DE2808006A1 - METHOD FOR PRODUCING PROSTACYCLIN AND ITS ANALOGS - Google Patents

Description

¹ AFTER,

Patent attorney Dr. -! ng. Lofferbas

Lici.fsnsfsinsfraßa 3

D-όΟΟΟ Frankfurf / Main 1

Phone: 06 11/55 50 61

d. October 5, 1978

Chinoin Gyogyszer es Vegyeszeti Tennekek Gyara RT., To utca 1-5, Budapest, Hungary

VBRFAHBBEN FOR THE PRODUCTION OF PROSTACYCLIN AND ITS ANALOGUE

When investigating the biological role of prostaglandins, the mechanism that regulates the blood coagulation process in the mammalian organism has only recently been clarified (Chemical and Engineering News, 2O.XII _e 1976, p. 17)

According to this, the common precursor of the prostaglandins during their biosynthesis in the mammalian _{organism t} the prostaglandin dop © roxydg is partly transformed by an enzyme produced by the blood platelets (throtsbocytes) into a very active one that induces blood clotting

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2809006

Substance, the throuiboxan A, on the other hand, with the help of an enzyme found in the aorta wall, to another very active substance that prevents blood coagulation. -Desoxy-6,9oc-oxydo - ^ - PGF ₁₀₆ and was named Prostacycline

The prostacyclin was biochemically produced from the prostaglandin endoperoxide with the help of the tissue derived from mammalian enzyme systems, its biological effectiveness has also been demonstrated in vitro «In the experiment, the aggregation of thrombocytes triggered by adenosine diphosphate was interrupted by the compound (Prostaglandins, VoI * 12, No. 5, 685 / Ϊ976 /).

The invention relates to a process for the preparation of compounds of the general formula J

COÜlO 20th

where 0% ^k

B ¹ for hydrogen, for optionally by aryl, amino,

Hydroxyl or halogen substituted alkyl group or the equivalent of a physiologically compatible organic or inorganic cation,

R ^{2 stands} for hydrogen, hydroxyl group or protected

809886/0574

Hydroxyl group,
3
Rr for hydrogen or lower alkyl group,

Rh represents hydrogen or a group suitable for protecting the hydroxyl group and
κ

R for optionally interrupted by a hetero atom Alkyl group which is straight or branched and optionally substituted by one Aryl group can be substituted

The prostacyclin mentioned at the beginning, which is also referred to as PGX in the specialist literature, is one

1 * 3 compound of the general formula X, in which R ₁ K and

Room 2 *>

R ⁺ for hydrogen, R for hydroxyl and R ^ for n ^ pentyl «If R stands for methyl instead of hydrogen, the PGX methyl ester is present .

The alkyl group R can be an alkyl group optionally substituted by aryl, amino, hydroxyl or halogen with, for example, 1-10 carbon atoms. The alkyl group R preferably stands for straight or branched alkyl with 1-6 carbon atoms, in particular with I-; , such as the methyl, ethyl, n- and laopropyl, n-, iso-, sec «and tert -butyl groups * The aryl group possible as a substituent of this alkyl group preferably has 6-10 carbon atoms and V ^ T ₁ Ti optionally be substituted; however, it is preferably an unsubstituted aryl group, such as the phenyl and the 1- or 2-naphthyl group «The alkyl group R can be substituted by one or more of the groups mentioned above at any point if R is the equivalent of one

809886/0574

inorganic or organic cation "is as organic cations, the different primary, secondary, _t tertiary and qua ternary en Amtnoniumkationen as inorganic cations mainly the alkali metal and Brdalkalikationen in question" As examples of R = ropes cation sodium, lithium, Potassium, ammonium, trishydroxymethyl-methylammonium, piperidinium, pyrrolidinium and morpholinium ions called "

If the hydroxyl group R is protected, the protective group is either different from that for the meaning named by Ic *, to protect a hydroxyl group suitable group, or they are identical to R «The latter case is preferred« As protecting groups for hydroxyl all protective groups customary in prostaglandin chemistry for this purpose come into question «As examples and without any restriction to this is the tetrahydropyranyl group, the different alkylsilyl, alkanoyl and aroyl groups, especially the lower alkanoyl groups, for example the Acety! group, and also the Benzoyl and p-phenylbenzoyl groups, the different ones

It

Carbamoy! Groups, such as the methylcarbamoyl, ethylcarbamoyl, Phenylcarbamoyl and the p-phenylphenylcarbamoyl group called"

It can 'referred to in the definition of R "lower alkyl group be straight or branched and preferably has 1-6, especially 1-jr, carbon atoms · Examples are the methyl, ethyl, n- and isopropyl, n-, Xso -, sec " and tert" -butyl, the pentyl and the hexyl group called "

Said at the meaning of R, optionally interrupted by a hetero atom alkyl group may be straight or branched and preferably has 1-10,

809886/0574

Especially 1-6 atoms KohXens toff "Hs examples are the various decyl ₉ nonyl, octyl, heptyl, hexyl, pentyl, butyl, propyl and further the _s

η
Methyl and ethyl group called "The alkyl group may be interrupted _8, preferably by a Sauer =" atom or a -NH = group "Di © mentioned as substituent of said alkyl group preferably has 6-10 Ärylgruppe Kohlenstoffatotne and may be substituted _6, However it my least nothing Examples are the phenyl-substituted or unsubstituted, 1- and 2 thylgruppe · groups as substituents of these Ary! are preferably halogen, lower alkyl and / or Alkosy questioned further di © Trifluormethy! group ₀ the Yerfoindungen the general Formula X become er = fittdungsgsin & S au © prostaglandin => F_ or des = ·

"lake

sen ßsrivaten the general FoothqI II on

CouT

If

obtained, in which the meaning of
Br and R is the same as above, R for hydrogen, optionally by aryl, araino,

Hydroxyl or halogen substituted © alkyl group, the η

Equivalent of a physiologically acceptable organic or inorganic cation or one for protection the group suitable for the hydroxyl group, R ^ is hydrogen, hydroxyl group or protected hydroxyl · =

group means and
R stands for hydrogen or one to protect the hydroxyl group

suitable group is "

The protective group of the protected hydroxyl group R and those mentioned for the meaning of R and R, groups suitable for protecting a hydroxyl group may be the same as those for the meaning of R and R have already been mentioned «

If R stands for optionally substituted alkyl

n
group or for the equivalent of a cation, these preferably have the meaning already mentioned in connection with R «

The compounds of the general formula IX are easily accessible compounds «Das Prostaglandin F ₂

(PGF 1, ie the ^{hydrogen for K 6} , R ³ and R ⁸ , for R ⁷

κ
Hydroxyl group and containing n-pentyl group for R

Compounds of general formula II and their salts are commercially available as medicaments. Numerous processes are also known _{for the production of prostaglandin F 0 esters.}

For the inventive preparation of the compounds of general formula I, the compounds of the general formula II in the presence of a solvent or without one with a brominating agent treated «Any brominating agent known from the literature can be used as a brominating agent, for example the elemental bromine per se, also bromine bound in complexes, preferably the fyridine bromine complex, as well as the various known N-bromine reagents, such as N, N-dibromodimethy! hydantoin, N- -Broraacetamide, N-bromosuccinimide, or the tribromide ions (BrT) donating reagent systems. The bromination can can be carried out in both acidic and alkaline media «Any inert organic solvent can be used as a solvent.

80988S / Q574

2808005

be used Gallic, protic or aprotic solvents · As protic solvents AlkamoXe and organic acids oxide as aprotic solvent is acetonitrile, dimethylformamide, BimethyXsulf, chlorinated hydrocarbons and ether in Brage _o Further, water may be used as a solvent ₉ also can Ge "mix of the listed Solvents are used »Depending on the reactivity of the reagent ₈ used, the bromination is carried out at temperatures between -78 and +100 ⁰ C, preferably at room temperature. ^,

The mentioned Bromierungamittel grip the £ j "ice · double bond of compounds of the general formol II directing selectively to give the corresponding bromonium Xon arises" The resulting _s positively charged Xonen stabilize in any case below Einbesiafoung the hydroxyl group at 9-position, the compounds of the general formula XXX

form in which the meaning of B? , R ⁵ , R, R ⁷ and R are the same as above and X stands for bromine atom «

In the implementation of the compounds according to the invention of the general formula IX with sprinkling agents

809886/0574

resulting compounds of the general formula III exist in two isomeric forms. With regard to the spatial position of the hydrogen on carbon atom 6, these are in accordance with the usual for prostaglandic acid Numbering) to be addressed as epimers (exo-endο isomerism) By using different brominating agents and depending on the type of reagents and the Reaction conditions can be the exo- and endoforra of the compounds of the general formula III in relation Sneeze from 1: 1 to 1:10 in favor of the end product can be obtained «The Epiraer mixture can, if desired, for example, by column chromatography on silica gel, this separation can be carried out particularly favorably in the case of the esters, i.e. matographiert compounds of the general formula III in which R represents an alkyl group optionally substituted by aryl, amino, hydroxyl or halogen or for a group suitable for protecting the hydroxyl group is available as starting materials of the general formula

II the Pro3taglandin-F _o -acid or its salts the

dec

Subjected to bromination, the compounds of the general formula HI obtained can be known per se The way to be esterified «The methyl esters of the general formula III (in which R stands for methyl group)

the simplest way is to react with diazomethane in ether obtain"

The compounds of the general formula I are made from the compounds of the general formula III Eliminating Hydrogen Bromide Preserve «The Elimination tion can be done, for example, by connecting the applications of the general formula III, optionally treated with heating with a base «A preferred embodiment

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26Ü6Ö06

This reaction is carried out by reacting the compound of the general formula II in an alkanol with alkali metal alcoholates or heating it together with tertiary aliphatic or aromatic bases, for example pyridine, picoline or triethylamine commonly known reagents _s for example Diassahicyclo-undecane (DBU) or Diasabicyclo = "nonane (DEN) used in the usual solvents werdQn ₀ in order to avoid side reactions used is particularly preferred as the base reagent _s the weaker n than those listed Bas © _s for example potassium carbonate in an alkanol as a solvent _o The solution is preferred at temperatures between rooms

temperature «ad 200

Of the two epimsrexi. represent connections of all « common formula HE, the elimination reaction before the endo isomer is much faster. than at the exo isomer, however, is the product of elimination for both isomers the 5 (z) isomer corresponding to the general formula I «,

The compounds of the general formula I are isolated from the reaction mixture in a customary manner Since they contain an enol ether structure that is extremely sensitive to acids, they are useful for low temperatures with the addition of a small amount of base, preferably sodium carbonate

The in the course of the ergß

resulting intermediary © the general formula are new connections «, Si © also form the state of the art »

The © E "fimduaagsg © niä.S established ®n connections

of general formula I are capable of in one concentration of 0.2-20 ng / iiil, for example by adenosine diphosphate to prevent triggered aggregation of human platelets or one already to dissolve formed thrombus "

The aggregation-inhibiting or thrombus-dissolving effect of the compounds of the general formula I is _{shown using the example of the PGX methyl ester (prepared according to the invention for example from PGF 206} methyl ester), ie a compound of the general formula I in which K ³ and R ″ represent hydrogen, R ² for hydroxyl group, R for methyl group and R ^ for n-pentyl group.

To investigate the anti-aggregation respectively thrombus-dissolving effect · was caused by thrombus- bocyte-rich plasma (PRP) is used. In each case 1 ml of plasma was examined in the modified Born aggrometer

l) The aggregation of the control sample was carried out by

-5
1x10 mol of adenosine diphosphate triggered * The measured aggregation (in scale divisions) is shown as a function of time in Fig. 1 by the curve "-.-, -"

z) 5-20 ng PGX methyl ester were dissolved in 0.05 molar TRIS hydrochloric acid buffer of pH 7.5 and incubated together with 1 ml PRP at room temperature for 1.5 minutes. Then the solution was in the aggregometer

-5 introduced and by adding 1x10 mol adenosine diphoephate the aggregation induced «Xn the aggregation was an inhibition observed« The aggregation as The function of time is illustrated by the curve x-x-x-x-x «

3) The one triggered by adonosine diphosphate

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- yL-

Aggregation was by adding 20 ng PGX Methyles- * be made ter 50 i "reversed. _{The result of this investigation is previewed} in Fig. 1 by the curve Χ ββ Χ _οο Χ.

The method according to the invention is explained in more detail using the following examples; i-räx-® ₀ does not intend to be restricted to these examples

example 1

290 mg (0.82 mmol) PGP_ WeS ¹ SsKa. niiril dissolved in 2 and to the solution under Hühr © n at 0 C IKO mg (0.52 mmol) of N ₁ H ^s -! '© Dibrotadim thy hydantoin g © © g ben _c The reaction proceeds within ¥ oa 5 mewed from ₀ resulting products 6 ~ ikid0 <= i

approximately in the proportion of 5 Sl and © ntia®lt © n in raiaiaal amounts Impurities less ¹ © d © rity »On silica gel laa t ait © ines

of benzene ^ Diosaa.
the Eado connection

R value of O _f 22 _s the

0.27.

The one after the

tenen & 30 rag raw product xff © E> d © a asa Silikag ©! chromatographic (liösiamgstaittislgaalacl

ßlozan's acetic acid see 20 ^ 5 Sl) in r® ± n® © in Qemlsoiii © tag? Ex © <=> and

The pure ones
mix can through

at 0 ⁰ C in approximately quantitative J & asfoeut® su a®u corresponding methyl © θteESi ixsi3g © s © 'solid tjos'desa.o B®2l

layer chromatography under the above conditions, the methyl esters have the following R _f values: Endo - compound: 0.35, Eaco compound »0, ^ 1«

Example 2

175 g (0, ^ 9 mmol) 2 &? _{2 <£} are dissolved in 5 ml of dichloromethane and 1 ^ 1 mg (0.55 mmol) of N-bromo-campherimide are added to the solution at tree temperature with stirring. The reaction takes place within 3 hours. The products 6-Endo-6, Poc-oxydo-Soc-bromo-lloCjlSoc-dihydroxy-13 (e) -prostanoic acid and 6-Exo-6,9oc-oxydo-5β -bromo-lloc, 15oo- -dihydroxy-13 (e) -prostensäure arise in the ratio of about 2 ti "the obtained after removal of the Lösungemittels 320 mg of crude product are purified by column chromatography on beschiebene in example 1." the following products are obtained t Exo -Compound: ^ 5 mg,

Mixture of endo and exo compoundsχ 6Ζ mg, endo compound: 6O mg
The values of the compounds agree with those given in Example 1,
Example 3

973 mg (2.7%. Mmol) of ^PGF _2oC are dissolved in 10 ml of dichloromethane and the solution of 535 ^m 6 (3 80-90 minutes from «The reaction produces endo- and exo-isomers in a ratio of about J *:! · The compounds are separated into the following fractions using the column chromatographic method described in Example 1:

131 mg exo compound, 578 mg mixture of exo and endo Compound and 293 mg Endo compound. The R_ values of the Compounds agree with those given in Example 1

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4%

match

Example ^

251 mg * ^^ ^who 2NC ^<* s ^ ⁿ a mixture of 10 ml of water and 10 ml of acetic acid dissolved to the solution, the solution of 1 g of potassium bromide in 5 ml setter _s is first then the solution of 4O Kaiiumbromat mg in 5 ml of water given · The reaction takes place within 3 = * 4 hours «

The reaction mixture is shaken out with 20 ml of ether, the ethereal phase first with 0 _? 5 tal 10% sodium thiosulphate solution then Z ₁ . Washed times with 5 ml of water each time and finally dried over magnesium sulphate at 0 ° C in the absence of light. Thereafter, the ethereal solution is filtered, evaporated and the residue is freed from the acetic acid at 1 Torr to sur weight lsonstans Product are obtained. This crude product is purified in the manner described in Example 1 and subjected to column chromatography. The following fractions are obtained: 65 mg of exo compound, 103 % of mixture of exo and endo compound, and 72 mg Endo connection «The R. values of the products agree with those mentioned in Example 1.

Example 5

278 mg (0.62 mmol} 6 _t 9 <£ -Qxydo ~ 5-bromo-llcz _il 1.5cc- -dibydroay-13 (e) -prostensäure-methylester are dissolved in 5

Il

ml of absolute ethanol dissolved * To the solution 3 tal an ethanolic potassium ethoside solution of concentration 0, ^ mol / l given «The reaction table is at

ο "

70 C for 6 hours and then the ethanol is removed.

ο ⁿ ferrite. 50 ml of ether are added to the residue at 0 C.

28Q8Q06

and 20 ml of water are added. After shaking, the ethereal phase is separated off and dried at 0 ° C. over anhydrous potassium carbonate. After evaporation of the ether, 1 ^ 5 mg (6 ^ fi) 5 (Z) -9 ~ deoxy-6.905 are obtained -oxydo- ^ -PGF - ^ - methyl ester (PGX methyl ester) in the form of an oil »
NMR Spelctruni: 5, ^ 5 (2H, ra), 4, 55 (lH, m) ppm.

JR spectrum \ l · - = 1730 and 1705 cm "· γ max "

On one soaked with a mixture of triethylamine and ether Silica gel layer shows the product with a mixture

from acetone and ethyl acetate in a ratio of 1: 1 as a flow agent an R "- ¥ ert of 0.58"
Example 6
220 mg (0.51 BiMoI) o ^ oe-Oxydo ^ -bromo-ll ^ lSoc- -dihydroxy-13 (E} -prostenic acid methyl ester are dissolved in 10 ml of absolute tert-butanol and added to the solution under argonate biosphere 'Ji ^ O mg (3 »1 Tamol) of potassium tert" - where butoxide the solution is' stirred at 60 ⁰ C I ₁ hours the reaction mixture is worked up as described in example 5 Veise I4I mg (75 "h... ) PGX methyl esters are obtained, the physical constants of which are identical with those of the product according to Example 5 *

Example 7

233 mg (0.5 ^ mmol) 6,9oc-Oxydo-5-bromo-llö;, 15oc- -dihydroxy-13 (E) -prostic acid methyl ester are used in 10

It

Dissolved nl of absolute ethanol * 1 g of anhydrous potassium carbonate is added to the solution and the suspension is ^{stirred at 70 °} C. for 22 hours. The reaction mixture is worked up in the manner described in Example 5. 137 mg (72 %) of PGX methyl ester are obtained. The physical constants of the product agree

match those of the product according to Example 5

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COOR

I.

COOR ⁶

COOR ⁶

III.

809886/057 «

Claims (1)

Claims (Process for the preparation of compounds of the general formula I. wherein R "^ for hydrogen, for _{alkyl optionally substituted by aryl s} amino, hydroxyl or halogen group or the equivalent of a physiologically compatible organic or inorganic cation, ο
R stands for hydrogen, hydroxyl group or protected Hydroxyl group, R- * for hydrogen or lower alkyl group, R stands for hydrogen or one to protect the hydroxyl group suitable group and R for possibly interrupted by a heteroatom ne alkyl group which is straight or branched and optionally substituted by one Ary! Group is substituted, because it denotes that one compounds of the general formula II COOV ^ S 809886/0574 INSPECTED in which the meaning of 3 5
R and R are the same as above, R is hydrogen, an alkyl group optionally substituted by aryl, amino, hydroxyl or halogen, η
the equivalent of a physiologically compatible organic or inorganic cation or a group suitable for protecting the hydroxyl group, R is hydrogen, hydroxyl group or protected hydroxyl group means and represents hydrogen or a group suitable for protecting the hydroxyl group, in the presence of a solvent or without such reacting with brominating agents and the compounds obtained of the general formula XXX o. "* - ^ coot ti wherein the meaning of R, R, R, R and R is the same as above and X stands for bromine atom, optionally subjected to an elimination reaction in the form of their esters, and, if desired, from those as substituents R and / or R is a group suitable for protecting the hydroxyl group and / or as a substituent R is a split hydroxyl group containing compounds of the general formula X, the protective groups are removed and / or if desired as the substituent R is a physiologically acceptable one 809886/0574 -ιοί organic or inorganic cation or an optionally by aryl, amino, hydroxyl or halogen substituted alkyl group-containing derivatives and / or the ester derivatives obtained hydrolyzed «2, process according to claim 1, characterized in that that elemental bromine, complex-bonded elemental bromine, is preferably used as bread crumbs the pyridine bromo complex, U-bromo reagents, preferably N, N-dibromodimethy hydantoin, N-bromoacetamide, N-bromosuccinimide or reagents yielding tribromide ions (Br ") used 3, method according to claim 1 or 2, characterized in, that the elimination reaction is carried out by using the compounds of the general formula IXX, wherein the meaning of R *, R, R, R, R and X the is the same as in claim 1, with an inorganic or organic base, preferably with alkali metal alcoholates in an alkanol or with tertiary aliphatic or aromatic nitrogen bases, in particular pyridine, Kollfl in, picoline or triethylainin optionally in In the presence of a solvent and / or reacts with heating * ^ _{0 The} method according to claim 3 »characterized in that the elimination reaction is carried out with alkali bases, preferably alkali carbonates, in particular potassium carbonate in a solvent, preferably in an alkanol at temperatures between room temperature and 200 ° C. 5 · Process according to claims 1- ^ for production of as substituents R and R hydrogen, as Substituents R ^ hydrogen or lower alkyl, as substituents R ^ hydroxyl and as substituents R n-pentyl 809886/0574 280800ό containing compounds of the general formula I _1, characterized in that the starting compound of the general formula II PGF or the lower alkyl esters of PGF "_" are used. 6 "Method according to. Claims 1-5 for production of compounds of general formula I, in T 2 & ^ where the meaning of R, RR and R ^ is the same as in claim 1 and R stands for lower alkyl, characterized in that the compounds of the general formula III, in which Br, R ^ ₁ r '', R and X have the same meaning as in claim 1 and R is hydrogen, esterified in a manner known per se with a lower diazoalkane, the ester isolated and then subjected to the elimination reaction · 7 · Process according to claims 1-6, characterized that the reactions are carried out in inert organic and / or inorganic solvents or mixtures thereof, _o 8 _# compounds of the general formula III in wherein the meaning of R ^ ₁ R ^ _R 6 ^ _R 7 ^ _R 8 is the same as in claim 1 _# 809886/0574