WO1995029159A1 - SULFAMIDES SUBSTITUES UTILISES COMME AGONISTES SELECTIFS VIS-A-VIS DES RECEPTEURS β3-ADRENERGIQUES, POUR LE TRAITEMENT DU DIABETE ET DE L'OBESITE - Google Patents

SULFAMIDES SUBSTITUES UTILISES COMME AGONISTES SELECTIFS VIS-A-VIS DES RECEPTEURS β3-ADRENERGIQUES, POUR LE TRAITEMENT DU DIABETE ET DE L'OBESITE Download PDF

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Publication number
WO1995029159A1
WO1995029159A1 PCT/US1995/004956 US9504956W WO9529159A1 WO 1995029159 A1 WO1995029159 A1 WO 1995029159A1 US 9504956 W US9504956 W US 9504956W WO 9529159 A1 WO9529159 A1 WO 9529159A1
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WO
WIPO (PCT)
Prior art keywords
ethyl
hydroxy
amino
phenyl
pyridinyl
Prior art date
Application number
PCT/US1995/004956
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English (en)
Inventor
Michael H. Fisher
Elisabeth M. Naylor
Dong Ok
Ann E. Weber
Thomas Shih
Hyun Ok
Original Assignee
Merck & 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 US08/404,566 external-priority patent/US5541197A/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to KR1019960705994A priority Critical patent/KR970702252A/ko
Priority to EP95917116A priority patent/EP0757674A1/fr
Priority to JP52779795A priority patent/JP3149186B2/ja
Priority to AU23937/95A priority patent/AU687558B2/en
Priority to SK1361-96A priority patent/SK136196A3/sk
Priority to MXPA/A/1996/005192A priority patent/MXPA96005192A/xx
Priority to NZ284718A priority patent/NZ284718A/en
Publication of WO1995029159A1 publication Critical patent/WO1995029159A1/fr
Priority to NO964548A priority patent/NO964548L/no
Priority to FI964314A priority patent/FI964314A0/fi

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    • C07—ORGANIC CHEMISTRY
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
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    • A—HUMAN NECESSITIES
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    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
    • C07C311/47—Y being a hetero atom
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    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/36—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/32—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
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    • 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
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • ⁇ -Adrenoceptors have been subclassified as ⁇ i and ⁇ 2 since 1967. Increased heart rate is the primary consequence of ⁇ i -receptor stimulation, while brohchodilation and smooth muscle relaxation typically result from ⁇ 2 stimulation.
  • Adipocyte lipolysis was initially thought to be solely a ⁇ i -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 substituted sulfonamides 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. DESCRIPTION OF THE INVENTION
  • the present invention provides compounds having the formula I:
  • A is (1) a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen,
  • R2 and R3 are independently
  • X is (1) -CH2-
  • R6 i is (1) hydrogen or
  • R7 i is Z-(Rla) n ;
  • R a is (l) Rl, with the proviso that when A is phenyl, R ⁇ a is not
  • phenyl optionally substituted with up to 4 groups independently selected from R , NR R8 ? OR8, SR8 and halogen, or
  • Z is (1) phenyl
  • R8 is (1) hydrogen
  • R9 is (l) R8 or
  • RlO is (1) Cl-ClO alkyl, or
  • A is a 5 or 6- membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, a benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen.
  • A is phenyl or benzene fused to a C3-C8 cycloalkyl ring.
  • R2 and R3 are hydrogen or methyl;
  • X is -CH2-;
  • n is 0 to 3;
  • m is 1;
  • r is 0 to 2;
  • R4, R5 and R6 are hydrogen.
  • A is phenyl or a 6-membered heterocyclic ring with 1 or 2 heteroatoms selected from nitrogen and sulfur;
  • Rl is hydroxy, halogen, cyano, trifluoromethyl, NR8R8,
  • NR8SO2R 9 NR8COR9, NR8CO2R8, C1-C6 alkyl optionally substituted by hydroxy; and r is 0 or 2.
  • (8) a 5 or 6-membered heterocycle with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with up to four groups independently selected from oxo, halogen, R8, NR8R8, OR , and SR 8 ;
  • Z is (1) phenyl
  • X is -CH2-
  • R8 and R9 are as defined under formula I.
  • n 0 or 1 ;
  • R 1 is NR R8;
  • R2 and R3 are independently
  • Rl a is (1) halogen
  • a 5 or 6-membered heterocycle with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with up to four groups independently selected from oxo, R8, SR8, OR8, and NR8R8 ; when B and the benzene ring form a fused ring system, Rla is attached to either ring; R8 is (1) hydrogen,
  • Cl-ClO alkyl having 1 to 4 substituents selected from hydroxy, halogen, Cl-ClO alkyl, C3-C8 cycloalkyl, and Z optionally substituted by from 1 to 4 of halogen, Cl-ClO alkyl or Cl-ClO alkoxy;
  • R9 is (l) R8 or
  • RlO is (1) Cl-ClO alkyl, or
  • Rl is (1) hydroxy
  • (6) a 5 or 6-membered heterocycle with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with up to three groups independently selected from oxo, halogen, R8, NR8R8, OR8 and SR8;
  • Z is (1) phenyl
  • X is -CH2-
  • R2 and R3 are independently hydrogen or methyl.
  • antiobesity and antidiabetic compounds of the present invention include the following:
  • 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 depending upon the nature of the various substituents on the molecule, in particular, R2 and R3. 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.
  • n, m, r, A, Rl, R 2 , R3, R4, R5 ? R6, R7 an d x are as defined above under formula I.
  • 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.
  • Examples of 5 and 6-membered heterocycles and fused heterocycles of A, Z and Rla include pyridyl, quinolinyl, pyrimidinyl, pyrrolyl, thienyl, imidazolyl, thiazolyl, benzimidazolyl, thiadiazolyl, benzothiadiazolyl, indolyl, indolinyl, benzodioxolyl, benzodioxanyl, benzothiophenyl, benzofuranyl, benzoxazinyl, benzisoxazolyl, benzothiazolyl, tetrahydronaphthyl, dihydrobenzofuranyl, tetrahydroquinolinyl, furopyridine and thienopyridine.
  • a and Z are phenyl, naphthyl, benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or heterocycles with from 1 to 4 heteroatoms independently selected from one of oxygen or sulfur, and/or 1 to 4 nitrogen atoms.
  • A is phenyl, pyridyl, quinolinyl, pyrimidinyl, pyrrolyl, thienyl, imidazolyl, and thiazolyl.
  • Z are phenyl, naphthyl, quinolinyl, thienyl, benzimidazolyl, thiadiazolyl, benzothiadiazolyl, indolyl, indolinyl, benzodioxolyl, benzodioxanyl, benzothiophenyl, benzofuranyl, benzoxazinyl, benzisoxazolyl, benzothiazolyl, tetrahydronaphthyl, dihydrobenzofuranyl, triazolyl, tetrazolyl, oxadiazolyl, imidazolyl, oxazolyl, thiazolyl, imidazolidinyl, pyrazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazolyl, tetrahydrobenzothiazolyl and tetrahydroquinolinyl.
  • Z When Z is attached to -NS ⁇ 2(CH2)r ⁇ , it is preferably phenyl, naphthyl or a benzene ring fused to a 5 or 6- membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen.
  • Z is part of the definition of R8, it is preferably phenyl, a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrog * en, a benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or a 5 or 6- membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a C3-C8 cycloalkyl ring.
  • Rla The preferred heterocycles of Rla are thienyl, thiadiazolyl, triazolyl, tetrazolyl, oxadiazolyl, imidazolyl, oxazolyl, thiazolyl, imidazolidinyl, pyrazolyl, isoxazolyl, pyridyl, pyrimidyl, and pyrazolyl.
  • NR8R8 may represent NH2, NHCH3, N(CH3)CH2CH3, and the like.
  • THF tetrahydrofuran The compounds (I) of the present invention can be prepared from epoxide intermediates such as those of formula II and amine intermediates such as those of formula III. The preparation of these intermediates is described in the following schemes.
  • n, m, r, A, Rl, R 2 , R 3 , R 4 , R 5 , R6, R7 and X are as defined above.
  • the enantiomerically enriched (R) and (S) epoxides II are readily available by asymmetric reduction of haloketones 2 using chiral reducing agents such as (-) or (+)-DIP-Cl, (R) or (S)- Alpine borane or (/?) or (-S')-tetrahydro-l-methyl-3,3- diphenyl-l /,3 -pyrrolo[l,2-c][l,3,2]oxazaborole-borane ((R) or (5)- OAB-BH 3 ).
  • chiral reducing agents such as (-) or (+)-DIP-Cl, (R) or (S)- Alpine borane or (/?) or (-S')-tetrahydro-l-methyl-3,3- diphenyl-l /,3 -pyrrolo[l,2-c][l,3,2]oxazaborole-borane ((R) or (5)- OAB-
  • Methylketone 4 may be converted to the corresponding haloketone using a variety of reagents known to those in the art and summarized in Larock Comprehensive Organic Transformations; VCH: New York, 1989, 369-372. Conveniently, methylketone 4 is treated with chlorine or -V-chlorosuccinimide in acetic acid with an additional acid source such as hydrogen chloride or aluminum chloride.
  • an additional acid source such as hydrogen chloride or aluminum chloride.
  • X Br
  • bromine, dibromobarbituric acid or NBS with hydrogen bromide or aluminum bromide may be used.
  • the chloro or bromoketones 2 may be commercially available.
  • methylketones 4 are commercially available or readily prepared by methods described in the literature and known to those skilled in the art. Rl substituents on the acid chlorides 1 or methylketones 4 may need to be protected during the subsequent procedures. A description of such protecting groups may be found in: Protective Groups in Organic Synthesis. 2nd Ed., T. W. Greene and P. G. M. Wuts, John Wiley and Sons, New York, 1991.
  • Compounds III can be conveniently prepared by a variety of methods familiar to those skilled in the art.
  • a convenient route for their preparation when R6 is hydrogen is illustrated in Scheme 3.
  • Compound 5 is selectively protected as a suitable carbamate derivative 6 with, for example, di- rf-butyl dicarbonate or carbobenzyloxy chloride.
  • This compound is then treated with a sulfonyl halide, preferably the sulfonyl chloride 7-. 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, to provide the sulfonamide 8.
  • the protecting group is then removed with, for example, trifluoracetic acid in the case of Boc or catalytic hydrogenation in the case of Cbz, to give the desired amine 9.
  • the sulfonyl chlorides 7, many of which are commercially available, can also be readily prepared by a number of methods familiar to those skilled in the art.
  • One suitable method involves the addition of an organolithium reagent or a Grignard reagent to sulfuryl chloride following the procedure of S. N. Bhattacharya, et. al., J. Chem. Soc. (C), 1265-1267 (1969).
  • Another convenient method involves the treatment of a thiol with sulfuryl chloride and a metal nitrate according to the procedure of Y. J. Park, et. al., Chemistry Letters, 1483-1486 (1992).
  • Sulfonic acids are also conveniently converted to the corresponding sulfonyl chloride by treatment with PCI5, PCI3 or SOC12 (J. March, Advanced Organic Chemistry. 4th Ed., John Wiley and Sons, New York: 1992, pi 297 and references sited therein).
  • Aromatic and heteroaromatic compounds may be chlorosulfonylated directly by treatment with Vilsmeier's reagent or chorosulfonic acid (Organic Synthesis, I, 8).
  • the diamines 5 are commercially available or readily prepared by methods described in the literature or known to those skilled in the art.
  • Compound 5 where R2 or R3 is methyl can be prepared from the corresponding amino acid following the method of J. D. Bloom, et. al., J. Med.
  • Diamines 5 or sulfonamide amines ° . where X is -CH2O- and m is 1 are also readily prepared by methods described in the literature or known to those skilled in the art.
  • the sodium salt of 4-nitrophenol 16 is alkylated with 1- bromo-2-chloroethane, conveninetly in refluxing 2-butanone with a base such as potassium carbonate to give chloro derivative 17.
  • the chloride is converted to the corresponding amine by treatment with lithium azide followed by reduction with, for example, triphenylphosphine in aqueous tetrahydrofuran.
  • diamine 5 where X is -CH2O- and m is 1 is available from intermediate 19 by treatment with trifluoroacetic acid.
  • This diamine may then be modified as illustrated in Scheme 3.
  • Diamines 5 and sulfonamide amines 9 where X is -CH2CH2- and m is 1 are also readily prepared by methods described in the literature or known to those skilled in the art. For example, as shown in Scheme 7, bromo derivative 21 is treated with sodium cyanide to provide nitrile 22. The nitro group is selectively reduced by treatment with hydrogen and catalytic palladium to provide amine 23. Amine 23 is acylated with sulfonyl chloride 7 to give the corresponding sulfonamide 24. Reduction of compound 24 with cobalt chloride and sodium borohydride provides the desired amine 25.
  • diamine 5 where X is -CH2CH2- and m is 1 is available from intermediate 23 .
  • This diamine may then be modified as illustrated in Scheme 3.
  • the product is purified from unwanted side products by recrystallization, trituration, preparative thin layer chromatography, flash chromatography on silica gel as described by W. C. Still, et. aL, J- Org. Chem. 43, 2923 (1978), medium pressure liquid chromatography, or HPLC.
  • Compounds which are purified by HPLC may be isolated as the corresponding salt. Purification of intermediates is achieved in the same manner.
  • the coupling product I from the reaction described in Scheme 8 may be further modified, for example, by the removal of protecting groups or the manipulation of substituents on, in particular, Rl and R7. 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.
  • An alternate method for the synthesis of compound I is illustrated in Scheme 9.
  • Epoxide II is coupled to amine 5 as described above for coupling intermediates II and III (Scheme 8) to give aniline derivative 27.
  • the secondary amine is selectively protected, for example, as a carbamate by treatment with di-terf-butyldicarbonate to provide carbamate 29.
  • nitro amine 26 is used in the coupling reaction to provide 28.
  • the nitro group is reduced, for example, by catalytic hydrogenation with palladium catalyst or raney nickel, to provide intermediate 29.
  • other group may be reduced concomitantly.
  • R is halogen in intermediate 28, it may be converted to hydrogen in intermediate 29.
  • compound I from the reaction sequence illustrated in Scheme 9 may be further modified, for example, by the removal of protecting groups or the manipulation of substituents on, in particular, Rl and R7, as described above.
  • manipulation of substituents on any of the intermediates in the reaction sequence illustrated in Scheme 9 may occur.
  • One such example is illustrated in Scheme 10.
  • Compound 30, which is prepared as outlined in Scheme 9 from the corresponding epoxide, is subjected to reduction using tin(II) chloride to provide compound 21.
  • substituents on compound I which may be reduced to the corresponding amine by methods commonly known to those skilled in the art include nitro groups, nitriles, and azides.
  • the compounds (I) of the present invention can also be prepared from amine intermediates such as those of formula III and haloketone intermediates such as those of formula 2, as shown in Scheme 11.
  • Amine III is alkylated with haloketone derivative 2, conveniently by treatment of a mixture of III and 2 with base such as potassium carbonate or triethylamine in a polar solvent such as acetonitrile, acetone or dimethylformamide.
  • base such as potassium carbonate or triethylamine
  • a polar solvent such as acetonitrile, acetone or dimethylformamide.
  • the resultant aminoketone 32 is reduced with, for example, sodium borohydride in methanol to give the desired aminoalcohol I.
  • the product I from the reaction described in Scheme 11 may be further modified, for example, by the removal of protecting groups or the manipulation of substituents on, in particular, Rl and R7.
  • 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.
  • compound I may be synthesized directly from intermediate 27 without protection of the secondary amine.
  • aniline derivative 27 is treated with sulfonyl chloride 7 and a base such as pyridine in a solvent such as dichloromethane at a temperature of -30 to 50 °C, typically 0 °C, to provide compound I.
  • the product I from the reaction described in Scheme 13 may be further modified, for example, by the removal of protecting groups or the manipulation of substituents on, in particular, Rl and R7, as described above.
  • R 3 are hydrogen can also be prepared from acid intermediates of formula 36 and aminoalcohols of formula 37, as shown in Scheme 14.
  • Acid 36 is available from the corresponding ester 35, typically a methyl or ethyl ester, by treatment with sulfonyl chloride 7 and a base such as pyridine, followed by hydrolysis of the ester with aqueous acid or base.
  • Acid 36 is coupled to amine 37, which is known in the literature or readily prepared by methods known to those skilled in the art, using a coupling agent such as benzotriazolyl-N-oxy- tris(dimethylamino)phosphonium hexafluorophosphate or l-(3- dimethylaminopropyl)-3-ethylcarbodiimide methiodide to provide the amide 38- This is treated with a reducing agent, typically borane, to provide the desired compound I.
  • a coupling agent such as benzotriazolyl-N-oxy- tris(dimethylamino)phosphonium hexafluorophosphate or l-(3- dimethylaminopropyl)-3-ethylcarbodiimide methiodide
  • Compounds of the general 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.
  • 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 may be obtained by stereospecific synthesis using optically pure starting materials of known configuration.
  • the instant compounds can be isolated in the form of their pharmaceutically acceptable acid addition salts, such as the salts derived from using inorganic and organic acids.
  • acids are hydrochloric, nitric, sulfuric, phosphoric, formic, acetic, trifluoroacetic, propionic, maleic, succinic, malonic and the like.
  • certain compounds containing an acidic function such as a carboxy or tetrazole, can be isolated in the form of their inorganic salt in which the counterion can be selected from sodium, potassium, lithium, calcium, magnesium and the like, as well as from organic bases.
  • the compounds of the present invention have valuable pharmacological properties.
  • the present invention also provides a compound of the general Formula I or a pharmaceutically acceptable salt thereof for use as an active therapeutic substance.
  • the present invention provides a compound of the general Formula I or a pharmaceutically acceptable ester thereof: or a pharmaceutically acceptable salt thereof for use in the treatment of obesity in human or non-human animals.
  • the present invention further provides a compound of the general Formula I, or a pharmaceutically acceptable ester thereof; or pharmaceutically acceptable salt thereof, for use in the treatment of hyperglycemia (diabetes) in human or non-human animals.
  • the disease diabetes mellitus is characterized by metabolic defects in production and utilization of glucose which result in the failure to maintain appropriate blood sugar levels. The result of these defects is elevated blood glucose or hyperglycemia.
  • Research on the treatment of diabetes has centered on attempts to normalize fasting and postprandial blood glucose levels. Treatments have included parenteral administration of exogenous insulin, oral administration of drugs and dietary therapies.
  • Type I diabetes or insulin-dependent diabetes
  • Type II diabetes or insulin-independent diabetes
  • Most of the Type II diabetics are also obese.
  • the compounds of the present invention lower triglyceride levels and cholesterol levels and raise high density lipoprotein levels and are therefore of use in combatting medical conditions wherein such lowering (and raising) is thought to be beneficial.
  • they may be used in the treatment of hyper- triglyceridaemia, hypercholesterolaemia and conditions of low HDL (high density lipoprotein) levels in addition to the treatment of atherosclerotic disease such as of coronary, cerebrovascular and peripheral arteries, cardiovascular disease and related conditions.
  • the present invention provides a method of lowering triglyceride and/or cholesterol levels and/or increasing high density lipoprotein levels which comprises administering, to an animal in need thereof, a therapeutically effective amount of a compound of the formula (I) or pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating atherosclerosis which comprises administering, to an animal in need thereof; a therapeutically effective amount of a compound of the formula (I) or pharmaceutically acceptable salt thereof.
  • the compositions are formulated and administered in the same general manner as detailed below for treating diabetes and obesity.
  • They may also contain other active ingredients known for use in the treatment of atherosclerosis and related conditions, for example fibrates such as clofibrate, bezafibrate and gemfibrozil; inhibitors of cholesterol biosynthesis such as HMG-CoA reductase inhibitors for example lovastatin, simvastatin and pravastatin; inhibitors of cholesterol absorption for example beta-sitosterol and (acyl Co A: cholesterol acyltransf erase) inhibitors for example melinamide; anion exchange resins for example cholestyramine, colestipol or a dialkylaminoalkyl derivatives of a cross-linKed dextran; nicotinyl alcohol, nicotinic acid or a salt thereof; vitamin E; and thyromimetics.
  • fibrates such as clofibrate, bezafibrate and gemfibrozil
  • inhibitors of cholesterol biosynthesis such as HMG-CoA reductase inhibitors for example lova
  • the compounds of the instant invention also have the effect of reducing intestinal motility and thus find utility as aiding in the treatment of various gastrointestinal disorders such as irritable bowel syndrome. It has been proposed that the motility of non-sphincteric smooth muscle contraction is mediated by activity at ⁇ 3 adrenoreceptors. The availability of a ⁇ 3 specific agonist, with little activity at ⁇ l and ⁇ 2 receptors will assist in the pharmacologic control of intestinal motility without concurrent cardiovascular effects.
  • the instant compounds are administered generally as described below with dosages similar to those used for the treatment of diabetes and obesity.
  • the compounds which act as agonists at B3 adrenoreceptors may be useful in the treatment of gastrointestinal disorders, especially peptic ulcerations, esophagitis, gastritis and duodenitis, (including that induced by H. pylori), intestinal ulcerations (including inflammatory bowel disease, ulcerative colitis, Crohn's disease and proctitis) and gastrointestinal ulcerations.
  • ⁇ 3 receptors have been indicated to have an effect on the inhibition of the release of neuropeptides in certain sensory fibers in the lung.
  • sensory nerves may play an important role in the neurogenic inflammation of airways, including cough
  • the instant specific ⁇ 3 agonists may be useful in the treatment of neurogenetic inflammation , such as asthma, with minimal effects on the cardio- pulmonary system.
  • ⁇ 3 adrenoreceptors are also able to produce selective antidepressant effects by stimulating the ⁇ 3 receptors in the brain and thus an additional contemplated utility of the compounds of this invention are as antidepressant agents.
  • the active compounds of the present invention may be orally administered as a pharmaceutical composition, for example, with an inert diluent, or with an assimilable edible carrier, or they may be enclosed in hard or soft shell capsules, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet.
  • these active compounds may be incorporated with excipients and used in the form of tablets, pills, capsules, ampules, sachets, elixirs, suspensions, syrups, and the like.
  • 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 effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated.
  • the compounds of the present invention are administered at a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of animal body weight, preferably given in divided doses two to six times a day, or in sustained release form.
  • the total daily dosage is from about 1.0 milligrams to about 1000 milligrams, preferably from about 1 milligrams to about 50 milligrams.
  • the total daily dose will generally be from about 7 milligrams to about 350 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 1 milligram to about 1000 milligrams per kilogram of animal body weight, preferably given in divided doses two to six times a day, or in sustained release form.
  • the total daily dosage is from about 10 milligrams to about 10,000 milligrams, preferably from about 10 milligrams to about 500 milligrams.
  • the total daily dose will generally be from about 70 milligrams to about 3500 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
  • 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.
  • active compounds 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.
  • the form mus be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • 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.
  • Hexylamine 12.15 ml (9.2 mmol) was added dropwise to a solution of 10 ml (9.2 mmol) of phenyl isocyanate in THF (150 ml) at 0°C, and stirring was continued for 1 h. The solvent was removed in vacuo, and the resultant hexyl phenyl urea was used without further purification.

Abstract

L'invention concerne des sulfamides substitués ayant la formule I. Ce sont des agonistes sélectifs vis-à-vis des récepteurs β3-adrénergiques avec très peu d'activité vis-à-vis des récepteurs β1 et β2-adrénergiques. Par conséquent, ces composés sont capables d'augmenter la lipolyse et la consommation énergétique des cellules. Ces composés sont très efficaces pour le traitement du diabète juvénile et de l'obésité. Ces composés peuvent également être utilisés pour diminuer les niveaux des triglycérides et du cholestérol, pour augmenter la concentration des lipoprotéines de haute densité ou encore pour accélérer le transit intestinal. En plus ces composés peuvent être utilisés pour combattre les inflammations d'origine nerveuse ou comme antidépresseurs. On prépare ces composés en couplant un aminoalkylphényl sulfamide avec un époxyde portant un substituant approprié. On décrit également des compositions et les méthodes d'utilisation des composés dans le traitement du diabète et de l'obésité, pour diminuer les niveaux des triglycérides et du cholestérol, pour augmenter le niveau des lipoprotéines de haute densité ou encore pour accélérer le transit intestinal.
PCT/US1995/004956 1994-04-26 1995-04-21 SULFAMIDES SUBSTITUES UTILISES COMME AGONISTES SELECTIFS VIS-A-VIS DES RECEPTEURS β3-ADRENERGIQUES, POUR LE TRAITEMENT DU DIABETE ET DE L'OBESITE WO1995029159A1 (fr)

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KR1019960705994A KR970702252A (ko) 1994-04-26 1995-04-21 당뇨병 및 비만증의 치료를 위한 선택적인 β₃-효능제로서의 치환된 설폰아미드(Substituted sulfonamides as selective β₃agonists for the treatment of diabetes and obesity)
EP95917116A EP0757674A1 (fr) 1994-04-26 1995-04-21 SULFAMIDES SUBSTITUES UTILISES COMME AGONISTES SELECTIFS VIS-A-VIS DES RECEPTEURS $g(b) 3?-ADRENERGIQUES, POUR LE TRAITEMENT DU DIABETE ET DE L'OBESITE
JP52779795A JP3149186B2 (ja) 1994-04-26 1995-04-21 糖尿病および肥満の治療のための選択的β▲下３▼作用物質としての置換スルホンアミド
AU23937/95A AU687558B2 (en) 1994-04-26 1995-04-21 Substituted sulfonamides as selective beta 3 agonists for the treatment of diabetes and obesity
SK1361-96A SK136196A3 (en) 1994-04-26 1995-04-21 Substituted sulfonamides as selective 'beta '3 agonists and pharmaceutical composition containing them
MXPA/A/1996/005192A MXPA96005192A (en) 1994-04-26 1995-04-21 Sulfonamides substituted as agonistasó3selectivas for the treatment of diabetes yobesi
NZ284718A NZ284718A (en) 1994-04-26 1995-04-21 Heterocyclic or aryl substituted sulphonamides; medicaments
NO964548A NO964548L (no) 1994-04-26 1996-10-25 Substituerte sulfonamider som selektive 3 agonister for behandling av diabetes og fedme
FI964314A FI964314A0 (fi) 1994-04-26 1996-10-25 Substituoidut sulfonamidit selektiivisinä beta3-agonisteina diabeteksen ja liikalihavuuden hoitoon

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US40456595A 1995-03-21 1995-03-21
US233,166 1995-03-21
US08/404,566 US5541197A (en) 1994-04-26 1995-03-21 Substituted sulfonamides as selective β3 agonists for the treatment of diabetes and obesity
US404,565 1995-03-21
US404,566 1995-03-21

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WO2014151200A2 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions utiles pour le traitement de troubles gastro-intestinaux
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US9035059B2 (en) 2011-03-14 2015-05-19 Taisho Pharmaceutical Co., Ltd. Nitrogen-containing condensed heterocyclic compound
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CZ315196A3 (en) 1997-08-13
EP0757674A1 (fr) 1997-02-12
IL113410A0 (en) 1995-07-31
CA2187932A1 (fr) 1995-11-02
MX9605192A (es) 1997-09-30
HUT76442A (en) 1997-09-29
CN1149869A (zh) 1997-05-14
SK136196A3 (en) 1997-05-07
NZ284718A (en) 1998-02-26
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