EP0968209A1 - THIAZOLE BENZENESULFONAMIDES UTILISES COMME AGONISTES $g(b) 3? POUR LE TRAITEMENT DU DIABETE ET DE L'OBESITE - Google Patents

THIAZOLE BENZENESULFONAMIDES UTILISES COMME AGONISTES $g(b) 3? POUR LE TRAITEMENT DU DIABETE ET DE L'OBESITE

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Publication number
EP0968209A1
EP0968209A1 EP98903677A EP98903677A EP0968209A1 EP 0968209 A1 EP0968209 A1 EP 0968209A1 EP 98903677 A EP98903677 A EP 98903677A EP 98903677 A EP98903677 A EP 98903677A EP 0968209 A1 EP0968209 A1 EP 0968209A1
Authority
EP
European Patent Office
Prior art keywords
ethyl
phenyl
thiazol
amino
benzenesulfonamide
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.)
Withdrawn
Application number
EP98903677A
Other languages
German (de)
English (en)
Inventor
Robert J. Mathvink
Emma R. Parmee
Samuel Tolman
Ann E. Weber
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck and Co Inc
Original Assignee
Merck and Co Inc
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from GBGB9705041.3A external-priority patent/GB9705041D0/en
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP0968209A1 publication Critical patent/EP0968209A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07D417/14—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 three or more hetero rings

Definitions

  • ⁇ -Adrenoceptors have been subclassified as ⁇ l and ⁇ 2 since 1967. Increased heart rate is the primary consequence of ⁇ l -receptor stimulation, while bronchodilation and smooth muscle relaxation typically result from ⁇ 2 stimulation.
  • Adipocyte lipolysis was initially thought to be solely a ⁇ l -mediated process. However, more recent results indicate that the receptor mediating lipolysis is atypical in nature. These atypical receptors, later called ⁇ 3-adrenoceptors, are found on the cell surface of both white and brown adipocytes where their stimulation promotes both lipolysis (breakdown of fat) and energy expenditure.
  • a major drawback in treatment of chronic diseases with ⁇ 3 agonists is the potential for stimulation of other ⁇ -receptors and subsequent side effects.
  • the most likely of these include muscle tremor ( ⁇ 2) and increased heart rate ( ⁇ l).
  • ⁇ 2 muscle tremor
  • ⁇ l increased heart rate
  • these phenylethanolamine derivatives do possess some ⁇ 3 selectivity, side effects of this type have been observed in human volunteers. It is reasonable to expect that these side effects resulted from partial ⁇ l and/or ⁇ 2 agonism.
  • the instant invention is concerned with thiazole substituted benzenesulfonamides which are useful as antiobesity and antidiabetic compounds.
  • a still further object is to describe processes for the preparation of such compounds.
  • Another object is to describe methods and compositions which use the compounds as the active ingredient thereof. Further objects will become apparent from reading the following description.
  • the present invention provides compounds having the formula I:
  • X is (1) a bond
  • C1-C3 alkylene wherein said alkylene contains an oxygen, optionally substituted with 1 or 2 groups selected from methyl and halogen; m is 0 to 5; A is (1) phenyl, (2) a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen,
  • Rl is (1) Cl-ClO alkyl optionally substituted with up to 5 groups selected from
  • R4 is (1) H, or
  • X is (1) a bond
  • Rl is (1) Cl-ClO alkyl optionally substituted with up to 5 halogens
  • R is (1) Cl-Cio alkyl
  • A is selected from phenyl, naphthyl, a 5 or 6- membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygenk sulfur and nitrogen fused to a benzene ring, and a 5 or 6- membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen.
  • A is selected from phenyl, naphthyl, thienyl, pyridinyl, benzothienyl, quinolinyl, indolyl, and benzofuranyl.
  • A is (1) phenyl
  • Rl is (1) Cl-ClO alkyl optionally substituted with up to 5 halogens
  • R3 is (1) Cl-ClO alkyl; and Q is (1) 0; or a pharmaceutically acceptable salt thereof.
  • X is (1) a bond, (2) CH 2 ,
  • A is (1) phenyl, (2) a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen,
  • Rl is (1) Cl-ClO alkyl optionally substituted with up to 5 halogens; (2) halogen,
  • R is (1) hydrogen
  • Q is (1) O; and either the benzenesulfonamide moiety or X (or A, if X is a bond) is attached to the C2 of the thiazole ring, and the other to the C4 positions of the thiazole ring; or a pharmaceutically acceptable salt thereof.
  • Representative antiobesity and antidiabetic compounds of the present invention include the following: l. N-[4-[2-[[.2-hydroxy-2-(3- ⁇ yridinyl)ethyl]aminolethyl] ⁇ henyll-4-[4-(2- naphthylmethyl)thiazol-2-yl]benzenesulfonamide; 2. N-[4-[2-[[2-hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-[4- [4-(trifluoromethyl)phenyl]thiazol-2-yl]benzenesulfonamide;
  • the compounds of the instant invention all have at least one asymmetric center as noted by the asterisk in structural Formula I. Additional asymmetric centers may be present on the molecule. Each such asymmetric center will produce two optical isomers and it is intended that all such optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof, be included within the ambit of the instant invention.
  • the asymmetric center represented by the asterisk in Formula I it has been found that the compound in which the hydroxy substituent is above the plane of the structure, as seen in Formula Ic, is more active and thus more preferred over the compound in which the hydroxy substituent is below the plane of the structure.
  • the following stereospecific structure represents the preferred stereoisomers of the instant invention:
  • the thiazolyl moiety is numbered as follows:
  • Alkylene means -(CH2) ⁇ - where p is the designated carbon number; one or two of the hydrogen may be optionally replaced by methyl or halogen. Where the optionally substituted alkylene contains an oxygen, the oxygen may be at either end of the alkylene chain, or it may be embedded within the chain. Examples include OCH2, CH20, CH2OCH2, C(CH3)2 ⁇ , etc.
  • alkyl groups specified above are intended to include those alkyl groups of the designated length in either a straight or branched configuration.
  • exemplary of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl, isohexyl, and the like.
  • alkoxy groups specified above are intended to include those alkoxy groups of the designated length in either a straight or branched configuration. Exemplary of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.
  • halogen is intended to include the halogen atoms fluorine, chlorine, bromine and iodine.
  • a benzene ring fused to a C5-C10 carbocyclic ring includes naphthyl, tetrahydronaphthyl, indanyl and indenyl.
  • a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a C5-C10 carbocyclic ring includes benzene fused to a heterocyclic ring as well as a non-aromatic carbocyclic ring fused to a heterocyclic ring.
  • the carbocyclic ring preferably is C5-C7.
  • a 5 and 6-membered heterocyclic ring is intended to include aromatic and unsaturated non-aromatic heterocycles; and where the heterocycle is part of a fused ring, at least one of the rings is aromatic.
  • Examples of a 5 or 6- membered ring include pyridyl, pyrimidinyl, pyrrolyl, furyl, thienyl, imidazolyl, thiazolyl, thiadiazolyl, tetrazolyl, oxadiazolyl, oxazolyl, imidazolidinyl, pyrazolyl, isoxazolyl.
  • Examples of a benzene ring fused to a 5 or 6-membered heterocyclic ring include benzothiadiazolyl, indolyl, indolinyl, benzodioxolyl, benzodioxanyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazinyl, benzisoxazolyl, benzothiazolyl, 2,3-dihydrobenzofuranyl, quinolinyl, benzotriazolyl, benzoxazolyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinolinyl.
  • Examples of a 5 or 6-membered heterocyclic ring fused to a non-aromatic carbocyclic ring include tetrahydrobenzothiazolyl, 5,6,7,8-tetrahydroquinolinyl, 2,3- cyclopentenopyridyl, 4,5,6,7-tetrahydroindolyl, 5,6,7,8- tetrahydroisoquinolyl, 5,6,7, 8-tetrahydroquinoxalinyl.
  • composition as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • prodrugs are derivatives of compounds of Formula I that are transformed in vivo to the active drug molecule; prodrugs include derivatives of free hydroxy, amino or carboxylic groups such as esters, ethers, amides, carbonates, carbamates, and N-alkyl derivatives.
  • prodrugs of compounds of Formula I include: (a) derivation of the secondary amine such as N-alkylation (methyl, ethyl, isopropyl and 2- methoxy ethyl), and N-acylation (1-pyrrolidinylacetyl, 4- morpholinylacetyl, (l-acetoxy)ethoxycarbonyl, and dimethylaminoacetyl); (b) derivation of the secondary hydroxy such as O-alkylation (ethyl) and O-acylation (acetyl, t-butoxycarbonyl, benzoyl, cyclopropylcarbonyl); and (c) the vicinally positioned secondary amine and secondary hydroxy taken together form a group of the formula
  • U and V are independently a bond, carbonyl, methylene, CH(OH) or C(OH)(CH3).
  • Prodrugs of the above-described types may be readily prepared from compounds of Formula I using methods well know to persons skilled in the art.
  • NR 2 R 2 may represent NH2, NHCH3, N(CH3)CH2CH3, and the like.
  • the compounds (I) of the present invention can be prepared as described in the following schemes. Thiazoles la, lb and Ic are prepared via the Hantzsch thiazole synthesis (Sainsbury, M. In “Rodd's Chemistry of Carbon Compounds", Coffey, S., Ausell, M. F., Eds.; Elsevier: Amsterdam, 1986; Vol. IV C, 399-455) from the appropriate thioamide and 2-halocarbonyl derivative.
  • the protected aniline derivative 5 (Fisher, et. al, US 5,561,142, Oct. 1, 1996) is treated with sulfonyl chloride 4, and a base such as pyridine in an anhydrous solvent such as dichloromethane or chloroform for 0.5 to 24 hours at temperatures of -20 to 50°C, preferably 0°C, followed by removal of the protecting group with, in the case of a tert-butylcarbamate, acid such as trifluoroacetic acid or methanolic hydrogen chloride, provides the thiazole la.
  • a base such as pyridine
  • an anhydrous solvent such as dichloromethane or chloroform
  • the chloroketones 2 are commercially available, known in the literature, or readily prepared by methods commonly known to those skilled in the art. Conveniently, the corresponding acid chloride 6 is treated with diazomethane followed by hydrogen chloride to provide chloroketone 2, as illustrated in Scheme 2.
  • Nitrile 7 (Fisher, et. al, US 5,561,142, Oct. 1, 1996) is converted to the corresponding thiamide by treatment with hydrogen sulfide in the presence of base such as triethylamine.
  • the thiazole is formed from chloroketone 2 as described above.
  • Removal of the t-butoxycarbonyl (Boc) protecting group by treatment with acid such as trifluoroacetic acid in dichloromethane or methanolic hydrogen chloride provides the desired thiazole (la).
  • Thiazoles lb are prepared as illustrated in Scheme 4.
  • Thioamide 8 is treated with the appropriate 2-bromoaldehyde 9 at elevated temperatures, conveniently in an inert solvent such as acetonitrile or acetonitrile/chloroform mixtures at reflux temperature, to provide, after deprotection as described above, thiazole lb.
  • Bromoaldehydes 9 are known in the literature or readily prepared by methods comonly known to those skilled in the art. Conveniently, the corresponding alcohol 10 is oxidized to aldehyde H, for example by treatment with o-iodoxybenzoic acid in DMSO (Frigerio and Santagostino, Tetrahedron Lett. 1994, 35, 8019). Bromination may be accomplished by treatment with a brominating agent, conveniently t- butyldimethylsilyl bromide/DMSO (Bellesia, et. al., J. Chem. Research (S) 1986, 428), to provide the desired bromoaldehydes 9. SCHEME 5.
  • a brominating agent conveniently t- butyldimethylsilyl bromide/DMSO (Bellesia, et. al., J. Chem. Research (S) 1986, 428), to provide the desired bromoaldehydes 9. SCHEME 5.
  • Thiazoles Ic are synthesized as oulined in Scheme 6.
  • the appropriate nitrile 12 which is commercially available, known in the literature, or readily synthesized by methods known to those skilled in the art, is treated with hydrogen sulfide in the presence of a base such as triethylamine, and the resultant thioamide is treated with ⁇ ,4- dibromoacetophenone ( 13) at elevated temperature, conveniently in refluxing ethanol, to provide thiazole 14.
  • This compound is then protected at the 5-position, for example as the 5-trimethylsilyl derivative by treatment with n-butyllithium followed by trimethylsilyl chloride.
  • Thiazoles Id may be prepared as illustrated in Scheme 7.
  • Aminoacetophenone 1_S is prepared from bromo derivative J_3 using a modified Delepine reaction (Goddard, C. J. /. Heterocyclic Chem. 1991, 28, 17), by treatment of compound 13 with hexamethylenetetramine 17 followed by hydrochloric acid in methanol. Amine 18 . is then treated with the appropriate acid chloride to give ketone 20. Formation of the thiazole is accomplished by treatment with Lawesson's reagent at elevated temperature, conveniently in refluxing toluene. The resultant bromo derivative 21 is converted to the desired thiazole Id as described above in Scheme 1 for thiazole la.
  • Acid chlorides 19 are commercially available, known in the literature, or readily prepared using methods commonly known to those skilled in the art.
  • the product I from the reactions described in Schemes 1-7 may be further modified, for example, by the removal of protecting groups or the manipulation of substituents on Rl. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions which are commonly known to those skilled in the art.
  • Compounds of Formula I contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention is meant to comprehend all such isomeric forms of the compounds of Formula I.
  • Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.
  • Some of the compounds described herein may exist as tautomers such as keto-enol tautomers.
  • the individual tautomers as well as mixture thereof are encompassed with compounds of Formula I.
  • Compounds of the Formula I may be separated into diastereoisomeric pairs of enantiomers by, for example, fractional crystallization from a suitable solvent, for example methanol or ethyl acetate or a mixture thereof.
  • the pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active acid as a resolving agent.
  • any enantiomer of a compound of the general Formula I or la may be obtained by stereospecific synthesis using optically pure starting materials of known configuration.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl- morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • basic ion exchange resins such as
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
  • Compounds of the present invention are potent agonists of the ⁇ 3-adrenoceptor, and as such are useful in treating or preventing diseases, disorders or conditions mediated by the activation of ⁇ 3- adrenoceptor.
  • one aspect of the present invention provides a method for the treatment, control or prevention of such diseases, disorders, or conditions in a mammal which comprises administering to such mammal a therapeutically effective amount of a compound of Formula I.
  • mammal includes human and non-human animals such as dogs and cats and the like.
  • the diseases, disorders or conditions for which compounds of the present invention are useful in treating or preventing include, but are not limited to, (1) diabetes mellitus, (2) hyperglycemia, (3) obesity, (4) hyperlipidemia, (5) hypertriglyceridemia, (6) hypercholesterolemia, (7) atherosclerosis of coronary, cerebrovascular and peripheral arteries, (8) gastrointestinal disorders including peptid ulcer, esophagitis, gastritis and duodenitis, (including that induced by H.
  • any suitable route of administration may be employed for providing a mammal, especially a human with an effective dosage of a compound of the present invention.
  • a mammal especially a human with an effective dosage of a compound of the present invention.
  • oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
  • compounds of Formula I are administered orally.
  • the effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the species of mammals being treated, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art of human or veterinary medicine.
  • the compounds of the present invention are administered at a daily dosage of from 0.01 milligram to about 100 milligrams per kilogram of animal body weight, preferably given in a single dose or in divided doses two to six times a day, or in sustained release form.
  • the total daily dose will generally be from about 0.7 milligrams to about 3500 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
  • the compounds of the present invention are administered at a daily dosage of from about 0.001 milligram to about 100 milligram per kilogram of animal body weight, preferably given in a single dose or in divided doses two to six times a day, or in sustained release form.
  • the total daily dose will generally be from about 0.07 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
  • compositions which comprises a compound of Formula I and a pharmaceutically acceptable carrier.
  • the pharmaceutical compositions of the present invention comprise a compound of Formula I as an active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids.
  • the compounds of Formula I can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
  • any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations- being preferred over the liquid preparations.
  • oral liquid preparations such as, for example, suspensions, elixirs and solutions
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations- being preferred over the
  • tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained.
  • the active compounds can also be administered intranasally as, for example, liquid drops or spray.
  • the tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin.
  • a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
  • tablets may be coated with shellac, sugar or both.
  • a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
  • Compounds of formula I may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxy- propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • Compounds of Formula I may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which compounds of Formula I are useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of Formula I.
  • a pharmaceutical composition containing such other drugs in addition to the compound of Formula I is preferred.
  • the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of Formula I.
  • insulin sensitizers including (i) PPAR ⁇ agonists such as the glitazones (e.g. troglitazone, pioglitazone, englitazone, MCC-555, BRL49653 and the like), and compounds disclosed in W097/27857, 97/28115, 97/28137 and 97/27847; (ii) biguanides such as metformin and phenformin; (b) insulin or insulin mimetics;
  • PPAR ⁇ agonists such as the glitazones (e.g. troglitazone, pioglitazone, englitazone, MCC-555, BRL49653 and the like), and compounds disclosed in W097/27857, 97/28115, 97/28137 and 97/27847; (ii) biguanides such as metformin and phenformin; (b) insulin or insulin mimetics;
  • ⁇ -glucosidase inhibitors such as acarbose
  • cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin and pravastatin, fluvastatin, atorvastatin, and other statins), (ii) sequestrants (cholestyramine, colestipol and a dialkylaminoalkyl derivatives of a cross-linked dextran), (ii) nicotinyl alcohol nicotinic acid or a salt thereof, (iii) proliferator- activater receptor agonists such as fenofibric acid derivatives (gemfibrozil, clofibrat, fenofibrate and benzafibrate), (iv) inhibitors of cholesterol absorption for example beta-sitosterol and (acyl CoA: cholesterol acyltransferase) inhibitors for example melinamide, (v) probucol, (vi) vitamin E, and (vii) thyromimetics;
  • PPAR ⁇ agonists such as those disclosed in W097/28149;
  • antiobesity compounds such as fenfluramine, dexfenfluramine, phentermine, sibutramine, orlistat, and other ⁇ 3 adrenergic receptor agonists;
  • feeding behavior modifying agents such as neuropeptide Y antagonists (e.g. neuropeptide Y5) such as those disclosed in WO 97/19682, WO 97/20820, WO 97/20821 , WO 97/20822 and WO 97/20823;
  • neuropeptide Y antagonists e.g. neuropeptide Y5
  • WO 97/19682 WO 97/20820, WO 97/20821 , WO 97/20822 and WO 97/20823;
  • cAMP production in response to ligand is measured according to Barton et al (1991-, Agonist-induced desensitization of D2 dopamine receptors in human Y-79 retinoblastoma cells. Mol. Pharmacol. v3229:650-658) modified as follows. Chinese hamster ovary (CHO) cells, stably transfected with the cloned ⁇ -adrenergic receptor (Bl , ⁇ 2 or B3) are harvested after 3 days of subculturing.
  • the cell lysate is diluted 5-fold in 0.1 N HCl and then acetylated by the mixture of 150 ⁇ L of acid-diluted sample with 6 ⁇ L of acetylation mixture (acetic anhydride/triethylamine, 1 :2.5).
  • the cAMP produced in response to the ligand is measured in the lysate by competing against l 2 5 ⁇ _ c ]yrp f or binding to a l ⁇ i-cAMP-directed antibody using an automated RIA machine (ATTOFLO, Atto Instruments, Baltimore, MD, Brooker et al 1979, Radioimmunoassay of Cyclic AMP and Cyclic GMP.
  • cAMP level is determined by comparing levels to a standard curve.
  • cAMP is measured using the cAMP SPA kit (code number RPA 556) from Amersham according to the manufacturer's instructions. Samples tested with the latter method do not need to be acetylated.
  • the non-selective, full agonist ⁇ -adrenergic ligand isoproterenol is used at all three receptors to determine maximal stimulation.
  • the human B3 adrenergic receptor (AR) selective ligand (S -N-[4-[2-[[2-hydroxy-3-(4- hy droxyphenoxy )propy 1] amino] ethyl] -phenyl] -4-iodobenzenesulf onamide is used as a control in all assays.
  • Isoproterenol is titrated at a final concentration in the assay of 10" 10 M to 10" 5 M for the B3 AR and 10-11 M t0 ⁇ o-6 M for the Bl AR and B2 AR assays.
  • (S)-N-[4-[2-[[2-Hydroxy-3-(4- hydroxyphenoxy)propyl]amino]ethyl]-phenyl]-4-iodobenzenesulfonamide is titrated at the B3 receptor at concentration of 10 "1 1 M to 10 -6 M.
  • the concentrations used are 10"8 M, 10" 7 M, 3X10" 7 M, 10" 6 M, 3X10"6 M and 10 ⁇ 5 M
  • Unknown ligands are initially tested at the B3 AR at a final concentration in the assay of 10 ⁇ 7 M. Compounds that have an activation at this concentration equal to or greater than 35% of the isoproterenol stimulation are titrated at the B3 AR at concentrations equal to those used to titrate the control (S )-N- [4- [2- [[2-hy droxy-3-(4-hy droxyphenoxy )propyl] amino]ethyl]phenyl]-4-iodobenzenesulfonamide to determine the EC50.
  • the EC50 is defined as the concentration of compound that gives 50% activation of its own maximum.
  • Binding Assay Compounds are also assayed at the Bl and B2 receptors to determine selectivity. This is done for all compounds using a 6 point binding assay as follows: CHO cells expressing the Bl and the B2 receptors are grown for 3-4 days after splitting. The attached cells are washed with PBS and lysed in ImM Tris, pH 7.2 for 10 minutes in ice. The flasks are scraped and the membranes centrifuged at 38,000 x g for 15 minutes at 4 °C.
  • the membranes are resuspended in TME buffer (75 mM Tris, pH 7.4, 12.5 mM MgCl2, 1.5 mM EDTA) at a concentration of 1 mg protein/ml. Large batches of membranes can be prepared, aliquoted and stored at -70°C for up to a year without loss of potency.
  • the binding assay is performed by incubating together membranes (20-50 ⁇ g of protein), the radiolabelled tracer 125 ⁇ _ cyanopindolol ( l 2 5i_CYP, 45pM), and the test compounds at final concentrations ranging from 10-10 M to 10 " 5 M in a final volume of 250 ⁇ L of TME buffer.
  • the tubes are incubated for 1 hour with shaking at room temperature and the samples are filtered in an IMSCO 96-well cell harvester.
  • the filters are counted in a Gamma counter and the data are analyzed using a 4 parameter fit routine in RS 1 (program developed in house using well documented statistical analysis programs) to determine the IC50.
  • the IC50 is defined as the concentration of the compound capable of inhibiting 50% of the binding of the radiolabelled tracer (l 2 5 ⁇ _CYP).
  • a compound's selectivity for the ⁇ 3 receptor may be determined by calculating the ratio (IC50 Bl AR, B2 AR)/(EC50 B3 AR).
  • the yellow oily residue was dissolved in 40 mL of dry ether, cooled in ice, and a solution of hydrochloric acid in methanol (prepared from 0.30 mL of acetyl chloride and 2.0 mL of methanol at 0°C) was added dropwise. After lh, the solution was concentrated under reduced pressure.
  • Step B 2-(4-Bromophenyl)-4-(2-naphthylmethyl)thiazole.
  • Step C 4-[4-(2-Naphthylmethyl)thiazol-2-yl1benzenesulfonyl chloride.
  • a solution of the above aryl bromide (0.53 g) in 10 mL of dry tetrahydrofuran was cooled to -78°C, and a solution of n-butyllithium (1.0 mL of 1.6 M in hexanes) was added dropwise. After 30 min, a steady stream of sulfur dioxide was introduced into the surface of the deep brown-red solution for a period of 5 min. The resulting yellow solution was stirred at -78°C for 10 min, and was then allowed to warm to room temperature.
  • Step A (R -N-[4-r2-[N-(l.l-Dimethylethoxycarbonyl -N-r2-hvdroxy-2- (pyridin-3-yl ethyl]amino1ethyl]phenyl]-4-aminothiocarbonyl benzene sulfonamide.
  • Step B (R -N-r4-r2-r[2-Hvdroxy-2-(pyridin-3-yl ethvnaminolethyll phenyl1-4-r4-(4-trifluoromethylphenyl)thiazol-2-yl1benzenesulfonamide.
  • Step A ⁇ -Amino-4-bromoacetophenone hydrochloride.
  • the general procedure for the modified Delepine reaction (Goddard, C. J. J. Heterocyclic Chem. 1991, 28, 17) was used.
  • the precipitated solid was collected, washed with chloroform, dried in vacuo, and was then suspended in a mixture of 6 mL of concentrated hydrochloric acid and 30 mL of methanol and stirred overnight.
  • the precipitated solid was collected, washed with methanol and dried in vacuo, affording 1.38 g of white powder, which was used without further purification.
  • Step B ⁇ -Amino-4-bromoacetophenone 4-(Trifluoromethyl benzamide.
  • a mixture of the above hydrochloride salt (1.38 g) and triethylamine (1.50 mL) in 40 mL of chloroform was cooled in an ice- water bath, and a solution of 4- (trifluoromethyl)benzoyl chloride (1.21 g) in 5 mL of chloroform was added dropwise. The mixture was stirred at 0°C for 1 h, diluted with 30 mL of chloroform and washed sequentially with water, 5% aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and saturated brine.
  • Step C 5-(4-Bromophenyl -2-(4-Trifluoromethylphenyl)thiazole.
  • Step D 5-(4-Chlorosulfonylphenyl)-2-(4-Trifluoromethylphenyl thiazole.
  • a solution of the above aryl bromide (0.356 g) in 6 mL of dry THF was treated with n-butyllithium (0.63 mL of 1.6 M in hexanes), followed by sulfur dioxide and then N-chlorosuccinimide as described in Example 1 , Step C above.
  • Step E (R -N-r4-r2-r[2-Hvdroxy-2-(p ⁇ ridin-3-yl ethyllaminolethyll phenyll-4-[2-(4-trifluoromethylphenyl)thiazol-5-yl1benzenesulfonamide
  • a solution of 0.131 g of (R)-N-[2-[4-(aminophenyl)]ethyl]-2-hydroxy-2- (pyrid-3-yl)ethylcarbamic acid 1,1-dimethylethyl ester in 1.6 mL of dichloromethane was treated with the above sulfonyl chloride (0.171 g) and 0.040 mL of pyridine, followed by addition of trifluoroacetic acid, as described in Example 1, Step D.
  • Step B (R -N-[4-r2-r[2-Hvdroxy-2-(pyridin-3-yDethyllaminolethyll phenyll-4-[5-(4-fluorophenyl)thiazol-2-ynbenzenesulfonamide.
  • Step A 4-(Trifluoromethyl )thiobenzamide.
  • 4-(Trifluoromethyl)benzonitrile (3.42 g) was treated with triethylamine (2.12 g) and hydrogen sulfide in pyridine solution as described in Example 2, Step A.
  • Step B 4-(4-Bromophenyl)-2-(4-Trifluoromethylphenyl thiazole.
  • Step C 4-f4-Bromophenyl)-2-(4-Trifluoromethylphenyl)-5- ftrimethylsilyPthiazole.
  • a solution of the aryl bromide obtained above (0.576 g) in 10 mL of dry tetrahydrofuran (THF) was cooled in a dry ice-acetone bath, and a solution of n-butyllithium (1.0 mL of 1.6 M in hexanes) was added dropwise. After an additional 10 min, trimethylsilyl chloride (0.196 g, 0.23 mL) was added in one portion. After an additional 15 min, the cooling bath was removed, and the reaction mixture was allowed to warm to room temperature over 1 h.
  • Step D 4-f4-Chlorosulfonylphenyl -2-(4-Trifluoromethylphenyl)-5- (trimethy lsily Dthiazole .
  • the aryl bromide from above (0.456 g) was treated with n-butyllithium, followed by sulfur dioxide and then N-chlorosuccinimide as described in Example 1, Step C above.
  • the crude product (0.223 g) was used without further purification.
  • Step E (RVN-r4-r2-rr2-Hvdroxy-2-(pyridin-3-yl ethyllaminolethyllphenyn-4- [2-( , 4-trifluoromethylphenyl)thiazol-4-yllbenzenesulfonamide.

Abstract

Les benzènesulfonamides à substitution thiazole sont des agonistes du récepteur adrénergique β3 présentant une très faible activité de récepteur adrénergique β1 et β2, et en tant que tels, ces composés peuvent accroître la lipolyse et la dépense énergétique dans les cellules. Ces composés sont par conséquent très efficaces dans le traitement du diabète de type II et de l'obésité. Ces composés peuvent également être utilisés pour abaisser les taux de triglycéride et de cholestérol ou augmenter les taux de lipoprotéine haute densité ou diminuer le transit intestinal. En outre, ces composés peuvent être utilisés pour réduire l'inflammation neurogène ou comme antidépresseurs. Ces composés sont préparés par couplage d'un aminoalkylphénylsulfonamide avec un époxyde substitué de façon approprié. L'invention concerne également des composés et des méthodes pour utiliser les composés dans le traitement du diabète et de l'obésité et pour abaisser les taux de triglycéride et de cholestérol ou augmenter les taux de lipoprotéine haute densité ou diminuer le transit intestinal.
EP98903677A 1997-01-28 1998-01-23 THIAZOLE BENZENESULFONAMIDES UTILISES COMME AGONISTES $g(b) 3? POUR LE TRAITEMENT DU DIABETE ET DE L'OBESITE Withdrawn EP0968209A1 (fr)

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GBGB9705041.3A GB9705041D0 (en) 1997-03-12 1997-03-12 Thiazole benzenesulfonamides as selective B3 agonists for the treatment of diabetes and obesity
GB9705041 1997-03-12
PCT/US1998/001317 WO1998032753A1 (fr) 1997-01-28 1998-01-23 THIAZOLE BENZENESULFONAMIDES UTILISES COMME AGONISTES β3 POUR LE TRAITEMENT DU DIABETE ET DE L'OBESITE

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