DD287500A5 - PROCESS FOR THE PRODUCTION OF SUBSTITUTED AMINOMETHYLETRALINES AND THEIR HETEROCYCLIC ANALOGUE - Google Patents

Abstract

The invention relates to a process for the preparation of substituted Aminomethyltetralinen and their heterocyclic analogs. According to the invention, compounds of formula (I) are prepared in which R1, A, B, C, D, E, F, Y, Z are as defined in the specification and in the claims. Formula (I) {Novel substituted aminomethyltetralines; heterocyclic analogs; serotonin antagonistic action; Effect on central nervous system; Application of medicines; Human, veterinary medicine}

Description

2 8 7S0O - ι -

Process for the preparation of substituted aminomethyltetralines and their heterocyclic analogs

Field of application of the invention

The invention relates to a process for the preparation of substituted Aminomethyltetralinen and their heterocyclic analogues and their use in medicaments.

Characteristic of the known state of the art

It is known that 2-N-dipropyl-amino-8-hydroxy-tetralin binds with high affinity and selectivity to central receptors of 5-HT _1- TyPS. Furthermore, it is known that substituted aminomethylbenzdioxanes have high affinity for receptors of 5-HT ₁ -type P and have both an effect on the cardiovascular and on the central nervous system (EP-A 0 236 930).

In addition, it is known that 3-aminochromans and 3-aminomethylchromans have a stimulating effect on the central nervous system (Ind., O., ex., Svsct., B. 21B (4), 344-347).

Object of the invention

The aim of the invention is to provide new substi-

taut aminomethyitetraline with improved central nervous system action and fewer side effects,

Explanation of the essence of the invention

The invention has for its object to find new compounds with the desired properties and processes for their preparation.

According to the invention substituted aminomethyitetralins and their heterocyclic analogs of the general formula

in which

Y - denotes a straight-chain or branched, saturated or unsaturated alkylene chain having up to 6 carbon atoms,

Z - a group of the formula

- \\ {, -OR ⁴ , -SO ₀₁ R ⁵ , -COOR ⁶ or -CONR ⁷ R ⁸ \ ³

means, where

- 2a -

ά R and R are the same or different and represent hydrogen, alkyl, alkenyl, cycloalkyl, aryl or aralkyl,

R and R are the same or different and are hydrogen, alkyl, alkenyl or cycloalkyl,

for aryl, aralkyl or heteroaryl ethene, wherein the aryl and heteroaryl radicals may optionally be substituted by halogen, cyano, alkyl, alkoxy or trifluoromethyl, for a group of the formula

An-Ch ₃

stand or

CH ₃

represent a group of the formula -COR ⁹ or SO ₂ R ¹⁰ ,

in which

R - is hydrogen or

alkyl or alkoxy represents aryl or aralkyl which may be optionally the same or different up to 3 times by alkyl, alkoxy, alkylthio, halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino, alkylamino or dialkylamino, or - for keteroaryl stands,

" _N which may optionally be substituted by alkyl, alkoxy, alkylthio, halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino, alkylamino or dialkylamino up to three times, identically or differently, or

Le A 26 080

stands for a group NHR * ¹ , p

R ¹¹ - for Alkyl stahti which may optionally be substituted by cyano, halogen, trifluoromethyl or trifluoromethoxy, or

- is aryl or aralkyl, which may be up to 3 times the same or different by alkyl, alkoxy, alkylthio, halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino, alkylamino or

Dialkylamino may be substituted

R * 0 - is alkyl which may optionally be substituted by cyano, halogen, alkoxycarbonyl, trifluoromethyl or trifluoromethoxy, or

is aryl, aralkyl or heteroaryl, optionally up to 3: as the same or different substituted by alkyl, alkoxy, alkylthio, halogen, cyano, triflucrmethyl,

Trifluoromethoxy, trifluoromethylthio, amino, Alkylpmino or dialkylamino or

for a group of Formula 8? ^CH 3

stands, or 35

Le A 26 080

, ry ft

for a group of the formula -NR R is "where

V ft

R and R have the abovementioned meaning, or

R and R together with the nitrogen atom is a heterocycle of the series

H ₂ C- (CH ₂ ) _O

< ^CH 2> w

0

O = C

NH / 'sn'

2 '

I ^CH 2>

-N NR ¹²

Le A 26 080

or

-A

form,

in which

w - the number 0, 1 or 2 means

ο - the number 1 or 2 means 15

R ¹² - represents acyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, alkylarylsulfonyl, carbamoyl or sulfamoyl

R ⁴ - is hydrogen, alkyl or alkenyl

or

represents cycloalkyl or

represents alkoxycarbonyl or represents aryloxycarbonyl or aralkoxycarbonyl,

R ⁵ - is alkyl, alkenyl or cycloalkyl, or is aryl or aralkyl, optionally up to 3 times the same or different sub- ³ ^ substituted by halogen, cyano, alkyl, alkoxy, trifluoromethyl or trifluoromethoxy, or a group of Formula -NR ^ R® Bteht, where

Le A 26 080

7 ft. R and R have the abovementioned meaning,

m - stands for the number O, 1 or 2,

R ⁶ - represents hydrogen, alkyl, alkenyl, cycloalkyl,

Aryl or aralkyl, 10

R is hydrogen, alkyl or aralkyl, or heteroarylalkyl, or

the group - (Y ¹ - Z ¹ ), wherein Y ¹ and Z ^{1 may be the} same or different from Y and Z and have the meaning of Y and Z as indicated above.

A and D is a group of the formula -CH ₂ , O, S, NR ¹³ or

the -CH or N part of a C = C or C = N

Mean double bond,

with the proviso that either only A or only D is oxygen, sulfur or N-R, in which

_R 13 _ f _r ^ is hydrogen, alkyl, alkoxy, acyl, alkoxycarbonyl or alkylsulphonyl,

B - a group of the formula -CH ₂ - * -CH or

the CH or N part of a C = C or C = N

Doppler bonding means

C represents a group of the formula -CH or the C part of a C =C or C =N double bond,

Le A 26 080

8 7 5

E and F are the same or different and 5

Hydrogen, alkyl, alkoxy, halogen, nitro, cyano, trifluoromethyl or trifluoromethoxy, or

a group of the formula -CONR ² R ³ , 10

wor in

R ² and R ^{3 have} the abovementioned meaning, or

E and F together form a saturated or unsaturated carbocycle of 6 carbon atoms

and their salae,

² ^ In the present invention, compounds of the invention have several asymmetric carbon atoms and therefore exist in various stereochemical forms. In addition, compounds with a sulfoxide group can also be

^ΛΟ retired union stereochemical forms exist Examples include the following isomeric forms of the substituted heterocyclic Aminomethyltetraline and its analogues,

r ^ V ^ BR ¹

CH ₂ -NYZ

Le A 26 080

287

The compounds according to the invention can also be present in the form of their salts. In general, salts with inorganic or organic acids may be mentioned here,

In the context of the present invention, physiologically acceptable salts are preferred.

Physiologically acceptable salts of the substituted aminomethyltetralins and their heterocyclic analogues may be salts of the substances according to the invention with mineral acids "carboxylic acids or sulfonic acids. Particular preference is given, for example, to salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid or benzoic acid.

The substances according to the invention surprisingly show a beneficial effect on the central nervous system

and can be used for the therapeutic treatment of humans and animals. Compared to the already known structurally related compounds, they are distinguished by a greater selectivity for the 5-HT ₁ ^ receptor, due in part to serotonin antagonistic action and lower side effects.

Le A 26 080

287 SQo

- 10 -

In the context of the present invention, the substituents generally have the following meanings:

Alkyl is generally a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms. Preferred is lower alkyl having 1 to about 6 carbon atoms. Examples which may be mentioned are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl and isooctyl.

Alkenyl is generally a straight chain

or branched hydrocarbon radical having 2 to 12 carbon atoms and one or more, preferably with one or two double bonds. Preferred is the lower alkyl group having 2 to about 6 carbon atoms and a double bond. Particularly preferred is an alkenyl group having 2 to 4 carbon atoms and a double bond. For example, allyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, isopentenyl, hexenyl, isohexenyl, heptenyl, isoheptenyl, octenyl and

Called isooctenyl.

Cycloalkyl generally represents a cyclic hydrocarbon radical having 5 to 8 carbon atoms. The cyclopentane and the cyclohexane rings, for example, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, are preferably mentioned.

Le A 26 080

2 δ 7 5 O

- 11 -

Aryl is generally an aromatic radical having from 6 to about 12 carbon atoms. Preferred aryl radicals are phenyl, naphthyl and biphenyl,

Aralkvl is generally an aryl radical having 7 to 14 carbon atoms attached via an alkylene chain. Preference is given to aralkyl radicals having 1 to carbon atoms in the aliphatic part and 6 to 12 carbon atoms in the aromatic part. The following aralkyl radicals may be mentioned as examples: benzyl, naphthylmethyl, phenethyl and phenylpropyl.

Alkoxy generally represents a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms bonded via an oxygen atom. Preferred is lower alkoxy having 1 to about 6 carbon atoms. Particularly preferred is an alkoxy radical having 1 to 4 carbon atoms. Examples which may be mentioned are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, isopentoxy, hexoxy, isohexoxy, heptoxy, isoheptoxy, octoxy or isooctoxy.

Alkylthio is generally a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms bonded via a sulfur atom. Lower alkylthio having 1 to about 6 carbon atoms is preferred.

Particularly preferred is an alkylthio radical having 1 to 4 carbon atoms. For example, be methylthio,

Le A 26 080

2 8 7 5

- 12 -

Ethylthio, propylthio, isopropylthio, butylthio, iso

butylthio, pentylthio, isopentylthio, hexylthio, iso

hexylthio, heptylthio, isoheptylthio, octylthio or isooctylthio.

Acyl is generally phenyl or straight or branched lower alkyl having 1 to about 6 carbon atoms attached via a carbonyl group. Preference is given to phenyl and alkyl radicals having up to 4 carbon atoms, for example: benzoyl, acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl and isobutylcarbunyl.

Alkoxycarbonyl , for example, by the formula

-C-Oalkyl

H

being represented.

Alkyl here stands for a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms. Lower alkoxycarbonyl having 1 to about 6 carbon atoms in the alkyl moiety is preferred. Particularly preferred is an alkoxycarbonyl having 1 to 4 carbon atoms in the alkyl moiety. For example, the following alkoxycarbonyl radicals may be mentioned: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl or isobutoxycarbonyl.

Le A 26 080

- 13 -

Aryloxycarbonyl can be represented, for example, by the formula -COO-aryl, aryl in this case generally being an aromatic radical having 6 to 12 carbon atoms. For example, these include: phenoxycarbonyl and naphthyloxycarbonyl.

Ar a IkOK ye ar bon vl , for example, by the Fc.rmel

Aralkyl is in this case generally an aryl radical having 7 to 14 carbon atoms bonded via an alkylene chain. Bc-preferred are aralkyl radicals having 1 to 6 carbon atoms in the aliphatic part and 6 to 12 carbon atoms in the aromatic part. For example, aJs Aralkoxycarbonylreste be called: benzyloxycarbonyl, Naphthylmethyloxycarbonyl,

Heteroaryl in Fahmen the given above definition in general for a 5- to 6-membered aromatic Hing, which can contain as hetero atoms oxygen, sulfur and / or nitrogen and may be fused to the <~ in further aromatic ring before are Trains t 5 and 6-membered aromatic rings which contain an oxygen, a sulfur and / or up to 2 nitrogen atoms and which are optionally benzo-fused. As particularly preferred Heteroarylresteseien called:

Thionyl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, thiazolyl, benzthiazolyl, isothiazolyl, oxazolyl, benzoxazolyl, isoxazolyl, imidazolyl, benzimidazolyl,

Pyrazolyl and indolyl,

Le A 26 080

- 14 -

Halogen is generally fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine. Halogen is particularly preferably fluorine or chlorine,

SuIfamovl (aminosulfonyl) stands for the group -SO 2 -NH 2 .10

Alkylsulfonyl generally represents a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms which is bonded via an SO ₂ group. Lower alkylsulfonyl having 1 to about 6 carbon atoms is preferred. Examples include: methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, pentylsulfonyl, isopentylsulfinyl, hexylsulfonyl, isohexylsulfonyl,

Arylsulfonyl is generally an aromatic radical having from 6 to about 12 carbon atoms, which is bonded via an SOg group, for example: phenylsulfonyl, naphthylsulfonyl and biphenylsulfonyl,

2b, in particular phenylsulfonyl,

Aralkvlsulfonvi generally represents an aralkyl recc having from 7 to about 14 carbon atoms wherein the alkyl groups are linked through an SC ^ chain. Aralkylsulfonyl radicals having from 1 to 6 carbon atoms in the aliphatic part and 6 to 12 carbon atoms in the aromatic part are preferred. The following aralkylsulfonyl radicals may be mentioned: benzylsulfonyl, naphthylmethylsulfonyl, phenethylsulfonyl and phenylpropylsulfonyl, in particular benzylsulfonyl.

Le A 26 080

237 50

- 15 -

Preference is given to compounds of the general formula (I)

in which

Y represents a straight-chain or branched, saturated or unsaturated alkylene chain having up to 6 carbon atoms,

Z - a group of the formula

2 _R 7

-N, -SOo-N or -CONR ⁷ R ⁸ ,

in which

R ⁷ and R ^{8 are the} same or different and

are hydrogen, lower alkyl, lower alkenyl, cycloalkyl, phenyl, benzyl or phenothyl,

2 3

R ^ and R ° are the same or different and

is hydrogen, lower alkyl or lower alkenyl, or

are cycloalkyl, or

are phenyl, benzyl or pyridyl, which are optionally substituted by fluorine, chlorine, bromine, cyano, lower alkyl, lower alkoxy or trifluoromethyl, or a group of the formula

Le A 26 080

- 16 -

i ~ ^CH 3

stand or

CH ₃

represent a group of the formula -COR ⁹ or -SO ₂ R ¹⁰ in which

R ⁹ - for hydrogen or

is lower alkyl or lower alkoxy or is phenyl, benzyl, benzyloxy, thienyl, furyl, pyridyl, pyrimidyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, thiazolyl, oxazolyl, isoxazolyl or isothiazolyl, which may optionally be substituted up to twice by lower alkyl , Lower alkoxy, fluorine, chlorine, bromine, trifluoromethyl, dimethylamino or diethylamino cd er

for a group of the formula -NHR ¹¹ Gteht, 25

in which

R ^{11 is} lower alkyl optionally

by cyano, fluorine, chlorine or bromine.

can be tuxed or

Le A 26 08 0

- 17 -

phenyl, benzyl, thionyl, furyl, pyridyl,

Pyrimidyl, quinolyl, isoquinolyl, benzothia

zolyl, benzoxazolyl, thiazolyl, oxazolyl, isoxazolyl, or isothioazolyl, optionally substituted by lower alkyl, lower alkoxy, fluoro, chloro, bromo, trifluoromethyl,

Substituted dimethylamino or diethylamino

are

plO_ is lower alkyl, which may be optionally substituted by cyano, fluoro, chloro, bromo, trifluoromethyl or lower alkoxycarbonyl, or

is phenyl, naphthyl, benzyl, thionyl, furyl, pyrimidyl, pyridyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, thiazolyl, oxazolyl, isoxazolyl or isothiazolyl optionally substituted up to 2 times by lower alkyl, lower alkoxy, fluoro, chloro, bromo, trifluoromethyl , Dimethylamino or diethylamino or for a group of the formula

stands or

is a group of the formula NR ⁷ R ⁸ ,

where 35

Le A 26 080

- 18 -

7 ft

R and R have the abovementioned meaning , or

R ^ and R ^ together with the nitrogen atom is a heterocycle of the series

H ₂ C- (CH ₂ ) _O

/ SO ₂ , (CH ₂ ) _W

j ^CH 2> o

CHr

SO-

-N

or

Le A 26

- 19 -

form «5

in which

w - a number O ₁ 1 or 2, ο - a number 1 or 2 means

R * is hydrogen, lower alkyl or benzyl, or

- the group - (Y ¹ ^ Z ¹ ), where Y ¹ and Z ^{1 may be} identical or different to Y and Z and have the abovementioned meaning of Y and Z,

A and D - a group of the formula -CH ₂ »or oxygen, sulfur, NR ¹³ or the CH- or N-

Part of a C = C or C = N double bond,

with the proviso that either only A or only D is a group of formula O, S or NR * ³ and

wherein

R ¹³ - is hydrogen, lower alkyl, lower alkoxy, ³ ^ lower alkoxycarbonyl or lower alkylsulfonyl

stands

Le A 26 080

287 50Q

- 20 -

B- a group of the formula -CH ₂ "» -CH

or the CH part of a C = C or C = N double bond,

C- is a group of formula -CH or the C part of a C = C or C = N double bond.

E and F are the same or different and 15

Mean hydrogen, lower alkyl or lower alkoxy, or

Fluorine, chlorine, bromine, cyano or a group of the formula -CONR ² R ³ ,

I would like to

R ² and R ^{3 are} hydrogen 25

or E and F together form a phenyl or cyclohexane ring

form, 30

and their salts.

Particularly preferred are the compounds of the formula in which

Le A 26

- 21 -

represents a geradketlige alkylene ketene with 2-5 carbon atoms,

a group of the formula

-N means "^ ³

where 15

R and R are the same or different and are hydrogen, methyl, ethyl, propyl, or

are phenyl, benzyl or pyridyl, which optionally substituted chlorine, methyl or methoxy

optionally substituted by fluorine,

for a group of the formula

ο

^ N-CH ₃

stand or

CH ₃

Le A 26

287

- 22 -

are a group of the formula -COR ⁹ or -SO ₂ R ¹⁰ ,

wherein

R ⁹ - is methyl, ethyl or ethoxy or

is phenyl or benzyl, optionally substituted by methyl, methoxy, fluorine or chlorine

15 _R 10_

is methyl, ethyl or propyl, or

is phenyl, naphthyl or benzyl, which is optionally substituted by fluorine or chlorine, or

for a group of the formula

stands, or

and R ° together with the nitrogen atom of a heterocycle from the series

N "S ^>

(CH ₂ ) _W

Le A 26 080

- 23 -

(CH ₇ ). I ² '

or

form,

in which

a number 0, 1 or 2 means

1 _

a number 1 or 2 means

Is hydrogen, ethyl, methyl, propyl or benzyl, or

the group - (Y ^ Z ¹ ), where Y ¹ and Z ^{1 may be the} same or different from Y and Z and have the above-mentioned meaning of Y and Z have

A and D are a group of the formula -CHg "» for oxygen or for the CH or N part of a C = C-C = N double bond, with the proviso that either only A or only D may be oxygen,

Le A 26 080

2 8 7 ο Ο Ο

- 24 -

B - for a group of formula 5

«Ν" ν

CH ₂ or -CH or for the. CH part of a

C = C or C = N double bond

stand <\, 10

C - represents a group of the formula -CH or the C part of a C = C or C = N double bond,

**> E and F are the same or different and represent hydrogen, ethoxy, methoxy, fluorine, cyano or a group of the formula -CONR ² R ³ , in which R ² and R are hydrogen,

or

E and F together form a phenyl or cyclohexane ring,

and their salts,

Very particular preference is given to the compounds of the formula I

in which

Y represents a straight-chain alkylene chain with 2-5 carbon atoms,

Z - a group of the formula

Le A 26

- 25 -

-N means, "-R ³

wherein 10 R and R ° are the same or different and are hydrogen, methyl, benzyl or pyridyl represent a group of the formula

N-CHO

stand or

20 ^y

• · · 9 in

represent a group of the formula -COR or SO ₂ R,

wor in

R - stands for phenyl or ethoxy

R ¹⁰ - is phenyl or naphthyl which may be substituted by fluorine or

- for methyl is a group of the formula

35V ₁ ?^CH3

or Le A 26 080

- 26 -

R ^ and R ° together with the nitrogen atom, a heterocycle of the formula

⁹ ^ O

O,

-N s-

or

N-SO ₂ -CH ₃

-N

wherein

w is a number 0, 1 or 2 and ο - a number 1 or 2 means

form,

R ^{1 is} hydrogen, methyl, propyl or benzyl or

a group - (Y ^ -Z ¹ ) means

wherein Y ¹ and Z * may be the same or different from Y and Z and have the above-mentioned meaning of Y and Z.

Le A 26 080

- 27 -

A and D are a group of the formula -CHO "ι for salier or for the CH or N part of a C = C-C = N double bond, with the proviso that either only A or only D may be oxygen,

B - for a group of formula 10

CH _? or -CH or for the CH part of a

C = C or C = N double bond

is, 15

C - represents a group of the formula -CH or the C part of a C = C or C = N double bond,

E and F are the same or different and are hydrogen, ethoxy, methoxy, fluorine, cyano or a group of the formula -CONR ² R ³ , in which R ² and R are hydrogen,

E and F together can form cyclohexane or phenyl ring,

and their salts.

Furthermore, processes for the preparation of the compounds of general formula (I) according to the invention were found, characterized in that

[A] compounds of the general forms ?. (II) 35

Le A 26

- 28 -

R ¹

(in,

EKC-CH ₂ -NH

in which

A, B, C, D, E, F and R have the meaning given above,

(Al) miL alkylating agent in the formula (III) 15

L-Y-Z (III), in the

Y and Z have the abovementioned meanings, with the provisos that Z is not L for amino sLehL and R is not L for water or LiL if

R ^{3 is} alkyl or aryl sLehL, 25

Le A 26

- 29 -

and 5

L represents a leaving group for alkylating agent,

converts, 10

or

(A2) with aldehydes of the formula (IV) OCH-Y ² -Z (IV),

in which

Z has the abovementioned meaning and Y is an alkylene chain Y abbreviated to a methylene group ,

reductively alkylated, or

(A3) with reactive acid derivatives of the general formula (V)

M-CO-Y ² -Z (V) in which

Y ² and Z have the meanings given under the process variants (Al) and M denotes a leaving group for acylating agent,

Le A 26 080

30 -

implements,

and reducing the corresponding acid amides with hydrogen in the presence of a catalyst, with boranes or with complex metal hydrides,

or (A4) with nitriles of the formula

G-CN

in which

G is monochlorinated lower alkyl (C 1 to C 3), vinyl or lower alkyl (C j to Cg) -substituted vinyl,

to compounds of the formula (VI) and (VII)

D ^ C-CH ₂ -N-CH ₂ CN (VI)

EKC-CH ₂ -N-CH ₂ CH ₂ CN (VII),

wor in

A, β, C, D, E, F and R ¹ are as defined above,

alkylated

Lg A 26 080

- 31 -

the resulting nitriles to the amines (VIII) and (IX)

E ~ f [Γ I I (VIII)

F 10

ri ^ V ^ ^{AxB r1}

(IX /

wherein

A, B, C, D, E, F and R have the abovementioned meaning,

hydrated,

and this in a conventional manner

Alkylation, reductive alkylation, acylation,

Reaction with isocyanates or sulfonylations,

or by

[B] Compounds of the general formula (X)

H (X), EKC-CH ₂ -NYZ

in which

Le A 26 080

- 32 -

in which SA, B, Ci, D, E, Fi Y and Z have the meanings given above ι

with the provisos that Z is not amino and R 1 is not hydrogen when R ^{3 is} alkyl or aryl,

(B1) with alkylating agents of the formula (XI) 15

R ^x -L (XI),

wherein R ^{1 has} the meaning given above and

L represents a leaving group for alkylating agent,

alkylated, or

(B2) with aldehydes of the formula (XII) 30

R ¹⁴ -CHO (XII),

in which R ^{14 is} a radical R ¹ shortened by one methylene group, 35

Le A 26

- 33 -

reductively alkylated 5

or (B3) with reactive acid derivatives of the general

Formula (XIII) 10

M-CO-R ¹⁴ (XIII) in which R has the meaning given above and

M is a leaving group for acylating agent,

implements

and the corresponding acid amides with hydrogen in the presence of a catalyst or complex metal

hydride reduced, 25

or by reacting [C] aldehydes of the formula (XIV)

(XIV)

in the 35th

Le A 26

- 34 -

A, B, C, D, E and F are as defined above,

with amines of the formula (XV), (XVI) or (XVII)

_in HN H ₇ NR ¹ H ₇ NYZ

^ Y-Z

(XV) (XVI) (XVII),

wor in

R, Y and Z have the abovementioned meaning with the provisos that

Z does not stand for Amino and 20

R ^{2 is} not hydrogen when R ^{3 is} alkyl or aryl,

in a conventional manner aminiert reductive,

or by " _n- CD" compounds of the general formula (XVIII)

E-f Μ I (XVIII),

D ^ C-CH ₂ -L

Le A 2 6

- 35 -

in which

A, B, C, D, E and F and X have the abovementioned meaning and

L meaning a leaving group for alkylating agents,

with amines of the formulas

- "

_1C HN H ₇ NR ¹ H ₇ NYZ

ν _γ _ _ζ 2

(XV) (XVI) (XVII),

wherein R, Y and Z have the abovementioned meaning, with the provisos that Z is not amino and

R does not stand for hydrogen, though

R ^{3 is} alkyl or aryl,

implements,

or reacting with an alkali azide and then reducing the Azidofunkt ion to a Aminofunkt ion redu-

or by calling Le A 26

- 36 -

[E] reactive carboxylic acid derivatives of the formula (XIX) 5

F 10

wherein

A, B, C, D, E and F are as defined above, and

M is a leaving group for acylating agent,

with amines of the formulas

HN H ₂ NR ¹ H ₂ NYZ

(XV) (XVI) (XVII), 25

in which R ¹ , Y and Z have the abovementioned meaning,

with the provisos that Z does not stand for amino, and

R ^ does not stand for hydrogen when 35

Le A 26

- 37 -

R ^{3 is} alkyl, or aryl,

and RUe thus obtained amides of the formulas (XX) and (XXI)

R ₁ E

F 0

(XX) (XXI),

in which

A, B ₁ C, D, E, F, R ¹ , Y and Z are as defined above,

reduced catalytically with hydrogen, with complex metal hydrides or with boranes,

or by

[F] Compounds of the general formula (XXII) E - f Π (XXII), ^] I

• O

Le A 26 080

- 38 -

in which A, E and F have the abovementioned meaning with formaldehyde and amines of the formula (XV)

HN (XV),

^ YZ

wherein

R, Y and Z are as defined above.

with the provisos that 15

Z is not amino and R is not hydrogen when R ^{3 is} alkyl or aryl,

and the resulting intermediates of general formula (XXIII)

in which

A, E, F, R ¹ , Y and Z are as defined above,

Le A 26

- 39 -

by reducing the carbonyl function or by partial reduction of the carbonyl function to the alcohol function "subsequent elimination of water and, if appropriate, hydrogenation of the C = C double bond continues to be reacted with hydrogen."

The following formula schemes illustrate the processes for preparing the compounds of general formula Ii according to the invention

Le A 26

287 50

- 40 -

Method A: 5 Variant Al:

Br (CHg) ₄ -N

OCH ^

- (CHO) ₄ -N.

ochr

Variant A2:

OCH.

OCHCH ₂ CH ₃ H ₂ / Pd-C

ochr

Variant A3:

LiAlH ₄

THF

Le A 26

- 41 -

Variant A4:

OCH,

H H

Method B: Variant Bl:

- (CH ₂ J ₄ -N

CH ₃ J

35 OCHR

Le A 26

- 42 -

8 7 5 0

- (CH ₂ J ₄ -N

Variant B2;

OCH.

OCH ^

Variant B3:

λ OCHCH ₂ CH ₃

NaCNBH ₃

-SO.

ochr

-SO.

ClCOCH ₂ CH ₃

OCH ₃

-SO"

LiAlH ₄

OCH ₃ Le A 26

-SO-

- 43 -

Method C:

8 7 5 0

HN

^ CHO

OCH.

NaCNBH ₃

Method D:

H ₂ N (CH ₃ ) ₃ N-SO ₂

m: h ₂ ci

OCH.

OCH

Method E:

H ₂ N (CH ₂ ) ₂ N-SO ₂

OCl

^B 2 ^H 6

Le A 26 080

28 7

- 44 -

H H

N-SO

Method F;

NaBH ₄

CH ₂ O

OH

HCl

H ₂ / Pd-C

The amines of the formulas (II) and (X) used as starting materials are known per se and can be prepared in known manner from the corresponding ketones by reductive amination, alkylation or reductive alkylation (cf., GB 1 043 857, J, Med Chem. 29, 1619, 1968, J. Med. Chem., 844 (1968), EP-A-0 192 288), PA Robins, J. Walev, J, Chem. Soc., 1958, 409, J, Chem, Soc, 1942, 689).

Le A 26 080

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As a solvent for the reaction of the amines (II) and (X) with the alkylating agents (III) and (XI), the customary organic solvents which do not change under the reaction conditions can be used here. These include, preferably, alcohols such as methanol "ethanol" propanol or isopropanol, or ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or butyl methyl ether, or ketones such as acetone or butanone, or amides such as dimethylformamide or hexamethylphosphoric triamide, or dimethyl sulfoxide, acetonitrile, ethyl acetate or halohydrocarbons such as methylene chloride, chloroform or carbon tetrachloride, or pyridine, picoline or N-methylpiperidine, mixtures of these solvents can also be used ·

Suitable bases are the customary inorganic or organic bases. These include, preferably, alkali metal hydroxides such as, for example, sodium or potassium hydroxide, or alkali metal carbonates such as sodium or potassium carbonate, or alkali metal alcoholates such as, for example

Sodium or potassium methoxide, or sodium or

Potassium ethanolate, or organic amines such as triethylamine, picoline or N-methylpiperidine, or amides such as sodium amide or lithium diisopropylamide, or metal 1-organic compounds such as butyllithium or phenyl-lithium.

Leaving groups for alkylating agents (L) are known per se (Ref. H.R. Christen, Grundlagen der organischen Chemie Sauerländer-Diesterweg-SalIe 1975), Example-35

Le A 26 080

8 7 5

- 46 -

here are chlorine, bromine, Jcd, tosylate, mesylate or the group -OSO2CF3 called,

Leaving groups for acylating agents (M) are known per se (Lit, H, R, Christen, Grundlagen der organischen Chemie, Sauerland-Diesterweg-SalIe 1975). For example, here are chlorine, bromine, alkoxy (C ₁ to C ₄ ), aryloxy , Imidazolyl, thiazolyl, methanesulfonyloxy or alkoxy (C ₁ to C ₄ ) called carbonyl,

The reaction is generally carried out in a temperature range from O ⁰ C to +150 ⁰ C, preferably in a range from room temperature to + 8D ⁰ C.

The reaction is generally carried out at atmospheric pressure, but it is also possible to carry out the reaction at elevated or reduced uck,

As reaction accelerator: alkali metal iodides are generally used, preferably sodium iodide or potassium iodide,

The base is used here in an amount of from 1 to 5, preferably from 1 to 2, mol, based on 1 mol of the halogen compound. The halogen compound is preferably converted in an amount up to 10 times, preferably in an up to 5 times, excess amount the compounds of the formula (II) or (X) are used,

Le A 26 080

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The reductive alkylation of the amines (II) and (X) with the aldehydes (IV) and (XII) is generally carried out in one step. If the amine (II) is a primary amine, the reaction can also be carried out in two stages, initially a Schiff 'see base' or an enamine is obtained,

The preparation of Schiff'sehen bases or enamines in the first step is carried out in inert organic solvents «optionally in the presence of a catalyst and optionally in the presence of a water-binding agent. The process according to the invention can be carried out in 2 steps "with the isolation of the intermediates. It is likewise possible to carry out the reduction as a one-pot process.

Suitable inert solvents here are the customary organic solvents which do not change under the reaction conditions. These preferably include alcohols such as methanol, ethanol, propanol or isopropanol, or ether, diethyl ether, butyl methyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol diethyl ether, or halogenated hydrocarbons, such as For example, methylene chloride, chloroform or carbon tetrachloride «or hydrocarbons such as benzene, toluene, xylene, or petroleum fractions, or amides such as dimethylformamide or hexamethylphosphoric triamide or acetic acid · It is also possible to use mixtures of said solvents.

Le A 26 080

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Proton acids are generally used as catalysts, These include preferably inorganic acids such as hydrochloric acid or sulfuric acid, or organic carboxylic acids having 1-6 C atoms, optionally substituted by fluorine, chlorine and / or bromine, such as acetic acid, trifluoroacetic acid, trichloroacetic acid or propionic acid , or sulfonic acids with Cj-C ^ alkyl radicals or with aryl radicals such as Methansulfcnsäuro, ethanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid.

The water formed in the reaction may optionally in admixture with the solvent used during or after the reaction z, B _t by distillation or by the addition of water-binding agents such as phosphorus pentoxide or preferably by

Molecular sieve are removed,

The reaction is generally carried out in a temperature range from ⁰ C to 150 ⁰ C, preferably +20 ⁰ C to +100 ⁰ C, carried out

 25

The reaction can be carried out at normal, elevated and reduced pressure (e.g., vT, 5 -5 bar). In general, one works at atmospheric pressure.

In carrying out the compound (XV) in an amount of 0.1 - 1Ü, preferably from 0.5 to 5 mol, based on 1 mol of the compounds (II) odar (X), is used.

Le A 26 080

2 8 7 5 C

The reduction of the Schiff bases or enamines in the second step takes place either by hydrogen in water or in inert organic solvents, such as alcohols, ethers or halohydrocarbon streams. or their mixtures, with catalysts such as Raney nickel, palladium palladium on animal charcoal or platinum, or with hydrides in inert solvents, if appropriate in the presence of a catalyst,

The reaction is preferably carried out with hydrides, such as complex borohydrides or aluminum hyaides. Particular preference is given here to using sodium borohydride, lithium aluminum hydride or sodium cyanoborohydride.

Suitable solvents here are all inert organic solvents which do not change under the reaction conditions. For this ¹ preferably include alcohols such as methanol, ethanol, propanol or isopropanol, or ethers such as diethyl ether, dioxane. Tetrahydrofuran, glycol dimethyl ether, or diethylene glycol dimethyl ether or amides such as hexamethylphosphoric triamide or dimethylformamide, or acetic acid, It is also possible to use mixtures of said Löjemittel.

As catalysts in the reduction with Natriumeyanoborhydrid protonic acids are generally verwen det. These preferably include inorganic acids, such as, for example, hydrochloric acid or sulfuric acid, or any organic carboxylic acids with 1-6 C-ALOMUN.

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if substituted by fluorine, chlorine and / or bromine / such as acetic acid, Trifluoreesigeaure, trichlorethylene or propionic acid, or sulfonic acids with Cj-C ^ alkyl or aryl radicals such as methanesulfonic acid, ethanesulfonic acid, benzene sulfonic acid or toluenesulfonic acid · 10th

In carrying out the process of the invention, it has it proved favorable, the reaction of the aldehydes (IV) and (XII) with the amines (II) and (X) in an inert solvent Mittal, preferably ^ in acetic acid or alcohols such as methanol, ethanol, Propanol or isopropanol or mixtures thereof, in the presence of inorganic or organic acids such as hydrochloric acid or acetic acid, and in the presence of a reducing agent, preferably of complex hydrides such as sodium borohydride or sodium cyanoborohydride, optionally in the presence of a dehydrating agent, preferably molecular sieve, as a one-pot process.

In this case, the reaction is carried out in a temperature range from O ⁰ C to +150 ⁰ C, preferably from ^{0 0} C to + 100 ⁰ C at atmospheric pressure. It is also possible to carry out the reaction under reduced pressure or under excess pressure (eg in the bomb tube).

The transfer of functional groups into other functional groups in the abovementioned

Le A 26 080

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Depending on the type of functional groups, the method of preparation is carried out by oxidation, reduction, hydrolysis or by reaction with electrophilic reagents and will be explained below.

1. The reduction of the nitrile group to the amino group is generally carried out with metal hydrides, preferably with lithium aluminum hydride, aluminum hydride (prepared for example by reaction of lithium aluminum hydride with lOOXiger sulfuric acid or aluminum chloride) or mixtures thereof in inert solvents such as ethers or chlorinated hydrocarbons, preferably in ethers such as tetrahydrofuran , diethyl ether or dioxane in a temperature range from -20 ⁰ C to +100 ⁰ C, preferably from ⁰ ° C to +50 ⁰ C, at atmospheric pressure,

The reduction is also by hydrogenating the nitriles in inert solvents such as alcohols such as methanol, ethanol, propanol or isopropanol in the presence of a noble metal catalyst such as platinum, palladium, palladium on charcoal or Raney nickel, in a temperature range of ^{0 0} C to + 150 ⁰ C, preferably from room temperature to + 100 ⁰ C, at atmospheric pressure or at overpressure possible,

The reaction can be illustrated by the following scheme:

Le A 26 080

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OCH

2, The reduction of alkoxycarbonyl in alcohol groups is generally carried out with hydrides, preferably with lithium aluminum hydride in inert solvents such as ethers, hydrocarbons or halogenated hydrocarbons or mixtures thereof, preferably in ethers such as diethyl ether, tetrahydrofuran or dioxane in a temperature range from ^{0 0} C to +150 ⁰ C, preferably from + 20 ⁰ C to + 100 ⁰ C, at atmospheric pressure.

The reaction can be illustrated by the following scheme:

OCH

The hydrolysis of the nitrile group to the carboxamide group is generally carried out with the aid of strong mineral acids, preferably with hydrogen chloride in inert solvents such as water and / or alcohols such as methanol, ethanol, propanol or isopropanol in a temperature range from ⁰ ° C. to + 150 ^° C. , preferably from +20 ⁰ C to +100 ⁰ C, at atmospheric pressure.

Le A 26 080

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The reaction can be explained by the following scheme:

hydrolysis

OCH ₃

Il

H ₂ -N-CH ₂ -CH ₂ -C-NH ₂

^0CH :

4, By reaction of NH- or OH-acidic compounds (Z in formula (I) is NR ² R ³ , wherein R ² = H and R ³ = H, alkyl, aryl or aralkyl), with electrophilic reagents to obtain a Variety of further compounds according to the invention:

a) The conversion of amines into carbonamides is generally carried out by reaction with car-

in the presence of bases such as alkali metals, alkali metal hydrides, alkali metal alcoholates or organolithium compounds, preferably in the presence of alkali metals, such as in the presence of bases such as ethers or their mixtures or hydrocarbons, preferably ethers such as diethyl ether, tetrahydrofuran or dioxane.

Le A 26 080

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- 54 -

For example, sodium or alkali metal hydrides wio sodium hydride or potassium hydride in a temperature range of +20 ⁰ C to + 15O ⁰ C, preferably at the boiling point of the solvent used at atmospheric pressure ·

In addition, it is possible to use the amides

Carboxylic acid halides or anhydrides, preferably with carboxylic acid chlorides in inert solvents such as ethers or hydrohalocarbons or their mixtures, preferably in ethers such as diethyl ether, tetrahydrofuran, or halogenated hydrocarbons such as methylene chloride or chloroform, optionally in the presence of bases such as alkali metal carbonates, for example sodium carbonate or potassium carbonate, or organic amines such as triethylamine or pyridine, in a temperature range from -20 ⁰ C to + 100 ⁰ C, preferably from O ⁰ C to +60 ⁰ C, at atmospheric pressure to produce.

The reaction can be illustrated by the following scheme:

Le A 26 080

- 55 -

-OCH

b) The conversion of amines into carbamates is generally carried out with carbonic acid esters, preferably with carbonic acid esters which carry a phenyl ether radical or with chlorocarbonic acid esters, in inert solvents such as ethers, hydrocarbons or halogenated hydrocarbons or mixtures thereof, preferably in ethers such as diethyl ether, tetrahydrofuran or dioxane. in a temperature range of +20 ⁰ C to +150 ⁰ C, preferably from +20 ⁰ C to +100 ⁰ C, at atmospheric pressure. The reaction can also be carried out in a two-phase system, wherein the di & aqueous phase contains a Hilfebase such as sodium or potassium carbonate or bicarbonate.

The reaction can be explained by the following scheme:

Le A 26

2 β 7 5 O

- 56 -

ClCOOC ₂ H ₅

OCH

c) Dig conversion of amines into ureas is generally carried out by reaction with isocyanates in inert solvents such as ethers, hydrocarbons or halogenated hydrocarbons or mixtures thereof, preferably in ethers such as diethyl ether or tetrahydrofuran, or in halogenated hydrocarbons such as methylene chloride or chloroform, in a temperature range of -20 ⁰ C to + 15O ⁰ C, preferably from ^{0 0} C to + 100 ⁰ C, at atmospheric pressure.

The reaction can be illustrated by the following scheme ί

N = C = O

OCH

Le A 26

- 57 -

d) The conversion of amines into sulfonamides or amino-sulfamoyl derivatives is generally carried out with sulfonyl halides or with amidosulfonyl halides, preferably with the corresponding chlorides in inert solvents such as ethers or halogenated hydrocarbons or their derivatives

Mixtures «preferred in halogenated hydrocarbons

such as methylene chloride or chloroform, optionally in the presence of bases such as alkali metal hydroxides "alkali metal carbonates, alkali metal or alcoholic or organic amines" preferably with alkali metal hydroxides

J.5 such as sodium hydroxide or potassium hydroxide, alkali metal carbonates such as sodium carbonate or potassium carbonate "or organic amines such as triethylamine or pyridine, in a temperature range from -20 ⁰ C to + 10O ⁰ C, preferably from O ⁰ C to +50 ⁰ C.

Normal pressure

CHo ^- N - CHo ^- CHo ^- NHo

H ₂ -N-CH ₂ CH ₂ -N-SO ₂ H

OCH.

SO ₂ Cl

e) Cyclic sulfonamides are generally synthesized by the reaction of intramolecular electrophiles in inert dipolar aprotic solvents. «

Le A 26 080

- 58 -

preferably in dimethylformamide "hexamethylphosphoric triamide or dimethyl sulfoxide, optionally in the presence of bases such as alkali metals, alkali metal hydrides, alkali metal amides, alkali metal or alcohol organolithium compounds, preferably in the presence of alkali metal hydrides such as sodium hydride or potassium hydride, or alkali amides such as sodium or lithium diisopropylamide, optionally in the presence of catalytic amounts of Alkali iodides, for example, sodium iodide or potassium iodide in a temperature range from -20 ⁰ C to + 100 ⁰ C, preferably from ^{0 0} C to + 50 ⁰ C, produced at atmospheric pressure It.

The reaction can be illustrated by the following scheme!

H ₂ -N-CH ₂ -CH ₂ -NHSO ₂ ' cyclization

υ γ

H ₂ -N-CH ₂ -CH ₂ -

La A 26 080

2 8 7 5 0

- 59 -

f) The conversion of the hydroxy group into carbonic acid esters is generally carried out by reaction with halogenoformic esters, preferably with chloroformates in inert solvents, such as ethers, hydrocarbons or halogenated hydrocarbons, preferably in halogenated hydrocarbons, such as methylene chloride or chloroform. or in ethers such as diethyl ether or tetrahydrofuran "optionally in the presence of bases such as alkyl hydroxides, alkali metal carbonates or organic amines", preferably in the presence of organic amines such as triethylamine, pyridine, picoline or dimathylaminopyridines in a temperature range from -20 ⁰ C to +100 ⁰ C. , preferably from O ⁰ C to room temperature at normal pressure,

The reaction can be illustrated by the following scheme:

, ^ V ^ O ^^ Ho-N-CHo-CHo-OH + ClCOOCoHn Γ T I

Γ T I

2H ₂ -N-CH ₂ -CH ₂ -OCOOC ₂ H ₅ 30

Le A 26 080

- 60 -

The oxidation of the thioether group to sulfoxides or Sulfo'.ien is generally carried out with oxidizing agents such as peroxo compounds or hydrogen peroxide itself * preferably with hydrogen peroxide, in inert solvents such as carboxylic acids and carboxylic anhydrides, preferably in acetic acid «in a temperature range from -20 ⁰ C to +100 ⁰ C, preferably from O ⁰ C to + 50 ⁰ C.

The reaction can be illustrated by the following scheme:

The amines of the general formula (XV), (XVI) and (XVII) used as starting materials are known or can be prepared by known methods [Houben-Weyl'β "Methods of Organic Chemistry" Bd XI / 1 and XI / 2).

Le A 26

2 3 7

- 61 -

As amines can be verwenclet example, according to the invention:

Ammonia "methylamine, ethylamine, fopropylamine, isopropylamine, butylamine, 4-dimethylaminobutylamine, 4-diethylaminobutylamine, 3-dimethylaminopropylarcine, 3-diethylaminopropylamine, 2-dimethylaminoethylam, n, 2-diethylaminoethylamine, 2-amino-1-ethoxycarbonylamidoethane, 3 Amino-1-ethoxycarbonylamido-propane, 4-amino-1-ethoxycarbonylamido-butane, 3-aminoquinuclidine, 2 - [(phenylaminocarbonyl) amino] ethylamine, 2-C (phenylaminocarbonyl) amino] propylamine, 4-aminomethyl -piperidine, 4- (ethoxycarbonyl) aminoethylpiperidine _> N-methylpiperazine, 4-amino-1-carboxyethyl-piperidine, N, N-dimethylpropylidene-diamine _# Ν, Ν-diethy? propylidenediamine, Ν, Ν-diethylethylidenediamine, N ₍ N-dimethylethylenediamine, N- (2-aminoethyl) ethylcarbamate, N- (2-aminoethyl) propylcarbamate,

Reactions of the compounds of the general formula (XIX), (XXII) and (XIV) are carried out with amines of the general formula (XV), (XVI) and (XVII) in inert organic solvents, if appropriate in the presence of a catalyst and optionally in the presence of water-binding agents "

Suitable inert solvents are the customary organic solvents which do not change under the reaction conditions. Mierzu preferably include alcohols such as methanol, ethanol, propanol or isopropanol, or ethoxyl such as diethyl ether, butyl methyl ether,

Le A 26 080

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Dioxane, tetrahydrofuran, GlyKoldimethylether or diethylene glycol dimethyl ether, or halocarbons such as methylene chloride, chloroform or carbon tetrachloride, or hydrocarbons wio benzene, toluene, xylene, or petroleum fractions, or amides such as dimethylformamide or hexamethylphosphoric triamide, or acetic acid "AufJerogm it is possible mixtures of said solvents to use.

As catalysts, acids are generally used, These include preferably inorganic acids such as hydrochloric acid or sulfuric acid, or organic sulfonic or carboxylic acids such as methanesulfonic acid, ethane sulfonic acid, benzenesulfonic acid, toluenesulfonic acid, acetic acid or propionic acid ·

The water formed in the reaction may optionally be in admixture with the solvent used during or after the reaction, -3, B, by distillation or by the addition of water-binding agents such as phosphorus pentoxide or preferably by

Molecular sieve, to be removed,

The reactions are generally carried out in a temperature range from ⁰ ° C to + T5c ° C, preferably from +20 ⁰ C to + 10O ⁰ C, carried out

 30

The reaction may be carried out at normal, elevated or reduced pressure (e.g., 0.5-5 bar). In general, one works at normal pressure,

Le A 26 080

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The reductions of the compounds of the formulas (XX), (XXI) and (XXIII) are carried out either by hydrogen in water or inert organic solvents such as alcohols, ethers or halogenated hydrocarbons, or mixtures thereof, with catalysts such as Raney nickel, palladium, palladium on animal charcoal or platinum; or with hydrides in inert solvents, if appropriate in the presence of a catalyst,

The reactions are preferably carried out with hydrides, such as complex borohydrides or aluminum hydrides. Particular preference is given to using sodium borohydride, lithium aluminum hydride, sodium cyanoborohydride or hydrohalic acid.

Suitable solvents here are all inert organic solvents which do not change under the reaction conditions. These preferably include alcohols such as methanol, ethanol, propanol or iscopropanol, or ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or amides such as hexamethylphosphorus. acid triamide, or dimethylformamide or acetic acid. It is also possible to use mixtures of said solvents.

As catalysts in the reduction with sodium cyanoborohydride, acids are generally used. These preferably include inorganic acids, such as, for example, hydrochloric acid or sulfuric acid, or organic carboxylic acids or sulfonic acids, such as, for example,

Le A 26 080

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wise acetic acid! Trifluoroacetic acid, trichloroacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid,

The reduction of the acid amides is carried out either by hydrogen in water or inert organic solvents in alcohols »ethers or halogenated hydrocarbons or mixtures thereof, with catalysts such as Raney nickel, palladium, palladium on animal charcoal or platinum, or with hydrides in inert solvents, if appropriate in the presence a catalyst, or with boranes, diboranes or their complex compounds,

Preferred are the reactions with hydrides, such as

complex borohydrides or aluminum hydrides,

··

leads. Particular preference is given to using sodium borohydride, lithium aluminum hydride, sodium cyanoborohydride or hydrohalic acid.

The compounds of the general formula (XIX) are known per se or can be prepared by customary methods (J. Med, Chem. 1972, 15, 8650, J, Gen. Chem. (USSR) 36, 3856 (1960).

The compounds of the formula (XXII) are known or can be prepared by customary methods (J. Med. Chem., 1972, 15, No. 8, Publs. Soc, Chim, Tr, 1958, 325, J. Am. Chem. Soc. (9, 2341, 1947).

Le A 26 080

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The halogen compounds of the general formulas (III) and (XI) are known or can be prepared by known methods [Beilstein's Handbook of Organic Chemistry 2, 197 »201, 250, 278; 3, 9, 10; 2JL, 461, 462, 463],

As halogen compounds can be used for example according to the invention!

Chloroacetonitrile, 2-chloropropionitrile, 3-chlorobutyronitrile, 3-bromopropylphthalimide, 3-chloropropylphthalimide, 2-bromoethylphthalimide, 4-bromobutylphthalimide, 4-chlorobutylphthalimide, chloroacetic acid diethylamide, chloroethyldimethylamide, methyl chloroacetate, ethyl chloroacetate, ethyl bromoacetate, bromoacetic acid methyl ester, 2-6- Bromobutyl-1,2-benzoisothiazol-3 (2H) -one-1,1-dioxide, 2-V-bromopropyl, 2-ben2-isothiazol-3 (2H) -one-1,1-dioxide,

The aldehydes of the general formulas (IV) and (XII) used as starting materials are known or can be prepared by known methods

° [Beilstein's Handbook of Organic Chemistry 1_, 594, 629, 662],

As aldehydes can be used for example according to the invention!

Acetaldehyde, propionaldehyde, butyraldehyde, benzaldehyde «

The compounds according to the invention can be used as active ingredients in medicaments

Le A 26 080

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The substances according to the invention have a particularly high affinity for cerebral 5-hydroxy-tryptamine receptors of the 5-HT ₁ type.

They have agonistic, partial agonistic or antagonistic effects on the serotonin receptor. In comparison to the structurally related known compounds, they surprisingly have a greater therapeutic range »

The high-affinity ligands for the serotonin-1 receptor described in the present invention thus represent active substances for combating diseases caused by disturbances of the serotoninergic system, especially in the involvement of receptors

Have affinity to 5-hydroxytryptamine (5-HTj type),

Marked are. They are therefore suitable for the treatment of central nervous system disorders such as anxiety, tension and depression, CNS-related sexual dysfunction and sleep and feeding disorders, Furthermore, it is suitable for the elimination of cognitive deficits, to improve learning and memory and to treat Alzheimer's See disease ·

Furthermore, these active substances are also suitable for modulating the cardiovascular system, they also intervene in the regulation of cerebral blood flow and thus represent effective means of combating migraine.

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They are also suitable for the prophylaxis and control of the consequences of cerebral infarct events (apoplexiacerebri) such as stroke of cerebral ischaemias. Likewise, the compounds according to the invention can be used for controlling pain conditions. They are also suitable for combating diseases of the intestinal tract which are characterized by disorders of the serotoninergic system as well as by disturbances in the carbohydrate balance.

The new agents can in a known manner in the

conventional formulations such as tablets, dragees, pills, granules, aerosols, syrups, emulsions, suspensions, and solutions using inert non-toxic pharmaceutically suitable carriers or solvents. In this case, the therapeutically active compound should in each case be at a concentration of approximately 0, 5 to 90% by weight of the total mixture may be present "d, h" in amounts "sufficient" to achieve the stated dosage margin,

For example, the formulations are prepared by stretching the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants. in the case of using water as the diluent, organic solvents may optionally be used as the suspending agent.

Examples of adjuvants include: water "non-toxic organic solvents" such as

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Paraffins (ζ, B, petroleum traps), vegetable oils (e.g., peanut / sesame oil), alcohols (e.g., ethyl alcohol, glycerol), carriers such as e.g. ground natural minerals (eg kaolins, clays, telkum, chalk), ground synthetic minerals (eg highly disperse silicic acid, silicates), sugars (eg pipe, milk and dextrose), emulsifying agents (eg polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers) , Dispersants (eg lignin, liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (eg magnesium stearate, talc, stearic acid and sodium sulfate).

The application is carried out in a customary manner, preferably orally or parenterally, in particular perlingually or intravenously. In the case of oral administration, tablets may, of course, besides the abovementioned excipients, also contain additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives, such as starch, preferably potato starch, gelatine and the like. Further, lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used for tableting. In the case of aqueous suspensions, the active ingredients may be added to the abovementioned excipients with various flavor enhancers or dyes.

For the case of parenteral administration, solutions of the active substances may be prepared using appropriate

liquid carrier materials are used. 35

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In general, it has proved advantageous on intravenous administration to administer amounts of about O ₁ OOl to 1 mg / kg, preferably to administer ßtwu 0.01 to 0.5 mg / kg of body weight to achieve effective results, and on oral administration the Dosage about 0.01 to 20 mg / kg, preferably 0.1 to 10 mg / kg body weight.

Nevertheless, it may be necessary, depending on the body weight or the type of application route, the individual behavior towards the drug, the nature of its formulation and the time or interval, to dodge the said amounts a ^k administration is _t Thus, it may be sufficient in some cases to manage with less than the abovementioned minimum amount, while in other cases the upper limit mentioned must be exceeded. In the case of the application of larger quantities, it may be advisable to distribute these in several single doses throughout the day.

embodiment

The invention is explained in more detail below with reference to some examples.

- 70 -

Preparation Examples

Unless otherwise stated, the Rz values listed in each case were determined by thin-layer chromatography on silica gel (aluminum foil, Kieselgel 60 F 254). The visualization of the substance stains was done by viewing under UV light and / or by spraying with 1% potassium permanganate solution.

Flash chromatography was performed on silica gel 60, 0.040-0.064 mm (see Still et al., O. Org. Chem. 43, 2923, 1978; for simpler separation problems, see Aldrichimiea Acta 1J3, 25, 1985). Solvent gradient elution means: Starting with the pure non-polar solvent mixture component, the polar solvent component is added to an increasing extent until the desired product is eluted (TLC control).

For all products, the solvent was distilled off last at about 0.1 Torr. Salts were stored at this pressure overnight over potassium hydroxide and / or phosphorus pentoxide.

- 71 -

Starting compounds and preparation examples

^]

example 1

2-Aminomethyl-5-methoxy-crenomane 10

OMe

H ₂ NH ₂ 15

To the boiling suspension of 0.30 g (8.2 mmol) of lithium aluminum hydride in 5 ml of THF was added dropwise 0.85 g (4.1 mmol) of 2-carbonamido-5-methoxychroman, in 5 ml of THF, after 3 h Heating to reflux was

cooled and treated successively with 0.3 ml of water and 0.5 ml of 20 % sodium hydroxide solution. Filtration over kieselguhr and concentration gives 0.62 g of crude product, which was purified by flash chromatography (toluene-ethyl acetate, then ethanol gradients).

Yield: 0.52 g (66 X). Rf: (toluene / methanol 4: 1) = 0.16

IR (CHCl _3): 3389, 3009, 2947, 1607, 1593, 1470,

Le A 26

- 72 -

Example 2 5

2- (N-propyl) aminonethy1-chromene

The compound was prepared analogously to the instructions of Example 1.

IR (CHCl _3)! 3320 (wide), 3010, 2965, 2879, 1607,

1584, 1490, 1457, 1235.

Example 3

2- (N-propyl) aminomethyl-5-methoxy-chroman

OMe

The compound was analogous to the requirement of

Example 1 prepared. 30

¹ H-NMR (CDCl ₃ )! 0.85 (t; 3H), 1.55 (quint. J 3H), 1.7

(m; IH), 2.0 (m; IH, 2.5-3.0 UM 6H), 3.7 (sj 3H), 4.1 (m, IH), 6.4

(dj IH), 6.5 (dj IH), 7.0 (t, IH). 35

Le A 26

287

73

Example 4

2-aminomethyl-benzo (h) chroman-hydrachlor id

× HCl

The compound was prepared analogously to Example 24 from 2-carbonamido-benzo (h) chroman.

Example 5

1-Methoxy-5,6-dihydro-7-nitromethyl-1-naphtha

44.1 g of 8-methoxy-tetralone-2 (0.25 mol) were dissolved in

402 ml of nitromethane (7.50 mol) and 2.5 ml of ethylenediamine

Stirred for 3 hours under argon at 70 ^° C., after the reaction

Le A 26

- 74 -

cooled to room temperature , a yellow crystals is filtered off with suction. "From the solution, the nitromethane is distilled off under vacuum. The residue is dissolved in 50 ml of toluene. The solvent is distilled off again under vacuum to remove nitromethane residues. Then the residue is redissolved in 200 ml of toluene. An insoluble portion is filtered off and the solution is concentrated to 50 ml Concentrated solution chromatographed on 500 g of silica gel with toluene, After concentration of the main fraction to obtain the final product as a yellow oil. 15

Yield · 40.4 g - 73% of theory Rf = 0.45

Example 6 20

2-Aminomethyl-8-methoxytetralin

OCH ₃

14.9 g of the compound from Example 5 (68 mmol) of methanol are hydrogenated with elementary hydrogen in 300 ml, as a catalyzer is added 3.4 g of palladium / activated carbon used "The temperature is limited by slight cooling to 25-30 ⁰ C.

Le A 26 080

2ö7 5 0

- 75 -

The catalyst is then filtered off with suction and the reaction solution is largely concentrated under vacuum.

Then 300 ml of toluene are added and distilled off again under vacuum to remove residual methanol. "The residue is redissolved in 300 ml of toluene" and the solution is washed with 5 Xiger Kaiiumcarbonatlösung and * 0 water, the organic phase is dried over sodium sulfate the solvent is distilled off again under vacuum.

The crude product is dissolved in 25 ml of toluene and the solution applied to 60 g of silica gel 60 (Fa ₁ Merck). First, washed with toluene and then with methanol / triethylene ¹ nin 95: 5 eluting the final product. After concentration of the methanolic solution is obtained

pale yellow oil

 20

Yield! 9.5 g = 73 X theory Rf: 0.28! Silica gel; Methanol / triethylamine 95: 5)

Example 7 25

2- (N-benzyl) aminomethyl-8-methoxytetralin

OCH ₃

13.4 g of 2-amiomethyl-8-methoxytetralin (70 mmol) are dissolved in 420 ml of methanol. Then, 3.0 ml of 35

Le A 26 080

- 76 -

Acetic acid (52.5 mmol) was added dropwise. After 5 minutes, 5.3 g of sodium cyanoborohydride (84 ml) are added. The reaction solution is heated to 60 ⁰ C and then a solution is added dropwise to 7.4 g of benzaldehyde (70 mmol) in 74 ml of methanol within 30 min, then the mixture is refluxed after 3h,

After cooling, the solvent is distilled off under reduced pressure and the residue is dissolved in 420 ml of dichloromethane and 210 ml of water. The organic phase is washed again with water and dried over sodium sulfate, the solvent is distilled off again under reduced pressure and the residue is stirred with 700 ml of diethyl ether and 140 ml of 5N sodium hydroxide solution. The organic phase is washed neutral with water and dried over sodium sulfate. The solvent is distilled off under vacuum,

The residue is chromatographed on 200 g of silica gel 60 (Merck). The eluent used is diisopropyl ether. The end product is obtained as a colorless, viscous oil,

Yield: 11.7 g = 59 % of theory Rf = 0.25 (silica gel, toluene / methanol 95: 5) 30

Le A 26 080

- 77 -

Example 8

2- [N-benzyl-N-2'-cyanoethyl] aminomethyl-8-methoxytetralin

OCH,

Under argon, 7 g of the compound from Example 7 (41.6 mmol) and 0.15 g of copper acetate in 13.7 ml of acrylonitrile (208 mmol) under reflux for 2h cooked. 11 The batch was then diluted with 7 ml of acrylonitrile. After the batch had slowly cooled to room temperature, it was cooled to 10 ^° C. after ² hours. The crystals were filtered off and dried at 40 ° C under vacuum.

Yield: 10.6 g = 76 Y. of theory Rf = 0.77 (silica gel, toluene / methanol 95: 5)

Mp = 111-112 ⁰ C.

Example 9

2-CN-benzyl-N-3-aminopropyl] aminomethyl-8-methoxytetralin

OCH,

Le A 26

28 7 50

- 78 -

Under argon, 4.8 g of lithium aluminum hydride (125.6 mmol) are suspended in 315 ml of absolute diethyl ether. Then, within 20 min. 10.5 g of the compound from Example 8 (31.4 mmol) added in portions. The temperature is thereby limited by gentle cooling to 20-25 ⁰ C. Thereafter, the mixture is stirred for 3 h at room temperature.

Subsequently, a mixture of 260 ml of tetrahydrofuran and 15 ml of water is added dropwise. The approach is after 30 min. stirred and the precipitate sucked off afterwards,

The solution is concentrated to 250 ml and 2.5 l

Water stirred. The mixture is extracted with toluene and the organic phase is washed neutral with water and dried over sodium sulfate. After the solvent is distilled off under vacuum, the final product remains as a pale yellow oil.

Yield: 10.1 g = 95 Y, theory Rf = 0.32 (Kieselgelj methanol / toluene 95: 5)

Le A 26 080

- 79 -

Example 10 and Example

2- {N- [4- (1i-Dioxo-G-oxo-Z, 3-dihydro-benzisothiazol-2-yl) -butyl] -aminomethyl} -8-methoxy-tetralin

OCH

(10)

2- {N-Di [4- (1,1-Dioxo-3-oxo-2,3-dihydro-benzisothiazol-2-yl) -benzyl-daminomethyl} -8-methoxytetralin

(11)

OCH

0.95 g of 2-aminomethyl-8-methoxytetralin (5 mmol), 0.70 ml of triethylamine (5 mmol) and 1.59 g of 2- (4-bromobutyl) -1,2-benzimidazol-3 (2H) -one -i, 1-dioxide (5 mmol)

Le A 26

287

- 80 -

are stirred in 19 ml of dimethylformamide for 24 h at 40 ⁰ C. Subsequently, the reaction solution is stirred into a mixture of 190 ml of 5% sodium chloride solution, 60 ml of toluene and 5 ml of 1N hydrochloric acid. After the organic phase was separated, the aqueous phase is stirred with the resinous precipitated as the hydrochloride end product with 60 ml of toluene and 7 ml of triethylamine (50 mmol). The organic phase is separated again, washed neutral with water and dried over sodium sulfate. The solvent is distilled off under vacuum. The residue is chromatographed on silica gel 60. Toluene / methanol 85:15 serves as the eluent. The main fractions contain the two final products as yellow, tough die.

Both bases can be precipitated from toluene solution with ethereal hydrogen chloride solution as hydrochloride.

Example 10 Yield: 0.59 g = 28 % of theory Rf: 0.30 silica gel; (Toluene / methanol 85:15) Example 11 Yield: 0.50 g = 15 % of theory Rf: 0.73 silica gel; (Toluene / methanol 85:15)

- 81 -

Example 12 5

2- {N-methyl-NC4 (l, l-dioxido-3-oxo-2,3-dihydro-benzisothiazol-2-yl) butyl] aminomethyl} -8-methoxytetralin

2.9 g each of 2-aminomethyl-8-methoxytetralin (15 mmol), 2.1 ml of triethylamine (15 mmol) and 4.8 g of 2- (4-bromobutyl) -1,2-benzisothiazol-3 <2H) -one 1,1,1-dioxide (15 mmol) are stirred in 58 ml of dimethylformamide for 50 h at 40 ° C. Then a solution of 1.4 g of methyl iodide (10 mmol) and

-r 3.2 ml of dimethylformamide was added dropwise and stirred for an additional 18 h at 40 ⁰ C.

Subsequently, the reaction solution is stirred into a mixture of 600 ml of water, 3.8 g of potassium carbonate (27.5 mmol) and 300 ml of toluene. The organic phase is washed neutral with water and dried over sodium sulfate. The solvent is distilled off under vacuum.

_3Q The residue is dissolved in a diisopropyl ether-toluene mixture (80:20) and prepurified by filtration over 20 g of silica gel. From the residue obtained after distilling off the solvent, the end product is isolated by column chromatography on silica gel 60 (Merck). The mobile phase used is ethyl acetate.

Le A 26 080

- 82 -

From Loluolischer solution leaves itself, with ethereal Chlorwasserertoff solution the Hydrochloric! precipitate as a solid,

Yield! 0.85 = 12.9 Y, the theory

R f = 0.25 (silica gel, ethyl acetate or toluene / methanol 95: 5)

Example 13 and Example

2- {N-t4- (l, l-dioxido-2H-naphth [l, 8-cd] isothiazol-2-yl) butyl] aminomethyl} -8-methoxytetralin

OCH

(13)

2- {N-di [4- (l, l-dioxido-2H-naphth [l, 8-cd] isothiazol-2-yl) butyl] aminomethyl} -8-methoxytetralin

(14)

OCH

Le A 26

- 83 -

1.6 g of 2-amino-8-methoxytetra, l in (8.4 mmol), 1.16 ml of triethylamine ^ö (8.4 mmol) and 1.59 g of 2- (4-bromobutyl) -2H-1 naphthC , 8-i: d] isothiazole-1,1-dioxide are stirred in 32 ml of dimethylformamide for 48 h at 40 ° C. Then the reaction solution is poured into a mixture of 320 ml of 5% sodium chloride solution, 100 ml of toluene, 8.4 ml of IN Hydrochloric acid and diatomaceous earth stirred in. The diatomaceous earth with the end product hydrochloride solidified therein is filtered off with suction and introduced into a mixture of 300 ml of water and 100 ml of toluene. By dropwise addition of 9 ml of 1N sodium hydroxide solution, the end product is transferred to the organic phase.

After filtration, the organic phase is separated, washed neutral with water and dried over sodium sulfate. After the solvent

was distilled off under vacuum, the residue is separated by a column chromatography on silica gel 60 (Fa, Merck) to the two final products. The eluent used is ethyl acetate.

Both bases can be precipitated from ethereal solution with ethereal hydrogen chloride solution as the hydrochloride.

Example 13

Yield: 1.51 g = 39.8 x /. Theory Rf = 0.28

Beispiel 14

Yield! 0.63 g = 10.6% of theory Rf = 0.60

Le A 26 080

- 84 -

Example 15 5

2- {N- [4- (1, l-dioxido-3-oxo-4-phenyl-3,4-dihydro-2H-l, 2,4-benzothiadiazin-2-yl) butyl] aminomethyl} 8-methoxytetralin

0.95 g of 2-aminomethyl-8-methoxytetralin (5 mmol), 0.70 ml of triethylamine (5 mmol) and 2.05 g of 2- (4-bromobutyl) -3-OXO-4-phenyl-3,4- dihydro-2H-l, 2,4-benzothiadiazine-l, l-dioxide are stirred in 19 ml of dimethylformamide for 24 h at 40 ⁰ C, then the reaction solution in a mixture bus 190 ml of 5% sodium chloride solution, 60 ml of toluene and 5 ml Stirred in hydrochloric acid, after the organic phase separated

² ^ was the aqueous phase is stirred with the resinous hydrochloric acid end product with 60 ml of toluene and 7 ml of triethylamine (50 mmol), the organic phase is separated again, washed neutral with water and dried over sodium sulfate, the solvent is distilled off under vacuum · The residue is chromatographed on Kieeelgel 60 (Fa, Merck), toluene / methanol 85:15 serves as the eluent,

From toiuolischer solution can be with ethereal

Hydrogen chloride solution to drop the hydrochloride as a solid,

Le A 2 6,080

- 85 -

Yield! 0.83 g = 31.9 Y. of theory Rf = 0.28 (silica gel, toluene / methanol 85:15). Mp: 148 ⁰ C

Example 16

2- {N-Benzyl-N- [3- (4-fluorophenylsulphonylamido) ρropyl] aminomethyl} 8-niethoxytetralin

OCH ₃

0, ^ 5 g (2.8 mmol) of the compound of Example 9 are dissolved in 19 ml Di chlormeU -in, After addition of 0.39 g (2.8 mmol) of finely ground potassium carbonate, a solution of 0.60 g 4-i ^r f luorbenzolsul onsäurechlor id and 9.5 ml of dichloromethane at 15-20 ⁰ C was added dropwise, then the reaction solution is stirred at room temperature for 18h,

Thereafter, 15 ml of water are added, the organic phase is washed neutral with water, dried over sodium sulfate and concentrated under vacuum. The residue is dissolved in 50 ml of diisopropyl ether and the solution is filtered. The solution is then concentrated again to about 10 ml and chromatographed on 25 g Kijselgel. As eluent diisopropyl ether is used *. The final product is obtained as a light brown viscous oil.

Le A 26 080

- 86 -

Yield! 1.08 g = 78 Y, theory Rf = 0.58 (silica gel, toluene / methanol 95: 5)

Rf = 0.23 (silica gel; diisopropyl ether)

Example 17 10

2- {Ν- [3- (4-fluorophenylsulfonylamido) ρropy1] aminomethyl} 8-methoxytetralin

H H 15

OCH

1.0 g of the compound from Example 16 (2 mmol) are hydrogenated in 50 ml of methanol and 2.4 ml of methanolic hydrogen chloride solution (0.9 mmol / ml) with elemental hydrogen, as a catalyst, 0.1 g of palladium / carbon activated .

The catalyst is then filtered off and the solution is concentrated under reduced pressure to 10 ml. The solution is then stirred into a mixture of 100 ml of water, 50 ml of dichloromethane and 2.5 ml of 1N sodium hydroxide solution. The organic phase is washed neutral with water, dried on sodium sulfate and concentrated in vacuo.

The residue is applied to 20 g of silica gel, eluting first with diisopropyl ether starting product residues, then with methanol, the final product. After the ^{3 '} methanol has been distilled off, the residue is passed through

Le A 26 080

- 87 -

Stir with di isopropyl ether crystalline. The white crystals are filtered off with suction and dried at 50 ° C. under reduced pressure,

Yield: 0.47 g = 58 X of theory R f = 0.25 (silica gel, toluene / methanol 85:15) mp! 111 ° C / 112-114 ° C

Example 18

2- {N-Benzyl-N- [3- (ethoxycarbonylamido) propyl] aminomethyl} 8-methoxytetralin

OC, H

2 "5

OCH ₃

The compound is obtained analogously to the procedure for the compound 16 from 1.80 g of the compound from Example 9 (5.3 mmol) and 0.55 ml of ethyl chloroformate (5.8 mmol) as a viscous oil.

Yield: 2.00 g = 92 V, of the theory R f = 0.50 (silica gel toluene / methanol 95: 5) R f = 0.30 (silica gel; diisopropyl ether)

Example! 9

2- {N- [3- (ethoxycarbonylamido) propylDaminomethyl} 8-methoxytetralin

Le A 26 080

- 88 -

OCH

H,

OC ₂ H ₅

χ HCl

The compound is obtained analogously to the procedure for compound 17 from 1.80 g of the compound from Example 18, 90 ml of methanol, 7.3 ml of methanolic hydrogen chloride solution and 0.22 g of palladium / activated carbon after hydrogenation as a viscous oil.

The base was dissolved in ether and filtered off an insoluble fraction, With ethereal hydrogen chloride solution from the solution, the hydrochloride is precipitated. The white dye is filtered off and dried at 40 ⁰ C in a vacuum.

Yield: 0.60 ^g: 38% of theory Rf = 0.40 (silica gel; toluene / methanol 70:30) Rf = 0.20 (base) mp: 188 ° / 191-193 ⁰ C.

Example 20

2- {N- [4- (1,1-dioxo-3-oxo-2,3-dihydro-benzisothiazol-2-yl) -butyl-N-propyl] -aminomethyl} -chroman

Le A 26 080

- 89 -

The mixture of 4.90 g (24 mmol) of 3,4-dihydro-2- (N-propyl) aminomethyl-2H-chromene, 8.60 g (27 mmol) of 2- (4-bromobutyl) -l, 2- Benzisothiazole-3 (2H) -one-l, l-dioxide, 6.6 g (48 mmol) of powdered potassium carbonate and 0.1 g Natriuir.jodid in 100 ml of anhydrous dimethylformamide was stirred at 60-70 ⁰ C for 12 h.

After filtration and concentration at ca, 2 Torr was purified by flash chromatography (toluene-ethyl acetate gradient, silica gel). In this way, 4.5 g (44 yt) of product was recovered as a viscous oil.

Rf: (toluene / methanol 4: 1) 0.47

IR (CHCl _3): 3011, 2958, 2874, 1733, 1598, 1584,

1489. The hydrochloride was recovered by treatment with ethereal hydrochloric acid in ether as a colorless, amorphous solid.

¹ H-NMR (CD ₃ OD): 1.0 (t, 3H), 1.6-2.2 (m, 8H), 2.7-3.0

(m; 2H), 5.2-3.6 (m, including solvent signal, CHD ₂ OD), 3.9 (mj 2H), 4.5 (m; IH), 6.75-7.1 (m; 4H), 7.8-8.2 (m; 4H), 7.9 (s; -OH, -NH-)

Le A 26

- 90 -

Example 21 5

3- {N- [4- (1,1-dioxo-3-oxo-2i3-dihydro-benzisothiazo I-2-yl) -butyl] -amino-methyl} -chroman

10 35

ocr

The reaction was carried out analogously to the procedure of Example 20 from 3-aminomethylchroman.

Rf: (toluene / methanol 4: 1): 0.33,

The hydrochloride is obtained by precipitation with ethereal hydrochloric acid,

Amorphous, hygroscopic solid,

¹ H-NHR (hydrochloride; CD ₃ OD):

1.8-2.0 (m; NH). 2.4 (m; IH), 2.65 ("dd", IH) 2.9-3.2 (m; 5H), 3.75 (t; 2H), 4.0 (m; IH), 4.25 (m; IH), 6.7-7.1 (m; 4H), 7.9-8.1 (m; 4H)

30

Le A 26 080

- 91 -

example

3- {N, N-Di [1, 1-dioxo-3-oxo-2,3-dihydro-benzisothiazol-2-yl) -butyl] -aminomethyl} -chroman

In addition to Example 21, compound 22 was formed in the reaction of 3-aminomethylchroman with 4-bromobutylsaccharin.

Rf: (toluene / ethyl acetate 1: 1): 0.58

The hydrochloride was recovered by treatment with ethereal hydrochloric acid as an amorphous solid:

¹ H-NMR (hydrochloride, CD3OD): 1.8-2.0 (m, 8H), 2.5-2.8 (m, 2H), 2.9-3.4 (m, contains signals of the LM ), 3.75 (m, 4H), 4.0 (m, IH), 4.25 (m, IH), 6.7-7.1 (m, 4H). 7.9-8.1 (m; 8H) and signals of ca, 8 % diethyl ether

Le A 26

- 92 -

Bejjpjel

2- [N-2- (4-fluorophenylsulphonamido) ethyllcarbonamido-2H-chroman

The reaction of 2-chromanecarbonyl chloride and 2- (4-fluorophenylsulfonamido) ethylamine in the presence of sodium bicarbonate in ethor / dioxane gives Example 23,

Rf: (toluene / ethyl acetate 1: 1): 0.35 example

2-CN- (4-Fluorphenylsulfonylamido) ethylJaminomethylchroman hydrochloride

χ HCl

Le λ 26

- 93 -

The solution of 4 * 50 g (11.9 mmol) of the compound from Example 23 in 100 ml of absolute THF was added at ⁰ ° C. to 16.6 ml (16.6 mmol) of an IM solution of BHg in THF.

Then, 50 ml of THF were added dropwise · After stirring for 2h at room temperature was cooled to 0 ° and treated with 2 ml of concentrated hydrochloric acid.

The precipitate was filtered off with suction after 30 minutes and washed with THF and η-hexane. 3.35 g (70 X) of product were thus obtained as colorless crystals.

Melting point! 212-214 ⁰ C

MSi 364, 231, 176 (100 * /.), 95

IH-NMR (CD ₃ OD)! 1.75 (m; IH), 2.1 (m; IH), 2.7-3.0

(m; 2H), 3.1-3.5 (m; contains signal of the solvent), 4.4 (m; IH), 6.8 (mj 2H), 7.1 (m; 2H), 7, 2-7.4 (m;

2H), 8.0 (m, 2H). 25

Example 25

2-Aminomethyl-7,8,9,10-tetrahydro-benzo (h) chroman

hydrochloride 30

j ^ Y ^ Ck ^ X ^ NHY

χ HCl

Le A 26 080

2 δ 7 5 O

- 94 -

The preparation is carried out from the corresponding carbonamide with borane-THF complexes analogous to the working procedure of Example 24,

¹ H-NMR (CD ₃ OD)! 1.4-1.9 (m; 5H), 2.0-2.1 (mj IH),

2.6-3.0 (m; 6H), 3.1-3.4 (m;

H; also CD ₂ HOD), 4.2-4.3 (m; IH), 4.9

(s; H ₂ O, -NH ₂ ), 6.6 (d; IH), 6.8 (d; IH).

With sodium bicarbonate / ethyl acetate extraction, the free base was obtained.

Rf! (Dichloromethane / methanol 10T): 0.27 Example 26

2- {Κ- [4- (1, l-dioxido-3-oxo-2,4-dihydro-benzisothiazol-2-yl) butyl] aminomethyl) -7,8,9,10-tetrahydro-benzo ( H) chroman

N SO ₂

The compound of Example 25 was prepared analogously to the procedure of Example 20.

Le A 2 6,080

2 87 50Q

- 95 -

MS: 454, 424, 267, 200 5 Rf: (CH ₂ Cl ₂ ZCH ₃ OH 10: 1), 0.58

The corresponding hydrochloride is amorphous:

10

2025

H-NMR (CD ₃ OD)

: 1.6-2.1 (m; 10H), 2.5-3.0 <m; 5H), 3.1-3.4 (m, several H, including CD ₂ HOD), 3.9 (t; 2H), 4.3 (m; IH), 4.9 (g; H ₂ O, NH), 6.6 (d; IH), 6.75 (d; IH). 7.9-8.1 (m; 4H).

(d; IH), 7.9-8.1 (m; 4H).

15 example

2- (N, N-di {[4- (l, l-dioxido-3-oxo-2,3-dihydro-benzisothiazol-2-yl) butyl} aminomethyl) -7,8,9,10-tetrahydrobenzo ( h) chroman

30 The connection arises in the presentation of Example 26.

Le A 26

- 96 -

Rf: (CH ₂ Cl ₂ / CH ₃ OH 10: J) 0.86 5

The amorphous Hydrochloric! the compound was precipitated with ethereal hydrochloric acid in ether.

¹ H-NMR (CD ₃ OD): 1.4-2.1 (m; 14H), 2.5-3.0 (m; 7H) ₁ 3.2-3.6 (m; several H, below

CD ₂ KOD), 3.9 (m, 4H), 4.5 (mj IH), 4.9 (s, H ₂ O, NH), 6.5 (dj IH), 6.75 (dj IH ), 7.9-8.1 (m, 8H).

Example 28

2- (N- [4- (1,1-dioxo-3-oxo-2,3-dihydro-benzisothiazol-2-yl) -butyl] -aminomethyl} chroman

^ ^

The compound is prepared analogously to the procedure of Example 20 from 2-aminomethyl-3,4-dihydro-2H-chromene

 30

The corresponding hydrochloride has a melting point of 188 ° C-195 ° C.

Rf: (toluene / EBBigGBter 1: 1) = 0.37 35

Le A 26 080

97 -

Example 29

2- {N- [4- (1-1-dioxo-3-oxo-2,3-dihydro-benzisothiazol-2-yl) -butyl] -aminomethyl} -8-methoxy-chroman

OMe

The connection is analogous to the working instructions of Example 20 from 2-aminomethyl-3,4-dihydro-8-methoxy

2H-chromen represented ·

Rf! (Toluene / methanol 4! L)! 0.33

The corresponding Hydrochloric! has a melting point of 173 ° -178 ⁰ C,

Example 30

2- {N- [4- (1,1-dioxo-3-oxo-2 ₎ 3-dihydro-benzisothiazol-2-yl) -butyl] -aminomethyl} -5-methoxy-chroinane

OMe

Le A 26 080

- 98 -

The connection is analogous to the working instructions of Example 20 from 2-aminomethyl-3,4-dihydro-5-methoxy

2H-chromen presented «

Rf} (toluene / methanol 4: 1) 0.3 The hydrochloride has a melting point of 253-

257 ⁰ C,

Example.

2- {N- [4- (1,1-dioxo-3-oxo-2,3-dihydro-benzisothi-enol-2-yl) -butyl-N-ρropy1] -aminomethyl} -5-methoxy-chroman

OMe

The compound is prepared from 3,4-dihydro-2- (N-propyl) aminomethyl-5-methoxy-2H-chromene analogously to the working preface of Example 20.

RfS (toluene / methanol 4: 1), 0.33 MS! 472, 309, The corresponding hydrochloride shows the following shifts:

Le A 26

- 99 -

¹ H-NMR (CD ₃ OD): 1.0 v'tj 3H)., 1.6-2.2 (m; 8H), 2.5-2.9

(mj 2H), 3.1-3.5 (mj contains signal from CD ₂ HOD), 3.7 (a; 3H), 3.9 (tj 2H), 4.4 (m; IH), 4, 9 (b; H ₂ O, -NH), 6.5 (m; 2H), 7.0 (mi IH), 7.8-8.1 (mj 4H).

example

2- {N- [4 (1,1-dioxo-3-oxo-2,3-dihydro-benzisothiazol-2-yl) bu '.. yl laminomethyl} benzo (h) chroman

The compound is prepared analogously to the procedure of Example 20 from 2-aminomethyl-3,4-dihydro-2H-benzo (h) chromene hydrochloride.

Mp: 97-102 ⁰ C

example

2- {N- [4- (l, l-dioxido-2H-naphth [l, 8-cd] isothiazol-2-yl) butyl] aminomethyl} chroman

Le A 26

- 100 -

The compound is prepared according to the procedure of Example 20 from 2-aminomethyl-3,4-dihydro-2H-chromene and 2- (4-bromobutyl) -2H-naphtho [1,8-cd] isothiazol-1, ldioxid ( accessible from 2H-naphtho [1,8-cd] isothiazole-1,1-dioxide and 1,4-dibromobutane with base).

10 Rf; (Toluene / ethyl acetate 1: 1) = 0.41

The corresponding hydrochloride is amorphous,

¹ H-NMR (CD ₃ OD)

1.7 (m; IH), 2.0 (m; 5H), 2.6-2.9 (m; 2H), 3.2-3.5 (m, including signals of the solvent), 3.9 (m; 2H), 4.5 (m; XH), 6.65 (ddj IH), 6.75 (ddd; IH), 6.9-7.1 (m; 2H), 7.5-7 , 6 (mj 2H), 7.8 (dd; IH), 8.05 (d; IH), 8.2 (d; IH),

20 example

2- {N-Benzyl-N- [3- (N-benzyl-4-fluorophenyl-sulfonamido) -propyl] -aminomethyl} -8-methoxy-tetralin

OCH

Le A 26

287 50

- 101 -

79 mg of sodium hydride (3.3 mmol) are suspended under argon in 15 ml of dry dimethylformamide, an-Echließend is within 30 min, a solution of 1.49 g of the compound from Example 16 (3 mmol) in 15 ml of dry dimethylformamide at 20 -25 ⁰ C are added dropwise, Then, the mixture is heated to 30 ° C lh, then is added dropwise within 15 min a solution of 0.56 g of benzyl bromide (3 mmol) in 15 ml of dry dimethylformamide, to complete the reaction, the mixture is stirred at room temperature for another 18 h,

For working up, the mixture is stirred for 5 Xiger sodium chloride solution and 150 ml of toluene in a mixture of 450 ml The orga ^r before phase is washed neutral with water, distilled over Natr .usulfat ge Rocknet and the solvent,

The crude product is chromatographed on 90 g of silica gel 60 with diisopropyl ether, giving a colorless resin,

Yield: 1.26 g = 76 Y. of theory Rf = 0.52 (silica gel, diisopropyl ether) Example 35

2- {N- [3- (N-benzyl-4-fluorophenylsulphonamido) propyl] aminomethyl} 8-methoxytetralin

OCH ₃

Le A 26 080

- 102 -

The compound is analogous to the procedure for Example 17 from 1.15 g of the compound from Example (2 1 mmol), 55 ml of methanol, 5.9 ml of methanolic hydrogen chloride solution (3.2 mmol) and 0.11 g of palladium / carbon obtained after hydrogenation as a viscous oil.

The base does not crystallize here from diisopropyl ether and was therefore precipitated by dropwise addition of ethereal hydrogen chloride solution as the hydrachloride. The precipitate was filtered off and dried at 50 ° C / 0, lmb, giving a white F'eststoff,

Yield: 0.70 g = 70 X of theory

Mp: 130 ° C / 157-158 ° C

Rf = 0.40 (silica gel, toluene / methanol 85:15) example

2- {N-Benzyl-N- [3- (N-methyl-4-fluorophenylsulfonamido) propyl] aminomethyl} 8-methoxytetralin

OCH.

The compound is prepared analogously to the procedure for Example 34 from 3.97 g of the compound from Example (8 mmol), 211 mg Natriumh / drid (8.8 mmol) and 1.14 g of methyl iodide (8 mmol) in dry dimethylformamide.

Le A 26

- 103 -

The crude product is concentrated on 250 g of silica gel 60 with diisobutyl

propylated, giving a colorless

Resin,

Yield: 4.03 g = 99 % of theory Rf = 0.47 (silica gel, diisopropyl ether) Example 37

2- {N- [2- (2-carbonamido-N- (8-methoxytetralin-2-ylmethyl) phenylsulfonamido) ethyl] aminomethyl} 8-methoxytetralin

N ^ SO

OCH

× HCl

1.90 g of the compound of Example 6 (10 mmol), 1.00 g of triethylamine (10 mmol) and 2.90 g of 2- (2-bromobutyl) -1,2-benzisothiazol-3 (2H) -one-1 , 1-dioxide are stirred in 38 ml of dimethylformamide for 24 h at 40 ° C,

For workup, the mixture is stirred into a mixture of 380 ml of 5 Xiger sodium chloride solution, 130 ml of toluene and 10 ml of hydrochloric acid, wherein the final product precipitates as a hydrochloric resin. The liquid phases are poured off and the resin is mixed with 400 ml of 5 × sodium chloride solution and 130 ml of toluene, then carefully added dropwise with stirring in sodium hydroxide solution, wherein the pH at max, 11 is maintained. The organic phase is then washed neutral with water and dried over sodium sulfate, then the solvent is at 30 ⁰ C and 40 mb abdest i ated 11,

Le A 26 080

- iO4 -

The crude product obtained is chromatographed on 90 g of silica gel 60 with ethyl acetate. A yellow resin is obtained.

The base let fell from toluene solution by dropwise addition of ethereal hydrogen chloride solution as the hydrochloride.

Yield: 1.51 g = 51 % of theory Rf = 0.32 (silica gel, toluene / methanol 5.15)

Rf = 0.15 (ethyl acetate) 15

example

2- {N- [3- (N-methyl-4-fluorophenylsulphonamido) propyl] -

aminomethyl} 8-methoxytetralin 20

OCH ₃

The connection is analogous to the working instructions for

Example 17 from 3.90 g of the compound from Example (7.6 nunol), 195 ml of methanol, 2 ml of methanolic hydrogen chloride solution (11.4 mmol) and 0.38 g of palladium / charcoal obtained after hydrogenation as a viscous oil.

The base crystallizes from diisopropyl ether. A white solid is obtained.

AuJeuteJ 2,15 g - 67% of theory; Fp.5 66-67 ⁰ C Rf = 0.23 (Kiefceigel; toluene / methanol 85:15)

Le A 26

- 105 -

Example 39

2- {N-benzyl-N- [3- (phenylcarbonamido) propyl] aminomethyl} 8-methoxytetralin

OCH ₃

The compound was prepared analogously to the procedure for Example 16 from 3.39 g animal compound from Example 9 g (10 nunol), 1.38 g of potassium carbonate (10 mmol) and 1 «41 g of benzoyl chloride (10 nunol) in dichloromethane

The crude product was chromatographierLι on 90 g of silica gel 60 with diisopropyl ether (for application in a little toluene dissolved) The reino product then crystallized from the main fraction from · The crystals were filtered off with suction and dried at 50 ⁰ Cl mb. A white crystals are obtained.

Yield: 3.6 g = 82 X of theory Fp! 95.5-96.5 ⁰ C.

R f = 0.10 (silica gel; toluene / methanol 85 l5) R f = 0.10 (diisopropyl ether)

Le A 26 080

- 106 -

Example 40

2- {N-Benzyl-N- [3- (N-benzyl-phenylcarbonamido) propyl] aminomethyl) 8-methoxytetralin

OCH

The compound is prepared analogously to the procedure for Example 34 from 1.77 g of the compound from Example (4 mmol), 106 mg of sodium hydride (4.4 mmol) and 0.68 g of benzyl bromide (4 mmol) in dry dimethylformamide,

The crude product is chromatographed on 90 g of silica gel 60 with diisopropyl ether, giving a colorless resin,

Yield: 1.73 g = 81 V. of theory Rf = 0.28 (silica gel diisopropyl ether /

Le A 26 080

2 8/500

- 107 -

Example 4 1

2- {N-Benzyl-N- £ 3 "(N-methylphenylcarbonamido) propyl] -amino-methyl} 8-methoxytetralin

OCH

The Ve.-bond is prepared analogously to the procedure for Example 34 from 1.77 g of the compound from Example 39 (4 mmol), 106 ml of sodium hydride (4 _# 4 nrnol) and 0.57 g of methyl iodide (4 mmol) in dry dimethylformamide ,

The crude product is chromatographed on 250 g of silica gel 60 with diisopropyl ether / methanol 95: 5, giving a colorless resin, yield: 1.62 g = 89 Y. of theory Rf = 0.52 (silica gel, toluene / methanol 90:10)

Example 42

2- {n- [3- (N-Benzyl- ^1- phenylcarbonamido) propyl] aminone my1} 8-methoxytetralin

OCH

Le A 26 080

- 108 -

The compound is analogous to the procedure for Example 17 from 1.6S g of the compound from Example 40 (3.2 mmol), 84 ml of methanol, 8.9 ml of methanolic hydrogen chloride solution (4.8 mmol) and 0.16 g of palladium / Activated carbon obtained after hydrogenation as a tough oil

 10

The base was added to the Hydrochloric! convicted A white solid is obtained Yield: 1.18 g = 76 Y, theory Rf = 0.32 (silica gel, toluene / methanol 85:15) Be itpiel 43

2- {N- [3- (N-methyl-phenyicarbonamidoipropyllaminomethyl) 8-methoxytetralin

OCH ₃ 0 xHCl

The compound is analogous to the working title for Example 17 from 1.46 g of the compound from Example 41 (3.2 mmol), 73 ml of methanol, 8.9 ml of methanolic hydrogen chloride solution (4.8 mmol) and 0.16 g of palladium / Activated carbon obtained after hydrogenation as a tough oil,

Le A 26 080

- 109 -

The base was converted into the hydrochloride analogously to the work instructions of Example 19,

A white solid is obtained

Mp.! 128-130 ⁰ C

Rf = 0.38 (silica gel, toluene / methanol 70S30) Rf = 0.28 (base)

example

* 2- {N- [3- (phenylcarbonamido) -propylaminomethyl} 8-methoxytetralin

OCH ₃ O x HCl

The compound is prepared analogously to the procedure for Example 17 from 1.20 g of the compound from Example (2.7 nunol), 60 ml of methanol, 7, *> ml methanolic hydrogen chloride solution (4.1 nunol) and 0.14 g of palladium / Activated carbon obtained after hydrogenation as a tough oil.

The base was converted into the hydrochloride analogously to the procedure described in Example 19,

You get a white solid. 35

Le A 26

- 110 -

Mp: 134.5-137 ⁰ CRf = 0.35 (silica gel; toluene / methanol 70:30) Rf = 0.22 (base)

example

2- {N-Methyl-N- [3- (N-methyl-4-fluorophenylsulfonamido) propyl] aminomethyl} -8-methoxytetralin

OCH ₃

The compound is prepared analogously to the procedure for Example 7 from 1.05 g of the compound from Example (2.5 mmol), 0.12 g of acetic acid (1.88 mmol), 0.19 g

Sodium cyanoborohydride (3.0 mmol), 33 ml of methanol and

a solution of 0.21 g of 37 Xiger aqueous formaldehyde solution (2.5 mmol) in 5 ml of methanol,

The base is obtained as a colorless, viscous oil. 25

Yield: 1.03 g = 95 Y, theory Rf = 0.47 (Kieselgol, toluene / methanol 85:15).

Le A 26

287 - in -

Example 46

2- {N- [4- (1,1-0,10X100-3-0X0-2,3-dihydro-benzisothiazo-1-2-yl) -butyl] -aminomethyl} -quinol in

^ g To a mixture of 4.9 g (31 mmol) of 2-aminomethylquinoline and 2.8 g (28 mmol) of triethylamine in 100 ml of anhydrous dimethylformamide is added dropwise the solution of 8.91 g (28 mmol) of 2- (4- Bromobutyl) -1,2-benzisothiazol-3 (2H) -one-1,1-dioxide in 30 ml of anhydrous

2Q dimethylformamide and stirred for 14 h at 40 ⁰ C, then the mixture is poured into 600 ml of water, extracted with ethyl acetate, the organic phase is washed with water and dried over sodium sulfate. After filtration and evaporation of the solvent, 8 g of a

2 g of brown, viscous oil, which is purified by column chromatography on silica gel (eluent: methylene chloride / methanol / conc, ammonia solution (10 * 0.1: 0.1)).

Yield: 1.75 g = 16 X of theory, yellow oil, R f = 0.32 (silica gel, methylene chloride / methanol 100: 5).

Le A 26 080

- 112 -): 1.65-1.72 (m; -CH ₂ -CH ₂ -; 2H), 1.9-2.0

/ __ · / ** U OtJ \ OO O £ - I ha t VII.I \ OO

¹ H-NMR (CD ₂ Cl ₂ ): 1.65-1.72 (m; -CH ₂ -CH ₂ -; 2H), 1.9-2,

(m; -CH ₂ -; 2H), 2.3-2.6 <m; NH), 2.8 (t; NH-CH ₂ -; 2H), 3.82 (L; -CON-CJi ₂ ;

^ \I ff \jk ^ \^% / ^Λ VfIf # ^ ff. ,^^_Λ ^ i f f ^ vjkf *

2H), 4.09 (s, NH-CH ₂ -ar; 2H), 7.45-8.15 (m; Ar; 1OH).

The base can be made from methanolic solution

Cases dropwise addition of equimolar amounts of methanolic naphthalene- 1, 5-disulfide i'onsäure solution as naphthalene-1,5-disulfide fonsaures salt, mp 224 ⁰ C,

Example 47:

2- {N- [4- (1,1-dioxo-2,3-dihydro-benzisothiazol-2-yl) -butyl] -aminomethyl} -8-methoxy-tetralin

OCH ₃

2 g of 2-aminomethyl-8-methoxytetralin (10.5 mmol), 3.2 g

2- (4-bromobutyl) -1,2-benzisothiazol- (2H) -1,1-dioxide (10.5 mmol) and 1.46 ml triethylamine (10.5 mmol) are dissolved in 40 ml dimethylformamide at 40 ° for 24 h stirred ° C, arrival _"n closing the reaction solution is poured into a mixture

stirred from 440 ml of water and 140 ml of toluene, the organic phase is washed with water and dried over sodium sulfate. The solvent is absorbed

Le A 26 080

- 113 -

Vacuum distilled off. The residue is purified by column chromatography on silica gel 6Ö with toluene / methanol 70:30. The residue obtained after distilling off the solvent from the main fraction crystallizes after trituration with ether.

Yield: 900 mg = 21 % d. theory

Mp: 94-95 ⁰ C DC: Rf = 0.3

Silica gel / toluene-methanol 70:30

Example 48

2- (N- (4- (N-methyl-4-fluorphenylsuIfonamido) butyl) aminomethyl) -8-methoxy-tetralin

The compound is prepared analogously to the procedure of Example 47 from 1 g of 2-aminomethyl-8-methoxytetralin (5.2 mmol), 1.7 g of N-methyl-N- (4-bromobutyl) -4-fluorophenylsulfonamid (5.2 mmol ) and 0.73 ml of triethylamine (5.2 mmol) in 20 ml of dimethylformamide.

The final product is precipitated from ethereal solution with ethereal hydrogen chloride solution as hydrochloride.

Yield: 400 mg = 16 % d. theory

28 7

- 114 -

Fp! 144 ⁰ C DC! Rf = 0.44

Silica gel / toluene-methanol 70i30 example

2- {Ν- [4- (N-methyl-naphthalenyl-2-sulfonamido) butyl] aminomethyl} -8-methoxy-tetralin

OCH

The compound is prepared analogously to the procedure of Example 47 from 1 g of 2-aminomethyl-8-methoxytetralin (5.2 nunol), 1.9 g of N-methyl-N- (4-bromobutyl) naphthalene-2-sulfonamide (5, 2 nunol) and 0.73 ml of triethylamine (5.2 mmcl) in 20 ml of dimethylformamide. "

The final product is chronographed on silica gel with toluene / methanol 85: 15,

The end product is dissolved in dichloromethane and precipitated with ethereal hydrogen chloride solution as the hydrochloride,

Le A 26

- 115 -

Yield: 9o0 mg = 35 % d. Theory 5

Fp! 194-196 ⁰ C DC! Ff = 0.13

Silica gel / toluene-methanol 85:15 example

2- {Ν- [4- (N-Methyl-naphthalenyl-1-sulfonamide) -butyl] -aminomethyl} -8-methoxy-tetralin

OCH ₃

The connection becomes analogous to the working procedure in ZU

Example 47 from 2 g of 2-aminomethyl-8-methoxytetralin (10.5 mmol), 3.7 g of N-methyl-N- (4-bromobutyl) -naphthalene-2-sulfonamide (10.5 mmol) and 1.46 ml of triethylamine (10.5 mmol) in 40 ml of dimethylformamide.

The final product is chromatographed on silica gel with ethanol chromato-

graphiert,

The end product is dissolved in ethanol and precipitated with ethereal hydrogen chloride solution as the hydrochloride,

Yield! 1, Og = 19% d, theory

Mp: 161-164 ⁰ C DC! Rf = 0.45

Silica gel / toluene-methanol 70:30

Le A 2 6

- 116 -

example

2- {Ν- [4- (N-pyridinyl-2-methanesulfonamido) butyl] aminomethyl} -8-methoxy-tetralin

OCH

1.60 g of 2-aminomethyl-8-methoxytetralin (8.4 mmol), 2.28 g of N- (4-bromobutyl) -pyridinyl-2-methanesulfonamide (7.4 mmol) and 0.85 g of triethylamine (8, 4 nunol) are stirred under argon in 32 ml of dimethylformamide for 24 h at 40 ° C,

The reaction solution is then stirred in a mixture of 160 ml of 5% strength sodium chloride solution, 80 ml of toluene and 8.5 ml of 1N sodium hydroxide solution. The organic phase is washed 1 × with 40 ml of water and dried over sodium sulfate.

After the solvent was distilled off under vacuum, the crude product obtained is chromatographed on silica gel (Fa, Merck) with methanol.

Yield! 1.9 g = 6154 d, theory

DCi Rf = 0.25

Silica gel / methanol

Le A 26

- 117 -

At game 52

8'-MeLhoxy-2 ¹ - [4 (2-methylsulfonyl-imino-1,2-dihydropyridin-1-yl) -butyl-aminomethyl-1> 2,3- _r 4-tetrahydronaphthalene

OCH

The compound is prepared analogously to the procedure in Example 51 from 1.60 g of 2-aminomethyl-8-methoxytetralin (8.4 mmol), 2.28 g of 1- (4-bromobutyl) -2-methylsulfony1 imino-1,2-dihydropyridine (7.4 mmol) and 0.85 ml of triethylamine (8.4 mmol) in 32 ml of dimethylformamide Hergestel 11,

Yield: 2.1 g = 68V · d. theory

TLC: Rf = 0.15 silica gel / toluene-methanol 70:30 Rf = 0.43 silica gel / methanol-triethylamine 95: 5

Le A 26 080

- 118 -

example

2- {N- [4- (1,1-dioxo-3-oxo-2,3-dihydro-benzisothiazol-2-yl) pentyl] amino} -B-methoxychroman hydrochloride

χ HCl

OCH

The title compound was prepared in analogy to the procedure for Example 20.

Mp 110 ⁰ -108 ° C (after sintering) Example

2- {N- [2- (N-methyl- <WU-fluorophenylsulfonamido) ethyl] amino-1-yn-yl-hy'-anol id

The title compound was prepared in analogy to the procedure for Example 20.

Mp: 143 ° C-155 ° C

Le A 26

- 119 -

Example 55

2- {N- [4- (5,5-dioxo-6H-dibenzo [c, l] [1,2] thiazine-6-yl) -butyl} -aminomethylchroman-15-nap! ithaiindisulfonic acid salt (stoichiometry 2: 1)

SO ₃ H

Π χ 1/2

SO ₃ H

The free base [Rp (CH ₂ Cl ₂ / CH ₃ OH 10! 1) = 0 _# 39] was converted into the 2 l salt by stirring with 1.5 N-Na; -hthalene disulfonic acid in acetone / Et 2 O 3 Light beige solid ·

Fp! > 240 ⁰ C (decomposition)

In the implementation, the connection of example 56 was also preserved «

Example 56

2- {N, N-Bis (5,5-dioxo-6H-dibenzo [c, e] [l, 2] -thiazin-6-yl) -butyl]} aminomethyl-chroman-115-naphthalenedisulfonic acid salt (2: 1)

Le A 26 080

2 3 7

- 120 -

/ (CH ₂ )

(CH ₂ ) ₄

O ₂ S

The free base was obtained in addition to the compound of Example 55 as a non-polar component; R f (CH ₂ Cl ₂ / CH ₃ OH 10: 1) = 0.91.

The 2: 1 SaI? with 1 "5-naphthalenedisulfonic acid was obtained as in Example 55 (colorless dye). mp: from 170 ^° C. (decomposition),

Example 57

2- {N- [4- (5,5-dioxo-6H-dibenzo [c, e] [l _l 2] -thiazin-6-yl) -butyl] -aminomethyl-8-methoxy-chroman hydrochloride

OCH

HCl

The free base [Rp (CH ₂ Cl ₂ ZCH ₃ OH 10: 1) = 0.25? after treating with ethereal hydrogen chloride in methanol gave the hydrochloride as an amorphous, beige dye.

Le A 26 080

- 121 -

example

2- {N- [4- (1,1-dioxo-2H-naphtho [l, 8-cd] isothiazol-2-yl) -butyl]} aminomethyl-8-methoxy-chroman hydrochloride

CCH

SO

HCl

The free base [Rp (CH ₂ Cl ₂ ZCH ₃ OH 10! 1} = 0.3] gave, after treatment with ethereal hydrogen chloride in ethyl acetate, the hydrochloride as a slightly greenish crystals.

Mp = 159 ° -162 ⁰ C.

example

2- {N- [3- (l, 3-Dimethyl-uracil-6-yl) -amino] -propyl} -nino-methyl-8-methoxy-chormane hydrochloride

-CH

χ HCl

OCH

The title compound was prepared in analogy to the procedure for Example 20.

Le A 26

- 122 -

The free base [R _f (CH ₂ Cl ₂ / CH ₃ OH 1 OÜ) = 0.1.9], dissolved in methanol, was treated with ethereal hydrogen chloride. After adding ether, the hydrachloride was obtained as a colorless Feetetoff. Fp! from 195 ⁰ C decomposition (foaming).

Example 60

2- {N- [4- (2,3-dihydro-l, l-dioxo-benzisothiazol-2-yl) -butyl]} aminomethylchroman hydrochioride id

VVvNVV ^ N,

χ HCl

The title compound was analogous to the protocol

prepared for Example 20.

The hydrochloride was recrystallized from isopropanol

 25

Mp: 215 ° -216 ⁰ C Example 61

2- {N-C4- (2,3-dihydro-1,1-dioxo-benzisothiazol-2-yl) -butyl]} aminomethyl-8-methoxy-chroman hydrochloride

χ HCl OCHo

Le A 26 080

- 123 -

The title compound was prepared in analogy to the procedure for Example 20,

The free base [R _F (CH ₂ Cl ₂ ZCH ₃ OH 10: 1) = 0.27] was dissolved in methanol and treated with ethereal hydrogen chloride, the hydrochloride precipitated after the addition of ether was recrystallized from ethyl acetate.

Fp! 135 ° -138 ⁰ C.

Example 62 15

2- {N- [4- (4-fluorophenylsulphonamido) butyl] Jaminomethylchroman hydrochloride

^ s ^^ clS '^ ^ KTv / \ /\w.cn.- C "ι-n · _x HCl

The title compound was prepared in analogy to the procedure for Example 24.

Mp 202-206 ⁰ C

The compounds (63-70) listed in Table 1 were prepared analogously to the following procedure.

gestelIt:

1.89 g of 8-methoxy-2-aminomethyl-l, 3-dihydronaphthalene (10 mmol), χ g of I (10 mmol) and 1.39 ml triethylamine (10 mmol) are dissolved in 19 ml of dimethylformamide under argon - 24 h at Stirred at 40 ° C,

Le A 26 080

- 124 -

The reaction solution is then poured slowly into a stirred mixture of 90 ml of 5 × sodium chloride solution> 10 ml of 1 N sodium hydroxide solution and 50 ml of toluene. The mixture is stirred for a further 10 minutes and then the organic phase is separated off. The aqueous phase is further washed 1 × with 25 ml Extracted toluene. The combined organic phases are washed 2 χ with 25 ml of water, dried over sodium sulfate and the solvent was distilled off at 40 ° C under vacuum.

The resulting crude product is purified by column chromatography on silica gel with ethanol (Example 63-67) or ethyl acetate (Example 68-70) as eluant.

The acidic base is dissolved in ether / ethanol 90:10 (Example 63-67) or ether (Example 68-70) and treated with ethereal hydrogen chloride solution as Hydrochloric! Freak It.

The yields are between 30 to 40 Y · d, theory. 25

Table 1

OCH ₃

Le A 26 080

- 125 -

Eg no.

Y -Z RF value on silica gel with toluene / methanol 70:30

Fp ⁰ C

20 65

66

67

S =

Il

O = S

Il

0.48

0.30

0.40

0.58

0.48

180 ⁰ C

150-152 ⁰ C

196-198 ⁰ C

183-185 ⁰ C

Le A 26

- 126 -

2 3 7 5 0

Fp ⁰ C

Rf value on silica gel with toluene / methanol 70:30

70

Examples 71 and 72 listed below were prepared analogously to the instructions for Examples 65 and 66 from 8-methoxy-2-aminomethyl-1,2,3,4-tetrahydronaphthalene, 2- (3-bromopropyl-1) benzoisothiazole-1, 1-dioxide, or, prepared 2- (2-bromomethyl-1) benzisothiazol-1-dioxide and triethylamine in dimethylformamide.

In game

8-methoxy-2-aminomethyl-N [3- (benzisothiazol-1,1-dioxyd-2-yl) propyl] -1,3,3,4-tetrahydronaphthalene

Le Λ 26

- 127 -

OCH.

-S = O

Il

Rp = 0.393 (hydrochloride), on silica gel with toluene / methanol (70:30), mp = 166-168 ⁰ C (hydrochloride) Yield! 27 * /. theory

example

8-methoxy-2-aminomethyl-NC 2- (benzisothiazole-1,1-dioxide-2-yl) ethyl-1] -l, 2,3,4-tetrahydronaphthalene

OCH

Rp = 0.483 (hydrochloride) on silica gel with toluene / methanol (70:30), mp 236-238 ⁰ C. (hydrochloride) Yield: 38 '/. theory

In analogy to the procedure of Example 20, the compounds listed in Table 2 were prepared:

Le A 26

- 128 -

Table 2

Example Nr:

-Y Z

ochr

Y - Z DC Fp ⁰ C FF value or MS

salt

73 - (CHg) ₃ -N

74 - (CH ₂ J ₂ -N

195-197 χ HCL

0.50 CH ₂ Cl ₂ / CH ₃ OH

(10: 1)

75

- (CH ₂ J ₄ -N

25 76

- (CH ₂ J ₃ -N

77 - (CH ₂ J ₂ -N

78

79

- (CH ₂ J ₄ - ¹ J ¹ O ₂ S

- (CH ₂ ) ₄ - ^N

MS: (free base) 382, ₂ 19 (lOOy.) 84

MS: (free base) 430, 267 (100%) amorphous 105, 86, 84

Le A 26 080

- 129 -

Table 2 (continued)

Example No.:

Y Z

DC Fp ⁰ C

RF value or MS

salt

80

O ₂ S

81

- <CH ₂ ) ₂ -

0.16 CHCl ₂ /

C ₃ H ₈ OH 158-159 oxa

(20.Ί) lat

In analogy to the procedure of Example 20, the compounds listed in Tables 3, 4 and 5 were prepared:

table Sample N,

YZ DC / R _f value on silica gel toluene / methanol (70:30) * or ethanol **

Fp ⁰ C

82

0.25 **

109-111 ⁰ C

Le A 26

- 130 -

Table 3 (continued)

Sample N,

Y Z

DC / R _f value Fp ⁰ C

on silica gel toluene / methanol (70:30) * or ethanol **

83

0.49 *

199-201 ⁰ C

25

0.38 *

216-218 ° C

Le A 26 OGO

- 131 -

table

-Y-Z χ HCl

CO-NH-

Sample Hr. Y Z

86

87 DC / Rp value Fp ⁰ C on silica gel / ethanol

0.28 140-142 ⁰ C

88

-S = O

I! 0

89

Le A 26

- 132 -

table

-Y-Z χ HCl

OC ₂ H ₅

Example no. Y Z

DC / R _F value Fp ⁰ C

90

0.38 ClCH.

ιο: Γ

185 ⁰ C

ClCH ₂ CH ₂ CWlPrOH

91

0.22

153 ⁰ C.

ClCH ₂ CH ₂ Cl / IPrOH 10: 1

Le A 26

Example 92

(-) - {2- [N- (4- (1,1-dioxido-3-oxo-2,3-dihydro-benzisothiazol-2-yl) butyl] aminomethyl] -chromane} and

(+ L - ^ - N - ^ - d.i-dioxido-S-oxo-L.A-dihydro-benziso-thiazol ^} -yDbutyllaminomethyllchroman

Example 92 A Chroman carboxylic acid chloride

89.0 g (0.5 mol) of chroman-2-carboxylic acid and 71.4 g (0.6 mol) of thionyl chloride are heated to 8O ⁰ C (4-5 hours) until the overall development is buried. Distillate provides 96.0 g (98%) of chroman-2-carboxylic acid chloride of melting point 77-80 ° C / 0.1 Torr

Example 92 B Chroman-2-carboxylic acid N- [1- (S) -phenyl-ethyl-amide (diastereomers)

me

In the solution of 69.0 g (0.3 mol) of Chrorv "" i-2-carboxylic acid chloride in 200 ml of dichloromethane are stirred at 10 ° C with stirring 39.9g

(S) - (-) - 1-Phenylelthylamine and 30.9 g (0.3 mol) of triethylamine were added dropwise. After stirring overnight, the Ansa ζ is placed on ice.

Separate the phases, wash the organic phase with saturated brine and dry over anhydrous Sodium sulfate provides 87.8 g of crude chroman-2-carboxylic acid N- [1- (S) -phenylethyl] amide as a 1: 1 mixture of the oiasteromers. To Crystallize (4x) from ethanol, 15.8 g of a uniform diastereomer (de a 99.5) of melting point 127-128 ⁰ C.

receive; O ₀ = +17.5 (c =!, Tetrahydrofuran).

C ₈ H ₁₉ NO ₂ calc. C 76.84 H 6.81 N 4.98

(281,4) gef. C76.9 H7.18 N4.97

Evaporation of the mother liquors gave 61.2 g of a mixture of diastereomers.

Example 92 C

Chroman-2-carboxylic acid N [1- (R) - [phenylethyl] amide

(Diastereomers)

According to Example 92B is obtained when using the (R) - (+) - 1-Phonylethylamins after crystallization (4x) from ethanol 15.0 g of a single diastereomer (de = 100%) of melting point 127-128 ⁰ C; Ci ₀ = 17.2 (C =!, Tetrahydrofuran).

C ₁₈ H ₁₉ NO ₂ calc. C 76,84 H 6,81 N 4,98 (281.4) gef. C 76,8 H 7,22 N5.17

Example 92 D

N-II - (Sl-phenylethyl-1-aminomethylchroman (Diasteromer A)

In the to ⁰ ° C cooled solution of 0,2MoI diborane in 400ml of dry tetrahydrofuran are Resting 16.2 g (0,058MoI) of Example 92 after B single diastereomer produced (chroman ^ -carboxylic acid-N-MSL-phenylethyllamid; α = + 17.5 °) in 300 ml of dry tetrahydrofuran. After stirring overnight at 20 ° C, the mixture is heated to reflux for 1 hour, cooled and carefully decomposed with 10% aqueous hydrochloric acid.

After removal of the solvent in vacuo, the residue is made alkaline with dilute sodium hydroxide solution (pH ~ 8.5) and etherified. Wash the combined organic extracts with saturated brine, dry over anhydrous sodium sulfate, and evaporate to give 17.4 g of crude N- [1- (S) -phenethyl] -2-aminomethylchroma: i; DE> 99.5. For analysis, 0.5 g are distilled in a Kugelrohr at 190 ° C / 0.02 Torr.

C ₁₈ H ₂₁ NO calc. C 80.86 H 7,92 N 5.24 (267.4) gef. C 80,7 H 8.01 N 5.41

Example 92 E

(+) - N- [1- (G) phenylethyl] -2-aminomethylchroman

(Diastereomer B)

NH> Mö

According to Example 92 D, 42.2 g (0.15 mol) of the obtained in the separation of the uniform diastereomer according to Example 92 B mixture of diastereomers with 0.3 mol of diborane in tetrahydrofuran. Work-up gives 42.8 g of crude N- [1- (S) -phenylethyl-2-aminomethylchroman as a mixture of the diastereomers which is chromatographed on 600 g of silica gel with toluene / ethyl acetate. This gives 9.0 g of a uniform N- [1- (!) -Phenyl-thyl] -2-aminomethylchroman, which is identical to a preparation obtained according to Example 92 D (diasteromer A), and 25.4 g of a uniform, less polar N-h -ISl-phenylethyll-aminomethylchromans.'de> 99.5 (diastereomer B). For analysis, 0.5 g in a Kugelrohr at 195 "C / 0.05 Torr distilled a ₀ = + 42.3" (c =!, Tetrahydrofuran)

gef.

C 80,7

H 8.08

N 5.38 f.

Example 92 F (-) - 2-aminomethylchroman

(Produced according to Example 92D) 27.5 g (0.1 mol) of uniform N- [1- (S) -Phenylethyll-2-aminomethylchroman in 400ml of ethanol for 24 hours at 5O ⁰ C and 10bar hydrogenated (Pd / C 5%) , After evaporation, 15.6 g of colorless oil are obtained. Filtration over silica gel with toluene / ethyl acetate and then with methanol yield 12.5 g of 2-aminomethylchroman of melting point 100-110 ° C / 0.04 Torr (Kugetrohr); 06 a 97.5% Q ₀ = -122.8 · (c = I.Trichlormethan).

C ₁₀ H ₁₃ NO calc. C 73.59 H 8.03 N 8,58 (163.2) gef. C 73,7 H 8,39 N 8,85

Example 92 G (+) - 2-aminomethylchroman

21.5 g (0.08 mol) of uniform N- [1- (S) -phenylethyl] -2-aminomethylchroman (prepared according to Example 92 E, a ₀ = + 42.3) are hydrogenated in 400 ml of ethanol analogously to Example 92 F (Pd / C 5%). 10.2 g of uniform (+) - 2-Aminomethylchroman of melting point 100 b 110 ° C / 0.03 Torr (Kugelrohr) are obtained; ee s 97.0%, a _D = + 128.8 ° (c = 1, trichloromethane).

gef.

C 73.3

H 8,11

N 8,82

Example 92 H 2- | N- [4- (1,1-Dioxo-3-oxo-2,3-dihydro-benzisothiazol-2-yl) -butylaminomethyl] chroman and hydrochloride ((-) - isomer]

5.4 g (0.033 mol) 2-aminomethylchroman (Example 92 F, a _D = -122.8 °), 6.1 g (0.06 mol) triethylamine, 9.5 g (0.03 mol) N-4 bromobutyl saccharin and 80 ml of dry dimethylformamide are heated to 60 ° C for 4 hours. After stripping off the solvent at 0.01 torr, the residue (13.5 g) is taken up in toluene / ethyl acetate (5: 1) and chromatographed on 300 g of silica gel. The rr ^{: <} toluene / acetic acid ester (1: 1) eluted product (5.8g) is rechromatographed on 150g silica gel to give 3.7g of uniform 2- [N- [4- (1,1-dioxo-3-oxo-2 , 3-dihydrobenzisothiazol-2-yl) butyl] aminr> methyl] chroman. Hydrochloride: mp 192-194 ° C (mol. Ms capillary) are obtained; ee a 99%, α ₀ = -42.2 (c =!, trichloromethane).

C ₂₁ H ₂₄ N ₂ O ₄ S X CHI calc. C 57,72 • H 5.78 N 6,41 (437) gef. C 57.5 H 5.81 N 6,40

Example 921

2- | N- [4- (1,1-dioxo-3-oxo-2,3-dihydro-benzisothiazol-2-yl) -butyl] -aminomethylchroman and hydrochloride I (+) - isomeres)

5.4 g (0.033 mol) of 2-aminomethylchroman from Example 92 G (a ₀ - + 122.8 °) are reacted analogously to Example 92 H with N- (4-BrombutyDsaccharin, chromatography of the crude product (11.6 g) on silica gel with toluene Ethyl acetate (5: 1 to 2: 1) gives 5.4 g of crude product, which is rechromatographed on 175 g of kiosel gel, 4.2 g of uniform 2- [N- [4- (1,1-dioxo-3-oxo-2,3 -dihydro-benzothiazol-2-yl) butyl] aminomethyl] chroman hydrochloride: Melting point: 192-194 ° C (melted capillary), ee> 99%, a ₀ = + 43.5 ° (c =!, trichloromethane).

C ₂₁ H ₂₄ N ₂ O ₄ S χ HCI gef. C 57.4 H 5.72

N 6,33

Example 93

(+) - {2- | N- [4-1,1-Dioxo-3-oxo-2,3-dihydro-benzisothiazol-2-yl) -butyl} -aminomethyl) -8-methoxy-chroman} and (-) - {2- | N · [4-1.1-dioxido-3-oxo-2,3-dihydro benzίsothίazol · · · 2 yl) butyl | aminomethyll * 8 *} methoxy-chroman

Example 93A e-Mothoxychroman carboxylic acid

OMo

100.7 g (0.43 mol) of e-Methoxychroman ^ -carboxylic acid ethyl ester and 20.1 g (0.50 mol) of sodium hydroxide are stirred in 800 ml of ethanol at 20 ° C for 24 hours. After concentrating the solution, the residue is combined with water, extracted with diethyl ether and the aqueous phase is acidified. Extraction with diethyl ether yields 95.2% crystalline 8-methoxychroman-2-carboxylic acid after usual work-up.

Example 93B

8 Methoxychromancarboxylic acid chloride

OHQ

Analogous to Example 92 A e-Methoxychroman ^ -carboxylic acid chloride was obtained from Example 93 A and further processed as a crude product.

Example 93C

e-Mothoxychroman ^-carboxylic acid N-IHSI-phenylethyiiamid

(Oiastereomere)

me

OMe

88.7 g (0.39 mol) of crude e-Methoxychroman ^ -carboxylic acid chloride (Example 93 B) in 600 ml of dichloromethane with 64.9 g (0.54 mol) of (S) - (-) - 1-phenylethylamine and 54.1 g (0.64 mol) of triethylamine reacted at 10 ° C.

Work-up yields 135.2 g of crude e-methoxychromane-carboxylic acid N-H-isl-phenylethyl amide as a 1: 1 mixture of the diastereomers. Chromatography on 2000 g of silica gel with toluene / ethyl acetate gives 47.9 g of uniform diastereomer A and 33.9 g of uniform diastereomer B. 29.2 g of a mixture of the two diastereomers A and B are rechromatographed.

e-methoxychroman ^-carboxylic acid N-li-ISL-phenylothyllamid

Diastereomer A

Melting point 123-124 ⁰ C (dichloromethane / petroleum ether)

de> 99%, dD = +6.3 ⁰ Ic =!, tetrahydrofuran)

about

 gef.

C 73.29 C 73.0

H 6.80 H 6.69

N 4,50 N 4,53

Diastereomer B

Melting point 108-109 ° C (dichloromethane / petroleum ether)

100%, a _a = + 40.2 "(C = 1, tetrahydrofuran)

gof.

C 73.2

H 6,93

N 4.61

Example 93 D (+) - N- [1 (S) -phenylethyl] -2-aminomethyl-8-methoxychroman

OHQ

46,7g (0.15 mol) of 8-methoxychroman-2-carboxylic acid-N- [1- (S) -phenylothyl] amide (Diastoreomer A from Example 93D Melting point 123-124 ⁰ C) analogous to Example 92C in 500 ml of dry Tetrahydrofuran added dropwise to 0.35 mol of diborane in 650 ml of dry tetrahydrofuran bsi 10 ° C. Workup provides 50.8 g of crude N- [1- (S) -phenylethyl] -8-2-aminomethyl-8-methoxychroman.

Chromatography of the crude products obtained from two batches in silica gel (2000 g) with toluene / ethyl acetate (10: 1 to 5: 1) gives 69.2 g of uniform (+) - N- | 1- (S) -phonylethyl | -2-aminomethyl- 8-mothoxy-chromane, and 21.1 g of 8-methoxychroman-2-carboxylic acid N- [1- (S) -phenyl-thyl] -amide.

For analysis, 1 g is distilled in a bulb tube at 160-170 ° C / 0.55 Torr, de = 100%, a ₀ = +30.3 "(c = 1, tetrahydrofuran)

about

 gef.

C 76.73 C 76.5

H 7,80 H 7,84

N 4.71 N 4.66

Example 93 F

N- [1- (S) -phenylethyll-2-aminomethyl-8-methoxychroman (other oliereomer)

OHQ

Analogous to Example 93 D diastereomer B of Example 93 C (mp 108-109 ⁰ C) was the diastereomer to Example 93D obtained. For analysis is distilled in a bulb tube at 175 ° C / 0.05 Torr.

gef.

C 76,8

H 7,87

N 5.03

Example 93 F (+) - 2-aminomethyl-8-methoxychroman

OMe

49.2 g (0.16 mol) of 2-N · (1 · (S) · Pheny! Ethyll-aminomethyl · 8 · methoxychroman, obtained according to Example 93 D, are in two batches in 400 ml of ethinol for 24 hours at 5O ⁰ C. and 10 bar hydrogenated (Pd / C 5%). Filtration and evaporation afforded 34.8 g of crude 2-aminomothyl-8-meihoxychroman, which was chromatographed on 600 g of silica gel with toluene / ethyl acetate, obtained with toluene / ethyl acetate (1: 2) Fraction is Kugelrohr distilled at 170-180 "C / 0.02 Torr to give 20.1 g of uniform 2-aminomethyl-8-methoxychroman ee = 96.7%, Q ₀ = + 111.5 ° (c =! , chloroform)

about

 gef.

C 68.37 C 68.3

H 7,82 H 8,02

N 7,25 N 7,34

Example 93 Q (-) - 2-aminomethyl-8-methoxychroman

ΟΜθ

From Example 93F, the enantiomer to Example 93F was obtained from Example 93E. Boiling point: 160-170 ° C / 0.07 Torr (Kugelrohr) Melting range: 49-55 ⁰ C

ee = 96.1%, a ₀ = -110.8 ° (c =!, trichloromethane)

Found

C 68.0

H 7,88

N 7.23

Example 93 H

2- [N- [4- (1,1-dioxido-3-oxo-2,3-dihydro-benzisothiazol-2-yl) butyl) aminomothyl] methoxy-chromanundHydrochlorid [(+) - enantiomer)

OHQ

The solution of 5.3 g (0.027 mol) of 2-aminomethyl-8-methoxychroman, 9.5 g (0.03 mol) of N-4-bromobutyl saccharin, 3.03 g (0.03 mol) of triethylamine and 80 ml of dimethylformamide is stirred for 5 hours at 60 ° C. Concentration of the solution in vacuo, taking up the residue in dichloromethane, adding dilute sodium hydroxide solution (0.1 η NaOH) and water to pH 8 and separating the phases yields after washing the organic phase to pH 7 with saturated brine and Evaporation 17.9 g of crude product which is chromatographed on 250 g of silica gel with toluene / methanol (10: 1).

This gives 10.5 g of crude 2- [N- [4- (1,1-dioxo-3-oxo-2,3-dihydro-benzisothiazol-2-yl) butyl] aminomethyl] -methoxy-chroman, the 300g of silica gel is rechromatographed. With toluene / methanol (10: 1) gives 6.6 g of uniform product.

hydrochloride

Melting point: 205-208 ° C (melted capillary) after recrystallization from dichloromethane / petroleum ether.

ee> 99%, a ₀ = +53.1 "(c = 1, trichloromethane).

C ₂₂ H ₂ SN ₂ O ₆ SxHCI calc. C 56.58 H 5.83 N 6.00

(467,0) gef. C, 56.8, H, 5.98, N, 5.97

Example 931

2- [N- [4- (1,1-Dioxo-3-oxo-2,3-dihydro-benzisothiazol-2-yl) -butyl] -aminomethyl-8-methoxy-chroman and hydrochloride [(-) - enantiomer]

OMe

5.3 g (0.027 mol) of 2-aminomethyl-8-methoxychroman prepared according to Example t) 3G, 9.5 g (0.03 mol) of N-4-bromobutyl saccharin, 3.05 g (0.03 mol) of triethylamine and 80 ml of dimethylformamide are heated at 50 ⁰ C for 4 hours. Work-up, as described in Example 93 H, provides 16.6 g of crude product, which is filtered through 175 g of silica gel with toluene / ethyl acetate. 3.4 g of dialkylation product and 7.1 g of monoalkylation product are obtained. Rechromatography of the monoalkylation product on 230 g silica gel with toluene / methanol (10: 1) yields 2.5 g of uniform 2- [N- [4- (1,1-dioxo-3-oxo-2,3-dihydrobenzisothiazol-2-yl) -butylaminomethyl -8-rnethoxy-chroman.

hydrochloride

Melting point: 208-210 ⁰ C (melted-off capillary) after recrystallization from dichloromethyl / petroleum ether:

ee & 9%, a _D = -51.2 ° (c = I.Trichlormethen).

Cj ₂ Hj ₆ N ₂ O ₅ SxHCl. C 56.5 H 5.82 N 5.95

Claims (1)

Paten t claims 1. Process for the preparation of substituted aminomethyltetralines and their heterocyclic analogs of the formula R ¹ jT - | CH ₂ -NYZ in which Y - a straight-chain or branched, saturated or unsaturated alkylene chain having up to 6 carbon atoms means! Z - a group of the formula , -OR ⁴ , -SO _m R ⁵ , -COOR ⁶ or -CONR ⁷ R ⁸ means 287 where 5 R and R are the same or different and are hydrogen, alkyl, alkenyl, cycloalkyl, aryl or aralkyl, ? * 3 R and R are the same or different and for hydrogen, alkyl, alkenyl or cycloalkyl stand, are aryl, aralkyl or heteroaryl, where the heteroaryl and aryl radicals optionally by halogen, cyano, alkyl, alkoxy or Trifluoromethyl may be substituted, for a group of the formula N-CHO I stand, or CH ₃ 25 represent a group of the formula -COR ⁹ or SO ₂ R ¹⁰ , where 30 R ⁹ - is hydrogen or is alkyl or alkoxy or is aryl or aralkyl, optionally up to 3 times the same or different from 35 Le A 26 Alkyl ι alkoxy, alkylthio, halogen, cyano, TrifluormeLhyl, TrifluormeLhoxy, trifluoromethylthio, amino, alkylamino or dialkylamino may be substituted or - for heteroaryl), which may optionally be substituted by alkyl, alkoxy, alkylthio, halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino, alkylamino or dialkylamino, optionally or differently, by alkyl, alkoxy, alkylthio, or stands for a group NHR, 15 R - stands for alkyl, if necessary through Cyano, halogen, trifluoromethyl or trifluoro- methoxy can be substituted, for aryl or aralkyl, the given if up to 3 times the same or different by alkyl, alkoxy, alkylthio, halogen, Cyano, trifluoromethyl, trifluoromethoxy, Trifluoromethylthio, amino, alkylamino or Dialkylamino may be substituted 25 R ¹⁰ - is alkyl optionally substituted by Cyano, halogen, alkoxycarbonyl, trifluoromethyl or trifluoromethoxy may be substituted, or
30 represents aryl, aralkyl or heteroaryl, optionally substituted up to 3 times, identically or differently, by alkyl, alkoxy, Alkylthio, halogen, cyano, tri-fluoromethyl, 35 Le A 26 080 Trifluoromethoxy> TrifluoromethylLhio, amino, alkylamino or dialkylamino, or for a group of the formula -NH-CH stands or represents a group of the formula -NR ⁷ R ⁸ , I would like to 7 ft
R and R have the abovementioned meaning, R and R ° together with the nitrogen atom is a heterocycle of the series Le A 26 080 -j ^CH 2> o or CH- -7 ¥ 3 O = C ^ JC ₆ H ₅ -N- j ^CH 2> NR ^J -N form, in which w - the number 0, 1 or 2 means ο - the number 1 or 2 means R - represents acyl, alkoxycarbonyl, alkylsulfonyl> arylsulfonyl, aralkylsulfonyl, alkylaryl sulfonyl, carbamoyl or sulfamoyl Le A 26 080 R ⁴ - for hydrogen j is alkyl or alkenyl or represents cycloalkyl or
represents alkoxycarbonyl or Aryloxycarbonyl or aralkoxycarbonyl is R ⁵ - is alkyl or alkenyl or cycloalkyl, or is aryl or aralkyl, optionally up to 3 times the same or different substituted by halogen, cyano, alkyl, alkoxy, trifluoromethyl or trifluoromethoxy or - is a group of the formula -NR ⁷ R ⁸ , wöbe i ft R and R are as defined above, _rn - is the number 0, 1 or 2, R ^{6 represents} hydrogen, alkyl, alkenyl, cycloalkyl, aryl or aralkyl, R ^{1 is} hydrogen, alkyl or aralkyl, or Heteroarylalkyl means or the group - (Y - Z), where Y and Z * may be the same or different from Y and Z and the meaning of Y and Z have, A and D denote a group of the formula -CH ₂ , 0, S, NR ¹³ or the -CH or N part of a C =C or C =N double bond, Le A 26 080 with the proviso that either only A or only D for 13 is oxygen, sulfur or N-R, in which 13
R- is hydrogen, alkyl, alkoxy, acyl, alkoxy carbonyl or alkylsulfonyl, B denotes a group of the formula -CH ₂ -, -CH or the CH or N part of a C =C or C =N double bond, C represents a group of the formula -CH or the C part of a C =C or C =N double bond, E and F are the same or different and - hydrogen, alkyl or alkoxy, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy mean j or 2 3 - a group of the formula -CONR R mean 2 3
R and R have the abovementioned meaning or E and F together form a saturated or unsaturated carbocycle of 6 carbon atoms and their salts, characterized in that [A3 compounds of the general formula (II) R ¹ I TV ^ D-TJ-CH ₂ -NH in which A, B, C, D) E, F and R have the abovementioned meaning, (Al) with alkylating agents of the formula (III) L-Y-Z (III), in the Y and Z have the meanings given above, with the provisos that Z does not stand for Amino and Le A 26 R is not hydrogen when R ^{J is} alkyl or aryl, and L is a leaving group for alkylating means, or (A2) with aldehydes of the formula (IV) OCH-Y ² -Z (IV), in which 15 Z has the abovementioned meaning and Y is an alkylene chain Y abbreviated to a methylene group, reductively alkylated, or (A3) with reactive acid derivatives of the general formula (V) M-CO-Y ² -Z (V), in which 30 Le A 26 2 8 7 5 Y and Z have the meanings given under the authors.svar lanten [Al] and M means a leaving group for alkylating agent, converts, 10 and reducing the corresponding acid amides with hydrogen in the presence of a catalyst, with boranes or with complex metal hydrides, or 15 (A4) with nitriles of the formula G-CN 20 in which G for monochlorinated lower alkyl (Cj to Vinyl or lower alkyl (C ₁ to C ₃ ) - substituted vinyl stands, to compounds of the formula (VI) and (VII). BR ¹ ^^ s ^ A ^ BR ¹ ₂₂ (VI) (VII), Le A 26 worm A, B, C, D, E, F and R * have the abovementioned meaning, alkylated
10 the obtained Ni '.rile to the amines (VIII) and (IX) »., ... (VIII) R ¹ E-f ^ Il I I (ix), F wor in A, B, C, D, E, F and R have the abovementioned meaning, hydrated, and this in a conventional manner Alkylation, reductive alkylation, acylation, Reaction with isocyanates or ΓίΙfonylations, Le A 26 080 450 or by 5 [B] Compounds of the general formula (X) in which A) B, C, D, E, F, Y and Z have the above-mentioned Bedeu lungs, with the provisos that Z does not stand for amino and R is not hydrogen when R ^{3 is} alkyl or aryl, (B1) with alkylating agent In d & r forms (XI) R ^X -L (XI), wherein R has the meaning given above and 30 L is a leaving group for AlkylierungsmiLLeI means alkylated, 35 or Le A 26 (B2) with aldehydes of For.nel (XII) 5 R ¹⁴ -CHO (XM), in the R aa around a methylene group shortened Reut R ¹ means 10 reductively alkylated or (B3) with reactive acid derivatives of the general formula (XIII) M-CO-R ¹⁴ (XIII) ,, in which R has the meaning given above and M is a leaving group for acylation center 1, reacted and the corresponding acid amides with hydrogen in Presence of a catalyst or reduced with complex metal hydrides, Le A 26 287 ASl or by adding CC] aldehydes of the formula (XIV) (XIV) F in the A, B, C, D, E and F are as defined above, with amines of the formula (XV), (XVI) or (XVII) HN H ₂ NR ¹ H ₂ NYZ (XV) (XVI) (XVII), wor in OC i R ₁ Y and Z have the meaning given above with the provisos that Z does not stand for amino and 30 R is not hydrogen, when R ^{3 is} alkyl or aryl, 3 ^ in a conventional manner reductively aminated, Le A 26 or by reacting [D] compounds of general formula (XVIII) E-4 MI (XVIII) ₁ F in which A, B, C, D, E and F and X have the meaning indicated above and L is a leaving group for AlkylierungsmiLLeI meaning -Leu, with amines of formulas ^{R 1} HN H ₂ NR ¹ H ₂ NYZ ^ Y-Z (XV) (XVI) (XVII), 25 wherein R ¹ , Y and Z have the abovementioned meaning, with the provisos that Z not L for amino sLehL and Le A 26 080 R is not hydrogen when 5 R ^{3 is} alkyl or aryl,
implements, I ^ or reacted with a Alkaliazid and then reduces the Azidofunkt ion to a Aminofunkt ion, this is carried out in a manner known per se by alkylation, reductive alkylation, acylation, reaction with isocyanates or sulfonations, or by
[E] reactive carboxylic acid derivatives of the formula (XIX) (XIX) wherein A, B, C, D, E and P 'are as defined above have and
30 M is a leaving group for acylating agent, with amines of the formulas _{/ R} 1 HN ^ HoN-R ¹ HoN-YZ ^ YZ (XV) (XVI) (XVII), Le A 26 080 wherein R, Y and Z have the above meaning, with the provisos that Z is not LichL, and R is not LichL, if R ^{3 is} alkyl or aryl sLehL, umseLzt, and the amides of the formulas (XX) and (XXI) thus obtained E- (XX) E- R ι ι (XXI) in WGIcher A, B, C, D, E, F, R ¹ , Y and Z are as defined above, catalyzed by water-based leaching using complex metal hydrides or with boranes, Le A 26 080 2 8 7 S O or by adding [F] compounds of general formula (XXII) (XXII) in which A, E and F have the abovementioned meaning with formaldehyde and amines of the formula (XV) HN (XV), wor in R, Y and Z are as defined above. with the provisos that Z does not stand for Amino and 25 R 1 does not stand for hydrogen when R ^{3 is} alkyl or aryl, and the intermediates obtained general formula (XXIII) 1 I (XXIII), Le A 26 in which A ₁ E, F, R »and Z have the abovementioned meaning, by reduction of the carbonyl function or by partial reduction of the carbonyl function to the alcohol function, subsequent elimination of water and optionally hydrogenation of the C = C double bond with hydrogen.