Classifications

• • 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
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
• • 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
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
  • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
  • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

• This invention relates to a method of treating cancer with anti-cancer agents. More specifically, it relates to the use of anti-cancer agents, in conjunction with leukotriene (LTB4) antagonists which enhance the effectiveness of the anti-cancer agents.
• 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 which 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 squamous cell carcinoma.
• US Patent 5,543,428 discloses a group of phenylphenol leukotriene antagonists that 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 vinblastine, vincristine, vindesine, navelbine, daunorubicin, doxorubicin, mitroxantrone, etoposide, teniposide, mitomycin-C, actinomycin-D, taxol, topotecan, mithramycin, colchicine, puromycin, podophylotoxin, emetine, gramicidin-D, and valinomycin.
• compositions and methods useful for treating cancers which are not multi-drug resistant.
• the compositions of the present invention include anti- cancer agents in combination with leukotriene (LTB4) antagonists of formula A, formula I and formula II.
• LTB4 leukotriene
• 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 anti-cancer agents defined below and also leukotriene B4 antagonist compounds generically described by formula A as well as diphenyl leukotriene B4 antagonist compounds generically described by formula A, formula I and formula II or the list of specific diphenyl compounds disclosed, infra., as well as a combination of a anti-cancer agent and a leukotriene B4 antagonist described by formula A or formula I 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 .
• 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 .
• mammal and “mammalian” include human.
• N-sulfonamidyl means the radical
• R12 is C]_-C ⁇ o 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, C1-C alkyl, aryl, benzyl, C2-C5 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, alkoxy, C1-C haloalkyl (e.g. , -CF3) .
• radical selected from halo, C1-C alkyl, aryl, benzyl, C2-C5 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, alkoxy, C1-C haloalkyl (e.g. , -CF3) .
• substituted aryl means an aryl group further substituted with one or more radical (s) selected from halo, C1-C alkyl, aryl, benzyl, C2-C alkenyl, C2-C5 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 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 anti-cancer agent and (b) the LTB4 antagonist, either simultaneously or separately.
• the types of cancers which 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 Myeoma, Neurologic Carcinoma, Brain Cancer, Non-Small Cell Lung Cancer, Pancreatic Carcinoma, Prostate Carcinoma, Ewings Sarcoma, Osteosarcoma, Soft Tissue Sarcoma, Pediatric Malignancies and the like.
• anti cancer agents which may be used include:
• ALKYLATING AGENTS Busulfan, Carboplatin, Carmustine, Cisplatin, Cyclophosphamide, dacarbazine, Ifosfamide, Lomustine, Streptozocin, Oxaliplatin, Temozolomide;
• ANTIBIOTICS Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Idarubicin, Mitomycin-C, Plicamycin, Cryptophycin;
• ANTIMETABOLITES Cytarabine, Floxuridine, Fludarabine, 5- Fluorouracil, Hydroxyurea, 6-Mercaptopurine, Methotrexate, Thioguanine; Capecitabine;
• BIOLOGICALS Aldesleukin, Interferon Alfa-2A, Interleukin- 2, Interleukin-12 (recombinant), Interferon Alfa-2B (recombinant), Interferon Alfa-n3, Interferon Gamma-IB, Herceptin interleukin-2 , interleukin-12;
• HORMONAL AGENTS Aminoglutethimide, Anastrozole, Flutamide, Goserelin, Leuprolide, Megestrol, Mitotane, Tamoxifen;
• NITROGEN MUSTARD DERIVATIVES Chlorambucil , Estramustine, Mechlorethamine, Melphalan, Thiotepa; PLANT ALKALOIDS: Docetaxel, Etoposide, Irinotecan HCl, Paclitaxel, Teniposide, Topotecan, Vinblastine, Vincristine, Vinorelbine;
• OTHERS Altretamine, Amifostine Asparaginase-Escheri ⁇ ia coli strain, BCG Live (Intravesical) , Cladribine, Leucovorin, Levamisole, Mitoxantrone, Pegaspargase, Pentostatin, Procarbazine, and the like.
• the anti-cancer agents may be used alone or in combinations of one or more anti-cancer agents. When used in combination, the anti-cancer agents may be administered at the same time, sequentially or in more complicated regimens where the agents may be administered alternately. Such combinations and dosing regimens are well known to those skilled in the art.
• the anti-cancer agents 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 may be formulated as sustained relief dosage forms and the like.
• 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 an 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 may be 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) antagonists 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) .
• LTB4 leukotriene
• the methods of administration of the leukotriene LTB4 antagonist and the anti-cancer agent may vary.
• one agent may be administered orally, while the other is administered intravenously.
• one of the products may be administered as a continuous infusion while the other is provided in discreet dosage forms.
• the anti-cancer drug be given in the manner known to optimize its performance.
• the leukotriene (LTB4) antagonists useful in the present invention include those given in formula A.
• R4 ' is Rg or taken from one of the following formulae:
• each Rg is independently -COOH, 5-tetrazolyl, CON ( R 9 ) 2 . or -CONHSO2R10; each R7 is hydrogen, C1-C4 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, benzyl, methoxy, -W-R ⁇ , -T-G-R6, (C1-C4 alkyl )-T- (C1-C4 alkylidenyl) -0-, or hydroxy;
• R8 is hydrogen or halo; each R9 is independently hydrogen, phenyl, or C1-C4 alkyl, or when taken together with the nitrogen atom form a morpholino, piperidino, piperazino, or pyrrolidino group;
• R ⁇ is C1-C4 alkyl or phenyl
• R4 ' is selected from the following formulae:
• Preferred compounds or pharmaceutically acceptable acid salt derivatives thereof are those wherein said compound selected 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;
• HHH 3- [4- [9-0x0-3- [3- [2-ethyl-4- (4- fluorophenyl) -5-hydroxyphenoxy] propoxy] -9H- xanthene] ] propanoic acid; III) 3- [2- [l-[2-Ethyl-4- (4-fluorophenyl) -5- hydroxyphenoxy] propoxy] -4- (5-oxo-5- morpholinopentanamido) phenyl] propanoic acid; JJJ) 2-Fluoro-6- [2-propyl-3- [3- [2-ethyl-5- hydroxy-4- (4- fluorophenyl ) phenoxy] propoxy] phenoxy] benzoic acid disodium salt hydrate;
• AAAA 3- (2- (3- (2-Ethyl-4- (4-fluorophenyl) -5- hydroxyphenoxy) propoxy) phenyl ) -E-propenoic acid;
• 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-f1ouropheny1 ) phenoxy] propoxy] phenoxy] benzoic acid which can also be named 2- [3- [3- (5-ethyl-4 ' - flouro-2-hydroxybiphen-4-yloxy) propoxy] -2- propylphhenoxy] benzoic acid, described in U.S. Patent 5,462,954 as example 66 and also shown below as Compound A (Formula B) :
• 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.
• the subject Heterocycle substituted diphenyl leukotriene antagonists are also 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 C ] _-C ] _o alkyl, aryl, C3-C10 cycloalkyl, C 2 -C 10 alkenyl, C 2 -C ⁇ 0 alkynyl, Cg-C 2 o aralkyl, C -C 2 o alkaryl, C ⁇ -C ⁇ o haloalkyl, C5-C20 aryloxy, or C ⁇ -C ⁇ o alkoxy;
• R2 is hydrogen, halogen, C ⁇ -C ⁇ o haloalkyl, C ⁇ -C ⁇ o alkoxy, C ⁇ -C]_o alkyl, C3-C8 cycloalkyl, Acidic Group, or - (CH2) ⁇ _7 (Acidic Group) ;
• R3 is hydrogen, halogen, C ⁇ -C ⁇ o alkyl, aryl, C]_-C ⁇ o haloalkyl, C]_-C]_o alkoxy, C ⁇ -C ⁇ o aryloxy, C3-C8 cycloalkyl;
• R4 is C1-C4 alkyl, C3-C4 cycloalkyl,
• n 0, 1, 2, 3, 4, 5, or 6;
• Preferred LTB4 Antagonists include the following:
• a "substituted heterocyclic radical” is preferably
• Preferred LTB4 compounds of the invention include 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 l _c 4 alkyl
• Rll is a radical selected from hydrogen, halo, C ⁇ -C ⁇ o alkyl, haloalkyl, C ⁇ -C ⁇ o alkoxy, aryl, or C -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; Location of attachment bond for pyrrole,
• 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 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 of the invention include those wherein Y ⁇ is a divalent linking group selected from the group consisting of substituents represented by the following formulae: -o-
• 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 Y ⁇ 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 C]_-C]_o alkyl, aryl, C -C20 alkaryl, or C -C20 aralkyl .
• Preferred R12 groups are represented by the formulae:
• Preferred Group 2 of Z substituent (symbol, "PG2-Z") : Highly preferred are the acidic groups; -5- tetrazolyl,
• 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.
• 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. III 0.
• Preferred Group 1 of R4 substituent symbol, "PG1-R4":)
• 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 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 antagonists are represented by the following structural formulae:
• the salts of the above diphenyl LTB4 antagonists of the invention 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 . , "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.
• a racemic mixture may be reacted with a single enantiomer of some other compound. This changes the racemic form into a mixture of diastereomers . Then, because the diastereomers have different melting points, different boiling points, and different solubilities, they can be separated by conventional means, such as crystallization.
• Prodrugs are derivatives of the compounds of Formulae (A), (I) and (II), supra., which have chemically or metabolically cleavable groups and become by hydrolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo.
• 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. Particularly
• 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 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
• Ethyl ester prodrugs are prepared in similar fashion using ethanol in place of methanol.
• 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).
• LTB4 antagonists include compounds of Formula A, 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.
• IV. Method of Making the Compounds of the Invention General reaction schemes (not represented to be specific Examples) applicable for synthesis of the LTB4 antagonist compounds represented by formula (I) are set out below. Numerous literature references and Chemical Abstract registry numbers (e.g., RN 152609-60-4) are supplied as additional aids for preparing reagents used in practicing the synthesis schemes of the invention.
• Example (1) a 4-substituted oxazole LTB4 receptor antagonist:
• 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 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) .
• piperidinium salt (122) By the teaching of 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) .
• PdCl 2 (dppf) (-15 mg) were added and heating continued at 110 °C for 20 h.
• the mixture was cooled to room temperature, concentrated in vacuo, diluted with methylene chloride, and filtered down a short plug of silica gel with 20% ethyl acetate/80% hexane. The filtrate was concentrated in vacuo.
• the resulting colorless oil was dissolved in methylene chloride (4 mL) , cooled to 0 °C, and treated with iodotrimethylsilane (0.40 mL, 2.7 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 18 h.
• 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 present invention are a combination of therapeutically effective amounts of the leukotriene (LTB4) antagonists, noted above, and a therapeutically effective amount of an anti-cancer agent or anti-cancer agents.
• 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 anti-cancer agents are formulated independently of the leukotriene (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 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 I and Formula II 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, microcrystalline 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, dichlorodifluoromethane and dich
• 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.
• the pharmaceutical composition of the invention comprises as essential ingredients: (a) an LTB4 antagonist, and
• composition of the invention is prepared in injectable form it is a composition comprising as ingredients: (a) an LTB4 antagonist,
• an injectable liquid carrier (c) an injectable liquid carrier.
• Pharmaceutically acceptable carriers are those well known in the medical arts, such as sterile water, sterile water containing saline, and sterile water containing sugars and/or saline.
• the essential ingredients (a) an LTB4 antagonist and (b) anti-cancer compound are present in the formulation in such proportion that a dose of the formulation provides a pharmaceutically effective amount of each ingredient to the patient being treated.
• the weight ratio of LTB4 antagonist to anti-cancer agent 1:100 to 100 to 1, preferable from 10:1 to 1:10 and most preferable from 1:4 to 4:1.
• formulation examples may employ as active compounds any of the leukotriene (LTB4) antagonists noted above.
• LTB4 leukotriene
• the examples are illustrative only and are not intended to limit the scope of the invention in any way.
• Hard gelatin capsules are prepared using the following ingredients :

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