Patent Publication Number: US-2005143456-A1

Title: Carboxamide-substituted phenylurea derivatives, process for their preparation and their use as medicaments

Description:
This application claims the benefit of foreign priority under 35 U.S.C. §119 of German patent application no. 10125567.5, filed on May 25, 2001 and German patent application no 10207369.4, filed on Jan. 22, 2002 the contents of both of which are incorporated by reference herein.  
      The invention relates to carboxamide-substituted phenylurea derivatives and their physiologically tolerated salts and physiologically functional derivatives.  
      Acylphenylurea derivatives of similar structure have already been described in the prior art as insecticides (EP 0 136 745, EP 0 167 197, DE 29 26 480, J. Agric. Food Chem. 1999, 47, 3116-3424).  
      In one embodiment, the invention is based on the object of providing compounds which display a blood glucose-lowering effect which can be utilized in therapy.  
      The invention therefore, for example, relates to compounds of the formula I,  
                 
 
 in which 
      A is phenyl or naphthyl, where the phenyl or naphthyl is unsubstituted or substituted 1, 2, or 3 times wherein each substituent is independently chosen from F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, O—(C 2 -C 6 )-alkenyl, O—(C 2 -C 6 )-alkynyl, S—(C 1 -C 6 )-alkyl, S—(C 2 -C 6 )-alkenyl, S—(C 2 -C 6 )-alkynyl, SO—(C 1 -C 6 )alkyl, SO 2 —(C 1 -C 6 )-alkyl, SO 2 —NH 2 , (C 1 -C 6 )alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C 3 -C 7 )-cycloalkyl, (C 3 -C 7 )-cycloalkyl-(C 1 -C 4 )-alkylene, (C 0 -C 6 )-alkylene-COOH, (C 0 -C 6 )alkylene-COO—(C 1 -C 7 )-alkyl, (C 0 -C 6 )-alkylene-COO—(C 2 -C 7 )-alkenyl, CONH 2 , CONH—(C 1 -C 6 )-alkyl, CON—[(C 1 -C 6 )-alkyl] 2 , CONH—(C 3 -C 6 )-cycloalkyl, (C 0 -C 6 )-alkylene-NH 2 , (C 0 -C 6 )-alkylene-NH—(C 2 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-N—[(C 1 -C 6 )-alkyl] 2 , NH—CO—(C 1 -C 6 )-alkyl, NH—CO-phenyl, and NH—SO 2 -phenyl, wherein the phenyl of NH—CO-phenyl and NH—SO 2 -phenyl is unsubstituted or substituted 1 or 2 times wherein each substituent is independently chosen from F, Cl, CN, OH, (C 1 -C 6 )-alkyl, O—(C 1 -C 6 )-alkyl, CF 3 , OCF 3 , COOH, COO—(C 1 -C 6 )-alkyl and CONH 2 ;     R1, R2 are, independently of one another, H, (C 1 -C 6 )-alkyl, O—(C 1 -C 6 )-alkyl, CO—(C 1 -C 6 )-alkyl, or COO—(C 1 -C 6 )-alkyl;     R3, R4, R5, R6 are, independently of one another, H, F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, O—(C 2 -C 6 )-alkenyl, O—(C 2 -C 6 )-alkynyl, S—(C 1 -C 6 )-alkyl, S—(C 2 -C 6 )-alkenyl, S—(C 2 -C 6 )-alkynyl, SO—(C 1 -C 6 )-alkyl, SO 2 —(C 1 -C 6 )-alkyl, SO 2 —NH 2 , (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C 3 -C 7 )-cycloalkyl, (C 3 -C 7 )-cycloalkyl-(C 1 -C 4 )-alkylene, COOH, COO—(C 1 -C 6 )-alkyl, CO—NH 2 , CO—NH—(C 1 -C 6 )-alkyl, CO—N—[(C 1 -C 6 )-alkyl] 2 , CO—NH—(C 3 -C 7 )-cycloalkyl, NH 2 , NH—(C 1 -C 6 )-alkyl, N—[(C 1 -C 6 )-alkyl] 2 , NH—CO—(C 1 -C 6 )-alkyl, NH—CO-phenyl, or NH—SO 2 -phenyl, wherein the phenyl of NH—CO-phenyl and NH—SO 2 -phenyl is unsubstituted or substituted 1 or 2 times wherein each substituent is independently chosen from F, Cl, CN, OH, (C1-C6)-alkyl, O—(C1-C 6 )-alkyl, CF 3 , OCF 3 , COOH, COO—(C 1 -C 6 )-alkyl and CO—NH 2 ;     R7 is H, (C 1 -C 6 )-alkyl, or CO(C 1 -C 6 )-alkyl;     R8 is H, (C 1 -C 10 )-alkyl, where the alkyl is unsubstituted or substituted 1, 2, or 3 times wherein each substituent is independently chosen from OH, CF 3 , CN, COOH, COO—(C 1 -C 6 )-alkyl, CO—NH 2 , NH 2 , NH—(C 1 -C 6 )-alkyl, N—[(C 1 -C 6 )-alkyl] 2 , NCO—(C 1 -C 6 )-alkyl, NCOO—(C 1 -C 6 )-alkyl, NCOO—(C 1 -C 6 )-alkenyl, NCOO—(C 1 -C 6 )-alkynyl and NCOO—(C 1 -C 4 )-alkylene-(C 6 -C 10 )-aryl; or      (CH 2 ) m -aryl, where m ranges from 0-6, and aryl is phenyl, O-phenyl, CO-phenyl, benzo[1,3]dioxolyl, heterocycloalkyl, pyridyl, indolyl, piperidinyl, tetrahydronaphthyl, naphthyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,5]thiadiazolyl, pyrrolidinyl, or morpholinyl, where the aryl is unsubstituted or substituted by at least one R9;     R9 is F, Cl, Br; OH, NO 2 , CF 3 , OCF 3 , (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl-OH, O—(C 1 -C 6 )-alkyl, S—(C 1 -C 6 )-alkyl, (C 1 -C 4 )-alkylphenyl, COOH, or COO—(C 1 -C 6 )-alkyl; 
 
 and their physiologically tolerable salts. 
   

      In one embodiment, the compounds of the formula I are those in which 
      A is phenyl, where the phenyl is unsubstituted or substituted 1, 2, or 3 times wherein each substituent is independently chosen from F, Cl, and Br;     R1, R2 are H;     R3, R4, R5, R6 are, independently of one another, H, F, Cl, Br, NO 2 , O—(C 1 -C 6 )-alkyl, or (C 1 -C 6 )-alkyl;     R7 is H, or CH 3 ;     R8 is H, (C 1 -C 10 )-alkyl, where the alkyl is unsubstituted or substituted 1, 2, or 3 times wherein each substituent is independently chosen from OH, CF 3 , CN, COOH, COO—(C 1 -C 6 )-alkyl, CO—NH 2 , NH 2 , NH—(C 1 -C 6 )-alkyl, N—[(C 1 -C 6 )-alkyl] 2 , NCO—(C 1 -C 6 )-alkyl, NCOO—(C 1 -C 6 )-alkyl, NCOO—(C 1 -C 6 )-alkenyl, NCOO—(C 1 -C 6 )-alkynyl or NCOO—(C 1 -C 4 )-alkylene-(C 6 -C 10 )-aryl; or      (CH2)m-aryl, where m ranges from 0-6, and aryl is phenyl, O-phenyl, CO-phenyl, benzo[1,3]dioxolyl, heterocycloalkyl, pyridyl, indolyl, piperidinyl, tetrahydronaphthyl, naphthyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,5]thiadiazolyl, pyrrolidinyl, morpholinyl, where the aryl is unsubstituted or substituted by at least one R9;     R9 is F, Cl, Br; OH, NO 2 , CF 3 , OCF 3 , (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl-OH, O—(C 1 -C 6 )-alkyl, S—(C 1 -C 6 )-alkyl, (C 1 -C 4 )-alkylphenyl, COOH, or COO—(C 1 -C 6 )-alkyl; 
 
 and their physiologically tolerable salts. 
   

      In another embodiment, the compounds of the formula I are those in which 
      A is phenyl, where the phenyl is unsubstituted or substituted 1, 2, or 3 times wherein each substituent is independently chosen from F, Cl, and Br;     R1, R2 are H;     R3, R4, R5, R6 are, independently of one another, H, F, Cl, Br, NO 2 , O—(C 1 -C 6 )-alkyl, or (C 1 -C 6 )-alkyl;     R7 is H, or CH 3 ;     R8 is (C 1 -C 10 )-alkyl, where the alkyl is unsubstituted or substituted 1, 2, or 3 times wherein each substituent is independently chosen from OH, CF 3 , CN, COOH, COO—(C 1 -C 6 )-alkyl, CO—NH 2 , NH 2 , NH—(C 1 -C 6 )-alkyl, N—[(C 1 -C 6 )-alkyl] 2 , NCO—(C 1 -C 6 )-alkyl, NCOO—(C 1 -C 6 )-alkyl, NCOO—(C 1 -C 6 )-alkenyl, NCOO—(C 1 -C 6 )-alkynyl or NCOO—(C 1 -C 4 )-alkylene-(C 6 -C 10 )-aryl; or      (CH 2 ) m -aryl, where m ranges from 0-6, and aryl is phenyl, O-phenyl, CO-phenyl, benzo[1,3]dioxolyl, heterocycloalkyl, pyridyl, indolyl, piperidinyl, tetrahydronaphthyl, naphthyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,5]thiadiazolyl, pyrrolidinyl, morpholinyl, where the aryl is unsubstituted or substituted by at least one R9;     R9 is F, Cl, Br; OH, NO 2 , CF 3 , OCF 3 , (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl-OH, O—(C 1 -C 6 )alkyl, S—(C 1 -C 6 )-alkyl, (C 1 -C 4 )alkylphenyl, COOH, or COO—(C 1 -C 6 )-alkyl; 
 
 and their physiologically tolerable salts. 
   

      In one embodiment, the invention further relates to the use of the compounds of the formula I  
                 
 
 in which 
      A is phenyl or naphthyl, where the phenyl or naphthyl is unsubstituted or substituted 1, 2, or 3 times wherein each substituent is independently chosen from F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, O—(C 2 -C 6 )-alkenyl, O—(C 2 -C 6 )-alkynyl, S—(C 1 -C 6 )-alkyl, S—(C 2 -C 6 )-alkenyl, S—(C 2 -C 6 )-alkynyl, SO—(C 1 -C 6 )-alkyl, SO 2 —(C 1 -C 6 )-alkyl, SO 2 —NH 2 , (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C 3 -C 7 )-cycloalkyl, (C 3 -C 7 )-cycloalkyl-(C 1 -C 4 )-alkylene, (C 0 -C 6 )-alkylene-COOH, (C 0 -C 6 )-alkylene-COO—(C 1 -C 7 )-alkyl, (C 0 -C 6 )-alkylene-COO—(C 2 -C 7 )-alkenyl, CONH 2 , CONH—(C 1 -C 6 )-alkyl, CON—[(C 1 -C 6 )-alkyl] 2 , CONH—(C 3 -C 6 )-cycloalkyl, (C 0 -C 6 )-alkylene-NH 2 , (C 0 -C 6 )-alkylene-NH—(C 1 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-N—[(C 1 -C 6 ) alkyl] 2 , NH—CO—(C 1 -C 6 )-alkyl, NH—CO-phenyl, NH—SO 2 -phenyl, wherein the phenyl of NH—CO-phenyl and NH—SO 2 -phenyl is unsubstituted or substituted 1 or 2 times wherein each substituent is independently chosen from F, Cl, CN, OH, (C 1 -C 6 )-alkyl, O—(C 1 -C 6 )-alkyl, CF 3 , OCF 3 , COOH, COO—(C 1 -C 6 )alkyl and CONH 2 ;     R1, R2 are, independently of one another, H, (C 1 -C 6 )-alkyl, O—(C 1 -C 6 )-alkyl, CO—(C 1 -C 6 )-alkyl, or COO—(C 1 -C 6 )-alkyl;     R3, R4, R5, R6 are, independently of one another, H, F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, O—(C 2 -C 6 )-alkenyl, O—(C 2 -C 6 )-alkynyl, S—(C 1 -C 6 )-alkyl, S—(C 2 -C 6 )-alkenyl, S—(C 2 -C 6 )-alkynyl, SO—(C 1 -C 6 )-alkyl, SO 2 —(C 1 -C 6 )-alkyl, SO 2 —NH 2 , (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C 3 -C 7 )-cycloalkyl, (C 3 -C 7 )-cycloalkyl-(C 1 -C 4 )-alkylene, COOH, COO—(C 1 -C 6 )-alkyl, CO—NH 2 , CO—NH—(C 1 -C 6 )-alkyl, CO—N—[(C 1 -C 6 )-alkyl] 2 , CO—NH—(C 3 -C 7 )-cycloalkyl, NH 2 , NH—(C 1 -C 6 )-alkyl, N—[(C 1 -C 6 )-alkyl] 2 , NH—CO—(C 1 -C 6 )-alkyl, NH—CO-phenyl, or NH—SO 2 -phenyl, wherein the phenyl of NH—CO-phenyl and NH—SO 2 -phenyl is unsubstituted or substituted 1 or 2 times wherein each substituent is independently chosen from F, Cl, CN, OH, (C 1 -C 6 )-alkyl, O—(C 1 -C 6 )-alkyl, CF 3 , OCF 3 , COOH, COO—(C 1 -C 6 )-alkyl and CO—NH 2 ;     R7 is H, (C 1 -C 6 )-alkyl, or CO(C 1 -C 6 )-alkyl;     R8 is H, (C 1 -C 10 )-alkyl, where the alkyl is unsubstituted or substituted 1, 2, or 3 times wherein each substituent is independently chosen from OH, CF 3 , CN, COOH, COO—(C 1 -C 6 )-alkyl, CO—NH 2 , NH 2 , NH—(C 1 -C 6 )-alkyl, N—[(C 1 -C 6 )-alkyl] 2 , NCO—(C 1 -C 6 )-alkyl, NCOO—(C 1 -C 6 )-alkyl, NCOO—(C 1 -C 6 )-alkenyl, NCOO—(C 1 -C 6 )-alkynyl or NCOO—(C 1 -C 4 )-alkylene-(C 6 -C 10 )-aryl; or      (CH 2 ) m -aryl, where m can be 0-6, and aryl can be phenyl, O-phenyl, CO-phenyl, benzo[1,3]dioxolyl, heterocycloalkyl, pyridyl, indolyl, piperidinyl, tetrahydronaphthyl, naphthyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,5]thiadiazolyl, pyrrolidinyl, morpholinyl, where the aryl is unsubstituted or substituted by at least one R9;     R9 is F, Cl, Br; OH, NO 2 , CF 3 , OCF 3 , (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl-OH, O—(C 1 -C 6 )-alkyl, S—(C 1 -C 6 )-alkyl, (C 1 -C 4 )-alkylphenyl, COOH, or COO—(C 1 -C 6 ) alkyl; 
 
 and their physiologically tolerable salts, for producing a medicament for reducing the blood glucose level and treating type II diabetes. In another embodiments, these compounds are useful in methods for reducing the blood glucose level and treating type II diabetes of a mammal, for example a human. 
   

      The compounds of the formula I may be present in the form of their racemates, racemic mixtures, pure enantiomers, and diastereomers, and mixtures thereof. The alkyl radicals in the substituents R1, R2, R3, R4, R5, R6, R7, R8, R9 and A may be both straight-chain and branched.  
      Pharmaceutically acceptable salts may be particularly suitable for medical applications because of their greater solubility in water compared with the starting or base compounds. In one embodiment, these salts must have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention are salts of inorganic acids such as hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids, and of organic acids such as, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic and tartaric acids. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts).  
      Salts with a pharmaceutically unacceptable anion such as, for example, trifluoroacetate likewise belong within the scope of the invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and/or for use in nontherapeutic, for example in vitro, applications.  
      The term “physiologically functional derivative” used herein refers to any physiologically tolerated derivative of a compound of the formula I of the invention, for example an ester which is able, on administration to a mammal such as, for example, to a human, to form (directly or indirectly) a compound of the formula I or an active metabolite thereof.  
      Physiologically functional derivatives also include prodrugs of the compounds of the invention, as described, for example, in H. Okada et al., Chem. Pharm. Bull. 1994, 42, 57-61. Such prodrugs can be metabolized in vivo to a compound of the invention. These prodrugs may themselves have activity or not.  
      The compounds of the invention may also exist in various polymorphous forms, for example as amorphous and crystalline polymorphous forms. All polymorphous forms of the compounds of the invention belong within the scope of the invention and are a further aspect of the invention.  
      All references hereinafter to “compound(s) of formula I” refer to compound(s) of the formula I as described above, and to the salts, solvates and physiologically functional derivatives thereof as described herein.  
      The compound(s) of the formula (I) may also be administered in combination with other active ingredients.  
      The amount of a compound of formula I necessary to achieve the desired biological effect depends on a number of factors, for example the specific compound chosen, the intended use, the mode of administration and the clinical condition of the patient. In one embodiment, the daily dose is generally in the range from 0.3 mg to 100 mg (typically from 3 mg to 50 mg) per day and per kilogram of bodyweight, for example 3-10 mg/kg/day. An intravenous dose may be, for example, in the range from 0.3 mg to 1.0 mg/kg, which can suitably be administered as infusion of 10 ng to 100 ng per kilogram and per minute. Suitable infusion solutions for these purposes may contain, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg, per milliliter. Single doses may contain, for example, from 1 mg to 10 g of the active ingredient. Thus, ampoules for injections may contain, for example, from 1 mg to 100 mg, and single-dose formulations which can be administered orally, such as, for example, capsules or tablets, may contain, for example, from 1.0 to 1000 mg, typically from 10 to 600 mg. For the therapy of the abovementioned conditions, the compounds of formula I may be used as the compound itself, but they are preferably in the form of a pharmaceutical composition with an acceptable carrier. The carrier must, of course, be acceptable in the sense that it is compatible with the other ingredients of the composition and is not harmful for the patient&#39;s health. The carrier may be a solid or a liquid or both and is preferably formulated with the compound as a single dose, for example as a tablet, which may contain from 0.05% to 95% by weight of the active ingredient. Other pharmaceutically active substances may likewise be present, including other compounds of formula I. The pharmaceutical compositions of the invention can be produced by one of the known pharmaceutical methods, which may essentially consist of mixing the ingredients with pharmacologically acceptable carriers and/or excipients.  
      Pharmaceutical compositions of the invention are those suitable for oral, rectal, topical, peroral (for example sublingual) and parenteral (for example subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable mode of administration depends in each individual case on the nature and severity of the condition to be treated and on the nature of the compound of formula I used in each case. Coated formulations and coated slow-release formulations also belong within the framework of the invention. Preference is given to acid- and gastric juice-resistant formulations. Suitable coatings resistant to gastric juice comprise cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.  
      In one embodiment, suitable pharmaceutical compounds for oral administration may be in the form of separate units such as, for example, capsules, wafers, suckable tablets or tablets, each of which contain a defined amount of the compound of formula I; as powders or granules, as solution or suspension in an aqueous or nonaqueous liquid; or as an oil-in-water or water-in-oil emulsion. These compositions may, as already mentioned, be prepared by any suitable pharmaceutical method which includes a step in which the active ingredient and the carrier (which may consist of one or more additional ingredients) are brought into contact. The compositions are generally produced by uniform and homogeneous mixing of the active ingredient with a liquid and/or finely divided solid carrier, after which the product is shaped if necessary. Thus, for example, a tablet mau be produced by compressing or molding a powder or granules of the compound, where appropriate with one or more additional ingredients. Compressed tablets may be produced by tableting the compound in free-flowing form such as, for example, a powder or granules, where appropriate mixed with a binder, glidant, inert diluent and/or one or more surface-active/dispersing agent(s) in a suitable machine. Molded tablets may be produced by molding the compound which is in powder form and is moistened with an inert liquid diluent in a suitable machine.  
      In one embodiment, pharmaceutical compositions which are suitable for peroral (sublingual) administration comprise suckable tablets which contain a compound of formula I with a flavoring, normally sucrose and gum arabic or tragacanth, and pastilles which comprise the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic.  
      The pharmaceutical compositions suitable for parenteral administration may, for example, comprise sterile aqueous preparations of a compound of formula I, which are isotonic with the blood of the intended recipient. These preparations may be administered intravenously, although administration may also take place by subcutaneous, intramuscular or intradermal injection. These preparations may may be produced by mixing the compound with water and making the resulting solution sterile and isotonic with blood. Injectable compositions of the invention generally contain from 0.1 to 5% by weight of the active compound.  
      Pharmaceutical compositions suitable for rectal administration may be, for example, in the form of single-dose suppositories. These may be produced by mixing a compound of the formula I with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting mixture.  
      Pharmaceutical compositions suitable for topical use on the skin are preferably in the form of ointment, creme, lotion, paste, spray, aerosol or oil. Carriers which can be used are petrolatum, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances. The active ingredient is generally present in a concentration of from 0.1 to 15% by weight of the composition, for example from 0.5 to 2%.  
      Transdermal administration is also possible. Pharmaceutical compositions suitable for transdermal uses may be in the form of single plasters which are suitable for long-term close contact with the patient&#39;s epidermis. Such plasters, for example, suitably contain the active ingredient in an aqueous solution which is buffered where appropriate, dissolved and/or dispersed in an adhesive or dispersed in a polymer. A suitable active ingredient concentration is, for example, about 1% to 35%, preferably about 3% to 15%. One embodiment, is for the active ingredient to be released by electrotransport or iontophoresis as described, for example, in Pharmaceutical Research, 2(6): 318 (1986).  
      Further active ingredients suitable for combination products are: all antidiabetics mentioned in chapter 12 of the Rote Liste 2001. They may be combined with the compounds of the formula I of the invention in particular for synergistic improvement of the effect. Administration of the active ingredient combination may take place either by separate administration of the active ingredients to the patients or in the form of combination products in which a plurality of active ingredients are present in one pharmaceutical preparation.  
      Antidiabetics include insulin and insulin derivatives such as, for example, Lantus® or HMR 1964, GLP-1 derivatives such as, for example, those disclosed in WO 98/08871 of Novo Nordisk A/S, and orally active hypoglycemic active ingredients.  
      The orally active hypoglycemic active ingredients include, for example, sulfonylureas, biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1 agonists, potassium channel openers such as, for example, those disclosed in WO 97/26265 and WO 99/03861 of Novo Nordisk A/S, insulin sensitizers, inhibitors of liver enzymes involved in the stimulation of gluconeogenesis and/or glycogenolysis, modulators of glucose uptake, compounds which alter lipid metabolism, such as antihyperlipidemic active ingredients and antilipidemic active ingredients, compounds which reduce food intake, PPAR and PXR agonists and active ingredients which act on the ATP-dependent potassium channel of the beta cells.  
      In one embodiment of the invention, the compounds of the formula I are administered in combination with an HMG-CoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin.  
      In one embodiment of the invention, the compounds of the formula I are administered in combination with a cholesterol absorption inhibitor such as, for example, ezetimibe, tiqueside, pamaqueside.  
      In one embodiment of the invention, the compounds of the formula I are administered in combination with a PPAR gamma agonist such as, for example, rosiglitazone, pioglitazone, JTT-501, GI 262570.  
      In one embodiment of the invention, the compounds of the formula I are administered in combination with PPAR alpha agonist such as, for example, GW 9578, GW 7647.  
      In one embodiment of the invention, the compounds of the formula I are administered in combination with a mixed PPAR alpha/gamma agonist such as, for example, GW 1536, AVE 8042, AVE 8134, AVE 0847.  
      In one embodiment of the invention, the compounds of the formula I are administered in combination with a fibrate such as, for example, fenofibrate, clofibrate, bezafibrate.  
      In one embodiment of the invention, the compounds of the formula I are administered in combination with an MTP inhibitor such as, for example, Bay 13-9952, BMS-201038, R-103757.  
      In one embodiment of the invention, the compounds of the formula I are administered in combination with bile acid adsorption inhibitor such as, for example, HMR 1453.  
      In one embodiment of the invention, the compounds of the formula I are administered in combination with a CETP inhibitor such as, for example, Bay 194789.  
      In one embodiment of the invention, the compounds of the formula I are administered in combination with a polymeric bile acid adsorbent such as, for example, cholestyramine, colesevelam.  
      In one embodiment of the invention, the compounds of the formula I are administered in combination with an LDL receptor inducer such as, for example, HMR1171, HMR1586.  
      In one embodiment of the invention, the compounds of the formula I are administered in combination with an ACAT inhibitor such as, for example, avasimibe.  
      In one embodiment of the invention, the compounds of the formula I are administered in combination with an antioxidant such as, for example, OPC-14117.  
      In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein lipase inhibitor such as, for example, NO-1886.  
      In one embodiment of the invention, the compounds of the formula I are administered in combination with an ATP citrate lyase inhibitor such as, for example, SB-204990.  
      In one embodiment of the invention, the compounds of the formula I are administered in combination with a squalene synthetase inhibitor such as, for example, BMS-188494.  
      In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein(a) antagonist such as, for example, Cl-1027 or nicotinic acid.  
      In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipase inhibitor such as, for example, orlistat.  
      In one embodiment of the invention, the compounds of the formula I are administered in combination with insulin.  
      In one embodiment, the compounds of the formula I are administered in combination with a sulfonylurea such as, for example, tolbutamide, glibenclamide, glipizide or gliclazide.  
      In one embodiment, the compounds of the formula I are administered in combination with a biguanide such as, for example, metformin.  
      In another embodiment, the compounds of the formula I are administered in combination with a meglitinide such as, for example, repaglinide.  
      In one embodiment, the compounds of the formula I are administered in combination with a thiazolidinedione such as, for example, troglitazone, ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed in WO 97/41097 of Dr. Reddy&#39;s Research Foundation, in particular 5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]-phenyl]methyl]-2,4-thiazolidinedione.  
      In one embodiment, the compounds of the formula I are administered in combination with an α-glucosidase inhibitor such as, for example, miglitol or acarbose.  
      In one embodiment, the compounds of the formula I are administered in combination with an active ingredient which acts on the ATP-dependent potassium channel of the beta cells, such as, for example, tolbutamide, glibenclamide, glipizide, gliclazide or repaglinide.  
      In one embodiment, the compounds of the formula I are administered in combination with more than one of the aforementioned compounds, for example in combination with a sulfonylurea and metformin, a sulfonylurea and acarbose, repaglinide and metformin, insulin and a sulfonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc.  
      In a further embodiment, the compounds of the formula I are administered in combination with CART agonists, NPY agonists, MC4 agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, β3 agonists, MSH (melanocyte-stimulating hormone) agonists, CCK agonists, serotonin reuptake inhibitors, mixed serotoninergic and noradrenergic compounds, 5HT agonists, bombesin agonists, galanin antagonists, growth hormone, growth hormone-releasing compounds, TRH agonists, decoupling protein 2 or 3 modulators, leptin agonists, DA agonists (bromocriptine, Doprexin), lipase/amylase inhibitors, PPAR modulators, RXR modulators or TR-βagonists.  
      In one embodiment of the invention, the other active ingredient is leptin.  
      In one embodiment, the other active ingredient is dexamphetamine or amphetamine.  
      In one embodiment, the other active ingredient is fenfluramine or dexfenfluramine.  
      In a further embodiment, the other active ingredient is sibutramine.  
      In one embodiment, the other active ingredient is orlistat.  
      In one embodiment, the other active ingredient is mazindol or phentermine.  
      In one embodiment, the compounds of the formula I are administered in combination with dietary fiber materials, preferably insoluble dietary fiber materials such as, for example, Caromax®. Combination with Caromax® is possible in one preparation or by separate administration of compounds of the formula I and Caromax®. Caromax® can moreover be administered in the form of foodstuffs such as, for example, in bakery products or muesli bars.  
      It is self-evident that any suitable combination of the compounds of the invention with one or more of the aforementioned compounds and optionally one or more other pharmacologically active substances is regarded as falling within the protection conferred by the present invention.  
      The invention further relates to a process for the preparation of the compounds of the formula I, which comprises obtaining the compounds of the formula I by proceeding in accordance with the following reaction scheme:  
                 
 
      For this purpose, compounds of the formula II  
                 
 
 in which 
      R9, R10, R11, R12 are, independently of one another, H, F, Cl, Br, O-(PG-1), CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, O—(C 2 -C 6 )-alkenyl, O—(C 2 -C 6 )-alkynyl, S—(C 1 -C 6 )-alkyl, S—(C 2 -C 6 )-alkenyl, S—(C 2 -C 6 )alkynyl, SO—(C 1 -C 6 )-alkyl, SO 2 —(C 1 -C 6 )alkyl, SO 2 —N-(PG-2) 2 , (C 1 -C 6 )alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C 3 -C 7 )-cycloalkyl, (C 3 -C 7 )cycloalkyl-(C 1 -C 4 )-alkylene, COO-(PG-3), COO—(C 1 -C 6 )-alkyl, CON-(PG-2) 2 , CO—NH—(C 1 -C 6 )-alkyl, CO—N—[(C 1 -C 6 )-alkyl] 2 , CO—NH—(C 3 -C 7 )-cycloalkyl, N-(PG-2) 2 , NH—(C 1 -C 6 )-alkyl, N—[(C 1 -C 6 )-alkyl] 2 , NH—CO—(C 1 -C 6 )-alkyl, NH—CO-phenyl, and NH—SO 2 -phenyl, wherein, the phenyl of NH—CO-phenyl and NH—SO 2 -phenyl is unsubstituted or substituted 1 or 2 times wherein each substituent is independently chosen from F, Cl, CN, O-(PG-1), (C 1 -C 6 )-alkyl, O—(C 1 -C 6 )-alkyl, CF 3 , OCF 3 , COO-(PG-3), COO—(C 1 -C 6 )-alkyl and CON-(PG-2) 2 ; 
 
 in which R2 has the meaning described above, and 
    PG-1 is a generally known protective group for alcohols, such as, for example, benzyl, allyl, tetrahydropyranyl or tetrahydrofuranyl;     PG-2 is a generally known protective group for amino groups, such as, for example, (C 1 -C 6 )-alkylcarbonyl, (C 1 -C 6 )-alkyloxycarbonyl or (C 6 -C 12 )-aryl-(C 1 -C 4 )-alkyloxycarbonyl, which replaces either both hydrogen atoms or only one hydrogen atom in the amino group;     PG-3 is a generally known protective group for esters, such as, for example, (C 1 -C 6 )-alkyl, benzyl or p-methoxybenzyl; 
 
 are reacted with isocyanates of the formula III  
                 
 
 in which 
    A′ is phenyl or naphthyl, where the phenyl or naphthyl is unssubstituted or substituted 1, 2 or 3 times wherein each substituent is independently chosen from F, Cl, Br, O-PG-1, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, O—(C 2 -C 6 )-alkenyl, O—(C 2 -C 6 )-alkynyl, S—(C 1 -C 6 )alkyl, S—(C 2 -C 6 )-alkenyl, S—(C 2 -C 6 )alkynyl, SO—(C 1 -C 6 )-alkyl, SO 2 —(C 1 -C 6 )-alkyl, SO 2 —N-(PG-2) 2 , (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C 3 -C 7 )-cycloalkyl, (C 3 -C 7 )-cycloalkyl-(C 1 -C 4 )-alkylene, (C 0 -C 6 )-alkylene-COO-(PG-3), (C 0 -C 6 )-alkylene-COO—(C 1 -C 7 )-alkyl, (C 0 -C 6 )-alkylene-COO—(C 2 -C 7 )-alkenyl, CO—N-(PG-2) 2 , CO—NH—(C 1 -C 6 )-alkyl, CO—N—[(C 1 -C 6 )-alkyl] 2 , CONH—(C 3 -C 6 )-cycloalkyl, (C 0 -C 6 )-alkylene-N-(PG-2) 2 , (C 0 -C 6 )-alkylene-NH—(C 1 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-N—[(C 1 -C 6 )-alkyl] 2 , NH—CO—(C 1 -C 6 )-alkyl, NH—CO-phenyl, and NH—SO 2 -phenyl, wherein the phenyl of NH—CO-phenyl and NH—SO 2 -phenyl is unsubstituted or substituted 1 or 2 times wherein each substituent is independently chosen from F, Cl, CN, O-(PG-1), (C 1 -C 6 )-alkyl, O—(C 1 -C 6 )-alkyl, CF 3 , OCF 3 , COO-(PG-3), COO—(C 1 -C 6 )-alkyl and CO—N-(PG-2) 2 ; 
 
 in which PG-3, PG-2 and PG-1 have the meaning described above, 
 
 in anhydrous organic solvents such as, for example, benzene, toluene or acetonitrile, under a protective gas atmosphere at reaction temperatures between 10° C. and the boiling point of the solvent employed, to give compounds of the formula IV  
                 
 
 in which R2, R9, R10, R11, R12, and A′ have the meaning described above. 
   

      Compounds of the formula IV are reacted with coupling reagents customary in peptide synthesis, such as, for example, carbodiimides such as dicyclohexylcarbodiimide (DCC) or diisopropylcarbodiimide, carbonyldiazoles such as carbonyldiimidazole and similar reagents, propylphosphonic anhydrides, O-((cyano(ethoxycarbonyl)methylene)amino)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TOTU) and many others, or with formation of the acid chloride, for example using thionyl chloride, with compounds of the formula V  
                 
 
 in which R7 has the meaning described above, and 
      R13 is (C 1 -C 10 )-alkyl, where the alkyl is unsubstituted or substituted 1, 2 or 3 time wherein each substituent is independently chosen from 0-(PG-1), CF 3 , CN, COO-(PG-3), COO—(C 1 -C 6 )-alkyl, CO—N-(PG-2) 2 , NH-(PG-2), NH—(C 1 -C 6 )-alkyl, N—[(C 1 -C 6 )-alkyl] 2 ; 
        phenyl, O-phenyl, CO-phenyl, benzo[1,3]dioxolyl, heterocycloalkyl, pyridyl, indolyl, piperidinyl, tetrahydronaphthyl, naphthyl, 2,3-dihydrobenzo[1,4]dioxinyl, benzo[1,2,5]thiadiazolyl, pyrrolidinyl, and morpholinyl, where the rings are each independently unsubstituted or substituted by at least one R14;    
        R14 is F, Cl, Br; O-(PG-1), NO 2 , CF 3 , OCF 3 , (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl-OH, O—(C 1 -C 6 )-alkyl, S—(C 1 -C 6 )-alkyl, (C 1 -C 4 )-alkylphenyl, COO-(PG-3), or COO—(C 1 -C 6 )-alkyl; 
 
 to give compounds of the formula VI  
                 
 
 the compounds of the formula VI can, if R1 in compounds of the formula I is not a hydrogen atom, be alkylated by reaction with compounds of the formula VII 
 
R15-LG  (VII) 
 
 in which 
    LG is a generally known leaving group such as, for example, halogen, arylsulfonyloxy or alkylsulfonyloxy; and     R15 is (C 1 -C 6 )-alkyl, O—(C 1 -C 6 )-alkyl, CO—(C 1 -C 6 )-alkyl, or COO—(C 1 -C 6 ) alkyl, 
 
 using a base such as, for example, 1,8-diazabicyclo[5.4.0]undec-7-ene, in organic solvents such as, for example, dichloromethane or acetonitrile, to give compounds of the formula VIII  
                 
 
 in which R2, R7, R9, R10, R11, R12, R13, R15 and A′ have the meaning described above, 
 
 and after elimination known from the literature of some or all protective groups which may be present, for example, in the radicals R9, R10, R11, R12, R13, R14 and A′, compounds of the formula I are obtained. Compounds of the formula I are converted into the salts thereof by adding one equivalent of the appropriate acid or base in an organic solvent such as, for example, acetonitrile or dioxane or in water and by subsequent removal of the solvent. 
   

      Another possibility for preparing compounds of the formula I in which R2 is a hydrogen atom is depicted in the following scheme:  
                 
 
 in which compounds of the formula XIII  
                 
 
 in which R9, R10, R11, R12 and PG-3 have the meaning described above, are converted into isocyanates of the formula X  
                 
 
 by known methods, such as, for example, reaction with oxalyl chloride in organic solvents such as, for example, 1,2-dichloroethane or dichloromethane, at reaction temperatures between room temperature and the boiling point of the solvent, the isocyanates of the formula X are reacted with amides of the formula XI  
                 
 
 in which A′ has the meaning described above, to result in compounds of the formula XI  
                 
 
 in which R9, R10, R11, R12 and PG-3 have the meaning described above, compounds of the formula XII can, if R1 is not a hydrogen atom, be converted as described above by alkylation with compounds of the formula VII to give compounds of the formula XIII, selective deprotection of the COO-(PG-3) group and subsequent amide coupling with compounds of the formula V to give compounds of the formula XIV and, if necessary, by subsequent elimination of the protective groups into compounds of the formula I. Compounds of the formula I are converted into the salts thereof by addition of one equivalent of the appropriate acid or base in an organic solvent such as, for example, acetonitrile or dioxane or in water and by subsequent removal of the solvent. 
 
      The examples detailed below serve to illustrate the invention without, however, restricting it. The measured solidification and decomposition points (Fp.) have not been corrected and generally depend on the heating rate.  
               TABLE 1                          Examples                                                                                               Ex.   A   R1*   R2   R3   R4   R6   R5   Amide**   R7   R8***   MS****                                                                   1   Phenyl-2-Cl   H   H   2-Cl   3-H   4-H   6-H   5   H                         ok               2   Phenyl-2-Cl   H   H   2-H   4-H   5-H   6-H   3   H                         ok               3   Phenyl-2-Cl   H   H   2-H   4-H   5-H   6-H   3   H   (CH 2 ) 5 —OH   ok               4   Phenyl-2-Cl   H   H   2-H   4-H   5-H   6-H   3   H   (CH 2 ) 6 —OH   ok               5   Phenyl-2-Cl   H   H   2-H   4-H   5-H   6-H   3   H                         ok               6   Phenyl-2-Cl   H   H   2-H   4-H   5-H   6-H   3   H                         ok               7   Phenyl-2-Cl   H   H   2-H   4-H   5-H   6-H   3   H                         ok               8   Phenyl-2-Cl   H   H   2-H   4-H   5-H   6-H   3   H                         ok               9   Phenyl-2-Cl   H   H   2-H   4-H   5-H   6-H   3   H                         ok               10   Phenyl-2-Cl   H   H   2-H   4-H   5-H   6-H   3   H                         ok               11   Phenyl-2-Cl   H   H   2-H   4-H   5-H   6-H   3   H                         ok               12   Phenyl-2-Cl   H   H   2-H   4-H   5-H   6-H   3   H   (CH 2 ) 3 —COOtBu   ok               13   Phenyl-2-Cl   H   H   2-H   4-H   5-H   6-H   3   H                         ok               14   Phenyl-2-Cl   H   H   2-H   4-H   5-H   6-H   3   H                         ok               15   Phenyl-2-Cl   H   H   2-H   4-H   5-H   6-H   3   H   (CH 2 ) 5 —CH 3     ok               16   Phenyl-2-Cl   H   H   2-H   4-Cl   5-H   6-H   3   H   (CH 2 ) 5 —OH   ok               17   Phenyl-2-Cl   H   H   2-H   4-Cl   5-H   6-H   3   H   (CH 2 ) 6 —OH   ok               18   Phenyl-2-Cl   H   H   2-H   4-Cl   5-H   6-H   3   H                         ok               19   Phenyl-2-Cl   H   H   2-H   4-Cl   5-H   6-H   3   H                         ok               20   Phenyl-2-Cl   H   H   2-H   4-Cl   5-H   6-H   3   H                         ok               21   Phenyl-2-Cl   H   H   2-H   4-Cl   5-H   6-H   3   H   (CH 2 ) 5 —CH 3     ok               22   Phenyl-2-Cl   H   H   2-CH 3     3-H   4-H   6-H   5   H                         ok               23   Phenyl-2-Cl   H   H   2-CH 3     3-H   4-H   6-H   5   H   (CH 2 ) 5 —OH   ok               24   Phenyl-2-Cl   H   H   2-CH 3     3-H   4-H   6-H   5   H   (CH 2 ) 6 —OH   ok               25   Phenyl-2-Cl   H   H   2-CH 3     3-H   4-H   6-H   5   H                         ok               26   Phenyl-2-Cl   H   H   2-CH 3     3-H   4-H   6-H   5   H                         ok               27   Phenyl-2-Cl   H   H   2-CH 3     3-H   4-H   6-H   5   H                         ok               28   Phenyl-2-Cl   H   H   2-CH 3     3-H   4-H   6-H   5   H                         ok               29   Phenyl-2-Cl   H   H   2-CH 3     3-H   4-H   6-H   5   H                         ok               30   Phenyl-2-Cl   H   H   2-CH 3     3-H   4-H   6-H   5   H                         ok               31   Phenyl-2-Cl   H   H   2-CH 3     3-H   4-H   6-H   5   H                         ok               32   Phenyl-2-Cl   H   H   2-CH 3     3-H   4-H   6-H   5   H                         ok               33   Phenyl-2-Cl   H   H   2-CH 3     3-H   4-H   6-H   5   H                         ok               34   Phenyl-2-Cl   H   H   2-CH 3     3-H   4-H   6-H   5   H   (CH 2 ) 5 —CH 3     ok               35   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               36   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               37   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H   (CH 2 ) 5 —OH   ok               38   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H   (CH 2 ) 8 —OH   ok               39   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               40   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               41   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               42   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               43   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H   (CH 2 ) 5 —CH 3     ok               44   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               45   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               46   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               47   Phenyl-2-Cl   H   H   2-H   4-NO 2     5-H   6-H   3   H                         ok               48   Phenyl-2-Cl   H   H   2-H   4-NO 2     5-H   6-H   3   H   (CH 2 ) 5 —OH   ok               49   Phenyl-2-Cl   H   H   2-H   4-NO 2     5-H   6-H   3   H   (CH 2 ) 6 —OH   ok               50   Phenyl-2-Cl   H   H   2-H   4-NO 2     5-H   6-H   3   H   (CH 2 ) 5 —CH 3     ok               51   Phenyl-2-Cl   H   H   2-H   4-H   5-H   6-H   3   H   (CH 2 ) 3 —COOH   ok               52   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H   (CH 2 ) 3 —COOH   ok               53   Phenyl-2,6-Cl 2     H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               54   Phenyl-2,6-Cl 2     H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               55   Phenyl-2,6-Cl 2     H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               56   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               57   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               58   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               59   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               60   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               61   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               62   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               63   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               64   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               65   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               66   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               67   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               68   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               69   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               70   Phenyl-2-Cl   H   H   2-H   4-NO 2     5-H   6-H   3   H                         ok               71   Phenyl-2-Cl   H   H   2-H   4-NO 2     5-H   6-H   3   H                         ok               72   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               73   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               74   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H   CH 2 —CF 3     ok               75   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               76   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               77   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               78   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               79   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H   (CH 2 ) 2 —CH 3     ok               80   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               81   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               82   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               83   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               84   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               85   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               86   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               87   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               88   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               89   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               90   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               91   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               92   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               93   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               94   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               95   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               96   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               97   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               98   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               99   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               100   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               101   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               102   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               103   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               104   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               105   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H   (CH 2 ) 5 —CN   ok               106   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               107   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               108   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               109   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               110   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               111   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               112   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               113   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               114   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               115   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               116   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               117   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               118   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               119   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               120   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               121   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               122   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               123   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               124   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               125   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               126   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               127   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               128   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               129   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               130   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               131   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               132   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               133   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               134   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               135   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               136   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               137   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               138   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               139   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               140   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               141   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               142   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               143   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               144   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               145   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               146   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               147   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               148   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               149   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               150   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               151   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               152   Phenyl-2,4-Cl 2     Na   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               153   Phenyl-2-Cl   H   H   2-H   4-H   5-NO 2     6-H   3   H   (CH 2 ) 5 —OH   ok               154   Phenyl-2-Cl   H   H   2-H   4-H   5-NO 2     6-H   3   H   (CH 2 ) 6 —OH   ok               155   Phenyl-2-Cl   H   H   2-H   4-H   5-NO 2     6-H   3   H                         ok               156   Phenyl-2-Cl   H   H   2-H   4-H   5-NO 2     6-H   3   H                         ok               157   Phenyl-2-Cl   H   H   2-F   4-F   5-F   6-H   3   H                         ok               158   Phenyl-2-Cl   H   H   2-F   4-F   5-F   6-H   3   H                         ok               159   Phenyl-2-Cl   H   H   2-F   4-F   5-F   6-H   3   H                         ok               160   Phenyl-2-Cl   H   H   2-F   3-H   4-H   6-H   5   H   (CH 2 ) 5 —OH   ok               161   Phenyl-2-Cl   H   H   2-F   3-H   4-H   6-H   5   H                         ok               162   Phenyl-2-Cl   H   H   2-F   3-H   4-H   6-H   5   H                         ok               163   Phenyl-2-Cl   H   H   2-F   3-H   4-H   6-H   5   H                         ok               164   Phenyl-2,4-Cl 2     H   H   2-H   4-H   5-NO 2     6-H   3   H   (CH 2 ) 5 —OH   ok               165   Phenyl-2,4-Cl 2     H   H   2-F   4-F   5-F   6-H   3   H   (CH 2 ) 5 —OH   ok               166   Phenyl-2,4-Cl 2     H   H   2-F   4-F   5-F   6-H   3   H   (CH 2 ) 6 —OH   ok               167   Phenyl-2,4-Cl 2     H   H   2-F   3-H   4-H   6-H   5   H   (CH 2 ) 5 —OH   ok               168   Phenyl-2,4-Cl 2     H   H   2-F   3-H   4-H   6-H   5   H   (CH 2 ) 6 —OH   ok               169   Phenyl-2,4-Cl 2     H   H   2-F   3-H   4-H   6-H   5   H                         ok               170   Phenyl-2,4-Cl 2     H   H   2-F   3-H   4-H   6-H   5   H                         ok               171   Phenyl-2,4-Cl 2     H   H   2-F   3-H   4-H   6-H   5   H                         ok               172   Phenyl-2,4-Cl 2     H   H   2-F   3-H   4-H   6-H   5   H                         ok               173   Phenyl-2,4-Cl 2     H   H   2-F   3-H   4-H   6-H   5   H                         ok               174   Phenyl-2,4-Cl 2     H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               175   Phenyl-2,4-Cl 2     H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               176   Phenyl-2,4-Cl 2     H   H   2-OCH 3     3-H   4-H   6-H   5   H   (CH 2 ) 2 —COOH   ok               177   Phenyl-2,4-Cl 2     H   H   2-OCH 3     3-H   4-H   6-H   5   H   (CH 2 ) 3 —COOH   ok               178   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               179   Phenyl-2,4-Cl 2     H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               180   Phenyl-2,4-Cl 2     H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               181   Phenyl-2,4-Cl 2     H   H   2-OCH 3     3-H   4-H   6-H   5   H   (CH 2 ) 4 —COOH   ok               182   Phenyl-2,4-Cl 2     H   H   2-OCH 3     3-H   4-H   6-H   5   H   (CH 2 ) 5 —COOH   ok               183   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               184   Phenyl-2-Cl   H   H   2-OCH 3     3-H   4-H   6-H   5   H   (CH 2 ) 4 —COOH   ok               185   Phenyl-2,4-Cl 2     H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               186   Phenyl-2,4-Cl 2     H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               187   Phenyl-2-Cl   H   H   2-NO 2     3-H   5-H   6-H   4   H   (CH 2 ) 5 —OH   ok               188   Phenyl-2-Cl   H   H   2-NO 2     3-H   5-H   6-H   4   H   (CH 2 ) 6 —OH   ok               189   Phenyl-2-Cl   H   H   2-NO 2     3-H   5-H   6-H   4   H                         ok               190   Phenyl-2-Cl   H   H   2-NO 2     3-H   5-H   6-H   4   H                         ok               191   Phenyl-2-Cl   H   H   2-NO 2     3-H   5-H   6-H   4   H                         ok               192   Phenyl-2-Cl   H   H   2-NO 2     3-H   5-H   6-H   4   H                         ok               193   Phenyl-2-Cl   H   H   2-NO 2     3-H   5-H   6-H   4   H                         ok               194   Phenyl-2-Cl   H   H   2-NO 2     3-H   5-H   6-H   4   H                         ok               195   Phenyl-2-Cl   H   H   2-NO 2     3-H   5-H   6-H   4   H                         ok               196   Phenyl-2-Cl   H   H   2-NO 2     3-H   5-H   6-H   4   H                         ok               197   Phenyl-2-Cl   H   H   2-H   3-Cl   5-H   6-H   4   H                         ok               198   Phenyl-2-Cl   H   H   2-H   3-Cl   5-H   6-H   4   H   (CH 2 ) 5 —OH   ok               199   Phenyl-2-Cl   H   H   2-H   3-Cl   5-H   6-H   4   H                         ok               200   Phenyl-2-Cl   H   H   2-H   3-Cl   5-H   6-H   4   H                         ok               201   Phenyl-2-Cl   H   H   2-H   3-H   5-H   6-H   4   H   (CH 2 ) 5 —OH   ok               202   Phenyl-2-Cl   H   H   2-H   3-H   5-H   6-H   4   H   (CH 2 ) 6 —OH   ok               203   Phenyl-2-Cl   H   H   2-H   3-H   5-H   6-H   4   H                         ok               204   Phenyl-2-Cl   H   H   2-H   3-H   5-H   6-H   4   H                         ok               205   Phenyl-2-Cl   H   H   2-H   3-H   5-H   6-H   4   H                         ok               206   Phenyl-2-Cl   H   H   2-H   3-H   5-H   6-H   4   H                         ok               207   Phenyl-2-Cl   H   H   2-H   3-H   5-H   6-H   4   H                         ok               208   Phenyl-2-Cl   H   H   2-H   3-H   5-H   6-H   4   H                         ok               209   Phenyl-2-Cl   H   H   2-H   3-H   5-H   6-H   4   H                         ok               210   Phenyl-2-Cl   H   H   2-H   3-H   5-H   6-H   4   H                         ok               211   Phenyl-2-Cl   H   H   2-Cl   3-H   5-H   6-Cl   4   H   (CH 2 ) 6 —OH   ok               212   Phenyl-2-Cl   H   H   2-Cl   3-H   5-H   6-Cl   4   H   (CH 2 ) 5 —OH   ok               213   Phenyl-2-Cl   H   H   2-Cl   3-H   5-OCH 3     6-H   4   H   (CH 2 ) 5 —OH   ok               214   Phenyl-2-Cl   H   H   2-Cl   3-H   5-OCH 3     6-H   4   H   (CH 2 ) 6 —OH   ok               215   Phenyl-2-Cl   H   H   2-Cl   3-H   5-OCH 3     6-H   4   H                         ok               216   Phenyl-2-Cl   H   H   2-Cl   3-H   5-OCH 3     6-H   4   H                         ok               217   Phenyl-2-Cl   H   H   2-Cl   3-H   5-OCH 3     6-H   4   H                         ok               218   Phenyl-2-Cl   H   H   2-Cl   3-H   5-OCH 3     6-H   4   H                         ok               219   Phenyl-2-Cl   H   H   2-Cl   3-H   5-OCH 3     6-H   4   H                         ok               220   Phenyl-2-Cl   H   H   2-NO 2     3-H   5-H   6-H   4   H                         ok               221   Phenyl-2-Cl   H   H   2-H   3-H   5-H   6-H   4   H                         ok               222   Phenyl-2-Cl   H   H   2-H   3-H   5-H   6-H   4   H                         ok               223   Phenyl-2-Cl   H   H   2-OCH 3     3-H   5-H   6-H   4   H   (CH 2 ) 5 —OH   ok               224   Phenyl-2-Cl   H   H   2-OCH 3     3-H   5-H   6-H   4   H   (CH 2 ) 6 —OH   ok               225   Phenyl-2-Cl   H   H   2-OCH 3     3-H   5-H   6-H   4   H                         ok               226   Phenyl-2-Cl   H   H   2-OCH 3     3-H   5-H   6-H   4   H                         ok               227   Phenyl-2-Cl   H   H   2-Cl   3-H   5-H   6-H   4   H   (CH 2 ) 5 —OH   ok               228   Phenyl-2-Cl   H   H   2-Cl   3-H   5-H   6-H   4   H   (CH 2 ) 6 —OH   ok               229   Phenyl-2-Cl   H   H   2-Cl   3-H   5-H   6-H   4   H                         ok               230   Phenyl-2-Cl   H   H   2-Cl   3-H   5-H   6-H   4   H                         ok               231   Phenyl-2-Cl   H   H   2-Cl   3-H   5-H   6-H   4   H                         ok               232   Phenyl-2-Cl   H   H   2-F   3-F   5-F   6-F   4   H   (CH 2 ) 5 —OH   ok               233   Phenyl-2,4-Cl 2     H   H   2-OCH 3     3-H   5-H   6-H   4   H   (CH 2 ) 5 —OH   ok               234   Phenyl-2,4-Cl 2     H   H   2-OCH 3     3-H   5-H   6-H   4   H   (CH 2 ) 6 —OH   ok               235   Phenyl-2,4-Cl 2     H   H   2-OCH 3     3-H   5-H   6-H   4   H                         ok               236   Phenyl-2,4-Cl 2     H   H   2-OCH 3     3-H   5-H   6-H   4   H                         ok               237   Phenyl-2,4-Cl 2     H   H   2-OCH 3     3-H   5-H   6-H   4   H                         ok               238   Phenyl-2,4-Cl 2     H   H   2-OCH 3     3-H   5-H   6-H   4   H                         ok               239   Phenyl-2,4-Cl 2     H   H   2-OCH 3     3-H   5-H   6-H   4   H                         ok               240   Phenyl-2,4-Cl 2     H   H   2-Cl   3-H   5-H   6-H   4   H   (CH 2 ) 5 —OH   ok               241   Phenyl-2,4-Cl 2     H   H   2-Cl   3-H   5-H   6-H   4   H   (CH 2 ) 6 —OH   ok               242   Phenyl-2,4-Cl 2     H   H   2-Cl   3-H   5-H   6-H   4   H                         ok               243   Phenyl-2,4-Cl 2     H   H   2-Cl   3-H   5-H   6-H   4   H                         ok               244   Phenyl-2,4-Cl 2     H   H   2-Cl   3-H   5-H   6-H   4   H                         ok               245   Phenyl-2,4-Cl 2     H   H   2-Cl   3-H   5-H   6-H   4   H                         ok               246   Phenyl-2,4-Cl 2     H   H   2-Cl   3-H   5-H   6-H   4   H                         ok               247   Phenyl-2,4-Cl 2     H   H   2-Cl   3-H   5-H   6-H   4   H                         ok               248   Phenyl-2,4-Cl 2     H   H   2-OH   3-H   5-H   6-H   4   H   (CH 2 ) 6 —OH   ok               249   Phenyl-2,4-Cl 2     H   H   2-NO 2     3-H   5-H   6-H   4   H                         ok               250   Phenyl-2-Cl   H   H   2-OCH 3     3-H   5-H   6-H   4   H                         ok               251   Phenyl-2,4-Cl 2     H   H   2-OCH 3     3-H   5-H   6-H   4   H                         ok               252   Phenyl-2-Cl   H   H   2-Cl   3-H   5-H   6-H   4   H                         ok               253   Phenyl-2,4-Cl 2     H   H   2-Cl   3-H   5-H   6-H   4   H                         ok               254   Phenyl-2,4-Cl 2     H   H   2-OCH 3     3-H   4-H   6-H   5   H                         ok               255   Phenyl-2-Cl-4-F   H   H   2-OCH 3     3-H   5-H   6-H   4   H   H   ok               256   Phenyl-2,4-Cl 2     H   H   2-OCH 3     3-H   5-H   6-H   4   H   H   ok               257   Phenyl-2-Cl-4-F   H   H   2-OCH 3     3-H   5-H   6-H   4   H   CH 3     ok               258   Phenyl-2,4-Cl 2     H   H   2-OCH 3     3-H   5-H   6-H   4   H   CH 3     ok               259   Phenyl-2-Cl-4-F   H   H   2-OCH 3     3-H   5-H   6-H   4   H   (CH 2 ) 3 —NHCOO—CH 2 —Ph   ok               260   Phenyl-2-Cl-4,5-F 2     H   H   2-OCH 3     3-H   5-H   6-H   4   H   (CH 2 ) 3 —NHCOO—CH 2 —Ph   ok               261   Phenyl-2-Cl-4-F   H   H   2-OCH 3     3-H   5-H   6-H   4   CH 3     CH 3     ok               262   Phenyl-2,4-Cl 2     H   H   2-OCH 3     3-H   5-H   6-H   4   CH 3     CH 3     ok               263   Phenyl-2-Cl-4,5-F 2     H   H   2-OCH 3     3-H   5-H   6-H   4   H   CH 3     ok               264   Phenyl-2-Cl-4,5-F 2     H   H   2-OCH 3     3-H   5-H   6-H   4   CH 3     CH 3     ok               265   Phenyl-2-Cl-4,5-F 2     H   H   2-OCH 3     3-H   5-H   6-H   4   H   (CH 2 ) 2 —NHCO—CH 3     ok       266   Phenyl-2-Cl-4,5-F 2     H   H   2-OCH 3     3-H   5-H   6-H   4   H   (CH 2 ) 3 —NH 2     ok                                               TFA       267   Phenyl-2-Cl-4,5-F 2     H   H   2-Cl   3-H   5-H   6-H   4   H   CH 3     ok       268   Phenyl-2-Cl-4,5-F 2     H   H   2-Cl   3-H   5-H   6-H   4   CH 3     CH 3     ok       269   Phenyl-2-Cl-4,5-F 2     H   H   2-Cl   3-H   5-H   6-H   4   H   H   ok       270   Phenyl-2-Cl-4,5-F 2     H   H   2-OCH 3     3-H   5-H   6-H   4   H   (CH 2 ) 3 —N(CH 3)2     ok                                               TFA       271   Phenyl-2-Cl-4,5-F 2     H   H   2-OCH 3     3-H   5-H   6-H   4   H   (CH 2 ) 2 —N(CH 3)2     ok                                               TFA       272   Phenyl-2,4-Cl 2     H   H   2-Cl   3-H   5-H   6-H   4   H   (CH 2 ) 2 —NHCOO—CH 2 —   ok                                               CH═CH 2         273   Phenyl-2-Cl-4,5-F 2     H   H   2-OCH 3     3-H   5-H   6-H   4   H   (CH 2 ) 4 —NH 2     ok                                               TFA       274   Phenyl-2,4-Cl 2     H   H   2-Cl   3-H   5-H   6-H   4   H   (CH 2 ) 2 —NH 2     ok                                               TFA       275   Phenyl-2-Cl-4-F   H   H   2-OCH 3     3-H   5-H   6-H   4   H   (CH 2 ) 3 —NH 2     ok                                               TFA       276   Phenyl-2-Cl-4,5-F 2     H   H   3-H   4-H   5-   6-H   2   H   CH 3     ok                               COOH       277   Phenyl-2-Cl-4,5-F 2     H   H   2-OCF 3     3-H   5-H   6-H   4   H   CH 3     ok       278   Phenyl-2-Cl-4,5-F 2     H   H   2-OCF 3     3-H   5-H   6-H   4   CH 3     CH 3     ok       279   Phenyl-2-Cl-4,5-F 2     H   H   3-H   4-H   5-H   6-H   2   H   H   ok       280   Phenyl-2-Cl-4,5-F 2     H   H   2-OCF 3     3-H   5-H   6-H   4   H   CH 2 —COO—CH 3     ok       281   Phenyl-2-Cl-4,5-F 2     H   H   2-OCF 3     3-H   5-H   6-H   4   CH 3     CH 2 —COO—CH 3     ok       282   Phenyl-2-Cl-4,5-F 2     H   H   2-OCF 3     3-H   5-H   6-H   4   H   (CH 2 ) 2 —COO—CH 3     ok       283   Phenyl-2-Cl-4,5-F 2     H   H   2-OCF 3     3-H   5-H   6-H   4   H   (CH 2 ) 3 —COO—CH 3     ok       284   Phenyl-2-Cl-4,5-F 2     H   H   2-OCF 3     3-H   5-H   6-H   4   H   CH 2 —COOH   ok       285   Phenyl-2-Cl-4,5-F 2     H   H   2-OCF 3     3-H   5-H   6-H   4   CH 3     CH 2 —COOH   ok       286   Phenyl-2-Cl-4,5-F 2     H   H   2-OCF 3     3-H   5-H   6-H   4   H   (CH 2 ) 2 —COOH   ok       287   Phenyl-2-Cl-4,5-F 2     H   H   2-OCF 3     3-H   5-H   6-H   4   H   (CH 2 ) 3 —COOH   ok                 *“Na” means the sodium salt of the corresponding compound with R1 = H            **In the “Amide” column, the position of the carboxamide group —(C═O)—N(R7)(R8) on the phenyl radical is indicated.            ***Where structural formulae are indicated for R8, the bonding of R8 to the nitrogen takes place via the short depicted bond            ****The statement “MS is ok” means that a mass spectrum was measured and, in this, the molecular peak (molecular mass +H + ) was detected.             
 
      The compounds of the formula I are distinguished by beneficial effects on glucose metabolism; in particular they lower the blood glucose level and are suitable for treating type II diabetes. The compounds can be employed alone or in combination with other blood glucose-lowering active ingredients (antidiabetics). Examples of such blood glucose-lowering active ingredients are sulfonylureas (such as, for example, glimepiride, glibenclamide, gliclazide, glibornuride, gliquidone, glisoxepide), metformin, tolbutamide, glitazones (such as, for example, troglitazone, rosiglitazone, pioglitazone, repaglinide), alpha-glucosidase inhibitors (such as, for example, acarbose, miglitol) or insulins. All antidiabetics mentioned in chapter 12 of the Rote Liste 2001 can be combined with the compounds of the formula I of the invention for improving the effect. Administration of the active ingredient combination can take place either by separate administration of the active ingredients to the patients or in the form of combination products in which a plurality of active ingredients are present in one pharmaceutical preparation.  
      The compounds of the formula I are additionally suitable for the treatment of late complications of diabetes such as, for example, nephropathy, retinopathy, neuropathy and mycocardial infarction, peripheral arterial occlusive diseases, thromboses, arteriosclerosis, syndrome X, obesity, inflammations, immune diseases, autoimmune diseases such as, for example, AIDS, asthma, osteoporosis, cancer, psoriasis, Alzheimer&#39;s, schizophrenia and infectious diseases.  
      The activity of the compounds was assayed as follows:  
      Glycogen Phosphorylase a Activity Assay  
      The effect of compounds on the activity of the active form of glycogen phosphorylase (GPa) was measured in the reverse direction by following the synthesis of glycogen from glucose 1-phosphate by determining the liberation of inorganic phosphate. All the reactions were carried out as duplicate determinations in microtiter plates with 96 wells (Half Area Plates, Costar No 3696), measuring the change in absorption owing to the formation of the reaction product at the wavelength specified hereinafter in a Multiskan Ascent Elisa Reader (Lab Systems, Finland).  
      In order to measure the GPa enzymic activity in the reverse direction, the general method of Engers et al. (Engers H D, Shechosky S, Madsen N B, Can J Biochem 1970 July; 48(7): 746-754) was used to measure the conversion of glucose 1-phosphate into glycogen and inorganic phosphate, with the following modifications: human glycogen phosphorylase a (for example with 0.76 mg of protein/ml (Aventis Pharma Deutschland GmbH), dissolved in buffer solution E (25 mM β-glycerophosphate, pH 7.0, 1 mM EDTA and 1 mM dithiothreitol) was diluted with buffer T (50 mM Hepes, pH 7.0, 100 mM KCl, 2.5 mM EDTA, 2.5 mM MgCl 2 .6H 2 O) and addition of 5 mg/ml glycogen to a concentration of 10 μg of protein/ml. Test substances were prepared as 10 mM solution in DMSO and diluted to 50 μM with buffer solution T. To 10 μl of this solution were added 10 μl of 37.5 mM glucose, dissolved in buffer solution T, and 5 mg/ml glycogen, plus 10 μl of a solution of human glycogen phosphorylase a (10 μg of protein/ml) and 20 μl of glucose 1-phosphate, 2.5 mM. The baseline glycogen phosphorylase a activity in the absence of test substance was determined by adding 10 μl of buffer solution T (0.1% DMSO). The mixture was incubated at room temperature for 40 minutes, and the liberated inorganic phosphate was measured by the general method of Drueckes et al. (Drueckes P, Schinzel R, Palm D,  Anal Biochem  1995 Sep. 1; 230(1): 173-177) with the following modifications: 50 μl of a stop solution of 7.3 mM ammonium molybdate, 10.9 mM zinc acetate, 3.6% ascorbic acid, 0.9% SDS are added to 50 μl of the enzyme mixture. After incubation at 45° C. for 60 minutes, the absorption at 820 nm was measured. To determine the background absorption, in a separate mixture the stop solution was added immediately after addition of the glucose 1-phosphate solution.  
      This test was carried out with a concentration of 10 μM of the test substance in order to determine the particular inhibition of glycogen phosphorylase a in vitro by the test substance.  
               TABLE 2                          Biological activity:                                 % inhibition at           Ex.   10 μM                                         1   87           2   73           3   75           4   79           5   77           12   92           20   35           29   78           30   76           31   86           41   50           44   11           46   36           47   46           49   13           51   36           53   22           60   36           70   86           75   41           80   50           84   44           89   90           90   34           100   78           101   93           102   14           106   35           111   88           112   100           116   100           117   99           118   70           119   97           120   40           122   12           128   95           147   88           149   76                      
 
      It is to be inferred from the table that the compounds of the formula I inhibit the activity of glycogen phosphorylase a and are thus very suitable for lowering the blood glucose level.  
      The preparation of some examples is described in detail below, and the other compounds of the formula I were obtained analogously:  
      Experimental Part: 
    
    
     EXAMPLE 1  
     a) 2-Chlorobenzoyl Isocyanate  
      2-Chlorobenzamide was dissolved in dichloromethane, mixed with 1.5 eq. of oxalyl chloride and heated to reflux for 16 hours. The reaction mixture was concentrated under high vacuum and reacted in stage b without further purification.  
     b) 4-Chloro-3-[3-(2-chlorobenzoyl)ureido]Benzoic Acid  
      1 g (5.8 mmol) of 3-amino-4-chlorobenzoic acid were mixed with 0.75 g (5.8 mmol) of diisopropylethylamine and 1.06 g (5.8 mmol) of 2-chlorobenzoyl isocyanate in 5 ml of dichloromethane and reacted at room temperature for 12 hours. The solvent was evaporated, the residue was mixed with 5% strength sodium bicarbonate solution and extracted twice with diethyl ether, and the aqueous phase was adjusted to pH 3 with HCl. The resulting precipitate was filtered off with suction.  
     c) Ethyl 4-{4-chloro-3-[3-(2-chlorobenzoyl)ureido]benzoylamino}piperidine-1-carboxylate  
      100 mg (0.28 mmol) of 4-chloro-3-[3-(2-chlorobenzoyl)ureido]benzoic acid, 93 mg (0.28 mmol) of TOTU and 37 mg (0.28 mmol) of diisopropylethylamine were coupled in 1 ml of dimethylformamide. The reaction solution was washed once each with 5% strength sodium bicarbonate solution and 10% strength citric acid solution, and the organic phase was dried and concentrated.  
      Examples 2-52 and 188-220 were synthesized in analogy to example 1.  
     EXAMPLE 94  
     a) 4-[3-(2,4-Dichlorobenzoyl)ureido]-3-methoxybenzoic Acid  
      36.1 g (167.5 mmol) of 2,4-dichlorobenzoyl isocyanate, which was prepared in analogy to example 1 a, were added to a solution of 20 g (119.6 mmol) of 4-amino-3-methoxybenzoic acid in 400 ml of acetonitrile. The mixture was heated to reflux for 2 hours and cooled to room temperature. The precipitate was filtered off with suction, washed with acetonitrile and methanol, stirred with 5% strength potassium bisulfate solution, again filtered off with suction and dried under high vacuum. 44 g (96%) of the desired product were obtained.  
     b) 4-[3-(2,4-Dichlorobenzoyl)ureido]-3-methoxybenzoyl Chloride  
      11.25 g (37.2 mmol) of 4-[3-(2,4-dichlorobenzoyl)ureido]-3-methoxybenzoic acid from stage a were heated to reflux with 150 ml of thionyl chloride for 3 hours and evaporated in a rotary evaporator under high vacuum. The residue was twice mixed with toluene and again evaporated under high vacuum to result in 10.88 g (27.09 mmol, 73%) of acid chloride (loss due to foaming over). The product obtained in this way was employed in the next stage without further purification.  
     c) 3-[3-(2,4-Dichlorobenzoyl)ureido]-4-methoxy-N-(2,2,6,6-tetramethylpiperidin-4-yl)benzamide Sodium Salt  
      A suspension of 157 mg (0.39 mmol) of acid chloride from stage b and 4 ml of dichloromethane was added to a solution of 65 μl (0.8 mmol) of pyridine and 63 mg (0.4 mmol) of 2,2,6,6-tetramethylpiperidin-4-ylamine in 2 ml of dichloromethane, and the reaction mixture was reacted at room temperature for 16 hours. The reaction mixture was diluted with 2.5 ml of acetonitrile, filtered and washed with 5 ml of acetonitrile, and the filtrate was evaporated. The residue was taken up in a mixture of 2N of sodium hydroxide solution, acetonitrile and dimethylformamide (1/2/2), whereupon the product precipitated.  
      Examples 95-152 were synthesized in analogy to example 94. If required, the products were purified by preparative reverse phase HPLC (acetonitrile/water/TFA).