DE2830211A1 - SUBSTITUTED INDOL DERIVATIVES, THEIR PRODUCTION AND USE - Google Patents

Description

SANDOZ-PATENT GMBH Loerrach

Case 100-4851

SUBSTITUTED INDOL DERIVATIVES, THEIR PRODUCTION AND USE

809885/0782

r-6

100-4851

The invention relates to new compounds of the formula I,

) CH_CHCH NH-R

means in which

wherein

R is the group A-X- <

A alkylene with 2 to 5 carbon atoms, X a bond, oxygen or sulfur, R ^ hydrogen, hydroxy, alkoxy with 1-4 carbon atoms, Halogen with an atomic number from 9 to 35, cyano, carbamoyl or a group NHCOR,

wherein F is alkyl with 1-4 carbon atoms, d

mean and

. Denotes hydrogen and, if R denotes alkoxy with 1-4 carbon atoms, also denotes alkoxy with 1-4 carbon atoms or, if R_ denotes halogen with an atomic number from 9 to 35, in addition can also stand for halogen with an atomic number from 9 to 35,

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either

i) R ^ hydrogen or methyl and

EL Cyano, CONR \, COOR or CH ₀ OR, where R, R,, R * S 'c ^ e abc

and R independently of one another for hydrogen e

or alkyl with 1-4 carbon atoms,

mean

or

ii) either R, methyl and R "halogen with an atomic number from 17 to 35

or R, halogen with an atomic number of 17

to 35 and R- are hydrogen or methyl,

with the measures that

a) X by at least 2 carbon atoms from the nitrogen atom the 3-amino-2-hydroxypropoxy chain is removed,

b) if X is a bond, R- is not hydrogen and

c) if R stands for cyano, R also includes alkyl

May mean 3-7 carbon atoms.

R preferably represents a group A-X- (O-V ^ R ' X preferably denotes a bond or oxygen »R preferably denotes hydrogen, hydroxy or Alkoxy. R. preferably denotes hydrogen or alkoxy. R preferably represents hydrogen or Halogen. R preferably represents methyl, cyano or

CONR R,. R / R, and R preferably represent hydrogen, a b a b e ^

R preferably denotes alkyl.

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Alkyl (except as indicated below for R and R) and /

Cn

or alkoxy preferably contain 1-2, in particular 1 carbon atom. If R stands for alkyl, it preferably contains 3-5 carbon atoms and is preferably branched, especially in the α-position to the nitrogen atom, to which it is bound. Interesting alkyl radicals R are e.g. isopropyl, tert-butyl and 3-pentyl. Is R for alkyl, it preferably contains 1-3 carbon atoms J if it contains more than 2 carbon atoms, it is preferably branched, as in isopropyl.

Halogen is preferably bromine or chlorine, in particular chlorine. A preferably represents branched, especially branched alkylene in the α-position to the nitrogen atom to which it is attached, e.g. the groups of the formulas -CH (CK.) - (CH), -, -C (CH,), - CH, - or

α ^{J 2} . cc

-C- (CH-J ₀ - (CH) -, or for ethylene. Α - ⁵ ^

If R and R are hydrogen, X is preferably oxygen. If R is not hydrogen, X is preferably a bond. If R and R do not stand for hydrogen, they are preferably in the para or meta position. If R. is alkoxy or halogen, it is preferably identical to R ₃ .

A group of compounds of the formula I consists of the compounds of the formula Ix,

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CH ₂ CIICH ₂ NH-R

IX

wherein
, χ

means in which

R "the group A-X - <

A has the above meaning
either
i) X is oxygen or sulfur and

... to R. the meaning given above for R to R. own,

or

ii) X stands for a bond and

either j) R_ alkoxy with 1-4 carbon atoms or Means halogen with an atomic number from 9 to 35,

R ^X denotes hydrogen and, if R ^X denotes alkoxy with 1-4 carbon atoms, also for alkoxy with 1-4 carbon atoms or, if R ^X denotes halogen with an atomic number from 9 to, also for halogen with an atomic number from 9 to can stand

R is hydrogen or methyl and

R ^X CONR _a

R, where R and R are above Be

have meaning, mean,

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or j j) R hydroxy, cyano, carbaitioyl or

NHCOR ,, where R has the above meaning,

R. stands for hydrogen, and

R and R- those indicated above for R. and R_

have the same meaning

with the measure that X is separated by at least 2 carbon atoms from the nitrogen atom of the 3-amino-2-hydroxypropoxy chain away.

A group of compounds of the formula Ix consists of the compounds of the formula Ix ',

OCH ₂ CHCH NII-AX * -

IX ¹

wherein

A has the above meaning

X ^{x represents} oxygen or sulfur and

x ¹

to R has the meaning given _{above for R 1} to R ₄

own,

with the measure that X is replaced by at least 2 carbon atoms from the nitrogen atom of the 3-amino-2-hydroxypropoxy chain away.

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According to the invention one arrives at the compounds of Formula I by adding corresponding compounds of the formula II,

II

where R ₁ and R_ have the above meaning and R stands for a radical which, when reacted with an amine, results in a 2-amino-1-hydroxyethyl group, with corresponding compounds of the formula III,

R - NH ₂ III

wherein R has the above meaning.

The reaction according to the invention is an amination by a primary amine. It can be carried out using conditions known for the preparation of known 3-amino-2-hydroxypropoxyaryl compounds. For example, the group —CH — CH, or a reactive derivative of this O is used as the group R ₀
Group, for example a group of the formula -CH-CH-Y,

I *

OH

wherein Y stands for halogen, preferably chlorine or bromine, or for a group R -SO-O-, wherein R is phenyl, tolyl or

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means lower alkyl stands. Y especially stands for chlorine. The reaction is preferably carried out in one of the Reaction conditions inert organic solvent, e.g. carried out in an ether such as dioxane. Possibly the compound of the formula III is used in excess as the solvent. The Implementation also carried out in the melt. The reaction temperature is, for example, between about 20 and about 200 ° C, preferably at the boiling point of the reaction mixture, unless you are working in the melt.

The compounds of the formula I can be in free form or in salt form, for example in acid addition salt form. From the compounds of the formula I in free form, acid addition salts can be prepared in a known manner, for example bis [base] fumarate, hydrogen malonate or the hydrogen maleate or, if R is hydroxy or

R denotes hydrogen, salts with strong bases, beic

for example with caustic soda, win and vice versa.

In the compounds of the formula I, the carbon atom of the hydroxypropoxy side chain which bears the hydroxyl group is "asymmetrically substituted, " and they can therefore occur in the form of racemates or optically active compounds. Of the compounds of the formula I in optically active form, those are preferred in which the (S) configuration exists on the asymmetrically substituted carbon atom of the hydroxypropoxy side chain.

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The enantiomers of the compounds of formula I can can be obtained in a manner known per se, for example by splitting with optically active acids or by carrying out the inventive implementation starting from corresponding, optically active starting products.

If the production of the required starting materials is not described, these are known or can produced and purified by known processes or analogously to processes known per se. The 4-hydroxyindole ~ 2-carbonitrile or /. 4-hydroxy-3-methylindole-2-carbonitrile is obtained by removing water from the water with e.g. titanium tetrachloride 2-carboxamide derivative.

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

Example 1 ;

5g 3-chloro-4- (2,3-epoxypropoxy) -2-methylindole, 4.3g Phenoxyethylamine and 75 ml of dioxane are 15 hours in heated to 130 ° C in an autoclave. After cooling, the dioxane and the excess in a water jet vacuum distilled off in phenoxyethylamine in a high vacuum at 80 °, the residue is shaken between tartaric acid solution and methylene chloride, the acidic phase with conc. Ammonia alkaline and extracted with methylene chloride. After the solvent has been evaporated off, the residue crystallizes from methanol using 0.5 mol of malonic acid (M.p. of the hydrogen malonate 135-137 °).

Analogously to Example 1, reaction of corresponding compounds of the formula II, in which R _{0 is} -CHCH-Cl, with corresponding compounds is obtained

OH
of the formula III , the following compounds of the formula I:

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100-4851

icep.

R-,

M.p.

-C (CH ₃ J ₃

-CH ₂ CH ₂ O-

'OCH.

-CH ₂ CH- (OVoCH,

H H

CN
CN

CN

CH.

-C-CH ₂ - (O

CH 3

CH

-OH

CN

CN

CONH,

CH

-CH ₂ CH ₂ -O- (O

₂ CH ₂

10

11

OCH

CH -C-CH ₂ - (O

⁰¹¹

CONH,

CONH,

CONH,

CONH

CON '

β
CH.

f 259-261 ° hmi 166-169 °

hcl from 88 ° (foaming)

f 172-175 '

b 198-2OO ^c

f 209-212 '

111-113 '

f 170-173 °

hcl from 94 ° (foaming)

f 157-16O ^c

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Example no.

M.p.

CH

i

12 -C-CI

13th

14th

15th

! 16

17th

18th

20th

CH.

CONH,

f 236-238

H ί COOCH (CH ₃ ) ₂ b 121-124 °]

-C-CH ₂ - (O ^ " ^0Η CH

-C-CH ₂ - (O 'CH 3

) H CH.

3 OCH CH.

OCH-

-CH ₂ CH ₂ -

Pa

S J

Cl

CH.

\ Cl

COOCH (CH ₃ J ₂

COOCH ₂ CH ₃

Cl

CH.

Br

CH.

CONHCIT

b 203-205 '

f 241-243 ° a

b 129-131 '

hf from 99 ° (sintering)

b 126-128 '

f 141-143 '

Γ 121-124 '

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BATH ORIGINAL

- ie -

100-4851

830211

Ex.
No. R. ^R l ^R 2 M.p. 21st / V ^0CH 3 H CH ₂ OCH ₃ f 103-106 ° 22nd ^ CH - / "VOH H CH "OCH" b 149-151 ° CH \ /
3 b = free form f = Bis [base] fumarate hcl = Hydrochloride hf = Hydrogen fumarate hmi = Hydrogen maleate

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The compounds of formula I, i.e. the compounds of Formula I in free form or in the form of their physiologically tolerable salts have interesting pharmacological properties Properties. They can therefore be used as a remedy will.

They have a blocking effect on the adrenergic α and ß receptors and can therefore be used for prophylaxis, among other things and therapy of disease states associated with adrenergic vasoconstriction, in particular of myocardial and peripheral circulatory disorders, as well as of coronary diseases, in particular of angina pectoris. They are also suitable for the treatment of disease states with paralysis of the intestinal motility, e.g. from paralytic hay. Because of their antiarrhythmic Effect, they can also be used to treat cardiac arrhythmias.

Particularly interesting as α- and (3-blockers are the Compounds of Examples 1 and 19.

The compound is particularly interesting as a ß-blocker of example 10.

The compounds of the formula I also have antihypertensive effects Properties. Because of their antihypertensive effect, they can be used as antihypertensive agents, e.g. are used in high pressure therapy.

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The compound of Example 1 is of particular interest in this indication.

The compounds of the formula I also show interesting ones Substance interactions by the mobilization of glucose and fatty acids induced by psychological stress inhibit in the blood. Due to their metabolic effect, they can be used in conditions / which are caused by psychological ones Unwanted metabolic mobilization caused by stress lead, be used.

Particularly interesting in this indication are the compounds of Examples 2, 5 and 19, in particular those Connection of example 5.

Of the compounds of the formula I, the compounds of the formula Iu, OH '·

OCH CHCH NH-R

Iu

worm u

R the group A-

A has the above meaning and

means in which

100-4851

R ₂ and R _{4 have} the same meaning as above, and

and R ₄ indicated

R- has the meaning given above for R, with the exception of hydrogen,

with the measures that

a) the phenyl ring through at least 2 carbon atoms from the nitrogen atom of the 3-amino-2-hydroxypropoxykefcte is removed, and

b) if R denotes cyano, R _{n can} also denote alkyl with 3-7 carbon atoms,

and including in particular the compounds of the formula Iu '

OH

OCH ₂ CHCH ₂ NH-R

U ¹

Iu '

r;

wherein

the group A-

, u '

means in which

has the above meaning,

Alkoxy with 1-4 carbon atoms or halogen with an ordinal number from 9 to 35, means

u ¹ denotes hydrogen and, if R denotes alkoxy with 1-4 carbon atoms, also for alkoxy with 1-4 carbon atoms or, if

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283Q211

Halogen with an ordinal number from 9 to 35 means, also for halogen with a Atomic number can be from 9 to 35,

either

i) R _{1 is} hydrogen or methyl and

u '

R_ cyano. COOR or C
2 c

Have meaning
or

Cyano, COOR _c or CH ₃ OR ₆ , where R _ß and R above

ii) either R ₁ methyl and R_ halogen with an atomic number from 17 to 35

u ¹
or R ₁ halogen with an atomic number of 17

up to 35 and r! J hydrogen or methyl mean,

with the measures that

a) the phenyl ring by at least 2 carbon atoms from Nitrogen atom of the 3-amino-2-hydroxypropoxy chain is removed and

u ¹ u ¹

b) if R denotes cyano, R can also denote alkyl with 3-7 carbon atoms,

a particularly interesting effect compared to compounds of similar structure.

Of the compounds of the formula I in optically active form, the (S) -antipodes are in general with respect to the Carbon atom of the hydroxypropoxy side chain, which is the Hydroxy group carries, ß-blocking, hypotensive and metabolically more active than the corresponding (R) -antipodes.

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The invention also relates to medicaments which contain a compound of formula I in free form or in the form of a contain physiologically compatible salt. These remedies, such as a solution or tablet, can be prepared by known methods using the customary auxiliaries and carriers.

SANDOZ-PATENT GMBH

3700 / VA / GD

809885/0782

Claims (9)

100-4851 Expectations; , 'LJ process for the preparation of the new compounds of the formula I, OH OCH CHCH-NH-R ι 2 2 PJn wherein R the group A-X- means in which A alkylene with 2 to 5 carbon atoms, X is a bond, oxygen or sulfur, R is hydrogen, hydroxy, alkoxy with 1-4 carbon atoms, Halogen with an atomic number from 9 to 35, cyano, carbamoyl or a group NHCOR,, wherein Ri is alkyl with 1-4 carbon atoms, mean and R _{4 is} hydrogen and, if R is alkoxy with 1τ4 carbon atoms, also for alkoxy with 1-4 carbon atoms or, if R is halogen 809885/0782 ORIGINAL INSPECTED - 2 - 100-4851 with an ordinal number from 9 to 35 means, also for halogen with an ordinal number of Can stand 9 to 35, either i) R is hydrogen or methyl and R_ Cyano, CONRΛ, COOR or CH ,, OR, where R, R,, R and. ί a .. c ί. e abc R independently of one another for hydrogen or e Are alkyl with 1-4 carbon atoms or ü) either R ₁ methyl and R_ halogen with an atomic number from 17 to 35 or R, halogen with an atomic number of 17 to 35 and R_ are hydrogen or methyl, with the measures that a) X by at least 2 carbon atoms from the nitrogen atom the 3-amino-2-hydroxypropoxy chain is removed, b) if X is a bond, R _{3 is} not hydrogen and c) if R stands for cyano, R can also mean alkyl with 3-7 carbon atoms, and their salts, characterized in that corresponding compounds of the formula II, 809885/0782 - 3 - 100-4851 Ii wherein R and R have the above meaning and R is one The remainder which, when reacted with an amine, gives a 2-amino-1-hydroxyethyl group, with corresponding Compounds of formula III, R - NH ₂ III in which R has the above meaning, and the compounds of the formula I thus obtained are converted in free form Form or in salt form. 2. The method according to claim 1, characterized in that 1- (3-chloro-2-methylindol-4-yloxy) -3- (2-phenoxyethylamino) 2-propanol manufactures. 3. The method according to claim 1, characterized in that 4- [3- (3, 4-Dimethoxyphenäthylamino) -2-hydroxypropoxy] indole-2-carboxamide manufactures. 4. The method according to claim 1, characterized in that 4- [2-hydroxy-3- (l-p-hydroxyphenyl-2-methyl-2-propylamino) propoxy] indole-2-carbonitrile manufactures. 5. Compounds of the formula I in which R, R. and R have the meaning given in claim 1, and their salts. 809885/0782 - 4 - 100-4851 6. The 1- (3-chloro-2-methylindol-4-yloxy) -3- (2-phenoxyethylamino) -2-propanol and its salts. 7. 4- [3- (3,4-Dimethoxyphenethylamino) -2-hydroxypropoxy] indole-2-carboxamide and its salts. 8. The 4- [2-hydroxy-3- (l-p-hydroxyphenyl-2-methyl- 2-propylamino) propoxy] indole-2-carbonitrile and its salts. 9. Remedies, characterized in that they compounds of the formula I or their physiologically compatible Contain salts. 809885/0782