WO2004033418A2 - Sulfonylamino-acetic derivatives and their use as orexin receptor antagonists - Google Patents

Sulfonylamino-acetic derivatives and their use as orexin receptor antagonists Download PDF

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Publication number
WO2004033418A2
WO2004033418A2 PCT/EP2003/011021 EP0311021W WO2004033418A2 WO 2004033418 A2 WO2004033418 A2 WO 2004033418A2 EP 0311021 W EP0311021 W EP 0311021W WO 2004033418 A2 WO2004033418 A2 WO 2004033418A2
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WIPO (PCT)
Prior art keywords
amino
acetamide
ethyl
tert
pyridin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/EP2003/011021
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French (fr)
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WO2004033418A3 (en
Inventor
Hamed Aissaoui
Martine Clozel
Thomas Weller
Ralf Koberstein
Thierry Sifferlen
Walter Fischli
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Actelion Pharmaceuticals Ltd
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Actelion Pharmaceuticals Ltd
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Publication date
Priority to NZ538749A priority Critical patent/NZ538749A/en
Priority to JP2004542433A priority patent/JP4528125B2/en
Priority to DE60335891T priority patent/DE60335891D1/en
Priority to CA2498091A priority patent/CA2498091C/en
Priority to EP03785607A priority patent/EP1554239B1/en
Priority to BR0315115-8A priority patent/BR0315115A/en
Priority to AT03785607T priority patent/ATE496884T1/en
Priority to US10/529,637 priority patent/US7279578B2/en
Priority to MXPA05003295A priority patent/MXPA05003295A/en
Priority to AU2003294671A priority patent/AU2003294671A1/en
Application filed by Actelion Pharmaceuticals Ltd filed Critical Actelion Pharmaceuticals Ltd
Publication of WO2004033418A2 publication Critical patent/WO2004033418A2/en
Publication of WO2004033418A3 publication Critical patent/WO2004033418A3/en
Priority to NO20051102A priority patent/NO20051102L/en
Anticipated expiration legal-status Critical
Priority to US11/756,008 priority patent/US7435815B2/en
Ceased legal-status Critical Current

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    • C07D277/28—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to novel sulfonylamino-acetic acid derivatives of the general formula (I) and their use as pharmaceuticals.
  • the invention also concerns related aspects including pharmaceutical compositions containing one or more compounds of formula I, and especially their use as orexin receptor antagonists.
  • the orexins (hypocretins) comprise two neuropeptides produced in the hypothalamus: the orexin A (OX-A) (a 33 aminoacid peptide) and the orexin B (OX-B) (a 28 aminoacid peptide) (Sakurai T. et al., Cell, 1998, 92, 573-585).
  • Orexins are found to stimulate food consumption in rats suggesting a physiological role for these peptides as mediators in the central feedback mechanism that regulates feeding behavior (Sakurai T. et al, Cell, 1998, 92, 573-585). On the other hand, it was also proposed that orexins regulate states of sleep and wakefulness opening potentially novel therapeutic approaches for narcoleptic patients (Chemelli R.M. et al, Cell, 1999, 98, 437-451). Two orexin receptors have been cloned and characterized in mammals which belong to the G-protein coupled receptor superfamily (Sakurai T.
  • Orexin receptors are found in the mammalian host and may be responsible for many pathologies including, but not limited to, depression; anxiety; addictions; obsessive compulsive disorder; affective neurosis; depressive neurosis; anxiety neurosis; dysthymic disorder; behaviour disorder; mood disorder; sexual dysfunction; psychosexual dysfunction; schizophrenia; manic depression; delerium; dementia; severe mental retardation and dyskinesias such as Huntington's disease and Tourette syndrome; feeding disorders such as anorexia, bulimia, cachexia and obesity; diabetes; appetite/taste disorders; vomiting/nausea; asthma; cancer; Parkinson's disease; Cushing's syndrome/disease; basophil adenoma; prolactinoma; hyperprolactinemia; hypopituitarism; hypophysis tumor/adenoma; hypothalamic diseases; inflammatory bowel disease; gastric diskinesia; gastric ulcus; Froehlich's syndrome; adrenohypo
  • HIN post-chemotherapy pain
  • post-stroke pain post-operative pain
  • neuralgia conditions associated with visceral pain such as irritable bowel syndrome, migraine and angina
  • urinary bladder incontinence e.g. urge incontinence
  • tolerance to narcotics or withdrawal from narcotics sleep disorders; sleep apnea; narcolepsy; insomnia; parasomnia; jet-lag syndrome; delayed or advanced sleep phase syndrome; sleep related dystonias
  • neurodegerative disorders including nosological entities such as disinhibition-dementia-parkinsonism-amyotrophy complex; pallido-ponto-nigral degeneration epilepsy; seizure disorders including febrile seizures and other hyperthermia disorders; and other diseases related to orexin.
  • the present invention comprises sulfonylamino-acetic acid derivatives which are non-peptide antagonists of the human orexin receptors, in particular the human orexin-2 receptor.
  • These compounds are of potential use in the treatment of disturbed homeostasis and eating disorders (e.g. bulimia, obesity, food abuse, compulsive eating or irritable bowel syndrome), as well as disturbed sleep/wake schedule, sleep disorders (e.g. insomnias, apneas, dystonias) or stress-related diseases (e.g. anxiety, mood and blood pressure disorders) or any other disease related to orexin dysfunction.
  • disturbed homeostasis and eating disorders e.g. bulimia, obesity, food abuse, compulsive eating or irritable bowel syndrome
  • sleep disorders e.g. insomnias, apneas, dystonias
  • stress-related diseases e.g. anxiety, mood and blood pressure disorders
  • WO 00/50391 discloses certain sulfonamide derivatives as modulators of the production of amyloid ⁇ -protein.
  • WO 02/32864 discloses certain sulfanilide derivatives useful in the treatment of diseases mediated by oxytocin and/or vasopressin.
  • the present invention relates to novel sulfonylamino-acetic acid derivatives of the general formula (I).
  • A represents 4-ethylphenyl-, 4-isopropylphenyl, 4-tert.-butyl ⁇ henyl-, 2-methylphenyl-, 3 -methylphenyl-, 4-cyclopropylphenyl, 3-fluorophenyl-, 2-chlorophenyl-, 3-chlorophenyl-, 4-bromophenyl-, 2-trifluoromethylphenyl-, 3-trifluoromethyl ⁇ henyl-, 4-( 1 -hydroxy- 1- methyl-ethyl)-phenyl-, 3-chloro-4-methylphenyl-, 2-methoxy-4-methylphenyl-, 3,4- difluorophenyl-, l,2,3,4-tetrahydroisoquinolin-7-yl, 2-methyl-l,2,3,4-tetrahydroisoquinolin- 7-yl, 2-formyl-l,2,3,4-tetrahydroisoquinolin-7-yl, phen
  • B represents a phenyl, a 6-membered heteroaryl or a nine- or ten-membered bicyclic heteroaryl group, which groups are unsubstituted or independently mono- or di- substituted with cyano, halogen, hydroxy, lower alkyl, hydroxy lower alkyl, amino lower alkyl, aminocarbonyl lower alkyl, sulfonylamino lower alkyl, lower alkenyl, lower alkoxy, trifluoromethyl, trifluoromethoxy, cycloalkyloxy, aryloxy, aralkyloxy, heterocyclyloxy, heterocyclyl lower alkyloxy, amino, aminocarbonyl or sulfonylamino; or a cyclohexyl, 3- piperidinyl or 4-piperidinyl group, which groups are unsubstituted or mono-substituted with hydroxy, lower alkyl, hydroxy lower alkyl, aminocarbonyl lower alkyl,
  • R 1 represents lower alkyl, cycloalkyl, hydroxy lower alkyl or cyano lower alkyl
  • R 2 represents lower alkyl, lower alkenyl, hydroxy lower alkyl, amino lower alkyl, sulfonylamino lower alkyl, cycloalkyl; an unsubstituted or mono- or disubstituted phenyl group substituted independently with cyano, halogen, hydroxy, lower alkyl, lower alkoxy, cycloalkyloxy, amino, amino lower alkyl, aminocarbonyl or sulfonylamino; an unsubstituted or mono- or di-substituted five- or six-membered heteroaryl group substituted independently with cyano, halogen, hydroxy, lower alkyl, lower alkoxy, cycloalkyloxy, amino, amino lower alkyl, aminocarbonyl or sulfonylamino; an unsubstituted or mono- or di-substituted nine- or ten-membered bicyclic heteroaryl group substituted independently with cyano,
  • lower alkyl means a straight-chain or branched-chain alkyl group with 1-5 carbon atoms as for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert.-butyl, isobutyl and the isomeric pentyls.
  • lower alkenyl means a straight-chain or branched-chain alkenyl group with 2 to 5 carbon atoms, preferably allyl and vinyl.
  • lower alkoxy alone or in combination, means a group of the formula lower alkyl-O- in which the term “lower alkyl” has the previously given significance, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert- butoxy, preferably methoxy and ethoxy.
  • cycloalkyl alone or in combination, means a cycloalkyl ring with 3 to
  • C 3 -C 6 cycloalkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, preferably cyclopropyl, cyclohexyl and particularly cyclohexyl or lower alkyl substituted cycloalkyl which may preferably be substituted with lower alkyl such as methyl-cyclopropyl, dimethyl-cyclopropyl, methyl-cyclobutyl, methyl-cyclopentyl, methyl-cyclohexyl or dimethyl-cyclohexyl.
  • aryl means a phenyl or naphthyl group which optionally carries one or more substituents, preferably one or two substituents, each independently selected from cyano, halogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, trifluoromethyl, trifluoromethoxy, amino, or carboxy.
  • substituents preferably one or two substituents, each independently selected from cyano, halogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, trifluoromethyl, trifluoromethoxy, amino, or carboxy.
  • aralkyl means a lower alkyl group as previously defined in which one hydrogen atom has been replaced by an aryl group as previously defined.
  • heterocyclyl means a 5- to 10-membered monocyclic or bicyclic ring, which may be saturated, partially unsaturated or aromatic containing for example 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulphur which may be the same or different.
  • heterocyclyl groups are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, thienyl, thiazolyl, isothiazolyl, furyl, imidazolyl, pyrazolyl, pyrrolyl, indazolyl, indolyl, isoindolyl, isoxazolyl, oxazolyl, quinoxalinyl, phthalazinyl, cinnolinyl, dihydropyrrolyl, pyrrolidinyl, isobenzofuranyl, tetrahydrofuranyl, dihydropyranyl.
  • the heterocyclyl group may have up to 5, preferably 1, 2 or 3 optional substituents.
  • suitable substituents include halogen, lower alkyl, amino, nitro, cyano, hydroxy, lower alkoxy, carboxy and lower alkyloxy-carbonyls .
  • the term "6-membered heteroaryl group” means e.g. a pyridyl, pyrimidinyl, pyrazinyl or a pyridazinyl group.
  • node- or ten-membered bicyclic heteroaryl group means e.g. an indazolyl, indolyl, isoindolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, cinnolinyl, quinazolinyl or a naphthyridinyl group.
  • 5-membered heteroaryl group means e.g. a pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl or thiadiazolyl group.
  • amino in terms like “amino”, “amino lower alkyl”, “aminocarbonyl” or “aminocarbonyl lower alkyl” represents a NH 2 -, NHR 3 - or a NR 3 R 4 -group.
  • R 3 and R 4 are lower alkyl groups, which might be equal or different.
  • _r c represents a R S(O) NR -group.
  • R represents a lower alkyl group, a phenyl group, a 6- membered heteroaryl group or a 5-membered heteroaryl group.
  • halogen means fluorine, chlorine, bromine or iodine and preferably chlorine and bromine and particularly chlorine.
  • a preferred group of compounds of formula (I) are those in which B, R 1 and R 2 have the meaning given in formula (I) above and A represents a 4-ethylphenyl group; and pure enantiomers, mixtures of enantiomers, pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates and the meso-form and pharmaceutically acceptable salts, solvent complexes, and morphological forms, thereof.
  • Another preferred group of compounds of formula (I) are those in which B, R 1 and R 2 have the meaning given in formula (I) above and A represents a 4-isopropylphenyl group; and pure enantiomers, mixtures of enantiomers, pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates and the meso-form and pharmaceutically acceptable salts, solvent complexes, and morphological forms, thereof.
  • Another preferred group of compounds of formula (I) are those in which B, R 1 and R 2 have the meaning given in formula (I) above and A represents a 4-tert.-butylphenyl group; and pure enantiomers, mixtures of enantiomers, pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates and the meso-form and pharmaceutically acceptable salts, solvent complexes, and morphological forms, thereof.
  • Another preferred group of compounds of formula (I) are those in which B, R 1 and R 2 have the meaning given in formula (I) above and A represents a 2-methylphenyl group; and pure enantiomers, mixtures of enantiomers, pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates and the meso-form and pharmaceutically acceptable salts, solvent complexes, and morphological forms, thereof.
  • Another preferred group of compounds of formula (I) are those in which B, R and R have the meaning given in formula (I) above and A represents a 3 -methylphenyl group; and pure enantiomers, mixtures of enantiomers, pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates and the meso-form and pharmaceutically acceptable salts, solvent complexes, and morphological forms, thereof.
  • Another preferred group of compounds of formula (I) are those in which B, R and R have the meaning given in formula (I) above and A represents a 4-(l -hydroxy- 1-methyl-ethyl)- phenyl group; and pure enantiomers, mixtures of enantiomers, pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates and the meso-form and pharmaceutically acceptable salts, solvent complexes, and morphological forms, thereof.
  • Another preferred group of compounds of formula (I) are those in which B, R and R have the meaning given in formula (I) above and A represents a 3-chloro-4-methylphenyl group; and pure enantiomers, mixtures of enantiomers, pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates and the meso-form and pharmaceutically acceptable salts, solvent complexes, and morphological forms, thereof.
  • Another preferred group of compounds of formula (I) are those in which B, R 1 and R 2 have the meaning given in formula (I) above and A represents a 2-formyl-l,2,3,4- tetrahydroisoquinolin-7-yl group; and pure enantiomers, mixtures of enantiomers, pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates and the meso-form and pharmaceutically acceptable salts, solvent complexes, and morphological forms, thereof.
  • Another preferred group of compounds of formula (I) are those in which B, R and R have the meaning given in formula (I) above and A represents a 2-naphthyl group; and pure enantiomers, mixtures of enantiomers, pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates and the meso-form and pharmaceutically acceptable salts, solvent complexes, and morphological forms, thereof.
  • Another preferred group of compounds of formula (I) are those in which B, R and R have the meaning given in formula (I) above and A represents a 3-methyl-pyridin-2-yl group; and pure enantiomers, mixtures of enantiomers, pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates and the meso-form and pharmaceutically acceptable salts, solvent complexes, and morphological forms, thereof.
  • Another preferred group of compounds of formula (I) are those in which B, R and R have the meaning given in formula (I) above and A represents a 5-isopropyl-pyridm-2-yl group; and pure enantiomers, mixtures of enantiomers, pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates and the meso-form and pharmaceutically acceptable salts, solvent complexes, and morphological forms, thereof.
  • Another preferred group of compounds of formula (I) are those in which B, R and R have the meaning given in formula (I) above and A represents a 6-dimethylamino-pyridin-3-yl group; and pure enantiomers, mixtures of enantiomers, pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates and the meso-form and pharmaceutically acceptable salts, solvent complexes, and morphological forms, thereof.
  • Examples of particularly preferred compounds of formula (I) are: 2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N,N-diethyl-acetamide;
  • the present invention encompasses physiologically usable or pharmaceutically acceptable salts of compounds of formula (I).
  • This encompasses salts with physiologically compatible mineral acids such as hydrochloric acid, sulphuric or phosphoric acid; or with organic acids such as formic acid, methanesulphonic acid, acetic acid, trifluoroacetic acid, citric acid, furnaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid and the like.
  • physiologically compatible mineral acids such as hydrochloric acid, sulphuric or phosphoric acid
  • organic acids such as formic acid, methanesulphonic acid, acetic acid, trifluoroacetic acid, citric acid, furnaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid and the like.
  • the compounds of formula (I) which are acidic can also form salts with physiologically compatible bases.
  • salts are alkali metal, alkali earth metal, ammonium and alkylammoniumsalts such as ⁇ a, K, Ca or tefraaU- lammonium salt.
  • the compounds of formula (I) can also be present in the form of a zwifterion.
  • the present invention encompasses also solvation complexes of compounds of general formula (I). The solvation can be effected in the course of the manufacturing process or can take place separately, e.g. as a consequence of hygroscopic properties of an initially anhydrous compound of general formula (I).
  • the present invention further encompasses different morphological forms, e.g. crystalline forms, of compounds of general formula (I) and their salts and solvation complexes. Particular heteromorphs may exhibit different dissolution properties, stability profiles, and the like, and are all included in the scope of the present invention.
  • the compounds of formula (I) might have one or several asymmetric centres and
  • optically pure enantiomers can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates and the meso- forms.
  • Preferred compounds as described above have IC 50 values below 100 nM, particularly preferred compounds have IC 50 values below 20 nM which have been determined with the FLIPR (Fluorometric Imaging Plates Reader) method described in the beginning of the experimental section.
  • FLIPR Fluorometric Imaging Plates Reader
  • the compounds of formula (I) and their pharmaceutically usable salts can be used for the treatment of diseases or disorders where an antagonist of a human orexin receptor is required such as obesity, diabetes, prolactinoma, narcolepsy, insomnia, sleep apnea, parasomnia, depression, anxiety, addictions, schizophrenia and dementia or any other disease related to orexin dysfunction.
  • an antagonist of a human orexin receptor such as obesity, diabetes, prolactinoma, narcolepsy, insomnia, sleep apnea, parasomnia, depression, anxiety, addictions, schizophrenia and dementia or any other disease related to orexin dysfunction.
  • the compounds of formula (I) and their pharmaceutically usable salts are particularly useful for the treatment of disturbed homeostasis and eating disorders (e.g. bulimia, obesity, food abuse, compulsive eating or irritable bowel syndrome), as well as disturbed sleep/wake schedule, sleep disorders (e.g. insomnias, apneas, dystonias), stress- related diseases (e.g. anxiety, mood and blood pressure disorders), or any other disease related to orexin dysfunction.
  • the compounds of formula (I) and their pharmaceutically usable salts can be used as medicament (e.g. in the form of pharmaceutical preparations).
  • the pharmaceutical preparations can be administered enterally, such as orally (e.g.
  • the administration can also be effected parenterally, such as intramuscularly or intravenously (e.g. in the form of injection solutions), or topically, e.g. in the form of ointments, creams or oils.
  • the compounds of formula (I) and their pharmaceutically usable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, dragees, and hard gelatine capsules.
  • Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. can be used, for example, as such adjuvants for tablets, dragees, and hard gelatine capsules.
  • Suitable adjuvants for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols, etc.
  • Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc.
  • Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.
  • Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols, etc.
  • the pharmaceutical preparations can contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants.
  • the compounds of formula (I) may also be used in combination with one or more other therapeutically useful substances. Examples are anorectic drugs like fenfluramine and related substances; lipase inhibitors like orlistat and related substances; antidepressants like fluoxetine and related substances; anxiolytics like alprazolam and related substances; sleep-inducers like zopiclone and related substances; or any other therapeutically useful substance.
  • the dosage of compounds of formula (I) can vary within wide limits depending on the disease to be controlled, the age and the individual condition of the patient and the mode of administration, and will, of course, be fitted to the individual requirements in each particular case. For adult patients a daily dosage of about 1 mg to 1000 mg, especially about 50 mg to about 500 mg, comes into consideration.
  • the pharmaceutical preparations conveniently contain about 1 - 500 mg, preferably 5 - 200 mg of a compound of formula (I).
  • the compounds of general formula (I) of the present invention are prepared according to the general sequence of reactions outlined in the schemes below, wherein A, B, R 1 , R 2 are as defined in formula (I) above.
  • A, B, R 1 , R 2 are as defined in formula (I) above.
  • any compound obtained with one or more optically active carbon atom may be resolved into pure enantiomers or diastereomers, mixtures of enantiomers or diastereomers, diastereomeric racemates and the meso-forms in a manner known per se.
  • the compounds obtained may also be converted into a pharmaceutically acceptable salt thereof in a manner known per se.
  • the compounds of formula (I) may be prepared as single compounds or as libraries of compounds comprising at least 2, typically 5 to 200 compounds of formula (I).
  • Compound libraries are prepared by multiple parallel synthesis using solution phase chemistry.
  • the compounds of formula (I) have been prepared by following one out of three possible synthetic pathways.
  • the first pathway starts with the reaction of an amine B-NH 2 with an ⁇ -bromoacetamide, which might be synthesised starting from bromoacetyl bromide and an amine NHR ⁇ C ⁇ R 2 ) either in situ or separately.
  • the respective aminoacetamide was reacted with a sulfonyl chloride A-SO Cl (Scheme 1).
  • the second synthetic route starts with the reaction of an amine B-NH with a sulfonyl chloride A-SO Cl. From the intermediate sulfonamides the target molecules can be obtained by reaction with the respective ⁇ -bromoacetamide (Scheme 2).
  • a sulfonamide is synthesized starting from an amine B-NH and a sulfonyl chloride A-SO 2 Cl.
  • the obtained sulfonamide is transformed to a t-butyl- or methyl acetate derivative by reaction with either tert-butyl bromoacetate or methyl bromoacetate.
  • the ester is hydrolyzed and the obtained acid is coupled with an amine -STHR ⁇ C ⁇ R 2 ) to give the desired amide (Scheme 3).
  • Orexin receptor antagonistic activity was determined in accordance with the following experimental method.
  • culture medium Ham F-12 with L- Glutamine
  • FCS foetal calf serum
  • the cells were seeded at 80O00 cells / well into 96-well black clear bottom sterile plates (Costar) which had been precoated with 1% gelatine in Hanks' Balanced Salt Solution (HBSS). All reagents were from Gibco BRL. The seeded plates were incubated overnight at 37°C in 5% CO 2 .
  • Human orexin-A as an agonist was prepared as 1 mM stock solution in methano water (1:1), diluted in HBSS containing 0.1 % bovine serum albumin (BSA) and 2 mM HEPES for use in the assay at a final concentration of 10 nM.
  • Antagonists were prepared as 10 mM stock solution in DMSO, then diluted in 96-well plates, first in DMSO, then in HBSS containing 0.1 % bovine serum albumin (BSA) and 2 mM HEPES.
  • BSA bovine serum albumin
  • TBTU (6.5 mmol) was added to a solution of 6-bromo-pyridine-2-carboxylic acid (5.0 mmol) in DMF (30 mL).
  • Water (100 mL) and ethyl acetate (100 mL) were added, the layers were separated, and the aqueous layer was extracted with ethyl acetate (2 x 100 mL).
  • N-Bromosuccinimide (190 mmol) was added portionwise to a solution of 2-(dimethylamino)- ⁇ yridine (200 mmol) in DCM (1.0 L). After 10 min a HPLC- MS indicated complete conversion. The solvent was removed in vacuo and the residue was purified by flash-chromatography (ethyl acetate/heptane 1:19) to give 25.7 g (128 mmol, 64%) of the desired arylbromide as a white solid.
  • 6-Dimethylamino-pyridine-3-sulfonyl chloride Hydrochloric acid (25%, 1.13 mL) was added to a solution of 6-dimethylamino- pyridine-3 -thiol (0.50 mmol) in DCM (10 mL) at -78°C. A solution of sodium hypochlorite in water (6-14%, 5.2 mL) was added at -78°C and the reaction mixture was stirred for additional 2 min. The layers were separated and the aqueous layer was extracted with DCM (3 x 20 mL). The solvents were removed in vacuo and the obtained 6-dimethylamino-pyridine-3-sulfonyl chloride was used immediately in the next synthetic step.
  • p-Tolylamino-acetic acid A solution of crude p-tolylamino-acetic acid tert-butyl ester (200 mmol) in DCM
  • Example 72 2-[(4-tert-ButyI-benzenesuIfonyl)-p-tolyl-amino]-iV-ethyl-iV-(3H-imidazol-4- ylmethyl)-acetamide:
  • Example 80 iV-Benzyl-2-[(4-tert-butyl-benzenesulfonyl)-quinolin-6-yl-amino]-iV-ethyl- acet amide:
  • Example 105 2-[(4-tert-Butyl-benzenesulfonyl)-(lH-indazol-6-yl)-amino]-N-ethyl-N- py ridin-2-ylmethyl-acetamide :
  • Example 110 2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N-ethyl-iV-quinolin-2- ylmethyl-acetamide:
  • Example 120 2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N-(6-dimethylamino-pyridin-
  • Example 125 2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N-cyclopropyl-N-(3,4- dimethoxy ⁇ benzyl)-acetamide:
  • Example 128 2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N-methyl-N-pyridin-3- ylmethyl-acetamide:
  • Example 136 2-[(4-tert-Butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-7Y- cyclopropyl-N ⁇ (3,4-dimethoxy-benzyl)-acetamide:
  • Example 139 2-[(4-tert-Butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-iV- methyl-N-pyridin-3-ylmethyl-acetamide:
  • Example 144 N-Ethyl-2-[(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-iV-thiazol-2- ylmethyl-acetamide:
  • Example 154 N-Ethyl-N-(4-hydroxy-benzyl)-2-[(2-methoxy-phenyI)-(toluene-2-sulfonyl)- amino]-acetamide:
  • Example 159 iV-EthyI-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-iV-thiazol-2- ylmethyl-acetamide:
  • Example 160 iV-Ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-N-(6-methyl- pyridin-2-ylmethyl)-acetamide:
  • Example 162 iV-Ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-iV-pyridin-3- ylmethyl-acetamide:
  • Example 165 N-(4-Cyano-benzyl)-N-ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)- amino]-acetamide:
  • Example 173 2-[(6-Amino-pyridin-3-yl)-(4-tert-butyl-benzenesulfonyl)-amino]-N-ethyl-N- pyridin-2-ylmethyl-acetamide:

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Abstract

The invention relates to novel sulfonylamino-acetic acid derivatives and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including processes for the preparation of such compounds, pharmaceutical compositions containing one or more of those compounds and especially their use as orexin receptor antagonists.

Description

ACTELION 26A/OR4
Sulfonylamino-acetic acid Derivatives
The present invention relates to novel sulfonylamino-acetic acid derivatives of the general formula (I) and their use as pharmaceuticals. The invention also concerns related aspects including pharmaceutical compositions containing one or more compounds of formula I, and especially their use as orexin receptor antagonists. The orexins (hypocretins) comprise two neuropeptides produced in the hypothalamus: the orexin A (OX-A) (a 33 aminoacid peptide) and the orexin B (OX-B) (a 28 aminoacid peptide) (Sakurai T. et al., Cell, 1998, 92, 573-585). Orexins are found to stimulate food consumption in rats suggesting a physiological role for these peptides as mediators in the central feedback mechanism that regulates feeding behavior (Sakurai T. et al, Cell, 1998, 92, 573-585). On the other hand, it was also proposed that orexins regulate states of sleep and wakefulness opening potentially novel therapeutic approaches for narcoleptic patients (Chemelli R.M. et al, Cell, 1999, 98, 437-451). Two orexin receptors have been cloned and characterized in mammals which belong to the G-protein coupled receptor superfamily (Sakurai T. et al, Cell, 1998, 92, 573-585), the orexin-1 receptor (OXO which is selective for OX-A and the orexin-2 receptor (OX2) which is capable to bind OX- A as well as OX-B.
Orexin receptors are found in the mammalian host and may be responsible for many pathologies including, but not limited to, depression; anxiety; addictions; obsessive compulsive disorder; affective neurosis; depressive neurosis; anxiety neurosis; dysthymic disorder; behaviour disorder; mood disorder; sexual dysfunction; psychosexual dysfunction; schizophrenia; manic depression; delerium; dementia; severe mental retardation and dyskinesias such as Huntington's disease and Tourette syndrome; feeding disorders such as anorexia, bulimia, cachexia and obesity; diabetes; appetite/taste disorders; vomiting/nausea; asthma; cancer; Parkinson's disease; Cushing's syndrome/disease; basophil adenoma; prolactinoma; hyperprolactinemia; hypopituitarism; hypophysis tumor/adenoma; hypothalamic diseases; inflammatory bowel disease; gastric diskinesia; gastric ulcus; Froehlich's syndrome; adrenohypophysis disease; hypophysis disease; pituitary growth hormone; adrenohypophysis hypofunction; adrenohypophysis hyperfunction; hypothalamic hypogonadism; Kallman's syndrome (anosmia, hyposmia); functional or psychogenic amenorrhea; hypopituitarism; hypothalamic hypothyroidism; hypothalamic-adrenal dysfunction; idiopathic hyperprolactinemia; hypothalamic disorders of growth hormone deficiency; idiopathic growth deficiency; dwarflsm; gigantism; acromegaly; disturbed biological and circadian rhythms; sleep disturbances associated with deseases such as neurological disorders, neuropathic pain and restless leg syndrome; heart and lung diseases, acute and congestive heart failure; hypotension; hypertension; urinary retention; osteoporosis; angina pectoris; myocardinal infarction; ischaemic or haemorrhagic stroke; subarachnoid haemorrhage; ulcers; allergies; benign prostatic hypertrophy; chronic renal failure; renal disease; impaired glucose tolerance; migraine; hyperalgesia; pain; enhanced or exaggerated sensitivity to pain such as hyperalgesia, causalgia, and allodynia; acute pain; burn pain; atypical facial pain; neuropathic pain; back pain; complex regional pain syndrome I and II; arthritic pain; sports injury pain; pain related to infection e.g. by HIN; post-chemotherapy pain; post-stroke pain; post-operative pain; neuralgia; conditions associated with visceral pain such as irritable bowel syndrome, migraine and angina; urinary bladder incontinence e.g. urge incontinence; tolerance to narcotics or withdrawal from narcotics; sleep disorders; sleep apnea; narcolepsy; insomnia; parasomnia; jet-lag syndrome; delayed or advanced sleep phase syndrome; sleep related dystonias; and neurodegerative disorders including nosological entities such as disinhibition-dementia-parkinsonism-amyotrophy complex; pallido-ponto-nigral degeneration epilepsy; seizure disorders including febrile seizures and other hyperthermia disorders; and other diseases related to orexin.
Up to now some low molecular weight compounds are known which have a potential to antagonise either specifically OX1 or OX2, or both receptors at the same time. In WO 99/09024, WO 99/58533, WO 00/47576, WO 00/47577 and WO 00/47580 formerly SmithKline Beecham reported phenylurea, phenylthiourea and cinnamide derivatives as OXi selective antagonists. More recently WO 01/85693 from Banyu Pharmaceuticals has been published wherein Ν-acyltetrahydroisoquinoline derivatives are disclosed. 2-Amino-methylpiperidine derivatives (WO 01/96302), 3-aminomethyl- morpholine derivatives (WO 02/44172) and Ν-aroyl cyclic amines (WO 02/89800, WO 02/90355, WO 03/51368 and WO 03/51871) have been suggested by formerly SmithKline Beecham as orexin receptor antagonists. Related compounds are disclosed in WO 03/02559, WO 03/02561, WO 03/32991, WO 03/41711, WO 03/51872 and WO 03/51873. In WO 03/37847 formerly SmithKline Beecham reported benzamide derivatives as orexin receptor antagonists. International patent applications WO 01/68609 and WO 02/51838 disclose 1,2,3,4-tetrahydroisoquinoline and novel benzazepine derivatives as orexin receptor antagonists. The novel compounds of the present invention belong to an entirely different class of low molecular weight compounds as compared to all prior art orexin receptor antagonists so far published.
The present invention comprises sulfonylamino-acetic acid derivatives which are non-peptide antagonists of the human orexin receptors, in particular the human orexin-2 receptor. These compounds, therefore, are of potential use in the treatment of disturbed homeostasis and eating disorders (e.g. bulimia, obesity, food abuse, compulsive eating or irritable bowel syndrome), as well as disturbed sleep/wake schedule, sleep disorders (e.g. insomnias, apneas, dystonias) or stress-related diseases (e.g. anxiety, mood and blood pressure disorders) or any other disease related to orexin dysfunction.
WO 00/50391 discloses certain sulfonamide derivatives as modulators of the production of amyloid β-protein. WO 02/32864 discloses certain sulfanilide derivatives useful in the treatment of diseases mediated by oxytocin and/or vasopressin.
The present invention relates to novel sulfonylamino-acetic acid derivatives of the general formula (I).
Figure imgf000004_0001
Formula (I)
wherein:
A represents 4-ethylphenyl-, 4-isopropylphenyl, 4-tert.-butylρhenyl-, 2-methylphenyl-, 3 -methylphenyl-, 4-cyclopropylphenyl, 3-fluorophenyl-, 2-chlorophenyl-, 3-chlorophenyl-, 4-bromophenyl-, 2-trifluoromethylphenyl-, 3-trifluoromethylρhenyl-, 4-( 1 -hydroxy- 1- methyl-ethyl)-phenyl-, 3-chloro-4-methylphenyl-, 2-methoxy-4-methylphenyl-, 3,4- difluorophenyl-, l,2,3,4-tetrahydroisoquinolin-7-yl, 2-methyl-l,2,3,4-tetrahydroisoquinolin- 7-yl, 2-formyl-l,2,3,4-tetrahydroisoquinolin-7-yl, phenylethenyl-, 1 -naphthyl-, 2-naphthyl-, 3-methyl-pyridin-2-yl, 5-methyl-pyridin-2-yl, 5-isopropyl-pyridin-2-yl, 6-dimethylamino- pyridin-3-yl, 6-bromo-5-chloro-pyridin-3-yl or 8-quinolinyl-;
B represents a phenyl, a 6-membered heteroaryl or a nine- or ten-membered bicyclic heteroaryl group, which groups are unsubstituted or independently mono- or di- substituted with cyano, halogen, hydroxy, lower alkyl, hydroxy lower alkyl, amino lower alkyl, aminocarbonyl lower alkyl, sulfonylamino lower alkyl, lower alkenyl, lower alkoxy, trifluoromethyl, trifluoromethoxy, cycloalkyloxy, aryloxy, aralkyloxy, heterocyclyloxy, heterocyclyl lower alkyloxy, amino, aminocarbonyl or sulfonylamino; or a cyclohexyl, 3- piperidinyl or 4-piperidinyl group, which groups are unsubstituted or mono-substituted with hydroxy, lower alkyl, hydroxy lower alkyl, aminocarbonyl lower alkyl, sulfonylamino lower alkyl, amino, aminocarbonyl or sulfonylamino; with the proviso that in case A represents 2-methylphenyl- or 4-bromophenyl the phenyl ring as represented by B is substituted;
R1 represents lower alkyl, cycloalkyl, hydroxy lower alkyl or cyano lower alkyl;
R2 represents lower alkyl, lower alkenyl, hydroxy lower alkyl, amino lower alkyl, sulfonylamino lower alkyl, cycloalkyl; an unsubstituted or mono- or disubstituted phenyl group substituted independently with cyano, halogen, hydroxy, lower alkyl, lower alkoxy, cycloalkyloxy, amino, amino lower alkyl, aminocarbonyl or sulfonylamino; an unsubstituted or mono- or di-substituted five- or six-membered heteroaryl group substituted independently with cyano, halogen, hydroxy, lower alkyl, lower alkoxy, cycloalkyloxy, amino, amino lower alkyl, aminocarbonyl or sulfonylamino; an unsubstituted or mono- or di-substituted nine- or ten-membered bicyclic heteroaryl group substituted independently with cyano, halogen, hydroxy, lower alkyl, lower alkoxy, cycloalkyloxy, amino, amino lower alkyl, aminocarbonyl or sulfonylamino;
and pure enantiomers, mixtures of enantiomers, pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates and the meso-form and pharmaceutically acceptable salts, solvent complexes, and morphological forms, thereof. In the present description the term "lower alkyl", alone or in combination, means a straight-chain or branched-chain alkyl group with 1-5 carbon atoms as for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert.-butyl, isobutyl and the isomeric pentyls.
The term "lower alkenyl" means a straight-chain or branched-chain alkenyl group with 2 to 5 carbon atoms, preferably allyl and vinyl.
The term "lower alkoxy", alone or in combination, means a group of the formula lower alkyl-O- in which the term "lower alkyl" has the previously given significance, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert- butoxy, preferably methoxy and ethoxy. The term "cycloalkyl", alone or in combination, means a cycloalkyl ring with 3 to
6 carbon atoms. Examples of C3-C6 cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, preferably cyclopropyl, cyclohexyl and particularly cyclohexyl or lower alkyl substituted cycloalkyl which may preferably be substituted with lower alkyl such as methyl-cyclopropyl, dimethyl-cyclopropyl, methyl-cyclobutyl, methyl-cyclopentyl, methyl-cyclohexyl or dimethyl-cyclohexyl.
The term "aryl" means a phenyl or naphthyl group which optionally carries one or more substituents, preferably one or two substituents, each independently selected from cyano, halogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, trifluoromethyl, trifluoromethoxy, amino, or carboxy. The term "aralkyl" means a lower alkyl group as previously defined in which one hydrogen atom has been replaced by an aryl group as previously defined.
The term "heterocyclyl" means a 5- to 10-membered monocyclic or bicyclic ring, which may be saturated, partially unsaturated or aromatic containing for example 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulphur which may be the same or different. Examples of such heterocyclyl groups are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, thienyl, thiazolyl, isothiazolyl, furyl, imidazolyl, pyrazolyl, pyrrolyl, indazolyl, indolyl, isoindolyl, isoxazolyl, oxazolyl, quinoxalinyl, phthalazinyl, cinnolinyl, dihydropyrrolyl, pyrrolidinyl, isobenzofuranyl, tetrahydrofuranyl, dihydropyranyl. The heterocyclyl group may have up to 5, preferably 1, 2 or 3 optional substituents. Examples of suitable substituents include halogen, lower alkyl, amino, nitro, cyano, hydroxy, lower alkoxy, carboxy and lower alkyloxy-carbonyls . The term "6-membered heteroaryl group" means e.g. a pyridyl, pyrimidinyl, pyrazinyl or a pyridazinyl group.
The term "nine- or ten-membered bicyclic heteroaryl group" means e.g. an indazolyl, indolyl, isoindolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, cinnolinyl, quinazolinyl or a naphthyridinyl group.
The term "5-membered heteroaryl group" means e.g. a pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl or thiadiazolyl group.
The term "amino" in terms like "amino", "amino lower alkyl", "aminocarbonyl" or "aminocarbonyl lower alkyl" represents a NH2-, NHR3- or a NR3R4-group. R3 and R4 are lower alkyl groups, which might be equal or different.
The term "sulfonylamino" in terms like "sulfonylamino" or "sulfonylaminoalkyl"
_r c represents a R S(O) NR -group. R represents a lower alkyl group, a phenyl group, a 6- membered heteroaryl group or a 5-membered heteroaryl group. The term "halogen" means fluorine, chlorine, bromine or iodine and preferably chlorine and bromine and particularly chlorine.
A preferred group of compounds of formula (I) are those in which B, R1 and R2 have the meaning given in formula (I) above and A represents a 4-ethylphenyl group; and pure enantiomers, mixtures of enantiomers, pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates and the meso-form and pharmaceutically acceptable salts, solvent complexes, and morphological forms, thereof.
Another preferred group of compounds of formula (I) are those in which B, R1 and R2 have the meaning given in formula (I) above and A represents a 4-isopropylphenyl group; and pure enantiomers, mixtures of enantiomers, pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates and the meso-form and pharmaceutically acceptable salts, solvent complexes, and morphological forms, thereof.
Another preferred group of compounds of formula (I) are those in which B, R1 and R2 have the meaning given in formula (I) above and A represents a 4-tert.-butylphenyl group; and pure enantiomers, mixtures of enantiomers, pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates and the meso-form and pharmaceutically acceptable salts, solvent complexes, and morphological forms, thereof.
Another preferred group of compounds of formula (I) are those in which B, R1 and R2 have the meaning given in formula (I) above and A represents a 2-methylphenyl group; and pure enantiomers, mixtures of enantiomers, pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates and the meso-form and pharmaceutically acceptable salts, solvent complexes, and morphological forms, thereof.
Another preferred group of compounds of formula (I) are those in which B, R and R have the meaning given in formula (I) above and A represents a 3 -methylphenyl group; and pure enantiomers, mixtures of enantiomers, pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates and the meso-form and pharmaceutically acceptable salts, solvent complexes, and morphological forms, thereof.
Another preferred group of compounds of formula (I) are those in which B, R and R have the meaning given in formula (I) above and A represents a 4-(l -hydroxy- 1-methyl-ethyl)- phenyl group; and pure enantiomers, mixtures of enantiomers, pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates and the meso-form and pharmaceutically acceptable salts, solvent complexes, and morphological forms, thereof.
Another preferred group of compounds of formula (I) are those in which B, R and R have the meaning given in formula (I) above and A represents a 3-chloro-4-methylphenyl group; and pure enantiomers, mixtures of enantiomers, pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates and the meso-form and pharmaceutically acceptable salts, solvent complexes, and morphological forms, thereof. Another preferred group of compounds of formula (I) are those in which B, R1 and R2 have the meaning given in formula (I) above and A represents a 2-formyl-l,2,3,4- tetrahydroisoquinolin-7-yl group; and pure enantiomers, mixtures of enantiomers, pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates and the meso-form and pharmaceutically acceptable salts, solvent complexes, and morphological forms, thereof.
Another preferred group of compounds of formula (I) are those in which B, R and R have the meaning given in formula (I) above and A represents a 2-naphthyl group; and pure enantiomers, mixtures of enantiomers, pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates and the meso-form and pharmaceutically acceptable salts, solvent complexes, and morphological forms, thereof.
1 9
Another preferred group of compounds of formula (I) are those in which B, R and R have the meaning given in formula (I) above and A represents a 3-methyl-pyridin-2-yl group; and pure enantiomers, mixtures of enantiomers, pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates and the meso-form and pharmaceutically acceptable salts, solvent complexes, and morphological forms, thereof.
1 9
Another preferred group of compounds of formula (I) are those in which B, R and R have the meaning given in formula (I) above and A represents a 5-isopropyl-pyridm-2-yl group; and pure enantiomers, mixtures of enantiomers, pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates and the meso-form and pharmaceutically acceptable salts, solvent complexes, and morphological forms, thereof.
1
Another preferred group of compounds of formula (I) are those in which B, R and R have the meaning given in formula (I) above and A represents a 6-dimethylamino-pyridin-3-yl group; and pure enantiomers, mixtures of enantiomers, pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates and the meso-form and pharmaceutically acceptable salts, solvent complexes, and morphological forms, thereof.
Examples of preferred compounds of formula (I) are:
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N,N-diethyl-acetamide;
N,N-Diethyl-2-[(naphthalene-2-sulfonyl)-p-tolyl-amino]-acetamide;
N,N-Diethyl-2-[(toluene-3-sulfonyl)-p-tolyl-amino]-acetamide; N,N-Diethyl-2-[(4-ethyl-benzenesulfonyl)-p-tolyl-amino]-acetamide;
N,N-Diethyl-2-[(toluene-2-sulfonyl)-p-tolyl-amino]-acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-phenyl-amino]-N,N-diethyl-acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-(4-methoxy-phenyl)-amino]-N,N-diethyl-acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-cyclohexyl-amino]-N,N-diethyl-acetamide; 2-[(4-tert-Butyl-benzenesulfonyl)-(4-methyl-cyclohexyl)-amino]-N,N-diethyl-acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-(6-chloro-pyridin-3-yl)-amino]-N,N-diethyl-acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-(3-methoxy-phenyl)-amino]-N,N-diethyl-acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-m-tolyl-amino]-NN-diethyl-acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-o-tolyl-amino]-N,N-diethyl-acetamide; 2-[(4-tert-Butyl-benzenesulfonyl)-(2-methoxy-phenyl)-amino]-N-cyclopropyl-methyl-N- n-propyl-acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-(6-chloro-pyridin-3-yl)-amino]-N-cyclo-propylmethyl-
N-n-propyl-acetamide;
2-[(4-tert-Butyl-berιzenesulfonyl)-m-tolyl-amino]-N-cyclopropylmethyl-N-n-propyl- acetamide;
2-[(6-Dimethylammo-pyridine-3-sulfonyl)-p-tolyl-amino]-N-ethyl-N-pyridin-2-ylmethyl- acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N,N-di-n-propyl-acetamide;
N-Benzyl-2-[(4-tert-butyl-benzenesulfonyl)-p-tolyl-ammo]-N-ethyl-acetamide; 2-[(4-tert-Butyl-benzenesulfonyl)-p olyl-amino]-N-eώyl-N-pyridin-4-ylmethyl- acetamide;
N-Benzyl-N-ethyl-2-[(toluene-2-sulfonyl)-p-tolyl-ammo]-acetamide;
NN-Diethyl-2-[(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-acetamide; 2-[(4-tert-Butyl-benzenesulfonyl)-(6-methoxy-pyridin-3-yl)-amino]-N,N-diethyl- acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-(2-methoxy-phenyl)-amino]-N,N-diethyl-acetamide;
N-Benzyl-N-ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-acetamide; N-Benzyl-N-ethyl-2-[(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-acetamide;
N-Benzyl-2-[(4-tert-butyl-benzenesulfonyl)-(2-methoxy-phenyl)-amino]-N-ethyl- acetamide;
N-Benzyl-N-emyl-2-[(6-methoxy-pyridin-3-yl)-(naphthalene-2-sulfonyl)-amino]- acetamide; N-Benzyl-N-ethyl-2-[(2-methoxy-phenyl)-(naphthalene-2-sulfonyl)-amino]-acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N-ethyl-N-(2-hydroxy-ethyl)-acetamide;
N,N-Diethyl-2-[(4-isopropyl-benzenesulfonyl)-p-tolyl-amino]-acetamide;
2-[(3-Chloro-4-methyl-benzenesulfonyl)-p-tolyl-amino]-N,N-diethyl-acetamide;
N,N-Diethyl-2-[(5-isopropyl-pyri<hne-2-sulfonyl)-p-tolyl-amino]-acetamide; N-BerLzyl-2-[(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-N-(2-hydroxy-ethyl)- acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N,N-bis-(2-hydroxy-ethyl)-acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N-(2-cyano-ethyl)-N-ethyl-acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N-ethyl-N-pyridin-2-ylmethyl- acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N-ethyl-N-ρyridin-3-ylmethyl- acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N-ethyl-N-(6-methyl-pyridin-2- ylmethyl)-acetamide; 2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-ammo]-N-ethyl-N-thiazol-2-yhnethyl- acetamide;
N-Benzyl-2-[(4-tert-butyl-benzenesulfonyl)-quinolin-6-yl-amino]-N-(2-hydroxy-ethyl)- acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-quinolin-6-yl-amino]-N-ethyl-N-thiazol-2-ylmethyl- acetamide;
N-Benzyl-2-[(4-tert-butyl-benzenesulfonyl)-quinolin-6-yl-amino]-N-ethyl-acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-quinolin-6-yl-amino]-N-ethyl-N-(6-methyl-pyridin-2- ylmethyl)-acetamide; 2-[(4-tert-Butyl-benzenesulfonyl)-(3-dimemylamino-phenyl)-amino]-N,N-diethyl- acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-N-ethyl-N-pyridin-2- ylmethyl-acetamide; 2-[(4-tert-Butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-N-ethyl-N-pyridin-3- ylmethyl-acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-N-ethyl-N-thiazol-2- ylmethyl-acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-N-ethyl-N-(6- methyl-pyridin-2-ylmethyl)-acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N-(4-dimethylamino-benzyl)-N-ethyl- acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N-ethyl-N-(3-hydroxy-benzyl)- acetamide; 2- {(4-tert-Butyl-benzenesulfonyl)-[(ethyl-thiazol-2-ylmethyl-carbamoyl)-methyl]- amino } -benzamide;
2-((4-tert-Butyl-benzenesulfonyl)-{[ethyl-(6-methyl-pyridin-2-ylmethyl)-carbamoyl]- methyl} -amino)-benzamide;
2-[[(Benzyl-ethyl-carbamoyl)-memyl]-(4-tert-butyl-benzenesulfonyl)-amino]-benzamide; 2-[(4-tert-Butyl-benzenesulfonyl)-(lH-indazol-6-yl)-amino]-N,N-diethyl-acetamide;
N-Beιιzyl-2-[(4-tert-butyl-benzenesulfonyl)-(lH-indazol-6-yl)-amino]-N-(2-hydroxy- ethyl)-acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-(lH-indazol-6-yl)-amino]-N-ethyl-N-thiazol-2- ylmethyl-acetamide; 2-[(4-tert-Butyl-benzenesulfonyl)-(lH-indazol-6-yl)-amino]-N-ethyl-N-(6-methyl-pyridin-
2-ylmethyl)-acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-(lH-indazol-6-yl)-amino]-N-ethyl-N-(2-hydroxy-ethyl)- acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-(lH-indazol-6-yl)-amino]-N-ethyl-N-pyridin-2- ylmethyl-acetamide;
2-[(4-tert-Butyl-berιz;enesulfonyl)-(lH-indazol-6-yl)-amino]-N-ethyl-N-pyridin-3- ylmethyl-acetamide; 2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N-(2-hy(iroxy-ethyl)-N-pyridin-2- ylmethyl-acetamide;
2-[(4-tert-Butyl-benz;enesulfonyl)-p-tolyl-amino]-N-(3-hydroxy-propyl)-N-pyridin-2- ylmethyl-acetamide; 2-[(4-tert-Butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-N-(2-hydroxy- ethyl)-N-pyridin-2-ylmethyl-acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-N-(3-hydroxy- propyl)-N-pyridin-2-ylmethyl-acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N-(6-dimethylamino-pyridin-2- ylmethyl)-N-ethyl-acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N-cyclopropyl-N-(3-methoxy-benzyl)- acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N-cyclopropyl-N-(3,4-dimethoxy- benzyl)-acetamide; 2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N-cyclopropyl-N-(3-methyl-benzyl)- acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N-cyclopropyl-N-(3,5-dimethoxy- benzyl)-acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N-methyl-N-pyridin-3-ylmethyl- acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-quinolin-6-yl-amino]-N-cyclopropyl-N-(3-methoxy- benzyl)-acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-N-cyclopropyl-N-(3- methoxy-benzyl)-acetamide; 2-[(4-tert-Butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-N-cyclopropyl-N-(3- methyl-benzyl)-acetamide;
N-Ethyl-2-[(5-isopropyl-pyridme-2-sulfonyl)-p-tolyl-amino]-N-pyri(hn-2-ylmethyl- acetamide;
N-Ethyl-2-[(5-isoproρyl-pyridme-2-sulfonyl)-p-tolyl-amino]-N-(6-metiιyl-pyridin-2- ylmethyl)-acetamide;
N-Ethyl-2-[(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-N-thiazol-2-ylmethyl- acetamide; N-Ethyl-2-[(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-N-(6-methyl-pyridin-2- ylmethyl)-acetamide;
N-Benzyl-N-(2-hydroxy-ethyl)-2-[(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]- acetamide; N-Ethyl-2-[(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-N-pyridin-3-ylmethyl- acetamide;
N-Ethyl-2-[(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-N-pyridin-2-ylmethyl- acetamide;
N-(2-Cyano-ethyl)-N-ethyl-2-[(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]- acetamide;
N-Ethyl-2-[(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-N-(l-methyl-lH-pyrrol-2- ylmethyl)-acetamide;
N-Ethyl-N-(4-hydroxy-benzyl)-2-[(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]- acetamide; N-Ethyl-N-(3-hydroxy-benzyl)-2-[(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]- acetamide;
N-Ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-N-thiazol-2-ylmethyl- acetamide;
N-Ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-N-(6-methyl-pyridin-2- ylmethyl)-acetamide;
N-Benzyl-N-(2-hydroxy-ethyl)-2-[(6-methoxy-pvridin-3-yl)-(toluene-2-sulfonyl)-amino]- acetamide;
N-Ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-annno]-N-pyridin-3-ylmethyl- acetamide; N-Ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-N-pyridin-2-ylmethyl- acetamide;
N-(2-Cyano-ethyl)-N-ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]- acetamide;
N-Ethyl-2-[(6-memoxy-pvridm-3-yl)-(toluene-2-sulfonyl)-amino]-N-(l-methyl-lH-pyrrol- 2-ylmethyl)-acetamide;
N-Benzyl-N-(2-hydroxy-ethyl)-2-[(toluene-2-sulfonyl)-p-tolyl-amino]-acetamide;
N-Ethyl-N-pyridin-3-ylmethyl-2-[(toluene-2-sulfonyl)-p-tolyl-amino]-acetamide;
N-Ethyl-N-tMazol-2-ylmethyl-2-[(toluene-2-sulfonyl)-p-tolyl-amino]-acetamide; N-Ethyl-N-(6-methyl-pyridin-2-ylmethyl)-2-[(toluene-2-sulfonyl)-p-tolyl-amino]- acetamide;
N-(2-Hydroxy-ethyl)-N-pyridin-2-ylmethyl-2-[(toluene-2-sulfonyl)-p-tolyl-amino]- acetamide; N-Ethyl-2-[(3-methyl-pyridine-2-sulfonyl)-p-tolyl-amino]-N-pyridin-2-ylmethyl- acetamide;
N-Ethyl-2-[(3-methyl-pyridine-2-sulfonyl)-m-tolyl-amino]-N-(6-methyl-pyridin-2- ylmethyl)-acetamide;
N-Ethyl-2-[(2-methoxy-phenyl)-(3-methyl-pyridine-2-sulfonyl)-amino]-N-(6-methyl- pyridin-2-ylmethyl)-acetamide;
N-Benzyl-N-ethyl-2-[(2-methoxy-phenyl)-(3-methyl-pyridine-2-sulfonyl)-amino]- acetamide;
N-Ethyl-N-pyridin-2-ylmethyl-2-[(l,2,3,4-tefrahydro-isoquinoline-7-sulfonyl)-p-tolyl- amino]-acetamide; N-Ethyl-2-[(5-isopropyl-pyridine-2-sulfonyl)-m-tolyl-amino]-N-(6-methyl-pyridin-2- ylmethyl)-acetamide;
N-Ethyl-2-[(5-isopropyl-pyridine-2-sulfonyl)-(2-methoxy-phenyl)-amino]-N-(6-methyl- pyridin-2-ylmethyl)-acetamide;
N-Benzyl-N-ethyl-2-[(5-isopropyl-pyridine-2-sulfonyl)-(2-methoxy-phenyl)-amino]- acetamide;
N-Ethyl-2-[(5-isopropyl-pvridine-2-sulfonyl)-(6-methoxy-pyridin-3-yl)-amino]-N-pyridin-
2-ylmethyl-acetamide;
N-Ethyl-2-[(5-isopropyl-pyridine-2-sulfonyl)-(6-methoxy-pyridin-3-yl)-amino]-N-(6- methyl-pyridin-2-ylmethyl)-acetamide; N-Berizyl-N-ethyl-2-[(5-isopropyl-pyridine-2-sulfonyl)-(6-methoxy-pyridin-3-yl)-amino]- acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-(6-methyl-pyridin-3-yl)-amino]-N-ethyl-N-pyridin-2- ylmethyl-acetamide;
N-Ber-zyl-2-[(4-tert-butyl-berιzenesulfonyl)-(6-methyl-pyridin-3-yl)-amino]-N-ethyl- acetamide;
N-Ethyl-2-[(6-methoxy-pyridin-3-yl)-(3-methyl-pyridine-2-sulfonyl)-amino]-N-pyridin-2- ylmethyl-acetamide; N-Ethyl-2-[(6-memoxy-pyridin-3-yl)-(3-methyl-pyridine-2-sulfonyl)-amino]-N-(6-methyl- pyridin-2-ylmethyl)-acetamide;
N-Benzyl-N-ethyl-2-[(6-methoxy-pyridm-3-yl)-(3-methyl-pyridine-2-sulfonyl)-amino]- acetamide; 2- {(3-Dimethylamino-phenyl)-[4-(l-hydroxy- l-methyl-ethyl)-benzenesulfonyl]-amino}- Ν-ethyl-Ν-pyridin-2-ylmethyl-acetamide;
Examples of particularly preferred compounds of formula (I) are: 2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N,N-diethyl-acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-(4-methoxy-phenyl)-amino]-N,N-diethyl-acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-(3-methoxy-phenyl)-amino]-N,N-diethyl-acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-m-tolyl-amino]-N,N-diethyl-acetamide;
2-[(6-Dimethylamino-pyridine-3-sulfonyl)-p-tolyl-amino]-N-ethyl-N-pyridin-2-ylmethyl- acetamide;
N-Benzyl-2-[(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-N-ethyl-acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N-ethyl-N-pyridm-4-ylmethyl- acetamide;
N,N-Diethyl-2-[(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-acetamide; N-Benzyl-N-ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-acetamide;
N-Benzyl-N-ethyl-2-[(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-acetamide;
N-Benzyl-2-[(4-tert-butyl-benzenesulfonyl)-(2-methoxy-phenyl)-amino]-N-ethyl- acetamide;
N-Benzyl-N-emyl-2-[(6-methoxy-pyridin-3-yl)-(naphthalene-2-sulfonyl)-amino]- acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N-ethyl-N-(2-hydroxy-ethyl)-acetamide;
2-[(3-Chloro-4-methyl-benzenesulfonyl)-p-tolyl-amino]-N,N-diethyl-acetamide;
N-Benzyl-2-[(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-N-(2-hydroxy-ethyl)- acetamide; 2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N-(2-cyano-ethyl)-N-ethyl-acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-ammo]-N-emyl-N-ρyridin-2-ylmethyl- acetamide; 2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N-ethyl-N-pyridin-3-ylmethyl- acetamide; 2-[(4--tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N-ethyl-N-(6-methyl-pyridin-2- ylmethyl)-acetamide; 2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N-ethyl-N-tMazol-2-ylmethyl- acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-N,N-diethyl- acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-N-ethyl-N-pyridin-2- ylmethyl-acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-N-ethyl-N-(6- memyl-pyridin-2-ylnιethyl)-acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N-ethyl-N-(3-hydroxy-benzyl)- acetamide; 2-[(4-tert-Butyl-benzenesulfonyl)-(lH-indazol-6-yl)-amino]-N-ethyl-N-(6-methyl-ρyridin-
2-ylmethyl)-acetamide;
2- [(4-tert-Butyl-benzenesulfonyl)-( 1 H-indazol-6-yl)-amino] -N-ethyl-N-pyridin-2- ylmethyl-acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N-(2-hydroxy-ethyl)-N-pyridin-2- ylmethyl-acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-N-(2-hydroxy- ethyl)-N-pyridin-2-ylmethyl-acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N-cyclopropyl-N-(3-methoxy-benzyl)- acetamide; 2-[(4-tert-Butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-N-cyclopropyl-N-(3- methoxy-benzyl)-acetamide;
N-Ethyl-2-[(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-N-thiaz l-2-ylmethyl- acetamide;
N-Benzyl-N-(2-hydroxy-ethyl)-2-[(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]- acetamide;
N-Ethyl-2-[(2-methoxy-phenyl)-(toluene-2-sulfonyl)-ammo]-N-pyridin-2-ylmethyl- acetamide; N-Ethyl-N-(3-hydrpxy-benzyl)-2-[(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]- acetamide;
N-Ethyl-2-[(6-methoxy-ρyridin-3-yl)-(toluene-2-sulfonyl)-amino]-N-(6-methyl-pyridin-2- ylmethyl)-acetamide; N-Benzyl-N-(2-hydroxy-emyl)-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]- acetamide;
N-Ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-N-pyridin-3-ylmethyl- acetamide;
N-Ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-N-pyridin-2-ylmethyl- acetamide;
N-Ethyl-2-[(2-methoxy-phenyl)-(3-methyl-pvridine-2-sulfonyl)-amino]-N-(6-methyl- pyridin-2-ylmethyl)-acetamide;
N-Benzyl-N-ethyl-2-[(2-methoxy-phenyl)-(3-methyl-pyridine-2-sulfonyl)-amino]- acetamide; 2-[(4-tert-Butyl-benzenesulfonyl)-(6-methyl-pyridin-3-yl)-amino]-N-ethyl-N-pyridin-2- ylmethyl-acetamide;
N-Beιιzyl-2-[(4-tert-butyl-benzenesulfonyl)-(6-methyl-pyridin-3-yl)-amino]-N-ethyl- acetamide;
N-Ethyl-2-[(6-methoxy-pyridin-3-yl)-(3-methyl-ρyridine-2-sulfonyl)-amino]-N-(6-methyl- pyridin-2-ylmethyl)-acetamide;
N-Benzyl-N-ethyl-2- [(6-methoxy-pyridin-3 -yl)-(3 -methyl-pyridine-2-sulfonyl)-amino] - acetamide;
The present invention encompasses physiologically usable or pharmaceutically acceptable salts of compounds of formula (I). This encompasses salts with physiologically compatible mineral acids such as hydrochloric acid, sulphuric or phosphoric acid; or with organic acids such as formic acid, methanesulphonic acid, acetic acid, trifluoroacetic acid, citric acid, furnaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid and the like. The compounds of formula (I) which are acidic can also form salts with physiologically compatible bases.
Examples of such salts are alkali metal, alkali earth metal, ammonium and alkylammoniumsalts such as Νa, K, Ca or tefraaU- lammonium salt. The compounds of formula (I) can also be present in the form of a zwifterion. The present invention encompasses also solvation complexes of compounds of general formula (I). The solvation can be effected in the course of the manufacturing process or can take place separately, e.g. as a consequence of hygroscopic properties of an initially anhydrous compound of general formula (I).
The present invention further encompasses different morphological forms, e.g. crystalline forms, of compounds of general formula (I) and their salts and solvation complexes. Particular heteromorphs may exhibit different dissolution properties, stability profiles, and the like, and are all included in the scope of the present invention.
The compounds of formula (I) might have one or several asymmetric centres and
, can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates and the meso- forms.
Preferred compounds as described above have IC50 values below 100 nM, particularly preferred compounds have IC50 values below 20 nM which have been determined with the FLIPR (Fluorometric Imaging Plates Reader) method described in the beginning of the experimental section.
The compounds of formula (I) and their pharmaceutically usable salts can be used for the treatment of diseases or disorders where an antagonist of a human orexin receptor is required such as obesity, diabetes, prolactinoma, narcolepsy, insomnia, sleep apnea, parasomnia, depression, anxiety, addictions, schizophrenia and dementia or any other disease related to orexin dysfunction.
The compounds of formula (I) and their pharmaceutically usable salts are particularly useful for the treatment of disturbed homeostasis and eating disorders (e.g. bulimia, obesity, food abuse, compulsive eating or irritable bowel syndrome), as well as disturbed sleep/wake schedule, sleep disorders (e.g. insomnias, apneas, dystonias), stress- related diseases (e.g. anxiety, mood and blood pressure disorders), or any other disease related to orexin dysfunction. The compounds of formula (I) and their pharmaceutically usable salts can be used as medicament (e.g. in the form of pharmaceutical preparations). The pharmaceutical preparations can be administered enterally, such as orally (e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of nasal sprays) or rectally (e.g. in the form of suppositories). However, the administration can also be effected parenterally, such as intramuscularly or intravenously (e.g. in the form of injection solutions), or topically, e.g. in the form of ointments, creams or oils.
The compounds of formula (I) and their pharmaceutically usable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, dragees, and hard gelatine capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. can be used, for example, as such adjuvants for tablets, dragees, and hard gelatine capsules. Suitable adjuvants for soft gelatine capsules, are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols, etc. Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc. Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc. Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols, etc.
Morever, the pharmaceutical preparations can contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. The compounds of formula (I) may also be used in combination with one or more other therapeutically useful substances. Examples are anorectic drugs like fenfluramine and related substances; lipase inhibitors like orlistat and related substances; antidepressants like fluoxetine and related substances; anxiolytics like alprazolam and related substances; sleep-inducers like zopiclone and related substances; or any other therapeutically useful substance.
The dosage of compounds of formula (I) can vary within wide limits depending on the disease to be controlled, the age and the individual condition of the patient and the mode of administration, and will, of course, be fitted to the individual requirements in each particular case. For adult patients a daily dosage of about 1 mg to 1000 mg, especially about 50 mg to about 500 mg, comes into consideration.
The pharmaceutical preparations conveniently contain about 1 - 500 mg, preferably 5 - 200 mg of a compound of formula (I).
The compounds of general formula (I) of the present invention are prepared according to the general sequence of reactions outlined in the schemes below, wherein A, B, R1, R2 are as defined in formula (I) above. As the case may be any compound obtained with one or more optically active carbon atom may be resolved into pure enantiomers or diastereomers, mixtures of enantiomers or diastereomers, diastereomeric racemates and the meso-forms in a manner known per se.
The compounds obtained may also be converted into a pharmaceutically acceptable salt thereof in a manner known per se.
The compounds of formula (I) may be prepared as single compounds or as libraries of compounds comprising at least 2, typically 5 to 200 compounds of formula (I).
Compound libraries are prepared by multiple parallel synthesis using solution phase chemistry.
The compounds of formula (I) have been prepared by following one out of three possible synthetic pathways. The first pathway starts with the reaction of an amine B-NH2 with an α-bromoacetamide, which might be synthesised starting from bromoacetyl bromide and an amine NHR^C^R2) either in situ or separately. In a second step the respective aminoacetamide was reacted with a sulfonyl chloride A-SO Cl (Scheme 1).
Figure imgf000022_0001
Scheme 1
The second synthetic route starts with the reaction of an amine B-NH with a sulfonyl chloride A-SO Cl. From the intermediate sulfonamides the target molecules can be obtained by reaction with the respective α-bromoacetamide (Scheme 2).
Figure imgf000022_0002
Scheme 2
In a third pathway a sulfonamide is synthesized starting from an amine B-NH and a sulfonyl chloride A-SO2Cl. The obtained sulfonamide is transformed to a t-butyl- or methyl acetate derivative by reaction with either tert-butyl bromoacetate or methyl bromoacetate. The ester is hydrolyzed and the obtained acid is coupled with an amine -STHR^CΗ^R2) to give the desired amide (Scheme 3).
Figure imgf000023_0001
R = t-Bu,Me
R1
Figure imgf000023_0002
Scheme 3
Experimental Section
Abbreviations: bp Boiling point BSA Bovine serum albumine
CHO Chinese hamster ovary d Day(s)
DCM Dichloromethane
DMSO Dimethylsulfoxide DIPEA N,N-Diisopropylethylamine
EDC 1 -(3-Dimethylaminopropyl)-3-ethylcarbodiimide
ES Electron spray ether Diethylether
FCS Foetal calf serum FLIP R Fluorescent imaging plate reader h Hour(s)
HBSS Hank's balanced salt solution
HEPES 4-(2-Hydroxyethyl)-piperazine-l-ethanesulfonic acid
HPLC High pressure/performance liquid chromatography MS Mass spectroscopy
LC Liquid chromatography min Minute(s)
Rt retention time
RT Room temperature TBTU O-Benzotriazol- l-yl-N,N,N'N'-tetramethyluronium tetrafluoroborate
TFA Trifluoroacetic acid
THF Tetrahydrofuran I. Biology
Determination of Orexin receptor antagonistic activity The Orexin receptor antagonistic activity of the compounds of formula (I) was determined in accordance with the following experimental method.
Experimental method: Intracellular calcium measurements
Chinese hamster ovary (CHO) cells expressing the human orexin- 1 receptor and the human orexin-2 receptor, respectively, were grown in culture medium (Ham F-12 with L- Glutamine) containing 300 μg/ml G418, 100 U/ml penicillin, 100 μg/ml streptomycin and 10 % inactivated foetal calf serum (FCS).
The cells were seeded at 80O00 cells / well into 96-well black clear bottom sterile plates (Costar) which had been precoated with 1% gelatine in Hanks' Balanced Salt Solution (HBSS). All reagents were from Gibco BRL. The seeded plates were incubated overnight at 37°C in 5% CO2. Human orexin-A as an agonist was prepared as 1 mM stock solution in methano water (1:1), diluted in HBSS containing 0.1 % bovine serum albumin (BSA) and 2 mM HEPES for use in the assay at a final concentration of 10 nM.
Antagonists were prepared as 10 mM stock solution in DMSO, then diluted in 96-well plates, first in DMSO, then in HBSS containing 0.1 % bovine serum albumin (BSA) and 2 mM HEPES.
On the day of the assay, 100 μl of loading medium (HBSS containing 1% FCS, 2 mM HEPES, 5 mM probenecid (Sigma) and 3 μM of the fluorescent calcium indicator fluo-3 AM (1 mM stock solution in DMSO with 10% pluronic acid) (Molecular Probes) was added to each well. The 96-well plates were incubated for 60 min at 37° C in 5% CO2. The loading solution was then aspirated and cells were washed 3 times with 200 μl HBSS containing 2.5 mM probenecid, 0.1% BSA, 2 mM HEPES. 100 μl of that same buffer was left in each well. Within the Fluorescent Imaging Plate Reader (FLIPR, Molecular Devices), antagonists were added to the plate in a volume of 50 μl, incubated for 20 min and finally 100 μl of agonist was added. Fluorescence was measured for each well at 1 second intervals, and the height of each fluorescence peak was compared to the height of the fluorescence peak induced by 10 nM orexin- A with buffer in place of antagonist. For each antagonist, IC5o value (the concentration of compound needed to inhibit 50 % of the agonistic response) was determined. Selected compounds are displayed in Table 1.
Figure imgf000026_0001
Table 1
II. Chemistry
The following examples illustrate the preparation of pharmacologically active compounds of the invention but do not at all limit the scope thereof.
All temperatures are stated in °C.
All analytical and preparative HPLC investigations were performed using RP-C18 based columns.
A Synthesis of starting materials
A.1 Synthesis of amines
Al.l Synthesis of amines via reductive amination (general procedure): A solution of the respective amine in THF (2.0 mol/L, 5.0 mL) was added to a solution of the respective aldehyde (10.0 mmol) in methanol (20 mL). Activated molecular sieves (4A) were added and the reaction mixture was stirred for 16 h. After addition of sodium borohydride (12 mmol) the solution was stirred for 3 h, treated with water (10 mL), stirred for 1 h and purified by ion-exchange chromato- graphy [amberlyst 15, methanol / ammonium hydroxide solution (10 mol/L) 1:1].
After removal of methanol in vacuo the aqueous layer was extracted with ethyl acetate (3 x 100 mL). The solvents were removed in vacuo, the residue was dissolved in ethanol and the product was precipitated by addition of a solution of hydrogen chloride in ether (2.0 mol/L). The following amines were obtained:
3-Ethylaminomethyl-phenol:
„OH
prepared by reaction of ethylamine with 3-hydroxy-benzaldehyde LC-MS: rt = 0.55 min, 152 (M+1, ES+).
Ethyl-quinolin-3-yImethyl-amine:
Figure imgf000027_0001
prepared by reaction of ethylamine with quinoline-3-carbaldehyde LC-MS: rt = 0.58 min, 187 (M+1, ES+).
Ethyl-quinolin-4-yImethyl-amine:
Figure imgf000027_0002
prepared by reaction of ethylamine with quinoline-4-carbaldehyde LC-MS: rt = 0.50 min, 187 (M+1, ES+).
(4-Ethylaminomethyl-phenyl)-dimethyl-amine:
Figure imgf000027_0003
prepared by reaction of ethylamine with 4-dimethylamino-benzaldehyde LC-MS: rt = 0.49 min, 179 (M+1, ES+). 4-Ethylaminomethyl-phenol:
Figure imgf000028_0001
prepared by reaction of ethylamine with 4-hydroxy-benzaldehyde LC-MS: rt = 0.54 min, 152 (M+1, ES+).
EthyI-(lH-imidazol-2-yImethyI)-amine:
Figure imgf000028_0002
prepared by reaction of ethylamine with lH-imidazole-2-carbaldehyde LC-MS: rt = 0.16 min, 126 (M+1, ES+).
Ethyl-(6-methyl-pyridin-2-ylmethyl)-amine:
Figure imgf000028_0003
prepared by reaction of ethylamine with 6-methyl-pyridine-2-carbaldehyde LC-MS: rt = 0.48 min, 151 (M+1, ES+).
Ethyl-(3H-imidazol-4-ylmethyl)-amine: N prepared by reaction of ethylamine with 3H-imidazole-4-carbaldehyde LC-MS: rt = 0.16 min, 126 (M+1, ES+).
Ethyl-thiazol-2-ylmethyl-amine:
I> prepared by reaction of ethylamine with thiazole-2-carbaldehyde LC-MS: rt = 0.17 min, 143 (M+1, ES+). Ethyl-(lH-indol-3-ylmethyl)-amine:
Figure imgf000029_0001
prepared by reaction of ethylamine with lH-indole-3-carbaldehyde LC-MS: rt = 0.75 min, 175 (M+1, ES+).
Ethyl-pyridin-2-ylmethyI-amine :
Figure imgf000029_0002
prepared by reaction of ethylamine with pyridine-2-carbaldehyde LC-MS: rt = 0.47 min, 137 (M+1, ES+).
EthyI-pyridin-3-yImethyl-arnine:
Figure imgf000029_0003
prepared by reaction of ethylamine with pyridine-3-carbaldehyde LC-MS: rt = 0.16 min, 137 (M+1, ES+).
4-Ethylaminomethyl-benzonitrile:
Figure imgf000029_0004
prepared by reaction of ethylamine with 4-formyl-benzonitrile LC-MS: rt = 0.62 min, 161 (M+1, ES+).
Ethyl-(l-methyl-lH-pyrrol-2-ylmethyl)-amine:
Figure imgf000029_0005
prepared by reaction of ethylamine with l-methyl-lH-pyrrole-2-carbaldehyde LC-MS: rt = 0.56 min, 139 (M+1, ES+). 2-[(Pyridin-2-yImethyI)-amino]-ethanol:
prepared by reaction of 2-amino-ethanol with pyridine-2-carbaldehyde LC-MS: rt = 0.16 min, 153 (M+1, ES+).
3-[(Pyridin-2-ylmethyl)-amino]-propan-l-ol:
Figure imgf000030_0001
prepared by reaction of 3-amino-propan-l-ol with pyridine-2-carbaldehyde LC-MS: rt = 0.16 min, 167 (M+1, ES+).
2-[(Quinolin-2-ylmethyl)-amino]-ethanol:
HO
prepared by reaction of 2-amino-ethanol with quinoline-2-carbaldehyde LC-MS: rt = 0.53 min, 203 (M+1, ES+).
3-[(Quinolin-2-ylmethyl)-amino]-propan-l-ol:
H prepared by reaction of 3-amino-propan-l-ol with quinoline-2-carbaldehyde LC-MS: rt = 0.56 min, 217 (M+1, ES+).
Ethyl-quinolin-2-ylmethyl-amine:
prepared by reaction of ethylamine with quinoline-2-carbaldehyde LC-MS: rt = 0.58 min, 187 (M+1, ES+). Al .2 Synthesis of 6-Ethylaminomethyl-pyridin-2-ylamines : Al.2.1 Synthesis of 6-Bromo-pyridine-2-carboxylic acid ethylamide:
Figure imgf000031_0001
TBTU (6.5 mmol) was added to a solution of 6-bromo-pyridine-2-carboxylic acid (5.0 mmol) in DMF (30 mL). A solution of ethylamine in THF (1.0 mol/L, 5.0 mL) and DIPEA (15.0 mmol) were added and the reaction mixture was stirred for 16 h. Water (100 mL) and ethyl acetate (100 mL) were added, the layers were separated, and the aqueous layer was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and concentrated in vacuo to give 1.1 g (4.8 mmol, 96%>) of the desired amide as a yellow oil which was used without further purification. LC-MS: rt = 0.85 min, 229 (M+1, ES+).
Al.2.2 Synthesis of 6-Amino-pyridine-2-carboxyIic acid ethylamides (general procedure):
A solution of the respective amine in methanol (2.0 mol/L, 5.0 mL) was added to 6-bromo-pyridine-2-carboxylic acid ethylamide (4.38 mmol). The reaction mixture was heated for 5 min in a microwave oven at 150W and purified by preparative HPLC chromatography to give the following aminopyridines:
6-(Ethyl-methyl-amino)-pyridine-2~carboxylic acid ethylamide:
Figure imgf000031_0002
prepared by reaction of ethyl-methyl-amine with 6-bromo-pyridine-2-carboxylic acid ethylamide LC-MS: rt = 0.82 min, 208 (M+1 , ES+). 6-Dimethylamino-pyridine-2-carboxylic acid ethylamide:
Figure imgf000032_0001
prepared by reaction of dimethyl-amine with 6-bromo-ρyridine-2-carboxylic acid ethylamide
LC-MS: rt = 0.72 min, 194 (M+1, ES+).
6-Ethylamino-pyridine-2-carboxylic acid ethylamide:
Figure imgf000032_0002
prepared by reaction of ethylamine with 6-bromo-ρyridine-2-carboxylic acid ethylamide; in contrast to the general procedure the reaction was carried out by heating a solution of the starting materials in ethanol/water for 72 h at 100°C in an autoclave LC-MS: rt = 0.55 min, 194 (M+1, ES+).
Al.2.3 Synthesis of 6-Ethylaminomethyl-pyridin-2-ylamines (general procedure):
Lithium aluminum hydride (7.6 mmol) was added to a solution of the respectiveό- amino-pyridine-2-carboxylic acid ethylamide (3.8 mmol) in THF (10 mL). The reaction mixture was stirred for 2 h at RT and for 7 h at reflux, allowed to reach RT, treated with water (0.50 mL), NaOH solution (2.0 mol/L, 0.50 mL) and water (1.50 mL) and filtered. The residue was washed with ethyl acetate (3 x 20 mL) and the filtrate was dried over Na2SO4 and concentrated in vacuo to give the following pyridine derivatives:
Ethyl-(6-ethylaminomethyl-pyridin-2-yl)-methyl-amine:
Figure imgf000032_0003
prepared by reduction of 6-(ethyl-methyl-amino)-ρyridine-2-carboxylic acid ethylamide LC-MS: rt = 0.50 min, 194 (M+1, ES+).
(6-Ethylaminomethyl-pyridin-2-yl)-dimethyl-amine:
Figure imgf000033_0001
prepared by reduction of 6-dimethylamino-pyridine-2-carboxylic acid ethylamide LC-MS: rt = 0.42 min, 180 (M+1, ES+).
Ethyl-(6-ethylaminomethyl-pyridin-2-yl)-amine:
Figure imgf000033_0002
prepared by reduction of 6-ethylamino-pyridine-2-carboxylic acid ethylamide
LC-MS: rt = 0.46 min, 180 (M+1, ES+).
A1.3 Synthesis of Benzyl-cyclopropyl-amines (general procedure):
Cyclopropylamine (30.0 mmol) was added to a solution of the respective benzaldehyde (30.0 mmol) in methanol (30 mL). After 2 h sodium borohydride
(30.0 mmol) was added. The reaction mixture was stirred for 2 h, treated with an aqueous NaOH-solution (1.0 mol/L, 2.0 mL), and concentrated in vacuo. Ethyl acetate (100 mL) and an aqueous NaOH-solution (1.0 mol/L, 50 mL) were added, and the layers were separated. The organic layer was washed with an aqueous NaOH-solution (1.0 mol/L, 30 mL) and brine (30 mL), dried over Na2SO4, and concentrated in vacuo to give the following amines which were used without further purification:
Cyclopropyl-(3,4-dimethoxy-benzyl)-amine:
Figure imgf000033_0003
prepared by reaction of cyclopropylamine with 3,4-dimethoxy-benzaldehyde LC-MS: rt = 0.67 min, 208 (M+1, ES+). Cyclopropyl-(3-methyl-benzyl)~amine:
Figure imgf000034_0001
prepared by reaction of cyclopropylamine with 3-methyl-benzaldehyde LC-MS: rt = 0.53 min, 162 (M+1, ES+).
Cyclopropyl-(2,5-dichloro-benzyl)-amine:
.A α C» prepared by reaction of cyclopropylamine with 2,5-dichloro-benzaldehyde.
Cyclopropyl-(3-methoxy-benzyl)-amine:
Figure imgf000034_0002
prepared by reaction of cyclopropylamine with 3-methoxy-benzaldehyde LC-MS: rt = 0.52 min, 178 (M+1, ES+).
A.2 Synthesis of sulfonyl chlorides
A.2.1 Synthesis of 6-Dimethylamino-pyridine-3-sulfonyl chloride
Figure imgf000034_0003
(5-Bromo-pyridin-2-yl)-dimethyl-amine:
N-Bromosuccinimide (190 mmol) was added portionwise to a solution of 2-(dimethylamino)-ρyridine (200 mmol) in DCM (1.0 L). After 10 min a HPLC- MS indicated complete conversion. The solvent was removed in vacuo and the residue was purified by flash-chromatography (ethyl acetate/heptane 1:19) to give 25.7 g (128 mmol, 64%) of the desired arylbromide as a white solid.
LC-MS: rt = 0.46 min, 201 (M+1, ES+). 6-Dimethylamino-pyridine-3-thiol:
At -78°C a solution of (5-bromo-pyridin-2-yl)-dimethyl-amine (15.0 mmol) in THF (50 mL) was added dropwise to a solution of n-BuLi in Hexane (1.6 mol/L, 10.0 mL). The reaction mixture was stirred for 15 min and sulfur (20.0 mmol) was added. After 1 min a solution of n-BuLi in Hexane (1.6 mol/L, 20.0 ml) was added. The reaction mixture was stirred for 10 min at -78°C and purified immediately by flash-chromatography (ethyl acetate/heptane 1 :3) without previous work-up. A second flash-chromatography (gradient: ethyl acetate/heptane 1:19 to 1:9) yielded 0.50 g (3.24 mmol, 21%) of 6-dimethylamino-pyridine-3 -thiol as a yellow oil. LC-MS: rt = 0.46 min, 155 (M+1, ES+).
6-Dimethylamino-pyridine-3-sulfonyl chloride: Hydrochloric acid (25%, 1.13 mL) was added to a solution of 6-dimethylamino- pyridine-3 -thiol (0.50 mmol) in DCM (10 mL) at -78°C. A solution of sodium hypochlorite in water (6-14%, 5.2 mL) was added at -78°C and the reaction mixture was stirred for additional 2 min. The layers were separated and the aqueous layer was extracted with DCM (3 x 20 mL). The solvents were removed in vacuo and the obtained 6-dimethylamino-pyridine-3-sulfonyl chloride was used immediately in the next synthetic step.
A.2.2 Synthesis of 5-Isopropyl-pyridine-2-sulfonyl chloride
Figure imgf000035_0001
Hydrochloric acid (25%, 63 mL) was added to a suspension of 5-isopropyl- pyridine-2-thiol (90 mmol) in DCM (150 mL) at RT. The reaction mixture was cooled to -15°C, a solution of sodium hypochlorite in water (6-14%, 240 mL) was added dropwise and the reaction mixture was stirred for additional 15 min. After separation of the layers DCM (150 mL) was added to the aqueous layer. Another portion of a solution of sodium hypochlorite in water (6-14%, 90 mL) was added at -15°C. The layers were separated and the aqueous layer was extracted with DCM (2 x 150 mL). All organic layers were combined and dried with a2SO4. The solvents were removed in vacuo and the obtained 5-isopropyl-pyridine-2- sulfonyl chloride was used immediately in the next synthetic step.
A.2.3 Synthesis of 5-Methyl-pyridine-2-sulfonyl chloride
Figure imgf000036_0001
Hydrochloric acid (25%, 21 mL) was added to a suspension of 5-methyl-pyridine- 2-thiol (30 mmol) in DCM (50 mL) at RT. The reaction mixture was cooled to -15°C, a solution of sodium hypochlorite in water (6-14%, 80 mL) was added dropwise and the reaction mixture was stirred for additional 15 min. After separation of the layers DCM (150 mL) was added to the aqueous layer. Another portion of a solution of sodium hypochlorite in water (6-14%, 30 mL) was added at -15°C. The layers were separated and the aqueous layer was extracted with DCM (3 x 100 mL). All organic layers were combined and dried with Na2SO4- The solvents were removed in vacuo and the obtained 5-methyl-pyridine-2- sulfonyl chloride was used immediately in the next synthetic step.
A.2.4 Synthesis of 3-Methyl-pyridine-2-sulfonyl chloride
Figure imgf000036_0002
3-Methyl-pyridine-2-thiol:
Thiourea (174 mmol) was added to a solution of 2-bromo-3-methylpyridine (87 mmol) in ethanol (500 mL). The reaction mixture was refluxed for 5 h, cooled to RT, treated with an aqueous solution of sodium hydroxide (25%, 1.0 mL) and refluxed for additional 60 min. The mixture was concentrated in vacuo to 50 mL, water (300 mL) and ethyl acetate (300 mL) were added, the layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 100 mL). Brine (50 mL) was added to the combined organic layers, the layers were separated and the solvents were removed in vacuo. The crude oil was crystallized from ether to give 7.1 g (56.7 mmol, 65%) of the thiol as pale yellow crystals. LC-MS: rt = 0.48 min, 126 (M+1, ES+). 3-Methyl-pyridine-2-sulfonyl chloride:
Hydrochloric acid (25%, 9.0 mL) was added to a solution of 3-methyl-pyridine-2- thiol (16 mmol) in DCM (60 mL) at RT. The reaction mixture was cooled to -15°C, a solution of sodium hypochlorite in water (6-14%, 42 mL) was added dropwise and the reaction mixture was stirred for additional 10 min. After separation of the layers the aqueous layer was extracted with DCM (3 x 50 mL). The organic layers were combined and dried with Na2SO4. The solution of the obtained 3-methyl-pyridine-2-sulfonyl chloride was used immediately in the next synthetic step.
A.3 Synthesis of other intermediates
A.3.1 Synthesis ofN-Ethyl-N-pyridin-2-ylmethyl-2-p-tolylamino-acetamide
Figure imgf000037_0001
p-Tolylamino-acetic acid tert-butyl ester: A solution of/ oluidine (200 mmol) in THF (500 mL) was treated with tert-butyl bromoacetate (220 mmol) and DIPEA (440 mmol) at RT. The reaction mixture was heated to reflux for 16 h and cooled to RT. Water (200 mL) and EE (500 mL) were added, the layers were separated and the aqueous layer was extracted twice with ethyl acetate (100 mL). The combined organic layers were washed with water and brine. The solvents were removed in vacuo and the residue (44 g) was used without further purification. LC-MS: rt = 0.96 min, 222 (M+1, ES+).
p-Tolylamino-acetic acid: A solution of crude p-tolylamino-acetic acid tert-butyl ester (200 mmol) in DCM
(600 mL) was cooled to 0°C and treated with TFA (150 mL). The reaction mixture was allowed to reach RT and stirred for 4 d. Water (200 mL) was added, the layers were separated and the aqueous layer was extracted with DCM (4 x 200 mL). The aqueous layer was adjusted to pH 8 by addition of saturated NaHCOβ solution and extracted with ethyl acetate (4 x 200 mL). The combined organic layers were dried with Na SO4 and the solvents were removed in vacuo to give the crude acid (18 g) which was used in the next step without further purification. LC-MS: rt = 0.54 min, 166 (M+1, ES+).
N-Ethyl-N-pyridin-2-ylmethyl-2-p-tolylamino-acetamide:
A suspension of ethyl-pyridin-2-ylmethyl-amine (29.0 mmol) and DIPEA (78.0 mmol) in DMF (50 mL) was cooled to -20°C and added to a cold (-20°C) solution of p-tolylamino-acetic acid (26.0 mmol) and TBTU (34.0 mmol) in DMF (100 mL). The reaction mixture was stirred for 15 min at -20°C. Water (300 mL) and ethyl acetate (400 mL) were added, the layers were separated and the organic layer was washed with water (4 x 100 mL). The combined aqueous layers were extracted with ethyl acetate (200 mL). The combined organic layers were washed with ΝaOH solution (1.0 mol/L, 100 mL) and brine (100 mL) and dried with Νa2Sθ4. The solvents were removed in vacuo and the obtained solid was dissolved in ethanol. By addition of a solution of hydrogen chloride in ether a byproduct precipitated which was filtered off. Dilution of the remaining solution with ether led to precipitation of the desired acetamide, which was obtained as a white solid (5.3 g). LC-MS: rt = 0.64 min, 284 (M+1, ES+).
A.3.2 Synthesis of 6-Methyl-pyridin-3-ylamine
Figure imgf000038_0001
(6-Methyl-pyridin-3-yl)-carbamic acid benzyl ester:
To a suspension of 6-methylnicotinic acid (36.4 mmol) in toluene (100 mL) was added DIPEA (120 mmol) and Diphenylphosphoryl azide (91.1 mmol). The reaction mixture was heated to reflux for 1 h, cooled to RT and treated with benzyl alkohol (120 mmol). After 30 min ethyl acetate (200 mL) and water (200 mL) were added, the layers were separated and the organic layer was washed with water (3x100 mL). The solvents were removed in vacuo and the residue was purified by preparative HPLC chromatography to give (6-methyl-pyridin-3-yl)- carbamic acid benzyl ester (5.2 g, 21.5 mmol, 59%) as a colourless oil. LC-MS: rt = 0.68 min, 243 (M+1, ES+).
6-Methyl-pyridin-3-ylamine:
To a solution of (6-methyl-pyridin-3-yl)-carbamic acid benzyl ester (21.5 mmol) in methanol (100 mL) was added ammonium formate (107 mmol) and palladium on activated carbon (10%, wet, 1.0 g). The reaction mixture was stirred under nitrogen for 1 h and filtered over Celite. The solvents were removed in vacuo and the residue was dissolved in ethyl acetate. The organic layer was washed with water (2x100 mL) and the combined aqueous layers were extracted with ethyl acetate (3 x 100 mL). The organic layers were combined and dried with Na2SO4-
The solvents were removed in vacuo and the crude 6-methyl-pyridin-3-ylamine (0.80 g, 7.40 mmol, 34%) was used without further purification. LC-MS: rt = 0.16 min, 109 (M+1, ES+).
Synthesis of sulfonylamino-acetic acid derivatives via α-aminoacetamide intermediates (one-pot procedure)
Figure imgf000039_0001
General Procedure:
A solution of 2-bromoacetyl bromide (0.30 mmol) in THF (0.50 mL) was cooled to 0°C and treated dropwise with the respective dialkylamine (0.30 mmol). After addition of ethyldiisopropylamine (1.80 mmol) the reaction mixture was allowed to reach RT and was stirred for 60 min. A solution of the primary amine B-NH2
(0.30 mmol) in THF (0.50 mL) was added. The suspension was stirred at 60°C for 16 h, cooled to RT and treated with a solution of the respective sulfonyl chloride (0.30 mmol) in THF (0.50 mL). After 60 min the solvent was removed in vacuo and the residue was purified by preparative HPLC chromatography to give the following sulfonamides: Example 1: 7Y,iV-Diethyl-2-[(quinoIine-8-sulfonyl)-p-tolyl-amino]-acetanιide:
Figure imgf000040_0001
prepared by reaction of 2-bromoacetyl bromide with diethylamine, /?-toluidine and
8-quinolinesulfonyl chloride
LC-MS: rt = 0.92 min, 412 (M+1, ES+).
Example 2:
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N,N-diethyl-acetamide:
Figure imgf000040_0002
prepared by reaction of 2-bromoacetyl bromide with diethylamine, ^-toluidine and 4-tert-butyl-benzenesulfonyl chloride LC-MS: rt = 1.10 min, 417 (M+1, ES+).
Example 3:
2-[(4-Bromo-benzenesulfonyl)-p-tolyl-amino]-N,N-diethyl-acetamide:
Figure imgf000040_0003
prepared by reaction of 2-bromoacetyl bromide with diethylamine, />-toluidine and 4-bromo-benzenesulfonyl chloride LC-MS: rt = 1.04 min, 439 (M+1, ES+). Example 4: iV,iV"-Diethyl-2-[(naphthalene-2-sulfonyl)-p-tolyI-amino]-acetamide:
Figure imgf000041_0001
prepared by reaction of 2-bromoacetyl bromide with diethylamine, /?-toluidine and 2-naphthalenesulfonyl chloride LC-MS: rt = 1.04 min, 411 (M+1, ES+).
Example 5:
2-[(3-Chloro-benzenesulfonyl)-p-tolyl-amino]-iV,N-diethyl-acetamide:
Figure imgf000041_0002
prepared by reaction of 2-bromoacetyl bromide with diemylamine, -tol dine and 3-chloro-benzenesulfonyl chloride LC-MS: rt = 1.02 min, 395 (M+1, ES+).
Example 6:
N,iV-Diethyl-2- [(3-fluoro-b enzenesulf onyl)-p-tolyl-amino] -acetamide :
Figure imgf000041_0003
prepared by reaction of 2-bromoacetyl bromide with diethylamine, ?-toluidine and 3-fluoro-benzenesulfonyl chloride LC-MS: rt = 0.97 min, 379 (M+1, ES+). Example 7:
2-[(2-Chloro-benzenesulfonyl)-p-tolyl-amino]-iV,7y-diethyl-acetamide:
Figure imgf000042_0001
prepared by reaction of 2-bromoacetyl bromide with diethylamine, ^-toluidine and 2-chloro-benzenesulfonyl chloride LC-MS: rt = 0.98 min, 395 (M+1, ES+).
Example 8: N,iV-Diethyl-2-[(toluene-3-sulfonyl)-p-tolyl-amino]-acetamide:
Figure imgf000042_0002
prepared by reaction of 2-bromoacetyl bromide with diethylamine, ^-toluidine and toluene-3 -sulfonyl chloride
LC-MS: rt = 0.99 min, 375 (M+1, ES+).
Example 9:
7Y,N-Diethyl-2-[(4-ethyl-benzenesulfonyl)-p-tolyl-amino]-acetamide:
Figure imgf000042_0003
prepared by reaction of 2-bromoacetyl bromide with diethylamine, />-toluidine and 4-ethyl-benzenesulfonyl chloride LC-MS: rt = 1.03 min, 389 (M+1, ES+). Example 10:
iV,iV-Diethyl-2-[(toluene-2-sulfonyl)-p-tolyl-amino]-acetamide:
Figure imgf000043_0001
prepared by reaction of 2-bromoacetyl bromide with diethylamine, »-toluidine and toluene-2-sulfonyl chloride
LC-MS: rt = 0.98 min, 375 (M+1, ES+).
Example 11: iY,N-Diethyl-2- [p-tolyl-(2-trifiuoromethyl-b enzen esulf onyl)-amino] - acetamide:
prepared by reaction of 2-bromoacetyl bromide with diethylamine, /?-toluidine and 2-trifluoromethyl-benzenesulfonyl chloride LC-MS: rt = 1.00 min, 429 (M+1, ES+).
Example 12:
2-[(3,4-Difluoro-benzenesulfonyl)-p-tolyl-amino]-N,7Λr-diethyl-acetamide:
Figure imgf000043_0003
prepared by reaction of 2-bromoacetyl bromide with diethylamine, -toluidine and 3,4-difluoro-benzenesulfonyl chloride
LC-MS: rt = 1.00 min, 397 (M+1, ES+). Example 13:
2-[(4-tert-Butyl-benzenesulfonyl)-phenyl-amino]-N,iV-diethyl-acetamide:
Figure imgf000044_0001
prepared by reaction of 2-bromoacetyl bromide with diethylamine, aniline and 4-tert-butyl-benzenesulfonyl chloride LC-MS: rt = 1.07 min, 403 (M+1, ES+).
Example 14:
iV,N-Diethyl-2-[(naphthaIene-2-suIfonyl)-phenyI-amino]-acetamide:
Figure imgf000044_0002
prepared by reaction of 2-bromoacetyl bromide with diethylamine, aniline and naphthalene-2-sulfonyl chloride LC-MS: rt = 1.00 min, 397 (M+1, ES+).
Example 15:
N,N-Diethyl-2- [phenyl-(toluene-3-sulfonyl)-amino]-acetamide :
Figure imgf000044_0003
prepared by reaction of 2-bromoacetyl bromide with diethylamine, aniline and toluene-3 -sulfonyl chloride LC-MS: rt = 0.94 min, 361 (M+1, ES+). Example 16:
N,iV-Diethyl-2-[(4-ethyl-benzenesulfonyl)-phenyl-amino]-acetamide:
Figure imgf000045_0001
prepared by reaction of 2-bromoacetyl bromide with diethylamine, aniline and 4-ethyl-benzenesulfonyl chloride LC-MS: rt = 0.99 min, 375 (M+1, ES+).
Example 17:
2-[(4-tert-Butyl-benzenesuIfonyl)-p-tolyl-amino]-N-ethyl-N-methyl-acetamide:
Figure imgf000045_0002
prepared by reaction of 2-bromoacetyl bromide with ethylmethylamine, />-toluidine and 4-tert-butyl-benzenesulfonyl chloride LC-MS: rt = 1.06 min, 403 (M+1, ES+).
Example 18:
2-[(4-tert-Butyl-benzenesulfonyl)-phenyl-amino]-N-ethyl-7Y-methyl- acetamide:
Figure imgf000045_0003
prepared by reaction of 2-bromoacetyl bromide with ethylmethylamine, aniline and 4-tert-butyl-benzenesulfonyl chloride
LC-MS: rt = 1.02 min, 389 (M+1, ES+). Example 19:
2-[(4-tert-Butyl-benzenesulfonyl)-(4-methoxy-phenyl)-amino]-N,N-diethyl- acetamide:
Figure imgf000046_0001
prepared by reaction of 2-bromoacetyl bromide with diethylamine, /?-anisidine and 4-tert-butyl-benzenesulfonyl chloride LC-MS: rt = 1.07 min, 433 (M+1, ES+).
Example 20:
2-[(4-tert-Butyl-benzenesulfonyl)-cyclohexyl-amino]-N,N-diethyl-acetamide:
Figure imgf000046_0002
prepared by reaction of 2-bromoacetyl bromide with diethylamine, cyclohexyl- amine and 4-tert-butyl-benzenesulfonyl chloride LC-MS: rt = 1.16 min, 409 (M+1, ES+).
Example 21:
2-[(4-tert-ButyI-benzenesulfonyI)-(4-methyI-cycIohexyl)-amino]-iV, V-diethyl- acetamide:
Figure imgf000046_0003
prepared by reaction of 2-bromoacetyl bromide with diethylamine, 4-methyl- cyclohexylamine and 4-tert-butyl-benzenesulfonyl chloride LC-MS: rt = 1.20 min, 423 (M+1, ES+). Example 22:
2-[(4-tert-Butyl-benzenesulfonyl)-(6-chloro-pyridin-3-yl)-amino]-N,N-diethyI- acetamide:
Figure imgf000047_0001
prepared by reaction of 2-bromoacetyl bromide with diethylamine, 5-amino-2- chloropyridine and 4-tert-butyl-benzenesulfonyl chloride LC-MS: rt = 1.08 min, 438 (M+1, ES+).
Example 23: 2- [(4-tert-Butyl-b enzenesulf onyl)-(3-methoxy-phenyl)-amino] -N,N-diethyl- acet amide:
Figure imgf000047_0002
prepared by reaction of 2-bromoacetyl bromide with diethylamine, -anisidine and 4-tert-butyl-benzenesulfonyl chloride LC-MS: rt = 1.08 min, 433 (M+1, ES+).
Example 24:
2-[(4-tert-Butyl-benzenesulfonyl)-(4-ethyl-phenyl)-amino]-N,N-diethyl- acetamide:
Figure imgf000047_0003
prepared by reaction of 2-bromoacetyl bromide with diethylamine, 4-ethylaniline and 4-tert-butyl-benzenesulfonyl chloride LC-MS: rt = 1.15 min, 431 (M+1, ES+). Example 25: 2-[(4-tert-Butyl-benzenesulfonyl)-m-tolyl-amino]-N,N-diethyl-acetamide:
Figure imgf000048_0001
prepared by reaction of 2-bromoacetyl bromide with diethylamine, m-toluidine and 4-tert-butyl-benzenesulfonyl chloride LC-MS: rt = 1.12 min, 417 (M+1, ES+).
Example 26:
2-[(4-tert-Butyl-benzenesuIfonyI)-o-tolyl-amino]-N,iV-diethyl-acetamide:
Figure imgf000048_0002
prepared by reaction of 2-bromoacetyl bromide with diethylamine, σ-toluidine and 4-tert-butyl-benzenesulfonyl chloride LC-MS: rt = 1.12 min, 417 (M+1, ES+).
Example 27:
2-[(4-tert-ButyI-benzenesulfonyl)-(4-trifluoromethyl-phenyl)-amino]-N,N- diethyl-acetamide :
Figure imgf000048_0003
prepared by reaction of 2-bromoacetyl bromide with diethylamine, 4-trifluoro- methyl-aniline and 4-tert-butyl-benzenesulfonyl chloride
LC-MS: rt = 1.14 min, 471 (M+1, ES+). Example 28:
2-[(4-tert-Butyl-benzenesulfonyl)-(2-methoxy-phenyl)-amino]-7Λr-cyclopropyl- methyl-N-n-propyl-acetamide:
Figure imgf000049_0001
prepared by reaction of 2-bromoacetyl bromide with N-cyclopropylmethyl-N- propylamine, σ-anisidine and 4-tert-butyl-benzenesulfonyl chloride LC-MS: rt = 1.17 min, 473 (M+1, ES+).
Example 29:
2-[(4-tert-Butyl-benzenesulfonyl)-(4-methoxy-phenyl)-amino]-N-cyclopropyl- methyl-iV-n-propyl-acetamide:
Figure imgf000049_0002
prepared by reaction of 2-bromoacetyl bromide with N-cyclopropylmethyl-N- propylamine, >-anisidine and 4-tert-butyl-benzenesulfonyl chloride LC-MS: rt = 1.16 min, 473 (M+1, ES+).
Example 30:
2-[(4-tert-Butyl-benzenesulfonyI)-cyclohexyl-amino]-N-cyclopropylmethyI-iV- n-propyl-acetamide:
Figure imgf000049_0003
prepared by reaction of 2-bromoacetyl bromide with N-cyclopropyhnethyl-N- propylamine, cyclohexylamine and 4-tert-butyl-benzenesulfonyl chloride LC-MS: rt = 1.24 min, 449 (M+1, ES+). Example 31:
2-[(4-tert-Butyl-benzenesulfonyl)-(6-chloro-pyridin-3-yl)-amino]-N-cyclo- propylmethyl-N-n-propyl-acetamide:
Figure imgf000050_0001
prepared by reaction of 2-bromoacetyl bromide with N-cyclopropylmethyl-N- propylamine, 5-amino-2-chloropyridine and 4-tert-butyl-benzenesulfonyl chloride LC-MS: rt = 1.16 min, 478 (M+1, ES+).
Example 32:
2-[(4-tert-ButyI-benzenesulfonyl)-(3-methoxy-phenyl)-amino]-N-cyclopropyl- methyl-iV-n-propyl-acetamide:
Figure imgf000050_0002
prepared by reaction of 2-bromoacetyl bromide with N-cyclopropylmethyl-N- propylamine, -anisidine and 4-tert-butyl-benzenesulfonyl chloride
LC-MS: rt = 1.17 min, 473 (M+1, ES+).
Example 33:
2-[(4-tert-Butyl-benzenesulfonyl)-(2-chloro-phenyl)-amino]-N-cyclopropyl- methyl-JV-n-propyl-acetamide:
Figure imgf000050_0003
prepared by reaction of 2-bromoacetyl bromide with N-cyclopropylrnethyl-N- propylamine, 2-chloroaniline and 4-tert-butyl-benzenesulfonyl chloride LC-MS: rt = 1.21 min, 477 (M+1, ES+).
Example 34:
2-[(4-tert-Butyl-benzenesulfonyI)-m-toIyl-amino]-iV-cyclopropyImethyI-N-n- propyl-acetamide:
Figure imgf000051_0001
prepared by reaction of 2-bromoacetyl bromide with N-cyclopropylmethyl-N- propylamine, m-toluidine and 4-tert-butyl-benzenesulfonyl chloride LC-MS: rt = 1.20 min, 457 (M+1, ES+).
Example 35:
2-[(6-Dimethylamino-pyridine-3-sulfonyl)-p-tolyl-amino]-iV,N-diethyl- acetamide:
►OK
XX prepared by reaction of 2-bromoacetyl bromide with NN-diethylamine, p-toluidine
6-dimethylamino-pyridine-3-sulfonyl chloride; in contrast to the general procedure the intermediate N,N-diethyl-2-p-tolylamino-acetamide was isolated LC-MS: rt = 0.87 min, 405 (M+1, ES+).
Example 36:
2-[(6-Dimethylamino-pyridine-3-sulfonyl)-p-tolyl-amino]-N-ethyl-N-pyridin- 2-ylmethyl-acetamide:
Figure imgf000051_0002
prepared by reaction of 6-dimethylamino-pyridine-3-sulfonyl chloride with N- ethyl-N-pyridin-2-ylmethyl-2-p-tolylamino-acetamide
LC-MS: rt = 0.75 min, 468 (M+1, ES+).
Synthesis of sulfonylamino-acetic acid derivatives via isolated sulfanilide- intermediates (two step procedure)
Figure imgf000052_0001
C.l Synthesis of sulfanilide-intermediates (general procedure):
The respective sulfonyl chloride (100 mmol) was added portionwise to a solution of the respective aromatic amine (100 mmol) and ethyldiisopropylamine (120 mmol) in THF (100 mL) at RT. The suspension was stirred for 16 h, the solvent was removed in vacuo and the residue was redissolved in ethyl acetate. After washing the organic phase with water and brine the solvent was removed in vacuo. The residue was purified either by crystallization from diethylether or methanol/water or by preparative HPLC chromatography to give the following sulfonamides:
4-tert-Butyl-N-p-tolyl-benzenesulfonamide:
Figure imgf000052_0002
prepared by reaction of p-toluidine with 4-tert-butyl-benzenesulfonyl chloride LC-MS: rt = 1.18 min, 304 (M+1, ES+). 2-Methyl-iV-p-tolyl-benzenesulfonamide:
Figure imgf000053_0001
prepared by reaction of -toluidine with 2-methyl-benzenesulfonyl chloride LC-MS: rt = 1.06 min, 523 (2M+1, ES+).
7Λ (6-Methoxy-pyridin-3-yl)-2-methyl-benzenesulfonamide:
Figure imgf000053_0002
prepared by reaction of 6-methoxy-pyridin-3-ylamine with 2-methyl- benzenesulfonyl chloride LC-MS: rt = 0.85 min, 279 (M+1, ES+).
/Λr-(2-Methoxy-phenyl)-2-methyl-benzenesulfonamide:
Figure imgf000053_0003
prepared by reaction of o-anisidine with 2-methyl-benzenesulfonyl chloride LC-MS: rt = 0.93 min, 278 (M+1, ES+).
4-tert-Butyl-N-(6-methoxy-pyridin-3-yl)-benzenesulfonamide:
Figure imgf000053_0004
prepared by reaction of 6-methoxy-pyridin-3-ylarnine with 4-tert-butyl- benzenesulfonyl chloride
LC-MS: rt = 0.96 min, 321 (M+1, ES+). 4-tert-Butyl-N-(2-methoxy-phenyI)-benzenesulfonamide:
Figure imgf000054_0001
prepared by reaction of o-anisidine with 4-tert-butyl-benzenesulfonyl chloride LC-MS: rt = 1.02 min, 320 (M+1, ES+).
Naphthalene-2-sulfonic acid (6-methoxy-pyridin-3-yl)-amide:
Figure imgf000054_0002
prepared by reaction of 6-methoxy-pyridin-3-ylamine with naphthalene-2-sulfonyl chloride
LC-MS: rt = 0.91 min, 315 (M+1, ES+).
NaphthaIene-2-sulfonic acid (2-methoxy-phenyl)-amide:
Figure imgf000054_0003
prepared by reaction of o-anisidine with naphthalene-2-sulfonyl chloride
LC-MS: rt = 0.97 min, 314 (M+1, ES+).
4-tert-Butyl-N-quinolin-6-yl-benzenesulfonamide:
Figure imgf000054_0004
prepared by reaction of quinolin-6-ylamine with 4-tert-butyl-benzenesulfonyl chloride LC-MS: rt = 0.82 min, 341 (M+1, ES+).
4-tert-Butyl-N-(3-dimethylamino-phenyl)-benzenesulfonamide:
Figure imgf000055_0001
prepared by reaction of NN-dimethyl-benzene-l,3-diamine with 4-tert-butyl- benzenesulfonyl chloride LC-MS: rt = 0.89 min, 333 (M+1, ES+).
4-tert-Butyl-N-isoquinolin-5-yl-benzenesulfonamide:
Figure imgf000055_0002
prepared by reaction of isoquinolin-5-ylamine with 4-tert-butyl-benzenesulfonyl chloride
LC-MS: rt = 0.80 min, 341 (M+1, ES+).
2-(4-tert-Butyl-benzenesulfonylamino)-benzamide:
Figure imgf000055_0003
prepared by reaction of 2-amino-benzamide with 4-tert-butyl-benzenesulfonyl chloride
LC-MS: rt = 0.96 min, 333 (M+1, ES+).
4-tert-Butyl-N-(lH-indazol-6-yl)-benzenesuIfonamide:
Figure imgf000055_0004
prepared by reaction of lH-indazol-6-ylamine with 4-tert-butyl-benzenesulfonyl chloride LC-MS: rt = 0.93 min, 330 (M+1, ES+).
5-Isopropyl-pyridine-2-sulfonic acid m-tolylamide:
Figure imgf000056_0001
prepared by reaction of m-tolylamine with 5-isopropyl-pyridine-2-sulfonyl chloride
LC-MS: rt = 0.96 min, 291 (M+1, ES+).
5-Isopropyl-pyridine-2-sulfonic acid (2-methoxy-phenyl)-amide:
Figure imgf000056_0002
prepared by reaction of 2-methoxy-phenylamine with 5-isopropyl-pyridine-2- sulfonyl chloride
LC-MS: rt = 0.94 min, 307 (M+1, ES+).
5-Isopropyl-pyridine-2-sulfonic acid (6-methoxy-pyridin-3-yl)-amide:
Figure imgf000056_0003
prepared by reaction of 6-methoxy-pyridin-3-ylamine with 5-isopropyl-pyridine-2- sulfonyl chloride
LC-MS: rt = 0.89 min, 308 (M+1, ES+).
5-Isopropyl-pyridine-2-sulfonic acid p-tolylamide:
Figure imgf000056_0004
prepared by reaction of p-tolylamine with 5-isopropyl-pyridine-2-sulfonyl chloride LC-MS: rt = 0.97 min, 291 (M+1, ES+).
5-Methyl-pyridine-2-sulfonic acid p-tolylamide:
Figure imgf000057_0001
prepared by reaction of p-tolylamine with 5-methyl-pyridine-2-sulfonyl chloride LC-MS: rt = 0.88 min, 263 (M+1, ES+).
4-tert-Butyl-iV-(6-methyl-pyridin-3-yl)-benzenesulfonamide:
Figure imgf000057_0002
prepared by reaction of 6-methyl-pyridin-3-ylamine with 4-tert-butyl-benzenesulfonyl chloride LC-MS: rt = 0.78 min, 305 (M+1, ES+).
N-[5-(4-tert-Butyl-benzenesuIfonylamino)-pyridin-2-yl]-acetamide:
Figure imgf000057_0003
prepared by reaction of N-(5-amino-pyridin-2-yl)-acetamide with 4-tert-butyl- benzene-sulfonyl chloride
LC-MS: rt = 0.90 min, 348 (M+1, ES+). 3-Methyl-pyridine-2-sulfonic acid p-tolylamide:
Figure imgf000058_0001
prepared by reaction of p-tolylamine with 3-methyl-pyridine-2-sulfonyl chloride LC-MS: rt = 0.89 min, 263 (M+1, ES+).
3-Methyl-pyridine-2-sulfonic acid m-tolylamide:
Figure imgf000058_0002
prepared by reaction of m-tolylamine with 3-methyl-pyridine-2-sulfonyl chloride LC-MS: rt = 0.89 min, 263 (M+1, ES+).
3-Methyl-pyridine-2-sulfonic acid (2-methoxy-phenyl)-amide:
Figure imgf000058_0003
prepared by reaction of 2-methoxy-phenylamine with 3-methyl-pyridine-2- sulfonyl chloride LC-MS: rt = 0.85 min, 279 (M+1, ES+).
3-Methyl-pyridine-2-sulfonic acid (6-methoxy-pyridin-3-yl)-amide:
Figure imgf000058_0004
prepared by reaction of 6-methoxy-pyridin-3-ylamine with 3-methyl-pyridine-2- sulfonyl chloride
LC-MS: rt = 0.79 min, 280 (M+1, ES+). 2-(2,2,2-Trifluoro-acetyl)-l ,2,3,4-tetrahydro-isoquinoline-7-sulfonic acid p- tolylamide:
Figure imgf000059_0001
prepared by reaction of p-tolylamine with 2 -(2,2,2-trifluoro-acetyl)- 1,2,3,4- tetrahydro-isoquinoline-7-sulfonyl chloride LC-MS: rt = 0.98 min, 399 (M+1, ES+).
Synthesis of sulfonylamino-acetic acid derivatives (general procedure):
To a solution of 2-bromoacetyl bromide (0.20 mmol) in THF (1.0 mL) was added a solution of the respective amine (0.20 mmol) in THF (0.50 mL) at RT. A solution of potassium tert-butoxide (0.20 mmol) in THF (0.50 mL) was added and the reaction mixture was stirred for 2 h. To this suspension a solution of the respective potassium N-tolylsulfonamide was added, which was obtained by adding potassium tert-butoxide (0.20 mmol) to a solution of the respective sulfonamide (0.20 mmol) in THF (2.5 mL) and diluting with DMSO (0.50 mL). The obtained suspension was stirred at 60°C for 1 h, the solvent was removed in vacuo and the residue was purified by preparative HPLC chromatography to give the following sulfonamides:
Example 37:
2-[(4-tert-ButyI-benzenesulfonyI)-p-toIyI-amino]-N,N-di-n-propyl-acetamide:
Figure imgf000059_0002
prepared by reaction of 2-bromoacetyl bromide with di-n-propylamine and 4-tert- butyl-N-p-tolyl-benzenesulfonamide LC-MS: rt = 1.20 min, 445 (M+1, ES+). Example 38:
N-Benzyl-2-[(4-tert-butyl-benzenesuIfonyl)-p-tolyl-amino]-iV-ethyI-acetamide:
Figure imgf000060_0001
prepared by reaction of 2-bromoacetyl bromide with N-benzyl-N-ethylamine and 4-tert-butyl-N-p-tolyl-benzenesulfonamide
LC-MS: rt = 1.19 min, 479 (M+1, ES+).
Example 39:
2-[(4-tert-Butyl-benzenesuIfonyl)-p-tolyl-amino]-iV-ethyl-iV-pyridin-4- ylmethyl-acetamide:
Figure imgf000060_0002
prepared by reaction of 2-bromoacetyl bromide with N-ethyl-N-pyridin-4- ylmethylamine and 4-tert-butyl-N-p-tolyl-benzenesulfonamide LC-MS: rt = 0.83 min, 480 (M+1, ES+).
Example 40:
N,iV-Di-n-propyl-2-[(toluene-2-sulfonyl)-p-tolyl-amino]-acetamide:
Figure imgf000060_0003
prepared by reaction of 2-bromoacetyl bromide with di-n-propylamine and 2- methyl-N-p-tolyl-benzenesulfonamide
LC-MS: rt = 1.20 min, 403 (M+1, ES+). Example 41:
N-Benzyl-N-ethyl-2-[(toluene-2-sulfonyI)-p-tolyl-amino]-acetamide:
Figure imgf000061_0001
prepared by reaction of 2-bromoacetyl bromide with N-benzyl-N-ethylamine and
2-methyl-N-p-tolyl-benzenesulfonamide
LC-MS: rt = 1.20 min, 437 (M+1, ES+).
Example 42:
N,N-Diethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]- acetamide:
Figure imgf000061_0002
prepared by reaction of 2-bromoacetyl bromide with diethylamine and N-(6- methoxy-pyridin-3-yl)-2-methyl-benzenesulfonamide
LC-MS: rt = 0.93 min, 392 (M+1, ES+).
Example 43:
N,N-Diethyl-2-[(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-acetamide:
Figure imgf000061_0003
prepared by reaction of 2-bromoacetyl bromide with diethylamine and N-(2-methoxy-phenyl)-2-methyl-benzenesulfonamide
LC-MS: rt = 0.96 min, 391 (M+1, ES+). Example 44:
2-[(4-tert-Butyl-benzenesulfonyl)-(6-methoxy-pyridin-3-yl)-amino]-iV iV- diethyl-acetamide:
Figure imgf000062_0001
prepared by reaction of 2-bromoacetyl bromide with diethylamine and 4-tert-butyl-
N-(6-memoxy-pyridin-3-yl)-benzenesulfonamide LC-MS: rt = 1.02 min, 434 (M+1, ES+).
Example 45:
2-[(4-tert-Butyl-benzenesulfonyl)-(2-methoxy-phenyl)-amino]-N,N-diethyl- acetamide:
Figure imgf000062_0002
prepared by reaction of 2-bromoacetyl bromide with diethylamine and 4-tert-butyl- N-(2-methoxy-phenyl)-benzenesulfonamide LC-MS: rt = 1.04 min, 433 (M+1, ES+).
Example 46:
N-Benzyl-N-ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]- acetamide:
Figure imgf000062_0003
prepared by reaction of 2-bromoacetyl bromide with N-benzyl-N-ethylamine and
N-(6-methoxy-pyridin-3-yl)-2-methyl-benzenesulfonamide
LC-MS: rt = 1.01 min, 454 (M+1, ES+). Example 47:
N-Benzyl-iV-ethyl-2-[(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]- acetamide:
Figure imgf000063_0001
prepared by reaction of 2-bromoacetyl bromide with N-benzyl-N-ethylamine and
N-(2-methoxy-phenyl)-2-methyl-benzenesulfonamide
LC-MS: rt = 1.04 min, 453 (M+1, ES+).
Example 48:
iV-Benzyl-2-[(4-tert-butyl-benzenesulfonyl)-(6-methoxy-pyridin-3-yl)-amino]- N-ethyl-acetamide :
Figure imgf000063_0002
prepared by reaction of 2-bromoacetyl bromide with N-benzyl-N-ethylamine and 4-tert-butyl-N-(6-methoxy-pyridin-3-yl)-benzenesulfonamide
LC-MS: rt = 1.08 min, 496 (M+1, ES+).
Example 49:
JV-Benzyl-2-[(4-tert-butyl-benzenesulfonyl)-(2-methoxy-phenyl)-amino]-iV- ethyl-acetamide:
Figure imgf000063_0003
prepared by reaction of 2-bromoacetyl bromide with N-benzyl-N-ethylamine and
4-tert-butyl-N-(2-methoxy-phenyl)-benzenesulfonamide
LC-MS: rt = 1.10 min, 495 (M+1, ES+).
Example 50:
N-Benzyl-iV-ethyl-2-[(6-methoxy-pyridin-3-yl)-(naphthalene-2-sulfonyI)- amino]-acetamide:
Figure imgf000064_0001
prepared by reaction of 2-bromoacetyl bromide with N-benzyl-N-ethylamine and naphthalene-2-sulfonic acid (6-methoxy-pyridin-3 -yl)-amide
LC-MS: rt = 1.05 min, 490 (M+1, ES+).
Example 51 :
N-Benzyl-iV-ethyl-2-[(2-methoxy-phenyl)-(naphthalene-2-sulfonyl)-amino]- acetamide:
Figure imgf000064_0002
prepared by reaction of 2-bromoacetyl bromide with N-benzyl-N-ethylamine and naphthalene-2 -sulfonic acid (2-methoxy-phenyl)-amide LC-MS: rt = 1.06 min, 489 (M+1, ES+). Example 52:
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-iV-ethyl-iV-(2-hydroxy-ethyl)- acetamide:
Figure imgf000065_0001
prepared by reaction of 2-bromoacetyl bromide with N-ethyl-N-(2-hydroxy-ethyl)- a ine and 4-tert-butyl-N-p-tolyl-benzenesulfonamide; in contrast to the general procedure the intermediate 2-bromo-N-ethyl-N-(2-hydroxy-ethyl)-acetamide was isolated before being used in the coupling with the potassium N-tolylsulfonamide. LC-MS: rt = 0.97 min, 433 (M+1, ES+).
D Synthesis of sulfonylamino-acetic acid derivatives via isolated 2-bromo-N,N- diethylacetamide (two step procedure)
Figure imgf000065_0002
D.l Synthesis of 2-bromo~N,N-diethyIacetamide :
A solution of 2-bromoacetyl bromide (20.2 g, 100 mmol) in THF (300 mL) was cooled to 0°C and treated with diethylamine (7.31 g, 100 mmol). After dropwise addition of ethyldiisopropylarmne (15.5 g, 120 mmol) the reaction mixture was allowed to reach RT and was stirred for 90 min. Water (250 mL) and ethyl acetate (300 mL) were added, the layers were separated and the aqueous layer was extracted twice with ethyl acetate (100 mL). The solvents were removed in vacuo and the residue was purified by destination (bp 120 - 121°C / 24 mbar) to give
5.24 g (21%) of the title compound as pale yellow oil. Synthesis of sulfonylamino-acetic acid derivatives (general procedure):
A solution of the respective sulfonyl chloride (0.20 mmol) in DCM (1.0 mL) was added to a solution of -toluidine (0.20 mmol) and ethyldiisopropylamine (0.24 mmol) in DCM (1.0 mL) at RT. After stirring for 16 h water was added, the layers were separated and the aqueous layer was extracted twice with DCM (2.0 mL). The combined organic extracts were concentrated in vacuo and dissolved in dry THF (1.0 mL). A solution of potassium tert-butoxide (0.20 mmol) in THF (0.50 mL) was added. The reaction mixture was treated with a solution of 2-bromo-N,N- diethylacetamide (0.20 mmol) in THF (0.50 mL) and stirred for 16 h at RT. The solvent was removed in vacuo and the residue was purified by preparative HPLC chromatography to give the following sulfonamides:
Example 53:
N,N-Diethyl-2-[(4-isopropyl-benzenesulfonyl)-p-tolyl-amino]-acetamide:
Figure imgf000066_0001
prepared by reaction of 2-bromo-N,N-diethylacetamide withp-toluidine and 4-isopropyl-benzenesulfonyl chloride LC-MS: rt = 1.04 min, 403 (M+1, ES+).
Example 54:
N,N-Diethyl-2-[(2-methoxy-4-methyl-benzenesulfonyl)-p-tolyl-amino]- acetamide:
Figure imgf000066_0002
prepared by reaction of 2-bromo-N,N-diethylacetamide with ?-toluidine and
2-methoxy-4-methyl-benzenesulfonyl chlori.de LC-MS: rt = 0.96 min, 405 (M+1, ES+). Example 55:
2-[(3-Chloro-4-methyl-benzenesulfonyl)-p-tolyl-amino]-iV iV-diethyl- acetamide:
Figure imgf000067_0001
prepared by reaction of 2-bromo-N,N-diethylacetamide withp-toluidine and 3-chloro-4-methyl-benzenesulfonyl chloride LC-MS: rt = 1.03 min, 409 (M+1, ES+).
Example 56:
N,N-Diethyl-2-[p-tolyl-(3-trifluoromethyl-benzenesulfonyl)-amino]- acetamide:
Figure imgf000067_0002
prepared by reaction of 2-bromo-NN-diethylacetamide with j»-toluidine and 3 -trifluoromethyl-benzenesulfonyl chloride LC-MS : rt = 1.03 min, 429 (M+1 , ES+).
Example 57:
2-[(6-Bromo-5-chloro-pyridine-3-suIfonyl)-p-tolyI-amino]-N,iV-diethyI- acetamide:
Figure imgf000067_0003
prepared by reaction of 2-bromo-N,N-diethylacetamide with -toluidine and 6-bromo-5-chloro-pyridine-3-sulfonyl chloride LC-MS: rt = 1.04 min, 474 (M+1, ES+). Example 58:
Λ^7Y-Diethyl-2-[((E)-2-phenyl-ethenesulfonyI)-p-tolyI-amino]-acetamide:
Figure imgf000068_0001
prepared by reaction of 2-bromo-N,N-diethylacetamide with -toluidine and (E)-2-phenyl-ethenesulfonyl chloride LC-MS: rt = 1.01 min, 387 (M+1, ES+).
Example 59:
N,N-Diethyl-2-[(5-isopropyl-pyridine-2-sulfonyl)-p-tolyl-anιino]-acetamide:
Figure imgf000068_0002
prepared by reaction of 2-bromo-NN-diethylacetamide withp-toluidine and 5-isopropyl-pyridine-2-sulfonyl chloride; in contrast to the general procedure the intermediate 5-isopropyl-pyridine-2-sulfonic acid p-tolylamide was isolated and crystallized from methanol/water 10/1 LC-MS: rt = 1.00 min, 404 (M+1, ES+).
Synthesis of sulfonylamino-acetic acid derivatives via an amide coupling
Figure imgf000068_0003
E.l Synthesis of sulfonylamino-acetic acids via tert-butyl acetates (general procedure):
A solution of the respective sulfonamide A-S(O)2NH-B (1.6 mmol) in DMSO (5.0 mL) was added to solid potassium tert-butoxide (1.6 mmol) which was dissolved by ultrasound. Tert-butyl bromoacetate (1.69 mmol, 0.25 mL) was added and the reaction mixture was stirred at RT for 12 h. Water (20 mL) and ethyl acetate (15 mL) were added, the layers were separated and the aqueous layer was extracted with ethyl acetate (15 mL). The solvents were removed in vacuo and the residue was either purified by preparative HPLC chromatography or used without further purification.
A solution of the obtained tert-butyl acetate in DCM (5.0 mL) was treated with TFA (1.6 mL) and stirred for 12 h at 35°C. Water (10 mL) and ethyl acetate (20 mL) were added, the layers were separated and the aqueous layer was extracted twice with ethyl acetate (2 x 20 mL). The solvents were removed in vacuo and the residue was purified by preparative HPLC chromatography to give the following acetic acid derivatives:
[(4-tert-Butyl-benzenesulfonyl)-p-toIyl-amino]-acetic acid:
Figure imgf000069_0001
prepared by reaction of 4-tert-butyl-N-p-tolyl-benzenesulfonamide with tert-butyl bromoacetate LC-MS: rt = 0.99 min, 362 (M+1, ES+).
[(4-tert-Butyl-benzenesulfonyl)-quinoIin-6-yl-amino]-acetic acid:
Figure imgf000069_0002
prepared by reaction of 4-tert-butyl-N-quinolin-6-yl-benzenesulfonamide with tert- butyl bromoacetate LC-MS: rt = 0.84 min, 399 (M+1, ES+).
[(4-tert-Butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-acetic acid:
Figure imgf000070_0001
prepared by reaction of 4-tert-butyl-N-(3-dimethylamino-phenyl)-benzene- sulfonamide with tert-butyl bromoacetate LC-MS: rt = 0.90 min, 391 (M+1, ES+).
[(4-tert-Butyl-benzenesulfonyI)-isoquinoIin-5-yl-amino]-acetic acid:
Figure imgf000070_0002
prepared by reaction of 4-tert-butyl-N-isoquinolin-5-yl-benzenesulfonamide with tert-butyl bromoacetate
LC-MS: rt = 0.80 min, 399 (M+1, ES+).
[(4-tert-Butyl-b enzenesulf onyl)-(2-carb amoyl-phenyl)-amino] -acetic acid :
Figure imgf000070_0003
prepared by reaction of 2-(4-tert-butyl-benzenesulfonylamino)-benzamide with tert-butyl bromoacetate
LC-MS: rt = 0.88 min, 391 (M+1, ES+).
[(4-tert-Butyl-benzenesulfonyl)-(lH-indazol-6-yl)-amino]-acetic acid:
Figure imgf000070_0004
prepared by reaction of 4-tert-butyl-N-(lH- dazol-6-yl)-benzenesulfonamide with tert-butyl bromoacetate
LC-MS: rt = 0.91 min, 388 (M+1, ES+).
[(5-Isopropyl-pyridine-2-sulfonyl)-m-tolyl-amino]-acetic acid:
Figure imgf000071_0001
prepared by reaction of 5-isopropyl-pyridine-2-sulfonic acid m-tolylamide with tert-butyl bromoacetate
LC-MS: rt = 0.94 min, 349 (M+1, ES+).
[(5-Isopropyl-pyridine-2-sulfonyl)-(2-methoxy-phenyl)-amino]-acetic acid:
Figure imgf000071_0002
prepared by reaction of 5-isopropyl-pyridine-2-sulfonic acid (2-methoxy-phenyl)- amide with tert-butyl bromoacetate LC-MS: it = 0.89 min, 365 (M+1, ES+).
[(5-Isopropyl-pyridine-2-sulfonyI)-(6-methoxy-pyridin-3-yl)-amino]-acetic acid:
Figure imgf000071_0003
prepared by reaction of 5-isopropyl-pyridine-2-sulfonic acid (6-methoxy-pyridin-
3-yl)-amide with tert-butyl bromoacetate LC-MS: rt = 0.87 min, 366 (M+1, ES+). [(5-Isopropyl-pyridine-2-suIfonyI)-p-tolyl-amino]-acetic acid:
Figure imgf000072_0001
prepared by reaction of 5-isopropyl-pyridine-2-sulfonic acid p-tolylamide with tert-butyl bromoacetate
LC-MS: rt = 0.93 min, 349 (M+1, ES+).
[(2-Methoxy-phenyl)-(toluene-2-sulfonyI)-amino]-acetic acid:
Figure imgf000072_0002
prepared by reaction of N-(2-methoxy-phenyl)-2-methyl-benzenesulfonamide with tert-butyl bromoacetate
LC-MS: rt = 0.89 min, 336 (M+1, ES+).
[(6-Methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-acetic acid:
Figure imgf000072_0003
prepared by reaction of N-(6-methoxy-pyridin-3-yl)-2-methyl-benzenesulfon- amide with tert-butyl bromoacetate LC-MS: rt = 0.85 min, 337 (M+1, ES+).
[(ToIuene-2-suIfonyl)-p-tolyI-amino] -acetic acid :
Figure imgf000072_0004
prepared by reaction of 2-methyl-N-p-tolyl-benzenesulfonamide with tert-butyl bromoacetate
LC-MS: rt = 0.91 min, 320 (M+1, ES+). [(5-Methyl-pyridine-2-suIfonyl)-p-tolyl-amino]-acetic acid:
Figure imgf000073_0001
prepared by reaction of 5-methyl-pyridine-2-sulfonic acid p-tolylamide with tert- butyl bromoacetate LC-MS: rt = 0.85 min, 321 (M+1, ES+).
{p-Tolyl-[2-(2,2,2-trifluoro-acetyl)-l,2,3,4-tetrahydro-isoquinoline-7-sulfonyl]- amino}-acetic acid:
prepared by reaction of 2-(2,2,2-trifluoro-acetyl)- 1,2,3 ,4-tetrahydro-isoquinoline-
7-sulfonic acid p-tolylamide with tert-butyl bromoacetate LC-MS: rt = 0.95 min, 457 (M+1, ES+).
Synthesis of sulfonylamino-acetic acids via methyl acetates (general procedure):
A solution of the respective sulfonamide A-S(O)2NH-B (10.0 mmol) in DMSO (10.0 mL) was treated with solid potassium tert-butoxide (10.0 mmol). Methyl bromo- acetate (11.0 mmol, 1.0 mL) was added at RT and the reaction mixture was heated to
60°C for 4 h. Water (40 mL) and ethyl acetate (40 L) were added, the layers were separated and the aqueous layer was extracted twice with ethyl acetate (2 x 30 mL). The combined organic layers were washed with water (4 x 50 mL) and brine (50 mL) and the solvents were removed in vacuo. A solution of NaOH (100 mmol) in water (50 mL) was added to a solution of the crude methyl acetate in methanol (500 mL) and stirred either at 60°C for 1 h or at RT for 16 h. Hydrochloric acid (2.0 mol/L) was added to pH 7 and methanol was removed in vacuo. The aqueous layer was exfracted with ethyl acetate (4 x 100 mL) and the combined organic layers were washed with brine (50 mL). The solvents were removed in vacuo and the residue was purified by preparative HPLC chromatography to give the following acetic acid derivatives:
[(4-tert-Butyl-benzenesulfonyl)-(6-methyl-pyridin-3-yl)-amino]-acetic acid:
prepared by reaction of 4-tert-butyl-N-(6-methyl-pyridin-3-yl)-benzenesulfon- amide with methyl bromoacetate LC-MS: rt = 0.80 min, 363 (M+1, ES+).
[(6-Amino-pyridin-3-yl)-(4-tert-butyl-benzenesulfonyl)-amino]-acetic acid:
Figure imgf000074_0002
prepared by reaction of N-[5-(4-tert-butyl-benzenesulfonylamino)-pyridin-2-yl]- acetamide with methyl bromoacetate LC-MS: rt = 0.74 min, 364 (M+1, ES+).
[(3-Methyl-pyridine-2-sulfonyl)-p-tolyl-amino]-acetic acid:
preparedα by reaction of 3-methyl-pyridine-2-sulfonic acid p-tolylamide with methyl bromoacetate LC-MS: rt = 0.85 min, 321 (M+1, ES+).
[(3-Methyl-pyridine-2-sulfonyl)-m-tolyl-amino]-acetic acid:
Figure imgf000074_0003
prepared by reaction of 3-methyl-pyridine-2-sulfonic acid m-tolylamide with methyl bromoacetate
LC-MS: rt = 0.85 min, 321 (M+1, ES+).
[(2-Methoxy-phenyl)-(3-methyl-pyridine-2-sulfonyl)-amino]-acetic acid:
Figure imgf000075_0001
prepared by reaction of 3-methyl-pyridine-2-sulfonic acid (2-methoxy-phenyl)- amide with methyl bromoacetate LC-MS: rt = 0.80 min, 337 (M+1, ES+).
[(6-Methoxy-pyridin-3-yl)-(3-methyl-pyridine-2-sulfonyl)-amino]-acetic acid:
Figure imgf000075_0002
prepared by reaction of 3-methyl-pyridine-2-sulfonic acid (6-methoxy-pyridin-3- yl)-amide with methyl bromoacetate LC-MS: rt = 0.80 min, 338 (M+1, ES+).
Synthesis of sulfonylamino-acetic acids (TBTU coupling, general procedure):
A solution of the respective acetic acid derivative (0.10 mmol) in DMF (1.0 mL) was treated with the respective amine (0.10 mmol). DIPEA (0.30 mmol) and TBTU (0.13 mmol) were added. The reaction mixture was stirred at RT for 16 h and purified by preparative HPLC chromatography to give the following sulfonamides: Example 60:
N-Benzyl-2-[(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-iV-(2-hydroxy- ethyl)-acetamide :
Figure imgf000076_0001
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with 2-benzylamino-ethanol LC-MS: rt = 1.04 min, 495 (M+1, ES+).
Example 61 :
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-iV-(2-hydroxy-ethyl)-N- isopropyl-acetamide :
Figure imgf000076_0002
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with 2-isopropylamino-ethanol LC-MS : rt = 1.00 min, 447 (M+1 , ES+).
Example 62:
2-[(4-tert-Butyl-benzenesuIfonyl)-p-tolyI-amino]-N,N-bis-(2-hydroxy-ethyl)- acetamide:
Figure imgf000076_0003
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with 2-(2-hydroxy-ethylamino)-ethanol
LC-MS: rt = 0.90 min, 449 (M+1, ES+). Example 63:
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N-(2-cyano-ethyl)-N-ethyl- acetamide:
Figure imgf000077_0001
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with 3-ethylamino-propionitrile LC-MS: rt = 1.04 min, 442 (M+1, ES+).
Example 64: N-Benzyl-2-[(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-iV-(4-hydroxy- butyl)-acetamide:
Figure imgf000077_0002
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino] -acetic acid with 4-benzylamino-butan-l-ol LC-MS: rt = 1.05 min, 523 (M+1, ES+).
Example 65:
N-Benzyl-2-[(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-iV-(2-cyano-ethyl)- acetamide:
Figure imgf000077_0003
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with 3-benzylamino-propionitrile LC-MS: rt = 1.09 min, 504 (M+1, ES+).
Example 66:
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-iV-ethyl-N-pyridin-2- ylmethyl-acetamide :
Figure imgf000078_0001
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with ethyl-pyridin-2-ylmethyl-amine
LC-MS: rt = 0.92 min, 480 (M+1, ES+).
Example 67:
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-iV-ethyl-iV-pyridin-3- ylmethyl-acetamide:
Figure imgf000078_0002
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with ethyl-pyridin-3-ylmethyl-amine LC-MS: rt = 0.88 min, 480 (M+1, ES+). Example 68:
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-/y-(4-cyano-benzyl)-iV-ethyI- acetamide:
Figure imgf000079_0001
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with 4-ethylaminomethyl-benzonitrile LC-MS: rt = 1.10 min, 504 (M+1, ES+).
Example 69:
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyI-amino]-N-ethyl-N-(l-methyl-lH- pyrrol-2-ylmethyl)-acetamide:
Figure imgf000079_0002
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with ethyl-(l-methyl-lH-pyrrol-2-ylmethyl)-amine LC-MS: rt = 1.11 min, 482 (M+1, ES+).
Example 70:
2-[(4-tert-Buryl-benzenesulfonyl)-p-tolyl-amino]-N-ethyl-iV'-(lH-imidazol-2- ylmethyl)-acetamide:
Figure imgf000079_0003
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with ethyl-(lH-imidazol-2-ylmethyl)-amine
LC-MS: rt = 0.85 min, 469 (M+1, ES+). Example 71:
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-iV-ethyl-iV"-(6-methyl-pyridin- 2-ylmethyl)-acetamide:
Figure imgf000080_0001
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino] -acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine LC-MS: rt = 0.90 min, 494 (M+1, ES+).
Example 72: 2-[(4-tert-ButyI-benzenesuIfonyl)-p-tolyl-amino]-iV-ethyl-iV-(3H-imidazol-4- ylmethyl)-acetamide:
Figure imgf000080_0002
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with ethyl-(3H-imidazol-4-ylmethyl)-amine LC-MS: rt = 0.85 min, 469 (M+1, ES+).
Example 73:
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-iV-ethyl-/V-thiazol-2- ylmethyl-acetamide:
Figure imgf000080_0003
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with ethyl-thiazol-2-ylmethyl-amine LC-MS: rt = 1.06 min, 486 (M+1, ES+). Example 74:
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N-ethyl-iV-(lH-indol-3- ylmethyl)-acetamide:
Figure imgf000081_0001
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with ethyl-( 1 H-indol-3 -ylmethyl)-amine LC-MS: rt = 1.09 min, 518 (M+1, ES+).
Example 75:
2-[(4-tert-Butyl-benzenesulfonyl)-quinolin-6-yl-amino]-N,N-diethyl- acetamide:
Figure imgf000081_0002
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-quinolin-6-yl-amino]- acetic acid with diethylamine LC-MS: rt = 0.92 min, 454 (M+1 , ES+).
Example 76:
N-Benzyl-2-[(4-tert-butyl-benzenesulfonyl)-quinolin-6-yl-amino]-iV-(2- hydroxy-ethyl)-acetamide :
Figure imgf000081_0003
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-quinolin-6-yl-amino]- acetic acid with 2-benzylamino-ethanol LC-MS: rt = 0.90 min, 532 (M+1, ES+).
Example 77:
2-[(4-tert-Butyl-benzenesulfonyl)-quinolin-6-yl-amino]-N-ethyl-N-pyridin-3- ylmethyl-acetamide:
Figure imgf000082_0001
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-quinolin-6-yl-amino]- acetic acid with ethyl-pyridin-3-ylmethyl-amine
LC-MS: rt = 0.78 min, 517 (M+1, ES+).
Example 78:
2-[(4-tert-Butyl-benzenesulfonyl)-quinolin-6-yl-amino]-N-ethyl-N-thiazol-2- ylmethyl-acetamide:
Figure imgf000082_0002
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-quinolin-6-yl-amino]- acetic acid with ethyl-thiazol-2-ylmethyl-amine LC-MS: rt = 0.91 min, 523 (M+1, ES+). Example 79:
2-[(4-tert-Butyl-benzenesulfonyl)-quinolin-6-yl-amino]-N-ethyl-N-(2-hydroxy- ethyl)-acetamide:
Figure imgf000083_0001
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-quinolin-6-yl-amino]- acetic acid with 2-ethylamino-ethanol LC-MS: rt = 0.81 min, 470 (M+1, ES+).
Example 80: iV-Benzyl-2-[(4-tert-butyl-benzenesulfonyl)-quinolin-6-yl-amino]-iV-ethyl- acet amide:
Figure imgf000083_0002
prepared by reaction of [(4-tert-butyl-berιzenesulfonyl)-quinolin-6-yl-anιino]- acetic acid with benzyl-ethyl-amine LC-MS: rt = 1.00 min, 516 (M+1, ES+).
Example 81:
2-[(4-tert-Butyl-benzenesulfonyl)-quinolin-6-yl-amino]-iV-ethyl-N-(6-methyI- pyridin-2-ylmethyl)-acetamide:
Figure imgf000083_0003
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-quinolin-6-yl-amino]- acetic acid with ethyl-(6-methyl-pyridin-2-ylrnethyl)-amine LC-MS: rt = 0.79 min, 531 (M+1, ES+). Example 82:
2-[(4-tert-Butyl-benzenesulfonyl)-(3-dimethylamino-phenyI)-amino]-N,N- diethyl-acetamide:
Figure imgf000084_0001
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)- amino] -acetic acid with diethylamine LC-MS: rt = 0.96 min, 446 (M+1, ES+).
Example 83:
2-[(4-tert-Butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-JV-ethyl- N-pyridin-2-ylmethyl-acetamide:
Figure imgf000084_0002
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)- amino] -acetic acid with ethyl-pyridin-2-ylmethyl-amine
LC-MS: rt = 0.86 min, 509 (M+1, ES+).
Example 84:
N-Benzyl-2-[(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)- amino]-N-(2-hydroxy-ethyl)-acetamide:
Figure imgf000085_0001
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-ρhenyl)- amino]-acetic acid with 2-benzylamino-ethanol LC-MS: rt = 0.95 min, 524 (M+1, ES+).
Example 85:
2-[(4-tert-Butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-iV-ethyl-
N-pyridin-3-ylmethyl-acetamide:
Figure imgf000085_0002
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)- amino]-acetic acid with ethyl-pyridin-3-ylmethyl-amine LC-MS: rt = 0.82 min, 509 (M+1, ES+).
Example 86:
2-[(4-tert-Butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-N-ethyl- iV-thiazol-2-ylmethyl-acetamide :
Figure imgf000085_0003
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)- amino]-acetic acid with ethyl-thiazol-2-ylmethyl-amine LC-MS: rt = 0.96 min, 515 (M+1, ES+). Example 87:
2-[(4-tert-Butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-iV-ethyl- N-(6-methyl-pyridin-2-ylmethyl)-acetamide:
Figure imgf000086_0001
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)- amino]-acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine LC-MS: rt = 0.85 min, 523 (M+1, ES+).
Example 88: 2-[(4-tert-Butyl-benzenesulfonyl)-(3-dimethyIamino-phenyl)-amino]-iV-ethyl-
N-(2-hydroxy-ethyl)-acetamide:
Figure imgf000086_0002
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)- amino] -acetic acid with 2-ethylamino-ethanol LC-MS: rt = 0.85 min, 462 (M+1, ES+).
Example 89:
2-[(4-tert-Butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-iV-ethyl- N-(lH-imidazol-2-ylmethyl)-acetamide:
Figure imgf000086_0003
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)- amino]-acetic acid with ethyl-(lH-imidazol-2-ylmethyl)-amine LC-MS: rt = 0.80 min, 498 (M+1, ES+). Example 90:
iV-Benzyl-2-[(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)- amino]-N-ethyl-acetamide:
Figure imgf000087_0001
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-ρhenyl)- amino]-acetic acid with benzyl-ethyl-amine LC-MS: rt = 1.05 min, 508 (M+1, ES+).
Example 91: 2-[(4-tert-Butyl-benzenesulfonyl)-isoquinolin-5-yl-amino]-N,N-diethyl- acetamide:
Figure imgf000087_0002
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-isoquinolin-5-yl-amino]- acetic acid with diethylamine LC-MS: rt = 0.86 min, 454 (M+1, ES+).
Example 92:
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]~N-(4-dimethylamino-benzyl)- iV-ethyl-acetamide:
Figure imgf000087_0003
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with (4-etfrylaminomethyl-phenyl)-dimethyl-amine
LC-MS: rt = 0.93 min, 522 (M+1, ES+). Example 93:
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-7Vr-ethyl-iV-(3-hydroxy- benzyl)-acetamide:
Figure imgf000088_0001
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with 3-ethylaminomethyl-phenol LC-MS: rt = 1.05 min, 495 (M+1, ES+).
Example 94:
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-7Y-ethyl-iV-quinolin-3- ylmethyl-acetamide :
Figure imgf000088_0002
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with ethyl-quinolin-3 -ylmethyl-amine LC-MS: rt = 0.96 min, 530 (M+1, ES+).
Example 95:
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-iV-ethyl-iV-quinolin-4- ylmethyl-acetamide:
Figure imgf000088_0003
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with ethyl-quinolin-4-ylmethyl-amine
LC-MS: rt = 0.93 min, 530 (M+1, ES+).
Example 96:
2-[(4-tert-Butyl-benzenesulfonyl)-diethylcarbamoylmethyl-amino]- benzamide:
Figure imgf000089_0001
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(2-carbamoyl-phenyl)- amino] -acetic acid with diethylamine
LC-MS: rt = 0.96 min, 446 (M+1, ES+).
Example 97:
2-{(4-tert-Butyl-benzenesulfonyl)-[(ethyl-thiazol-2-ylmethyl-carbamoyl)- methyl]-amino}-benzamide:
Figure imgf000089_0002
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(2-carbamoyl-phenyl)- amino]-acetic acid with ethyl-thiazol-2-ylmethyl-amine LC-MS: rt = 0.94 min, 515 (M+1, ES+). Example 98:
2-((4-tert-Butyl-benzenesulfonyl)-{[ethyl-(6-methyl-pyridin-2-ylmethyl)- carbamoyl]-methyl}-amino)-benzamide:
Figure imgf000090_0001
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(2-carbamoyl-phenyl)- amino] -acetic acid with ethyl-(6-methyl-ρyridin-2-ylmethyl)-amine LC-MS: rt = 0.80 min, 523 (M+1, ES+).
Example 99: 2-[[(Benzyl-ethyl-carbamoyl)-methyl]-(4-tert-butyl-benzenesuIfonyl)-amino]- benzamide:
Figure imgf000090_0002
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(2-carbamoyl-phenyl)- amino] -acetic acid with benzyl-ethyl-amine LC-MS: rt = 1.02 min, 508 (M+1, ES+).
Example 100:
2-[(4-tert-Butyl-benzenesulfonyl)-(lH-indazol-6-yl)-amino]-iV,N-diethyl- acetamide:
Figure imgf000090_0003
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(lH-indazol-6-yl)-amino]- acetic acid with diethylamine
LC-MS: rt = 0.98 min, 443 (M+1, ES+). Example 101: iV-Benzyl-2-[(4-tert-butyl-benzenesulfonyl)-(lH-indazol-6-yl)-amino]-iV-(2- hydroxy-ethyl)-acetamide:
Figure imgf000091_0001
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(lH-indazol-6-yl)-amino]- acetic acid with 2-benzylamino-ethanol LC-MS: rt = 0.97 min, 521 (M+1, ES+).
Example 102: 2-[(4-tert-Butyl-benzenesulfonyl)-(lH-indazol-6-yl)-amino]-N-ethyl-N-thiazol-
2-ylmethyl-acetamide:
Figure imgf000091_0002
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(lH-indazol-6-yl)-amino]- acetic acid with ethyl-thiazol-2-ylmethyl-amine LC-MS: rt = 0.97 min, 512 (M+1, ES+).
Example 103:
2-[(4-tert-ButyI-benzenesulfonyl)-(lH-indazoI-6-yI)-amino]-N-ethyl-N-(6- methyl-pyridin-2-ylmethyl)-acetamide:
Figure imgf000091_0003
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(lH-indazol-6-yl)-amino]- acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-arrιine LC-MS: rt = 0.75 min, 520 (M+1, ES+). Example 104:
2-[(4-tert-Butyl-benzenesulfonyl)-(lH-indazol-6-yl)-amino]-iV-ethyl-N-(2- hydroxy-ethyl)-acetamide:
Figure imgf000092_0001
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(lH-indazol-6-yl)-amino]- acetic acid with 2-ethylamino-ethanol LC-MS: rt = 0.82 min, 459 (M+1, ES+).
Example 105: 2-[(4-tert-Butyl-benzenesulfonyl)-(lH-indazol-6-yl)-amino]-N-ethyl-N- py ridin-2-ylmethyl-acetamide :
Figure imgf000092_0002
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(lH-indazol-6-yl)-amino]- acetic acid with ethyl-pyridin-2-ylmethyl-amine LC-MS : rt = 0.78 min, 506 (M+1 , ES+).
Example 106:
2-[(4-tert-Butyl-benzenesulfonyl)-(lH-indazol-6-yl)-amino]-N-ethyl-N- py ridin-3-ylmethy I-acetamide :
Figure imgf000092_0003
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(lH-indazol-6-yl)-amino]- acetic acid with ethyl-pyridin-3-ylmethyl-amine LC-MS: rt = 0.81 min, 506 (M+1, ES+).
Example 107:
2-[(4-tert-Butyl-benzenesulfonyl)-p-toIyl-amino]-/y-(2-hydroxy-ethyl)-N- pyridin-2-ylmethyl-acetamide:
Figure imgf000093_0001
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with 2-[(pyridin-2-ylmethyl)-amino]-ethanol
LC-MS: rt = 0.86 min, 496 (M+1, ES+).
Example 108:
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N-(3-hydroxy-propyl)-N-
Figure imgf000093_0002
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with 3 - [(pyridin-2-ylmethyl)-amino]-propan- 1 -ol LC-MS: rt = 0.87 min, 510 (M+1, ES+).
Example 109:
2-[(4-tert-Buryl-benzenesulfonyl)-p-tolyl-amino]-iV-(3-hydroxy-propyl)-iV- quinolin-2-ylmethyl-acetamide:
Figure imgf000094_0001
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with 3 -[(quinolin-2-ylmethyl)-amino] -propan- 1 -ol LC-MS: rt = 0.95 min, 560 (M+1, ES+).
Example 110: 2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N-ethyl-iV-quinolin-2- ylmethyl-acetamide:
Figure imgf000094_0002
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with ethyl-quinolin-2-ylmethyl-amine LC-MS: rt = 1.01 min, 530 (M+1, ES+).
Example 111:
2-[(4-tert-Butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-iV-(2- hydroxy-ethyl)-N-pyridin-2-ylmethyl-acetamide:
Figure imgf000094_0003
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)- amino]-acetic acid with 2-[(pyridin-2-ylmethyl)-amino]-ethanol LC-MS: rt = 0.80 min, 525 (M+1, ES+).
Example 112:
2-[(4-tert-Butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-N-(3- hydroxy-propyl)-N-pyridin-2-ylmethyl-acetamide:
Figure imgf000095_0001
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-ρhenyl)- amino]-acetic acid with 3-[(pyridin-2-ylmethyl)-amino]-propan-l-ol LC-MS: rt = 0.80 min, 539 (M+1, ES+).
Example 113:
2-[(4-tert-Butyl-benzenesuIfonyI)-(3-dimethyIamino-phenyl)-amino]-N-(2- hydroxy-ethyl)-N-quinolin-2-ylmethyl-acetamide:
Figure imgf000095_0002
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)- amino]-acetic acid with 2-[(quinolin-2-ylmethyl)-amino]-ethanol LC-MS: rt = 0.89 min, 575 (M+1, ES+). Example 114:
2-[(4-tert-Butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-N-(3- hydroxy-propyl)-iV-quinolin-2-ylmethyl-acetamide:
Figure imgf000096_0001
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)- a ino] -acetic acid with 3-[(quinolin-2-ylmethyl)-amino]-propan-l-ol LC-MS: rt = 0.89 min, 589 (M+1, ES+).
Example 115: 2-[(4-tert-Butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-iV-ethyl-
N-quinolin-2-ylmethyl-acetamide:
Figure imgf000096_0002
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)- a ino] -acetic acid with ethyl-quinolin-2-ylmethyl-amine LC-MS: rt = 0.96 min, 559 (M+1, ES+).
Example 116:
2-[(4-tert-Butyl-benzenesulfonyl)-quinolin-6-yl-amino]-N-(2-hydroxy-ethyl)- /Y-pyridin-2-ylmethyl-acetamide:
Figure imgf000096_0003
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-quinolin-6-yl-amino]- acetic acid with 2-[(pyridin-2-ylmethyl)-amino]-ethanol LC-MS: rt = 0.75 min, 533 (M+1, ES+).
Example 117:
2-[(4-tert-Butyl-benzenesulfonyl)-quinolin-6-yl-amino]-iV-(3-hydroxy-propyl)- N-pyridin-2-ylmethyl-acetamide:
Figure imgf000097_0001
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-quinolin-6-yl-amino]- acetic acid with 3-[(pyridin-2-ylmethyl)-amino]-propan- 1 -ol
LC-MS: rt = 0.76 min, 547 (M+1, ES+).
Example 118:
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-iV-ethyl-iV-(6-ethylamino- pyridin-2-ylmethyl)-acetamide:
Figure imgf000097_0002
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino] -acetic acid with ethyl-(6-ethylaminomethyl-pyridin-2-yl)-amine
LC-MS: rt = 0.94 min, 523 (M+1, ES+). Example 119:
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N-ethyl-iV-(6-ethylamino- methyl-pyridin-2-ylmethyl)-acetamide:
Figure imgf000098_0001
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with ethyl-(6-ethylaminomethyl-pyridin-2-ylmethyl)-amine
LC-MS: rt = 0.91 min, 537 (M+1, ES+).
Example 120: 2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N-(6-dimethylamino-pyridin-
2-yImethyl)-N-ethyI-acetamide :
Figure imgf000098_0002
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino] -acetic acid with (6-ethylaminomethyl-pyridin-2-yl)-dimethyl-amine LC-MS: rt = 0.92 min, 523 (M+1, ES+).
Example 121:
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-iV-ethyl-iV-[6-(ethyl-methyl- amino)-pyridin-2-ylmethyl]-acetamide:
Figure imgf000098_0003
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with ethyl-(6-ethylaminomethyl-pyridin-2-yl)-methyl-amine
LC-MS: rt = 0.94 min, 537 (M+1, ES+).
Example 122:
2-[(4-tert-Butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-iV-(6- dimethylamino-pyridin-2-ylmethyl)-N-ethyl-acetamide:
Figure imgf000099_0001
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-ρhenyl)- amino] -acetic acid with (6-ethylaminomethyl-pyridin-2-yl)-dimethyl-amine
LC-MS: rt = 0.89 min, 552 (M+1, ES+).
Example 123:
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N-cycIopropyI-N-(3- methoxy-benzyl)-acetamide:
Figure imgf000099_0002
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with cyclopropyl-(3-methoxy-benzyl)-amine
LC-MS: rt = 1.14 min, 521 (M+1, ES+). Example 124:
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-iV-cyclopropyl-N-(2,5- dichloro-benzyl)-acetamide:
Figure imgf000100_0001
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with cyclopropyl-(2,5-dichloro-berιzyl)-amine LC-MS: rt = 1.16 min, 559 (M+1, ES+).
Example 125: 2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N-cyclopropyl-N-(3,4- dimethoxy~benzyl)-acetamide:
Figure imgf000100_0002
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with cyclopropyl-(3,4-dimethoxy-benzyl)-amine LC-MS: rt = 1.12 min, 551 (M+1, ES+).
Example 126:
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-iV-cyclopropyl-iV-(3-methyl- benzyl)-acetamide:
Figure imgf000100_0003
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with cyclopropyl-(3-methyl-benzyl)-amine
LC-MS: rt = 1.12 min, 505 (M+1, ES+). Example 127:
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-iV-cyclopropyl-N-(3,5- dimethoxy-benzyl)-acetamide:
Figure imgf000101_0001
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with cyclopropyl-(3,5-dimethoxy-benzyl)-amine LC-MS: rt = 1.15 min, 551 (M+1, ES+).
Example 128: 2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N-methyl-N-pyridin-3- ylmethyl-acetamide:
Figure imgf000101_0002
prepare by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with methyl-pyridin-3 -ylmethyl-amine LC-MS: rt = 0.86 min, 466 (M+1, ES+).
Example 129:
2-[(4-tert-Butyl-benzenesulfonyl)-quinolin-6-yl-amino]-iV-cyclopropyl-7y-(3- methoxy-benzyI)-acetamide:
Figure imgf000101_0003
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-quinolin-6-yl-anιino]- acetic acid with cyclopropyl-(3-methoxy-benzyl)-amine LC-MS: rt = 1.02 min, 558 (M+1, ES+).
Example 130:
2-[(4-tert-Butyl-benzenesuIfonyI)-quinolin-6-yl-amino]-Λr-cycIopropyI-N-(3,4- dimethoxy~benzyl)-acetamide:
Figure imgf000102_0001
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-quinolin-6-yl-amino]- acetic acid with cyclopropyl-(3,4-dimethoxy-benzyl)-amine LC-MS: rt = 0.99 min, 588 (M+1, ES+).
Example 131:
2-[(4-tert-Butyl-benzenesulfonyl)-quinolin-6-yl-amino]-iV-cyclopropyl-N-(3- methyl-benzyl)-acetamide:
Figure imgf000102_0002
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-quinolin-6-yl-amino]- acetic acid with cyclopropyl-(3-methyl-benzyl)-amine LC-MS: rt = 1.05 min, 542 (M+1, ES+).
Example 132:
2-[(4-tert-Butyl-benzenesulfonyl)-quinolin-6-yl-amino]-N-cycIopropyl-iV-(3,5- dimethoxy-benzyl)-acetamide:
Figure imgf000102_0003
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-quinolin-6-yl-amino]- acetic acid with cyclopropyl-(3,5-dimethoxy-benzyl)-amine LC-MS: rt = 1.02 min, 588 (M+1, ES+).
Example 133:
2-((4-tert-Butyl-benzenesulfonyl)-{[cyclopropyl-(3-methoxy-benzyl)- carbamoyl]-methyl}-amino)-benzamide:
Figure imgf000103_0001
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(2-carbamoyl-phenyl)- amino]-acetic acid with cyclopropyl-(3-methoxy-benzyl)-amine
LC-MS: rt = 1.05 min, 550 (M+1, ES+).
Example 134:
2-((4-tert-Butyl-benzenesulfonyl)-{[cyclopropyl-(3-methyl-benzyl)- carbamoyl]-methyl}-amino)-benzamide:
Figure imgf000103_0002
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(2-carbamoyl-phenyl)- amino]-acetic acid with cyclopropyl-(3-methyl-benzyl)-amine LC-MS: rt = 1.07 min, 534 (M+1, ES+). Example 135:
2-[(4-tert-Butyl-benzenesuIfonyl)-(3-dimethylamino-phenyl)-amino]~N- cyclopropyl-N-(3-methoxy-benzyl)-acetamide:
Figure imgf000104_0001
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)- amino]-acetic acid with cyclopropyl-(3-methoxy-benzyl)-amine LC-MS: rt = 1.08 min, 550 (M+1, ES+).
Example 136: 2-[(4-tert-Butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-7Y- cyclopropyl-N~(3,4-dimethoxy-benzyl)-acetamide:
Figure imgf000104_0002
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)- amino] -acetic acid with cyclopropyl-(3,4-dimethoxy-benzyl)-amine LC-MS: rt = 1.05 min, 580 (M+1, ES+).
Example 137:
2-[(4-tert-Butyl-benzenesuIfonyl)-(3-dimethylamino-phenyl)-amino]-iV- cycϊopropyl-N-(3-methyl-benzyl)-acetamide:
Figure imgf000104_0003
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)- amino]-acetic acid with cyclopropyl-(3-methyl-benzyl)-amine LC-MS: rt = 1.10 min, 534 (M+1, ES+). Example 138:
2-[(4-tert-Butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-N- cyclopropyl-iV-(3,5-dimethoxy-benzyl)-acetamide:
Figure imgf000105_0001
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)- amino]-acetic acid with cyclopropyl-(3,5-dimethoxy-berιzyl)-amine LC-MS: rt = 1.08 min, 580 (M+1, ES+).
Example 139: 2-[(4-tert-Butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-iV- methyl-N-pyridin-3-ylmethyl-acetamide:
Figure imgf000105_0002
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)- amino] -acetic acid with methyl-ρyridin-3-ylmethyl-amine LC-MS: rt = 0.81 min, 495 (M+1, ES+).
Example 140:
7Y-Ethyl-2-[(5-isopropyl-pyridine-2-sulfonyl)-p-tolyl-amino]-iV-pyridin-2- ylmethyl-acetamide:
Figure imgf000105_0003
prepared by reaction of [(5-isopropyl-pyridine-2-sulfonyl)-p-tolyl-amino]-acetic acid with ethyl-pyridin-2-ylmethyl-amine LC-MS: rt = 0.84 min, 467 (M+1, ES+).
Example 141:
iV-Ethyl-2-[(5-isopropyl-pyridine-2-sulfonyl)-p-tolyl-amino]-iV-(6-methyl- pyridin-2-ylmethyl)-acetamide:
Figure imgf000106_0001
prepared by reaction of [(5-isopropyl-ρyridine-2-sulfonyl)-p-tolyl-amino]-acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-arnine
LC-MS: rt = 0.83 min, 481 (M+1, ES+).
Example 142:
iY-(2-Hydroxy-ethyl)-2-[(5-isopropyl-pyridine-2-sulfonyl)-p-tolyl-amino]-iV- pyridin-2-ylmethyl-acetamide:
Figure imgf000106_0002
prepared by reaction of [(5-isopropyl-pyridine-2-sulfonyl)-ρ-tolyl-amino]-acetic acid with 2-[(pridin-2-ylmethyl)-amino]-ethanol LC-MS: rt = 0.79 min, 483 (M+1, ES+). Example 143:
N-Ethyl-2-[(5-isopropyl-pyridine-2-suIfonyl)-p-toIyl-amino]-iV-thiazol-2- ylmethyl-acetamide:
Figure imgf000107_0001
prepared by reaction of [(5-isopropyl-pyridine-2-sulfonyl)-p-tolyl-amino]-acetic acid with ethyl-thiazol-2-ylmethyl-amine LC-MS: rt = 0.99 min, 473 (M+1, ES+).
Example 144: N-Ethyl-2-[(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-iV-thiazol-2- ylmethyl-acetamide:
Figure imgf000107_0002
prepared by reaction of [(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-acetic acid with ethyl-thiazol-2-ylmethyl-amine LC-MS: rt = 0.96 min, 460 (M+1, ES+).
Example 145:
N-Ethyl-2-[(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-iV-(6-methyl- pyridin-2-ylmethyl)-acetamide:
Figure imgf000107_0003
prepared by reaction of [(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine LC-MS: rt = 0.80 min, 468 (M+1, ES+).
Example 146:
N-Benzyl-N-(2-hydroxy-ethyl)-2-[(2-methoxy-phenyl)-(toluene-2-sulfonyl)- amino]-acetamide:
Figure imgf000108_0001
prepared by reaction of [(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-acetic acid with 2-benzylamino-ethanol
LC-MS: rt = 0.96 min, 469 (M+1, ES+).
Example 147:
N-Ethyl-2-[(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]- V-pyridin-3- ylmethyl-acetamide:
Figure imgf000108_0002
prepared by reaction of [(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-acetic acid with ethyl-ρyridin-3-ylmethyl-amine LC-MS: rt = 0.78 min, 454 (M+1, ES+). Example 148:
iV-Ethyl-2-[(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-N-pyridin-2- ylmethyl-acetamide:
Figure imgf000109_0001
prepared by reaction of [(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-acetic acid with ethyl-pyridin-2-ylmethyl-amine LC-MS: rt = 0.82 min, 454 (M+1, ES+).
Example 149:
iV-(2-Cyano-ethyl)-N-ethyl-2-[(2-methoxy-phenyl)-(toluene-2-sulfonyl)- amino] -acetamide:
Figure imgf000109_0002
prepared by reaction of [(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-acetic acid with 3-ethylamino-propionitrile LC-MS: rt = 0.94 min, 416 (M+1, ES+).
Example 150:
N-(4-Cyano-benzyl)-iV-ethyl-2-[(2-methoxy-phenyl)-(toluene-2-sulfonyl)- aminoj-acetamide:
Figure imgf000109_0003
prepared by reaction of [(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino] -acetic acid with 4-ethylaminomethyl-benzonitrile LC-MS: rt = 1.03 min, 478 (M+1, ES+).
Example 151:
N-Ethyl-2-[(2-methoxy-phenyl)-(toIuene-2-sulfonyl)-amino]-N-(l-methyl-lH- pyrrol-2-ylmethyl)-acetamide:
Figure imgf000110_0001
prepared by reaction of [(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-acetic acid with ethyl-(l-methyl-lH-pyrrol-2-ylmethyl)-amine LC-MS: rt = 1.03 min, 456 (M+1, ES+).
Example 152:
N-Benzyl-Y-cyanomethyI-2-[(2-methoxy-phenyl)-(toluene-2-suIfonyl)-amino]- acetamide:
Figure imgf000110_0002
prepared by reaction of [(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino] -acetic acid with benzylamino-acetonitrile LC-MS: rt = 1.02 min, 464 (M+1, ES+). Example 153:
N-Benzyl-7V-(2-cyano-ethyl)-2-[(2-methoxy-phenyl)-(toluene-2-sulfonyl)- amino]-acetamide:
Figure imgf000111_0001
prepared by reaction of [(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-acetic acid with 3-benzylamino-propionitrile LC-MS: rt = 1.02 min, 478 (M+1, ES+).
Example 154: N-Ethyl-N-(4-hydroxy-benzyl)-2-[(2-methoxy-phenyI)-(toluene-2-sulfonyl)- amino]-acetamide:
Figure imgf000111_0002
prepared by reaction of [(2-methoxy-ρhenyl)-(toluene-2-sulfonyl)-amino]-acetic acid with 4-ethylaminomethyl-phenol LC-MS: rt = 0.85 min, 469 (M+1, ES+).
Example 155:
N-Ethyl-2-[(2-methoxy-phenyl)-(toluene-2-suIfonyI)-amino]-N-quinolin-3- ylmethyl-acetamide:
Figure imgf000111_0003
Ill
prepared by reaction of [(2-methoxy-ρhenyl)-(toluene-2-sulfonyl)-amino]-acetic acid with ethyl-quinolin-3-ylmethyl-amine LC-MS: rt = 0.87 min, 504 (M+1, ES+).
Example 156:
N-Ethyl-2-[(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-N-quinolin-4- ylmethyl-acetamide :
Figure imgf000112_0001
prepared by reaction of [(2-methoxy-ρhenyl)-(toluene-2-sulfonyl)-amino]-acetic acid with ethyl-quinolin-4-ylmethyl-amine
LC-MS: rt = 0.84 min, 504 (M+1, ES+).
Example 157:
N-(4-Dimethylamino-benzyl)-N-ethyl-2-[(2-methoxy-phenyl)-(toluene-2- sulfonyl)-amino]-acetamide:
Figure imgf000112_0002
prepared by reaction of [(2-methoxy-ρhenyl)-(toluene-2-sulfonyl)-amino]-acetic acid with (4-ethylaminomethyl-phenyl)-dimethyl-amine LC-MS: rt = 0.83 min, 496 (M+1, ES+). Example 158:
N-Ethyl-N-(3-hydroxy-benzyl)-2-[(2-methoxy-phenyl)-(toluene-2-sulfonyl)- aminoj-acetamide:
Figure imgf000113_0001
prepared by reaction of [(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-acetic acid with 3-ethylaminomethyl-phenol LC-MS: rt = 0.97 min, 469 (M+1, ES+).
Example 159: iV-EthyI-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-iV-thiazol-2- ylmethyl-acetamide:
prepared by reaction of [(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]- acetic acid with ethyl-thiazol-2-ylmethyl-amine LC-MS: rt = 0.93 min, 461 (M+1, ES+).
Example 160: iV-Ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-N-(6-methyl- pyridin-2-ylmethyl)-acetamide:
Figure imgf000113_0003
prepared by reaction of [(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]- acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine LC-MS: rt = 0.77 min, 469 (M+1, ES+). Example 161: iV-Benzyl-N-(2-hydroxy-ethyl)-2-[(6-methoxy-pyridin-3-yl)-(toluene-2- sulfonyl)-amino]-acetamide:
Figure imgf000114_0001
prepared by reaction of [(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]- acetic acid with 2-benzylamino-ethanol LC-MS: rt = 0.93 min, 470 (M+1, ES+).
Example 162: iV-Ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-iV-pyridin-3- ylmethyl-acetamide:
Figure imgf000114_0002
prepared by reaction of [(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]- acetic acid with ethyl-pyridin-3-ylmethyl-amine LC-MS: rt = 0.75 min, 455 (M+1 , ES+).
Example 163:
7Y-Ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-iV-pyridin-2- ylmethyl-acetamide :
Figure imgf000114_0003
prepared by reaction of [(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]- acetic acid with ethyl-pyridm-2-ylmethyl-amine LC-MS: rt = 0.78 min, 455 (M+1, ES+). Example 164:
N-(2-Cyano-ethyl)-N-ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)- amino]-acetamide:
Figure imgf000115_0001
prepared by reaction of [(6-methoxy-pyridin-3 -yl)-(toluene-2-sulfonyl)-amino] - acetic acid with 3-ethylammo-propionitrile LC-MS: rt = 0.91 min, 417 (M+1, ES+).
Example 165: N-(4-Cyano-benzyl)-N-ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)- amino]-acetamide:
Figure imgf000115_0002
prepared by reaction of [(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]- acetic acid with 4-ethylaminomethyl-benzonitrile LC-MS: rt = 1.00 min, 479 (M+1, ES+).
Example 166:
N-Ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-N-(l-methyl- lH-pyrrol-2-ylmethyl)-acetamide:
Figure imgf000115_0003
prepared by reaction of [(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]- acetic acid with ethyl-(l -methyl- lH-pyrrol-2-ylmethyl)-amine LC-MS: rt = 1.00 min, 457 (M+1, ES+).
Example 167: iV-Benzyl-/y-(2-hydroxy-ethyl)-2-[(toluene-2-sulfonyl)-p-tolyl-amino]- acetamide:
Figure imgf000116_0001
prepared by reaction of [(toluene-2-sulfonyl)-p-tolyl-amino]-acetic acid with 2-benzylamino-ethanol
LC-MS: rt = 0.98 min, 453 (M+1, ES+).
Example 168:
N-Ethyl-N-pyridin-3-yImethyl-2-[(toluene-2-sulfonyl)-p-toIyl-amino]- acetamide:
Figure imgf000116_0002
prepared by reaction of [(toluene-2-sulfonyl)-p-tolyl-amino]-acetic acid with ethyl- pyridin-3-ylmethyl-amine
LC-MS: rt = 0.80 min, 438 (M+1, ES+). Example 169:
N-Ethyl-N-thiazol-2-ylmethyl-2-[(toluene-2-suIfonyl)-p-tolyl-amino]- acetamide:
Figure imgf000117_0001
prepared by reaction of [(toluene-2-sulfonyl)-p-tolyl-arnino]-acetic acid with ethyl- thiazol-2-ylmethyl-amine LC-MS: rt = 0.98 min, 444 (M+1, ES+).
Example 170:
N-Ethyl-/Y-(6-methyl-pyridin-2-ylmethyl)-2- [(toluene-2-sulfonyl)-p-tolyl- amino]-acetamide:
Figure imgf000117_0002
prepared by reaction of [(toluene-2-sulfonyl)-p-tolyl-amino] -acetic acid with ethyl- (6-methyl-pyridin-2-ylmethyl)-amine LC-MS: rt = 0.82 min, 452 (M+1, ES+).
Example 171:
N-(2-Hydroxy-ethyl)-N-pyridin-2-ylmethyl-2-[(toluene-2-suIfonyl)-p-tolyl- aminoj-acetamide:
Figure imgf000117_0003
prepared by reaction of [(toluene-2-sulfonyl)-ρ-tolyl-amino]-acetic acid with
2-[(ρyridin-2-ylmethyl)-arrιino]-ethanol
LC-MS: rt = 0.78 min, 454 (M+1, ES+). Example 172:
N-Ethyl-iV-quinolin-2-ylmethyl-2-[(toluene-2-sulfonyl)-p-tolyl-amino]- acetamide:
Figure imgf000118_0001
prepared by reaction of [(toluene-2-sulfonyl)-ρ-tolyl-amino]-acetic acid with ethyl- quinolin-2-ylmethyl-amine LC-MS: rt = 0.94 min, 488 (M+1, ES+).
Example 173: 2-[(6-Amino-pyridin-3-yl)-(4-tert-butyl-benzenesulfonyl)-amino]-N-ethyl-N- pyridin-2-ylmethyl-acetamide:
Figure imgf000118_0002
prepared by reaction of [(6-annno-pyridin-3-yl)-(4-tert-butyl-benzenesulfonyl)- amino] -acetic acid with ethyl-pyridin-2-ylmethyl-amine LC-MS : rt = 0.73 min, 482 (M+1 , ES+).
Example 174:
2-[(6-Amino-pyridin-3-yl)-(4-tert-butyl-benzenesuIfonyl)-amino]-N-ethyl-iV- (6-methyl-pyridin-2-ylmethyl)-acetamide:
Figure imgf000118_0003
prepared by reaction of [(6-ammo-pyridin-3-yl)-(4-tert-butyl-benzenesulfonyl)- amino] -acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine LC-MS: rt = 0.71 min, 496 (M+1, ES+). Example 175:
2-[(6-Amino-pyridin-3-yl)-(4-tert-butyl-benzenesulfonyl)-amino]-iV-benzyl-N- ethyl-acetamide:
Figure imgf000119_0001
prepared by reaction of [(6-amino-pyridin-3-yl)-(4-tert-butyl-benzenesulfonyl)- amino]-acetic acid with benzyl-ethyl-amine LC-MS: rt = 0.88 min, 481 (M+1, ES+).
Example 176:
N,N-Diethyl-2- [(3-methyl-py ridine-2-sulf onyl)-p-tolyl-amino] -acetamide :
Figure imgf000119_0002
prepared by reaction of [(3-methyl-pyridine-2-sulfonyl)-p-tolyl-amino]-acetic acid with diethylamine
LC-MS: rt = 0.94 min, 376 (M+1, ES+).
Example 177:
N-Ethyl-2-[(3-methyl-pyridine-2-suIfonyl)-p-tolyl-amino]-N-pyridin-2- ylmethyl-acetamide:
Figure imgf000119_0003
prepared by reaction of [(3-methyl-pyridine-2-sulfonyl)-p-tolyl-amino]-acetic acid with ethyl-pyridin-2-ylmethyl-amine LC-MS: rt = 0.78 min, 439 (M+1, ES+). Example 178:
N-Ethyl-2-[(3-methyl-pyridine-2-sulfonyl)-p-tolyl-amino]-iV-(6-methyl- pyridin-2-ylmethyl)-acetamide:
Figure imgf000120_0001
prepared by reaction of [(3 -methyl-pyridine-2-sulfonyl)-p-tolyl-amino] -acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine
LC-MS: rt = 0.78 min, 453 (M+1, ES+).
Example 179: N,N-Diethyl-2-[(3-methyI-pyridine-2-suIfonyl)-m-tolyI-aminol-acetamide:
Figure imgf000120_0002
prepared by reaction of [(3-methyl-pyridine-2-sulfonyl)-m-tolyl-amino]-acetic acid with diethylamine
LC-MS: rt = 0.94 min, 376 (M+1, ES+).
Example 180:
N-Ethyl-2-[(3-methyl-pyridine-2-sulfonyl)-m-tolyl-amino]-iV-pyridin-2- ylmethyl-acetamide :
Figure imgf000120_0003
prepared by reaction of [(3-methyl-pyridine-2-sulfonyl)-m-tolyl-amino]-acetic acid with ethyl-pvridin-2-yimethyl-amine LC-MS: rt = 0.78 min, 439 (M+1, ES+). Example 181:
N-Ethyl-2-[(3-methyl-pyridine-2-sulfonyl)-m-tolyl-amino]-iV-(6-methyl- pyridin-2-ylmethyl)-acetamide:
Figure imgf000121_0001
prepared by reaction of [(3 -methyl-pyridine-2-sulfonyl)-m-tolyl-amino] -acetic acid with ethyl-(6-methyl-pyridm-2-ylmethyl)-amine
LC-MS: rt = 0.78 min, 453 (M+1, ES+).
Example 182:
N-(2-Hydroxy-ethyl)-2-[(3-methyl-pyridine-2-sulfonyl)-m-tolyl-amino]-N- pyridm-2-ylmethyl-acetamide:
Figure imgf000121_0002
prepared by reaction of [(3-methyl-pyridine-2-sulfonyl)-m-tolyl-amino]-acetic acid with 2-[(pyridin-2-ylmethyl)-amino]-ethanol LC-MS : rt = 0.72 min, 455 (M+1 , ES+).
Example 183:
N,iV-Diethyl-2-[(2-methoxy-phenyl)-(3-methyl-pyridine-2-sulfonyl)-amino]- acet amide:
Figure imgf000121_0003
prepared by reaction of [(2-methoxy-phenyl)-(3-methyl-pyridine-2-sulfonyl)- amino]-acetic acid with diethylamine LC-MS: rt = 0.87 min, 392 (M+1, ES+). Example 184: iV-Ethyl-2-[(2-methoxy-phenyl)-(3-methyl-pyridine-2-sulfonyl)-amino]-iV-(6- methyl-pyridm-2-ylmethyl)-acetamide:
Figure imgf000122_0001
prepared by reaction of [(2-methoxy-phenyl)-(3-methyl-pyridine-2-sulfonyl)- amino]-acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine LC-MS: rt = 0.72 min, 469 (M+1, ES+).
Example 185:
iV-Benzyl-N-ethyl-2-[(2-methoxy-phenyl)-(3-methyl-pyridine-2-sulfonyl)- amino]-acetamide:
Figure imgf000122_0002
prepared by reaction of [(2-methoxy-phenyl)-(3-methyl-pyridine-2-sulfonyl)- amino] -acetic acid with benzyl-ethyl-amine LC-MS: rt = 0.98 min, 454 (M+1, ES+).
Example 186:
iV-Ethyl-2-[(2-methoxy-phenyl)-(3-methyl-pyridine-2-sulfonyl)-amino]-iV- py ridin-2-ylmethyl-acetamide :
Figure imgf000122_0003
prepared by reaction of [(2-methoχy-phenyl)-(3-methyl-ρyridine-2-sulfonyl)- amino] -acetic acid with ethyl-pyridin-2-ylmethyl-amine LC-MS: rt = 0.70 min, 455 (M+1, ES+).
Example 187:
N,N-Diethyl-2-[(l,2,3,4-tetrahydro-isoquinoline-7-sulfonyl)-p-tolyl-amino]- acetamide:
Figure imgf000123_0001
prepared by reaction of [(l,2,3,4-tetrahydro-isoquinoline-7-sulfonyl)-p-tolyl- amino] -acetic acid with diethylamine; due to the presence of formic acid in the eluent of the HPLC chromatography the product contained considerable amounts of N,N-diethyl-2-[(2-formyl- 1 ,2,3,4-tetrahydro-isoquinoline-7-sulfonyl)-p-tolyl- amino]-acetanιide (LC-MS: rt = 0.91 min, 444 (M+1, ES+)) LC-MS: rt = 0.74 min, 416 (M+1, ES+).
Example 188:
iV-Ethyl-N-pyridin-2-ylmethyl-2-[(l,2,3,4-tetrahydro-isoquinoline-7-sulfonyl)- p-toIyl-amino]-acetamide:
Figure imgf000123_0002
prepared by reaction of [( 1,2,3 ,4-tetrahydro-isoquinoline-7-sulfonyl)-p-tolyl- amino]-acetic acid with ethyl-pyridin-2-ylmethyl-amine; due to the presence of formic acid in the eluent of the HPLC chromatography the product contained considerable amounts of Ν-ethyl-2-[(2-formyl-l,2,3,4-tetrahydro-isoquinoline-7- sulfonyl)-p-tolyl-amino]-N-pyridin-2-ylmethyl-acetamide (LC-MS: rt = 0.77 min, 507 (M+1, ES+)) LC-MS: rt = 0.64 min, 479 (M+1, ES+). Synthesis of sulfonylamino-acetic acids (EDC coupling):
A solution of the respective acetic acid derivative (0.10 mmol) in DMF (1.0 mL) was treated with solutions of DMAP (0.30 mmol) and of EDC hydrochloride (0.15 mmol) in DMF. A solution of the respective amine (0.12 mmol) in DMF was added. The reaction mixture was stirred at RT for 12 h and purified by preparative HPLC chromatography to give the following sulfonamides:
Example 189:
iV-Ethyl-2- [(5-isopropyl-pyridine-2-sulfonyl)-m-tolyl-amino]-N-(6-methyl- pyridin~2-ylmethyl)-acetamide:
Figure imgf000124_0001
prepared by reaction of [(5-isopropyl-pyridine-2-sulfonyl)-m-tolyl-amino]-acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine LC-MS: rt = 0.83 min, 481 (M+1, ES+).
Example 190:
7Λr,iV-Diethyl-2-[(5-isopropyl-pyridme-2-sulfonyl)-(2-methoxy-phenyl)-amino]- acetamide:
Figure imgf000124_0002
prepared by reaction of [(5-isopropyl-pyridine-2-sulfonyl)-(2-methoxy-phenyl)- amino] -acetic acid with diethylamine LC-MS: rt = 0.96 min, 420 (M+1, ES+). Example 191:
N-Ethyl-2-[(5-isopropyl-pyridine-2-sulfonyl)-(2-methoxy-phenyl)-amino]-iV- (6-methyl-pyridin-2-ylmethyl)-acetamide:
Figure imgf000125_0001
prepared by reaction of [(5-isopropyl-pyridine-2-sulfonyl)-(2-methoxy-phenyl)- amino]-acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine LC-MS: rt = 0.80 min, 497 (M+1, ES+).
Example 192:
7Y-Benzyl-/Y-ethyl-2-[(5-isopropyl-pyridine-2-sulfonyl)-(2-methoxy-phenyl)- aminoj-acetamide:
Figure imgf000125_0002
prepared by reaction of [(5-isopropyl-pyridine-2-sulfonyl)-(2-methoxy-phenyl)- amino]-acetic acid with benzyl-ethyl-amine LC-MS: rt = 1.05 min, 482 (M+1, ES+).
Example 193:
N-Ethyl-2-[(5-isopropyl-pyridine-2-sulfonyI)-(6-methoxy-pyridin-3-yl)- amino]-N-pyridin-2-yImethyl-acetamide:
Figure imgf000125_0003
prepared by reaction of [(5-isopropyl-pyridine-2-sulfonyl)-(6-methoxy-pyridin-3- yl)-amino]-acetic acid with ethyl-pyridin-2-ylmethyl-amine LC-MS: rt = 0.80 min, 484 (M+1, ES+). Example 194:
N-Ethyl-2-[(5-isopropyl-pyridine-2-sulfonyl)-(6-methoxy-pyridin-3-yl)- amino]-iV-(6-methyl-pyridin-2-ylmethyl)-acetamide:
Figure imgf000126_0001
prepared by reaction of [(5-isoρropyl-pyridine-2-sulfonyl)-(6-methoxy-pyridin-3- yl)-amino]-acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine LC-MS: rt = 0.79 min, 498 (M+1, ES+).
Example 195: N-(2-Hydroxy-ethyl)-2- [(5-isopropyl-pyridine-2-sulfonyl)-(6-methoxy-pyridin-
3-yl)-amino]-N-pyridin-2-ylmethyl-acetamide:
Figure imgf000126_0002
prepared by reaction of [(5-isopropyl-pyridine-2-sulfonyl)-(6-methoxy-pyridin-3- yl)-amino] -acetic acid with 2-[(pyridin-2-ylmethyl)-amino] -ethanol LC-MS: rt = 0.75 min, 500 (M+1, ES+).
Example 196:
N-Benzyl-iV-ethyl-2-[(5-isopropyl-pyridine-2-sulfonyl)-(6-methoxy-pyridin-3- yl)-amino]-acetamide:
Figure imgf000126_0003
prepared by reaction of [(5-isopropyl-ρyridine-2-sulfonyl)-(6-methoxy-pyridin-3- yl)-amino]-acetic acid with benzyl-ethyl-amine LC-MS: rt = 1.03 min, 483 (M+1, ES+). Example 197:
N-Ethyl-2-[(5-methyl-pyridine-2-sulfonyl)-p-tolyl-amino]-iV-(6-methyl- pyridin-2~ylmethyl)-acetamide:
Figure imgf000127_0001
prepared by reaction of [(5-methyl-pyridine-2-sulfonyl)-p-tolyl-arnino]-acetic acid with ethyl-(6-methyl-pyridin-2-yhnethyl)-amine LC-MS: rt = 0.77 min, 453 (M+1, ES+).
Example 198:
N-Ethyl-2- [(5-methyl-pyridine-2-sulfonyl)-p-tolyl-amino]-iV-pyridin-3- ylmethyl-acetamide:
Figure imgf000127_0002
prepared by reaction of [(5-methyl-pyridine-2-sulfonyl)-p-tolyl-amino]-acetic acid with ethyl-pyridm-3-ylmethyl-amhιe LC-MS: rt = 0.75 min, 439 (M+1, ES+).
Example 199:
2-[(4-tert-Butyl-benzenesulfonyl)-(6-methyl-pyridin-3-yl)-amino]-iV,N-diethyl- acetamide:
Figure imgf000127_0003
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(6-methyl-pyridin-3-yl)- amino]-acetic acid with diethylamine LC-MS: rt = 0.87 min, 418 (M+1, ES+). Example 200:
2-[(4-tert-Butyl-benzenesulfonyl)-(6-methyl-pyridin-3-yl)-amino]-/N-ethyl-N- pyridin-2-ylmethyl-acetamide:
Figure imgf000128_0001
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(6-methyl-pyridin-3-yl)- a ino] -acetic acid with ethyl-pyridin-2-ylmethyl-amine LC-MS: rt = 0.78 min, 481 (M+1, ES+).
Example 201: 2-[(4-tert-Butyl-benzenesulfonyl)-(6-methyl-pyridin-3-yl)-amino]-/y-ethyl-N-
(6-methyl-pyridin-2-yImethyl)-acetamide:
Figure imgf000128_0002
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(6-methyl-pyridin-3-yl)- amino] -acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine LC-MS: rt = 0.77 min, 495 (M+1, ES+).
Example 202:
2-[(4-tert-Butyl-benzenesuIfonyI)-(6-methyl-pyridin-3-yl)-amino]-N-(2- hydroxy-ethyl)-N-pyridin-2-yImethyI-acetamide:
Figure imgf000128_0003
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(6-methyl-pyridin-3-yl)- amino]-acetic acid with 2- [(pyridm-2-ylmethyl)-amino] -ethanol LC-MS: rt = 0.72 min, 497 (M+1, ES+). Example 203:
JV-Benzyl-2-[(4-tert-butyl-benzenesulfonyl)-(6-methyl-pyridin-3-yl)-amino]-N- ethyl-acetamide:
Figure imgf000129_0001
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(6-methyl-pyridin-3 -yl)- amino]-acetic acid with benzyl-ethyl-amine LC-MS: rt = 0.95 min, 480 (M+1, ES+).
Example 204: N-EthyI-2-[(6-methoxy-pyridin-3-yl)-(3-methyl-pyridine-2-sulfonyl)-amino]-
N-pyridin-2-yImethyI-acetamide:
Figure imgf000129_0002
prepared by reaction of [(6-methoxy-pyridin-3-yl)-(3-methyl-pyridine-2-sulfonyl)- amino]-acetic acid with ethyl-pyridin-2-ylmethyl-amine LC-MS: rt = 0.70 min, 456 (M+1, ES+).
Example 205:
N-Ethyl-2-[(6-methoxy-pyridin-3-yl)-(3-methyl-pyridine-2-sulfonyl)-amino]- N-(6-methyI-pyridin-2-ylmethyl)-acetamide:
Figure imgf000129_0003
prepared by reaction of [(6-methoxy-pyridin-3-yl)-(3-methyl-pyridine-2-sulfonyl)- amino] -acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine LC-MS: rt = 0.72 min, 470 (M+1, ES+). Example 206:
N-(2-Hydroxy-ethyl)-2-[(6-methoxy-pyridin-3-yl)-(3-methyl-pyridine-2- suIfonyl)-amino]- V-pyridin-2-ylmethyl-acetamide:
Figure imgf000130_0001
prepared by reaction of [(6-methoxy-pyridin-3-yl)-(3-methyl-pyridine-2-sulfonyl)- aminoj-acetic acid with 2-[(pyridin-2-ylmethyl)-amino] -ethanol LC-MS: rt = 0.67 min, 472 (M+1, ES+).
Example 207: N-Benzyl-N-ethyl-2-[(6-methoxy-pyridin-3-yl)-(3-methyl-pyridine-2-sulfonyl)- amino]-acetamide:
Figure imgf000130_0002
prepared by reaction of [(6-methoxy-pyridin-3-yl)-(3-methyl-pyridine-2-sulfonyl)- amino] -acetic acid with benzyl-ethyl-amine LC-MS: rt = 0.98 min, 455 (M+1, ES+).
Synthesis of N-Ethyl-2-[(2-methyl-l,2,3,4-tetrahydro-isoquinoline-7-sulfonyl)-p-
Figure imgf000130_0003
To a solution of N-ethyl-N-pyridin-2-ylmethyl-2-[(l,2,3,4-tefrahydro-isoquinoline-7- sulfonyl)-p-tolyl-amino]-acetamide (0.46 mmol) in methanol (15 mL) was added a solution of formaldehyde in water (37%, 0.92 mL), sodium cyanoborohydride (675 mg) and acetic acid (3.07 mL). After 2 h a saturated NaHCO3-solution (25 mL), water (25 mL) and ethyl acetate (50 mL) were added, the layers were separated and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers were concentrated in vacuo and the residue was purified by preparative HPLC chromatography to give 66.7 mg (0.14 mmol, 29%) of the desired product. LC-MS: rt = 0.65 min, 493 (M+1, ES+).
Synthesis of 2-{(3-Dimethylamino-phenyl)-[4-(l-hydroxy-l-methyl-ethyl)- benzenesuIfonyl]-amino}-N-ethyl-N-pyridin-2-ylmethyl-acetamide:
Figure imgf000131_0001
(3-Dimethylamino-phenylamino)-acetic acid methyl ester:
To a solution of NN-dimethyl-m-phenylenediamine (120 mmol) in THF (500 mL) was added methyl bromoacetate (132 mmol) and DIPEA (264 mmol). The reaction mixture was refluxed for 16 h. Water (200 mL) and ethyl acetate (300 mL) were added, the layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 200 mL). The combined organic layers were washed with water (4 x 100 mL) and brine (100 mL) and dried over Νa2SOφ The solvents were removed in vacuo and the residue was purified by flash-chromatography (ethyl acetate/heptane 1 :4) to give 17.5 g (84.0 mmol, 70%) of an oily product which crystallized slowly. LC-MS: rt = 0.51 min, 209 (M+1, ES+).
(3-Dimethylamino-phenylamino)-acetic acid:
To a solution of (3-dimethylamino-phenylamino)-acetic acid methyl ester (84 mmol) in methanol (300 mL) was added a solution of sodium hydroxide in water (2.0 mol/L, 150 mL) at 0°C. The reaction mixture was stiπed at RT for 16 h and methanol was removed in vacuo. Water (200 L) and ethyl acetate (300 L) were added, the layers were separated and the aqueous layer was acidified to pH 2 by addition of hydrochloric acid (2.0 mol/L). The aqueous layer was extracted with ethyl acetate (3 x 200 mL) and concentrated in vacuo. Methanol (100 mL) was added and the obtained suspension was filtered. The filtrate was concentrated in vacuo and the obtained solid was crystallized from methanol / ethyl acetate to give 15.0 g (56.2 mmol, 61%) of (3-dimethylamino-phenylamino)-acetic acid dihydrochloride as pink crystals.
LC-MS: rt = 0.40 min, 195 (M+1, ES+).
2-(3-Dimethylamino-phenylamino)-N-ethyl-N-pyridin-2-ylmethyl-acetamide:
A suspension of ethyl-pyridin-2-ylmethyl-amine (41.1 mmol) and DIPEA (112 mmol) in DMF (200 mL) was cooled to -20°C and added to a cold (-20°C) solution of (3-dimethylamino-phenylamino)-acetic acid (37.4 mmol) and TBTU (48.6 mmol) in DMF (300 mL). The reaction mixture was stiπed for 10 min at -20°C. Water (500 mL) and ethyl acetate (500 mL) were added, the layers were separated and the organic layer was washed with water (4 x 200 mL). The combined aqueous layers were exfracted with ethyl acetate (300 L). The combined organic layers were washed with NaOH solution (1.0 mol/L, 100 mL) and brine (100 mL) and dried over Na2SO4. The solvents were removed in vacuo and the obtained solid was dissolved in ethanol. A solution of hydrogen chloride in ether was added at 0°C, the solvents were removed and the residue was crystallized from ethanol / ether to give 7.6 g product as white crystals. LC-MS: rt = 0.49 min, 313 (M+1, ES+).
2-[(4-Acetyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-N-ethyl-N- pyridin-2-ylmethyl-acetamide:
A solution of 2-(3-dimethylamino-phenylamino)-Ν-ethyl-Ν-pyridin-2-ylmethyl- acetamide (2.50 mmol) and of DIPEA (5.00 mmol) in THF (10 L) was added to a solution of 4-acetyl-benzenesulfonyl chloride (2.50 mmol) in THF (10 L). The reaction mixture was stiπed for 2 h, the solvents were removed and the residue was purified by preparative HPLC chromatography to give 451 mg (0.91 mmol, 36%>) product as a brownish foam.
LC-MS: rt = 0.75 min, 495 (M+1, ES+). Example 209
2-{(3-DimethyIamino-phenyI)-[4-(l-hydroxy-l-methyl-ethyl)-benzenesulfonyl]- amino}-N-ethyl-N-pyridin-2-ylmethyl-acetamide:
At -78°C a solution of methyllithium in ether (1.60 mol/L, 0.25 mL) was added to a solution of titamum(ιN) chloride in DCM (1.00 mol/L, 0.40 mL). The reaction mixture was treated with a solution of 2-[(4-acetyl-benzenesulfonyl)-(3-dimethyl- amino-phenyl)-amino]-N-ethyl-N-pyridin-2-ylmethyl-acetamide (0.10 mmol) in DCM (1.0 mL), allowed to reach RT, stiπed for 1 h and purified by preparative HPLC chromatography. LC-MS: rt = 0.70 min, 511 (M+1, ES+).

Claims

Claims
1. Compounds of formula (I)
Figure imgf000134_0001
Foraiula (I)
wherein: A represents 4-ethylphenyl-, 4-isopropylphenyl, 4-tert.-butylphenyl-, 2-methylphenyl-, 3 -methylphenyl-, 4-cyclopropylphenyl, 3 -fluorophenyl-, 2-chlorophenyl-, 3-chlorophenyl-, 4-bromophenyl-, 2-trifluoromethylphenyl-, 3-trifluoromethylphenyl-, 4-( 1 -hydroxy- 1- methyl-ethyl)-phenyl-, 3-chloro-4-methylphenyl-, 2-methoxy-4-methylphenyl-, 3,4- difluorophenyl-, 1 ,2,3 ,4-tetrahydroisoquinolin-7-yl, 2-methyl- 1 ,2,3 ,4-tefrahydroisoquinolin- 7-yl, 2-formyl-l,2,3,4-tetrahydroisoquinolin-7-yl, phenylethenyl-, 1-naphthyl-, 2-naphthyl-, 3-methyl-pyridin-2-yl, 5-methyl-pyridin-2-yl, 5-isopropyl-pyridin-2-yl, 6-dimethylamino- pyridin-3-yl, 6-bromo-5-chloro-pyridin-3-yl or 8-quinolinyl-;
B represents a phenyl, a 6-membered heteroaryl or a nine- or ten-membered bicyclic heteroaryl group, which groups are unsubstituted or independently mono- or di- substituted with cyano, halogen, hydroxy, lower alkyl, hydroxy lower alkyl, amino lower alkyl, aminocarbonyl lower alkyl, sulfonylamino lower alkyl, lower alkenyl, lower alkoxy, trifluoromethyl, trifluoromethoxy, cycloalkyloxy, aryloxy, aralkyloxy, heterocyclyloxy, heterocyclyl lower alkyloxy, amino, aminocarbonyl or sulfonylamino; or a cyclohexyl, 3- piperidinyl or 4-piperidinyl group, which groups are unsubstituted or mono-substituted with hydroxy, lower alkyl, hydroxy lower alkyl, aminocarbonyl lower alkyl, sulfonylamino lower alkyl, amino, aminocarbonyl or sulfonylamino; with the proviso that in case A represents 2-methylphenyl- or 4-bromophenyl the phenyl ring as represented by B is substituted; R1 represents lower alkyl, cycloalkyl, hydroxy lower alkyl or cyano lower alkyl; R2 represents lower alkyl, lower alkenyl, hydroxy lower alkyl, amino lower alkyl, sulfonylamino lower alkyl, cycloalkyl; an unsubstituted or mono- or disubstituted phenyl group substituted independently with cyano, halogen, hydroxy, lower alkyl, lower alkoxy, cycloalkyloxy, amino, amino lower alkyl, aminocarbonyl or sulfonylamino; an unsubstituted or mono- or di-substituted five- or six-membered heteroaryl group substituted independently with cyano, halogen, hydroxy, lower alkyl, lower alkoxy, cycloalkyloxy, amino, amino lower alkyl, aminocarbonyl or sulfonylamino; an unsubstituted or mono- or di-substituted nine- or ten-membered bicyclic heteroaryl group substituted independently with cyano, halogen, hydroxy, lower alkyl, lower alkoxy, cycloalkyloxy, amino, amino lower alkyl, aminocarbonyl or sulfonylamino; and pure enantiomers, mixtures of enantiomers, pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates and the meso-form and pharmaceutically acceptable salts, solvent complexes, and morphological forms, thereof.
2. Compounds of formula (I) wherein: A represents a 4-ethylphenyl group;
B, R1 and R2 have the meaning given in claim 1 ; and pure enantiomers, mixtures of enantiomers, pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates and the meso-form and pharmaceutically acceptable salts, solvent complexes, and morphological forms, thereof.
3. Compounds of formula (I) wherein: A represents a 4-isopropylphenyl group; B, R1 and R2 have the meaning given in claim 1 ; and pure enantiomers, mixtures of enantiomers, pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates and the meso-form and pharmaceutically acceptable salts, solvent complexes, and morphological forms, thereof.
4. Compounds of formula (I) wherein:
A represents a 4-tert.-butylphenyl group;
B, R and R have the meaning given in claim 1; and pure enantiomers, mixtures of enantiomers, pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates and the meso-form and pharmaceutically acceptable salts, solvent complexes, and morphological forms, thereof.
5. Compounds of formula (I) wherein:
A represents a 2-methylphenyl group; B has the meaning given in claim 1 with the proviso that the phenyl group is substituted; R and R have the meaning given in claim 1 ; and pure enantiomers, mixtures of enantiomers, pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates and the meso-form and pharmaceutically acceptable salts, solvent complexes, and moφhological forms, thereof.
6. Compounds of formula (I) wherein: A represents a 3 -methylphenyl group;
1
B, R and R have the meaning given in claim 1; and pure enantiomers, mixtures of enantiomers, pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates and the meso-form and pharmaceutically acceptable salts, solvent complexes, and moφhological forms, thereof.
7. Compounds of formula (I) wherein: A represents a 4-(l-hydroxy-l-methyl-ethyl)-phenyl group; B, R1 and R2 have the meaning given in claim 1; and pure enantiomers, mixtures of enantiomers, pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates and the meso-form and pharmaceutically acceptable salts, solvent complexes, and moφhological forms, thereof.
8. Compounds of formula (I) wherein:
A represents a 3-chloro-4-methylphenyl group; B, R1 and R2 have the meaning given in claim 1; and pure enantiomers, mixtures of enantiomers, pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates and the meso-form and pharmaceutically acceptable salts, solvent complexes, and moφhological forms, thereof.
9. Compounds of formula (I) wherein:
A represents a 2-formyl-l,2,3,4-tetrahydroisoquinolin-7-yl group; B, R1 and R2 have the meaning given in claim 1 ; and pure enantiomers, mixtures of enantiomers, pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates and the meso-form and pharmaceutically acceptable salts, solvent complexes, and moφhological forms, thereof.
10. Compounds of formula (I) wherein: A represents a 2-naphthyl group; B, R and R have the meaning given in claim 1; and pure enantiomers, mixtures of enantiomers, pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates and the meso-form and pharmaceutically acceptable salts, solvent complexes, and moφhological forms, thereof.
11. Compounds of formula (I) wherein:
A represents a 3-methyl-pyridin-2-yl group;
1
B, R and R have the meaning given in claim 1 ; and pure enantiomers, mixtures of enantiomers, pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates and the meso-form and pharmaceutically acceptable salts, solvent complexes, and moφhological forms, thereof.
12. Compounds of formula (I) wherein:
A represents a 5-isopropyl-pyridin-2-yl group; B, R1 and R2 have the meaning given in claim 1; and pure enantiomers, mixtures of enantiomers, pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates and the meso-form and pharmaceutically acceptable salts, solvent complexes, and moφhological forms, thereof.
13. Compounds of formula (I) wherein: A represents a 6-dimethylamino-pyridin-3-yl group; B, R1 and R2 have the meaning given in claim 1; and pure enantiomers, mixtures of enantiomers, pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates and the meso-form and pharmaceutically acceptable salts, solvent complexes, and moφhological forms, thereof.
14. A compound according to claim 1, selected from the group consisting of 2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N,N-diethyl-acetamide; 2-[(4-tert-Butyl-benzenesulfonyl)-(4-methoxy-phenyl)-amino]-N,N-diethyl-acetamide; 2-[(4-tert-Butyl-benzenesulfonyl)-(3-methoxy-phenyl)-amino]-N,N-diethyl-acetamide;
2-[(4-tert-Butyl-berιzenesulfonyl)-m-tolyl-arnino]-N,N-diethyl-acetamide;
2-[(6-Dimethylanιino-pyridine-3-sulfonyl)-p-tolyl-amino]-N-et ιyl-N-pyridin-2-ylmethyl- acetamide; N-Benzyl-2-[(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-N-ethyl-acetamide;
2-[(4-tert-Butyl-berrzenesulfonyl)-p-tolyl-amino]-N-ethyl-N-pyridin-4-ylmethyl- acetamide;
N,N-Diethyl-2-[(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-acetamide;
N-Benzyl-N-ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-acetamide; N-Benzyl-N-ethyl-2-[(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-acetamide;
N-Benzyl-2-[(4-tert-butyl-benzenesulfonyl)-(2-methoxy-phenyl)-amino]-N-ethyl- acetamide;
N-Benzyl-N-ethyl-2-[(6-methoxy-pyridin-3-yl)-(naphthalene-2-sulfonyl)-amino]- acetamide; 2-[(4-tert-Butyl-berιzenesulfonyl)-p-tolyl-amino]-N-ethyl-N-(2-hydroxy-ethyl)-acetamide;
2-[(3-Chloro-4-methyl-benzenesulfonyl)-p-tolyl-amino]-N,N-diethyl-acetamide;
N-Benzyl-2-[(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-N-(2-hydroxy-ethyl)- acetamide;
2-[(4-tert-Butyl-berιzenesulfonyl)-p-tolyl-anιino]-N-(2-cyano-ethyl)-N-ethyl-acetamide; 2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N-ethyl-N-pyridin-2-ylmethyl- acetamide;
2-[(4-tert-Butyl-berιzenesulfonyl)-p-tolyl-amino]-N-ethyl-N-pyridin-3-ylmethyl- acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N-ethyl-N-(6-methyl-pyridin-2- ylmethyl)-acetamide;
2-[(4-tert-Butyl-berιzenesulfonyl)-p-tolyl-amino]-N-ethyl-N-thiazol-2-ylmethyl- acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-N,N-diethyl- acetamide; 2-[(4-tert-Butyl-berιzenesulfonyl)-(3-dimethylan ino-phenyl)-amino]-N-ethyl-N-pvridin-2- ylmethyl-acetamide;
2-[(4-tert-Butyl-berιzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-N-ethyl-N-(6- methyl-pyridin-2-ylmethyl)-acetamide; 2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N-ethyl-N-(3-hydroxy-benzyl)- acetamide;
2-[(4-tert-Butyl-berizenesulfonyl)-(lH-indazol-6-yl)-amino]-N-ethyl-N-(6-methyl-pyridin-
2-ylmethyl)-acetamide; 2-[(4-tert-Butyl-benzenesulfonyl)-(lH-indazol-6-yl)-amino]-N-ethyl-N-pyridin-2- ylmethyl-acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N-(2-hydroxy-ethyl)-N-pyridin-2- ylmethyl-acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-N-(2-hydroxy- ethyl)-N-pyridin-2-ylmethyl-acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-p-tolyl-amino]-N-cyclopropyl-N-(3-methoxy-benzyl)- acetamide;
2-[(4-tert-Butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-N-cyclopropyl-N-(3- methoxy-benzyl)-acetamide; N-Ethyl-2-[(2-methoxy-phenyl)-(toluene-2-sulfonyl)-ammo]-N-tmazol-2-ylmethyl- acetamide;
N-Benzyl-N-(2-hydroxy-ethyl)-2-[(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]- acetamide;
N-Ethyl-2-[(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-N-pyridin-2-ylmethyl- acetamide;
N-Ethyl-N-(3-hydroxy-benzyl)-2-[(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]- acetamide;
N-Ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-N-(6-methyl-pyridin-2- ylmethyl)-acetamide; N-Berιzyl-N-(2-hydroxy-ethyl)-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]- acetamide;
N-Ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-N-pyridin-3-ylmethyl- acetamide;
N-Ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-N-pyridin-2-ylmethyl- acetamide;
N-Ethyl-2-[(2-methoxy-phenyl)-(3-methyl-pyridine-2-sulfonyl)-amino]-N-(6-methyl- pyridin-2-ylmethyl)-acetamide; N-Benzyl-N-ethyl-2-[(2-methoxy-phenyl)-(3-methyl-pyridine-2-sulfonyl)-amino]- acetamide;
2-[(4-tert-Butyl-berιzenesulfonyl)-(6-methyl-pyridin-3-yl)-amino]-N-ethyl-N-pyridin-2- ylmethyl-acetamide; N-Benzyl-2-[(4-tert-butyl-berιzenesulfonyl)-(6-methyl-pyridin-3-yl)-amino]-N-ethyl- acetamide;
N-Ethyl-2-[(6-methoxy-pyridin-3-yl)-(3-methyl-pyridine-2-sulfonyl)-amino]-N-(6-methyl- pyridin-2-ylmethyl)-acetamide;
N-Berizyl-N-ethyl-2-[(6-methoxy-pyridin-3-yl)-(3-methyl-pyridine-2-sulfonyl)-amino]- acetamide;
15. Pharmaceutical compositions for the treatment of disorders which are associated with the role of orexin, comprising one or more compounds of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, and usual carrier materials and adjuvants.
16. Pharmaceutical compositions for the treatment of eating disorders, sleep disorders, cardiovascular disorders, cancer, pain, depression, anxiety, schizophrenia, neurodegenerative disorders or hyperthermia syndromes, comprising one or more compounds of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, and usual carrier materials and adjuvants.
17. The compounds of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, for use as medicaments for the treatment of disorders which are associated with a role of orexins.
18. The compounds of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, for use as medicaments for the treatment of eating disorders, sleep disorders, cardiovascular disorders, cancer, pain, depression, anxiety, schizophrenia, neurodegenerative disorders or hyperthermia syndromes.
19. A method of treating or preventing diseases or disorders where an antagonist of human orexin receptors is required, which comprises administering to a subject in need thereof an effective amount of a compound as claimed in any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof.
20. A process for the manufacture of pharmaceutical compositions for the freatment of disorders mentioned in claim 15 or 16, containing one or more compounds as claimed in any one of claims 1 to 14, or a pharmaceutically acceptable salt or salts thereof, as active ingredients which process comprises mixing one or more active ingredient or ingredients with pharmaceutically acceptable excipients and adjuvants in a manner known per se.
21. Use of one or more compounds of any one of claims 1 to 14 in combination with other pharmacologically active compounds comprising other orexin receptor antagonists, lipid lowering agents, anorectic agents, sleep inducing agents, antidepressants or other drugs beneficial for the prevention or treatment of disorders given in any one of claims 15 to 19.
22. A compound as described as end-product in any one of examples 1 to 209.
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MXPA05003295A MXPA05003295A (en) 2002-10-11 2003-10-06 Sulfonylamino-acetic derivatives and their use as orexin receptor antagonists.
DE60335891T DE60335891D1 (en) 2002-10-11 2003-10-06 SULPHONYLAMINE ACID DERIVATIVES AND THEIR USE AS OREXIN RECEPTOR ANTAGONIST
CA2498091A CA2498091C (en) 2002-10-11 2003-10-06 Sulfonylamino-acetic acid derivatives
EP03785607A EP1554239B1 (en) 2002-10-11 2003-10-06 Sulfonylamino-acetic acid derivatives and their use as orexin receptor antagonists
BR0315115-8A BR0315115A (en) 2002-10-11 2003-10-06 Compounds, pharmaceutical compositions, method for treating or preventing diseases or disorders in which a human orexin receptor antagonist is required, process for the manufacture of pharmaceutical compositions, and use of one or more compounds in combination with other pharmacologically active compounds.
AT03785607T ATE496884T1 (en) 2002-10-11 2003-10-06 SULPHONYLAMINOACETIC ACID DERIVATIVES AND THEIR USE AS OREXIN RECEPTOR ANTAGONISTS
US10/529,637 US7279578B2 (en) 2002-10-11 2003-10-06 Sulfonylamino-acetic acid derivatives
NZ538749A NZ538749A (en) 2002-10-11 2003-10-06 Sulfonylamino-acetic acid derivatives and their use as orexin receptor antagonists
JP2004542433A JP4528125B2 (en) 2002-10-11 2003-10-06 Sulfonylamino-acetic acid derivatives
AU2003294671A AU2003294671A1 (en) 2002-10-11 2003-10-06 Sulfonylamino-acetic derivatives and their use as orexin receptor antagonists
NO20051102A NO20051102L (en) 2002-10-11 2005-03-01 Sulfonylamino-acetic acid derivatives
US11/756,008 US7435815B2 (en) 2002-10-11 2007-05-31 Sulfonylamino-acetic acid derivatives

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US20070244156A1 (en) 2007-10-18
US7279578B2 (en) 2007-10-09
JP2006502209A (en) 2006-01-19
JP4528125B2 (en) 2010-08-18
KR20050043988A (en) 2005-05-11
ATE496884T1 (en) 2011-02-15
DE60335891D1 (en) 2011-03-10
CA2498091C (en) 2011-03-22
NZ538749A (en) 2006-11-30
NO20051102L (en) 2005-05-04
US20060014783A1 (en) 2006-01-19
EP1554239A2 (en) 2005-07-20
US7435815B2 (en) 2008-10-14
BR0315115A (en) 2005-08-16
ZA200502791B (en) 2006-02-22
RU2334735C2 (en) 2008-09-27

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