NO791413L - PROCEDURE FOR PREPARING 5- (2-ANILINOALKYLAMINO-1-HYDROXYALKYL) SALICYLAMIDES - Google Patents

PROCEDURE FOR PREPARING 5- (2-ANILINOALKYLAMINO-1-HYDROXYALKYL) SALICYLAMIDES

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Publication number
NO791413L
NO791413L NO791413A NO791413A NO791413L NO 791413 L NO791413 L NO 791413L NO 791413 A NO791413 A NO 791413A NO 791413 A NO791413 A NO 791413A NO 791413 L NO791413 L NO 791413L
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Norway
Prior art keywords
hydroxyethyl
salicylamide
formula
methylanilino
acid
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NO791413A
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Norwegian (no)
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Bernard Ray Neustadt
Elijah Herman Gold
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Scherico Ltd
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Priority to NO791413A priority Critical patent/NO791413L/en
Publication of NO791413L publication Critical patent/NO791413L/en

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Description

Foreliggende oppfinnelse angår nye 5-(2-anilinoalkyl-amino-l-hydroxyalkyl)-salicylamider med verdifulle farmakologiske egenskaper, i særdeleshet antihypertensiv aktivitet, fremgangs- The present invention relates to new 5-(2-anilinoalkyl-amino-1-hydroxyalkyl)-salicylamides with valuable pharmacological properties, in particular antihypertensive activity, progress-

måte for fremstilling av disse og farmasøytiske komposisjoner inneholdende disse. method for producing these and pharmaceutical compositions containing them.

Oppfinnelsen tilveiebringer således 5-(2-anilino-alkyl-amino-l-hydroxyalkyl)salicylamider av formelen The invention thus provides 5-(2-anilino-alkyl-amino-1-hydroxyalkyl)salicylamides of the formula

13 13

hvori R og R er uavhengige hydrogenatomer eller lavere alkylgrupper, wherein R and R are independent hydrogen atoms or lower alkyl groups,

2 2

R er et hydrogenatom eller en lavere alkyl-, lavere alkoxylavere-alkyl- eller hydrolavere alkylgruppe-, R is a hydrogen atom or a lower alkyl, lower alkyl lower alkyl or hydro lower alkyl group,

Alk er en acyklisk eller cyklisk alkylenbro inneholdende 2-10 carbonatomer, forutsatt at det er 2 - 6 carbonatomer som skiller nitrogenatomene som danner bro, Alk is an acyclic or cyclic alkylene bridge containing 2-10 carbon atoms, provided there are 2-6 carbon atoms separating the bridging nitrogen atoms,

Z er et hydrogenatom eller en lavere alkyl, lavere alkanoyl, Z is a hydrogen atom or a lower alkyl, lower alkanoyl,

lavere alkylsulfonyl, arylsulfonyl, laverealkoxylaverealkyl, 2,2,2-trifluorethyl eller benzylgruppe, lower alkylsulfonyl, arylsulfonyl, lower alkoxylower alkyl, 2,2,2-trifluoroethyl or benzyl group,

1 2 1 2

Y og Y er uavhengig hydrogen eller halogenatomer eller hydroxy, trifluormethyl, lavere alkyl, lavere alkoxy, nitro, amino, monolaverealkylamino, di-laverealkylamin, laverealkanoylamino, laverealkylsulfonylamino, arylsulfonylamino, N-laverealkyl-N-laverealkanoylamino eller N-lavérealkyl-N-laverealkylsulfinylaminogrupper, Y and Y are independently hydrogen or halogen atoms or hydroxy, trifluoromethyl, lower alkyl, lower alkoxy, nitro, amino, monolower alkylamino, di-lower alkylamine, lower alkanoylamino, lower alkylsulfonylamino, arylsulfonylamino, N-lower alkyl-N-lower alkanoylamino or N-lower alkyl-N-lower alkylsulfinylamino groups ,

og farmasøytisk akseptable syreaddisjonssalter derav. and pharmaceutically acceptable acid addition salts thereof.

De lavere alkylgrupper som angitt ovenfor inneholder 1-6 carbonatomer og eksemplifiseres ved methyl, ethyl, propyl, butyl, pentyl, hexyl og de tilsvarende forgrenede isomerer derav. De lavere alkoxygrupper inneholder likeledes 1-6 carbonatomer The lower alkyl groups indicated above contain 1-6 carbon atoms and are exemplified by methyl, ethyl, propyl, butyl, pentyl, hexyl and the corresponding branched isomers thereof. The lower alkoxy groups also contain 1-6 carbon atoms

og kan typisk være methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sek-butoxy og t-butoxy. and can typically be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy and t-butoxy.

De lavere alkanoylgrupper inneholder 1-6 carbonatomer og eksemplifiseres ved formyl, acetyl, butyryl og valeryl. The lower alkanoyl groups contain 1-6 carbon atoms and are exemplified by formyl, acetyl, butyryl and valeryl.

1 2 1 2

Halogenatomene representert ved Y og Y innbefatter fluor, klor, brom og jod. The halogen atoms represented by Y and Y include fluorine, chlorine, bromine and iodine.

Alk-broene med 2-6 carbonatomer som skiller nitrogenatomene er representert ved acykliske grupper slik som ethylen, trimethylen, tetramethylen og pentamethylengrupper eventuelt sub-stituert med lavere alkylgrupper. Således er representative acykliske Alk-grupper ifølge oppfinnelsen ethylen, 1-methylethylen, trimethylen, 2-methylethylen, 1-methyltrimethylen, tetramethylen, 1-methyltetramethylen, 1,1-dimethyltrimethylen, 1,2-dimethyltrimethylen, 1-ethyltrimethylen, l-methyl-2-ethyltetramethylen,-pentamethylen og 1,l-dimethyl-3-methylpentamethylen. (Nummererin-gen av Alk-broen starter ved carbonatomet bundet til nitrogenatomet i ethanolaminresten i 5-stilling av salicylamiddelen i formel The alk bridges with 2-6 carbon atoms that separate the nitrogen atoms are represented by acyclic groups such as ethylene, trimethylene, tetramethylene and pentamethylene groups optionally substituted with lower alkyl groups. Thus, representative acyclic Alk groups according to the invention are ethylene, 1-methylethylene, trimethylene, 2-methylethylene, 1-methyltrimethylene, tetramethylene, 1-methyltetramethylene, 1,1-dimethyltrimethylene, 1,2-dimethyltrimethylene, 1-ethyltrimethylene, l-methyl -2-ethyltetramethylene, -pentamethylene and 1,1-dimethyl-3-methylpentamethylene. (The numbering of the Alk bridge starts at the carbon atom bound to the nitrogen atom in the ethanolamine residue in the 5-position of the salicyl agent in formula

I.) IN.)

En gruppe av foretrukne forbindelser med en acyklisk A group of preferred compounds with an acyclic

bro Alk kan representeres ved formelen: bro Alk can be represented by the formula:

hvori n er 1 - 4, og R<1>, R<2>, R<3>, z, Y<1>og Y<2>er som tidligere definert. En særlig foretrukket bro er av formelen: wherein n is 1 - 4, and R<1>, R<2>, R<3>, z, Y<1> and Y<2> are as previously defined. A particularly preferred bridge is of the formula:

dvs. n er 2 i formel II. i.e. n is 2 in formula II.

En gruppe av foretrukne forbindelser med en cyklisk bro Alk kan representeres ved formelen A group of preferred compounds with a cyclic bridge Alk can be represented by the formula

hvori n-j^ er 0 - 2, n2er 1 - 5, n-^+ n2er 2 - 6, n^og n4er uavhengig 0 eller 1, R, R og R er uavhengig hydrogenatomer eller lavere alkylgrupper, forutsatt at det totale antall carbonatomer i Alk-broen ikke overstiger ti, wherein n-j^ is 0 - 2, n2 is 1 - 5, n-^+ n2 is 2 - 6, n^ and n4 are independently 0 or 1, R, R and R are independently hydrogen atoms or lower alkyl groups, provided that the total number of carbon atoms in The Alk bridge does not exceed ten,

12 3 12 12 3 12

og R , R , R , Z, Y og Y er som tidligere definert. and R , R , R , Z, Y and Y are as previously defined.

Det er en direkte binding fra nitrogenatomet til carbonatomet i ringen når ng eller n^er lik'null, og en direkte binding mellom to ringcarbonatomer som bærer radikalene R og R^ når n^er lik null. There is a direct bond from the nitrogen atom to the carbon atom in the ring when ng or n^ is equal to zero, and a direct bond between two ring carbon atoms carrying the radicals R and R^ when n^ is equal to zero.

Cykliske Alk-broer kan ha lavere alkylsubstituenter og innbefatter 1,2-cyclopentylen, 1,3-cyclopentylen, 1,2-cyclohexylen, 1,3-cyclohexylen, 1,4-cyclohexylen, 1-methyl-l,4-cyclohexylen og 1,4-cycloheptylen, i deres trans- og cis-former. Cykliske Alk-broer som inneholder acykliske deler innbefatter de av føl-gende formler (i deres cis- og trans-former): Cyclic Alk bridges may have lower alkyl substituents and include 1,2-cyclopentylene, 1,3-cyclopentylene, 1,2-cyclohexylene, 1,3-cyclohexylene, 1,4-cyclohexylene, 1-methyl-1,4-cyclohexylene and 1,4-cycloheptylene, in their trans and cis forms. Cyclic Alk bridges containing acyclic moieties include those of the following formulas (in their cis and trans forms):

I en foretrukket gruppe av forbindelser av formel I 2 3 1 er R og R hydrogenatomer og R er en methylgruppe eller spesielt 1 2 et hydrogenatom, Y er et hydrogenatom, Y er en methylgruppe eller et hydrogen- eller halogenatom, Z er et hydrogenatom eller en methyl- eller benzylgruppe og Alk er en trimethylen, tetramethylen eller 1,4-.cyclohexylengruppe (spesielt i trans-f ormen) eller en gruppe av formelen In a preferred group of compounds of formula I 2 3 1 R and R are hydrogen atoms and R is a methyl group or especially 1 2 a hydrogen atom, Y is a hydrogen atom, Y is a methyl group or a hydrogen or halogen atom, Z is a hydrogen atom or a methyl or benzyl group and Alk is a trimethylene, tetramethylene or 1,4-cyclohexylene group (especially in the trans form) or a group of the formula

hvori n er 1 - 4. where n is 1 - 4.

Spesielt foretrukneforbindelser ifølge oppfinnelsen er 5-{2-[3-(N-methylanilino)-2-propylamino]-1-hydroxyethyl}salicylamid, Particularly preferred compounds according to the invention are 5-{2-[3-(N-methylanilino)-2-propylamino]-1-hydroxyethyl}salicylamide,

5-{2-[4-(N-methylanilino)-2-butylamino]-1-hydroxyethyl}salicylamid, 5-{2-[4-(N-methylanilino)-2-butylamino]-1-hydroxyethyl}salicylamide,

5-{2-[5-(N-methylanilino)-2-pentylamino]-1-hydroxyethyl}salicylamid, 5-{2-[5-(N-methylanilino)-2-pentylamino]-1-hydroxyethyl}salicylamide,

5-{2-[4-(4,N-dimethylanilino)-2-butylamino]-1-hydroxyethyl}-salicylamid, 5-{2-[4-(4,N-dimethylanilino)-2-butylamino]-1-hydroxyethyl}-salicylamide,

5-{2-[4-(4-fluor-N-methylanilino)-2-butylamino]-1-hydroxyethyl}-salicylamid, og 5-{2-[4-(4-fluoro-N-methylanilino)-2-butylamino]-1-hydroxyethyl}-salicylamide, and

5-{2-[4-(4-klor-N-methylanilino)-2-butylamino]-1-hydroxyethyl}-salicylamid. 5-{2-[4-(4-chloro-N-methylanilino)-2-butylamino]-1-hydroxyethyl}-salicylamide.

De farmasøytisk akseptable syreaddisjonssalter av forbindelsene av formel I kan avledes fra organiske og uorganiske syrer slik som svovelsyre, fosforsyre, saltsyre, hydrobromsyre, sulfamsyre, sitronsyre, melkesyre, oljesyre, ravsyre, vinsyre,0cinnaminsyre, eddiksyre, benzoesyre, gluconsyre, ascorbinsyre og beslektede syrer. The pharmaceutically acceptable acid addition salts of the compounds of formula I may be derived from organic and inorganic acids such as sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, sulfamic acid, citric acid, lactic acid, oleic acid, succinic acid, tartaric acid, cinnamic acid, acetic acid, benzoic acid, gluconic acid, ascorbic acid and related acids. .

Forbindelsene av formel I og deres farmasøytisk akseptable syreaddisjonssalter kan fremstilles for eksempel ved føl-gende metoder: The compounds of formula I and their pharmaceutically acceptable acid addition salts can be prepared, for example, by the following methods:

a) Reduksjon av en forbindelse av formel a) Reduction of a compound of formula

hvori X er et ocygenatom eller (H,OH), Alk, R og R<3>er som ovenfor definert, Pg er et hydrogenatom eller en reduktivt fjernbar wherein X is an oxygen atom or (H,OH), Alk, R and R<3> are as defined above, Pg is a hydrogen atom or a reductively removable

2a a 2 2a a 2

beskyttende gruppe, R og Z er respektivt R og Z som ovenfor definert eller en reduktivt f jernbar beskyttende gruppe, og Y"<*>"<a>2a 12 protecting group, R and Z are respectively R and Z as defined above or a reductively f ironable protecting group, and Y"<*>"<a>2a 12

og Y er Y og Y som ovenfor angitt, and Y is Y and Y as above,

eller en hydroxy eller en aminogruppe (innbefattet usubstituerte og mono-substituerte aminogrupper, men ikke innbefattet di-substituerte aminogrupper, tidligere definert for Y 1 og Y 2), bærende en reduktivt fjernbar beskyttende gruppe, or a hydroxy or an amino group (including unsubstituted and mono-substituted amino groups, but not including di-substituted amino groups, previously defined for Y 1 and Y 2 ), bearing a reductively removable protecting group,

forutsatt at når R 2a , Pg, Z a, Y la og Y 2a er gruppene R 2, H, Z, provided that when R 2a , Pg, Z a, Y la and Y 2a the groups R 2 , H, Z,

1 2 1 2

Y og Y , er X et oxygenatom, Y and Y , X is an oxygen atom,

i et egnet løsningsmiddel. in a suitable solvent.

Reduksjonen av gruppen CX når X er et oxygenatom til gruppen CHOH kan utføres med et utall reduksjonsmidler. Reduk-sjonsmidlet er fortrinnsvis et borhydrid, f.eks. lithiumborhydrid, kaliumborhydrid eller spesielt- natriumborhydrid. Reduksjonen utføres fortrinnsvis i en vann-blandbar alkohol som løsningsmid-del, f.eks. methanol, ethanol eller isopropanol. The reduction of the group CX when X is an oxygen atom to the group CHOH can be carried out with a number of reducing agents. The reducing agent is preferably a borohydride, e.g. lithium borohydride, potassium borohydride or especially sodium borohydride. The reduction is preferably carried out in a water-miscible alcohol as solvent, e.g. methanol, ethanol or isopropanol.

Gruppen CX kan også reduseres ved hjelp av hydrogen og en katalysator, f.eks. palladium, spesielt 5 - 10 % Pd-C, i nær vær av et organisk løsningsmiddel slik som en lavere alkanol, f.eks. methanol eller ethanol. The group CX can also be reduced using hydrogen and a catalyst, e.g. palladium, especially 5 - 10% Pd-C, in the presence of an organic solvent such as a lower alkanol, e.g. methanol or ethanol.

Det skal bemerkes at mange reduksjonsprosesser, spesielt de som anvender hydrogen og en katalysator, ikke er egnet for fremstilling av forbindelser hvori Y 1 og/eller Y 2 er en nitrogruppe. Envidere er prosesser som gjør bruk av hydrogen og en katalysator ikke egnet for fremstilling av forbindelser hvori Z er en benzylgruppe. It should be noted that many reduction processes, especially those using hydrogen and a catalyst, are not suitable for the preparation of compounds in which Y 1 and/or Y 2 is a nitro group. Furthermore, processes which make use of hydrogen and a catalyst are not suitable for the preparation of compounds in which Z is a benzyl group.

Reduktivt fjernbare beskyttende grupper som kan fore- Reductively removable protecting groups that can pre-

la 2a 2a let 2a 2a

ligge i Y eller Y eller kan være til stede som R , Pg eller Z innbefatter benzyl, benzhydryl, trityl og benzyloxycarbonyl. Disse grupper kan alle fjernes ved hjelp av hydrogen og en kata-lystor, fortrinnsvis som ovenfor beskrevet. lie in Y or Y or may be present as R , Pg or Z include benzyl, benzhydryl, trityl and benzyloxycarbonyl. These groups can all be removed using hydrogen and a catalyst, preferably as described above.

En særlig foretrukket utførelsesform av denne prosess omfatter reduksjonen av en forbindelse av formel A particularly preferred embodiment of this process comprises the reduction of a compound of formula

hvori R<1>,R<2a>, R<3>, Pg, Alk, X, Y"1" og Y<2>er som ovenfor definert, og Z° er gruppen Z definert ovenfor unntatt en benzylgruppe, wherein R<1>, R<2a>, R<3>, Pg, Alk, X, Y"1" and Y<2> are as defined above, and Z° is the group Z defined above except for a benzyl group,

2a 2 2a 2

forutsatt at når R<2>a og Pg er R og et hydrogenatom, er X et oxygenatom. Når X er et oxygenatom og R<2a>og/eller Pg er en reduktivt fjernbar beskyttende gruppe, kan denne utførelsesform utføres i et trinn ved hjelp av hydrogen og en katalysator, eller i to trinn ved hjelp av et borhydrid og deretter hydrogen og en katalysator, idet reaksjonsbetingelsene er som ovenfor definert. Når mer enn én reduktiv fjernbar gruppe er til stede, er alle slike grupper fortrinnsvis identiske, f.eks. alle er benzyl-grupper eller alle er benzyloxycarbonylgrupper. provided that when R<2>a and Pg are R and a hydrogen atom, X is an oxygen atom. When X is an oxygen atom and R<2a>and/or Pg is a reductively removable protecting group, this embodiment can be carried out in one step using hydrogen and a catalyst, or in two steps using a borohydride and then hydrogen and a catalyst, the reaction conditions being as defined above. When more than one reductive leaving group is present, all such groups are preferably identical, e.g. all are benzyl groups or all are benzyloxycarbonyl groups.

Forbindelsene av formel V eller VI kan fremstilles etter standard metoder. Eksempelvis kan forbindelser av formel The compounds of formula V or VI can be prepared by standard methods. For example, compounds of the formula

VI fremstilles ved en.kondensasjon av en forbindelse av formel med en forbindelse av formel VI is prepared by a condensation of a compound of formula with a compound of formula

hvori R"*",R<2a>,R<3>,Alk,Pg, Y"*", Y2 og Z*3 er som ovenfor definert og Hal er et klor- eller bromatom. Denne kondensasjon utføres i nærvær av en syreakseptor og et organisk løsningsmiddel. En organisk base, f.eks. pyridin eller triethylamin, kan tjene som in which R"*",R<2a>,R<3>,Alk,Pg, Y"*", Y2 and Z*3 are as defined above and Hal is a chlorine or bromine atom. This condensation is carried out in the presence of an acid acceptor and an organic solvent. An organic base, e.g. pyridine or triethylamine, can serve as

løsningsmiddel og syreakseptor. Hvis et nøytralt løsningsmiddel slik som et dialkylamid, f.eks. dimethylformamid eller alkohol anvendes, kan en uorganisk base slik som natrium eller kaliumcarbonat anvendes som syreakseptor. solvent and acid acceptor. If a neutral solvent such as a dialkylamide, e.g. dimethylformamide or alcohol is used, an inorganic base such as sodium or potassium carbonate can be used as acid acceptor.

I særdeleshet de etterfølgende forbindelser kan fremstilles ved denne prosess: 5-{2-[4-(N-methylanilino)-2-(2-methyl)-butylamino]-1-hydroxye ethyl}salicylamid, 5-{2-[trans-4-(N-methylanilino)-1-cyclohexylamino]-1-hydroxyethyl } salicylamid , sm.p. 159 - 161° C, In particular, the following compounds can be prepared by this process: 5-{2-[4-(N-methylanilino)-2-(2-methyl)-butylamino]-1-hydroxyethyl}salicylamide, 5-{2-[trans -4-(N-methylanilino)-1-cyclohexylamino]-1-hydroxyethyl } salicylamide , m.p. 159 - 161° C,

5-{2- [cis-4-(N-methylanilino)-1-cyclohexylamino]-1-hydroxyethyl} salicylamid , 5-{2- [cis-4-(N-methylanilino)-1-cyclohexylamino]-1-hydroxyethyl} salicylamide,

5-{2-[trans-4-(N,4-dimethylanilino)-1-cyclohexylamino]-1-hydroxyethyl } salicylamid , 5-{2-[trans-4-(N,4-dimethylanilino)-1-cyclohexylamino]-1-hydroxyethyl} salicylamide,

5-[2-(trans-4-anilino-l-cyclohexylamino)-1-hydroxyethyl]-salicylamid, 5-[2-(trans-4-anilino-1-cyclohexylamino)-1-hydroxyethyl]-salicylamide,

5-{2-[trans-3-(N-methylanilino)-1-cyclohexylamino]-1-hydroxyethyl} salicylamid , 5-{2-[trans-3-(N-methylanilino)-1-cyclohexylamino]-1-hydroxyethyl} salicylamide,

5-{2-[cis-3-(N-methylanilino)-1-cyclohexylamino]-1-hydroxyethyl}-salicylamid, 5-{2-[cis-3-(N-methylanilino)-1-cyclohexylamino]-1-hydroxyethyl}-salicylamide,

5-{2-[trans-3-(N-methylanilino)-1-cyclopentylamino]-1-hydroxyethyl} salicylamid, 5-{2-[trans-3-(N-methylanilino)-1-cyclopentylamino]-1-hydroxyethyl} salicylamide,

5-{2-[cis-3-(N-methylanilino)-1-cyclopentylamino]-1-hydroxyethyl}-salicylamid,5-{2-[trans-3-(N,4-dimethylanilino)-1-cyclopentylami-no] -1-hydroxyethyl} sjjiicylamid, 5-{2-[cis-3-(N-methylanilino)-1-cyclopentylamino]-1-hydroxyethyl}-salicylamide, 5-{2-[trans-3-(N,4-dimethylanilino)-1-cyclopentylami- no] -1-hydroxyethyl} sylcylamide,

5-[2-(trans-3-anilino-l-cyclopentylamino)-1-hydroxyethyl]-salicylamid, 5-[2-(trans-3-anilino-1-cyclopentylamino)-1-hydroxyethyl]-salicylamide,

5-{2-[trans-3-(N-methylanilino)-1-cyclobutylamino]-1-hydroxyethyl } salicylamid , 5-{2-[trans-3-(N-methylanilino)-1-cyclobutylamino]-1-hydroxyethyl} salicylamide,

5-{2-[cis-3-(N-methylanilino)-1-cyclobutylamino]-1-hydroxyethyl}-salicylamid, 5-{2-[cis-3-(N-methylanilino)-1-cyclobutylamino]-1-hydroxyethyl}-salicylamide,

5-{2-[trans-3-(N,4-dimethylanilino)-1-cyclobutylamino]-1-hydroxyethyl } salicylamid , 5-{2-[trans-3-(N,4-dimethylanilino)-1-cyclobutylamino]-1-hydroxyethyl} salicylamide,

5-[2-trans-3-anilino-l-cyclobutylamino)-1-hydroxyethyl]salicylamid , 5-[2-trans-3-anilino-1-cyclobutylamino)-1-hydroxyethyl]salicylamide,

5-{2-[trans-2-(N-methylanilino)-1-cyclopentylamino]-1-hydroxyethyl }salicylamid, 5-{2-[trans-2-(N-methylanilino)-1-cyclopentylamino]-1-hydroxyethyl }salicylamide,

5-{2-[cis-2-(N-methylanilino)-1-cyclopentylamino]-1-hydroxyethyl}-salicylamid, 5-{2-[cis-2-(N-methylanilino)-1-cyclopentylamino]-1-hydroxyethyl}-salicylamide,

5-{2-[cis-4-(N-methylanilino)-1-cycloheptylamino]-1-hydroxyethyl}-salicylamid, 5-{2-[cis-4-(N-methylanilino)-1-cycloheptylamino]-1-hydroxyethyl}-salicylamide,

5-{2-[trans-4-(N-methylanilino)-1-cycloheptylamino]-1-hydroxyethyl } salicylamid , 5-{2-[trans-4-(N-methylanilino)-1-cycloheptylamino]-1-hydroxyethyl} salicylamide,

5-{2-[trans-2-(N-methylanilino)-1-cyclohexylamino]-1-hydroxyethyl } salicylamid , 5-{2-[trans-2-(N-methylanilino)-1-cyclohexylamino]-1-hydroxyethyl} salicylamide,

5-{2-[cis-2-(N-methylanilino)-1-cyclohexylamino]-1-hydroxyethyl}-salicylamid, 5-{2-[cis-2-(N-methylanilino)-1-cyclohexylamino]-1-hydroxyethyl}-salicylamide,

5-{2-[trans-2-(N-methylanilino)-1-methyl-l-r-cyclohexylamino]-1-hydroxyethyl}salicylamid, 5-{2-[trans-2-(N-methylanilino)-1-methyl-1-r-cyclohexylamino]-1-hydroxyethyl}salicylamide,

5-{2-[cis-2-(N-methylanilino)-1-methyl-l-r-cyclohexylamino]-1-hydroxyethyl}salicylamid, 5-{2-[cis-2-(N-methylanilino)-1-methyl-1-r-cyclohexylamino]-1-hydroxyethyl}salicylamide,

5-{2-[trans-4-(4-fluor-N-methylanilino)-1-cyclohexylamino]-1-hydroxyethyl}salicylamid, 5-{2-[trans-4-(4-fluoro-N-methylanilino)-1-cyclohexylamino]-1-hydroxyethyl}salicylamide,

5-{2-[cis-4-(4-fluor-N-methylanilino)-1-cyclohexylamino]-1-hydroxyethyl}salicylamid, 5-{2-[cis-4-(4-fluoro-N-methylanilino)-1-cyclohexylamino]-1-hydroxyethyl}salicylamide,

5-{2-[trans-4-(4-trifluormethyl-N-methylanilino)-1-cyclohexyl-amino] -1-hydroxyethyl}salicylamid, 5-{2-[trans-4-(4-trifluoromethyl-N-methylanilino)-1-cyclohexyl-amino]-1-hydroxyethyl}salicylamide,

5-{2-[cis-4-(4-trifluormethyl-N-methylanilino)-1-cyclohexylamino]-1-hydroxyethyl}salicylamid, 5-{2-[cis-4-(4-trifluoromethyl-N-methylanilino)-1-cyclohexylamino]-1-hydroxyethyl}salicylamide,

5-{2-[trans-4-(N-acetylanilino)-1-cyclohexylamino]-1-hydroxyethyl }salicylamid, 5-{2-[trans-4-(N-acetylanilino)-1-cyclohexylamino]-1-hydroxyethyl }salicylamide,

5- {2- ["Cis-4- (N-acetylanilino) -1-cyclohexylamino] -1-hydroxyethyl }-salicylamid, 5-{2-[trans-4-(N-ethylanilino)-1-cyclohexylamino]-1-hydroxyethyl }salicylamid , 5- {2- ["Cis-4-(N-acetylanilino)-1-cyclohexylamino]-1-hydroxyethyl }-salicylamide, 5-{2-[trans-4-(N-ethylanilino)-1-cyclohexylamino]- 1-hydroxyethyl}salicylamide,

5-{2-[cis-4-(N-ethylanilino)-1-cyclohexylamino]-1-hydroxyethyl}-salicylamid, 5-{2-[cis-4-(N-ethylanilino)-1-cyclohexylamino]-1-hydroxyethyl}-salicylamide,

5-{2-[trans-4-(N-methansulfonylanilino)-1-cyclohexylamino)-1-hydroxyethyl}salicylamid, 5-{2-[trans-4-(N-methanesulfonyl anilino)-1-cyclohexylamino)-1-hydroxyethyl}salicylamide,

5-{2-[cis-4-(N-methansulfonylanilino)-1-cyclohexylamino]-1-hydroxyethyl}salicylamid, 5-{2-[cis-4-(N-methanesulfonyl anilino)-1-cyclohexylamino]-1-hydroxyethyl}salicylamide,

5-{2-[cis-4-(N-methylanilino)-methyl-l-cyclohexylamino]-1-hydroxyethyl}salicylamid. 5-{2-[cis-4-(N-methylanilino)-methyl-1-cyclohexylamino]-1-hydroxyethyl}salicylamide.

5-{2-[trans-4-(N-methylanilino)-methyl-l-cyclohexylamino]-1-hydroxyethyl)salicylamid, 5-{2-[trans-4-(N-methylanilino)-methyl-1-cyclohexylamino]-1-hydroxyethyl)salicylamide,

5-{2-[cis-3-(N-methylanilino)-methyl-l-cyclohexylamino]-1-hydroxyethyl}salicylamid, 5-{2-[cis-3-(N-methylanilino)-methyl-1-cyclohexylamino]-1-hydroxyethyl}salicylamide,

5-{2-[trans-3-(N-methylanilino)-methyl-l-cyclohexylamino]-1-hydroxyethyl}salicylamid, 5-{2-[trans-3-(N-methylanilino)-methyl-1-cyclohexylamino]-1-hydroxyethyl}salicylamide,

5-{2-[cis-2-(N-methylanilino)-methyl-l-cyclohexylamino]-1-hydroxyethyl}salicylamid, 5-{2-[cis-2-(N-methylanilino)-methyl-1-cyclohexylamino]-1-hydroxyethyl}salicylamide,

5-{2-[trans-2-(N-methylanilino)-methyl-l-cyclohexylamino]-1-hydroxyethyl}salicylamid, 5-{2-[trans-2-(N-methylanilino)-methyl-1-cyclohexylamino]-1-hydroxyethyl}salicylamide,

5-{2-[cis-3-(N-methylanilino)-methyl-l-cyclopentylamino]-1-hydroxyethyl}salicylamid, 5-{2-[cis-3-(N-methylanilino)-methyl-1-cyclopentylamino]-1-hydroxyethyl}salicylamide,

5-{2-[trans-3-(N-methylanilino)-methyl-l-cyclopentylamino]-1-hydroxyethyl}salicylamid, 5-{2-[trans-3-(N-methylanilino)-methyl-1-cyclopentylamino]-1-hydroxyethyl}salicylamide,

5-{2-[cis-2-(N-methylanilino)-methyl-l-cyclopentylamino]-1-hydroxyethyl}salicylamid, 5-{2-[cis-2-(N-methylanilino)-methyl-1-cyclopentylamino]-1-hydroxyethyl}salicylamide,

5-{2-[trans-2-(N-methylanilino)-methyl-l-cyclopentylamino]-1-hydroxyethyl)salicylamid, 5-{2-[trans-2-(N-methylanilino)-methyl-1-cyclopentylamino]-1-hydroxyethyl)salicylamide,

5-{2-[cis-3-(N-methylanilino)-methyl-l-cyclobutylamino]-1-hydroxyethyl}salicylamid, 5-{2-[cis-3-(N-methylanilino)-methyl-1-cyclobutylamino]-1-hydroxyethyl}salicylamide,

5-{2-[trans-3-(N-methylanilino)-methyl-l-cyclobutylamino]-1-hydroxyethyl}salicylamid, 5-{2-[trans-3-(N-methylanilino)-methyl-1-cyclobutylamino]-1-hydroxyethyl}salicylamide,

5-{2-[cis-4-(N-methylanilino)-methyl-l-cycloheptylamino]-1-hydroxyethyl}salicylamid, 5-{2-[cis-4-(N-methylanilino)-methyl-1-cycloheptylamino]-1-hydroxyethyl}salicylamide,

5-{2-[trans-4-(N-methylanilino)-methyl-l-cycloheptylamino(-1-hydroxyethyl}salicylamid, 5-{2-[trans-4-(N-methylanilino)-methyl-1-cycloheptylamino(-1-hydroxyethyl}salicylamide,

5-{2-[1-(cis-4-(N-methylanilino)methyl-l-cyclohexyl)ethylamino]-1-hydroxyethyl}salicylamid, 5-{2-[1-(cis-4-(N-methylanilino)methyl-1-cyclohexyl)ethylamino]-1-hydroxyethyl}salicylamide,

5-{2-[l-trans-4-(N-methylanilino)methyl-l-cyclohexyl)ethylamino]-1-hydroxyethyl}salicylamid, 5-{2-[l-trans-4-(N-methylanilino)methyl-l-cyclohexyl)ethylamino]-1-hydroxyethyl}salicylamide,

5-{2-[l-cis-3-(N-methylanilino)methyl-l-cyclohexyl)ethylamino]-1-hydroxyethyl}salicylamid, 5-{2-[l-cis-3-(N-methylanilino)methyl-l-cyclohexyl)ethylamino]-1-hydroxyethyl}salicylamide,

5-{2-[1-(trans-3-(N-methylanilino)methyl-l-cyclohexyl)ethylamino]-1-hydroxyethyl}salicylamid, 5-{2-[1-(trans-3-(N-methylanilino)methyl-1-cyclohexyl)ethylamino]-1-hydroxyethyl}salicylamide,

5-{2-[1-(cis-2-(N-methylanilino)methyl-l-cyclohexyl)ethylamino]-1-hydroxyethyl}salicylamid, 5-{2-[1-(cis-2-(N-methylanilino)methyl-1-cyclohexyl)ethylamino]-1-hydroxyethyl}salicylamide,

5-{2-[1-(trans-2-(N-methylanilino)methyl-l-cyclohexyl)ethylamino]-1-hydroxyethyl}salicylamid , 5-{2-[1-(trans-2-(N-methylanilino)methyl-1-cyclohexyl)ethylamino]-1-hydroxyethyl}salicylamide,

5-{2-[1-(cis-3-(N-methylanilino)methyl-l-cyclopentyl)ethylamino]-1-hydroxyethyl}salicylamid, 5-{2-[1-(cis-3-(N-methylanilino)methyl-1-cyclopentyl)ethylamino]-1-hydroxyethyl}salicylamide,

5-{2-[1-(trans-3-(N-methylanilino)methyl-l-cyclopentyl)-ethylamino] -1-hydroxyethyl}salicylamid, 5-{2-[1-(trans-3-(N-methylanilino)methyl-1-cyclopentyl)-ethylamino]-1-hydroxyethyl}salicylamide,

5-{2- [1- (cis-2- (N-methylanilino)meth.yl-l-cyclopentyl) ethylamino] - 1-hydroxyethyl}salicylamid, 5-{2- [1- (cis-2-(N-methylanilino)meth.yl-1-cyclopentyl)ethylamino]-1-hydroxyethyl}salicylamide,

5-{2-[1-(trans-2-(N-methylanilino)methyl-l-cyclopentyl)-ethylamino (-1-hydroxyethyl}salicylamid, 5-{2-[1-(trans-2-(N-methylanilino)methyl-1-cyclopentyl)-ethylamino (-1-hydroxyethyl}salicylamide,

5-{2-[1-(cis-3-(N-methylanilino)methyl-l-cyclobutyl)ethylamino] - 1-hydroxyethyl}salicylamid, 5-{2-[1-(cis-3-(N-methylanilino)methyl-1-cyclobutyl)ethylamino]-1-hydroxyethyl}salicylamide,

5-{2- [1-(trans-3-(N-methylanilino)methyl-l-cyclobutyl)ethylamino] -1-hydroxyethyl}salicylamid, 5-{2- [1-(trans-3-(N-methylanilino)methyl-1-cyclobutyl)ethylamino]-1-hydroxyethyl}salicylamide,

5-{2-[1-(cis-4-(N-methylanilino(methyl-l-cycloheptyl)ethylamino]-1-hydroxyethyl}salicylamid, 5-{2-[1-(cis-4-(N-methylanilino(methyl-1-cycloheptyl)ethylamino]-1-hydroxyethyl}salicylamide,

5-{2-[1-(trans-4-(N-methylanilino)methyl-l-cycloheptyl)ethylamino ]-1-hydroxyethyl}salicylamid, 5-{2-[1-(trans-4-(N-methylanilino)methyl-1-cycloheptyl)ethylamino]-1-hydroxyethyl}salicylamide,

5-{2- [1- (cis-4- (N-methylanilino) -1-cyclohexyl).-ethylamino] -1-hydroxyethyl}salicylamid, 5-{2- [1- (cis-4-(N-methylanilino)-1-cyclohexyl).-ethylamino]-1-hydroxyethyl}salicylamide,

5- 2-[1-(trans-4-(N-methylanilino)-1-cyclohexyl)ethylamino]-1-hydroxyethyl salicylamid, 5- 2-[1-(trans-4-(N-methylanilino)-1-cyclohexyl)ethylamino]-1-hydroxyethyl salicylamide,

5- 2-[3-(N-methylanilino)-1-propylamino]-1-hydroxyethy11-salicylamid, sm.p. 149 - 150° C og 5- 2-[3-(N-methylanilino)-1-propylamino]-1-hydroxyethyl-11-salicylamide, m.p. 149 - 150° C and

5- 2-[4-(N-methylanilino)-butylamino]-1-hydroxyethyl salicylamid, sm.p. 156 - 158° C. 5- 2-[4-(N-methylanilino)-butylamino]-1-hydroxyethyl salicylamide, m.p. 156 - 158° C.

b) Forbindelser av formel IA: b) Compounds of formula IA:

12 3 12 12 3 12

hvori R , R , R , Y , Y og Z er som ovenfor definert og Alk<1>in which R , R , R , Y , Y and Z are as defined above and Alk<1>

H H

er en acyklisk eller cyklisk alkylenbro som ovenfor definert for Alk forutsatt at det angitte hydrogenatom i Alk' og nitrogenato-t is an acyclic or cyclic alkylene bridge as defined above for Alk provided that the indicated hydrogen atom in Alk' and nitrogen atom-t

H H

met i ethanolamindelen -CHOH.CHR"'" er bundet til samme carbonatom, met in the ethanolamine part -CHOH.CHR"'" is attached to the same carbon atom,

kan fremstilles ved reduktiv kondensasjon av en forbindelse av formel can be prepared by reductive condensation of a compound of formula

hvori Alk', Y 1 , Y 2 og Z er som ovenfor definert, med en forbindelse av formel hvori R<1>, R2 og R<3>er som ovenfor definert, i nærvær av et organisk løsningsmiddel, fortrinnsvis en lavere alkanol slik som methanol, ethanol eller propanol. Reduksjonen kan utføres ved hjelp av katalytisk hydrogenering (som beskrevet for prosess a)), eller lithium-thexyllimonyl-borhydrid eller 9-borbicyclo[3,3,1]-nonan, men fortrinnsvis ved hjelp av natriumborhydrid eller natriumcyanoborhydrid. Ved'en særlig foretrukket utførelsesform av denne prosess fremstilles en forbindelse av formel II ved reduktiv kondensasjon av en forbindelse av formel med en forbindelse av formel X, hvori R<1>, R<2>, R<3>, Y1, Y2, Z og n er som definert for formel II. Denne prosess er foretrukket fremfor fremgangsmåte a) for fremstilling av forbindelser av formel II; i særdeleshet kan følgende forbindelser fremstilles ved denne prosess: 5-{2-[5- (4-fluor-N-methylanilino)-2-pentylamino]-1-hydroxyethyl}-salicylamid, sm.p. (kvart-hydrat), 160 - 162° C, wherein Alk', Y 1 , Y 2 and Z are as defined above, with a compound of formula wherein R<1>, R2 and R<3> are as defined above, in the presence of an organic solvent, preferably a lower alkanol such such as methanol, ethanol or propanol. The reduction can be carried out by means of catalytic hydrogenation (as described for process a)), or lithium-thexyllimonylborohydride or 9-borbicyclo[3,3,1]-nonane, but preferably by means of sodium borohydride or sodium cyanoborohydride. In a particularly preferred embodiment of this process, a compound of formula II is prepared by reductive condensation of a compound of formula with a compound of formula X, wherein R<1>, R<2>, R<3>, Y1, Y2, Z and n are as defined for formula II. This process is preferred over process a) for preparing compounds of formula II; in particular, the following compounds can be prepared by this process: 5-{2-[5-(4-fluoro-N-methylanilino)-2-pentylamino]-1-hydroxyethyl}-salicylamide, m.p. (quarter-hydrate), 160 - 162° C,

5-{2-[5-(N-benzylanilino)-2-pentylamino]-1-hydroxyethyl}salicylramid, sm.p. (hemihydrat) 144 146° C, 5-{2-[5-(N-benzylanilino)-2-pentylamino]-1-hydroxyethyl}salicylamide, m.p. (hemihydrate) 144 146° C,

5-{2-[4-(N-methylanilino)-2-butylamino]-1-hydroxyethyl}salicylamid, sm.p. 150 - 152° C, 5-{2-[4-(N-methylanilino)-2-butylamino]-1-hydroxyethyl}salicylamide, m.p. 150 - 152° C,

5-{2-[4-(4,N-dimethylanilino)-2-butylamino]-1-hydroxyethyl}-salycylamid, sm.p. 123 - 126° C, 5-{2-[4-(4,N-dimethylanilino)-2-butylamino]-1-hydroxyethyl}-salicylamide, m.p. 123 - 126° C,

5-{2-[4-(4-klor-N-methylanilino)-2-butylamino]-1-hydroxy-ethyl}-salicylamid, sm.p. 127° C, 5-{2-[4-(4-chloro-N-methylanilino)-2-butylamino]-1-hydroxy-ethyl}-salicylamide, m.p. 127°C,

5-{2-[4-(3-klor-4-methoxy-N-methylanilino)-2-butylamino]-1-hydroxyethyl}salicylamid, 5-{2-[4-(3-chloro-4-methoxy-N-methylanilino)-2-butylamino]-1-hydroxyethyl}salicylamide,

5-{2-[4-(4-fluor-N-methylanilino)-2-butylamino]-1-hydroxyethyl}-salicylamid, 5-{2-[4-(4-fluoro-N-methylanilino)-2-butylamino]-1-hydroxyethyl}-salicylamide,

5-{2-[4-(4-hydroxy-N-methylanilino)-2-butylamino]-1-hydroxyethyl } salicylamid , 5-{2-[4-(4-hydroxy-N-methylanilino)-2-butylamino]-1-hydroxyethyl} salicylamide,

5-{2-[4-(4-methoxy-N-methylanilino)-2-butylamino]-1-hydroxyethyl}salicylamid, 5-{2-[4-(4-methoxy-N-methylanilino)-2-butylamino]-1-hydroxyethyl}salicylamide,

5-{2-[4-(4-nitro-N-methylanilino)-2-butylamino]-1-hydroxyethyl}-salicylamid, 5-{2-[4-(4-nitro-N-methylanilino)-2-butylamino]-1-hydroxyethyl}-salicylamide,

5-{2-[4-(4-amino-N-methylanilino)-2-butylamino]-1-hydroxyethyl}-salicylamid, 5-{2-[4-(4-amino-N-methylanilino)-2-butylamino]-1-hydroxyethyl}-salicylamide,

5-{2-[4-(4-acetamido-N-methylanilino)-2-butylamino]-1-hydroxyethyl } salicylamid , 5-{2-[4-(4-acetamido-N-methylanilino)-2-butylamino]-1-hydroxyethyl} salicylamide,

5-{2-[4-(4-methylamino-N-methylanilino)-2-butylamino]-1-hydroxyethyl } salicylamid , 5-{2-[4-(4-methylamino-N-methylanilino)-2-butylamino]-1-hydroxyethyl} salicylamide,

5-{2-[4-(4-methansulfonamido-N-methylanilino)-2-butylamino]-1-hydroxyethyl}salicylamid, 5-{2-[4-(4-methanesulfonamido-N-methylanilino)-2-butylamino]-1-hydroxyethyl}salicylamide,

5-{2-[4-(4-trifluormethyl-N-methylanilino)-2-butylamino]-1-hydroxyethy1}salicylamid, 5-{2-[4-(4-trifluoromethyl-N-methylanilino)-2-butylamino]-1-hydroxyethyl}salicylamide,

5-{2-[4-(3-trifluormethyl-N-methylanilino)-2-butylamino]-1-hydroxyethy1}salicylamid, 5-{2-[4-(3-trifluoromethyl-N-methylanilino)-2-butylamino]-1-hydroxyethyl}salicylamide,

5-{2-[4-(3-methoxy-N-methylanilino)-2-butylamino]-1-hydroxyethyl }salicylamid, 5-{2-[4-(3-methoxy-N-methylanilino)-2-butylamino]-1-hydroxyethyl }salicylamide,

5-{2-[4-(3-hydroxy-N-methylanilino)-2-butylamino]-1-hydroxyethyl }salicylamid, 5-{2-[4-(2,N-dimethylanilino)-2-butylamino]-1-hydroxyethyl}-salicylamid, 5-{2-[4-(3-hydroxy-N-methylanilino)-2-butylamino]-1-hydroxyethyl }salicylamide, 5-{2-[4-(2,N-dimethylanilino)-2-butylamino]- 1-hydroxyethyl}-salicylamide,

5-{2-[4-(2-klor-N-methylanilino)-2-butylamino]-1-hydroxyethyl}-salicylamid, 5-{2-[4-(2-chloro-N-methylanilino)-2-butylamino]-1-hydroxyethyl}-salicylamide,

5-{2-[4-(4-ethoxy-N-methylanilino)-2-butylamino]-1-hydroxyethyl}-salicylamid, 5-{2-[4-(4-ethoxy-N-methylanilino)-2-butylamino]-1-hydroxyethyl}-salicylamide,

5-{2-[4-(4-isopropyl-N-methylanilino)-2-butylamino]-1-hydroxyethyl } salicylamid 5-{2-[4-(4-isopropyl-N-methylanilino)-2-butylamino]-1-hydroxyethyl } salicylamide

5-{2-[4-(N-methylanilino)-2-butylamino]-l-hydroxy-2-methylethyl}-salicylamid, 5-{2-[4-(N-methylanilino)-2-butylamino]-1-hydroxy-2-methylethyl}-salicylamide,

5-[2-(4-anilino-2-butylamino)-1-hydroxyethyl]salicylamid, 5-{2-[4-(N-methansulfonylanilino)-2-butylamino]-1-hydroxyethyl}-salicylamid, 5-[2-(4-anilino-2-butylamino)-1-hydroxyethyl]salicylamide, 5-{2-[4-(N-methanesulfonylanilino)-2-butylamino]-1-hydroxyethyl}-salicylamide,

5-{2-[4-(N-acetylanilino)-2-butylamino]-l-hydroxyethyll-salicylamid, 5-{2-[4-(N-acetylanilino)-2-butylamino]-1-hydroxyethyl-salicylamide,

5-{2-[4-(N-(2,2,2-trifluorethyl)anilino)-2-butylamino]-1-hydroxyethyl }salicylamid, 5-{2-[4-(N-(2,2,2-trifluoroethyl)anilino)-2-butylamino]-1-hydroxyethyl }salicylamide,

5-{2-14-(N-ethylanilino)-2-butylamino]-1-hydroxyethylIsalicylamid, 5-{2-[3-(N-methylanilino)-2-propylamino]-1-hydroxyethyl}-salicylamid, sm.p. 143 - 145° C, 5-{2-14-(N-ethylanilino)-2-butylamino]-1-hydroxyethylIsalicylamide, 5-{2-[3-(N-methylanilino)-2-propylamino]-1-hydroxyethyl}-salicylamide, sm. p. 143 - 145° C,

5-{2-[3-(N,4-dimethylanilino)-2-propylamino]-1-hydroxyethyl}-salicylamid, 5-{2-[3-(N,4-dimethylanilino)-2-propylamino]-1-hydroxyethyl}-salicylamide,

5-[2-(3-anilino-2-propylamino)-1-hydroxyethyl]salicylamid, 5-{2-[5-(N-methylanilino)-2-pentylamino]-1-hydroxyethyl}-salicylamid, sm.p. 155 - 157° C, 5-[2-(3-anilino-2-propylamino)-1-hydroxyethyl]salicylamide, 5-{2-[5-(N-methylanilino)-2-pentylamino]-1-hydroxyethyl}-salicylamide, m.p. . 155 - 157° C,

5-{2-[5-(N,4-diméthylanilino)-2-pentylamino]-1-hydroxyethyl}-salicylamid, 5-{2-[5-(N,4-dimethylanilino)-2-pentylamino]-1-hydroxyethyl}-salicylamide,

5-[2-(5-anilino-2-pentylamino)-1-hydroxyethyl]-salicylamid, sm.p. 138 - 140° C, 5-[2-(5-anilino-2-pentylamino)-1-hydroxyethyl]-salicylamide, m.p. 138 - 140° C,

5-{2-[6-(N-methylanilino)-2-hexylamino]-1-hydroxyethyl }salicyl-' amid, sm.p. 15 7 - 160° C, 5-{2-[6-(N-methylanilino)-2-hexylamino]-1-hydroxyethyl }salicyl-' amide, m.p. 15 7 - 160° C,

5-{2-[6-(N,4-dimethylanilino)-2-hexylamino]-1-hydroxyethyl}-salicylamid, 5-{2-[6-(N,4-dimethylanilino)-2-hexylamino]-1-hydroxyethyl}-salicylamide,

5- [2-(6-anilino-2-hexylamino)-1-hydroxyethyl]salicylamid, 5-{2-[4-(N-methylanilino)-2-(3-methy1)butylamino]-1-hydroxyethyl }salicylamid, 5- [2-(6-anilino-2-hexylamino)-1-hydroxyethyl]salicylamide, 5-{2-[4-(N-methylanilino)-2-(3-methyl1)butylamino]-1-hydroxyethyl }salicylamide ,

5-{2-[4-(N-methylanilino)-2-pentylamino]-1-hydroxyethyl}-salicylamid, 5-{2-[4-(N-methylanilino)-2-pentylamino]-1-hydroxyethyl}-salicylamide,

5- {2-[3-(N-methylanilino)-2-butylamino]-1-hydroxyethyl }salicylamid, 5- {2-[3-(N-methylanilino)-2-butylamino]-1-hydroxyethyl}salicylamide,

2-methoxy-5- {2-[4-N-methylanilino)-2-butylamino]-1-hydroxyethyl}-benzamid, 2-methoxy-5- {2-[4-N-methylanilino)-2-butylamino]-1-hydroxyethyl}-benzamide,

2-(2-ethoxy)ethoxy-5- {2-[4-(N-methylanilino)-2-butylamino]-1-hydroxyethyl }benzamid, 2-(2-ethoxy)ethoxy-5- {2-[4-(N-methylanilino)-2-butylamino]-1-hydroxyethyl }benzamide,

2-(2-hydroxy)ethoxy-5-{2-[4-(N-methylanilino)-2-butylamino]-1-hydroxyethyl }benzamid, 2-(2-hydroxy)ethoxy-5-{2-[4-(N-methylanilino)-2-butylamino]-1-hydroxyethyl }benzamide,

5-{2-[4-(N-methylanilino)-2-butylamino]-1-hydroxyethyl}-N-methyl-salicylamid, og 5-{2-[4-(N-methylanilino)-2-butylamino]-1-hydroxyethyl}-N-methyl-salicylamide, and

5-{2-[4-(N-methylanilino)-2-butylamino]-1-hydroxyethyl}N-ethyl-salicylamid.. 5-{2-[4-(N-methylanilino)-2-butylamino]-1-hydroxyethyl}N-ethyl-salicylamide..

Forbindelsene av formel I kan isoleres fra de ovenfor angitte prosesser som de fri baser eller som deres farmasøytisk akseptable syreaddisjonssalter. The compounds of formula I can be isolated from the above processes as the free bases or as their pharmaceutically acceptable acid addition salts.

Forbindelsene ifølge oppfinnelsen utviser en eller flere asymmetriske carbonatomer og fremstilles ved de ovenfor angitte fremgangsmåter som stereoisomere blandinger. Forbindelsene kan anvendes som slike blandinger eller separeres i deres enantiomere og diastereoisomere rene former under anvendelse av vanlige metoder for separering av slike blandinger, slik som fraksjonert krystallisering og kromatografi, f.eks. på silicagel. I tillegg kan en ønsket diastereoisomer erholdes ved syntese under anvendelse av rene chirale forbindelser. The compounds according to the invention exhibit one or more asymmetric carbon atoms and are produced by the above-mentioned methods as stereoisomeric mixtures. The compounds can be used as such mixtures or separated in their enantiomeric and diastereoisomeric pure forms using conventional methods for separating such mixtures, such as fractional crystallization and chromatography, e.g. on silica gel. In addition, a desired diastereoisomer can be obtained by synthesis using pure chiral compounds.

De etterfølgende' eksempler illustrerer oppfinnelsen. Enkelte av de anilino-alkanoner som anvendes som utgangsmateria-ler i eksemplene ble fremstilt ifølge Craig et al., J.Org. Chem. 29 , 410 (1964) . The following examples illustrate the invention. Some of the anilino-alkanones used as starting materials in the examples were prepared according to Craig et al., J.Org. Chem. 29, 410 (1964).

Eksempel 1 Example 1

5-{ 2-[ 4-( N- methylanilino)- 2- butylamino]- 1- hydroxyethyl} salicylamid 5-{ 2-[ 4-( N- methylanilino)- 2- butylamino]- 1- hydroxyethyl} salicylamide

Tilsett til en løsning av 3,92 g (20 mmol) 5-(2-amino-1-hydroxyethyl)-salicylamid og 3,54 g (20 mmol) 4-(N-methylanilino) -2-butanon i 100 ml ethanol, 1,26 g (20 mmol) natriumcyanoborhydrid. Omrør i 16 timer, konsentrer og del blandingen mellom ethylacetat og IN natriumbicarbonatløsning. Tørk og konsentrer det organiske lag. Omkrystalliser residuet fra methanol under dannelse av et hvitt fast materiale med sm.p. 150 - 152° C. Add to a solution of 3.92 g (20 mmol) 5-(2-amino-1-hydroxyethyl)-salicylamide and 3.54 g (20 mmol) 4-(N-methylanilino)-2-butanone in 100 ml ethanol , 1.26 g (20 mmol) of sodium cyanoborohydride. Stir for 16 hours, concentrate and partition the mixture between ethyl acetate and IN sodium bicarbonate solution. Dry and concentrate the organic layer. Recrystallize the residue from methanol to form a white solid of m.p. 150 - 152° C.

Eksempel 2 Example 2

5-{ 2-[ 3-( N- methylanilino)- 2- propylamino]- 1- hydroxyethyl} salicylamid 5-{ 2-[ 3-( N- methylanilino)- 2- propylamino]- 1- hydroxyethyl} salicylamide

Tilsett til en løsning av 20 mmol 5-(2-amino-l-hydroxyethyl)-salicylamid og 3,26 g (20 mmol) N-methylanilino-acetat i 100 ml methanol, 2,51 g (40 mmol) natriumcyanoborhydrid. Omrør i 16 timer, konsentrer og del blandingen mellom ethylacetat og IN natriumbicarbonatløsning. Tørk og konsentrer det organiske lag. Oppløs det resulterende skum i kloroform og vask med vann. Filtrer fra det faste materiale som dannes og omkrystalliser dette fra ethylacetat under' dannelse av et hvitt fast materiale med sm. p. 143 - 145° C. To a solution of 20 mmol of 5-(2-amino-1-hydroxyethyl)-salicylamide and 3.26 g (20 mmol) of N-methylanilino-acetate in 100 ml of methanol, add 2.51 g (40 mmol) of sodium cyanoborohydride. Stir for 16 hours, concentrate and partition the mixture between ethyl acetate and IN sodium bicarbonate solution. Dry and concentrate the organic layer. Dissolve the resulting foam in chloroform and wash with water. Filter from the solid material that forms and recrystallize this from ethyl acetate to give a white solid with sm. b. 143 - 145° C.

Eksempel 3 Example 3

5-{ 2-[ 5-( N- methylanilino)- 2- pentylamino]- 1- hydroxyethyl}-salicylamid 5-{ 2-[ 5-( N- methylanilino)- 2- pentylamino]- 1- hydroxyethyl}- salicylamide

(a) 5-( N- methylanilino)- 2- pentanon (a) 5-(N-methylanilino)-2-pentanone

Tilsett til 49,4 g (0,30 mol) 5-klor-2-pentanon-ethylen-ketal og 64,2 g (0,60 mol) N-methylanilin i 100 ml toluen, 27,7 g (0,33 mol) natriumbicarbonat og 2,0 g kaliumjodid. Kok under tilbakeløpskjøling med en vannseparator over natten. La blandingen avkjøles, filtrer og konsentrer. Destiller ved 50°C/0,1 mm for å fjerne N-methylanilin. Omrør restvæsken med 175 ml IN saltsyre i 2 timer. Nøytraliser med natriumbicarbonat og ekstraher med ether. Tørk, konsentrer og destiller for å oppsamle en frak-sjon med k.p. 103 - 110° C/0,1 mm. Add to 49.4 g (0.30 mol) 5-chloro-2-pentanone-ethylene ketal and 64.2 g (0.60 mol) N-methylaniline in 100 ml toluene, 27.7 g (0.33 mol) of sodium bicarbonate and 2.0 g of potassium iodide. Boil under reflux with a water separator overnight. Allow the mixture to cool, filter and concentrate. Distill at 50°C/0.1 mm to remove N-methylaniline. Stir the residual liquid with 175 ml IN hydrochloric acid for 2 hours. Neutralize with sodium bicarbonate and extract with ether. Dry, concentrate and distill to collect a fraction with b.p. 103 - 110° C/0.1 mm.

b) 5-{ 2-[ 5-( N- methylanilino)- 2- pentylamino]- 1- hydroxyethyl } salicylamid b) 5-{ 2-[ 5-( N- methylanilino)- 2- pentylamino]- 1- hydroxyethyl } salicylamide

Kombiner det ovenfor angitte keton (4,3 g, 21 mmol) Combine the above ketone (4.3 g, 21 mmol)

med 20 mmol 5-(2-amino-l-hydroxyethyl)salicylamid og 2,0 g 10 %-ig Pd/C i 200 ml methanol. Hydrogener ved 4,2 kg cm i 2 timer. Fiitrer fra katalysatoren, konsentrer og del residuet mellom ethylacetat og IN natriumbicarbonatløsning. Det organiske lag avsettes som et fast materiale. Filtrer fra og omkrystalliser .dette fra methanol under dannelse av et hvitt fast materiale med sm.p. 155 - 157° C. with 20 mmol of 5-(2-amino-1-hydroxyethyl)salicylamide and 2.0 g of 10% Pd/C in 200 ml of methanol. Hydrogenate at 4.2 kg cm for 2 hours. Filter from the catalyst, concentrate and partition the residue between ethyl acetate and 1N sodium bicarbonate solution. The organic layer is deposited as a solid material. Filter off and recrystallize this from methanol to form a white solid with m.p. 155 - 157° C.

Eksempel 4 Example 4

5-{ 2- [ 4- ( 4- klor- N- methylanilino)- 2- butylamino]- 1- hydroxyethyl}-salicylamid 5-{ 2- [ 4-( 4- chloro- N- methylanilino)- 2- butylamino]- 1- hydroxyethyl}- salicylamide

Tilsett til en løsning av 20 mmol 5-(2-amino-l-hydroxy-. ethyl)-salicylamid og 4,22 g (20 mmol) 4-(4-klor-N-methylanilino)-2-butanon (sm.p. 60 - 61° C) i 100 ml methanol, 2,52 g (40 mmol) natriumcyanoborhydrid. Omrør 1 6 dager, konsentrer og del blandingen mellom ethylacetat og IN natriumbicarbonatløsning. Vask det organiske lag med IN saltsyre. Nøytraliser den vandige del med natriumbicarbonat og ekstraher med ethylacetat. Tørk, konsentrer og omkrystalliser residuet fra ethylacetat-hexan under dannelse av et hvitt fast materiale mes sm.p. 127 - 129° C. Add to a solution of 20 mmol of 5-(2-amino-1-hydroxy-.ethyl)-salicylamide and 4.22 g (20 mmol) of 4-(4-chloro-N-methylanilino)-2-butanone (sm. p. 60 - 61° C) in 100 ml methanol, 2.52 g (40 mmol) sodium cyanoborohydride. Stir 1 6 days, concentrate and partition the mixture between ethyl acetate and IN sodium bicarbonate solution. Wash the organic layer with IN hydrochloric acid. Neutralize the aqueous portion with sodium bicarbonate and extract with ethyl acetate. Dry, concentrate and recrystallize the residue from ethyl acetate-hexane to form a white solid m.p. 127 - 129° C.

Eksempel 5 Example 5

5-{ 2-[ 4-( 4, N- dimethylanilino)- 2- butylamino]- 1- hydroxyethyl}-salicylamid 5-{ 2-[ 4-( 4, N-dimethylanilino)- 2- butylamino]- 1- hydroxyethyl}-salicylamide

Tilsett til en løsning av 20 mmol 5-(2-amino-l-hydroxyethyl)-salicylamid og 5,7 g (30 mmol) 4-(N,4-dimethylanilino)-2-butanon (k.p. 93 - 96°C/0,1 mm) i 150 ml methanol, 1,9 g (30 mmol) natriumcyanoborhydrid. Konsentrer etter 20 timer og del blandingen mellom ethylacetat og IN natriumbicarbonatløsning. Tørk og konsentrer. Varm skummet med ethylacetat under dannelse av et hvitt fast materiale med sm.p. 123 - 126° C. Add to a solution of 20 mmol of 5-(2-amino-1-hydroxyethyl)-salicylamide and 5.7 g (30 mmol) of 4-(N,4-dimethylanilino)-2-butanone (b.p. 93 - 96°C/ 0.1 mm) in 150 ml methanol, 1.9 g (30 mmol) sodium cyanoborohydride. Concentrate after 20 hours and partition the mixture between ethyl acetate and IN sodium bicarbonate solution. Dry and concentrate. Heat the foam with ethyl acetate to form a white solid of m.p. 123 - 126° C.

Eksempel 6 Example 6

5-{ 2-[ 6-( N- methylanilino)- 2- hexylamino]- 1- hydroxyethyl}-salicylamid 5-{ 2-[ 6-( N- methylanilino)- 2- hexylamino]- 1- hydroxyethyl}-salicylamide

(a) 2- benzyloxy- 5-{ 2-[ N- benzyl- 6-( N- methylanilino)- 2-hexylamino]- 1- hydroxyethylIbenzamid (a) 2-benzyloxy-5-{2-[N-benzyl-6-(N-methylanilino)-2-hexylamino]-1-hydroxyethylIbenzamide

Tilsett til N-(5-benzylaminohexyl)-N-methylanilin (3,06 g = 10 mmol) og 3,48 g (10 mmol) 2-benzyloxy-5-bromacetylbenzamid i 35 ml dimethylformamid, 2,70 g (20 mmol) kaliumcarbonat. Om-rør i 20 timer og hell over 150 ml vann. La gummien avsettes, dekanter og oppløs gummien i ether. Ekstraher med IN saltsyre og nøytraliser deretter med natriumbicarbonat og ekstraher med ethylacetat. Tørk og konsentrer og oppløs oljen i 50 ml ethanol. Tilsett 0,3 g (8 mmol) natriumborhydrid, omrør i 20 timer, og konsentrer. Oppdel residuet mellom ethylacetat og IN natriumbicarbonat. Tørk det organiske lag og konsentrer under dannelse av et gult skum. Add to N-(5-benzylaminohexyl)-N-methylaniline (3.06 g = 10 mmol) and 3.48 g (10 mmol) of 2-benzyloxy-5-bromoacetylbenzamide in 35 mL of dimethylformamide, 2.70 g (20 mmol ) potassium carbonate. Stir for 20 hours and pour over 150 ml of water. Allow the gum to settle, decant and dissolve the gum in ether. Extract with IN hydrochloric acid and then neutralize with sodium bicarbonate and extract with ethyl acetate. Dry and concentrate and dissolve the oil in 50 ml of ethanol. Add 0.3 g (8 mmol) sodium borohydride, stir for 20 hours, and concentrate. Partition the residue between ethyl acetate and IN sodium bicarbonate. Dry the organic layer and concentrate to form a yellow foam.

(b) 5-{ 2-[ 6-( N- methylanilino)- 2- hexylamino]- 1- hydroxyethyl}-salicylamid (b) 5-{ 2-[ 6-( N- methylanilino)- 2- hexylamino]- 1- hydroxyethyl } salicylamide

Tilsett det ovenfor angitte amin til 250 ml ethanol Add the above amine to 250 ml of ethanol

_2 inneholdende 1,0 g 5 % Pd/C. Hydrogener ved 4,2 kg cm i 20 timer, filtrer og konsentrer. Omkrystalliser det klebrige faste materiale, fra methanol under dannelse av et hvitt fast materiale med sm.p. 157 - 160° C. _2 containing 1.0 g 5% Pd/C. Hydrogenate at 4.2 kg cm for 20 hours, filter and concentrate. Recrystallize the sticky solid from methanol to give a white solid, m.p. 157 - 160° C.

Forbindelsene ifølge oppfinnelsen er anvendbare ved behandling av cardiovasculære forstyrrelser og i særdeleshet ved behandling av hypertensjon i pattedyr. De administreres fortrinnsvis oralt men kan også administreres ved injeksjon. Laboratorietester indikerer at den effektive dose (ED^q) ved oral administrering for en forbindelse ifølge oppfinnelsen typisk vil ligge innen området 0,05 til 10 mg/kg kroppsvekt. The compounds according to the invention are useful in the treatment of cardiovascular disorders and in particular in the treatment of hypertension in mammals. They are preferably administered orally but can also be administered by injection. Laboratory tests indicate that the effective dose (ED^q) upon oral administration for a compound according to the invention will typically lie within the range of 0.05 to 10 mg/kg body weight.

Oppfinnelsen tilveiebringer således farmasøytiske komposisjoner inneholdende som aktiv bestanddel én eller flere forbindelser av formel I eller farmasøytisk akseptable syreaddisjonssalter derav, sammen med en farmasøytisk bærer eller eksipient. Komposisjonene er fortrinnsvis i form av enhetsdoser, f.eks. tabletter, kapsler eller injiserbare preparater i ampuller. Komposisjonene kan også foreligge i form av siruper, eliksirer eller suspensjoner. Den nødvendige daglige dose kan administreres i en enkel eller oppdelt dose. Den nøyaktige dose som skal administreres vil selvsagt være avhengig av forskjellige faktorer slik som den bestemte forbindelse som anvendes, alder og vekt på ..patte-dyret og den individuelle respons. Enhetsdoser inneholder fortrinnsvis fra 2 til 500 mg, helst fra 25 til 250 mg aktiv bestanddel av formel I (eller farmasøytisk akseptabelt syreaddisjonssalt derav). The invention thus provides pharmaceutical compositions containing as active ingredient one or more compounds of formula I or pharmaceutically acceptable acid addition salts thereof, together with a pharmaceutical carrier or excipient. The compositions are preferably in the form of unit doses, e.g. tablets, capsules or injectable preparations in ampoules. The compositions can also be in the form of syrups, elixirs or suspensions. The required daily dose can be administered in a single or divided dose. The exact dose to be administered will of course depend on various factors such as the particular compound used, the age and weight of the mammal and the individual response. Unit doses preferably contain from 2 to 500 mg, more preferably from 25 to 250 mg of active ingredient of formula I (or pharmaceutically acceptable acid addition salt thereof).

Typiske farmasøytiske akseptable bærere for bruk i for-muleringene som ovenfor beskrevet eksemplifiseres ved: sukker slik som lactose, sucrose, mannitol og sorbitol, stivelse slik som maisstivelse, tapioca-stivelse og potetstivelse, cellulose og derivater slik som natriumcarboxymethylcellulose, ethylcellulose og methylcellulose, kalciumfosfater slik som dikalciumfosfat og trikalciumfosfat, natriumsulfat, kalciumsulfat, polyvinylpyrroli-don, polyvinylalkohol, stearinsyre, jordalkalimetallstearater slik som magnesiumstearat og kalciumstearat, vegetabilske oljer slik som peanøttolje, bomullsfrøolje, sesamolje, olivenolje og maisolje, ikke-inoniske, kationiske og anioniske overflateaktive midler, ethylenglycolpolyme-rer, (3-cyclodextr in , f ettalkoholer , hydrolyserte cerealmaterialer og andre ikke-toksiske forenlige fyllstoffer, bindemidler, oppløsnende midler og smøremidler som vanligvis anvendes i farmasøytiske formuleringer. Typical pharmaceutically acceptable carriers for use in the formulations as described above are exemplified by: sugars such as lactose, sucrose, mannitol and sorbitol, starches such as corn starch, tapioca starch and potato starch, cellulose and derivatives such as sodium carboxymethylcellulose, ethylcellulose and methylcellulose, calcium phosphates such as dicalcium phosphate and tricalcium phosphate, sodium sulfate, calcium sulfate, polyvinylpyrrolidone, polyvinyl alcohol, stearic acid, alkaline earth metal stearates such as magnesium stearate and calcium stearate, vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, and corn oil, nonionic, cationic, and anionic surfactants, ethylene glycol polymers -rer, (3-cyclodextrin, fatty alcohols, hydrolysed cereal materials and other non-toxic compatible fillers, binders, solubilizers and lubricants that are commonly used in pharmaceutical formulations.

Ved behandling av visse pasienter med forbindelsene ifølge oppfinnelsen, kan det væreønskelig å innbefatte andre farmasøytiske aktive bestanddeler i samme komposisjon. Ved behandling av for eksempel pasienter for hvilke salt og vannreten-sjon er et problem, kan effektive mengder av et diureticum, for eksempel hydroklorthiazid eller triklormethiazid innbefattes. When treating certain patients with the compounds according to the invention, it may be desirable to include other pharmaceutical active ingredients in the same composition. When treating, for example, patients for whom salt and water retention are a problem, effective amounts of a diuretic, for example hydrochlorothiazide or trichloromethiazide, can be included.

Farmasøytiske formuleringer Pharmaceutical formulations

I de etterfølgende eksempler er den aktive bestanddel fortrinnsvis 5-{2-[5-(N-methylanilino)-2-butylamino]-1-hydroxyethyl }salicylamid eller et farmasøytisk akseptabelt syreaddisjonssalt derav, men en ekvivalent mengde av en annen forbindelse (eller mer enn én forbindelse) av formel I, spesielt en forbindelse som angitt heri, kan anvendes i stedet: In the following examples, the active ingredient is preferably 5-{2-[5-(N-methylanilino)-2-butylamino]-1-hydroxyethyl }salicylamide or a pharmaceutically acceptable acid addition salt thereof, but an equivalent amount of another compound (or more than one compound) of formula I, in particular a compound as indicated herein, may be used instead:

Fremstillingsprosedyre: Manufacturing Procedure:

Oppløs p-hydroxybenzoat i en del av vann for injeksjon ved 60 - 70° C og avkjøl løsningen til 25 - 35° C. Tilsett og oppløs alle de andre eksipienter og den aktive bestanddel. Bring løsningen til et sluttvolum, filtrer den gjennom en steriliseren- de membran og fyll den i sterile beholdere. Dissolve p-hydroxybenzoate in a portion of water for injection at 60 - 70° C and cool the solution to 25 - 35° C. Add and dissolve all the other excipients and the active ingredient. Bring the solution to a final volume, filter it through a sterilizer- de membrane and fill it in sterile containers.

Orale formuleringer: Oral formulations:

a) Kapsler: a) Capsules:

Fremstillingsprosedyre: Manufacturing Procedure:

Bland den aktive bestanddel, lactose og maisstivelse inntil det oppnås en jevn blanding, og bland deretter magnesiumstearat i det resulterende pulver. Innkapsl blandingen i egnede todelte harde gelatinkapsler. b) Tabletter Mix the active ingredient, lactose and corn starch until a smooth mixture is obtained, then mix magnesium stearate into the resulting powder. Encapsulate the mixture in suitable two-piece hard gelatin capsules. b) Tablets

Fremstillingsprosedyre Manufacturing procedure

Bland den aktive bestanddel med lactosen inntil det oppnås en jevn blanding. Bland den mindre mengde av maisstivelsen med vann og tilsett den resulterende maisstivelsepasta, bland deretter inntil det oppnås en jevn fuktet masse. Tilsett den gjenværende del av maisstivelsen til den resulterende fuktige masse og bland inntil jevne granuler erholdes. Sikt granulene gjennom en egnet målemaskin under anvendelse av en 19,05 mm's rustfri stålsikt. Tørk de malte granuler i en egnet tørkeovn inntil den ønskede fuktighetsirinhold oppnås. Mal de tørkede granuler gjennom en egnet målemaskin under anvendelse av en 16 mesh rustfri stålsikt. Bland i magnesiumstearatet og press den resulterende blanding til tabletter med ønsket form, tykkelse hardhet og oppløsning. Mix the active ingredient with the lactose until a smooth mixture is obtained. Mix the smaller amount of the cornstarch with water and add the resulting cornstarch paste, then mix until a smooth moistened mass is obtained. Add the remaining part of the cornstarch to the resulting moist mass and mix until smooth granules are obtained. Sieve the granules through a suitable measuring machine using a 19.05 mm stainless steel sieve. Dry the ground granules in a suitable drying oven until the desired moisture content is achieved. Grind the dried granules through a suitable measuring machine using a 16 mesh stainless steel sieve. Mix in the magnesium stearate and press the resulting mixture into tablets of the desired shape, thickness, hardness and dissolution.

Claims (36)

1. En forbindelse av formelen 1. A compound of the formula hvori R 1 og R 3 uavhengig er hydrogenatomer eller lavere alkylgrupper, R 2er et hydrogenatom eller en lavere alkyl, laverealkoxylaverealkyl eller hydroxylaverealkylgrupper, Alk er en acyklisk eller cyklisk alkylenbro inneholdende 2 - 10 carbonatomer, forutsatt at det er 2 - 6 carbonatomer som skiller nitrogenatomene som danner bro, Z er et hydrogenatom eller en lavere alkyl, lavere alkanoyl, lavere alkylsulfonyl, arylsulfonyl, laverealkoxylaverealkyl, 2,2,2-trifluorethyl eller benzylgruppe, og Y 1 og Y 2 er uavhengig hydrogen eller halogenatomer eller hydroxy, trifluormethy1, lavere alkyl, lavere alkoxy, nitro, usub-stituert amino, monolaverealkylamino, di-laverealkylamino, laverealkanoylamino, laverealkylsulfonylamino, arylsulfonylamino, N-laverealkyl-N-laverealkanoylamino eller N-laverealkyl-N-lavere-alkylsulfonylaminogrupper, og farmasøytisk akseptable syreaddisjonssalter derav, idet de lavere alkyl, lavere alkoxy og lavere alkanoylgrupper inneholder fra 1 til 6 carbonatomer.wherein R 1 and R 3 are independently hydrogen atoms or lower alkyl groups, R 2 is a hydrogen atom or a lower alkyl, lower alkoxy lower alkyl or hydroxyl lower alkyl groups, Alk is an acyclic or cyclic alkylene bridge containing 2 - 10 carbon atoms, provided that there are 2 - 6 carbon atoms separating the bridging nitrogen atoms, Z is a hydrogen atom or a lower alkyl, lower alkanoyl, lower alkylsulfonyl, arylsulfonyl, lower alkoxylower alkyl, 2,2,2-trifluoroethyl or benzyl group, and Y 1 and Y 2 are independently hydrogen or halogen atoms or hydroxy, trifluoromethyl, lower alkyl, lower alkoxy, nitro, unsubstituted amino, monolower alkylamino, di-lower alkylamino, lower alkanoylamino, lower alkylsulfonylamino, arylsulfonylamino, N-lower alkyl-N-lower alkanoylamino or N -lower alkyl-N-lower alkylsulfonylamino groups, and pharmaceutically acceptable acid addition salts thereof, the lower alkyl, lower alkoxy and lower alkanoyl groups containing from 1 to 6 carbon atoms. 2. Forbindelse ifølge krav 1,karakterisertved at Alkbroen er en acyklisk alkylengruppe.2. Compound according to claim 1, characterized in that the Alkbro is an acyclic alkylene group. 3. Forbindelse ifølge krav 1, med formel 12 3 1 2 hvori n er 1 - 4, og R , R , R , Z, Y og Y er som definert i krav 1.3. Compound according to claim 1, with formula 12 3 1 2 wherein n is 1 - 4, and R , R , R , Z, Y and Y are as defined in claim 1. 4. Forbindelse ifølge krav 3,karakterisertved at n er 2.4. Compound according to claim 3, characterized in that n is 2. 5. Forbindelse ifølge krav 1 av formelen 5. Compound according to claim 1 of the formula hvori er 0 - 2, n 2 er 1 - 5, + n 2 er 2 - 6, n 3 og n . er uavhengig 0 eller 1, R, R 4 og R 5 er uavhengige hydrogenatomer eller lavere alkylgrupper forutsatt at det totale antall carbon-12 3 1 2 atomer i Alk-broen ikke overstiger ti, og R , R , R , Z, Y og Y er som definert i krav 1.where is 0 - 2, n 2 is 1 - 5, + n 2 is 2 - 6, n 3 and n . is independently 0 or 1, R, R 4 and R 5 are independent hydrogen atoms or lower alkyl groups provided that the total number of carbon-12 3 1 2 atoms in the Alk bridge does not exceed ten, and R , R , R , Z, Y and Y is as defined in claim 1. 6. Forbindelse ifølge hvilket som helst av kravene 1-5,karakterisert vedat R 2 og R er hydrogenatomer og R"'" er et hydrogenatom eller en methylgruppe.6. Compound according to any one of claims 1-5, characterized in that R 2 and R are hydrogen atoms and R"'" is a hydrogen atom or a methyl group. 7. Forbindelse ifølge krav 1,karakterisert12 3 1 2 ved at R , R , R og Y er hydrogenatomer, Y er en methylgruppe eller et hydrogen- eller halogenatom, Z er et hydrogenatom eller en methyl- eller benzylgruppe og Alk er en trimethylen-, tetramethylen- eller 1,4-cyclohexylengruppe eller en gruppe av formel hvori n er 1 - 4.7. Compound according to claim 1, characterized 12 3 1 2 in that R , R , R and Y are hydrogen atoms, Y is a methyl group or a hydrogen or halogen atom, Z is a hydrogen atom or a methyl or benzyl group and Alk is a trimethylene, tetramethylene or 1,4-cyclohexylene group or a group of formula where n is 1 - 4. 8. 5-{2-[3-(N-methylanilino)-2-propylamino]-1-hydroxyethyl} salicylamid .8. 5-{2-[3-(N-methylanilino)-2-propylamino]-1-hydroxyethyl} salicylamide. 9. 5-{2-[5-(N-methylanilino)-2-pentylamino]-1-hydroxyethyl} salicylamid.9. 5-{2-[5-(N-methylanilino)-2-pentylamino]-1-hydroxyethyl} salicylamide. 10. 5-{2-[4-(N-methylanilino)-2-butylamino]-1-hydroxyethyl } salicylamid .10. 5-{2-[4-(N-methylanilino)-2-butylamino]-1-hydroxyethyl} salicylamide. 11. 5- £2-[4-(4,N-dimethylanilino)-2-butylamino]-1-hydroxyethyl }salicylamid .11. 5-[4-(4,N-dimethylanilino)-2-butylamino]-1-hydroxyethyl}salicylamide. 12. 5-{2-[4-(4-klor-N-methylanilino)-2-foytylamino]-1-hydroxyethyl }salicylamid.12. 5-{2-[4-(4-chloro-N-methylanilino)-2-foytylamino]-1-hydroxyethyl }salicylamide. 13. 5-{2-[4-(4-fluor-N-methylanilino)-2-butylamino]-1-hydroxyethyl}salicylamid.13. 5-{2-[4-(4-fluoro-N-methylanilino)-2-butylamino]-1-hydroxyethyl}salicylamide. 14. Forbindelse ifølge hvilket som helst av kravene 1 - 13, i form av et syreaddisjonssalt med svovelsyre, fosforsyre, saltsyre, hydrobromsyre, sulfamsyre, citronsyre, melkesyre, oljesyre, ravsyre, vinsyre, cinnaminsyre, eddiksyre, benzoesyre, gluconsyre eller ascorbinsyre.14. Compound according to any one of claims 1 - 13, in the form of an acid addition salt with sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, sulphamic acid, citric acid, lactic acid, oleic acid, succinic acid, tartaric acid, cinnamic acid, acetic acid, benzoic acid, gluconic acid or ascorbic acid. 15. Fremgangsmåte for fremstilling av en forbindelse av formel I som definert i krav 1 eller et farmasøytisk akseptabelt syre- addis jonssalt derav,karakterisert vedat en forbindelse av formelen 15. Process for the preparation of a compound of formula I as defined in claim 1 or a pharmaceutically acceptable acid- Addis ion salt thereof, characterized by a compound of the formula hvori X er-et oxygenatom eller (H,OH), Alk, R 1 og R 3 er som definert i krav 1, Pg er et hydrogenatom eller en reduktivt fjernbar . beskyttende gruppe, R 2 a og Z a er respektivt R 2 og Z som definert i krav 1 eller en reduktivt fjernbar beskyttende gruppe, og Y<la>2 a 1 2 og Y er Y og Y som definert i krav 1, eller en hydroxy- eller aminogruppe (innbefattet usubstituerte og mono-substituerte aminogrupper, men ikke innbefattet di-substituerte aminogrupper, defi-1 2 nert i krav 1 for Y eller Y ) bærende en reduktivt fjernbar beskyttende gruppe, 2 cl cl 1 cl 2 cl forutsatt at når R , Pg, Z , Y a og Y er respektivt gruppene 2 12 R , H, Z, Y og Y , er X et oxygenatom, reduseres i et egnet løsningsmiddel.wherein X is an oxygen atom or (H,OH), Alk, R 1 and R 3 are as defined in claim 1, Pg is a hydrogen atom or a reductively removable . protecting group, R 2 a and Z a are respectively R 2 and Z as defined in claim 1 or a reductively removable protecting group, and Y<la>2 a 1 2 and Y is Y and Y as defined in claim 1, or a hydroxy or amino group (including unsubstituted and mono-substituted amino groups, but not including di-substituted amino groups, defi-1 2 nert in claim 1 for Y or Y ) bearing a reductively removable protecting group, 2 cl cl 1 cl 2 cl provided that when R , Pg, Z , Y a and Y are respectively the groups 2 12 R , H, Z, Y and Y , X is an oxygen atom, is reduced in a suitable solvent. 16. Fremgangsmåte ifølge krav 15,karakterisertved at X er et oxygenatom og at reduksjonen av gruppen CX til gruppen CHOH utføres med et borhydrid i en vannblandbar alkohol som løsningsmiddel.16. Method according to claim 15, characterized in that X is an oxygen atom and that the reduction of the group CX to the group CHOH is carried out with a borohydride in a water-miscible alcohol as solvent. 17. Fremgangsmåte ifølge krav 16,karakterisertved at reduksjonen utføres med natriumborhydrid i methanol, ethanol eller isopropanol.17. Method according to claim 16, characterized in that the reduction is carried out with sodium borohydride in methanol, ethanol or isopropanol. 18. Fremgangsmåte ifølge krav 15,karakterisertved at X er et oxygenatom og/eller minst én reduktivt fjernbar be- la 2a 2a skyttende gruppe er til stede i Y og Y eller som R , Pg og a12 Z , forutsatt at hverken Y- eller Y er en nitrogruppe og Z ikke er en benzylgruppe, og hvori reduksjonen utføres ved hjelp av hydrogen og en katalysator i nærvær av et organisk løsningsmiddel.18. Method according to claim 15, characterized in that X is an oxygen atom and/or at least one reductively removable be- let 2a 2a shooting group is present in Y and Y or as R , Pg and a12 Z , provided that neither Y- nor Y is a nitro group and Z is not a benzyl group, and wherein the reduction is carried out by means of hydrogen and a catalyst in the presence of an organic solvent. 19. Fremgangsmåte ifølge krav 17,karakterisertved at reaksjonen utføres ved hjelp av hydrogen og palladium i en lavere alkanol.19. Method according to claim 17, characterized in that the reaction is carried out using hydrogen and palladium in a lower alkanol. 20. Fremgangsmåte ifølge krav 18 eller 19,karakterisert vedat de reduktivt fjernbare beskyttende grupper som la 2a 2a kan være til stede i Y eller Y eller være til stede som R , Pg eller Za er valgt fra benzyl, benzhydryl, trityl og benzyloxycarbonylgrupper.20. Method according to claim 18 or 19, characterized in that the reductively removable protective groups which let 2a 2a can be present in Y or Y or be present as R, Pg or Za is selected from benzyl, benzhydryl, trityl and benzyloxycarbonyl groups. 21. Fremgangsmåte ifølge hvilket som helst av kravene 15 - 20,karakterisert vedat en forbindelse av formelen 1 3 1 2 b hvori R , R , Alk, Y og Y er som definert i krav 1, Z er gruppen Z som definert i krav 1 unntatt en benzylgruppe, og X,R<2a>ogPg er som definert i krav 15, forutsatt at når R 2a og Pg er R 2 og et hydrogenatom, er X et oxygenatom, reduseres.21. Method according to any one of claims 15 - 20, characterized in that a compound of the formula 1 3 1 2 b in which R , R , Alk, Y and Y are as defined in claim 1, Z is the group Z as defined in claim 1 except for a benzyl group, and X, R<2a> and Pg are as defined in claim 15, provided that when R 2a and Pg are R 2 and a hydrogen atom, X is an oxygen atom, is reduced. 22. Fremgangsmåte for fremstilling av en forbindelse av formel IA: 22. Process for preparing a compound of formula IA: eller et farmasøytisk akseptabelt syreaddisjonssalt derav, 12 3 12 hvori R , R , R , Y , Y og Z er som definert i krav 1 og Alk' H er en acyklisk eller cyklisk alkylenbro som definert i krav 1 for Alk forutsatt at det angitte nitrogenatom i Alk<1>og nitrogenatomet I H i ethanolamindelen -CHOH .CHR"'"- er bundet til samme carbonatomer,karakterisert vedat en forbindelse av formel hvori Alk<1>er som ovenfor definert og Y 1 , Y 2 og Z er som definert i krav 1, reduktivt kondenseres med en forbindelse av formelen or a pharmaceutically acceptable acid addition salt thereof, 12 3 12 wherein R , R , R , Y , Y and Z are as defined in claim 1 and Alk' H is an acyclic or cyclic alkylene bridge as defined in claim 1 for Alk provided that the indicated nitrogen atom in Alk<1> and the nitrogen atom IN H in the ethanolamine part -CHOH .CHR"'"- is bound to the same carbon atoms, characterized in that a compound of formula in which Alk<1> is as defined above and Y 1 , Y 2 and Z are as defined in claim 1, is reductively condensed with a connection of the formula hvor R 1, R 2 og R 3 er som definert i krav 1, i nærvær av et organisk løsningsmiddel.where R 1, R 2 and R 3 are as defined in claim 1, in the presence of an organic solvent. 23. Fremgangsmåte ifølge krav 22,karakterisertved at reduksjonen utføres ved hjelp av katalytisk hydrogenering, eller lithium-thexyllimonyl-borhydrid eller 9-borbicyclo[3,3,1]-nonan.23. Method according to claim 22, characterized in that the reduction is carried out by means of catalytic hydrogenation, or lithium thexyllimonyl borohydride or 9-borbicyclo[3,3,1]-nonane. 24. Fremgangsmåte ifølge krav 22,karakterisertved at reduksjonen utføres ved hjelp av natriumborhydrid eller natriumcyanoborhydrid i methanol, ethanol eller propanol.24. Method according to claim 22, characterized in that the reduction is carried out using sodium borohydride or sodium cyanoborohydride in methanol, ethanol or propanol. 25. Fremgangsmåte ifølge hvilket som helst av kravene 22 - >24,karakterisert vedat en forbindelse av formel II som definert i krav 3, fremstilles ved reduktiv kondensasjon av en forbindelse av formel 25. Method according to any one of claims 22 - > 24, characterized in that a compound of formula II as defined in claim 3 is produced by reductive condensation of a compound of formula med en forbindelse av formel X som definert i krav 22, hvori R ,with a compound of formula X as defined in claim 22, wherein R , 2 3 12 R , R , Y , Y , Z og n er som definert for formel II i krav 3.2 3 12 R , R , Y , Y , Z and n are as defined for formula II in claim 3. 26. Fremgangsmåte ifølge hvilket som helst av kravene 15 - 25,karakterisert vedat produktet av formel I isoleres som den fri base.26. Method according to any one of claims 15 - 25, characterized in that the product of formula I is isolated as the free base. 27. Fremgangsmåte ifølge hvilket som helst av kravene 15 - 25,karakterisert vedat produktet av formel I isoleres som et farmasøytisk akseptabelt syreaddisjonssalt.27. Method according to any one of claims 15 - 25, characterized in that the product of formula I is isolated as a pharmaceutically acceptable acid addition salt. 28. Fremgangsmåte for fremstilling av en forbindelse ifølge krav 1, hovedsakelig som her beskrevet med referanse til hvilket som helst av eksemplene 1 - 6.28. Process for producing a compound according to claim 1, mainly as described here with reference to any of examples 1 - 6. 29. Forbindelser av formel I som definert i krav 1, og farmasøytisk akseptable syreaddisjonssalter derav, fremstilt ved en fremgangsmåte ifølge hvilket som helst av kravene 15 - 28.29. Compounds of formula I as defined in claim 1, and pharmaceutically acceptable acid addition salts thereof, prepared by a method according to any one of claims 15 - 28. 30. Farmasøytiske komposisjoner inneholdende som aktiv bestanddel minst én forbindelse eller salt ifølge hvilket som helst av kravene 1 - 14 og 2 9 sammen med en farmasøytisk bærer eller eksipient.30. Pharmaceutical compositions containing as active ingredient at least one compound or salt according to any of claims 1 - 14 and 29 together with a pharmaceutical carrier or excipient. 31. Komposisjoner ifølge krav 30, i form av enhetsdoser.31. Compositions according to claim 30, in the form of unit doses. 32. Komposisjoner ifølge krav 31, i form av tabletter, kapsler eller injiserbare preparater i ampuller.32. Compositions according to claim 31, in the form of tablets, capsules or injectable preparations in ampoules. 33. Komposisjoner ifølge krav 31 eller 32, inneholdende fra 2 til 500 mg aktiv bestanddel pr. enhetsdose.33. Compositions according to claim 31 or 32, containing from 2 to 500 mg of active ingredient per unit dose. 34. Komposisjoner ifølge krav 30 i form av suspensjoner, siruper eller eliksirer. • 34. Compositions according to claim 30 in the form of suspensions, syrups or elixirs. • 35. Komposisjoner ifølge krav 30, hovedsakelig som her beskrevet i hvilket som helst av formuleringseksemplene.35. Compositions according to claim 30, essentially as described herein in any of the formulation examples. 36. Metode for behandling av hypertensjon og dets symptomer,karakterisert vedat det til et pattedyr som lider av hypertensjon, administreres en terapeutisk effektiv mengde av en forbindelse ifølge hvilket som helst av krav 1 - 14 og 29.36. A method for treating hypertension and its symptoms, characterized in that a therapeutically effective amount of a compound according to any one of claims 1 - 14 and 29 is administered to a mammal suffering from hypertension.
NO791413A 1979-04-27 1979-04-27 PROCEDURE FOR PREPARING 5- (2-ANILINOALKYLAMINO-1-HYDROXYALKYL) SALICYLAMIDES NO791413L (en)

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