FOR THE IDENTIFICATION OF BIOLOGICAL AND

PHARMACOLOGICAL ACTIVITY

Field of the invention

The field of the invention is medicinal chemistry. The invention relates to N- substituted-iV-phenylethylsulfonamides useful be for the identification of biological and pharmacological activity in drug discovery.

Background of the invention

Novel compounds are continually sought after to treat and prevent diseases and disorders. Pharmaceutical companies interested in owning new active molecules develop or purchase chemical compounds or libraries in order to screen their activity against a particular target, aiming at the identification of new industrially useful products.

Therefore, there is a market of customer companies for which the acquisition of novel chemical compounds, not already biologically explored, is a key issue. And for the companies whose core business is the design and preparation of chemical compounds or chemical libraries, their commercialization has a clear industrial interest.

Although many research groups work to find novel compounds to be used in the treatment of known or novel diseases, the number of active new chemical entities in the market doesn't grow in the same extension. Over the past few years, there has been a progressive reduction in the number of medicines entering the market mainly due to the more stringent regulatory requirements that have raised the bar on safety and efficacy of new drugs.

The compounds described in this invention are useful for contributing to the exploration of the chemical space, for incrementing the structural diversity of valuable molecules in the pharmaceutical sector and for incrementing the elements of structural recognition in order to study their interaction with or modulation of targets of pharmaceutical or medicinal chemistry interest. For instance, the molecules may be therapeutically useful as anti-inflammatory or anticoagulation agents, among many other applications. Compounds described in this invention are useful for being biologically and pharmaceutically explored, and therefore to contribute in the research and identification of new drug leads exhibiting the ability of target modulation, since these molecules are sources of chemical diversity not currently explored. The compounds of the present invention may be explored by means of any known method of biological screening. These methods comprise, but are not limited to, receptor affinity assays, ELISA assays, "southern", "western" and "northern blot", and competitive binding assays.

US 7,126,006 B2 (The Scripps Research Institute) describes glycoluryl type molecules as scaffolds in the preparation of combinatorial libraries.

US 6,939,973 Bl (The Scripps Research Institute) describes glycoluryl type molecules as scaffolds in the preparation of combinatorial libraries.

Description of the invention

The present invention concerns the compounds represented by formula (I)

(I)

and the salts and stereoisomers thereof, wherein

R ¹ is hydrogen, halo, hydroxy, nitro, cyano, carboxyl, Ci-βalkyl, Ci_6alkoxy, Ci_ 6alkoxyCi_ ₆ alkyl, Ci_ ₆ alkylcarbonyl, amino, mono- or diCi_ ₆ alkylamino, azido, mercapto, polyhaloCi-βalkyl, and polyhaloCi-βalkoxy, aryl, Het;

R ² is Ci_ ₆ alkyl, Ci_ ₆ alkylcarbonyl, Ci_ ₆ alkyl optionally substituted with aryl, Ci_ 6alkoxyCi_ ₆ alkyl, or C ₃ - ₇ cycloalkyl, Ci_ ₆ alkyl optionally substituted with Het, C _{3- 7} Cycloalkyl optionally substituted with Ci_ ₆ alkyl, Ci_ ₆ alkyl optionally substituted with C ₃ _ ₇ Cycloalkyl, aryl or Het, C ₂ - ₆ alkenyl optionally substituted with C ₃ . 7Cycloalkyl or aryl; aryl; Het; R ³ is Ci-βalkyl, Ci_ ₆ alkoxy, Ci_ ₆ alkoxyCi_ ₆ alkyl, Ci_ ₆ alkylcarbonyl, mono- or diCi_ 6alkylamino, polyhaloCi_ ₆ alkyl, and polyhaloCi-βalkoxy, Ci_ ₆ alkoxyCi_ ₆ alkyl, or C ₃ - ₇ cycloalkyl, Ci_ ₆ alkyl optionally substituted with C ₃ - ₇ cycloalkyl or aryl, Ci_ 6alkyl optionally substituted with Het, C ₃ _ ₇ Cycloalkyl optionally substituted with Ci-βalkyl, C ₂ - ₆ alkenyl optionally substituted with C ₃ - ₇ cycloalkyl, aryl or Het; aryl, Het; Ci_ ₆ alkyl optionally substituted with -NR ^4a R ^4b , wherein R ^4a and R ^4b are, each independently, Ci_ ₆ alkyl, or R ^4a and R ^4b together with the nitrogen to which they are attached form a 5- or 6-membered saturated heterocyclic ring; n is one, two, three, four or five; each aryl as a group or part of a group is phenyl or naphthalenyl, each optionally substituted with one, two or three substituents selected from halo, hydroxy, nitro, cyano, carboxyl, Ci_ ₆ alkyl, Ci_ ₆ alkoxy, Ci_ ₆ alkoxyCi_ ₆ alkyl, Ci_ ₆ alkylcarbonyl, amino, mono- or diCi_6alkylamino, azido, mercapto, polyhaloCi_6alkyl, and polyhaloCi-βalkoxy; each Het as a group or part of a group is a monocyclic ring with 5 or 6 ring atoms or a bicyclic ring structure comprising a 6 membered ring fused to a 4, 5, or 6 membered ring; each of the rings being saturated, partially unsaturated, or completely unsaturated; at least one of the rings containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulphur; and any one of the rings being optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, hydroxy, nitro, cyano, carboxyl, Ci_ ₆ alkyl, Ci_ ₆ alkoxy, Ci_ ₆ alkoxyCi_ ₆ alkyl, Ci_ ₆ alkylcarbonyl, amino, mono- or diCi_6alkylamino, azido, mercapto, polyhaloCi-βalkyl, polyhaloCi_ βalkoxy, and C ₃ _ ₇ Cycloalkyl.

The invention further relates to methods for the preparation of the compounds of formula (I), the N-oxides, addition salts, quaternary amines, metal complexes, and stereochemical^ isomeric forms thereof, their intermediates, and the use of the intermediates in the preparation of the compounds of formula (I).

The invention relates to the compounds of formula (I) per se, the N-oxides, addition salts, quaternary amines, metal complexes, and stereochemically isomeric forms thereof, for use as lead compounds to be biologically and pharmacologically explored in the search and identification of new drugs. As used in the foregoing and hereinafter, the following definitions apply unless otherwise noted.

The term halo is generic to fluoro, chloro, bromo and iodo.

The term "polyhaloCi_6alkyl" as a group or part of a group, e.g. in polyhaloCi-βalkoxy, is defined as mono- or polyhalo substituted in particular Ci_6alkyl substituted with up to one, two, three, four, five, six, or more halo atoms, such as methyl or ethyl with one or more fluoro atoms, for example, difluoromethyl, trifluoromethyl, trifluoroethyl. Preferred is trifluoromethyl. Also included are perfluoroCi_ ₆ alkyl groups, which are Ci_6alkyl groups wherein all hydrogen atoms are replaced by fluorine atoms, e.g. pentafluoroethyl. In case more than one halogen atom is attached to an alkyl group within the definition of polyhaloCi_ ₆ alkyl, the halogen atoms may be the same or different.

As used herein "Ci_4alkyl" as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as for example methyl, ethyl, 1 -propyl, 2-propyl, 1 -butyl, 2-butyl, 2 -methyl- 1 -propyl; "C _1- βalkyl" encompasses Ci_4alkyl radicals and the higher homologues thereof having 5 or 6 carbon atoms such as, for example, 1-pentyl, 2-pentyl, 3-pentyl, 1-hexyl, 2-hexyl, 2- methyl-1-butyl, 2-methyl-l-pentyl, 2-ethyl-l-butyl, 3-methyl-2-pentyl, and the like. Of interest amongst Ci_ ₆ alkyl is Ci_ ₄ alkyl.

The term "C2-6alkenyl" as a group or part of a group defines straight and branched chained hydrocarbon radicals having saturated carbon-carbon bonds and at least one double bond, and having from 2 to 6 carbon atoms, such as, for example, ethenyl (or vinyl), 1-propenyl, 2-propenyl (or allyl), 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2- propenyl, 2-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 2-methyl-2-butenyl, 2-methyl-2-pentenyl and the like. Of interest amongst C ₂ - ₆ alkenyl is C ₂ - ₄ alkenyl.

C ₃ - ₇ cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Ci_6alkoxy means Ci_6alkyloxy wherein Ci_6alkyl is as defined above. It should be noted that the radical positions on any molecular moiety used in the definitions may be anywhere on such moiety as long as it is chemically stable.

Radicals used in the definitions of the variables include all possible isomers unless otherwise indicated. For instance pyridyl includes 2-pyridyl, 3-pyridyl and 4-pyridyl; pentyl includes 1-pentyl, 2-pentyl and 3-pentyl.

When any variable occurs more than one time in any constituent, each definition is independent.

Whenever used hereinafter, the term "compounds of formula (I)", or "the present compounds" or similar terms, it is meant to include the compounds of formula (I), each and any of the subgroups thereof, their prodrugs, N-oxides, addition salts, quaternary amines, metal complexes, and stereochemically isomeric forms. One embodiment comprises the compounds of formula (I) or any subgroup of compounds of formula (I) specified herein, as well as the N-oxides, salts, as the possible stereoisomeric forms thereof. Another embodiment comprises the compounds of formula (I) or any subgroup of compounds of formula (I) specified herein, as well as the salts as the possible stereoisomeric forms thereof.

The compounds of formula (I) may have one or more centers of chirality and may exist as stereochemically isomeric forms. The term "stereochemically isomeric forms" as used herein defines all the possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures which are not interchangeable, which the compounds of formula (I) may possess.

With reference to the instances where (R) or (S) is used to designate the absolute configuration of a chiral atom within a substituent, the designation is done taking into consideration the whole compound and not the substituent in isolation.

Unless otherwise mentioned or indicated, the chemical designation of a compound encompasses the mixture of all possible stereochemically isomeric forms, which said compound may possess. Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said compound. All stereochemically isomeric forms of the compounds of the present invention both in pure form or mixed with each other are intended to be embraced within the scope of the present invention. Pure stereoisomeric forms of the compounds and intermediates as mentioned herein are defined as isomers substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure of said compounds or intermediates. In particular, the term "stereoisomerically pure" concerns compounds or intermediates having a stereoisomeric excess of at least 80% (i.e. minimum 90% of one isomer and maximum 10% of the other possible isomers) up to a stereoisomeric excess of 100% (i.e. 100% of one isomer and none of the other), more in particular, compounds or intermediates having a stereoisomeric excess of 90% up to 100%, even more in particular having a stereoisomeric excess of 94% up to 100% and most in particular having a stereoisomeric excess of 97% up to 100%. The terms "enantiomerically pure" and "diastereomerically pure" should be understood in a similar way, but then having regard to the enantiomeric excess, and the diastereomeric excess, respectively, of the mixture in question.

Pure stereoisomeric forms of the compounds and intermediates of this invention may be obtained by the application of art-known procedures. For instance, enantiomers may be separated from each other by the selective crystallization of their diastereomeric salts with optically active acids or bases. Examples thereof are tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and camphosulfonic acid. Alternatively, enantiomers may be separated by chromatographic techniques using chiral stationary phases. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably, if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.

The diastereomeric racemates of the compounds of formula (I) can be obtained separately by conventional methods. Appropriate physical separation methods that may advantageously be employed are, for example, selective crystallization and chromatography, e.g. column chromatography.

For some of the compounds of formula (I), their N-oxides, salts, solvates, quaternary amines, or metal complexes, and the intermediates used in the preparation thereof, the absolute stereochemical configuration was not experimentally determined. A person skilled in the art is able to determine the absolute configuration of such compounds using art-known methods such as, for example, X-ray diffraction.

The present invention is also intended to include all isotopes of atoms occurring on the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.

The term "pro drug" as used throughout this text means the pharmacologically acceptable derivatives such as esters, amides, and phosphates, such that the resulting in vivo biotransformation product of the derivative is the active drug as defined in the compounds of formula (I). The reference by Goodman and Gilman (The Pharmacological Basis of Therapeutics, 8th ed, McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs", p 13-15) describing prodrugs generally is hereby incorporated. Prodrugs preferably have excellent aqueous solubility, increased bioavailability and are readily metabolized into the active inhibitors in vivo. Prodrugs of a compound of the present invention may be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either by routine manipulation or in vivo, to the parent compound.

Preferred are pharmaceutically acceptable ester prodrugs that are hydrolysable in vivo and are derived from those compounds of formula (I) having a hydroxy or a carboxyl group. An in vivo hydrolysable ester is an ester, which is hydro lysed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically acceptable esters for carboxy include Ci_6alkoxymethyl esters for example methoxymethyl, Ci_ ₆ alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C ₃ _ ₈ CycloalkoxycarbonyloxyCi_ ₆ alkyl esters for example 1- cyclohexylcarbonyloxy ethyl; l,3-dioxolen-2-onylmethyl esters for example 5-methyl- l,3-dioxolen-2-onylmethyl; and Ci_ ₆ alkoxycarbonyloxyethyl esters for example 1- methoxycarbonyl-oxyethyl which may be formed at any carboxy group in the compounds of this invention.

An in vivo hydrolysable ester of a compound of the formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters and α-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxy-methoxy. A selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxy acetyl. Examples of substituents on benzoyl include morpholino and piperazino linked from a ring nitrogen atom via a methylene group to the 3- or 4-position of the benzoyl ring.

For therapeutic use, salts of the compounds of formula (I) are those wherein the counter-ion is pharmaceutically acceptable. However, salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention.

The pharmaceutically acceptable acid and base addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds of formula (I) are able to form. The pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic (i.e. hydroxybutanedioic acid), tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.

Conversely said salt forms can be converted by treatment with an appropriate base into the free base form.

The compounds of formula (I) containing an acidic proton may also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.

The term addition salt as used hereinabove also comprises the solvates which the compounds of formula (I) as well as the salts thereof, are able to form. Such solvates are for example hydrates, alcoholates and the like.

The term "quaternary amine" as used hereinbefore defines the quaternary ammonium salts which the compounds of formula (I) are able to form by reaction between a basic nitrogen of a compound of formula (I) and an appropriate quaternizing agent, such as, for example, an optionally substituted alkylhalide, arylhalide or arylalkylhalide, e.g. methyliodide or benzyliodide. Other reactants with good leaving groups may also be used, such as alkyl trifluoromethanesulfonates, alkyl methanesulfonates, and alkyl p- toluenesulfonates. A quaternary amine has a positively charged nitrogen. Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate and acetate. The counterion of choice can be introduced using ion exchange resins.

The N-oxide forms of the present compounds are meant to comprise the compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called N-oxide.

It will be appreciated that the compounds of formula (I) may have metal binding, chelating, complex forming properties and therefore may exist as metal complexes or metal chelates. Such metalated derivatives of the compounds of formula (I) are intended to be included within the scope of the present invention.

Some of the compounds of formula (I) may also exist in their tautomeric form. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.

One embodiment of the present invention concerns compounds of formula (I) or of any subgroup of compounds of formula (I), wherein one or more of the following conditions apply:

R ¹ is hydrogen, aryl, Het;

R ² is Ci_ ₆ alkyl optionally substituted with aryl, Ci_ ₆ alkyl optionally substituted with Het, C ₃ - ₇ cycloalkyl optionally substituted with C _h alky!, Ci_ ₆ alkyl optionally substituted with C ₃ - ₇ cycloalkyl or aryl, C ₂ - ₆ alkenyl optionally substituted with C _{3- 7} Cycloalkyl, aryl or Het; aryl; Het;

R ³ is Ci-βalkyl, Ci_6alkoxy, Ci_6alkoxyCi_6alkyl, Ci_6alkylcarbonyl, polyhaloCi-βalkyl, and polyhaloCi-βalkoxy, Ci_ ₆ alkoxyCi_ ₆ alkyl, C ₃ _ ₇ Cycloalkyl, Ci_ ₆ alkyl optionally substituted with C ₃ _ ₇ cycloalkyl or aryl, Ci_ ₆ alkyl optionally substituted with Het, C ₃ _ 7Cycloalkyl optionally substituted with Ci_ ₆ alkyl, C ₂ - ₆ alkenyl optionally substituted with C ₃ - ₇ cycloalkyl, aryl or Het; aryl; Het; n is one or two; each aryl as a group or part of a group is phenyl or naphthalenyl, each optionally substituted with one, two or three substituents selected from halo, hydroxy, nitro, cyano, carboxyl, Ci-βalkyl, Ci_ ₆ alkoxy, Ci_ ₆ alkoxyCi_ ₆ alkyl, Ci_ ₆ alkylcarbonyl, amino, mono- or diCi_6alkylamino, azido, mercapto, polyhaloCi_6alkyl, and polyhaloCi-βalkoxy; each Het as a group or part of a group is a monocyclic ring with 5 or 6 ring atoms or a bicyclic ring structure comprising a 6 membered ring fused to a 4, 5, or 6 membered ring; each of the rings being saturated, partially unsaturated, or completely unsaturated; at least one of the rings containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulphur; and any one of the rings being optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, hydroxy, nitro, cyano, carboxyl, Ci_6alkyl, Ci_ ₆ alkoxy, Ci_ ₆ alkoxyCi_ ₆ alkyl, Ci_ ₆ alkylcarbonyl, amino, mono- or diCi_ βalkylamino, azido, mercapto, polyhaloCi_6alkyl, polyhaloCi-βalkoxy, and C3_ 7cycloalkyl.

One embodiment of the present invention concerns compounds of formula (I) or of any subgroup of compounds of formula (I), wherein one or more of the following conditions apply:

R ¹ is hydrogen; R ² is aryl or Het;

R ³ is Ci_ ₆ alkyl, Ci_ ₆ alkoxy, Ci_ ₆ alkoxyCi_ ₆ alkyl, Ci_ ₆ alkylcarbonyl, mono- or diCi_ 6alkylamino, polyhaloCi-βalkyl, and polyhaloCi-βalkoxy, Ci_6alkoxyCi_6alkyl, or C _{3- 7} Cycloalkyl, Ci_ ₆ alkyl optionally substituted with C ₃ _ ₇ Cycloalkyl or aryl, Ci_ ₆ alkyl optionally substituted with Het, C ₃ _ ₇ Cycloalkyl optionally substituted with Ci_ ₆ alkyl, C ₂ - ₆ alkenyl optionally substituted with C ₃ _ ₇ Cycloalkyl, aryl or Het; aryl, Het, Ci_ 6alkyl optionally substituted with -NR ^4a R ^4b , wherein R ^4a and R ^4b are, each independently, Ci_ ₆ alkyl, or R ^4a and R ^4b together with the nitrogen to which they are attached form a 5- or 6-membered saturated heterocyclic ring; n is one; each aryl as a group or part of a group is phenyl or naphthalenyl, each optionally substituted with one, two or three substituents selected from halo, hydroxy, nitro, cyano, carboxyl, Ci_ ₆ alkyl, Ci_ ₆ alkoxy, Ci_ ₆ alkoxyCi_ ₆ alkyl, Ci_ ₆ alkylcarbonyl, amino, mono- or diCi_6alkylamino, azido, mercapto, polyhaloCi_6alkyl, and polyhaloCi-βalkoxy; each Het as a group or part of a group is a monocyclic ring with 5 or 6 ring atoms or a bicyclic ring structure comprising a 6 membered ring fused to a 4, 5, or 6 membered ring; each of the rings being saturated, partially unsaturated, or completely unsaturated; at least one of the rings containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulphur; and any one of the rings being optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, hydroxy, nitro, cyano, carboxyl, Ci-βalkyl, Ci_ ₆ alkoxy, Ci_ ₆ alkoxyCi_ ₆ alkyl, Ci_ ₆ alkylcarbonyl, amino, mono- or diCi_ 6alkylamino, azido, mercapto, polyhaloCi-βalkyl, polyhaloCi-βalkoxy, and C _{3- 7} Cycloalkyl.

Another embodiment of the present invention concerns compounds of formula (I) or of any subgroup of compounds of formula (I), wherein one or more of the following conditions apply:

R ¹ is hydrogen;

R ² is aryl, Het or C ₂ - ₆ alkenyl optionally substituted with C ₃ _ ₇ Cycloalkyl, aryl or Het;

R ³ is Ci_ ₆ alkyl optionally substituted with C ₃ _ ₇ Cycloalkyl or aryl, Ci_ ₆ alkyl optionally substituted with Het, C ₃ _ ₇ cycloalkyl optionally substituted with Ci_ ₆ alkyl, C ₂ - ₆ alkenyl optionally substituted with C ₃ - ₇ cycloalkyl, aryl or Het; aryl; Het; n is one; each aryl as a group or part of a group is phenyl or naphthalenyl, each optionally substituted with one, two or three substituents selected from halo, hydroxy, nitro, cyano, carboxyl, Ci-βalkyl, Ci_ ₆ alkoxy, Ci_ ₆ alkoxyCi_ ₆ alkyl, Ci_ ₆ alkylcarbonyl, amino, mono- or diCi_6alkylamino, azido, mercapto, polyhaloCi_6alkyl, and polyhaloCi-βalkoxy; each Het as a group or part of a group is a monocyclic ring with 5 or 6 ring atoms or a bicyclic ring structure comprising a 6 membered ring fused to a 4, 5, or 6 membered ring; each of the rings being saturated, partially unsaturated, or completely unsaturated; at least one of the rings containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulphur; and any one of the rings being optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, hydroxy, nitro, cyano, carboxyl, Ci_6alkyl, Ci_ ₆ alkoxy, Ci_ ₆ alkoxyCi_ ₆ alkyl, Ci_ ₆ alkylcarbonyl, amino, mono- or diCi_ βalkylamino, azido, mercapto, polyhaloCi_6alkyl, polyhaloCi-βalkoxy, and C ₃ . 7cycloalkyl.

The compounds of the present invention may be prepared according to the procedures described hereinafter, which are meant to be applicable for as well the racemates, stereochemical^ pure intermediates or end products, or any stereoisomer^ mixtures. The racemates or stereochemical mixtures may be separated into stereoisomeric forms at any stage of the synthesis procedures.

Scheme 1

As shown in the above scheme 1, coupling of a compound of formula [2] with compounds of formula R ₂ -SO ₂ -LG, where LG means "leaving group", being said LG group preferably an halogen atom, more preferably bromine or chlorine, yields the corresponding substituted sulfonamides of formula [4]. The reaction solvent is a chlorinated solvent, preferably dichloromethane, 1 ,2-dichloroethane or chloroform, or a polar aprotic solvent, preferably acetonitrile, tetrahydrofuran, or dimethylformamide, at a temperature preferably between 0° C and 4O ⁰ C, more preferably between 10° C and 25 ⁰ C.

Under substitution or coupling conditions with compounds of formula R ₃ -Y, where Y means "leaving group" in substitution reaction and "activating group" in coupling reactions, being said Y preferably is a halogen atom, more preferably bromine or chlorine in substitution reaction, or an activated carboxyl derivative in coupling reactions, compound [4] is converted to the final compounds of formula (I). The reaction solvent is anhydrous or non anhydrous polar aprotic solvent, preferably acetonitrile, tetrahydrofuran, or dimethylformamide, at a temperature preferably between -78 ⁰ C and 6O ⁰ C, more preferably between -78 ⁰ C and 25 ⁰ C.

Both racemic as well as pure enantiomers of (I) can be accessed by this approach depending on the stereochemical integrity of the starting material.

As such, in one embodiment, the present invention relates to a process for preparing a compound of formula (I) as described herein, said process comprising a) reacting in a suitable medium compound of formula (II) with a compound of formula

(III)

(II) (III), and b) optionally further reacting in a suitable medium the product of step a) with R ₃ -Y; wherein

Ri, R ₂ , R3, and n have the same definition as provided herein; LG is a leaving group;

Y is an activating group in coupling reactions or a leaving group in substitution reactions.

The suitable medium of the reaction in step a) is anhydrous or non anhydrous chlorinated solvent, preferably dichloromethane, 1 ,2-dichloroethane or chloroform, or a anhydrous or non anhydrous polar aprotic solvent, preferably acetonitrile, tetrahydrofuran, or dimethylformamide, at a temperature preferably between 0° C and 4O ⁰ C, more preferably between 0° C and 25° C.

The suitable medium of the reaction in step b) is in the presence of an inorganic or organic base, such as sodium hydride, potassium tert-butoxidc or lithium diisopropylamide, at a temperature preferably between -78 ⁰ C and 6O ⁰ C, more preferably between -78 ⁰ C and 25 ⁰ C. The reaction solvent is a polar aprotic solvent, preferably acetonitrile, tetrahydrofuran, dimethylformamide, or dimethylsulfoxide. The term "leaving group" is preferably a halogen atom, more preferably bromine or chlorine.

The term "activating group" is preferably but not limited to a carboxyl activant in coupling reactions, preferably in the form of an acid chloride, anhydride, or active esters, such as O-acylisoureas or acyloxyphosphonium derivatives.

Compounds of formula (I) may be converted into each other following art-known functional group transformation reactions. For example, amino groups may be N- alkylated, nitro groups reduced to amino groups, a halo atom may be exchanged for another halo.

The compounds of formula (I) may be converted to the corresponding N-oxide forms following art-known procedures for converting a trivalent nitrogen into its N-oxide form. Said N-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarbo-peroxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. tert-butyl hydroperoxide. Suitable solvents are, for example, water, lower alcohols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.

Pure stereochemically isomeric forms of the compounds of formula (I) may be obtained by the application of art-known procedures. Diastereomers may be separated by physical methods such as selective crystallization and chromatographic techniques, e.g., counter-current distribution, liquid chromatography and the like.

The compounds of formula (I) may be obtained as racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures. The racemic compounds of formula (I), which are sufficiently basic or acidic may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid, respectively chiral base. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali or acid. An alternative manner of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography, in particular liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifϊcally. Preferably if a specific stereoisomer is desired, said compound may be synthesized by stereospecifϊc methods of preparation. These methods may advantageously employ enantiomerically pure starting materials.

The compounds of the present invention or any subgroup thereof may therefore be used for being biologically and pharmacologically explored in the search and identification of new lead compounds in the drug discovery process. The abovementioned use comprises the compounds of formula (I)

(I) wherein

R ¹ is hydrogen, halo, hydroxy, nitro, cyano, carboxyl, Ci-βalkyl, Ci_6alkoxy, Ci_ 6alkoxyCi_ ₆ alkyl, Ci_ ₆ alkylcarbonyl, amino, mono- or diCi_ ₆ alkylamino, azido, mercapto, polyhaloCi-βalkyl, and polyhaloCi-βalkoxy, aryl, Het;

R ² is Ci_ ₆ alkyl, Ci_ ₆ alkylcarbonyl, Ci_ ₆ alkyl optionally substituted with aryl, Ci_ 6alkoxyCi_ ₆ alkyl, or C ₃ - ₇ cycloalkyl, Ci_ ₆ alkyl optionally substituted with Het, C _{3- 7} Cycloalkyl optionally substituted with Ci_ ₆ alkyl; Ci_ ₆ alkyl optionally substituted with C ₃ _ ₇ Cycloalkyl or aryl, C ₂ - ₆ alkenyl optionally substituted with C ₃ _ ₇ Cycloalkyl, aryl or Het; aryl; Het;

R ³ is Ci-βalkyl, Ci_ ₆ alkoxy, Ci_ ₆ alkoxyCi_ ₆ alkyl, Ci_ ₆ alkylcarbonyl, mono- or diCi_ βalkylamino, polyhaloCi_ ₆ alkyl, and polyhaloCi-βalkoxy, Ci_ ₆ alkoxyCi_ ₆ alkyl, or C ₃ - ₇ cycloalkyl, Ci_ ₆ alkyl optionally substituted with C ₃ - ₇ cycloalkyl or aryl, Ci_ 6alkyl optionally substituted with Het, C ₃ _ ₇ Cycloalkyl optionally substituted with Ci-βalkyl, C ₂ - ₆ alkenyl optionally substituted with C ₃ - ₇ cycloalkyl, aryl or Het; aryl, Het, Ci_ ₆ alkyl optionally substituted with -NR ^4a R ^4b , wherein R ^4a and R ^4b are, each independently, Ci_ ₆ alkyl, or R ^4a and R ^4b together with the nitrogen to which they are attached form a 5- or 6-membered saturated heterocyclic ring; n is one, two, three, four or five; each aryl as a group or part of a group is phenyl or naphthalenyl, each optionally substituted with one, two or three substituents selected from halo, hydroxy, nitro, cyano, carboxyl, Ci_ ₆ alkyl, Ci_ ₆ alkoxy, Ci_ ₆ alkoxyCi_ ₆ alkyl, Ci_ ₆ alkylcarbonyl, amino, mono- or diCi_6alkylamino, azido, mercapto, polyhaloCi_6alkyl, and polyhaloCi-βalkoxy; each Het as a group or part of a group is a monocyclic ring with 5 or 6 ring atoms or a bicyclic ring structure comprising a 6 membered ring fused to a 4, 5, or 6 membered ring; each of the rings being saturated, partially unsaturated, or completely unsaturated; at least one of the rings containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulphur; and any one of the rings being optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, hydroxy, nitro, cyano, carboxyl, Ci_ ₆ alkyl, Ci_ ₆ alkoxy, Ci_ ₆ alkoxyCi_ ₆ alkyl, Ci_ ₆ alkylcarbonyl, amino, mono- or diCi_6alkylamino, azido, mercapto, polyhaloCi-βalkyl, polyhaloCi_ βalkoxy, and C ₃ _ ₇ Cycloalkyl.

Examples

The following examples are intended to illustrate the present invention and not to limit it thereto.

Example 1: Preparation of TV-phenethylbenzenesulfonamide

To a stirred solution of 2-phenylethylamine (2 g, 16.5 mmol) in 105 ml DMF at room temperature was added Et ₃ N (2.75 ml, 19.8 mmol). This mixture was stirred for 5 min, and then benzenesulfonyl chloride (2.3 ml, 18.1 mmol) was added at this temperature. The reaction was stirred for 2.5 h, and then, the mixture was evaporated to dryness and the crude was chromatographically purified over SiO ₂ using Hexane/ AcOEt 60/40 as the eluant, yielding 3.12 g (72 %) of the desired product.

¹ H-NMR (400MHz, DMSO-d ₆ ): 7.79 (d, 2H, J= 7.6 Hz, H _a ), 7.7 (sa, IH, NH), 7.60 (m, 3H, 2H _b + H _c ), 7.26 (t, 2H, J = 7.6 Hz, H _d ), 7.19 (m, IH, H _e ), 7.15 (m, 2H, H _f ), 2.9 (t, 2H, J= 7.3 Hz, NHCH ₂ CH ₂ ), 2.6 (t, 2H, J= 7.4 Hz, NHCH ₂ CH ₂ ) ppm.

CAS nr: [77198-99-3]

Example 2: Preparation of TV-phenethylnaphthalene-l-sulfonamide

To a stirred solution of 2-phenylethylamine (3.5 mmol, 1 eq) in 40 ml CH ₂ Cl ₂ were consecutively added, Et ₃ N (0.58 ml, 4.18 mmol, 1.2 eq) and the corresponding sulfonyl chloride (2-naphthalenesulfonyl chloride, 0.87 g, 3.84 mmol, 1.1 eq). The reaction was performed at room temperature during 4 h, until the total consumption of the starting material. Once the solvent was evaporated, the crude mixture was chromatographically purified over AI2O3 using Hexane/ AcOEt (70:30) as the eluant. The final yield of the product obtained was 91%, and the purity > 99% (expressed in % HPLC area).

¹ H-NMR (400 MHz, CDCl ₃ ): 8.39 - 7.61 (m, 7H, H^ _Phe ), 4.43 (sa, IH, NH), 3.27 (c, 2H, J = 6.3 Hz, NHCH ₂ CH ₂ ), 2.77 (t, 2H, J = 6.6 Hz, NHCH ₂ CH ₂ ) ppm.

CAS nr: [126402-52-6]

Example 3: Preparation of 4-Chloro-7V-phenethylbenzenesulfonamide

Following a procedure analogous to that described in Example 2, using 4- chlorobenzenesulfonyl chloride as the starting material, the title compound was obtained in 91% yield (Purity > 99%)

¹ H-NMR (400 MHz, CDCl ₃ ): 7.74 (d, 2H, J= 4.7 Hz, H _b ), 7.47 (d, 2H, J= 4.7 Hz, H _a ), 7.28 (m, 3H, 2H _e + H _c ), 7.10 (m, 2H, H _d ), 4.46 (t, IH, J = 6 Hz, NH), 3.26 (c, 2H, J = 6.7 Hz, NHCH ₂ CH ₂ ), 2.80 (t, 2H, J= 6.8 Hz, NHCH ₂ CH ₂ ) ppm.

CAS nr: [133276-82-1] Example 4: Preparation of 7V-phenethylquinoline-8-sulfonamide

Following a procedure analogous to that described in Example 2, using 8- quinolinesulfonyl chloride as the starting material, the title compound was obtained in 93% yield (Purity > 99%)

¹ H-NMR (400 MHz, CDCl ₃ ): 8.64 (dd, IH, ³ J _a . _f = 4.3 Hz, ⁴ J _a . _c = 1.7 Hz, Ha), 8.42 (dd, IH, ³ J _b . _e = 7.3 Hz, ⁴ J _b . _d = 1.2 Hz, Hb), 8.23 (dd, IH, ³ J _c . _f = 8.3 Hz, ⁴ J _c . _a = 1.7 Hz, Hc), 8.03 (dd, IH, ³ J _d . _e = 8.2 Hz, ⁴ J _d . _b = 1.2 Hz, Hd), 7.64 (dd, IH, ³ J _e . _d = 8 Hz, ³ J _e . _b = 7.6 Hz, He), 7.46 (dd, IH, ³ J _fc = 8.3 Hz, ³ J _fa = 4.3 Hz, Hf), 7.14 (m, 3H, Hg + Hh), 6.95 (m, 2H, Hi), 6.35 (t, IH, J= 5.8 Hz, NH), 3.15 (c, 2H, J= 6.6 Hz, NHCH ₂ ), 2.76 (t, 2H, J= 6.5 Hz, NHCH ₂ CH ₂ ) ppm.

CAS nr: [289500-01-2]

Example 5: Preparation of 5-(Dimethylamino)-7V-phenethylnaphthalene-l- sulfonamide

Following a procedure analogous to that described in Example 2, using dansyl chloride as the starting material, the title compound was obtained in 95% yield (Purity > 99%) ¹ H-NMR (400 MHz, CDCl ₃ ): 8.55 (d, IH, J= 8.6 Hz, Ha), 8.24 (dd, IH, ³ J _M = 7.3 Hz, %. _c = 1.3 Hz, Hb), 8.17 (d, IH, J= 8.6 Hz, Hc), 7.50 (m, 2H, Hd + Hd'), 7.16 (m, 4H, H _AT ), 6.93 (m, 2H, H _A1 ), 4.62 (t, IH, J= 6.2 Hz, NH), 3.17 (c, 2H, J= 6.5 Hz, NHCH ₂ ), 2.89 (s, 6H, N(CHs) ₂ ), 2.65 (t, 2H, J= 6.9 Hz, NHCH ₂ CH ₂ ) ppm.

CAS nr: [5282-81-5]

Example 6: Preparation of (E)-7V-phenethyl-2-phenylethenesulfonamide

Following a procedure analogous to that described in Example 2, using trans-omega- styrenesulfonyl chloride as the starting material, the title compound was obtained in 75% yield (Purity > 94%)

¹ H-NMR (400 MHz, CDCl ₃ ): 7.43 (m, 6H, H _A1 ), 7.29 (m, 2H, H _A1 ), 7.24 (d, IH, ³ J _a . _b = 15.1 Hz, Ha), 7.18 (m, 2H, H _A1 ), 6.60 (d, IH, ³ J _b . _a = 15.4 Hz, Hb), 4.37 (t, IH, J = 6.1 Hz, NH), 3.35 (c, 2H, J= 6.7 Hz, NHCH ₂ ), 2.88 (t, 2H, J= 6.8 Hz, NHCH ₂ CH ₂ ) ppm.

CAS nr: [464902-17-8]

Example 7: Preparation of 5-chloro-7V-phenethylthiophene-2-sulfonamide

Following a procedure analogous to that described in Example 2, using 5- chlorothiophene-2-sulfonyl chloride as the starting material, the title compound was obtained in 98% yield (Purity > 97%).

¹ H-NMR (400 MHz, CDCl ₃ ): 7.33 (d, IH, ⁵ J _a . _b = 4 Hz, Ha), 7.30 - 7.11 (m, 5H, H _A1 ), 6.89 (d, IH, ³ J _b . _a = 4 Hz, Hb), 4.59 (t, IH, J = 5.8 Hz, NH), 3.31 (c, 2H, J = 6.7 Hz, NHCH ₂ ), 2.82 (t, 2H, J= 6.9 Hz, NHCH ₂ CH ₂ ) ppm.

CAS nr: [900407-92-3]

Example 8: Preparation of 7V-f2-flH-indol-3-yl)ethyl)-N-phenethylnaphthalene-l- sulfonamide

Under inert atmosphere, to a stirred solution of NaH (0.016 g, 0.36 mmol) in 0.20 ml anhydrous DMF at O ⁰ C, was added a solution of compound of Example 2 (0.108 g, 0.35 mmol) in 0.60 ml anhydrous DMF. The temperature was maintained during 1.5 h. After this time, a solution of 3-(2-Bromoethyl)indole (0.088g, 0.39 mmol) in 0.6 anhydrous DMF was added dropwise to the reaction mixture of step at O ⁰ C, and was stirred during 2.5 h. Once the solvent was evaporated, the crude mixture was chromatographically purified over SiO ₂ using Hexane/ AcOEt (70:30) as the eluant, furnishing 133 mg of the desired product in 84% yield (purity > 80%, expressed in % HPLC area).

FT-IR (KBr): 3408 cm ^"1

¹ H-RMN (400 MHz, CD ₃ OD): 8.38 (m, IH, 7.98 (m, 3H, 7.76 (m, IH, HAr-Naf), ?.64 (m, 2H, HAr-Naf), 7.41 (m, IH, HAr-Ph), 7.28 (m, IH, H^), 7.20 - 6.92 (m, 8H, 4HAr-Ph + 4HAr-ind), 3.50 (t, 2H, J = 7.4 Hz, NCH ₂ CH ₂ In(I), 3.12 (t, 2H, J = 7.4 Hz, NCH ₂ CH ₂ Ph), 2.93 (t, 2H, J = 7.4 Hz, NCH ₂ CH ₂ In(I), 2.70 (t, 2H, J = 7.7 Hz, NCH ₂ CH ₂ Ph) ppm.

Example 9: Preparation of (Ε)-7V-(ϊl-methylpiperidin-3-yl)methyl)-7V-phenethyl-2- phenylethenesulfonamide

Step 1 : Under inert atmosphere, to a stirred solution of NaH (20 mg, 0.45 mmol) in 0.20 ml anhydrous DMF at O ⁰ C, was added a solution of compound of Example 6 (0.101 g, 0.20 mmol) in 0.60 ml anhydrous DMF. The temperature was maintained during 1.5 h. Step 2: Simultaneously, in another reaction vessel, NaOH 0.1M was added dropwise up to pH=12.5.The aqueous phase was extracted with CHCI3/IPA 3:1 (3x2 ml). Once the solvent was completely removed, the obtained product was 10 mg (0.067 mmol) of the free base reactant. The solid was dissolved in 0.6 ml of anhydrous DMF. Step 3: After 1.5h, the solution of step 2 was slowly added to the solution of step 1, stirring at O ⁰ C during 2.5 h. The final product crystallized in the solvent when the crude mixture was maintained overnight at -18 ⁰ C. The obtained solid was in vacuum filtered and washed with acetone at O ⁰ C, furnishing 16 mg (60 % yield) of the desired product.

¹ H-NMR (400 MHz, CDCl ₃ ): 7.51 (m, 2H, Ha), 7.38 (m, 3H, Hb), 7.30 (d, IH, J = 15.6Hz, Hc), 7.18 (m, 5H, NHCH ₂ CH ₂ Ph), 6.8 (d, IH, J = 15.6 Hz, Hd), 3.18 (m, 2H, NHCH ₂ ), 2.81 (t, 2H, J= 7.3 Hz, NHCH ₂ CH ₂ ) ppm. Example 10: Preparation of 5-chloro-7V-((2-(diaminomethyleneamino)thiazol-4- yl)methyl)-7V-phenethylthiophene-2-sulfonamide

Step 1 : Under inert atmosphere, to a stirred solution of NaH (9 mg, 0.19 mmol) in 0.2 ml anhydrous DMF at O ⁰ C, was added a solution of compound of Example 7 (0.053 g, 0.17 mmol) in 0.50 ml anhydrous DMF. The temperature was maintained during 1.5 h. Step 2: After the first Ih of step 1, in another reaction vessel, buthyllithium (2.2 eq) was added dropwise to a solution of l-(4-Bromomethyl-2-thiazoyl)guanidine, hydrobromide salt (45 mg, 0.20 mmol) in 0.5 ml anhydrous DMF at -7O ⁰ C. The reaction was stirred during 15 minutes.

Step 3: After 1.5h of step 1 and 15 minutes of step 2, the solution of step 2 was slowly added to the solution of step 1, stirring at O ⁰ C during 2.5 h.

The crude mixture was diluted in a proportion 1/5 H ₂ CVDMF and chromatographically purified using preparative HPLC in reverse phase conditions, using MeOH/H ₂ O 65/35 as the mobile phase. The eluant was completely evaporated, furnishing 48 mg (60 % yield) of the desired product.

¹ H-NMR (400 MHz, CDCl ₃ ): 7.24 (m, 4 HA ₁ ), 7.07 (d, 2H, 1 U _M + 1 Hyphen), 6.89 (d, 1 H, J= 4 Hz, H _thl ophen), 6.65 (sa, IH, 4.30 (s, 2H, NCH ₂ ttαazoie), 3.41 (t, 2H, J = 7.5 Hz, NCH ₂ CH ₂ Ph), 2.80 (t, 2H, J= 7.5 Hz, NCH ₂ CH ₂ Ph) ppm.

MS: Positive mode [M+H ⁺ ] = 459.3 Example 11: Preparation of (Ε)-7V-(Y2-guanidinothiazol-4-yl)methyl)-7V-phenethyl- 2-phenylethenesulfonamide

Step 1 : Under inert atmosphere, to a stirred solution of NaH (10 mg, 0.24 mmol) in 0.2 ml anhydrous DMF at O ⁰ C, was added a solution of compound of Example 6 (0.053 g, 0.19 mmol) in 0.50 ml anhydrous DMF. The temperature was maintained during 1.5 h. Step 2: After the first Ih of step 1, in another reaction vessel, buthyllithium (2.3 eq) was added dropwise to a solution of l-(4-Bromomethyl-2-thiazoyl)guanidine, hydrobromide salt (50 mg, 0.22 mmol) in 0.5 ml anhydrous DMF at -1O ⁰ C. The reaction was stirred during 15 minutes.

Step 3: After 1.5h of step 1 and 15 minutes of step 2, the solution of step 2 was slowly added to the solution of step 1, stirring at O ⁰ C during 2.5 h.

The crude mixture was diluted in a proportion 1/5 H ₂ CVDMF and chromatographically purified using preparative HPLC in reverse phase conditions, using MeOH/H ₂ O 65/35 as the mobile phase. The eluant was completely evaporated, furnishing 30 mg (42 % yield) of the desired product.

¹ H-NMR (400 MHz, CDCl ₃ ): 7.60 (~ d, 2H, HA ₁ ), 7.41 (m, 2H, HA ₁ ), 7.37 (d, IH, ³ J _a . _b = 15.7 Hz, Ha), 7.30-7.12 (m, 6H, H _A1 ), 6.94 (d, IH, ³ J _b . _a = 15.5 Hz, Hb), 6.65 (sa, IH, Htazoi), 4.33 (s, 2H, NCH ₂ tiazol), 3.42 (t, 2H, J= 7.6 Hz, NCH ₂ CH ₂ Ph), 2.92 (t, 2H, J = 7.5 Hz, NCH ₂ CH ₂ Ph) ppm.