PT95692A - PROCESS FOR THE PREPARATION OF INDOLE-, INDENO-, PYRANOINDOLE- AND TETRA-HYDROCARBAZOLE-ALCANOIC ACID DERIVATIVES, OR WHICH ARE USEFUL AS PLA2 INHIBITORS AND LIPOXIGENASE - Google Patents

Description

ί

'i 1 ϊ Ο present invents refers to β. new substituted alkanoic acid derivatives of indene-, indols-, pyranoindols- tetrahydracarbazole, which have inhibitory activity of the powder; phospholipase A inhibitor and leukotriene antagonist and are useful as anti-inflammatory, anti-allergic and cytoprotective agents. It is now generally accepted that arachidonic acid (AA) is metabolized in mammals by two routes The metabolism of arachidonic acid by cyclooxygenase enzymes results in the production of thromboxanes and thromboxanes. The physiological activity of prostaglandins has been widely elucidated in recent years. It is now known that prostaglandins originate from the endoperoxides PGE 2, and PBH 3 through of the cydoDoxygenase by the route of arachidonic acid metabolism. These endoperoxides are also precursors of the thromboxanes (Tx) A "and B.t = 0 TxA0 is a vasa constrictor which stimulates the aggregation of the platelets. vasoconstricting and aggregation properties of the platelets of thrombosanes are compensated for by another product, produced from the endoperó the prostaglandin < PGI.J, which is a vasodilator with platelet aggregation inhibitory activity. If the prostaglandin synthesis is weakened and / or platelet activation is implemented, thrombosis is prevented. vasoconstriction are favored. The role of prostanoids in haemostasis and thrombosis is analyzed by R. Brygleirtskx, CRC Crit. Rev. Biochem., 7, 291 (1983) and JB, Smith, Am. 743 (1998). The metabolites of cyclodexycinase are known to participate directly in the inflammatory reaction [see Higgs et al., Annals of Clinical Investigation, 16, 287-299 (1984)]. This is due to its vaso- depressants, ie, participation in pain and fever, increase in vascular permeability through the peptide mediator and edema formation properties. Finally, various aspects of mediated immunity-by cells are influenced by the products of the cytokine. pathway of AA metabolism involves the enzymes of 1-lipoxygenase and results in the production of a series of ductant products called leukotrienes. These latter are designated by the LT nomenclature system and the most significant products of the metabolic pathway of lipo-Migenase are madro-trienes s The slow-reacting substance of the anaphylaxis (SRB-A) was shown to consist of a mixture of leukotrienes, 1 1ΤΛΛ and LTD. in the form of main products, comprising several amounts of other leukotriene metabolites < see Bach et al., J. Immunol., 515. Ibid. Res. "Cammun.c5 935 1121-1126 < 1980) 3. The importance of these leukotrienes is that many evidence has accumulated which show that leukotrienes participate in inflammatory reactions, exhibit chemotactic activity, stimulate lysosomal release and act as important factors in the immediate hypersensitive reaction. LTC3 and LTD4 have been shown to be bronchoconstrictors of human bronchi Cver Dahlen et al. Nature, 288, 484-486 (1980) and Piper * Int. Appl. Immunol., 76, suppl. (1985) 3, which stimulate the release of mucus from the airways in vitro. Amador et al., Am., Rev. Resp. Dis ". 12, 449 (1982), are potent vasodilators in the skin Ever Bisgaard et al. Prostamines. 25. 79? < 1982) 3 and produce a marked and rapid response ECsmp et al., Br. Pharmacol., 80, 497 (1983). Non-peptidic leukotriene and LTB4γ is a potent chemotactic factor for the leukocytes Ever A. W. Ford-Hutchinsort, 3. Roy, Soc., Et al., 74, 831-833 (1981), which stimulates cellular accumulation and affects vascular smooth muscle Cver Bray, Br "Sied = Bu. 11 c. 39249 (1983). The action of leukotrienes as mediators of infiltration and hypersensitivity is discussed in detail in Bailey and Casey,

An π · - · Reports Hsd, Chenj, 87 (1986) = The phospholipase <PL.ft._J is the critical rate-limiting enzyme in the arachidonic acid cascade CAA), since it is responsible for the hydrolysis of AA esterified from the C2 position of the membrane phospholipids. This reaction produces two products (1) without the AA which is available for subsequent metabolism by means of the cyclooxygenase or 1apos; enzymes and (2) the lysophospholipide, The production of the platelet-activating factor CFAP) is initiated when al-quaternary amphibanyl-β-alkoxyphosphatidylcholine is activated by PLA1 and FAP is pro-inflammatory Cver Wedmore et al., Br. J. Pharmacol. (1981). In this regard, it is noted that anion-inflammatory steroids are believed to inhibit eicosanoid synthesis by inducing the synthesis of a PLA-inhibitory protein, termed macro-curtin or lipomodulin Flores et al., Naturs, London, 278, 45, (1979) and Hirata et al. ? Proc. Natl. Acad. Sci. "77, 2533 (1980) 3 =

Since it is the initial step that leads to the subsequent conversion of AA to various sanoanoids via cyclooxygenase and lipoicrisase, the release of PLA-mediated AA from membrane phospholipids is a critical factor in the treatment of the various physiological manifestations that occur. based on the activity of the eicosanoids and / or PAF. Thus, although PLA has been shown to be necessary for the aggregation of platelets EPickett et al., Biochem.-1, 4, 5, ) 3, for the contraction of cardiac systomies (Ge e ler et al =? Pharm. Res. Commun., 9, 117 (1977). 3, well for the synthesis of. prostaglandin IVogt, AdvPrgstaq 1, Thromb = Res., 3.89 (1978) 3 = the inhibition of FIA-, is indicated in the therapeutic treatment of physiological diseases either induced by 1-AP or mediated by a cyclooxygenase- enase and / or lipoxygenase. it is evident that the cyclooxygenase pathway products play important roles in the pathogenesis of gastric mucosal damage caused by extracellular agents (gastric and intestinal contents, microorganisms, etc.) or intracellular ischemia, etc.), as well as cytoprotec-çSq against these damages. On the one hand, prostaglandins exert a cytoprotective effect on the gastric mucosa Cver Rofoert, Bastraenteroloqv, 77, 761-767 (1979) 3 and this action of prostaglandins, especially the E series, is considered important for the treatment of gastro-intestinal ulceration Cver Isselbacher, Sruqs, 33, (suppl.), 38-46 &lt; 1987). On the other hand, live skins have shown that the gastric mucosa tissue of rats pretreated with ethanol is capable of producing LTC3 and that this production of LTC3 is quantitatively related to the severity of the damage caused by Cver ethanol Lange et al., Naunnon-SchmiedeberqLs. ftrch. Pharmacol, Suppl., 33, (1985). It has also been shown that CTL can induce vasoconstriction in both the venous vessel and the submandibular vessel of the Cver Whittle rat, IUPHAR Ninth Int. Cong. of Pharm., 55Θ-2,

London, England (1984) 3. This is important since the gastric mucosal formation of an ethanol-induced lesion may be ratifying with, for example, the gastric blood flow asymmetry that contributes significantly to the development of necrotic haemorrhagic aspects of the injured tissue Cver Buth et al. al., Sastrosnteroloov "8", 1983, 49 (198493).

Furthermore, in an anesthetized cat, the exogenous LTD provoca causes both increased pepsin secretion and decreased transqastric potential CPendleton et al., Eur. J. Pharmacol., 125, 297-99 (1986). particularly important in relation to this subject is that the 5-1-lipoxygenase 8-t i-V and

and some leukotriene agonists protect the gastric mucosa against those induced by the oral or parenteral administration of most non-steroidal anti-inflammatory drugs, Evans Rainsford, Effects and Actions, 21, 316-319 (1987) 1. The activation factor of piai.elst.es (FAP) is also implicated as a mediator of gastrointestinal damage and it has recently been demonstrated that 5-1Ιράκigenase inhibitors inhibit FAP-induced gastric mucosal damage (Sastrosntgrolqqy, 96, A55, A434 , 1989). Thus, a significant amount of evidence demonstrates the involvement of lipoxinase products in the development of pathological features associated with gastric mucosal lesions, such as those induced by exposure to ethanol and induced by the administration of non-steroidal anti-inflammatory drugs. Thus, compounds which inhibit the biological effects of leukotrienes and FAP and / or control the biosynthesis of these substances, for example by inhibition of 5-Iipoxygenase, are considered important as cytoprotective agents.

In this way3 a. biological activity of leukotrienes and BRS, and lipoxygenase as an enzyme that leads to the metabolism of AA in leukotrienes, indicates that a rational approach to drug therapy to prevent, eliminate or ameliorate the symptoms of allergies, anaphylaxis, asthma and inflammation, and to cytoprotection; should not only focus on blocking the release of mediators of these diseases, but also antagonize their effects. Thus, compounds which inhibit the biological effects of leukotrienes &amp; of SRS and / or controlling the thiosynthesis of these substances, for example by inhibition of PLA-mediated release of arachidonic acid from membrane phospholipids or by inhibition of lipoxygenase, are considered important for the treatment of diseases such as Allergic bronchial asthma, allergic rhinitis, as well as other

of the I n ibem o ds. lipoxygenase.

He discovered what he determined to be | 2-O-benzoylbenzoene-5-carboxylate and 2-O-benzoic acid salt and antagonists for the preparation of the compounds of formula (I):

An anti-inflammatory, anti-allergic agent is provided by the invention to provide novel compounds with ores. wherein A is C1-6 alkyl, phenoxyphenyl phenol, or a group of the formula

RV ΧΎ or R2 'is the same as either -M- or --- 0 -K; · -' R ' In which R 1 is hydrogen, R 2 is hydrogen, R 2 is hydrogen or C 1 -C 4 alkyl; oromethyl? lower or lower alkyl, or R and F 'taken at. together form a bsRzene ring * c

(CH 2) n A R 9

I do not know

Du

N (OH) ~ N (UH) CR

MHCNHOH, -CNCOH). jMH and Π _ ψί

A compound according to claim 1 wherein R 1 and R 2 are as defined in claim 1 wherein R 1 is hydrogen or phenyl or phenyl Thu. 1 t.xο χπτsriorr. lower alkylsulfonyl; the proviso that when Ra &lt; i

The terms "alkyl" and "alkyl" and b = 0. The reaction mixture is cooled to -10 ° C. The term &quot; ha1 &quot; refers to fluorine, chlorine and bromine from a grouping of 5 to 5 carbon atoms. The previous definition opens to the next page. pyrrolyl, pyranyl, pyridyl, pyrazinyl, pi? ity? 5- or 6-membered heterocycles containing sulfur or monoglyceride heterocycles optionally substituted by lower alkyl or by phenyl. QKazoliIo? thiazolyl, imidazolidinyl, benzofuranyl. benzothienyl, benzothiazolyl, indolyl, benzoyl, benzoyl, benzoxazolyl, benzoxazolyl, benzoxazolyl, benzoxazolyl, benzoxazolyl, benzoxazolyl, benzoxazolyl, benzoxazolyl, Preferred are s-ac-quinolinyl, benzothiazolyl, benzimidazolyl and 2-phenylethyl compounds compounded by the invention to form pharmaceutically acceptable salts thereof.

1 · 5.'Τ'0ί! C -5-C -5-C -5-C -5-C -5-C -5-C -5-C -5-C -5-C -5- The compounds of formula (I) are prepared in the following manner:

sulfuric, sulfuric, phosphoric, nitric, maleic, fumaric, benzoic, ascorbic, succinic, succinic, methanesulfonic, acetic, propionic, tartaric, citric, lactic, malic, mandelic, cinnamic, palmitic, itaconic and benzenesulfonic acids. Compounds which are carboxylic acids are capable of forming alkali metal alkali or alkaline earth metal carhoxylates and phospho- logically acceptable alkali metal carbosylates derived from ammonia or a basic amine. Examples of the latter are, but are not limited to, cations such as ammonium, mono di- and trimethylammonium, mono-, di- and triethylammonium, mono-, di- and tripropylammonium and normal, ethyldimethylammonium, benzyldimethylammonium, cyclohexylammonium, benzylammonium, dibenzylammonium, piperidinium, morpholinium, pyrrolidinium, piperazinium, 4-ethylpiperidinium, 1-isopropylpyrrolidinium, 1,4-dimethylpiperazinium, 1-n-butylpiperidinium, 2-methylpiperidinium, 1-ethyl-2-methylpiperidinyl, mono-, di-triethanolammonium, diethanolammonium , n-butylmonoethanolammonium, trisChidroxy-nvetil> methylammonium, phenylmonoethanolammonium, etc.

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

For example, is reacted with propionic anhydride and is then subjected to reduction in ring closure to give the intermediate 6-methoxy-2-methyl-1-indanone

(C2 H5 CO) 20

sodium propionate CHO

Ho

Pd / C CH = C-COOH Hch 3

and the resulting hydroxynanthanone is composed of suitable haloalkyl-A, as defined above, in which A is as defined in claim 1, wherein R 1 and R 2 are as defined above.

the CHq

A (CH 2) n Q A (CH 2) nal K 2 CO 3/18 * -coroa-6 is the last intetermetrile, where π -1h is upstream. The title compound was obtained using sodium triethoxyphosphonoacetate and sodium chloride to give a median value which is sodium ethyl ester

p 1 X &quot; f ί C 3 Q 3. 3.30 η π χ f- ng 1 nilmethylsno introduced from usn aprupamsnta p ·

O

II

(C 2 H 50) 2 PCH 2 CO 2 C 2 H 5 / NaH-1 ......... 1 - toluene

s

Compounds in which the R3 group is lower alkylthiophanyl may be prepared by the use of an alkyl 5 &quot; lower thiobenzaldehyde. Compounds wherein K is a lower alkylsulfinylamino group may be prepared from the compounds containing lower alkyl thiophenyl by reaction with 3% in chloroform / acetic acid. Hi

30% H202 - --- Jp-

CHCl3 / CH3COOH sch3

sch3 i a

According to an alternative scheme, the thiokinucanone intermediate can be reacted with cyanoacetic acid to produce the corresponding hydroquinone-3-acetic acid. which is then esterified before being introduced into the R3 -methylene group * in order to facilitate purification of the desired intermediates. Since the introduction of the N-methyl group is accompanied by ester hydrolysis, the free intermediate acid is re-esterified to facilitate

ncch2cooh NH4OAc / HOAc

ch2cooh

-ch2cooch3 ch3

p-toluenesulfonyl-β

CH3OH

HO

1. NaOCH 3 / CH 3 OH CHO

Cl 2. p-toluenesulfonic acid

V * S

K2 CO3 / 18-crown-6 A (CH2) n

CH2COOCH3

ch2cooch3

Cl w ^ ..v 0

Compounds of the formula halo

may be prepared by reaction with a halo-independent-3-acetic acetic acid with a benzaldehyde-containing CH2Cl2 prepared from the corresponding individual components

0- (CH3) nA

In all of the reaction schemes mentioned above, the free acids of the final product may be esterified by conventional methods in the like manner, whereas the esters of the final product may be hydrolyzed by known procedures to obtain the corresponding free acids

Lys of the present invention of formula

in which X is -CH2- can be prepared by first reacting 4-methoxyphenylhydrazine with, for example, 2-carbomethoxy-2-alkylcyclobenanone, and then ring closure to give the title compound as a white solid. tetrahydro-methoxy-1H-carbazole acid

O

The latter intermediate is demethylated with hydrobromic acid to give the corresponding hydroxy compound which is then reacted with a suitable lower alkoxy-A compound by one of several routes. In one of these preparative steps two equivalents of the starting material , ACCH2, are reacted with a metal derivative of the hydrochloric acid-1-acetic acid to form an intermediate stereo ether which is hydrolyzed to yield desired end products. The metal derivative of hydrazicarbazole-1-acetic acid can be prepared by treating the acid with an alkali metal alkoxide such as sodium methoxide.

In the above sequence, A, n, m and ri 'are as defined above and hal is chloro, bromo or iodo.

According to an alternative sequence, it is possible to employ only one equivalent of the starting material A &lt; CB2 &gt; nhal with the metal derivative to directly obtain the Λ

.V of the desired end product? without having to go through the intermediate preparation ethyl ester *

Still according to another reaction sequence? the desired end products can be prepared by alkylating the alkyl esters of 1-hydroxycarbbasole-1-acetic acid

K2CO3 / Acetone &quot; A- (CH2) n hydrolysis

7? n ' ms H? k R &quot; ' The hydrolysis is carried out by the use of dilute hydroxide, such as, for example, sodium hydroxide.

The compounds of the present invention have the formula

in which V J ... Λ% r? ~ u-? you may be prepared. The reaction is carried out in the presence of a compound of the formula: ## STR4 ## in which R 1 is hydrogen, In addition, the compounds of the present invention may also be prepared by the following general formula: ## STR1 ## wherein R is as defined in formula (I). The latter starting materials may be prepared by reacting them with a compound of formula (I). with an inner alkyl alkanoyl of the formula: ## STR8 ## in boron trifluoride ether to give the corresponding 1-amino-3-methyl ester. d r-is &gt; -1-phenylethynyl) pyrano [3,4-b] indole, which is then reduced to give the corresponding δ-hydroxyl ester

O

R 2 -C (CH 2) m COOCH 3 BF 3 · Et 2 O

The latter intermediate may be made, as referred to above, with a compound A? CH? Desired final compounds'

A further scheme, by which the ester of the acid will comprise &quot;-hydroxy; 4-b] indole can be prepared comprises reducing the 7-lower alkyl triptolel in 7-lower alkyl-2,3-dihydrotriptofol followed by the addition of the latter with potassium nitrous disulfonate to afford a 7-lower alkyl-5-hydroxyKitryptophal, which is then reacted with a lower alkyl-3-methoxy-lower alanine

T **. The title compound is prepared from the title compound as a white solid, mp 228 DEG-228 DEG C., to give the ester intermediate of formula (III): ## STR1 ##

-CH 2 CH 2 OH trifluoroacetic acid + NaBH 4 ---: -

-CH 2 CH 2 OH

H (KS03) 2N0 OCH3 -ch2ch2oh r7-cchcooch3

NR3

HO

The R 3 R 7 N (CH 2) m COOCH 3 groups include the derivatives of the indene-1-acetic acid cathode, the acid XXV Γ S 5 of the product are esterified by methods of converting them to formers of the final product and the esters of the final product and are hydrolyzed by the procedures described above. t.-Acid Acids. x vi e ~ · corrssp ondentes »

R9 can be prepared by reaction of the lower Î ± -indol-3-alkanoic Acid with 1 N in the presence of pyridine hydrochloride. the acid derivative of A &lt; CH3) t2 n5 which is then esterified to 1 s x. The bifon silo or bensoil produces a fine orthophoretic rms. A preferred compound of the formula: ## STR10 ## for the alkanoic indole compound contained therein is reacted with a compound of formula The present invention relates to an ester, which may and by conventional methods.

HNMR

(CH 2 COOH N 4 CHa

H A (CH 2) nhal

NaOCH 3 / CH 3 OH / dimethylformamide

A (CH2) n O

(CH 2) m COOH

CH2 N2 / Et2O tetrahydrofuran

A (CH 2) n (CH 2) m COOCH 3

/ A ch3

NaH / dimethylformamide R 9hal (CH 2) m COOCH 3

A (CH2) n O

CH3R9

The composites were prepared using the following formula: w / < 28A (CH 2) n O-

(I.e.

R7CHC02R3

can be prepared by meie? of the following 4-benzyloxyaniline reaction schemes is reacted with sodium nitrite in the presence of the acid chloride to produce 4 "benzyloxy-hydrazinols which is reacted with acetic acid of methyl-3-deoctyl-cloexanone for to produce an intermediate, α-methyl-tetrahydrocarbazole acetic acid; which is esterified with ethanoi to yield the intermediate ethyl ester. &gt;

or

ch2o

ch3

The ester of the acetic acid of the intermediate α-methyltetrahydrocarbazols is reacted under reflux with chloroanil in methanol under nitrogen. the acetic acid of methylcarbamate which is reduced by hydrogenation to remove the benzyl group yielding the acetic acid ester of intermediate Î ± -hydroxy-Î ± -methyl-carbazole.

Λ Ο 'ΗΟ CH3 • chcooch2ch3

KOH CH3OH Ν 'Η

H 1 • J-ch 2cooh

A (CH 2) nhal τ DMSO / NaOH

The materials &lt; 5 reactions reactions commercially or otherwise; of the conventional starting materials used hereinbefore may be prepared by methods known in the art. Thus, for example, 1-amino-campiquinone can be prepared through

sequmtn schematic

ch3ch = chcho HC1 N CH, or

The cast-fused heterocyclic compounds used in the foregoing reaction are commercially available or can be prepared by conventional methods known in the art. Thus, for example, these intermediates. such as methylammonium 2-chloromethylbenzimidazal, 2-chloromethylbenzothiazole and 2-chloroethyl benzoxazole, can be prepared by the following reaction scheme

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

Certain compounds within the scope of the present invention exist in the form of the stereoisomers E and Z and the V isomers.

Individuals can be differentiated by the prefixes E ε Z, as defined in the accepted sequence rules procedures. Accordingly, the present invention encompasses the E, Z and mixed isomeric forms of the compounds of the final product which exhibit these forms of stereoisomerism.

The compounds of the present invention5 by virtue of their ability to inhibit PLA enzyme activity as well as 1ipoxygenase enzyme and to antagonize mediators produced by the enzymatic pathway are useful for the treatment of diseases mediated by oxidation products of srachidonic acid. Thus, the compounds are indicated for the treatment of diseases such as reuinatoid arthritis, inflammatory bowel disease, Dysteoarthritis, tendinitis, bursitis, psoriasis (and related inflammations of the skin) and similar diseases involving inflammation. by virtue of their ability to antagonize the effect of LTC *, LTD e and LTE,, which are constituents of SRS-A, they are useful in inhibiting the symptoms induced by these leukotrienes. Thus, the compounds are indicated for prevention of the treatment of diseased states in which LTC1, L1 and L4 are provocative factors, for example allergic rhinitis, allergic bronchial asthma and other diseases of non-bronchial airway obstruction mediated by leukotriene , as well as other immediate hypersensitivity reactions, such as allergic conjunctivitis. The compounds are spatially important for the prevention and treatment of allergic bronchial asthma.

The compounds of the invention are cytoprotective agents and are considered especially useful when they are administered in combination with non-steroidal anti-inflammatory drugs, the major side effect of which is gastrointestinal irritation. The cytoprotective effect of the compounds of the invention significantly reduces the gastrointestinal impact of medicines

The present invention is based on the ability of the compounds of the present invention to inhibit the biological effects of the leukotrienes and / or the anti-inflammatory agents. synthesis of these substances, for example by inhibition of lipoxygenase, but also in a by-pass effect, whereby control of the lipoxygenase pathway causes &quot; the oxidation of arachidonic acid to the cyclooxygenase pathway, giving rise to an increase in the formation of the prostaglandin-cytoprotective agents. These biological effects render the compounds of the present invention especially useful for the treatment of diseases such as sore throats , inflammatory bowel disease and induced haemorrhagic lesions, such as those induced by alcohol or non-steroidal anti-inflammatory drugs (CMAINE), hepatic ischemia, injury induced by a toxic agent or hepatic necrosis = renal, pancreatic or tissue of the myocardium? parenchymal liver injury caused by hapatotoxic agents such as carbon tetrachloride and D-gaXactosamine? ischemic renal insufficiency? liver injury induced by a disease? pancreatic or gastric injury induced by. bi 1 iss cell injury induced by trauma or &quot; stress &quot;? s glycerol-induced renal failure *

When the compounds of the invention are used in the treatment of allergic airway disorders, in the form of anti-inflammatory agents and / or cytoprotective agents, they are formulated into oral dosage forms such as tablets, capsules, etc. 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, low melting wax, , cocoa butter, etc. Diluents, flavoring agents, solvents, lubricants, suspending agents, suspending agents, tablet disintegrating agents, etc. may also be employed. The compounds may be mixed with or without other carriers In all cases, the ratio of active to 3% The compounds of formula (I) may be prepared by reacting the compound of formula (I) with the compound of formula (I) in the same manner as in Example 1. d e x tx tx dx by adm in ist .r e. The compounds of this invention may be used in the form of a sterile solution containing other solutes. for example saline or. q 1 ic pink, in sufficient quantity to make the solution isotonic. adm. i n i s t r a. c 3 &gt; by inhalation or by insufflation, the compounds may be converted into an aqueous or partially aqueous solution. which is then used in the form. Q8 a - £ 5-0 '' OSΟ i. "C Qift i. Π t S T V 1 1 PLA0 and da. And the anti-inflammatory effects of the present invention.

The dosage requirements vary depending on the specific composition employed, the route of administration, the severity of the symptoms and the individual to be treated. The treatment will normally be initiated with small dosages, less than the optimum dose of the compound. The dosage is increased until an optimal action is obtained for those circumstances. In general, the compounds are preferably administered at a concentration which produces effective results without causing these harmful side effects and can be administered as a single unit dose. , or if desired, the dosage may be divided into suitable sufunidades that are appropriate at the time of day "

The rivers and gastro-stimulants may be demonstrated by standard pharmacological procedures which will be described in greater detail in the examples below, in which procedures, otherwise, Specification of the compounds of the present invention as inhibition of PLA0? . as measured by. its ability to inhibit the synthesis of L.TB2 and PBE2 by the polymorphonuclear leukocytes produced by the mouse glycoprotein is well-measured by its ability to inhibit the release of arachidonic acid mediated by the human and non-human source of PL . These procedures further measure the ability of the compounds of the present invention to inhibit the activity of PLA in vivo. Pharmacological assays further demonstrate the ability of the compounds of the present invention to inhibit the activity of PLA. inhibit, in vivo, the pathways of. lipoxygenase and arachidonic acid metabolism and in inhibiting, in vitro, the leukotriene antagonist activity of the compounds of the present invention and also measures the in vivo activity. of the compounds as anti-inflammatory agents in the ens. Paw edema. the potency of the compounds in inducing a proliferation in rats is measured in a Di 1 quot; SflSSlO a

The following examples show the preparation and the topical assays of the compounds of the present invention:

Example 1: 5-Ethyl (4-chlorophenyl) methylene-3-12-methyl-6- (5-quinolinylmethoxy) -1H-pyrazine-1-carboxylic acid A p-Methoxy-Î ± -methylcinnamic acid

A mechanically stirred mixture of β-methoxybenzene 1-thiisobenzoate (47.6 g, 0.35 mol), propionic anhydride (78.3 g, Î'6.00 mmol) and sodium propionate (33.5 g, 0.35 mol) mole) is placed under nitrogen in an oil bath heated to 150 ° C for 15 hours. After addition of water (130 ml) under vigorous stirring, a yellow solid is obtained. This is redissolved in 100 ml. The aqueous phase is acidified (ice-bath) with concentrated HCl. A white solid is collected, which is washed with water and is poured into the title compound C47, 69 g, 71% f. 153-154 ° C. NMR (DMSO-d 6, 400 MHz): δ 8.21 (d, J 1.34 Hz, 3H, 2-CHâ,ƒ), 3.77 (s, 3H, OCHâ,ƒ), 6998 Cd, J 8.81 Hz, 2H, ArH), 7.43 (d, d 8.7 Hz, ArH), 7.53 (brs, 1H, ArCH = C). EH (EI, m / 2) s 192 (bp, MK)

Anal.

Calculated C, 6S, 74s H, 6.29 =

Found: C, 8.8; H, 6.43; 8.7. of p-methoxy, α-methyl

A mixture of Step A and 10% Pd / C (44 g, 0.229 mole) in dry methanol (500 ml) is hydrogenated overnight at 3.52 kg / cm @ The mixture is filtered CSolka-Floc) and the filtrate is evaporated to dryness to give a pale yellow oil, which is used without further purification (44.5 g). 38 - 38 -

mm CCDCl-, 400 MBz) = &amp; 1.16 (d, J = 6.9 Hz, 3H, 2-CHâ,ƒ), 2562, dd, 1H, ArCH) and 2 = 70 <m, 1> 5 ArCH), 3, θθ <dd, 1H, CH ), 3.83 (d, 2H, ArH), 7.09 (d, 2H, ArH). , 12 (b), 6-Methoxy-1-indanyl

A mechanically stirred mixture of the crude propionic acid (44 g, 3.227 mole) Stage. B is added to warm polyphosphoric acid C10 O4, 420. The mixture is then placed in an oil bath heated to 95Â ° C for 9 minutes (TLC, 9: 1 dichloromethane-methanol: UV). water is then extracted with ether and ethyl acetate and the combined extracts are washed with NaHCl to neutrality.The organic phase is washed with brine and is dried (MgSO C) Removal of the solvent affords the title compounds as an amber oil. This is purified by flash chromatography (on silica gel-dichloromethane as eluent) to give 25.58 g (64%) as a white solid. (d, J = 7.4 Hz, 3H, 2-CHâ,ƒ), 2.65 (dd, 1H, ArCH) 1 H, ArH), 7.34 (d, 1H, ArH), 7.33 (d, 1H, ArH) . EI (EI, m / z 176) +, 161 (bp, 1H-CH3) +, D = 6-Hydr 6-1-methyl-1-indanone To a stirred solution of bromide of anhydrous aluminum (69.82 g, 0.261 mol), anhydrous benzene (250 ml) kept under nitrogen is added dropwise over 30 minutes a solution of the methanone indanone (18 g, Θ, 12 moles) of Step C , in benzene (6 ml) = The mixture is refluxed gently for 3 hours &gt; , 4: 1 (TLC, dichloromethane, ethyl acetate 8: 2, UV), cooled in an ice bath and treated dropwise with HCl-N (ca. 200 ml ) to decompose the aluminum complex. The aqueous phase is extracted with ether &lt; 3 times), the extracts are concentrated under reduced pressure and extracted with 2.5 N MaOH &lt; 2.75 ml and 1 x 50 ml). The combined extracts are washed with brine, dried (Na2 SO4) and evaporated to give a solid (0.8 g) of the title compound as a colorless oil. oil which readily solidifies. The crude material is flash chromatographed (on silica Merck-60, gradient CH 3 Cl 3 -acetate 85: 5) to give the title compound (13.60 g, almost colorless solid , 82% &gt;.

 € ƒâ € ƒâ € ƒRm (CDCl3, 400 Hz): 1.31 (d, J = 7.44 Hz, 3H), 2.65

. (Dd, 1H, CH), 6.68 (s, 1H, OH), 7.18 (dd, 1H, ArCH) and 2.76 (m, 1H, ArCH) 1H, ArH), 7.3 (m, 2H, ArH) = EH (EI, m / z): 162 <W> + <147> (I.e.

(2R-Quinolino) imoxy) -2-methyl-1-indanone

A mixture of the anhydride potassium carbonate (15.96 g, 93.58 mmol) from Step D, powdered anhydrous potassium carbonate (12.93 g, 93.6 mmol), Î'-chloro-Î ± -2.47 g, 36 mmol) and dry acetonitrile (200 ml) is stirred at room temperature under nitrogen for 15 minutes. A 2-chloromethylquinoline (free base, prepared from 18.29 g or 102.96 mmol of the salt hydrochloride) and the mixture is placed in an oil bath heated at 65 ° C for 11 hours (TLC, dichloromethane-methanol 9: 1). The solvent is removed in vacuo and the residue is partitioned between ethyl acetate and water. washed with brine, dried (MgSOâ, ") and evaporated to give an oil which solidifies after trituration with hexane (ca, 31 g). The crude product is purified by flash chromatography (Herck-60 silica gel, absorbed in methylene chloride, eluted with CHâ,ƒClâ,, -acetate (9: 10, 10: 15) to give 5.95 g of crude, m), 7.35 (1H, d, J = 7.6 Hz), 7.85 (1H, d, CH 2), 2.65

(Dd, 1H, CH), 5.41 (s, 2H, ArCH2 O), 7.3-7.38 (m, 2H) (m, 3H, ArH), 7.55 (t, J = 7 Hz, 1H, ArH), 7.64 (d, J 8.5 Hz, 1H, ArH), 7.74 here. 7 Hz, 1H, ArH), 7.83 (d, J8 Hz, 1H, ArH2), 8.11 (d, J = 8.4 Hz, 1H, ArH), 8.20 (d, J = 8 Hz). , 4 Hz, 1H, ArH) .1H NMR (EI, m / z): 303 (M +), 142 (b.p. methyl-S - (2-quinolinyl) methyl) indan-5-acetic acid

Triethylphosphonoacetate (22.41 g, 10.0 mmol) is added dropwise under nitrogen to a stirred mixture at 0øC. of NaH (57% in oil, 4.27 g, 10Θ mmol) in dry toluene (250 ml). The cooling bath is removed and the stirring is maintained at room temperature for 60 minutes to give a nearly homogeneous solution. A solution of the indanone (15.15 g, 50 mmol) from Step E in toluene (50 ml) is then added. The flask is placed in a 60 ° C bath and heated at 95 ° C for 19 hours (TLC, traces of the material The reddish solution is cooled, diluted with water and extracted with ethyl acetate (3 times). The combined extracts are washed with brine, dried (MgSO4), dried (MgSO4), and evaporated. The residue (dark brown oil) was subjected to flash chromatography (on silica Merck-68, eluted using a dichloromethane gradient -> dichloromethane-ethyl acetate) ; to provide the title compound

4 · j. jJSSrO &quot; title s ob d form ds? one isomer of the endo and exo isomers (1 = 6.3 g / l) and 1 (50%) and the starting material (5). (1.84 g, 12% of collection) MS (EI, m / z): 373.4 (M + H) +. * {} η ò Η 'H' < τ »30® (M-COOC-H-) ', 143 (d, e), 115.8 = 3-C Acid <4 - ο1ογο f en yl> To a vigorously stirred mixture of the ester (mixture of the isomers, 6.9 g, 1: 5, 1: 1), prepared from . The title compound was prepared as described in Step F, and ρ-chlorobenzaldehyde (2.86 g, 2%, 1.1 mmol) in dry methanol (43 ml) was added dropwise under nitrogen sodium methoxide is then subjected to one night in the same manner as in Example 1, which is treated in the same manner as in Example 1). The present invention relates to a method for the preparation of a compound of formula (I). &quot; '/'. The mixture is homogeneous and the mixture is homogeneous. The mixture is homogeneous. The mixture is homogeneous. The mixture is homogeneous. 65 ° C5 temp. After cooling to room temperature, the mixture (yellow precipitate treated dropwise with water (35 ml) and with a small amount of four hours (dark red) was cooled to 0 ° C. methanol is and the gelatinous precipitate is sack to give the salt as a bright yellow solid. The latter is mixed in water to be neutralized (to pH 6-6.5) with 1% acetic acid. The extract is washed with brine and evaporated to dryness. The residue is subjected to flash chromatography to give a C7.5 orange slurry. (most important) and E (minor). This material is mixed with ether, stirred for 3 minutes, filtered and dried (4.32 42-42 ° C)

(G) The solid was stripped with hot ethyl acetate (containing only methanol and dichloromethane) until dissolved in acetonitrile almost completely. The filtrate is concentrated in vacuo to give precipitation, the residue is diluted with ethyl ether and the yellow solid is collected and dried (3.1 g, 2.8%). The concentration of the liquors The combined yield is 4.4 g (51%). The NMR spectrum is consistent with Lvers Shumari et al., J, et al. (DMSO-dâ, †), 4.04 (s, 3H, CCHâ,ƒ), 3.54 (s, 3H) s, 2H, CH 2 COO), 55326 (s, 2H, OCH 2 Ar), 6.60 (d, 1H, ArH), 6.95 (d, 7.52 &lt; m, 4H, ArH), 7.6 (t, 3 7.03 Hz, 1H, ArH), 7.66 (d, J 8.39 Hz, 1H, ArH), 7.77 (1H, ArH), 7.99 (m, 2H, ArH), 8.4 (d, J = 8.9 Hz, 1H, ArH). UV (ISmbed max, MeOH, nm) s 232 (39 39,594), 285.2 (14,830), 287.8 (14,921), 288 (14,921), 338.2 &lt; 10,839). EH <+ FAB, m / z) s 468 (101, M + H) &quot; **, 237, 131, 91 (b.p.).

For C a aHClClClN₂O,. i x. /I Q

Calc'd C, 74.43; H, 4.76Hz N, 2.99 =

Found: C, 74.54; H, 4.67; N, 3.13 (m,

2-methyl-3- (4-methyl-3- (4-methylthio) phenyl) methylene 3-6- (2-quinolinecarboxylic acid) -3 H -naphth-1-acetic acid To a vigorously stirred mixture of the ester (mixture of isomers, (4-methylthio) benzaldehyde &lt; 3.5 g, 19.06 mmol, 1.1 equiv) in dry methanol (75 mL, ) 25% methanolic sodium methoxide (7.7 ml, 2 mol) was added dropwise under nitrogen under nitrogen. The mixture was heated to homogeneous (ca. 65 ° C, bath temp) and then refluxed for a total of -Ν /; (I.e.

The mixture (bright yellow precipitate) is treated dropwise with 5 ml of water and a small amount of methanol and refluxing for 1 hour. After stirring at -78øC for 1 hour, is maintained for a further 5 = 5 hours (reaction is cooled to -78 ° C). the water and the skin of the gelatine are the same as those of the gelatin capsules. sec. Γ Γ Γ sto sto sto sto sto sto sto Ο. x 'tu. The compound of formula (I) in the presence of a compound of formula (I) The composition of the present invention may be prepared by the following methods: '.5. . . i. mr 3 sec. i. raxda with acetabulum L? e and t x 1 ο λ v o i. The extract is washed with brine and evaporated to dryness. The residue is azepan flashed with benzene to give a yellow solid (4.47 g, 52%). This material is mixed in ether, stirred for 3 minutes, filtered and dried (4.13 g, 205øC), dec. The precipitate was collected and dried (3.5 g., NMR spectrum is compatible 1914, 1977). (containing some amount of methanol and dichloromethane) until almost fully dissolved. The filtrate is concentrated, diluted with ether (35%). p ... f = 207-209 ° C? Bhuman et al., J. Biochem., Chem., 42, pp.

NMR δ DMSO-d4): δ 2.18 (s, 3H, CCH2), 2.51 &lt; s, 3H, SCHX &gt;, 3.673 sec. 2H, CH2 ClO): δ = 32 Cs, 2H; OCH 3 Ar), 6.60 (d, 1H, ArH), 6.95 (d, 1H, J = 2.35 Hz), 7.13 (s, 1H, ArH), 7.3

(S, 3H, ArH), 7.47 (d, 2H, -3.8.4 Hz, ArH), 7.8 (s,

Hz, 1H, ArH), 7.66 (d, 1H, J 8.47 Hz, ArH), 7.77 (t, 1H, J ca. 7 Hz, ArH), 7.99 (ArH). (m, 2H, ArH), 8.4 (d, 1H, -J 8.49 Hz) (ISmax max, HeOH, nm): 231.5 (37.382), 33.33 (9.739) 307.5 ( 9.342), 315 (10.525), 352.5 (13.407) = EH <FAB, m / z): 40® <M + H) +.

Analysis for C30H25ND3B

Calculated C, 75.13% C, 5.25% N, 2.92%

Found: C, 75.3; H, 5.25% H, 2.95 =

Example 5 2-Ethyl-3-ETH-4-methylsulfanyl) phenyl] methylene] -3- (2-guinolinylmethoxy) -3H-indene-1-acetic acid

A mixture of the thioether (1.87 g, 3.48 mmol) of Example 2 in an cold mixture of chloroform and glacial acetic acid (65:35, 40 ml) is treated dropwise (via syringe) with Ha. The mixture is stirred for 3 minutes in the cold and then at room temperature for 24 hours. A clear solution is obtained after 2 hours and a small amount of H2 O7 is added after 4 and 7 hours, respectively, to bring the reaction to completion, followed by TLC, water-treated aliquot and extracted with ethyl acetate). The chloroform is evaporated, the residue diluted with water. and is quenched to the cold with the calculated amount of NH4 OH. The precipitate is filtered, the mixture is mixed in water, collected, washed and dried in vacuo (over Na 2 SO 4) to give the crude acid as a yellow solid. The solid is redissolved in a large volume of hot ethyl acetate (35%) -35 ° C &gt; (containing

concentrated in vacuo until the precipitation begins and is diluted with ether. The precipitate is collected, washed with ether and is dried (fluffy solid, m.p. 136-37 ° C, sinters and forms foam). KMN (DHSO-d - ... 4Θβ ti 'MH 2) s δ 2.12 i TU n = "" U Λ -X * 1} V! â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ1 â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € "·"; . it. (1-ArCl-UO), 6.58 &gt; 1H, ArH). or 5 Ύα / 4-β1. (S, 1H, ArH), 7.55 (d, J = 8.3 Hz, 1H, ArH), 7.22 (m, 7H, ArH), 7.98 (m, 1H). 214, ArH), 7.18 (1H, br s), 8.39 (d, J 8.5 Hz, 1H, ArH)? 12.36 (s, 1H, CHCl3). MS (+ FAB) m / z): 518 (M +). [+] +, 496 (M + H) +. Analysis for C₂ ,H₂ --N₂O NN.S. T t t t t t t H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H 2 CU I B.OQ r. U n / k? r. 191 Hz; OK? % N r. dd Found: C, 69. 15: H, 4.93; i. .

5-Butyl-2-methyl-1- [4- (5-quinolinylmethoxy) phenyl] methylene] -1H-indene-3-acetic acid

To a solution of sodium metal (0.9 g, 39.1 g, aq) in hexane (50 ml) was added sodium bicarbonate (50 ml) A solution of 4-hydroxybenzohydrazide (50.4%) in ethanol (5 ml) was added dropwise under nitrogen to the reaction mixture. The mixture was refluxed gently for 1 hour then treated with a solution of 2-chloromethylquinazoline (free base), 24 g (45%) as a white solid (just prepared from the HCl salt) in ethanol (50 ml). The mixture is refluxed for 24 hours. The residue is partitioned between organic water and 5% NaOH in ethanol.

is 5. hours, the solvent is evaporated to ethyl acetate. The CpH layer (8), water and brine until removal of the solvent produced

The title compound as a yellow solid (9.81 g), the crude material is further purified by flash chromatography (on silica Merck-60, 9: 1 hexane-ethyl acetate) to remove less polar extracts and 8 hr to elute the product) . Yield 7.37 g (71.57%), m.p. 82-83 ° C. = NMR &lt; CDC11? 200 MHz): δ 5.5 (s, 2H, ArCH3 O), 7.2-8.8 (m, 9H,

ArH), 9.80 (s, 1H, CHO) b. 3-acetic acid To a mixture of 5-fluoro-2-methyl-indene-3-acetic acid (prepared according to the process disclosed in U.S. Patent 3,654. 349.2 g, 9.7 mmol) and the aldehyde from Step A (3.2 g, 12.19 mmol) in dry methanol (4 ml) is added dropwise under nitrogen sodium metabxide at 25 (6.48 ml). The mixture is heated to homogeneous and then refluxed for a total of 16 hours, the solvent is evaporated and the residue is partitioned between water. The gelatinous precipitate is collected, washed with water and dried, then mixed with ether, filtered and dried to give the sodium salt of the title compound as a yellow solid &lt; 2.03 g , 46.3%). The salt is mixed in water and neutralized to pH 6.5 with 10% acetic acid. The acid is extracted with ethyl acetate (large volume), dried (Na₂SO)) and evaporated to dryness. The crude acid is recritalized from a warm mixture of methanol and ethanol (large volume is required for dissolving, which is then concentrated to a smaller volume after filtration). The yellow solid (mp 21S-221 '-C, dec.) Is a mixture of the Z and E isomers at a ratio of 6: 1 CRS1N), 4

NMR &lt; DMSO-d1, 400 MHz): δ 1.84 <5, 2-CH3, lower E isomer E, 2,1 Cs, 2-CH- and 5 higher E isomer, (s, 2H, CHâ,ƒCCOO). 5.41 &lt; (dt, 1H, ArH), 6.85-7.3 (m, 1H, ArH), 7.18 (d, 2H, d 8 , 7 Hz, ArH), 7.28 &lt; 5, 1H, ArH), 7.32-7.40

(D, 2H, J 8.6 Hz, ArH), 7.62 (t, 1H, ca, 7 Hz, ArH), 7.68-7.76 (1H, ArH), 8.44 (d, 1H, 8.5 Hz, ArH), 12.4 (1H, ArH), 7.79 (t, amine, 1 H, COOH). MS (CI, m / z): 452 (M + H) +, 408 (M-CODH) +.

For C 19 H 18 FN 3 O 2.

Calculated C, 77.15 | H, 4.91; N, 3.10.

Found: C, 77.085; H, 4.93; N, 3.12,

Exegu3.1o_5

2-methyl-5 - [(4-methylthio) phenylmethylene] -6- (2-naphthyl) amino] -3H-indene-1-acetic anhydride

A mixture of the indanone &lt; 14 q, 86.4 mmol) prepared as described in Example 1, Step D, of anhydrous &lt; 11.24 g, 86.4 mmol) (2.27 g, 6.4 mmol) and 2-bromomethylnaphthalene (11.6 g, 95 mmol) in acetonitrile (275 ml) was heated under nitrogen for 24 hours (in a bath The reaction mixture is evaporated and the residue is dissolved in water, extracted with ethyl acetate, dried (MgSO4), and the crude product is evaporated to dryness (tan solid ) is flash chromatographed (on silica Merck-60, pre-afrosorbed on CH 2 Cl 2, eluted with hexane-ethyl acetate) to provide the title compound as a white solid &lt; 13, 49 g, 527.) â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒMc.

(S, 2H, ArCH3), 3H, ArH), 7.85 (m, 4H, ArH). 70 < m, 2H, ArHH-p), 3.35 (m, 7332 (m, 3H5 ArH), 7.5 æm, EH <EI m / ξ) s 302 (11) * - "U" 5: · ... - «* - - · ·" -indan-1-yl] -acetic acid, the title compound is prepared as follows: ) Î ± -I- (2-naphthyl) methoxy] -2-methylindan-1-ylidenecyclohexanecarboxylic acid ethyl ester E) 5-E (2-naphthyl) 3-2-methylthien-5-acetic acid I)

Tristilphosphonoacetate (19.8 g, 88.3%) as a chilled suspension of NaH (60% in oil, 3.53 g, 88.2 mmol) in toluene (225 mL) is added dropwise. ml). The cooling bath is then removed. A clear solution is obtained for 1 minute at room temperature. A solution of the indanone (13.3 g, 44 mmol) from Step A in toluene (46 ml) is added dropwise and the mixture is placed in an oil bath heated at 1θ ° C for 54 hours (followed by TLC The layers are separated and the aqueous phase is partitioned between ethyl acetate (3x) and the extracts are dried (K2 CO3) and evaporated to dryness to afford the crude product as a Smbar oil (21.5 g), which is a solid of the endo and isomers. Flash chromatography of this material (on silica Merck-60, pre-absorbed in CH2 Cl2, hexane-ethyl acetate 9: 1) yields small amounts of each of the pure isomers (i.e. I, II and III) together with mixed fractions and the part of the unreacted starting material (ca. 5.24 g.) The structures of the isomers are confirmed by E1r and NMR and are assigned by NOE. ando es and esxo es used

The title compound is prepared from the title compound of formula (I): ## STR1 ## in which the title compound is prepared as described above. 1 H-NMR (CDCl3): Î'1.26 (d, 3 AP), 5.8 Hz, 3H, 7-CHâ,ƒ), 1.32 (s, j), 2.54 (d, 31, 5 Hz, 1H, Ar CHC), 3.1 (m, 2H). L-H-L-L-H), 4.22 (s, 1H); ES-tSrT Γη Π 5! 2R) = 5 ^ 213 < (2H, ArCH2 -), 5.85 (s, 1H, C = CH = COO); (dd, 1H, J 8.4 Hz and 2.0 Hz, ArH), TJ / 517 δ, J 8.4 Hz, 1H, ArH), 7.48 (ai, 2H, ArH), 7 (S, 1H, Arl, 1), 8.6 (s, 1H, ArH), 7.9 (s, H, ArH). (EI, m / z): &lt; M1, 231, 141 C (KBe): 5.00 (m, 2H), 1.33 (m, 2H);

Cu, 1H, U / Hz, 2-CHâ,ƒ), 3.13 (d, 3 Ã-1, 3 Hz, 1H, ArCH3) ArCH3), 3.88 (m, 1H, CCH) • S ter CHO), 5.23 (s, 2H, ArCH3), 6.19 (s, 1H, C-COOEt), 7.06 dd, J 4, 4 and 2.4 Hz, 1H, ArH), 7.17 (d 5 J 2, 3 Hz, 1 H, ArH), 7.23 (d, J 8.4 Hz, ArH), 7.4? (2H, m, 2H, ArH), 7.54 (dd, Δ4 -4), 1.6 (1H, ArH) 373 (M + H +, 26: 1)

Ischemia-JLU. NMR CDCl 3, δ 4.46 MHz &gt; s &amp; 1.20 (3H, 2-CH3), 3.28 (s, 2H, ArO-k.), 3.4B, 2H2, CH2 CH3 (S, 2H, ArCH2 O), 6.79 (dd, 3H), 2.3 ArH), 7.24 (d, 8.8 Hz, 1H, ArH), 7.48 (m, 2H, ArH), 7.56 (dd, J = 8.4, 1.7 Hz, 1H, ArH), 7.87 (m, 4H, ArH), MS (Cl, m / z), C = (Methylthio) phenyl] methylene] -6-Li-naphthylmethyl] -3H-inden-1-acetic acid To a mixture of the ester (mixture of isomers prepared in the manner described above (2.5 g, 6.71 mmol) and 4-methylthio) -faaldaldide &lt; 1.124 g, 7.38 mmol) in anhydrous methanol (0.5 ml) is added dropwise under nitrogen, 25% strength sodium methoxide. The mixture is refluxed for 16 hours, the solvents are removed and the residue is partitioned between water overnight and the initial yellow oil becomes solid.) Water is evaporated in vacuo and the residue is triturated with ether (to remove the unreacted aldehyde), is filtered, washed with ether and dried (yellow solid, 2.65 g), the crude sodium salt is mixed with water and acidified (to pH 6.5) with 1% acetic acid. The acid is collected, washed and dried in vacuo, is washed again with ether and dried <1.02 g, 32%, p = 2  € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ ¹H NMR

NMR (DMSO-dâ, †), 400 MHz, 8 1.81 &lt; s, 2-CHâ,ƒ, minor isomer E), 2.11 (s, 2-C ,,). (s, 3H, SCH-ç), 3.54 (s, 2H, CH₂COO), 5.23 (s, 6H)

ArCH3 O-isomer Σ) and 5.28 (s, ArCH2 O, E-isomer), 6.6 (d, 1H, ArH), 6.90 &lt; d, J 2.2 Hz, 1H, ArH ), 7.12 (s, 1H, ArH), 7.27-7.36 (m, 3H, ArH), 7.46-7.62 m, 5H, ArH), 7.88-8.0 ; 4H, ArH), 12.33 (br s, 1H, COOH) = EH (Cl, m / z) s 479 +, 435 (M + H-COQ) +, '1',,

Calc'd for C 20 H 20 N 4 O • • Calculated C, 77.8; H, 5.48.

Found: C, 77.44; H, 5.47.

Example. 6

5-E (4-chlorophenyl) methylen-2-methyl-6- (2-guinolinylmethoxy) -3-3H-indene-1-acetic acid A-amyloxacrylate

A mixture of the indanone &lt; 1.81 g, 11.17 mmol) from Example 1, Step D, of cyanoacetic acid (1.05 g, 1.23 mmol), ammonium acetate (0.17 g), acetic acid (8.66 g) and toluene (5 ml) is heated to reflux with removal of water (Dean-Sark) for 24 hours. The residual yellow solid is redissolved in ethanol (6 ml) containing KOH-2.2 N (1.4 ml) and a solution of KOH (2.2 g, 85 mmol) in water <15 ml) and , solution at reflux under nitrogen for 1 hour. The ethanol is evaporated, the residue is diluted with water and extracted with ether (2 times). The aqueous layer is acidified in the cold with HCl-6N (to pH 3) and extracted with ethyl acetate. The extracts are washed with brine, dried (Na2 SO4) and evaporated to give the crude title compound in the same manner as the title compound. . Traces of unreacted indanone. This is used in this form in the next Step. 1 H-NMR (DMSO-d 6, 2 MHz): δ 2.02 (s, 3H, 2-CH-), 3.2 Hz,

(D, 1H, ArH), 9.68 (s, 1H, ArH), 7.1 (d, 1H, ArH) 08 (broad, 1H, OH). To a solution of the crude acid prepared by the procedure described in Example 1, in Step A, above, in dry methanol (12 ml), p-toluenesulfonic acid monohydrate (1.9 g) is added and the mixture is stirred gently for 1.5 hours. The methanol is evaporated, the residue is dissolved in ethyl acetate, washed with brine and dried (MgSO4). Removal of the solvent affords a brown oil which solidifies readily after drying in vacuo. The residue is flash chromatographed (silica gel, taken up in dichloromethane, eluted with dichloromethane-ethyl acetate 99: 2 and 94-26) to give the pure title compound as a nearly solid white solid (9.4 g, 81%): δ 2.1 (s, 3H, 2-CHT), 3.26 (s, 2H,

3.97 (s, 3H, COOCH 3), 4.89 (broad s, OH), 6.59 (d, ArH), 6 , 75 (d, 1H, J 2.4 Hz, ArH), 7.18 (d, 1H, 7.9 Hz, ArH). EH (EI, m / z): 218 (M) +, 158 (b.p.). To a solution of the sodium metal (Θ Θ Θ Θ Θ Θ,, 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 ga) in anhydrous methanol (2.5 ml) under nitrogen is added dropwise with

-I.-. Θ. The compounds of the invention may be prepared by the following methods: 0). After cooling to the point of cooling, a solution of the product from Step B, in methanol (5 ml) followed by β-chlorobenzaldehyde (ν 531 g, 1 mmol) and the mixture was stirred at 65 ° C for 6 hours, followed by After stirring overnight at room temperature (TLC, CHCl3), ethyl acetate (93 ml) is added and water (100 ml) and methanol (100 ml) are added and the mixture is refluxed under nitrogen. (2x) The aqueous phase is cold acidified with HCl-6N (to give H 3) and is extracted with evaporates to give a yellowish green solid. The spectrum RHM shows that it is a mixture of the title compound and 5-hydroxyl-2-methyl- -3-acetic acid, which are separated in a most effective manner in the form of the corresponding m-ethyl esters (see below). -acetic acid-4-hydroxy-3H-indene

A solution of the crude acids 246 mmol, obtained in the manner described, Step C4 above) in methanol (50 ml), i.e. &quot; Methanol is evaporated to dryness. s x. d. washed with brine and the residue and subjected to evaporation, the residue absorbed in the acetate is dried (MgSO / τ) and solvent ώ and flash chromatography on dichloromethane-hexane , eluted with toluene-isopropanol (95% yield). to afford the title compound (less polar spot, &gt; 103 g, yellow solid) together with the impure material (390 g oil which solidified upon standing). The Z-configuration is confirmed by NQE. The more polar spot is the same as &lt; RTI ID = 0.0 &gt; RTMS &lt; / RTI &gt; by using methyl-3-hydroxyl-2-methylene-3-acetate =

J = 2.3 Hz, 1Η, ArΗ), 7.01 (s, 1H), 7.14 (d, J = 8.3 Hz, 1H,

ArH &gt;, 754 (dd, 4H, ArH). (EI, m / z 342/340 &lt; 1Cl, M) +, 231 &gt; &lt; EMI ID = 16.1 &gt; 3- [4- (4-chlorophenyl) ethyl] A mixture of the potassium carbonate ester of Step (D) and potassium carbonate (Step II) (50 ml) in acetanitrile (7 ml) is stirred at room temperature for 15 minutes. 2-Chloromethylquinoline (free base) is added, mp 149 g , 1.42 mmol, freshly prepared from the hydrochloride salt) and the resulting dark red mixture stirred under nitrogen for 15 hours in an oil bath heated to 65 ° C. An excess of 1% potassium, crown ether and 2-chloromethyl quinolines at reflux is maintained for two hours (TLC, hexane-isopropanol 93%). The solvent is evaporated and the residue is partitioned between water and acetic acid The organic phase is washed with brine, dried over MgSO4, and evaporated to dryness. The crude product is identical to the material described in the following Example 7 (E) - [3 - [(4-chlorophenyl) methyl] -3-methoxy-2- t = 1. methoxy) -3H-indeno-1-acetic acid

Add dropwise. To a warm solution of the ester (1524 mmoles) of Step E in methanol (7 ml) was added dropwise at reflux under nitrogen for 3 hours. After stirring overnight at room temperature (TLC, hexane-isopropanol 93.7) the methanol is evaporated and the residue is washed with ether. The solid is mixed in water and cold neutralized with 10% The extracts are washed with brine, dried (MgSOâ, ") and evaporated to yield the crude acid (0.250 g. , 43%). This is recrystallized from hot ethyl acetate / methylene chloride (dissolve in a large volume and concentrate the filtrate until precipitation starts). The pure title compound: 216-218 °: (C) is identical CCGF, RMM 5 to the material described in Example 1, Step 8 (Z)).

Example 7 3- (4-Chlorophenyl) methylene-3- (2-methyl-6 - [2-quinolinylmethoxy) -3H-indene-1-acetic acid methyl ester

A suspension of the acid (1.88 nmol, crude material before purification, obtained in the manner described in Example 1, Step 8) in methanolic HCl (15 ml) is refluxed until the reaction is complete by TLC < The methanol is evaporated and the residue is partitioned between ethyl acetate and dilute NH4 OH. The extracts are washed with brine, dried (Na2 SO4) and evaporated to dryness to give (0.90 g). The crude product is subjected to flash chromatography (on silica Msrck-60, toluene-hex-isopropsol-5Θ; 56%) as a white solid. as eluent) to give the pure title compound (0.636 g, yellow foam which solidifies after trituration with ethanol, 69.6% after two steps). The mixture of the Z and E isomers at a ratio of 4% (with base on the position of the 2-O-Er signal on the EHN spectrum) "

ι. h x ογο'ργι ρ ί ,, ο τ Η, α h

A mixture consisting of θ = 148 mol) and in 2 ml trifluoroacetic acid is stirred at ambient temperature. The pellets of sodium borohydride (5.4 g,

0.45 mmol) are added over a period of 4 hours. After 3. C ΟΠ C. The. The reaction mixture is dextylated on ice and is neutralized with 2.5% NaOH to pH 10. The aqueous layer is dried over sodium sulfate and evaporated to dryness. The reaction mixture is then made alkaline with 5% NaOH and extracted with ether (3 κ 20®) and the layers are washed with ether (50 ml). washed with water (2 g, 2 ml) and once with brine (2 ml), dried (MgSOâ, ") and dried (MgSOâ,"). 1 to 10% by weight of ethyl acetate / hexane / dichloromethane at 0 DEG C. The product was purified by flash chromatography on silica gel, to &gt; and then t-acetate

7-Et-1-yl-S-hydroMitriptophal

To a suspension of pH 7 (76 ml) was added the title compound as a white solid (0.8 g) in dichloromethane (5 ml) and evaporated to dryness. The reaction mixture was stirred at reflux for 2 hours and then cooled to -78 ° C for 24 hours. The reaction mixture was stirred at reflux for 30 minutes. The reaction mixture was diluted with acetonitrile to give the title compound as a white solid. The effect layers are combined with distilled water (2%) and once with brine (200 ml), dried with MgSO4. The crude product is introduced into a flash chromatography column on the following day which is subjected to fl ash chromatography by direct evaporation of the crude product. The title compound was prepared according to the procedure described in Example 1 to give 2.5 g of the title compound as a white solid. . . (M + H) +, 43%. 6.97 (d, 1H). 3 = - 5 Hz, 2H * ar om ») * &amp; , 6 (d 3 J = 2.1 Hz, 1 H, arom), 6.46 (d, J = 9 Hz, 1H, arom) , 5.45 (1H, d, J = 9Hz); (M, 2H) 3 O 5 O · .cl. 1: 1: 1. ', 2.7 (1H, 5H);  € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒMS: 205 (M) 15 O / B Analysis for B c 1 Li 2 * '15 ND? Calc'd C, ** 70 * H * £ 5 H, &lt;? 3 0/3 N, 6 3 H / c m d n nated. P 7 0 5151 H 5; 7 ' 3? C.methylmethylelic acid 1,8-bisdisticyl-1,3,4,9-tetrahydro-6-hydroxymethyl-3,4-dihydro-acetic acid

A mixture consisting of 7-ethyl-5-hydroxytryptophol (15.5 g, 0.076 mole), 2% methylene chloride / fetrabrofuran / methylene chloride (17: 5 g, 0.6121 mol) and boron trifluoride etherate (23.6 ml, 187 mmol) is stirred at ambient temperature for 28 hours. The reaction mixture is diluted with water. 1 ml of methylene chloride and is washed with 5% NaHCO 3 (500 ml) and again with water, dried over MgSO 4 and concentrated to give 30.3 g of the crude product. Chromate- Flash chromatography by use of 25% ethyl acetate / hexane as eluent yields 16.0 g of the title compound, mp 153-154 ° C. NMR (CDCl3): δ 8.90 Cbs, 1H &gt; , 6.74 (d, J = 23 Hz, arom.), 6.49 (d, J = 2.4 Hz, 1H, arom.), 4.5 (S, 1H, Ar-OH), 4.00 (m, 2H), 3.7 (s, 3H &gt;, 3.0-2.70 (m, 6H), 2.20 (m, 2H), 1.33 &lt; t, J = 7 , 6 Hz, 3H5, 0.82 (tt, J = 7.6 Hz, 3H). IN; 317 CM) &quot; 5 &quot;, 288, 244.

ANALYSIS __mra5 cÍQH27jmA

Calculated; C, 68.12; H, 7.30; N, 4.41.

Found; C, 67.73; H, 7.23; N, 4.24. D. 1,8-Ethyl-1,3,4,9-tetrahydro-6-hydroxy-pyrimidine-3,14- !-acetic

An. A mixture consisting of the methyl ester (43.1 g, 0.136 mol) of Step C, potassium hydroxide (2.4 g, 0.467 mole), 160 ml of methanol and 160 ml of water is subjected to. The reaction mixture was stirred at reflux for 5 hours under a nitrogen atmosphere. Excess methanol was evaporated and water (1000 ml) added to the residue. The mixture was extracted with ether (3 x 50 ml). The aqueous layer was made acidic with 5% HCl (pH 2) and then extracted with chloroform (4 κ 3 Θ 0

ml). The combined chloroform layers were washed with water (25 ml) and brine (50 ml), dried over MgSO4, and concentrated in vacuo to give 43 g of foam. Flash chromatography using 15% acetone / toluene yields 4% foam. This is crystallized from acetonitrile / toluene to give 35.4 g of the pure title compound, mp 72-73 ° C  € ƒâ € ƒâ € ƒ1 H NMR (DMSO-d6): Î'8.44 (s, 1H, -NH), 6.51 (d, J = 2.1 Hz, 1H, Ar), 6.39 (d, 3 = 1.96 Hz, 1H, Ar), 3.89 (m, 2H), 2.89 &quot; 2H &gt;, 2.87 (d, J = 13.5 Hz, 1H, CH 2 COOH), 2.75 (d, &lt; 3 = 15.8 Hz, 1H, CHOHOH), 2.71-2.57 (m, 2H), 1.99 (q, J = 7.2 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H &gt; 3H). IR (KBr) cm-1: 5359 (OH), 172 (CO). UV (neOH, nm): 276 &lt; 994 ()), 295 (M +).  € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ244 DE Calc'd C, 67.31; H, 6.98; M, 4.62. Found: C, 66.99; H, 6.8; N, 4.96; N, 4.96; N, 4.96; N, 4.96; N, 4.96; N, 4.96; .a.43fa.lÁD.d.gr.

A mixture consisting of 1,8-diethyl-1,3,4,9-tetrahydro-4-hydroxy-3 H -pyrazine-3-acetic acid methyl ester (5.6 g, 0.015 mole), dimethylsulfoxide (300 ml) and potassium iodide (158 mg) is stirred at room temperature. A solution of sodium hydroxide (3.9 g, 200 ml of Η 7.0) is added and the mixture is stirred the resulting solution is cooled to room temperature. 2-Chloromethyl-quinoline hydrochloride (8.4 g, 0.092 mol) is then added. The reaction mixture is heated at 70-80 ° C for 3 hours. , 5 hours, is cooled and diluted with water (100 ml). The mixture is made acidic with 1M HCl pH 4 and is extracted with

The organic layers were washed with water (3 x 200 ml) and washed with brine (50 ml), dried over Mn 3 O 4 (50 ml) and evaporated to dryness. (I.e. The crude product is chromatographed on silica gel using 7% methanol / methylene chloride as the customary silica gel 259 g of the crude product are obtained, the latter is dissolved in 28 ml of ethyl acetate and precipitated by 3-bromo-4-isopropylcarboxamide. β. petroleum ether (7.7%) of the title compound (0.7%) of the title compound (0.17 g, Ml) to afford 00 MHz, DMSO-d .. &gt; . Q 3'-8.5H (40); 8-Q), 7.97 (d, J = 7.7, 1H), 7.75 (dt, J = 9 Hz), 7.71 (d, J = 1 H-NMR (DMSO-d 6):?

1 H NMR? (B) 3 (3H, t, J = 9 Hz), 7.67 (1H, d, J = 9 Hz) 3 = =; 3 &gt; 2H-Dt, M XJ / y Q) 3 & 3 H &gt; 3 2 ' 1 H NMR (DMSO-d 6, d 6): δ (2H, t, J = 3 H-NMR (DMSO-d 6, 300 MHz): δ 0.75 (s, 3H); H 5 CH); \ K.LA '&quot; (C = O) -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -O-

Ana. 1 iss pa ra »Γ: * * * * * * * * * * * * * * * * * * * * * C C C C C C C C C C C C C C C C C C C C , 7, 304 | h5 A -19 ξ M »6 2 2i

. EXAMPLE 1 1-Atilis-13β-9-methoxy-5-hydroxy-6- (quinolinylmethyl) -pyrrolidine-3-carboxylic acid 1-yl] -1,4,4,4-tetrahydro-α- (phenyl) -methyl] -oxazolo [4,3-c] [1,4] oxazepine; co

A further mixture of 5-benzyloxytripramethylsulfonyl chloride, methylene chloride,

(16.8 g, 177 mol) and boron trifluoride etherate (2 ml) is stirred at room temperature for 3 hours. The reaction mixture is washed with NaHCO 3 (2 x 200 ml) and brine (200 ml), dried over MgSO4, filtered and concentrated to give 38.0 g of crude product. This is flash chromatographed on silica gel eluting with 20% ethyl acetate / hexane as eluent to give 29.0 g of the pure title compound, mp 8-100ø 1 H NMR (CDCl 3) δ 8.87 (BS, 1H NH), 7.47 (d, J = 7.3, 2H, Bz), 7.36 &lt; t, J = 7.6, 2H , 7.29 (d, J = 7.5, 1H), 7.04 (d, J = 2.4, 1H), 6.91 (d, -8.7, J2 = 2.4, 1H), 5.10 (s, 2H G-CH2 --Bz), 4.06-3.9 (m, 2H), 3.71 (s, 3H, CH J = 16.6, 1H), 2.89 (d, J = 16.6 1 H), 2.75 (m, 2H &gt;, 2.0 (m, 2H ), 0.81 (t, 3H), 3.07 (3H, CH), 4.42

Mass (M) 3/9, 350, 2g.

Analysis for C 23 H 25 NO 4

Calculated C, 72.8; H, 6.64; N, 3.69. (c) 72.01; H, 6.63; N, 3.69. B. 1-Ethyl-1,5,4,9-tetrahydro-2-phenyl-methoxy) pyrano [3,4-b] indole-1-acetic acid

A mixture consisting of the ester (29.0 g, 0.765 mole) of the title compound. Step A, methanol <8 ml), water (5 ml) and potassium hydroxide (16.0 g, 0.29 mol) is refluxed for 4 hours. The reaction mixture is cooled to room temperature, concentrated and diluted with water (50 ml). The aqueous layer is washed with ether &lt; 2 x 250 ml) and the mixture is acidified with 1% concentrated HCl and water to pH 2.71. is extracted with chloroform &lt; 4 x 300 ml) and the combined chloroform layers are washed once with water (12 x 30 ml) once with brine (30 ml),

2H), &quot; 8.7 s 5.10 (t-H NMR (400 MHz, CDCl 3): δ 8.39 (BS, NH), 7.4 (d, J = 7.4. , 8.31 (d, J = 8.8, 2H), 7.30 (m, 1H), 7.22 (d,

1H &gt; ? 7.04 (d, J = 2, 4, 1H), 6.93 (d, 0, = 8, a = 02 = 2, 4 1H); f &quot;. (c) (CH 2 Bz), 4.08 (c), 2H ' , 3.02 (t, J = 1.64 Hz), 2.01 (t, J = 16.3, 1H), 2.8 (q, O = = 5.0 2H> 2.06 <m5 2H) 5 & B 0 = 7.3 3H CH, XH &gt; , IR (KBr 5, 3380 (NH), 1710 (COC)).

- X

Calc'd. H, 6.34; N, 3.83. C, 72.17; H, 6.29; N, 3.65; C, 1-Ethyl-3,4,9,9-tetrahydropyridines; A mixture of consists of &amp; co. vogo ta 1 (3, b; (30.0 g) in tetrahydrofuran (30 ml), tetraacetic acid (21.0 g, 0.056 mole) in EtOAc B (30 psi) for 1 hour. The concentrated mixture was evaporated to dryness what without purification, the x x ~ 0 x f an o l. . &gt; hydragnose to &gt;: kg Kg / cm &quot; The reaction mixture is filtered and filtered.

A mixture which is in the acid of the formula (3 g, 5.07 mole) Step C, dimethyl. (180.0 g in 100 ml of H2 O) and 2-chloroethylquinazinium hydrochloride (23.0 g, β 10% / mole) is heated to 0 ° C. The reaction mixture is cooled, poured into water, and the water is washed with water. the color π H1 / r4 for. pH 4 · φ V with ethyl acetate (4 x 500 m 3) and the combined organic layers were washed with water, (300 ml) are dried with MgSO4. are filtered conesnt r ad 3. s for pr aduzire iX \ 3 V &gt; (1) (1) (1) (1) (1) (1) (1) (1) 1 / c1orst D ds meti! sn or a. (1) (b) (b) (b) (b) (c) (b) (b) (b) 1 ml of acetate is prepared by chromatography (3: 1) and the solvent is removed by filtration, 9 of the process which is characterized in the following manner: (a) the compound of formula (I): wherein R 1, R 2, R 3, ° C IO SC u> 8

1H, 40) IR <KBr>! 340 ° C 1 (NH, OH), 1705 cm -1 <C = G>. FAB Masses M + H 417 Î ± H + 357.3 = 8.2, 1H550), 7.78 (dt, 855, 1H, 3H), 7.60 (dt-ar.), 7 = =, 1H, Ar, 5.54 (s, = 13.6, 1H), 2.62 (2H,

Analysis for; C25 H25 N2 O4

Calc'd C, 72.17; H, 5.81; N, 6 = 73%

Found: C, 72.25; B, 5.915 N, 6.48.

Example 10 1-Methyl-1,3,4,9-tetrahydro-2-quinolinylmethyl-pyridine-4,4-b] indole-1-acetic acid methyl ester 1-methyl Tetrahydro-6- (phenylmethoxy) pyranoCS4-b3-indole-1-acetic acid

A mixture consisting of 5-benzyloxytriptofol (4.5

gt; 0.01 mol), benzene &lt; 220 ml), ethyl acetoactate (-5.4 g, 0.026 mole), p -tolenesulfonic acid (0.5 g) is refluxed for 2,3 hours by employing a Dean-Stark siphon to remove the water. The reaction mixture is cooled to room temperature, washed with 5% sodium bicarbonate (200 ml), water (2.0 ml) and brine (100 ml), filtered and concentrated to give 8.0 g of the product as a thick oil which is flash chromatographed on silica gel using 20% ethyl acetate / hexane as eluite to yield 5.5 g of an oil which solidifies on standing, = 96-98 ° C

x H 5 rr · P ², 90 æl † † † † † † ‡ † † † † † † † † † † † † † † 22-4: 1 4 Πϊ 3 2H) 4 c 01 < , 2.98 (d, 2H), 2.98 (d, J = 8.9 Hz). J; "" Iu "-H-? J. n. = 7, 7, 5, 5, 6, 6, 7, 7,

CrL) = 1.3 C t, J = 3H COOCH3 .CH3). Masses EI; M / as 379, ions 292, 1.58 = Î ± -methyl-11β-

A mixture consisting of the ester (5.5 .alpha., .Beta.) And the mixture was stirred for 4 hours (4.0 g.). The reaction mixture is inlet, is diluted with

ΓΠ + ΐ14Λ 5íí;;;;;;; The mixture is extracted with dichloromethane, dried over anhydrous sodium sulfate, and evaporated to dryness. C A orof ογπκιο (3 x 15 m m 1), DS SM trac mio com ΧΠ ΧΠ ΧΠ ΧΠ ΧΠ ΧΠ ΧΠ ΧΠ ΧΠ ΧΠ ΧΠ ΧΠ ΧΠ ΧΠ ΧΠ. in water (2 v / v). and dried with Mg. x 100; concentrated to afford 4.6 g of the product, which was used in the following ration, p = 1 = 5.7 - 15.5 ° C (dec.), Compound No. 40 (MH +), BMSO-d, 5.s = 11.98 , 1H), 7.34 (d, 1H, NH), 7.45 (d, J = 7, 1H, Bz), 7.38 (d, J = 7.1, = I, B, 2H, Bz &gt;, 7.30 Cm, 1H, Bz &gt; , 7.18 (d, O = 8.7, 1H, Ar,), 6.99 (d, J = 2, 3, 1H, Ar =), 6.76 &lt; d-7-O-7- (4-chlorophenyl) (Ar), 5.07 (s, 2H, OCH3), C, 95.54; 2H), 2.78 (d, J = 13.8, 1H), 2.68 (d, J = 1, 3H), 3.40 , 2H), 1.56 (s, 3H) =

This mass M / es 35I, iSes 292, 26Θ, 13 Eis

W. Acetyl-4,9-tetrahydro-4 H -hydroxy-pyrano [4,5-b] indole-1-acetic acid

A mixture consisting of the acid (4.5 g, 0.013 mole) of Step B, ethyl &lt; 15 ml), tetrahydrofuran <20 ml) and 10% Pd / ca on vegetable charcoal (Β Θ mg) is hydrogenated at 30 psi for 18 hours. The mixture is filtered and concentrated to yield 3.1 g of the product, which is used in the next ration without further purification. 1H NMR (400MHz, DMSO-d6): Î'7.19 (d, J = 7.5, 1H, Ar), 6.7  € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ (d, Î'= 2.5, 1H Arâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ6.55 (dd, 3, = 8.56, , 2.76 (d, J1 = 16.0, 1H &gt;, 2.66 (d, J = 16.0, 1H), 2.55 (m, 2H), 1.55 (s, 3H).

Elemental Mass Spec .: 261, ions 216, 160, 101 «D» β-methyl-1,3,4β-tetrahydro-β-Cβ-guityleryrilmethoxy) -pyrene-15β- -acetic acid

A mixture consisting of 1-methyl-1,3,4,9-tetrahydro-6-hydroxy-pyrano [3,4-b] indole-3-acetic acid (3.0 g, 0.011 mole) of Step C in dimethylsulfoxide (30 ml), potassium iodide (<0.00 mg) and sodium hydroxide (2.5 g in 20 ml of water) is stirred at room temperature. (5.8 g, 0.022 mol) and the reaction mixture is heated for 3.5 hours, cooled and diluted with water (700 ml). The mixture is made acidic (pH 4) with 1N HCl , is extracted with ethyl acetate (4 x 3 ml) and the combined organic layers are washed once with water (2 x 2 ml) and once with brine (2 x ml), dried (MgSO 4), filtered and concentrated to afford the crude product, which is chromatographed on silica gel using 10% methanol / methylene chloride as eluent to give 1.0 g of product.

Dissolved in ethyl acetate (2 ml) and precipitated by dropwise addition to petroleum ether (5 ml) to give the pure title compound, mp 175 DEG- / ° C (dec =) =

1 H NMR (400 MHz, CDCl 3) δ 11.2 (s, 1H, CH), 8.37 (d, 3H); , 7.77 (d, J = 8.6, 1H, 5H), 7.77 (dt, J = 6.9, J2 = 1H), 7.69 (d, J = 8.5, 1H, 3H), 7.58

Cdt, J1 = 7, Î', J2 = 1.0, 1H, 6β, 7.18 (d, J = 8.7, 1H, Arâ € ²), 7.0

J = 2.3, 1H, Ar), 5.38 (dd, J =

2H), 2.88-3.84 (m, 2H), 2.62 (bs, 2H), 2.48 (s, 2H), 1.56 (s, 3H, (KBr): 344 cm-1 (broad NH, OH), 17.8 cm-1 (O = O) =

Eis Masses M / es M '402, ions 2®2, 157 ,,

Analysis: Calculations: C24H22N2D4 (a). H, 5.57; N, 6.96%.

Found: C, 69.2; = H, 5.38; N, 6.60 =

Example 11 i-Ethoxy-2, 5, 4, 9-tetradecyl-6- 2-yl) -1H-imidazo [1,2-a] pyrazole-1-acetic acid ethyl ester -methyloxy-1-methyl-1 H -purine

A mixture consisting of 4-methoxyphenylhydrazine (25.0 g, 26.62 mole), 2-carboxymethyl-2-ethylcyclohexanone (42.0 g, 0.212 mol) and toluene (10 ml) is refluxed for 24 hours under a nitrogen atmosphere. Water is removed by use of a Dean-Stark trap. The reaction mixture is cooled and concentrated to yield the crude hydrazone in 56 g. = The crude hydrazone (56 g) is dissolved in glacial acetic acid (50 ml) and refluxed for 25Â ° -

The reaction mixture is cooled to room temperature, poured into water (50 ml) and extracted with ethyl acetate (4: 5: 0 ml). The organic layers are dried over sodium sulfate. combined, washed with 1 N NaOH (2 x 50 ml), water (2 x 5 ml) and once with brine (560 ml), are dried with H2 SO4, filtered and concentrated to give 47 g of the crude product. The crude product is subjected to flash chromatography using 10% ethyl acetate / hexane as eluent to afford 18.0 g of product. 72-74 ° C =

1H, NH), 7.19 (d, J = 8.4 Hz, 1 H-NMR] 400HHz, CDClâ,ƒ or 8.94 Cbs,

1H

Ar.), 6590 (d-3 = 2.3H1 A 5% 6.76 <dd, 3, = 8.6, 3 "= 2.3, Ar.), 3.81 (s, 3H , COOCH *), 3.64 &lt; s, 3H, OCR *), 2.68-2.62

(M, 4H), 1.95-1.61 (m, 6H), 0.8 (t, 3H, 7.6, 3H, CH3 CH3). This is M / e; 301, iSes 272, 228 (base peak). The compound of formula (I) wherein R 1 and R 2 are as defined in claim 1, wherein R 1 and R 2 are as defined above.

A mixture consisting of the methoxy compound (18.0 g, 0.060 mol) of Step A in 48% hydrobromic acid &lt; 45 &gt; ml) is heated at 125 ° C for 6 hours. The reaction mixture is cooled, diluted with water (1500 ml) and extracted with ethyl acetate (3 x 500 ml). The combined organic extracts are washed with water time with water (2 κ 30 ml) once with brine (50 ml), dried &lt; H 2 SO 4), filtered and concentrated to afford 15.8 g of product as a foam (1: 10 MHz, DMSO-d 6): δ 10.21 (s, 1H, COOH) (Bs, 1H, MH), 7.03 (d, J = 8.3, 1H Ar '), 6.63 (d, 3 = 1.9, 1H Ar'), 6.48 & 3.1 = 7.3, J1.1! (M, 6H &gt;, 0.7 # &lt; t, .delta. = 7.3, CH 2 QH 3)

Mass spectra were prepared according to the procedure described in Example 1, except that the solvent was evaporated under reduced pressure to give the title compound as a white solid. MS m / e 273: 244, 214, 198; acetic acid

A mixture consisting of hydroxy acid (8.0 g, 0.02%

) of Step B, dimethyl sulfoxide (500 ml). potassium iodide (100 mg) and sodium hydroxide (7.0 g in 30 ml of CH2 Cl2, 175 mmol) is stirred at room temperature for 15 minutes. 2-Chloromethylquinoline hydrochloride is added , 8 g, 0.055 mole), and the mixture is stirred at 70-80Â ° C for 3 hours. The mixture is cooled to room temperature and is poured into water (15 ml), made acidic ( The organic layers are combined, washed once with water (2.times.30 ml and once with brine (30 ml)), dried (Na2 SO4) and dried (Na2 SO4). dried with Na2 SO4, filtered and concentrated to afford 9.5 g of the crude product which is subjected to flash chromatography using 1% methanol / methylene chloride as eluent to give 3.5 g of the crude product which was dissolved in ethyl acetate (20 ml) and added dropwise to petroleum ether (50 ml). The precipitate is extracted by filtration to give 2.5 g of products mp 128-125 ° C. 1 H NMR (40%), DMSO-d6): δ 10.80 (bs, 1H, m), 8.37 &lt; d , J = 8.5, 1H, 4G), 8.0 (d, J = 8.5, 1H, 83), 7.98 (d, J = 8.2, 1H), 7.77 &lt; (d, J = 8.5, 1H), 7.61 (dt, J = 7.9 Hz, 1H) (D, J = 2, 1H, Ar = 6), 6.10 (1H, d, J = , 76.16 (d, 2H, CH3), 2.52 (bs, 2H). , 1.82-1.72 (m, 8HJ, 0.71 &lt; t, J = 7.3, 3H, CH2CH3). IR (KBDs 3410 cm -1 (NB, OH, broad), 1710 cm -1 (C = O) Mass% M4-41

Analysis for C 26 H 26 N 2 O 3

Calc'd C, 75.34; H, 6.32; N, 6.76; Found: C, 73.49; H,. 6.27; N, 6.48. fcKegiplo lv

1, 3,4,9-tetrahydro-1-propyl-6- (2-quinolinylmethoxy)

Pyrano [4,5-b] indole-1-acetic acid A, Ethoxy-1-propyl-1,3,4,9-tetrahydro-6- phenylmethoxy) oltrans-3-methyl ester of the title compound.

A solution of S-benzyloxytriptophos (4.72 g, 17 mmol) and butyryl lactone (3.16 g, 20 mmole) in methylene chloride (75 ml) is treated dropwise with boron trifluoride etherate &lt; 3 ml) and is stirred under nitrogen at room temperature overnight. The reaction mixture is diluted with methylene chloride (25 ml) and washed sequentially with 5% aqueous sodium bicarbonate (2 x 100 ml) water (2 x 50 ml). The organic phase is dried (MgSOâ, "), filtered and evaporated to give 7.0 g of a crude dark oil. Purification by flash column chromatography (ethyl acetate-hexane, eluent) on silica gel (reaction 50Â °) s), the title compound (5.5 g, 79%) yields the title compound (5.5 g, 79%) as an oil, a further homogeneous amber, -6-hydroxy-1H-pyrazol-3-yl) -phenyl] -benzoic acid methyl ester

A suspension of the 6-benzyloxypyranoindole (5.4 g, 13.25 mmol) from Step A of the 10% Pd / c catalyst (60 mg) in ethanol (150 ml) is hydrogenated for 6 hours on a Parr shaker. Filtration of the catalyst by evaporation of the solvent affords the title compound (C 3.75 g, 89%) as a homogeneous foam by TLC (1 H NMR (20 MHz), CDCl3: 8.90 Cbs , 1H, NH &gt;, 7.20 (d, J = 9.3

Hz? 1H, 8-ArB), 6.92 (d, J = 2.8 Hz, 1H, 7-ArH), 4.9 Î'(hs, 1H, OH), 3.85-4.40 (m, 4H, (m, 2H, 4-H), 2.57-2.88 (m, 2H), 3.85 (s, s &gt;, 1.82-2.20 (m, 2H, 1-CH3), 1.25 &lt; t, J = 7.1 Hz, 3H, ester

CHU), 1.00-1.60 (m, 2H, 1-CH, (f3)>, 0.87 (t, J = 7.0 Hz, 3H, 1-CHâ,,) 3-Aza-tetrazol-3-yl) -benzyl] -1,2,3,4-tetrahydro-1H-indazole.

A suspension of the 6-hydroxypyrrolindole (3.5 g, 11 mmol) from Step B in dimethylsulfoxide (8 ml) is treated with 2.5 M NaOH (20 ml, 50 mmol) and stirred at 4 ° C under nitrogen for 5 hours. minutes. 2-Chloromethylquinoline hydrochloride (4.71 g, 22 mmol) is added as a solid in an aliquot and the reaction mixture is heated to 8Â ° C for 30 minutes. After cooling, the reaction pH is adjusted to 12.0 with NaOH 2.51-4 = After extraction with ether &lt; 3 x 250 ml), the aqueous layer was carefully acidified (pH 3.0) with 2N HCl and 1N HCl (near the end point), (4 x 30 ml). The combined ether extracts are washed with water (2 x 250 ml), dried over Râ,,SOâ, "and filtered. Evaporation

of the solvent yields a crude yellow foam (4.16 g, 88%). Purification by flash column chromatography (methanol / methylene chloride / eluent 5 s 95> on silica gel (ratio 1 € &gt; > 230-400 mssh) affords a homogeneous amber (2.08 gs, 61%) foam by TLC. A solution of concentrated methylene chloride to cooled and rapidly stirred petroleum ether (200 ml) is added dropwise, , Filtration of the resulting precipitate affords the title compound as a amorphous cream (3.2 g, 61%) homogeneous by TLC. After drying under high vacuum (36 hours), the compound still retains some solvent from the crystallization, as indicated by RnN, m.p. IR (KBr): 3404 cm-1 (NH, OH), 1710 (C = O) cm-1. > 1 NMR (400 MHz, CDCl3) Î'8.93 (s, 1H, NH), 8.26 (d, J = 8.5 Hz, 1H, 4-B), 8.19 (d, , 3 = 8 Hz, 1H, 8-Q), 7.85 (d, 3 = 8.2 Hz, 1H, 5-Q), 7.81 (d, J = 8.5 Hz, (Dt, J = 7.0, 1.2 Hz, 1H, 7-8), 7.58 (T, J = 7.0 Hz, 1H, 6-Q> , 6.84 (d, J = 8.8 Hz, 1H, 8-ArH), 6.84 (d, J = 8.8 Hz, 2.4 Hz, 1H, 7-ArH), 5.49 (s, 2H, OCHCH2 Q) 4.03 (ddd, J = 11.4, 4.7, 4.3 Hz, Hsq.), 3.92 (ddd, J = 11.4, 7.2, 4.8 Hz, 1H), 3.56 (d, 4-Hax), 266 (ddd, Î'= 15.4, 4.7, 4.7 Hz, 1H, 4-Heq.), Î'91-2.14 &lt; m, 2H, 1 -CH. _s &lt; α &gt; ), Δ, 1.48 (m, 2H, 1-CH 2), 0.88 (t, J = 7.0 Hz, 3H, CH- 430 (1.4, M +>, 160 &lt; 50, QCH, OH, +3.143 (100, CHCl3 +).

For C 26 H 26 N 2 O 4

Calc'd C, 2.54; H, 6.09; M, 6.51, Found: C, 72.64; H, 7.52; N, 5.41.

Ad 1 c io ns-if, B g j ..... LT X met yls ylidid-3β-xA. .. no C ml, 1 νν'Υ 0 {|; (2-methyl-1-methyl-1,3,4,6,7,8-tetrahydronaphthyridin-2-yl) (1: 9) and the title compound as a white solid (0.8 g). (150 ml of methanol) and the balance of the reaction mixture is very difficult to obtain. The reaction mixture is stirred at room temperature for 1/2 to give 1.2 g of the oily residue, the residue is dissolved in dichloromethane The hydrochloric acid salt is from methanol / ether to yield 75.0 g of the pure compound, mp 185 DEG-185 DEG C., 1 H-NMR (DMSO-d 6): δ (CDCl 3): δ (CDCl 3) , 8.31 (2H, t, J = 8 Hz), 7.96 (1H, d, J = ts J-7 3 Hz? 1H); Ar), 4? 1 0! (d, J = 2.6), 4.43 (1H, m), 6.86 (1H, t, J = 7.0 Hz). ST. (1), (1), (1) and (2), (1), and (2) 7 Hz, 1H), 2.74 (t, J = 13, D Hz, 1H), 2.56 (m, 2H) , V (q, J = 7.4 Hz, J = 7.2 Hz, 3H, 1H), 2.56 &lt; m, 2H ), 1.93 (t, J = 7.4 Hz, 2H), 0.60 (t, J = 7, 1740 cm -1 CH2 Cl2).  € ƒâ € ƒâ € ƒIR (KBr): 34.03 cm -1, 320 Âμ cm -1 (NH, OH), â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ

Analysis for Ca leu lake? C, Found C, Π H 2 O 4 = H + 66.88; H, 5.83; N, 6.09; 66.58; H, 5.75; N, 5.96

indole

A mixture consisting of 5-benzyloxytryptoph I, 3, Ξ Θ, Θ 12 mole), acetone (7 ml), C3 -30 henzene) and p-toluoyl C50? ; m) and refluxed for 95 hours if a Dean-3tark siphon to remove Θ. The mixture is mixed with water. ΐ &quot; 'W. (1 x 2 ml), water (2 ml), and brine (200 ml) were added to the reaction mixture. The crude product was flash chromatographed with 15% ethyl acetate / hexane acetate as eluent to afford the title compound as a white solid. produce 2,

to, p u T 13.4 =; 9-yl-tetrahydro-1,1-dimethyl-6-hydroxy-pyrrole. 34- b Ϊ indole

(4.2 g, 0.04 mole) Liqc. &lt; 3Θ psi.) d u. r a n t 18 hor as o A

A mixture consisting of 10% Pd / C on vegetable carbon (0.7 g), ethanol (15 ml) and 1,3,4,9-Tetrahydro-1-1-dimethyl- 1-methoxy-1-pyran-3,4-b] indole and C4,

Step h is hydrogenated at 2.11 kg / cm 3 The reaction mixture is filtered and is cored to produce 3.5 g of product which is used in the following reaction without further purification =

W,

A mixture consisting of anhydrous potassium carbonate (6.8 g, 8.843 mole), potassium iodide (188 mg) and 2-chlorostilquinoiine (6.8 g, 8.843 mole) in dry dimethylformamide (100 ml) &lt; 2.9 g, 8.816 mol) is heated at 68 ° C for 24 hours. a temperature at which temperature is reached, is> diluted with water (888 æl) and washed with ethyl acetate (3 κ 158 ml). The organic layers were washed with 25 M MaOH, water (2 x 188 ml) and once with methylene chloride. (188 mmoles), and dried (with water). MgSO 4, are filtered and concentrated to afford 3.8 g of the crude product. The crude product is flash chromatographed on silica gel using 48% ethyl acetate / hexane as eluant to afford 2.3 g of the product, which is recrystallized from methanol to afford 1.69 g of the product. title compound, mp = 164-165 ° C. 1 H NMR (488 MHz, DMSO-dt) δ 1.61, 6B (s, 1 W K K U) 30 (d, J = 8, 6 Hz, 1H, J = 4), 8.8 (d, J = 8.4 Hz, 1H) 5Q) 7 7 = 77 <t5 J- = 7.1 Hz, 1H, 1 H-NMR (DMSO-d 6, d 6):? J = 2.4 Hz, 1H Ar), 6.82 (dd, 3, J = 8.6, 3, J = 2.4,

Ar), 5.34 (s, 2H, OCH3), 3.85 (KSr5 and 3418 cm -1) (broad NH),

Masses EI (e) 358 (rf-), 343 143

Anώ.x xss pciv ~ s. there"

Calculated C? 779Θ7; H, 6.19; N, 7.81 Found: C 76.76; H, 6.25; N, 7.70 *

1?, 5?, 4?, 9? -Tetrahydro-1,1-diazabicyclo [3.3.1] heptan-3-yl (phenylmethyl) pyran. 4-b3 indole

A subset consisting of S-benzyloxytriphenylTD 1 (0.02 g, 0.062 mole)? distil cetane (10 ml)? (4â € ¢ 5 ml of p-toluenesulfonic acid is refluxed for 3.5 hours using a Dean-Stark syringe to remove water. The mixture Vâ,,Oâ, ... S-Siâ "¢ XD ()) 0 L L L L L L L L sal sal gu sal sal sal sal sal sal sal sal sal sal sal sal sal sal sal sal sal sal sal sal sal sal sal sal sal sal sal sal sal sal sal sal sal sal sal sal sal sal sal i ο ϋ á á á á á. 1. The reaction mixture is cooled to 0 DEG C. The product is subjected to nitrogen addition to give the crude product as a white powder, The title compound was prepared as eluent to afford 6.5 g of the title compound as a white solid.

One of the most important things in Pd / c s V t? and Er 13.1 \ X ςΚ? y / ethanol 1125 ml) and 1,3,4,9-Tetramethylsilyloxy of 4 g, 5 g5%, 0.01% is hydrogenated. at 2, 11 kq / cm 2 and 50! psi) last for ο a. titan 5 ") .¾1 · · · · · C C W. W. W. W. W. W. W. W. W. W. W. W. W. W. W. W. W. W. W. W. W. W. W. W. W. W. W. W. W.. J. Exp. -. The reaction mixture is filtered and concentrated to give 5.2 g of product which is used in the same manner as described in Reaction Scheme # 2.

. κ- ^ en. W. 3,4,9-tetrahydro-1,1-diazyl-6- (2-quinolinyl) ethyl) pyran-C33,47b3where, 1, and

A mixture consisting of the compound 6-hydroxy (C5.2 g, 0.202 mole) of Step B, dimethyl sulfoxide (150 ml), sodium hydroxide (15 g,), 15 mol in 2 ml of water) and hydrochloride hydrochloride is heated at 70-80Â ° C for 6 hours. The reaction mixture is cooled to room temperature. The organic layers are washed once with water (2 x 15 ml) and once with ethyl acetate (3 x 15 ml). The organic layers are washed once with water (2 x 15 ml) brine (1 x 10 mm), dried over MgSO 4, filtered and concentrated to yield 9.9 g of the crude product. The crude product is flash chromatographed on silica gel using ethyl acetate / hexane as eluent to give 4.5 g of product as a thick oil. The precipitate is collected by filtration and the product is crystallized from methanol / ether to yield 2.6 g of product under nitrogen. form a yellow crystalline solid, m.p. 164-165Â ° C; 1 H NMR (400 MHz, DMSO-d6): Î'8.16 (1H, m), 8.7Â °

Q

Hz, 1H, 4Q), 8.21 (d, J = 8.5 Hz, 1H, 8Q), 8.13 (d, J = 8.1 Hz, 1H, 50), 7.95-7.88 , 2H, 3 and 70), 7.74 (t, J = 7.3 Hz, 1H, 6Q), 7.21 (d, J = 8.6 Hz, 1H Ar), 7.8 (d, J = 2) , 4 Hz, 1H Ar), 6.84 (dd, J1 = 8.7, J2 = 2.4 Hz, 1H Ar, 5.5 C, 2H, OCH3), 3.85 (t, J = = 5.3 Hz, 2H), 2.57 (t, J = 1.54 Hz, 2H), 1.8 (m, 4H, CH3 CH3, 1-diethyl),. 3 ~ 753 Hz, 6H, CH3 CH3, 1,1-diethyl). s 341 cm-1 CNH) Mass% EI &lt; m / e) 386 &lt; Μ + &gt; EXAMPLES 357, 216, 128, Calc'd for C 17 H 18 N 3 O 3. N, 6.62 Found: C, 71.2; H, 6.431; N, 6.66%

Example 16

A quarter of 1-t- (4-chlorophenyl) methyl-5-methyl-5- (2-quinolinylmethoxy) -1H-indole-5-acetic acid hydrochloride hydrate

One-tenth of 2-methyl-5- (2-quinolinyl)

A previously degassed mixture of dimethylformamide (76 ml) and a solution of sodium methoxide / methanol (25% by weight, 2 equivalents, 8.8 ml) is added 5-hydroxy-2-methyl-1H-indole-5-acetic acid (4.0 g, 19.5 mmol) at room temperature. After 15 minutes, 2-chloromethylquinoline (3.46 g, 19.5 mmol) is added and the mixture is stirred overnight. The dimethylformamids are evaporated and the mixture is partitioned between a buffer solution of pH 4 and The organic phase is dried over MgSOâ, ", filtered, and partially concentrated. The solid is filtered off and crystallized with ethanol-water. The title compound (2 , 96%) yield 44%, mp = 28-42Â ° C. Analysis for C21 H28 N2 O5

Calc'd C, 72.44; H, 5.26; N, 8.04.

Found: C, 72.29; H, 5.38; N, 7.93. B. 2-Methyl-5- [2-methyl- To a stirred mixture of the indole-acetic acid substrate (1.2 g, 3.4 mmol) in tetrahydrofuran (25 ml) is slowly added: a finished solution of prepare diacetone / diethyl ether at room temperature. After the starting material has been consumed, a few drops of acetic acid are added. The solvent is evaporated and the methylene chloride is added. the organic phase is washed with water. s is dried (MgSO4). Removal of the solvent affords the product as an oil (1

g). 1-C (4-chlorophenyl) methyl] -6-methyl-Î ± - (2-quinolylmethyl) -1H-indole-5-acetic acid methyl ester To a stirred mixture (0.8 g, 2.2 mmol) in dimethylformamide (15 ml) is added sodium hydride (0.058 g, 2.4 mmol). The reaction is stirred for 3 hours. # minutes at room temperature. 4-Chloro-benzylchloride (0.35 g, 2.2 mmol) is then added. After 2 hours the dimethylformamide is evaporated and the residue is partitioned using a buffer solution of pH 4 and ethyl acetate. The organic phase is separated, dried (MgSO 4) and filtered. Removal of the solvent affords a solid which is subjected to flash chromatography employing chloroform as the eluent and which is then crystallized from acetonitrile to afford the product as a crystalline solid &lt; 0.162 g, 16%), mp 132 DEG-144 DEG »

Analysis for ΟΗΗ^^ΟΟΟΟΙΟΙΟΙΟΙΟΙΟΙΟΙΟΙΟΙΟΙΟΙΟΙΟΙΟΙΟΙΟΙΟΙΟΙΟΙΟΙΟΙΟΙΟΙΟΙΟΙΟΙΟΙΟΙΟΙΟΙΟΙΟΙ. 5, 5, 5, 7, 8, 10, 12, 12,

Found: C, 71.48; H, 5.17; N, 5.88; D, one quarter of 1-C (4-chloro-4-methoxyethoxy) -1H-indol- 3-acetic acid The above ester &lt; 2.2 g, 4.5 mmol) is combined with tetrahydrofuran (50 ml) and 1W NaOH solution &lt; 5 ml) a is heated to reflux &lt; The tetrahydrofuran is removed in vacuo and the aqueous phase is acidified with 1N HCl. The crude solid is filtered and recrystallized to yield 1.16 g of product as the hydrochloride salt (yield 58%), mp 249-251 ° C =

Analysis oara; C 19 H 19 ClNO 2 O 3 CH 2 -1H 4 O, Calc'd C, 65.69; H, 4.82; N, 5.47 = Found C, 65.64; H, 4 = 92; N, 5.41 = όχοπιρίο 17

Three quarts of 1- (4-chlorobenzoyl) -2-methyl-5- (2-quinolinyl) imidazolyl) -1H-indol-3-acetic acid A- To a solution of 2-methyl-5-methoxy-1-methoxy-1H-indole-5-acetic acid methyl ester 2-quinolinylmethoxy) -1H-indole-3-acetic acid (0.95 g, 2.6 mmol) (see Example 16B) in dimethylformamide (18 ml) at 0 ° C is added sodium hydrate (¢, 12 g, 50% dispersion) and the mixture is stirred for 2 minutes. 4-Chlorobenzyl chloride (¢, 45 g, 2.6 mmol) is then added and the mixture is stirred overnight. 1% 5% acetic acid is used to temper the reaction. After extraction with a mixture Of ethyl acetate, the organic phase is washed with water, saturated NaHCO 3 solution with water and brine, then is separated and dried (H 2 O 3). Removal of the solvent yields a crude solid which is subjected to Flash chromatography by the use of methylene chloride-methanol (99-1) as eluant. The product is isolated and is crystallized from acetonitrile (10.4 g, p = 1; 15%.

Analysis for C 69 69H₂ΟNΘOΘ: C, 69.55; H, 4.66; N, 5.59. Found: C, 69.35; H, 4.48; N, 5.56.

tilde

B. Trgs quarts of Î ± - [4 - [[[[[(4-methylphenyl) -2-

: Θ3 y y y y y y55 s s s s s s s s · · · · · · · · BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er er: er::::::::::: n; (I) mixture. Sr, s is washed with a solution of NaHCO 3, which is cooled to 0 DEG C. A mixture of the ester &lt; RTI ID = 0.0 &gt; acetonitrile (2 ml). a d i c i d n -a-se q 3 2 p 2 sTiTiC Iss) = A re fl ected by &gt;. diluted with ethyl acetate and water (10%), which is &amp; &gt;; brought by τι. and which is dried in vacuo to give the title compound as a solid (0.15 g) as a white powder (0.05 mol). 1 Í. S8 Γ; Λ Γ; H-NMR (DMSO-d6):? Calculated c. 67: 4755 N = 4 H 53 s N? -5? 2? Found? 67., 68 pSi 2 i st 4 p 22 j N 3 5 94 t -KainpiQ 2-methyl-5- (2-quinolinyl) methoxy-1,2-thienyl] methyl-1 H -indole-3-acetic acid ethyl ester. . &quot; Ί. &quot; &quot; W &quot; / y 2 nm 1 in) d imeti 1 for ma mi. The title compound was prepared according to the procedure described in Example 1, starting from (4-methoxyphenyl) -1- (4-methoxyphenyl) tj 7 ò iTiiTIO 1 © * s \? The end of one hour after the addition of 2-chloro-thiophene in C 3 s 44 g 5 19 Λ OM This is due to the fact that it has a long-term impact on the environment, and that it has a significant impact on the environment. tj. The organic extract is dried over MgSO4 and evaporated to dryness. The organic extracts are dried over MgSO4 and evaporated to dryness. The organic extracts are dried over MgSO4 and evaporated to dryness. With ethanol and hot ethanol from ethanol. (52%) of a compound of formula (5), mp 198 DEG-200 DEG C.

gn, Li, at 5 ° C,

Calc'd C, 76.37; H, 5.17; N, 3.62. Found: C, 72.71; H, 5.24; N, 8.74.

Example 19 1-C <4-chlorophenyl) methoxy] -5- (hexyl) -2-methyl-1H-indole-5-acetic acid A - 5- (H) -Hydroic acid (i) -2'- To a solution of 3-hydroxy-2-methyl-1H-indol-3-acetic acid &lt; 7.17 g, 35.0 mmol) in methanol (40 ml) The solution is evaporated, dimethylformamide (40 ml) and then hexane iodide (35.3 mmol) is added. After 2 days the solvent is evaporated to dryness. The residue is partitioned between ethyl acetate and pH = 4 buffer. The organic layer is separated, dried over MgSO4 and evaporated to give 8.6 g of a brown solid. Recrystallization from ethanol / water produces 6.23 g (62%) of white crystals, mp = 65-67 ° C.

Anal. Calc'd for C 20 H 18 N 3 O 4 • • • • • • • • • • • • • • • • • • •

Found: C, 73.52; H, 7.935; N, 4.83; N, 4.31 (s, 3H) A is converted to the methyl ester &lt; p »148 148 &gt; (see Example 16B). To a solution of the ester (4.5 g, 14.83 mmol) in dimethylformamide (40 ml) is added sodium hydride (1.42 g , 29.6 mmol). After 30 minutes, 4-chlorobenzylchloride (2.38 g, 14.83

Carboxylic acid is prepared in the presence of crystals (36%). from ether and isopropanol yields, 148-150 °.

Analysis for C 20 H 15 ClN 2 O 2: 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 82 5 N, 3 388 found to C 7 0 0 3ΘΘΘΘΘΘ H H H H H H H H H H H H H H H H H H H H H H H H H H C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C

2-methyl-5-methyl-2-quinolinecarboxylic acid ethyl ester; i xni. 1 ifte Lxl) -ΐΗ-ιπϋυ 1 s ~

In one case, QS was Q S Θ. The title compound was prepared from the title compound as a white solid, mp 228-221øC. 1 H NMR (CDCl3): .delta. 1A (10) - (5) - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - The reaction mixture was stirred at ambient temperature for several hours. The mixture is stirred at 0Â ° C for 1 hour and then the mixture is stirred at 0Â ° C for 1 hour. (which has been shown to be from L-L-1) is Sd-S and hot. u i x i trsuo proauz o produjo desj <3do / 0 q. V / v. / Sub a. The composition of the present invention relates to a process for the preparation of a lithium aluminum silicate. 1.1. and R 2 is hydrogen. et al. g? P. mp 162 DEG-163 DEG C. The recrystallant yields the pure product &lt; δ 42

Hi.......... i ad o C. 76.363% H 3.43 to 3 N 3 83 30 Found C 76.205 H 3 5 3 59: 5 N, 83 11.

Scxemglo 21

G-methyl-2- (2-quinolyl) imino] -9- (2-chiriolyl) phytol-9H-carbazole-2-acetic acid A. 4-Tetrahydroxyphenylhydrazine hydrochloride

A solution of sodium nitrite (3.86 g, 0.055 mol) in 20 ml of H₂O was added dropwise to a stirred, ice-cooled suspension of 4-benzyloxyaniline (13.0 g, , Θ55 moles in 15 ml of concentrated HCl) The reaction mixture is stirred for 90 minutes at a temperature between -B and + ° C A solution of SnCl3 -ZH3 O (32 g, 0.14-2 mol in 50 ml of concentrated HCl) is added stirred for 1 hour at 6Â ° C. The reaction mixture is taken from the ice cube and stirred at room temperature for 2 hours. The mixture is then filtered and washed with water to afford 135.4 g (95% yield) of product, mp 182-185Â ° C. B: Calculated: Calc'd: Calc'd: Calc'd: Calc'd: Calc'd: Calc'd: Calc'd: Calc'd: , 3,4-tetrahydrocarbazole-2-acetic acid

A mixture containing 4-fluoro-3-methylphenylhydrazine hydrochloride (37.0 g, 0.148 mole), and acetic acid of -3-OKDcycl SDHane (40.0 g, 0.235 mole), glacial acetic acid (100 ml) is stirred at room temperature under a nitrogen atmosphere for 2.5 hours. The mixture is then refluxed for 2 minutes, cooled and poured into ice / H2 O, the precipitate is filtered to give 8 g of a red crude product. The crude product is dissolved in ether (60 ml), concentrated H 2 SO 4 (5 ml) is added and the mixture is refluxed for 24 hours. The reaction mixture is cooled, and the reaction mixture is cooled. &gt;. x &gt; ', ι. and concentrated in vacuo to give the title compound as a white solid.

NaDH IN <2 x 2> ml), water <2 κ2 @@ mI> and finally again with brine (2 x 10 ml), is dried over anhydrous magnesium, filtered and concentrated to give 4 g of crude product as a thick oil. ... Ethyl................... of 6-benzoylmethylglycerol

A mixture consisting of γ-benzenyl-Î ± -methyl-1,2,3,4-tetrahydrocarbazone-2-acetic acid ethyl ester &lt; 15.0 g, 0.03 mole) in xylene (50 ml) and chloranil (10.0 g, 4. 4 mole) is refluxed in the dark under a nitrogen atmosphere for 24 hours. The reaction mixture is concentrated to 2 ml and the precipitate is removed by filtration. The precipitate is triturated with benzene (3 x 1 ml), the solvent fractions are combined and washed with NaOH (3 X 1.5 ml ), washed with water until the pH becomes neutral, dried over MgSOâ, ", filtered and concentrated to give 15.8 g of crude product. The crude product is flash chromatographed on silica gel employing # 15% ethyl acetate / hexane as eluent to afford 7.5 g of product as a white oil. 6-Hydroxy-1-methylcarbazole-2-acetic acid ethyl ester

A mixture consisting of Î ± -benzyl 5β-methylcarbazole-2-acetic acid ethyl ester (7.3 g, 195 mmol) and ethanol (13 ml) is hydrogenated over Pd / ca 1% (?, 9 g) for 18 hours at 35 psi (2.66 kg / cm 2). The reaction mixture is filtered and concentrated to afford 5.0 g of product as a foam.

A mixture consisting of the ester. : ι ································· CS3® solica-2-acetic acid. gt; 021 mole), hydr. Dt. (10.0 g, 0.089 mole) nifephanol &lt; 3.0 ml) and water (2 ml)

ml) is subjected to the reaction for 15 hours. The reaction mixture is cooled to &lt; RTI ID = 0.0 &gt; B as a solution. SAW* . AU 1s1 ds HC1 concentrate atio and water ρ ara. pH 1 = The bed of the aqueous Φ, extracted with ether &lt; (1 g) of the title compound as a white solid. The title compound was prepared according to the procedure described in Example 1. The filtrate was concentrated to yield 2.6 g of the product as a white foam: α-Methylquinolinylmethyl) -9H-1α- c * · £ Ο X 6 * '-' Τ '* - rs tL · ->

A mixture consisting of? 1 d r 6 κ i &quot; O. - 1 and t x i. -carbamic acid tert.-butyl ester as a white solid (0.25 g). H 2, r! R 5 x 50 D 5o XO -L. 0.1 g in 20 ml of CH2 Cl2, 0.05 mol) in 2 ml of water. yl] pyrimidine. The reaction mixture was stirred at reflux for 1 hour. 1, 2, 3, 4). tea 80 ° P t uu rt ss u rs u ft mi s of Γ 'SB.C /' • ca. the temperature of the furnace is 5 ° C. in the DU. (100 ml) and the pH was adjusted to 4 with 1N HCl. The residue was extracted with ethyl acetate (4 x λ 100 ml) and the organic layers (3Θ m1,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, using 10% methanol / methylene chloride as eluent to give 8 g of product, mp 197-199 ° C.

An is. The title compound was prepared from the title compound as a white solid (0.25 g). • • • • • • • • • • • • • • • • • • • • • • • • • • ? 1, 2, 3, 4, 5 and 15,

(4-chlorophenyl) methyl 3-2-methyl-N-Chydroxy) -5- (2-quinolylmethoxy) -1H-indol-3-acetamide To a solution of N, N-methylhydroxylamine hydrochloride &lt; 0.35 g, 42.41 mmol) and benzyltriazol-1-yl KY-tris &lt; Dimethylamino &gt; -phosphonium hexafluorophosphate &lt; 188 g, θ, 42 mmol) in methylene chloride (5 ml), triethylamine (12 ml, 2 ml) is added. The reaction mixture is stirred overnight and then cooled. seasoned by addition of brine. After sequential washing with water with 5N HCl and water, the organic layer is dried over NaHSO 4 and evaporated to give a crude solid, which upon recrystallization (twice) with chloroform gives a crystalline solid, mp 192 DEG- 194 ° C. This material is washed sequentially with 0.5N NaOH and water to yield white crystals, m.p. 191-193 ° C. Analysis for C 20 H 13 N 3 O 3 úH 2 O

Calculated! C, 07.81; H, 5.39; N, 8518 »

Found: C, 67.87; H, 5.11; N, B, 39.

Example 23 1- (4-Chlorophenyl) methyl-2-methyl-N- (phenylsulfonyl) -5- (2-quinolinyl) methoxy) -1H-indole-3-acetamide To a solution of the acid of Example 1 ; Benzenesulfonamide &lt; 0.34 g, 2.12 mmol) and benzotriazole-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (δ, 94 g, 2.12 mmol) 12 mmol) in methylene chloride (25 ml) is added triethylamine <0.6 ml, 2 equiv). The reaction mixture is stirred overnight and then quenched by addition of brine. After sequential washing with water, 1N HCl and water, the organic layer is dried over MgSOâ, "and evaporated to give a solid &quot; , Which after recrystallization from toluene yields a crystalline solid, mp = 94-97 ° C =

Calc'd for C 34 H 21 ClN 3 O 4 S Calc'd: C, 6659.3; H, 14.605; N, 6.89.

Found: C = 67.06, H, 4.16, 66.4,

Example 24

(4-Fluorophenyl) methyl] -2-methyl-5- (2-quinolinyl) isoquinoline-1 H -indole-3-acetic acid hydrazide The title compound is prepared according to the method of Example 16 using 4-fluorobenzyl bromide. A crystalline solid is obtained. mp 199-2Â ° C. = C =

Anal. Calc'd for C 28 H 23 FN 2 O 3 • 1 / 2H 2 •

Calc'd C * 72.55p H? 5 = 21p N, 6.4.

Found: C, 72.84; H, 5.31; N, 5.68;

Example 25

1-C (4-bromophenyl) ethyl] -2-methoxy-1H-indole-5-acetic acid The title compound is prepared according to the method of Example 16 using 4-bromobenyl bromide A crystalline solid is obtained, mp 215 DEG-217 DEG C. =

Analysis for C 28 H 23 BrN 2 O 3 • 1 / 2H 2 O Calc'd C 4.0 = 12.4 H 4.64 N Found: C, 64.44; N, 5.40.

The title compound is prepared according to the method of the procedure described in Example 1, except that the title compound is prepared according to the method of the procedure described above. Example 16 Using bensyl bromide A crystalline solid is obtained. I99-202 ° C.

For 1 H 2 O

Calc'd C, 76.72; H, 5.56, N *

Found: C * 76 * 3β; Δ, 5.37? M, 6.34 =

The title compound is prepared according to the method of Example 1 by employing the title compound as a white crystalline solid, mp 218 DEG- 4-Cyclooctyl) -nicotinic acid ... A crystalline solid is obtained. mp 232-234 ° C.

Anal. Calcd. For C29 H24 N2 O5

Cajc-Mlados C, 72.49; Η, 5, Θ 3; N, 5.83.

Found: C, 72.44; H, 5.18; N, 5.98.

Example 28

The title compound is prepared according to the method described in Example 1, except that the title compound is prepared according to the method described in Example 1 and the title compound is prepared according to the method of Example 1.6 using 4- (2-quinolinyl) methoxy &gt; benzoyl chloride. A crystalline solid is obtained, mp 182-185 ° C.

Analysis for 1 / 2H20

Calculated C, 75.73; H, 5.35; N, 6.97 =

Found: C, 75.41; H, 5.33; N, 6.78.

Example 29

2-methyl-1-pentyl-5- (2-quinolinylphlethoxy) -1H-indole-5-acetic acid hemihydrate The title compound is prepared according to the method of Example 16 using pentyl iodide. a crystalline solid is obtained, q = 9-9 ° C.

Analysis for 1 / 2H-O

Calc'd C, 73.38; H, 8.61; N, 6.58.

Found: C, 73.37; B, 7.11; N, 6.41 =

Example 5

Three quarts of 1-hexylethyl-2-methyl-5- (2-quinolinylmethoxy) -1H-indole-3-acetic acid hydrate The title compound is prepared according to the method of Example 16 using hexyl iodide. A crystalline solid is obtained, mp = 122-124Â ° C.

Analysis for; * 3/4 H 2 O

Calculated C, 73.03; H, 7.15; N, 6.30 =

Found: C, 73.25; H, 7.1; N, 6.3.

The title compound is prepared according to the method of Example 16 by the use of the compound of formula (I) in which the title compound is prepared according to the method of Example 16, using the title compound as a white solid. heptyl iodide = A solution of

crystalline solid, m.p. 12-131 ° C, crystalline, mp C28 H32 N2 O3: C, 75.65; Δ, 7.26; N, 6.30.

Found: C, 75.80; H, 7.19; N, 6.26 =

EXAMPLE 32 1-Methyl-2-methyl-5- (2-quinolinyl) -1H-indole-3-acetic acid The title compound is prepared according to the method of Example 16 using methyl iodide. A crystalline solid is obtained, mp 168 DEG -18 DEG.

Analysis for C₂ HH N ^N₂O-,

Calcd. C, 73.32; H, 5.59; N, 7.77 =

Found: C, 73.33; H, 5.68; N, 7.57 =

The title compound is prepared according to the method of Example 16 using 5- (4-chlorophenyl) methyl-5- (2-quinolinylmethyl) -1H-indole- -1H-indole-3-acetic acid The desired product is obtained in the form of white crystals, m.p. = 58-95 ° C = AOa to give the title compound as a white crystalline solid. M = -, O-

Calc'd C, 76.97; H, 4.63; N, 6.13 = Found C, 71.13; H, 4.67; N, 6, Θ 3 =

The title compound is prepared according to the method of Example 16 using 2- (bromomethyl) naphthalene. A 168-I700 is obtained! crystalline solid, p "f

In-T f k ** ij ^ j · bi Çi-β.Γβ £ 24

Cl, N-L, &lt; RTI ID = 0.0 &gt; ICL1 &lt; / RTI &gt; w or 1 · IJ | 1 | H S | Found: C, 74.43; H, 5.315; . -ij * 7 Λ / &quot; Ta

b.KgfflPlO 3S

1-Methyl-5- (2-phenylmethoxy) -1H-indole-3-acetic acid The title compound is prepared according to the method of Example 1 ò S π J f * £ 5 € | 3 ' The title compound was prepared from the title compound as a colorless oil, mp 148 DEG-141 DEG C. Analysis for C 19 H 31 N 3 O requires C, 71.51; H, 5.285; Found: C, 71.54; H, 5.29; H, 6.4;

U.S.A.

The title compound is prepared according to the method of formula (4-chloroethyl) pyrrolo [2,1-a] [1,4] benzodiazepine-4-carboxylic acid The title compound was prepared as white crystalline solid.

Annals of parag • Ν

Calculated C, 68.49 = δ, 5 ', 3' S, 6.66 =

N, 6.69 Found: C, 68.61; H, 5.12; N, 6.39.

Example 37 Acid 1-1 &lt; 4-chlorophenyl) methyl] -2-methyl-5- (2-benzothiazolylmethoxy) -1H-indole-3-acetic acid To 2-methyl- To a mixture of 5-hydroxy-2-methyl-1H-indole-5-acetic acid ethyl ester (5.6 g, 17.15 mol) in dichloromethane ) and cesium carbonate (15.0 g, 46.4 mmol) in dry dimethylsiloxane (7 ml), which had been stirred for 3 minutes, was added 2-chloromethyl) benzoic acid (4.6 g, 8 mmol). After 1 hour the reaction was poured into ice-water and extracted with ethyl acetate. The organic layer was washed sequentially with 0.1 N NaOH water and brine, dried over ice and evaporated to give a black oil which was evaporated to dryness. purified by flash chromatography (eluents ethyl acetate-hexane) to give 5.4 g (59%) of the alkylated ester. (4-chlorophenyl) ethyl] -2-methyl-1 H -imidazo [1,2-b]

The title compound is prepared according to the method of Example 16 using 2-methyl-5- (2-benzyloxyphenylmethoxy) ethyl ester. However, the hydrolysis is carried out in aqueous methanol. Recrystallization from acetonitrile yields crystals never more than 175-176Â ° C. =

The title compound is prepared according to the method of Example 4- (4-chloromethyl) -2-phenylaminoacetamide.

White crystals, mp 150 DEG-150 DEG C.

Analyze the CH3 -

Calc'd C, 66.86; H, 4.61; N, 5.57. Found: C, 66.46; 4: 59: N, 5.59,

Example 59

4-Trifluoromethyl-phenyl) -4-thiazolyl-3-methyl-1H-indole-5-acetic acid The title compound is prepared was prepared according to the method of Example 37 to give 4-chloromethyl-C (4-trifluoromethyl) -2-

An S. 5 5. H-O 3. Γ Γ Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η. (I.e.

The title compound is prepared. The title compound is prepared according to the procedure described in Example 1. The title compound is prepared according to the procedure described in Example 1. The title compound is prepared as a white solid (0.25 g). according to the method of Example 37 using 4-chloromethoxy) -2-phenyl-1-thiacole and benzyl chloride. White crystals are obtained from toluene, mp 150 DEG-150 DEG C. =

Ané. 1 for LWH.

Calculated C, 71.77; H, 5.16; N, 5.98.

Found: C, 71.53; H, 5.04; N, 559.

Example 41 2-Methyl-5- (β-quinolinylacetoxy) -1- [14- (2-quinolinylmethoxy) phenyl] methylene] -1H-indene-3-acetic acid Acid, 2-methyl-5- (2-quinolinylmethoxy) -1H-imidazol-3-yl) ethanone

A mixture of 2-methyl-5-hydroxy-1H-indene-3-acetic acid methyl ester (0.8 g, 8.25 mmol), potassium carbonate anhydrous powder (1.13 g, 8.25 ) and 18-crown-6 (0.219 g) in acetonitrile (21 ml) is stirred at room temperature for 15 minutes. 2-chloromethylquinoline (1.6 g, 9.8 mmol) is added and the mixture is stirred for 15 hours at 65 DEG C. After the solvent has been removed, the residue is partitioned between water and ethyl acetate, A The organic phase is dried. (MgSOâ, ") and evaporated, the crude product is purified by flash chromatography (eluents methyl ethyl acetate-ethyl acetate) to give 2.35 g (79%) of the desired product,

Β = 2-methyl-Î ± -α-β-Î ± -hexanoic acid; -? 1 - C14 - &lt; To a solution of the above ester &lt; 1.77 g, 4.93 mmol) in anhydrous methanol (2 ml) was added sodium bicarbonate ) is added 4-E (2-quinolinyl-methoxyl-benzaldehyde &lt; 1.63 g, 6.19 mmol), which is followed by dropwise addition of 25% methanolic sodium methoxide (3.46 ml) After the reaction mixture was refluxed for 1 hour, for 13 hours, the solvent is removed and water is added. The pH is adjusted to 6.5 and the resulting precipitate is extracted sequentially with methylene chloride and ethyl acetate. The combined extracts are dried over MgSO4 and evaporated to give a crude solid which is triturated with diethyl ether and then redissolved in hot ethyl acetate. After the insolubles have been removed by filtration, the solution is concentrated until precipitation begins. The precipitate is filtered, washed with diethyl ether and hexane and dried to give 1.31 g (45%) of the desired product as a Z / E (7.6 / 1) mixture, mp 191-193 ° C (dec. ). "Shall we?" C3 &lt;? H30N2O4

Anal. Calc'd: C, 79.30; H, 5.12; N, 4.74.

Found: C, 79.11; H, 5.40; N, 4.59.

Example 42 M-CCl-R <4-C1-propyl) -2-methyl-5- (2-quinolinylmethyloxy) -1H-indole-1-ylmethyl] -4- -Hydroxyurea To a solution of the acid of Example 16 (0.3 g, 1.52 mmol) in H 2 O (25 mL) is added triethylamine (23 mL, 1.1 mL, 1.1 equiv), which is followed by diphenylphosphoryl azide (46.6 g, 1.0 equiv). After heating the reaction mixture at 9Â ° C for 1 hour, a solution of hydroxylamine hydrochloride water (a) in a mixture of triethylamine (& 4 A ml) and (iii) and this resulting flash mixture is stirred at 90 ° C overnight, the reaction is quenched by addition of a solution of ammonium chloride and the precipitate is filtered off. 1 of the filtrate, washed with ethyl acetate, tl 11D &amp; And dry to yield ij. (59%) of a white solid: mp 134 DEG-130 DEG C. = c. n c on c r a d o; Î'-4, Î ± -cyclohexanecarboxylate; N, 11 IP. 1 H NMR (DMSO-d6):? I just

The C DIB's are acid 5 &quot; b 12-hydro &lt; 5-HETE and 12-HETE) and LBT, are the initial products of arachidonic acid in ca. sc a d a. of the lipoxigenase 5 LÀS of D; 1, 3, 4, 5, 6, 7, 8, 8, 9, 10, 11, 13, 13), which is also referred to as LTt-Me-Med, * which have been shown to mediate the various aspects of the 5 -12-diHETE, which refers to Ford-Hitchinson's? J- Roy, Soc,

Compounds which inhibit arachidonic liberation are prevented by the following steps: In the present invention, the activity specificity of the PLA0 inhibitors can be determined by the activity of the test compounds in this assay which determines the ability of the compounds in inhibiting the synthesis of LTB2 produced by the polymorphic leukocytes in the phonuclear (PHM) produced by the substrate of the skunk, in the following manner polyvinylphonuclear leukocytes from CPnN) rats are obtained from female Wistar rats (159 -209 g &gt; which receive a Î ± 2% glycogen injection (10 ml). The rats are sacrificed 18-24 hours post-injection by asphyxiation with CQ.s and the cells produced are harvested by washing (9.9% MaCl) = The exudate is centrifuged at 499 g for 10 minutes. The supernatant fluid is discarded at the cellular pellet and resuspended to give the desired product. concentration of 2.9 x 1 €> cells / ml and HBsAg containing Ca and Mg and 1 μg L-cysteine. To 1 ml aliquots of the cell suspension are added the test drugs or vehicle, and then those are incubated at 37 ° C for 19 minutes. A23187 (1 μΜ, Γ "ΠΑΑ Π C3.0 pCi / ml) and unreferenced AA Μ μΜ) are then added and the samples are incubated for another 19 minutes. The reaction is terminated by centrifugation and by pelletizing the cells. The supernatants are then analyzed by HPLC analysis on a 15 cm x 4.6 mm column of supelcosyl ID LC-18 (Supelco) (3H) using a system of two solvents at a flow rate of 1.4 m 3 of total flow, as follows

Solvent The 79: 39 of 17.4 mM H₂O ^SCH₂CN +

Gradients (the system is equilibrated with solvent A).

Time Percent Percenta; 9 100 0 15 5 9 10Θ 9 29 9 9 65 35 40.9 65 35 42.9 10 90 50.0 10 99 59.1 100 0

Injections 14 €> μ1 of each supernatant are injected DS ms * t. 1, 2, 3, 4, 5, 6, 7, 7, 8, 9, 10, 10, 10, 10, 10, 10, and 10 are defined as follows: : · directa directa · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · by. Radiocompetent use of online radios CRamone F a i r 'f 1 e 1 d a NJ 5 =

Standards 10 £ |. "2, €? &gt; 10 μg of eicosanide in a single dose of 10 μl of a Hcocktail U. EtOH; (Li 4 B 4) * 5 * standard. A medium of F 1 M if TiO 2. 1 and exposed to the drug / drug compared to that found in a medium of the drug. not yours i tac us

a / ρí.ji ". ts: r &gt; In order to reduce the amount of inhibition,

The results are set forth as the percussion of the X-ray for a given dose of LU. i n th e o f th e s. as an IC 50 value. The compounds of the present invention provided the following results in this experiment: Example 1: Carprofen -10 * (a.u.) etodolac 21 &lt; tb &gt; â Θ r, 5μΜ) indomethacin 31Â ° C to 10μΜ) sulindac-Î'0 &quot; Ι ΙΘ ΙΘ ΙΘ ΙΘ ΙΘ ΙΘ ΙΘ ΙΘ ΙΘ ΙΘ ΙΘ ΙΘ ΙΘ ΙΘ £ £ £ £ £ £ £ £ £ £ £ £ £ £ £ £ £ £ £ £ £ £ £ £ £ £ £ £ £ £ £ £ £ £ £ £ £ £ £ £ £ £ £ £ £ (At 10μΜ) 16 96 ta ΙΘμΜ) 160 82 Ca 0.5μΜ) 17 46 ta 0.5μη) 17A 96 Ca 10UI1) 18 BB 0,5 0.5μΜ) 20 92 Ca 10μΜ) 21 92 ta ΙΘμΜ) 24 97 Ca ΙΘμΜ ) 93 Ca 10μΜ &gt; 26 as C at 10μΜ5 29 88 (a ΙΘμΜ) 30 90 Ca ΙΘμΜ) 31 85 1 1 ΘμΜ-> 41 100 Ca ΙΘμΜ) a negative value means potentiation »

The process of Example 43 is also employed in the determination of the extent of. inhibiting the synthesis of the PGE.- product from the oxidation of the arachidonic acid eeloeloxygenase provided by the compounds of the present invention

In this assay, the process of Example 43 is carried out as previously described. However, in order to determine 101 ->

-ϊ ^ &quot;

; .-ίΟ.Ο &gt; - cyclosporinase activity, the samples are co-chromatographed with the authentic reference C '&quot; H1-PGE &quot;

The results are calculated in the same manner as in Example 43 and are followed

Quadrundo II

Compound of Exemola NQ% inhibition carprofen 83 Ca ΙθμΜ) etadolac 100 (3. 0.5μΜ) indomethacin 23 (a ΙθμΜ) sulindac 100 (a ΙθμΜ) 1 23 Ca ΙβμΜ) 2 92 < at 1 μg &gt; 4 7 Ca 0 5 5μΗ) S 47 10 10μΜ) 9 75 * Ca ΙθμΜ) 1Θ -41 "'Ca 1ΘμΜ) 11 80 * C at 10μΜ) 14 -48 * Ca ΙθμΜ) 16 I Ca ΙθμΜ) Í6C Ca 0" 5μΜ &gt; 17 60 Ca 0.5μΜ) 17A 50 * Ι ΙθμΜ) IS -31 * Ca 035u.M5 20 * Ca ΙθμΜ) 21 -94 * Ca ΙθμΜ) 24 -126: Ca 10uM) 25 -67 * Ca 10μΜ &gt; 26 -125 ;: Ca ΙθμΜ) 29 -123 * Ca ΙθμΜ) 3Θ -13 ©: Ca 10uM) 31 -145: <a ΙθμΜ) 41 -21 * Ca ΙθμΜ) a negative value means a potentiation of the cyclooxygenase ßsynthesis of PGE .7,) =

The compositions of Hâ,,Sâ,,â, are present in the presence of a compound of the formula: â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ. A The CD-ROM of the CD-ROMs of the CD-ROMs of the CD-ROM is shown in Fig. w ιαο a raquidóni .CD by me da. Z a Π ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ. This test is shown in the following manner. To an ilen tube of 15; ml? adds Substances

V

I saw you, al. * Gèàc · Fine ·? 1 H-NMR (DMSO-d6):? Î »RT. -and Tris-HCl &lt; 0.5M) pH 7.5 &lt; RTI ID = 0.0 &gt; 501 &lt; / RTI &gt; 50 mH F'LA "25 volurne which produced) hydrolysis at 10 * .... , -. pre-incubating the Lemperaoura 1ΘΘ for 3 minutes after addition of the substrate,

Prepared pHr 1 * B & 2 οι 1 ι S. Q ώ ώ ώ ώ 3. 3. 3. 3. 3. 3. H 2 O: H 2 O: s x q n a d o by E =. In one embodiment of the invention, the compound of formula (I) i3. designated as the substrate material. (upper counts) 5 ρβ · ·, and a total having 10W sTi τη the 1-phosphorylipid) is obtained. year for s if lIviuseís qd sniura,

Tr isoa-Base ® "ts m Btock" fissa-BC-i D ffi Ο ρΗ was adjusted for the enzyme> ! Deionized and distilled water. 10 mH Stock Reserved for I τ ò κ i a o d dim tilo »| ~ 0 | _f. 0. The reaction was carried out for 1 sec. dimethylethylenediamine, and the like. A test tube of € 1 &gt; &gt; μ 1a

(A) Semi-purified human acid extract (in 10æl of sodium acetate buffer, pH 4.5) = Protein precipitate was removed by centrifugation at about 22ΘΘ rpm for 1 minutes. (H) Synavial fluid human being purified »

Incubate the 1Âμ® of the rescue mixture for 10 minutes at 37 ° C in a shaking water bath. The reaction is quenched by addition of 2 ml of tetrahydrofuran followed by vortexing. 10Âμg / ml-Analytichem International) with 0.5 ml of tetrahydrofuran followed by 0.5 ml of tetrahydrofuran / water (2 ml), the sample is introduced into the columns and extracted slowly 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 quantitated by β-count analysis. Prepare A sample of &quot; total counts &quot; is added by addition of a 25 Âμl pipette of &quot; H-arachidonate &quot; directly into a scintillation vial, to which 1 ml of tetrahydrofuran is added. 1 ml of aquasol (cocktail dextilation) o) to all samples »Cáleuloss L3HjAA apm (sample)% hydrolysis = ------------- total counts dpm

ve i c u. 1 q d pui medicament dom d s v a r i s a veicu □ pm (μΜ)

Pl_H OO &amp; **

Meei iuame · &gt; you look good

Human Synovial Acid Acids Mortality to 0 = 0 · - * 3. 0 * 14 make up

When tested in this way, the compounds of the present invention provided the following compounds: E &gt; emo 1 ϋ_N9 sund 5.1 ac i n d oirs taci na 1

1 to 18 2 ^ 24 • ~ ••••••••••••••••••••••••••••••••••••••••••••••••••••••••• " 1 Qun

mP 46 -

HSF '38 (at 59μ 48) 48 58 -μ-} 04 5ò AO 46 39 a · a 42 9Φ

Cl-, (uM) ........................ HP HSF .va 5 ai 44 ή 8 ** · 5 i 1 £! · * ~ 7 * iOqO 14.4

39 40 4Ψtt p Í Í Í Í hu hu hu hu hu hu hu hu hu hu hu hu hu hu hu hu hu hu hu hu hu hu hu hu hu hu hu hu hu hu hu hu hu hu 4 mol. The novial huwano H C 8, oaci d ad of the ompost edem of the paw X Q O p0 i 3. aomu raed. through the 8Π5 aio in ηί ivG iv = &gt; I q l PLA

- i7

This test is performed from the following &quot; In non-fasted CD8 + mice (8 weeks of ides, 3i-36 grams), they are placed in plastic boxes in groups of six. The right posterior mouse volume is measured using mercury plethysmography (time zero). The compounds are administered orally (5 ml of 5% Tween-S0 to 5%) 1 to 3 hours before the injection of PLA3 or intravenously (Θ52 ml in dimethylsulfoxide / 3% saline) 3 minutes of the PLA injection - * A solution of purified PLA4 from the snake &quot; diamond back cottorâ "mouth &quot; (A, piscivorus piscivorus) is prepared in saline at the concentration g / ml, Fifty (50) μΐ (θ = 3 æg) of this solution of PLAn are injected subcutaneously into the right hind paw by means of a plastic syringe of 1 ml (1% 27 gauge needle), the injected paw volume is measured after 10 minutes3 30 minutes and 6 minutes after PLA-1 injection. Animals are killed with CO at the end of the study, the edema of paw is calculated by subtracting the zero volume volume from the volume recorded in each period, the mean paw edema for each. the treatment group is then calculated and is expressed as (μΐ ± S, E). The effects of the drug are expressed as a percentage variation relative to the control values (vehicle). The statistical significance is determined by an analysis of one via. of the variance with comparison of the USD with the control (ρ &lt; ®, Θ5). The ED50 values are determined by use of regression analysis. The activity of the standard drugs in this assay was a. The following examples are given in the following examples. 1 t * 0 1Θ 18 N3o Active No Actiyd yaffisoêto

Ciprohsptadine

BW755C

From y. aís tason a *

Naproxen

Aristolic Acid â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ4 p.o ~ 3 hours

Some activity (inhibition at 30%) only when injected with an enzyme

When rehearsed in this essay? the compounds of the invention showed the following results

Bugdxo ..... x

Dose Compound% Edema Variation Example N3 mq / kq 1Θ min 30 min 60 min indomethacin 10 <p = o *> -32. (M / e): + 42.26 (M + H) + - In the present invention, the present invention relates to intravenous intravenous intravenous infusion and intravenous intravenous intravenous infusion.

The results show that the compounds of the present invention are very effective in vivo in inhibiting edema induced by the exogenous administration of PLA2 from snake venom.

Example 47

The compounds of the present invention are evaluated relative to their ability to inhibit pathways of the invention. lipoxygenase and / or cixooxygenase inhibitors of arachidonic acid metabolism in the in vivo murine pituonitis zymosan test

This assay is carried out in the following manner, male CD-I mice (8 weeks old) are placed in plastic boxes in groups of six animal animals injected with 1 ml of 1% zymosan in saline at θ, 9 % free of pyrogen, or saline (control not stimulated). The compounds are administered orally 1 hour prior to the injection with zymosan. Twenty minutes after injection with zymosan, the mice are asphyxiated by inhalation with GC , and the peritoneal cavity is washed with 2 ml of a cold Hanks Balanced Salt Solution (HESS) without CaCl 3; 7H-O and MgClO-δ-tO. 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 ice, the respective volume being recorded. The preparation of the samples by evaluation by ELISA is as follows: The samples are centrifuged at ΒβΘ g for 15 minutes, 1 ml of the supernatant is added to 8 ml of ice-cold methanol and the mixture is maintained at 70 ° C overnight to precipitate the? the samples are then centrifuged a. 800Â ° C for 15 minutes and then followed by a drying procedure in a Savant speed concentrator. Samples are reconstituted with Ϊ ml of an ice-cold ELISA buffer and stored at -70Â ° C until assayed. The compounds of formula (I) are reacted with a compound of the general formula (IV): ## STR1 ## The compounds of formula (I) to be tested in tetrahydrofuran and suspended in methyl cellulose at 5% wt. a d; 1

The level of metabolite at t 1 in the lavage / rat fluid is calculated ε its value is determined by the ratio of one pathway to the other. comparisons of LSD for CpBi control d-05). The effects of the Scopo template were expressed as a percentage change in the control values. In this assay, d-acylated The standard procedures are as follows: (a) (b) (b) and (b). -r BW755C / * a Phenidone 24.0 <30, © J n cl om '~ · L · s i ns Not active Itmprof en Non activG

When tested in this assay, one invention and the anti-inflammatory etodolac compound of the following are: the prssen-provided

L-Juadru Vi Compound of O013 &gt; % tis Inhibition b. ; in the ratio of 1 to 6% to 1% by weight of the compound of formula (I): ## STR1 ## 11.5 ° C),

Administered intraperitone. The present invention relates to compounds of the general formula (I). The results show that the invention has a potent inhibitory effect, but is not a carrier. cxcioQKXQensse

EkshipIg The antagonist activity towards LTD2 of the compounds of the invention is determined in the guinea pig trachea assay isolated in vitro.

This test is performed in the following ways: male Hartley guinea pigs <350-4θ g) are killed by a blow to the head, the neck is opened and the trachea is removed. The trachea is maintained in a solution physiological saline * the connective tissue and the fat are removed and are cut into rings approximately 2 mm wide &lt; each ring contains two cartilaginous segments). Two pieces of seda- ture of silk are then passed through the ring lumen of the trachea and those are attached around the cartilage on each side of the tracheal muscle. The tracheal ring is suspended between a glass hook and a force-displacement transducer in a 1-ml organ bath. Measurement of the isometric tension The tissues are maintained at 37øC in a gaseous physiological saline solution (95% CO 3/5% CO 2 with the following composition NaCl <100 mM) 1 * 18 mM), KOI <4 "74 mM) * CaCl 2 (2.5 mM) 5 * Tl.

(25 mM) of β-trosis (11.1 mM) and indomethacin (ÂμM). The tracheal rings are maintained at a residual tension of 2 Âμm. and are equilibrated for 45 minutes (with frequent washing and residual voltage readjustment)

The tracheal rings are first contracted by the addition of carbachol (3 x 10 · · ·ώώώ) to determine the tissue reaction and establish a reference contraction. After a stable contraction level is reached about 30 minutes) The tissues are then washed several times until the starting voltage is restored and then equilibrated for 30 minutes. The tissues are then incubated for 45 minutes. f

with a suitable control solvent (untreated controls). A tissue from each group serves as a counterpart to twenty-one prior to the construction of the concentration curve. (Î ± -cysteine (final concentration of 1 x 20â † 'Tiâ †' â · ‡ â · ‡ â · ‡ â · ‡ ‡ â · ‡ â · ‡ â · †) ir et al.

Uu! individual tissue reactions to L1 and L2 are measured as percentages relative to the reference control of that tissue to carbachol. The LTD antagonist activity is determined to be equal to the concentration curves of the concentration curves treated with the solvent (control) is calculated as a concentration ratio (Eq.A.) and the ratio of the LiB2 in the presence or in the presence of a compound of the formula to the right COfR the antagon is ta re to tx vemente of tl 0 ci xoo x. r a. w is used in the present invention to provide the compounds of formula (I) The value of? of the antagonist (Eqs "H Q C). In the event that the maximal reaction to the LTD2 decreases, the calculation is carried out for the particular curve, which indicates the apparent pKR &quot; and the CE-λ compound of the drawn tissue A) Concentration Rate (TC)

Chj-Λ of control

Kr ECO of Test 3 TC-I} 1 oq

KB «pKB

Just a c ompos t t. r to be active and / or show ba x; ; The reaction is then diluted with water to give the title compound as a colorless oil. C oncentrations of the test compound qui ti tiates • cr. In order to carry out a Schiid analysis in the determination of a value pft0? if appropriate. The reference activity of the trinene antagonists are as follows:

As used in this experiment, a compound of the present invention provides the following results

Ly-1 f 1 «88-3 / s 44 Ί O W á P ORO i W K W Λ- &amp; η 9Θ .1, Λ. * &quot; 1 &quot; 3 * -C. there, ·"*

VIJ

Quad

All Rights Reserved.

The concentration rate of the compound of the formula (I) may be obtained from the compound of the formula: ## STR1 ## in which R 1 is as defined in formula (I). 10 • 3 r · * i. w • rr qer & 4 - * n. ϋϋ -i. The foregoing shows that the tested compound is a pharmaceutically acceptable salt and diluent according to the results shown. in the trachea assay of pOrQUiTi ΠΟ G 5. &quot; -india isolated in vit.ro »

fc-Example 4v

The compounds of the present invention are further subjected to the rat paw edema assay induced by carrageenan to determine their ability to inhibit the acute inflammatory reaction.

This assay is performed in the following ways Sprague-Dawley male rats with 140-18 μg, in groups of 6 animals, are injected subcutaneously into the right paw with 6.1 ml of 1% carrageenan at time zero. Mercury plsthymographic readings ( ml) were made at time zero and 3 hours later. The test compounds were suspended or dissolved in methyl cellulose. 5% and are administered for at least one hour prior to carrageenan administration. The increase in the volume of the keremein in ml) produced by the carrageenan is then measured. This is calculated (volume of time equal to 3 hours minus the volume at zero time ), then the percentage inhibition of edema is determined. For the determination of statistical significance, the Student's t-test is used. The activity of the standard drugs in this assay is as follows

Medication

Indomethacin Aspirin F in 1 Butazide DE (5%) (95 ° C) L / kg 3,7 '(0,6, 23,8) 145,4 <33,1,645, 6) 26.2 (2.3, 291, β) -? X - '..

When tested in this experiment, a compound of the present invention is the stool antidote medicament " the following results? guadr.

Compound of the formula

Dose 1 '<mq / kg)% Inhibition 50 mg / kg

.W. / etodolac 1Θ 50 11 5Θ 14 50 admin stracía perora 1 rr.ante

The results show that the compounds tested have a significant activity in the rat paw edema assay induced by carrageenan, evidencing effects on the acute inflammatory reaction. Example 5 The assay of this example measures the ability of the compounds tested to inhibit 5-1 ipoxig- enase in whole human blood.

This assay will be carried out as follows in 50-100 ml quantities from male donors. The counts are calculated and the differentials of the white blood cells are calculated. Two ml of blood are placed in a 15 ml polypropylene test tube. Compounds are dissolved in dimethylsulfoxide and diluted in 100% bovine serum albumin in phosphate buffered saline, pH 7, 4, obtaining

a final concentration in the blood of dimethylsulfoxide of Θ 5 1%. Then the compounds are added to the blood in a shaking water bath at 37øC for 10 minutes before the addition of 3θμΜ of calcium ionophore (Sigma A231S7s). Following administration of the ionophores the whole blood samples are mixed and incubated for 2 minutes at 37øC in a stirring water bath. Incubation is terminated by placing the samples in an ice bath and by the immediate addition of glycol-bis- (β-aminoethyl ether) -N5 N3 N * SN'-ethylacetic acid ethyl ester &lt; 1mM). Samples are mixed and centrifuged at 1200kq for 15 minutes at 4 ° C. The preparation of samples for the evaluation by RIA or ELISA is performed by the following protocol. The plasma is removed from the sample tubes, placed in 15 ml polypropylene test tubes containing 8 ml of methanol and then vortexed to precipitate the protein. Samples are stored at -7Â ° C overnight. The next day the samples are centrifuged at 2 ° C for 15 minutes at 4 ° C to pellet the precipitate. The samples are dried in a Sav-ant speed concentrator, the original volume is reconstituted with an ice cold RIA or ELISA buffer and they are stored at -70øC until assayed. The assay for the eicosanoids (TLB-, TkB, and PSE) is carried out as described by the manufacturer. from the EIA system, Vi 3 -RIA or the CLTB-Amersham ELISA system - TxB_ and 4 * 2 PGE3 -Caymsn Chemical). The total level of eicosanoids in 2 ml of blood is calculated as recorded as ng / l of neutrophils. The significance is determined by an analysis of a variance pathway with comparisons of the Significant Riordian Difference (CLSD) relative to the &lt; pl &gt; control, &5;), and the values of .alpha. = .Alpha. (.Mu.m) are determined by regression analysis (Finney, 1978). The effects of the medicament are expressed as a percentage change in control values.

0- = Γ'3'-U. 1 t.SuQi-tested; Compounds of the present invention may also be used. are presented in Table 1. Example Ny (uii) A-A0 0 / L-663536 V6

Claims (1)

jFTfll A &lt; ch ^ &gt; u-a in which either a group with A is phenethyl-alkyl-phenoxy, R ' ## STR1 ## wherein R 1, R 2, R 3, R 4 and R 5 are each independently selected from the group consisting of: 1: C-5! "ONE- ? -N 1! = C-y-N-y-S-OR -0-5 A compound of formula (I) wherein R 1 and R 2 are as defined above. phenyl is phenyl or lower alkyl; or  € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ (CH2) n CHR5 " (CH2) m R4, R4, R4, R4, R7, R7, (OH) 2 R 3 (CH 2) n A R 9 in which is -C (O) R 3, or --CNHBGUN ffi è U ~ O? (CH 2) 0, - (CH 2) or phenyl of phenyl substituted by halo, lower thio, lower alkylsulfinyl or lower sulfonylsulfonylalkyl; ACCHL) 0- or halos with 13 for haloϋ K &quot; ' to be (CH2) R6 is lower alkyl, R6 is lower alkyl or -CH2), -CH2), -CH2), -CH2- ; R1 * is lower alkyl; phenyl, phenyl substituted by R 1 is H or lower alkyl or phenyl. characterized in that it comprises one of the following processes: a) when the final product has the formulas: . a compound HO wherein R3 is as previously defined and X is a leaving group, followed by reaction with triethylphosphonoacetate, hydrolysis of the resulting acetic acid ester intermediate, and then reaction with a correspondingly substituted henzaldehyde to introduce the desired portion of the intermediate to give the desired end product, or ii> The reaction of an intermediate having the formulas HO Wherein R "in the -CDDR- moiety is lower alkyl, with an appropriately substituted benzaldehyde in order to introduce the desired moiety R 5 CH = into said intermediate and then the etherification of said intermediate with a compound of formulas A &lt; Wherein X is as previously defined, and X is a leaving group if necessary, hydrolyzing the intermediate to give a final product in which R1 is hydrogen or b) when the final product has the formulas in which in .1 d, f ϊ \ -press ACCB ^ o θ Η "s? η Béq CDíTsd anLeriDfíHen composed of formulas -, * Υ s' &gt; S 5a V &quot; defined τ sb. halogen, CH3COOH, C where A and n are as previously defined; and, if desired etherification of the acidic product (i) when the final product has the formula; R7 is CHC02R3 â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒa. in which Y, R1, R 5, R 5, R 5, R 5, R 5, A and n are as defined above. i) the etherification of a compound of formula t-ΟϊΤϊ Uiít composed of Λ * ......... Ί .. i u uiu. j. (a) and (b) in the above-mentioned group, if necessary, as the ester function -GC-R or -CO-R " A compound according to claim 1 wherein R 1 and R 2 are as defined in claim 1 wherein R 1 and R 2 are hydrogen. Q ..1 ... Uc: a • formulas υ.ίΐι qrapo Π · 5. or -L-ϋ. with a compound having the formula R 1 'wherein R 1' is as defined above and hal represents a halogen atom in order to give the final product d) the hydrolysis of a compound of formula I, wherein, -CD-R "or -CD-R '&quot;' is an ester function? in order to obtain a compound in which R * &quot; or R "" in said moiety is hydrogen or a pharmaceutically acceptable salt thereof or e) converting a compound of formula 1 ' II "III ου. IV in a pharmacologically acceptable salt. A process according to claim 5, wherein the compound of the formula (I) is prepared by preparing the compound of the formula (3-methyl-3-methyl-4-methylthio) -piperidine-3-carboxylic acid, which is prepared by the procedure described in Example 1, 2-quinolinylmethyl) -3β-indene-1-acetic acid. A process according to claim 1, characterized in that 1,2-methyl-3- (4-methylphenyl) phenyl] methylene] -6- (2-quinolinylmethoxy) -3H-indene-1-acetic acid. &quot; · * -X; X χ 5 · r ·. A process according to claim 15 characterized in that the preparation of 5-fluoro-2-methyl-1-EC4 [2-quinolinylmethyl) phenyl] methylphenyl] -4-acetic acid A process according to claim 15 characterized in that the 2-methyl-3- (4-methyl-4-methylthio) phenylmethyl-3- (2-naphthyl) A method according to claim 1, which is characterized in that the compound is prepared by preparing 1,3-E-4-chlorophenyl) methylene-3- (2-methyl-6-methoxy- The process according to claim 15, which is characterized in that the 1,3-cis-4-acetic acid silyl ester -phenyl) methylene-3- (2-methyl-6-2- (2-quinolinylmethoxy) -3H-indeno] acetic acid. A process according to claim 15, (2-quinolinylmethoxy) methanesulfonyl-5H-indole-1-carboxylic acid The process according to claim 1, wherein the compound is prepared by the preparation of 3-ethyl-3,4,5,6-tetrahydro-6- (quinolinylmethoxy) pyrano 4-bindole-1-acetic acid = 111. A process according to claim 1, (2-quinolinylmethoxy) pyrano [3,4-b] indole-1-acetic acid. A process according to claim 5, characterized in that the compound for the preparation of 1-ethyl-2β, 3β, 4β-tetrahydro-6- (2-quinolinyl) -1-methylpiperazin-1-yl] acetic acid = . (i.e. U.S.A. 3. The composition of the compound of formula (I) , 3â € ²-4,9-tetrahydro-1-propyl- (2-quinolylmethyl) pyrano [4,3-b] indole-1-acetic acid, rOChIBS according to. The title compound was prepared according to the procedure described in Example 1 for the preparation of the title compound. The title compound was obtained by the addition of 1-methyl-quinoline-4-methoxy-5-pyrano [3,4-c] quinoline. according to claim 1, Γ 3Ρ · 3Γ-1 T /! rj-te t.r a-h i d ro-1? (±) -dimethyl-2-oxo-1,2,3,4-tetrahydro-1 H -imidazo [1,2-a] (4-chlorophenyl) methyl] -2-methyl-1H-indole-3-carboxylic acid carboxylic acid methyl ester was obtained in the title compound as a white solid.1H NMR (CDCl3): Î'13.41 (s, 1H) The compound according to claim 1, which is characterized in that the compound of formula (I) is prepared according to the procedure of Claim 1, which process comprises preparing a compound of formula (I). The title compound was prepared from (1R, 4R) -4- (4-chlorobenzoyl) -2-quinolinecarboxylic acid The title compound was prepared according to the procedure described in Example 1, except that the title compound was prepared according to the procedure described in Example 1. (x) - 3, Η-χηϋοΙe ~ 3 ~ acistico; to prepare or to The. The process according to any of claims 1 to 5, wherein the compound of formula (I) is prepared as described above. 2-methyl-11H-indole-3-acetic acid, trifluoroacetic acid salt. : optimized by itself-Great 1 x n x 1 me to ΟΓί 2-methyl-5 - (2'-tx-1-yl) indole-2-carboxylic acid methyl ester A compound according to any of claims 1 to 4, characterized in that the compound of the formula (I) is prepared by preparing a compound of the formula: ## STR1 ## (2-methoxyphenyl) -N-methyl-2-quinolinecarboxylic acid; • 2-acét. ............... characterized by the preparation of. (4-chloroethyl) methyl] -4- [4- (trifluoromethyl) A process as claimed in claim 1, characterized in that the compound of formula (I) is prepared by reacting a compound of formula (I) with a compound of formula (I). The title compound was prepared in the same manner as in Example 1, to give 1-chlorophenylmethyl-2-phenylsulfonyl) -5- (2-quinolinylmethoxy) -1H-indole-3-acetamide. ss u utf? The title compound was prepared in the same manner as in Example 1 to give the title compound as a yellow oil. 4-bromo-phenyl; I love you 1 H-NMR (CDCl3):? 1-quinolin-1-one; i) -1H-indole-3-acetic acid. A process according to claim 1, A process according to claim 1, which is characterized in that 1-C-phenylmethyl-2-methyl-4-2-4-quinolinylmethoxy) -1H-indol-3- (4-carboxyphenyl) methyl-2-methyl-5 '- (2-quinolinyl) ethoxy) -propionic acid methyl ester The compound according to claim 13, indole-3β-acetic acid. A process according to claim 1, characterized in that 2-phenylphenoxy-5-quinolinylmethyl) -1-L4- (2-quinolinylmethoxy) phenyl A process according to claim 1, wherein the compound of formula (I) 2-quinolin-1-yl-methoxy) -1H-pyrazole-3-acetic acid, the title compound was obtained as a white solid. A process according to claim 1, characterized in that 1-hexyl-S-methyl-5- (2-quinolinylmethyl) -1H-indole-5-acetic acid ,. A process according to claim 1, which comprises the preparation of 1-heptyl-2-methyl-5-2- (2-quinolinecarboxylic acid) -L-indole-3-acetic acid. 1-methyl-2-methyl-5- (2-quinolinylmethoxy) -41-1-1,00013-3-30-01100 = 36. A process according to claim 1, which is characterized by the preparation of (4-chlorophenyl) methyl] -5-42-quinolinylmethoxy) -1H-indole-3-acetic acid A process according to claim 1, which comprises reacting the compound of formula (I) with a compound of formula (I). (S) - (Phenylmethoxy) -IH-indole ··· &quot; A process according to claim 1, characterized in that 1-methyl-4-chlorophenylmethyl-2-methyl-5- (2-pyridinylmethyl) (4-chlorophenyl) methyl-5- (4-chlorophenyl) -2-methyl- 1-yl) -1H-indole-1-yl] acetic acid. The title compound was prepared according to the procedure described in Example 1, with the title compound as a white solid, mp 218-223øC. Anal. Calc'd. -acetic acid. The process is carried out according to the procedure described in Example 1. <4-chlorophenylmethyl] -2-methyl-5- [2- (4-trifluoromethylphenyl) -4-thiazolyl] -3H-indole-3-acetic acid * 43ã. The title compound was prepared according to the procedure described in Example 1 for the preparation of the title compound as a white solid. 1 - [(2-thiazole-1-yl) methyl] -1H-indol-1-yl ester. The title compound was prepared according to the procedure described in Example 2, which was prepared by preparing 2-methyl-5- (2-chloroethyl) -piperidin- κx) -1 -1-4-4-2-quinolylmethyl) methyl] -3-1H-indol-1-ol; - Acylated Urea. The term " . Preparation of N- (4-chlorophenyl) -6- (2-quinolinecarboxylic acid) -7- (4-chlorophenyl) 2-yl] indol-3-yl] thiophene-3-carboxylic acid amide. J. PEREIRA DA CRUZ Official Agent for Industrial Property RUA yiCTOR CORDON, 10-A 3 * 1200 LISBOA