TWI435722B - Use of benzo-fused heterocycle sulfamide derivatives as neuroprotective agents - Google Patents

Description

Use of benzofused heterocyclic sulfonamide derivatives as neuroprotective agents

The present application claims the benefit of U.S. Provisional Application Serial No. 60/751,494, the entire disclosure of which is incorporated herein by reference.

This invention relates to the use of benzofused heterocyclic sulfonamide derivatives as neuroprotective agents. The invention further relates to the use of a benzofused heterocyclic sulfonamide derivative for the manufacture of a medicament for the treatment of acute and/or chronic neurodegenerative diseases, in particular for the treatment of neuronal damage or death. Therapy for acute or chronic neurodegenerative diseases.

Neurodegenerative conditions are annoying to many individuals in the United States or abroad. For example, many individuals suffer from neurodegenerative diseases. These diseases include a group of severe debilitating conditions such as Parkinson's disease, amyotrophic lateral sclerosis (ALS, 〝Lou Gehrig's disease〞), multiple sclerosis, and Huntington's disease. , Tychem's disease, diabetic retinopathy, multi-infarct dementia, macular degeneration, and the like.

The gradual increase in human life has led to an increase in the prevalence of neurodegenerative diseases. The relatively high incidence of these diseases (70-year-old population reported in the range of 2-15%) poses significant medical, social, and financial burdens for deaf patients, caregivers, and the general public. When these diseases begin, they cause death very quickly, or, optionally, they can slowly approach for a period of more than a few years, usually the most in patients who require careful care.

The probability of being diagnosed with a neurodegenerative disease increases dramatically with the age of the population, especially those with degenerative conditions such as Alzheimer's disease. The number of individuals with Alzheimer's disease has grown exponentially and is estimated to have as many as 24 million individuals worldwide.

Alzheimer's disease (AD) is caused by a degenerative process in patients characterized by progressive degradation of cells derived from the basal forebrain, cerebral cortex, and other brain regions. Acetylcholine transmits signals to neurons and their target nervous system is particularly affected. Old age classes and neurofibrillary tangles appear. In addition to the slower clinical course and the defined atrophy (which primarily affects the frontal and temporal lobes), Pick's disease has a clinical manifestation similar to Alzheimer's disease. An animal model of Alzheimer's disease and other dementia shows that heredity tends to form such plaques. It is believed that if a drug has an effect in this mode, it may be beneficial for at least some versions of Alzheimer's or Pick's disease. There is currently no reduction in the function of patients with Alzheimer's disease.

Parkinson's disease (PD), a middle-aged or elderly disease with a very progressive course and an extended sequence. Harrison's Principles of Internal Medicine (Vol. 2, 23d ed., Ed by Isselbacher, Braunwald, Wilson, Martin, Fauci and Kasper, McGraw-Hill Inc., New York City, 1994, pg. 2275.). The most frequently found change in patients with Parkinson's disease is the accumulation of melanin-containing nerve cells in the brainstem [substantia nigra, blue spot locus 20], where there are varying degrees of neuronal loss accompanied by obvious hobbies The reactive globular cytoplasm contains reactive gliosis (most often in the substantia nigra) together with (eosinophilic intracytoplasmic inclusions). In its complete onset mode, PD is easily recognized in patients, with common features such as stooped posture, stifness, and slowness of movement, and fixation of facial expression. Expression), rhythmic tremor of the limbs, which disappear when active will or complete relaxation. Often, the other feature associated with a fully ill disease is the festinating gait, which causes the patient to travel or walk with quick shuffling steps that seem to catch up with the accelerating rhythm of the body's center of gravity.

The treatment of Parkinson's disease is pharmacologically associated with levodopa combined with stereotactic surgery and preferably only local treatment. The potential for many remedies is that none of these therapeutic measures have an effect on the underlying disease process, which is made up of neurodegeneration. Finally, pharmacology does not necessarily offset the loss of dorsal ganglion dopamine, which seems to have to be achieved.

Other neurodegenerative conditions that plague humans are at least partially caused or caused by stroke or other trauma or injury. According to one source, as many as 700,000 new cases of stroke occur each year. In the United States, a stroke occurs every minute. The vast majority of stroke patients suffer from permanent disability, and stroke is the leading cause of neurological disability affecting 3-4 million American citizens.

There is still a need to provide an effective therapy for acute and chronic neurodegenerative diseases. Furthermore, there remains a need for a prophylactic agent that is neuroprotective and therefore useful for neuronal death and/or injury.

The present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the protection of nerves, Wherein R ¹ and R ² are each independently selected from the group consisting of hydrogen and lower alkyl; R ⁴ is selected from the group consisting of hydrogen and lower alkyl; a is from 1 to 2 An integer; Is selected from the group consisting of: as well as Wherein b is an integer from 0 to 4; and wherein c is an integer from 0 to 2; each R ⁵ is independently selected from the group consisting of halogen, lower alkyl and nitro; for or And a is 1.

The invention further relates to the use of a compound of formula (II) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the protection of neuroprotection:

The invention is exemplified by the use of any of the above compounds for the manufacture of a medicament for use in neuroprotection.

In one embodiment, the invention relates to the use of any of the above compounds for the manufacture of a medicament for use in the treatment of acute neurodegenerative diseases. In another example, the invention relates to a use for the manufacture of a medicament for use in the treatment of chronic neurodegenerative diseases.

Further, the present invention is exemplified by the use of any of the above compounds for the manufacture of a medicament for preventing death or damage of neurons after invasion or injury in the brain, central nervous system or peripheral nervous system.

Detailed description of the invention

The invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof,

,among them , a, R ¹ , R ² and R ⁴ are as defined herein for the manufacture of a medicament for use in neuroprotection. The invention is more related to the use of a therapy for acute or chronic neurodegenerative diseases. The invention further relates to a use for preventing death or damage to a neuron after injury.

The term "neuroprotective" as used herein shall mean protection of neurons in the brain, central nervous system or peripheral nervous system, preferably in the brain or spinal cord, from death and/or injury. Preferably, the neuronal systems are protected from death or damage due to oxidative stress (e.g., oxygen free radicals).

Acute neurodegenerative diseases included in the method of the present invention include, but are not limited to, various types of acute neurodegenerative diseases associated with neuronal death or injury [including cerebrovascular insufficiency, local Focal brain trauma, diffuse brain damage, and spinal cord injury], ie cerebral ischemia or infarction, including acute occlusion and thrombocytic occlusion, acute Reperfusion after acute ischemia, perinatal hypoxic-ischemic injury, cardiac arrest, and any type of intracranial hemorrhage (including but Not limited to subdural, subdural, subarachnoid, and intracranial), and intracranial and intracranial injuries (including but not limited to contusions, penetrating wounds, scratches, crushes, and lacerations), and infants' concussion shaking Whiplash shaken infant syndrome. Preferably, the acute neurodegenerative diseases are the result of a stroke, acute ischemic injury, head injury or spinal cord injury.

The chronic neurodegenerative diseases included in the method of the present invention include Alzheimer's disease, Pick's disease, diffuse Lewy body disease, progressive supranuclear palsy (history) - Lie's syndrome), multisystem degeneration (Shy-Drager syndrome), chronic epilepsy associated with neurodegeneration, motor neuron diseases including amyotrophic lateral sclerosis, degenerative atrophy Ataxias), cortical basal degeneration, Guam complex ALS-Parkingson's-Dementia complex of Guam, subacute sclerosing panencephalitis, hang Dyton's chorea, Parkinson's disease, synucleinopathies (including multiple systemic degeneration), primary progressive aphasia, striatonigral degeneration , Machado-Joseph disease / type 3 spinal cerebellar atrophy (spinocerebellar ataxia type 3 ) and olivopontocerebellar degeneration, Gilles De La Tourette's disease, bulbar and pseudobulbar palsy, spinal cord and spinal cord muscular atrophy (Gandhi 's disease', multiple sclerosis, primary lateral sclerosis, familial spastic paraplegia, Werdnig-Hoffman disease, Coog Kugelberg-Welander disease, Tay-Sachs disease, Sandhoff's disease, familial spastic disease, Wofat-Kugb -Wohlfart-Kugelberg-Welander disease, spastic paraparesis, progressive multifocal leukoencephalopathy, familial dysautonomia (Riley-Day syndrome) And pathogenic prion disease (including but not limited to CJJ, GSS disease, Creut disease and familial Insomnia). Preferably, the chronic neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, multiple sclerosis or cerebral palsy.

Other diseases that are intended to be included in the methods of the invention that represent neuronal death or injury, and the like, include dementia, regardless of latent etiology (including age-associated dementia and other dementias), and memory loss. Conditions [including dementia associated with Alzheimer's disease, vascular dementia, generalized white matter lesions (Binswanger's disease), endocrine or metabolic causes of dementia, head trauma and pan Dementia of brain damage, boxing dementia and frontal dementia].

Also included in the present invention is a neuroprotective method (i.e., a method for protecting neuronal death and/or injury) after injury to the brain, central nervous system, or peripheral nervous system, wherein the damage is caused by Chemical, toxic, infectious, radiation and/or traumatic injuries. Preferably, the method of the invention relates to preventing neuronal death or injury after trauma or injury to the brain, head and/or spinal cord, for any reason.

The term "patient" as used herein refers to an animal, preferably a mammal, preferably a human, which has been the subject of therapy, observation or experimentation.

The term "therapeutically effective amount" as used herein, refers to the amount of active compound or agent that causes a biological or pharmacological effect of a tissue, animal or human being sought by a researcher, veterinarian, physician or other clinician. The response, which includes amelioration of the symptoms of the disease being treated or the symptoms of the disease.

In one embodiment of the invention, R ¹ is selected from the group consisting of hydrogen and methyl. In another embodiment of the invention, R ² is selected from the group consisting of hydrogen and methyl. In still another embodiment of the present invention, R ¹ and R ² are each hydrogen or R ¹ and R ² are each a methyl group.

In one embodiment of the invention, -(CH ₂ ) _a - is selected from the group consisting of -CH ₂ - and -CH ₂ -CH ₂ -. Another embodiment of the invention -(CH ₂ ) _a - is -CH ₂ -.

In one embodiment of the invention, R ⁴ is selected from the group consisting of hydrogen and methyl, preferably R ⁴ is hydrogen.

In one embodiment of the invention, a is 1.

In one embodiment of the invention, b is an integer from 0 to 2. In another embodiment of the invention, c is an integer from 0 to 2. In another embodiment of the invention, b is an integer from 0 to 1. In another embodiment of the invention, c is an integer from 0 to 1. In still another embodiment of the present invention, the sum of b and c is an integer from 0 to 2, preferably an integer from 0 to 1.

In still another embodiment of the present invention, b is an integer from 0 to 2 and c is 0.

In a specific example of the present invention, Is selected from the following group: as well as . In another specific example of the present invention, Is selected from the following group: , as well as .

In a specific example of the present invention, Is selected from the group consisting of 2-(2,3-dihydro-benzo[1,4] Dioxinyl, 2-(benzo[1,3] Dioxolyl, 3-(3,4-dihydro-2H-benzo[1,4]dioxepinyl), 2-(6-chloro-2,3-dihydro- Benzo[1,4] English), 2-(6-fluoro-2,3-dihydro-benzo[1,4] English), 2-( Base, 2-(5-fluoro-2,3-dihydro-benzo[1,4] English), 2-(7-chloro-2,3-dihydro-benzo[1,4] English), 2-(6-chloro-benzo[1,3] Azyl), 2-(7-nitro-2,3-dihydro-benzo[1,4] English), 2-(7-methyl-2,3-dihydro-benzo[1,4] English), 2-(5-chloro-2,3-dihydro-benzo[1,4] English), 2-(6-bromo-2,3-dihydro-benzo[1,4] English), 2-(6,7-dichloro-2,3-dihydro-benzo[1,4] English), 2-(8-chloro-2,3-dihydro-benzo[1,4] English), 2-(2,3-dihydro-naphtho[2,3-b][1,4] English) and 2-(4-methyl-benzo[1,3] Azolyl).

In another specific example of the present invention, Is selected from the group consisting of 2-(benzo[1,3] Azyl), 2-(2,3-dihydro-benzo[1,4] English), 2-(6-chloro-2,3-dihydro-benzo[1,4] English), 2-(7-chloro-2,3-dihydro-benzo[1,4] English), 2-(7-methyl-2,3-dihydro-benzo[1,4] English), 2-(6-bromo-2,3-dihydro-benzo[1,4] English) and 2-(6,7-dichloro-2,3-dihydro-benzo[1,4] Yingji). In another specific example, Is selected from the group consisting of 2-(2,3-dihydro-benzo[1,4] English), 2-(7-methyl-2,3-dihydro-benzo[1,4] English) and 2-(6-bromo-2,3-dihydro-benzo[1,4] Yingji).

In one embodiment of the invention, R ⁵ is selected from the group consisting of halogen and lower alkyl. In another embodiment of the invention, R ⁵ is selected from the group consisting of chlorine, fluorine, bromine and methyl.

In one embodiment of the invention, the stereocenter of the compound of formula (I) is in the S-configuration. In another embodiment of the invention, the stereocenter of the compound of formula (I) is in the R-configuration.

In one embodiment of the invention, the compound of formula (I) is present as a mixture enriched in the image isomer, wherein the image enrichment (% enee) is higher than about 75%, preferably higher than about 90%, more preferably above about 95%, optimally above about 98%.

Additional specific examples of the invention, including those wherein the selected substituents are used independently for one or more of the variations defined herein (i.e., R ¹ , R ² , R ³ , R ⁴ , X-Y, and A) The ground is selected to be any individual substituent or any subgroup selected from the substituents as defined herein.

Representative compounds of the invention are listed in Table 1 below. Additional compounds of the invention are listed in Table 3. In Tables 1 and 2 below, the head 〝 stereo is defined as the stereo-configuration of the heterocyclic carbon atom attached to the asterisk bond. If no mark is listed, the compound is prepared as a mixture of stereo-configurations. If a 〝R〞 or 〝S〞 mark is listed, the steric-configuration is based on a starting material rich in mirror image isomerism.

Unless otherwise mentioned, hydrazine fluorene as used herein shall mean chloro, bromo, fluoro and iodo.

Unless otherwise mentioned, the term "indenyl" as used herein includes both straight and branched chain, whether used alone or as part of a substituted group. For example, the alkane radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, di-butyl, tert-butyl, pentyl and the like. Unless otherwise mentioned, when a bonded alkyl group is used, a lower hydrazine represents a carbon chain composition of one to four carbon atoms.

Unless otherwise mentioned, the decyloxy fluorene used herein shall mean the monooxyether radical of the above linear or branched alkyl group. For example, methoxy, ethoxy, neo-propoxy, secondary butoxy, tertiary-butoxy, neo-hexyloxy, and the like

As used herein, the symbol 〝 ^* 〞 shall mean the presence of a stereogenic source.

When a particular group is substituted with hydrazine (such as alkyl, aryl, etc.), the group may have one or more substituents independently selected from the list of substituents, preferably one to five. More preferably, one to three substituents, most preferably one to two substituents.

With respect to substituents, the term "independently" means that when more than one such substituent is feasible, such substituents may be the same or different from each other.

Under the standard nomenclature disclosed throughout this specification, the end portion of the designated side chain will be described first, followed by the adjacent functionality close to the point of attachment. Thus, for example, a monophenyl-alkyl-amino-carbonyl-alkylhydrazine substituent refers to a group having the formula below.

The abbreviations used in this specification, particularly the schemes and examples, are as follows: DCC = dicycloheximide methane DCE = dichloroethane DCM = dichloromethane DIPEA or DIEA = diisopropylethylamine DMF = dimethyl Methotrexate DMSO = dimethyl hydrazine EDC = ethyl carbodiimide Et ₃ N or TEA = triethylamine Et ₂ O = diethyl ether A or EtOA _C = ethyl acetate EtOH = ethanol IPA = 2-propanol Hept =heptane HOBT=1-hydroxybenzotriazole HPLC=high pressure liquid chromatography LAH=lithium aluminum hydride M or MeOH=methanol NMR=nuclear magnetic resonance Pd-C=palladium on carbon catalyst RP HPLC=reverse high pressure liquid phase Chromatography RT or rt = room temperature TEA = triethylamine TFA = trifluoroacetic acid THF = tetrahydrofuran TLC = thin layer chromatography

If the compounds according to the invention have at least one chiral center, they may thus be present as mirror image isomers. If the compounds have two or more chiral centers, they may additionally exist as non-image isomers. It is to be understood that all such isomers and mixtures thereof are included within the scope of the invention. Furthermore, certain crystalline forms with respect to these compounds may exist as polymorphs and are intended to be included in the present invention. In addition, some of these compounds may form solvates with water or common organic solvents (as a hydrate with water), and such solvates are also intended to be encompassed within the scope of the invention.

With regard to use in medicine, the salts of the compounds of the invention refer to non-toxic pharmaceutically acceptable salts. However, other salts may be employed in the preparation of the compounds according to the invention or their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of such compounds include acid addition salts which are, for example, permeable to a solution of the compound and a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid Formed by acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Further, if the compound of the present invention has an acidic moiety, suitable pharmaceutically acceptable salts thereof include alkali metal salts (such as sodium or potassium salts); alkaline earth metal salts (such as calcium or magnesium salts); A salt formed by a suitable organic acid ligand (such as a quaternary amine salt). Thus, representative pharmaceutically acceptable salts include the following: acetate, besylate, benzoate, bicarbonate, hydrogen sulfate, hydrogen tartrate, borate, bromide, calcium edetate (calcium) Edetate), camphor sulfonate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, backing Estolate, esylate, fumarate, glucoheptonate, gluconate, glutamate, beta arsenate, hexylresorcinate, seabamine (hydrabamine), hydrobromide, hydrochloride, hydroxynaphate, iodide, isosulfonate, lactate, lactate, laurate, malate, maleate, mandelate , mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, naphthalene sulfonate, nitrate, N-methyl reduced glucosamine ammonium, oil Acid salt, palmitic acid salt (enpo acid salt), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylic acid , Stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate (teoclate), p-toluenesulfonic acid, triethylamine salt and valerate.

Representative acids and bases which may be employed in the pharmaceutically acceptable salts include the following: acids including acetic acid, 2,2-dichloroacetic acid, acetamino acid, adipic acid, alginic acid, ascorbic acid, L- Aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamide benzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, citric acid, Acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecanesulfuric acid, ethane-1,2-disulfonic acid, ethanedisulfonic acid, 2-hydroxy-ethanedisulfonic acid, formic acid, fumaric acid , galactosedioic acid, gentisic acid, glucoheptanoic acid, D-gluconic acid, glucuronic acid, L-glutamic acid, α-side oxygen-glutaric acid, glycolic acid, hipuric acid, hydrogen Bromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactulic acid, maleic acid, (-)-L malic acid, malonic acid, (±)-DL-bitter Mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid , palmoic acid, phosphoric acid, L-pyroic acid, Salicylic acid, 4-amino-salicylic acid, sebaic acid, stearic acid, succinic acid, sulfuric acid, citric acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and Undecylenic acid; and bases include ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2 -(diethylamine)-ethanol, ethanolamine, ethylenediamine, N-methyl-reducing glucosamine, hydrabamine, 1H-imidazole, L-isoamine, magnesium hydroxide, 4-(2- Hydroxyethyl)-morpholine, hexahydropyridyl , potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodium hydroxide, triethanolamine, tromethamine, and zinc hydroxide.

Compounds of formula (I) can be prepared according to the procedures outlined in Scheme 1.

Thus, a suitably substituted compound of formula (X) (a known compound or a compound prepared by known methods), preferably wherein the sulfonamide is present in an amount ranging from about 2 to about 5 equivalents Exist in an organic solvent such as THF, two The alkane, and the like, preferably reacts with a sulfonamide (a known compound) at an elevated temperature in the range of from about 50 ° C to about 100 ° C, more preferably at about reflux temperature, to produce A corresponding compound of the formula (Ia).

Alternatively, a suitably substituted compound of formula (X) (a known compound or a compound prepared by a known method), in the presence of a base such as TEA, DIPEA, pyridine, and the like, Reacting with a suitably substituted compound of formula (XI) (a known compound or a compound prepared by a known method) in an organic solvent such as DMF, DMSO, and the like to produce a chemical formula Corresponding compound of (I).

among them for Compounds of formula (X) can be prepared as outlined in Scheme 2.

Thus, a suitably substituted compound of formula (X II) [a known compound or by known methods (as described in Scheme 3 below)] optionally in an organic solvent such as acetonitrile, and the like Reacts with NH ₄ OH (a known compound) to produce the corresponding compound of formula (X III).

The compound of the formula (XIII) is reacted with a suitably selected reducing agent such as LAH, and the like, in an organic solvent such as THF, diethyl ether or the like to give the formula (Xa). Corresponding compound.

among them Selected from The compound of formula (X) can be prepared as outlined in Scheme 3.

Thus, a suitably substituted compound of formula (XIV) (a known compound or a compound prepared by known methods) is optionally present in the presence of a coupling agent such as DCC, and the like, optionally In an organic solvent of acetonitrile, and the like, it is reacted with NH ₄ OH to give a corresponding compound of the formula (XV).

The compound of the formula (XV) is reacted with an appropriately selected reducing agent such as LAH, and the like in an organic solvent such as THF, diethyl ether or the like to give a corresponding formula (Xb). Compound.

among them Selected from And a compound of formula (X) wherein a is 2 can be prepared as outlined in Scheme 4.

Thus, a suitably substituted compound of formula (XVI) wherein J ¹ is a suitable cleavage group such as bromine, chlorine, iodine, toluenesulfonyl, methanesulfonyl, trifluoromethanesulfonyl, and the like [A known compound or a compound prepared by a known method (for example, by activating a corresponding compound in which J ¹ is OH)] in an organic solvent such as DMSO, DMF, THF, or the like, and The reaction of cyanide, such as potassium cyanide, sodium cyanide, and the like, to produce the corresponding compound of formula (XVII).

The compound of formula (XVII) is reduced according to known methods [e.g., by reaction with a suitable reducing agent (e.g., LAH, borane, and the like) to yield the corresponding compound of formula (Xc).

among them Selected from And a compound of formula (X) wherein a is 1 can be prepared as outlined in Scheme 5.

Therefore, a suitably substituted compound of the formula (XVIII) (a known compound or a compound prepared by a known method) is activated according to a known method to produce a corresponding compound of the formula (XIX), wherein J ² is a suitable cleavage group such as toluenesulfonyl, chloro, bromo, iodo, methanesulfonyl, trifluoromethanesulfonyl, and the like.

A compound of the formula (XIX) and a benzodiazepine salt (such as potassium benzodiazepine, sodium benzodiazepine, and the like) are in an organic solvent such as DMF, DMSO, acetonitrile or the like. The reaction, preferably, is an elevated temperature in the range of from 50 to about 200 ° C, more preferably at about reflux temperature, to yield the corresponding compound of formula (XX).

The compound of the formula (XX) is reacted with N ₂ H ₄ (a known compound) in an organic solvent such as ethanol, methanol, and the like, preferably at a temperature ranging from about 50 ° C to about 100 ° C. The elevated temperature within, more preferably, about the reflux temperature, and the like, to produce the corresponding compound of formula (Xd).

Those skilled in the art will recognize that: Selected from

The compound of formula (X) is permeable to the benzo-fused starting material selected and substituted with a corresponding naphtho-fused compound, either according to known methods or, for example, according to the steps outlined in Schemes 2 to 5 above. The ground is prepared.

Those skilled in the art will be more aware of a compound of formula (X) in which a single mirror image isomer (or a mixture of mirror image isomers rich in one of the mirror image isomers) is desired, such as a scheme The above listed steps in 1 to 5 can be applied by substituting a suitable starting material for a single mirror image isomer (or a mixture of mirror image isomers in which a mirror image isomer is enriched).

It will be appreciated by those skilled in the art that one of the reaction steps of the present invention can be carried out in a variety of different solvent or solvent systems, and the reaction step can also be carried out in a mixture of the appropriate solvent or solvent system.

As used in the preparation steps of the compounds according to the invention, mixtures of stereoisomers are produced which can be separated by conventional techniques such as preparative chromatography. The compounds can be prepared in a racemic form, or individual mirror image isomers can be prepared by enantiospecific synthesis or by ionization. Such compounds may, for example, be passed through standard techniques [eg by passage of an optically active acid such as (-)-di-p-tolylmethyl-D-tartaric acid and/or (+)-di-p-toluene. The non-mirrored pair formed by the salt of the methylidene-L-tartaric acid followed by the partial crystallization and the regeneration of the free base] is segregated in their component mirror image isomers. The compounds can also be resolved by the formation of a non-image-isomerized ester or an amine followed by chromatographic separation and removal of a chiral auxiliary. Alternatively, the compounds can be resolved using a chiral HPLC column.

In any preparation step with respect to the compounds of the invention, it is necessary and/or desirable to protect the sensitivities or reactive groups on any of the molecules involved. This can be done by conventional methods of protecting groups (such as those described in Protective Groups in Organic Chemistry , ed. JFW McOmie, Plenum Press, 1973; and TW Greene & PGM Wuts, Protective Groups in Organic Synthesis , John Wiley & Sons, 1991). Achieved. These protecting groups can be removed at a known subsequent stage using methods known in the art.

The invention further comprises a pharmaceutical composition of one or more compounds of formula (I) and a pharmaceutically acceptable carrier. A pharmaceutical composition comprising one or more of the compounds of the present invention as described herein as an active ingredient can be admixed by mixing the compound or the compound with a pharmaceutically acceptable carrier according to conventional pharmaceutical compounding techniques. The carrier can take a variety of different forms depending on the route of administration desired (such as oral, injection). Thus suitable for use in liquid oral preparations (such as suspensions, elixirs and solutions), suitable carriers and additives including water, glycols, oils, alcohols, perfumes, preservatives, stabilizers, colorants and the like; For solid oral preparations (such as powders, sachets, and lozenges), suitable carriers and additives include starch, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like. Solid oral preparations may also be coated with a sugar material or coated with a casing to adjust the primary location of absorption. For administration by injection, the carrier will typically consist of sterile water and other ingredients may be added to provide solubility or preservation. Injectable suspensions or solutions can also be prepared using aqueous carriers and suitable additives.

To prepare the pharmaceutical composition of the present invention, one or more compounds of the present invention as an active ingredient are skillfully mixed with a pharmaceutical uploading agent according to a conventional pharmaceutical compounding technique, and the carrier can be prepared according to the desired preparation form. (such as oral or intramuscular injection)] in a variety of different types. For the preparation of a composition in an oral dosage form, any of the usual pharmaceutical vehicles can be employed. Thus, for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, perfumes, preservatives, colorants and the like; for solid oral administration Preparations such as powders, sachets, caplets, gelcaps, and lozenges, suitable carriers and additives including starch, sugar, diluents, granulating agents, lubricants, binders, disintegration And similar. Tablets and sachets represent the most advantageous oral dosage unit form for their ease of administration, in which case solid pharmaceutical carriers are clearly employed. If desired, the lozenge can be coated with sugar or coated with a casing by standard techniques. For injection, the carrier will typically contain sterile water, which may be included via other ingredients (for example, to enhance solubility or for preservation). Injectable suspensions may also be prepared, in which case suitable liquid carriers, suspensions and the like may be employed. The pharmaceutical composition herein may comprise, per dosage unit (such as a troche, a sachet, a powder, an injection, a teaspoon amount, and the like) required to achieve an effective ingredient amount as one of the above-described effective doses. The pharmaceutical composition herein may comprise from about 0.1 to 1000 mg per dosage unit (such as lozenges, sachets, powders, injections, teaspoon amounts and the like) and may be predetermined to be from about 0.01 to 200.0 mg/kg. The dose of /day is preferably from about 0.1 to 100 mg/kg/day, more preferably from about 0.5 to 50 mg/kg/day, more preferably from about 1.0 to 25.0 mg/kg/day or any of range. However, the dosage can vary depending on the needs of the patient, the severity of the condition being treated, and the compound employed. The use of either daily or post-periodic doses can be employed.

Preferably, the composition is in the form of a tablet, a pill, a sachet, a powder, a capsule, a sterile injectable solution or suspension, a metered dose or a liquid spray, a drop, an injection, an autoinjector device or a suppository. Type; for oral, injection, intranasal, sublingual or rectal administration, or for administration by inhalation or aeration. Optionally, the composition may be presented in a form suitable for administration once a week or once a month; for example, one of the active compounds insoluble salts (such as citrate) may be employed to provide a muscle for use. Preservative preparation for intrainjection. To prepare a solid composition (such as a tablet), the main active ingredient is combined with a pharmaceutical carrier (such as a conventional ingot ingredient such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, phosphoric acid). Calcium or gum), and other pharmaceutically acceptable diluents (such as water) are mixed to form a solid pre-formulation composition comprising a compound of one of the inventions, or a pharmaceutically acceptable salt thereof. Mixture. When referring to the homogenization of these pre-prescription compositions, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition is readily subdivided into equal effective dosage forms (e.g., lozenges, pills or sachets). This solid pre-prescription composition is then subdivided into unit dosage forms of the above type containing from 0.1 to about 1000 mg of the active ingredient of the present invention. The lozenges or pills of the novel compositions can be coated or synthesized to provide a dosage form for the benefit of prolongation. For example, the tablet or pill may contain an inner dosage and an outer dosage component, the latter being a sleeve type that coats the former. The two components can be separated by an enteric layer which acts as an anti-disintegration in the stomach and allows the inner component to pass intact through the duodenum or prolonged release. A variety of different materials can be used for this casing layer or coating, such materials including some polymeric acids such as shellac, cetyl alcohol or cellulose acetate.

The liquid form, wherein the novel composition of the present invention can be incorporated for oral administration or by injection, including aqueous solutions, suitably flavored sugar gums, aqueous or oily suspensions, and seasoned and Emulsifiers for edible oils [such as cottonseed oil, sesame oil, coconut oil or peanut oil], as well as elixirs and similar pharmaceutically acceptable vehicles. Suitable dispersion or suspending agents for aqueous suspensions, including synthetic or natural gums such as gum arabic gum, gum arabic, alginate, polyglucose, sodium carboxymethylcellulose, methylcellulose, polyethylene - Pyrrolidone or gelatin.

The method of treating depression in the present invention can also be practiced using a pharmaceutical composition comprising any of the compounds described herein and a pharmaceutically acceptable carrier. The pharmaceutical composition may contain between about 0.1 mg and 1000 mg, preferably from about 50 to 500 mg, of the compound, and may be formulated in any form suitable for the mode of administration. The carrier includes both necessary and inert pharmaceutical excipients including, but not limited to, binders, suspending agents, lubricants, flavoring agents, sweetening agents, preservatives, dyes, and coatings. Compositions suitable for oral administration include solid forms [eg, pills, troches, capsules, sachets (each including immediate release, time-release or sustained release formulations), granules and powders], liquid types (eg, solutions) , syrups, tinctures, emulsifiers, and suspensions). Formulations for administration by injection include sterile solutions, emulsifiers and suspensions.

Advantageously, the compounds of the invention may be administered in a single daily dose, or the total daily dose may be divided into two, three or four daily doses. Further, the compounds used in the present invention can be administered in an intranasal form via topical use of a suitable intranasal vehicle, or via transdermal skin patches known to those of ordinary skill in the art. As a mode of administration in a transdermal delivery system, the dosing will of course be continuous rather than free of charge throughout the dose regimen.

For example, for oral administration in the form of a lozenge or sachet, the active pharmaceutical ingredient may be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water or the like. Further, suitable binders, lubricants, disintegrants, and color formers can be incorporated into the mixture as desired or desired. Suitable binders include, but are not limited to, starch, gelatin, natural sugars (such as glucose or beta-lactose), corn sweeteners, natural and synthetic gums such as gum arabic, gum arabic gum or sodium oleate, Sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, but are not limited to, starch, methyl cellulose, agar, bentonite, sansin, and the like.

In a suitably flavored suspension or dispersion liquid form such as synthetic or natural gums such as gum tragacanth, gum arabic, methylcellulose and the like. For administration by injection, sterile suspensions and solutions are required. When intravenous injection is desired, an isotonic preparation, usually containing a suitable preservative, is employed.

When depression therapy is desired, the compounds of the invention can be administered in any of the foregoing compositions and in accordance with the dosage regimen established in the art.

The daily dose of such products can vary from 0.01 to 200 mg/kg per adult per day. For oral administration, the composition preferably contains 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250, 500 and 1000 mg of active ingredient. A lozenge pattern is provided for symptom adjustment of the patient being treated. An effective amount of the drug is typically provided at a dose level of from 0.01 mg/kg to about 200 mg/kg per kilogram of body weight per day. Preferably, the range is from about 0.1 to about 100.0 mg/kg per kilogram of body weight per day, more preferably from about 0.5 mg/kg to about 50 mg/kg per kilogram of body weight per day, and more preferably, from about 1.0 to about 25.0 mg/kg per kilogram of body weight per day. The compound can be administered in a regimen of one to four times per day.

The optimal dosage for administration will be readily determined by those skilled in the art and will vary with the particular compound employed, the mode of administration, the strength of the preparation, the mode of administration, and the progression of the condition. In addition, the factors associated with the patient being treated, including the patient's age, weight, diet, and time of administration, will result in the need to adjust the dose.

It is recognized by those skilled in the art that both in vivo or in vitro assays using appropriate, known, and generally accepted cellular and/or animal models are predictive of the ability to treat or prevent test compounds for a predetermined disease. Sex.

It is even more common for those skilled in the art to recognize human clinical tests in healthy patients and/or those suffering from a predetermined disease, including first-in-human, dose range, and efficacy testing. It is done according to methods known in the clinical and medical arts.

The following examples are presented to assist in the understanding of the present invention and are not intended to be,

Example 1

((3,4-Dihydro-2H-benzo[b][1,4]dioxohept-3-yl)methyl)sulfonamide (Compound #3)

Catechol (5.09 g, 46.2 mmol) and potassium carbonate were combined in acetonitrile and heated to reflux for one hour. 2-Chloromethyl-3-chloro-1-propene (5.78 g, 46.2 mmol) was added and the reaction was continued under reflux for 24 hours. The solution was cooled to room temperature and filtered. The filtrate was evaporated and the residue was diluted with water and extracted with diethyl ether (3x). By combination of the organic solution is dried over MgSO _4, and concentrated. Chromatography (2% diethyl ether in hexanes) gave 3-methylene-3,4-dihydro-2H-benzo[b][1,4]dioxane as a colorless oil.

MS (ESI): 163.2 (M + H +) 1 H NMR (300 MHz, CDCl 3), δ: 6.94 (m, 4H), 5.07 (S, 2H), 4.76 (s, 4H).

3-Methylene-3,4-dihydro-2H-benzo[b][1,4]dioxane (5.00 g, 30.8 mmol) was dissolved in dry THF (100 mL). Borane-THF (1.0 M in THF, 10.3 mL) was added at 0 °C. The reaction was stirred at room temperature for 5 hours. Aminesulfonic acid (6.97 g, 61.6 mmol) was added. The reaction was heated to reflux overnight. The reaction was cooled to room temperature and aqueous sodium hydroxide (3.0 M, 100 mL) was added. The solution was extracted with ethyl acetate (3 x 100 mL). The organic solution was compounded was dried over MgSO _4. The solution is concentrated under vacuum and subjected to chromatography (2% to 8% methanol in dichloromethane) to give a colorless oil ((3,4-dihydro-2H-benzo[b]] [1,4]dioxohept-3-yl)methyl)amine.

MS (ESI): 180.1 (M + H +) 1 H NMR (300 MHz, DMSO), δ: 6.92 (m, 4H), 4.21 (m, 2H), 4.07 (m, 2H), 3.33 ( broad, 2H), 3.16 (d, J = 4 Hz, 1H), 2.72 (d, J = 4 Hz, 1H), 2.30 (m, 1H).

((3,4-Dihydro-2H-benzo[b][1,4]dioxohept-3-yl)methyl)amine (2.90 g, 16.2 mmol) and sulfonamide (3.11 g, 32.4) Mm) is compounded in two Acetone (60 ml) was heated to reflux overnight. Chloroform was added and the precipitate was removed by filtration. The filtrate was concentrated under vacuum and purified by chromatography (2% to EtOAc EtOAc)

258.8(M+H ⁺ ) ¹ H NMR (300 MHz, DMSO), δ: 6.92 (m, 4H), 6.71 (W, 1H), 6.59 (W, 2H), 4.19 (m, 2H) 4.04 (m, 2H) , 3.00 (m, 2H), 2.39 (m, 1H).

Example 2

N-(2,3-dihydro-benzo[1,4] Inox-2-ylmethyl)sulfonamide (Compound #1)

Racemic 2,3-dihydro-1,4-benzoic acid Indole-2-ylmethylamine (4.4 g, 26 mmol) and sulfonamide (5.1 g, 53 mmol) were combined in 1,4 In English (100 ml) and refluxed for 2 hours. The reaction was cooled to room temperature and a small amount of solid was filtered and discarded. The filtrate was evaporated in vacuo and the residue was purified using flash column chromatography (DCM:MeOH - 10:1) to give a white solid. The solid was recrystallized from DCM to give the title compound as a white solid.

Mp: 97.5-98.5 ° C Elemental analysis: C, 44.25; H, 4.95; N, 11.47: S, 13.13 Analysis found: C, 44.28; H, 4.66; N, 11.21; S, 13.15 ¹ H NMR (DMSO d6), δ: 6.85 (m, 4H), 6.68 (bd s, 3H, NH), 4.28 (m, 2H), 3.97 (dd, J = 6.9, 11.4 Hz, 1H), 3.20 (m, 1H) ), 3.10 (m, 1H).

Example 3

(Benzo[1,3] II Zin-2-ylmethyl)sulfonamide (Compound #2)

Catechol (10.26 g, 93.2 mmol), sodium methoxide (25% by weight of methanol, 40.3 g, 186 mmol), and methyl dichloroacetic acid (13.3 g, 93.2 mmol) were combined in dry methanol (100 mL) in. The solution was heated to reflux overnight. The reaction was cooled to room temperature, acidified by addition with concentrated hydrochloric acid and then reduced to a volume of ca. 50 mL under vacuum. Water was added and the mixture was extracted with diethyl ether (3 x 100 mL). The compound was in the organic solution is dried over MgSO _4, concentrated to a brown solid, and chromatographed (2% ethyl acetate in hexanes to ligand) to give a colorless oil such as a benzo [1,3] Methyl azole-2-carboxylate.

MS (ESI): 195.10 (M+H ⁺ ) ¹ H NMR (300 MHz, CDCl ₃ ), δ: 6.89 (width, 4H), 6.29 (s, 1H), 4.34 (q, J = 7 Hz, 2H), 1.33 (t, J = 7 Hz, 3H).

Ammonium hydroxide (29% in water, 10 mL) and sufficient acetonitrile were added to benzo[1,3] Methyl azole-2-carboxylate (7.21 g, 40.0 mmol) was made as a homogenized mixture (~5 mL). The solution was stirred at room temperature for 2 hours and then distilled water was added. Benzo[1,3] The guanamine-2-carboxylic acid decylamine precipitates as a white solid and is collected by filtration and used without further purification.

MS (ESI): 160.0 (M+H ⁺ ) ^: NMR (3, MH), δ: 7.79 (s, s, 1H), 7.72 (s, s, 1H), 6.94 (m, 2H), 6.86 (m) , 2H), 6.30 (s, 1H).

Benzo[1,3] The oxazol-2-carboxylic acid decylamine (5.44 g, 32.9 mmol) was dissolved in tetrahydrofuran (THF, 100 mL). Lithium aluminum hydride (LAH, 1 M in THF, 39.5 mL, 39.5 mmol) was slowly added to the solution at room temperature. The reaction was stirred at room temperature for 24 hours. Distilled water was added to destroy excess LAH. Aqueous sodium hydroxide (3.0 M, 100 mL) was added and the solution was extracted with ethyl acetate (3 x 100 mL). This was washed and dried over MgSO ₄ organic solution with water over the compound. The solution is evaporated to give C-benzo[1,3] as a colorless oil. Zin-2-yl-methylamine.

MS (ESI): 152.1 (M+H ⁺ ) ¹ H NMR (300 MHz, CDCl ₃ ), δ: 6.87 (m, 4H), 6.09 (t, J = 4 Hz, 1H), 3.13 (d, J = 4 Hz, 2H ).

C-benzo[1,3] Zin-2-yl-methylamine (2.94 g, 19.4 mmol) and sulfonamide (3.74 g, 38.9 mmol) were combined in dry two The solution was heated to reflux overnight (50 mL). The reaction was concentrated and the residue was purified eluting with EtOAc EtOAc

MS (ESI): 230.0 (M + H +) 1 H NMR (300 MHz, CDCl 3), δ: 6.87 (m, 4H), 6.25 (t, J = 4Hz, 1H), 4.79 ( broad, 1H), 4.62 ( Width, 1H), 3.64 (d, J = 4Hz, 2H).

Example 4

(2S)-(-)-N-(2,3-dihydro-benzo[1,4] Inox-2-ylmethyl)sulfonamide (Compound #4)

Catechol (13.2 g, 0.12 mol) and potassium carbonate (16.6 g, 0.12 mol) were stirred in DMF (250 mL) and (2R)-glycidyl sulfonate (22.8 g, 0.10 mol) was added and reacted. It was stirred at 60 ° C for 24 hours. The reaction was cooled to room temperature and diluted with ice water (1 L) and extracted with diethyl ether (4). The combined organic solution was washed 3 times with 10% potassium carbonate, 1 time with water, 1 time with brine, and evaporated in vacuo to give a white solid which was purified by flash column chromatography (DCM: Methanol-50:1) was purified to give a solid ((2S)-2,3-dihydro-benzo[1,4]) Inox-2-yl)methanol.

The solid (13.3 g, 68 mmol) was dissolved in pyridine (85 mL) cooled to 0 ° C, p-toluenesulfonium chloride (13.0 g, 68 mmol) was added and the reaction mixture was stirred at room temperature for 20 hours. . The reaction was diluted with diethyl ether (1 L) and 1N HCl (1.2 L). The organic layer was separated and 1N HCl (500 mL) and washed twice with water (150 mL) and washed 4 times, brine once, dried (MgS04 ₄₎ and in vacuo was evaporated to yield a white solid, which Purified by flash column chromatography (Hept: EA-2:1) to give toluene-4-sulfonic acid (2S)-2,3-dihydro-benzo[1,4], as a white solid. In-2-methyl methyl ester.

The white solid was combined with potassium benzoate (14.4 g, 78 mmol) in DMF (250 mL) and warmed to reflux for 1 hour, cooled to room temperature and poured into vigorously stirring water (1.5 L) Stir for 30 minutes. The white solid was filtered off and the solid was washed several times with water, 2% NaOH and then washed with water and dried to give (2S)-2-(2,3-dihydro- as a white powdery solid. Benzo[1,4] Inox-2-ylmethyl)-isoindole-1,3-dione.

The pulverulent white solid was combined with EtOAc (EtOAc: EtOAc (EtOAc) (EtOAc) The white solid was filtered off and washed with fresh EtOAc (EtOAc) and evaporated. The diethyl ether solution was dried (Na ₂ SO ₄ ) and evaporated in vacuo to yield a pale yellow oil. The oil was purified by flash column chromatography (DCM; MeOH-10:1) to yield an oil. A portion of this oil (4.82 g, 29 mmol) in 2-propona (250 mL) was treated with 1N HCl (30 mL) and heated in a steam bath until homogenized and then allowed to cool to room temperature. After 3 hours, the mixture was ice-cooled for 2 hours. a white flake solid ((2S)-C-(2,3-dihydro-benzo[1,4]) The corresponding HCl salt of indole-2-yl)-methylamine was filtered off and then recrystallized from 2-proponamide to give a white solid.

[α] _D =-69.6 (c=1.06, EtOH)

The white solid was separated between DCM and dilute NaOH to and the DCM was dried (NaSO ₄₎ and evaporated in vacuo to yield an oil as one of (2S) -C- (2,3- dihydro - benzo [1, 4] two Inox-2-yl)-methylamine.

[α] _D = -57.8 (c = 1.40, CHCl ₃ )

The oil (2.1 g, 12.7 mmol) and sulfonamide (2.44 g, 25.4 mmol) were refluxed in two The residue was purified by flash column chromatography (DCM: MeOH 10:1) to afford a white solid that was recrystallised from DCM to yield a title as a white crystalline solid. Compound.

Mp 102-103 ° C [α] _D = -45.1 (c = 1.05, M) ¹ H NMR (DMSOd6) δ 6.86 (m, 4H), 6.81 (bd s, 3H, NH), 4.3 (m, 2H), 3.97 (dd, J = 6.9, 11.4 Hz, 1H), 3.20 (dd, J = 5.5, 13.7 Hz, 1H), 3.10 (dd, J = 6.9, 13.7 Hz, 1H). Elemental analysis: analytical calculated value: C , 44.25; H, 4.95; N, 11.47: S, 13.13 Analysis found: C, 44.20; H, 4.69; N, 11.40; S, 13.22

Example 5

N-(2,3-dihydro-benzo[1,4] Inox-2-ylmethyl)N',N'dimethylsulfonamide) (Compound #6)

Racemic 2,3-dihydro-1,4-benzoic acid Indole-2-ylmethylamine (8.25 g, 5.0 mmol) and triethylamine (1.52 g, 15 mmol) were combined in DMF (10 mL) and dimethylamine sulfonium chloride (1.44 g, 10 mmol) When added, it is cooled in an ice bath. The reaction mixture was then stirred with continuous cooling for 3 hours. The reaction mixture was interposed between ethyl acetate and water, separated, and the ethyl acetate solution was washed with brine-based, dried (MgSO ₄₎ and evaporated in vacuo to yield an oil. The oil was purified by flash column chromatography (ethyl acetate: hexane - 1:1) to give a white solid which crystallised (ethyl acetate/hexanes) Title compound.

Mp 76-78 ° C. MS 273 (MH ⁺ ) calc.: calc.: C, 48.52; H, 5.92; N, 10.29: S, 11.78 Analysis found: C, 48.63; H, 5.62; N, 10.20; , 11.90 ¹ H NMR (CDCl ₃ ) δ 6.87 (m, 4H), 4.59 (bd m, 1H, NH), 4.35 (m, 1H), 4.27 (dd, J = 2.3, 11.4 Hz, 1H), 4.04 ( Dd, J = 7.0, 11.4 Hz, 1H), 3.36 (m, 2H), 2.82 (s, 6H)

Example 6

N-(2,3-dihydro-benzo[1,4] Inox-2-ylmethyl)-N-methylsulfonamide (Compound #7)

Racemic 2,3-dihydro-1,4-benzene Indole-2-ylmethylamine (825 mg, 5 mmol) was dissolved in ethyl formate (15 mL) and refluxed for 30 min and evaporated in vacuo to yield N- (2, 3- Hydrogen-benzo[1,4] Inox-2-ylmethyl)carhamamine.

The oil was taken up in EtOAc (2 mL) (EtOAc) The reaction was cooled in an ice bath and quenched with water (0.50 mL) then 3N NaOH (0.50 mL) and water (0.50 mL). The mixture was then stirred at room temperature for 1 hour. The solid was filtered off and the filtrate was evaporated in vacuo to give a residue which was partitioned between 1N HCl and diethyl ether. The aqueous phase was salted with 1 N NaOH and extracted with diethyl ether. The organic phase was dried (MgSO ₄₎ and evaporated in vacuo to yield an oil as one of (2,3-dihydro - benzo [1,4] Inox-2-ylmethyl)methyl-amine.

MS 180 (MH ⁺ ) ¹ H NMR (CDCl ₃ ) δ 6.85 (m, 4H), 4.30 (m, 2H), 4.02 (dd, J = 7.9, 11.6 Hz, 1H), 2.85 (m, 2H), 2.50 (s, 3H).

This oil (380 mg, 2.1 mmol) and sulfonamide (820 mg, 8.5 mmol) were combined in two Alkane (15 mL) was refluxed for 1.5 h and evaporated in vacuo to give a crude residue. The residue was purified by column chromatography (EtOAc EtOAc EtOAc)

Mp 97-98 ° C MS 257 (M ^-1 ) calc.: calc.: C, 46.50; H, 5.64; N, 10.85: S, 12.41 Analysis found: C, 46.48; H, 5.65; N, 10.90; S, 12.07 ¹ H NMR (CDCl ₃ ) δ 6.86 (m, 4H), 4.52 (bs, 2H), 4.46 (m, 1H), 4.29 (dd, J = 2.3, 11.5 Hz, 1H), 4.05 (dd, J = 6.5, 11.5 Hz, 1H), 3.51 (dd, J = 6.7, 14.9 Hz, 1H), 3.40 (dd, J = 5.9, 14.9 Hz, 1H), 2.99 (s, 3H).

Example 7

(2S)-(-)-N-(6-chloro-2,3-dihydro-benzo[1,4] Inox-2-ylmethyl)-sulfonamide (Compound #8)

Following the procedure outlined in Example 4 above, 4-chlorocatechol was reacted to yield one (2S)-C-(7-chloro-2,3-dihydro-benzo[1,4] Indole-2-yl)methylamine and (2S)-C-(6-chloro-2,3-dihydro-benzo[1,4] A mixture of indole-2-ylamine (by HPLC, a ratio of 6-chloro:7-chloro isomer of about 3:1).

The mixture was dissolved in 1-propanol (100 mL) and 1N HCl in diethyl ether was added until pH = 1.0. The precipitated hydrochloride was filtered (2.65 g) and re-crystallized from methanol/IPA to yield white crystals. The white crystals were separated between DCM and diluted NaOH. The DCM is dried and evaporated in vacuo to yield purified (2S)-C-(6-chloro-2,3-dihydro-benzo[1,4] Inox-2-yl)methylamine.

[α] _D = -67.8 (c = 1.51, CHCl ₃ ) The oil (7.75 mmol) and sulfonamide (1.50 g, 15.5 mmol) were combined in two Acetone (50 mL) was refluxed for 2 h, cooled to rt and evaporated in vacuo to give a solid. The product was purified via a flash column using DCM /MeOH 20:1 to yield the title compound as a white solid.

MS 277(M ^-1 )[α] _D = -59.9° (c = 1.1) ¹ H NMR (CDCl ₃ ) δ 6.90 (d, J = 2.2 Hz, 1H), 6.81 (m, 2H), 4.76 (m) , 1H), 4.55 (s, 2H), 4.40 (m, 1H), 4.29 (dd, J = 2.4, 11.5 Hz, 1H), 4.05 (dd, J = 7.1, 11.5 Hz, 1H), 3.45 (m, 2H). Elemental analysis: analytical value: C, 38.78; H, 3.98; N, 10.05 Analysis found: C, 38.80; H, 3.67; N, 9.99

The filtrate of the (2S)-C-(6-chloro-2,3-dihydro-benzo[1,4]dic-2-yl)methylamine-formed hydrochloride salt prepared above was recovered ( 6-Chloro: 7-chloro isomer is about 3:1 ratio) and is evaporated in vacuo to give a solid which is separated between DCM (200 mL) and diluted NaOH (0.5 M, 50 mL) . The DCM solution was washed once with brine, dried (Na ₂ SO ₄₎ and evaporated in vacuo to yield an oil, which via a reverse phase HPLC (0.16% TFA having the 10-50% ACN with 0.20% TFA to a ligand of Purified in water to give (2S)-C-(7-chloro-2,3-dihydro-benzo[1,4] two as a residue Inox-2-yl)-methylamine.

The residue was combined with sulfonamide (0.90 g, 9.4 mmol) in two The alkane (25 mL) was refluxed for 2.5 h, cooled to rt and evaporated in vacuo to give an oil. The oil was purified by flash column chromatography using DCM/methanol-10:1 to yield (2S)-(-)-N-(7-chloro-2,3-dihydro-benzene as a white solid. And [1,4] two Inox-2-ylmethyl)sulfonamide.

MS 277(M ^-1 ) ¹ H NMR (CDCl ₃ /CD ₃ OD) δ 6.88 (d, J = 0.7 Hz, 1H), 6.81 (m, 2H), 4.37 (m, 1H), 4.30 (dd, J =2.3, 11.6 Hz, 1H), 4.04 (dd, J=7.0, 11.6 Hz, 1H), 3.38 (m, 2H).

Example 8

-2-ylmethylsulfonamide (compound #10)

2-carboxylic acid (4.5 g, 25 mmol) and HOBT (3.86 g, 25 mmol) were combined in DCM (40 mL) and DMF (10 mL).

Dimethylaminopropylethylcarbodiimide salt (EDC, 4.84 g, 25 mmol) was added at room temperature and the reaction mixture was stirred for 30 min. Ammonium hydroxide (2.26 mL, 33.4 mmol) was added and the reaction mixture was stirred for 16 h. The reaction mixture was diluted with DCM (50 mL) and water (50 mL) and the pH of the mixture was adjusted to about pH = 3.0 with 1 N HCl. The DCM was separated and the aqueous phase was extracted twice with DCM. The compound of DCM phase was dried (Na ₂ SO ₄₎ and evaporated in vacuo to yield an oil which was purified by flash column chromatography (ethyl acetate) to yield an oil.

When 1 M LAH in THF (36 mL, 36 mmol) was added, the oil (5.35 g, 30 mmol) in THF (90 mL) was stirred and the mixture was then stirred at room temperature for 20 hour. The reaction is stopped by water, stirred for 2 hours, the solution was decanted, dried (Na ₂ SO ₄₎ and evaporated in vacuo to yield an oily amine C- -2-yl-methylamine.

The oily amine (1.63 g, 10 mmol) and sulfonamide (1.92 g, 20 mmol) were combined in two The alkane (50 mL) was refluxed for 2 hours. The solution was cooled and evaporated in vacuo to give an oil which was purified by column chromatography (DCM:MeOH 10:1) to yield a white solid. The solid was recrystallized from ethyl acetate/hexane to give a white solid. -2-ylmethylsulfonamide.

MS 241 (M ^-1 ) mp. S, 13.33

Example 9

2-(2,3-dihydro-benzo[1,4]di Inox-2-yl)ethylsulfonamide (Compound #16)

Potassium cyanide (2.05 g, 31.5 mmol) was added to 2-bromomethyl-(2,3 dihydrobenzo[1,4]2 in DMSO (90 mL) English (6.87 g, 30 mmol) and stirred at ambient temperature for 20 hours. The reaction mixture was diluted with water (250 mL) and extracted twice with diethyl ether. The diethyl ether was washed with water, then washed twice with brine, dried (Na ₂ SO ₄₎ and evaporated in vacuo to yield a white solid such as a cyanomethyl-2 - (2,3-dihydrobenzo [ 1,4] two English).

¹ H NMR (CDCl ₃ ) δ 6.89 (m, 4H), 4.50 (m, 1H), 4.31 (dd, J = 2.3, 11.5 Hz, 1H), 4.08 (dd, J = 6.2, 11.6 Hz, 1H), 2.78 (d, J = 6.1 Hz, 2H).

The 2-cyanomethyl-(2,3-dihydrobenzo[1,4]di United Kingdom) was dissolved in THF (50 mL) and the ligand in THF (80 mL, 80 mmol) of 1M BH ₃ is added and the reaction was refluxed for 5 hours period, then stirred at ambient temperature over 16 hours. When cooled in an ice bath, 2N HCl was added until pH = 1.0 was reached. The reaction mixture was then stirred at room temperature for 1 hour and evaporated in vacuo to yield an oil. The separated oil is interposed between 3N NaOH and diethyl ether, and the diethyl ether solution was washed with brine, dried (Na ₂ SO ₄₎ and evaporated in vacuo to give crude 2- (2,3 dihydrobenzo [1,4] two Ethyl-2-yl)ethylamine.

MS(M+H) ⁺ 180

The match Crude 2-(2,3-dihydrobenzo[1,4]di in alkane (100 mL) Ethyl-2-yl)ethylamine was combined with sulfonamide (3.0 g, 31 mmol) and heated to reflux for 2 h. The solution was cooled and evaporated in vacuo to give an orange solid, which was purified by column chromatography (DCM:MeOH-10:1) to give a white solid. The solid was recrystallized from DCM to give the title compound as a solid.

MS (M ^-1 ) 257 mp 101-103 ° C (corr) ¹ H NMR (CDCl ₃ ) δ 6.86 (m, 4H), 4.70 (m, 1H), 4.52 (s, 2H), 4.30 (m, 2H) 3.94 (dd, J = 7.4, 11.3 Hz, 1H), 3.43 (dd, J = 6.4, 12.9 Hz, 2H), 1.94 (dd, J = 6.5, 12.9 Hz, 2H). Elemental analysis: measured: C, 46.48; H, 5.60; N, 10.81: S, 12.41 calculated: C, 46.50; H, 5.46; N, 10.85; S, 12.41

Example 10

(2S)-(-)-N-(6,7-dichloro-2,3-dihydro-benzo[1,4] Inox-2-ylmethyl)-sulfonamide (Compound #29)

4,5-dichloroatechol (8.6 g, 48 mmol) and potassium carbonate (6.64 g, 48 mmol) were stirred in DMF (200 mL). (2R)-epoxypropyltoluenesulfonic acid (9.12 g, 40 mmol) was added and the reaction mixture was stirred at 60 ° C for 24 hours. The reaction mixture was cooled to room temperature and then diluted with ice water (600 mL) and extracted with diethyl ether (4 times). The compound of the organic solution was washed three times with 10% potassium carbonate, washed with brine twice, dried (MgSO ₄₎ and evaporated in vacuo to yield a (2S) -2- (6,7- dichloro-2 ,3-dihydro-benzo[1,4] British) methanolic mucilage oil.

The (2S)-2-(6,7-dichloro-2,3-dihydro-benzo[1,4] Methanol oil (6.4 g, 27 mmol) was dissolved in pyridine (50 mL) cooled to 0. Subsequently, p-toluenesulfonium chloride (5.2 g, 27 mmol) was added and the reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with diethyl ether and 1N EtOAc (EtOAc) (EtOAc) (EtOAc) MgSO ₄ ) and evaporated in vacuo to give a pale-yellow solid of toluene-4-sulfonic acid (2S)-6,7-dichloro-2,3-dihydro-benzo[1,4] In-2-methyl methyl ester.

¹ H NMR (CDCl 3 ) δ 7.79 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 6.94 (s, 1H), 6.83 (s, 1H), 4.37 (m, 1H) ), 4.2 (m, 3H), 4.03 (dd, J = 6.3, 11.7 Hz, 1H), 2.47 (s, 3H).

Toluene-4-sulfonic acid (2S)-6,7-dichloro-2,3-dihydro-benzo[1,4] Indole-2-ylmethyl ester (8.0 g, 20.5 mmol) was combined with potassium benzodiamine (6.1 g, 33 mmol) in DMF (75 mL) and heated to reflux for 1 hour, then cooled. It was poured into vigorously stirred water (0.5 L) at room temperature and then stirred for 30 minutes. The white solid was filtered off and the solid was washed with water, 2% NaOH and once again with water and then allowed to air dried to yield (2S)-2-(6,7-dichloro- as a white powdery solid. 2,3-dihydro-benzo[1,4] Inox-2-ylmethyl)-isoindole-1,3-dione (6.0 g, 80%).

The white powdery solid was combined with hydrazine (1.06 g, <RTI ID=0.0>> 1 N HCl was added to adjust the pH of the reaction mixture to pH 1.0 and the reaction mixture was then stirred for 15 minutes. The white solid was filtered off and washed with fresh EtOH (solids were discarded) and the filtrate was evaporated in vacuo to a solid which was partitioned between diethyl ether and diluted aqueous NaOH. The diethyl ether solution was dried (Na ₂ SO ₄ ) and evaporated in vacuo to yield (2S)-2-aminemethyl-(6,7-dichloro-2,3-dihydro-benzo[1] , 4] two British) viscous oil.

¹ H NMR (CDCl 3 ) δ 6.98 (s, 1H), 6.96 (s, 1H), 4.25 (dd, J = 2.0, 11.2 Hz, 1H), 4.15 (m, 1H), 4.0 (m, 1H), 2.97 (d, J = 5.5, 2H).

A portion of this oil (3.8 g, 16 mmol) and sulfonamide (3.1 g, 32.4 mmol) in two The alkane (100 mL) was taken from EtOAc (EtOAc) elute Crystallization to give the title compound as a white crystalline solid.

MS[M-H] ^- 311.0 mp 119-121 ° C [α] _D = -53.4 (c = 1.17, M) ¹ H NMR (DMSOd6) δ 7.22 (s, 4H), 7.20 (s, 1H), 6.91 (bd s, 1H), 6.68 (bd s, 2H), 4.35 (m, 2H), 4.05 (dd, J = 6.5, 11.5 Hz, 1H), 3.15 (m, 2H). Elemental analysis: measured: C,34.52;H,3.22;N,8.95:Cl,22.64;S,10.24 calculated: C,34.64;H,2.68;N,8.87;Cl,22.94;S,10.35

Example 11

(2S)-(-)-N-(7-Amino-2,3-dihydro-benzo[1,4] Inox-2-ylmethyl)sulfonamide (Compound #36)

(2S)-(-)-N-(2,3-dihydro-7-nitro-benzo[1,4] Intra-2-ylmethyl)-sulfonamide (1.2 g, 4.15 mmol) was prepared from 4-nitrocatechol according to the procedure outlined in Example 4. The (2S)-(-)-N-(2,3-dihydro-7-nitro-benzo[1,4] Inox-2-ylmethylsulfonamide was subsequently combined to equip 10% Pd/C in methanol (120 mL) and shaken in a hydrogen atmosphere (39 psi) for 3 hours at room temperature. The solid was filtered off and washed with 10% MeOH in DCM and the filtrate evaporated in vacuo to yield crude. The crude product was dissolved in EtOAc (25 mL).

MS[M+H] ⁺ 260 ¹ H NMR (DMSO d6): δ 10.2 (bd s, 3H), 6.86 (m, 1 s), 6.85 (s, 1H), 6.74 (dd, J = 2.5, 8.4 Hz, 1H ), 4.22 (m, 2H), 3.88 (dd, J = 6.7, 11.4 Hz, 1H), 3.04 (m, 2H).

Example 12

(2S)-(-)-N-(7-methyl-2,3-dihydro-benzo[1,4] Inox-2-ylmethyl)-sulfonamide (Compound #19)

The title compound was prepared according to the procedure described in Example 4 above, starting from 4-methyl catechol to give a white solid which was recrystallised from ethyl acetate/hexane to yield as white solid. The title compound.

MS[M-H] ^- 257 ¹ H NMR (CDCl3): δ 6.76 (m, 1H), 6.66 (m, 2H), 4.80 (m, 1H), 4.57 (bd s, 1H), 4.40 (m, 1H) ), 4.28 (m, 1H), 4.03 (dd, J = 6.9, 11.4 Hz, 1H), 3.45 (m, 2H), 2.25 (s, 3H). Elemental analysis; calculated: C, 46.50; H, 5.46 ; N, 10.85; S, 12.41 found: C, 46.65; H, 5.60; N, 10.84; S, 12.61

Example 13

Cell titer glow/in vitro analysis of cell viability This analysis was performed according to the procedure outlined in the inserts from the Promega kit (see attachment at the end of the text of this application).

Cell culture was prepared as follows. The dissociated hippocampus and cortical cells were established from the 18th day of the embryonic rat fetus. The fetuses were removed via Caesarean section from a female dam (Harlan Sprague-Dawley) anesthetized according to the Halothane of the American Veterinary Association's Euthanasia Committee. The small animals were decapitated and the brain was removed and placed in Hank's Balanced Salt solution (1x HBSS; Gibco, Rockville, MD). The hippocampus and cortex are broken down and concentrated according to the tissue-type. Tissues were trypsinized for 15 minutes (1 mg/ml trypsin-HBSS; Worthington, Lakewood, NJ), washed with fresh HBSS, and cultured in trypsin inhibitor (1 mg/ml; Sigma, St. Louis, MO) After 5 minutes in the medium, it was again washed with fresh HBSS and then ground in 1 ml of fresh HBSS with a fire-polished glass dropper. Dissociated cells were seeded at 10,000 cells/well to a poly-D-lysine coating and supplemented with 26 mM NaHCO ₃ (Sigma), 40 mM glucose (Sigma), 20 mM KCl (Sigma), 1 mM acetone Sodium (Sigma), 10% (v/v) heated non-activated fetal bovine serum (Hyclone, Logan, UT), and 0.001% statin sulfate (Sigma) (pH 7.4) 100 μl / well eagle 96-well plate (BD BioScience, Bedford, MA) with minimal nutrient medium (Eagle's Minimal Essential Media, MEM; Gibco). Serum-free cultures were plated and maintained in neurobasal medium + B27 supplement (Gibco). Prior to the experimental treatment, cells were allowed to attach for 24 hours in an incubator humidified at 37 ° C 5% CO ₂ .

Test compounds were prepared as follows: Each compound was diluted in DPBS at 1:50 with a 10 mM stock in DMSO to yield a final stock of 200 μM. The stock solution was further diluted in DPBS to obtain a final concentration of 0.1, 1, and 120 μM of compound in each well of 100 μL. An equal amount of vehicle or diluted compound is added to each well.

A 30% hydrogen peroxide (H ₂ O ₂ ; Sigma) stock solution was diluted 1:100 in DPBS to produce a 3 mM stock solution. 5 microliters carrier or H ₂ O ₂ stock solution was added per 100 μl culture well to produce a final concentration of 150 μM.

Compound #8 was tested according to the procedure described herein and the results are listed in Tables 4 and 5 below. Note that in the data shown below, each flat disk is executed in three iterations to obtain a total of n=9.

Thus, the data shows that Compound #8 protects neurons from death and/or damage caused by oxidative stress or oxidative damage (eg, the result of mono/peroxide radicals).

Example 14

As a specific example of an oral composition, 100 mg of Compound #8 prepared as in Example 7 is formulated with a sufficient amount of finely divided lactose to provide a total amount of 580 to 590 mg 俾 to meet an O size. capsule.

While the foregoing specification has been described with respect to the exemplary embodiments of the present invention, it is understood that the embodiments of the present invention are intended to include all such modifications as fall within the scope of the Adapt to changes and/or modifications.

Claims (18)

Use of a compound of the following formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for neuroprotection against oxidative stress: Wherein R ¹ and R ² are each independently selected from the group consisting of hydrogen and C _1-4 alkyl; R ⁴ is selected from the group consisting of hydrogen and C _1-4 alkyl; An integer from 1 to 2; Is Wherein b is an integer from 0 to 4; each R ⁵ is independently selected from the group consisting of halogen and C _1-4 alkyl. The use of claim 1, wherein R ¹ and R ² are each independently selected from the group consisting of hydrogen and C _1-4 alkyl; R ⁴ is selected from hydrogen and C _{1- a} group consisting of ₄ alkyl groups; a is an integer from 1 to 2; Is Wherein b is an integer from 0 to 2; each R ⁵ is independently selected from the group consisting of halogen and C _1-4 alkyl; or a pharmaceutically acceptable salt thereof. The use of claim 2, wherein R ¹ and R ² are each independently selected from the group consisting of hydrogen and C _1-4 alkyl; and R ⁴ is selected from hydrogen and methyl. a group consisting of; a is an integer from 1 to 2; Is selected from the group consisting of 2-(2,3-dihydro-benzo[1,4] English), 2-(6-chloro-2,3-dihydro-benzo[1,4] English), 2-(6-fluoro-2,3-dihydro-benzo[1,4] English), 2-(5-fluoro-2,3-dihydro-benzo[1,4] English), 2-(7-chloro-2,3-dihydro-benzo[1,4] English), 2-(7-methyl-2,3-dihydro-benzo[1,4] English), 2-(5-chloro-2,3-dihydro-benzo[1,4] English), 2-(6-bromo-2,3-dihydro-benzo[1,4] English), 2-(6,7-dichloro-2,3-dihydro-benzo[1,4] English) and 2-(8-chloro-2,3-dihydro-benzo[1,4] English) or a pharmaceutically acceptable salt thereof. The use of claim 3, wherein R ¹ and R ² are each independently selected from the group consisting of hydrogen and methyl; a is an integer from 1 to 2; Is selected from the group consisting of 2-(2,3-dihydro-benzo[1,4] English), 2-(6-chloro-2,3-dihydro-benzo[1,4] English), 2-(7-chloro-2,3-dihydro-benzo[1,4] English), 2-(7-methyl-2,3-dihydro-benzo[1,4] English), 2-(6-bromo-2,3-dihydro-benzo[1,4] English) and 2-(6,7-dichloro-2,3-dihydro-benzo[1,4] English) or a pharmaceutically acceptable salt thereof. The use of the compound of formula (I) is selected from the group consisting of (2S)-(-)-N-(6-chloro-2,3-dihydrogen, as claimed in claim 1 of the scope of the patent application. -Benzo[1,4] Indol-2-ylmethyl)-sulfonamide and pharmaceutically acceptable salts thereof. Use of a compound for the manufacture of a medicament for neuroprotection selected from (2S)-(-)-N-(6-chloro-2,3-dihydro-benzo[1,4] two Group consisting of en-2-methylmethyl)-sulfonamide and its pharmaceutically acceptable salts. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of oxidative stress caused by an acute neurodegenerative disease, Wherein R ¹ and R ² are each independently selected from the group consisting of hydrogen and C _1-4 alkyl; R ⁴ is selected from the group consisting of hydrogen and C _1-4 alkyl; An integer from 1 to 2; system Wherein b is an integer from 0 to 4; each R ⁵ is independently selected from the group consisting of halogen and C _1-4 alkyl. The use of claim 7, wherein R ¹ and R ² are each independently selected from the group consisting of hydrogen and C _1-4 alkyl; and R ⁴ is selected from hydrogen and methyl. a group consisting of; a is an integer from 1 to 2; Is selected from the group consisting of 2-(2,3-dihydro-benzo[1,4] English), 2-(6-chloro-2,3-dihydro-benzo[1,4] English), 2-(6-fluoro-2,3-dihydro-benzo[1,4] English), 2-(5-fluoro-2,3-dihydro-benzo[1,4] English), 2-(7-chloro-2,3-dihydro-benzo[1,4] English), 2-(7-methyl-2,3-dihydro-benzo[1,4] English), 2-(5-chloro-2,3-dihydro-benzo[1,4] English), 2-(6-bromo-2,3-dihydro-benzo[1,4] English), 2-(6,7-dichloro-2,3-dihydro-benzo[1,4] English) and 2-(8-chloro-2,3-dihydro-benzo[1,4] English) or a pharmaceutically acceptable salt thereof. The use of the compound of formula (I) is selected from the group consisting of (2S)-(-)-N-(6-chloro-2,3-dihydro-benzo[1,4], as claimed in claim 7. two Inox-2-ylmethyl)-sulfonamide. Use of a compound for the manufacture of a medicament for the treatment of an acute neurodegenerative disease selected from the group consisting of (2S)-(-)-N-(6-chloro-2,3-dihydro-benzo[1] , 4] two Group consisting of en-2-methylmethyl)-sulfonamide and its pharmaceutically acceptable salts. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of oxidative stress caused by chronic neurodegenerative diseases: Wherein R ¹ and R ² are each independently selected from the group consisting of hydrogen and C _1-4 alkyl; R ⁴ is selected from the group consisting of hydrogen and C _1-4 alkyl; An integer from 1 to 2; system Wherein b is an integer from 0 to 4; and wherein c is an integer from 0 to 2; each R ⁵ is independently selected from the group consisting of halogen and C _1-4 alkyl. The use of claim 11, wherein R ¹ and R ² are each independently selected from the group consisting of hydrogen and C _1-4 alkyl; and R ⁴ is selected from hydrogen and methyl. a group consisting of; a is an integer from 1 to 2; Is selected from the group consisting of 2-(2,3-dihydro-benzo[1,4] English), 2-(6-chloro-2,3-dihydro-benzo[1,4] English), 2-(6-fluoro-2,3-dihydro-benzo[1,4] English), 2-(5-fluoro-2,3-dihydro-benzo[1,4] English), 2-(7-chloro-2,3-dihydro-benzo[1,4] English), 2-(7-methyl-2,3-dihydro-benzo[1,4] English), 2-(5-chloro-2,3-dihydro-benzo[1,4] English), 2-(6-bromo-2,3-dihydro-benzo[1,4] English), 2-(6,7-dichloro-2,3-dihydro-benzo[1,4] English) and 2-(8-chloro-2,3-dihydro-benzo[1,4] English) or a pharmaceutically acceptable salt thereof. The use of the compound of formula (I) is selected from the group consisting of (2S)-(-)-N-(6-chloro-2,3-dihydro-benzo[1, 4] two Group consisting of en-2-methylmethyl)-sulfonamide and its pharmaceutically acceptable salts. Use of a compound for the manufacture of a medicament for the treatment of chronic neurodegenerative diseases selected from the group consisting of (2S)-(-)-N-(6-chloro-2,3-dihydro-benzo[1] , 4] two Group consisting of en-2-methylmethyl)-sulfonamide and its pharmaceutically acceptable salts. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing neuronal death or injury caused by oxidative stress in the brain, head or spinal cord after trauma or injury, wherein R ¹ and R ² are each independently selected from the group consisting of hydrogen and C _1-4 alkyl; R ⁴ is selected from the group consisting of hydrogen and C _1-4 alkyl; An integer from 1 to 2; system Wherein b is an integer from 0 to 4; and wherein c is an integer from 0 to 2; each R ⁵ is independently selected from the group consisting of halogen and C _1-4 alkyl. The use of claim 15 wherein R ¹ and R ² are each independently selected from the group consisting of hydrogen and C _1-4 alkyl; and R ⁴ is selected from hydrogen and methyl. a group consisting of; a is an integer from 1 to 2; Is selected from the group consisting of 2-(2,3-dihydro-benzo[1,4] English), 2-(6-chloro-2,3-dihydro-benzo[1,4] English), 2-(6-fluoro-2,3-dihydro-benzo[1,4] English), 2-(5-fluoro-2,3-dihydro-benzo[1,4] English), 2-(7-chloro-2,3-dihydro-benzo[1,4] English), 2-(7-methyl-2,3-dihydro-benzo[1,4] English), 2-(5-chloro-2,3-dihydro-benzo[1,4] English), 2-(6-bromo-2,3-dihydro-benzo[1,4] English), 2-(6,7-dichloro-2,3-dihydro-benzo[1,4] English) and 2-(8-chloro-2,3-dihydro-benzo[1,4] English) or a pharmaceutically acceptable salt thereof. The use of the compound of formula (I) is selected from the group consisting of (2S)-(-)-N-(6-chloro-2,3-dihydro-benzo[1,4], as claimed in claim 15. two Inox-2-ylmethyl)-sulfonamide. A compound for the manufacture of a medicament for preventing neuronal death or injury after trauma or injury to the brain, head or spinal cord, the compound being selected from the group consisting of (2S)-(-)-N-(6-chloro -2,3-dihydro-benzo[1,4] Group consisting of en-2-methylmethyl)-sulfonamide and its pharmaceutically acceptable salts.