Note: Descriptions are shown in the official language in which they were submitted.
~` 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.
;: :
.
`' ,
':
600-6796
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
/CH2
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 `
- 10 - 600-6796
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
;' . '
;
.: ,
,. , : ~ . - , : ~ . ,
.
: - ' '
- 13 - 600-6796
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
,. :
- 14 - 600-6796
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
., .
- 15 - 600-6796
'
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~ `
:
- 21 600-6796
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 ,, . ~.
,. . .
-
, .
.
,
- 22 - - 600-6796
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~ ~
- 25 - 600-6796
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 ~
- 30 - 600-6796
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
,' . ._ _ _ ____ _ __ -
. ~ .
.. ~ . . . .:
, ~' ,
- 31 - 600-6796
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.
.. ~
