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  • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
  • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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 with substituted hydrocarbon radicals, directly attached to ring carbon atoms
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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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  • C07D261/08—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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  • C07D285/02—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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  • C07D307/10—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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  • 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

• eukotriene B ( TB4) is one of many products resulting from the arachidonic acid cascade.
• LTB4 in high concentration has been detected at the sites of various inflammatory conditions, for example, rheumatism, spinal arthritis (see Lanestein L.B., Shapleigh, C. and Goetzl, E. J. (1980) J. Clin. Invest., 66, 1166-1170), gout (Rae, S. A., Davidson, E. M. and Smith, M. J. H. (1982) Lancet II 1122-1123), psoriasis (see Grabbe, J., Czarnetzki, B. M. , Rosenbach, T. and Mardin, M. (1984) J. Invest. Dermatol., 82, 477-479), ulcerative colitis (see Sharon, P. and Stenson, W. F.
• LTB4 is deeply related to various forms of inflammation. It has been suggested that compounds antagonizing LTB4 activity may be valuable in the treatment of inflammatory diseases caused by tissue degrading enzymes and reactive chemicals liberated by tissue-infiltrating and aggregating polymorphonuclear leukocytes. For example, PCT Japanese National Publication No.
• 6- 502164 describes novel monocylic or bicyclic aryl compounds are selectively antagonistic to LTB4 and are useful for treatment of rheumatoid arthritis, gout, psoriasis and inflammatory bowel disease.
• Japanese Unexamined Patent Publication (Kokai) No. 4-244023 describes that omega 6 series unsaturated fatty acids such as ⁇ -linolenic acid are useful for treatment of arrhythmia, acute myocardial infarction etc, by inhibiting production of LTB4.
• 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
• anti-inflammatory drugs are classified as steroidal and non-steroidal . Although these drugs provide anti-inflammatory action they all have drawbacks which limit their use. A more recent approach to the moderation of inflammation focuses on blocking the action of arachidonic acid metabolites.
• Leukotriene B4 antagonists are useful for a wide variety of Inflammatory Diseases, but it is expected that various of these antagonists will show superior results with particular disease states. This is one reason it is desirable to develop new leukotriene B4 antagonists such as the compounds of this invention.
• the present invention is directed to novel heterocycle substituted diphenyl compounds of formula (I)
• compositions containing the compounds of formula (I) are pharmaceutical compositions containing the compounds of formula (I) .
• Another aspect of this invention is a method of using the compounds of the invention in the prevention and treatment of LTB4 induced illnesses.
• Another aspect of this invention is a compound of formula (I) for use as a medicament in the treatment or prevention of Inflammatory Diseases.
• Another aspect of this invention is a process for preparing a compound of Formula (I) .
• Acidic Group means an organic group which when attached as the "Z" substituent of formula (I) or the "Z2" substituent of formula (II) acts as a proton donor capable of hydrogen bonding.
• An illustrative acidic group is carboxyl.
• Active Ingredient means the diphenyl leukotriene B4 antagonist compounds generically described by formula I and formula II or the list of specific diphenyl compounds disclosed, infra., as well as the salts, solvates, and prodrugs of such compounds.
• alkenyl means a monovalent radical of the generic formula C n H2 n such as ethenyl, n-propenyl , isopropeneyl, n-butenyl, isobutenyl, 2-butenyl, and 3-butenyl .
• alkyl by itself or as part of another substituent means, unless otherwise defined, a straight or branched chain monovalent hydrocarbon radical such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, sec-butyl, n-pentyl, and n-hexyl .
• alkaryl means an aryl radical substituted with an alkyl or substituted aryl group, for example:
• C5-C20 alkaryl the numerical subscripts refer to the total number of carbon atoms in the radical.
• C5-C20 aralkyl means an alkyl radical substituted with an aryl or substituted aryl group, for example:
• C5-C20 aralkyl the numerical subscripts refer to the total number of carbon atoms in the radical.
• Carbocyclic group refers to a five, six, seven, or eight membered saturated, unsaturated or aromatic ring containing only carbon and hydrogen (e.g., benzene, cyclohexene, cyclohexane, cyclopentane) .
• cycloalkyl means a carbocyclic non- aromatic monovalent radical such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl .
• halo means fluoro, chloro, bromo, or iodo.
• heterocyclic radical refers to a radical having a saturated, unsaturated or aromatic five membered substituted or unsubstituted ring containing from 1 to 4 hetero atoms .
• Inflammatory Diseases refers to diseases such as inflammatory bowel disease, sepsis, septic shock, adult respiratory distress syndrome, pancreatitis, trauma- induced shock, bronchial asthma, allergic rhinitis, rheumatoid arthritis, cystic fibrosis, stroke, acute bronchitis, chronic bronchitis, acute bronchiolitis, chronic bronchiolitis, osteoarthritis, gout, spondylarthropathris, ankylosing spondylitis, Reiter's syndrome, psoriatic arthropathy, enterapathric spondylitis, Juvenile arthropathy or juvenile ankylosing spondylitis, reactive arthropathy, infectious or post-infectious
• LTB4 antagonist means a pharmaceutical agent capable of preventing or reducing to a therapeutically significant degree the adverse activity of LTB4 in mammals and having a average CDllb/CDl8 ICso(nM) assay result of 10000 or less and preferably of 100 or less.
• mamal includes human.
• N-sulfonamidyl means the radical:
• R12 is C ⁇ -CIQ alkyl, aryl, C1-C6 alkyl substituted aryl, C5-C20 alkaryl, or C5-C20 aralkyl.
• substituted alkyl means an alkyl group further substituted with one or more radical (s) selected from halo, C- ⁇ -Cg alkyl, aryl, benzyl, C2-C5 alkenyl, C2-C5 alkynyl, C3-C8 cycloalkyl, Ci-C ⁇ alkoxy, C- ⁇ -Cg haloalkyl (e.g. , -CF3) .
• radical selected from halo, C- ⁇ -Cg alkyl, aryl, benzyl, C2-C5 alkenyl, C2-C5 alkynyl, C3-C8 cycloalkyl, Ci-C ⁇ alkoxy, C- ⁇ -Cg haloalkyl (e.g. , -CF3) .
• substituted aryl means an aryl group further substituted with one or more radical (s) selected from halo, C1-C5 alkyl, aryl, benzyl, C2-C alkenyl, C2-C5 alkynyl, C3-C8 cycloalkyl, C ⁇ -Cg alkoxy, C ⁇ -Cg haloalkyl (e.g., -CF 3 ) .
• radical selected from halo, C1-C5 alkyl, aryl, benzyl, C2-C alkenyl, C2-C5 alkynyl, C3-C8 cycloalkyl, C ⁇ -Cg alkoxy, C ⁇ -Cg haloalkyl (e.g., -CF 3 ) .
• tetrazolyl refers to an acidic group represented by either of the formulae:
• the present invention is directed to novel heterocyclic substituted diphenyl compounds of formula (I)
• X is selected from the group consisting of,
• Yl is a bond or divalent linking group containing 1 to 9 atoms;
• Y2 and Y3 are divalent linking groups independently selected from -CH2", -0-, and -S-;
• Z is an Acidic Group
• Rl is C-]_-C ⁇ o alkyl, aryl, C3-C10 cycloalkyl, C 2 -C ⁇ o alkenyl, C -C 10 alkynyl, C 6 -C 2 o aralkyl, C 6 -C o alkaryl, C1-C10 haloalkyl, C5-C20 aryloxy, or C -CIQ alkoxy;
• R2 is hydrogen, halogen, CI-CIQ haloalkyl, CI-CIQ alkoxy, C- ⁇ -C]_Q alkyl, C3-C8 cycloalkyl, Acidic Group, or - (CH2) 1-7 (Acidic Group);
• R3 is hydrogen, halogen, CI ⁇ CIQ alkyl, aryl, CI-CI Q haloalkyl, CI ⁇ CIQ alkoxy, CI ⁇ CIQ aryloxy, C3-C8 cycloalkyl;
• R4 is C1-C4 alkyl, C3-C4 cycloalkyl,
• n 0, 1, 2, 3, 4, 5, or 6 ;
• 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"
• Preferred compounds of the invention are those wherein X is a heterocyclic radical selected from the group consisting of substituents represented by the following structural formulae:
• RIO is a radical selected from hydrogen or C -C4 alkyl
• Rll is a radical selected from hydrogen, halo, C1-C10 alkyl, CI-CI haloalkyl, CI-C Q alkoxy, aryl, or C5-C20 aryloxy.
• Preferred RIO groups are hydrogen, methyl, or phenyl.
• any of the above heterocyclic radicals illustrated by structural formulae may attach to the diphenyl leukotriene antagonist of formulae (I) by any monovalent bond originating on a suitable carbon or nitrogen atom in its ring structure.
• the pyrrole radical may attach to the diphenyl molecule by a single bond originating at any carbon atom or any nitrogen atom which has less than three bonds in the hererocyclic ring;
• a preferred form of the substituent X is a fused bicyclic radical wherein a carbocyclic group is fused to two adjacent carbon atoms of the five membered heterocyclic radical, for example:
• X substituents are the heterocyclic radicals
• the heterocyclic radical X of Formula (I) does not include 3-bromo-l, 2 , 4 thiadiazole since the LTB antagonist activity of compounds containing this radical is considered too low to be an aspect of this invention.
• Yl is a bond or divalent linking group containing 1 to 9 atoms independently selected from carbon, hydrogen, sulfur, nitrogen, and oxygen;
• 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 :
• R13 is hydrogen, methyl, or ethyl
• R13 is hydrogen, methyl, or ethyl
• the above divalent groups may be used in their forward or reversed positions.
• the Y2 and Y3 substituents are preferably selected from -S- and -0- .
• Z is the Acidic Group as previously defined, Preferred s an acidic group selected from the following:
• R12 is C- _ -C-]_ Q alkyl, aryl, C -C20 alkaryl, or C5-C20 aralkyl .
• Preferred R12 groups are represented by the formulae :
• N-acyl sulfonamide, -SO3H, and carboxyl N-acyl sulfonamide, -SO3H, and carboxyl.
• n 1.
• a preferred Rl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and 2-propenyl; with n- propyl being most preferred.
• Preferred Group 1 of R2 substituent (symbol, "PG1-R2")and Preferred Group 1 of R3 substituent (symbol, "PG1-R3”) :
• Preferred R2 and R3 groups are those wherein R2 and R3 are independently selected from hydrogen or methyl, ethyl, methoxy, ethoxy, halo, or -CF3 ; with R2 and R3 both being hydrogen as most preferred.
• Preferred R4 substituents are ethyl, propyl, and isopropyl .
• R-Table is used to select combinations of general and preferred groupings of the variables Rl, R2 , R3 and R4 for substitution in formula (I), as follows:
• 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:
• any of the individual 16 combinations of the R substituents depicted in the R-Table may be used in combination with any of the 27 individual combinations of Y substituents depicted in the Y-Table, which may be used with any of the 24 combinations of XZn substituents depicted in the XZn-Table.
• the substituent combination choice "R07, Y21, XZn03" defines substituent set selections for a subset of formula (I) useful in the practice of the invention.
• X2 is a heterocyclic radical selected from,
• R21 is ethyl, 2-propen-l-yl, 3-propen-l-yl, n-propyl, iso-propyl, n-butyl, sec-butyl, or tert-butyl; and R22 is hydrogen, n-butyl, sec-butyl, flouro, chloro, -CF3 , or tert-butyl.
• Z2 is carboxyl, tetrazolyl, N-sulfonamidyl .
• LTB4 antagonists are represented by the following structural formulae:
• the salts of the above diphenyl LTB4 antagonists of the invention represented by formulae (I) and (II) and the specific compounds set out by structural formulae in sections IIIR and HIS herein, are an additional aspect of the invention.
• the compounds of the invention possess an Acidic Group (s) and at these sites various salts may be formed which are more water soluble and/or physiologically suitable than the parent compound in its acid form.
• Representative pharmaceutically acceptable salts include but are not limited to, the alkali and alkaline earth salts such as lithium, sodium, potassium, calcium, magnesium, aluminum and the like. Sodium salts are particularly preferred.
• Salts are conveniently prepared from the free acid by treating the acid form in solution with a base or by exposing the acid to an ion exchange resin.
• the (Acidic Group) of the Z of Formula (I) may be selected as -CO2H and salts may be formed by reaction with appropriate bases (e.g., NaOH, KOH) to yield the corresponding sodium or potassium salt.
• salts include the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention, for example, ammonium, quaternary ammonium, and amine cations, derived from nitrogenous bases of sufficient basicity to form salts with the LTB4 antagonist compounds of this invention (see, for example, S. M. Berge, et al . ,
• Certain compounds of the invention may possess one or more chiral centers and may thus exist in optically active forms. All such stereoisomers as well as the mixtures thereof are intended to be included in the invention. If a particular stereoisomer is desired, it can be prepared by methods well known in the art, for example, by using stereospecific reactions with starting materials which contain the asymmetric centers and are already resolved or, alternatively, by methods which lead to mixtures of the stereoisomers and subsequent resolution by known methods. For example, a racemic mixture may be reacted with a single enantiomer of some other compound. This changes the racemic form into a mixture of diastereomers .
• Prodrugs are derivatives of the compounds of Formula (I) and (II), supra., which have chemically or metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo.
• Derivatives of the compounds of this invention have activity in both their acid and base derivative forms, but the acid derivative form often offers advantages of solubility, tissue compatibility, or delayed release in a mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985).
• Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acidic compound with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a suitable amine. Simple aliphatic or aromatic esters derived from acidic groups pendent on the compounds of this invention are preferred prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy) alkyl esters or ( (alkoxycarbonyl) oxy) alkyl esters.
• esters as prodrugs are methyl, ethyl, propyl, isopropyl, n- butyl, isobutyl, tert-butyl, morpholinoethyl, and N,N- diethylglycolamido .
• Esters of carboxylic acids are preferred prodrugs of the compounds of the invention (viz., the compounds of Formula I, Formula II and the specific compounds set out in Section IIIR and HIS, herein) .
• Methyl ester prodrugs may be prepared by reaction of the acid form of a compound of formula (I) in a medium such as methanol with an acid or base esterification catalyst (e.g., NaOH, H2SO4). Ethyl ester prodrugs are prepared in similar fashion using ethanol in place of methanol.
• a medium such as methanol
• an acid or base esterification catalyst e.g., NaOH, H2SO4
• N,N-diethylglycolamido ester prodrugs may be prepared by reaction of the sodium salt of a compound of Formula (I) (in a medium such as dimethylformamide) with 2-chloro-N,N- diethylacetamide (available from Aldrich Chemical Co., Milwaukee, Wisconsin USA; Item No. 25,099-6) .
• Morpholinylethyl ester prodrugs may be prepared by reaction of the sodium salt of a compound of Formula (I) (in a medium such as dimethylformamide) 4- (2- chloroethyl)morpholine hydrochloride (available from Aldrich Chemical Co., Milwaukee, Wisconsin USA, Item No. C4, 220-3).
• Preferred compounds of the invention are compounds of Formula (I) , or Formula (II) or the specific compounds of sections IIIR and HIS shown above by structural formula; wherein the acid, salt and prodrug derivatives thereof are respectively selected from: carboxylic acid, sodium salt, and ester prodrug.
• 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).
• Scheme 2 The following scheme illustrates a process for making Example (2), a 5 (4) -substituted imidazole LTB 4 receptor antagonist: Scheme 2
• the trimethylsilyl enol ether of acetophenone (32) is formed and treated with N-chlorosuccinimide followed by tetra-n- butylammoniu fluoride to provide the chloroketone (40) .
• Treatment of (40) with 2-benzyl-2-thiopseudourea and base provides imidazole (42) , that is treated with boron trifluoride etherate and ethanethiol to give imidazole (44) .
• Hydrolysis and protonation provide Example (2) as the hydrochloride salt .
• Example (3) a 4-substituted thiazole LTB 4 receptor antagonist:
• enone (50) Treatment of acetophenone (32) with N,N-dimethyl formamide dimethyl acetal gives enone (50) , that may be hydrolyzed, protonated, and then heated with hydrazine hydrate to provide pyrazole (52). Debenzylation of the resulting pyrazole with boron trifluoride etherate and ethanethiol gives Example (4) .
• Known phenol (30) is alkylated with known chloride (58) to give aryl bromide (60).
• Heating (62) with trimethylsilyl azide provides triazole (64) , that is debenzylated with boron trifluoride etherate and ethanethiol to give triazole (66) .
• Hydrolysis and protonation provides Example (6).
• Example (7) a 1-substituted pyrrole LTB 4 receptor antagonist:
• Example ((88)) aa 55-- ⁇ substituted 1, 2 , 4-thiadiazole LTB 4 receptor antagonist :
• Example 15 a 3-substituted tetrahydrofuran LTB 4 receptor antagonist:
• Phenol (30) is alkylated with l-bromo-3-chloropropane to give chloride (116) , that is in turn to be treated with known aldehyde (118) and a base, followed by benzylation with benzyl bromide and a base, to provide aldehyde (120)
• aldehyde (120) From aldehyde (120) is made the thioacetal by treatment with 1, 2-ethanedithiol .
• the resulting thioacetal is then to be treated with base to provide the thioacid.
• Treatment with piperidine makes piperidinium salt (122).
• Alkyne (62) is to be treated with trithiazyl trichloride by the method of Thomas et. al . (infra., the disclosure of which is incorporated herein by reference) to provide thiadiazole (132).
• Debenzylation with boron trifluoride etherate and ethanethiol, followed by hydrolysis and protonation, will provide the product of Example (20) .
• Sche e 21 The following scheme illustrates a process for making Example (21), a 2-substituted 1, 3 , 4-thiadiazole LTB 4 receptor antagonist :
• Thiophene (114) may be reduced in the presence of triethylsilane and trifluoroacetic acid by the method of Kursanov et . al . (infra., the disclosure of which is incorporated herein by reference) to provide the thiophane (142) . Hydrolysis and protonation will provide the product of Example (24) .
• 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.
• compositions containing the compound of Formula (I) may be provided in dosage unit form, preferably each dosage unit containing from about 5 to about 500 mg (from about 5 to 50 mg in the case of parenteral or inhalation administration, and from about 25 to 500 mg in the case of oral or rectal administration.
• dosage unit form preferably each dosage unit containing from about 5 to about 500 mg (from about 5 to 50 mg in the case of parenteral or inhalation administration, and from about 25 to 500 mg in the case of oral or rectal administration.
• Dosages from about 0.5 to about 300 mg/kg per day, 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.
• 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:
• the components are blended and compressed to form tablets each weighing 665 mg
• Formulation 3 An aerosol solution is prepared containing the following components :
• the Active Ingredient is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to -30°C and transferred to a filling device. The required amount is then fed to a stainless steel container and diluted with the remainder of the propellant. The valve units are then fitted to the container.
• Formulation 4 Tablets each containing 60 mg of Active Ingredient, are made as follows:
• the Active Ingredient, starch and cellulose are passed through a No . 45 mesh U.S. sieve (355 ⁇ m) and mixed thoroughly.
• the aqueous solution containing polyvinylpyrrolidone is mixed with the resultant powder, and the mixture then is passed through a No . 14 mesh U.S. sieve (1.4mm) .
• the granules so produced are dried at 50°C and passed through a No. 18 mesh U.S. sieve (1.00mm).
• the sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No. 60 mesh U.S. sieve (250 ⁇ m) are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
• the Active Ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No . 45 U.S. sieve (355 ⁇ m) , and filled into hard gelatin capsules in 200 mg quantities .
• 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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