CS249127B2 - Method of bicyclic compounds with benzene ring - Google Patents

Description

The present invention relates to a process for the preparation of benzene ring bicyclic compounds, in particular to novel 5-hydroxy-7-substituted-3,4-dihydro-2H-benzopyranes which are also substituted in the 3 or 4 position, the corresponding tetrahydroquinoline and tetra-analogs and their derivatives and pharmaceutically acceptable cationic salts and acid addition salts. These compounds are effective as substances affecting the functioning of the nervous system, so that they can be used as analgesics, anti-erythema and diarrhea agents in mammals, including humans. The compounds can be formulated in conventional manner into pharmaceutical compositions.

Although a number of analgesics are currently available, research into these substances with a new and better effect is continuing, as there is still no substance available that can be used for some types of pain conditions, while having as few side effects as possible. The most common analgesic, aspirin, is not suitable for severe pain and, moreover, has various undesirable side effects. Other more active substances of this type, for example d-propoxyphene, codeine and morphine, are compounds whose use leads to addiction. It is quite obvious that there would be registries No. 3,507,885.

856 821 3 928 598

143 139 describes the need to find analgesics with a strong effect without side effects.

U.S. Pat

636 058, 3649'650,

944,673, 3,953,603 and a variety of dibenzo [b, d] pyran derivatives having an alangesic effect; these are substituted in the 9-position, for example by an alkyl, hydroxy or alkoxy group. A particularly important compound of this group is dl-ti? ^I and ns-l-hychOxy-3- (l, l-dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H -dibenzo [b, d] pyran-9-one, a compound that has anti-emetic properties and is effective against anxiety states while having analgesic properties in various animals, is now commonly referred to as nabilone.

U.S. Pat. No. 4,152,450 discloses various 3-alkyl-1-hydroxyxytetrahydrate ^. The α-hexahydriodibenzine [b, d] pyrains having an amino or amidino group at the 9-position are effective as analgesics, anti-depressant and anti-anxiety compounds and as blood pressure lowering agents.

U.S. Pat. No. 4,188,495 discloses analgesic 1,9-dihydroxyoctahydrophenanthrenes, 1-hydroxyoctahydrophenanthren-9-ones and derivatives thereof of Formula XI

where

X9 is CHOH or C = O,

Мз stands for CH2,

R1 represents a hydrogen atom, a benzyl or an alkanoyl of 1 to 5 carbon atoms,

Z and W are as defined below for formula XIX and

R4 and R5 are methyl radicals.

Bergel et al., J. Chem. Soc., 286 (1943) investigates the substitution of the pentyl group at the 3-position 7,8,9,10-etrahydro-3-pentyl-6,6,9-trifluoromethyl-6H-dibenzo [b, d] pyran It has been shown that these substances have a similar effect to hashish at a dose of 10 to 20 mg / kg, but this effect was very small.

Loev et al., J. Med. Chem., 16, 1,200-1,206 (1973), compares 7,8,9,11-tetrahydro-3-substituted-6,6,9-ιίιηβ · β1-6 1-ΰ ^ θηζιθ [[ C 1-4 H-1-ol, wherein the substituent at the 3-position is - OCH (CH 3) C 5 H 11, - CH 2 CH (CH 3) i C 5 H 11, or - CH (CH 3) C 8 H 11. A compound that contained an ether side chain was 50% less central nervous system than the corresponding substances in which the alkyl side chain was directly bound to the aromatic ring and five times more potent than the compound in which the oxygen atom was replaced by a methylene group .

Mechoulam and Edery in Marijuana, Macholam, Academic Press, New York, 1973, page 127, suggest that major structural changes in the tetrahydrocannabnoil molecule appear to reduce analgesic efficacy.

U.S. Pat. No. 4,087,545 discloses the anti-emetic and photizvring effect of certain 1-hydroxy-3-alkyl-6,6a, 7,8,10,10a-hexahydrate-9H-di-hexyl derivatives. b, d] pyran-9-ones.

Sallan et al., N. E. J. Med. 293, 795 (1975) describe the oral thaememetic properties of tetrahydnocannablnol when administered orally in patients with antitumor therapy.

9-Tetrahydrocannabromol is described in Shannoin et al. (Life Sciences 23: 49-54, 1978) as having no auntiemetic effects in dogs in which vomiting was induced by apomiorfin administration. Borisoln et al., N. England J. of Med. 298, 1480 (1978) disclose the use of non-anesthetized cats as a model for determining the anti-emetic effect of the compounds, particularly in connection with the emesis induced by the compounds used in the treatment of cancer. The preliminary dropping of 1-hydroxy-3- (Γ, Γ-dimethylhtpeyl) -6,6-dimethyl-6,6.a ·, 7,8,10,10a-hexahydro-9H-dibeinzo [b, d] pyran has been shown -9 (8H) -one (nabilone) to nonthanphistetized cats protects these cats to a large extent from vomiting, which otherwise occurs after injection of compounds having an anti-tumor effect.

The starting materials used in the preparation of the following compounds of formula (XIX) are known. They are compounds of formula IV

where

R1, M, Z and W are as defined below.

A method for producing starting compounds in which M is an oxygen atom is disclosed in U.S. Patent 4,143,139 of March 6, 1979 and U.S. Patent 4,235,913 of November 25, 1980. A method for producing starting materials wherein M is is CH 2, as described in U.S. Patent No. 4,188,495, issued Feb. 12, 1920.

It has now been found that certain 3,4-dihydro-2H-benzopyranes, the corresponding tetralins and derivatives of the compounds of formula (XIX), the method of manufacture of which is the subject of the present invention, are active agents which can be used in substances, anticonvulsants, diuretics, anti-diarrhea and cough and anti-glaucbm. These compounds are particularly effective in mammals, including humans, as analgesics, anti-diarrhea, and for the treatment and prevention of emesis and naulezel, particularly when these conditions are caused by anti-tumor agents. The compounds do not have an anti-narcotic effect and do not give rise to addiction. They can be represented by the general formula XIX

where

M2 represents an oxygen atom or a group = CH2,

R1 is hydrogen or acetyl,

Z represents an alkylene radical of 1 to 9 carbon atoms or a group O (alk2) wherein (alkjj represents an alkylene radical of 4 to 9 carbon atoms,

W represents a hydrogen atom or phenyl;

Q 3 represents a COQK group wherein

Q 3 denotes CH 2 COOR 5, NHOH, NR 12 R 13, NHSO 2 R 17, or CH 2 CN, wherein

R12 and R13 are each hydrogen or alkyl of 1 to 4 carbon atoms,

Ar represents groups

R 5 represents a hydrogen atom, methyl or ethyl,

Q4 represents CN group neto> COORs,

R19 is C1-C4, alkyl of 1 to 4 carbon atoms, benzyl, phenyl or phenylethyl,

R 17 represents alkyl of 1 to 4 carbon atoms, benzyl or phenyl.

These compounds can be obtained by the process of the invention by the compound of formula XX

where

M2, Z and W are as defined above, contacting a compound of formula

MetQi

Met is hydrogen, sodium, potassium or lithium;

0з ‘is as defined above, in the presence of a solvent at a temperature of 20 to 160 ° C followed by debenzylation of the resulting intermediate.

Pharmaceutically acceptable cationic salts and acid addition salts of the compounds of formulas (XIX) are also within the scope of the invention. The term pharmaceutically ^1-acceptable katlontových salts of the compounds according to the invention is meant the salts of those compounds of the formula XIX, in which the substituent Q 3 contains karboixylovou group, a salt formed by neutralizing the carboxyl groups of the principles that are derived LOD of pharmaceutically acceptable metals, amloniaku and amines. Examples of metals are sodium, potassium, calcium and magnesium. Examples of suitable amines are ethanolamine and N-methylglucamine.

Pharmaceutically acceptable acid addition salts are understood to mean addition salts formed between compounds of formula XIX and one or more basic nitrogen atoms in substituent Q3 with a pharmaceutically acceptable acid. Examples of this acid are acetic, benzoleic, bromo-ovoic, hydrochloric, citric, sulfosalicylic, tartaric, glycolic, malonic, maleic, fumaric, malic, 2-hydroxy-3-naphthoic, pampic, salicylic, phthalic, succinic, gluconic, almond, lactic, sulfuric, phosphoric, nitric and methainsulfoin. Of course, if the violet of formula (I) contains more than 1 basic nitrogen atom, higher addition salts may also be obtained by using one, two or more equivalents of acid to form the desired addition salt.

Compounds of formula (XIX) contain an asymmetric atom at the 4-position, another asymmetric center may be formed at the 7-position (ZW). It will be understood that the invention encompasses racemic mixtures of compounds of formula (XIX), mixtures of diastereomers, pure enantiomers, and diastereomers. The use of racemic mixtures, mixtures of diastereomers and pure enantiomers and diastereomers is dependent on biological evaluation, as discussed below.

As mentioned above, the compounds produced by the process of the invention are particularly valuable as analgesics, anti-diarrhea agents, antiemetics and pnoti nausea agents in mammals including humans. The use of these agents can induce analgesic conditions in mammals, and it is possible to suppress vomiting and nausea by administering an orally or pareinterally effective amount of a pharmaceutically acceptable compound of formula (XIX) or a salt thereof.

The compounds of the present invention may be formulated as pharmaceutical compositions having analgesic activity by treating an effective amount of a compound of the present invention or a salt thereof with a pharmaceutically acceptable carrier.

The 4-amido and 4-imido compounds of formula (XIX) can be obtained, for example, according to the reaction scheme:

About OCH ^ Hs

ICHCH2CH2CH2CH2O2, POCR

R

CONHz осн ^ с ₆ i ₆ zw

OH / HOGH _? CH ^p OH

Z. 5 · (XX) + 5-aImnotetra2u, ------ H2, Pd / C C \ ^s C g) n N R10CONH2, R17ÍSO2NH2, ArNH2, NH2OH, NHR12R13, LiCHžQ.1 ¹ ' ^/ CH N - / / ^X r ⁷ ' н <7 <,, o (IV)

where Q3 is

N ~ N

COHH — tg | l

N-N

CONHCOR19, CONHSO2R17, CONHAr, CONR12R13, CONHOH or

COCH2Q4

R4 and R5 are methyl radicals,

M represents an oxygen atom or a methylene group,

Z, W, R 12, R 13, R 17, R 19 and Ar are as defined for Formula XIX a

Q 4 is a cyano or COOR 5 group, wherein R 5 is as defined for formula XIX.

Hydrogenolysis of the benzyl group in the presence of palladium on activated carbon catalyst can be carried out using any of the above intermediates except α, ε-unsaturated nitrile to give the corresponding

5-Hydroxy derivatives.

Esters of compounds of formula XIX, wherein R represents a benzoyl radical or · an alkanoyl group can be easily prepared by reacting a compound of ^one of formula XIX in which R is hydrogen with benzoic acid, the appropriate alkanoic acid in the presence of a condensing agent , for example, dicyclohexylcarbodiimide. Similarly, they can also be reacted by reacting a compound of formula XIX wherein R 1 is hydrogen with an appropriate acid chloride or anhydride such as benzyl chloride, acetyl chloride or acetic anhydride in the presence of a base such as pyridine.

However, acid addition salts are also formed using the resulting compounds of the process of the invention. These salts can also be obtained in a conventional manner.

The analgesic properties of the compounds of the present invention can be determined using experiments that utilize thermal stimuli that are experimentally avoided, such as animal tails, with a twitch of the mouse tail, and chemical stimuli can also be used, e.g., by measuring the compound's ability · Suppress pain in the phenylbenzochtoon in mice. These experiments will be described below.

Experiments in which thermal stimuli were used

a) Experiment with hot mouse plate

In these experiments, ^one was used · modified method described by Woolfe and MacDonald, J. Pharmacol. Evp. Ther., 80, 300-307 (1944). A controlled thermal stimulus is applied to the mouse paws by means of a 3 mm thick aluminum plate. A 250 W infrared bulb is placed underneath the plate. A thermal controller that is coupled to a thermistor on the plate surface ensures that the lamp is at a constant temperature of 57 ^° C. Each mouse is placed in a glass cylinder about 15 cm in diameter. the hot plate and the time starts counting when the animal's limb touches the plate. After half an hour and two hours after ¹ administration of the test compound, the time at which the mouse withdraws one or both hind paws or the dose is determined. which ensures 10 seconds without these movements. In this case, the morphine has an MPE 50 = 4 to 5.6 mg / kg subcutaneously.

b) Mouse tail withdrawal experiment

The mouse tail withdrawal experiment was performed in a modification of the method described by D‘Am | cour and Smith, J. Pharmacol.

Exp. Ther., 72, 74-79 (1941), high intensity controlled heat was applied to the tail. Each mouse was placed in a metal cylinder from which its tail protruded at one end. This cylinder has been placed so that the tail is above the bulb. The bulb was covered with an aluminum lampshade. At the beginning of the experiment, the lampshade is removed, the light from the bulb is passed through the slit to heat the tail end. At the same time, the time counts down. A sudden withdrawal of the tail is observed after a certain latency period. Untreated mice usually respond within 3 to 4 seconds. The end point of the experiment is to achieve a latency of 10 seconds. Each mouse is followed half and two hours after treatment with morphine and test substance. Morphine has an MPE 50 of 3.2 to 5.6 mg / kg subcutaneously.

c) Tail immersion

In this experiment ¹ was used modification of the method described by Benbasset et al, Arch. int. Pharmacodyn., 122, 434 (1959). To do this, male white mice weighing 19-21 g of Charles River CD-1 strain are weighed and labeled for identification. Usually, five animals are used for each test group, with each animal being its own control. Usually, the novel compounds are administered at a dose of 56 mg / kg intraperitoneally or subcutaneously as the first dose, in a volume of 10 ml / kg. After treatment, the animal is placed in a cylinder after half an hour and two hours. The control treatment is carried out before the active substance is administered. Each cylinder is perforated to provide sufficient air supply and is closed with a nylon plug through which the animal's tail passes. The cylinder is held in an upright position so that the tail is fully immersed in a bath whose temperature is still maintained at 56 ° C. The end point of the experiment is always a vigorous tail jolt, which is associated with the movement response of the entire animal. In some cases, when the analgesic active substances are administered, the response of the animal is not as pronounced. To avoid tissue damage, the experiment is always terminated and the tail is always removed from the water bath after. 10 seconds. The measured latency time shall always be expressed to the nearest half second. In addition to the new active substances, control experiments are always carried out with a solvent and with a standard active substance of known effect. If the substance is still active after a normal time of two hours, further experiments are carried out after 4 to 6 hours. The attempt is always ended after). 24 hours if the potency of the test compound can still be demonstrated after this time.

Experiments using chemicals

Suppression of painful cramps induced by phenylbenoquinone

Groups of five mice of the Carworth Farms CF-1 strain are pretreated subcutaneously or orally with saline, morphine, codeine or the test compound. 20 minutes after subcutaneous treatment or 50 minutes after oral administration, each animal of each group is administered intraperitoneally with phenylbenzoquinone, an irritant that induces abdominal contractions. After the irritant is administered, 5 minutes are waiting, after which the mice are observed for 5 minutes and the presence of painful convulsions is recorded. The MPE 50 value is determined to prevent these convulsions.

Experiments using pressure

Haffner's Tail Compression Test

In these experiments, a modification of the procedure described in Haffner, Experimentelle Prufuing Schmerzstillender was used. Dr. Mittel Deutch Med. Wschr., 55, 731-732 (1929). In this way, the ability of the active substances produced by the process according to the invention to aggressive tail compression behavior of the tail was investigated. Male rats weighing 50-60 g Charles River (Sprague-Dawley) CD were used in the experiment. A 7.5 centimeter clamp (Johns Hopkins) is placed on the root of the rat tail before administration of the drug and again at 0.5, 1, 2 and 3 hours after treatment. The end point of each attempt is a bite attack, aimed at this stimulus with latency, which is recorded in seconds. In the absence of an attack, the clamp is removed after · 30 seconds. Morphine is effective at a dose of 17.8 milligrams per kg intraperitoneally.

Experiments with electric current

Defense reflex test

In these experiments, the defensive reflex test of Tenen, Psychopharmacologia, 12, 278-285 (1968) was used to determine the pain threshold. Male white rats weighing 175-200 g of the Charles River (Sprague-Dawley) CD strain were used in the experiment. Before administration of the drug, the limbs of each rat are immersed in a solution of sodium chloride with 20% glycerol. The animals are then placed in the chamber and exposed to electrical stimuli for 1 second, the intensity of these stimuli increasing at intervals of 30 seconds. Intensities of 0.26, 0.39, 0.52, 0.78, 1.05, 1.31, 1.58, 1.86, 2.13, 2.42, 2.72 and 3.04 mA are used. The behavior of each animal is evaluated by the presence of a) defensive movement with withdrawal of the paws, b) squeaking, and c) jumping up or forward at the start of the stimulus. A series of stimuli are taken in each rat before administration of the active substance at 0.5, 2, 4 and 24 hours after administration of the active substance.

The results of the above experiments are expressed as a percentage of the maximum possible effect (% MPE). This value for each active substance is statistically evaluated in comparison with the same value for the standard substance and the pre-drug control values. This value is expressed by the following formula% MPE = Experiment Time - Control Time End Time - Control Time

X 100

As already mentioned, the compounds of the invention are useful as antiemetics and as nausea suppressants in mammals. They are particularly useful as anti-emesis and nausea-inhibiting compounds for the administration of antitumor agents.

Antiemetic properties were determined on non-anesthetized cats according to Proc. Soc. Exptl. Biol. and Med., 160: 437-440 (1979).

Against the diarrhea effect of the compounds produced by the method of the invention in mice in PGE2-induced diarrhea (prostaglandin E2)

The anti-diarrhea effect of the compounds produced by the method of the invention is determined by modification of the method described by Dajani et al., European Jour. Pharmocol., 34, 105-113 (1975). In this way, diarrhea can be induced in otherwise untreated mice for 15 minutes. Pre-treated animals that do not suffer from diarrhea are considered to be protected by the active substance. The effect of these substances is evaluated only according to whether or not there are watery stools that are significantly different from normal mouse faeces.

Charles River CD-1 white mice were used in the experiment. These mice are used for experiments one week after intake. The mice weigh 20-25 g. They are fed ad libitum within 18 hours prior to the experiment, at which time the feed is removed.

Animals are weighed and labeled for identification. Usually five mice are used for each active substance. Mice weighing 20-25 g are housed in cages in p groups and are not fed at night before the experiment, water is ad libitum. The animals are then coped with PGE2 at a dose of 0.32 mg / kg intaporitoneally in 5% ethanol one hour after drug administration and the animals are immediately placed one at a time in transparent 15 x 15 X 18 cm acrylic cages. The removable pad at the bottom of each cage is removed at the end of 15 minutes to determine whether or not diarrhea has occurred. In the control experiment, solvent + PGE 2 and another solvent-only group were used.

Data are analyzed using linear regression of probits using logarithmic dose, maximum probability determined.

A computer is used to evaluate the results by analyzing linear regression including the degree of Freedom, the sum of the squares, the diameter of the squares and the critical values of F05 and Chi ² . If the regression is statistically significant, ED30, ED50, ED70 and EDao are calculated and then 95% confidence limits.

The compounds of the present invention are useful as analgesics, anti-diarrhea agents, nausea and nausea agents for oral and parenteral administration, and can be administered to the subject in the form of compositions containing the active ingredient and a pharmaceutical carrier selected according to the route of administration. . Thus, it may be, for example, tablets, pills, powders or granules containing carriers such as starch, milk sugar, some types of clay and the like. It may also be a capsule containing the active ingredient together with the same or similar carrier. Oral administration is also suitable for suspensions, solutions, emulsions, syrups and elixirs, which may contain flavoring and coloring agents. For oral administration, tablets or capsules containing from 0.01 to 100 mg of active ingredient are suitable for the vast majority of cases.

Suspensions and solutions of the active compounds, especially those in which R 1 is hydroxy, are usually prepared just prior to use in order to avoid, for example, oxidation or precipitation from the suspension or solution. In this case, a solid is supplied which can also be used for the preparation of injectables.

The physician will readily determine the dose that will be most appropriate in each case and will vary depending on the age, weight and reactivity of each patient and the route of administration. Usually, however, the initial analgesic dose as well as the dose to suppress or treat nausea in adults is in the range of 0.01 to 500 mg per day in a single dose or in several divided doses. In many cases it is not necessary to exceed the 100 mg daily dose. For oral administration, the dose ranges from 0.01 to 300 mg / day, preferably 0.10 to 50 mg / day. For parenteral administration, a dosage range of 0.01 to 100 mg / day is preferred, a range of 0.01 to 20 mg / day is preferred.

The analgesic and anti-diarrhea effect of the compounds of formula (XIX) is shown in the following table. The results were obtained as described above.

O o r-H

Λ

O rH

AND

O r-f

AND

O тЧ

AND

Analgesic and diarrhea effects of compounds of formula XIX

/ ⁴⁴ H *) * 4. * 9 x

with т-4

Λ p

v4

AND

O тЧ

Λ

CQ

CQ

ж Ж я ,. <Ό Ό X i i z ™ ť ^z 1 Ύ 1 of -r z s> 1 OF 0 0 ГЛ of 0 0 0

O

II

S о

Рн а PQ Рн o o

оо о

Η CD хф гН О О I СО

О

АЛ Л

ООО см см о 1 СО СО гЧ о 1 см со о о гЧ л л л л л

о о о CM 1 I and II i О О | т-Ч гЧ А л \ л л

СО оьТгчсмсмсмсмОгЧО гЧ СО СО СО СО гЧ гЧ

Л VAAAAAVA

Ч со

О СО I I о т-ч 1 1 гЧ 1 ^ω 1 ю со со ю ю I со со со см см << ι << 5 1 гЧ ю 1 ю ш ю 00 со л л л л V л л л л V л

о ° 0 t <what “о гЧ о гЧ 13 о гЧ О гЧ IS 1 1 | со о со со со 1 юююю о СМ СМ СМ СМ СО гЧ “со со со со со ю ю л л IN Л IN Л АЛ Л л л л л

МРЕ50 (mg / kg) and рр Рм

Н см “см” см ^г о гЧ

IN

О т-Г о гЧ

А о гЧ

Л

О I О гЧ I гЧ

А Л

СО i i оо со i см см см со i ю

I. I

см со гЧ CD О 1 о о со о о 1 1 см о гЧ со гЧ А

сон СО гЧ о о 1 ° о гЧ гЧ 1 т-Ч гЧ IN л л

5S5 1111

Л Л- Л

СМ О ~ co in in I см СМ СМ СМ I I со со со со I

АЛЛА tO а

СР СР to й <N о з й 2 ω о о и о й й z z о о ω о ю й со —ω

PQ PQ CQ ffi CQ PQ pQ

CQ СР СР СР о и о <<<<<<<<<<<

it ю

Л2 Л2 й ° й й 7S - □ оио о о о о ииии

НН 1—4 НМ НМ Ну * НН ин нм нм нм мм нм нм нм

Ом

N 02 Д ¢ 0

Й <ЙЙЙЙЙ <ЙЙ to й £ ж д £ a g Д о Q Q о 2 О К К Ϊ Я Я Яу5о022 ООО

ДДДДДД§Дsggg θΖΖΖΖΖ?> Ϋ’ύ ““> With оооооодоокдд ьо

Example 1

General procedure for hydrochloric acid addition salt formation

To a ether solution of the corresponding free compound of formula XIX wherein one or more of M, R 1 and Q are basic nitrogen-containing groups, a molar excess of anhydrous hydrogen chloride is added, the resulting precipitate is separated and recrystallized from an appropriate solvent, e.g. from a mixture of methanol and ether.

Similarly, the free compound of Formula XIX can be converted to the corresponding hydrobromide, sulfate, nitrate, phosphate, acetate, butyrate, citrate, matonate, maleate, fumarate, malate, glycolate, gluconate, laictate, salicylate, sulfosalicylate, succinate, pamoate and tartrate.

Example 2

100 mg of dl-5-hydroxy-4- (2-hydroxy-ethyl) -2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihydrlo-2H-benzopyran are mixed thoroughly and milled with 900 mg of starch . The resulting mixture is then stored in telescopic gelatin capsules, each capsule containing 10 mg of active ingredient and 90 mg of starch.

Example 3

The tablet matrix is prepared from the following mixture:

Ingredient parts saccharose80,3 tapioca starch13,2 magnesium stearate6,5

Sufficient dl-5-acetoxy-4- (2-acetylaminoethyl) -2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihydro-2H-benzopyran is added to this matrix to provide to give tablets containing 0.1, 0.5, 1, 5, 10 and 25 mg of active ingredient.

Example 4

A suspension of dl-5-hydroxy-3- (3-hydroxypropyl) -2,2-dimethyl-7- (5-phenyl-2-pentytyloxy) -3,4-dihydro-2H-benzopyran can be prepared by the addition of sufficient amount of the above compound to a 0.5% methylcellulose solution to form suspensions containing 0.05, 0.1, 0.5, 1, 5 and 10 mg of active substance per ml.

Example 5

5-Benzyloxy-4-cyano-2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihydro-2H-benzopyran

A. A mixture of 5.0 g (12.3 mmol) of 5-benzyloxy-2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihydro-2H-benzopyran-4-one and 20 ml of benzene was stirred under a nitrogen atmosphere and 2.04 ml of trimethylsilyltril, 80 mg of zinc iodide were added and the resulting mixture was stirred at room temperature for 3 hours. Then, 16 ml of pyridine and 9.4 g of phosphorus oxychloride are added and the mixture is heated at reflux for 3.5 hours, then cooled to room temperature, poured into a mixture of ice and 35 ml of concentrated hydrochloric acid. The resulting mixture was extracted with ethyl acetate, dried over magnesium sulfate and the solvent was evaporated in vacuo to give 5.63 g of an oily residue which was purified by silica gel chromatography eluting with hexane / ethyl ether. Product containing fractions were evaporated to give 3.93 g of 5-benzyloxy-4-cyano-2,2-dimethyl-7- (1,1-dimethylheptyl) -2H-benzopyrain. If the process is repeated with five times the reagents, 24.5 g of crude material is obtained, which is purified on silica gel. 19.06 g of product are obtained.

1 H-NMR spectrum (CDCl 3) ppm ((5): 5.05 (s, 2H),

6.10. (S, 1H).

6.35 (s, 2H).

7.20 (m, 5H).

B. A mixture of 418 mg (1 mmol) of the unsaturated nitrile obtained in Step A, 485 mg of magnesium piEin, 15 ml of methanol and 5 ml of tetrahydrofuran was stirred overnight under nitrogen at room temperature. The mixture was cooled in ice and water was added to the flask to precipitate. The mixture was then adjusted to pH 3.0 with hydrochloric acid and the clear solution was extracted with ethyl acetate. The extracts were washed with water and saturated sodium chloride solution and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 422 mg of crude material, which was purified by chromatography on silica gel, eluting the column with a mixture of hexane and ethyl ether. The fractions containing the prioiduct were combined and evaporated to give the title compound (294 mg, 70%).

¹ H-NMR (CDCl 3) ppm (? 5): 4.00 (t, 1H),

5.10 (s. 2H);

6.40 (s, 2H).

7.30 (m, 5H).

Example 6

5-Benzyl-oxy-4-carboxamido-2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihyidro-2H-benzopyran

To 3.4 g (8.2 mmol) of 5-benzyloxy-4-cyano-2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihydro-2H-benzoipyran, a solution of potassium hydroxide is added. The mixture was heated to 150 ° C in an argon atmosphere for 24 hours, then diluted with 700 mL of water, acidified to pH 5 and extracted with ethyl acetate. saturated sodium chloride solution, dried over magnesium sulfate, and the solvent was evaporated, yielding 7.5 g of crude product, which was purified by silica gel chromatography, eluting with 1: 4 ethyl ether: hexane then 1: 4. 1. Product fractions were combined and evaporated to give 2.0 g of the title amide The starting material fractions were also combined and evaporated to dryness and then hydrolyzed under the above conditions for 48 hours and treated as above to give the title compound. yields 1.5 g of a crude substance which Silica gel column chromatography gave 1.0 g of the amide and 550 mg of the corresponding carboxylic acid.

The amide fruit was combined and crystallized from methylene chloride / hexane to give the title compound (2.55 g), m.p. 117-120 ° C.

1 H-NMR spectrum (CDCl 3) ppm:

3.70 (t, 1 H), 5.00 (s, 2 H),

5.75 and 6.15 (broad singlets 1H -j-H),

6.50 (s, 2H).

7.30 (m, 5 H).

Example 7

4-Carboxamido-5-hydroxy-2,2-dimethyl-7-

- (1,1-dimethylheptyl) -3,4-dihydro-2H-beinzopyrain

A mixture of 1.6 g of 5-benzyloxy-4-kaoboxamido-2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihydro-2H-benzopyraine, 320 mg of 10% palladium on charcoal and 50 ml The catalyst was separated by filtration and the filtrate was evaporated to give 1.21 g of a solid which was crystallized from ethyl acetate to give 520 mg of the title compound, m.p. 5 ^DEG- 175 ^DEG C. An additional 220 mg of the title compound is obtained from the mother liquor.

1 H-NMR spectrum (CDCl 3) ppm (<5):

2.10 (d, 2H),

3.65 (t, 1H,

4.80 (broad s, 3H),

6.30 (dd, 2 H).

Example 8

4-Cyano-5-hydroxy-2,2-dimethyl-7-

- (1,1-dimethylheptyl) -3,4-dihydro-2H-benzopyran

Hydrogenation of 5-benzyloxy-4-cyano-2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihydro-2H-benziopyran as described above affords the resulting hydroxynitrile, m.p. 142-144 ° C.

1 H-NMR spectrum (CDCl 3) ppm (d):

2.20 (d, 2H); 4.05 (t, 1H);

6.40 (m, 2 H).

Example 9

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) -3,4-dihydro-2H-benzopyran-4-carboixyl

A mixture of 2.0 g of 5-benzyloxy-4-cyano-2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihydro-2H-benzopyirane, 20 g of potassium hydroxide and 100 ml of ethylanglycol is heated in of nitrogen atmosphere to reflux for 18 hours and then cooled to room temperature. The mixture was acidified to pH 3 with concentrated hydrochloric acid, extracted with ethyl acetate, and the extracts dried over magnesium sulfate. Evaporation of the solvent gave an oily residue which was mixed with ethyl ether, washed with water, saturated sodium chloride solution, dried (MgSO4) and evaporated to give 2.09 g of a crude solid. This crude product was purified by silica gel chromatography eluting with a mixture of ethyl ether and hexane. The product fractions were combined and the solvent was evaporated, yielding 1.69 g of the title product, m.p. 137-138 ° C.

B. Methyl-5-benzyloxy-2,2-dimethyl-7-

- (1,1-dimethylheptyl) -3,4-dihydro-2H-benzopyran-4-carboxylate

A solution of 550 mg of the carboxylic acid obtained above was dissolved in 20 ml of anhydrous ethyl ether and a molar excess of diazoloethane was added. The mixture was allowed to stand at room temperature for 15 minutes, washed with dilute sodium bicarbonate solution, dried over magnesium sulfate, and evaporated to give 470 mg of the methyl ester, which was used in the next step without further purification.

C. The product of step V (470 mg) was mixed with 200 mg of 10% palladium on charcoal catalyst and 40 ml of methanol. The mixture is hydrogenated with shaking at 300 kPa for 2 hours. The catalyst was removed by filtration and the solvent was evaporated, yielding 320 mg of crude product, which was purified by silica gel chromatography, eluting the column with hexane / ethyl ether 1: 1 to give 300 mg of the resulting 5-hydroxy compound.

@ 1 H NMR Spectrum (CDCl3) ppm .delta.

2.10 (dd, 2H).

3.75 (s, 3H);

3.80 (t, 1 H),

5.0 (s, 2H).

6.50 (s, 2H).

7.30 (s, 5H);

8.10 (s, 1 H).

3.80 (t, 1 H),

6.40 (s, 2H).

6.50 (s, 1 H).

Example. 10

4-N-Acetylcarboximido-5-hydroxy-2,2-dimethyl-7- (1,1,1-dihydro-11H-4'-yl) -3,4-dih. ydro-2H-ben: zopyran

A. p-Nitrophenyl-5'-benzyloxy-2,2 * (diethyl-)

-7- (1,1-dimethylheptyl) -S-4-dihydro-4H-banzopyran-4-carboxylate

A mixture of 3.3 g (7.53 mmol) of 5-benzyloxy-2,2-dimethyl-17- (11-dimethylheptyl) -3,4-dihydrio-2H-benzoic acid ^. 4-carboxylic acid, 5.0 g (21.3 mmol) of p-nitrophenyltrifluoroacetate and 100 ml of anhydrous pyridine are stirred under nitrogen at room temperature for 3 hours. The pyridine was evaporated in vacuo, ethyl ether was added to the residue, and the solution was washed with 1 N sodium hydroxide, Blue, 10% hydrochloric acid, saturated sodium chloride solution, dried over magnesium sulfate, and the solvent was evaporated to give 4.5 g of a crude oil. This was dissolved in pentane and the solution was cooled, yielding 3.38 g of crystals, m.p. 87-87.5 ° C.

B. 4-N-Acetylcarboxboxido-5-benzyloxy-2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihydro-2H-benaopyrain

To 301 mg (5.1 mmol) of acetamide was added 35 ml of anhydrous tetrahydrofuran and nitrogen was passed through the solution while 103 mg of 99% sodium hydride (4.3 mmol) were added. The resulting mixture was stirred overnight under a nitrogen atmosphere, 400 mg (0.716 mmol) of the p-nitrophenyl ester obtained in step A were added and the mixture was stirred at room temperature for an hour. The mixture was poured into a mixture of water and crushed ice, adjusted to pH 3.0 by addition of 10% hydrochloric acid, and extracted with ethyl acetate. The extracts were washed with saturated sodium chloride solution, saturated sodium bicarbonate solution, again with saturated sodium chloride solution, and dried over magnesium sulfate. The solvent was evaporated to give 416 mg of crude product. This product was dissolved in methylene chloride, washed with sodium bicarbonate solution, brine, dried (MgSO 4) and the solvent was evaporated to give 331 mg of a pan product. Upon addition of hexane, 249 mg of crystalline product precipitated. These crystals were mixed with hot hexane to give 216 mg of product after cooling and filtration, m.p. 157-158 ° C.

¹ H-NMR-spectrum (CDCl 3) ppm:

2.20 (s, 3H).

C. 216 mg of the product from Step B, 45 mg of 5% palladium on charcoal and 25 ml of ethyl acetate were shaken with hydrogen at atmospheric pressure for 2.5 hours. After filtration and evaporation of the filtrate, 158 mg of the title compound of melting point 146 DEG-147 DEG C. are obtained.

D. Repeat the procedure of Step B using the appropriate amide of formula R 19 CONH 2, sulfonamide of formula R 17 SO 2 NH 2 or urea instead of acetamide, hydrogenating the product according to Step C to give the corresponding imido compounds of formula

where

Q3 is CONHCOR19, CONHSO2R17 or CONHCONH2;

R17 and R19 are as defined above

Q3 = CONHCOR19:

R19 Note

CH (CH 3) 2, mp 143-148 ^° C.

C (CH3) 3 Mass spectrum m / e:

M + 431, base peak 360 1 H-NMR - (CDCl 3) -sector PPm (δ): 4.05 (t, 1H),

6.50 (m, 2H).

7.1 (s, 1 H).

M.p. 172-173 ° C.

M.p. 141-146 ° C. (diastereo- Mass spectrum m / e: mer A) M + 479.

@ 1 H NMR Spectrum (CDCl3) ppm

3.85 (t, 1 H),

4.3 (q, 1 H),

6.2 (m, 2H).

7.2 (s. 5H).

C 6 H 5 CH (CH 33) Melting point 144-149 3C.

(diastereo- Mass spectrum m / e:

mer B) M + 479, base peak 105.

¹ H-NMR-spectrum (CDCl 3) ppm (δ):

3.90 (t, IH);

4.40 (q, IH);

R19

Note

6.35 (m, 2H).

7.25 (s, 5H).

C6H5CH2 -

P-N4-Q3 is equal to melting point 154-158 ° C

CONHCONH2 Mass Spectrum m / e:

M ⁺ 390 (M-NH 3) 373

Q3 =

CONHSO2R17

R17 Note

Mp 155-156 ° C.

Mass spectrum m / e: M ⁺ 425, base peak 303

Example 11

5-Hydroxy-2,2-dimethyl-7-

- (1,1-dimethylheptyl) -3,4-dihydro-2H-benzopynan-4-hydroxamic acid

A. 5-Hydroxy-2,2-dlmethyl-7-

- (1,1-Dimethylheptyl) -

-3,4-dihydro-2H-beinzopyran-4-carbioxyl

A mixture of 5.0 g of 5-benzyloxy-2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihydro-2H-benzopyran-4-carboxylic acid prepared according to the method of Example 9, Step A, 500 mg of 5% palladium on charcoal catalyst and 150 ml of ethyl acetate were hydrogenated for 18 hours as in Example 7. After removal of the catalyst and evaporation of the solvent, 4.25 g of foam was obtained. The foam was purified by silica gel chromatography, eluting with 2: 1 hexane / ethyl ether to give 1.84 g of product 10, m.p. 147-148 ° C.

B. p-Nitro-phenyl-5-hydroxy-2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihydro-2H-

- b en тар у r an-4 - к a r box у 1 a t

A mixture of 4.25 g (12.3 mmol) of the product from Step A, 8 67 g (37 mmol) of p-nitrophenyl vinyl fluoroacetate and 50 ml of anhydrous pyridine was stirred at room temperature for 65 hours. The residue was treated as described in Example 10, Part A to give 5.085 g of the title ester in 88% yield.

¹ H-NMR spectrum (CDCl 3) ppm (δ):

6.5 (m, 2H).

6.7 (s, OH).

7.0-7.3 (m, 2H), 8.0-8.3 (m, 2H).

C. A mixture of powdered sodium hydroxide (43 mg, 1.066 mmol) in pyridine (10 ml) was stirred and heated to dissolve under nitrogen and then cooled to room temperature.

^Q 0 C. To the mixture was added 111 mg (1.6 mmol) of hydroxylamine hydrochloride and the mixture was stirred for 15 minutes. A solution of 250 mg (0.533 mmol) of the product of Step V in 3.0 ml of pyridine was then added, the mixture was allowed to warm to room temperature and stirred overnight. The pyridine was evaporated, the residue was mixed with water and the solution was extracted with ethyl acetate. The extracts are combined, washed with water and saturated sodium chloride solution and dried over magnesium sulfate. Evaporation of the solvent afforded 260 mg of crude product which was chromatographed on a column containing 30 g of silica gel. The column was eluted with 1: 1 hexane / ethyl ether, ten fractions were collected and then eluted with ethyl acetate to elute the desired product. Evaporation of the solvent from fractions 18-20 gave 158 mg of the title compound.

Mass spectrum (M ^1363). 1 H-NMR spectrum (CDCl 3) ppm (δ):

6.20 (4H, 2 aromatic, NH, OH),

10.0 (1H, exchange for D2O).

Example 12

N-2-Pyridyl-5-hydroxy-2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihydro-2 H -benzopyrainecarboxamide

A. N-2-Pyridyl-5-benzyloxy-2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihydro-2H-benzoipyrancarboxamide

A mixture of 1.118 g (2.0 mmol) of 4-nitrophenyl-5-benzyloxy-2,2-dimethyl-7- (1,2-dimethylheptyl) -3,4-dihydro-2H-beinzopyrancarboxylate, 376 mg ( 4.0 mmol of 2-aminopyridine and 4 ml of pyridine are placed in a sealed tube and heated at 155-157 ° C for 18 hours. After cooling, the tube is opened, the mixture is evaporated to dryness in vacuo, the residue is dissolved in ethyl ether. The solution was washed with 1N hydrochloric acid (25 ml), 1N sodium hydroxide (3 x 25 ml), water (2 x 25 ml) and brine (25 ml), then the washed ether solution was dried over magnesium sulfate and the solvent was evaporated to give 966 mg of oil. The oil was purified by silica gel chromatography, eluting with 1: 4 hexane / methylene chloride and then with 15% ethyl ether in methylene chloride. The product fractions were combined and the solvent was evaporated in vacuo to give the title amide (823 mg, 80%).

B. A mixture of 691 mg of amide and 691 mg of 10% palladium and on activated carbon catalyst, 1.08 g of 1,4-cyclohexadiene and 25 ml of anhydrous ethanol was hydrogenated as described above. The solvent was evaporated in vacuo to give 680 mg of crude debenzylated product. The product was purified by silica gel column chromatography, eluting with methylene chloride, then methylene chloride containing 10% ethyl ether and finally only ethyl ether to give 515 mg of debenzyllovian material in 90% yield, which was crystallized from ethyl acetate / hexane to give the title compound. Yield: 398 mg (70%). M.p. 166-167 ° C.

Mass spectrum m / e: 424 (molecular ion), 119 baseline.

C. Using the appropriate amine ArNH 2 instead of 2-pyrlidylamine, the following compounds can be obtained as described above:

Ar

сн _ъ

Mass Spectrum (m / e)

238.5 to 239

M + 430, base peak 127

............................... M4 534;

° \ / 2d8 to 209 M + 444 -X, cargo peak 141 ^ ^ N Gx N ^x - MM25, base peak 96

сн _ъ

CsHs

N ~ N

Example 13

S-Hydroxy-4-dimethyl-β-

- (1'-dimethylheptyl) Spiro [3,4-dihydro-2H-benzopyran-4,3'-pyrrolidin-2 ', 5'-dian]

A. S-Beinzyloxy-4-ethoxycarbonylmethyl-4-methoxycarbonyl-2,2-dimethyl-7-

- (II-dirnethynieptyl) -

-3 4-Dihydro-2H-benzopyran

In the absence of water, 5.31 ml of 1.6 M n-butyllithium in a hexane dd flask containing 80 ml of anhydrous tetrahydrofuran at -78 ° C are charged under nitrogen. Then a solution of 1.2 ml, 848 mg (8.4 mmol) of freshly distilled diisopropylamine was added dropwise to the resulting mixture with stirring at -78 ° C over 3 hours.

Then there was added slowly a solution of 3.1 g (6.85 mmol) of methyl 5-benzyloxy-2,2-dimethyl-7- () ^{-3,4-dihydro-2H-i} bein zopyran-4-carboxylate in 10 ml of tetrahydrofuran and the resulting mixture was stirred at -78 ° C for 3 hours. Ethyl bromoacetate (1.40 g, 8.4 mmol) was added dropwise and the mixture was stirred for 15 minutes. The reaction was quenched by the addition of acetic acid and allowed to warm to room temperature. The product was isolated, yielding 2.89 g of the title diester, Rf 0.29 (78%) with hexane / ethyl ether (3: 1).

B. 5-Benzyloxy-2,2-dimethyl-7-

- (1,1) spino- [3,4-dihydro-2H-beinzoipyrian-4 _/ 3'-tetrahydrofuran-2 ', 5'-dioin]

A mixture of 2.355 g (4.37 mmol) of the diester from step A, 17.5 g of ethylene glycol, 1 ml each and 8.74 g of potassium hydroxide was stirred under nitrogen at 150 ° C for 2 hours, then the mixture was cooled and stirred. overnight at room temperature. The mixture is then poured into 350 ml of a mixture of water and crushed ice, acidified to pH 2-3 with 1N hydrochloric acid and extracted with ethyl acetate. The extracts were combined, washed with water, saturated sodium chloride solution and then dried over magnesium sulfate. The solvent was evaporated in vacuo to give 2.0 g of the dicarboxylic acid. In a separate flask, 50 ml of acetic acid anhydride are stirred under a nitrogen atmosphere while heating to 140 ° C under reflux. A solution of 2.0 g of the above dicarboxylic acid in 10 ml of ethyl acetate was added dropwise to the flask over 4 minutes. The resulting mixture was stirred at 140 ° C for 10 minutes and then allowed to cool to room temperature. The solvent was evaporated, the residue was dissolved in ethyl ether, washed with water, saturated sodium chloride solution and then dried over magnesium sulfate. Evaporation of the solvent gave 1.9 g of a light brown solid.

1 H-NMR spectrum (CDCl 3) ppm (?):

3,15 doublets,

5,1 singlet,

6.25 singlet a

7.3 singlet.

Infrared spectrum in chloroform, Vmax ^cm-1: 1787 (C = O anhydrides).

C. A mixture of 100 mg (0.209 µmol) of the product of Step B and 125 mg (2.08 mmol) of urea was heated to 200 ° C under nitrogen for 20 minutes and then allowed to cool. . The solidifying reaction mixture was dissolved in ethyl ether. The solution was washed with water, saturated sodium chloride solution and dried over magnesium sulfate. Evaporation of the solvent gave 67 mg of 5-benzyl ether of the title compound. This material was dissolved in 15 mL of ethyl acetate and hydrogenated using 50 mg of 10% palladium on charcoal catalyst. The catalyst was separated by filtration, solvent ¹ was evaporated and the residue was dissolved in 15 ml of ethanol and hydrogenated again with fresh catalyst at 250 kPa. The product was isolated by filtration and evaporation of the solvent to give 54 mg of a solid, m.p. 105-120 ° C. Recrystallization gave a crystalline product, mp 141-143 ° C.

Mass spectrum: molecular ion m / e 387.

The infrared spectrum in chloroform has a maximum at cm -1 of ¹ : 1715 (C = O).

Example 14

5-Benzyloxy-2,2-dimethyl-7- (2-methylpropyl) -3,4-dihydro-2H-benzo-pyran-4-one

A. 3,5-HydroxyP-biphenylbenzene

A mixture of 66.2 g of N-hydroxy-1- (N, N-dimethoxylphenyl) -2-methylprolpane (formed by the reaction of 3,5-dimethoxybenzaldehyde and isopropylmagnesium chloride in ethyl ether at 0-5 ° C) and 230 g of pyridine hydrohydride are heated in nitrogen atmosphere at 190 ° C for 3.5 hours. The resulting mixture was cooled to 30 ° C, poured into 500 ml of a mixture of water and crushed ice, and then the mixture was acidified to pH 3.0 by addition of 10% hydrochloric acid. The acidic mixture was extracted three times with ethyl acetate, the extracts were washed with water, saturated sodium chloride solution, dried over magnesium sulfate and the solvent was evaporated in vacuo to give 50.9 g of an oily residue. The residue was dissolved in methylene chloride, filtered and the solvent was cdpaří · to give 43 g of crude · 3 · ^5-d ihrdroxyisobutenrlbe'nzenu which was purified by chromatography on a column containing 1200 g of silica gel. The column was eluted with a mixture of ethyl ether and methylene chloride to give 31.9 g of purified olefin.

¹ H-NMR (CDCl 3) ppm (δ): 1.75 (d, 6H),

5.95 (s, 1 H),

6.05 to 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 charcoal and the mixture was hydrogenated at 300-40 ° C for 6 hours. The product was isolated by conventional means to give 15.4 g of material which was used in the next step.

¹ H-NMR spectrum (-CDCl 3) ppm (δ): 0.85 (d, 6H),

2.20 (d, 2H).

6.15 (s, 3H);

6.60 (s, 2 H).

B. 5-Hydroxy-2 2 _{5-dimethyl-7-} (2-methylpropylj- (+ 3-dihydro-2H-benzopyran-4-o _l ⁱ n

Mixture of 20,3 ml methanesulfonic acid and

1.0 g of phosphorus pentoxide was heated to 70 ° C under nitrogen and added

2.1 g (127 mmol) of the product of Step A in 5 ml of ethyl ether. 1,27 g (12,7 mmol) of 3,3-dimethylacrylic acid are added and the mixture is kept at 70 ° C for 15 minutes, then poured into ice-water and extracted with ethyl acetate, and the extracts are washed with water and a saturated solution. The residue was purified on a silica gel column, eluting with methylene chloride to give 1.04 g of the title product, o-Rf 0.75, using methylene chloride.

1 H-NMR spectrum (CDCl 3) ppm (δ):

2.30 (d, 2H).

2.65 (s, 2H).

6.10 to 6.25 (m, 2H);

II.6 (s, 7H).

C. A mixture of 2.0 g of the product of Step B, 50 ml of acetone and 5.55 g of powdered potassium carbonate was stirred for 5 minutes, after which 1.38 g of benzyl bromide was added. The mixture was stirred at reflux for 16 hours, then cooled, filtered and the filtrate was evaporated to give an oily residue from which it was crystallized from cold; hexane, 1.49 g, m.p. 77.5-78 ° C.

1 H-NMR spectrum (CDCl 3) ppm (δ):

2.30 (d, 2H).

2.60 (s, 2H); 5.04 (s, 2H);

6.25 (s, 2H).

7.05 to 7.60 (m, 5H).

Example 15

5-Benzylkxx-cyano-2,2-dimethyl-7-

- (2-Methoxyphyl) -

-3- (4'-dihydro-2H-4 '- (4', 4'-oxopyran)

A. Using the method of Example 5, Step A, a mixture of 1.49 g (4.43 mmol) of 5-benzyl ^: oxp-2 2-dimethyl-7- (2- (4-trimethyl-propyl) -3-phenyl) -3 4-d ,, ^ Oydro benzoppřan-2H-4-one, 10 ml of benzene, 0.8 mL trimethylsilpl ^l nitriles. 30 mg of zinc iodide, 6 ml of pyridine and 3,5-phosphorus oxychloride were converted to 2.2 g of 5-benzyl-oxy-4-cyano-2,2-dimethyl-7- (2-methloro-ethyl) -2H-benzopyran.

1 H-NMR spectrum (CDCl 3) ppm (δ): 25 (d, 2H), 5.05 (s, 2H),

6.15 (s, 1 H),

6.23 (s, 2H); from 7.05 to 7.60 (m, 5H).

B. Hydrogenation of the above olefin according to Example 5, Step B, using 1.94 g of magnesium sawdust and 100 ml of methanol, yielded 12.3 g of crude dihydronitrile, which was purified by silica gel chromatography, eluting the column with a mixture of ethyl acetate and methylene chloride in the ratio of 1: 4

7.8 g of the title compound.

^^ MR-spectrum (CDCl3) ppm (δ):

3.85 (t, 1H), 5.04 (s, 2H), [delta] 20 (s, 2H), 7.05 to 7.60 (m, 5H).

Example 16

4-Nitrophenyl-5-benzyloxy-2,2-dimethyl-7-

- (2-Methylpropyl) -3,4-dihydro-2H-

-benzopyranine-k-carboxylate

A. 5-Benzploxp-2,2-dimethyl-7-

- (2-Methylpyropyl) -

-3,4-dihydrobenzopyran-4-carboxylic acid

A mixture of 7.8 g (22.2 mmol) of the product of the previous example, 12.5 g of potassium hydroxide pellets and 200 ml of ethylene glycol was reacted as described in Example 9, Step A to give 8.25 g of crude acid which Purification by column chromatography, eluting the column with ethyl ether-methylene chloride (1: 4), then ether and finally methanol / ethyl ether (1: 9) to give the title compound as a colorless oil.

6.13 g of product having a melting point of 152 DEG-153 DEG C. after crystallization from methylene chloride / hexane.

B. A mixture of 3.0 g (8.15 mmol) of the acid from Step A, 2.87 g (12.2 mmol) of p-phenylliprophenyltrifluorobutyrate and 40 ml of anhydrous pyridine was stirred for 60 minutes. The pyridine is evaporated in vacuo, the residue is washed three times with 25 ml of 1 N hydrochloric acid, four times with 25 ml of 1 N sodium hydroxide, water, saturated sodium chloride solution and then dried over magnesium sulphate. 0 g of crude foam which crystallized from methylene chloride / hexane gave 3.67 g of the title compound, m.p. 125 DEG-126 DEG.

Example 17

5-Hydroxy-2,2-dimethyl-7- (2-methylpropyl) -3,4-dihydro-2H-benzopyirane-4-carboxylic acid

The title compound, m.p. 185 DEG-187 DEG C., is obtained by catalytic hydrogenolysis of the corresponding 5-benzyl ether obtained in Example 16, step A.

Example 18

A. Using the procedure of Examples 10 and 12, but using the p-nitrophenyl ester obtained according to Example 16 and the corresponding amide or urea, the following compound was obtained.

Q3 Melting point ° C

CONHCOCH3 156-157

CONHCOCH (CH3) 2117-120

CONH2 226-207

Example 19

A. If 3,3-dimethyl-6- is used

(5-Phenyl) -4- (8-benzyloxy-1-tetronone) obtained according to U.S. Pat. No. 4,188,495 as a starting material and carried out according to the procedure of Example 5, Step A, yielding 8-Benzyloxy-1-cyano-3,3-dimethyl-6- (5-phenyl-2-pentyloxy) -3,4-dihydronaphthalene- as an orange oil was obtained in quantitative yield.

B. The oily product of Step A is hydrogenated according to the procedure of Example 5, Step B to give the corresponding tetraine, i.

8-benzylxxy-1-cyano-3,3-dimethyl-6- (5-phenyl-2-pentyloxy) ethoxymethyl, which was obtained in 89% yield as an orange oil.

C. The above tetralinonitrile is hydrolyzed in ethylene glycol by treatment with potassium hydroxide as described in Example 9, Step A to give the corresponding acid, i.e. 8-benzyloxy-3,3-dimethyl-6- (5-phenyl-2-pentyloxy) acid. 1-carboxylic acid as a white foam in a yield of 39 percent.

D. A mixture of 1.6 g of the product of Step C, 20 ml of methanol and 320 mg of 5% palladium on activated carbon catalyst was hydrogenated at 300 kPa for a total of 3 levels, and the product was isolated by filtration and evaporation of the filtrate to give 1. 2 g of a colorless solid foam which is a mixture of di-astereomers having a purity of 92.5%, as evidenced by high pressure liquid chromatography (on Zo-bax Sil (E. I. DuPont de Nemours and Co., Inc.). (Wilmingt-on, Del., USA), using 2% isicopropyl alcohol in hexane at a rate of 1 ml per minute.

Ή-NMR (CDCl 3) ppm (δ):

0.8 (s, 3 H),

0 (s, 3H),

1.2 (d, 4H);

1.74 (m, 6H).

2.5 (m. 4H),

3.7 (m, 1 H),

4.16 (m, 1H)

6.1 (s. 2H);

7.1 (s. 5H);

8.1 (broad s, 1H), which is consistent with the structure of 8-eyedroxy-3,3-dimethyl-6- (5-phenyl-2-pentzoxyl) tetrafluoro-1-oxylic acid.

E. Reaction of 3.14 mmol of the above acid and 3.45 mmol of p-titrophethyltrifluoroacetate in 15 mL of pyridine according to the procedure of Example 11, Step B, yielded 69 g (69%) of p-mtrophenyl-4-hydroxy-4-dimethyl- 6- (5-phenyl-2-pentyloixyl) tetraline-1-carboxylate as a yellow oil.

F. Using the betzzlether obtained in Step C, the process of Step E yielded 90% yield of p-nitro-benzyl-8-benzyl-oxo-3,3-dimethyl-6- (5-ethyl-2-pe). ntyloxyl) tetealin-1-carboxylate in oil. TLC ₍ 0.68, 2: 1 hexane-ethyl acetate).

Example 20

8-Hyd roxy ^{ι-3,3-dimethyl-6-}

- (5-Phenyl-2-pentytyloxy) tetralin-1-carboxylate

A. Reaction of 2.3 g (3.9 mmol) of p-ti ^{'rofenzl-8-benzyloxy-3,3-dimethyl-G-} (5-phenyl-2-pentzЬoxy) tetгallt L-karbox.ylátu with excess liquid ammonia took 30 minutes at -70 ° C followed by evaporation of excess ammonia gives a yellow paste prcdukt which was chromatographed on silica gel etezlacetátu -a hexane 1: 1 to give 730 mg of amide R _t 0 TLC (2: 1 ethyl acetate / hexane). In addition, 1.15 g of starting material was obtained.

B. Hydrogenation of the product from Step A in 50 ml of methanol in the presence of 400 mg of 5% palladium on activated carbon catalyst

After 4.5 hours at 300 kPa a crude product was obtained after routine work-up, which was purified on a silica gel column using 2: 1 ethyl acetate: hexane to give 130 mg of the title compound as a white powder, m.p. 155-157. degrees Celsius.

1 H-NMR spectrum (CDCl 3) ppm: 0.8 (s, 3H), 1.0 (s, 3H),

1.16 (d. 3H);

1.7 (Ш, 6Hj)

2.47 (m, 4H);

3.57 (m, 1H),

4.16 (t, 1H),

6.1 (d. 3H);

7.2 (s. 5H).

C. Reaction of 0.55 g (1.1 mmol) of p-nitrophenyl-8-hydroxy-3,3-diimethyl-6- (5-phenyl-2-pentyloxy) tetralin-1-carboxylate in 10 mL tetrahydrofuran using excess plyinmethylamine at room temperature, after pouring the reaction mixture into 10% hydrochloric acid, extracting with ethyl acetate and working up in conventional manner, yields 0.50 g of N-methyl-8-hydroxy-3-methoxy-6- (3-dimethyl-6- ( 5-phenyl-2-pentyoolxy) tetralin-1-carboxamide as a foam.

4 H-NMR spectrum (CDCl 3) ppm (s): 0.8 (s, 3H), 1.0 (s, 3H),

1.2 (d, 4H)

1.7 (Ш, 6H),

2.53 (m, 6HJ)

3.6 (b, 1H),

4.23 (m, NH),

6.2 (d, 2H).

7.13 (s, 5H).

Example 21

8-Hydroxy-3,3-dimethyl-6- (5-phenyl-2-pentyloxy) -tetraline-1-carbonylurea

1.2 g (2 mmol) of p-nitrophenyl-8-benzyloxy-3,3-dimethyl-6- (5-phenyl-2-pentyloxy) tetraline-1-carboxylate, 0.3 g (5 mmol) were introduced into the reaction. of urea and 0.248 g (10 mmol) of sodium hydride in 12 ml of dimethylsulfoxide for 1 hour at room temperature and the product is isolated as in Example 10, step B, and then the benzyl group is removed by hydrogenolysis according to Example 10, step C to give a pure title compound in an overall yield of 36%.

δ (CDCl 3) ppm (δ): 0.77 (s, 3H),

1.1 (b, 8H),

1.7 (b, 4H),

2.5 (4H),

3.6 (b, 1H),

4.16 (t, 1H),

5.7 (s, 1 H),

6.1 (s. 2H);

7.1 (s. 5H),

8.2 (s. 2H).

Example 22

Reaction of 1.1 g (1.9 mmol) of p-nitrophenyl-8-hydroxy-3,3-dimethyl-6- (5-phenyl-2-pentytylollxyietraliu-1-carboxylate), 1.0 g (17 mmol) of acetamide, 361 mg (15 mmol) of sodium hydride in 70 ml of tetrahydrofuran according to Example 10, steps B and C, B-hydroxy-1,3,3-dimethyl-16,11 (5-enyl-12-piperidinyl) -11H-acphtyl- cartoxoxide in the form of foam.

Δ- (CDCl 3) ppm (δ): 0.7 (s, 3H), 1.0 (s, 3H),

1.16 (d, 3H);

1.6 (Ш, 6H),

2.3 (s, 3H).

2.5 (4H),

3.73 (m, 1H),

4.13 (m, 1H),

6.1 (s. 2H);

7.1 (s. 5H),

8.5 (NH).

Example 23

Ethyl 3- [8-hydroxy-3,3-diethyl-6- (5-tetralin-llyl) -3-toxoproptonate

A solution of 0.50 g (1 mmol) of 8-6-zyloxy-3,3-dilomethyl-6- (5-phenyl-2-pentyl-oxy) -tetyl-11-cyclohexylic acid in 5 ml of ethyl ether is cooled to 0 ° C. and 0.25 g (1.2 mmol) of phosphorus pentachloride is added. The mixture was stirred at 0 ° C for 30 minutes and then at room temperature for 30 minutes. Evaporation of the ether in vacuo gave the acid chloride 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 M n-butyllithl was added and the mixture was allowed to warm to 0 ° C. Stir at this temperature for 30 minutes. The mixture was then cooled to -78 ° C and 0.30 mL (3.1 mmol) of anhydrous distilled ethyl acetate was added and the mixture was stirred

2.5 hours at -78 ° C. The above acid chloride in 2 ml of tetrahydrofuran was then added to the mixture and the mixture was stirred at -78 ° C for 2 hours. The reaction was quenched with water, allowed to warm to room temperature, poured into 10% hydrochloric acid, and extracted with ethyl ether. The extracts were washed with sodium saturated sodium chloride solution and dried over magnesium sulfate. Evaporation of the solvent gave 0.55 g of a yellow oil which was purified by chromatography on silica gel using hexane / ethyl ether (3: 1) to give 0.13 g of beinzylether of the title compound in 24% yield which was hydrogenated according to the method of of Example 10, Step C, to give 110 mg of a colorless oil, which was further purified by chromatography.

34 phi on. silica gel. Yield: 61 mg (56%).

^! 1 H-NMR spectrum (CDCl 3) ppm (δ): 0.8 (s, 3H), 1.07 (s, 3H),

1.2 (m, 7H);

1.7 (m, 5H);

2.53 (t, 4H, 35 (s, 2H),

3.8 (m, 2H).

4.13 (m. 2H);

6.13 (s. 2H);

6.5 (s, 1H)

7.13 (s. 5H).

Mass spectrum (m / e): M ⁺ 452.

Example 24

3- [4- (4-Methyl-6- (5-phenyl-2-pentyloxy) -tetralin-1-yl] -3-oxo-propiolinitiril)

To a solution of 2.4 mL of 2.1 M n-butyllithium in THF

A solution of 0.26 ml (5 mmol) of acetontril in 3.7 ml of tetrahydrofuran was added to 3.7 ml of tetrahydrofuran at -78 ° C and the mixture was stirred at -78 ° C for 1 hour. Then a solution of 1.1 g (2.0 mmol) of p-nitrophenyl-8-benzyl-3,3-dimethyl-6- (5-phenyl-2-pentyllooyl) tetrafuran-1-carboxylate in 3.7 ml of tetrahydrofuran and the mixture was stirred at -78 ° C for 30 min. The reaction mixture was warmed to room temperature, 7 mL of 10% hydrochloric acid was added and the mixture was extracted with ethyl ether. The product was isolated as in the previous example to give 1.13 g of crude benzyl ether, from which 500 mg of purified intermediate was obtained after silica gel chromatography.

Mass Spectrum - Molecular Ion 495.

Removal of the benzyl group by hydrogenolysis according to the procedure of Example 10, Step C affords the pure end product.

@ 1 H NMR Spectrum (CDCl3) ppm (.delta.): 0.8 (s, 3H), 1.06 (s, 3H),

1.2 (m, 5H);

1.7 (m, 4 H),

2.5 (m. 4H),

3.5 (s, 2H); 4.0 (m, 2H);

6.1 (s. 2H);

7.1 (s. 5H).

Example 25

8-Hydroxy-1-trifluoromethylaminomethyl-3,3-dimethyl-6- (5-phenyl-2-pentyloyy) tetralin

To a suspension of 114 mg (3 mmol) of lithium aluminum hydride in 10 mL of ethyl ether was added a solution of 1.36 g (3.0 min) of 8-benzyloxy-1-cyano-3,3-dimethyl-6- (5- phenyl-2-penryIιoyytteraaιИn ₁ UV 10 ml of tetrahydrofuran and the mixture heated 2 hours at reflux. After cooling to 0 DEG C. was added 30 ml of ether and quenched with 150 mL of water and 150 ml of sodium hydroxide. Then, 450 ml of water are added, the reaction mixture is stirred for 15 minutes, filtered, washed with ether and the organic layers are separated, dried over magnesium sulphate and evaporated to a volume of approximately 50 ml.To 0.70 ml of triethylamine is added to this cask amine solution. and 565 microliters (4.0 mmol) of trifluoroacetic anhydride for 15 minutes at room temperature, then diluted with 50 mL of ether and washed with 25 mL of 10% hydrochloric acid, 25 mL of water, saturated sodium bicarbonate, saturated sodium bicarbonate and brine. The solvent was evaporated and the residue was chromatographed on a silica gel column, eluting with a 1: 9 mixture of methanol and methylene chloride, to give 500 mg of the benzyl ether of the title compound, which was debenzylated according to Example 10. Step C to give 250 mg of an oily product.

Mass Spectrum (m / e): 367, 337.

191, 91, 69.

1 H-NMR spectrum (CDCl 3) ppm (δ):

0.7 (s, 3 H),

0.8 (s, 3 H),

1.1 (d, 3 H),

1.2 to 2.0 (m, 6H), 2.0 to 3.0 (m, 7H), 4.0 (m, 1H),

5.8-6.0 (m, 2H);

6.1 (NH), 7.0 (s, 5H).

Example 26

2- [8-Acetoyl-3,3-dimethyl-6- (5-phenyl-2-pentyloyy) tetralin-1-yl] acetic acid

To a solution of sodium methoxide, prepared from 0.2 g of sodium metal and 32 ml of methanol, is added a solution of 0.20 g (0.53 mmol) of 2- [8-hydroxy-3,3-methyl-lactone] lactone. Dimethyl-6- (5-phenyl-2-penyl-tyl-tetralin-1-yl) -acetic acid was added and the mixture was stirred for 30 minutes, the methanol was evaporated in vacuo, the residue was cooled in ice and cold solution 6 added. 4 ml of acetyl chloride in 12.8 ml of ethyl acetate and the resulting mixture was stirred for another 15 minutes, then evaporated in vacuo to dryness, the residue was dissolved in fresh ethyl acetate, washed with water, saturated sodium chloride solution and dried over magnesium sulfate. The oil was purified on a silica gel column, eluting with a mixture of methylene chloride and methanol to give the title compound (110 mg, 47%).

1 H-NMR-spectrum (CDCl 3) ppm (δ):

0.8 (s, 3 H),

1.03 (s, 3H),

1.23 (d, 4H);

1.7 (m, 6H).

2.3 (s. 3H),

2.5 (m, 4 H),

2.9 (m, 1 H),

3.13 (m. 1H);

4.2 (m, 1 H),

6.4 (s. 2H);

7.13 (s. 5H).

Example 27

2- [8-Hydroxy-3,3-dimethyl-6- (5-phenyl-2-pentyloxy) -tetralin-1-yl] -acetamide

A solution of 0.76 g (2 mmol) of 2- [8-hydroxy-3,3-dimethyl-6- [5-phenyl-2-pentyloxy) tetralin-1-yl] acetic acid in the form of lactone in 10 ml of ethyl ether was added to an excess of liquid ammonia at -30 ° C and the mixture was stirred while slowly warming to room temperature over 2 hours. The solvent was evaporated to give a white solid residue, which was dissolved in ethyl acetate, washed with water, saturated sodium chloride solution and then dried over magnesium sulfate. The solvent was evaporated to give the title compound (800 mg, 100%), mp 67-72 ° C.

1 H-NMR spectrum (CDCl 3) ppm (δ):

0.86 (s, 3H);

1.06 (s, 3H).

1.26 (d, 5H);

H (m, 6H),

2.6 (m. 6H);

3.4 (m, 1 H),

4.26 (m. 1H);

5.6 (m, 2H, NH2),

6.2 (m, 2H).

7.2 (s. 5H).

Claims (1)

OBJECT OF THE INVENTION A process for preparing a benzene ring bicyclic compound of formula (XIX) wherein R1 represents a hydrogen atom or a CH3CO group, M2 represents an oxygen atom or a group = CH2, W is hydrogen or phenyl, Z represents an alkylene radical having 1 to 9 atoms or an Oalkalk group) where (alkz) denotes an alkylene radical having 4 to 9 carbon atoms, Q 3 represents the group СОСз ', where Оз' is selected from NESOn, NHAr, NR 12 R 13, NHOH, CH 2 CN or CH 2 COOR 5 and R 5 represents hydrogen, methyl or ethyl, R 12 and R 13 represent hydrogen, alkyl of 1 to 4 atoms R (17) is hydrogen, C1-C4 alkyl, benzyl, phenyl or phenyl; phenylethyl and Ar represent a group wherein R 5 is as defined above, characterized in that the compound of formula XX About where Mz, Z and W are as defined above, contacting a compound of formula MetQ3 ‘ Met is hydrogen, sodium, potassium, or lithium; Q 3 ‘is as defined above, in the presence of a solvent at a temperature of 20 to 160 ° C, followed by debenzylation of the resulting intermediate.