Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• This invention relates to a method of treating cancer with anti-cancer agents. More specifically, it relates to the use of 2 ', 2 ' -difluoronucleoside anti-cancer agents, in conjunction with leukotriene (LTB4) antagonists which enhance the effectiveness of the anti-cancer agent.
• LTB4 leukotriene
• Leukotriene B4 is a proinflammatory lipid which has been implicated in the pathogenesis of psoriasis, arthritis, chronic lung diseases, acute respiratory distress syndrome, shock, asthma, inflammatory bone diseases and other inflammatory states characterized by the infiltration and activation of polymorphonuclear leukocytes and other proinflammatory cells. Thus activated, the polymorphonuclear leukocytes liberate tissue-degrading enzymes and reactive chemicals causing the inflammation.
• US Patent 5,462,954 discloses phenylphenol leukotriene antagonists that are useful in the treatment of psoriasis, arthritis, chronic lung diseases, acute respiratory distress syndrome, shock, asthma, inflammatory bone diseases and other inflammatory states characterized by the infiltration and activation of polymorphonuclear leukocytes and other proinflammatory cells.
• US Patent 5,910,505 discloses that certain phenylphenol leukotriene B4 (LTB4) antagonists are useful as agents for the treatment of oral sguamous cell carcinoma.
• US Patent 5,543,428 discloses a group of phenylphenol leukotriene antagonists which have the property of reversing multi drug resistance in tumor cells.
• the use of the leukotriene antagonist will reverse the drug resistance of resistant tumor cells to vinblasine, vincristine, vindesine, navelbine, daunorubicin, doxorubicin, mitoxantrone, etoposide, teniposide, mitomycin C, actinomycin, taxol, topotecan, mithramycin, colchicine, puromycin, podophylotoxin, emetine, gramicidin, and valinomycin.
• compositions and methods useful for treating cancers, in particular, cancers that are not multi drug resistant include the 2 ', 2 ' -difluoronucleoside anti-cancer agents described in US Patent 5,464,826 in combination with leukotriene (LTB4) antagonists of formula A, formula I and formula II, described below.
• LTB4 leukotriene
• 2 ' , 2 ' -difluoro nucleoside anti-cancer agents with leukotriene (LTB4) antagonists act synergistically against cancers which are not multi-drug resistant.
• the types of cancers that may be treated with the compositions of the present invention include: Breast Carcinoma, Bladder Carcinoma, Colorectal Carcinoma, Esophageal Carcinoma, Gastric Carcinoma, Germ Cell Carcinoma e.g. Testicular Cancer, Gynecologic Carcinoma, Lymphoma Hodgkin's, Lymphoma - Non-Hodgkin' s, Malignant Melanoma, Multiple Myeloma, Neurologic Carcinoma, Brain Cancer,
• Pancreatic Carcinoma Prostate Carcinoma, Ewings Sarcoma, Osteosarcoma, Soft Tissue Sarcoma, Non-Small Cell Lung Cancer, Pediatric Malignancies and the like.
• Figures 1 through 6 are horizontal bar graphs displaying the data of Tables 1 through 6 provided in the "ASSAY EXAMPLE 1", infra.
• the vertical axis of the graph in each Figure forms the origin of the numbered horizontal bars, wherein each bar is a separate Treatment as set out in the Tables.
• the horizontal axis is tumor growth delay (TGD) in days .
• 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 refers both to certain 2', 2 ' -difluoronucleoside compounds and also leukotriene B4 antagonist compounds generically described by formula A as well as 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 a combination of a 2', 2 ' -difluoronucleoside and a leukotriene B4 antagonist described by formula A or formulas I and/or II, and 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 .
• heterocyclic radical (s) refers to a radical having a saturated, unsaturated or aromatic five membered substituted or unsubstituted ring containing from 1 to 4 hetero atoms .
• mammal and “mammalian” include human.
• N-sulfonamidyl means the radical where R12 is C ⁇ -C ⁇ o alkyl, aryl, C1-C6 alkyl substituted aryl, C5-C20 alkaryl, or C -C20 aralkyl.
• substituted alkyl means an alkyl group further substituted with one or more radical (s) selected from halo, C- j _-Cg alkyl, aryl, benzyl, C2-C5 alkenyl, C2-C alkynyl, C3-C8 cycloalkyl, C -Cs alkoxy, C ⁇ -Cg haloalkyl (e.g., -CF 3 ) .
• radical selected from halo, C- j _-Cg alkyl, aryl, benzyl, C2-C5 alkenyl, C2-C alkynyl, C3-C8 cycloalkyl, C -Cs alkoxy, C ⁇ -Cg haloalkyl (e.g., -CF 3 ) .
• substituted aryl means an aryl group further substituted with one or more radical (s) selected from halo, C ⁇ -Cg alkyl, aryl, benzyl, C2-C5 alkenyl, C2-C alkynyl, C3-C8 cycloalkyl, C ⁇ -Cs alkoxy, C1-C haloalkyl (e.g., -CF3).
• radical (s) selected from halo, C ⁇ -Cg alkyl, aryl, benzyl, C2-C5 alkenyl, C2-C alkynyl, C3-C8 cycloalkyl, C ⁇ -Cs alkoxy, C1-C haloalkyl (e.g., -CF3).
• tetrazolyl refers to an acidic group represented by either of the formulae:
• terapéuticaally effective interval is a period of time beginning when one of either (a) the 2', 2' difluoronuceoside anti-cancer agent or (b) the LTB4 antagonist is administered to a mammal and ending at the limit of the anti-cancer beneficial effect in treating cancer of (a) or (b) .
• the anti-cancer agents and the leukotriene (LTB4) antagonist are administered within 24 hours of each other, more preferably within 4 hours and most preferably within 1 hour.
• terapéuticaally effective combination means administration of both (a) the 2', 2 ' -difluoronuceoside anti-cancer agent and (b) the LTB4 antagonist, either simultaneously or separately, in any order.
• anti cancer agents which may be used are 2 ' , 2 ' difluoronucleoside compounds of the formula:
• R2 is hydrogen or
• R2 is a base defined by one of the formulae
• X is N or C-R 4
• R3 is hydrogen, C1-C4 alkyl or
• R 4 is hydrogen, C1-C4 alkyl, amino, bromo, fluoro, chloro or iodo;
• Each R5 independently is hydrogen or C1-C4 alkyl; and the pharmaceutically-acceptable salts thereof.
• R6 is hydrogen, C1-C4 alkyl
• R 7 is a base of one of the formulae
• X is N or C-R 4 ;
• RS is hydrogen or C1-C4 alkyl
• R 4 is hydrogen, C1-C4 alkyl; amino, bromo, fluoro, chloro and iodo; and the pharmaceutically-acceptable salts thereof; with the proviso that R ⁇ and R ⁇ may both be hydrogen only when X is N and
• R6 is hydrogen or C1-C4 alkyl
• preferred 2 ' 2 ' -difluoronucleoside compounds are compounds represented by the formula:
• R 1 is hydrogen
• R 2 is a base defined by one of the formulae:
• X is C-R ;
• R 3 is hydrogen
• R 4 is hydrogen, C ⁇ -C alkyl, bromo, fluoro, chloro or iodo; and pharmaceutically acceptable salts thereof.
• anti-cancer agents are selected from the group consisting of the following compounds or a pharmaceutically acceptable salt thereof:
• the most preferred compound is gemcitabine HCl which is a nucleoside analogue that exhibits antitumor activity.
• Gemcitabine HCl is 2 ' -deoxy-2 ' , 2 ' -difluorocytidine monohydrochloride ( ⁇ -isomer) , also known as 2 ' , 2 ' -difluoro- 2 ' -deoxycytidine monohydrochloride, or also as 1- (4-amino-2- oxo-lH-pyrimidin-1-yl) -2-desoxy-2 ' , 2 ' -difluororibose .
• the anti-cancer agents are generally mixed with a carrier which may act as a diluent, or excipient the anti- cancer agents may be administered in the form of tablets, pills, powders lozenges, sachets, cachets, elixirs, suspensions, emulsion, solution, syrups or aerosols. Sterile injectable solutions may also be used.
• the leukotriene (LTB4) antagonists useful in the present invention include those given in formula A.
• R4' is R5
• each R ⁇ is independently -COOH, 5-tetrazolyl , -
• each R7 is hydrogen, C1-C4 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, benzyl, methoxy, -W-R6, -T-G-R6, (C1-C4 alkyl )-T- (C1-C4 alkylidenyl) -0-, or hydroxy;
• R8 is hydrogen or hale- each Rg is independently hydrogen, phenyl, or C1-C4 alkyl, or when taken together with the nitrogen atom form a orpholino, piperidino, piperazino, or pyrrolidino group; Rio is C1-C4 alkyl or phenyl;
• Preferred LTB4 antagonists of Formula A are those compounds wherein R 4 ' is selected from the following formulae:
• LTB4 antagonist of Formula A are those compounds wherein R ' is:
• LTB4 antagonist compounds or pharmaceutically acceptable acid or salt derivatives thereof are listed herein from the group (A) to (KKKK) consisting of:
• AAA 2- [2-Propyl-3- [3- (2-ethyl-5-hydroxy-4- phenylphenoxy) propoxy] phenoxy] benzoic acid sodium salt hemihydrate;
• RRR 2- [2-Propyl-3- [3- [2 -ethyl-5-hydroxy-4- (4- fluorophenyl ) phenoxy] propoxy] benzoyl ] benzoic acid;
• SSS 2-[ [2-Propyl-3-[3- [2-ethyl-5-hydroxy-4- (4- fluorophenyl ) phenoxy] propoxy] phenyl ] methyl ] b enzoic acid;
• TTT 2- [2-Propyl-3- [3- [2-ethyl-4- (4- fluorophenyl ) -5- hydroxyphenoxy] propoxy] thiophenoxy] benzoic acid;
• AAAA 3- (2- (3- (2-Ethyl-4- (4-fluorophenyl) -5- hydroxyphenoxy) propoxy) phenyl) -E-propenoic acid;
• DDDD 3- ( 2 - (3- (2-Ethyl-4- (4-fluorophenyl) -5- hydroxyphenoxy) propoxy) -4- (4- carboxybutyloxy) phenyl) propionic acid; EEEE) 5- [3- [4- (4-Fluorophenyl) -2-ethyl-5- hydroxyphenoxy] propoxy] -3, 4-dihydro-2H-l- benzopyran-2-one; FFFF) 3- (3- ⁇ 3- [2-Ethyl-4- (4-fluorophenyl) -5- hydroxyphenyloxy] propoxy ⁇ phenyl ) propanoic acid;
• JJJJ 3- ⁇ 3-[3-(2-Ethyl-5- hydroxyphenyloxy) propoxy] -2- propylphenyl ⁇ propanoic acid disodium salt
• LTB4 leukotriene
• LTB4 antagonists are well known in the art, and are fully described in U.S. Patent 5,462,954, which is hereby specifically incorporated by reference for its disclosure of the methods of preparation of specific leukotriene B 4 antagonists and compounds or formulations of the leukotriene antagonists which may be administered to patients.
• a preferred compound is 2- [2-propyl-3- [3- [2- ethy1-5-hydroxy-4- ( 4-flouropheny1 ) phenoxy] propoxy] phenoxy benzoic acid which can also be named 2- [3- [3- (5-ethyl-4 ' - flouro-2-hydroxybiphen-4-yloxy) propoxy-2- propylphenoxy] benzoic acid, described in U.S. Patent
• a second class of LTB4 antagonists to use as the essential co-agent in the compositions and practice of the method of this invention are those disclosed in copending provisional patent application, titled, "Heterocycle Substituted Diphenyl Leukotriene Antagonists" (inventor, Jason Scott Sawyer) containing 97 pages and identified as Eli Lilly and Company Docket No. B-13240), filed on November 11, 1999, and now Provisional patent Application Serial Number 60/164,786.
• This second class of heterocycle substituted diphenyl leukotriene antagonists are described in more detail below:
• X is selected from the group consisting of,
• Yi 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 C1-C10 alkyl, aryl, C3-C10 cycloalkyl, C 2 -C 10 alkenyl, C 2 -C ⁇ 0 alkynyl, Cg-C 2 o aralkyl, C 6 -C 2 o alkaryl, C ⁇ -C ⁇ o haloalkyl, C5-C20 aryloxy, or C -CIQ alkoxy;
• R2 is hydrogen, halogen, CI-CIQ haloalkyl, CI-C Q alkoxy, c l _c 10 alkyl, C3-C8 cycloalkyl, Acidic Group, or - (CH2) 1-7 (Acidic Group);
• R3 is hydrogen, halogen, CI-CIQ alkyl, aryl, CI-CI Q haloalkyl, C -CI Q alkoxy, CI-CI Q aryloxy, C3-C8 cycloalkyl;
• R4 is C1-C4 alkyl, C3-C4 cycloalkyl,
• n O, 1, 2, 3, 4, 5, or 6 ;
• Preferred LTB4 Antagonists include the following:
• a "substituted heterocyclic radical” is preferably substituted with from 1 to 3 groups independently selected from hydrogen, halo, CI-CI Q alkyl, CI-CI Q haloalkyl, CI-CI Q alkoxy, aryl, or C5-C20 aryloxy.
• Preferred Group 1 of X substituent symbol, "PG1-X”
• Preferred LTB4 antagonist compounds used in the composition 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
• Rll is a radical selected from hydrogen, halo, C1-C10 alkyl, CI-C Q haloalkyl, CI-CIQ 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 heterocyclic 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; or
• the heterocyclic radical X of Formula (I) does not include 3-bromo-l, 2 , 4 thiadiazole since the LTB4 antagonist activity of compounds containing this radical is considered too low to be an aspect of this invention.
• Y is a bond or divalent linking group containing 1 to 9 atoms independently selected from carbon, hydrogen, sulfur, nitrogen, and oxygen;
• Preferred LTB4 compounds included in the composition of the invention are those wherein Yi 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 most preferred divalent Yi substituent is the group ;
• the Y2 and Y3 substituents are preferably selected from -S- and -0-.
• Y2 and Y3 are the group
• Z is the Acidic Group as previously defined, Preferred is an acidic group selected from the following:
• R12 is CI-CI Q alkyl, aryl, C5-C20 alkaryl, or C6-C20 aralkyl.
• Preferred R12 groups are represented by the formulae :
• N-acyl sulfonamide, -SO3H, and carboxyl N-acyl sulfonamide, -SO3H, and carboxyl.
• Carboxyl is the most preferred Z substituent.
• 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.
• R2 and R3 groups are those wherein R2 and R3 groups
• R3 are independently selected from hydrogen or methyl, ethyl, methoxy, ethoxy, halo, or -CF3 ; with R2 and R3 both being hydrogen as most 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.
• Rl is selected from the preferred set of variables, "PG1-R1", that is, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-but
• 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 composition and method of 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;
• R22 is hydrogen, n-butyl, sec-butyl, flouro, chloro, -CF3 , or tert-butyl.
• Z2 is carboxyl, tetrazolyl, N-sulfonamidyl .
• LTB4 antagonist component of the composition and method of the invention are represented by the following structural formulae:
• Known chloride (26) may be alkylated with benzyl bromide to provide chloride (28).
• Oxidation with bis (trifluoroacetoxy) iodobenzene gives alpha- hydroxy ketone (34) , that may be cyclized with triflie 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 LTB4 receptor antagonist: Scheme 2
• the trimethylsilyl enol ether of acetophenone (32) is formed and treated with N-chlorosuccinimide followed by tetra-n- butylammonium 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 LTB4 receptor antagonist:
• Chloroketone (40) is treated with thioformamide and magnesium carbonate to give thiazole (46), that is debenzylated with boron trifluoride etherate and ethanethiol giving thiazole (48) .
• Hydrolysis and protonation provides Example (3) .
• enone (50) Treatment of acetophenone (32) with N,N-dimethylformamide 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 (8) a 5-substituted 1, 2 , 4-thiadiazole LTB4 receptor antagonist :
• piperidinium salt (122) Treatment with piperidine makes piperidinium salt (122).
• Ikeda, infra, (the disclosure of which is incorporated herein by reference) treatment of (122) with 2- chloropyridinium methyl iodide followed by azide ion will give the 1, 2 , 3 , 4-thiatriazole (124).
• Debenzylation with boron trifluoride etherate and ethanethiol, followed by hydrolysis and protonation, will provide the product of Example (18) .
• 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) .
• Scheme 21 The following scheme illustrates a process for making Example (21), a 2-substituted 1, 3 , 4-thiadiazole LTB4 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) .
• 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
• LTB4 antagonists and anti- cangel agents used in the composition and method of the invention are often advantageously used in the form of salt derivatives which are an additional aspect of the invention.
• 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 -C0 2 H and salts may be formed by reaction with appropriate bases (e.g., NaOH, KOH) to yield the corresponding sodium or potassium salt.
• appropriate bases e.g., NaOH, KOH
• pharmaceutically acceptable 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 . , "Pharmaceutical Salts," J. Phar. Sci., 66: 1-19 (1977)).
• 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 LTB4 antogonist and anti-cancer compounds used in the invention 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 composition of the invention.
• 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).
• the compositions of the present invention are a combination of therapeutically effective amounts of the leukotriene (LTB4) antagonists, noted above, and a therapeutically effective amount of the anti-cancer agents noted above.
• LTB4 leukotriene
• composition may be formulated with common excipients, diluents or carriers, and compressed into tablets, or formulated elixirs or solutions for convenient oral administration or administered by intramuscular intravenous routes.
• the compounds can be administered transdermally and maybe formulated as sustained relief dosage forms and the like.
• the invention in another embodiment, relates to a method of treating a patient suffering from a non-multi drug resistant cancerous condition which comprises the separate administration of a therapeutically effective amount of the leukotriene (LTB4) antagonists, and the anti-cancer agent.
• the leukotriene (LTB4) antagonists, and the anti-cancer agent may be administered on a different schedule. One may be administered before the other as long as the time between the two administrations falls within a therapeutically effective interval.
• Therapeutically effective interval is a period of time beginning when one of either (a) the leukotriene (LTB4) antagonist or (b) the anti-cancer agent is administered to a human and ending at the limit of the beneficial effect in the treatment of cancer of the combination of (a) and (b) .
• the methods of administration of the leukotriene LTB4 antagonist and the anti-cancer agent may vary. Thus, one agent may be administered orally, while the other is administered intravenously. It is possible that one of the products may be administered as a continuous infusion while the other is provided in discreet dosage forms. It is particularly important that the anti-cancer drug be given in the manner known to optimize its performance.
• Preferably compounds of the invention 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.
• compositions of the invention are prepared by combining (e.g., mixing) a therapeutically effective amount of the anti-cancer agent (e.g., a 2',2'- difluoronucleoside and an LTB4 antagonist, such as the compound of Formula A, Formula I, II) together with a pharmaceutically acceptable carrier or diluent therefor.
• the anti-cancer agent e.g., a 2',2'- difluoronucleoside and an LTB4 antagonist, such as the compound of Formula A, Formula I, II
• a pharmaceutically acceptable carrier or diluent therefor.
• 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, injectable liquids, 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 sterile water, sterile saline, or sterile water or saline containing sugars and/or buffers 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.
• 0.5 to 20 mg/kg, of Active Ingredient may be administered although it will, of course, readily be understood that Dosages from about 0.5 to about 300 mg/kg per day, preferably 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.
• a 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 2 ', 2 ' -difluoronucleoside or a compound according to Formula A, Formula (I) or (II) or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
• compositions of the present invention are a combination of therapeutically effective amounts of the leukotriene (LTB4) antagonists, noted above, and a therapeutically effective amount of a 2',2'- difluoronucleoside anti-cancer agent.
• the composition may be formulated with common excipients, diluents or carriers, and compressed into tablets, or formulated elixirs or solutions for convenient oral administration or administered by intramuscular intravenous routes .
• the compounds can be administered transdermally and maybe formulated as sustained relief dosage forms and the like.
• the 2 ', 2 ' -difluoronucleoside anti-cancer agents are formulated independently of the leukotrienes (LTB4) antagonists and are administered separately.
• the anti-cancer agents may be formulated with common excipients, diluents or carriers and administered by intravenous infusion.
• the anti-cancer agents may be formulated into liquids suitable for oral administration.
• Anti-cancer agents may also be compressed into tablets and administered orally. If the anti-cancer agents and the leukotrienes (LTB4) antagonists are administered separately, the anti-cancer agents may be administered before, after or during the administration of the leukotriene (LTB4) antagonists. If the anti-cancer agents are administered separately from the leukotrienes (LTB4) antagonists, they must be administered within a therapeutically effective interval.
• the method of treating a human patient according to the present invention includes both the administration of the combination of leukotriene (LTB4) antagonists and an anti- cancer agent as well as the separate administration of the leukotriene (LTB4) antagonists and the anti-cancer agent.
• the leukotriene (LTB4) antagonists are formulated into formulations which may be administered by the oral and rectal routes, topically, parenterally, e.g., by injection and by continuous or discontinuous intra-arterial infusion, in the form of, for example, tablets, lozenges, sublingual tablets, sachets, cachets, elixirs, gels, suspensions, aerosols, ointments, for example, containing from 1 to 10% by weight of the active compound in a suitable base, soft and hard gelatin capsules, suppositories, injectable solutions and suspensions in physiologically acceptable media, and sterile packaged powders adsorbed onto a support material for making injectable solutions.
• formulations which may be administered by the oral and rectal routes, topically, parenterally, e.g., by injection and by continuous or discontinuous intra-arterial infusion, in the form of, for example, tablets, lozenges, sublingual tablets, sachets, cachets, e
• compositions 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) of a compound of Formula I or Formula II.
• 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 including the condition to be treated, the choice of compound to be administered and the choice of route of administration and therefore the above preferred dosage range is not intended to limit the scope of the present invention in any way.
• the formulations useful for separate administration of the leukotriene (LTB4) antagonists will normally consist of at least one compound selected from the compounds of Formula A and Formula I mixed with a carrier, or diluted by a carrier, or enclosed or encapsulated by an ingestible carrier in the form of a capsule, sachet, cachet, paper or other container or by a disposable container such as an ampoule.
• a carrier or diluent may be a solid, semi-solid or liquid material which serves as a vehicle, excipient or medium for the active therapeutic substance.
• diluents or carrier which may be employed in the pharmaceutical compositions of the present invention are lactose, dextrose, sucrose, sorbitol, mannitol, propylene glycol, liquid paraffin, white soft paraffin, kaolin, fumed silicon dioxide, microcrystallme cellulose, calcium silicate, silica, polyvinylpyrrolidone, cetostearyl alcohol, starch, modified starches, gum acacia, calcium phosphate, cocoa butter, ethoxylated esters, oil of theobroma, arachis oil, alginates, tragacanth, gelatin, syrup, methyl cellulose, polyoxyethylene sorbitan monolaurate, ethyl lactate, methyl and propyl hydroxybenzoate, sorbitan trioleate, sorbitan sesquioleate and oleyl alcohol and propellants such as trichloromonofluoromethane, dichlorodifluoromethan
• a lubricant may be incorporated to prevent sticking and binding of the powdered ingredients in the dies and on the punch of the tableting machine.
• a lubricant may be employed for instance aluminum, magnesium or calcium stearates, talc or mineral oil.
• Preferred pharmaceutical forms of the present invention are capsules, tablets, suppositories, injectable solutions, creams and ointments.
• formulations for inhalation application such as an aerosol, and for oral ingestion.

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