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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
• • 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
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
  • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
• • 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
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
  • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• Squamous cell carcinoma is the most common malignant neoplasm of the head and neck. It constitutes at least 75% of head and neck cancer in which patients show a high incidence of immunologic deficiencies and inflammatory symptoms. Despite improvements in the treatment modalities over the past 40 years, the 5-year survival rate of approximately 30% has not changed in the same period . Oral squamous cell carcinoma has been linked to excessive cigarette smoking and alcohol abuse, both individually and in combination. Other factors associated with oral cancer include poor dental hygiene and malfitting dentures or broken teeth that cause chronic mucosal irritation. Occupational hazards include chronic dust exposure among woodworkers, which has been associated with cancer of the nasopharynx, and exposure to nickel compounds, which increases the risk of paranasal sinus cancers.
• Epstein-Barr virus (EBV) , the etiologic agent of infectious mononucleosis, has been associated with nasopharyngeal carcinoma.
• Other viruses have also been implicated, including oral herpes simplex virus type 1 and endogenous oncornaviruses .
• Radiation exposure may also predispose persons to head and neck cancers.
• asymptomatic oral cancer appears most often as a red (erythroplastic) lesion.
• Squamous cell carcinoma not diagnosed in its earliest stages appears later as a deep ulcer with smooth, indurated, rolled margins, fixed to deeper tissues. Biopsy is necessary to diagnose carcinoma.
• Squamous cell carcinomas are often diagnosed early because such cancers lead to local symptoms such as pain, hoarseness, and difficulty in swallowing. In many cases, however, diagnosis is delayed because local symptoms or pain from nerve involvement does not occur until a large primary tumor develops. In such cases, regional nodal metastases may be the initial manifestation. Distant metastases rarely occur without locally advanced primary disease or nodal involvement .
• Head and neck cancer may be a panmucosal disease of the upper aerodigestive tract; additional silent synchronous primary lesions occur frequently. Patients with such a clinical picture are predisposed to additional primary head and neck cancers at a later date (the incidence is approximately three to five percent a year) .
• serum ferritin level is reported to accurately reflect the stage and course of disease. (Ferritin is a major iron-storage protein of human tissues and is found in small quantities in the serum. ) However, an elevated serum ferritin level is not specific for head and neck cancer; its level is also elevated in other cancers and in nonmalignant conditions.
• Levels of antibodies to EBV in both established and occult nasopharyngeal carcinoma may be used as a diagnostic tool.
• Measurements of IgA antibodies to viral capsid antigen (anti-VCA) and of IgG antibodies to early antigen (anti-EA) are the most specific tests, particularly for the undifferentiated types of Nasopharyngeal Carcinoma (NPC) .
• Cancers of the head and neck are staged according to the TNM system of the American Joint Committee on Cancer. The classification of the primary tumor (T) varies depending on its site, size, and extent of invasion of and attachment to the surrounding tissues; only tumors of the oral cavity and oropharynx are classified using the same criteria.
• Cervical lymph nodes are classified by the size, number, and distribution (homolateral or bilateral) of affected nodes.
• Disease is also classified by the presence or absence of distant metastases (M) .
• stage I and stage II diseases which are considered limited diseases, are accurately assessed by clinical evaluation
• stage III or locally advanced, disease mainly includes larger primary tumors with or without regional nodal spread (T3NO T1-3N1)
• stage IV disease consists of either massive, extensively invasive primary lesions with variable patterns of nodal involvement (T1-4N2-3,- T4N0-I, or locally advanced disease) or any other TN combination with distant metastases (Mi, or metastatic disease) .
• Chemotherapy is used for palliation of metastatic or recurrent disease or as initial treatment, in combination with surgery and radiotherapy, for locally advanced disease. Because squamous cell carcinoma of the head and neck is a heterogeneous disease that can arise in multiple sites, the response rates to surgery, irradiation, and chemotherapy vary with the primary site of disease. Thus, prognosis is related not only to stage and histopathologic features but also to site and, for patients who are undergoing chemotherapy, to prior treatment.
• arachidonic acid derivatives formed by the action of lipoxygenases are related to various disease states.
• Some of these arachidonic acid metabolites have been classified as members of a family of eicosatetraenoic acids termed leukotrienes .
• Three of these substances are currently thought to be major components of what has been previously called slow reacting substance of anaphylaxis (SRS-A) and have been designated leukotrienes C 4 , D4, and E 4 (LTC4, LTD 4 , and LTE 4 , respectively) .
• LTB4 Another arachidonic acid metabolite, leukotriene B4 (LTB4), is a proinflammatory lipid which has been implicated in the pathogenesis of psoriasis, arthritis, chronic lung diseases, acute respiratory distress syndrome, shock, asthma, inflammatory bowel 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. Antagonism of LTB4 should therefore provide a novel therapeutic approach to treatment of these and other LTB4 mediated conditions.
• Rl is C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C1-C4 alkoxy, (C1-C4 alkyl) thio, halo, or R2- substituted phenyl; each R2 and R3 are each independently hydrogen, halo, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, (C1-C4 alkyl) -S (O)q-, trifluoromethyl , or di-(C ⁇ -C3 alkyl) amino;
• Y is -0- or -CH2-
• Z is a straight or branched chain C1-C10 alkylidenyl ;
• each R ⁇ is independently -COOH, 5-tetrazolyl, -CON ( Rg ) 2, or -CONHSO2R1O;
• each R7 is hydrogen, C1-C4 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, benzyl, methoxy, -W-R6/ -T-G-R6, (C1-C4 alkyl) -T-(Ci-C4 alkylidenyl) -0-, or hydroxy;
• R8 is hydrogen or halo; each R9 is independently hydrogen, phenyl, or Ci- C4 alkyl, or when taken together with the nitrogen atom form a morpholino, piperidino, piperazino, or pyrrolidino group;
• RIO is C1-C4 alkyl or phenyl
• Rll is R2, -W-R6, or -T-G-R6;
• each W is a bond or straight or branched chain divalent hydrocarbyl radical of one to eight carbon atoms
• each G is a straight or branched chain divalent hydrocarbyl radical of one to eight carbon atoms
• each q is independently 0, 1, or 2;
• p is 0 or 1
• t is 0 or 1;
• A is -0- or -S-, R4 is not R ⁇ ;
• A is -0- or -S- and Z is a bond, Y is not -0-;
• W is not a bond when p is 0; or a pharmaceutically acceptable salt or solvate thereof.
• Ci-C ⁇ alkyl refers to the straight and branched aliphatic radicals of 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert- butyl, n-pentyl, 2 , 2-dimethylpropyl, hexyl, and the like. Included within this definition are the terms “C1-C3 alkyl", “C1-C4 alkyl” and "C 1 -C 5 alkyl”.
• C1-C4 alkoxy refers to methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, and tert-butoxy.
• halo refers to fluoro, chloro, bromo, and iodo.
• C 1 -C1 0 alkylidenyl refers to a divalent radical derived from a C 1 -C1 0 alkane such as -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH(C 2 H 5 )-, -CH 2 CH 2 -, -CH 2 CH (CH 3 ) - , -CH(CH 3 )CH 2 -, -CH(CH 3 )CH(CH 3 )-, -CH 2 C (CH 3 ) 2 ⁇ -CH 2 CH (C 2 H 5 ) - , -CH2CH 2 CH 2 - , -CH (CH 3 ) CH 2 CH 2 - , -CH 2 CH (CH 3 ) CH 2 - , -CH 2 CH(C 2 H5)CH 2 -, -CH 2 CH 2 CH (C 2 H 5 ) - , -C (CH 3 ) 2 CH 2 CH 2 -
• C 1 -C 4 alkylidene and “C 2 -C4 alkylidene” .
• C4-C8 cycloalkyl refers to a cycloalkyl ring of four to eight carbon atoms, such as cyclobutyl, cyclopentyl, cyclohexyl, 4, 4-dimethylcyclohexyl, cycloheptyl, cyclooctyl, and the like.
• straight or branched chain divalent hydrocarbyl residue of one to eight carbon atoms refers to a divalent radical derived from a straight or branched alkane, alkene, or alkyne of one to eight carbon atoms. Depending upon the branching and number of carbon atoms, as will be appreciated by organic chemists, such a moiety can contain one, two or three double or triple bonds, or combinations of both. As such, this term can be considered an alkylidene group as defined above containing from 1 to 8 carbon atoms optionally containing one to three double or triple bonds, or combinations of the two, limited as noted in the preceding sentence.
• This invention includes the pharmaceutically acceptable base addition salts of the compounds of Formula I.
• Such salts include those derived from inorganic bases, such as ammonium and alkali and alkaline earth metal hydroxides, carbonates, bicarbonates, and the like, as well as salts derived from basic organic amines, such as aliphatic and aromatic amines, aliphatic diamines, hydroxy alkylamines, and the like.
• bases useful in preparing the salts of this invention thus include ammonium hydroxide, potassium carbonate, sodium bicarbonate, calcium hydroxide, methyl amine, diethyl amine, ethylene diamine, cyclohexylamine, ethanolamine, and the like.
• the potassium and sodium salt forms are particularly preferred.
• This invention includes both mono-salt forms, i.e., a 1:1 ratio of a compound of Formula I with a base as previously described, as well as di-salt forms in those instances where a compound of Formula I has two acidic groups.
• this invention includes any solvate forms of the compounds of Formula I or salts thereof, such as ethanol solvates, hydrates, and the like. It is recognized that in compounds having branched alkyl, alkylidenyl, or hydrocarbyl functionality, and in those compounds bearing double or triple bonds, various stereoisomeric products may exist. This invention is not limited to any particular stereoisomer but includes all possible individual isomers and mixtures thereof.
• the term "5-tetrazolyl” refers to both tautomers, ie, (lH)-5- tetrazolyl and (2H) -5-tetrazolyl .
• a most preferred group of compounds employed in the methods of the present invention are those compounds of Formula la:
• R2 is halo, particularly fluoro.
• Preferred Ri substituents are propyl and especially ethyl.
• Preferred Z substituents include C 2 -C 4 alkylidene, particularly -CH 2 CH2- and -CH2CH 2 CH 2 CH2- .
• Preferred A groups include -0-, -CH 2 -, -CH (R7-substituted phenyl)-, and - ( CH 3 ) 2 -.
• R 4 groups include -COOH, 5-tetrazolyl, or a mono-, di-, or tri-cyclic group as drawn above wherein there is at least one acidic group attached to a ring, such as -W-COOH, -T-G-COOH, or the corresponding tetrazole derivatives.
• the preferred W moiety is that of a bond or straight chain C 1 -C4 alkylidene; preferred G moieties are straight chain C 1 -C 4 alkylidene. It is preferred that R 5 or R 7 be C 1 -C 4 alkyl, especially n-propyl .
• Particularly preferred groups are those wherein A is -CH (R 7 -substituted phenyl)- and R 4 is -COOH or 5- tetrazolyl . Also preferred are those compounds wherein A is -0- and R 4 is
• Preferred aspects of this substructure are those wherein R 7 is C 1 -C 4 alkyl, especially n-propyl, and R 6 is -W-COOH. Particularly preferred are those compounds wherein T is -0- or -S- and W is a bond.
• Particularly preferred compounds of the instant invention include:
• LTB 4 leukotriene B 4 antagonists employed in the methods of the present invention may be synthesized essentially as described in US Patent No. 5,462,954 issued
• Mass spectral data were determined on a CEC-21-110 spectrometer using electron impact (El) conditions, a MAT-731 spectrometer using free desorption (FD) conditions, or a VG ZAB-3F spectrometer using fast atom bombardment (FAB) conditions.
• Silica gel chromatography was performed using ethyl acetate/hexane gradients unless otherwise indicated.
• Reverse-phase chromatography was performed on MCI CHP20P gel using an acetonitrile/water or methanol/water gradient unless otherwise indicated.
• Tetrahydrofuran (THF) was distilled from sodium/benzophenone ketyl immediately prior to use. All reactions were conducted under argon atmosphere with stirring unless otherwise noted. Where structures were confirmed by infra-red, proton nuclear magnetic resonance, or mass spectral analysis, the compound is so designated by "IR”, “NMR”, or “MS”, respectively.
• Example 2 (21.5 g, 38.5 mmol) was hydrolyzed as described above for the preparation of Example 2. The acid was converted to the sodium salt and purified as described above for the preparation of Example 1(D) to provide 16.7 g (77%) of the desired title product as a white amorphous solid: NMR
• the methods of the present invention describe the use of leukotriene antagonists for the treatment or prevention of oral squamous cell carcinoma which is characterized by the excessive release of leukotriene B4.
• leukotriene release refers to an amount of the leukotriene sufficient to cause oral squamous cell carcinoma.
• the amount of leukotriene which is considered to be excessive will depend on a variety of factors, including the amount of leukotriene required to cause the disease, and the species of the mammal involved.
• the success of treating a mammal suffering from or susceptible to oral squamous cell carcinoma characterized by an excessive release of leukotriene with a compound of Formula I will be measured by the regression or prevention of the symptoms of the condition.
• [ 3 H] -LTB 4 (196-200 Ci/mmole) was purchased from New England Nuclear (Boston, MA) . All other materials were purchased from Sigma (St. Louis, MO). Incubations (555 mL) were performed in polypropylene minitubes for 45 minutes at 30°C and contained 25 mg of guinea pig lung membrane protein
• the filters were washed three times with 1 mL of wash buffer. Retained radioactivity was determined by liquid scintillation counting at 50% counting efficiency using Ready Protein Plus cocktail (Beckman, Fullerton, CA) . Nondisplaceable binding was determined in the presence of 1 mM LTB4 and was usually less than 10% of total binding. Data were analyzed using linear regression analysis of log-logit plots of the values between 10% and 90% of control binding to calculate IC 50 S and slope factors (pseudo-Hill coefficients) . IC 50 values thus obtained were corrected for radioligand concentration (Cheng and Prusoff, Biochem. Pharmacol .. 22, 3099 (1973)) to calculate Ki values. pKi is the mean -log Ki for n experiments.
• Tumor development is induced by painting the right cheek pouches of Syrian hamsters (1.5 to 2 months of age) with 0.5% solution of 9 , 10-dimethyl-1, 2-benzanthracene (DMBA) in heavy mineral oil (USP) three times per week for 15 weeks.
• DMBA 10-dimethyl-1, 2-benzanthracene
• USP heavy mineral oil
• the animals are killed, autopsies are performed and both cheek pouches examined for the number and size of tumors.
• the nature of the lesions are subsequently determined histologically after fixing the tissue in 4% formalin and staining with haematoxylin and eosin.
• a dose response is obtained by dividing the animals into 4 experimental groups of 10 hamsters each.
• the groups are: vehicle-treated; 10, 25, and 50 mg/kg/day of a compound of formula I administered orally to the animals.
• the effectiveness of a treatment is accessed by comparing the size and number of squamous cell carcinomas and the number of atypical papillomas of the treated group to that of the vehicle control .
• Clinical Studies Human clinical trials may also be employed to assess the value of the compounds of Formula I in treating oral squamous cell carcinoma.
• the design of clinical trials, use of assessment instruments, and interpretation of these results are well known to clinicians in the field.
• Five to fifty patients are selected for the clinical study. The patients suffer from squamous cell carcinoma.
• the study has a placebo control group, i.e., the patients are divided into two groups, one of which receives a compound of formula I as the active agent and the other receives a standard treatment for squamous cell carcinoma.
• Patients in the test group receive between 30-1500 mg of the drug per day by the oral or parenteral route. They continue this therapy for 3-12 months.
• the therapeutic and prophylactic treatments provided by this invention are practiced by administering to a mammal in need thereof a dose of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, that is effective to inhibit or treat oral squamous cell carcinoma.
• inhibitor includes its generally accepted meaning which includes prohibiting, preventing, restraining and slowing, stopping or reversing progression, severity or a resultant symptom.
• the present method includes both medical therapeutic and/or prophylactic administration as appropriate.
• the compounds are usually administered in the form of pharmaceutical formulation comprising a pharmaceutically acceptable excipient and at least one compound of the present invention.
• the compounds or formulations of the present invention 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 0.01 to 90% 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.
• Such formulations are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. See, e.g.. REMINGTON
• the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container.
• a carrier which can be in the form of a capsule, sachet, paper or other container.
• the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
• Suitable carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, tragacanth, gelatin, water, syrup, and methyl cellulose.
• the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates ; sweetening agents; and flavoring agents.
• the compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art .
• the compounds of this invention may be delivered transdermally using known transdermal delivery systems and excipients.
• a compound of this invention is admixed with permeation enhancers including, but not limited to, propylene glycol, polyethylene glycol monolaurate, and azacycloalkan-2-ones, and incorporated into a patch or similar delivery system.
• permeation enhancers including, but not limited to, propylene glycol, polyethylene glycol monolaurate, and azacycloalkan-2-ones, and incorporated into a patch or similar delivery system.
• Additional excipients including gelling agents, emulsifiers, and buffers may be added to the transdermal formulation as desired.
• a compound of this invention ideally can be admixed with any variety of excipients in order to form a viscous liquid or cream-like preparation.
• a compound of this invention ideally can be admixed with carriers and diluents and molded into tablets or enclosed in gelatin capsules.
• 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 include capsules, tablets and injectable solutions. Especially preferred are capsules and tablets.
• compositions may be provided in unit dosage 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.
• 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 specific dose of a compound administered according to this invention to obtain therapeutic or prophylactic effects will, of course, be determined by the particular circumstances surrounding the case, including, for example, the route of administration the age, weight and response of the individual patient, the condition being treated and the severity of the patient ' s symptoms .
• a preferred embodiment when administering compounds of Formula I orally to mammals comprises administering compounds bearing a single acidic Re functionality .
• Hard gelatin capsules are prepared using the following ingredients :
• a tablet is prepared using the ingredients below: Ouantity (mg/tablet)
• the components are blended and compressed to form tablets each weighing 665 mg.
• An aerosol solution is prepared containing the following components:
• Propellant 11 10.25 ( trichlorofluoromethane)
• Tablets each containing 60 mg of active ingredient are made up as follows:
• Capsules each containing 80 mg of medicament are made as follows:
• the active ingredient, cellulose, starch and magnesium stearate are blended, passed through a No . 45 mesh U.S. sieve, and filled into hard gelatin capsules in 200 mg quantities .
• Suppositories each containing 225 mg of active ingredient are made as follows:
• the medicament is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethylcellulose, sugar, and a portion of the water to form a suspension.
• the parabens, flavor and color are dissolved and diluted with some 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 ingredients generally is administered intravenously to a subject at a rate of 1 ml per minute.

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