DE2143745A1 - 3,4-DIHYDRO-2H-ISOCHINOLIN-1-THIONE AND THE METHOD FOR MANUFACTURING IT - Google Patents

Description

3, ^ - Dihydro-2H-isoquinoline-l ~ thione and process for their Manufacturing

The invention ^{relates to 3> i} * ~ dihydro-2H-isoquinoline-1-thiones of the general formula

₂
where R ₁ and R _? in each case identical alkyl radicals with 4 carbon atoms or R ^ a phenylalkyl radical with 7 or 8 carbon atoms or a phenyl radical and at the same time R _ *) a straight-chain or branched alkyl radical with 1-6 carbon atoms or a phenyl radical, where R. and Rp, together with the carbon atom in the ^ position, can form a saturated, carbocyclic 5- or 6-membered ring, R, hydrogen or an alkoxy group with 1-4 carbon atoms and R ^. Hydrogen or, together with R, the 6,7-oxymethylene group. *) Hydrogen,

The invention also relates to a method for production as well as pharmaceutical preparations of these compounds.

The process for the preparation of the compounds according to the invention is characterized in that either

a) Compounds of the general formulas

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Ha

or

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lib

wherein R. - R ₂ , have the above meaning and Y optionally

substituted amino group, 0- or S-alkyl- or an S-phenyl-

rest means cyclized by treatment with acidic catalysts or

b) in compounds of the general formula III

III

3 "1" 2

replaced the oxygen atom by sulfur in a manner known per se.

The preparation of the starting materials II a and II b for the procedure a) takes place via the amines of the general formula IV

IV

which by catalytic hydrogenation of the corresponding nitriles V

can be produced. These nitriles of the general formula V can, for example, by alkylation of the corresponding diphenylacetonitriles or benzyl cyanide VI

CH - CN

VI

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(R ₁ = H or phenyl) by alkylation with an alkyl halide
in the presence of sodium amide in the inert solvent 2.B.
according to the method described in Liebigs Annalen Vol. 56I (1949) pages 52 ff (here referred to as method A). The preparation of diphenylacetonitriles which carry substituents in one of the Phenylrihge succeeds according to a method by T.
Kametani et. al. J. Org. Chem. J56, 327 (1971). Here, ortho-haloalkoxybenzenes are reacted with NaNHp in an inert solvent such as benzene, toluene or THF to give the corresponding dehydrobenzenes, which add benzyl cyanide in situ and give the desired substituted derivatives (method B). The nitriles shown are listed in Table 1 along with the method used.

Table 1

Nitrile method Kp. Or F.

1-cyano-1.1-diphenylpropane A 183 ° C / 13 mm

1-cyano-1.1-diphenylethane A 130-134 ° C / 0.1 mm

4-cyano-4,4-diphenylbut-1-en A 122-129 ° C / 0.1 mm

1-cyano-1.1-dipheny1-3-methyl-butane A 145-147 ° C / 0.3 mm

1-cyano-1.1-dipheny1-pentane A 168-170 ° C / 0.4 mm

1-cyano-l.1-dipheny1-heptane. ' A 154-158 ° C / O, O2 mm

1-cyano-1.1.2-triphenylethane A P: 123-124 ° C

1-cyano-1,2-diphenylethylene *) P: 85 - 87 ^° C

3-ethoxyphenyl-phenyl-acetonitrile B P: 55 ° C

1-cyano-1- (3'-ethoxyphenyl) -1-pheny1- B, A 155-160 ° C / 0.5 mm propane

l-cyano-l-ethyl-l- (3'-methoxyphenyl) - A 148-152 ° C / O, 9 mm

l-cyano-l-ethyl-l- (3 ', 4'-methylenedioxi- A 138-145 ° C / 0.9 mm

propane (l-cyano phenyl) propane

1-cyano-1-phenyl-cyclopentane A 90 ° C./0.5 mm

1-cyano-l- (3 ', 4'methylendioxyphenyl) - A 16O - 165 ⁰ C / 0.5 mm

cyclopentane

*) according to Org.Synth. 29, 83 (1949)

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-n-

The nitriles (V) thus represented are then, for example, in ethanol saturated with ammonia or methanol with Raney nickel as
Catalyst, hydrogenated at 70-120 atmospheric pressure and 100-125 ° C. for 8-36 hours to give the amines (iv). It is advisable to work according to the method described in Org. Synth. 23 » 71 (19 ^ 3) specified regulation. The amines (iv) shown are given in Table 2.

Table 2

Ami η

2.2-diphenylbutylamine

2.2-diphenylethylamine

2.2-diphenylpropylamine
W 2.2-diphenylpentylamine

2.2-Diphenyl- ⁱ J-methylpentylamine 2.2-Diphenylhexylamine

2.2-diphenyloctylamine

2.2.3-triphenylpropylamine 2,3-diphenylpropylamine

2- (3 '~ ethoxyphenyl) -2-phenylethylamine 2- (31-ethoxiphenyl) -2-phenylbutylamine 2-ethyl-2- (3'-methoxyphenyl) butylamine 2-ethyl-2- (3 ', 4'-methylenedioxipheny1) butylamine

Cyclopentyl-1-phenyl-1-methylamine Cyclopentyl-1- (3 ', 4-methylenedioxiphenyl) -

methylamine

Sat ./Kp Fp .: 182 ° C .HCl Fp. 60 ⁰ C .HCl Pp .HCl Fp. .HCl Fp. .HCl Pp .HCl Fp. .HCl Fp. .HCl Fp. .HCl Fp .: .HCl Pp .: .HCl Fp .: .HCl Fp .: : 191-193 ° C : 168-169 ° C : 260-262 ⁰ C - 2O5-2O8 ° C 193-197 ° C • 188-19O ° C 142-146 ⁰ C. 310 ⁰ C 194-197 ^O C 165-168 ° C 173 ° C 183-184 ° C Bp 115-120 (0.4 mm) .HCl Pp.:

The amines IV thus obtained are now known per se
Methods converted into derivatives of isothiocyanic acid II a and II b capable of ring closure. The isothiocyanates II b are prepared, for example, according to J. Am. Chem. Soc. 8l, (1959) page 4328.

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The amines (IV) are converted with CS and a base (eg triamine) in the presence of chloroformic acid esters into dithiocarbcic acid esters, which give the corresponding isothiocyanates in the event of an excess of base (eg triethylamine). Or m «'<n reacts the amine (IV) or its hydrochloride with thiophosgene in the presence of a base such as Na ₂ CO or CaCO in an aqueous medium (cf. Houben-Weyl" Methods of Organic Chemistry ", Vol. IX, 875 (1955)).

For the preparation of thiocarbamic acid esters (II a, Y = OR), it is most expedient to start from the isothiocyanates (II b) which, with an alcohol or an alcoholate, give the desired compounds at temperatures between 20 ^° C. and 80 ^° C. without solvents or . Reacts the alcoholate dissolved in the corresponding alcohol. These methods are, for example, in J. Am. Chem. Soc. 77, 581 (1955) or 6jj, 900, (19 * J3).

The dithiocarbamic esters (II a, Y = SR) can also be obtained from the isothiocyanates (II b) by reaction with mercaptans. The procedure is such that the mercaptan is dissolved in 20-30 % sodium hydroxide solution and the mustard oil is added dropwise and then acidified (cf. Chem. Abstr. (1910), 910).

To prepare the thioureas (Ha, Y = NH ₂ ) one starts, for example, with either the amine (IV), which is reacted with ammonium thiourea in water in the presence of a mineral acid (e.g. HCl) at an elevated temperature to give the thiourea (cf.Professional Porschg. 2_, 125 (1952)) - you can also work in an inert solvent, e.g. chlorobenzene, which is saturated with HCl - or the mustard oil (II b) is converted to thiourea at room temperature in an aqueous, alcoholic ammonia solution (see Chem . Ber. £ K), 275 (19 ^ 7)) ·

For the representation of the variously substituted thioureas (II a, Y s NH-R) one follows the information in J, Am. Chem. Soc. 51 , 1909 (1929), the amine (IV) being reacted with a mustard oil or the mustard oil (II b) with an amine without a solvent or dissolved in alcohol under reflux. For thioureas (II a, Y = NRR ')

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the mustard oil (II b) with a secondary amine at 0 ° C or. reacted under reflux in an inert solvent such as benzene, toluene, chlorobenzene or ethyl acetate (cf. Chem. Ber. 2 £ 5, 2935 (1895)).

The preferred compounds of the formula II a include thiocarbamic esters (Y = 0-alkyl with 1-4 carbon atoms), O-phenyl and thiourea derivatives with Y = N-alkyl (1-4 carbon atoms), N-phenyl. The reaction according to procedure a) takes place according to methods known per se. The compounds of the formulas II a or II b are reacted in the presence of a catalyst with or without the presence of a solvent. Particularly suitable catalysts are anhydrous or practically anhydrous catalysts, for example polyphosphoric acid, phosphorus oxychloride or conventional sulfuric acid or Lewis acids such as, for example, AlCl. Indifferent anhydrous organic solvents which are _s for example, chlorinated hydrocarbons such as OCl ₁ - Suitable solvents - if they are ever used for implementation. or trichlorethylene, also CSp or aromatic hydrocarbons such as benzene, toluene or xylene. The temperatures used depend upon the reactants used and may vary between -15 ° C and 150 ⁰ C. The starting compounds of formula III for the Vei * ride example b) can also be prepared according to methods known per se. Suitable starting materials are compounds which correspond to the general formulas II a and II b, but contain an oxygen atom instead of sulfur, ie isocyanic acid _{derivatives according to formula II b s} ureas and carbamic acid derivatives according to formula II a, in which instead of S each contain an oxygen atom is.

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The preparation takes place analogously from the amines of the formula IV.

Isocyanates are prepared, for example, starting from the amines (IV) with phosgene in an inert solvent such as benzene, toluene, ethyl acetate or chlorobenzene. It is expedient to follow the instructions given in Org. Synth. Coil. Vol. II, 453 (19 ¹ O) or in Liebigs Ann. Chem. 562, IO5, 106

Carbamic acid esters (Y = OR) are most simply described in Org. Synth using a modified method. Coll. Vol. II, 278 (19 ^ 3). In the presence of a base (eg Na ₃ CO ₃ or NaOH), the amine is reacted with a chloroformic acid ester in an inert solvent such as toluene, benzene, chlorobenzene, ethyl acetate or a chlorinated hydrocarbon such as CCl ₁ J at elevated temperature. Or you can start from the isocyanates (II b) and heat them with the calculated amount of alcohol with or without the addition of an inert solvent (benzene, ethyl acetate, for example) (cf. J. Am. Chem. Soc. 62 :, 218 (19 ¹ IO).

For the representation of the ureas one uses, for example, the regulation in J. Am. Chem. Soc. 5.1, 1797 (1929). Here, the amine (IV) is reacted with nitrourea in water or a water / water / alcohol mixture at room temperature or with gentle heating to form urea. Alkylated ureas (Y = NHR or NRR ¹ ) are obtained from the isocyanates (II b) with a primary or secondary amine in an inert solvent such as benzene, toluene, chlorobenzene or an aliphatic, chlorinated hydrocarbon according to R. 5_1, 4 32 (1932).

To convert the compounds of the formula III into the corresponding Sulfur derivatives of the formula I according to procedure b) are used as reactions known per se. The is particularly suitable Reaction with PjiS-q in pyridine or toluene with or without additives an acid-binding agent such as CaO or one proceeds so that

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(III) reacted with PCI in pyridine, benzene or toluene to form the imide chloride that with HpS or a thiourea, possibly after hydrolysis of the isothiuronium salt formed as an intermediate yields compounds of the formula I.

Unsubstituted 3,4-dihydro-2H-isoquinolir-1-thione and in the 4-position 3,4.-Dihydro-2H-iso ~ substituted with an alkyl radical Quinoline-1-thiones were first published in DOS No. 1 911 519 mentioned as intermediate products in the manufacture of substances that affect blood pressure. 3,4-Dihydro-2H-isoquinoline-l ~ thiones, which are found in ^ -Position carry at least one aryl radical or two alkyl substituents, on the other hand, are new compounds,

As compounds according to the invention, in addition to those in the examples The following are preferably produced:

4-phenyl "4-isopropyl-3, Jj-dihydro ^ H -isoquinoline-1-thione ^ l-phenyl-i} -sec.butyl-3, ¹ l-dihydro-2H-isoquinoline-1-thione 4-phenyl -iJ- (pentyl-3 ') -3, ^ - dihydro-2H-isoquinoline-1-thione

4-phenyl-4- (2'-methyl-butyl-l ^t ) -3,4-dihydro-2H-isoquinoline-l-thione 4-phenyl-4- (3 ^l -methyl-butyl-l ') -3 , ¹ <-dihydro-2H-isoquinoline-1-thione

4-phenyl-4- (n-pentyl-2 ') -3,4-dihydro-2H-isoquinoline-1-thione

! »- Phenyl - *» - (3 '-methy 1-buty 1-2) -3,4-dihydro-2H-isoquinoline-1-thione 4-phenyl-4- (2', 2 ^l -dimethyl-propyl ) -3,4-dihydro-2H-isoquinoline-1-thione

4-phenyl-4- (n-penfyl-l ') - 3, ¹ J-dihydro-2H-isoquinolin-l-thione ^4-phenyl-i l- (n-hexyl-2 ·) -3,4-dihydro -2H-isoquinoline-1-thione 4-phenyl-il- (n-hexyl-3 ') -3,' J-dihydro ^ H-isoquinoline-1-thione

4-phenyl-4- (2'-methyl-n-pentyl-l ') -3, ⁱ -dihydro-2H-isoquinoline-l-thione 4-phenyl-4- (3'-methy1-n-penty1- 1 ') -3,4-dihydro-2H-isoquinoline-1-thione 4-phenyl-4- (2 ^f -methyl-n-pentyl-3 ^f ) -3,4-dihydro-2H-isoquinoline-1-thione 4-phenyl-4- (4'-methyl-n-pentyl-2 ') -3, ^z "-dihydro-2H-isoquinoline-1-thione 4-phenyl-4- (2', 2 ^I -dimethyl-n -butyl-l ^! ) -3, ¹ <-dihydro-2H-isquinoline-

-1-thion

4-Phenyl-4- (3 ^f , 3'-dimethyl-n-butyl-1 ') -3,4-dihydro-2H-isoquinoline ~

-1-thion

4-phenyl-i- (3 ^f , 3 ^f -dimethy1-n-buty1-2 ') - 3,4-dihydro-2H-isoquinoline-

-1-thion

lJ-phenyl-4- (2 ^! -ethyl-n-butyl-1 ') -3, ⁱ l-dihydro-2H-isoquinoline-1-thione

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ty-Spiro-1 ¹ -cyclohexanol »^ -dihydro ^ H-isoquinoline-l-thione 4, ij-di- (n-propyl) -3, ¹ l-dihydro-2H-isoquinoline-l-thione 4,4- Di-isopropyl-3 » ¹ * - 'dihydro-2H-isoquinoline-l-thione i |, ^ - Di-n-butyl-3 _J ¹ l-dihydro-2H-isoquinoline-l-thione 4,4-di- sec.butyl-3, ⁱ {-dihydro-2H-isoquinoline-1-thione

6-methoxy- ¹ l, ⁱ l-di-n-propyl-3,4-dihydro-2H-isoquinoline-l-thione 6-methoxy- ⁱ J, ^ - di-isopropyl-3, ⁱ * -dihydro-2H ~ isoquinoline-1-thione 6-methoxy- ⁱ i _i 4-di-n-butyl-3,4-dihydro-2H-isoquinoline-1-thione 6-methoxy-4,4-di-sec.butyl-3, ⁱ } -dihydro ~ 2H-isoquinoline-1-thione

6,7-methylenedioxy-4, lJ-di-n-propyl-3, ⁱ l-dihydro-2H-isoquinoline - l-thione 6,7-methylenedioxy-4, ¹ i-di-isopropyl-3> 4- dihydro-2H ~ isoquinoline-1-thione 6,7-methylenedioxy-ii, 4-di-n-butyl-3, ¹ <-dihydro-2H-isoquinoline-l-thione 6,7-methylenedioxy-4,4-di -sec.butyl-3 » ⁱ J-dihydro ~ 2H-isoquinoline-1-thione

These compounds of the invention have valuable therapeutic properties Properties. In addition to having an anti-logistical effect, they have an effect above all a lowering of the cholesterol and triglyceride levels in the serum. The latter is explained in more detail below.

It is well known that it is responsible for the development of coronary heart disease an increased blood fat content is the most important risk factor. In general, elevated serum lipid levels are significant Risk factors for the development of arteriosclerotic symptoms also in other localizations, not only in the area of the coronary vessels. For the prophylaxis and therapy of atherosclerosis, especially in the area of the coronary arteries, the decrease is therefore greater Serum lipids are extremely important. The ones described in more detail above Substances are able to lower normal and elevated serum lipids in animals so that they can be used in treatment and prophylaxis of human and animal arteric sclerotic diseases, in particular in the area of the coronary vessels, but also other vascular areas are useful. The lipid-lowering properties of the compounds according to the invention are very surprising, since compounds of a similar structure have not yet become known as lipid lowering agents.

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The listed compounds are found to be comparative extremely low toxicity in the following animal models hypolipidemic active:

^{1 #} Male rat with normal serum lipid content. The values given in the tables represent the changes in the serum concentrations of certain lipid classes after a one-week treatment in the various daily dosages listed there. The application was carried out orally with the stomach tube in a dosage of 100, 30, 10 or 3 mg / kg / Day. As a rule, blood was taken before and after the treatment and the concentration of cholesterol in the serum was determined using the LAUBER and RICHTERLICH method, that of triglycerides using the SGGSTEIN and KREUTZ method and: lipid phosphorus using the BOEHRINGER / Mannheim method In the examples given in Table 3 below, the serum lipid changes that occurred as a result of treatment with the substances are defined as follows:

a) the percentage changes in the post-value of the treated group, based on the pre-value of the treated group, the pre-value being set at 100 % and

b) the change in the post-value of the treated group in relation to the post-value of an accompanying untreated control group, the untreated control group being set at 100 % . The value before a dash represents the percentage change compared to the initial value, the value after a dash represents the percentage change in the preparation group, based on an untreated control group.

2. The compounds are also hypolipidemically active in female , ovariectomized rats.

3. The carbohydrate- induced hypertriglyceridemia in male rats caused by the administration of fructose is greatly reduced by a three-day pretreatment with the substances listed compared with untreated controls.

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- li -

4. The substances are able to reduce the lipid content of the liver to varying degrees. In the examples given, the percentage reduction in individual lipids in the livers of male rats, based on untreated control animals, is given. The substances listed were administered orally on 16 days at a dose of 30 mg / kg / day.

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Table 3 Example no.

co O CD CO

cn CD

1.) 2.) 13.) 9.) • -4 / -2 12.) f ■ -655? LD ₁ -Q house ρ. ο. (r.fr/kg) > 8000 1500 > 8000 2000
I. -48 / -50 ■ 550 -45 Carbo-induced hypertriglyceride -12 ä ~: ie the c? Rat 100 afj / kg -8256 -69? 5 -3 / + I -7 55.5. -65 -75 -17 / -51 / -15 10, Oi. -54 -40 -17 -D9 / -46 5.3 c. -40 -8th -21 / -15 Corsican lipemic d * rat cholesterol -19 / -I2 -12 / -22 / -S -17 / -48 / -4O 100 mg / kg ■ triglycerides -79 / -6O -49 / . -66 / -3I 30 rsg / kg cholesterol -15 / -12 / -12 -10 / + 3 / Triglycerides -54 / -5Ö -56 / -47 - -29 / -I2 -4 / Lipid phosphor / -15 /-8th / -4 10 mg / kg cholesterol -8 / -18 -12 / -5 Triglyoerids -25 / -I4 -41 / -20 -50 / 5 ng / kg ~ cholesterol -I5 / -I9. -11 / -5 -21 / -10 Triglycoride -I7 / -I5 -15 / -19 -10 / -16 -5 / -I4 Ovarsctonated rat cholesterol -14 / -5 / -54 / -I6 / -22 100 E £: / kg triglycerides -64 / -4S -43 / -41 -14 / -8 50 nig / kg cholesterol -9 / -18 -11 / -18 -9 / -16 / -5 y Trißlyccride -56 / -5Ο -32 / -49 -25 / -17 / -3 y L ip i ά 'oho π "ohor / -12 / -21 / -S Leberiipida: cholesterol / -16 / - • 15 16 applications of triglycerides / -35. / -41 30 r.g / k *? Lipid phosphor / -7 j / -22

ro

-tr-

CJl

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The new compounds can be used either alone or mixed with pharmacologically acceptable carriers. Oral use is preferred. For this purpose, the active compounds are mixed with substances known per se and brought into suitable dosage forms by methods known per se, such as tablets, hard capsules, aqueous or oily suspensions or aqueous or oily solutions. As inert carriers, for example, magnesium carbonate, milk sugar or corn starch can be used with the addition of other substances such as magnesium stearate. The preparation can take place either as dry or wet granules. Vegetable and animal oils, such as sunflower oil or cod liver oil, are particularly suitable as oily carriers or solvents. A possible single dose is around 1 - 200 mg / kg / day.

A special application of the new compounds lies in the combination with other active ingredients. In addition to other suitable substances, these include above all:

Antidiabetic agents such as glycodiazine, tolbutamide, glibenclamide or circulatory drugs in the broadest sense, but especially coronary dilators such as chromonar or prenylamine and substances that lower blood pressure such as reserpine, i ^ -methyl-dopa or clonidines, other lipid-lowering agents such as clofibrate, psychotropic drugs such as chlordiazepoxide or mepiazepoxide Vitamins.

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Examples :

1. 4-Ethyl-4-phenyl-3 ^ -dihydro ^ H -isoquinoline-1-thione

a) N- (2,2-Diphenyl-n-butyl) -carbamic acid ethyl ester

65.4 g (0.25 mol) of 2,2-diphenylbutylamine hydrochloride are in Suspended 650 ml of toluene and added 71.6 g (0.68 mol) of anhydrous soda. 46.4 g (0.43 mol) are added dropwise with stirring Ethyl chloroformate and then refluxed for 5 hours. The inorganic material is sucked off and the piltrate concentrated in vacuo. The residue is made from petroleum ether recrystallized.

Yield: 67.1 g (90 % of theory ). Mp .: 67-69 ° C. Bp _{Q 3: 182-185 ° C}

b) 4-Ethyl-4-pheny1-3,4-dihydro-2H-isoquinolin-1-one

59.4 g (0.2 mol) of N- (2,2-diphenyl) butyl-carbaminsäureäthylester is in 500 g hot (130 ⁰ C) stirred polyphosphoric acid was added so that the temperature is between 13O j-l4O ° C remains. The temperature is kept at 140 ° C. for 10 minutes and, after cooling to 70-80 ° C., poured into 2.0 l of ice water. After standing overnight, the water is decanted off and the residue is extracted twice with water. The undissolved resin is taken up in benzene, dried and concentrated in vacuo. The remaining oil is dissolved in approx. 40 ml of methanol and crystallized by adding seed crystals. After recrystallization from methanol, the product is dried at 70 ° -75 ° C. in vacuo.

Yield: 24.4 g (48 % of theory) pp .: (114 ° C sint.) 118-121 ° C.

c) 3-ethyl-4-phenyl-3,4-dihydro-2H-isoquinoline-1-thione

22.6 g (90 mmol) of 4-ethyl-4-phenyl-3,4 ~ dihydro-2H-isoquinoline- -1-on v / earth dissolved in 35 ml of pyridine and 9.0 g (40 mmol) Phosphorus pentasulfide added with stirring. The solution is refluxed for 4 hours and, after cooling, in 400 Poured ml of water. The pH is adjusted to 8-8.5 with 10% potassium hydroxide solution and the mixture is stirred for 4 hours. After suction

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is washed off with water. The product is air dried and. recrystallized from ethanol / dimethylformamide ( ¹ I :!).

Yield: 11.2 g (47 % of theory) pp .: 171-173 ° C (168 ° C sint.)

d) 4-Ethyl-4-phenyl-3,4-dihydro-2H-isoquinoline-1-thione

5.0 g (20 mmol) of 4-ethyl-4-phenyl-3, ^ - dihydro-2H-isoquinoline- -1-one (see ib) are in a suspension of 1.8 g (8 mmol) Phosphorus pentasulphide and 1.8 g (32 mmol) of calcium oxide in 50 ml Added toluene with stirring and heated under reflux for 6 hours. The hot toluene solution is passed through a filter Poured off resinous residue and extracted the Hara twice with 50 ml of benzene each time. The combined organic solutions are constricted and ■: *?.? remaining oil with ethanol rubbed and then recrystallized from xthinol / dimethylformamide (4: 1) .

Yield: 3.0 g (56 % of theory) pp .: 171-173 ° C (168 ° C sint.)

e) 4-Ethyl-4-phenyl-3,4-dihydro-2H ~ isoquinoline-1-thione

5.0 g (20 m mol) of 4-ethyl ~ 4-phenyl-3,4-dihydro-2H-isoquinoline -1-οή (see 1b) is dissolved in a suspension of 4.2 g (20 mmol) of phosphorus pentachloride registered in 20 ml of toluene and then refluxed for 3 hours. Then H _? S initiated until the evolution of HCl has ended. The solvent is driven off iV and the residue is triturated with ethanol. After recrystallization from ethanol / dimethylformamide, 2.6 g are obtained.
(48 % of th.) F .: 168-172 ⁰ C (l60 ° C sint.)

f) 2,2-diphenylbutyl isothiocyanate

107 ml (0.77 mol) of triethylamine are added dropwise to a stirred solution of 92.0 g (0.35 mol) of 2,2-diphenylbutylamine hydrochloride in 140 ml of dry chloroform. At - 10 ⁰ C is allowed to run in within 30 minutes with stirring a solution of 25.0 ml (0.4l mol) of carbon disulfide in 100 ml of chloroform

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-Ib-

and stirs for 1 hour. A solution of 40.0 ml (0.41 mol) of ethyl chloroformate in 70.0 ml of chloroform is then added dropwise at ⁰ ° C. over the course of 30 minutes, and the mixture is also stirred at room temperature for one hour. A solution of 57.0 ml (0.4l mol) of triethylamine in 140 ml of chloroform is then added over a period of 15 minutes and the mixture is again stirred for 1 hour. After adding 420 ml of chloroform, a clear solution is obtained which is washed twice with 250 ml of 5% sodium hydroxide solution and 5% hydrochloric acid and water each time. After drying with Na _? S0 ^ is evaporated in vacuo and the crude isothiocyanate is immediately reacted further.
Yield: 95.0 g of crude product

g) 4-ethyl-4-phenyl-3,4-dihydro-2H-isoquinoline-1-thione 95 g of crude 2,2-diphenylbutyl isothiocyanate are introduced into 500 ml of cone. sulfuric acid with stirring and cooling in the course of 30 minutes, with the reaction temperature should not be above 40 ° C. The mixture is stirred for 1 hour at room temperature. The reaction solution is then poured in a thin stream onto 5.0 l of ice water and the product is extracted with chloroform. The solution is dried _{with Na 3 SO 4 and concentrated} and the residue triturated with ethanol. This gives 52 g of crystalline crude product. (mp .: 168-172 ^o C). This is then recrystallized from ethanol / dimethylformamide.

Yield: 41.0 g (44 % of theory based on 2.2.-diphenylbutylamine hydrochloride).

The implementation with cone. Sulfuric acid can also be used at -10 C to -15 ° C can be carried out, with appropriate stirred for a few hours will.

h) 4-Ethy1-4-phenyl-3,4-dihydro-2H-isoquinoline-1-thione 2.7 g (10 mmol) of 2,2-diphenylbutyl isothiocyanate (see if) is added to a suspension of 2.0 g (15 mmol) of aluminum chloride was added _{dropwise to 0 ml of carbon disulfide in 3 s} at room temperature and refluxed for 15 minutes. Then 10 ml of water are added dropwise with cooling. The product is extracted with benzene, dried and the solvent evaporated in vacuo.

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The amorphous residue is triturated with ethyl acetate and the

Sucked off crystals.

Yield: 0.6 g (22 % of theory) pp .: 170-173 ° C (165 ° C sint.)

i) 4-ethyl-4-phenyl-3> ^ - dihydro-2H-isoquinoline-1-thione 1 * 0 g (3.7 mmol) 2,2-diphenylbutyl isothiocyanate (see 1 f) and 1.0 g ( 7 »5 mmol) of aluminum chloride are triturated well and left at room temperature for 24 hours. Water is then carefully added with cooling, the mixture is extracted with benzene, dried and concentrated. After recrystallization from ethanol, 0.15 g (15 % of theory) is obtained. Pp .: 165 - 170 ⁰ C (158 ° C sint sint.)

k) 2,2-diphenylbutyl isocyanate

26.2 g (0.1 mol) of 2,2-diphenylbutylamino hydrochloride are introduced into 200 ml of 1 M solution of phosgene in toluene and refluxed for 10 hours. After cooling, the insoluble matter is separated off, evaporated in vacuo and distilled. Yield: 17.8 g (71 % of theory) bp _{n Λ} : 123-127 ° C

1) 4-Ethyl-4-phenyl-3,4-dihydro-2H-isoquinolin-1-one 5.0 g (20 mmol) of 2,2-diphenylbutyl isocyanate become a suspension of 2.9 g (22 mmol) of aluminum chloride in 20 ml of 1,2-diehlorethane was added dropwise with stirring over the course of 15 minutes and the temperature was kept below 30.degree. The mixture is stirred for 1 hour at room temperature and then carefully mixed with 30 ml of water. After adding 20 ml of dichloroethane, the organic phase is separated off, dried and concentrated. The residue is dissolved in 20 ml of methanol, the undissolved material is filtered off and the solvent is evaporated off. Crystals are obtained from a little methanol.
Yield: 2.3 g (46 % of theory) pp .: 116-119 ° C (112 ° C sint.)

m) 4-ethyl-iJ-phenyl "3,4-dihydro-2H-isoehinolin-1-thione (Implementation see 1 d)

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2. 4-Pheny1-3,4-dihydro-2H-isoquinoline-1-thione

a) N- (2,2-diphenyl-ethyl) carbaric acid ethyl ester reaction analogous to la from 2,2-diphenylethylamine Yield: 95 % of theory Pp .: 69-70 ⁰ C

b) 4-phenyl-3 _s 4-dihydro-2H-isoquinolin-1-one

Implementation analogous to 1 b from N- (2,2-Diphenylathy1) -carbamic acid ethyl-

ester

Yield: 55 % of theory Pp .: 170 - 173 ° C (167 ° C sint.)

c) 4-Phenyl-3, ^/ l-dihydro-2H ~ isoquinoline-1-thione

Reaction analogous to 1 c from ^ l-phenyl-3, ⁱ l-dihydro-2H-isoquinolin-l-one ^ Yield: Hj% of theory Mp .: 126 - 128 ° C (124 ° C sint.)

3. i} -Methyl-4-phenyl-3, ¹ l-dihydro-2H-isoquinoline-i-thione

a) N- (2,2-Dipheny1-propy1) -carbamic acid ethyl ester Reaction analogous to 1 a from 2,2-Diphenyl-propylamine Yield: 91 % of theory Mp .: 110-112 ° C (106 ° C sint.)

b) 'l-Methyl- ^ - phenyl-3,4-dihydro-2H-isoquinolin-1-one

Implementation analogous to 1 b from N- (2,2-diphenylpropyl) carbamic acid ethyl

ester

Yield: 60 % of theory Fp .: l65 - l69 ° C (155 ° C soften)

c) i | -Methyl-4-phenyl-3 _J 4-dihydro-2H-isoquinoline-1-thione reaction analogous to 1 c from 4-methyl-4-phenyl ~ 3 » ¹ J ~ dihydro-2H-isoquinoline-1- on

Yield: 41 % of theory Mp .: 186-189 ° C (182 ° C sint.)

k. 4-Phenyl-4-propyl-3, ⁱ l-dihydro-2H-isoquinoline-l-thione reactions analogous to 1 f and then 1 g from 2,2-diphenyl

peiitylamin-.

Yield: ^ Q% _t based on the starting amine. Mp .: 198 to 200 ⁰ C

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5. l | "isobutyl-4-phenyl-3, ¹ i-dihydro-2H-isoquinoline-1-thione

a) 2,2-Diphenyl-Jl-methyl-pentylisothiocyanate conversion analogous to 1 f from 2,2-diphenyl-H-methyl ~ pentylamine Yield: 6U% of theory _{Bp Q 6} 162-167 ° C

b) i | -Isobutyl- ^J 4-phenyl-3 »l ^{i-dihydro-2H-isoquinolin-l-thione} reaction analogously to 1 g of 2,2-diphenyl - ^ - methyl-pentyl isothiocyanate yield: 53% of theory Fp .: 16 l - 163 ° C (158 ° C sint.)

6. I | -Butyl- ⁱ l-phenyl-3, ii-dihydro-2H ~ isoquinoline-1-thione

a) N- (2,2-Dipheny1-hexy1) carbamic acid ethyl ester reaction analogous to 1 a from 2,2-diphenylhexylamine Yield: 91 % of theory Pp .: ^132-0

b) iJ-Butyl-M-phenyl-3 »4-difcydro-2H-isoquinolin-one Implementation analogous to 1 b from N- (2,2-diphenyl-hexyl) carbaminsäureäthy1 ester

Yield: 52 % of theory Pp .: 119 - 122 C (112 ° C sint.)

c) il-butyl- ⁱ l-phenyl-3, ¹ l-dihydro-2H-isoquinoline-l-thione conversion analogous to 1 c from 4-butyl-4 ~ phenyl-3, ¹ * -dihydro-2H-isoquinoline-1 -on

Yield: M7 % of theory Pp .: 155-157 ° C

7. 4-Hexyl - ^ - phenyl-3j4-dihydro-2H-isoquinoline-1-thione Reactions analogous to 1 f and then 1 g from 2,2-diphenyloctyl amine

Yield: 35 % of theory based on the starting amine, Pp .: 120-122 ⁰ C

8. ^f l-benzyl-4-phenyl-3 _J ⁱ * dihydro-2H-isoquinolin-l-thione

a) N- (2.2.3-Tripheny1-propy1) -carbamic acid ethyl ester reaction analogous to 1 a from 2.2.3-triphenylpropylamine Yield: 58 % of theory Pp .: 1 ^ 5 - 148 ° C

b) ^t t-Benzyl- ⁱ ) -phenyl-3. ¹ <-dihydro-2H-isoquinolin-1-one conversion analogous to 1b from N- (2.2.3-triphenyl-propyl) -carbamic acid

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ethyl ester

Yield: 10 % of theory Fp .:

c) 4-Benzyl-4-phenyl-3,4-dihydro-2H-isoquinoline-1-thione

Reaction analogous to 1 c from 4-benzyl-4-phenyl-3j4 ~ dihydro-isoquinoline ~

-1-on

Yield: 43 % of theory M.p .: 158-160 ° C

9. 4-Bensyl-3 _i 4-dihydro-2H-isoquinoline-1-thione

a) N- (2,3-Diphenylpropyl) -carbamic acid ethyl ester Reaction analogous to 1 a from 2,3-Diphenylpropylamine Yield: 91 % of theory . Kp _{n o:} 190-193 ⁰ C.

b) 4-Benzy1-3,4-dihydro-2H-isoquinolin-one

Reaction analogous to 1 b from N- (2,3-diphenyl-propyl) -carbamic acid-

ethyl ester

Yield: 47 % of theory M.p .: 123-124 ° C

c) 4-Benzyl-3> 4-dihydro-2H-isoquinoline-1-thione

Reaction analogous to 1 c from 4-benzyl-3,4-dihydro-2H-isoquinolin-1-one Yield: 60 % of theory M.p .: 125-126 ° C

10. 6-Ethoxy-4-phenyl-3,4-dihydro-2H-ioquinoline-1-thione Reactions analogous to 1 f and then 1 g from 2- (3'-Ä'thoxiphenyl) - -2-phenylethylamine. The implementation according to Example 1g is already in progress

'at - 15 ⁰ C smooth.

Yield: 30 % of theory based on the starting amine. M.p .: 175-176 ° C

11.6 ~ Ethoxy-4-ethyl-4-phenyl-3,4-dihydro-2H-isoquinoline-1-thione reactions analogous to 1 f and then 1 g from 2 ~ (3 ^I -ethoxyphenyl) -2-phenyl-- butylamine

Yield: 36 % of theory based on the starting amine. Fp .:

12. l \ , H-diethyl-6-methoxy-3, i-di

a) N-Z2-ethyl-2- (3'-methoxyphenyl) -butyi7-carbamic acid ethyl ester

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Reaction analogous to 1 a from 2 ™ ethyl-2- (3 '~ methoxyphenyl) -butylamine Yield: 95 % of theory Pp .: 69-70 ⁰ C

b) 4, H-diethyl-6-methoxy ~ 3,4-dihydro-2H-isoquinolin-1-one

300 g (1.08 mol) of N- ^ 2-ethyl-2- (3'-methoxyphenyl) -buty37-carbamic acid ethyl ester are in 2.2 l of phosphorus oxychloride for 3 hours

Boiled under reflux, excess phosphorus oxychloride is drained off i.V. cone, drawn and the residue poured onto ice water / ■ 'sodium hydroxide solution is made alkaline. The product is extracted with benzene, washed with water, dried and concentrated. The residue is in Ether added. The crystals which separate out are filtered off with suction and recrystallized from ethanol.

Yield: 121.6 g (50 % of theory), pp .: 130-132 ° C

e) ¹ J, 4-diethyl-6-methoxy-3,4-dihydro-2H-isoquinoline-1-thione reaction analogous to 1 e from k , 4-diethyl-6-methoxy-3,4-dihydro-2H -

isoquinolin-1-one

Yield: 73 % of theory Pp .: ^145-0

13. ^ -Diethyl-e ^ -methylendioxy ^^ - dihydro ^ H-isoquinoline-l- -thion

a) N-Z2-ethyl-2- (3 ', 4-niethylenedioxiphenyl) -butyr7-carbamic acid-

ethyl ester

Reaction according to 1 a from 2-ethyl-2- (3,4 ~ methylenedioxiphenyl) butylamine

Yield: 89 % of theory Kp _Q J. _1: I83 - 185 ⁰ C.

b) '{, ^ - diethyl-ö, 7-methylenedioxi-3,4-dihydro-2H-isoquinolin-1-one reaction analogous to 12 b from N- / I2-ethyl-2 ~ (3', 4 ', methylenedioxiphenyl) butyl7-carbamic acid ethyl ester
Yield: 61 % of theory Th. Pp .: 169 ° C

c) 4,4-diethyl-6,7-methylenedioxy-3,4-dihydro-2H-isoquinoline-1-thione reaction analogous to 1 c aun h , 'l-diethyl-o, 7-methyldioxi-3,4-dihydro -

-2H-ioquinolin-1-one

Yield: 71 % of theory Pp .: 176-177 ° C

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_ ο? -

14. 4-Spiro- (1'-cyclopentano) -3,4-dihydro-2H-isochiiiolin-1: -fefaiGh .- ^ 1 Reactions analogous to 1 f and 1 g from cyclopentyl-l-phenyl-i-methylamine

Yield: 39 % of theory Th., Based on starting ami η ,. Pp: 112 ° C

15 ♦ 6.7 "Methy lendioxi-ij-spiro- (1 '-cyclopentano) -3,4-dihydro-2H- -isoquinoline-1-thione

Reactions analogous to 1 f and then 1 g from cyclopentyl-1- (3'j 4 ^T -methylenedioxyphenyl) -1-methylamine.

Yield: 25 % based on the starting amine, pp .: 138 ° C

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Claims (10)

Patent claims: wherein R ₁ and R ₉ each have the same alkyl radicals with 1-4 C atoms, · * · CL or R _{1 is} a phenylalkyl radical with 7 or 8 carbon atoms or a phenyl radical and at the same time R_ is hydrogen, a straight-chain or branched alkyl radical with 1-6 carbon atoms or a phenyl radical, where R. and R _? auch.gemeinsam can form a saturated, carbocyclic 5- or 6-membered ring with the carbon atom in the 4-position, R, hydrogen or an alkoxy group with 1 - 4 carbon atoms, and R ₁ . Hydrogen or, together with R, the 6,7-oxymethylene group. 2. i {-Ethy 1-4-phenyl-3, ⁱ } -dihydro-2H-isoquinoline-1-thione 3. 4-Phenyl-3,4-dihydro-2H-isoquinoline-1-thione 4. 4-Isobutyl-4-phenyl ~ 3> 4-dihydro ~ 2H-isoquinoline-1-thione 5. 4- ^Benzyl-1 ^ -phenyl-3 »4-dihydro-2H-isoquinoline-1-thione 6. 4,4-Diethyl-6,7-methylenedioxy-3,4-dihydro-2H-isoquinoline-1-thione 7. 4-Spiro- (1'-cyclopentano) -3,4-dihydro-2H-isoquinoline-1-thione 8. Process for the preparation of 3> ^ - dihydro-2H-isoquinoline-l- thions of the general formula I. 3 0 9 8.1 ü / 1 (J b ii -2H- 2U3745 wherein R ₁ and R "each have the same alkyl radicals with 1 - H carbon atoms, or R _{1 is} a phenylalkyl radical with 7 or 8 carbon atoms or a phenyl radical and at the same time Rp is hydrogen, a straight-chain or branched alkyl radical with 1-6 carbon atoms or denote a phenyl radical, where R ₁ and R together with the carbon atom in ^ -position can form a saturated, carbocyclic 5- or 6-membered ring, R is hydrogen or an alkoxy group with 1- h carbon atoms, and R ^ Hydrogen or together with R, the 6,7-oxymethylene group, characterized in that either a) Compounds of the general formulas or Ha Man wherein R ₁ - R _{1 have} the above meaning and Y is a gg £. substituted araino group, an O- or S-alkyl or S-plienyl radical, cyclized or cyclized by treatment with acidic catalysts b) in compounds of the general formula III III replaced the oxygen atom by sulfur in a manner known per se. 9Ö10 / lüb9 2H37A5 9. Process for the production of pharmaceutical preparations with lipidsenkencier effect, characterized in that one compounds according to claim 1, optionally together with pharmaceutical carriers or stabilizers in a suitable for therapeutic purposes Application form brings. 10. Pharmaceutical preparations with lipid-lowering effect, characterized in that they contain a compound according to claim 1. 309810/1059