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  • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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  • 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
  • C07D333/06—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—Ortho-condensed systems

Definitions

• the present invention generally relates to compounds interacting with retinoid binding proteins, and more particularly to compounds that interact selectively with retinoid X receptors ("RXRs”) as well as methods for their production and therapeutic use.
• RXRs retinoid X receptors
• RARs and RXRs have distinct differences in their tissue distribution.
• RARs are expressed at high levels in visceral tissues, whereas RXR ⁇ is most abundant in the liver, kidney, lung, muscle, and intestine.
• RXR ⁇ is most abundant in the liver, kidney, lung, muscle, and intestine.
• X is CR 1 or N, where R 1 is halogen, H, or CH 3 ; Z is O, S, or NH; M is N, C, or CR 2 , when M is N, the A ring is non-aromatic, when M is C, the A ring is aromatic, when M is CR 2 , then R 2 is H or - Y(CH 2 ) n R 6 , and the A ring is non-aromatic; Y is O or CH 2 ; when n is 0 to 6, R 6 is H, alkyl, or CF 3 , but when n is 2 to 5, R 6 is H, alkyl, CF 3 , SO 2 NHR 23 , NHSO 2 R 23 , or NR 23 R 24 , where R 23 is alkyl, aryl optionally substituted, heteroaryl optionally substituted or combined with R 24 to form a ring of 3 -7
• J is CHO, CO 2 R 7 , SQR 7 , PO3R 7 , CONHOH, or J forms a thiazolidinedione ring with R 8 ;
• R 7 is H or alkyl;
• R 8 and R 9 are independently H, halogen, alkyl, or CF 3 ;
• y and z are each 0, 1 , or 2;
• Q is CR 4 , CR 4 R 5 , O, NR 10 , or S, where R 4 and R 5 are independently H or alkyl, provided that when Q is CR 4 , the A ring is aromatic;
• R 10 is alkyl, COR 11 , CONHR 11 , CO 2 R 11 , CONR 11 R 12 , SO 2 R 11 , aryl, or cycloalkyl;
• R 1 and R 12 are independently alkyl or cycloalkyl;
• R 3 is
• each R 19 is, independently, H or alkyl; y and z are as defined above; or R 3 is
• each R 18 is, independently, as defined above; and M3 is C-(R 16 ) 3 or N-(R 16 ) 2 , when M3 is N-(R 16 ) 2 , an R 16 may combine with an R 18 to form a 5- or 6-membered ring.
• said alkyl is C 1-5 alkyl; when R 6 is alkyl, said alkyl is C 1-6 alkyl; when R 7 is alkyl, said alkyl is C 1-5 alkyl; when either R 8 or R 9 or both are alkyl, said alkyl is C 1-3 alkyl; when R 10 is alkyl, said alkyl is C 1-6 alkyl; when either R 11 or R 12 or both are alkyl, said alkyl is C 1-5 alkyl; when either R 13 or R 14 or both are alkyl, said alkyl is C 1-3 alkyl; when R 5 is alkyl, said alkyl is C M alkyl; when either R 16 or R 17 or both are alkyl, said alkyl is C 1-4 alkyl; when R 18 is alkenyl, said alkenyl is C 1- alkenyl; when R 18 is alkyl, said alkyl is C 1-4 alkyl; when R 18 is alkenyl, said alkenyl is C 1-
• X is CH
• Z is O
• Q is CH 2
• M is CH
• G is
• X is CR 1 or N, where R 1 is halogen, H, or CH 3 ;
• Z is O, S, or NH;
• G is CO 2 R 7 , SQR 7 , PO 3 R 7 , CONHOH, or
• J is CHO, CO 2 R 7 , SQR 7 , PO 3 R 7 , CONHOH, or J forms a thiazolidinedione ring with R 8 ;
• R 7 is H or C 1-5 alkyl;
• R 8 and R 9 are independently H, halogen, C 1-3 alkyl, or CF 3 ;
• y and z are each 0, 1 , or 2;
• R 3 is
• R is as defined above; or R is
• R 18 is as defined above; and M3 is C-(R 16 ) 3 or N-(R 16 ) 2 , when M3 is N-(R 16 ) 2 , an R 16 may combine with an R 18 to form a 5- or 6-membered ring;
• R 20 is H or C 1-4 alkyl;
• R 21 is H, OR 6 , where R 6 is as defined for Formula I, or may combine with R 22 to form a carbonyl; and R 22 is H, or may combine with R 21 to form a carbonyl.
• J is CO 2 H
• R 8 and R 9 are each H
• y and z are each 1
• the double bond exists
• the olefin geometry is trans.
• R 3 is where D is CR 13 R 14 ; R 13 , R 4 , R 16 , and R 17 are each methyl; and R 18 is H.
• Particularly preferred compounds of formula II include:
• Another aspect of the present invention includes methods for treating, including treatment and prophylaxis, a disorder in a mammal, wherein the disorder is characterized by the need for retinoid therapym through the administration to the mammal an effective amount of a compound of formula I or II.
• disorders characterized by the need for retinoid therapy and therefore included herein, but without exclusion include metabolic conditions and disorders, dermatological conditions, cancerous and pre-cancerous conditions, hyperthyroidism, dyslipidemia, and hypertension.
• the disorder is diabetes or obesity.
• Another aspect of the present invention includes compounds of formulas I or II for use as an active therapeutic substance. Preferably such use is for retinoid therapy.
• Another aspect of the present invention includes the use of a compound of formulas I or II in the manufacture of a medicament for use in retinoid therapy, preferably for use in the treatment or prophylaxis of diabetes or obesity.
• Another aspect of the present invention includes compounds of formulas I or
• Another aspect of the present invention includes a method for manufacturing a retinoid comprising: a) reacting a compound of Formula III, Formula IV, a combination of Formulas
• cycloalkyl represents a saturated carbon chain forming a ring and includes, but should not be limited to cyclopropyl, cyclobutyl, cyclopentyl, and the like.
• carbonyl refers to the group -C(O)-.
• R 21 and R 22 combine to form a carbonyl the following example compounds are referred to:
• the present invention includes salts, solvates, and physiologically functional derivatives of the compounds of the present invention.
• Salts include addition salts, metal salts, or optionally alkylated ammonium salts, such as hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, trifluoroacetic, trichloroacetic, oxalic, maleic, pyruvic, malonic, succinic, citric, mandelic, benzoic, cinnamic, methane sulphonic, ethane sulphonic, picric and the like. Salts also include acids related to the salts listed within Journal of Pharmaceutical Science 1997, 66, 2 , incorporated herein by reference as relevant to salts. Further acceptable salts include lithium, sodium, potassium, magnesium, and the like.
• solvate refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula I or II, or a salt or physiologically functional derivative thereof) and a solvent.
• solvents for the purpose of the invention, should not interfere with the biological activity of the solute.
• suitable solvents include, but are not limited to water, methanol, ethanol, and acetic acid.
• the solvent used is a pharmaceutically acceptable solvent.
• suitable pharmaceutically acceptable solvents include water, ethanol, and acetic acid. Most preferably the solvent used is water.
• the term "effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought, for instance, by a researcher or clinician.
• therapeutically effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
• the term also includes within its scope amounts effective to enhance normal physiological function.
• a therapeutically effective amount of a compound of the present invention will depend upon a number of factors including, for example, the age and weight of the animal, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration. Therapeutic effectiveness ultimately will be at the discretion of the attendant physician or veterinarian. Generally, however, an effective amount of a compound of formula (I) or (II) for RXR mediated diseases and conditions should be in the range of about 0.1 to about 100 mg/kg body weight of recipient (mammal, preferably human) per day. Preferably the effective amount will be in the range of 0.5 to 10 mg/kg body weight per day. More preferably in the range of about 1 to 5 mg/kg body weight per day. An effective amount of a salt or solvate, or physiologically functional derivative thereof, may be determined as a proportion of the effective amount of the compound of formula (I) or (II) per se.
• compositions of the present invention include those especially formulated for oral, buccal, parental, transdermal, inhalation, intranasal, transmucosal, implant, or rectal administration. Among the variety of administrations, oral administration typically is preferred. For buccal administration, the formulation may take the form of tablets or lozenges formulated in conventional manner.
• formulations of the present invention may be formulated for parenteral administration by injection or continuous infusion.
• Formulations for injection may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
• the active ingredient may be in powder form for constitution with a suitable vehicle, for example, sterile, pyrogen-free water, before use.
• E represents either bromine, preferably, or iodine and, as is relevant throughout this description, wherein D, M3, R 16 , R 17 , and R 18 are defined as above for formula I.
• Compounds of formula II can be prepared by reacting a compound of Formula XVII, wherein X, Z, and R 20 are defined as before, with compounds of Formula V, VI or VII, shown above, where E is as hereinabove defined.
• a toluene solution (10 mL) was mixed with 4-(5,5,8,8-tetramethyl-5,6,7,8- tetrahydro-2-naphthalenyl)-4,5,6,7-tetrahydro-1-benzofuran]-2-carboxaldehyde (100 mg, 0.30 mmol), 2,5-thiazolidinedione (62 mg, 0.53 mmol), morpholine (200 mg, 2.3 mmol), molecular sieves and 10 mL of anhydrous toluene.
• the reaction mixture was stirred at reflux for 4.0 hours at which time it was cooled to 0-5 °C.
• the resulting yellow solid was filtered in vacuo and washed with 10 mL of cold toluene.
• the resulting solid was dried in vacuo for 17 hours to afford 34 mg of pure solid.
• the reaction was allowed to warm to RT where it stirred for 4.0 hours followed by quenching via the addition of 1.0 N HCI (20 mL).
• the reaction mixture was extracted using ether.
• the organics were separated and dried over MgSO 4 followed by concentrating to dryness.
• the resulting oil was chromatographed on silica gel (90%hexanes/10% ethyl acetate) to afford 487 mg of pure oil.
• the resulting mixture was made acidic using 3.0 N HCI.
• the reaction mixture was then extracted into ether and dried over MgSO 4 .
• the mixture was concentrated to dryness and chromatographed on silica gel (80%hexanes/ 20%EtOAc) yielding 45 mg of pure acid.
• the reaction was allowed to warm to RT where it stirred for 7 hours.
• the reaction was quenched by the addition of 1.0 N HCI (100 mL).
• the reaction mixture was extracted using ether.
• the organics were separated and dried over MgSO 4 followed by concentrating to dryness.
• the resulting oil was dried under high vacuum to give a total of 8.2 g (100%) of crude oil.
• the product was used without further purification.
• the magnesium turnings were agitated until the Grignard salt began to form.
• the formation was allowed to proceed for a period of 1.0 hour.
• the reaction mixture was mixed with a THF solution (25 mL) of compound B (3.5 g, 0.0129 moles).
• the reaction was allowed to warm to RT over a period of 1.0 hour and was then cooled to 0-5 °C.
• the reaction was slowly quenched with water.
• the aqueous mixture was neutralized (pH 7.0) with dilute HCI and extracted with ether.
• the organics were dried over MgSO and concentrated to afford a crude oil.
• the oil was purified using silica gel chromatography (90%hexanes/10% EtOAc) to yield a total of 2.6 g of pure oil (53%).
• Binding Assay The compounds were tested for their ability to bind to hRXR ⁇ using a
• SPA Scintillation Proximity Assay
• the RXR ⁇ ligand binding domain (LBD) was expressed in E. coli as an amino-terminal polyhistidine tagged fusion protein. The LBD was then labeled with biotin and immobilized on streptavidin-modified scintillation proximity beads. 9-cis[3H]-Retinoic acid (9-cis) was the radioligand used for the assay. To each well to be assayed was added the desired concentration of the previously prepared solution of 9-cis previously incubated with receptor-coated SPA bead slurry.
• the plates were incubated for at least 1 hour at room temperature and bound radioactivity for each well was determined in a Wallac 1450 Microbeta counter.
• Transfection mixes contained 4 ng of receptor expression vector, 8 ng of reporter plasmid, 25 ng of ⁇ -galactosidase expression vector (used as an internal control), and 43 ng of carrier plasmid. Transfections were performed with Lipofectamine according to the manufacturer's instructions. Drug dilutions were prepared in phenol red-free DMEM/F-12 with 15 mM HEPES supplemented with 10% charcoal-stripped, delipidated calf serum. Cells were incubated for 24 h in the presence of drugs, after which the medium was sampled and assayed for SPAP activity.
• B-galactosidase which measures transfection efficiency activity, was determined by using 3.6 mM o-nitrophenyl-D-galactopyranoside in 0.1 M sodium phosphate pH 7.2 buffer containing 0.13% Triton X-100 as substrate. These plates were read on a Molecular Devices Vmax spectrophotometer, at a 405nm endpoint reading. Data were reduced using RoboFit.
• pEC 50 values were > 6.0 for all examples with the exception of Examples 13, 18, and 19, which each had pEC 50 ⁇ 6.0.

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