WO2011084503A1 - Phenoxy thiophene sulfonamides and their use in the treatment of neurodegenerative diseases - Google Patents

Abstract

A compound, of formula (I): or a pharmaceutically acceptable salt thereof and a method of treating subject in need of potentiator of NGF-induced neurite growth using a compound of formula (I).

Description

PHENOXY THIOPHENE SULFONAMIDES AND THEIR USE IN THE TREATMENT OF NEURODEGENERATIVE DISEASES

This application claims the benefit of U.S. Provisional Patent Application Serial No. 61/286,990 filed December 16, 2009, the contents of which is incorporated herein by reference.

This invention was supported in part by funds from the U.S.

Government (National Institute of General Medical Sciences 1SC3GM081092). The U.S. government may therefore have certain rights in the invention.

This invention relates generally to compounds that are potentiators of Nerve Growth Factor (NGF) - induced neurite outgrowth. In particular, this invention relates to phenoxy thiophene sulfonamides, but other compounds, for instance pyridine sulfonyls, benzene sulfonyls, thiophene sulfonyls, thiazole sulfonyls, thiophene carbonyls, and thiazole carbonyls, are also contemplated. Also

contemplated are pharmaceutical compositions including one or more of such compounds and methods of using one or more of such compounds to treat neurodegenerative diseases.

Abbreviations

B = bromine

C = chlorine

DCM = Dichloromethane

DMEM = Dulbecco's Minimal Essential Media

DMF = Dimethylformamide

DMSO = Dimethylsulfoxide

ERK = Extracellular regulated kinase

F = fluorine

FBS = Fetal Bovine Serum

H = hydrogen

I = iodine

MAPK = Mitogen activated protein kinase

l MHz = megahertz

mmol = millimole

NGF = Nerve Growth Factor

NMR = nuclear magnetic resonance

NS-1 = Neuroscreen 1 cells

NT = Neurotrophin

NTR = Neurotrophin receptor

PI-3K = Phosphoinositol-3 kinase

PLC-γ = Phospholipase C (gamma)

PMB = j3-methoxybenzyl

ppm = parts per million

TBAI = tetrabutylammonium iodide

TFA = Trifluoroacetic acid

Background

Neurodegenerative diseases encompass an assortment of central and peripheral nervous system disorders characterized by progressive loss of neural tissue, marked decline in cognitive abilities, dementia, and ultimately, severe loss of mental capacity. Neurodegenerative diseases pose some of the most difficult challenges for modern medicine, and with incremental gains in life expectancy there has been an epidemic rise in the proportion of these classes of diseases. It is well documented that most neurodegenerative diseases are caused by gene or protein malfunction.

Predominant among these diseases are Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic lateral sclerosis (ALS) and Multiple Sclerosis (MS). An estimated 37 million people worldwide are afflicted with dementia of which 5 million patients reside in the US. Approximately 90% of all patients with dementia have AD support. The cognitive deficits seen in AD patients are a consequence of the widespread death of neurons in the entorhinal cortex, the hippocampus and the basal forebrain cholinergic neurons (BFCN) (1-3). Among the suspected causes of AD is a deficit in neurotrophic support provided by the NGF, a member of the neurotrophin family of growth factor hormones. Neurotrophic factors mediate the temporal and spatial coordination of mechanisms that regulate survival, growth, and differentiation in the central nervous system (4, 5). Members of the mammalian neurotrophin family include nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), and neurotrophin 4/5 (NT 4/5). The physiological targets of the neurotrophins include all neuronal cell types that are affected by neurodegenerative diseases. Signaling by the neurotrophins is mediated in part by two classes of receptors, tropomyosin-related kinase (Trk) which belongs to the family of receptor tyrosine kinases and the p75 neurotrophin receptor (p75NTR) which belongs to the tumor necrosis factor (TNF) receptor superfamily (6-8). The ligands interact with the receptors in complex ways to exert their influence on the full program of neuronal development.

The Trk receptors consist of three family members (TrkA, TrkB, and TrkC) which bind neurotrophins with higher affinity than p75NTR. The Trk receptors display some selective binding exemplified by the exclusive binding of NGF to TrkA, binding of BDNF and NT-4 to TrkB, and selective binding of NT-3 to TrkC. However, they lack specificity in part because of the low affinity binding of NT-3 to all the receptors (9,10). Unlike the Trk receptors, p75NTR exhibits promiscuity with the neurotrophins, binding all members with similar affinity (11,12). Neurotrophins are synthesized as precursor proteins encoded by separate genes. The biologically active forms are derived by proteolytic cleavage of their precursor proteins. Both mature and precursor NGF proteins have been shown to bind TrkA and p75NTR with different affinities to elicit the activation of different response pathways, thereby suggesting a role for proteolytic processing of neurotrophic factors as a determinant of receptor interaction and biological activity. Investigations into the role of NGF in neuronal development established that neurons require continued exposure to neurotrophic factors for survival (13).

A considerable amount of data has been published that demonstrates NGF's neuroprotective role. It is well established that the regulation of neuronal differentiation and neuronal survival by Ras oncogene is mediated through MAPK and PI-3K pathways via a programmed mechanism that is dependent on the duration (transient or prolonged) of ERK activation. In PC 12, activation of either pathway relies on the protein scaffold recruited to the TrkA docking site upon NGF binding (14). Ras-dependent activation of the PI-3K/Akt pathway during NGF signaling results in prolonged and sustained stimulation of MAPK activity. These pathways in conjunction with the calcium mobilizing PLC-γ pathway are believed to be the key determinants of neuronal survival.

The convincing neuroprotective effect of NGF observed in animal models of neurodegeneration suggests that the protein may be useful in the treatment of neurodegenerative diseases. However, despite the encouraging results in animal models, administration of exogenous NGF in human clinical trials has failed to demonstrate any therapeutic benefit (15). The ineffectiveness of NGF as a treatment modality is hampered by a number of factors, including penetration of the blood- brain barrier, metabolic instability and ineffective protein delivery (16). The failure of recombinant NGF as therapy for neurodegeneration focused the efforts of researchers on the development of small organic molecules and peptidomimetics as alternative treatments for neurodegenerative disorders. Small molecules that possess NGF-like properties can be classified into three mechanistic categories: (i) agonists for the TrkA receptor, (ii) stimulators of NGF synthesis or secretion, and (iii) enhancers of NGF (i.e., increase the cellular response to NGF, but lack intrinsic activity in the absence of NGF). Similar to clinical observations with the recombinant proteins, small molecules mimetic with agonist activity have also failed in clinical trials.

Summary Of The Invention

The present invention relates to a compound for treating neurodegenerative diseases which comprises one or more compounds that potentiate NGF- induced neurite outgrowth. In an aspect of the invention the compound is of formula (I) as described below, which are phenoxy thiophene sulfonamides. In another aspect of the invention, the compound may be a pyridine sulfonyl, benzene sulfonyl, thiophene sulfonyl, thiazole sulfonyl, thiophene carbonyl, and/or thiazole carbonyl.

The present invention also relates to a composition for treating neurodegenerative diseases which comprises one or more compounds that potentiate NGF-induced neurite outgrowth. In an aspect of the invention the compound is of formula (I) as described below, which are phenoxy thiophene sulfonamides. In another aspect of the invention, the compound may be a pyridine sulfonyl, benzene sulfonyl, thiophene sulfonyl, thiazole sulfonyl, thiophene carbonyl, and/or thiazole carbonyl.

The present invention also relates to a method for synthesizing compounds for treatment of neurodegenerative diseases. In an aspect of the invention the compound used is of formula (I) as described below, which are phenoxy thiophene sulfonamides. In another aspect of the invention the compound used may be a pyridine sulfonyl, benzene sulfonyl, thiophene sulfonyl, thiazole sulfonyl, thiophene carbonyl, and/or thiazole carbonyl.

The present invention also relates to a method for treating a neurodegenerative disease in a subject in need thereof which comprises administering to the subject one or more compounds that potentiate NGF-induced neurite outgrowth. In an aspect of the invention the compound used is of formula (I) as described below, which are phenoxy thiophene sulfonamides. In another aspect of the invention the compound used may be a pyridine sulfonyl, benzene sulfonyl, thiophene sulfonyl, thiazole sulfonyl, thiophene carbonyl, and/or thiazole carbonyl.

In particular, the present invention relates to a compound of the formula (I):

(I)

or a pharmaceutically acceptable salt thereof wherein: each of Ri and R₂ is the same or different and is selected from H, naphthalene, naphthalene-(Ci-C4) alkyl, naphthalene- 1-ylmethyl, naphthalene- 1- ylethyl, naphthalene- 1-ylpropyl, 3-fluorobenzyl, 3-chlorobenzyl, 3-bromobenzyl, 3- iodobenzyl, 3-(trifluoromethyl)benzyl, 3-(trichloromethyl)benzyl, 3-(tribromomethyl) benzyl, 3-(triiodomethyl)benzyl, 3-(Ci-C4 alkyl)-benzyl, 3-methylbenzyl, 3- ethylbenzyl, 3-propylbenzyl, 3,5-dichlorobenzyl, 3,5-difluorobenzyl, 3,5,- dibromobenzyl, 3,5-diiodobenzyl, 3-chlorophenzyl, 3-fluorophenyl, 3-bromophenyl,

3- iodophenyl, 3-(Ci-C₄ alkyoxy) phenyl, 3-methoxyphenyl, 3-ethoxyphenyl, 3- propoxyphenyl, 4-methoxyphenyl, 4-(Ci-C₄ alkyoxy) phenyl, 4-ethoxyphenyl, 4- propoxyphenyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-fluorobenzyl, 3- fluorobenzyl, 4-fluorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 2- iodobenzyl, 3-iodobenzyI, 4-iodobenzyl, 3-(Ci-C₄ alkyoxy) benzyl; 3-methoxybenzyl,

4- methoxybenzyl, 3-ethoxybenzyl, 4-ethoxybenzyl, 3-propoxybenzyl, 4-(Ci-C₄ alkyoxy)phenyl and 4 propoxybenzyl, each of R₃ and ¾ is the same or different and is selected from H, F, CI,

Br, and I, and

R₅ is selected from 3-(R-l-yl)phenyl, and of 4-(R-l-yl)phenyl, wherein R is selected from piperazin, 4-(Q-C₄ alkyl) piperzin, 4-methylpiperazin, 4- ethylpiperazin, and 4-propylpiperazin.

The compounds of the invention are useful in the treatment of neurological disorders and neurodegenerative diseases, including but not limited to Alzheimer's disease, Huntington's disease, Parkinson's disease, migraine, depression, peripheral neuropathy, pain, cerebral amyloid angiopathy, cognitive dysfunction, epilepsy, spinal cord injury, wound healing, burns, amyotrophic lateral sclerosis, and multiple sclerosis.

Detailed Description Of The Invention

For purposes of the following detailed description, it is to be understood that the invention may assume various alternative variations and step sequences, except where expressly specified to the contrary. Moreover, other than in any operating examples, or where otherwise indicated, all numbers expressing, for example, quantities of ingredients used in the specification and claims are to be understood as being modified in all instances by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard variation found in their respective testing measurements.

Also, it should be understood that any numerical range recited herein is intended to include all sub-ranges subsumed therein. For example, a range of "1 to 10" is intended to include all sub-ranges between (and including) the recited minimum value of 1 and the recited maximum value of 10, that is, having a minimum value equal to or greater than 1 and a maximum value of equal to or less than 10.

In this application, the use of the singular includes the plural and plural encompasses singular, unless specifically stated otherwise. In addition, in this application, the use of "or" means "and/or" unless specifically stated otherwise, even though "and/or" may be explicitly used in certain instances.

In the present invention, 60 phenoxythiophene sulfonamides from a 35,000 compound diversity set library were tested for their ability to potentiate the activity of NGF-induced neurite outgrowth when compared to NGF alone. The structures and potentiator activity of the compounds are shown in Table 1.

In the present invention, 18 analogs of BRITE-355252 were synthesized and tested to initially explore the structural relationship these compounds display towards neurite outgrowth potentiation. The structures and potentiator activity of the 18 analogs of BRITE 355252 are shown in Table 2. Compounds of formula (I)

wherein Ri, R₂, R3 R4 and R5 are as defined above can be prepared by a process comprising the steps of

(a) reacting a halo thiophene-sulfonyl halo and Ri-N-H, to form a resultant N-monoprotected thiophene sulfonamide having a first N-protecting group comprising Ri,

(b) reacting the resultant N-monoprotected amide with R₂-N-halo and a catalyst in a base, to form a resultant Ν,Ν-diprotected thiophene sulfonamide having also a second N-protecting group comprising R₂,

(c) reacting the resultant Ν,Ν-diprotected thiophene sulfonamide with Cs₂C0₃ and 3-(R-l-yl)phenyl or 4-(R-l-yl)phenyl, wherein R is selected from piperazin, 4-methylpiperazin, 4-ethyl- piperazin, and 4-propylpiperazin, in a solvent, and then removing the solvent, to obtain a resultant Ν,Ν-diprotected phenoxy thiophene sulfonamide, and

(d) reacting the resultant Ν,Ν-diprotected phenoxy thiophene sulfonamide with a deprotecting agent that is selective for deprotecting the second N- protecting group, thereby removing the second N-protecting group, and forming a N- monoprotected phenoxy thiophene sulfonamide.

The halogen atom of the halo thiophene-sulfonyl halo compound is selected from bromine, chlorine, fluorine and iodine. Any base that will in combination with the N-monoprotected amide with R₂-N-halo and a catalyst result in a Ν,Ν-diprotected thiophene sulfonamide can be used.

Non-limiting examples of bases that can be used are Et₃N, Na₂C0₃, K₂C0₃ and NaH and any base described in the examples.

In an embodiment of the invention the halo thiophene-sulfonyl halo is dichlorothiophene-sulfonyl chloride and Rl-N-H is naphthylmethylamine. These groups are mixed and cooled to form a N-monoprotected thiophene sulfonamide, having a first N-protecting group that comprises naphthylmethyl.

In an embodiment of the invention the resultant N-monoprotected thiophene sulfonamide, is mixed with methoxybenzyl bromide and a catalyst in sodium hydride, and cooled thereby forming a Ν,Ν-diprotected thiophene

sulfonamide having also a second N-protecting group that comprises methoxybenzyl, and the resultant Ν,Ν-diprotected thiophene sulfon-amide, and Cs₂C0₃ and butyl (hydroxyphenyl)piperazine-carboxylate in a solvent, are mixed and heated. The solvent is then removed to obtain a resultant Ν,Ν-diprotected phenoxy thiophene sulfonamide.

In an embodiment of the invention the resultant N,N-diprotected phenoxy thiophene sulfonamide is mixed with a deprotecting agent that is selective for deprotecting the second N-protecting group, thereby removing the methoxy benzyl that is the second N-protecting group, and thereby forming a N-monoprotected phenoxy thiophene sulfonamide.

Examples of non-limiting embodiments of the invention are where: the dichlorothiophene-sulfonyl chloride is 4,5-dichlorothiophene-2-sulfonyl chloride; the naththylmethylamine is 1 -naphthylmethylamine; the methoxybenzyl bromide is 4- methoxybenzyl bromide; the catalyst is tetrabutyl-ammonium iodide; the butyl (hydroxyphenyl)piperazine-carboxylate is tert-butyl-4-(3-hydroxyphenyl)piperazine- 1-carboxylate; he solvent is dimethyl formamide and/or the selective deprotecting agent comprises dichloromethane and triflouroacetic acid; or a combination thereof. Non-limiting examples of solvents that can be used are DMSO and dioxane and the solvents described in the examples.

The following reaction Scheme 1 illustrates the preparation of compounds within the scope of the present invention:

Scheme 1 Preparation of 5-phenoxy-4-chloro-N-(aryl/alkyl)thiophene- 2-sulfonamides

Scheme 1 refers to the preparation of compounds of formula I. Referring to Scheme 1, compounds of the formula I are prepared by reacting commercially available 4,5-dichlorothiophene-2-sulfonyl chloride 1 with an amine to generate dichlorothiophene sulfonamide 2. PMB (p-methoxybenzyl) protected 4,5- dichlorothiophene sulfonamide 3 is generated by reacting compound 2 with NaH in DMF, ^methoxybenzyl bromide and a catalytic amount of TBAL Nucleophilic displacement of the C-5 chlorine with a phenol in the presence of Cs₂C0₃ produce Ν,Ν-diprotected 5-(3-phenoxy)-thiophene-2-sulfonamide 3. In the final step, the protecting group is removed using TFA in DCM (1:1) to give the desired compound.

The term "pharmaceutically acceptable salts" refers to the non-toxic, inorganic and organic acid addition salts and base addition salts of compounds of the present invention.

Such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acid; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmoic, maleic, hydroxy- maleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic acid. Pharmaceutically acceptable salts from amino acids may also be used. Such as salts of arginine and lysine.

Pharmaceutically acceptable salts may be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts may be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two.

As used herein, the terms "treatment" and "therapy" and the like refer to alleviate, slow the progression, prophylaxis, or attenuation of existing disease. "Prevention", as used herein, refers to delaying, slowing, inhibiting, reducing or ameliorating the onset of disease.

The pharmaceutical compositions of this invention comprise one or more compounds that potentiate NGF-induced neurite outgrowth and one or more pharmaceutically acceptable carriers, diluents, and excipients.

Pharmaceutical composition of the present invention may be in a form suitable for use in this invention for examples compositions may be formulated for i) oral use, for example, aqueous or oily suspensions, dispersible powders or granules, elixirs, emulsions, hard or soft capsules, lozenges, syrups, tablets or trouches; or ii) parenteral administration, for example, sterile aqueous or oily solution for intravenous, subcutaneous, intraperitoneal, or intramuscular or iii) delivered intracerebrally.

As used herein the term "pharmaceutically acceptable" is meant that the carrier, diluent, excipients, and/or salt must be compatible with the other ingredients of the formulation including the active ingredient(s), and not deleterious to the recipient thereof.

"Pharmaceutically acceptable" also means that the compositions, or dosage forms are within the scope of sound medical judgment, suitable for use for an animal or human without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved.

An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the age, sex, and weight of the subject. Dosage regimens can be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.

The invention is further understood by reference to the following Examples, which are intended to be purely exemplary of the invention. The present invention is not limited in scope by the exemplified embodiments, which are intended as illustrations of single aspects of the invention only. Any methods that are functionally equivalent to those described in the Examples are within the scope of the invention. Various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description. Such modifications fall within the scope of the appended claims.

Example 1

Potentiation of Neurite Outgrowth Assay

The ability of compounds or the pharmaceutically acceptable salts thereof to induce morphological differentiation and neurite outgrowth, and consequently, demonstrate their effectiveness for treating neurodegenerative diseases is shown by in vitro assays described herein. Neurite length induced by synthetic compounds in neuronal cells and cell models were measured via manual phase contrast microscopy and automated imaging platform. The rat pheocromacytoma cell line PC 12 or the clonal derivative neuroscreen-1 (NS-1) cells were cultured in clear bottom 96-well collagen-coated plates at 3,000 cells/well in growth media (F12:DMEM supplemented with 10% horse serum (HS), 5% fetal bovine serum (FBS), and 2 mM L-glutamine at 37°C with 5% C0₂ and 90% humidity). After 24 h, the growth media was replaced with assay media (F12:DMEM with 2% HS, 1% FBS and 2 mM L-glutamine) containing various concentrations of test compounds and NGF (2 ng/mL), and incubation continued at 37 °C. Stock solutions of test compounds were prepared in DMSO at 10 mM and diluted to different concentrations in the assay. After 48 h the media was changed to assay media without test compounds for additional 24 h. The cells were enumerated either manually on a phase contrast microscope or processed further with gamma tubulin specific antibody or various cell stains for analysis on the BD Pathway 855 high content bioimager. For manual counting, cells with neurite processes greater than the diameter of the cell body were indicative of differentiation and were scored as neurite-bearing cells. The ratio of neurite-bearing cells to total cells (with at least 100 cells examined/viewing area; 3 viewing areas/well; 4 wells/sample) was determined and expressed as a percentage. For the cellular processing in the automated bioimager, the Cellomics neurite outgrowth kit (Cellomics Inc, Pittsburg, PA) was employed as specified by the manufacturer. Briefly, compound treated cells were fixed by adding 200 μΐ pre- warmed fixation solution containing Hoechst dye to each well for 15 min, then sequentially with 100 μΐ of primary antibody solution for lh and 50 μΐ of secondary antibody solution for lh. All incubations were carried out at 37°C protected from light. Following each incubation step, the wells were washed with 200 μΐ of neurite outgrowth buffer. The final wash step consisted of two washes with 200 μΐ of IX wash buffer-M, with the buffer from the final wash left in the wells. The plates were sealed and analyzed on the BD Pathway 855 high content bioimager.

Example 2

Preparation of Analogs of BRITE 355252

General procedures for the preparation of analogs of BRITE 355252

All solvents and reagents were obtained from commercial sources and used without further purification unless otherwise stated. All reactions were performed in oven-dried glassware (either in RB flasks or 20 ml vials equipped with septa) under an atmosphere of nitrogen and the progress of reactions was monitored by thin-layer chromatography and LC-MS. Analytical thin-layer chromatography was performed on precoated 250 um layer thickness silica gel 60 F₂₅4 plates (EMD Chemicals Inc.). Visualization was performed by ultraviolet light and/or by staining with phosphomolybdic acid (PMA) or ?-anisaldehyde. All the silica gel

chromatography purifications were carried out by using Combiflash^® Rf (Teledyne Isco) and CombiFlash® Companion® (Teledyne Isco) either with EtOAc/hexane or MeOH/CH₂Cl2 mixtures as the eluants. Melting points were measured on a MEL- TEMP® capillary melting point apparatus and are uncorrected. Proton nuclear magnetic resonance(Ή NMR) spectra and carbon nuclear magnetic resonance (¹³C NMPv) spectra were recorded on a Varian VNMRS-500 (500 MHz) spectrometer. Chemical shifts (<S) for proton are reported in parts per million (ppm) downfield from tetramethylsilane and are referenced to it (TMS 0.0 ppm). Coupling constants (J) are reported in Hertz. Multiplicities are reported using the following abbreviations: br = broad; s = singlet; d = doublet; t = triplet; q = quartet; m = multiplet. Chemical shifts (<5) for carbon are reported in parts per million (ppm) downfield from

tetramethylsilane and are referenced to residual solvent peaks: carbon (CDC1₃ 77.0 ppm). Mass spectra were recorded on an Agilent 1200 Series LC/MS instrument equipped with a XTerra®MS (C-18, 3.5 μηι) 3.0 x 100 mm column.

Representative Procedure for the preparation of 4,5-dichloro- V

(aryl/alkyl)thiophene-2-sulfonamides

To a solution of 4,5-dichlorothiophene-2-sulfonyl chloride (1.000 g, 4.002 mmol) in anhydrous CH₂C1₂ (20 mL) was added 1-naphthylmethylamine (0.630 g, 4.007 mmol) followed by Et₃N (0.84 mL, 6.027 mmol) and stirred at room temperature for 2 h. The reaction mixture was diluted with water (20 mL) and extracted with CH₂C1₂ (100 mL), washed with brine, dried (Na₂S0₄) and concentrated under vacuo. The residue was purified by recrystallization from CH₂Clr-hexane to afford the pure 4,5-dichloro-N-(naphthalen-l-ylmethyl)thiophene-2-sulfonamide (1.350 g, 91%) as a white crystalline product. Representative Procedure for the PMB protection of 4,5-dichIoro-N

(aryl/alkyl)thiophene-2-sulfonamides

Sodium hydride (0.081 g, 3.375 mmol) was slowly added in portions to a solution of 4,5-dichloro-N-(naphthalen-l-ylmethyl)thiophene-2-sulfonamide (1.250 g, 3.358 mmol) in anhydrous DMF (10 mL) at 0°C and stirred for 15 min. Then, 4- methoxybenzyl bromide (PMBBr) (0.675 g, 3.357 mmol), and a catalytic amount of TBAI (0.030 g, 0.081 mmol) were added at 0°C, and allowed to stir at room temperature for 2 h. After completion of the reaction, it was quenched by slow addition of water (5 mL) and extracted with EtOAc (100 mL), washed with water and brine, dried (Na₂S0₄), concentrated under vacuo and the residue purified by flash silica gel column chromatography (Combiflash® Rf) using EtOAc-hexane (1:9) as eluant to afford 4,5-dichloro-N-(4-methoxybenzyl)-N-(naphthalen-l-ylmethyl) thiophene-2-sulfonamide (1.500 g, 91%) as a white solid.

Representative procedure for the coupling of phenols with PMB protected 4,5- dichloro-iV-(aryl/aIkyI)thiophene-2-suIfonamides

A mixture of 4,5-dichloro-N-(4-methoxybenzyl)-N-(naphthalen-l- ylmethyl)thiophene-2-sulfonamide (0.100 g, 0.203 mmol), tert-butyl 4-(3- hydroxyphenyl)piperazine-l -carboxylate (0.068 g, 0.244 mmol) and Cs₂C0₃ (0.099 g, 0.304 mmol) in anhydrous DMF (2 mL) was heated at 80°C for 2.5 h. The solvent was removed under vacuo and the residue was purified by Combiflash® Rf (Isco) using EtOAc-hexanes (1 :9) to obtain a white solid (0.140 g, 94%).

Representative procedure for the deprotection PMB group

To a solution of ter/-butyl 4-(3-(3-chloro-5-(N-(4-methoxybenzyl)-N- (naphthalen- 1 -ylmethyl)sulfamoyl)thio-phen-2-yloxy)phenyl)piperazine- 1 - carboxylate (0.085 g, 0.116 mmol) in anhydrous CH C1₂ (2 mL) was added TFA (2 mL) and stirred at room temperature for 3 h. The solvent mixture was removed under vacuo and the residue was re-dissolved in CH₂C1₂ (20 mL)_s washed with aqueous sat. NaHC0₃ followed by brine, dried (Na₂S0₄), and concentrated under vacuo. is BRITE-355252

4-ChIoro-N-(naphthaIen-l-ylmethyI)-5-(3-(piperazin-l- yl)phenoxy)thiophene-2-suIfonamide

The crade product was purified by flash silica gel column chromatography using MeOH-CH₂Cl2 (1 :9) to afford a light orange solid (0.055 g, 92%). 1H NMR (500 MHz, DMSO-de):*? (ppm): 2.81 (t, 4H, J= 5.0 Hz), 3.09 (t, 4H, J= 5.0 Hz), 4.56 (s, 2H), 6.43 (dd, IH, J= 2.0, 8.0 Hz), 6.75 (t, IH, J= 2.5 Hz), 6.83 (dd, IH, J= 2.5, 8.0 Hz), 7.26 (t, IH, J= 8.0 Hz), 7.43-7.48 (m, 3H), 7.54-7.58 (m, 2H), 7.87 (dd, IH, J= 1.5, 7.5 Hz), 7.93-7.96 (m, IH), 8.06-8.09 (m, IH). APCI/ESI MS: m/z 513.9 [M+H]⁺

BRITE-492796

4-Chloro-N-methyl-iV-(naphthalen-l-ylmethyl)-5-(3-(piperazin-l- yl)phenoxy)thiophene-2-sulfonamide

The product was prepared in 89%% yield; White solid, mp: 144-

146°C;

Ή NMR (500 MHz, DMSO-d₆): δ (ppm): 2.55 (s, 3H), 2.86 (t, 4H, J= 4.5 Hz), 3.14 (t, 4H, J= 4.5 Hz), 4.63 (s, 2H), 6.62-6.66 (m, IH), 6.84-6.88 (m, 2H), 7.30 (t, IH, J = 8.0 Hz), 7.48-7.62 (m, 4H), 7.91 (s, IH), 7.94 (d, IH, J = 8.0 Hz), 7.98 (d, IH, J= 9.0 Hz), 8.29 (d, IH, J= 8.0 Hz). APCI/ESI MS m/z 527.9 [M+H

BRITE-492794

4-ChIoro-5-(3-(4-methyIpiperazin-l-yl)phenoxy)-N-(naphthalen-l- yImethyl)thiophene-2-suIfonamide

The product was prepared in 89%% yield; White solid, mp: 156- 158°C; ^lE NMR (500 MHz, DMSO-d₆): δ (ppm): 2.21 (s, 3H), 2.43 (t, 4H, J = 5.0 Hz), 3.17 (t, 4H, J= 5.0 Hz), 4.55 (d, 2H, J= 4.5 Hz), 6.44 (dd, IH, J= 2.0, 8.0 Hz), 6.78 (t, IH, J= 2.0 Hz), 6.84 (dd, IH, J= 2.0, 8.0 Hz), 7.27 (t, IH, J= 8.0 Hz), 7.43- 7.48 (m, 3H), 7.53-7.58 (m, 2H), 7.88 (dd, IH, J = 1.5, 7.5 Hz), 7.93-7.97 (m, IH), 8.05-8.09 (m, IH), 8.52 (t, IH, J= 4.5 Hz, NH). APCI/ESI MS Im/z 527.9 [M+H]⁺ BRITE-492809

4-Chloro-N-(3-fluorobenzyl)-5-(3-(piperazin-l- yl)phenoxy)thiophene-2-sulfonamide

The product was prepared in 75% yield; White solid, mp: 86-88°C (decomposed); Ή NMR (500 MHz, DMSO-d₆): δ (ppm): 3.06 (t, 4H, J = 5.0 Hz), 3.20 (t, 4H, J= 5.0 Hz), 4.23 (s, 2H), 6.54 (dd, 1H, J = 2.5, 8.0 Hz), 6.67 (t, 1H, J = 2.5 Hz), 6.77 (dd, 1H, J= 2.5, 8.0 Hz), 6.95-7.02 (m, 2H), 7.04 (d, 1H, J = 7.0 Hz), 7.23-7.32 (m, 2H), 7.33 (s, 1H).

APCI/ESI MS∞z481.9 [M+H]⁺

BMTE-354873

4-Chloro-5-(3-(piperazin-l-yI)phenoxy)-N-(3- (trifluoromethyl)benzyl)thiophene-2-sulfonamide

The product was prepared in 71% yield; White solid, mp: 58-60°C (decomposed): 1H NMR (500 MHz, CDC1₃): δ (ppm): 3.03 (t, 4H, J= 5.0 Hz), 3.17 (t, 4H, J = 5.0 Hz), 4.29 (s, 2H), 6.53 (dd, 1H, J= 2.5, 8.0 Hz), 6.66 (t, 1H, J= 2.5 Hz), 6.76 (dd, 1H, J = 2.5, 8.0 Hz), 7.22-7.25 (m, 1H), 7.31 (s, 1H), 7.43-7.50 (m, 3H), 7.56 (d, lH, J= 7.0 Hz).

APCI/ESI MS m z531.9 [M+H]⁺

BRITE-492808

4-ChIoro-N-(3-methylbenzyl)-5-(3-(piperazin-l- yl)phenoxy)thiophene-2-suIfonamide

The product was prepared in 71% yield; White solid, mp: 122-124°C: 1H NMR (500 MHz, CDC1₃): δ (ppm): 2.33 (s, 3H), 3.03 (t, 4H, J = 5.0 Hz), 3.17 (t, 4H, J= 5.0 Hz), 4.20 (s, 2H), 6.52 (dd, 1H, J= 2.5, 8.0 Hz), 6.66 (t, 1H, J= 2.5 Hz), 6.76 (dd, 1H, J= 2.5, 8.0 Hz), 7.02 (d, 1H, J = 8.0 Hz), 7.04 (s, 1H), 7.11 (d, 1H, J = 7.5 Hz), 7.20 (d, 1H, J = 8.0 Hz), 7.23 (d, 1H, J = 8.0 Hz), 7.32 (s, 1H). APCI ESI- MS m/z477.9 [M+H]⁺ BRITE-492807

4-Chloro-iV-(3,5-dichlorobenzyl)-5-(3-(piperaziii-l- yl)phenoxy)thiophene-2-sulfonamide

The product was prepared in 89% yield; Yellowish syrup: Ή NMR (500 MHz, CDC ): δ (ppm): 3.06 (t, 4H, J= 5.0 Hz), 3.20 (t, 4H, J= 5.0 Hz), 4.19 (s, 2H), 6.56 (dd, IH, J= 1.5, 8.0 Hz), 6.68 (s, IH), 6.77 (dd, IH, J= 1.5, 8.0 Hz), 7.14 (d, 2H, J = 0.5 Hz), 7.24-7.29 (m, 2H), 7.31 (s, IH). APCI/ESI MS m/z 531.8 [M+H]⁺

BRITE-354909

4-Chloro-N-(4-methoxyphenyl)-5-(3-(piperazin-l- yl)phenoxy)thiophene-2-suIfonamide

The product was prepared in 89% yield; White solid, mp: 118-120°C: Ή NMR (500 MHz, CDCI3+CD₃OD): δ (ppm): 3.02 (t, 4H, J= 5.0 Hz), 3.16 (t, 4H, J = 5.0 Hz), 3.79 (s, 3H), 6.48 (dd, IH, J= 1.5, 8.0 Hz), 6.60 (t, IH, J = 1.5 Hz), 6.74 (dd, IH, J= 2.0, 8.5 Hz), 6.81-6.85 (m, 2H), 7.05-7.09 (m, 2H), 7.18 (s, IH), 7.22 (t, lH, J= 8.0 Hz). APCI/ESI MS m/zA19.9 [M+H]⁺

BRITE-492806

4-ChIoro-N-(naphthalen-l-yImethyI)-5-(4-(piperazin-l- yl)phenoxy)thiophene-2-suIfonamide

The product was prepared in 97% yield; Light orange solid, mp: 156— 158 °C: ¾ NMR (500 MHz, CDCI3): δ (ppm): 3.04-3.07 (m, 4H), 3.13-3.16 (m, 4H), 4.65 (s, 2H), 6.89-6.92 (m, 2H), 7.02-7.05 (m, 2H), 7.32 (s, IH), 7.37-7.42 (m, 2H), 7.52-7.55 (m, 2H), 7.83 (dd, IH, J = 2.0, 7.0 Hz), 7.86-7.89 (m, IH), 7.92-7.94 (m, IH).

APCI/ESI MS m/z 514.0 [M+H]⁺ BRITE-492805

4-ChIoro-iV-(2-chlorobeiizyI)-5-(3-(piperazin-l- yl)phenoxy)thiophene-2-suIfonamide

The product was prepared in 83% yield; Light orange solid, mp: 99- 101°C: Ή NMR (500 MHz, CDCI₃): δ (ppm): 3.02-3.04 (m, 4H), 3.15-3.18 (m, 4H), 4.35 (s, 2H), 6.49 (dd, IH, J= 2.0, 8.0 Hz), 6.64 (t, IH, J= 2.0 Hz), 6.75 (dd, IH, J= 2.5, 8.5 Hz), 7.20 (s, IH), 7.22 (d, IH, J= 0.5 Hz), 7.24 (s, IH), 7.30 (s, IH), 7.32- 7.35 (m, 2H).

APCI/ESI MS m/z 497.9 [M+H]⁺ BRITE-355123

4-Chloro-N-(3-chlorobeiizyi)-5-(3-(piperazin-l- yl)phenoxy)thiophene-2-suIfonamide

The product was prepared in 85% yield; White solid, mp: 123-125°C: 1H NMR (500 MHz, CDC1₃): δ (ppm): 3.01-3.04 (m, 4H), 3.15-3.18 (m, 4H), 4.21 (s, 2H), 6.54 (dd, IH, J= 2.5, 8.0 Hz), 6.67 (t, IH, J= 2.5 Hz), 6.77 (dd, IH, J= 2.5, 8.0 Hz), 7.13-7.16 (m, IH), 7.21-7.30 (m, 4H), 7.32 (s, IH). APCI/ESI MS m/z 497.9 [M+H]⁺

BRITE-492802

4-Chloro-N-(4-cMorobenzyl)-5-(3-(piperazin-l- yI)phenoxy)thiophene-2-suLfonamide

The product was prepared in 78% yield; Light orange solid, mp: 118— 120°C: Ή NMR (500 MHz, CDC1₃): δ (ppm): 3.01-3.04 (m, 4H), 3.15-3.18 (m, 4H), 4.20 (s, 2H), 6.53 (ddd, IH, J = 0.5, 2.0, 8.0 Hz), 6.67 (t, IH, J = 2.0 Hz), 6.77 (dd, IH, J= 2.0, 8.0 Hz), 7.18-7.21 (m, 2H), 7.22 (s, IH), 7.29-7.32 (m, 2H), 7.34 (s, IH).

APCI/ESI MS m/z 497.9 [M+H]⁺

BRITE-492803

4-Chloro-N-(4-methoxybenzyI)-5-(3-(piperazin-l- yI)phenoxy)thiophene-2-sulfonamide

The product was prepared in 48% yield; White solid, mp: 106-108°C: Ή NMR (500 MHz, CDCI₃): δ (ppm): 2.97 (t, 4H, J = 5.0 Hz), 3.12 (t, 4H, J = 5.0 Hz), 3.77 (s, 3H), 4.14 (s, 2H), 6.51 (dd, IH, J= 2.0, 8.0 Hz), 6.64 (t, IH, J= 2.0 Hz), 6.73 (dd, IH, J= 2.0, 8.0 Hz), 6.82 (d, 2H, J= 8.5 Hz), 7.14 (d, 2H, J= 8.5 Hz), 7.23 (t, IH, J= 8.5 Hz), 7.28 (s, IH). APCI ESI MS m/z 494.0 [M+H]⁺ BRITE-355227

4-ChIoro-N-(3-methoxybenzyi)-5-(3-(piperazin-l- yI)phenoxy)thiophene-2-sulfonamide

The product was prepared in 31% yield; White solid, mp: 60-62°C: Ή NMR (500 MHz, CDC1₃): δ (ppm): 2.97 (t, 4H, J= 5.0 Hz), 3.12 (t, 4H, J= 5.0 Hz), 3.76 (s, 3H), 4.18 (s, 2H), 6.52 (dd, 1H, J= 2.0, 8.0 Hz), 6.64 (t, 1H, J= 2.0 Hz), 6.73 (dd, 1H, J= 2.0, 8.5 Hz), 6.76 (s, 1H), 6.78-6.83 (m, 2H), 7.22 (ABq, 2H, J= 8.5 Hz), 7.28 (s, 1H). APCI/ESI MS m/z 494.1 [M+Hf

BRITE-492800

4-ChIoro-N-(3-chIorophenyl)-5-(3-(piperazin-l- yl)phenoxy)thiophene-2-sulfonamide

The product was prepared in 78% yield; White solid, mp: 154-156°C: ^!H NMR (500 MHz, CDCI₃): δ (ppm): 3.17 (t, 4H, J = 5.0 Hz), 3.28 (t, 4H, J = 5.0 Hz), 6.49 (dd, 1H, J = 2.0, 8.0 Hz), 6.74 (s, 1H), 6.78 (d, 1H, J = 7.5 Hz), 6.83 (dd, 1H, J= 2.0, 8.0 Hz), 6.86 (dd, 1H, J= 1.0, 7.5 Hz), 6.96 (s, 1H), 7.10 (t, 1H, J= 8.0 Hz), 7.23 (s, 1H), 7.26 (t, 1H, J = 8.0 Hz), 8.34 (br s, 1H, NH). APCI/ESIMS m/z

BRITE-492799

4-Chloro-N-(3-methoxyphenyl)-5-(3-(piperazin-l- yl)phenoxy)thiophene-2-sulfonamide

The product was prepared in 78% yield; White solid, mp: 180-182°C: Ή NMR (500 MHz, CDC1₃): δ (ppm): 3.03 (t, 4H, J = 5.0 Hz), 3.14 (t, 4H, J =-5.0 Hz), 3.78 (s, 3H), 6.47 (dd, 1H, J= 2.0, 8.0 Hz), 6.59 (t, 1H, J= 2.0 Hz), 6.65-6.68 (m, lH), 6.71-6.76 (m, 3H), 7.18-7.23 (m, 2H), 7.27 (s, 1H). APCI/ESI MS m/z 480.0 [M+Hf

BRITE-492798

4-Chloro-5-(3-(piperazin-l-yl)phenoxy)thiophene-2-sulfonamide

To a solution of tert-butyl 4-(3-(5-(N,N-bis(4-methoxybenzyl) sulfamoyl)-3-chlorothiophen-2-yloxy)phenyl)piperazine- 1 -carboxylate (0.430 g, 0.602 mmol) in anhydrous CH₂C1₂ (0.5 mL) was added TFA (4.5 mL) and stirred at room temperature for 4 h. The solvent mixture was removed under vacuo and the residue was re-dissolved in CH₂C1₂ (30 mL)_j washed with aqueous sat. NaHC0₃ followed by brine, dried (Na₂S0₄), and concentrated under vacuo. The residue was purified by Combiflash^® Rf (Isco) using MeOH-CH₂Cl (1:5) to give a white solid (0.180 g, 80%). ^]H NMR (500 MHz, CD₃OD): δ (ppm): 3.02-3.05 (m, 4H), 3.19-3.22 (m, 4H), 6.56 (dd, 1H, J= 2.0, 8.0 Hz), 6.73 (t, 1H, J= 2.0 Hz), 6.84 (dd, 1H, J= 2.0, 8.5 Hz), 7.27 (t, 1H, J= 8.5 Hz), 7.40 (s, 1H).

APCI/ESI MS m/z 374.0 [M+H]⁺

BRITE-492797

iV-(Naphthalen-l-ylmethyl)-5-(3-(piperazin-l- yl)phenoxy)thiophene-2-suIfonamide

The product was prepared in 87% yield; Light orange solid, mp: 65- 67°C: 'H NMR (500 MHz, CDC1₃): δ (ppm): 2.92 (t, 4H, J= 5.0 Hz), 3.08 (t, 4H, j = 5.0 Hz), 4.62 (s, 2H), 6.43 (d, 1H, J= 4.5 Hz), 6.56-6.60 (m, 1H), 6.65 (t, 1H, J= 2.5 Hz), 6.71 (dd, 1H, J= 2.0, 8.5 Hz), 7.23 (t, 1H, J= 8.5 Hz), 7.37 (d, 2H, J= 4.5 Hz), 7.39 (d, 1H, J= 4.0 Hz), 7.48-7.54 (m, 2H), 7.79 (t, 1H, J= 4.5 Hz), 7.82-7.86 (m, 1H), 7.95 (dd, 1H, J = 1.0, 7.5 Hz). APCI/ESI MS m/z 480.1 [M+Hf

References

1. Perry EK. Nerve growth factor and the basal forebrain cholinergic system: a link in the etiopathology of neurodegenerative dementias? Alzheimer Dis Assoc Disord. 1990; 4:1-13.

2. Geula C, Greenberg BD, Mesulam MM. Cholinesterase activity in the plaques, tangles and angiopathy of Alzheimer's disease does not emanate from amyloid. Brain Res. 1994, 644:327-30.

3. Giacobini E. Cholinergic function and Alzheimer's disease. Int J Geriatr Psychiatry. 2003, 18:Sl-5.

4. Eide FF, Lowenstein DH, Reichardt LF. Neurotrophins and their receptors-current concepts and implications for neurologic disease. Exp Neural. 1993, 121 :200-14.

5. Bibel M, Barde YA. Neurotrophins: key regulators of cell fate and cell shape in the vertebrate nervous system. Genes Dev. 2000, 14:2919-37.

6. Casaccia-Bonnefil P, Kong H, Chao MV. Neurotrophins: the biological paradox of survival factors eliciting apoptosis. Cell Death Differ. 1998, 5:357-64.

7. Tang BL. Inhibitors of neuronal regeneration: mediators and signaling mechanisms. Neurochem Int. 2003, 42:189-203.

8. Chao MV. Neurotrophins and their receptors: a convergence point for many signaling pathways. 2003, Nat Rev Neurosci. 4: 299-309.

9. Ibanez CF. Structure-function relationships in the neurotrophin family. J Neurobiol. 1994, 25:1349-61.

10. Ibanez CF. Emerging themes in structural biology of neurotrophic factors. Trends Neurosci. 1998,21:438-44. 11. Meakin SO, Shooter EM. The nerve growth factor family of receptors.

Trends Neurosci. 1992, 15:323-31.

12. Hempstead B. The many faces of p75NTR. Curr Opin Neurobiol 2002, 12: 260-267.

13. Davies AM. Regulation of neuronal survival and death by extracellular signals during development. EMBO J. 2003, 22:2537-45.

14. Patapoutian A, Reichardt LF. Trk receptors: mediators of neurotrophin action. Curr Opin Neurobiol. 2001,11:272-80.

15. Apfel, S. C. Neurotrophic factor therapy-prospects and problems. Clin Chem Lab Med. 2001, 39, 351-5.

16. Hughes RA, O'Leary PD. Exploiting neurotrophic factors for the treatment of neurodegenerative conditions: An Australian perspective. Drug Dev Res. 1999, 46 (3-4): 268-76.

Table 1. Potentiator activity of phenoxythiophene sulfonamides

BRITE-354989 137.46

BRITE-354909 164.10

BRITE-354725 118.16

BRITE-355417 130.21

BRITE-355017 100.68

BRITE-354979 167.95

BRITE-355004 227.57

BRITE-354667 120.09

0

BRITE-354966 117.58

BRITE-355262 101.57

BRITE-354965 105.69

BRITE-354615 141.47

BRITE-355016 136.81

BRITE-354517 123.09

BRITE-354958 105.06

BRITE-355360 268.37

BRITE-355227 122.75

BRITE-355423 118.48

BRITE-355468 110.22

BRITE-355003 101.19

BRITE-354946 101.12

BRITE-354983 139.90

BRITE-355015 153.43

BRITE-354627 152.71

BRITE-354993 116.44

BRITE-354956 123.12

BRITE-354984 150.01

0

BRITE-354974 113.69

BRITE-354392 106.09

BRITE-355045 116.78

BRITE-354994 122.68

BRITE-355074 109.54

BRITE-354998 146.50

BRITE-354955 146.98

BRITE-355296 113.17

BRITE-355005 150.85

BRITE-354839 272.75

BRITE-354428 113.12

BRITE-355224 174.18

BRITE-355018 122.75

BRITE-355240 - . 132.09

BRITE-355329 120.22

BRITE-355250 102.23

BRITE-355339 119.12

BRITE-355319 102.40

BRITE-355243 130.55

BRITE-355180 150.96

BRITE-355214 199.30

BRITE-355030 103.45

BRITE-355169 117.11

BRITE-355211 165.79

BRITE-355233 8*c« 111.17

BRITE-355221 102.48

BRITE-355253 106.54

BRITE-354532 123.44

Table 2. Structure and Activity of BRITE-355252 analogs

Claims

1. A method of treating a subject in need of potentiator of NGF-induced neurite growth, comprising administering to the subject a composition comprising an amount of compound that is effective as a potentiator of NGF-induced neurite growth, or a pharmaceutically acceptable salt of the compound.

2. The method of claim 1, wherein the compound is selected from one or more of phenoxy thiophene sulfonamides, pyridine sulfonyls, benzene sulfonyls, thiophene sulfonyls, thiazole sulfonyls, thiophene carbonyls, and thiazole carbonyls.

The method according to claim 1, wherein the compound is of formula

or a pharmaceutically acceptable salt thereof wherein:

each of Ri and R₂ is the same or different and is selected from H, naphthalene, naphthalene-(C]-C₄) alkyl, naphthalene- 1-ylmethyl, naphthalene- 1- ylethyl, naphthalene- 1-ylpropyl, 3-fluorobenzyl, 3-chlorobenzyl, 3-bromobenzyl, 3- iodobenzyl, 3-(trifluoromethyl)benzyl, 3-(trichloromethyl)benzyl, 3-(tribromomethyl) benzyl, 3-(triiodomethyl)benzyl, 3-(Ci-C₄ alkyl)-benzyl, 3-methylbenzyl, 3-ethyl- benzyl, 3-propylbenzyl, 3,5-dichlorobenzyl, 3,5-difluorobenzyl, 3,5,-dibromobenzyl, 3,5-diiodobenzyl, 3-chlorophenzyl, 3-fluorophenyl, 3-bromophenyl, 3-iodophenyl, 3- (C₁-C₄ alkyoxy) phenyl, 3-methoxyphenyl, 3-ethoxyphenyl, 3-propoxyphenyl, 4- methoxyphenyl, 4-(C]-C₄ alkyoxy) phenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 2- chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4- fluorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 2-iodobenzyl, 3- iodobenzyl, 4-iodobenzyl, 3-(Ci-C₄ alkyoxy) benzyl; 3-methoxybenzyl, 4-methoxy- benzyl, 3-ethoxybenzyl, 4-ethoxybenzyl,

3-propoxybenzyl, 4-(Ci-C4 alkyoxy)phenyl and 4 propoxybenzyl, each of R₃ and R4 is the same or different and is selected from H, F, CI,

Br, and I, and

R5 is selected from 3-(R-l-yl)phenyl, and 4-(R-l-yl)phenyl, wherein R is selected from piperazin, 4-(Ci-C4 alkyl) piperzin, 4-methylpiperazin, 4-ethyl- piperazin, and OF 4-propylpiperazin.

4. A compound comprising a potentiator of NGF-induced neurite growth, or a pharmaceutically acceptable salt of the compound, wherein the compound is chosen from one or more of phenoxy thiophene sulfonamides, pyridine sulfonyls, benzene sulfonyls, thiophene sulfonyls, thiazole thiophene carbonyls, and thiazole carbonyls.

5. The compound of claim 4, wherein the compound is chosen from one or more of phenoxy thiophene sulfonamides, pyridine sulfonyls, benzene sulfonyls, thiophene sulfonyls, thiazole sulfonyls, thiophene carbonyls, and thiazole carbonyls.

6. A compound of formula (I)

(I)

or a pharmaceutically acceptable salt thereof wherein:

each of Ri and R₂ is the same or different and is selected from H, naphthalene, naphthalene-(Ci-C4) alkyl, naphthalene- 1-ylmethyl, naphthalene- 1- ylethyl, naphthalene- 1-ylpropyl, 3-fluorobenzyl, 3-chlorobenzyl, 3-bromobenzyl, 3- iodobenzyl, 3-(trifluoromethyl)benzyl, 3-(trichloromethyl)benzyl, 3-(tribromomethyl) benzyl, 3-(triiodomethyl)benzyl, 3-(Ci-C₄ alkyl)-benzyl, 3-methylbenzyI, 3-ethyl- benzyl, 3-propylbenzyl, 3,5-dichlorobenzyl, 3,5-difluorobenzyl, 3,5,-dibromobenzyl, 3,5-diiodobenzyl, 3-chlorophenzyl, 3-fluorophenyl, 3-bromophenyl, 3-iodophenyl, 3- (C₁-C4 alkyoxy) phenyl, 3-methoxyphenyl, 3-ethoxyphenyl, 3-propoxyphenyl, 4- methoxyphenyl, 4-(Ci-C₄ alkyoxy) phenyl, 4-ethoxyphenyL 4-propoxyphenyl, 2- chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4- fluorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 2-iodobenzyl, 3- iodobenzyl, 4-iodobenzyl, 3-(Ci-C₄ alkyoxy) benzyl; 3-methoxybenzyl, 4-methoxy- benzyl, 3-ethoxybenzyl, 4-ethoxybenzyl, 3-propoxybenzyl, 4-(C]-C4 alkyoxy)phenyl and 4 propoxybenzyl,

each of R₃ and R4 is the same or different and is selected from H, F, CI,

Br, and I, and

R5 is selected from 3-(R-l-yl)phenyl, and 4-(R-l-yl)phenyl, wherein R is selected from piperazin, 4-(Ci-C₄ alkyl) piperzin, 4-methylpiperazin, 4-ethyI- piperazin, and 4-propylpiperazin,

or a pharmaceutically acceptable salt of the compound.

7. A method for making a compound, of formula (I):

or a pharmaceutically acceptable salt thereof,

wherein said compound comprises a potentiator of NGF-induced neurite growth, and wherein:

each of Ri and R₂ is the same or different and is selected from H, naphthalene, naphthalene-(Ci-C4) alkyl, naphthalene- 1-ylmethyl, naphthalene- 1- ylethyl, naphthalene- 1-ylpropyl, 3-fluorobenzyl, 3-chlorobenzyl, 3-bromobenzyl, 3- iodobenzyl, 3-(trifluoromethyl)benzyl, 3-(trichloromethyl)benzyl, 3-(tribromomethyl) benzyl, 3-(triiodomethyl)benzyl, 3-(Q-C₄ alkyl)-benzyl, 3-methylbenzyl, 3-ethyl- benzyl, 3-propylbenzyl, 3,5-dichlorobenzyl, 3,5-difluorobenzyl, 3,5,-dibromobenzyl, 3,5-diiodobenzyl, 3-chlorophenzyl, 3-fluorophenyl, 3-bromophenyl, 3-iodophenyl, 3- (C1-C₄ alkyoxy) phenyl, 3-methoxyphenyl, 3-ethoxyphenyl, 3-propoxyphenyl, 4- methoxyphenyl, 4-(Ci-C₄ alkyoxy) phenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 2- chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4- fluorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 2-iodobenzyl, 3- iodobenzyl, 4-iodobenzyl, 3-(Ci-C₄ alkyoxy) benzyl; 3-methoxybenzyl, 4- methoxybenzyl, 3-ethoxybenzyl, 4-ethoxybenzyl, 3-propoxybenzyl, 4-(Ci-C4 alkyoxy)phenyl and 4 propoxybenzyl,

each of R₃ and R4 is the same or different and is selected from H, F, CI,

Br, and I, and

R5 is selected from 3-(R-l -yl)phenyl and 4-(R-l-yl)phenyl, wherein R is selected from piperazin, 4-(Ci-C4 alkyl) piperzin, 4-methylpiperazin, 4-ethyl- piperazin, and 4-propylpiperazin,

comprising the steps of:

(a) reacting a halo thiophene-sulfonyl halo and RpN-H, wherein Ri as defined above to form an N-monoprotected thiophene sulfonamide having a first N-protecting group comprising Rj,

(b) reacting the N-monoprotected thiophene sulfonamide with R₂- N-halo wherein R₂ is as defined above and a catalyst in a base, forming a resultant Ν,Ν-diprotected thiophene sulfonamide having a second N-protecting group comprising R₂,

(c) reacting the Ν,Ν-diprotected thiophene sulfonamide of step (b) with Cs₂C0₃; and 3-(R-l-yl)phenyl or 4-(R-l-yl)phenyl, wherein R is selected from piperazin, 4-methylpiperazin, 4- ethylpiperazin, and 4-propylpiperazin, in a solvent, and then removing the solvent, to obtain Ν,Ν-diprotected phenoxy thiophene sulfonamide, and

(d) reacting the Ν,Ν-diprotected phenoxy thiophene sulfonamide with a deprotecting agent that is selective for deprotecting the second N-protecting group, removing the second N-protecting group, and forming a N-monoprotected phenoxy thiophene sulfonamide.

8. The method of claim 7, wherein:

(a) the dichlorothiophene-sulfonyl chloride and

naphthylmethylamine are mixed and cooled, thereby forming a N-monoprotected thiophene sulfonamide, having a first N-protecting group that comprises

naphthylmethyl, (b) adding with mixing and cooling to the resultant N- monoprotected thiophene sulfonamide, methoxybenzyl bromide and a catalyst in sodium hydride, thereby forming a Ν,Ν-diprotected thiophene sulfonamide having also a second N-protecting group that comprises methoxybenzyl,

(c) adding with mixing and heating to the resultant N,N- diprotected thiophene sulfonamide, and Cs₂C0₃ and butyl (hydroxyphenyl) piperazine-carboxylate in a solvent, and then removing the solvent, to obtain a resultant N,N-diprotected phenoxy thiophene sulfonamide, and

(d) mixing the resultant Ν,Ν-diprotected phenoxy thiophene sulfonamide with a deprotecting agent that is selective for deprotecting the second N- protecting group, thereby removing the methoxy benzyl that is the second N- protecting group, and forming a N-monoprotected phenoxy thiophene sulfonamide.

9. The method of claim 8, wherein (i) the dichlorothiophene-sulfonyl chloride is 4,5-dichlorothiophene-2-sulfonyl chloride, (ii) the naththylmethylamine is 1-naphthylmethylamine, (iii) the methoxybenzyl bromide is 4-methoxybenzyl bromide, (iv) the catalyst is tetrobutylamonium iodide, (v) the butyl (hydroxyphenyl) piperzine-carboxylate is tert-butyl-4-(3-hydroxyphenyl)piperazine-l-carboxylate, (vi) the solvent is dimethyl formamide, or (vii) the selective deprotecting agent comprises dichloromethane and triflouroacetic acid; or a combination of two or more thereof.