Oxa- and thiazole-derivatives as antidiabetic agents and agents against obesity

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula: or wherein x means 1, 2, 3 or 4; m means 1 or 2; n means 1 or 2; Q represents carbon atom (C) or nitrogen atom (N); A represents oxygen atom (O) or sulfur atom (S); R1 represents lower alkyl; X represents -CH; R2 represents hydrogen (H) or halogen atom; R2a, R2b and R2c can be similar or different and they are chosen from hydrogen atom (H), alkyl, alkoxy-group or halogen atom; R3 represents aryloxycarbonyl or alkoxyaryloxycarbonyl; Y represents -CO2R4 wherein R4 represents hydrogen atom (H) or alkyl, and including all their stereoisomers, their prodrugs as esters and their pharmaceutically acceptable salts. These compounds are useful antidiabetic and hypolipidemic agents and agents used against obesity also.

EFFECT: valuable medicinal properties of compounds.

29 cl, 12 tbl, 587 ex

 

The technical field

The present invention relates to new substituted derivatives of acids that modulate the level of blood glucose, triglyceride levels, insulin levels and the level neeterificirovannah fatty acids (NEFA) and, therefore, particularly useful for the treatment of diabetes and obesity, as well as to a method of treating diabetes, especially type 2 diabetes, as well as hyperglycemia, hyperinsulinemia, hyperlipidemia, obesity, atherosclerosis and related diseases, the application of such substituted derivatives of acids alone or in combination with another antidiabetic agent and/or a hypolipidemic agent.

Description of the invention

In accordance with the present invention proposed substituted derivatives of acids of the formula I:

where x has a value of 1, 2, 3 or 4; m is 1 or 2; n is 1 or 2;

Q represents C or N;

And represents O or S;

R1represents lower alkyl;

X represents CH;

R2represents H or halogen;

R2a, R2band R2cmay be the same or different and are selected from H, alkyl, alkoxy or halogen;

R3is aryloxyalkyl or alkoxysilane carbonyl;

Y represents CO2R4where R4- N or and the keel;

including all stereoisomers, prodrugs in the form of esters and their pharmaceutically acceptable salts.

Preferred are the compounds of formula I according to the invention, having the structure

As a more preferred are the compounds of formula I according to the invention, having the structure

or

Preferred compounds according to the invention include the following:

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where R3d=

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where R3d=

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where R3=

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where R3h=

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where R3h=

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where R3=(±)-Me, (±)n-Buwhere R3=(±)Et, (±)I-Bu(±)

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In addition, in accordance with the present invention, a method for treating diabetes, particularly diabetes type 2 and related diseases, such as reducing blood glucose, insulin resistance, hyperglycemia, hyperinsulinemia, increased levels of fatty acids or glycerol in the blood, hyperlipidemia, obesity, hypertriglyceridemia, and atherosclerosis, in which a person in need of treatment is administered a therapeutically effective amount of a compound of structure I.

Detailed description of the invention

The compounds of formula I of the present invention can be obtained in accordance with the following General synthesis schemes, as well as in the published literature relevant methods that use the specialists of this level of technology. Examples of the reagents and methods of these reactions are described hereafter, as well as in the working examples. Protection and the concept of protection schemes, below can be carried out by methods well known in the prior art (see, for example, Greene, T. W. and Wuts, P. G. M., Protecting Groups in Organic Synthesis, 3rdEdition, 1999 [Wiley]).

Scheme 1 describes a General synthesis of amino acids described in the present invention. Alcohol II (R5(CH2)xHE (the most preferred is 2-phenyl-5-methoxazole-4-ethanol) condense with hydroxyaryl or heteroanalogues III (preferably 3 - or 4-hydroxybenzaldehyde) in a standard reaction conditions Mitsunobu(Mitsunobu) (for example, Mitsunobu, O., Synthesis, 1981, 1). The resulting aldehyde IV is then subjected to reductive aminating using methods known from the prior art (for example, AbdeI-Magid, etc., J. Org. Chem. 1996, 61, 3849) hydrochloride α-aminoether V. PG in figure 1 indicates the preferred protective group for carboxylic acids, such as methyl or tert-butyl methyl ether. The resulting secondary aminoether VI then subjected to repeated recovery aminating using methods known from the prior art (for example, AbdeI-Magid, etc., J. Org. Chem. 1996, 61, 3849) with R3athe aldehyde VII. The final removal of the protective groups with ether carboxylic acid under standard conditions known in the art (Greene), while applying the basic conditions (for methyl esters) or acidic conditions (tert-butyl esters) then leads to the auchenia desired products, which are the amino acids ID.

An alternative path to the aldehyde IV is shown in scheme 1A. Alcohol II (R5(CH2)xIT) (of which the most preferred is 2-[2-phenyl-5-methoxazole-4-yl]-ethanol) treated with methanesulfonamide to obtain the corresponding nelfinavir VIII. Mesilate then alkylate the standard basic conditions using hydroxyaryl or hydroxycitronellal III with obtaining aldehyde IV.

An alternative route to amino acids IF shown in scheme 2. Secondary aminoether VI remove a protective group under standard conditions (basic conditions, if the protecting group (PG) is methyl; acidic conditions, if PG is tert-bootrom) to obtain the corresponding amino acids IE. Reductive amination with R3aaldehyde under similar conditions as described in scheme 1, results in the desired tertiary products of amino acids IF the quality of the products.

Alternatively, as shown in figure 3, the tertiary amino acids IF can also be obtained by alkylation of the secondary aminoether alkylating agent VI DC (with a suitable leaving group (LG)such as halogen, mesilate or toilet) under standard conditions known in the prior art, with the subsequent standard by removing the protective groups, ether carboxylic acids X to obtain amino acids IF.

As shown in figure 4, the tertiary amino acid IF it can be formed via reductive amination first R3aaldehyde XI with a suitable hydrochloride aminoether V. the Resulting secondary aminoether XII then subjected to reductive aminating with a suitable aldehyde alkyl, aryl or heteroaryl IV (scheme 1), followed by removing the protective groups of an ether carboxylic acid to obtain the desired analogues of amino acids IF.

Further amino acid substitution is shown in the General scheme of the synthesis of 5. Reductive amination of the appropriate amine XIII aryl or heteroanalogues XIV in standard conditions leads to the corresponding secondary amine XV, which is then subjected to reaction with halogenation XVI (for example, tert-butylbromide) to obtain the corresponding α-aminoether XVII. I received aminoether XVII then remove the protective group under standard conditions to obtain the desired analogues of amino acids IF.

The method of synthesis in scheme 5 also shows a General scheme of the synthesis of the corresponding aminophosphonic acids IFA, as shown in figure 5A. Secondary amine XV is subjected to reaction with an appropriate protected halogenerator XVIA to obtain the corresponding aminophosphate ether XVIIA, which then remove the protective group under standard conditions (Greene &Wuts with getting aminophosphonic acid IFA. In the diagram 5b shows the synthesis aminophosphinic acids IFB, which also include the reaction of suitably protected halogenosilanes ether XVIB with a secondary amine XV. Removing the protective groups formed aminophosphonates ether then leads to the production of phosphine acid IFB.

An alternative method to the sequence in scheme 5 shown in scheme 6. Hydroxyaryl or heteroaryl XVIII selectively protect the nitrogen of obtaining protected amine XIX. Preferred R5(CH2)nOH (II) is then subjected to reaction with XIX under the reaction conditions Mitsunobu (Mitsunobu) to obtain the corresponding simple ether, followed by removal of the protective groups of the amine, to obtain the free amine XX. The free amine XX then trigger standard trigger group (2,4-dinitrobenzenesulfonic; .Fukuyama, etc., Tetrahedron Lett. 1997, 38, 5831) and then treated α-halogenation XVI, as shown in scheme 5. With 2.4 dinitrobenzenesulfonic XXI remove a protective group under conditions known from the prior art (.Fukuyama and others, Tetrahedron Lett., 1997, 38, 5831) obtaining secondary α-aminoether XXII, which is then subjected to reductive aminating with R3athe aldehyde XI with subsequent removal of the protective groups with ether X with obtaining the desired analogues IF.

Scheme 7 describes an alternative way to analogs of amino acids IG. Hydroxyurea is or wateroriented III is subjected to normal conditions of reductive amination with a suitable hydrochloride aminoether V. The resulting secondary aminoether XXIII functionalitywith in this case, repeated by reductive amination with R3athe aldehyde VII to obtain the corresponding tertiary hydroxy of aminoether XXIV. It can be subjected to reaction Mitsunobu with the corresponding alcohol II (R5(CH2)nIT) and then removing the protective groups of the ester XXV, which results in obtaining the desired analogues IG.

Scheme 8 describes a General synthesis of diaryl and Allgeier-substituted analogues of amino acids IH. Secondary aminoether XXII subjected to reductive aminating with suitably substituted formylphenylboronic acid XXVI under standard conditions to obtain the corresponding tertiary aminoethers Bronevoy acid XXVII. Arylboronic acid XXVII can then undergo condensation Suzuki (Suzuki) (for example, the conditions described in Gibson, S. E., Transition Metals in Organic Synthesis, A Practical Approach, pp.47-50, 1997) with aryl or heteroarylboronic XXVIII (especially bromine) with a suitable mirandamiranda dialling products XXIX. Removing the protective groups from aminoether XXIX results in the desired analogues of amino acids IH.

Scheme 9 describes the total synthesis of diaryl and Allgeier afrosamurai analogues of amino acids IJ. Tertiary aminoethyl Bronevoy acid XXVII, which is described in scheme 8, can be powerget condensation is suitably substituted by Fanelli XXX in conditions known from the prior art (D.A.Evans, etc., Tetrahedron Lett., 1998, 39, 2937) to obtain the corresponding diaryl or arylheteroacetic XXXI, which after removing the protective groups, leading to amino acid analogues IJ.

Alternatively, as shown in scheme 10, reductive amination of secondary aminoether XXII with a suitably substituted hydroxyaryl or hydroxymatairesinol XXXII leads to the corresponding tertiary femalemanaegre XXXIII. Phenol XXXIII may further be subjected to binding with the appropriate aryl or heteroaryl boronowski acids XXXIV under conditions known from the prior art (D.A.Evans, etc., Tetrahedron Lett., 1998, 39, 2937) to obtain the corresponding diaryl or arylheteroacetic-amino esters XXXI. The desired analogues IJ can then be obtained by removing the protective groups aminoether XXXI.

Figure 11 shows the synthesis carbonatation analogues IK. Secondary aminoether XXII can respond with the appropriate chloroformate XXXV under conditions known from the prior art (optimally in CH2Cl2or CHCl3in the presence of a base such as Et3N) the corresponding carbonatation. The desired analogues IK then get after removing the protective groups from carbamaaepine. Alternatively, the secondary aminoether XXII may react with phosgene to obtain consistent is his carbamoylated XXXVI. Specified intermediate carbamoylated XXXVI can react with R3a-OH (XXXVII) (optimally substituted phenols) to give the corresponding carbamate-acid IK after removing the protective groups.

Figure 12 shows further funktsionalizatsiya aryl carbonatation analogues IK. Secondary aminoether XXII subjected to reaction with arillotta XXXVIII (containing a protected hydroxy-group) obtaining XXXIX. With a hydroxyl group is then selectively removed protection in the presence of an ether with obtaining XL, then alkylate suitable R6-LG (XLI) (where LG is Galand, mesilate or toilet and R6is the most preferable CHF2or CH3CH2-) in the presence of a base. Removing the protective groups with ether then results in the desired carbonatation analogues IL.

Secondary aminoether XXIIA can be funktsioniroval substituted aryl or aliphatic carboxylic acids XLII in standard conditions for peptide as shown in scheme 13. The formation of the amide bond is carried out in accordance with standard methods of obtaining peptide, known from the prior art. Optimally, the reaction is carried out in a solvent such as DMF, at a temperature of from 0°to room, using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDAC or EDCI Il the WSC), 1-hydroxybenzotriazole (NOVT) or 1-hydroxy-7-asobancaria (NEAT) and a base, such as base Janiga (Hunig) (diisopropylethylamine), N-methylmorpholine or triethylamine. Removing the protective groups from amidoamine then results in the desired aminokislotnykh analogues IM.

Secondary aminoether XXIIA can also react with the aliphatic or aryl isocyanates XLIII with obtaining appropriate urea-ethers. Removing the protective groups of the urea-ethers results in the desired urea-acid analogues of 1N, as shown in figure 14. Alternatively, as shown in scheme 15, the intermediate carbamoylated XXXVI described in scheme 11, can react with suitable aliphatic or aryl amines XLIV in the presence of tertiary amine (for example, Et3N) to obtain the three - or Tetra-substituted mechelininkatu counterparts 10 or IP after removing the protective groups from the air.

Secondary aminoether XXIIA may also respond with appropriate sulphonylchloride XLVI under standard conditions known from the literature (optimally in the presence of a base, such as pyridine, pure or in mixture with chloroform as a co-solvent), followed by removing the protective groups to obtain the corresponding sulfonamidnuyu acids IQ, as shown in scheme 16.

The substitution of a functional group of carboxylic acid in these analogues n is tetrazol can be carried out, as shown in scheme 17. Acid analogue IK is condensed with the amine (containing a suitable tetrazolo protective group) XLVII (preferably 3-aminopropionitrile) under standard conditions to obtain the peptide. The resulting secondary amide XLVIII then subjected to reaction Mitsunobu under standard conditions with trimethylsilylacetamide (TMSN3) to obtain the protected tetrazole XLIX. Removing the protective groups with cyanoethylene group carried out preferably in the presence of base to give the desired free analog tetrazole IR.

Scheme 18 describes the total synthesis hydrazinoacetate analogues IS. Substituted arylcarbamoyl acid 1 is treated with methanesulfonamide in the presence of a base; an intermediate connection then subjected to reaction with the protected hydrazinolysis VA to obtain the corresponding acylated hydrazine 1A (see: Synthesis, 1989,745-747).

Acylhydrazone 1A condense with a suitable substituted arilaldegidov IV under conditions of reductive amination to obtain the corresponding protected hydrazide ester 3 (see: Can. J. Chem., 1998, 76, 1180-1187). Removing the protective groups with ether 3 then yields a hydrazide-acid analogues IS.

Alternative synthesis related to hydrazinoacetate IS shown in figure 19. Killdevil IV can be restored to the corresponding alcohol in standardsapproved (for example, NaBH4). The listed alcohol is then converted into the corresponding bromide 4 using standard conditions (e.g., Ph3R/CBr4or PBr3). Bromide 4 then subjected to reaction with hydrazinium 1A (see: Tetrahedron Lett., 1993, 34, 207-210) to obtain the protected Herzegovina 3, which then remove the protective group to obtain hydrazinoacetate analogues IS.

Different approaches to obtain analogs α-alkylbenzenesulfonate and carbamate-acid IT and IU are presented on the following synthesis schemes. Figure 20 suitable substituted killdevil IV is treated with a suitable ORGANOMETALLIC reagent (for example, a Grignard reagent R10MgBr) under standard conditions to obtain the corresponding secondary alcohol, which is then oxidized under standard conditions (for example, Swern oxidation with (COCl)2/DMSO/Et3N or using Chloramin pyridinium) to obtain the corresponding ketone 5. Reductive amination of ketone 5 with a suitably substituted aminoethanol 6 leads to the corresponding α-alkylbenzenesulfonic 7. It is clear that in aminoether 6 balancedoes not necessarily represent two repeating units.

Acylation of aminoether 7 with a suitable substituted aryl - or heteroarylboronic XXXV, followed by removing the protective groups leads to the auchenia racemic carbonatation analogues of IT. Reductive amination of alkylbenzenesulfonic 7 arilaldegidov VII, followed by removing the protective groups yields a racemic amino acid analogues IU.

Alternatively, as shown in scheme 21, asymmetric recovery (for example, using the method oxazaborolidine recovery Corey; see: E.J.Corey & S. Helal, Angew. Chem. Int. Ed. Engl., 1998, 37, 1986-2012) arylketones 5 results in any desired enantiomeric alcohols 8 (although only one enantiomer is shown in the diagram). Processing chiral alcohol 8 azide in the reaction, such reaction Mitsunobu (see: A.S.Thompson et. al., J. Org. Chem. 1993, 58, 5886-5888) leads to the corresponding chiral azide (with the handling of stereochemistry with respect to the source of the alcohol). Azide is then converted into the amine 9 standard recovery techniques (e.g., gidrogenizirovanii or Ph3R/THF/H2About). Processing chiral amine 9 ether XVIA (containing a suitable leaving group) results secondary aminoether 10. Acylation of aminoether 10 aryl - or heteroarylboronic XXXV, followed by removing the protective groups leads to the production of chiral carbonatation analogues ITa (which can be any enantiomers, depending on the stereochemistry of compound 8). Reductive amination of alkylamidoamines 10 arelargely VII followed is the adoption of protective groups leads to the production of chiral amino acid analogues IUa (which can be any enantiomers, depending on the stereochemistry of compound 8).

An alternative path to the circuit 21 shown in scheme 22. Suitably protected oxicillin 11 is subjected to an asymmetric recovery with obtaining chiral alcohol 12. It transformed into a chiral amine 13 in accordance with methods similar to those described in scheme 21 (via chiral azide). Processing chiral amine 13 ether XVIA (LG = halogen or mesilate) leads to the corresponding secondary aminoether 14. The acylation 14 aryl - or heteroarylboronic XXXV yields a corresponding carbamaaepine. Selective removal of the protective groups results in a free finalternatives 15. Alkylation of phenol 15 halide or mesilate VIII, followed by removing the protective groups results in carbonatation analogues ITa. A similar sequence involving reductive amination of secondary aminoether 14 aryl - or heteroanalogues VII, then selective removal of the protective groups, alkylation with the eighth and final removal of the protective groups) results in amino acid analogues IUa.

Obviously, (R)- or (S) -enantiomers ITa or IUa can be obtained in accordance with the charts of 21 or 22, depending on the chirality used restorative agent.

The fourth sequence of the synthesis shown in scheme 23. Substituted aldehyde IV condense the hydrochloride aminoether 6 to obtain the corresponding imine 16, which is then treated in situ with a suitable substituted allergologicum 17 in the presence of metal India (see: Loh, T.-P., and others, Tetrahedron Lett., 1997, 38, 865-868) obtaining α-allianceandempire 18. Acylation of amine 18 aryl - or heteroarylboronic XXXV, followed by removing the protective groups results in carbonatation analogues I. Reductive amination of alkylamidoamines 18 aryl - or heteroanalogues VII, followed by removing the protective groups results in amino acid analogues IW.

Figure 24 shows the desired intermediate 2-aryl-5-methoxazole-4-iletileri 21 (following the General procedure described in Malamas, M. S.. and others, J. Med. Chem., 1996, 39, 237-245). Substituted killdevil 19 condense with butane-2,3-daemonversion in acidic conditions to obtain the corresponding oxazol-N-oxide 20. Deoxyadenosine oxazol-N-oxide 20 with a concomitant chlorination results in the desired hermeticallysealed 21. Hydrolysis of chlormethiazole 21 in the basic conditions leads to the receipt of oxazolidinone 22. Oxidation of the alcohol 22 to the corresponding aldehyde is carried out with subsequent conversion into the corresponding dibromide 23 (e.g., Ph3R/CBr4). Dibromide 23 turn in the appropriate quinil ion balance (use organolithium reagent, is the aka, as n-BuLi), which can be subjected to reaction in situ with a suitable electrophile, such as formaldehyde, to obtain the corresponding acetylenic alcohol (see: Corey, E.J., and others, Tetrahedron Lett. 1972, 3769, or Gangakhedkar, K. K., Synth. Commun. 1996, 26, 1887-1896). The specified alcohol can then be converted into the corresponding mesilate 24 and is alkylated with a suitable phenol 25 obtaining analogues Ix. Further stereoselective reduction (for example, N2/Lindlar catalyst) results in E - or Z-albanianlove IV.

Scheme 25 describes the total synthesis aminobenzotriazole analogues IZ (reference: Sato, Y., and others, J7. Med. Chem. 1998, 41, 3015-3021). Suitable substituted ortho-aminophenol 26 is treated with CS2 in the presence of a base to obtain the corresponding mercaptobenzoxazole 27. Processing the received thiol 27 appropriate gloriouse agent (for example, PCl5) leads to the production of a key intermediate chlorobenzoxazole 28, which is subjected to reaction with a secondary aminoether VI obtaining after removing the protective groups aminobenzonitrile analogues IZ.

TietoEnator IZa synthesized in accordance with the General scheme of the synthesis outlined in scheme 26 (see Collins, J.L., and others, J. Med. Chem. 1998, 41, 5037). Secondary aminoether XXIII subjected to reaction with aryl - or heteroarylboronic XXXV in the presence of a suitable base (e.g. pyridine is or triethylamine) to obtain the corresponding hydroxycarbamoyl 29. Hydroxyaromatic 29 then subjected to reaction with suitable substituted α-brompheniramine 29A (S3=CH3for example, Weyerstahl, P., and others, Flavour Fragr. J., 1998, 23, 177 or Sokolov, N.., and others, Zh. Org. Khim., 1980, 16, 281-283) in the presence of a suitable base (For example, a2CO3) to obtain the corresponding adduct reaction Michael, α-brancheorganisatie 30. α-Bratton 30 then subjected to the condensation reaction with suitable substituted arylamido 31 (=O) or arylthioureas 31 (A=S) and receiving the corresponding oxazole (amide) or thiazole (from thioamide) (see: Malamas, M.S., and others, J. Med. Chem., 1996, 39, 237-245). Finally, removing the protective groups of the esters 31 then leads to the production of substituted oxazol and thiazolecarboxamide analogues IZa.

It is obvious that in the following diagrams, where get carbonatation counterparts, the corresponding analogues of amino acids can also be obtained by substitution reaction with CHLOROFORMATES on the aldehyde in the recovery aminating (as in figure 20 with the intermediate amine 7).

Scheme 27 describes the total synthesis of acids IZb and IZc. Halogen-substituted killdevil 32 (preferably iodide or bromide) is subjected to reductive aminating, using the technique known from the prior art (for example, Abdel-Magid, etc., J. Org. Chem. 1996, 61, 3849) with hydrochlorot α-amino acid ester V. the Resulting secondary is minafer 33 then subjected to reaction with aryl - or heteroarylboronic XXXV in the presence of a suitable base (for example, pyridine or triethylamine) to obtain the corresponding halogenerator 34. Aryl halides 34 are then subjected to reaction with an appropriate aryl - or heteroarylboronic acetylene 35 (preferred acetylene is 5-phenyl-2-methoxazole-4-yl-methylacetylene) in the presence of a suitable palladium catalyst (for example, (Ph3R)2PdCl2and salts of copper (I) (e.g., CuI) in the condensation reaction by Sonogashira (Sonogashira) (see: Organocopper Reagents, a Practical Approach, R.J..Taylor, Ed., Chapter 10, pp.217-236, Campbell, I.B., Oxford University Press, 1994) to obtain the key intermediate arylacetylenes ether 36.

With arylacetylenes ether 36 remove a protective group to obtain the corresponding arylacetylenes analogues IZb. Acetylene group 36 may be recovered by standard methods (for example, hydrogenomonas, see: .Hudlicky, Reductions in Organic Chemistry, 2ndEdition, ACS, 1996, Chapter 1) to obtain the corresponding fully saturated alkylarylsulphonates ether, which then remove the protective group to obtain alkylarylsulfonate analogues IZc. Stereoselective recovery of acetylene ether 36 by standard methods (for example, the Lindlar catalyst; see: Preparation of Alkenes, A Practical Approach, J.J.Williams, Ed., Chapter 6, pp.117-136, Oxford University Press, 1996) can be performed to obtain the corresponding CIS-alkenylsilanes is a, which then remove the protective group to obtain Z-alkenylzirconocene analogues IZd (Scheme 28). Alternatively, this sequence can be reversed, i.e. the initial step is the removal of the protective groups with acetylene ether 36 obtaining acetylene acid with subsequent stereoselective recovering acetylene group with obtaining Z-ascencion analogues IZd.

The corresponding TRANS-alkenylsilanes acid IZe can be obtained in accordance with the General method of scheme 29. Aryl - or heterogenisation 35 (preferred group again is 5-phenyl-2-methoxazole-4-yl-methylacetylene) halogenous under standard conditions (see: Boden, .D.J. etc., J. Chem. Soc. Perkin Trans. I, 1996, 2417; or Lu, W. et. al., Tetrahedron Lett. 1998, 39, 9521) to obtain the corresponding halogenation, which is then converted into the corresponding TRANS-alkenylsilanes 37 (see: Boden, .D.J., J. Chem. Soc., Perkin Trans. I, 1996, 2417). The resulting aryl - or heteroaryl-substituted TRANS-alkenylsilanes 37 then associated with halogenoalkanes ether 34 in the standard combination of condensation on Still (Stille) (see: Farina, V. E., and others, "The Stille Reaction", Organic Reactions, 1997, 50, 1) to obtain the corresponding TRANS-alkenylsilanes ester 38. With the specified carbamaaepine then remove the protective group under standard conditions to obtain the desired TRANS-alkenyl recarbonation analogues IZe.

Appropriate cyclopropyl analogues IZf and IZg receive in accordance with the Scheme 30. For CIS - or (Z) cyclopropyl analogues using stereoselective reduction (N2/Lindlar catalyst) alkenylphenol group interim akinrinola ether 36 (as analogues for IZd) with subsequent cyclopropylamine under standard conditions (Zhao, Y., and others, J. Org. Chem. 1995, 60, 5236-5242) and the subsequent removal of the protective groups leads to the production of CIS-cyclopropanecarbonitrile analogues IZf. For TRANS-cyclopropyl analogues IF used a similar cyclopropylamine E-alkinoos group intermediate connection 38 with the subsequent removal of the protective groups, resulting in TRANS-cyclopropanecarboxylate analogues IZg.

In this and the following reaction schemes:

An alternative scheme 1A to obtain the aldehyde IV

Unless otherwise specified, the term "lower alkyl", "alkyl" or "ALK"as used here by itself or as part of another group includes linear and branched chain hydrocarbons containing from 1 to 20 carbon atoms, preferably from 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms in the normal chain, and may optionally include an oxygen or nitrogen in the normal chain, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the various branched isomers, and the like as well as such groups, which include 1 to 4 substituents such as halogen, for example F, Br, Cl or I or CF3, alkoxy, aryl, aryloxy, aryl(aryl) or diaryl, Ari is alkyl, arylalkylamine, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylation, amino, hydroxy, hydroxyalkyl, acyl, heteroaryl, heteroaromatic, cyclogeranyl, Allgeier, arylethoxysilanes, heteroallyl, heteroaromatics, aryloxyalkyl, aryloxyalkyl, alkylamino, alkanolamine, arylcarboxamide, nitro, cyano, thiol, halogenated, trihalomethyl and/or alkylthio and/or any of R3groups.

Unless otherwise specified, the term "cycloalkyl"which is used herein by itself or as part of another group includes saturated or partially unsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groups containing from 1 to 3 rings, including monocyclohexyl, bicycloalkyl and tricyclohexyl containing in total from 3 to 20 carbons forming the rings, preferably from 3 to 10 carbon atoms forming the ring and which may be condensed with 1 or 2 aromatic rings as described for aryl, which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, cyclohexenyl,

,,,,,

any of these groups can be optionally substituted from 1 to 4 cover the firs, such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy, arylalkyl, cycloalkyl, alkylamino, alkanolamine, oxo, acyl, arylcarboxamide, amino, nitro, cyano, thiol and/or alkylthio and/or any of the substituents for alkyl.

The term "cycloalkenyl"which is used herein by itself or as part of another group, refers to a cyclic hydrocarbon containing from 3 to 12 carbon atoms, preferably from 5 to 10 carbon atoms and 1 or 2 double bonds. Examples cycloalkenyl groups include cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctyl, cyclohexadienyl and cycloheptadiene, which may be optionally substituted as defined for cycloalkyl.

The term "cycloalkyl", which is used here, means "cycloalkyl" group, which includes free links and, therefore, is a linker group, such as,and the like, and may optionally be substituted as indicated above for the "cycloalkyl".

The term "alkanoyl"which is used herein by itself or as part of another group refers to alkyl associated with the carbonyl group.

Unless otherwise specified, the term "lower alkenyl" or "alkenyl"which is used herein by itself or as part of another group refers to a linear or razvetvlenno the m radicals, containing from 2 to 20 carbon atoms, preferably from 2 to 12 carbon atoms and more preferably from 2 to 8 carbon atoms in the normal chain, which include one to six double bonds in the normal chain, and may optionally include an oxygen or nitrogen in the normal chain, such as vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3 nonenal, 4-decenyl, 3-undecenyl, 4-dodecenyl, 4,8,12-tetradecanoyl and the like, and which may be optionally substituted from 1 to 4 substituents, namely, halogen, halogenation, alkyl, alkoxy, alkenyl, quinil, aryl, arylalkyl, cycloalkyl, amino, hydroxy, heteroaryl, cyclogeraniol, alkanolamine, alkylamine, arylcarboxamide, nitro, cyano, thiol, alkylthio and/or any Deputy for alkyl above.

Unless otherwise specified, the term "lower quinil" or "quinil"which is used herein by itself or as part of another group, refers to linear or branched radicals containing from 2 to 20 carbon atoms, preferably from 2 to 12 carbon atoms and more preferably from 2 to 8 carbon atoms in the normal chain, which include one triple bond in the normal chain, and may optionally include an oxygen or nitrogen in the normal chain, such as 2-PROPYNYL, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenal, 4-decenyl, 3-undecenyl, 4-dodecenyl and the like, and which may be optionally substituted from 1 to 4 substituents, namely, halogen, halogenation, alkyl, alkoxy, alkenyl, quinil, aryl, arylalkyl, cycloalkyl, amino, heteroaryl, cyclogeraniol, hydroxy, alkanolamine alkylamino, arylcarboxamide, nitro, cyano, thiol, and/or alkylthio, and/or any of the substituents for alkyl above.

The terms "arylalkyl and arylalkyl", which are used by themselves or as part of another group, refers to alkenyl and alkynylaryl groups as described above having an aryl Deputy.

Where the alkyl groups defined above are simple for connection to other groups and two different carbon atoms, they are called "alkylene group, and can optionally be substituted as indicated above for "alkyl".

Where alkeneamine group, as defined above, and alkyline group, as defined above, respectively, are simple for connection to two different carbon atoms, they are called "alkenylamine group" and "alkenylamine group", respectively, and may optionally be substituted as indicated above for the "alkenyl" and "al is inila".

(CH2)x, (CH2)m, (CH2)nor (CH2)yincludes alkylene, alltel, albaniles or alkenylamine group, as here defined, each of which may optionally include oxygen or nitrogen in the normal chain, which may optionally include 1, 2 or 3 substituent which include alkyl, alkenyl, halogen, cyano, hydroxy, alkoxy, amino, thioalkyl, keto,3-C6cycloalkyl, alkylcarboxylic or alkylcarboxylic; alkyl Deputy may be Allenova group with from 1 to 4 carbon atoms that may join one or two carbon atoms in (CH2)xor (CH2)mor (CH2)nthe group with the formation of cycloalkyl group.

Examples (CH2)x, (CH2)m, (CH2)n, (CH2)y, alkylene, Alcanena and akinlana include

,,,,

,,,

,,,,,

, ,,,,

,,,,

,,,,

,,,,

,,,

,,,

,,,,

,,or.

The term "halogen" or "halo"as used here by itself or as part of another group refers to chlorine, bromine, fluorine and iodine, as well as CF3, preferably chlorine or fluorine.

The term "metal ion" refers to ions of alkali metals such as sodium, potassium or lithium, and alkaline-earth metals such as magnesium or calc the th, as well as zinc and aluminum.

Unless otherwise specified, the term "aryl"as used here by itself or as part of another group refers to monocyclic or bicyclic aromatic groups containing from 6 to 10 carbon atoms in the ring (such as phenyl or naphthyl including 1-naphthyl and 2-naphthyl)and may optionally include one to three additional rings condensed with carbocyclic or heterocyclic ring (such as aryl, cycloalkyl, heteroaryl or cycloheptatriene rings, for example

,,,,,

,,,,

,,,

and they can be optionally substituted through an acceptable carbon atoms 1, 2 or 3 groups selected from hydrogen, halogen, halogenoalkane, alkyl, halogenoalkane, alkoxy, halogenoalkane, alkenyl, trifloromethyl, triptoreline, quinil, cycloalkyl-alkyl, cyclogeranyl, cyclohexanoltramadol, aryl, heteroaryl, arylalkyl, alloc and, aryloxyalkyl, Allakaket, alkoxycarbonyl, arylcarbamoyl, arylalkyl, aminocarbonylmethyl, aaltio, arylsulfonyl, arylazo, heteroallyl, heteroallyl, heteroarylboronic, heteroaromatic, hydroxy, nitro, cyano, amino, substituted amine, where the amine has 1 or 2 substituent (which are alkyl, aryl or any of the other aryl compounds mentioned in the description in the section "definitions"), thiol, alkylthio, aaltio, heteroaromatic, alltoall, alkoxyaryl, alkylcarboxylic, arylcarbamoyl, alkylaminocarbonyl, arylenecarborane, alkoxycarbonyl, aminocarbonyl, alkylcarboxylic, arylcarboxylic, alkylcarboxylic, arylcarboxamide, arylsulfonyl, arylsulfonate, arylsulfonate or arylsulfonyl and/or any substituent for the alkyl mentioned herein.

Unless otherwise specified, the term "lower alkoxy", "alkoxy", "aryloxy" or "arakaki"which is used herein by itself or as part of another group includes any of the above alkyl, aracelio or aryl group linked to the oxygen atom.

Unless otherwise specified, the term "substituted amino"as used here by itself or as part of another group, refers to an amine substituted by one or two substituents, which may be the same or different, is mi, as alkyl, aryl, arylalkyl, heteroaryl, heteroaromatic, cyclogeranyl, cyclohexanoltramadol, cycloalkyl, cycloalkenyl, halogenated, hydroxyalkyl, alkoxyalkyl or thioalkyl. These substituents may be further substituted by carboxylic acid and/or any Deputy for alkyl above. In addition, aminosalicylic can be taken together with the nitrogen atom to which they are attached with the formation of 1-pyrrolidinyl, 1-piperidinyl, 1-azepine, 4-morpholinyl, 4-thiomorpholine, 1-piperazinil, 4-alkyl-1-piperazinil, 4-arylalkyl-1-piperazinil, 4-varilly-1-piperazinil, 1-pyrrolidinyl, 1-piperidinyl or 1-azepine, optionally substituted by alkyl, alkoxy, alkylthio, halogen, trifluoromethyl or hydroxy.

Unless otherwise specified, the term "lower alkylthio", alkylthio", "aristeo" or "Uralkali"which is used herein by itself or as part of another group includes any of the above alkyl, aracelio or aryl group associated with the sulfur atom.

Unless otherwise specified, the term "lower alkylamino", "alkylamino", "arylamino" or "arylalkylamine"which is used herein by itself or as part of another group includes any of the above alkyl, aryl or arylalkyl groups connected to the nitrogen atom.

Unless otherwise specified, the term "acyl", which is used in isoamsa by itself or as part of another group, as defined here, refers to an organic radical linked to a carbonylgroup; examples of acyl groups include any R3group attached to a carbonyl, such as alkanoyl, alkanoyl, aroyl, arkanoid, heteroaryl, cycloalkenyl, cyclohexanol and the like.

Unless otherwise specified, the term "cyclogeranyl"which is used herein by itself or as part of another group denotes a 5-, 6 - or 7-membered saturated or partially unsaturated ring which includes 1 to 2 heteroatoms, such as nitrogen, oxygen and/or sulfur, linked through a carbon atom or a heteroatom, where possible, optionally via the linker (CH2)p(where p denotes 1, 2 or 3),such as

,,,,

,,,,

,,,

,,,

and like them. The above groups may include 1 to 4 will replace the lei, such as alkyl, halogen, oxo and/or any of the substituents for alkyl or aryl, shown here. In addition, any of cyclogeranyl rings may be condensed with cycloalkyl, aryl, heteroaryl or cyclogeranyl ring.

Unless otherwise specified, the term "heteroaryl"which is used herein by itself or as part of another group denotes a 5 - or 6 - membered aromatic ring which contains 1, 2, 3 or 4 heteroatoms, such as nitrogen, oxygen or sulfur, and such rings fused with aryl, cycloalkyl, heteroaryl or cyclogeranyl ring (for example, benzothiophene, indolyl), and includes possible N-oxides. Heteroaryl group may optionally include 1 to 4 substituents such as any of the substituents for alkyl or aryl above. Examples of heteroaryl groups include the following:

,,,,

,,,,,,

,,,, ,,

,,,,,

and similar to them.

The term "cyclohexanoltramadol"which is used herein by itself or as part of another group, refers to cyclogeranyl groups as defined above linked via an atom or heteroatom with (CH2)pchain.

The term "heteroaromatic" or "heteroaromatic"which is used herein by itself or as part of another group, refers to a heteroaryl group as defined above linked via an atom or heteroatom -(CH2)p- chain, alkylene or Alcanena, as defined above.

The term "POLYHALOGENATED", which is used here, refers to "alkyl" group as defined above which includes from 2 to 9, preferably from 2 to 5 halogen substituents, such as F or Cl, preferably F, such as CF3CH2, CF3or CF3CF2CH2.

The term "polygalacturonic", which is used here, means "alkoxy" or "alkyloxy" group as defined above which includes from 2 to 9, preferably from 2 to 5 halogen substituents, such as F or Cl, preferably F, such as CF3CH2Oh, CFsub> 3On or CF3CF2CH2O.

The term "Proletarskoye esters", which is used here, includes proletarienne essential forms, which are known from the prior art for esters of carboxylic and phosphoric acids, such as methyl, ethyl, benzyl and the like. Other examples procarcinogen ether R4include the following groups: (1 alkanoyloxy)alkyl, such as

or

where Ra, Rband Rcrepresent H, alkyl, aryl or aryl-alkyl;

however, RaO may not be BUT.

Examples of such proletarienne esters R4include

,,or.

Other examples of suitable proletarienne esters R4include

,,,,

,

where Racan be H, alkyl (such as methyl or tert-butyl), arylalkyl (such as benzyl) or aryl (such as phenyl); Rdrepresents H, alkyl, halogen or alkoxy, Rerepresents alkyl, aryl, arylalkyl or alkoxy and n1and EET 0 1 or 2.

Where compounds of structure I are in the acid form, they can form pharmaceutically acceptable salt, such as alkali metal salts, such as lithium, sodium or potassium, salts of alkaline-earth metals such as calcium or magnesium as well as zinc or aluminum and other cations such as ammonium, choline, diethanolamine, lysine (D or L), Ethylenediamine, t-butylamine, tert-octylamine, Tris-(hydroxymethyl)aminomethan (TRIS), N-methylglucamine (NMG), triethanolamine and dehydroabietylamine.

All stereoisomers of the compounds of the present invention refers to either in a mixture or in pure or nearly pure form. Compounds of the present invention can have asymmetric centers at any of the carbon atoms including any one or R substituents. Therefore, the compounds of formula I can exist in enantiomeric or diastereomeric forms or in mixtures. Methods of obtaining can use the racemates, enantiomers or diastereomers as starting materials. Upon receipt of the diastereomeric or enantiomeric products they can be separated by conventional methods, for example, chromatographic or fractional crystallization.

Optionally, compounds of structure I may be used in combination with one or more hypolipidemic agents or lipid-lowering AG is new and/or one or more other types of therapeutic agents, including anti-diabetic agents, agents, anti-obesity, anti-hypertensive agents, inhibitors of aggregation of platelets and/or agents against osteoporosis, which can be administered orally at the same dose form, in a separate oral dose form or by injection.

The hypolipidemic agent or lipid-lowering agent, which may optionally be used in combination with compounds of the formula I according to the invention may include 1, 2, 3 or more MTP inhibitors, inhibitor of HMG COA reductase inhibitor salanova synthetases, an inhibitor of fibrin derivatives acids, ACAT inhibitors, lipoxygenase inhibitor, an inhibitor of cholesterol absorption, inhibitor iliac cotransporter Na+/bile acid, a regulator of the activity of the LDL receptor, substances that increase the excretion of bile acid and/or nicotinic acid and derivatives thereof.

MTP inhibitors, applicable here include MTP inhibitors, is described in US 5595872, US 5739135, US 5712279, US 5760246, US 5827875, US 5885983 and request US 09/175180 filed 20.10.1998, currently US 5962440. Preferred are any of the preferred MTP inhibitors, is described in each of the above patents and applications.

All of the above US patents and applications listed here as references.

The most preferred MTP inhibitors, applicable in accordance with this is Subramaniam, include preferred MTP inhibitors, which are described in US 5739135 and 5712279, and US 5760246.

The most preferred MTP inhibitor is 9-[4-[4-[[2-(2,2,2-triptoreline)benzoyl]amino]-1-piperidinyl]butyl]-N-(2,2,2-triptorelin)-N-fluoren-9-carboxamide

The hypolipidemic agent may be an inhibitor of HMG COA reductase, which includes, but is not limited to such compounds as mevastatin and related compounds, which are described in US 3983140, lovastatin (mevinolin) and related compounds, which are described in US 4231938, pravastatin and related compounds, which are described in US 4346227, simvastatin and related compounds, which are described in US 4448784 and 4450171. Other HMG inhibitors COA reductase, which can be used include, but are not limited to, fluvastatin, described in US 5354772, tseriwastatina described in US 5006530 and 5177080, atorvastatin, described in US 4681893, 5273995, 5385929 and 5686104, itavastatin (Nissan/Sankyo nicastrin (NK-104)described in US 5,011,930, Shionogi-Astra/Zeneca visitation (ZD-4522), described in US 5260440, and related compounds statin described in US 5753675, pyrazol analogues mevalonate derivatives, which are described in US 4613610, indene analogues mevalonate derivatives, which are described in PCT application WO 86/03488, 6-[2-(substituted-pyrrol-1-yl)-alkyl)Piran-2-ones and their derivatives, which are described in US 647576, Searle SC-45355 (3-substituted derivative of pentanedionato acid) dichloracetate, imidazole analogues of mevalonate, which are described in PCT application WO 86/07054, derivatives of 3-carboxy-2-hydroxypropan-phosphoric acid, which is described in FR 2596393, 2,3-disubstituted pyrrole, furan and thiophene derivatives, which are described in the application EP 0221025, raftiline analogues of mevalonate, which are described in US 4686237, octahydronaphthalene, such as described in US 4499289, keto-analogues of mevinolin (lovastatin), which are described in the application EP 0142146 A2, and quinoline and pyridine derivatives described in US 5506219 and 5691322.

In addition, the compounds of phosphinic acid, are useful for inhibiting HMG COA reductase, suitable for use here, is described in GB 2205837.

Inhibitors salanova synthetases, suitable for use here include, but are not limited to, α-phosphosulfate described in US 5712396 described Biller and others, J. Med. Chem., 1988, Vol.31, No.10, R-1871, including isoprenoid (phosphinyl-methyl)phosphonates, as well as other known inhibitors salanova synthetases, such as that described in US 4871721 and 4924024 and Biller, S.A., Neuenschwander, K., Ponpipom, M.M., and Poulter, C.D., Current Pharmaceutical Design, 2, 1-40(1996).

In addition, other synthetase inhibitors suitable for use in accordance with the invention, include terpenoid pyrophosphates described R. Ortiz de Montellanq etc., J. Med. Chem. 1977, 20, 243-249, diphosphates similar farnesyl and Paskaleva pyrophosphate (PSQ-PP) analogues, which are described Soju and Volante, J. Am. Chem. Soc., 1976, 98, 1291-1293, fashinistas described McClard, R.W., and others, J.A.C.S., 1987, 109, 5544 and cyclopropanes described Capson, T.L., PhD dissertation, June. 1987, Dept. Med. Chem. U of Utah, Abstract, Table of Contents, pp.16, 17, 40-43, 48-51, Summary.

Other lipolipidemicescoe agents suitable for use here include, but are not limited to, derivatives of fibrin acid, such as fenofibrate, gemfibrozil, clofibrate, bezafibrat, ciprofibrate, clinofibrate and the like, probucol and related compounds, which are described in US 3674836, probucol and gemfibrozil are the preferred substances that increase the excretion of bile acids, such as cholestyramine, colestipol and DEAE-Sephadex (Secholex®, Policexide®) and cholestagel (Sankyo/Geltex), as well as LIPOSTABIL (Rhone-Poulenc), Eisai E-5050 ( an N-substituted ethanolamine derived), manickal (NOAH-402), tetrahydrolipstatin (THL), stigmastadienol (SPC, Roche), aminocyclohexane (Tanabe Seiyoku), Ajinomoto AJ-814 (Aslanova derived), melinamide (Sumitomo), Sandoz 58-035, American Cyanamid CL-277,082 and CL-283,546 (disubstituted urea derivatives), nicotinic acid (Niacin), acipimox, acifran, neomycin, n-aminosalicylic acid, aspirin, a derivative of poly(diallylmethylamine), such as that described in US 4759923, Quaternary amine poly(diallyldimethylammonium holdem is reed) and ionene, such as described in US 4027009, and other known agents that reduce the level of cholesterol in the plasma.

The hypolipidemic agent may be an ACAT inhibitor, such as described in Drugs of the Future 24, 9-15 (1999), (Avasimibe); "The ACAT inhibitor, Cl-1011 is effective in the prevention and regression of aortic fatty streak area in hamsters", Nicolosi and others, Atherosclerosis (Shannon, Irel). (1998), 137(1), 77-85; "The pharmacological profile of FCE 27677: a novel ACAT inhibitor with potent hypolipidemic activity mediated by selective suppression of the hepatic secretion of ApoB 100-containing lipoprotein", Ghiselli, Giancarlo, Cardiovasc. Drug Rev. (1998), 16(1), 16-30; "RP 73163: a bioavailable alkylsulfinil-diphenylimidazole ACAT inhibitor", Smith, C., and others, Bioorg. Med. Chem. Lett. (1996), 6(1), 47-50; "ACAT inhibitors: physiologic mechanisms for hypolipidemic and anti-atherosclerotic activities in experimental animals", Krause and others, Editor(s): Ruffolo, Robert R., Jr.; Hollinger, Mannfred A., Inflammation: Mediators Pathways (1995), 173-98, Publisher: CRC, Boca Raton, Fla.; "ACAT inhibitors: potential anti-atherosclerotic agents", Sliskovic and others, Curr. Med. Chem. (1994), 1(3), 204-25; "Inhibitors of acyl-CoA:cholesterol O-acyl transferase (ACAT) as hypocholesterolemic agents. 6. The first water-soluble ACAT inhibitor with lipid-regulating activity. Inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). 7. Development of a series of substituted N-phenyl-N'-[(l-phenylcyclopentyl)methyl] ureas with enhanced hypocholesterolemic activity. Stout and others, Chemtracts: Org. Chem. (1995), 8(6), 359-62, or TS-962 (Taisho Pharmaceutical Co. Ltd.

The hypolipidemic agent may be a regulator of the activity of the receptor LD2 such as MD-700 (Taisho Pharmaceutical Co. Ltd) and LY295427 (Eli Lilly).

The hypolipidemic agent may be an inhibitor of cholesterol absorption, preferably Schering-Plough's SCH48461, as described in Atherosclerosis 115, 45-63 (1995) and J. Med. Chem. 41, 973 (1998).

Gipolipidemiceski the agent may be an inhibitor iliac cotransporter Na +/bile acid, such as described in Drugs of the Future, 24, 425-430 (1999).

Preferred hypolipidemic agents are pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin, tseriwastatina, itavastatin and visitation.

The above US patents are listed here as references. The applied quantity and dose will be the same as specified in Physician''s Desk Reference and/or in the patents listed above.

The compounds of formula I according to the invention is used in a mass ratio to the lipid-lowering agent (present), which lies in the range from about 500:1 to about 1:500, preferably from about 100:1 to about 1:100.

Enter the dose should be carefully chosen in accordance with age, weight and condition of the patient, as well as the route of administration, dosage form and regimen and the desired result.

Doses and compositions for lipid-lowering agent are as described in various patents and applications described above.

The doses and formulations used for other lipid-lowering agents, where possible, are as described in the latest edition of the Physicians' Desk Reference.

In the case of oral administration a satisfactory result can be obtained when using MTP inhibitor, taken in an amount ranging from about 0.01 mg to about 500 mg, and preferably from about 0.1 mg to about 100 mg, from one is about up to four times daily.

Preferred oral dose form, such as tablets or capsules, may contain MTP inhibitor, taken in an amount from about 1 to about 500 mg, preferably from about 2 to about 400 mg, and more preferably from about 5 to about 250 mg, one to four times daily.

For oral administration can be obtained a satisfactory result using an inhibitor of HMG COA reductase, for example, pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin or tseriwastatina used in doses that are specified in Physician''s Desk Reference, in a number ranging from about 1 to 2000 mg, and preferably from about 4 to about 200 mg.

Inhibitor salanova synthetases can be used in doses in amounts ranging from about 10 mg to about 2000 mg, and preferably from about 25 mg to about 200 mg

Preferred oral dose form, such as tablets or capsules, may contain an inhibitor of HMG COA reductase in an amount of from about 0.1 to about 100 mg, preferably from about 0.5 to about 80 mg, and more preferably from about 1 to about 40 mg

Preferred oral dose form, such as tablets or capsules, may contain an inhibitor salanova synthetases in the amount of from about 10 to about 500 mg, preferably from about 25 to about 200 mg

The hypolipidemic agent may be an inhibitor libocsigen the SHL, including the inhibitor of 15-lipoxygenase (15-LO), such as benzimidazole derivatives, which are described in WO 97/12615, 15-LO inhibitors, which are described in WO 97/12613, isothiazolone, which are described in WO 96/38144, and 15-LO inhibitors, which are described Sendobry and other "Attenuation of dietret-induced atherosclerosis in rabbits with a highly selective 15-lipoxygenase ingibitor lacking significant antioxidant properties", Brit. J. Pharmacology (1997) 120, 1199-1206, and Cornicelli and others, "15-Lipoxygenase and its Inhibition: A Novel Therapeutic Target for Vascular Disease", Current Pharmaceutical Design, 1999, 5, 11-20.

The compounds of formula I and lipid-lowering agent can be used together in a single oral dose form or in separate oral dose forms taken at the same time.

The compositions described above may be administered in unit dosage forms, as described above, in single or divided doses one to four times daily. It is advisable to start treatment with a low dose combination and gradually to achieve high-dose combination.

The preferred lipid-lowering agent is pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin or tseriwastatina, as well as Niacin and/or cholestagel.

Antidiabetic agent, which may optionally be used in combination with the compound of the formula I may represent 1, 2, 3 or more antidiabetic agents or antihyperglycemic agents, including substances that increase secrets the Yu insulin or insulinemia sensitizing substances, which may include biguanides, sulfonylureas, glucosidase inhibitors, PPAR γ agonists, such as preparations of thiazolidinediones, or inhibitors, PPAR α/γ dual agonists, dipeptidyl peptidases IV (DP4) inhibitors, SGLT2 inhibitors, and/or meglitinides, as well as insulin, and/or glucagon-like peptide-1 (GLP-1).

Anti-diabetic agent may be administered orally with antihyperglycemic agent, preferably biguanides, such as Metformin or phenformin or their salts, preferably Metformin HCl.

Where antidiabetic agent is biguanidine, the compounds of structure I may be used in a mass ratio to biguanidine, which is in the range from about 0.001:1 to about 10:1, preferably from about 0.01:1 to about 5:1.

Antidiabetic agent may also be preferably a sulfonylurea, such as gliburid (also known as glibenclamide), glimepiride (described in US 4379785), glipizide, gliclazide or hlorpropamid, other known sulfonylureas or other antihyperglycemic agents, which act on the ATP-dependent channel of the P-cells are preferred gliburid and glipizide, which can be entered in one or in different oral dose forms.

Compounds of structure I may be used in a mass ratio with sulfonylurea, which lies in the region is from about 0.01:1 to about 100:1, preferably from about 0.02:1 to about 5:1.

Oral input antidiabetic agent may also glucosidase inhibitor such as acarbose (described in US 4904769) or miglitol (described in US 4639436)that can be entered in one or in separate oral dose forms.

Compounds of structure I may be used in a mass ratio with the glucosidase inhibitor, which is in the range from about 0.01:1 to about 100:1, preferably from about 0.05:1 to about 10:1.

Compounds of structure I may be used in combination with a PPAR γ agonist, such as thiazolidinedione oral anti-diabetic agent or other insulin sensitizing substance (which have insulin-sensitive effect in NIDDM patients)such as troglitazone (Wamer-Lambert's Rezulin®described in US 4572912), rosiglitazone (SKB), pioglitazone (Takeda), Mitsubishi's MCC-555 (described in US 5594016), Glaxo-Welcome's GL-262570, englitazone (CP-68722, Pfizer) or darglitazone (CP-86325, Pfizer, isopetasin (MIT/J&J), JTTPET-501 (JPNT/P&U), L-895645 (Merck), R-119702 (Sankyo/WL), NN-2344 (Dr. Reddy/NN), or YM-440 (Yamanouchi), preferably rosiglitazone and pioglitazone.

Compounds of structure I may be used in a mass ratio with thiazolidinedione in an amount which ranges from about 0.01:1 to about 100:1, preferably from about 0.05 to about 10:1.

The sulfonylurea and thiazolidinedione in the amount of less than about 150 the g oral antidiabetic agent may be incorporated in a single tablet with compounds of structure I.

Compounds of structure I may also be used in combination with antihyperglycemic agent such as insulin or with glycohaemoglobin peptide-1 (GLP-1) such as GLP-1(1-36) amide, GLP-1 (7-36) amide, GLP-1 (7-37) (which are described in US 5614492 Habener, described here as a reference), as well as AS (Amylin) and LY-315902 (Lilly), which can be administered by injection, intranasal, inhalation, or via transdermal or buccal devices.

Where Metformin, sulfonylureas, such as gliburid, glimepiride, glipizide, glipizide, hlorpropamid and gliclazide and glucosidase inhibitors, acarbose or miglitol or insulin (injection, intra-lungs, buccal or oral) can be used in the compositions defined above, and in the number and dose, as indicated in Physician''s Desk Reference (PDR).

Where Metformin or its salt, it can be used in amounts lying in the range from about 500 to about 2000 mg per day, which can be entered in one or divided doses one to four times daily.

Where there is thiazolidinedione antidiabetic agent, it can be used in amounts lying in the range from about 0.01 to about 2000 mg/day, which may be given in one or two doses one to four times daily.

Where is insulin, it can p is to change any in the compositions, the number and doses as stated in Physician''s Desk Reference.

Where GLP-1 peptides, they can be administered orally in the buccal compositions, nazalnam introduction or parenterally as described in US 5346701 (TheraTech), 5614492 and 5631224 listed here as references.

Antidiabetic agent may also be a PPAR α/γ dual agonist such as AR-H039242 (Astra/Zeneca), GW-409544 (Glaxo-Wellcome), KRP297 (Kyorin Merck)as well as those described Murakami and others, "A Novel Insulin Sensitizer Acts As a Coligand for Peroxizome Proliferation-Activated Receptor Alpha (PPAR alpha) and PPAR gamma. Effect on PPAR alpha Activation on Abnormal Lipid Metabolism in Liver of Zucker Fatty Rats", Diabetes 47, 1841-1847 (1998).

Antidiabetic agent may be an SGLT2 inhibitor, such as described in US application 60/158773 published 12.10.1999 (attorney file LA49), using doses that are shown there. Preferred are the compounds mentioned as preferred in the application.

Anti-diabetic agent may be an inhibitor, such as described in application US 09/391053 published 7.09.1999, US 60/127745 published 5.04.1999 (attorney file LA27*), using doses that are shown there. Preferred are the compounds indicated as preferred in this application.

Anti-diabetic agent may be a DP4 inhibitor, such as described in the application 60/188555 published 10.03.2000 (attorney file LA50), W099/38501, W099/46272, W099/67279 (PROBIODRUG), W099/67278 (PROBIODRUG), W099/61431 (PROBIODRUG), NVP-DPP728A(1-[[[2-[(5-cyano-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)-pyrrolidine) (Novartis) (preferred), as described by Hughes and others, Biochemistry, 38(36), 11597-11603, 1999, TSL-225 (tryptophyl-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid (described Yamada and others, Bioorg. & Med. Chem. Lett. 8 (1998) 1537-1540, 2-cyanopyrrolidine and 4-cyanopyrrolidine described Ashworth and others, Bioorg. & Med. Chem. Lett., Vol.6, No.22, R-1166 and 2745-2748 (1996) using doses that are listed in the references.

Meglitinides, which can optionally be used in combination with the compound of the formula I according to the invention can be Repaglinide, nateglinide (Novartis) or KAD1229 (PF/Kissei), preferably Repaglinide.

The compound of the formula I can be used in a mass ratio with meglitinide, PPAR γ agonist, PPAR α/γ dual agonist, an inhibitor, a DP4 inhibitor, or SGLT2 inhibitor, which is in the range from about 0.01:1 to about 100:1, preferably from about 0.05 to about 10:1.

Another type of therapeutic agent, which may optionally be used with the compound of the formula I, may be 1, 2, 3 or more agent against obesity, including beta-3 adrenergic agonist, a lipase inhibitor, an inhibitor of serotonin (and dopamine), ar inhibitor, agonist thyroid receptor and/or anorectics agent.

Beta-3 adrenergic agonist, which may optionally be used in combination with the compound of the formula I, can be AJ9677 (Takeda/Dainippon), L750355 (Merck), or SR (Pfizer) or other known beta 3 agonists, which is s described in US 5541204, 5770615, 5491134, 5776983 and 5488064, preferred are AJ9677, L750.355 and SR.

A lipase inhibitor, which can optionally be used in combination with the compound of the formula I, can be orlistat or ATL-962 (Alizyme), preferred is orlistat.

Inhibitor of serotonin (and dopamine), which can optionally be used in combination with the compound of the formula I, can be sibutramine, topiramate (Johnson & Johnson) or axokine (Regeneron), preferred are sibutramine and topiramate.

Agonist thyroid receptor, which may optionally be used in combination with the compound of the formula I, may be the ligand of thyroid receptor, which is described in W097/21993 (U. Cal SF), W099/00353 (KaroBio), GB 98/284425 (KaroBio), and bid US 60/183223 published 17.02.2000, preferred are compounds KaroBio applications and specified US application.

Anorectics agent, which may optionally be used in combination with the compound of the formula I, can be dexamfetamine, phentermine, phenylpropanolamine or mazindol, it is preferable to dexamfetamine.

Various agents against obesity, described above, can be used in the same dosage form with the compound of the formula I or in different dosage forms, doses, and modes, which are well known from the prior art or of the PDR.

Antihypertensive agents that can be used in the conjunction with the compound of the formula I according to the invention, include ACE inhibitors, receptor antagonists angiotensin II, NEP/ACE inhibitors, as well as calcium channel blockers, β-adrenergic blockers and other antihypertensive agents, including diuretics.

Inhibitor angiotensinconverting enzyme, which can be used here, includes containing mercapto (-S-) group, such as substituted prolinnova derivatives, such as described in US 4046889 Ondetti and others mentioned above, it is preferable captopril, which is 1-[(2S)-3-mercapto-2-methylpropionyl]-L-Proline and mercaptopurine derivatives substituted prolinol, such as described in US 4316906, the preferred zofenopril.

Other examples mercaptoacetic ACE inhibitors that may be used include renipril (pentopril, Santen) described in Clin. Exp. Pharmacol. Physiol. 10:131 (1983); as well as pivotal and YS980.

Other examples of inhibitors of angiotensin-transforming enzyme that may be used include any of the features described in US 437482, preferred is N-(1-etoxycarbonyl-3-phenylpropyl)-L-alanyl-L-Proline, or enalapril, any of phosphonates substituted amino or aminocyclo or salts described in US 4452790 is preferred (S)-1-[6-amino-2-[[hydroxy-(4-phenylbutyl)phosphinyl]oxy]-1-oxohexyl]-L-Proline or (ceronapril), ethinylestradiol, described in US 4168267 above, it is preferable to fosinopril, any of offineelina substituted prolinol described in US 4337201, and phosphoramidate described in US 4432971 above.

Other examples of ACE inhibitors that may be used include Beecham's BRL 36,378, which are described in EP 80822 and 60668; Chugai's MC-838 described in SA 102:72588V and Jap. J. Pharmacol. 40:373 (1986); Ciba-Geigy''s CGS 14824 (3-([1-etoxycarbonyl-3-phenyl-(1S)-propyl]amino)-2,3,4,5-tetrahydro-2-oxo-1-(3S)-benzazepin-1 acetic acid HCl), described in UK 2103614 and CGS 16,617, (3(S)-[[(1S)-5-amino-1-carboxypentyl]amino]-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-ethanoic acid), described in US 4473575; Cetaphil (alacepril, Dainippon) described in Eur. Therap. Res. 39:671 (1986); 40:543 (1986); ramipril (Hoechsst), described in EP 79-022 and Curr. Ther. Res. 40:74 (1986); Ru 44570 (Hoechst), described in Arzneimittelforschung 34:1254 (1985), cilazapril (Hoffman-LaRoche), described in J. Cardiovasc. Pharmacol. 9:39 (1987); R 31-2201 (Hoffman-LaRoche), described in FEBS Lett. 165:201 (1984); lisinopril (Merck), inaapril (delapril), described in US 4385051; indonepal (Schering), described in J. Cardiovasc. Pharmacol. 5:643, 655 (1983), spirapril (Schering), described in Acta. Pharmacol. Toxicol. 59 (Supp. 5):173 (1986); perindopril (Servier), described in Eur. J. din. Pharmacol. 31:519 (1987); quinapril (Warner-Lambert), described in US 4344949 and CI925 (Warner-Lambert) ([3S-[2[R(*)R(*)]]3R(*)]-2-[2-[[1-(amoxici-carbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-3-izohinolinove acid HCl), described in Pharmacologist 2:243, 266 (1984), WY-44221 (Wyeth), described in J. Med. Chem. 26:394 (1983).

Preferred ACE inhibitors are captopril, fosinopril, enalapril, lisinopril, quinapril, benazepril, pentopril, ramipril and moexipril.

NEP/ACE inhibitors, which can also be used here include those that possess inhibitory activity of neutral endopeptidase (NEP) and inhibitory activity angiotensinconverting enzyme (ACE). Examples of NEP/ACE inhibitors suitable for use here include described in US 5362727, 5366973, 5225401, 4722810, 5223516, 4749688, US 5552397, US 5504080, US 5612359, US 5525723, EP 0599444, 0481522, 0599444, 0595610, EP A, 534396 and 534492, and E A.

Preferred are those NEP/ACE inhibitors and their dosages, which are indicated as preferred in these patents/applications US here as links; most preferred is omapatrilat, BMS 189,921 ([S-(R*,R*)]-hexahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-2,2-dimethyl-7-oxo-1H-azepin-1-acetic acid (gemopatrilat)) and CGS 30440.

Receptor antagonist of angiotensin II (also referred to here as the antagonist of angiotensin II or AII antagonist), suitable for use here includes, but is not limited to irbesartan, losartan, valsartan, candesartan, telmisartan, tasosartan or eprosartan, are preferred irbesartan, losartan or valsartan.

A preferred oral dosage form, such as tablets or capsules, may contain the ACE inhibitor or an antagonist in an amount which ranges from about 0.1 to about 500 mg, preferably from about 5 to about 200 mg, and more preferably from about 10 to about 150 mg

For parenteral administration of the ACE inhibitor, antagonist of angiotensin II or NEP/ACE inhibitor can be used in an amount which ranges from about 0.005 mg/kg to about 10 mg/kg and preferably from about 0.01 mg/kg to about 1 mg/kg

With the introduction of intravenous drug means it can be in a conventional solvent such as distilled water, brine, saline solution, ringer's solution or other conventional media.

Considered that the preferred dose of ACE inhibitor and an AII antagonist, as well as other antihypertensive agents described herein may be such as specified in the latest edition Physician''s Desk Reference (PDR).

Other examples of preferred antihypertensive agents suitable for use here include omapatrilat (Vanlev®), amlodipine, besilate (By®), prazosin HCl (Minipress®), verapamil, nifedipine, nadolol, diltiazem, felodipine, nisoldipine, isradipine, nicardipine, atenolol, carvedilol, sotalol, terazosin, doxazosin, propranolol and clonidine HCl (Catapres®).

Diuretics, which can be used in combination with compounds of the formula I, include hydrochlorothiazide, torsemide, furosemide, spironolactone and indapamide.

Antithrombotic agents that can be used in combination with compounds of the formula I accor