DD153207A5 - PROCESS FOR THE PREPARATION OF NEW CARBONIC ACID AMIDES - Google Patents

Abstract

The invention relates to production processes of novel carboxylic acid derivatives of general formula I, wherein R, R & ind1! to R & ind4!, X, Y and Z have the meaning given in point 1, and their acid addition salts, which have an effect on the metabolism. They are in particular hypoglycemic and / or lipid-lowering. The compound of the general formula I can be prepared by conventional methods for analogous compounds.

Description

· Berlin, 29 «10« 1980 AP 0 07 D / 222 511

> ^{2 12}

Process for the preparation of new carboxylic acid derivatives

The invention relates to processes for the preparation of novel carboxylic acid derivatives with valuable pharmacological properties which can be used as medicaments in medicine *

Characteristic of the known technical solutions

So far, no relevant technical solutions have become known «

It is the object of the invention to enrich the state of the art with new hypoglycemic and / or lipid-lowering agents «

The. Invention has for its object to develop processes for the preparation of new carboxylic acid derivatives *

According to the invention, new carboxylic acid derivatives of the general formula are prepared

05/04/1981

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(I)

their physiologically acceptable salts with inorganic or organic acids and also bases _s if. Z represents or contains a carboxy group

The new compounds of the general formula are v? full pharmacological properties on _$ namely an effect on the metabolism. Thus, the compounds of the general formula I have, in particular, a blood glucose lowering and / or lipid-lowering W

In the above general formula I means

_s represents a hydrogen chlorine or bromine atom or a cyclic alkyleneimino 4- to 7 carbon atoms in the Iminoring,

a hydrogen, Fluoi> - _$ oder.Bromatom chlorine, an alkyl »or alkoxy group each having 1 to 6 carbon atoms, a substituted by a phenyl group

with Λ to 3 carbon atoms, a nitro, "Amino *" _g ™ cyano or carboxy group, a Aikanoylamino-, alkoxycarbonyl "" or dialkylamido · »sulfony! group, viobei the alkyl moiety may contain 1 to 3 carbon atoms.

2 2 2 5 11 ~ ³ ~ 4.5.1981

AP C Ο? D / 222 57 672/12

and Eo _? <3, which may be the same or different, are alkyl groups having 1 to 7 carbon atoms, alkenyl groups having 3 to 7 carbon atoms, cycloalkyl groups having 3 to 7 carbon atoms, alkyl groups having 1 to 3 carbon atoms substituted by a phenyl group, phenyl or adamantyl groups, or the like.

and Ελ, together with the intervening nitrogen · = · atom, is an unbranched alkylenimino group having 4-5 carbon atoms in the imino ring, represented by one or two alkyl groups each having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a hydroxy. ·, Phenyl · », carboxy or alkoxycarbonyl group having a total of 2 to 4 carbon atoms and / or one methylene group of the above-mentioned AlkyIeηiminoringe by an imino group, which by an alkyl group having 1 to 3 carbon atoms ₉ an alkoxycarbonyl group out a total of 2 to 4 carbon "atoms, eine'Phenyl-, halophenyl, benzyl _g pyridyl" or furoyl be substituted, can can sain ₉ replaced by a iauerstoff · »or sulfur atom through a carbonyl, sulfoxide or Sulfony! group, a saturated vein partially unsaturated Azabicycloalkyl · * group of 7 to 10 carbon atoms, one in 3 ° = * and 5 ~ by a total of 3 ode Piperic acid group of 4 alkyl groups, each containing 1 to 3 carbon atoms, a 1,4-dioxa-8-alpha-aspiroic alkyl group having 6 to 9 carbon atoms, a trimethyleneimino, pyroxylamine. , Te t rahyd ro pyid ino, hepat amyl niiaino, octamethyleneimino, Honamethylenimino-, Decamethyleη- »imino-j Undscamethyleniraino» or Dodocamethylenimino «group j

  APC 07 D / 222 511 '57 672/12

R ₂ J. a substance atom or an alkyl group having 1 to 3 carbon atoms,

X is a nitrogen atom or a CH group,

X is an oxygen atom, an imino group or an optionally substituted by one or zv ee alkyl groups each having 1 to 3 carbon atoms methylene group and

Z is a hydrogen - or halogeno-coumin, a nitro-, amino-, cyano-, formyl-, hydroxymethyl- or hydroxycarbonyl-ethylene group _{s is} an optionally esterified carboxy- ¹ group, j is optionally substituted by 2 or 3 alkoxy groups carboxy · "" alkoxy carbonyl ™ or It hy lend ioxygrup'pe substituted methyl group _t wherein the Alkosqy "= * group can contain from 1 to 3 carbon atoms, an optionally by a Garboxygruppe or alkoxy =" carbonyl group having 2 to 4 carbon atoms substituted Äcetylgruppe, a substituted by one or two Alkoxycarbonylgrupperx having a total of 2 to 4 carbon of fat omen or by two carboxyl groups substituted Äthyl- »or lthylengruppe _s an optionally by an alkyl group having 1 to 7 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms and / or alkenyl group with. From 3 to 7 carbon atoms mono- or di-substituted aminocarbonyl group, a piperidino-carbonyl-, morpholinocarbonyl-, thiomorpholino carbonyl- or N-alkyl-1-piperazocarbonyl group, where the alkyl group is from 1 to 3 Carbon atoms, or else an ethyl substituted by one carbozy group. group _s if the remains E ₂ and E ₃ together with the

.-5. 4.5

AP C 07 D / 222.511 5? 6? 2/12 '

zviisehenliegenden nitrogen atom mean one of the initially mentioned cyclic Iminoraste, »

For the in the definition of the radicals R, R ^ and R ^ T and Z mentioned at the beginning

for E the meaning of the hydrogen, chlorine, or bromine atoms of the pyrrolidino-piperidino- or hexamethylene in the ino group _f

for IL · that of the hydrogen, fluorine, or bromine atom, the dex * methyl, ethyl, propyl, isopropyl, butyl, ispbutyl, PentyD, ^, isopentyl, _S, hexyl, hydroxy - _S methoxy · »·, ethoxy-propylene, isopropoxy, butoxy, isobutoxy, tert-butoxy-s-pentyloxy, isopentyloxy, keto-pentyloxy, tert-pentyloxy, hexyloxy, benzyloxy-j 1-Ph θ ny lath oxy-j 2 ~ phenylethoxy, 1-phenylpropoxy ", 2-phenylpropoxy-j 3 * = phenylpropoxy, nitro, cyano, amino, foriny!

Acetamido, propionylamino, carboxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, dimethylamidosulphonyl, diethylamidosulphonyl, dipropylamidosulphonyl, ethylmethylamidosulphonyl, methylpropylamidosulphonyl or ethylpropylamidosulphonyl group,

'I

for R ₂ and R ₃ together with the intervening nitrogen atom, which is the dimethylamino, diethylamino, dipropylamino, di, isopropylamino, dibutylamino, diisobutylamino, diphenylamino, dihexylamino -, diheptylamino, N-methyl-ethylj amino, N-methyl-propylamino , N-isopropyl-prqpy! Amino-, / N , n-butyl-propylamine- ", N-methyl-isopropyl-a-, N-methyl- butylamino, N-ethyl-butylamino, N-ethyl-isopropyl · pylamino-, N-Hthyl ^m pentylamino, N-propyl-butylamino ~> jj N-propyl-heptylamino · = -, dicyclohexylamino, N-methyl -cyclo-1-hexylamino, N-ethylcyclohexylamino, N-propylcyclo ^[ -

hexylamino, N-isobutylcyclohexylamino, dibenzylamino, ^l

j N-methylbenzylamino, N-ethylbenzylamino, N-propyl

, '

j benzylamino, N-isopropylbenzylation, N-butylbenzyl

amino, N-heptyl-benzylamino, N-methyl-phenylethylamino, N-methyl-phenylpropylamino, K-ethyl-phenylethylamino,: N-propyl-phenylethylamino, N-butyl-phenylpropylamino, diallylamino ", dibutenylamino -, dipentenylamino, diheptenylamino, N-methyl-adamantylaraino, N-ethyl-adamantylamino, N-propyl-adamantylaraino, trimethyleneimino, ^ 5 j pyrrolidino, piperidino, hexamethyleneimino -, heptamethyleneimino, octamethyleneiroino -, Nonamethylenimino-, ι Decamethylenimino ™, undecamethyleneimino, dodecamethylene: imino, methyl-pyrrolidino, dimethylpyrrolidino, 1,2,: 3,6-tetrahydropyridino, methyl-piperidino, Dirnethylpiperidino-, trimethyl- pipssridino, tetramethyl! piperidino, ethyl piperidino, diethyl piperidino, methyl ethyl piperidino, propyl piperidino, dipropyl piperi-, dino, methyl propyl piperidino, isopropyl piperidino, ethyl propyl-piperidino, butyl-piperidino, isobutyl-piperidino, tert-butyl-piperidino, cis-3,5-dimethyl-piperidino, trans-3- _t 5-dime thyl ~ piperidino,

ethyl-piperidino, trans-3,5-dipropyl-piperidino, hydroxy-pyrrolidino-, hydroxy-piperidino ™, methoxy-pyrrolidino, methoxy-piperidino, ethoxy-piperidino, propoxy-piperidino, isopropoxy-piperidino -, Pheny! -Piperidino-, hydroxycarbonyl-pyrrolidino-, Kydroxycarbonylpiperidino-, Methoxycarbonyi-piperidino-, Äthoxycarbonylpiperidino-, propoxycarbonyl-piperidino-, isopropoxycarbonyl-piperidino-f 3,3 _f 5,5-tetramethyl-piperidino- ,. 3,3,5,5-tetraethylpiperidino, 3,3,5,5-tetrapropylpiperi-10j dino, pyrrolidon-1-yl, piperidone-1-yl, hexahydroazepinone-1-yl- _f Morpholino, methylmorpholino, dimethylmorpholino, propylmorpholino, thiomorpholino, methylthiomorpholino, dimethylthiomorpholino, 1-0xidothiomorpholino, dimethyl-i-oxidothiomorphollno-, 1,1-dioxideothiornorpholino, dimethyl-1, _1-f dioxidothiomorpholino- piperazino, N-methyl-piperazino, N-ethyl-piperazino, N-propyl-piperazino, N-isopropyl-piperazino, N-phenyl piperasino-, N-chlorophenyl-piperazino, N-bromophenylpiperazino, N-pyridyl-piperazino ', N-methoxycarbonyl ~

piperazino ™, N-ethoxy-carbonyl-piperazino, N-propoxycarboxylic

carbonyl-piperazino ™, N-furoyl-piperazino, tetrahydro-iso-J quinolin-2-yl, octahydro-isoquinolin-2-yl, decahydro

isoquinolin-2-yl, tetrahydro-S-benzazepin-S-yl, decahydro-3-benzazepin-3-yl, octahydro-isoindol-2-yl, 3 ~

j aza-bicyclo-nonane-S-yl, 1, ^ dioxa-s ^ aza-spiro ^, 57decan

8-yl. Or I, 4-1

for R. the of the hydrogen atom, the methyl, ethyl, propyl

'or Isopropy! group,' "

! ·

-. -

for Y that of the "oxygen atom, which is the imino, methylene, me-

30! methyl-methylene, ethyl-methylene, propyl-methylene, di-

methyl-methylene, diethyl-methylene or methyl-propyl

j methylene group and

   -

for 1, the meaning of the hydrogen, chlorine or bromine atom,

those of nitro, amino, cyano, formyl, hydroxymethyl,

2 2 2511 "-β- A.5.1981

AP C 07 D / 222 511 57 672/12

Carboxy-, methoxycarbonyl-, ithoxycarbonyl-, propoxycarbonyl-, isopropoxycarbonyl-, butoxycarbonyl-, isobutoxy-, carbonyl-, tert-butoxycarbonyl-, pentoxycarbonyl-, hexoxycarbonyl-, heptoxycarbonyl-, allyloxycarbonyl-, phenoxycarbonyl-, benzyloxycarbonyl · * "~ Phenyläthosycarbonyl, CyclopropO2iycarbonyl" Cyclopentoxycarbonyl-j Cyclohe3qyl = "oxycarbonyl-j _{Cycloheptoxycarbonyl-"}} methyl "Diiaethoxy ·" methyl · "Diäthoxymethyl-, üriäthoxymethyl- _s Dipropoxyme" thyl-, Tripropoxymethyl-, Hydroxycarbonylmathyl-, Methosycarbonylmethyl, itboxycarbonylmothyl, propoxycarbonylmethyl, 1,3-sioxolan-2-yl-, acetyl-, hydroxycarbonyl- * acetyl-, methoxycarbonylacetyl-, -ethoxycarbonylacetyl-, isopropoxycarbony! Acetyl-, 2-hydroxycarbonylethyl-, 2 -Hydroxycarbonyläthy1-, 2 «methoxycarbonyläthylen-, 2-Äthoxycarbonyläthylen · = -, 2-methoxycarbonyl-ethyl- _f 2-Äth» oxycarbonyl-ethyl, 2-isopropoxycarbonyl-ethyl, 2,2-bis · hydroxycarbonyl-ethyl = », 2,2 ~ Bis-ä thoxycarbonyl-ethyl-, aminocarbonyl-, methyl-aminocarbonyl-, ethylaminocarbonyl-, isopxophenylaminocarbonyl-Batylaminocarbonyl-, pentoxy-1-aminocarbonyl-, Hexylaminocarbonyl "Ηθ ρ ty! Amino carbonyl _s aliy! Aminocarbonyl ₉ Diallylaminocarbonyl-, dimethyl ·" aminocarbonyl, Diäthylaminocarbonyl- "Dipropylaminocar- bonyl-, Dihexylarainocarbonyl-, H-Methyläthylaminocarbonyl-., Cyolopropylaminocarbonyl-, Cyclopentylaminocarbonyl-g cyclohexylaminocarbonyl -, Cycloheptylaminocarbonyl-, Di 'cyolohexylaminocarbonyl ^ j N-Methylcyclohexylamiriocarbonyl-, N-ethyl-cyclohexylaminocarbonyl-, N-propyl-cyclohexylaminocarbonyl-, N-pentyl-cyclohexylaniinocarbonyl-, piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl "~ _f N-methyl- piperazinocarbonyl-, N-ethylpiperazinocarbonyl- or N-propyl-piperazinocarbony!

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However, preferred compounds of the above general formula I are those in which

R a water of fatoinj.

2L a water off-j. Fluo3> - _S chlorine or bromine _s an Al orxygruppe with 1 to 6 carbon atoms ^ an alkyl group having 1 to Λ carbon atoms _sa Alkoxycarbo "ny group having 2 to 4 carbon atoms ^ a hydroxy, 'cyano, Carboy- _s! Hitro ~ ₈ amino, acetamido, dimethylaminosulfonyl, or bensyloxy group,

Ep is an "aryl group of 1 to 6 carbon atoms, a cyclohexyl" f "_s" phenyl ", benzyl, adamantly 1- or allyl group".

an alkyl group having 1 to 6 carbon atoms or an allyl group or

and B ₀ together with the intervening nitrogen atom represent an unsubstituted alkylenimino group having h to 12 carbon atoms in the imino ring, an alkyl group having 1 to 4 carbon atoms, a phenyl, hydroxy-methoxy, carboxy or alkoxycarbonyl group with a total of 2 to 4 carbon atoms substituted piperidino group, one in 3 ~ - ¹ ^ d 5 "° depending on a Alley! Group of 1 to 3 carbon atoms di" - substituted piperidino group, a la 3 ^w and ^ position depending on zviei'Allqflgruppen with in each case 1 to 3 carbon atoms - tetrasubstituted piperidino group _- a mojpholino-1-thiomorpholino, 1-oxido-thio-inorpholino or 1-i-dioxo-thiomorpholino group optionally substituted by one or two methyl groups

'4.5.1981

AP C 07 D / 222 57 6? 2/12

optionally substituted in the position by a piperazino group substituted by a methyl, benzyl, phenyl, *, chlorophenyl, pyridyl, furoyl or alkoxycarbonyl group having a total of from 2 to 4 carbon atoms, a pyrrolyl, piperidone

aza ~ spiro / 4 _t § / deoan-8 »yl-, 1, ^" Dioxa-S-aza-spiro ^, 6 / unde "can ~ 8 ~ yl ~ y Ootafayd: ro-iso: indole-2 yl, 1 _f 2, _f 3, 4-tetrahydro-i-bochinolin-2-yl-j, 1,2,3,4,5,6,7,8-ootahydro-isooquinoline-2-yl, peoahydro-isoquinoline ^ -yl-, 1,2,4,5-> tetrahydro-3-yl-ban2azepin ~ 3-yl-i decahydro ^ -benzazepine-S-yl- or

E ₂ , a hydrogen atom or a methyl group, X is a CH group or a nitrogen atom ^

X is a methylene, methyl-methylene or dimethyl methylene group, an NH group or an oxygen atom and

Z is a carbosyl, cyano, formyl or hydroxyme group, an alkoxycarbony group with a total of. 2 to 7 carbon atoms, a Cyelohexyloxycarbonyl-, Benzyloxyoarbonyl-, Diäthoxymethyl-, Hydroxycarbonylmethyl "", bis-2,2 · ethoxycarbonyl-ethyl-5 2 ~ hydroxy ~ carbonyl-ethyl ~ or 2-Äxoxycarbonyl ~ ethyl group, one by a hydroxycarbonyl or an ethoxycarbonyl group substituted acetyl group or also a 2-hydroxycarbonyl-ethyl group, if the best K ₂ ^ ¹ ^ 3 together with the intervening nitrogen atom represent one of the cyclic imino radicals mentioned in the beginning, mean

i - 11 ~ 4.5-1981

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and their salts, but especially those compounds,

in which the radical R ^ is in position 5 of the benzene ring?

However, particularly preferred compounds of general formula I are those in which

R is a hydrogen atom, -. ,

Bu in ^ position a hydrogen, fluorine * chlorine or Brornatonij an alkyl or Allcoxygruppe each having 1 to 3 carbon atoms, a carboxy, cyano or nitro groups

Rp and Rt together with the intervening nitrogen atom a Μ, Μ-Dialkylamino ™ or N-alkyl-cyclohexylaminogruppe each having 1 to 3 carbon atoms in the alkyl moiety, a Pyrrolidino-} piperidino, Hexamethylenimine-, Heptamethylenimino-j Octamethyleniinino- or HonametJLyleniminogruppe, a by an alkyl group having from 1 to 4 carbon atoms by a piperidino group substituted by a methoxy or phenyl group, a piperidino group substituted in each case by one or two methyl or ethyl groups in 3- and 5-position, each optionally substituted by a methyl group in the 2- and 6-position -. tuted morpholino or Tiiiomorpholinogruppe, a 1,4-Dioxa »8 ~ aza-spiro / ^ 4- _? 5j ^ decan-8-yl, 1,4-dioxa ~ 8 ~ aza-- spiro / * 4,67-l-decan-yl-f octahydro-isoindol-a-yl,

'1 _i 2,3 _i 4 ~ tetrahydro-.isochinolin-2-yl ~ _s 1,2,3,4,596,7,8-Octyhydro-isoquinoline ~ 2-yl _i DecpJiydro-isoquinolin-2 ~ yl _s 1, 2.4, 5-2etrahydro ~ 3H-3 benzazepine ~ ~ 3 ~ yl ™ ', decahydro ~ 3H ~ 3' ~ benzazepin-3-yl ~, 3 "aza ~ bicyclo / 3 _s 2,2 / 3 ~ ~ nonane yl or N-methyl-adamantyl (1) amino group _e -

AP G 07 D / 222 511 5? 672/12

a water toff atom or a methyl group, X the

X. a methylene _t methylamines thy Ie nj Dirnethyl-methylene "or odex ⁱ an oxygen atom and

Z is an alkoxycarbony group having a total of 2 to 4 carbon atoms, a carboxy, pormyl or hydroxymethyl group

mean * and the> sn physiologically compatible acid addition salts with inorganic or organic acids and also bases _f if Z represents a carboxy group

According to the invention, the new compounds are obtained by the following methods!

a) reaction of an aminobenzoic acid of the general formula

0OH

(ID

in the .

R »R, -j Rpi Ko and X are as hereinbefore defined are _$ or their optionally .in the reaction mixture produced reactive £ _ar: iA ät mi * an amine of general formula?

4-.5..1981

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(HD

.in the

Κ *, Y and Z are initially defined, or with an inactivatable affinity of the general formula III optionally formed in the reaction mixture, Ytenn is an aminobenzoic acid of the general formula II and if Z in an inactivated amine is general Formula III contains no carboxy or amino group,

The process thus relates to the acylation of an amine of the general formula III with an aminobenzoic acid of the general formula II in the presence of a SaUx ¹ Q activating or a water-attracting agent or with their functional derivatives or

the reaction of an aminobenzoic acid Q £ general Fox * - »times II with an amine of general formula III, in which Z represents no carfaoxy or amino group _? in the presence of an amino group-activating agent or its reactive derivatives »

Examples of suitable functional derivatives of an aminobenzoic acid of the general formula II which are prepared in the reaction mixture are their alkyl radicals _. Aryl or aralkyl esters or "thioesters" viiedex ¹ methyl "," ethyl "," phenyl "or benzyl esters, their copper complexes, their imidazolides, their acid halides such as the acid chloride,

2 2 251 1

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57 672/12

or "" bromide, their anhydrides, d-sren mixed anhydrides with aliphatic or aromatic carboxylic, sulfenic, suifin "or sulfonic acids or carbonic esters ^ ζ" _β of acetic acid, propionic acid, p-toluenesulfonic acid or O-ethyl-carbonic acid, their 0 = triphenylphosphonium, their N-Aoyloxyimide, their ftzide or nitriles or the corresponding amino-thiobensoesäure derivatives, and as optionally prepared in Reaktionsgamisch reactive derivatives of an amine of the general'formula III, V "Z" no carboxy or Contains amino group whose Phosphazoderivate considered

As acid-activating and / or vtasserentziehende means, for example, get a Chlorameisensäuraostex '· as ethyl chloroformate, thionyl chloride, phosphorus trihalides chloride, phosphorus pentoxide, NjN'-Dicyclohexylcarbodiimidj N _s N ^f -Carbonyldiimidazolj N, N' -Thionyldiimidazol, boron trifluoride etherate or Sriphenylphosphin / tetrac hlorkohlen "material into consideration ^ _:

The reaction is ZTseokmäßigerweise in a solvent such as methylene chloride ₈ chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene _$ toluene or dimethylformamide, optionally in the presence of a anoa> »ganic base such as sodium carbonate or a tertiary organic base such as triethylamine or pyridine, which at the same time as Solvent can serve, and optionally in the presence of an acid-activating agent at temperatures between - »25 to 250 ⁰ C, but preferably at temperatures between -10 ⁰ C and the boiling temperature of the solvent used, carried out hereby a possibly resulting in Eeaktionsgemisch funkti <~

2 2 2 5 1 1 -15 ™ Λ · 5 · 1981 ·

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Onelies derivative of a compound of general formula II or III not to be isolated _} Furthermore, the reaction can also be carried out without a solvent. »Further, during the reaction resulting water by azeotropic distillation, z _e B _e by heating with toluene on a water separator, or separated by the addition of a desiccant such as magnesium sulfate or molecular sieve «

b) For the preparation of compounds of general formula in the IL except for the hydroxy and ^ -minogruppe as defined above, .Xe ine.CH group and

Y represents a methylene group which is optionally substituted by one or two alkyl groups each having 1 to 3 carbon atoms *

Reaction of a compound of general formula

fl /.

CO - NH - Y - CH ^ i /

in the , .

R, B ₁ , and Z as in the beginning and

It and Y are as defined above and E represents a halogen atom with an amine of the general formula

2 2 25 11 -16-, '4 May 1981

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^H - ^N (ν),

in the

and Eo as defined above

Among the term "a halogen atom" used in the definition of the interchangeable radical E is in particular. · To understand a chlorine or bromine atom or even a fluorine atom, if IL is the kitro group

The reaction is more useful than ise in a water is water, water / methanol, water / ethanol _s water / Isopropanolj dimethylformamide or in an excess of the amine used in the general Formal V. optionally in. Presence of an inorganic or tertiary organic base, optionally in the presence a Keäktionsbeschleunigers such as copper and optionally in a D _r uckgefäß at temperatures between 20 and 150 ⁰ C, but preferably at the boiling point DES Eeaktions ~ mixture _$ z _e B ₉ at 100 ° G conducted _S "However, the reaction can also be carried out without solvent become"

c) For the preparation of compounds of the general formula I in which Z represents a carboxy group and T does not represent an NH group. ·

«17-» 4.5 ·. 1981

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Oxidation of a compound of general formula

^E CO - NH - χ - CH - ( ^{A x} > - A (VI)

IL Η "I, B ₂

in the

Β? Bu to B ^ and X are defined at the outset, Y Y except uqs: NH group as defined at the outset

A is a group which can be converted by oxidation into a carboxy group

Examples of such an oxidisable group are the Pormy! Group and its acetals, the hydroxymethyl group and its ether, an unsubstituted or substituted acyl group such as the acetyl- _S chloroacetyl, propionyl or malonic acid (i) y! «Group or a Ma onester- (I) ^ yI =" in consideration * ''.

The reaction is carried out with an oxidizing agent in a suitable solvent such as water, glacial acetic acid, lyridirt or carbon tetrachloride at temperatures between 0 and 100 ⁰ C ₄ , but expediently at temperatures between 20 and 50 ⁰ Cg. However, the reaction is preferably carried out with SjQb _erO xi ( 3 / i $ atronlaug9, manganese dioxide / acetone or methylene chloride _s hydrogen peroxide / hydroxide solution ₉ bromine or chlorine / sodium or potassium hydroxide solution or chromium trioxide / pyridine carried out ''

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d) For the preparation of "compounds of the general formula I in which Z represents a carboyl group j

Hydrolysis of a compound of the general formula

CÖ - NH-Ϊ-CH *. (' > .B (VII),

-4 * Ύ

A. _N ^

H ₃

in the

Ej E _- - to E ^ j Z and Y are as defined above and B represents a group which can be converted by hydrolysis into a carboxy group <>

Examples of such hydrolyzable groups are the nitrile group _s functional derivatives of the arboxygruppe as their unsubstituted or'substituted amides _? Ester _s £ 'hioQster ₈ orthoester imino ether, amidines or anhydrides _f a malonate (i) yl group the tetrazolyl group may be an optionally substituted 1,3-oxazol (2) -yl or di-hydroc-1 _f 3-oxazole. (2) -yl group in consideration

The hydrolysis is suitably carried out either in the presence of an acid, hydrochloric acid, sulfuric acid, phosphoric acid or trichloroacetic acid, or in the presence of an acid

9 9'2 5 1 1- -19- 4 * 5 * 1981

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Base such as sodium hydroxide or potassium hydroxide in a ge = * suitable solvent such as Ithanol, water / lthanol, ^ ater / isopropanol or water / dioxane, at temperatures from -10 to 120 ⁰ G ₁ 55 "B ₀ at temperatures between room temperature and the boiling temperature of Reaktionsge ". misch run

If the cyano group _s in a compound of the general formula VII B is reacted in the presence of ethanol / hydrogen chloride, the corresponding imino and orthoester is formed in the reaction mixture after addition of water hydrolysed

e) For the preparation of compounds of the general formula I _s in the E _? an alkyl group having 1 to 7 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an alkyl group having 1 to 3 carbon atoms substituted by a phenyl group or an alkenyl group having 3 to 7 carbon atoms, R ^ an alkyl group having 1 to 7 carbon atoms, a cyanoalkyl group having 3 to 7 carbon atoms, an alkenyl group having 3 to 7 carbon atoms, an alkyl group having 1 to 3 carbon atoms substituted by a phenyl group, or an adamantyl group or R ₂ ^{un <3 E} 3 together with the intervening nitrogen atom 7-membered alkyleneimino ring, a piperidino group substituted by an alkyl group having 1 to 4 carbon atoms or one each in the 3- and 5-positions by an alkyl group

2 2 2511 - ₂ o- 4.5.1981

AP C 07 D / 222 511 57 672/12

with 1 to 3 carbon atoms substituted Piperldinogruppe and Y represents an optionally substituted by one or two alkyl groups each having 1 to 3 carbon atoms methylene group ^ ·

Reaction of a compound of the general formula which is optionally formed in the reaction mixture

r / -λ

(viii) _t

CO - KH - Y - CH

in the

R, IL, R ₂ ). X ωι3 Z vssie initially defined are _$ Ik ^{f represents} a Vfesserstoffatom or has the meaning of R ^ above "meanings, and

Y has the meanings mentioned above, with a compound of the general formula

R ₂ * ~ G (IX),

5 1

AP G Ο? D / 222 511 57 672/12

in the

Ep * has the meanings mentioned for R ₂ or, together with the radical Bo ^{ΐ of} the formula IX, a straight-chain alkylene group having 4 to 6 carbon atoms _? represents an n-pentylene group substituted by an alkyl group having 1 to 4 carbon atoms or an n-pentylene group substituted by an alkyl group having 1 to 3 carbon atoms in 2 and 4 positions, and G represents a nucleophilic nucleus © viiie a halogen atom or a §Sulfonyloxy group _s ζ _β · Β * a chlorine-bromine or iodine atom _s a met bans ulfonyloKy ™ or p "" ioluenesulfonyloxy group means ©

Thus, for example, all the halides or sulfates vaie methyl iodide, ethyl iodide, _s propylbromiä _? Benzyl chloride ₉ BenzylbroEiidj dimethyl sulfate or diethyl sulfate into consideration

The reaction vüird zvjeckmäßigGrfleise in a solvent \ t ± Q acetone Tetrahydrofui'an _s, Dirnethylformami <3 ₉ Dimöthylsulfoxid or Hexamethylphosphorsäuretriamidj optionally in ^G ^ ay of an inorganic base such as carbonate Natriuaw art Ealiumkarbonat or Ealium ° .tert _e bu.tylat or a tertiary organic Base such as pyridine, at temperatures between 0 and 150 ⁰ C _9, preferably, however, carried out at temperatures between 20 and 75 ⁰ Oj Substituted a © carboxylic acid of the general formula VIII-ein ₉ so this can be depending on the reaction conditions used ₈ z _e B ₁₉ at temperatures above room temperature and in the presence of an alcoholate as base _t . at the same time be transferred to the appropriate Ister « ^:

2 2 2 5 11 ~ ²² ~ ^Λ · 5

AP C 07 D / 222 57 672/12

The methylation can also be performed in such a manner ₅ that a compound of general formula VIII with formalin in the presence of a Eeduktionsmittels, z "B _e formic acid or hydrogen in the presence of a hydrogenation catalyst, 2" B _e palladium or platinum, optionally in a solvent such as formic acid or glacial acetic acid at iemp.eraturen reacted to the boiling point of the reaction mixture

A compound of general formula VIII can also be prepared in the reaction mixture by reacting a correspondingly substituted isatoic anhydride with a corresponding amine of general formula III.

f) for the preparation of compounds of general formula I, wherein Y represents the NH group or an oxygen atom; j

Reaction of a compound of the general formula

in

R, - R ₁ to R ₃ and X are as defined above and Y has the meanings mentioned above, or their alkali metal salt with a phenyl derivative of the general formula

CH

in the

R. and Z are as defined above and L is a nucleophilic leaving group such as a halogenatora

or a sulphonyloxy group, Z ₀ B. a chlorine, bromine or iodine atom, a Methylsulfohyloxy- _f p-Toluolsulfonyloxy-. ^: or metho.xysulfonyloxy group, means.

The reaction is expediently carried out in a solvent such as water / ethanol, water / isopropanol, tetrahydrofuran dioxane, acetone, dimethylmorphamide, dimethyl sulfoxide or hexamethylphosphoric triarynide, preferably in countercurrent conditions.

a base such as sodium carbonate, sodium hydroxide or potassium hydroxide _f potassium tert-butoxide at temperatures between; 0 and 150 ⁰ C, but preferably at the boiling temperature of the reaction mixture, for example at temperatures between 50 and 100 ⁰ C performed. If you use this an ester. so this can be converted simultaneously into the corresponding carboxylic acid depending on the reaction conditions used, for example at elevated temperatures and in the presence of an excess of the base used.

jg) For the preparation of compounds of general formula I _f in the

R ₁ excluding the hydroxy, carboxy, amino, and alkanoylamino groups as defined above, X represents a CH group, and y represents a methylene group substituted by one or two alkyl groups each having from 1 to 3 carbon atoms;

Reaction of an amide of the general formula

in the '

R, R ₂ and R are as defined above and R ₁ "has the meanings mentioned above, or its alkali salt with a compound of the general formula

5 11. - .25-

M-Y- CH

in the

R. and Z are as defined above, ι Y has the abovementioned meanings and I M is a nucleophilic leaving group such as a halogen atom

Represented \ or a sulphonyloxy

i The reaction is conveniently carried out in a solvent

: such as tetrahydro furan _f dioxane, toluene, dimethylformamide,! Dimethylsulfoxide or hexamethylphosphoric triamide ^; if appropriate in the presence of a base such as sodium hydride or '. Potassium tert-butylate at temperatures between 20 and 180 C, but preferably carried out at temperatures between 50 and 150 C, \ .

\ h) For the preparation of compounds of general formula j I in which ^v . ,

<j5 R _{1 is} a hydrogen, fluorine, chlorine or bromine atom, a

Alkyl or alkoxy group each having 1 to 6 carbon atoms, a substituted by a phenyl alkoxy group having 1 to 3 carbon atoms, a ^hydroxy,: nitro, carboxy or alkanoylamino group, X is a CH group,

Y is an optionally substituted by one or two alkyl groups each having 1 to 3 carbon atoms Me-. thylengruppe. and Z represents a carboxy group;

, Acylation of a compound of the general formula

R ₁ . R co - < Y - CH   HH - -O ^R 2 ^R 3

:. in the i

, R and R ₀ to R are as defined above,

R. and Y have the meanings mentioned above, with a

ι oxalyl halide or phosgene in the presence of a Lewis

j acid.

The Friedel-Crafts acylation is conveniently carried out in a solvent such as Nitro'benzol or carbon disulfide in the presence of a Lewis acid such as aluminum chloride, at temperatures between .0 and 80 ° C, but preferably at temperatures between 20 and 6O ⁰ C is performed.

i) For the preparation of compounds of the general formula I, in which R is a hydrogen, fluorine, chlorine or bromine atom, an alkyl or alkoxy group each having 1 to 6 carbon atoms, a substituted by a phenyl group

Alkoxy group having 1 to 3 carbon atoms, a nitro, carboxy, alkanoylamino or alkoxycarbonyl group each having 1 to 3 carbon atoms in the alkyl moiety, X is a CH group,

 , Y is an optionally substituted by one or two alkyl groups each having 1 to 3 carbon atoms methylene group and. '. Z is the carboxy group

Reaction of a compound of the general formula

CO-NK- Υ'- CH

C "OCH

in the

R and R to R are as defined above , R ₁ and Y have the abovementioned meanings _f with an optionally prepared in the reaction mixture

Rypohalogenit.

The reaction is carried out in a solvent zweckmäßigerveise _w i _e water / tetrahydrofuran or water / dioxane at temperatures between 0 and 80 C, but preferably at temperatures between 25 and 50 C _f.

Is obtained according to the invention a carboxylic acid amide of general) formula I in which Z represents a carboxy group, this may, if desired, by esterification or by amidation in |

I '

a corresponding compound of the general formula I in which 1 is an esterified carboxy group or an optionally represented by '' an alkyl group having 1 to 7 carbon atoms, a cycloalkyl; mono- or di-substituted aminocarbonyl group, a piperidinocarboriyl, morpholinocarbonyl, thio-20morpholinocarbonyl or N-alkyl-piperazinocarbonyl group, and / or alkenyl group having from 3 to 7 carbon atoms and / or alkenyl group having from 3 to 7 carbon atoms

a carboxylic acid amide of the general formula I, in which R. and / or Z represent a nitro group, this can by means of reduction

iin a corresponding compound of general formula I / in Ider R ₁ and / or Z represent an Araino group be transferred to the _f and / or

a carboxylic acid amide of the general formula I, in which R ₁ and / or \ Z represent an amino group, this can be replaced by a! Talking diazonium salt into a corresponding compound of ^'general formula I, in which R ₁ is hydroxy or cyano group,

ι '

pure fluorine, chlorine or bromine atom and / or Z is a chlorine or. :

jBromatom or the nitrile group represent / are _performed: Q jwobei such optionally obtained compound of the general, NEN formula I in which represents R. hydroxyl group, anschliesjsend-means can be converted alkylation into a corresponding compound of 'general formula I, R.sup.1 represents an alkoxy group having 1 to 6 carbon atoms or an alkoxy group having 1 to 3 carbon atoms substituted by a phenyl group, and / or;

a carboxylic acid amide of the general formula I in which R 1 represents the IAmino group may be prepared by acylation to give a corresponding compound of the general formula I in which R 1 is an alkanoylamino group having 1 to 3 carbon atoms in the Al. represents kanoylteil, be converted ^ and / or

a carboxylic acid amide of general formula I in which R _{1 is} a _; Alkoxycarbonyl group and / or R ₀ and R together with the

intermediate nitrogen atom form a nylgruppe Alkoxycarbo- by a '3-substituted imino group. with 4 to 6 carbon atoms, the alkoxy moiety each containing 1 to 3 carbon atoms, by hydrolysis to a corresponding compound of the general formula Γ in which R _{1 represents} the carboxy group and / or R ~ and R ^ together with the intermediate moiety lying nitrogen atom represents a substituted by a carboxy group imino group having 4 to 7 carbon atoms in the imino ring, are converted, and / or

a carboxamide of the general formula I in which R "and R together with the intervening nitrogen atom represents an N-benzylpiperazino group, by means of debenzylation in a leasily corresponding compound of the general formula I in which R ₀ and R-. together with the intervening nitrogen atom | represents a piperazino group, are transferred _t and / or

a carboxylic acid amide of the general formula I in which R _{1 is} a. *

Chlorine or bromine atom, by means of dehalogenation in

a corresponding compound of the general formula I, in which 10'R _{1 represents} a hydrogen atom, are converted, and / or

a carboxylic acid amide of the general formula I in which Z represents an optionally esterified carboxy group, this can be converted by reduction with a metal hydride into a corresponding compound of the general formula I in which Z represents the hydroxymethyl group, and / or

a carboxylic acid amide of the general formula I, in which Z represents the hydroxymethyl group, this can be converted by oxidation into a corresponding compound of the general formula I in which Z is the formyl group, and / or

\ 20 ^! a carboxamide of the general formula I in which Z represents the hydroxymethyl group, this

genierung and subsequent reaction with a malonic acid ester in a corresponding compound of the general formula I, in which Z is an alkyl group substituted by two alkoxycarbonyl, are converted, and / or

a carboxamide of the general formula I in which Z represents the formyl group, this can be converted by acetalization into a corresponding compound of the general formula I in which Z 'is a dialkoxymethyl group, and / or

2 2 251 1 ...- 3O- · 4 ·· 5

AP. G Ο? D / 222 57 672/12

a carboxylic acid amide of the general formula I in which Z represents the formyl group, this may be converted into a corresponding compound of the general formula I _t in the Z by means of condensation and optionally subsequent hydrolysis of an ethylenyl group substituted by a hydroxycarbonyl or alkoxycarbonyl group _s are transferred, and / or

a carboxylic acid amide of general formula I in which Z represents a hydrogen atom _$ it may be prepared by means of peace graft acylation into a corresponding compound of general formula I in which Z represents an acetyl group optionally substituted by an alkoxycarbonyl group , be transferred, and / or.

a'carboxylic acid amide of the general formula I ₈ in which IL and / or Z represents a nitrile group, this can be prepared by alcoholysis via a corresponding iminoester in a corresponding compound of general formula I ₉ in the It, and / or Z a Trialkoxymethy! Represents group, be transferred, and / or

a carboxylic acid amide of the general. Formula I, in which IL and / or Z represents a rialkoxymethy! Group, converted by hydrolysis into a corresponding compound of general formula I in which E ^ and / or Z represents an alkoxycarbonyl group, and / or

a carboxylic acid amide of the general formula I in which Z represents the acetyl groups, this can be converted by heating with an amine and sulfur and then with an organic base in a corresponding compound of general formula I, in which Z represents the 2-hydroxycarbonylmethyl group , and or

APC 07 E / 222 51 5? 672/12

a carboxamide of the general formula I ₈ in which Z represents the -_ carboxy group, this can be converted into the formyl group by conversion into a sulfonic acid hydrazide and subsequent disproportionation into a corresponding compound of the general formula I ₉ in aer Z and / or

a carboxylic acid amide of the general formula I in which R _{1 is} a hydrogen, fluorine, chlorine or bromine atom, an alkyl or alkoxy group each having 1 to 6 carbon atoms or an alkoxy group having 1 to 3 carbon atoms substituted by a phenyl group, X is a CH Y is a methyl group optionally substituted by one or two alkyl groups each having 1 to 3 carbon atoms and Z is a chlorine or bromine atom, this may be converted to a corresponding organometallic compound with carbon dioxide in a corresponding compound of general formula I, in which Z is the carboxy group.

ι.

The subsequent esterification or amidation is conveniently carried out in a suitable solvent, e.g. in a corresponding alcohol or amine, pyridine, toluene or dioxane, in the presence of an acid-activating and / or dehydrating agent such as thionyl chloride, ethyl chloroformate, N, N'-dicyclohexylcarbodiimide or carbonyldiimidazole or by Um-. esterification, e.g. with a corresponding carbonic acid diester, at temperatures between 0 and 50 ° C., but preferably at room temperature.

-0; temperature, performed.

The subsequent reduction of the kitro compound is preferably carried out in a solvent such as water, water / ethanol, methanol, glacial acetic acid, ethyl acetate or dimethylformamide, advantageously with hydrogen in the presence of a hydrogenation catalyst ^:

! Lysators such as Raney nickel, platinum or palladium / carbon, with metals such as iron, tin or zinc in the presence of an acid, with salts such as iron (II) sulfate, stannous chloride or sodium dithionite, or with hydrazine in the presence of Raney nickel at temperatures between 0 u:

Temperature, performed.

between 0 and 50 ° C, but preferably at room tempera-

Subsequent reaction of a diazonium salt, e.g. of the fluoroborate, of the hydrosulfate in sulfuric acid or of the hydrochlorides in the presence of copper or of a corresponding copper (I) salt, such as copper (I) chloride / hydrochloric acid, copper (I)

jbromide / hydrobromic acid or trisodium copper (I) tetra } icyanide at pH 7, is used at slightly elevated temperatures, eg at,

'O!

Temperatures between 15 and 100 C, performed. The diazonium salt required for this purpose is expediently in a ge! suitable solvents, eg B. in water / hydrochloric acid, methanol / hydrochloric acid or * dioxane / hydrochloric acid, by diazotization of an appropriate amino compound with a nitrite, e.g. Sodium nitrite or an ester of nitrous acid, at low temperatures, e.g. at temperatures between -10 and 5 ° C, prepared.

The subsequent acylation is expediently in one! Solvents such as methylene chloride, ether, tetrahydrofuran or in an excess of the acylating agent used, e.g. ; Formic acid, acetic acid or propionic acid or their anhydrides, acid chlorides or esters, optionally in the presence of an inorganic or a tertiary organic base, can simultaneously also serve as a solvent, and optionally in the presence of an acid activating or dehydrating agent at temperatures between -25 and 150 C, but preferably at temperatures between -10 ° C u <3.er boiling temperature of the reaction mixture, performed.

The subsequent hydrolysis is expediently either in the presence of an acid such as hydrochloric acid. Sulfuric acid, phosphorus ^; acid or trifluoroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as ethanol, water / ethanol, water / isopropanol or water / dioxane at elevated temperatures , for example at the boiling temperature of the reaction mixture.

Subsequent debenzylation and / or dehalogenation is conveniently carried out in a solvent such as methanol /; Ethanol, ethyl acetate or glacial acetic acid by means of catalytically activated

hydrogen, e.g. with hydrogen in the presence of platinum or palladium / carbon, at temperatures between 0 and 75 C, but preferably at room temperature, and at a hydrogen pressure of 1-5 bar.

2 2 25 11

The subsequent O-alkylation is expediently with a corresponding halide or sulfonic acid, z.B-. with methyl; iodide, dimethylsulfate, ethyl bromide, p-toluenesulfonic acid benzyl ester or methanesulfonic acid isopropyl ester, optionally in 5; presence of a base such as sodium hydride, potassium hydroxide or potassium potassium tert-butylate and preferably in a solvent such as ',' diethyl ether, tetrahydrofuran , Dioxane, ethanol, pyridine or! Dimethylformamide at temperatures between 0 and 75 C, but preferably at room temperature.

The subsequent reduction with a metal hydride is expedient: carried out in a solvent such as diethyl ether, tetrahydrofuran or dioxane at temperatures between 0 and 1OO ^G C, but preferably at the boiling temperature of the reaction mixture, dürchgeführt with a complex metal hydride such as lithium aluminum hydride.

The subsequent oxidation of a hydroxymethyl group is expediently carried out with a metal oxide such as manganese dioxide in a solvent such as acetone or dichloromethane at temperatures between O and un.

between 0 and 50 C, but preferably at room temperature,

The subsequent conversion of a hydroxymethyl group to a halomethyl group is carried out with a halogenating agent such as thionyl chloride, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride in a solvent such as methylene chloride, carbon tetrachloride, benzene or nitrobenzene and their subsequent reaction with a malonic ester, e.g. with an alkali salt of Mälonsäurediäthylester, at temperatures between 0 and 1OO ° C, but preferably at temperatures between 20 and 50 C performed. '· Ί

The subsequent acetal formation is conveniently carried out in the corresponding alcohol as a solvent, for example .B. in methanol or ethanol, in the presence of an acid such as hydrochloric acid or sulfuric acid, or by trans-acetalisation with a corresponding

Orthoester, e.g. Triethyl orthoformate, at temperatures between 0 and 100 C, but preferably at temperatures i o ...

between 30 and 60 C, performed.

:,}!

The subsequent condensation of a forrayl compound is: suitably in a solvent such as pyridine or tetrahydrofuran with malonic acid, with a "malonic acid ester or a iTrialkylphosphon-acetic acid optionally in the presence of a base as a condensing agent, for example in the presence of piperidine, potassium tert-butylate or Natriümhydrid, at Tempera- 10 doors between 0 and 100 C carried out, by subsequent, acidification, eg with hydrochloric acid or sulfuric acid, you get the, desired acid »

Subsequent Friedel-Crafts acylation is carried out with a corresponding acid halide or acid anhydride in a suitable solvent such as carbon disulfide, methylene chloride, dichloroethane or nitrobenzene and in the presence of a Friedel-Crafts catalyst such as aluminum chloride at temperatures between 0 and 50 C, but preferably at Room temperature, performed.

The subsequent alcoholysis is preferably carried out in a corresponding anhydrous alcohol as a solvent, for example in X anhydrous methanol, ethanol or propanols in the presence of an acid such as hydrogen chloride or sulfuric acid at elevated temperatures, but preferably at the boiling temperature of the reaction mixture.

The subsequent Willgerodt reaction is conveniently carried out in an alcoholic solvent such as methanol, ethanol or isopropanol by heating the acetyl compound with an amine, e.g. with morpholine, carried out in the presence of sulfur; The corresponding thioamide thus obtained is then converted into the corresponding acetic acid derivative by heating in the presence of an inorganic base such as sodium hydroxide. The reaction is particularly advantageously carried out at the boiling point of the reaction mixture.

2 2 2 5 11 «3 & ~. · 4.5

APC 07 D / 222 '57 672/12 · -

The subsequent hydrolysis of a Orthoesters is conveniently '' carried out in a solvent such as water / methanol, water / dioxane, water / ethanol or water / propanol in the presence of an acid? Iie hydrochloric acid or sulfuric acid at lower temperatures, _e B _e at room temperature is carried out *. -

The subsequent disproportionation of a ^s ulfonsäurahydrazide which is obtained by reacting .One corresponding Hydra · »interest with a corresponding reactive carboxylic acid" derivative is in the presence of a base such as sodium carbonate in a solvent such as Ithylenglykol at tempera · = doors between 100 and 200 ⁰ C. , but preferably carried out at 160 to 170 ⁰ Cj;

The conversion of a corresponding compound of general formula (I) into a corresponding organometallic compound is expediently carried out in an inert solvent such as diethyl ether, tetrahydrofuran, dioxane or tetrahydrofuran / η-hexane, if appropriate under protective gas, _{e e} B ₀ Nitrogen, preferably with a corresponding lithium compound, _{e e} B ₉ butyl-lithium in n ~ hexane, at temperatures between - »60 and 50 ⁰ C ₈ Subsequently, a solution of a corresponding organometallic compound optionally under protective gas is preferably added to solid carbon dioxide« .

The compounds of general formula I obtained may be further into the physiologically acceptable salts with inorganic or organic acids or bases when Z represents a carboxyl group or Z ent a carboxy group "= hälty transfer" Suitable acids are here, for example, hydrochloric acid, BromwasserstoffSaUXe ₁ sulfuric acid , Phosphoric acid _s

2 2 2511

'"'. AP G Ο? D / 222 511

57 672/12

Lactic acid, citric acid, tartaric acid, succinic acid ₉ maleic acid or fumaric acid and as bases sodium hydroxide ,. Potassium hydroxide or cyclohexylamine

The compounds used as starting materials of general formulas II to XV are known in the literature _s or "they are obtained by processes known per se ^ Thus, for example, a compound of general formula II by reaction of a 2-chloro ~ or 2-bromo ~ nitro Carboxylic acid or its derivatives with a corresponding Am in, followed by reduction of the nitro group in a 2-amino compound thus obtained by means of catalytically excited hydrogen by means of NaegGierendem hydrogen by means of metals or metal salts and transfer of the so ex ¬ retaining amino group via a corresponding diazonium salts in a corresponding compound of the general formula H ₀ For the preparation of a starting compound of the general formula II in which IL- represents an alkoxy- or phenylalkyloxy group, a hydroxycarboxylic acid thus prepared is subsequently alkylated and, if necessary, subsequently hydrolyzed.

A compound of the general formula IH ₉ in which Y represents no NH group and no oxygen atom is obtained, for example, by reacting a corresponding 4 '' (c &'bpomalkyl) -benziol derivative with sodium cyanide and subsequent catalytic hydrogenation of the product thus obtained cyano compound "

A compound of the general formula III in which Y represents the NH-group or an oxygen atom is obtained, for example, by reacting a corresponding 4-. (Θ / bromoalkyl) benzbl derivative with a hyroxamic acid or an ester thereof. or with an acylhydrazine and if necessary

4.5.1981-

AP C 07 D / 222 511

57 672/12

subsequent hydrolysis ©

A compound of the general formula IH ₉ in which Y is the NH group is obtained by reacting a 4-formyl or 4-acylbenzene derivative with an N-acylhydrazine, followed by reduction of the hydrazone obtained. Z ₄ B _e by means of catalytic hydrogenation., And subsequent hydrolytic cleavage of the acyl radical. An ester of the general formula III thus obtained can if desired be converted into the corresponding carboxylic acid by means of hydrolysis.

A compound of the general formulas IV * VI to VIII, XII ₈ XIV and XV used as starting material is obtained by reacting a corresponding carboxylic acid with ammonia or a corresponding amine in the presence of an acid-activating or water-removing agent.

Bine used as starting material compound of general formula X is obtained by reacting a corresponding carboxylic acid ester with hydrazine or hydroxylamine.

The compound of general formulas XI or XIII used as starting material is obtained by halogenation of a corresponding alcohol or reaction of a sulfonic acid with a corresponding alcohol in the presence of a base,

As already ermähnt hereinbefore, the exercises general formula I are valuable Pharmak © lo.gische properties j namely an effect on metabolism, the new compounds. '

2 2 2 5 11 '- ^ ^- "^ .5 · ΐ98ί. *

• ^ "AP C Ο? D / 222

57 672/12

Thus, the compounds of general formula I have in particular a hypoglycemic and / or lipid-lowering effect,

For example, the compounds were

A s 4 ^^ ~ (5-chloro-2-> dimethylamino-benzoyl-aiiino.) Ethylethyl benzoate

, acid,. ·. , '

B =; 4 ~ ^ "(5 ~ ^B roni - 2 ~ dimethylamino ~ benzoylaraino) - ' ⁱ i; hyl7benzo © · = · saura;

C ss ^^ 2 «(5

e eure me is hy le ster _f

2 2 2511 -

D = 4- / J 2 - (5-chloro-2-piperidino-benzoylamino) -äthy ^ benzoic acid,

E = 4- / 2- (5-chloro-2- (2-methylpiperidino) benzoylamino ) ethyl benzoic acid,

F = 4- / 2- (5-chloro-2- (3-methyl-piperidino) -benzoylamino) -ethyl / -I-benzoic acid,

G = 4 - / "2- (5-chloro-2 ~ (4-methyl-piperidino) -benzoylamino) -ethyl-7-benzoic acid,

H = 4- / 2- (5-chloro-2- (3,5-dimethyl-piperidino) -benzoylamino) ethyl-benzoic acid methyl ester

I = 4- / 2- (5-chloro-2- (3,5-diynethylpiperidino) benzoylamino) ethyl benzoic acid,

K = 4- / 2- (5-chloro-2- (4-methoxy-piperidino) -benzoylamino) -ethyl_7-benzoic acid,

L = 4- / 2- (5-methoxy-2-piperidino-benzoylamino) -ethyl / -benzoic acid hydrochloride,

M = 4- ^ 2- (5 ™ chloro-2-heptamethyleneiminO "benzoylamino) ethyl-7-benzoic acid,

N = 4- / 2- (5-chloro-2- (1-dioxa-e-aza-spiro ^, S / decan-e-yl) -benzoylamino) -ethyl / benzoic acid,

'20 O = 4- / 2- (5-chloro-2-hexamethyleneiminobenzoylamino) ethyl / benzoic acid,

P = 4- / 2- (5-chloro-2-thiomorpholinobenzoylamino) ethyl benzoic acid,

Q = 4 - / _ 2 ~ (5-bromo-2-piperidinobenzoylamino) ~ ethylbenzoic acid,

R = 4 - / ^ 2- (5-chloro-2-piperidino-benzoylamino) -1-methyl-äthyl7 ~ \

benzoic acid, i

S-4 "/ 2- (5-bromo-2- (2-methyl-piperidino) -benzoylamino) -äthyi7- [

, 'benzoic acid,' |

'. i

T = 4- _< / 2- (5-chloro-2 ~ (2,6-dimethyl-moypholino) benzoylamino) - '; äthybenzoic acid,

ü - 4 - ^ - (5-Chloro-2- (2,6-dimethyl-thiomorpholino) -benzoylamino) -äthy! ^ benzoic acid, * ''

V ~ 4 ~ 2- (5-bromo-2-heptamethyleneiminO "benzoylamine) -ethyl / benzoic acid ethyl ester,

W = 4- / 2- (5-bromo-2-heptamethyleneimino-benzoylamino) -ethyl 7 ~

benzoic acid,. ;

X = 4- / 2- (5-chloro-2-octaraethyleneimino-benzoylamino) -äthyJL / benzoic acid,

Y = 4- _> 2- (5-chloro-2- (decahydro-isoquinolin-2-yl) -benzoylamirio) -ethyl ^ -benzoic acid-hydrochloric acid, · ^;

Z = 4- / 2- (5-bromo ~ 2-octamethyleneiminobenzoylamino) -ethylbenzoic acid hydrochloride, ι

ΑΆ = 4-y / 2 ~ (5-ethyl-2-piperidino-benzoylamino) -ethyl / benzoic acid, BB = 4- / 2- (5-methyl-2-piperidino-benzoylamino) -ethyl / benzoic acid _f

CC = 4- / 2- (2- (N-adamantyl- (1) -N-methyl-amino) -5-chloro-benzoyl ": amino) -ethyl / benzoic acid,

DD - 4- ^ 2- (2-piperidino-nicotinylamino) -ethylbenzoic acid,

2 2 2 5 11 -ft, - 4.5.1981

* \ AP C. 07 D / 222 511

57 672/12

IB κ4- (5-chloro-2-octamethyl) -lenimino-benzoylamino) ethyl-7-benzoic acid ethyl ester,

FF a 4 - ^ (5-chloro-2-octametbyleniminobenzylamino) -amethyl-benzyl alcohol,

GG a N ' ¹ ~ (1 - = (4 "» carboxyphenyl) "> ethyl-N ² "(5-chloro> -2-piperidinobenzoyl) -hydrazine and

HH ss 4 ~ A- (5 "chloro-2-octaraethyleneiminoben2oylaminoxy) ethyl-bexizoic acid compared to

II = 4 ~ / 2 "(2" ethylamino ~ 5 ~ ctilQr ~ benzoylamino) -äthy3 "7benzoe" = acid (see Example 5 of BB-PS 837 311)

on their antihypertensive properties \ iie examined?

1 «Hypoglycemic effect;

The hypoglycaemic effect of the substances to be tested was tested on female rats of their own breed weighing 180 to 22 g which were

Search beginning were set sober. The substances to be investigated were suspended immediately before the start of the test in 1.5% methylcellulose and applied by gavage.

The blood was taken immediately before administration of the substance, as well as 1, 2, 3 and 4 hours after each from the retroorbital venous plexus. Of these, 50 μΐ were each with. 0 _f 5 ml 0.33 N perchloric acid de-oxygenated and centrifuged = In the supernatant glucose was determined by the hexokinase method using an analysis photometer. The statistical output; Evaluation was carried out according to the student t-test with ρ = 0.05 as the significance limit. , :

The following table contains the values found in percent over control:

Table 1

Sub 1 25 mg / kg -10 4 10 mg / kg 1 2 I -18 3 4 hours n.s. 1 5 mg / kg 3 n.s. 4 punching 2 3 n.s. - 9 n.s. n.s. 2 hours n.s. -31 hours -23 -10 -32 -26 n.s. -14 »12 n.s. -18 n.s. »33 -21 -41 n. So "14 -37 -23 -26 n.s. n.s. -28 n.s. 20 A -44 -23 -38 -24 -41 -24 -36 n.s. -31 -21 n.s. -15 B -44 -37 -41 -38 -33 -40 -14 -39 -37 -34 -38 -30 C -42 -43 -27 -31 -34 -26 -44 n.s. -31 -18 -21 n.s. D -51 -43 -44 -40 .-41 -46 ii t kv a »20 -44 -42 -42 -35 e -30 -48 -38 , -25 -24 -38 -33 -40 -24 -20 -49 -13 25 F -35 -24 -39 -38 -39 -34 -30 n.s. -42 -47 -20 -43 G -41 -41 -29 -40 -39 N.s -16 -16 -47 -46 n.s. -50 H -43 -37 -38 -34 -40 -15 -36 -40 -32 -40 n. s. I -47 -44 -27 -34 -37 -38 -37 -29 n.s. K. -38 -39 -36 -38 -42 -41 -34 30 L -40 M

4.5 * 3981

AP C 07 D / 222 511

57 672/12 "'

Continuation table *

s tarn 5 1 25 mg / kg -36 4 , 10 days Ag 2 3 -24 4 5 ι 1 ag Ag 3 hours -36 -17 -10 n.se 2 3 -33 1 Hours' -25 2 -33 -26 -28 -15 -43 hours -32 -25 -34 -26 -19 "29 "" 19 n * _{e e} n _e s _e N -41 -41 -34 -24 -35 -39. -43 -22 -32 -40 -32 -23 ό -37 -37 -37 -30 -42 -30 "21 -21 -27 -25 n _e s _e P -38 -41 -38 -37 -37 -42 -24 "" 44 Q -52 -39 -25 -30 = -40 "28 -21 R "42 -37 -32 -25 - »34 -41 "12 S -48 " -44 -39 -33 -39 "24 T -29 -41 ^ 4-3 ^ 38 -40 U -34 -39 ~ 40 -41 -19 ™ 45 -26 " -37  -43 -37 -49 V -44 -43 "* 45 -46 -19 -36 -38 -46 -79 -38 -46 , V / -51 "49 -41 "34 »43 "" 46 -45 -43 "42 -35 X -40 -44 "49 ^ 45 -29 -41 -40 -32 '-32 • γ -45 -40 -31 -14 u's _# Z -44 • "39 -39 "42 -41 -38 AA -22 -40 -28 -17 n _e s _ö n _e s «, ^: BB -43 »40 "42 .-41 "40 "43 CC "39 -25 -18 n _e s _e "35 -36 -28 -23 DD -42 -26 "41 "-37 -41 -33 -43 -15 -25 -13 n _e s _e 11 -41 "" 42 "41 -21 n _ö s _e  n.s.- FF _{e. e} -31 -22 GG n _e s ₆ HH n _e s _e n _e s < II n _e s _e

s not statistically significant

4 * 5 * 1981

AP C 07 D / 222 511

J? 672/12

2 _β Acute toxicity

In female and male mice of their own breed with the weight of 20 to 26 g, the toxic effect of the substances was tested after oral administration (suspension in 1% methylcellulose) a single "dose at a Nachbeobendenzeit of at least 7 days." The following table contained the found value

Substance-oriented toxicity

A> 2,000 mg / kg p _e o (0 of 6 animals died)

B> 1 000 mg / kg p _o oe (0 out of 5 animals died)

D> 2 000 mg / kg p _& o _e (0 out of 6 animals died)

H 71 000 rag / kg p o _o (0 of 6 animals died)

0> 1 000 mg / kg p _s o _e '(O of 10 animals died)

T> 1 000 mg / kg poo (O of 10 animals died)

V> 1 000 BigAg Poo "(O of 10 animals died)

W 71 000 mg / kg p _e o _e (0 out of 6 animals died)

X> 1 000 mg / kg ρ _β ο _Φ (0 of 6 animals died)

Due to their pharmacological properties, the compounds of the general formula I and their physiologically acceptable salts for the treatment of diabetes mellitus © invention are suitable purpose, they can be _f optionally in combination with other active substances, into the conventional pharmaceutical preparation forms väie tablets, coated tablets, capsules, powders or incorporate suspensions "** The single dose in adults is 1 to 50 mg, but before it is 2.5 to 20 mg _? 1 or 2 times a day «,

The following examples are intended to explain the invention in more detail

2 2 25

Preparation of the starting materials:

Example A

2- (decahydro-isochlnolin-2-yl) -5-nitro-benzoic acid

In 500 ml of ethanol, 19 g (0.136 mol) of decahydro-isoquinoline, 27.3 g (0 _r 136 mol) of 2-chloro-5-nitro-benzoic acid and 38.6 g of potassium carbonate are heated with stirring for 18 hours under reflux. After distilling off the ethanol, the residue is dissolved in 800 ml of water and adjusted by the addition of 2N hydrochloric acid to pH 4, whereby the product crystallized

Output: 38 g (92% of theory) ,

Melting point: 132-134 C (isopropanol) Ber.i C 63.14 H 6.62 N 9.20 F .: 63.02 6.48 9.38

Example B 2- ( 1,4-dioxa-8-aza-spiro £ / S , 57decari-8-yl) -5-nitro- benzoic acid

20.1 g (0.1 mol) of 2-chloro-5-nitro-benzoic acid in 200 ml of ethanol with 42.9 g (0.3 mol) of 1,4-dioxa-8-aza-spiro / 4,5j7decan Heated to reflux for 8 hours. After distilling off the solvent, the evaporation residue is taken up in water and adjusted to pH 5.2 with 2N hydrochloric acid, during which the product precipitates out After extraction with chloroform and drying over sodium sulfate, the solvent is distilled off after the solvent has been distilled off : .12 g (39% of theory),

Melting point: 155 ° C (ethanol).

Calc .: C 54.54 H 5.23 N 9.09 F: 54.20 5.13 8.97

Analogous to Examples A and B, the following compounds were prepared s'.

    : '*

, 2- (2-methyl-piperidino) -5-nitrobenzoic acid Yield: 99% of theory, m.p .: 164 ° C.

2- {3-Methyl-piperidino) -5-nitro-benzoic acid Yield: 85% of theory, m.p .: 161 ° C.

.2- (4-Methyl-piperidino) -5-nitro-benzoic acid Yield: 85% of theory, m.p .: 155 ° C

2- (3-Ethyl-6-ethyl-piperidino) ~ 5-nitro-benzoic acid. Yield: 76% of theory, m.p .: <20 ° C.

2- (3,5-Dimethyl-piperidino) -5-nitro-benzoic acid. Yield: 65% of theory, m.p .: 172 ° C. ·,

2- (4-methoxy-piperidino) -5-nitro-benzoic acid ... Yield: 68% of theory, melting point: 140 ° C.

5-nitro-2- (4-phenyl-piperidino) -benzoic acid Yield: 88% of theory, m.p .: 196 ° C.

2- (4-ethoxycarbonyl-piperidino) -5-nitrobenzoic acid. Yield: 82% of theory, melting point: 160 ^° C.

5-Nitro-2-thiomorpholino-benzoic acid Yield: 80% of theory, m.p .: 235 ° C. ·

5-nitro-2- (1,2,4,5-tetrahydro-3-benzazepino) benzoic acid. Yield: 68% of theory, m.p .: 222 ° C.

5-nitro-2- (1,2,3,4-tetrahydro-isoquinolino) -benzoic acid Yield: 70% of theory, m.p. 19 5 ° C.

5-Nitro-2- (4-phenyl-piperazino) -benzoic acid Yield: 88% of theory, m.p .: 196 ° C.

5-Nitro-2- (4-pyridyl- (2) -piperazino) -benzoic acid Yield: 66% of theory, m.p .: 192 ° C.

2- (trans-3,5-dimethylpiperidino) -5-nitrobenzoic acid Yield: 63% of theory, m.p .: 132 ° C.

2- (3,3,5,5-tetramethyl-piperidino) -5-nitro-benzoic acid Yield: 98%> of theory, m.p .: 138 ° C.

2- {3,5-Dimethy 1-morpholino) -5-nitro-benzoic acid Yield: 75% of theory, m.p .: 164 ° C.

2- (3,5-dimethylthiomorpholino) -5-nitrobenzoic acid. Yield: 70% of theory, m.p .: 118 ° C,

2- (3-azabicyclo / p, 2 , 2J nonan-3-yl) -5-nitro-benzoic acid. Yield: 72% of theory, m.p .: 221 ^° C.

5-nitro-2-nonamethyleniminobenzoic acid Yield: 80% of theory, m.p .: 127 ° C.

5-nitro-2-decamethyleneiminobenzoic acid Yield: 92% of theory, m.p .: 128 ° C.

5-Nitro-2-undecamethylenimino-benzoic acid Yield: 91% of theory, m.p .: T20 ° C.

5-nitro-2-dodecame thy lenimino-benzoic acid. 95% of theory, melting point: 115 ° C.

2- (N-He'thyl-N-phenylamino) -5-nitro-benzoic acid. Yield: 10% of theory, m.p .: 115 ° C.

2 2 2 5 11

2- (N-ethyl-N-cyclohexy! Amino) -5-nitro-benzoic acid. Yield: 78% of theory, melting point: 74 ° C.-

, '2- (N-butyl-N ~ cyclohexyl-amino) -5-nitro-benzoic acid. Yield: 84% of theory, m.p .: 56 ° C.

2- (N-cyclohexyl-N-isobutylamino) -5-nitro-benzoic acid Yield: 63% of theory, m.p .: <f 20 ° C.

2- (decahydro-3-benzazepin-3-yl) -5-nit: ro-benzoic acid yield: 98% of Theo-rie, melting point: 20 ⁰ C. ζ ·

2- (octahydro-isoindol-2-yl) -5-nitro-benzoic acid. Yield: 80% of theory, m.p .: 128 ° C.

2- (4-Isopropyl-piperidino) -5-nitro-benzoic acid. Yield: 79% of theory, m.p .: 142 ° C.

2- (4-tert-butylpiperidino) -5-nitrobenzoic acid; Yield: 57% of theory, melting point: "136 ^° C.

2- (1,4-dioxa-8-aza-spiro £ 4.6 / undecan-8-yl) -5-nitro ~ benzoic acid

Yield: 75% of theory, melting point: 135 ^° C.

2,4-Dipiperidino-5-nitrobenzoic acid Yield: 31% of theory, m.p .: 152 ° C.

4-Chloro-2-piperidino-5-nitro-benzoic acid Yield: 18% of theory, m.p .: 133 ° C.

5-Nitro-2- (1,2,3,6-tetrahydropyridino) benzoic acid Yield: 58% of theory, m.p .: 215 ° C.

2- (N-methyl-N-benzylamino) -5-nitro-benzoic acid Yield: 93% of theory, m.p .: 123-T26 ° C.

2- £ 4- (4-chlorophenyl) -piperazino-7-5-nitrobenzoic acid hydrochlo-. chloride yield: 71.5% of theory, mp: 225-227 ° C (dec.).

2- (4-Carbethoxy-piperazino) -5-nitro-benzoic acid Yield: 23.1% of theory, m.p .: 155-156 ° C.

7.-Qi- (2-Furoyl) -piperazine-J-S-nitro-benzoic acid yield: 64.8% of theory, m.p .: 200-205C.

2- (4-Benzyl-piperazino) -S-nitro-benzoic acid hydrochloride. Yield: 86.6% of theory, m.p .: 142-145 ° C.

Example C

2-Hexam ethylenimino-5-nitro-benzoic acid nitrile

18.4 g (0.11 mol) of 2-chloro-5-nitro-benzoic acid nitrile are heated in ... 250 ml of ethanol with 22.4 g (0.21 mol) of hexamethyleneimine for 4 hours at reflux temperature. After cooling, the product is oily precipitated by adding 500 ml of water. The precipitate is taken up in chloroform. After drying with sodium sulfate and distilling off the chloroform, the evaporation residue is recrystallized from ethanol.

Yield: 19.7 g (73% of theory), m.p .: 70 ° C.

Ber .:. C 63.65 H 6,16 H 17,13 Found: 63,80 6,07 17,05

Example] Q ·

5-amino-2- (de cahydro-isoquinolin-2-yl) benzoic acid

In 250 ml of dimethylformamide, 36 g (0.118 mol) of 2- (Decahydroisochinolin-2-yl) -5-nitro-benzoic acid are dissolved and a

Hydrogen pressure of 5 bar with 10% palladium carbon as catalyst. hydrogenated at room temperature. After completion of the hydrogen uptake, the catalyst is afafiltered; the solvent) is distilled off vacuo and the residue recrystallized from ethanol.

Yield: 31.2 g (96% of theory), m.p .: 252 ° C.

Ber. : C 70 , 04 H 8th , 08 N 10 20 Gef .: 70 , 09 7 85 10 12 example   e

5-Airiino-2- (1,4-dioxa-8-aza-spiro / 4,5-decan-8-yl) benzoic acid

12 g (0.039 mol) of 2 ~ (1,4-dioxa-8-aza-spiro ^ 4, S / decan-S-yl) -5-hitro-benzoic acid are dissolved in 100 ml of dimethylformamide at a hydrogen pressure of 5 bar at room temperature hydrogenated with 10% palladium carbon as a catalyst. After completion of the hydrogen uptake, the catalyst is filtered off, the solvent is distilled off and recrystallized from ethanol. Yield: 9 g (83% of theory).

Melting point: 2O9 ° C

 Calc .: C 60.42 H 6.52 N 10.07. · Gef .: 60.18 6.58 · 10.12

Analogously to Examples 1 and 2 , the following compounds were prepared:. '- ·

5-Amino-2-pyrrolidino-berizoic acid Yield: 79% of theory, m.p .: 2O8 ° C.

5-Amino-2- (2-methyl-piperidino) -benzoic acid Yield: 84% of theory, m.p .: 24O ° C.

5-amino-2- (3-methyl-piperidino) benzoic acid yield: 75% of theory, Melting point: 192 ⁰ C.

5-amino-2- (4-methylpiperidino) benzoic acid. Yield: 88% of theory, m.p .: 215 ° C.

5-amino-2- (3-ethyl-6-methyl-piperidino) benzoic acid Yield: 59% of theory, m.p .: 219 ° C. -

5-Amino-2- (cis-3,5-dimethyl-piperidino) benzoic acid. Yield: 87% of theory, m.p .: 234 ° C.

5-Amino-2- (4-methoxy-piperidineb) benzoic acid. Yield: 80% of theory, m.p .: 228 ° C.

5-Amino-2-heptamethyleneiminobenzoic acid Yield: 64% of theory, m.p .: 214 ° C.

5-Amino-2- (4-phenyl-piperidino) benzoic acid Yield: 76% of theory, m.p .: 275C.

5-Amino-2- (4-ethoxycarbonylpiperidino) benzoic acid Yield: 85% of theory, m.p .: 2O3 ° C.

5-Amino-2-thiomorpholinobenzene acid. Yield: 75% of theory, m.p .: 193 ° C.

5-amino-2- (1,2,4,5-tetrahydro-3-benzazepino) benzoic acid. Yield: 86% of theory, m.p .: 258 ° C.

5-amino-2- (1,2,3,4-tetrahydroisoquinolino) benzoic acid. Yield:. 66% of theory, melting point: 22O ° C.

5-Amino-2- (4-phenyl-piperazino) -benzoic acid Yield: 83% of theory, m.p .: 255 ° C.

5-Amino-2 "(4-pyridyl- (2) -piperazino) -benzoic acid Yield ί 80% of theory, melting point: 248 ° C.

5-Amino-2- (trans -3,5-dimethyl-piperidino) benzoic acid. Yield: 89% of theory, m.p .: 156 ° C.

5-Amino-2- (3,3,5,5-tetramethyl-piperidino) benzoic acid. Yield: 98% of theory, m.p .: <20 ° C.

5-Amino-2- (3,5-dimethyl-morpholino) benzoic acid. Yield: 83% of theory, melting point: 255 ° C.

"i 5 5-Arnino-2- (3,5-dimethyl-1-thiomorpholino) benzoic acid. Yield: 50% of theory, m.p .: 233 ° C.

5-Aroino-2- (3-aza-bicyclo / 3, 2, 2, 7nonan-3-yl) benzoic acid. Yield: 86% of theory, m.p .: 288 ° C.

5-Amino-2-octame-thyl-leno-benzoic acid Yield: 88% of theory, m.p .: 191 ° C.

5-Amino-2-nonamethyleneiminobenzoic acid Yield: 80% of theory, m.p .: 212 ° C.

5-Amino-2-decamethyleniminobenzoic acid Yield: 52 % of theory, m.p .: 2O2 ° C.

5-Amino-2-undecamethyleneiminobenzoic acid Yield: 93% of theory, m.p .: 242 ° C.

5-Ananoic-2-dodecamethyleneiminobenzoic acid Yield: 59% of theory, m.p .: 224C.

5-Amino-2- (N-methyl-N-phenylamino) benzoic acid Yield: 47% of theory, m.p .: 184C.

5-Amino ~ 2 ~ (N-ethyl-N-cyclohexylamino) benzoic acid Yield: 66% of theory, m.p .: 160 ° C

5-Amino-2- (N-butyl-N-cyclohexylamino) benzoic acid. Yield: .48% of theory, m.p .: 14O ° C.

5 ~ Amino-2- (N-cyclohexyl-N-isobutylamino) -benzoic acid Yield: 62% of theory, melting point -20 ° C. .

5-amino-2- (decahydro-3-benzazepin-3-yl) benzoic acid. Yield: 54% of theory, m.p .: 204 ° C.

5-amino'-2- (octahydro-isoindol-2-yl) benzoic acid. Yield: 43% of theory, melting point: 228 ° C.

5 ~ Axtiino-2- (4-isopropyl-piperidino) -benzoic acid Yield: 50% of theory, m.p .: 231 ° C.

5-Amino-2- (4-tert-butylpiperidino) benzoic acid Yield: 81% of theory, m.p .: 276 ° C.

5-Amino-2- (V, 4-dioxa-8-aza-spiro / 4,6_ / undecan-8-yl) benzoic acid Yield: 49% of theory, melting point 235 ° C.

5-amino-2- (1, 2,3, 6-tetrahydro-pyridino) benzoic acid yield: 51% of theory ,. Melting point: 232 ° C.

5-Amino-2- (4-methyl ~ piperazin p ± ± no) -benzoic acid hydrochloride '(yield: 90% of theory, Melting point: <.20 ⁰ C.

5- * Amino ~ 2 ~ (N-methyl-N-benzyl-amino) -benzoic acid Yield: 95% of theory, m.p .: <(20 ° C.

Yield: 80.5% of theory, m.p .: 305 ° C (decomposition): 5-aminol-2 "-1- (4-chlorophenyl) -piperazino / benzoic acid hydrochloride.

: 5-Amino-2- (4-carbethoxy-piperazino) benzoic acid Yield: 87.5% of theory, Melting point: 195-197 ⁰ C.

t -

f5-.Amj.no - 2-A4- (2-furoyl) -piperazino / benzoic acid Yield: 97% of theory, m.p .: 20 ° C.

5-amino ~ 2- (4-benzyl-piperazino) benzoic acid hydrochloride Yield: 80% of theory, Melting point: 200-21O ⁰ C.

Example β L

5-Chloro- 2- (decahydro-isoquinolin-2-yl) -benzoic acid .

10 g (0.0365 mol) of i5-amino-2- (decahydroisoquinolin-2-yl) benzoic acid are dissolved in 55 ml of half-concentrated hydrochloric acid and: at ⁰ ° C., with a solution of 2.7 g (0.039 mol) Sodium nitrite: diazotized in 10 ml of water with a dropwise addition. After completion of the addition is stirred for 15 minutes and then the diazonium salt in a suspension of 4 g of copper powder in 40 ml of conc. Hydrochloric acid dripped. After stirring overnight, a deep green homogeneous solution is obtained which, after dilution with 100 ml of water, is extracted exhaustively with chloroform. After drying over sodium sulfate, the chloroformabdampfrückstand over a silica column with a mixture of ethyl acetate / methanol = 9.5: 0.5 purified by chromatography.

Yield: 4.8 g (45% of theory). M.p .: 138 ° C. '·

Ber. : C 65.41 H 6.85 N 4.76 Cl 12.06 Found: 65.51 7.07 4.89 12.32

example

5-chloro-2- (1,4-dioxa-8-aza-spiro / 1i, 57decan-8-yl) benzoic acid

8.5 g (0.031 mol) of 5-amino "2 ~ (1 ^ - 8-yl) benzoic acid are dissolved in 28 ml of half-concentrated hydrochloric acid and at 0 ⁰ C with a solution of 2.4 g (0.034 mol) of sodium nitrite The diazonium salt solution is added dropwise with stirring to a suspension of 3 g of copper powder in 3 ml of concentrated hydrochloric acid. After completion of the nitrogen evolution is stirred for two hours, diluted with water and extracted with chloroform. After drying over

Natr5 sodium sulfate, the solvent is distilled off. Upon digestion of the evaporation residue with petroleum ether, 6.1 g (66% of the yield) are obtained »melting point: 180 ° C.

Ber .:. C 56.47 H 5.42 N 4.71 V .: 56.11 5.37 4.83;

Analogous to the examples | and f the following compounds were prepared:

5-Chloro-2-pyrrolidino-benzoic acid Yield: 30% of theory, m.p .: 164 ° C.

5-Chloro-2- (2-methyl-piperidino) -benzoic acid Yield: 74% of theory, m.p .: 124 ° C.

5-Chloro-2- (3-methylpiperidino) benzoic acid Yield: 47% of theory, m.p .: 165 ° C.

5-chloro ~ 2- (4-methyl ~ piperidino) benzoic acid yield: 52% of theory, Melting point: 107 ⁰ C.

2- (3-ethyl-6-methyl-piperidi-NO) -5-chloro-benzoic acid. Yield: 73% of theory, m.p .: <20 ° C.

5-Chloro-2- (cis-3,5-dimethyl-piperidino) benzoic acid Yield: 46% of theory, m.p .: 167 ° C.

: 5-Chloro-2- (trans ~ 3,5-dimethyl-piperidino) -benzoic acid Yield: 63% of theory, m.p .: 132 ° C.

S-chloro-2- (4-methoxy-piperidino) benzoic acid. Yield: 63% of theory, m.p .: 136 ° C.

5 ~ Chloro-2-heptamethyleneiminobenzoic acid Yield: 58% of theory, m.p .: 20 ° C '

5-Chloro-2- (4-phenyl-piperidino) -benzoic acid Yield: 51% of theory, m.p .: 217 ° C.

5-chloro-2- (4-ethoxycarbonyl-piperidino) benzoic acid J

Yield: 97% of theory, melting point: <20 ^o c,

^: 5-chloro-2-hexamethyleneiminobenzoic acid. Yield: 34% of theory, melting point: 113 ° C.

5-Chloro-2-thiomorpholino-benzoic acid Yield: 16% of theory, m.p .: 160 ° C.

5-Chloro-2- (1,2,4,5-tetrahydro-3-benzazepino) benzoic acid Yield: 59% of theory, m.p .: 174 ° C.

5-Chlorof-2- (1,2,3,4-tetrahydro-isoquinolino} -benzoic acid Yield: 50% of theory, m.p .: 182 ° C.

^: 5-Chloro-2- (4-phenyl-piperazino) -benzoic acid. Yield: 42% of theory, m.p .: 154 ° C.

5-Chloro-2 ~ (4-pyridyl- (2) -piperazino) -benzoic acid Yield: 45% of theory, m.p .: 168 ° C.

5-Bromo-2- (2-methyl-piperidino) -benzoic acid Yield: 31% of theory, m.p .: 168 ° C.

5-Chloro-2- (3 / 3,5,5-tetramethyl-piperidino) -benzoic acid Yield: 62% of theory, m.p .: 20 ° C.

, 5-Bromo-2- (4-methoxy-piperidino) benzoic acid. Yield: 48% of theory, m.p .: 138 ° C.

5 ~ Chloro-2- (3,5-dimethylmorpholine) -benzoic acid Yield: 50% of theory, m.p .: 174 ° C.

5-chloro-2- (3,5-dimethyl-thiomorpholino) -benzoic acid. Yield: 18% of theory, melting point: 134 ° C.

5 ~ bromo-2-heptamethyleneiminobenzoic acid Yield: 15% of theory, mp 104C.

: 5-Chloro-2- (3-aza-bicyclo / _3,2,2-ynanan-3-yl) -benzoic acid Yield: 16% of theory, m.p .: 199 ° C.

5-chloro-2-octamethyleneiminobenzoic acid. Yield: 70% of theory, melting point: 84 ° C.

5-Chloro-2-nonamethyleniminobenzoic acid Yield: 30% of theory, m.p .: 78 ° C.

5-Chloro-2-decamethyleniminobenzoic acid Yield: 65% of theory, m.p .: 70 ° C.

O 9 5

5-Chloro-2-undecamethyleniminobenzoic acid Yield: 41% of theory, m.p .: 41 ° C

5-Chloro-2-dodecamethyleneiminobenzoic acid Yield: 36% of theory, m.p .: 40 ° C.

5-Chloro-2- (N-phenyl-N-methylamino) -benzoic acid Yield: 27% of theory, m.p .: 164 ° C.

2- (N-ethyl-N-cyclohexylamino) -5-chloro-benzoic acid. Yield: 24 % of theory, m.p .: 152 ° C.

2- (N-butyl-N-cyclohexylamine) -5-chloro-benzoic acid Yield: 16% of theory, m.p .: 145 ° C.

5-chloro-2- (N-cyclohexyl-N-isobutylamino) benzoic acid. Yield: 22% of theory, melting point: 131 ° C.

δ-Chloro-^ - (decahydro-3-benzazepin ~ 3-yl) -benzoic acid yield: 70% of theory, m.p .: 153C.

5-Bromo-2- (decahydro-3-benzazepin-3-yl) -benzoic acid Yield: 54% of theory, m.p .: 154 ° C.

5 »Chloro-2- (octahydro-isoindol-2-yl) -benzoic acid Yield: 33% of theory, m.p .: 164 ° C.

5-Bromo-2-octamethyleneiminobenzoic acid Yield: 48% of theory, m.p .: 94 ° C.

5-Chloro-2- (4-isopropyl-piperidino) -benzoic acid Yield: 43% of theory, m.p .: 172 ° C.

5-Chlorof-2- (4-tert-butylpiperidino) benzoic acid Yield: 35% of theory, m.p .: 161 ° C.

5-chloro-2- (1,4-dioxa-8-aza-spiro / 4,6 / undecan-8-yl) benzoic acid, yield: 42% of theory, m.p .: 163 ° C.

, 5-chloro-S- (1,2,3,6-tetrahydropyridino) benzoic acid / yield: 73% of theory, m.p .: 173C.

5'-chloro-2- (4-methylpiperazino) benzoic acid hydrochloride / Yield: 75% of theory, m.p .: 132 ° C (dec.).

! 5-Chloro-2- (N-methyl-N-benzylamino) benzoic acid. Yield: 18.2% of theory, mp 156-157 ° C.

'5-Chloro-2- ^ 4- (4-chloro-phenyl) -piperaze / benzoic acid. Yield: 30.5% of theory, m.p .: 228-23O ° C.

2- (4-Carbethoxy-piperazino) -5-chloro-benzoic acid Yield: 52% of theory, m.p .: 129-130 ° C.

3-Chloro-2- / 4- (2-furoyl) ~ piperazino_ / benzoic acid ... Yield: 33.1% of theory, m.p .: 200-202 ° C.

2- (4-Benzyl-piperazino) -5-chloro-benzoic acid hydrochloride Yield: 42.8% of theory, m.p .: 23O-232 ° C (dec.).

Example | * |

5-Amino-2-hexamethyleneimino-benzoesäurenitril

21.4 g (0.087 mol) of 2-hexamethyleneimino-5-nitro-benzoesäurenitril be dissolved in 200 ml of dioxane and 500 ml of methanol and hydrogenated at room temperature and a hydrogen pressure of 5 bar in the presence of 10% Palladiumkphle as a catalyst. After filtering off the catalyst and distilling off the solvent, 20 g (100% of theory) are obtained. , , Melting point: <f20 ° C.

_ "2 ~ 2" 5TT ~ - "A - -. ··,.

Example J L 5-Chloro-2- hexamethylene glycolamido-benzoic acid nitrile

20 g (0.092 mol) of 5-amino-2-hexamethylenimino-benzoesäurenitril are dissolved in 90 ml of half-concentrated hydrochloric acid and diazotized at ^{0 0} C with a solution of 6.5 g (0/094 mol) of sodium nitrite in 30 ml of water with dropwise addition , After the addition is stirred for 15 minutes. The Diazoniumsalζlösung is added with stirring to a solution of copper (I) chloride is heated to 70 C in concentrated Salζsäure _f, added dropwise. , 10 After completion of nitrogen evolution is extracted with chloroform. After drying over sodium sulfate and distilling off the chloroform, the evaporation residue is purified by chromatography on a silica gel column. As a flow agent toluene is used.

Yield: 5 g (23% of theory), m.p .: 20 C.

Example jt * \, ·,

, 5-chloro-2-hexamethyleneimino-benzoic acid

5 g (0.021 mol) of 5-chloro-2-hexamethylenimino-benzoic acid nitrile ) are heated to 170 ° C. in 32 g of potassium hydroxide solution and 20 ml of water for 8 hours. The cooled melt is dissolved in water. By acidification to pH 5, the amide is precipitated quantitatively, which is then hydrolyzed with half-concentrated hydrochloric acid .. Yield: 3.6 g (67.4% of theory), 25 melting point: 113 ° C.

The following compounds were prepared in analogy to Examples β to r.

2-morpholino-5-nitro-benzoic acid nitrile. Yield: 78% of theory, m.p .: 138 ° C.

2 2 5 1 1 -... -

5-Amino-2-morpholino-benzoic acid nitrile, yield: 68% of theory, melting point: 142 ° C.

 5-Chloro-2-morpholino-benzoic acid nitrile Yield: 20% of theory, m.p .: 57 ° C.

: 5-chloro-2-morpholino-benzamide

Yield: 98% of theory, melting point: 28O ° C,

.5-chloro ~ 2 ~ morpholino-benzoic acid

 Yield: 60% of theory, melting point: 157 ° C.

Example: 5-cyano-2-octamethyleneiminine O "benzoic acid

.26.2 g (0.1 mol) of 5-amino-2-octamethyleneiminobenzoic acid are dissolved in 38 ml of concentrated hydrochloric acid, diluted with 280 ml of water and treated at 0 ° C. with a solution of 7.6 g (0, 11 moles) of sodium nitrate diazotized in 30 ml of water with dropwise addition.

After half an hour of stirring, the solution with sodium carbon. : nat to pH 7. To the diazonium salt solution, wi-rd on. Finally, a solution of trisodium-tetracyano-copper (I) complex was added dropwise at 0 ° C

This copper (I) complex solution is obtained as follows: 32 g (o, 128 mol) of copper sulfate χ 5 H ₂ O and 8.7 g of sodium chloride in 100 ml of water are mixed with a sodium hydrogen sulfite solution consisting of 6, 6 g (0.0635 mol) of sodium hydrogen sulfite, 4.4 g of sodium hydroxide in 50 ml of water to the copper (I) chloride reduced. The precipitated copper (I) chloride is filtered off, suspended in 50 ml of water and dissolved in a solution of 17 g (0.346 mol) of sodium cyanide in 30 ml of water.

After completion of the evolution of nitrogen, the reaction mixture is heated to 70 C for one hour. After cooling, it is adjusted to pH 5.5 with 2N hydrochloric acid and extracted with chloroform.

30hiert. The chloroform phases: are dried over sodium sulfate

and after distilling off the chloroform, the crude product obtained is purified on a silica gel column with ethyl acetate as eluant. ·.

Yield: 9 g (30% of theory), m.p .: 20 ° C.

N 10,28 10,10

Calc .: C 70 , 56 H 7 40 Found .: 70 , 38 7 20 example / L

2-Heptarne thylenimino-5 ~ hy droxybenzoic acid

26.7 g (0.107 mol) of 5-amino-2-heptamethylenimino-benzoic acid are dissolved in 190 ml of 3N sulfuric acid and at 0 ° C with a solution of 8.3 g (0.12 mol) of sodium nitrite in 30 ml of water at diazotized dropwise addition. After half an hour of stirring 2 g finely powdered urea are added. With good stirring, the diazonium salt solution is added dropwise to 320 ml of 50% sulfuric acid, which is heated to 90 ° C. After completion of '.. Nitrogen evolution is at room temperature with ammonia. Adjusted pH 4 and extracted with chloroform. The after drying over sodium sulfate and distilling off. The dry residue obtained from the chloroform is purified on a silica gel column with chloroform as eluent.

After recrystallization from isopropanol, 8 g (30% of theory) are obtained

 Melting point: 199 ° C.

Ber.j. C 67.45 H 7 _f 68 N 5.61 _F .: 66.87 7.71 5.65

, '.. ".." L-. '.

 The following compounds were prepared analogously to Example f:

2-hexamethyleneimino-5-hydroxy-benzoic acid. Yield: 24% of theory, m.p .: 214 ° C.

5 ~ Hydr oxy-2-oc camouflaged thy lenimino.be nzoe acid

O.

  Yield: 27% of theory, melting point: 208 × C

5-Hydroxy = 2- (4-tert-butyl-piperidino) -benzoic acid Yield: 33% of theory, m.p .: 24O ° C.

5-Hydroxy-2- (cis-3,5-dimethyl-piperidino) -benzoic acid Yield: 67.4% of theory, m.p .: 248-25O ⁰ C.

example

, 5-methoxy-2-octamethyleneiminobenzoic acid

3.2 g (12.2 mmol) of 5-hydroxy-2-octamethylenimino-benzoic acid are added in 20 ml of absolute dimethylformamide with 0.6 g (25 mmol) of sodium hydroxide and heated to 50 ⁰ C, thereby partially precipitates the sodium salt , After addition of 5.2 g (36.6 mmol) of methyl iodide in 3 ml of absolute dimethylformamide is stirred for 5 hours at room temperature. After distilling off the dimethylformamide, the crude methyl S-methoxy-.beta.-octamethylenimino-benzoate is purified on a silica gel column using chloroform as eluent. -

"Yield: 90% of theory, melting point: <20 ° C. This ester is hydrolyzed with sodium hydroxide solution at 80 ° C. After acidification to pR 5.2, the mixture is extracted with chloroform, dried on sodium sulfate and the evaporation residue is digested with petroleum ether.

Yield: 85% of theory,

Melting point: 84C.

Calcd .: C 69.28 H 8.35 N 5.04

G .: 69.12 8.29 4.95.

Analogously to Example 0, the following compounds were prepared:

2-hexamethyleneimino-5-methoxybenzoic acid

Yield: 88% of theory, melting point: 141 ° C.

2-heptamethylene-1-nitro-5-methoxy-benzoic acid

Yield: 30% of theory, melting point: 120 ° c

2-Heptamethyleneimino-5-isopropyloxybenzoic acid Yield: 78% of theory, m.p .: 120 ^° C.

5-ethoxy-2-octamethyleniraino-benzoic acid Yield: 87% of theory, m.p .: <20 ° C

5-Isopropyloxy-2-octamethyleneiminobenzoic acid Yield: 60% of theory, m.p .: 78 ° C

Yield: 48% of theory, melting point: 20 ° C.

5-Butyl (2) oxy-2-octamethylenimino-benzoic acid

5-Methoxy-2- (4-tert-butyl-piperidino) benzoic acid Yield: 22% of theory, m.p .: 156 ° C.

5-Methoxy-2- (3,5-cis-dimethyl-piperidino) -benzoic acid Yield: 90% of theory, m.p .: 124 ° C. '

5-hexyloxy-2-piperidinobenzoic acid; ·. Yield: 73% of theory, melting point: 72 ° C.

5-benzyloxy-2-piperidino-benzoic acid

Yield: 41% of theory, melting point: 188 ° C.

Production of the end products of the general. Formula I:

Example 1 . ,

4- (Τ.- (5-chloro-2-dimethylamino-benzoylamino) -ethyl / benzoesäuremethylestejr _ ^ _ __ - '

To a solution of 1.06 g (5.3 mmol) of 5-chloro-2-dimethylaminobenzoic acid in 5 ml of absolute tetrahydrofuran is added at room temperature 1.03 g (6.3 mmol) of Ν, Ν'-carbonyl-diimidazole. After 1-2 hours, a solution of 1.13 g (6.3 mmol) of methyl 4 = (2-aminoethyl) benzoate in 2 ml of tetrahydrofuran is added to the imidazolide formed. After 16 hours' standing at room temperature, the tetrahydrofuran is distilled off on a rotary evaporator. The crude ester is purified by chromatography on a column of silica gel with toluene / ethyl acetate (9: 1) as eluant "." The dry residue of the combined fractions containing the purified ester is treated with petroleum ether

 Yields 0.9 g (47.5% of theory), m.p .: S4 ° C

Calcd. C 62.7 H 5.88 N 7.57 Vs. 63.3 5.86 7.75

Example 2 ...

4- / 2- (5-chloro-2-methylamino-dime ben zoylamin o) -äthyiybenzoesäure

0.55 g (1.5.6 mmol) of methyl 4- ^ 2- (5-chloro-2-dimethylaminobenzoylamino) ethyl / benzoate are dissolved in 40 ml of a mixture of methanol / dioxane (2: 1). After addition of 0.29 g (4.8 mmol) of potassium hydroxide, dissolved in 3 ml of water, 30 ml of water are added dropwise at room temperature so slowly that there is no precipitation of the 'ester. After a few hours, the organic solvent is distilled off on a rotary evaporator, the aqueous

Shaken out with chloroform and the aqueous phase with 2N hydrochloric acid to pH 5.5, thereby the acid precipitates.

1

Yield: 0.38 g (70% of theory), melting point: 165 ° C

iBer.i C 62.45 H 5.52 N 8.06 Gef. 62.30 5.62 7.87

Example 3

4 "/. 2- (5-chloro-2-d- imethylaminobenzoylamino) ethylbenzoic acid

0.32 g {1 mmol) of 4 - ^ / 2- (2-amino-5-chloro-benzoylamino) -ethyl / benzoic acid (melting point 196 ° C., prepared from 2-amino-5-chloro-benzoic acid and 4- (2-amino "ethyl) benzoic acid methyl ester analogously to Example 1 and subsequent alkaline saponification analogously to Example 2) are dissolved in 10 ml of formalin and 30 ml of glacial acetic acid after addition of 500 mg of 10% palladium carbon at room temperature Autoclave treated with hydrogen at 5 bar After filtration and removal of the solvents by distillation, the acid is dissolved in caustic soda ]

dissolved and precipitated with 2N hydrochloric acid. j

Yield? 0.11 g (30% of theory),. ί

Melting point; 165 ° C

Ber. ί C 62 45 H 5 , 52 N 8th , 06 Found .: 62 , 38 5 , 68 7 90

Example 4

4- / 2- (5-chloro-2- dimethylamino- benzoylamino) -ethyl / benzoic acid

Prepared from 4- / 2- (5-chloro-2-methylamino-benzoylamino) -ethyl / benzoic acid (melting point: 2O5 ° C) analogously to Example 3. Yield: .30% of theory, melting point: 165 ° C.

1.1: -

i Example 5

^ 4- ^ 2- (5-Chldr-2-dimethylamino-benzoylamino) -ae-yiylobenzoic acid

^: methyl ester .

1 _r 06 g (5.3 mmol) of 5 ~ chloro-2-dimethylamino ~ ben2oesäure be with 7 ml of thionyl chloride at 4O-5O ° C to the acid chloride exceed ¹ performs. After distilling off the thionyl chloride is the.

crude acid chloride in 10 ml of absolute pyridine with 0.95 g: (5.3 mmol) of methyl 4 - = (2-aminoethyl) -ben2oesäure reacted.

After 2 hours of stirring at room temperature is approx. 20 minutes ^:

; heated to 5O-7O ° C and then the pyridine on a rotary i; distilled off evaporator. The dry residue is dissolved in ice water, made alkaline with sodium hydroxide solution and this solution with .

Extracted chloroform. The dry residue of over sodium ^:

Sulfate dried chloroform extracts is purified by chromatography on a silica gel column with toluene: ethyl acetate = 9s1 as flow agent.

Yieldί 1.4 g (73% of theory),

melting point 94 ° C H 5, 88 N 7 , 57 Ber.! C 62 , 7 5, 73 7 , 63 Gef.i 62 , 9

4-Z, 2- (5-bromo-2-dimethylamino-benzylamino) ethyl / benzoic acid methyl ester.

, Prepared from 5-bromo-2-dimethylaminobenzoic acid and 4 ~ (2-amino-ethyl) -benzoic acid methyl ester analogously to Example 1. Yield: 93.5% of theory,

melting point : 99 ° C H 5 , 21 N 6 90 Bef .: 'C 56 35 5 , '32 7 , 01 Found .: 56 10

j Example 7

' 4- / 2 "(S- Brix ^ -dimethylaminobenzoylamino ) ethyl / benzoic acid

ί.

Prepared from 4- ^ 2- (5-bromo-2-dimethylamino-benzoylamino) -; ethyl / benzoic acid methyl ester by alkaline hydrolysis; analogously to Example 2.

Yield: 77% of theory,

Melting point: 187 ° C

Ber.i C 55.4 H 4.89 N 7.16

:. Found. 55.2 4.97 7.01

Example 8. '

4-12- (5-fluoro-2-dimethylaminobenzoylamino) ethyl / benzoic acid

in ethyl ester .

Prepared from 5-fluoro-2-dimethylamino-benzoic acid and methyl 4- (2-amino-ethyl-benzoate analogous to Example 1.

Yield: 44% of theory,

Melting point: 56 C

Calc .: C 66.30 H 6,14 N 8,13

! Gef .: 66,28 6,22 8,13

Example 9 4- (2-fluoro-2-dimethylaminobenzoylamino) -äthy ^ / benzoic acid

Prepared from 4 - ^. 2- (5-Fluoro-2-dimethylamino-benzoylamino) ethyl / benzoic acid methyl ester by alkaline hydrolysis analogous to Example 2.

Yield: 73 % of theory, melting point: 1080 ° C,

Ber ,: C 65.55 H 5.80 N 8.47 F .: 64.98 5.68 8.38 '.

Example 10 .

A-12- (2-Dimethylamino-benzoyl-amino) -ethyl-benzoic acid methyl ester

Prepared from 2-dimethylaminobenzoic acid and 4- (2-aminoethyl) benzoic acid methyl ester analogously to Example 1. The reaction was carried out at 6O-7O ° C j.

[.. Yield: 98% of theory, J Melting point: 74 ° C

Bar. S C 70 0 H 6 , 78 N 8th, 56 ! 0 Found .: 69, 8th 6 , 92 8th, 54 example 11

• _i 4 ~ £ 2 ^ 2 ~ -dimethylamino ~ benz: oylamino) ~ ethyl.

Prepared from 4 = · 2- (2-dimethylaminobenzoylanu.no) - * ethyl / -I-benzoic acid methyl ester by alkaline hydrolysis analogously with! game 2.

'Yield: 84% of theory,

! Melting point 1O7 ° C

! Calc .: C 69.25 H 6.45 N 8.96

Gef .:. 69.50 6.62 9.00

Example 12

Methyl 4- {2- (5-chloro-2-diethylaminobenzoylamino) ethyl / benzoate ter _

Prepared from 5-chloro-2-diethylaminobenzoic acid and 4- (2-aminoethyl) benzoic acid methyl ester analogously to Example 1. Yield: 51% of theory,

22 251T

Melting point: 93 C 'j

Calc .: C 64.86 H 6.48 N 9.12 'l

F .: 65.01 6.54 9.38 "· |

• '!

Example 13 ...!

4-i {. 2- (5-Chloro-2-diethylamino-benzoylamino) -thylbenzoic acid j

Prepared from 4- / 2- (5-chloro-2-diethylamino-benzoylamino) -1-ethylbenzoic acid methyl ester by alkaline hydrolysis analogously,

Example 2. j

Yield: 80% of theory,!

Melting point: 95 C · '

Ber .:. C 64.1 H 6.17 N 7.46. j Gef .: 64.2 6.09 7.32

Example 14

  4- ^ 2- (5-chloro-2-diisobutylaminobenzoylamino) ethyl / benzoic acid

I acid ethyl ester _ "_____ ^ _________» ____ «_________

- - -; -

Prepared from 5-chloro-2-diisobutylamino-benzoic acid and ethyl 4- (2-aminoethyl) benzoate analogously to Example 1

 Yield: 20% of theory,

, i Melting point: (20 C

j Ber .: C 68.03 H 7.69 N 6.10 Cl 7.72 V .: 63.59 7.68 5.93 7.51

Example 15

4- £ 2 ~ (5-chloro-2-diisobutylamino-benzoylamino) ethyl / benzoic

acid

Prepared from ethyl 4- / 2- (5-chloro-2-diisobutyl-amino-benzoylamino) ethylbenzoate by alkaline hydrolysis analogously to Example 2.,. - -. ·.

1 1 -

Yield 90% of theory

I t Melting point: 1 13 ° C H  7, 24 N 6 , 49 Cl 8th , 22 I I i Ber.s C 66 , 88 7, 28 6 , 32 8th 40 I J Found "t 66 50 I i

Example 16. ·,

  - '! i 4 »£ 2 ~ (5- = chloro-2 - = - dipentylaminobenzoylamino) -ethyl / benzoic acid- i

, ethyl ester, '

Prepared from 5-chloro-2-dipentylaminobenzoic acid and 4- (2-;

  Amino-ethyl) "> benzoic acid ethyl ester analogously to Example 1.; O; Yield? 83% of theory, i

Melting point? 118-120 ⁰ C; Ber.? C 69.05 H 8.07 N 5.75 Cl 7.28 Gef.s 68.84 7.99 6.05 7.54

^: 4-Z2 ~. (5 ~ Chloro-2-dipentylamino-benzoyl-amino) ° athviybenzoic acid

Prepared from 4- ^ 2- (5-chloro-2-dipentylamino-benzoylamino) ethyl / benzoic acid ethyl ester by alkaline hydrolysis analogously to Example 2.

^; Yield; 36.5% of theory,

Melting point; <20 ° C. ·

Calc .: C, 68.03, H, 7.68, N, 6.10, C, 7.72, Found: 67.93, 7.64, 6.72, 7.86

Example 18

4 - ^ / 2- (5-chloro-2- (1-pyrrolylyl) benzoylamino) ethyl / benzoic acid-25

2 2 2511

Prepared from 5-chloro-2- (1-pyrrolyl) benzoic acid and 4 ~ (2-JAmino-ethyl) -benzoic acid methyl ester analogously to Example 1. Yield: 64% of theory, Melting point: 12O-121 ° C

! Ber .: G 65.88 H 5.00 N 7.32 GI 9.2 D E: 65.86 4.85 7.47 9.38

Example 19

4- / 2- (5-chloro-2- (1-pyrrolyl) Hbenzoy! Amino) »ethyljbenzoic acid e

'Prepared from 4- ^ 2- (5-chloro-2 ~ (1-pyrrolyl) benzoylamino) "ethyl / benzoic acid methyl ester by alkaline hydrolysis analogously: Example 2.

Yield: 26% of theory, melting point: 25O-255 ° C

Calc .: C 65.13 H 4.65 N 7.59 Cl 9.61 15 ^: Found: 65.07 4.74 7.34 9.07

; Example 20. ,

i- / 2- (5-chloro-2- (N-cyclohexyl-methylamino) -benzoylamino) ethyl / benzoic acid ° ethyl ester -

Prepared from 2- (N-cyclohexyl-methyl-amino-J-S-chloro-benzoic acid and ethyl 4- (2-amino-ethyl) -benzoate analog

Example 1.

Yield: 45% of theory,

Melting point: 98 ° C.

Calc .: C 67.78 H 7.05 N 6.33 Found: 67.60 6.81 6.28

4- / 2- {5-chloro-2 ~ £ N-cyclohexyl-methylam'ino / benzoylainino) ethyl / -

i benzoic acid. _{m r} _ _; · ^ »__ ^ __

Prepared from 4- ^ 2- (5-chloro-2 - ^ - cyclohexylrnethylcm \ ino7-benzoylamino) -äthyl7-benzoic acid ethyl ester by alkaline hydrolysis analogously to Example 2

 Yield: 58% of theory, ·

Melting point: 166 ° C

Ber.i C 66.58 H 6.56 N 6.75 'F .: 66.63 6.79 6.66

22

(5-bromo-2-piperidino-benzoylamino) ~ ay! / Benzoic acid ·

Prepared from 5-bromo-2-piperidinobenzoic acid and 4- (2-aminoethyl) benzoic acid "ethyl ester analogously to Example 1. Yield: 87% of theory,

Melting point: 76 ° C H 5 , 92 N 6 , 09 Ber .: C 60 13 5 97 6 19 Gef .: 60 , 35.

: 0 Example 23

Prepared from 4- / 5- (5-Brora-2 ~ piperidino-benzoyl-amino) ethyl ethylbenzate "by alkaline hydrolysis analogously to Example 2.

 Yield: 99% of theory,

Melting point: 2O1 ° C H C Jt , 37 N 6 , 49 Ber. % C 58 , 47 5 40 6 , 55 Gef .: 58 , 56

Πϊ 2 2 2 5 1 Υ

Example 2 4

j 4- (2- (5-Chloro-2-pyrrolidinobenzoylamino) ethyl / benzoic acid

I methy lester, __ "___ _" __ "" ______

ι.

Prepared from 5-chloro-2-pyrrolidino-benzoic acid and methyl 4- (2-amino-ethyl-benzoate analogously to Example 1. Yield: 43% of theory,

; Melting point: 164 C

I Ber .: C 65.19 H 5.99 N 7.24

I F .: 65.35 6.00 7.23 *

i Example 25

! 4-J2- (5-chloro-2-pyrrolidino-benzoylarnino) ~

ι -

Prepared from 4 ι «* ^ 2- (5-chloro-2 ~ ⁱ pyrrolicllno-benzoylainino) -

; methyl ethylbenzate by alkaline hydrolysis I analogously to Example 2.

, Yield: 68% of theory,

I melting point: 184 ° C

Calc .: C 64 42 H 5 , 68 N ' 7, 52nd Cl 9 51 ί ι Found .: 64 46 5 96 7, 47 9 38

26

4- ^ 2- (5-chloro-2-piperidinobenzoylQmino) ~ ethylbenzoic acid, -; we thy! emost _; ,^ ₁  .

Prepared from 5-chloro-2-piperidino-b.enzoic acid and 4- (2-ηη-ethyl) -benzoic acid ~ methyl ester analogously to Example 1. Yield: 72% of theory,. ·

Melting point: 98 ⁰ C. H 6 , 29 N 7 00 Ber .: C 66 , CO 6 , 37 6 , 81 Gef. J 66 00

Example 27 'I

j 4- / 2- (5-chloro-2-piperidinobenzoylanu.no) ethyl / benzoic acid!

Made from 4- / 2- (5-chloro-2-piperidino-benzoylamino) -ethyl 7- _:

i benzoic acid methyl ester by alkaline hydrolysis analogously Beij

play 2. j

j Yield 82% of theory, j

Melting point 20O ⁰ C:

Ber.ί C 65.20 H 5.98 N 7.24 _:

Gef: 65.10 6.00 7.30. ;

'4- / 2- (5-chloro-2- (2-methylpiperidino) benzoylamino) ethyl / benzoic acid methyl ester. _rt _, _m ^ ^. ;. _{a lj} ... '' ... ,, ',, ..., ..,:.,., ...., ... .- - - I-

  '!

Prepared from 5 ~ Chloro ~ 2 ~ (2-methyl-piperidino) benzoic acid and methyl 4- (2-aminoethyl) benzoate analogous to Example 1. Yield? 23% of theory,!

I melting point: 82 ⁰ C H 6 , 56 N 6 75 : Ber .: C 66 , 57 6 , 42 ⁶ ' 78 j Gef .: I 66 , 82 ! Example 29

ZQ ; 4- / 2- (5-chloro-2- (2-methyl-piperldino) »benzoylamino) -ethyl / benzoic

Prepared from 4- / 2- (5-chloro-2- (2-methyl-piperidino) -benzoyl- |

; amino) -ethyl / benzoic acid methyl ester by alkaline saponification

j analogously to Example 2. '·

ί .ΐ

, Yield: 57% of theory,. i

j Melting point: 178 ⁰ CI

j Ber.ί C 65,91 H 6,29 N 6,9 9!

• 'Gef .:. , 65.73 6.28. 7.13

2 2 2511 -

Example 30

ι

4-Z2- (5 ~ chloro-2- (3 ~ inethyl-piperldino) -benzOylainino) -äthyl7-

, benzoic acid re-me thy! ester . ^ __ ^ _| _

'. Prepared from 5% chloro-2- (3-methylpiperidino) benzoic acid and 2- (2-aminoethyl) benzoic acid methyl ester analogously to Example Yield: 51% of theory,

Melting point: 93 ⁰ C H 6 56 N 6 75 Ber .: C 66 , 57 38 81 Found .: 66 , 52

Belsple1 31.

4- £ 2 ~ (5 ~ Chloro-2- (3-methyl-piperidino) - benzoylaminoj-ethyl ^ - benzoic acid _u __ _ / ^ _ _r .. _ti ^ __ ^

Prepared from 4 - ^, 2 ~ · (5-chloro-2- (3-methyl-piperidino) ~ bensoylaminoj-ethyljbenzoic acid methyl ester by aljcalische hydrolysis analogous to Example 2.

Yield:. 83% of theory, melting point: 194C

Calc .: C 65 _r 91 H 6,29 N 6,99 Found: 66,20 6,25 6,95

Example 32.

b-ß, - \ 5-Chloro-2 ~ (4-methyl-piperidino) -benzoy! amino) -ethyl / -

bengoe ^ s au re ~ mgithy_ l_e s te r

Prepared from 5-chloro-2 ~ (4-ethyl-piperidino) -benzoic acid and 4- {2 ~ amino-ethyl) -benzac-acid methyl ester analogously to Example S5 Yield: 48% of theory, melting point: 55 ° C

Ber.5 C 66.57 H 6 ₅₆ N 6.75 Gef .: 66.38 6.82 6,3.5

ο ο ο κ 1 i - ^ -

- ^ 2- (5-chloro-2 ~ (4-Mnethyl-pipexidino) benzoylamino) ethyl / -

Prepared from 4 ~ ^ 2 ~ (5-chloro-2- (4 ~ methylpiperidino) benzoylamino) ethyl / benzoic acid methyl ester by alkaline hydrolysis analogously to Example 2

 Yield; 83% of theory., Melting point! 211 ° C

Ber. ϊ C 65 91 H 6 , 29 N 6 99 Found ": 66 , 07 6 25 7 , 02 Example 34

-2 · "(5-ethoxy-2-ethyl-piperidino) -benzoylamino)

Made of 5 ~ Chloro-2- (5 ~ ethyl ~ 2-methyl ~ plperidino) benzo!

acid and 4- (2 ~ aminoethyl) benzoic acid ~ methyl ester analogously to Example 1.

Yield 10% of theory,

Melting point: <20 ° C

Ber.! C · 67.78 H 7.05 N 6.33 Gef.s 68.00 7.10 6.50

| teidl £ iel _H> JSJ5

4 ~ £ 2 ~ (5 ~ chloro ~ 2 ~ (5-ethyl ~ 2 ~ methyl ~ piperidino) -benzoylamino) ·

ay thy. 1 ^ / η ZQ e sau r e ____; · _,

Prepared from 4- / 2- (S-chloro-2- (5-ethyl-2-methyl-piperidino) benzoylamino) ethyl / benzoic acid methyl ester by alkaline.

Hydrolysis analogously to Example 2.

Yield? 60% of theory, melting point: 40 ° C. · : ... ".....: '

Calc .: C 67, 19 Found .:  * 67, 30 example 36

H 6,81 N 6,53 6,98 6,42

4- £ 2- (5 ~ chloro-2 ~ (3,5-dimethy piperidino) benzoylamino!) Ethyl / -

benzoic acid methylester. . ..... , -

Ί ι

Prepared from 5-chloro-2 ™ (3,5-dimethyl-piperidino) -benzoic acid I and 4- (2-amino-ethyl) -benzoic acid methyl ester analogously to Example 1.

i Yield: 85% of theory ^;

ί ο -i

; Melting point: 95 ° C. !

Calc .: C 67.20 K 6.81 N 6.53!

j Gef .: 67,14 6,62 6,68 ^!

! 4- ^ 2- (5-chloro-2-bis (3,5-diniethyl-1-piperidino) -benzoyl-amino) -ethyl ^; benzo ea mure - me t hy 1 ester ^ _λ - _-

! 2.7 g (0.01 mol) of 5-chloro-2- (3,5-dimethyl-piperidino) benzoic acid; with 3.57 g (0.03 mol) of thionyl chloride in 20 ml of chloroform!

I · I

! Heated under reflux for 4.5 hours. Thereafter, the reaction mixture is concentrated in vacuo. The residue is dissolved in 10 ml of chloroform and stirred into a solution at room temperature with stirring

I * j

0.j of 2.16 g (0.01 mol) of ethyl 4- (2-amino-ethyl) benzoate hydrochloride and 3.03 g (0.03 mol) of triethylamine dissolved in 15 ml

• chloroform, dripped. After 15 minutes, the addition is complete. | The mixture is then heated to reflux for a further 30 minutes.

After cooling, the reaction mixture is washed twice with water and once, with dilute acetic acid. The chloroform phase is dried over sodium sulfate and concentrated. For further cleaning 'account the residue obtained is out via a silica gel Eäule' give (Chloroforrn / acetone = 9. 1). The pure fractions are 'after evaporation of the solvent again from methylene chloride /

recrystallized from petroleum ether (20sl). ' ^!

Yield: 3.3 g (77% of theory), m.p. 94-95 ° C "

Calc .: C 67/20 H 6.81 N, 6.53 Cl, 8.27

Gef. ': 67.11' 6.78 6.70 8.39

Example 38

2.15 g (0.005 mol) of methyl 4-^ - (5-chloro-2- (3,5-dimethyl-piperidino) -; benzoylamino) ethyl / ~ benzoate are dissolved in 50 ml of ethanol and 10 ml of 1N Sodium hydroxide solution heated for 30 minutes under reflux. ; After cooling, most of the alcohol is removed in vacuo and mixed with 60 ml of water. Upon weak acidification with acetic acid to about pH 6, a precipitate precipitates, which is sucked off after standing j and recrystallized from isopropanol

becomes* !

Yield: 1.82 g (87.5% of theory).

Melting point 204 - 2O6 ° C. !

: C 66.58 H 6.56 N 6.75 Cl 8.55 F .: 66.59 6.48 6.71 8.45

4- ^ 2- (5-chloro-4- (4-methoxy-piperidino) benzoylaraino) -ethyl / ~

benzoesä \ ire-like thy! ester _. _i - _

Made from 5-chloro-2- (4-methoxy-piperidino) benzoic acid

and 4- (2-aminoethyl) benzoic acid ethyl ester analogously to Example 1

Yield: 60% of theory,

Melting point <20 ° C ''

Ber.i C 64.78 H 6.57. N 6,30 ·:

Gef .: 64.9 5 ·. 6,62 6,15

Example 40

4-p-2- (5-chloro-2- (4-methoxy-piperidino) -enzenzoyl-amino) -ethyl / benzoic acid _: _ _t . _ _ ·

Prepared from 4- / 2- (5-chloro-2 ~ (4-methoxy-piperidino) -benzoylamino) ethyl / benzoic acid ethyl ester by alkaline hydrolysis • analogously to Example 2.

Yield: 85% of theory,

Melting point: 188 ° C ',' ..-

Calc .: C 63 38 H 6 , 04 N 6 72 ΪΟ Found .: 63 46 5 95 6 72 example 41

4- {2 ~ (5-methoxy-2-piperidinobenzoylamino) -ethylbenzoic acid ether_ι ^ ~ ".

Prepared from 5-methoxy-2-piperidino-benzoic acid and 4- (2-amino-ethyl) -benzoic acid ethyl ester analogously to Example 1.

Yield: 66% of theory,

Melting point: 11 8 ° C

Calc .: C 70.22 H 7.36 N 6.82 F .: 70.76 7.42. 7.36

Example 4 2

4- ^ 2- (5-methoxy-2-piperidino-benzoylamino) -ethyl / benzoic acid hydrochloride · _{> yyy}

Prepared from 4 "· ^ 2- (5-methoxy-2" -piperidino-benzoylamino) -ethyl / benzoic acid ethyl ester by alkaline hydrolysis analogously to Example 2. The compound obtained was converted into the hydrochloride in acetone with isopropanolic hydrochloric acid Yield: 91 % of theory, '· ·

22251 1

Calc .: C 63.07 H 6.49 N 6.68 F .: 63.00 6.31 6.61

Example 4 3

4- / 2- (5-chloro-2-heptamethylene-amino-benzoyl-amino) -ethylbenzene

  Prepared from 5-chloro-2-heptamethyleneiminobenzoic acid and 4- (2-aminoethyl) benzoic acid ethyl ester analogously to Example

Yield: 24 % of theory, melting point: <-> 20 ° C

Calc .: C 67.78 H 7.05 N 6.33: F: 67.95 7.16 6.33

Example 44

· '

^ "L?" (5 ~ Chloro-2 ~ heptamethyleneiminobenzoylamino) ~ äthyjL_7 «

Made from 4- £ 2- (5 »chloro-2" heptamethyleneimino-benzoylamino). " ethyl / benzoic acid ethyl ester by alkaline hydrolysis analogously to Example 2.

Yield ϊ 47% of theory, melting point: 18'6 ° C

IQ Ber.j C 66.57 H 6.56 N 6.75 Vessels 66.45 6.43 6.70

I ^ "D-" (5-nitro-2 ~ plperidino ~ benzoyland.no) ethyl / benzoic acid! ethyl ester

j

ι

, Prepared from 5-nitro-2-piperidinobenzoic acid and 4-ethyl (2-aminoethyl) -benzoate analogously to Example 1. Yield: 70% of theory,

j melting point: 104 ^° C.

C: 64.92 H 6.40 N 9.87 I Gef .: 65.17 6.38 9.67

; Example 4 6

4 ~ ^ 2 ~ (5 ~ nitro ~ 2 ~ piperidino "benzgylam _j ino) ~ ethylated, prepared from 4- (2- (5-nitro-2-piperidinobenzoylamino) -ethyl) ~

benzoic acid ethyl ester by alkaline hydrolysis analogue \

Example 2. j

Yield: 69% of theory, j

; Melting point: 194-195 ° C j

, Ref .: C 63.46 H 5.83 N 10.57 ': ^! Found: 63 _f 2O 5.79 10.38

Example 47

i -

^ ' 4- ^ 2- (5 "chloro-2" (4-phenyl-piperidino) benzoylamino) -ethyl "

ben z oe s ^ e ^ CDCR m et hy Ie most ^ ^ ^ ^^ ^. ., """

¹ Prepared from 5-chloro ~ 2 ~ (4-phenyl-piperidino) benzoic acid

and 4- (2-Ani.ino-ethyl) -benzoesäure- »methyiester analogous to Example 1 •; Yield; "62% of theory,> 5. Melting point: 124 ° C

Ber, j C 7O _f 5O H 6,13. N 5.87: Gef .: 70.60 6.26 5.84

Example 48

4- / 2- (5-chloro ~ 2- (4-phenyl-piperidino) -benzoylamino) -äthyl7-

benzoic acid . ^

Prepared from 4- (2- (5-chloro-2- (4-phenyl-piperidino) -benzoylamino) ethyl / benzoic acid methyl ester by alkaline hydrolysis analogously to Example 2.

Yield: 92 % the Theory, , 88 N 6 , 05 Melting point: 188 ° C , 08 6 , 05 Ber .: C 70.04 H 5 Found .: 70.12 6 Example 49

4- \ £ 2- (5 ° chloro-2- (1,4-dioxa-8-aza-spiro ^ l, 5 decan-y1 {8)?) - benzoyl-

amino) ~ ä thy ΐν ^ ηζοΒΞ ^ μΓΒ-πΐΒ thy reading it '

Prepared from 5-chloro-2- (1,4-dioxa-8-aza-spiro / 4, 5_ / decan-yl- (8)) benzoic acid and 4- (2-aminoethyl) benzoic acid methyl! ester analogously to Example 1

 Yield? 45% of theory, '

Gef.r 62.80 5.89 5.93 y

Melting point: 1 67 ° C 5 , 93 N. 6.11 Ber .: C, 62 , 81 H 5 , 89 5.93 Found .: 62 80 Example 50

4 ~ £ 2- (5-chloro-2- (1,4-dioxa-8-aza-spiro / 4, 5_7decane-y 1- (8)) benzoyl 1-

amino) -a thyiybenzoic acid _ ^ __ ^ · ,. , -

Prepared by 4- ^ 2- (5-chloro-2- (1,4-dioxa-8-aza-spiro / 4,5 / decanyl- (8)) -benzoylamino) -ethyl / berizoic acid methyl ester by alkaline Hydrolysis analogously to Example 2.

2 225 11.

Yield: 82% of theory,

Melting point: 190 ° C H 5 , 88 N 6 28 Ber.s C 61, 95 6 , 03 6 52 Gef ₅ : 61, 74 Example 51

' 4- ^ 2- (5-Chloro-2- (4-ethoxycarbonyl-piperidino) -benzoylamino) -sythyl-benzoic acid-in-ethyl ester _ _

Prepared from 5-chloro-2- (4-ethoxycarbonylpiperidino) benzoic acid and 4- (2-aminoethyl) benzoic acid methyl ester analogously to Example 1,

Yield: 17% of theory, melting point: 70 ° C

Calc .: C, 63.48, H, 6.18, N, 5.92, F, 63.30, 6.0, 5.91

Example 52. '

4- ^ 2 »(5-chloro-2- (4-hydroxycarbonyl-piperidino) -benzoylamino} ethyl / benzoic acid

Prepared from 4- {2 '' (5-chloro-2 '> (4-ethoxycarbonyl-piperidino) benzoylamino) -äthyVbenzoesäure methyl ester by alkaline hydrolysis analogous to Example 2.

Yield: 7.1% of theory,

Melting point; 238 ° C

Calc .: C 61.32 H 5.38 N 6.50 V .: 61.32 5.33 6.71

Example 53

4- / 2- (5-chloro-2-hexa-F, ethyleniminobenzoylamino) ethyl / 1-yneoic acid methyl ester . __1_ ™™ * _ "

"2'2 2 5Ί Ί

Prepared from 5-chloro-2-hexaniethyleniminobenzoic acid and ethyl 4:: (2-amino-ethyl) benzoate analogously to Example 1.

! Yield: 72 % the theory . N 6 75 ¹ melting point: 81 ° C 6 , 67 5 months: C 66 60 H 6 , 56 Incl ..: 66 , 28 6 30 ! example ^

(S-chloro ^ -hexamethylenimino-benzoylarminoHäthyl / benzoic

, Prepared from 4- ^ 2- (5-chloro-2-hexarnethylenirnino ~ benzoylaniino) · I ethyl / benzoic acid methyl ester by alkaline hydrolysis analogously: Example 2.

Yield: 89% of theory,

Melting point: 182 ° C

15: Calc .: C 66.00 H 6.29 N 6.99 i Gef .:. 66.20 6.40. 7.15

Bjaisßiel ^ JJ!)

: A- [T.- (5-chloro-2-inorpholino-benzoyl-amino-ethyl) -benzoic acid

: Methyl ester _ __ _rr!.

Prepared from 5-chloro-2-morpholinobenzoic acid and methyl 4- (2-aminoethyl ethylbenzoate analogously to Example 1.

Yield: 80% of theory,

Melting point: 111 C

Calc .: C 62.55 H 5.75 N 6.95 2i> F .: 62.48 5.74 6/94

Example 56 4-Chloro -2-chloro-2- morpholino-benzoyl amino-ethyl / benzoic acid

Prepared from AQ.- (S-chloro-morphino-benzoyl-amino) -ethyl / · benzoic acid methyl ester by alkaline hydrolysis analogously to Example 2.

Yield! 78% of theory, melting point; 186 ° C.

Ber.j C 61.75 H 5.44 N 7.20 F .: 61.60 5.41. 7, -10 -

Example 57 ·.

4 - / _ 2- (5-chloro-2-thiomorpholino-benzoylamino) -ethyl-benzoic acid

roeth yles ter .. ^. ^, .. "^. ^ _ ^ _____ «___« __ _: " .

Prepared from 5-chloro-2-thiomorpholino-benzoic acid and 4- (2-amino-ethyl) -benzoic acid methyl ester analogously to Example 1. Yield; 45% of theory,

melting point : 1 60 ° C H 5 , 53 • 69 Ber.j C 60 20 5 , 76 N 6, 96 Gef .: 60 62 6 Example 58

4-Z2- (5-chloro-2-thiprnprpholino-ben _ι zoylJmlno) ethyl / benzoic acid

  Prepared from 4- ^ 2- (5-chloro-2-thiomorpholino ~ benzoylamino) ethyl / benzoic acid ethyl ester by alkaline hydrolysis analogously to Example 2.. Yield: 57% of theory,. · Melting point: 210 ° C

Re: C 59.32 H 5.23 N 6.92 F .: 59.25 5.19 6.80

j Example ^ 5 9

I4- / 2- (5-chloro-2- "thiomorpholinobenzoylamino) ~ ethylbenzoic acid

jniethylester-S-oxide _____ "_ ^" _____________

Prepared from 5-chloro-2 = thiomorphelino-benzoic acid-S-oxide and U- (2-amino-ethyl) -benzoic acid ~ methyl ester analogously to Example 1.

Yield: 63% of Theory, 33 N 6.44 Melting point: 152 ° C 22 6.52 Ber «: C 57.99 H 5, Found .: 58.30 5, Beis £ iel6O

I4 ^ 2- (5-chloro-2-thiomorpholino-ben2oylamino) -äthyl7benzoesäure-

JS-oxide _i ; · ________

i. '*

Prepared by 4- / 2- (5- »chloro-2-thiOiriOrpholino-benzoyl-amino-ethyl) -benzoic acid methyl ester» S-oxyd by alkaline hydrolysis janalog Example 2.

Yield: 82% of theory,

Melting point: 2O2 ° C. '

Calc .: C 57.07 H 5.03 N 6.66

Found: 57.46 5.07 6.30

Example 61

2 ~ / F, 2,4,5-tetrahydro-SH-Sbenzazepin-yl- (3) J · benzoylamino) ethyl benzoic acid methyl ester

, Prepared from 5-chloro-2 ~ _/ / f1,2,4,5-tetrahydro-3H ~ 3benzazepine · = yl- (3 ^ -benzoic acid and 4- (2-aminoethyl) ~ benzoic acid methyl ester analogously to Example 1 , Yield: 69% of theory,

Melting point? 126 C

Calcd .: C 7O _f O 4 H 5.88 N 6.05 Gef.i 70.20 5.81 5.94

Example 62

ι "

J4-Z2- (5-chloro-2 - </ f, 2,4,5-tetrahydro-3H-3benzazepin-yl (3,7-dibenzoyl)

'zoylanyino) * - ether: hy] l7b enzoic acid

Prepared from 4- ^ 2- (5-chloro-2 - / * 1,2,4,5-tetrahydro-3H-3-benzazepin ~ yl ~ (3) benzoylamino) ethylbenzoic acid ethylbenzene alkaline hydrolysis analogously to Example 2, Yield; 89% of theory, melting point: 148 ° C

LBER .: 63 C 69 , 55 H 5 , 61 N 6 24 Gef .: j i 69 , 87 5 90 6 10 example

"{SC \\ lox-2-β, 2 ₁ 3 , 4-tetrahydro-isoquinoline ~ y 1» (2) Jbenzoylamino) -ethyl] benzoic acid "methyl ester. _ ·, ._.

Prepared from 5-chloro-2- / T, 2,3,4-tetrahydro-isoquinolyl- (2 \ J ~

jbenzoic acid and methyl 4- (2-aminoethyl) benzoate

janalog Example 1.

Yield: 43% of theory,

Calc .: C 69 , 55 H 5 , 61 N 6 24 Found .: 69 65 5 / 65 6 example 64

U-Z2- (5-chloro-2- ^ i, 2, _3-f 4 t.eträhydro-isoquinolin-yl- (2-amino) ethyl _t 7ben2oesäure

»Ne ί- / ϊ- / ί.

T -> ^ "^ - J U --- 3 J 1_ j ι j

yl ~ (2) _ / benzoylamino) ethyl / benzoic acid methyl ester by alkaline hydrolysis analogously to Example 2

 Yield: 86% of theory,

Melting point: 173 ° C H 5, 33 N 6 44 cl 8th 15 Eer .: C 69, 04 5, 56 6 21 8th , 57 Found .: 68 45 Example 65

4- ^ 2- (5-chloro-2- (4-phenyl-piperazino) -benzoylamino) -ethyl / -benzoic acid-methyl ester

10; Prepared from 5-chloro-4- (4-phenyl-piperazino) -benzoic acid and 4- (2-amino-ethyl) -benzoic acid methyl ester analogously to Example 1; ; Yield: 40% of theory,

, Melting point: 132 ° C \

 · Calc .: C 67.84 H 5.90 N 8.79:

15 ... Gef.: 67.72 5.92 8.66 _i

4- / 2- (5-chloro-2- (4-phenyl-piperazino) -benzoylamino) -ethyl / benzoic acid _{n : m} _ _{ί :} ^^. _ _. j

'Prepared from 4- / 2- (5-chloro-2- (4-phenyl-piperazino) benzoyl-'

amino) -ethyl / benzoic acid methyl ester by alkaline hydrolysis,

analogously to Example 2; , Yield: 82% of theory,

Melting point: 166 C , ,

Calc .: C 67.07 H 5.65 N 9.06 ^: Found :. 67.30 5.96 8.99

Example 67

4- £ M5 ~ chloro-2M 4-pyridy 1 ^ 2) -piperazino) -benzoylamino) -ethyl 7 ·

benzo it's anure-rne thy! ester ^ _

Prepared from 5-chloro-2- _< / 4 ™ (2-pyridyl) -piperazino / benzoic acid and methyl 4- (2-aminothiazole-benzoate hydrochloride in the presence of thionyl chloride and triethylamine analogously to Example

Yield: 44.6% of theory,

Melting point of the hydrochloride: 153-154 ° C

Calc .: C 60 58 H 5, 48 N 10 , 87 Cl 13 , 76 Found .: 60 31 52 10 , 68 13 , 93 example 68

4 ~ 2 ~ (5-chloro- 2- (4-pyridyl-2- (2-piperazino) -benzoylamino-ethyl-benzoic acid

"<5 Prepared from 4- ^ 2- (5-chloro-2 ~ (4-pyridy 1- (2) -piperazino) benzoylamino-ethyl / benzoic acid methyl ester by alkaline: hydrolysis analogous to Example 2

 Exploits 27% of theory,

Melting point: 120 ⁰ C (dec.).

Ber. : C 64 58 H 5 , 42 N 12 05 Cl 7 , 63 Found .: , 64 36 5 , 49 11 87 7 48

Example 69.

4- / 2- (5-chloro-2 "-piperidino-benzoylamino) -1-methyl-ethyl / benzoic acid"

Prepared from 5-chloro-2-piperidin.o ~ benzoic acid and methyl 4- (2-amino-1-methyl-ethyl) benzoate analogous to Example 1.

Yield; 42.7% of theory, melting point: 93-94 ° C

E: C 66.57 H 6.56 Cl 8/54 N 6.75 F .: 66.82, 6.57, 8.47, 6.58

70

4- / 2- (5-chloro ~ 2-piperidino "benzoylamino)" 1-inethyl-ethyl / - benzo esäure

Prepared from 4- ^ 2- (5-chloro-2-piperidino-benzoylamino) -1-methyl-ethyl / benzoic acid methyl ester by alkaline hydrolysis analogous to Example 2.

Yield: 76% of theory,

'Melting point: 192-194 ° C

Calc .: C 65, 91 H 6 28 Cl 8th, 84 N 6 99 Found .: 66 00 6 30 8th, 77 6 , 87 example 71

4 - / _ 2 " (5-chloro-2-dimethylaminobenzoylamino) -1-methyl-ethyl / benzoic acid ' ,

Prepared by 4- / J2- (5-chloro-2-dimethylamino-benzoylaniino) 1-methyl-ethyl / methyl benzoate by alkaline hydrolysis analogous to Example 2.

Y Yield: 86% of theory, Melting point: 159-161 ° C

Ex .: J C 63 23 H 5 , 87 Cl 9 83 N 7 , 76  pef .: I i 63 42 6 , 07 9 56 7 , 67 j example 72

I4 ^ 2- (5-chloro-2-dimethylamlno-benzoylamino) -1-methyl-ethyl / -

'benzoic acid methyl ester.

Prepared from 5-chloro-2-dimethylamino-benzoic acid and methyl 4- (2-amino-1-methyl-ethyl-benzoate analogous to Example 1.

Yield: 61.5% of theory, melting point: 79-8O ° C

Ber. j C 64 , 07 H 6 , 18 Cl 9 46 N 7, 47 Found .: 64 40 6 , 52 9 14 7, 20

Example 73

4- / 5- (5-amino-2-piperidinobenzoylamino) -äthy l7benzoesäure-

• jäth yles t_er ._

J30 g (70.5 mmol) of ethyl 4- ^ 2- (5-nitro-2-piperidinobenzoylamino) ethyl | benzoate are dissolved in 500 ml of methanolic ethanol

H 2 O (1: 1) and palladium-carbon as catalyst, hydrogenated at room temperature and a hydrogen pressure of 5 bar. After separation of the catalyst and Abdestillleren of the solvent, the compound is purified by filtration through silica gel with Ässigsäureäthylester as the eluent.

Yield: 93% of theory, mp. Melting point: <C 20 ° C

C t 12: H ίΐ 1 N si , 62 Calc .: 69, 84 7, 39 10 , 43 Found .: 74 70 10 7, 2 NC 10 example

4- / 2- (5-amino-2-piperidino-benzoylamino) -ethyl / benzoic acid dihydrochloride

Prepared from 4-_2 ~ (5-amino ~ 2-piperidino ~ benzoylamino) ethyl / benzoic acid ethyl ester by alkaline hydrolysis analogously to Example 2. Subsequently, the product is converted in acetone with isopropanolic hydrochloric acid in the dihydrochloride. Yield; 87% of theory, melting point: 70 ° C

Calc .: C 57 , 26 H 6 , 18 N 9 , 54 Found .: 57 40 6 30 9 , 52 example 75

4- £ 2- (5-Äcetamino-2-piperidino-benzoylamino) -ethyl / benzoic

acid ethyl ether _ _ / ·

Prepared from 2.5 g (6.3 mmol) of ethyl 4- (2- (5-aminop-2-piperidinobenzoylamino) ethyl) benzoate and 25 ml of acetic acid. acid anhydride at room temperature. The reaction product precipitates -0 and is washed with ether. Yield: 1.9 g (69% of theory), m.p .: 165 ° C

Calc .: C 68.62 H 7,14 N 9,60 F .: 68,92 7,09 9,50

2 2251 1. - 95 - · '

Example 76

.) '

4- / 2- (5-acetamido-2-piperidino-benzoylamino) -äthyl7benzoe-

acid e

Prepared from 4- ^ 2- (5-acetamino-2-piperidinobenzoylamino) -. ethyl / benzoic acid ethyl ester by alkaline hydrolysis analogously to Example 2.

Yield: 98% of theory, melting point ί 212 ° C

Calc .: C 67.46 H 6.64 N 10.26 Fe.i 67.00 6.67 10.04

' At game 77

4 - /. 2- (5-Dimethylaminosulfonyl-2-piperidinobenzoylamino) -

ethyl. / benzoic ° methyj.este_r_

Prepared from 5-Dimethylarhinosulfonyl ~ 2-piperidino ~ benzoic "j acid and 4- (2-Äfefeyii" 44®iö) - benzoic acid analog'methylester

Example 1.

Yield 77% of theory, m.p .: 138-140 ° C

Calc .: C, 60.87, H, 6.60, N, 8.87, S, 6.77

. Found! 61.08 6.67 8.86 6.80

Example 78

4- / 2- (5-dimethylaminosulfonyl-2-piperidino-benzoylamino) -ethyl-benzoic acid ^

Prepared from 4- / 2- (5-dimethylaminosulfonyl "2-piperidino · - benzoylaraino) ~ ethyl / benzoic acid methyl ester by alkaline saponification analogously to Example

Yield; 91% of theory, melting point: 22O ° C

Calc .: C 60 11 H 6 , 36 N 9 14 S 6 , 98 Found .: 60 30 6 , 42 8th, 96 6 , 98 example 79

⁴ "/ 2 * ° (5-cyano-2-pi.peridino-benzoylamino) -ethyl / benzoic acid

ethyl ester; _| _ · _ ^ ..-- .. ". ___

Prepared from 5-cyano-2-piperidinobenzoic acid and 4- (2-aminoethyl) benzoic acid ethyl ester analogously to Example 1. Yield: 76% of theory, melting point: 97 ° C.

Ber. : C 71 80 , 08 H 6 , 71 N 10 36 Found .: 71 , 37 6 , 74 10 33 example

4- ^ 2- (5-cyano-2-piperidinobenzoylamino) -ät hy! / Benzoic acid

Prepared from 4- / 2- (5 ~ cyano ~ 2-piperidino »benzoylamino) ethyl / benzoic acid ethyl ester by alkaline hydrolysis analogously

Example 2.

Yield 40% of theory,

Melting point: 190 ° C

Calc .: C 70.00 H 6.14 N 11.13

G .: 69.81 6.03 10.98

Example 81

4- / 2- (S-ethoxycarbonyl ^ piperidino-benzoylamlno) ethyl / -

benzo esäure- ethyl ester hydrochloride '_ ____ "_

2.5 g (6.2 mmol) of ethyl 4- ( 2- (5-cyano = 2-piperidinobenzoylamino) ethyl / benzoate are dissolved in 80 ml of ethanol and saturated with hydrogen chloride. After standing for six days at room temperature, the solvent is evaporated. The residue is dissolved in ice-water, adjusted to pH 9 with sodium hydroxide solution and extracted with chloroform. After drying over "10 sodium sulfate and distilling off the solvent, the evaporation residue is converted in ether with ethereal hydrochloric acid into the hydrochloride

 Yield? 2.5 g (89.1% of theory),

Melting point: 86 ~ 88 ° (

Ber ,: C 63 85 H 6 80 N 5 72 Cl 7, 24 Gef .: 63 f ⁷¹ 6 69 5 , 74 7, 11 example 82

4- / 2- (5-hydroxycarbonyl-2-piperidino-benzoylarnino) -ethyl 7 ~

benzoic acid _ _ .__ ..

Prepared by alkaline hydrolysis of 4 ~ / 2 ~ (5 »ethoxycarbonyl" »2-piperidino-benzoyamino) -ethyl / benzoic acid ethyl ester hydrochloride analogously to Example 2. Yield: 92% of theory,

Melting point: 242 ° C H 6 10 N 7 , 06 25 Re: C 66 65 6 18 7 , 23 Gef .: 65 96

'Example 83' ·.

ί. ,

; 4- / 2- (2- (4-hydroxy-piperidino -) - 5-nitro-benzoylamino) -ethyl?

benzoic acid methyl ester · ;

a) methyl 4- / 2- (2-chloro-5-nitrobenzoylamino) ethyl benzoate

-J g (40 mmol) of 2-chloro-5-nitro-benzoic acid are dissolved in 40 ml. absolute tetrahydrofuran with 6.8 g (44 mmol) Ν, Ν'-carbonyldiimidazole converted into the imidazolide, After a Reaktionsj time of 2 hours, 7.9 g (44 mmol) of 4- (2-amino-ethyl) -i , benzoic acid methyl ester added at room temperature and j stirred for about 16 hours. After distilling off the solvent, the crude product is purified by chromatography on a silica gel column with toluene: ethyl acetate (1: 1) as the eluent.

Yield; 12 g (83% of theory) Melting point: 163 ° C Ber .; C Gef .:

56 28 H 4 17 N 7 72 56 58 4 , 41 7 , 82

b) 4-12- (2- (4-Hydroxy-piperidino) -5-nitrobenzoylamino) -ethyl / -

O. be η ζ ο es ure-me thy1 es te r _____ ^ ___ ^ _______, __ ___

A solution of 5 g (14 mmol) of methyl 4- / J- (2-chloro-5-nitrobenzoylamino) ethylbenzoate in 100 ml of ethanol is treated with 2.83 (28 mmol) of 4-hydroxy-piperidine for 14 hours Reflux temperature heated. After distilling off the solvent in a rotary evaporator, the dry residue is dissolved in ice water, adjusted to pH 5 with dilute hydrochloric acid and extracted with chloroform. After drying over sodium sulfate, distilling off the chloroform, the residue is crystallized from isopropanol.

Yield: 5.5 g (92% of theory), m.p .: 147 ° C

Example 84 ·.

4 ~ £ 2M5-amino ~ 2- (4-hydroxy-piperidino) -benzoylamino) -äthyl7- benzoesä u re-met hyleste · r '

5.3 g (12.4 mmol) of methyl 4- and 2- (2- (4-hydroxy-piperidino) -5-nitrobenzoylamino) ethyl / benzoate are dissolved in 100 ml of methanol with 10% palladium-carbon at room temperature and a water toffdruck of 1 bar hydrogenated. Yield; 91% of theory, melting point; 78 ° C

Example 85

4- / 2- (5-chloro ~ 2 * "(4-hydroxy-piperidino) -benzoylamino) -äthyl7 ~ benz oesä acid-methylester

20.5 g (52 mmol) of 4- / 2- (5-amino-2- (4-hydroxy-piperidino) benzoyl amino) ethyl / benzoic acid methyl ester are dissolved in 80 ml of half-concentrated ice-cold hydrochloric acid and washed with a solution of 4 g of sodium nitrite diazotized in 25 ml of ice-cold water. This solution is added dropwise to a suspension of 6 g of copper powder and 10 ml of HCl. After completion of nitrogen development, a viscous oil precipitates. This oil is extracted with chloroform and, after drying over sodium sulfate on a silica gel column with the eluent ethyl acetate: methanol (9: 1).

Yield: 30% of theory, m.p .: <20 ° C

Ber *: C 63.38 H 6.04 N 6.72 V .: 63.62 6.21 6.55

2 2 2 5 11

4 - / ^ 2- (5 "-chloro-2- (4-hydroxy-piperidino) -benzoylamino) -ethyl- benzoic acid re_ _ " ___

4.5 g (11.3 mmol) of methyl 4/2 (5-amino-2- (4-hydroxy-piperidino) benzoylamino) -ethyl / benzoate are dissolved in 20 ml of half-concentrated hydrochloric acid and dissolved at ⁰ C with 0.87 g (12.4 mmol) of sodium nitrite, dissolved in 6 ml of water, diazotized. ' This solution is added dropwise to a suspension of 1.2 g of copper powder in 3 ml of concentrated hydrochloric acid. After 2 hours of stirring is heated to 75 ° C for about 20 minutes. The cooled solution is extracted with chloroform, the chloroform solution is dried with sodium sulfate and the evaporation residue is purified on a silica gel column with chloroforno-methanol (9: 1) as eluent.

Yield: 2.4 g (52% of theory),

Melting point: 190 ⁰ C 5, 75 N 6 , 93 Ber .; C 62 , 6 H 5, 84 6 , 83 Gef .: 62 , 14 " Example 87

4- / 2- (5-chloro-2- (3-hydroxy-piperidino) -benzoylamino) -äthy1 / - benzoic acid methylester

Prepared from 4- / 2- (5-amino-2- (3-hydroxy-piperidino) -benzoylamino) ethyl / benzoic acid methyl ester analogously to Example 85. Yield: 30% of theory, melting point: 20 ° C.

Calc .: C 63 38 H 6 , 04 N 6 72 Gef .: 63 48 6 , 21 6 / 6 5

Ex iel 88

4- / 2- (5-chloro-2- (3-hydroxy-piperidi.no) -benzoylamino) -äthy_l / -benzoic acid -hy drat '

Prepared from 4- / 2- (5-Araino-2- (3-hydroxy-piper'idino) benzoylamino) ethyl / benzoic acid methyl ester analogously to Example Yield: 40% of theory,

Melting point: 100-11O ° C

Calc .: C 59.93 H 5.98 N 6.65 Vessel: 60.19 6.08 6.62

Example 89

4- £ 2- (2 ~ (3-hydroxy-piperidino) -5-nitro-benzoylamino) -ethyl / -benzoic acid inethylester

Prepared from 4- / 2- (2-chloro-5-nitro-benzoylamino) -äthy.l7-benzoic acid methyl ester and 3-hydroxy-piperidine ^& analogously to Example 83.

Yield: 43.5% of theory, m.p .: 78 ~ 8O ° C

4- / 2- (5-amino-2- (3-hydroxy-piperidino) -benzoylaroino) -äthy] / · · methylester-benzo esäure

Prepared from 4- / 2- (3-hydroxy-piperidino) -5-nitro-benzoy1-amino) -äthy1 / benzoic acid-raethy! Ester by catalytic hydrogenation analogous to Example 84

 Yield: 90% of theory, 'Melting point: 82 ° C

Example 91

4- / 2- (2-piperidino-5-propyloxy-benzoylamino) -ethylbenzoic acid ·

ethyl ester "_ _____

To a solution of 2 g (7.6 mmol) of 2-piperidino-S-propyloxybenzoic acid in 60 ml of absolute tetrahydrofuran is added 1.3 g (8 mmol) of NfN'-carbonyl-diimidazole and then, with exclusion of moisture, about 10-14 Heated to reflux temperature for hours. After the imidazolide has formed almost quantitatively, the solution is treated with 1.5 g (8 mmol) of ethyl 4- (2-methylbenzoate / ethyl benzoate and heated to boiling for a further 4-6 hours after distilling off the tetrahydrofuran on a rotary evaporator, the crude ester is a silica gel column using toluene / Essigester (9: 1). purified graphically as a flow agent to chroma the fractions containing the purified> ester, are combined and the solvent distilled off.

Yield · 2.4 g (72% of theory), m.p .: 20 C

Ber.i C 71.20 H 7.81 N 6.38 Gef .; 71.30 8.02 6.54

Example g2

4- £ 2 ~ U-piperidino-S-propyloxy-benzoylamino-ethyl / benzoic acid hydrochloride -

1.8 g (4.1 mmol) of A- [2- ^ -piperidino-S-propyloxy-benzoylamino) -ethyl / benzoic acid ethyl ester are dissolved in a mixture of 15 ml of methanol and 15 ml of dioxane. At room temperature, 1 ml of 30% sodium hydroxide solution, diluted with 30 ml of water, is slowly added dropwise with stirring to the ester solution, so that no permanent precipitation of the ester occurs. The addition is complete after about 2 hours. After stirring for a few hours, the organic solvents are distilled off on a rotary evaporator,

9 «

The aqueous phase is extracted by shaking with chloroform and the aqueous phase with 2 N hydrochloric acid to pH. 4 asked. After extraction with chloroform, drying of the chloroform phase and distilling off the chloroform, the hydrochloride is precipitated from a solution in acetone with isopropanolic hydrochloric acid. Yield: 1.65 g (90% of theory),

Melting point: 236 ° C 48 H 7 00 - 6 • 26 Cl 7, 93 Calc .: C 64, 24 7 , 06 N 6 17 8th, 13 Found .: 64 10 example_ £ 2

4- / 2- (5-isopropyloxy-2-piperidino-benzoylamino) -ethyl / benzoic acid ethyl ester. ^ ___ _r _ ^ __

Prepared from 5-isopropyloxy-2-piperidinobenzoic acid and 4- (2-amino-ethyl) benzoic acid ethyl ester analogously to Example 91 Yield 58% of theory, melting point: 7O-72 ° C.

Calc .: C 71.20 H 7.81 N 6.38 "Gef .: 71.10 7.74 6.40

4- / 2- (5-isopropyloxy »2-piperidino-benzoylamino) -äthyl7benzoesäure hydrochloride

Prepared from 4 - / ^ 2- (5-isopropyloxy-2-piperidino-benzoylamino) ethyl / benzoesciure ethyl ester by alkaline hydrolysis analogous to Example 92.

Yield: 82% of theory, melting point: 225-226 ° C

Ber. ·: "C 64.48 K 6.98 N 6.26 Cl 7.93 Goth .: 64.77 7.30 6.40 7.79

2 2 2 5 1 1.. - -ion- '

Example 95

4 - / _ 2- (5-hexyloxy-2-piperidinobenzoylamino) -

Prepared from 5-hexyloxy-2-piperidinobenzoic acid and 4- (2-aminoethyl) benzoic acid ethyl acetate analogously to Example 92. Yield: 61% of theory,

Melting point: 6 6 ° C H 8th , 38 N 5 , 82 Ber .: C 72 , 47 8th , 29 5 , 87 Found .: 72 , 68

 4 - / _ 2 ~ (5 ~ hexyioxy-2-piperidino-benzoyi amino) -ätnyi / ben zoesaure-

hydroch lorid ^ ___ "______

Prepared from 4 - / _ 2 ~ (5-hexyloxy-2-piperidino-benzoylamino) ethyl / benzoic acid ethyl ester by alkaline hydrolysis analogous to Example 92. "" * *.

Yield: 87% of theory, m.p .: 152 ~ 154 ° C

Calc .: C 66 30 H 7, 62 N 5, 72 Cl 7 24 Found .: 66 43 7, 98 5, 77 7 , 26

Example 97

4- / 2- (5-benzyloxy-2-piperidino ~ benzoylamino) -ethyl / benzoic acid ·

ethyl ester " -

Prepared from 5-benzyloxy-2-piperidino-benzoic acid and ethyl 4- (2-aminoethyl) benzoate analogously to Example 91.

2 225

Yield: 55 % the ° c theory 7 , 04 N 5 75 Melting point: 120 , 04 7 , 14 6 , 03 Ber .: C .74 90 H Found .: 73

Example _98

4- / 2- (5- »benzyloxy-2-piperidino » -benzoyl-amino) -äthyiybenzoesäure

Prepared from 4 - ^ / 2- (5-benzyloxy ~ 2-piperidino-benzoylamino) ethyl / benzoic acid ethyl ester by alkaline hydrolysis analogous to Example 92. Yield: 86% of theory,

melting point C 1 76 ° C H 6 , 59 N 6 10 Calc .: 73 , 34 6 , 76 6 13 Gef'j 99 73 , 34 example

A- / 2- (5-chloro-2-piperidino-benzoylamino) -2-ethyl-ethylbenzoic acid-3-methyl ester

Prepared from 5-chloro-2-piperidinobenzoic acid and methyl 4- (2-aminopropyl) benzoate analogously to Example Yield? 54% of theory, melting point: <20 ° C.

2 2 2 5 11

Example 10Q ·.

4 » _< / 2- (5-chloro-2-piperidino-benzoylamino) -2-methyl-ethylbenzoic acid

Prepared by 4 - </ 2- (5-chloro-2-piperidino-benzoylamino) -2-methyl-ethyl / benzoic acid methyl ester by alkaline hydrolysis

as in Example 92. '

Yield: 49% of theory,

Melting point: 142-145 °

Ber.i C 65.90 H 6.28 Cl 8.84 N 6.98

> Gef .: 65.85 6.45 8.83 6.99

4- ^ 2- (3 ~ cnior-2-piperidino-benzoyiaminoj-stnyi / benzoic acid

itiethyl ester:

Prepared from 3-chloro-2-piperidinobenzoic acid and 4- {2-amino ~ ^; Ethyl benzoate analogous to Example 91 · Yield: 63% of theory,.

Melting point: 92 ~ 94 ° C i

Calc .: C, 65.91, H, 6.28, Cl, 8.85, N, 6.99

F .: 65.71 6.19 9.07 6.93

Example 102

4-Z2 ~ (3-chloro-2-piperidino-benzoylamino) _ ^ ayrl / benzoic acid

Prepared from 4 - / ^ - (3-chloro-2-piperidino-benzoylamino) ethyl 7 · benzoic acid methyl ester by alkaline hydrolysis analogous to Example 92. ·.

_ ti

Yield: 57% of theory,

Melting point: 155-158 ° C

Calc .: C 65.19 H 5.99 Cl 9.17 N 7.24 Found: '* 64.96 5. 99.99 7.50

Example 103.

'4- / 2- (4 ~ chloro-2 ~ piperidino-benzoylamino) -ethyl / benzoic acid

ethyl ester

* "

Prepared from 4-chloro-2-piperidino-benzoic acid and 4- (2-aminoethyl) -benzoic acid ethyl ester analogously to Example 91. Yield: 71% of theory, melting point: <20 ° C.

Calc .: C 66.58 H 6.56 N 8.54 Cl 6.75 V .: 66.58 6.57 8.42 6.99

Example ..104

Prepared from 4- / 2- (4-chloro-2-piperidino-benzoylamino) ethyl / benzoic acid ethyl ester by alkaline saponification analogously to Example 92 »

Yield «66.7% of theory, melting point 164-166 ° C

Calc .: C 65.20 H 5.99 N 9.16 Cl 7> 24 Found: 65.31 5.96 9.25 7.48

Example 105 '.

4- / J- (5-bromo-2- {2-methylpiperidino) -benzoylamlrio) -ethyl-berizoate · acid ethyl ester. ..

Prepared from 5-bromo-2- (2-methyl-piperidino) -benzoic acid and 4- (2-amino-ethyl) -benzoic acid ethyl ester analogously to Example 91.

Yield: 74% of theory,

Melting point: 98 ° C

Calcd .: C, 60.89, H, 6.18, N, 5.92, Found: 60.99, 6.43, 5.78

Example 106

4- / 2 - {5-bromo-2 ~ (2-methyl-piperidino) benzoylamino) ethyl / benzoic acid ... ", .., -. ^ r, "-. ^^ - ^^ -

Prepared from 4- ^ 2- (5-bromo-2 ™ · (2 "methyl-piperidino)» benzoylamino) - * ethylbenberigoesäure ethyl ester by alkaline hydrolysis analogous to Example 92. ~

Outliers 73% of theory, melting point: 183 ° C

Calc .: C 65.91 H 6.29 N 6.99 Gef! 65.70 6.35 6.80

IQ Example 107

-2- (3,5-trans-dimethyl-piperidino) benzoylamino) ethyl / benzoic acid methyl ester

Prepared from 5-chloro-2- (3,5-trans-dimethyl-piperidino) benzoic acid and 4- (2-aminoethyl) benzoic acid ethyl ester analogously to Example 5 '91'.

222511

Yield: 75 C 67 % of theory, 6 , 81 N 6 , 53 Cl 8, 27 Melting point: 67 1O5-1O7 ° C 6 , 92 6 , 47 8th, 26 Ber ,: * 108 , 20 H - Found *.:. 40 example

4- / 2- (5 "Chloro-2" (3 _i .5-trans-dimethyl-piperidino) -benzoylamino) -Sthyl / be ^ n benzoic acid '"

Prepared from 4- ^ 2- (5-chloro-2- (3, 5 ~ trans -dimethylpiperidino) -benzoylamino) -äthyf7bsn2oesäure ~ methyl ester by alkaline hydrolysis analogous to Example 92 "Yield: 86% of theory, melting point: 164 -167 ° C

Ber. % C 66 , 58 H 6 56 N 6 75 Cl 8th, 55 Found .: 66 _r 80 6 71 6 65 8th, 63

Example 109

4 ~~ 2- (5-bromo-2- (3,5-cis -dimethyl-piperidino) -benzoylamino) -ethyl-benzoate ^

Prepared from 5-bromo-2- (3,5-cis-dimethyl-piperidino) benzoic acid and methyl 4- (2-aminoethyl) benzoate analogously to Example 91

Yield: 82% of theory,. ,

Melting point: C 1 42-144 ° C 6 17 N 5, 92 Cl 1 6 , 88 Ber .; 60  6 " 08 5, 85 1 6 72 Found .: 60 _; 89 H , 81

- (5-ßrom ~ 2- (3,5-cis ~

Prepared from 4- / 2- (5-bromo ~ 2- (3,5-cis-dimethyl-piperidino) -ben2oylamino) ethyl / benzoic acid methyl ester by alkaline hydrolysis analogous to Example 92.

Yield: 88% of theory, m.p .: 184-185 ° C.

Calc .: C, 60.13, H, 5.92, N, 6.10, Cl, 17.40, F, 59.98, 5.87, 6.12, 17.30

4- ^ 2- (5 ~ methoxy-2 · »(3,5- cis -dimethyl-piperidino) -ben2; oyla- nino) ~

Ethyl ethyl / benzoate _r - ^, ^ ^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^.

Prepared from 5-methoxy-2- (3,5-cis-dimethyl-piperidino) -benzoic acid and 2- (amino-ethyl) - = benzoic acid ethyl ester analogously to Example 91 "yield: 14% of theory,

Melting point; 97 -99 ° C 7, 81 N 6 , 39 Ber .: C 71, 21 h 7, 78 6 16 0 Gef .: 71, 29 Example 112

, 4- / _> 2- (5-methoxy-2- (3, S-cis -dimethyl-piperidino-1-benzoylamino) -äthy ^ / benzoic acid ^ __

Prepared from 4- / 2- (5-methoxy-2- <(3,5-cis-dimethyl-piperidino) · benzoylaminoj-ethyl / benzoic acid ethyl ester by alkaline hydrolysis analogous to Example 92 _O.

Yield: 53% of theory,

Melting point: 2OO-2O3 ° C

Example: C 70.22 H 7.37 N 6.82

J .: 70.22 7.38 6.82

ι.

! Example 113

~ / 2- (5-chloro-2- (3,3,5,5-tetramethyl-piperidino) -benzoylamino) ethyl / benzoic acid ethyl ester

Prepared from 5-chloro-2- (3,3,5,5-tetramethylpiperidino) benzoic acid and ethyl 4- (2-aminoethyl) benzoate ana, log Example 91.

Yield: 34% of theory,

Melting point: 108 C

Jsser .: C 68,85 H 7,49 N 5,94 Cl 7,52 ^! Gef .: 68,75 7,37 5,79 7,69

I Example 114

4 ~ ₁ / 2- (5-chloro-2- (3,3,5,5-tetramethylpiperidino) benzoylamino) ^! äthyl7benzoesäure

Prepared from 4- ^ 2- (5-chloro ~ 2- (3,3,5, 5-> tetramethyl ~ piperidino) ^L! Benzoylamino) -äthyl7benzoesäure ~ ethyl ester by alkaline hybrid! ""

: Drolysis analogous to Example 92. j

'Yield: 99 % of theory,. I

Melting point: 17O-172 ° C

: Calc .: C 67, 78 H' 7 , 05 N 6 32 Cl • 8th 00 Gef .: 67, 60 7 , 09 • 6, 13 7 95

2 2 25 1 1 -

Example 115 .

4- / 2- (5-chloro-2- (piperidone- (2) -yl- (1)) - berizoylamino) .- ethyl ethylbenzate ethyl ester ___ ^ '

Prepared from 5-chloro-2- (piperidone ™ (2) -yl- (1)) benzoic acid and ethyl 4- (2-aminoethyl) -benzoate analogously to Example Yield: 42% of theory, melting point: 118 ° C

Calc .: C 64.40 H 5.88 N 6.53 • Found: 64.32 5.87 6.58

Example 116

4 - / ^ 2- (5-chloro-2- (piperidone- (2) -yl (1) -benzoylamino) -ethyl)

benzoic hydrate ^

Prepared from 4- ^ 2- (5-chloro-2- (piperidone- (2) -yl (1)) - benzoylamino) ethyl / benzoic acid ethyl ester by alkaline hydrolysis analogous to Example 92.

Yield: 64 % the theory H t 56 N 6 72 Melting point: 190-1 9 3 ° C 47 6 96 Ber .: C 60.48 5, Found .: 60.74 5,

? ' Example 117

4- ^ 2- (5-bromo-2- (4-methoxy-piperidino) -benzoylamino) -ethyl / -benzoic acid ethyl ester. __ _:

Prepared from ethyl 5-bromo-2- (4-methoxy-piperidino) benzoate and ethyl 4- (2-aminoethyl) -benzoate analogously to Example 91.

2 2 2511

Yield: 82% of theory, melting point: <20 ° C

Calc .: C 58.90 H 5.97 N 5.72 F .: 59.25 6.08 5.27

Example 118

 4- / 2- (5-bromo-2- (4-methoxy-piperidino) benzoylamino) ethyl / benzoic acid

Prepared by 4- / 2- (5-bromo ~ 2 ~ (4-methoxy-piperidino) -benzoylamino) -ethyl / benzoic acid ethyl ester by alkaline hydrolysis

10 analogous example 92nd theor ie I N 6.07 Yield: 65 % the 5.85 "Melting point: 1 86 ° C H 5, 46 Re: C 57 , 28 46 Gef .: 56 40

BeJ _; s £ IEJ _u __119 · ".

4 ~ / 2 ~ (5-chloro-2- (2,6-dimethyl-morpholino) benzoylamino) benzoic acid ethyl ester ''

Prepared from 5-chloro-2- (2,6-dimethyl-morpholino) benzoic acid and 4- (2-aminoethyl) -benzoic acid ethyl ester analogously to Example 91 / Yield: 52% of theory, mp 111-112 ° C.

Calc .: C 64.78 H 6.57 N 6.30 F .: 64.72. 6.64 6.24

ZZZOl ]

Example 12.0

4- / 2- (5-chloro-2- (2,6-dimethyl-morpholino) benzoylamino) -ethyl- benzoic acid ___;

Prepared from ethyl 4- (2- (5-chloro-2- (2,6-dimethyl-morpholino) -benzoylamino) -äthyiybenzoesäure by alkaline hydrolysis analogous to Example 92

 Yield: 86% of theory, melting point: 232 ° C

Calc .: 121 C 63 38 H 6 , 04 N 6 72 10 Found .: 63 38 6 , 28 6 69 example

4 ~~ 2- (5'-chloro-2 ~ (2,6-dimethyl-thiornorpholino) -benzoylamino) -

Prepared from 5-chloro-2- (2,6-dimethyl-thiomorpholino) benzoic acid and 4- (2-aminoethyl) benzoic acid ethyl ester analogously to Example 91.

Yield: 71% of theory, m.p .: 2O <0> C

Calc .: 122 C 62 53 H 6 34 N 6 , 08 0 Found .: 62 60 6 52 6 , 08 example

4- / 2- (5-chloro-2- (2,6-dimethylthiomorpholino) benzoylamino) ethyl / benzoic acid ____ ™ _ _ «___» __ "_-_" _

Prepared from 4- / 2- (5-chloro-Z- (2,6-dimethyl-thiomorpholino) benzoylamino) ethyl / benzoic acid ethyl ester by alkaline hydrolysis analogous to Example 92.

2 2 2 5 11

Yield: 51% of theory, melting point: 183-185 ° C

Ber. : C 61 , 03 H. 5 , 82 N 6 , 47 Ge f .: 60 , 62 6 , 01 6 30

Example 123

Ethyl 4/2 (5-chloro-2- (thiomorpholine-1,1-dioxyd) benzoylamino) ethyl / benzoate ,

Prepared from 5-chloro-2- (thiomorpholine-1,1-dioxyd) -b-benzoic acid and 4 ~ (2-aminoethyl) benzoic acid ~ ethyl ester analogously to Example 91 · Yield: 40% of theory,

Melting point: 1 58 ° C 83 H 5, 42 N 6 , 02 Calc .: C 56 78 5, 78 6 15 Gef.i. 56 Example 124

4- ^ 2- (2-hexamethyleneimino-5-methoxy-benzoylamino) -ethyl / benzoyl-Jthyfester _

Prepared from 2-hexamethyleneimino-5-methoxy-benzoic acid and 4- (2 ~ Ami.nO "= ethyl) ~ benzoic acid ethyl ester analogously to Example 91 Yield * 46 % of theory, melting point 92 ° C.

Calc .: C 70.73 H 7.60 N 6.60

Gef .: 70.46 7.53 6 ^ 72

Example 125

4- / 2- (2-hexamethyleneimino-5-methoxybenzyl-amino) -ethyl / benzoic acid hydrochloride ₎

Prepared from ethyl 4- [4- (2-hexoxyethylene) -N-niethoxybenzoylamino) ethyl / benzoic acid by alkaline hydrolysis analogously to Example 92

 Yield: 92% of theory,

Melting point: 1 26 ° C H 6, 75 N 6 46 Cl 8 , 18 Ber.s C 63 30 7, 24 6 57 7 , 62 IO Gef, s 63 80 Bjeisp_l_el_126

4-O-2-heptamethyleneimino-S-methoxy-benzoyl-amino-1-ethyl-benzoic acid ~ ay! Ester ^ __ ^ ___ ™

Prepared from 2 ~ Heptamethyleniinino-5-methoxy-benzoic acid and 4- (2 ~ Ämino ~ ethyl) ~ benzoic acid ethyl ester analogously to Example 91. Yield: 30% of theory, melting point ^ C 20 ⁰ C

Example 127. · '

4- / 2- (2-heptamethyleneimino-5-methoxy-benzoylamino) -ethyl- benzoic acid hydrochloride J

Prepared from 4 ~ 2 ~ (2-heptamethyleneimino-5-methoxy-benzoyl-amino) -ethyl / benzoic acid ethyl ester by alkaline saponification analogously to Example 92

 Yield: 97% of theory,

Melting point: 110-112 ⁰ C;

Calcd .: C, 59.68, H, 6.88, N, 5.80, Found: 60.80, 6.87, 5.63

^ Example 128

'4- / 2- (2-Heptamethyleniinino-5-isopropyloxy-benzoylamino) ~ äthyl7 "i benzoic acid ä th yle art

! Prepared from 2-heptamethyleneimino ~ 5-isopropyloxy-benzoic acid and A- (2-Amino-ethyl) -benzoic acid ethyl ester in analogy to Example 92 "Yield: 62% of theory, Melting point: <20 ⁰ C: SSER .: C 72.07 H 8,20 N 6,00

JGef .: 72.20. 8,16 5,90

4 - ^ / 2- (2-heptamethyleneimino-5-isopropyloxybenzoylamino) ethyl / benzoic acid ¹ ; hydrochloride

Prepared from A- [I- (2 ~ 5 ~ heptamethyleneimino-isopropyloxy-ben I; soylamino) ethyl ~ / benzoic acid ethyl ester by alkaline Hy ^ ^1; drolyse analogously to Example 92nd

Yield: 91 % the theory C / 42 N 5 ,so - 46 Melting point: 202 ° , 73 H 58 5 , 82 23 Calc .: C 65 / 85 7, Cl 7, Gef. S 65 7, 7,

A- £ 2- (5-bromo-2-heptamethyleneimino-ben2oylamino) -ethyljbenzo

Prepared from 5-bromo-2-heptamethyleneiminobenzoic acid and 4- (2-aminoethyl) benzoic acid ethyl ester analogously to Example 91 »Yield: 42.5% of theory, melting point: 81 ° C.

Ber ": C 61 80 H 6 50 N 5, 78 br 16 40 Gef.: · 61 60 6 40 5, 74 16 40

^ Example 131 ·

J4- / 2- (S-Bromo - ^ -heptamethyleneiminobenzoylamino) ~ ethyl_7benzoic

sour _i _

Prepared from 4-π / 2- (S-bromo - ^ -heptamethyleneimino-benzoylamino)

Ethyl ethylbenzoate by alkaline hydrolysis analogously Example 92

Yield; 94% of theory,. <·

Melting point: 189 ° C

tar .: C 60.13 H 5.92 N 6.10 Br 17.39

> Gef.s 59.97 6.01 6.05 '17.51

Example 13g

j - _ -

4- (2- (3-Aza-bicyclo-3,2,2-nonan-3-yl) -5-chloro-benzoylamino) -

SthyrL / bengoesgure ° ethyl ester __ ^

Made from 2 ~ (3-Aza ™ bicyclo </ 3,2, 2 / nonan ~ 3 ~ yl) -5-chloro

benzoic acid and 4- (2-aminoethyl) benzoic acid α-thyl ester analogue

! Example 91. |

Yield? 82% of theory,

Melting point: 114 ° C ''

Calcd. C 68.63 H 6.87 N 6.16

Gef .: 68.78 7.08 6.16

: · I

Example 133 |

• ι

4 - / ^ - (2- (3-azabicyclo / 3.2 _r 2 / nonan-3-yl) -5-chloro-benzoyl-amino) -!

ethylbenzoic acid hydrochloride. ί

Prepared from 4- ₍ / 2- ₍ 2-O-aza-bicyclo), 2,2'-nonan-3-yl) -5-chloro;

Benzoylaminoj-ethyl / benzoic acid ethyl ester by alkaline Hy j

hydrolysis analogously to Example 92.. , i

Yield: 98 C % 1 the theory , 03 N 6 , 05 Cl 15, 30 : Melting point: 62 5 8 ° C , 37 6 , 07 15 25 Ber. ί I 134 62 20 H 6  Gef .: j'i , 76 6 ! j example

ΐ4- 2- 2- (5-chloro-2-octamethyleneimino-O-benzoylamino) -ethyl _; -benzoic acid ethyl ester .

Prepared from 5-chloro-2-octamethyleneimino-benzoic acid and 4-j (2-amino-ethyl) '- benzoic acid ~ ethyl ester analogously to Example 91 ·' Yield; 41% of theory,

Melting point: i [ 20 ° C H 7, 28 N 6 13 Ber.s C 68 , 33 7, 10 6 , 09 Gef .s 68 15 i Example 135

j4 ~ ^ ~ (5 ~ chloro-2-octamethyleneiminine O "-ben2oylamino) ~ ethylbenzoin--

Prepared from 4 ~ / 2- (5 "= chloro-2-octamethyleneimino-benzoylamino) - ethyl / benzoic acid ethyl ester by alkaline hydrolysis analogously to Example 92

Yield: 94% of theory,

'Melting point: 172 ° C'

Calc .: C 67, 20 H 6 , 81 N 6 53 Found .: 66 90 6 , 76 6 39

Example 136

: 4- / 2- (S-chloro-nonamethylenimino-benzoylamino) ethyl / benzo

[s ur e e te t hey e s he . ...

i,.

j ·

Prepared from 5-chloro-2-nönamethylenimino-benzoic acid and 4 · i (2-Aralno-ethyl) -benzoic acid ethyl ester analogously to Example 91. Yield: 24% of theory, melting point: ^ 20 ° C.

C: 69.14 H 7.09 N 5.97 Cl 7.56

^! F .: 69.38 7.28 6.13 7.88

BelspielJ37

i. !

4/2 "(5-chloro-2-nonamethylenirninobenzoylamino) ethyl / benzoine

Prepared from 4 - / ^ 2- (5 ~ chloro-2-nonamethyleniinino-benzoylamino) ethyl / benzoic acid ethyl ester by alkaline hydrolysis analogously to Example 92.

Yield; 82% of theory, melting point 173-174 ⁰ C.

Calc .: C 68 00 H 6 , 63 N 6 35 Cl 8th , 04 Oef .: 67 , 62 6 , 78 6 , 23 ' 7 60

⁴ "^. ² ""( ⁵ " ^Cnlor "* ² " * decamethyleninino-benzoylaiTiino) -ethyl / benzoic-acid-esters. ^^. , .., .., ^. ^, " _U. .. · , ·

Prepared from 5-chloro-2-decamethylenixnino-benzoic acid and '4- (2 "aminoethyl) benzoic acid ethyl ester analogously to Example 91.' Yield: 65% of theory,

Melting point: 20 ° C

Ber.i C 69.33 H 7.69 N 5.78: F .: 69.29 7.64 5.92

Example 139

; 4- / T (5-chloro-2 ~ de ^ camethylenim

Prepared from 4- ^ 2- (5-chloro-2-decamethylenimino-benzoylaminp) - 'ethyl / benzoic acid ethyl ester by alkaline hydrolysis analog. Example 92.

Yieldί 58% of theory _f ! Melting point? 177 C

Calc .: C 68.33 H 7.28 N 6.13. Gef .: 68.43 7.28 6.41

A "(J," (5 "" chloro-2 ~ undecamethyleneimino "benzoylamino) ethylbenzobenzene

J.

Prepared from 5-chloro-2-undecamethyleniinino-benzoic acid and ethyl 4- (2-aminoethyl) benzoate analogously to Example 91.

Yield? 71% of theory,

^; Melting point 80 C

• Calc .: C 69.79 H 7.88 N 5.61 F .: 69.35 7.66 5.84

4- / 2- (5-chloro-2-undecamethylenimino-benzoylamino) -ethyl / benzoic acid __ ^^^ _____- »___

Prepared from ethyl 4- ₍ / J 2 - (5-chloro-2-undecamethylenimino-benzoyl-amino) -ethylbenzoate by alkaline hydrolysis analogously to Example 92.

222511

Yield: 77% of theory, Melting point: 218-220 ° C

; Calc .: C 68 84 H 7 , 49 N 5, 95 ^; Found .: 68 34 7 , 21 6 19

: Beisplel_142 -

i. · ._

, 4- / 2- (5-chloro-2-dodecamethyleneimino-benzoylamino) -a thy1 / benzoic

Prepared from 5-chloro-2-dodecamethyleniminobenzoic acid and

, 4- (2-aminoethyl) benzoic acid ethyl ester analogously to Example 92. Yield: 53% of theory, mp: ζ20 ° C.

; Calc .: C 70 22 H 8th , 05 N 5 , 46 ^: Gef .: 70 56 7 77 5 , 71

143

14- £ 2 (5 "~ chloro-2-dodecaraethyleneiminobenzoylamino) ethyl / benzoic acid

j j

Prepared from 4 "_< / _> 2 - = (5-chloro-2-dodecarnethyleniinino = benzoyl-1-amino) -ethyl / -benzoic acid ethyl ester by alkaline saponification analogously to Example 92.

Yield: 33% of theory, '

Melting point: 185-187 ° C

Calc .: C 69.33 H 7.69 N 5.78

Gef.i 69,17 7,54 5,95

! Example 144

14- / 2- (5-chloro-2- (N-methylanilino) benzoylamino) ~ ethyl / benzoic

^! acid ethyl ester ; _____, ^

Prepared from 5-chloro-2- (N-methylanilino) benzoic acid and 4-. (2-aminoethyl) benzoic acid ethyl ester analogously to Example 91. Yield: 70% of theory, melting point: 20 ° C.

example

A "l2" (5-chloro-2 ~ (N-methyl-anilino) -benzoylaminoj-ethyl / benzoic acid ' _f

Prepared from 4- ^ 2- (5 »chloro-2- (N-methyl-anilino) -benzoyl-j amino) ethyl / benzoic acid ethyl ester by alkaline hydrolysis analogous to Example 92.

Yield: 65% of theory,

Melting point: 186 ~ 188 ° C

; Ber .: C 67.56 H 5.80 N 6.85

: Gef .: 67.81 5.66 6.87. ,

⁴ ~ /. ² ~ (2- (N- ^ ethylcyclohexylamino) -5-chloro-benzoylamino) -ethyl / -j

benzoic acid athy! ester .. - '... '

  · I

: - ι

Prepared from 2- (N-ethylcyclohexylaminoV-S-chloro-benzoic acid) and 4- (2-aminoethyl) benzoic acid ethyl ester analogously to Example 91, yield: 41% of theory,

Melting point: 94 ° C "·

Ber .: 'C 68.33 H 7.28. N 6,13 F .: 68,00 7,10 6,03 ^: '

!Example

Prepared from 4- / 2- (2- (N-ethylcyclohexylamino) -5-chlorobenzoylamino) ethyl / benzoic acid ethyl ester by alkaline hydrolysis analogously to Example 92.

Yield: 6 3% the theory t N 6 , 53  Melting point: I 1 63 ° C 6 45 JBer. ·: C 67, 20 H 6, 81 JGf .: I j 67, 25 6 67 i; example2 £ 8

; 4- £ 2- (2- (N-butyl-cyclohexylaminoJ-S-chloro-benzoylaminoJ-ethyl / -

! benzoic acid e-ethyl ester _ _{l ·} ^^ ^

Prepared from 2- (N-butylcyclohexylamino) -J-chloro-benzoic acid and ethyl 4- (2-aminoethyl) benzoate "analogously to Example 91.

melting point 77 ⁰ C H 7, - r N 5, 78 Ber ,: C 69, 33 7, 60 5, 78 • Gef.i 69, 12 69 Example 149

i _ -

\ A ~ l2- (2- (N -Xthylcyclohexylamino) J-S-chloro-benzoylamino-1-yhylyi "j

'benzoic acid '

. 4 "V ² ~ (2 ~ (N-butyl ~ cyclohexylamino) -5-chloro-benzoylamino) -ethyl / - '

be r. S ο it sjjr e ^ ' >

Prepared from 4- / 2- (2- (N-butylcyclohexylamino) - S-chloro-benzoylaminoj-ethyl / benzoic acid ethyl ester by alkaline hydrolysis analogous to Example 92. j

2 2 25Tt

Yield: 79% of theory, melting point: 85 ° C

Calc .: C 6 8.33 H 7,28 N 6,13 Found: 68,44 7,18 6,40

Example 150

-12- (5-chloro-2 ~ (N-isobutylcyclohexylamino) benzoylamino) -

Prepared from 5-chloro-2- (N-isobutylcyclohexylamino) benzoic acid and 4- (2-aminoethyl) benzoic acid ethyl ester analogously to Example 91.

'Yield? 46 % of theory, Melting point: 83 ° C

Calcd .: C 69.33 H 7.69 N 5.78 F .: 69.17 7.54 5.66

j Example .. 1.51

4 £ 2- (5-chloro-2- (N-isobutylcyclohexylamino) benzoylamino) -

Prepared from 4- / 2- (5-chloro-2-N-isobutylcyclohexylamino) -benzoylamino-ethyl- / benzoic acid ethyl ester by alkaline saponification analogously to Example 92. Yield: 62% of theory, m.p. ° C

Example: C 68.33 H 7.28 N 6.13 Eff .: 68.30 7.18 6.17

Example 152

-12- (5-chloro-2-dimethylaminobenzoylamino) -2-ethylethylethylamine

j be nzoesäure --inethyles ter _r

Prepared from 5-chloro-2-dimethylaminobenzoic acid and methyl 4- (2-amino-propyl-benzoic acid analogously to Example 91.I. Yield: 34% of theory,

[Melting point: "<20 ° C

Example 153

i4 ~ £ 2 »(5 ~ chloro-2-dimethylamino" -benzoylamino) -2-methyl-äthyl7-.benzoesäure

Prepared from 4- {2 ~ <5 ™ chloro-2-dimethylmino-benzoylamino) -2-ethyl-ethyl / benzoic acid ethyl ester by alkaline hydrolysis analogously to Example 92

 Yields 49 S of theory, 5! Melting point: 142-145 ° C

Ber.i C 63.22 H 5.86 N 7.76

CSef.i 62,90 5,98 7,54

'Example

i4- / 2- (3-chloro-2-dimethylamino-benzoylamino) ~ ethylbenzoic acid! 0; g £ thyj._e sjbe r_

Prepared from 3-chloro-2-dimethylamino-benzoic acid and methyl 4- (2-amino-ethyl) benzoate analogously to Example 91. Yield: 76% of theory, m.p .: <20 ^° C.

5 11- W-.

Example -p · -. (3 ~ Chloro-2-aminoethylbenzoylamino) ethyl / benzoic acid

Prepared from 4- ^ ~ {3 ~ chloro-2-dimethylaminoH3enzoylamino) -jethyl / benzoic acid methyl ester by alkaline hydrolysis analogously! Example

Yield: 76% of theory, m.p .: 175-178 ° C

by: C 62.33 H 5,52 N 8,08 Cl 10,22

JGef: 62.60 5.56 8, .26 10.27

'Example

4 ~ 12- (2-diraethylamino-5-raethoxy-benzoylamino) ~ ethyl / benzoic acid · jTj \ ethy_lester

, Prepared from 2-dimethylamino = 5-methoxybenzoic acid and 4- (2-

Amino-ethyl) »benzoic acid methyl ester analogously to Example ^ 5 'Yield: 81% of theory,. "Melting point: ^ 20 ° C

! Example ^ 57

| """ ^m ·"" ¹ ^ ¹ " ¹¹ "" = " ¹ 1 ^ i 'ii'l'l'"

ZRZ2r. (2 ~ Dimjethj ^ l _j mnjj2 £ zJl ^^

Prepared from methyl 4- ^ 2- (2-dimethylamino-5-methoxybenzylamino) ethyl / benzoate by alkaline hydrolysis analogously, Example Yield: 71% of theory Melting point: 14 7-15O ° C Ex. : C 66,65 H 6,48 N 8,18 Gef.i * 66,85 6,35 8,12

222511

Example 158

Ethyl 4- (2,4-chloro-2-dimethylaminobenzoylamino) ethyl / benzoate ""

3.55 g (10 mmol) of ethyl 4- / 2- (4-amino-2-dimethylaminobenzoylamino) -ethyl / benzoate (melting point: 135-136 C, prepared by hydrogenation of 4- / 2- (2-dimethylamino-4-nitrobenzoylaminoj-ethyl / benzoic acid ethyl ester with palladium / carbon) in 4 ml of concentrated hydrochloric acid and about 5 g of ice by dropwise addition of a solution of 820 rag (11.6 mmol) of sodium nitrite After 30 minutes, the diazonium salt solution is added dropwise at room temperature to a suspension of 1.2 g copper broth in 1 ml concentrated hydrochloric acid. "After standing overnight, it is diluted with water and extracted with chloroform Purified (fluid, toluene / ethyl acetate = 1: 1, R _f * 0.75), Yusbeutes 27% of theory, [Melting point 97 ~ 99 ° C

Ber.'j C 64 _f O8 H 6,18 N 9,46 Cl "7,47 Gef.s 64,37 6,42 9,32 7,44

(.4 ^ chloro-2-amino-benzoyl dImethy 1 1 amino) ™ ä thyl / benzoin; _säure

Prepared by alkaline saponification of ethyl 4- / 2- (4-chloro-2-dimethylaminobenzoylamino) ethyl / benzoate analog, Example 92.

j Exploits 95% of theory,! melting point; 163-165 ^O C ex .: C 62.34 H-5.52 N 10.22 Cl 8.08

Results: 61.92 5.55 10.60 8.15

example

160

j4- / 2- (2-dimethylamino-4-nitro-benzoylamino) -ethyl / benzoic acid; ethyl ester

(Prepared analogously to Example 91 from 2-dimethylamino-4-nitro ~ jbenzoic acid and ethyl 4 ~ (2-aminoethyl) benzoate ~! Yield: 95% of theory, melting point: 145 ° C

JBer.i C 62.33 H 6.01 N 10.90 Gef.i 62.73 6.00 11.09

j4- / 2 ~ (6 ~ Chloro-2-dimethylan-n-benzylethylamino) ~ ethyl / benzoic acid · Imethylp-Hter _w

Prepared from 6-chloro-2-dimethylaminobenzoic acid and methyl 4- (2-axninoethyl) benzoate analogously to Example 91. Yield? 25% of theory,

 • Melting point: 115-117 ° C

iBer.i C 63.24 H 5.87 N 7.76 Cl 9.83

iGef .: 63.33 5.73 7.90 9.92

162

^ ® .4 '' / - ^ ~ (^, "Chloro-2-dimethyl-amino-1-benzoic acid

Prepared from 4 - ^ _ 2 ~ (6 ~ chloro ~ 2 ~ dimethylamino ~ ben2oylamino) ethyl / benzoic acid methyl ester by alkaline hydrolysis analogously

Example 92. '

¹ yield; 35% of theory, melting point: 155-158 ° C ·

iBer.i C 62.34 H 5.52 N 8.08. Cl 10,22

Found .: 62.98 · 5.73 7.92 10.11

Example 163

I ·

'4- / 2- / 2- (4-benzyl-piperazino) -5-chloro-benzoylamino / -ethyl / -

jbenzoic acid methyl ester,. '

Prepared from 2- (4-benzyl-piperazino) ~ 5-chloro-benzoic acid and 4- (2-AmJ: no-ethyl) -benzoic acid ethyl ester analogously to Example 91 »! Yield: 39% of theory.,! Melting point <20 ⁰ C.

iBer.s j C 68 83 H 6 , 37 N 7 00 Cl 8th 30 Gef .: I 68 97 6 , 52 6 , 93 8th , 21 O i i 5eraz :> Enj2Oj rla minoj 7benz oesäu re -athylester

Prepared from 4- / 2- / 2- (4-benzyl-pipera2ino) -5-chloro-benzoylamino / ethylbenzene 2-ethyl acetate by catalytic hydrogenation with palladium / carbon at room temperature and a hydrogen pressure of 1 bar

Yield? 60% of theory, melting point ζ 20 ° C '

Ber.i C 69.27 H 7,13 N 11,01 Found: 69,22 7,11 10,90

2 2 2511

example

4- ^ 2- (5-chloro-2- (decahydro-isoquinolin-2-yl) benzoylamino) ethyl / benzoic acid ethyl ester

In 30 ml of absolute tetrahydrofuran, 2.5 g (8.5 mmol) of S-chloro-2- (decahydro-isoquinolin-2-yl) -benzoic acid are heated to boiling for 8 hours with 1.4 g (8.6 mmol) of carbonyldiimidazole , To the imidazolide formed are added 1.64 g (8.6 mmol) of 4- (2-aminoethyl) benzoic acid ethyl ester and the reaction mixture is heated at reflux temperature for a further 12 hours. After distilling off the solvent, the ester is chromatographed over a silica gel column with the mobile phase toluene / ethyl acetate (9: 1) chro-

purified matographically.

Yield: 2.7 g (68% of theory),

Melting point: ζ 20 ° C.

15 Ber. : C 69, 14 H 7 , 09 N 5 97 Cl 7 , 55 Gef .: 69, 43 6 , 98 6 10 7 , 76 example 166

4- (2- (5-chloro-2- (decahydroisoquinolin-2-yl) benzoylamino) -. ethyl / benzoic acid hydrochloride

1.9 g (4.1 mmol) of ethyl 4- (2- (5-chloro-2-bis (decahydro-isoquinolin-2-yl) -benzoylamino) -ethyl / benzoate are dissolved in 40 ml of a mixture of dioxane and Dissolved methanol (1: 1). After addition of 5 ml of 30% sodium hydroxide solution, diluted with 20 ml of water, is hydrolyzed at room temperature. After a few hours, the or-

-5 ganic solvent distilled off. After extraction with chloroform, the aqueous phase is adjusted to pH 4-5 with 2N hydrochloric acid and the acid which precipitates at this pH is extracted with chloroform. After drying and distilling off the chloroform, the hydrochloric acid is dissolved in acetone. with isopropanolic

> Osalic acid precipitated.

Yield: 1.5 g (77% of theory),

Melting point: 226 ° C. 6 , 33 N 5 , 86 Ber .: C 62 6 , 36 5 , 93 Gef .: 62 Example 167 , 88 H 60

Cl 14,85 14,76

⁴ ~ Z. ² ~ (5-chloro-2- (decahydro-3-benzazepin ~ 3-yl) benzoylamino) -

-. ** ethyl / benzoic acid ethyl ester

Prepared from 5-chloro-2- (decahydro-3-benzazepin-3-yl) benzoic acid and 4- (2-aminoethyl) benzoic acid ~ ethyl ester analogously to Example 165.

Yield: 97% of theory, melting point: <"20 ° C.

Calc .: C, 69.62, H, 7.30, N, 5.80; Cl, 7.33; F, 69.88, 7.22, 5.63, 7.46

15 Example 168 "

- (5-Chloro-2- (decahydro ~ 3-benzazepin-3-yl) -benzoylamino) -ethyl-benzoic acid hydrochloride

Prepared from 4- ^ 2- (5-chloro-2- (decahydro-S-benzazepin-S-yl) benzoylamino) "ethyl / benzoic acid ethyl ester by alkaline hydrolysis analogous to Example 166th

 Yield: 84% of theory,

Melting point: 216 ° C H 6 56 N 5 , 69 Cl 1 4 , 42 Re: C 63, 53 6 59 5 , 76 1 4 35 Gef .: 63, 51

Example I69

; 4- / J 2 - (5-bromo-2- (decahydro-S-benzazepin-S-yl) -benzoylamino) ethyl-benzoic acid ethyl ester

Prepared from S-bromo-2- (decahydro-3-benzazepin-3-yl) benzoic acid and ethyl 4- (2-aminoethyl) benzoate analogously to Example 165.. ·. ·. Yield: 98% of theory, m.p .: 20 ^° C.

Calc .: C 63.75 H 6.68 N 5.31 Br 15.14 F .: 64.06 6.56 5.16 15.00

Example 170

4- / 2- (5-bromo-2- (decahydro-3-benzazepin-3-yl) -benzoylamino) -äthy 1 / benzoic acid hydrochloride id ,

Prepared from 4 - ^ * 2- (5-bromo-2 ~ (decahydro-3-benzazepin-3-yl) benzoylamino) ethyl ethylbenzoate by alkaline hydrolysis analogously to Example 166

Yield: '84% of theory, melting point: 216 ^° C.

Calc .: C 58.26 H 6.01 N 5.22 Cl 6.61 Br 14.91 F .: 58.22 5.85 5.34 6.65 15.00

Example 171

4- / 2- (5-Chloro-2- (octahydro-isoindol-2-yl) -benzoylamino) -äthy ^ l / - benzoic acid- ethyl ester -

Prepared from 5-chloro-2- (octahydro ~ isoindol-2-yl) benzoic acid and 4- (2 ™ / vnino-ethyl) -benzoic acid ethyl ester analogously to Example 165, Yield. 72% of theory, melting point: <20 ° C. 'C .: C 68.63 H 6,86 N 6,15 Cl 7,79 F .: 68,72 6,92 6,20 7,94

2 2 2 5 11

Example 172

4- (2- (5-Chloro-2- (octahydro-isoindol-2-yl) -benzoylamirio) -ethyl / benzoic acid hydrochloride . _ _. !

Prepared from 4-12- (5-chloro-2- (octahydro-isoindol-2-yl) -j

benzoylamino) ethyl / benzoic acid ethyl ester by alkaline Hy-;

dehydration analogous to Example 166. j

Yield: 83% of theory,. ·

Melting point: 214 ° C. '' i

Calc .: C, 62.20, H, 6.09; N, 6.0 Cl. 15.32 '

10Fiv .: 62.45 6.23 6.13 15.70 j

Example 173

4- / 2- (S-Bronv - ^ - octamethyleneiminobenzoylamino) ethyl / benzoic acid ethyl ester. ^ ^ ^ _{-1 |} _ ^ _r . "."", _ ... , '_.

Prepared from 5-bromo-2-octamethylenimino-benzoic acid and 4- (2- _| Amino-ethyl) ~ benzoic acid ethyl ester analogously to Example 165. Yield: 84% of theory,

Melting point: <C 20 ° C. , !

Calc .: C 62.27 H 6.63 N 5.58 Br 15.93 F .: 62.40 6.66 5.53 15.96

174-

4- (2- (5-Bromo-2-octamethyleneiminobenzoyl-amino) ethyl / benzoic acid

hydrochloride ·

Prepared from 4-_2- (5-bromo-2-octamethylenimino-benzoylamino) ethyl / benzoic acid ethyl ester by alkaline hydrolysis analogous to Example 166th

Yield: 90% of theory.,

Melting point: 164 ° C. '

Calcd .: C 56.53 H 5.92 N 5.49 Br 15.67 Cl 6.95 F .: 56.82 5.96 5.47 14.85 6.59

2 2 5Ί 1

Example 175

4 - / _ 2- (5-Cyano-2-octamethyleneimino-benzoylamino) -ethyl / benzoic acid ethyl ester _:

Prepared from 5-cyano-2-octamethyleneiminobenzoic acid and 4- (2-aminoethyl) benzoic acid ethyl ester analogously to Example 165. Yield: 30% of theory,

Melting point: 94 ° C. 7, 43 N 9 , 38 Re: C 72 , 45 H -7, 50 9 , 41 Gef .: 72 50 Example 176

4 - / _ 2- (5-cyano-2-octamethylenetrinobenzoylamino) ethyl / benzoic acid

acid __________

Prepared from 4-__ / 2- (5-cyano-2-octaraethyleneiminobenzoylamino) ethyl / benzoic acid ethyl ester by alkaline hydrolysis analogously to Example 166..

Yield: 87% of theory, melting point: 186 ° C.

Ber. : C 71 , 57 H 6 96 N 10 , 01 Found .: 71 50 7 , 14 9 , 66 example 177 '

4- / 2- (2-Octamethylenimino ~ 5-nitro-benzoylamino) -ethyl / benzoic acid ethyl ester

Prepared from 2-octamethyltinimino-5-nltrobenzoic acid and 4- (2-amino-ethyl) -benzoic acid ethyl ester. analogously to Example 165. Yield: 50% of theory, melting point: 116 ° C.

Calc .: C 66.79 H 7.11 N 8.98

Gef .: 67.00 7,17 9,04

Example 178 .

A- (T.- (2-octamethyleneimino-5-nitrobenzoylamino) ethyl / benzoic acid hydrochloride

Prepared from ethyl 4-ethylbenzoate (2-octamethyleneimino-5-nitrobenzoylaraino) by alkaline hydrolysis analogously to Example 166.

Yield: 93% of theory,

Melting point: 148 ° C.

Calc .: C 62.06 H 6.74 N 9.24 Cl 4.53 F .: 62.46 6.46 9.10 4.76

Example 179

A- / J.- (5-amino-2-octamethyleneiminobenzoylamino) ethyl / benzoic acid

acid ethyl ester dihydrochloride ·

Prepared from 4- [2 ~ ^ octamethylenimino-S-nitro-benzoylamino) ethyl / benzoic acid ethyl ester by catalytic hydrogenation in methanolic solution at a hydrogen pressure of 5 bar at room temperature with 10% palladium carbon as a catalyst. Yield: 79% of theory, '"

Melting point 162 ° C.

0 Ber. : C 61 180 16 H 7 30 N 8th , 22 Cl. 1 3 90 Gef .: 61 50 7 , 84 8th , 54 1 3 50 example

'4- / 2- (5-amino-2-octamethyleneimino-benzoylamino) ethyl 7benzoic acid hydrochloride __ ^ -.

Prepared from 4 - ^ _ 2- (5-amino-2-octamethyleneimino-benzoylamino) ethyl / benzoic acid ethyl ester hydrochloride by alkaline Hy-. Drolysis analogous to Example 166. - -

Yield: 50 % 1 the theory H 7, 23 N 9 , 42 Cl 7 , 94 Melting point: 64 30 ° C. 7 ,. 10 9 20 7 , 74 Ber .: G 63 , 62 Gef .: 90

Example 181 ·

4 ~~ 2- (2-Octamethyleneimino-5-methoxy-benzoylamino) -thyiyl / benzoic

• acid ethyl ester _; __.

Prepared from 2-octamethyleneimino-5-methoxy-benzoic acid and 4- (2-aminoethyl) benzoic acid ethyl ester analogously to Example 165. Yield: 80% of theory, melting point: <20 ° C.

Calc .: C 71.65 H 8.01 N 6.18 Found: 71.65 8.15 6.25

Example 182

4 ~ (/ 2 ~ ^ octamethyleneimino-S-methoxy-benzoylamino) -ethyl / benzoic acid hydrochloride ^ ____

Prepared from '4- ^ 2- (2-Octamethylenimino-5-inethoxy-benzoyl ~ amino) -äthyiybenzoesäure ethyl ester by alkaline hydrolysis analogous to Example 166th

Yield: 83 % of theory, melting point: 216 ^° C.

Calc .: C 65.13 H 7.21 N 6.07 Cl 7.68 F .: 64.53 7.39 5.96 7.70

Example 183 '·.

4- / 2- (5-kthoxy-2-octamethylene-amino-benzoylamino) -ethyl / benzoic acid ethylstyrene .

Prepared from 5-iodothoxy-2-octaniethyleniminobenzoic acid and

2 0 O ^ "1 1 £ £, Q \ 8

Ethyl 4- (2-aminoethyl) benzoate analogous to Example 165 Yield: 66% of theory, melting point: <20 ° C.

Calc .: C 72 , 07 H 8th, 20 N 6 00 Found .: 72 25 8th, 21 6 , 06 Example· 184

4- ^ 2- (5-ethoxy-2-octamethylenimino-benzoylamino) ethyl / benzoic

acid hydrochloride '_;

Prepared from ethyl 4-ethylbenzoic acid 4- [2- (5-ethoxy-2-octa-ethyleniminobenzoylamino) ethyl ester by alkaline hydrolysis analogously to Example 166.

Yield: 98% of theory, melting point: 172 ° C.

Ber. : C 65, 73 H 7 , 42 N 5, 89 Cl 7 , 46 15 Gef .: 65, 50 7 20 5, 79 7 19 example 185

4 - </ 2 ~ (5 ~ isopropyloxy-2-octamethyleneimino-benzoyl-amino) -ethyl-7'-benzoic acid ethyl ester ^

Prepared from 5-Isopropyloxy ~ 2-octamethylenimino-benzoic acid and 4- (2 ~ AjTiino-ethyl) -benzoic acid ethyl ester analogously to Example 165.

Yield: 87% of theory,

Melting point: ζ. 20 ° C.

Calcd .: C, 72.47, H, 8.38, N, 5.82;

Gef .: 73.04 8.44 5.76

Example 186 -

4- / 1- (S-isopropyloxy-octamethyleneiminobenzoylamino) ethyl / benzoic acid hydrochloride

Prepared from 4- ^ 2- (5-isopropyloxy ~ 2 ~ octamethyleneiminobenzoylamino) ethyl / benzoic acid ethyl ester by alkaline hydrolysis analogously to Example 166.

Yield: 93% of theory,

Melting point: 152 ° C.

Calc .: C 66.30 H 7.62 N 5.72 Cl 7.24

Gef .: 66.40 7.50 5.54 7.11

Example 187

4- / 2- (5-Butyl (2) ~ oxy-2-octamethylenimino-benzoylamino) ethyl / ~

benzoic acid-a- methyl ester.

Prepared from 5-butyl (2) oxy-2-octamethyleneiminobenzoic acid 5 'and ethyl 4- (2'-aminoethyl) benzoate analogous to Example 165 Yield: 64 % of theory, m.p .: (20 C.

Calc .: C, 72.84, H, 8.56, N, 5.66

Gef .: 72.58. 8:48 5:27

Example 168

4- ( 1- (5-butyl- (2) -oxy-2-octamethyleneiminobenzoylamino) -ethyl / -benzoic acid hydrochloride '_ '

Prepared from 4- ^ 2- (5-butyl- (2) -oxy-2-octamethyleneiminobenzoylamino) ethyl / benzoic acid ethyl ester by alkaline hydrolysis analogously to Example 166.

Yield: 88% of theory, melting point: 142 ° C.

Ex .: C 66.84 H 7.81 N 5.56 Cl 7.04

Gef .: 66.40 7.84. 5,20 6,71 |

2 2 2511

Example 189

4- ₍ 2-chloro-2- (4-isopropyl-piperidino) -benzoylamino) -äthyV-

benzoic acid ethyl ester __-__

Prepared from 5-chloro-2- (4-isopropyl-piperidino) -benzoic acid 5-ethyl and 4- (2-amino-ethyl) -benzoic acid ethyl ester analogously to Example 165, yield: 72% of theory,

Melting point: <20 ° C.

Calc .: C 68.03 H 7.69 N 6.10 Cl 7.73 F .: 68.20 7/62 6.20 7.41

Example 19Q

4- {2- (5-chloro-2- (4-isopropyl-piperidino) -benzoylamino) -ethyl-benzoic acid _ "____ ^ ____ ^ _

Prepared from 4- ^ 1- (S-chloro - (4-isopropyl-piperidino) -benzoylamino) -ethyl / benzoic acid ethyl ester by alkaline hydrolysis' 5 analogously to Example 166th

Yield: 75% of theory,

Melting point: 164 ° C.

Calc .: C 67.20 H 6.81 N 6.53 Cl 8.27 V: 67.40 6.94 6.74 8.41

Example 191 '

4- / 2- (5-Chloro-2- (4-tert-butyl-piperidino) -benzoylamino) -ethyl-benzoic acid styrene ester ™

Prepared from S-chloro-2- (4-tert-butyl-piperidino) -benzoic acid and 4- (2-amino-ethyl) -benzoic acid ethyl ester analogously to Example 165. Yield: 63% of theory,. ,

Melting point: 103 ° C.

Ber. : C 68 84 H 7, 49 N 5, 95 Cl 7, 53 .Gef. : 69, 10 7, 60 6 20 7, 90

Example 19.2

4- / 2- (S-chloro-2- (4-tert-butyl-piperidino) -benzoyl-amino) -ethyl / -benzoic acid _a

Prepared from 4- / 2- (5-chloro-2- (4-tert-butyl-piperidino) benzoylamino) ethyl / benzoic acid ~ ethyl ester analogously to Example 166. Yield: 87% of theory, melting point: 160 ° C.

Calc .: C, 67.78, H, 7.05, N, 6.33; Cl, 8.00;

Gef .: 67.93 '7,21 6,50. 8,20!

Example 193 -

4- (2- (5-Chloro-2-bis (1,4-dioxa-8-aza-spiro _/ / 4,6 / undecan-8-yl) benzoyl)

Prepared from 5-chloro-2- (1,4-dioxa-8-aza-spiro ^ 4,6 / undecan-8-yl) -benzoic acid and 4- (2-amino-ethyl) -benzoic acid ethyl ester analogously to Example 165 . /.

Yield: 43% of theory, melting point; <20 ° C.

Ber. : C 64 12 H 6 , 42 N 5 , 75. Cl 7 , 28 Gef .: 64 40 6 , 31 6 , 01 7 , 62 example 194

4- / 2- (5-chloro-2 - (1,4-dioxa-8-aza-spiro / 4,6 / undecan-8-yl) benzoylamino) ethyl / benzoic acid. '

Prepared from 4 ~ _2- (5-chloro-2- (1,4-dioxa-8-aza-spiro / 4, 6'-undecan-8-yl) -benzoylamino) -ethyl / benzoic acid ethyl ester by alkaline Hydrolysis.analog Example 166,

Yield: · 71% of theory,. ·

Melting point: 185 ° C.

Calc .: C, 62.81, H, 5.93, N, 6.10, Cl, 7.72, Found: 63.02. 6.05 6.11 7.98

20 O ζ 1 1 V ^ jr ^ Jt a S βα »« Sw ^^ · β

Example Iff ^ '

4-Ethyl 2- (2-diallylamino-5-chloro-benzoylamino) ethyl benzoate

Prepared from 2-diallylamino-5-chloro-benzoic acid and 4- (2-amino-ethyl) -benzoic acid ethyl ester analogously to Example 165., Yield: 48% of theory, melting point :. <20 ° C.

Calc .: C 67.52 H 6.29 N 6.55 V: 67.64 6.38 6.56

-) Example 196_

4 ~ / _2 ~ (2- dialylamino-5-chloro-benzo y! Amino) -ethyl / benzoic acid

Prepared from 4- ^ 2- (2-diallylamino-5-chloro-benzoylamino) ethyl / benzoic acid ethyl ester by alkaline hydrolysis analogous to Example 166th

Yield: 75% of theory, melting point: 130 ° C.

Ber. : C 66 24 H 5, 81 N 7 , 02 Found .: 66 50 83 6 , 92 example 197

4-l, - (5-nitro-2,4-dipiperidino-benzoylamino) -ethyl-benzoic-benzoic acid ester.

Prepared from 5-nitro-2,4-dipiperidino-benzoic acid and ethyl 4- (2-aminoethyl) benzoate ~ analogously to Example 165.

Yield: 40% of theory, melting point: <20 ° C.

Calc .: C 66,12 H 7,13 N 11,01. , 66.13 7.09 11.05

Example 198 * / W - ² ~ (5 ~ nitro ~ 2, 4-diplperidino-benzoylaml no) -äthy], _ / benzoic acid

Prepared from 4- / 2- (5 ~ nitro ~ 2,4-dipiperidinobenzoylamino) ethyl / benzoic acid ethyl ester by alkaline hydrolysis analogously to Example 166. *

Yield: 95% of theory, melting point: 2O8 ° C,

Calc .: C 64.98 H 6.71 "N 11.65 Fe.i 64.40" 6.72 11.03.

Example 199

4 ~ £ 2- {5-amino-2,4-dipiperidino-benzoylamino) ethyl / benzoic acid ethyl ester.

1.4 g (2.8 mmol) 4- ^ 2- (5-nitro-2,4-dipiperidino-benzoylamino) ethyl / ethyl benzoate are dissolved in 100 ml of ethanol 5 and at room temperature and a hydrogen pressure of 5 bar hydrogenated with 10% palladium carbon as a catalyst. After filtering off the catalyst and distilling off the methanol is obtained on crystallization from acetone 0.8 g (60% of theory) of melting point 172 ° C,

20 Ber. : C 70 26 Gef .: 70 39 example 200

H 8,00 N 11,70 8,19 11,72

"U-" (5-amino-2,4-dipiperidinobenzoylamino) ethyl / benzoic acid

hydroch 1 or id _: ^ ^ ^

Prepared from 4- / 2- (5-amino-2,4-dipiperidino-benzoylamino) ethyl / benzoic acid ethyl ester by alkaline hydrolysis analogous to Example 166th

2 ο 9 ες 1 1 <£><£, ^ I 8

Yield: 95% of theory,

Melting point: 271 ° C. '

Calcd .: C, 64.11, H, 7.24, N, 11.50, Cl, 7.27

Gef .: 64.40 7.27 11.33 7.50

Example 201

4- £ 2- (2- (N-adamantyl (1) -N ~ methyl-amino) -5-chloro-benzoylamino) -äthyiybenzoesäure ethyl ester

Prepared from 2- (N ~ adamantyl ~ (1) -N ~ methyl-amino) -5-chlorobenzoic acid and 4- (2 ~ -Amino ~ ethyl) benzoic acid ethyl ester analogously to Example 165.

Yield? 0.85 g (34% of theory),.

Melting point: K, 20 ° C.

Calc .: C 70.36 H 7,13 N 5,66 Cl 7,16 Found: 70,05 7,08 5,46 7,07

Example 202

- (2 ~ (N ~ adarnantyl ~ (1) ~ N -methyl-amino) -5-chloro-benzoylamino) -äthy-L / benzoic acid g . _.

Prepared from 4- / 2- (2- (N-adamantyl- (1) -N-methyl-amino) -5-chlorobenzoylamino) ethyl / benzoic acid ethyl ester by alkaline hydrolysis analogous to Example 166. '

Yield: 0.33 g (64% of theory),

Melting point: 207 ⁰ C H 6 69 N 6 00 Cl 7, 59 Ber. : C 69, 44 6 44 6 , 02 7, 93 Found .: 69, 13

Example 203 '.

4-L- 2- (S-chloro-2- (1,2,3,6-tetrahydro-pyridino) -benzoylamino) -ethyl lybenzoic acid ester . .

Prepared from 5-chloro-2- (1,2,3,6-tetrahydropyridino) benzoic acid and 4- (2-amino-ethyl-benzoic acid ethyl ester analogously to Example 165.

Yield: 4.7 g (88% of theory)

Melting point: <2O ° C. '

Calcd .: C 66.90 H 6.10 N 6.78, Cl 8.59 F .: 67.60 6.21 7.02 8.54

Example 204

A- [1- (5-Chloro-2- (1,2,3,6-tetrahydropyridino) -benzoylamino) -

ff t hy ΐ7 η ζ ο it mu re _n __ '

Prepared from 4- / 2- (5-chloro-2- (1,2,3,6-tetrahydro-pyridino) -benzoylamino) ethyl / benzoic acid ethyl ester by alkaline hydrolysis analogous to Example 166. ' Yield: 2.27 g (73.7% of theory), m.p .: 181-182 ° C.

H 5,50 N 7,28 Cl 9,21 5,49 7,32 9,12

Calc .: C 65, 54 20 Gef .: 65, 50 example 205

4 - / _ 2- (5-Chloro-2- (N-isobutyl-N-propyl-amino) "benzoylamino) -äthy ~ L / - benzoic acid- ethyl ester

Prepared from 5-chloro-2- (N-isobutyl-N-propyl-amino) -benzoic acid and ethyl 4- (2-amino-ethyl-benzoate analogous to Example 165. Yield: 5.8 g (86.8% of the Theory),

Sciimelzpunkt: <20 ° C. , ".:

Calc .: C 67.48 II 7.47 N 6.30 Cl '7.97 j

F .: 67.70 7.63 6.26 7.96 ''

2 2 2 5 11

Example 206

4- / 2- (5-chloro-2- (N-isobutyl-N-propyl-amino) -benzoylamino) -ethyl / -benzoic acid - ,,.,., __.._ ^ ___ ^ ____

Prepared from 4- / 2- (5-chloro-2- (N-isobutyl-N-propyl-amino) -benzoylamino) -ethyl / benzoic acid ethyl ester by alkaline hydrolysis analogous to Example 166th

 Yield: 2.7 g (79% of theory), m.p .: 128 ° C.

Ber ..: C 66.25 .H 7.01 N 6.72 Cl 8.50 Gef .: 66.60 7.08 6.66 8.64

Example 207

sjure-methylester

Prepared from 2-N, N-diethylamine-3-methylbenzoic acid and 4- (2-amino-ethyl) benzoic acid methyl ester analogously to Example

Yield: 57% of theory, "

Melting point: <ζ 20 ° C.

Ber. t C

Found .:

71 , 71 H 7 , 66 N 7 , 61 71 , 71 7 , 83 7 , 55

^ "D-" (2-N, N-diethylamino-3-methyl-benzoyl-amino) -ethylbenzoic acid

Prepared from 4- / 2- (2-N, N-diethylamino-3-ethyl-benzoylaminoj-ethyl / benzoic acid methyl ester by alkaline Versei tion analogous to Example 166 «.

Yield: 63.1% of theory,

Melting point: 150-152 ° C.

Calc .: C 71.15 H 7.39 N 7.51

Gef .: 71.01 7.38 8.13

  Step Example! 209

4-Z.2- (5-Chloro-2- (4- (2-furoyl) -piperazino) -benzoylamino) -ethyl / -benzoic acid methyl ester _____ ^ _

Prepared analogously to Example 165 from 5-chloro-2- (4- (2-furoyl) -piperazino) benzoic acid and methyl 4- (2-aminoethyl) benzoate

 Yield: 88.4% of theory,

Melting point; 62 93-95 ° C. 5, 28 N 8, 47 Cl 7 15 Ber .: C 62 , 97 ..H- 5, 30 8th, 36 * 7 , 32 10 Gef .: , 88 Example 210

4- / 2- (5-Chloro-2- (4- (2-furoyl) -piperazino) -benzoylamino) ethyl-7-benzoic acid

Prepared from '4- / 2- (5-chloro-2- (4- (2-furoyl) -piperazino) -' 5 .benzoylamino) ethyl / benzoic acid methyl ester by alkaline saponification analogous to Example 166

 Yield: 26.4% of theory, m.p .: 187-188 ° C.

Calc .: C 62.31 H 5.02 N 8.72 Cl 7.36 F .: 62.08 4.95 8.56 7.61

Example 211

4-Z.2 "(5-Chloro-2- (N-methyl-N-benzylamino) ethyl) benzoate " "

Prepared from 5-chloro-2- (N-ethyl-N-benzylamino) r-benzoic acid ethyl-5- _{unc, ethyl} 4- (2-aminoethyl) benzoate analogously to Example 165. Yield: 4.7% of Theory, mp: 93-95 ° C.

Calc .: C 69.25 H 6.03 N 6.21 Cl 7.86

G .: 69,50 6,35 6,31 7,90

222511

Example 212

4 - <_> - (5-Chloro-2 ~ (N-methyl-N-benzylamino) -benzoylamino) -ethyl / -benzoic acid _ .

Prepared from 4- / 2- (5-chloro-2- (N-methyl-N-benzylamino) -benzoylaminoj-ethyl / benzoic acid ethyl ester by alkaline saponification analogous to Example 166th

 Yield: 64.2% of theory, m.p .: 127-128 ° C.

Ber /: C 68.16 H 5.48 N. 6.62 Cl 8.38 F .: 68.01 5.59 6.81 8.54

Example 21?

4-Y 2 - (2- (4-ethoxycarbonylpiperazino) -5-chloro-benzoylamino) ethyl / benzoic acid ethyl ester

Prepared from 2- (4-oxthoxycarbonyl-piperazino) -5-chloro-benzoic acid

acid and 4- (2-aminoethyl) benzoic acid ethyl ester analogously to Example 165.

Yield: 71.2% of theory,

Melting point: 20 ^° C.

Calc .: C 61.53 H 6.20 N 8.61 Cl 7.26

> Gef .: 61.78 6.30 8.23 7.21

Example 214

4- [2- (2- (4-ethoxycarbonyl-piperazino) -5-chloro-benzoyl-amino) -ft-thi- 1 -benzoic acid __ ___. ^ _m ^ ___ ^ _m _ _m ________ _m _ ^ _ ^ _

Prepared from 4 - ^ / 2- (2- (4-ethoxycarbonyl-piperazino) -5-chlorobenzoylamino) ethyl / benzoic acid ethyl ester by alkaline saponification analogous to Example 166th.

2 2 2 5 11

Yield: 93% of theory, m.p .: 168-170 ° C. "

Calc .: C 60.06 H 5.70 N 9.14 Cl 7; 71 F .: 59.93 5.91 9.20 7.97

Example 215

4- £ 2- (5-Ä "thyl-2 ~ piperidino-benzoylamino) -ethyl / äthyles benzoic acid ter ·

Prepared from 6-ethyl-1- (5-bromo-pentyl) -4H-3,1-benzoxazine-2,4- (1H) -dione and 4- (2-amino-ethyl) -benzoic acid ethyl ester analogously to Example 217 ,

Yield: 55.6% of theory,

Melting point! ζ 20 ° C

Calc .: C 73.50 H 7.90 N 6.86 '\

Gef .: 73,26 7,88 6,97;

Example 216;

4- / 2- (5-ethyl -2- piperidino- benzylamino ) -ethyl / benzoic acid

Prepared from 4- / 2- (5-ethyl-2-piperidino-benzoylamino) -ethyl ^ / -; benzoic acid ethyl ester by alkaline saponification analogously play 166,,

Yield: 84.5% of theory,. ;

Melting point: 177 ° C. '

Ber .: C 72 60 H 7 , 42 N 7, 36 Gef .: 72 , 59 7 , 28 7, 16 Example 217

4- ^ 2- (5-methyl-2-piperidino-benzoylamiho) - "ethyl / benzoesäureäth_ylester

i "10.6 g (32.5 mmol) of 1- (5-bromo-pentyl) -6-methyl-4H-3,1-benzoxazine; 2,4- (1H) -dione" prepared from 1, 5-dibromopentane and 6-methyl-4H-:

2 22511

3, i-benzoxazine-2,4- (1H) -dione? are stirred in 100 ml of absolute dioxane with 19.3 g (0.1 mol) of ethyl 4- (2-aminoethyl) benzoate and 13 g of N-A'thyl-diisopropylamine for 4 days at room temperature. It is then concentrated, treated with water and extracted with chloroform. The dried chloroform extracts are concentrated and chromatographed on silica gel with 10: 1 toluene / ethyl acetate as eluent

 Yield: 6.85 g (53.5% of theory), mp: <20 ° C

1QBer .: c 73.07 H 7,66 N 7,10 F .: 72,62 7,15 7,12

Ex iel 218

4 - / _ 2 ~ (5-methyl-2-piperidino-b enzoylamj.no) -äthyl7b ^en2Oes ^ ^acid

Prepared from 4- / 2- (5 ~ methyl-2-piperidino-benzoylamino) -äthyJL / benzoic acid ethyl ester by alkaline saponification analogous to Example 166th

Yield: 80% of theory, melting point: 199-200 ° C.

Ber. : C 72 , 11 H 7, 15 N 7 , 64 ! 0 Gef .: 72 10 6 95 7 70 example 219

4 ~ 12 ~ (5-chloro-2- (4-p-chlorophenyl-piperazino) -benzoylamino) -ethyl / benzoic acid-ay ! Ter ter

Prepared from 5-chloro-2- (4-p-chlorophenyl-piperazino) -benzoic acid and 4- (2-amino-ethyl) -benzoic acid ethyl ester analogously to Example 165.

Yield: 6 4.1% of theory, melting point: 153-155 ° C.

Calcd .: C, 63.88; H, 5.55; N, 7.98, Cl, 13.47; F: 63.77, 5.47. 7,93: 13,40

Ex iel 220

A- [J.- (2-Plperldino- nicotinoylamine o) -äthyl / benzoic acid ethyl ester

Prepared from "2-PiperidinO-nicotinic acid and 4- (2-amino-ethyl) benzoic acid ethyl ester analogously to Example 165

Yield: 70.3% of theory, melting point: 56-58 ^Q C.

Calc .: C 69.27 H 7,13 N 11,02 Found: 69,23 7,14 11,55

Example 221/0 4-J2 ~ (2 ~ piperid ino ~ nicotinoy lamino) "; 8thy3,7ben2oesäure

Prepared from ethyl A- [2 <- (2-piperidino-nicotinoylamino) ethyl / benzoate by alkaline saponification analogously to Example 166. Yield: 54.2% of theory,

Melting point: 153-155 ° C. ;

15 Ber. : C 67, 97 H 6 , 56 N 11 , 89 Gef .: 68 23 6 , 39 11 60 example 222

A- / 2- (2-Octamethyleneimino-nicotinoylamino) ethyl / benzoic acid methyl ester "____ _

Prepared analogously to Example 165 from 2 ~ 0ctamethylenimino-nlcotinic acid and 4 ~ (2 ~ Ain.ino ~ ethyl) ~ ben2oesäure methyl ester.

Yield: 41% of theory,

Melting point: 20 ° C.

Calc .: C 111 / Μ H 7,13 N 1 O, II ·:

Gef .: 7OfIf 7, ff 10 ^ 2

Example 223

A "12- (2-Oct amethylenimino- nicoti noylainlno) -äth y! / Benzoic acid

Prepared by alkaline saponification of Λ- / 2- (2-0ctamethylenimino-nicotinoylamj.no) ethyl / benzoic acid methyl ester analog

example 166 C % • 69 the theory I N 10 • Yield: : 63 70 179-181 ° C. 10 63 melting point 224 , 84 H 7, 39 42 Ber. : , 02 I ₁ 51 5 Gef .: example

Methyl 4- (2- (5-chloro-2- (4-methyl-piperazino) -benzoyl-amino) -ethyl / -benzoate).

Prepared from 5-chloro-2- (4-methyl-piperazino) benzoic acid hydrochloride and ethyl 4- (2-aminoethyl) benzoate analogously to Example 165

 Yield: 52% of theory, melting point: <2O ° C.

Calc .: C 63.53 H 6,30 N 10,11 Cl 8,5.2 V .: 63,62 6,05 10,23 8,28

4 ™ / 2- (5-chloro-2-piperidino-benzoylamino) -2-me ^ hyl ~ propyl / benzoic

acid-ajbhy1 est er ^ ₁

Prepared from 5-chloro-2-piperidino-benzoic acid and ethyl 4- (2-amino-2-ethyl-propyl) benzoate hydrochloride (melting point: 199 ° C) analogously to Example 165

 Yield: 51% of theory, melting point: <20 ° C.

Calc .: C, 67.78, H, 7.05, N, 6.32, Cl, 8.00, -5, Found: 67.75, 6.91, 6.05, 7.87

• Example 226

A- [2- {S-chloro-2-piperoxy} benzoylamino) -2-methylpropyl / henzoic acid., · ,, /,,; .......

Prepared from ethyl 4 - {2- (S-chloro-4-piperidinobenzoylamino) -2-5Q-methylpropyl / benzoic acid by alkaline saponification analogously to Example 166.

2 9 9 *? 1 <&<£ * <* # Ϊ

Yield: 62% of theory,

Melting point: 208C.

Ber ", C 66.58 H 6.56 N 6.75 Cl 8.55

Gef .: 66.90 6.71 6.50 8.52

Example 227

4- / 2- (5-Chloro-2- (1,2,3,4,5,6,7,8-octahydro-isoquinolin-2-yl) -benzoylamino) -ethyl thybenic acid e-ethyl ! ester

Prepared from 5-chloro-2- (1,2,3,4,5,6,7,8-octahydro-isoquinolin-2-yl) benzoic acid and ethyl 4- (2-aminoethylbenzoate) analog Example 165

 Yield: 58% of theory, melting point: <-> 20 ° C.

Calc .: C 69.44 H 6.68 N 5.99 Cl 7.59 "Found: 69.62 6.72 6.10 7.72

Example 228

A- (2- (5-Chloro-2 ~ (1,2,3,4,5,6,7,8-octahydro-isoquinolin-2-yl) -benzoylamine o) -ethyl / benzoic acid e-hydrochloride. ,.

Prepared by A- [I- (5-chloro-2- (1,2,3,4,5,6,7,8-octahydro-isoquinolin-2-yl) -benzoylamino) ethyl / benzoic acid ethyl ester Hydrolysis analogous to Example 166.. Yield: 82% of theory, melting point: 22O ° C.

Calc .: GC 63.15 H 5 , 93 N 5 , 89 Cl 1 4, 93 Gef .: 63.45 6 , 09 6 , 02 1 5, 90 Example 229 -2-oetamet hy lenimin no ) Ethyl / benzoic acid-methyl-ester

Made of 5-chloro-2-octamethyleneimino-benzoic acid and

4- (2-aminoethyl) benzoic acid methyl ester analogously to Example 165

 Yield: 83% of theory,

Melting point: 20 ^° C.

Calc .: C 67.78 H 7.05 N 6.32 Cl 8.00

5: 67.96 7,21 6,54 8,20

Example 230 |

4- [2 ~ (S-chloro-O-octamethyleneimino-benzoylamino) ethyl] benzoic acid ethyl ester

Prepared from A- [2- (5-chloro-2-octamethyleneimino-benzoylamino) -,

'0 ethyl / benzoic acid and absolute ethanol with stoichiometric

Amounts of thionyl chloride. , !

Yield: 86% of theory, [

Melting point: <20 ° C. j

Calc .: C 68.33 H 7.27 N 6.13 Cl 7.75;

Gef .: 68,21 7,40 6,20 7,62 |

, Example 231!

    'i

4- / J 2 - (5-chloro-2-octamethyleneiminobenzoylamino) -ethyl / benzoyl

3 g (7 mmol) 4- / 2- (5-chloro-2-octamethyleneimino-benzoylamino) - |

-0-ethyl / benzoic acid in 30 ml of absolute pyridine with 1.2 g of j (7.4 mmol of) carbonyldiimidazole at room temperature in the imide | azolide transferred. After addition of 1.48 g (14.8 mmol) of cyclohexa

nol is heated to boiling temperature for 2 to 3 hours. After completion] distill the solvent the crude product is chromato- i

! 5 graphically on a silica gel column with toluene-Essigsäureäthyl-;

ester purified as a flow agent. j

Yield: 2.7 g (75% of theory), '. ^!

Melting point: 88 ° C. · '<

Ber. : C 70 50 H 7, 70 N 5 48 Cl 6 , 93 Gef .: 70 60 8th, 23 5 , 26 6 , 69

-ISS

• Example 232

4- {2 ~ (5-chloro-2-octamethyleneimino-benzoylamino) ethyl / benzoic acid tert - butyl ester,,

4.3 g (0.01 mol) of 4- (2- (5-chloro-2-octamethyleneiminobenzoylamino) ethyl / benzoic acid are suspended in 150 ml of tert-butyl acetate, with 1.43 g (0.011 mol. ) 70% perchloric acid comparable \ sets and stirred for 24 hours at room temperature. The reaction mixture is taken up in 500 ml of chloroform. The chloroform

solution is shaken thoroughly with water. The crude product obtained from the chloroform phase after drying over sodium sulphate is purified by chromatography on a silica gel column using toluene-ethyl acetate as eluant. ;

Yield: 3g (62% of theory), '<

Melting point: ζ_ 20 ° C. ·

Calc .: C 69.33 H 7.68 N 5.77 Cl 7.30! G .: 69.64 7.78 5.78 7.40 \

Analogously to Examples 229 to 231, the following compounds ^! manufactured:

4 ~ ZJ2 ~ (5 ~ chloro-2 ~ octamethyleneiminobenzoylamino) ethyl / benzoic acid;

acid propyl ester I

Exploits 70% of theory, melting point <20 ° C.

4- {2 ~ (5-chloro-2-octo-ethylimino-benzoylamino) -äthyV'benzoic acid isopropyl ester

Yield: 84% of theory, melting point: 20 ^° C.

4- ^ 2- (5-chloro-2-octamethyleneiminobenzoylamino) ethyl / benzoic acid butyl ester "

Yield: 90% of theory, melting point; <20 ° C.

4- (2- (5-chloro-2-octamethylene-imino-benzoylamino) -äthylybenzoesäure-isobutyl ester Yield: 74% of theory, m.p .: <20 ° C.

_ ASi

A-12 ~ (5-chloro-2-octamethyleneimino-benzoylamino) -ethyl / benzoic acid hexyl ester

Yield: 63% of theory, melting point: <20 ° C.

4 - / _ 2- (5-chloro-2-octamethylenimino-benzoylamino) -äthy_l_ / ben2: oesäure benzyl ester

Yield: 83% of theory, melting point: <20 ° C.

Example 233

4 '- - / 2- (5-chloro-2-octamethyleneimino-benzoylamino) -ethyl _> / benzyl alcohol ^ ______, _ «________; ____

4.57 g (0.01 mol) of 4 ~ / 2 ~ (S-chloro-o-octamethylene-amino-benzoylamino) -ethyl / benzoic acid ethyl ester are dissolved in 100 ml of absolute ether and added to a suspension of 0.72 g (0.011 Mol) of lithium aluminum hydride in 30 ml of absolute ether and heated to boiling temperature for one hour. After cooling, 15 ml of water are added carefully. After filtration, the ether phase is dried over sodium sulfate. The crude product is purified by chromatography on a silica gel column with toluene / ethyl acetate = 1: 1 as flow agent. Yield: 3.5 g (84% of theory),

) Melting point: ζ 20 ° C.

Calc .: C 69 _f 46 H 7, 52 N 6 75 Cl 8th , 54 Found .: 69 , 32 7, 58 6 75 8th 80 example 234

4- £ 2 (S-chloro - ^ - octamethylenimino-benzoylamino) ethyl / benzyl> malonic acid diäthyle art ^

2.58 g (5.5 mmol) of 4- / 2- (5-chloro-2-octamethyleneimino-benzoyl-amino) -ethyl / benzyl chloride hydrochloride (prepared from 2.3 g (5.5 mmol)) - / 2- (5-chloro-2-octamethyleneimino-benzoylamino) -ethyl / benzyl alcohol and thionyl chloride in chloroform) are dissolved in 25 ml of absolute ethanol and added to a solution of 3.2 g

2 2 2511

(20 mmol) of diethyl malonate and 20 mmol Natriuraäthylat added dropwise in absolute ethanol. The mixture is then heated for 4 hours to reflux, then concentrated, acidified with dilute hydrochloric acid and extracted with chloroform. After concentration of the extracts is purified on silica gel with toluene / ethyl acetate = 10: 1 by column chromatography, / yield: 1.7 g (60.7% of theory),

Melting point: 8O ~ 82 ° C.

Ber. : iel C 66 , 83 10 Ge f: 66 , 83 Ex 235

H 7,42 N 6,36 Cl 5,03 7,51 6,62 5,07

/ _2 ~ (5- chloro-2-octamethylene- imino-benzoyl-arnino) ~ ay! / Benzo I

Prepared from 5-chloro-2-octamethyleneiminobenzoic acid and 2-phenyl-ethylamine analogously to Example 165

 Yield: 69% of theory,

N 7,17 Cl 9,39 • 7,27 '. 9.21

Melting point: 71 66 ° C. H 7, 59 Ber .: C 72 , 76 7, 6.5 Gef .: 00 Example 236

4- ^ 2 ~ _i (5 ~ chlpr-2-piperidinobenzylamino ) ethyl / acetophenone

2 g (15 mmol) of aluminum chloride are added in 10 ml of dichloroethane while cooling with 0.6 g (7.6 mmol) of acetyl chloride. After subsequent addition of 1 g (2.92 mmol) / 2- (5-chloro-2-piperi ~ dino ~ benzoylamino) -a'thyl / benzene is stirred at 4O ~ 45 ° C for 3 hours. It is then concentrated and the residue is decomposed with ice-cold dilute hydrochloric acid. After extraction with chloroform and drying of the extracts over sodium sulfate, the mixture is evaporated and chloroform / ethyl acetate = 10: 1 are chromatographed on silica gel in the elution solvent. ·. ·

11 - "-

  Yield: 0.42 g (37.4% of theory), m.p .: 61-63 ° C.

Calcd .: C, 68.65, H, 6.55, N, 7.28, Cl, 9.01

Results: - 68.73 6.76 7.33 9.16

5 Example 237

4- / 2- (5-chloro-2-octamethyleneimino-benzoylamino) -ethyl -7-acetophene non-hyd trichloride

Prepared analogously to Example 236 by reacting 2-octamethylenimino-benzoylamino) -ethyl / benzene with acetyl chloride in the presence of aluminum chlorides.

Yield: 41% of theory, melting point: 16O ° C.

Ber. ; C 64 , 79 H 6 96 N 6 , 04 Gef .: 64 91 7 , 05 5 , 98 example 238

Cl 15,30 15,11

4 ~ Z.2 ~ (5 ~ chloro-2-piperidino ~ benzoylamino ) ~ ayr! ^ / Phenylacetic acid \

? 4.86 g (1OmMoI) of 4- / 2- (5-chloro ~ 2-piperidino ~ ben2: oylamino) ethyl - phenyl · -thioessigsaure morpholide (melting point: <^ 20 ⁰ C, manufactured; represents 4 - / 2- (5-chloro-2-piperidino-benzoylamino) -ethyl / -acetophenone by Willgerödt reaction with sulfur and morpholine: lin) in 50 ml of ethanol with 2 g (50 mmol) of sodium hydroxide; Cooked for 2 days. It is then concentrated, treated with water and extracted with ether. The aqueous phase is then acidified, the precipitate formed is filtered off with suction and extracted from acetone.

5 nitrile recrystallized.

Yield: 0.96 g (24% of theory), '

Melting point: 151 ° C.

Calc .: C 65 91 H 6 / 28 N 6 99 Cl 8th , 84 Gef .: • 65 , 61 6 , 34 7 , 18 8th 77

Example 239

4- £ 2- (S-chloro ^ -octamethylenimino-benzoylamino) ethyl / benz aldehyde, 4 '

To a stirred suspension of 0.35 g finely powdered anhydrous sodium carbonate in 3.5 ml of ethylene glycol in a bath of 160-17O ⁰ C is added 0.35 g (0.59 mmol) of N ¹ -4- (2- (5-chloro -2-octa

methylenimino-benzoylamino) -ethyl) -benzoyl-N -tosyl-hydrazine of melting point 153-158 ° C, prepared from 4 - / "2- (5-chloro-2-octamethylenimino-benzoylamino) -ethyl / benzoic acid and tosylhydrazine with carbonyldiimidazole After 1.5 minutes (completion of evolution of gas), the heating bath is removed and a few minutes later a lot of ice is added, the mixture is extracted twice with ether, dried and the combined extracts are filtered off and evaporated in vacuo to purify the resulting pale yellow resinous oil By column chromatography on silica gel with the eluent chloroform / acetone = 20: 1. Yield: 66% of theory, melting point: <^ 20 ° C.

 M.p .: m.p. m / e = 412/414 (1CI) Found: Mol peak rn / e = 412/414 (1CI) Melting point of hydrochloride χ 0.5H "0: 156 ° C.

Calc .: C 62 , 88 H 6 82 N 6 , 11 Cl 15 46 Gef: 62 85 7, 11 6 , 05 15 4 3 example 240

-IJ1- (S-chloro-O-octamethyleneiminobenzoylamino) -ethyl / benzaldehyde

The solution of 0.50 g (1.2 mmol) of 4- (2- (5-chloro-2-octamethyleneiminobenzoylamino) ethyl / benzyl alcohol in 75 ml of absolute acetone is shaken with 7.5 g of active Manganese dioxide for two hours at room temperature, filtered through a Celite layer on a G4 frit and the filtrate evaporated in vacuo. The resulting brownish viscous oil is purified by column chromatography on silica gel (chloroform / acetone = 20: 1).

Yield: 5% of theory, m.p .: <20 ° C

 Calcd .: Molpeak m / e = 412/414 (1CI) Found: Molpeak m / e »412/414 (1CI)

Example 241

4 ~ 12 ~ (5-chloro-2-octamethyleneiminobenzoylamino) -thathiyi-benzaldehyde

hyd diethyl acetal · ^ _ ^ "

A mixture of 0.23 g (0.5β mmol) of 4- / J- (5-chloro-2-octamethyleneiminobenzoylamino) -ethyl / benzaldehyde, 0.20 ml (1.2 mmol) of triethyl orthoformate, 0 , 02 g of ammonium chloride and 0.2 ml of anhydrous ethanol are heated for 30 minutes at 90 ° C. After cooling, poured into 2N ~ ammonia and extracted with Xther. The extract, dried over sodium sulfate, is evaporated in vacuo and the evaporation residue is purified by column chromatography on silica gel (toluene / acetone - 10: 1). Yield: 23% of theory, melting point: <-> 20 ° C

 Ber .: Molpeak m / e = 486/488 Found: Molpeak m / e = 486/488

Example 242

4 ~ Z J ~ (5 ~ chloro-2 ^ octamethyleneimine o-b enzoylamino) ethyl / cinnamic acid

1 g (2.4 mmol) of 4- / 2- (5-chloro-2-octamethyleneimino-benzoylamino) ethyl / benzaldehyde and 1 g (10 mmol) of malonic acid are dissolved in 10 ml of absolute pyridine after the addition of 0.5 ml of piperidine heated to 100 ⁰ C for one hour. Then you give: on ice / dilute hydrochloric acid and the precipitate formed is filtered off with suction «. For purification is chromatographed on silica gel with toluene / ethyl acetate = 1: 1 as flow agent.

Yield: 21% of theory,

Melting point: 90 ° C. · ·

Calc .: C 68.63 H 6.87 N 6.16. Cl 7,79. Gef .: 68.69 6 _V 82 6.10 7.83 '

Example · 243

^ "Z. ² ""(5-chloro-2-piperidino-benzoylamino) -äthy 1 / benzoylessigsäureäthylester" _______________.- ,

Prepared by Friedel-Crafts acylation of (2- (5-chloro-2-piperidinobenzoylamino) ethyl / benzene with malonic acid ethyl ester chloride analogously to Example 236.

Yield: 21% of theory, melting point: <20 ° C.

Ber .: m / e 456/458 (1 Cl)

Gef .: m / e 456/458 (1 Cl)

Example 244

4-Z.2- (5-chloro "2 ~ ~ benzoyl oct amethylenimino

Prepared from 5-chloro-2-octaraethyleneiminobenzoic acid and 4- (2-aminoethyl) -nitrobenzene analogously to Example 165. Yield? 85% of theory, melting point: 1O2 ° C.

Calc .: C, 64.25, H, 6.56, N, 9.77, Cl, 8.24, F, 64.45, 6.57, 9.73, 8.24

Example 24g

/ imino-be-ethyl / aniline

Prepared from 4 ~ 2- (5-chloro-2-octamethyleneimino-benzoylamino) ethyljitrobenzene by reduction with stannous chloride in hydrochloric acid «

Yield: 74% of theory,

Melting point: 87 ° C.

Calc .: C 69.07 H 7.56 N 10.50 Cl 8.86 F .: 69.10. 7,77 10,61 9,10

Example 246 '

4 ~ ₍ / 2- {5-chloro-2-octamethyleniraino-benzoylamino) -ethyl / toluene

hydrochloride _ »________ -.

Prepared from 5-chloro-2-octamethyleneimino "benzoic acid and 4- (2-amino-ethyl) -toluene analogously to Example 165. Yield; 69% of theory,

Melting point: 167-171 ° C. , , C: C 66.20 H 7.41 N 6.44 Cl 16.29 V: 66.78 7.39 6.87 15.90

Beisp_ie, l_247

^ "L?" (5-chloro-2-octamethyleneimino-benzoyl-amino) -ethyl_ / chloro

benzol _ ^ _a ^^ ^ ^ _n . ^ _ ^ _. "^, __."'_-_-

Prepared from 5-chloro-2-octamethyleneimino-benzoic acid and 4- (2-amino-ethyl) -chlorobenzene analogously to Example I65. Yield: 66% of theory, melting point 58 ° C. ^

Ber. : C 65 , .87 H 6 , 73 N 6 , 68 Gef .: 65 99 6 , 55 6 , 51 example 248

4 - ^ _ 2- (5-chloro-2-octamethyleneimino-benzoylamino) -äthyiy'benzoe-

acids! tr 11 _ ^ ₁ ^ _r ^ _ _ ' _n .

4.36 g (0-, 01 mol) of A-ß. ™ (5-chloro-2-octamethylenimino-benzoyl-amino) -ethyl / aniline are in 3.8 ml of concentrated hydrochloric acid

1 1

dissolved, diluted with 28 ml of water and dlazotiert at OC with a solution of 0.76 g (0.011 mol) of sodium nitrite in 3 ml of water with dropwise addition. After stirring for half an hour, the pH is adjusted to 6 with sodium carbonate. This diazonium salt solution is added dropwise to a freshly prepared solution of trisodium tetracyano copper (I) complex at 0 ° C. The complex solution is prepared from 3.2 g (0.0128 mol) of copper sulfate. 5 H ₂ O and 0.87 g of sodium chloride dissolved in 10 ml of water. After reduction to copper (I) chloride with a solution of 0.66 g of sodium bisulfate and 0.44 g of sodium hydroxide in 5 ml of water, the washed copper (I) chloride becomes a solution of 1.7 g of sodium cyanide in 30 ml of water added. After completion of the evolution of nitrogen, the Reaktions ™ mixture is heated to 70 ° C for one hour. After cooling, it is extracted with chloroform at pH 8. The crude product obtained from the chloroform extracts is purified over a silica gel column (eluant: toluene / ethyl acetate = 8: 2).

Yield: 38 70 % the Theory, , 88 N 10 25 cl 8th , 64   Melting point: 70 102 ⁰ C. , 59 10 45 8th , 92 20 days: C 249 31 H 6 Gef .: 50 6 Example <

4-p-2- (5- "chloro-2-octamethyleneiminobenzoylamino) -ethyl / ortho-n-butyl ω-ω-hydroxyethyl ester.

Quantities of A- [ 1- (5-chloro-2-octamethyleneiminobenzoylamino) ethyl / benzoic acid nitrile and absolute ethanol are saturated in ether with hydrogen chloride. The reaction mixture is allowed to stand for 4 days at 4 C, wherein the imino ether as hydrochloride partly oily partly crystalline precipitates. After decanting the solvent, washing with ether, an excess of absolute Ätha.nol is added at 4 ° C and left the reaction mixture-2 days at this temperature. After distilling off the solvent, the crude product over a

Silica gel column purified by chromatography with toluene as eluant.

Yield: 30% of theory, melting point: <20 ° C.

Calc .: C 67.84 H 8,16 N. 5,27 Cl 6,67 Found: 67,60 8,05 5,14 6,43

Example 250

4 ~ £ 2 ~ (5-chloro ~ 2 ~ octamethylenimino-benzoylaminu) ethyl / benzoic acid

morphqlid ^ __ ] ^ "_ _ "

2 g (4.7 mmol) of 4 - ^ * 2- (5-chloro-2-octamethyleneimino-beri2oylamino) -ethyl / benzoic acid are dissolved in 20 ml of absolute pyridine and added at room temperature by adding 0.83 g (5.1 mmol) carbonyldiimidazole quantitatively converted into the imidazolide. After addition of 0.41 g of morpholine, it is heated to reflux for 6 hours. Then, pyridine is distilled off and the evaporation residue on a silica gel column with the flow agent toluene /; Ethyl acetate = 6: 4 purified by chromatography. ; Yield; 1.8 g (76.5% of theory), '

Melting point: <20 ^° C. i

20 Calc .: C 67 , 52 H 7, 29 N - 8th , 44 Found .: 67 , 01 7, 35 8th 17 example 251

- £ 2 ~ (5-chloro-2-octamethylenimino ~ benzoylamino) -äthyl7benzoe-

6ß -

* - '2 g (4.7 mmol) of 4- / 2- (5 ~ chloro-2 ~ octamethylenimino-benzoylamino) are -Sthyl / benzoic acid suspended in 30 ml of absolute toluene and transferred to 0.65 ml of triethylamine in the salt · , After cooling to -10 ° C, 0.5 g (4.7 mmol) of ethyl chloroformate are added and stirred for 30 minutes. To the mixed anhydride is added 0.4 g (4.7 mmol) of piperidine.

£, d, ^ i s

After 2 hours, the solvents are distilled off and the crude product is purified by chromatography on a silica gel column with the eluent ethyl acetate. Yield: 2 g (86% of theory) Melting point: <20 ° C.

Calc .: C 70.21 H 7.72 N 8.47 F .: 70.42 7.83 8.51

The following compounds are prepared analogously to Examples 250 and 251:

4-L-2- (5-chloro-2-octa-methyl-imino-benzoyl-amino) -ethyl-benzoic acid amide

Yield 75% of theory, m.p .: 122 C. Ber .; C 67.35 H 7.07 N 9.82 67.95 7.48 9.78 GEFC ι

4- ₍ 2-chloro-2-octamethyleneiminobenzoylamino) ethyl / benzoic acid dipropylamide

Yield: 75% of theory, melting point: <20 ° C. Calc .: C 70.35 H 8.27 N 8.21 Found: 69.95 8.04 7.94

4-V2- (5-chloro-2-octa-ethylenimino-benzoylamino) -ethyl / benzoic acid diallyl-aide

Yield: 70% of theory, melting point: <20 ° C. Calc .: C 70.90 H 7.54 N 8.27 F .: 70.23 7.30 7.98

4 ~ </ 2 ~ (5-chloro-2-octamethyleneimino-benzoylamino) -α-acid thiomorpholide

Yield: 70% of theory, m.p .: "(20 ° C Cl.: C, 65.41, H, 7.06, N, 8.17, F, 65.54, 7.14, 7.93

4 - </ 2> (5-chloro-2-octamethyleneiminobenzoylamino) ethyl / benzoic acid N-methyl-piperazide

Yield: 75% of theory, melting point: - <20 ° C. Calc .: C 68.15 H 7.69 N 10.96 F .: 68.23 7.73 11.08

4- / 2- (5-chloro-2-octamethylenimino-berizoylamino) -äthyl7benzoesäure-N-ethyl-N-cyclohexylamide

Yield: 58% of theory, melting point: <20 ° C. Calc .: C 71.42 H 8.24 N 7.81 F .: 71.60 -8.30 7.57

^ 'D-' ( 5-chloro-2-octamethyleneimino-benzoylamino) -äthy ^ benzoic acid isopropylamide

Yield: 54% of theory, Melting point: 171 ⁰ C Calc .: C 68.99 H 7.72 N 8.94 Found .: 69.34 7.52 8.74

A "[2- (5-chloro-2-octamethyleniraino-benzoylamino) ethyl] benzoic acid-butylamide

Yield: 53% of theory, melting point: 163 ° C. Calc .: C 69.47 H 7.91 N 8.68 F .: 69.53 7.95 8.72

example

N ¹ - (1- (4-X-thoxycarbonyl-phenyl) -ethyl) ~ N ² - (5-chloro-2-piperidino-benzoyl) -hydrazine ^. _UJ ".

2.4 g (10 mmol) of 5-chloro-2-piperidinobenzoic acid in 15 ml of anhydrous tetrahydrofuran are mixed with 1.62 g (10 mmol) of N, N-carbodiimidazole, stirred for 5 minutes at 20 ° C. and for 4 minutes under reflux. To the cooled solution is added at 20 ° C, a solution of 2.08 g (10 mmol) 4- (1-hydrazine ~ ethyl) benzoate / freshly prepared from the appropriate amount

2 2 2 5 11

4- (i-hydrazino-ethyl-benzoic acid-ethyl ester hydrochloride of melting point 98-100 ° C by addition of the stoichiometric amount of aqueous sodium hydroxide solution with ice cooling, extraction with chloroform and evaporation of the dried chloroform extract at 30 ° C in vacuo / After stirring overnight at room temperature, the mixture is evaporated in vacuo and partitioned between water and chloroform, the combined chloroform extracts are dried, filtered and concentrated by evaporation in vacuo.The reddish brown oily deicing residue is purified by column chromatography on silica gel (toluene / acetone = 8/1).

Yield: "41.9% of theory, melting point: <20 ° C (light yellow oil). Ber .: Molpeak m / e = 429/431 (1 Cl).

15Gef .: 'Molpeak m / e = 429/431 (1CI)

Example 253

1 7

N - (1- (4-ethoxycarbonyl-phenyl) -ethyl) -N - (B-chloro-dimethyl)

aniino-benzoyl) -h ydrazine ; _

Prepared from 5 ™ chloro-2-dimethylaminobenzoic acid _/ carbonyldimidazole and ethyl 4- (1-hydrazinoethyl) benzoate in anhydrous tetrahydrofuran analogously to Example 252 »Yield: 18% of theory,

Melting point: <20 ° C

 , Calc .: Molpeak m / e = 389/391 (1CI) 25Gef: Molpeak m / e = 389/391 (1CI)

Example 25A. , ,

1 2

N - (1 ~ (4-carboxyphenyl) -ethyl) ~ N - (5-chloro-2-piperidino-

benzoyl) hydrazine, ' ______

1.8 g (4.2 mmol) of N - (1- (4-ethoxycarbonyl-phenyl) -ethyl) -N ~ (5-chloro-2-piperidino-benzoyl.) -Hydrazine and 0.20 g

(5 mmol) of sodium hydroxide in 8 ml of ethanol and 8 ml of water at 60 ° C. for 5 hours. After evaporation of the ethanol in vacuo is adjusted to pH 6 with 2N hydrochloric acid and extracted several times with ethyl acetate. The combined extracts are washed with water, dried over sodium sulfate, filtered and evaporated in vacuo. The solid evaporation residue is recrystallized from methanol.

Yield: 45.8% of theory, melting point: 212-215 ° C.

Ber.i C 62.76 H 6.02 N 10.45 Found: 62.90 6.07 10.44

Example 255

N ¹ - (1- (4-carboxyphenyl) -ethyl) -N ² - (5-chloro-2-dimethylamino-benzyl-hydrazine).

^ 5 Prepared from N - (1- (4-ethoxycarbonyl-phenyl) -ethyl) -N - (5-chloro-2-dimethylamino-benzoyl) -hydrazine by saponification with sodium hydroxide analogously to Example 254 «.

Yield: 34.4% of theory, melting point: 210-212 ° C

20Ber .: C 59,75 H 5,57 H 11,61 Found: 59,32 5,60 11,41

Example 256

4- / 1- (5-chloro-2-octamethylenimino-benzoylaminoxy) -äthyl_ / benzoic acid methylester '

25 g (7.1 mmol) of S-chloro-octamethyleneiminobenzoic acid and 1.2 g (7.4 mmol) of carbonyldiimidazole are stirred in 10 ml of anhydrous pyridine at 20 ° C. for 40 minutes. Then there are added 1.4 g (7.2 mmol) of 4 ~ (1-aminoxy-ethyl) -benzoic acid methyl ester / 1 freshly prepared analogously to Example 252 from 4- (1-aminoxy-ethyl) -benzoic acid methyl ester hydrochloride of melting point 158 ~ 16O ° /

• and stirred overnight at 100 ⁰ C. It is concentrated to dryness in vacuo and the evaporation residue purified by column chromatography on silica gel (toluene / ethyl acetate = 9: 1). Yield: 41% of theory, melting point: <20 ^° C.

Example 257

3- {5-chloro-2-octamethylene-amino-ben2: oylaminooxy-ethyl) -benzoic acid methyl ester.

Prepared from 5-chloro-2-octamethyleneiminobenzoic acid, carbonyldiimidaol and 4- (aminoxymethyl) benzoic acid methyl ester, / freshly prepared from the hydrochloride of melting point 252-255 C / in anhydrous pyridine analogous to Example 256-5. Yield : 33% of theory,

Melting point: <(20 ° C

 Ber .: Molpeak m / e = 444/446 (1CI)

Found Molpeak m / e = 444/446 (1 Cl)

, Example 258 ·

3-1 / 1- (5-chloro-2-dimethylamino-benzoylaminoxy) -äthy ^^ s ¹¹²⁰⁰³ ^ ¹¹¹ ' ⁶ "

methy le st he.

Prepared from S-chloro-2-dimethylamino-benzoic acid, carbonyldiimidazole and methyl A- (1-amxnoxy-ethyl) benzoate analogously to Example 256 but in anhydrous tetrahydrofuran at 20 ° C and 16 hours reaction time

Yield: 59 % of theory,

25- melting point: <20 ° C.

2 2 2511

Example 259

4- ^ 1- (5-chloro-2- (cis-3,5-dimethyl-piperidino) -benzoylaminoxy) -

ethyl benzoate acid methyl ester

Prepared from 5-chloro-2- (cis-3,5-dimethyl-piperidino) benzoic acid, carbonyldiimidazole and 4- (1-aminooxy-ethyl) -benzoic acid ethyl ester analogously to Example 256

Yield: 85% of theory, melting point: 20 ^° C.

Example 260

4- / 1- (5-chloro-2 "-piperidino-benzoylaminoxy) -ethyl / benzoic acid-me thy! Ester ___ ______"

The mixture is stirred with 7.55 g (25.8 mmol) of 5-chloro-2-piperidino-benzhydroxamic acid potassium salt (melting point: 153 ° C. (dec.)) And 6.30 g of 4α (1-bromoethyl) -benzoic acid Methyl ester in 20 ml of dimethylformamide for 18 hours at 20 ⁰ C, then added with three times the amount of water and extracted with ether. The dried and filtered ether extract is evaporated in. Vacuum. The evaporation residue is purified by column chromatography on silica gel (cyclohexane / ethyl acetate - 1/1).

Yield? 69.2% of theory

Melting point: {20 C.

Calc .: C 63.37 H 6.04 Cl 8.50 N 6.72 V .: 63.54 6.17 8.49 6.63

Example 261 4- (5-chloro-2-y

To 4.8 g (19 mmol) of 5-chloro-2-dimethylamino-benzhydroxamic acid potassium salt (mp 140 ° C (dec)) and 1.06 g (19 mmol) of potassium hydroxide in 50 ml of ethanol / water (1 / 1) give 4.2 g

2 225 1 1

(19 mmol) 4-bromo-ethyl-benzoic acid and heated at reflux for 6 hours. It is evaporated in vacuo and the evaporation residue dissolved in water with the addition of potassium hydroxide solution. Nach.Extraktion with ethyl acetate is the aqueous phase to pH 7 and extra freeze again with ethyl acetate. This ethyl acetate extract is dried, filtered and evaporated in vacuo. The evaporation residue is purified by double column chromatography on silica gel (chloroform / methanol = 9/1 and 4/1). Combine the uniform fractions, evaporate them and partition the evaporation residue between water and ethyl acetate. From the ethyl acetate extract is obtained by evaporation in vacuo an almost colorless oil which crystallizes on trituration with ether. Yield: 1.5% of theory, melting point: 160-161 ° C.

15 Ber. : C 58 53 H 4 91 N 8th , 03 Gef .: 58 49 5 10 7 , 88 example 262

4- / I- (S-chloro ~ 2 ^ piperidine

A solution of 6.0 g (14.4 mmol) of methyl 4- / T- (5-chloro-2-piperidinobenzoylaminoxy) ethyl / benzoate and 1.15 g (28.8 mmol) of sodium hydroxide is heated 100 ml of ethanol for 6 hours at 50-60 ° C. After evaporation in vacuo, the mixture is partitioned between dilute hydrochloric acid and chloroform. The dried and filtered chloroform extract is evaporated in vacuo and the evaporation residue is crystallized from a chloroform / methanol. Mixture with the addition of petroleum ether to. Yield: 44.8% of theory, melting point: 2O1-2O3 ° C.

Calc .: C 62 , 61 H 5 , 76 Cl 8th, 80 N 6 96 Gef .: 62 , 68 5 , 67 8th, 76 6 96

Example, 263

4 ~ ZT ~ (5-chloro-2-dimethylarnino-b enoyl, 3-aminoxy) ethyl / benzoic acid

Prepared from 4 ~ / T- (5 ~ chloro-2 ~ dimethylaminobenzoylaminoxy) ethyl / benzoic acid methyl ester by saponification with sodium hydroxide in ethanol / water analogously to Example 252; however, it was extracted with ethyl acetate and recrystallized from ethanol. Yield: 65.7% of theory,

Melting point: 2O2-2O5 ° C. :

Calc .: C 59.58 H 5.28 Cl 9.77 N 7.72 Found: 59.70 5.34 10.00 7.90

Example 264

4 ~ _T- (5-chloro ~ 2 ~ (cis ~ 3,5 ~ dimethyl-piperidino) -benzoylaminoxy) -

äthy! / b enzoic acid ^^ ·; ___ "

Prepared from '4 / T (5-chloro-2- (cis-3,5-dimethyl ~ piperidino) -benzoylaminoxyj-ethyl / benzoic acid-methylester by saponification with sodium hydroxide in ethanol / water in analogy to Example ^252, yield: 63 , 8% of theory, i

Melting point: 2O5-2O8 ° C.

Ber. : C 64 10 H 6 , 32 Cl 8th , 23 N 6 50 20 Gef .: 64 40 6 , 66 8th , 44 50 Example. 265

4- (5-chloro-2-octamethyleneimino-benzoylaminoxy-methyl) -benzoic acid _

Prepared from 4- (5-chloro-2-octamethyleneimino-benzoylaminoxymethyl) benzoic acid methyl ester by saponification with sodium hydroxide in ethanol / water analogously to Example 252.

Yield: 43.1% of theory, "

Melting point: 135-138 ° C. (from ether)

 Calc .: C 64.10 H 6.32 Cl 8.23 'N 6.50 F .: 64.29 6.29 8.33. 6.73

Example 266

4 - / _ 1-i5-chloro-2-octafnethyleniminobenzoylaminoxy) - a'thylybenzoe-

acid ^^ _i \ .

Prepared from 4 ~ / 1- (5-chloro-2-octamethylene-imino-benzoyl-amino-oxy) -ethyl / benzoic acid methyl ester by saponification with sodium hydroxide in ethanol / water analogously to Example 252. Yield: 69% of theory, melting point: 187-19O ° C.

Ber.i C 64.78 H 6.57 Cl 7.97 N 6.30 Found: 64.60 6.58 7.88 6.16

Example 267 I

³ "Z 1 ~ Z 2 ~ (5-chloro-2-piperidinobenzoyl'amino) -äthyijpheny ^ propion-

acid ethyl ester _r

1.2 g (5 mmol) of 5-chloro-2-piperidinobenzoic acid, 1.5 g (5 _f 8 mmol) of 3 - "/ J- (2-amino-ethyl) -phenyl-propionic acid, ethyl ester hydrochloride and 1.84 g (7 mmol) of triphenylphosphine are initially charged in 30 ml of absolute acetonitrile and 0.5 ml (5 mmol) of carbon tetrachloride and 2.45 ml (17.5 mmol) of triethylamine are added in succession after 20 hours is stirred at room temperature, is filtered off from the precipitate and the filtrate is concentrated by evaporation.The concentration residue is purified by column chromatography on silica gel in toluene / ethyl acetate -5: 1

 , Yield: 1.2 g (54.5% of theory), m.p .: 20 ° C

 Ber .; C

Found .:

67, 78 H 7 , 05 N. 6 32 Cl 8th 00 67, 33 6 91 6 18 8th , 09

Example 268

3- £ 4- / 2 ~ (5-chloro-2-piperidino-benzoylamino) -äthy ^ Tphenyl / propionic acid __ ^. '

Prepared by alkaline saponification of 3- / T- / 2- (5-chloro-2-piperidino-benzoylamino) -äthyJL / phenyl / propionic acid ethyl ester analogously to Example 166th

Yield: 8C % the theory H 6 , 56 N 6 / 75 Cl 8th / 54 • melting point: 139 ° C. 6 , 62 6 60 8th / 40 Ber .: C 66 / 57 10 items: 66 , 51 Example 269

3- ^ 4- / 2- (5-chloro-2-octamethyleniraino-benzoylamino) -äthyJL / phenyi / -

propionic acid ethyl ester ^ ·

Prepared from 5 ~ Chloro ~ 2-octamethyleneiminobenzoic acid and 3- / 1- * • 5 (2-aminoethyl) phenyl / propionic acid ~ ethyl ester hydrochloride ana-;

log Example 267. ^l .

Yield: 76% of theory,

Melting point: <20 ° C. ',

Calc .: C 69.33 H 7.69 N 5.78 Cl 7.31 F .: 69.22 7.59. 5.66 7.26 '

Example 270 i

3 ~~~ ~ [2 ~ (5 ~ chloro-2-octamethyleneiminobenzoylamino) ethyl / phenyl} -

p ropic acid. '

Prepared from 3 ~ / _4 - / _ 2- (5-chloro-2-octamethyleniInino-benzoy ^ - "-? - amino) -äthyiyphenyl / propionic acid ethyl ester by alkaline saponification analogous to Example 166th. '

2 2 25.1.1

Yield: 79 % of theory.

Melting point: 92-94 ° C.

Calc .: C 68.33 H 7.28 N 6.13 Cl 7.76 F .: 68.54 7.38 6.28 7.81

Example 271

4- / 2- (2-piperidino-5-propyl-benzoylamino) -ethyl / benzoic acid, he reads ^ __.

Prepared from 1- (5-bromo-pentyl) ~ 6-propyl-4H ~ 3,1-benzoxazine ~ 2, 4- (1H) -dione and 4- (2-aminoethyl) -benzoic acid ethyl ester analogously to Example 217 ,

Yield: 41% of theory, melting point: <20 ° C.

Calc .: C 73.90 H 8.11 N 6.63 F .: 73.45 7.92 6.42

Example 272

4- / 2- (5 ~ butyl-2-piperidino ~ benzoylamino) -ethyl / benzoic acid

Prepared from 6-butyl-1-bis (5-bromo-pentyl) -4H-3, T-benzoxazine-2,4- (1H) -dione and 4- (2-amino-ethyl) -benzoic acid ethyl ester ana-201og Example 217.

Yield? 59% of theory, melting point: ζ 20 ° C

 Calc .: C 74.28 H 8,31 N 6> 42 Found: 73,90 8,05 6,13

Example 273 '

4- £ 2- (4-chloro-5-nitro-2-piperidino-ben2oylamino) - "äthyl7benzoe-acid-ester'ithy \ - ^ _i __

Prepared from 4-chloro-5-nitro-2-piperidino-benzoic acid and 4- (2-Amino-ethyl) -benzoic acid ethyl ester analogous to Example 165 · yield: 20% of theory, Melting point: ζ 20 ° C.

Calc .: C 60.06 H 5.70 N 9.13 Cl 7.70 V .: 60.20 5.78 9.25 7.85

Example 274

4- / 2- (5-chloro-2 ~ octamethylenimino-benzoylamino) -äthyl7benzoe acid ~ _i _ ^

A mixture of 0.45 g (1 mmol) of 4- / 2- (5-chloro-2-octaroethylene-4-aminobenzoylamino) -ethyl / benzaldehyde hydrochloride, 5 ml of 0.5 N sodium hydroxide and 0.30 g (1 , 3 mmol) of silver oxide is heated with vigorous stirring for 4 5 minutes on the steam bath. After cooling, the mixture is acidified with 2N sulfuric acid and extracted with ether. The organic phase is dried, filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (chloroform / methanol = 10/1). Yield; 34% of theory, melting point: 172 ° C.

Example 275.

A- / 2- (5-chloro-2-octamethyleneiminobenzoylamino) -ethylbenzoic acid-sodium salt, -.

5 g (11.7 mmol) 4- / 2- (S-chloro - ^ - octamethyleneimino-benzoylamino) -äthy_l / benzoic acid are dissolved in 20 ml of absolute tetrahydrofuran and • dissolved with a Natrlumäthylatlösung, prepared from 0.27 g ( Ti, 7 mmol) of sodium and 10 ml of Kthanol, -, this drops

Natriuinsalz from. After addition of 80 ml of ether, stirring is continued for one hour, filtered off with suction and dried at 80 C in a .Umlufttrockenschrank. , '-. ". Yield: ^rf 4.5 g (85% of theory),

Melting point: 29O ° C.

Calc .: C 63.92 H 6,26 N 6,21 F .: 63,90 6,35 6> 18

Example 276

4- / 2- (5 "-chloro-2-octamethyleneimino-benzoylamino) -äthyljbsnzoe-

1 acid hydrochloride __ ^

5 g (11/7 mmol) 4- / 2- {5-chloro-2-octamethyleneimino-benzoylamino) ethyl / benzoic acid are dissolved in 150 ml of hot acetone and filtered. With isopropanolic hydrochloric acid, the hydrochloride is precipitated.

Yield: 5 g (92% of theory), m.p .: 2O5 ° C.

Ber. : C 61, 93 H 6 50 N 6 , 01 Cl 15 , 23 Gef .: 62 10 6 , 86 6 24 '14 85 example 2'77

4- / 2- (5-Xthyl-2-octamethyleneimino-benzoylamino) -ae-acid methyl ester

Prepared from 5-ethyl-2-octamethyleneiminobenzoic acid and 4- (2-aminoethyl) benzoic acid ethyl ester analogously to Example 165. Yield: 78% of theory, melting point: <20 ° C.

Ber .:. C 74.63 H 8.50 N 6.22 F .: 74.41 8.10 6.01

Example 278 '. ·

j.

J4- £ 2- (5-K: ethyl-2-octa-ethylenimino-benzoyl-amino) -ethyl / benzoic ~

! acid ^ _i __.

Prepared from ethyl A- [2- (5-ethyl-2-octamethyleneimino-benzoylamino) ethyl] benzoate by alkaline saponification analogously to Example 166

Yieldί 85 % of theory,

Melting point: 145 ° C.

Calc .: C 73.90 H 8.11 N 6.63.

Gef .: 74.15 8.15 6.42

Example 279

A-12- (5-chloro-2-octamethyleneiminobenzoylamino) ethyl / benzoic acid

JsMure ^ äthy] L_ester ^, _. _T ". _ .. ^,.

j.

5-Chloro-2-octamethyleneiminobenzoic acid (5.6 g, 0.02 mol) is treated with 2 g (0.02 mol) of triethylamine in 50 ml of absolute toluene and mixed with 2.2 g of (~ 5 ° C.). 0.02 mol) of ethyl chloroformate are converted into the mixed / hydrofluid. After stirring for half an hour, ethyl 4- (2-aminoethyl) benzoate solution in 30 ml of chloroform is added, which is extracted from 4.59 (0.02 mol) of ethyl 4- (2-aminoethyl) benzoate hydrochloric acid and the equivalent amount of 2 g (0.02 mole) of triethylamine was prepared. After stirring for 3 hours at room temperature, dilute with water

'Hydrochloric acid is added, the organic phases separated and dried over! Sodium sulfate. After distilling off the solvent, the 4- (2-Äthjoxycarbonylamino-ethyl) -benzoic acid ethyl ester formed as a by-product is separated on a silica gel column with the mobile phase toluene / ethyl acetate = 9: 1.

, Yield: 1.6 g (18% of theory),

Melting point: <20 ° C '

 Ber .: '68.33 H 7.28. N 6,13.

Appearance: 68.62 7.25 5.90 '

; Beis piel 280

 i. '· - .-.

4-__ 2- (5-chloro-2-octamethylene-amino-benzoylamino) -ethyl / benzoic acid; ____

[5.6 g (0.02 mol) of 5-chloro-2-octamethyleneiminobenzoic acid are dissolved in 50 ml of absolute toluene with 2 g (0.02 mol) of triethylamine and incubated at -5 ° C. with 2.2 g (0.02 mol) of ethyl chloroformate converted into the mixed anhydride. After half an hour of stirring, a solution of 3.3 g (0.02 mol) of 4- (2-aminoethyl) benzoic acid in 20 ml of 1N sodium hydroxide solution is added and stirred at .'_ room temperature for 4 hours. Then 30 ml of water are added, the organic phase separated and again ^! shaken out with chloroform. The acid is precipitated from the aqueous phase by acidification with .1N hydrochloric acid to pH 5.5 and recrystallised from ethyl acetate.

Yield: 1.2 g (14% of theory), m.p .: 172 ° C.

Calc .: C 67,20 H 6,81 N 6,53 F .: 66,92 6,77 '6,43 \

Example 281 '

4- ^ 2- (5-5-chloro-2-octame-ylyleneimino-berizypylamino) -ethyl-benzoic acid

8.87 g (12.6 mmol) of copper (II) di- / 5-chloro-2-octamethyleneiminobenzoate / dihydrochloride complex / prepared from 5-amino-2-octa-methylene-benzoic acid via the diazonium salt with copper (I) chloride, melting point: 177-178 ° C / are dissolved in 25 ml of absolute ipyridine and added dropwise with ice cooling with 3 g (25.3 mmol) of 'thionyl chloride, so that the temperature at 2O ~ 3O ° C remains. After stirring for half an hour, 4.9 g (25.3 mmol) of ethyl 4- (2-aminoethyl) benzoate, dissolved in 5 ml of absolute pyridine, are added and the mixture is heated at 70 ° C. for 3 hours. After distilling off the pyridine, the residue is in 'a mixture

from 50 ml of methanol and 50 ml of dioxane and, after the addition of I, 4.6 g of potassium hydroxide, dissolved in 90 ml of water,

Room temperature stirred. The solvents are then distilled off, the evaporation residue is dissolved in 140 ml of water, the product is precipitated by adjusting the pH to 5.5 and the product is recrystallized from ethyl acetate. Yield: 4.1 g (38% of theory). Melting point: 172 ° C.

, Ref .: C 67.20 H 6.81 N 6/52. Cl 8,26 'Gef .: 61,10 6,72 6,45 8,20

j.

Example 282

! "

4 - / _ 2- (S-'- chloro - ^ - octamethylenimino-benzoylamino) ethyl / benzoei acid ethyl ester '. ^ _

110.5 g. {15 mmol) of copper (II) di- ^ / S-chloro-octamethylene-aminobenzoyltitrochloride complex prepared from 5-amino-2-octa-methyleneiminobenzoic acid via the diazonium salt and copper - (I) -; chloride, melting point: 177-178 ° C / are added in 25 ml of absolute jpyridin with 5.4 g (33 mmol) of carbonyldiimidazole, iKohiendioxidentwicklung occurs. After half an hour of stirring

At room temperature, 6.8 g (35 mmol) of ethyl 4- (2-aminoethyl) benzoate IsSure ester, dissolved in 5 ml of absolute pyridine, are added and then heated to 70 ° C. for 3 hours. After distilling off pyridine, the residue is dissolved in water, shaken out at pH 4 with chloroform and the chloroform extracts are dried over sodium sulfate. After concentration, the residue 'is purified by chromatography on a silica gel column with the eluent toluene / acetic acid.

Yield: 10 g (66% of theory), Melting point: 20 ° C.

Calc .: C 68.33 H 7,28 N 6,13 Cl 7,75 F .: 68,30 7,22 5,91 7,66

'Example 283

i 4 ~ £ 2- (S-chloro -octamethyleneimino-benzoylamino) -ethyl / benzoic acid ' . '

8.4 g (0.02 mol) of 4- / 2- (5-chloro-2-octamethyleneimino-benzoylamino) -: ethyl 7chlorobenzene (melting point: 58 ° C) are dissolved in 80 ml of tetrahydrofuran, cooled to -60 ° C. and under nitrogen with fl8 ml (0.04 mol) of a pre-cooled 2.3 molar solution of n-! Butyl-Llthium in hexane. This reaction mixture is' after 15 minutes in about 10 g finely ground carbon dioxide under.

Nitrogen entered. After warming to room temperature, the mixture is evaporated and the evaporation residue is dissolved in water. The product is adjusted by adjusting the pH to 5.5 in water ^! falls, recrystallized from ethyl acetate and then purified by chromatography.

Yield: 1 g (12% of theory), m.p .: 172 ° C.

Calc .: C 67 20 H 6 81 N 6 52 Cl 8th, 26 Found .: 67 00 6 72 6 46 8th, 19 example 284

4-L-2- (5-chloro-2-octamethyleneamino-benzoylamino) -ethyl / benzoic acid.

I,.

I ·

To a solution of 11.5 g (0.03 mole) of 2- (5-chloro-2 ™ octamethylenelimino-benzoylamino) ethylbenzene in 50 ml of carbon disulfide at 0-5 C is added 7.6 g (0.06 mole) of oxalyl chloride Dropped and! then 8 g (0.06 mol) of aluminum chloride added. After stirring for one hour, the same amounts of oxalyl chloride and aluminum chloride are added again, and then heated to 50 C for 2 to 3 hours. After adding the cooled 'solution with ice water and hydrochloric acid, it is extracted with chloroform. The dried Chloroformeindamprückückstand is recrystallized from ethyl acetate using activated carbon twice.

Yield: 2.4 g (19% of theory), m.p .: 172 ° C

E .: C 67.20 H 6,81 N 6,52 Cl 8,26 Gei: 67,11 6,45 '6,45 8,19

  i

Example 285

\ 4 ~ L ~ ~ (5- ^ C hIQr-2- piperidino-be nzoylaminp) ~ ethyl / benzoic acid

To a stirred sodium hypobromite solution prepared from O, 92 g (23 mmoles) of sodium hydroxide dissolved in 4.5 ml of water and 0.36 ml (7 mmoles) of bromine under ice-cooling / is added dropwise within

The solution of 0.60 g (1.56 mmol) of 4-O-2- (5-chloro-2-piperidino-benzoylamino) -ethyl / acetophenone in 6 ml of dioxane at 35 ° -40 ° C. for 15 minutes. After 40 minutes at 35 ° -40 ° C., aqueous sodium hydrogen sulphite solution and water are added, and the mixture is evaporated in a vacuum. Dissolve the residue: in water, acidify the solution

15 with 2N hydrochloric acid with cooling and takes the precipitated j precipitate in an ether / ethyl acetate mixture on. The organic phase is dried over sodium sulfate, filtered, and evaporated in vacuo. The almost colorless solid residue (0.45 g) is crystallized from hot acetone, filtered and dried at 110 ° C / 30 Torr. Yield: 0.06 g (10% of theory), m.p .: 2O1-2O3 ° C

 Example: C 65.19 H 5.99 Cl 9.16 N 7.24 Yf .: 65.53 5.91 9.32 7.10

ί

^! Example 286

4- [2- (S-chloro-O-octamethyleneimino-benzoylamino) -ethyl / benzoic acid _{i (}

- · 'i

Prepared analogously to Example 285 from 4- (2-C5-chloro-2-octamethyleneiminobenzoylamino) ethyl / acetophenone with sodium hypobroarine solution.

Yield: 11% of theory,

Melting point: 171-172 ° C.

Calc .: C 67.19 H 6.81 € 1 8.26 N 6.53 V: 67.50 6.75 x 8.53 6.24

Example 287

A-12- (5-chloro-2-piperidinobenzioylamino) -ethyl / benzoic acid

' ethyl ester r' ____

0.82 g (0.002 mol) of ethyl A-β- (2-bromo-5-chloro-benzoylamino) -ethyl-7-benzoate / m.p .: 116-118 C, prepared by reacting 2-bromo-5-chloro benzoic acid with ethyl 4- (2-aminoethyl) benzoate analogously to process a) are heated to 100 ° C. with 0.85 g (0.01 mol) of piperidine and 1 spatula tip of copper powder for one hour with stirring. After cooling, the reaction mixture is acidified with acetic acid and extracted 3 times ^ 5 with chloroform. The combined chloroform phases were dried over sodium sulfate. After distilling off the solvent, the remaining residue is purified on a silica gel column (eluent: chloroform / ethyl acetate = 19: 1). , Yield: 0.49 g (48% of theory), 'Ber ,: Moipeak m / e: 414/416 (1 Cl), Gef, Moipeak m / e: 414/416 (1 Cl)

Example 288

j A-12- (5-chloro-2-piperidino-benzoylamino) -ethyl / benzoic acid

äth y le st he ^ _ __

o, 48 g (0.002 mol) of 5 "chloro-2-piperidino-benzoic acid amide (melting point: 14O-142 ° C, prepared from 5-chloro ~ 2 ~ piperi ~, dino-benzoic acid by reaction with carbonyldiimidazole and ammonia) are _i After stirring the evolution of hydrogen, 0.09 g (0.002 mol) of 55% sodium hydride are heated with stirring in 5 ml of absolute toluene for 10 minutes to about 60 ° C. The mixture is cooled to room temperature and the solution of 0.51 g (0.002 mol) 4

-2-

^: (2 ~ bromo ~ ethyl) -benzoic acid ethyl ester (M ⁺ = 256/258 m / e 1 Br,

prepared from 4- (2-hydroxyethyl ~ benzoic acid ~ ethyl ester with j

Thionyl bromide) in 2 ml of absolute toluene. Thereafter, it is heated to reflux for 6 hours. After cooling the reaction mixture is mixed with aqueous ethanol and extracted several times with chloroform. The combined chloroform extracts are dried over sodium sulfate and the solvent is distilled off. The residue is purified on a silica gel column (eluent: chloroform / ethyl acetate = 19: 1), yield: 0.2 g (25% of theory)

 Calc .: Molpeak m / e = 414/416 (1CI); Found: Molpeak m / e = 414/416 (1CI)

Example 289

'A ~ [2- (5-chloro-2-octamethyleneiminobenzoylamino) ethyl / benzoic acid

acid ethyl ester ^ ____ _. '

| 8f2 g (0.02 mol) of A- / 2- (5-chloro-2-octamethyleneimino-benzoylamino) - ^! ethyl / benzoic acid nitrile (melting point, 102 ° C) are dissolved in 80 ml of ethanol and saturated with hydrogen chloride. After 24 hours, heat to 50 C for one hour and remove the solvents.

20, distilled. The evaporation residue is dissolved in ice-water / adjusted to pH 9 and shaken out with chloroform. After concentration of the organic phase, the residue is chromatographed over a silica gel! column purified by chromatography

 i yield: 6.4 g (70% of theory),

Melting point: <20 ° C.

Ber. : C 68 33 H 7 , 27 N 6 12 Cl 7 75 Gef .: 68 32 7 , 29 6 12 7 90

Claims (3)

invention claim E is a Wassersίοff- ₉ chlorine or bromine atom or a cyclic alkyleneimino with 4 to 7 · ^Λ coals " atoms in iminoring, a hydrogen, fluorine, chlorine or bromine atom, an alkyl or alkoxy group each having 1 to 6 carbon atoms, a substituted by a phenyl group alkoxy group having 1 to 3 carbon atoms, a hydroxy, nitro, amino, cyano or Carboxyl group, an alkanoylamino, alkoxycarbonyl or dialkylamidosulfony group in which the alkyl portion of each alkylene atom may contain from 1 to 3 carbon atoms ₈ ωι <3 Ros> which may be identical or different, alkyl groups having 1 to 7 carbon atoms, alkenyl groups having 3 to 7 carbon atoms, cycloalkyl groups having 3 to 7 carbon atoms, alkyl groups substituted by a phenyl group having 1 to 3 carbon atoms. Phenyl or adainantyl groups or R ₂ and R ₃ together with the intervening nitrogen atom 'are an unbranched Alkyleniminogruppe having 4 to 6 carbon atoms in the imino ring, by one or two alkyl groups each having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a hydroxy -,; Phenyl, carboxy or alkoxycarbonyl group in total | May be substituted 2 to 4 carbon atoms and / or ^a methyl group of the above-mentioned Alkylenimlnoringe by an imino group, which kylgruppe by an Al · having 1 to 3 carbon atoms, an alkoxycarbonyl group having a total of 2 to 4 carbon atoms, a "phenyl, halophenyl , Benzyl, pyridyl or furoyl group may be replaced by an oxygen or sulfur atom, by a carbonyl, sulfoxide or sulfonyl group, a saturated or partially unsaturated aza-bicycloalkyl group having 7 to 10 carbon atoms, a in 3- and 5-membered by a total of 3 or 4 alkyl groups each having 1 to 3 carbon atoms substituted piperidino group, a 1,4-dioxa-8 ~ aza-spxro ~ alkyl group having 6 to 9 carbon atoms, a Trimethylenimino-, pyrrolyl, tetrahydropyridine- , Heptamethyleneimino, octamethyleneiranolo, nonamethyleneimino, decamethyleneimino, undecamethylene ™ imino or dodecamethyleneimino group ^; R is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, X is a nitrogen atom or a CH group, Y is an oxygen atom, an imino group or a methylene group optionally substituted by one or two alkyl groups each having 1 to 3 carbon atoms, Z is a hydrogen or halogen atom, a nitro, amino, cyano, formyl, hydroxymethyl or hydroxycarbonylethylene group, an optionally esterified carboxy- » 2 2 2 5 11 group, an optionally substituted by 2 or 3 alkoxy groups, by a carboxy, "alkoxycarbonyl or Äthylendioxygruppe methyl group, wherein the alkoxy group may each contain 1 to 3 carbon atoms, optionally substituted by a carboxy or alkoxycarbonyl group having a total of 2 to 4 carbon atoms Acetyl group, an ethyl or ethyl group substituted by one or two alkoxycarbonyl groups each having in each case 2 to 4 carbon atoms or by 2 carboxy groups, one optionally represented by an alkyl group having 1 to 7 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms and / or alkenyl group having 3 to 7 carbon atoms mono- or di-substituted aminocarbonyl group, a piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl or N-alkyl-piperazinooarbonyl group, wherein the alkyl group may contain 1 to 3 carbon atoms, or also substituted by a carboxy group ethyl group, if the radicals R ₀ and R, together with the intervening nitrogen atom represent one of the initially mentioned cyclic imino radicals, as well as their physiologically acceptable salts with inorganic or organic acids and also bases, if Z represents or contains a carboxy group, characterized in that a) an aminobenzoic acid of the general formula ^COOH In the i R, Rx, R, R and X are as defined above, or optionally prepared in Reaktiorisgemisch. reactive derivative with an amine of the general formula H ₂ H -Y- in the R., Y and Z are as defined above, or with an optionally formed in the reaction mixture N ~ activated AmIn the general formula%, if a  ar , AminobenEoesäure the general formula is used and when Z in an N-activated amine of the general formula " no carboxy" or amino group is reacted or b) for the preparation of compounds of general formula I, in.der R- with the exception of the hydroxyl and amino group as defined above, X is a CH group and Y represents an optionally substituted by one or two alkyl groups each having 1 to 3 carbon atoms methylene group, a compound of the general formula NH - Y - CH in which R, R and Z are as defined above, R and Y have the meanings mentioned above and E represents a halogen atom, with an amine of the general formula H-N in which R ₀ and R, as defined above, is reacted or c) for the preparation of compounds of the general formula > I / in which Z is a carboxy group and Y is not an NH ~ group, a compound of the general formula CO - KH - Y - CH in which R, R ₁ to R ₄ and X are as defined above, Y, with the exception of the NH group as defined above and A is a group which is converted by oxidation into a carboxy group, is oxidized or d) for the preparation of compounds of the general formula I in which Z represents a carboxy group, a compound of the general formula CO-NH- in the
Rf Ri to R ₄ , X and Y are as defined above and B represents a group which can be converted into a carboxy group by hydrolysis, is hydrolyzed or e) for the preparation of compounds of general formula I in which R, an alkyl group having 1 to 7 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an alkyl group having 1 to 3 carbon atoms substituted by a phenyl group or an alkenyl group having 3 to 7 carbon atoms, R _{3 is} an alkyl group having 1 to 7 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an alkenyl group having 3 to 7 carbon atoms, a phenyl group-substituted alkyl group having 1 to 3 carbon atoms or an adamantyl group or R ~ and R_ with the intervening nitrogen atom is a 5- to 7-membered alkyleneimino ring, a piperidino group substituted by an alkyl group having 1 to 4 carbon atoms or a piperidino group substituted at 3- and 5-positions each by an alkyl group having 1 to 3 carbon atoms, and Y is an optionally. by one or two alkyl groups each with 1 to 3 carbon atoms substituted methylene group, a compound optionally formed in the reaction mixture of the general formula " 2 2 2 5 11 in the R, R ^, R, X and Z are as defined above, R ₃ ^{1 represents} a hydrogen atom or has the meanings mentioned above for R ₃ and Υ has the abovementioned meanings, with a compound of general formula in the R ₀ ^{1 has} the meanings mentioned above for R ₀ or together with the radical R ₃ ^{1 of} the formula T is a straight-chain alkylene group having 4 to 6 carbon atoms, a substituted by an alkyl group having 1 to 4 carbon atoms n-pentylene group or one in 2- and Represents 4-member each substituted by an alkyl group having 1 to 3 carbon atoms substituted n-pentylene group and G represents a nucleophilic leaving group such as a halogen atom or a sulphonyloxy group, or is reacted f) for the preparation of compounds of the general formula 1 in which Y represents the NH group or an oxygen atom, a compound of the general formula 222511 GO-NH-T-H in the R, R ₁ to R ₃ and X are as defined above and Y has the meanings mentioned above, or their alkali metal salt with a phenyl derivative of the general formula h - CH - // \ V «Z, (XI) in the R 'and Z are as defined above and L is a nucleophilic leaving group such as a halogen atom or a sulphonyloxy group is reacted g) for the preparation of compounds of general formula I, in which R. except the hydroxy, carboxy, amino or alkanoylamino group as defined above, X is a CH group and Y represents an optionally substituted by one or two alkyl groups each having 1 to 3 carbon atoms methylene group, an amide of the general formula 2n c «« in the R, R "and R" are as defined above and R _{1 has} the abovementioned meanings, or its alkali metal salt with a compound of the general formula M-Y - CH ~ {ry- in the R ₄ and Z are as defined above, Υ has the abovementioned meanings and M represents a nucleophilic leaving group such as a halogen atom or a sulphonyloxy group, is reacted or h) for the preparation of compounds of the general formula I in which R _{1 is} a hydrogen, fluorine, chlorine or bromine atom, an alkyl or alkoxy group each having 1 to 6 carbon atoms, an alkoxy group having from 3 to 3 carbon atoms substituted by a phenyl group , a hydroxy, nitro, carboxy or alkanoylamino group,
X is a CH group, 2 2 2 5 11 Methyl an optionally substituted by one or two alkyl groups each having 1 to 3 carbon atoms methylene group and Z is a carboxy group, a compound of the general formula. ^R 4 in the R and R ₂ to R _{4 are} as defined above, R. and Y have the abovementioned meanings, is acylated with an oxalyl halide or phosgene in the presence of a 'Lewis acid or X) for the preparation of compounds of the general formula I, in which R _{1 is} a hydrogen, fluorine, chlorine or bromine atom, an alkyl or alkoxy group each having 1 to 6 carbon atoms, an alkoxy group substituted by a phenyl group 1 to 3 carbon atoms, a nitro, carboxy, alkanoylamino or alkoxycarbonyl group with in each case 1 to 3 carbon atoms in the alkyl part,
X is a CH group, Y is an optionally substituted by one or two alkyl groups each having 1 to 3 carbon atoms methylene group and Z represents a carboxy group, "a compound of the general formula 2 2 2511 CO - I - Y - CH - F - COCH ^ in the R and R until R _{4 are} as defined above, R. and Y have the meanings mentioned above, is reacted with a hypohalogenite optionally prepared in the reaction mixtures and if desired, then a ^{thus-obtained:} Compound of the general formula I in which Z represents a Carboxygx'uppe, by esterification or amidation into a corresponding compound of general formula I in which Z is an esterified carboxy group or an optionally by an alkyl group having 1 to 7 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms and / or alkenyl group having 3 to 7 carbon atoms mono- or di-substituted aminocarbonyl group, a piperidinocarbonyl ", morpholinocarbonyl, Thiomorpholinocarbonyl- or N-Älkylpiperazinocarbonylgruppe is converted, and / or a compound of the general formula I in which R ₁ and / or 2 represent a nitro group is converted by reduction into a corresponding compound of the general formula I in which R. and / or Z represents an amino group, and / or 2 2 2 5 11 a compound of the general formula I in which R ₁ and / or Z is an amino group, via a corresponding diazonium salt, into a corresponding compound of the general formula I in which R _{1 is} the hydroxyl or cyano group, a fluoro, Chlorine or bromate and / or Z represents a chlorine or bromine atom or the cyano group ^; , is converted, wherein a thus optionally obtained compound of the general formula I, in which R _{1 represents} the hydroxyl group, by alkylation into a corresponding compound of the general formula I, in the R. an alkoxy group having 1 to 6 atoms carbon atoms or by represents a phenyl group substituted alkoxy group having 1 to 3 carbon atoms, can be converted, and / or · a compound of the general formula I in which R _{1 is} an amino group is converted by acylation into a corresponding compound of the general formula I I in which R _{1 is} an alkanoylamino group having 1 to 3 carbon atoms in the alkanoyl part, and / or a resulting compound of the general formula I, in which R ₁ is an alkoxycarbonyl group and / or R and R ^ represents a substituted-alkoxycarbonyl Alkylenimlnogruppe having 4 to 6 carbon atoms together with the intervening nitrogen ^atom: wherein the alkoxy groups each containing 1 to 3 carbon atoms can, by hydrolysis in a corresponding compound of general formula I, in the R _1, the carboxy group and / or R ₂ and R ~ together with the intervening nitrogen atom by a carboxy 'substituted Alkyleniminogruppe with 4 to 6 Represents carbon atoms in the imino ring, is transferred and / or a compound of the general formula I in which R "and R ₃ together with the intervening nitrogen atom represents an N-benzylpiperazino group, by debenzylation in a corresponding compound of the general formula I, in which R" and R_ together with the intervening nitrogen atom, a piperazino group represents, is transferred and / or an obtained compound of the general formula I, in which R 1 represents a chlorine or bromine atom, is converted by means of dehalogenation into a corresponding compound of the general formula I, in which R 1 represents a hydrogen atom, and / or a carboxylic acid amide of general formula I in which Z represents an optionally esterified carboxy group, by means of reduction with a metal hydride into a corresponding compound of general formula I in which Z represents the hydroxymethyl group, is carried over and / or 2 2 2511 - an obtained compound of general formula I, in the Z represents the hydroxymethyl group, with the help of Oxi ~ j dation into a corresponding connection of the general nen formula I, in which Z represents the formyl group, j is transferred and / or j a resulting compound of general formula ^I; in which Z represents the hydroxymethyl group, is converted by means of halogenation and subsequent reaction with a malonic acid ester in a corresponding compound of general formula I in which Z is an ethyl group substituted by two alkoxycarbonyl groups, is transferred and / or a compound of the general formula I in which Z represents the formyl group is converted by acetalization into a corresponding compound of the general formula I in which Z represents a dia-decoxymethyl group, and / or a compound of the general formula I in which Z represents the formyl group is converted by condensation and optionally subsequent hydrolysis into a corresponding compound of the general formula I in which Z represents an ethylenyl group substituted by a hydroxycarbonyl or alkoxycarbonyl group and / or or a compound of the general formula I in which Z represents a hydrogen atom is converted by means of Friedel-Crafts acylation into a corresponding compound of the general formula I in which Z represents an acetyl group optionally substituted by an alkoxycarbonyl group and / or 05/04/1981 AP C 07 D / 222 57 672/12 an obtained compound of the general formula I, in which 3L and / or Z represents a nitrile group, by alcoholysis via a corresponding iminoester into a corresponding compound of the general formula I in which III and / or Z represents a trialkoxy group ^ converted vsird and / or ·. a compound of the general formula I in which L and / or Z represents a trialkoxymethyl group is converted by hydrolysis into a corresponding compound of the general formula I in which H and / or Z is an alkoxycarbonyl group; /or a compound of the general formula I in which Z represents the acetyl group is converted by heating with an amine and sulfur and then in the presence of an inorganic base into a corresponding compound of the general formula I in which Z represents the hydroxycarbonyl-methyl group and or a resulting compound of the general formula I wherein Z represents the carboxy group by means of conversion into a · Sulfonsäurehydrazid and subsequent disproportionation into a corresponding compound of the general formula I in which Z represents the formyl group überge _$ ^ leads wiird and / or. an obtained compound of the general formula I in which IL is a hydrogen, fluorine, chlorine or bromine atom, an "alkyl" or alkoxy group each having 1 to 6 carbon atoms or a substituent substituted by a phenyl group-- 2 2 2 5 1 1 ~ ao $ - '' 4 * 5.1.981 AP C 07 D / 222 57 672/12 te alkoxy group having 1 to 3 carbon atoms, X is a CH-§ruppe, Y _s represent an optionally substituted by one or two alkyl groups mit.jeweils 1 to 3 carbon atoms, methyl group and Z represents a chlorine or bromine atom on its corresponding organometallic ^ connection by means of carbon dioxide in a corresponding compound of the general formula X, in which Z represents the carboxy group, is converted and / or a compound of general formula I obtained in its physiologically acceptable salts with inorganic or organic acids and also bases, ταβϊΐη Ζ contains a carboxyl group, is transferred « 2 «Method according to item 1, characterized in that the reaction is carried out in a solvent» 3 "process according to item 1a and 2, characterized in that the reaction is carried out in the presence of an acid-activating agent or of a water-withdrawing agent, if appropriate in the presence of an inorganic or tertiary organic base, The process according to items 1a and 2, characterized in that the reaction is carried out in the presence of an amine-activating agent, if appropriate in the presence of an inorganic or tertiary organic base. 5 "Process according to item 1a and 2, characterized in that the water formed during the reaction is removed by azeotropic distillation or by adding a drying agent." 05/04/1981    - AP C 07 D / 222 37 672/12 6 _e method according to item 1a and 2 to 5 »characterized in that the reaction at ^ eraperaturan between -25 and 250 ⁰ C, but preferably at temperatures between -10 ⁰ C and ^ Qr boiling temperature of the solvent used, carried out«, 7e method according to point 1b and 2 _f characterized by _? that the reaction in the presence of an excess of the amine used of the general formula V durchge--. leads _θ 8 © Method according to items 1b, 2 and 7, characterized in that the reaction is carried out in the presence of an inorganic or tertiary organic base, in the presence of a reaction accelerator such as copper and / or in a pressure vessel « 9c method of item 1b, 7 UNAE 8, characterized in that the _s Umsetzung- is performed at temperatures between 20 and 150 ⁰ C, but preferably at the boiling temperature of the reaction mixture jz _e B _e at 100 ⁰ C, performed ©. 10 _e method according to item 1c and 2 _S characterized in that • the reaction at temperatures between 0 and 100 ⁰ C, but preferably at temperatures between 20 and 50 ⁰ C, is performed « 11 * Process according to item 1d and 2, characterized in that the hydrolysis is carried out in the presence of an acid or base © 2 2 2511 " _m 4.5.1981   , AP C 07 D / 222 511 57 672/12 12 »Process according to item 1d, 2 and 11, characterized in that the reaction is carried out at the boiling point of the reaction mixture - 13e method according to item 1e and 2, characterized in that the reaction is carried out in the presence of an inorganic or tertiary organic base * 14, process according to item 1e and 2, characterized in that 'the methylation is carried out with formaldehyde in the presence of a reducing agent', 15 «method according to item 1e, 2, 13 and 14, characterized in that the reaction at temperatures between 0 and 150 ⁰ C, but preferably carried out at temperatures between 20 and 75 ° C $» 16 _e method according to item 1f and 2, characterized in that the reaction is carried out in the presence of a base » 17 # Verfahren'nach item 1f, 2 and 1b, characterized in that the reaction at temperatures between 0 and 150 ⁰ C, but preferably at temperatures between 50 and 100 ⁰ C, carried out _{ö ö ö} 18 _e method according to item 1g and 2, characterized in that the. Reaction carried out in the presence of a base such as sodium hydride or potassium tert- _e . 05/04/1981 AP C 07 D / 222 672 57 672/12 19 «A method according to item 1 g, 2 and 18, characterized in that the reaction is performed at temperatures between 20 and 180 · ⁰ Cj but preferably carried out at temperatures between 50 and 150 ⁰ C." 20 _e method according to item 1h and 2, characterized in that is used as levas acid aluminum chloride * · β method according to item 1h _s 2 and 20 _f characterized in that the reaction at temperatures between 0 and 80 ⁰ G, but preferably carried out at temperatures between 20 and 60 ⁰ C ^ viirdo 22 _e method according to item 1i and 2 _$ characterized in that the reaction at temperatures between 0 and 80 ⁰ C, but preferably at temperatures between and • 50 ⁰ Cj performed,