DE2106816A1 - Alkanolamine indenvates - Google Patents

Description

PATENT LAWYERS

DR.-ING. H. FINOKE DLPL. -ING. H. BOHR DiPL.-ING. S. STAEGER

Telephone: · 26 60 äO

8 MUNICH 5, Ί *. ΓΓΠ IQn *

Müllerstra6e 31 '^' '

Folder 22489 - Dr Case PH, 22519

oi am · »ηά & ΛΜΛ? a fc «

Prioritii'l; · r '3 «i? El> 3: na ::; i9? ü

gesiBolie BAocl ;; ie / i> .. uj! v: iaki;: Liri'üät

eleljö df; s> al "b" κή Uö.rj ^ ^ Lei Hla "^ odor prevention frü.k / ^ ikhiiitöa, wio j.." 3 _c - Aagina pix Loris and cardia'i. A rv-iiytlyaio, uad. he L (Ιει ^ι BehaijdXmig from Hypertons.io-a ia ^ Gyijoiaio b ^ in Blensc-hen "brauc} iba.r- ai / id:

According to the Ecx. _; .niiung i-. ^r erf.ii; a ttj.iao aeuö Alk der l'Orme.i.

τ mi. λ

y ~ -

omi _? . CHOHo oh

Γ7

./οι ia R 'for viiu AUr, / *. ,! {yrtroxyrilkyl- _t Ar-al'r / i. · - ode ·: * ·

109834/1693

- sl,

ajJLjTlr & dikal st-3lit _; , ϊΓ ~ for an At yix-cKu-kal si .int I ?. "'' Mr a hydrogen ·· or ei'a Halogef.atoEi oä« r: · iltr ·?.: ': n λ. ϊ ■: :.?! * alkenyl ", BTitro --- hydroxy-. Aikyi.-bh.Lo-- i-ikozy-. ^ Ik ^ tv / u aralkoxy-, acyl- ·: Amino- A.cyle \ nuio- · χ) .α: <· ϋ ^ Γ · αο.ν. · ν · 1τ! ^: Α; stands in the middle of A Tu ?: an AlkylsnraaikaJ. ^ «« Hb; sokX'ü ..L · »üüüüj avjL, - the ..äldahydkoutifmsa '} iian &, jr!; duk» T3 ös-x ⁱ sf »}. b3o. uvi .ls3 »Isrsslben voT, 5ö £ ichlü _£ jt) ii,

It v? ^ Rd iaraaf hinewrleson “. dans 4? .y ob.Li;, t. ü-; f ini-ii ο; ·. -τοπ AlkarioXa>j; .iud3rlYatßa all © inög "1 if.vj: mf ^; i; erüö: i.« oirior: -e dixtsalb and mixtures thereof.

_{Is a} suitable value for R ''? ma \ c. ^ i ? .ui: aiii \ 11qj \. uxrr Hydroxyalä.yiradi? cal 8Ü-iht _: is ö ^ i.spt ilsi ^ ici e; i: i AUcyl your Hydroxyalky! radical vait jet / etla to ¹ Ju 6 lic] ι.Ιοΐιstoff- · atoms, nnd. especially 3, - 4 or ^l ) KohJ.siioccffatomen- wöl before-2Ugsweiisa at the Οι-Eohlenstoffatora is-wis. ⁷ S = B-. the isopropyl ".; s-butyl- _s t ~ butyl-. 2-Hy (iro: cy-;, · ethyl- or 2-kydrozy ~] -methylethy '.' radicals

A suitable 32 'value for R ^f , xienn it for an Ars lh; /! is radical, for example, sin Alky! radical is not to au. 5 carbon atoms, which is' / orKUgsweiee ai-i Ci-Kohlen.TiTu Yeraweigt, imd which is oubsti ™ ttixert by a phenyl radical, which can denote one or more, inrihedondöre one or two lower alkyl or alkoxy substituents or dialogue substituents. -. Έ: ίη be semi ore r Warl; f ill ¹ R, »ami es for an aralky! radikal ü vü / ri; is ί; For example, the t- »Hethyl-ii-phen ^ lpropyl- or 2- ':: Λ-'ΰοΑα ^ ϊιαχν- phenyl} - äthyl.t-adikai, -.

10983 ^ / 1693

BATH ORIGINAL

A larger value i'ur R ¹ , if äs for ice. Öycloalkylradlkal stell! · ;, lot "bsir-piela ^ eiise -'sin PyeloaZky! Radical with toi« to 6 K .- • ii.lenf.HVi f - ': r-; cnen _? Vrie κ, .B, the G 'yeiopropyl- ·, Oyclobutylod e r Oy el op eirh.rlr ad ikei _o

2
EIb a suitable fourth for R is, for example, an alkanoyl oil ßr Alkcno ^ loadikal Rj.t «in each case up to a \ ?. 7 carbon atoms, wi.e ε.-B ^ the Foixayl-. Acetyl-, ProiJioayl-. ·, Butyryl- .!. · χιι aroyl, Ars.lkanoyl- or Aralkerioylradikal with up su 10 carbon atoms, such as σ · _(Β ^,.: ,, Isobuityi'yl Josanoyl- ileptsxioyl- acryloyl odar Crotoaoyl- * _s or radically ·.? das bc-iiz-oyl--, px ^l c \ t ".oyl ·" - is-OhlOj'obeuaoyl-j Piienylacetyl- o

Sir signed value for Ii ?, Tr © _{nn es} füj. ^ t ₁₁ Halogenatüiu tateht. This is the example of the Ii ¹ IuQr-, 0hlov- _r bromo- odei * iodate cm ^

A suitable value for R " - _r ^ exin ea for ei: o. IJ.kyl- or alkeayl radical is, for example, eixi i-.llryl- or Älkenylraäikal with each bja sau 6 carbon atoms & n. Like Zr-Bc the methyl ! ~ _f n-propyl-- s-3utyl- or al-lyl radical _r

Sirj suitable ¥ eri; fü3: R, Vieim es for «in alkylthio- _; A ".koxy ~ or alkeny3.Qü ^ radikaleteth. Is at £.; Pielßwsisfc an alkylthio-> alkoxy- or alkenylxyradikal with up to 5 K-ohllenetoTfat onsen, vTie s _r Bc the Metbylthio-, Meth. Oxy - ^ Ä ozy- or allylosyradikalo

A canceled value for R '. if it stands for an aralkoxy radical: 'at 1) f;: i riplelavrcise an aralkoxy radical with up to 10 carbon aso-nje-ii, ώο eg the benzyloxy radical ■

109834/1693

BATH ORIGINAL

A suitable value for Br, if it stands for an aoyl radical, is, for example, an acyl radical with up to 6 carbon atoms, such as a »Bo the acetyl adder PropicmylradiksüU

A suitable value for R if it is an acylamino radical

stands * is for example a radical of the formula S -EH «-.«

2
where R has the meaning given above ₃ such as "Bo the acetamido" or propionamido radical "

A suitable value for Δ is, for example, a straight-chain one or branched-chain alkylene radical with up to 4 carbon atoms, such as ZoBo the methylene or ethylene radical

Suitable esters of the alkanolamine derivatives of the invention are, for example, esters which are derived from an aliphatic carboxylic acid with up to 20 carbon atoms - such as a, B _o vinegar? Palmitic, stearic or oleic acid, or esters derived from an aromatic carboxylic acid with up to 10 carbon atoms, such as benzoic acid _t , and the acid addition salts thereof _o

Suitable aldehyde condensation products of the alkanolamine derivatives of the invention are, for example, the 5-aryloxymethyl-3-alkyloxazolidine derivatives which, by condensation, are an aldehyde of the formula R ⁴ α CHO, in which R ^{4 represents} a water atom or an alkyl or aryl radical, with a alkanol «amine derivative according to the invention, and the acid addition salts thereof ..

A suitable value for E when it is an alkyl radical is for example an alkyl radical with up to 4 carbon atoms? like ζ =, B "the laopropy! radical".

109834/1693

4th
A suitable value for R when ea is an aryl radical is, for example, an aryl radical with up to 10 carbon atoms _s vie a, B. the phenyl radical ο

Suitable acid addition salts of the alkanolarine derivatives of the invention or the esters thereof or the aldehyde condensation products thereof are, for example, salts which are derived from inorganic acids, such as Z ₀ B * the hydrochlorides, hydrobromide ₂ phosphates or sulfates, or salts »derived from organic acids * such as the oxalates, laetate, iartrate _? Acetate _t Salicylate, Citrate »Benaoate _r ß-Sfaphthoate., Adipate or" *, 1 -Methylene-bis "(2-hydroxy ~ 3-naphthoate), or salts derived from acidic synthetic resins? Such as Z ₀ B * sulfonated polystyrene resins, for example "Zeo-Karb" 225 ("Zeo ~ Karb" is a registered trademark).

A preferred group of alkanolamine derivatives of the invention are the connections of the formula

R ⁵ COMCH ₂ - ^ V) -OCE ₂ . CHOHo CH ^ IIHR '

1 3

where R stands for an isopropyl or t-butyl radical, H stands for a hydrogen or a halogen atom or an alkyl, _t alkenyl or alkoxy radical each having up to 3 carbon atoms and B? for an alkyl radical with up to 5 carbon atoms or for the phenyl or p-chlorophenyl radical

5 stands; and the acid addition room derselberxo Il is before ~ Zugsweiea the methyl or ethyl radical »

10983471893

This is the preferred group of alkanolaroids and derivatives of the Invention are the compounds of formula

-OCH ₂ . OEQH

CH ₂ KHOOR ⁵

1 '3

in which R stands for the isopropyl or t-butyl radical; R for a hydrogen atom or for an alkyl radical with Ms to 3

5
Carbon atoms and R has the meaning given above; as well as the acid addition salts of the same _o

Specific alkanolamine derivatives of the invention are the3emgen _? which are described in the examples below, and of these in turn those compounds are preferred which have the second above-mentioned Pormsl,

1 row

a) R stands for the isopropyl or t ~ buty! radical _P R ^

stands for the methyl radical and R for the hydrogen, Chlorine or bromine atom or for the methoxy or allyl radical stands? or

b) R stands for the isopropyl or t-butyl radical _t

stands for the ethyl radical and R stands for the bromine atom;

o) R stands for isopropyl radical, R ^ for the ethyl radical and R stands for the n-propyl or allyl radical stands; or

d) b} stands for the isopropyl radical, R stands for the methyl radical and R stands for the n-propyl radical; as well as the acid addition salts of the same,

109834/1693

According to the invention, there is also a method of production the AlkanolaminderiTrate of the invention proposed, which is carried out by a compound the formula

Ε ² -ΗΗ · -Δ

2 "5
wherein R “R and Δ have the meanings given above

and where X is the group -CH - CHp or the group -CEOH ^ CHpY (where Y is a replaceable radical) _s or a mixture of such compounds; where X has the two meanings above «with an amine of"", ^ aiel HHpR ^? s wherein R ^{1 has} the meaning given above, converts c

A suitable value for Y is, for example, a halogen atom, such as s _n B ", the chlorine or bromine atom, or a _{SuIfonyloxyradikal}} as Zc Bc having up to 6 carbon atoms or a Arensulfonyloxyradikal with up to 1O carbon atoms _t is a Alkansulf onyloxyradikal such as the methanesulfonyloxy -, Benzolsulfonyloxy- or Soluene-p-sulfonyloxy radical. The reaction can be carried out at room temperature, or it may be accelerated by the application of heat or be completed, for example by heating to a temperature of 90 to \ '■ O "C and may or- at atmospheric pressure at an elevated pressure be executed _?

109834/1693

ö "*

wisely by heating in a closed container? and it may be performed in an inert Verdünnungsaiittel or solvent such _a methanol or ethanol Bo * _s or it may be an excess of the amines of the formula NELR,

-j ^

in which R has the meaning given above, can be used as a diluent or solvent ₀

The starting material used in the above method ₇ which is or an epoxy in which Y represents a halogen atom, the corresponding phenol can such _o B _o epichlorohydrin * are obtained "The above-mentioned starting material can be isolated by reaction with a epihalohydrins, or it can be prepared and used in situ without isolation. Said phenol can be obtained by acylation of the corresponding aminomethylphenol of the formula

3
wherein R and A have the meanings given above?

with an acylating agent that differs from an acid of the

2 2

Formula R -OH derives? wherein R has the meaning given above owns, can be obtained. The aminomethylphenol can itself either by reducing the corresponding hydroxybenzonitrile, for example with lithium aluminum hydride, or by reducing the oxime of the corresponding hydroxybeneoaldehyde, for example with hydrogen in the presence of one Hydrogenation catalyst, such as a palladium catalyst "

109834/1693

", Q

It should be noted that the reduction of the citrile or oxime and the acylation of this obtained Arainoraethylphenols optionally in the same Reaction vessel can be run with the aoylating agent is present while the reduction is in progress.

According to the invention there is also a method for production proposed the alkanolamine derivatives of the invention, which is carried out by using a phenol of the formula

wherein R, R ^ and A have the meanings given above?

1 1 with a compound of the formula ZCH ₂ .SHR, in which R and X have the meanings given above, reacted

The last-mentioned reaction is carried out in the regular manner in the presence of an acid-binding agent, such as Z ₀ B ₀ 3 sodium hydroxide. Alternatively, an alkali metal derivative of the phenol reactant, such as Z ₀ Bo the sodium or potassium derivative, can be used as the starting material. The reaction can be carried out in a diluent or solvent such as methanol or ethanol, and it can be accelerated or completed by the application of heat, for example by heating to the boiling point of the diluent or solvent

According to the invention there is also a method for production the alkanolamine derivatives of the invention are proposed, which is carried out by a compound of the formula

R ² ~ KH-A

ι W

12 3
where R _t R, R waä. A has the meanings given above

6th
sitsen and in which R stands for a hydrogenolysable radical, or that an acid addition salt thereof is subjected to hydrogenolysis.

A suitable value for R is for example a (X-arylalkyl radical, such as the BenzylradikaJ.n The hydrogenolysis may, for example dureh katalytieche € Hydri _ining? Beit example by hydrogenation in the presence of a palladium -HoLzkohle ~ Catalyst A, in an inert diluent or solvent such as “ethanol or aqueous ethanol can be carried out”. The process can be accelerated or brought to _{an end by the presence of an acidic catalyst such as Z 3} B, hydrochloric acid or oxalic acid.

The starting material used in the latter process can be obtained by a similar method as the above mentioned method, with dsm difference that one

1 6

Amine the SOarmel HHR R instead of an official formula or a compound which the group -JiR Γ. contains «

109834/1693

instead of the corresponding connection - which the group -NHR ^? contains, is used _o

According to the invention there is also a method for production the alkanolamine derivatives of the 'invention presented, which is carried out by having an amino derivative of the formula

R ² -IH ~ A

9 "3

wherein R, R and A have the meanings given above, -, or an acid addition salt of the same _f either with a

1 1
Compound of the formula EZ, wherein EZ is a reactive ,. Esters; which is derived from an alcohol of the formula H OH, in which R 'has the meaning given above, or for the preparation of those alkanolamine derivatives of the invention., In which R' is a radical of the formula -CHR ^ R ⁸ _?

7 8

where R is an alkyl radical and R is an alkyl, aralkyl or hydroxyalkyl radical, or in which R and R are together are connected and form a Cyeloalkylradikal with the neighboring carbon atom, with a carbonylverbin-

7 R 7 R

formation of the formula R Ό CO »R, in which R ¹ and R have the meanings given above, urasetst under reducing conditions.

A suitable fourth for Z is, for example, the chlorine- ₁ bromine or iodine atom, the toluene-p-sulfonyloxy radical or a radical of the formula -OSOpOR ', in which R is as indicated above

109834Π693

Meaning «A particularly suitable compound of the formula R'Z is isopropylbromido. The reaction in which a compound of the formula R * Z is used is carried out in the presence of a base such as e-.3 _o sodium or potassium carbonate j in a diluent or solvent such as KoBo ethanol or isopropanol, at an elevated temperature? as Z ₀ B ₀ at the boiling point of the diluent or solvent, executed *

Are these suitable re & usable conditions? by the presence of hydrogen and a hydrogenation catalyst such as ,, κ, Bo palladium or platinum, in an inert diluent or solvent, such as S = Bo in one or more solvents ;, the water _ans? Ethanol and an excess of the carbonyl compound used as starting material are selected, or formed by the presence of an alkali metal borohydride, such as S ₀ B ₀ sodium borohydride, in an inert diluent or solvent j such as _c .B _e in one cd of several solvents , -the outside water, ethanol »methanol and an excess of the carbonyl compound used as starting material are selected j, are formed» It is pointed out * that _P \ jfsmx in the starting material R stands for a halogen atom or for an alkenyl. Bfitro- "alkyl thio, oxy alkenyl ™, Aralkocsy-, acyl ™ or cyano radical is hydrogen and _{p s} are sin Hydrieningskatalysator Vora \ ?. gsweise not used sur production of reducing conditions to prevent the radical P. * '' is influenced by catalytic hydrogenation.

The one used in the last-mentioned procedure as the AM input material Amiixorlerxval · karm by Umtivjt ^ ung doe ontaprechenaen

109834/1693

Epoxy & s or Halogenfey & rins obtained with ammonia

According to the invention, a method for the production of the alaminolamine & derivatives of the invention is also proposed? which wiixt thereby carried out _? that mam a compound of the formula

H ₂ KA

V // W

GHOH ₃ CH HHE ¹

1 ^
in which RjH "and A. have the meanings given above, with an acylating agent j, which is derived from an acid of the formula R-OH _? wherein fi has the meaning given above, acylated under such conditions that neither the hydrocyclic nor the secondary amino radical of the alkali. amine side chain is aoylated "

A suitable AcylierongSBiittel is "beispielsweiBe an acyl chloride or anhydrite, the check is derived from eggs ² -0H acid of the formula R, or the acid of lormel ^R2 ~ 0H even in the presence of a EondeBaationsmittels- such, B, a carbodiimides j examplesi / eieei if .l-Dicyclohexylcarbodiiiaido

β-emäss the invention is further IIP ¹ Preparation of Alkanolarainderivate of the invention "is proposed, which is performed by a method DAAs a compound of the formula

10983 ^ / 1693

R ² -BH-A

FV

, 00Η_. CH - OH.

^ ο y *
it

"where R and R together with the adjacent carbon atom form the carbonyl radical (^ 0« 0) odsr - ^ oi ⁱ in B: 'stands for a water-idt off atom and R * has the meaning given above for R _} hydrolyzed. ,

"i ί G

• The hydrolysis of a compound? where E " .. R \ xoä the adjacent carbon atom a carbony! radical form (this is an oxazolidinone derivative) can with a base, such as, a, Bo of an alkali metal hydroxide _? in a Feräünn ^ ngßmittel or solvent, such _o B * water, methanol, ethanol or a mixture thereof _{3 are} carried out _o The Ozasolidinonderi ^ at used as Av-agangsmatei-ial can be formed by reaction of the corresponding oxazolidinone derivative dsr

R ² -SH-A

2 '* »
where R _? R "and A dia! Iedeu fcmige-n given above have _f with a compound of the formula R ' %., Before in Li' xmd Z the abovementioned.

109834/1693

The hydrolysis of a compound in which R ^ is hydrogen and R ^{1 has} the same meaning as R (that is an oxasolidine derivative) can be carried out with the aid of an acid such as κ, B- a mineral acid, for example aqueous hydrochloric acidj, and it can besides, with an increased ^f J: evQperati? .r, like s , Bc. at a temperature up to 1 OO C _? executed. The "OxasjülidinderiTat" used as the starting material constitutes itself an object of the invention and can be obtained as described below;

According to the invention, there is also a method of production the ester of the alkanols & in & errvate of the invention proposed, which is carried out by adding an acid addition salt of the corresponding unesterified Alkanolamine derivative with an acylating agent. ' implements.

A geeignotea acylating agent is, for example, an acid halide or an acid anhydride derived from an aliphatic carboxylic acid, such as _o B "van of such an acid with not more 20 carbon atoms or which is derived as _s from an aromatic carboxylic acid such as sSoBg of such an acid , with no more than 10 carbon atoms »So is a suitable sr; Acylating agents, for example acetic acid aahydride, acetyl chloride or benzoyl chloride. The acylation can be carried out in a diluent or solvent which, in the case in which an acid ashydride is used as the acylation agent, is expediently reduced in volume. the acid is "from which the anhydrite" is derived

According to the 3r; a.3.aung ■ Ird continues to be a procedure üur l? Sr

10 9 8 3 4/1693

BATH

Position of the Aldehydkoiiaeiisaticiisprodufcte (OX vate) of the invention proposal a * soft executed thereby Yiircu that one ocier the corresponding Alkanolaminäarivat an acid addition sala of the same, with an aldehyde the

Δ 4.

3 onnel R _'u Choj: * Sitat which R HE the above mentioned Badeutung, implements ■>

The ünisetsung mentioned, in a diluent or solvent such as ₇ s _o B- ethanol if given _f in the presence of a catalyst such as _a-!; The water formed during the reaction can, if necessary, be carried out by azeotropic distillation using a suitable solvent, such as s ^ B «. Benaol, l'oluene oil, chloroform, can be removed as an entrainment agent, or it can optionally be removed by means of a pehydration agent, tfie S..B, aqueous alkaline carbonate _t

the invention is also a process for the preparation of the position Cteasölidinäerivate-vorgösehlag the invention which thus is carried out _f the & MSU an epoxy of the formula

Ä ² -MA

, CH-CH _n

ο 3

where R "\ R unä A have the meanings given above,

109834 / U93

with a Schiff's base of the formula R ¹ IMJHR ⁴ ", wherein R ¹

4th
and R those given above. Have meanings * implements *

The reaction mentioned can, in the presence of a Lewis saturation _? like SoBo ZIiWi (IV) -GhIQTMi boron trifluoride or zinc chloride? Drilled out Tri <5T <ien _t waä they can continue to be carried out in a diluent or solvent »such as z _o B, carbon tetrachloride ^ at a low temperature _f such as Z ₀ I ₀ at a {temperature between 10 and 20 ⁰ C ₉ * The as Schiff's base used as the starting material can be obtained by reacting an amine of the formula E HBL »" where ^ iri R has the meaning given above with an aldehyde of the formula R CHO ₅ where R has the meaning given above _} ,

According to the invention, a process for the preparation of the oxasolidine derivatives & .ev invention is further proposed; which is carried out by using a phenol, the formula

R ² -HH-A

2 3
wherein R _f Ά and A have the meanings given above, with an oxaaolidine of the formula

₀₀ CH - C8L
Q HR ¹

109834/1693

■ -18

1 4
wherein R , R and X have the meanings given "? umsetat,

The ümsetsung mentioned, in a diluent or Lösungsmittelj as a ₀ B _c methanol _s "at an elevated temperature, for example, been carried out at the boiling point dos diluent or solvent,?., And it can vfeiter-Mn ia the presence of a base such as _κ ο Β, An alkali metal al-hjclrOXJaB _3, for example, hatriim hydroxide, can be used.-The oxasolidine used as the starting material can be converted into a compound of the I formula

where 1 © di above Beclsuitatg has such _a 'B _{a Bpicblorhydrin?} with a Schiff see Ba.se the formula RH = CHS ₃ in which R and E the Bodeutursgen given above are obtained in the presence of a Lewis acid.

The AlIs according to the invention: anola; TiinderiTati? and the ester and aldehyde condensation products of the same in the form of their free base can be carried out in the usual way in acid addition salsa by reacting with an acid,

As already mentioned above, the AlkanolSBrUierivate de: f.-Invention xaad the esters, the Aldeliydkondensatloiisprodukte and the acid addition salts thereof are of value in the treatment or prophylaxis of Hersskrankhaiteuio.

109834/1693

table blocking activity. Compounds that make this selective Effects have a greater degree of specificity in blocking the cardiac ß-receptors as the ß-reseptors in peripheral blood vessels and in the bronchial muscle. Thus, with such a compound, a dose can be selected in which the compound has the inotrppen and ohronotropic cardial eddies of a catecholamine (such as e.g. isoprenaline, that is 1- (3,4-Dih; ydraxyphenyl) -2-isopro ~ pylaminoethanol) blocks the relaxation of the smooth Tracheal muscles53, which are produced by isoprenaline or the peripheral The vasodilator effect of isoprenaline is produced, not blocked. Against this selective effect one can do one of these Connections in an advantageous way together with a sympathomimetic Bronchodilators, such as isoprenaline, orciprenaline, adrenaline or ephedrine, in the treatment of Use asthma or other respiratory diseases in that the selective compound is largely the undesirable Stimulating effects of the bronchodilator on the heart but does not inhibit the desired therapeutic effect of the bronchodilator.

Many compounds that have β-adrenergic blocking activity are known. Many of these are 1-aryloxy-5-anino-2-propanol derivatives. It is also known that some of these compounds, especially those in where the I-aryloxy radical has an acylamino substituent carries a selective ß-adrenergic blocking activity own. It is a desirable, if not absolutely necessary, characteristic of a ß-adrenergic blocking agent to which is to be used clinically that there is no substantial intrinsic sympathetic sympathetic activity

10983AM693

The compound with which the most clinical experience has been gained, namely propranolol (1-isopropylamine © »? - (^ pkth ~ 1 ~ ylc ^ y) - ^" propanols which is described in the "britiseheii patent specification 994 918") has no intrxBBisehe sympathomimetiselie activity ο However, "previously known no compound © ine selective beta-adrenergic blocking activity has according to the above definition and which no intrinsic w see sympathomimetic activity has besitst selective beta-adrenergic Blockierungsmittela _o in particular, with which most clinical experience has been obtained, namely Practolol ( ¹ I ~ (4-AcetainidGphenoxy y - ^ - isopropylamino - 2-propanol j which is described in British Patent 1,078,852), a considerable intrinsic sympathomimetic activity _c

It has been found that some of the compounds of the invention and in particular the compounds 1- (2 ™ bromo-4-propionamidomethylphenozy) -3-isopropylamiiio ~ and -3-t-butyl ~. affiino-2 ~ propaiiolj e3.ne have selective β-adrenergic blocking activity, as is evident from the inhibition of isoprenaline-induced iCachycardia in Katsen and from the lack of antagonism of isoprenaline-induced yasodilation in Katsen or the relief caused by Isoprenaline is sucked up in guinea pigs during bronchospasm induced by histamine. However, these compounds have no intrinsic sympathomimetic activity, which results from the lack of an increase in the beat rate of rats from which the natural pyrocateeh; uiaiu: u '>. O have been removed by pretreatment with syrosingopine.

108834/1693

According to the invention there are also pharmaceutical compositions proposed which as the active ingredient one or more Älkanolamine derivatives of the invention or esters thereof or aldehyde condensation products thereof or acid addition salts thereof together with a pharmaceutically acceptable diluent or ! Carrier included for this «

Suitable compositions are, for example, tablets, ₉ capsules, aqueous or oily solutions or suspensions, emulsions, injectable aqueous or oily solutions or suspensions, dispersible powders; Sprays with aerosol preparations are mentioned *

The pharmaceutical compositions according to the invention can, in addition to the alkanolamine base of the invention, contain ice or several active ingredients selected from the following: Sedatives, such as a, B _o phenobarbitone? Mepro ~ bamat, Ghlorproiaazin and the aedative Benssodiaaepin active substances, like ZoB "chlordiazepoxide and Diaaepamj yasodilators, like Z ₀ Bo GrIy ceryl trinitrat, Pentaerythrit-te tranitrat and Isosorbiddinitratj Diui'etica, like eg." hypotensive agents, such as zobo Reeerpin, bethanidine and Guanethidinj myocardial Depressante such _e B "Chinidinj agent used to treat Parkinson ³ watch disease, such as a.Bo Benzhexöl. cardiotonic agents, such as ZoBo digitalis preparations j and sympathomimetic bronchodilators, such as z, B _o isoprenaline, orciprenalinj adrenaline and sphedrin ,,

109134/1693

«22 -

The alkanolamine derivatives are administered to humans in mimicked oral doses between 20 mg and 600 mg daily at intervals of 6 "to 8 hours or in intravenous doses aryan 1 mg and 20 mg. Preferred oral dosage forms are tablets or capsules between 10 and 100 mg mg and preferably 10 or 40 mg of the active ingredient. Preferred intravenous dosage forms are sterile aqueous solutions of the alkanolamine derivative or a non-toxic acid addition salt thereof, which are between 0.05 and 1 ia (wt / yol) of the active ingredient - and especially 0 , 1 # (Crewo / Yol-) of the active ingredient contained »

The invention is illustrated in more detail by the following examples

example 1

A mixture of 2 g of 1- (2 ~ bromo »4-propionamidO2aethylphenoxy) - 2,3-epoxypropaa and 20 ml of isopropylamine is kept at room temperature for 8 hours ml of aqueous 2N hydrochloric acid and 25 ml of ether was stirred _o the acidic aqueous phase is separated and basified with aqueous sodium hydroxide _t 18a and the mixture is extracted twice with 50 ml of ethyl acetate ^ e. The combined extracts are dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure, and the residue is crystallized from ethyl acetate. In this way, 1- (2 ~ bromo-4 "-propionamidomethylphenoxy) -3- ± sopropylamino-2-» propanol with a melting point of 116 ° C. is obtained.,

103834/1693

Then 1- (2-bromo-4-propion ~ amiclomethylphe-noxy} -2; 3 "eposypropane was obtained as follows:

Its solution of 5 g of 3-bromo-'4-hydroxy'benzonit: ril becomes . a stirred solution of 1 _? 17 g of lithium aluminum hydride and 3.32 g of aluminum chloride in 40 ml of ether, which is kept at room temperature, are added ,, The mixture is filtered? and the FiItrat 51 is set si hydrochloric acid to pH 7 with aqueous ". 60 ml Propionsäureauhyärid been _issued.? st and the mixture is 4 to 90 ⁰ C, cooled and adjusted to pH 7 with Katriumbioarbonat" The mixture is washed twice with 50 ml Ithylacetat extracted, and the combined extracts are evaporated over anhydrous Magnesiumsiiifat dried under reduced pressure treatment dryness "the Eückstand is with 550 ml of aqueous Hatriumhydroxydlösung 30 min heated J) BSi mixture ^T" ird cooled _f acidified with aqueous tin hydrochloric acid and in 50 ml Äthylaeetat extracted ₀ the ethyl acetate extract is evaporated dried over anhydrous magnesium sulfate and concentrated under -vermindertem pressure to dryness »2 * 34 ml of epichlorohydrin are eye give zn a solution of 2F5 S of the remaining oil and ', 2g Hatriumhydroxyd in 20 ml of water, and the mixture is stirred for 18 hours at room temperature: The mixture is extracted twice with 50 ml of chloroform each time. and the combined extracts are dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. The residue consists of 1 '"(2 ~ 3romo-4 ~ p"? opion3midomethy! phenoxy ) -2, 3-epoxypropane and is vex- applies _o

109334/1893

Example 2

A mixture of 4 g of 2,3 ~ Isteoxy-1 ~ (2 ~ methQxy ~ 4 "propio: namido-" methylpheno: xy) ~ propane _for 25 ml of isopropylamine and 25 ml of methanol are heated under reflux for 3 hours. The 8-eraiseh is _"f evaporated under reduced pressure to dryness and the Rüekstana is this way is crystallized from ethyl acetate to 3-" isopropylamino-1 '(S-metlioxy- ^ propionsiaidomethyl ™ phenoxy) -2 ~ propanol with a Pp of 108 ⁰ G obtained

The procedure described above is repeated, however 25 ml of t-butylamine were used instead of the 25 ml isopropylamine will. In this way 1 ~ (2- "methoxy-4-propionamido ~ methyl phenoxy 5 ~ 3-t ™ butylaffiiiio ~ 2-propanol with a pp of 112 ° C obtained

The 2 _? 3-Bpoxy-1- (2-methoxy-4-propionamidomethylphenoxy) propane can be obtained as follows;

A mixture of 15? 2 g of 4-hydroxy-3- "ethoxybenzaldehyde _? 7.7 g% hydroxylamine hydrochloride, 100 ml of ethanol, 8 g of sodium hydroxide and 20 ml of water is kept at room temperature for 18 hours. The mixture is cooled with aqueous 11% hydrochloric acid acidified and filtered and the filtrate is evaporated to dryness under reduced pressure. The residue is dissolved in 25 ml of water, the pH of the solution is adjusted to 6.2 with sodium carbonate, and the emisoh is extracted twice with 50 ml of ethyl acetate each time. The combined extracts are extracted dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure, and the residue is crystallized from benzene

109834/1693

. 4-H3Tciro3i ^ - »3 ™ sietbi> sybeßg! Alde} iyd-oxIm with an 'Fp of

t14 Ms Γϊ8 ° 0 obtained.

A mixture of 12 g of the above oxime, 60 ml of ethanol _t 40 ml of propionic anhydride and 1.2 g of a 5 liter palladium-on-charcoal catalyst is shaken with hydrogen "at room temperature and atmospheric pressure until no further absorption of hydrogen takes place" the mixture is filtered, the filtrate τχαά is evaporated under reduced pressure stir Srookne _e. the residue is crystallized vnä from mixture of equal VoliUQina ethyl acetate Fetroläther (K # 60 MS 80 ⁰ G), VNA to this Weifie is 2-Methöxy-4- ProprionamidomethylphenQl with an MP of 106 to 108 ° 0 obtained © ,,,

An amount of 7.2 g of S-methoxy ^ -propioneuBidcBnethylpheBolj 4.8 g HatriiEBhydroxyd 100 hlI water and 9.36 ml of spichlorohydrin is stirred at raised temperature t8 st. The mixture is filtered, and the solid residue is washed with water. In this way, 2 _i 3-epoxy ~ 1 «(2-methoxy-4'-propionamidomethylphenoxy)» propane with a melting point of 108 "to ItO ⁰ g received

Example 5

A mixture of 2.1 g 2 _? 3 - Epoxy - i- (4 "'propionaniidOBiethylphenoxy) -propane and 20 ml of isopropylamine is kept at room temperature for 18 h» The mixture is evaporated to dryness under reduced bridge »and the residue is crystallized from ethyl acetate -Isopropylamino-t-C4-propionamidomethy! phenoxy) -2-propanol with a Wp of 10e ° 0 obtained »

1 098 34/169 3

Sas used 2j3 ~ epoxy-1- {4-propicm-amido-diethylphenoxy) -propane as a starting material can be obtained as follows

Am Cremlsch from 5 _? 48 g of 4-HydrG: sybenaalclehyd- "Oxiiü _i '100 ml of ethaaol, 20 μl of propionic anhydride and 0.5 g of a 5% alladium-on-Hol2 & ohle-Kätalysatars were shaken with hydrogen" at room temperature under atmospheric pressure until no more Water off would take more takes place ο Daa ψ Cieiaiseh is filtered? wad the filtrate is evaporated under vexwtoiu.m * '" tem Bruek zwt dryness, the supernatant is crystallized from a mixture of two volumes of ethyl acetate and one volume (Sp 60 Ms 80 ° 0), and on this

4 "Propionamido! Beti3ylpiieiiol with an MP γοη 96 Ms 98 G received.

Bine dissimg too, 4? 0g 4-Bropionaaidomethylplienol _for 2.4 g hatritußhydroxyd, 50 ml water and 7 * 8 al epichlorohydrin is "stirred at the main temperature 18 hours. The mixture is filtered and the solid Büekstanä is washed in barrels _fc this manner, 2 _i 3-epoxy-1 - (4 ~ £ propion Baidoaethylphenoxy) propane

with an I? p of 70 to 76 ⁰ C obtained.

Example 4

Sine solution of 2.1 g 2 _i 3 '~ t Spo.xy-C4-propionamidofiiethyl'-phenoxy) propane, 20 jal t-Butylamia and 20 ml of methanol is 18 st to Baumteiaperatur held Bas mixture under reduced pressure aur ÜJrockne evaporated, and the residue is stirred with 20 ml of aqueous 2N acetic acid and 20 ml of ether. The aqueous acidic phase? is separated off, waxed with aqueous tin sodium hydroxide solution and aweimal

Etaylaeetat was extracted with 3e 50. The combined extracts are dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure * The residue is crystallized from ethyl acetate and applied to this Way is i- (4 ~ pionamidomethylphenoxy) ~ 3 ~ t-butylamino-2 ~ propanol obtained with a Pp of 98 to 100 ° C

In sp iel 5

A mixture of 4 g of 1 ~ (3 ~ aetaridomethyl phenoxy) -2,3-epoxypropane and 25 ml of isopropylamine is 18 st to room temperature held. The mixture is 3ur under reduced pressure Evaporated to dryness and the residue becomes more aqueous with 25 ml 2N hydrochloric acid and 25 ml of ether were stirred. The aqueous acidic phase is separated off with aqueous 11% sodium hydroxide solution made basic and extracted twice with 50 ml of ethyl acetate each time. The combined extracts are over anhydrous magnesium sulfate and dried under reduced Pressure jsiu * evaporated to dryness The residue is turned off Ethyl acetate crystallizes, and in this way 1 ^ (3-acetamidonietnylphenoxy) -3 - isopropylamino-2 "propanol obtained with a pp of 138 ° C.

The 1- (3-acetamidomethyl-phenoxy) -2,3-epoxypropane used as the starting material can be obtained as follows;

A device made from 18 g of 3-hydroxybene aldehyde oxime ^ 100 ml of ethanol and 5 g of a 5 # palladium on charcoal catalyst is with hydrogen at a pressure of 1 00 at and Shaken at Raraatearperatur until no more hydrogen The mixture is filtered and the filtrate is taken to dryness under reduced pressure

10983W1693

evaporated «The residue is crystallized from ethanol, and in this way 3-aromethylphenol is obtained with an mp of 17O ⁰ C»

A mixture of 3 g of 3-aminomethylphenol and 12 ml of acetic acid anhydride wi2 * d "at room temperature was stirred for 5 min» The mixture is cooled and filtered, and the solid residue is crystallized from ethyl acetate, In this way, 3 ^m Acetamidomethylphenol having a m.p. of 98 ⁰ O obtained

A mixture of 3? 7 g 3 ~ Aeetamidomethylphenoly 1 _f 1 g Natriumhydroxyds 25 ml of water and 5 _S 25 al Epichlorohydrin is the SST at Bäumtemperatur 5 stirred The mixture is extracted twice with 3e 50 ml of chloroform, and the combined extracts are dried over anhydrous magnesium sulfate and concentrated under reduced pressure ssur Evaporated dry The residue consists of 1- (3-Aeetamidomet} .aylphenozy) ~ 2,3-epo2cy ~ propane and is used without further purification »

Example __6
W The procedure described in Example 2 is repeated, with the difference that 2 _? 3 ~ epoxy-1-acylaminomethylphenoxypropane and the appropriate amount of amine can be used as starting materials. In this way, the compounds described in the table below are obtained:

R ⁵ CO ₀ HH (JH ₂ - ^ \ - OCH ₃₀ CHOHo

109834/1693

E ¹ R ³ methyl 3? P (° 0) Xsopropyl Mstlioxy methyl 112-114 t-butyl Methoxy n-? ropyl 102-104 t-butyl Methosy Ieopropyl 90-92 Isopropyl Methozy n «hexyl 106 t-butyl Metiiosy ethyl 94-96 Isopropyl A tkozy ethyl 116 t-butyl Aefehoxy methyl Acetate j
114-116 Isopropyl chlorine methyl Hemihydrates
84-85 t-batyl Oilor ethyl Acetate j 124 Isopropyl CM or n-'hexyl 106 t-butyl chlorine methyl Aoetatj 108 2 ~ {3 , 4-Dia »UhOXy--
phenyl) ~ ai; hyl chlorine methyl 130 ~ ί32 Isopropyl bromine methyl Hydrate,
86-88 t-butyl bromine ethyl Acetate.
120-122 * t-batyl bromine Isopropyl Acetate"
110-112 Isopropyl bromine methyl 138-140 Isopropyl n .-- propyl ethyl 135 Isopropyl rt-propyl methyl 128 Isopropyl Allyl methyl 114 • fc-Batyl Allyl ethyl oil Ieopropyl Allyl n-propyl 104 Isopropyl hydrogen ethyl 116-117 2-hydroxy ~ 1.1 -
diethylethyl Waeöeratoff 120

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0GH ₂ , CHOH

CHJiH ₀ COS '

r ' H ³ E ⁵ B ¹ P (° G) Isopropyl H ethyl 88 + * t-butyl H methyl Acetate _? 102-104 Iaopropyl H Isopropyl ti 2 Isopropyl H n-hexyl 78-80 Isopropyl H p-chloro- 84-86 phenyl Isopropyl methyl methyl
- fa oil

All free bases and hydrates were crystallized from ethyl acetate (with the exception of _t which aas a mongrel from ethyl acetate and petroleum ether with a boiling point of 60 Ms 80 ° G was crystallized) and all Acetatsalae were from acetone (crystallized with the exception, which was crystallized from ethyl acetate ).

The various 2,3-epoxy-i-acylamino-diethylphenoxypropane derivatives used as starting materials can be obtained by reacting the corresponding Aeylaminomethy! Phenol with spichlorohydrin by a method similar to that described in the last Afcsata of Examples 2, 3 and 5 .

109834/1693

The various phenols used as intermediates can be obtained either by acylation of the corresponding aminomethylphenol or by reductive acylation of the corresponding G: dfflinomöthylphenol by a method similar to that described in US Pat. Examples i _? -2 _f 3 and 5 is described _F can be obtained "The phenols" which have been characterized are described in the following table "

OH

Isopropyl 2? P ( ⁰ C) Methoxy Ityl 118-ΐ 20 Ethcrsy methyl t 24-126 Qiilor ethyl 150 _β chlorine n-hexyl 106 chlorine Methyl. 88 ■ bromine methyl 174-176 Allyl ethyl 78-82 ⁺ Allyl methyl 86-88 ⁺ n-Px'opyl ethyl 112-114 ⁺⁺ n-Pi'opyl 1i7-118 ⁺⁺

The VerhiBduiigen _; in which R ^ stands for the allyl radical can be obtained by an oil iron rearrangement by using the corresponding Ai:!. ylH-acylaminomethylphenyl ether

109834/1693

40 min heated to 220 ⁰ G. The ethers themselves can be obtained by heating the corresponding 4-acylaminomethylphenol with allyl bromide in acetal solution and in the presence of potassium carbonate. Allyl-4-aGetsm.idomethylplienyl ether has a Pp of 80 to 84 C and allyl-4-propionamidomethylphenyl --ether has an mp of 80 to 82 ⁰ C ₀

• 5

++ The compounds in which R represents n-3 that is ropylra.dikal? _T can be obtained ,, that the decision-

'5

Speaking compounds, where Ir stands for the allyl radical, hydrogenated by means of hydrogen in the presence of a 5 # ± gene Palladivja-auf-Holslcohle catalyst in. Ethanol solution

3-Ethoxy ™ 4-hydroxybenaaldehyde "OxJjfi has a p of 92 to 94 ⁰ Co 3-Ohloro ™ 4-hydroxybenaldehyde ~ oa: iffi has an mp of 140 ⁰ Ce 2-chloro ~ 4 ~ aminomethylphenol (Hydroch3.orid Fp 246 to 248 ⁰ G) can be obtained min _o 2 "hydro by chlorination of a-As methylphenol hydrochloride with chlorine gas in Essigaäurelösung at 10 C vrälirend 10: ybenzaldehyd-osiia-hydroGhloria has a mp 148-152 ° C.

A mixture of 5.4 S 1-p- (2 "acetamidoethyl) -phenoxy-2» 3-epoxypropane, 25 ml of t-butylamine and 25 ml of water is kept at room temperature for 18 hours. The mixture is evaporated to dryness under reduced pressure _f and the residue is shaken with 25 ml of aqueous 2N hydrochloric acid and 25 ml of ether. The aqueous acid phase is separated off and made basic with 18N sodium hydroxide solution, and Greiniseh is extracted twice with 50 ml of ethyl acetate each time Magnesium sulfate

109834/1693

dried and veminderfcesi pressure aur Srockne evaporated "and the residue is ISS Ithylacetat resolved lia excess of a Greiplsehs from 1 VoI _o -rope acetic acid and 5 vol." ropes Äthey is _specified? wan, the mixture is filtered Pas solid product is crystallized aug Ätlaylacstat, and atJdf this ^ Weiae is ip ™ (2-aoetamidoät33yl) -pheiio5cy'-3''t ~ "but? laiaiaQ-2'-propa ^ ol ~ acetate with its Pp of 126 ⁰ G

The 1-p- (2-aoetaraido§ltliyl) ~, which is used as a starting material

as follows get »bei

Sin & eiaise} i from Sj 65 g of Eyramia hydrochloride (p ~ 2-Äiaiaoätliylpheaol-hydrQChlorid), 2 g of Ifatrimohydroxyd and 50 ml of water are " stirred at room temperature for 15 min , and then 20 * 4 g Esaiga acid anhydride is poured out" st heated to 90 ⁰ C and then under reduced 3) ruok sur dryness

evaporated aqueous, and the residue is dissolved in 50 ml / 2N sodium hydroxide solution. The solution is acidified with 11 η hydrochloric acid, and the G-emisoh is filtered o I> it solid © Huek ~ öta & d is crystallized from water and on this white © is p "(2 ~ AcetajnidQäthyl) -phenol with a Pp of 128 ⁰ O ar-

A solution of 8.25 g of the above phenol, 6 g of sodium hydroxide 100 ml of water and 1t, 7 ral of Bpiohlorohydrin is stirred for 18 atm at room temperature. The mixture is extracted twice with 50 ml of chloroform and the combined extracts are over anhydrous magnesium sulfate dried and under reduced © «! Pressure aur frockne ein & edampfto The Rtioketand consists of 1 ρ ■ (2-AQQtamidoethyl) -phenoa; 3r "-2 _i 3-

109834/1693

epoxypropa «, which is used without space? © Sanctification- ο

The process is repeated ot'iga _f wherein jeloch Isoprop.yl amine and 1 ~ p "(2 x = φΓopiOlxεmidQä'όllyl} '^ ΐil eao3: y ■ -2', 3- ■ ■ · 3poxyp3r opaϊl as Ausga ^ gsraaterialie" It has been partially rounded off, vasd a.uz this way. 1 ~ p- (2-Propionaiaidoätliyl) - phai! I03: 7 ~ 3 - isopi'opyl "· araino ~ 2 ~ propa" ol with an fp of 112 O ( kx-metallized from ethyl acetate) obtained ο

Example 8

A mixture of 3.4 g ^ -Chloro-i-'t ^ propifÄiaj pheBOxy) -2- * prop £ m-Olj 25 ml Isoprcpylaaixn. «Ad 25 ml is, tmter EUck ^ luse 1Ü st erliitato bits fiesd-Ecli yiz'd ua.-er Tsarainclertaiß Drucfc zur Srockns eiiigedaiiprCt, itncl der Illl (i.: - stood wired % n 25 bH 2n hydrochloric acid dissolved,« ad which is twice ad-t ^ o 25 ial Ither esti'aliijgjsrfe "the acidic bladder is made _f taaisch with wäseriger 18ix JiatriuEibyäro and the excraliiert (xemisch irird w ^ uimüL · ΐπχΐ .je 50 sil Äthylaeetat. the Toreinigtea. Ätliylaeetatestr be Waer anhydrous Magnesium sulphate geti-ociraet urjd ■ reduced under Yenaiaderteia pressure to the srockne and

The residue is crystallized from ethyl acetate. This way cS-Isopropylaminowi - (4-propio3iaiBidoaet] hyXpheno>: y) 2-propaj) .ol with a Wj? tob 106 to 108 ⁰ C ex'halta ».

ggal VerwaiidetQ 3-CM.oro ~ 1- (4 * -propioiiaüaidQaiethylpheiioxy) -2-propa »ol can be obtained as follows

A mixture of 4 * 5 S 4-TPropioii8Taidoi? IetJbylphe »oI _i " 50 ml SpL-ohlorohydri » % md 0» t ail Pipericlii \ wxrd β.: · *; ^{Nut l} 10 ° 0 obtained, and the mixture is uiater v & xtniBdeictera Jui ^ cli au?

101334/1693

"evaporated, the residue" consists of 3-chloro-1- (4-propionamido; aetbylpheaozy) -2'-propanol _f which used without further purification wircL

That in the first. The procedure described above is repeated, except that 3 ~ 0W.oro-1 ~ (4 ~ acetamidomethylphenoxy) -2 ~ propanol and either isopropylamine or t-titylamine are used as starting materials. In this way i - ^ - Acetaaidomethylphenoxy) - 3- "isopropyls2nino-2 ~ propanol bsw (crystallized from ethyl acetate) having an I? p 90-92 ⁰ C. T- (4 ~ ÄcetamidometbylpIienoxyJ.-Jt-toutylami χΐ.ο-2-propanol (146 ° Ip acetate _t G _? After crystallization from a mixture of atbylacetate and ethanol) is obtained.

The 3 = "chloro ~ i - (4 ~ ac6>tarariidomethylpheno:> cy) -2-propanol used as the starting material can be obtained in a similar process to that described above, but with 4 ~ acetamidoinetJvjf! Phenol instead from 4- * 3? i * opioasaiidoffiethyl · - phenol is used ^ -Acetaiaidoiaethylpheno.L ,, which after crystallization from ethyl acetate has a melting point of 132 to 134 ⁰ C axdT », can be obtained by a similar process, as it is in the pages 5 part of example 3 is described, with 3 similarly acetic anhydride being used instead of propionic anhydride,

Example 9

A mixture of 4.3 g of 3 ~ (Sf-Benzyl ~ li-isopropyli'nJLno) -1- (4-propionamidoaiefchylphenozy) -2-propanol, 50 ml of ethanol, 5 ml of aqueous 11n B & 3zsäv-re and 0.5 g of a 5 fSig ^ n Palladii ^ nauf »Holzkoh3.®" Xö * .talysators is shaken with hydrogen at room temperature v: a & atiüosplrärischom Dru.ek, bi & d: »e

109834/1693

The uptake of hydrogen ceased. The gel is filtered and the piltrate is evaporated to dryness under reduced pressure. The residue is crystallized from ethyl acetate from 106 to 108 ⁰ O obtained.

The 3- (iff "Ben3yl-Iif-isopx * opylamino) -1- (4-propionamidoniethylphenoxy)" 2- propanol used as starting material can be obtained as follows:

A mixture of 4 »3 g of 3-chloro ~ 1 ~ (4 ~ propionaiaidomethylphen ~ oiy) -2-'propaziol, 3.8 g of N-benzyl-ÜJ-isopropylamine and 50 ml n-Propanol is heated under reflux for 18 st, and the mixture is then evaporated to dryness under reduced pressure. The liquid is dissolved in 25 ral aqueous 2N hydrochloric acid dissolved, and the solution is twice with 25 bü. ether extracted »The acidic aqueous layer is made basic with 1Bn JiatriuinhydroÄyd aqueous solution, and the mixture is extracted twice with 50 HiI ethyl acetate each time * The vezv Combined ethyl acetate extracts are dried over anhydrous magnesium sulfate dried and under reduced pressure Evaporated to dryness. The residue consists of 3 ~ (N-benzyl-N-isopr opylamino) -1 - (4-propionamidcsae thy lphenoxy) ~ 2-propanol, which is used without further purification.

Example 10

A solution of 0.8 g of sodium hydroxide in a mixture of 4 »1 water and 20 ml of ethanol is added to a stirred solution of 1.79 g of 4-propionamidoethylphenol, 25 ml of ethanol and 1» 34 g of i-chloro ^ -isopropylamino- a-propanol-hyarochloride

109834/1693

added »and the mixture is refluxed for 3 hours and filtered »and the filtrate is evaporated to dryness under reduced pressure., The residue is washed with 2f> ml Viaeser and 25 ml ethyl acetate shaken, and the ethyl acetate phase is separated off, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. The residue is crystallized from ethyl acetate and thus 3-isopropylamino-1- (4-propionamidoraethylphenoxy) -2-propanol is obtained obtained with a mp of 106 to 108 ° C.

1088 34/1693

Claims (1)

ΡΔ-IBHTAHSPHÖCHB Alkanolaiaine derivatives of the formula R ² ~ HH ~ A wherein R is an alkyl, hydroxyalkyl * aralkyl or ρ -κ Cycloalkyl radical, R stands for an ayl radical, Br for a hydrogen or a halogen atom or an alkyl, alkenyl, nitro, hydroxy, alkylthio, alkoxy, * alkenyloxy, aralkoxy, acyl, amino, acylamino - or Cyanora ikal and A stands for an alkylene radical as well as the esters thereof j the aldehyde condensation products thereof; xmä the Säxir addition salae of the same " 2o AlkanolaminderiTate according to claim 1, characterized gekeanzöichaet, that ß is an alkyl, hydroxyalkyl or oyeloalkyl radical each with up to 6 carbon atoms or for an alkyl radical with up to 6 carbon atoms aa, which is substituted by a Fhenylradikal, the viedermi a or two lower alkyl, lower alkoxy or halogen Can carry 2 substituents; R for an alkanoyl or Alkenoylradikai each with up to 7 carbon atoms or for an aroyl, aralkancyl or aralkenoyl radical »it in each case up to 10 carbon atoms, i S stands for hydrogen or a halogen atom or an alkyl, alkenyl or Aoyl radical with in each case up to 6 carbon atoms or for 1098 ^ 4/1693 an alkylthio ~ _r alkoxy or alkenyloxy radical with in each case up to 5 carbon atoms or for an aralkoxy radical with up to 10 carbon atoms or for the nitro, hydroxy, amino or cyano radical or for a radical of the formula 2 2 H-IiH--, wherein R has the meaning indicated above, is j and A represents a straight-chain or veraweigtkettiges alkylene radical having up sa 4 carbon atoms, j and the esters thereof, which are aromatic of aliphatic carboxylic acids having up za 20 carbon atoms, or of carboxylic acids with up to 10 carbon atoms derive the condensation products thereof with an aldehyde of the formula Ir. CHOj where Ir stands for a hydrogen atom or for an alkyl radical with up to 4 carbon atoms or for an aryl radical with up to. 1 0 carbon atoms; and the acid addition salts of the same _r 3c alkanolamine derivatives according to claim 2 * characterized in that dfcss R stands for an alkyl or hydroxyalkyl radical each having 3 * 4 or 5 carbon atoms, which is branched em Of-Kohl east off atom. 4 c alkaiiolamine derivatives according to claim 1, 2 "or 3 o characterized in that R for» the isopropyl, s-butyl, t ~ butyl, 2 "hydroxy-1,1-dimethylethyl, 2-hydroxy-t- methylethyl-r 1-methyl-3-phenylpropyl, 2- (3 »4 ~ dim © thoxyphenyl) ethyl, cyelopropyl, glyclobutyl or glyclopentyl radical; R stands for the IOrmyl-, Acetyl-, Propionyl-, Butyryl-, Isobutyryl-, Hexanoyl-, Heptanoyl-, Aeryloyl-, Crotonoyl-, Benaoyl-, p-Ioluoyl- ^ p-ChlorobMiEoyl-, Ehenylacetyl- or Cinnamoylraöikal? R ^ for a hydrogen, fluorine, chlorine, bromine or iodine atom or for the methyl, n-propyl, 109834/1693 ~ 40 s ~ butyl- ₉ allyl-j IFitro-, hydroxy-;, methylthio- _? Methoxy, ethoxy, isopropoxy, allyloxy, beaaayloxy, acetyl, propionyl, amino, acetamido, propionmido or cyano radical; and A represents the methylene or ethylene alkyl; © eowi the esters thereof which look vo: a vinegar _"f palmitic, stearic derived, oil or Eenaoesatsre; the de-ionization products of the same with an aldehyde de?. "· Peiv R ο OHO» where R stands for a hydrogen atom or for the propyl or phenyl radical} and the acid addition oil 5 ο AlkanolamiBc? .Erii? Ate the formula 'W W , GHOH, QE ₂ where R ^{1 stands} for in alkyl, hydroxyalkyl or Gyclof.akylradi »kai with in each case up to -su 6 carbon atoms eteht * B. for P is an alkanoyl or alcoholic radical, each with up to 6 carbon atoms, or an aroyl, arelkanoyl or aralkenoyl radical, each with up to 10 carbon atoms, and R is a hydrogen or hydrogen atom or an alkyl - _f Alkenyl or acyl radical with Mf? au 6 carbon atoms or for an alkylthio- _f alkoxy or alkenyloxy radical oil kit, in each case "bit in the 5 carbon" or for an analkoxy radical with bit of throats "to ff a-uOiaen or for that miter--;,! vdroxy-, Amino or C '^ anidical or for a radical of the' ro-like:!. R "-M (where}"{'* d: x <; olx-ir »ß. Given meaning bcu:'. Ϊ> · Λ) tjüehi ;; sovri.u die>"; etör 109 8 3 4/1693 2106818 which see derived from an aliphatic carboxylic acid with up to 20 carbon atoms or from an aromatic carboxylic acid with up to 10 carbon atoms; the condensation products of the same with an aldehyde of the formula R ^f "CHO, wherein R represents a hydrogen atom or an alkyl radical with up to 4 carbon atoms? and the acid addition salae the same,, 6 ο alkanolamine derivatives of the formula R ⁵ CO * HHCH ₂ - / y ~ OQH ₂ O CHOH 1 3 where R stands for the isopropyl or t-butyl radical, R · 'stands for a hydrogen or halogen atom or for an alkyl, alkenyl or alkoxy radical with in each case up to 3 carbon atoms and R stands for an alkyl radical with up to 5 carbon atoms or represents the phenyl or p-chlorophenyl radical; as well as the acid addition salae of the ointments _c 7ο Alkanolamine dimes according to claim 6, characterized in that that R stands for the methyl or ethyl radical " So alfranolamine derivatives of Foimel —— ^ y— OCHgo CHOH, CH ₂ HHR. ¹ ^ 5 CH ₂ SHCOR ³ 109834/1133 1 "3 R stands for the isopropyl or t-butyl radical,: X for a hydrogen atom or for a sin alkyl radical with bxe c stands for 3 carbon atoms, and E stands for an alkyl radical with up to 5 carbon atoms or for the phenyl odes * p-chloropheoyl radical; as well as the acid addition salts the same. »9o alkanolamine derivatives according to Ansxiruch 8, thus can-5
aeichnet that H stands for the methyl "· or ethyl radical _o 1Oo Alkaiiolasiinderivate of the formula R ⁵ COo HHCH ^ - ^ V ~ 0OH ₂ C CHOH ₀ wherein (a) R ^{7 stands} for the isopropyl or t-butyl radical, R ^{2 stands} for the methyl radical and R ^ for a hydrogen _? Chlorine or bromine atom or for the kethoxy or allyl radical atehtj or (h) R ^{1 stands} for isopropyl or t-butyl radical, 3? stands for the ethyl radical, and R ^ stands for the bromine atom? or (e) R ¹ stands for ¹ the isopropyl radical, R stands for the ethyl radical, and Έ? for the n-Prcpyl- or AHylradi.ii-J. stands? or (d) R ^{1 stands} for the isopropyl radical, R ^{5 stands} for the methyl radical, where R stands for the propyl radical, as well as the acid addition scale of the same " 109834/1 ^ 93 "i 1" The v \ 3rbin & img 1 »• (2-Bromo ~ 4 ™ pi ^v opioKamicLoHiethyl- pl-ieno3cy) ~ 5-i? Opropyl8Piaiio-2-propa3iol aowie the Siiiaread & i Ί 2ο acid ~ ade.it ioiiasalse of Mks & olaininderiTate or eier] i! stor- the same or the Aidehyakondeneationsprodui "^ ciers the same ηε.ο1ι olu.em of claims 1 to \ 1 _f dadt? rch gek aeiclmet, öai-a they hydrochloride, hydrobromids _? Pliofjjib ^ -e. i5ü.lfate> oxalates , Lactate, l'artrate ^ Acetate? Salicylate, Citrate, Benzoate _; ß-Caphthoate _? Adipate or 1, ΐ »Msthjlen bis- (2-hydro: ry" -3 ~ i> ap] itlaoate) or salts that are of; 3 ried poly-tyrolliarsea ablsit ^ n, sindo ■ ί 5o Yerfί · 3ΐί2 · © η sur Her3telliing by and esters of the same and aldehyde condensate batioas; oroducts of the same, she said χϊ>. to claims 1 to 12, if R _f S ^, R- "', E mid A, in the sequence, have the notions given in" dnsrn d · ?? * i, nspring 1 "? is 12 _: dac- ixr separatediai3 £ .. = i; y that bisä
(a). a 1 "egg-bind \ * ng of the ForiaeX where X. for the group * -CH - CH ₂ or the group (sror-in Y for oin erset ^ bai'cs Eadilcal ateht) or &: <. from soilcueii "? 'f :: ./ b5.r" Iuii.sexi _i . ViOX ¹ IrI X die ¹ Ue-IdSxI above, nii benen S-ec-eirlMr-i .. ^ «^ öf ^ liis-i; ,, with; a; , 4ai> :. the ί ^Λ οι ·: ηβ '.> 10983A / 1893. BATH ORIGINAL implements s caev that men (Ib) a phenol, of the formula wx.% a VerTslndimg der? Oji * mel XOH ₀ * MKU _s t-.oi'ia i :! di. specified Eedetitrsg, iJsisstKt? or- eVäütj iuan (e) a "Verbixiäuiag ler" 'ojci i ", OH (I-, GEL ·? c d where E for a liydjiOgenQlysbarenoti eraser;!. oteht _? od «5in acid acMitionno & .In cl ^ icaelber !. dei * · H ^ di-ogeaol.ce mrftj or that ι · ο? .ε. (ά) a &jflinoderi; '7a-b of the Forrual . / ~ 0GH _o n C ¹ EUHo ÜF JeH. a SaureacWi.to.o: ^ - ^ !! «de ^ same itati ^: oc3i: with e5.ne.r · BATH der- ιΌϊϊ, ιθΙ R ¹ Pi, «oieän R Z a reactive ester be * j interprets the ε-; I from © raam alcohol of the formula H ¹ OH a "blo: I.tir-i,:> ds2 ⁱ z & F Eer-aielX'Gig of those AlkanolanaiideriTflate., R ^{J stands} for an IU & ikg.l the Pormel ™ CHiÄ ⁸ ,.-Jroria h Alisy! Radical iiiid E ~ 'e ±: a. "Akjl-", Aral.ky3, - or H kö.l or in which E means land R ° mitsiiiaBdei ¹ Terb-oiü. © :). Are and form with the oenae & bart <3 &carbonatoai exn Oycloalkyi / -radikal, with βϊ: αατ GartoayXverbimduBg der Fozs.eL 7 p H »COoR mitei * reduai er end needs. waiset-at s or sKteng the K ' ' HoOH-O (? H0HoCH "H.HR ^! \ I / 2 c with an Ao; - 'liexojiiäsinitte "j. ₃ das isicii? o«. sisinr acid "© 2 formula E '--CM derives, -niter such conditions that neither the hydroxy radical nor the seliandüre Ap kai of the Allcanolamissfe.-ltoiikette. acylated trird | or dai-ui maz ?. (f) fine i & rbiad.s.iuf eggs .formula I 0 _v R. ¹ \ ^1Ü 109334/1693 QIQ • where either E isnd R together with the tensolibaTtea C) .Carbon atom represents the carbonyl radical. or R Viasserstoff is wad R has the same TSedeutimg i.-la B. besitstj hydrolysis w £ or <le, one ss (g) z \ ar manufacture ^ oa Etetern a ßäu-feadfilfeioiiBaals dss corresponding ujiTsresfeertea Äl} cenol! iiitiaderi- / ats mi; an acylation aiaittol? or .that you (h) ZVT production of aldehyde coiiclerissationüpiOduktfin (Ozasolidine) u & b en * i; sprecliendo / ilkaiiolaHiiiidox'iTat öler e; L: i acid additionsals desaolfeaa. encircled with a klaiihvä tar t? oraa! L a οCHO; or that one (i) 2mr Hera division of ösasolidinön mz> Epo ^ y'd. dor Fonael ßfc "STTT A rait a ship ⁵ see base of the formula R ^1- IMiEa ⁴ - ^ isc ^ ü or that one (j) for the manufacture of ÖxasolieU.nen e - '. ii PheiiOl c.e; c- ]? ormel r '"- ish - a 4 = / with an ootazolidine dor formula 109834/1693 BATH ORIGINAL 0H ₀ imsetst, whereupon the alkanolamine derivative or ester thereof or tlaa AMeiiyakondenaationeprcdukt of the same, in the Free Baserform by never converting an acid ia to ε? i "known whiteness possibly in an acid additicmsBali: - t4 «" Verfaferen according to claim 13? thereby g-akemng; * ± that Y stands for sin logostom or for an alkane sulfcnylraiii3v.al rait up to 6 Eolilßi; material atoms or for an arenesulfonyl radical with "tis su 10 carbon atoms, 15o procedure rcch claim 14? characterized by the fact that Y stands for (Lzb Chloraijoni B ^ eht, 16. The method according to any one of claims 13 (a) j 13 {b} _>; i4 and 15j characterized by the fact that it is accelerated or brought to an end by the application of heat, 17c Method according to one of claims 13 (a), 13 (b} j 14 _f '5 "" nd 16 ", characterized in that it is carried out in methanol or ethanol as a thinning agent or solvent" 18, method according to one of claims i3 (b), 14 _? 15 _f 16 waäi 17, characterized in that it is carried out in the presence of Qi.asu säT23? 8binding agent or that an alkali metal derivative of? AieuolreakuionB Participate ala imegan ^ ra- 109834/1693 BATH material is weclly used 19o method according to claim i; 5 (c) ,, characterized in that that R stands for the Bensylraäikal Process according to claim 13 (c) or 19 , characterized in that the hydrogenolysis is carried out by catalytic hydrogenation in an inert diluent or solvent ο 21 ο method according to claim 20, characterized in that _f hydrogenolysis by hydrogenation in the U-egenwart a palladium on charcoal catalyst and is carried out in the presence of ethanol " 22 * Method according to claim? 3 (e) _f 19 »20 and 21, characterized in that an acidic catalyst is present« 23 ο Procedure according to. Address t3 (d) _? in that Z stands for the chlorine, bromine or iodine atom or for the toluene-p ~ eulfonyloxy radical or for a radical of the film -OSO ₂ OR 24o method according to claim 1; 5 (d) or 23, characterized in that it is exported in the presence of egg bast , 25ο Method according to spoke 13 (d), characterized in that that dia redusierer-dan conditions clutch lie .ijaweaenheit of What? Er material p.nd a ^ 'drationacatalyst in one inert Yerdürmm, '5.: ^ Ittel or i.oaungemit (; <»1.; ^:. Uj;; · f: ce;> 109834/1693 BATH ORIGINAL 2βο procedure according to. Claim 13 (&) ϊ characterized in that that the reducing conditions are met by the application of an AlkaliM $ talXfcG2 * ohydrias in ai & eia inertea diluent or solvents are created 27o method according to claim 13 (e)? dactureh & ekeBB £ 3eichnet, that the acylating agent eixL Säarelialogeyiid or that Acid anhydride ₅ derives the sicli το: α of the acid of the formula R OH; iSto 28, 7erfahren according to claim 13 (©) _s thereby gekimnisaiijhGQt that the acylienangsmittel the acid dei ' Tormel R'"OF. In the presence of an Oarbodiimidis a3.s condensation agent, 29o method according to Aiaspriieh 13 (f) _? because of this, that the idolysis of the oxasolidinone derivative helps? a base in a Verdtinr / tiBgsjaittsl or IiösixBgemittsl s, usgaftihrt. ■ will ,, 3Oo Tferfaiiren after Anspraeh 13 (f)? characterized geteeatjselehnet DAAs the hydrolysis of OitasolidinderlTatB _f with the aid of a mineral acid is performed. 31 »Method according to claim 13 (g) siui ^f Ksi-stelluric; νο: α esters, thereby ^ ekomiKailühnet thatö "dtxf? Ae3" li © nwigt;? i fc - '; el an acid chloride or an acid anhydrite! 'Lsi ;, 32o cooking. according to claim 13 (fe) κϊιγ H ^ retelb.: ajf, vo; i aldehyde cond "5nBabionnproduTcten (üEa" olidiß.d <ii'iva'I; on) _} characterized by the "30: l * ?. Ethanol as Tordtiiinun ^ i ^ iii-jt '?! or Löaungöiilttel executed vrirdo 10 9 8 3 4/1693 - ^: -.i '-. a bad origin ^ - Procedure according to. Claim i3 (i) for the production of aterty characterized in that it is carried out in the presence of a Lewis acid in Ü? etrachlorocarbon at a temperature between 10 and 20 ⁰ C, 34ο method of claim ¹ Mj) aur producing Oxasolidinderivaten, characterized in that _f ss is carried out in a diluent or solvent in the presence of a base " 35c Pharmaceutical Compositions j. thereby geker ο-draws _? that they as an active ingredient one or see.'f Alkanolaraindari-irate or Estor same or Aldehydko ?. .den sationsproaukte same or Säar-eaäditionssaliie according to one of claims 1 to Ί? together with a pharmaceutically sulphurous diluent or for this purpose. 3S ₅ compositions according to address 35? thereby g! draws _? Eat them in the form of tablets _t Eapselri. _: . »Räs £ 5ige or oily solutions or suspensions ^ emulsions., Injectable aqueous or large solutions or suspensions =, dispersible in powders ^, sprays or aerosol preparations have» 37 »compositions Naeh one of claims 35 ocer 36, characterized in that they _t" u.sS.ti5li3h cn η o "5etmehrere WirJcatofle contain from ijedativ3n ₉ VaaodiJatoren, diuretics" hypotensive agents "myoce.rdial Pepreasanten, agents for Parkinson Behandlxing ^! Disease, cardioconiscb.3 agents and bronchodilators selected oindo 10983A / 1693