PT94432B - SUBSTITUTED SULFONAMIDES AND COMPOUNDS USED IN THE TREATMENT OF ASTHMA, ARTHRITIS AND RELATED DISEASES - Google Patents

Abstract

Preparation of substituted sulphonamides, treatment of asthma, arthritis

Description

INVENTION PATENT

M2 94,432

NAME: PFIZER INC., North American, industrial ·, in

235 42nd Street, New York, N.Y. 10017 - U.S.:

EPIGRAPH: PROCESS FOR THE PRODUCTION OF SULPHONAMIDES

SUBSTITUTES AND RELATED COMPOUNDS USEFUL IN THE TREATMENT OF ASTHMA, ARTHRITIS AND RELATED DISEASES

IHVENTORES 'JAMES F. EGGLER, ANTHONY MARFAT, LAWRENCE S. MELVIN and HIROKO MASAMUNE

Claim of the right of priority under Article 42 of the Paris Union Convention of 20 March 1883.

June 1989 under PCT / US89 / 02748 in the UNITED STATES OF NORTH AMERICA

PFIZER INC. PROCESS FOR USEFUL AFFINITES

PRODUCTION OF REPLACED SULPHONAMIDES AND COMPOUND TREATMENT OF ASTHMA, ARTHRITIS AND RELATED DISEASES ”i MEMORY OF SORITIVA ι

Production summary

The present invention of a compound with respect to the formula:

a process for

wherein R tf R are S, NH or and Z is, p is, for example, quinolyl each of which is H or OH; Y to NR '; R ^y is (Cj-C) alkyl; for example, CONHW, in quw W or. substituted quinolyl; R ^ CH._O, C ^ H._, or Ο .-, Η; X is CH., 0, n is an integer from Θ-3; is, for example, SO ^ H.

said preparation process consists of the reaction of a compound with formulas

IIIII

COOR ⁵ where R is p-nitrophenyl, with a compound of the formula NHW, in a reaction-inert solvent.

These compounds are inhibitors of the enzyme 5-1 lipoxygenase and antagonists of leukotriene B4, leukotriene C4, leukotriene D4 and leukotriene E4, the present invention is directed to substituted sulfonamides and related compounds of formula I, indicated below, which here inhibit the enzyme 5-1 lipoxyqenase and / or blocking leukotriene receptors, are useful in preventing asthma, arthritis, psoriasis, ulcers, myocardial infarction, stroke, irritable bowel syndrome and related disease states in mammals, the present invention is also addressed to pharmaceutical compositions of, and to a method of treatment using said compounds of formula (I).

It is known that leukotrienes are compounds produced in mammals by the metabolism of arachidonic acid. Arachidonic acid is metabolized in mammals via two distinct pathways, one leading to prostaqlandins and troroboxanes, and the other to various oxidative products known as leukotrienes, which are indicated by letter-number combinations such as leukotriene 54 (LTB4), leukotriene C4 (LTC4) and leukotriene D4 (LTD4). The first step in this oxidative pathway is the oxidation of arachidonic acid under the influence of the enzyme 5-1 ipox.igenase, an enzyme that is generally inhibited by the compounds of the present invention, thereby blocking the synthesis of all leukotrienes. This alone provides the sufficient mechanism for these compounds to be useful in the treatment or prevention of asthma (where L.TC4 and LTD4 are considered to be mediators), arthritis (where LTB4 is considered to be a mediator), psoriasis (where LTB4 is considered to be a mediator), ulcers (where LTC4 and LTD4 are considered to be mediators), myocardial infarction (where LTB4 is considered to be a mediator), stroke (where LTD4 is considered to be a mediator) and syndrome irritable bowel (where LTB4 is considered to be a mediator). Supplementing this enzyme inhibiting activity

4 there exists the general ability of the present compounds to antagonize (i.e., to block receptors for) LTB4, LTC4, LTD4 and L.TE4. For a review of 1eucotrienes, see Bailey et a Ι. ,, ftnn. Reports Ned. Chem. 17, pp. 23-217 (1982).

Egqler et al. , in PCT patent application PCT / US87 / c> 2745, describes racemic or optically active substituted tetralins, chromans and related compounds that inhibit the enzyme 5-lipoxygenase and antagonize L.TB4 and LTD4, and are thus useful in the prevention and treatment of asthma, arthritis, psoriasis, ulcers, and myocardial infarction.

Kreft et al., U.S. Patent No. 4,661,596, describes disubstituted naphthalenes, dihydronaphthalenes and tetralins that inhibit the enzyme 1; igenase and antagonize LTD4, and are thus useful in. prevention and treatment of asthma.

the present invention relates to compounds of the formula

on what

R ¹ is quinolyl, substituted quinolyl, benzothiazolyl, substituted benzothiazolyl, benzopyrimidinyl, or substituted benzopyrimidinyl, wherein said substituted quinolyl, substituted benzothiazolyl, and substituted benzapyrimidinyl are substituted with one or more substituents that are independently selected from the group consisting of in fluoro, bromo, chloro, phenyl, hydroxy, trifluoromethyl and (C -C) alkyl-, -T 14

R and R- 'are each H or OH;

Y is CH _o 0, C ^ H ₄ or C ^ H ^;

X is CH _OJ 0, S, MH or MR ⁷ ;

R 'is (C ^-C ^) alkyl; n is an integer from 0-3;

Z is COMHW or CON (Me) ,,;

W to S0 _o 0, COO or 0; and is hydrogen, phenyl, substituted phenyl, (C1 -C _R ) alkyl, cycloalkyl, tetrazolyl, or thiazolyl, wherein the above substituted phenyl groups are substituted with one or more substituents independently selected from the group consisting of chlorine, fluoro and (C.-C.) alkoxy;

4 and its normally acceptable salts.

addition of acid and pharma cations Preferred compounds of the invention are compounds of formula (I) where R is 5-fluoro-2-benzothiazole, X is 0, R ^ is hydrogen, n = 1, R '' is hydroxy, and Z is selected from the group consisting of carboxamide, fonyl carboxamide, M-acetyl carboxamide, and N-tetrazolyl carboxamide.

independent M-methanesul A most preferred compound of the invention is the compound having formula I wherein R, R, R ' ^- ', X and n are as defined in the previous paragraph, and Σ is N-phenylsulfonyl carboxamide.

Specific compounds of the invention are cis-3-C 7-E (5-f 1 uoro-2-benzthiazole) methoxy 3-4,5-dihydro-5-hydroxy2H-1 - benzohomopyl-4-i 1 meti 1 3 -N- (phenyl sulphide) 1-benzamide, ois-3-1a-i (2-quinolinyl) methoxy 3-3,4-dihydro-4-hydroxy-2H-1-benzopyran-3-i Imeti 1 3 -N- (pheni lsu.lf oni 1) benz amide, cis-3-Εά-E (6-fluoro-2-quinolini1) methoxy 3-3,4-dihydro-4-hydroxy-2H-1-benzopyran-3 -i1 meti 13-N- (methanesulfoni1) benzamide, cis-3-Εά-C (t-fluoro-2-quinolinyl) methoxy3-3,4-dihydro-4-hydroxy-2H-1-ben zopi ran-3- i1 mei i13-N- (2-meylphenylsulfonyl) benzamide;; CIS-3-E7-E (5-fluoro-2-benzothiazolyl) methoxy.i3-4,5-dihydro-5-hydroxy -2H - 1 - benzohomopyl ran-4-i Imeti13-N- (methanesulfoni1) benzamide, cis-3-Efc-E (5-fluoro-2-benzothiazoli1) methoxy 3-4-hydroxy-1,2,3 , 4-tetrahydronaftalen-3-iImeti13-N- (methanesulfoni1) benzamide, cis-3-E6-E (2-quinolini1) methoxy 3-4-hydroxy-1,2,3,4-tetrahydronaftalen-3-iImeti1 3- N- (pheni 1 sul foni 1) ben z amide, cis-3-Εά-Ε (2-quinolinyl) methoxy i 3-3,4-di hydro-4-hidrDxi-2N-1-benzopyran-3-iImeti13-benzamide,

OIS-3-E5-E (5-flucro-2-benzothiazole) methoxy 3-3-hydroxy indan-2-i1methyl 1 3-N- (phenylsu.lfoni 1) benzamide, cis-3-E7-E ( 2-quinolinyl) methoxy 3-4,5-dihydro-5-hydroxy-2H-1-benzohomopyl ran-4-i 1 methyl 13-N- (methanesulfoni1) benzamide, çis-3-Εά-Ε (2-quinolinyl) methoxy 3-4-hydroxy-1,2,3,4-tetrahydroquinol. in-3-i 1 methyl 3-N- (phenyl-sulfonon 1) benzamide, and cis-3-ES-E (6-fluoro-2-quinolini1> vini13-3,4-dihydro ~ 4-hydroxy -2H-1-ben zopyran-3-i1methyl 13 —N- (2-methylphenylsulfon i1) benzamide.

The preferred stereochemical configurations for

The compounds of this invention in which R ^{- is} hydrogen and R'- 'are hydroxy are those in which the hydroxy group is cis with respect to the benzyl D side chain substituted on the adjacent carbon, i.e. the hydroxy group and the substituted benzyl side chain are or both above or both below the plane of the heterocyclic ring to which they are attached.

The compounds of formula I have optical centers and thus occur in different stereo-isomeric configurations. The invention includes all the stereoisomers of these compounds of formula I, including their racemic mixtures.

The invention also relates to pharmaceutical compositions for administration to a mammal comprising a compound of formula I or a pharmaceutically acceptable acid or cation addition salt and a pharmaceutically acceptable carrier. Said pharmaceutically acceptable acid addition salts include, but are not limited to, those formed with HCl, HBr, HNO-, H „50., Η, ΡΟ. , CH-SO-H, ρ-ΟΗ-Χ, Η.δΟ, Η, CH.CO _n H, acid

- · 'Ζ Η' O 'Ο Ο ύ Ο Μ- ύ Gluconic Z, tartaric acid, maleic acid, and succinic acid. In the case of these compounds of formula (I), which still contain a basic nitrogen, it will, of course, be possible to form diacid addition salts as well as monoacid addition salts. Said pharmaceutically acceptable cationic salts include, but are not limited to, those formed with sodium, potassium, calcium, magnesium, ammonia, M, N-dibenzylethylenediamine, N-methylamine (meglumine, ethanolamine, and diethanolamine).

□ invention also relates to a method for the treatment or prevention of asthma, arthritis, psoriasis, gastrointestinal ulcers, myocardial infarction, stroke or. syndrome, irritable bowel, comprising a. administration to a mammal in need of such treatment or prevention of a compound of formula I in an amount effective to treat or prevent that disease.

The following reaction schemes illustrate the preparation of the compounds using formula I. For the purpose of illustrating the different preparation methods, these compounds are subdivided into compounds with formula IA and compounds with formula IB.

-9Scheme 1

F, CCOOR ⁵ Ψ ^J

IA

CONHW

Layout 2

nh ₂ q

IB

(CF ₃ so ₂ ) ₂ o

COOMe

SAW

VII

VIII

VII

X

Compounds of formula IA, in which R, R ^- , R, X, n and W are as previously defined, are typically prepared by reacting an ester with formula III, in which R *,

7, 5

R, R, X, and n are as previously defined and R is p-nitroferyl, with a compound having the formula NHW, where W is reaction p-dioxane.

benzene, 1,2 dimethoxyethane.

as defined above, in an inert solvent. Preferred solvents are tetrahydrofuran and Other suitable solvents are ethane and toluene. The temperature is not of critical importance, for example about 0-100 ° C ^: satisfactory, with room temperature being preferable for reasons of convenience.

As used herein, the term inert reaction solvent refers to a solvent that does not interact with starting materials, reagents, intermediates or products in a manner that adversely affects the yield of the desired product.

ester with formula III is prepared by reacting a 1 to 7 compound having formula II, where R, R, R ~, X and n are as 4 as defined above and R is hydrogen, with a 5 5 compound with the formula F_.CCOOR, where R is p-nitrophenyl, in an inert reaction solvent. The preferred solvent for this reaction is pyridine. The temperature is not of critical importance, for example about 0 ~ 1C> 0 ' ^:, C is satisfactory, with room temperature being preferable for reasons of convenience.

Compounds of formula IB, where R, R ^, R- ', X, π and Q are as defined above, can be prepared as described above for the preparation of compounds of formula IA, using a reagent with the formula NHW, where W is 0. Compounds with the formula IB can be prepared,

-14 ternativaíisente, as indicated in Scheme 2, from an anhydride intermediate having formula IV. This is done 1 r as dry. A compound of formula II, in which R, R *, R ~,

R, X and n are as defined above, is to react with a compound of the formula R ^ COOCl, in which isobutyl is made, in the presence of such a triethylamine base and in an inert reaction solvent, after which a compound with the NHQ formula, where Q is as defined in the reaction mixture. 0 solvent

Appropriate temperatures are those that range from about 0-30 ° C, with 0 ^,:, C being the preferred temperature.

previously, it is added to the preferred one is tetrahydrofuran.

COIM Compound (Me) may be a feed of compounds using the NH (Me) of the invention having formula I prepared in a similar manner with formula IB according to as a reagent instead of NHQ.

where Z is the one of the preparation scheme 2,

Compounds of formula II (the starting material used in Schemes 1 and 2), where Y is CH ^ O, can be prepared as described in application F'CT PCT / US 87/02795. The compounds of formula II, where Y is C ^H,,., Or C ^H H, can be prepared as indicated in part in Scheme 3 and described below.

A compound of formula V is reacted with trifluoromethanesulfonic anhydride in an inert reaction solvent and in. presence of an acidic cleaning agent to form a compound of formula VI. Temperatures of about -7S * C to 0 ^; 'C are appropriate, with temperatures from -78 to -O0'-C being preferred. The preferred solvent is dichloromethane. The preferred acid cleaning agent is triethylamine, although other

-15 cleaning agents such as IM, N-dimethylamino pyridine and pyridine. The compound of formula VI thus prepared is then reacted with a compound of formula R RCHCH ^ ,,, for example 2-vinyl-5 fluorobenzotizole, in the presence of palladium (II) chloride (triphenylphosphine), triethylamine and tri-ethylamine o-toli1fosfina a reaction inert solvent, preferably dimeti1formamida at a temperature ranging between about 50 and 150 ° C, to produce a compound of formula VII. Temperatures between 13 °-150 ° C are preferred. The reaction is preferably carried out in a sealed tube and under a nitrogen atmosphere. The compound of formula VII thus prepared can be converted into the corresponding compound of formula VIII by reducing it with hydrogen in an inert reaction solvent and in the presence of a palladium / carbon catalyst. The reaction is preferably carried out under a pressure of about 15 to 40 psi. Methanol is the preferred solvent, although other suitable solvents such as ethyl acetate are also used.

Compounds of formulas VII and VIII can be reduced to form compounds of formulas IX and X, respectively, by reacting them with sodium borohydride and cerium chloride hexahydrate in an inert reaction solvent, preferably methanol, to a temperature ranging between about -78 and 30 ^C 'C. Temperatures between 25 and 30 ° C are preferred. The compounds of formulas IX and X thus formed can be converted to the corresponding carboxylic acids of formula II by hydrolysis with sodium hydroxide in methanol.

In each of the reactions mentioned above, the pressure is not of critical importance. Unless otherwise indicated, pressures ranging from 1 to 2 atmospheres are

-16 appropriate, with ambient pressure being preferred for reasons of ven on?

The new compounds of formula I are useful as inhibitors of the enzyme 5-lopoxygenase and antagonists of leukotriene Β4, leukotriene 04, leukotriene E4 and leukotriene E4.

The in vitro activity of the compounds of formula I can be tested as follows. RBL-1 cells, maintained in a monolayer form, are grown for 1 or 2 days in culture, rotated in Minimum Essential Medium (Ea.gle) with Earl's Salts plus 157. Fetal Bovine Serum supplemented with antibiotic / antimycotic solution ( GIBCO). The cells are washed 1 time with RF'MI 1640 (GIBCO) and resuspended in RF'MI 1640 plus glutamate microM 1 until a cell density of 1 x 10 cells / ml is obtained. A volume of 0.5 ml of cell suspension is incubated at 30 ^C ° C with 0.001 ml of solution in dimethylsulfoxide of the drug for 10 minutes. The reaction is initiated by the simultaneous addition of 0.005 ml of (14C) -arachidonic acid in ethanol and 0.002 ml of A23187 in dimethylsulfoxide to give final concentrations of 5.0 and 7.6 microM, respectively. After a 5 minute incubation at 30 ° C, the reaction is stopped by adding 0.27 ml of acetonitrile / acetic acid / 100 / 0.3) and the medium is clarified by centrifugation. The analysis of the product profile is made by an injection of 0.2 ml of the HPLC clarified floating product. The separation of radioactive products is effected on a radial PAX CN column (5 mm ID, Waters) with a solvent system of acetonitrile / H ₀ 0 / acetic acid (0,1Z) with a linear gradient Jl.

acetonitrile from 357 ° to 707 ° for 15 minutes at 1 ml / minute. Quantification is performed with a Berthold Radioactivity Monitor equipped with an integrated integrator and one.

mixture of € -5.2 ml of cell flow 2.4 ml / minute Omnifluor (NEW) with column effluent. The integration units for each product are calculated as a percentage of the total integration units, and are then compared with the average control levels. The results are expressed as Control Percentage and are recorded vs the drug concentration log. IC values are assessed by graphical inspection.

The ability of compounds of formula I to compete with radio-labeled LTB4, LTC4, LTD4 and LTE4 for specific receptor sites on pig lung membranes can be tested as described by Chenq et al, Biocbemical and Biophysical Research Communication, 118, 1, 20-26 (1884).

To evaluate the compounds of formula (I) in vivo, the compounds are tested by the process called the lethality test PAF:

Materials:

Mice: Male DC1, all approximately the same weight (approximately 23 grams), 12 per group „

Vehicle for dosing the oral drug: EES (57. ethanol, 57. emulfor, 807 saline). Stored at room temperature.

Drugs: For routine evaluation at 50 mg / kg, 2C5 mg of the drug is dissolved in 4 ml of

EES, using sonication in a sonicator bath or grinding in a Ten crusher

Broeck in order to dissolve drugs if necessary. If solubility is still a problem, the drug is used, as

-13a suspension.

Injection Vehicle i.v .: Saline solution with 2.5 mg / ml of Bovine Serum Albumin (E <SA,

Siqma # A4378) and 0.05 mg / ml of

Fropranolol (sigma # P0884>. Prepared fresh daily and kept at room temperature.

Platelet Activating Factor (PAF): A stock solution of IO microM is prepared by dissolving 1 mg of PAF (Calbiochem # 429460) in 0.13 ml of ethanol. It is stored at -20 ° C and diluted in a vehicle (see above) on the day of use. The concentration of PAF used is calibrated so that when injected at 0.1 ml / 10 grams of body weight, it will kill approximately 807 of the untreated controls. This usually consists of about 0.028 q / k.g (a 1 to 2034 dilution from stock). The solution is prepared in glass containers and is used with glass syringes to minimize adhesion to the surface by the PAF. It is kept at room temperature.

Positive Control: έ ED 50

Method:

used Fenidone to approximate).

mg / kg (its treated minutes before PAF injection, mice are orally drugmed using 0.1 ml / ΙΘ grams of weight

19corporal. For 35 to 40 minutes, they are placed under a heat lamp in order to dilate the caudal vein for PAF injection. PAF is injected i.v. at 0.1 ml / 10 grams of body weight, and death usually occurs within 30 minutes, rarely after 60 minutes. Results are expressed as percent mortality compared to controls. Because the assay appears to be sensitive to endogenous catacolamines (ie, beta agonists protect mice), Propranolol is used to overcome this potential problem. It also helps if the mice are acclimated to the room before the test, and if ambient noise and temperature are kept moderate and constant. The distance from the heat lamp should be calibrated to allow vasodilation without visible stress for the mice. One should avoid subjecting mice to a

Variations:

1. The time for the oral dose can be changed.

2. Dosing of the intravenous drug is possible by co-injecting the drug with F'AF in the same solvent and vehicle as previously described. For co-injection, F'AF is prepared at twice the desired concentration in saline with BSA and Propranolol as before, and the drug is prepared at twice the desired concentration in the same vehicle. The two preparations are mixed in equal volumes just before injection.

For use in the prevention or treatment of asthma, arthritis, psoriasis, gastrointestinal ulcers, or myocardial infarction in a mammal, including humans, a compound of formula I is administered in an amount effective to treat any of these diseases, and about &, 5 to about 50 from the doctor beyond the limit usually mg / kg / day, in single or daily doses. divided. A more preferred dosage range is from about 2 to about 20 mg / kg / day, although in particular cases, depending on the assistant opinion, higher doses may be required. The preferred route of administration is oral, but parenteral administration (eg, intramuscular, intravenous, intradermal) will be preferred in special cases, for example, when oral absorption is compromised by the disease, or when the patient is unable to swallow . The compounds of formula I can also be administered topically, for example to treat psoriasis, or in aerosol, for example, to treat asthma.

The compounds of the present invention are generally administered in the form of pharmaceutical compositions comprising at least one of the compounds of formula I, together with a pharmaceutically acceptable carrier or diluent. Such compositions are generally formulated in a conventional manner using solid or liquid carriers or diluents as is appropriate for the mode of administration desired; for oral administration, in the form of tablets, hard or soft gelatin capsules, suspensions, granules, powders, etc .; and, for parenteral administration, in the form of injectable solutions or suspensions, etc .; for topical administration, in the form of a gel, lotion or cream; and for administration by inhalation, in the form of an aerosol spray.

The present invention is illustrated by the following, but is not limited to its details.

examples that

Example 1

Cis-3-Ct-6-C (5-fluoro-2-benzothiazolyl) methoxy 3-3,4) dihydra-4-hydraxi-2H-1-benzopyran-3-yl 3-methyl 3-N <metariessul f on i 1 ) benzamide

314 milligrams sodium hydride was added a solution containing 1.13 ai grams methane sulfonamide in 40 ml of tetrahydrofuran _y. The reaction mixture was allowed to stir at room temperature overnight. 1.18 grams of cis-4-nitrophen 1 -3-1 C6-C (5-fluoro-2-benzothiazole i 1) methoxy. 3-3,4-dihydro-4-hydroxy-2H-1-benzopyran-3-i13methyl13benzoate was added in one portion and the reaction mixture was left under stirring for an additional 24 hours. The mixture was then quenched with water, acidified to pH 3 and extracted with ethyl acetate. The ethyl acetate extracts were dried over sodium sulfate and evaporated to give 1.2 bulk of the crude product. The crude product was purified on silica gel, eluting with methylene dichloride / ethyl acetate to give 670 mg of the product. Recrystallization from tetrahydrofuran / ethyl acetate gave 385 mg of the product, mp

, ^1185-186 ° C.

Mass Spectrum: Calc, for C ^ H ^ N ^ O ^ SF, 524.0876.

Found, 524.0720 ..

)

Example 2

Cis-5 · -E E6-E5-fluoro — 2 ~ benzothiazolyl) methoxy3-3,4-dihydro4-hydro>; i-2H-1-ben zopirart-5-i 13meti1 3-N- <aceti1) benzamide

The synthesis was carried out as in Example 1, but using 85 grams of acetamide instead of methane sulfonamide. From 1,1S grams of çris-4-nitrQphenyl-3-EEé.-E (5-fluoro ~ 2-benzothiazali1) methoxy i 3-3,4-dihydro-4-hydraxi-2H ~ l-benzopyran-3 -i13meti13benzoate, 173 milligrams of the product were obtained, mp 191-190 * C.

Ε x in peep 3

Cis-3-CC8-C (5-fluoro-2-benzothiazolyl) methoxy 3-3,4-dihydro-4-hydroxy-2H-1-benzopyran-3-i13methyl 13-N- (2-methyl benzoi? Benzamide

The synthesis was carried out as in example 1, but using 1.93 grams of o-toluamide instead of methane sulfonamide, from 1.17 grams of cis-4-nitropheni1-3-E C & -C (5- fluoro-2-benzothiazole i 1) methoxy 3-3,4-dihydro-4-hydroxy ~ 2H-1-benzopyran-3-i13methyl13benzoate, 550 milligrams of the product were obtained, mp 139-141 ^° C.

J

Example 4

C1-5-3-EC ó-L (5-fluoro-2-benzothiazo1i1) methoxy 3-3,4-dihydro-43 hydroxy-2H-1-benzopyran-3-i1Imeti13-N- (phenylsulfoni1) benzamide

The synthesis was carried out as in example 1, but 2.22 grams of benzenessuphonamide was used instead of methanesulfonamide. From 1.7 grams of ç_i-4-nitrophenyl-3-EC6 - [(5-fluoro-2-benzothiazolyl) methoxy 3-3,4-dihydro-4-hydroxyl-2H-1-ben zopiran3-yl3methyl3benzoaro , 436 milligrams of product were obtained, mp 174-175 ° C.

Example 5 <+1 -Cis-3-CC6-C <5-fluoro-2-benzothiazoli1) methoxy3-3,4dihydro-4-hydroxy-2H-1-benzopyran-3-i13meti 13-N- (methanesulfonyl) benzamide

The synthesis was carried out. as in example 1, but using 1.7 grams of (+) isis-4-nitropheni1-3-CCo-C <5-fluoro-2-benzothiazolyl) methoxy3-3,4-dihydro-4-hydroxy-2H- Optically pure 1-benzopyran-3-i13methyl1benzoate, 41 milligrams of sodium hydride and 1.65 grams of methanessuphonamide. 1B7 milligrams of product were obtained. Ε «ρ3 = 33.4 ^o ; c = .005 in tetrahydrofuran.

-24Ε χem pio 6 <~ '> -Cis-3-Ε Eó-C (5-f 1 uoro-2-benzothiazoli 1) methoxy3-3,4'í dihydro-4-hydroxy-2H-1-benzopyran-3 ~ i 1 3methyl 3 — N (methanesulphonium) benzamide

The synthesis was carried out as in example 1, but using 460 milligrams of (-) cis-4-nitropheni1-3-CE6-E (5-fluoro-2ϊ-benzothiazole i 1) me tox i 3-3,4- dihydro-4-hydroxy-2H-1-benzopyran-3 - .1 optically pure 13methyl13benzoate, 1.18 grams of methane sulfonamide and 324 milligrams of sodium hydride. 260 milligrams of the product were obtained, Είίθΐ ~ ~ 35.9 ' ^: '; c = .005 in tetrahydrofuran.

Example 7

Çis-3-CCó-C (5-fluor0-2-benzothiazoli1) methoxy 3-3,4-dihydro-4-hydroxy-2H-1-benzopyran-3-i13meti 13-N- (tetrazolyl) ben zamide

The synthesis was carried out as in example 1, but * using 1.45 grams of 5-amino tetrazole monohydrate instead of methanesulfonamide, and using 314 milligrams of sodium hydride.

From 1.17 qrams of çis.-4-nitropheni 1-3-C Có-E (5-fluoro-2-benzothiazolil) methoxy i 3—3,4-d ihydro-4-hyd rox i-2H -1-benzopyran-3-i. 1 3.meti 1 3 benzoate, 103 milligrams of the product were obtained, m.p.

óó — 1 ó8 ’-‘ C.

Example 8 +) -Cis-3-Γ [6-E (5-f 1 uoro-2-benzothizole i 1) metho: ·; i 3-3,4-dihydro-4-hydroxy-2H ~ 1-benzopyran- 3-i 1 3 me ti 1 3-N- (phenilsij.lfoni 1) benzamide

The synthesis was carried out as in example 1 but using 2.2 grams of benzene sulfonamide instead of methane sulfonamide. From 1.07 grams of cis-4 — nitropheni1-3-C C6 ~ C (5-fluoro-2-benzathiazole i. 1) methoxy 3-3,4-dihydro-4-hydroxy-2H-l- optically pure benzopyran-3-i13methi13benzoate, 243 milligrams of the product were obtained, mp 169-1 69.5 ° C. = 33.2 ’'; c = .005 in tetrahydrofuran.

Example 9 (-) - Cis-3-CC6-C (5-fluoro-2-benzothiazoli1) methoxy3-3,4d hydro-4-hydroxy-2H-1-benzopyran-3-i13methyl 13-N- (phenylsulfonyl) benzamide

The synthesis was carried out as in example 1, but using 4.4 grams of benzene sulfonamide instead of methane sulfonamide, and using 2.4 grams of (-) c is-4-ni trc · pheni 1-3 -C C6-C (5-fluoro-2-benzatiazoli1) methoxy 3-3,4-dihydro ~ 4-hydroxy-2H-1 ~ benzopyran-3-i 1 3methyl optically pure benzoate and 628 milligrams of sodium hydride . There was obtained 1.02 g of product, mp 161 ~ 162 ^r -'C. C «p'j = -30 °; c = .005 in tetrahydrofuran.

Example 10

Cis-3-CC6-C (5-fluoro-2-benzothiazoli1) methoxy 3-3,4dihydro-4-hydroxy: i-2H-1-benzopyran-3-yl Imeti 13 benzamide

710 milligrams of is-4-nitrophenyl-3-tto-t (5-fluoro-2-benzothiazole) 1) metho: ·; i 3-3,4-dihydro-4-hydrox i-2H-1-benzopyran-3-yl3methyl3benzoate were dissolved in 10 milliliters of tetrahydrofuran and 30 milliliters of ether and cooled to -65 ° C. An excess of anhydrous ammonia was bubbled into the reaction mixture for 1 minute. The reaction mixture was then left under stirring at room temperature. The volatile elements were evaporated and the residue was dissolved in ethyl acetate and washed with a 10 percent sodium hydroxide solution. The ethyl acetate layer was then dried over sodium sulfate and evaporated to give 510 milligrams of the crude product. The crude product was recrystallized from acetone to give 225 milligrams of the product, mp 193-194 ^° C.

Mass Spectrum: Calculated for. Cf 25 ^H 21 ^ 2 ° 4 ^FS '464.1. ^ 00.

Found, 464.1197.

Example 11

Uis-5-C [6-U 5-fluoro-2-benzthiazole i 1) methoxy 3-3,4-dihydro4-hydroxy ~ 2H-1-benzopyran-3-i 3methyl. 13 ~ N, N ~ dimethyl benzamide

364 milligrams of triethylamine were added to a solution containing 1.5 grams of is-4 ~ nitrophenyl-3 -!;! -C (5-fluaro-2-benzothiazole .i 1) methoxy 3-3,4-di hydro-4-hydroxy-2H-1-benzopyran-3 — i13methyl13benzoate in tetrahydrofuran at 0 * C. After stirring for 5 minutes at 0 ° C, a solution of isobutyl chloroformate in 5 milliliters of tetrahydrofuran was added dropwise. After stirring at 1 ° C for 15 minutes, 364 milligrams of anhydrous dimethylamine were bubbled into the reaction mixture for 1-2 minutes. The reaction mixture was allowed to warm to room temperature and the volatile elements were evaporated. The residue was purified by chromatography on silica gel, eluting with methylene dichloride / ethyl acetate to give 535 mg of the product.

Mass Spectrum: Found: 493.1504.

Calculated for C2 H2 N2 O.FS, 492.1505.

And in peep 12

Cis-3-CC 6-C (5-fluoro-2-benz zothiazoli1) methoxy1-3,4 — d hydroxy-hydroxy-2H-i-benzopyran-3-i1 Dmeti 13-M- <2-thiazoli1) benzamide

The synthesis was carried out as in example 1, but using 1.43 grams of 2-aminothiazole instead of methane sulfonamide, and using 1.17 grams of cis-4-nitropheni1-3-E [6-C (5- fluoro-2-benzothiazoli1> methoxy 3-3 ,, 4-dihydro-4 ~ hydroxy-2H ~ 1-benzopyran-3-yl 3methyl Ibenzoate, 145 milligrams of the product were obtained, mp 120 ° C.

Mass Spectrum: Calculated for C ^ _A H ^. ~ _T M- _r O ^ FS.- ,, 547.1009.

Found, 547. 1006 ..

faxemolo 15

Cis-3-CE6-L (5-fluoro-2-benzothiazoli1) methoxy 3-3,4-dihydro4-hydroxy-2H-1-benzopyran-3-yl 3-methyl 3-W- <3-thiopiridoi 1) ben zamid

The synthesis was carried out as in example 1, but using 1.1 grams of thionicotinamide instead of methane sulfonamide, and using 150 milligrams of sodium hydride and 586 milligrams of cis-4-nitrophenyl-3-C Cò-í ( 5-fluoro-2-benzothiazoli1) methoxy.3-3,4-dihydro-4-hydroxy-2H-1-benz opi-3-yl 3-methyl 1 benzoa.

170 milligrams of the product were obtained in the form of a foam.

Example 14

Çis-3-C C6-l (5-fluor0-2-benzothiazoli1) methoxy 3-3,4-dihydro-4-hydroxy-2H-1-benzopyran-3-i13meti 13-N- (4-methoxy-2-ben zotiazoliI ) benzamide

The synthesis was carried out as in example 1, but using 2.56 grams of 2-amino — 4-methoxy benzothiazole, and using 1.17 grams of cis-4-nitrophenyl-3-tL6-E (5-fluoro ~ 2 -benzothiazo1yl) -methoxy 3-3,4-dihydro-4-hydroxy-2H-1-benzopyran-3-i13methyl 13benzoate. 447 milligrams of the product were obtained in the form of a foam.

Mass Spectrum: Calculated for C .-. ^ - Hr -. ^ N-O ^ SF, 462.1213.

xi xl · xL vJ

Found, 462-1208.

-29 Viridical kings

there „- Process for O production of a composed with formula: R ¹ R ² R ³ \ ___AA: 1 I jJ, l ¹ n z on what R ¹ is quinolyl, quinoli replaced it, benzothiazoli1 o,

substituted benzothiazolyl, benzopyrimidinyl, substituted benzopyrimidinyl, wherein said substituted quinolyl, substituted benzothiazolyl, and substituted benzopyrimidinyl are substituted with an or. further substituents which are independently selected from the group consisting of fluoro, bromo, chloro, phenyl, hydroxy, trifluoromethyl and (C4 -C4) alkyl;

R 'and R ^- ' are each H or OH;

Y is CH ^ .O, C _n H _r , or C _O H ^; a is CH ._, O, S, NH or NR ^Z ;

R? is alkyl;

n is an integer from 0-3; and Z is CONHW or CONíMe) ₇ ; in which W is Q S0, 0 or COO; wherein it is hydrogen, phenyl, substituted phenyl, (C1 -Cg) alkyl, cycloalkyl, tetrazolyl, or thiazolyl, wherein the foregoing substituted phenyl groups are substituted with one or more independent substances, fearfully known from among the group consisting of chlorine, fluoro and alkoxy;

C iTi characterized by eonprehend — the reaction of a compound formula

(III)

2 3 where X, Ύ, R, R, R and n are as defined before 5

Claims (9)

later and R is p-nitrophenyl, with a compound of the formula NHW, where W is as defined above, in a reaction inert solvent. 2nd. Process according to claim 1, characterized in that said solvent is tetrahydrofuran, p-dioxane, benzene, 1,2-dimethoxyethane and toluene, and the reaction is carried out at a temperature varying between about ô ' ^:, C and 10Ci ° C. 3e. Process according to claim 1, characterized in that said compound of formula III is reacting a compound of formula: prepared COOR (II) where R, R ^, R '',. ό 4 '\ riorior and R is F-JjCiJOR' ^- ', in which reaction. Y, X and n are as defined as anhydrogen, with a compound of the formula R ^J is p-nitrophenyl, in a solvent inert to 4§. - Process according to claim 3, characterized in that the preparation of said compound of formula III is carried out using pyridine as a solvent at a temperature ranging from about δ ' ^: ' C to about 10 ° C. 5-â Process for the production of a compound with the formula: wherein p1 is quinolyl, substituted quinolyl, benzothiazolyl, substituted benzothiazolyl, benzopyrimidinyl, substituted benzopyranidinyl wherein said substituted quinolyl, substituted benzothiazolyl, and substituted benzopyrimidinyl are replaced with an or. further substituents which are independently selected from the group consisting of fluoro, bromo, chloro, phenyl, hydroxy, trifluoromethyl and (C4 - C4) alkyl; R ^ and R '' are each H or OH; Y is CH ^ O, or C ^ H; X is CH ^O, S, NH or NR; R4 is alkyl; η is an integer from 0--3; and 7. is CONHW or CONÍME) ^; where W is · SO ^ Q, COQ or £ 3; wherein it is hydrogen, phenyl, substituted phenyl, (C. -C _a ) ¹ alkyl, cycloalkyl, tetrazolyl, or thiazolyl, wherein the above substituted phenyl groups are substituted with one or more substituents independently selected from the group which consists of chlorine, fluoro and alkoxy; 1 4 characterized by the reaction of a compound with the formula: (IV) in which R, R ^, R ' ^- ', X, Yen are defined as above and R ^ÍJ is isobutyl, with a compound of the formula NHQ, where Q is as defined above, in an inert solvent reaction. look. - Process for the production of a compound with formula 1 a: (I) in which it is quinolyl, substituted quinolyl, benzothiazolyl, substituted benzothiazolyl, benzopyrimidinyl, substituted benzopyrimidinyl wherein said substituted quinolyl, substituted benzothiazolyl, and substituted benzopyrimidinyl are substituted with an or. further substituents which are independently selected from the group consisting of fluoro, bromo, chloro, phenyl, hydroxy, trifluoromethyl and (C1 -C4) alkyl; R ^- and R '·' are each H or OH; Y is CH ₂ 0, C ₂ H ₂ or 0 ₂ Ηλ; X CH ^O, S, NH or NR '; R ⁷ is (C ^-C ^) alkyl; n is an integer from 0-3; and Z is CONHW or CON (Me) - ,; where W is S0 _o Q, COO du 0; on what Q is hydrogen, phenyl, substituted phenyl, (C1 -Cg) alkyl, cycloalkyl, tetrazolyl, or thiazolyl, wherein the above substituted phenyl groups are substituted with one or more substituents independently selected from the group consisting of chlorine, fluoro and alkoxy; characterized in that said process comprises the reaction of a compound with the formula: (II) where R, earlier and X, Y and n are as defined before hydrogen, with a compound with the formula R & C00C1, where it is isobutyl, in an inert reaction solvent, and then adding a compound of the formula NHQ, where Q is as defined above, to the reaction mixture. 7th. Process according to claim 6, characterized in that the reaction between said compound of formula II and R RCOOCl is conducted in the presence of a base. j 8ê. Process according to any one of claims 5 to 7, characterized in that said inert reaction solvent is tetrahydrofuran. carac 9â. Process according to claim 7, characterized in that said base is a triethylamine. 10th. Process according to any one of claims 5 to 7, characterized in that said process is carried out at a temperature ranging between about 0 ° C and about