DE2552563A1 - ORGANIC COMPOUNDS, THEIR USE AND MANUFACTURING - Google Patents

Description

R alkyl with 1-4 carbon atoms, alkenyl with 3-7 carbon atoms or alkynyl with 3-7 carbon atoms whose multiple bond is not is in the α-position to the nitrogen atom to which the alkenyl or alkynyl group is attached, cycloalkyl with 5-7 carbon atoms, through Cycloalkyl with 3-7 carbon atoms monosubstituted Alkyl with 1-4 carbon atoms, hydroxyalkyl with 2-4 carbon atoms, whose hydroxyl group is replaced by at least 2 carbon

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OWGJNAL INSPECTED

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substance atoms are separated from nitrogen atoms, to which the hydroxyalkyl group is attached,

a group - (CH ₀ ) -CO-A, in which

Δ ρ

p is an integer from 1 to 3 and A is alkyl of 1-4 carbon atoms or alkoxy of 1-4 carbon atoms
mean, or

a group - (CH ₂ ) -x / QjT / wherein

R_ and R. hydrogen, alkyl with 1-4

Carbon atoms, alkoxy with 1-4 carbon atoms or Halogen mean and

either X for a simple tie,

the vinylene or carbonyl group and η is an integer from 1 to 5

or X is a group of the series -0-, -S-,

-SO-, -SO "- or -NR ₅ - and η are an integer from 2 to 5, where R _{5 is} hydrogen, phenyl, alkyl with 1-4 carbon atoms or alkanoyl with 2-4 carbon atoms,

means.

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Any alkyl or alkoxy radicals preferably contain 1 or 2, especially 1 carbon atom.

R ₁ preferably denotes hydrogen, alkyl, alkoxy, fluorine or chlorine.

R ₀ preferably represents the groups defined above alkyl, alkenyl, hydroxyalkyl, - (CH ₂ ) -COA or

- (CH ₂ ) -XO ^ T ^. R _{2 stands} for the one defined above

^R 4
Hydroxyalkyl group, it preferably contains 2

or 3 carbon atoms. If R _{0 stands} for a group - (CE ₀ ) -COA, ρ is preferably the number 2 or 3. If R _{0 stands} for the cycloalkylalkyl group defined above, this radical is preferably cyclopropylmethyl.

A preferably represents an alkyl group.

X preferably represents a single bond or a group from the -0-, -S-, -SO ₂ - or -CO- series, in particular a single bond or a carbony group. If X stands for a single bond or vinylene, η is preferably an integer from 1 to 4. If X stands for a group of the series -O-, -S-, -SO-, -SO ₂ -, -CO- or - NR ₅ -, η is preferably the number 2 or 3. If R- is alkanoyl with 2-4 carbon atoms, this radical preferably contains 2 or 3 carbon atoms.

R ₃ preferably denotes hydrogen, halogen or an alkyl group. R. preferably stands for water

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Material. If R_ and / or R. stand for halogen, then mean these radicals fluorine, chlorine or bromine, preferably fluorine or chlorine.

According to the invention one arrives at the new compounds of formula I by

a) in the 1-position of compounds of the formula II in which R _{1 has the} above meaning, a group R-, which has the above meaning, introduces or

b) for the preparation of compounds of the formula Ia, in which

R, hydrogen, alkyl with 1-4 carbon atoms, Is alkoxy with 1-4 carbon atoms, fluorine or chlorine and

E hydrogen, alkyl with 1-3 carbon atoms, cycloalkyl with 3-7 carbon atoms, by cycloalkyl with 3-7 carbon atoms monosubstituted alkyl with 1-3 carbon atoms

substance atoms or a group (CH ₀ ) "(Ο /

where m is an integer from 0 to 4 and R ₃ and R. have the above meaning,

in compounds of the formula III in which R has the above meaning and D is alkoxy having 1-4 carbon atoms or has the meaning given for E, a COD group is reduced _{to a CH 2 E group.}

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The inventive method can be analogous to known methods are carried out.

In process a) one proceeds, for example, under the conditions of an alkylation of a secondary amine. Process a) is therefore referred to below as alkylation. The compounds are alkylated of formula II e.g. by reaction with a compound of the formula V, in which R "has the above meaning and Y for one in an SN ^ reaction removable radical, or with other known alkylating agents, for example with a compound which can be obtained from a compound of the formula V by splitting off HY. Y means for example the acid residue of a - reactive

Esters, e.g. halogen such as chlorine, bromine or iodine, preferably chlorine or bromine, or the acid residue an organic sulfonic acid such as an alkyl sulfonyloxy group like methylsulfonyloxy, or one Arylsulfonyloxy such as phenylsulfonyloxy or p-tolylsulfonyloxy.

The alkylation of the compounds of the formula II with compounds of the formula V is expedient in an organic solvent, for example in an amide of an aliphatic carboxylic acid such as dimethylformamide or in an aromatic hydrocarbon such as toluene. It is advantageous to work in the presence of a basic condensing agent, e.g. Alkali metal carbonate such as potassium carbonate. The reaction temperature

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can vary from room temperature to about 120 °; one works preferably at the reflux temperature .

Suitable compounds which are obtained from a compound of the formula V by splitting off HY can include α, ß-unsaturated carbonyl compounds

bindings, to introduce --— one

Remainder - (CH ₉ )., - COA

or - (CH ₀ ) -, - CO- (OJ, where A,

4th
R_ and R, have the above meaning and 1,2-alkylene

oxides to introduce a 2-hydroxyalkyl group. The reaction of the compounds of the formula II with α, β-unsaturated carbonyl compounds such as methyl vinyl ketone or acrylic acid (lower) alkyl ester is expediently carried out in a suitable organic Solvent, e.g. in glacial acetic acid, a lower alkanol such as methanol, ethanol and while stirring. The reaction temperature can be between room temperature and reflux temperature vary the reaction mixture; the reaction mixture is preferably heated to about 20-80 °.

When the compounds of the formula II are reacted with 1,2-alkylene oxides, the reaction temperature can vary between about -10 to 100 °.

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Groups of the radical R ₂ which are not inert under the conditions of process a) can be protected and, after introduction of the protected radical R ₀ in the 1-position of the compounds of the formula II

split off v / earth. Thus, for example, end compounds of the formula Ib in which r is an integer from 1 to 5 and R ₁ , R_ and R. have the above meanings, are obtained by

a radical - (CH) -COKi T) ³ t where r, R-2'r N ^ Cp ³

and R. have the above meaning, in the form of a ketal analogously to the methods described above in the 1-position of a compound of the formula II and of the protected end compounds thus obtained, for example of the formula VI, in which R ₁ , r, R ₇ and R. have the above meaning

JL. »5 ⁴ X

and either R, and R 'are alkyl of 1-4 carbon atoms or R, and R 'together represent an alkylene radical having 2-4 carbon atoms which Protective group or groups are split off.

In the compounds of formula I, the carbon atom of the radical R ₂ , which is in the α-position of the

Nitrogen atom

Hydrogen atom, and _{if R 2 is} inert under the conditions of a reductive alkylation, this radical can also be obtained by reductive alkylation of the compounds of the formula II with the aldehydes or ketones corresponding to _{R 2.}

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The reductive alkylation can be carried out by known methods, e.g. hydrogenolytic or according to Leuckart-Wallach be performed.

Process b) can, for example, be carried out analogously to those for the reduction of tert-araids or N, N-disubstituted Urethanes can be carried out to tert-amines known methods. You reduce that Compounds of the formula III e.g. with optionally complex metal hydrides or diborane. Particularly suitable metal hydrides are aluminum hydrides such as aluminum hydride, dialkyl aluminum hydrides, Lithium aluminum hydride or lithium aluminum hydride / aluminum chloride are suitable.

In general, the reduction is expediently carried out in an inert atmosphere under the reaction conditions Solvent carried out. Suitable solvents are, for example, cyclic or open-chain Ethers such as tetrahydrofuran.

The reduction can be carried out between about room temperature and about 100 °, for example at about 30 ° to the boiling point of the reaction mixture, in the reduction of the tert-amides Formula III is preferably used at about 40 to 60 °, in the case of the reduction of the urethanes Formula III preferably at the boiling point of the reaction mixture.

Is in the compounds of the formula III a chlorine or Brora substituent present, one uses

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expediently aluminum hydride or a dialkyl aluminum hydride as metal hydride, or also diborane.

Process b) is particularly suitable for the reduction of an N-alkoxycarbonyl group to the N-methyl group ¹ and for the introduction of the cyclopropylraethyl group.

The .Verbindungen of the formula I can be in free form as a base or in the form of addition salts present with acids.

Acid addition salts, for example the

Bis [base] naphthalene-l, 5-disulfonate or the hydrogen malonate, to produce and vice versa.

The compounds of the formulas II and III are new. They can be produced analogously to known methods will.

The compounds of the formula Ha, in which R «is above Has meaning can e.g. by splitting off an alkoxycarbony! Protective group from the compounds of the formula HIa, in which R has the above meaning and Alk is alkyl having 1-4 carbon atoms, obtained v / ground.

Ether cleavage of a compound of the formula Ha, in which R- denotes alkoxy with 1-4 carbon atoms, with e.g. Lewis acids or with alkali

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metal hydride / mercaptan such as sodium hydride / methyl mercaptan supplies the corresponding hydroxy derivative.

The compounds of the formula IHa can, for example, with the help of a Grignard synthesis from compounds of the formula IV, in which Alk has the above meaning, are prepared. This implementation is proceeding stereospecific.

N-acylation or N-formylation of the compounds of the formula II provides the corresponding ^ NCOD derivatives of the formula III, in which D is the for E has given meaning.

The compound of the formula IV in which Alk is ethyl is known. The remaining connections of formula IV can be prepared analogously to that compound.

If the preparation of the starting compounds is not described, these are known or according to methods known per se or analogously to those described here or analogously to per se known processes can be produced.

The compounds of the formula I in free form or in the form of their physiologically compatible addition salts with acids, hereinafter referred to as substances of the formula I, have interesting pharmacodynamic properties

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stocks. They can therefore be used as a remedy.

They have an antiarrhythmic effect. Because of this effect, they are used for treatment suitable for cardiac arrhythmias.

Suitable for use as antiarrhythmics

especially the substances

of formula I, in which R. is hydrogen, 3-methoxy, 4-methyl, 4-fluorine or 4-chlorine means as well

the substances of formula I in which

R ₀ methyl, allyl, a group - (CH ₀ ) -CO-CH. ,, where ρ has the above meaning, phenylalkyl with 7-10 carbon atoms, phenoxyalkyl with 8-9 carbon atoms, 3-p-chlorophenylthiopropyl, 3 ~ p- Chlorophenylsulfonylpropyl or a

Group (CH ₂ ) _r " ^cc Hj5) - ^R 3 f

R *

χ where r has the above meaning, R hydrogen, Fluorine, chlorine or methyl and R * denote hydrogen or methyl.

The substances of the formula I.

also show an antidepressant effect. Because of this effect, they are used for treatment suitable for depression.

The substances of are particularly suitable for use as antidepressants

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Formula I in which R. is 4-chlorine and the substances of the formula I in

where R _{2 is} methyl, allyl or 2-hydroxyethyl,

The invention also relates to medicaments which contain a substance of the formula I.

These remedies / for example a solution or a tablet, can according to known methods ^ using the usual auxiliaries and carriers.

In the following examples, all temperatures are given in degrees Celsius and are uncorrected.

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Example 1;

(Method a)

14.8 g of (3aRS, 4SR _f 7aRS) -hexahydro-4-phenyl-4-indolinol, 18.9 g of phenethyl bromide and 18 g of potassium carbonate are heated to reflux in 170 ml of dimethylformamide for 15 hours. After cooling, it is concentrated and extracted with water / ethyl acetate. The organic phase is dried over sodium sulfate, filtered off and concentrated (melting point of the hydrogen malonate 133-135 ° from ethanol / ethyl acetate).

The starting product was produced as follows:

a) Phenylmagnesium bromide (made from 40 g bromobenzene and 5 g magnesium) is used with 30 g of ethyl cis-hexahydro-4-oxo-1-indoline-xaxate to tetrahydrofuran. After stirring for 4 hours at room temperature, the reaction mixture is mixed with 100 ml of 2N Hydrochloric acid and 200 ml of ether are added. The organic phase is separated off with water washed and dried over sodium sulfate. After the ether has evaporated, the (3aRS, 4SR, 7aRS) -Hexahydro-4-hydroxy-4-pheny1-1-indoline carboxylic acid ethyl ester as OeI back.

b) 30 g (3aRS, 4SR, 7aRS) -hexahydro-4-hydroxy-4-phenyl-1-indoline-carboxylic acid ethyl ester are dissolved in 300 ml of methanol, after adding

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300 ml of ION sodium hydroxide is stirred at boiling temperature overnight. After cooling down is exhaustively extracted with methylene chloride. The methylene chloride phase is extracted with 2N tartaric acid solution, which aqueous tartaric acid solution, made alkaline again and extracted with methylene chloride. The (3aRS, 4SR, 7aRS) -hexahydro-4-phenyl-4-indolinol is obtained after conventional work-up of the organic phase (Mp. Of the hydrogen naphthalene-l, 5-disulfonate 228-230 ° - from ethanol).

Example 2: JSaRS _x ^ SR _- , 7aRS) _- g-Fluor-4 -_ (hexa-

(Method a)

6 g of (3aRS, 4SR, 7aRS) -hexahydro-4 ~ m-methoxyphenyl ~ 4-indolinol with 3 g of 2- (3-chloropropyl) -2-p-fluorophenyl-1,3-dioxolane at 150 ° for 1 hour heated. The solidified melt {(3aRS, 4SR, 7aRS) -1- [3- (2-p-fluoropheny1-1,3-dioxolan-2-yl) propy1] -

4 ~ m-methoxyphenyl-hexahydro-4-indolino] r becomes with 2N sodium hydroxide made alkaline and extracted exhaustively with methylene chloride. The after The oily residue obtained in the usual work-up is dissolved in 165 ml of acetone and mixed with 16.5 ml of 2N Hydrochloric acid left to stand for 48 hours at room temperature. After evaporation to dryness crystallizes the _____

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Title compound from ethanol / ether as the hydrochloride with melting point 168-170 °.

Example 3;

(Method b)

15 g (3aRS, 4SR, 7aRS) -4-p-chlorophenylhexahydro-4-hydroxy-1-indoline carboxylic acid ethyl ester and 4 g of lithium aluminum hydride in 100 ml of tetrahydrofuran are refluxed for 15 hours heated. The excess lithium aluminum hydride is destroyed by adding water. distribution between water and ether results after separation and customary work-up of the organic phase the title compound as OeI (m.p. of ease 98 to 101 ° - from ether / petroleum ether).

Example 4;

indolinol
(Method b)

A solution of 5.2 g (3aRS, 4SR, 7aRS) -A- p-chlorophenyl-i-cyclopropylcarbonylhexahydro-4-indolinol in 30 ml of tetrahydrofuran is added to a solution of 1/3 g of lithium aluminum hydride in 30 ml of tetrahydrofuran . The mixture is stirred at 50 ° for 30 minutes.

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then decomposed with saturated ammonium sulfate solution and filtered. The evaporated filtrate a concentrated solution of naphthalene-1,5-disulfonic acid is added. To Addition of ether crystallizes the bis [(3aRS, 4SR, 7aRS) -4-p-chlorophenyl-1-cycropropylmethylhexahydro-4-indolinol] naphthalene-1,5-disulfonate from m.p. 240-242 °.

The starting material can be produced as follows:

To a solution of 7.2 g (3aRS, 4SR, 7aRS) -4-p-chlorophenylhexahydro-4-indolinol and 2.5 ml

Pyridine in 30 ml of methylene chloride is at

0 to 10 ° a solution of 2.74 g of cyclopropanecarboxylic acid chloride was added dropwise. The mixture will then stirred for 1 hour at room temperature, then successively with 10% tartaric acid solution, - Sodium hydrogen carbonate and

Shaken saturated saline solution, dried over sodium sulfate and evaporated, whereby the (3aRS, 4SR, 7aRS) -4-p-chlorophenyl-1-cyclopropylcarbonylhexahydro-4-indolinol of m.p. 167-169 °.

In an analogous manner, starting from the corresponding compounds of the formula II (process a) or of the formula III (process b), the following compounds of the formula I:

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Ul M ol tsj

rH Cl

Ol CM

U]

Ι-ι ΟΙ

in r ^

CJ cn Cl cn O c-i rH - $ ■ CM rH I. CM CJ O cn I. CM 00 I. I. I. co I. co I. I. O cr \ cn vO rH O VO O O CM co CTi rH oo iH CJ CM CM

in c4

Xi

Ul

ι; U]

c.

pi

Ul

ti

φ ρ.

co

approx ■ a

«Ι

CU M

CU

(I.

QJ (U μι

Cl Pm do : ij C. do I. ο υ ^r ü O P. ο σ O O I. ι O I. S. Q I. Π Π

cn

CJ

ι
ρ *

υ
ρ.

CO CO CJ CO rH rH te do I. Ui CJ CJ O CJ P. CJ I. I. O O O P. Cu I. I. I. Ii ίΐ U

m \ o

co cn CM

in vo

oo

I-i

609824/1017

Example no.

M.p.

ß) Using procrastinator, a). analogous to examples 1 and d 2:

20 21 22 23 24

25th

26th

n-OCE,

m-OCK ₃

p-Cl

B-OCH,

in-OCH "

m-OCH,

- (CK ₂ ) ₃ -CO- <G> - Cl

- (CE ₂ ) ₃ -C

- (CH ₂ ) ₃ -

- (CH ₀ ) -CC- <O) -CH ζ jj—

CK "

- (CH J-CO- (O) -OCH,

OCH,

- (CH) -C0-h (O> -0CH ₃

b 97-99 ° r.s 237-239 ° hcl 224-226 ° b 125-126 ° HS 196-198 °

206-208 '

Using method a), analogously to Example 1 and method b), analogous to example 4

U)

27 still 28 p-Cl 29 still 30th H 31 still 32 p-Cl 33 still 34 D-Cl

-CH ₂ - (O

- (CH ₂ ), - (CH ₂ ) ₂ · ^) - (CH ₀ ) - ©

b 102-104 ° b 98-101 ° hf 173 ° ns 211-213 ° ns 240-241 ° b 105-107 ° hme 142-144 ° b 92-94 °

OO

r- TnJ O
O cn I. cn ro σ> 1 \ ^ ω cn GO co

Example no. V H Verv m-OCH ^R 2 M.p. ii) hmo analogous to the two 35 P-OCH ₃ H - (CH ₂ ) ₂ - (O ^ - OCH ₃ 36 p-F -CCH ₂ ) ₂ ^> 156-158 ° £) Under P-CH ₃ and procedure b), 229-231 ° 0-CH ₃ 159-161 ° Using method a), p-OCH hf 130 ° [decomp.] play 3 and 4 o-Cl analogous to 3 example 1 as 121-123 ° 37 hf 38 -CH ₃ hf 39 -CH ₃ hf 40 -CH ₃ 133-135 41 -CH ₃ 42 -CH ₃ 43 -CH ₃ 6) Under -CH ₃ 44 completion of procedure b), H analogous to example 4 - (CH) - / q)

i) starting from the corresponding compounds of formula III in which D is ethoxy. ii) starting from the corresponding compounds of the formula III in which D is the meaning of E

(Formula Ia) has, ns " bis [base] naphthalene-1,5-disulfonate hmo = hydrogen malonate

hf *> hydrogen fumarate hcl = hydrochloride

b «· Base nine = hydrogen maleate

.ΓΙΟ
CTi CO

cn

cn r-o cn

co

100-4263

Yes

R,

(CH ₂ ) _r -CO

R.

Ib

II

HO

R,

Ha

III

HO

^H COOAIk

Ilia

6 0 "■ · ■■ ^;; '/ 1017

6 O ^ * ί 2 Λ / 1 0 1 7

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COOAlk

IV

Y-R,

Claims (6)

Patent claims: R ₂ alkyl with 1-4 carbon atoms, alkenyl with 3-7 carbon atoms or alkynyl with 3-7 carbon atoms whose multiple bond is not in the α-position to the nitrogen atom to which the alkenyl or alkynyl group is attached, cycloalkyl with 5 -7 carbon atoms, alkyl with 1-4 carbon atoms monosubstituted by cycloalkyl with 3-7 carbon atoms, hydroxyalkyl with 2-4 carbon atoms, the hydroxy group of which is separated by at least 2 carbon atoms from the nitrogen atom to which the hydroxyalkyl group is attached, a group - (CH ₂ J-CO-A, wherein ρ is an integer from 1 to 3 and A is alkyl with 1-4 carbon atoms or alkoxy with 1-4 carbon atoms
mean, or R-, a group - (CH,) _n -X- (CaJ * wherein 609824/1017 - 23 - 100-4263 R ₃ and R. hydrogen, alkyl with 1-4 Carbon atoms, alkoxy with 1-4 carbon atoms or Halogen mean and either X for a simple tie, the vinylene or carbonyl group and η is an integer from 1 to 5 or X is a group of the series -0-, -S-, -SO-, ~ SO ₂ ~ or -NR ₅ - and η is an integer from 2 to 5, where R _{5 is} hydrogen, phenyl, alkyl with 1- 4 carbon atoms or alkanoyl with 2-4 carbon atoms, means, and their acid addition salts, characterized in that one a) in the 1-position of compounds of the formula II in which R _{1 has the} above meaning, a group R ₂ , which has the above meaning, introduces or b) for the preparation of "compounds of the formula Ia, in which R ^ hydrogen, alkyl with 1-4 carbon atoms, Is alkoxy with 1-4 carbon atoms, fluorine or chlorine and 6 0 "■ '■'. M 0 1 7 - 24 - 100-4263 Hydrogen, alkyl with 1-3 carbon atoms, Cycloalkyl with 3-7 carbon atoms, through cycloalkyl with 3-7 carbon atoms, monosubstituted alkyl with 1-3 carbon atoms or a group (CH ₂ ) "( ¹ Q / where m is an integer from 0 to 4 and R ₃ and R. have the above meaning, in compounds of the formula III, v / orin R, has the above meaning and D is alkoxy with 1-4 carbon atoms means or has the meaning given for E, reducing a COD group to a CH ^ E group, and the compounds of the formula I obtained in this way as a base or as acid addition salts. 2. The method according to claim 1 for the preparation of (3aRS, 4SR, 7aRS) -hexahydro-l-phenethyl-4-phenyl-4-indolinol, characterized in that one a) in the 1-position of (3aRS, 4SR, 7aRS) -hexahydro-4-phenyl-4-indolinol the Phenäthy! group introduces or b) in (3aRS ₇ 4SR, 7aRS) -hexahydro-4-phenyl-1-phenacetyl-4-indolinol reduces the benzylcarbonyl group. 6-0 9-8 /! /, / 10 17 - 25 - 100-4263 3. The method according to claim 1 for the production of (3aRS, 4SR, 7aRS) -4-p-chlorophenylhexahydro-1- (2-hydroxyethyl) -4-indolinol, characterized in that in the 1-position of (3aRS, 4SR, 7aRS) -4-p -chlorophenylhexahydro-4-indolinol introduces the 2-hydroxyethyl group. 4. The method according to claim 1 for the production of (3aRS, 4SR, 7aRS) -l-allyl-4-p-chlorophenylhexahydro-4-indolinol, characterized in that in the 1-position of (3aRS, 4SR, 7aRS) -4-p-chlorophenylhexahydro-4-indolinol introduces the allyl group. 609824/1017 Germany-West 100-4263 5. Compounds of the formula I in which R .. and R _{2 have} the meaning given in claim 1 and their acid addition salts. 6. Remedies, characterized in that they contain compounds of the formula I or their physiological contain compatible acid addition salts. 3700 / VA / GB SANDOZ-PATENT GMBH 60 9 824/1017