NR ⁶ R ⁷ , NR ⁸ SO ₂ R ⁹ , SR ¹⁰ , SOR ⁹ or SO ₂ R ¹⁰ , wherein R ⁶ and R ⁷ may be the same or different. It may be hydrogen or, hydroxy, -CONH ₂ or C ₁ -C ₃ alkoxy (preferably methoxy) optionally substituted by a C ₁ -C ₃ alkyl, or by; Or R ⁶ and R ⁷ together with the nitrogen atom to which they are attached form a morpholine, pyrrolidine or piperidine ring, each of which may be substituted by OH or CONH ₂ ; R ⁸ is hydrogen, hydroxyethyl or methyl (preferably hydrogen); R ⁹ is methyl, ethyl, isopropyl, trifluoromethyl or methoxyethyl; R ¹⁰ is methyl or ethyl; Oxdiazolyl, triazolyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl or pyrimidinyl groups.

More preferably,

R ¹ and R ² may be the same or different and are hydrogen or methyl;

If present, R ³ is methyl or ethyl; Z and Y are joined together with the linking atoms to form a conjugated 5 to 7 membered heterocyclic ring comprising 1 or 2 sulfur atoms;

R ⁴ and R ⁵ may be the same or different and — (CH ₂ ) _p -X wherein p is 0 or 1; X is hydrogen, hydroxy, CONR ⁶ R ⁷ , SO ₂ NR ⁶ R ⁷ or NR ⁸ SO ₂ R ⁹ , wherein R ⁶ and R ⁷ may be the same or different and are hydrogen, hydroxy, -CONH ₂ or C ₁ -C ₃ alkyl optionally substituted with C ₁ -C ₃ alkoxy (preferably methoxy); R ⁸ is hydrogen, hydroxyethyl or methyl (preferably hydrogen); R ⁹ is methyl, ethyl, isopropyl, trifluoromethyl or methoxyethyl; Triazolyl, imidazolyl or pyrazolyl.

More preferably,

R ¹ and R ² may be the same or different and are hydrogen or methyl;

If present, R ³ is methyl or ethyl; Z and Y are joined together with the linking atoms to form a conjugated 5 to 7 membered heterocyclic ring containing 1 or 2 sulfur atoms;

R ⁴ is hydrogen;

R ⁵ is-(CH ₂ ) _p -X, wherein p is 0 or 1; X is hydrogen, hydroxy, CONR ⁶ R ⁷ , SO ₂ NR ⁶ R ⁷ or NR ⁸ SO ₂ R ⁹ ; Wherein, R ⁶ and R ⁷ may be the same or different, are hydrogen, hydroxy, -CONH ₂ or C ₁ -C ₃ alkoxy group optionally substituted by C ₁ -C ₃ alkyl, by (preferably, methoxy) ego; R ⁸ is hydrogen, hydroxyethyl or methyl (preferably hydrogen); R ⁹ is methyl, ethyl, isopropyl, trifluoromethyl or methoxyethyl; Triazolyl, imidazolyl or pyrazolyl.

More preferably, both R ⁴ and R ⁵ are not hydrogen.

Preferred compounds

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] benzeneamide (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).

According to a second aspect of the invention there is provided the following formula (I) and pharmaceutically acceptable salts or solvates thereof, or formula (XIX) and pharmaceutically acceptable salts or solvates thereof, provided that both R ⁴ and R ⁵ are not H This is provided:

<Formula I>

In the above formulas (in this aspect)

R ¹ and R ² may be the same or different and are independently H, C ₁ -C ₆ alkyl or (CH ₂ ) _d (C ₃ -C ₆ cycloalkyl), wherein d is 0, 1, 2 or 3 Is); When taken together with ^{NR 1 R 2, NR 1 R} 2 is, R ¹ and R ² together represents a 4-membered ring represents a C ₃ alkyl; Z and Y are independently -SR ³ (wherein when Z is -SR ³ , Y is halogen, -OR ^a , -R ^a or -SR ^a , and when Y is -SR ³ , Z is halogen,- OR ^a , -R ^a or -SR ^a , and R ³ and R ^a independently represent C ₁ -C ₄ alkyl (optionally substituted with a fluorine atom, eg, —CF ₃ ); Z and Y together are a conjugated 5 to 7 membered ring as illustrated in Formula XIX above; Wherein said 5 to 7 membered ring may be saturated, unsaturated or aromatic; Optionally may include one or more heteroatoms P and Q; Wherein P and Q can be independently O, S or N; E, F or G independently represent CH or CH ₂ ; k and p are independently 0, 1, 2 or 3 and m is 1, 2 or 3;

R ⁴ and R ⁵ independently represent AX, wherein A is — (CH ₂ ) _n — where n is 0, 1 or 2; X is H, F, Cl, Br, I, CONR ⁶ R ⁷ or SO ₂ NR ⁶ R ⁷ , OH, NR ⁸ SO ₂ R ⁹ , NO ₂ , NR ⁶ R ¹¹ , CN, CO ₂ R ¹⁰ , CHO, S (O) _m R ¹⁰ where m is 0, 1 or 2; R ⁶ , R ⁷ , R ⁸ and R ¹⁰ are independently hydrogen or C _1-6 alkyl; R ⁹ is C _1-6 alkyl; R ¹¹ is H, C _1-6 alkyl, C (O) R ⁶ , CO ₂ R ⁹ , C (O) NHR ⁶ or SO ₂ NR ⁶ R ⁶ , wherein the C _1-6 alkyl group is OH, CO 5 containing ₂ , C _3-6 cycloalkyl, NH ₂ , CONH ₂ , C _1-6 alkoxy, C _1-6 alkoxycarbonyl, and 1, 2 or 3 heteroatoms selected from N, S and O Optionally substituted by one or more groups selected from 6 membered heterocyclic rings); Or k and p are not zero when P and Q are oxygen, with the condition that Z and Y together do not form a conjugated 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; R ⁶ and R ⁷ may also form a 5 or 6 membered heterocyclic ring which may be optionally substituted with the nitrogen atom to which they are attached.

Without question, unless indicated otherwise, the term "substituted" means substituted by one or more defined groups. If selectable from multiple optional groups, the selected groups may be the same or different.

Without question, the term “independently” means that when one or more substituents are selected from a number of possible substituents, those substituents may be the same or different.

According to a third aspect, the present invention provides a compound of formula (I) and a pharmaceutically acceptable salt thereof, which satisfy the following conditions.

Wherein R ¹ , R ² , R ³ , Z and Y are as defined in the first embodiment; R ⁴ and R ⁵ may be the same or different and are — (CH ₂ ) _p —A ′ wherein p is 0, 1 or 2 and A ′ is a polar group. In this embodiment, polar groups can be defined as those with negative π values (see C Hansch and A Leo, 'substituent Constants for Correlation Analysis in Chemistry and Biology', Wiley, New York, 1979). In this system, H has a pi value of 0.00, -OCH ₃ has a pi value of -0.02, and -SO ₂ NH ₂ has a pi value of -1.82 (for example, see Table VI-I, 'Well-Characterized). Aromatic Substituents', p 49]. More preferred polar groups have a more negative π value: Thus, preferred groups have a negative π value than -0.1, more preferably a negative π value than -0.5, most preferably more than -1.0 Has a negative π value. Even if p is not zero in the above definition, the definition of A 'is based on the same as above when p is zero.

Unless otherwise specified, compounds of the first, second and third embodiments are defined below as compounds of the present invention.

The compounds of the present invention are those that are selective inhibitors (SRIs) for resorption of serotonin (so will have reduced side effects), are fast initiation of action (suitable for administration just before an effect is required), desirable efficacy and related properties. Has the advantage. Preferred are compounds that selectively inhibit the reuptake of serotonin, but compounds that are not noradrenaline or dopamine.

We have found that compounds of formula (I) having these properties have relatively polar groups in R ⁴ / R ⁵ .

Pharmaceutically or veterinary acceptable salts of compounds of formula (I) containing a basic center are, for example, non-toxic acid moieties formed with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, with carboxylic acids or organic sulfonic acids. It is salting. Examples include HCl, HBr, HI, sulfate or bisulfate, nitrate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, saccharide, fumarate, maleate, lactate, citrate, tartarate, gluconate , Chamlate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate salts. The compounds of the present invention may also provide pharmaceutically or veterinary acceptable metal salts, in particular non-toxic alkali and alkaline earth metal salts with bases. Examples are sodium, potassium, aluminum, calcium, magnesium, zinc, diolamine, olamine, ethylenediamine, tromethamine, chlorine, megulamine and diethanolamine salts. For reference to suitable pharmaceutical salts see Berge et al, J. Pharm. Sci., 66, 1-19, 1977; P 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.

Hereinafter, compounds, pharmaceutically acceptable salts, solvates and polymorphs thereof (except intermediate compounds in chemical processes), as defined in any embodiment of the present invention, are referred to as "compounds of the present invention".

Pharmaceutically acceptable solvates of the compounds of the present invention include hydrates thereof.

The compounds of the present invention may have one or more chiral centers and therefore exist in a number of stereoisomeric forms. All stereoisomers and mixtures thereof are included within the scope of the present invention. Racemic compounds can be separated using preparative HPLC and columns with chiral stationary phases, or resolved using methods known in the art to produce individual enantiomers. Chiral intermediate compounds can also be resolved and used to make chiral compounds of the present invention.

When the compounds of the present invention exist as E and Z isomers, the present invention includes not only mixtures thereof, but also individual isomers.

When the compounds of the present invention are present as diastereomers, the present invention includes not only mixtures thereof, but also individual diastereomers.

Separation of diastereomers or E and Z isomers can be carried out by conventional techniques such as fractional crystallization, chromatography or H.P.L.C. Individual enantiomers of the compounds of the present invention may be prepared from the corresponding optically pure intermediates or by using a suitable chiral support for the H.P.L.C. Or by fractional crystallization of the diastereomeric salt formed by reacting a suitable optically active acid or base with the corresponding racemate, if appropriate.

The compounds of the present invention may exist in one or more tautomeric forms. All tautomers and mixtures thereof are included in the scope of the present invention. For example, a claim for 2-hydroxypyridinyl will also include its tautomeric form, α-pyridonyl. Those skilled in the art will appreciate that certain protected derivatives of the compounds of the invention, which may be made before the final deprotection step, may not have pharmacological activity on their own, but in certain instances, are administered orally or parenterally and then in the body. It will be appreciated that it may be metabolized to produce the pharmacologically active compound of the present invention. Thus, such derivatives may be described as "prodrugs". Furthermore, certain compounds of the present invention may act as prodrugs of other compounds of the present invention.

All protected derivatives and prodrugs of the compounds of the present invention are within the scope of the present invention. Examples of suitable prodrugs for the compounds of the present invention include Drugs of Today, Volume 19, Number 9, 1983, pp 499-538 and Topics in Chemistry, Chapter 31, pp306-316 and "Design of Prodrugs". by H. Bundgaard, Elsevier, 1985, Chapter 1 (the contents of which are incorporated herein by reference).

In addition, if you are skilled in the art, for example, H. Certain portions known to those of skill in the art as "pro-moiety" as described in Bundgaard in "Design of Prodrugs", the disclosures of which are incorporated herein by reference. It will be appreciated that when functional groups are present in the compound, they can be placed on appropriate functional groups.

Preferred prodrugs for the compounds of the invention include esters, carbonate esters, hemi-esters, phosphate esters, nitro esters, sulfuric esters, sulfoxides, amides, carbamates, azo compounds, phosphoamides, glycosides, ethers, acetals And ketals.

In addition, the present invention includes all suitable isotopic variations of the compounds of the present invention. An isotope variant is defined as having at least one atom replaced by an atom having an atomic mass different from the atomic mass normally found in nature. Examples of isotopes that may be incorporated into the compounds of the invention include ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ^{36, respectively.} Isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine such as Cl. Certain isotopic variants of the invention (eg those incorporating radioisotopes such as ³ H or ¹⁴ C) are useful for studying drug and / or matrix tissue distribution. Tritium, ie ³ H and carbon-14, ie ¹⁴ C isotopes are particularly preferred because of their ease of preparation and detection. In addition, heavy hydrogen, i.e., can provide certain therapeutic advantages substitution is due to a higher metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) of the same isotopes ² H, therefore It may be desirable in some circumstances. Isotope variants of the compounds of the present invention can generally be prepared by conventional procedures, such as the methods or preparations described in the Examples and Preparations below, using isotope variants of suitable reaction reagents.

The compounds of the present invention can be prepared by known methods in a variety of ways. In the following schemes and unless otherwise indicated below, R ¹ to R ¹³ , Z and Y are as defined in the first embodiment. These methods form a further aspect of the invention.

Throughout the specification, chemical formulas are represented by Roman numerals I, II, III, IV, and the like. Subgroups of this formula are defined as Ia, Ib, Ic, etc., ... IVa, IVb, IVc, etc.

Compounds of formula (I) can be prepared from compounds of formula (II) by reacting an amine of formula HNR ¹ R ² or a suitable salt form thereof with a hydride reducing agent in a suitable solvent (see Scheme 1). When either R ¹ or R ² is hydrogen, suitable solvents include protic solvents such as ethanol and sodium borohydride is a suitable reducing agent as illustrated in Example 36. When neither R ¹ nor R ² is hydrogen, tetrahydrofuran / dichloromethane is a suitable solvent system and sodium triacetoxyborohydride is a suitable reducing agent. In this reaction, the use of a salt form of HNR ¹ R ² , such as hydrochloride, is preferred, and as illustrated in Example 25, an auxiliary base to aid in the solubility of the HNR ¹ R ² salt, such as triethylamine, is combined with acetic acid. Can be added accordingly.

The compound of formula II is a compound of formula IV or an aldehyde compound of formula III wherein L is a suitable leaving group such as halogen (F, Cl, Br or I) or a sulfonic acid ester such as trifluoromethanesulfonate or methanesulfonate , Preferably F or Cl). The coupling reaction can be carried out by techniques known in the art (eg, via reaction with potassium carbonate in a suitable solvent such as dimethylformamide under inert atmosphere under appropriate reaction conditions such as elevated temperature).

Thus, according to a further aspect, the present invention provides a process for preparing a compound of formula (I) from a compound of formula (II).

Alternatively, R ⁴ and / or R ⁵ may be introduced after ether coupling (see Scheme 2). Compounds of formula (I) can be prepared from compounds of formula (Ia), ie compounds of formula (I) wherein R ⁴ and R ⁵ are hydrogen. Compounds of formula (Ia) may be prepared from formula (IIa) in a manner similar to the preparation of formula (I) from formula (II), and compounds of formula (IIa) are prepared in a similar manner to preparation of formula (II) And IIIa.

Thus, according to a further aspect, the present invention provides a method for preparing a compound of formula (I) from a compound of formula (Ia).

Methodologies for introducing R ⁴ and / or R ⁵ into a compound of formula la include the following methods:

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

ii) when R ⁴ / R ⁵ is —NO ₂ , the reaction of formula Ia with a suitable nitrating agent such as an alkali metal nitrate in a solvent that does not adversely affect the reaction at temperatures below room temperature. Suitable nitrating agents are trifluoromethanesulfonic acid / potassium nitrate, and suitable solvents are trifluoroacetic acid.

iii) when R ⁴ / R ⁵ is —SO ₂ NR ⁶ R ⁷ , reaction of the intermediate sulfonyl chloride with the required amine of formula HNR ⁶ R ^{7 in} a suitable solvent. Suitable solvents include mixtures of water and dichloromethane, and the reaction is generally carried out at temperatures below room temperature. Intermediate sulfonyl chlorides may or may not be subjected to subsequent treatment with a chlorinating agent such as phosphoric acid chloride, phosphorus pentachloride, oxalyl chloride or thionyl chloride in a solvent that does not adversely affect the reaction in the presence of a solvent that does not adversely affect the reaction. It can be prepared from the compound of formula (Ia) by reaction with chlorosulfonic acid under low temperature conditions. Suitable solvents for this reaction with chlorosulfonic acid include trifluoroacetic acid, with a typical reaction temperature of 0 ° C. Suitable solvents for this reaction with the chloroating agent include acetonitrile and suitable conditions include the reflux temperature, as illustrated in Example 12.

For example, a compound of Formula Iq, wherein R ⁵ is -SO ₂ NR ⁶ R ⁷ , may or may not be subjected to subsequent treatment with a chlorinating agent, such as phosphoric acid chloride, phosphorus pentachloride, oxalyl chloride or thionyl chloride, After the reaction of formula (Ia) with sulfonic acid, it can be prepared from the compound of formula (Ia) via intermediate sulfonyl chloride XVIII by reaction with HNR ⁶ R ⁷ (see Scheme 2a). Reaction conditions generally include low temperatures. The reaction can occur in either case under pure conditions, i.e. in the absence of a solvent or in the presence of an inert solvent which does not adversely affect the reaction. Intermediate sulfonyl chloride XVIII can be isolated, purified and then reacted with HNR ⁶ R ⁷ , or alternatively, it can occur without isolation in situ and then with HNR ⁶ R ⁷ .

Accordingly, according to a further aspect, the present invention provides a method for preparing a compound of formula (I) from a compound of formula (II). In a preferred embodiment, the compound of formula (Ia) is reacted with chlorosulfonic acid in a suitable solvent to provide a compound of formula (XVIII) with or without subsequent treatment with a chlorinating agent such as phosphorus acid chloride, phosphorus pentachloride, oxalyl chloride or thionyl chloride. Thereafter, a method of preparing a compound of formula Iq is provided, which is reacted with HNR ⁶ R ⁷ to provide a compound of formula Iq. It is preferred that the compound of formula (XVIII) be generated in situ and react with HNR ⁶ R ⁷ without isolation.

Alternatively, compounds of formula (I) having certain R ⁴ / R ⁵ substituents can be converted to other compounds of formula (I) using known techniques. For example:

i) when R ⁴ / R ⁵ is halogen such as chloro, bromo or iodo, it is converted to cyano via reaction with a cyanide salt in the presence of a Pd (0) or (II) catalyst in a high boiling solvent at elevated temperature You can. As illustrated in Example 78, suitable Pd catalysts include palladium tetrakis (triphenylphosphine), suitable cyanide salts include Zn (CN) ₂ , and suitable solvents that do not adversely affect the reaction. Has dimethylformamide;

ii) when R ⁴ / R ⁵ is halogen such as chloro, bromo or iodo, it is either Pd (0) or (II) in an alcohol solvent (ROH where R is C ₁ -C ₄ alkyl) in the presence of a base at elevated temperature ) And the catalyst under high pressure can be converted to the corresponding ester -CO ₂ R. For example, the reaction can be carried out under pressure in the region of about 100 p. Si. As illustrated in Preparation Example 50, a suitable Pd catalyst is dichlorobis (triphenylphosphine) palladium (II) and a suitable base. Furnace is triethylamine, and a suitable alcohol solvent is methanol;

iii) When R ⁴ / R ⁵ is nitro, it can be reduced to the corresponding -NH ₂ group by treatment with a reducing agent in a protic solvent at a temperature above room temperature. As illustrated in Example 103, suitable reducing agents are iron powder / calcium chloride, suitable protic solvents are aqueous ethanol, and typical reaction temperatures are from about 70 ° C. to about 100 ° C., preferably about 90 ° C. ;

iv) when R ⁴ / R ⁵ is -NH ₂ , it is reacted with the corresponding -NHSO ₂ R ⁹ by reaction with a sulfonylating agent in the presence of a base in an inert solvent that does not adversely affect the reaction at temperatures below room temperature Can be converted to As illustrated in Example 128, suitable sulfonylating agents are methanesulfonyl chloride, suitable bases are triethylamine, and suitable inert solvents are dichloromethane;

v) If R ⁴ / R ⁵ is a —NHSO ₂ R ⁹ group, it may be converted to the corresponding NR ⁸ SO ₂ R ⁹ group via treatment with a base and an alkylating agent in a suitable inert solvent. As illustrated by Preparation 88, suitable alkylating agents are methyl iodide, suitable bases are potassium carbonate, and suitable inert solvents are acetonitrile;

vi) When R ⁴ / R ⁵ is nitrile —CN, it may be converted to the corresponding —C (O) NH ₂ group by hydrolysis under basic, oxidative or acid conditions. Basic hydrolysis is preferably carried out with a hydroxide salt such as potassium hydroxide in a protic solvent such as t-butanol at elevated temperature, as illustrated in Example 79;

vii) When R ⁴ / R ⁵ is ester —CO ₂ R, it may be reduced to the corresponding alcohol group —CH ₂ OH by treatment with a hydride reducing agent such as lithium aluminum hydride, as illustrated in Preparation 69. .

viii) When R ⁴ / R ⁵ is ester —CO ₂ R, it may be converted to the corresponding acid —CO ₂ H by treatment with a suitable hydroxide salt in the presence of water and a suitable cosolvent. As illustrated by Preparation 55, suitable hydroxide salts are lithium hydroxide and suitable cosolvents are tetrahydrofuran.

ix) If R ⁴ / R ⁵ is acid —CO ₂ H, this is the corresponding amide —CONR ⁶ R ⁷ by treatment with a coupling agent, base and amine HNR ⁶ R ⁷ in a suitable inert solvent which does not adversely affect the reaction Can be converted to As illustrated by Preparation 59, suitable coupling agents include 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (hydrochloride) in the presence of 1-hydroxybenzotriazole, suitable Base is triethylamine and suitable solvent is dichloromethane;

x) When R ⁴ / R ⁵ is halogen such as chloro, bromo or iodo, it is acrylamide, Pd (0) or (II) catalyst and suitable base in an inert solvent which does not adversely affect the reaction at elevated temperature By treatment with, it is possible to convert to α, β-unsaturated amide. As illustrated in Example 50, suitable Pd catalysts include palladium (II) acetate in the presence of tri (o-tolyl) phosphine, suitable bases are triethylamine, and suitable inert solvents are acetonitrile There is;

xi) When R ⁴ / R ⁵ is an α, β-unsaturated amide, it is converted to —CH ₂ CH ₂ CO ₂ NH ₂ by treatment with a suitable reducing agent under appropriate temperature in a suitable solvent that does not adversely affect the reaction. Can be. As illustrated by Example 51, suitable reducing agents include room temperature samarium iodide and suitable solvents include tetrahydrofuran containing small amounts of water;

xii) when R ⁴ / R ⁵ is —CH ₂ OH, it is converted to —CH ₂ NR ⁸ SO ₂ R ⁹ by a Mitsunobu reaction under appropriate temperature in a suitable solvent that does not adversely affect the reaction You can. As illustrated by Preparation 72, suitable reactants include diethylazodicarboxylate, triphenylphosphine and t-butyl methylsulfonylcarbamate, suitable reaction temperature is 0 ° C., suitable solvent Tetrahydrofuran.

Alternatively, compounds of formula (I) with specific NR ¹ R ² groups can be converted to other compounds of formula (I) with different NR ¹ R ² groups.

For example,

i) R ¹ or R ² the compound of either formula (Ib) one is a hydrogen of the be converted to compounds of formula (Ic) instead of R ¹ or R ² hydrogen neither by reaction with an aldehyde and a hydride reducing agent of the compound of formula Ib Can be. As illustrated by Example 12, suitable aldehydes are formaldehyde, suitable reducing agents are sodium tri (acetoxy) borohydride, and the reaction interferes with the reaction, such as dichloromethane at temperatures below room temperature. It is preferable to carry out in a solvent which does not.

ii) A compound of formula (Ib), wherein R ¹ or R ² is hydrogen, reacts the compound of formula (Ib) with a formylating agent in a suitable solvent, followed by intermediate N-formyl to a hydride reducing agent in an inert solvent, preferably at elevated temperature Subsequent reduction of the compound allows conversion to compounds of formula (Ic) wherein R ¹ or R ² is methyl. Suitable formylating agents are pentafluorophenyl formate (formed from formic acid, pentafluorophenol and dicyclohexylcarbodiimide), and suitable solvents for formylation are dichloromethane. As illustrated by Example 110, suitable reducing agents are borane-tetrahydrofuran complexes and suitable inert solvents for reduction are tetrahydrofuran.

Alternatively, compounds of formula I can be prepared from compounds of formula V (see Scheme 3), where L is as defined in Scheme 1 and T is a group capable of converting to CH ₂ NR ¹ R ² . . Examples of suitable T substituents are -CO ₂ R ¹⁰ , -CN and -C (O) NR ¹ R ² .

Methods of converting Formula V to I include the following methods:

i) when T is —CO ₂ R ¹⁰ and R ¹⁰ is methyl or ethyl, forms an amide by reaction with the formula NHR ¹ R ² and then provides the amine by reduction.

ii) when T is -CN, it is reduced to its corresponding amine of formula -CH ₂ NH ₂ .

iii) when T is -C (O) NR ¹ R ² , provide the amine by reduction.

Compounds of formula (V) may be prepared in turn by coupling compounds of formula (VI) with compounds of formula (IV). Reagents and conditions for the coupling reaction are as described above for the coupling of compounds of Formulas IV and III in Scheme 1.

Compounds of formula VI may be prepared sequentially from compounds of formula VII (see Scheme 4).

Compounds of formula (VI) can be prepared in such a way that they provide the compounds of formula (VI) directly by aromatic electrophilic substitution of the compounds of formula (VII). Alternatively, the compound of formula VI may be prepared in two or more steps: providing an intermediate compound by aromatic electrophilic substitution of the compound of formula VII, followed by further reaction to provide a compound of formula VI. The intermediate compound can be isolated or produced in situ without isolation. Preferred routes are shown in Scheme 5.

The compound of formula VII is reacted with sulfonyl chloride to give a compound of formula VIII and then with NHR ⁶ R ⁷ to obtain a compound of formula VIa.

According to a further aspect, the present invention provides compounds of formula II, IIa and V above.

Compounds of formula (III), (IIIa), (IV), (VI) or (VII) are known and can be purchased or obtained from commercially available materials using known techniques (see Examples below).

Those skilled in the art will appreciate that sensitive functional groups may require protection and deprotection during the synthesis of the compounds of formula (I). This may be accomplished by conventional techniques, for example, as described in 'Protective Groups in Organic Synthesis', 3rd edition, by T W Greene and P G Wuts, John Wiley and Sons Inc, 1999. Example 35 provides examples of protecting group strategies used in the synthesis of one compound of the invention.

Skilled chemists will appreciate that diaryl ethers can be prepared using a number of synthetic methods. For reference to the methodology, see J S Sawyer, Tetrahedron, 56 (2000) 5045-5065, which is incorporated herein by reference.

The compounds of the present invention are useful because they have pharmacological activity in mammals, including humans. In particular, they are useful for the treatment or prevention of disorders involving the regulation of monoamine transporter function. Diseases that may be mentioned include hypertension, depression (eg, depression in cancer patients, depression in Parkinson's disease, post-myocardial infarction, subsyndromal symptomatic depression, depression in pregnant women, childhood depression, major depression, single episodes). Depression, repetitive depression, child abuse-induced depression, postpartum depression and grumpy old man syndrome, general anxiety disorder, phobia (e.g. agoraphobia, social phobia and simple fear), post-traumatic stress syndrome, evasiveness Personality disorders, premature ejaculation, eating disorders (e.g. anorexia and bulimia), obesity, drug dependence (e.g. alcohol, cocaine, heroin, phenobarbital, nicotine and benzodiazepine poisoning), cluster headache, migraine, pain, Alzheimer's disease, obsessive compulsive disorder, panic Disorders, memory disorders (eg dementia, forgetfulness and memory loss due to aging (ARCD)), Parkinson's disease (eg dementia during Parkinson's disease, neuroleptic-induced Parkinsonism and limbs) Sexual dysfunction), endocrine disorders (e.g. hyperprolactinemia), vasospasm (especially cerebrovascular), cerebellar ataxia, gastrointestinal disorders (including changes in motility and secretion), negative symptoms of schizophrenia, premenstrual syndrome , Fibromyalgia, stress incontinence, Tourette syndrome, baldness, pathological barrier, male impotence, attention deficit hyperactivity disorder (ADHD), chronic paroxysmal striasis, headache (vascular disorders headache), emotional instability, pathological crying, sleep disorder (Seizure seizures) and sprains.

Diseases of particular interest include depression, attention deficit hyperactivity disorder, obsessive compulsive disorder, post-traumatic stress syndrome, substance abuse disorders and sexual dysfunction, including premature ejaculation. Premature ejaculation is defined as a continuous or repeated ejaculation before, at or immediately after insertion of the sex partner's penis. This may be defined as a situation that occurs before the individual desires (see 'The Merck Manual', 16th edition, p 1576, published by Merch Research Laboratories, 1992).

Thus, according to a further aspect, the present invention provides the following objects:

i) a compound of the present invention for use as a medicament;

ii) in the manufacture of a medicament for the treatment or prevention of disorders involving the regulation of monoamine transporter functions (e.g. depression, attention deficit hyperactivity disorder, obsessive compulsive disorder, post-traumatic stress disorder, substance abuse disorder or sexual dysfunction including premature ejaculation) The use of the compounds of the invention;

iii) use of a compound of the invention in the manufacture of a medicament for the treatment or prevention of premature ejaculation;

iv) depression, attention deficit hyperactivity disorder, obsessive-compulsive disorder, post-traumatic stress disorder, substance abuse disorder or premature ejaculation, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the invention. Methods of treating or preventing sexual dysfunction;

v) a method of increasing ejaculation delay comprising administering an effective amount of a compound of the invention to an increased ejaculatory latency desired by a male; And

vi) Compounds of the invention for the treatment or prevention of disorders involving the regulation of monoamine transporter functions (e.g. depression, attention deficit hyperactivity disorder, obsessive compulsive disorder, post-traumatic stress disorder, substance abuse disorder or sexual dysfunction including premature ejaculation) ,

vii) Compounds of the invention for treating premature ejaculation.

It is to be understood that all references to treatment herein include healing, alleviation and prophylactic treatment.

The compounds of the present invention may be administered alone or as part of a combination treatment. If a combination of active agents is administered, they can be administered simultaneously, separately or sequentially. In particular, the compounds of the present invention may be preferably combined with the following components for the treatment of PE:

i) alpha-blockers (eg phentolamine, doxazosin, tamsulosin, terrazosin, prazosin and Example 19 of WO 9830560). Evidence for alpha-blockers to treat premature ejaculation is as follows. Muscle movement of the ejaculatory smooth muscle (vessel closure, seminal vesicles and urethra) is regulated by the sympathetic nervous system through the release of noradrenaline. Noradrenaline acts on the alpha 1 adrenoreceptor, which stimulates muscle contraction and leads to sperm followed by ejaculation. Thus, blocking the receptor will inhibit ejaculation.

ii) Apomorphine—Teaching about the use of apomorphine as a medicament can be found in US Pat.

iii) Dopamine D2 agonists (eg, Premiprixal, Pharmacia Upzon Compound No. PNU95666).

iv) melanocortin receptor agonists (e.g. Melanotan II)

v) PGE 1 receptor agonists (eg alprostadyl).

vi) monoamine transporter inhibitors, in particular noradrenaline reuptake inhibitors (NRIs) (eg Reboxetine), other serotonin reuptake inhibitors (SRIs) (eg paroxetine) or dopamine reuptake inhibitors (DRIs).

vii) 5-HT3 antagonists (eg ondansetron and granistron). The basis for the 5-HT3 antagonist for treating premature ejaculation is as follows. The 5-HT3 receptor present in the lumen posterior to the urethra is stimulated by 5-HT in semen during lacrimal tract, leading to sensitization of the spinal cord relaxation pathway leading to ejaculation. Thus, antagonists will prevent this sensitization and delay ejaculation.

viii) PDE inhibitors and in particular PDE5 inhibitors (eg, PDE2 (eg, erythro-9- (2-hydroxy-3-nonyl) -adenine) and Example 100 of EP 0771799, incorporated herein by reference); 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 BA38-9456 or IC351 (see following structure, Icos Lilly). Evidence for PDE inhibitors to treat premature ejaculation is as follows. The cAMP and cGMP levels of ejaculatory smooth muscle control muscle elasticity of these ejaculatory muscles to delay ejaculation.

ix) potassium channel opener

x) P2X purinergic receptor antagonists

xi) endothelin receptor antagonist

For human use, the compounds of the present invention may be administered alone, but in human therapy it will generally be administered with a suitable pharmaceutical excipient, diluent or carrier selected for the desired route of administration and standard pharmaceutical practice.

For example, the compounds of the present invention may be used in oral, buccal or sublingual tablets, capsules (soft gel capsules), for immediate-, delayed-, modified-, sustained-release, dual-, controlled release- or pulsatile delivery applications. It may be administered in the form of obules, elixirs, solvents or suspensions, which may contain fragrances or coloring agents. The compounds of the present invention can also be administered via rapid dispersion or rapid dissolution of the dosage form.

The tablets include excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine and starch (preferably corn, potato or tapioca starch), sodium starch glycolate, croscarmellose sodium and certain complexes. Disintegrants such as silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. In addition, lubricants such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.

Solid compositions of a similar type may also be used as fillers in gelatin capsules. Preferred excipients in this regard are lactose, starch, cellulose, lactose or high molecular weight polyethylene glycols. In the case of aqueous suspensions and / or elixirs, the compounds of the present invention and pharmaceutically acceptable salts thereof are prepared with various sweeteners or fragrances, pigments or dyes, emulsifying and / or suspending agents, and water, ethanol, propylene glycol And diluents such as glycerin, and combinations thereof.

Modified release and pulsatile release dosage forms are excipients, such as those described for immediate release dosage forms, with additional excipients that act as release modifiers (which may be included in or coated on the body of the device). It may contain these. Release rate modifiers include hydroxypropylmethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, polyethylene oxide, xanthan gum, carbomer, ammonio methacrylate copolymer, hydrogenated castor oil, carnauba Waxes, paraffin waxes, cellulose acetate phthalates, hydroxypropylmethyl cellulose phthalates, methacrylic acid copolymers and mixtures thereof, but is not limited thereto. Modified release and pulsatile release dosage forms can contain one or a combination of controlled release excipients. Release rate controlling excipients may be present in dosage forms, ie, in a substrate and / or on a dosage form, ie, on a surface or a coating.

Fast disperse or dissolution dosage forms (FDDFs) may contain the following ingredients: aspartame, acesulfame potassium, citric acid, croscarmellose sodium, crospovidone, diascorbic acid, ethyl acrylate, ethyl cellulose, gelatin, hydroxy Propylmethyl cellulose, magnesium stearate, mannitol, methyl methacrylate, mint fragrance, polyethylene glycol, fumed silica, silicon dioxide, sodium starch glycolate, sodium stearyl fumarate, sorbitol, xylitol. The term dispersion or dissolution as used herein to describe FDDFs depends on the solubility of the drug used. That is, rapid dispersible dosage forms can be prepared when the drug is insoluble, and rapid dissolution dosage forms can be prepared when the drug is soluble.

In addition, the compounds of the present invention may be administered parenterally, eg, intravenously, intraarterally, intraperitoneally, subarachnoid, intraventricular, intraurethral, intrasternal, intracranial, intramuscular or subcutaneous, May be administered. For such parenteral administration, they are best used in the form of sterile aqueous solutions which may contain enough substances or glucose to make the solution isotonic with the blood. The aqueous solution should be suitably buffered (preferably to pH 3-9) if necessary. Preparation of suitable parenteral formulations under sterile conditions can be readily accomplished by standard pharmaceutical techniques known to those skilled in the art.

The following dosage levels and other dosage levels herein are for an average human subject weighing about 65-70 kg body weight. The skilled person will readily be able to determine the dosage level required for subjects of corresponding body weight outside this range, such as children and older people.

For oral and parenteral administration to human patients, the daily dosage level of a compound of the present invention or a salt or solvate thereof will generally be between 10 and 500 mg (single or divided doses).

Thus, for example, tablets or capsules of the compounds of the present invention may contain from 5 mg to 250 mg of the active compound, if necessary, when administered once or two or more times. In either case, the physician will determine the actual dosage best suited for any individual patient, which will vary with the age, weight and response of the particular patient. The dosage is an example of an average case. Thus, there may be individual examples where a higher or lower dosage range is reasonable, and such is within the scope of the present invention. The skilled person will also appreciate that in the treatment of certain symptoms (including PE), the compounds of the invention may be administered in a single dose as "as required" (ie, as required or desired).

Exemplary Tablet Formulations

In general, tablet formulations may contain from about 0.01 mg to 500 mg of a compound of the present invention, but the weight range of the tablet may be from 50 mg to 1000 mg. An exemplary formulation of one 10 mg tablet is as follows:

ingredient % w / w

Compounds of the Invention10.000 *

Lactose 64

Starch

Croscarmellose Sodium3.000

Magnesium Stearate1.500

* The amount is usually adjusted according to drug activity.

The compounds of the invention may be administered intranasally or by inhalation, in the form of dry powder inhalers, or suitable propellants such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoro-ethane, Hydrofluoroalkanes (e.g., 1,1,1,2-tetrafluoroethane (HFA 134A ™) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA) ]), Carbon dioxide or other suitable gas, which is conveniently delivered in the form of providing aerosol spray from a pressurized vessel, pump, nebulizer or nebulizer, in the case of a pressurized aerosol, the dosage unit is a weighed amount. The pressure vessel, pump, nebulizer or medical nebulizer can be determined by providing a valve for the delivery of a liquid, using a solution or suspension of the active compound, for example a liquid using a mixture of ethanol and propellant as a solvent. And may additionally contain lubricants (eg sorbitan trioleate) Capsules and cartridges (eg made of gelatin) for use in inhalers or blowers are suitable such as lactose or starch It can be formulated to contain a powder base and a powder mix of a compound of the invention.The aerosol or dry powder formulation may be formulated at each weighed dose or " puff to contain 1 to 50 mg of the compound of the invention for delivery to a patient. It is desirable to have a total daily dose in the range of 1 to 50 mg for aerosol, which can be administered throughout the day, in single doses, or more typically in divided doses.

The compounds of the present invention may also be formulated for delivery via an atomizer. Formulations for nebulizer devices may contain solubilizers, emulsions or suspending agents: water, ethanol, glycerol, propylene glycol, low molecular weight polyethylene glycols, sodium chloride, carbon fluoride, polyethylene glycol ethers, sorbitan trioleate, Oleic acid.

Alternatively, the compounds of the invention may be administered in the form of suppositories or pessaries, or they may be topically applied in the form of gels, hydrogels, lotions, solutions, creams, ointments or spray powders. The compounds of the present invention may also be administered by skin or transdermal, for example, using skin patches. They may also be administered by the ocular, pulmonary or rectal route.

For ophthalmic use, the compounds may be formulated in finely divided suspensions in isotonic pH adjusting sterile saline, optionally with preservatives such as benzylalkonium chloride, or may be formulated as solutions in isotonic pH adjusting sterile saline. Can be. Alternatively, they may be formulated in an ointment such as petrolatum.

For topical application to the skin, the compounds of the invention may be formulated as suitable ointments containing the active compounds suspended or dissolved in mixtures with one or more of the following materials: mineral oil, liquid petrolatum, white petrolatum , Propylene glycol, polyoxyethylene polyoxypropylene compound (emulsifies wax and water). Alternatively, they may be formulated, for example, as suitable lotions or creams suspended or dissolved in a mixture of one or more of the following materials: mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl Esters, waxes, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

The compounds of the present invention may also be used in combination with cyclodextrins. Cyclodextrins are known to form inclusion and non-inclusion complexes with drug molecules. Formation of the drug-cyclodextrin complex can change the solubility, dissolution rate, bioavailability and / or stability properties of the drug molecule. Drug-cyclodextrin complexes are generally useful for most dosage forms and administration routes. As an alternative to direct complexation with the drug, cyclodextrins can be used as auxiliary additives such as carriers, diluents or solubilizers. 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, the daily dosage level of a compound of the present invention will be from 0.01 to 30 mg / kg (single or divided dose), with 0.01 to 5 mg / kg being preferred. Thus, tablets, if appropriate, will contain from 1 mg to 0.4 g of compound for two or more administrations in a single or at a time. The physician will in any case determine the actual dosage that will be best suited for any particular patient, which will vary depending on the age, weight and response of the particular patient. The dosage is of course only an example of an average case, and higher or lower doses may be justified, as such is within the scope of the present invention.

Oral administration is preferred. Preferably the administration takes place just before the effect is required.

For veterinary use, the compounds of the present invention are administered as suitably acceptable formulations in accordance with conventional veterinary practice, and the veterinarian will determine the route of administration and dosage regimen that will be most suitable for the particular animal.

Thus, according to a further aspect, the present invention provides a medicament containing a compound of the present invention and a pharmaceutically acceptable adjuvant, diluent or carrier.

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

Arbocel (TM) filter agent

brwide

Boctert-butoxycarbonyl

CDIcarbonyldiimidazole

δ chemical shift

ddouble line

Δ column

DCCI dicyclohexylcarbodiimide

DCM dichloromethane

DMFN, N-dimethylformamide

DMSO dimethyl sulfoxide

ES ⁺ Electrospray Ionization Positive Scan

ES ^- Electrospray Ionization Voice Scan

Ex Example

h hours

HOBt1-hydroxybenzotriazole

HPLC High Pressure Liquid Chromatography

m / z mass spectrum peak

min minutes

MS mass spectrum

NMR nuclear magnetic resonance

Prec Precursor

Prep Production Example

qquartet

single line

t triplet

Tftrifluoromethanesulfonyl

TFAtrifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography

TS ⁺ Thermal Spray Ionization Positive Scan

WSCDI1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride

¹ H nuclear magnetic resonance (NMR) spectra were identical to the proposed structures in all cases. Characteristic chemical shifts (δ) use common abbreviations for indicators of the main peak (eg, s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, wide) It is provided in low field parts fraction from tetramethylsilane.

The following abbreviations have been used for conventional solvents: CDCl ₃ , deuterium chloroform; DMSO, dimethyl sulfoxide. The abbreviation psi means pounds per square inch, and LRMS means low resolution mass spectroscopy. When thin layer chromatography (TLC) is used, this refers to silica gel TLC using silica gel 60 F ₂₆₄ plates, where R _f is the distance traveled by the compound divided by the distance traveled by the solvent on the TLC plate. Melting point was determined using Perkin Elmer DSC7 (heating rate 20 ° C / min).

If indicated, the compounds were characterized as their hydrochloride salts. An exemplary method for the formation of hydrochloride is given in Example 12. The procedure can be performed with other solvents such as diethyl ether or DCM.

Starting materials were purchased from a commercial company [Aldrich Chemical Co, Lancaster Synthesis Ltd or Acros Organics].

Example 1

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

The amide of Preparation Example 8 (760 mg, 2.07 mmol) was slurried in THF (10 ml) 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 was heated to reflux under a dry nitrogen atmosphere for 5 hours. The reaction was cooled to room temperature and carefully treated with 6M HCl solution (6 ml). The resulting mixture was heated to reflux for 30 minutes. After cooling to room temperature, the mixture was diluted with water (10 ml) and potassium carbonate solid was added carefully to make it basic. The aqueous layer was extracted with EtOAc (20 ml), which gave a precipitate to the organic layer and the aqueous layer was further extracted with DCM (2 × 20 ml). The EtOAc fraction was washed with 2M NaOH (20 ml) to give a clean two-phase separation and the basic layer was extracted with DCM (4 × 25 ml). All organic fractions were collected, washed with brine (20 ml), dried (MgSO ₄ ) and evaporated to give a colorless oil. Flash chromatography [SiO ₂ ; 95: 5: 0.5 to 90: 10: 1 (EtOAc / MeOH / 880 NH ₃ )] to give a white powder (646 mg, 89%) of the desired amine.

δ _H (300 MHz, d ₆ -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 (1 H, t), 7.98 (1 H, d); MS m / z (TS ⁺ ) 353 (MH ⁺ ).

Compounds of formula (Id), ie, compounds of formula (I) shown in Table 1 below, wherein R ¹ is methyl, R ² is hydrogen, and R ⁵ is —SO ₂ NH ₂ , are similar to Example 1 from the indicator precursor Prepared.

<Continued in Table 1>

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)

Formaldehyde (37% aqueous solution, 282 μl, 3.76 mmol) was added to a suspension of secondary amines (409 mg, 1.16 mmol) from Example 1 in DCM (20 mL) at room temperature under nitrogen. The resulting mixture was stirred for 15 minutes, then sodium triacetoxyborohydride (984 mg, 4.64 mmol) was added. The resulting reaction mixture was stirred for 5 hours, then made basic with saturated NaHCO ₃ solution (10 ml) and extracted with DCM (3 × 20 ml). The organic layer was washed with brine (10 ml), dried (MgSO ₄ ) and evaporated to a yellow oil. This was purified by HPLC (Phenomonex Luna C ₁₈ 75 × 4.6 mm column, CH ₃ CN, H ₂ O, TFA). Fractions containing the main product were evaporated and the residue was treated with saturated NaHCO ₃ solution (5 ml) and extracted with DCM (3 × 30 ml). The collected organic fractions were washed with brine (30 ml), dried (MgSO ₄ ) and evaporated to give the white foam of Example 12 (155 mg, 36%); δ _H (300 MHz, CDCl ₃ ) 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 (1 H, d), 8.08 (1 H, s); MS m / z (TS ⁺ ) 367 (MH ⁺ ).

Side products were also obtained after HPLC purification. Relevant fractions were evaporated and the residue was treated with saturated NaHCO ₃ solution (5 ml) and extracted with DCM (2 × 30 ml). The collected organic fractions were washed with brine (30 ml), dried (MgSO ₄ ) and evaporated to give a gum. This was taken up in DCM (5 ml), treated with 1 M HCl ether solution (2 ml) and evaporated to afford the white powder of Example 13 (39 mg, 9%); HCl salt: δ _H (CDCl ₃ , 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, column chromatography [SiO ₂ ; using 1 equivalent of formaldehyde relative to the amine of Example 1; 95: 5: 0.5 to 90: 10: 1 (EtOAc / MeOH / 880 NH ₃ )] to give the compound of Example 12 in 78% yield. It was taken up in EtOAc and converted to HCl salt by addition of 1M HCl ether solution. The resulting precipitate was filtered and dried in vacuo to give the HCl salt of Example 12 (melting point 188 ° C.).

Alternatively, Example 12 may be formed from the amine of Example 1 by the method of Example 110.

Example 12 was also prepared as follows.

A solution of the hydrochloride salt of Example 94 (20 g) in trifluoroacetic acid (100 ml) was added slowly to the solution of chlorosulfonic acid (72 g) while maintaining the temperature at 0-5 占 폚. After 1 hour, the reaction mixture was slowly quenched with 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 collected organic layer was 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 pentachloride (28.8 ml) was added to this slurry. The solution was then heated to reflux overnight. The reaction mixture was cooled to room temperature and quenched into a stirred mixture of ammonia (90 ml), dichloromethane (240 ml) and water (100 ml) while maintaining the temperature between 0 ° C and 10 ° C. The mixture was adjusted to pH above 8 with ammonia (if needed). After 15 minutes, the reaction mixture was allowed to warm to room temperature and the layers separated. The organic layer was concentrated in vacuo to give a dark brown oil. It was dissolved in acetone (100 ml), slurried with carbon (Norit SX plus, 50% w / w), filtered and treated once more with carbon (Norit SX plus, 50% w / w). This mixture was filtered again, the solution was concentrated and replaced with water (200 ml). The slurry 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-benzooxathiin-7-yloxy) -3-[(dimethylamino) methyl] -benzenesulfonamide and 4- (2,3-dihydro-1 , 4-benzooxathiin-7-yloxy) -3-[(dimethylamino) methyl] -N-methylbenzenesulfonamide

This compound was prepared in a similar manner to Examples 12 and 13 starting from the secondary amine of Example 5.

Compounds of formula (Ie), ie compounds of formula (I) wherein R ¹ and R ² are methyl and R ⁵ is —SO ₂ NH ₂ , shown in Table 2 below, were prepared according to Example 12 from the indicated precursors. N-methyl sulfonamides similar to Example 13 were not isolated in this reaction and did not require HPLC purification.

<Continued in Table 2>

Example 24

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

The title compound was prepared from the secondary amine of Example 9 by the method of Example 110;

Example 25

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

Dimethylamine hydrochloride (424 mg, 5.2 mmol), Et ₃ N (725 μl, 5.2 mmol), AcOH (298 μl, 5.2 mmol) and sodium triacetoxyborohydride (1.10 g, 5.2 mmol) were treated with THF (15 ml) and To a solution of aldehyde (1.00 g, 3.47 mmol) of Preparation 24 in DCM (15 ml) was added and the mixture was stirred at rt for 16 h. After the solvent was removed in vacuo, the residue was taken up in 2M HCl (20 ml) and washed with ether (2 × 15 ml). The aqueous layer was made basic with NaOH pellets and extracted with DCM (4 × 20 ml). The collected DCM extracts were washed with brine, dried (MgSO ₄ ) and evaporated. The residue was taken up in a small amount of DCM and treated with 1M HCl ether solution to precipitate the HCl salt. This was filtered, washed with ether and dried to give a white solid (936 mg) having triethylamine hydrochloride as an impurity. It was dissolved in 1M NaOH (10 ml) and extracted with EtOAc (3 × 15 ml). The organic extract was washed with brine (10 ml), dried (MgSO ₄ ), evaporated, redissolved in EtOAc and evaporated again. The residue was taken up in DCM and treated with 1M HCl ether solution to precipitate the HCl salt which was filtered off, washed with ether and dried to give a white solid (635 mg, 52%); δ _H (CDCl ₃ , 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 (1 H, s), 6.90 (2 H, m), 7.18 (1 H, d), 7.65 (1 H, s), 12.83 (1 H, brs); MS m / z (TS ⁺ ) 318 (MH ⁺ ).

Compounds of formula If, ie compounds of formula I, shown in Table 3 below, wherein R ¹ and R ² are methyl, were prepared according to Example 25 from the indicated precursors.

<Continued in Table 3>

Example 34

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

Chlorosulfonic acid (106 μl, 1.6 mmol) was added to a solution of Example 29 (50 mg, 0.16 mmol) in DCM (2 mL) and the mixture was stirred at rt for 3 h. Water (2 ml) was added and the mixture was adjusted to pH 6 with saturated aqueous NaHCO ₃ solution and extracted with DCM (2 × 5 ml). The organic extract was dried (MgSO ₄ ), filtered and a solution of 8M methylamine in EtOH (0.3 ml) was added. After standing for 1 hour, the solvent was removed in vacuo and the residue was subjected to column chromatography [SiO ₂ ; 95: 5: 0.5 (DCM / MeOH / 880 NH ₃ )]. The product was taken up in EtOAc and converted to HCl salt by addition of HCl ether solution. The desired product (3 mg, 5%) was obtained as a hygroscopic solid;

Example 35

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

Trifluoroacetic anhydride (0.96 ml, 6.8 mmol) was added to a solution of Example 48 amine (900 mg, 3.4 mmol) and triethylamine (1.9 ml, 13.6 mmol) in CH ₂ Cl ₂ (15 ml) at 0 ° C. The mixture was stirred for 5 minutes. The solvent was removed in vacuo and the residue was partitioned between CH ₂ Cl ₂ and water. The organic layer was washed with brine, dried (MgSO ₄ ) and evaporated to give a yellow oil which was used without further purification. This crude oil was taken up in CH ₂ Cl ₂ (20 ml), cooled to 0 ° C. and ClSO ₃ H (2.4 ml, 36.1 mmol) was added dropwise. The mixture was allowed to warm to rt, stirred for 4 h and then poured into ice water. The mixture was extracted with CH ₂ Cl ₂ (50 ml) and the organic layer was treated with saturated NH ₃ solution in MeOH (10 ml). After stirring for 4 hours, 1 M LiOH (20 ml) was added and stirring continued overnight. TLC analysis showed the reaction was not complete, therefore additional 1M LiOH (50 ml) was added and the mixture was stirred for 2 hours. The mixture was acidified to pH 8 with 2M HCl and extracted with CH ₂ Cl ₂ (3 × 200 ml). The collected organic extracts were dried (MgSO ₄ ), evaporated and the residue triturated with ether to give the title compound (500 mg, 43%) as a yellow solid;

Example 36

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

Aldehyde (1.10 g, 3.28 mmol) of Preparation Example 19 was dissolved in a solution of 8M methylamine in EtOH (4.1 ml, 32.8 mmol) and stirred for 5 hours, followed by NaBH ₄ (372 mg, 9.83 mmol) in 30 minutes. Divided several times over. EtOH (100 ml) was added and the reaction stirred for 16 h and then concentrated in vacuo. The residue was quenched with 6M HCl until 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%); δ _H (CDCl ₃ , 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 (1 H, s), 7.19 (1 H, d), 7.39 (1 H, d), 7.80 (1 H, s); MS m / z (ES ⁺ ) 350, 352 (MH ⁺ ).

Compounds of formula (Ig), ie compounds of formula (I) wherein R ¹ and R ⁴ are hydrogen and R ² is methyl, shown in Table 4 below, were prepared according to Example 36 from the indicated precursors. For those compounds isolated as free base, after the reaction solvent was removed in vacuo, the reaction mixture was partitioned between 2M HCl and ether. The aqueous layer was then basified, extracted with DCM, the DCM layer was dried (MgSO ₄ ) and evaporated to afford the desired secondary amine.

<Continued in Table 4>

^a -2M methylamine in MeOH (2 equiv) and Ti (O ⁱ Pr) ₄ (2 equiv) in EtOH (aldehyde -0.1M solution) are used in place of the metalamine in EtOH. After isolation of the free base, it is converted to the maleate salt by standard methods.

Example 50

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

The bromide of 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) in acetonitrile (15 ml) and A mixture of tri-o-tolylphosphine (33.4 mg, 0.11 mmol) was heated to reflux for 72 hours. After cooling to rt, the solvent was removed in vacuo and the residue was partitioned between EtOAc (50 ml) and 2M HCl (50 ml). The aqueous phase was basified with 2M NaOH and extracted with EtOAc (3 × 50 ml). The collected base extracts were dried (MgSO ₄ ) and evaporated. The residue was subjected to column chromatography [SiO ₂ ; 96: 4: 0.5 (increased polarity to 90: 10: 1 in DCM / MeOH / 880 NH ₃ ) to afford the title compound (196 mg, 50%) as a beige foam;

Example 51

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

A solution of Sml ₂ in THF (0.1M, 21.9ml, 2.19mmol) was added to a solution of Example 50 alkene (194mg, 0.55mmol) in THF (5ml) under nitrogen, followed by water (1ml). After stirring for 10 minutes at room temperature, the reaction was quenched with 6M NaOH (10 ml) and stirred for 30 minutes. The organic phase was separated and the aqueous phase extracted with EtOAc (2 x 20 ml). The collected organic layer was dried (MgSO ₄ ) and evaporated to give an oil, which was subjected to column chromatography [SiO ₂ ; 93: 7: 1 (DCM / MeOH / 880 NH ₃ ) to 90: 10: 1 increased polarity] to afford the title compound (90 mg, 46%);

Compounds of formula If, ie, compounds of formula I, wherein R ¹ and R ² are methyl, shown in Table 5 below, were prepared according to Preparation 50 from the indicated precursors.

<Formula If>

Compounds of formula If, ie, compounds of formula I, wherein R ¹ and R ² are methyl, shown in Table 6 below, were prepared according to Preparation 55 from the indicated precursors.

Compounds of formula If, ie compounds of formula I, wherein R ¹ and R ² are methyl, shown in Table 7 below, were prepared according to Preparation 59 from the indicated precursors.

Compounds of formula If, ie compounds of formula I, wherein R ¹ and R ² are methyl, shown in Table 8 below, were prepared according to Preparation 69 from the indicated precursors.

Example 60

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

The protected amine of Preparation 59 (317 mg, 0.76 mmol) was dissolved in a saturated solution of HCl in DCM (25 ml) at 0 ° C., left for 1 hour, and then neutralized by addition of a 10% aqueous solution of K ₂ CO ₃ (25 ml). I was. Water (50 ml) was added and the layers separated. The aqueous layer was extracted with DCM (25 ml) and the collected organic layers were dried (MgSO ₄ ) and evaporated. The resulting oil was dissolved in EtOAc (10 ml) and treated with 1M HCl (1 ml) ether solution. The white precipitate was collected by filtration and dried in vacuo to give the desired product (211 mg, 77%);

Compounds of formula Ig, ie compounds of formula I, shown in Table 9 below, wherein R ¹ and R ⁴ are hydrogen and R ² is methyl, were prepared according to Example 60 from the indicated precursors.

<Formula Ig>

<Continued in Table 9>

Example 77

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

The compound of Example 77 was prepared from the Boc protected sulfonamide of Preparation 74 by the method of Example 60; HCl salts;

Example 78

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

Zn (CN) ₂ (700 mg, 5.96 mmol) and Pd (PPh ₃ ) ₄ (1.97 g, 1.7 mmol) were added to a solution of bromide (3.0 g, 8.52 mmol) of Example 44 in DMF (20 mL) and the mixture. Heated at 100 ° C. for 17 h. The reaction was cooled to rt, diluted with water (100 ml) and extracted with ether (2 × 100 ml, then 3 × 50 ml). The collected organic layers were washed with water (3 x 50 ml), dried (MgSO ₄ ) and evaporated to a yellow oil. Column chromatography [SiO ₂ ; 95: 5: 0.5 (DCM / MeOH / 880 NH ₃ )], but was unsuccessful and thus the material was chromatographed again [SiO ₂ ; Increased polarity from 50% pentane to 0% pentane in 95: 5: 0.5 (DCM / MeOH / 880 NH ₃ ) to give the product (1.275 g, 50%) as pale yellow oil. The sample was placed in DCM (5 ml) and treated with 1M HCl ether solution, and the HCl salt was collected by filtration as a white powder;

Example 79

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

The mixture of Example 78 nitrile (404 mg, 1.35 mmol) and KOH (304 mg, 5.42 mmol) in tert-butanol (10 ml) was heated to reflux under nitrogen for 1 hour. After cooling to room temperature, the solvent was removed in vacuo and the residue was partitioned between water (10 ml) and DCM (10 ml). The aqueous layer was extracted with DCM (4 × 20 ml) and the collected organic layers were washed with brine, dried (MgSO ₄ ) and evaporated. The residue was subjected to column chromatography [SiO ₂ ; 93: 7: 1 (DCM / MeOH / 800 NH ₃ )] to afford the desired product (376 mg, 88%) as a white foam.

Compounds of formula (Ih), ie compounds of formula (I) shown in Table 10 below, wherein R ¹ and R ² are methyl and R ⁴ is hydrogen, were prepared according to Example 12 from the indicated precursors.

<Continued in Table 10>

Example 94 was also prepared as follows.

A solution of product from Preparation 30 (200 g, 0.78 mmol) 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) were added successively to this mixture. The temperature was adjusted to 20 ° C. and after 3 hours sodium triacetoxyborohydride (246 g, 1.16 mol) was added (after 20 hours the work up was continued when the reaction was completed; Reference). Dichloromethane (2 L) was added and 8% sodium bicarbonate solution (0.9 L) was added over 0.5 h. The layers were separated and the organic layer was washed with water (1 L). The layers were separated again and the organic layer was concentrated. Ethyl acetate (0.27 L) was added and the solvent was removed while replacing 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 while maintaining the temperature below 10 ° C. After stirring for 1 h at a temperature below 5 ° C., the slurry was filtered, washed with ethyl acetate (3 × 0.2 L) and dried overnight in a vacuum oven at 50 ° C. to give the desired product as a solid powder (141.5 g, 56% Obtained). [X: If the reaction is not completed after 20 hours, further add dimethylamine hydrochloride (13 g, 0.16 mol) and triethylamine (43.4 g, 0.43 mol) in succession. After 2 hours at room temperature, add sodium triacetoxyborohydride (46 g, 0.22 mol). Leave for another 20 hours and walk up as described above.]

Compounds of formula (Ii), ie compounds of formula (I) wherein R ² is methyl, R ⁴ is hydrogen, and R ⁵ is —C (═O) NH ₂ shown in Table 11 below, are prepared in Example 79 from the precursors indicated. Prepared accordingly.

Example 103

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

The mixture of Example 27 nitro compound (2.0 g, 6 mmol), Fe powder (2.51 g, 44.9 mmol) and CaCl ₂ (300 mg, 2.7 mmol) in EtOH (20 ml) and water (4 ml) was heated to reflux for 20 hours. . After cooling to room temperature, the solvent was removed in vacuo and the residue was partitioned between brine (100 ml) and ether (100 ml). The aqueous layer was extracted with ether (50 ml) and the collected organic layers were dried (MgSO ₄ ) and evaporated to give the product (1.47 g, 81%) as orange oil;

Example 104

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

The title compound was prepared from the nitro compound of Example 28 by the method of Example 103;

Example 105

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

Nitrile (720 mg, 1.99 mmol) of Preparation Example 95 was dissolved in a BH ₃ .THF 1M solution in THF (10 ml, 10 mmol) and the mixture was heated to reflux for 3 hours. After cooling to room temperature, the reaction was quenched by the careful addition of MeOH (10 ml). The solvent was evaporated and the residue was treated with 6M HCl (10 ml) and heated to reflux for 1 hour. After cooling, the mixture was basified with 2MNaOH and the pH was adjusted to 7 with saturated aqueous NH ₄ Cl solution. The mixture was extracted with EtOAc (3 x 50 ml) and DCM (2 x 50 ml), the collected organic layers were dried (MgSO ₄ ) and evaporated to give beige foam (685 mg, 94%) which was used without further purification. Was done;

Compounds of formula Ij, ie compounds of formula ^I , shown in Table 12 below, wherein R ¹ , R ² and R ⁴ are hydrogen and R ⁵ is —NR ⁸ —SO ₂ Me are prepared according to Example 105 from the indicated precursors. Prepared.

Example 110

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

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 was stirred for 2 hours, then filtered and the residue was washed with ether. The filtrate was concentrated to ˜5 ml and a solution of Example 105 (411 mg, 1.1 mmol) primary amine in DCM (10 ml) was added. The mixture was stirred for 16 hours and then concentrated to give an oily residue. This crude oil was added to a solution of BH ₃ .THF in THF (1M, 20 ml, 20 mmol) and heated to reflux under N ₂ for 1.5 h. After cooling to room temperature, the reaction was quenched by the careful addition of MeOH (10 ml) and then concentrated in vacuo. The oily residue was treated with 6M HCl and heated to reflux for 30 minutes. After cooling to rt, the mixture was basified with K ₂ CO ₃ and extracted three times with DCM. The collected organic extracts were dried (MgSO ₄ ) and evaporated. The residue was subjected to column chromatography [SiO ₂ ; 90: 10: 1 (DCM / MeOH / 880 NH ₃ )] to give a colorless oil, which was poured into EtOAc (20 ml) and treated with 1M HCl ether solution (2 ml). After stirring for 1.5 hours, the solids were collected by filtration to give the title product (282 mg, 60%); δ _H (CD ₃ OD, 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 of Formula Ik, ie, compounds of Formula I, shown in Table 13 below, wherein R ¹ and R ⁴ are hydrogen, R ² is methyl, and R ⁵ is —NHSO ₂ Me are shown in Example 110 from the indicated precursors. Prepared accordingly.

Compounds of formula Im, ie compounds of formula I, shown in Table 14 below, wherein R ¹ and R ⁴ are hydrogen, R ² is methyl and R ⁵ is —NR ⁸ SO ₂ Me are prepared from the precursors indicated Prepared according to 110.

<Continued in Table 14>

^a -also prepared from Example 108 by the method of Example 110.

Compounds of Formula In, ie, compounds of Formula I, shown in Table 15 below, wherein R ¹ and R ² are methyl, R ⁴ is hydrogen, and R ⁵ is —NR ⁸ SO ₂ Me are prepared from the precursors indicated Prepared according to 12.

<Continued in Table 15>

Example 128

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

Methanesulfonyl chloride (371 μl, 4.79 mmol) was added to a solution of Example 103 aniline (725 mg, 2.4 mmol) and Et ₃ N (1 mL, 7.17 mmol) in DCM (10 mL) at 0 ° C. After stirring at 0 ° C. for 1 hour, the reaction was allowed to warm to room temperature and then the solvent was removed in vacuo. 2M NaOH (10 ml) was added to the residue and the mixture was stirred overnight. The resulting clear solution was neutralized with saturated aqueous NH ₄ Cl solution and extracted with DCM (2 × 30 ml). The collected organic layer was dried (MgSO ₄ ) and evaporated to give an oil. It was taken up in EtOAc (10 ml), 1M HCl ether solution was added to precipitate the HCl salt and the product (669 mg, 67%) was collected by filtration;

Compounds of Formula (Ip), ie, compounds of Formula (I) wherein R ¹ and R ² are methyl, R ⁴ is hydrogen and R ⁵ is —NHSO ₂ R ⁹ shown in Table 16, It was prepared according to.

Production Example

Preparation Example 1

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

5- (aminosulfonyl) -2-fluorobenzoic acid in THF (500 ml) at room temperature. Pharm. Bull. Carbonyldiimidazole (17 g, 105 mmol) under nitrogen was added to a solution of the preparation method (22.98 g, 105 mmol) according to 1995, 43, 582-7]. After stirring for 2.25 hours, a solution of methylamine in THF (2M, 70 ml, 140 mmol) was added dropwise and the reaction stirred for 18 hours. The crude reaction mixture was concentrated to a small volume and EtOAc (150 ml) was added to the resulting thick oil. The mixture was stirred and the particulate precipitate formed was collected by filtration. This crude product, which had imidazole as an impurity, was suspended in DCM (300 ml) and heated to reflux for 5 hours. After cooling to room temperature, the mixture was filtered to give the desired product (19.8 g, 81%) containing less than 2% (w / w) imidazole; ¹ H NMR δ _H (300 MHz, d ₄ -MeOH) 2.97 (3H, s), 7.40 (1H, t), 8.05 (1H, m), 8.29 (1H, d); MS m / z (TS ⁺ ) 250 (MNH ₄ ⁺ ).

Preparation Example 2

3-chloro-4- (methylsulfanyl) phenol

(i) Preparation of 2-Chloro-1- (methylsulfanyl) -4-nitrobenzene

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

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

To a mixture of the compound (14.08 g, 69 mmol) and water (60 ml) in acetic acid (300 ml) was added Fe powder (23 g, 412 mmol) and the reaction mixture was stirred until all starting material dissolved. After the mixture was left for 1.5 hours, acetic acid was removed under reduced pressure. The residue was taken up in saturated NaHCO ₃ (aq) (500 ml) and EtOAc (500 ml) and filtered through Arbocel®. The layers were separated, the aqueous layer was extracted with EtOAc (300 ml), the collected organics were washed with brine, dried (MgSO ₄ ) and the solvent removed in vacuo to afford the title compound (11.52 g, 96%) as a beige solid. ; δ _H (400 MHz, CDCl ₃ ) 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 ⁺ ).

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

The aniline (11.5 g, 66.2 mmol) was dissolved in minimum THF (-15 ml), water (500 ml) was added under vigorous stirring, followed by concentrated H ₂ SO ₄ (25 ml). The mixture was cooled in an ice water bath and a solution of NaNO ₂ (5.0 g, 72.5 mmol) in ice water (10 ml) was added by pipette below the surface of the reaction mixture. The reaction was stirred at 0 ° C. for 1.5 h and the resulting yellow / brown solution was decanted from the residual solid into a dropping funnel containing ice (˜200 g). This solution was added to a mixture of vigorously stirred Cu (NO ₃ ) ₂ (230 g, 0.99 mol) and Cu ₂ O (8.52 g, 67.4 mmol) in water (1 L) at constant rate over 7 minutes at room temperature. After completion, the mixture was stirred for an additional 15 minutes and then extracted with ether (500 ml). The remaining red / brown solid in the reaction flask was placed in MeOH (100 ml), diluted with ether (300 ml) and poured into the aqueous layer from above. The ether layer was separated and the collected organic layer was extracted with 1M NaOH (3 × 100 ml). The aqueous extract was acidified with concentrated HCl and then extracted with ether (2 × 150 ml). The ether layer was 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; δ _H (400 MHz, CDCl ₃ ) 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 (MH ⁺ ).

Preparation Example 3

3-fluoro-4- (methylsulfanyl) phenol

This compound was prepared using a method analogous to that described for Preparation Example 2 starting with commercially available 3,4-difluoronitrobenzene;

Preparation Example 4

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

1,2-dibromoethane (2.3 ml, 26.7 mmol) and K ₂ CO ₃ (8.21 g, 59.4 mmol) are slurried with acetone (250 ml) and _2- sulfanyl-1,4 in acetone (50 ml) A solution of -benzenediol (prepared according to J. Org. Chem. 1990, 55, 2736) (4.22 g, 29.7 mmol) was added to this stirred mixture over 4 hours. After the addition was completed, stirring was continued for an additional 10 hours, and then the solvent was 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 collected organic layers were dried (MgSO ₄ ) and evaporated. Column chromatography [SiO ₂ ; 9: 1 (pentane / EtOAc)] gave the title compound (2.48 g, 55%) as pale orange oil;

Preparation Example 5

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

The title compound was prepared in a similar manner to the compound of Preparation 4 starting from 4-sulfanyl-1,3-benzenediol (prepared according to J. Org. Chem. 1979, 26, 4971-4973); δ _H (CDCl ₃ , 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 ⁺ ).

Preparation Example 6

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

1,3-dihydro-2-benzofuran-5-amine (prepared according to US Pat. No. 4000286) (2.7 g, 20 mmol) was dissolved in a mixture of water (300 ml) and concentrated H ₂ SO ₄ (21 ml) and , Cooled to 0 ° C. and NaNO ₂ (1.43 g, 20.7 mmol) in water (10 ml) was added over 15 minutes. After stirring for 1 hour at 0 ° C., the mixture was stirred at 10 ° C. for 30 minutes and urea was added until stark test was observed with starch / KI paper. The solution was then poured into a mixture of water (180 ml) and concentrated H ₂ SO ₄ (12.6 ml) at 90 ° C. over 2 minutes and stirred at this temperature for 1.5 hours. The hot mixture was then filtered and then cooled to room temperature. The aqueous mixture was extracted with EtOAc (2 × 100 ml) and the collected organic layers were dried (MgSO ₄ ) and evaporated to afford the title phenol (974 mg, 36%) as a cream solid. δ _H (CDCl ₃ , 400 MHz) 5.03 (4H, s), 6.71 (2H, m), 7.08 (1H, d).

Preparation Example 7

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

(i) Preparation of 2,3-dihydro-1-benzothiophen-6-ol 1,1-dioxide

2,3-dihydro-1-benzothiophene-6-amine 1,1-dioxide in water (500 ml) and concentrated H ₂ SO ₄ (35 ml). Am. Chem. Soc. 1955, 77, 5939] (15.73 g, 85.8 mmol) was warmed until solution. The mixture was cooled to 0 ° C., then a solution of NaNO ₂ (6.22 g, 90 mmol) in water (15 ml) was added over 5 minutes. The reaction was stirred at 0 ° C. for 1 hour and then urea was added to remove excess nitrile until a negative test was obtained with starch / KI paper. The mixture was allowed to warm to room temperature and then added to a mixture of concentrated H ₂ SO ₄ (55 ml) and water (750 ml) at 90 ° C. with stirring. The reaction was reheated to 90 ° C. and stirred at this temperature for 30 minutes. The hot reaction mixture was filtered through Arbocel® and then stirred overnight at room temperature. The aqueous mixture was extracted with ether (2.5 L), then extracted with EtOAc (5 x 500 ml), the collected organic layers were dried (MgSO ₄ ) and evaporated to afford the desired phenol (12.7 g, 80%), which was added Used without purification; δ _H (CDCl ₃ , 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 (MH ⁺ ).

(ii) Preparation of 2,3-dihydro-1-benzothiophen-6-ol

A solution of sulfone (4.84 g, 26.3 mmol) from step (i) in toluene (100 ml) and THF (70 ml) was added to a solution of DIBAL (1M, 100 ml, 100 mmol) in toluene and the mixture was heated to reflux for 16 h. . After cooling to room temperature, EtOH (75 ml) was added carefully and then water (100 ml) was added with stirring. 6M HCl was added to the resulting thick suspension and the organic layer was separated. The aqueous layer was extracted with EtOAc (3 x 150 ml) and the collected organic layers were dried (MgSO ₄ ) and evaporated to a beige solid. Column chromatography [SiO ₂ ; Purification by increasing the polarity from DCM / MeOH / 880 NH ₃ (97: 3: 0.25) to (95: 5: 0.5) afforded the desired title phenol as a beige solid (1.85 g, 53%); δ _H (CD ₃ OD, 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 (MH ⁺ ).

Preparation Example 8

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

Fluoroamide (732 mg, 3.15 mmol) of Preparation Example 1 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). It was. The mixture was heated to 100 ° C. for 5 hours. The solvent was evaporated off under reduced pressure and the residue was treated with 2M HCl (10 ml). The resulting suspension was extracted several times with dichloromethane. The collected dichloromethane layer contained a suspension and evaporated to leave a solid residue. The residue was triturated with ether (5 ml) and the residual solid was washed with ether (3 x 10 ml) to yield an off-white solid (765 mg, 66%).

Preparation Example 9-18

Compounds of formula Va, ie, compounds of formula V wherein T is -C (= 0) NHMe, R ⁴ is hydrogen, and R ⁵ is -SO ₂ NH ₂ , shown in Table 17 below are sulfonamides of Preparation Example 1 And according to Preparation Example 8 using the indicated phenol.

<Continued in Table 17>

Preparation Example 19

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

5-bromo-2-fluorobenzaldehyde (1.08 g, 5.32 mmol), 5-hydroxy-2,3-dihydrobenzothiophene in DMF (5 ml) (Synth. Commun. 1991, 21, 959- 808) (808 mg, 5.31 mmol) and K ₂ CO ₃ (1.47 g, 10.6 mmol) were heated to 90 ° C. for 16 h. After cooling to rt, the mixture was partitioned between water (50 ml) and ether (50 ml) and the aqueous layer was extracted with ether (50 ml). The collected organic extracts were washed with water (50 ml), dried (MgSO ₄ ) and evaporated. The residue was subjected to column chromatography [SiO ₂ ; 9: 1 (pentane / EtOAc)] and then triturated with ether to give the product (1.1 g, 62%) as a pale yellow solid; δ _H (CDCl ₃ , 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 (1 H, d), 8.00 (1 H, s), 10.43 (1 H, s).

The compound of formula II shown in Table 18 was prepared according to Preparation Example 19 by reacting the required 2-fluorobenzaldehyde with the indicated phenol. In most cases the crude reaction product after aqueous workup was used directly in the next step without further purification.

<Continued in Table 18>

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

The product from Preparation Example 30 was also prepared as follows.

Potassium carbonate (334.1 g, 2.42 mol) and 4- (methylthio) -m-cresol (273.4 g, 1.77 mol) were added successively to DMF (2 L). Then 2-fluorobenzaldehyde (200 g, 1.61 mol) was added to this slurry and the mixture was heated at a temperature in the range of 100 to 110 ° C. After 48 hours, the reaction mixture was cooled to room temperature and water (1.2 L) was added. The solution was cooled to below 10 ° C., the pH was adjusted to 5 with concentrated HCl (0.37 L) and the temperature kept 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 was distilled off to remove water equipotentially. Fresh dichloromethane was added as needed. The dry dichloromethane solution was then concentrated in vacuo to afford the crude product as an oil (422 g, 100%).

Compounds of formula (IX) shown in Table 19 below were prepared according to Preparation Example 19, using either chloro-nitrobenzaldehyde or 2-chloro-5-nitrobenzonitrile and the indicated phenols. For this reaction, generally shorter reaction times (about 2 to 3 hours) were sufficient to achieve good conversion. In most cases the crude reaction product after aqueous workup was used directly in the next step without further purification.

Preparation Example 44

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

The hydrochloride salt of Example 36 (1.04 g, 2.7 mmol) was slurried with DCM (12 mL), Et ₃ N (750 μL, 5.38 mmol) was added, followed by di-tert-butyl dicarbonate (766 mg, 3.51 mmol). Was added. After stirring for 20 minutes at room temperature, the reaction was quenched by the addition of 0.2 M HCl (20 ml). The well shaken mixture was separated and the aqueous layer was extracted with DCM (10 ml). The collected organic layers were dried (MgSO ₄ ) and evaporated to afford the product (considered quantitative yield) as a colorless oil which was used without further purification;

The compounds of formula (X) shown in Table 20 below were prepared according to Preparation 44 starting from the precursors indicated.

<Continued in Table 20>

Preparation 49

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

The title compound was prepared from the bromide of Preparation 47 by the method of Example 78;

Preparation 50

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

A mixture of bromide (1.22 g, 2.7 mmol), Et ₃ N (1.13 ml, 8.11 mmol) and dichlorobis (triphenylphosphine) palladium (II) (190 mg, 0.27 mmol) of Preparation 44 in MeOH (14 ml) Heated at 80 ° C. under a pressure of 100 psi of CO for 18 h. Analysis by TLC indicated that the reaction was incomplete and an additional amount of catalyst (190 mg, 0.27 mmol) was added and the mixture was heated at 100 ° C. under CO pressure 100 psi for 24 h. The mixture was diluted with EtOAc (20 ml) and filtered through a pad of silica gel eluted with excess EtOAc. The solvent was removed in vacuo and the residue 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 collected organic layers were dried (MgSO ₄ ) and evaporated. Column chromatography [SiO ₂ ; 4: 1 (pentane / EtOAc)] gave the product (970 mg, 84%) as an oil;

The compounds of formula (XI) shown in Table 21 below were prepared according to Preparation 50 starting from the precursors indicated.

<Continued in Table 21>

Preparation Example 55

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

A solution of the ester of Preparation 50 (970 mg, 2.26 mmol) in THF (20 ml) and 1 M LiOH (20 ml) was heated to reflux for 16 hours. After cooling to room temperature, THF was removed in vacuo, the residue was neutralized with saturated aqueous NH ₄ Cl solution, the mixture was extracted with DCM (100 ml) and then ether (100 ml). The collected organic layer was dried (MgSO ₄ ) and evaporated to give a white foam (960 mg) which was used without further purification;

The compounds of formula (XII) shown in Table 22 below were prepared according to Preparation 55 from the indicated precursors.

Preparation Example 59

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

Et ₃ N (267 μl, 1.92 mmol), HOBt.H ₂ O (129 mg, 0.84 mmol) and WSCDI (191 mg, 1.0 mmol) were added to a solution of the acid of preparation 55 (318 mg, 0.77 mmol) in DCM (10 ml). After the addition, the mixture was stirred for 1 hour and then a saturated solution of NH ₃ in THF (2 ml) was added. After stirring for a further 16 h, the reaction was diluted with water (50 ml), 0.2 M HCl (20 ml) and DCM (25 ml). The organic layer was separated and the aqueous layer was extracted with DCM (25 ml). The collected organic layers were dried (MgSO ₄ ) and evaporated to give a white foam (considered in quantitative yield), which was used without further purification;

The compounds of formula (XIII) shown in Table 23 below were prepared according to Preparation 59 from the indicated precursors.

<Continued in Table 23>

Preparation Example 69

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

A solution of LiAlH ₄ in THF (1M, 2ml, 2mmol) was added dropwise under N ₂ to a solution of ester (452mg, 1mmol) of Preparation 52 in THF (10ml). If the reaction was determined to be complete by TLC analysis, ether (10 ml) was added and excess LiAlH ₄ was quenched by careful addition of 2M NaOH. The organic layer was separated, washed with brine, dried (MgSO ₄ ) and evaporated. Column chromatography [SiO ₂ ; 39: 1 (DCM / MeOH)] to afford the desired alcohol (200 mg, 47%) as a gum white solid; δ _H (CDCl ₃ , 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 of formula (XIV) shown in Table 24 below were prepared according to Preparation 69 starting from the precursors indicated.

Preparation Example 72

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

A solution of diethyl azodicarboxylate (505 μl, 3.21 mmol) in THF (5 mL) was added to tert-butyl methylsulfonylcarbamate in THF (15 mL) (Tetrahedron Lett. 1994, 35, 379-380). (655 mg, 3.36 mmol), alcohol (1.226 g, 3.04 mmol) and triphenylphosphine (880 mg, 3.36 mmol) in Preparation Example 71 were added dropwise at 0 ° C. The reaction was stirred at 0 ° C. for 2 h, then diluted with EtOAc (80 ml) and washed with 10% aqueous K ₂ CO ₃ solution (100 ml). The organic layer was washed with brine, dried (MgSO ₄ ) and evaporated. The residue was subjected to column chromatography [SiO ₂ ; 1: 4 EtOAc: pentane] to give the title compound (1.406 g, 80%) as a colorless oil.

Preparation Example 73

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

The title compound was prepared from the alcohol of Preparation 70 by the method of Preparation 72;

Preparation Example 74

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

The title compound was prepared from the alcohol of Example 59 by the method of Preparation 72. The crude product was used directly in the next step without purification by column chromatography; δ _H (CDCl ₃ , 400 MHz) 1.39 (9H, s), 2.22 (6H, 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).

Preparation 75

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

The title compound was prepared from the alcohol of Preparation 71 by the method of Preparation 72 using trifluoromethanesulfonamide instead of tert-butyl methylsulfonylcarbamate. The desired product is 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 was contained as an impurity and obtained as a mixture ; MS m / z (ES ^_ ) 533 (MH ⁺ ).

The compounds of formula (XV) shown in Table 25 below were prepared according to Preparation 44 using the indicated precursors.

Preparation Example 79

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

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 of Preparation 39 (21.0 g, 69.2 mmol) in EtOH (100 ml) was added 8M methylamine solution (86.5 ml, 692 mmol) in EtOH. After stirring the obtained solution for a short time, a precipitate was observed. It was redissolved by the addition of THF (100 ml) and the solution was cooled to 0 ° C. and then NaBH ₄ (7.85 g, 208 mmol) was added. The reaction was allowed to slowly warm to room temperature, stirred overnight, and then the solvent was removed in vacuo. The residue was taken up in water (150 ml) and ether (150 ml) and 2M HCl was carefully added until pH was 1. The layers were separated and the aqueous layer was washed with ether (2 x 100 ml). The collected organic extracts were dried and evaporated to afford {2- [3-methyl-4- (methylsulfanyl) phenoxy] -5-nitrophenyl} methanol (18.9 g, 89%) as a yellow solid; δ _H (CDCl ₃ , 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 (1 H, d), 8.07 (1 H, dd), 8.41 (1 H, d).

The aqueous layer from above was poured into excess solid K ₂ CO ₃ and neutralized. The basic solution was extracted with ether (2 x 100 ml), the ether extract was dried (MgSO ₄ ) and evaporated to N-methyl-N- {2- [3-methyl-4- (methylsulfanyl) phenoxy ] -5-nitrobenzyl} amine (1.65 g, 7.5%) was obtained as an orange oil; MS m / z (ES ⁺ ) 319 (MH ⁺ ).

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

Methanesulfonyl chloride (4.81 ml, 61.9 mmol) was dissolved in {2- [3-methyl-4- (methylsulfanyl) phenoxy] -5-nitrophenyl} methanol (18.9 g, 61.9 mmol) in DCM (60 ml) and To the solution of Et ₃ N (9.5 ml, 68.2 mmol) was added slowly. The mixture was stirred at rt for 3 h, then poured into water and extracted with DCM (3 times). The collected organic extracts were dried (MgSO ₄ ) and evaporated to give a black viscous oil. The oil was poured into DCM (50 mL) and 8M methylamine solution (200 mL, 1.6 mol) in EtOH followed by Et ₃ N (10 mL, 71.7 mmol). After stirring for 18 hours, 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

Crude amine from above was dissolved in DCM (100 ml) at 0 ° C., Et₃N (11.4 ml, 81.8 mmol) was added followed by di-tert-butyl dicarbonate (15.0 g, 68.7 mmol). The reaction was allowed to warm to rt, stirred for 16 h and then concentrated in vacuo. The residue was partitioned between EtOAc and water and the aqueous layer was extracted with EtOAc (twice). The collected organic layers were dried (MgSO)₄), And evaporated. Residue was purified by column chromatography (SiO)₂; First column-3% MeOH in DCM; Purification by second column EtOAc: pentane 1: 3) gave the title compound (14.2 g, 54%) as a yellow oil; δ_H (CDCl₃, 400 MHz) 1.44 (9H, s), 2.32 (3H, s), 2.44 (3H, s), 2.95 (3H, s), 4.56 (2H, br), 6.75 (1H, d), 6.84 (2H, m ), 7.17 (1 H, d), 8.00 (1 H, d), 8.18 (1 H, br); MS m / z (TS⁺) 419 (MH)⁺).

The compounds of formula XVI shown in Table 26 below were prepared according to Example 103 from the indicated precursors.

Preparation Example 84

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

Methanesulfonyl chloride (4.16 ml, 53.7 mmol) was added dropwise at 0 ° C. to a solution of aniline (9.5 g, 24.5 mmol) and Et ₃ N (7.5 ml, 53.8 mmol) of Preparation 83 in DCM (50 ml). After 30 min stirring at 0 ° C., the reaction was allowed to warm to room temperature and then the solvent was removed in vacuo. 2M NaOH (50 ml) was added to the residue and the mixture was stirred for 30 minutes. The mixture was extracted with EtOAc, the organic layer was washed with brine, dried (MgSO ₄ ) and evaporated to an oil. Column chromatography [SiO ₂ ; 97.5: 2.5: 0.25 (DCM / MeOH / 880 NH ₃ )] gave the product (9.0 g, 79%) as a brown foam;

The compounds of formula (XVII) shown in Table 27 below were prepared according to Preparation 84 from the indicated precursors.

Preparation Example 88

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

MeI (1.07 ml, 17.2 mmol) was added dropwise under N ₂ to a mixture of sulfonamide (2.0 g, 4.3 mmol) and K ₂ CO ₃ (592 mg, 4.3 mmol) of Preparation 84 in CH ₃ CN (10 ml). The mixture was stirred for 16 h and then partitioned between EtOAc (50 ml) and 2M NaOH (50 ml). The organic layer was washed with brine, dried (MgSO ₄ ) and evaporated. The residue was subjected to column chromatography [SiO ₂ ; 590: 10: 1 (DCM / MeOH / 880 NH ₃ )] to give the product (1.23 g, 60%) as a yellow oil;

Preparation Example 89

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

2-bromoethanol (1.34 ml, 18.9 mmol) was added to a mixture of sulfonamide (2.0 g, 4.3 mmol) and K ₂ CO ₃ (2.605 g, 18.8 mmol) of Preparation 84 in CH ₃ CN (10 ml) under nitrogen. Was added. The mixture was heated to reflux for 16 h, cooled and partitioned between EtOAc (50 ml) and 2M NaOH (50 ml). The organic layer was washed with brine, dried (MgSO ₄ ) and evaporated. The residue was subjected to column chromatography [SiO ₂ ; 390: 10: 1 (DCM / MeOH / 880 NH ₃ )] to give the product (524 mg, 24%) as a pink foam;

Preparation 90

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

Fe powder (930 mg, 16.7 mmol) was added to the nitro compound of Preparation 41 (740 mg, 2.38 mmol) in AcOH (5 ml) and water (1 ml), and the mixture was stirred at room temperature for 16 hours. The solvent was removed in vacuo and the residue was taken up in EtOAc (50 ml) and 10% K ₂ CO ₃ aqueous solution (50 ml) and filtered through Arbocel®. The organic layer was separated and the aqueous layer was extracted with EtOAc (50 ml). The collected organic extracts were dried (MgSO ₄ ) and evaporated to give a brown foam (670 mg, 99%) which was used without further purification;

Compounds of formula Vb, ie, compounds of formula V wherein T is cyano, R ⁴ is hydrogen and R ⁵ is amino, shown in Table 28 below, were prepared according to Preparation 90 from the indicated precursors.

Preparation Example 94

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

The title compound was prepared from the nitro compound of Preparation 43 by the method of Example 103;

Compounds of Formula (Vc), ie, compounds of Formula (V), shown in Table 29 below, wherein T is cyano, R ⁴ is hydrogen and R ⁵ is —NHSO ₂ Me, were prepared according to Preparation 84 from the indicated precursors .

Preparation Example 100

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

The title compound was prepared from the sulfonamide of Preparation 98 by the method of Preparation 88;

Preparation Example 101

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

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

Dimethyl 4- (allyloxy) phthalate {Inouye, M .; Tsuchiy, K .; Kitao, T. Angew. Chem. Prepared according to 1992, 104, 198-200 (see also Angew. Chem., Int. Ed. Engl., 1992, 204-205)} (9.9 g, 38 mmol) dissolved in THF (40 ml) and brought to 0 ° C. After cooling, lithium aluminum hydride (1M solution in THF, 77 ml, 77 mmol) was added dropwise over 10 minutes. The mixture was then stirred at room temperature for 3 hours and then quenched by the careful addition of water (1.4 ml) followed by 2M NaOH (1.4 ml). Excess MgSO ₄ was added followed by water to form a granular precipitate (about 5 ml). The mixture was then filtered and evaporated to give a brown oil (7.1 g, about 95%). ¹ H NMR showed the material to be about 85% pure. It was used directly in the next step without further purification;

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

Crude diol (3.5 g, 18 mmol) from step (i) was dissolved in DCM (60 mL), treated with Et ₃ N (10 mL, 72 mmol) and the solution cooled to 0 ° C. Methanesulfonyl chloride (4.2 ml, 54 mmol) was added dropwise and the solution was stirred for 1 hour while allowing to reach room temperature. The reaction was then quenched by addition of water followed by 2M HCl (50 ml). The DCM layer was separated and the aqueous layer was reextracted with DCM (50 ml). The collected organic fractions were washed with water (50 ml), dried (MgSO ₄ ) and concentrated to about 30 ml in volume. Benzyltriethylammonium chloride (1 g) was added followed by a solution of sodium sulfide (5 g, 91 mmol) in water (50 ml). The mixture was stirred rapidly for 15 hours under a nitrogen atmosphere. The organic layer was separated and the aqueous layer was reextracted with DCM (50 ml). The collected organic layer was dried (MgSO ₄ ) and evaporated to a yellow oil. Flash chromatography gave two fractions; The first fraction was pure product and the second fraction was product contaminated with dimer material. Grinding of the second fraction resulted in crystallization of the dimer material, which was removed by filtration. The filtrate was combined with the first chromatography fraction to give the desired product (800 mg, 23%). δ _H (CDCl ₃ , 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).

(iii) Preparation of 1,3-dihydro-2-benzothiophen-5-ol

Allyl ether (800 mg, 4.16 mmol) from step (ii) 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). It was. The mixture was then heated to 45 ° C. and stirred at this temperature for 15 hours. After cooling to room temperature, THF was evaporated and the residue was partitioned between 2M NaOH solution (25 ml) and diethyl ether (25 ml). The aqueous layer was separated and the organic layer was reextracted with 2M NaOH solution (25 ml). The collected aqueous layers were neutralized to pH 7-8 with concentrated hydrochloric acid and extracted with EtOAc (2 × 25 ml). The collected organic extracts were dried (MgSO ₄ ) and evaporated to afford the title compound as a clear oil (540 mg, 85%) which solidified on standing; 4.14 (2H, s), 4.17 (2H, s), 6.63-6.68 (2H, m), 7.04 (1H, d).

Biological activity

A number of compounds were tested for their biological activity by their ability to inhibit reuptake of serotonin by human serotonin transporters as described below.

(i) cell culture

Human embryonic kidney cells (HEK-293) stably transfected with human serotonin transporter (hSERT), noradrenaline transporter (hNET), or dopamine transporter (hDAT) are standard cell culture techniques (cell DMEM-medium (10% dialysis). Fetal calf serum (FCS), 2 mM I-glutamine, and 250 μg / ml geneticin supplemented) were grown under 5% CO ₂ and 37 ° C.). The cells were harvested for analysis to yield a cell suspension of 750,000 cells / ml.

(ii) determination of inhibitory efficacy

All test compounds were dissolved in 100% DMSO and diluted in assay buffer to the appropriate test concentration. Analysis was performed on a 96-well filter bottom plate. Cells (7500 cells / assay wells) were preincubated for 5 minutes in standard assay buffer containing either test compound, standard inhibitor or compound vehicle (1% DMS). ^The reaction was initiated by adding either ³ H-serotonin, ³ H-noradrenaline or ³ H-dopamine substrate. All reactions were performed at room temperature in a shake incubator. Incubation time was 5 minutes for hSERT and hDAT and 15 minutes for hNET analysis. The reaction was terminated by removing the reaction mixture using a vacuum manifold and then quickly washed with ice-cold assay buffer. The amount of ³ H-substrate introduced into the cell was then quantified.

The assay plate was dried in a microwave oven, flashing fluid was added and radioactivity was measured. The efficacy of test compounds was quantified as IC ₅₀ values (concentration of test compound required to inhibit 50% specific reuptake of radiolabeled substrates into cells).

(iii) Standard Assay Buffer Composition:

Trisma Hydrochloride (26mM)

NaCl (124 mM)

KCl (4.5mM)

KH ₂ PO ₄ (1.2mM)

MgCl ₂ .6H ₂ O (1.3 mM)

Ascorbic Acid (1.136mM)

Glucose (5.55mM)

pH 7.40

CaCl ₂ (2.8mM)

Pargiline (100 μM)

Note: The pH of the buffer was adjusted to 7.40 with 1M NaOH followed by the addition of CaCl ₂ and pargiline.

(iv) Summary of Analysis Parameters

hSERT analysis hDAT analysis hNET analysis Cell concentration per assay well 75,000 75,000 75,000 Substrate concentration ³ H-5HT (50 nM) ³ H-dopamine (200 nM) ³ H-noradrenaline (200 nM) Incubation time (minutes) 5 5 15

Compounds with serotonin reuptake inhibition (SRI) IC ₅₀ values of 100 nM or less are shown in Examples 1-6, 8-23, 25, 26, 29-32, 34-36, 43, 45-49, 51, 56-102 , 109-130, the title compound.

Compounds with a serotonin reuptake inhibition (SRI) IC ₅₀ value of 100 nM or less and 10 times more potent in inhibiting serotonin reuptake than dopamine reuptake or noradrenaline reuptake were found in 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 Compound.

Compounds having a serotonin reuptake inhibition (SRI) IC ₅₀ value of 100 nM or less and at least 100 times more potent in inhibiting serotonin reuptake than dopamine reuptake or noradrenaline reuptake are 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 having a serotonin reuptake inhibition (SRI) IC ₅₀ value of ₅₀ nM or less and at least 100 times more potent in inhibiting serotonin reuptake than dopamine reuptake or noradrenaline reuptake are 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 Include.

In particular, the compound of Example 16 has a serotonin reuptake inhibition (SRI) IC ₅₀ value of 4.7 nM; The title compound of Example 29 has a serotonin reuptake inhibition (SRI) IC ₅₀ value of 2.0 nM; The title compound of Example 62 has a serotonin reuptake inhibition (SRI) IC ₅₀ value of 3.7 nM.

Claims (32)

A compound of formula (I), or a pharmaceutically acceptable salt, solvate or polymorph thereof. <Formula I> In the formula, R ¹ and R ² may be the same or different and H, C ₁ -C ₆ alkyl or (CH ₂ ) _d (C ₃ -C ₆ cycloalkyl), where d is 0, 1, 2 or 3 Or; R ¹ and R ² together with the nitrogen atom to which they are attached form an azetidine ring; Z or Y is -SR ³ and the remaining Z or Y is halogen or -R ³ ; Wherein R ³ is, independently, C ₁ -C ₄ alkyl optionally substituted with fluorine except when R ³ is CF ₃ ; Z and Y are joined together with a linking atom to form one conjugated 5 to 7 membered carbocyclic or heterocyclic ring which may be saturated, unsaturated or aromatic, wherein Z and Y form a heterocyclic ring When formed, the linking group contains, in addition to carbon atoms, one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; When R ⁵ is fluorine and R ² is methyl, the conjugate ring is not 1,3-dioxolane and Z and Y together do not form a conjugated phenyl ring; R⁴And R⁵May be the same or different, and A-X [where A is -CH = CH- or-(CH₂)_p-Wherein p is 0, 1 or 2; X is hydrogen, F, Cl, Br, I, CONR⁶R⁷, SO₂NR⁶R⁷, SO₂NHC (= O) R⁶, OH, C_1-4Alkoxy, NR⁸SO₂R⁹, NO₂, NR⁶R¹¹, CN, CO₂R¹⁰, CHO, SR¹⁰, S (O) R⁹Or SO₂R¹⁰ego; R⁶, R⁷, R⁸And R¹⁰May be the same or different and are hydrogen or one or more R¹²Independently substituted by C_1-6Alkyl; R⁹Is one or more R¹²Independently substituted by C_1-6Alkyl; R¹¹Is hydrogen or at least one R¹²Independently substituted by C_1-6Alkyl, C (O) R⁶, CO₂R⁹, C (O) NHR⁶Or SO₂NR⁶R⁷ego; R¹²Is F, OH, CO₂H, C_3-6Cycloalkyl, NH₂, CONH₂, C_1-6Alkoxy, C_1-6Alkoxycarbonyl or contain 1, 2 or 3 heteroatoms selected from N, S and O and at least one R¹³Is a 5 or 6 membered heterocyclic ring optionally substituted by independently; Or R⁶And R⁷One or more with the nitrogen atoms to which they are attached R¹³Independently forms an optionally substituted 4, 5 or 6 membered heterocyclic ring; or at least one R¹³A 5 or 6 membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, S and O independently substituted by¹³Silver hydroxy, C_One-C₄Alkoxy, F, C_One-C₆Alkyl, haloalkyl, haloalkoxy, -NH₂, -NH (C_One-C₆Alkyl) or -N (C_One-C₆Alkyl)₂being). The compound of claim ₁ , or a pharmaceutically acceptable salt, solvate or polymorph thereof, wherein R ¹ and R ² may be the same or different and are hydrogen or C ₁ -C ₆ alkyl. The compound or pharmaceutically acceptable salt, solvate or polymorph thereof according to claim 1 or 2, wherein when Z or Y is -SR ³ , R ³ is methyl or ethyl. 3. The compound as claimed in claim 1, or a pharmaceutically acceptable salt, solvate or polymorph thereof, when Z and Y are joined to form a conjugated ring. The compound of claim 4, or a pharmaceutically acceptable salt, solvate or polymorph thereof, in addition to the carbon atom, wherein the linking group contains one or two sulfur atoms. The method according to any one of claims to 5, wherein, R ⁶ and R ⁷ may be the same or different, are hydrogen, hydroxy, -CONH ₂ or C ₁ -C optionally substituted with C ₁ -C ₃ alkoxy ₃ alkyl, or a pharmaceutically acceptable salt, solvate or polymorph thereof. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, solvate or polymorph thereof, wherein R ⁸ is hydrogen, hydroxyethyl or methyl. 8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, solvate or polymorph thereof, wherein R ⁹ is methyl, ethyl, isopropyl, trifluoromethyl or methoxyethyl. 9. The compound, pharmaceutically acceptable salt, solvate or polymorph according to any one of claims 1 to 8, wherein p is 1 or 0. 10. The compound of claim 1, wherein R ⁴ and R ⁵ may be the same or different, and wherein — (CH ₂ ) _p —X where p is 0, 1 or 2; X is hydrogen, Hydroxy, CONR ⁶ R ⁷ , SO ₂ NR ⁶ R ⁷ , NR ⁸ SO ₂ R ⁹ , SR ¹⁰ , SOR ⁹ or SO ₂ R ^10, wherein R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ Is a 5 or 6 membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, S and O, or a pharmaceutically acceptable salt thereof, Solvates or polymorphs. The compound of claim 1, wherein R ⁴ and R ⁵ may be the same or different, and — (CH ₂ ) _p -X wherein p is 0 or 1; X is hydrogen, hydroxy , CONR ⁶ R ⁷ , SO ₂ NR ⁶ R ⁷ or NR ⁸ SO ₂ R ^9, wherein R ⁶ and R ⁷ may be the same or different and are hydrogen, hydroxy, -CONH ₂ or C ₁ -C C ₁ -C ₃ alkyl optionally substituted with ₃ alkoxy (preferably methoxy) R ⁸ is hydrogen, hydroxyethyl or methyl R ⁹ is methyl, ethyl, isopropyl, trifluoromethyl or meth Methoxyethyl), or triazolyl, imidazolyl or pyrazolyl, or a pharmaceutically acceptable salt, solvate or polymorph thereof. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt, solvate or polymorph thereof, wherein both R ⁴ and R ⁵ are not hydrogen. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate or polymorph thereof, wherein R ⁴ is hydrogen. The method of claim 1, 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] benzeneamide (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) A compound selected from the group consisting of: or a pharmaceutically acceptable salt, solvate or polymorph thereof. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate or polymorph thereof, for use as a medicament. A pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt, solvate or polymorph thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier. Use of a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate or polymorph thereof, for the treatment or prevention of a disorder involving the modulation of monoamine transporter function. 18. The use of claim 17, wherein the disorder is depression, attention deficit hyperactivity disorder, obsessive compulsive disorder, post traumatic stress disorder, drug abuse disorder or sexual dysfunction. The use of claim 18, wherein said disorder is premature ejaculation. Monoamine transporter function, comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate or polymorph thereof. Method of treatment or prevention of disorders involving the regulation of. Treatment of premature ejaculation, comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate or polymorph thereof. Prevention method. An increase in ejaculation delay comprising administering an effective amount of a compound according to any one of claims 1-14, or a pharmaceutically acceptable salt, solvate or polymorph thereof, to a male wishing to increase ejaculation delay. How to let. A process for preparing a compound of formula (I) comprising reacting a compound of formula (Ia) under suitable reaction conditions to produce a compound of formula (I). [At this time, suitable reaction conditions i) when R ⁴ / R ⁵ is halogen, reacting the compound of formula Ia with a suitable halogenating agent in an inert solvent that does not adversely affect the reaction; ii) when R ⁴ / R ⁵ is —NO ₂ , reacting the suitable nitrating agent with the compound of formula (Ia) in a solvent that does not adversely affect the reaction at temperatures below room temperature; or iii) when R ⁴ / R ⁵ is —SO ₂ NR ⁶ R ⁷ , reacting the intermediate sulphonyl chloride with the required amine of formula HNR ⁶ R ^{7 in} a suitable solvent; <Formula I> Wherein R ¹ , R ² , R ⁴ , R ⁵ , X and Z are as defined in any one of claims 1 to 14. <Formula Ia> The method of claim 23, wherein a) reacting a compound of formula (Ia) with chlorosulfonic acid optionally in a suitable solvent to give a compound of formula (XVIII) b) reacting with HNR ⁶ R ⁷ to obtain a compound of formula A process for preparing compounds of formula Iq, ie, compounds of formula I wherein R ⁵ is -SO ₂ NR ⁶ R ⁷ and R ⁴ is hydrogen. <Formula XVIII> <Formula Iq> The method of claim 24, wherein the compound of formula XVIII is produced in situ and reacted without isolation with HNR ⁶ R ⁷ . The compound of formula (Ia) according to any one of claims 23 to 25, wherein the compound of formula (IIa) is reacted with a compound of formula (HNR ¹ R ² ) or a suitable salt form thereof with a hydride reducing agent in a suitable solvent. Forming a compound of formula (Ia). <Formula IIa> An intermediate compound of formula (IIa) or (XVIII) as described in claims 23-26. A process for preparing a compound of formula (I) comprising reacting a compound of formula (II) with a hydride reducing agent in a suitable solvent with a compound of formula HNR ¹ R ² , or with a suitable salt form thereof. <Formula II> <Formula I> Wherein R ¹ , R ² , R ⁴ , R ⁵ , X and Z are as defined in any one of claims 1 to 14. The method of claim 28, further comprising coupling the compound of formula III with a compound of formula IV to provide a compound of formula II under suitable reaction conditions. <Formula III> [Wherein L is a suitable leaving group such as halogen or sulfonic acid ester such as trifluoromethanesulfonate or methanesulfonate] <Formula IV> An intermediate compound of formula II as described in claim 28. R ¹ , R ² , Y and Z are as defined in claim 1; R ⁴ and R ⁵ may be the same or different and are-(CH ₂ ) _p -A 'wherein p is 0, 1 or 2 and A' is a polar group, or a pharmaceutical thereof Acceptable salts, solvates or polymorphs. 24. The compound of claim 23, wherein said polar group has a negative pi value greater than -0.1.