DE2143744A1 - 3,4-DIHYDRO-2H-ISOCHINOLIN-1-ONE AND THE METHOD FOR MANUFACTURING IT - Google Patents

Description

3 _> ¹ Ji) ihydro-2H-isoquinolin-l-ones and process for their preparation

The invention relates to 3, 'i-dihydro-2H-isoquinolin-1-ones of the general formula (i)

v / orin R ₁ and R _? in each case identical alkyl radicals with 1 to 4 carbon atoms, or R. a phenylalkyl radical with 7 or 8 carbon atoms and R ₂ at the same time hydrogen, a straight-chain or branched alkyl radical with ί - 6 carbon atoms or a phenyl radical, or R. a Phenyirost and R _? at the same time denote an alkyl radical with 2-6 carbon atoms, where R and R ₂ , together with the carbon atom in the ¹ J position, can also 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 ₇ , the 6,7-oxyniethylene group, where, if R, alkoxy or R, and R, together mean the oxyraethylene group, In addition to R _{1 as a phenyl radical, R 2 can} also mean hydrogen or a methyl group.

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 one either

Q.). Compounds of the general formulas (lla, b) *) fc-eradkoItic odei- v

309810/1058

BAO OBtGINAL

2H37A4

or

lib

wherein R ₁ - R ₂ . have the above meaning and Y denotes an optionally substituted amino group, O- or S-alkyl or an S-phenyl radical, or cyclized by treatment with acidic catalysts

b) in compounds of the general formula III

S Ri

III

replaced the sulfur atom by oxygen 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

VI

3098 10/1058

(R ₁ = H or phenyl) by alkylation with an alkyl halide in the presence of sodium amide in an inert solvent, for example according to the method described in Liebigs Annalen Vol. 561 (19 ^ 9) pages 52 ff (referred to here as method A). The preparation of diphenylacetonitriles which carry substituents in one of the phenyl rings is achieved using a method by T. Kametani et. al. J. Org. Chem. J56, 327 (1971). Here, ortho-haloalkoxybenzenes are reacted with NaNH 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 K p. or F.

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

Jl-Cyano-Jj. ^ - diphenylbut-l-en A 122 - 129 ° C / 0.1 mm

l-cyano-l-diphenyl-3-methyl-butane A 1 * 15 - H »7 ° C / 0.3 now

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

1-cyano-1.1.2-triphenylethane. AF: 123 - 12 ^ ⁰ C

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

3-ethoxyphenyl-pheny-acetonitrile B F: 55 ° C

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

l-cyano-l-ethyl-l-o-methoxyphenyl) - A Hl8 - 152 ⁰ CVO ^ mm propane

l-cyano-l-ethyl-l- (3 ', 4' -methylenedioxi- A 138-145 ° CVO, 9 mm phenyl) propane

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

) to Ore. Synth. 2_9, 83

309810/1058

The nitriles (V) thus represented are then, for example, in with Ammonia saturated ethanol or methanol with Raney nickel as a catalyst, at 70-120 atmospheric pressure and 100-125 ° C for 8-36 Hydrogenated to the amines (IV) for hours. It is advisable to work according to the method described in Org. Synth. 2J5, 71 (19 ^ 3) specified regulation. The illustrated Amines (IV) are given in Table 2.

Table 2

Amine

2.2-Diphenylbutylamine 2.2 ~ Diphenylpentylamine 2.2-Diphenyl-4-methyl-pentylamine 2.2-Diphenyl-hexylamine 2.2.3-Triphenylpropylamine 2.3-Diphenylpropylamine 2- (3'-Ethoxiphenyl) -2-phenylethylamine 2- (3'-Ä'thoxiphenyl) -2-phenyl-butyl-lamin 2-ethyl-2- (3 ^l -methoxiphenyl) -butylamine 2-ethyl-2- (3 ', ^ ^f -methylenedioxiphenyl) -butylamine
Cyclopentyl-1-phenyl-1-methylamine

The amines IV obtained in this way are now converted into isocyanic acid derivatives capable of ring closure by methods known per se II a and II b transferred.

Isocyanates are, for example, starting from the amines (IV) with phosgene in an inert solvent such as benzene, toluene, ethyl acetate or Chlorobenzene shown. It is advisable to follow the rule given in Org. Synth. Coil. Vol. II, 453 (19 * 13) or in Liebigs Ann. Chem. 562, 105, 106 (19 ^ 9).

Carbamic acid esters (ila, 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 ₂ CO-. Or NnOH), the amine is treated with a chloroformic acid ester in an inert solvent such as toluene, benzene, chlorobenzene, ethyl acetate

309810 / 1Ü58

BAD ORfGfNAL

Fp./ 182 ⁰ C .HCl Fp. .HCl Fp. .HCl Fp. .HCl Fp. .HCl Fp. .HCl Fp .: .HCl Fp .: .HCl Fp .: .HCl Fp .: Kp. 'Kp. .HCl : 191-193 ^O C : 2O5-2O8 ° C 193-197 ° C 188-19O ° C 310 ⁰ C 19 ^ -197 ° C 165-168 ° C 173 ° C 183-184 ° C 115-120 (0.4mm) Fp .:

- _5th 2U37U

or a chlorinated hydrocarbon such as CCIk, reacted at elevated temperature. Or you can start from the isocyanates (il · 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 ^ O).

The specification in J. Am. Chem. Soc. J51., 1797 (1929). Here, the amine (iv) is reacted with nitrourea in water or a water / alcohol mixture at room temperature or with gentle heating to form urea. Alkylated ureas (Ha ₅ Y = NHR or, NRR ') are made from isocyanates (lib) with a primary or secondary amine in an inert solvent such as benzene, toluene, chlorobenzene or an aliphatic, chlorinated hydrocarbon according to R. JH., H32 ( 1932).

Thiocarbamic acid esters (ila, Y = SR) are described according to the method shown in Liebigs Annalen 562, 210. (19 * 1-9). At increased Temperature is the isocyanate (ilb) with a mercaptan im Autoclave implemented.

The preferred compounds of the formula II a include carbamic acid esters (Y = O-alkyl with 1-4 carbon atoms), O-phenyl and urea derivatives with Y = N-alkyl (1- * I 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 conc. Sulfuric acid or Lewis acids such as AlCl ,. Al3 solvents come into consideration - if they are used at all for the reaction - inert anhydrous organic solvents, for example chlorinated hydrocarbons such as CCl ^ or trichlorethylene, furthermore CS ₂ or aromatic hydrocarbons such as benzene, toluene or xylene. The temperatures used depend upon the reactants used and may vary between -15 ° C and 15O ⁰ C.

The starting compounds of the formula III for procedure b) are also produced by methods known per se. Suitable starting materials are compounds that have the general Corresponds to formulas II a and II b, but instead of the

309810/1058

Oxygen containing a sulfur atom, ie isocyanic acid derivatives according to formula II b, ureas and carbamic acid derivatives according to formula II a, each containing a sulfur atom instead of 0. The preparation takes place analogously from the amines of the formula IV.

The isothiocyanates are represented, for example, according to J. Am. Chem. Soc. 81, (1959) page 4328.

The amines (IV) are converted into dithiocarbamic esters with CS “and a base (eg triethylamine) in the presence of chloroformic acid esters, which give the corresponding isothiocyanates in the event of an excess of base (eg triethylamine). Or you put 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. goes

is most conveniently of the isothiocyanates, which with an alcohol or an alkoxide to the desired compounds at temperatures between 20 ° C and 8O ⁰ C without a solvent or the alcoholate dissolved in the corresponding alcohol is reacted. These methods are, for example, in J. Am. Chem, Soc. 21 "581 (1955) or §5_ 900 _t described (19 * 13).

* The dithiocarbamic acid esters can also be obtained from the isothiocyanates 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. (19IO), 910).

For the preparation of the thioureas one starts, for example, either from the amine (IV), that with ammonium thiocyanate in water in the presence a mineral acid (e.g. HCl) is converted to thiourea at elevated temperature (cf. Arzneimittel Forschg. 2_, 125 (1952)) - you can also use an inert solvent, e.g. chlorobenzene, that is saturated with HCl, work - or you set that

309810/1058

2H37U

- 7 -

Mustard oil at room temperature in an aqueous, alcoholic ammonia solution to thiourea (cf. Chem. Ber. 80, 275 (IW)).

For the representation of the N-mono-substituted thioureas one follows the information in J. Am. Chem. Soc. ^, 1909 (1929), the amine (IV) being reacted under reflux with a SetüTöl without a solvent or dissolved in alcohol. For Ν, Ν-disubstituted thioureas, the mustard oil (II b) is reacted with a secondary amine at 0 ° C or under reflux in an inert solvent such as benzene, toluene, chlorobenzene or ethyl acetate (see Chem. Ber. 28 , 2935 (1895 )).

Reactions known per se are used to convert (III) into (I) by procedure b). The reaction with an alkyl halide, which can also be basic substituted, is suitable, the thione of the formula III reacting formally in its tautomeric imino form. You may work in the presence of a base, such as potassium carbonate, in an inert solvent such as benzene, toluene, xylene, acetone or methyl ethyl ketone at elevated temperature, giving an S-alkyl compound which is then mixed with mineral acid such as hydrochloric acid at the temperature is to (i) entschw'ef elt. one can also (ill directly with mineral acid at elevated temperature in (I) transfer. Furthermore, the compounds of the general formula (III) may be with a peroxide such as _Na? 0 "in an alkaline medium In addition, the 3,4-dihydro-2H ~ isoquinoline-1-thiones can also be oxidized to the oxygen compounds with SeO "in alcohol at elevated temperature. Furthermore, one can also use hexacyanoferrate- (III) in Ethanol or with silver nitrate in aqueous alcohol convert the sulfur compounds into the corresponding oxygen compounds (see R. Boudet Bl. / 5 / j 18, 8H6 (195D)).

3, ⁱ l-dihydro-2H-isoquinolin-l-ones, which can also be substituted in the ^ -position, are from J. Chem. Soc. 1956, 2557, US Patent 2,67,902 and English Patent 721,286. Some of these known compounds have a local anesthetic effect.

30981Ü / 1Ü58

2U374A

The compounds according to the invention with the indicated substitution are, however, new compounds with lipid-lowering properties.

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

4-phenyl- * ln-pentyl-3, il-dihydro-2H-isoquinolin-1-one '.iJ-phenyl- ⁱ ] -isopropyl-3, ii-dihydro-2H-isoquinolin-1-one ⁱ l-phenyl - ^ - sec.butyl-3 » ⁱ '-dihydro-2H-isoquinolin-1-one il-Phenyl-i | - (pentyl-3') -3, ⁱ <-dihydro-2H-isoquinolin-1-one 1 -Phenyl-iJ- (2'-methyl-butyl-1 '-) - 3, ^| 1-dihydro-2H-isoquinolin-1-one iJ-Phenyl-iJ- (3'-methyl-butyl-1 ') -3,4-dihydro ~ 2H-isoquinolin-1-one 4-phenyl-4- (i.d. -pentyl-2 ') -3,4-dihydro-2H-isoquinolin-1-one i | -Phenyl - ^ - (3'-methyl-butyl-2 ¹ ) -3, ⁱ »-dihydro-2H-isoquinoline- l-on

ⁱ »- (2 ', 2'-dimethyl-propyl) -3, ² <-dihydro-2H-isoquinolin-l-one ^ -Cn-hexyl-l ·) -3, ⁱ l-dihydro-2H-isoquinoline- l-cn H-phenyl-ii- (n-hexyl - 2 ') -3, il-dihydro-2H-isoquinolin-l-one ^ -phenyl- ^ l- (n-hexyl-3') - 3, 4-dihydro-2H-isoquinolin-1-one ^ -phenyl - ^ - (2'-methyl-n-pentyl-1 ¹ ) -3, i | -dihydro-2H-isoquinolin-1-one Jj-Phenyl-Jl -O'-methyl-n-pentyl-l ¹ ) -3, ⁱ <-dihydro-2H-isoquinolin-1-one ^ 1-phenyl-it- (2 '-methyl-n-pentyl-3') -3 , iJ-dihydro-2H-isoquinolin-1-one l | -Phenyl ~ ⁱ 4-O ^! -methyl-n-pentyl ~ 2 ^f ) -3, ² i-dihydro-2H-isoquinolin-1-one ii-phenyl-i | - (2 ^f , 2'-dimethyl-n-butyl-1 ¹ ) -3 , ^ - dihydro-2H-isquinolin-1-one

i »-Phenyl-4- (3 ', 3' -dimethyl-n-butyl-1 ') -3,' i-dihydro-2H-isoquinoline- -1-on

^ -Phenyl-i »- (3 ', 3 ^f -dimethyl-n-butyl-2') -3, ¹ <-dihydro-2H-isoquinolin- ~ l-one

^ -Phenyl - ^ - (2'-ethyl-n "butyl-l ') - 3, ^ - dihydro-2H-isoquinolin-l-one ^ -Spiro-1'-cyclohexano-3, ^ - dihydro-2H- isoquinolin-1-one i | _> iJ-Di- (n-propyl) -3, ⁱ i-dihydro-2H-isoquinolin-1-one ^, i | -di-isopropyl-3, ^ ~ dihydro-2H-isoquinoline ~ l-one i <, ^ - di-n-butyl-3, ^ - dihydro-2H-isoquinolin-l-one ^, ^ - di-sec.butyl-3, ⁱ <-dihydro-2H-isoquinoline "l -on

309810/1058

6-methoxy- ¹ ], ⁱ <-di-n-propyl-3, ¹ i-dihydro-2H-isoquinolin-1-one 6-methoxy- ¹ , i <-di-isopropyl-3, 1 i-dihydro -2H-isoquinolin-l-one 6-methoxy ^J <, ^ - di-n-butyl-3, '4-dihydro-2H ~ isoquinolin-l-one 6-Metboxy-'l, il-di-sec. butyl-3,4-dihydro-2H-isoquinolin ~ l-one

6,7 ~ ⁱ J methylenedioxy, ¹ J-di-n-propyl-3, ⁱ J-dihydro-2H ~ isoquinolin-l-one 6,7-methylenedioxy ^I J, ¹ _{l-di-isopropyl-3>} 4-dihydro-2H-isoquinolin-1-one 6,7-methylenedioxy-4,4-di-n-buty1-3, ^ - dihydro-2H-isoquinolin-1-one 6,7-methylenedioxy- ^J l, ¹ l-di-sec.butyl-3, ¹ i-dihydro-2H-isoquinolin-l-one

The 3 »^ ~ dihydro-2H-isoquinolin-1-ones have valuable therapeutic properties Properties. These include lowering cholesterol and Serum triglyceride levels. It is explained in more detail below.

It is generally accepted that 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 one in the patent application The substances listed are able to lower normal and elevated serum lipids in animals and it can therefore be assumed that they also in the treatment and prophylaxis of human and animal arteriosclerotic diseases, especially in the field the coronary vessels, but also other vascular areas, are useful. The compounds listed were found to be comparative extremely low toxicity in the following animal models hypolipidemic active:

* · 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 took place

309810/1058

2 H 37 44

orally with the stomach tube in a dosage of 100, 30 and 10 mg / kg / day. As a rule, blood was drawn before and after the treatment and the concentration of cholesterol in the serum according to the method of LAUBER and RICHTERICH and those of triglycerides determined by the EGGSTEIN and KREUTZ method. In the examples given are the changes in serum lipids resulting from treatment with the substances the serum lipid content is defined as follows:

a) The percentage changes in the postvalue of the treated group based on the previous value of the treated group, where the previous value

- was set at 100 % and

b) the changes in the post-value of the treated group in relation for the post-value of an accompanying untreated control group, whereby the untreated control group was set to 100 / S. 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 con-

troll group, represent.

2. The carbohydrate- induced hypertriglyceridemia in male rats caused by the administration of fructose is

'Action with the listed substances versus untreated controls greatly diminished.

3. The substances are able to reduce the lipid content of the liver to varying degrees. Using example no. 1, the percentage reduction in individual lipid classes in the livers of male

. borrowed rats, based on untreated control animals. the

The substance was administered orally on 16 days at a dose of 30 mg / kg / day. The decrease in liver cholesterol is - 14 %, the decrease in liver phospholipids - 7%. ·

309810/1058 _{ΛΛΙΛ <Λ}

ORfGINAL INSPECTED

.. 'j % Change after 8 c
r Serum-
Trialycerides Three applications on the
ng / kg / day Serum-
Tri-glycerides cyRatte with Serum-
Tri-glycerides /oVi.-rcindorung dor
KH-induced hyper-
triglyceridaemi gardens
_r j ρ _ ^ + r. m; + 30 ·
mq / kq 10
mq / kq • -1 in 1
mg / kg
LD 50 p.o. > 1000 i ■■■■ 100 -07 / -35 30th -37 / -10 -20 / 100
mq / kq • Ma υ
ip 3348 S. SeisD.
N- ' This way-
cholesterol -5O / -31 Serum-
cholesterol 10 -69 -13 820 “1000 1 -27 / -2 -50 / -42 -19 / -1 -17 / -29 Serum-
cholesterol 7th -6 / -8 -43 / -39 -12 / -8 -8Al 4
j -26 / -0 -19 -16 8th -1 / + 5 -45 / -16 - 8 / + 15 -22 / -20 I.
I.
i -20 / -36 -13 Q
I * -16 / -1 -18 / + 2 - I.
i -6 I.
10 + 1 / + 2 -Π / + 2 ' + 1 / -6 309 ί
I. 1
i
. i
i
ι

JO · OD 1 j- * > K

ils

i OO

ro co

The new compounds can be used either alone or mixed with pharmaceutically 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. Inert carriers which can z.bI Magneriumkarbonat, lactose or corn starch with the addition of other substances, such as are used for example Magnesiurnstearat. The preparation can take place either as dry or moist 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 agents in the broadest sense, but especially coronary dilators such as chromonary or prenylamine and antihypertensive substances such as reserpine, oil -methyl-dopa or clonidines, other lipid-lowering agents such as clofibrate, Psychοp harmaka such as chlordiazepoxide, diazepam or meprobamate and vitamins.

■■: .: - "-." 209 i.1 Ί 0 '1

21A37AA

Examples:

1. _i 4-Ethy] -4-phenyl-3,4-dihydro-2H-isoquinolin-1-one α) N- (2,2-diphenyl-n-butyl) -carbamic acid ethyl ester

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

Yield: 67.1 g (.. 90% of theory) M.p .: 67-69 ° C Kp _ -. 182-185 ° C

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

59.4 g (0.2 mol) of N- (2,2-diphenyl) -butyl-carbamic acid ethyl ester is. added to 500 g of hot (130 ° C) stirred polyphosphoric acid so that the temperature remains between 130-140 ° C. The temperature is kept at 140 ° C. for 10 minutes and, after cooling to 70-80 ° C., poured into 2 _{ml 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.

c) 2,2-diphenylbutyl isothiocyanate

To a stirred solution of 92.0 g (0.35 mol) of 2,2-diphenylbutylamine hydrochloride 107 ml (0.77 mol) of triethylamine are added dropwise to 140 ml of dry chloroform. At -10 C one leaves within 30 minutes a solution of 25.0 ml (0.41 mol) carbon disulfide in Run in 100 ml of chloroform with stirring and stir for 1 hour. then one drips at 0 C a solution of 40.0 ml (0.41 mol) of Chloromisen- ' acid ethyl ester in 70.0 ml of chloroform within 30 minutes and

309810/10 58 OFUGiNAL INSPECTED

stir at room temperature for one hour. A solution of 57.0 ml (0.41 mol) of triethylomine in 140 ml of chloroform is then added over the course 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 ₉ SO. will i. V. evaporated and the crude isothiocyanate immediately reacted further.

Yield: 95.0 g of crude product

d) 4-ethyl ~ 4-phenyl-3,4-dihydro-2H-isoquinoline-1-thione.

95 g of crude 2,2-diphenylbutyl isothiocyanate is poured into 500 ml of cone within 30 minutes. Sulfuric acid entered with stirring and cooling, the reaction temperature should not be above 40 C. The mixture is subsequently stirred at room temperature for 1 hour. 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 with Na_S0. dried, concentrated and the residue triturated with ethanol. 52 g of crystalline crude product are obtained. '__

(M.p .: 108-172 C). This is then made from ethanol / dimethylformamide recrystallized.

Yield: 41.0 g (44 % of theory based on 2.2.-diphenylbutylamine hydrochloride) mp: 170-171 ° C.

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

2.7 g (10 mol) of 2,2-diphenylbutyl isothiocyanate are added dropwise to a suspension of 2.0 g (15 mol) of aluminum chloride in 3.0 ml of carbon disulfide at room temperature and refluxed for 15 minutes. Then 10 rol of water is added dropwise with cooling. The product is extracted with benzene, dried and the solvent evaporated in vacuo. The amorphous residue is triturated with ethyl acetate and the crystals are filtered off.

Yield: 0.6 g (? 2 % of theory ) mp: 170-173 ° _C (165 ° C Sint)

309810/1058

ORJGJNAL INSPECTED

" ¹⁵ " 2H37U

f) ^ -Ä

1.0 g (3.7 m mol) of 2,2-diphenylbutyl isothiocyanate and 1.0 g (7.5 m mol) of aluminum chloride are ground thoroughly and left at room temperature for 24 hours. Water is then carefully added with cooling, extracted with benzene, dried and concentrated. Recrystallization from ethanol gives o _f 15 g (15 % of theory ). Mp .: 165 - 170 ° C sint.)

g) The m3,4-dihydro-2H-isoquinoline-1-thiones obtained in this way are after 6 b converted to 4-ethyl-4-phenyl-3,4-dihydro-2H-isoquinolin-one.

h) 2,2-diphenylbutyl isocyanate

26.2 g (0.1 mol) of 2,2-diphenylbutylamino hydrochloride are in 200 ml 1 M solution of phosgene in toluene and 10 hours under reflux heated. After cooling, the insoluble matter is separated off, i. V. evaporated and distilled.

Yield: 17.8 g (71% d.-Th.) _Kp: 123-127 ° C.

V ₁ I

5.0 g (20 mol) of 2,2-diphenylbutyl isocyanate become a suspension of 2.9 g (22 mol) of aluminum chloride in 20 ml of 1,2-dichloroethane Stirring was added dropwise 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 added then carefully 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 and filtered off from the insoluble and the solvent evaporated. Crystals are obtained: from a little methanol.

Yield: 2.3 g (46% of theory ) Mp .: 116-119 C (112 C Sint.)

: - ■ U ⁽ i V- 1 ί ^/ 1 (J 5 8 ORIGINAL INSPECTED

" ¹⁶ " 2H3744

2. 4-Phenyl-4-propyl »3,4-dihydro-2H-isoquinolin-1-one

α) N- (2,2-diphenylpentyl) carbamic acid ethyl ester Implementation analogous to 1 α from 2,2-diphenylpentylamine

, Yield: 85 % of theory Th. M.p .: 84-86 ° C (82 ° C sint.)

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

Reaction analogous to 1 b from N- (2,2-diphenylpentyl) carbamic acid lithium ester.

Yield: 65 % of theory Th. Mp .: 160 - 163 ° C (155 ° C sint.)

3. 4-Butyl-4-phenyl-3,4-dihydro-2H-isoquinolin ~ 1-one

a) N- (2 _/ 2-diphenylhexyl) carbamic acid ethyl ester reaction analogously to 1 α from 2,2-diphenylhexylamine

Yield: 91 % of theory Th. Mp: 132-134 ° C

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

Reaction analogous to 1 b from N- (2,2-diphenylhexyl) carbamic acid lithium t ester

Yield: 52 % of theory Th. - Mp .: 119 - 122 ° C (112 ° C Sint.)

4. 4-Isobutyl-4-phenyl-3,4-dihydro-2H-isoquinolirin-1-one

a) N- (2.2-Diphcnyl-4-methyl-pentyl) carbamic acid ethyl ester Reaction analogous to 1 α from 2.2-diphenyl-4-methylpentylamine. The connection is used raw for ring closure.

3 0 9 8 1 0/1058

ORIGINAL! NSPEC ¹ TEO

"*" ~

b) 4 ~ isobutyl-4-phenyl-3,4-dihydro-2H-isoquinolin-1-one Reaction analogous to 1 b from crude N- (2.2-diphenyl-4-methyi pentyl / carbamic acid ethyl ester)

Yield: 15 % of theory Th. Based on the starting amine. Mp .: 137 - 140 ° C (132 ° C sint.)

5. 4-Benzyl ~ 4-phenyl-3 <.4-dihydro-2H-isoquinolin-1-one

ο) N- (2.2.3-Tr.i phenyl-propyl) -c α rbamin acid ethyl ester Implementation analogous to 1 α from 2.2.3-triphenylpropylamine

Yield: 58 % of theory Th. Mp .: 145-148 ° C

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

Reaction analogous to 1 b from N- (2.2.3-triphenyl-propyl) -carbamic acid ethyl ester

, Yield: 10 % of theory M.p .: 149 ° C

6. 6-Ethoxy-4-phenyl-3,4-dihydro-2H-isoquinolin-1-one α) 6-Ethoxy-4-phenyl-3,4-dihydro-2H-isoquinoline-1-thione

Reactions analogous to 1 c and then 1 d from 2- (3'-ethoxyphenyl) 2-phenylethylamine

Yield: 30 % of theory Th. Related to the starting amine. M.p .: 175-176 ° C

b) 6-A * thoxy-4-phenyl-3,4-dihydro-2H-isoquinolin-1-one

5.7 g (0.02 mol) of 6-ethoxy-4-phenyl-3,4-dihydro-2H-isoquinoline-1-thione are together with 5.42 g (0.04 mol) Ν, Ν-diethylaminoethyl chloride in 100 ml of toluene refluxed for 5 hours. The cooled solution is extracted internally with water / water and then with 2 η HCl. The acidic aqueous

309810/1058 ORIGINAL .NSPECTHD

2U37U Ar

Phase is started with cone. NFL solution made alkaline and with

form extracted. After drying and concentrating the chloroform solution an oil remains which is refluxed for 3 hours with 100 ml of 2N HCl. The oil that separates out is extracted with chloroform, the chloroform solution washed neutral, dried and concentrated. Recrystallize from isopropyl ether.

Yield: 3.8 g ( ie 70% of theory ). Mp .: 174 ° C

7. 6-Ethoxy-4-ethyl-4-phenyl-3,4-dihydro-2H-isoquinolin-1-one

a) o-Ethoxy-4-ethyl-4-phenyl-3,4-dihydro-2H-isoquinoline-1-thione "Reactions analogous to 1 c and then 1 d from 2- (3'-ethoxyphenyl) -2-phenyl-butylamine

Yield: 36 % of theory Th. Related to the starting amine. M.p .: 184 C.

b) o-Ethoxy ^ i-ethyl- ^ - phenyl-S ^ -dihydro ^ H-isoquinolin-i -one

Implementation analogous to 6 b from 6-ethoxy-4-ethyl-4-phenyl-3 _/ 4-dihydro-

2H-isoquinoline-1-thione

Yield: 72 % of theory M.p .: 148.5 ° C

8. 4-Benzyl-3,4-dihydro-2H-isoquinolin-1-one

a) N- (2,3-Diphenylpropyl) -carbamic acid ethyl ester. Implementation analogous to 1 α from 2,3-diphenylpropylamine

Yield: 91 % of theory Th. Bp ₉ : 190-193 ° C

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

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

■ ester

Yield: 47 % of theory Th. Mp .: 123-124 ° C

309810/1058 ORIGINAL INSPECTED

2H37U

9. 4,4-Diethyl-6-methoxy-3,4-dihydro-2H-isoquinolin-1-one

α) N- [_2-ethyl-2- (3'-methoxyphenyl) -butyl] -carbamic acid ethyl ester Reaction analogously to 1 α from 2 ~ ethyl-2- (3'-methoxyphenyl) -butylamine

Yield: 95 % ά. Th. Mp .: 69-70 ° C

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

300 g (1.08 mol) of N- [2-ethyl-2- (3'-fliethoxiphenyl) -buty3-carbamic acid ethyl ester are refluxed for 3 hours in 2.2 l of phosphorus oxychloride. Excess phosphorus oxychloride is i. V. deducted and the residue poured onto ice water. With cone. Caustic soda is made alcoholic. The product is extracted with benzene, washed with water, dried and concentrated. The residue is taken up in ether. The separating crystals are suctioned off and recrystallized from ethanol.

Yield: 124.6 g (50 % of theory ). Mp .: 130-132 ° C

10. 4,4-Diethyl-6 _/ 7-methylenedioxy-3,4-dihydro-2H-isoquinolin-1-one

a) N-L 2-ethyl-2- (3 ' _/ 4'-methylenedioxiphenyl) butyl] carbamine acid ethyl ester

Reaction according to 1 α from 2-ethyl-2- (3 "^ '- methylenedioxiphenylj-butylomin

Yield: 89 % of theory Th. Bp. _N .: 183-185 ° C

U, 4

b) _{4/4-diethyl-6,7-methylendioxi-3,4-dihydro-2H-isoquinolin} -1-one reaction analogously 9 b of N- [2-ethyl-2- (3 ', 4'-methylendicxiphenyl) -butyJT] -carbamic acid ethyl ester

Yield: 61 yrs d. M.p .: 169 ° C

309810/1058

2U37U

iv

4-spiro- (1'-cyclopentano) -3,4-dihydro-2H-isoquinolin-1-one

a) 4-Spiro- (i'-cyclopentano) -3,4-dihydro-2H-isoquinoline-1-thione Reactions analogous to 1 c and 1 d from cyclopentyl-1-phenyl-1-methylamine

Yield: 39 % of theory Th. Related to the starting amine. M.p .: 112 ° C

b) 4-spiro- (1'-cyclopentano) -3,4-dihydro-2H-isoquinolin-1-one

6.8 g (0.031 mole) of 4-spiro- (i'-cyclopentano) -3,4-dihydro-2H-isoquinoline-1-thione are together with 21.6 g (0.16 mol) of Ν, Ν-diethyleaniinoa'thyichlorid and 4.3 g (0.031 mol) of potassium carbonate in 50 ml of methyl ethyl ketone Boiled under reflux for 5 hours. Extract with 1 η HCl, make with cone. Nl-L solution becomes alkaline and extracts the free base

ο -

with chloroform. The organic phase is washed neutral and dried and narrowed. The remaining oil is 3 hours with 100 ml 2 η HCl refluxed. The separated oil is taken in chloroform on, washes neutral, dries and restricts. Recrystallize from isopropyl ether.

"Yield: '2.7 " g "(dTT. 42 '. '% DTTh.T", melting point: 102 ° C

c) 4-Spiro- (i'-cyclopentano) -3,4-dihydro-2H-isoquinolin-1-one

• 4.3 g (0.02 mol) of 4-spiro- (V-cyclopentano) -3,4-dihydro-2H-isoquinoline-1-thione together with 21.3 g (0.15 mol) of methyl iodide in 150 ml of toluene refluxed for 6 hours. It is concentrated, 100 ml of 2 HCl are added and the mixture is refluxed for a further 3 hours. The precipitated crude product is taken up in chloroform, the solution washed neutral, dried and concentrated.

Yield: 2.9 g ( ie 71% of theory ). Mp .: 102 ° C

309810/1058 ORIGINAL INSPECTED

21A374A

d) 4-Spiro- (1'-cyclopentano) -3,4-dihydro-2H-isoquinolin-1-one

4.3 g (0.02 moles) of 4-spiro- (l'-cyclopentGno) -3,4-dihydro-2H-isoquinoline-1-thione are refluxed for 4 hours with 50 ml of half-concentrated hydrochloric acid. It is taken up in chloroform and wash the organic phase once with sodium bicarbonate solution and then with water, dries and constricts.

Yield: 2.1 g ( ie 51% of theory ). Mp .: 102 ° C

e) 4-Spiro- (l '-cyclopentan.o) -3,4-dihydro-2H-isoquinolin-one

4.3 g (0.02 mol) of 4-spiro- (l ^l -cyclopentano) -3 _/ 4-dihydro-2H-isoquinolin-1-one are dissolved in 50 ml Äthnol and 1.1 g (0.01 mol ) Selenium dioxide added. The mixture was refluxed for 4 hours, cooled, insolubles were filtered off and concentrated.

Yield: 3.6 g ( ie 87% of theory ). Mp .: 101-102 ° C

3Ü9810 / 1058 ORIGINAL INSPECTED

Claims (9)

Patent claims: wherein R ₁ and FL each represent the same alkyl radicals with 1 to H carbon atoms, or R. a phenylalkyl _{radical with 7 or 8 carbon atoms and R 2} simultaneously denotes hydrogen, a straight-chain or branched alkyl radical with 1 to 6 carbon atoms or a phenyl radical , or R ^ denotes a phenyl radical and R "simultaneously denotes an alkyl radical having 2 to 6 carbon atoms, where R. and R _? also, together with the carbon atom in the 4-position, can form a saturated, carbocyclic 5- or 6-membered ring, R, hydrogen or an alkoxy group with 1 carbon atoms and Rj, hydrogen or together with R, the 6, 7-oxymethylene group, where, if R, alkoxy or R, and R ₁ . together mean the oxymethylene group, Rp can also mean hydrogen or a methyl group in addition to R. as a phenyl radical. 2. 4-Ethyl-4-phenyl-3, ⁱ <-dihydro-2H-isoquinolin-1-one 3. 4-Isobutyl-4-phenyl-3, il-dihydro-2H-isoquinolin-1-one H. 4-ßenzyl-4-phenyl-3, ⁱ l-dihydro-2H-isoquinolin-1-one 5. H , 4-Diethyl-ß, 7-methylenedioxi-3,4-dihydro-2H-isoquinolin-1-one 6. 4 ~ Spiro- (1 ^f cyclopentano) -3,4-dihydro-2H-isoquinolin-1-one 7 · Process for the preparation of 3,4-dihydro-2H-isoquinoline-1-oene "NII the general formula 309810/1058 -23- 2U374A wherein R ₁ and Rp each have the same alkyl radicals with 1 to 4 carbon atoms, or R _{1 is} a phenylalkyl radical with 7 or 8 carbon atoms and R "is simultaneously hydrogen, a straight-chain or branched alkyl radical with 1-6 carbon atoms or a phenyl radical or R. is a phenyl radical and Rp is simultaneously a gsEdkafcifijan. or verawed ^ t αϊ alkyl radical having 2-6 bocbuten G-atoms, '"in R ₁ mi P also, together with the carbon atom in position k, form a saturated carbocyclic 5 ~ may or may form 6-membered ring, R, hydrogen or an alkoxy group with 1 - ¹ C atoms and Rj. Hydrogen or together with R, the 6,7-oxymethylene group, where, if R, alkoxy or R ₇ and Rj. Together mean the oxymethylene group, In addition to R. as a phenyl radical, Rp can also mean hydrogen or a methyl group, characterized in that either a) Compounds of the general formulas Ha · "1 2 Hb wherein R ₁ - Rj, have the above meaning and Y is an optionally substituted amino group, O- or S-alkyl or an S-phenyl radical, or cyclized by treatment with acidic catalysts b) in compounds of the general formula III III replaced the sulfur atom by oxygen in a manner known per se. 309810/1058 2U37U 8. Process for the production of pharmaceutical preparations with lipid-lowering 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. 9. Pharmaceutical preparations with lipid-lowering ■ effect characterized by a content of a compound according to claim 1. ■ 3 0 9 8 1 night / 1 0 b 8