CA1185181A - Alkylurea derivatives for the treatment of diseases of the lipometabolism, processes for the preparation thereof their use in medicaments containing these alkylurea derivativesand process for the preparation of the medicaments - Google Patents

Abstract

Abstract of the Disclosure The invention relates to pharmaceutical compositions comprising an alkylurea of formula wherein Y represents R or a radical in which n1 and n2 denote integers from 3 to 9 and ? denotes 0 or 1, R represents a straight-chain, branched, cyclic, saturated or unsaturated aliphatic hydro-carbon radical with up to 20 carbon atoms, which is optionally substituted by halogen, hydroxyl, alkoxy, alkoxycarbonyl or optionally substituted aryl, R1 represents hydrogen or lower alkyl, R2 represents lower alkyl and R3, R4 and R5 are identical or different and each represent hydrogen, halogen, hydroxyl, cyano, lower alkyl, lower alkoxy, lower alkoxycarbonyl, lower alkylmercapto, lower alkylsulphonyl, lower alkylsulphinyl, lower alkylcarbonyl, optionally substi-tuted aryl or optionally substituted aryloxy, X denotes oxygen or sulphur and A represents one of the following radicals in which R' and R" arc identical or different and each denote 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 and (iii) R represents straight chain, branched or cyclic alkyl or alkenyl with 6 to 18 carbon atoms, the said alkyl or alkenyl groups optionally being sub-stituted by chlorine, bromine, fluorine or alkoxy with 1 to 4 carbon atoms, or by phenyl, then R1 is not hydrogen, methyl or ethyl; and (B) if (i) Y is other than R and (ii) X is 0, then R1 is not hydrogen;
which alkylurea is in admixture with a suitable diluent or carrier. The alkylureas are useful hypolipacmic agents.

Description

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 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 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) 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) ~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.

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 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.

35~

V~
~' ~ ~ -.~ ~t ~ ~t ~ oo ~ L
h ~ t~ t t~

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:

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~

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 .

.

+' ' c~ a~ ~ o : ~r rr~
~1~
~ O
, . .

-1' Q) Ul h ::1 o ~ ~ ~ ;~
~ O P
c)~l E
h ~ X
~, .

o a co ~ o ~ cr~
a~ ~H ' ~rl O
?~ æ
_~
_~ C:~ ~ ~ ~ O O

~ ~ ~1 ~ ll~i ~n ,_ ~ er ~ ~ ~ ~ ~

I"
.
V

C) ~
rl ,n X u~ o E~ ~ ~`~ ~ ~ ' Le A 19 942 - 1~
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 -h o ~D ~D ~ ~t f~ O ~ r-r~ ~ r~ c~ r fJ~ C
a) ~
~0 o ~ C.) ~ O
~ O O O
~1 ~t t ? C.~ . f~
rl o o o f~ f~ O
~_ ~ W ~ ~ f~l ~0 o I t i .n .,~ ,~1 ft~
S ~ f~t r` ~ O ~ O -~ ~) f~t 0 1~7 f'~
f'~ I ~ r:
P~ ~: -'1 C f`~ ~ X C ) C.) 1~ ~ ~ ~
f.~t ~C X !r :1:
~ ~ ~ U U U
S'~ f" f'~ ~ ) t~) f'l f~
,) U C.. J C.) C.~ C.3 I
~ ~ O
X LnX O O It') ~ f~t ~ ) i ~ .C 5 C t ~) C
O O ~3 0 ~t I f~t ~ U C~ ~ U C.) ~'-- f" ~) .
.C ~ . t~ :~ t r-- t~t 5 t iY U U ~ ~) C.) ~ 5 f t_) S

X O OOOOO O OO
l l l I f~l f`~ f~l I I f`l f~
V O I ~
I t ~ 5 V C) t ~) t f~ f~t ~_) I f~ I f~ t ~t . U ~ U ~ g ~ - U ~_) C_) ~¢ I I ~ I f't I
t~) O
l ft') ~ f.-~
. ~O ~r) ~t ~ f') t-') f~ f~ f~) . ~ ~_1 r~ ~d E~ r~l Le A 19 942

Claims (6)

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

1. A pharmaceutical composition comprising an alkylurea of formula wherein Y represents R or a radical in which n1 and n2 denote integers from 3 to 9 and ? denotes 0 or 1, R represents a straight-chain, branched, cyclic, saturated or unsaturated aliphatic hydro-carbon radical with up to 20 carbon atoms, which is optionally substituted by halogen, hydroxyl, alkoxy, alkoxycarbonyl or optionally substituted aryl, R1 represents hydrogen or lower alkyl, R2 represents lower alkyl and R3, R4 and R5 are identical or different and each represent hydrogen, halogen, hydroxyl, cyano, lower alkyl lower alkoxy, lower alkoxycarbonyl, lower alkylmercapto, lower alkylsulphonyl, lower alkylsulphinyl, lower alkylcarbonyl, optionally substi-tuted aryl or optionally substituted aryloxy, X denotes oxygen or sulphur and A represents one of the following radicals 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, provided that (A) if (i) X represents oxygen, (ii) A is other than and (iii) 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 or alkoxy with 1 to 4 carbon atoms, or by phenyl, then R1 is not hydrogen, methyl or ethyl; and (B) if (i) Y is other than R and (ii) X is o, then R1 is not hydrogen;
which alkylurea is in admixture with a suitable diluent or carrier.

2. A composition according to claim 1 wherein, in the alkylurea, R
represents a straight chain, branched, cyclic, saturated or unsaturated ali-phatic hydrocarbon radical with up to 20 carbon atoms, which is optionally substituted by halogen, hydroxyl, alkoxy, alkoxycarbonyl or aryl optionally substituted by chlorine, fluorine, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms and R3, R4 and R5 are identical or different and each represent hydrogen, halogen, hydroxyl, cyano, lower alkyl, lower alkoxy, lower alkoxycarbonyl, aryl optionally substituted by chlorine, fluorine, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms.

3. A composition according to claim 1 wherein, in the alkylurea, R
represents a straight-chain, branched, cyclic, saturated or unsaturated ali-phatic hydrocarbon radical with 4 to 20 carbon atoms, which is optionally substituted by halogen, hydroxyl or alkoxy or alkoxycarbonyl, with, in each case, 1 to 6 carbon atoms in the alkoxy radical, or by phenyl, the phenyl radical in turn optionally carrying 1 or 2 substituents from the group compris-ing halogen, trifluorometllyl, hydroxyl, alkyl with 1 to 2 carbon atoms or alkoxy with 1 to 2 carbon atoms, R1 represents hydrogen or alkyl with 1 to 4 carbon atoms, R2 represents alkyl with 1 to 4 carbon atoms, R3, R4 and R5 are identical or different and each represent hydrogen, halogen, hydroxyl, cyano, trifluoromethyl, alkyl, alkylmercapto, alkylsulphonyl, alkylsulphinyl, alkyl-carbonyl, alkoxy and alkoxycarbonyl, the abovementioned alkyl and alkoxy radicals containing 1 to 4 carbon atoms in each case, or represent phenyl or phenoxy, the phenyl radicals optionally being monosubstituted or disubstituted by halogen, trifluoromethyl or alkoxy with 1 to 2 carbon atoms, X denotes oxygen or sulphur and A represents one of the following radicals:

in which R' and R" are identical or different and each denote hydrogen or alkyl with 1 to 4 carbon atoms, R''' denotes alkyl with 1 to 4 carbon atoms and m represents 0 or 2.

4. A composition according to claim 1 wherein the alkylurea is N-n-dodecylaminocarbollyl-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline.

5. A composition according to claim 1 wherein the alkylurea is N-

6-chloro-n-hexylaminocarbonyl-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline.