DE2509562A1 - THIENOBENZOPYRANE AND THIOPYRANOBENZOPYRANEESTER, PROCESS FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS CONTAINING THESE - Google Patents

Description

Patent attorneys

Dr. Dicier F. r /; orf Dr. Hans-A. L / au ns

March 5, 1975 3111-S

SHARPS ASSOCIATES

North Chicago, 111,
V.St.A.

Thienobenzopyran and thiopyranobenzopyran esters, processes for their preparation and pharmaceuticals containing them

The invention relates to compounds of the general formula

OR ₃

where mean:

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η = 0 to 3; m = 0 to 3, the sum being (m + n) -'2 or 3; R ₁ = an alkyl group with 1 to 6 carbon atoms; Rp = an alkyl group with 1 to 20 carbon atoms or a.

(Cycloalkyl) -alkyl group _s in which the cycloalkyl radical has 3 to 8 carbon atoms and the alkyl radical has 1 to 6 carbon atoms;

R ₁ . = Hydrogen or an alkyl group with 1 to 6 carbon atoms;

Rp. = Hydrogen or an alkyl group with 1 to 6 carbon atoms;

R, =
³ O

II C

where mean:

Y = one straight chain? or branched alkylene group with

1 to 8 carbon atoms, a = an integer from 1 to 4, b = an integer from 1 to ^, Rg = hydrogen or an alkyl group with 1 to

C atoms, X = -CH ₂ -, 0, S or -NR ₇ -, where R _{7 is} hydrogen or an alkyl group with 1 to 6 C atoms,

where (oQ when X = 0, S or -NR ₇ -, a and b both mean 2 and

(β) Y is a branched-chain alkylene group and / or at least one of the radicals R ^, R ₁ . and Rg is an alkyl group with 1 to 6 carbon atoms,

and the acid addition salts of these compounds.

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They are especially valuable
Compounds in which Y has 2 to 5 carbon atoms. The compounds in which Y contains 3, Ί or 5 carbon atoms are very particularly preferred. The compounds in which Y has at least 2 carbon atoms in a chain between the carbonyl group and the nitrogen atom are also preferred.

If m and η have the meaning 1, the 1,3-dihydro-4H-thieno- / 3 »4-c7 / l7-benzopyrans are by the general formula

OR,

II

shown.

If m has the meaning 2 and η has the meaning 0, the 1,2-dihydro-4H-thieno- / 2,3-c7 / l7-benzopyrans have the general formula

III

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If η has the meaning 2 and m is O, then the 2,3-dihydro- * IH-thieno- / 3,2-c7 / l7-benzopyrane the general formula

OR ₃

If η has the meaning 2 and m has the meaning 1, the 3> ^ - dihydro-IH, 5H-thiopyrano- / i, 3-c7 / 17-benzopyrans have the general formula

OR ₃

If η has the meaning 3 and m has the meaning 0, the 2,3-dihydro-4H, 5H-thiopyrano- / 3,2-c7 / l7-benzopyrans have the general formula

R.

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If m has the meaning 2 and η = 1, the 1,2-dihydro-MH have 5H-thiopyrano- / 3,4-c7 / l7-benzopyrans the general formula

R5 R4

OR ₃

VII

and if m is 3 and η is 0, the l, 2-dihydro-3H, 5H-thiopyrano- / 2,3-c7 / l7-benzopy rane the general formula

OR-

VIII

R ₁ , Rp, _{R 1, R 1 and R 1} - each have the meaning given above and the restrictions given for formula I apply in the event that X denotes oxygen, sulfur or NR 1.

The term "lower alkyl" used here denotes saturated, monovalent aliphatic radicals, including straight-chain and branched radicals with 1 to 6 carbon atoms,

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for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, amyl, hexyl and the like.

The term "alkyl" denotes saturated, monovalent aliphatic Residues, including straight-chain and branched radicals with 1 to 20 carbon atoms, e.g. methyl, n-amyl, n-hexyl, 2-heptyl, n-heptyl, 3-methyl-2-octyl, n-octyl, 2-nonyl, 2-tetradecyl, n-hexadecyl, 2-eicosanyl, and the like.

The term "cycloalkyl" denotes cyclic, saturated aliphatic radicals having 3 to 8 carbon atoms, for example Cyclopropyl, cyclobutyl, 2-methylcyclobutyl, cyclohexyl, 4-methylcyclohexyl, cyclooctyl, and the like.

The term “acid addition salts ¹¹ denotes non-toxic salts which are prepared by reacting the basic esters of thiopyranobenzopyrans or thienobenzopyrans with an organic or inorganic acid or by reacting the pyran with the appropriate salt of the acid. Representatives of the salts include the hydrochloride, hydrobromide, sulfate , Bisulfate, acetate, valerate, oleate, laurate, borate, benzoate, lactate, phosphate, toxylate, citrate, maleate, succinate, tartrate, etc. Such salts are known to those skilled in the art and are considered "pharmaceutically acceptable".

The new esters according to the invention are prepared by adding equimolar amounts with the appropriate thienobenzopyran or thiopyranobenzopyran in an appropriate acid or acid salt in the presence of a slight excess of one Carbodiimides, such as dicyclohexylcarbodiimide, are reacted in a suitable solvent.

The reaction mixture is filtered to remove the by-product dicyclohexylurea, which can be solvent

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■ V

distilled off using a rotary evaporator will. The residue can be crystallized directly from suitable solvents, such as benzene / ether, or the The residue can be chromatographed and the desired material isolated from the appropriate chromatographic fractions. If the basic esters are obtained, the acid addition salts are obtained, if necessary, according to known methods Methods.

The thienobenzopyrans and thiopyranobenzopyrans used as starting materials are produced by using the appropriate Oxo compound of formula IX with a lower alkyl magnesium halide according to the following equation implements:

OK

OH

IX

Therein m, n, R; ,, Rp, R ₁ , and R, - have the meaning given above and X is an active halogen atom. The reaction is carried out in an organic solvent which is inert under the reaction conditions. Suitable solvents are diethyl ether, dibutyl ether, tetrahydrofuran, anisole, pyridine and the like.

Many compounds of the formula X are in DT-OS 2 04l

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described.

The pyrone of the formula IX can by reaction with a compound of the formula XI with a 5-alkyl or 5-cycloalkyl-lower alkyl resorcinol (XII) as shown below:

In it have m, n,

OH

XII

IX

R ₁ , and R ₁ . the previously specified

The 5-alkyte or S-cycloalkyl-lower alkyl resorcinol intermediates of the formula XII can be prepared by known processes (US Pat. No. 3,576,798).

The ketoesters, 4-oxo-2,3, ¹ *, 5- "alkyl tetrahydrothiophene-3-carboxylates and alkyl 3-oxo-2,3,4,5-tetrahydrothiophene-2-carboxylates can be prepared by the method of Woodward and Eastman, J. Am. Chem. Soc., J6_8, 2229 (19 ^ 6); alkyl 4-oxo-2 »3,5,6-tetrahydro- ¹ JH-thiopyran-3-carboxylate can be prepared by the method of GM Bennet and LVD Scorah, J. Am. Chem. Soc, 194 , (1927); and alkyl 3-0x0-2,3,4,5-tetrahydro-6H-thiopyran-2-carboxylate can be prepared by the method of Leonard and Figueras, J. Chem. Soc, 74 , 917 (1952).

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^ -Methyl ^ -oxo-tetrahydrothiophene ^ -carboxylic acid methyl ester is described in Chemical Abstracts, £ 3.5 ^ 91 (1965). Ethyl 5,5-dimethyl-3-oxo-tetrahydrothiophene-2-carboxylate is produced by reacting diethyl 4,4-dimethyl-3-thiahexanedioate with potassium tert-butoxide. 5-methyl-3-oxotetrahydrothiophene-2-carboxylic acid ethyl ester is obtained by adding diethyl jj-methyl-3-thiahexanedioate with potassium tert-butoxide implements.

The compounds of the formula I are suitable as mild tranquilizers, in doses of 5.0-20 mg / kg body weight, daily. Although the compounds show activity by both oral and intraperiotoneal administration, preferred however, the oral route of administration is currently used.

Activity as a tranquilizer has been demonstrated using a series of standard tests used in Psychopharmacology, A Ten Year Review, Public Health Service Publication No. 1836, includes observation of the overt Behavior of mice, rats, dogs and monkeys, blocking the fight reaction in mice, blocking of learning achievements, etc.

1,2-Dihydro-5,5-dimethy 1-8- (3-methyl-2-octyl) -10- / Ii- (pipe ridino) -butyryloxy / -3H, 5H-thiopyrano- / 2,3-c7 / l7-benzopyran hydrochloride shows moderate activity in that performed on the mouse at an oral dose of 20 mg / kg body weight modified DOPA potentiation test (G.M. Everett, Proc. First Internat. Sympos. Antidepressant Drugs, Excerpta Med. Int. Congr. Of the. No. 122, 1966), which means that this compound has activity as an antidepressant. At a

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Oral dose of 5 mg / kg this compound caused a 7% decrease in spontaneous motor activity the rat, indicating that this compound also has a sedative effect.

1,2-dihydro-5,5-dimethyl-8- (3-methyl-2-octyl) -10- / 2-methyl-4- (piperidino) -butyryloxyy-3H, 5H-thiopyrano- / 2,3- -c7 / l7-benzopyran hydrochloride at an oral dose of 20 mg / kg showed little activity in mice in the modified DOPA potentiation test. At an oral dose of 10 mg / kg of this compound, a 76% decrease in the combat response was seen in mice. (Tedeschi et al., J. Pharmacol. Exp. Therap., 125 _a 28 (1959) with modifications; the reaction was measured when a shock was administered to the foot). This compound thus has activity as both an anti-fear agent and a tranquilizer.

1,2-Dihydro-4,4-dimethyl-9- / 3-Gnorpholino) -butyryloxy. 7-7- (3-methyl-2-octyl) -4H-thieno / 2,3-c7 / 17-benzopyran hydrochloride , administered at an oral dose of 20 mg / kg showed activity in the mouse in the modified DOPA potentiation test. An oral dose of 10 mg / kg resulted in a 56% decrease in the combat response in the mouse. In the hot plate test for mice (G. Woolfe and coworkers, J. Pharmacol. Exper. Therap., JK), 300, 19 * 14) at an oral dose of 50 mg / kg, it showed mild activity and caused an increase in MjSige the pain transmission threshold. In the sound-induced seizure test (Plotnikoff, J. Pharmacol. Exp. Therap., 119 "2" 5 ¹ I, 1957) at an oral dose of 100 mg / kg, this compound protected 100% of the mice from convulsions. These activities show indicate that the compound is useful as an antidepressant, an anti-tranquilizer, an analgesic and an anti-seizure agent.

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• / t / t.

1,2-Dihydro-4, 4-dimethy 1-9- / ^ - (piperidino) -butyryloxy_7-7- (3-methyl-2-octyl) -4H-thieno- / 2,3-c7 / 17 Benzopyran hydrochloride, when administered orally at a dose of 20 mg / kg, showed activity in mice in the modified DOPA potentiation test. An oral dose of 10 mg / kg caused a 503 decrease in the combat response in mice. In the pain test caused by acetic acid in mice (writhing reaction) (BA Whittle, Brit. J. Pharmacol., £ 2_, 246-253, 1964) a low activity was found, namely an ED ₁ -Q of 24 mg / kg for the Inhibition of writhing from pain. In the convulsion test triggered by noise (Plotnikoff, H. Pharmacol. Exp. Therap., 119 , 234, 1957) at an oral dose of 100 mg / kg, 20 % of the mice shook with convulsions. The activity found in these experiments indicates the usefulness of this compound as an anti-anxiety agent (tranquilizer), analgesic, or anti-seizure agent.

1,2-Dihydro-7- (3-methyl-2-octyl) -9- / 2-methyl-4- (piperidino) -butyrylox27-1,4,4-dimethyl-4H-thieno- / 2,3- When administered orally at a dose of 5 mg / kg to rats, c7 / l7-benzopyran hydrochloride showed an 81 % decrease in motor activity. At an oral dose of 5 mg / kg, this compound caused an 82% reduction in methamphetamine-induced hyperactivity in rats in the methamphetamine antagonism test. In the rat tail patch test (P. D ¹ Armor and coworkers, J. Pharmacol. Exper. Therap. 7 £, 74, 1941) this compound showed noticeable activity at an oral dose of 2 mg / kg and caused a 57i increase in the pain threshold . Activity in these tests indicated sedative, antipsychotic, and analgesic activity.

¹ »2-Dihydro-7- (3-methyl-2-octyl) -9- / i- (piperidino) -butyryloxy-7-1, 4, 4-trimethyl- ¹ JH-thieno / 2,3-c7 / 17 Benzopyran showed an 82% decrease in motor activity in rats when administered orally at 5 mg / kg. At an oral dose of 5 mg / kg, a 70% reduction in methamphetamine-induced hyperactivity was found in rats in the methamphetamine antagonism test. In the rat tail-flick test, the compound at a oral dose of ^ O showed mg / kg some activity and caused a 8 ^l \% increase of the pain threshold. At an oral dose of 20 mg / kg, there was clear activity in mice in the modified DOPA potentiation test. At an oral dose of 10 mg / kg it caused a 100% decrease in the combat response in mice. It is suitable as a sedative, as a psychotherapeutic, as an analgesic, as an antidepressant or as an anti-fear drug (tranquilizer),

The compounds of the invention are thus useful as antidepressants, anti-anxiety agents (tranquilizers), analgesics, and anti-seizure agents effective, with some compounds generally not exhibiting all of these activities at the same time.

The amount of active ingredients administered can be varied; however, it is required that the amount of active One component is sufficient for a sufficient dosage. The particular dosage chosen depends on the desired therapeutic Effect depends on the method of administration and the duration of treatment. Dosages from 0.1 to 25 mg / kg body weight per day, preferably in divided doses, that is, three to four times a day, can be administered.

The active agents according to the invention can be living beings,

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including humans, can be administered as pure compounds. However, it is advisable to do one or more of these first Combine compounds with a suitable pharmaceutical carrier to make an amount sufficient for dosing and thereby then to get a pharmaceutical composition.

The pharmaceutical carriers can be liquid or solid. Solid carriers are starch, sugar, talc and can be in the form of a powder. The powders can be used directly for administration or they can be in tablet or filled form Gelatin capsules are used. Suitable lubricants such as magnesium stearate, binders such as gelatin or Dissolving agents, such as sodium carbonate combined with citric acid, can be used for. used in the manufacture of tablets will. Solvents and flavors can also be admitted.

Unit dosage forms such as tablets and capsules can contain any suitable predetermined amount of one or more of the active Contain funds and they can be used one or more times on a regular basis Administered at intervals. Such unit dosage forms should generally have a concentration of 0.1 to 50 wt. contained on one or more of the active compounds. Unit dosage forms such as tablets or capsules may contain about 2 to 300 mg of active compound.

A typical tablet can have the following composition:

mg of active ingredient (1) 100

Strength 57

Lactose 73

Talc 9

Stearic acid 12

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(1) 1,2-dihydro-4, il-dimethy 1-9- / 4- (piperidino) -butyry loxy / -7- (3-methyl-2-oetyl) -4H-thieno- / 2,3- c7 / l7 benzopyran hydrochloride.

The compound of formula I shows both oral and parenteral Activity and, as a result, can be in formulations for both oral and parenteral Administration are suitable for a patient.

Close solid dosage forms for oral administration Capsules, tablets, pills, powders, granules, and the like.

Liquid dosage forms for oral administration are emulsions, solutions, suspensions, syrups and the like, which contain the diluents commonly used here, such as water. In addition to inert diluents Such preparations can also contain adjuvants such as wetting agents, emulsifiers or suspending agents and solvents, taste improvers and odor improvers.

Preparations for parenteral administration include sterile, aqueous or non-aqueous solutions. Examples for non-aqueous solutions or carriers are propylene glycol, polyethylene glycol, vegetable oils such as olive oils and injectable organic esters such as ethyl oleate. The parenteral Preparations are sterilized in the usual way.

If R _{2 is} an alkyl group, this preferably contains 1 to 6 carbon atoms and thus corresponds to the radical R ₁ .

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example

1,2-Dihydro-5,5-dimethyl-8- (3-methyl-2-octyl) -10 - [4- (piperidino) butyryloxy3-3H, 5H-thiopyrano [2,3-c3 [13 benzopyran hydrochloride

OCCH ₂ CH ₂ CH ₂ I.

.HCl

1 * 5 g (4.0 mmol) 1,2-dihydro-5,5-dimethyl-10-hydroxy-8- (3-methyl-2-octyl) -3H, 5H-thiopyrano / 2,3-c7 / 17-benzopyran were combined with 0.83 g (4.0 mmol) of T ^ piperidinobutyric acid hydrochloride, 0.88 g (4.25 mmol) of dicyclohexylcarbodiimide and 75 ml of methylene chloride and stirred at room temperature for 6 hours. The reaction mixture was cooled and the dicyclohexyl urea formed as a by-product was removed by suction. The mother liquor was evaporated to give a foamy residue which was recrystallized from 25 ml of cyclohexane. The solid was filtered and dried to give 1.8 g (80% yield) of colorless crystals with a melting point of 136-138 ° C. The material is clean as determined by thin layer chromatography (10 % CH-OH / CHCl,) and determined by infrared and nuclear magnetic resonance spectroscopy to conform to the structure indicated.

Analysis calculated for C ₅₂ H ₁₅₀ ClNO, S (molecular weight 564.18):

C 68.12; H 8.93; N 2.48; Found: C, 67.93; H 9.05; N 2.50.

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example

1,2-Dihydro-5, S-dimethyl-8- (3-methyl-2'-octyl) -10- [2-methyl-4- (piperidino) butyryloxy] -3H, 5H-thiopyrano [2,3- c] [1] benzopyran. - hydrochloride

OCCHCH ₂ CH ₂ N \

CH ₃ >'

CH-CH-C ₅ H ₁₁ CH 3 CH 3

.HCl

A combination of 0.5 g (1.33 mmol) 1,2-dihydro-5,5 ~ dimethy1-10-hydroxy-8- (3-methy1-2-octy1) -3H, 5H-thiopyrano- / 2, 3-c7 / 17-benzopyran, 0.30 g (1.45 mmol) of dicyclohexylcarbodiimide, 0.29 g (1.33 mmol) of 2-methyl-4-piperidinobutyric acid hydrochloride and 25 ml of methylene chloride were stirred at room temperature for 16 hours. The reaction mixture was cooled for several hours and the dicyclohexylurea formed as a by-product was separated off by filtration. After the solvent had been removed using a rotary evaporator, 15 ml of diethyl ether were added to the residue and a further amount of dicyclohexylurea was separated off by filtration. The solvent was evaporated and the residue dried thoroughly to give 0.1 g (50 %) of a beige solid. Thin layer chromatography (10 % CH ^ OH / CHCl,) showed that the product is pure and the IR and nuclear magnetic resonance spectrum is consistent with the structure of the desired product.

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Analysis: calculated for C ₃₃ H ₅₂ ClNO ₃ SH ₂ O (molecular weight 596.28)

C 66.44; H 9.13; N 2.35; found C, 65.84; H 9.01; N 2.70.

The 2-methyl-4-piperidinobutyric acid hydrochloride that is here used can be made as follows:

A. 4-Bromo-2-methylbutyric acid ethyl ester

Following the procedure described in US Pat. No. 3,299,100 of-methyl-J'-butyrolactone was made and this compound was made in the 4-bromo-2-methylbutyric acid ethyl ester according to the method described by 6. Jones and J. Wood according to "The Synthesis of 9-Azasteroids-II ", Tetrahedron, 21, 296I (1965) convicted.

B. Ethyl 2-methyl-4-piperidinobutyric acid ester

10.5 g (0.05 mol) of 4-bromo-2-methylbuttersäureäthylester were combined with 17.0 g (0.20 mol) of piperidine and 100 ml of benzene and stirred for 16 hours at room temperature and then heated for 4 hours at 6O ⁰ C . The reaction mixture was cooled and the resulting colorless pesticide was separated by filtration. The mother liquor was concentrated to give a mobile yellow liquid which, after distillation (boiling point 78 ^° C. at 0.25 mm), gave a colorless liquid (6.7 g; 63 % yield).

C. 2-Methyl-4-piperidinobutyric acid hydrochloride

6.5 g (0.030 mol) of 2-methyl-4-piperidinobutyric acid ethyl ester were combined with a mixture of 45 ml of water and 45 ml of concentrated hydrochloric acid and refluxed

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Heated for 16 hours. The solution was concentrated under reduced pressure (water aspirator) to give a residue. which crystallized after the addition of 50 ml of diethyl ether. The ether was decanted and the plague was triturated with acetone * and filtered. Recrystallization from acetic acid / acetone gave 3.38 g of colorless crystals with the melting point 166 to 168 ° C and another 1.27 g of a pesticide with a melting point of 165 to 168 ° C. The overall yield was thus 69J5.

Analysis calculated for

found

(Molecular weight 221.72): C 5 * 1.20; H 9.09; N 6.32; C 54.17; H 9.15; N 6.36.

Example 3

l, 2-dihydro-7- (3-methyl-2-octyl) -9 / _2-methyl-4; (piperidino) -butyryloxy / -1,4,4-trimethy1-4H-thieno / 2,3 -c7 / | 7-benzopyran hydrochloride * "

OCCHCHoCH ₅ N CH, II ² CH

.HCl

CH-CH-C ₅ H ₁₁

Il

CH ₃ CH ₃

2.16 g (5.75 mmol) 1,2-dihydro-9-hydroxy-7- (3-methyl-2-octyl) -

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were with

1 * 27 g (5.75 mmol) of 2-methyl- ¹ l-piperidinobutyric acid hydrochloride, 1.25 g (6.07 mmol) of dicyclohexylcarbodiimide and 110 ml of methylene chloride combined and stirred at room temperature for 18 hours. The reaction mixture was cooled and the dicyclohexylurea formed as a by-product was removed by filtration. The solvent was removed on a rotary evaporator to give a foamy residue which was dissolved in 50 ml of diethyl ether. Another amount of a colorless solid was obtained and this amount was also separated off by filtering. The diethyl ether was removed and the residue obtained was dried thoroughly to give 2.70 g (81 %) of a colorless solid. Thin layer chromatography (10 % CH ^ OH / CHCl,) showed that the product was pure and the IR and nuclear magnetic resonance spectrum were consistent with the structure indicated.

Analysis calculated for 0,., H _1. ^ INO, S (molecular weight 578.27)

C 68.5 ^; H 9.06; N 2.42; found C, 68.48; H 9.11; N 2.43.

1,2-dihydro-1,4,4-trimethyl-9-hydroxy-7- (3-methyl-2-octyl) -4H-thieno / 2,3-c7 / l7-benzopyran, used above can be prepared in the manner described below will.

A solution in dry benzene of equimolar amounts of 4-methyl-3-oxo-tetrahydrothiophene-2-carboxylic acid methyl ester and 5- (3-methyl-2-octyl) resorcinol and phosphorus oxychloride (5 ml benzene / g resorcinol) was heated to 35 to 37 ° C in an oil bath for 13 days. The largest proportion of benzene and hydrochloric acid was under removed under reduced pressure and the dark, tarry residue was stirred with ether and water until everything was dissolved.

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AC

The ether layer was successively coated with dilute solutions of sodium bicarbonate, sodium hydroxide and sodium carbonate washed and then with water and a saturated sodium chloride solution. After drying and concentrating the obtained organic solution gave a crumbly, foamy, brick-red solid.

The pyrone was obtained from this crude product by chromatography over a magnesium silicate column using 100 % CHCl and 1:99 CH-OH / CHCl as solvent systems. Fractions containing the desired material were concentrated to dryness and allowed to solidify by standing under petroleum ether. The compound was then further purified to give a yellow solid with a melting point of 105-107 ° C (yield 41 %).

A solution of 4.6 g (0.0128 mol) 1,2-dihydro-9-hydroxyl-methyl-7- (3-methyl-2-octyl) -4-oxo-4H-thieno / 2,3-c7 / l7-benzopyran in 1 * 10 ml of anhydrous diethyl ether was within Added for 30 minutes with stirring to a solution of methyl magnesium bromide in 140 ml of anhydrous ether. the Methyl magnesium bromide solution had been made from 3.7 g (0.154 mol) of magnesium turnings, to which methyl bromide gave until the solid material had dissolved. After stirring for a further 15 minutes at room temperature the reaction mixture heated to reflux temperature for 1.5 hours.

The excess Grignard compound was decomposed by Addition of a saturated solution of ammonium sulfate and subsequent addition of water and dilute hydrogen chloride acid. The organic layer was separated with

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-3, / I.

Washed water until neutral, dried and evaporated on a rotary evaporator. The residue was -in 30 ml of warm methanol dissolved and dehydrated by adding 2 drops of concentrated hydrochloric acid and heating. The reaction mixture was washed with water and the product was washed with Ethyl ether extracted. The ethereal solution was washed free of acid, dried and concentrated on a rotary evaporator, 5.2 g of a brown oil were obtained.

The oil was purified by column chromatography (silica gel, ethyl ether / petroleum ether), 4.3 g (90 %) of the product being obtained as a cloudy, pale yellow oil from the fractions containing 1:99 and 2:98 ethyl ether / petroleum ether eluted. In thin-layer chromatography, the material showed a single spot (silica gel, 1: 4 ethyl acetate / hexane) and the nuclear magnetic resonance spectrum and the infrared spectrum agreed with that for the compound 1,2-dihydro-1,4,4-trimethyl-9-hydroxy- 7 ~ (3-methyl-2-octyl) -4H-thieno / 2.3 "c // l7-benzopyran shown.

Analysis calculated for Ορ, Η ^ Ο ^ (molecular weight 37 ^, 6)

C 73.74; H 9.15; S 8.56; found C, 73.64; H 9.15; S 8.51.

Example l \

1,2-Dihydro-1,4,4-trimethyl 1-9 / 3 "(morphglino) -butryoxyy-7- (3-methyl-2-octyl) -4H-thieno72,3-c7 / 17-benzopyran -hydro-

chloride

1,2-dihydro-2,4,4-trimethyl 1-9-hydroxy-7- (3-methyl-2-octyl)

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4H-thieno- / 2,3-c7 / l7-benzopyran, dicyclohexylcarbodiimide and T'-morpholinobutyric acid hydrochloride are combined in methylene chloride and stirred at room temperature. The insoluble dicyclohexyl urea is removed by filtration and the methylene chloride is separated off on a rotary evaporator. The residue is crystallized from ether, 1,2-dihydro-2,4,4-trimethyl-9- / ^T i- (morpholino) -butyryloxyl7-7- (3-methyl-2-octyl) - ¹ iH- thieno / 2,3-c7 / l7-benzopyran hydrochloride is obtained.

The l, 2-dihydro-2 ^, 4-trimethyl-9-hydroxy-7- (3-methyl-2-octyl) - lH-thieno- ⁱ / 2 _J 3-c7 / l7-benzopyran, using here was used as the starting material, can be produced as follows:

A. Diethyl 4-methyl-3-thiahexanedioate

CH,

I ³

2 g of sodium were added to 250 ml of ethanol and then added 117 g of ethyl mercaptoacetate and then 100 g of methyl acrylic acid ethyl ester are added. The mixture was refluxed for 17 hours treated, cooled and added 500 ml of ether. The reaction mixture was washed with water and then twice extracted with aqueous sodium bicarbonate solution. The essential Solution was dried over magnesium sulfate and then distilled, giving 139 g of diethyl 4-methyl-3-thiahexanedioate with a boiling point of 90 to 95 ° C / 0.5 mm.

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B. S-methyl - ^ - oxo-tetrahydrothiophene - ^ - carboxylic acid ethyl ester

COOC ₀ H _n
2 5

Diethyl 4-methyl-3-thiahexanedioate was dissolved in 5-methyl-3-oxotetrahydrothiophene-2-carboxylic acid ethyl ester converted by reaction with potassium tert-butoxide in ether on an ice bath. Acetic acid and water were added thereto, and then the product was extracted with ether. The crude product (27 g) boiled at 70 to 75 ° C / 0.3 mm.

C. l, 2-dihydro-9-hydroxy-2-methyl-7- (3-methyl-2-octyl) - ⁱ i oxo-4H-thieno / _2> 3-c7 / I7-benzopyran

8.8 g of 5-methyl-3-oxo-tetrahydrothiophene-2-carboxylate are added to 45 ml of ethanol and 5 g of 5- (3-methyl-2-octyl) -

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resorcinol. The mixture is cooled in ice and hydrogen chloride is bubbled through for half an hour. The mix will Left in a closed vessel at room temperature for a period of 3 days. The reaction mixture is concentrated and dissolved in ether. The ethereal solution becomes twice with water and once with aqueous sodium bicarbonate solution extracted. The solution is dried over magnesium sulfate and concentrated. 1,2-Dihydro-9-hydroxy-2-methyl-7- (3-methyl-2octyl) -4-oxo-4H-thieno / 2,3-c7 / 17-benzopyran is recrystallized from acetonitrile to give 4.65 g with a melting point of 146 to 149 ° C.

Analysis calculated for ^c ₂ i ^H 28 ° 3 ^S ( ^Molecular S ^{ew: 5} - ^cht 360.6)

C 69.97; H 7.83; found C, 69.89; H 8.03.

1,2-Dihydro-9-hydroxy-2-methyl-7- (3-methyl-2-octyl) -4-oxo-4H-thieno / 2,3-c7 / | 7-benzopyran is indicated in a manner similar to Example 8 of DT-OS 2 263 129, implemented, where one 1,2-dihydro-2,4,4-trimethyl-9-hydroxy-7- (3-methyl-2-octyl) -4H-thieno / 2,3-c7 / l7-benzopyran obtained in 8l yield as a yellow oil.

Analysis calculated for Cp, H, jO ₂ S (molecular weight 374.6)

C 73.76; H 9.15; S 8.54; found C, 74.09; H 9.68; S 8.25.

Example 5

1,2-Dihydro-7- (3-methyl-2-octyl.) - 9- / 4-pyrrolidino) -butyryloxy _i 7-2,2,4,4-tetramethyl-4H-thieno- / 2,3- c7 / l7 benzopyran hydrobromide

By reacting l, 2-dihydro-9-hydroxy-7- (3-methyl-2-octyl) -

509837/0957

2,2,4, Ji-tetramethyl- ^ H-thieno - / !, 3 ~ c7 / l7-benzopyran with the # "- pyrrolidine butyric acid hydrobromide salt and dicyclohexyl carbodiimide according to that described in DT-OS 2,263,129 in Example 10 Procedure is 1,2-dihydro-7- (3-methyl-2-octyl) -9 ~ / 5- (pyrrolidino) butyryloxv / -2,2,4,4-tetramethyl-4H-thieno- / 2,3- c7 / l7 benzopyran hydrobromide manufactured.

1,2-Dihydro-9-hydroxy-7- (3-methyl-2-octyl) -2,2,4,4-tetramethyl-4H-thieno / 2,3-c7 / l7-benzopyran, used in this example can be made as follows:

A. Diethyl 4 _> 4-dimethyl-3-thiahexanedioate

0 CH, 0

! 1I ³ I.

C ₀ H ₁ -OCCH ₀ CSCH ₀ COc ₀ H, -

A mixture of 85 g of ethyl dimethylacrylate, 88 g of ethyl mercaptoacetate, 185 ml of ethanol and sodium ethylate, prepared from 1.6 g of sodium, was refluxed for 16 hours, cooled and 500 ml of ether were added. The reaction mixture was extracted with dilute aqueous sodium chloride and hydrochloric acid and then twice with aqueous sodium bicarbonate solution. The reaction mixture was dried over magnesium sulfate and then distilled, 128 g of diethyl ¹ J, 4-dimethyl-3-thiahexanedioate having a boiling point of 90 to 95 ° C./0.5 being obtained.

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3111-S

B. 5 »5-Dimethyl-3-oxo-tetrahydrothiophene-2-carboxylic acid · ethyl ester

C _o H _c 00C

To a stirred suspension of 60 g of potassium tert-butoxide 100 g of diethyl 4,4-dimethy1-3-thiahexanedioate were added dropwise to 250 ml of ether in 100 ml of ether over a period of 1 hour and with cooling in an ice bath given. The mixture was stirred for an additional 60 minutes on an ice bath and then 35 g of acetic acid and 150 ml Water added. The mixture was extracted with ether and dried over magnesium sulfate. Received when distilling one 60.4 g of the product with the boiling point 70 to 75 ° C / 0.5 mm.

C. l ^ -Di

4-oxo-4H-thieno- / 2 ₃ 3-c7 / 17-benzopyran

CH:

CHCHC ₅ H ₁₁ CH 3

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6.2 g of 5- (3-methyl-2-octyl) resorcinol and 6.2 g of 5j5-dimethyl-3-oxo-tetrahydrothiophene-2-carboxylic acid ethyl ester are added to 100 ml of ethanol. The mixture is cooled in ice and hydrogen chloride is bubbled through for half an hour. The mixture is stored in a closed vessel and kept at room temperature for three days. It is then concentrated and ether is added to it, extracted with water and then washed with dilute aqueous sodium bicarbonate solution. The ethereal solution is dried over magnesium sulfate and concentrated. 1,2-Dihydro-2,2-dimethyl-9-hydroxy-7- (3-methyl-2-octyl) -4-oxo- ⁱ } H-thieno / 2,3-c7 / | 7-benzopyran is crystallized from acetonitrile, 5 * 0 g with a melting point of 155 to 163 ° C being obtained.

Analysis calculated for ^c ₂ 2 ^H 30 ⁰ 3 ^S ( ^{molecular weight} 37 ¹ Jj 59) J

C 70.56; H 8.08; S 8.5 ¹ J; Found: C, 70.06; H 8.15; S 8.87-

10 g of 2-dihydro-2,2-dimethyl-9-hydroxy-7- (3-methyl-2-octyl) -4-oxo- ^{1 are added to a solution of methyl magnesium bromide (from 10 g of magnesium) in 150 ml of ether} IH-thieno- / 2,3-c7 / l7-benzopyran in 100 ml of benzene and 25 ml of ether. The mixture is stirred at 45 ° C. overnight. The reaction mixture is then treated with saturated ammonium chloride solution. The product is mixed with 50 mg of p-toluenesulfonic acid in 250 ml of benzene and refluxed for three hours. The reaction mixture is rinsed with sodium bicarbonate solution and dried over magnesium sulfate. The mixture is concentrated and chromatographed over activated magnesium silicate and eluted with 5% ethyl ether in petroleum ether. 7.85 g of 1,2-dihydro-

- 27 509837/0957

509562

3111-S

9-hydroxy-7- (3-methyl-2-octyl) -2,2,4,4-tetramethyl-4H-thieno / 2,3-c7 / 17-benzopyran as a yellow oil.

Analysis calculated for C _{2l {} H, g0 ₂ S (molecular weight 388.61):

C 74.19; H 9.3 ^; found: C, 73.94; H 9.73.

Example 6

1,2-Dihydro-7- (3-methyl-2-octyl) -9- [4- (piperidino) butyryloxy] -1, 4,4-trimethyl-4H-thieno [2 _/ 3-c] [1] • benzopyran

Ii

OCCH ₂ CH ₂ CH N

CH ₃

CH-CH-CSH ₁₁ CHo

A combination of 2.4 g (6.4 mmol) 1,2-dihydro-9-hydroxy-7- (3-methyl-2-octyl) -1, 4,4-trimethyl-4H-thieno- / 2, 3-c7 / i7-benzopyran, 1.33 g (6.4 mmol) of ^ -piperidinobutyric acid hydrochloride, 1.40 g (6.75 mmol) of dicyclohexylcarbodiimide and 125 ml of methylene chloride were used at room temperature for 18 hours touched. The reaction mixture was cooled and the as Dieyelohexy! Urea formed by-product was caused by

- 28 509837/0957

509562

3111-S

Filter removed. The methylene chloride was distilled off on a rotary evaporator to give a colorless, foamy residue which was purified over 80 g of magnesium silicate (60 to 100 mesh) using a methanol / chloroform solvent system. The fractions were separated by thin layer chromatography and the respective fractions were combined to give 1.23 g (37 %) of the desired material as a golden, rubbery material. The IR and nuclear magnetic resonance spectrum agreed with the formula of the desired product.

Analysis calculated for C ₃₂ H ₁₁₉ NO ₃ S (molecular weight 527.7):

C 72.82; H 9.36; N 2.65; Found: C, 72.88; H 9, IO ^1; N 2.58.

example

1,2-Dihydro-8- O-methyl (^ - octyl) -10- [2-methyl-4- (piperidino) butyryloxy] -1,5,5-trimethyl-3H, 5H-thiopyrano [2,3- c] [I] - benzopyran hydrochloride

PCCH CH ₂ CH 2 N

CH-CH-C ₅ H ₁ -, I \ "

CH ₃ CH ₃

- 29 -

509837/0957

A. * 1-Bromo-2-methylbutyric acid methyl ester

M-Bromo-2-methylbutyric acid ethyl ester was obtained in 65% Yield from conversion of methanol. Hydrogen bromide with 2-methyl-4-butyrolact; on according to that of Jones and Wood in Tetrahedron, 21, 2966 (1965) described procedure for the preparation of the ethyl ester of bromic acid. The product was a colorless, mobile liquid that boiled at 85 to 90 C / 15 mm.

B. 4- (Methoxycarbonylmethylthio) -2-methylbutyric acid methyl ester

I | - (Methoxycarbonylmethylthio) -2-methylbutyrate was obtained in 79 ^{% yield by reacting 1} l-BrOm-2-methylbutyrate with methyl mercaptoacetate and sodium methylate in methanolic solution according to that of Baas and coworkers in Tetrahedron, 22, 285 (1966) described procedure. The ester was a colorless liquid which boiled at 92 to 95 ° C / 0.1 mm.

C. ^ t-Me thy l-3 ~ oxotetrahydrothiopyran-2-carboxylic acid thy read he

i-Hethyl-3-oxotetrahydrothiopyran-2-carboxylic acid methyl ester obtained in 50% yield from methyl 4- (methoxycarbonylmethylthio) -2-methylbutyrate by slightly modifying that of Baas and co-workers in Tetrahedron, 22, 285 (1966) described procedure. Sodium methylate was thereby used and used toluene in place of sodium hydride and benzene as used by Baas and co-workers. Of the

- 30 509837/0957

Ketoester was a viscous, yellow liquid that boiled at 75 to 85 ° C (0.1 mm) and which appeared to consist of a 1: Mixture of the keto and enol tautomers existed.

D. 1,2-Dihydro-10-hydroxy-1-methyl-8- (3-methyl-2-octyl) -5- oxo-3H, 5H-thiopyrano- / 2,5-c // 17-benzopyran

_t A solution of 4.1 * 1 g (0.022 mol) of 4-methyl-3-oxotetrahydrothiopyran-2-carboxylic acid methyl ester and 4.72 g (0.02 mol) of 5- (3-methyl-2-oetyl) -resorcinol in 20 ml of anhydrous ethanol was saturated with dry hydrogen chloride at ice temperature. After standing for 9 days at room temperature, the reaction mixture was concentrated on a rotary evaporator and the dark residue was dissolved in benzene.

A large part of the unreacted starting material was extracted with 5 # sodium hydroxide, and the benzene layer was washed with water and with sodium chloride and then dried and concentrated. The residue (3 »52 g) of the crude pyron was a dark brown liquid which was purified by repeated chromatography on a magnesium silicate column using diethyl ether / petroleum ether and 100% chloroform as the eluent. The desired pyrone was obtained from the fractions which had been eluted with 35:65 ethyl ether / petroleum ether and with trichloromethane. The fractions containing the best quality pyrone were combined to give 1.06 g (40 %) of the 1,2-dihydro-10-hydroxy-1-methyl-8- (3-methyl-2-octyl) -5-oxo-3H, 5H-thiopyrano- / 2,3-c7 / l7-benzopyran was obtained as a dark amber-colored resin.

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methyl-3H, 5H-thiopyrano- / 2 ₅ 3-c7 / 17-benzopyran

A solution of 2.1 g (0.0056 mol) 1,2-dihydro-10-hydroxyl-methyl-8- (3-methyl-2-octyl) -5-oxo-3H, 5H-thiopyrano- / 2, 3-c7- / l7-benzopyran in 20 ml of anhydrous diethyl ether became to an ice-cold, well-stirred solution of the Grignard reagent which had been prepared by passing methyl bromide through a mixture of 1.4 g (0.057 mol) of magnesium turnings and bubbled 60 ml of anhydrous diethyl ether. The ice bath was removed and the reaction was allowed to proceed for 15 minutes at room temperature, the yellow color subsiding. the reaction mixture was then refluxed for 1.5 hours heated.

The excess Grignard compound was by adding a Solution of methanol in diethyl ether decomposed and the reaction mixture became 50 ml of a cold, saturated ammonium chloride solution poured. The clear, aqueous layer was extracted with diethyl ether. The united layers of ether became washed, dried and concentrated. The greenish oil remaining as residue was dissolved in methanol and the transfer the triol into the pyran was caused by dehydration by adding 3 drops of concentrated hydrochloric acid and then heating for 5 minutes on a hot water bath. The solvent was removed and the dark red oil that remained was taken up in diethyl ether and the solution was washed with water, dried and concentrated to give 2.15 g of a yellow-black oil. The pyran was recovered from this oil by column chromatography over magnesium silicate. The factions that eluted with diethyl ether / petroleum ether 1:99 and 2:98

- 32 -

509837/0957

were combined to give 1.20 g (55%) of a very viscous, pale yellow syrup that slowly darkened over time.

Analysis calculated for C ₂ H ₃₆ O ^ ₀ S: C 74.18; H 9.33; S 8.25; found: C 73 ₃ 96; H 9.47; S 8.08.

P. 1,2-Dihydro-8- (3-methyl-2-octyl) -10- / 2-methyl >> 4- (piperidino) -butryloxy / - !, 5, 5-trimethyl-3H, 5H-thiopyrano - / 2 _t 3 ~ g7 / l7-ben2Gp Yran ^ hydrochloride

1,2-Dihydro-10-hydroxy-G-Oiiiethy1-2-octyI) -I ₃ 5,5-trimethyl-3H, 5H-thiopyrano / 2,3-c7 / 17-banzopyran is reacted with 2-methyl-4 piperidinobutyric acid hydrochloride in methylene chloride in the presence of dicyclohexylcarbcdxiraid, the procedure of Example 2 being obtained and the desired ester.

example

1,3-Dihydro-4, i} -dimethyl-7- (3-methyl-2 ₌ octyl) -2- / 2,2-dimethyl-Jj- (piperidino J-butyrylox ^ - ^ H-thieno - / ^ , ^ -c7 / l / -benzopyran hydrochloride " ~

2,2-Dimethyl- ⁱ t-piperidinobutyric acid hydrochloride is combined with 1,3-dihydro- ^, 4-diir _1- ethyl-7- (3-methyl-2-octyl) -9-hydroxy-MH-thieno- / 3j ^ - c7 / I7-benzopyran reacted in methylene chloride in the presence of dicyclohexylcarbodiimide, using 1,3-dihydro k, 4-dimethy1-7- (3-methyl-2-octyl) -9- / 2,2-dimethy1-4- ( piperidino) -butyryloxy_7- MH-thieno- / 3 i ^ ~ c / / 17-benzop7ran-hydro chloride.

- 33 -

509837/08 ^

The ^{2,2-dimethyl-i!} -Piperidinobutter3äiirehydrochlorid that used in this process wii ^s d _like can be prepared as described hereafter "

The procedure of Eaas and coworkers in Tetrahedron, 22, 288 (1966) was used for the conversion of / "- butyrolactone in 2,2-dimethy.l - ^ - turyrolactone in * J5 $ iger Yield.

A procedure Ede Shnlich was described by Jones and Wood, Tetrahedron ,, 21, 2961 (1965), was used for the preparation of 2 ₅ ^2-i-i rimethyl- brombuttersäureäthylester. To a ki-Llf-cn (G to 10 ^C C) solution of 16.5 g (0.1 * 15 mol) of 2,2-Dirceihyl ~ - ¹ >'L - u': - :; roIaci; on ^{κ ^ ίθ "1} -" * r hydrogen bromide was added to 70 ml of anhydrous ethanol. Here it was gfc & EHTE ^ j ■ -; .., r: vurde 3 maintaining the temperature between O and 10 ^0C. Di ^ addition took 2 _S 5 hours. After standing at room temperature for 2½ hours, the reaction mixture was cooled again and hydrogen bromide was bubbled through for a further hour. After standing for 48 hours at room temperature, the reactor mixture was added to 80 g of ice. The aqueous layer was separated off and. extracted three times with ether and the organic layers were combined, washed twice with 53% sodium bicarbonate solution and water. The solution was dried over sodium salad, evaporated and distilled, 25.2 g (73 %) of a colorless liquid with a boiling point of 83 to 85 ⁰ G (10 mm) being obtained. The product was su 95 % pure.

An aliquot of this sample was converted into the piperidino derivative transferred and subsequently hydrolyzed using the procedure, which is similar to that of looks and

5 IS

2509552

Employees in J. Am. Chem. Soc, 63, 2488 (1941) is.

A mixture of 10.0 g (0.045 mol) of ethyl 2,2-dimethyl-4-bromobutyrate, 15.3 g (0.18 mol) of piperidine and 125 ml of benzene was ^{heated to 60 to 70 °} C. for a total of 4 hours then left to stand for 3 days at room temperature. The reaction mixture was cooled and filtered to remove precipitated amine hydrobromide. The mother liquor was concentrated, distilled and four fractions were collected. The first three fractions contained various amounts of unreacted bromine compound. Fraction 4 (3.60 5) was pure.

3.3 U (1 * 1.5 mmol) of ethyl 2,2-dimethyl-4-piperidinobutyric acid were combined with 25 ml of concentrated hydrochloric acid and 25 ml of water and the mixture was stirred under reflux for 18 hours. The reaction mixture was concentrated under reduced pressure to give a semi-solid residue which distilled on trituration with 30 ml of acetone. The solid was filtered, washed with diethyl ether and dried over potassium hydroxide in vacuo, giving 2.25 U (66 %) of colorless crystals with a melting point of 232 to 23 ¹ I ⁰ C.

Analysis calculated for C ₁₁ H ₂₂ ClNO, (molecular weight 235.75):

C 56.00; H 9.36; N 5.96; Found: C, 56.04; H 9.41; N 5.9 **.

509837/0957

- 35 -

Claims (1)

, ίΙί-S si ■■ "": ■ '- "O- sunny n = O to ~ | S = O eis 33 where iis Si-mme is ^ 2ΐ ^. s 2 or 5 is 3 H ^ = an alkyl group with 1 ils ^; 5 carbon atoms | ! Hp = an alkyl group sit i-2C-O Ätomen or {cycloalkyl) -alky group, ¹ Ir ^ -ielehsr ier Gycloalkyl-2 * est 3 to 3 v-Atcsis' mn eggs alkyl group has 1 to ^S carbon atoms has ; Hj ^ = hydrogen or an alkyl group with i to β O atoms; H ₅ . = Hydrogen or an alkyl group from 1 to β carbon atoms 1 . C - T U -J W W ■ ". ' ί '»ι · ϊ,' 3111-S where mean: Y = a straight-chain or branched alkylene group with 1 to 8 carbon atoms,
a = an integer from 1 to 4, b = an integer from 1 to 4, Rg = hydrogen or an alkyl group with 1 to 6 Carbon atoms,
X = -CHp-, 0, S or -NR ₇ -, where R _{7 is} hydrogen or an alkyl group with 1 to 6 carbon atoms, where (cO when X = 0, S or -NR ₇ -, a and b both mean 2 and (β) Y is a branched-chain alkylene group and / or at least one of the radicals R _1. , R, - and Rg is an alkyl group with 1 to 6 carbon atoms, and the acid addition salts of these compounds. 2. Compound according to claim 1, characterized in that X has 2 to 5 carbon atoms. 3. A compound according to claims 1 or 2, characterized in that Y has 3 »4 or 5 carbon atoms. 4. A compound according to the preceding claims, in which Y contains at least 2 carbon atoms which are between the carbonyl group and the nitrogen atom. 5. A compound according to claims 1 to Ί, characterized by the general formula 9837/0957 3111-S • 5 * - wherein R ₁ , R have a lot of meaning. R ,, Rj. And R- are given in claim i. 1,2-Dihydro ~ 7- (3-methyl-2-octyl) -9- / 2-methy1-4- (piperidino ) -butyry Ιοχχ? - 1, 4, ίΙ-trimethyl- ilH-thieno- / 2, 3-c7 / l7-benzopyran and its acid addition saline. 7. 1,2-dihydro-2,4,4-trimethy1-9- / 3- (morpholino) -butyryl-0x ^ 7-7- (3-methyl-2-octyl) -4H-thieno- / 2, 3-c7 / l7-benzopyran and its acid addxtxon salts. 8. 1,2-Dihydro-7- (3-methy1-2-octy1) -9- / 5- (pyrrolidino) -butyrylox27-2,2,4,4-tetramethyl-4H-thieno- / 2 _s 3- c7 / l7-benzopyran and its acid addxtxon salts. 9. 1,2-Dihydro-7- (3-methy1-2-octyD-9- / 3- (piperidino) -butyryloxy / -1,4,4-trimethy1-4H-thieno- / 2,3-c7 / I7-benzopyran and its acid addxtxon salts. 10. 1,2-Dihydro-9- / 3- (piperiäino} -propionyloxg7-4,4,7-triraethyl-4H-thieno- / 2 _s 3-c7 / 17-benzopyran and its acid addition salts. 50S337 / 095T
- 38 - 11. Eire Vevbin- ^ ung according to ^ "'. Io ^ üe *: ^'..:". j -.;.; net aurcli the ailgesöine .rc-r ^: re ^ 1? ■ 4 -i Ji 3 Ή Be-Jeai; '^ ig have. 12. 1,2Oi hydro-5,5-diseth7l -? - · ■■ "$ iperidino) -but7zyiox2 / ~ 3H _i ^ benzopyran and its sa ^ r ^ i 13. l, 2-Tue Biethyl-A- (piperidino) -t 1,2-Dihydro-3- <3-methyl-2-oc ^ V ₃ -IC- / 2-siejl-vl dino) -butyrylox27-l _s 5 ₃ 5-trii! i3chvl »JH ₂ n" -i = -tM2p / l7-benzopyran and its acid addition salae 15. A connection according to Ansc-rLisher,. to 4, denoted by the general formula 509837/0937 3111-S in which R ₁ , R ", R", R ₁ . and R ^ have the meaning given in claim l. 16. 1,3-Dihydro-4, it-dimethyl-7- (3-methyl-2-octyl) -9- / 2,2-dimethyl 1- 4- (piperidino) -butyry loxy_7-IIH-thieno- / 3, 4-c7- / 17-benzopyran and its acid addition salts. 17. A compound according to claims 5, H or 15, wherein Y has 3 or ¹ I C atoms and X has the meaning 0 or -CHp- and, if Y has the meaning -CHp-, the sum of (a + b ) Is 3, ¹ ^ or 5. 18. A compound according to claims 5, 11, 15 or 17, characterized by having the group (CH ₂ ) _a a morpholino, piperidino, pyrrolidino or a K-alkylpiperazino group with 1 to 6 carbon atoms is in the alkyl group or a homopiperidino or thiomorpholino group. 509 8 3 7/0957 19. Process for the preparation of thienobenzopyrans or
Thiopyranobenzopyrones according to claim 1 or the acid addition salts thereof, characterized in that one
a thienobenzopyrone or a thiopyranobenzopyrone of
general formula in which R ^, Rp, R ₁ ^, R-, m and η have the meaning given in claim 1, with an acid of the general formula R ^ OH, in which R has the meaning given in claim 1, or with a salt of such an acid in the presence of a carbodiimide. 20. Medicament, characterized by a content of a compound of claims 1 to 18 in addition to customary carrier materials or diluents. 509837/0957 ORIGINAL INSPECTED