DE2531312A1 - AMINE DERIVATIVES, PROCESS FOR THEIR MANUFACTURING AND MEDICINAL PRODUCTS CONTAINING THEM - Google Patents

Description

Dr. Hans-Heinrich Willrath

Dr. Dieter Weber Dipl.-Phys. Klaus Seifet

PATENT LAWYERS

D - "52 WIESBADEN" J- 7.1975 Plague compartment 1327 11 / ep

Gustav-Freyta ^ -SrraSe 23 S (0 6121) 3727 £ 0

Telegram address: WILLPATENT

New postal address:

east compartment 41 45, KH-453-1

AB Hässle S-431 20 Mölndal 1 (Sweden)

Amine derivatives, processes for their preparation and pharmaceuticals containing them

Priority: 11 August 1974 in Sweden Note No .: 7413 789-4

The invention relates to new amines with β-receptor blocking activity which are useful in the treatment of cardiovascular diseases and have the general formula I.

EAR ³ R ⁵

> ArCC

M! ff

2 /

R ⁴

609819/1285

Here, R ¹ denotes the group -CH ₂ CH = CH ₂ , -CH ₂ C = CH, -OCH ₂ CH -OCH ₂ C = CH, an alkyl group, alkoxyalkyl group, alkoxyalkoxy group, alkoxycarbonylarainoalkyl group, alkoxycarbonylaminoalkoxy group, alkoxycarbonylaminoalkenyl group, the group KOCH ₂ CH ₂ NHCOCh ₂ O-, CH OCH CH ₂ NH-COCH ₂ O- or -CH = NOR, where R is a hydrogen atom or an alkyl group with 1 to 6 carbon

lenstoffatoirien means, R a hydrogen atom, a halogenator, an alkyl group or alkoxy group, R a hydrogen

4th
atom or an alkyl group, R a hydrogen atom, an alkali

5 6 noyl group or benzyl group, R and R each a water

7 fl

substance atom or an alkyl group, R and R each a hydrogen atom, Halogen atom, an alkyl group or alkoxy group,

R is a hydrogen atom, an alkano group, sulfo group, sulfino group, cyano group, trifluoromethyl group, alkoxycarbonylaminoalkyl group, the group -CHNR ¹⁰ R ¹¹ or -CONHNR ¹⁰ R ¹¹ 'in which R and R are individually hydrogen atoms or with the nitrogen atom to which they are bonded are, taken together a heterocyclic ring, such as the pyrrolidine ring, piperidine ring, piperazine ring or morpholine ring, Y is -0- or -CH ₀ -, η is an integer from 0 to 5, m is an integer from 0 to and Ar is a phenyl radical, Thiazolyl radical or thiadiazolyl radical, where R is in the 2- or 3-position to the phenyl radical, in 4- or

1 2 5-position on the thiazolyl radical and R or R in the 4-position are bound to the thiadiazolyl radical. If Y ~ CH- means η is preferably 1 to 5. If R is a methyl group, it is preferably not in the 2-position to the phenyl radical.

bonded, except when R is an alkoxycarbonylaminoalkyl group. If R is an isobutyl radical in the 3-position, both groups R and R are preferably not methyl groups,

609819/1285 - ³ "

'; ^ b 3 1 3 1 2

and when R is an acetylaminomethyl group in the 3-position, is preferably not 0. The thiazolyl radical Ar

is bonded to the oxygen atom in the 2-position ^ where he

1 2

alternatively carries R and R in the 4-position and 5-position.

The thiadiazolyl radical Ar is the 1,2,5-thiadiazolyl radical which is bonded to the oxygen atom in the 3-position and has R or R ² in the 4-position.

Kc 7

R and R can be the same or different. Also R and R

can be the same or different.

The alkyl group R has up to 7 carbon atoms, preferably up to 4 carbon atoms, and is straight-chain or branched-chain. Thus, the alkyl group R is preferably methyl, ethyl, n-propyl, isopropyl, η-butyl, sec-butyl and tert-butyl. The alkyl group R is preferably not
Methyl in position 2 on the phenyl radical.

The alkoxyalkyl group R has up to 7 carbon atoms in each alkyl chain, preferably up to 4 carbon atoms
in any alkyl chain, and each alkyl chain can be straight or branched chain. Thus, the alkoxyalkyl group R is, for example, methoxymethyl, methoxyethyl, A "thoxyethyl, isopropoxyethyl, n-propoxymethyl and tert-butyloxymethyl.

The alkoxyalkoxy group R ¹ has up to 7 carbon atoms in each alkyl chain, preferably up to 4 carbon atoms in

ORlGlMAL INSPECTED

O b 3 1 3 1 2

each alkyl chain, each alkyl group being straight-chain or can be branched-chain. Thus, the alkoxyalkoxy group R is, for example, methoxymethoxy, methoxyethoxy, ethoxyethoxy, Isopropoxyethoxy, 2-ethoxy-1-methylethoxy and tertiary butoxyethoxy.

The alkoxycarbonylarainoalkyl group R has up to 7 carbon atoms, preferably up to 4 carbon atoms in the Alkoxy group, which is straight or branched chain such as methoxy, ethoxy and isopropoxy. The alkyl group also has up to 7 carbon atoms, preferably up to 4 carbon atoms and is straight or branched chain. The alkoxycarbonylaminoalkyl group R is thus, for example, methoxycarbonylaminomethyl, Methoxycarbonylaminoethyl, l-methyl-2-methoxycarbonylaminoethyl, Isopropoxycarbonylaminoethyl and Isopropoxycarbony laniinopropy 1.

The alkoxycarbonylaminoalkoxy group has R in each alkoxy group up to 7 carbon atoms, preferably up to 4 carbon atoms, and these groups are straight or branched chain. Thus is the alkoxycarbonylaminoalkoxy group R for example methoxycarbonylaminomethoxy, methoxycarbonylaminoethoxy, Ethoxycarbonylaminoethoxy, isopropoxycarbony1-aminoethoxy and isopropoxycarbonylaminopropyl.

The alkoxy part of the alkoxycarbonylaminoalkenyl group R has the same meaning as the alkoxy part of the alkoxycarbonyl

6098 19/1285

ORIGINAL INSPECTED

* b 3 1 3 1

aminoalkyl group R- and is therefore methoxy, for example? Ethoxy and isopropoxy. The alkenyl part, which is the alkoxycarbonylamino part carries, has up to 7 carbon atoms, preferably up to 4 carbon atoms, and is straight-chain or branched chain, such as, for example, ethenyl, allyl, 1-methylethenyl and 2-methylallyl.

The alkoxycarbonylaminoalkenyl group R is thus for example Methoxycarbonylaminoäthenyl, Äthoxycarbonylaminoallyl or isopropoxycarbonylaminoallyl.

When R is the group -CH = NOR, in which R is a hydrogen atom or an alkyl group with 1 to 6 carbon atoms is, for example, isonitroso methyl, methyl isonitrosomethyl, Ethyl isonitrosomethyl, n-propylisonitrosomethyl or isopropylisonitrosomethyl.

The halogen atom R is, for example, chlorine, fluorine or bromine.

The alkyl group R has up to 7 carbon atoms, preferably up to 4 carbon atoms, and is straight-chain or branched and, for example, methyl, ethyl, n-propyl, Isopropyl, η-butyl, sec-butyl or tert-butyl.

The alkoxy group R has up to 7 carbon atoms, preferably up to 4 carbon atoms, and is straight-chain or branched-chain, such as methoxy, ethoxy, n-prop-

60981 9 / 12SS ORIGINAL INSPECTED

- - 6 - 2 b 3 1 3 1 2

oxy, isopropoxy, n-butoxy and tertiary butoxy.

The alkyl group R has the same meaning as the alkyl

group R and is, for example, methyl, ethyl, n-propyl, isopropyl, n-3utyl, secondary-butyl or tert-butyl.

The alkanoyl group R has up to 7 carbon atoms, preferably up to 4 carbon atoms and is straight or branched chain, such as formyl, acetyl, propionyl, butyryl, isopropionyl and see.-butyryl.

5 6

The alkyl group R and alkyl group R have the same function

Meaning like the alkyl group R and are, for example, methyl, ethyl, n-propyl, isopropyl, η-butyl, sec-butyl and tert-butyl.

The halogen atom R is, for example, chlorine, fluorine or bromine.

7 8

The alkyl group R and the alkyl group R have the same meaning as the alkyl group R and are, for example Methyl, ethyl, propyl, isopropyl, η-butyl, sec-butyl and

tert-butyl.

7 R

The alkoxy group R and the alkoxy group R have the same

Meaning like the alkoxy group R and are, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy and tert-but- ^οχ Υ · - 7 -

60981 9/1285

· "" 7 - ■

7. b 3 1 3 1 2

The Formy! Group R is the group -HCO.

The alkanoyl group R has the same meaning as that

4th
Alkanoyl group R and is, for example, acetyl, propionyl,

n-butyryl and tert-butyryl.

9
The sulfo group R is the group HO ₃ S-. The SuIfino group

9 9

R is the group HO ₂ S-. The cyano group R is the group NC-. m is preferably 0 and 1, η is preferably 1 and 2,

The new compounds have valuable pharmacological properties. Thus, they block the ß-receptors of the heart, which leads to the termination of the antagonism of tachycardia after an intravenous injection of 0.5 / Ug / kg of d / 1 isoproterenol sulfate in an anesthetized cat at an intravenous dose of 0.002 to 2 mg / kg. So block they reduce the vascular ß-receptors, which results in the termination of the vasodilator antagonism after an intravenous Injection of 0.5 µg / kg of d / 1-isoproterenol sulfate an anesthetized cat at an intravenous dose of 3 mg / kg or more. The compounds are therefore cardiac selective.

The new compounds can be used as cardiac selective antagonists adrenergic ε -receptor stimulants, such as in the treatment of exogenous or endogenous arrhythmias and angina pectoris. They can also be used as intermediates in the manufacture of other valuable pharmaceutical products

Use connections. - 8th -

6 0 9 8 1 9/1 2 B B

I b 3 1 3 1 2

Preferred amine derivatives are those of the general formula Ia

EAR ^3a R ^5a ϋ ^? *

Wed

9
R- ^a ) (Fr ^a ) Ar-aCH_CHCHNC-

_CHCHNC- (CH ₀ ) -Y ^ - {' Ά)

' ⁶ V

4a (CH ₉ ) R

2 m

R ^{la means} the group -CH ₂ CH = CH or -CH ₂ C = CH. R is a hydrogen atom, halogen atom, an alkyl group

3a

or alkoxy group, R is a hydrogen atom or a

4a
Alkyl group, R is a hydrogen atom, an alkanoyl group or benzyl group, R and R are each hydrogen atoms

7a 8a

or alkyl groups, R and R are each hydrogen atoms,

9a halogen atoms, alkyl groups or alkoxy groups, R is a hydrogen atom, an alkanoyl group, sulfo group, sulfino group, cyano group, trifluoromethyl group, alkoxycarbonylaminoalkyl group, the group -CONR R or the group -COKHNR ^1Oa R ^lla , in which R ^loa and R ^{lla are} hydrogen atoms or together with form a heterocyclic ring with the nitrogen atom to which they are attached. Y is a divalent group consisting of -0- or -CH ₃ -, η is an integer from 0 to 5, m is an integer from 0 to 2, and Ar is a phenyl radical, thiazolyl radical or thiadiazolyl radical, where, if Y ^a denotes CH ₂ , η is 1 to 5, and R is bonded in the 2- or 3-position to the phenyl radical, in the 4- or 5-position to the thiazolyl radical and in the 4-position to the thiadiazolyl radical. In addition, the concept of the invention also includes the therapeutically acceptable salts of all of the amine derivatives described above. - 80v-

609819/1285

ORIGINAL INSPECTED

Of the compounds of the formula Ia, particularly advantageous compounds are those in which R ^{a is} the group o-CH CH = CH, m-CH ₂ CH = CH ₂ , o ~ CH ₂ C = CH or m-CH ₂ C = CH, R ^2a denotes a hydrogen atom, chlorine atom, bromine atom, a methyl group, ethyl group, methoxy group or ethoxy group, R

4a denotes a hydrogen atom or a methyl group, R denotes a hydrogen atom, a formyl group, acetyl group or benzyl group, R ^a and R ^a each denote hydrogen atoms, methyl groups or ethyl groups, R ^a and R ^a each denote hydrogen atoms, chlorine atoms, Bromatoir.e, methyl groups , A * denotes ethyl groups, methoxy groups or ethoxy groups, R ^a denotes a hydrogen atom, a formyl group, acetyl group, sulfo group, sulfino group, cyano group, trifluoromethyl group, methoxycarbonylaminoethyl group, ethoxycarbonylaminoethyl group, carbamyl group, methylcarbyl group or morphonyl group or methylcarbamyl group, dimethylcarbyl group -CH-- denotes, η denotes an integer from O to 5 and m denotes an integer from O to 2, Ar denotes a phenyl radical or thiazolyl radical, where, when Y denotes the group CH, η denotes 1 to 5, where R ^a is bonded to the phenyl radical in the 2- or 3-position and to the thiazolyl radical in the 4- or 5-position. The therapeutically acceptable salts of these amine derivatives are also advantageous.

Those compounds of the formula Ia may be mentioned as preferred in which R is the group 0-CH ₂ Cl = CH ₂ or 0-CH ₂ = CE, R is a hydrogen atom, a chlorine atom, a methyl group or

_ Q -

6 0 9 3 19/1285 OR! G!. \ 'AL INSPECTED

^ 531312

Methoxygruppa means, R means a hydrogen atom, R ^{a means} a hydrogen atom, R ^a and R each Was-

7a 8a represent hydrogen atoms or methyl groups, R and R each

9a

because hydrogen atoms or methyl groups mean, R is a Hydrogen atoms, a carbarayl group, methoxycarbonylaminoethyl group, Methylcarbamyl group or morpholinocarbonyl group means, Y means -0-, η means 1 or 2, m means 0, 1 or 2 means and Ar means a phenyl radical. The same applies to the therapeutically acceptable salts of these compounds.

Appropriate amines are those of the general formula Ib

, 7b

0HR ^3b R ^5b

Γ \ jni ULrI loUI IvI IiV

(R ^XD ) iR ^ ^a ) ArCCH ₂ CHCHN-C- (CH ₂ ^ _n - '

, 6b

Ib

or their therapeutically acceptable salts, wherein R is the

- 2 B)

Group -OCH ₂ CH = CK ₂ or -OCH ₂ C = CH means, R means a hydrogen atom, halogen atom, an alkyl group or alkoxy group, R means a hydrogen atom or an alkyl group

4b

R denotes, R denotes a hydrogen atom, an alkanoyl group or benzyl group, R ° and R denote hydrogen atoms or alkyl groups, R and R V denotes hydrogen atoms, halogen atoms, alkyl groups or alkoxy groups, R denotes a hydrogen atom, an alkanoyl group, sulfo group, sulfo group, cyano group, trifluoromethyl group, alkoxycarbonylaminoalkyl group, the group -CONR R or the group -CONHiIR ¹⁰¹⁵ R ^{1 Ib} , in which R 10b and R ^{11b are} hydrogen atoms

6 0 9 8 19/1285 - ίο -

ORIGINAL INSPECTED

^ 2S31312

'rl

or together with the nitrogen atom to which they are bonded denote a heterocyclic ring, Y denotes a divalent radical -0- or -CH ₃ -, η denotes an integer from 0 to 5 and m denotes an integer from 0 to 2 and Ar denotes a phenyl radical, thiazolyl radical or thiadiazolyl radical, where Y is preferably “CH ₃ - udd η preferably 1 to 5 and where R is in the 2- or 3-position on the phenyl radical, in the 4- or 5-position on the thiazolyl radical and in the 4 Position is bound to the thiadiazolyl radical.

Of the compounds of the formula Ib, those are particularly advantageous in which R ^{lb is} the group -OCH ₂ CH = CH ₂ or -OCH ₂ C ^ cH, R is a hydrogen atom, chlorine atom, bromine atom, methyl group, ethyl group, methoxy group or ethoxy group / R denotes a hydrogen atom or a methyl group, R denotes a hydrogen atom, a formyl group, acetyl group or benzy group, R and R denote hydrogen atoms, methyl groups or ethyl groups, R and R denote hydrogen atoms, chlorine atoms, bromine atoms, methyl groups, ethyl groups, methoxy groups or ethoxy groups, R denotes a hydrogen atom, a formyl group, acetyl group, sulfo group, sulfino group, cyano group, trifluoromethyl group, methoxycarbonylaminoethyl group, ethoxycarbonylaminoethyl group, carbamyl group, methylcarbamyl group, dimethylcarbamyl group or morpholinocarbonyl group, Y denotes _{an integer from 0 to -CH 2} - denotes an integer from 0 to 5 and m is an integer from 0 to 2, Ar denotes the phenyl radical or thiazolylre st means, where, when Y ^{b is} the group -CH ^, η means 1 to 5, and where-

609-19 / 17-5 -H-

ORIGiNAL INSPECTED

Ib 3 1 3 1 2

when R is bonded to the phenyl radical in the 2- or 3-position and to the thiazolyl radical in the 4- or 5-position. The same also applies to the therapeutically acceptable salts of these amines. Preference is given to those compounds of the formula Ib in which R is the group 0-OCH ₂ CH = CH ₂ or 0-OCH ₂ C = CH, R is a hydrogen atom, chlorine atom, a methyl group or methoxy group, R is a hydrogen atom, R ^4b denotes a hydrogen atom, R ^5b and R ^6b denote hydrogen atoms or methyl groups, R and R denote hydrogen atoms or methyl groups, R denotes a hydrogen atom, a Carbarny group, methoxycarbonylaminoethy group,

Means methylcarbamyl group or morpholinocarbonyl group, Y is -0-, η is 1 or 2, m is 0, 1 or 2 and Ar means the phenyl radical. The same applies to the therapeutically acceptable salts of these amines.

Favorable amines are also those of the general formula Ic

_0HR 3c _R 5c ^ ^

tR ^lc ) (R ^2c ) ArOCH, CHCHN-C (CH ₉ ) -Ί ^ Μ ^ V ^Ic

R ^6c
10 iCH ₂ ) _m R ^9c

wherein R is an alkyl group or alkoxyalkyl group, R ^{2c is} a hydrogen atom, halogen atom, an alkyl group or

3c

Alkoxy group means, R a hydrogen atom or a Alkyl group means, R a hydrogen atom, an alkanoyl

- 12 -

60981 9/1285
ORIGINAL INSPECTED

η ?. b 5 1 3 1 2

group or Benzy! group means, R ^c and R ^c hydrogen

7c Sc atoms or alkyl groups, R and R denote hydrogen atoms, Mean halogen atoms, alkyl groups or alkoxy groups,

9c
R is a hydrogen atom, an alkanoyl group, sulfo group, sulfino group, cyano group, trifluoromethyl group, alkoxy group

lOc lic carbonylaminoalkyl group, the group -CONr r or the

lOc lic IQf- lic

Group -CONHNR R denotes in which RR denotes hydrogen atoms or when taken together with the nitrogen atom to which they are bonded form a heterocyclic ring, Y ^c denotes the divalent group -0- or -CH--, η denotes an integer from 0 to 5 and m is an integer from 0 to 2 and Ar is a phenyl radical, thiazolyl radical or thiadiazolyl radical, where, when Y ^{c is} the group ~ CH ₂ ~, η is 1 to 5, and where R is in the 2- or 3-position the phenyl radical is bonded in the 4- or * 5-position to the thiazolyl radical and in the 4-position to the thiadiazolyl radical,

Ic
where, when R is methyl, this is not in the 2-position

9c is bonded to the phenyl radical, except when R is an alkoxy

Ic means carbonylaminoalkyl group, and when R ~ isobutyl

5c 6c means that both groups R and R are methyl groups.

Of the compounds of the general formula Ic, those are particularly advantageous in which R is an alkyl or alkoxyalkyl

2c
group means, R a hydrogen atom, chlorine atom, bromoarom, a methyl group, ethyl group, methoxy group or

3c

Ethoxy group means, R is a hydrogen atom or a

4c
Methyl group means, R a hydrogen atom, a phenyl

5c 6 c denotes a residue, acetyl residue or benzyl residue, R and R each

- 13 -

609819/1285 ORIGINAL INSPECTED

wells denote hydrogen atoms, methyl groups or ethyl groups, R ^C and R ^c each denote hydrogen atoms, chlorine atoms, bromine atoms, methyl groups, ethyl groups, methoxy groups or

9c

Represents ethoxy groups, R, represents a hydrogen atom, a formyl group, acetyl group, sulfo group, sulfino group, cyano group, trifluoromethyl group, Methoxycarbonylaminoäthylgruppe, Äthoxycarbonylaminoäthylgruppe, carbamyl, Methylcarbamylgruppe, Dimethylcarbaraylgruppe, .Morpholincarbonylgruppe, Y -0- or -CH ₂ ^- means a whole η Number from 0 to 5 and m is an integer from 0 to 2, Ar is the phenyl radical or thiazolyl radical, where, when Y ~ ^c ^ 7 ~ , η is 1 to 5, and where R ^lc in 2- or 3- Position is bonded to the phenyl radical and in the 4- or 5-position to the thiazolyl radical.

Those compounds of the formula Ic are preferably mentioned in which R is methyl, ethyl, ethoxymethyl, methoxyethyl or eth-

2c

oxyäthyl means, R is hydrogen, chlorine, methyl or meth-

3 c 4 c

oxy denotes, R denotes a hydrogen atom, R denotes a hydrogen atom, R ^c and R ^c each denote hydrogen atoms or methyl groups, R ^c and R ^c each denote hydrogen

9c denotes atoms or methyl groups, R denotes a hydrogen atom, carbamyl, methoxycarbonylaminoethyl, methylcarbamyl or morpholine ^{carbonyl, R c} denotes -0-, η denotes 1 or 2 and m denotes 0, 1 or 2 and Ar denotes the phenyl radical. The same applies to the therapeutically acceptable salts

of these connections.

- 14 -

6 0 9 8 1 _{9/1 2 8 5 cn}

ORIGINAL! KSPECTED

2b31312

Preferred amines are also those of the general formula Id

_R 7d 0HR ^3d R ^5d _> _ .R ^8d

IrI ? Rt 111 d '/ ^! \ * '

1- ^ LH υπ »Μ ~ L ILn ^ J -Υ - * ^NN

(R ^u ) (R MrOCH ₇ CHCHN-C (CH ₇ ) -Υ—> / ^A ^ Id

4d

where R is an alkoxyalkoxy group, R is hydrogen atom, halogen atom, an alkyl group or alkoxy group, R denotes a hydrogen or an alkyl group,

4d
R denotes a hydrogen atom, an alkanoyl group or benzyl group, R and R each denote hydrogen atoms or alkyl groups, R and R each denote hydrogen atoms, halogen

9d

atoms, alkyl groups or alkoxy groups, R a hydrogen atom, an alkanoyl group, sulfo group, sulfino group, cyano group, trifluoromethyl group, alkoxycarbonylaminoalkyl group, the group -CONR ^10d R ^lld or the group -CONHNR ^10d R ^lld , in which R and R are hydrogen atoms or together with the nitrogen atom to which they are bonded form a heterocyclic ring, Y denotes the divalent group -0- or -CH “-, η denotes an integer from 0 to 5 and m denotes an integer from 0 to 2 and Ar denotes the phenyl radical, thiazolyl radical or thiadiazolyl radical, where R is bonded in the 2- or 3-position to the phenyl radical, in the 4- or 5-position to the thiazolyl radical and in the 4-position to the thiadiazolyl radical and where, when Y ~ ^CH 2 ~ * ^st ' ⁿ 1 ^{b; i} - ^s 5 means.

- 15 -

609819/12

Ai ^ b 3 1 3 1 2

Of the compounds del * Formula Id, there are particularly those Salts or their therapeutically acceptable salts are advantageous, in which R is alkoxyalkpxy, R is hydrogen, chlorine, Brozti, methyl, ethyl, methoxy or ethoxy means, R was

4d
signifies hydrogen or methyl, R signifies hydrogen, formyl, acetyl or benzyl, R and R each signify hydrogen, methyl or ethyl, R and R each signify hydrogen, chlorine, bromine, methyl, ethyl, methoxy or ethoxy, R signifies hydrogen, formyl, Acetyl, sulfo, sulfino, cyano, trifluoromethyl, methoxycarbonylaminoethyl, ethoxycarbonylaminoethyl, carbamyl, methylcarbamyl, dimethylcarbamyl or morpholine carbonyl mean, Y means -O- or "CH -" * means, η is an integer from 0 to 5, m is an integer from O. to 2, Ar denotes the phenyl radical or thiazolyl radical, where, when Y ^{d is} -CH ₂ -, η denotes 1 to 5 and where R ^{ld is} in the 2- or 3-position on the phenyl radical and in the 4- or 5-position on the thiazolyl radical is bonded.

Those compounds of the formula Id and their therapeutically acceptable salts are preferably mentioned in which R is methoxymethoxy, methoxyethoxy or ethoxyethoxy, R is hydrogen, chlorine, methyl or methoxy, R is hydrogen, R is hydrogen, R and R are each hydrogen or methyl, R ^7d and R ^{8d is} each hydrogen or methyl, R is hydrogen, carbamyl, methoxycarbonylaminoethyl, methylcarbamyl or morpholine carbonyl. Y is -Ο-, η is 1 or 2, m is 0, 1 or 2 and Ar is phenyl.

- 16 -

6Π9819 / 1285 ORIGINAL INSPECTED

I b 3 1 3 1 1

Advantageous amines are also those of the general formula Ig

P ⁸ S

jArDCH ^ HCH ^ C (CH-J -Y * / '

ig

(CH ₉ ) R 2 m

wherein R ^g denotes an alkoxycarbonylaminoalkoxy group, the group HOCH ₂ CH ₂ NHCOCh ₂ O- or the group CH ₃ OCH ₂ NHCOCh ₂ O-, R "denotes a hydrogen atom, a halogen atom, an alkyl group or an alkoxy group, R" denotes a hydrogen atom or a Denotes alkyl group and R denotes a hydrogen atom, an alkanoyl group or benzyl group, R "and R ^ each denote hydrogen atoms or alkyl groups, R" and R ^ each denote hydrogen atoms, halogen atoms, alkyl groups or alkoxy groups, R denotes a hydrogen atom, an alkanoyl group, sulfo group, sulfino group, cyano group, Trifluprmethy! group, Alkoxycarbonylaminoalkylgruppe, the group -CONR ^1OG R ^llg or the group -CONHNR ¹⁰¹ ^ R ^{1 lg,} where R ^g and R ^g are hydrogen or taken together with the nitrogen atom to which they are attached, a heterocyclic ring form, Y ^{g is} the divalent group -0- or ~ CH ₂ ~, η is an integer from 0 to 5, m is an integer from 0 to 2 and Ar d s phenyl, thiazolyl or thiadiazolyl, where R is 2-odar bonded in the 3-position to the phenyl radical in the 4- or 5-position on the Thiazolylrast and in the 4-position of the thiadiazolyl _r and wherein when Y ^g ~ ^CH 2 ~ ^is ' ⁿ ^ ^{to 5 mean} ~. _ γη _

609819/1285

2 b 3 1 3 1 2

Of the compounds of the formula Ig, particularly preferred compounds and their therapeutically acceptable salts are those in which R "is an alkoxycarbonylaminoalkoxy group, the group KOCH ₂ CH ₂ NHCOCh ₂ O- or the group CH, R ^{g is} hydrogen, chlorine, bromine, methyl, ethyl , Methoxy or ethoxy, R ^g denotes hydrogen or methyl, R ^ denotes hydrogen, formyl, acetyl or benzyl, R ^g and R ^g each denote hydrogen atoms, methyl or etnyl, R ^g and R ^g each denote hydrogen atoms, chlorine, bromine, methyl mean ethyl, methoxy or ethoxy, R ^g is hydrogen, formyl, acetyl, SuIfο, SuIfino, cyano, trifluoromethyl, Methoxycarbönylaminoäthyl, Äthoxycarbonylaminoäthyl, carbamyl, methylcarbamyl, dimethylcarbamyl or morpholinocarbonyl, Y is -0- or -CH ^g ₃ - is, η an integer from to 5, m e'an integer from Ό to 2 and Ar denotes the phenyl radical or 2-thiazolyl radical, where, when Y ^g denotes -CH ₂ -, η is 1 to 2, and where R ^g in 2 - or 3-position at de n is phenyl radical and is bonded to the thiazolyl group in the 4- or 5-position.

Those compounds according to the formula Ig and their therapeutically acceptable salts are preferably mentioned in which R is methoxycarbonylaminomethoxy, methoxycarbonylaminoethoxy, ethoxycarbonylaminomethoxy, ethoxycarbonylaminomethoxy, the group HOCh ₂ CH ₂ NHCOCH ₂ O- or the group CH ₃ OCH ₂ Ch ₂ NHCOCH ₂ O-, R ^ signifies hydrogen, chlorine, methyl or methoxy, R ^3g signifies hydrogen, R ^4g signifies hydrogen, R ^g and R ^g each signify hydrogen, hydroxyl or methyl,

- 18 609819/1285

2 b 3 1 3 1 2

R ^g and R ^g each denote hydrogen or methyl, R ^g denotes hydrogen, carbamyl, methoxycarbonylaminoethyl, methylcarbamyl or morpholine ^{carbonyl, Y g} denotes -0-, η is 1 or 2, m is 0, 1 or 2 and Ar denotes the phenyl radical.

Advantageous amines are also those of the general formula Ih

R ^7h

0HR ^3h R ^5h i _sh

III 7 Γ ^ N ^ - R

(R ^lh ) (R ^2h ) Ar0CH _o CHCHN C (CH ₀ ) -Y-— (/ ■ - ^ T _Ih

'Bh R

R ^4h

wherein R denotes an alkoxycarbonylaminoalkyl group, R denotes a hydrogen atom, halogen atom, an alkyl group or an alkoxy group means, R is a hydrogen atom or an alkyl

4h
group denotes, R denotes a hydrogen atom, an alkanoyl group or benzyl group, R and R each denote hydrogen atoms or alkyl groups, R and R each denote hydrogen atoms, halogen atoms, alkyl groups or alkoxy groups, R hydrogen atoms, alkanoyl groups, sulfo groups, sulfino groups, cyano groups, trifluoromethyl groups, alkoxycarbonylaminoalkyl groups , the group -CONR R or the group -COMHNR ¹⁰¹¹ R ^{1 lh} , in which R ^1Oh and R ^{llh are} hydrogen atoms or taken together with the nitrogen atom to which they are bonded form a heterocyclic ring, Y ^{1 is} the divalent group -0- or -CKp- denotes, η denotes an integer from 0 to 5, into an integer of

- 19 -

609819/1? 85

- »- 2S31312

Jit)

O to 2 and Ar denotes the phenyl radical, thiazolyl radical or thiadiazolyl radical, where R is bonded in 2- or 3-position to the phenyl radical, in 4- or 5-position to the thiazolyl radical and in 4-position to the thiadiazolyl radical, where when Y denotes -CH ₃ -, η is 1 to 5, and when R denotes acetylaminomethyl in the 3-position, m is not 0.

Of the compounds of the formula Ih, particularly advantageous compounds and their therapeutically acceptable salts are those in which R is an alkoxycarbonylaminoalkyl group, R ^{n is} hydrogen, chlorine, bromine, methyl, ethyl, methoxy and ethoxy, R is hydrogen or methyl, R is hydrogen, formyl , Acetyl or benzyl, R and R each denote hydrogen, methyl or ethyl, R and R each denote hydrogen, chlorine, bromine, methyl, ethyl, methoxy or ethoxy, R hydrogen, formyl, acetyl, sulfo, sulfino , Cyano, Trifluprmethyl, Methoxycarbonylaminoathyl, Äthoxycarbonylarainoäthyl, Carbamyl, Methylcarbamyl, Dimethylcarbaryl or Morpholincarbonyl means, Y means -0- or ~ CH_-, η means an integer from 0 to 5, m means an integer from 0 to 2 and Ar denotes Phenyl radical or thiazolyl radical, where, when Y ~ ^Cii o ~ bleeds, η is 1 to 5, and where R is in the 2- or 3-position on the phenyl radical and in the 4-position or 5-position on the thiazolyl radical g is bound.

Those compounds of the formula Ih and their therapeutically acceptable salts are preferably mentioned in which R is methoxycarbonylaminomethyl, Methoxycarbonylaminoethyl or Äthoxycar-

6 0 9 8 19/1285 - 20 -

1 b 3 1 3 1 1

bonylaminoäthyl denotes, R denotes hydrogen, chlorine, methyl or methoxy, R denotes a hydrogen atom, R denotes a hydrogen atom, R and R each denote hydrogen or methyl, R or R each denote hydrogen or methyl, R denotes hydrogen, carbamyl, methoxycarbonylaihinoethyl, methylcarbamyl or Morpholine carbonyl is, Y ^{h is} -0-, η is 1 or 2, m is 0, 1 or 2 and Ar is phenyl.

Advantageous amines are also those of the general formula Ii

ρ "

_0HR 3i _n 5i j _D Bi

CR ¹¹ ) ( ~ ²ⁱ ) ArCCH ₂ CHCHN-C- (CH ₉ ) "-Υ—

-Ui

Ii 2i

wherein R is an alkoxycarbonylaminoalkenyl radical, R a hydrogen atom, halogen atom, an alkyl group or AIk-

3i

oxy group means, R a hydrogen atom or an alkyl group means R is a hydrogen atom, an alkanoyl group or benzyl group, R and R are each hydrogen

7i 8i

Atoms or alkyl groups are, R and R are each hydrogen atoms, halogen atoms, alkyl groups or alkoxy groups

9 i

mean, R a hydrogen atom, an alkanoyl group, sulfo group, Sulfino group, cyano group, trifluoromethyl group, Alkoxycarbonylaminoalkyl group, the group -CONR R or

- 21 -

60981 9/1285

denotes the group -CONHNR ¹⁰¹ R ¹¹¹ , in which R ¹⁰¹ and R ¹¹¹ denote hydrogen atoms or taken together with the nitrogen atom to which they are bonded form a heterocyclic ring, Y denotes a divalent group -0- or -CH ₂ ~, η denotes a integer from 0 to 5 and m an integer from 0 to 2 and Ar denotes a phenyl radical, thiazolyl radical or thiadiazolyl radical, where R is in the 2- or 3-position on the phenyl radical, in the 4- or 5-position on the thiazolyl radical and is bonded in the 4-position to the thiadiazolyl radical and where, when Y ~ ^CH 2 "" tet, η is 1 to 5.

Of the compounds of the formula II, such compounds and their therapeutically acceptable salts are particularly advantageous

Ii 2i

sticky, where R is alkoxycarbonylarainoalkenyl, R is hydrogen, Means chlorine, bromine, methyl, ethyl, methoxy or ethoxy,

R ^{31 is} hydrogen or methyl, R is hydrogen, formyl, acetyl or benzyl, R and R are each hydrogen,

7i 8i are methyl or ethyl, R and R are each hydrogen, Mean chlorine, bromine, methyl, ethyl, methoxy or ethoxy,

9i
R denotes hydrogen, formyl, acetyl, sulfo, sulfino, cyano, trifluoromethyl, methoxycarbonylaminoethyl, ethoxycarbonylaminoethyl, carbamyl, methylcarb_amyl, dimethylcarbamyl or morpholine carbonyl, Y denotes -0- or -CH_- denotes a whole number from 0 to 5 and m denotes an integer from 0 to 5 Number from 0 to 2, Ar denotes the phenyl radical or thiazolyl radical, where, when Y ¹ ~ ^CH ₂ ~ ^is ' ⁿ * ^{to 5} , and where R ^{11 is} in the 2- or 3-position on the phenyl radical and in 4- or 5-position is bound to the thiazolyl radical.

609819/1285 -22-

2B31312

Those compounds according to the formula Ii and their therapeutically acceptable salts are preferably mentioned, in which R ^χ methoxycarbonylarainoäthenyl, Methoxycarbonylaminoallyl, Äthoxycarbonylaminoätbenyl or Äthoxycarbcnylaminoallyl be

2i

R means hydrogen, chlorine, methyl or methoxy, R means hydrogen, R means hydrogen, R and R each denotes hydrogen or methyl, R and R

9i are each hydrogen or methyl, R is hydrogen, carbamyl, methoxycarbonylaminoethyl, methylcarbamyl or Morpholine carbonyl means, Y means -0-, η means more 2 and m is 0, 1 or 2 and Ar is the phenyl radical.

Advantageous amines are also those of the general formula Ik

H ³ T

"'-""" 2 ^W ° 7 ι 2 η / Ik

_R 4k

where R is the group -CH = NOR, where R is a hydrogen atom or an alkyl group with 1 to 6 carbon

2k
atorr.en is, R is a hydrogen atom, halogen atom, an alkyl

3k group or alkoxy group, R a hydrogen atom

4k or an alkyl group, R denotes a hydrogen atom, an alkanoyl group or benzyl group, R 'and R ^K each

7k because hydrogen atoms or alkyl groups mean R and

8k
R each is hydrogen atoms, halogen atoms, alkyl groups

- 23 -

609819/1285

9 k

or alkoxy groups, R a hydrogen atom, a Alkanoyl group, sulfo group, sulfo group, cyano group, Trifluoromethyl group, alkoxycarbonylanimoalkyl group, the

1Ok 11k lOk 11 Tc

Group -CONR R or the group -CONHNR R means, wherein R and R are hydrogen atoms or, taken together form a heterocyclic ring with the nitrogen atom to which they are attached, Y the divalent group -0- or -CH-- means, η means an integer from 0 to 5, m is an integer from 0 to 2 and Ar is the phenyl radical, thiazolyl radical or thiadiazolyl radical,

Ik
where R is in the 2- or 3-position on the phenyl radical, in the 4- or 5-position on the thiazolyl radical and in the 4-position on the

k Thiadiazolylrest is bonded and where, if Y ~ ^CH 2 ~

indicates η is 1 to 5.

Of the compounds of the formula Ik, such compounds and their therapeutically acceptable salts are particularly preferred

Ik
added, where R is the group -CH = NOR, where R is a hydrogen atom or an alkyl group with 1 to 6 carbon atoms, R is hydrogen, chlorine, bromine, methyl, ethyl,

3k
Methoxy or ethoxy denotes, R denotes hydrogen or methyl

4k

means, R means hydrogen, formyl, acetyl or benzyl, R and R are each hydrogen, methyl or ethyl

7k 8k

interpret, R and R each hydrogen, chlorine, bromine, methyl,

9k is ethyl, methoxy or ethoxy, R is hydrogen, formyl, acetyl, sulfo, sulfino, cyano, trifluoromethyl, methoxycarbonylaminoethyl, Äthoxycarbonylairinoäthyl, Carbamyl, Me thy lc ar b any 1, Diinethylcarbamyl or morpholine carbonyl means, Y -0-

- 24 -

609819/1285

-JK-

ZS I S 313 1 1

or -CHy- denotes, η denotes an integer from 0 to 5 and m denotes an integer from 0 to 2, Ar denotes the phanyl radical or * hiazolyl radical, where, when Y is -CH -, η

Ik
1 to 5, and where R is bonded in the 2- or 3-position to the phenyl radical and in the 2-position to the thiazolyl radical.

Those compounds of the formula Ik and their therapeutically acceptable salts may preferably be mentioned in which

Ik
R is the isonitrosomethyl radical, methylisonitrosomethyl radical, ethyl isonitrosomethyl radical, propylisonitrosomethyl radical or

2k is tert-butylisonitrosomethyl radical, R is hydrogen, Means chlorine, methyl or methoxy, R means hydrogen,

41c ^ Tc file

R denotes hydrogen, R and R each denote hydrogen or methyl, R and "R are each hydrogen or

9k
Methyl, R is hydrogen, carbamyl, methoxycarbonylaminoethyl, methylcarbamyl or morpholine carbonyl, Y is -O-, η is 1 or 2, m is O, 1 or 2 and Ar is the phenyl radical.

The following compounds deserve special mention:

1) 1- / 2- (4-Carbamy! Phenoxy) -äthylaminoZ-S- (2-allylphenoxy) -propanol-2,

2) 1- / 2- (4-carbamylphenoxy) ~ ethylamino7-3- (2-chloro-5-methylphenoxy) -propanol-2,

3) 1- / 2- (4-carbamylphenoxy) -äthyIamino / -3- (2-methoxyethylphenoxy) -propanol-2,

- 25 -

609819/1 2 B 5

4) 1- / 2- (4-Carbamylphenoxy) -äthylaminoJ-S- (4-chloro-3-thiazoloxy.) -propanol-2,

5) 1- / T-Methy 1-2- (4-carbamylphenoxy) -äthylamino / - ^ - (2-allylphenoxy) -propanol-2,

6)! - / T-Methyl-2- (2-methylphenoxy) -äthylaminoZ-S- (2-allylphenoxy) -propanol-2,

7) l- / T-methyl-2- (4-methylphenoxy) -äthylamino7-3- (2-allylphenoxy) -propanol-2,

8) 1/2 "- (4-methoxycarbonylaminoethylphenoxy) -ä (2-methoxycarbonylaminoethylphenoxy) -propanol-2,

9) l - / _ T-methyl-2- (4-methylcarbamylphenoxy) -ä 2- (carbamylethylphenoxy) -propanol-2,

10) 1- / Ί- (2-trifluoromethylphenylamino) -äthy1amino / -3- (3 methylcarbonylaioinoäthylphenoxy) -propanol-2,

11) I - /! ·? (4-carbamy lphenoxy) -äthylaminoZ-S- (2-methoxycarbonylaminoallylphenoxy) -propanol-2,

12) 1- / 2- (4-Morpholincarbonylphenoxy) -äthylaminoZ-S- (2-allylphenoxy) -propanol-2,

13) 1- / T-methyl-2- (4-carbamyl-phenoxy) -ethylamino7-3- (2-methylisonitrosomethylphenoxy) -propanol-2,

14) 1- / T- (2-methoxycarbonylamino) -ethyl) -phenoxyäthylamino / -3- (2-methylphenoxy) -propanol-2,

15) 1- / 1- (4-Carbamylphenoxy) -äthylamino7 ~ ³ ~ (3-allylphenoxy) -propanol-2,

16) 1- / 2- (4-carbamylphenoxy) -äthylaminoZ-S- (2-chlorophenoxy) -propanol-2,

17) 1- / 7- (4 ⁱ -carbamylphenoxy) -äthylaminoZ-S- (2-dichlorophenoxy) propanol-2.

60981 9/1285

- 26 -

The new compounds are obtained according to methods known per se. For example, a connection becomes the general Formula II

X ¹ R ³

12 3 1

wherein Ar, R, R and R have the above meanings, X is a hydroxyl group and Z is a reactive, esterified hydroxyl group or X and id Z taken together represent an epoxy group form, with an amine of the general formula III

R ⁵

Ill

HIi - C -

converted, wherein R, R, R, R, R, R, Y, m and η as above are defined.

A reactive esterified hydroxyl group is particularly a hydroxyl group that is bound with a strong inorganic or organic acid is esterified, preferably with hydrohalic acid such as hydrochloric acid, hydrobromic acid or hydriodic acid, furthermore with sulfuric acid or a strong organic sulfonic acid, such as a strong aromatic sulfonic acid, such as benzenesulfonic acid, 4-bromobenzenesulfonic acid or 4-toluenesulfonic acid. Thus Z is before-

- 27 -

609819/1285

ORIGINAL INSPECTED

preferably chlorine, bromine or iodine.

This implementation takes place in the usual way. When using a reactive ester as a starting material finds the Production preferably in the presence of a basic condensing agent and / or with an excess of an amine instead of. Suitable basic condensing agents are, for example, alkali hydroxides, such as sodium or potassium hydroxide, Alkali carbonates, such as potassium carbonate, and alkali metal alcoholates, such as sodium methylate, potassium ethylate and potassium tert-butoxide.

Furthermore, a compound of the general formula IV

γ ■ -

CR ¹ ,) (R ² ) Ar0CH ₂ CH0HCHN (R ⁴ ) H IV

12 3 4
wherein Ar, R, R, R and R have the above meaning, with

a compound of the general formula V

Z-C- (CH, 1-Y

(CH ₂ I _n R ⁹

C r * l QQ

wherein R, R, R, R, R, Y, m, η and Z have the above meaning have to be implemented.

This reaction takes place in the customary manner, preferably in the presence of a basic condensing agent and / or one

- 23 ΒΠ98 1 9/1 285

Excess of an amine. Suitable basic condensation agents are, for example, alkali metal alcoholates, preferably Sodium or potassium alcoholate, or also alkali metal carbonates, such as sodium or potassium carbonate.

You can also use a compound of the general formula VI

(R ¹ ) (R ² JAr-OM VI

1 2

wherein Ar _# R and R have the above meaning and M is a hydrogen atom or an alkali metal, with a compound of the general formula VII

R ⁷ X ¹ R ³ R ⁵ ' _R 8

.Z-CH ₂ CHCH-KC- (CH ₂ I _1n Y '/ ^) VII

R ⁴ R ⁶ '\ t /

react, wherein R ³ , R ⁴ , R ⁵ , R ⁶ , R, R, R, m, n, Y, Z and Y have the above meaning.

This implementation takes place in the usual way. In those cases where reactive esters are used as starting material, can the compound of formula VI expediently in the form of its metal phenolate, such as alkali phenolate, preferably as Sodium phenolate, can be used, or one works in the presence an acid binder, preferably in the presence of a condensing agent which is a salt of the compound of Formula VI can form, such as an alkali metal alcoholate.

- 29 -

609819/128 5

²⁰ 2B31312

Furthermore, nan can split off a radical from a compound of the above formula I, in which R, R, R, R, R, R, R,

8 9
R, R , Y ₁ m and η have the above meaning and in which the nitrogen atom of the amino group and / or the hydroxyl group has a removable radical attached to it.

Such cleavable residues are particularly those which can be cleaved off by solvolysis, reduction, pyrolysis or fermentation are.

Residues that can be split off by solvolysis are preferably radicals that can be split off by hydrolysis or ammonolysis.

Residues that can be split off by hydrolysis are, for example, acyl residues, which, if they are present, are functionally varied carboxy groups, such as oxycarbonyl radicals, such as alkoxycarbonyl radicals, e.g. tert-butoxycarbonyl radicals or ethoxycarbonyl radicals, Aralkoxycarbonyl radicals, such as phenyl-lower alkoxycarbonyl radicals, z.3. Carbobenzyloxy radicals, halocarbonyl radicals, such as Chlorocarbon residues, furthermore arylsulfonyl residues, such as toluenesulfonyl residues or bromobenzenesulfonyl radicals, and optionally halogenated, such as fluorinated lower alkanoyl radicals, such as Formyl, acetyl or trifluoroacetyl radicals, or benzyl radicals or cyano groups or SiIylreste, such as trimethylsilylreste.

Of the abovementioned radicals on the hydroxyl groups which can be split off by hydrolysis, the Oxycarbonyl radicals and the lower alkanoyl radicals or the benzoyl

609819/1285. -3ο-

leftovers used.

In addition to the residues mentioned above, there are also double-bonded residues that can be split off at the amino group by hydrolysis are used, such as alkylidene radicals or phosphorylidene groups, such as a triphenylphosphorylidene group, where the nitrogen atom then receives a positive charge.

Residues which can be split off by hydrolysis on the hydroxyl group and the amino group are also divalent radicals, as may be the case substituted methylene groups. Any organic radicals can be used as substituents on the methylene groups can be used, it being immaterial in the hydrolysis which compound is the substituent on the methylene group is. For example, aliphatic or aromatic radicals, such as those mentioned above, can be used as methylene substituents Alkyl groups or aryl radicals such as phenyl or pyridyl can be used. The hydrolysis can be in any usual way Manner, expediently in a basic or preferably in an acidic medium.

Compounds with residues that can be split off by hydrolysis,

4 are also the compounds according to the formula VIII, if R

means a hydrogen atom,

- 31 -

609819 / 12B5

NR ¹³ VIII

12 13

wherein Ar, R and R have the above meaning, R is a group of the formula IX

j · R "

IX

V " ⁿ W

and X is a carbonyl or thiocarbonyl radical.

The hydrolysis is carried out in a manner analogous to that in the presence of a hydrolyzing agent as in the presence of one acidic agent, e.g. in the presence of dilute mineral acids such as sulfuric acid or hydrohalic acid, or in the presence of basic agents such as alkali hydroxides, e.g. sodium hydroxide. Oxycarbonyl radicals, arylsulfonyl radicals and cyano groups can be split off in a suitable manner with acidic agents, such as with a hydrohalic acid, expediently hydrobromic acid. Preferably can cleavage using dilute hydrobromic acid, optionally in a mixture with acetic acid. Cyano groups are preferably formed with the aid of hydrogen bromide acidic split off at elevated temperature, as in boiling hydrobromic acid, according to the bromine

- 32 -

609819/1285

253) 312

cyan method (von Braun). Furthermore, for example, a tert-3utoxycarbonyl radical can be used under anhydrous conditions by treatment with a suitable acid such as trifluoroacetic acid. Acidic agents are preferred used in a hydrolysis of compounds of the formula VI.

Residues which can be split off by ammonolysis are preferably the Halocarbonyl radicals, such as the chlorocarbonyl radical. The Ammonolyoe can be carried out in the usual way, such as with the aid of an amine which has at least one bonded to the nitrogen atom Contains hydrogen atom, as with the help of a mono- or Di-lower alkylamine, such as methylamine or dimethylamine, or especially with ammonia, preferably at an elevated temperature. Instead of ammonia, one can also use an agent that releases ammonia, such as hexamethylenetetramine.

Agents which can be split off by reduction are, for example, a "^ - -Ar ylalkylrest, such as a benzyl radical, or a <5 ^ -aralkoxycarbonyl radical, like a Benzyloxycarbonylrest, which in usual Can be split off with the help of hydrogenolysis, especially with the help of catalytically activated hydrogen, such as by hydrogen in the presence of a hydrogenation catalyst, e.g. Raney nickel. Others can be split off by hydrogenolysis The radicals are 2-haloalkoxycarbonyl radicals, such as 2,2,2-trichloroethoxycarbonyl radicals or 2-iodoethoxy- or 2,2,2-tribromoeth-

- 33 -

609819/1285

oxycarbonyl radicals which can be split off in the customary manner, expediently by metallic reduction (so-called nascent hydrogen). Nascent hydrogen can
can be obtained by the influence of metal or metal alloys, such as amalgam, on compounds which give off hydrogen, such as carboxylic acids, alcohols or water, in which case zinc or zinc alloys in particular can be used together with acetic acid. The hydrogenolysis of 2-haloalkoxycarbonyl radicals can also take place using ^ hrom or chromium (II) compounds, for example chromium (II) chloride or chromium (II) acetate.

A radical that can be split off by reduction can also be an arylsulphonyl group, such as a toluenesulphonyl group, which is split off in the customary manner by reduction using hydrogen, for example with the aid of an alkali metal such as lithium or sodium, in liquid ammonia, and expediently from a nitrogen atom can be. When carrying out the reduction, care must be taken that other reducing groups are not influenced
will.

Residues which can be split off by pyrolysis, in particular radicals which can be split off from the nitrogen atom, are optionally substituted, but expediently unsubstituted, carbamoyl groups. Suitable substituents are, for example, lower alkyl groups or
Aryl lower alkyl groups, such as methyl or benzyl, or aryl

- 34 -

609819/1285

residues, such as phenyl- The pyrolysis takes place in the usual way, paying attention to other thermally sensitive groups.

Residues that can be split off by fermentation, especially from the nitrogen atom Removable radicals are optionally substituted but appropriately unsubstituted carbamoyl groups. Suitable substituents are, for example, lower alkyl groups or aryl lower alkyl groups, such as methyl or benzyl, or aryl radicals such as phenyl. The fermentation takes place in the usual way In a manner such as the enzyme urease or soybean extract at around 20 ° C or at a slightly higher temperature.

Furthermore, a Schiff base of the formula X or XI,

4 5 6
when R, R and R are hydrogen atoms,

OH R ³

(R ¹ ) (R ² ) ArOCH ₂ CH-C = NR

OH R ³

- ₂ j I 13 _XI (R MR ^) Ar-OCH ₂ CB-CH-N = R

or a cyclic one corresponding to the compound of the formula XI Tautoner of the formula XII

(R ¹ ) (R ² ) Ar-CCH ₂ CH CHR ' _χΙΙ

> 3

13th

- 35 -

60981

are reduced, wherein Ar, R, R, R and R the above

13 "13

Have meaning and R H has the same meaning as R. and where the compounds of the formulas XI and XII can also occur together next to one another. This reduction takes place in the usual way, such as using a Dileichtmetallhydride, such as sodium borohydride, lithium aluminum hydride, using a hydride, such as borane, with formic acid, or by catalytic hydrogenation, such as with Hydrogen in the presence of Raney nickel. During the reduction, care must be taken that no other groups are impaired will.

In addition, the oxo group in the compound can be of the general Formula XIII

OR ³ R ⁵

Γ ί I // 'W "XIiI

GCH ₂ C - CHN -C- tCH ₂ ) _n Y-

(CH ₂ ) _m R ⁹

wherein Ar, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , m, η and Y are as defined above, are reduced to a hydroxyl group. This reduction is carried out in the usual way, especially using a dilute metal hydride, as mentioned above, or according to the "Meerwein-Pondorf-Verley" method or a modification thereof, expediently using an alkanol as a reaction component and as a solvent, such as using of isopropanol, and

- 36 -

609819/1285

using a metal alkoxide such as metal isopropoxide, e.g. aluminum isopropoxide.

Furthermore, in a compound of the general formula XIV

R ³ R ⁵ '° ⁸

OCH ₀ CHOHCHN-C-CCh ₀ ] Y-2 ι 2 m

wherein Ar, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , m _f η and Y die

have the above meaning and X denotes a radical which is converted into a radical R with the same meaning as above.

2 1

can convert X to R.

2 1

A residue X that can be converted into R is

2 1

for example a radical X which can be converted into an alkoxyalkyl radical R, such as a Z -alkyl radical. A connection

1 2

dung XIV with such a radical Z -alkyl as X can be used in

be reacted with a compound alkyl-Z,

1 2

wherein one of Z and Z is a hydroxyl group and the other of the two groups has the above meaning. So you can either use a compound of the formula XV

XV

HQ-alkyl- (R ² ) Ar

R ⁴

609819/1285

with a compound alkyl-Z or a compound of

Formula XVI ^

Z- ^ lkyl (R ² ) Ar GCh ₂ CHOHCHNR ¹³ XVI

R ⁴

2 3

react with a compound alkyl-OH, where R, R, R, R and Z have the above meanings. The implementation takes place in the usual way, e.g. as implementation of a compound of Formula II with an area of the formula

HHR ¹³

2 1

A radical X that is convertible to R is, for example

2 1

a radical X which can be converted into an alkoxyalkoxy radical R.

is, like a radical Z -alkyl-O- or a hydroxyl group.

A compound XIV with such a radical Z -alkyl-O-

2

as X can in the usual manner with a compound alkyl-Z ^ be reacted, wherein one of the radicals Z and Z is a hydroxyl group and the other of the two radicals is the above

Has meaning.

So you can use a compound of the general formula XVII

R ³

ι ι 1 "\ WTT

HO- ^ lkyl-0 (R IAr OCHjCHOHCHjNR ^lo

R ⁴

with a compound alkyl-Z or a compound of the formula XVIII

- 38 -

609819/128 5

NR ¹³

OCh ₀ CHOHCHNR

R ⁴ = ■

React 2 3 4 with a compound alkyl-OH, where R, R, R, R and Z have the above meanings. The implementation takes place in the usual manner, such as the implementation of a compound of Formula II with an amine

HNR ¹³

k *

A compound of the general formula XIV with a hydroxyl

group as radical X can be unset in the usual way with a compound alkoxyalkyl-Z, where Z has the above meaning Has.

So you can use a compound of the general formula XIX

R ³ HQ-R ² ) Ar CCH ₉ CHOHCHr] R ¹³

2 3

react with a compound alkoxyalkyl-Z, in which R, R, R, R and Z have the above meanings. The implementation takes place in the usual manner, such as, for example, the implementation a compound of the formula II with an amine of the formula

HN-R ¹³

Furthermore, the oxo group in a compound corresponding to those of the formula I, ie in the cases where R ³ , R ⁵ and R ⁶

- 39 -

60981 9 / 12P5

Mean hydrogen atoms and the compound is an oxo group on a carbon atom bonded to a nitrogen atom, can be reduced to two hydrogen atoms. The radical R is preferably one of the radicals which is a carbonyl group

Il

contains. These compounds are, for example, those of the formula XX

(R ¹ HR) Ar OCH ₂ CHOHCNR

XX

4!

wherein R, R, R and R have the above meaning when R Means hydrogen.

The reduction can be carried out in the manner described above using complex metal hydrides such as lithium aluminum hydride »; or diisobutyl aluminum hydride. Appropriate the reaction takes place in an inert solvent such as an ether, for example diethyl ether or tetrahydrofuran.

In a customary manner, the substituents can be attached to those in the end product compounds obtained can be varied, and the compounds obtained can be introduced into other compounds, split off from these or transformed into such, what

- 4o -

609819/1 285

takes place in the usual way. Thus it is possible to be analytical C-C double bonds or C-C triple bonds with the aid of hydrogen in the presence of a hydrogenation catalyst, such as, for example To hydrogenate platinum, palladium or nickel, such as Raney nickel, to a C-C single bond. One has to note that other reducible groups are not reduced.

In compounds obtained that contain a C-C triple bond, this can still be converted into a C-C double bond and, if necessary, stereospecifically to a C-C-cis- or C-C trans double bond are hydrogenated. The hydrogenation of a C-C triple bond to a C-C double bond can for example using one mole of hydrogen in the presence of a less active hydrogenation catalyst than Iron or palladium take place, as with Raney iron or palladium with barium sulfate, preferably at an elevated temperature. The hydrogenation to a C-C-cis double bond can take place, for example, between one mole of water and a deactivated catalyst take place, as with palladium on activated carbon and in the presence of quinoline, with palladium on calcium carbonate in the presence of lead salts or with Raney nickel.

The hydrogenation to a C-C-trans double bond can be carried out with the aid of sodium in liquid ammonia, with im With regard to other reducible groups, shorter reaction times can be used and no excess of the reducing agent

- 41 -

609819/1285

is used, where appropriate an ammonium halide, such as ammonium chloride, is added as a catalyst.

With the above-mentioned reduction one has to pay attention to that no further reducible groups are reduced. In the reduction using Raney nickel with hydrogen one has to pay particular attention to a possibly present halogen atom on the aromatic ring, so that this is not replaced by hydrogen. In addition, one has in all reductions, especially in catalytic hydrogenations to consider a possibly existing thioether group. Sulfur-resistant catalysts are preferably used, and in individual cases the volume of hydrogen to be absorbed is calculated, and if the calculated amount is

is absorbed, the reduction is terminated.

1 2

A radical X that can be converted into R is, for example, a radical X that can be converted into an alkoxycarbonylaminoalkoxy radical R is like a hydroxyl group.

A compound XIV with a hydroxyl group as X can be reacted in the customary manner with an alkoxycarbonylaminoalkyl-Z radical will. So you can use a compound of the formula XIX

R ³

9 1 λ q XIX

HG (R ^) Ar-CCH ₂ CHGHCHNR

R - 42 -

609819/1585

V3 7 5 31312

react with a compound alkoxycarbonylamino-Z, in which R ² , R ³ , R ⁴ , R ¹³ and Z have the above meanings. The reaction takes place in the customary manner, as for the reaction of a compound of the formula III with an amine

HN-R ¹³

2 1

was mentioned. A residue X convertible to R is

2
for example a radical X which can be converted into an alkoxycarbonylaminoalkoxy radical R, such as a radical H ₂ N-alkoxy.

A compound XIV with such a radical H ^ N-alkoxy can be reacted in the usual way with an alkoxycarbonyl chloride.

So you can use a compound of the general formula XXI

R ³

H ₂ N-alkoxy (R ² JAr-OCH ₂ CHOHCHNR ¹³

R ^4:

2 3 4

react with an alkoxycarbonyl chloride, where R, R, R and R have the above meaning. The reaction is carried out in the customary manner, such as reaction of a compound of the formula III with an amine

HN R ¹³

A «

was mentioned. - 43 -

609B1 9/1295

^ 531312

A remainder that can be converted to R is, for example, a remainder X, which can be converted into an alkoxycarbonylaininoalkoxy radical R, such as a radical Z ^ CO-NH-alkoxy.

A compound XIV with such a radical Z -CO-NH-alkoxy

2 2

as X can in the usual manner with a compound alkyl-Z

1 2

are implemented, where Z and Z have the above meaning.

So you can use a compound of the general formula XXII

R ³ '

¹ =>: y (R ² 3Ar-OCH ₂ CHOHCHNR ^{13 XXI1}

R ⁴

2 2 3 4

react with a compound alkyl-Z, where R, R, R,

13 1 2
R, Z and Z have the above meanings.

1 2

A radical X that can be converted into R is, for example, a radical

2 1

X, which can be converted into an alkoxycarbonylaminoalkyl radical R.

is like a radical H ₂ N-alkyl.

A compound XIV with such an H ₂ N-alkyl radical can be reacted in the customary manner with an alkoxycarbonyl chloride. So you can use a compound of the general formula XXIII

3 ^R XXIII

H ₉ N-AlKyI- (R ² Mr-OCH ₀ CHOHCHNR ¹³

R ⁴

609819/1285

react with an alkoxycarbonyylchloride, where Ar, R, R,

4 13
R and R have the above meaning. The reaction takes place in the customary manner, as for the reaction of a compound of the formula III with an amine of the formula

HNR ¹³

was mentioned.

1 2

A remainder that can be converted into R is, for example, a remainder X,

which can be converted into an alkoxycarbonylaminoalkyl radical R, like a radical Z ^ CO-NH-lower alkyl.

A compound XIV with such a radical Z -CO-NH-alkyl

2 2

as X can in the usual manner with a compound alkyl-Z

1 * 2

are implemented, where Z and Z have the above meaning.

So you can use a compound of the general formula XXHa

■ -CC-f / H-alkyl CR ² 3Ai-DChUChOHCHNR ¹ °

XXIIa

react with a compound alkyl-Z ² , where Ar, R ² , R ³ , R ⁴ ,

13 1 2 R, Z and Z have the same meaning as above.

1 2

A radical X that cannot be converted into R is, for example, a radical

2 1

X, which can be converted into an alkoxycarbonylaminoalkenyl radical R. is like a radical Z-alkenyl.

- 45 -

609819 / 128B

1 2

A radical X that can be converted into R is also an example

a radical X which is converted into an alkoxycarbonylaminoalkenyl radical

R is convertible like a radical H ₂ N-alkenyl.

A compound XXIV with such a radical H ₂ H-alkenyl can be reacted in the usual way with an alkoxycarbonyl chloride.

So you can use a compound of the general formula XXIV

• · f;

Η, Ν-alkenyl (R ² ) Ar-OCH ₀ CHOHCH NR ^{13 2 l} '; XXIV

0 * ί Α

react with an alkoxycarbonyl chloride, where R, R, R and R have the above meaning. The implementation takes place in customary manner, such as for the reaction of a compound of formula III with an amine

HNR ¹³

was mentioned.

1 2

A radical that can be transformed into R is, for example, a radical X, which can be converted into an alkoxycarbonylaminoalkenyl radical R, like a radical Z —CO — NH-alkenyl.

A compound XIV with such a radical Z ■ '• -CO-NH-alkenyl

2

as X can in the usual manner with a compound alkyl-Z

- 46 - 609819/128 5

2b31312

12th
are implemented, where Z and Z have the above meaning.

So you can use a compound of the general formula XXV

: ¹ -CO-NH-Alkenyl (R ² ) Ar-OCH ₂ CHOHCHNR ¹³

R "

XXV

2 2 3 4

react with a compound alkyl-Z, where R, R, R,

13 1 "2
R f Z and Z have the meaning above.

You can also use a compound of the general formula XXVI

EAR ³ R ⁵

(X ³ ) (R ¹ ) Ar-OC ⁴ H ₉ CHCHM-C- (CH ₉ ) -Y-

(CH ₂ ) _m R ⁹

wherein Ar, R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , m, η and Y are the

3 2

Have the above meaning and X is in a radical R with the

3 2 above meaning is convertible residue, convert X to R.

A compound of the formula XXVI with a hydroxyl group as radical X can in the usual manner with a compound alkyl-Z implemented, where Z has the above meaning.

So you can use a compound of the general formula XXVII

- 47 -

R ³

ι · ■ f «-a XXVII} ArOCHCHOHCHNR ^J

HO- (R

, 4

13 4 react with a compound alkyl-Z, in which Ar, R, R, R, R and Z have the above meanings. The implementation takes place

for
in the usual way, such as / the implementation of a compound of the

Formula III with a min

HNR ¹³

was mentioned.

In addition, in a compound of the formula XXVIII

EAR ³

, 1 2 I '4 XXVIII

(R HR) Ar-OCH ^ CHCHNX

wherein Ar, R, R ² , R; and R have the above meaning and X denotes a radical which is in the radical R with the above

4 13 interpretation can be converted, convert X to R.

4 13

A ReSt ₁ X which can be converted into R is, for example, a radical X / which can be converted into an optionally substituted phenoxyalkyl radical R, such as a Z -alkyl radical. A compound XXVIII with such a radical Z -alkyl

as X can in the usual manner with an optionally substituted Compound Phenyl-Z are implemented, with a

- 48 -

609819/1285 ORIGINAL INSPECTED

t / 9

of the groups Z and Z denotes a hydroxyl group and the other of the two has the above meaning. So you can either a compound of the formula XXIX

R ⁵

XXIX

C.
I.

with an optionally substituted compound phenyl-Z or a compound of the general formula XXX

! XXX

_Λ 14 i fpn "> _7

with an optionally substituted compound phenyl-OH

5 6
implement, where R, R and η have the above meaning and

R the group

(R ¹ J (R ² 5Ar-OCHCHDHCH (R ³ ) N-

R *

12 3 4 means in which Ar, R, R, R and R have the above meaning to have. The reaction takes place in the customary manner like the reaction of a compound of the formula II with an amine

Formula,.,

HNR

In addition, in a compound of the general formula XXXI

- 49 -

6Π9819 / 12 B 5

- m -SO

EAR ³ . R ⁵

* 7 II 'I.

(R ¹ 3 (R ^) Ar-OCH ₂ CHuHN-C- (CH ₂ ) _η -

XXXI

tCH ₂ ) _m R ⁹ j

wherein Ar, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ⁹ , Y, η and m have the above meaning and X is a radical which can be transformed into R as defined above, R in R can be converted. A radical R that can be converted into R is, for example, a radical X that can be converted into an alkoxy radical R, such as a radical from

formula

Jj ~ \

, 9 i

where R

15th

15th

R ⁵ R ³ OH

R!

I 1 I

Y- (CH-J -C-NCHCHCH-, GAr

kl ·

is.

R '

A compound with such a radical X can in usual

2 ways to be reacted with a compound Alky-Z, wherein

1 2

Z and Z have the above meanings. So you can either use a compound of the general formula XXXII

- 5o -

609819/1285

, 15

with a compound alkyl-Z or a compound of the general Formula XXXIII

.8th

CH-) R ⁹ XXXIII 2 m

react with a compound alkyl-OH, where R, R , R and xn have the above meaning.

Furthermore, in a compound of the general formula XXXIV R ⁷ '

R -> ι / - ^ \ XXXIV

15 7 9 7

where R, R, R and m have the above meaning and X

8 7

is a residue convertible to R as defined above, X

8 7 R.

be converted to R. A remainder X that is convertible to R. is, for example, a radical X which is converted into an alkoxy radical

R is convertible, like a remainder

p: (Ι Π p 1 Q / 1 "· - r

ORiGiMAL INSPECTED

3Ί3Ί2

A connection with such a remainder as x 'becomes more common in Way reacted with a compound alkyl-Z, wherein

1 2

Z and Z have the above meanings. So you can either use a compound of the general formula XXXV

, 9 ^;

XXXV

with a compound alkyl-Z or a compound of

g Formula XXXVI "'

R ¹⁵ xxxvi

15 7 9 react with a compound alkyl-OH, where R, R, R,

m and Z have the above meanings.

Furthermore, in a compound of the general formula XXXVII R _ö

XXXVII

15 7 8 8

wherein R, R and R have the above meanings and X one

9 9

in - (CH ₀ ) R is a convertible radical and m and R denotes the ζ m

8 9

have the above meaning, _{convert X into - (CH 9} ) R.

8th
A remainder X, which in -

can be converted is

for example a radical X ⁸ which can be converted into a group - (CH ₂ )

- 52 -

609819/1285

Sl

and is convertible into a group - (CH ») CONHNR R if R and R together with the adjacent nitrogen atom form a morpholinyl radical or piperazinyl radical, such as a

rest

7 - - Γ Η Γ u,

or a remainder

N (NH) CO (CH ₉ )

ι «15

K ₂ NCK ₂ CH,

ZCH ₂ CH-

Ni NH) COfCH-)

7 8 9 15 1 2 where R, R, R, R, m Z, Z and Z have the above meaning to have. These radicals are reacted in the usual way, with ring closure, as in the reaction between one Compound of formula II with a compound of formula III.

8 9

A radical X which can be converted into a group - (CH-) R,

2'm

.8th

is, for example, a radical X which belongs to a group

¹⁰ R ¹¹

R or a group - (CH ₂ J _n CONHNR R ^-1 " ¹ convertible 1st, like a radical

- 53 -

6098 19/12% ~ 5

si

₁₀ £ 531312

which is reacted in the usual way with a compound RR NH or a compound RR HH _2.

The reaction takes place in the same way as the reaction between a compound of the formula II with a compound of formula II.

3 9

A radical X which can be converted into (CH ₂ ) _m R is, for example,

show a radical X, which is converted into an alkoxycarbonylaminoalkyl- (CH ₂ ) _m '

Group as a group - (CH-) R is convertible. These implementations

and radicals are the same as in the case when X is a radical which can be converted into an alkoxycarbonylaminoalkyl radical R can.

Furthermore, in a compound of the general formula XL

P ³

^R B

0H RR ² HR ² 3ArGCH ^ CHCHNO

XL

wherein Ar, R ³ YR ² , R ³ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , Y, m and η die

IO 4 have the above meaning and X is a in R, which is a water

10 is 4 atom of material, is convertible radical, X is converted to R. will.

- 54 -

609819/128 5

'ίο 4 2b 31312

A radical X, which is in R, which is a hydrogen atom, can be converted is benzyl or alkanoyl, which can be hydrolyzed.

The above-mentioned reactions can optionally be carried out simultaneously or sequentially in any order be performed.

The above-mentioned reactions are carried out in any manner known per se in the presence or absence of diluents, Condensing agents and / or catalysts at a low room temperature or an elevated temperature, optionally carried out in a closed vessel.

Depending on the process conditions and the starting material, the end product is obtained either in free form or in the form of its acid addition salt, and these salts are also within the scope of the invention.

For example, basic, neutral or mixed salts and also hemiamino-, sesqui- or polyhydrates can be obtained will. The acid addition salts of the new compounds can be converted into free compounds in a manner known per se by using, for example, basic agents, such as alkali, or ion exchangers. On the other hand you can the free base salts obtained with organic or inorganic

- 55 -

609819/1285

S6

2 b 3 1 3 1 2

form niche acids. In the production of acid addition salts those acids are preferably used which form suitable therapeutically acceptable salts. Such acids are, for example, hydrohalic acid and sulfuric acid, Phosphoric acid / nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic acids or sulfonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, Tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid or pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, anthranilic acid, p-hydroxybenzoic acid, Salicylic acid or p-aminosalicylic acid, emboxylic acid, methanesulf onic acid, ethanesulphonic acid, hydroxyethanesulphonic acid, hydroxyethanesulphonic acid, ethylene sulphonic acid), halobenzenesulph onic acids, toluenesulfonic acid, naphthylsulfonic acid or Sulfanilic acid, methionine, tryptophan, lysine or arginine.

These or other salts of the new compounds, such as Picrates, can serve as a cleaning agent for the free bases obtained when the free bases are converted into salts, these are separated and the bases are then released again from the salts. In terms of the close relationship between the new compounds in the free form and in the form of their salts are possibly the corresponding salts included in the free link.

- 56 -

6Π9819 / 1 2 8 B.

The invention also relates to any embodiment of the method according to the invention, in which any one obtained as an intermediate at any stage of the process Connection goes out and only carries out the remaining process steps, or by turning the process into any Stage terminates or in which a starting material is formed under the reaction conditions or in which a reaction component is formed optionally used in the form of the salt.

So you can an aldehyde of the general formula XXXVIII

(R ¹ ) (R ² JAr-OCH ₂ CHOHCHO XXXVIII

1 2

wherein R and R are as defined above, with an amine

the general formula

HN-R ¹³

4 13

wherein R and R are as defined above, in the presence of a suitable reducing agent such as one that is mentioned above. This gives a compound of the formula X as an intermediate, which is then according to the invention is reduced.

An amine of the general formula III with an aldehyde or a ketone can also be used in a manner known per se

the formula. - ,,

^{0 = R} - 57 -

609819/1 285

13 '

implement, where R has the above meaning and the Settlement in the presence of a suitable reducing agent, such as one of those mentioned above, is carried out. Receives a compound of the general formula XI or XII as an intermediate, which is then reduced according to the invention will.

Furthermore, a phenol of the formula V can be mixed with an acetidinol of the formula XXXIX in a manner known per se

CH ₂ -NR ¹³ HO-CH-CH ₂ XXXIX

implement, in which R has the above meaning and a compound of formula I is obtained.

This implementation takes place in the usual way. This is how it is implemented under alkaline conditions in a suitable solvent such as benzyl alcohol by boiling the reaction mixture for a few hours. This is where the phenol converted primarily to its metal phenate, such as alkali phenate, before it is added to the acetidinol of Formula XXXIX will.

It is evident in the above methods for the preparation of the compounds according to the invention that the different Substituents can also be introduced by analogous processes. So can introduce the group

- 58 -

609819/1285

-OCH ₂ CH = CH ₂ and -OCH ₂ C = CH as R in the same way as the

Introduction of the alkoxy groups R take place. Analogues alkoxy

7 8

groups R and R can in the same way as the alkoxy

group R. Similar analogs can also

for other leftovers.

The new compounds can vary depending on the selection of the starting material and the method are present as optical antipodes or racemates, or if they are at least one asymmetric Containing carbon atom, they can exist as a mixture of isomers (mixture of racemates).

The isomer mixtures obtained (mixtures of racemates) can, depending on the physico-chemical differences between the components separated into the two stereoisomeric (diastereomeric) forms, as by chromatography and / or frakr ionized crystallization.

The racemates obtained can be separated by known methods, such as optically by recrystallization from one active solvent, with microorganisms or through a reaction with optically active acids, the salts of the compound form, and separation of the salts thus obtained, as due to their different solubility in the diastereoisomers, from which the antipodes can then be released by treatment with a suitable agent. Appropriate Usable optically active acids are, for example

609819/1 285

so

L- and D-forms of tartaric acid, di-o-tolyltartaric acid, malic acid, Mandelic acid, camphor sulfonic acid or quinic acid. The more active part of the two antipodes is preferably isolated.

Appropriately, those starting materials are used for carrying out the reactions according to the invention which give rise to groups of end products that are particularly desired and special represent described and preferred end products.

The starting materials are known or, if they are new, can be obtained by processes known per se will.

In clinical use, the compounds of the invention will normally be administered orally, rectally or by injection administered in the form of a pharmaceutical preparation containing an active compound either as a free base or as a a pharmaceutically acceptable, non-toxic acid addition salt, such as the hydrochloride, lactate, acetate, sulfamate or the like, in combination with a pharmaceutically acceptable carrier material. The mention concerns of the new compounds according to the invention here either the free amine base or the acid addition salts of the free base, even if the connections are described generally or specifically, provided that the accompanying text in which such Expressions occur, for example in the examples,

- 60 -

609819/1285 ORIGINAL INSPECTED

* 2 b 3 1 3 1 2

is consistent with this broad meaning. The carrier material can be a solid, semi-solid or liquid Be a diluent or a capsule. These pharmaceutical preparations are also the subject of the invention. Usually the amount of active compound is between 0.1 and 95 wt .-% of the preparation, expediently between 0.5 and 20% by weight for preparations for injection and between 2 and 50% by weight for preparations for oral administration.

In the manufacture of pharmaceutical preparations containing a compound according to the present invention in In the form of dosage units for oral administration, the selected compound can be mixed with a solid, powdery Carriers, such as with lactose, sucrose, sorbitol, mannitol, starch, such as potato starch, corn starch or amylopectin, Cellulose derivatives or gelatin as well as with a friction-reducing agent Agents such as magnesium stearate, calcium stearate, polyethylene glycol waxes or the like, mixed and added Tablets are compressed. If coated tablets are desired, the tablet cores prepared above can be used with more concentrated Sugar solutions containing e.g. gum arabic, gelatin, talc, titanium dioxide or the like are coated can. In addition, the tablets can also be mixed with a highly volatile organic solvent or solvent mixture dissolved varnish are coated. A coloring agent can be added to this coating to make it easy between tablets with different active compounds or with different

- 61 -

609819/1285

different amounts of the active compound contained, differentiate *

When making soft gelatin capsules (pearl-shaped closed capsules), which consist of gelatin, for example glycerine, or in the production of similar closed capsules Capsules, the active compound is mixed with a vegetable oil. Hard gelatin capsules can have granules contain the active compound in combination with a solid, powdery carrier material, such as lactose, Sucrose, sorbitol, mannitol, starch (such as potato starch, corn starch or amylopectin), cellulose derivatives or gelatin.

Dosage units for rectal administration can be prepared in the form of suppositories, which contain the active Substance contained in a mixture with a neutral fat base, or they can be in the form of gelatin rectal capsules which contain the active substance in a mixture with a vegetable oil or paraffin oil.

Liquid preparations for oral administration may be in the form of syrups or suspensions, such as solutions, the about 0.2% to about 20% by weight of the described active The remainder is made up of sugar and a mixture of ethanol, water, glycerine and propylene glycol.

- 62 -

609819/1285

& 2 b 3 1 31 2

stands. If desired, such liquid preparations can also contain coloring agents, flavoring agents, saccharin and carboxymethyl cellulose Contained as a thickener.

Solutions for parenteral administration by injection can be used as an aqueous solution of a water-soluble pharmaceutical compatible salt of the active compound, preferably at a concentration of from about 0.5% to about 0.10 wt%. These solutions can also contain stabilizers and / or buffering agents, and they can expediently be in ampoules of different dosage units.

The production of pharmaceutical tablets for oral use is carried out according to the following method:

The solid substances used are ground or sieved to a certain particle size. The binder will homogenized and suspended in a certain amount of solvent. The therapeutic connection and required Auxiliaries are mixed with the binder solution with continuous and constant mixing and so moistened that the solution is evenly distributed in the mass without any overmoistening of any parts. The solution center! Set is usually adjusted so that the consistency of the mass obtained is reminiscent of wet snow. The moistening of the powdery mixture with the binding

- 63 -

609819/1285

Medium solution causes the particles to aggregate somewhat stick together, and the actual granulation process is carried out in such a way that the mass is passed through a sieve in the form of a stainless steel net with a mesh size of about 1 mm is pressed. The mass is then placed in a thin layer on a floor in order to be transformed into a Drying chamber to be dried. This drying takes place for 10 hours and should be carefully standardized, because the water vapor content of the granulate is of the utmost importance for the following process and for the characteristics of these tablets is. Drying in a fluidized bed is also possible. In this case the crowd will not be on one Soil given, but poured into a container with a mesh bottom.

After the drying step, the granules are sieved to obtain the desired particle size. Under certain Powder must be removed under certain circumstances.

The disintegrating agents, the friction agents and the adhesives are added to the so-called final mixture. After this When mixed, the mass should have its composition ready for the tableting stage.

The cleaned tablet punching machine comes with a certain Set of punches and forming tools, whereupon the

- 64 -

609819/1285

Appropriate setting for the weight of the tablets and the degree of compression is tested. The weight of the tablets determines the size of the dose in each tablet and is calculated based on the amount of the therapeutic agent in the granules. The degree of compression affects the size of the tablet ^ its strength and their ability to dissolve in water. Especially with regard to the latter two properties, the selection of the Compression pressure (0.5 to 5 tons) something like an equilibrium. When the correct setting is achieved, begins tablet production, which takes place at a rate of 20,000 to 200,000 tablets / hour. That Compression of the tablets requires different times and depends on the size of the neck.

The tablets are made of adhesive powder in a special Apparatus freed and then stored in a closed package until they are used.

Many tablets, especially those that are rough or bitter, are coated. This means that they with a layer of sugar or a similar coating be provided.

The tablets are usually machined with an electronic Packed counter. The different types of packaging consist of glass or plastic bottles, but also

- 65 -

609819/1 285

from boxes, tubes and special packs designed for dosing.

The daily dose of the active substance varies and depends on the route of administration, but can be used as a rule of thumb say that they are 100 to 400 mg / day of active substance for peroral administration and 5 to 20 mg / day for incravenous Administration is.

The following examples serve for further explanation der Erfiung, where the temperature is given in degrees Celsius is.

example 1

1.9 g 1,2-epoxy-3- (2-allylphenoxy) propane and 1.8 g 4- (2-aminoethoxy) benzamide were refluxed in 25 ml of isopropanol for 1.5 hours Evaporated in vacuo, whereupon the residue dissolved in acetone and the hydrochloride of 1- / 2- (4-carbamylphenoxy) -äthy1-amino7-3- (2-allylphenoxy) -propanol-2 was precipitated by the introduction of HCl-containing ether. M.p. = 211 ° C. The structure was confirmed by NMR spectroscopy.

Example 2

2.8 g of 1,2-epoxy-3 ~ (2-chloro-5-methylphenoxy) propane and 2.7 g 4- (2-Aminoethoxy) benzamide were refluxed in 25 ml of isopropanol for 5 hours. The mixture was

- 66 -

609819/1285

steamed. The residue was dissolved in acetone and the hydrochloride of 1- / 2- (4-carbamylphenoxy) ethylamino / 3- (2-chloro-5-methy! Phenoxy) -propanol-2 was precipitated with HCl-containing ether. F. = 250 ° C (with decomposition). The structure was confirmed by NMR spectroscopy.

Example 3

2.1 g of 1,2-epoxy-3- / 3- (2-methoxyethy 1) -phenoxy _ / - propane and 1.8 g of 4- (2-aminoethoxy) benzamide were reacted with one another according to Example 1. The melting point of 1- / 2- (4-carbamylphenoxy) ethylaminoJ-S- (2-methoxyethyl) phenoxypropanol-2-hydrochloride was 105 ° C. The structure was confirmed by NMR spectroscopy.

Example 4

0.4 g of 3- (1,2-epoxy-3-propoxy) -4-chlorothiazole and 0.4 g 4- (2-Aminoethoxy) benzamide were reacted according to Example 1.

The hydrochloride of 1- / 2- (4-carbamylphenoxy) -äthylainino7-3- (4-chloro-2-thiazoloxy) -propanol-2 decomposed at 215 ° C.

The structure was determined using NMR spectroscopy

confirmed.

Example 5

1.9 g of 1,2-epoxy-3- (2-allylphenoxy) propane and 2.5 g of 4- (2-aminopropoxy) benzamide were reacted according to Example 1. The hydrochloride of l- / l-methyl-2- (4-carbamylphenoxy) -äthy1amino / -3- (2-allylphenoxy) -propanol-2 melted at

- 67 -

6098 19/1285

94 ^ C. The structure was confirmed by NMR spectroscopy.

Example 6

3.8 g of 1,2-epoxy-3- (2-allylphenoxy) propane and 3.3 g of 1- (2-methylphenoxy) -2-propylarain were implemented according to Example 1. The hydrochloride of 1- / T-Methy1-2- (2-methylphenoxy) -äthylamino7-3- (2-allylphenoxy) -propanol-2 melted at 142 ° C. The structure was confirmed by NMR spectroscopy.

Example 7

3.8 g of 1,2-epoxy-3- (2-allylphenoxy) propane and 3.3 g of 1- <4-methylphenoxy) -2-propylamine were implemented according to Example 5.

The hydrochloride of 1- / T-methyl-2- (4-methylphenoxy) -ethy1-amino7-3- (2-allylphenoxy) -propanol-2 melted at 146 ° C. the

Structure was confirmed by NMR spectroscopy.

Example 8

1.8 g of l-Araino-3- (2-methylisonitrosomethylphenoxy) propanol-2 and 1.55 g of 4-Methylcarbonylmethoxybenzamid were dissolved in 25 ml methanol and cooled to 0 ⁰ C. 1.8 g NaBH. were then suspended for 1/2 hour. 50 ml of water were added and the product was extracted with ethyl acetate. The ethyl acetate phase was evaporated in vacuo and the substance, 1- / T-Methy1-2- (4-carbamoylphenoxy) -äthylaminoT-S- (2-methylisonitrosomethylphenoxy) -propanol-2, was with ether and ethyl

acetate washed. M.p. = 106 ° C (HCl).

- 68 -

6098 19/1 285

Example 9

According to Example 1, 1- / 4- (2-methoxycarbonylamino) -ethyl) -phenoxyethylamino / -3- (2-methylphenoxy) -propanol-2 from 1,2-epoxy-3- (2-methy! phenoxy) propane and 1- (4-methoxycarbonylaminoethylphenoxy) -2-ethylamine manufactured. M.p. = 93 ° C as

Base.

Example 10

1- / 2- (4-Carbamylphenoxy) -ethylaminoZ-S- (3-allylphenoxy) -propanol-2 was according to Example 1, starting from 1,2-epoxy-3- (3-allylphenoxy) propane and 4-aminoethoxybenzamide. M.p. = 228 ° C as hydrochloride.

Example 11

1- / 2- (4-Carbamoylphenoxy) ethylamino / - ^ - (2-chlorophenoxy) propanol-2 was according to Example 1 starting from 1,2-epoxy-3- (2-chlorophenoxy) propane and 4-aminoethoxybenzamide. M.p. = 228 ° C as hydrochloride.

Example 12

1- / 2- (4-Carbamylphenoxy) -ethylamine £ / -3- (2,3-dichlorophenoxy) -propanol-2 was prepared according to Example 1 from 1,2-epoxy-3- (2,3-dichlorophenoxy) propane and 4-aminoethoxybenzamide. M.p. = 245 ° C as the hydrochloride and 156 ° C as the base.

Example 13

A syrup with a content of 2% (weight per volume)

- 69 -

609819/1 285

90

3ΓΟ1 ¹ JI 1

active substance was made from the following components:

1- / 2- (4-carbamyl phenoxy) ethylamino7 ~

3- (2-allylphenoxy) propanol-2 · HCl 2.0 g

Saccharin 0.6 g

Sugar 1 30.0 g

Glycerin 5.0 g

Flavor 0.1 g

Ethanol, 96%, 10.0 ml

distilled water to 100.0 ml

Sugar, saccharin and the ether salt were warm in 60 g Dissolved in water. After cooling, glycerin and a solution of the flavor in ethanol were added. In addition Mixture was then added water to 100 ml.

The active substance indicated above can also be replaced by other pharmaceutically acceptable acid addition salts will.

Example 14

1/2 "- (4-Carbamy! Phenoxy) ethylamino 7-3- (2-chloro-5-methylphenoxy) propanol-2-hydrochloride (25Ο g) was made with lactose (175.8 g), potato starch (169.7 g) and colloidal silica (32 g) mixed. The mixture was with a IO% strength Solution of gelatin moistened and granulated through a 12-mesh sieve. After drying, potato starch (160 g),

- 7o -

009819/1285

ORIGINAL INSPECTED

Talc (50 g) and magnesium stearate (5 g) mixed in, and the mixture thus obtained was compressed into tablets (10,000) containing 25 mg of the substance. The tablets were sold in the market with break lines to allow for a dosage other than 25 mg or a multiple thereof.

Example 15

Granules were made from 1- / 2- (4-carbamylphenoxy) -ethyIamino7 ~ 3- (2- (2-methoxyethyl) -phenoxy) -propanol-2-hydrochloride (250 g), lactose (175.9 g) and an alcoholic solution of polyvinylpyrrolidone (25 g). After the drying stage, the granules were filled with talc (25 g), potato starch (40 g) and magnesium stearate (2.50 g) mixed and 10 compressed biconvex tablets. These tablets were primarily made with a 10% alcoholic solution from Shellak and then coated with an aqueous solution containing 45% sucrose, 5% gum arabic, 4% gelatin and 0.2% dye. Talc and powdered sugar were used to powder after the first five coats. The coating was then covered with a 66% sugar syrup and coated with a 10% Carnauba wax solution polished in carbon tetrachloride.

Example 16

1- / 7- (4-Carbamylphenoxy) -ethylaminoT-S- (4-chloro-3-thiazoloxy) propanol-2-hydrochloride (Ig), sodium chloride (0.8 g) and ascorbic acid (0.1 g) were in a sufficient amount dissolved in distilled water to give 100 ml of solution.

- 71 -

609819/1285

U Ü531312

This solution / containing 10 mg of active substance per ml was used to fill ampoules, which should be filled for 20 minutes Heating to 120 C were sterilized.

Biological effects

The β-receptor blocking agents according to the present invention Invention were tested for their biological properties. All connections were thereby anesthetized Cats (male and female cats weighing 2.5 to 3.5 kg) who received reserpine (5 mg / kg body weight, administered intramuscularly) about 16 hours before the experiments. The animals were given reserpine pretreated to endogenous sympathetic control of heart rate and tone of vascular smooth muscle turn off. The cats were anesthetized with pentobarbital (30 mg / kg body weight, administered i.p.) and artificially ventilated with room air. A bilateral vagotomy was performed on the neck. The blood pressure was determined a cannulated carotid artery, and heart rate recorded with a cardiotachometer, stimulated by the electrocardiogram (EKG). The ß-mimetic intrinsic activity on the heart increased the heart rate after drug administration. The test compounds were administered intravenously in logarithmically increasing doses administered. The values obtained were plotted on dose-response curves, from which affinity values (ED-) were determined became. At the end of each experiment, high doses of iso-

- 72 -

609819/1 285

- «- 2b31312

prenalin given to maximize heart rate response to obtain.

The compounds were also tested on conscious dogs. Beagle dogs were trained to lie quietly and be raised into an upright position by their front paws were placed on a table for 2 minutes. The arterial blood pressure was measured using a blood pressure transducer, which had been placed on the animal at heart level, registered. The heart rate was recorded by the EKG. All Dogs were pretreated with methylscopolamine to prevent vagal effects. The records were made before as well Made 15 and 75 minutes after administration of the test compound, initially in the lying position for 2 minutes and then in the upright position for 2 minutes. The test compounds were given in increasing doses with 2 hour intervals administered "

The following table shows the affinity values and the ß-mimetic intrinsic activity in those treated with reserpine Cats as well as the effects on blood pressure in dogs with conscious compounds of the invention. Appropriate Values for propanolol (l-isopropylamino-3- (l-naphthoxy) -propanol-2), Practolol (4- (2-hydroxy-3-isopropylaminopropoxy) acetanilide), Metoprolol (1-isopropylamino-3- / 4- (2-methoxyethyl) -phenoxy_7-propanol-2) , Tolamolol (4- / 2- (2-hydroxy-3-o-

- 73 -

609819/128 5

tolyloxypropylamino) -ethoxy_7 ~ benzamide) and AH 5158 (5- / T-Hydroxy-2-7- (l-methyl-3-phenylpropyl) -amino / ethyl ^ Z-salicylaitiid) are given for reasons of comparison.

- 74 -

609819/1285

Tabel link

cats treated with reserpine. Isoprene blocking intrinsic activity , ED ₅₀ mg / kg beats / minute

MR

PR

Conscious dogs

Blood pressure in now Hg after 1/5 mg / kg i.v.

lying

erect

CO (St.

Ex 6
Ex 9
Ex 11
Ex 17
Ex 18
Ex 19
Ex 20

cn

Propranolol 0.1 Practolol 0.3 Metoprolol ' 0.2 Tolamolol 0.1 AH 5158 0.2 Ex 1 0.3 Ex 2 . 0.3 Ex 3 1.1 Ex 5 0.0

0.5
0 _r 3
0.05
0.1

α ₁ 04

0 _f 03

0.1 '

0.6 1.8 4.6 8.5 0.2 0 _f 5

² I ⁴ l _r 0

I » ⁵ 0.3

> 8 _f 5> 8 _f 5

+ 0

+

+

• 0

+ +24 + + + + 0 + + 5

-43

• 28 • 23

-5 -32 23 -67 38 -45 2 B

-42

-20 -46

The experiments show that the tested compounds are good ß-receptor antagonists with or without ß-mimetic Are self-activity. The compounds also lower blood pressure in conscious dogs much more than Propanolol, Practolol and Metroprolol and to the same extent as Tolamolol. The orthostatic effects of the new compounds are not as strong as that of AH 5158, i.e. the blood pressure increases from the lying position to the upright position Position does not decrease significantly.

The following connections were also made:

R ^J

ArOCH-CHOHCH-f.'HCHCCH.,)

example

Ar

7 5 q FT R ³ η m R ^a

Phenyl

2-CH ₂ = CH-CH ₂ O- H H 1 0 4-NH ₂ CO- 13B-7 (HCl) 2-CH = C-CH ₂ O- H H 1 0 4-NH-CO- 215 CHCl) 2-NH ₂ COCH ₂ -. H H 1· 0 4-NH ₂ CO- 175 CHCl) 2-HIGH ₂ CH ₂ NHCOCh ₂ O- H H 1 0 4-NH ₂ CO- .BS Cp -2-CH ₂ = CH-CH ₂ O- H H- 2 Ö 4-NH ₂ CO- 200 CHCl) 2-CH ₂ = CH-CH ₂ O H H 4th 0 4-NH ₂ CO- oil (HClJ liadiazolyl 4 -Cl H 1 0 4-NH ₂ CO- > 250 (HC13

- 76 -

609819/1285

Claims (1)

Claims 1. Araine of the general formula I 7 (R ^] ) iR ² } Ar-C-CH ₉ CH-CH-RC-li: HJ _n -YV γ _(Ι) and their therapeutically acceptable salts, in which R in the 2- or 3-position represents the group -CH ₂ CH = CH ₂ , -CH ₂ C = CH, -OCH ₂ CH = CH ₂ , -OCH ₂ C = CH, an alkyl group, Alkoxyalkyl group, alkoxyalkoxy group, alkoxycarbonylaminoalky group, alkoxycarbonylaminoalkoxy group, alkoxycarbonylaminoalkenyl group, the group HOCH ₂ Ch ₂ NHCOCH ₂ O-, CH ₃ OCH ₂ CH ₂ NHCOCh ₂ O- or -CH = NOR, where R is a hydrogen atom or an alkyl group with 1 to 6 Carbon atoms means, R a hydrogen atom, halogen atom / an alkyl group or AIk- oxy group denotes, R denotes a hydrogen atom or an alkylol
group means, R a hydrogen atom, an alkanoyl group or benzyl group, R and R are hydrogen atoms 7 8 or alkyl groups, R and R are hydrogen atoms, Halogen atoms, alkyl groups or alkoxy groups, R denotes a hydrogen atom, an alkoxycarbonylaminoalkyl group, alkanoyl group, sulfo group, sulfino group, cyano group, trifluoromethyl group, the group -CONR ¹⁰ R ¹¹ or -CONHNR ¹⁰ R ¹¹ , in which R and R are hydrogen atoms or together with the nitrogen atom to which they are bonded, a heterocyclic ring such as a pyrrolidine ring, piperidir.ring, piperazine ring 609819/1285 - 77 - oder.Morpholinering, Y is the divalent group -O- or -CH ₂ -, η is an integer from O to 5, m is an integer from O to 2 and Ar is a phenyl radical, thiazolyl radical or thiadiazolyl radical, where R is bonded to the phenyl radical in the 2- or 3-position, is bonded to the thiazolyl radical in the 4- or 5-position and R or R is bonded to the thiadiazolyl radical in the 4-position are. 2. Amines and their therapeutically acceptable salts Claim 1, characterized in that η is 1-5 if and ι
Y-CH ₂ - means / when R means methyl alone, it is not bonded to the phenyl radical in the 2-position, except when R is an alkoxycarbonylaminoalkyl group. 3. Amines according to claim 1 of the general formula Ia ? ^7s EAR R I ρ 8a CR ") (R ²⁵ ) Ar-OCH ₂ CHCHnC-CCH ₂ ) _n -Y - </ ^) (Ia) [ßa \ -r— / and their therapeutically acceptable salts, in which R is the group -CH ₂ CH = CH ₂ or -CH ₃ C-CH, R ^{2a is} a hydrogen atom, halogen atom, an alkyl group or 3a
Alkoxy group R means a hydrogen atom or a 4a Alkyl group means, R a hydrogen atom, a 609819/1 285 - 78 - Alkanoyl group or benzyl group denotes, R ~ and R are each hydrogen atoms or alkyl groups n_ ft a mean, R and R a hydrogen atom, halogen atom, 9a denotes an alkyl group or alkoxy group, R denotes a hydrogen atom, an alkanoyl group, sulfo group, sulfino group, cyano group, trifluoromethyl group, alkoxycarbonylaminoalkyl group, the group -CONR ^a R ^a or -CONHNR ¹⁰³ R ¹¹³ , where R ^1Oa and R ^11a denote hydrogen atoms or together with the Nitrogen atom to which they are bonded form a heterocyclic ring, Y ^{a is} the group -0- or - "CH ₂ -, η is an integer from 0 to 5, m is an integer from 0 to 2 and Ar is one Phenyl radical, thiazolyl radical or thiadiazolyl radical, where, when Y ^{a is} -CH ₂ -, η is 1-5, where R ^{1a is} in the 2- or 3-position on the phenyl radical, in the 4- or 5-position on the thiazolyl radical and is bound in the 4-position to the thiadiazolyl radical. 4. Amines and salts according to claim 3, wherein R ^{a is} the group 0-CH ₂ CH = CH ₂ , ITi-CH ₂ CH = CH ₂ , 0-CH ₂ C = CH or m-CH ₂ C = CH R denotes a hydrogen atom, chlorine atom, bromine atom, a methyl group, ethyl group, methoxy group or ethoxy group, R ^a denotes a hydrogen atom or a methyl group, R ^a denotes a hydrogen atom, a formyl group, acetyl group or benzyl group, R ^5a and R ^6a each denotes hydrogen atoms, Methyl- 7 a 8a groups or ethyl groups, R and R each Hydrogen atoms, chlorine atoms, bromine atoms, methyl groups, Mean ethyl groups, methoxy groups or ethoxy groups, 60981 9/1285 - 79 - R ^a Viasserstoff / formyl, acetyl, GaIfο / SaIfino, cyano, Tr if luorinethyl, Methoxycarbonylaminoäthyl, Äthoxycarbony! Aminoethyl, carbamyl, dimethylcarbamyl or morpholinocarbonyl means methylcarbamyl, Y ^a represents -0- or ~ CH_-, η is an integer of 0 to 5 and m is an integer from 0 to 2, Ar is a phenyl radical or thiazolyl radical, where, when Y ^a "is" CH? ", η is 1 to 5, and where R ^{a is} in the 2- or 3-position the phenyl radical and is bonded to the thiazolyl radical in the 4- or 5-position. 5. Amines and their salts according to claim 4, wherein R is the group 0-CH ₂ CH = CH ₂ or 0-CH ₂ C = CH, R ^{2a is} hydrogen, chlorine, methyl or methoxy, R ^{a is} a hydrogen atom, R ^a denotes a hydrogen atom, R ^a and R a each denotes hydrogen or methyl * 7 2 »Aa mean, R and R each hydrogen or methyl 9a R is hydrogen, carbamyl, methoxycarbonylaminoethyl, methylcarbamyl or morpholine ^{carbonyl, Y a is} -0-, η is 1 or 2 and m is 0, 1 or 2 and Ar is the phenyl radical. 6. amines and their salts according to claim 1 of the general formula Ib , 3b "5b I" 8b CR ^lb HR ^2b ) Ar GCH ₂ J ⁰ T Γ / ty * CHCHN-C- (CH ₀ J -Y - // \\ ¹ t »v, ^b (CH _n ) R ⁹ Z m 609819/1 285 - «0 tA where R ^{1b is} the group -OCH ₂ CH = CH ₂ or -OCH ₂ C = CH / R is hydrogen, halogen, alkyl or alkoxy, R ^{3b is} hydrogen or alkyl, R is hydrogen, alkanoyl or benzyl, R and R each Signify hydrogen or alkyl, R and R each signify hydrogen, halogen, alkyl or alkoxy, R signify hydrogen, alkanoyl, sulfo, sulfino, cyano, trifluoromethyl, alkoxycarbonylaminoalkyl, the group -CONR ^10b R ^11b or -CONHNR ¹⁰¹³ R ¹¹¹³ , where R and R denotes hydrogen atoms or together with the nitrogen atom to which they are bonded form a heterocyclic ring, 3Γ ⁵ denotes the -0- or -CH ₂ - group, η is an integer from 0 to, m is an integer from 0 to 2 and Ar denotes a phenyl radical, thiazolyl radical or thiadiazolyl radical, where, when Y. ^{b is} -CH ₃ -, η is 1 to 5, and where R is in the 2- or 3-position on the phenyl radical, in 4- or 5-position Position is bound to the thiazolyl radical and in the 4-position to the thiadiazolyl radical. 7. Amines and salts according to claim 6, wherein R is the group -OCH ₂ CH = CH ₂ or -OCH ₂ C = CH, R ^{2b is} hydrogen, chlorine, bromine, methyl, ethyl, methoxy or ethoxy, R ^{3b is} hydrogen or Methyl denotes, R ^4b denotes hydrogen, formyl, acetyl or benzyl, R and R each denote hydrogen, methyl or ethyl, R and R each denote hydrogen, chlorine, bromine, methyl, ethyl, methoxy or ethoxy, R denotes hydrogen, formyl, acetyl , SuIfο, SuIfino, Cyano, Trifluormethyl j ^ ^e thoxy- 60981 9/1285 - 81 - carbonylaminoethyl, ethoxycarbonylaminoethyl, carbamyl, methylcarbamyl, dimethylcarbamyl or morpholine carbonyl, r ³ denotes -0- or -CH ₂ -, η denotes an integer from 0 to 5 and m denotes an integer from 0 to 2, Ar denotes the phenyl radical or thiazolyl radical where, when Y is ^ -CH ₂ -, η is 1 to 5, and where R is connected in the 2- or 3-position to the phenyl radical and in the 4- or 5-position to the thiazolyl radical. 1 v »8. Amines and salts according to claim 7, wherein R is the group 0-OCH ₂ CH = CH ₂ or 0-OCH ₂ C = CH means R ^{2b is} hydrogen, "i vv Chlorine, methyl or methoxy means, R is a hydrogen atom and R represents a hydrogen atom, R and R "7V * RVv each denotes hydrogen or methyl, R and R each denote hydrogen or methyl, R hydrogen, Carbamyl, methoxycarbonylaminoethyl, methylcarbamyl or morpholine carbonyl means, Y means -0-, η denotes 1 or 2 and m denotes 0, 1 or 2 and Ar denotes the phenyl radical. 9. amines and salts according to claim 1 of the general formula Ic R ^7c 3c 5c I ³ 3c (Ic) 4c f Pu 609819/1285 -82- 1c lc where R is alkyl or alkoxyalkyl, R is hydrogen, halogen, alkyl or alkoxy, R ^{c is} water Ac
substance or alkyl, R is hydrogen, alkanoyl or benzyl, R ^c and R ^c each represent hydrogen atoms or alkyl groups, R and R each hydrogen, halogen, alkyl or alkoxy 9c
interpret, R hydrogen, alkanoyl, SuIfο, SuIfino, Cyano, tr ^- Ifluoromethyl, alkoxycarbonylaminoalkyl, the 1Or * 11 e 1Πγ 11 γ Group -CONR ^iuc r ' ^ic or -CONHNR ^IUC R ^C means, where- 1Oc 11c rin R and R denote hydrogen atoms, or taken together with the nitrogen atom to which they are bonded form a heterocyclic ring, Y denotes the -0- or -CH-- group, η denotes an integer from 0 to 5 and Ar denotes the phenyl radical , Is thiazolyl radical or thiadiazolyl radical, where, when Y ^{c is} -CH ₂ -, η is ^{1-5 and where R 1c is} in the 2- or 3-position on the phenyl radical, in the 4- or 5-position to the thiazolyl radical and in the 4-position to the thia- 1c diazolyl radical is bonded, where if R denotes methyl, this is not in the 2-position to the phenyl radical 9
is bonded, except when R is alkoxycarbonylaminoalkyl 1c
means, and wherein when R is isobutyl, not both groups R and R are methyl groups. 1c 10. amines and salts according to claim 9, wherein R is alkyl or 2c
Alkoxyalkyl means, R hydrogen, chlorine, bromine, 3c is methyl, ethyl, methoxy or ethoxy, R - 83 609819/1 285 4 c Denotes hydrogen or methyl, R denotes hydrogen, formyl, acetyl or benzyl, R ^c and R ^c each denote hydrogen, methyl or ethyl, R and R each denote hydrogen, chlorine, bromine, methyl, ethyl, methoxy or ethoxy, R ^c denotes hydrogen , Formyl, acetyl, sulfo, sulfino, cyano, trifluoromethyl, methoxycarbonylaminoethyl, ethoxycarbonylaminoethyl, carbamyl, methylcarbamyl, dimethylcarbamyl or morpholine ^{carbonyl denotes, Y c} denotes -0- or -CH-, η denotes an integer from 0 to 5 and m denotes an integer denotes from 0 to 2 and Ar denotes the phenyl radical or thiazolyl radical, where, when Y ^{c is} —CH—, η 1-5 1c
and where R is bonded to the phenyl radical in the 2- or 3-position and to the thiazolyl radical in the 4- or 5-position. 1c 11. amines and salts according to claim 10, wherein R is methyl, ethyl, methoxymethyl, methoxyethyl or ethoxyethyl 2c
R is hydrogen, chlorine, methyl or methoxy, R ^{3c is} hydrogen, R is hydrogen, R ^c and R ^{c are} each hydrogen or methyl, R ^c and R ^{c are} each hydrogen or methyl 9c R is hydrogen, carbamyl, methoxycarbonylaminoethyl, methylcarbamyl or morpholine ^{carbonyl, Y is C} -0-, η is 1 or 2 and m is 0, 1 or 2 and Ar is the phenyl radical. 12. amines and salts according to claim 1 of the general formula Id 609819/1285 -84- 7d: EAR ^3d R ^5d JL / ^RÖd ld 2d I ' ^! d Z ⁷ ' K ^l f _Ml (R ¹⁰ J (R JArOCH-CHCHN-C-CCH-) -Y--; 'A < ^Ici) 2 ι ζ η \ where R Alkoxyalkoxy denotes, R denotes hydrogen, halogen, alkyl or alkoxy, R denotes hydrogen or 4d
Alkyl denotes, R denotes hydrogen, alkanoyl or benzyl, R and R each denote hydrogen or alkyl, R and R each denote hydrogen, halogen, alkyl or alkoxy., R denotes hydrogen, alkanoyl, sulfo, sulfino, cyano, trifluoromethyl, alkoxycarbonylaminoalkyl, the Group -CONR ^1Od R ^11d or -CONHNR ¹⁰⁰ R ^11d , in which R and R denote hydrogen atoms or together with the nitrogen atom to which they are bonded form a heterocyclic ring, Y denotes the group -0- or -CH ₃ -, η is an integer from 0 to 5 and m is an integer from O to 2, and Ar represents the phenyl, thiazolyl or thiadiazolyl, wherein R ^{in the} 2- or 3-position to the phenyl radical in the 4- or 5-position on the Thiazolyl radical and is bonded in the 4-position to the thiadiazolyl radical and where, when Y ^CH 2, η is 1 to 5. - 85 609819/1285 13. Amines and salts according to claim 12, wherein R is alkoxyalkoxy, R is hydrogen, chlorine, bromine, methyl, ethyl, methoxy or ethoxy, R is hydrogen or methyl, R is hydrogen, formyl, acetyl or benzyl, R and R each Hydrogen, methyl or ethyl, R and R each denote hydrogen, chlorine, bromine, methyl, ethyl, methoxy or ethoxy, R hydrogen, formyl, acetyl, sulfo, sulfino, cyano, trifluoromethyl, methoxycarbonylaminoethyl, ethoxycarbonylaminoethyl, carbamyl, methylcarbamyl, dimethylcarbamyl or morpholine carbonyl, Y is -O- or -CH ₂ -, η is an integer from O to 5 and m is an integer from O to 2 and Ar is the phenyl radical or thiazolyl radical, where, when Y ~ ^ ^Η 2 ~ means, η is 1 to 5, and where R in 2- or 3- at Position / the phenyl radical and in the 4- or 5-position the thiazolyl radical is bonded. 14. amines and salts according to claim 13, wherein R is methoxyiaethoxy, Methoxyethoxy or ethoxyethoxy means, R means hydrogen, chlorine, methyl or methoxy, R is hydrogen and R is hydrogen, R and R are each hydrogen or methyl, R and R each denotes hydrogen or methyl, R denotes hydrogen, carbamyl, methoxycarbonylaminoethyl, Is methylcarbamyl or morpholine carbonyl, Y is -O-, η is 1 or 2 and m is O, 1 or 2 and Ar denotes the phenyl radical. 609819/1285 - 86 - 15. Amines and salts according to claim 1 of the general formula Ig, ) r — V -> / '' F ^{( LU} 2 \ - Υ ¹ " ^{77 X} ) _{i (} lg) (CH-,)
2 in where R "is an alkoxycarbonylaminoalkoxy group, the group HOCH ₂ CH ₂ NHCOCh ₂ O- or, R ^{g is} hydrogen, halogen, alkyl or alkoxy, R ^{y is} hydrogen or alkyl, R ^ is hydrogen, alkanoyl or benzyl, R ^g and R ^ each denotes hydrogen or alkyl, R "and R ^ each denote hydrogen, halogen, alkyl or alkoxy, R ^g denotes hydrogen, SuIfο, SuIfino, cyano, trifluoromethyl, alkoxycarbonylaminoalkyl, the group -CONR ^10g R ^11g or -CONHNR ^10g R ¹¹ wherein R ^1OG and R ^g represent hydrogen atoms or, taken together with the nitrogen atom to which they are attached form a heterocyclic ring, Y ^{g is} the group -0- or -CH ₂ ", η is an integer from 0 to and m is an is an integer from 0 to 2 and Ar is the phenyl radical, thiazolyl radical or thiadiazolyl radical, where R ^{g is} bonded in the 2- or 3-position to the phenyl radical, in the 4- or 5-position to the thiazolyl radical and in the 4-position to the thiadiazolyl radical is and where, w when Y ^{g means} "CH ₂ ", η is 1-5. 609819/128 5 " ⁸⁷ " 16. Amines and salts according to claim 15, wherein R ^{g is} alkoxycarbonylaminoalkoxy, HOCH ₂ Ch ₂ NHCOCH ₂ O- or CH ₃ OCH ₂ CH-NHCOCH ₂ O-, R ^{2g is} hydrogen, chlorine, bromine, methyl, ethyl, methoxy or ethoxy means, R ^{g means} hydrogen or methyl, R ^{y means} hydrogen, formyl, acetyl or benzyl, R ^g and R ^g each denote hydrogen, methyl or ethyl. » R ^g and R ^g each denote hydrogen, chlorine, bromine, methyl, ethyl, methoxy or ethoxy, R ^y denote hydrogen, formyl, acetyl, SuIfο, SuIfino, cyano, Tr i fluorine thy 1, methoxycarbonylaminoethyl, ethoxycarbonylaminoethyl, carbamyl, methylcarbamyl, dimethylcarbamyl or morpholine ^{carbonyi, Y g is} -0- or -CH ₂ -, η is an integer from 0 to 5, m is an integer from 0 to 2 and Ar is the phenyl radical or 2-thiazolyl radical, where, when Y ^g -CH ₃ - 1g means, η is 1 to 5, and where R · in the 2- or 3-position is bonded to the phenyl radical and in the 4- or 5-position to the thiazolyl radical. 17. Amines and salts according to claim 16, wherein R ^g methoxycarbonylaminoethoxy, methoxycarbonylaminoethoxy, ethoxycarbonylaminoethoxy, ethoxycarbonylaminomethoxy, the group HOCH ₂ Ch ₂ NHCOCH ₂ O- or means, R ^{g means} hydrogen, chlorine, methyl or methoxy, R ^g and R ^g mean hydrogen atoms, R " 809819/1285 " ⁸⁸ " and R ^ each denote hydrogen or methyl, R ^ and R ^ each denote hydrogen or methyl, R ^g denotes hydrogen, carbamyl, methoxycarbonylaminoethyl, methylcarbamyl or morpholine carbonyl, Y ^g denotes -0-, η 1 or 2 and m 0.1 or 2 means and Ar means the phenyl radical. 18. Amines and salts according to claim 1 of the general formula You 7h _nuo 3h _D 5h y _ uiii \ i, \ ; i ^ i (R ^lh ) (R ^2h ) ArOCH ₂ CHC C ^^ (/ ^X ^ ^{Sb 4h} * (CH ₇ ) ^9h 2 m 1 V \ OVi where R is alkoxycarbonylaminoalkyl, R is hydrogen, halogen, alkyl or alkoxy, R ^{3h is} hydrogen or alkyl, R ^{4h is} hydrogen, alkanoyl or benzyl, R and R are each hydrogen atoms or alkyl groups, R ^7h and R ^{8h are} each hydrogen, halogen, Alkyl or alkoxy denote, R is hydrogen, alkanoyl, SuIfο, SuIfino, cyano, trifluoromethyl, alkoxycarbonylaminoalkyl, the group -CONR ¹⁰¹¹ R ¹¹¹¹ or -CONHNR ¹⁰¹¹ R ¹¹¹¹ , in which R and R denote hydrogen atoms or taken together with the nitrogen atom to which they are bonded, form a heterocyclic ring, Y is the group -0- or -CH ₂ -, 609819/1285 η is an integer from 0 to 5 and m is an integer from 0 to 2 and Ar denotes the phenyl radical, thiazolyl radical or thiadiazolyl radical, where R is in the 2- 'or 3-position on the phenyl radical, in the 4- or 5-position on the Thiazolyl radical and is bonded to the thiadiazolyl radical in the 4-position and where, when χ denotes -CH-, η is 1 to 5, and when R denotes acetylaminomethyl in the 3-position, m is not 0. 19. Amines and salts according to claim 18, wherein R is alkoxycarbonylaminoalkyl means R. Hydrogen, chlorine, bromine, methyl, ethyl, methoxy or ethoxy means, R water 4h
substance or methyl, R is hydrogen, methyl, ethyl, formyl, acetyl or benzyl, R and R are each hydrogen, methyl or ethyl denotes, R and R are each hydrogen, chlorine, bromine, methyl, ethyl, methoxy or ethoxy , R is hydrogen, formyl, acetyl, sulfo, sulfino, cyano, trifluoromethyl, methoxycarbonylaminoethyl, ethoxycarbonylaminoethyl, carbamyl, methylcarbamyl, dimethylcarbamyl or morpholine carbonyl, χ the group -O- or -CH ₃ - is an integer from O to 5 and m is an integer from O to 2 and Ar is the phenyl radical or thiazolyl radical, where, when Y ^{h is} -CH ₂ -, η is 1 to 5, and where R is in the 2- or 3-position on the phenyl radical and in 4- or 5-position is bonded to the thiazolyl radical. 20. amines and salts according to claim 19, wherein R is methoxy 609819/1285 _ ₉₁ _ carbonylaminomethyl, methoxycarbonylaminoethyl, ethoxycarbonylaminoethyl, methylcarbonylaminomethyl, methylcarbonylaminoethyl or ethylcarbonylaminoethyl denotes, R denotes hydrogen, chlorine, methyl or methoxy, R ³ * ¹ and R denote hydrogen atoms, R ^5h and R each denote hydrogen or methyl, R. oi— Q Vt and R each denotes hydrogen or methyl, R denotes hydrogen, carbamyl, methoxycarbonylaminoethyl, methylcarbamyl or morpholinearbony1, Y denotes -0-, η denotes 1 or 2 and m denotes 0, 1 or 2 and Ar denotes the phenyl radical. 21. Amines and salts according to claim 3 of the general formula Ii M ³¹ f " Ί "O * lit (r ¹ HR ¹ MrOCH-CHCHiV-C- (CH.,) -γί i R 4i ² IL ^{2 n} \ / (Ii) 1 i 2i where R is alkoxycarbonylaminoalkenyl, R is hydrogen, halogen, alkyl or alkoxy, R is hydrogen or alkyl, R is hydrogen, alkanoyl or benzyl, R and R ^{x are} each hydrogen or alkyl, R and R are each Hydrogen, halogen, alkyl or alkoxy, R is hydrogen, alkanoyl, SuIfο, SuIfino, cyano, tri- - 92 - 609819/1285 1312 fluoromethyl, alkoxycarbonylaminoalkyl, the group -CONR ¹⁰¹ R ¹¹¹ or -CONHNR ¹⁰¹ R ¹¹¹ , in which R and R are hydrogen atoms or together with the nitrogen atom to which they are attached form a heterocyclic ring, Y is the group -0- or - C ^ - denotes, η denotes an integer from 0 to 5 and m denotes an integer from 0 to 2 and Ar denotes the phenyl radical, thiazolyl radical or thiadiazolyl radical, where R is in the 2- or 3-position on the phenyl radical, in 4- or 5-position is bonded to the thiazolyl radical and in the 4-position to the thiadiazolyl radical and where, when Y is - ^CH o ~, η is 1 to 5. 22. amines and salts according to claim 21, wherein R is alkoxy 2i carbonylaminoalkenyl means, R means hydrogen, chlorine, bromine, methyl, ethyl, methoxy or ethoxy, 3i 4i R denotes hydrogen or methyl, R denotes hydrogen, formyl, acetyl or benzyl, R and R each 7i mean hydrogen, methyl or ethyl, R 8i and R each hydrogen, chlorine, bromine, methyl, 9i ethyl, methoxy or ethoxy, R is hydrogen, formyl, acetyl, SuIfο, SuIfino, cyano, trifluoromethyl, Methoxycarbonylaminoäthyl, Äthoxycarbonylaminoäfehyl, carbamyl, methylcarbamyl, dimethylcarbamyl or morpholinocarbonyl, Y is -0- or -CH ₃ - means an integer η Number from 0 to 5 and m is an integer from 0 to and Ar denotes the phenyl radical or thiazolyl radical S09819 / 1285 where, when Y is "C ¹¹ T", ^{n is} 1, and where R is bonded to the phenyl radical in the 2- or 3-position and to the thiazolyl radical in the 4- or 5-position. 23. Amines and salts according to claim 22, wherein R is methoxycarbonylaminoäthenyl , Hethoxycarbonylaminoallyl, Äthoxycarbonylaminoäthenyl or Äthoxycarbonylamino- 2i
allyl, R is hydrogen, chlorine, methyl or 31 4i
Methoxy denotes, R and R denote hydrogen atoms, R and R each denote hydrogen or methyl 71 81.
mean, R and R each hydrogen or methyl Qj denote, R denotes hydrogen, carbamyl, methoxycarbonylaminoethyl, methylcarbamyl. ^{or morpholine carbonyl, Y denotes 1-} -O-, η denotes 1- or 2 and m denotes 0, 1 or 2, and Ar denotes the phenyl radical. 24. Amines and salts according to claim 1 of the general formula Ik HR ^3k R ^5k ■ DHR - 94 - 609819/1285 1k where R is the group -CH = NOR, where R is a hydrogen atom or an alkyl group with 1 to 6 2k
Carbon atoms, R is hydrogen, halogen, 3k is alkyl or alkoxy, R is hydrogen or 4k
Alkyl denotes, R hydrogen, alkanoyl or 5k 61c
Benzyl is, R and R are each hydrogen 7Tc 8k or alkyl, R and R are each water 9k is substance, halogen, alkyl or alkoxy, R Hydrogen, alkanoyl, suIfο, suIfino, cyano, Trifluoromethyl, alkoxycarbonylaminoalkyl, the 10V 1 11c 1 OV 11V Group -CONR ¹ IR ¹ or -CONHNR ¹ * R means, 1Ok 11k where R and R are hydrogen atoms or taken together with the nitrogen atom to which they are attached form a heterocyclic ring, Y ^ is the group -0- or -CH ₃ -, η is an integer from 0 to 5 and ra is an integer from 0 to 2 and Ar is a Phenyl radical, thiazolyl radical or 1k denotes thiadiazolyl radical, where R is in the 2- or 3-position to the phenyl radical, in the 4- or 5-position to the thiazolyl radical and in the 4-position to the thiadiazolyl radical is bonded and where, when Y is indicative, η is 1 to 5. 1k 25. Amines and salts according to claim 24, wherein R is the group -CH-NOR, wherein R is hydrogen or alkyl with 2k 1 to 6 carbon atoms, R is hydrogen, - 95 - 609819/1285 2S31312 Means chlorine, bromine, methyl, ethyl, methoxy or ethoxy, R means hydrogen or methyl, R ^{4k means} hydrogen, formyl, acetyl or benzyl, R ^5k and R ^{6k are} each hydrogen, methyl or ethyl 7k 8k mean, R and R each mean hydrogen, chlorine, bromine, methyl, ethyl, methoxy or ethoxy, 9k
R hydrogen, formyl, acetyl, sulfo, sulfino, cyano, trifluoromethyl, methoxycarbonylaminoethyl, methoxycarbonylaminoethyl, carbamyl, methylcarbamyl, dimethylcarbamyl or morpholine carbonyl denotes, Y denotes -O- or -CH “- denotes an integer, η is an integer from 0 to 5 and m is an integer from 0 to 5 Number from O to 2 and Ar denotes the phenyl radical or thiazolyl radical, where, k 1k when Y is -CH, -, η is 1 to 5, and where R is bonded in the 2- or 3-position to the phenyl radical and in the 4-position to the thiazolyl radical. 26. amines and salts according to claim 25, wherein R isonitrosomethyl, Methyl isonitrosomethyl, ethyl isonitrosomethyl, Propylisonitrosomethyl or tert-sutylisonitrosomethyl R means hydrogen, chlorine, methyl or methoxy 3k AY 5k means, R and R mean hydrogen atoms, R 6k 7k and R are each hydrogen or methyl, R 8k 9k and R each denotes hydrogen or methyl, R denotes hydrogen, carbamyl, methoxycarbonylaminoethyl, methylcarbamyl or morpholine carbonyl, Y denotes -O-, η denotes 1 or 2 and m denotes 0, 1 or 2 and Ar - 96 - 6 0 9 8 1 9/1? ft S means the phenyl radical. 27. 1- / 2- (4-Carbamylphenoxy) ethylamino_7-3- (2-allylphenoxy) ■ propanol-2, and its therapeutically acceptable salts. 28. 1 - / 2- (4-Carbamylphenoxy} -äthylamino_7-3- (2-chloro-5 methyl-phenoxy) -propanol-2 and its therapeutically acceptable salts. 29. 1 - {% - <4-Carbamylphenoxy) -äthylamino_y-3- / 2 ~ - (2-methoxyethyl) -phenoxy__7 ~ P ^ opanol-2 and its therapeutically acceptable salts. 30. 1- / 1- (4-Carbamylphenoxy) -äthylamino_7-3- (4-chloro-3-thiazoloxy) -propanol-2 and its therapeutically acceptable salts. 31. 1- / T-methyl-2- (4-carbamylphenoxy) -ethylamino_7-3- (2-allylphenoxy) -propanol-2 and its therapeutically acceptable salts. 32. 1- / T-Methy 1-2- (2-methylphenoxy) -äthylamino__7 "3- (2-alylphenoxy) -propanol-2 and its therapeutically acceptable salts. 33. 1- / T-Methy1-2- (4-methylphenoxy) -äthylamino_7-3- (2-allylphenoxy) -propanol-2 and its therapeutically acceptable salts. 609819/1285. _ ₉₇ - . 1 - / 2 * - {4-Methoxycarbonylaininoäthylphenoxy) -äthylamino_7 -3- (2-methoxycarbonylaminoethylphenoxy) propanol-2 and its therapeutically acceptable salts. 35. 1 - / T-Methyl -2 - (4 -methylcarbamylphenoxy) -äthylamino__7 -ό- (2-carbamyläthylphenoxy) -propanol-2 and its therapeutically acceptable salts. 36. 1- / 2 - (2-Trifluoromethylphenylamino) -äthylamino_7-3- (3-methylcarbonylaminoethylphenoxy) -propanol-2 and its therapeutically acceptable salts. . 1 - / 2- (4-Carbamylethylphenoxy) -äthylamino ^ - ^ - (2-methoxycarbonylaminoallylphenoxy) -propanol-2 and its therapeutically acceptable salts. 38. 1- / 2- (4-morpholinylcarbonylphenoxy) -ethylaminoZ-S- (2-allylphenoxy) -propanol-2 and its therapeutically acceptable salts. 39. 1- / T-methyl-2- (4-carbamylphenoxy) -ethylamino7-3- (2-methyl-isonitrosomethylphenoxy) -propanol-2 and its therapeutically acceptable salts. 40. 1- / T- (2- (2-methoxycarbonylamino) ethyl) phenoxyethylanino7-3- (2-methylphenoxy) propanol-2 and its compatible salts. _ QQ _ 809819/1285 3ο 41. 1 - / 2- (4-carbamylphenoxy) -äthylamino / 'S- (3-allylphenoxy) ■ propanol-2 and its therapeutically acceptable salts, 42. 1 - / 2- (4-carbamylphenoxy) -äthylaminoZ-S- (2-chlorophenoxy) -propanol-2 and its therapeutically acceptable salts. 43. 1- / 2- (4-carbamylphenoxy) ethylaminoZ-S- (2,3-dichlorophenoxy) propanol-2 and its therapeutically acceptable salts. 44. Process for the preparation of amines and their therapeutically acceptable salts according to claim 1 to 43 , characterized in that one a) a compound of the general formula II IR ¹ ) (R ² JArOCH ₂ ITHCH-Z 12 3 wherein Ar, R, R and R have the above meaning and X is a hydroxyl group and Z is a reactive, esterified Hydroxyl group or X and Z taken together form an epoxy group with an amine of general formula III R ⁵ R ⁴ R ⁶ 60981 97 1 2 ft 5 4 5 6 7 8 9 in which R, R, R, R, R, R, Y, η and m have the above meaning, or b) a connection of the. general formula IV EAR ³ IR J (R JAi υυηρί, πι. R ⁴ 12 3 4
wherein Ar, R, R, R and R have the above meaning with a compound of the general formula V R ^{7 l} R ^{8 r5} A- Π-ίΠΗ_1 -Y / ' \\ ₂ -C- (CH ₂ ) _n -Y - R ^{8 V} (CH ₂ ) _m R ⁹ C C. "7 OQ wherein Z, R, R, R, R, R, Y, η and m have the above Have meaning, implements or c) a compound of the general formula VI (R ¹ HR ² ) Ar-OM 1 2
wherein Ar, R and R have the above meaning and M is a hydrogen atom or an alkali metal, with a compound of the general formula VII 609819/1285 -100- X ¹ R ³ R ⁵ in which Z, X ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , Y _f η and m have the above meaning, reacts or d) from a compound of the general formula I in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , Y, η and m have the above meaning, a cleavable one Or e) see a Schiff base of the general formula X or XI EAR ³ I < ^X > (R ¹ HR ² MrOCH ₂ CHC-NR ¹³ OH R ³ (R ¹ ) (R ² JArOCH ₂ CH-CN = R ^{13 (XI)} or a cyclic tautor of the formula XII corresponding to the formula XI - 101 60981 9/1285 ) (R-) ArGCH_CH CHR ³ 12 3 wherein Ar, R, R and R have the above meaning and R is a group of the general formula IX (IX) means in which S, R, R, R, R, Y, η and m are the 13 '
have the above meaning and RH has the same meaning as R, reduced, where the compounds XI and XII can also be present next to one another at the same time, or f) a compound of the general formula XIII CR '.) (R ^) ArOCH ₂ CCHN-C- (CH ₂ ) _n -Y v; orin Ar, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , Y, η and in are hydrogenated or g) in a compound of the general formula XIV 609819/1285 - 102 - EAR R 'Γ ~ - \ ^ - Κ ' (X ² ) (R ² ) ArOCH ₂ CHCHN-C- (CH ₂ 3 _n -Y - / ^) R ⁴ R ⁵ wherein Ar, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , Y, η and m 2 1 have the above meaning and X is a radical which can be converted into R, X ^{2 is converted} into R ¹ or h) in a compound of the general formula XXVI , _B R ⁷ (X ³ ) (R ¹ ) ArQCH-XHCHN-C- (CH-J -Y / '^> 2 ι, 2 η \ ■ i
4 ^r wherein Ar, R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , Y, η and m 3 2 have the above meaning and X converts one to R. 3 2 means, X converted into R or i) in a compound of the general formula XXVIII EAR ³ (R ¹ ) (R ² IArQCH ₂ CHCHNX ⁴ (XXVIII) R ⁴ 12 3 4 wherein Ar, R, R, R and R have the above meaning and where X converts a meaning in R d «r above 4 13 means, X converted into R or k) in a compound of the general formula XXXI - 103 609819/1285 EAR ³ R ⁵
(R ² IArOCH ₂ CHCHN-C- (CH ₂ I _n -Y V ^N V (XXXI) wherein Ar, R ¹ , R ² , R ³ , R ⁴ _f, R ⁵ , R ⁶ , R ⁸ , R ⁹ , Y, η and m have the above meanings and X is a radical convertible into R, X converts into R or 1) in a compound of the general formula XXXIV EAR ³ R ⁵ 1 -? ^! I ^j (R 3 (R-IArOCH ₀ CHCHN-C- (CH ₀ ) -Y- R ⁴ R ⁶ (CH ₀ ) R 2 m wherein Ar, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁹ , Y, η and m 7 8 have the above meaning and X is a radical which can be converted into R, X ^{7 is converted} into R ⁸ or m) in a compound of the general formula XXXVII J. (R ^) ArOCH ₂ CHCHN-C- (CH ₂ ) _n -Y- '/ ^N > (XXXVII) - 104 - X ⁸ ■ · ■ 6098 19/1285 2b3l312 wherein Ar, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , Y and n have the above meaning and X is one in group 9 - (CH-) R means convertible radical and m and R λ m 8 9 have the above meaning, X in group- (CH ₂ ) R convicted or n) a compound of the general formula V. (R ¹ ) (R ² ) ArOM (V) 1 2 wherein Ar, R and R are as defined above and M is a hydrogen atom, with a compound of the general formula XXXVIII R ³ -CH-NR ¹³ j j, (XXXVIII) HD -CH-CH ₂ 3 13 wherein R and R are as defined above o) in a compound of the general formula XL EAR ³ R ⁵ 12 Π (R ^) (R) ArOCH ₂ CHCHN-C- (CH ₂ ) _n -Y 10 (CH ₀ ) R Z m 60981 9/1285 2o3 1312 wherein Ar, R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , Y, m and η 10 4 have the above meaning and X has one in R, which is a VZasser substance atom, means convertible radical, X ^{10 converted} into R ⁴ and optionally the isomer mixtures obtained into pure isomers and / or the obtained Raze ^ ate into the optical antipodes and / or the obtained free Bases converted into their salts and / or the salts obtained converted into their free bases. 45. Medicaments containing at least one amine or its therapeutically acceptable salt according to claims 1 to 43 , preferably together with a conventional therapeutically acceptable carrier material. 609819/1 285