Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
The present inventioll relates -to the use of alkylurea deriva-tives
in medicamellts -for inEluencing the lipometabolism. Some o:E the alkylurea deri-
vatives are new and are the subject oE our Application No. 364,269. This
application, which is divided out of Application 364,269, relatcs to pharma-
ceutical compositions containi.ng known alkylurea derivatives.
Some of the alkylurea derivatives which can be used according to
the invention are already known (compare M. ~laz~a et al, ~armaco, Ed. Sc:i.
32, No. l, 54-66 (1977)). Phytotoxic e:E-Eects have already been described ~Eor
thcse kllown compounds. Some derivatives o:f ethoxyquin can also be used as
inllibitors of iron poisoni.ng (compare DT-OS (German Published S~ec:i-Eicat:ion)
2,502,630). Their ef:Eoct on the lipometabolism, and in par-ticular -their l:i.pid
absorption-inhibiting efEect, has not yet been di.sclosed hitherto.
The present inventi.on relates to the use of alkylurea derivatives
of the general formula (I)
\ N ~ R2
X=C-NIl-Y
:in wllich
Y represents R or a radical 3
X '~
R N
-(CH2)n -(X)l-(C112)n -NH-C-X R5
-- 1 --
Le A 19 942
59~
1]1 i cll
nl i-nd n2 denote integers from 3 to 9 and
1 denotes 0 or l and
in which
R represents a straight-chain, branched, cyclic, saturated or un-
saturated aliphatic hydrocarbon radical with up to 20 carbon
atoms, which is optionally substituted by halogen, hydroxyl,
allcoxy, alkoxycarbonyl or optionally substituted aryl,
R represents hydrogen or lower alkyl,
1.0 R represents lower alky:l ancl
R3, R~ and R5 are identical or d:iffererlt and each represent hycl:rogen,
halogell, hydroxyl, cyano, lower all<yl, lower alkoxy, lower alkoxycarbonyl,
lower alkylmercapto, lower alkylsulphonyl, lower alkylsulphinyl, lower alkyl-
carbonyl, optionally substitu-ted aryl or optionally substituted aryloxy,
X denotes oxygen or sulphur and
A represents one of the following radicals
R' R' R' R' R~
-C- , -C-CH2- , -C=CH- , -0-C- , -N C
. . .
R" R" R" R"
R'
S()m C~
R"
in which
R' and R" are identical or different and each denote hydrogen or
lower alkyl,
R"' denotes lower alkyl and
m denotes 0, 1 or 2,
s~
in the treatment of diseases of the lipometabolism and also in -the preparation
of medicaments which influence the lipometabolism.
Novel alkylureas which are the subject of application No. 364,269
are compounds of -~ormula I
R4 ~ ~ X
R X=C-N}I-Y
wherein Rl represents hydrogen or alkyl with 1 or 2 carbon atoms, R represen-ts
alkyl with 1 or 2 carbon atoms, R3, 1~4 and R5 are identi.cal or di:E~Eerent and
each represent hydrogen, chlorine, bromine, trifluoromethyl, alkyl, alkyl-
mercapto or alkoxy, the said alkyl, alkylmercapto or alkoxy radicals each con-
taining 1 to ~ carbon atoms, or represent phenoxy or chlorophenoxy; A represel-lts
one of the following radicals
R' R' R' R'
- C - , - C - C}l - , - 0 - C - , - S - C -
R" R" 2
:in which R' and R" are identical or dif:Eerent ancl each denotes hydrogen, metllyl
or ethyl; X represents oxygen; Y represents R or a radical
><
~(CI-12)n -(X)Q-(C}12)Tl -N}l-C=X R
in ~h.ich R ~ R , R , R , R , A cmd X are as defined above, nl and n2 denote
integers from 3 to 9, ~ denotes 0 or 1, and R represents straight-chain,
branched or cyclic alkyl or alkenyl with 6 to 18 carbon atoms, the said alkyl
or alkenyl groups optionally being substituted by chlorine, bromine~ fluorine
~5~
o-r alkoxy of 1 to 4 carbon atoms, or by phenyl, provided that when Y represents
R then R is no-t hydrogen~
T}le present application relates to pharmaceutical compositions com-
prising an alkylurea of formula
R3
N ~\
X =C-NI-I-Y
wherein Y represents R or a radical
R
`:~
R N~ R5
-(CH2)n -(X)Q-(CH2)n -Nl-l-C=X
in which nl and n2 denote integers from 3 to 9 and Q denotes 0 or 1, R represents
a straight-cllain, branchecl, cyclic, sa-turated or unsaturatecL aliphatic hydro-
carbon radical with up to 20 carbon atoms, which is optionally substit-lted by
halogen, hyd:roxyl, alkoxy, allcoxycarbonyl or optionally substitutecl a:ryl, R
represeilcs hydrogen or lower al]cyl, R represents lower allcyl allcl R , 1~ alld R
;I:re :iclelltic11 or clif-t`erent and eacll represent hyclrogen, halogen, llydroxyl, cyano,
lower alkyl, lower a:Lkoxy, lower alkoxycarbonyl, lower alky.Lmercap-to, lOWel'
alky:lsu:Lphollyl, lowe:r alkylsulph:inyl, lower al]cylcarbollyl, op-tionally substi-
-tutecl aryl or optionally substituted aryloxy, X denotes oxygen or sulpllur and
A represents one of the following radicals
R' R' R' R' R"' R~
- C - , - C - CH2 - , - C = CH - , - 0 - C - , - N - C - ,
R" R"
~" R~
5~
S~)m
R"
in which R' and R" are :iden-tical or diE:Eerent and each clellote hydrogen or lower
alkyl, R"' denotes lower alkyl and m denotes 0, 1 or 2, provided that
(A) if (i) X represents oxygen, (ii) A is other than
R' R' R'
- C = Cl~ SO - C or - S02 - C and (i:i.:i) R represen-ts strcl:igllt
" R"
Ch::l.:ill, brnllchecl or cycli.c alky:L or alkonyl with 6 to 18 ca:rbon atoms, tho sa:id
a:lky.L o:r alkclllyl groups optionally being substituted by chlorille, bromine,
:EI.uorine or alkoxy with l to 4 carbon atoms, or by phenyl, then Rl :is not
hydrogen, methyl or ethyl; and
(B) i:E (i~ Y i.s o-ther than R and (ii) X ;s 0, tholl R :is not
hydrogell;
wll:icil allcylllroa is in ad~i.xture with a s~litable cl:i:L~Ient or ca:rr-i.o:r.
Surp:ri.sillgly, ~:he a:Lkylure,l cle:r:iv.lt:ivQs o:E-tlle gencrra:L Eorml.lLa (:1)
cl:isl).kly n powel~:EIll l:ip:icl nbsorpt:ioll-inll:i.biti.ng act:ion. Kllow:i.ng the p:r:i.or
n:rt, i.t coulcl not be oxpectecl that compouncls o:E th:is cn~og1o:ry ol s~ t~ (.s
Cnll bo ~ISC3CI as L ipi.cl nbSO:rpt:iOIl -:illll:i.b:i.t:i.llg act:i\ro Sllb';tanC(:`S .
rl`ho IlSo o:i- tll(~ co~ )oLIllcls llcco~ g t.o tho :i.llVolltiOIl Eol~ tllo l`:il~st
tlnllo ill thr~l ~olltrc):L o:(-` hyper:L:ipaolll:ia malcos :i.t poss:ib:Lc.~ ~l.Lso to tro~l:t thoso
pnt:i~llts l~llo cllsp:L:Iy :i.ntoLornllco or hal):itlll.lt:i.oll tow;lrcls tho :Li.p:i.~l ahso:rpt:i.oll-
:inll:;l)itors whicll aro alreacly knowll. Tllese compoulids -thus rep:resen-t an enrich-
~0 mellt of` pharmacy.
The allcylurea derivatives, according to the invention, of the general
:Eormula (I) are prepared in a manner which is in itself known~ by
s~
a) reacting an amine of the general formula (II)
R~ ~ N R2 ([1)
R5 1-1
in whlch
A and Rl to R5 have the abovementioned meaning with a compound of
the general formula (LII)
R-N=C-X (II[)
wll :i c~l
R nllCI X ]laVe the abovon1o11tio1locl meaning o:r w:ith i1 COlllpOIllld O:~ thc
gollot.ll :Eormula (:[V)
X=C=N-(C1-12)n -(X)l-(C~-12)n - N=C=X (IV)
in which
X, nl n2 and l have the abovementio1led meall:i.ng o1)tio1l.1:L1y in an
inert organic solvent and optionally in the presol1ce o:f cat11ysts wil:ich aro
in themselves known, for :isocyanate reactions, at tempo:rcltllres botween 20
al1c1 120C, or
b) roact:i1lg an ami1le of the genernl :~ormula (:t:[) Wit}l plleny:l cllloro-
formato o:E-the :~ormu1n (V)
C1(00~,115 (V~
nt te1l1pe.r1tures betwoe1l 0 a11(1 ~ C a1ld ro.lct:i1lg tho rosl11ti11l! p11clly1c11:11)alll:ic
nc.id ester oE tho genor;l.l :I`ormuln (V:[)
A X )~ (VI)
COOC6115
~s~
in which
A and Rl to R5 possess the abovementioned meaning, di:rect or aEter
it has been isolated, with an amine of the general formula (VII)
112N-R (V:[ I)
or with a diamine o:E the general :Eormula (VIII)
~ 12N-(C~l2)n -(X)l-(CI-12) -NH2 (VlII)
in which
R, nl, n2 and 1 llave the abovemelltioned meanings, in an i:nert organ:ic
solvollt at temperatures between 20 and 140C.
:I0 Ihe presellt :invelltioll preEerent:ially re:latos to the use o:E alky:l-
ron dor:ivtlt:ives o:E tho genera:l :Eormula(l)
:i~ll wll:icl~
R represen-ts a straight-chain, branched) cycllc, satura-tod o:r 1111-
saturated aliphatic hydrocarbon radical with 4 to 20 carbon atoms, whicil is
optionally substituted by halogen, hydroxyl or allcoxy or alkoxycarbollyl, w:itll,
:in each case, 1 to 6 carbon atoms in the alkoxy radical, o:r by phollyl, the
phenyl ra(lica:L in turn optionally carrying 1 or 2 substit~lents :E:rom the group
compr:is:i.llg h;llogen, t:rl:Eluorollletllyl, hyclroxyL, alkyl wlth 1 to 2 ca:rbon atoms
or alkoxy with 1 to 2 carbon atoms,
Rl represen-ts l~ydrogen or allcy:l with 1 to ~I caYI)oll at:ollls,
Ic rol)Losollts a:lky:L w:itll L to ~1 ca:rbon atoms,
R`, Rl nlld R5 aro :iclolltlc(l:L or d:i:E:Eorollt alld oacll :rel~resollt ilyd:Logoll,
Il:uioL~oll, hyclroxylJ cyallo, tr:i:Elllorometlly:L, nllcy:L, allcyllllerclipto, a:LIiylsll:LI?llolly
ulliyls~l:LI)ll:illy.l, ulky:lcllrl)olly:L, a:Lkoxy allCI .IllCOXyC;lrl)Ollyl~ thc al)OVelllellt:iOllOd
~allcyl allcl alkoxy radicals contailling 1 to ~ carbon atoms in each case, or
represent phenyl or phenoxy, the phenyl radicals op-tionally being monosubstituted
or disubstituted by halogen, trifluoromethyl or alkoxy with 1 to 2 carbon atoms,
~ 7 -
5~
X denotes oxygen or sulphur and
A represents one of the following radicals:
R' R' R' R' R"' R' R'
-C-, -C-Cil2- , -C=C}I-, -O-C-, -N-- C-, -S()m~IC~
R" R" R" R" R"
in which
R' and R" are identical or dif:Eerent and each denote hydrogen or
alkyl with 1 to 4 carbon atoms,
R" ' denotes alkyl with 1 -to 4 carbon atoms and
m represents O or 2.
The preparation of the new compounds from the category of substances
cle:Eined by the general formula (I) is likewise effec-ted by methods which are
:in themselves known, in accordance with the abovementioned process variants
a) and b), and the isocyanate derivatives, amines and phenylcarbamic acid
esters of the general formulae (III), (IV), (VI), (VII) and (VIII), which are
used as starting materials, are Icnown compounds or can be prepared by known
methods [compare R. Wagner et al, Synthetic Organic Chemistry, Wiley,
New York, (1953), pages 640, 645 cmd 653, and Beilstein, Volume XX, 2nd
supplementary volume, pages 180, 192 and 210].
The alkylurea derivatives display an advantageous inhibition o:E
lipid absorption in humans and animals. When fat-containing :Eood is taken in,
the compoullds result in a lower alimentary hyperlipaemia, coup:Led w:i.th simul-
tnneous :;nhibi.tion of cholesterol absorpti.on, so that they can be usecl in
p<lrtlcl.llar for the treatment of lipometabolism disorders, such as, for example,
hyperlipoproteinaemi.a, arteriosclerosis or a.diposity.
The advantageous effect can be demonstrated on rats using the
following test arrangement.:
2.5 ml/kg of olive oil are administered per os to one group of rats
~ _
(cDntrol group) in order to produce an alimentary hyperlipaemia. ~ correspond-
ing group of other rats receives the active substance in -the form of a
suspension in gum tragacanth, administered by probang, at tlle same -time as
the olive oil is administered. Gum tragacanth only is administerecl to a fur-
ther control group of rats.
2 hours after the administration o:E olive oil, the concentrat:ions
of the serum triglycerides are determined in all three groups of rats (method:
J. Ziegenhorst, ~lin. Chem. 21, (1975) 1,627). Two hours after the aclministra-
tion of fat, the rats trea-ted with olive oil only (group 1) show a distinc-t
rise in the serum triglycerides, compared with the rats to which no fat was
administered (group 3). The lesser rises in tlle serum triglyceri.de levels
in the anima.ls treated with active substance and olive oil (group 2) are
compared with this rise, which is taken as 100%. It was -Eound that even low
dosages of the al~ylurea derivatives cause a signi:Eicant lowering in the ser~m
triglyceride levels. In addi-tion to the powerful lipid absorp-tion-illhi.b:iting
action, the compounds also display an outstandingly good tolerance.
The present invention includes pharmaceutical :Eormula-tions which,
in addition to non-toxic, inert pharmaceutically suitable excipients, contain
one or more compounds of the above -formula, or which consist o:E one or more
compounds of the above :Eormula, as well as processes for the preparation of
these EGrmulations.
The present invention also includes phclrmaceut:ical forlllulations
in dosage units. This means that the formulations are in the :Eorm o:E
individual parts, for example tablets, dragees, capsules, pills, suppositories
and ampoules, of which the content of active compound corresponds to a fraction
or a multiple of an individual dose. The dosage units can contain, for
example, l, 2, 3 or 4 individual doses or 1/2, 1/3 or 1/4 of an individual
_ g
~5~
dose. An individual dose preferably contains the amount of active compound
which is given in one administration and which usually corresponds to a whole,
a half or a third or a quarter of a daily dose.
By non-toxic, inert pharmaceutically suitable excipients there are
to be understood solid, semi-solid or liquid diluents, fillers and formulation
auxiliaries of all kinds.
Tablets, dragees, capsules, pills, granules, solutions, suspensions
and emulsions and pastes may be mentioned as preferred pharmaceutical formu-
lations.
Tablets, dragees, capsules, pills and granules can contain the
active compound or compounds alongside the customary excipients, such as (a)
Eillers and extenders, for example starches, lactose, sucrose, glucose,
mannitol and silica, (b) binders, :Eor example carboxymethylcellulose, alginates,
gelatine and polyvinylpyrrolidone, (c) humectants, for example glycerol, (d)
disintegrating agents, for example agar-agar, calcium carbonate and sodium
bicarbonate, (e) solution retarders, for example paraffin, and (f) resorption
accelerators, for example quaternary ammonium compounds, (g) wetting agents,
for example cetyl alcohol or glycerol monostearate, (h) adsorbents, :Eor
example kaolin and bentonite, and (i) lubricants, for example talc stearate,
calcium stearate and magnesium stearate and solid polyethylene glycols, or
mixtures of the substances listecl under (a) - (i).
The tablets, dragees, capsules, pills and granules can be provicled
with the customary coatings and shells, optionally containing opacifying
ager.ts, and can also be of such composition that they release the active
compound or compounds only, or preferentially, in a certain part oE the in-
testinal tract, optionally in a delayed manner, examples of embedding composi-
tions which can be used being polymeric substances and waxes.
- 10 -
Tlle active compound or compounds, optionally toge-ther with one or
more of the abovementioned excipients, can also be in a micro-ellcapsu:la-ted
form.
Solutions and emulsions can contain, in acldition to the active
compou]ld or compounds, the customary excipients, such as solven-ts, solubilis-
ing agents and emulsifiers, for example water, ethyl alcohol, isopropyl
alchol, e-thyl carbonate, ethyl acetate~ benzyl alco~ol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, especially
cottonseed oil, groundnut oil, maize germ oil, olive oil, castor oil and sesame
oil, glycerol, glycerol-formal, tetrahydrofurfuryl alcohol, polye-thylene
glycols and Eatty acid esterso:Esorbitane, or mixtures oE these subs-tances.
For parenteral administration, the solutions and emulsiolls can
also be in a sterile Eorm which is isotonic with blood.
Suspensions can contain, in addition to the active compound or
compo~mds, the customary excipients, such as liquid diluents, for example water,
ethyl alcohol or propylene glycol, suspending agents, for example e-thoxylated
isostearyl alcohols, polyoxyethylene sorbitolestersand sorbitane esters,
micro-crystalline cellulose, aluminiwn methanehydroxide, ben-tonite, agar-agar
and tragacanth, or mixtures of these substances.
The formulation Eorms mentioned can also contain coLorants, pre-
servatives and additives which improve the odour and flavour, -Eol examE)lo
cppermint oil and eucalyptus oil, and s~ee-teners, Eor example saccllarin.
The therapeutically active compounds should be preson-t in the
abovelllentioned pharmaceutical :Eormulations in a concelltratioll of about O.L to
99.5, preEerably of about 0.5 to 95, per cent by weight oE the total mix-t~re.
The abovementioned pharmaceutical formulations can also contain
other pharmaceutical active compounds in addition to compounds of the above
- 11 -
5~
formula.
The abovementiolled pharmaceutical formula-tions are preparecl in the
customary manner according to known methods, for example by mixing the active
compound or compounds with the excipient or excipients.
The present invention also inclucles the use of the compounds of
the above formula and the use of pharmaceutical formulations which contain one
or more compounds of the abovementioned formula, in human medicine alld
veterinary medicine, for the prevention, alleviation and/or cure of diseases
of the lipometabolism.
The active compounds or the pharmaceuticai :Eormulations can be
administered orally or parellterally, preferably orally.
In general, it has proved advantageous both in human medicine and
in veterinary medicine to administer the active compowld or compounds in amowlts
of about 0.1 to about 100, preferably 1 to 50, mg/kg of body weight every 2
hours, divided into 1 to 6 administrations, and speciEically to do so before
and/or during and/or after meals. An individual administration preferably
contaills the active compound or compounds in amounts of about 0.1 to about
20 mg/kg of bocly weight. Ilowever~ it can be necessary to devia-te Erom the
dosages mentioned, and in particular to do so as a :Eunction of the species alld
the body weight of the subject to be treated, the nature ancl thc sever:i-ty o:E
-the illn.ess, the nature of the :Eormula-tion and o:E the aclmillistrat:ioll oE tl~e
mc)d:iccl~ llt, and the time or interval over whicll thct adminis-trat:ion -talcos pLace.
Thlls it can suf:Eice in some cases to manage wi.th less tharl the abovementiolled
.Imoullt o:E active compo~md, whilst in other cases tlle abovemen-tionecl amount of
active compound must be exceeded. The particular optimum dosage required ancl
the type of administration of the active compounds can easily be cletermined by
~5~
anyone skilled in the art, on the basis of his expert knowledge.
The formulation examples which follow illustrate the preparation
of medicinal :Eormulations to be used according to the invention:
Examples_of the preparation o-E -tablets
1. 100 mg of -the compound oE Example 1 are mixed with 69 mg of lactose
and 30 mg oE maize starch, -the mixture :is then kneaded with a paste of ].5 mg
of maize starch and the whole is pressed through a sieve of 3 - 5 rmm mesh
width. The mixture is then dried in a drier at 60 - 80C.
The resulting granules are forced through a sieve oE 0.8 mm mesh
width, a further l5 mg of maize starch, 10 mg of talc and 1 mg oE magnesiur
stearate a:ro mi.xed in and the resulting mixture is compressecd with the aicl
of a convc?nt:ional tablet press to give row~d tablets with a diameter of 9 mm
and total weight of 2~0 m~.
2. 200 mg of -the compound of Example 13 are mixed w:ith 97 mg of secon-
dary calcium phosphate and the mixture is kneaded with an aqueous gelatine
solution which contains 2 mg of gelatine. The resulting mixture is -then
pressed through a sieve of 3 - 5 mm mesh width and dried at 60 - 80C. The
dry granules are seived (0.8 mm), 20 mg of wheat starch and I mg of magnesium
stearate are then mixed in and the resulting mixture is -tablet-ted in the
known manner. Round table-ts with a diameter of 8 mm and a total we:i.ght of
320 mg are obtained.
t:i.on Lxalllples
am~) I e 1 (variarlt .1)
0~1 mol of 2,2,~-tr:i.methyl-1,2,3,~-tetrallydroquillol:ille are dis-
solved in 50 ml o:E et}ler alld the solution is mixed with 0.1 mol o:E n-clodecyl
isocyanclte. A spatula tip of diazabicyclooc-tane is then added, the mixture
is left to stand for 7 days at 20 to 25C and coolecl to -70C ancl the
S~
precipitate WhiC]l has separated out is filtered off. N-n-Dodecylaminocarbonyl-
2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline with a melting point of 48 -
50C is obtained.
Yield: 66% of t}-leory.
Example 2 (variant b)
l mol of 2-methylindoline is dissolved in 300 ml of toluene and
1 mol of methyl isocyanate is added, the temperature not rising above 25C.
The mixture is left to stand for 1 day and the resulting precipitate is then
filtered off. N-Methylaminocarbonyl-2-methylindoline with a melting point of
158 - 160C is obtained.
Yield: 89% of theory.
Example 3 (variant b)
A solution of 0.1 mol of 2-methylindoline, 0.12 mol of triethyl-
amine, lO0 ml of toluene and 0.1 mol of phenyl chloroformate is kept at 40C
for 10 hours and is then Gooled to 20C and stirred with 250 ml of water for
15 minutes. The toluene phase is separated off, the solvent is evaporated in
vacuo, the residue is dissolved in 100 ml of n-hexylamine and this solution
is heated under reflux at 130C for 6 hours. After cooling, the solvent is
evaporated oEf at 50C/10 mm llg and the residue is taken up in 250 ml oE
toluene. The solution is then extracted successively with 200 ml o-E lN sodium
hydroxide solution, 200 ml of lN hydroc}lloric acid and 200 ml oE watcr. Al`ter
concelltrating the solution, the residue is recrystallised from petroleulll
ether. N-n-~lexyl-aminocarbonyl-2-methylindoline with a melting point of 57 -
59C is obtained.
Y:iekl: 53% of theory.
The compounds in the table which follows are obtained analogously
to Example 1.
- 14 -
35~
V~
~'
~ ~ -
.~ ~t ~ ~t ~ oo ~ L
h ~ t~ t t~
1 0
Q~ O a~
,~o
b~
1:~ t ~ t~ ~t
O o ~ O ~D ~ ~ Lr~
' o ~ o
U~
3U~
~ O O
t~)~
~`)
~X~ t'l t'~ t~ t~ t~ t~ tr) tr~
~ ~Z ~ ~ X ~ 3 ~ ~, 3 ~, 3
t
~: ~ t~ n t~ t ~ t ~ ~ tl~ t~ t~ t~
~t ~ 3 ~ ~ X, ~ 3 ~ 3
u~ tr~ I
r~ ~ ~ t,,
~ ~ 3
o o ~ o o o o o
, ~r\l ~r~l ~r~l ~r
X
3 3 ~ 3 ~., 3 ~ " ~ '~ ~ ''
" rj ~ 1l 3 1l 3 3 3 3 3 3 ~ ~ r~
a~
a>
.D ~ ~t ~ ~D r- r;o ~ o
Ul Z:
- 15 -
L
E~
c~ r
r1
~1 o r-1 oo ~ ~1 ~ rr~
r~ ~ r~ ~ Lr~
~. 0\o ~
bl) r-~ r~
r-l r~ o o rr~ o r~ ~ o
r l ~ ~) ~ L~ 1~ r-1 r l r-l 1 ro
r rl ~ r~ ~ ~ ~ ~ a~ r~
~ ~ `J r~ r-l
n
tY X X X ~ ~ X X 5' X X
~ ~ ~ r/~ ~ X r~ r~
~ ~ x~ ~X, 3 ~,~, x ~,~, 5'
~ ~ r~l ~
r-l~ t~ a x ~ x ~ x ~ x x
r~
x r~
5~ L~
~ ~ X ~ 5r`1 ,~
v~ I o t~h X ~r~
~ r1 r~ r1 rY ~ ~) `J ~ ¢
~ O O O O O O O O Ov~
r i ~c x x x
1' 5~ X ~ 5~ X ~C X 5' X 5' 5~ x`r'l 5~
r~ l l l l l ll l l l
o
t.) o
r~ O (~1 r~ n ~ o r
~ x z r-l r. I r-l r~ r~ r~ r~ (~1
- ~6 -
~ ~r-D~
17
Exam~le 22
___ _ _ ,
16.8 g of he~amethylene diisocyanate are added
-to a solution of 35 g of 2,2,4-trimethyl-1,2,3,4-tetra-
hydroquinoline in 100 ml of ether. After 1 day, 1/2 g
of DABC0 (diazabicyclooctane) is added, -the mixture is
left to stand for 3 days and 23.8 g of 1,6-bis-(N-Z,2,4-
trimethyl-1,2,3,4 tetrahydroquinolyl)-carbonylamino-
hexane are filtered off. A further 25.1 g are obtained
from the mother liquor (to-tal yield: 41.8 g = 9Lr %)u
Melting point 125 - 1280CG
Exam~le 23
18.2 g of 19 7-diisocyana-toheptane are added to
a solution of 35 g of 2,2,4-trimethyl-1,2,394-tetrahydro-
quinoline in 100 ml of absolute te-trahydrofuraneO After
1 day, 1/2 g of DABC0 is added. After standing for
some time 9 a lit-tle undissolved matter is filtered off,
the filtrate is concentrated, the residue is dissolved
in about 100 ml of ether, the solution is diluted with
200 ml of petroleum ether and cooled down to -70C~ and
the precipitate is filtered off after 1 day. Yield
o~ 197-bis-(N-2,2,4-~trimethyl-1,2 ? 3 9 4--tetrahydroquinolyl~-
carbonylamino-heptane: 42i9 g; melting poin-t 112 116C.
Exam~le 24
A solution of 35 g of 2,2,4-trimethyl-1~2,3,4-
tetrahydroquinoline 9 23 8 g of l,ll-diisocyanatoundecane
and 1/2 g o~ DABC0 is left to stand for 3 days, 150 ml
of toluene/petroleum ether (lol) are added, the whole is
briefly hea-ted -to the boil and the precipitate is fil-
t~red off. Yield: 46~4 g (83 %) of 1,11-b~s-(N~2,2,4-
t:rimethyl-1,2,3,4-tetrahydroquinolyl)-carbonylamino-
undecane. ~elting poin-t 102 - 108C.
l'he further products were prepared analogously -to
Example 22, 23 or 24 (see Table 2 which follows, wherein
the products of -the process are defined in accordance
with the general formula
Q~C ~H-(C~ ) -(S~l-(CH2) r~H-C-Q~.
Le A 19 942
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Le A 19 942
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The compo~nds in Table 3 which fol.lows were
obtained analogously to Example 1, A, X, Rj Rl, R2 and
R~ being defined in accordance with Table 1.
Le A 19 942
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