DE2650781A1 - 1,2,3,4-TETRAHYDRO-2,3-NAPHTHALINDIOLS AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS - Google Patents

Description

"1,2,3,4-tetrahydro-2,3-naphthalenediols and these compounds containing medicinal products "

Priority: November 6, 1975, V.St.A., No. 629 335

The invention relates to the subject matter characterized in the claims. In the compounds of the general formula I mean the lower alkyl and alkoxy radicals are preferably radicals having 1 to 4 carbon atoms. The halogen atoms are fluorine, Chlorine, bromine and iodine atoms are possible. The cycloalkyl radical can be a radical having 3 to 6 carbon atoms. Specific examples for acyl radicals are the acetyl, propionyl, butyryl, isobutyryl, Trimethylacetyl, hexanoyl, heptanoyl ", decanoyl, dodecanoyl, benzoyl, o-tolyl, p-nitrobenzoyl, phenylacetyl, 3-Ph.enylpropionyl and 3- (p-chlorophenyl) -butanoyl group,

The salts of the compounds of the general formula I can be derived from inorganic and organic acids. Examples

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the acids used for salt formation are hydrogen halides acids, especially hydrochloric acid and hydrobromic acid, Sulfuric acid, nitric acid, phosphoric acid, boric acid, acetic acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, Benzoic acid, ascorbic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid.

The compounds of the general formula I are valuable medicinal substances. They block the ß-receptors in the myocardium and can be used to treat cardiac arrhythmias. The medicines are used orally or parenterally in the usual dosage forms administered.

In the compounds of the general formula I, the R ₁ O groups can be in the cis and trans configuration. You can choose from the corresponding cis or trans ~ ^{1,2,3 »i} -tetrahydro-5- ^ 2-hydroxy-3- (alkylamino) -propoxy_7-2,3-naphthalenediols of the general formula II

O - CH ₀ - CH - CH "-NR

(ID

getting produced. The radical Rf- can be a hydrogen atom or mean an aryl-lower-alkyl radical. The connections of the general formula II are described in US Pat. No. 3,935,267.

The 2,3-trans- (or cis) -l, 2,3, ⁱ t-tetrahydro-5-Z2-hydroxy-3- (alkylaiiino> -propoxy7-2,3-naphthalenediols of the general formula

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mel II are produced as follows: First, a naphthol of the general formula III

OH

(III)

with an alkali metal such as sodium or lithium ^ in liquid Ammonia, which is an alcohol such as ethanol, isopropanol or tert, Contains butanol, reduced by the method described, for example, in Organic Synthesis Coll., Vol. 4 (1963), p. 887. It becomes the corresponding 5,8-dihydronaphthol of the general Formula IV

OH

(IV)

get that with acetic anhydride in Gegerorart an organic Base, such as pyridine, into the corresponding acetate of the general formula V

(V)

is convicted.

The acetate of the general formula V is dissolved in acetic acid and with about '2 to 4 equivalents of silver acetate and about 1 to

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Equivalent iodine added. The mixture is heated for about 1 to 2k hours under nitrogen as protective gas to about 80 to 120 ° C. After alkaline hydrolysis, a trans-5 »6,7» 8-tetrahydro-1,6,7-naphthalene triol of the general formula YI

(VI)

obtain. The compound of the general formula VI is then treated by treatment with an alkali metal alkoxide, such as sodium methoxide, in an ^{alcohol boiling below about 100 °} C., such as methanol, and under nitrogen as a protective gas. The solvent is then distilled off, the residue in a polar aprotic solvent , such as dimethyl sulfoxide, hexamethylphosphoric acid triamide or dimethylformamide, and mixed with epichlorohydrin under nitrogen as a protective gas. A 2,3-trans- ^{1,2,3, /} i-tetrahydro-5-Z ~ 2,3- (epoxy) -propoxyL7-2,3-naphthalenediol of the general formula VII is formed

(VII)

O - CH "- CH CH

The compound of the general formula VII is then with an alkylamine of the general formula VIII

HN-R ₄ R ₅ (VIII)

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converted to 2,3-trans- _{1,2,3 J} ¹ * -Tetrahydro-5- / r2-hydroxy-3- (alkylamino) -propoxy7-2,3-naphthalenediol of the general formula II.

The corresponding cis isomer of general formula II is produced as follows: The dihydronaphthalene acetate of. general formula V is 92 to 98 percent, preferably 96% acetic acid dissolved. The solution is made with silver acetate and iodine are added and heated under nitrogen as a protective gas. After alkaline hydrolysis, the cis-5,6,7 »8-tetrahydro-1,6,7-naphthalenetriol becomes of the general formula IX

(IX)

obtain. This compound can be converted into the cis compound of the general formula VII and the cis compound of the general formula II can be converted.

The träns compounds of the general formula II can also be prepared as follows from a 5,8-dihydro-l-naphthol: A cooled to below about 30 ⁰ C solution of 5,8-dihydro-1-naphthols of the general formula IV in ethyl acetate is m-chloroperbenzoic acid added _? and a mixture of diethyl ether and aqueous sodium bicarbonate solution is added to the resulting slurry. A 5,6,7,8-tetrahydro-6,7-epoxy-1-naphthol of the general formula ^{x is formed}

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265078Ί

(X)

A solution of the compound of the general formula X in tetrahydrofuran is reacted with aqueous perchloric acid at a temperature of 0 to 60 ° C. The trans-5,6,7,8-tetrahydro-1,6,7-naphthalene triol is formed of the general formula VI, which is converted in the manner described above into the trans compound of general formula VII and is converted into the trans compound of general formula II.

The compounds of general formula I in which PL is a hydrogen atom means d. H. the compounds of the general formula XI

(XI)

are prepared as follows: First, the adjacent hydroxyl groups in a compound of the general formula II, in which R _{5 is} an aryl-lower-alkyl radical, are blocked by the process described in US Pat. No. 3,856,813. A compound of the general formula XII

CH ₀ - NO. 2, 4

R, -

(XII)

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obtain. This compound can with an acylating agent, for example a carboxylic acid anhydride of the general formula XIII

(R ₂ CO) ₂ O (XIII)

or an acid chloride of the general formula XIV

R ₂ COCl (XIV)

be acylated. A compound of the general formula XV

alkyl • \ / \ / W OR R

O - CH ₇ - CH - CH ₉ - NR ¹²

obtain. The compound of the general formula XV is hydrolyzed by treatment with acid. It will connect the general formula XVI

O - CH ₀ - CH - CH_- N - R.

² I ² I ⁴

R ₅ (XVI)

obtain. The catalytic hydrogenation of the compound of the general Formula XVI in the presence of a catalyst such as palladium provides the corresponding compound of the general formula XI. The acylation is carried out by methods known per se in an organic solvent and in the presence of an organic solvent Base, for example pyridine.

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If the radical R _{2 is} a bulky acyl radical, for example a trimethylacetyl group, the compounds of the general formula XI can be prepared in a one-step process. In this process, a compound of the general formula II, in which R ₁ - is a hydrogen atom, is acylated. The acylating agent is preferably used in an amount of 1 equivalent in order to obtain the monoester in maximum yield.

Those compounds of the general formula I in which R ₁ and R ~ are the same acyl radicals are prepared as follows: First, an amine of the general formula II, in which Rj- is a hydrogen atom, is converted with an acid into the corresponding salt in order to obtain a Avoid acylation of the amino group. The salt is then acylated in a manner known per se. Those compounds of the general formula I in which R ^ and Rp are different acyl radicals are prepared as follows: First, a monoester of the general formula XI is converted into the salt by reaction with an acid and then the salt is acylated in the manner described above.

The methods described above can also be modified. For example, a compound of the general formula XI can be prepared from a compound of the general formula II in which Rj- is a hydrogen atom. The amino group is converted into the ammonium group by treatment with an acid and thereby protected against acylation. The compounds of general formula I in which R ^ and R ₂ acyl

ORIGINAL INSPECTED

radicals can be prepared from the compounds of the general formula II in which R ₁ - is an aryl-lower-alkyl radical. In this case the tertiary amine still has to be catalytically hydrogenated to the secondary amine.

The examples illustrate the invention.

example 1

cis-5-Z3-Z (l, l-dimethylethyl) -a.Tiino7-2- (2 _> 2-dimethyl-l-oxo-propoxy) -propoxy7-1 , 2.3 % 4-tetrahydro-2,3-naphthalenediol

A solution of 6.0 g of trimethyl acetic anhydride and 2.5 g of 2,3-cis-l, 2,3, ^z »-Tetrahydro-5-r2-hydroxy-3 - ^ (l, l-dimethylethyl) -amino7-propoxx7 -2,3-naphthalenediol in 70 ml of anhydrous pyridine is stirred for 18 hours at room temperature and 4 1/2 hours at 50 to 65 ^° C. with exclusion of moisture. The solution is then cooled to room temperature, diluted with 5 nil methanol and stirred for 15 minutes. The solvent is then distilled off under reduced pressure, the residue is taken up in chloroform, the chloroform solution is washed with saturated aqueous sodium bicarbonate solution and sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. 4.5 g of a semi-solid product are obtained. The product is suspended in diethyl ether and filtered. The crystals: are washed with diethyl ether and dried under reduced pressure. Yield 1.6 g of white crystals. Another yield of 0.15 g of crystals is obtained from the filtrate. The total yield is 1.75 g. After recrystallization from benzene

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1.2 g of the title compound from P. 1 ^ 5 to 149 ⁰ C are obtained.

Example 2

5 »/f3-£Hi.l-Di^ethyläthyl)-amineQ7~2-(2 _t 2-dimethyl-l-oxopropoxy) -propoxy_7-l, 2 ^ 3 _i ^ -tetrahydro-cis-2 ^ 3-naphthalenediol -diacet ■ at- _ι hydrochloride (1; 1)

A solution of 1.37 g of the compound prepared in Example 1 in 150 ml of benzene is with a slight excess of one. Acidified solution of anhydrous hydrogen chloride in isopropanol. The solution is then evaporated under reduced pressure. A white, foamy residue remains which is dissolved in 25 ml of cold trifluoroacetic acid. The solution is cooled in a cooling bath set to -10 ° C. and 1.5 ml of acetyl chloride are added dropwise with exclusion of moisture. Then, the solution is stirred first for 30 minutes at -10 ⁰ C and 1 hour at room temperature. The solvent is then distilled off under reduced pressure and the residue is taken up in 200 ml of ethyl acetate. The ethyl acetate solution is washed with saturated aqueous sodium bicarbonate solution and sodium chloride solution, dried over magnesium sulfate and sodium sulfate and evaporated under reduced pressure. 1.7 g of an oil remain. The oil is dissolved in 100 ml of hexane. The hexane solution is decanted from a small amount of insoluble matter. The hexane is then distilled off under reduced pressure. There remain 1.55 g of crude product. The crude product is dissolved in a mixture of diethyl ether and hexane (100: 20) and treated with a solution of anhydrous hydrogen chloride in iso-

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-Yes -

acidified propanol. The solvent is then reduced under reduced pressure Pressure, distilled off. 1.6 g of a foamy product remain. After recrystallization from a mixture of diethyl ether and diisopropyl ether, 1.36 g of the title compound with a melting point of 177 ° to 183 ° C. are obtained.

Example3

2 _t 3-cis-5- / 2- (acetyloxy) -3 - / ^ 1 »l-dimethylethyl) -amino_7-propoxy7-Ii2 _> 3,4-tetrahydro-2 ₁ 3-naphthalenediol diacetate hydrochloride (1,: ' 1)

3.09 g of 2,3-cis-l, 2,3, ^z l-tetrahydro-5-Z2-hydroxy-3-Zr (l, l-dimethylethyl) -amino_7-propoxy7-2,3-naphthalenediol are dissolved in isopropanol in a saturated solution of hydrogen chloride. The solution is then evaporated to dryness under reduced pressure. 50 ml of trifluoroacetic acid are added to the salt obtained, and 6.4 ml of acetyl chloride are added dropwise to the resulting solution at 0 to 5 ° C. while stirring. When the addition is complete, the solution is left to stand for 1 hour at room temperature, then evaporated under reduced pressure, the residue is treated with aqueous sodium bicarbonate solution and the mixture is extracted with ethyl acetate. The ethyl acetate extract is washed with saturated sodium chloride solution, dried and evaporated under reduced pressure. The residue is dissolved in anhydrous diethyl ether and a solution of isopropanol saturated with hydrogen chloride is added in the cold. The resulting precipitate is filtered off and recrystallized from a mixture of isopropanol and diethyl ether. Yield 1.7g

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of the title compound with a melting point of 150 to 156 ° C.

Example 4

cis-5-./^-"(acetyloxy)-3-Zr(lil-dlniethyläthyl)-aniinQ7propoxyJ ^r l , i2 »3, A-tetrahydro-2 ₁ 3-naphthalene diol

A solution of 20 mmol 3a, 9a-cis-l- £ (l, l-dimethylethyl) - (phenylmethyl) -araino7-3- £ '(3a, ⁱ l _> 9 _> 9a-tetrahydro-2 _i 2-diniethyl- 2H-naphthoZ2,3-d7dioxol-5-yl) -oxy_7-2-propanol in 70 ml of pyridine and 30 ml of acetic anhydride is left to stand for about ten hours at room temperature. The pyridine and excess acetic anhydride are then distilled off under reduced pressure. The residue is taken up in a mixture, cooled to 0 to 5 ° C., of 225 ml of 5 percent strength hydrochloric acid and 25 nil of methanol, and the mixture is stirred at 0 to 5 ° C. for 2 hours. Most of the methanol is then distilled off under reduced pressure and the solution is made alkaline with 5 percent strength aqueous sodium bicarbonate solution and extracted with diethyl ether. The ether extract is dried over magnesium sulfate and evaporated under reduced pressure. The residue obtained is taken up in 250 ml of glacial acetic acid, 1 equivalent of concentrated hydrochloric acid is added and the mixture is hydrogenated in the presence of 5 g of 10 percent palladium-on-carbon at 3.5 to 4 atmospheres. After 1 equivalent of hydrogen has been taken up, the catalyst is filtered off and the piltrate is evaporated under reduced pressure. The title compound remains.

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Examples 5-11

According to Example 4, but using those listed in column 1 Compounds, the products listed in column 2 are obtained.

example

II

10

11

Lauric anhydride

Benzoic anhydride

o-Toluylic anhydride

p-nitrobenzoic acid anhydride

p-chlorobenzoic acid anhydride

o-methoxybenzoic acid anhydride

Phenylacetic acid cis-5- / 3- £ i 1,1-dimethylethyl) amino_7-2- (dodecanoyloxy) -propoxy7-l, 2,3,4-tetrahydro-2,3- naphthalenediol

cis -5- £ 2- (benzoyloxy) -3- £ "(l, dimethylethyl) -aminoj-propoxy7-1,2,3,4-tetrahydro-2,3-naphthalenediol

cis -5-C - / "(1,1-dimethylethyl) -amino7-2- (o-tolyloxy) -propoxy7-1,2,3,4-tetrahydro-2,3-naphthalenediol

cis-5- £ 3- £ U, l-dimethylethyl) -amino7-2- (p-nitrobenzoyloxy) -propoxyj-l, 2,3,4-tetrahydro-2,3-naphthalenediol

cis-5- £ 2- (p-chlorobenzoyloxy) -3 - / "(l , 1-diinethylethyl) amino7-propoxy7 -1,2,3,4-tetrahydro-2,3-naphthalenediol

cis-5- / 2- (o-14ethoxybenzoyloxy) -3-ZU, l-dimethylethyl) -amino7 propoxy7-1,2,3,4-tetrahydro-2,3-naphthalenediol

cis-5- £ 3-ZT (l, l-dimethylethyl) -amino7-2- (phenylacetyloxy) -propoxy7 -1,2,3,4-tetrahydro-2,3-naphthalenediol

Examples 12-15

According to Example 2, but using those listed in column I. Compounds are those listed in Column II

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Products received.

example

12 II

Butyryl chloride

13th

Benzoyl chloride

p-toluyl chloride

15th

3-phenylpropionyl chloride , 1-dimethylethyl) amino? · 2- (2,2-dimethyl-1-oxopropoxy) -propoxy7-1,2,3,4-tetrahydro-cis-2,3-naphthalenediol-dibutyrate hydrochloride

5-Z3-Z ~ (1,1-dimethylethyl) -amino7 2- (2,2-diniethyl-1-oxopropoxy) propoxy 7-1, 2,3,4-tetrahydro-cis-2,3-naphthalenediol dibenzoate hydrochloride

5- £ 3-Λΐ, 1-dimethylethyl) amino? ■ 2- (2,2-dimethyl-1-oxopropoxy) -

propoxy7-l, 2,3 _J ⁱ l-tetrahydro-cis-

2,3-naphthalenediol di (p-toluate) hydrochloride

5-Z3-ZT (l, l-Diniethyläthyl) -aTiino7 · 2- (2,2-di.iiethyl-l-oxopropoxy) -propoxy7-l, 2,3, ¹ l-tetrahydro-cis-2,3- naphthalenediol di (3-phenylpropionate) hydrochloride

Examples 1 6 to 18

According to Example 3, but using those listed in column I. Compounds, the products listed in column II are obtained.

703820/1057

example

Caproyl chloride

Benzoyl chloride

p-chlorobenzoyl chloride

II

2,3-cis-5- £ 2- (hexanoyloxy) -3- £ X 1,1-dimethylethyl) -aminoj-propoxyj -1 ,, 2,3,4 -tetrahydro-2,3-naphthalenediol-dihexanoate-hydro - chloride

2,3-cis-5-Z "2- (benzoyloxy) -3 - /" (l _l ldimethyläthyl) -aniinoJ7-propoxy7- ¹ 1 ² "3,4-tetrahydro-2,3-dibenzoate hydrochloride napnthalindiol

2,3-cis-5 - / ^ - (p-chlorobenzoyloxy) -3- £ l 1,1-dimethylethyl) -amino_7-prop · oxy7-l, 2,3, ¹ l-tetrahydro-2,3-naphthalenediol -di (p-chlorobenzoate) hydrochloride

Example 19

trans-5-Z "3-ZTl, 1-diniethylethyl) -aniino7-2- (2 ₁ 2-dimethy 1-1 -oxo propoxy) -PrOPOXyZ-I ₃ 2,3i ^ -tetrahydro-2,3-naphthalenediol

According to Example 1, but using 2,3-trans-1,2,3 _i ^ - tetrahydro-5-ZT2-hydroxy-3-ZT (1,1-dimethylethyl) -amino7-2,3-naphthalenediol, is Get the Tite! connection.

709820/1057

Claims (1)

Patent claims Ι · l, 2,3,4-tetrahydro-2,3-naphthallndlole of the general formula I. O-CH ₉ -CH-CK ₉ -NH-R. in which R _{1 is} a hydrogen atom or an acyl radical, Rp is an acyl radical, R is a hydrogen atom, a lower alkyl or alkoxy radical, an aryl, lower-alkyl or cycloalkyl radical or a carboxyl group and R ₂ . represents a lower alkyl radical and the acyl radicals the general formula O
XC- have, in which X is an unbranched or branched alkyl radical with 1 to 11 carbon atoms or optionally by one or two lower alkyl or alkoxy radicals, halogen atoms or Phenyl or phenyl'-lower-alkyl group substituted by nitro groups and all of the alkyl and alkoxy radicals mentioned contain 1 to 3 carbon atoms, and their salts with acids. 2. Compounds according to claim 1 of the general formula I, in which R 1 denotes a hydrogen atom. 3. Compounds according to claim 2 of the general formula I in the R, denotes a hydrogen atom. ORIGINAL INSPECTED 709820/1057 ¹ I. Compounds according to claim 2 of the general formula I, in which R _{1 is} an acyl radical. 5 «Compounds according to claim 4 of the general formula I, in the R. and Rp have the same meaning. β » Compounds according to claim H of the general formula I, in which R ^ and Rp have different meanings. 7. Compounds according to claim 2 of the general formula I, in which R ^ j is an isopropyl or tert-butyl group. 8. cis-5-Zr3-Z "(l, l-dimethylethyl) -amino7-2- (2,2-dimethyl-loxopropoxy) -propoxy.7-1, 2,3, ^ - tetrahydro-2 _l 3- naphthalenediol. 9. 5-Z3 - / (l, l-Diniethyläthyl) -aminoJ-2- (2 _l 2-dimethyl-loxopropoxy) -propoxyy-1,2,3, ^ - tetrahydro-cis-2,3-naphthalenediol diacetate- hydrochloride. 10. 2,3-cis-5- / 2- (acetyloxy) -3-Z '(l, l-dimethylethyl) -amino7-propoxy / -l, 2,3, ² l-tetrahydro-2,3-naphthalenediol -diacetate hydrochloride. 11. Medicament with ß-Receptorenblocleerwirkung containing
a compound according to claims 1 to 10. 709820/1057