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WO1997030019A1 - Derives d'aniline ayant une activite antihyperglycemique - Google Patents

Derives d'aniline ayant une activite antihyperglycemique Download PDF

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Publication number
WO1997030019A1
WO1997030019A1 PCT/US1997/002289 US9702289W WO9730019A1 WO 1997030019 A1 WO1997030019 A1 WO 1997030019A1 US 9702289 W US9702289 W US 9702289W WO 9730019 A1 WO9730019 A1 WO 9730019A1
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WO
WIPO (PCT)
Prior art keywords
amino
acetyl
compound
fluorophenyl
benzoic acid
Prior art date
Application number
PCT/US1997/002289
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English (en)
Inventor
Donald E. Bierer
Larisa G. Dubenko
Original Assignee
Shaman Pharmaceuticals, 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
Application filed by Shaman Pharmaceuticals, Inc. filed Critical Shaman Pharmaceuticals, Inc.
Priority to AU21241/97A priority Critical patent/AU2124197A/en
Publication of WO1997030019A1 publication Critical patent/WO1997030019A1/fr

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Classifications

    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups

Definitions

  • This invention pertains to a novel group of aniline derivatives that are useful as antihyperglycemic agents and useful for the treatment of diabetes mellitus, pharmaceutical compositions comprising the aniline derivatives and methods of using the same.
  • X is a hydrogen or halogen atom, or a straight or branched alkyl group having from 1 to 4 carbon atoms
  • R 1 is a hydrogen atom or a straight or branched alkyl group having from 1 to 4 carbon atoms
  • R 2 is an hydroxy, amino, hydrazino or alkoxy group, where alkoxy has from 1 to 4 carbon atoms
  • n is 1 or 2, have antihyperglycemic activity.
  • U.K. Patent 1,153,884 discloses that the administration to mammals of N-phenylglycine compounds, including N-o- fluorophenylglycine, results in antihyperglycemia.
  • plant growth regulators such as indole-3-acetic acid and L- tryptophan, and natural and synthetic analogues such as anthranilic acid, nicotinic acid, and 4-chlorophenoxyacetic acid have been shown to inhibit insulinase in vitro, potentiate the effect of insulin in vitro , and to act as hypoglycemic agents in vivo in normal rats ((1) Oliver-Bever, B. ; Zahnd, G.R. Quart . J . Crude Drug Res .
  • WO 91/11997 discloses that hydroxy- or nitro-substituted aminobenzoic acids are useful for treating or preventing various complications of diabetes.
  • R 0 is fluorine, chlorine, bromine, nitro or trifluoromethyl
  • R is hydrogen, C 1-6 alkyl or C 2 _ 4 alkanoyl; and R j is hydrogen or C : _ 6 alkyl, possess antidiabetic activity.
  • R is hydrogen, C 1-6 alkyl or C 2 _ 4 alkanoyl; and R j is hydrogen or C : _ 6 alkyl, possess antidiabetic activity.
  • A is an aryl, aralkyl or arylvinyl radical optionally substituted by hydroxy, halogen, trifluromethyl, alkyl, alkylthio, alkoxy, alkenyloxy, alkoxyalkoxy, alkyl-substituted amino, aryloxy or alkoxy-substituted aryloxy, or is an aryloxyalkyl or arylthioalkyl radical or a heterocyclic ring system optionally substituted by halogen, alkyl or alkoxy;
  • Y is a valency bond or an unbranched or branched lower alkylene radical containing up to 3 carbon atoms
  • X is a straight or branched, saturated or unsaturated divalent aliphatic hydrocarbon radical containing 2 to 8 carbon atoms, there being at least 2 carbon atoms between the benzene ring and the carboxyl group;
  • R is a hydrogen atom or a lower alkyl radical; and the physiologically compatible salts, esters and amides thereof, have hypoglycemic properties. Also see GB 1484848.
  • UK patent application GB 2090834A describes amides according to the general formula (F) :
  • R x and R 2 which may be the same or different, each represents an alkyl group containing 1 to 6 carbon atoms or a cycloalkyl group containing 6 to 7 carbon atoms, or R ⁇ and R ; together with the nitrogen atom to which they are attached represent an unbranched alkyleneimino group containing 3 to 6 carbon atoms optionally substituted by 1 or 2 alkyl groups, each containing 1 to 3 carbon atoms, or by a hydroxy group and in which a methylene group may optionally be replaced by a carbonyl group, by an oxygen or sulfur atom or by an imino group (which may optionally be substituted by an alkyl group containing 1 to 3 carbon atoms, an aralkyl group containing 7 to 10 carbon atoms or by a phenyl or halophenyl group) or an ethylene group may optionally be replaced by an O-phenylene group; and unbranched alkenylenei ino group containing 4 to 6 carbon
  • R 4 represents a hydrogen atom or an alkyl group containing 1 to 3 carbon atoms
  • R 5 represents a hydrogen atom, a halogen atom or an alkyl group containing 1 to 3 carbon atoms
  • A represents a bond, a methylene or ethylene group optionally substituted by an alkyl group containing 1 to 5 carbon atoms, a methylene or ethylene group substituted by two alkyl groups each containing 1 to 3 carbon atoms, a methylene group substituted by a cycloalkyl group containing 3 to 7 carbon atoms or by a hydroxyalkyl, alkoxyalkyl, cyano, carboxyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aryl or aralkyl group, wherein each of the alkyl parts may contain from 1 to 3 carbon atoms, a cycloalkylidene group containing 3 to 7 carbon atoms or a vinylidene group of formula
  • R 6 and R 7 which may be the same or different, each represents a hydrogen atom or an alkyl group containing 1 to 3 carbon atoms or one of the radicals R 6 and R 7 represents a cycloalkyl group containing 3 to 7 carbon atoms or an aryl or aralkyl group and the other is as defined above or R 6 and R 7 together with the carbon atom to which they are attached, represent a cycloalkylidene radical containing 5 to 7 carbon atoms;
  • B represents a methylene or ethylene group optionally substituted by an alkyl group containing 1 to 3 carbon atoms and
  • W represents a hydrogen or halogen atom, a nitro group, an amino group (optionally substituted by an alkanoyl group containing 1 to 3 carbon atoms) an alkyl group containing 1 to 3 carbon atoms (optionally substituted by a hydroxy or carboxy group or by one or two alkoxycarbonyl groups containing 2 to 4 carbon atoms each) , an alkenyl group containing 2 to 5 carbon atoms substituted by a carboxy or alkoxycarbonyl group containing 2 to 4 carbon atoms, an alkanoyl group containing 1 to 3 carbon atoms, a dialkoxymethyl or trialkoxymethyl group containing 1 to 3 carbon atoms in each alkyl part, an alkylenedioxymethyl group containing 2 or 3 carbon atoms in the alkylene part, a 1,3- oxazoline-2-yl or cyano group, an aminocarbonyl group (optionally substituted by one or two alkyl groups containing 1 to 4 carbon atom
  • R 1 and R ? independently represent one or the other of a hydrogen, a halogen, a small alkyl radical, a nitro radical, the radical -OR 6 , the radical R ? —.N—R 8 , a small alkanoyloxy radical or a trifluoromethyl radical;
  • R 3 represents the radical OR 6 or the radical R 7 —N—R 8 ;
  • R 4 represents a hydrogen atom, a halogen atom, a trifluoromethyl radical, a small alkyl radical, a cycloalkyl radical, a bridged cycloalkyl radical, an aryl radical, or a small aryl radical;
  • R 5 represents a hydrogen atom, a small alkyl radical, a cycloalkyl radical, a bridged cycloalkyl radical, an aryl radical, a small arylalkyl radical, a small alkanoyl radical, or the radical R 9 ; m and n represent 1, 2, or 3, or less than or equal to 4;
  • R 6 , R 7 , and R e represent independently one or the other of a hydrogen atom, a small alkyl radical, a cycloalkyl radical, a bridged cycloalkyl radical, an aryl radical, or a small arylalkyl radical;
  • R 9 represents the formula
  • X is halogen of hydrogen
  • Y is NH
  • R is benzyl, substituted benzyl, benzoyl, heteroaroyl, arylalkyl, or heteroarylalkyl are hypoglycemic agents.
  • EP Patent Application 023 569A1 discloses that anthranilic acid derivatives of the general formula (D)
  • R is hydrogen, halogen, dialkylamino or a hexamethyleneimino group
  • Rj is hydrogen, halogen, alkyl or branched alkyl groups, alkoxy groups, arylalkoxy groups, nitro, cyano, amino, alkanoylamino, carboxy, alkoxycarbonyl groups, or dialkylamido sulfonyl groups;
  • R 2 and R 3 are branched or nonbranched alkyl groups of 3 - 7 carbon atoms, alkyl groups from 1 to 7 carbon atoms, alkenyl groups with 3 - 7 carbon atoms, cycloalkyl groups with 3 - 7 carbon atoms, a phenylalkyl group, phenyl, or adamantyl; or R 2 and R 3 can be part of a ring or substituted ring;
  • R 4 is hydrogen or an alkyl group with 1 - 3 carbon atoms;
  • X can be a nitrogen or CH group;
  • Y is an oxygen atom, an imino group, an alkylimino group, or a dialkylimino group, methylene, or a substituted methylene group;
  • Z is hydrogen, halogen, nitro, amino, cyano, formyl, hydroxymethyl or a hydroxymethylene group, carboxy, alkoxylcarbonyl, or alkyl groups;
  • R 5 is halogen, amino, cyano, hydroxy, alkoxy groups, or arylalkoxy groups; are useful agents for lowering blood sugar levels.
  • R 5 is halogen, amino, cyano, hydroxy, arylalkoxy group containing 1 - 3 carbons, or alkoxy groups with 4 - 6 carbon atoms;
  • R 6 and R 7 in combination with a nitrogen atom make a heterocyclic ring or a substituted heterocyclic ring;
  • W is carboxy, aminocarboxyl, cyano, or an alkoxycarbonyl group which has 2 - 4 atoms; which are purported to be useful agents for lowering blood sugar levels.
  • R is hydrogen, halogen, nitro, amino, alkanoylamino, alkoxy, cyano, carboxyl, alkoxycarbonyl, or dialkylaminosulfonyl groups in which the carbon part can contain 1 - 3 carbon atoms;
  • R 2 and R 3 can be branched or nonbranched alkyl groups with 1 - 7 carbon atoms, or cycloalkyl groups with 3 - 7 carbon atoms; or R 2 and R 3 can be part of a 3 - 7 membered substituted or unsubstituted ring;
  • R 4 is hydrogen or an alkyl group with 1 - 4 carbons
  • R 5 is a hydrogen, or an alkyl group with 1 - 4 carbons; and pharmaceutically acceptable salts; are useful as blood sugar lowering agents.
  • X can be a substituted amino group, possess antidiabetic activity.
  • hypolipidemic agents for lowering levels of cholesterol, triglycerides, and phospholipids in serum.
  • novel compounds and method of using them of the present invention fill a persistent need for effective anti ⁇ hyperglycemic and/or anti-diabetic agents.
  • the present invention provides novel aniline derivatives, as well as pharmaceutically acceptable salts thereof, having antihyperglycemic activity, particularly in diabetic subjects; pharmaceutical compositions comprising the novel aniline derivatives of the present invention; as well as methods for their use.
  • the invention provides compounds of formula I:
  • R j , R 2 , R 3 , R 4 , and R 5 are independently selected from the group consisting of hydrogen, halogen, 0R X1 , C(X) 3 , a C ⁇ C- alkyl group, (CH 2 ) n CH 2 OH, (CH 2 ) r COOR 12 , and (CH 2 ) n -5-tetrazolyl, where one but not more than one of R x , R 2 , R 3 , R 4 , and R 5 is selected from the group consisting of (CH 2 ) n COOR 12 and (CH 2 ) n -5-tetrazoly1;
  • R_ and R 12 are independently selected from the group consisting of hydrogen and a C ⁇ Cg alkyl group; X is halogen; n is 0 or 1;
  • R 7 , R 8 , R 9 , and R 10 are independently selected from the group consisting of hydrogen, halogen, 0R 13 , SR 14 , C(Y) 3 , a C 1 -C 6 alkyl group, and phenyl;
  • R 13 and R 14 are independently selected from the group consisting of hydrogen, a C 1 -C 6 alkyl group, and phenyl;
  • Y is halogen
  • Preferred compounds of formula I useful as antihyperglycemic agents are: 2- (2- (( (2-fluorophenyl)amino)acetyl) amino)benzoic acid (Compound AB) ;
  • the present invention further provides compositions comprising the novel aniline derivatives of formula I for use as antihyperglycemic agents and methods for their use.
  • the present invention also provides compounds of the general formula II
  • R lf R 2 , R 3 , R 4 , and R 5 are independently selected from the group consisting of hydrogen, halogen, OR lir C(X) 3 , a alkyl group, (CH 2 ) n CH 2 OH, (CH 2 ) r COOR 12 , and (CH 2 ) n -5-tetrazolyl, where one but not more than one of R j , R 2 , R 3 , R 4 , or R B is selected from the group consisting of (CH 2 ) ⁇ COOR ⁇ and (CH 2 ) n -5-tetrazolyl;
  • R_ and R 12 are independently selected from the group consisting of hydrogen and a C ⁇ -C 6 alkyl group
  • X is halogen; n is 0 or 1; R 6 ' R7 ' ⁇ 8 and R 10 are independently selected from the group consisting of hydrogen, halogen, OR 13 , SR 14 , C(Y) 3 , a C j -Cg alkyl group, and phenyl;
  • R 13 and R 14 are independently selected from the group consisting of hydrogen, a alkyl group, and phenyl;
  • Y is halogen
  • A is CH 2 ;
  • B is selected from the group consisting of NH, oxygen, and sulfur, which have surprisingly been discovered to be useful as antihyperglycemic agents.
  • a preferred compound of formula II useful as a antihyperglycemic agent is 1- (2-carboxyphenyl)amino) -2-( (2- fluorophenyl)amino)ethane (Compound BN) .
  • composition ⁇ comprising the aniline derivates of formula II for use as antihyperglycemic agents and methods for their use.
  • the present invention further provides novel methods for using compounds of the general formula III:
  • R : , R 2 , R 3 , R 4 , and R 5 are independently selected from the group consisting of hydrogen, halogen, OR ⁇ , C(X) 3 , a Q- ⁇ -Q b alkyl group, (CH 2 ) r CH 2 OH, (CH 2 ).COOR 12 , and (CH 2 ) n -5-tetrazolyl, where one but not more than one of R ⁇ r R 2 , R 3 , R 4 , or R s is selected from the group consisting of (CH 2 ) r COOR 1?
  • R_ and R 12 are independently selected from the group consisting of hydrogen and a Cj-Cg alkyl group;
  • X is halogen;
  • n is 0 or 1;
  • R 6 , R 7 , R B , R 9 , and R 10 are independently selected from the group consisting of hydrogen, halogen, 0R 13 , SR 14 , C(Y) 3 , a C 1 -C 6 alkyl group, and phenyl;
  • B is selected from the group consisting of NH, oxygen, and sulfur, useful as antihyperglycemic agents.
  • Preferred compounds of formula III useful as antihyperglycemic agents are:
  • Methyl 2- ( (2- (4- (trifluoromethyl)phenyl)amino) acetyl) amino) benzoate (Compound CB) ;
  • Methyl 4- ( (2- (4- (Trifluoromethyl)phenyl)amino) acetyl) amino) benzoate (Compound CJ) ;
  • a further preferred compound of the invention is 1, 2-Bis( (2-Carboxyphenyl) amino)ethane (Compound BM) , and pharmaceutically acceptable salts thereof.
  • the present invention further provides compositions comprising the aniline derivatives of formula III for use as antihyperglycemic agents and methods for using the same.
  • FIGURES Figure 1 is a flow chart illustrating generally preparation of the aniline derivatives 4 whereby an optionally substituted aniline 1 is first acylated with a haloacetyl halide and then condensed with nucleophile 3.
  • R ! -R 5 , R 6 -R 10 , and B are defined above in Section 3; W is bromine or chlorine.
  • Figure 2 is a flow chart illustrating an alternative preparation of the aniline derivatives 4 whereby aniline, phenol, or thiophenol 3 is first alkylated, and then condensed with an optionally substituted aniline 1.
  • Ri-R 6 , R 6 -R 10 , and B are defined above in Section 3; X is OH or OBn.
  • Figure 3 is a flow chart describing a general preparation of aniline derivatives 7, 8, and 9.
  • R ⁇ R B , R 6 -R 10 , and B are defined above in Section 3; W is bromine or iodine.
  • Figure 4 is a flow chart illustrating another general preparation of the aniline derivative 7.
  • R1-R 5 , R 6 -R 10 , and B are defined above in Section 3.
  • aniline derivatives of the present invention can be prepared by methods known to those skilled in the art or by the synthetic methods outlined below.
  • aniline derivatives 4 can be prepared from optionally substituted anilines 1.
  • the general procedure outlined in Figure 1 has been modified from previously described procedures known to synthesize acylaniline derivatives ((1) Yamato, M. ; Takeuchi, Y.; Chang, M-r.; Hashigaki, K. Chem . Pharm . Bull . 1992, 40 , 528; (2) Yamato, M. ; Takeuchi, Y.; Chang, M-r.; Hashigaki, K. ; Tsuruo, T.; Tashiro, T. ; Tsukagoshi, S. Chem . Pharm . Bull .
  • the optionally substituted anilines 1 are acylated with chloroacetyl chloride or bromoacetyl bromide in a polar solvent such as DMF, dioxane, or DMF/dioxane mixtures to provide haloacylanilines 2 ((1) Ossman, A. E. ; El-Zahabi, M. M.; El-Hakim, A. E. ; Osman, A. N. Egypt . J . Chem . 1988, 31 , 381; (2) U.S. Patent No. 3,374,264 to Uskokovic et al.) .
  • FIG. 2 shows an alternative preparation of aniline derivatives 4 using modified literature methods ((1) Yamato, M. ; Hashigaki, K. EP 0376166; (2) Yamato, M. U.S. Patent No. 4,826,850; (3) Sunder, S. ; Peet, N. P. J. Heterocyclic Chem . 1978, 15 , 1379; (4) Gorlitzer, K. ; Weber, J. Arch. Pharm (Weinheim) 1980, 314 , 76) .
  • Optionally substituted 3 is alkylated with chloroacetic acid or bromoacetic acid, providing acetic acids 6.
  • optionally substituted 3 (when B is NH or O) is alkylated with benzyl bromoacetate or benzyl chloroacetate in the presence of a base such potassium car bonate, sodium carbonate, sodium acetate, potassium acetate, or other common bases known to those skilled in the art, to provide acetate 5, which is then subjected to hydrogenolysis to provide acetic acid 6 (Zahler, R. ; Koster, W. H. ; Slusarchyk, W. A. EP 138 407) .
  • Figure 3 illustrates a general preparation of anilines 7, 8, and 9 using modified literature conditions optimized to provide the previously unreported unsymmetrical anilines 7.
  • the references listed below provide for the formation of symmetrical anilines 8 and 9 ((1) Formanovskii, A. A. Zh . Org . Khim . 1986, 22 , 1103; (2) Sandhu, G. K. ; Verma, S. P. ; Moore, L. S. ; Parish, R. v. J . Organomet . Chem . 1986, 315 , 309; (3) Wanzlick, H. -W. ; L ⁇ chel, W. Chem . Ber . 1953, 86 , 1463; (4) Jaunin, R. Helv . Chim .
  • Figure 4 illustrates a general preparation of the previously unreported anilines 7 by reduction of anilines 4 using a borane reagent such as BH 3 »THF, (see general procedure reported by Rapoport et al. for amide reductions (i.e. Grote, C.W.; Kim, D.J. ; Rapoport, H. J . Org . Chem . 1995, 60 , 6987) , BH 3 »DMS, Red-Al (see amide reduction procedure reported in Hipskind, P.A. ; Howbert, J.J.; Cho, S.; Cronin, J.S.; Fort, S.L.; Ginah, F.O. ; Hansen, G.J.
  • a borane reagent such as BH 3 »THF
  • anilines 1 and anilines, phenols, or thiophenols 3 are commercially available, or can be prepared by methods known to those skilled in the art.
  • Aniline derivatives 4 and 7 can be further elaborated as appropriate according to methods commonly employed in the art.
  • the aniline derivatives of the present invention are useful in veterinary and human medicine for lowering the blood glucose level in a mammal.
  • the aniline derivatives due to the potent activity of the aniline derivatives of the present invention, are advantageously useful in veterinary and human medicine for the therapeutic treatment of insulin-dependent or non-insulin-dependent diabetes mellitus, either primary (idiopathic) or secondary to the use of diabetogenic drugs (e.g., diuretics, corticosteroids, etc.)
  • the described aniline derivatives can be advantageously used as antihyperglycemic agents to reduce the blood glucose levels in situations of acute stress such as experienced by animals or patients with hyperthermia, trauma, sepsis, and burns and undergoing general anesthesia.
  • Hyperglycemia sometimes associated with severe head injury, cerebral thrombosis, encephalitis and heat stroke can also be therapeutically treated with these aniline derivatives.
  • the aniline derivatives are useful as antihyperglycemic agents for rare congenital metabolic glycogen storage disease associated with hyperglycemia.
  • the present inventors do not wish to be limited to any particular mechanism of action to explain the antihyperglycemic activity of the aniline derivatives of the present invention, it is envisaged that they may advantageously be useful for the treatment of both insulin-dependent (IDDM) or type I diabetes (formerly termed juvenile-onset or ketosis-prone diabetes) and non-insulin-dependent (NIDDM) or type II diabetes (formerly termed adult-onset diabetes) .
  • IDDM insulin-dependent
  • type I diabetes originally termed juvenile-onset or ketosis-prone diabetes
  • NIDDM non-insulin-dependent
  • type II diabetes originally termed adult-onset diabetes
  • the aniline derivatives When administered to a mammal for veterinary use or to a human for clinical use, the aniline derivatives can be used alone, or as a pharmaceutical composition comprising a physiologically acceptable carrier such as water, an aqueous solution, normal saline, or other physiologically acceptable excipient.
  • a physiologically acceptable carrier such as water, an aqueous solution, normal saline, or other physiologically acceptable excipient.
  • the dosage of such pharmaceutical composition ranges from about 10-2000 mg/kg/day, preferably about 10-250 mg/kg/day.
  • compositions comprising the aniline derivatives of the present invention can be administered by a number of routes, including, but not limited to: orally, injection including, but not limited to intravenously, intraperitoneally, subcutaneously, intramuscularly, etc; topically, nasally; and parenterally.
  • routes including, but not limited to: orally, injection including, but not limited to intravenously, intraperitoneally, subcutaneously, intramuscularly, etc; topically, nasally; and parenterally.
  • the preferred route of administration is oral.
  • aniline derivatives can be administered in conjunction with another antihyperglycemic agent including such as insulin; a biguanide such as metformin or buformin; a sulfonylurea such as acetohexa ide, chlorpropamide, tolazamide, tolbutamide, glyburide, glypizide or glyclazide; a thiazolidinedione such as troglitazone or ciglitazone; an ⁇ -glycosidase inhibitor such as acarbose or miglatol; an ⁇ 2 - adrenergic antagonist such as midaglizole, or a S 3 -adrenergic receptor agonist such as CL-316,243, LY 104119, Ro 40-2148, etc.
  • another antihyperglycemic agent including such as insulin; a biguanide such as metformin or buformin; a sulfonylurea such as aceto
  • compositions of the present invention suitable for oral administration may be administered as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the aniline derivative(s) ; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion and as a bolus, etc.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the aniline derivative in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface- active or dispersing agent known to those skilled in the art. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the aniline derivative(s) therein.
  • Formulations suitable for topical administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the aniline derivative in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the aniline derivative to be administered in a suitable liquid carrier.
  • Pharmaceutical compositions suitable for topical administration to the skin may be administered as ointments, creams, gels, and pastes comprising the aniline derivative (s) to be administered in a pharmaceutically acceptable carrier.
  • a preferred topical delivery system is a transdermal patch containing the aniline derivative to be administered.
  • compositions suitable for nasal administration wherein the carrier is a solid include a coarse powder having a particle size, for example, in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • suitable formulations for nasal administration wherein the carrier is a liquid include aqueous or oily solutions of the aniline derivative(s) .
  • compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostat ⁇ and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multidose containers, for example, sealed ampules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the kind described above.
  • Preferred unit dosage formulations are those containing a daily dose or unit, daily sub-dose, as recited above, or an appropriate fraction thereof, of the administered aniline derivative(s) .
  • the compositions of this invention may include other agents conventional in the art having regard to the type of composition in question, for example, those suitable for oral administration may include flavoring agents.
  • aniline derivatives of the present invention can be administered in an effective amount either as neutral compounds or as anionic or cationic pharmaceutically acceptable salts using counter ions such as acetate, chloride, bromide, iodide, tartrate, fumarate, succinate, ascorbate, gluconate, malate, citrate, sodium, potassium, ammonium, trialkylam onium, etc.
  • counter ions such as acetate, chloride, bromide, iodide, tartrate, fumarate, succinate, ascorbate, gluconate, malate, citrate, sodium, potassium, ammonium, trialkylam onium, etc.
  • an "antihyperglycemically effective" amount is an amount of an aniline derivative of the present invention capable of lowering the blood glucose level in a mammal having hyperglycemia, to a level of blood glucose within the normal range for the mammal, following administration thereto.
  • the aniline derivatives of the present invention are used in mammals to lower abnormally high glucose levels to normal levels of blood glucose.
  • Example 5 2- (2- (( (4- (Phenyl)phenyl)amino)acetyl)amino)benzoic Acid (Compound AE)
  • a solution of 2-( (2-bromoacetyl)amino)benzoic acid from Example l (8.00 g, 31.0 mmol) and para-aminobiphenyl (13.12 g, 77.5 mmol) in DMF (80 mL) was heated to 80 'C for 8 h. The mixture was cooled, poured over H 2 0 (1 L) and 5% KOH (300 mL) , and then washed with CH 2 C1 2 (3 x 300 mL) .
  • Example 12 2-(2-( ( (2-(Trifluoromethyl) henyl)amino)acetyl)amino) enzoic Acid (Compound AL)
  • a solution of 2- ( (2-bromoacetyl)amino)benzoic acid from Example 1 (1.74 g, 6.7 mmol) and 2-aminobenzotrifluoride (2.17 g, 1.7 mL, 200 mol%) in anhydrous DMF (20 mL) was heated at 100 * C for 40 h, and then cooled to rt.
  • the mixture was poured into ice-water, 5% KOH was added to adjust the pH of the mixture to 9, and then the solution wa ⁇ extracted with CH 2 C1 2 (3 x 50 mL) .
  • the separated water layer was acidified to pH 5 with 5% HCl and extracted with EtOAc (3 x 100 mL) .
  • EtOAc 3 x 100 mL
  • the EtOAc layer was dried, filtered, concentrated, dried in vacuo for lh, and then triturated several times with cold ether.
  • the separated water layer was acidified to pH 5 and was extracted with EtOAc (3 x 70 mL) .
  • EtOAc 3 x 70 mL
  • the combined EtOAc layer was dried, filtered, concentrated, and then the light-yellow crystalline compound which was obtained was triturated several times with ether.
  • Example 15 2-(2-( ( (2-Fluorophenyl)thio) cetyl)amino)benzoic Acid (Compound AO)
  • a solution of 2- fluorothiophenol (3.97 g, 200 mol%) in anhydrous THF (50 mL) was cooled to 10-15 "C and then NaH (1.4 g, 200 mol% of 50% despersion in oil ) was added slowly.
  • the reaction mixture was stirred at 15 * C for 40 min, and then 2-((2- bromoacetyl) amino)benzoic acid from Example 1 (4.0 g, 0.016 mol) was added in one portion.
  • the reaction mixture was stirred for 24 h at rt before TLC showed the disappearance of the starting acid.
  • Example 28 2-(2-( (Phenylamino)acetyl)amino)-3-chlorobenzoic Acid (Compound AX)
  • a ⁇ olution of 2-( (2-bromoacetyl) amino) -3-chlorobenzoic acid from Example 27 (7.5 g, 0.026 mol) , and aniline (5.8 mL, 250 mol%) in anhydrou ⁇ DMF (60 mL) was heated to 95-100 * C for 20 h, cooled, and then stirred for 4 h at rt.
  • the reaction mixture was poured into ice-water (400 mL) and the precipitated product was solubilized by adding aqueous 5% KOH (60 mL) .
  • the milky homogenous solution was extracted with CH 2 C1 2 (3 x 70 L) .
  • the combined CH 2 C1 2 extracts were set aside and the aqueous layer was acidified with aqueous 5% HBr to pH 3.
  • the oil which was formed wa ⁇ extracted into EtOAc (3 x 100 mL) , and then the combined extract was wa ⁇ hed with brine, dried, filtered, and then concentrated.
  • Example 35 2-( (2-Bromoacetyl)amino)-6-chlorobenzoic Acid
  • 2-amino-6-chlorobenzoic acid (10.0 g, 0.06 mol) in anhydrous DMF (30 mL) and anhydrous dioxane (30 mL) was cooled to 0 'C in 300 mL 3-necked flask fitted with a magnetic stirring bar and constant additional funnel.
  • Bromoacetyl bromide was added dropwise over a 20-25 min period, while maintaining the internal temperature between 0 * C to 1 'C. After the addition was completed, the ice-bath was removed and stirring was continued for 20 h.
  • Example 37 2-( (2-Bromoacetyl)amino)-5-methoxybenzoic Acid To a solution of 2-amino-5-methoxybenzoic acid (5.0 g, 0.03 mol) in anhydrous DMF (30 mL) and dioxane (30 mL) was added, dropwise, bromoacetyl bromide (6.0 g, 2.6 mL, 100 mol%) while keeping the internal temperature between 0° and 2 * C After the addition was completed (-30 min) , the reaction mixture was stirred overnight at rt.
  • 2-amino-5-methoxybenzoic acid 5.0 g, 0.03 mol
  • dioxane 30 mL
  • bromoacetyl bromide 6.0 g, 2.6 mL, 100 mol
  • the reaction mixture was diluted with water (100 mL) , and then the precipitated product was filtered, washed sequentially with 5% HBr (300 mL) and water (300 mL) , and then dried in a vacuum oven at 40-45 * C, affording 5.6 g (65%) of the title compound as a light grey solid: mp 171.5-172.7 'C; *H NMR (DMSO-d 6 ) ⁇
  • Example 46 Phenylmercaptoacetyl Chloride To thiophenoxyacetic acid (8 g, 0.05 mol) wa ⁇ added S0C1 2 (8 mL) and the reaction mixture was heated to reflux for 1 h. TLC showed disappearance of the starting material. The excess S0C1 2 rfas removed in vacuo (hood!) and the product di ⁇ tilled to give 8.6 g (98%) of the title compound: bp 85-86 * C, 4-5 Torr (lit. 117-119 'C, 6 Torr (Mooradian, A. ; Cavallito, C.J.; Bergman, A.J.; Lawson, E.J.; Suter, CM. J . Am . Chem .
  • reaction mixture wa ⁇ stirred at rt overnight.
  • the reaction mixture was diluted with water (100 mL) and the white crystalline compound which precipitated was filtered, washed sequentially with 5% HBr (100 mL) and water (200 mL) , and then dried in a vacuum oven
  • Example 55 1-( (2-Carboxyphenyl)amino)-2-( (2-fluorophenyl)amino)ethane (Compound BN) To a solution of BH 3 *THF (1.00 M, 10.0 mL 300 mol%) at 5 'C was added a solution of 2-(2- (((2- fluorophenyl) amino)acetylamino)benzoic acid from Example 2 (1.0 g, 3.47 mmol) in anhydrous THF (10 mL) . After stirring for 5 min at 10 * C, the reaction mixture was refluxed for 2.5 h and then cooled to rt.
  • Example 56 4-(2-(Bromoacetyl)amino) henylacetic Acid To a solution of 4-aminophenylacetic acid (8.0 g, 0.053 mol) in anhydrous dioxane (30 mL) and anhydrous DMF (30 mL) was added, dropwise, bromoacetyl bromide (10.68 g, 4.6 mL) while keeping the internal temperature between 0 * C and 2 * C After the addition was completed (-30 min) , the reaction mixture was stirred overnight at rt.
  • Example 59 (0.4 g, 1.4 mmol) in anhydrous DMF (10 mL) was added NaN 3 (0.12 g, 130 mol%) , NH 4 C1 (0.1 g, 130 mol%) , and a catalytic amount of LiCl (30 mg) .
  • This mixture was heated and stirred at 127 * C for 30 h, and then stirred for several days at rt.
  • the reaction mixture was heated to 80 "C, filtered while hot, and then the nonorganic residue was washed with small amount of DMF.
  • the DMF solution was concentrated, giving dark-orange oily product, which was stirred with H 2 0 (50 mL) .
  • Example 64 2-(2-( ( (4-(Trifluoromethoxy)phenyl)amino)acetyl)amino) enzoic Acid (Compound B ⁇ )
  • 2- ( (2-bromoacetyl)amino)benzoic acid (2.57 g, 10 mmol) and 4-trifluoromethoxyaniline (2.7 mL, 3.54 g, 20 mmol) in anhydrous DMF (60 mL) was heated to 100°C overnight with stirring under N 2 .
  • the solution was cooled, poured into 600 L of ice-water, and then a 5% KOH solution was added until the pH of the solution was 10.
  • Example 65 2-(2-( ( (4-Phenyl)phenoxy)acetyl)amino)benzoic Acid (Compound BV)
  • a solution of 4-phenylphenol (5.1 g, 30 mmol) was dissolved in anhydrous THF (100 mL) with stirring under N 2 .
  • the reaction mixture was cooled using an ice-bath, and then NaH (1.33 g, 60% dispersion in mineral oil) was added to the solution, causing some bubbling.
  • the ice-bath was removed and then the reaction mixture was stirred for 30-min before
  • Example 69 3-Methoxy-2- (2-( (phenylamino)acetyl)amino) enzoic Acid
  • a solution of 3-methoxy-2-( (bromoacetyl)amino)benzoic acid (6.0 g. 21 mmol) and aniline (6 L, 6.14 mL, 66 mmol) in anhydrous DMF (50 mL) was heated to 95-100°C overnight with stirring under N 2 .
  • the solution was cooled to room temperature, poured into 500 mL of ice-water, and then a 5% KOH solution was added until the pH of the solution was 10.
  • Example 81 4-((Bromoacetyl)amino)-l-butoxyaniline A solution of 4-butoxyaniline (3.0 g, 18 mmol) in a mixture of anhydrous DMF (30 mL) and anhydrous dioxane (30 mL) in a 250 mL 3-necked round-bottomed flask equipped with a constant addition funnel (60 mL) was cooled to 0°C using an ice-bath. Bromoacetyl bromide (3.68 g, 1.60 mL, 18 mmol) was added dropwise, keeping the internal temperature between 0 and 5°C over a 1/2 h period.
  • reaction mixture was stirred overnight at rt, poured into 500 mL of ice-water, and then extracted with 3 x 50 mL of ethyl acetate. The layers were separated and the organic layer was dried (MgSO , filtered, and then concentrated.
  • Example 99 4-( ( (2-(2-(Trifluoromethyl)phenyl)amino)acetyl)amino)benzoic Acid (Compound CM)
  • a solution of 4- ( (bromoacetyl)amino)benzoic acid (1.5 g, 5.81 mmol) and 2-trifluoromethylaniline (2.0 g, 12.41 mmol) in anhydrous DMF (30 mL) was heated to 90-100°C overnight with stirring under N 2 .
  • the solution was cooled, poured into 5 500 mL of ice-water, and then a solution of 5% KOH was added until the pH of the solution was 10.
  • Example 105 4,5-Difluoro-2-( (bromoacetyl)amino) enzoic Acid
  • a solution of 4, 5-difluoro-2-aminobenzoic acid (20.0 g, 115.5 mmol) in a mixture of anhydrous DMF (50 mL) and anhydrous dioxane (50 mL) was cooled to 0°C under N 2 using an ice-bath.
  • Bromoacetyl bromide (23.3 g, 10.1 L, 115.5 mmol) was added dropwise, keeping the internal temperature between 0 and 5°C over a 3/4 h period.
  • mice Genetically altered obese diabetic mice (designated C57BL/Ks- j /dh) were purchased from the Jackson Laboratory (Bar Harbor, ME, USA) , and served as experimental animals. Male animals between the ages of 8-9 weeks were employed in the studies described here. Animals were hou ⁇ ed (4 mice/cage) under standard laboratory conditions at 22 "C and provided with Purina rodent chow and water ad libitum . Prior to treatment, blood was collected from the tail vein of each animal. Mice that had plasma glucose levels between 350 and 600 mg/dL were used in these studies. Each treatment group consisted of eight mice that were distributed so that mean glucose levels were equivalent in each group at the start of the study.
  • Diabetic designated C57BL/Ks-dJ /dj mice were dosed orally by gavage once daily for 1 or 2 days with either vehicle, the experimental compound administered at 100 mg/kg/day (unless otherwise noted) , or metfor in (250 mg (1510 mmol) /kg/day) .
  • Compounds were delivered in aqueous vehicle formulation, including component ⁇ such as cremephor,
  • HPMC HPMC, RH40, 0.25% (w/v) carboxymethylcellulose, 1% (v/v)
  • TweenTM 60 and up to 10% (v/v) dimethyl sulfoxide (DMSO) in a volume of 10 mL/kg.
  • DMSO dimethyl sulfoxide
  • each cage were also measured after 24-27 h.
  • aniline derivatives tested for antihyperglycemic activity were prepared a ⁇ described above in Sections 5.1 or
  • Metformin (1, 1-dimethylbiguanide) was purchased from Sigma Chemical Co. (St. Louis, MO, USA; catalog #
  • Plasma glucose levels were determined colorimetrically using a glucose oxidase assay (Sigma Chemical Co. ; Sigma catalog #325) . Significant differences between groups
  • Methyl 2-( ( (2-(2-(Trifluoromethyl)phenyl)amino)acetyl)amino) benzoate (Compound CE) ;
  • Methyl 4-(( (2-(4-(Trifluoromethyl)phenyl)amino)acetyl)amino) benzoate (Compound CJ) ;
  • Compound AG Compound AK, Compound BE, Compound AP, Compound AW, Compound AN, Compound BL, Compound CB, Compound CL, Compound CM, Compound CN, and Compound CR.
  • Compounds that trended to significant reductions i.e., p value greater than 0.05 but less than 0.1, included Compound AF, Compound AU, Compound AL, Compound BB, Compound CJ and Compound CP.
  • test compounds did not result in a substantial reduction in plasma glucose in the 3-27 h time period under the conditions of the in vivo experiments, as described below Section 7.2, Compounds AC, AD, BN, BF, AV, AH, Al, AJ, AZ, BG, BK, AO, and BM did result in increased glucose transport in an in vitro, art-recognized system. This in vitro system represents an important mode of action for glucose utilization and disposal in mammals.
  • Murine 3T3-L1 preadipocytes (American Type Culture Collection CL 173) were maintained in Dulbecco's modified Eagle ⁇ medium (DMEM) containing 10% (v/v) supplemented calf serum, antibiotics, and 25 mM glucose. Cells were seeded in 24-well cluster plates (10,000 cells/well) , grown to confluence (typically 5 days) , and induced to differentiate 2 days post-confluence (day 0) according to the standard protocol of Frost and Lane (Frost, S. and Lane, M. D. J . Biol . Chem . 1985, 260 , 2646-2652).
  • DMEM Dulbecco's modified Eagle ⁇ medium
  • adipocytes were maintained in DMEM containing 10% fetal bovine serum, and provided with fresh medium every 2-3 days. Adipocytes employed in this study were used on days 7-10 post-differentiation. On the day before the experiment, adipocytes were washed with phosphate-buffered saline and switched to serum-free DMEM medium.
  • DMSO dimethyl sulfoxide
  • concentration of DMSO was 0.5% (v/v) which wa ⁇ also included in basal and insulin controls.
  • Metformin was dissolved directly into culture medium and further diluted into the same medium.
  • Adipocytes were treated (in triplicate) for 18 h with a te ⁇ t compound, i.e., an aniline derivative (at 3, 10, and 30 ⁇ M final concentration ⁇ ) or metformin.
  • the in vitro assay according to Method A was conducted as follows: After overnight (18 h) treatment, the adipocyte cell monolayers were washed, and the medium was switched to Krebs- Ringer Hepes (KRH) buffer. The compounds were tested at 3 , 10 and 30 ⁇ m (triplicate incubations) . Compound treated adipocytes were given the insulin vehicle KRH/1% Bovine Serum Albumin (KRH/1% BSA) (containing no insulin) . The final concentration of KRH/1% BSA was 4%, which was also included in the basal control.
  • KRH Bovine Serum Albumin
  • a concentrated porcine insulin stock was freshly diluted into KRH/1% BSA. The final concentration of insulin in the insulin control was
  • 2-deoxy-D-glucose uptake (a non-metabolizable analogue of glucose) was measured in the absence of insulin stimulation.
  • Glucose transport assays were initiated by the addition of 2-deoxy-D- ( 3 H)glucose (0.5 Mci/mL; 100 mM final concentrations) to each well followed by incubation for
  • the in vitro assay according to Method B was conducted as follows: After overnight (18 h) treatment, the cell monolayers were washed, and the medium was switched to
  • KRH Krebs-Ringer Hepes
  • Basal control adipocytes were given the insulin vehicle KRH/1% bovine serum albumin (KRH/1% BSA) .
  • the final concentration of KRH/1% BSA was 4%.
  • a concentrated porcine insulin stock was freshly diluted into KRH/1% BSA and given to the compound treated adipocytes and to the insulin control adipocytes.
  • the final concentration of insulin was 0.5 nM in 4% KRH/1% bsa. The plates were then incubated for 30 min at 37 "C.
  • 2-deoxy-d-glucose uptake (a non-metabolizable analogue of glucose) was measured in the presence of insulin stimulation.
  • Glucose transport assays were initiated by the addition of 2-deoxy-d- ( 3 H)glucose (0.5 Mci/mL; 100 mM final concentrations) to each well followed by incubation for 10 min at 22 "C. Assays were terminated by aspirating the media and rapidly washing the monolayer two times with ice-cold phosphate-buffered saline solution. Cell monolayers were solubilized in 0.1N NaOH, transferred to scintillation vials, and radioactivity wa ⁇ determined by liquid ⁇ cintillation counting. All data were corrected for non-specific hexose uptake determined in parallel samples treated for 5 minutes with 200 mM cytochalasin B. The following compounds were tested in the in vitro assay of Method B:
  • the ability of the aniline derivatives to significantly stimulate glucose transport in 3T3-L1 adipocytes in the absence of insulin is shown in Table 3.
  • the magnitude of stimulation ranged from approximately 110% of basal to approximately 160% .
  • 3 mM metformin the maximally effective concentration
  • these data indicate that the aniline derivatives listed in Table 3 directly stimulate glucose transport m vitro , an effect that is consistent the enhancement of glucose dispo ⁇ al and the ability to lower blood glucose in vivo .
  • This results demonstrate that the compounds "active" in this assay, are useful for treating Type I and Type II diabetes (i.e., insulin dependent diabetes mellitus and non-insulin dependent diabetes mellitus) .
  • Values shown for stimulatory activity are expressed as a percent of insulin control glucose transport (typically _ 0.3 nmoles 2-deoxyglucose/10 min/well), and represent the maximum stimulation observed along with the corresponding concentration) . All compound ⁇ li ⁇ ted above demonstrated significant stimulation of glucose transport (P ⁇ 0.05 or better) as judged u ⁇ ing a Student's t-test (one-tailed, 0 independent) .

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Abstract

L'invention se rapporte à des dérivés d'aniline utilisés comme agents antihyperglycémiques, à des compositions pharmaceutiques comprenant ces dérivés d'aniline et à leurs procédés d'utilisation. Ces dérivés d'aniline sont utilisés dans le traitement des diabètes sucrés, insulinodépendents (IDDM ou de Type I) et des diabètes sucrés non insulodépendents (NIDDM ou de Type II).
PCT/US1997/002289 1996-02-13 1997-02-13 Derives d'aniline ayant une activite antihyperglycemique WO1997030019A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1066245A4 (fr) * 1998-04-03 2001-01-24 Advanced Medicine Inc Nouveaux composes d'anesthesique local et leurs utilisations
US6462034B1 (en) 1998-04-03 2002-10-08 Theravance, Inc. Local anesthetic compounds and uses
WO2006085112A1 (fr) * 2005-02-14 2006-08-17 Smithkline Beecham Corporation Derives de l'acide anthranilique comme agonistes du recepteur hm74a
WO2006085108A1 (fr) * 2005-02-14 2006-08-17 Smithkline Beecham Corporation Dérivés d'acide anthranilique et leur emploi dans le traitement de maladies du métabolisme lipidique, en particulier de dyslipidémies

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ARCH. PHARM., (Weinheim, Ger.), 1975, Vol. 83, GOERLITZER, "1,3-Dicarbonyl Compounds. 3-beta-Ketoesters", Abstract No. 79112h, page 651. *
J. INDIAN CHEM. SOC., 1987, Vol. 109, SHAH et al., "Studies on Acetamide Derivatives. Part II. Preparation, Antimicrobial and Anthelmintic Activity of N-Arylaminoacetylbenzimidazole/Sulfadiazine or Sulfamethazine and N-Arylbenzimidazol-1-Yl/Sulfadiazine-4-Yl or Sulfamethazin-4-Yl/Acetamides", Abstract *
J. INST. CHEM., (India), 1981, Vol. 95, PANDYA et al., "Studies on Amides", Abstract No. 95:132436t, page 632. *
J. PHARM. BELG., 1981, Vol. 95, EL-KERDAWY et al., "Synthesis and Some Spectral Identification of Certain Triazoles and Benzotriazoles", Abstract No. 95:169081z, page 732. *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1066245A4 (fr) * 1998-04-03 2001-01-24 Advanced Medicine Inc Nouveaux composes d'anesthesique local et leurs utilisations
US6337423B1 (en) 1998-04-03 2002-01-08 Advanced Medicine, Inc. Local anesthetic compounds and uses
US6462034B1 (en) 1998-04-03 2002-10-08 Theravance, Inc. Local anesthetic compounds and uses
US6495681B1 (en) 1998-04-03 2002-12-17 Theravance Inc. Local anesthetic compounds and uses
US6576791B1 (en) 1998-04-03 2003-06-10 Theravance, Inc. Local anesthetic compounds and uses
WO2006085112A1 (fr) * 2005-02-14 2006-08-17 Smithkline Beecham Corporation Derives de l'acide anthranilique comme agonistes du recepteur hm74a
WO2006085108A1 (fr) * 2005-02-14 2006-08-17 Smithkline Beecham Corporation Dérivés d'acide anthranilique et leur emploi dans le traitement de maladies du métabolisme lipidique, en particulier de dyslipidémies

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