OA16264A - Anti-inflammatory agents. - Google Patents

Abstract

Disclosed herein are methods of preventing or treating inflammatory diseases using sulfonamide analogs of 3-aminolactam compounds, each with aromatic "tail groups". Compounds as defined by formulae (I) and (I'), and the medical uses of the compounds, are described herein.

Description

1) Cambridge Enterprise Limited

2) Boehringer Ingelheim International Gmbïï

Apti-inflammatorv agents

The invention relates to aryl substituted 3-aminolactaïn dérivatives and their use in preventing or treating inflammatory discases. ^;

Inflammation is an important component of physiological host defence. Increasingly, however, ît is clear that temporally or spatially inappropriate inflammatory responses play a part in a wide range of diseases, including those with an obvious leukocyte component (such as autoimmune diseases, asthma or atherosclerosis) but also in diseases that hâve not traditionally been considered to involve leukocytes (such as osteoporosis or Alzheimer’s disease).

The chemokines are a large family of signalling molécules with homology to interieukin-8 which hâve been implicated în regulating leukocyte trafficking both in physiological and pathological conditions. With more than fifty ligands and twenty receptors involved in chemokine signalling, the System has tire requîsite information density to address leukocytes through the complex immune regulatory processes from the bone marrow, to the periphery, then back through secondary lymphoîd organs. However, this complexity of the chemokine

System has at first hindered pharmacological approaches to modulating inflammatory responses through chemokine receptor blockade. It has proved diflicult to détermine which chemokine receptor(s) should be inhibited to produce therapeutic bcnefit in a given inflammatory disease.

More recently, a family of agents which block signalling by a wide range of chemokines simultaneously lias been described (see Reckless et al., Bîochem J. (1999) 340: 803-811). The first such agent, a peptide termed “Peptide 3”, was found to inhibit leukocyte migration induced by 5 different chemokines, wliile leaving migration in response to other chcmoattractants (such as fMLP or TGF-beta) unaltercd. This peptide, and its analogs such as NR58-3.14.3 (i.e. c(DCys-DGln-DIie-DTrp-DLys-DGln-DLys-DPro-DAsp-DLeu-DCys)-NH₂ [SEQ ID NO: 1]), are collectively termed “Broad Spectrum Chemokine Inhibitors” (BSCIs). Grainger et al. (2003, Bîochem. Pharm. 65:1027-1034) hâve subsequently shown BSCIs to hâve potentially useful anti-inflammatory activity in a range of animal niodels of diseases. Iiiterestingly, simultaneous blockade of multiple chemokines is not apparently associated with acutc or chronic toxicity, suggesting tliis approach may be a useful strategy for developîng new anti-inflammatory médications with similar benefits to steroids but with reduced sidecffects. Tliis bénéficiai riskibencfit profile most likely results from the unexpcctcd mcclianism of action of these compounds (see International Patent Appl. No. PCT/GB2010/000354 in the name of Cambridge Enterprise Limited filed 28 Fcbruary 2010, and International Patent Appl.

No. PCT/GB2010/000342 in the name of Cambridge Enterprise Limited filed 26 February

2010).

However, peptides and peptoid dérivatives such as NR58-3.14.3, may not be optimal for use in vivo. They are quite expensive to synthesise and hâve relatively unfavourable pharmacokinetic and pharmacodynamie properties. For example, NR58-3.14.3 is not orally bioavailable and is cleared from blood plasma with a half-life period of less than 30 minutes after intravenous injection.

Two parallel strategies hâve been adopted to identify novel préparations that retain the antiinflammatory properties of peptide 3 and NR58-3.14.3, but hâve improved characteristics for use as pharmaceuticals. Firstly, a sériés of peptide analogs hâve been developed, some of which hâve longer plasma half-lives than NR58-3.14.3 and which are considerably cheaper to synthesise (see for example W02009/017620). Secondly, a detailed structure: activity analysis of the peptides has been carried out to identify the key pharmacophores and design small non-peptidic structures which retain the bénéficiai properties of the original peptide.

This second approach yielded several structurally distinct sériés of compounds that retained the anti-inflammatory properties of the peptides, including 16-amino and 16-aminoalkyl dérivatives of the alkaloid yohimbine, as well as a range of N-substituted 3-aminoglutarimides, identified from a small combinatoriai library (see Fox et al., 2002, J Med Chem 45: 360-370; WO 99/12968 and WO 00/42071 ). Ail of these compounds are broad-spectrum chemokine inhibitors that retain selectivity over non-chemokine chemoattractants, and a number of them hâve been shown to block acute inflammation in vivo.

The most potent and sélective of the above-mentioned aminoglutarimides was (S)-3-(undecIO-enoyl)-aminoglutarimide (NR58,4), which inhibited chemokine-induced migration in vitro with an ED₅₀ of 5nM. This compound was orders of magnitude more potent than 3aminoglutarimides with more complex acyl side chains (such as benzoyl or tert-butyloxo (Boc) groups). As a resuit, subséquent studies of aminoglutarimide and aminolactam BSCIs hâve focussed aimost exclusively on compounds with simple linear and branched alkyl side chains.

However, further studies revealed that the aminoglutarimide ring was susceptible to enzymatic ring opening in sérum. Consequently, for some applications (for example, where the inflammation under treatment is chronic, such as in autoimmune diseases) these compounds may not hâve optimal properties, and a more stable compound with similar anti-inflammatory properties may be superior.

As an approach to identifying such stable analogs, various dérivatives of (S)- 3-(undec-l0enoyl)-aminoglutarimide hâve been tested for their stability in sérum. One dérivative, the 6deoxo analog (S)-3-(undec-l0-enoyl)-tetrahydropyridin-2-one, is completely stable in human sérum for at least 7 days at 37°C, but has considerably reduced potency compared with the parental molécule.

One such family of stable, broad spectrum chemokine inhibitors (BSCIs) are the 3-amino caprolactams, with a seven-membered monolactam ring (see, for example, W02005/053702 and W02006/016152). However, further useful anti-inflammatory compounds hâve also been generated from other 3-aminolactams with different ring size (see for example W02006/134385). Other modifications to the lactam ring, including introduction of heteroatoms and bicyclolactam ring Systems, also yield compounds with BSCI activity (see, for example, W02006/018609 and W02006/085096).

In general, these earlier studies hâve demonstrated that the BSCI activity is conferred on the molécule by the cyclic “head group” (a 3-amino lactam or imide) and defined, to an extent, the structural limitations for activity (for example, bulky substituents on the ring nitrogen are detrimental for activity, but variations in ring size hâve little impact). To be active as a BSCI, this “head group” must hâve an acyl “tail group” attached. Compounds with a 3-amino group, either free or N-alkyl substituted, bearing a positive charge at physiological pH are completely inactive as BSCIs. Previous disclosures hâve shown that this “tail group” can be lînked to the “head group” through simple amide, sulfonamide, urea or carbamate linkers.

While the structure of the “head” group and linker are critical for BSCI activity, it has been shown that a wide variety of “tail groups” can be selected with out affecting the primary pharmacology of the compound, at least in vitro. As a resuit, modification of the “tail group” has been extensively used to optimise the physical and pharmaceutical properties of the compounds. Changes in the structure of the “tail group” can, for example, change the primary route of metabolism or excrétion, modify the pharmacokinetics or oral bioavailability, and thus act as the primary déterminant of the ADME properties of a selected compound.

Although the universe of possible “tail groups” known to retain BSCI activity for suitable aminolactam “head groups” is very large, some “tail groups” hâve been described as preferred. In some cases, structural features of the “tail group” hâve been identified which increase the potency of BSCI activity of the aminolactam compound. The most obvious such example is the introduction of 2’,2’ disubstitution, with a tetrahedral sp3 arrangement at the 2’ carbon centre in the tail group (the so-called “key carbon”), which confers a I0-fold increase in potency as a BSCI, at least in vitro, compared to a related compound lacking 2’2’- ·_ disubstitution. For example, 2’2’-dimethyldodecenanoyl-3-aminocaprolactam is I0-fold more potent as a BSCI in the MCP-l induced THP-l cell migration than assay than dodecanoyl-3aminocaprolactam (as disclosed previously in W02005/053702), or indeed any other related compound with a linear alkyl “tail group”. The increased potency for branched alkyl “tail groups” is restricted to branching at the 2’ position - 3’3’-dimethyldodecanoyl-3aminocaprolactam is no more potent than the linear alkyl analogs.

In other cases, structural features of the “tail group” hâve been identified which are associated with improved ADME properties. For example, the pivoyl “tail group” of 2’2’dimethylpropanoyl-3-ammovalerolactam contributes to the unexpected, and particularly favourable, pharmaceutical properties of this molécule (as disclosed previously in W02009/016390). In particular, the pivoyl group is résistant to met aboi ism, and therefore contributes to the unusually prolonged biological half-life of this compound.

In marked contrast, other possible “tail groups” hâve generally been less preferred. For example, compounds with a planar (sp2) carbon centre at the 2’ position (such as dodec-2’,3*enoyl-3-ammocaprolactam) hâve markedly lower potency as BSCIs than compounds with corresponding saturated alkyl “tail groups”. Sîmilarly, the data from the original library of glutarimides suggested that aromatic rings at the 2-position were also substantially less active (Fox et al., 2002, J Med Chem 45: 360-370), Taken together, these two findings hâve led to the reasonabie assumption that aminolactams with aromatic “tail groups”, such as benzoyl or substituted benzoyl, would not be useful as BSCIs. As a resuit, previous disclosures of compounds with BSCI activity hâve all excluded such aromatic “tail groups”.

The présent invention discloses a sériés of sulfonamide analogs of 3-aminolactam compounds, each with aromatic “tail groups”, as well as pharmaceutical compositions comprising the compounds, and medical uses of the compounds and compositions such as for the treatment of inflammatory diseases. Surprisingly, all of the compounds as set out below hâve substantiel BSCI activity (greater than either 2’,3’-unsaturated acyl 3-aminolactams or benzoylaminoglutarimides).

In one aspect of the invention, there is provided a compound of general formula (I), or a pharmaceutically acceptable sait thereof, for use in the treatment of an inflammatory disorder:

wherein n is an integer from l to 4;

k is an integer from 0 to 5, representing the number of groups substituting C₂, C₂, C₄, C5 and/or C₆ of the benzyl ring; and

X are linear or branched groups substituting the benzyl ring independently selected from any one of the group consisting of: alkyl, haloalkyl, hydroxyalkyl, hydroxy, alkoxy, amino, aminoalkyl, aminodialkyl, carboxy, and halogen.

The carbon atom at position 3 of the lactam ring is asymmetric and consequently, the compounds according to the présent invention hâve at least two possible enantiomeric forms, that is, the “R” and “S” configurations. The présent invention encompasses each of the two enantiomeric forms and ail combinations of these forms, including the racemic “RS” mixtures. With a view to simplicity, when no spécifie configuration is shown in the structural formula, it should be understood that each of the two enantiomeric forms and their mixtures are represented.

Also provided according to the invention is a compound of formula (Γ), or a pharmaceutically acceptable sait thereof, for use in the treatment of an inflammatory disorder:

wherein n, k and X are defined as above.

Compounds (Γ), having the (S)-configuration at the stereocentre, are 5-100 fold more potent as a BSCIs than the (R)-enantiomer of the same compound.

The invention additionally provides the use of a compound of general formula (I), or a pharmaceutically acceptable sait thereof, in the manufacture of a médicament for the treatment of an inflammatory disorder:

wherein n is an integer from l to 4;

k is an integer from 0 to 5, representing the number of groups substituting C₂, C,, C₄, C₅ and/or C₈ of the benzyl ring; and

X are linear or branched groups substituting the benzyl ring independently selected from any one of the group consisting of: alkyl, haloalkyl, hydroxyalkyl, hydroxy, alkoxy, amino, aminoalkyl, aminodialkyl, carboxy, and halogen.

Also provided according to the invention is the use of a compound of formula (I’), or a pharmaceutically acceptable sait thereof, in the manufacture of a médicament for the treatment of an inflammatory disorder:

wherein n, k and X are defïned as for general formula (I) above.

Certain compounds hâve been found to be novelperse. Thus, in another aspect of the invention, there is provided a compound of general formula (I):

wherein n, k and X are as defïned for (I) above, with the proviso that:

when n = 3, then at least one of C₂-Cè on the benzyl ring is substituted with a group other than halogen, C1-C7 alkyl, or C1-C7 haloalkyl; and when η = l, 2 or 3, then

C₂ or Cf, on the benzyl ring are other than hydrogen or fluorine, or

Ci on the benzyl ring is other than hydrogen, halogen, C]-C₆ alkyl, C_rC₆ alkoxy, or Ci-C₆ haloalkyl, or

C₄ on the benzyl ring is other than hydrogen, halogen, C]-C₆ alkyl, C_t-C₆ alkoxy, Ci-C₆ haloalkyl, amino, aminoalkyl or aminodialkyl, or

C5 on the benzyl ring is other than hydrogen or halogen; and provided that the compound is neither of the group consisting of: 3-(2'carboxybenzenesulfonylamino)-tetrahydropyridin-2-one, and (R)-3-(4'methylbenzenesulfonylamino)-caprolactam.

For the avoidance of doubt, it is noted that according to the invention the compounds of general formula (I) do not include the compounds 3-(4'-methylbenzenesulfonylammo)tetrahydropyridin-2-one, 3-(4'-chlorobenzenesulfonylamino)-caprolactam, 3-(4'bromobenzenesulfonylamino)-caprolactam, (R)-3-(4'-trifluoromethylbenzenesulfonylamino)16264 caprolactam, 3-(4'-chlorobenzenesulfonylamino)-caprolactam, and 3-(4’methylbenzenesulfonylamino)-caprolactam.

Also encompassed by the invention is a compound of formula (!’):

wherein n, k and X are defined as for general formula (I) above, provided that the compound is none of the group consisting of: (S)-3-(4'methylbenzenesulfonylamino)-tetrahydropyridin-2-one, (S)-3-(4^Tmethylbenzenesulfonylamino)-caprolactam, (S)-3-(4'-bromobenzenesulfonylamino)caprolactam, and (S)-3-(4’-chlorobenzenesulfonylamino)-caprolactam.

W02005/042489 teaches sulphonamide compounds of formula 9.0 (page 91) as intermediates for the préparation in “Scheme 3” of N-substituted benzenesulfonamides that are stated to be for use in treating cognitive disorders. Overlap with these intermediate compounds is hereby disclaimed from the présent invention.

US2007/0037789 teaches fluoro substituted 2-oxo-azepan dérivâtes as γ-secretase inhibitors. Intermediate compounds such as according to formula IV in Scheme l (see paragraph [0085]) are used in the synthesis of those dérivâtes. Overlap with the intermediate compounds is hereby disclaimed from the présent invention.

W02006/005486 teaches sulphonamide dérivâtes for the treatment of Alzheimer’s disease or common cancers. Intermediate compounds such as according to formula IV (see page 12) are used in the synthesis of those dérivâtes. Overlap with the intermediate compounds is hereby disclaimed from the présent invention.

W02007/0038669 teaches diarylamine-containing compounds and their use as modulators of c-kit receptors. Various intermediate compounds are used în the synthesis of the diarylaminecontaining compounds. Any overlap of the intermediate compounds is hereby disclaimed from the présent invention, k.

The prior art also discloses spécifie compounds, for example:

S-P'-carboxybenzenesulfonylaniinol-tetrahydropyridin^-one is disclosed in Gombar et al. (1991) Quantitative Structure-Activity Relationships 10: 306-332;

3-(4'-methylbenzenesulfonylamino)-tetrahydropyridin-2-one is disclosed in Gut & Rudinger (1963) Collection of Czechoslovak Chemical Communications 28: 29532968;

(S)- 3-(4'-methylbenzenesulfonylamino)-tetrahydropyridin-2-one is disclosed in Maguire et al. (1990) J. Organic Chem. 55: 948-955;

3-(4’-bromobenzenesulfonylamino)-caprolactam (in (S)- and (R)- forms, and with unspecified stereochemistry) and (S)-3-(4'-chlorobenzenesulfonyIamino)-caprolactam are disclosed in Parker et al. (2007) Bioorganic & Médicinal Chemistry Letters 17: 5790-5795;

3-(4'-methylbenzenesulfonylamino)-caprolactam is disclosed in W02004/033455; and (R)-3-(4'-methylbenzenesulfonylamino)-caprolactam is disclosed in DE4117507.

However, none of the above prior art compounds hâve been shown to hâve BSCI activity, or to be useful for the treatment of inflammatory diseases. As a resuit, compounds disclosed in the prior art documents mentioned herein in no way teach or suggest our unexpected fïnding that the class of sulfonamide analogs of aryl-substituted aminolactams as defined herein hâve useful BSCI activity, and the prior art compounds are hereby disclaimed.

In another aspect of the invention, there is provided a pharmaceutical composition comprising, as active ingrédient, a compound per se as defined above, or a pharmaceutically acceptable sait thereof, and at least one pharmaceutically acceptable excipient and/or carrier.

By pharmaceutically acceptable sait is meant in particular the addition salts of inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulphate, phosphate, diphosphate and nitrate or of organic acids such as acetate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulphonate, p-toluenesulphonate, palmoate and stéarate. Also within the scope of the présent invention, when they can be used, are the salts formed from bases such as sodium or potassium hydroxide. For other examples of pharmaceutically acceptable salts, reference can be made to “Sait sélection for basic drugs” (1986) Int. J. Pharm. 33: 201-217.

The pharmaceutical composition can be in the form of a solid, for example powders, granules, tablets, gelatin capsules, liposomes or suppositories. Appropriate solid supports can be, for example, calcium phosphate, magnésium stéarate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyi cellulose, polyvinylpyrrolidine and wax.

Other appropriate pharmaceutically acceptable excipients and/or carriers will be known to those skilled in the art.

The pharmaceutical compositions according to the invention can also be presented in liquid form, for example, solutions, émulsions, suspensions or syrups. Appropriate liquid supports can be, for example, water, organic solvents such as glycerol or glycols, as well as their mixtures, in varying proportions, in water.

Exemplar compounds according to general formula (I) and formula (I’) for medical uses according to the invention may be selected from the group consisting of:

(S)-3-(3'-fluorobenzenesulfonylamino)-tetrahydropyridin-2-one, (S)-3-(4'-fluorobenzenesulfonylamino)-tetrahydropyridin-2-one, (S)-3-(2’-trifluoromethylbenzenesulfonylamino)-tetrahydropyridin-2-one, (S)-3-(3'-trifluoromethylbenzenesulfonylamino)-tetrahydropyridin-2-one, (S)-3-(4’-trifluoromethylbenzenesulfonylamino)-tetrahydropyridin-2-one [also known as (S)N-(2-oxopiperidin-3-yl)-4-(trifluoromethyl)benzenesulfonamide or (S)-3-(4'20 trifluoromethylbenzenesulfonylamino)piperidin-2-one], ( S)-3 -(2',4'-di fluorobenzenesulfonylamî no)-tetrahydropyridin-2 -one, (S)-3-(2',5'-difluorobenzenesulfonylamino)-tetrahydropyridin-2-one, (S)-3-(2',6'-difluorobenzenesulfonylamino)-tetrahydropyridin-2-one, (S)-3-(3',4'-difluorobeiizenesulfonylaniino)-tetrahydropyridin-2-one, (S)-3-(3',5'-dtfluorobenzenesulfonylamino)-tetrahydropyridin-2-one, (S)-2-Fluoro-N-(2-oxopiperidin-3-yl)benzenesulfonamide [also known as (S)-3-(2'fluorobenzenesulfonylamino)-tetrahydropyridin-2-one], (S)-3-(4'-Ethylbenzenesulfonylamino)-azepan-2-one, (S)-3-(4'-Butylbenzenesulfonylamino)-azepan-2-one, (S)-3-(4'-reri-Butylbenzenesulfonylamino)-azepan-2-one, (S)-3-(4^,-teri-Butylbenzenesulfonylamino)-tetrahydropyridin-2-one, (S)-3-(4’-Octylbenzenesulfonylamino)-azepan-2-one, and (S)-3-(4’-Octylbenzenesulfonylamino)-tetrahydropyridin-2-one, and pharmaceutically acceptable salts thereof. _

Exemplar per se compounds of the invention according to general formula (I) and/or exemplar compounds according to general formula (I*) for medical uses according to the invention may be selected from the group consisting of:

(R)-3-(4'-Ethylbenzenesulfonylamino)-tetrahydropyridin-2-one, (R)-3-(4'-re/ï-Butylbenzenesulfonylamino)-tetrahydropyridin-2-one, (R) -3-(4'-Octylbenzenesulfonylamino)-tetrahydropyridin-2-one, and pharmaceutically acceptable salts thereof.

Exemplar per se compounds of the invention according to general formula (I) and formula (F) may be selected from the group consisting of:

(S) -3-(3^,-fluorobenzenesulfonylamino)-tetrahydropyridin-2-one, (5)-3-(4'-fluorobenzenesulfonylamino)-tetrahydropyridin-2-one, (S)-3-(2^,-trifluoromethylbenzenesulfonylamino)-tetrahydropyridin-2-one, (S)-3-(3'-trifluoromethylbenzenesulfonylamirio)-tetrahydropyridin-2-one, (S)-3-(4'-trifluoromethylbenzenesulfonylamino)-tetrahydropyridin-2-one, (S)-3-(2’,4'-difluorobenzenesulfonylamino)-tetrahydropyridin-2-one, (S)-3-(2',5'-difluorobenzenesulfonylammo)-tetrahydropyridin-2-one, (S)-3-(2',6'-difluorobenzenesulfonylamino)-tetrahydropyridin-2-one_! (S)-3-(3',4'-difluorobenzenesulfonylamino)-tetrahydropyridin-2-one, (S)-3-(3’,5^,-difluorobenzenesulfonylamino)-tetrahydropyridin-2-one, (S)-2-Fluoro-N-(2-oxopiperidin-3-yl)benzenesulfonamide, (S)-3-(4'-Ethylbenzenesulfonylamino)-azepan-2-one, (S)-3-(4’-Butylbenzenesulfonylamino)-azepan-2-one, (S)-3-(4'-A?ri-Butylbenzenesulfonylamino)-azepan-2-one, (S)-3-(4'-ter/-ButylberLzenesulfonylamino)-tetrahydropyridin-2-one, (S)-3-(4'-Octylbenzenesulfonylamino)-azepan-2-one, and (S)-3-(4'-Octylbenzenesulfonylamino)-tetrahydropyridin-2-one, and pharmaceutically acceptable salts thereof.

An exemplar compound according to general formula (I) or (Γ) for medical uses according to the invention is (S)-3-(4'-methylbenzenesulfonylamino)-caprolactam, or a pharmaceutically acceptable sait thereof.

Il

An exemplar cornpound per se or for medical use according to formula (Γ ) _is (S)-3-(4'trifluoromethylbenzenesulfonylaniino)-tetrahydropyridin-2-one, or a pharmaceutically acceptable sait thereof.

According to the invention, inflammatory disorders (which term is used herein interchangeably with “inflammatory disease”) intended to be prevented or treated by the compounds of formula (I) or (Γ), or pharmaceutically acceptable salts thereof or pharmaceutical compositions or médicaments containing them as active ingrédients, include notably:

autoimmune dîseases, for example such as multiple sclerosis, rheumatoid arthritis, lupus, irritable bowel syndrome, Crohn’s disease;

vascular disorders including stroke, coronary artery dîseases, myocardial infarction, unstable angina pectoris, atherosclerosis or vasculitîs, e. g., Behçet's syndrome, giant cell arteritis, polymyalgia rheumatica, Wegener's granulomatosis, Churg-Strauss syndrome vasculitis, Henoch-Schônleîn purpura and Kawasaki disease;

asthma, and related respiratory disorders such as allergie rhinitis and COPD;

organ transplant rejectîon and/or delayed graft or organ function, e.g. in rénal transplant patients;

psoriasis;

skîn wounds and other fîbrotic disorders including hypertrophie scarring (keloid formation), adhesion formations following general or gynaecological surgery, lung fibrosis, liver fibrosis (including alcoholic liver disease) or kidney fïbrosis, whether idiopathic or as a conséquence of an underlying disease such as diabètes (diabetic nephropathy); or allergies.

The inflammatory disorder may be selected from the group consisting of autoimmune dîseases, asthma, rheumatoid arthritis, a disorder characterised by an elevated TNF-α level, psoriasis, allergies, multiple sclerosis, fibrosis (including diabetic nephropathy), and formation of adhesions.

The above clinical indications fall under the general définition of inflammatory disorders or disorders characterized by elevated TNFa levels.

In one aspect of the invention, merely in order to circumvent any potentially conflicting prior art (for example as noted above), the term inflammatory disorder may exclude cognitive dîsorders such as Alzheimer’s disease and/or memory loss.

Compounds of formula (I) or (Γ) are particularly useful for local delivery, and also for the préparation of médicaments for local delivery, including creams and ointments for topical delivery, powders, aérosols or émulsions for inhaled delivery, and solutions or émulsions for injection. Pharmaceutical compositions containing one or more excipients suitable for such local delivery are therefore envisaged, and subsequently claimed.

Also provided according to the invention is a method of treatment, amelioration or prophylaxis of the symptoms of an inflammatory disease (including an adverse inflammatory reaction to any agent) by the administration to a patient of an anti-inflammatory amount of a compound, pharmaceutical composition or médicament as defined herein.

Administration of a compound, composition or médicament according to the invention can be carried out by topical, oral, parentéral route, by intramuscular injection, etc.

The administration dose envisaged for a compound, composition or médicament according to the invention is comprised between O.l mg and 10 g depending on the formulation and route of administration used.

The invention further encompasses a library consisting of éléments ail of which hâve structures according to the formula (I) or (I’), and hence which ail hâve anti-inflammatory activity, useful for screening compounds for novel or improved properties in a particular assay of anti-inflammatory activity.

The invention includes compounds, compositions and uses thereof as defined, wherein the compound is in hydrated or solvated form. Unless specified otherwise, compounds of the invention include tautomers, resolved enantiomers, resolved diastereomers, racemic mixtures, solvatés, métabolites, salts and prodrugs thereof, including pharmaceutically acceptable salts and prodrugs.

In any of the compounds according to formula (I) or (I’) described above (per se and/or for medical use), n may be 2. Altematively, n may be 3.

X may be haloalkyl, for example trifluoromethyl.

An exemplar group of compounds per se and/or for medical use according to any aspect of the invention is selected from among compounds according to formula (I) or (I’) where X is halogen or haloakyl and where k is between 1 and 3. For example, X may be fluoro or fluoroalkyl (such as trifluoromethyl) and k may be between 1 and 3.

In particular, where permissible according to the formulae herein, the benzyl ring may be monosubstituted with a group X as defîned above (i.e. k = 1). For example, the benzyl ring may be monosubstituted with an alkyl (such as other than para-methyl), haloalkyl (such as trifluoromethyl, for example para-trifluoromethyl [i.e. 4’-trîfluoromethyl]). The benzyl ring may be monosubstituted with a halogen. The benzyl ring may be monosubstituted with orthocarboxy (i.e. 2’-carboxy).

In one aspect, the above features for k=l apply when n=2.

According to the invention, the compounds of general formula (I) or (I’) can be prepared using the processes described hereafter.

DEFINITIONS

The term “about” refers to an interval around the considered value. As used in this patent application, “about X” means an interval from X minus 10% of X to X plus 10% of X, and preferably an interval from X minus 5% of X to X plus 5% of X.

The use of a numerical range in this description is intended unambiguously to include within the scope of the invention ail individual integers within the range and ail the combinations of upper and lower limit numbers within the broadest scope of the given range. Hence, for example, the range of 0. lmg to 10g specified in respect of (inter alia) a dose of a compound or composition of the invention to be used is intended to include ail doses between 0. lmg and 10g and ail sub-ranges of each combination of upper and lower numbers, whether exemplified explicitly or not.

As used herein, the term “comprising” is to be read as meaning or encompassing both comprising and consisting of. Consequently, where the invention relates to a “pharmaceutical composition comprising as active ingrédient” a compound, this terminology is intended to cover both compositions in which other active ingrédients may be présent and also compositions which consist only of one active ingrédient as defîned.

The term “alkyl” or “alkyl group” as used herein refers to a saturated linear or branched- chain monovalent hydrocarbon radical, for example of one to twenty carbon atoms, one to twelve carbon atoms, one to six carbon atoms, one to four carbon atoms, or as otherwise specified herein. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH₃), ethyl (Et, —/

-CH₂CH₃), l-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH₃)₂), lbutyl (n-Bu, n- butyl, -CH₂CH₂CH₂CH₃), 2-methyl-l-propyl (i-Bu, i-butyl, -CH₂CH(CH₃)2), 2butyl (s- Bu, s-butyl, -CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH₃)₃), lpentyl (n- pentyl, -CI ΙίΉΥΗ.ΛΊΙ-ίΉι), 2-pentyl (-Cl·f(CH₃)CH2CH₂Cl·F), 3-pentyl (CH(CH,CH,)Y 2-methyl-2-butyl (-C(CHs)₂CH2CH₃), 3-methyl-2-butyl (CH(CH₃)CH(CH₃)₂), 3-methyl-l -butyl (-CH₂CH₂CH(CH₃)2), 2-methyl-l -butyl (CH₂CH(CH₃)CH2CH₃), 1-hexyl (-CH₂CH2CH2CH₂CH2CH₃), 2-hexyl (CH(CH₃)CH2CH2CH₂CH₃), 3-hexyi (-CH(CH₂CH₃)(CH₂CH₂CH₃)), 2-methyl-2-pentyl (C(CHs)₂CH₂CH₂CH₃), 3-methyl-2-pentyl (-CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2- pentyl (CH(CH₃)CH₂CH(CH₃)2), 3-methyl-3-pentyl (-C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl (CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (-C(CH₃)₂CH(CH₃)₂), 3,3- dimethyl-2-butyl (CH(CH₃)C(CH₃)₃,1-heptyl, and 1-octyl.

The term “haloalkyl” or “haloalkyl group” as used herein refers to an alkyl group (as defined above) except that one or more or ail of the hydrogens of the alkyl group is replaced by a halogen, which replacement can be at any site on the alkyl, including the end. Examples include, but are not limited to, CH₂F, CHF₂, CF₃, CH2CH2F5 CH₂CHF₂, CH₂CF₃, CHFCF₃, CF₂CF₃, CH2CI, CHCI2, CC1₃, CH2CH2CI, CH2CHCI2, CHîCClj, CHC1CC1₃, and CC1₂CC1₃,

The term “halogen” (which may be abbreviated to “halo”) or “halogen group” as used herein includes fluorine (F), bromine (Br), chlorine (Cl), and iodine (I).

The tenu “hydroxy” or “hydroxy group” dénotés the group “-OH”.

The term “hydroxyalkyl” or “hydroxyalkyl group” as used herein refers to an alkyl group (as defined above) except wherein one or more or ail of the hydrogens of the alkyl group is replaced by an hydroxy group, which replacement can be at any site on the alkyl, including the end.

The term “alkoxy” or “alkoxy group” dénotés an alkyl group as defined above attached via a divalent oxygen atom to the rest of the molécule. Examples include but are not limited to methoxy (-OCH₃), ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, neopentoxy, hexoxy, and 3-methylpentoxy.

The term “amino” or “amino group” dénotés the group “-NH₂”.

The term “aminoalkyl” or “aminoalkyl group” refers to an amino group in which one of the hydrogen atoms has been replaced by an alkyl group as defined above.

The terrn “aminodialkyl” or “aminodialkyl group” refers to an amino group in which both of the hydrogen atoms hâve been replaced by an alkyl group as defined above. The alkyl groups attached to the nitrogen atom may be different or the same.

The terrn “carboxy” or “carboxy group” dénotés the group “-C(O)OH”.

The terrn “benzyl ring” (also known as a “phenyl group”) refers to a 6 carbon aryl group in compounds of general formulae (I) and (I*) shown above. For the purposes of the general formulae of the présent invention, numbering to locate the carbon atoms C₂-Cô within the benzyl ring is in a clockwise direction from C| which is linked to the 3-aminolacîam group. However, numbering of ring carbons with respect to one or more substituent groups on the benzyl ring for spécifie compounds follows the IUP AC rule that the second substituent in a clockwise or counter clockwise direction is afforded the lower possible location number. Where two or more substituents are présent in a spécifie compound, the IUP AC rule is that they are listed in alphabetical order. Location numbers on the ring are assigned according to the IUP AC rule to the substituents so that they hâve the lowest possible number (starting from C, which is linked to the 3-aminolactam group), counting in either a clockwise or counterclockwise direction.

As would be understood by a person skilled in the art, where there are fewer than 5 groups substituting the benzyl ring in compounds of general formulae (I) and (I*), i.e., where lc=0, l 2, 3 or 4, the or each unsubstituted position is occupied by a hydrogen atom.

Unless otherwise defined, ail the technical and scientific tenus used here hâve the same meaning as that usualiy understood by an ordinary specialist in the field to which this invention belongs. Similarly, ail the publications, patent applications, ail the patents and ail other référencés mentioned here are incorporated by way of reference (where legally permissible).

Préparation of the compounds of general formula (1) or (F)

Typically, such compounds are made by coupling the “tail group” in the form of a suitably activated acid (such as an acid chloride) with the appropriate 3-aminolactam. Methods for the préparation of 3-aminolactams with 5, 6, 7 and 8 membered rings, encompassing ail the compounds claimed herein, hâve been extensively described in the literature. For example, we hâve provided suitable methods for the préparation of 6-membered aminolactams from omithine (see W02009/016390) and 7-membered aminolactams from lysine (see —16

W02005/053702), as well as methods for 5- and 8-membered aminolactams (see W02006/134385). We hâve described in particular detail various synthesis routes to the 6membered aminolactam, including processes suitable for scaling up the manufacture to Kg quantities (W02009/016390). Various other methods for the synthesis of 3-aminolactams of various ring sizes hâve also been described in the literature (see for example Pellegata et al., 1978, Synthesis 614-616 and Boy le et al., 1979, J Org Chem 44:4841-4847), and any suitable method for the préparation of the aminolactam “head group” may be employed in accordance with the method of the présent invention.

In the second step, the 3-aminolactam product is reacted with an appropriate sulfonyl chloride, for example as previously described for 7-ring aminolactams (Fox et al., 2005, J Med Chem 48: 867-74) but using a sulfonyl chloride (RS(O₂)C1) instead of a carboxylic acid derived acid chloride (RC(O)Cl). This reaction may be carried out, for example, in chloroform or dichloromethane. The most preferred reaction solvent is dichloromethane, and is preferably carried out in the presence of a base, for example Na₂COi or triethylamine (e.g. by a method similar to that described in WO 2006/005486 or Parker et al. (2007) Bioorganic & Médicinal Chemistry Letters 17: 5790-5795). The above reaction may be carried out at ambient température (about 25 °C) or more generally at a température between 20 and 50 °C. The two reactions may be carried out independently, with séparation and purification of the 3aminolactam between the reactions, or altematively, the reactions may be performed in a single vessel without purification of the 3-aminolactam prior to its derivatisation with sulfonyl chloride.

As noted previously (see W02009/016390) care must be exercised during the acylation reaction when preparing an enantiomerically pure compound, according to formula (Γ) by acylating an enantiomerically pure 3-aminolactam. In particular, the base, such as sodium carbonate, must be added slowly continually monitoring the pH of the reaction vessel to ensure that the pH of the reaction remains below pH 9.0 throughout. Excess basicity, for example due to rapid or excessive addition of sodium carbonate, increases the racémisation of the 3aminolactam and yields enantiomerically impure product.

The following examples are presented in order to illustrate the above procedures and should in no way be considered to limit the scope of the invention.

FIGURES

Fig. I shows the chemical structure of various examples of compounds according to the invention and reference examples; and

Fig. 2 is a graph showing the results of a murine sub-lethal endotoxemia test. In the graph, column A shows data from a control group (l% CMC lOml/kg p.o.), column B shows data from a group treated with lOmg/kg p.o. thalidomide, column C shows data from a group treated with lOmg/kg p.o. (S)-3-(4'-trifluoromethylbenzenesulfonyl-amino)-tetrahydropyridin-

2- one (a compound according to one embodiment of the présent invention - see also Example 4 below) and column D shows data from a group treated with l mg/kg p.o. of the somatotaxin (S)-3-(adamantane-l-carbonyl) aminocaprolactam (see W02006/016I52). The y-axis shows levels of TNF-α in pg/ml.

EXAMPLES

In the following examples, 'H-NMR and ^l3C-NMR spectra were recorded on a Bruker Avance DRX 400 MHz fourier transform machine and ^l9F-NMR spectra were recorded on a Bruker Avance DRX 300. Chemical shifts are given in ppm and coupling constants, J, are given in Hz to the nearest 0.5. IR spectra were recorded on an Avatar 320. HRMS data was gained via an Esquire 2000. [a]o values were recorded on an optical activity AA 1000 polarimeter set at 598 nm (Sodium D line). The samples were made using spectroscopic grade MeOH.

Reference Example 1: 3-(4’-Methylbenzenesulfonylamino)tetrahydropyridin-2-one:

3- aminotetrahydropyridin-2-one hydrochloride (10 mmol), K₂CO₃ (30 mmol) and 4methylbenzenesulfonyl chloride (10 mmol) were reacted according to the above procedure to give the product (1.64 g, 69%):

Vmax/cm'¹ 3224, 1658 (secondary CONH, lactam), 1598, 1494 (aromatic ring), 1324, 1161 (SO₂-N), 814, 802 (pora-disubstituted benzene).

‘H NMR: Ô_f[ (400MHz, CDClj) 7.77 (2H, d, J 8.5, ortho-H), 7.29 (2H, d, J 8.0, meta-H), 5.79 (IH, br d, J 1.0, C₇H₇-SO₂N//)> 5.56 (IH, brs, CONH-CH₂), 3.49-3.42 (IH, m, CH-CO), 3.313.24 (2H, m, CTriNH), 2.53-2.45 (IH, m, lactam CH₂), 2.40 (3H, s, CHj), 1.97-1.88 (IH, m, lactam CH₂), 1.88-1.68 (2H, m, lactam CH₂).

ⁿC NMR: ô_c (100MHz, CDCl₃) 172.2 (lactam C=O), 142.2 (ipso-C), 136.2 (para-C), 129.7 (aromatic CH), 127.3 (aromatic CH), 53.3 (CH-CO), 42.0 (CH₂-NH), 29.6 (lactam CH₂), 28.6 (lactam CH₂), 27.9 (lactam CH₂), 21.5 (CH₃).

HRMS (+ESI) C₁₂H|₆N₂O.,S + Na⁺: calcd 291.0774; found 291.0777.

Référencé Example 2: 3-(4’-Methylbenzenesulfonylamino)azepan-2-one:

3-aminoazepan-2-one hydrochloride (10 mmol), K.₂CO₃ (30 mmol) and 4methylbenzenesulfonyl chloride (10 mmol) were reacted according to the above procedure to give the product (1.70 g, 67%):

Vmax/cm'¹ 3393, 1658 (secondary CONH, lactam), 1598, 1496 (aromatic ring), 1324, 1164 (SO₂-N), 818, 802 (para-disubstituted benzene).

'H NMR: δ_Η (400MHz, CDC1₃) 7.70 (2H, d, J 8.5, ortho-H), 7.25 (2H, d, J 8.0, meta-H), 6.226.03 (2H, m, NH), 3.79 (IH, ddd, J 11.0, 5.0, 2.0, CH-CO), 3.19-3.10 (IH, m, CH₂NH), 3.082.98 (IH, m, CH₂NH), 2.38 (3H, s, CH₃), 2.14-2.08 (IH, m, lactam CH₂), 2.03-1.93 (IH, m, lactam CH₂), 1.82-1.71 (IH, m, lactam CH₂), 1.70-1.54 (2H, m, lactam CH₂), 1.38-1.25 (IH, m, lactam CH₂).

¹³C NMR: 5c (100MHz, CDCi₃) 174.5 (lactam C=O), 143.6 (ipso-C), 137.2 (para-C), 129.9 (aromatic CH), 127.2 (aromatic CH), 55.6 (CH-CO), 42.4 (CH₂-NH), 33.6 (lactam CH₂), 28.9 (lactam CH₂), 28.2 (lactam CH₂), 21.7 (CH₃).

HRMS (+ESI) C₁₃H_1gN₂O₃S + Na⁺: calcd 305.0930; 305.0938.

With respect to the examples below, the general procedure for the synthesis of 3sulfonylaniino-2-oxopiperidines was: potassium carbonate (3 mmol) and (5)-3-amino-2oxopiperidine hydrochloride (1.5 mmol) were dissolved in water (5 ml) and the solution was cooled to 0 °C, and a solution of substituted benzenesulfonyl chloride (1 mmol) in tetrahydrofuran (5 mL) was added. The mixture was stirred for 16 hours, and then the reaction was extracted with dichloromethane or chloroform. The combined organic layers were dried over sodium sulfate and reduced in vacuo to give a solid. This solid was redissolved in a minimum amount of dichloromethane and crystallised by addition of petroleum ether 40-60 °C. The solid product was isolated by filtration and dried over potassium pentoxide.

Example 1: (5)-4-Fluoro-N-(2-oxopiperidin-3-yl)benzenesulfonamide

0.196 g white fine powder (48 %). mp 153-156 °C; [a]²⁴D +30.35 (c 0.1, MeOH); vmax/cm⁴ 1656, 1650 (C=O, amide), 1493 (N-H, amide), 1329 (C-F), 1158 (-SO2-). Anal. (CnHnFNjOjS) C, H, N: calcd C 48.52, H 4.81, N 10.29; found C 48.13, H 4.74, N 10.18. ’HNMR Ôh ’H-NMR Ô_h. 7.90 (2H, dd, J 9 and 5, ArW2 and ArH6), 7.17 (2H, t, J 8.5, Ar/73 and ArH5), 5.82 (2H, NHCH and NHCH₂), 3.48 (1H, dd, J 11 and 6, C77NH), 3.31-3.25 (2H, m, CH₂NH), 2.48-2.41 (1H, m, CA9CH), 1.99-1.88 (2H, m, CH₂CH₂NH), 1.87-1.66 (1H, m, CAACH). ^l3C-NMRÔc 169.74 (CHCONH), 165.1 (d, 7255, ArC4), 135.2 (d, J3, CSO₂), 130.1 (d, 79, ArC2/6), 116.4 (d, 7 23, ArC3/5), 53.3 (CHNH), 41.9 (CH₂NH), 28.6 (CH₂CHNH),

20.8 (CH₂CH₂NH). ¹⁹F-NMR Ô_f -105.1. HRMS (+ESI) C_I(H|₃FN₂O₃SNa; calcd 295.0523; found 295.0517.

Example 2: (₁S^r)-3-Fluoro-N-(2-oxopiperidin-3-yl)benzenesulfonamide

0.215 g oiï-white fine powder (53 %). mp 159-160 °C; [a]²⁴D +29.80 (c 0.1, MeOH); vraax/cm'' 1669, 1644 (C=O, amide), 1552 (N-H, amide), 1303 (C-F), 1158 (-SO2-). Anal. (CnHl3FN2O3S) C, H, N: calcd C 48.52, H 4.81, N 10.29; found C 48.10, H 4.71, N 10.05. 'HNMR ÔH 7.69 (1H, dt, 7 8 and 1, ArH2), 7.60 (1H, dt, 78 and 2.5, AiH5), 7.49 (1H, td, J 8 and 6, ArH4), 7.26 (1H, tdd, 7 8, 2.5 and 1, ArH6), 5.89 (III, s, NWCH), 5.69 (1H, s, NHCH2), 3.52 (1H, dd, 7 11 and 6, CHNH), 3.32-3.27 (2H, m, CH2NH), 2.51-2.44 (1H, m, CH2CH), 1.98-1.89 (2H, m, CH2CH2NH), 1.87-1.67 (1H, m, CH2CH). ^,JC-NMR ôc 169.1 (CHCONH), 162.4 (d, 7 250, ArC3), 141.2 (d, 7 7, CSO₂), 130.9 (ArC5), 123.0 (ArC6), 120.1 (d, 7 21, ArC4), 114.8 (d, 7 24, ArC2), 53.4 (CHNH), 41.9 (CH₂NH), 28.6 (CH₂CHNH), 20.7 (CH₂CH₂NH). ^,9F-NMR Ô_f -109.4. HRMS (+ESI) C_HH|₃FN₂O₃SNa: calcd 295.0523; found

295.0535.

Example 3: (S)-2-Fluoro-N-(2-oxopiperidin-3-yl)benzenesulfonamide

0.197 g white powder (48 %). mp 180-183 °C; [a]²⁴D +35.80 (c 0.1, MeOH); vjcra¹ 1659, 1647 (C=O, amide), 1474 (N-H, amide), 1332 (C-F), 1157 (-SO2-). Anal. (ChHbFNjOjS.I/ô H₂O) C, H, N: calcd C 47.99, H 4.88, N 10.18; found C 47.94, H 4.76, N 10.01. 'H-NMR ô_h 7.87 (IH, td, J7.5 and 2, ArZ/4), 7.56 (IH, dddd, J8, 7, 5 and 2, Ar/73), 7.21 (2H, m, J 7.5 and 1, ArH5 and ArH6), 6.05 (IH, s, NWCH), 5.84 (IH, s, NHCH₂), 3.58 (IH, dt, J 10.5 and 6, CHNH), 3.29-3.24 (2H, m, C//₂NH), 2.51-2.43 (IH, m, CH₂CH), 1.98-1.89 (2H, m, CH₂CH₂NH), 1.88-1.69 (IH, m, CH₂CH). ⁿC-NMR ô_c 169.6 (CHCONH), 159.2 (d, J 256, ArC2), 135.2 (d, J 9, ArC4), 130.6 (ArC5), 127.2 (d, J 14, CSO₂), 124.2 (d, 24, ArC6), 117.2 (d, J 21, ArC3), 53.7 (CHNH), 41.9 (CH₂NH), 28.9 (CH₂CHNH), 20.9 (CH₂CH₂NH). ^I9FNMR ôf

-108.5. HRMS (+ESI) CnH₁₃FN₂O₃SNa: calcd 295.0523; found 295.0516.

Example 4 : (S)-N-(2-Oxopiperidin-3-yl)-4-(trifluoromethyl)-benzenesuIfonamide

0.222 g off-white fine powder (46 %). mp 181-183 °C; [ot]²⁴D +21.15 (c 0.1, MeOH); ν^,/cm¹ 1669, 1644 (C=O, amide), 1552 (N-H, amide), 1303 (C-F), 1158 (-SO2-). Anal. (C₁₂Hi₃F₃N₂0₃S) C, H, N: calcd C 44.72, H 4.07, N 8.69; found C 44.39, H 3.98, N 8.54. ’HNMR Ô_tl. 8.03 (2H, d, J 8, Ar/β and ArW6), 7.76 (2H, d, J 8, ArH3 and ArH5), 5.99 (IH, s, NHCH), 5.85 (IH, s, NHCH₂), 3.53 (IH, dd, J 11 and 6, CHNH), 3.31-3.26 (2H, m, CH₂NH), 2.49-2.42 (IH, m, CH₂CH), 1.99-1.91 (2H, m, CH₂CH₂NH), 1.89-1.67 (IH, m, CH₂CH). ^,3CNMR ôc 169.5 (CHCONH), 142.9 (CSO₂), 134.5 (q, 232, ArC4), 127.9 (ArC2/6), 126.3 (q, J 4, ArC3/5), 123.3 (q, J 270, CF₃), 53.4 (CHNH), 41.9 (CH₂NH), 28. 7 (CH₂CHNH), 20.8 (CH₂CH₂NH). ^l9F-NMR Ô_f -63.1. HRMS (+ESI) C_l2H_l3F₃N₂O₃SNa: calcd 345.0491; found

345.0478.

Exarnple 5: (S)-N-(2-Oxopiperidin-3-yl)-3-(trïfluoromethyl)benzene$ulfonainÎde

NH

0.156 g off-white needle crystals (32 %). mp 158-160 °C; [ot]²⁴D +22.90 (c 0.1, MeOH); vjctn¹ 1632, 1614 (C=O, amide), 1496 (N-H, amide), 1362 (C-F), 1138 (-SO2-). Anal. (C₁₂H₁₃F₃N₂O₃S) C, H, N: calcd C 44.72, H 4.07, N 8.69; found C 44.56, H 3.93, N 8.63. ’HNMR Ô_h‘H-NMRÔ_h. 8.17 (1H, s, ArR2), 8.09 (1H, d, J 8, ArH6), 7.82 (1H, d, J 8, ArR4), 7.66 (1H, t, J 1.5, ArHS), 5.97 (1H, s, NHCH), 5.83 (1H, s, NHCH₂), 3.55 (1H, dd, J 10.5 and 6, C/7NH), 3.32-3.26 (2H, m, C/ANH), 2.49-2.41 (1H, m, CR₂CH), 1.98-1.89 (2H, m, CR₂CH₂NH), 1.87-1.67 (1H, m, CW₃CH). ^BC-NMR 5C 169.6 (CHCONH), 140.7 (CSO2), 131.7 (q,J34, ArC3), 130.5 (ArC5), 129.9 (Ai€6), 129.4 (q, J3, ArC2), 124.5 (q, J3, ArC4), 123.2 (q, J 272.5, CF3), 53.4 (CHNH), 41.9 (CH2NH), 28.7 (CH2CHNH), 20.8 (CH2CH2NH). ^,9F-NMR 5f -62.7. HRMS (+ESI) C₁₂H₁₃F₃N₂O₃SNa: calcd 345.0491; found 345.0480.

Example 6: (5)-N-(2-oxopiperidin-3-yl)-2-(trifiuoromethyl)benzenesulfonamide

NH

0.191 g off-white fine powder (40 %). mp 161-163 °C; [a]²⁴D +36.70 (c 0.1, MeOH); ν^αη⁴ 1669, 1644 (C=O, amide), 1552 (N-H, amide), 1303 (C-F), 1158 (-SO2-). Anal. (C₁₂H₁₃F₃N₂O₃S) C, H, N: calcd C 44.72, H 4.07, N 8.69; found C 44.51, H 3.89, N 8.62. *HNMR δ_Η. 7.74 (1H, td, J 9 and 3.5, Ar/76), 7.42 (1H, dt, J 9and 4, Ar/73), 7.22-7.15 (2H, m, Ar/74 and ArR5), 6.78 (1H, d, J 5, NHCH), 6.08 (III, s, NHCH₂), 4.42 (1H, dt, J 11 and 6, CRNH), 3.35 (2H, td, J 6 and 2, CH₂NH), 2.73 (1H, dq, J 13 and 6, CH₂CH), 1.99-1.91 (2H, m, CH₂CH₂NH), 1.59 (1H, dq, J 12 and 8, CH₂CH). ^l3C-NMR Ô_c 169.9 (CHCONH), 138.1 (CSO₂), 132.8 (ArC5), 132.2 (ArC6), 131.1 (ArC4), 128.7 (q, J 6, ArC3), 128.1 (q, J 34,

ArC2), 122.9 (q, J 273, CF₃), 53.7 (CHNH), 41.9 (CH₂NH), 28.9 (CH₂CHNH), 20.9 (CH₂CH₂NH). ^I9F-NMR -57.9. HRMS (+ESI) C,₂H_l3F₃N₂O₃SNa: calcd 345.0491; found

345.0502.

Example 7: (5)-2,4-difluoro-N-(2-oxopiperidin-3-yl)benzenesulfonamide

NH

0.193 g off-white fine powder (44 %). mp 162-163 °C; [a]²²R +31.55 (c 0.1, MeOH); ν^^/εηι'¹ 1679, 1655 (C=O, amide), 1475 (N-H, amide), 1342 (C-F), 1160 (-SO2-). Anal. (ChH₁₂F₂N₂O₃S) C, H, N: calcd C 45.51, H 4.17, N 9.65; found C 45.37, H 4.14, N 9.38. ^lHNMR ôt]. 7.94 (IH, td, J 8.5 and 6, ArH3), 6.9 (1H, m, ArH5 and Ar/76), 6.09 (IH, s, N/fCH), 6.03 (1H, s, N/7CH2), 3.65 (IH, dt, J 11 and 5.5, C7/NH), 3.35-3.29 (2H, m, Crt2NH), 2.522.45 (IH, m, CH2CH), 2.03-1.95 (2H, m, C/f2CH2NH), 1.92-1.75 (IH, m, C/72CH). ⁿC-NMR 5C 169.7 (CHCONH), 165.9 (dd, J 260 and 11.5, Ar€2), 160.1 (dd, 7258 and 13, ArC4), 131.9 (d, J 10.5, ArC6), 123.9 (dd, J 12.5 and 3.5, CSO₂), 111.6 (dd, J 22 and 4, ArC5), 105.8 (t, J 20, ArC3), 53.6 (CHNH), 41.9 (CH₂NH), 28.9 (CH₂CHNH), 20.9 (CH₂CH₂NH). ¹⁹F-NMR Ô_F 100.5 (d, J 12), -103.3 (d, J 12). HRMS (+ESI) C_llH₁2F₂N₂O_îSNa: calcd 313.0429; found 313.0440.

Example 8: (5)-2,5-difluoro-N-(2-oxopiperidin-3-yl)benzenesulfonamide

NH

0.234 g white fine powder (54 %). mp 183-185 °C; [a]²²p> +26.30 (c 0.1, MeOH); v^Jcm'¹ 1692, 1635 (C=O, amide), 1576 (N-H, amide), 1352 (C-F), 1166 (-SO₂-). Anal. (CnH₁₂F₂N₂O₃S) C, H, N: calcd C 45.51, H 4.17, N 9.65; found C 45.35, H 4.11, N 9.42. 'HNMR δ_Η. 7.64 (IH, ddd, J 7, 5 and 3, ArTfo), 7.26 (2H, tq, J 8 and 4, Arf/3 and Ar/74), 5.91 (2H, s, N77CH and NHCH₂), 3.69 (IH, dt, J 11.5 and 6, C/fNH), 3.36-3.31 (2H, m, C/ANH), 2.55-2.47 (IH, m, CH₂CH), 2.04-1.95 (2H, m, CH₂CH₂NH), 1,94-1.76 (IH, m, CH₂CH). ^,3C23

NMR ôc 171.3 (CHCONH), 169.5 (CCONH), 157.7 (dd, J 248 and 2, ArC5), 155.3 (dd, J 252 and 2, ArC2), 128.6 (dd, J 26 and 6, CS0₂), 121.5 (dd, J 26 and 8, ArC3), 118.5 (dd, 723.5 and 8.5, ArC4), 117.0 (d, 7 28, ArC6), 53.7 (CHNH), 41.9 (CH₂NH), 28.9 (CH₂CHNH), 20.9 (Œ₂CH₂NH). ⁱ⁹F-NMR Ô_f -114.6 (d, 7 18), -115.9 (d. 7 19). HRMS (+ESI) Ci iH,₂F₂N₂O₃SNa: calcd 313.0429; found 313.0418.

Example 9: (5)-2,6-difluoro-N-{2-oxopiperidin-3-yl)benzenesuIfonamÎde

0.173 g white coarse powder (40 %). mp 152-153 °C; [a]²²D +15.95 (c 0.1, MeOH); v^/cm¹ 1659, 1621 (C=O, amide), 1493 (N-H, amide), 1326 (C-F), 1161 (-SO2-). Anal. (CuH₁₂F₂N₂O₃S) C, H, N: calcd C 45.51, H 4.17, N 9.65; found C 45.18, H 4.10, N 9.20. 'HNMR Ô₁₍. 7.54 (1H, qt, 7 8.5 and 6, ArW4), 7.06 (2H, t, 7 8.5, AiHl and ArZ/5), 6.25 (1H, s, N/7CH), 5.93 (1H, s, NWCH₂), 3.79 (1H, dd, J 11.5 and 6, C77NH), 3.36-3.31 (2H, m, C/f₂NH), 2.60-2.55 (1H, m, C/ÇCH), 2.04-1.97 (2H, m, CXCH₂NH), 1.87 (1H, qd, 7 12 and 4, C//_:CH). ^l3C-NMR Ô_c 169.7 (CHCONH), 159.8 (dd, 7 260 and 4, ArC2 and AiC6), 134.5 (t, 7 11, Ar€4), 117.4 (t, 7 16, CSO₂), 113.0 (dd, 723 and 4, ArC3 and ArC5), 53.8 (CHNH),

41.8 (CH₂NH), 28.9 (CH₂CHNH), 20.9 (CH₂CH₂NH). ^|9F-NMR Ô_F -107.5. HRMS (+ESI) C_uH₁₂F₂N₂O₃SNa: calcd 313.0429; found 313.0417.

Example 10: (5)-3,4-difluoro-N-(2-oxopiperidin-3-yI)benzenesulfonamÎde

NH

0.200 g white fine powder (46 %). mp 153-155 °C; [a]²² _D +25.60 (c 0.1, MeOH); v^/cm'¹

1656, 1603 (C=O, amide), 1501 (N-H, amide), 1331 (C-F), 1160 (-SO₂-). Anal. (CuHuFîNîOjS) C, H, N: calcd C 45.51, H 4.17, N 9.65; found C 45.39, H 4.11, N 9.49. ^]HNMR δ_Η. 7.79 (1H, dq, 7 7 and 2, Ar//5), 7.73 (1H, t,7 8.5, Ar/76), 7.34 (1H, q, 78.5, ArH2),

6.00 (2H, s, N//CH and N/fCH₂), 3.59 (1H, dd, 7 il and 6, C/7NH), 3.36-3.32 (2H, m,

C/ANH), 2.52-2.45 (ÎH, m, Œ₂CH), 2.03-1.97 (2H, m, CH₂CH₂NH), 1.83 (ÎH, qd, J 12 and 4, CH₂CH). ⁿC-NMR 5c 169.6 (CHCONH), 153.2 (dd, 7256 and 11, ArC3), I50.1 (dd, 7 256 and 12, ArC4), 136.1 (t,74, CSO2), 124.4 (q,73.5, ArC6), 118.2 (d, 7 18, ArC5), 117.4 (d,7 22, ArC2), 53.4 (CHNH), 41.9 (CH2NH), 28.7 (CH2CHNH), 20.8 (CH2CH2NH). ^,9F-NMR ÔF -129.3 (d, 7 18), -133.5 (d. 7 19). HRMS (+ESI) CnH^F^^SNa: calcd 313.0429; found 313.0417.

Example 11: (5)-3,5-difluoro-N-(2-oxopiperidîn-3-yl)benzenesiilfonainide

NH

0.193 g off-white fine powder (44 %). mp 170-174 °C; [a]²²D +21.10 (c 0.1, MeOH); vmax/cm⁴ 1658, 1604 (C=O, amide), 1491 (N-H, amide), 1332 (C-F), 1163 (-SO2-). Anal. (CiiH₁₂F₂N₂O₃S) C, H, N: calcd C 45.51, H 4.17, N 9.65; found C 45.42, H 4.12, N 9.41. 'HNMR Ô_[(. 7.49 (1H, ddt, 7 11, 6.5 and 2.5, ArH4), 7.05 (2H, tt, 7 8.5 and 2, Ar//2 and Ar/76), 6.09 (2H, s, N/7CH and NWCH₂), 3.64 (1H, dd, 7 11.5 and 6, C7YNH), 3.36-3.32 (2H, m, C/ANH), 2.52-2.45 (1H, m, C/ACH), 2.04-1.96 (2H, m, C/f₂CH₂NH), 1.84 (1H, qd, 7 12 and 6, C//_:CH). ^L1C-NMR ô_c 169.6 (CHCONH), 162.8 (dd, 7252 and 13, ArC3 and ArC5), 142.8 (t, 7 8.5, CSO₂), 110.9 (dd,72i and 7, ArC2 and ArC6), 108.5 (t,725, AiC4), 53.5 (CHNH),

41.9 (CH₂NH), 28.6 (CH₂CHNH), 20.8 (CH₂CH₂NH). ¹⁹F-NMR 5_F -105.4. HRMS (+ESI) Ci|H|₂F₂N₂O₃SNa: calcd 313.0429; found 313.0431.

Example 12: (S)-3-(4'-Ethylbenzenesulfonylamîno)-azepan-2-one

2 (S)-3-amino-azepan-2-one hydrochloride (0.55 g, 3.34 mmoles) was dissolved in H₂O (20 mL) and cooled to 0°C. 4-Ethylbenzenesulfonyl chloride (5 mmoles) in dichloromethane (30 mL) was added and triethylamine (1.3 mL, 9 mmoles) and the reaction was stirred over night. The reaction was extracted with dichloromethane and washed with pH 2 buffer (3 * 20 mL) and reduced in vacuo. The product was purified by silica column chromatography (petroleum ether:ethyl acetate 75:25 to 0:100) to give the product as a white solid 0.17 g (19 %); δ_Η (400 MHz, CDClj) 7.72 (d, 2H, J 8, CH-C-ΈΧ), 7.28 (d, 2H, J 8, CZ/-C-SO₂), 6.40 (br.t, IH, J 6, NH-C1), 6.18 (d, 1H, J 5, NH-CH), 3.83-3.74 (m, 1H, C//-C4), 3.19-3.11 (m, 1H, Hl), 3.03 (ddd, 1H, J16, 11.5,5.5, Hl), 2.08 (q, 2H, J 8, H5), 2.15-2.09 (m, 1 H, H4), 2.0-1.95 (m, 1H, H2), 1.80-1.77 (m, 1H, H3), 1.66-1.52 (m, 2H, H3 & H4), 1.37-1.26 (m, 1H, H2) and 1.23 (t, 3H, J 8, H6); Ô_c (100 MHz, CDC1₃) 174.4 (Ç=O), 149.5 (Ç-Et), 137.2 (Ç-SO₂), 126.2 (ÇH phenyl), 55.4 (ÇH-NH), 42.2 (Cl), 33.4 (C4), 28.8 (C5), 28.6 (C2), 28.0 (C3) and 15.1 (C6); ES1 m/z 100 %, 319.1 (MNa⁺) and 58 %, 614.6 (M2Na⁺); HR ESI m/z (Ci14H₂oN₂0₃SNa⁺ requires 319.1087) found 319.1085; [a]²⁵ _D(c = 0.235, CHCfi) +128.79.

Example 13: (R)-3-(4'-Ethylbenzenesulfonylamino)-tetrahydropyridin-2-one

(R)-3-amino-y-lactam (4 mmoles) was dissolved in H₂O (20 mL) and cooled to 0°C. 4Ethylbenzenesulfonyl chloride (4 mmoles) in dichloromethane (25 mL) was added and triethylamine (1.7 mL, 12 mmoles) and the reaction was stirred over night. The reaction was extracted with dichloromethane and washed with pH 2 buffer (3 ^x 20 mL) and reduced in vacuo. The product was purified by silica column chromatography (petroleum ether: ethyl acetate:methanol 75:25:0 to 0:90:10) to give the product as a white solid 0.25 g (21 %); Ôc (100 MHz, CDClj) 170.0 (Ç=O), 149.7 (Ç-Et), 136.2 (Ç-SO2), 129.1, 128.6, 127.5 (ÇH phenyl), 55.3 (ÇH-NH), 41.9 (Cl), 28.8 (C3), 28.5 (C4), 20.8 (C2) and 15.1 (C5); ESI m/z 100 %, 305.1 (MNa⁺) and 56 %, 586.7 (M2Na ); HR ESI m/z (C_1?H₁₈N₂O₃SH⁺ requires 283.1111) found 283.1114;

Example 14: (S)-3-(4'-Butylbenzenesulfonylamino)-azepan-2-one -26

(5)-3-amino-azepan-2-one hydrochloride (1.15 g, 7 mmoles) was dissolved in H₂O (20 mL) and cooled to 0°C. 4-Butylbenzenesulfonyl chloride (7 mmoles) in dichloromethane (30 mL) was added and triethylamîne (2.95 mL, 21 mmoles) and the reaction was stirred over night. The reaction was extracted with dichloromethane and washed with pH 2 buffer (3 x 20 mL) and reduced in vacuo. The product was purified by silica column chromatography (petroleum etherrethyl acetate 75:25 to 0:100) to give the product as a white solid. S_H (400 MHz, CDClj) 7.76 (d, 2H, J S, C/f-CBu), 7.31 (d, 2H, J 7.5, CW-C-SO₂), 6.76 (br.t, 1H, J 6, NH-C1), 6.28 (d, 1H, J5, N/f-CH), 3.85 (ddd, 1H, Jll, 5,2, C/7-C4), 3.24-3.16 (m, 1H, Hl), 3.06 (ddd, 1H, J 15, 12, 5, Hl ),2.68 (t, 2H, J 8, H5), 2.18-2.11 (m, 1H, H4), 2.03-1.93 (m, 1H, H3), L84-1.73 (m, 1H, H2), 1.69-1.55 (m, 4H, H3, H4 & H6), 1.38 (sextet, 2H, J7.5, H7), 1.36-1.25 (m, 1H, H2) and 0.95 (t, 3H, J 7.5, H8);ô_c (100 MHz, CDCl,) 175.6 (Ç=O), 148.3 (Ç-Bu), 137.1 (ÇSO₂), 129.1, 127.0 (ÇH phenyl), 55.3 (ÇH-NH), 42.1 (Cl), 35.5 (C4), 33.3 (C5), 33.1 (C3), 28.6 (C6), 28.0 (C7), 22.3 (C2) and 13.9 (C8); ESI m/z 100 %, 670.6 (M₂Na⁺), 86 %, 347.1 (MNa’) and 43 %, 325.1 (MH⁺).

Example 15: (S)-3-(4'-rert-Butylbenzenesulfonylamino)-azepan-2-one

((S)-3-amino-azepan-2-one hydrochloride (2.35 g, 9.18 mmoles) was dissolved in H₂O (20 mL) and cooled to 0°C. 4-‘Butylbenzenesulfonyl chloride (1.92 g, 8.25) in THF (40 mL) was added and triethylamîne (3.5 mL, 25 mmoles) and the reaction was stirred over night. The THF was removed in vacuo and the product was dissolved in ethyl acetate and washed with pH 2 buffer (3 ^x 20 mL) and reduced in vacuo. The product was purified by silica column chromatography (petroleum ether.ethyl acetate 50:50:0 to 0:80:20) to give the product as a white solid 0.67 g (25 %); mp 189-190 ° C; (400 MHz, CDC1₃) 7.74 (d, 2H, J 8.5, C/7-C27 'Bu), 7.47 (d, 2H, J 8.5, CH-C-SO₂), 6.27 (br.t, ÎH, J 6.5, NH-Cl), 6.19 (d, ÎH, J 4.5, NHCH), 3.88-3.81 (m, ÎH, CÆ-C4), 3.21-3.12 (m, IH, Hl), 3.05 (ddd, ÎH, J I4.5, 11.5, 5, Hl),

2.l9-2.l3(m, IH, H4), 2.02-1.96 (ni, 1H, H3), 1.81-1.74 (m, 1H, H2), 1.71-1.54 (m, 2H, H3 & H4), 1.33-1.29 (m, IH, H2) and 1.31 (s, 3H, C(C^)₃); 8_C (100 MHz, CDClj) 175.5 (Ç=O), 156.4 (Ç-C(CH₃)₃), 137.0 (Ç-C=O), 126.8, 126.1 (ÇH phenyl), 55.4 (ÇH-NH), 42.3 (Cl), 35.2 (£(CH₃)₃), 33.5 (C4), 31.1 (C(ÇH₃),) and 28.7 (C2), 28.0 (C3); υ^/οπΛ 3219 (NH indole), 2968 (C-H), 1668 (amide C=O), 1594 (aromatic), 1361 (SO₂) and 1159 (SO₂); ESI m/z 100 %, 347.1 (MNa⁺) and 26 %, 670.6 (M2Na'); HR ESI m/z (C16H24N2O3SH⁺ requires 325.1580) found 325.1580; [ct]²³D(c = 0.532, CHC1₃) +109.68.

Example 16: (S)-3-(4'-rerf-Butylbenzenesulfonylamino)-tetrahydropyridin-2-one

(5)-3-amino-y-lactam (10 mmoles) was dissolved in H₂O (40 mL) and cooied to 0°C. 4‘Butylbenzenesulfonyl chloride (1.88 g, 8.08 mmoles) in dichloromethane (25 mL) was added and triethylamine (3.5 mL, 25 mmoles) and the reaction was stirred over night. The réaction was extracted with dichloromethane (3 x 20 mL), the organic layer was washed with a pH 2 buffer (3 ^x 20 mL) and reduced in vacuo. The product was purified by silica column chromatography (petroleum etheriethyl acetate:methanol 50:50:0 to 0:80:20) to give the product as a white solid 0.76 g (30 %); mp 155-156 ° C; δ1( (400 MHz, CDC13) 7.79 (d, 2H, J 8.5, C/f-C-'Bu), 7.47 (d, 2H, J 8.5, C£f-SO2), 6.38 (br.s, IH, NH-C1), 5.98 (d, IH, J 3.5, N/fCH), 3.51-3.46 (m, IH, CÆ-C4), 3.28-3.22 (m, 2H, Hl), 2.49-2.42 (m, IH, H3), 1.93-1.87 (m, IH, H2), 1.86-1.67 (m, 2H, H2 & H3) and 1.31 (s, 9H, C(CH,)j); Sc (100 MHz, CDC13) 170.1 (Ç=O lactam), 156.5 (Ç-C(CH3)3), 136.0 (Ç-SO2), 127.1, 126.2 (ÇH phenyl), 53.2 (ÇH-NH), 41.8 (Cl), 35.2 (Ç(CH3)j), 31.1 (C(ÇH3)3), 28.4 (C3) and 20.7 (C2); ESI m/z 100 %, 333.1 (MNa⁺) and 44 %, 642.6 (M2Na⁺); Mmf¹: 3220 (NH), 2946 (C-H), 1665, 1596 (aromatic), 1331 (SO2) and 1134 (SO2); HR ESI m/z (C15H22N2O3SH⁺ requires 311.1424) found 311.1425; [a]²³D(c = 0.525, CHC1₃) +122.92.

Example 17: (R)-3-(4'-im-Butylbenzenesulfonylamino)-tetrahydropyridin-2-one

(R)-3-amino-y-iactam (2.5 mmoles) was dissolved in H₂O (30 mL) and cooled to 0°C. 4'Butylbenzenesulfonyl chloride (0.61 g, 2.62 mmoles) in dichlorométhane (25 mL) was added and triethylamine (l.l mL, 7.5 mmoles) and the reaction was stirred over night. The reaction was extracted with dichlorométhane (3 x 20 mL), the organic layer was washed with a pH 2 buffer (3 ^x 20 mL) and reduced in vacuo. The product was purified by silica column chromatography (petroleum ethenethyl acetate 75:25 to 0:100) to give the product as a white solid 0.33 g (43 %); δ_Η (400 MHz, CDClj) 7.80 (d, 2H, J 8.5, C/f-C-’Bu), 7.50 (d, 2H, J 8.5, CW-SO₂), 5.99 (br.s, IH, NH-C1), 5.90 (br.d, IH, J 2, N/f-CH), 3.51-3.46 (m, IH, CH-C4), 3.31-3.26 (m, 2H, Hl), 2.53-2.43 (m, IH, H3), 1.96-1.89 (m, IH, H2), 1.85-1.69 (m, 2H, H2 & H3) and 1.32 (s, 9H, Ô_c (100 MHz, CDClj) 169.9 (Ç=O lactam), 156.6 (Ç-C(CH₃)₃),

135.8 (Ç-SO₂), 127.2, 126.2 (ÇH phenyl), 53.3 (ÇH-NH), 42.0 (Cl), 35.2 (Ç(CH₃)₃), 31.1 (C(ÇH₃)₃), 28.5 (C3) and 20.8 (C2); ESI m/z 37 %, 642.6 (M₂Na⁺); HR ESI m/z (C15H22N2O3SH^< requires 311.1424) found 311.1427; [ot]²⁵D (c = 0.114, CHC1₃) -116.52.

Example 18: (S)-3-(4*-OctylbenzenesulfonyIamino)-azepan-2-one

(S)-3-amino-azepan-2-one hydrochloride (0.73 g, 4.45 mmoles) was dissolved in H₂O (30 mL) and cooled to 0°C. 4-Octylbenzenesulfonyl chloride (2.2 mmoles) in dichlorométhane (25 mL) was added and triethylamine (0.93 mL, 6.6 mmoles) and the reaction was stirred over night. The reaction was extracted with dichlorométhane (3 x 20 mL) the organic layer was washed with a pH 2 buffer (3 * 20 mL) and reduced in vacuo. The product was purified by silica column chromatography (petroleum ethenethyl acetate 50:5 to 0:100) to give the product as a white solid 0.49 g (59 %); Ô_H (400 MHz, CDC1₃) 7.71 (d, 2H, J 8.5, CH-C-Oct), 7.25 (d, 2H, J

8.5, CH-CSO2), 6.68 (dd, IH,77.5,5,5 NZ7-C1), 6.22 (d, IH, 75, NH-CH), 3.81 (ddd, 1H,72,

5, Il C£f-C4), 3.20-3.3II (m, 1H, H 1),3.02 (ddd, IH, J 16, 11.5, 5, Hl), 2.63 (t, 2H,J8,H5), 2.12-2.07 (m, 1H, H4), 1.98-1.93 (m, 1H, H3), 1.79-1.72 (m, 1H, H2), 1.65-1.55 (m, 4H, H3, H4&H5), 1.33-1.21 (m, UH, H2, H7, H8, H9, H10 & Hll) and 0.86 (t, 3H, J 7, HI2); 5_C (100 MHz, CDC1₃) 174.6 (Ç=O lactam), 148.4 (Ç-Oct), 137.2 (Ç-SO₂), 129.1, 128.8 (ÇH phenyl), 127.0 (ÇH phenyl), 55.3 (CH-NH), 42.1 (Cl), 35.8 (C4), 33.3 (C5), 31.8 (C3), 31.0 (C6), 29.4 (C7), 29.2 (C8), 28.6 (C9), 28.0 (CIO), 22.7 (C2), 22.6 (Cil) and 14.1 (C12); ES1 m/z 100 %, 403.2 (MNa') and 40 %, 381.2 (MH⁺); HR ES1 m/z (CafeNASH’ requires 381.2206) found 381.2205.

Example 19: (S)-3-(4'-Octylbenzenesulfonylamino)-tetrahydropyridin-2-one

(.5)-3 -amino-γ-lactam (2.5 mmoles) was dissolved in H₂O (40 mL) and cooled to 0°C. 4Octylbenzenesulfonyl chloride (1.34 mmoles) in dichloromethane (25 mL) was added and triethylamine (0.57 mL, 4 mmoles) and the reaction was stirred over night. The reaction was extracted with dichloromethane (3 ^x 20 mL) the organic layer was washed with a pH 2 buffer (3 ^x 20 mL) and reduced in vacuo. The product was purified by silica column chromatography (petroieum ether.ethyl acetate:methanol 50:50:0 to 0:80:20) to give the product as a white solid 0.31 g (63 %); mp 98-99 ° C; δΗ (400 MHz, CDCfi) 7.76 (d, 2H, J, CW-C-Oct), 7.27 (d, 2H, J 8, CH-CSO2), 6.50 (br.s, 1H, NH-C1), 6.00 (d, 1H, J 2.5, NH-CH), 3.51-3.45 (m, 1H, CH-C3), 3.27-3.31 (m, 2H, Hl), 2.62 (t, 2H, J 7, H4), 2.45-2.36 (m, 1H, H3), 1.92-1.85 (m, 1H, H2), 1.80-1.67 (m, 2H, H2 & H3), 1.62-1.55 (m, 2H, H5), 1.31-1.20 (m, 10H, H6, H7, H8, H9 & H10) and 0.85 (t, 3H, J 7, Hll); 8C (100 MHz, CDCU) 170.1 (Ç=O lactam), 148.5 (ÇOct), 136.3 (Ç-SO2), 129.1 (ÇH phenyl), 127.3 (ÇH phenyl), 53.2 (ÇH-NH), 41.8 (Cl), 35.9 (C4), 31.8 (C5), 31.0 (C3), 29.4 (C6), 29.3 (C7), 29.2 (C8), 28.4 (C9), 22.7 (C10), 20.7 (C2) and 14.1 (Cil); ESI m/z 100 %, 389.2 (MNa⁺) and 36 %, 367.2 (MH*); HR ESI m/z (C19HioN₂03SNa^< requires 389.1869) found 389.1865; umax/crn’¹: 3207 (NH), 2920 (C-H), 1664, (C=O), 1544 (aromatic), 1310 (SO2) and 1188 (SO₂); [a]²⁴ _D(c = 0.515, CHClj) +99.97.

Example 20: (R)-3-(4'-Octylbenzenesulfonylamino)-tetrahydropyridin-2-one —

(/?)-3-amino-y-lactam (2.5 mmoles) was dissolved in H₂O (30 mL) and cooled to 0°C. 4Octylbenzenesulfonyl chloride (1.34 mmoles) in dichloromethane (25 mL) was added and triethylamine (0.57 mL, 4 mmoles) and the reaction was stirred over night. The reaction was extracted with dichloromethane (3 ^x 20 mL) the organic layer was washed with a pH 2 buffer (3 x 20 mL) and reduced in vacuo. The product was purified by silica column chromatography (petroleum ether:ethyl acetate 50:50 to 0:100) to give the product as a white solid 0.22 g (45 %); δΗ (400 MHz, CDC10 7.76 (d, 2H, J 8, CÆ-C-Oct), 7.26 (d, 2H, J 8, CH-CSOJ, 6.85 (br.s, 1H, NR-Cl), 6.14 (d, 1H, J 3, N/f-CH), 3.52-3.46 (m, 1H, CÆ-C3), 3.23-3.16 (m, 2H, Hl), 2.62 (t, 2H, JT, H4), 2.38-2.31 (m, 1H, H3), 1.87-1.81 (m, 1H, H2), 1.74-1.65 (m, 2H, H2 & H3), 1.62-1.54 (m, 2H, H5), 1.32-1.20 (m, 10H, H6, H7, 118, H9 & H10) and 0.84 (t, 3H, J 7, Hl 1); 6C (100 MHz, CDCl·,) 170.2 (Ç=O lactam), 148.4 (Ç-Oct), 136.5 (Ç-SO2), 129.0 (CH phenyl), 127.3 (ÇH phenyl), 53.2 (ÇH-NH), 41.5 (Cl), 35.8 (C4), 32.0 (C5), 31.8 (C3), 29.4 (C6), 29.3 (C7), 29.1 (C8), 25.5 (C9), 22.7 (C10), 20.7 (C2) and 14.1 (Cil); ESI m/z 15 %, 389.2 (MNa⁺); HR ES! m/z (Ci9H₃₍₎N₂O₃SNa⁺ requires 389.1869) found 389.1872; [a]^2; _D(c = 0.238, CHClj) -102.94.

Pharmacological study of the products of the invention

A. Inhibition of MCP-1 induced leukocyte migration

Assay principîe

The biological activity of the compounds of the current invention may be demonstrated using any of a broad range of functional assays of leukocyte migration in vitro, including but not limited to Boyden chamber and related transwell migration assays, under-agarose migration assays and direct visualisation chambers such as the Dunn Chamber.

For example, to demonstrate the inhibition of leukocyte migration in response to chemokines (but not other chemoattractants) the 96-well format micro transwell assay System from Neuroprobe (Gaithersburg, MD, USA) has been used. In principîe, this assay consists of two chambers separated by a porous membrane. The chemoattractant is piaced in the lower compartment and the cells are piaced in the upper compartment. After incubation for a period 31 at 37°C the cells move towards the chemoattractant, and the number of cells in the lower compartment is proportional to the chemoattractant activîty (relative to a sériés of controls).

This assay can be used with a range of different leukocyte populations. For example, freshiy prepared human peripheral blood leukocytes may used. Alternatively, leukocyte subsets may be prepared, including polymorphonuclear cells or lymphocytes or monocytes using methods well known to those skilled in the art such as density gradient centrifugation or magnetic bead séparations. Alternatively, immortal cell lines which hâve been extensively validated as models of human peripheral blood leukocytes may be used, including, but not limited to THPl cells as a model of monocytes or Jurkat cells as model of naïve T cells.

Although a range of conditions for the assay are acceptible to demonstrate the inhibition of chemokîne-induced leukocyte migration, a spécifie example is hereby provided.

Materials

The transwell migration Systems are manufactured by Neuroprobe, Gaithersburg, MD, USA.

The plates used are ChemoTx plates (Neuroprobe 101 -8) and 30 pl clear plates (Neuroprobe MP30).

Geys’ Balanced Sait Solution is purchased from Sigma (Sigma G-9779).

Fatty acid-free BSA is purchased from Sigma (Sigma A-8806).

MTT, i.e. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, is purchased from Sigma (Sigma M-5655).

RPMI-1640 without phénol red is purchased from Sigma (Sigma R-8755).

The THP-l cell line (European Cell culture Collection) were used as the leukocyte cell population.

Test protocol

The following procedure is used for testing the invention compounds for MCP-l induced leukocyte migration: s

First, the cell suspension to be placed in the upper compartment is prepared. The THP-l cells are pelleted by centrifugation (770 x g; 4 mins) and washed with Geys Balanced Sait Solution with lmg/ml BSA (GBSS + BSA). This wash is then repeated, and the cells repelleted before being resuspended in a small volume of GBSS + BSA for counting, for example using a standard haemocytometer.

The volume of GBSS + BSA is then adjusted depending on the number of cells présent so that the cells are at final density of 4.45 x ÎO⁶ cells per ml of GBSS + BSA. This ensures that there are 100,000 THP-l cells in each 25μΐ of the solution that will be placed in the upper chamber of the plate.

To test a single compound for its ability to inhibit MCP-1 induced migration, it is necessary to préparé two lots of cells. The suspension of THP-l cells at 4.45 x 10⁶ cells/ml is divided into two pots. To one pot the inhibitor under test is added at an appropriate final concentration, in an appropriate vehicle (for example at ΙμΜ in not more than 1% DMSO). To the second pot an equal volume of GBSS + BSA plus vehicle as appropriate (e.g. not more than 1% DMSO) is added to act as a control.

Next, the chemoattractant solution to be placed in the lower compartment is prepared. MCP-1 is diluted in GBSS + BSA to give a final concentration of 25 ng/ml. This is divided into two pots, as for the cell suspension. To one pot, the test compound is added to the same final concentration as was added to the cell suspension, while to the other pot an equal volume of GBSS + BSA plus vehicle as appropriate (e,g. not more than 1% DMSO) is added.

Note that the volume of liquid that needs to be added to make the addition of the text compound needs to be taken into account, when establishing the final concentration of MCP-1 in the solution for the lower compartment and the final concentration of cells in the upper compartment.

Once the chemoattractant solutions for the lower wells and cell solutions for the upper chambers hâve been prepared, the migration chamber should be assembled. Place 29 μΐ of the appropriate chemoattractant solution into the lower well of the chamber. Assays should be performed with at least triplicate déterminations of each condition. Once ail the lower chambers hâve been filled, apply the prous membrane to the chamber în accordance with the manufacturer’s instructions. Fînally, apply 25 μΐ of the appropriate cell solution to each upper chamber. A plastic lid is placed over the entire apparatus to prevent évaporation.

The assembled chamber is incubated at 37 °C, 5% CO₂, for 2 hours. A suspension of cells in

GBSS + BSA is also incubated under identical conditions in a tube: these cells will be used to construct a standard curve for determining the number of cells that hâve migrated to the lower chamber under each condition,

At the end of the incubation, the liquid cell suspension is gently removed from the upper chamber, and 20μ1 of ice-cold 20mM EDTA in PBS is added to the upper chamber, and the apparatus is incubated at 4°C for 15 mins. This procedure causes any cells adhering to the underside of the membrane to fall into the lower chamber.

After this incubation the filter is carefully flushed with GBSS + BSA to wash off the EDTA, and then the filter is removed.

The number of cells migrated into the lower chamber under each condition can then be determined by a number of methods, including direct counting, labelling with fluorescent or radioactive markers or through the use of a vital dye. Typically, we utilise the vital dye MTT. 3 μΐ of stock MTT solution are added to each well, and then the plate is incubated at 37 “C for l-2 hours during which time dehydrogenase enzymes within the cells convert the soluble MTT to an insoluble blue formazan product that can be quantified spectrophotometrically.

In parallel, an 8-poînt standard curve is set up. Starting with the number of cells added to each upper chamber (100,000) and going down in 2-fold serial dilutions in GBSS + BSA, the cells are added to a plate in 25 μΐ, with 3 μΐ of MTT stock solution added. The standard curve plate is incubated along side the migration plate.

At the end of this incubation, the liquid is carefully removed from the lower chambers, taking care not to disturb the precipitated formazan product. After allowing to air dry briefly, 20μ1 of DMSO is added to each lower chamber to solubilise the blue dye, and absorbance at 595nm is determined using a 96-weIl plate reader. The absorbance of each well is then interpolated to the standard curve to estimate the number of cells in each lower chamber.

The MCP-1 stimulated migration is determined by subtracting the average number of cells that reached the lower compartment in wells where no MCP-1 was added from the average number of cells that reached the lower compartment where MCP-1 was présent at 25ng/ml.

The impact of the test substance is calculated by comparing the MCP-1-induced migration which occurred in the presence or absence of various concentrations of the test substance. Typically, the inhibition of migration is expressed as a percentage of the total MCP-1 induced migration which was blocked by the presence of the compound. For most compounds, a doseresponse graph is constructed by determining the inhibition of MCP-1 induced migration which occurs at a range of different compound concentrations (typically ranging from lnM to 34

I μΜ or higher in the case of poorly active compounds). The inhibitory activity of each compound is then expressed as the concentration of compound required to reduce the MCP-linduced migration by 50% (the ED₅₀ concentration).

Results

The compounds of reference examples l to 2 were tested and were shown to hâve an ED_J0 of 100 nM or less in this test.

B. In vivo assay

The anti-inflammatory efficacy of an exemplar compound according to the présent invention was tested using the murine sub-lethal endotoxemia model. This model has been widely used to demonstrate the anti-inflammatory effect of compounds in vivo - see for example Fox et al., 2009, J Med Chem. 52(l l): 3591-3595.

Briefly, the method is as follows. Female CD1 mice (28-3 0g, ~7 weeks of âge) were dosed with their respective treatment in stérile filtered 1 % CMC by oral gavage in a dose volume of lOml/kg one hour prior to an endotoxin (LPS) challenge. The endotoxin challenge was injected by the intraperitoneal route containing 675,000 Endotoxin Units of LPS (E. coli strain 0111 :B4 (Code L4130)) in endotoxin free PBS. Mice were left for two hours and then exsanguinated under terminal anaesthesia and blood was taken. Sérum was prepared from this terminal bleed and aliquoted and stored at -20’C. Sérum TNF-α levels were measured by ELISA per manufacturers instructions (R and D Systems).

Eight animais were treated in each group, and the data for the animal with the highest and lowest TNF-α level in each group were eliminated, and the mean and standard error reported for the remaîning six animais.

A single dose of (S)-3-(4'-trifluoromethylbenzenesulfonylamino)-tetrahydropyridin-2-one (see Example 4; compound also known as (S)-N-(2-Oxopiperidin-3-yl)-4-(trifluoromethyl)benzenesulfonamide) administered by oral gavage, inhibited endotoxin-stimulated TNF-alpha levels by 60-70% (see Fig. 2). The anti-inflammatory effect on TNF-a levels in vivo using (S)-3-(4'-trifluoromethylbenzenesulfonylamino)-tetrahydropyridin-2-one was quantitatively similar to a maximally effective dose of the positive control compound thalidomide.

Thalidomide is used clinically as an anti-inflammatory agent, reducing the level of TNF-α, for the treatment of leprosy. The anti-inflammatory effect in vivo of (S)-3-(4'- — trifluoromethylbenzenesulfonylamino)-tetrahydropyridin-2-one was also similar to the earlier somatotaxin (S)-3-(adamantane-l-carbonyl)aminocaprolactam (see W02006/016152).

These data demonstrate that the compounds of the présent invention hâve clinically useful anti-inflammatory activîty in vivo, comparable to other anti-inflammatory agents used for the treatment of a wide range of dîsorders with an inflammatory component,

0 NOV 2012a

Claims (20)

1. A compound of general formula (I), or a pharmaceutically acceptable sait thereof, for use in the treatment of an inflammatory disorder:

Claims wherein n is an integer from 1 to 4;

k is an integer from 0 to 5, representing the number of groups substîtuting C₂, C₃, C₄, C₅ and/or C₆ of the benzyl ring; and

10 X are iinear or branched groups substîtuting the benzyl ring independently selected from any one of the group consisting of: alkyl, haloalkyl, hydroxyalkyl, hydroxy, alkoxy, amino, aminoalkyl, amînodialkyl, carboxy, and halogen.

2. A compound of formula (I’), or a pharmaceutically acceptable sait thereof, for use in the treatment of an inflammatory disorder;

wherein n, k and X are defined as in claim 1.

3. Use of a compound of general formula (I), or a pharmaceutically acceptable sait thereof, in the manufacture of a médicament for the treatment of an inflammatory disorder: s' wherein n is an integer from l to 4;

5 k is an integer from 0 to 5, representing the number of groups substituting the benzyl ring; and

X are linear or branched groups substituting the benzyl ring independently selected from any one of the group consisting of: alkyl, haloalkyl, hydroxyalkyl, hydroxy, alkoxy, amino, aminoalkyl, aminodialkyl, carboxy, and halogen.

4. Use of a compound of formula (I’), or a pharmaceutically acceptable sait thereof, in the

10 manufacture of a médicament for the treatment of an inflammatory disorder:

wherein n, k and X are defmed as in claim 3.

5. A compound of general formula (I):

(I) wherein n, k and X are defined as în claim 1, with the proviso that:

when n = 3, then at least one of C₂-C₆ on the benzyl ring is substituted with a group other than halogen, C]-C₇ alkyl, or C₍-C₇ haloalkyl; and when η = 1,2 or 3, then

C₂ or Cô on the benzyl ring are other than hydrogen or fluorine, or

C₃ on the benzyl ring is other than hydrogen, halogen, alkyl, Cj-C₆ alkoxy, or C)-C(, haloalkyl, or

C₄ on the benzyl ring is other than hydrogen, halogen, C₍-C₆ alkyl, Cj-C₆ alkoxy, Cj-C₆ haloalkyl, amino, aminoalkyl or aminodialkyl, or

C₅ on the benzyl ring is other than hydrogen or halogen;

provided that the compound is neither of the group consisting of: 3-(2'carboxybenzenesulfonylamino)-tetrahydropyridin-2-one, and (R)-3-(4'methylbenzenesulfonylamîno)-caprolactam.

6. A compound of formula (I’):

wherein n, k and X are defined as in either of claim 1 or claim 5, provided that the compound is none of the group consisting of: (S)-3-(4'methylbenzenesulfonylamino)-tetrahydropyridin-2-one, (S)-3-(4'methylbenzenesulfonylamino)-caprolactam, (S)-3-(4’-bromobenzenesulfonylamino)caprolactam, and (S)-3-(4'-chlorobenzenesulfonylamino)-caprolactam.

7. A pharmaceutical composition comprising, as active ingrédient, a compound as defined in either of daims 5 or 6, or a pharmaceutically acceptable sait thereof, and at least one pharmaceutically acceptable excipient and/or carrier.

8. The compound, use or composition according to any preceding claim, wherein n=2.

9. The compound, use or composition according to any preceding claim, wherein n=3.

10. The compound, use or composition according to any preceding claim, wherein X is haloalkyl, for example trifluoromethyl.

11. The compound according to any of daims 1, 2 or 5, or the use according to daims 3 or 4, wherein the compound is selected from the group consisting of:

(S)-3-(3'-fluorobenzenesulfonylamino)-tetrahydropyridin-2~one, (S)-3-(4'-fluorobenzenesulfonylamino)-tetrahydropyridin-2-one, (S)-3-(2'-trifluoromethylbenzenesulfonylamino)-tetrahydropyridin-2-one, (S)-3-(3'-trifluoromethylbenzenesulfonylamino)-tetrahydropyridin-2-one, (S)-3-(4'-trifluoromethylbenzenesulfonylamino)-tetrahydropyridin-2-one, (S)-3-(2’,4'-difluorobenzenesulfonylamino)-tetrahydropyridin-2-one, (S)-3-(2',5’-difluorobenzenesulfonylamino)'tetrahydropyridin-2-one, (S)-3-(2^,,6'-difluorobenzenesulfonylamino)-tetrahydropyridin-2-one, (S)-3-(3',4'-difluorobenzenesulfonylamino)-tetrahydropyridin-2-one, (S)-3-(3',5'-difluorobenzenesulfonylamino)-tetrahydropyridin-2-one, (S)-2-Fluoro-N-(2-oxopiperidin-3-yl)benzenesulfonamide, (S)-3-(4’-Ethylbenzenesulfonylamino)-azepan-2-one, (S)-3-(4'-Butylbenzenesulfonylamino)-azepan-2-one, (S)-3-(4'-/i?rAButylbenzenesulfonylamino)-azepan-2-one, (S)-3-(4'-/er/-Butylbenzenesulfonylamino)-tetrahydropyridin-2-one, (S)-3-(4'-Octylbenzenesulfonylamino)-azepan-2-one, and (S)-3-(4'-Octylbenzenesulfonylamino)-tetrahydropyridin-2-one, and pharmaceutically acceptable salts thereof.

12. The compound according to any of daims 1 or 5, or the use according to daim 3, wherein the compound is selected from the group consisting of:

(R)-3-(4'-Ethylbenzenesulfonylamino)-tetrahydropyridin-2-one, — (R)-3-(4'-fôr/-Butylbenzenesulfonylamino)-tetrahydropyridin-2-orie, and (R) -3 -(4’-Octylbenzenesul fonylamino)-tetrahydropyridin-2-one, and pharmaceutically acceptable salts thereof.

13. The compound according to 6, wherein the compound is selected from the group consisting of:

(S) -3-(3'-fluorobenzenesulfonylamino)-tetrahydropyridin-2-one, (S)-3-(4'-fluorobenzenesulfonylamino)-tetrahydropyridin-2-one, (S)-3-(2'-trifluoromethylbenzenesulfonylamino)-tetrahydropyridin-2-one, (S)-3 -(3 '-tri fluoromethy lbenzenesulfonylamino)-tetrahydropyridin-2-one, (S)-3-(4'-trifluoromethylbenzenesulfonylamino)-tetrahydropyridin-2-one, (S)-3-(2',4’-difluorobenzenesulfonylamino)-tetrahydropyridin-2-one, (S)-3-(2',5’-difluorobenzenesulfonylamino)-tetrahydropyridin-2-one, (S)-3-(2',6^,-difluorobenzenesulfonylamino)-tetrahydropyridin-2-one, (S)-3-(3',4^,-difluorobenzenesulfonylamino)-tetrahydropyridin-2-one, (5)-3-(3',5’-difluorobenzenesulfonylamino)-tetrahydropyridin-2-one, (S)-2-Fluoro-N-(2-oxopiperidin-3-yl)benzenesulfonamide, (S)-3-(4'-Ethylbenzenesulfonylamino)-azepan-2-one, (S)-3-(4'-Butylbenzenesulfonylamino)-azepan-2-one, (S)-3-(4’-teri-Butylbenzenesulfonylamino)-azepan-2-one, (S)-3-(4'-ierr-Butylbenzenesulfonylamino)-tetrahydropyridin-2-one, (S)-3-(4’-Octylbenzenesulfonylamino)-azepan-2-one, and (S)-3-(4'-Octylbenzenesulfonylamino)-tetrahydropyridin-2-one, and pharmaceutically acceptable salts thereof.

14. The compound according to claims 1 or 2, or the use according to claims 3 or 4, wherein the compound is (S)-3-(4'-methylbenzenesulfonylamino)-caprolactam, or a pharmaceutically acceptable sait thereof.

15. The compound according to claim 2 or 6, or the use according to claim 4, wherein the compound is (S)-3-(4'-trifluoromethylbenzenesulfonylamino)-tetrahydropyridin-2-one, or a pharmaceutically acceptable sait thereof.

16. The compound according to either of claims 1 to 2 or the use according to either of claims 3 or 4, wherein the inflammatory disorder is selected from the group consisting of autoimmune diseases, asthma, rheumatoid arthritis, a disorder characterised by an elevated TNF-α level, — psoriasis, allergies, multiple sclerosis, fibrosis (including diabetic nephropathy), and formation of adhesions.

17. The compound or use according to claim 16, wherein the inflammatory disorder is formation of adhesions.

5

18. The compound or use according to claim 16 or claim 17, wherein the compound is administered locally.

19. Use of a compound, pharmaceutical composition or médicament as defined in any preceding claim in the manufacture of a médicament for the treatment, amelioration or prophylaxis of the symptoms of an inflammatory disease (including an adverse inflammatory

10 reaction to any agent).

20. A library consisting of éléments ali of which hâve structures according to the formula (I) or (Γ) as defined in any of claims lto 18, and hence which ail hâve anti-inflammatory activity, useful for screening compounds for novel or improved properties in a particular assay of antiinflammatory activity. y planche de l'abrégé