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  • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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  • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
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  • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
  • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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  • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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  • C07D285/01—Five-membered rings
  • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
  • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
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  • C07D285/01—Five-membered rings
  • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
  • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
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  • C07D285/01—Five-membered rings
  • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
  • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
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  • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
  • C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no 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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  • C07D307/34—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
  • 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
  • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
  • C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms

Definitions

• LTB4 Leukotriene B4 Receptor Antagonists: A Series of (Hydroxyphenyl)pyrazoles" by Richard W. Harper, et . al . , J. Med Chem, 1994, 37, pgs . 2411-2420.
• Leukotriene B4 antagonists inclusive of diphenyl ethers such as 2- [2-propyl-3- [3- [2-ethyl-5-hydroxy-4- (4- fluorophenyl)phenoxy] propoxy] phenoxy] benzoic acid, are described in United States Patent No. 5,462,954, the disclosure of which is incorporated herein by reference.
• diphenyl ether leukotriene B antagonists in combination with a 2 ' , 2 ' -difluoronucleoside analog (e.g., GEMCITABINE HCl) , have also been found to have utility in the treatment of various cancers, as further described in Provisional Patent Application Serial Number 60/164786, filed 11 November 1999, the disclosure of which is incorporated herein by reference.
• a 2 ' , 2 ' -difluoronucleoside analog e.g., GEMCITABINE HCl
• Another aspect of this invention is a method of using the compounds of the invention in the prevention and treatment of LTB4 induced illnesses.
• the present invention is directed to novel heterocyclic substituted diphenyl compounds of formula (I)
• Z is an Acidic Group
• a “substituted heterocyclic radical” is preferably Substitued with from 1 to 3 groups independently selected from hydrogen, halo, C -CI Q alkyl, CI-CIQ haloalkyl, CI-CIQ alkoxy, aryl, or C -C20 aryloxy.
• Preferred Group 1 of X substituent symbol, "PG1-X"
• X substituents are the heterocyclic radicals
• Preferred compounds of the invention are those wherein Yl is a divalent linking group selected from the group consisting of substituents represented by the following formulae :
• the Y2 and Y3 substituents are preferably selected from -S- and -0- .
• Preferred R4 substituents are ethyl, propyl, and isopropyl .
• R14 describes a substituent combinatorial choice for Formula (I) wherein Rl is selected from the preferred set of variables, "PG1-R1", that is, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and 2-propenyl; the R2 substituent is selected from the preferred set of variables, "PG1-R2", that is, hydrogen or methyl, ethyl, methoxy, ethoxy, halo, or -CF3 ; the variable R3 has the scope defined in the generic formula (I) , and the substituents suitable for R4 are selected from the preferred group, "PG1-R4" having the preferred set of variables, ethyl, propyl, and isopropyl.
• Y-Table is used to select broad and preferred groupings of the variables Yl, Y2 , and Y3 for substitution in formula (I), as follows:
• Z2 is carboxyl, tetrazolyl, N-sulfonamidyl .
• esters as prodrugs are methyl, ethyl, propyl, isopropyl, n- butyl, isobutyl, tert-butyl, morpholinoethyl, and N,N- diethylglycolamido .
• Known chloride (26) may be alkylated with benzyl bromide to provide chloride (28) .
• Reaction with known ester (30) catalyzed by a suitable base, provides acetophenone (32) .
• Oxidation with bis (trifluoroacetoxy) iodobenzene gives alpha- hydroxy ketone (34), that may be cyclized with triflic anhydride and formamide to give the 4-substituted oxazole (36) .
• Debenzylation with boron trifluoride etherate and ethanethiol gives oxazole (38), that is hydrolyzed and protonated to provide Example (1).
• Example (7) a 1-substituted pyrrole LTB 4 receptor antagonist:
• Example 9 Preparation of 2- ⁇ 3- [3- (2-Ethyl-5-hydroxy-4-thiophen-2-yl- phenoxy)propoxy] -2-propyl-phenoxy ⁇ benzoic acid sodium salt.
• A. Preparation of 2- ⁇ 3- [3- (2-ethyl-5-hydroxy-4-thiophen-2- yl-phenoxy)propoxy] -2-propylphenoxy ⁇ benzoic acid methyl ester.
• the reaction mixture was diluted with water, concentrated in vacuo, and extracted with diethyl ether.
• the organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo.
• the residue was triturated twice with hexane and the residue dissolved in methanol (5 mL) .
• This solution was treated with 1 N lithium hydroxide solution (5 mL) at -95 °C for 2 h.
• the mixture was concentrated in vacuo and the residue diluted with water, washed twice with diethyl ether, and the aqueous layer acidified with 1 N hydrochloric acid.
• the resulting solution was extracted with diethyl ether.
• the organic layer was dried (magnesium sulfate) , filtered, and concentrated in vacuo. Chromatography (silica gel, 10% methanol/90% methylene chloride) provided 338 mg (57%) of
• the aqueous layer was acidified with concentrated hydrochloric acid and the resulting solution extracted with ethyl acetate.
• the ethyl acetate layer was washed once with water, once with saturated sodium chloride solution, dried (sodium sulfate), filtered, and concentrated in vacuo.
• the resulting colorless oil was dissolved in diethyl ether and treated with 1 N aqueous sodium hydroxide solution (1.72 mL) .
• the resulting biphasic mixture was diluted with chloroform and concentrated in vacuo. Diethyl ether was added and the mixture concentrated in vacuo.
• the resulting white foam was dried in vacuo at room temperature for 60 h to provide 0.78 g (84%) of the title compound: mp 67-71 °C.
• compositions of the Invention Preferably compounds of the invention (per Formulae I or II) or pharmaceutical formulations containing these compounds are in unit dosage form for administration to a mammal.
• the unit dosage form can be a capsule, an IV bag, a tablet, or a vial.
• the quantity of Active Ingredient in a unit dose of composition is a therapeutically effective amount and may be varied according to the particular treatment involved. It may be appreciated that it may be necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration.
• the compound can be administered by a variety of routes including oral, aerosol, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal.
• Pharmaceutical formulations of the invention are prepared by combining (e.g., mixing) a therapeutically effective amount of the compounds of the invention (e.g., compounds of Formula I, II) together with a pharmaceutically acceptable carrier or diluent therefor.
• the present pharmaceutical formulations are prepared by known procedures using well known and readily available ingredients .
• the Active Ingredient will usually be admixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container.
• a carrier which may be in the form of a capsule, sachet, paper or other container.
• the carrier serves as a diluent, it may be a solid, lyophilzed solid or paste, semi-solid, or liquid material which acts as a vehicle, or can be in the form of tablets, pills, powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium) , or ointment, containing, for example, up to 10% by weight of the active compound.
• the compounds of the present invention are preferably formulated prior to administration.
• the carrier may be a solid, liquid, or mixture of a solid and a liquid.
• the compounds of the invention may be dissolved in at a concentration of about 0.05 to about 5.0 mg/ml in a 4% dextrose/0.5% Na citrate aqueous solution.
• Solid form formulations include powders, tablets and capsules.
• a solid carrier can be one or more substances which may also act as flavoring agents, lubricants, solubilisers, suspending agents, binders, tablet disintegrating agents and encapsulating material.
• Tablets for oral administration may contain suitable excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, together with disintegrating agents, such as maize, starch, or alginic acid, and/or binding agents, for example, gelatin or acacia, and lubricating agents such as magnesium stearate, stearic acid, or talc.
• suitable excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate
• disintegrating agents such as maize, starch, or alginic acid
• binding agents for example, gelatin or acacia
• lubricating agents such as magnesium stearate, stearic acid, or talc.
• the carrier is a finely divided solid which is in admixture with the finely divided Active Ingredient.
• the Active Ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
• Powders and tablets preferably contain from about 1 to about 99 weight percent of the Active Ingredient which is the novel compound of this invention.
• Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low melting waxes, and cocoa butter.
• Sterile liquid form formulations include suspensions, emulsions, syrups and elixirs.
• the Active Ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent or a mixture of both.
• a pharmaceutically acceptable carrier such as sterile water, sterile organic solvent or a mixture of both.
• pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
• the Active Ingredient can also be dissolved in a suitable organic solvent, for instance aqueous propylene glycol.
• suitable organic solvent for instance aqueous propylene glycol.
• Other compositions can be made by dispersing the finely divided Active Ingredient in aqueous starch or sodium carboxymethyl cellulose solution or in a suitable oil.
• Active Ingredient refers to a compound according to Formula (I) or (II) or a pharmaceutically acceptable salt, solvate, or prodrug thereof .
• Hard gelatin capsules are prepared using the following ingredients :
• Formulation 2 A tablet is prepared using the ingredients below:
• Formulation 3 An aerosol solution is prepared containing the following components :
• Formulation 4 Tablets each containing 60 mg of Active Ingredient, are made as follows:
• Formulation 6 Suppositories, each containing 225 mg of Active Ingredient, are made as follows:
• the Active Ingredient is passed through a No . 60 U.S. sieve (250 ⁇ m) and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2g capacity and allowed to cool.
• Formulation 7 Suspensions, each containing 50 mg of Active Ingredient per 5 ml dose, are made as follows:
• the Active Ingredient is passed through a No . 45 mesh U.S. sieve (355 ⁇ m) and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste.
• the benzoic acid solution, flavor and color are diluted with a portion of the water and added, with stirring. Sufficient water is then added to produce the required volume.
• Formulation 8 An intravenous formulation may be prepared as follows:
• the solution of the above materials generally is administered intravenously to a subject at a rate of 1 ml per minute.
• This invention is a method for preventing or treating LTB4 induced inflammation in a mammal by contacting the LTB4 in a mammal with an LTB4 antagonizing amount of the heterocyclic substituted diphenyl compounds of the invention (as per formula I or II) or a salt, solvate or prodrug of said compounds.
• Another aspect of this invention is a method for preventing or treating Inflammatory Diseases such as inflammatory bowel disease, septic shock, adult respiratory distress syndrome, panceatitis, trauma, bronchial asthma, allergic rhinitis, rheumatoid arthritis, osteoarthritis, and related diseases which comprises administering to a mammal (including a human) a therapeutically effective dose of heterocyclic substituted diphenyl compounds of the invention (as per formula I or II) or a salt, solvate or prodrug of said compounds.
• Inflammatory Diseases such as inflammatory bowel disease, septic shock, adult respiratory distress syndrome, panceatitis, trauma, bronchial asthma, allergic rhinitis, rheumatoid arthritis, osteoarthritis, and related diseases
• a mammal including a human
• a therapeutically effective dose of heterocyclic substituted diphenyl compounds of the invention as per formula I or II
• a salt, solvate or prodrug of said compounds
• Typical daily doses will contain a non-toxic dosage level of the compound of formulae (I) .
• route of administration is parenteral the dose is about 0.1 to about 100 milligrams per day.
• Intravenous administration can include a continuous drip.
• the route is oral the dose is about 1 to about 1000 milligrams per day.
• Preferred dosages are from about 0.5 to about 300 mg/kg per day, most preferably 0.5 to 20 mg/kg, of Active Ingredient may be administered although it will, of course, readily be understood that the amount of the compound or compounds of Formula I actually to be administered will be determined by a physician, in the light of all the relevant circumstances .
• the compound C (within the scope of the invention) was evaluated for LTB4 antagonist efficacy.
• Compounds A and B were control compounds .
• Compound A is a leukotriene B4 antagonist known to be effective, but belonging to a different class of compounds than represented by formulae I or II, supra.
• Comparison compound B is structurally similar to the compounds of the invention, but lacks certain essential functional groups necessary for an effective LTB4 antagonist .
• the assay buffer used throughout the studies consisted of Hanks Balanced Salts Solution (HBSS) with added 0.5% bovine serum albumin, low endotoxin (ICN Biomedicals Catalog # 16-980-49) . After dissolving the BSA in the HBSS, the buffer was membrane-filtered (0.2 ⁇ ) before use.
• HBSS Hanks Balanced Salts Solution
• bovine serum albumin 0.5% bovine serum albumin, low endotoxin
• Human blood was drawn into 3 x 10 ml EDTA-K3 Vacutainer tubes, which were pooled and mixed in a 50 ml, blue cap polypropylene tube.
• An additional 0.3 ml of PBS (phosphate buffered saline) was added to each tube and mixed with the MPRM by vigorous vortexing. Exactly 3.5 ml of the blood was carefully layered on top of the four MPRM-water mixtures. The tubes were gradually accelerated to 400 x g and spun at this speed for 30 min at room temperature.
• Tubes were removed from the centrifuge and both the plasma and top cell (mononuclear) layers were removed and discarded. The second layer of cells was carefully collected, pooled and washed with assay buffer. The collected neutrophil cell preparation was then spun at 400 x g for 5 min and re-washed once again. The cells were resuspended in assay buffer and counted using a Cell-Dyn 1600 cell counter (Abbott Diagnostics Co.). They were then resuspended in buffer at 9 x 10 6 cells/ml and held briefly for addition in a later step of the assay.
• LTB4 (Biomol ; ETOH stock @ 148.5 ⁇ M) was diluted to a 3.9 ⁇ M stock in assay buffer by dilution of 10 ⁇ l ETOH stock + 371 ⁇ l assay buffer, mixed well and further diluted 1:100 (100 ⁇ l + 9.9 ml buffer) to make a use stock of 39 nM in buffer for later use.
• FITC Fluorescein Isothiocyanate; Biosource Intl., # AHS1148) was carefully added to the bottom of 12 x 75 mm polypropylene tubes (Falcon # 2063) as determined by the experimental design. Following this, 100 ⁇ l of the human neutrophil preparation (9E6/ml) was added and mixed well by vortexing. The compound/cell mixtures were incubated together for 15 minutes at room temperature. Following this incubation, 10 ⁇ l of diluted LTB stock was added (to make 3 nM final LTB concentration) , mixed by vortexing and incubated in a 37°C shaking water bath for 30 min.
• the tubes were immediately placed on ice for 10 minutes. Following this 1 ml of diluted BD FACS Lyse (Becton Dickinson Fluorescense Activated Cell Sorting Lyse) was added to the tubes and vortexed. 10 minutes later the tubes were spun at 400 x g at room temperature. After centrifugation, the tubes were aspirated and re-suspended in 1.0 ml of 1% paraformaldehyde solution.
• BD FACS Lyse Becton Dickinson Fluorescense Activated Cell Sorting Lyse
• the samples were then analyzed for fluorescence intensity (linear scale) using an EPICS XL flow cytometer and the "Mo-1 Isolated Neutrophil" protocol.
• the mean fluorescence intensity (MFI) for each sample was computed using WinList software and expressed as percentage of maximum MFI .Microsoft Excel and further graphed and analyzed using linear regression.

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