PL140273B1 - Method of obtaining novel bicyclic benzene derivatives - Google Patents

Description

The present invention relates to a process for the preparation of new bicyclic benzene derivatives, in particular certain 5-hydroxy-7-substituted-3,4-dihydro-2H-benzopyran which are also unsubstituted in the 4-position, their corresponding analogs and derivatives. tetralin as well as pharmaceutically acceptable cationic or acid addition salts useful as agents acting on the peripheral nervous system and in particular as analgesics, antidiarrheals and antiemetics in mammals, including humans. In addition, methods for using these compounds have been reported. Although many painkillers are available today, the search for new and improved painkillers is ongoing, which indicates that there is no drug suitable for alleviating various types of pain, with minimal simultaneous action. side. The most widely used agent, aspirin, is of virtually no importance in the treatment of severe pain and is known to have various undesirable side effects. Other stronger painkillers, such as d-propoxyphene, codeine, and morphine, cause narcotic addiction. Therefore, the need for improved and powerful analgesics is evident. A number of dibenzo [b, d] pyran analgesics having substituents in the 9-position, such as alkyl, hydroxyl and oxo, are described in the descriptions U.S. Patent Nos. 3,507,885, 3,636,058, 3,649,650, 3,856,821, 3,928,598, 3,944,673, 3,953,603, and 4,143,139. A particularly interesting compound is dl-trans-1-hydroxy-3. (1,1-dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,10, -10a-hexahydro-9H-dibenzo [b, d] pyranone-9, antiemetic and antiemetic agent with properties analgesics in animals, now commonly referred to as nitrous. U.S. Patent No. 4,152,450 discloses certain 3-alkyl-1-hydroxy-tetrahydrodibenzo [b, d] pyranes and 3-alkyl-1- hydroxyhexahydrodibenzo [b, d] pyran, having an amino group or an amide group at the 9-position, useful as analgesics, antidepressants and In U.S. Patent No. 4,188,495, the analgesic 1,9-dihydroxyoctahydrophenanthrenes, 1-hydroxyoctahydrophenanthrenones-9 and their derivatives of general formula I, and X§ represent the CHOH group or the C group, are disclosed. = 0, M8 is CH2, and Ri, R4, R5, Z and W are as defined above. U.S. Patent 4,260,764 discloses compounds of formula 1 in which M8 is NR6 and X9, Ri , R4, R§, R6, Z and W are as defined above. They are useful as painkillers, anesthetic agents, kayaks, diuretics, antihypertensives, and treatments for glaucoma. U.S. Patent No. 4,228,169 discloses that the same compounds are useful as antiemetics. Bergel et al., H. J. Chem. Soc. 286 (1943) studied the substitution of the pentyl group in the 3-position at the 7, 8, 9, 10-tetrahydro-3-pentyl-6,6,9-trimethyl-6H-dibenzo [b, d] pyranol-1 by alkoxy groups containing 4-8 carbon atoms and found that these compounds showed no or at most minimal hashish activity at doses of 10-20 mg / kg. In a new study, Loew et al. in J. Med. Chem. 16, 1200-1206 (1973) presented a comparison of 7,8,9,10-tetrahydro-3-substituted-6,6,9-trimethyl-6H-dibenzo [b, d] pyranol-1, in which substituent 3 is an OCH / CH8 / C5Hn group, a -CH2CH / CH8 / C5HH group or a -CH / CHs / CgHn group. The compound containing the side ether chain shows 50% less activity in relation to the peripheral nervous system. A compound in which the alkyl side chain is attached directly to the aromatic ring, not through an oxygen atom, and is 5 times more active than a compound in which the oxygen atom is replaced with a mhylene group. Mechoulam and Edery in Marijuana "published by Mechoulam, Academic Press, New York, (1973), page 127, have observed that, as a result of more significant structural changes in the tetrahydrocannabinol molecule, there is a gradual reduction in the analgesic effect. U.S. Patent No. 4,087,545 discloses antiemetic and counter-proportional properties of l-hydroxy-3-alkyl-6.6a, 7,8,10,10a-hexahydro-9H-dibenzo- [b, d] pyran-9. Sallan et al., NEJ Med. 293, 795 (1975) found that orally administered 8-9-tetrahydrocannabinol had an antiemetic effect in patients who received anticancer drugs. Shannon, et al. (Life Sciences 23, 49-54, 1978) found that 8-9-tetrahydrocannabinol was not shown to be anti-emetic. ¬ zuje d antiemetic treatment of apomorphine induced vomiting in dogs. Barison et al., N. England J. of Med. 298, 1480 (1978) describe the use of non-anesthetized cats as model animals in determining the antiemetic effect of compounds, especially in association with anticancer drug induced vomiting. They found that the initial administration of 1-hydroxy-3- (1,1 ', 1'-dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,10,10a-hexahydride to non-anesthetized cats -9H-dibenzo [b, d] pyranone-9 (8H) (saturated) provides significant protection against spontaneous vomiting after injection of anticancer drugs. * Starting materials of formula 2 where Ri, R4 ,. R5, M, Z and W have the meanings given above, which are useful in the preparation of the compounds according to the invention, are known in the art. Specific methods for the preparation of such starting materials in which M is oxygen are described in U.S. Patent No. 4,143-139, and U.S. Patent No. 4,235,913. Similarly, detailed methods for the preparation of the above starting materials, in which M represents the CH2 group are described in U.S. Patent No. 4,188-495 and U.S. Patent No. 4,228,169. It has now been found that certain 3,4-dihydro-2H-benzopyran, suitable tetralins and their derivatives of general formula III are effective medicinal substances useful in mammals as sedatives, anticonvulsants, diuretics, anti-diarrheal agents, anti-cough agents, and agents for treating glaucoma. They are especially useful for mammals, including also people, as painkillers, anti-diarrheal agents Graz, drugs for treatment or prevention Vomiting and vomiting, especially that induced by antineoplastic drugs. Such compounds produced by the method of the invention, which are not drugs and do not cause narcotic addiction, are defined by Formula 3, which also includes their pharmaceutically acceptable cationic salts and acid addition salts, in which M2 is an oxygen atom or a CH2 group, Ri is a hydrogen atom, Z is an alkylene group of 4-9 carbon atoms or an O (alk2) group, in which alk is an alkylene group of 4-9 carbon atoms ¬ gla, W is a hydrogen atom or a phenyl group, Q8 is a COQ4 group, in which Q4 is a NHCOR19, NHSO2Ri7, NR12R18 * NHOH, CH2CN, CH2COOR5 or NHAr group, in which R5 is a hydrogen atom, a methyl or an ethyl group, JRi2 and Ru each represent a hydrogen atom or an alkyl group of 1-4 carbon atoms, Ri7 is an alkyl group of 1-4 carbon atoms, a benzyl or phenyl group, Ri9 is a hydrogen atom, a B alkyl group of 1-4 carbon atoms, a phenyl, benzyl or phenyleth group and Ar is a group of formula 6, 7, 8, 9 or 10. The process of the present invention also includes pharmaceutically acceptable cationic salts and acid addition salts of compounds of formula 3. Pharmaceutically acceptable cationic salts of the compounds of the invention The method of the invention refers to the salts of the compounds of formula III wherein Q8 contains a carboxyl group, these salts being prepared by neutralizing the carboxylic acid with bases of pharmaceutically acceptable metals, ammonia or amines. Examples of such metals are sodium, potassium, calcium and magnesium. Examples of suitable amines are ethanolamine and N-methylglutamine. The term pharmaceutically acceptable acid addition salts denotes addition salts formed by a compound of Formula III having one or more basic nitrogen atoms in the Q8 substituent and a pharmaceutically acceptable acid. such acids include acetic acid, benzoic acid, hydrobromic acid, hydrochloric acid, citric acid, sulfosalicylic acid, tartaric acid, glycolic acid, malonic acid, maleic acid, fumaric acid, malic acid, 2-hydroxy acid. 3-naphthoic acid, 4,4'-methylene bis (3-hydroxy-2-naphthalenecarboxylic acid, salicylic acid, phthalic acid, succinic acid, glycic acid, mandelic acid, lactic acid, sulfuric acid, phosphoric acid) , nitric acid, and methanesulfonic acid. Of course, if there is more than one basic nitrogen atom in a compound of formula III in the form of the free base, mono, double or multiple addition salts can be obtained by using one, two or more acid equivalents to obtain the desired salt. The compounds represented by formula 3 contain an asymmetric center in position 4. Additional asymmetric centers may be present in the substituent at position 7 (ZW). The invention includes rechemes of the compound of formula III, as well as diastereoisomeric mixtures and pure enantiomers thereof. and diastereoisomers. The usefulness of racemic mixtures, diastereomeric mixtures as well as pure enantiomers and diastereoisomers is determined by the biological methods described below. As mentioned above, the compounds of the invention are particularly useful as analgesics, anti-diarrheal agents and anti-diarrheal agents. torsion for use in mammals, including humans. The alleviation of pain in mammals, and the method of preventing and treating vomiting in mammals in which such vomiting occurs, is in each case the oral or parenteral administration of an effective amount of a compound of formula III or a pharmaceutically acceptable salt thereof. The compounds of the present invention are formulated as pharmaceutical compositions for use as pain relieving agents as well as for use in the prevention or treatment of torsion, containing an effective amount of the compound of the method. according to the invention and a pharmaceutically acceptable carrier. The 4-amide and 4-imide compounds of formula III are prepared, for example, in accordance with reaction scheme 1. The method of producing compounds of formula III according to the invention consists in the fact that the compound of formula III is prepared according to the invention. On r.16, where M2, Z, and W have the meaning as above, contact a compound of formula H — Qf or Met ^ Oi, where Qj is as defined above and Met is sodium, potassium or lithium in the presence of a solvent , at a temperature of 20-160 ° C, followed by an intermediate de-denzylation in a known manner. "Hydrogenolysis of the benzyl group in the presence of palladium on carbon as a catalyst can be easily carried out with any of the above product intermediates, except the α, β-unsaturated nitrile, to give the corresponding 5-hydroxyl compounds. Acid addition salts may be formed with certain compounds in a preferred manner. According to the invention, such salts are prepared by known methods.6 The compounds of the invention can be easily converted into derivatives of the compounds of formula III, for example by reacting the corresponding ester of formula III in which Qt is 5 COOR7 group, for example with ethyl lithiumacetate at -70 ° C, hydrolysis of the resulting diester, cyclization of the spiroanhydride and heating it with ammonia or urea at 100-250 ° C produces spiroimides of the compound of formula 3 wherein Q8 is a group of formula 17. Also by reacting compounds of formula III in which R1 is hydrogen with benzoic acid or a suitable alkanoic acid in the presence of s A condensation agent such as dicyclohexylcarbodiimide gives the corresponding esters. Alternatively, they may be prepared by reacting a compound of formula III in which R 1 is hydrogen with a suitable acid chloride or anhydride, for example benzoyl chloride. acetyl chloride or acetic anhydride in the presence of a base such as pyridine. The analgesic properties of the compounds according to the invention are determined in tests using a thermal pain stimulus, such as a mouse tail flutter test, or a chemical pain stimulus such as Measure of the ability of a compound to attenuate convulsions in mice induced by the irritant action of phenylbenzoquinone. These and other studies are described below. Studies using the thermal pain stimulus. A) Test of the anesthetic effect of mice on a hot plate. The method used is the modified Wolfe and MacDonald method. J. Pharmacol. Exp. Ther., 80, 300-307 (1944). The feet of the mice are subjected to an adjustable thermal stimulus on a 3.2 mm thick aluminum plate. An infrared heater of 250 Watt power is placed under the aluminum plate. A thermal regulator, connected to the thermistors on the surface of the plate, programs the heat emitted by the lamp to maintain a constant temperature of 57 ° C. Each mouse is placed in a glass cylinder with a diameter of 1 (54 mm set on a hot plate and the timing begins as soon as the animal's feet touch the plate. 50 Tests are carried out at 0.5 and 2 hours after the test compound is fed, observing time the mouse first starts bouncing on one or both hind legs, or when 10 seconds have elapsed without such movements. MPE value for subcutaneous morphine 4-5.6 mg / kg (subcutaneously). b) Testing of anesthetic effect by the mouse tail flapping method The method used is a modified tail flutter method by Wetilug D'Amour and Smith, J. Pharmacol. Exp. Ther. 72, 74 ^ 79 (1941), in which the tail is subjected to a regulated amount of high intensity heat. Each mouse is placed in a matched line in a metal rope so that its tail protrudes from one end of it. The cylinder is positioned so that the tail lies freely on the covered heating lamp. At the beginning of the experiment, the aluminum shroud around the lamp moves away, allowing the light beam to pass through the aperture and focus on the end of the tail. At the same time, a timer is activated. The delay of the sudden tail flutter is measured. A mouse that is not dosed with any compound typically reacts within 3-4 seconds after being exposed to the lamp. The maximum period of protection is 10 seconds. Each test mouse is 0.5 and 2 hours after administration of morphine and the test compound. The MPE60 value for morphine is 3.2-5.6 mg / kg (subcutaneously). c) Tail dip test This method is a modification of the vascular test developed by Benbassef et al., Arch. int. Pharmacedyn. 122, 444 (1959). Male white mice weighing 19-21 g, derived from the Charles River CD-1 strain, are weighed and labeled for identification. Typically 5 animals are used in each group for drug testing, with each animal also serving as its own control. For general classification, new test agents are first used at 56 mg / kg, intraperitoneally or subcutaneously administered by at a volume of 10 ml / kg. Before administering the drug and at 0.5 and 2 hours after its administration, each animal is placed in the cylinder. Each cylinder is provided with holes to ensure adequate ventilation and is closed by a round nylon plug through which the tail of the animal protrudes. The cylinder is kept upright so that the tail is completely immersed in a water bath at a constant temperature of 56 ° C. The ending point of any attempt is a sudden jerk or twitch of the tail coupled with a motor response. In some cases, the end point may be less noticeable after administration. To prevent undesirable tissue damage, the sample is terminated and the tail is removed from the water bath within 10 seconds. The delay of the reaction is measured in seconds with an accuracy of 0.5 seconds. Selected animals are tested simultaneously with a control medium and a known standard. activity. If the activity of the test agent did not return to the initial value during the test after two hours after its administration, the delay of the reaction was determined after 4 and 6 hours. The final test is done after 24 hours if the test compound is still active at the end of the test day. Tests using a chemical pain stimulus. Weakening of convulsions caused by phenylbenzoquinone irritant. Carworth Farma CD-1 mice in groups of 5 are pre-treated with saline, morphine, codeine or the test compound subcutaneously or orally. After 20 minutes (with subcutaneous administration) or 50 minutes (with oral administration), phenylbenzoquinone is administered to each group by intraperitoneal injection, an irritant known to induce an abdominal cuticle. Observations are made for 5 minutes for convulsions in the mice, starting 5 minutes after injection of irritant. The MPE60 for blocking convulsions x for each pre-administered drug is assessed. Pressure pain stimulus trials 10. Effect on tail pinching by Haffner's method. Modified Haffner's method, Experimentalle Priifung Schmerzatillender, Mittel Deutch Med. Schr. 55, 731-732 (1929) was used to study the effect of an administered compound on aggressive attacking responses induced by stimulus tail pinching. Male albino rats of the Charles River (Sprague-Dawley) CD strain weighing 50-60 g were used. Before dosing and again at 0.5 1, 2 and 3 hours after dosing, 63 mm of the rat tail is clamped on the end of the drug. Johns Hopkins' toothed buckle. The end point of each trial is a clear action directed at the irritating stimulus, consisting in attacking and biting it. Attack delay is measured in seconds, Clamp is removed after 30 seconds if attack has not yet occurred, assuming then a response delay of 30 seconds. Morphine is active at 17.8 mg / kg when administered intraperitoneally. with the use of electrical pain stimuli The "trample-jump" test. In order to determine the pain thresholds, the modified OK "trample-jump" method was used, according to Tener, Psychopharmology, 12 278-285 (1968). Male albino rats of the Charles River (Sprague-Dawley) CD strain weighing 175-200 g were used. Before dosing, the paws of each rat were immersed in 20% glycerol in saline solution. The animals are then placed in the chamber and given a series of 1 second shocks to the feet with increasing intensity at 30 second intervals. These intensities are 0.26, 0.39, 45 0.52, 0.78, 1.05, 1.31, 1.58, 1.86, 2.13, 2.24, 2.72 and 3, 04mA. Each rat's behavior progresses into (a) trotting, (b) squeaking, and (e) a leap or rapid forward movement in response to shock. Each rat is subjected to a single series of shocks of increasing intensity just before, and at 0.5, 2, 4 and 24 hours after drug administration. The results of the above trials are reported as the maximum possible effect as a percentage of C ° / MPE) 55 The% MPE of each group is compared statistically with the MPE for the reference and the pre-drug control. % MPE is calculated as follows: time for test compound - time for standard% MPE * 60 maximum test time - time for standard X 100 As mentioned above, the compounds prepared according to the invention are particularly useful as antiemetics and anti-emetic agents. -140 273 10 Civics for mammals. They are particularly useful in the prevention of vomiting and vomiting induced by antineoplastic agents. The antiemetic properties of compounds of formula 3 have been determined in non-anesthetized, deprived cats according to the method described in Proc. Soc. Exptl. Biol. and Med., 160, 437-440 (1979). Treatment of Diarrhea PGE2 (Prostaglandin E2) Diarrhen in mice The antidiarrhoeal effect of the compounds of the invention is described by the modified method of Dajanfe et al., European Jour. Pharmacol. 34, 105-113 (1975). This method reliably causes diarrhea in untreated mice within 15 minutes. Diarrhea-free animals are considered to be protected by the test compound. The suppressive effect of the test compounds is denoted as "all or none" reactions, with diarrhea defined as watery unformed stool, very different from the common phases, which are composed of well-formed, compact and relatively dry bobs. Charles River CD-1 male albino mice are used. They are kept in collective cages and examined within a week after birth. The weight of the animals at the time of testing is 20-25 g. Pasteurized rat chow is freely available up to 18 hours before the test, after which the food is removed. The animals are weighed and marked for identification. ¬ custom of 5 animals. Mice weighing 20-25 g. Table of testing the analgesic and antiemetic effect of compounds of formula 3, in which M represents an oxygen atom or the group —CH2— Qa M - oxygen atom CONH - formula 6 CONH - formula 20 CONH - formula 24 CONHCONH2 CONHCOCHCH3 QH5 CONHCOCH3 CONHCOC6H5 CONHCOCH (CH3) ^ CONHCOC (CH3) 3 COOH | Formula 5 COCH2C02Et COCH2CN CONHOH CONH2 CONH2, COON CONHCOCH3 M = -CH 2 COOH CONH2 CONHCH3 CONHCOCH3 CONHCOCH3 CONHCONH2 CH2NHCOCF3 COCH2CN COCH2C02Et CH2CONH2 1 CH2CONHCOCH3 HHHHHHHHHHHHHHHHHHHHA HHHHHHH R * ZW) BBBBBBBBBBBBBBBBCCCAA AAAAAAAA MPEB0 (mg / kg) POPGE2 10 10 '10 10 10 * 3 , 6 <10 10 10 - 10 10 10 10 - - - - - - 3.2 5.0 - 32 32 32 32 - MTF 100 100 100 100 - 7.3 31.2 100 320 - - 100 - - 100 - - - - - - - - - - - - - PBQ 10 10 10. 10 10 0.22. 2.8 2.1 1.2 <10 100 10 10 - 10 - 42 MPw 100 100 9.9 MPa 100 - - 28.4 56 - 32 <32 32 32 5.6 SCPBQ 10 10 10 10 10 0, 08 7.9 10 <10 10 - 10 <ro - 10 2 - - - 56 56 56 56 6.4 32 32 32, 32 1.0 56 MTF | PGE2 ^ 100 100 100 100 - 0.21 320 100 320 - '- 100 - - 100 16.4 - - - 56 56 56 - <56 56 56 32 32 17.8 56 10 10 10 10 10 ¦ 0.07 4 , 1 10 3.7. 10 - 10 10 10 10 2 - - - 10 10 10 7.0 <1 32 32 ¦ 32 32 <1 10 A - means OCH (CH3) CH2CH2CH2C6H6 B - means C (CH3) 2 (CH2) 5CH3 C - means CH2CH (CH8), 140 273 11 are hid in group cages without feeding them overnight prior to testing. Water is freely available. The animals are administered PGE2 (0.32 mg / kg i.p., as a solution in 5 / • ethanol) one hour after drug administration and immediately placed individually in 15 x 15 x 18 cm clear acrylic boxes. After 15 minutes, diarrhea is assessed for on disposable sheets of cardboard placed at the bottom of the box according to a two-step absolute scale. Vehicle and PGE * and vehicle-only groups serve as controls in the daily study. Data are analyzed using important regression. linear probit response to dose on a logarithmic scale. The programmed computer prints the results in the form of a linear regression analysis including the degrees of freedom, sum of squares, mean squares, and the critical values F05 and CHi square. If the regression is significant, compute ED, EDM, ED7 + EDW and 95 Confidence limits. The analgesic and anti-diarrheal activity of the compounds of formula III in mice is shown in the table below. The results were obtained using the methods described above. The compounds of the invention are active analgesics, anti-diarrheal, anti-emetic or anti-emetic. For oral or parenteral administration, and for such applications, they are conveniently administered in the form of a composition. Such compositions contain a pharmaceutical carrier selected according to the intended method of use and standard pharmaceutical practice. For example, these compounds may be administered in the form of a composition. in the form of tablets, pills, powders or granules, containing additives such as starch, milk sugar, Any types of clays and the like can be administered in capsules in a mixture with the same or equivalent additives. It is also possible to use them in the form of oral suspensions, solutions, emulsions, syrups or elixirs, which may contain flavors and coloring agents. For oral administration, tablets or capsules containing from about 0.01 to about 100 mg of a compound according to the invention are most suitable for most applications. Suspensions and solutions of such compounds of Formula 3, i.e., where Ri is hydrogen. are usually prepared just before use to avoid problems with drug stability (eg, oxidation) or with the stability of suspensions or solutions (eg, settling out) of the drug upon storage. Dry solid compositions are usually best suited for such applications and are adapted to be administered by injection. The dose that will be most appropriate for an individual patient depending on the age, weight, and response of the individual patient and the method of administration. will be determined by the physician. Typically, however, the starting dose of Iowa analgesia, as well as the starting dose for the prevention or treatment of adult vomiting, may be 0.01-500 mg per day in a single administration or in portions. In sixty-six cases it is not necessary to exceed 100 mg / day. The indicated oral dose range is from about 0.01 to about 300 mg / day and the preferred range is from about 0.10 to about 50 mg / day. The indicated parenteral dose range is from about 0.01 to about 100 mg / day, and the preferred range is from about 0.01 to about 20 mg / day. The following examples illustrate the method of the invention without limiting its scope. 5-benzyloxy-4-cyano-2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihydro-2H-benzopyran A. Mixture 5.0 g (12.3 mmol) 5-benzyloxy-20 -2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihydro-2H-4-benzopyranone and 20 ml of benzene were stirred under a nitrogen atmosphere. 2.04 ml of trimethylsilylnitrile and 80 mg of zinc iodide were added to the resulting solution, and stirring was continued at 2 ° C at room temperature for 3 hours. 16 ml of pyridine and 9.4 ml of phosphorus oxychloride were added, the mixture was heated under reflux for 3.5 hours, cooled to room temperature and poured into a mixture of ice and 35 ml of concentrated hydrochloric acid. the mixture was extracted with ethyl acetate, dried over MgSO 4 and the solvent was evaporated under reduced pressure to give 5.63 g of an oil residue which was purified by chromatography on silica gel using hexane / ethyl ether to elute. After evaporation of the solvent from the product fractions, 3.93 g of 5-benzyloxy-4-cyano-2,2-cimethyl-7- (1,1-dimethylheptyl) -40-2H-benzopyran was obtained. on a 5-times larger scale, 24.5 g of crude material was obtained, which was purified on silica gel to give 19.05 g of product. 1 H-NMR (CO? t 8) in ppm (6): 5.05 (s, 2H). 6.10 (s 2H), 7.20 (m; 5H). B. A mixture of 418 mg (1 mmol) of unsaturated nitrile obtained in Part A above, 485 mg of magnesium turnings, 15 ml of methanol and 5 ml of tetrahydrofuran was stirred under nitrogen M overnight at room temperature. The mixture was cooled in ice and water was added to the flask to settle a precipitate, the pH of the mixture was adjusted to 3.0 with hydrochloric acid, and the clear solution was extracted with ethyl acetate. The extracts were washed with water and brine, then dried over MgSO 4. After evaporating the solvent under reduced pressure, 422 mg of crude material was obtained, which was purified by chromatography on silica gel using hexane / diethyl ether as elution. Evaporation of the combined fractions containing the product gave 294 mg (70%) of the title compound. &lt; 1 &gt; H-NMR (CDCl) &lt; ppm ([delta]), 4.00 6.40 (s, 2H), 7.30 (m, 5H). 65 Example II. 5-benzyloxy-4-carboxamido-13 140 273 14 -2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihydro -2H-benzopyran Up to 3.4 g (8.2 mmol) 5-benzyloxy-4-cyano--2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihydro-2H-benzopyran was added a solution of 40 g of potassium hydroxide in 160 g of ethylene glycol and 10 ml of water. The mixture was heated at 150 ° C. under argon for 24 hours, diluted with 700 ml of water, acidified to pH 5 and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over MgSO 4, then the solvent was evaporated to give 8.5 g of a crude product which was subsequently purified by chromatography on silica gel, eluting with ethyl ether / hexane 1: 4, then 1: 1. The combined product fractions were evaporated to give 2.0 g of the desired amide. The fractions containing the starting material were pooled, evaporated to dryness, further hydrolyzed under the above conditions for 48 hours and processed as described above to give 1.5 g of crude material which, after purification on a silica gel column, gave an additional 1.0 g of amide and 550 mg of the corresponding carboxylic acid. The combined amide fractions were crystallized from methylene chloride / hexane to give 2.55 g of product, mp 117-120 ° C. iH-NMR 'CDClI) ppm (6): 3.70 (t, 1H), 5.00 (s, 2H), 5.75 and 6.15 (broad singlets 1H + 1H), 6.50 (c, 2H), 7.30 (m, 5H). Example III. 4-carboxamido-5-hydroxy--2,4-dimethyl-7- (1,1-dimethylheptyl) 3,4-dihydro -2H-benzopyran Mixture 1.6 g 5-benzyloxy-4-carboxamide -2, 2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihydro-2H-benzopyran, 320 mg of 10% palladium on carbon and 50 ml of methanol were hydrogenated by shaking at 0.3 MPa overnight. The catalyst was removed by filtration and the filtrate was evaporated to give 1.21 g of solid which was recrystallized from ethyl acetate to give 520 mg of product, mp 174.5-175 ° C. An additional 220 mg of product was recovered from the crystalline liquors. * H-NMR (CDC18) ppm (o): 2.10 (d, '2H), 3.65 (t, 1H), 4.80 (broad s, 3H), 6.30 (dd, 2H). Example IV. 4-cyano-5-hydroxy-2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihydro-2H-benzopyran By hydrogenation 5-benzyloxy-4-cyano-2,2 -dimethyl-7- (1,1-dimethylheptyl) -3,4-dihydro-2H-benzopyran was obtained by the method described above to obtain titular hydroxynitrile, m.p. 142-144 ° C. '. - iH-NMR (CDClI) ppm (o): 2.20 (d, 2H), 4.05 (t, 1H), 6.40 (m, 2H). Example V. 5-hydroxy-4-methoxycarbonyl- 2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihydro-2H-benzopyran A. 5-benzyloxy-2,2-dimethyl-7- (1,1-dimethylheptyl) acid) -3,4-dihydro-2H-benzopyran-4-carboxyl. A mixture of 2.0 g 5-benzyloxy-4-cyano-2,2-dimethyl-7- (1,1-dimethylheptyl) 3,4- dihydro-2H-benzopyran, 20 g of potassium hydroxide and 100 ml of ethylene glycol were refluxed under nitrogen for 18 hours and then cooled to ambient temperature. The mixture was acidified to pH13 with concentrated hydrochloric acid and extracted with ethyl acetate, then the extracts dried over MgSO 4. Evaporation of the solvent gave an oil which was dissolved in diethyl ether, washed with water and brine, dried over MgSO 4 and the solvent was evaporated to give 2.09 g of crude solid. The crude product was purified by silica gel chromatography as applied to. elution with ether / hexane mixture. The product fractions were combined and the solvent was evaporated to give 1.69 g of product, mp 137-138 ° C. 20.: 'I- B. 5-benzyloxy-2,2-dimethyl-7- (1,1-dimethylhepyl) -3,4-dihydro-2H-benzopyran-4-carboxylate of methyl solution 550 mg of acid The carboxylic acid prepared in A, dissolved in 20 ml of dry diethyl ether, was treated with an excess of diazorhetane. The mixture was allowed to stand at room temperature for 15 minutes, washed with dilute sodium bicarbonate solution, dried over MgSO 4 and the ether evaporated to give 470 mg of the methyl ester, which was used in the next step without purification. C. 470 mg of the product from Part B above was mixed with 200 mg of 10% palladium on carbon catalyst and 40 ml of methanol. The mixture was hydrogenated under a shaking pressure of 0.3 MPa for 3 hours. After removal of the catalyst by filtration and evaporation of the solvent, 320 mg of crude product was obtained, which was purified by chromatography on silica gel, eluting with hexane / ethyl ether 1: 1. 300 mg of the desired compound 5 was obtained. hydroxyl. * H-NMR (CDCl 8) ppm (6): 1.10 (dd, 2H), 3.75 (s, 3H), 3.80 (t, 1H, 6.40 (s, 2H) ), 6.50 (s, 1H). '; Example VI. 4-N-acetylcarboxyimido-5- -N-hydroxy-2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihydro 2H-benzopyran A. 5-benzyloxy-2,2-dimethyl-7- (1,1-dimethylhep-50-yl) -3,4-dihydro-2H-benzopyran-4-carboxylate p-nitrophenyl Mixture 3.3 g (7.53 mmol) of 5-benzyloxy-2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihydro-2H-benzopyran-4-carboxylic acid, 5.0 g (21.3 55 mmoles) of p-nitrophenyl trifluoroacetate and 100 ml of dry pyridine were stirred under nitrogen at room temperature for 3 hours. The pyridine was evaporated under reduced pressure, and diethyl ether was added to the residue. the anhydrous product was washed with 1 N sodium hydroxide, water, 10% hydrochloric acid and brine, dried over MgSO 4 and the solvent was evaporated to give 4.5 g of a crude oil. The oil was dissolved in pentane and cooled to give 3.38 g of crystal of talc, m.p. 87-87.5 ° C, 140 273 15 B. 4-N-acetylcarboximido-5-benzyloxy-2,2-dimethylmethyl. 7 - (-1,1-dimethylheptyl) -3,4-dihydro-2H-benzopyran. 35 ml of dry tetrahydrofuran were added to 301 mg (5.1 mmol) of acetamide and nitrogen was passed through the solution while adding 103 mg of hydride. sodium 99% (4.3 mmoles). The resulting mixture was stirred overnight under a nitrogen atmosphere, then 400 mg (0.716 mmoles) of p-nitrophenyl ester obtained in part A were added and stirring was continued for 1 hour at room temperature. The mixture was poured into ice-water, adjusted to pH 3.0 with 10% hydrochloric acid, and extracted with ethyl acetate. The extracts were washed with brine, saturated sodium bicarbonate and brine again, then dried over MgSO. Evaporation of the solvent gave 416 mg of crude solid which was dissolved in methylene chloride, washed with sodium bicarbonate solution and brine, dried over MgSO 4 and the solvent was evaporated to give 331 mg of foam. On addition of hexane, 249 mg of crystals were formed. Treatment with hot hexane and cooling and filtering yielded 216 mg of product, mp 157-158 ° C. iH-NMR (CDC18) ppm (?): 2.20 (s, 3H), 3.80 (t, 1H), 5.0 (S, 2H), 6.50 (s, 2H), 7.30 (s, 5H), 8.10 (s, 1H). C. The product from Part B above in an amount of 216 mg, 45.5% palladium on carbon and 25 ml of ethyl acetate were shaken under an atmosphere of hydrogen under atmospheric pressure for 2.5 hours. After filtration and evaporation of the filtrate, 150 mg of product were obtained, mp 146-147 ° C. By repeating the procedure of part B above and using instead of acetamide the appropriate amide of formula R10CONH2, sulfonamide of formula R17SO2NH2 or urea and hydrogenation of the obtained product according to the method of Part C above, the corresponding imide compounds of formula 18 are obtained, in which Q $ represents the CONHCOR19 group, the CONHSO2R17 group or the CONHGONH2 group, and R17 and Rji are as defined below: 1Q ". - CONHCOR19: Ri.CH (CH8) a C (CH8), CH, CeH5CH (CHa) (diastereoisomer A) C6H, CH (CH1) (diastereoisomer B) Remarks mp 143-148 ° C | mass spectrum, m / c: M + 431, base peaks 360 i H-NMR- (CDCl,) ppm (8): 4.05 (t, 1H) 6.50 (m, 2H), 7.1 (s, 1H ). mp 172-173 ° C mp 141-146 ° C 1 mass spectrum, m / c: M + 479. 1H-NMR (DCC18) ppm (8): 3.85 (t, 1H), 4.3 (q , 1H), 6.2 (m, 2H), 7.2 (s, 5H). mp 144-149 ° C mass spectrum, m / c: M + 479, base peak 105 i H-NMR (CDCl 3 (ppm) δ): 3.90 (t, IH), 4.40 (q, IH), 6 , 35 (m, 2H), 7.25 (s, 5H) 1 16 Q3-CONHCOR19: R19 1 C6H5CH2 n — QH9 Q3 == CONHCONHa Q3 = CONHS02R17: Ri7 = CH3 Remarks - mp 154—158 ° C. Mass spectrum, m / c: M5 390, (M — HN3) 373 Comments mp 155-156 ° C, mass spectrum, m / c: M + 425, base peak 303 Example VII. 5-Hydroxy-2,2-dimethyl-15 -7- (1,1-dimethylheptyl) -3,4-dihydro-2H-benzppyran-4-hydroxamic acid. A. 5-Hydroxy-2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihydro-2H-benzopyran-4-carboxylic acid. 20 A mixture of 5.0 g of 5-benzyloxy-2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihydro-2H-benzopyran-4-carboxylic acid, obtained by the method of Example V, Part A, 500 mg of 5% and palladium-on-carbon catalyst and 150 ml of ethyl acetate were hydrogenated for 18 hours by the method of Example III. Removal of the catalyst and evaporation of the solvent gave 4.25 g of foam. Purification by silica gel chromatography, eluting with 2: 1 hexane / ethyl ether, gave 1.84 g of product, mp 147-148 ° C. P-nitrophenyl 5-hydroxy-2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihydro-2H-benzopyran-4-carboxylate. A mixture of 4.25 g (12.3 mmoles) of the product from Part A, 8.67 g (37 mmoles) of p-nitrophenyl trifluoroacetate and 50 ml of dry pyridine was stirred for 65 hours at room temperature. The mixture was evaporated to remove pyridine and the remainder was treated as in Example VI, Part A to give 5.085 g (88%) of the desired ester. i H-NMJl (CDCl) ppm (δ): 6.5 CH), 7.0-7.3 (m, 2H), 8.0-8.3 (m, 2H). 45 ° C. A mixture of 43 mg (1.066 mmol) of powdered sodium hydroxide in 10 ml of pyridine was stirred with heating until dissolved in nitrogen and then cooled to 0 ° C. 111 mg (1.6 mmol) was added to this solution. 50 of hydroxylamine hydrochloride and the mixture was stirred for 15 minutes. Subsequently, a solution of 250 mg (0.533 mmol) of the product from Part B in 3.0 ml of pyridine was added. The mixture was allowed to warm to room temperature and stirred overnight. The pyridine was evaporated and the residue was dissolved in water and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over MgSO 4 and the solvent evaporated to give 260 mg of crude product which was applied to a 30 g silica gel column. Elution was carried out with hexane / ethyl ether for 10 fractions. and then with ethyl acetate to elute the desired product. After evaporating the solvent (fraction 18-20), 158 mg of the title compound were obtained. Spectrum ma-140 273 17 18 sugar (M + 363), 1 H-NMR (CDCl 1) ppm (δ): 6.20 <4H, 2 aromatic, NH, OH), 10.0 (1H, with AO). Example VIII. N-2-pyridyl-5-hydroxy--2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihydro -2H-benzopyrancarboxamide A. N-2, -pyridyl-5-benzyloxy- 2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihydn-2H-benzopyrancarboxamide Mixture 1.118 g (2.0 mmol) 5-benzyloxy-2,2-dimethyl-7- (l) , 4-nitrophenyl 2-dimethylheptyl (3,4-dihydro-2H-benzopyranecarboxylate), 376 mg (4.0 mmol) of 2-aminopyridine and 4 ml of pyridine were placed in a sealed tube and heated for 18 hours at 155-157 ° C . After cooling, the tubes were opened, the mixture was concentrated to dryness under reduced pressure, the residue was dissolved in diethyl ether, washed with 25 ml of N hydrochloric acid, three 25 ml portions of 1N sodium hydroxide, two 25 ml portions each. water and 25 ml of brine. The washed ether solution was dried over MgSO 4 and the solvent was evaporated to give 966 mg of an oil. The oil was purified by chromatography on a silica gel column, eluting with hexane / methylene chloride 1: 4 followed by 15% ethyl ether in methylene chloride. The product fractions were combined and the solvent was evaporated under reduced pressure to yield. 823 mg (80%) of the desired amide B. A mixture of the above amide and 10% palladium on carbon catalyst, 691 mg each, 1.08 g of 1,4-cyclohexadione and 25 ml of dry ethanol was hydrogenated at 0.28 MPa for 14 hours in the presence of palladium on carbon. After removal of the solvent under reduced pressure, 680 mg of crude denzylated product was obtained, which was purified on a silica gel chromatography column, eluting first with methylene chloride, then with methylene chloride containing 10% of ethyl ether, and then with the end is diethyl ether itself. 515 mg (90%) of the depenzylated material was obtained, which was recrystallized from an ethyl acetate / hexane mixture to give 398 mg (70%) of product, mp 166-167 ° C. Mass spectrum, m / c: 424 (molecular ion), 119 base peak C. By using the corresponding amine of formula ArNH * in place of 2-pyridylamine, the following compounds of formula 19 were obtained as above: Ar Formula 20 Formula 21 Formula 22 | formula 23 Formula 54 "Melting point, ° C 238.5—239 - 208—209 —Mass spectrum (m / c) M + 430, base 127 M + 534, base 91 M + 444, base 141 M + 425, base 96 | Example IX. 5-hydroxy-2,2-dimethyl-7- (1,1-dimethylheptyl) -spiro [3,4-dihydro-2H-benzopyran-4,3'-pyrrolidine-2 ', 5'- dione] A. 5-benzyloxy-4-ethoxycarbonylmethyl-4-methoxycarbonyl-2,2-dimethyl-7- (1,1-dimethylheptyl) - -3,4-dihydro-2H-benzopyran Under anhydrous conditions under nitrogen atmosphere 5.31 ml of 1.6 ml of n-butyllithium in hexane was added to a kdtba containing 80 ml of dry tetrahydrofuran at -78 ° C. A solution of 1.2 ml (848 mg, 8.4 mils) was added dropwise. - moles) of freshly distilled diisopropylamine and the resulting mixture was stirred at -78 ° C for 3 hours. A solution of 3.1 g (6.85 mmol) of 5-benzyloxy-2,2-dimethyl-7-) was then slowly added. Methyl 1,1-dimethylheptyl / 3,4-dihydro-2H-benzopyran-1-carboxylate (Example V, Part B) in 10 mL of THP, and the resulting mixture was stirred for 3 hours at -78 ° C. Then, 1.40 g (8.4 mmol) of ethyl bromoacetate were added dropwise and stirring was continued for 15 minutes. The reaction was quenched by adding acetic acid and the mixture was allowed to warm to ambient temperature. 50 ml of saturated sodium bicarbonate solution were then added, followed by 50 ml of diethyl ether. The layers were separated. The organic layer was washed with three 25 ml portions of cold 1 N hydrochloric acid, 99 ml of a saturated sodium bicarbonate solution and 30 ml of water, and dried with anhydrous MgSO 4 - after evaporating the solvent, 2.89 g (78%) of the desired diester were obtained. with Rf 0.29 when developed with 3: 1.B hexane / ethyl ether. 5-benzyloxy-2,2-dimethyl-7- (1,1-dimethylhep-yl) -spiro [3,4-dihydro-2H-benzopyran-4,3'-tetrahydrofuran-2 ', 5'-dione ] A mixture of 2.355 g (4.37 mmoles) of diester with part A above, 17.5 g of ethylene glycol, 1 ml of water and 8.74 g of potassium hydroxide was stirred at 150 ° C. under nitrogen atmosphere for 2 hours. It was then allowed to cool and stirred overnight at room temperature. The mixture was poured into 350 ml of ice water, acidified to pH 2-3 with 1N hydrochloric acid and extracted with ethyl acetate. The combined extracts were washed with water and brine then dried over MgSO 4. After evaporating off the solvent under reduced pressure, 2.0 g of the desired dicarboxylic acid were obtained. 50 ml of acetic anhydride were stirred in a separate flask while heating it under nitrogen to reflux (140 ° C). A solution of 2.0 g of the dicarboxylic acid dissolved in 10 ml of ethyl acetate was added dropwise to the anhydride over 4 minutes. The resulting mixture was stirred at 140 ° C. for 10 minutes and then allowed to cool to room temperature. The solvent is evaporated off and the residue is dissolved in diethyl ether, washed with water and brine, then dried over MgSO 4. After evaporation of the solvent, 1.9 g of a light brown solid are obtained. &Lt; 1 &gt; H-NMR (CDC18) ppm ([delta]): 3.15, doublet, 5.1 singlet, 6.25 singlet and 7.3 singlet. Infrared (CHClt): 1787 cm -1 (anhydride C = O). C. A mixture of 100 mg (0.209 mmol) of the product obtained in Part B and 125 mg (2.08 mmol) of urea was heated under nitrogen in tern-19 140 The mixture was dissolved in diethyl ether, washed with water and brine, and then dried over MgSO 4 after evaporation of the solvent. After evaporation of the solvent, 67 mg of the title compound 5-benzyl ether were obtained. which was dissolved in 15 ml of ethyl acetate and hydrogenated against 50 mg of 10% palladium on carbon as a catalyst. The catalyst was removed by filtration, the solvent was evaporated and the residue was dissolved in 15 ml of ethanol and rehydrated against a fresh catalyst under pressure. 0.25 MPa. After the product was isolated by filtration and evaporation of the solvent, 54 mg of solid title compound was obtained, m.p. 105-120 ° C., from which crystals having a melting point of enia 141-143 ° C. Mass spectrum: molecular ion m / c 387. Sub-red (CHC18) 1715 cm-1 (C = O). Example X. 5-benzyloxy-2,2-dimethyl-7- / 2 - -methylpropyl) -3,4-dihydro-2H-benzopyranone-4 A. 3,5-dihydroxyisobutylbenzene Mixture 66.2 g of 1-hydroxy-1- (3,5-dimethoxyphenyl) -2-methylpropane (obtained from reaction of 3,5-dimethoxybenzaldehyde with isopropylmagnesium chloride in diethyl ether at 0 ° -5 ° C.) and 230 g of pyridine hydrochloride were heated under nitrogen at 190 ° C. for 5 hours. The resulting mixture was cooled to 30 ° C, poured into 500 ml of ice water and acidified to pH 3.0 with 10% hydrochloric acid. The acid mixture was extracted three times with ethyl acetate and the extracts washed with water and brine. and then dried over MgSO 4 and the solvent is evaporated off under reduced pressure to give 50.9 g of an oily residue. This oil is dissolved in methyl chloride, filtered and the solvent evaporated to 43 g of crude 3,5-dihydroxyisobutinylbenzene which is purified. by chromatography on a 1200 g silica gel column, eluting with ether / methylene chloride. This gave 31.9 g of purified olefin. 1 H-NMR (CDC18) ppm (8): 1.75 (d, 6H). 5.95 (s, 1H), 6.05-6.35 (m, 3H), 6.50 (s, 2H). To 16 g of this olefin in 100 ml of ethyl acetate was added 1.6 g of 10% palladium on carbon, and the mixture was hydrogenated at 0.3-0.4 MPa for 6 hours. After isolating the product in the usual way, 15.4 g of material was obtained and used in the next step. 1 H-NMR (d, 2H), 6.15 (s, 3H), 6.60 (s, 2H). B. 5-hydroxy-2,2-dimethyl-7- (2-methylpropyl) -3,4-dihydro-2H-benzopyranone-4. A mixture of 20.3 ml of methanesulfonic acid and 1.0 g of phosphorus pentoxide was heated under nitrogen. to 70 ° C and 2.1 g (12.7 mmol) of Part A product in 5 ml of diethyl ether are added. Then, 1.27 g (12.7 mmol) of 3,3-dimethylacrylic acid were added and the mixture was kept at 70 ° C for 15 minutes, then poured into ice water and extracted with ethyl acetate. After washing with water and brine, the extracts were dried over MgSO 4 and the oil to yield was evaporated. Purification on a silica gel column, eluting with methylene chloride, gave 1.04 g of the desired product, Rf 0.75, using CH 2 Cl 2. Δ H-NMR (CDCl 8) ppm (δ): 2.30 (d, 2H), 2.65 (s, 2H), 6.10-6.25 (m, 2H), 11.6 (m, 7H C. A mixture of 2.0 g of the product from Part B above, 50 ml of acetone and 5.55 g of powdered potassium carbonate was stirred for 5 minutes, and 1.38 of benzyl bromide was added. The mixture was stirred at reflux for 16 hours, cooled, filtered, and the filtrate was evaporated to an oil which gave crystals in cold hexane. Mp 77.5-78 ° C, 1.49 g. 1 H-NMR (CDCl 8) ppm (?): 2.30 (d, 2H), 2.60 (s, 2H), 5.04 ( s, 2H), 6.25 (s, 2H), 7.05-7.60 (m, 5H). Example XI. 5-benzyloxy-4-cyano-2,2-dimethyl-7- (2-methoxypropyl) 3,4-dihydro-2H-benzopyran. A. By the method of example I, part A, a mixture of 1.49 g (4.43 mmol) of 5-benzyloxy-2,2-dimethyl-7- (2-methylpropyl) -3,4-dihydro-2H-benzopy - ranon-4, 10 ml of benzene, 0.8 ml of trimethylsililinitrile, 30 mg of zinc iodide, 6 ml of pyridine and 3.5 g of phosphorus oxychloride were transformed into 5-benzyloxy -4-cyano-2,2-dimethyl-7 - / - 2-methylpropyl / -2H-benzopyran at 2.2 g. IHrNMR (CDCl5) ppm (8): 2.25 (d, 2H),? 5.05 (s, 2H), 6 , 15 (s, 1H), 6.23 (s, 2H), 7.05-7.60 (m, 5H) B. By hydrogenating the above olefin according to example I, part B, using 1.94 Magnesium turnings and 100 ml of methanol yielded 12.3 g of crude dihydronitrile which was purified by chromatography on silica gel using a 1: 4 ethyl acetate / methylene chloride mixture as elution. From the fractions containing the product, 7.8 g of the title compound were obtained. 1 H-NMR (CDCl 8) ppm (?): 3.85 (t, 1H), 5.04 (s, 2H), 6.20 (s, 2H), 7.05-7.60 (m, 5H Example XII. 5-benzyloxy-2,2-dimethyl-7- (2-methylpropyl) 3,4-dlhydro-2H-benzopyran-4-carboxylan-4'-nitrophenyl A. 5-benzyloxy-2,2-dimethyl acid -7- (2-methyl-proplo) -3,4-dihydrobenzopyran-4-carboxylic acid. A mixture of 7.8%, 2 mmoles of the product of the previous example, 12.5 g of KOH in the form of pellets and 200 ml of ethylene glycol was reacted as in Example V, Part A, to give 8.25 g of crude acid, which was purified by chromatography on silica gel, eluting first with 1: 4 diethyl ether / chloromethylene, then ether alone, and finally methanol / diethyl ether 1: 9. 6.13 g of product were obtained, from which crystals were formed in the methylene chloride / hexane mixture, m.p. 152-153 ° C. B. A mixture of 3.0 g (8.15 mmoles) of the acid obtained in part A 2.87 g (12.2 mmoles) of p-nitrophenyl trifluoroacetate and 40 ml of dry pyridine were stirred at room temperature for 60 hours. The pyridine was evaporated under reduced pressure and the residue was washed with three 250 ml portions of 1N hydrochloric acid. , four 25 mL portions of N N sodium hydroxide, water and brine, and then dried over MgSO 4. After evaporation of the solvent, 4.0 g of a crude foam product were obtained, which was crystallized from methylene chloride / hexane to give 3.67 g of the title product, mp 125-126 ° C. Example XIII. 5-Hydroxy-2,2-dimethyl -7- (2-methylpropyl) -3,4-dihydro-2H-benzopyran-4-carboxylic acid The title compound with a melting point of 185—187 ° C was obtained by catalytic hydrogenolysis the corresponding benzyl 5-ether obtained in example XII, part A, using the methods described above. Example XIV. A. By following the procedure of Examples VI and VII, but starting from the p-nitrophenyl ester obtained in Example XII and the corresponding amide or urea, the following compounds of formula 25.Q3 - CONHCOCH3 CONHCOCH (CH3) 2 were similarly obtained. CONH2 mp. ° C 156-157 117-120 206-207 'Example XV. A. Using 3,3-dimethyl-6- (5-phenyl-2-pentyloxy) -8-benzyloxytetralone as a starting material (prepared according to US Patent No. 4,188,495) in the method of Example 1 , part A, was obtained in quantitative yield, the corresponding unsaturated nitrile, 8-benzyloxy-1-cyano-3,3-dimethyl-6- (5-phenyl-2-pentyloxy) -3,4-dihydronaphthalene in the form an orange-colored oil B. The oil from Part A above was hydrogenated by the method of Example I, Part B, giving the corresponding tetraline, 8-benzyloxy-1-cyano-3,3-dimethyl-6- (5-phenyl-2-pentyloxy) - tetraline in the form of an orange-colored oil, yield 89 ° / ° C The tetralin nitrile obtained above was hydrolyzed in ethylene glycol with potassium hydroxide according to the method of Example V, Part A, to give the corresponding acid, 8-benzyloxy-3,3-dimethyl-6- (5-phenyl-2) acid. -pentyloxy) -tetroline-1-carboxylic acid, in the form of a white-colored foam, yield 39%. A mixture of 1.6 g of the product from the portion above, 20 ml of methanol and 320 mg of 5% palladium-on-carbon catalyst, was hydrogenated at 0.3 MPa for 3 hours, then the product was isolated by filtration and filtration evaporation to give 1.2 g of a colorless solid foam, 92.5% pure mixture of diastereoisomers as shown by analysis by high pressure liquid chromatography (HPLC) on a Zobax Sil column (registered trade name of EI duPont de Nemours and Co., Inc. , Wilmington, Del.), Using 2% isopropyl alcohol in hexane to elute at a rate of 1 ml / minute. 1H-NMR (CDCl,) ppm (?): 0.8 (s, 3H), 1.0 (s, 3H), 1.2 (d, 4H), 1.74 (m, 6H), 2, 5 (m, 4H), 3.7 (m, 1H), 4.16 (m, 1H), 6.1 (s, 2H), 7.1 (m, 5H), 8.1 (broad s, 22 1H), which is consistent with the structure of 8-hydroxy -3,3-dimethyl-6- (5-phenyl-2-pentyloxy) tetraline-1-carboxylic acid. Reaction of 3.14 mmoles of the above acid 5 with 3.45 mmoles of p-nitrophenyl trifluoroacetate in 15 ml of pyridine according to example VII, part B, yielded 1.1 g (69%) of 8-hydroxy-3,3-dimethyl P-Nitrophenyl 6- (5-phenyl-2-pentyloxy) tetralin-1-carboxylate in the form of a yellow-colored oil. ^ F. Using the benzyl ether obtained in Part C above, in Method E above, 8-benzyloxy-3,3-dimethyl-6- (5-phenyl-2-pentyloxy) p- tetra-lino-1-carboxylate was obtained nitrophenyl as oil 15 with 90% yield. TLC: Rf 0.68 using 2: 1 hexane / ethyl acetate as solvent. Example XV. 8-hydroxy-3,3-dimethyl-6- (5-phenyl-2-pentyloxy) tetraline-1-carboxamide. 20 A. Reaction of 4.3 g (3.9 mmol) of p-nitrophenyl 8-benzyloxy-3,3-dimethyl-6- (5-phenyl-2-pentyloxy) tetraline-1-carboxylate with excess liquid ammonia at 70 ° C for 30 minutes, followed by evaporation of the excess ammonia to a yellow paste, which after chromatography on silica gel using a mixture of ethyl acetate / hexane 1: 1, 730 mg of the amide was obtained with Rf 0.15 by TLC with solvent system ethyl acetate / hexane 2: 1. Also 1.15 g of starting material was recovered. B. Hydrogenation of Part A in 50 ml of methanol with 400 mg of 5% palladium on carbon as catalyst at a pressure of 0.3 MPa for 4.5 hours and the usual treatment gave the crude product, which was purified in a silica gel column using 2: 1 ethyl acetate / hexane as solvent; 40,130 mg of the title compound were obtained in the form of a white solid, mp 155-157 ° C. iH-NMR (CDCl,) ppm (δ): 0.8 (s, 3H), 1.0 (s, 3H), 1.16 (d, '3H), 1.7 (m, 6H), 2 , 47 (m, 4H), 3.57 (m, 1H),? 4.16 (m, 1H), 6.1 (d, 3H), 7.2 (s, 5H). By reacting 0.55 g (1.1 mmol) of p-nitrophenyl 8-hydroxy- • -3,3-dimethyl-6- (5-phenyl-2-pentyloxy) tetralin-1-carboxylate in 10 ml of tetrahydrofuran with an excess of gaseous methylamine at room temperature, pouring the resulting mixture into 10% hydrochloric acid, extraction with ethyl acetate and working up in a known manner, 0.50 g of N-methylamide: N-methyl-8-hydroxy-3,3- was obtained. dimethyl-6- (5-phenyl-2-pentyloxy) -tetraline-1-carboxamide foam. 1H-NMR (CDCl,) ppm (?): 0.8 (s, 3H), 1.0 (s, 3H), 1.2 (d, 4H), 1.7 (m, 6H), 2, 53 (m, 6H), 3.6 (m, 1H), 4.23 (m, NH), 6.2 (d, 2H), 7.13 (s. 5H). Example XVII. 8-hydroxy-3,3-dimethyl-6- (5- 60-phenyl-2-pentyloxy) tetralin-1-carbonylurea. By reaction 1.2 g (2 mmol) of 8-benzyloxy -33-dimethyl-6- (P-nitrophenyl 5-phenyl-2-pentyloxy) tetraline-1-carboxylate, 0.3 g (5 mmoles) of urea and 0.248 g (10 mmoles) of sodium hydride in 65 12 ml of dimethyl sulfoxide at room temperature 140 273 After 1 hour, isolating the product by the method of example VI, part B, and removing the benzyl group by hydrogenolizing the method of example VI, part C, pure title compound was obtained with a total yield of 36%. 1H-NMR (CDCl2) ppm (?): 0.77 (m, 3H), 1.1 (m, 8H), 1.7 (m, 4H), 2.5 (m, 4H), 3, 6 (m, 1H), 4.16 (m, 1H), 5.7 (s, 1H), 6.1 (s, 2H), 7.1 (s, 5H), 8.2 (s, 2H) Example XVIII. By reacting 1.1 g (1.9 mmol) of p-nitrophenyl 8-hydroxy-3,3-dimethyl-6- (5-phenyl-2-pentyloxy) tetralin-1-carboxylate, 10 g (17 millimoles) of acetamide, 361 mg (15 mmoles) of sodium hydride in 70 ml of tetrahydrofuran according to the method of Example VI, Parts B and C, similarly obtained 8-hydroxy-3,3-dimethyl-6- (5-phenyl-2) -pen-yloxy (-1N-acetylcarboximide yield 55%, in the form of a foam). 1H-NMR (CDCl8) ppm (?): 0.7 (s, 3H), 1.0 (s, 3H), 1.16 (d, 3H), 1.6 (m, 6H), 2.3 (s, 3H), 2.5 (m, 4H), 3.73 (m, 1H), 4.13 (m, 1H), 6.1 (s, 2H), 7.1 (s, 5H) , 8.5 (NH). Example XIX. Ethyl 3- [8-hydroxy-3,3-dimethyl-6- -5-phenyl-2-pentyloxy / tetralin-1-yl] -3-oxopropionate. Solution 0.50 g (1 mmol) of 8- benzyloxy -3,3-dimethyl-6- (5-phenyl-2-pentyloxy) tetraline-1-carboxylic acid in 5 ml of diethyl ether was cooled to 0 ° C and 0.25 g (1.2 ml of limola) phosphorus pentachloride. The mixture was stirred at 0 ° C for 30 minutes, then at room temperature also for 30 minutes. Evaporation of the ether under reduced pressure gave the chloride, acidic, as a brown oil. In a separate flask, 0.5 ml (3.4 mmol) of diisopropylamine in 6 ml of tetrahydrofuran was cooled to -78 ° C and 1.4 ml of 2.1 molar n-butyl lithium was added, and the mixture was allowed to warm to a temperature. 0 ° C and stirred at this temperature for 30 minutes. The mixture was re-cooled to -78 ° C, 0.30 mL (3.1 mmol) of dry distilled acetate was added and the mixture was stirred at -78 ° C for 2.5 hours. The acid chloride obtained above was added and 2 ml of tetrahydrofuran was added, and stirring was continued at -78 ° C for 2 hours. The reaction was stopped by adding water, the mixture was warmed to room temperature, poured into 10% hydrochloric acid and extracted with ethyl ether. May The extracts were washed with water and brine, then dried over MgSO 4. Evaporation of the solvent gave 0.55 g of a yellow oil which was purified by chromatography on silica gel using a hexane / ethyl ether mixture as solvent. 3: 1, 0.13 g (24%) of the benzyl ether of the title compound was obtained, which was hydrogenated according to Example VI, Part C, to give 110 mg of a colorless oil which was further purified by chromatography on silica gel. 61 mg was obtained. (56%) of the product. 1H-NMR (CDC18) ppm (6): 0.8 (s, 3H), 1.07 (s, 3H), 1.2 (m, 7H), 1.7 (m, 5H), 2.53 m, 4H), 3.5 (s, 3.8) (m, 2H), 4.13 24 (m, 2H), 6.13 (s, 2H), 6.5 (s, 1H), 7 . 13 (s. 5H). Mass Spectrum (m / c): M + 452. Example XX. 3- [8-hydroxy-3,3-dimethyl-6- (5-phenyl-2-pentyloxy) tetralin-1-yl] -3-oxo-propio-5 nitrile. To a solution of 2.4 ml 2.1 molar n -butyllithium in 3.7 ml of tetrahydrofuran at -78 ° C a solution of 0.26 ml (5 mmol) of acetonitrile in 3.7 ml of THF was added and the mixture was stirred for 1 hour at -78 ° C. Solution 1 was added. 1 g (2.0 mmol) of p-nitrophenyl 8-benzyloxy -3,3-dimethyl-6- (5-phenyl-2-pentyloxy) tetralin-1-carboxylate in 3.7 ml THF and mixing continued at -78 ° C for 30 minutes. The mixture was warmed to room temperature, the reaction was quenched by the addition of 7 ml of 10% hydrochloric acid and then extracted with ethyl ether to yield 1.13 g of crude benzyl ether. Chromatography on silica gel gave 500 mg of purified derivative. Mass Spectrum - Molecular Ion 495. After removal of the benzyl group by hydrogenolysis according to the method of Example VI, part C, the pure title compound was obtained. iH-NMR (CDCl,) ppm (?): 0.8 (s, 3H, 1.06 (s, 1.2), m, 5H, 1.7 (m, 4H), 2.5 (m, 4H), 3.5 (m, 2H), 4.0 (m, 2H), 6.1 (s, 2H), 7.1 (s, 5H). Example XXI. 8-hydroxy-1-trifluoroacetyl- aminomethyl-3,3-dimethyl-6- (5-phenyl-2-pentyloxy) tetralin. To a suspension of 114 mg (3 mmoles) of lithium aluminum hydride in 10 ml of diethyl ether at room temperature was added a solution of 1 36 g (3.0 millioles) of 8-benzyloxy-1-cyano-3,3-dimethyl-5- (5-phenyl-2-pentyloxy) tetralin in 10 ml of tetrahydrofuran, and the mixture was refluxed under a chiller. reflux for 2 hours. After cooling to 0 ° C., 30 ml of ether were added and the reaction was stopped by adding 150 ml of water and 150 ml of sodium hydroxide. 450 ml more of water were added, the mixture was stirred for 15 minutes, filtered and washed. with ether, then the separated organic layer was dried over MgSO 4 and concentrated to a volume of about 50 ml. To this crude amine solution was added within 15 minutes at room temperature 0.70 ml of triethyl amine and 565 ml (4.0 mmol) of trifluoroacetic anhydride. The mixture was then diluted with 50 ml of ether and washed with 25 ml of 10% hydrochloric acid, 25 ml of water, saturated sodium bicarbonate solution and brine, then dried over MgSO 4. Evaporation of the solvent and chromatography of the residue on a silica gel column using a 1: 9 mixture of methanol / methylene chloride to elute gave 500 mg of benzyl ether of the title compound, which was debenzylated according to Example VI. Part C, yielding 250 mg of oil. Mass spectrum (m / c): 367, 337, 191, 91, 69.1H-NMR (CDCl8) ppm (o): 0.7 (s, 3H), 0.1 8 (s, 3H), 1.1 (s, 3H), 1.2-2.0 (m, 6H), 2.0-3.0 (m, 7H), 4.0 (m, 1H) ), 5.8-6.0 (m, 2H), 6.1 (NH), 7.0 (s, 5H). 140 273 26 Example XXII. 2- [8-hydroxy-3,3-dimethyl-6 / -5-phenyl-2-pentyloxy / tetralin-1-yl] acetamide Solution 0.76 g (2 mmol) of 2- [8-hydroxy acid lectone -3,3-dimethyl-6- (5-phenyl-2-pentyloxy) tetralin-1-yl] acetic acid in 10 ml of diethyl ether was added to the excess liquid ammonia at -30 ° C and the mixture was stirred while heating it to room temperature for 2 hours. After evaporation of the solvent, a white solid was obtained, which was dissolved in ethyl acetate, washed with water and brine, then dried over MgSO 4. After evaporation of the solvent, 800 mg (100%) of the title compound were obtained, m.p. 72 ° C. 1 H-NHR (CDC18) ppm (5): 0.86 (s, 3H), 1.06 (s, 311), 1.26 (d, 5H), 1.7 (m, 6H ), 2.6 (m, 3.4), m, 1H (4.23m, 1H (5.6) m, 2H (, NH2), 6.2 (m, 2H), 7.2 ( s, 5H). The compounds of formula III prepared in the above examples are converted into their salts or acid addition salts as follows: By an ether solution of the corresponding free base of formula III in which there is at least one group containing a basic atom nitrogen, a molar excess of anhydrous hydrogen chloride is passed through and the resulting precipitate is separated and recrystallized from a suitable solvent, for example a methanol / ether mixture. The free bases of formula III are likewise converted into their corresponding hydrobromide, sulfate, nitrate, phosphate, oc tan, maslate, malonate, maleate, fumarate, malate, glycolate, glyconate, lactate, salicylate, sulfosalicylate, succinate, 4,4-methylenebis (3-hydroxy-2-naphthalenecarboxylate) and tartrate. Claims A process for the preparation of new bicyclic benzene derivatives of formula III, wherein M2 is oxygen or CH2, Ri is hydrogen, Z is an alkylene group of 4-9 carbon atoms or O (alk2), where alk is an alkylene group of 4-9 carbon atoms, W is a hydrogen atom or a phenyl group, Q3 is a COQ4 group in which Q4 is NHCOR19, NHSO2R17, NHAr, NR12R18, NHOH, CH2CN or CH2COOR5 in which R5 represents a hydrogen atom, a methyl or ethyl group, R12 and R18, each independently, is a hydrogen atom or an alkyl group of 1-4 carbon atoms, R17 is an alkyl group of 1-4 carbon atoms, a benzyl or phenyl group , Ri9 represents a hydrogen atom, an alkyl group of 1-4 carbon atoms, a phenyl, benzyl or phenylethyl group, and Ar is a group E of formula 6, 7, 8, 9 or 10, characterized in that the compound of formula 16, wherein M2, Z and W have the above meanings, is contacted with a compound of formula HQ8 or MetQ8, wherein Q8 has the above meaning the meaning given, and Met is sodium, potassium or lithium, in the presence of a solvent, at a temperature of 20 to 160 ° C, followed by an intermediate de-denzylation in a known manner. CU! ≥ 19 pRi R5- ^ M3 ZW r ^ M ^^ z Formula 1 Q3 OR, CH3 / o Pattern 3 cTVo Pattern 5 ^ 5 Pattern 8 ZW 1 Pattern 6 $ Pattern 9 Pattern 2 NI ^ I-CO WzcH -es1 N Pattern 7 Pattern 10140 273 OCH2C6H5 CH3 CK CN OCH2C6H5 M (C ^ SiCN. chAJ Pattern 12. . . Formula 13 • ZW 2 POCl3 Formula 11 CN OCH2g-l5 Exemplary 14 KOH / HOCH2CH2OH t reflux condenser Scheme 1 Scheme 1 c.d. ", conh9ch ^ k MeOH c ^ M ^ zW 150 ° C ^^ I COOH OCH ^ H, CHUfYl CRCOO - ^ - NOAK Ch ^ M ^ ZW Wzcir 15 C0 (K-N02C6H, OCH2C6H5 (Wzflr16 + F, 9CONH2 R7S02NH2 ArNH2 NH, OH NHF ^ Ra L! CH, Q4 then L ... H2I · d / c "CH Scheme 1 Wzdr 3a where Q ^ is CONHCOR, 9 CONHS02R17 CONHAr CONRJ ^ CONHOH iub140 273 Formula 17 CONHAr OH Q3 OH CH CH, 'v ^ v O' CH3 CH, Formula 18 CH3 CH Wals 19 (CH? K; h MoD2Q, ^ CH3 Formula 22 Cl Formula 23, CH3 Formula 21 Moisture 24 Q3 OH, N CH3 CONHCO ^ jf n_s U UH3 Formula 25 Formula 11 PL

Claims (1)

Claim 1. Process for the preparation of new bicyclic benzene derivatives of formula III, wherein M2 is oxygen or CH2, Ri is hydrogen, Z is an alkylene group of 4-9 carbon atoms or O (alk2) wherein alk is an alkylene group of 4-9 carbon atoms, W is a hydrogen atom or a phenyl group, Q3 is a COQ4 group, in which Q4 is NHCOR19, NHSO2R17, NHAr, NR12R18, NHOH, CH2CN or CH2COOR5 in where R5 is hydrogen, methyl or ethyl, R12 and R18, each independently, is hydrogen or alkyl group of 1-4 carbon atoms, R17 is alkyl group of 1-4 carbon atoms, benzyl or phenyl Y1, Ri9 represents a hydrogen atom, an alkyl group of 1-4 carbon atoms, a phenyl, benzyl or phenylethyl group, and Ar is a group of the formula 6, 7, 8, 9 or 10, characterized by the compound of formula 16, wherein M2, Z, and W have the meanings given above, contacting a compound of formula HQ8 or MetQ8, wherein Q8 has the above-mentioned The meaning, and Met, is sodium, potassium or lithium, in the presence of a solvent, at a temperature of 20 to 160 ° C, followed by an intermediate de-denzylation in a known manner. CU!? 1 9 pRi R5- ^ M3 ZW r ^ M ^^ zw Formula 1 Q3 OR, CH3 / o Pattern 3 cTVo Pattern 5 ^ 5 Pattern 8 ZW 1 Pattern 6 $ Pattern 9 Pattern 2 NI ^ I-CO WzcH - es1 N Formula 7 Formula 10140 273 OCH2C6H5 CH3 CK CN OCH2C6H5 M (C ^ siCN. chAJ Formula 12. ", conh9ch ^ k MeOH c ^ M ^ zW 150 ° C ~ ^^ Formula 13 • ZW 2 POCl3 Formula 11 CN OCH2g-l5 Sample 14 KOH / HOCH2CH2OH t reflux condenser Scheme 1 Scheme 1 cd I COOH OCH ^ H, CHUfYl CRCOO - ^ - NOAK Ch ^ M ^ ZW Wzcir 15 C0 (K-N02C6H, OCH2C6H5 (Wzflr16 + F, 9CONH2 R7 ArNH2 NH, OH NHF ^ Ra L! CH, Q4 then L ... H2I? D / c "CH Scheme 1 Wzdr 3a where Q ^ is CONHCOR, 9 CONHS02R17 CONHAr CONRJ ^ CONHOH iub140 273 Formula 17 CONHAr OH Q3 OH CH CH, 'v ^ v O' CH3 CH, Formula 18 CH3 CH Moisture 19 (CH? K; h Moisture2Q, ^ CH3 Formula 22 Cl Formula 23, CH3 Formula 21 Moisture 24 Q3 OH, N CH3 CONHCO ^ jf n_s U UH3 Formula 25 Model 11 PL