RU2005119981A - SUBSTITUTED ARILALKANIC ACID DERIVATIVES AS RAP PAN-AGONISTS WITH HIGH ANTIHYPERGLYCEMIC AND ANTIHYPERLIPIDEMIC ACTIVITY - Google Patents

Claims (28)

1. The compound of formula I

wherein ring A and ring B fused to a ring containing X and N each independently represents a 5-6 membered ring ring, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen, and may optionally substituted with one or more halogen, hydroxy, nitro, cyano, alkyl, alkenyl, alkenyl, aralkyl, heteroarylalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, hydroxyalkyl, thioalkyl, heterocyclyl, alkoxy, aryl, aralkoxy, heteroaryl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, amino, alkylamino, arylamino or aralkylamino; ring A and ring B may be saturated or contain one or more double bonds or may be aromatic; X is a valence bond, CH ₂ CH ₂ , CH = CH, O, S, or NR ⁶ , where R ⁶ is H, alkyl, alkenyl, alkenyl, aralkyl, heteroarylalkyl, heterocyclyl, aryl, or heteroaryl; R ¹ represents H, alkyl, alkenyl, alkenyl, aralkyl, heteroarylalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, hydroxyalkyl, thioalkyl, heterocyclyl, OH, halogen, alkoxy, aryl, aryloxy, aralkoxy, heteroaryl, heteroaryl acyloxy, amino, alkylamino, arylamino or aralkylamino; R ² represents H, alkyl, alkenyl, alkenyl, aralkyl, heteroarylalkyl, heterocyclyl, aryl or heteroaryl; R ³ represents H, alkyl, alkenyl, alkenyl, aralkyl, heteroarylalkyl, heterocyclyl, aryl or heteroaryl; R ⁴ and R ⁵ independently are H, alkyl, alkenyl, alkenyl, aralkyl, heteroarylalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, hydroxyalkyl, thioalkyl, heterocyclyl, OH, halogen, alkoxy, aryl, aryloxy, aryloxy, aryloxy, aryloxy, heteroaralkoxy, acyl, acyloxy, amino, alkylamino, arylamino or aralkylamino; R ⁴ and R ⁵ may form a 5- or 6-membered ring optionally substituted with one or more halogen, hydroxy, nitro, cyano, alkyl, alkenyl, alkenyl, aralkyl, heteroarylalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, hydroxyalkyl, thioalk heterocyclyl, alkoxy, aryl, aryloxy, aralkoxy, heteroaryl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, amino, alkylamino, arylamino or aralkylamino; Alk ¹ is C _1-6 alkylene; Alk ² is C _1-2 alkylene; Ar ¹ represents an arylene, heteroarylene, or divalent heterocyclic group, optionally substituted with one or more halogen, C _1-6 alkyl, amino, hydroxy, C _1-6 alkoxyl or aryl; Ar ² represents an aryl group optionally substituted with one or more halogen, C _1-6 alkyl, amino, hydroxy, C _1-6 alkoxyl or aryl; a heteroaryl or heterocyclyl group optionally substituted with one or more halogen, C _1-6 alkyl, amino, hydroxy, C _1-6 alkoxyl or aryl. 2. The compound according to claim 1, where ring A is a 6 membered aromatic ring; ring B is a 6 membered aromatic ring; X is a valence bond, CH ₂ CH ₂ , CH = CH, O or S; R ¹ is H or alkyl; R ² is H or alkyl; R ³ is H or alkyl; R ⁴ and R ⁵ are independently H or alkyl; Alk ¹ is C _2-3 alkylene; Alk ² is C _1-2 alkylene; Ar ¹ is an arylene group; Ar ² is a substituted aryl group. 3. The compound according to claim 1, where ring A is a 6 membered aromatic ring; ring B is a 6 membered aromatic ring; X is a valence bond, CH ₂ CH ₂ , CH = CH, O or S; R ¹ is H or alkyl; R ² is H or alkyl; R ³ is H or alkyl; R ⁴ and R ⁵ form a 6-membered aromatic ring; Alk ¹ is C _2-3 alkylene; Alk ² is C _1-2 alkylene; Ar ¹ is a 6 membered aromatic ring; Ar ² is a substituted aryl group. 4. The compound according to claim 1, where ring A is a benzene ring; ring B is a benzene ring; X is a valence bond, CH ₂ CH ₂ , CH = CH, O or S; R ¹ is H; R ² is H; R ³ is H; R ⁴ is methyl; R ⁵ is H; Alk ¹ is CH ₂ CH ₂ ; Alk ² is CH ₂ ; Ar ¹ is a benzene ring; Ar ² is a benzene ring optionally substituted with one or more fluorine. 5. The compound according to claim 1, where ring A is a benzene ring; ring B is a benzene ring; X is a valence bond, CH ₂ CH ₂ , CH = CH, O or S; R ¹ is H; R ² is H; R ³ is H; R ⁴ and R ⁵ form a benzene ring; Alk ¹ is CH ₂ CH ₂ ; Alk ² is CH ₂ ; Ar ¹ is a benzene ring; Ar ² is a benzene ring optionally substituted with one or more fluorine. 6. The compound according to claim 1, where ring A is a benzene ring; ring B is a benzene ring; X is a valence bond, CH ₂ CH ₂ , CH = CH, O or S; R ¹ is H; R ² is H; R ³ is H; R ⁴ is methyl; R ⁵ is H; Alk ¹ is CH ₂ CH ₂ ; Alk ² is CH ₂ ; Ar ¹ is a benzene ring; Ar ² is a pyridine ring optionally substituted with one or more halogen. 7. The compound according to claim 1, where ring A is a benzene ring; ring B is a benzene ring; X is a valence bond, CH ₂ CH ₂ , CH = CH, O or S; R ¹ is H; R ² is H; R ³ is H; R ⁴ and R ⁵ form a benzene ring; Alk ¹ is CH ₂ CH ₂ ; Alk ² is CH ₂ ; Ar ¹ is a benzene ring; Ar ² is a pyridine ring optionally substituted with one or more fluorine. 8. The method of obtaining the compounds of formula I

wherein ring A and ring B fused to a ring containing X and N each independently represent a 5-6 membered ring, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen, and may optionally be substituted by one or more halogen, hydroxy, nitro, cyano, alkyl, alkenyl, alkenyl, aralkyl, heteroarylalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, hydroxyalkyl, thioalkyl, heterocyclyl, alkoxy, aryl, aryl heteroaryl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, amino, alkylamino, arylamino or aralkylamino; ring A and ring B may be saturated or contain one or more double bonds or may be aromatic; X is a valence bond, CH ₂ CH ₂ , CH = CH, O, S, or NR ⁶ , where R ⁶ is H, alkyl, alkenyl, alkenyl, aralkyl, heteroarylalkyl, heterocyclyl, aryl or heteroaryl; R ¹ represents H, alkyl, alkenyl, alkenyl, aralkyl, heteroarylalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, hydroxyalkyl, thioalkyl, heterocyclyl, OH, halogen, alkoxy, aryl, aryloxy, aralkoxy, heteroaryl, heteroaryl acyloxy, amino, alkylamino, arylamino or aralkylamino; R ² represents H, alkyl, alkenyl, alkenyl, aralkyl, heteroarylalkyl, heterocyclyl, aryl or heteroaryl; R ³ represents H, alkyl, alkenyl, alkenyl, aralkyl, heteroarylalkyl, heterocyclyl, aryl or heteroaryl; R ⁴ and R ⁵ independently are H, alkyl, alkenyl, alkenyl, aralkyl, heteroarylalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, hydroxyalkyl, thioalkyl, heterocyclyl, OH, halogen, alkoxy, aryl, aryloxy, aryloxy, aryloxy, aryloxy, heteroaralkoxy, acyl, acyloxy, amino, alkylamino, arylamino or aralkylamino; R ⁴ and R ⁵ may form a 5- or 6-membered ring optionally substituted with one or more halogen, hydroxy, nitro, cyano, alkyl, alkenyl, alkenyl, aralkyl, heteroarylalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, hydroxyalkyl, thioalk heterocyclyl, alkoxy, aryl, aryloxy, aralkoxy, heteroaryl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, amino, alkylamino, arylamino or aralkylamino; Alk ¹ is C _1-6 alkylene; Alk ² is C _1-2 alkylene; Ar ¹ represents an arylene, heteroarylene, or divalent heterocyclic group, optionally substituted with one or more halogen, C _1-6 alkyl, amino, hydroxy, C _1-6 alkoxyl or aryl; Ar ² represents an aryl group optionally substituted with one or more halogen, C _1-6 alkyl, amino, hydroxy, C _1-6 alkoxyl or aryl; heteroarylene, or a divalent heterocyclic group, optionally substituted with one or more halogen, C _1-6 alkyl, amino, hydroxy, C _1-6 alkoxyl or aryl, its stereoisomer, enantiomer, diastereomer, hydrate, or pharmaceutically acceptable salts thereof, comprising the steps of a) initiating a condensation reaction between compound 1 and β-diketone 2 to obtain analogs of the vinyl amide series 3

b) performing O-alkylation 3 to give compound 4

c) performing N-alkylation 4 to give substituted arylalkanoic acid derivatives 6

9. The production method of claim 8, in which (a) a condensation reaction is carried out in ethanol at reflux temperature; (b) O-alkylation is achieved by treating compound 3 KOH and dibromoalkane in ethanol; (c) N-alkylation is achieved by treating compound 4 with NaOH and compound 5 in the presence of tetrabutylammonium bromide. 10. The compound of claim 1, wherein said compound is a RAPP pan agonist activating PXP / RAPPalfa, PXP / RAPPgamma, and PXP / RAPPdelta heterodimers. 11. The compound of claim 10, wherein said compound is a partial RAPP pan agonist activating PXP / RAPPalfa, PXP / RAPPgamma, and PXP / RAPP delta heterodimers to various degrees. 12. A pharmaceutical composition for activating nuclear receptors, comprising an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof with at least one pharmaceutically acceptable carrier or diluent. 13. The pharmaceutical composition of claim 11, wherein the nuclear receptors include a Retinoid X Receptor (PXR) and peroxisomal proliferator activated receptors (RAPP). 14. The pharmaceutical composition according to item 12 in a standard (dosage) dosage form containing from about 0.05 to about 200 mg of the compound. 15. The pharmaceutical composition according to 14, in a standard (dosage) dosage form containing from about 0.1 to about 100 mg of the compound. 16. The pharmaceutical composition according to item 12, suitable for oral, intranasal, transdermal, pulmonary (inhalation) or parenteral administration. 17. A method of treating or preventing a condition caused by at least one nuclear receptor, comprising administering to a subject in need thereof an effective amount of a compound of formula I

wherein ring A and ring B fused to a ring containing X and N each independently represents a 5-6 membered ring ring, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen, and may optionally substituted with one or more halogen, hydroxy, nitro, cyano, alkyl, alkenyl, alkenyl, aralkyl, heteroarylalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, hydroxyalkyl, thioalkyl, heterocyclyl, alkoxy, aryl, aralkoxy, heteroaryl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, amino, alkylamino, arylamino or aralkylamino; ring A and ring B may be saturated or contain one or more double bonds or may be aromatic; X represents a valence bond, CH ₂ CH ₂ , CH = CH, O, S, or NR ⁶ , where R ⁶ represents H, alkyl, alkenyl, alkenyl, aralkyl, heteroarylalkyl, heterocyclyl, aryl or heteroaryl; R ¹ represents H, alkyl, alkenyl, alkenyl, aralkyl, heteroarylalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, hydroxyalkyl, thioalkyl, heterocyclyl, OH, halogen, alkoxy, aryl, aryloxy, aralkoxy, heteroaryl, heteroaryl acyloxy, amino, alkylamino, arylamino or aralkylamino; R ² represents H, alkyl, alkenyl, alkenyl, aralkyl, heteroarylalkyl, heterocyclyl, aryl or heteroaryl; R ³ represents H, alkyl, alkenyl, alkenyl, aralkyl, heteroarylalkyl, heterocyclyl, aryl or heteroaryl; R ⁴ and R ⁵ independently are H, alkyl, alkenyl, alkenyl, aralkyl, heteroarylalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, hydroxyalkyl, thioalkyl, heterocyclyl, OH, halogen, alkoxy, aryl, aryloxy, aryloxy, aryloxy, aryloxy, heteroaralkoxy, acyl, acyloxy, amino, alkylamino, arylamino or aralkylamino; R ⁴ and R ⁵ may form a 5- or 6-membered ring optionally substituted with one or more halogen, hydroxy, nitro, cyano, alkyl, alkenyl, alkenyl, aralkyl, heteroarylalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, hydroxyalkyl, thioalk heterocyclyl, alkoxy, aryl, aryloxy, aralkoxy, heteroaryl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, amino, alkylamino, arylamino or aralkylamino; Alk ¹ is C _1-6 alkylene; Alk ² is C _1-2 alkylene; Ar ¹ represents an arylene, heteroarylene, or divalent heterocyclic group, optionally substituted with one or more halogen, C _1-6 alkyl, amino, hydroxy, C _1-6 alkoxyl or aryl; Ar ² represents an aryl group optionally substituted with one or more halogen, C _1-6 alkyl, amino, hydroxy, C _1-6 alkoxyl or aryl; heteroaryl, or a heterocyclic group, optionally substituted with one or more halogen, C _1-6 alkyl, amino, hydroxy, C _1-6 alkoxyl or aryl. 18. The method according to 17, where the nuclear receptors include Retinoid X Receptor (RXR) and receptors activated by peroxisomal proliferator (RAPP). 19. A method of treating or preventing a condition caused by reduced activity of at least one nuclear receptor, comprising administering to a subject in need thereof an effective amount of a compound of formula I

wherein ring A and ring B fused to a ring containing X and N each independently represents a 5-6 membered ring ring, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen, and may optionally substituted with one or more halogen, hydroxy, nitro, cyano, alkyl, alkenyl, alkenyl, aralkyl, heteroarylalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, hydroxyalkyl, thioalkyl, heterocyclyl, alkoxy, aryl, aralkoxy, heteroaryl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, amino, alkylamino, arylamino or aralkylamino; ring A and ring B may be saturated or contain one or more double bonds or may be aromatic; X represents a valence bond, CH ₂ CH ₂ , CH = CH, O, S or NR ⁶ , where R ⁶ represents H, alkyl, alkenyl, alkenyl, aralkyl, heteroarylalkyl, heterocyclyl, aryl or heteroaryl; R ¹ represents H, alkyl, alkenyl, alkenyl, aralkyl, heteroarylalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, hydroxyalkyl, thioalkyl, heterocyclyl, OH, halogen, alkoxy, aryl, aryloxy, aralkoxy, heteroaryl, heteroaryl acyloxy, amino, alkylamino, arylamino or aralkylamino; R represents H, alkyl, alkenyl, alkenyl, aralkyl, heteroarylalkyl, heterocyclyl, aryl or heteroaryl; R ³ represents H, alkyl, alkenyl, alkenyl, aralkyl, heteroarylalkyl, heterocyclyl, aryl or heteroaryl; R ⁴ and R ⁵ independently are H, alkyl, alkenyl, alkenyl, aralkyl, heteroarylalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, hydroxyalkyl, thioalkyl, heterocyclyl, OH, halogen, alkoxy, aryl, aryloxy, aryloxy, aryloxy, aryloxy, heteroaralkoxy, acyl, acyloxy, amino, alkylamino, arylamino or aralkylamino; R ⁴ and R ⁵ may form a 5- or 6-membered ring optionally substituted with one or more halogen, hydroxy, nitro, cyano, alkyl, alkenyl, alkenyl, aralkyl, heteroarylalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, hydroxyalkyl, thioalk heterocyclyl, alkoxy, aryl, aryloxy, aralkoxy, heteroaryl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, amino, alkylamino, arylamino or aralkylamino; Alk ¹ is C _1-6 alkylene; Alk ² is C _1-2 alkylene; Ar represents an arylene, heteroarylene, or divalent heterocyclic group, optionally substituted with one or more halogen, C _1-6 alkyl, amino, hydroxy, C _1-6 alkoxyl or aryl; Ar represents an aryl group optionally substituted with one or more halogen, C _1-6 alkyl, amino, hydroxy, C _1-6 alkoxyl or aryl; heteroaryl, or a heterocyclic group, optionally substituted with one or more halogen, C _1-6 alkyl, amino, hydroxy, C _1-6 alkoxyl or aryl. 20. The method according to claim 19, where the specified condition is selected from the group consisting of type 1 diabetes, type 2 diabetes, dyslipidemia, syndrome X, cardiovascular disease, atherosclerosis, hypercholesterolemia and obesity. 21. The method according to claim 20, where the effective amount of the compound is in the range from about 0.05 to about 200 mg / kg body weight per day. 22. The method according to item 21, where the effective amount of the compound is in the range from about 0.1 to about 100 mg / kg body weight per day. 23. The method according to item 22, where the effective amount of the compound is in the range from about 0.1 to about 50 mg / kg body weight per day. 24. The method of treating or preventing the condition of claim 19, comprising administering to a subject in need thereof an effective amount of a compound in combination with at least one agent selected from the group consisting of a lipid-lowering agent, a lipid lowering agent, an agent modulating the content of lipids, an antidiabetic agent, an agent for obesity, an antihypertensive agent and an inhibitor of platelet aggregation; which can be administered orally in the same standard (dosage) form, in a separate oral dosage form, or as an injection. 25. The method of treating or preventing the condition of claim 24, wherein the lipid-lowering agent or lipid lowering agent or lipid modulating agent is selected from the group consisting of at least one MTP inhibitor, an HMG-CoA reductase inhibitor, an inhibitor squalene synthetase, fibrous acid derivative, ACAT inhibitor, lipoxygenase inhibitor, cholesterol absorption inhibitor, co-transporter (inhibitor) Na ⁺ / ileal bile acid, positive regulator of LDL receptor activity, sequestran t bile acid; and nicotinic acid or derivatives thereof. 26. The method of treating or preventing the condition of claim 24, wherein the at least one antidiabetic agent is selected from the group consisting of an insulin secretion stimulator, an insulin sensitizing agent, a biguanide, a sulfonylurea, a glycosidase inhibitor, a partial agonist or antagonist of RAPP γ, thiazolidinedione , P2 inhibitor, dipeptidyl peptidase IV (DP4) inhibitor, SGLT2 inhibitor, meglitinide, insulin, glucagon-like peptide-1 (GLP-1). 27. The method of treating or preventing the condition according to paragraph 24, where at least one agent is selected from the group comprising an anti-obesity agent, beta-3-adrenergic agonist, lipase inhibitor, serotonin (and dopamine) reuptake inhibitor, P2 inhibitor , thyroid receptor agonist and anorectic (anorexigenic) agent. 28. The method of treating or preventing the condition of claim 24, wherein the at least one antihypertensive agent is selected from the group consisting of an ACE inhibitor, an angiotensin II receptor antagonist, a NEP / ACE inhibitor, a calcium channel blocker, a β-adrenergic receptor blocker, and a diuretic .