HU182727B - Process for producing 20-methyl-13,14-didehydro-pgi2-derivatives - Google Patents

Abstract

20-Methyl-13, 14-didehydro- PGl2 derivatives of formula: <IMAGE> where R is hydrogen or methyl and M is hydrogen or a pharmaceutically acceptable cation have a greater effect than PGl2 or 20-methyl-PGl2 in disaggregating platelets in the bloodstream and in vasodilating action. They can be prepared by dehydrohalogenation of dihalo compounds of formula (II> <IMAGE> where R and M have the meanings given above and X1 and X2 are independently bromine, chlorine or iodine. A sodium or potassium alkoxide is the preferred dehydrohalogenating agent.

Description

According to the present invention, a dihalo compound of formula II wherein R and M are as defined above and X ₁ and X ₂ are the same or different halogen atoms, i.e. bromine, chlorine or iodine, is dehydrogenated, and optionally converting the resulting compound into a salt. The compounds obtained have valuable therapeutic effects, such as vasodilator and platelet aggregation inhibitory activity, and are therefore useful as active ingredients in pharmaceutical formulations.

-1182.727

The present invention relates to 20-methyl-13,14-didehydro-PGIp derivatives, more particularly to compounds of formula I wherein:

R is hydrogen or methyl; and

M is hydrogen or a pharmaceutically acceptable cation.

The present invention also provides a process for the preparation of a pharmaceutical composition comprising the compounds of Formula I as an active ingredient.

M is preferably an alkali metal cation such as sodium or potassium.

In the formulas herein, the dashed line / · ί means that the ring-linked substituent has the X / or endo configuration and the chain-linked substituent has the S configuration; and the wavy line / / indicates that the ring-linked substituent has the configuration of w / y '/ endo / desire / exo / and the chain-linked substituent may be S or R. Each configuration isomer. for example, the preparation of 16S-methyl and 16R-methyl epimers and mixtures thereof is within the scope of the present invention.

In accordance with the present invention, compounds of formula I are prepared by reacting a compound of formula II wherein R and M are as defined above and X and X ₂ are the same or different halogen atoms, i.e., bromine, chlorine or iodine. - dehydrohalogenating and, if desired, converting the resulting compound into a salt.

X _{2 is} preferably bromine.

Preferably, the dehydrohalogenation is carried out by reacting a compound of formula II with an excess dehydrohalogenating agent, such as a dimethylsulfinylcarbdione, an alkali metal such as sodium or potassium, an alkoxide, preferably sodium or propyl, butylate, and the reaction is carried out in an inert, anhydrous solvent, preferably a straight or branched C 1 -C 6 alcohols such as methyl, ethyl, propyl, butyl, isopropyl alcohol, dimethyl sulfoxide or hexamethylene phosphoric acid amide.

The reaction temperature may vary between room temperature and the boiling point of the solvent used, and the reaction time may be from a few minutes to several hours.

The reaction is preferably carried out at a temperature between 20 ° C and 45 ° C for 2-3 hours.

On completion of the reaction, the solvent was distilled off in vacuo and the product crystallized. Water or aqueous alcoholic solutions are used for crystallization.

The salt formation is carried out in the usual manner.

The compounds of formula II are known and can be prepared, for example, by one of the processes disclosed in German Patent Application No. 2,757,919. By the way, this disclosure corresponds to Belgian Patent Specification 862 514.

A'prostacyclin or PGI _? / Prostaglandins, 12, 6 December 1976, p. 915 / Known vasodilator and aggregation inhibiting agent that is biosynthesized in the arteries and lungs of mammals and man from arachidonic acid / et al., Gryglewski et al., Prostaglandins, 12, 658 · 1976 · / PGI ₂ inhibits platelet aggregation 2182.727 and more importantly it disrupts platelet aggregates in the bloodstream. In humans, variable percentages of total platelets circulate in the form of small aggregates, and their numbers are statistically higher in atherosclerotic patients, where this causes a high risk of infarction (Wu, KK and Haak, JC, Ch.

Apart from its ectodilatory action, pro-azacycline is also capable of disrupting / disaggregating these compounds in humans / Sezeklik, A., et al., Pharmacol. Gap. Comm.

1978./. The compounds of the present invention are characterized by the predominance of this disaggregating effect, while also being able to relax coronary arteries. Both effects superior to _PGI2 Ós PGI ₂ 20-methyl derivative of the impact;

In addition, the compounds of the present invention, like pro-pacaclinine and 20-methyl-prostacyclin, are completely devoid of prostaglandin-like and thromboxane-like activity, i.e., only PGI ₂ activity.

The PGIp limit of the compounds was determined on the basis of the relaxing capacity of the caudal iron haematopoietic haematopoietic unit and the ADP-induced platelet aggregation inhibitory capacity on platelet rich rabbit plasma.

Prostaglandin-like activity, particularly PGEp activity, was determined in rat colon, and thromboxane activity, especially ΤΣΑρ activity, was determined on the basis of the capacity to induce contraction in rabbit carotid artery.

Compounds of the present invention, in particular 13,14-didehydro-20-methyl-PGI _{2, were} compared with known compounds such as PGI ₂ , 20-methyl-PGI ₂ , PGH _2.

11,9-epoxyl-methano analogue, which is a known prostaglandin-producing company: Upjohn Co., 6 '> - and 6 <-20-methyl-PGI-. methyl-13,14-didihydro-PGI1. Below

Table I summarizes the PGI _{2 to} PGE ₂ and TIAg activity of the above mentioned compounds.

Table -3182.727

24 A Ν ο d 3 dxl Ο Φ -ρ 44 Ν φ -1 π Λ Ό 00 1 , Ο: θ

the á-ss

The Ό

I

Φ M OJ ρ Ρ »ra Φ: O Λ h ra I Ör-Í ^ ŐJ cxmJ'ew> σ pq jsd.nO U + s te n PH Λ« β ö Ph ρ Xl

9

Ρ »

I

Φ

Α faithful m ra α} Ό-Φ I · Η43 Η Ο φ 'Φ Φ 0 hO «J

-Ρ φ

xt

I

Ρ- I • η φ φ νΌ φ ra _ Α ΦΌ χΐ * ο

Φ

Ρ if \ 4 and \ r-1

Ο Ο Ο L 7 ΝΛ

Ο Ο Ο Ο ο ο γ4 γ · I

ΙΓ \ ο

-fíra Φ OJt>

3

Ph n

3 γη> r4 η ο

A ο φ tqjd ra η ο Φ ο ο ο

ιη

ΙΓ \ ο ο

ο

C0

W -Μ Α

* 3

Ό

4J

Φ

W

A A Α

> φ \ ώ 3 »γ4 χΐ φ τΗ • d I Α Ό «Η χΐ φ Ό τΗ 1 3 • Η XI 3 • Η »d I 04 ι-1 γ4 4 r4 4 r4 4 r4 Η Η Η • « NEW Ο Ο κ \ ·> Κ \ Ρη Ρη ΡΗ ί-1 <'· r4 < γ4 1 1 1 ι ω ι ω 1 r4 .-4 ι-4 Η γ4Χ. γ4 1 • τΗ τΗ • Η Ή ι • Η τΗ • • Ρ +3 +3 +3 -Ρ -Ρ Φ Φ 2 Φ Η Φ ι-4 Φ 04 • im β ! SHE 0Η ÖH ÖH the Η 1 1 Ιϋ ιΰ • NEW ο ο ο Ο Ρη ΟΡη ο Ρη Μ Ρη 04 <Μ 04 ίΜ 1 04 I 04 1

-4182.727

Comparison of the experimental results in Table I shows the importance of the triple bond at the 13,14 position for biological activity. In the compound of the present invention, the pure PGI ₉ effect of 2O-methyl-13,14-didehydro-PGI _{3 is} amplified even with respect to the 20-methyl-PGI ₉ analog. II. Table shows the vasodilatory and platelet inhibitory effect aggregáclót ^ and measured the effect of in vivo measured in vitro disaggregation of 13,14-didehydro-20-methyl PGI _2, the PGIg and 20-methyl PGI _p analogs.

The vasodilatory activity of these compounds was determined in vitro by simultaneously evaluating their relaxing capacity in bovine cardiovascular and rabbit gut. The other two are from. unlike 13,14-dihydro-stem glaze, both arteries were affected at the same dose.

Platelet aggregation inhibitory activity was also determined in platelet-rich rabbit plasma heparin-treated cat blood using the Gryglewski method '/ Naunym-Schmledeberg, Aroh. Pharmacol., 302 .. 25-30, 1978/.

Disaggregating activity was determined in vivo in anesthetized and heparin-treated cats, and the test compound was infused / Gryglewxki, R.J., Korbut, B., Ooetkiewioz, A. and Stachufa, J.t. Naunym Schmiedeberg, Arch. Pharmaool., 302, 1978 · / ·

-5182.727

II. Table π

Ο £ Ö \

O ra r Xl Ο Φ t> A

Ό · Η \, bOPN. Φ -rt 60 R fl magic = 3 N +

Ό i-t O * d 43 • bû-rl Φ PR bOfl bû * rt

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ΦΟ i-I I — I R 43 dd t> bű o

R

P>

fl a

needle

P • ra a

43 ^ ra bû xl q n

Ό $

o • rt <Ö d appear 4) ra Rd b0 +> bû-H (0 d R φ O -M * 4 M (0 <D N A a ra o Φ ra H

I-I -H \

R 5 »'0)>

ra a q • H43 ra url.3 ra Φ ra Pl n o Φ φ ra w-m a

Ά bora - ^ ra ^ö tíra d ra H Φ ra ra X. á rt «-1 O φ bû Pi A <~ 4 rj Ü rqdwd φ b \ t» x> q | üA r4 R d Φ X> I »

R r4 O rj% j £ »p fe * 4 Φ Ál a o ra ra cd ra t> o S * ra ra <o 03 -d R tt d o Et o

neither

SP

P>

Ό s

She SHE SHE THE THE SHE K \ THE r t

She CM THE r · » i-1 She CJ

Ό 1 rt ü d the SHE SHE R World Championships ·· World Championships 43 THE 4 Ri q « φ sorrow She q d She * 4 • to Ό d 43 43 3 3 l> She SHE She Ρ » Ή World Championships ·. World Championships rl u 4 1-1 She -M 43 43 d d 1 ά tA SHE sorrow She THE to LA She CM TENDON d to 3 43 * "* World Championships d 43 <0 Ri She n She 43 to the 43 xl 03 1 43 to • H d rt to • d • rt the d to the • rí T • rl • H m CM the you S the H « the the e> THE rt to THE H CM q to 1 1 hl • H II r4 R4u the II • rl i n fi c 43 43 I II She IX Φ Φ O THE fiction cm the a r Q She 0 é also bf ►r g THE CJ CM XS H w w

-6182.727

The compounds of the present invention were tested in the form of their alkali metal salts. however, the values in Table 1 are equimolar amounts of the corresponding free acids. II. table shows that the products of the present invention are superior to PGIp is vasodilator and antiplatelet action and the PGI ₂ 20-methyl-származéfcát. Like natural prostate cyclin and 2O-methyl prostacyclin, the compounds of the present invention do not form substrates for 15-prostaglandin dehydrogenase. In particular, the 16S and 16E-methyl derivatives are effective, which do not form a substrate for the 15-hydroxy-prostaglandin dehydrogenase enzyme, and their antiplatelet activity is 2-5 times higher than the corresponding 16-unsubstituted derivatives. Because of their vasodilatory and anti-aggregating activity, the compounds of the present invention are particularly useful in the treatment of acute myocardial infarction, in the resolution of angina pectoris attacks, in the prevention of platelet aggregation with or without heparin-like agents, in the prevention of aggregation in hemodialysis The toxic compounds of the invention are completely negligible in their toxicity and thus safe to use in therapy.

The compounds of the present invention may be used in conventional manner. For example, they may be administered by intravenous injection or infusion, or by subcutaneous or intramuscular injection, orally, by sublingual absorption, or rectally by sth. In urgent cases, they are preferably administered by intravenous infusion using sterile buffers of pH 8.5-9 in aqueous solutions containing various concentrations of the compounds of the invention, for example 0.0005-0.01%. In this case, administration can be effected, for example, through an intravenous cannula fitted with a three-position tap inserted into, for example, the left middle forearm vein, e.g. For intravenous infusions, the dose is preferably from 0.2 to 25, in particular from 0.5 to 2.0, ng / kg body weight per minute. Preferably, the total daily dose for injection or infusion is 0.005 to 20 mg / kg, the exact dosage depending on the age, weight and condition of the patient and the route of administration. For subcutaneous or intramuscular injection, sterile solutions or suspensions in aqueous or non-aqueous media may be employed. For example, the active ingredient may be dissolved in sterile water or in a solution of lidocaine hydrochloride, preferably maintaining the pH of the solution at 8.5 to 9, or in any conventional solvent used for physiological saline or such administration. In such cases, the daily dose is about 0.05 to 50 mg. As mentioned above, the compounds of the present invention may be administered by other routes such as orally in the form of tablets, capsules or syrup, rectally in the form of suppositories or in the form of sublingual absorption in the form of tablets or sublingual square tablets. For the preparation of pharmaceutical compositions, customary carriers and excipients may be used, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, talc, potassium or sodium for oral administration.

-7182.727 magnesium stearate, glycols, starches, acacia, tragacanth, alginates, lecithin or polysorbates, and lauryl sulfates, preferably lauryl sulfates of alkaline or alkaline earth.

The following examples illustrate the invention.

Example 1

0.58 g of 14-bromo-5 (S), R (iodo) -6 (S), R (-20) methyl PGI. A solution of 4 ml of anhydrous dimethyl sulfoxide and 0.34 g of sodium tert-butylate was stirred for 3 hours under an inert gas atmosphere. The solvents are then distilled off under vacuum (0.2 mm Hg) and the residue is taken up in a stoichiometric amount of 2N sodium hydroxide solution. The solution was cooled to 0 ° C and filtered

l ·, <.dbd. + - 10 ^{D in} ethanol /; Yield: 80%.

Example 2

A solution of 0.42 g of 14.5 (S), R 1 -dibromo-6 (S), R 20 -methyl-PGI ₁ and 0.45 g of potassium tert-butylate in anhydrous methanol is kept at room temperature for 20 days. The solvents were evaporated in vacuo and the residue crystallized from 2N potassium hydroxide solution in methanol / water. This gives the 13,14-didehydro-20-methyl-PGI ₂ potassium salt; _D = + 108 ° (in ethanol); yield: 72%.

The same compound can also be prepared by reacting the potassium tert-butylate in tert-butanol for 8 days at 38 ° C.

3 · Example

A solution of 0.3 g of 16S-methyl-14-bromo-5 / S, R-iodo-6 / S, R-20-methyl-PGI and 0.35 g of sodium lumethylate in 4 ml of ethanol was heated at 50 ° C for 15 days. C is maintained. The solvents were then evaporated in vacuo, the residue was diluted with 2N sodium hydroxide solution and cooled to 0 ° C, and the crystalline product was filtered off. This gives 13,14-didehydro-16S, 20-dimethyl-PGI ₂ sodium salt; ^r λ.'p = + 118 ° / in ethanol /.

Similarly, the 13,14-didehydro-16R, 20-dimethyl-PGI ₂ sodium salt is prepared; . p ⁼ + 102 ° (in ethanol).

Claims (5)

Patent claims A process for the preparation of a compound of formula I wherein: Hydrogen or methyl; and M is a hydrogen atom or a pharmaceutically acceptable cation, characterized in that a dihalo compound of the formula II wherein R and M are as defined above and és and the groups represent the same or different halogen atoms, i.e., bromine, chlorine or iodine. dehydrohalogenating and, if desired, converting the resulting compound into a salt. -8182.727 Process for the preparation of the 20-methyl-13,14-didehydro-PGI ₂ sodium salt according to claim 1, characterized in that the starting material is 14-bromo-5 / S, B-iodo-6 / S, R (-20-methyl-PGI) is used and the resulting free acid is converted to the salt with sodium hydroxide. 3. A process according to claim 1 for the preparation of the 2O-methyl-13,14-didehydro-PGI ₂ potassium salt, characterized in that the starting material is 14,5- / S, B / -dibromo-6 / S, B / -20-methyl-PGI was used and the resulting free acid was converted to the salt with potassium hydroxide. The process of claim 1 for the preparation of the 13,14-didehydro-16S, 20-dimethyl-PGI ₂ sodium salt, wherein the starting material is 16S-methyl-14-bromo-5 / S, B-iodine. -6 / S, B / -20-methyl-PGI _{1 was} used and the resulting free acid was converted to sodium hydroxide with ^{x 2} ... 5. A process for the preparation of a pharmaceutical composition, wherein a compound of the formula I as claimed in any one of the preceding claims, wherein B and 1 have the meaning given in claim 1, is formulated with pharmaceutical carriers and / or other excipients.