DE2810869A1 - 3-AMINO-2-HYDROXYPROPOXY DERIVATIVES, THEIR PRODUCTION AND USE - Google Patents

Description

SANDOZ PATENT GmbH. Case 100-4767

7850 Loerrach

3-AMINO-2-HYDROXYPROPOXY DERIVATIVES, THEIR PRODUCTION AND USE

809839/0780

100-4767

The invention relates to new compounds of the formula I ₇ wherein

either ρ the number O, η the number 1 or 2 and into the number 1
or ρ the number 1, η the number 1 and m the number O

or 1
or ρ the number 1, η the number 2 and m the number O

mean,

R _{1 represents} alkyl with 3-7 carbon atoms or a phenylalkyl, phenoxyalkyl or phenylthioalkyl radical with 8-11 carbon atoms, which is optionally substituted in the phenyl ring by alkyl with 1-4 carbon atoms,

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Alkoxy with 1-4 carbon atoms, halogen with an atomic number from 9 to 35, trifluoromethyl or cyano is mono- or identically or differently disubstituted, the phenyl radical being separated by at least 2 carbon atoms from the nitrogen atom to which R _{1 is} bonded,

either R ₀ and R together for straight chain alkylene

with 4-6 carbon atoms

or R »and R, independently of one another, are hydrogen or alkyl of 1-4 carbon atoms

mean, where, if ρ is the number 0 and m and η are the number 1,
Ry and R- not both hydrogen
mean, and

R. and R ₁ . independently for hydrogen or

Are alkyl of 1-4 carbon atoms.

Preferably either ρ denotes the number 0 or 1 and m and η the number 1 or ρ the number 1, m the number 0 and η the number 2.

Unless otherwise stated below, alkyl and / or alkoxy preferably contain 1 or 2, in particular - 1 carbon atom (s). Halogen preferably means
Chlorine or bromine, especially chlorine. Contains alkylene
preferably 4 or 5, especially

4 carbon atoms.

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Phenylalkyl, phenoxyalkyl and / or phenylthioalkyl preferably contain 2-4 carbon atoms in the alkyl part if they contain more than 2 carbon atoms in the alkyl part, this part is preferably branched, in particular in the α-position to the nitrogen atom to which the radical R. is attached, the radical in the phenyl ring is substituted, so the substituents are preferably in the 3- and / or 4-position ^ is the radical in the phenyl ring disubstituted, these are substituents of the phenyl ring preferably identical.

If R _{1 is} alkyl, this radical preferably contains 3-5 carbon atoms, in particular 3 or 4 carbon atoms, and is preferably branched, in particular in the position relative to the nitrogen atom to which the radical R is attached.

R is preferably alkyl or phenylalkyl, in particular alkyl, R ₂ and R are preferably either alkyl or together are alkylene, R and R are preferably hydrogen.

According to the invention, the compounds of the formula I are obtained by using compounds of the formula II in which R "to R_, m, η and ρ have the above meaning and R stands for a radical which, when reacted with an amine, has a 2-amino- 1-hydroxyethyl group results, with compounds of the formula III, wherein R _{1 has the} above meaning, reacts.

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The reaction according to the invention is an amination through a primary amine. It can be carried out using conditions known for the preparation of known S-amino - ^ - hydroxypropoxyaryl compounds. The group R used, for example, is the group —CH — CR , or a reactive derivative thereof

Group, for example a group of the formula -CK-CH-Y,

OH

in which Y is halogen, preferably chlorine or bromine, or a group R -SO ₃ -O-, in which R is phenyl, tolyl or lower alkyl. Y especially stands for chlorine. The reaction is preferably carried out in an organic solvent which is inert under the reaction conditions, for example in an ether such as dioxane. If appropriate, the compound of the formula III is used in excess as the solvent. The reaction is also expediently carried out in the melt. The reaction temperature is, for example, between about 20 and about 200.degree. C., preferably at the boiling point of the reaction mixture, unless it is processed in the melt.

The compounds of the formula I can be in free form or in acid addition salt form. From the connections of the formula I in free form can be acid addition salts in a known manner, for example the bis [base] fumarate or hydrogen maleate, and vice versa.

In the compounds of formula I, the carbon atom of the hydroxypropoxy side chain is the hydroxyl group carries, asymmetrically substitutedj they can therefore in the form of racemates or optically active

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bonds occur. If R and R or if R and R are not identical, they can occur as a mixture of diastereoisomers. If a carbon atom in α-position to the carbonyl group carries a hydrogen atom, epimerization can occur occur at this carbon atom, especially under basic conditions. Preferred are the compounds of formula I in which R "and R- or R and R- are identical, and the (S) -configuration on the asymmetrically substituted carbon atom of the hydroxypropoxy side chain.

The enantiomers or diastereoisomers of the compounds of the formula I can be obtained in a manner known per se v / grounding, for example by splitting with optically active acids or by carrying out the processes according to the invention Implementation based on appropriate, optically active starting products.

The. Starting products can be obtained analogously to known methods:

The compounds of the formula II are obtained, for example, by ether cleavage of the corresponding compounds of the formula IV, before R ₀ to R ₁ . and m, η and ρ have the above meaning and R denotes methyl or benzyl and subsequent 0-alkylation of the HO group of the phenols thus obtained to form a group -OCH-R.

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The compounds of the formula IVa, V7orin

R has the above meaning,

η means the number 1 or 2 and

either R "and R_ together for straight-chain alkylene with 4-6 carbon atoms or R and R independently of one another are hydrogen

or alkyl of 1-4 carbon atoms

mean,

with the restriction that if η is the number 2, then R and R are not both at the same time

Mean hydrogen,

obtained e.g. by Grignard conversion of the compounds of the formula V, in which R and η are as defined above and Z is chlorine or bromine, with the compounds of the formula VI, in which R_ and R_ have the above meaning, and R, - alkyl with 1-4 carbon atoms means subsequent hydrolysis of the compounds of the formula VII thus obtained, in which R, R ", R-, R- and • n have the above meaning, subsequent C0 "cleavage from the reaction products thus obtained and subsequent cyclization of the compounds thus obtained of formula VIII, wherein R, R ", R- and own, with ζ.B..Polyphosphoric acid.

of the formula VIII, in which R, R ", R- and η have the above meaning

If η in the compounds of the formula VIII is 1 and R and R are both hydrogen, one sets preferably cyanoethylene with the compounds of formula V and receives the corresponding directly after hydrolysis Compounds of formula VIII.

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The compounds of the formula IVaa, in which R has the above meaning is obtained, for example, by oxidation of the corresponding benzosuber-5-ols with e.g. Chromic acid or manganese dioxide.

The compounds of the formula IVb, in which R has the above meaning,

together

stand with 4-6 carbon atoms,

either R and R_ together for straight chain alkylene

or R "and R_ independently of one another are hydrogen or alkyl of 1-4 carbon atoms

mean,
R. and R independently of one another for alkyl with 1-4

Carbon atoms stand, and

either η is the number 1 and in the number 0 or 1 or η is the number 2 and m is the number 0,

obtained, for example, by alkylating the corresponding compounds monoalkylated in the 5-position.

The compounds of the formula IVc, in which R, R, R, R,

II I 2 3 4

η and m have the above meaning, one obtains e.g.

by Wittig reaction of the compounds of the formula IVd, wherein R, R, R, η and m have the above meaning, with a compound of the formula

IX, in which R has the above meaning, and then

Implementation of the compounds of the formula X obtained in this way, in which R, R, R, R, η and m have the above meanings, with thallium trinitrate in the presence of a primary, lower alcohol. If in the compounds of formula X

ORiGINAL INSPECTED

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m stands for the number O and none of the radicals R

II

and R is hydrogen, these compounds can be used of the formula X also by converting the corresponding compounds of the formula IVd by Grignard reaction obtained in the corresponding carbinols and subsequent dehydration.

The compounds of formula IVda, wherein

R has the above meaning,

η stands for the number 1 or 2,

either R_ and R- together for straight-chain alkylene

with 4-6 carbon atoms,

or R_ and R_ independently of one another are hydrogen or alkyl with 1-4 carbon atoms, with the restriction that R_ and R_

not both mean hydrogen at the same time,

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obtained e.g. by mono- or transalkylation of the corresponding, compounds unsubstituted in the 6-position.

If the production of the required starting materials is not described, these are known or can according to known processes or analogously to those described here or in the examples or analogously to per se known processes are produced and cleaned.

The compounds of formula I, ie. the connections of the Formula I in free form or in the form of its physiologically acceptable acid addition salts have interesting pharmacological properties. You can therefore use it as a Remedies are used.

They show interesting material interactions by they inhibit the mobilization of glucose and fatty acids in the blood induced by psychological stress.

Due to their metabolic effect, they can e.g. • in conditions that lead to an undesired mobilization of fatty acids caused by psychological stress and glucose lead, used v / earth.

In addition, they have a blocking effect on the adrenergic ß-receptors and can therefore, among other things, for Prophylaxis and therapy of coronary diseases, in particular for the treatment of angina pectoris, use.

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Due to their antiarrhythmic effect, they are also used to treat cardiac arrhythmias suitable.

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 that carries the hydroxyl group is more active than the corresponding (R) -antipodes in the above indications.

The compounds of the formula I also have one salidiuretic effect. Because of this effect, they are suitable for use as salidiuretics, for example suitable for the treatment of edema and hypertension.

The compounds of Examples 1 and 2 are pharmacological especially interesting.

The invention also relates to medicaments that have a compound of formula I in free form or in the form of a physiologically acceptable acid addition salt. These remedies, for example a solution or a tablet, can be prepared according to known methods, using the usual auxiliary and carrier materials, getting produced.

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

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■ Example '1 : 1ζ! 2ζ £ §Ε £ ζ2ΰέΥΐ ⁵ Εϊ22ζ2ΐ'ΰ ^ £ 2ϊ · Υ.Β ^ΓΟ Ε ^οχ Ι ") Z * ° iP l 8 _i 9-tetrahvaro-7 _i 7-diirethvl -SH-benzocvclohegten -6-on

2.2 g of crude 1- (3-chloro-2-hydroxypropoxy) -6,7,8,9-tetrahydro-7 ^ -dimethyl-SH-benzocyclohepten-ö-one are in 20 ml of dioxane and 10 ml of tert-butylamine in the autoclave Boiled for 20 hours at 130 °, then concentrated and between 10% aqueous tartaric acid solution and Aether distributed. The aqueous part is made alkaline and extracted with ether (melting point of the hydrogen maleate the title compound 186-188 ° - from ethanol).

The starting material can be obtained as follows:

a) A solution of 4 4.0 g of 5-methoxy-1-tetralone is added to a suspension of 21 g of sodium hydride in tetrahydrofuran added dropwise in tetrahydrofuran. The mixture is then treated with a solution of 14 2 g of methyl iodide implemented in tetrahydrofuran. 5-Methoxy-2,2-dimethyl-1-tetralone is obtained (bp 162-17O ° / 12 mm).

b) A solution of methyl magnesia iodide (prepared from 69.7 g of methyl iodide urdll, 9 g of magnesium shavings in ether) with a solution of 66.5 g 5-methoxy-2,2-dimethyl-l-tetralone in ether, added the reaction solution with a solution of 62 g of ammonium chloride in water, extracted the obtained Carbinol with ether and, dissolved in eenzene, add 0.5 g of toluene-p-sulfonic acid.

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Topical purification on basic alox with petroleum ether gives methyl 1- [5 , 6,7,8-tetrahydro-6, 6-dimethyl-S-methylene-naphthyl] ether (crude oil - directly processed).

c) 125 g of thallium trinitrate trihydrate in methanol with 55 g of methyl 1- [5, 6, 7, 8-tetrahydro-6, 6-diinethyl-5-methylene-naphthyl] ether reacted in benzene, the precipitated thallium nitrate is filtered off and the Solution extracted with methylene chloride. 6,7,8,9-Tetrahydro-1-methoxy-7,7-dimethyl-5H-benzocycloheptene 6-one melts at 58-59 ° (from hexane).

d) 4.0 g of 6,7,8,9-tetrahydro-1-methoxy-7,7-dimethyl-5H-benzocyclohepten-6-one is treated with 45 ml of acetic acid and 5 ml of 48% hydrogen bromide solution for 20 hours boiled under reflux, then the solution concentrated, diluted with water and extracted with ether. That 6,7,8,9-tetrahydro-7,7-dirr.ethyl-6-oxo-5H-benzocyclohepten-1-ol remaining after removal of the solvent melts at 152-154 ° (from toluene).

e) To a solution of 1.8 g of 6,7,8,9-tetrahydro-7,7-dimethyl-ö-oxo-SH-benzocyclohepten-1-ol 2 drops of piperidine are added to 8 ml of epichlorohydrin and the mixture is stirred at 100 ° for 4 hours. the The solution is evaporated, taken up in ether, filtered and concentrated, the crude 1- (3-chloro-2-hydroxypropoxy) -6,7,8,9-tetrahydro-7,7-dimethyl-5H-benzocyclohepten-6-one remains behind.

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Example '2:

The procedure is analogous to Example 1, starting from 8 '- (3-chloro-2-hydroxypropoxy) -spiro [cyclopentane-1,2' (I ¹ H) -naphthalene] -4 '(3 ¹ H) -one and is obtained the title compound (melting point of the hydrogen maleate: 188-190 ° - from ethanol).

The starting material can be obtained as follows:

a) To a solution of 2-methoxybenzylnagnesium chloride (made from 5.3 g magnesium and 31.2 g 2-methoxybenzyl chloride in 400 ml of ether) is a solution of 39.9 g of ethyl cyclopentylidenecyanoacetate added dropwise in 350 ml of tetrahydrofuran and stirred for 2 hours at room temperature. The mixture is then with 300 ml of 15% strength Ammonium chloride solution is added, the product is extracted with ether and the ether solution is concentrated. Man receives the crude cc-cyano- {l- (2-methoxybenzyl) cyclopentane] -acetic acid ethyl ester, which is distilled at 140-180 ° / 0.002 mm (further processed raw).

b) To a solution of 32.4 g of ethyl cc-cyano- (1- (2-methoxybenzyl) cyclopentaneacetate) 33.6 g of potassium hydroxide are added in 300 ml of ethylene glycol and the solution is stirred at 180 ° for 40 hours. The solution is cooled, poured onto ice-water

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and the neutral by-products vegextracted with ether. The aqueous part is made with hydrochloric acid acidified and extracted with ether. After concentrating the solvent, the [1- (2-methoxybenzyl) cyclopentane] acetic acid remains (M.p. 85-87 ° - from hexane) back.

c) 5.7 g of [1- (2-methoxybenzyl) cyclopentane] acetic acid are added to 30 g of polyphosphoric acid at 110 ° with stirring and the mixture is subsequently stirred for 10 minutes. The mixture is cooled and 250 ml of water are added. Extraction with ether and concentration of the ether extract gives 8'-methoxy-spiro [cyclopentane-1,2 · '(1 ¹ H) -naphthalene] -4' (3 ¹ H) -On (melting point 62- 66 ° - directly processed / processed).

d) The procedure is analogous to Example 1, stage d), starting from 8'-methoxy-spiro [cyclopentane-1,2 '(1 ¹ H) naphthalene] -4' (3 ¹ H) -one and the S 'is obtained -Rydroxyspiro [cyclopentane-1,2 '(1 ¹ H) -naphthalene] -4.' (3 ¹ H) -On (m.p. 163-165 ° - from toluene).

e) The procedure is analogous to Example 1, step e), starting from 4.6 g of 8'-hydroxy-spiro [cyclopentane-1,2 '(1 ¹ H) -naphthalene] -4' (3 ^r H) -one and receives the 8 ^f - (3-chloro-2-hydroxypropoxy) -spiro [cyclopentane-1,2 '- (I ¹ H) -naphthalene] -4' - (3 ¹ H) -one (crude).

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Analogously to Examples 1 and 2, by reacting the corresponding compounds of the formula II, v / orin R stands for -CKCH-Cl, with corresponding

Ah

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

ORIGINAL,

IÜIS3S /

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0 ιη ro ο co ro ro O ro ro O CO ro O in in co O O ro , * K O CN O co CO r% f \ λ - λ co ro ro ■ Η '"cn • ^ f te K VD tr: K CN te K O ta te .- ^ VD in K U ro CO te 28K te CN te ro in U U ro cn U U in U U CN CN CO iH [^ U • Η Ed O U co ro U U ro rH υ rH ¹ I. r-l ¹ ■ -ι ¹ CN U U CN , - ι I. CN CN te r-l I. I. te I. ^^ U I. U I. I. U I. I. I. CJ I. I. ^M yes I. I. CN CJ σ » I. U CN U O ο CO U CN ro in in U I. U • ι-Ι I. in I. σ \ ro in \ ^ O r- { r- O i-l U O I. ■ Η I. α r-l ■ Η rH ■ Η O CN CN r-i CN CN CN rH ε
CO (0 ro (0 ro cn ro tn CN I. Hm JU Jn te U, roU _m co U, U-I co r-l CN CU O ro O O CJ O UU U O O O U-U-U O co r-1 H rH U-I rH • Η CN U U •H CN I. rH r-l U rH B. ■ Η rH r-l I. l-l I. rH r-l r-l I-l ro O I. rH ιη te ι I. I. I. I. { I. I. U te U I. te in VO I. te I. Γ4 I. I. ¹ I. I. I. I. 1 I. te * I. O CO K I. I. I. CN K ro _ ^ ro CtJ K CJ U I. t CU ω U P 2; co

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0 ro ro O O ro ro O ro ro ro • VD OO do ro IT) CM te ro CM te te ro rH O U te O ro CJ te rH CJ U te CM I. CJ CM I { I. U CM I. I. CJ I. U I. I. U I. CJ • VQ te I. ro O 1 O ro
te I. CU O I. O ro te t— { U ε CM ro CM rH I. CM I. ω rH MH te m A. "H 04 rH I. rH te rH rH I. CM ε "-H O O ro ro ID ro te te te te U CJ CJ I. I. I. t • φ pi te I. ro te I. CM C * J te ro ro rH te pi CJ U I. 0 * 4 to M CQ 2 rH

-μ + j ■ ω «J (ti • Η ε β M. CQ U ■ Η η O ω ε Eu rH «Η U ε Γ— QJ C. QJ • Η Q) QJ Cp id U 0 UH U Ό Ö ■ Η te

Il Il

(d

2310359

OJ M QJ

O U) • Η O QJ U QJ -μ W. rd • Η Q

809839 / 07SO

OH

OCH ₂ CHCH ₂ NH-R

(CH) 2. η

(CR.

.0

? ^CH 2 " ^R x

^(CH ₂ V

• ^R 3 ⁰ Vm

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II

R ₁ -

III

RO

^(C Vn

p ^ R ₃

IV

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RO

(CH ₂ )

IVa

IVaa

RO

Il

Il

.R

IVb

R ^J

(CH,

R-

II

R-IVc

IVd

III

IV there

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RO

(CH) I.

2 n.

R.ÖOC

«Ϊ

CN

VI

'"Vn ¹

R ^ OOC-6 CN

VII

RO

VIII

^ P-CH- R,

IX

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Claims (7)

- <"- 100-4767 claims; 1. Compounds of the formula I, CCH, ) '
(CR ₄ R ₅ ). - ² » .0 wherein either ρ the number O, η the number 1 or 2 and m the Number 1 or ρ the number 1, η the number 1 and m the number O or 1
or ρ the number 1, η the number 2 and m the number 0 mean, R, for alkyl with 3-7 carbon atoms or a phenylalkyl, phenoxyalkyl or phenylthioalkyl radical with 8-11 carbon atoms, which optionally in the phenyl ring by alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, halogen with one Atomic number from 9 to 35, trifluoromethyl or cyano is mono- or identically or differently disubstituted, the phenyl radical having at least 2 carbon atcme is separated from the nitrogen atom to which R- is attached, 809839/0780 100-4767 2 3 Ί 0 ε ο either R ₀ and R_ together for straight-chain alkylene with 4-6 carbon atoms are • or R and R independently of one another are hydrogen or alkyl with 1-4 carbon atoms -, where, if ρ is the number 0 and m and η denote the number 1, R and R are not both hydrogen mean, and R. and R ₁ . independently represent hydrogen or alkyl with 1-4 carbon atoms, and their acid addition salts. 2. 1- (3-tert-Butylamino-2-hydroxypropoxy) -6,7,8,9-tetrahydro-7,7-dircethyl) -SH-benzocyclohepten-6-one and its acid addition salts. 3. 8 '- (3-tert-Butylamino-2-hydroxypropoxy) -spiro [cyclopentane-1,2' (I ¹ E) -naphthalene] -4 '(3'H) -one and its acid addition salts. 4. Process for the preparation of compounds of the formula I in which p, n, m and R ₁ to R ^ have the meaning given in claim 1 and their acid addition salts, characterized in that compounds of the formula ^I3C 80 9839/07 80 'ORIGINAL INSPECTED -JlT- 100-4767 wherein R "to R ₁ -, m, η and ρ have the meaning given in claim 1 and R represents a radical which, when reacted with an amine, results in a 2-amino-1-hydroxyethyl group, with compounds of the formula III, R ₁ - NH III in which R _{1 has} the meaning given in claim 1, and the compounds of the formula I thus obtained are obtained in free form or in acid addition salt form. 5. The method according to claim 4, characterized in that 1- (3-tert-butylamino-2-hydroxypropoxy) -6,7,8,9-tetrahydro-7,7-dimethyl) -SH-benzocyclohepten-ö-one manufactures. 6. The method according to claim 4, characterized in that 8 '- (3-tert-butylamino-2-hydroxypropoxy) spiro [cyclopentane-1,2 ¹ (1 ¹ H) -naphthalene] -4' (3 ¹ H ) -on manufactures. 7. Remedies characterized in that they Compounds of the formula I or their physiologically ver. contain acceptable acid addition salts. 809839 / 07SO