EA002742B1 - Leukotriene antagonists for oral squamous cell carcinoma - Google Patents

Abstract

1. A method for treating or inhibiting oral squamous cell carcinoma in a mammal which comprises administering to a mammal in need thereof an effective amount of a compound of the formula or a pharmaceutically acceptable salt thereof of an addition base, wherein R1 is C1-C5 alkyl, C1-C4 alkenyl, (C1-C4 alkyl)thio, halo, or R2 substituted phenyl; each R2 and R1 are each independently hydrogen, halo, hydroxy, C1-C4 alkyl, C1-C4 alkoxy; Y and X are -O- or -CH2-; Z is CH2-CH2 or CH2CH2CH2CH2; A is -O-, -CH2-, CH(R7-substituted phenyl)- or -C(CH3)2-; R4 is each R7 is hydrogen, C1-C4-alkyl, R8 is hydrogen or halogen; and with the proviso that when X is -O-, Y is not O. 2. The method as claimed in Claim 1, wherein a compound is 2-[2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]propoxy]phenoxy]benzoic acid or a pharmaceutically acceptable salt or solvate thereof. 3. The method as claimed in Claim 1, wherein a compound is 3-(2-(3-(2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy)propoxy)-6-(4-carboxy-phenoxy)phenyl)propionic acid or a pharmaceutically acceptable salt or solvate thereof. 4. The method as claimed in Claim 1, wherein a compound is 1-(4-(carboxy-methoxy)phenyl)-1-(1H-tetrazol-5-yl)-6-(2-ethyl4- (4-fluorophenyl) -5-hydroxyphenoxy)hexane or a pharmaceutically acceptable salt or solvate thereof. 5. The method as claimed in Claim 1, wherein a compound is 3-[4-[7-carboxy-9-oxo-3-[3-[2-ethyl-4-(4-fluorophenyl)-5- hydroxyphenoxyi -propoxy] -9H-xanthene] ] propanoic acid or a pharmaceutically acceptable salt or solvate thereof. 6. The method as claimed in Claim 1, wherein a compound is 5- [3-[2-(1-carboxy)-ethyl]-4-[3-[2-ethyl-4-(4-fluorophenyl)-5- hydroxyphenoxy] -propoxy] phenyl] -4-pentynoic acid or a pharmaceutically acceptable salt or solvate thereof. 7. The method as claimed in Claims 1 to 6 in which the mammal is a human.

Description

Epithelial squamous cell carcinoma is the most common malignant neoplasm of the head and neck. It accounts for at least 75% of head and neck cancers, and in these patients immunodeficiency and inflammation symptoms are detected with a high frequency. Despite improvements in treatment over the past 40 years, a 5-year survival period of approximately 30% of patients has not changed during the same period.

Epithelial squamous cell carcinoma of the oral cavity is associated with excessive cigarette smoking and alcohol abuse, both separately and in combination. Other factors associated with oral cancer include poor oral hygiene and improper fitting of dentures or broken teeth that cause chronic inflammation of the mucous membrane. Occupational hazards include chronic exposure to dust in woodworkers, carpenters, and wood turners associated with nasopharyngeal cancer, and contact with nickel compounds, which increases the risk of sinus cancer.

Epstein-Barr virus (EBV), an etiological agent of infectious mononucleosis, is associated with nasopharyngeal carcinoma. Other viruses are suspected, including the herpes simplex virus (Negre8 simplex) type 1 of the oral cavity and endogenous oncornaviruses.

Radiation exposure, as well as deficiencies in the diet, can also predispose individuals to head and neck cancer.

Approximately 90% of oral cancer with a high risk of occurrence is found only in some areas: the bottom of the oral cavity, the ventrolateral side of the tongue and the soft palate complex. It is necessary to take into account cancer of the cheeks and lips of the vestibule of the mouth in people who use smokeless tobacco.

Head and neck cancer occurs in four main places:

oral cavity, pharynx, larynx, and nasal and paranasal sinuses. These localizations are divided into various constituent areas. The most common places for disease localization are the oral cavity and oropharynx, which is a little less common than in 50% of cases, after which there is a larynx, which occurs in about 30% of cases.

In the early stages, asymptomatic oral cancer most often has the appearance of reddish (erythroplastic) lesions. Squamous epithelial carcinoma, not diagnosed in the early stages, later looks like a deep ulcer with smooth, densified flattened edges fused with deeper tissues. A biopsy is needed to diagnose carcinoma.

Squamous cell epithelial carcinoma is often diagnosed in its early stages due to local symptoms such as pain, hoarseness, and difficulty swallowing. However, in many cases, the diagnosis is delayed, because local symptoms or pain from the nerves involved in the process do not appear until a large primary tumor develops. In such cases, regional nodular metastases may be the initial manifestation. Distant metastases rarely appear without a locally manifested primary disease or the appearance of nodes.

Cancer of the head and neck can be a disease of the entire mucosa of the upper respiratory and digestive tracts, often there are additional silent synchronous primary lesions. Patients with this clinical picture are predisposed to additional primary cancers of the head and neck at a later date (the frequency of occurrence is approximately three to five percent per year).

Although there are several markers of head and neck cancer, it is reported that ferritin levels accurately reflect the stage and course of the disease (ferritin is the main protein that stores iron and is found in small amounts in serum). However, elevated serum ferritin levels are not specific to head and neck cancer; its level also increases with cancer of a different localization and with pathological conditions without malignant neoplasms.

The level of antibodies to EBV with established and latent carcinoma of the nasopharynx can be used as a diagnostic tool. The most specific tests are titers of IgA antibodies to viral capsid antigen (anti-VCA) and IgG antibodies to early antigen (anti-EA), especially for unidentified types of nasopharyngeal carcinoma (NGC, NPC).

Head and neck cancer is divided into stages under the TNM system of the American Joint Committee on Cancer. The classification of the primary tumor (O, T) varies depending on its location, size and degree of invasion into the surrounding tissue and its binding; only oral and oropharyngeal tumors are classified using similar criteria. When the lesion cannot be accurately measured, the number of affected locations is used to determine stage T. Cervical lymph nodes (Y, N) are classified by size, number and location (homolateral or bilateral) of the affected nodes. The disease is also classified by the presence or absence of distant metastases (M). The general stage of the disease is determined by TNM stage: stage I and stage II diseases, which are considered limited diseases, are accurately determined using clinical evaluation; stage III disease, or locally far advanced disease, mainly includes large primary tumors with or without regional distribution of nodes (T ₃ N ₀ , T _1-3 N ₁ ); and stage IV disease is a massive, extensively invasive primary lesion with a variety of types of nodular lesions (T _1-4 N0-i or locally advanced disease) or any other combination of TN with metastases removed (M ₁ or metastatic disease).

Although surgical treatment and radiotherapy remain the basis of treatment, chemotherapy is playing an increasingly important role in the treatment of this disease. Chemotherapy is used to reduce metastasis and relapse, or as an initial treatment in combination with surgery and radiotherapy in a locally advanced process.

Since epithelial squamous cell carcinoma of the head and neck is a heterogeneous disease that can occur in many places, the degree of reaction to surgery, radiation and chemotherapy varies depending on the site of the primary disease. Thus, the prognosis is associated not only with the stage and with histopathological features, but also with localization, and for patients who undergo chemotherapy, with previous treatment.

The treatment strategy is determined by the stage of the disease. At the early stage of the disease, either surgical treatment or radiotherapy can be used, since they give similar survival results. The choice depends on the expected manifestations of the disease during treatment (for example, loss of speech or a functional defect in surgical treatment, or severe dry mouth, or a changed taste due to radiotherapy), as well as the urgency of treatment. With a more advanced local disease, surgical treatment and radiotherapy are combined, as this approach provides the best suppression of local disease. Radiotherapy can be used either before or after surgery. Prophylactic radiotherapy is often used to drain locations in the lymph nodes, which have a high risk of microscopic inclusions. For patients with a far-reaching local disease, chemotherapy is included in the initial treatment plan, since a five-year life expectancy without a disease is usually low for such patients (10-30%) when conventional surgery, radiotherapy, or both are used.

There is an increased interest in the fact that treatment methods such as surgical, radiotherapy and chemotherapy can adversely affect the patient's natural immunity, which possibly increases the chances of growth of residual or metastatic tumor cells. This focused not only on early detection and better treatment, but also on expanding research into the possible etiology of the disease.

Studies in the field of allergic reactions of the lung have confirmed that the derivatives of arachidonic acid formed by the action of lipoxygenases are associated with various painful conditions. Some of these metabolites of arachidonic acid have been classified as members of a family of eicosatetraenoic acids called leukotrienes. Three of these substances are now thought to be the main components of what was previously called the slow anaphylaxis reaction substance (SRS-A), and have been called the leukotrienes C4, D4 and E4 (LTC ₄ , LTD ₄ and LTE ₄ , respectively) .

Another metabolite of arachidonic acid, leukotriene B4 (LTB4), is a pro-inflammatory lipid that is believed to be involved in the pathogenesis of psoriasis, arthritis, chronic lung disease, acute respiratory distress syndrome, shock, asthma, inflammatory bowel disease and other inflammatory conditions characterized by infiltration and activation of neutrophilic white blood cells and other pro-inflammatory cells. Neutrophilic leukocytes activated in this way secrete tissue-destroying enzymes and reactive chemicals that cause inflammation. The antagonism of LTB4 should therefore provide a new therapeutic approach to the treatment of these and other LTB4 mediated pathological conditions.

Due to the debilitating effect of epithelial squamous cell carcinoma, there remains a need for its effective treatment.

This invention is a method of treating or suppressing epithelial squamous cell carcinoma of the oral cavity, which comprises administering to the mammal, if necessary, an effective amount of a compound of formula I

Ri where

R ₁ represents C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, QQ alkynyl, C ₁ -C ₄ alkoxy, (C ₁ -C ₄ alkyl) thio, halogen, or I ₂ -substituted phenyl;

each R ₂ and R ₃ independently represents hydrogen, halogen, hydroxy, C ₁ -C ₄ -alkyl, C ₁ -C ₄ alkoxy, (C _g C ₄ -alkyl) ^ (O) d-, trifluoromethyl or di- (C ₁ -C ₃ -alkyl) amino;

X represents —O—, —S—, —C (═O) or —CH ₂ -;

Y represents —O— or —CH ₂ -; or when taken together, —XY— represents —CH═CH — or —C = C—;

Z represents a straight or branched chain Ci-Ci-alkylidenyl;

A is a bond, —O—, —S—,

- CH = CH- or -CR _a R _b -, where

R _a and R _b each independently represent hydrogen, QQ-alkyl or Rv-substituted phenyl, or when taken from the carbon atom to which they are attached, they form a C ₄ -C ₈ cycloalkyl ring;

R ₄ represents R

where each R independently represents COOH, 5-tetrazolyl, —CON (R ₉ ) ₂ , or CONHSO ₂ R ₁₀ ; each R ₇ represents hydrogen,

C ₁ -C ₄ -alkyl, C ₂ -C ₅ -alkenyl, C ₂ -C ₅ -alkynyl, benzyl, methoxy, -W-Re, -TG-R6, (C ₁ -C ₄ -alkyl) -T ( C ₁ -C ₄ -alkylidenyl) -O- or hydroxy;

R8 represents hydrogen or halogen;

each R ₉ independently represents hydrogen, phenyl or C ₁ -C ₄ alkyl or, when taken together with a nitrogen atom, forms a morpholino, piperidino, piperazino or pyrrolidino group;

R ₁₀ represents QQ alkyl or phenyl;

R ₁₁ represents R ₂ , —W — R6, or —T ^GR 6;

each W represents a bond or a divalent hydrocarbyl radical with a straight or branched chain of one to eight carbon atoms;

each G represents a divalent hydrocarbyl radical with a straight or branched chain of one to eight carbon atoms;

each T represents a bond, —CH ₂ -, —O—, —NH—, —NHCO—, —C (= O) - or —S (O) _q -;

K represents —C (═O) - or —H (OH) -; each q independently represents

0, 1 or 2;

p is 0 or 1; and t is 0 or 1;

provided that when X is —O— or —S—, then Y is not —O—;

provided that when A is —O— or —S—, then R _{4 is} not R ^;

with the proviso that when A is —O— or —S—, and Z is a bond, Y is not —O—; and provided that W is not a bond when p is 0;

or a pharmaceutically acceptable salt or solvate thereof.

The following definitions refer to the various terms used in this description.

The term “Q-Cb-alkyl” refers to straight or branched chain aliphatic radicals of 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, secondary butyl, tert-butyl, n-pentyl, 2 , 2 dimethylpropyl, hexyl and the like. The terms “Q-Qalkyl”, “C ₁ -C ₄ -alkyl” and “C ₁ -C ₅ -alkyl” are included in this definition.

The term “C ₂ -C ₅ alkenyl” refers to straight or branched chain aliphatic radicals of 2-5 carbon atoms containing one double bond, such as —CH = CH ₂ , —CH ₂ CH = CH ₂ , CH2CH2CH = CH2 , -CH2C (CH3) = CH2, -CH2CH = C _{(CH3) 2} and the like.

The term “C ₂ -C ₅ alkynyl” refers to aliphatic residues of 2-5 carbon atoms containing one triple bond, such as —CH — H, —CH ₂ —CH _— H, —CH ₂ CH ₂ C ξ CH, —CH ₂ CH (CH ₃ ) C ξ CH, —CH ₂ C ξ CHCH ₃ and the like.

The term “C ₁ -C ₄ alkoxy” refers to methoxy, ethoxy, propoxy, isopropoxy, butoxy, secondary butoxy and tert-butoxy.

The term "halogen" refers to fluorine, chlorine, bromine and iodine. The term "C ₁ -C ₁₀ alkylidenyl" refers to divalent radicals derived from a C ₁ -C ₁₀ alkane, such as -CH2-, -CH (CHe), -C (CHe) 2-, -CH (C2H5) - , -CH2CH2-, -CH2CH (CH3) -, -CH (CH3) CH2-, -CH (CH3) CH (CH3) -, -CH2 C (CH3) 2-, -CH2 CH ^^) -, -CH2CH2CH2 -, -CH (CH3) CH2CH2-, -CH2CH (CH3) CH2-, -CH2CH (C2H5) CH2-, -CH2 CH ₂ CH (C ₂ H ₅ ) -, -C (CH ₃ ) ₂ CH ₂ CH ₂ -, -CH (CH ₃ ) CH ₂ CH (CH3) -, -CH2CH2CH2CH2-, -CH2C (CH3) 2CH2CH2-, -CH2C (CH3) 2CH2-, -CH2CH2CH (C2H5) CH2-, -CH2CH2CH2CH2CH2CH2CH2 (CH3) CH2-SN2SN2SN2-, -SN2SN2SN2SN2SN2SN2-, _{(CH2) 10} -, and the like. The terms “C ₁ -C ₄ -alkylidene” and “C ₂ -C ₄ -alkylidene” are also included in this definition.

The term “C ₄ = C ₈ -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.

The term "divalent hydrocarbyl residue of one to eight straight or branched chain carbon atoms" refers to a divalent radical derived from an alkane, alkene or alkyn of one to eight straight or branched chain carbon atoms. Depending on the branching and the number of carbon atoms, as will be appreciated by those skilled in organic chemistry, such a substituent may contain one, two or three double or triple bonds, or a combination thereof. 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 a combination of the two, with the limitations indicated in the previous sentence.

This invention includes pharmaceutically acceptable salts with a base addition of compounds of formula I. Such salts include those obtained with inorganic bases such as ammonia and alkali and alkaline earth metal hydroxides, carbonates, bicarbonates and the like, as well as salts obtained with basic organic amines such as aliphatic and aromatic amines, aliphatic diamines, hydroxyalkylamines and the like. Such bases useful for preparing the salts of this invention thus include ammonium hydroxide, potassium carbonate, sodium bicarbonate, calcium hydroxide, methylamine, diethylamine, ethylenediamine, cyclohexylamine ethanolamine and the like. Potassium and sodium salts are particularly preferred.

This invention includes both monosalt forms, i.e. a compound of formula I with a base in a ratio of 1: 1, as described above, and disaltered forms, in cases where the compound of formula I has two acid groups. In addition, this invention includes any solvate forms of the compounds of formula I or their salts, such as ethanol solvates, hydrates and the like.

It is known that for compounds having branched alkyl, alkylidenyl or hydrocarbyl functional groups and for those compounds having double or triple bonds, various stereoisomeric products may exist. This invention is not limited to any particular isomer, but includes all characteristic isomers and mixtures thereof. The term “5-tetrazolyl” refers to both tautomers, i.e. (1H) -5-tetrazolyl; and (2H) -5-tetrazolyl.

The most preferred group of compounds used in the methods of this invention are compounds of formula 1a. He

Rl la and their pharmaceutically acceptable salts with the addition of a base. Particularly preferred are those compounds wherein R ₂ is halogen, in particular fluorine. Preferred R ₁ substituents are propyl, and especially ethyl.

Preferred Z-substituents include C ₂ -C ₄ alkylidene, particularly preferably —CH ₂ CH ₂ - and —CH ₂ CH ₂ CH ₂ CH ₂ -. Preferred A groups include —O—, —CH ₂ -, —CH ^ ₇ substituted phenyl) - and - (CH ₃ ) ₂ -.

Preferred R ₄ groups include —COOH, 5-tetrazolyl, or a mono-, di- or tricyclic group as described above, wherein at least one acid group attached to the ring exists, such as —W-COOH, - TG-COOH or the corresponding tetrazole derivatives. A preferred W moiety is that of a straight chain or C ₁ -C ₄ alkylidene; preferred G substituents are straight chain C ₁ -C ₄ alkylidenes. Preferably, R ₅ or R ₇ are C ₁ -C ₄ alkyl, especially n-propyl.

Particularly preferred groups are those in which A is —CH (K ₇ substituted phenyl) - and R 4 is —COOH or 5-tetrazolyl. Also preferred are those compounds wherein A is —O—, and R ₄ is

r ₇ r ₆

Preferred aspects of this substructure are also when R ₇ is C ₁ -C ₄ alkyl, especially n-propyl, and R ₆ is —W-COOH. Particularly preferred are those compounds in which T is —O— or —S—, and W is a bond.

Particularly preferred compounds of this invention include

2- [2-propyl-3- [3- [2-ethyl-4- (4-fluorophenyl) 5-hydroxyphenoxy] propoxy]] benzoic acid;

3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -6- (4-carboxyphenoxy) phenyl) propionic acid;

1- (4- (carboxymethoxy) phenyl) -1- (1Netetrazol-5-yl) -6- (2-ethyl-4- (4-fluorophenyl) -5hydroxyphenoxy) hexane;

3- [4- [7-carboxy-9-oxo-3- [3- [2-ethyl-4- (4fluorophenyl) -5-hydroxyphenoxy] propoxy] -9Hxanthene]] propanoic acid and

5- [3- [2- (1-carboxy) ethyl] -4- [3- [2-ethyl-4- (4fluorophenyl) -5-hydroxyphenoxy] propoxy] phenyl] -4-pentinic acid or their pharmaceutically acceptable salts or solvates.

Leukotriene B4 antagonists (LTB4) used in the methods of the invention can be synthesized essentially as described in US Pat. No. 5,462,2954, published October 31, 1995, the entire contents of which are incorporated herein by reference.

The following examples further illustrate the preparation of the compounds used in this invention. The examples are illustrative only and are not intended to limit the scope of the invention. Melting points are determined on a Thomas Huver apparatus and are uncorrected. NMR spectra were determined on a GE QE-300 spectrometer. All chemical shifts are presented in parts per million (_) relative to tetramethylsilane. Chemical shifts of aromatic protons of quinoline compounds in DMSO-b ₆ are concentration dependent. The following abbreviations were used to indicate the characteristics of the signals: c = singlet, d = doublet, t = triplet, q = quartet, w = wide, m = multiplet. Infrared spectra were determined on a Nicolet DX FT-IR spectrometer. Mass spectral data were determined on a SEC-21-110 spectrometer using electron impact conditions (El), a MAT-731 spectrometer using free desorption conditions (FD), or on a VG ZAB-3F spectrometer using fast atom bombardment conditions (FAB). Silica gel chromatography was performed using ethyl acetate / hexane gradients, unless otherwise indicated. Reverse phase chromatography was performed on an MCI CHP20P gel using acetonitrile / water or methanol / water gradients, unless otherwise indicated. Tetrahydrofuran (THF) was distilled from sodium benzophenonketyl immediately before use. All reactions are carried out in an argon atmosphere with stirring, unless otherwise indicated. Where structures have been confirmed by infrared spectral analysis, proton-nuclear magnetic resonance or mass spectral analysis, the compounds are respectively indicated as “IR”, “NMR” or “MS”.

Example 1. 3- [2- [3 - [(5-Ethyl-2-hydroxy [1,1'-biphenyl] -4-yl) oxy] propoxy] -1-dibenzofuran] propanoic acid disodium salt.

A. Preparation of 3,3-diethoxy-2,3-dihydro1H-benzofuro [3,2- £ | [1] benzopyran.

A solution of 2-hydroxydibenzofuran (5.00 g, 27.2 mmol), triethyl orthoacrylate (10.1 g, 54.3 mmol) and pivalic acid (1.39 g, 13.6 mmol) in toluene (100 ml) was boiled with reflux for 18 hours. The mixture was cooled to room temperature and washed once with water and once with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain an orange oil. This material was diluted with hexane and stored at -20 ° C for 18 hours. The resulting crystals were collected by vacuum filtration to obtain 5.67 g (67%) of the desired intermediate, mp. 64 ° C; NMR (CDCl ₃ ) 7.96 (d, J = 7.8 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.46 (t, J = 8 Hz, 1H) , 7.35 (m, 2H), 7.06 (d, J = 8.8 Hz, 1H), 3.82 (q, J = 7.2 Hz, 2H), 3.73 (q, J = 6.8 Hz, 2H), 3.35 (t, J = 6.9 Hz, 2H), 2.29 (t, J = 7.0 Hz, 2H), 1.23 (t, J = 7, 1 Hz, 6H); MC-FD m / e 312 (p); IR (CH ₃ , cm ^-1 ) 2982, 1494, 1476, 1451, 1434, 1251, 1090, 1054, 975.

Analysis for C ₁₉ H ₂₀ O ₄ :

Calculated: C 73.06; H 6.45;

Found: C, 72.81; H, 6.72.

B. Preparation of 3 [1 - (2-hydroxydibenzofuran)] - propanoic acid ethyl ester.

A mixture of 3,3-diethoxy-2,3-dihydro-1H-benzofuro- [3,2- £ | [1] benzopyran (3.50 g, 11.2 mmol) and a 10% aqueous solution of hydrochloric acid (5 ml) in ethyl acetate (30 ml) was stirred at room temperature for 1 h. The resulting mixture was washed once with water, dried over sodium sulfate, filtered and concentrated in vacuo to give a tan solid. Recrystallization from hexane / ethyl acetate gave 3.11 g (98%) of the desired intermediate as an off-white crystalline solid: mp. 128-131 ° C; NMR (CDCI3) 7.88 (d, J = 7.7 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.47 (t,

J = 7.2 Hz, 1H), 7.37 (d, J = 8.9 Hz, 1H), 7.36 (t,

J = 6.6 Hz, 1H), 7.13 (d, J = 8.8 Hz, 1H), 7.13 (q, J = 8.8 Hz, 2H), 3.43 (t, J = 5.8 Hz, 2H), 3.01 (t, J = 7.7 Hz, 2H), 1.23 (t, J = 7.2 Hz, 3H); MC-FD m / e 284 (100, p) 256 (65), 238 (17); IR (KBr, cm ^-1 ) 2985 (b), 1701, 1430, 1226, 1183, 1080.

Analysis for C ₁₇ H ₁₆ O ₄ :

Calculated: C 71.82; H 5.67;

Found: C, 71.90; H, 5.43.

C. Preparation of 3 [2- [3- [[5-ethyl-2- (phenylmethoxy) - [1,1'-biphenyl] 4-yl] oxy] propoxy] -1-dibenzofuran] propanoic acid ethyl ester.

3- [1- (2hydroxydibenzofuran)] propanoic acid ethyl ester (625 mg, 2.20 mol) was dissolved in dimethylformamide (10 ml) and carefully reacted at room temperature with 95% sodium hydride (58 mg, 2.4 mmol). When gas evolution ceased, 2-benzyloxy-1-phenyl-5-ethyl-4- (3-chloro-1-propyloxy) benzene (836 mg, 2.20 mmol) was added, and the resulting mixture was stirred for 18 hours. The mixture was diluted with ether and washed once with water.

The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a dark oil. Chromatography on silica gel (ethyl acetate / hexane) afforded 200 mg (14%) of the desired intermediate as a colorless oil: NMR (COC1 ₃ ), 8.11 (d, J = 7.7 Hz, 1H), 7.57 (m , 3H), 7.48 (t, J = 7.3 Hz, 1H), 7.20-7.44 (m, 10H), 7.17 (s, 2H), 7.08 (d, J = 8.9 Hz, 1H), 6.67 (s, 1H), 5.05 (s, 2H), 4.29 (t, J = 6.2 Hz, 2H), 4.26 (t, J = 6.1 Hz, 2H), 4.15 (q, J = 7.2 Hz, 2H), 3.54 (t, J = 8.5 Hz, 2H), 2.67 (m, 4H), 2 37 (t, J = 6.0 Hz, 2H); 1.21 (m, 6H).

D. Preparation of 3- [2- [3 [(5-ethyl-2-hydroxy- [1,1'-biphenyl] -4-yl) oxy] propoxy] -1-dibenzofuran] propanoic acid disodium salt.

To a 3- [2- [3 - [[5-ethyl-2- (phenylmethoxy) - [1,1'-biphenyl] -4-yl] oxy] propoxy] -1 dibenzofuran] propanoic acid ethyl purged solution of ethyl ester (200 mg, 0.318 mmol) in a methanol / tetrahydrofuran mixture (40 ml) 1: 1 was added 10% palladium-carbon (25 mg). The resulting suspension was subjected to hydrogenation at a pressure of 1 atm for 24 hours at room temperature. The mixture was filtered through a short pad of Florisil® (Florisil®), and the filtrate was concentrated in vacuo. The residue was dissolved in a 1: 1 methanol / tetrahydrofuran mixture (20 ml) and reacted with a 5N sodium hydroxide solution (2 ml) at room temperature for 24 hours. The resulting mixture was extracted once with diethyl ether. The aqueous layer was acidified with 5N hydrochloric acid and extracted twice with methylene chloride. The combined methylene chloride fractions were concentrated under reduced pressure. The residue was dissolved in at least 1 N sodium hydroxide solution and purified on 2P-20 resin to obtain 53 mg (30%) of the desired product as a fluffy white solid. NMR (DMSO-Y6) 8.12 (d, J = 6.9 Hz, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.37-7.57 (m, 5H) 7.30 (m, 2H), 7.14 (m, 2H), 6.96 (s, 1H), 6.93 (s, 1H), 4.30 (t, J = 7.3 Hz, 2H), 4.14 (t, J = 5.4 Hz, 2H), 2.48 (m, 4H), 2.23 (m,

4H), 1.10 (t, J = 7.6 Hz, 3H); MC-FAB m / e 555 (88, p + 1), 533 (62);

IR (CHC1 ₃ , cm ^-1 ) 3384 (b), 2969, 1566, 1428, 1257, 1181.

Analysis for C ^ H ^^ ay Calculated: C 69.31; H 5.09;

Found: C, 69.51; H, 5.39.

Example 2. Disodium Monohydrate

7-carboxy-9-oxo-3 - [3- (2-ethyl-5-hydroxy-4 phenylphenoxy) propoxy] -9H-xanthene-4-propanoic acid.

COONa

A mixture of 2-benzyloxy-1-phenyl-5-ethyl-4- (3 chloro-1-propyloxy) benzene (749 mg, 1.97 mmol), ethyl-7-carboethoxy-3-hydroxy-9-oxo9H-xanthene 4-propanoate (729 mg, 1.97 mmol), potassium carbonate (1.36 g, 9.85 mmol) and potassium iodide (33 mg, 0.20 mmol) were refluxed for 24 hours. Dimethyl sulfoxide ( 2 ml) and heating was continued for 24 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed once with water. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a tan solid. This material was dissolved in ethyl acetate (30 ml) and the resulting solution was purged with nitrogen. To this solution was added 10% palladium-carbon (120 mg) and the resulting suspension was hydrogenated under a pressure of 1 atm. The solution was filtered and concentrated in vacuo to give a colorless oil. This material was dissolved in a methanol / tetrahydrofuran solution (30 ml) 1: 1 and reacted with a 5N sodium hydroxide solution (2 ml) at room temperature for 18 hours. The resulting solution was extracted once with diethyl ether and the aqueous layer was acidified with a 5N hydrochloric acid solution. . The resulting precipitate was collected by suction filtration. This material was converted to the disodium salt and purified as described above for the preparation of Example 1 (D) to give 390 mg (56%) of the desired product as a fluffy white solid:

NMR (DMSO-b ₆ ) 12.65 (s, 1H, -OH), 8.65 (s, 1H), 8.28 (dd, J = 8.5, 2.0 Hz, 1H), 8, 01 (d, J = 8.9 Hz, 1H), 7.50 (m, 3H), 7.29 (t, J = 7.8 Hz, 2H), 7.17 (m, 2H), 6, 93 (s, 1H), 6.89 (s, 1H), 4.26 (m, 4H), 3.12 (m, 2H), 2.47 (m, 2H), 2.23 (m, 2H) ), 1.10 (t, J = 7.4 Hz, 3H); MC-FAB m / e 627 (24, p), 605 (40), 583 (24), 331 (24), 309 (100); IR (KBr, cm ^-1 ) 3419 (b), 2962, 1612, 1558, 1443, 1390, 1277, 1084.

Analysis for SzSh ^ OrKa ^ S ^:

Calculated: C 63.34; H 4.69;

Found: C, 63.36; H 4.50.

Example 3. Sodium salt of 2- [2-propyl-3 [3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy] propoxy]] benzoic acid.

A. Preparation of methyl ester

2- [2-propyl-3 - [3- [2-ethyl-4- (4-fluorophenyl) -5 (phenylmethoxy) phenoxy] propoxy] phenoxy] benzoic acid.

A mixture of 2-benzyloxy-1- (4-fluorophenyl) -5ethyl-4- (3-chloro-1-propyloxy) benzene (20.0 g, 50.2 mmol) and sodium iodide (75.3 g, 502 mmol) in 2-butanone (200 ml) was refluxed for 6 hours. The mixture was diluted with ether and washed once with water. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a colorless oil. This material was dissolved in dimethylformamide (100 ml) and reacted with 2- (3-hydroxy-2-propylphenoxy) benzoic acid methyl ester (14.4 g, 50.2 mmol) and potassium carbonate (20.8 g, 151 mmol) at room temperature for 24 hours. This mixture was diluted with water and extracted twice with ether. The aqueous layer was separated and again extracted once with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give a yellow oil. Chromatography on silica gel afforded 25.4 g (78%) of the desired intermediate as a pale gold oil: NMR (COC1 ₃ ) 7.91 (1, J = 7.8 Hz, 1H), 7.54 (d, J = 8 6 Hz, 1H), 7.52 (t, J = 8.5 Hz, 1H), 7.25-7.43 (m, 6H), 7.03-7.38 (m, 5H), 6 84 (d, J = 8.3 Hz, 1H), 6.71 (d, J = 8.1 Hz, 1H), 6.63 (s, 1H), 6.47 (d, J = 8, 1 Hz, 1H), 5.03 (s, 2H), 4.24 (t, J = 5.7 Hz, 2H), 4.21 (t, J = 5.8 Hz, 2H), 3.86 (s, 3H), 2.69 (t, J = 7.8 Hz, 2H), 2.64 (t, J = 7.7 Hz, 2H), 2.34 (quintet, J = 6.0 Hz , 2H), 1.60 (hexet, J = 5.0 Hz, 2H), 1.22 (t, J = 7.5 Hz, 3H), 0.94 (t, J = 7.5 Hz, 3H ); MCFD m / e 648 (p); IR (CHC1 ₃ , cm ' ¹ ) 2960, 1740, 1604, 1497, 1461, 1112.

Analysis for C ₄₁ H ₄₁ O ₆ F:

Calculated: C 75.91; H 6.37;

Found: C, 76.15; H, 6.45.

B. Preparation of 2- [2-propyl-3- [3- [2-ethyl-4- (4-fluorophenyl) -5 (hydroxy) phenoxy] propoxy] phenoxy] benzoic acid methyl ester.

2- [2-Propyl-3 [3- [2-ethyl-4- (4-fluorophenyl) -5- (phenylmethoxy) phenoxy] propoxy] phenoxy] benzoic acid methyl ester (33.0 g, 50.9 mmol) were debenzylated as described above for the preparation of Example 2 to give 27.3 g (96%) of the title intermediate as an amber oil: NMR (CDCl ₃ ) 7.90 (dd, J = 7, 8, 1.7 Hz, 1H), 7.42 (m, 3H), 7.05-7.23 (m, 4H), 6.99 (s, 1H), 6.84 (d, J = 8 , 1 Hz, 1H), 6.70 (d, J = 8.1 Hz, 1H), 6.55 (s, 1H), 6.46 (d, J = 8.1 Hz, 1H), 5, 05 (s, 1H, -OH), 4.23 (m, 4H), 3.86 (s, 3H), 2.68 (t, J = 7.4 Hz, 2H), 2.62 (q, J = 7.5 Hz, 2H), 2.36 (quintet, J = 6.0 Hz, 2H), 1.60 (hexet, J = 7.7 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H); 0.94 (t, J = 7.4 Hz, 3H); MC-FD m / e 558 (p); IR (CHC1 ₃ , cm ' ¹ ) 2965, 1727, 1603, 1496, 1458, 1306, 1112.

Analysis for C ₃₄ H ₃₅ O ^:

Calculated: C 73.10; H, 6.31;

Found: C, 73.17; H, 6.42.

C. Preparation of 2- [2-propyl3- [3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy] propoxy] phenoxy] benzoic acid sodium salt.

2- [2-Propyl-3- [3 [2-ethyl-4- (4-fluorophenyl) -5- (hydroxy) phenoxy] propoxy] phenoxy] benzoic acid methyl ester 921.5 g, 38.5 mmol) hydrolyzed as described above for the preparation of example 2. The acid was converted to sodium salt and purified as described above for the preparation of example 1 (D) to obtain 16.7 g (77%) of the desired product as a white amorphous solid: NMR (DMSO-0 ₆ ) 10.50 (mc, 1H, —OH), 7.51 (m, 3H), 7.20 (t, J = 7.4 Hz, 1H), 7.13 (m, 2H), 7.00 (m, 2H), 6.95 (s, 1H), 6.67 (dd, J = 8.2 3.3 Hz, 2H), 6.62 (s, 1H), 6 26 (d, J = 8.2 Hz, 1H), 4.14 (t, J = 5.8 Hz, 2H), 4.02 (t, J = 5.7 Hz, 2H), 2.60 (t, J = 6.8 Hz, 2H), 2.47 (q, J = 7.3 Hz, 2H), 2.16 (t, J = 5.9 Hz, 2H), 1.45 (hexet, J = 7.5 Hz, 2H), 1.07 (t, J = 7.5 Hz, 3H), 0.81 (t, J = 7, 4 Hz, 3H); MC-FAB m / e 568 (38, p + 1), 567 (100, p), 544 (86), 527 (77), 295 (65), 253 (45); IR (KBr, cm ' ¹ ) 3407 (b), 2962, 1603, 1502, 1446, 1395.1239, 1112.

Analysis for C ₃₃ H ₃₂ O ^ No.:

Calculated: C 69.95; H, 5.69; F 3.35.

Found: C, 69.97; H 5.99; F 3.52.

The methods of the present invention describe the use of leukotriene antagonists for the treatment and prevention of epithelial squamous cell carcinoma of the oral cavity, which is characterized by excessive release of leukotriene B ₄ .

The term "excess secretion" of leukotriene refers to the amount of leukotriene sufficient to cause squamous cell carcinoma of the oral cavity. The amount of leukotriene that is considered excessive will depend on a number of factors, including the amount of leukotriene needed to cause the disease and the type of mammal involved. As an experienced specialist will understand, the success of treating a mammal who is susceptible to disease or suffers from epithelial squamous cell carcinoma characterized by excessive secretion of leukotriene, the compound of formula I will be determined by alleviating or preventing the symptoms of this pathological condition.

Research

Research 1.

The effectiveness of the compounds of formula I in inhibiting the binding of tritium-labeled LBN ₄ membranes of light guinea pigs was determined as follows.

Study of [ ³ H] LTB ₄ radioligand binding in light guinea pigs [ ³ H] -LTB4 membranes (196-200 Curie / mmol) were purchased from New England Nuclear (Boston, MA). All other materials were purchased from Sigma (St. Louis, MO). Sample incubation (555 ml) was performed in polypropylene minipipes for 45 min at 30 ° C and contained 25 mg of guinea pig lung membrane protein (Silbaugh et al., European Journal of Pharmacology, 223 (1992) 5764), containing 25 mM MOPS, 10 mM MgCl2, 10 mM CaCl2, pH 6.5, about 140 pM [ ³ H] -LTB4 and a ligand or carrier (0.1% DMSO in 1 mM sodium carbonate, final concentration), respectively. The binding reaction was determined by adding 1 ml of washing buffer with ice temperature (25 mM TrisHCl, pH 7.5), followed by immediate vacuum filtration through Whatman GF / C glass fiber filters using a Brandel collector (Gaithersburg, MD) 48. The filters were washed three times 1 ml wash buffer. The remaining radioactivity was determined by counting in a liquid scintillator at 50% counting efficiency using a Ready Protein Plus coctail mixture (Beckman, Fullerton, Ca). Unrecoverable binding was determined in the presence of 1 mM LTB4; it usually comprised less than 10% of the total binding. Data were analyzed using linear regression analysis of logarithmic curves of values between 10 and 90% of the control binding to calculate IC ₅₀ and angular factors (pseudo-Hill coefficients). The IC ₅₀ values thus obtained were corrected for the concentration of the radioligand (Cheng and Prusoff, Biochem. Pharmacol., 22, 3099 (1973)) to calculate the K values _; . pKi is the average - log K, for n experiments.

The compounds of this invention tested in the above study were found to have pKi between 7 and 11.

The ability of a compound of formula I to exert an effective therapeutic effect on experimental oral cancer can be assessed by testing its effect on the induction of epithelial squamous cell carcinoma in the cheek pocket of Syrian hamsters (Pollack et al., Br. J. Cancer 23, 781-6, 1969).

Research 2.

Tumor development is caused by staining the right cheek pockets in Syrian hamsters (aged 1.5–2 months) with 0.5% solution of 9,10-dimethyl-1,2-benzanthracene (DMBA) in heavy mineral oil (USP) three times a week for 15 weeks. At the end of the above procedure, the animals were sacrificed, an autopsy was performed and both cheek pockets were examined for the number and size of the tumors. Then the nature of the lesions was determined histologically after tissue fixation in 4% formalin and staining with hematoxylin and eosin. A response to a specific dose was obtained by dividing the animals into 4 experimental groups of 10 hamsters each. The groups were: animals treated with a vehicle; and animals that were administered 10, 25 and 50 mg / kg / day of the compounds of formula I orally. Treatment efficacy was evaluated by comparing the size and number of squamous cell carcinomas and the number of atypical papillomas in the treated group with this indicator in the control group treated with the vehicle.

Research 3.

Clinical studies: to evaluate the significance of compounds of formula I in the treatment of squamous cell carcinoma of the oral cavity, clinical trials in humans can also be conducted. The clinical trial plan, the use of the necessary tools, and the interpretation of these results are well known to clinicians - specialists in this field. For example, five out of fifty patients are selected for clinical study. Patients suffer from epithelial squamous cell carcinoma. In this study, there is a control group receiving placebo, i.e. patients are divided into two groups, one of which receives a compound of formula I as an active substance, and the other receives standard treatment for epithelial squamous cell carcinoma. Patients in the test group receive a drug in the range of 30-1500 mg per day by the oral or parenteral route. They continue this therapy for 3-12 months. Accurate records of both the symptoms and the state of the cancer in both groups are kept, and at the end of the study, these results are compared. The results are compared for both members of each group, and the results for each patient are compared with the status recorded for each patient before the study begins.

The therapeutic and prophylactic treatment provided by this invention is carried out in practice by administering to a mammary, if necessary, dose of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, that is, effective to suppress or treat epithelial squamous cell carcinoma.

The term “suppresses” includes basically its generally accepted meaning, which includes obstructing growth, preventing, restraining and slowing down, arresting the growth of a tumor or regressing the severity of the symptoms that result from it. As such, this method includes both medical therapeutic and / or prophylactic use, respectively.

Although it is possible to administer the compound used in the methods of this invention directly without making any dosage form, these compounds are usually administered in the form of a pharmaceutical preparation containing a pharmaceutically acceptable excipient, and at least one compound of the present invention. The compounds or dosage forms of this invention can be administered (administered) by the oral or rectal route, topical application, parenteral, for example, by injection and by continuous or intermittent intra-arterial infusion, in the form of, for example, tablets, lozenges, sublingual tablets, powder sachets, capsules , elixirs, gels, suspensions, aerosols, ointments, for example, containing from 0.01 to 90% by weight of the active compound in a suitable base, soft or hard gelatin capsules, suppositories, injection solutions and with suspensions in a physiologically acceptable medium, sterile packaged powders adsorbed on a carrier material for the manufacture of injection solutions. Such dosage forms are prepared by a method well known in the art of pharmacy and contain at least one active compound. See for example. Remington's Pharmaceutical Sciences, (16 ^th ed. 1980).

In the manufacture of the dosage forms used in this invention, the active ingredient is usually mixed with an excipient (base), diluted with an excipient or contained in such a carrier, which may be in the form of a capsule, sachet, paper or other container. When the base serves as a diluent, it may be a solid, semi-solid or liquid material, which acts as a delivery vehicle, carrier or medium for the active ingredient. In the manufacture of the dosage form, it may be necessary to grind the active substance to obtain particles of the appropriate size before combining with other ingredients. If the active substance is substantially insoluble, it is usually milled to a particle size less than after a sieve 200. If the active compound is substantially soluble in water, the particle size is usually adjusted by grinding to obtain a substantially uniform distribution in dosage form, for example, about sieve 40.

Such examples of suitable carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, tragacanth, gelatin , syrup and methyl cellulose. Dosage forms may further include glidants, such as talc, magnesium stearate and mineral oil;

moisturizing agents; emulsifying and suspending agents; preserving agents such as methyl and propyl hydroxybenzoates; sweeteners; taste and odor enhancing substances. The compositions of this invention can be formulated to provide quick, continuous or delayed release of the active ingredient after administration to a patient by applying procedures known to those skilled in the art.

The compounds of this invention can be delivered transdermally using transdermal delivery systems and bases. Most preferably, the compound of this invention is mixed with penetration 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 adjuvants may be added to the transdermal dosage forms, including gelling agents, emulsifiers and buffers, if desired.

For topical use, the compound according to the invention can theoretically be mixed with any set of adjuvants to obtain a viscous-liquid or cream-like preparation.

For oral administration, the compound according to the invention can theoretically be mixed with carriers and diluents and formed into tablets or gelatine capsules.

In the case of tablets, a glidant may be included to prevent jamming of the powdered ingredients in the molds and sticking to the punches of the tabletting machine. For this purpose, for example, aluminum, magnesium or calcium stearates, talc or mineral oil can be used.

Preferred pharmaceutical forms of the present invention include capsules, tablets, and injection solutions. Especially preferred are capsules and tablets.

The therapeutic and prophylactic treatment of this invention is practiced by administering to the mammal, if necessary, a dose of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof that is effective in suppressing or treating epithelial squamous cell carcinoma.

For this purpose, the dosage forms can advantageously be presented in unit dosage form, it being preferable that each package of the dosage form contains from about 5 to 500 mg (from about 5 to 50 mg in the case of parenteral or inhalation administration and from about 25 to 500 mg per in case of oral or rectal administration) of a compound of formula I. Dosages from about 0.5 to 300 mg / kg per day, preferably 0.5 to 20 μm / kg of active ingredient, can be used, although it will of course be understood that the amount is connected I or the compounds of formula I that will actually be administered will be determined by the physician in the light of all significant circumstances, including the pathological condition that needs to be treated, the choice of the compound that needs to be administered, and the choice of route of administration, and therefore the above preferred dosage range is not intended limiting the scope of the invention in any way.

The specific dose of the compound administered according to the invention for therapeutic or prophylactic effects will, of course, be determined by the specific circumstances surrounding the case, including, for example, the route of administration, age, weight and response of the individual patient, the pathological condition to be treated, and the severity of symptoms in a patient.

In general, the compounds of the invention are more desirably administered in concentrations that will generally produce effective results without causing any serious side effects, and can be administered either as a single dose or, if desired, the dose can be divided into appropriate subunit doses entered at appropriate times during the day.

Although all of the compounds shown by way of illustration above are confirmed by examples of LTD ₄ suppression activity, it was also found that compounds bearing a single acid group (R ₆ ) have significantly greater biological activity when administered orally to mammals than those compounds that carry two such acidic groups. Thus, a preferred embodiment, when the compounds of formula I are administered to a mammal orally, includes the administration of compounds bearing one functional acid group.

In the following examples of dosage forms, any compounds of this invention may be used as active compounds. These examples are illustrative only and are not intended to limit the scope of this invention.

The drug 1.

Hard gelatin capsules are prepared using the following ingredients:

Amount (mg / capsule)

3- (2- (3- (2-Ethyl-4- (4-fluorophenyl) -5 hydroxyphenoxy) propoxy) -6- (4 carboxyphenoxy) phenyl) propanoic acid 250

Starch 200

Magnesium Stearate 10

The above ingredients are mixed and solid gelatin capsules are filled with 460 mg in this mixture.

The drug 2.

Tablets are prepared using the following ingredients:

Amount (mg / tablet)

1- (4- (carboxymethoxy) phenyl) -1- (1Netetrazol-5-yl) -6- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) hexane 250

Microcrystalline Cellulose 400

Silicone Fumes 10

Magnesium Stearate 5

The components are mixed and pressed to form tablets, each weighing 665 mg.

The drug 3.

An aerosol solution is prepared containing the following components:

Weight.%

3- [4- [7-carboxy-9-oxo-3- [3- [2-ethyl-4 (4-fluorophenyl) -5-hydroxyphenoxy] propoxy] -9H-xanthene]] propanoic acid 0.25

Ethanol 30.00

Propellant 11 (trichlorofluoromethane) 10.25

Propellant 12 (dichlorodifluoromethane) 29.75

Propellant 114 (dichlorotetrafluoroethane) 29.75

The active compound is dissolved in ethanol and the solution is added to the propellant 11, cooled to -30 ° C, and transferred to a filling device. The required amount is then fed into a container, which is additionally filled with pre-mixed propellants 12 and 114 by cold filling or pressure filling. The containers are then provided with valve devices.

Drug 4.

Tablets, each containing 60 mg of active ingredient, are made as follows:

2- [2-propyl-3 - [3- [2-ethyl-5-hydroxy-4- (4fluorophenyl) phenoxy] propoxy] phenoxy] benzoic acid sodium salt 60 mg

Starch 45 mg

Microcrystalline Cellulose 35 mg

Polyvinylpyrrolidone (as 10% solution in water) 4 mg

Carboxymethyl Sodium Starch 4.5 mg

Magnesium Stearate 0.5 mg

Talcum 1 mg

Total 150 mg

The active ingredient, starch and cellulose are passed through a No. 45 U.S. sieve. and mix thoroughly. The solution of polyvinylpyrrolidone is mixed with the obtained powders, which are then passed through a No. 14 U.S. sieve. The granules thus obtained are dried at 50-60 ° C. and passed through a No. 18 U.S. sieve. Carboxymethyl starch, magnesium stearate and talc, previously passed through a No. 60 U.S. sieve, are added to the granules, which, after mixing, are pressed on a tablet machine to give tablets, each weighing 150 mg.

Drug 5.

Capsules, each with a content of 80 mg of the drug substance, are prepared as follows:

5- [3- [2- (1-carboxy) ethyl] -4- [3- [2-ethyl-4- (4 fluorophenyl) -5-hydroxyphenoxy] propoxy] phenyl] -4-pentinic acid 80 mg

Starch 59 mg

Microcrystalline Cellulose 59 mg

Magnesium Stearate 2 mg

200 mg total

The active ingredient, cellulose, starch and magnesium stearate are mixed, passed through a No. 45 U.S. sieve. and 200 mg hard gelatin capsules are filled with this mixture in an amount of 200 mg.

Drug 6.

Suppositories, each with a content of 225 mg of active ingredient, are made as follows:

3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -6- (4-carboxyphenoxy) phenyl) propanoic acid 225 mg

Glycerides of unsaturated or saturated fatty acids up to 2000 mg

The active ingredient is passed through a No. 60 U.S. sieve. and suspended in the glycerides of fatty acids, previously melted using the minimum necessary heating. The mixture is then poured into a suppository mold with a nominal volume of 2 g and allowed to cool.

Drug 7. Suspensions, each of which 50 mg of drug substance per 5 are made as follows: contains ml dose 2- [2-propyl-3- [3- [2-ethyl-4- (4 fluorophenyl) -5-hydroxyphenoxy] propoxy] phenoxy] benzoic acid 50 mg Sodium carboxymethyl cellulose 50 mg Sugar 1 g Methylparaben 0.05 mg Propylparaben 0.03 mg Taste and odor enhancer enough Tinting agent new number enough Purified water to new number 5 ml

The drug substance is passed through a No. 45 U.S. sieve. and mixed with carboxymethyl cellulose, sugar and a portion of water until a suspension forms. Parabens that improve the taste and smell of the substance and the tinting substance are dissolved and diluted in a small amount of water and added with stirring. Then add enough water to get the required volume.

Drug 8.

A dosage form for intravenous administration is prepared as follows:

2- [2-propyl-3- [3- [2-ethyl-4- (4-fluorophenyl) 5-hydroxyphenoxy] propoxy] phenoxy] benzoic acid 100 mg

Isotonic solution of sodium chloride 1000 ml

A solution of the above ingredients is usually administered to the patient intravenously at a rate of 1 ml per minute.

Claims (7)

CLAIM 1. A method of treating epithelial squamous cell carcinoma in a mammal, which comprises administering to the mammal, if necessary, an effective amount of a compound of the formula or a pharmaceutically acceptable base addition salt thereof, in which R ₁ represents C ₁ -C ₅ alkyl, C ₁ -C ₄ alkoxy, (C ₁ -C ₄ alkyl) thio, halogen or R ₂ substituted phenyl; each R2 and R1 independently represents hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy; Y and X are —O— or —CH ₂ -; Z represents CH ₂ —CH ₂ or CH ₂ CH ₂ CH ₂ CH ₂ ; A is —O—, —CH ₂ -, CH (1C substituted phenyl) - or —C (CH3) 2-; R4 represents each R ₇ represents hydrogen, C ₁ -C ₄ alkyl, R ₈ represents hydrogen or halogen; and provided that when X is —O—, Y is not —O—. 2. The method according to claim 1, where the compound is 2- [2-propyl-3- [3- [2-ethyl-4- (4 fluorophenyl) -5-hydroxyphenoxy] propoxy] phenoxy] benzoic acid or a pharmaceutically acceptable salt thereof or solvate. 3. The method according to claim 1, where the compound is 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5 hydroxyphenoxy) propoxy-6- (4-carboxyphenoxy) phenyl) propionic acid or its pharmaceutically acceptable salt or solvate. 4. The method according to claim 1, where the compound is 1- (4-carboxymethoxy) phenyl-1- (1Netrazol-5-yl) -6- (2-ethyl-4 - (4-fluorophenyl) -5 hydroxyphenoxy) hexane or a pharmaceutically acceptable salt or solvate thereof. 5. The method according to claim 1, where the compound is 3- [4- [7-carboxy-9-oxo-3- [3- [2-ethyl4- (4-fluorophenyl) -5-hydroxyphenoxy] propoxy] 9H- xanthene]] propanoic acid or a pharmaceutically acceptable salt or solvate thereof. 6. The method of claim 1, wherein the compound is 5- [3- [2- (1-carboxyethyl] -4- [3- [2ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy] propoxy] phenyl] -4-pentinic acid or a pharmaceutically acceptable salt or solvate thereof. 7. The method according to p. 1-6, where the mammal is a human.