CA1123433A - Acylhydrocarbylaminoalkanoic acids, their production and use as well as pharmaceutical products containing same - Google Patents

Abstract

Abstract Compounds of the formula ;

wherein R1 is aliphatic or alicyclic hydrocarbyl or optionally substituted phenyl; R2 is hydrogen or aliphatic hydrocarbyl;
R3 is hydrogen,alkyl, cycloalkyl, optionally substituted phenyl or, with R4, alkylene; R4 is alkyl, cycloalkyl, optionally sub-stituted phenyl, optionally substituted phenalkyl or, with R3, alkylene; or R2, R3 and R4, together with the carbon to which each is bond, are adamantyl; and n is 3, 4 or 5; and salts there-of with a base are pharmacologically active. Physiologically-acceptable embodiments are administered, e.g.. in the form of an appropriate pharmaceutical composition to warm-blooded animals for protection against and treatment for stomach, intestine, pan-creas, bile and liver disorders. Syntheses of pharmacologically-active components, compounding such principles into pharmaceu-tical compositions and using such principles for preventing and treating the noted disorders are described.

Description

:llZ3433 The Invention relates to acylhydrocarbylaminoalkanoic acids, their production and use as well as pharmaceutical products containing them.
Benzyl N-lower-alkyl-~-aminobu~yrates or lower alkyl N-phenyl-~-aminobutyrates are used for the treatment of ~astric ulcers (JA-PS 38(63)-15368 or JA-PS 38(63)-7324). N-t2-alkoxybenzoyl)-amino acids are said to possess an antipyretic and analgesic action (DT-OS 24 07 016). Trialkoxybenzoyl-aminoalkanoic acids possess:great importance in the treatment of cardiopathies, for example cardiact infarct, cardiac ischaemia or cardiac arrhythmia (DT-OS 2 034 192, 20 50 949, 21 31 626, 21 31 674, 21 31 675, 21 31 679 and 21 31 680). N-propionyl - ~ -amino-caproic acid is used as an active principle for cosmetic pre-parations for the treatment of anomalies in the grain of the skin which are connected with disorders in the formation of the connected tissue (DT-AS 1 922 193). N-(benzoyl or alkanovl)-N-alkyl-~ -aminobutyric acid is claimed (USP 4,016,287) to be useful`for inhibiting sebaceous gland excretion and combatting skin inflammation. 4-[methyl-benzoyl-amino]-butyric acid and 6-[methyl-benzoyl-amino]-hexanoic acid-(1)-are described in Beilstein's Handbuch der organischen Chemie (EIII9, 1150 and 1158). A description of the production of 5-(N-methyl-acetami-do)-~aleric acid is to be found in J.Chem.Soc.(London) C 1969, 1863. N-benzoyl-N-phenyl--amino acids are said to possess an effect of inhibiting inflammation and analgesic effects (DT-OS
17 68 173), whereas during the investigation of N-benzoyl-ani- -lino-alkanecarboxylic acids (D. Evans e-t al., J.Med.Chem. 12 (t969)1006-10) the corresponding butyric acids did not show . ~ . . ~

- . , , , ~ ~ , . . ..

- ,~, ,' , ,; ' ' , - . , . .- ~.
~ . ~ . . . .

1:3L'~3~3 any effect in inhibiting inflammation. In DT-OS 19 17 036 acylated anilinocarboxylic acids are claimedwith a choleretic effect, to which further effects are also attributed ~DT-OS
24 5~ 680). ~-phenyl-benzylidene-~-aminoalkane-carboxylic acids and their derivatives are said to be used in agents which have an anti-epileptic effect (DT-OS 2 634 288). A new class of acylhydrocarbylaminoalkcmoic acids has now been synthesised which is not mentioned in the aforesaid publications nor has it been rendered obvious thereby. It has also been found that these acylhydrocarbylaminoalkanoic acids possess interesting and particularly advantageous pharmacological properties.
The Invention relates to acylhydrocarbylaminoalkanoic acids of the general formula I

I n 2n COOH (I)

2,1C 4 R

in which R1 signifies an aliphatic or alicyclic hydrocarbon radical or an optionally substituted phenyl:group, R2 is a hydrogen atom, an alkyl group, an alkenyl.group or an alkinyl.group, R is a hydrogen atom, an alkyl:group, a cycloalkyl.group or an optionally substituted phenyl radical, R4 is an alkyl.group, a cycloalkyl group, an optionally substituted phenyl group or an optionally substituted ;, -'' :

`` ~IL~Z3~L33 phenylalkyl group (with the proviso that R4 has at least

3 carbon atoms when R4 is alkyl, R2 is hydrogen or methyl, R3 is hydrogen, and R1 is alkyl or optionally substituted phenyl) or R3 and R4 together constitute an alkylene group or R2, R3 and R4 by including the neighbouring carbon atom form an adamantyl radical, n signifies 3, 4 or 5, and also theis salts of inorganic or organic bases.

The aliphatic hydrocarbon radicals can be straight or branched alkyl radicals with 1 to 7 carbon atoms. Straight alkyl radicals are the methyl, ethyl, propyl, butyl, pentyl, hexyl or heptyl radicals, of which those with 1 to 5, especially those with 1 or 2, carbon atoms are preferred. Branched alkyl radicals with 3 to 7 carbon atoms are, for example, the isopropyl, isobutyl, sec.-butyl or tert.butyl radical, of which those with 3 to 5, especially with 4, carbon atoms are preferred. Alkenyl and alkinyl radicals with 2 to 7 carbon atoms are, for example, the ethenyl, ethinyl, the 1-propenyl, 1,3-butadienyl, 2-butinyl radical. As alicyclic hydrocarbons one can use those with 3 to 10 carbon atoms, for example the cyclopropyl, cyclobutyl, cyclo-pentyl, cyclohexyl, cycloheptyl or cyclooctyl radical, of which those with 5 to 8 carbon atoms are preferred.

As optionally substituted phenyl groupSone may use those of the formula , . . . . . ... . : : . ~ . -,, - ; ., ." -, . . : , , : : .

~39L33 ~R6 in which R5, R6 and R are the same or different and signify a hydrogen atom, a halogen atom, an alkyl.group, a hydroxy :group, an alkoxy:group, an alkylmercapto:group, an acyloxy :group, an optionally substituted amino:group, a hydroxy:group, a nitro:group, atri~Luor~methyl group, a trifluoromethoxy group or a trlfluoromethylmercapto group As halogen atoms R5, R6 and R7 one can consider fluorine, chlorine or bromine, fluorine and chlorine being preferred, especially chlorine. As alkyl .groups or alkoxy groups or alkylmercapto:groups R , R and R
one should mention inter alia those with 1 to 4 carbon atoms, of which those with 1 to 3 carbon atoms, especially those with 1 carbon atom, are preferred. As acyloxy.groups one may consider inter alia -O-CO-R1.groups, in which R1 has the meaning.given above, of which the alkanoyloxy.groups with 1 to 7, especially with 2 to 5, carbon atoms, particularly the acetyl group, are preferred. Besides the unsubstituted amino.group one can have as substituents R5, R6 and R7 substituted amino groups, of which one may mention by way of example alkyl and dialkylamino.groups with 1 to 4, preferable 1.or 2 carbon atoms in the alkyl radical, as well as acylamino:groups with the usual acyl groups employed as protection of amino.group, such as alkanoyl.groups with 2 to 5 carbon atoms.

9L3 Z3~33 ~ 6 -,, .. ,~ . ~
If R3 and R together signify an alkylene group, they will be those with 2 to 8, preferably with 4 to 7, carbon atoms. If R2, R3 and R4 with the inclusion of the neighbouring carbon atom signify an adamantyl.group, then the term will signify the adamantyl-(1) radical.

The phenalkyl groups concerned are those with unsubstituted or substituted phenyl.groups and alkyl.groups which contain 1 to 4 carbon atoms, of which those with unsubstituted phenyl..groups and 1 to 4 carbon atoms in the alkyl radical, particularly with 1 carbon atom in the alkyl radicali are preferred. For example one may mention the benzyl, phenethyl and phenylpropyl groups, of which the benzyl group is preferred. Among the optionally substituted phenalkyl groups, those are preferred which are mono-substituted or di-substituted in the phenyl radical. One may mention by way of example the p-chlorobenzyl, the m-chloro-benzyl, the p-bromobenzyl, the o-fluorobenzyl, the p-fluoro-benzyl, the p-methylbenzyl, the p-methoxybenzyl group, the 3,4-dimethoxybenzyl group.

As salts one may consider salts of inorganic and organic bases.
Pharmacologically incompatible salts are converted by known methods into pharmacologically, that is to say biolDgically, tolerated salts which are preferred among the salts according to the Invention. As cations for the salt formation one may use alkali metals, alkaline earth metals or earth metals, but it is also possible to use the corresponding cations of organic ' ,.,' ' :, ' ' : ",'' .' ~ .' ' , -, . . ~ ~ , ; .

.. . , .; . ., . , : . : . ~, ~

~.23~L33 nitrogen bases such as amines, aminoalkanols, amino sugars or basic amino acids.

For example one may mention the salts of lithium, sodium, pot-assium, magnesium, calcium, aluminium, ethylenediamine, di-methylamine, diethylamine, morpholine, piperidine, piperazine, N-lower-alkyl-piperazine (e.g. N-methylpiperazine), methyl-cyclohexylamine, benzylamine, ethanolamine, diethanolamine, triethanolamine, tris-(hydroxymethyl)-aminomethane, 2-amino-2-methyl-propanol, 2-amino-2-methyl-1,3-propandiol, glucamine, N-methyl-glucamine, glucosamine, N-methylglucosamine, lysine, onithine, arginine, quinoline.
One form of embodiment of the Invention consists of acylhydro-carbylaminoalkanoic acids of the general formula I*

n* 2n* OH

2~ 4* (I*) R3*

in which R signifies an aliphatic hydrocarbon radical with 1 to S

carbon atoms, an alicyclic hydrocarbon radical with 5 . . . ..
to 7 carbon atoms or a phenyl radical RS*

~R6 ~ 7*
R2* signifies a hydrogen atom, an alkyl group with 1 to 5 carbon atoms, an alkenyl or an alkinyl radical with 2 . : . .
:. : :. :: ~ :
, . : - ::, , :: :. ~ :
,, ,.,,: . .. . ~, .,, . :
- . : -~ - ,. : : :

. . . :: :, : ::

~L~3~3~

to 5 carbon atoms, R3 signifies a hydrogen atom or an alkyl:group with 1 to 5 carbon atoms,

4*
R signifies an alkyl:group with 1 to 5 carbon atoms (with the proviso that R4 has at least 3 carbon atoms when R4 is alkyl, R2 is hydrogen or methyl, R3 is hydrogen, and R~ is allkyl or optionally sub-stituted phenyl), n* signifies 3, 4 or 5, R5 , R6 and R7 are the same or different and signify a hydrogen atom, a halogen atom, an alkyl:group with 1 to 4 carbon atoms, an alkoxy.group with 1 to 4 carbon atoms, an alkanoyloxy:group with 2 to 5 carbon atoms, an amino .group, a nitro:group, a trifluoromethyl:group or a hydroxy.group, and their salts of inorganic or organic bases.
Preferred representatives of the form of embodiment I* are those in which R1 signifies an aliphatic hydrocarbon radical with 1 to 5 carbon atoms or a phenyl radical substituted with R5 , R6 , or R7 , R2 signifies a hydrogen atom, an alkyl.group with 1 to 4 carbon atoms or an ethinyl group, R3 signifies a hydrogen atom or an alkyl:group with 1 to 3 carbon atoms, R4 signifies an alkyl group with 1 to 5 carbon atoms (with the proviso that R4 has at least 3 carbon atoms when R4 is alkyl, R2 is hydrogen or methyl, R3 is hydrogen, and R1 is alkyl or optionally sub-stituted phenyl~, R5 signifies a hydrogen atom and n signifies 3, 4 or 5, R6 and R7 are the same or different and signify a :~Z3433 hydrogen atom, a halogen atom, a methyl group, a methoxy group, an amino.group or a trifluoromethyl:group, and their salts of inorganic or organic bases.

Particularly preferred representatives of the form of embodiment I* are those in which Rl signifies an aliphatic hydrocarbon radical with 1 to 5 carbon atoms or a phenyl radical substituted with R5 , R6 or R7 , R2 signifies a hydrogen atom, a methyl group or an ethinyl:group, R3 signifies a hydrogen atom or a ~ethyl group, R4 signifies an alkyl.group with 1 to 5 carbon atoms (with the proviso that R4 has at least 3 carbon atoms when R4 is alkyl, R2 is hydrogen or methyl, R3 is hydrogen, and R1 is alkyl or optionally substituted phenyl), R5 signi-fies a hydrogen atom, R6 signifies a hydrogen atom, a chlorine atom, a methoxy:group or a trifluoromethyl:group, R7 signifies a hydrogen atom, a chlorine atom or a methoxy group, n* signifies 4 or 5, preferably 3, and their salts of lnorganic or organic bases.

Another form of embodiment of the Invention is to be found in . ~ .. , .. ..... . .... . .......... - . , acylhydrocarbylaminoalkanoic acids of the generel formula I**
.. . . . .
1 * *

(I**) R3**

~, .
..
- : . : ,.
- . ~ ,: : ,: ; .
. , - :, , . . :.

. ~ ~

3~3~
-- ~o --in which 1 * *
R signifies an aliphatic hydrocarbon radical with 1 to 5 carbon atoms, an alicyclic hydrocarbon radical with 5 to 7 carbon atoms or a phenyl radical R5**

~ 7**

R2 signifies a hydrogen atom, an alkyl:group with 1 to 5 carbon atoms, an alkenyl or an alkinyl radical with 2 to 5 carbon atoms, R3 signifies a hydrDgen atom, an alkyl.group with 1 to 5 carbon atoms or a cycloalkyl group with 5 to 7 carbon atoms, 4**
R signifies a cycloalkyl.group with 5 to 7 carbon atoms or 3** 4**
R and R together form an alkylene group ~(CH2)q** or 2** 3** 4**
R , R and R with the inclusion of the neighbouring carbon atom signify an adamantyl radical, n** signifies 3, 4 or 5, q** signifies 4, 5, 6 or 7, R5 , R6 and R7 are the same or different and signify a hydrogen atom, a halogen atom, an alkyl.group with 1 to 4 carbon atoms, an alkoxy group with 1 to 4 carbon atoms, ... .
- - an alkanoyloxy.group with 2 to 5 carbon atoms, an amino .group, a nitro:group, a trifluoromethyl group or a hydroxy :group, and their salts of inorganic or organic bases.

, : : , ~ .-,., . ;... . , . , ~

9L3~

Preferred representatives of the form of embodiment I** are those in which R1 signifies an aliphatic hydrocarbon radical with 1 to 5 carbon atoms or a phe~nyl radical substituted with Rs** R6** or R7* , R2 signifies a hydrogen atom, an alkyl .group with 1 to 4 carbon atoms or an ethinyl.group, R3 signifies a hydrogen atom, a methyl:group or a cyclohexyl group, R4 signifies a cyclohexyl group or R and R together form an alkylene:group ~(CH2)q** or else R2 , R3 and R4 with the inclusion of the nelghbouring carbon atom form an adamantyl-(1) radical, n** signifies 3, 4 or 5, q** signifies 4, 5, 6 or 7, R5 signifies a hydrogen atom, R and R are the same or different and signlfY a hydrogen atom, a halogen atom, a methyl :group, a methoxy group, an amino group or a triluoromethyl:group~
and their salts of inorganic and organic bases.
Particularly preferred representatives of the form of embodiment I** are those in which R signifies an aliphatic hydrocarbon radical with 1 to 5 carbon atoms or a phenyl radical substitu-ted with R5 , R6 or R , R signifies a hydrogen atom, 3** 4**a methyl.group or ethinyl:group, R and R together form an alkylene group ~(CH2)q** or else R2 , R3 and R4** with the inclusion of the neighbouring carbon atom constitute an . . .
adamantyl-(1) radical~ n** signifies 4 or 5, preferably 3, q** signifies 5 or 7, R signifies a hydrogen atom, R6 signifies a hydrogen atom, a chlorine atom, a methoxy group or a trifluoromethyl group, R signifies a hydrogen atom, a chlorine atom or a methoxy.group, and their salts of in-organic or orga:nic bases.

. -~2-A further form of embodiment of the Invention consists of acyl-hydrocarbylaminoalkanoic acids of the:general formula I***
1 ***
R -co-l-cn***H2n***-cOOH

R2***1 R4*** (I***), R3***

in which 1 ***
R signifies an aliphatic hydrocarbon radical with 1 to

5 carbon atoms, an alicyclic hydrocarbon radical with 5***
5 to 7 carbon atoms or a phenyl radical R

6*** ,~

R7***
2***
R signifies a hydrogen atom or an alkyl group with 1 to 5 carbon atoms ,:
3***
R signifies a hydrogen atom, an alkyl:group with 1 to 5 carbon atoms or a phenyl radical 5***

\~ R6*** ~ .
R7*** ~ :
.. : R4****
signifies a phenyl radical R5***

R7***

:, : ,, , ~

:: :. . . ;

or a phenàlkyl radical Rs***
--(CH2) p***~ R6***

R7***

n*** signi~ies 3, 4 or 5, p*** signifies 1, 2, 3 or 4, 5*** 6*** 7***
R , R and R are the same or different and signify a hydrogen atom, a halogen atom, an alkyl.group with 1 to 4 carbon atoms, an alkoxy group with 1 to 4 carbon atoms, an alkanoyloxy.group with 2 to 5 carbon atoms, an amino group, a nitro.group, a trifluoromethyl group `:
or a hydroxy.group, and their salts of inorganic or organic bases.
Preferred representatives o~ the form of embodiment I*** are those in which R1 signifies an aliphatic hydrocarbon radical with 1 to 5 carbon atoms, or a phenyl radical substituted with ;*** 6*** 7*** 2***
R , R or R , R signifies a hydrogen atom or an ~***
alkyl.group with 1 to 4 carbon atoms, R~ signifies a hydrogen.

atom, an alkyl group with 1 to 3 carbon atoms or a phenyl radical ~

7*** 4*** ::
substituted with R , R signifies a phenyl radical sub-stituted with R7 or a ben~yl radical substituted with R7 R5 signifies a hydrogen atom and n.*** signifies 3, 4 6*** 7***
or 5, R and R are the same or different and signify a hydrogen atom, a halogen atom, a methyl:group, a methoxy group, an amino group or a trifluoromethyl group, and their salts of inorganic or organic bases.

'~

:1~23~33 Particularly preferred representatives of the form of embodi-1 ***
ment I*** are those in which R . signifies an aliphatic hydro-carbon radical with 1 to 5 carbon atoms or a phenyl radical substituted with R ~ R6 or R7 r R2 signifies a 3***
hydrogen atom, R signifies a hydrogen atom, a methyl:group, 7*** 4***
or a phenyl radical substituted ~:ith R , R signifies a phenyl radical substituted with R7 or a benzyl radical sub-stituted with R7 ~ R5 signifies a hydrogen atom, R6 signifies a hydrogen atom, a chlorine atom, a methoxy group or a trifluoromethvlgroup, R7 signifies a hydrogen atom, a chlorine atom or a methoxy:group, n*** signifies 4 or 5, preferably 3, and their salts or inorganic or organic bases.
An alternative form of embodiment of the Invention consists of acylhydrocarbylaminoalkanoic acids of the general formula I****

R1****-CO-N-cn****H2n****-cOoH
C-_____ (I****) 2**** 4****

R3**** ..

in which 1 ****
R signifies an aliphatic hydrocarbon radical with 1 to 5 . .
carbon atoms, an alicyclic hydrocarbon radical with 5 to 7 carbon atoms or a phenyl radic~l \ 5****

6****
~X 7****

, . . . .
.. . . ~ ., :
. 1 . ' ' ~ . . . :

.: : , .

~23~33 ~ 15 -2***~
R signifies an alkenyl or an alkinyl radical with 2 to 5 carbon atoms, 3****
R signifies a hydrogen atom or an alkyl group with 1 to 5 carbon atoms, 4****
R signifies a phenyl radicaL Rs****

6****

~7****

or a phenalkyl radical RS
--~C1l2)P~ *~R}7 n**** signifies 3, 4 or 5, p**** signifies 1, 2, 3 or 4, 5**** 6**** 7****
R , R and R are the same or different and signify a hydrogen atom, a halogen atom, an alkyl group with 1 to 4 carbon atoms, an alkoxy.group with 1 to 4 carbon atoms, an alkanoyloxy.group with 2 to 5 carbon atoms, an amino:group, a nitro.group, a trifluoromethyl:group or a hydroxy.group, :
and their salts of inorganic or organic bases.
Preferred representatives of the form of embodiment I**** are those in which R1 signifies an aliphatic hydrocarbon radical with 1 to 5 carbon atoms or a phenyl radical substituted with 5**** 6**** 7**** 2****
R , R or R , R signifies an ethinyl.group, ¦:
3****
R signifies a hydrogen atom or an alkyl group with 1 to 3 1:
4****
carbon atoms, R signifieS a phenyl radical substituted : . , -. :, ~ . :
~, ' ' !~ ' ~ .
: ~ .~ . ,: :. :, . -:
.. . .
.-` ~ : . ' : '.

, '~: ' ' ~Z~

with R7 or a benzyl radical substituted with R7 5****
R signifies a hydrogen atom and n**** signifies 3, 4 or 5, R6 and R7 can be the same or different and signify a hydrogen atom, a halogen atom, a methyl group, a methoxy group, an amino group or a trifluoromethyl group, and their salts of inorganic or organic bases.
Particularly preferred representatives of the form of embodi-ment I**** are those in which R signifies an aliphatic hydrocarbon radical with 1 to 5 carbon atoms or a phenyl radical substituted with R , R or R7 , R signifies an ethinyl group, R3 signifies a hydrogen atom or a methyl 4****
group, R signifies a phenyl radical substituted with R7 or a benzyl radical substituted with R7 l R5 signifies a hydrogen atom, R6 signifies a hydrogen atom, a chlorine atom, a methoxy group or a trifluoromethyl group, R7**** signifies a hydrogen atom, a chlorine atom or a methoxy group, n**** signifies 4 or 5, preferably 3, and their salts of inorganic or organic bases.
The embodiment I*** is preferred to the other embodiments. The embodiments I* and I** are preferred to the embodiment I****.

As compounds comprised by the general formula I one may mention by way of example N-(2,6-dimethylbenzoyl)-4-~t3-ethyl-1-pentin-3-yl)-amino]-butyric acid, ~-(3,4-dichlorobenzoyl)-5-~(1-ethinyl-cyclohexyl-1)-amino]-valeric acid, N-(3-chlGro-4-fluorobenzoyl)-4-~(1-n-butyl-cyclopentyl-1)-amino]-butysic acid . ~.

~, :~LZ3~3~

N-isobutyryl-4-(tert.-butylamino)-butyric acid N-propionyl-6- E 2-(3,4-dimethoxyphenylethyl)-amino]-caproic acid, N-n-hexanoyl-4-[adamantyl ~ amino~-butyric acid, N-n-heptanoyl-5-(n-butylamino)-butyric acid, N-crotonoyl-4-r(1-propyl-cyclohexyl-1)-amino]-butyric acid, N-(3-nitrobenzoyl)-4-~(4-chlorobenzyl)-amino]-butyric acid, N-(2-acetoxybenzoyl)-4-[(1.1.3.3-tetramethylbutyl)-amino]-butyric acid, N-(2-bromobenzoyl)-4-~(3-ethyl-1-pentin-3-yl)-amino~-valeric acid, N-(3-chlorobenzoyl)-4-~(1-ethinyl-cyclohexyl-1)-amino~-butyric acid, N-(cyclohexylcarbonyl)-4-~(1-n-butyl-cyclopentyl-1)-amino~-caproic acid, N-(2-chlorobenzyl)-4-~(1-propyl-cyclohexyl-1)-amino]-butyric acid, N-(2-fluorobenzoyl)-4-[(~-methylbenzyl)-amino]-butyric acid, N-(3-nitrobenzoyl)-4-r(1,2-diphenylethyl3-amino]-butyric acid, N-(4-nitrobenzoyl)-5-r(3,4-dimethoxybenzyl)-amino]-butyric acid, N-(3-trifluoromethylbenzoyl)-6-[(~-methylbenzyl)-amino]-caproic acid, N-(3-toluoyl)-4-rbenzhydrylamino]-butyric acid, N-isovaleroyl-5-~(~-methylbenzyl)-amino~-valeric acid.

, ~2~3 Preferred compounds according to the Invention are N-p-chloro-benzoyl-4-(1-phenylethyl-amino)-butyric acid, N-acetyl-4-benzhydrylamino-butyric acid, N-p-chlorobenzoyl-4-benzhydrylamino-butyric acid, N-p-chloroben~oyi-4-benzylamino-butyric acid and their salts.

The acylhydrocàrbylaminoalkanoic acids of the general formula I
or of the modifications I*, I**, I*** and I**** posses on the carbon atom to which the R2, R3 and R4 (or the corresponding substituents of the modifications) are attached, a chirality center, if R2, R3 and R4 (or the corresponding substituents of the modifications) are different from one another. The Invention therefore relates both to the racemates and also to the enantiomers and their mixtures.
The compounds according to the invention posses valuable pharma-cological properties which render them commercially useful. In warmblooded animals they develop a stomach and liver protectiv action; in addition they bring about an increase in pancreas and liver (bile) secretion.

secause of their advantageous pharmacological activity the acyl-hydrocarbylaminoalkanoic acids of the general formula I are suitable for the treatment talleviating and reducing symptoms) and prophylaxis of diseases (which are attributable to stomach or intestine disorders or to reduced performance of the pancreas, the gall bladder and/or the liver), e.g. for treating gastric or intestinal ulcers, Billroth II, pancreatic insufficiency, . .

. ~ ~ : . .

~L~Z3~

sprue, indigestion and malabsorption of different aetiology, acute and chronic pancreatitis, indirect disturbances of the pancreatic function (suporting.the secretin and pancreozymine production), as well as gall bladder and:gall duct inflammation, disturbances in the flow of bile, motility disturbances of the :gall ducts, a feeling of repletion, flatulence, constipation, upper abdominal complaint, hepatobiliary functional disorders, acute and chronic hepatitis, liver intoxication and fatty liver.

A further object of the Invention consists of pharmaceutical products which contain as active ingredient one or more of the acylhydrocarbylaminoalkanoic acids of the.general formula I

R -CO-I-CnH2n-COOH
R2~ f ~R4 (I) in which R1 signifies an aliphatic or alicyclic hydrocarbon radical - - or an optionally substituted phenyl:group, R signifies a hydrogen atom, an alkyl group, an alkenyl .group or an alkinyl group, :
R3 signifies a hydrogen atom, an alkyl group, a cycloalkyl .group or an optionally substituted phenyl radical, R4 signifies an alkyl group, a cycloalkyl group, an optionally substituted phenyl group or an optionally substituted - phenylalkyl.group (with the proviso that R4 has at least , ..... . .
.~ : . - .: .: :
: . -, ~
. , . - -;. ~. : ..

. ~: " , : ..

3~33 3 carbon atoms when R is alkyl, R is hydrogen or methyl, R3 is hydrogen, and R1 is alkyl or optionally substi-tuted phenyl) or R3 and R4 together signify an alkylene group or R2, R3 and R4 with the inclusion of the neighbouring carbon ; ~ - atom signify an adamantyl radical, n signifies 3, 4 or 5, and/or their pharmacologically compatible salts of organic or inorganic bases.

Modifications of the pharmaceutical products are those which contain acylhydrocarbylaminoalkanoic acids of the formulae` I*, I**, I**, I**** or their preferred representatives and/or their pharmacologically compatible salts of inorganic or organic bases.
The pharmaceutical products are produced according to known processes. As pharmaceutical products the new compounds can be used as such or if desired in combination with suitable pharma-ceutical support substances. If the new pharmaceutical prepa-rations in addition to the active principles contain pharma-ceutical support substances, the active principle content of these mixtures is 1 to 95, preferably 15 to 85 per cent by weight of the total mixture.
In accordance with the Invention it is possible in the field of human and veterinary medicine to use the active principles in any desired form, for example systemic, provided that the formation or maintenance of adequate blood or tissue levels , .

.
, .. .

- ,.

. ' : .:: ` ~ ; ~:

or local concentrations of active principle is ensured. This can either be carried out by oral, rectal or parenteral ad-minitration in suitable doses. More advantageously the pharma-ceutical preparation of the active principle occurs in the form of unit doses which are designed for the particular form of administration desired. A unit dose can be, for example, a tablet, a pill, a capsule, a suppository, or a measured volume of a powder, a granulate, a solution, an emulsion, a suspension, a sol or a gel.
"Unit dose" in the sense of the present Invention is to be under-stood to mean a physically determined unit which contains an individual quantity of the active component in combination with a pharmaceutical carrier, the active principle content of which corresponds to a fraction or multiple of the therapeutical in-dividual dose. An individual dose preferably contains the quantity of active principle which is dispensed in a single application and which corresponds usually to a whole, a half or a third or a quarter of the daily dose. If for an individual therapeutical administration only a fraction, such as a half or a quarter of the unit dose is required, the unit dose is advantageously divisible, for example in the form of a tablet with a notch for breaking.
The pharmaceutical preparations according to the Invention, if they occur in unit doses and are intended for application, for example, to human beings, containl ~0.5 to 1000 mg, advan-tageously 1 to 500 mg and especially S to 400 mg of active principle.

- '~ :;, ' . .

:-~: :.. : . .:
, . : : .. . .
- :: . ~. . ~ :
':- ' .. ,' ' . ''' ',','. ~ ''~'.. '' ,'`' ''." '':;
,~ . . - ~

~Z3~33 Generally speaking, it has been found advantageously both in human medicine and in veterinary medicine, to administer the active principle or principles in oral administration in a daily dose of l0.01 to~ '40, preferably 0.1 to 30, especially 0.2 to 20 mg/kg body weight, possibly in the form of several, preferably 2 to 3 individual administrations, in order to achieve the desired results. An individual administration contains the active principle or principles in quantities of l0,01 to~ ~20, preferably 0.1 to 15, especially 0.2 to 10 mg/kg body weight.
In a parenteral treatment, for example intramuscular, intra-venous application, it is possible to use similar dosages.
With this therapy one applies ~--- 50 to 1000 mg of active principle.
The therapeutical administration of the pharmaceutical prepa-ration is carried out in the case of long-term medication generally at fixed points of time, such as 1 to 4 times a day, for example after all meals and/or in the evening. In the case of acute attacks the medication is carried out at varying points of time. Under certain circumstances it may be necessary to -differ from the said dos~ges, namely according to the nature, the body weight and the age of the patient to be treated, the nature and severity of the disease, the nature of the prepara-tion and the application of drug as well as the period of time or interval within which the administration takes place. Thus in some cases it may be sufficient to manage with less than the abovementioned quantity of active principle, whereas in ,-, . : ., . . :

, ~ ~ ',' ' .,. ~ . .: :~

:1~23~3;~

other cases the quantity of active principle mentioned above must be exceeded. The determination of the optimum dosage and type of application of the active principles necessary in each case can at any time be carried out by the expert on the basis of his technical knowledge.

T~ pharmaceutical preparations consist as a rule of the active principles according to the Invention and non-toxic pharmaceuti-cally compatible drug excipients which are used as an admixture or diluent in the solid, semi-solid or liquid form or as an en-capsulating agent, for example in the form of a capsule, a tablet coating, a bag or another container, for the therapeutically active component. An excipient can, for example, serve as a vehicle for the uptake of the medicament by the body, as a formulation aid, as a sweeting agent, as a flavour corrector, as a colouring material or as a preservative.

For oral use it is possible to use, for example, tablets, pills, hard and soft capsules, for example of gelatine, dispersible powder, granulates, aqueous and oily suspensions, emulsions, solutions or syrups.

Tablets can contain inert diluents, for example calcium carbonate, calcium phosphate, sodium phosphate or lactose; granulating and distributing agents, for example maize starch or alginates;
binders such as for example starch, gelatine or gum acacia; and lubricants, such as for example aluminium or magnesium stearate, ,.: . . .. . .... .... .

talcum or silicone oil. They can also be provided with a coating which can also be designed in such a way that it gives a delayed dis~olution and resorption of the drug in the :gastrointestinal tra~t and therefore ensures, for example, a better compatibility, protraction or retarding. Gelatine capsules can contain the pharmaceutical product mixed with a solid diluent, for example calciurn carbonate or kaolin, or an oily diluent, for example olive oil,-groundnut oil or liquid paraffin.
Aqueous suspensions can contain suspension agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl-cellulos~, sodium alginate, polyvinylpyrrolidone,.gum dragon or gum acacia; dispersants and wetting agents, for example poly ~
oxyethylene stearate, heptadecaethylene oxycetanol, polyoxyethylene sorbitol monooleate, pol~oxyethylene sorbitan monooleate or lecithin; preservatives, such as for example methyl or propyl hydroxybenzoates; flavouring materials; sweeting agents, for example saccharose, lactose, sodium cyclamate, dextrose, invert sugar syrup.
Oily suspensions can contain for example.groundnut oil, olive oil, sesame oil, coconut oil or liquid paraffin and thickeners such as for example beeswax, paraffin wax or cetyl alcohol;
also they may contain sweeteners, flavouring materials and anti-oxidants.
Powders and:granulates which are dispersible in water can contain the pharmaceutical products in admixture with dispersants, wetting agents and suspending agents, for example those mentioned .
-:
,, .
; . , - . . -: ', .- . .
; . - .: '., ' . ' " `
~ . i :~3L~3~3 above, as well as suspension agents, flavouring materials and colouring materials.
Emulsions can contain, for example, olive oil, groundnut oil or liquid paraffin as well as emulsifiers, such as for example gum acacia, gum dragon, phosphatides, sorbitan monooleate, polyoxyethylene sorbitan monooleate, and sweeteners and flavouring materials.
For rectal use of the pharmaceutical products one uses suppositories, which are produced with the help of binders which melt at rectal temperature, for example cocoa butter or polyethyleneglycols.
For parenteral use of the pharmaceutical products one uses sterile injectable aqueous suspensions, isotonic saline solutions or other solutions which can contain dispersants or wetting agents and/or pharmacologically compatible diluents, for example propyleneglycol or butyleneglycol.
The active principle or principles can if desired be fomulated with one or more of the said carrier materials or additives also in a microencapsulated form.
Besides the acylhydrocarbylaminoalkanoic acids according to the Invention and/or theirs salts, it is possible for the pharma-ceutical preparations to contain one or more other pharmacolo-gically active components of other groups of pharmaceutical products, such as anti-acids, for example aluminium hydroxide, magnesium aluminate; tranquilisers such as benzodiazepines, for example Diazepam; ~pasmolytica, such as for example Bi-etamiverin, Camylofin, anticholinergics, such as for example ,~

: .

3~3 Oxyphencyclimine, Phencarbamide; anti-froth agents such as for example dimethylpolysiloxane; laxatives, such as for example Bisacodyl,swelling agents; possibly also ferments, .gallic acids, antibiotics, vitamins, amino acids or fatty acid mixtures.

A further object of the Invention is a process for the prepa-ration of acylhydrocarbylaminoalkanoic acids of the:general formula I

n 2n COOH
I (I~

in which R1 signifles an allphatic or alicyclic hydrocarbon radical or an optionally ~ubstituted phenyl group, R2 1~ a hydrogen atom, an alkyl group, an alkenyl.group or an alkinyl.gxoup, R3 ls a hydrogen atom, an alkyl.group, a cycloalkyl.group-. or an optionally substituted phenyl radical, R4 ls an alkyl group, a cycloalkyl group, an optionally substituted phenyl group or an optionally substituted phenylalkyl.group (with the proviso that R4 has at least 3 carbon atoms when R4 is alkyl, R2 is hydrogen or methyl, R3 is hyd:rogen, and R1 is alkyl or optionally substituted phenyl) o:r ., . : ~ , . . . .

, ... . ~

., ': ', .~3~3 R3 and R4 together constitute an alkylene:group or R2, R3 and R4 by including the neighbouring carbon atom form an adamantyl radical, n ~ignifies 3, 4 or 5, as well as their salts of inorganic or organic bases, characterised by the fact that a) a hydrocarbylaminoalkanoic acid of the general formula II

7 n 2n COOH

2''1 ~ 4 (II) R3 :

in which R2, R3, R4 and n have the meanings given above, if desired with protection of the carboxyl.group, is acylated with an acyl derivative of the:general formula III
R -CO-R8 (III) in which R8 signifies a leaving group or a R1-CO-O.group, and R1 has the meaning given above, and if desired is then converted into the salts or else b) a hydrocarbylaminoalkenoic acid of the general formula IV-. R ~CO-I-CnH2n_2-cooH :

R2 1 \R4 (~) in which R1, R2V R3 and R4 and n have the meanings.given above, if desired with protection of the carboxyl.group, is hydrogen-ated and if desi.red is then converted into the salts or c) an acylaminoalkanoic acid of the:general formula V
R1 -CO- I -CnH2n-COOH[
- R9 (V) in which R1 and n have the meanings-given above and R9 is a hydrogen atom or a metal atom of an alkaline earth metal or preferably an alkali metal, optionally with protection of the carboxyl group, is reacted with a hydrocarbyl derivative of the general formula VI

R3 - C-~1O (VI) in which R2, R3 and R4 have the meanings.given above and R10 represents a leaving:group, and if desired is then converted into the salts or d) a functional acylhydrocarbylaminoalkanoic acid derivative - of the general formula VII

~ R2 F R4 (VII) . . R

in which R1, R2, R3, R4 and n have the meanings.given above and A is a functional derivative of a carboxyl.group, is sol-volysed and if desired is then converted into the salts.

If the hydrocarbylaminoalkanoic acids of Formula II are made to react with protection of the carboxyl.group, one uses those : ' : : :;

. ~ .. : .. ;- :. : :
- ~ - ......... . . .

a~33 representatives the protective groups of which do not react with the acyl derivatives III. Suitable representatives are for example salts of inorganic or organic bases such as alkali or alkaline earth metal salts, ammonium salts, salts of ter-tiary bases (e-.g. triethylamine, pyridine) or quaternary ammonium salts, or esters of alkanols or phenalkanols such as methyl, propyl, butyl, benzyl or phenethyl esters.
In the acyl derivatives III a leaving group R8 is for example a hydroxy group, a halogen atom, pref~rably a chlorine or bromine atom, an alkylsulphonyloxy or benzenesulphonyloxy group such as a mesyloxy or p-tolylsulphonyloxy group, an alkoxy group, preferably a methoxy or ethoxy group, an alkyl-mercapto group, such as a methylmercapto or ethylmercapto group.
The reaction of the hydrocarbylaminoalkanoic acids II with the acyl derivatives III is carried out according to known methods. The reaction is carried out in suitable soivents, such as water or hydrocarbons, for example benzene, toluene, xylene, or ethers, for example tetrahydrofuran, dioxan, 1,2-dimethoxyethane, or ketones such as ethylmethylketone, or amides, for example dimethylformamide, or sulphoxides, for example dimethylsulphoxide. Advantageously the acylation is carried out if R is a halogen atom in the presence of an acid-binding agent (proton acceptor). Suitable as such are, for example, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, or alkali metal carbonates, such as sodium carbonate, potassium carbonate, or ~ertiary amines such as pyridine, triethylamine, ethyldiisopropylamine. If the acyl ~.Z;~33 derivatives III are acid anhydrides, that is to say if R8 signifies a R1-CO-O group, it is also sufficient to heat the compounds II and III in an inert solvent.
The reaction can be varied with ~ide limits, for example -20 to +100C, temperatures around room temperature (10 to 30C) being preferred. If the compound~s II are acylated with the protection of the carboxyl group, then after the aclyation the protective group is split off again in the usual manner.
If salts are used as a protective group, the liberation of the acids I obtained is carried out by reaction with a suitable mineral acid, such as hydrochloric acid, sulphuric acid. If esters are used as protective groups, the acylation is followed by the saponification of the reaction product to form compounds of formula I. The saponiication is prefer-ably carried out with an alcoholic (e.g. ethanolic) alkali metal hydroxide (e.g. potassium hydroxide) solution at room temperature, if desired with the addition of an inert diluent such as dioxan or benzene.

The initial compounds of the formula II are produced according to various processes which are in themselves known. Thus they are obtained by reacting halogenalkanoic acids of the formula VIII, if desired with protection of the carboxyl group as an ester group, with a primary amine of the formula IX

n 2n COOH R2 (VIII) (IX) ,.

- : . .
~: . . . .
: . . :
:
.- . , .

~Z39L33 in which n, R2, R3 and R4 have the meanings given above and R11 signifies a halogen atom, preferably a chlorine or bromine atom. The reduction is advantageously carried out in the presence of an inert solvent, for example benzene, cyclohexane or diethylether, with the additi~n of a proton acceptor. As such one uses preferably an excess of the amine IX used for the reaction, which can also serve as a solvent. If desired, however, it is also possible to add a different proton acceptor.

The precursor products II are also obtained by reacting an amino acid X

H2N-CnH2n -COOH ( X ), in which n has the meaning given above, preferably with the protection of the carboxyl group, with a hydrocarbyl derivative VI. Suitable leaving groups R10 are halogen atoms, preferably chlorine or bromine atoms, trichloromethyl or tribromomethyl groups.
The reaction is advantageously carried out in the presence of an inert solvent, such as hydrocarbons, for example benzene, toluene, xylene or ethers, for example tetrahydrofuran, dioxan, . . . .
1,2-dimethoxyethane or ketones, for example ethylmethylketone, or amides, for example dimethylformamide, or sulphoxides, for example dimethylsulphoxide. Advantageously a proton acceptor is employed. As such the following are for example suitable:
alkali metal hydroxides, such as sodium hydroxide, potassium hydroxide or alkali metal carbonates, such as sodium carbonate, potassium carbonate, or tertiary amines, such as pyridine, tri-ethylamine, ethyldiisopropylamine. If the production of II is --. . : .. :

~2~3~33 carried out from amino acids X whose carboxyl.group is protected, the protective.group is advantageously only split off after the reaction of the intermediate products II ob-tained with the acyl derivatives III so as to obtain the end products I.

The initial compounds II are also obtained by the solvolysis of functional hydrocarbylaminoalkanoic acid derivatives of the general formula XI

HN-CnH2n-A

C (XI) in which R2, R3, R4 and A have the meanings.given above, by processes which are already known to the technician. Advan-tageous forms of embodiment are described under the process variant d).

The precursor products II are also obtained in a known manner by the solvolysis of lactams of the.general formula XII

CnH2n C=O

~ -N J (XII), ~`

: ,: .
: ;.. : :

in which R2, R3, R4 and n have the meanings given above. The solvolysis is carried out for example as hydrolysis by heating XII to temperatures of 80 ta 110C with aqueous or aqueous-alcoholic alkali metal hydroxide (e.g. sodium hydroxide) so-lutions, as alcoholysis by heating XII wit~ alcohols such as methanol or ethanol, in the presence of mineral acids such as sulphuric acid to the boiling point.

The intermediate products II are alternatively obtained by the hydrogenation of hydrocarbylaminoalkanoic acids XIII or alkyl-ideneaminoalkanoic acids XIV

I C (C 2)n-1 COOH ~ n 2n COOH

2'''¦ \ 4 12'' \ 13 (XIII), (XIV), in which R2, R3, R4 and n have the meanings given above and R12 signifies a hydrogen atom, an alkyl group or an optionally substituted phenyl radical and R13 signifies an alkyl group, an alkinyl group, an optionally substituted phenyl group or an optionally substituted phenylalkyl group or else R12 and R13 with the inclusion of the neighbouring carbon atom represent a cycloalkyl group, possibly with the protection of the carb-oxyl group, in a known manner. The hydrogenation is carried out for example with Raney-Nickel under hydrogen pressures of 1 to 250 atmospheres at room temperature in absolute ethanol.

- , I , ., . :
. , : : :: :

- .: :. .. . . : . :
. - : . . :. , . . . , : . :

.

~;23433 The acids XIII are available by the reaction of the amines IX with oxo-acid esters XV

O=CH-(CH2)n_1-CO-O-R (XV) in which n has the meaning given above and R14 signifies an alkyl group with 1 to 5 carbon atoms or a benzyl group. The acids XIV are obtained by reacting the amino acids X, if desired with protection of the carboxyl group, with the oxo compounds XVI

O C / (XVI) \ R13 in which R12 and R13 have the meanings given above.

The hydrogenation according to the process variant b) is carried out by methods such as are known to the technician.Thus the hydrocarbylaminoalkenoic acids IV are hydrogenated with hydrogen in the presence of a transition metal or noble metal catalyst or the corresponding oxides or complexes in inert soivents. Suitable metals are for example platinum, palladium, iridium, rhodium. A summary of the hydrogenation processes is to be found inter alia in Kirk-Othmer 11, 418-462; Ullmann 10, 109-114, 541-555; 1~, 630-649. The splitting off of any protective group which may be present is carried out in the usual manner.

- . : . ., ,: . : ,:
~- . ., :- :: ~ .. .. :
: " , . .
.: . . :

~L~Z3433 The alkenoic acids IV are obtained for example from the halogenalkenoic acid esters XVII

R ~CnH2n 2~C--R (XVII), in which R14 and n have the meanings given above and R15 is a halogen atom, preferably a bromine atom, by amination with an amine of the general formula IX, acylation with an acyl derivative III and if necessary subsequent saponification.
The production is carried out by means of processes which are in themselves known, halogenation and amination for example analogous to J.Heterocycl.Chem. 8 (1971) 21; acylation and saponification inter alia as described in the present Application.

The hydrocarbylation of the acylaminoalkanoic acids V (process variant c) is carried out in the usual manner. For example the compounds V are de-protonised in a suitable inert anhydrous solvent, such as benzene, toluene, xylene, tetrahydrofuran, dimethylformamide or dimethylsulphoxide, with an a~i metal hydride or amide, such as sodium hydride or amide, and then treated with the hydrocarbyl derivative VI, in which R10 signifies a halogen atom, preferably a chlorine or bromine atom, an alkyl-sulphonyloxy or benzenesulphonyloxy group, such as mesyloxy or p-tolylsulphonyloxy group. When one uses dimethylsulphoxide it is also possible to use potassium hydroxide as the de-protonising agent (cf. Isele and Luttringhaus Synthesis 1971, 266).

~23~33 The halogenalkanoic acids VIII and the lactams XII are known compounds or are produced by analog processes; for example the halogenalkanoic acids VIII are accessible by the solvo-lysis, such as-the hydrolysis or alcoholysis of the corres-ponding lactones followed by halogenisation or the lactams XII are accessible by the N-hyclrocarbylation of corresponding N-unsubstituted ~ctams.

The solvolysis according to process variant d) is carried out by means of processes which are known to the technician. A
functional acid derivative is to be understood in this case to mean a derivative whose unctional:group A is convertible by solvolysis into the free carboxyl.group. Typical represen-tatives are, for example, those in which A signifies a -CN group or a _C~yX group, in which X represents an oxygen or a sulphur atom or a substituted nitrogen atom, especially an imino, alkylimino or hydroxy-imino group and Y signifies a hydroxy group or a monovalent eliminable electrophilic radical, especially a free or substituted - amino group, preferably a monoalkyl or dialkyl or arylamino .group, a hydroxyamino or hydrazino group, a hydrazo-benzene group, a 2-hydroxyethylamino.group, a free or substituted mercapto.group, preferably an alkylthio group, a substituted hydroxy.group, preferably an alkoxy.group, an azido, a chloro or bromo radical, a morpholino group or a piperidino group, .

.~

, ..... .. . .
. ~ -: .. .. .

-, : : .. ..

; . , ~ , .: :: :

:13 23~

in which Y is not a hydroxy:group if X represents an oxygen atom.

An alkyl radical of an alkylimino, a dialkylamino, an alkylthio and an alkoxy group is understood to mean an alkyl radical with up to 6 carbon atoms, whilst an aryl radical of an arylamino group is understood to mean an aryl radical with up to 10 carbon atoms.

Preferred representatives of the acid derivatives VII are those in which A represents a -CN.group or a -C'~:group, in which X signifies an oxygen atom, an sulphur atom or an imino group and Y signifies an amino, monoalkylamino, dialkylamino, phenylamino, alkoxy, alkylthio, chloro or bromo radical.

Particularly preferred representatives of the acid derivatives VII are the corresponding acid amides, acid alkyl esters and nitriles.

For the solvolysis of the functional carboxylic acid derivatives VII one uses a water-splitting medium which consists wholly or partly of water or of agents which split off water under the conditions of hydrolysis. The reaction can be carried out as a homogeneous reaction, in which case one usually operates in the presence of a polar organic solvent or oE a solutiser. Advantage-~IZ3433 ously one uses as solvents, for example, low-molecular alcohols, dioxan, acetone, low-molecular carboxylic acids, N-methyl-pyrrolidone, sulfolan, or dimethylsulphoxide. However, it is also possible to carry out the hydrolysis as a heterogeneous reaction. The pH of the medium which splits off water depends upon the chemical nature of the acid derivative employed, but also on the nature of the desired compound of the general formula I;
it can therefore be neutral, acid or basic. It is adjusted to the desired value by means of acids, bases or buffers.

The hydrolysis temperatures are between 0C and the boiling point of the medium which splits off water, generally between 0 and 150C, especially between 20 and 120C. The hydrolysis temperatures depend individually also on whether the operation is carried out under pressure or without pressure. The reaction times are be-tween 1Q minutes and 20 hours according to the charge, reaction temperatures and other parameters. After the hydrolysis has been completed, the acids I are isolated by the usual methods, for example by recrystallisation or by acidification of their solutions, possibly whilst concentrating their solutions. For their puri-fication it is possible for their alkaline solution to be extracted with an organic solvent which is not miscible with the alkaline solution, for example ether, benzene, chloroben~ene, chloroform or methylene chloride.

- . :
,, ,.,; . ,.

.. ~ ~ .. : ::
: : . . . , . .
. :.. , . . .: ~ ~ :
~: - ~ . . : .

The carboxylic acid derivatives VII are obtained by methods which are current with the technician. For example they are obtained by reacting functional halogenalkanoic acid derivatives XVIII
n 2n A (XVIII), in which R11, n and A have the meaning given above, with amines IX followed by acylation with acyl clerivatives III. Alternatively it is possible for them to be produced by reacting the acylamino-alkanoic acid derivatives XIX
R1-CO-T-C H -A (XIX), in which R1, R9, A and n have the meanings given above, with the hydrocarbyl derivatives VI.

The conversion of the acids of the general formula I or of the modific-ations I*, I**, I***, I**** into their salts can be carried out by direct alkaline hydrolysis of the acid derivatives of the general formula VII. As alkaline reactants one uses the particular inorganic or organic base whose salt is desired. However, the salts can also be obtained by reacting the acids of the general formula I with the stoichiometric equivalent of a corresponding base, for example sodium hydroxide or sodium alcoholate, or else readily soluble salts are converted by double decomposition into sparingly soluble salts, or any salts are converted into salts which are pharmacologicaily compatible.

3~33 The following examples provide a further explana-tion and illustration OI the invention without restricting it. The abbreviations, M.P. and B.P., signify melting point and boiling point, respectively. A11 tempexatures are in degrees Centigrade.

~-tp-chZorobenzoyZ-4- [fl, 1., 3, 3 -te~ramethy~butyZ)amino]bu~yric ac*d Rl = p-chlorophenyl, R2 = R3 = -CH3, R4 = -CH2-C(CH3~3 n = 3 a) Eth~Z ~-(p-chZoro)be7l~0yZ-~- ~ fl, 1,3, 3-tetramethyZbutyZJamino~butyrete 19.5 g of ethyl 4-bromobutyrate, 25.9 g of 1,1,3,3-tetramethylbutylamine and 20 ml of cyclohexane are stirred together for 14 days at room temperature. The salt [ethyl 4-~1,1,3,3-tetramethylbutylamino)butyrate hydrobromide~ which separates out,is filtered off and washed wi~h cyclohexane. The filtrates are concentrated by evaporation, and all the volatile components are driven off from the residue under a pressure of approximately 0.5 mm Hg and at a bath temperature of at most 50.
The residue is dissolved Ln 30 ml of benzene and, after the addition of 8.8 g of ethyldiisopropylamine, 12.0 g of p-chlorobenzoyl chloride are added dropwise with stirring at room temperature. After half an hour the salt (which separates out) is filtered off; the filtrate is then .. . .: , : -.. . . . , ~ , .: .,: :::: :. ., . .: ~: :
. :: . -: .. : . .. . .,. :. ...................... ..

-, :: .:~: ~

~LZ3433 concentrated by evaporation, and the evaporation residue is recrystallized from cyclohexane ~o obtain 22.0 g (57.6% of theory) of ethyl N-(p -chloro)benzoyl-4~(1,1,3,3,-tetramethylbutyl)amino]butyrate, M.P. 79 to 81.
b) ~V- (p-chZoro)benzoyZ-4~(1,1, 3, 3-tet2~amethyZbutyZ)amino]buty~c acid A mixture of 17.0 g of ethyl N-~p-chloro)benzoyl-4-[(1,1,3,3-tetramethylbutyl1amino]butyrate in 100 ml of benzene is mixed with a solution of 3.5 g of potassium hydroxide in 20 ml of ethanol. The mixture is stirred for 20 hours at room temperature. The solvent is evaporated off in vacuo at a bath temperature of a maxi-mum of 50, and the residue is dissolved in water. The aqueous solution is extracted once with diethylether in order to remove impurities and unreacted initial mater-ial before acidifying the aqueous solution with dilute ;
hydrochloric acid. The resultant precipitate is ~;
filtered off, dried and recrystallized from benzene/li-groin to obtain 13.3 g (83.6% of theory) of N-(p-chloro)-benzoyl-4[(1,1,3,3-tetramethylbutyl)amino]butyric acid, M.P. 141~ to 143 C.

~X~LE 2 N-(p_fluo~J benzoyZ-~:-[~1,1,3,3-tetParne~hyZbutyZJcon??3o]bu~yPic acid Rl = p-fluorophenyl, R2 = R3 = -CH3, R4 = -CH2-~C(C~3)3, n = 3.
Analogously to Example 1, ethyl N-(p-fluoro)benzoyl-4-[(1,1,3,3-tetramethylbutyl)amino]butyrate is obtained as ; : . .; . , . . ~ ~,. :,.. ., ~ .

~3~33 a viscous oil by reacting the reaction product of ethyl 4-bromobutyrate and 1,1,3,3-tetramethylbutylamine with p-fluorobenzoyl chloride, the saponification of which gives ~-~p-fluoro)benzoyl-4-[(1,1,3,3-tetramethylbutyl)amino]-butyric acid (M.P. 114 to 117~).

EX~PLE 3 ~- fp-chZoro)benzoyZ-a- (te~t. butyZa~r~ino)butyric Qc?,d Rl = ~-chlorophenyl, R2 = R3 = R4 = -CH3, n = 3.
Analogously to Example 1, ethyl N-(p-chloro~ben oyl-4-(tert.-butylamino)butyrate (M.P. 62 to 63) is obtained by reacting the reaction product of ethyl 4-bromobu~yrate and tert.-butylamine with p-chlorobenzoyl chloride, the saponification of which yields N-(p-chloro)benzoyl-4-~tert.-butylamino)butyric acid (M.P. 126 to l27).

EXA~LE 4 ~- (3, ~, 5-t~*rnetho:~y)b~nzoy1,-6- (tert . Dutyzamino J capro~c aci,d Rl = 3,4,5-trimethoxyphenyl, R2 = R3 = R4 = -CH3, n = 5 Analogously to Example 1, ethyl N-(3,4,5-trimeth-oxy)benzoyl-6-(tert.-butylamino)caproate (a viscous oil which cannot be distilled without decomposition) is obtained by reacting the reaction product of ethyl 6-bromocaproate and tert.-butylamine with 3,4,5-trimethoxybenzoyl chloride,`
the saponification of which yields N-trimethoxybenzoyl-6-(tert.~butylamino)caproic acid (M.P. 83 to 85~).

~3~33 ~3 EX~PLE 5 N-(p-chZoroJbenzoyZ-4-~1,1-d~methyZpropyZJomnno]butyr~c ~cid Rl = p-chlorophenyl, R2 = R3 = -CH3, R4 = -C2H5, n = 3 Analogously to ~xample 1 ethyl N-(p-chloro)benzoyl-4-[ll,l-dimethylpropyl)amino~butyrate (M.P. 65 to 67) is obtained by react ng the reaction product of ethyl 4-bromo-butyrate and l,l-dimethylpropylamine with p-chlorobenzoyl chloride, the saponification of which yields N-(p-chloro)-benzoyl-4-~(1,1-diemthylpropyl)amino]butyric acid (M.P. 79 to 81).

D-(2,~-dichZoro)ben20yZ-~-[(l,l-dimethyZp~opyZ~emino]butyric acid R1 = 2,4-dichlorophenyl, R2 = R3 = -CH3, R4 = -C2H5, n-3 Analogously to Example 1, ethyl N-(2,4-dichloro)-benzoyl-4-~(1,1-dimethylpropyl)amino]butyrate (M.P. 75 to 77~) is obtained by reacting the reaction product of ethyl 4-bromobutyrate and l,l-dimethylpropylamine with 2,4-dichlorobenzoyl chloride~ the saponification of which yields 2,4-dichlorobenzoyl-4-[(1,1-dimethylpropyl)amino]-butyric acid (M.P. 124 to 126).

., . .. ~
. . .- ~ ~ .

EXA~LE 7 ~-(n-butyryZ)-4- [ f l, 1-~i,7e~hy1,propyZ)arrri,no]b?~tyric acid Rl = n-c3H7~ ~2 = R3 = -C~13, R4 = -C2~5, n = 3 19.5 g of ethyl 4-bromobutyrate, 26.1 g of 1,l-dimethylpropylamine and 20 ml of cyclohexane are stirred together at room temperature for lO days. The resultant precipitate is filtered off and the filtrate concentrated by evaporation. After all the volatile components have been removed at a bath temperature of 50 and a pressure of 0.5 mm Hg, the residue is stirred with 41 g of n-butyxic anhydride, 33.4 ml of pyridine and lO0 ml of benzene for S hours at room temperature. The mixture is concentrated by evaporation at a pressure of 10 mm Hg and a bath temperature of 90. The residue,taken up in lO0 ml of benzene,is mixed with a solution of 1.7 g of potassium hydroxide in 20 ml of ethanol. After standing for 20 hours at room temperature, the solvent is evaporated off at reduced pressure, and the residue is dissolved in water;
the aqueous solution is washed once with diethylether and then acidified with dilute hydrochloric acid. The preci-pitate which separates out and is at first oily is filtered off, dried and recrystallized from ethyl acetate/cyclohexane to obtain 8.9 g (36.6~ of theory) of N-(n-butyryl)-4-[(l,l-dimethylpropyl)amino]butyric acid (M.P. 70 to 72).

,.................................................................. . .

. .

,,,,~, N-(p-chZoro)ben20yl-~-[~2-methyZ-3-butyn-2-yZ)om~no]butyr%c acid Rl = p-chlorophenyl, R2 = -C_CH, R3 = R4 = -CH3, n = 3 Analogously to Example 1, ethyl N-(p-~hloro)benzoyl-4-[(2-methyl-3-butyn-2-yl)amino]butyrate (M.P. 68 to 70) is obtained by reacting the reaction product of ethyl - 4-bromobutyrate and 2-methyl-3-butyn-2-ylamine with p-chloro-benzoyl chloride, the saponification of which yields N-(p-chloro)benzoyl-4-[(2-methyl-3-butyn-2-yl)amino]butyric acid (M.P. 102 to 104).

EX~LE 9 ;.
~-(p-chZoroJbenzoy~-4-[(3-ethyZ-l-pentyn-3-yZ~ami~o]butyric acid Rl = p-chlorophenyl, R2 = -C-CH, R3 = R4 = -C2H5, n = 3 Analogously to Example 1 ethyl N-(p-chloro)benzoyl-4-[(3-ethyl-1-pentyn-3-yl)amino]butyxate (M.P. 73 to 75) is obtained by reacting the reaction product of ethyl 4-bromobutyrate and 3-ethyl-1-pentyn-3-ylamine with p-chloro-benzoyl chloride, the saponification of which gi~es N- (p -chloro)benzoyl-4-[(3-ethyl-1-pentyn-3-yl)amino]butyric acid (M.P. 92 to 94).

-.. . : -~L123433 N-fp-ch~oroJbenzoyZ-g-[(l-ethynyZcyclohe~yZ-lJ omino]butyr*c acid R = p-chlorophenyl~ R2 = -C-CH, R3 and R4 = -(CH2) -, n = 3 Analogously to Example 1, ethyl N-(p-chloro)benzoyl-4-1(1-ethynylcyclohexyl-1)-amino]butyrate (M.P. 84 to 86) is obtained by reacting the reaction product o~ ethyl 4-bromobutyrate and l-ethynylcyclohexylamine with p-chloro-benzoyl chloride, the saponification of which gives N-~p-chloro)benzoyl-4-[(1-ethynylcyclohexyl-1)-amino)butyric acid (M.P. 120 to 122).

N-ocetyZ-4-[~1-ethynyZcycZohexyZ-l)-omino]butyric acid Rl = -CH3, R2 = -C_CH, R3 and R4 = -(CH2)5-, n = 3 Analogously to Example 1 ethyl N-acetyl-4-[(1-ethynylcyclohexyl-l)-amino]butyrate (M.P. 73 to 75) is obtained by reacting the reaction product of ethyl 4-bromobutyrate and l-ethynylcyclohexylamine with acetyl chloride, the saponification of which gives N-acetyl-4- :
[(l-ethynylcyclohexyl-l)-amino]butyric acid (M.P. 103 to 105) . : . , , . : . ' ': : : ~ ' .

~23~33 ~?

N- (p-chZoro)benzoy1,-4- [ ~l -propyzcyczohe~yz-l ~ -cDnino]butyric acid Rl = p-chlorophenyl, R2 = n-C3H7, R3 and R4 = -(CH2)5-, n = 3 ~nalogously to Example 1 ethyl N-(p-chloro)benzoyl-4-1{1-(n-propyl)cyclohexyl-1}-amino]butyrate (a viscous oil which cannot be distilled without decomposition) is obtained by reacting the reaction product of ethyl 4-bromobutyrate and l-(n-propyl)cyclohexylamine with p-chlorobenzoyl chloride, the saponification of which gives N-(p-chloro)benzoyl-4-[{l-(n-propyl)cyclohexyl-l}-amino]butyric acid ~M.P. 110 to 117).

N- fp-chZoro~benzoyZ-~- [ {1- (n-butyZ)cycZopen~yZ-2 }ami,no]~utyr1,c ac~d ~ = p~o~enyl, R2 = n-C4Hg, R3 and R4 = -~CH2)4-, n = 3 Analogously to Example 1 ethyl N-(p-chloro)benzoyl-4-[{1-(n-butyl)cyclopentyl-1}-amino~butyrate (M.P. 85 to 87) is obtained by reacting the reaction product of ethyl 4-bromobutyrate and l-(n-butyl)cyclopentylamine with p-chlorobenzoyl chloride, the saponification of which gives N-(p-chloro~benzoyl-4-[{1-~n-butyl)cyclopentyl-1}-amino]-butyric acid ~M.P. 91 to 93).

... .

; . ~ -~23433 EXA~? T ~ 14 N- (p-ch~oro)benzoy2-~- ~1 -adc~7nantyZ)cDr~ncfbutyrw acid Rl = (p-chloro)phenyl, R and R3 and R4 = -CH~

n 8 3 CH2 S ff~nalogously to Exa~ple l, ethyl N-(p-chloro)benzoyl-4-~(1-adamantyl)amino]butyrate (M.P. 103 to 105) is obtained by reacting thhe reaction product of ethyl 4-bromobutyrate and l-aminoadamantane with p-chlorobenzoyl chloride, ~he saponification of which gives N-(p-chloro)benzoyl-4-[(1-ada-mantyl)amino]butyric acid (M.P. 164 to 166).

fY-(p-ch7oro)be?s~oy~-4-cyc~ooc~yIa~r~nobutyric acid Rl = p-chlorophenyl, R2 = -H, R3 and R4 = -(C~2)7-, n - 3 Analogously to Example 1, ethyl N-(p-chloro)benzoyfl-4-cyclooctylaminobutyrate (an oil which cannot be distilled f~
without decomposition) is obtained by reacting the reaction product of ethyl 4-bromobutyrate and cyclooctylamine with p-chlorobenzoyl chloride, the saponification of which yiel~s N-(p-chloro)benzoyl 4-cyclooctylaminobutyric acid (M.P. 109 to 110).

, . . - , ~ . . . ~: ; :.

... . ,. .:-.- .. . .,-.

- . . . ~ . . - -~1L23433 ~q EXAM:PI;E 1 6 ~-Denzoy?,-4-(n-butyZcr~7nno)butyric acid Rl = phenyl, R2 _ R3 = -H, R4 = n-C3H7, n = 3 15.5 g of n-butylpyrrolidone is heated for 20 hours ;
under reflux in a mixture of 15 g of sodium hydroxide in lO0 ml of water. Into the solution ~which is cooled to 0 and vigorously agitated) there is slowly introduced (drop by drop) 23.1 g of benzoyl chloride, which is then stirred for a further 5 hours; while further cooling, 5N hydrochloric acid is a~ded until the reaction mixture becomes acid. Th~
precipitated deposit, which still contains benzoic acid, i5 separated and recrystallized several times from ligroin to obtain 13.6 g (47% of theory) of N-benzoyl-4-(n-butyl)amino-butyric acid ~M.P. 62 to 64).

~-fp-chZoro~benzoyZ-S-(n-butyZominoJvaZerie acid Rl = p-chlorophenyl, R2 = ~3 = _~, R4 = n-C3~I7, n - 4 a) 1- (n-b2~t~yZ)-~-vaZeroZact~n To a solution of 49.6 g of ~-valerolactam in 300 ml of anhydrous dimethylsulfoxide one adds 33.6 g of finely-powdered potassium hydroxide and then one adds (drop by drop), while stirring and with occasional cooling, 82~2 g of l-bromobutane within l hour. The mixture is ' , ' ' ' ' ' .

~1;23~33 ~ o stirred for a further 3 hours at ~0 C and then cooled, mixed with 1.5 liters of water and then extracted with diethyl ether. The ether phase is washed with water, dried a~d evaporated to dryness. The evaporation residue is distilled in vacuo to obtain 42.5 g (54.7% of theory) of l-(n-butyl)-~-valerolactam (B.P. 122/13 mm Hg).

b) IY- (p-ch ~oro JbenzoyZ-5- (n-buty z~q~n~Jva~epic acid 18.0 g of l-(n-butyl)-~-valerolactam, 14.0 g of sodium . hydroxide and 280 ml of water are heated together for

8 hours to boiling point under reflux. The solutio~ is then cooled and adjusted to a pH of 7~5 with dilute hydrochloric acid. Then while stirring and continuously checking the pH, one simultaneously adds (drop by drop) 22.3 g of p-chlorobenzoyl chloride and 22.0 g of 25%
aqueous sodium hydroxide solution, the pH being main-tained between 7 and 8. After unreacted initial mater-ial and also impurities have been removed by extraction with diethyl ether, the aqueous solution is acidified with dilute hydrochloric acid and the oily deposit which separates out is taken up in methylene chloride. The residue remaining after drying and distilling off the methylene chloride is recrystallized from ethyl acetate/petrol ether to obtain 22.4 g (62% of theory) of N-(p-chloro)benzoyl-5-(n-butylamino)valeric acid (M.P. 64.5 to 65.5).

~2;~:33 ,~, I
.

N-(p-chtoroJ~enzoyZ-4-benzyZominobu~yric acid Rl = p-chlorophenyl, R2 = R3 = -H, R4 = phenyl, n = 3 27.0 g of N-benzylpyrrolidone is heated to boiling under a reflux for 30 hours with 3~0 ml of 5% sodium hydroxide solution. After cooling, the solution is adjusted to a pH
of 8 with dilute hydrochloric acid, and unreacted initial material is extracted with diethyl ether. To the clear . ~;
- aqueous solution 19.7 g of p-chlorobenzoyl chloride is ad~ed slowly (drop by drop) while stirring, while (at the same time) adding dilute caustic soda solution in order to maintain the pH at between i and 8. After ending the addi-tion of acid chloride, the solution is stirred for a further 30 minutes at pH 8 and then acidified to pH 3 with dilute lS hydrochloric acid. The deposit which is precipitated is taken up in ethyl acetate; the ethyl acetate phase is dried with magnesium sulfate and concentrated by evaporation.
After the addition of petrol ether and cooling, the product crystallizes out to yield 31 g (61% of theory) of N-(p-chloro)benzoyl -4-benzylaminobutyric acid (M.P. 101 to 102).

E ~ ~PLE 19 ~-(p-chZoro)benzoyZ~ e~izhydryZom*nobutyric acid Rl = p-chlorophenyl, R2 = -H, R3 = R4 = phenyl, n = 3 - ~ . . " : . . : .: :

~, . . . . ~ . , .

~I ~Z3433 a) EthyZ 4 benzhyd~yZaminobu~yrate 19.5 g of ethyl 4-bromobutyrate, 55 g of benzhydrylamine and 30 ml of cyclohexane are stirred at room temperature for 12 days. The resultant crystal paste is diluted with diethyl ether, filtered at the pump and the filtrate con-centrated by evaporation. The residue (after evaporation) is distilled in vacuo. The first run which distils over at 100 to 110 (0.02 mm ~g) is excess benzhydrylamine.
The main distillate obtained is 21.1 g ~71% of theory) of ethyl 4-benzylhydrylaminobutyrate 18.P. 150 to 155 ~0.02 mm Hg)].

b) EthyZ N-(p-chZoro)benzoyZ-4-b~n2hydryZcz~n*nobutyrate 6.8 g of p-chlorobenzoyl chloride is added drop by drop to a solution of 10.5 g of ethyl 4-benzhydrylaminobuty-lS rate and 5 g of ethyl diisopropylamine in 100 ml of ben-zene accompanied by cooling and agitation. After a further 2 hours the precipitate is filtered off, the filtrate is evaporated, and the residue on evaporation is recrystallized from ligroin to yield 9.S g (61.7%
of theory) of ethyl N-(p-chloro)benzoyl-4-benzhydryl-aminobutyrate (M.P. 68 D to 69~.

c) N-~p-chZoro)benzoyZ-4-benzhydryZom*nobutyr*c ac*d

9.1 g of N (p-chloro)benzoyl-4-benzhydrylaminobutyrate is dissolved in 90 ml of benzene and, after addition of a solution of 1.8 g of potassium hydroxide in 20 ml of .. . . . , ., ,, , ", . .

., .. . : - :,:-,. . -. :: . .. .: . , :

39~3~
,3 ethanol, is stirred at room temperature for 20 hours.
The solvent is then distilled off in vacuo, and the residue dissolved in water. The aqueous alkaline solu-tion is washed once with diethyl ether and then acidified with dilute hydrochloric acid. The precipitated product is filtered off, dried and recrystallized from ligroin to yield 8.0 g (94~ of theory) of N-~p-chloro)benzoyl-4-benzhydrylaminobutyric acid (M.P. 110 to 111).

iV-acetyZ-4-benæhydryZarm,nobutyr w acid Rl = -CH3, R2 = -H, R3 = R4 = phenyl, n = 3 Analogously to Example 19,10,8 g of ethyl 4-benæ-hydrylaminobutyrate and 5.2 g of ethyl diisopropylamine are dissolved in 100 ml of bsn2ene and reacted with 3.1 g of acetyl chloride. As reaction product one obtains 11.4 g (92.5% o~ theory) of ethyl N-acetyl-4-benzhydrylaminobutyrate as a viscous non-distillable oil. The saponification of this ester yi~lds 9.2 g (88% of theory) of N-acetyl-4-benzhydrylaminobutyric acid (M.P. 173 to 174).

N-(p-chIoro)benzoy~-4-(1-pheny~ethy~ominoJbutyric acid Rl = p-chlorophenyl, R2 = -H, R3 = -CH3, R4 = phenyl, n = 3 , . , - ~ . .

llZ3~L33 SY

Analogously to Example 1, ethyl N-(p-chloro)benzoyl-4-(1-phenylethylamino)butyrate (viscous non-distillable oil) is obtained by r~acting the reaction product of ethyl 4-bromobutyrate and dl-(l-phenylethyl)amine with p-chloro-benzoyl chloride, the saponification of which yields N-(p-chloro)benzoyl-4-(l-phenylethylamino)butyric acid (M.P. 110 to 112).

ExAMæLE 22 ~-(p-chZoro)benæoyZ-6-(1-phenylethylamino)caproic acid Rl = p-chlorophenyl, R2 = -H, R3 = -CH3, R = phenyl n = 5 Analogously to Example 1, ethyl N-(p-chloro)benzoyl-6-(1-phenylethylamino)caproate (viscous non-distillable oil) is obtained by reacting the reaction product of ethyl 6-bromocaproate and dl-(l-phenylethyl)amine with p-chloro-benzoyl chloride, the saponification of which yields N-(p-chloro)benzoyl-6-(1-phenylethylamino)caproic acid (M.P. 132 to 133).

EXAMPL~ 23 D-rp-chZoro)benzoyZ-~-homoveratryZaminobutyric acid Rl = p-chlorophenyl, R2 = R3 = -H, R4 - 3,4-dimethoxy-benzyl, n = 3 ., ,. , ~ , ... ..

13 ~3433 Analogously to Example 1 ethyl N-(p-chloro)benzoyl-4-homoveratrylaminobutyrate (viscous non-distillable oil) is obtained by reacting the reaction product of ethyl 4-bromobutyrate and homoveratryl,amine with p chlorobenzoyl chloride, the saponification o:f which yields N-(p-chloro)- ;
benzoyl-4-homoveratrylaminobutyric acid ~M.P. 101 to 103), EXAMPLE 2~

~-fp-chZoro)benzoyZ-4-[(1,2-diphenyZethyZ)om~no]butyric aeid Rl = p-chlorophenyl, R2 = -H, R3 - phenyl, R4 = benzyl, n = 3 Analogously to Example 1, ethyl N-(p-chloro)benzoyl-4-[(1,2-diphenylethyl)amino]butyrate, (viscous non-distillable oil) is obtained by reacting the reaction product of ethyl 4-bromobutyrate and 1,2-diphenylethylamine with p-chloro-benzoyl chloride, the saponification of ~7hich yields N-(p-chloro)benzoyl-4-[(1,2-diphenylethyl)amino]butyric acid ~M.P. 121 to 122).

Sodium ~-(p-ehZoro)benzoyZ-4-[tl,1,3,3-tetromethyZb~tyZJamino]butyrate 3.5 g of ~-(p-chloro)benzoyl-4-[(1,1,3,3-tetra-methylbutyl)amino]butyric acid is dissolved in 35 ml of boiling isopropyl alcohol, and to this there is added a hot ~L23~ '3 5 ~7 solution of 0.23 g of sodium metal in 17.5 ml of isopropyl alcohol. After cooling, the solution is mixed with the same volume of diethyl ether. After several hours the crystalline sodium N-(p-chloro)benzoyl-4-[(1,1,3,3-tetra-s methylbutyl)amino]butyrate is filtered off, washed with isopropyl alcohol/ether and dried. The yield is almost quantitative. The salt mel~s without a sharp mel~ing point at 187 to 190.

~-fp-chZoro)benzoyZ-s-benzyleminobutyric ~cid a) ~-~enzyZ~rrinobutyronitriZe 32.2 g of benzylamine, 14.8 g of 4 bromobutyronitrile and 30 ml of cyclohexane are stirred at room tempera-ture for 12 hours. After the addition of diethyl ether the separated benzylamine hydrobromide is filtered off;
the ether phase is washed with water, dried and con-centrated by evaporation. The residue is distilled in vacuo to yield 11.5 g (66~ of theory) of 4-benzylamino butyronit~ile (B.P. 114 to 120/0.05 mm ~g).

b) ~-fp-chl,oroJbenzoyZ-~-benzyZ ~ nobutyronitri1,e 9.0 g cf p-chlorobenzoyl chloride are added drop by drop at room temperature to a well-agitated mixture of 9-0 g of 4-benzylaminobutyronitrile, 6.7 g of ethyldiisopropyl-amine and 60 ml of benzene. After the addition has been completed, the stirring is continued for a further .~, . - :

- . , ., . ~ . .: ~:
,~,. .. , , . ~ . .
.

34~33 ~Q~
2 hours. The reac~ion mixture is mixed with diethyl ether and cooled in iced water; the separated salt is filtered off. The filtrate is concentrated by evapora-tion, and the residue is r.ecrystallized from ethyl acetate/petrol ether to yield 10.0 g (62~ of theory) of N-(p-chloro)benzoyl-4-benzylaminobutyronitrile (M.P. 48 to 50).

c) N-(p-c1~Zoro)benzoyZ-4-benæyZc~inobutyr*c ac*d A solution of-0.5 g of N-(p-chloro)benzoyl-4-benzyl-aminobutyronitrile in 5 ml of absolute ethanol is saturated with hydrochloric acid gas at 0. The solu-tion is heated to 70 for 30 minutes and then concentrated by evaporation; the residue is mixed with wa~er and extracted with diethyl ether. The residue of the ether extract is dissolved in 3 ml of benzene and mixed with a solution of 0.2 g of potassium hydroxide in 4 ml of ethanol. After standing for 2 days, the clear solution is concentrated by evaporation, and the residue is dissolved in water. The aqueous solution is first extracted with diethyl ether in order to remove impuri-- ties and is then acidified to a pH of 3 with dilute ~
hydrochloric acid. The precipitate, whlch is deposited, `
is taken up in methylene chloride. The residue remaining `
after distilling off the methylene chloride is recry-stallized from ethyl acetate/petrol ether to yield 0.4 g of N-(p-chloro)benzoyl-4-ben~ylaminobutyric acid (M.P. 101 to 102), the IR and NMR spectra of which are identica1 with those of the substance produced according to Example 18.

. ' ' .

i ' ~ '; ' '~ ' ' '; . . '. '............. .

' . . ' . ' "'. ':

~23433 EX~PLE 27 N-(p-chZoro)benzoyZ-4-benzy~om~nobutyr*c acid a) ~-(p-chZoroJben20yZ-~-om-~nobuty:r%c ocid To a solution of 10.3 g of 4-aminobutyric acid and 4.0 g of sodium hydroxide in 150 ml of water one adds slowly (drop by drop while stirri~lg) at room temperature 17.5 g of p-chlorobenzoyl chloride. By adding tat the same time) dilute caustic soda solution,a pH of 7 to 8 is maintained. The aqueous solution is washed once with diethyl ether and then acidified with dilute hydrochloric acid. The resultant precipitate is taken up in methylene ~hloride; the residue remaining after evaporating off the solvent is washed with diethyl ether to obtain 21.5 g (89~ of theory) of N-(p-chloro)benzoyl-4-aminobutyric acid (M.P. 107 to 108).

b) ~enzyZ ~-(p-ch~oroJbenzoyZ-~-benzyZominobutyrate In a solution of 7.25 g of N-(p-chloro)benzoyl-4-amino-butyric acid and 30 ml of dimethylsulfoxide there are suspended 4.0 g of potassium hydroxide powder. Into this suspension 9.1 g of benzyl chloride is slowly added - (drop by drop) while stirring. The mixture is stirred ~`
at room temperature for a further 7 hours and then mixed with 100 ml of water. The reaction product is extractecl with diethyl ether; the ether phase i5 washed with water, dried and concentrated by evaporation. The !,"
crude product is purified by chromatography over a ,. . ~ , , -, . .

1~39L33 _~

silica gel column with methylene chloride as eluent to obtain 5.8 g (46% of theory) of benzyl N-(p-chloro)benzoyl-4-benzylaminobutyrate as a colorless viscous oil. The NMR
spectrum confirms the structure.

c) N-(p-chZo~)benzoyZ-4 ben2yZfI~7nnoDutyric acid toi~ fo~rn) A solution of 2.0 g of benzyl N-(p-chloro)benzoyl-4-benzylaminobutyrate in 20 ml of benzene is mixed with a solution of 0.4 g of potassium hydro~ide in 5 ml of ethanol. After allowing the resulting reaction mixture to stand for 20 hours at room temperature, the solvent is evaporated off, and the residue is dissolved in water. The aqueous solution is washed with diethyl ether and then acidified to a pH of 3 with dilute hydrochloric acid. The precipitate is filtered off lS and recrystallized from ethyl acetate/ligroin to obtain 1.35 g (86% of theory) of N~ chloro)benzoyl-4-benzyl-aminobutyric acid (M.P. 111 to 112).

This is the cis form of the title compound. If one heats this for a few minutes to 230 and then recrystallizes once again from ethyl acetate/ligroin, one obtains crystals (with a melting point of 101 to 102) which are identical with those of compounds produced according to Example 18 and Example 26.

. ~ , . :, . , ~Z3~3 -: 6 N-(p-ch~oroJben20yt-4-ftert.-b~tyZominoJbutyric ~cid a) EthyI ~-(p chIoro)benzoyZ-4-tert.butyZar7~no)crotonate To a suspension of 8.4 g of ethyl-4-(tert.-butylamino)-s crotonate hydrochloride in 70 ml of benzene there is added ~drop by drop) while cooling 11.7 g of ethyldi-isopropylamine and then 7.9 g of p-chlorobenzoyl chloride. The mixture is stirred at room temperature for a further 5 hours and filtered; the filtrate is concentrated by evaporation. The residue is recrystal-lized from ligroin to obtain 10.0 g of ethyl N-(p-chloro)~
benzoyl-4-(tert.-butylamino)crotonate (M.P. 77 to 78).

b) N- fp-chZorc~JbenzoyZ-4-rte~.butyZ~rrino)crotonic af~id A solution of 8.0 g of ethyl N-(p-chloro)benzoyl-4-(tert.-butylamino)crotonate in 20 ml of benzene is mixed with a solution of 2.0 g of potassium hydroxide in 15 ml of ethanol. The mixture is stored at room temperature for 20 hours and then concentrated in a rotary evaporator. The evaporation residue is dissolved in water; the aqueous solution is washed with diethyl ether and then acidified with dilute hydrochloric acid.
_ The precipitate, which is formed, is recrystallized from cyclohexane to obtain 6.1 g of N-(p-chloro)benzoyl-4-(tert.-butylamino)crotonic acid (M.P. 113 to 114).

c ) ~- (p-chZoro)ben20yZ-4- (tert. -butyZ~no)butyr*c acid 5.O g of N-(p-chloro)ben~oyl-4-ttert.-butylamino)-crotonic acid is dissolvecl in 100 ml of tetrahydrofuran and, after the addition oi 3.0 g of palladium charcoal (5% Pd), is reated in a hydrogenation apparatus with hydrogen. After the termination of the taking up of hydrogen, it is filtered off from the catalyst and the solvent evaporated. The residue is recrystallized from ethanol/water (1:1) to obtain 4.9 g of N-(p-chloro)benzoyl-4-(tert.-butylamino)butyric acid (M.P. 126 to 127).
The melting point of a mixture with the substance produced according to Example 3 shows no depression.

~-(p-chZoroJbenzoyZ-~-[(p-metho~ybenzyZJ~msno~butyric ac*d Rl = p-chlorophenyl, R2 = R3 ~ -H, R4 = p-methoxyphenyl, n =

Analogously to Example 18 l-(p-methoxybenzyl)-pyrrolidone is heated with sodium hydroxide solution and then reacted with p-chlorobenzoyl chloride to obtain N-(p-chloro)benzoyl-4-[(p-methoxybenzyl)amino]butyric acid, M.P. 128.5 to 129.5.

~-~p-ch~oro)ben2oyZ-5-benzyZam~nova~er*c ac~

Rl = p-chlorophenyl, R2 = R3 = -H, R4 - phenyl, n - 4 . : :
.... ..
- :. ;. . , ~, . , .. . . .

~,~
Analogously to Example 18, l-benzyl-~-valerolactam is heated with sodium hydroxide solution and then reacted with p-chlorobenzoyl chloride to obtain N-(p-chloro)benzoyl-5-benzylaminovaleric acid, M.P. 93 to 94.

EXA~PLE 31 ~-fm-trifZuoro,~ethyZ)ben30yZ-~-[(1~1,3,3-tetromethyZbutyZ)omino]butyr*c ac~d R = ~,a,~-trifluaro-m-tolyl, R = R3 = -C~3, R4 = -CH2-C(CH3)3, n = 3 Analoyously to Example 1, ethyl N-(m-trifluoro-methylbenzoyV-4-[(1,1,3,3-tetramethylbutyl)amino]butyrate is obtained as a viscous oil by reacting the reaction product of ethyl 4-bromobutyrate and 1,1,3,3-tetramethyl-butylamine with m-trifluoromethylbenzoyl chloride, the saponification of which yields N-(m-trifluoromethyl)benzoyl-4-[(1,1,3,3-tetramethylbutyl)amino]butyric acid ~M.P. 86 to 87). .

I~-crotonoyZ-~-[~1,1,3,3-tetremethyZbutyZ)omino]butyric acid Rl = -CH=C~-CH3, R2 = R3 = -CH3, R4 = -CH2-C(CH3~3, n = 3 ~.

Analogously to Example 1, ethyl N-crotonoyl-4-[(1,1,3,3-tetramethylbu~yl)amino]butyrate is obtained as a viscous oil by reacting the reaction product of ethyl 4-bromobutyrat:e and 1,1,3,3-tetramethylbutylamine with , , . ., - , , . , . , . ,, : :-. : - ~ , .

~ ' : ' ,~ '.'. : -, -;.. : ,,. :

~23~33 ~3 crotonic acid chloride, the saponification of which yields ~-crotonoyl-4-[~1,1,3,3-tetramethylbutyl)amino]butyric acid (M.P. 92 to 93).

EXAMPLE ,3 R-propionyZ-$-~en2hydryZominobutyr*c acid Rl = -C2H5, R = -H, R = R = phenyl, n = 3 a) EthyZ ~-propi,onyZ-~-b~nzhydryZcorrLno~t~tyrate Analogously to Example 19, 9.0 g of ethyl 4-benzhydryl-aminobutyrate and 4.3 g of diisopropylethylamine in 100 ml of benzene ar~ reacted with 3.1 g of propionyl .
chloride. The reaction product is recrystallized from ethyl acetate~ligroin (1:1) to obtain 9.9 g (92.5~ of theory) of ethyl N-propionyl-4-benzhydrylaminobutyrate (M.P. 83 to 85).

b) N-propionyz-g-benzhydryzam*nob~tyric acid The saponification of 9.3 g of e~hyl N-propionyl-4-benzhydrylaminobutyrate in 100 ml of benzene with a solution of 2.2 g of potassium hydroxide in 20 ml of ethanol(analoyously to Example l9)yields [after recrystallization of the reaction product from ethyl acetate/ligroin (1:1)] 7.8 g (91% of theory) of N-propionyl-4-benzhydrylamino~utyric acid, M.P. 151.5 to 152.5. `

.-- . - . . . ,. : . ~ , : . ~ :
., .. ~ .. . , .. . : ~ , :
.: . :: .. .

~L~Z3~33 EX~MPLE 34 N-(5-ch~oro-2-methoxybenzoy~)-4-benzhydryZaminobutyric acid Rl = 5-chloro-2-methoxyphenyl, R2 = _~, R3 = R4 = phenyl, n= 3 Analogously to Example 19, 8.9 g of ethyl 4-benz-hydrylaminobutyrate and 4.3 g of ethyl diisopropylamine are dissol~ed ~n 80 ml of benzene ,~nd reacted with a solution - of 6.8 g of 5-chloro-2-methoxybenzoic acid chloride in 20 ml of benzene. As reaction product one obtains 13.8 g (99% of theory) of ethyl N-(5-chloro-2-methoxybenzoyl)-4-benzhydryl-aminobutyrate as a viscous non-distillable oil. The saponi-fication of this ester yields 11.1 g (85.5% of theory~ of N-(5-chloro-2-methoxybenzoyl)-4-benzhydrylaminobutyric acid (M.P. 176 to 178).

EXAMPLE 35 :

~1-acetyZ-6-benzhyd~yZaminoc~proie acid Rl = -CH3, R2 = -H, R3 = R4 = phenyl, ~ = 5 a) EthyZ 6-benzhydryZam~noc~proate 22.3 g of ethyl 6-bromocaproate, 55 g of benzhydrylamine and 30 ml of cyclohexane are stirred at room temperature for 20 days. Preparation analogously to Example 19 yields 22.5 g (69% of theory) of ethyl-6-benzhydryl-aminocaproate [B.P. 162 to 167~ (0.02 mm Hg)].
b) N-acetyZ-6-benzhydryZconinocaproic acid Analogous;ly to Exa~ple 19, 8 g of ethyl 6-benzhydrylamino-~123433 caproate and 3.5 g of ethyl diisopropylamine are dissolved in 100 ml of benzene and reacted with 2~1 g of acetyl chloride. As reaction product one obtains 9 g of ethyl N-acetyl-6-benzhydrylaminocaproate as a viscous non-distillable oil. The saponification of this ester gives 7.3 g (87.5%) of ~1-acetyl-6-benzhydrylamino-caproic acid (M.P. ll9~ to 20).

IY-isobuty~ryZ-6-oenzhydry Zom*nocopro3c ocid Rl = -CH(CH3)2, R2 = -H, R3 = R4 = phenyl, n = 5 Analogously to Example l9, 7 g of ethyl 6-benz- i`
hydrylaminocaproate and 3_1 g of ethyl diisopropylamine are dissolved in 100 ml of benzene and reacted with 2.5 g of isobutyryl chloride. As reaction product one obtains 7.8 g of ethyl N-isobu~yryl-6-benzhydrylaminocaproate as a viscous non-distillable oil. The saponification of this ester yields 6.1 g (77%) of N-isobutyryl-6-benzhydrylamino-caproic acid (M.P. 106 to 107).

ExAMæLE 37 ~-ocety~-5-benzhydryZ~m~novaZer*c acid Rl = -CH3, R2 = -H, R3 = R4 = phenyl, n = 4 , : . - : : ,, .

3~33 ~6 _ ~ _ a) Ethy1 5-benzhydry2c~rri,novaZerate 25.1 y of ethyl 5-bromovalerate, 66 g of benzhydryl-amine and 30 ml of cyclohexane are stirred at room temperature for 15 days. Processing analogously to Example 19 yields 23~4 g (6~.6~) of ethyl 5-benzhydryl-aminovalerate [B.P. 158 to 163 (0.01 mm Hg)].

b) ~-acetyZ-5-benzhydryZomnnovoZe~c acid Analogously to Example 19, 9 g of ethyl 5-benzhydryl-aminovalerate and 4~1 g of ethyl diisopropylamine are dissolved in 100 ml of benzene and reacted with 2.5 g of acetyl chloride. As reaction product one obtains

10 g of ethyl N-acetyl-5-benzhydrylaminovalerate as a viscous non-distillable oil. The saponification of this ester gives 7.4 g (78.7~) of N-acetyl-5-benz-hydrylaminovaleric acid (M.P. 135 to 136).

N-crotonoyZ-5-ben2hydrylominovaZer*c ac~d Rl = -CH=CH-C~3, R2 = _~, R3 = R4 = phenyl, n = 4 Analogously to Example 19, 7 g of ethyl 5-benz-hydrylaminovalerate and 3.2 g of ethyldiisopropylamine are dissolved in 100 ml of benzene and reacted with 2.6 g of crotonyl chloride. As reaction product one obtains 8.5 g of ethyl N-crotonoyl-5-benzhydrylaminovalerate as a viscous non-distillable oil. The saponification of this ester yields 6 g (76%) of N-crotonoyl-5-benzhydrylamin~valeric acid (M.P. 88 to 89).

3~3 ,~
~Q

N-(p-chZol~o)benzoyZ-~-tL(-)~ methyZbenzyZJamino]b~tyric acid Rl = p-chlorophenyl, p~2 = -H, R3 - -CH3, R4 = phenyl, n = 3 Analogously to Example 1, ethyl N-(p-chloro)benzoyl-4-L(-)-(~-methylbenzylamino)butyrate (viscous, non-distillable oil) is obtained by reacting the reaction product of ethyl 4-bromobutyrate and L(-)-a-methylbenzylamine with p~chloro-benzoylchloride, the saponiication of which gives N-(p-chloro~benzoyl-4-[~(-)-(a-methylbenzyl)amino]butyric acid (M.P. 93 to 94; [~]D -142.5).

~-saZicy~oyl-4-benzhy~yZominobutyr w acid Rl = o-hydroxyphenyl, R2 = _~, R3 = R4 = phenyl, n = 3 13.3 g of ethyl 4-benzhydrylaminobutyrate (Example l~a) and 6.4 g of ethyldiisopropylamine are dis-solved in 80 ml of benzene. A solution of 9.8 g of 0-acetyl-salicyloyl chloride i~ 20 ml of benzene is added dropwise thereto while cooling and stirring. The mixture is mixed with diethyl ether after a further 4 hours; the precipitated salt is filtered off: and the filtrate is concentrated by evaporation. The evaporation residue is purified by chromatography over a silica gel column with methylene chloride as eluent to obtain 18.6 g (90.5 percent of theory) ... : . ....

~lZ3~33 of ethyl N-(o-acetoxy)benzoyl-4-benzhydrylaminobUtyrate in the form of a colorless, viscous, non-distillable oil. This oil is dissolved in 200 ml of benzene. A solution of 5.7 g of potassium hydroxide in 30 ml of ethanol is added. The reaction mixture is kept for 20 hours at room temperature, diluted with diethyl ether and then extracted with water.
The aqueous phase is acidified with dilute hydrochloric acid. The resulting precipitate is filtered off, dried and recrystallized from ethyl acetate/ligroin to obtain 13.0 g t82.5 percent of theory) of N-salicyloyl~4-benzhydrylamino-butyric acid (M.P. 162 to 163~).

Ampoules with 600 mg of N-(p-chlorobenzoyl)-4-(1-phenylethylamino)butyric acid, size of batch 250 kg N-(p-chlorobenzoyl)-4-(1-phenyl-ethylamino)butyric acid 15 kg Caustic soda solution (10% by wt. NaOH) approx. 17 kg 1,2-propyleneglycol 25 kg Sodium pyrosulfite 0.0625 kg Double-distilled water to make up ,o 250 kg 25.0 kg of 1,2-propyleneglycol and 15C.0 kg of water are placed in a vessel, 15.000 kg of N-(p-chloroben-zoyl)-4-(1-phenylethylamino)butyric acid are added and then there is added slowly, while stirring, caustic soda solution.
When everything has dissolved, the resulting solution is - . - ::, , .- ,, - .
., " , , .. , , ~
. ! ` ', ' '. . , . . .. , ~:
: ~ . ' ' . . , ,~, ' ' . . : . . .
~. , ' ' ,' ' , ' . .

-~q-adjusted with caustic soda solution to a pH of from 7.5 to 8Ø Sodium pyrosulfite is added and the mixture stirred until everything has dissolved. It is made up to 250 kg with the rest of the water. The solution is packed in 10-ml ampoules and sterilized in an autoclave for 30 minutes at 120 C.

Ampoules containing 600 mg of N-(p-chloro)benzoyl-4-benz~ydrylaminobutyric acid, size of batch 250 kg.

N-(p-chloro)benzoyl-4-benzhydryl-aminobutyric acid 15 kg Caustic soda solution ~10~ by wt. NaOH) approx. 15 kg 1,2-propyleneglycol 50 kg Double-distilled water to make up to 250 kg 50 kg of 1,2-propyleneglycol and 150 kg of water are placed in a vessel. Then N-(p-chloro)benzoyl-~-benz-hydrylaminobutyric acid is added while stirring. 15 kg of caustic soda solution are added, and the resulting mixture is then adjusted to a pH of 8Ø This is made up to 250 kg with water. The solution is packed into 10-ml ampoules and sterilized in an autocalve for 30 minutes at 120.

, :~
:.

1~23433 1~

ExAMæLE 43 Tablets containing 50 mg of N-(p-chloro)benzoyl-4-benzylaminobutyric acid N-(p-chloro)benzoyl-4-benzylarninobutyric acid 25 kg Lactose 35 kg Maize starch 26 kg Polyvinylpyrrolidone (mol. wtapprox. 25,000) 2.5 kg Carboxymethylcellulose 8 kg Talcum 2.5 kg Magnesium stearate lO0 kg The N (p-chloro)benzoyl-4-benzylaminobutyric acid, the lactose and the maize starch are granulated with poly-vinylpyrrolidone in approximately 6 liters of water. The granulate is sieved through a sieve with a mesh width of 1.25 mm and, after drying, the carboxymethylcellulose, the talcum and the magnesium stearate are added. The dry granulate is pressed into tablets with a diameter of 8 mm, a weight of ~;
250 mg and a hardness of 5 to 6 kg.
In a similar way tablets are produced with N-acetyl-4-benzhydrylaminobutyric acid or N-(p-chloro)benzoyl-4-(l-phenylethylamino)butyric acid.

- ., ~ . , ~: . . . . .

~' '' ~ , ,,. `'' ': ' 1~3433 ~1 Ex~MæLE 44 Tablets containing 100 mg of N-(p chloro)benzoyl-4-~(1,2-diphenylethyl)amino]butyric acid N-(p~oro)benzoyl-4-~(1,2-diphenyl-ethyl)amino]butyric acid 40 kg Lactose 24 Xg Maize starch 1~ kg Polyvinylpyrrolidone (mol. wt. approx. 25,000) 4 kg Carboxymethylcellulose 10 kg Talcum 4 kg ~agnesium stearate 2 kg 100 kg The N-(p-chloro)benzoyl-4-[(1,2-diphenylethyl)-amino~butyric acid, the lactose and the maize starch are granulated with the polyvinylpyrrolidone in approximately 5.5 liters of water and forced through a sieve with a mesh width of 1.25 mm. After drying, the carboxymethylcellulose, the talcum and the magnesium stearate are added. The granulate is pressed on an eccentric tabletting machine into tablets of 9 mm. diameter, 250 mg weight and a hardness of from 4 to 5 kg.
In a similar manner N-(p-chloro)benzoyl-6~
phenylethylamino)caproic acid or N-(p-chloro)benzoyl-4-(l-adamantyl)aminobutyric acid is pressed into tablets with and active principle content of 100 mg.

., : .. ~ ; ~ .
.. ,: :

lL~LZ3~33 1~
~, EX~LE 45 Tablets containing 300 mg of N-(p chloro)benzoyl-4-cyclooctylaminobutyric acid.

N-(p-chloro)benzoyl-4-cyclooctylaminobutyric acid 60 kg ~actose 12 kg Maize starch 8 kg Polypyrrolidone (mol. wt. approx. 25,000)4 kg Carboxymethylcellulose 10 kg Talcum 4 kg Magnesium stearate 2 kg 100 kg N-(p-chloro)benzoyl-4-cyclooctylaminobutyric acid, the lactose and the maize starch are granulated with `
the polyvinylpyrrolidone in approximately 6 liters of water and pressed through a sieve with a mesh width of 1.25 m~. After drying the carboxymethylcellulose, the talcum and the magnesium stearate are added. The granulate is pressed on a rotary pelleting machine into tablets with a diameter of 11 mm, a weight of 500 mg and a hardness of 6 to 7 kg.

- : " ' .. .

: . ' ' ~ `;

1~3433 - q3 10,000 capsules with an active principle content of 50 mg are produced from the following ingredients:
500 g of N-~p-chloro)benzoyl-4-benzhydrylamino-butyric acicl 495 g of microcrystal.line cellulose 5 ~ of amorphous si.lica 1000 g The active principle in finely-powdered form, the cellulose and the silica are thoroughly mixed and packed into hard gelatin capsules of size 4.
' Pharmaco Zogy Acylhydrocarbylamino acids of formula I-and their pharmacologically-acceptable salts exert a marked influence on the pancreatic secretion of narcotized rats;
they influence the bile secretion of narcotized rats and exert an antihepatotoxic activity on wakeful rats, in which they are found to be superior to known commercial prepara-tions, such as Pipro~oline.
In the tables which follow the compounds investi-gated are characterized by a serial number which is allocated as follows:

,u : " ,, " ~ .
, ,~
.::

~L:lZ~433 q~

SeriaZ No. Name of Compo7~d 1 Piprozoline 2 N-(p-chloro)benzoyl-4-(tert.-butylamino)-butyric acid 3 N-(p-chloro)benzc)yl-4-[(2-methyl-3-butyn-2-yl)-amino]bl~tyric aci.d 4 N-(p-chloro)benzoyl-4-[53-ethyl-1-pentyn-3-yl)-amino]butyric aci.d N-(p-chloro)benzoyl-4-[(1-ethynylcyclohexyl-1)-amino]butyric acid 6 N-(p-chloro)benzoyl-4-(1-adamantyl)amino-butyric acid :
7 ~ N-(p-chloro)benzoyl-4-[(1,1,3,3-tetramethyl-butyl)amino]butyric acid 8 N-acetyl-4-[(1-ethynylcyclohexyl-1)-amino]-butyric acid 9 N-(p-chloro)benzoyl-4-homovçratrylamino-butyric acid N-(p-chloro)benzoyl-4-(1-phenylethylamino)-butyric acid

11 N-(2~4-dichloro)benzoyl-4-E(l~l-dimethylpropyl) amino]butyric acid

12 N-(p-chloro)benzoyl-4-benzhydxylaminobutyric :~
acid

13 N-(p-chloro)benzoyl-6-(1-phenylethylamino) caproic acid

14 N-acetyl-4-benzhydrylaminobutyric acid N-(p-chloro)benzoyl-4-benzylaminobutyric acid 16 N-(p-fluoro)benzoyl 4-(1,1,3,3-tetramethyl-butyl)aminobutyric acid 17 N-(p-chloro)benzoyl-4-[(1,2-diphenylethyl)-amino]butyric acid 18 N-(p-chloro)benzoyl-4-cyclooctylaminobutyric acid ,, ` '' ~ ' ,: .

- ~lZ39~33 Table I reflects data from investigations of the pancreatic secretion of narcotized rats af~er intraduodenal application (ED50) and the lethal actiorl on the mouse (LD50) after intraperitoneal application of representative compounds of formula I I - - -I according to the invention and also the therapeutic quotient (TQ =. LD50JDEso).

TA~3LE I

Pencreatic Secretion, ~o~icity end Therepe~t~c Quotient SerialToxicity Pancreatic &cretion TQ
10No.LD50 (mg~kg)ED50+) (mg/kg) (LD50/ED50) (mouse, i.p.) (rat, i.d.) .

11070+~) 35 31

15 7 220 2 110 8 >>1000 10 100 1200 ~20 ~ 60 12 250 ~ 0.1 ~2500 14 llO0 ~5 ~220 350 1;5 233

16 400 -10 ~40

17 160 -1 -160 2518 150 2.5 60 +) ED50 ' dose ~hich brings about an increa-~e in the pancreatic secretion (liquid volumle; 30-min. fraction~ by a maximum of 50X.
~+) LD50 (P--) cited from Herrmann et al, Ar~ne~m.-Forsch. 27 (1977) 467.

. ~ ~

,, . ` . , '.- .

- 1~

Table II reflects data from investigations of the bile secretion (choleresis) of narcotized rats after intra-duodenal application (ED50) and lethal action on the mouse (LD50) after intraperitoneal application of representative compounds of formula I according to the invention and also the therapeutic quotient (TQ = LD50/ED50).

TABLE II
Bi~e Secretion, To-~icity ond Therope~tic Q~o~ent Serial No. ToxicityBile Secretion TQ
LD50 (mg/kg)ED;o+t+) (mg/kg) 50 50) (use, i.p.)(rat, i.d.) 1 1070+~ 40 27 3 >100~ 25 >40 1200 -15 ~80 .
++~) ~D50 ~ the dose which brings about an increase in the bile secretion (liquid ~olume; 30-min. fraction) by a maximum of 50%
+*) LD50 (P~~) cited from ~errmann et al, Arzneim.-Forsch., 27 (1977) 467.

' .: .. ` , , '. , ' ,.

.

..
' : ' llZ3~33 Table III reflects data from investigations on the antihepatotoxic action (ED50) of compounds o~ formula -- II according to the invention after oral application on wakeful rats and the lethal action after intraperitoneal application on the ~ouse (LD50), as well as the therapeutic quotient (TQ = LD50/ED50).

TABLE III
Antihepatotoxic Effect, Toxicity ond Iheropeutic ~uotient . _ .
Serial No. Toxicity Antihepatotoxic Effect TQ
LD50 (mg/kg) 50++++) g g (LD50/ED
(mouse, i.p.) - (rat, p.o.) .. , ~, .. . .
11070++) ~300 <3.6 3>1000 100 >10 9780 100 7.8

18 150 8 18.8 Illl) ED50 ~ the dose which shortens the hexobarbital narcosis by - :
50Z of rats with liver da~age fro~ CC14.
~+) LD50 (p.o.) cited from Herrmann et al., Arzneim.-Forsch., 27 (1977) 467.

.

:., , . ~, ;, , ~
,. ! ., - ... , ... ,., ...... ~.,,- . ...... ...

.,. ` ~ . : .;',. ", . .... . : .

7~
~,Q
The determination of the pharmacological properties was carried out by the following methods:
InfZuence on the Poncreatic ond BiZe Secretion of the Norcoti~ed Ret Execution of e~per*men~:
Male Sprague Dawley rats (body weight from 250 to 300 g) are narcotized with 1.2 g/kg urethane i.m. Then the abdominal cavity is opened medially, the bile duct is ligatured snortly above the place where it leads into the duodenum aind also near to the hepatic duct, and both sections are catheterized towards the liver.
As in the rat all the pancreatic ducts lead out into the central section of the bile duct; it is possible in this way to discharge the panc~eatic secretion separately from the distal (ligatured) section and the bile separately from the proximal section of the bile duct.
The quantities of pancreatic juice and bile juice obtained are measured at intervals of 30 minutes over a period from 2 hours before to 3 hours after the intraduodenal (V. jugularis externa) administration of the compounds to be tested (quantity of liquid administered 5 ml/kg).
The body temperature of the animals is maintained `
at 36 to 38 C by means of electric blankets and radiation;
the temperature is monitored rectally.

2 5 EvaZt~a~ion:
The liquid volumes of the 30 minute fractions after the administration of the substance are related in each case .. . ........... . . .
., .: . ~-.: i . ,.
, ~ ~Z34~3 -: lq to the quantity of bile or pancreatic juice secreted prior to the application of the substance (- 100%, mean of the last two measurements). The maximum percentage increase in the pancreatic or bile secretion is represented in dependence upon dose, and from this the ED50 is detenmined by interpola~ion.

~est for A~t~hepatotos*c Effect In~Zuen~e on the Duratzon of ~e~oborb~ta~
SZeep of the Rat aJter Liver ~omage by CCZ~ -~ ecution of test:
In accordance with VOGEL et al. Cflr2neim.-Forsch., 25 (1975) 82], liver cell damage is produced in fasting female Sprague-Dawley rats tl90 + 10 g body weight, 10 animals/dose per test batch) by oral administration of carbon tetrachloride (0.15 mg/kg CC14 in 2.5 ml/kg olive oil), and the extent of this damage is determined by prolonging the sleeping periods induced by hexobarbital sodium (50 mg/ml/kg i.v.; caudal vein, duration of injection 45 to 60 seconds) 47 hours after the administration of the CC14. The compounds to be tested are administered 1 hour prior to the administration of CC14 orally in a liquid volume of 10 ml/kg.

EvaZuat~on The antihepatotoxic effect of the compounds to be tested (sodium salts in aqueous solution) is determined by . . . -, ~ :

: ~23433 the reduction of the prolongation of sleeping period caused by the CC14 liver cell damage in the groups treated, as compared with the prolongation of the sleeping period of the CC14 control group ~= 100%). The ED50 is determined by interpolation from the dose/effect curve.

Deterl7ri,rlation of ~osicity The toxicity investigations are carried out on female NMRI mice (body weight 22 to 26 g). The animals (5 animals per dose) are given food and water ad Zib.
Different doses of the substances are administered intra-peritoneally. The duration of observation is 14 days.
The LD50, i.e. the dose at which 50~ of the animals die, is determined graphically from the dose/effect curve.

Claims (40)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. Process for the production of acylhydrocarbylaminoalkanoic acids of the general formula I

(I) in which R1 signifies an alkyl radical with 1 to 7 carbon atoms, an alkenyl or alkinyl radical with 2 to 7 carbon atoms, a cycloalkyl radical with 3 to 10 carbon atoms or a phenyl radical R2 signifies a hydrogen atom, an alkyl group with 1 to 7 carbon atoms, an alkenyl or an alkinyl radical with 2 to 7 carbon atoms, R3 signifies a hydrogen atom, an alkyl group with 1 to 7 atoms, a cycloalkyl group with 3 to 10 carbon atoms or a phenyl radical R4 signifies an alkyl group with 1 to 7 carbon atoms, a cycloalkyl group with 3 to 10 carbon atoms, a phenyl radical or a phenalkyl radical with 1 to 4 carbon atoms in the alkyl group and with the phenyl radical (with the proviso that R4 has at least 3 carbon atoms when R4 is alkyl, R2 is hydrogen or methyl, R3 is hydrogen, and R1 is alkyl or a phenyl radical as defined above), or R3 and R4 together constitute an alkylene group with 2 to 8 carbon atoms, or R2, R3 and R4, together with the neighbouring carbon atom, form an adamantyl radical, n signifies 3, 4 or 5 R5, R6 and R7 are the same or different and signify a hydrogen atom, a halogen atom, an alkyl group with 1 to 4 carbon atoms, an alkoxy group with 1 to 4 carbon atoms, an alkylmercapto group with 1 to 4 carbon atoms, an alkanoyloxy group with 2 to 5 carbon atoms, an amino group, a hydroxy group, a nitro group, a trifluoromethyl group, a trifluormethoxy group or a trifluormethylmercapto group, and also their pharmacologically compatible salts of inorganic or organic bases, characterised by the fact that a) a hydrocarbylaminoalkanoic acid of the general formula II

(II) in which R2, R3, R4 and n have the meanings given above, if desired with protection of the carboxyl group, is acylated with an acyl derivative of the general formula III

R1-CO-R8 (III) in which R8 signifies a leaving group or a R1-CO-O group, and R1 has the meaning given above; or b) a hydrocarbylaminoalkenoic acid of the general formula IV

(IV) in which R1, R2, R3 and R4 have the meanings given above, if required with protection of the carboxyl group, is hydrogenated; or c) an acylaminoalkanoic acid of the general formula V

(V) in which R1 and n have the meanings given above and R9 is a hydrogen atom or a metal atom of an alkali or alkaline earth metal, if required with protection of the carboxyl group, is reacted with a hydrocarbyl derivative of the general formula VI

(VI) in which R2, R3 and R4 have the meanings given above and R10 represents a leaving group; or d) a functional acylhydrocarbylaminoalkanoic acid derivative of the general formula VII

(VII) in which R1, R2, R3, R4 and n have the meanings given above and A is a functional derivative of a carboxyl group, is solvolysed;
and where required a free acid of formula I is then converted into a pharmacologically compatible salt thereof with an inorganic or organic base.

2. A process according to claim 1 for the production of the acylhydrocarbylaminoalkanoic acids of the general formula I*

(I*) wherein R1* signifies an alkyl, alkenyl or alkinyl radical with up to 5 carbon atoms, a cycloalkyl radical with 5 to 7 carbon atoms or a phenyl radical R2* signifies a hydrogen atom, an alkyl, alkenyl or alkinyl group with up to 5 carbon atoms, R3* signifies a hydrogen atom or an alkyl group with 1 to 5 carbon atoms, R4* signifies an alkyl group with 1 to 5 carbon atoms (with the proviso that R4* has at least 3 carbon atoms when R2* is hydrogen or methyl, R3* is hydrogen, and R1* is alkyl or a phenyl radical as defined above), n* signifies 3, 4 or 5, R5*, R6* and R7* are the same or different and signify a hydrogen atom, a fluorine, chlorine or bromine atom, an alkyl group with 1 to 4 carbon atoms, an alkoxy group with 1 to 4 carbon atoms, an alkanoyloxy group with 2 to 5 carbon atoms, an amino group, a hydroxy group, a nitro group, or a trifluoromethyl group.

3. A process according to claim 1 for the production of the acylhydrocarbylaminoalkanoic acids of the general formula I**

(I**) wherein R1** signifies an alkyl, alkenyl or alkinyl radical with up to 5 carbon atoms, a cycloalkyl radical with 5 to 7 carbon atoms or a phenyl radical R2** signifies a hydrogen atom, an alkyl, alkenyl or alkinyl group with up to 5 carbon atoms, R3** signifies a hydrogen atom, an alkyl group with 1 to 5 carbon atoms or a cycloalkyl group with 5 to 7 carbon atoms, R4** signifies a cycloalkyl group with 5 to 7 carbon atoms or R3** and R4** together constitute an alkylene group -(CH2)q** or R2**, R3** and R4** together with the neighbouring carbon atom form an adamantyl radical, n** signifies 3, 4 or 5, q** signifies 4, 5, 6 or 7, R5**, R6** and R7** are the same or different and signify a hydrogen atom, a fluorine, chlorine or bromine atom, an alkyl group with 1 to 4 carbon atoms, an alkoxy group with 1 to 4 carbon atoms, an alkanoyloxy group with 2 to 5 carbon atoms, an amino group, a hydroxy group, a nitro group, or a trifluoromethyl group.

4. A process according to claim 1 for the production of the acylhydrocarbylaminoalkanoic acids of the general formula I***

(I***) wherein R1*** signifies an alkyl, alkenyl or alkinyl radical with up to 5 carbon atoms, a cycloalkyl radical with 5 to 7 carbon atoms or a phenyl radical R2*** signifies a hydrogen atom or an alkyl group with 1 to 5 carbon atoms, R3*** signifies a hydrogen atom, an alkyl group with 1 to 5 carbon atoms or a phenyl radical R4*** signifies a phenyl radical or a phenalkyl radical n*** signifies 3, 4 or 5, p*** signifies 1, 2, 3 or 4, R5***, R6*** and R7*** are the same or different and signify a hydrogen atom, a fluorine, chlorine or bromine atom, an alkyl group with 1 to 4 carbon atoms, an alkoxy group with 1 to 4 carbon atoms, an alkanoyloxy group with 2 to 5 carbon atoms, an amino group, a hydroxy group, a nitro group, or a trifluoromethyl group.

5. A process according to claim 1 for the production of the acylhydrocarbylaminoalkanoic acids of the general formula I****

(I****), wherein R1**** signifies an alkyl, alkenyl or alkinyl radical with up to 5 carbon atoms, a cycloalkyl radical with 5 to 7 carbon atoms or a phenyl radical R2**** signifies an alkenyl or an alkinyl radical with 2 to 5 carbon atoms, R3**** signifies a hydrogen atom or an alkyl group with 1 to 5 carbon atoms, R4**** signifies a phenyl radical or a phenalkyl radical -(CH2)p****

n**** signifies 3, 4 or 5, p**** signifies 1, 2, 3 or 4, R5****, R6**** and R7**** are the same or different and signify a hydrogen atom, a fluorine, chlorine or bromine atom, an alkyl group with 1 to 4 carbon atoms, an alkoxy group with 1 to 4 carbon atoms, an alkanoyloxy group with 2 to 5 carbon atoms, an amino group, a hydroxy group, a nitro group, or a trifluoromethyl group.

6. Process according to claim 1, characterised by the fact that A, A*, A**, A*** and A**** signify a -CN group or a group, in which X signifies an oxygen or a sulphur atom or a substituted nitrogen atom and Y signifies a hydroxy group or a monovalent eliminable electrophilic radical, Y not being a hydroxy group if X represents an oxygen atom.

7. Process according to claim 3, characterised by the fact that A, A*, A**, A*** and A**** signify a -CN group or a group, in which X signifies an oxygen or a sulphur atom or a substituted nitrogen atom and Y signifies a hydroxy group or a monovalent eliminable electrophilic radical, Y not being a hydroxy group if X represents an oxygen atom.

8. Process according to claim 5, characterised by the fact that A, A*, A**, A*** and A**** signify a -CN group or a group, in which X signifies an oxygen or a sulphur atom or a substituted nitrogen atom and Y signifies a hydroxy group or a monovalent eliminable electrophilic radical, Y not being a hydroxy group if X represents an oxygen atom.

9. Process according to claim 6, 7 or 8, characterised by the fact that X signifies an oxygen or a sulphur atom or an imino, alkylimino or hydroxyimino group and Y signifies a hydroxy group, or a group convertible thereto by solvolysis selected from a free or substituted amino group, a free or substituted mercapto group, a substituted hydroxy group, an azido group and chloro and bromo radicals, Y not being a hydroxy group if X represents an oxygen atom.

10. Process according to claim 6, 7 or 8, characterised by the fact that X signifies an oxygen or a sulphur atom or an imino, alkylimino or hydroxyimino group and Y signifies a hydroxy group or an amino group, a monoalkylamino or dialkylamino or arylamino group, a hydroxyamino or hydrazino group, a hydrazobenzene group, a 2-hydroxyethylamino group, a morpholino group, a piperidino group, a mercapto group, an alkylthio group, an alkoxy group, an azido, a chloro or bromo radical, Y not being a hydroxy group if X

represents an oxygen atom.

11. Process according to claim 6, 7 or 8, characterised by the fact that X signifies an oxygen atom, a sulphur atom or an imino group and Y signifies an amino, monoalkylamino, dialkylamino, phenylamino, alkoxy, alkylthio, chloro or bromo radical.

12. A process according to claim 1, 2 or 3 wherein n, n* or n** signifies 3.

13. A process according to claim 4 or 5 wherein n*** or n****
signifies 3.

14. A process according to claim 2 wherein R1* signifies an alkyl, alkenyl or alkinyl radical with up to 5 carbon atoms or a phenyl radical substituted with R5*, R6* and R7*, R2* signifies a hydrogen atom, an alkyl group with 1 to 4 carbon atoms or an ethinyl group, R3* signifies a hydrogen atom or an alkyl group with 1 to 3 carbon atoms, R4* and n* are as defined in claim 2, R5* signifies a hydrogen atom, R6* and R7* are the same or different and signify a hydrogen atom, a fluorine, chlorine or bromine atom, a methyl group, a methoxy group, an amino group or a trifluoromethyl group.

15. A process according to claim 2, wherein R1* signifies an alkyl, alkenyl or alkinyl radical with 1 to 5 carbon atoms or a phenyl radical substituted with R5*, R6* and R7*, R2* signifies a hydrogen atom, a methyl group or an ethinyl group, R3* signifies a hydrogen atom or a methyl group, R4* and n* are as defined in claim 2, R5* signifies a hydrogen atom, R6* signifies a hydrogen atom, a chlorine atom, a methoxy group or a trifluoromethyl group, and R7* signifies a hydrogen atom, a chlorine atom or a methoxy group.

16. A process according to claim 15, wherein n* signifies 3.

17. A process according to claim 3, wherein R1** signifies an alkyl, alkenyl or alkinyl radical with up to 5 carbon atoms or a phenyl radical substituted with R5**, R6** and R7**, R2** signifies a hydrogen atom, an alkyl group with 1 to 4 carbon atoms or an ethinyl group, R3** signifies a hydrogen atom, a methyl group or a cyclohexyl group, R4** signifies a cyclohexyl group, or R3** and R4** together constitute an alkylene group -(CH2)q** or R2**, R3**
and R4** together with the neighbouring carbon atom form an adamantyl-(l) radical, n** and q** are as defined in claim 3, R5**
signifies a hydrogen atom, and R6** and R7** are the same or different and signify a hydrogen atom, a fluorine, chlorine or bromine atom, a methyl group, a methoxy group, an amino group or a trifluoromethyl group.

18. A process according to claim 3, wherein R 1** signifies an alkyl, alkenyl or alkinyl radical with up to 5 carbon atoms or a phenyl radical substituted with R5**, R6** and R7**, R2** signifies a hydrogen atom, a methyl group or ethinyl group, R3** and R4**

together constitute an alkylene group -(CH2)q** or R2** , R 3** and R4** together with the neighbouring carbon atom constitute an adamantyl-(1) radical, n** is as defined in claim 3, q** signifies 5 or 7, R5** signifies a hydrogen atom, R6** signifies a hydrogen atom, a chlorine atom, a methoxy group or a trifluoromethyl group, and R7** signifies a hydrogen atom, a chlorine atom or a methoxy group.

19. A process according to claim 18, wherein n** signifies 3.

20. A process according to claim 4, wherein R1*** signifies an alkyl, alkenyl or alkinyl radical with up to 5 carbon atoms, or a phenyl radical substituted with R5***, R6*** and R7***, R2***
signifies a hydrogen atom or an alkyl group with 1 to 4 carbon atoms, R3*** signifies a hydrogen atom, an alkyl group with 1 to 3 carbon atoms or a phenyl radical substituted with R7***, R4***
signifies a phenyl radical substituted with R7*** or a benzyl radical substituted with R7***, n*** is as defined in claim 4, R5*** signifies a hydrogen atom and R6*** and R7*** are the same or different and signify a hydrogen atom, a fluorine, chlorine or bromine atom, a methyl group, a methoxy group, an amino group or a trifluoromethyl group.

21. A process according to claim 4, wherein R1*** signifies an alkyl, alkenyl or alkinyl radical with up to 5 carbon atoms or a phenyl radical substituted with R5*** , R6*** and R7***, R2***
signifies a hydrogen atom, R3*** signifies a hydrogen atom, a methyl group, or a phenyl radical substituted with R7***, R4*** signifies a phenyl radical substituted with R7*** or a benzyl radical substituted with R7***, n*** is as defined in claim 4, R5***

signifies a hydrogen atom, R6*** signifies a hydrogen atom, a chlorine atom, a methoxy group or a trifluoromethyl group, and R7*** signifies a hydrogen atom, a chlorine atom or a methoxy group.

22. A process according to claim 21, wherein n*** signifies 3.

23. A process according to claim 5, wherein R1**** signifies an alkyl, alkenyl or alkinyl radical with up to 5 carbon atoms or a phenyl radical substituted with R5****, R6**** and R7****, R2****
signifies an ethinyl group, R3**** signifies a hydrogen atom or an alkyl group with 1 to 3 carbon atoms, R4**** signifies a phenyl radical substituted with R7**** or a benzyl radical substituted with R7****, n**** is as defined in claim 5, R5**** signifies a hydrogen atom and R6**** and R7**** can be the same or different and signify a hydrogen atom, a fluorine, chlorine or bromine atom, a methyl group, a methoxy group, an amino group or a trifluoromethyl group.

24. A process according to claim 5, wherein R1**** signifies an alkyl, alkenyl or alkinyl radical with up to 5 carbon atoms or a phenyl radical substituted with R5****, R6**** and R7****, R2****

signifies an ethinyl group, R3**** signifies a hydrogen atom or a methyl group, R4**** signifies a phenyl radical substituted with R7**** or a benzyl radical substituted with R7****, n**** is as defined in claim 5, R5**** signifies a hydrogen atom, R6****
signifies a hydrogen atom, a chlorine atom, a methoxy group or a trifluoromethyl group, and R7**** signifies a hydrogen atom, a chlorine atom or a methoxy group.

25. A process according to claim 24, wherein n**** signifies 3.

26. A process according to claim 1, wherein R1 is p-chlorophenyl, R2 is H, R3 is CH3, R4 is phenyl and n is 3.

27. A process for the preparation of N-(p-chloro)benzoyl-4-(1-phenylethylamino)butyric acid which comprises acylating ethyl 4-(1-phenylethylamino)butyrate with p-chlorobenzoyl chloride, and saponifying the resulting intermediate.

28. A process according to claim 1 wherein R1 is CH3, R2 is H, R3 is phenyl, R4 is phenyl and n is 3.

29. A process for the preparation of N-acetyl-4-benzyhydryl-aminobutyric acid which comprises acylating ethyl 4-benzhydryl-aminobutyrate with acetyl chloride, and saponifying the resulting intermediate.

30. A process according to claim 1 wherein R1 is p-chlorophenyl, R2 is H, R3 is phenyl, R4 is phenyl and n is 3.

31. A process for the preparation of N-(p-chloro)benzoyl-4-benzhydrylaminobutyric acid which comprises acylating ethyl 4-benzhydrylaminobutyrate with p-chlorobenzoyl chloride, and saponifying the resulting intermediate.

32. A process according to claim 1 wherein R1 is p-chlorophenyl, R2 is H, R3 is H, R4 is phenyl and n is 3.

33. A process for the preparation of N-(p-chloro)benzoyl-4-benzylaminobutyric acid which comprises acylating 4-benzylamino-butyric acid with p-chlorobenzoyl chloride, and saponifying the resulting intermediate.

34. A process for the preparation of N-(p-chloro)benzoyl-4-benzylaminobutyric acid which comprises subjecting N-(p-chloro) benzoyl-4-benzylaminobutyronitrile to solvolysis.

35. A process for the preparation of N-(p-chloro)benzoyl-4-benzylaminobutyric acid which comprises reacting the N-potassium derivative of N-(p-chloro)benzoyl-4-aminobutyric acid with benzyl chloride and hydrolysing the resulting intermediate benzyl ester.

36. Acylhydrocarbylaminoalkanoic acids of the general formula I
defined in claim 1, and their pharmacologically compatible salts with inorganic or organic bases, when prepared by the process of claim 1 or by an obvious chemical equivalent thereof.

37. N-p-chlorobenzoyl-4-(1-phenylethylamino)butyric acid when prepared by the process of claim 27 or by an obvious chemical equivalent thereof.

38. N-acetyl-4-benzhydrylaminobutyric acid when prepared by the process of claim 29 or by an obvious chemical equivalent thereof.

39. N-p-chlorobenzoyl-4-benzhydrylaminobutyric acid when prepared by the process of claim 31 or by an obvious chemical equivalent thereof.

40. N-p-chlorobenzoyl-4-benzylaminobutyric acid when prepared by the process of claim 33, 34 or 35 or by an obvious chemical equivalent thereof.