DK144821B - METHOD OF ANALOGUE FOR THE PREPARATION OF 4-HEPTAMETHYLENIMINO-1-BUTYL-XANTHEN-9-CARBOXYLATE OR ACID ADDITION SALTS THEREOF - Google Patents

METHOD OF ANALOGUE FOR THE PREPARATION OF 4-HEPTAMETHYLENIMINO-1-BUTYL-XANTHEN-9-CARBOXYLATE OR ACID ADDITION SALTS THEREOF Download PDF

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DK144821B
DK144821B DK434872AA DK434872A DK144821B DK 144821 B DK144821 B DK 144821B DK 434872A A DK434872A A DK 434872AA DK 434872 A DK434872 A DK 434872A DK 144821 B DK144821 B DK 144821B
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heptamethylenimino
butyl
acid
carboxylate
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DK434872AA
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DK144821C (en
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E Karpati
K Felfoeldi
M Bartok
A Molnar
L Szporny
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Richter Gedeon Vegyeszet
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
    • C07D311/82—Xanthenes
    • C07D311/84—Xanthenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 9
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Description

o 1 144821o 1 144821

Denne opfindelse angår en analogifremcrancrsinåde til fremstilling af farmakologisk aktivt 4-heptamethylenimino-l-butyl--xanthen-9-carboxylat eller syreadditionssalte deraf.This invention relates to an analogous pharmaceutical method for the preparation of pharmacologically active 4-heptamethylenimino-1-butyl-xanthene-9-carboxylate or acid addition salts thereof.

Denne hidtil ukendte forbindelse har formlen 5This novel compound has the formula 5

CHo-CH0-CHo y? VCHo-CHO-CHo y? V

/ \ >=< CH„ N- (CH2) - 0 - C - / jp (I) \ / 4 >=< 10 >CH2-CH2-CH2 ° >>/ \> = <CH + N- (CH2) - 0 - C - / jp (I) \ / 4> = <10> CH2-CH2-CH2 ° >>

Den omhandlede forbindelse med formel I har værdi-15 fulde farmakologiske virkninger og kan først og fremmest anvendes som vasodilatoriske (anticholinerge) midler.The present compound of formula I has valuable pharmacological effects and can be used primarily as vasodilatory (anticholinergic) agents.

Coronaria-vasodllator-virkningen af 4-heptamethylen-imino-l-butyl-xanthen-9-carboxylat-hydrochlorid undersøgtes på isolerede rottehjerter ifølge metoden beskrevet af 20 Langendorff (E. van Remoortere et al.: Arch. int. Pharmacodyn.The coronary vasodilator effect of 4-heptamethylene-imino-1-butyl-xanthene-9-carboxylate hydrochloride was investigated on isolated rat hearts according to the method described by 20 Langendorff (E. van Remoortere et al .: Arch. Int. Pharmacodyn.

95, 466, 1953). Resultaterne er angivet i tabel I. Procentforøgelsen af coronarstrømningen er karakteristisk for størrelsen af den vasodilatoriske virkning. Virkningen af den hidtil .¾ ukendte forbindelse sammenlignes med virkningen af "Persantin" ' ' 25 et i vid udstrækning anvendt coronar-vasodilatorisk middel inden for terapien.95, 466, 1953). The results are given in Table I. The percent increase in coronary flow is characteristic of the magnitude of the vasodilatory effect. The effect of the novel compound is compared to that of "Persantin", a widely used coronary vasodilatory agent in therapy.

Tabel ITable I

30 Aktivt middel Dosis Forøgelse af jag coronarstrømmen, % "Persantin"® 5 11,8 15 17,6 50 32,4 35 4-Heptamethylenimino-l- 15 37,9 -butyl-xanthen-9-carboxy-lat-HCl 2 144821 oActive Agent Dose Increase in Jag Coronary Flow,% "Persantin" ® 5 11.8 15 17.6 50 32.4 35 4-Heptamethylenimino-1- 37.9 -butyl-xanthene-9-carboxy-lat-HCl 2 144821 o

Den her omhandlede analogifremgangsmåde er kendetegnet ved, at a) 4-halogenbutanol med den almene formel 5 Hal - (CH2)4 - OH (II) hvor Hal betyder et halogenatom, omsættes med heptamethylen-imin med formlen 10 / 2 2 2 CH, NH (III) O^-O^-OL, 15 hvorefter den fremkomne aminoalkohol med formlen ^ce2-ch2-ch2 CEn XN - (CH0), - OH (IV) ^2 / 2 4 CH2-CH2-CH2 20 omsættes med et reaktivt derivat af xanthencarboxylsyre med formlen 25 ^ ^ - COOH (V) eller b) et 4-heptamethylenimino-l-butylhalogenid med 30 den almene formel CHo-CH0-CH~ / 'i CH2 - (CH2)4 - Hal (VI) ^O^-O^-O^ hvor Hal har den ovenfor angivne betydning, omsættes med 35 o 3 144821 xanthencarboxylsyre med den almene formel (V), hvorefter den dannede forbindelse med formel (I) om ønsket overføres i et syreadditionssalt eller frigøres fra et sådant salt.The analogous process of this invention is characterized in that a) 4-halogenobutanol of the general formula 5 Hal - (CH 2) 4 - OH (II) where Hal represents a halogen atom is reacted with heptamethylene imine of the formula 10/2/2 CH NH (III) O ^-O ^ -OL, then the resulting amino alcohol of the formula ^ ce2-ch2-ch2 CEn XN - (CHO), - OH (IV) ^ 2/2 4 CH2-CH2-CH2 20 is reacted with a reactive derivative of xanthenecarboxylic acid of the formula 25 + - COOH (V) or b) a 4-heptamethylenimino-1-butyl halide of the general formula CH 2 -CHO-CH 2 - in CH 2 - (CH 2) 4 - Hal (VI Wherein Hal has the meaning given above, is reacted with xanthenecarboxylic acid of the general formula (V) and the compound of formula (I) formed, if desired, is transferred into an acid addition salt or released from such a salt.

Fortrinsvis fremstilles syreadditionssalte med 5 saltsyre, hydrogenbromidsyre, svovlsyre, phosphorsyre, eddikesyre, citronsyre, maleinsyre, vinsyre eller fumarsyre.Preferably, acid addition salts are prepared with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, maleic acid, tartaric acid or fumaric acid.

Ved egnet valg af reaktionsbetingelser opstår produktet umiddelbart i form af et syreadditionssalt.By appropriate choice of reaction conditions, the product immediately arises in the form of an acid addition salt.

Fremgangsmådevariant a) kan gengives ved følgende 10 formelskema: CH,-CH0-CH9 / \Process variant a) may be represented by the following formula: CH, -CHO-CH9

Cl-(CH2)4-OH + CH2 nh --^ 15 NvCH2-CH2-CH^/ -HCl J2H2-CH2~CH2 CH, \ - (CBU.-OH + Cl-C-ζ Np ->> 20 \ / >-< ch9-ch--ch0 o /\Cl- (CH2) 4-OH + CH2 nh - ^ NvCH2-CH2-CH2 / -HCl J2H2-CH2 ~ CH2 CH, \ - (CBU.-OH + Cl-C-ζ Np - >> 20 \ /> - <ch9-ch - ch0 o / \

.CH -CH--CH-J.CH -CH - CH-J

/ 2 < /—V/ 2 </ —V

25 CH2 N - (CH2)4-0-C-/ y , HCl ch2-ch2-ch2 o 30 Fremgangsmådevariant b) kan gengives ved følgende formelskema: ^ch2-ch2-ch2 <ςΐ3> 35 CH2 SN-(CH2)4-C1 + HO-C- S) -CH2 N - (CH2) 4-O-C- / y, HCl ch2-ch2-ch2 o Process variant b) may be represented by the following formula: ^ ch2-ch2-ch2 <ς SN3> 35 CH2 SN- (CH2) 4 -C1 + HO-C- S) -

Sxch2-ch2-ch^ OSxch2-ch2-ch ^ O

4 144821 0 CH2-CH2-CH2 y· W \-(CH9) -0-C- < % , HC1CH2-CH2-CH2 y · W \ - (CH9) -0-C- <%, HCl

™2 y' 2 4 X, X™ 2 y '2 4 X, X

xch2-ch2-ch2 0 ^ 5xch2-ch2-ch2 0 ^ 5

Det første trin ved fremgangsmådevariant a) udføres i nærværelse af et opløsningsmiddel. Som opløsningsmiddel kan der f.eks. anvendes alkoholer, chlorerede aliphatiske carbonhydrider eller aromatiske carbonhydrider. Især er det 10 fordelagtigt at udføre det første trin i ethanol i nærværelse af et syrebindende middel. Som syrebindende middel kan der f.eks. anvendes alkalimetalhydroxider, alkalimetalcarbonater eller alkalimetalhydrogencarbonater eller et overskud af aminreagenset. Aminobutanolen med formel (IV) , der fås ved 15 det første trin, renses på passende måde, f.eks. ved destillation eller omkrystallisation, og omsættes med et reaktivt derivat af xanthencarboxylsyre med formel (V) i nærværelse af et indifferent opløsningsmiddel.The first step of process variant a) is carried out in the presence of a solvent. As a solvent, e.g. alcohols, chlorinated aliphatic hydrocarbons or aromatic hydrocarbons are used. In particular, it is advantageous to perform the first step in ethanol in the presence of an acid binding agent. As an acid binding agent, e.g. alkali metal hydroxides, alkali metal carbonates or alkali metal hydrogen carbonates or an excess of the amine reagent are used. The amino butanol of formula (IV) obtained by the first step is suitably purified, e.g. by distillation or recrystallization, and reacted with a reactive derivative of xanthenecarboxylic acid of formula (V) in the presence of an inert solvent.

Som reaktivt derivat af syren anvendes fortrinsvis 20 det tilsvarende anhydrid eller halogenid, især chloridet, i et lille overskud, og reaktionen udføres i en chloreret aliphatisk carbonhydrid, en aromatisk carbonhydrid eller en lavere keton, fortrinsvis i chloroform, benzen eller acetone, ved tilbagesvaling af blandingen i én eller to timer. Reak-25 tionsblandingen afkøles, filtreres, og det krystallinske produkt omkrystalliseres fra et passende opløsningsmiddel eller opløsningsmiddelblanding fortrinsvis fra acetone, ethanol eller vand.As the reactive derivative of the acid, the corresponding anhydride or halide, especially the chloride, is preferably used in a small excess, and the reaction is carried out in a chlorinated aliphatic hydrocarbon, an aromatic hydrocarbon or a lower ketone, preferably in chloroform, benzene or acetone. the mixture for one or two hours. The reaction mixture is cooled, filtered and the crystalline product is recrystallized from a suitable solvent or solvent mixture preferably from acetone, ethanol or water.

Fremgangsmådevariant b) udføres i et opløsningsmiddel 30 under opvarmning. Som opløsningsmidler kan der anvendes alkoholer eller aromatiske carbonhydrider med højere kogepunkt.Process variant b) is carried out in a solvent 30 under heating. As solvents, alcohols or aromatic hydrocarbons having a higher boiling point can be used.

Det foretrækkes at anvende et chlorid eller bromid med den almene formel (VI) som udgangsforbindelse, og reaktionen udføres i isopropanol eller toluen ved kogepunktet for opløs-35 ningsmidlet.It is preferred to use a chloride or bromide of the general formula (VI) as the starting compound and the reaction is carried out in isopropanol or toluene at the boiling point of the solvent.

c 144821 5c 144821 5

OISLAND

Den farmakologisk aktive forbindelse med formel (I) anvendes i form af farmaceutiske produkter. De farmaceutiske produkter til enteral, parenteral eller topisk anvendelse indeholder forbindelserne sammen med farmaceutisk acceptable 5 organiske eller mineralske, faste eller flydende bærestoffer. Bærestofferne må ikke indgå i reaktionen med den aktive ingrediens. Som bærestoffer kan f.eks. anvendes vand, alkohol, gelatine, propylenglycol, vegetabilske olier, cholesterol, stivelse, lactose, talkum, gummi, magnesiumstearat eller 10 andre kendte farmaceutiske bærestoffer. De farmaceutiske produkter kan om ønsket steriliseres.The pharmacologically active compound of formula (I) is used in the form of pharmaceutical products. The pharmaceutical products for enteral, parenteral or topical use contain the compounds together with pharmaceutically acceptable organic or mineral, solid or liquid carriers. The carriers must not be included in the reaction with the active ingredient. As carriers, e.g. water, alcohol, gelatin, propylene glycol, vegetable oils, cholesterol, starch, lactose, talc, rubber, magnesium stearate or other known pharmaceutical carriers are used. The pharmaceutical products can be sterilized if desired.

De farmaceutiske produkter kan også indeholde hjælpestoffer, f.eks. præserveringsmidler, stabiliseringsmidler, befugtningsmidler, emulgeringsmidler, midler til at fremme 15 opløsningen, salte til indstilling af det osmotiske tryk eller puffere. I nogle tilfælde kan andre terapeutisk værdifulde stoffer også sættes til de farmaceutiske kompositioner. De farmaceutiske produkter kan fremstilles efter i og for sig kendt måde. De injicerbare præparater kan f.eks. fremstilles 20 som følger: Et syreadditionssalt eller et kvaternært salt af den aktive forbindelse opløses i pyrogenfrit fysiologisk saltvand eller to gange destilleret vand. Opløsningen steriliseres om nødvendigt og fyldes derpå i ampuller under sterile betingelser.The pharmaceutical products may also contain excipients, e.g. preservatives, stabilizers, wetting agents, emulsifiers, dissolution agents, salts for adjusting the osmotic pressure or buffers. In some cases, other therapeutically valuable substances may also be added to the pharmaceutical compositions. The pharmaceutical products can be prepared in a manner known per se. The injectable compositions may e.g. is prepared as follows: An acid addition salt or quaternary salt of the active compound is dissolved in pyrogen-free physiological saline or twice-distilled water. If necessary, the solution is sterilized and then filled into ampoules under sterile conditions.

25 Opfindelsen skal forklares nærmere ved hjælp af de følgende eksempler.The invention will be explained in more detail by means of the following examples.

Eksempel 1Example 1

Heptamethylenimino-l-butyl-xanthen-9-carboxylat--hydrochlorid.Heptamethylenimino-l-butyl-xanthene-9-carboxylate - hydrochloride.

Trin A: 4-Heptamethylenimino-butanol-l.Step A: 4-Heptamethylenimino-butanol-1.

En opløsning af 17,0 g af heptamethylenimin og 14,5 g l-chlor-butanol-4 i 150 ml vandfrit ethanol blandes med 30 g vandfrit kaliumcarbonat, og blandingen omrøres og tilbagesvales i 24 timer. Reaktionsblandingen afkøles og fil-A solution of 17.0 g of heptamethylenimine and 14.5 g of 1-chloro-butanol-4 in 150 ml of anhydrous ethanol is mixed with 30 g of anhydrous potassium carbonate and the mixture is stirred and refluxed for 24 hours. The reaction mixture is cooled and filtered.

OOISLAND ISLAND

treres, og filtratet inddampes. Remanensen opløses i 30 ml o 6 144821 acetone, og opløsningen fortyndes med 300 ml vandfri ether.and the filtrate is evaporated. The residue is dissolved in 30 ml of acetone and the solution is diluted with 300 ml of anhydrous ether.

De udskilte krystaller fraskilles ved filtrering.The separated crystals are separated by filtration.

Trin B: 4-Heptamethylenimino-l-butyl-xanthen-9--carboxylat-hydrochlorid.Step B: 4-Heptamethylenimino-1-butyl-xanthene-9-carboxylate hydrochloride.

5 En opløsning af 3,3 g 4-heptanmethylenimino-butanol-l i 50 ml benzen sættes dråbevis til en opløsning af 4,0 g xanthen-9-carboxylsyrechlorid i 20 ml benzen, og opløsningen tilbagesvales i 2 timer. Blandingen afkøles, og de udskilte krystaller samles ved filtrering og omkrystalliseres to gange 10 fra en 5:l-blanding af acetone og ethanol. Der fås 5,0 g 4-heptamethylenimino-l-butyl-xanthen-9-carboxylat-hydrochlorid, smp. 137-139°C.A solution of 3.3 g of 4-heptane methylenimino-butanol-1 in 50 ml of benzene is added dropwise to a solution of 4.0 g of xanthene-9-carboxylic acid chloride in 20 ml of benzene and the solution is refluxed for 2 hours. The mixture is cooled and the precipitated crystals are collected by filtration and recrystallized twice 10 from a 5: 1 mixture of acetone and ethanol. 5.0 g of 4-heptamethylenimino-1-butyl-xanthene-9-carboxylate hydrochloride are obtained, m.p. 137-139 ° C.

Eksempel 2 15 4-Heptamethylenimino-l-butyl-xanthen-9-carboxylat- -hydrochlorid.Example 2 4-Heptamethylenimino-1-butyl-xanthene-9-carboxylate hydrochloride.

En opløsning af 4 g 4-heptamethyleniminobutylchlorid og 4,6 g xanthen-9-carboxylsyre i 20 ml isopropanol tilbagesvales i 15 timer. Opløsningen afkøles og fortyndes med 30 ml 20 acetone og opbevares i et køleskab i 1 dag. De udskilte krystaller samles ved filtrering og omkrystalliseres fra 5:l-blan-ding af acetone og ethanol. Der fås 6,0 g af den ovennævnte forbindelse med et smeltepunkt på 137-139°C.A solution of 4 g of 4-heptamethyleneiminobutyl chloride and 4.6 g of xanthene-9-carboxylic acid in 20 ml of isopropanol is refluxed for 15 hours. The solution is cooled and diluted with 30 ml of 20 acetone and stored in a refrigerator for 1 day. The separated crystals are collected by filtration and recrystallized from 5: 1 mixture of acetone and ethanol. 6.0 g of the above compound are obtained with a melting point of 137-139 ° C.

Claims (2)

1. Analogifremgangsmåde til fremstilling af farmaceutisk aktivt 4-heptamethylenimino-l-butyl-xanthen-9-carboxy-lat med formlen 5 ^ch2-ch2-ch2 N=< ch2 ^n- (ch2)4 - o - c - /y (I) 10 '^CHj-CHj-Csf' ό eller syreadditionssalte deraf, kendetegnet ved, at 15 a) 4-halogenbutanol med den almene formel Hal - (CH2)4 - OH (II) hvor Hal betyder halogen, omsættes med heptamethylenimin med 20 formlen CH„-CH0-CH0 / 2An analogous process for the preparation of pharmaceutically active 4-heptamethylenimino-1-butyl-xanthene-9-carboxylate of the formula 5 ^ ch2-ch2-ch2 N = <ch2 ^ n- (ch2) 4 - o - c - / y (I) 10 '' CH 2 -CH 2 -Csf 'ό or acid addition salts thereof, characterized in that 15 a) 4-halogenobutanol of the general formula Hal - (CH 2) 4 - OH (II) where Hal represents halogen is reacted with heptamethylenimine with the formula CH 2 -CHO-CHO / 2 2 CH2 NH (III) \ch2-ch2-ch^ 25 hvorefter den dannede aminoalkohol med formlen CH0-CH0-CH0 / 2 2 sj CH~ N - (CH9) , - OH (IV) \ / CH2“CH2-CH2 30 omsættes med et reaktivt derivat af xanthencarboxylsyre med formlen 35 /""v i y - cooh (v) O2 CH2 NH (III) \ CH2-CH2-CH2 then the amino alcohol formed of the formula CHO-CHO-CH0 / 2S2 CH-N - (CH9), - OH (IV) \ / CH2 “CH2-CH2 reacted with a reactive derivative of xanthenecarboxylic acid of formula 35 / "viy - cooh (v) 0
DK434872A 1971-09-03 1972-09-01 METHOD OF ANALOGUE FOR THE PREPARATION OF 4-HEPTAMETHYLENIMINO-1-BUTYL-XANTHEN-9-CARBOXYLATE OR ACID ADDITION SALTS. DK144821C (en)

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