PT95690A - PROCESS FOR THE PREPARATION OF SUBSTITUTED DERIVATIVES OF BENZOYLBENZO-, BIPHENYL- AND 2-OXAZOL-ALCANOIC ACIDS, USEFUL AS PLA2 INHIBITORS AND LIPOXIGENASE - Google Patents

Description

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The present invention relates to novel substituted derivatives of benzoylbenzene, biphenyl- and 2-oxazole-alkanoic acid derivatives, which have phosphorylase inhibitor-1 inhibitory activity and leukotriene antagonist activity, and are useful as anti-allergic and cytoprotective anti-inflammatory agents. it is now accepted that arachidonic acid (AA) is metabolized in mammals by two distinct routes. The metabolism of arachidonic acid by the cyclooxygenase enzymes results in the production of prostaglandins and thromboxanes. The physiological activity of prostaglandins has been largely elucidated in recent years It is now known that prostaglandins have originated in the endoqeroxides PGG e and PGH através through cyclooxygenase via ui. of the metabolism of the arachidonic acid. These endoperoxides are also precursors of thromboxanes (Tx) In the normal situation, the vasoconstricting and aggregating properties of thromboxane platelets are compensated for by another product produced from the endoperoxides via cyclooxygenase. In the case of prostaglandin synthesis being weakened and / or plaque activation is implemented, thrombosis and vasoconstriction are favored. The role of the prostanoids haemostasis and thrombosis is analyzed by R-3 Brygle-skiP CRC Crit. Rev. Diochem., 7, 291 (1980 and JB, Smith J. Am., J., Pp. 5, 743 (1980).) Cyclooxyanase metabolites are known to participate directly in the (1984). This is due to its vaso-depressant activity, ie participation in pain and fever, increased vascular permeability by means of peptide mediator and edema formation properties. Finally, several aspects of

results in the production of serious lymphocyte production by untreated individuals. The latter are the LT nomenclature system and the other methods of AA metabolism involve the teachings of lymphocytes. i. metabolic pathway of iϊροοκigenase are the leukotrienes of trienes d CC e and D & · ·ϋϋ. The substance termed as rsacuuu Ien L. ibi Daf anaphylaxis <SRS-A> raostr or consisi of leucotri years? with c: i LTC. and LTD under the main foF. Compounding still several quant.id 'leukotriene metabolites &lt; Vsr Bach et al. 115-118 &lt; 19 80) 5 Biochem, Biophys. Consumption, 9, 1121-1 126 (1984) 3 The significance of these leucotriens is the fact that many pravastats have been accumulated which show that leukotrienes partieipam in. Inflammatory reactions have activity in the hypersensitive reaction. LTCfl and LTD have been shown to be bronchoconstrictors of human bronchus [see Dahlen et al. Matura, 288, 484-486, 1980) and Piper, Int. Arch. Fippl. I in. 1. as Tactiletimer 76-, SLIPI = 1, 40 (19B5) 3 which stimulate the release of mucus of the airways in vitro EMarom et ah, Am ... Re v. Ans., Dis., 126, 449 &lt; 1982) 3, are vasodilocyte α α ten · LSS ϊ J-da. p. 1 κ L VS i 982) 3 prod u i in a = J. S-1a is F α 1, 2, 3, 4, 4, 5, 6, 7, See A »For d -Hu 497 &lt; 1983) 3" leukotriene no 3 "Rov. b'oc

Med, 8.51-833 (1981), which stimulates cell accumulation and affects vascular smooth muscle Γ.ver Bray? Br «Hed« Bui 1 «. 39, 249 &lt; 1983). The activity of leukotrienes as mediators of inflammation and detail in tisziey and hypersensitivity is discussed in Ann. Reports fled »Chenu, 87 (1986). Tetrazepase (PLA-Â) is the critical rate-limiting enzyme in the arachidonic acid cascade (AA) = since it is responsible for the hydrolysis of the C-2 esterified AA of the membrane phospholipids. without the AA being available for subsequent metabolism by the cyclooxygenase or lipoxigenesis enzymes and C2) the lysophospholipid. The production of the platelet-activating factor (FAP) is initiated when the alkyl-arachidonoyl-glycerophosphate-phytidylcholine is activated by PLA2, the FAP is pro-inflammatory Lver

Wstímore et al. In this regard, it is noted that anti-inflammatory steroids are believed to inhibit eicosanoid synthesis by inducing the synthesis of an inhibitory protein (see, e.g., of PLA, termed macroportin or 11pomoduline [Flower et al. Ma tu re »London, 278 = 456 (1979) and Hirata et al., Proc. Natn. Acad = Sci. US, ..., 77, 2533 &lt; 1980), which is the initial step leading to subsequent convection of AA in various eicosanoids via the eukaryotic cell line, the Xzoeration of AA by FEL.A3 ratio of membrane phospholipids is a critical factor in the treatment of the various physiological manifestations which are based on the action of eicosanoids and / or FAP. In this way, although it has been shown that PLA ..-, is required for the aggregation of the platelets £ 't. , Biochem. (1976) 3, for cardiac contraction ESeiser et al., Pharm. Res. Comusu et al., 7 (3), as well as for the synthesis of orostaq1andina ΓVoqt,

AdvProstaal. ihromb. Res. Indicated in the therapeutic treatment of physiological diseases, whether induced by PAF or mediated by a product of the cyclosporin or in the presence of cytotoxigenic pathway products (Eg, gastric and intestinal contents, microorganisms, etc.), or ischemia = viroses5 to the TljtrriTl damage to Asbh for a period of time. fasm as in citopro-> 5 the prostaglandins exert UH! and this section of the prastaglandins, especially the E-series, is considered to be important for the treatment of gastrointestinal ulceration Evsr Isselbacher Druqs, 33, (su.pl o), 38-46 (1987) 3 = On the other hand. avo, have shown that the mucous membrane of rat rats is prosaic. .............. ... -... r * r that this production of LTC- is quantitatively related to

T the severity of the damage caused by ethanol Cver tange et al = Naunvn-Schiffliedebera's firch. Pharmacol. Suppl., 330, R27, (1985) 3 = has also been shown that LiU * can induce ~ F B. v a soc on s fc r ions? in the venous vessel 'or in the arterial vessel submucosa of the rat Ever tsJhittle, IliPHfiR Ninth Int = Cong. of Pharm = 536-2 =

London, England (1984) 3 = This is important, since the gastric mucosa formation of an ethanol-induced lesion may be multifactorial with, for example, stasis of gastric blood flow which contributes significantly to the development of the necrotic lemorrhograms In addition, in an anesthetized cat, the exogenous LTD2 causes both increased pepsin secretion and decreased potential (1961). CPendleton et al. Pharmacol = = 1 rp *, A remarkably important finding in this respect is the subject of inhibitors of β-β-cyclohexenase. Isukotriene protect the gastric mucosa against those parenterally induced lesions of most non-steroidal oral or anti-inflammatory drugs (see Rainsfard, Aqents and Actions, 21, 316-519 1987) 3 = Q factor (FAP) is on. also implicated as a mediator of gastrointestinal damage and it has recently been shown that 5-lipaxigenase inhibitors inhibit FAP-induced gastric mucosal damage (Bastrae et al., 96, A55, A434, 1989) = Thus, a significant amount of evidence demonstrate the involvement of lipid kinase products in the development of pathological features associated with gastric mucosal lesions such as

And induced by the administration of anti-coughs. Non-sterile. That way. The compounds of the present invention are suitable for the treatment of leukotrienes and FAP and / or which control the biosynthesis of these substances, for example by inhibiting leukotriene. 5-lipoxygenase, are considered important as cytoprotective agents.

Thus, the biological activity of leukotrienes SRSs and lipoxygenase as an enzyme that leads to the metabolism of AA in leukotrienes indicates that a rational approach to drug therapy is to prevent, eliminate or ameliorate the symptoms of allergies, anaphylaxis, asthma and inflammation, and for. cytoprotection, should focus not only on blocking the release of mediators of these diseases but also on antagonizing their effects. Thus, compounds which inhibit the biological effects of the leukotrienes are of the SRS and / or. which control the biosynthesis of these substances, for example by inhibition of PLA mediated release. of the arachidic acid of membrane phospholipids or by inhibition of lipoxygenase are considered important for the treatment of diseases such as bronchial asthma,

Allergic rhinitis, as well as other allergic reactions.

intermediate hypersensitivity, and to provide gastric cystastasis. the PLA_,

It has now been discovered that certain sufasti-ibenzoylbenzene-, biphenyl- and 2-Î ± -olearanoic derivatives of the compounds of the invention are thus useful as amphi-inflammatory, anti-allergic and cytoprotective agents . The present invention provides novel compounds having the following formula: (b)

Phenylphenyl or a group of formula

VN

i Z 2 em where · · i 5 5 5 5 5 ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ

is hydrogen or lower alkyl; or

The R ε R * &quot; taken together form a faenzene ring? R é is hydrogen or lower alkyl; I do not know

N V CH (CH 2) m COOR 5 0

wherein or are each independently H hydrogen

V

lower alkyl, and the pharmaceutically acceptable salts thereof. The term &quot; lower alkyl &quot; refers to moieties having 1 is carbon atoms in the carbon chain. The term &quot; halo &quot; refers to fluorine, chlorine or bromine. The A moiety comprises, inter alia, 5- or 6-membered unsubstituted nitrogen, mono- or benzo-fused heterocycles containing enkofre or OKiqenO2 optionally substituted by lower alkyl or. by phenyl. The above definition encompasses the following heterocyclic moieties furyl, pyrrolyl, thienyl, OKazolyl, D, thiazolyl. imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, benzofuranyl, benzothienyl, benzothiazolyl, indolyl, benzoylazolyl. quinazolin-5-one in the same manner as in Example 1. 1 ila r. q u. i η o x alinyl, q u i n a z o 1 i -n i lo. etc. Especially preferred are qunolinol, benzothiazolyl and benzimidazolyl.

The compounds of the invention may form pharmaceutically acceptable salts from pharmacologically acceptable organic and inorganic acids such as hydrochloric, hydrobromic, sulfonic, sulfuric, phosphoric, malic, ferric, benzoic, ascorbic, pamoic , sue cínico. methanesulfonic acid. Acetic, propionic, tartaric, citric, lactic, malic, mandé-11co? The compounds which are carboxylic acids are capable of forming alkali metal carboxylates or alkaline earth carboxylic carboxylates by the addition of ammonium salts or ammonium salts of ammonium or isopropanol. of a basic amine. Such as mono-, di- and triethylsilane, such as mono-, di- and triethylsilane, diethylammonium diethylammonium, and the like, without being limited to ammonium; mono-, di- and trimethyl &lt; mono-, di- and iripropylammonium (iso and normal), ben-dimethylammonium, cyclohexylammonium, benzylammonium, benzylammonium, piperidinium, morpholinium, pyrrolidinecyloxy, piperazinoylmethyloxypiperidinium, 4-ethylmorpholinyl, 1,4-dimethylpyrimidinecarboxylic acid, 1,4-dimethylpyrimidinecarboxylic acid, 1,4-dimethylpyrimidinecarboxylic acid, 1,4-dimethylpyrimidinecarboxylic acid, ethyl, n-butylmethanethanolammonium, tris &lt; hydroxymethyl) ammonium, phenylmonothaneammonium, etc. "

Compounds of the invention may be prepared from the following reaction schemes. In order to prepare the tosylates of formula

4-methoxybenzenitrile = dichloromethane followed by reaction, and the reaction mixture is cooled to -78 ° C. The reaction mixture is partitioned between ethyl acetate and dichloromethane. -C 4'-methoxy-3-benzafenone =

3-bromotolu and η or Mg

bromo j

BrCH2CH2Bry benzoyl peroxide

CH3

The bromo intermediate is reacted with sodium cyanide to give the cyano intermediate, which is hydrolyzed in the presence of a base to produce the carboxylic acid 3 which in turn is demethylated to give the intermediate of the formula hydrocarboxylic acids

CH3 ° Y + n V ^ (/ SxCH2Br or

NaCl dioxane / H2O

-CH

KOH Δ II 0

The intermediate of carboxylic acid hydroxamic acid in methyl ester by the use of methanol in the presence of toluenesulphonic acid followed by reaction with a suitable halo-alkyl-A compound, wherein A is as defined above and hal is halo, to give the desired end product under . I do not know

ch2cooh II ο ΗΟν ch3oh p-toluenesulfonic acid)

A (CH 2) n ha I K 2 CO 3/18-crown-6 pa. I ico

The ester can be hydrolyzed by methods to obtain the desired end product in the form of vinyl chloride,

The compounds of the invention of formula

The compounds in which R 1, R 2, R 3 and R 4 are nitro and R '. is the half-C-R &quot; may be prepared in the following manner, for example, 4-bromo-3-nitrazoacetophenones are reacted with 4-iodoanisole in the presence of bronze copper, to yield the methyl ester containing mexy which is demethylated with bromide The latter compound is reacted with a suitable haloalkyl compound, which A is as previously defined, and hal ρ h to obtain the desired end product,

AlBr3 benzene 1

The compounds in which R é is halo and K 'is -CH₂RJJ may be prepared by a process using the 4-methoxy-hyphenyl intermediate of the preceding scheme. Thus, the 4-acetyl-4-methylester intermediate of the above scheme is subjected to reduction with stannous chloride to give the intermediate amino derivative which is then subjected to. substitution of the amino group by a halo group. For example, the amino group can be replaced by fluorine via a transient intermediate of diazonium fluoroborate prepared from the amino intermediate by use of sodium nitrite and tetrafluoroboric acid. The resulting acetylfluoro-methoxyphenyl intermediate is converted to the corresponding carbbasilic acid followed by demethylation with hydrogen bromide to provide the intermediate 2-fluoro-4'-hydroxy-E1,1'-biphenyl-4-acetic acid or

SnCl,

HCl / EtOH 'OCH 3

(I.e.

(I.e.

och3

-19-

· Ν. ?? The carboxymic acid of the preceding step is esterified with methanol in the presence of p-toluenesulfonic acid and the latter is reacted with the appropriate halogenating compound A wherein A is as defined below and hal is halo to yield the desired end product in the form of methyl ester *

ch3oh ch3o2cch2 p-toluenesulphonic acid

OH A (CH 2) nhal &gt; K2C03 / 18-c .. i-6 i - · - · ch3o2cch2

O (CH2) nA

The ester can be hydrolyzed by all iodine atoms. Fig. f. The desired end product is obtained in the form of a compound of the formula:

The compounds of the invention of formula

The title compound was prepared as described in Example 1. of the compounds of formula (I). c. The composition of the present invention comprises a compound of the formula: ## STR2 ## wherein R is as defined in formula (I). . &quot; flte t. and D-phenyl-acetic acid

ch3o,

0 = C * "CH2CH2C00H toluene / Δ

oIInh2cnh2HOAc / Δ

The title compound was obtained as a yellow oil, and the title compound was prepared as a yellow oil, mp 218-221øC. 1 H NMR (CDCl 3):? ; ester hydroxyl. The reaction mixture is then reacted with a compound of the formula wherein R 1 is as defined for formula (I) the 'p-3. The final product is obtained from the compound of formula (III)

sJ

N

CH2CH2COOH

CH2CH2COOH

CH2CH2COOCH3 i

The ester can be hydrolyzed by conventional methods to yield the desired end product in the form of free carboxylic acid.

The conventional starting materials used in the above-mentioned reaction sequences are commercially available or can be prepared by methods known in the art. Thus for example, the intermediate compound 2-hamsamstilquinalin may be prepared by the following reaction scheme

Heterocyclic heterocyclic compounds used in the above reaction sequences are either commercially available or can be prepared by conventional methods known in the art. Thus, for example, these intermediates, such as i-methyl-2-chloromethylbenzimidazol-2-chloromethylbenzthiazole and 2-chloromethylbenzoylazoles can be prepared by the following reaction scheme

V

V

wherein X is O, S or MCh%. The ration is preferably carried out at a low temperature, which is controlled, in an organic solvent, such as methylene chloride.

The compounds of the invention, by virtue of their ability to inhibit the activity of the above PLA-1, as well as that of the enzyme pathway, and in antagonizing the mediators produced by the enzymatic route, are useful for the treatment of diseases mediated by products of the oxidation of arachidonic acid. Accordingly, the compounds are indicated for the treatment of diseases such as rheumatoid arthritis, inflammatory bowel disease, osteoarthritis, tendinitis, bursitis, psoriasis and similar inflammation of the skin) and similar diseases involving inflammation. In addition, and by virtue of their ability to antagonize the effect of LTC3, LTD4 and LTE4, which are constituents of 3RS-A, they are useful in inhibiting the symptoms induced by these leucoirenes. Thus, the compounds are indicated for. prevention and treatment of diseased states in which LTC3, LTER and LTE4 are provocative factors, for example allergic rhinitis, allergic bacterial asthma, and other leukotriene-mediated airway obstruction diseases, as well as other immediate hypersensitivity reactions, such as conjunctivitis

allergic-Os; compounds are especially important for the prevention and treatment of allergic bronchial asthma.

The compounds of the invention are agents; cytoprotective agents and are considered useful when they are administered together with non-estrogenic anti-inflammatory drugs whose greatest side effect is gastrointestinal irritation. The cytoprotective effect of the compounds of the invention significantly reduces the gastrointestinal impact of conventional anti-inflammatory drugs. This effect is based not only on the ability of the compounds of the present invention to inhibit the biological effects of isucotrienes and / or to control the biosynthesis of these substances, for example by inhibiting lipoxygenase, streets also in a bypass effect, control of the lipoxygenase pathway "causes" the oxidation of arachidonic acid to the cytoplasmic pathway, resulting in an increase in the formation of cytoprotective prostaglandins. These biological effects render the compounds of the present invention especially useful for the treatment of diseases such as erosive esophageal inflammatory bowel disease and induced hemorrhagic lesions such as those induced by alcohol or non-steroidal anti-inflammatory drugs (MAINE) , hepatic ischemia, injury induced by a toxic agent, or hepatic, pancreatic, renal or myocardial tissue necrosis, liver parenchyma lesion caused by hepatotoxic agents such as carbon tetrachloride and D-galactosamine, renal ischemia renal failure induced hepatic impairment. pancreatic or gastric lesion induced by bile? cell injury induced by trauma or stress 5 s glycerol-induced renal failure.

When the compounds of the invention are employed in the treatment of allergic airway disorders, in the form of ε anti-inflammatory agents or cytoprotective agents, they are

formulated in capsules. etc. oral dosage forms such as tablets,

The compounds may be administered alone or in combination with conventional carriers, such as magnesium carbonate, magnesium stearate, talc, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, melting point, cocoa butter. etc. Diluents, flavoring agents, solvents, lubricants, suspending agents, binders, tablet depressing agents, etc. may also be employed. The compounds may be encapsulated with or without other carriers. In all cases, the proportion of active agent present in said compositions, whether solid or liquid, will be such that at least the desired activity is obtained by oral administration. The compounds may also be injected parenterally, in which case they will be used in the form of a. sterile solution containing other solutes, for example saline or glucose, in an amount sufficient for. make the solution isotonic. For administration by inhalation or by insufflation, the compounds may be formulated in an aqueous solution or. partially aqueous, which can then be used in. form of an aerosol.

The dosage requirements vary depending on the. composite composite. i n d i v i d ua 1. or if so,

LdIII. n i s L ra bj · Si D »d-5. The treatment will normally be optimum for the optimal treatment of the patient. The patient will have an action. In general, the patient will be given a dose of 5. i-DS sscundár i osis as a B. dn SB LU! X t A Γ X B Γ B can be divided into t str ada 15 15 15 CD CD CD CD ΧΠ ΧΠ ΧΠ ΧΠ ΧΠ ΧΠ ΧΠ ΧΠ ΧΠ ΧΠ ΧΠ ΧΠ ΧΠ

These procedures? inter alia, the city of the section of the present PLA compounds, as measured by their capacity yi ΧΠ XQ Ο Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ. The compositions of the present invention may also be described in the following pharmacological proce- dures which will be described in more detail in the examples exempted from the prior art. determine the invention as inhibitors in inhibiting the synthesis of the Isares produced by their ability to co-mediated LTB source, and PBE by polysorionic leukocytes. 4-rat glycogen, as measured is to inhibit the release of PLA human arachidonic acid. Pharmacological tests further demonstrate cDNA. The invention also relates to the use of polyvinylpyrrolidone and polyvinylpyrrolidone in the presence of the polypeptides of the invention in vivo. the net value of arachidonic acid.

The following examples show the preparation and pharmacological tests of the compounds of the present invention.

J

A 4-Acetyl-4 '' - methoxy-2-pyridyl biphenyl

A stirred mixture of 4-bromo-3-nitro C4-6, 6 g, θ, 16.66 mol) and copper powder &lt; 43 = 65 g, 0.17 mole) ), kept under nitrogen, is placed in an oil bath heated to 8Â ° C. The temperature is varied from 1 to 11Â ° C. maintained at this time of 5 dxas < CCF s? Hexane-ethyl acetate). D for the first product, and for the first product to be used. 32%) of the solid Compound 11 compound

After cooling, the mixture is dissolved in dichloromethane and filtered through a pad of Celite. The filtrate and washings are evaporated and the dark brown thick residual oil (58.4 g) is flash chromatographed (on silica Merck 6, pre-absorbed in dichloromethane, eluted with 9% hexane-ethyl acetate The title compound was prepared from the title compound as a yellow oil, mp 124 DEG-26 DEG.

Θ0 MH2) s S 2 .4 / H w - <s, 3rr 1, CQCH _ =} = Tf q OU < s), 6.97 (d, 2H, J = 8.74, ArH &gt; , 7 &quot; 27 &lt; d, 2H, t, 4H); 3 7.56 &lt; d, 1H, J 8 Hz, ArH 8.15 (d, 1H, J8 H.2, ArH), 8.44 &lt; s, 1H, ArH (EI, m / z): 271 <M '>

The ume. stirred solution of Γ-. (45 ml) was added dropwise thereto under azotomethic ether (1 g, 45 mmol) of the title compound as a white solid. . Step A in

(12 ml) for 30 minutes. The resulting solution is stirred at room temperature for 3.5 hours (TLC, 8: 2 hexane-ethyl acetate). The mixture is cooled with ice-water and the complex is decomposed by the dropwise addition of t t. t Ton-HC1 / __. rr-? The organic layer is separated and the aqueous layer is extracted with ether (3x). The organic extracts are concentrated in vacuo. The combined extracts were dried over magnesium sulfate, dried over sodium sulfate, and evaporated to dryness. The combined extracts were dried over sodium sulfate and dried (MgSO4). the 0-3. are cooled and acidified with HC1 COnCSR &quot; (for PH 2 pair). A solid is collected, (4 = 21%) and used in the next step for additional purification

RTI ID = 0.0 &gt; (CDCl3, .delta.), &Lt; / RTI &gt; Cd, 2H, J'3, 56 Hz; ArH), and 2 (t, 2H, 7 s, 57 H's, ArH), 7.55 (d, 1H, J = 7 Hz, ArH), 8.16 LJ - 5 ϊ Π ~ ~ ~ ~ ~ ~ t t t t t t t t t t t 8 8. 34 v a 1 H 5 A rH) s

J

MS (EI m /

M. V

Nitro-4; -vinolinyl) -11-biphenyl-4-yl] -L

J

A mixture of the anhydrous potassium carbonate (4.4 g, m.sup.2) of the title B, potassium carbonate in anhydrous potassium carbonate (0.8 g, 1: 1 mmol), iso-crown- gt; 1.71 mmol) and acetonitrile (38 ml) is stirred at room temperature under a nitrogen atmosphere for 15 minutes. 1-Fluorocyclohexanecarboxylate For the free base to prepare the diastereomeric residue) and the mixture is refluxed for 10 hours (TLC,

/ s 3 of he x an o - a c s t. The solvent is removed and the residue is diluted with water and extracted with ethyl acetate (<3 g). The extracts were dried over sodium sulfate (1: 1) ). Flash chromatographed on silica gel (pre-absorbed in dichloranethane) is added to increase its polarity with 7: 3 hexane-ethyl acetate followed by ethyl acetate. ethyl acetate) to afford the pure title compound (2.59 g) as recrystallization from toluene yields a 30% solid) and NMR (CDCl3, 40 MHz): δ 2.66 (s, 3H, 1 H-NMR (DMSO-d 6): δ 0.9 (broad, 2H, Ar H), 7.27 (d, 2H, 3 B, 7 Hz, ArH), 7.56 (to, 2 Ή, ArH), 7, is> 8 (d, 1H, J η n = (D, 1H, ArH), 8.75 (d, 1H, J = 9 Hz, ArH), 7.75 (d, 1H, 1H), 8.22 (d, 1H, J 8.49 Hz, ArH), 8.34 (s, 1H, ArH) C, / 2 =. -3 'or ρ H, 4' -3b ρ N, lr-fyj &quot; -i &quot; C, 71.96; H, 4? 75 hrs.

Calculated

Found

-me &quot; c.ói i - λ ~ am i n o η, Βχfeni 1 ο of 4-acetyl-

To a solution of (II) (49.4 g, 72%) and ethanol (99 ml of hot ammonium chloride) was added dropwise over a period of 1 hour. The resulting yellow solution is refluxed for 3.5 hours (TLC, isopropanol) and the reaction mixture is stirred at reflux for 3 hours. hexane-ethyl acetate). The ethanol is removed and the residue is poured into a mixture of 50% NaOH (36 ml) and ice. The resulting solid is extracted with dichloromethane (dichloromethane, hexane). the former are shown in FIG. Q Ll cl e 5§d dry <Na "SQ"). The crude product afforded an amorphous solid (9.31 g, 97.8%), mp. NMR: δ 2.59 (s, 3H, COOH), 3.8 (s, 3H, OCI-U),: H, J 8.7 Hz, ArH); H), 7.40 (d, 2H, JH, u, 3 Hz, ArH),

.. .. .. .. .., 23 < d, 1H, J 7.4 Hz, ArH), 7.40 (d, 2H, J 8.7 Hz, ArH), -F-? (4-acetyl-4'-methoxy-2-fluoro) biphenyl To a stirred, cooled mixture of (9.2 g, 38.2 mmol) in tetrahydrofuran (26 ml 5, water (9.8 ml) and dichloromethane (40.85 mmol)) was added dropwise (5 ml ). below, during storage for a few days at 0-5 ° C. HBFa (48%, 35.1 mL) is slowly added a solution of sodium nitrite <2.82 g, 4, 8-5 mmol) in water (5 mL). The temperature, The mixture is

om r * | (4 to 1%) is decomposed in the presence of a compound of formula (I). 0 xile no. 11 i. 1 D 3 X 3) and diazonium is extracted by filtration, washed with Hbt, &quot; The methanol is heated to 100 ° C in ether and is dried in vacuo. The salt is decomposed by heating in 50 ml of methylene chloride to give the title compound as a white solid.

The combined extracts are washed with 10% sodium carbonate and brine and dried (MgSO4). Removal of the solvent affords an amber oil (7.3 g) which is purified by flash chromatography on silica Merck 60, pre-absorbed in dichloromethane and 1: 1 by weight 95: ethyl acetate) The title is obtained in the form of a single yellow liquid, 33-51% depending on UB. passage &gt; ρ p * f. 10-101 ° C. The compound (CDCl3, 4x), 3.86 (s, 3H, OCt), 73.0 (s, 3H, COCH3) 2H j; J = 8.9 Hz, ArH), 7.5-7.7? (EI, m / z): 244 (M +), 229 (b, M-CH 2) + C. 2-Fluoro-4'-methoxy- (4â € ², 4â € ² Hâ,,Clâ,ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ 17 hours s ri nh «P 1 day of work 1xca worked. with hexane, 8.2 g of hexane-acetonitrile) was added thereto, after addition of 5% acetic acid to the title compound (9 ml) (4 ml) was added and the residue was refluxed for 2 hours at 0 DEG C. The reaction mixture was cooled to 0 ° C. The combined extracts are concentrated to a small volume. &lt; tb &gt; Li Dii! The compounds of formula (I) are prepared by reacting the compound of formula (I) with a compound of formula (I). Ld in HC1 color? The title acid is the title compound (3: 1) and the title compound

with a melting point, dried and dried (MgSO4). Removal of solvent from brownish bruise <2, g / melting at 140-142Â ° C, MH 2 &gt; Δ 3.68 (s, 2H, CH3, 1, O), 3.32 (s, 2H). (s, 3H, OCHâ, ...), Î'-. (M, 7H, ArH), m is 0, 1, 2, 3 or 4; The title compound was prepared from methyl ether (1.31 g, 5.4 mmol) and triethylamine (1.31 g, 5.4 mmol) in dichloromethane. C Β0Ί! glacial acetic acid (17 ml) is added dropwise in acetic acid (25 ml) and the mixture is subjected to 24-

A methanol solution (1 ml) was treated with acid reflux. (1.1 g, 4.47 mmol) of Step D in p-toluenesulfonic acid (Hâ,ƒâ,, Θ 3115 g) is stirred for 1.5 hours (TLC, 7: 3 ethyl silica plate). The solvent is acetate-hexane or reflux for 4½ hours (TLC, 75% hexane-ethyl acetate).

A small amount of water is added and the mixture is extracted

with ether (3x). The extracts were washed and dried (MgSO)) ... 2%. Removal of the solvent affords the title compound as a tan solid (1.13 g, 92%), m.p. 2.28-210 ° C. NMR (DMSO-d 6, 40 MHz): δ 3.61 (s, 2H, CH 2 COO), 6.83 (d, 2H, J 2) In this form in the removal, the residue is obtained by the addition of a non-ionic surfactant. dissolved in ethyl acetate, washed with brine and dried (silica gel), mp 160-180C, yield as follows.

MS (EI 01 / Z 1)

3-fluoro-4 '- (2-quinalnyl) -6-acetic acid; 2H); CH3 COC)), 3.38 (s, 1H). L-UUL-ri-r / Cr? ¹H-NMR (DMSO-d 2H, δ, 2H, J = 8.8 Hz, 1 H, ArH); (M-COOCH3)

A syst. The reaction mixture was stirred for 1 hour at room temperature for 1 hour. ) of the carbonate of the anhydrous pClSB was present (€ 5.6-1 Q 4 q -i S-5), 1S-C-D 3 O 3, (445 mmoles) is added to the reaction mixture and the reaction mixture is stirred at room temp. for 15 minutes. 2-chloro-2-chloro-2-quinolinecarboxylic acid (4-chloro-2-chlorophenyl) -1- (3x) The extracts are washed and dried over sodium sulfate and dried over sodium sulfate. The extracts are washed with water, dried (Na2 SO4), dried (MgSO4) And potassium carbonate, potassium carbonate, 1B-crown and chloromethylquinoline and heating is continued for a further 6 hours at 0 ° C, 19% dichloromethane-methanol or 7% hexane-ethyl acetate). The solvent is removed and the residue is diluted with water and extracted with ethyl acetate and solvent removal yields a tan solid which is purified by chrom Flash chromatography (on silica Merck &amp;, pre-absorbed with dichloromethane, eluted with 7: 3 hexane-ethyl acetate) The title compound thus obtained (1.55 g, 87%) is recrystallised from from methanol. The white solid-phase melts

RHN and CHOH, 40 MHz, δ 3.64 (s, 2H), 5.43 (s, 2H, OCHOAr), 71 (m, 4H,

ArH), 7.35 (t, 1H, ArH), 7.47 (d, 2H, ArH), 7.55 (t, 1H, ArH), 7.69 (d, 1H, ArH), 7.74 (d, 1H, ArH), 7.64 (d, 1H, ArH),.

MS (EI, m / z): 401 (M + H) +, 142, 114 (p = s)

Dwarf 1 ise sara s FNO__

Calculated C, 74.4; H, 5.32; N, 3.49

Found: C, 74.68; H, 4.65; N, 3.49. r

2-Fluoro-β-Quinolinylphosphino) -1,1'-biphenyl-4-one ester solution (1.69 g, 4.21 mmol) from Step F in dry tetrahydrofuran <20 ml) (12.6 mL) and the mixture was stirred for 3 hours at room temperature (dichloromethane / dichloromethane / ethyl acetate / hexane / ethyl acetate = 0). solvent is removed, the residue is

4 - jr bounded with water and is Π td Γ Γ Γ Γ Γ Γ Γ 1. 1.. The reaction mixture is cooled to 0 DEG C. The reaction mixture is cooled to -10 DEG C. The reaction mixture is cooled to 0 ° C. The extracts were dried (MgSO4) to dryness to give an off-white solid (1.65 g), yield

The analytical sample is dried in vacuo at p = 190-193 ° C, dec.). Ethyl acetate affords a white solid.  € ƒâ € ƒâ € ƒ1 H-NMR (CDCl3): δ 3.62 (s, 2H, CHâ,ƒCOCO), 5.41 (s, 2H,

MS (- 1 H-NMR (DMSO-d 6):?

Analysis for C₂ HH₂ FN₂O,, C₂ HH₂ 4N₂O,;

Calculated C, 74; 41 ' Δ, 4.68? N, 3562 Found: C, 74.28; H, 4.48; N, 3.69.

N EXAMPLE 3 Acetic Acid (gm -chinolinyl) isoxy) benzoyl) -3-benzene A 5-Ma c 11-C 4'-methoxy-1-benzofuran

A .5-neck vial equipped with a condenser, with a mechanical stirrer and a dropper funnel is sealed. under nitrogen, with 1.92 g (79%) of magnesium turnings and the addition of 1 to 10% by weight of methanol in hexane. The solution was cooled to 0 ° C. The solution was cooled to 0 ° C. The solution was cooled to 0 ° C. The solution was cooled to 0 ° C. The solution was cooled to 0 ° C. (4 ml) were added simultaneously in order to initiate the reaction. The mixture was left dropwise and the mixture was mostly magnesium vanish, and the reaction mixture was evaporated to dryness. (Ι 3 ml) is cooled to 0 ° C. After cooling to room temperature, the reaction mixture is cooled to -78 ° C. mixture is subjected to u; 2 hours (TLC without the presence of ice bath) and is treated slowly with dichloromethane Ηο 30Λ diluted Cϊ, v, v / v, 25 ml A The decomposition of the complex is terminated by refluxing the mixture for 4 hours (followed by TLC, ethyl acetate-ethyl acetate). After stirring overnight at ambient temperature, the layers were separated and extracted with ether (3x). The extracts were washed with NaHCGS-a The crude material (an oil, 13.93 g) is purified by flash chromatography (on silica Merck 60, eluted with 8% petroleum ether acetate), dried over anhydrous magnesium sulfate, and evaporated to dryness. ethyl acetate) to give the title compound as a light yellow oil (1: 1), tb______________________________________ tb (1: 1), tb______________________________________ tb NMR (CDCl3, 400 MHz): δ 2.4 (s, 3H, CH3), 3.9 (s, 3H, DCH3), Î'=, 9β

A solution of ben20fanone (1 / 4d) in ethylene bromide (22.5 ml) was added dropwise to a solution of ethylene bromide (15 ml) of a compound of the formula (17) in the presence of a small refluxing agent (17.7%), in the same time that the product is subjected to irradiation The reaction is carried out over a period of 17 hours. The reaction mixture is allowed to warm to room temperature and the reaction mixture is allowed to warm to room temperature. gifts

Lignes of the starting material) are then removed in vacuo and the residue (brown oil, -59.22 g) is purified by flash chromatography on silica Herck® 6, dried over dichloromethane, , eluate. Of ethyl ether and ethyl acetate. to obtain α material of ρ-B. r mc. .1. (2.59%) of the title compound (2.59 g, 15%) was added sequentially with the desired product (0.136 g, 61%). The composition of the present invention is based on the non-reactive partitioning material 1 which is not reacted with a compound of formula (I). («« ««??????????? MHz «« «« «aro aro aro aro aro aro aro aro aro aro aro aro aro aro aro aro aro aro aro aro aro aro aro aro aro aro aro ΟΓ ΟΓ ΟΓ ΟΓ ΟΓ (2H, CH2) Br / 396 <lt; d 8.88 Hz, 2H, ArH (CH 3) &lt; / RTI &gt; &lt; / RTI &gt; 7 (44): 7.6 (1H, Ar, H), 7.7 (1H, (d, J = 9Hz, 1H), 7.76 (s, 1H,

ArH) δ 7.58 (d, J = 8 Hz, 1H, ArH)

CH3o

Br ΧΧ, ΧΧβγ) u u u u - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - Et Et Et Et Et Et Et Et Et Et solution is subjected to refluxing. The crude compound (14 g, dissolved in dioxygen (3 ml) <7 g) in water (285.5 ml) was added. At this time &lt; CCF, 8% petroleum ether-ethyl acetate &lt; / RTI &gt; is carbonized if necessary and is e> (3 &gt;). The s &gt; The compounds of formula (I) and is going s. tea (c) to give a brown oil (13.44 g). The crude product is purified by flash chromatography (on silica gel Merck-6, pre-absorbed Sm dichloromethane, is eluted with hexanes-ethyl acetate (6: 4) to give the pure product (IS, 69 g,%) as a light yellow oil, which is amorphous. 11a. (s, 3H), 3.68 (s, 3H), 3.68 (s, 3H), 3.68 (s, 3H) OCH2); * -? (D, d 8.6 Hz, 2H, ArH), 5.48 (t, 3 * 7 ~ 7/5 Hz, ArH) , ArH), / SJ (s + d, 1 · 75 Hz, 2H 3 ArH), 7.79 (d,

ArH)

The nitrile of Step Cs is dissolved in 4% NaOH (40 ml) and the solution is heated at reflux under nitrogen for 7 hours (TLC, toluene-ethanol). Water is added while cooling in an ice bath. The solution is washed with ethyl acetate and then acidified to cold with concentrated HCl (to pH 21). The acid is extracted with ethyl acetate 1 H-NMR (DMSO-d 6) δ (DMSO-d 6) δ (DMSO-d 6) ), 3.5 (s, 3H), 3.88 (s, 2H), 3.88 (s, 3H), 5.95 B-8 Hz, 2H, ArH), 7.43 (t-1H, ArH) s 7 5 48 <1, 1 ΐ 3 ΐ ArH) n / q CD < d 5 1H, ArH), t, 77.0 &lt; s, 1H, ArH), 7.81 (d, 1H, 3.86 Hz, 2H, ArH); 211 <M-CH <COOH> τ £ i. 2-5 !. ρ = SSΘΘ "E E E E 3-L-4-hydroxybenzoate 13-phenylacetic acid

A mixture of (8.51 g, 0.03 mole) of Step D and pyridine 1 . 3.87 g. The reaction mixture was stirred at room temperature for 2 hours and stirred for 2 hours at -78 ° C for 7 hours. The title compound was dissolved in dichloromethane The solution is extracted with NaOH, the extract is cold acidified with concentrated HCl and extracted with ethyl acetate (3x). After drying (MgSO4), the solvent is removed to give the compound

NMR (DMSO-d6):? MS (m / z): C11 + H) +; 5 S 3, 67 &lt; s, 2H, CH 2, θθθ), 6 WH d and J 8.84, 2H, Ar Ή), 5.5 (m, 5H, ArH), 7.65 , 2H, ArH), 10.4 (5H, m), 2.32 (3H, d, J = 9Hz) 4-hydroxybenzoic acid;

A mixture of the acid &lt; 8.56 g, 33.4 mmole) from Step E and p-toluenesulfonic acid monohydrate (1.6 g, 5.6 mmol) in methanol (7 ml) is subjected at reflux for 25 hours (TLC, methanol-toluene = 9). The methanol is evaporated and the residue is dissolved in ethyl acetate. is washed with brine, dried (MgSO4), the solvent is stripped brass (8.68 g, 96.2%, mp 111 DEG-143 DEG C.) is used as such in the next step. Stef gives a s 1-113 ° C &gt;

After 1 H NMR &lt; CDCl3 - 40 MHz): Î'3.6V (s, 2H). (CDCl 3): 6986 (d, J 8.4 Hz, 2 H, 3.69 <3H, ArH), 7.41 (t, 1H,

Hz 1H, ArH), 7.37 (d, 1H, ArH), 7.64 (s, 1H). 1H, Arl · 1), 7.74 (d, 2H, J 8.4 Hz, ArH); s 271 (H-H-i) 217, 131? 91 <p> e)

(2-quinolinecarboxylic acid) benzoyl-benzoic acid (2-quinolinecarboxylic acid)

A mixture of phenol (4 g, 14.8 mmol) of potassium carbonate (2.0 g, 14.8 mmol) and 18-crown-14.4 g, 1 , 48 mmol) in acetonitrile (35 ml) is stirred at room temperature under nitrogen for 15 minutes. 2-Chloromethylquinoyl C 259 g, 1.26 mmol, to be prepared from the cloridine salt) is added once and the mixture is warmed, num. oil bath which is maintained at -5 DEG-70 DEG for 8 hours (CHCl3, to 1: 1 methanesulphonate). An excess of 1% of the desired CO 2, and crown ether is added and the heating is continued for 8 hours. The acetonitrile is evaporated and the residue is partitioned between ethyl acetate and water. ; The β-ganic layer is S-O-C (Z) and evaporated to give a colorless solid. 57 g &gt; The product in 50 ml is purified by flash chromatography, pre-absorbed from ethyl acetate in the form of a pale yellow solid (MgSO4) (S, 5, h, CH 2, CO 2 +, OCH 3), 5.4 (ArCH 3), 7.8 (d , 8.8 Hz, 2H, ArH) (t, J = 7.8 Hz, 1H, ArH), 7.4 (d, J = 7 Hz, ArH); (1), (3) and (4) and (4) and (3) are &gt; (m, 3 H, ArH), 7.7-7.82 (<1 H, ArH), 8320 (d, J = 8.4 Hz, 1H). (M) +, 142, 121 [alpha] / ArH) on silica Merck-O €? with petroleum ether-acrylate: title compound G. NMR (CDCl3): Î': 1.01 (s, 1H); in dichloromethane, 1% of κ-3) to give

, Ν ο Η. 5-C4- (2-Cyclopentyloxyphenyl) benzoyl benzene: acetic acid. To a solution of the ester (6 g, 12.6 mmol) from Step 6 in dry tetrahydrofuran (66 ml) was added IN-LiOH (37 ml, 37 mmol) and the mixture was stirred under nitrogen at room temperature for 2 = 5 hours (TLC, toluene-MeOH 95% = tetrahydrofuran is

evaporated ε the residue is diluted with water, acidified (to pH = 5) with 10% acetic acid and extracted with ethyl acetate <3x). The extracts are washed with brine, dried (Na2 SO4), and dried. . evaporated to dryness. The crude product (4.94 g, pale yellow solid) is recrystallized from ethyl acetate to provide 3.65 g (75%) of the pure title compound (white solid, mp 146 DEG-147 DEG (S, 2H, CH = Cl), 5.48 (s, 2H, J =

ArCH, -; O) T · • * (d, 2H, J 8.8 Hz, 3 ArH), 3.41 (m, 1H, ArH), 3.38 (m, 2B, ArH) (D, J = 8 Hz, 1H, ArH); (M, 2H, ArH), 8.3 (d, 8.5 Hz, 1H, ArH), 12.39 (1H, C H H) = E 1 M (h -1, m / z): 39 / (p =

Treat for C-Si = -H =, -, ΝΟ

H, Al. 1 H-NMR (DMSO-d 6):? N

Calculated

Found: C, 53.22; H, 4.76; N, 3.39. 142

A = Methyl ester of acetic acid from benzene. π or C4- (2-naphthalen-1-ylmethoxy)

A mixture of phenol (4.5 g, 3.7 mmole) of Example 3F5 of K 2 CO 3, dried (MgSO 4, 48 g, 3.7 mmols), 18-propan-6 (Θ, Θ 98 g, 6 , 37 mmoles) and acetonitrile (ml)) is stirred under nitrogen for 15 minutes. 2-Bromamethylnaphthalene (496 g, 4.07 mmols) is added and the mixture is placed in a heated oil bath to 1% ethyl acetate in the presence of ethyl acetate. A compound of the formula: wherein: : m.p. wv; However, the residue is dried over anhydrous sodium sulfate and extracted with ethyl acetate (3x), evaporated with 1N NaOH and brine, dried (MgSO4) and evaporated to dryness The crude product (1.49 g, waxy solid) is used as such in the oven.

The title compound was prepared as a white solid (MgSO4), filtered and concentrated to give the title compound as a white solid (MgSO4). ArH), 6.63-7.68 (2H, ArH), 2.82 (m, 6H, ArH 5 MS <ffl / z), 41fi (M) ip.e. t '. 3-14- (2-naphth-1-yl-methoxy) benzoyl] benzene acetic acid

A solution of the (Î ±, Î ±, β, β, Î ± -molesoles) ester of Step A is treated dropwise with 1 N LiOH and the mixture is stirred overnight

in water is acidified in cold with acetic acid (to pH 35) and extracted with ethyl acetate (3x5). The extracts are dried (Na2 SO4) and evaporated to dryness. The residue (1.24 g, quantitative yield ) is recrystallized by dissolving in a reiatively large amount of ethylene-dichloromethane-5% acetate and then by concentration to one-half volume. The precipitate is collected and dried at 45 ° C in vacuo. (S, 2H, CH3), 3.55 (s, 2H, CH3), 3.53 (s, 3H) 3 (3H, ArH), 3.73 (3H, s), 3.95 (3H, ArH), 3.70 (2H, S 5 1 H, ArH) 5 12 3 47 (br s, 1H, C H 5 H 5 .delta .: (+ FAB) m / z).

Pars analysis --2 2 * 3 4

Calculated f * ~ 7 r * **? (I.e. 5 ' Found: 70.4%. 5.4%. T | I read "I

J

J

quinolinylmethoxy " 2-propanoic acid To a solution of KCH (o g) in water <35 ml) was added 3-chloro-4- (27.2 g, Φ, 2 mole), benzaldehyde (21.2 g, 0.90 mmol) (7 ml) was added. The mixture was refluxed for 4 hours. (200 ml) is added to the residue and the solution is distilled off under reduced pressure (to remove the unreacted remapping benzaldehyde). The process is repeated twice and the solvent is evaporated to dryness. the residual water is azeotroped with ethanol, the crude product (56.3 g, brown semisolid 3a) is purified by flash chromatography (on silica Merck-60, pre-absorbed in dichloromethane-ethyl acetate and eluted with hexane-ethyl acetate 8: 2) to give a clear pale yellow solid (50.5 g, 41.5%), mp 99-61 ° C.

(S, 3H, OCH3), 4.62 (broad s, 1H, OH), 5.88 (s, 1H); δ, 8.25 (d, zH, J = 8.94 Hz, ArH), 7.22 &quot; -7.38 (1H, 5H, ArH), 7.91 (d, 2H, 3hs, 94 Hz, ArH).

. (M + H) +, 243 (M + H) +, 225, 197, 137 (M-PhCOr), 4-methoxybenzoyl benzofuranate for 7 hours- SOb

H-

solution is poured into € &gt; The combined extracts are washed with ether and then cold acidified with HCl The liberated oil is extracted with ethyl acetate to give the title compound as a white solid. 1H NMR (DMSO-d6):? The extracts are washed with water and dried (MgSOâ, ") Removal of the solvent yields a yellow solid &lt; 2, 89 g, 73.8%), mp 104 DEG-104 DEG C. This is used in the next step without further purification. â € ƒâ € ƒâ € ƒNMR Î'CDClâ,ƒ, Î'HMMS δ 2.72-2.82 (mm, 4H, CHâ,ƒCHâ,,CHâ,,C), 3.82â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ3 H, 86 <d. 2H, J 9.1 Hz, ArH), 7.34-7.46 (m, 514, ArH), 7.92 (d, 2H, 9.1 Hz,

ArH). MS (EI, m / z): 342 (M + +, 135%).

A mixture of the crude 4-methoxybenzoin hemi-succinate (2.8 g, Î', 6 mmol) from Step B, urea (8.7 g, 3.146 mole) and acetic acid (6.73 mL) is heated to reflux under nitrogen for 5.5 hours. The mixture is cooled and poured into ice-water. The liberated oil is extracted with ethyl acetate (3x). The extracts are washed with water until neutral and then extracted with saturated sodium carbonate. The combined aqueous extracts are carefully acidified to cold with concentrated HCl and extracted with ethyl acetate. The organic extract is dried (MgSOâ, ") and evaporated to dryness to provide a waxy yellow oil (19.6 g â † 'A purification of the residue by flash chromatography (on silica Merck-6, dichloromethane-ethyl acetate-acetonitrile S2 &gt; yields a pale yellow solid &lt; 14.3 g, 72.7%), mp 100-108 ° C. NMR (CDCl 3, δ 4 MHz, s), 2.96 (t, 2H, CH 2 C), 3.20 (t, 2H, CH 2 O),

(C 6 H 12 ClN 2 O 2) Ar 1) Ar 1) MS (EI * m / z): To a sol. Step C, in acid the mixture is heated to 700-6 ° C. (m, 3H, ArH), ArH). (5,6-methoxyethoxy) -5-naphthyl-2-oxazole (5.6 g., ethyl acetate, 55 ml) is added g * W 8

The solution is ethyl acetate and the solution is ethyl acetate. The product is dried (MgSO)) and dried (MgSO)). The organic extracts were dried over sodium sulfate and evaporated to dryness. After cooling, ethyl acetate (3 x) = 0, extractive brown, 5.25 g, 99%) was used in the next step without further purification. flash chromatography of a small sample for analytical characterization (on silica Merck-60, eluent, dichloroethane-methanol 98: 2 and 9555),

NMR (DMSO d 6). 4-MHz): δ 2.75 (t, 2H, J = 7.14 Hz, CH2 Cl2), 3.20 (m, 2H), 6/7 (d, 2H), 8.1 and there

Hz '· x. 5 έη, .J /

Hz, ArH), 7.35 (d, 2H, J 8.55 Hz, ArH), νmax, 3H, J = 7.2 Hz, ArH), 7.5 (d, 2H, J = 7 Hz ArH), 9.94 (s, 1m, exchangeable 1). MS (EI, m / z): 334 (M-COOH), 12.2 (s, 1H). E. Propionic acid metal ester of 5-phenyl-4- (4- dihydroxyphenyl) -2-oxazole

A solution of the crude acid (5 g, 16.18 mmol) from Step B in methanol (40 ml) contained a small amount of p-toluenesulfonic acid. refluxed

They last for a while. The reaction mixture was stirred at &amp; &lt; / RTI &gt; for 1 hour. The compounds of general formula (I) are prepared by reacting a compound of the formula (II): ## STR1 ## in which R @ 3 is hydrogen, "O" H pr. j. .. &quot; The extracts are washed, yielding a thick oil, flash chromatography on tetramerethane, eluted with a dichloromethane-ethyl acetate gradient from 9: 1 to 75: 25) to afford a solid white &lt; 3.56 (q68%)), m.p. ? t. . ({2H-Î'-7.4 Hz, CHâ,,C), 3.2â € ², Jâ € ²-Hâ,,Nâ,,Hâ,,Oâ,,CHâ,, - CHCOâ,ƒ, 3,1 / (D, 2H, J 8.59 Hz, ArH 2, 7526-7, H 2 O, ArH), 7.54 (d, 2H, J = 8 Hz, ArH). 1 H-NMR (CDCl 3, δ 6 MHz): δ (CDCl 3, δ 6Hz): δH (EI, m / z): 323 (M + +, Î "5, 77 (p" e = V ρ

(1-methoxy) phenyl] -2-oxazole

A mixture of the ester &lt; 2.46 g, 75.1 mmol) of Step Er, K2 CO. (18 ml), 18-crown-6 (223 g), and acetonitrile (33 ml) is stirred at room temperature under nitrogen for 15 minutes. The 2-chloromethylquinoline (free base, freshly prepared from the hydrochloride salt, 1.35 g, 7.6 mmol) is added and the mixture is placed in an oil bath heated to 65 ° C for 16 hours (NBs after 6 hours an excess of chloromethylquinoline, 18-corona-6 and K_CO-) is added. The solvent is removed and the residue is partitioned between

1 H-NMR (CDCl 3): δ 2.29 (t, 2H, J = 7.2 Hz) (S, 2H, ArCH3), 7.62 (d, 2: Hz, ArH), 7.10 (s, 2H, ArCH3), 7.62 (s, 7.36 (m, b s, 4H), 54-84 (m, ca, 6H, ArH), 83.dbd.HCl, between ethyl acetate and ethyl acetate extracts (MgSOâ, ") 4â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ0 evaporated to give a solid, (on silica Merck-66, eluents toluene and then toluene-methanol 97.5-2.5) to give the title compound (3.5 g, quaternized yield: 5.11 g (D, 1H, J = 8.3 Hz, ArH), 1.89 (t, 1H, J = 0.5 Hz, ArH) · N)), 465 (M + i, H H) -χ.

X θ = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = ) of Step F in dry tetrahydrofuran (37 ml) is treated dropwise under nitrogen with 1N-LiOH <21.98 ml, 3 equiv.) and is stirred at r.t. at room temperature for 3 hours &lt; CCl &gt;, 1 of the standard aqueous sodium hydroxide solution or toluene-methanol 95%). The solvent is evaporated. the residue is dissolved in 2 N NaOH and quenched with 10% acetic acid (to pH 7.4). The extracts were washed with water and dried (Na2 SO4) s are washed with ether, dried (MgSOâ, ") and evaporated to yield a pale yellow solid &lt; 3.81 g, quantitative yield) of the crude product is recrystallised from ethyl ester ont. endo a sufficient amount of the desired compound. The solution is evaporated to a clear solution to produce a first solution of a compound of formula (I). 76-94 ° C). A second crop is obtained by concentrating the mother liquors <327 g dec. 172-193 ° C) The combined yield is 85.8% â € ƒâ € ƒâ € ƒR (KBr, cm-1): 1.26 (br. 2.76 <t, 2H, J / Hz, ch7c) / 't f. 3 (t, 2H, Î'-Hz, L-H.7.CL0), 5.38 (s, 2H) d, 2H, J 8.8 Hz, ArH2), 7: 7, p H3, 7H, Ar H)? / a • V! (4H, ArH), 7.9 (1H, 7 (d, 1H, 8.5 Hz H ArH) -¾ · η · η q / q / C5 < t, 1H, ArH), and δ, 7.9 Hz (t-1, ArH), 8.4 (1H, t, 1H, J 8.5 Hz); : ee or C.C, (R / Z) S 451 CM -i-H) +, 310 C ηΒρ_) 3

EXAMPLE 6

4- [4- [2- (2-naphthalenyl) phenyl] -5-phenyl-oxazole A, 4-C4-C2-naphthalenyl, isothiocyanate 11.1 (1H, s), 7.6 (1H, s) A compound of the formula: Λ L · Ό r. The title compound was prepared from the title compound as a white solid, mp 218-228øC. 1 H NMR (CDCl 3):? (18 ml) is stirred 2-bromomethyl-2-bromo-3-methyl-2-oxo-3- -! The mixture is placed in a U. S. at 8 to 9 hours C CCF at 0 ° C. (3H, O) -O-methyl-9-oxo-1-isopropyl-2-oxoethyl] -amide; 2, 17 g, 15: 5: 5: 5: 1: 1: 1:

Hisianoj. (a clear solution is obtained) by concentrating the same to a small volume and cooling in a bath of which the white solid is collected and dried overnight in vacuo. 134-135 ° C. IR (KBr-r, cm-1 &gt; 1740 (C0) â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒMRM (CDCl 3, Î'7.5 Hz, (s, 2H, ArCH2 O, NH2), 3.80 (s, 2H,

ArH) Î »1, λ ΗΓΗ> . (4Î ±, 5β,

V

A solution of the (3S, 3S, 3S) -dimethylsilyloxyphenylsulfonyl chloride (18 ml) (9.6 ml) is stirred under nitrogen for 1 h. The reaction mixture is evaporated and the residue is dissolved in water and dried under reduced pressure to give the title compound as a white solid. The mixture is extracted with ethyl acetate, the extracts are dried (MgSO4) and evaporated to give the crude product (1.39 g, mp 145 DEG-145 DEG C.). The product is dissolved in ethyl acetate (containing sufficient dichloromethane to give a clear solution), which is concentrated to one-half volume and precipitated for purification. The white solid melts at 151 DEG-152 DEG C. (decomp.) IR (KBr) cm-1: 172 ° (c) NMR (DMSO-d6, 4.0H) (S, 2H, ArCH2 -O2); 7.10 (d H z × ArH), 7534-7.6Â ° C (decomp.), 10H, (H-H). j. &quot; "'Ρ. (h). v f

EH (EI ,, m / z &gt; s 450 (M t H η 1)

bXEMPLQ

4-E (1-methyl-1 H -benzimidazol-1-yl) methoxy] phenyl] -β-anil-2-oxazole, propanoic Acid 4- 1-phenyl-2-oxazole, 5 g, 1555 mmol) of Example 13, 1.55 mmole) of 13-chloro-3-chloro-benzimidazoles: (Îμ, 155 mmol) and acetonitrile (6 ml) at 0 ° C. V 4 under nitrogen. ambient temperature for 15 minutes. Add 2-chloro-1-methyl-benzoimidazole (0.07 g, 1.7 mmol) and the mixture is stirred in an oil bath at -20 ° C. For 4 hours CCCF3, dichloromethane-ethyl acetate 9 sec. visualization of XOCJo /. In this example, a 2-methyl ester of 1-methyl-1-methylbenzimidazale is added and the 18-crown is kept for two hours. The reaction mixture was stirred at room temperature for 10 hours at room temperature and evaporated to 0 ° C. The residue is dissolved in water and evaporated with ethyl acetate. The plates are washed, dried (MgSOâ, ") and dried (MgSOâ,"). dryness The residue (1 Ã- 4 g) is purified by a small amount of methanol, eluted with dichloromethane-ethyl acetate (3.3) to give (7-chloroethyl) amide, mp = 142-144 ° C (dec.), NMR (CDCl3): δ 2.87 (m, 2H, d 7.1 Hz, OCH3), 3.79 (t.

2H); 3H), 3.90 (s, 3H, NCH3), 5.41 (s, 3H), 3.35 (s, 3H, NCH3) ArCH.-Ju 5 7507 δ, 2H. d 8 3 S H z 3 ArH). (M / H, ArH), 7 ur 25 (m / H, ArH) (1 H-3 H, ArH), 3.71 (d, 1H

ArH)

The title compound was prepared from Step A5 in 1N-LiOH (Et2O4) and each portion was heated under reflux for 2 hours. and dried in vacuo.

A solution of the ester &lt; 1 g, tetrahydrofuran (13 ml) containing 1 N-nitrogen at room temperature, tetrahydrofuran (9 ml) The solvent is evaporated, water is added and the pH is adjusted to pH 3.0 with water. .1. The clear yellow oil is collected, washed and evaporated. This is redissolved in hot ethyl acetate (contain a sufficient quantity of methanol to provide a clear solution), is concentrated to a smaller volume and collected in a boiler. The crystals are collected and dried C0.642 q, 6.6 L · '· * / m.p. 222-224Â ° C

NMR (DMSO-d6):? 76 < i.e. = 2H "J / Hz? CH3), 3.33 (13H, J7Hz, CH2 COO), 3.86 (s, 3H, NCH3), 5.43 (s3 2H5 ArCH3), 7.14-7.28 (m, 66 (Î ±, 13H, ArH) = MS (Cl

An is. 1 i know r a. s 454 (Μ + H) +, 147 (p, s «> Χ77Η7ΤΝ ^ 0δ

Calculated Γ / EXAMPLE 3 The title compound was prepared according to the procedure described in Example 1. The title compound was prepared according to the procedure of Example 1,

The compounds 5- and 12-hydroxyheicosateiraenoic acid (5-HETE and 12-HETE) and LTB_ are the initial products of the oxidation of β. which has been shown to mediate the varied aspects of inflammatory and allergic reactions. This is especially true with respect to Î ±, β-diHETE, which is also referred to as LiB &amp; 1 See Forri-Hitchinson, J. Rav. Soc., Med. Med. 74, S31 (M +) 1 =

Compounds which inhibit the release mediated by PLA2 of arachidonic acid prevent them by " the oxidation of the arachidonic acid in the various Jeucotriene products via the lipoxygenase cascade. Thus, the specificity of the action of the PLA inhibitors can be determined by the activity of the test compounds in this assay, which determines the ability of the compounds to inhibit the synthesis of the LTB produced by the polymorphic leukocytes (NPM) produced by rat glycogen in the presence of exogenous substrate.

This assay is carried out in the following ways: white blood cells (3.50-20 g gt; i 6% CΘΘSi 1¹ i. The rats are sacrificed by asphyxiation by means of asphyxiation. The cells are harvested by the pod using saline. NaCl (9%). The exudate is centrifuged at 400Â ° C for 1 & , OS at 0 ° C is discarded and the pellet is resuspended to a concentration of 2.0%. 1 ml of aliquots of the cells were added to the cells and the cells were incubated with 1 ml of aliquots of the cells. c u. 1 μl of 30 μl, and those are incubated at 37 ° C for 1 minute. A231S7 (1 μg) is then added to the analyte. ) And the samples are incubated for a further 10 minutes. The reaction is terminated by centrifugation and pelletisation of the cells. The supernatants are then analyzed by HPLC analysis on a 15 cm κ 4 column, is = mm of supelcosyl LC (3H), using a two solvent system at a flow rate of 1.4 ml total flow, in the manner that follows

Solvent The solvents are gradient 70s30 of 17.4 mH of HTPQd CH3 CN (the system is equilibrated with CH3 CN with solvent A) as a percentage Percent A B 0 100.0 15.0 100 0 20 5 65 35 40.0 65 35 42? 0 10 90 50.0 10 90 50.1 100 0 fts variations of solvent percentages are carried out linearly.

Injections 14μμl of each supernatant are injected directly onto the column and the metabolites of the arachidonic acid are monitored by means of a monitor using an on-line radioactivity detector (Ramona, IM / US, F-air-fieldj Nu) »

Padres 4 to 10-25 x 10⠻¹ dpm of the eicosanoids of interest, Fig. V, s-Va * · 'in 9β μΙ of a cocktail &quot; of EtOH. in a cg - chromatogram i xa. with PniM medium stimulated 1-succinic Aβ HCl CLTB) exposed to the medicament is compared to that found in a stimulated cell medium and does not result in the same percentages of any inhibitor inhibition ,. The results are expressed as a percentage of inhaled dose of a given compound or as a

The compounds of formula (I)

.and value C 5fc '

The test compounds of the present invention provided the following results in this assay

J yUm> HO ι

the irony

Exemino compound Compound 5N? a. 1 ΙΘ ΙΘ ΙΘ ΙΘ ΙΘ ΙΘ ΙΘ Φ Φ Φ Φ Φ Φ Φ Φ A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A (a Θ55μΜ) DH 94 <a ΙΘμπ) £. A negative value means a potentiation of the cyclooxygenase (PGE- synthesis) ", and a negative value means a potentiation of the cyclooxygenase (PGE-) synthesis.

EXAMPLE 9 The process of Example 5 In the case of the inhibition of the synthesis of the POE 2 product of the arachidonic acid cyclooxygenase κ κ κ κ ci ci ci ci ci ci ro ro ro ro ro ro ro ro ro ro ro ro ro ro by the compounds of the present invention

In this essay? The method of claim 1, further comprising the steps of: the cytokinease activity, the samples are co-chromato- authentic reference Ε qu ~ ~ ~ ~ »» »» »» »» »» »» »» »» »» »» »» »»

The results are calculated in the same manner as in Example 8 and follow the following: ο ς ι

? The compound of the present invention comprises a compound of the formula: ## STR1 ## wherein the compound of formula (I) ! 5 bpM &gt; -22Â ° C to Î'35Âμ) 7; 8 Ca θθΗΗ) -8 * í í â â â 5ΜΜ 4 4 4 4 4 4 Λ 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 -19iAa 1ΘμΜ &gt; -12 * (a θ "5μΜ> A -795 (a. ΙθμΜ) -29 * Ca θ, δμΜ) 7 -268 * &lt; a 10μΜ &gt; negative air means a potency of cyclohexane of P6E ") =

The compounds of the present invention are cyphil- in accordance with an Assay A. of the isolated phospholipid in vitro to determine the ability of the compounds to inhibit the binding of arachidonic acid to an arachidonic acid synthesis by the action of the enzyme of phospholipids from human and human sources'

This test is carried out in the following way, of polypropyls of .5 ml, the following substances are added

Agent

Volume, ul. r-nen

Jsâ 25 1

Substrate γ-βA (β1) CaCl2 (1M) Tris-HC1 (0.5M) pH735 (a) Water Measure to 100% PLA 5 nmoles PL 5 γγιγΙ 100 mM 50 πχΜ Volume which produced 12 &quot; of hydrolysis in 1 ° rain, preheating the reaction / curing environment for -50 minutes at: itss the addition of the substrate. by the addition of 2 ml of deionized water and 1 ml of 2 ml of lower Hâ,,Oâ,,), to which is designated as E. coli (contam. A total of 5 μm of the substrate was prepared (containing 1000 moles of phosphoric acid CaClâ,,) in vacuo. Stock, required for the activity of the enzyme

Z-? ffi - toe i

The pH was adjusted to pH 5 (optimum for the enzyme). 1 Deionized and distilled water. a dilution of ls2 with dimethyl sulfoxide, a test tube of 1 μM, was prepared using two human PLA enzymes. (a) Semi-purified human platelet acid test (1): Remove the (in 1% ml of sodium acetate buffer precipitated protein pH by centrifugation B. for 2 minutes. b) purified human synovial fluid.

Incubate the 1 &amp; ml of the reaction mixture for 1 minute at 37øC in a shaking water bath. The reaction is quenched with the addition of 2 ml of tetrahydrofuran, followed by vortexing. ug / ml-Analytichm International) was treated with 0.5 ml of tetrahydrofuran followed by 5 ml of tetrahydrofuran / water <2 ml / 1 ml, v / v> The sample is introduced into the columns and is slowly extracted therefrom. The hydrolyzed arachidonic acid retained in the columns is eluted therefrom with 1 ml of tetrahydrofuran / glacial acetic acid (2%). Arachidonic acid is transferred to scintillation vials and is quantified by β-count analysis. A sample of &quot; total counts &quot; by addition with a pipette

A solution of 1 ml of aquasol is added (cocktail of all samples, Calculations

(Sample) total counts dpm [3H] Ar dpm (non-specific hydrolysis and dh tagsn s) The pharmacokinetics of the medicinal products are given in the following table.

Metí icamento Piateiete Humana r L Ado Tm S i η o v. i a 1 man

B.C. Air Acid Monoalcium

invent

When will you rehearse in this essay? the following results;

uubimu ι i i

Compound of the above-mentioned human synovial membrane, the negative values of 15.1 m HSF potentiation of the HSF EXAMPLE 11 isomer. and / or in the assay in the same manner as in the prior art. C Si-C Si alkyl or C Si-C Si alkyl; at

Compounds of the living part of the murine simian are called murine.

This assay is carried out as follows: Rates of 8-week old rats are placed in groups of six. Animals are injected with rats and are administered to twenty-five mice asymmetry per 1-μm % in saline at 59.degree. C., free of pyroxene, or saline (non-stimulated control). Compounds were administered orally 1 hour prior to injection. injection with simvastatin, the inhalation medium is injected with GO2, and the peritoneal cavity is washed with 2 ml of a Hanks Balanced Salt Solution (HBSS) without CaCl2, MgSO4, 7H2 O s, MgCl2, The peritoneal lavage fluid from each rat is withdrawn by means of a syringe and placed in 5 ml plastic test tubes which are then placed in the same way as the specimen. The preparation of the samples by ELISA evaluation is as follows: The samples are centrifuged for 15 minutes and 1 ml of the supernatant is added to 2 ml of ice-cold methanol and the mixture is maintained at &lt; tb &gt; for overnight to pre-exert the protein. The samples are then centrifuged at 80� for 15 minutes and then followed by a drying procedure in a concentrator The samples are reconstituted with 1 ml of an ice-cold ELISA buffer and stored at -70 ° C until assayed. with respect to the eicosanoids (TCFα and ε-keto-FBFα, ..) is carried out according to conventional ELISA procedures

• X ν 's; S fsO. Test tubes orally are suspended Tween

CDiiipost: to test intraperitoneally are

the salt is suspended in methylene chloride at ΘH5% at 0 ° C. .......................... (a &lt; 0 5 05) MSs are expressed as a vs ¾;;;;;;;;;;;;;;;;;;;;;;;;;;;;;. . . 4 '). H eading V a tio ns of Control

In this test, the activity of the standard medicaments is as follows:

The compounds of the present invention may be prepared by the use of a compound of the formula: ## STR1 ## wherein R 1, R 2, R 3 and R 4 are independently selected from the group consisting of: Feri i dona 24 5 Θ < 30 5 Θ X n d inne t ina Not active 0? 126 Ibuprofen Unused 7 5 0

When tested in one of the compounds of the present invention and the anti-inflammatory compound, the following results were obtained: &gt;

IV Compound of Dose% of Inhibition Exemple N3 = fnq / k q LTC-? 'cc' * F * 0r * Zr Ό 10 * intraperitoneally, negative values indicate potentiation.

The results show that the compounds of the present invention exert a potent inhibitory effect on the lipoxyglycosis pathway, but not on the cyclooxygenase pathway.

Claims (2)

A compound of the formula: ## STR2 ## wherein A is as defined in formula (I). and the phenoxyphenyl group or a group of the formula R 2 R 1 In which R'-X is -N- or -C • γ · γ R ° R ''! R4 is hydrogen, C1-4 alkyl, C1-4 alkoxy, -M-S- or -u- R &quot; is hydrogen? lower alkyl or phenylop is hydrogen or lower alkyl or together form a benzene ring R 2 is hydrogen, -CH2-CH3 wherein: is independently lower alkyl, lower alkyl; R ° is halo or nitro; R è t! p I F) Or -COHCOOR 's is lower alkyl; iTi &amp; % 5 a) the etherification of a compound of the formula HO-CHCOOR5 H0- CH (CH 2) m COOR 5 R 4 -4 A in K 1 and R 2 are as defined above. an ! The compound of formula I wherein R1 and R2 are as defined above and X is a leaving group. ve1? and, if necessary, the hydrolysis of the product. in order to obtain a product in which R "is hydrogen or lower alkyl ρ or b) the hydrolysis of a compound of formula III which, to provide a compound wherein pharmacologically acceptable ρ wherein H and s isomorph is hydrogen or the same or one of which is c) protected with a compound of formula I; II, III or IV in a pharmaceutically acceptable salt. The process according to claim 1, which comprises the preparation of 1-C2-nitro-4 '- <2-quinolinylmethoxy) -1H-4-imidazolone. according to claim 1 characterized in that 2-fluoro-4 '- (2-quinolinylmethyl) -1,1'-biphenyl-4-acetic acid is prepared. A process according to claim 1, characterized in that the compound of the formula (I) is prepared as described above. irfu.tr.1 UJL.UU? (2-naphthalenylmethylamino) benzoylbenzoic acid, the title compound was prepared as described above. characterized in that the 5-phenyl-4-C4-C2-quinolinylmethoxy) phenyl] -2-D-azabicyclo [2.2.0] heptanecarboxylic acid, The title compound is prepared by preparing the propanoic acid of 4-L-4 ', 4-naphthoic acid. 5-phenyl-2-oxazole = 'V' · 1 ν · θ · ··························································································· 4-carboxylic acid propanoic acid methyl ester was prepared in the same manner as in Example 1, but the title compound was prepared as a white powder. The title compound was prepared in accordance with the procedure described in Example 1, with the title compound as a white solid. The title compound was prepared according to the procedure described in Example 1, with the title compound as a white solid. RUA VICTOR CORDON, 10-A 3 * 1200 LISBOA