AU2004212054A1 - Substituted 3-(benzoylureido)-thiophene derivatives, method for the production and use thereof - Google Patents
Substituted 3-(benzoylureido)-thiophene derivatives, method for the production and use thereof Download PDFInfo
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- AU2004212054A1 AU2004212054A1 AU2004212054A AU2004212054A AU2004212054A1 AU 2004212054 A1 AU2004212054 A1 AU 2004212054A1 AU 2004212054 A AU2004212054 A AU 2004212054A AU 2004212054 A AU2004212054 A AU 2004212054A AU 2004212054 A1 AU2004212054 A1 AU 2004212054A1
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- 238000004519 manufacturing process Methods 0.000 title claims description 3
- WGRIEMJPCBPTBI-UHFFFAOYSA-N n-(thiophen-3-ylcarbamoyl)benzamide Chemical class C1=CSC=C1NC(=O)NC(=O)C1=CC=CC=C1 WGRIEMJPCBPTBI-UHFFFAOYSA-N 0.000 title description 3
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- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 54
- -1 2 -piperidinyl Chemical group 0.000 claims description 41
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- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/28—Halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/30—Hetero atoms other than halogen
- C07D333/36—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/42—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms with nitro or nitroso radicals directly attached to ring carbon atoms
- C07D333/44—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms with nitro or nitroso radicals directly attached to ring carbon atoms attached in position 5
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Description
IN THE MATTER OF an Australian Application corresponding to PCT Application PCT/EP2004/000993 RWS Group Ltd, of Europa House, Marsham Way, Gerrards Cross, Buckinghamshire, England, hereby solemnly and sincerely declares that, to the best of its knowledge and belief, the following document, prepared by one of its translators competent in the art and conversant with the English and German languages, is a true and correct translation of the PCT Application filed under No. PCT/EP2004/000993. Date: 19 April 2005 C. E. SITCH Deputy Managing Director - UK Translation Division For and on behalf of RWS Group Ltd VU ZUU4/U (ZUbU U I /t HZUU4/UUUU9J 1 Description 5 Substituted 3-(benzoylureido)-thiophene derivatives, method for the production and use thereof The invention relates to substituted 3-(benzoylureido)thiophene derivatives and to their physiologically tolerated salts and physiologically functional derivatives. 10 EP 0 300 972 describes benzoylureidothiophenes having pesticidal, specifically insecticidal and acaricidal, action. It is an object of the invention to provide compounds which make it possible to 15 prevent and treat diabetes mellitus. To this end, the compounds should in particular exhibit a therapeutically utilizable blood sugar-reducing action. The invention therefore relates to compounds of the formula I R5 CI H H R2 RI N N R1R 20 R4 where R5 is F, Cl or Br; 25 R1 is H, F, Cl, Br; R2 is H, F, Cl, Br, (C1-C 6 )-alkyl, CF 3 , OCF 3 , NO 2 , CN, O-(C 1
-C
6 )-alkyl, CO
(C
1
-C
6 )-alkyl, COOH, COO(C1-C 6 )-alkyl, CONH 2 , CONH(C 1
-C
6 )-alkyl, CON((C1-C)-alkyl) 2 , S0 2
-(C
1
-C
6 )-alkyl, or the A radical; 5 R3 is H, (C 1 -Cs)-alkyl, COO(C 1 -Cs)-alkyl, S0 2
(C
1
-C
6 )-alkyl, (C 1
-C
6 )-alkyl phenyl, phenyl, S0 2 -phenyl, where the phenyl ring may in each case be up to disubstituted by F, Cl, CN, OH, (C 1
-C
6 )-alkyl, 0-(C 1
-C
6 )-alkyl, CF 3 ,
OCF
3 , COOH, COO(C 1
-C
6 )-alkyl or CONIH 2 ; 10 R4 is H, (C1-C 6 )-alkyl, COO(C 1
-C
6 )-alkyl, S0 2 -(C1-C 6 )-alkyl, S0 2 -piperidinyl, S0 2 -piperazinyl, (C1-C 6 )-alkylphenyl, where the phenyl ring, the piperidinyl ring and the piperazinyl ring may be up to disubstituted by F, Cl, CN, OH, (C 1
-C
6 )-alkyl, 0-(C1-C 6 )-alkyl, CF 3 , OCF 3 , COOH, COO(C 1 C 6 )-alkyl or CONIH 2 ; 15 A is a heterocyclic radical of the formula 2a, 2b, 2c or 3; NNN-N N-N N-1N 0 0 X 0 Y N 2a 2b 2c 3 20 X isOorNH; Y is OH or NH 2 ; Z is OH, O(C 1
-C
6 )-alkyl, NH 2 , NH(C1-C 6 )-alkyl, N((C 1
-C
6 )-alkyl) 2 ; 25 and their physiologically tolerated salts. Particular preference is given to compounds of the formula I where one or more radicals are defined as follows: 30 R5 is F, Cl or Br; R1 is H, F; R2 is H, F, Cl, Br, (C1-C)-alkyl, CF 3 , OCF 3 , NO 2 , CN, O-(C 1 -C)-alkyl, 5 CO(C 1 -C)-alkyl, COOH, COO(C 1 -C)-alkyl, CONH 2 , CONH(C 1
-C
6 )-alkyl,
CON((C
1
-C
6 )-alkyl) 2 , S0 2
-(C
1
-C
6 )-alkyl, or the A radical; R3 is H, (C1-O)-alkyl, COO(C-COs)-alkyl, SO 2 (C1-C)-alkyl, (C1-C6) alkylphenyl, phenyl, S0 2 -phenyl, where the phenyl ring may in each 10 case be up to disubstituted by F or Cl; R4 is H, (C 1 -C)-alkyl, COO(C-C)-alkyl, S0 2
-(C
1
-C
6 )-alkyl, S0 2 -piperidinyl, S0 2 -piperazinyl, (C1-C 6 )-alkylphenyl, where the phenyl ring, the piperidinyl ring and the piperazinyl ring may be up to disubstituted by F, 15 Cl, CN, OH, (C 1
-C
6 )-alkyl, 0-(C1-C 6 )-alkyl, CF 3 , OCF 3 , COOH, COO(C1 C)-alkyl or CONH 2 ; A is a heterocyclic radical of the formula 2a, 2b, 2c or 3; N-N N-N N- N 0 O X 0 Y N 20 2a 2b 2c 3 X is O or NH; Y is OH or NH 2 ; 25 Z is OH; and their physiologically tolerated salts. 30 Particular preference is given to compounds of the formula I where one or more radicals are defined as follows: 4 R5 is F; R1 is F; 5 R2 is COOH, COO(C 1
-C
6 )-alkyl, CONH 2 , CONH(C 1
-C
6 )-alkyl, CON((C 1
-C
6
)
alkyl) 2 , or the A radical; R3 is H, (C 1 -C)-alkyl, COO(C 1 -C)-alkyl, S0 2
(C
1 -C)-alkyl, (C 1
-C
6 )-alkyl 10 phenyl, phenyl, S0 2 -phenyl, where the phenyl ring may in each case be up to disubstituted by F; R4 is H, (C1-C)-alkyl, COO(C1-C)-alkyl, S0 2
-(C
1 -Cs)-alkyl, S0 2 -piperidinyl, S0 2 -piperazinyl, (C 1
-C
6 )-alkylphenyl, where the phenyl ring, the 15 piperidinyl ring and the piperazinyl ring may be up to disubstituted by F or (C1-C)-alkyl; A is a heterocyclic radical of the formula 2a or 2b; N-N N-N O x0 Xy 20 2a 2b X isOorNH; Y is OH or NH 2 ; 25 and their physiologically tolerated salts. Preference is further given to compounds of formula I in which at least one of the radicals R2, R3 and R4 is not hydrogen.
The invention relates to compounds of the formula 1, in the form of their racemates, racemic mixtures and pure enantiomers, and also to their diastereomers and mixtures thereof. 5 The alkyl radicals in the substituents R2, R3 and R4 may be either straight-chain or branched. When radicals or substituents can occur more than once in the compounds of the formula 1, for example A, they may all each independently be defined as specified, 10 and be the same or different. As a consequence of their higher water solubility compared to the starting or basic compounds, pharmaceutically tolerated salts are particularly suitable for medical applications. These salts have to have a pharmaceutically tolerated anion or cation. 15 Suitable pharmaceutically tolerated acid addition salts of the compounds according to the invention are salts of inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid, and also of organic acids, e.g. acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isethionic acid, lactic 20 acid, lactobionic acid, maleic acid, malic acid, methanesulfonic acid, succinic acid, p toluenesulfonic acid and tartaric acid. Suitable pharmaceutically tolerated basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts), alkaline earth metal salts (such as magnesium and calcium salts), trometamol (2-amino-2 hydroxymethyl-1,3-propanediol), diethanolamine, lysine or ethylenediamine. 25 Salts having a pharmaceutically unacceptable anion, for example trifluoroacetate, are likewise encompassed by the scope of the invention as useful intermediates for the preparation or purification of pharmaceutically tolerated salts and/or for use in nontherapeutic, for example in vitro, applications. 30 The term "physiologically functional derivative" used herein refers to any physiologically tolerated derivative of a compound of the formula I according to the invention, e.g. an ester which is able, on administration to a mammal, e.g. a human, to (directly or indirectly) form a compound of the formula I or an active metabolite thereof. The physiologically functional derivatives also include prodrugs of the compounds 5 according to the invention, for example as described in H. Okada et al., Chem. Pharm. Bull. 1994, 42, 57-61. Such prodrugs can be metabolized in vivo to a compound according to the invention. These prodrugs may or may not be active themselves. 10 The compounds according to the invention can also exist in different polymorphous forms, for example as amorphous and crystalline polymorphous forms. All polymorphous forms of the compounds according to the invention are encompassed by the scope of the invention and are a further aspect of the invention. 15 All references given below to "compound(s) of formula I" refer to compound(s) of the formula I as described above, and also to their salts, solvates and physiologically functional derivatives as described herein. In this context, an aryl radical is a phenyl, naphthyl, biphenyl, tetrahydronaphthyl, 20 alpha- or beta-tetralone, indanyl or indan-1-onyl radical. The terms "heterocyclic ring" and "heterocyclic radical" used here relate to heteroaryl radicals and heterocycloalkyl radicals which derive from 3 to 10 membered carbon rings in which one or more carbon atoms have been replaced by one or more atoms 25 selected from the group of oxygen, sulfur and nitrogen. Suitable "heterocyclic rings" and "heterocyclic radicals" are acridinyl, azocinyl, benzimidazolyl, benzofuryl, benzothienyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, 30 benzimidazalinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, quinazolinyl, quinolinyl, 4H quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]-tetrahydrofuran, furyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, I isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4 oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, 5 phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purynyl, pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadazinyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 10 1,3,4-thiadiazolyl, thienyl, triazolyl, tetrazolyl and xanthenyl. Pyridyl is either 2-, 3- or 4-pyridyl. Thienyl is either 2- or 3-thienyl. Furyl is either 2- or 3-furyl. 15 Also included are the corresponding N-oxides of these compounds, for example 1-oxy-2-, 3- or 4-pyridyl. Also included are singly or multiply benzofused derivatives of these heterocycles. 20 The compound(s) of the formula (I) can also be administered in combination with further active ingredients. The amount of a compound of formula I which is required in order to achieve the desired biological effect is dependent upon a series of factors, for example the 25 specific compound selected, the intended use, the mode of administration and the clinical condition of the patient. The daily dose is generally in the range from 0.3 mg to 100 mg (typically from 3 mg and 50 mg) per day per kilogram of bodyweight, for example 3-10 mg/kg/day. An intravenous dose may, for example, be in the range from 0.3 mg to 1.0 mg/kg and may advantageously be administered as an infusion of 30 from 10 ng to 100 ng per kilogram per minute. Suitable infusion solutions for these purposes may, for example, contain from 0.1 ng to 10 mg, typically from 1 ng to 10 mg, per milliliter. Individual doses may contain, for example, from 1 mg to 10 g of the active ingredient. Ampules for injections may therefore contain, for example, from 1 mg to 100 mg, and single dose formulations which can be administered orally, for example tablets or capsules, may contain, for example, from 1.0 to 1000 mg, typically from 10 to 600 mg. The compounds of formula I may be used for therapy of the abovementioned conditions as the compounds themselves, although they are preferably in the form of a pharmaceutical composition with an acceptable carrier. 5 The carrier of course has to be acceptable, in the sense that it is compatible with the other constituents of the composition and is not damaging to the health of the patient. 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. Further pharmaceutically active substances 1o may likewise be present, including further compounds of formula 1. The pharmaceutical compositions according to the invention may be produced by one of the known pharmaceutical methods which consist essentially of mixing the ingredients with pharmacologically acceptable carriers and/or excipients. 15 Pharmaceutical compositions according to the invention are those which are 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 type of the compound of 20 formula I used in each case. Coated formulations and coated slow-release formulations are also encompassed by the scope of the invention. Preference is given to acid- and gastric fluid-resistant formulations. Suitable gastric fluid-resistant coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and 25 methyl methacrylate. Suitable pharmaceutical compounds for oral administration may be in the form of separate units, for example capsules, cachets, lozenges or tablets, each of which contains a certain amount of the compound of formula I; as powder or granules; as 30 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. In general, the compositions are prepared 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. For example, a tablet can be produced by compressing or shaping a powder or granules of the compound, optionally with one or more additional ingredients. Compressed tablets can be 5 prepared by tableting the compound in free-flowing form, for example a powder or granules, optionally mixed with a binder, lubricant, inert diluent and/or one (or more) surfactants/dispersants in a suitable machine. Shaped tablets can be prepared by shaping the pulverulent compound moistened with an inert liquid diluent in a suitable machine. 10 Pharmaceutical compositions which are suitable for peroral (sublingual) administration include lozenges which contain a compound of formula I with a flavoring, customarily sucrose, and gum arabic or tragacanth, and pastilles which include the compound in an inert base such as gelatin and glycerol or sucrose and 15 gum arabic. Suitable pharmaceutical compositions for parenteral administration include preferably sterile aqueous preparations of a compound of formula I which are preferably isotonic with the blood of the intended recipient. These preparations are preferably 20 administered intravenously, although the administration may also be subcutaneous, intramuscular or intradermal as an injection. These preparations can preferably be produced by mixing the compound with water and making the solution obtained sterile and isotonic with the blood. The injectable compositions according to the invention generally contain from 0.1 to 5% by weight of the active compound. 25 Suitable pharmaceutical compositions for rectal administration are preferably in the form of single dose suppositories. These can be prepared by mixing a compound of formula I with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting mixture. 30 Suitable pharmaceutical compositions for topical use on the skin are preferably in the form of an ointment, cream, lotion, paste, spray, aerosol or oil. Useful carriers include petroleum jelly, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances. The active ingredient is generally present in a IU concentration of from 0.1 to 15% by weight of the composition, preferably from 0.5 to 2%. Transdermal administration is also possible. Suitable pharmaceutical compositions 5 for transdermal applications may be in the form of single plasters which are suitable for long-term close contact with the epidermis of the patient. Such plasters advantageously contain the active ingredient in an optionally buffered aqueous solution, dissolved and/or dispersed in an adhesive or dispersed in a polymer. A suitable active ingredient concentration is from approx. 1% to 35%, preferably from 1o approx. 3% to 15%. A particular means of releasing the active ingredient is by electrotransport or iontophoresis, as described, for example, in Pharmaceutical Research, 2(6): 318 (1986). Further useful active ingredients for combination products are as follows: 15 All antidiabetics mentioned in the Rote Liste 2001, chapter 12. They can be combined with the compounds of the formula I according to the invention, in particular for synergistic enhancement of the action. The active ingredient combination can be administered either by separately administering the active ingredients to the patient or in the form of combination products in which a plurality of 20 active ingredients are present in one pharmaceutical preparation. Most of the active ingredients listed hereinbelow are disclosed in USP Dictionary of USAN and International Drug Names, US Pharmacopeia, Rockville 2001. Antidiabetics include insulin and insulin derivatives, for example Lantus* (see www.lantus.com) or HMR 1964, fast-acting insulins (see US 6,221,633), GLP-1 25 derivatives, 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 preferably include sulfonylureas, biguanidines, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1 agonists, potassium channel openers, for 30 example those disclosed in WO 97/26265 and WO 99/03861 of Novo Nordisk A/S, insulin sensitizers, inhibitors of liver enzymes which are 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 l ' 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 5 in combination with an HMGCoA 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, for example, ezetimibe, 10 tiqueside, pamaqueside. In one embodiment of the invention, the compounds of the formula I are administered in combination with a PPAR gamma agonist, for example, rosiglitazone, pioglitazone, JTT-501, GI 262570. 15 In one embodiment of the invention, the compounds of the formula I are administered in combination with PPAR alpha agonist, for example, GW 9578, GW 7647. In one embodiment of the invention, the compounds of the formula I are administered 20 in combination with a mixed PPAR alpha/gamma agonist, for example, GW 1536, AVE 8042, AVE 8134, AVE 0847, or as described in PCT/US 11833, PCT/US 11490, DE10142734.4. In one embodiment of the invention, the compounds of the formula I are administered 25 in combination with a fibrate, 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, for example, implitapide, BMS-201038, R 103757. 30 In one embodiment of the invention, the compounds of the formula I are administered in combination with bile acid absorption inhibitor (see, for example, US 6,245,744 or US 6,221,897), for example, HMR 1741.
1z In one embodiment of the invention, the compounds of the formula I are administered in combination with a CETP inhibitor, for example, JTT-705. In one embodiment of the invention, the compounds of the formula I are administered 5 in combination with a polymeric bile acid adsorbent, 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 (see US 6,342,512), for example, 10 HMR1171, HMR1586. In one embodiment of the invention, the compounds of the formula I are administered in combination with an ACAT inhibitor, for example, avasimibe. 15 In one embodiment of the invention, the compounds of the formula I are administered in combination with an antioxidant, 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, for example, NO-1886. 20 In one embodiment of the invention, the compounds of the formula I are administered in combination with an ATP-citrate lyase inhibitor, for example, SB-204990. In one embodiment of the invention, the compounds of the formula I are administered 25 in combination with a squalene synthetase inhibitor, for example, BMS-1 88494. In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein(a) antagonist, for example, Cl-1 027 or nicotinic acid. 30 In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipase inhibitor, 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, for example, tolbutamide, glibenclamide, glipizide or glimepiride. In one embodiment, the compounds of the formula I are administered in combination with a biguanide, for example, metformin. 5 In yet another embodiment, the compounds of the formula I are administered in combination with a meglitinide, for example, repaglinide. In one embodiment, the compounds of the formula I are administered in combination with a thiazolidinedione, for example, troglitazone, ciglitazone, pioglitazone, io rosiglitazone or the compounds disclosed in WO 97/41097 of Dr. Reddy'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 a-glucosidase inhibitor, for example, miglitol or acarbose. 15 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, for example, tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide. In one embodiment, the compounds of the formula I are administered in combination 20 with more than one of the abovementioned 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. 25 In a further embodiment, the compounds of the formula I are administered in combination with CART modulators (see "Cocaine-amphetamine-regulated transcript influences energy metabolism, anxiety and gastric emptying in mice" Asakawa, A, et al., M.: Hormone and Metabolic Research (2001), 33(9), 554-558), NPY antagonists, e.g. naphthalene-1-sulfonic acid {4-[(4-aminoquinazolin-2-ylamino) 30 methyl]cyclohexylmethyl}amide hydrochloride (CGP 71683A)), MC4 agonists (e.g. 1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid [2-(3a-benzyl-2-methyl 3-oxo-2,3,3a,4,6,7-hexahydropyrazolo[4,3-c]pyridin-5-yl)-1-(4-chlorophenyl)-2-oxo ethyl]amide; (WO 01/91752)), orexin antagonists (e.g. 1-(2-methylbenzoxazol-6-y) 3-[1,5]naphthyridin-4-ylurea; hydrochloride (SB-334867-A)), H3 agonists I -+ (3-cyclohexyl-1 -(4,4-dimethyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)propan 1-one oxalic acid salt (WO 00/63208)); TNF agonists, CRF antagonists (e.g. [2-methyl-9-(2,4,6-trimethylphenyl)-9H-1,3,9-triazafluoren-4-yl]dipropylamine (WO 00/66585)), CRF BP antagonists (e.g. urocortin), urocortin agonists, P3 agonists 5 (e.g. 1-(4-chloro-3-methanesulfonylmethylphenyl)-2-[2-(2,3-dimethyl-1 H-indol 6-yloxy)ethylamino]ethanol hydrochloride (WO 01/83451)), MSH (melanocyte stimulating hormone) agonists, CCK-A agonists (e.g. {2-[4-(4-chloro-2,5 dimethoxyphenyl)-5-(2-cyclohexylethyl)thiazol-2-ylcarbamoyl]-5,7-d imethylindol-1 yl}acetic acid trifluoroacetic acid salt (WO 99/15525)), serotonin reuptake inhibitors 10 (e.g. dexfenfluramine), mixed serotoninergic and noradrenergic compounds (e.g. WO 00/71549), 5HT agonists e.g. 1-(3-ethylbenzofuran-7-yl)piperazine oxalic acid salt (WO 01/09111), bombesin agonists, galanin antagonists, growth hormone (e.g. human growth hormone), growth hormone-releasing compounds (6-benzyloxy-1-(2 diisopropylaminoethylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert 15 butyl ester (WO 01/85695)), TRH agonists (see, for example, EP 0 462 884), uncoupling protein 2 or 3 modulators, leptin agonists (see, for example, Lee, Daniel W.; Leinung, Matthew C.; Rozhavskaya-Arena, Marina; Grasso, Patricia. Leptin agonists as a potential approach to the treatment of obesity. Drugs of the Future (2001), 26(9), 873-881), DA agonists (bromocriptine, Doprexin), 20 lipase/amylase inhibitors (e.g. WO 00/40569), PPAR modulators (e.g. WO 00/78312), RXR modulators or TR-p agonists. In one embodiment of the invention, the other active ingredient is leptin; see, for example, "Perspectives in the therapeutic use of leptin", Salvador, Javier; Gomez 25 Ambrosi, Javier; Fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001), 2(10), 1615-1622. In one embodiment, the other active ingredient is dexamphatamine or amphetamine. In one embodiment, the other active ingredient is fenfluramine or dexfenfluramine. 30 In another 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.
10 In one embodiment, the compounds of the formula I are administered in combination with dietary fiber materials, preferably insoluble dietary fiber materials (see, for example, Carob/Caromax* (Zunft H J; et al., Carob pulp preparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY (2001 Sep-Oct), 18(5), 230-6.) 5 Caromax is a carob-containing product supplied by Nutrinova, Nutrition Specialties & Food Ingredients GmbH, Industriepark H6chst, 65926 Frankfurt/Main)). Combination with Caromax* is possible in one preparation or by separate administration of compounds of the formula I and Caromax*. Caromax* can also be administered in the form of foodstuffs, for example, in bakery products or muesli bars. 10 It will be appreciated that any suitable combination of the compounds according to the invention with one or more of the abovementioned compounds and optionally one or more further pharmacologically active substances is regarded as being covered by the scope of protection of the present invention. 15
CH
3
CH
3 0 N a OCH 3 OH HN)K N0 0 NH CH 3
H
3 C CH 3 S
CH
3 CH.
CH
3 OPC-14117 01 CH 3 JTT-705 CI 0I0 Br 0SB-204990 HO N N.7z O -- H 3 H N 0
CH
3 N O -1 8 8 6 H O H
H
3 C OH 0 CH 3 0 O C1-1027 slzlo0 Sl~oH 3 0 O 3 O O O~~ 0 H OH 3
H
3 0 CH 3 BMS-188494
H
3 N 0
OH
3 0 CH3OH
-
N0 0 GI 262570 0 O N 0 0 H '/ The examples recited hereinbelow serve to illustrate the invention, but without limiting it. In a similar manner, the compounds of the following examples were prepared: 5 R5 CI H H R2 N N R1 S o 0 R3 R4 Ex. R5 R1 R2 R3 R4 m.p. 1d F F N-N H H 236.1 0 10 2c F F N-N H H Resin 3b F F COOH H 227.7 -aF 4d F F - H 219.9 5 F F COOMe H H 6 F F CONH 2 H H 7 F F COOMe H SO 2 Me 8 F F COOMe H -- O-F 9 F F COOMe Me H 10 F F H COOMe H 11 F F NO 2 H H 12 F F COOH SO 2 Ph H 193.5 13 F F COOH SO 2 iPr H 164.8 14 F F COOMe H Ph 208.6 10 15 F F COMe H Ph 204.8 16 F F CONH 2 H tert-Butyl >300 17 F F CONH 2 H Ph >300 18 F F CONH 2 H >300 19 F F - N-Me H - 225.8 -N, M -S-N N-Me 0 20 F F H - 188.1 0 21 F F COOH H Ph 226.5 22 F F CONH 2 H 3-Thienyl >300(decomp.) 23 F F CONH 2 H 2-Thienyl >250(decomp.) 24 F F CONH 2 H O-Me 300 25 F F -CN H - F >200(decomp.) 26 F F COMe H H 180(decomp.) 27 F F CONH 2 H F 237.2 28 F F H F H 29 F F H COOMe COOMe 30 F F H Ph H 31 F F H F H 32 F F H Me H 33 F H N-N H H 219.8 NN 34 F F H H Phenyl 178.7 35 F F COOH H H 214.8 36c F F H F 206.2 N 37 F H H \FH217.8 N ~ /0 The effectiveness of the compounds was tested as follows: Glycogen phosphorylase a activity test 5 The effect of compounds on the activity of the active form of glycogen phosphorylase (GPa) was measured in the reverse direction by monitoring the synthesis of glycogen from glucose 1-phosphate by determining the release of inorganic phosphate. All reactions were carried out as duplicate determinations in 96-well microtiter plates 10 (half area plates, Costar No. 3696), and the change in absorption as a consequence of the formation of the reaction product was measured at the wavelength specified below in a Multiskan Ascent Elisa Reader (Lab Systems, Finland). In order to measure the GPa enzyme activity in the reverse direction, the conversion of glucose 1-phosphate to glycogen and inorganic phosphate was measured by the 15 general method of Engers et al. (Engers HD, Shechosky S, Madsen NB, Can J Biochem 1970 Jul;48(7):746-754) with the following modifications: human glycogen phosphorylase a (for example containing 0.76 mg of protein / ml (Aventis Pharma Deutschland GmbH), dissolved in buffer solution E (25 mM p-glycerophosphate, pH 7.0, 1 mM EDTA and 1 mM dithiothreitol) was diluted to a concentration of 10 pg of 20 protein/mI with buffer T (50 mM Hepes, pH 7.0, 100 mM KCI, 2.5 mM EDTA, 2.5 mM MgC 2 -6H 2 0) and addition of 5 mg/ml of glycogen. Test substances were prepared as a 10 mM solution in DMSO and diluted to 50 pM with buffer solution T. To 10 pl of this solution were added 10 pl of 37.5 mM glucose dissolved in buffer solution T and 5 mg/ml of glycogen, and also 10 pl of a solution of human glycogen phosphorylase a 25 (10 pg of protein/ml) and 20 pl of 2.5 mM glucose 1-phosphate. The base value of the activity of glycogen phosphorylase a in the absence of test substance was determined by adding 10 pl of buffer solution T (0.1% DMSO). The mixture was incubated at room temperature for 40 minutes and the released inorganic phosphate was determined by means of the general method of Drueckes et al. (Drueckes P, 30 Schinzel R, Palm D, Anal Biochem 1995 Sep 1;230(1):173-177) with the following modifications: 50 pl of a stop solution of 7.3 mM of ammonium molybdate, 10.9 mM of zinc acetate, 3.6% of ascorbic acid, 0.9% of SDS are added to 50 pl of the enzyme mixture. After 60 minutes of incubation at 45*C, the absorption was measured at 820 nm. To determine the background absorption, the stop solution was added immediately after the addition of the glucose 1-phosphate solution in a separate reaction. This test was carried out at a concentration of 10 pM of the test substance, in order to determine the respective inhibition of glycogen phosphorylase a by the test 5 substance in vitro. Table 2: Biological activity Ex. IC-50 (pM) Id 0.03 2c 0.45 3b 0.01 4d 0.11 6 0.70 15 0.17 17 0.03 21 0.01 23 0.05 24 0.04 30 1.40 33 0.08 10 It can be seen from the table that the compounds of the formula I inhibit the activity of glycogen phosphorylase a and are thus very suitable for reducing the blood sugar level. 15 The preparation of some examples is described in detail hereinbelow, and the remaining compounds of the formula I were obtained in a similar manner: Experimental section: Example 1: 20 a) 3-(tert-Butoxycarbonylamino)thiophene-2-carboxylic hydrazide 0.4 g of hydrazine hydrate is added to a solution of 1.3 g of methyl 3-(tert butoxycarbonylamino)thiophene-2-carboxylate in 10 ml of ethanol and the mixture is heated to reflux for 5 hours. After the volatile fractions had been removed under reduced pressure at 40 0 C, the remaining oil was purified by column chromatography 5 (silica gel, eluent: methylene chloride: methanol = 95:5). Yield: 740 mg m.p.: 146.5 0 C b) tert-Butyl [2-(5-oxo-4,5-di hyd ro[1,3,4]oxadiazol-2-yl)th iophen-3-yl]carbamate 4 ml of a 20% toluenic phosgene solution are added dropwise to a solution of 240 mg of 3-(tert-butoxycarbonylamino)thiophene-2-carboxylic hydrazide in 5 ml of THF and 10 the mixture is stirred at RT. After one hour, the mixture is admixed with 10 ml of water and, after brief digestion, extracted with ethyl acetate. After the ethyl acetate phase has been dried over sodium sulfate, the mixture is concentrated under reduced pressure and the remaining residue is used further without further purification. Yield: 120 mg m.p.: 180 0 C 15 c) 5-(3-Aminothiophen-2-y)-3H-[1,3,4]oxadiazol-2-one hydrochloride The mixture consisting of 100 mg of tert-butyl [2-(5-oxo-4,5-dihydro[1,3,4]oxadiazol-2 yl)thiophen-3-yl]carbamate and 5 ml of a 4 molar HCI solution in dioxane is stirred for one hour. Afterwards, the volatile fractions are removed under reduced pressure and the residue is stirred with 5 ml of tert-butyl methyl ether and the product is filtered off 20 with suction and dried under reduced pressure. Yield: 60 mg m.p.: 211*C d) 1-(2-Chloro-4,5-difluorobenzoyl)-3-[2-(5-oxo-4,5-dihydro[1,3,4]oxadiazol-2 yl)thiophen- 3-yl]urea 5-(3-Aminothiophen-2-yl)-3H-[1,3,4]oxadiazol-2-one hydrochloride (30 mg) is initially 25 charged in 3 ml of acetonitrile. The equimolar solution of 2-chloro-4,5-difluorobenzoyl isocyanate in acetonitrile is added. After 3 hours, the solid is filtered off with suction and dried under reduced pressure. Yield: 50 mg m.p.: 236.1'C 30 Example 2: a) tert-Butyl 2-(5-amino[1,3,4]oxadiazol-2-yl)thiophen-3-yl]carbamate The solution of 192 mg of 3-(tert-butoxycarbonylamino)thiophene-2-carboxylic hydrazide in 4 ml of acetonitrile is admixed with 0.17 ml of a 5 molar cyanogen bromide solution in acetonitrile and 60 mg of potash. The mixture is stirred at RT for 4 hours, the solid is filtered off and the filtrate is concentrated under reduced pressure. The desired product is then purified by column chromatography (silica gel, eluent: methylene chloride:methanol = 95:5). Yield: 90 mg m.p.: Resin 5 b) 5-(3-Aminothiophen-2-yl)-[1,3,4]oxadiazol-2-ylamine hydrochloride tert-Butyl 2-(5-amino[1,3,4]oxadiazol-2-yl)thiophen-3-yl]carbamate (90 mg) are added to 5 ml of 4 molar HCI solution in dioxane and the mixture is stirred at RT for one hour. After concentration under reduced pressure, the residue is stirred with tert-butyl methyl ether and the solid is filtered off with suction and dried under reduced 1o pressure. Yield: 60 mg m.p.: >250* (decomp.) c) 1-[2-(5-Amino[1,3,4]oxadiazol-2-yl)thiophen-3-y]-3-(2-chloro-4,5 difluorobenzoyl)urea 5-(3-Aminothiophen-2-yl)[1,3,4]oxadiazol-2-ylamine hydrochloride (30 mg) is initially 15 charged in 3 ml of acetonitrile. The equimolar solution of 2-chloro-4,5-difluorobenzoyl isocyanate in acetonitrile is added and stirred at RT. After 3 hours, the solid is filtered off with suction and dried under reduced pressure. Yield: 25 mg m.p.: Resin 20 Example 3: a) 3-Amino-5-(4-fluorophenyl)thiophene-2-carboxylic acid The mixture consisting of 500 mg of methyl 3-amino-5-(4-fluorophenyl)thiophene-2 carboxylate, 160 mg of lithium hydroxide, 2 ml of water, 2 ml of THF and 2 ml of methanol is stirred at RT for 3 days. After dilution with 15 ml of water, unhydrolyzed 25 ester is removed by extraction with ethyl acetate. The aqueous phase is adjusted to pH 5 using hydrochloric acid and stirred, and the precipitated solid is filtered off with suction and dried. Yield: 260 mg m.p.: 145.20C (crude) b) 3-[3-(2-Chloro-4,5-difluorobenzoyl)ureido]-5-(4-fluorophenyl)thiophene-2 30 carboxylic acid 3-Amino-5-(4-fluorophenyl)thiophene-2-carboxylic acid (50 mg) is initially charged in 3 ml of acetonitrile. The equimolar solution of 2-chloro-4,5-difluorobenzoyl isocyanate in acetonitrile is added and the mixture is stirred at RT. After 3 hours, the solid is filtered off with suction, stirred once more with methanol, filtered off with suction and dried under reduced pressure. Yield: 46 mg m.p.: 227.7*C 5 Example 4: a) 1-(5-Chloro-4-nitrothiophene-2-sulfonyl)piperidine and 1-(5-piperidino-4 nitrothiophene-2-sulfonyl)piperidine 1.7 g of piperidine are added dropwise to the solution of 2.6 g of 5-chloro-4 nitrothiophene-2-sulfonyl chloride in 8 ml of NMP with stirring and ice cooling. The 10 mixture is stirred at RT for another 30 minutes and diluted with 30 ml of water, and the precipitate which forms is filtered off with suction after stirring. The two products are separated by column chromatography (silica gel, solvent: ethyl acetate: n heptane = 1:1). 1-(5-Piperidino-4-nitrothiophene-2-sulfonyl)piperidine: yield: 1.3 g, m.p.: 151.3*C 15 1 -(5-Chloro-4-nitrothiophene-2-sufonyl)piperidine: Yield: 0.85 g m.p.: 136.4*C b) I -(3-N itro-5-piperidine-1 -sulfonylthiophen-2-yl)piperidine-4-carboxylic acid The mixture of 310 mg of 1-(5-chloro-4-nitrothiophene-2-sulfonyl)piperidine, 250 mg of piperidine-4-carboxylic acid and 3 ml of NMP is stirred at 85 0 C for 1 h, cooled, diluted with 15 ml of water and stirred. The precipitate is filtered off with suction, 20 washed with water and recrystallized from isopropanol/water (4:1). Yield: 310 mg m.p.: 165.8*C c) 1-[3-Amino-5-(piperidine-1 -sulfonyl)thiophen-2-yl]piperidine-4-carboxylic acid The solution of 300 mg of 1-(3-nitro-5-piperidine-1-sulfonylthiophen-2-yl)piperidine-4 25 carboxylic acid in 20 ml of ethyl acetate is admixed with 1.0 g of tin(II) chloride and stirred at 65 0 C for 8 h. After cooling, it is stirred with 30 ml of water and filtered off with suction through Celite, and the ethyl acetate phase is removed, dried and concentrated under reduced pressure. This crude product is used further without further purification. 30 Yield: 320 mg(crude) m.p.: Resin c) 1-[3-[3-(2-Chloro-4,5-difluorobenzoyl)ureido]-5-(piperidine-1-sulfonyl) thiophen-2-yl]piperidine-4-carboxylic acid 1-[3-Amino-5-(piperidine-1-sulfonyl)thiophen-2-yl]piperidine-4-carboxylic acid (0.2 g of crude product) is dissolved in 2 ml of acetonitrile and admixed with the equimolar solution of 2-chloro-4,5-difluorobenzoyl isocyanate in acetonitrile, and the mixture is stirred at RT. After 3 hours, the solid is filtered off with suction and dried under reduced pressure. Yield: 85 mg m.p.: 219.9*C 5 Example 36: a) 5-(4-Fluorophenyl)-2-(IH-tetrazol-5-yl)thiophen-3-ylamine The mixture consisting of 0.65 g of 3-amino-2-cyano-5-(4-fluorophenyl)thiophene, 7.5 ml of xylene and 0.93 g of trimethyltin azide is stirred at 130-140*C for 3 hours. 10 Afterwards, the mixture is concentrated at 40 0 C under reduced pressure and the residue is stirred with water with the addition of 1% trifluoroacetic acid. The precipitate is filtered off with suction and dried at 400C under reduced pressure. Yield: 0.6 g m.p.: 217.30C c) 1-[4-(4-Fluorophenyl-2-(tetrazol-5-yl)thiophen-3-yl]-3-(2-chloro-4,5 15 difluorobenzoyl)urea 5-(4-Fluorophenyl)-2-(1 H-tetrazol-5-yl)thiophen-3-ylamine (0.1 g) is dissolved in 2 ml of acetonitrile and admixed with the equimolar solution of 2-chloro-4,5 difluorobenzoyl isocyanate in acetonitrile and the mixture is stirred at RT. After 3 hours, the solid is filtered off with suction and dried under reduced pressure. 20 Yield: 73 mg m.p.: 206.20C The compounds of the formula I can be prepared by reacting ureas of the formula 5 or 3-aminothiophene derivatives of the formula 6 with benzoic acid derivatives of the formula 4, H R2 R5 CI H H R2 I I -N N N H xR S S RiO1R3 0 R3 R4 R4 25 5 where R1 to R5 are each as defined above and X1 may be CI or NCO, with acid chlorides or anhydrides or benzoyl isocyanates.
Claims (13)
1. Compounds of the formula 1 5 R5 CI H H R2 N N R1 --' S 0 0 R3 R4 where 10 R5 is F, CI or Br; R1 is H, F, Cl, Br; 15 R2 is H, F, CI, Br, (C 1 -C 6 )-alkyl, CF 3 , OCF 3 , NO 2 , CN, O-(C 1 -C)-alkyl, CO (C 1 -C 6 )-alkyl, COOH, COO(C 1 -C 6 )-alkyl, CONH 2 , CONH(C 1 -C 6 )-alkyl, CON((C 1 -C 6 )-alkyl) 2 , S0 2 -(C 1 -C 6 )-alkyl, or the A radical; R3 is H, (C 1 -C 6 )-alkyl, COO(C 1 -C 6 )-alkyl, S0 2 (C 1 -C 6 )-alkyl, (C1-C 6 )-alkyl 20 phenyl, phenyl, S0 2 -phenyl, where the phenyl ring may in each case be up to disubstituted by F, CI, CN, OH, (C 1 -C 6 )-alkyl, 0-(C 1 -C 6 )-alkyl, CF 3 , OCF 3 , COOH, COO(C1-C 6 )-alkyl or CONH 2 ; R4 is H, (C 1 -C 6 )-alkyl, COO(C 1 -C 6 )-alkyl, S0 2 -(C 1 -C 6 )-alkyl, S0 2 -piperidinyl, 25 S0 2 -piperazinyl, (C1-C 6 )-alkylphenyl, where the phenyl ring, the piperidinyl ring and the piperazinyl ring may be up to disubstituted by F, CI, CN, OH, (C1-C 6 )-alkyl, 0-(C1-C 6 )-alkyl, CF 3 , OCF 3 , COOH, COO(C 1 C 6 )-alkyl or CONH 2 ; Zb A is a heterocyclic radical of the formula 2a, 2b, 2c or 3; N-N N-N N-N NG o X 0 Y N N z 2a 2b 2c 3 X is O or NH; 5 Y is OH or NH 2 ; Z is OH, O(C 1 -C 6 )-alkyl, NH 2 , NH(C1-C 6 )-alkyl, N((C 1 -C 6 )-alkyl) 2 ; 10 and their physiologically tolerated salts.
2. Compounds of the formula I as claimed in claim 1, wherein 15 R5 is F, Cl or Br; R1 is H, F; R2 is H, F, Cl, Br, (C1-C 6 )-alkyl, CF 3 , OCF 3 , NO 2 , CN, O-(C1-C)-alkyl, 20 CO(C1-C 6 )-alkyl, COOH, COO(C 1 -C 6 )-alkyl, CONH 2 , CONH(C1-C 6 )-alkyl, CON((C 1 -C 6 )-alkyl) 2 , S0 2 -(C 1 -C 6 )-alkyl, or the A radical; R3 is H, (C1-C 6 )-alkyl, COO(C 1 -C 6 )-alkyl, S0 2 (C 1 -C 6 )-alkyl, (C 1 -C 6 ) alkylphenyl, phenyl, S0 2 -phenyl, where the phenyl ring may in each 25 case be up to disubstituted by F or Cl; R4 is H, (C 1 -C 6 )-alkyl, COO(C 1 -C 6 )-alkyl, S0 2 -(C 1 -C 6 )-alkyl, S0 2 -piperidinyl, S0 2 -piperazinyl, (C 1 -C 6 )-alkylphenyl, where the phenyl ring, the piperidinyl ring and the piperazinyl ring may be up to disubstituted by F, 30 Cl, CN, OH, (C 1 -Ce)-alkyl, 0-(C1-C 6 )-alkyl, CF 3 , OCF 3 , COOH, COO(C 1 C)-alkyl or CONH 2 ; A is a heterocyclic radical of the formula 2a, 2b, 2c or 3; N-N N-N N-N NN 0 o X O Y N Z 2a 2b 2c 3 5 X isOorNH; Y is OH or NH 2 ; Z is OH; 10 and their physiologically tolerated salts.
3. Compounds of the formula I as claimed in claim 1 or 2, wherein 15 R5 is F; R1 is F; 20 R2 is COOH, COO(C1-C 6 )-alkyl, CONH 2 , CONH(C 1 -C 6 )-alkyl, CON((C1-C 6 ) alkyl) 2 , or the A radical; R3 is H, (C1-C 6 )-alkyl, COO(C1-C 6 )-alkyl, S0 2 (C1-C 6 )-alkyl, (C1-C 6 )-alkyl phenyl, phenyl, S0 2 -phenyl, where the phenyl ring may in each case be 25 up to disubstituted by F; R4 is H, (C 1 -C 6 )-alkyl, COO(C1-C 6 )-alkyl, S0 2 -(C1-C 6 )-alkyl, S0 2 -piperidinyl, S0 2 -piperazinyl, (C 1 -C 6 )-alkylphenyl, where the phenyl ring, the piperidinyl ring and the piperazinyl ring may be up to disubstituted by F 30 or (C1-C 6 )-alkyl; Zoj A is a heterocyclic radical of the formula 2a or 2b; N-N N-N 0 X 0 y 2a 2b X is 0 or NH; 5 Y is OH or NH 2 ; and their physiologically tolerated salts. 10
4. A pharmaceutical comprising one or more of the compounds as claimed in one or more of claims 1 to 3.
5. A pharmaceutical comprising one or more of the compounds as claimed in one 15 or more of claims 1 to 3 and at least one further active ingredient.
6. A pharmaceutical as claimed in claim 5, which comprises, as a further active ingredient, one or more antidiabetics, hypoglycemic active ingredients, HMG-CoA reductase inhibitors, 20 cholesterol absorption inhibitors, PPAR gamma agonists, PPAR alpha agonists, PPAR alpha/gamma agonists, fibrates, MTP inhibitors, bile acid absorption inhibitors, CETP inhibitors, polymeric bile acid adsorbents, LDL receptor inducers, ACAT inhibitors, antioxidants, lipoprotein lipase inhibitors, ATP-citrate lyase inhibitors, squalene synthetase inhibitors, lipoprotein(a) antagonists, lipase inhibitors, insulins, 25 sulfonylureas, biguanides, meglitinides, thiazolidinediones, a-glucosidase inhibitors, active ingredients acting on the ATP-dependent potassium channel of the beta cells, CART agonists, NPY agonists, MC4 agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, p3 agonists, MSH (melanocyte-stimulating hormone) agonists, CCK agonists, serotonin reuptake 30 inhibitors, mixed serotoninergic and noradrenergic compounds, 5HT agonists, bombesin agonists, galanin antagonists, growth hormones, growth hormone- releasing compounds, TRH agonists, uncoupling protein 2 or 3 modulators, leptin agonists, DA agonists (bromocriptine, Doprexin), lipase/amylase inhibitors, PPAR modulators, RXR modulators or TR-p agonists or amphetamines. 5
7. The use of the compounds as claimed in one or more of claims 1 to 3 for producing a medicament for blood sugar reduction.
8. The use of the compounds as claimed in one or more of claims 1 to 3 for producing a medicament for treating type II diabetes. 10
9. The use of the compounds as claimed in one or more of claims 1 to 3 for producing a medicament for treating lipid and carbohydrate metabolism disorders.
10. The use of the compounds as claimed in one or more of claims 1 to 3 for 15 producing a medicament for treating arteriosclerotic symptoms.
11. The use of the compounds as claimed in one or more of claims 1 to 3 for producing -a medicament for treating insulin resistance. 20
12. A process for producing a pharmaceutical comprising one or more of the compounds as claimed in one or more of claims 1 to 3, which comprises mixing the active ingredient with a pharmaceutically suitable carrier and converting this mixture into a form suitable for administration. 25
13. A process for preparing the compounds of the formula 1, which comprises reacting ureas of the formula 5 or 3-aminothiophene derivatives of the formula 6 with benzoic acid derivatives of the formula 4 H R2 R5 CI H H R2 I N H R1 y H Y S 0 R3 R3 R4 R4 4 ~56 where R1 to R5 are each as defined in claim 1 and X1 may be Cl or NCO, with acid chlorides or anhydrides or benzoyl isocyanates to give compounds of the formula 1.
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DE10306502A DE10306502B4 (en) | 2003-02-17 | 2003-02-17 | Substituted 3- (benzoylureido) thiophene derivatives and medicaments containing them |
PCT/EP2004/000993 WO2004072060A1 (en) | 2003-02-17 | 2004-02-04 | Substituted 3-(benzoylureido)-thiophene derivatives, method for the production and use thereof |
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US7223786B2 (en) | 2004-11-15 | 2007-05-29 | Bristol-Myers Squibb Company | 2-aminonaphthalene derivatives and related glycogen phosphorylase inhibitors |
US7226942B2 (en) | 2004-11-15 | 2007-06-05 | Bristol-Myers Squibb Company | 2-amino-4-functionalized tetralin derivatives and related glycogen phosphorylase inhibitors |
US7214704B2 (en) | 2004-11-15 | 2007-05-08 | Bristol-Myers Squibb Company | 2-Amino-1-functionalized tetralin derivatives and related glycogen phosphorylase inhibitors |
WO2006055463A2 (en) | 2004-11-15 | 2006-05-26 | Bristol-Myers Squibb Company | 2-amino-3-functionalized tetralin derivatives and related glycogen phosphorylase inhibitors |
JP2008536932A (en) * | 2005-04-18 | 2008-09-11 | サイード・アール・カーン | Tubulin polymerization inhibitors: design and synthesis of bonzoylphenylurea (BPU) sulfur analogues |
PE20110235A1 (en) | 2006-05-04 | 2011-04-14 | Boehringer Ingelheim Int | PHARMACEUTICAL COMBINATIONS INCLUDING LINAGLIPTIN AND METMORPHINE |
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HUT48880A (en) * | 1987-07-20 | 1989-07-28 | Sandoz Ag | Insecticides and acaricides comprising new n-benzoyl-n'-thienyl urea derivative as active ingredient and process for producing the active ingredients |
CZ20024003A3 (en) * | 2000-06-09 | 2003-03-12 | Aventis Pharma Deutschland Gmbh | Acylphenyl urea derivatives, process of their preparation and use as a medicament |
DE10116768A1 (en) * | 2001-04-04 | 2002-10-10 | Aventis Pharma Gmbh | Hypoglycemic medicaments useful for treating type II diabetes contain new or known N-aroyl-N'-phenyl-urea derivatives which are glycogen phosphorylase a inhibitors |
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DE10215908B4 (en) * | 2002-04-11 | 2005-08-18 | Aventis Pharma Deutschland Gmbh | Acyl-3-carboxyphenyl-urea derivatives and their use as medicaments |
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- 2004-02-04 KR KR1020057015029A patent/KR20050105470A/en not_active Application Discontinuation
- 2004-02-04 EP EP04707896A patent/EP1597247B1/en not_active Expired - Lifetime
- 2004-02-13 TW TW093103411A patent/TW200505892A/en unknown
- 2004-02-13 AR ARP040100457A patent/AR043179A1/en unknown
- 2004-02-17 PE PE2004000163A patent/PE20050221A1/en not_active Application Discontinuation
-
2005
- 2005-07-07 ZA ZA200505487A patent/ZA200505487B/en unknown
- 2005-08-12 CO CO05080324A patent/CO5690549A2/en not_active Application Discontinuation
- 2005-08-16 HR HR20050715A patent/HRP20050715A2/en not_active Application Discontinuation
- 2005-08-16 MA MA28443A patent/MA27657A1/en unknown
- 2005-09-07 NO NO20054168A patent/NO20054168L/en unknown
Also Published As
Publication number | Publication date |
---|---|
CO5690549A2 (en) | 2006-10-31 |
EP1597247B1 (en) | 2008-07-23 |
WO2004072060A1 (en) | 2004-08-26 |
NO20054168D0 (en) | 2005-09-07 |
KR20050105470A (en) | 2005-11-04 |
ATE402160T1 (en) | 2008-08-15 |
MXPA05008331A (en) | 2005-09-30 |
DE502004007668D1 (en) | 2008-09-04 |
TW200505892A (en) | 2005-02-16 |
ZA200505487B (en) | 2006-08-30 |
RU2005129109A (en) | 2006-01-27 |
PL376753A1 (en) | 2006-01-09 |
DE10306502A1 (en) | 2004-09-09 |
CN1751036A (en) | 2006-03-22 |
DE10306502B4 (en) | 2005-03-17 |
PE20050221A1 (en) | 2005-04-04 |
AR043179A1 (en) | 2005-07-20 |
CA2516269A1 (en) | 2004-08-26 |
JP4589301B2 (en) | 2010-12-01 |
HRP20050715A2 (en) | 2006-09-30 |
JP2006517933A (en) | 2006-08-03 |
EP1597247A1 (en) | 2005-11-23 |
BRPI0407552A (en) | 2006-02-14 |
MA27657A1 (en) | 2005-12-01 |
NO20054168L (en) | 2005-11-11 |
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