UA47505C2 - A method for treatment a flat-cell cancer of mouth cavity by means of leicotrien antagonists - Google Patents

Abstract

This invention provides methods for the treatment or inhibition of oral squamous cell carcinoma which comprises administering to a mammal in need thereof an effective amount of a compound having activity as a leukotriene B4 antagonist.

Description

Description of the invention

Squamous cell carcinoma is the most common malignant tumor of the head and neck. It accounts for at least 275% of head and neck cancer cases in which patients exhibit a high level of immunological deficiency and inflammatory symptoms. Despite improvements in treatment methods over the past 40 years, the 5-year survival rate of approximately 3,095 patients has not changed over the same period.

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 dental hygiene and ill-fitting dentures or damaged teeth that cause chronic mucosal irritation. Occupational hazards include chronic exposure to dust among woodworking workers, which is associated with nasopharyngeal cancer, and exposure to nickel compounds, which increases the risk of paranasal sinus cancer.

Epstein-Barr virus (EBV), the etiological agent of infectious mononucleosis, is associated with nasopharyngeal cancer. 12 Other viruses have also been implicated, including oral herpesvirus type 1 and endogenous oncornaviruses.

Exposure to radiation, as well as poor nutrition, can also contribute to the development of head and neck cancer in humans.

About 9,095 cases of oral cancer are found in just a few high-risk sites: the floor of the mouth, the ventrolateral surface of the tongue, and the soft palate complex. The possibility of intraoral and labial-vestibular cancer in people who use chewing tobacco should be taken into account.

Head and neck cancer is localized in four main anatomical areas: oral cavity, pharynx, larynx and nasal / paranasal sinuses. The mentioned areas are divided into different component regions. The most typical sites affected by the disease are the oral cavity and oropharynx, with p 292 nearly 5,095 cases, and the larynx, with approximately 3,095 cases. Gee)

Early asymptomatic cancer of the oral cavity occurs most often in the form of a red (erythroplastic) lesion. Squamous cell carcinoma, which is not diagnosed in the early stages, occurs later as a deep ulcer with smooth, compacted, rounded edges, which is located in deeper tissues.

A biopsy is necessary to diagnose cancer. at

Squamous cell carcinoma is often diagnosed early because this type of cancer causes many local symptoms, such as pain, hoarseness, and difficulty swallowing. In many cases, however, diagnosis is delayed because local symptoms or pain due to nerve involvement occur only after the development of a large primary tumor. In such cases, initial manifestations may be metastases to regional lymph nodes. Distant metastases are rarely observed without a local past

From the primary process or involvement of lymph nodes. M

Cancer of the head and neck can cover the entire mucous membrane of the upper respiratory tract; additional "silent" synchronous primary lesions are often observed. Patients with such a clinical picture are often prone to the later occurrence of additional primary cancerous tumors of the head and neck (the number of cases is approximately three to five percent per year). C 50 Despite the existence of several markers of head and neck cancers, serum ferritin levels are reported to accurately reflect the extent and course of the disease. (Ferritin is the main iron-storing protein of tissues

From" a person and it is found in small amounts in serum). However, elevated serum ferritin is not specific for head and neck cancer; its levels are also elevated in other types of cancer and in non-malignant conditions.

Levels of antibodies to EVM, both in the case of overt and hidden nasopharyngeal cancer, can be used as a diagnostic tool. Determination of IdA antibodies to the viral capsid antigen (anti-MSA) and -I Id antibodies to the early antigen (anti-EA) are the most specific tests, in particular, for undifferentiated types of nasopharyngeal cancer (NSC). Cancer tumors of the head and neck are divided into stages according to the TMM system of the American United Av! 20 of the Cancer Committee. The classification of the primary tumor (T) is variable depending on the location of the latter, size, level of its penetration and attachment to surrounding tissues; the same criteria are used only for classification of tumors of the oral cavity and the oral part of the pharynx. If it is impossible to accurately determine the size of the lesion, the number of affected areas is used to determine the T stage. Cervical lymph nodes (M) are classified according to the size, number and location (unilateral or bilateral) of the affected nodes. 29 The disease is also classified by the presence or absence of distant metastases (M). General stage of the disease

HF) are determined according to the mentioned stage of TMM: stage I and II diseases, which are considered diseases of a limited type, are precisely determined by clinical evaluations; stage I disease or locally advanced process mainly includes enlarged primary tumors with/without spread to regional lymph nodes (TzMo, T4-3Mi1); stage IM disease involves massive, extensive, invasive primary lesions with variable patterns of involvement of 60 lymph nodes (T4.4M»o.z, TAMo.l or local old process), or any other TM combination with distant metastases (Mu or metastatic disease).

Although surgery and radiotherapy remain the mainstays of treatment, chemotherapy is playing an increasingly important role in the treatment of this disease. Chemotherapy is used for temporary 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 occur at multiple sites, the intensity of response to surgery, radiation, and chemotherapy will vary depending on the primary site of the disease. Thus, the prognosis is related not only to the stage or histopathological features, but also to the site, and for patients undergoing chemotherapy, to the primary treatment.

The treatment strategy is determined by the stage of the disease. In the early stage of the disease, surgery or radiotherapy may be used, as they provide the same survival results. The choice depends on the expected painfulness of the treatment (ie, loss of speech or functional disability due to surgery, 70 or severe dry mouth or change in taste due to radiotherapy) and the urgency of the treatment. In the case of an older local process, surgery and radiotherapy are combined, since this approach provides better results in the fight against the local process. Radiotherapy can be used preoperatively or postoperatively. Prophylactic radiotherapy is often used to drain areas of lymph nodes at high risk of microscopic involvement. Chemotherapy was 7/5 included in the initial treatment plan for patients with locally advanced disease, as the five-year disease-free survival rate for such patients is generally low (from 1095 to 3095).

There is growing concern that treatments such as surgery, radiotherapy, and chemotherapy can adversely affect a patient's natural immunity, possibly increasing the chances of residual or metastatic tumor cells growing. This directed attention not only to early detection and better treatment, but also to the expansion of research into the etiology of the mentioned disease.

A study of allergic lung reactions has provided evidence that arachidonic acid derivatives, which are formed under the influence of lipoxygenases, are associated with various disease states.

Some of the aforementioned metabolites of arachidonic acid have been classified as members of the family of eicosatetraenoic ACIDS, which have been named leukotrienes. Three of these substances are now believed to be the main components of what was previously called the slow-reacting substance of anaphylaxis (ZK5-A) and were named leukotrienes Su, UO/i) tav (ITS, 1 TO, and I TEH, respectively).

Another metabolite of arachidonic acid, leukotriene B, (I TV/), is a lipid that promotes inflammation and is involved in the pathogenesis of psoriasis, arthritis, chronic lung diseases, acute respiratory distress syndrome, shock, asthma, inflammatory disease rectum and other inflammatory conditions, which are characterized by infiltration and activation of polymorphonuclear leukocytes and other cells that contribute to the occurrence of inflammation. In an activated state, these polymorphonuclear leukocytes release tissue-lytic enzymes and reactive chemicals that cause inflammation. Antagonism of ITV in, thus, should provide a new therapeutic approach to the treatment of the mentioned and other conditions mediated by ITV. in.

As a result of the health disorder caused by squamous cell carcinoma of the oral cavity, there continues to be a need for effective methods of treatment.

Brief presentation of the essence of the invention

The present invention provides a method of treating or inhibiting squamous cell carcinoma of the oral cavity, which comprises administering to a mammal in need thereof an effective amount of a compound of Formula | "

Yu NO shi I ni Di

X-U-5-A-K, sh» h- Yuyu 1 oyu EK sl I 2 where:

Ki - Su - St alkyl, So - Sb alkenyl, So - St alkynyl, C- - C; alkoxy, (Si - Su alkyl)thio, halogen or K» - 22 substituted phenyl;

HF) each of Ko" and Kz is independently hydrogen, halogen, hydroxy, C - C - C alkyl, C - C alkyl, (C - C alkyl)-5(O) 4, trifluoromethyl or di-( C - C alkyl) )amino; where X is -0-, -8-, -С(хО) or -СНо-; in --О- or -СН»о-; 60 or, taken together, -X-y- - -- NASN- or chn 2-04 - Alkylideneyl side with a straight or branched chain; 65 A is a bond, -O-, -5-, -СНАСН- or -СКаКъ-, where each of Ka and Ku is independently hydrogen, C. - Св alkyl or K7 - substituted phenyl, or, taken together with the mentioned atom the carbon to which they are connected form a С y - Св cycloalkyl ring;

Kk - E, 70 X | / 2 s o

IS) Fr

IS) i- « « shi s ;» sh» -I 1 at 50 sl

F) name) 60 b5

? | --0-s6-85 ha 70 , | In o; (Snz) with o

I s o o h u | At 11 a.m.

CI

" « t s eh i I A shk i ih t -I

Fi B, or at 50 sl Ka zy is. | | I -

In t bo 7 with where: each Co is independently -COOH, 5-tetrazolyl, -SOM(Co)» or -SOMNZO»RM:o; 65 each K»)7 - hydrogen, S. - Su alkyl, Co - Cw alkenyl, Co - Cw alkynyl, benzyl, methoxy, -M/-Ka-, - T-9-Ke-, (Ci - Cw alkyl) -T-(C. - Su alkylidenyl)-O- or hydroxy;

Ka - hydrogen or halogen; each Co is independently hydrogen, phenyl or C. - C); alkyl, or, taken together with a nitrogen atom, forms a morpholino, piperidino, piperazine or pyrrolidine group;

Ko - Su - S; alkyl or phenyl;

Ka - E", -MI-Kv- or -T-6-Kb; each MU is a bond or divalent hydrocarbyl radical with a straight or branched chain consisting of one to eight carbon atoms; each C is a divalent hydrocarbyl radical with a straight or branched chain, 7/0 which consists of one to eight carbon atoms; each T is a bond, -CH»o-, -O-, -MH-, -MNOO-, -C(0)- or -Z(0)47;

K - -- "(50)- or -CH(OH)-; each d is independently 0, 1 or 2; p-0 or 1; and 1-0 or 1; provided that in the case when X is -O- or -5-, y is not -O-; provided that in the case when A is -O- or -5-, Ku is not Kb; provided that in the case when A is -O- or -5-, 7 - a bond, there is no -O-; and under the condition that in the case when MU is not a connection, p - 0; or a pharmaceutically acceptable salt or solvate thereof.

Detailed description

The following definitions relate to the various terms used in the disclosure of the present invention.

The mentioned term "Ci - C 1 alkyl" means aliphatic radicals with a straight or branched chain, which Ha gr; consists of 1-b carbon atoms, for example, methyl, ethyl, propyl, isopropyl, p-butyl, sec-butyl, tert-butyl, p-pentyl, 2,2-dimethylpropyl, hexyl, etc. This definition also covers the mentioned terms "C 1 -C 3 alkyl", "C 1 -C 1 alkyl" and "C 1 -C 1 alkyl".

The mentioned term "Со - Сб alkenyl" means aliphatic radicals with a straight or branched chain consisting of 2 to 5 carbon atoms, which includes one double bond, for example, -СНАСН », yuyu -СНСнНИеСсСНнН», -СНаоСнННСнНесСН» , -СНоС(СНУ)-СН», -СНОСНАС(СН 3)», etc.

The mentioned term "Co - Sv alkynyl" means aliphatic residues with a straight or branched chain, which consists of 2 - 5 carbon atoms, which includes one triple bond, for example, -С -СН, юю -бно-с- СН, -СНоСнНЖС- СН, -СНаСН(СН3)С- СН, -СНСС-ССН», etc. m

The term "C-C-Alkoxy" refers to methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy and tert-butoxy. "AND

The mentioned term "halogen" means fluorine, chlorine, bromine and iodine.

The mentioned term "Ci - Co alkylidenyl" means a divalent radical that was obtained from C - Co alkane, for example, -CH»o-, -CH(CH»5)-, -F(CH3z)»-, -CH( СНвь)-, -СНХСН»-, -СНХСН(СНУ3)-, -СН(СН3)СнН»-, « -СсН(СнНЗСн(СНУИ)-, -СНХС(СНУЗ)»-, -СНоСН(СоНв)-, -СНСНСН»о-, -СН(СНаз)СнНСН»о-, -СНСН(СНаз)СнН»-, -СНСННСН(СнНне)сСнН»е-, -СНоСНСНн(СНН)-, -С(СН3)»сСНоСНо- . »-, "» -сСн(сниз)СньсСнСньСН»-, -«СНСНСньСНоСньСН»-, -(СН»)1о-, etc. This definition also covers the mentioned "terms "C. - Su; alkylidene" and "C - Su alkylidene".

The mentioned term "C; - C 1 cycloalkyl" means a cycloalkyl ring consisting of four to eight carbon atoms, for example, cyclobutyl, cyclopentyl, cyclohexyl, 4,4-dimethylcyclohexyl, cycloheptyl, and cyclooctyl, etc. - The term "straight or branched divalent hydrocarbyl radical of one to eight carbon atoms" refers to a divalent radical which has been obtained from an alkane, alkene or alkyne with a straight or branched chain of one to eight carbon atoms . Depending on the branching or the number of carbon atoms, which will be clear to organic chemists, such a component may include one, two or three double or triple bonds, or combinations of said bonds. This term, sl as such, can be considered as an alkylidene group, the definition of which was given before, which includes from 1 to 8 carbon atoms, and which optionally includes from one to three double or triple bonds or a combination of the two mentioned bonds connections, with the restriction that was given in the previous sentence. oo This invention includes pharmaceutically acceptable salts of compounds of Formula I which have been obtained by addition of a base. o Such salts include salts that were obtained from inorganic bases, for example, hydroxides, carbonates, ammonium bicarbonates, alkali and alkaline earth metals, etc., as well as salts that were obtained from basic organic amines, for example, aliphatic and aromatic amines, aliphatic diamines, hydroxyalkylamines, etc. Such bases suitable 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. Particular preference is given to potassium and sodium salts.

This invention includes both one-component salt forms, i.e., a 1:1 ratio of a compound of Formula I with a base, the description of which, for example, was given before, and two-component salt forms in those cases where the compound of Formula I! has two acid groups. In addition, this invention includes any solvate forms of the said compounds of Formula I or salts thereof, for example, solvates, ethanol hydrates, etc.

It is generally accepted that compounds having a branched alkyl, alkylidenyl or hydrocarbyl functional group and compounds having double or triple bonds can have different stereoisomeric products. 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, (1H)-5-tetrazolyl and (2H)-5-tetrazolyl.

Preferred implementation options

The most preferred group of compounds which are used in the mentioned methods of this invention are the compounds

Ia formulas:

He t

Ia and their pharmaceutically acceptable salts obtained by the addition of a base. Particularly preferred are compounds where K 2 is a halogen, in particular, fluorine. Preferred Cu substituents are propyl and, in particular, ethyl.

The predominant 7 substitutes include So - Su; alkylidene, in particular, -"СНоСНо--а -СНОСНОСНьСН"-. Predominant A groups include -О-, -СН»-, -СН(К» - substituted phenyl)- and -СН3)»-.

To the prevailing Ku; groups include -СООН, 5-tetrazolyl or a mono-, di- or tricyclic group, the definition of which was given before, which has at least one acidic group attached to the ring, for example, -МЖ-СООН, -Т1-0 -COOH, or corresponding tetrazole derivatives. The mentioned predominant MU component is S. - Su alkylidene with a bond or straight chain; the predominant constituents are C) - Su; straight chain alkylidene.

Preference is given to K5 or KU; was S. - S; alkyl, in particular, p-propyl.

Particularly preferred groups include groups where A is CH(K7 - substituted phenyl) and K is COOH or 5-tetrazolyl. Preference is also given to compounds where A - -O-, K, - o

IS) cha t -

Kk, Co

Preferred aspects of this substructure are those where K7 is Su - Su alkyl, in particular, p-propyl, and Ke - -MU-COOH. "

Particular preference is given to those compounds where T is -O- or -5- and MU is a bond. with c Particularly preferred compounds according to this invention include: 2-I(2-propyl-3-I3-(2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy|propoxy|phenoxy|benzoic acid; ; » 3 -(2-(3-(2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy)propoxy)-6-(4-carboxy-phenoxy)phenyl)propionic acid; 1--(4--"carboxy -methoxy)phenyl)-1-(1H-tetrazol-5-yl)-6-(2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy)hexane; their 3-I4-(7-carboxy-9 -oxo-3-I3-(2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy|-propoxy|-9H-xantheniI|propanoic acid; and

Ш- 5-І3-(2-(1-carboxy)-ethyl|/-4-І3-(2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy|-propoxy|phenyl|-4-pentynova c acid or their pharmaceutically acceptable salts or solvates.

Said antagonists of leukotriene B, (I TV/), which are used in the mentioned methods of the present invention, can be synthesized essentially according to the description given in US patent No. 5,462,954, which was issued on October 31, 1995, and which in is incorporated herein by reference in its entirety.

The following examples further illustrate the preparation of the mentioned compounds used in the present invention.

The mentioned examples are purely illustrative and are not intended to limit the scope of the present invention. dv The melting temperature was determined on the Thomas-Hoover apparatus and was not corrected. NMR spectra were determined on a CE OE-300 spectrometer. All chemical shifts are given in parts per million ( ) relative to tetramethylsilane.

F) Chemical shifts of aromatic protons of quinoline species in dimethylsulfoxide (0OM5O-dv) are dependent on concentration. The following abbreviations are used to indicate signal structures: c-singlet, a-doublet, i-utriplet, d-quartet, B-broad, t-multiplet. Infrared spectra were determined on a Misoiei bo BHLOgT-IR spectrometer. Mass spectrometric data were determined on a SES-21-110 spectrometer under the influence of electron impact, a MAT-731 spectrometer under conditions of free desorption by an (electric) field, or on a MO2AV-ZE spectrometer under fast atom bombardment. Gel chromatography was performed using gradient mixtures of ethyl acetate/hexane, unless otherwise indicated. Reverse-phase chromatography was performed using MCI CHP2OR gel and acetonitrile/water or water-methanol gradient mixtures, unless otherwise specified. Tetrahydrofuran (THF) was distilled from the sodium/benzophenoneketyl mixture immediately before use. All reactions were carried out under argon atmosphere with stirring, unless otherwise indicated. When the structure was confirmed by infrared, proton nuclear magnetic resonance, or mass spectral analysis, the compound in question was labeled "IR," "MMK," or "M5," respectively.

Example 1

Disodium 3-(2-IZ3-K5-ethyl-2-hydroxy|1,1"-diphenyl|/|-4-yl)uoxy|propoxy|-1-dibenzofuran|propanoic acid

SOOE approx

EO

-31 A - o o o vvav ia Phi i oto s otv s soog o

Her Oma yu

Ge) o cha «

SOOMma

A. Preparation of 3,3-diethoxy-2,3-dihydro-THN-benzofuro-I3,2-YI IPbenzopyran. "

A solution of 2-hydroxydibenzofuran (5.00g, 27.2mmol), triethyl orthoacrylate (10.1g, 54.3mmol) and pivalic acid from 70 (1.39g, 13.bmmol) in toluene (100ml) was heated in a reflux flask at temperature from distillation for 18 hours. The resulting 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 into oil to give an orange oil. The obtained material was diluted with hexane and kept at a temperature of -207C for 18 hours. The resulting crystals were collected by filtration under a 15-degree vacuum to obtain 5.67 g (6795) of the required target intermediate, melting point 64"C;

NMR (SOCI3) 7.96 (a, 9 - 7.8Hz, 1), 7.57 (a, 9 - 8.00Hz, yin), 7.46 (5 9 - 8Hz, 1H), 7.35 ( t, 2H), 7.06 (a, -i U same v8,eHz, tn), 3.82 (a, 9U - 72Hz, 2H), 3.73 (a, U - beHzC, 2H), 3, 35 (5 9 - 6.9Hz, 2H), 229 (5 U sl 7.0Hz, 2H), 1.23 (9 - 7.1Hz, 6H), mass spectrometry with field desorption t / e 312 (р) ; infrared (СНО with, cm") 2982, 1494, 1476, 1451, 1434, 1251, 1090, 1054, 975. (ав) Analysis of Си9Н2оОХ «n Calculated: C, 73.06; H, 6.45;

Established: C, 72.81; H, 6.72.

B. Preparation of 3-(1-(2-hydroxydibenzofuran)|propanoic acid ethyl ether

A mixture of 3,3-diethoxy-2,3-dihydro-YAN-benzofuro-I|3,2-Y|(Ibenzopyran (3.50 g, 11.2 mmol) and 1095 aqueous solution of hydrochloric acid (ml) in ethyl acetate (30 ml) stirred at room temperature (F) for 1 hour.The resulting mixture was washed once with water, dried over sodium sulfate, filtered and

GI was concentrated from fat to obtain a yellow-brown solid. By recrystallization from a mixture of hexane/ethyl acetate, 3.11 g (9895) of the required target intermediate product was obtained in the form of a not quite white crystalline material: melting point 128 - 131"C. NMR (SOCI3) 7.88 (a,

U - 7.7Hz, tn), 7.59 (a, 9 - 84Hz, 1), 7.47 (9 - 72Hz, 1), 7.37 (a, 9 - 89Hz, 1), 7.36 ( 5, 9 - b, bHz, 1), 7.13 (a, 2 - 88Hz, 71Н), 7.13 (4, 9 - veHz, 2), 3.43 (5 9 - 58Hz, 2Н), 3 ... ); infrared (KVh, cm") 2985 (B), 1701, 1430, 1226, 1183, 1080. 65 Analysis of C47NivOX:

Calculated: C, 71.82; H, 5.67;

Established: C, 71.90; H, 5.43. with. Preparation of 3-(2-3-(5-ethyl-2-(phenylmethoxy)-I(1,1-diphenyl|-4-yl|Iioxy|propoxy|-1-dibenzofuranIpropanoic acid) ethyl ester

3-(1-(2-Hydroxydibenzofuran)|propanoic acid ethyl ether was dissolved in dimethylformamide (10 mL) and carefully treated at room temperature with 9595 sodium hydride (58 mg, 2.4 mmol). After gas formation ceased, 2-benzyloxy-1 -phenyl-5-ethyl-4-(3-chloro-1-propyloxy)benzene (83bmgH, 2.20mmol) and the resulting mixture was stirred for 18 hours. The said mixture was diluted with ether and washed once with water. The resulting organic layer was dried over sulfate sodium, filtered and concentrated ip/o huasco to give a dark oil. Gel chromatography (ethyl acetate/hexane mixtures) gave 200 mg (14905) of the desired target intermediate as a colorless oil: NMR (SOCI z) 8.11 (a, 9 -7.І7ХЦ, 1), 7.57 (t, ЗН), 7.48 (5.9 - 7.3ХЦ, 1Н), 7.20 - 7.44 (t, TON), 7.17 (in, 1H), 7.08 (a,

In 8.9Hz, 1H), 6.67 (8, 1H), 5.05 (in, 23), 429 (9 - 62Hz, 2H), 426 (5 9 - b61Hz, 2H), 4.15 (a , 9U - 7.2Hz, 2H), 3.54 (i, U - 8.5Hz, 2H), 2.67 (t, 4H), 2.37 (i, U - 6.0Hz, 2H), 1 ,21 (t, 6H). r. Preparation of disodium salt of 3-(2-3-Co-ethyl-2-hydroxy|1,1-diphenyl|/|-4-yl)oxy|)propoxy|-1-dibenzofuran|propanoic acid

To a solution of 3-(2-3-(5-ethyl-2-(phenylmethoxy)|1,1-diphenyl|/|-4-yloxy|propoxy|-1-dibenzofuranipropanoic acid) ethyl ether (20 mg, 0.318 mmol) , which was purged with nitrogen, in a mixture (1 : 1) of methanol/hetrahydrofuran (40 ml) was added 1095 palladium 2o on carbon (25 mg). The resulting suspension was hydrogenated under a pressure of 1 atmosphere for 24 hours at room temperature. The resulting mixture was filtered through a short plug Bryopsibb and the resulting filtrate were concentrated by mass.The resulting residue was dissolved in a mixture of (1:1) methanol/hetahydrofuran (20ml) and treated with 5M sodium hydroxide solution (2ml) at room temperature for 24 hours.

The resulting mixture was extracted once with diethyl ether. The resulting aqueous layer was acidified with a 5M hydrochloric acid solution and extracted twice with methylene chloride.

The mixed methylene chloride fractions were concentrated by weight. The resulting residue was dissolved in a minimum amount of i) 1M sodium hydroxide solution and purified on HP-20 resin to obtain 5mg (3095) of the mentioned required target product as a fluffy white solid. NMR (0M5O-y 65) 8.12 (a, 9 - 6.9Hz, 1H), 7.64 (0.9 - 8.2Hz, 1H), 7.37 - 7.57 (t, 5H), 7.30 (t, 2H), 7.14 (t, 2H), 6.96 (in, 1H), 6.93 (8, 1TN), yuyu zo 430 (69 - 7.3HZ, 2H), 4 ,14 (6 9 - 54Hz, 2H), 248 (t, 4H), 223 (t, 4H), 110 (5 9 - 7.6Hz, ЗН).

Mass spectrometry during bombardment with fast atoms t / e 555 (88, p. 1), 533 (62); infrared (SNSI", o cm") 3384 (B), 2969, 1566, 1428, 1257, 1181.

Analysis of C32NovOvMa»:

Calculated: C, 69.31; H, 5.09; -

Established: C, 69.51; N, 5.39. "Her

Example 2

Disodium salt monohydrate of 7-carboxy-9-oxo-3-I3-(2-ethyl-5-hydroxy-4-phenylphenoxy)propoxy|-9H-xanthene-4-propanoic acid «

ON o o c) p

And also 175 ol o o sh" - no t 50 COoOMa ("c) "p Mixture of 2-benzyloxy-1-phenyl-5-ethyl-4-(3-chloro-1-propyloxy)benzene (749mg, 1, 97mmol), ethyl 7-carboethoxy-3-hydroxy-9-oxo-9H-xanthene-4-propanoate (729mg, 1.97mmol), potassium carbonate (1.36g, 9.85mmol) and potassium iodide (ZZmg, O0, 20 mmol) was heated in a reflux flask at the temperature of distillation for 24 hours. Dimethyl sulfoxide (2 mL) was added and heating was continued for 24 hours. The resulting reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed once (F) with water. The resulting organic layer was dried over sodium sulfate, filtered, and concentrated in oil to obtain a yellow-brown solid. This material was dissolved in ethyl acetate (3 mL) and the resulting solution was purged with nitrogen. 1095 palladium on carbon (120 mg) was added to this solution and the resulting suspension was hydrogenated under a pressure of 1 atmosphere. The resulting solution was filtered and concentrated by mass to obtain a colorless oil. The obtained material was dissolved in a mixture (1:1) of methanol/tetrahydrofuran (30ml) and treated with a 5M solution of sodium hydroxide (2ml) at room temperature for 18 hours. The resulting solution was extracted once with diethyl ether, the resulting aqueous layer was acidified with a 5M solution of hydrochloric acid. The resulting sediment would be collected by filtration with suction. This material was converted to the disodium salt and purified as described above for the preparation of Example 1(0) to give 39Omg (36905).

said desired target product as a fluffy white solid. NMR (0M50O-yv) 12.65 (8, 1IN, -OH), 8.65 (in, 1H), 8.28 (aa, 9 - 8.5, 2.0Hz, 71), 8.01 ( a, 9 - 8.9Hz, 1H), 7.50 (t, ЗН), 7.29 (6 9 - 7.8Hz, 2H), 7.17 (t, 2H), 6.93 (v, 1H ), 6.89 (in, 1H), 4.26 (t, 4H), 3.12 (t, 2H), 2.47 (t, 2H), 2.23 (t, 2H), 1.10 (and, U - 7.4Hz, ЗН). Mass spectrometry during bombardment with fast atoms t / e 627 (24, p), 605 (40), 583 (24), 331 (24), 309 (100); infrared (KVh, cm") 3419 (B), 2962, 1612, 1558, 1443, 1390, 1277, 1084.

Analysis of SzaNovOo Ma" x noo:

Calculated: C, 63.34; N, 4.69;

Established: C, 63.36; H, 4.50.

Example C

Sodium salt of 2-(2-propyl-3-I3-(2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy|propoxy|phenoxy|benzoic acid)

E o cm (8) o a chn o X Y (so) o (av) bOOMe yu cha

E z5 Fi on «

Fe ikh -y R al shi s 8) c) o

From sooOMe r. m on -I («c) ut o o o sl

SOOMa. holding methyl ether (F. A o fiko 2-(2-propyl-3-I3-(2-ethyl-4-(4-fluorophenyl)-5-(phenylmethoxy)phenoxy|propoxy|phenoxy|benzoic acid

A mixture of 2-benzyloxy-1-(4-fluorophenyl)-5-ethyl-4-(33-chloro-1-propyloxy)benzene (20.0 g, 50.2 mmol) and sodium iodide (75.3 g, 502 mmol) in 2-butanone (200 ml) was heated in a reflux flask at the distillation temperature for b hours. The resulting mixture was diluted with ether and washed once with water. The resulting organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a colorless oil. The obtained material was dissolved in dimethylformamide (10 mL) and treated with 2-(3-hydroxy-2-propylphenoxy)benzoic acid methyl ether (14.4 g, 50.2 mmol) and potassium carbonate 65 (20.8 g, 151 mmol) at room temperature within 24 hours. The resulting mixture was diluted with water and extracted twice with ether. The resulting aqueous layer was separated and back-extracted once with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated to afford a yellow oil. By means of gel chromatography, 25.4 g (78905) of the required target intermediate was obtained in the form of a pale golden oil: NMR (SOCI3) 7.91 (a, 9 - 7.8Hz, tn), 7.54 (a, 9 - 8.6Hz, 1H), 7.52 (4, y - 8.5Hz, 1H), 7.25 - 7.43 (t, 6H), 7.03 - 7.38 (t, 5H), 6, 84 (a, 2 - 8.3Hz, 1H), 6.71 (a, - 8.1Hz, 1H), 6.63 (z, 1H), 6.47 (a, 2 - 81Hz, 1H), 5 ... , 2.64 (I, U - 7.7Hz, 2H), 2.34 (quintet, U - 6.0Hz, 2H), 1.60 (hexet, U - 5.0Hz, 2H), 1.22 ( 5.9 - 7.5 Hz, ZN), 0.94 (i,

U - 7.5 Hz, ZN), mass spectrometry with field desorption t / e 648 (r); infrared (SNSIIIZ, cm") 2960, 1740, 70. 1604, 1497, 1461, 1112.

SanAzOBE analysis:.

Calculated: C, 75.91; H, 6.37;

Established: C, 76.15; H, 6.45.

B. Production of methyl ether 75. 2-(2-propyl-3-(3-(2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy|propoxy|phenoxy|benzoic acid)

2-(2-Propyl-3-I3-(2-ethyl-4-(4-fluorophenyl)-5-«(phenylmethoxy)phenoxy|propoxy|phenoxy|benzoic acid methyl ester) (33.0 g, 50.9 mmol) was debenzylated according to the description given above for the mentioned preparation of Example 2, to give 27.3 g (9695) of the mentioned target product as an amber oil. , 1H), 7.42 (t, ЗН), 7.05 - 7.23 (t, 4H), 6.99 (in, 1H), 6.84 (а, 9 - 81Hz, 1), 6, 70 (04.9 - 81 GHz, yin), 6.55 (v, 1H), 646 (a, 9 - 81 GHz, 1H), 5.05 (5, IN, -OH), 4.23 (t, 4H ), 3.86 (v, ZN), 2.68 (56 9 - 74 GHz, 2H), 2.62 (a, 9U - 7.5Hz, 2H), 2.36 (quintet, U - 6.0HzC, 2H), 1.60 (hexet, U - 7.7 Hz, 2H), 1.20 (9 - 7.6 Hz, ZN), 0.94 (B 9 - 7.4 Hz, ZN), mass spectrometry with by field desorption t / e 558 (r); infrared (SNSIz, cm") 2965, 1727, 1603, 1496, 1458, 1306, 1112. s

Analysis of SzANzBOvE: Fr

Calculated: C, 73.10; H, 6.31;

Established: C, 73.17; H, 6.42. with. Preparation of the sodium salt of 2-I(2-propyl-3-I3-(2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy|propoxy|phenoxy|benzoic acid IS o)

Methyl ether //2-(2-propyl-3-(3-(2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy|propoxy|phenoxy|benzoic acid) (21.5g, 38.5mmol) was hydrolyzed by the description that was given before that for the mentioned drug by

of Example 2. The mentioned acid was converted to the mentioned sodium salt and purified according to the description that was IS o) given before for the mentioned preparation of Example 1(0), obtaining 16.7 g (7790) of the mentioned desired target product in the form of an amorphous white solid colors: NMR (0M50-4a 6) 10.50 (re, 1H, -OH), - 7.51 (t, ЗН), 7.20 (5 9 - 7.4HZ, 1H), 7.13 (t , 2H), 7.00 (t, 2H), 6.95 (v, 1H), 6.67 (aa, 9 - 8.2, 3.3Hz, chCHE 2H), 6.62 (v, 1) . ), 2.47 (a, 9 - 7.3Hz, 2H), 2.16 (5 9 - 59Hz, 2H), 1.45 (hexet, U - 7.5Hz, 2H), 1.07 (9 - 7.5 Hz, ZN), 0.81 (i, y - 7.4 Hz, ZN); mass spectrometry during bombardment with fast atoms - t / e 568 (38, r « t 1), 567 (100, r), 544 (86), 527 (77), 295 (65), 253 (45); infrared (KVg, sm") 3407 (B), 2962, 1603, 1502, 1446, 1395, 1239, 1112. t s Analysis of CzzNa2O6EMa: h Calculated: C, 69.95; H, 5.69; E, 3, 35; -" Established: C, 69.97; H, 5.99; E, 3.52.

The mentioned methods according to the present invention describe the use of leukotriene antagonists for the treatment or prevention of squamous cell cancer of the oral cavity, which is characterized by excessive leukotriene Wu secretion. - The mentioned term "excessive secretion" of leukotriene means an amount of said leukotriene sufficient to cause squamous cell carcinoma of the oral cavity. The amount of leukotriene thought to be excessive will depend on a variety of factors, including the amount of leukotriene required to cause said disease and the species of mammal involved. Those skilled in the art will appreciate that the success of treating a mammal suffering from or susceptible to oral squamous cell carcinoma characterized by excessive leukotriene secretion with a compound of Formula I will be measured by regression or prevention of symptoms of said condition.

Trial

Test 1

Gee! Effectiveness of compounds Formula | on inhibition of binding of tritiated | TV with guinea pig lung membranes was determined as follows. where Analysis of binding (NI-I. TVu ralioligand on guinea pig lung membranes

INITVA (196 - 200 Curie/mmol) was purchased from Mem/Epdiapa Misieag (Boston, MA). 60 All other materials were purchased from bZidta (St. Louis, MO). Incubation (555 ml) was carried out in polypropylene mini-tubes for 45 minutes at a temperature of 30°C; the incubation mixture included 25 mg of guinea pig lung membrane protein (Silbo (Ziratsody) et al. buffer, which included 25 mM MORZ (2-(M-morpholino)-propanesulfonic acid), 10 mM

MoSi, 100 mM CaCl, pH 5, approximately 140 mM (NO TV; and replacement ligand or carrier (0.195 ppm dimethylsulfoxide in 1 mM sodium carbonate, final concentration) as needed. Said binding reaction was stopped by adding ml of ice-cold wash buffer (25 mM Tris-buffer-HCII) followed by immediate vacuum filtration through MUpaytap OB/C glass fiber filters using a 48-position harvester from Wgapae! (Gaithersburg, MD). These filters were washed three times with ml of wash buffer.

The level of retained radioactivity was determined using a liquid scintillation counter with a 5090 counting efficiency using Keadu Rgoiewip Rees mixture (WesKtap Company, Fullerton, CA).

The level of binding without substitution was determined in the presence of MM and TV4; the mentioned level was generally less than 1095 of the total binding level. The data were analyzed by means of linear regression analysis of graphs in a logarithmic scale of values within 10 - 9095 of the control binding to calculate the IC s and 7/o coefficients of the slope of the curves (pseudo-Hill coefficients). The ISvo values obtained in this way were corrected for the radioligand concentration (Cheng (Spepo) and Prasof (Rgizoi), Viospet. РНагтасой!., 22, 3099 (1973)) to determine the K values; pKi represents the average - Isu K) for n experiments.

The pKi values of the tested compounds of this invention were found to be in the range of 7 to 11.

The ability of the compound of the formula | to the effective treatment of experimental cancer of the oral cavity can be determined by testing the effect on inducing squamous cell cancer of the buccal pockets in golden hamsters (Pollyak (RoiIask) and others, Vg. U. Sapseg, 23, 781 - 6, 1969).

Test 2

Tumor development was induced by applying a 0.595 solution of 9,10-dimethyl-1,2-benzanthracene (OMBA) in heavy mineral oil (US Pharmacopoeia) three times per week for 15 weeks to the right buccal pockets of golden hamsters (aged 1.5 months to 2 months). After the aforementioned treatment, the animals were sacrificed, necropsied, and both buccal pockets were examined for the number and size of tumors. The nature of the injuries was subsequently determined by histological methods after fixing the tissue in 495 formalin and staining with hematoxylin-gozin. The dose-dependent response was determined by dividing the animals into experimental groups of 10 hamsters each for 4 s; the animals of one group were injected with the vehicle, the animals of the other three groups were orally injected with 1Omg/kg/day, 25mg/kg/day and 5Omg/kg/day of the compound of the formula /!, respectively. and)

The effectiveness of the treatment was evaluated by comparing the size and number of squamous cell carcinomas and the number of atypical papillomas in the group of animals that were injected with the mentioned compound with the corresponding indicators in the animals of the control group that were injected with the vehicle. oh

Test Z

Clinical trials: In order to determine the effectiveness of compounds of Formula I in the treatment of squamous cell carcinoma - oral cavity, it is also possible to resort to clinical trials on humans. Clinical trial protocol, use of measurement equipment, and interpretation of results are well known to clinicians in the art. For example: From five to fifty patients are selected for clinical research. The mentioned patients suffer from squamous cell cancer. The research protocol provides for a placebo control group, i.e., patients are divided into two groups, one of which receives a compound of formula I as an active agent, while the other receives the standard treatment provided for squamous cell carcinoma. Patients in the mentioned experimental group receive from ZOmg to 1500 mg of the drug per day orally or parenterally. The duration of this treatment is from 3 months to 12 months. In both groups, the symptoms and condition of cancer tumors are carefully registered and these results are compared at the end of the studies. The mentioned results are compared between the members of each group. In addition, the mentioned results for each patient are compared with the status that each patient had before the beginning of the studies. and? The therapeutic and prophylactic treatments provided by the present invention are practically carried out by administering to a mammal in need thereof a dose of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, effective in inhibiting or treating oral squamous cell carcinoma. "restraint" The term "inhibition" referred to includes its common meaning, which includes hindering, preventing, restraining, retarding, stopping or reversing development or severity

She symptoms that are observed. This method, as such, includes both medical therapeutic and/or prophylactic administration, depending on the need.

A compound used in the methods of the present invention may be administered directly without any dosage forms, however, said compounds are typically administered in the form of pharmaceutical dosage forms which include a pharmaceutically acceptable excipient and at least one compound according to this invention.

Said compounds or dosage forms of the present invention may be administered orally or rectally, topically, parenterally, for example by injection, or continuously or intermittently

By intra-arterial infusion, in the form of, for example, tablets, cakes, tablets under the tongue, sachets, porridges, elixirs, gels, suspensions, aerosols, ointments, the composition of which, for example, can include from 0.0195 (wt.) to

F) 9095 (wt.) of the mentioned active compound in the appropriate base, soft or hard gelatin capsules, suppositories, injection solutions and suspensions in physiologically acceptable media, and sterile prepackaged powders adsorbed on a support material for the manufacture of injection solutions. because the methods of manufacturing such dosage forms, which include at least one active compound, are well known in the field of pharmaceuticals. See, for example, KEMIMOTOMYE RNAKMASEISHTISAY ZSIEMSEZ (16th edition, 1980).

In the manufacture of dosage forms according to this invention, the mentioned active ingredient is usually mixed with a filler, diluted with a filler, or placed in a carrier, which can be in the form of a capsule, sachet, or b5 Made in the form of a container made of paper or other material. If the filler is used as a diluent, it can be a solid, semi-solid or liquid material that acts as a carrier,

filler or medium for the active ingredient. In the manufacture of the dosage form, it may be necessary to grind the mentioned active compound to obtain particles of the appropriate size before combining with other ingredients. If the active compound is essentially insoluble, it is usually ground to a particle size of less than 0.074mm. If the active compound is essentially water-soluble, the size of its particles, as a rule, is brought by grinding to an essentially homogeneous distribution in the composition of the dosage form, for example, to about 0.420 mm.

Some examples of suitable carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum arabic, calcium phosphate, alginates, tragacanth, gelatin, calcium 7/0 oxalate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup and methylcellulose. The composition of the mentioned dosage forms may additionally include: lubricating substances, for example, talc, magnesium stearate and mineral oil; moisturizing substances; emulsifying and suspending substances; preserving substances, for example, methyl and propyl hydroxybenzoates; sweetening substances; and proofreaders. Said compositions of the present invention can be made in such a way as to provide a rapid, slow or sustained release of the active ingredient after administration to the patient using methods well known in the art.

Said compounds of the present invention can be delivered transdermally using known transdermal delivery systems and excipients. In a most preferred embodiment, a compound of the present 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 other similar delivery system. Additional excipients, including gel-forming substances, emulsifiers and buffers, can be included in the composition of the transdermal dosage form as needed.

For local administration, the compound of the present invention, in the most preferred embodiment, can be mixed with excipients of any variety to form a viscous liquid or cream-like preparation.

For oral administration, the compound of the present invention can most preferably be mixed with excipients and diluents and compressed into tablets or administered into gelatin capsules.

In the case of tablets, they may include a lubricant to prevent sticking or i) binding of the powdered ingredients to the punches or dies of the tablet machine. For this purpose, you can use, for example, stearates of aluminum, magnesium or calcium, talc or mineral oil.

Preferred pharmaceutical dosage forms of the present invention include capsules, tablets, and injectable solutions. Capsules and tablets are particularly preferred.

The therapeutic and prophylactic methods of treatment provided by the present invention are practically carried out by administering to a mammal in need thereof a dose of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof effective in inhibiting or treating squamous cell carcinoma of the oral cavity.

For this purpose, the mentioned dosage forms, in the preferred version, are produced in a standard dosage form, and each dose includes from about 5 mg to about 50 Ω (from about 5 mg to 5 Ω in the case of parenteral or inhalation administration and from about 25 mg to 50 Ωg in the case of oral or rectal administration) of a compound of Formula I. Doses of about 0.5 mg/kg/day to about 10 Ω/kg/day, preferably 0.5 mg/kg/day to 2 Ω/kg, can be administered; it is easy to understand, however, that the amount of compound or compounds of Formula | will be decided by the physician in light of the relevant circumstances, including consideration of the condition to be treated, the choice of compound to be administered and the choice of 7-3)c route of administration, and thus the preferred dosage ranges given above are not intended for any limitation of the scope of this invention. ;" The particular dose of a compound of the present invention administered to obtain therapeutic or prophylactic effects will, of course, be determined by the particular circumstances of the case, including the route of administration, the mass and response of the individual patient, the condition to be treated and the severity of the patient's symptoms.

In general, the compounds of the present invention are most preferably administered at a concentration which, in general, will provide effective results without causing any serious side effects, and may be administered as a single standard dose, or, in the case of if necessary, the said dose can be broken down into corresponding fractional doses, which can be administered at an acceptable time during the day. o All the compounds mentioned before can be given as examples of compounds that have the ability to suppress ITV; ip migo, however, we also found that compounds having one acid group (Kb) have significantly higher oral bioactivity when administered to mammals compared to compounds having two such acid groups. Thus, the preferred embodiment, in the case of oral administration of compounds of Formula ov to rodents, is the administration of compounds that have one acidic functional group Kb.

In the following examples of dosage forms, any compound according to this invention can be used as an active compound. The examples given are purely illustrative and are not intended to limit the scope of the present invention in any way.

Dosage form 1 in Hard gelatin capsules are made using the following ingredients:

Amount (mg/capsule) 3-(2-(3-(2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy)propoxy)-6-(4-carboxy-phenoxy)phenyl)propanoic acid 250

Starch 200 65 Magnesium stearate 10

The mentioned ingredients are mixed and poured into hard gelatin capsules in the amount of 46bOmg.

Medicinal form 2.

The tablet is made using the following ingredients: p.

Amount (mg/tablet) 1-(4-(carboxymethoxy)phenyl)-1-(1H-tetrazol-5-yl)-6-(2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy)hexane 250

Microcrystalline cellulose 400

Silicon dioxide, fumigated 10 70 Magnesium stearate B

The mentioned ingredients are mixed and pressed to form tablets, the weight of each of which is equal to 66b5mg.

Medicinal form Z

An aerosol solution is prepared, which includes the following components: (wt.) 90 3-I4-(7-carboxy-9-oxo-3-(3-(2-ethyl-4-(4-fluorophenyl)-5- hydroxyphenoxy|propoxy)|-9H-xanthene|propanoic acid 0.25

Ethanol 0.00

Propellant 11 (trichlorofluoromethane) 10.25

Propellant 12 (dichlorodifluoromethane) 29.75

Propellant 114 (dichlorotetrafluoroethane) 29.75

The mentioned active compound is dissolved in ethanol, the resulting solution is added to the mentioned propellant 11, cooled to a temperature of -30"C and transferred to the filling device. After that, the required amount is transferred to the container, which is additionally filled with a mixture of pre-mixed propellants 12 and c 25. 414 ( liquefied or under pressure) After that, the mentioned container is equipped with a valve device. Go)

Medicinal form 4

Tablets, each of which contains bOmg of the active ingredient, are made as follows:

Sodium salt of 2-(2-propyl-3-(3-(2-ethyl-5-hydroxy-4-(4-fluorophenyl)phenoxy|propoxy|phenoxy|benzoic acid))

Starch 45 mg o

Cellulose microcrystalline ZBmg

Polyvinylpyrrolidone (in the form of 1095 solution in water) / 4mg each)

Sodium carboxymethylated starch 4.5 mg -

Magnesium stearate 0.5mg 3o Talc mg -

Total 150 mg

The mentioned active ingredient, starch and cellulose are passed through a Mo45 sieve (0.353 mm) and thoroughly mixed. The solution of polyvinylrolidone is mixed with the formed powders and the resulting mixture is then passed through a Mo14 sieve (1.41 mm). The granules obtained in this way are dried at a temperature of 50 - 602C and passed through a sieve Mo18 (1.00 mm). Sodium carboxymethylated starch, magnesium stearate and talc, previously passed through a MobOO sieve (0.248 mm), are added to the above-mentioned granules, which, after mixing, are pressed on a tablet machine to form tablets, the weight of each of which is equal to 15Omg.

Medicinal form 5

Capsules, each of which contains 80 mg of the drug, are made as follows: g" - 5-I(3-(2-(1-carboxy)ethyl|-4-(3-(2-ethyl-4-(4- fluorophenyl)-5-hydroxyphenoxy|propoxy|-phenyl|4-pentenoic acid 8Omg

Starch 59mg 1 Microcrystalline cellulose 5Z9mg o 50 Magnesium stearate. /- 2 mg

Together, 200 mg sl

The mentioned active ingredient, cellulose, starch and magnesium stearate are mixed, passed through a Mo45 sieve (0.353 mm) and poured into hard gelatin capsules in the amount of 200 mg.

Pharmaceutical form 6 o Suppositories, each of which contains 225 mg of the active ingredient, are made as follows: ke 3-(2-(3-(2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy)propoxy)-6-( 4-carboxy-phenoxy)phenyl)propanoic acid 225 mg

Glycerides of unsaturated or saturated fatty acids, up to 2000 mg and 0. y y y

The mentioned active ingredient is passed through a MobOo sieve (0.248 mm) and suspended in glycerides of saturated fatty acids, previously melted at the minimum required temperature. After that, the mixture is poured into a suppository form with a nominal capacity of 2 g and left to cool.

Pharmaceutical form 7 65 Suspensions, a bml dose of each of which contains 5mg of the medicinal product, are made as follows:

2-(2-propyl-3-I3-(2-ethyl-4-(4-rtorphenyl)-5-hydroxyphenoxy|propoxy|phenoxy|benzoic acid Bomg)

Sodium carboxymethylated cellulose Bomg

Sugar 1 g

Methylparaben O, OBmg

Propylparaben O, OZmg

Proofreader as needed

Dye As needed

Distilled water up to Bml

M y M y y y What

The mentioned drug is passed through a Mo45 sieve and mixed with sodium carboxymethylated cellulose, sugar and part of water to form a suspension. The mentioned parabens, corrector and dye are dissolved and diluted with a portion of water and added with stirring. After that, water is added in the amount sufficient to obtain the required volume.

Medicinal form 8

The intravenous dosage form can be prepared as follows: 2-(2-propyl-3-I3-(2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy|propoxy|phenoxy|benzoic acid 100 mg)

Isotonic saline solution 100O0ml

The mentioned solution, which includes the above ingredients, is usually administered to the patient intravenously at a rate of Tml per minute.

Claims (8)

Gesch's invention formula c) 1. A method of treating or inhibiting squamous cell carcinoma of the oral cavity in a mammal, which includes administering to a mammal in need of it an effective amount of a compound of the formula: , Mon Kz « - "» i 2 iz 395 Ku - C1-Cv alkyl, Co-Cv alkenyl, Co-Cv alkynyl, Ci-C; alkoxy, (C4-Cv alkyl)thio, halogen or Co-substituted phenyl; -And each of Co and Kz is independently hydrogen, halogen, hydroxy, C4-C; alkyl, C4-C; alkoxy, (C4-C6 alkyl)-5(O)d-, trifluoromethyl or di-(C4-C3 alkyl)amino; x- -0-,-8-, - (0) or -CH»5-; av | 20 y- -0- or -CH»o-; sp or, taken together, -Х-y- -- -СНАСН- or -C C-; 2 -04-C3o alkylidenyl with a straight or branched chain; A is a bond, -O-, -5-, -СНеАСН- or СЕ аКъ, where each of Ka and Kъ is independently hydrogen, Si -Cv alkyl or K7-substituted phenyl, or, taken together with the mentioned carbon atom to which they are connected, form a C /-Cv cycloalkyl ring; (F. V, - Vv, ko bo b5 mon. V. ( K ) v'Ya-Ke --0-0-k Ko sch y o zo | - YUK iy ry y o - « oo « o - s a z" : about them -I 1 y: about | sha nia V. 1 sl t Zh (F. yuyu Kk 60 and b5 М-В 70 t -- y Co aro I What В b zh She I -K, sch zh r Da o Kk " IS c) , each Ko is independently -СООН, 5-tetrazolyl, СОМ(Ко)» or СОМНЗО» M 0; o each K; - hydrogen, C.i-C; alkyl, Co-C alkenyl, Co-Cv alkynyl, benzyl, methoxy, -M/-Kae-, -T-0-Kbe-, yu (C4 -Cu alkyl)-T-(C.-Cu alkylidenyl)-O- or hydroxy; Ka - hydrogen or halogen; - each Co is independently hydrogen, phenyl or C.4-Cu alkyl, or, taken together with a nitrogen atom, forms a morpholino, "piperidino, piperazino or pyrrolidine group; Clo-C4-Su alkyl or phenyl; Ka - E", -MI-Kv- or -1-65-Ke-; each MU is a bond or divalent hydrocarbyl radical with a straight or branched chain consisting of one to eight carbon atoms; each C is a divalent hydrocarbyl radical with a straight or branched chain consisting of one to eight carbon atoms; each T is a bond , -CH»o-, -O-, -MH-, -MNOO-, -C(0)- or -Z0)d-; K--F(50)- or -CH(OH)-; each d are independently 0, 1 or 2; iz p-0 or 1; and 1-0 or 1; - and provided , that in the case when X is -O- or -5-, M is not -O-; with the condition that in the case when A is -O- or -5-, Ku is not Kb; provided that in the case when A is -O- or -5-, 7 - a bond, U is not -O-; and ("c provided that in the case when p is 0, M/ is not a bond; sl or its pharmaceutically acceptable salt or solvate. 2. The method according to claim 1 with the use of a compound of the formula or z ОН Ф) име) d Vo О0-СНИ-е-А-К, b5 1 its pharmaceutically acceptable salt or solvate. C. The method according to claim 2 using 2-(2-propyl-3-I3-(2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy|propoxy|phenoxy|benzoic acid or its pharmaceutically acceptable salt or solvate). 4. The method according to claim 2 using 3-(2-(3-(2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy)propoxy)-6-(4-carboxyphenoxy)phenyl)propionic acid or its pharmaceutical of an acceptable salt or solvate. 5. The method according to claim 2 using 70 1--4--"carboxymethoxy)phenyl)-1-(1H-tetrazol-5-yl)-6-(2-ethyl-4-(4-fluorophenyl)-5- hydroxyphenoxy)hexane or its pharmaceutically acceptable salt or solvate. b. The method according to claim 2 using 3-I4-(7-carboxy-9-oxo-3-I3-(2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy|propoxy|-9H-xantheneI|propanoic acid or a pharmaceutically acceptable salt or solvate thereof. 7. The method according to claim 2 using 5-I3-(2-(1-carboxy)-ethyl|/-4-I3-(2-ethyl-4-(4-rtorphenyl)-5-hydroxyphenoxy|propoxy|phenyl) |-4-pentenoic acid or its pharmaceutically acceptable salt or solvate. 8. The method according to claims 1-7, where said mammal is a human. Official bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2002, M 7, 15.07.2002. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. s (8) IS) o IS) cha « shi s ;» sh» -I 1 o 50 sl F) ime) 60 b5