Pharmaceutically active sulfonyl hydrazide derivatives

The present application is a divisional of Ser. No. 10/088,074 filed Oct. 13, 2004, now U.S. Pat. No. 7,432,286, which is a 371 application of PCT/IB00/01381 filed Sep. 28, 2000 and claims the benefit of EP 99810870.8 filed Sep. 28, 1999.

The present invention is related to sulfonyl hydrazide derivatives notably for use as pharmaceutically active compounds, as well as pharmaceutical formulations containing such sulfonyl hydrazide derivatives. In particular, the present invention is related to sulfonyl hydrazide derivatives displaying a substantial modulatory, notably inhibitory activity of the JNK (Jun-Kinase) function or pathways respectively, and which are therefore particularly useful in the treatment and/or prevention of disorders of the autoimmune and the neuronal system. The present invention is furthermore related to novel sulfonyl hydrazide derivatives as well as to methods of their preparation.

Apoptosis denotes the complex contortions of the membrane and organelles of a cell as it undergoes the process of programmed cell death. During said process, the cell activates an intrinsic suicide program and systematically destroys itself. The following series of events can be observed:

The cell surface begins to bleb and expresses pro-phagocytic signals. The whole apoptotic cell then fragments into membrane-bound vesicles that are rapidly and neatly disposed of by phagocytosis, so that there is minimal damage to the surrounding tissue. The cell then separates from its neighbors.

The nucleus also goes through a characteristic pattern of morphological changes as it commits genetic suicide, the chromatin condenses and is specifically cleaved to fragments of DNA.

Neuronal cell death plays an important role in ensuring that the nervous system develops normally. It appears that the death of developing neurones depends on the size of the target that they innervate: cells with fewer synaptic partners are more likely to die than those that have formed multiple synapses. This may reflect a process, which balances the relative number of pre- to postsynaptic neurones in the developing nervous system. Although neuronal cell death was assumed to be apoptotic, it was only recently that neurones in developing rodent brain were conclusively shown to undergo apoptosis as classified by morphology and DNA fragmentation. As cell death during development is clearly not a pathological process, it makes sense that cells actually cease to exist.

Neuronal death occurs via either apoptotic or necrotic processes following traumatic nerve injury or during neurodegenerative diseases. Multiple components are emerging as key players having a role in driving neuronal programmed cell death. Amongst the components leading to neuronal apoptosis are members of the SAPK/JNK being a subfamily of MAP Kinases (MAPKs).

MAPKs (mitogen-activated protein kinases) are serine/threonine kinases that are activated by dual phosphorylation on threonine and tyrosine residues. In mammalian cells, there are at least three separate but parallel pathways that convey information generated by extracellular stimuli to the MAPKs. Said pathways consist of kinase cascades leading to activation of the ERKs (extracellular regulated kinases), the JNKs (c-Jun N-terminal kinases), and the p38/CSBP kinases. While both the JNK and p38 pathways are involved in relaying stress-type extramolecular signals, the ERK pathway is primarily responsible for transducing mitogenic/differentiation signals to the cell nucleus.

SAPK cascades represent a sub-family of the mitogen-activating protein kinase family, that are activated by different external stimuli including DNA damage following UV irradiation, TNF-α, IL-1β, ceramide, cellular stress, and reactive oxygen species and have distinct substrate specificities. Signal transduction via MKK4/JNK of MKK3/p38 results in the phosphorylation of inducible transcription factors, c-Jun and ATF2, which then act as either homodimers or heterodimers to initiate transcription of down-stream effectors. c-Jun is a protein that is forming homodimers and heterodimers (with e.g. c-Fos) to produce the transactivating complex AP-which is required for the activation of many genes (e.g. matrix metalloproteinases) involved in the inflammatory response. The JNKs were discovered when it was found that several different stimuli such as UV light and TNF-α stimulated phosphorylation of c-Jun on specific serine residues in the N-terminus of the protein.

In a recent publication of Xie X et al, ( Structure 1998, 6 (8); 983-991) it has been suggested that activation of stress-activated signal transduction pathways are required for neuronal apoptosis induced by NGF withdrawal in rat PC-12 and superior cervical ganglia (SCG) sympathetic neuronal cells. Inhibition of specific kinases, namely MAP kinase kinase 3 (3) and MAP kinase kinase 4 (MKK4), or c-Jun (part of the MKK-4 cascade) may be sufficient to block apoptosis (see also Kumagae Y et al, in Brain Res Mol Brain Res, 1999, 67(1), 10-17 and Yang D D et al in Nature, 1997, 389 (6653); 865-870). Within a few hours of NGF deprivation in SCG neurones, c-Jun becomes highly phosphorylated and protein levels increase. Similarly in rat PC-12 cells deprived of NGF, JNK and p38 undergo sustained activation while ERKs are inhibited. Consistent with this JNK3 KO mice are resistant to excitotoxicity induced apoptosis in the hippocampus and more importantly they display greatly reduced epileptic like seizures in response to excitotoxicity as compared to normal animals (Nature 1997, 389, 865-870).

More recently, it has been reported that the JNK signalling pathway is implicated in cell proliferation and could play an important role in autoimmune diseases ( Immunity, 1998, 9, 575-585 ; Current Biology, 1999, 3, 116-125) which are mediated by T-cell activation and proliferation.

Naive (precursor) CD4 + helper T (Th) cells recognise specific MHC-peptide complexes on antigen-presenting cells (APC) via the T-cell receptor (TCR) complex. In addition to the TCT-mediated signal, a costimulatory signal is provided at least partially by the ligation of CD28 expressed on T-cells with B7 proteins on APC. The combination of these two signals induces T-cell clonal expression.

After 4-5 days of proliferation, precursor of CD4 + T cells differentiate into armed effector Th cells that mediate the functions of the immune system. During the differentiation process, substantial reprogramming of gene expression occurs.

Two subsets of effector Th cells have been defined on the basis of their distinct cytokine secretion pattern and their immunomodulatory effects: Th1 cells produce IFNγ and LT (TNF-β), which are required for cell-mediated inflammatory reactions; Th2 cells secrete IL-4, IL-5, IL-6, IL-10 and IL-13, which mediate B cell activation and differentiation. These cells play a central role in the immune response. The JNK MAP Kinase pathway is induced in Th1 but not in Th2 effector cells upon antigen stimulation. Furthermore, the differentiation of precursor CD4 + T cells into effector Th1 but not Th2 cells is impaired in JNK2-deficient mice. Therefore, in recent years it has been realized that the JNK kinase pathway plays an important role in the balance of Th1 and Th2 immune response through JNK2.

With the objective of inhibiting the JNK kinase pathway, WO/9849188 teaches the use of a human polypeptide, i.e. JNK-interacting protein 1 (JIP-1), which is a biological product and which has also been assayed for overcoming apoptosis related disorders.

Active bio-peptides or bio-proteins are only obtained by means of rather comprehensive and expensive bio-synthesis which consequently frequently renders the resulting products fairly cost-intensive. The peptides are known to display poor membrane penetration and may not cross the blood brain membrane, The principal drawback to the use of peptide inhibitors or antagonists is the problem of low oral bioavailability resulting from intestinal degradation. Hence, they must be administered parenterally and finally, peptide inhibitors or antagonists are frequently viewed by the host body as intruding material to be eliminated, thus setting off an auto-immune response.

Hence, it is an objective of the present invention to provide relatively small molecules that avoid essentially all of the above-mentioned drawbacks arising from the use of peptides or proteins, however, which are suitable for the treatment of a variety of diseases, in particular of neuronal or the autoimmune system related disorders. It is notably an objective of the present invention to provide relatively small molecule chemical compounds which are able to modulate, preferably to down-regulate or to inhibit the JNK (Jun kinase) pathway so to be available as a convenient method of treating diseases which are preferably mediated by the JNK function. Moreover, it is an objective of the present invention to provide methods for preparing said small molecule chemical compounds. It is furthermore an objective of the present invention to provide a new category of pharmaceutical formulations for the treatment of diseases, preferably mediated by the JNK function. It is finally an objective of the present invention to provide a method for the treatment and/or prevention of diseases that are caused by disorders of the autoimmune and/or the neuronal system.

The aforementioned objectives have been met according to the independent claims. Preferred embodiments are set out within the dependent claims.

The following paragraphs provide definitions of the various chemical moieties that make up the compounds according to the invention and are intended to apply uniformly throughout the specification and claims unless an otherwise expressly set out definition provides a broader definition.

“C 1 -C 6 -alkyl” refers to monovalent alkyl groups having 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl and the like.

“Aryl” refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g. phenyl) or multiple condensed rings (e.g. naphthyl). Preferred aryl include phenyl, naphthyl, phenantrenyl and the like.

“C 1 -C 6 -alkyl aryl” refers to C 1 -C 6 -alkyl groups having an aryl substituent, including benzyl, phenethyl and the like.

“Heteroaryl” refers to a monocyclic heteroaromatic, or a bicyclic or a tricyclic fused-ring heteroaromatic group. Particular examples of heteroaromatic groups include optionally substituted pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl, [2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxazolyl, quinolizinyl, quinazolinyl, pthalazinyl, quinoxalinyl, cinnnolinyl, napthyridinyl pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl, quinolyl isoquinolyl tetrazolyl, 5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetra-hydroisoquinolyl, purinyl, pteridinyl, carbazolyl, xanthenyl or benzoquinolyl.

“C 1 -C 6 -alkyl heteroaryl” refers to C 1 -C 6 -alkyl groups having a heteroaryl substituent, including 2-furylmethyl, 2-thienylmethyl, 2-(1H-indol-3-yl)ethyl and the like.

“Alkenyl” refers to alkenyl groups preferably having from 2 to 6 carbon atoms and having at least 1 or 2 sites of alkenyl unsaturation. Preferable alkenyl groups include ethenyl (—CH═CH 2 ), n-2-propenyl(allyl, —CH 7 CH═CH 2 ) and the like.

“Alkynyl” refers to alkynyl groups preferably having from 2 to 6 carbon atoms and having at least 1-2 sites of alkynyl unsaturation, preferred alkynyl groups include ethynyl (—C≡CH), propargyl (—CH 2 C≡CH), and the like.

“Acyl” refers to the group —C(O)R where R includes “C 1 -C 6 -alkyl”, “aryl”, “heteroaryl”, “C 1 -C 6 -alkyl aryl” or “C 1 -C 6 -alkyl heteroaryl”.

“Acyloxy” refers to the group —OC(O)R where R includes “C 1 -C 6 -alkyl”, “aryl”, “heteroaryl”, “C 1 -C 6 -alkyl aryl” or “C 1 -C 6 -alkyl heteroaryl”.

“Alkoxy” refers to the group —O—R where R includes “C 1 -C 6 -alkyl” or “aryl” or “heteroaryl” or “C 1 -C 6 -alkyl aryl” or “C 1 -C 6 -alkyl heteroaryl”. Preferred alkoxy groups include by way of example, methoxy, ethoxy, phenoxy and the like.

“Alkoxycarbonyl” refers to the group —C(O)OR where R includes “C 1 -C 6 -alkyl” or “aryl” or “heteroaryl” or “C 1 -C 6 -alkyl aryl” or “C 1 -C 6 -alkyl heteroaryl”.

“Aminocarbonyl” refers to the group —C(O)NRR′ where each R, R′ includes independently hydrogen or C 1 -C 6 -alkyl or aryl or heteroaryl or “C 1 -C 6 -alkyl aryl” or “C 1 -C 6 -alkyl heteroaryl”.

“Acylamino” refers to the group —NR(CO)R′ where each R, R′ is independently hydrogen or “C 1 -C 6 -alkyl” or “aryl” or “heteroaryl” or “C 1 -C 6 -alkyl aryl” or “C 1 -C 6 -alkyl heteroaryl”.

“Halogen” refers to fluoro, chloro, bromo and iodo atoms.

“Sulfonyl” refers to group “—SO 2 —R” wherein R is selected from H, “aryl”, “heteroaryl”, “C 1 -C 6 -alkyl”, “C 1 -C 6 -alkyl” substituted with halogens e.g. an —SO 2 —CF 3 group, “C 1 -C 6 -alkyl aryl” or “C 1 -C 6 -alkyl heteroaryl”.

“Sulfoxy” refers to a group “—S(O)R” wherein R is selected from H, “C 1 -C 6 -alkyl”, “C 1 -C 6 -alkyl” substituted with halogens e.g. an —SO—CF 3 group, “aryl”, “heteroaryl”, “C 1 -C 6 -alkyl aryl” or “C 1 -C 6 -alkyl heteroaryl”.

“Thioalkoxy” refers to groups —S—R where R includes “C 1 -C 6 -alkyl” or “aryl” or “heteroaryl” or “C 1 -C 6 -alkyl aryl” or “C 1 -C 6 -alkyl heteroaryl”. Preferred thioalkoxy groups include thiomethoxy, thioethoxy, and the like.

“Substituted or unsubstituted”: Unless otherwise constrained by the definition of the individual substituent, the above set out groups, like “alkyl”, “alkenyl”, “alkynyl”, “aryl” and “heteroaryl” etc. groups can optionally be substituted with from 1 to 5 substituents selected from the group consisting of “C 1 -C 6 -alkyl”, “C 1 -C 6 -alkyl aryl”, “C 1 -C 6 -alkyl heteroaryl”, “C 2 -C 6 -alkenyl”, “C 2 -C 6 -alkynyl”, primary, secondary or tertiary amino groups or quarter-nary ammonium moieties, “acyl”, “acyloxy”, “acylamino”, “aminocarbonyl”, “alkoxycarbonyl”, “aryl”, “heteroaryl”, carboxyl, cyano, halogen, hydroxy, mercapto, nitro, sulfoxy, sulfonyl, alkoxy, thioalkoxy, trihalomethyl and the like. Alternatively said substitution could also comprise situations where neighboring substituents have undergone ring closure, notably when viccinal functional substituents are involved, thus forming e.g. lactams, lactons, cyclic anhydrides, but also acetals, thioacetals, animals formed by ring closure for instance in an effort to obtain a protective group.

“Pharmaceutically acceptable salts or complexes” refers to salts or complexes of the below-identified compounds of formula I that retain the desired biological activity. Examples of such salts include, but are not restricted to acid addition salts formed with inorganic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid, naphthalene disulfonic acid, and polygalacturonic acid. Said compounds can also be administered as pharmaceutically acceptable quaternary salts known by a person skilled in the art, which specifically include the quaternary ammonium salt of the formula —NR,R′,R″ + Z − , wherein R, R′, R″ is independently hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, —O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, fumarate, citrate, tartrate, ascorbate, cinnamoate, mandeloate, and diphenylacetate).

“Pharmaceutically active derivative” refers to any compound that upon administration to the recipient, is capable of providing directly or indirectly, the activity disclosed herein.

“Enantiomeric excess” (ee) refers to the products that are obtained by an essentially enantiomeric synthesis or a synthesis comprising an enantioselective step, whereby a surplus of one enantiomer in the order of at least about 52% ee is yielded. In the absence of an enantiomeric synthesis, racemic products are usually obtained that do however also have the inventive set out activity as JunK2 and/or 3 inhibitors.

Quite surprisingly, it was now found that sulfonyl hydrazide derivatives according to formula I are suitable pharmaceutically active agents, by effectively modulating, in particular by down-regulating inhibiting the action of JNK's, notably of JNK 2 and/or 3.

In said formula I

Ar 1 and Ar 2 are independently from each other unsubstituted or substituted aryl or heteroaryl;

X 1 and X 2 are independently from each other O or S;

R 1 , R 2 , R 3 are independently from each other hydrogen or a C 1 -C 6 -alkyl substituent. Alternatively R 1 could form a substituted or unsubstituted 5-6-membered saturated or unsaturated ring with Ar 1 .

According to a further alternative, R 2 and R 3 could form a substituted or unsubstituted 5-6-membered saturated or unsaturated ring.

n is an integer from 0 to 5, preferably 1 to 3 and most preferred 1.

G is selected from a group comprising or consisting of an unsubstituted or substituted 4-8 membered heterocycle containing at least one heteroatom, or G is a substituted or unsubstituted C 1 -C 6 -alkyl group.

The present invention also includes the geometrical isomers, the optical active forms, enantiomers, diastereomers of compounds according to formula I, as well as their racemates and also pharmaceutically acceptable salts as well as the pharmaceutically active derivatives of the sulfonyl hydrazide derivatives of formula I.

According to a particularly preferred embodiment of the present invention, G is

wherein, both X 3 and X 3′ are selected independently from each other from the group consisting of N, O, S or CHL′;

Y is O, S or NR 4 ; whereby R 4 is H or an unsubstituted or substituted C 1 -C 6 -alkyl, an unsubstituted or substituted aryl or heteroaryl;

n′ is an integer from 0 to 5, preferably between 1-3 and most preferred 3.

L and L′ are independently from each other selected from the group comprising or consisting of H, unsubstituted or substituted C 1 -C 6 -aliphatic alkyl, unsubstituted or substituted C 2 -C 6 -alkenyl, unsubstituted or substituted C 2 -C 6 -alkynyl, unsubstituted or substituted cyclic C 4 -C 8 -alkyl, optionally containing 1-3 heteroatoms and optionally fused with aryl or heteroaryl; or L and L′ are independently from each other selected from the group comprising or consisting of unsubstituted or substituted aryl or heteroaryl, aryl-C 1 -C 6 -alkyl, heteroaryl-C 1 -C 6 -alkyl, —C(O)—OR 5 , —C(O)—R 5 , —C(O)—NR 5′ R 5 , —NR 5′ R 5 , —NR 5′ C(O)R 5 , —NR 5′ C(O)NR 5′ R 5 , —(SO)R 5 , —(SO 2 )R 5 , —NSO 2 R 5 , —SO 2 NR 5′ R 5 .

In the above enumeration, R 5 and R 5′ are substituents being independently selected from the group comprising or consisting of H, unsubstituted or substituted C 1 -C 6 -alkyl, unsubstituted or substituted C 2 -C 6 -alkenyl, unsubstituted or substituted C 2 -C 6 -alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted aryl-C 1 -C 6 -alkyl, unsubstituted or substituted heteroaryl-C 1 -C 6 -alkyl.

All above mentioned aryl or heteroaryl groups could optionally be substituted by at least one of the following groups: unsubstituted or substituted C 1 -C 6 -alkyl, like trihalomethyl, unsubstituted or substituted C 1 -C 6 -alkoxy, unsubstituted or substituted C 2 -C 6 -alkenyl, unsubstituted or substituted C 2 -C 6 -alkynyl, amino, aminoacyl, aminocarbonyl, unsubstituted or substituted C 1 -C 6 -alkoxycarbonyl, aryl, carboxyl, cyano, halogen, hydroxy, nitro, sulfoxy, sulfonyl, C 1 -C 6 -thioalkoxy.

In preferred sulfonyl hydrazide derivatives according to formula I, Ar 1 and/or Ar 2 are independently selected from the group consisting of phenyl, thienyl, furyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, naphthyl, quinolyl, optionally substituted by unsubstituted or substituted C 1 -C 6 -alkyl, in particular tri-halomethyl, unsubstituted or substituted C 1 -C 6 -alkoxy, unsubstituted or substituted C 2 -C 6 -alkenyl, unsubstituted or substituted C 2 -C 6 -alkynyl, amino, acylamino, aminocarbonyl, unsubstituted or substituted C 1 -C 6 -alkoxycarbonyl, aryl, carboxyl, cyano, halogen, hydroxy, nitro, sulfoxy, sulfonyl C 1 -C 6 -thioalkoxy. Most preferred sulfonyl hydrazide derivatives according to formula I are those where-in Ar 1 is a substituted or unsubstituted phenyl, preferably 4-chlorophenyl and/or Ar 2 is a thienyl group.

According to a particularly preferred embodiment, Ar 1 is a substituted or unsubstituted phenyl, preferably 4-chlorophenyl, X 1 and X 2 are 0, while R 1 , R 2 , R 3 are all hydrogen, n is 1, Ar 2 is thienyl, G is selected from

wherein L is selected from the group comprising or consisting of H, substituted or unsubstituted C 1 -C 6 -aliphatic alkyl, substituted or unsubstituted cyclic C 4 -C 8 -alkyl optionally containing 1-3 heteroatoms and optionally fused with aryl. Also, L could be an unsubstituted or substituted aryl or heteroaryl, aryl-C 1 -C 6 -alkyl heteroaryl-C 1 -C 6 -alkyl, —C(O) OR 5 , —C(O)—R 5 , —C(O)NR 5′ R 5 , —NR 5′ R 5 , —NR 5′ C(O)R 5 , —NR 5′ C(O)NR 5′ R 5 , —SO)R 5 , —(SO 2 )R 5 .

Thereby, R 5 and R 5′ are substituents being independently selected from the group comprising or consisting of H, unsubstituted or substituted C 1 -C 6 -alkyl, unsubstituted or substituted C 2 -C 6 -alkenyl, unsubstituted or substituted C 2 -C 6 -alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted aryl-C 1 -C 6 -alkyl, unsubstituted or substituted heteroaryl-C 1 -C 6 -alkyl.

Said aryl or heteroaryl groups are optionally substituted by unsubstituted or substituted C 1 -C 6 -alkyl, like trihalomethyl, unsubstituted or substituted C 1 -C 6 -alkoxy, unsubstituted or substituted C 2 -C 6 -alkenyl, unsubstituted or substituted C 1 -C 6 -alkynyl, amino, aminoacyl, aminocarbonyl, C 1 -C 6 -alkoxycarbonyl, aryl, carboxyl cyano, halogen, hydroxy, nitro, sulfoxy, sulfonyl, C 1 -C 6 -thioalkoxy.

In a particularly preferred embodiment the residue G is

whereby L is as above defined, with most preferred groups L being substituted or unsubstituted pyridyl groups.

Specific examples of compounds of formula I include the following:

4-chloro-N-[(5-{[2-({2-[4-(1,3-dithiolan-2-yl)phenyl]-1,3-thiazol-4-yl}carbonyl)hydrazino]sulfonyl}thien-2-yl)methyl]benzamide 4-chloro-N-{[5-({2-[(2-phenyl-1,3-thiazol-4-yl)carbonyl]hydrazino}sulfonyl)thien-2-yl]methyl}benzamide 4-chloro-N-{[5-({2-[(2-{[(4-chlorophenyl)sulfonyl]methyl}-1,3-thiazol-4-yl)carbonyl]-hydrazino}sulfonyl)thien-2-yl]methyl}benzamide 4-chloro-N-{[5-({2-[(2-methyl-1,3-thiazol-4-yl)carbonyl]hydrazino}sulfonyl)thien-2-yl]methyl}benzamide 4-chloro-N-[(5-{[2-({2-[4-(1H-pyrrol-1-yl)phenyl]-1,3-thiazol-4-yl}carbonyl)hydrazino]-sulfonyl}thien-2-yl)methyl]benzamide 4-chloro-N-[(5-{[2-({2-[(4,5-dichloro-1H-imidazol-1-yl)methyl]-1,3-thiazol-4-yl}-carbonyl)hydrazino]sulfonyl}thien-2-yl)methyl]benzamide 4-chloro-N-[(5-{[2-({2-[5-(trifluoromethyl)pyridin-2-yl]-1,3-thiazol-4-yl}carbonyl)-hydrazino]sulfonyl}thien-2-yl)methyl]benzamide 4-chloro-N-[(5-{[2-({2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-1,3-thiazol-4-yl}carbonyl)hydrazino]sulfonyl}thien-2-yl)methyl]benzamide 4-chloro-N-[(5-{[2-({2-[2-chloro-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}-carbonyl)hydrazino]sulfonyl}thien-2-yl)methyl]benzamide 4-chloro-N-[(5-{[2-({2-[4-(trifluoromethyl)pyridin-3-yl]-1,3-thiazol-4-yl}-carbonyl)hydrazino]sulfonyl}thien-2-yl)methyl]benzamide 4-chloro-N-({5-[(2-{[2-(2,3-dichlorophenyl)-1,3-thiazol-4-yl]carbonyl}hydrazino)-sulfonyl]thien-2-yl}methyl)benzamide 4-chloro-N-{[5-({2-[(2-{[(2-furylmethyl)sulfonyl]methyl}-1,3-thiazolyl)carbonyl]hydrazino}sulfonyl)thien-2-yl]methyl}benzamide 4-chloro-N-[(5-{[2-({2-[(2-chlorophenoxy)methyl]-1,3-thiazol-4-yl}carbonyl)-hydrazino]sulfonyl}thien-2-yl)methyl]benzamide 4-chloro-N-({5-[(2-{[2-(2,6-dichlorobenzyl)-1,3-thiazol-4-yl]carbonyl}hydrazino) sulfonyl]thien-2-yl}methyl)benzamide N-[(5-{[2-({2-[4-(1,3-dithiolan-2-yl)phenyl]-1,3-thiazolyl}carbonyl)hydrazino]-sulfonyl}thien-2-yl)methyl]-3-nitrobenzamide N-[(5-{[2-{2-[4-(1,3-dithiolan-2-yl)phenyl]-1,3-thiazolyl}carbonyl)hydrazino]-sulfonyl}thien-2-yl)methyl]-3-methoxybenzamide N-[(5-{[2-({2-[4-(1,3-dithiolan-2-yl)phenyl]-1,3-thiazol-4-yl}carbonyl)hydrazino]-sulfonyl}thien-2-yl)methyl]nitrobenzamide N′-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]thiophene-2-sulfonohydrazide N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]sulfonyl}thien-2-yl)methyl]-1-nitrobenzamide N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]sulfonyl}-thien-2-yl)methyl]-3-hydroxybenzamide N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]sulfonyl}-thien-2-yl)methyl]-2-hydroxybenzamide N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]-sulfonyl}thien-2-yl)methyl]benzamide N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]-sulfonyl}thien-2-yl)methyl]-2-furamide N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]-sulfonyl}thien-2-yl)methyl]-2-thien-2-ylacetamide N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]-sulfonyl}thien-2-yl)methyl]-1-naphthamide N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]-sulfonyl}thien-2-yl)methyl]-2-naphthamide N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethylpyridin-2-yl]amino}butanoyl)hydrazino]-sulfonyl}thien-2-yl)methyl]-4-methylbenzamide N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]-sulfonyl}thien-2-yl)methyl]-4-ethylbenzamide 4-tert-butyl-N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)-hydrazino]sulfonyl}thien-2-yl)methyl]benzamide N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]-sulfonyl}thien-2-yl)methyl]-2-fluorobenzamide N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]-sulfonyl}thien-2-yl)methyl]-3-fluorobenzamide N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]-sulfonyl}thien-2-yl)methyl]-4-fluorobenzamide N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]-sulfonyl}thien-2-yl)methyl]-2,6-difluorobenzamide N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]-sulfonyl}thien-2-yl)methyl]-3,5-difluorobenzamide 2-chloro-N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]sulfonyl}thien-2-yl)methyl]benzamide 3-chloro-N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]sulfonyl}thien-2-yl)methyl]benzamide N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]-sulfonyl}thien-2-yl)methyl]-4-iodobenzamide 2,6-dichloro-N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]sulfonyl}thien-2-yl)methyl]benzamide 3,5-dichloro-N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]sulfonyl}thien-2-yl)methyl]benzamide 2-bromo-N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)-hydrazino]sulfonyl}thien-2-yl)methyl]benzamide 3-bromo-N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)-hydrazino]sulfonyl}thien-2-yl)methyl]benzamide 4-bromo-N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)-hydrazino]sulfonyl}thien-2-yl)methyl]benzamide N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]-sulfonyl}thien-2-yl)methyl]-2-iodobenzamide N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]-sulfonyl}thien-2-yl)methyl]-3-nitrobenzamide N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]sulfonyl}thien-2-yl)methyl]-2-nitrobenzamide N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]-sulfonyl}thien-2-yl)methyl]-4-(dimethylamino)benzamide N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]-sulfonyl}thien-2-yl)methyl]-3-methoxybenzamide N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]-sulfonyl}thien-2-yl)methyl]-2-methoxybenzamide N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]sulfonyl}thien-2-yl)methyl]-4-methoxybenzamide N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]-sulfonyl}thien-2-yl)methyl]-2,6-dimethoxybenzamide N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]-sulfonyl}thien-2-yl)methyl]-3,5-dimethoxybenzamide N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]-sulfonyl}thien-2-yl)methyl]-2-(trifluoromethyl)benzamide N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]-sulfonyl}thien-2-yl)methyl]-3-(trifluoromethyl)benzamide N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]-sulfonyl}thien-2-yl)methyl]-4-(trifluoromethyl)benzamide N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]-sulfonyl}thien-2-yl)methyl]-3,5-bis(trifluoromethyl)benzamide N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]-sulfonyl}thien-2-yl)methyl]nicotinamide N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]-sulfonyl}thien-2-yl)methyl]isonicotinamide 4-amino-N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]sulfonyl}thien-2-yl)methyl]benzamide N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]-sulfonyl}thien-2-yl)methyl]-4-hydroxybenzamide N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]-sulfonyl}thien-2-yl)methyl]-3,4-dihydroxybenzamide 3,4-diamino-N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)-hydrazino]sulfonyl}thien-2-yl)methyl]benzamide N-[(5-{[2-(4-{[3-chloro-5-trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]-sulfonyl}thien-2-yl)methyl]pyridine-2-carboxamide N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]sulfonyl}thien-2-yl)methyl]-6-hydroxypyridine-2-carboxamide 6-amino-N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)-hydrazino]sulfonyl}thien-2-yl)methyl]nicotinamide N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]-sulfonyl}thien-2-yl)methyl]-2-sulfanylnicotinamide N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethylpyridin-2-yl]amino}butanoyl)hydrazino]-sulfonyl}thien-2-yl)methyl]-6-sulfanylnicotinamide N-[(5-{[2-({[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]-sulfonyl}thien-2-yl)methyl]-2,6-dihydroxyisonicotinamide N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]-sulfonyl}thien-2-yl)methyl]-5-nitro-1H-pyrazole-3-carboxamide N-[(5-{[2-(4-{[3-chloro-5-trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]-sulfonyl}thien-2-yl)methyl]-2-hydroxy-6-methoxybenzamide N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]-sulfonyl}thien-2-yl)methyl]-8-hydroxyquinoline-7-carboxamide 2-amino-N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)-hydrazino]sulfonyl}thien-2-yl)methyl]nicotinamide N-[(5-{[2-({[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]-sulfonyl}thien-2-yl)methyl]-4-fluoro-3-nitrobenzamide 2-amino-N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)-hydrazino]sulfonyl}thien-2-yl)methyl]benzamide N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]-sulfonyl}thien-2-yl)methyl]-2,3,4-trihydroxybenzamide N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]-sulfonyl}thien-2-yl)methyl]-2-oxo-1,2-dihydropyridine-3-carboxamide N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]sulfonyl}thien-2-yl)methyl]-2,4-dihydroxybenzamide N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]-sulfonyl}thien-2-yl)methyl]-5-hydroxypyridine-2-carboxamide N-[(5-{[2-({[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]sulfonyl}thien-2-yl)methyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]sulfonyl}thien-2-yl)methyl]-1H-imidazole-4-carboxamide 4-chloro-N-(4-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]sulfonyl}benzyl)benzamide 4-chloro-N-(2-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)-hydrazino]sulfonyl}phenyl)benzamide 4-chloro-N-(3-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)-hydrazino]sulfonyl}phenyl)benzamide N-(4-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]-sulfonyl}benzyl)-3-nitrobenzamide 4-chloro-N-(3-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)-hydrazino]sulfonyl}benzyl)benzamide N-(3-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]-sulfonyl}benzyl)benzamide N-(3-{[2-({[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]-sulfonyl}benzyl)-2-hydroxybenzamide N-(3-{[2-({[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]sulfonyl}benzyl)-3-nitrobenzamide

Most preferred compounds are selected from thew groups consisting of:

4-chloro-N-[(5-{[2-({2-[4-(1,3-dithiolan-2-yl)phenyl]-1,3-thiazol-4-yl}carbonyl)hydrazino]sulfonyl}thien-2-yl)methyl]benzamide 4-chloro-N-[(5-{[2-({2-[(2-chlorophenoxy)methyl]-1,3-thiazol-4-yl}carbonyl)hydrazino]sulfonyl}thien-2-yl)methyl]benzamide N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]sulfonyl}thien-2-yl)methyl]-2-hydroxybenzamide N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]sulfonyl}thien-2-yl)methyl]-2-oxo-1,2-dihydropyridine-3-carboxamide 4-chloro-N-(4-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]sulfonyl}benzyl)benzamide

A further aspect of the present invention consists in the use of the sulfonyl hydrazide derivatives according to formula I for the preparation of pharmaceutical compositions for the modulation—notably for the down-regulation, e.g. up to the inhibition—of the JNK function or signalling pathway associated disorders, in particular against neuronal disorders and/or against disorders of the immune system as well as said pharmaceutical compositions themselves. Preferred JNK pathways are the JNK1 and/or JNK2 and/or JNK3.

As pointed out above, the compounds of formula I are suitable to be used as a medicament. Some very few of the compounds falling into the above generic formula I have been disclosed prior to the filing of the present application, but no medical or biological activity whatsoever was unveiled so far. Hence, it is herein reported that both the novel and the few known compounds falling under the above set out generic formula I are indeed suitable for use in treating disorders of the autoimmune system and neuronal system of mammals, notably of human beings. More specifically, the compounds according to formula I, alone or in the form of a pharmaceutical composition, are useful for the modulation of the JNK pathway, more specifically for treatment or prevention of disorders associated with abnormal expression or activity of JNK, notably of JNK1 and/or JNK2 and/or JNK3. Said modulation usually preferably involves the inhibition of the JNK pathways, notably of the JNK1 and/or JNK2 and/or JNK3. Such an abnormal expression or activity of JNK could be triggered by numerous stimuli (e.g. stress, septic schock, oxidative stress, cytokines) and could lead to out-of-control apoptosis or autoimmune diseases that is frequently involved in the below enumerated disorders and disease states. Hence, the compounds according to formula I could be used for the treatment of disorders by modulating the JNK function or signalling pathways. Said modulation of the JNK function or pathways could involve its activation, but preferably it involves the down-regulation up to inhibition of the JNK pathways, notably of the JNK1 and/or JNK2 and/or JNK3. The compounds according to formula I could be employed alone or in combination with further pharmaceutical agents, e.g. with a further JNK modulator.

Specifically, the compounds pursuant to formula I are useful for the treatment or prevention of immuno- and/or neuronal-related diseases or pathological states in which inhibition of JNK2 or JNK3 plays a critical role such as epilepsy, neurodegenerative diseases including Alzheimer's disease, Huntington's disease, Parkinson's disease; retinal diseases; spinal cord injury, head trauma, autoimmune diseases including multiple Sclerosis, inflammatory bowel disease (IBD), rheumatoid arthritis; asthma; septic shock; transplant rejection; cancers including breast, colorectal, pancreatic and cardiovascular diseases including stroke, cerebral ischemia, arterosclerosis, myocordial infarction, myorcordial reperfusion injury. Quite surprisingly it turned out that the inventively found compounds according to formula I do show a considerable activity as inhibitors of JNK2 and 3, notably of JNK3 being involved in neuronal disorders. In a preferred embodiment, the compounds according to the invention are essentially inactive in view of 2 further apoptosis modulating enzymes, i.e. p38 and/or ERK2—belonging incidentally to the same family as JNK2 and 3. Hence, the compounds according to the present invention offer the possibility to come selectively to grips with disorders related to the JNK pathways, while being essentially inefficient with regard to other targets like said p38 and ERK2, so that they could indeed be viewed as selective inhibitors. This is of considerable significance, as these related enzymes are generally involved in different disorders, so that for the treatment of a distinct disorder, it is desired to employ a correspondingly selective medicament.

As a matter of fact, prior to the herein reported, surprisingly found sulfonyl hydrazide derivatives according to formula I, nothing was known in respect of the use of small molecule chemical compounds as inhibitors of the JNK kinase pathway.

Still a further aspect of the present invention consists in the actually novel sulfonyl hydrazide derivatives of formula I, i.e. those JNK inhibiting sulfonyl hydrazide derivatives according to formula I that have not been disclosed by the prior art. As already indicated, a few compounds have been disclosed by the CEREP company (www.cerep.fr) in as far as they are offered in a company catalogue.

The sulfonyl hydrazide derivatives of formula having been disclosed by CEREP, without any biological or pharmaceutical effect though, are those, wherein Ar 1 is 4-chlorophenyl, Ar 2 is thienyl, X 1 and X 2 are O, R 1 , R 2 and R 3 are H, n is 1 and G is selected from the following group:

Hence, the entirely novel sulfonyl hydrazide derivatives of formula I are those of the above set out general formula I whereby the above identified known compounds of the CEREP company are excluded.

Still a further object of the present invention is a process for preparing the novel sulfonyl hydrazide derivatives of formula I which have been set out above. The compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures.

It will be appreciated that where typical or preferred experimental conditions (i.e. reaction temperatures, time, moles of reagents, solvents, etc.) are given, other experimental conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimisation procedures.

According to a preferred method of synthesis, the sulfonyl hydrazide derivatives of the invention are prepared by first coupling an amine of formula II:

R 1 HN—(CH 2 ) n —Ar 2   II

where Ar 2 and R 1 are as defined above, with an acyl chloride of formula M:

where Ar 1 and X 1 are as defined above, to provide an amide of formula IV:

Amines of formula II are either known compounds or can be prepared from known compounds by conventional procedures. Preferred amines as starting materials include thien-2-ylmethylamine, furan-2-ylmethylamine, pyridyl-2-ylmethylamine and the like.

The acyl chlorides of formula III are also commercially available or previously described compounds. Preferred acyl chlorides include 4-chlorobenzoyl chloride, 4-fluorobenzoylchloride, 4-trifluoromethylbenzoyl chloride and the like. If not known, the acid halide can be prepared by reacting the corresponding carboxylic acid with an inorganic acid halide, such as thionyl chloride, phosphorus trichloride or oxalyl chloride under conventional conditions.

Generally, the above set out reaction is conducted using about 1 to 5 molar equivalents of the inorganic acid halide or oxalyl chloride, either neat or in an inert solvent, such as carbon tetrachloride, at a temperature in the range of about 0° C. to about 80° C. for about 1 to about 48 hours. A catalyst, as N,N-dimethylformamide, may also be used in this reaction.

When an acyl halide is employed in the coupling reaction, it is typically reacted with amine II in the presence of a suitable base to scavenge the acid generated during the reaction. Suitable bases include, by way of example, triethylamine, diisopropylethylamine, N-methylmorpholine and the like. Alternatively, an excess of amine II may be used to scavenge the acid generated during the reaction.

Alternatively, the carboxylic acid of compound III can be employed in the coupling reaction. The carboxylic acids of III are usually commercially available reagents or can be pre-pared by conventional procedures.

The coupling reaction of carboxylic acid of III is conducted using any conventional coupling reagent including, for example, carbodiimides such as dicyclohexylcarbodiimide, N-(3-dimethylaminopropyl)-N′-Ethylcarbodiimide and other promoting agents, such as N,N-carbonyldiimidazole or PyBOP. This reaction can be conducted with or without the use of well known additives such as N-hydroxysuccinimide, 1-hydroxybenzotriazole and the like which are known to facilitate the coupling of carboxylic acids and amines.

The coupling reaction using either acid halide in or its carboxylic acid is preferably conducted at a temperature of from about −70° C. to about 60° C. for about 1 to about 24 hours. Typically, the reaction is conducted in a inert aprotic polar solvent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran and the like using about 1 to about 5 molar equivalents of the amine based on the carboxylic acid or its acid halide. Upon completion of the reaction, the carboxamide IV is recovered by conventional methods including precipitation, chromatography, filtration, distillation and the like. The sulfonyl chlorides of formula V necessary for the preparation of the hydrazides of formula I are either commercially available or prepared using conventional sulfonating methods:

A preferred sulfonating reagent for use in this reaction is chlorosulfonic acid. Typically, the sulfonation reaction is conducted by treating the carboxamide of formula IV with about 5 to about 10 molar equivalent of the sulfonating reagent in an inert solvent, such as dichloromethane, at a temperature ranging from about −70° C. to about 50° C. Preferably, the addition of chlorosulfonic acid takes place at −70° C. and leads to the formation of the intermediate sulfonic acid. Increasing the temperature to 20° C. allows the formation of the sulfonyl chloride of formula V.

In another preferred method of synthesis and when the above method is not applicable to the preliminary synthesis of sulfonyl chloride of formula V, the sulfonyl hydrazides of this invention are prepared by sequentially:

Protection of the amine function of compounds of formula II Chlorosulfonylation of the aromatic group Formation of the sulfonamide function Deprotection of the protection group Acylation of the above generated free amine

Amines of formula II are protected with a suitable protecting group of an amine moiety to provide intermediate of formula VI wherein P denotes the protecting group.

Numerous protecting groups P of the amine function as well as their introduction and removal, are well described in T. W. Greene and G. M. Wuts, Protecting groups in Organic Synthesis, Third Edition, Wiley, New York, 1998, and references cited therein. Preferred are protecting groups that are acids and bases stable and can be further removed by using metal transition complexes such as palladium complexes, for example the allylcarbamate group (Alloc) or the N,N′-bisallyl group. Another preferred protecting group is the maleimide group which is stable in a all range of experimental conditions.

The introduction of said groups can be performed by reacting the corresponding bisallyl-carbonate anhydride or allylbromide or maleic anhydride in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like in an aprotic solvent such as N,N-dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran and the like at a temperature ranging from about 0° C. to about 80° C.

Compounds of formula VI are then sulfonated using a conventional very mild sulfonating procedure that allows the obtention of sulfonyl chloride of formula VII.

Typically, protected amine VI is treated with a base such as n-butyllithium or tert-butyllithium under an inert atmosphere, in a polar aprotic solvent such as tetrahydrofuran, ether or dioxane at a temperature ranging from −70° C. to 0° C. during a time ranging from 15 minutes to 4 hours. The so formed anion is then treated with SO 2 Cl 2 or most preferably SO 2 by bubbling the gas into the reaction mixture at a temperature ranging from −70° C. to 20° C. during a time ranging from 5 minutes to 1 hour. The sulfonate obtained is then transformed “in situ” to the sulfonyl chloride of formula VII by contacting with N-chlorosuccinimide at a temperature ranging from 0° C. to 70° C.

The sulfonyl hydrazide derivatives of formula I are readily prepared from the corresponding sulfonyl chloride v or VII, by reaction with an acyl hydrazide of general formula VIII

wherein R 2 , R 3 , X 2 and G are as defined above

For G being selected from the group consisting of an alkylidene group of the formula —(CH 2 ) n —NR 4 -aryl or —(CH 2 ) n —O-aryl, —(CH 2 ) n —S-aryl, wherein n is an integer from 1 to 5, and R 4 is selected from hydrogen and lower alkyl, a preferred method of synthesis of derivatives of formula VIII, when they are not commercially available, involves in a first step the preparation of compounds of formula IX wherein n′, X are as described above

ROOC—(CH 2 ) n′ —X-Aryl  IX

A preferred route is the addition of compounds of type RO 2 C—(CH 2 ), —NHR 5 —, RO 2 C—(CH 2 ) n —OH, RO 2 C—(CH 2 ) n —SH—, (R═H, Me) onto an activated chloro-substituted aromatic moiety such as 2-chloro-pyridine, 2-chloropyrimidine and the like. The compounds used are either commercially available or of their preparation is well known by the one skilled in the art compounds. This reaction is performed in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine, potassium carbonate, cesium carbonate, and the like in a polar protic solvent such as methanol, ethanol and the like at a temperature ranging from about 20° C. to about 180° C.

In case that a reaction of aromatic nucleophilic substitution is not feasible, a further preferred route consists in the addition of suitably substituted phenol or suitably substituted thiophenol onto compounds of type RO 2 C—(CH 2 ) n —X, wherein X═Cl, Br, I, OTs, OMs (mesyl) and R=Me.

Another preferred route is the addition of suitably substituted anilines onto compounds of type RO 2 C—(CH 2 ) n —X, wherein X═Cl, Br, I, OTs, OMs and R=Me.

In that latter case, anilines may have to be protected in order to increase the nucleophilicity of the nitrogen or to avoid any double alkylation. Preferred is the use of a protecting group which withstands the addition conditions and which can be easily fixed as well as removed, like for instance CF 3 CO, BOC and the like. Numerous protected group of the amine function of an aniline and their introduction and removal, are well described in T. W. Greene and G. M. Wuts, “ Protecting groups in Organic Synthesis ”, Third Edition, Wiley, New York, 1998, and references cited therein.

Compounds of type IX are generally obtained in good yield when the addition is conducted in the presence of a base such as triethylamine, diisopropylethylamine, potassium carbonate and the like in solvent such as N,N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, ethanol, acetonitrile at a temperature from about 0° to about 100° C. When one of the above mentioned reactions is leading to the acid derivatives of IX (R═H), an esterification step, of conditions well known of one skilled in the art, is required to afford the ester necessary to obtain compounds of formula VII.

A preferred method of synthesis of derivatives of formula VIII is involving in a second step the addition of low molecular weight hydrazines of type R 2 NH—NHR 3 such as hydrazine, methyl hydrazine, 1,2-dimethylhydrazine and the like onto compounds of type IX (R=Me). This reaction is performed in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine, potassium carbonate, cesium carbonate, and the like in a polar protic solvent such as methanol, ethanol and the like at a temperature ranging from 20° C. to 150° C.

Upon completion of the reaction, the acyl hydrazine VIII is recovered by conventional methods including precipitation, chromatography, filtration, distillation and the like. For G being represented by a group of the formula:

wherein X 3 , X 3′ and L are as above defined, a preferred access to derivatives according to formula VII—provided they are not commercially available—involves in a first step the preparation of compounds of formula X.

Numerous methods are known in the literature for the preparation of derivatives of formula X depending on the nature of L as extensively described (see: “ Comprehensive Heterocyclic Chemistry II”, 1996, Eds: A. R. Katrisky, C W Ress; E. F. V. Scriven). The acid or ester function of compound X is then transformed into an acylhydrazide group using the methods described for the intermediate of type IX.

The sulfonyl hydrazides of formula I are readily prepared by contacting the sulfonyl chloride V with an amine of formula VIII in the presence of a suitable base to scavenge the acid generated during the reaction. Suitable bases include, by way of examples, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine and the like. The reaction is preferably conducted in a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, ethanol, acetonitrile or chloroform at a temperature from about 0° to about 100° C.

The use of sulfonyl chloride of type VII leads to amines that have to be deprotected using well known methods to afford amine of general formula XI

Derivatives of type XI are then acylated according to described methods for the preparation of amides by condensation of amines with acid chlorides or carboxylic acids in the preferred conditions described above leading to compounds of general formula I

An alternative method of preparation which has also to be considered as part of this invention, said method of preparation consisting in the condensation of a sulfonyl hydrazide derivative of formula XI

with electrophiles G which will be chosen taking into account parameters known by one skilled in the art. Procedures and methods to perform these types of condensation are well-known and have been well described on various synthesis of sulfonyl hydrazide derivatives. If the above general synthetic methods are not applicable for the obtention of compounds of formula I, suitable methods of preparation known by a person skilled in the art should be used. For example, if Ar 2 is phenyl, one should start from commercially available 4-cyanophenyl sulfonyl chloride and applies conventional methods known by a person skilled in the art to reach sulfonyl hydrazide derivatives of formula I.

A final aspect of the present invention is related to the use of the compounds according to formula I for the modulation of the JNK function, or signaling pathways, the use of said compounds for the preparation of pharmaceutical compositions for the modulation of the JNK pathway as well as the formulations containing the active compounds according to formula I. Said modulation of the JNK pathway is viewed as a suitable approach of treatment for various disorders. When employed as pharmaceuticals, the sulfonyl hydrazide derivatives of the present invention are typically administered in the form of a pharmaceutical composition. Hence, pharmaceutical compositions comprising a compound of formula I and a pharmaceutically acceptable carrier, diluent or excipient therefore are also within the scope of the present invention. A person skilled in the art is aware of a whole variety of such carrier, diluent or excipient compounds suitable to formulate a pharmaceutical composition. Also, the present invention provides compounds for use as a medicament. In particular, the invention pro-vides the compounds of formula I for use as JNK inhibitor, notably JNK2 and JNK3, for the treatment of disorders of the immune as well as the neuronal system of mammals, notably of humans, either alone or in combination with other medicaments.

The compounds of the invention, together with a conventionally employed adjuvant, carrier, diluent or excipient may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, or in the form of sterile injectable solutions for parenteral (including subcutaneous use). Such pharmaceutical compositions and unit dosage forms thereof may comprise ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.

When employed as pharmaceuticals, the sulfonyl hydrazide derivatives of this invention are typically administered in the form of a pharmaceutical composition. Such compositions can be prepared in any manner which is well known in the pharmaceutical art and comprise at least one active compound.

Generally, the compounds of this invention are administered in a pharmaceutically effective amount. The amount of the compound actually administered will be typically determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

The pharmaceutical compositions of these inventions containing the sulfonyl hydrazides according to formula I can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. Depending on the intended route of delivery, the compounds are preferably formulated as either injectable or oral compositions.

The compositions containing the sulfonyl hydrazides according to formula I for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampoules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the sulfonyl hydrazide derivative of formula I is preferably a minor component (preferably from about 0.1 to about 50% by weight, or more preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carries and processing aids helpful for forming the desired dosing form.

Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatine; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. As mentioned before, the sulfonyl hydrazide derivative of formula I in such compositions is typically a minor component, often being from 0.05 to 10% by weight with the remainder being the injectable carrier and the like.

The above described components for orally administered or injectable compositions are merely representative. Further materials as well as processing techniques and the like are set out in Part 8 of Remington's Pharmaceutical Sciences, 17 th Edition, 1985, Marck Publishing Company, Easton, Pa., which is incorporated herein be reference. The compounds of this invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can also be found in the incorporated materials in Remington's Pharmaceutical Sciences.

In the following the present invention shall be illustrated by means of some examples which are not construed to be viewed as limiting the scope of the invention.