CA1101871A - Long-chain fatty acid amides and hydrazides and cyclopropano analogues thereof, their production and their use as anti-atherosclerotic agents - Google Patents

Abstract

Abstract of the Disclosure:
The invention provides novel compounds of the type

Description

~` CaseC~`6~ '796 "

LoNG-cHAIN FATTY ACID AMIDES ANDHYDRAZIDES AN~ CYCLOPROP~NO
~ ND THEIR USE AS
ANTI-ATHEROSCLEROTIC AGENTS

:' T~e present invention provides compounds of formula I, . O Rl , .
A C - N - R
, ,:
in which A is (i) the residue of a long-chain,unsatur-ated fatty acid (minus the carboxylic acid `~
. function), which residue has 7 to ~3 carbon atoms and possesses from 1 to 4 ethylenic-ally unsaturated groupings, or (ii) a cor~
responding residue in which each ethylene ~-CH=CH-) grouping is replace~ by a cyclo-propanyl ~roup ( C/H 2\C~ ) ;
. ~
; and either a) Rl is hydrogen, and R~ is a radical of formula II, III, IV or V~ . , ~`.

' .:,' :: :
-:
.. ,. :
: ~ ~ , :, : ', 7~L

- 2 ~ ~0~-6796 ~~NH)h~CH~(CHz)g ~ II

in which h is 0 or 1, g is 0 or 11 R4 is hydrogen, fluorine, chloriner bromine or Cl 3alkyl or a lkoxy, R5 ls hydrogen, fluorine, chlorine, or Cl 3alkyl or alkoxy, and R3 is hydrogen, Cl 8alkyl or a radical of formula VI/

~CH2)j ~ VI

- in which j is 0 or 1, .~ ~o Y is hydrogen, fluorine, chlor-ine, bromine or C1 3alkyl or alkoxy, and Yl ls hydrogen, fluorine, chlor-:~ ine or Cl 3alkyl or alkoxy, )h ~ R5 III
,~
in which h and R5 are as def ined above, and R6 is hydrogen, f luorine, chlorine, ~; bromine, Cl 3alkyl or alkoxy, --: ,. ..... .

' 7~ :

- 3 600-~796 or a radical of formula ~

: ~(B)f ~ VII

in which B is -C~ or O
f is 0 or l, and R4 is as defined above, X ;:
-~NH)h-Ch-ch2 T~ ~ R4 IV

in which h and R4 are as defined above, X is hydrogen or -COOR7, in which R7 is Cl_8alkyl or benzyl, and R8 is hydrogen J Cl 8alkyl or benzyl, :

-(~H)h t ~ R54 in which h, R4 and R5 are as defined above, and k is l, 2, 3 or 4, provided that when R2 is a radical of formula II or III in which h is 0, then A is as defined under (ii), ~: ~ and that when R2 i6 a radical of~formula IV:, then when ., .
h is 0, X is -COOR7, and when h is 1~ X ls hydrogen.

;: :

.

`' , ':

or b) Rl and R2, together with the ni-troyen atom to which they are attached, slgnify a radical of formula VIII, .
R - .

11 ~ VIII

in which e~ther Rg and Rlo are independently hydrogen, fluorine, chlor-ine, trifluoxomethyl or Cl_4alkyl or alkoxy, and Rl~is hydrogen or Cl 4alkoxy, provided that when Rll is alkoxy, and R~ and Rln are : both other than hydrogen, :~
then at least one of R~ ~:
and Rlo is alkoxy, . or Rg and Rlo are bound to adjac-:: 15 ent carbon atoms and together signify -(CH2)m-, in which m is 3 or 4;
~: -CH=CH-CH=CH-; or -O-CH2- :
- B, in whlch B is as defined ~. .
. 20 above, and Rllis hydrogen, ~luorine, . :
; : chlorine, trifluoromethyl, .

-: , ~ 37~
_ 5 _ ~00-~796 or Cl 4alkyl or alkoxy. ~-In one group of compounds, in accordance with the inventionl A is as defined unaer (i) (A then bein~ A'), ~- i.e. a residue of a long-chain fatty acid, such residue 5 having 7-23 carbon atoms and having 1 to 4 ethylenically unsaturated positions. These residues are thus dexived from long chain fatty aclds of formula A'-COOH having 8 to 24 carbon atoms and 1 to 4 ethylenically unsaturated positions. These acids are preferably unbranched and are 10 preferably of the natural fatty acid order, i.e. those containing an even number of carbon atoms. A~ is thus preferably unbranched and preferably contains an odd number of carbon atoms.

Particularly preferred residues A' include those 15 of formula IX (Residues Al) and X ~Residues A2):-CH3-(CH2)n-(cH-cH~o(cH2)p IX
:` :
in which n i8 1 to 10, o is 1 to 4, and p is 3 to 9, provided that n ~ 2 xo ~ p does not exceed 22, CH3-(CH2~r~(CH=CH-CH2)s-(CH2)t- X

in which r i5 l to 4, -s is 2 to 4, and ;
t is ,1 to 7, ~, .
. .
. .: ... . .

: ' ' ; " ' . ;' .

37~

- 6 - - 600-67~

provided that r ~ 3 xs ~ t does not exceed 22.
Preferred residues of for~ula IX are those in which n ~ 2 x o + p is an even number, particularly those where n = 5 or 7, o = 1 and p - 7. Preferred residues of form-ula X are those where r is 1 or 4, s is 2 to 4, and t is 2 or 6.

It will be appreciated that the compounds in 10 which A is A' occur in isomeric forms due to the presence :
of one or more unsaturated positions. While the invention :
is not intended to be limited to any particular isomeric l~
. form, the compounds in whlch the hydrogen atoms on each 1~ :
pair of ethylenically unsaturated carbon atoms are in cis-configuration are preferred.

Particularly preferred radicals Al include those ¦~
derived from the following acids:- palmitoleic, oleic, petroselenic, vaccenic, punicic (or eleostearic3, parinaric, : gadoleic, cetoleic, linoleic, linolenic and arachidonic acids, more particularly, oleic, linoleic, linolenic, ~:~ arachidonic and palmitoleic acid.

: In another ~roup of compounds in accordance with the invention, A is as defined under (ii3 ~A then b~ing A"), i.e. cyclopropanyl derivatives of A' residues in which each ethylenP moiety -CH-CH- is replaced by the cyclopropanyl '~ ' ', , .. . . . .

~ 7 - 600 6796 moiety CH - CH-. It is preferred that A" residues are unbranched ~apart from the cyclopropanyl radical(s)].Partic~
ular residues A" are those of formula XI (A" then belng A;~

... ... .. ... . . .. ... .... . . . .

C~3-(CH2~U~C~--CH-CL~v-(CL2)w~ xr : in which u is 1 to 15, 5v is 1 or 2, and w is 1 to 13, provided that when ~ is 1, then u ~ w is 3 to 19, and . that when v is 2, then u ~ w is 2 . to~ 16.

Particular preferred A~ resiùues of formula XI
are as follows~
-~ ~1) when v is 1, then u ~ w = 7 to 19, ~ when v is 2, then u + w ~ 4 to 16;

: 15 (ii) when v is 1, then u ~ w = an odd number, when v is 2, then u + w = an even number; :

(iii) when v i9 1, then u = 5 or 7~and w = 6, when v is 2, then u = 4 and w = 6. ~ :

, . . .

:~ :

. .: .
. . : - , :

~ - ~00-6796 In view of these preferences, it will ~e appreciated that the preferred radicals ~" are derived from mono- or di-unsaturated fatty acids of the type found in nature, e.~.
palmitoleic or oleic acid (v = 1) and linoleic acid (v = 2).

. .
It will also be appreciated that the compounds in which A is A" exist in isomeric forms. While the invertion .
is not intended to be lLmited to any particular isomeric form, it is preferred that each pair of hydrogen atoms attached to the tertiary carbon atoms of the cyclopropyl moieties be in cis-configuration.

Since residues A" having a single cyclopropyl unit have a lesser number of asymmetric carbon atoms than those with a plurality, the former are generally easier i ~
to refine and are therefore preferred where ease of puri-fication is an important factor.

In one group of compounds (hereinafter compounds Ia~, A is A', Rl is hydrogen and R2 is a radical of formula IV, in which h is 0. In these compounds Ia, X is -COOR7.
When R7 is alkyl it is preferably unbranched and is more : 20 preferably ethyl. When R~ is alkyl, it is preferably methyl, when it is alkoxy, lt is preferably methoxy, and when it is halogen it Ls preferably fluorine or chlorine. ~:~

''' .

~0~7~
~ ~.
- 9 - 600-6796 ~ ~-When R~ is other than hydrogen J it is preferably in the 5-position of the indole nucleus. R4 is preferably hydro-gen, however. R8 is also preferably hydrogen.

In a second group of compounds (hereinafter com-pounds Ib~, A is A', Rl is hydrogen and R2 is a radical of formula V in which h is 0. In these compounds Ib, it is preferred that k is 1 and that the A-CO-NH- radical is bound to a carbon atom of the cycloalkyl moiety which is adjacent to a ring junction carbon. When R4 is other than hydrogen, it is preferably in a position ortho to a ring ; junction carbon. When R5 ~s also other than hydrogen, it i~ preferred that it is para to R4 and that it is the same as R4. When R3 or R~ is alkyl, it is preferably methyl and when R3 or R4 is alkoxy, it is preferably methoxy.

En a third group of compounds (hereinafter~Ic), A is A' ; Rl is hyarogen and R2 is a radical of formula II in which h is 1. In these compounds Ic, when R4 is otber than hydrogen and R5 ls hydrogen, then it is preferred that R~
be in the 2-position. When R4 and R5 are both other than hydrogen it is preferred that they are the same and occupy the 2- and 6-positions of the phenyl ring. When R3 is a ~`
- ~ radical of formula VI,~substituents Y and Y1 also occupy preferably the 2- and/~r 6-positions when they are other~

than hydrogen and are preferably the same when they are each other than hydrogen. When R4 or R5 or Y or Yl is .
' : .. . , ..... ,, .. =. .

:
:
, ' 37~L `

alkyl or alkoxy, it is preferably methyl or me~hoxy. :

In a fourth group of compounds (hereinafter com-pounds Id), A is A', Rl is hydrogen and R~ is a radical of formula III in which h is 1. In these compounds Id, it is preferred that when R5 is other than hydrogen and R6 is hydro~en, then R5 is located in the 2-position. When R5 and R5 are both other than hydrogen, it is preferred that they are the same ~except when R6 ls bromine or a radical : of formula VII) and that they occupy the 2~ and 6-positions Of the phenyl riny. When R6 is a radical of formula VII, ; it preferably occupi~s the para~position and when R~ is other than hydrogen, it preferably i5 also para.

In a fifth group of compounds (heréinafter com-: pounds Ie), A is A', Rl is hydrogen and R2 is a radical of ~; 15 formula IV in which h is l. In these compounds Ie, X is hydrogen. Otherwise the preferred situations are as des-.
cribed above for compounds Ia.

In a sixth group of compounds (hereinafter com~
pounds If), A is A', Rl is hydrogen and R2 is a radical of formula V in which h is 1. In these compounds If, the preferred situations are as described above for compounds Ib.
In a seventh group of compounds (hereinafter :
~; oompounds Ig), A is ~', and Rl and R2 together with the ~: 25 nitrogen atom to whlch they are attached signify a ra~ical - ' ~ ~ :
.- ' ;:

i~o~

~ 600~6796 of formula VIII. In these compounds Ig, when Rg, Rlo or Rll are al~yl or alkoxy, they preferably contain 1 to 2, more preferably 1 carbon atom. When ~9 and Rlo are together -~CH2)m-, -CH=CH-CH=CH- or -O~CH2-B-, then Rll is prefer-ably hydrogen. When Rg and Rlo are fluorine f chlorine oralkoxy, they are preferably identical. When ~here are 2 or 3 alkoxy substituents present, these are preferably identical. When both Rg and Rlo are trifluoromethyl, ~ these are preferably bound to non-adjacent carbon atoms : 10 and are preferably meta to each other and to the exocyclic double bond.

: In further groups of compounds, A is A" and Rl is hydrogen and R2 is a radical of formula II in which h is 0 (compounds Ih);
or Rl is hydrogen and R2 is a radical of formula III in which h is 0 (compounds Ii);
-or Rl is hydrogen and R2 is a radical of formula IV in -; which h is 0 (compounds Ij) î
or Rl is hydrogen and R2 is a radical of formula V in which h is 0 (compounds Ik);
- or Rl is hydrogen and R2 is a radical of formula II in which h is 1 ( compounds Il);
- or Rl is hydrogen and R2 iS a radical of formula III in which h is 1 (compounds Im);
or Rl is hydrogen and R2 is a radical of formula-IV in which h is 1 (compounas In~;

: ~ ` ' : .

37: IL

- 12 - 600-6796 .:

or Rl i5 hydrogen and R2 is a radical of formula V in : :
- which h is l (compounds Io), or R2 and R3 together with the nitrogen atom to which they are attached signify a radical of formula VIII
(compounds Ip);

The preferred situations for these compounds Ih to Ip are the same as those given above for the compounds in which A is A'.
The preferred compounds of the invention are those in which h is 0 and more preferably the compounds Ia.

The invention also provides a process for the production of the compounds of formula I, comprising acylating a compound of formula XII !

. ¦ XII
2 :
. ~
in which Rl and R2 are as defined above, ; ~ ~ :

with an acid of formula XIII, A ~ COOH XIII

in which A is as defined above, ; or a reactive derlvative thereof.

e~acylation may be carried out ln manner con- ~.

: ventional for converting an amine function into its cor-responding amlde. For example,:the process may be e~fected ;' . ' ;
.: , ,. , : ~ . - , : ~ . , .
: - ' ' using tlle mixed anhydride technique in which the compound of formula XII is treated with a compound of fo~mula XIIIa, ,~ O O
, . . .
- C - O - C ~ ~12 XIIIa in which A ls as defined above, and 5 This embodiment may suitably be effected at a temperature of from -10 to ~35C, and in an lnert organic medium, e.g. a chlorinated hydrocarbon, such as methylene chlorlde.
Alternatively, the compound of formula XII may be treated wlth an acyl halide of formula XIIIb, O
A - C - Hal X~IIb - 10 in which A is as deflned above, and ~Ial is chlorine or bromine.
This embodiment is suitably effected at a temperature of from 10 to 50C, preferably 20 to 30C, in an inert medium and in the presence of an acid acceptor.

In the acylation process, the compound of formula XII may be employed in the form of an acid addition salt and the reagents may be used in excess, when they are liquid under the reaction conditions, to serve as a reactlon medium.
It will be appreciated that the acylation process of the invention does not affect the isomeric form of the :, 137~1 ,. :

starting materials so that the products will result in the same isomeric form as the starting materials.

The resulting compounds of formula I may be ; isolated and purified using conventional techniques.

; S The compounds of formula XII are either known or may be produced in conventional manner rom available materials.
Compounds of formula XIIIc, A' - COOH XIIIc in which A' is as defined above, are also known or may be produced in conventional manner from available materia.ls.

The compounds of formula XIIId, A" - COOH XIIId ,. . :
in which A'l is as defined above, are also conventional and may, for example, be produced ` 15 by converting the ethylenically unsaturated positions in corresponding compounds of formula XIIIc into cyclopropanyl groups. This may be effected in conventional manner, for example by reaction with methylene diioclide by the method of Slmmons-Smith [J~AoC~S~ 81, 4256 (1959)]. For preparing compounds having a single cyclopropanyl group, the starting acids may be in cis or trans form and the product will have the same form. Likewise t mixtures of cis- and tr~ns forms .
-.

~.
: . .

37~L
., .

' will lead to corresponding mixtures o~ the product. When a cyclopropane acid (or derivative) is reacted with a com-pound of formula XII, having asymmetric carbon atoms, it wi11 be appreciated that the resulting compound of formula I will be obtainea as a mixture of diastereo-isomers, which may, if ~esired/ be sepaxated in known manner, by e.g.
chromatography or crystallisation. ~lternatively, if desired, the starting cyclopropane acid may be resolved into its antipodes and then reacted to give the correspond-ing isomeric product in relatively pure form. Similarly,for prepariny cyclopropane acids having 2 or more cyclopro-; panyl units, the starting olefinic acids have a correspond-ing number of double bonds and the Simmons-Smith reaction leads to a mlxture of diastereoisomers, which may, if desired, be separated before further reaction.

The compounds of formula XIIIa and XIIIb can be - produced from the free acids in conventional manner, if convenient in situ _ _ -The compounds of formula I of this lnvention possess pharmacological activity. In particular, the com-pounds of formula I are indlcated for use ln controlling the cholesterol ester content of mammalian arterial walls and are therefore partlcularly indicated for use as anti-atherosclerotic agents t i.e. agents useful in the prophy-lactic treatment of atherosclerosis and in the controlling :, .,, :

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

.:

~3L03L~t ~ 16 ~ ~0-6796 of atherosclerotic conditions due to cholesterol ester accumulation in the arterial walls. Such ability of the compounds of the formllla I is indicated by known test pro-cedures in which the total cholesterol ester content of cultured cells is shown to be reduced by a test compound~
as compared to untreated cells, and carried out, for example by the following procedures;

A) Cell culture Rhesus monkey smooth muscla cells (from the arterial, e.g. aorta, wall~ obtained by the method of X. Fisher-Dzoga et al (Experimental and Molecular Pathology 18, 162-176 (1~73)) are routinely grown in 75 cm2 tissue culture flasks using Minimum Essential Medium ~Eagle) supplemented with 10% fetal bovine serum. For testing, a 75 cm2 flask with a near confluent cell gro~th is selected.
The cells are removed from the flask surface by mild enzymatic treatment wi~h pronase. After centrifugation and decanting the enzyme solution, the cell pellet is resuspended in an appropriate volume of media for seeding the desired number of 60 mm tissue culture dishes. ~ive (5~ ml of the diluted cell suspension axe pipetted into each dish. After seeding, the dishes are labelled with the cell type, date and flask number of origin and incub-ated at 37C in approximately 5~ CO2 atmosphere in a high .: :

:.
: :, . .

.. ..

1101B~1 - 17 - 6~0-6796 humidity incubator. When the cultures are confluent, the actual drug testin~ is beyun. Test compounds are routinely solublisecl in 100% ethanol. An equivalent amount of ethan-ol is added to control groups as well~ The tiessue culture dishes are randomly divided into groups. To one group, hyperlipemic rabbit serum (NRS) is added at 5% by ~olume (control). To the remaining groups, 5~ HRS and 1 mg per 100 ml of media of the test compound are added. The dishes are returned to the incubatox for an additional 24 hours.
All ~perations throuyh to the flnal incubation are perfor-med using sterile technique in a laminar flow hood. After the incubation period, the dishes are microscopicall~
observed ~lith the Zeiss Axiomat with phase contrast~ optics and the conditions of the cultures are recordedi ~especi-~
ally in regard to the slze, number and configuration ofcytoplasmlc inclusions and to cellular morphology. ~he media is removed from the cultures and 0.9~ sodium chloride solution is added. The cells are removed from the flasks with the aid of a rubber policeman and transferred to a conical graduated centrifuge tube. The cells are washed ~ three times by suspending in an isotonic salt solutlon, ; centrifuging at 800 x g for 10 minutes and aspirating the supernatant fluid.

B) I c~tra_t-or_~ ec i~ 25 An appropriate volume of isopxopyl alcohol ~ (about 1 ml/mg protein) is then added to the cell pellet :

:~ :

.: , :

: ~ .: . :

~ 18 - 600-6796 and the sample sonicated with a micro pxobe (140 x 3 mm~
for 10 seconds wi~h a "LO" setting of 50 on a Bronwell Blosonik IV. ~fter centrifu~ation for 15 minutes at 800 x g, the clear supernatant is decanted and an aliquot ~ ;
taken for cholesterol analysis.

The residue is dissolved in O.lN sodium hydroxide and an aliquot taken for protein determination by the method of Lowry, et al. (J. ~iol. Chem. 193, 265; lg51).

C) Assay 10Free cholesterol: The isopropyl alcoholic sol-utions of standards, samples and blank (isopropyl alcohol alone) are treated in a similar manner. An aLiquot of 0.4 ml of free reagent (Reagent A, Table 1 below) is added to a 10 x 75 mm disposable glass test tube to which~20 ~1 of the isopropyl alcoholic solution is added~and mixed. After standing at room temperature or approximately S minutes, 0.8 ml of 0.5N sodium hydroxlde (Reagent C, Table 1) is added and mixed. The fluorescence is measured with an Aminco-Bowman spectrophotofluorometer with an excitation wavelength of 325 mm and emission wavelen~th of 415 nm.
A 1 cm light path cuvette is used with a xenon lamp, an ~ IP28 photomultiplier tube and 2 mm slits. ~
.; : ~., Total cholesterol: The same procedure described above for free cholesterol is followed fox total cholestarol - 25 except that the total reagent (Reagent B, Table l) is used .., , , ' . , ' ' ' ~ ' - 19 - 600-67g6 instead of the free rea~ent and the samples are lncubated for 20 minutes at 37~ before the addit:ion of the 0~5N
sodium hydroxide solution tReagent Cr Table 1).

Alternatively, the assay ~or cholesterol, i.e.
Step C ~above) obtained from Steps A and B, may be carried out by the method of Ishikawa et al (J. Lipid Res. 15, 286; 197fi).
~ The amount of cholesterol ester is found by sub-;~ tracting the amount of free cholesterol from the total cholesterol content of the cells determined by the assay.
A finding of a lower amount of cholesterol ester in the group of cells to which test compound was added, as com-pared to the control group (untreated~ shows that the test compound is active in reduclng the cholesterol ester in ;~ 15 the cells, TABLE l ~--Composition of Re ~ olesterol Determination A. Free Cholesterol Rea~ent Sodium phosphate buffer pH 7.0 .05 M
Cholesterol oxidase .08 Utml Horseradish pero~idase 30. U/ml p-Hydroxyphenylacetic acid .15 mg/ml B. ~

; Sodium phosphate buffer pH 7.0 .05 M
Cholesterol ester hydrolase.08 U/ml Cholesterol oxidase .08 U/ml Horseradish peroxidase 30. U/ml Sodium taurocholate 5 mM
Carbowax-6000 .17 mM

~Hydroxyphenylacetic acid .15 mg/ml :
C. Sodium Hydroxide Sol~tion .5N
.~, .~ .
.
;' .

. :

.

- 20 - 600~6796 For the above~mentioned use, an indicated sult-able daily dosaae is from about 100 mg to about 5,000 mg, suitably administered in divided doses of from 25 to 2,500 mg, two to four times daily, or in retard form.

The compounds may be admixed wlth conventional pharmaceutically acceptable diluents and carriers, and, optionally, other excipients, and administered in such forms as tablets or capsules. The compounds are prefer-ably administered orally.
The following Examples illustrate the invention.
-, .

.

, ~ :
..
. . .

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

37~ `
:

EXAMPI.E 1: a-[(1-Oxo-9,12-cis,cis~octadecadienylamino)~-~ --~ , lH-indole-3-~ro~anoic acid ethvl ester ~ o a solution of 7.0 g o linoleic acid in 150 ml methylene chloride cooled to ~20 is added 2.5 g tri-ethylamine and then 2.7 g ethyl chloroformate. The reac-tion mixture is stirred for two hours and gradually allowed to warm to room temperature. There is then added 2.5 g triethylamine followed by 6.7 g of ~L tryptophan ethyl ester hydrochloride and the reaction mixture is stirred for 18 hours. The reaction mixture is then extracted several times with 2N aqueous sodium hydroxide washed with saturated aq. sodium chloride so~ution, and the organic phase dried over anhydrous sodium sulphate r ~iltered and the filtrate evaporated i.v.~to dryness. The residue is~
then filtered over silica gel using chloroform as the eluant to obtain the title product in solvent, which is ; then evaporated to yield the title product as a waxy solid. ;~

EXAMPLE 2:
... , ... -In manner analogous to Example 1 and employing appropr~ate starting materials in approximately equivalent ~ amounts, the following compounds may be obtained:-; a) -[(l-oxo-9-cis-octadecenylamino)J-lH-indole-3-propan-oic acid/ ethyl ester (waxy solid);
b) a~ oxo-9,12,15-cis,cis,cis-octadecatrien~lamino)J-`~ 25 lH-indole~3-propanoic acid, ethyl ester;
,.

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

.
, c) ~-[~l-oxo-9-cis-hexadecenylamino)J-lH-indole-3-propanoic acid, ethyl ester;
d) ~-[(-~-oxo-5,8,11,14-cis,cis,cis,cis-eicosatetraenyl-amino)~-lH-indole-3-propanoic acid, ethyl ester;
; 5 e) 2-(1-oxo-9-cis-octadecenylamino)-3-(1-methylindolyl~-propanoic acid, ethyl es er;
f) 2-(1-oxo-9-cis-octadecenylamino)-3-(lH-5-methoxy-indolyl)-propanoic acid, ethyl ester;
g) 2-(1-oxo-9-cis-octadecenylamino)-3-(lH-5-chloroindolyl)-propanoic acid, ethyl ester;
h) 2-(1-oxo-9-cis-octadecenylamino)-3-(1-benzylindolyl)-propanoic acid, ethyl ester i) a-[(l-oxo-9,12-cis,cis~octadecadienylamino)]-lH-indole-3-propanoic acid, n-propyl ester; ~ :
-lS j~ a-~(l-oxo-9,12-cis,cis-octadecadienylAmino)]~IH- : ~-indole-3-propanoic acid, n-butyl ester;
k) a-t(1-oxo-9,12-cis,cis-octadecadienylamino)]-lH-indole-3-propanoic acid, _-octyl ester (m.p. 66 - 68C.);
1) -[(1-oxo-9,12-cis,cis-octadecadienylam1no)]-lH-i~dole-3-propanoic acid, benzyl ester;
m) a.-[(l-oxo-9-cis-ochadecenylamino)]-lH-indole-3-propanoic acid, n-propyl ester;
n) a- [ (l-oxo-9-cis-octadecenylamino)-lH-indole-3-propanoic ~cid, n-butyl ester; :

O) ~-[(l-oxo-9-cis-octadecenylamino)]-lH-indole-3 .~ propanoic acid, n-octyl ester;
. : .' !

. .
: . ' ~ " ~ ' ' ~ ' 7~

- 23 ~ 6796 p) ~-[(l-oxo-9-cis-octadecenylamino)-lH-indole-3-propanoic acid, benzyl ester;
q) N~ indanyl)-cis,cls-9,12-ocatadecadienamide,~viscous oil]j .
r) N~ indanyl)-cis-9-octadecenylamide;
s) N-(l-indanyl)-cis,cis,cis-9,12,15-octadecatrienyl~ ~: `
amide; ~.
t) N-(l-indanyl)-cis-9-hexadecenylamide;
u) N-(l-indanyl)-cis,cis,cis,cis-5t8,11,1~-eicosa~e-traenylamide;
v) N-(2-indanyl)-cis-9-octadecenylamide;
w) N-[1-(7-methylindanyl)]-cis-9-octadecenylamide;
x) N-[1-(7-chloroind~nyl)]-cis-9 octadecenylamide;
y) N-[1-(4,7-dimethoxyindanyl)]-cis-9-octadecenylamide;
z) N-[1-~1,2,3,4-tetrahydronaphthyl)]-cis-9-oc-taceden amide;
¦ aa) N-(a-methylbenzyl)-cis~2-octyl-cyclopropanoctanamide;
tm.p. 44-46] (produced from d(+)-~-methylbenzylamine);
ab) N-(l-indanyl)-cis-2-octyl-cyclopropanoctanamide;
ac) a-[(1-oxo-cis-2-octyl-cyclopropanocty.lamino)]-lH-:: indole-3-propanoic acid, ethyl ester ad) N-(a-methylbenzyl)-cis-2-octyl-cyclopropanoctanamide;
(mixture of 2 racemates; m.p. 30-32) (produced from d,l-~-methylbenzylamine);

25 ae) N-(o-methylphellyl)-cis-2~octyI-cyclopropanoctànamide;

, .

: ' `, . ' . : : .

.
; ' ' 37~
- - 2~ - 600-6796 af) N~[a-(p~methylbenzyl)-benzyl]-cis-2-octyl-cyclopro-panoctanamide(m.p. 78-81C.);
ag) N-~a-methylbenzyl)-cis-2~hexyl-cyclopropanoctanamide;
ah) N-(~-methylbenzyl)-trans-2-octyl-cyclopropanoctanamide;
5 ai) N-(a-methylbenzyl)-cis-2-tetradecylcyclopropanobutan-amide;
: aj) N-~a-(p-methylbenzyl)-p-methyl-phenylethyl]-cis-2-octyl-cycIopropanoctanamide(m.p. 60-65C.);
ak) N-(~-methylbenzyl-cis,cis-2-~(2-pentylcyclopxopyl)- ~:
methyl3cyclopropanoctanamide; [mixture of diastereo-isomers - oil - produced from d(~)-a-methylbenzylamine;
al) N-(l-indanyl)-cis,cis-2-[(2-pentylcyclopropyl)-methyl]-cyclopropanoctanamide;
am) a-cis,cis-[(l-oxo-2-pentylcyclopropyl)-methyl]-cyclo-propanoctanamino)]-lH-indole-3-propanoic acid, ethyl ester; (from DL-tryptophan ethyl ester, hydrochloride) ~ an) N-(a-methylbenzyl)-cis,cis-2-[2-pentylcyclopropyl)-; methyl]-cyclopropanoctanamide (mixture of diastereo-isomers) - produced from (d,l)-a-methylbenzylamine);

20 ao) N-(o-methylphenyl)-cis,cis 2-[(2-pentylcyclopropyl)-methyl]-cyclopropanoctanamidei :.
-~ ap) N-~a-(benzyl)-~-(phenyl)ethyl]-cis-2-octylcyclopro-.; panooctanamide [m.p. ~0-45]; ~ :~
~ aq) cis-2-octyl-cyclopropanoctanoic acid, 2-(o-methyl- ~:
: 25 phenyl)-hydrazide, twax~ solid];
~; - ' .

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

7~ ~

ar) cis-2-octyl-cyclopropanoctanoic acid, 2~ indanyl)-hydrazide~;
as) cis~Z-octyl-eyclopropanoctanoie acid, 2-[~-(3-indolyl-ethyl)]-hydrazide; Z
5 at) cis-2-octyl-cyclopropanoctanoic ac:id, 2-(a-methyl-benzyl)-hydrazide (mixture of racemates) - obtained from (d,l)-a-methylbenzyl hydrazine;
~ au) cis-2 octyl-cyclopropanoetanoie aeid, 2-(o-chloro-phenyl)-hydrazide;
: 10 av~ cis-2-octyl-cyclopropanoctanoie acid, 2-[~-~p-methyl-benzyl)-benzyl~-hydrazide;
aw~ eis-2-octyl-cyclopropanoctanoie acid, 2-benzyl-hydrazide (as a wax) - obtained from benzylhydrazine : ~ dihydrochloride;
. . .. ..
~ 15 ax) eis-2-hexyl-cyclopropanoctanoie acid, 2-(o-methyl :;~ phenyl)-hydrazide;
ay) trans-2-oetyl-eyclopropanoetanoic acid, 2-go-methyl-; phenyl)-hydrazide;
az) cis-2-tetradecylcyelopropano butanoie acid, 2-(o-; 20 methylphenyl)-hydrazide;
aaa) cisl eis-2-~(2-pentyleyclopropyl)-methyl]-cyclopropan-octanoic acid 2-(o-methylphenyl~-hydrazide;
aa~) eis-2-octyl-cycIopropanoctanoie acid, 2-[a-(p-methyl-benzyl)-p-methyl-phenylethyl~-hydrazide;
25 aae) cis,eis-2-[(2-pentyl-cyclopropyl)-methyl)-cyclopropan-: octanoic acid, 2-(1-indanyl)-hydrazide;

~ ' :
.: .

~ .

- 26 - 600-679~

aad) cis,cis-2-~(2-pentyl-cyclopropyl)-methyl-cyclopropan-octanoic acid, 2- r ~- t 3-indolyl-ethyl~]-hydrazide;
aae) cis,cis-2-[(2-pentyl-cyclopropyl)-:methyl~-cyclopropan- `
octanoic acid, 2-(~-methyl-benzyl)-hydrazide;
5 aaf) cis,cis-2-~(2-pentyl-cyclopropyl)-methyl-cyclopropan- j octanoic acid, 2-(o-chlorophenyl)~hydrazide;
aag) cis,cis-2-[(2-pentyl-cyclopropyl)-methyl-cyelopropan-octanoic acid, 2 ~a-~p-methyl-benzyl)-benzyl~-hydraz-ide, 10 aah) cis,cis-2-[(2-pentyl-cyclopropyl)-methyl-cyclopropan-octanoic acid, 2-benzyl-hydrazide;

aai) cis,cis-9,12-octadecadienoic aeid, 2-benzyl-hydrazide;
[viscous oilJ;
aaj) cis-9-octadecenoic:aeid, 2-benzyl-hydrazide;
aak) cis,cis,cis-9,12,15-octadecatrienoic acid, 2-benzyl-hydrazide;
aal) cis-9-hexadecenoic acid, 2-benzyl-hydrazide; ~
aam) cisrcis~cis~cis-s~8~ 4-eicosatetraenoic acid, ~.
2-benzyl-hyd~azide; ~ ~.
aan) cis,cis~9,12-octadeeadienoic aeid, 2-(o~methylphenyl)-hydrazide tas an oil); -aao) cis,cis-9,12-octadecadienoie acid, 2 (Z,6-dichloro- ~ `~
phenyl)-hydrazide, (as an oil); : :

, ~ ~' .~ :

: ~

7~ ~
- ~7 - 600-6796 aap~ cis, cis-9,12-octadecadienoic acid, 2-(o-chloro-.~ phenyl)-hydrazide (as an oil);
aaq~ cis-9-octadecenoic acid, 2-(o-me1hylphenyl)-hydraz-ide (as an o~
5 aar) cis-9-octadecenoic acid, 2-(2,6-dichlorophenyl)-hydrazide;
aas) cis-9-octadecenoic acid, 2-to chlorophenyl)-hydrazide;aat) cis,cis-9,12-octadecadienolc acid, 2-~-(3-indolyl-ethyl)]-hydrazide;
aau) cis,cis-9,12-octadecadienoic acid, 2-tl-indanyl) hydrazide;
aav) eis,cis-9,12-octadecadienoic acid, 2-(~-methyl-benzyl) hydrazide; (obtained from (d,l)-a-methylbenzylhydra-::~ 15 zine);
~ aaw) cis,cis-9,12-octadecadienoic acid, 2-[a-(p-methyl-: benzyl)-benzyl]-hydrazide;
aax) cis,cis-g,12-octadecadienoic acid, 2-~a-(p-methyl~
benzyl)-p-methylphenylethyl]-hydrazide;
20 aay) cls,cis-9,12-octadecadienoic acid, 2-(p-biphenylyl)-hydrazide;
aaz) cis,cis-9,12-octadecadienoic acid, 2-(p-benzyl-phenyl)-hydrazide;
aaaa) cis-9-octadecenoic acid, 2-[B-(3-indolylethyl)]-hydraziae;
aaab) cis-9~octadecenoic acid, 2-(1-indanyl)-hydrazide;

:' ~ , ' - -~Q~ ~t73 - 2~ - ~00-67~6 aaac) cls-9-oct~decenoic acid, 2-t~-methylbenzyl)-hydraz-ide;
aaad) cis-9-octadecenoic acid, 2- r~- (p-methylbenzyl)benzyl]~
hydrazide;
5 aaae) cis-9-octadecenoic acid, 2-[~-(p-methylbenzyl)-p-methylphenylethyl~-hydrazide;
aaaf) cis-9-octadeceno~c acid, 2-~p-biphenylyl)-hydrazide;
aaag) cis-9-octadecenoic acid, 2-(p-benzylphenyl)-hydrazide;
aaah) l-(l-oxo-9,12-cis,cis-octadecadienyl)-(3aRS, 4RS, 7aRS)-4-(Z)-(3,4-dimethoxy)-styryl-hexahydro-4- :~
indolinol [oil] [~roduced from (3a RS, 4RS, 7aRS)-

4-(Z)-(3,4-dimethoxy)-styryl-hexahdro-q-indolinol maleatel;
aaai) l-(l-oxo-9 cis-octadecenyl)-(3aRS, 4RS, 7aRS)-4-(Z)-,: ~~3,4-dimethoxy)-styryl-hexahydro-4-indolinol; and ;: the analogous aaaj) l-(l-oxo-9,12,15-cis,cis,cis-octadecatrienyl);
: aaak) l-(l-oxo-9-cis-hexadecenyl); and ~`
aaal) l-(l-oxo-5,3,11,14-cis,cis~cis,cis-eicosatetraenyl)-amides of the he~ahydroindolinol;
aaam) l-[l-oxo-2-cis-octylcyclopropanoctyl] (3aRS, 4RS, -.
7aRS)-4-(Z)-(3,4-dimethoxy)-styryl-hexahydro-4-indo :
linol.

,, ~ ' ~: ' ' ....... , ~' . , : ~ ' 7~
- - 2g - 600-67~6 aaan) l-~l-oxo-cisrcis-2-~(2-pentylcyclopropyl)-methyl]-cyclopropanoctyl}-~3aRS, 4RS, 7aRS)-4-Z-(3,4-dlmethoxy)-styryl-hexahydrc-4-indolinol.
aaao) 2-(l~oxo-9-cis-octadecenylamino)-3~(lH-5-fluoroiDdolyl)-propionic acid, ethyl ester (wax).

,~ .

.

, ' '' ' ' , ..

'; :
.' ' , ' ~ ~ .

~ 7 ~

In the following Tabl~ are given NMR dat~ for compounds o the preceding Examples. The NMR was effected in CDC13, figures are in ppm and dlgits in par~nthesis indicate the number of protons - s = single-t; d = doub]eti t = triplet;
b = broad.

. ..~
Ex. NMR data __ _ _ _ _ _. __ _ 1 t 5.3(2), d 6.2(1), s 9.2 (1) 2a t 5.3(4)j d 6.1(1), s 8.8(1) 2e t 5.35(2), d 6.0(1), s 3.7(3) [oil]

2f t 5.4(2), d 6.1(1), s 8.4(1), s 4.85(3) [wax]

21 t 5.35(4), d 6.1(1), s 8.5(1), s 5.1(2) ~oill .

2ac b -0.36(1), d 6.1(1), s 8.8~1) s 0.6(3) 2ak b ~0.7(5), ~ -0.3(2), d 6.0(1), s 7.3(5) ~-2am b ~0.7(5), b -0.3(2j, d 6.2(1), s 8 5(1) Ewax) 2an b +0.65(5), b -0.3(2), d 5.8(1), s 7.3(5) [oil]

2aaao ~ 5.3(2), d 6.1(1), s 8.7(1) ; 2q t 5.I5(4), d 6.4(I), s - -2aq b ~0.65(3), b -0.3(1), d 8.0(1), d 6.1(1), s 2.1(3 2aw b +o.6(3), b -0.3(1), d - , s 4,7(2~

2aaa b ~0.65(6), b -0.3(2), d 7.8(1), d 6.1(1), s 2.2(3) [oil]
2aai t 5.4(4), d -, s 4.8(2) 2aan t 5.4~4), d 7.7~1), d 6.1(1), s 2.1(3 2aao t 5.3(4), d 7.7(1~, s -2aaq t 5.4(2), d 7.8(1), d 6.1(1), s 2.1(3) 2aah t 5.4(4), d 6.5(1) t d 5.8(1)~ s 3.9~6), s 7.4 ,' . ._ _ _ ____ _ __ -. ~ .

.. ~ . . . .:
, ~' , The compounds of formula I, in particular the compound of Example 1, are also indicated for use as gen-eral agents for the lowerlng of serum cholesterol and cholesterol ester levels as indicated by oral administra-tion at a dose of 200 mg/kg of the test compound per aayfor 9 weeks to rabbits in ~on~unction with a high chol-esterol diet resulting in, compared to controls, a reduc-tion in cholesterol and cholesterol ester serum levels, as well as a lessened formation or absence of arterial wall plaques.
For this use, the indicated dosage is the same as described above.

.. ~

Claims (10)

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

1. A process for the product1on oI a compound of formula I, I

in which A is (i) the residue of a long-chain,unsatur-ated fatty acid (minus the carboxylic acid function), which residue has 7 to 23 carbon atoms and possesses from 1 to 4 ethylenic-ally unsaturated groupings, or (ii) a cor-responding residue ln which each ethylene (-CH=CH-) grouping is replaced by a cyclo-propanyl group (), and either as R1 is hydrogen, and R2 is a radical of formula II, III, IV or V, II

in which h is 0 or 1, g is 0 or 1, R4 is hydrogen, fluorine, chlorine, bromine or C1-3 alkyl or alkoxy, R5 is hydrogen, fluorine, chlorine, or C1-3alkyl or alkoxy, and is hydrogen, C1-8alkyl or a radical of formula VI.

VI

in which j is 0 or 1, Y is hydrogen, fluorine, chlor-ine, bromine or C1-3alkyl or alkoxy, and Y1 is hydrogen, fluorine, chlor-ine or C1-3alkyl or alkoxy III

in which h and R5 are as defined above, and R6 is hydrogen, fluorine, chlorine, bromine, C1-3alkyl or alkoxy, or a radical of formula VII, VII
in which B is -CH2- or -O-, f is 0 or 1, and R4 is as defined above, IV

in which h and R4 are as defined above, X is hydrogen or -COOR7, in which R7 is C1-8alkyl or benzyl, and R8 is hydrogen, C1-8alkyl or benzyl, V

in which h, R4 and R5 are as defined above, and k is 1, 2, 3 or 4, provided that when R2 is a radical of formula II or III in which h is 0, then A is as defined under (ii), and that when R2 is a radical of formula IV, then when h is 0, X is -COOR7, and when h is 1, X is hydrogen.

or b) R1 and R2, together with the nitrogen atom to which they are attached, signify a radical of formula VIII, VIII

in which either R9 and R10 are independently hydrogen, fluorine, chlor-ine, trifluoromethyl or C1-4alkyl or alkoxy, and R11 is hydrogen or C1-4alkoxy, provided that when R11 is alkoxy, and R9 and R10 are both other than hydrogen, then at least one of R9 and R10 is alkoxy, or R9 and R10 are bound to adjac-ent carbon atoms and together signify -(CH2)m-, in which m is 3 or 4;
-CH=CH-CH=CH-; or -O-CH2-B, in which B is as defined above, and R11 is hydrogen, fluorine, chlorine, trifluoromethyl, or C1-4alkyl or alkoxy, characterised by acylating a compound of formula XII, XII

in which R1 and R2 are as defined above, with an acid of formula XIII, A - COOH XIII

in which A is as defined above, or a reactive derivative thereof.

2. A compound of formula I as described in Claim 1 whenever prepared by a process as claimed in Claim or an obvious chemical equivalent thereof.

3. A process as claimed in Claim 1 wherein A is A' R1 is hydrogen R2 is a radical of formula IV in which h is O and x is COOR7.

4. A compound of formula I as described in Claim 1 wherein A is A' R1 is hydrogen R2 is a radical of formula IV in which h is O and x is COOR7 whenever prepared by a process as claimed in Claim 3 or an obvious chemical equivalent thereof.

5. A process as claimed in Claim 1 wherein A is A"
R1 is hydrogen and R2 is selected from the radicals of formulae II, III
IV and V wherein h is O.

6. A compound of formula I as described in claim 1 wherein A is A"
R1 is hydrogen and R2 is selected from the radicals of formulae II, III, IV and V wherein h is 0, whenever prepared by a process as claimed in Claim 5 or an obvious chemical equivalent thereof.

7. A process for the production of .alpha.-[(1-Oxo-9-cis-octadecenylamino)]-1H-indole-3-propanoic acid, ethyl ester which comprises acylating DL-tryptophan ethyl ester with oleic acid or a reactive derivative thereof.

8. .alpha.-[(1-Oxo-9-cis-octadecenylamino)]-1H-indole-3-propanoic acid, ethyl ester whenever prepared by a process as claimed in Claim 7 or an obvious chemical equivalent thereof.

9. A process for the production of N- [.alpha.-(benzyl)-.beta.-(phenyl)ethyl]-cis-2-octylcyclopropano-octanamide which comprises acylating a-(benzyl)-.beta.-(phenyl)-ethylamine with 2-octalcyclopropanoctanoic acid or a reactive derivative thereof.

10. N [.alpha.-(Benzyl)-.beta.-(phenyl)ethyl]-cis-2 octyl-cyclopropanooctanamide whenever prepared by a process as claimed in Claim 9 or an obvious chemical equivalent thereof.