GB1583962A

GB1583962A - Prostacyclin derivatives

Info

Publication number: GB1583962A
Application number: GB1938676A
Authority: GB
Original assignee: Wellcome Foundation Ltd
Current assignee: Wellcome Foundation Ltd
Priority date: 1976-05-11
Filing date: 1976-05-11
Publication date: 1981-02-04

Description

(54) PROSTACYCLIN DERIVATIVES (71) We, THE WELCOME FOUNDATION LIMITED, of 183-193 Euston Road, London N.W.I a company incorporated in England do hereby declare the invention for which we pray that a Patent may be granted to us and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to novel prostacyclin derivatives, their preparation, pharmaceutical formulations containing them, and their use in medicine and as chemical intermediates.

The novel compounds of the present invention are encompassed by the following formula (I):

wherein R is hydrogen, bromine or iodine and R' is hydrogen or alkyl of 1 to 4 carbon atoms (e.g. methyl) or a pharmacologically~ acceptable cation.

The present invention further includes, as intermediates for the preparation of compounds of formula (I), compounds corresponding to those of formula (I) in which at least one of the 1 1- and 15- hydroxy groups is protected by a hydroxy protecting group.

The compounds of formula (I) may be prepared by any of the methods known in the art for the preparation of compounds of analogous structure. In particular the compounds of formula (I) may be prepared from PGF2a, its C15 and/or C,1 protected derivatives and esters thereof defined in formula (II) by oxidative attack with a halogenating agent at the 5,6-double bond with simultaneous or subsequent cyclisation involving the 9-hydroxyl group, as illustrated in the following reaction scheme:

In the foregoing reaction scheme R' is as defined hereinabove; X is iodine or bromine; and Z' and Z2 are the same or different and each is selected from hydrogen and a protecting group such as carboxylic acyl, tetrahydropyran-2-yl, 1ethoxyethyl, or trialkylsilyl, for example trimethylsilyl.

When Z' and/or Z2 in formula (II) are protecting groups, the resulting protected derivatives of compounds of formula (I) are converted to the corresponding compounds of formula (I) by methods known in the art, for example acid or basic hydrolysis.

Oxidative attack may be achieved conveniently using a halogen or a derivative thereof, especially iodine, bromine, an alkali metal triiodide for example potassium tri-iodide, or N-bromosuccinamide in the presence of a base such as sodium bicarbonate. The reaction may be performed at room temperature or below in the presence of a solvent system for the base, the oxidative agent and the prostaglandin. A particularly useful solvent system is a two-phase system comprising one organic solvent for the prostaglandin and the halogen, for example diethyl ether or methylene chloride, and a further solvent for the base, for example water.

The halo compounds of formula (IA) may optionally be reduced to the corresponding compounds of formula (I) wherein R is hydrogen using for example tributyltin hydride. Unless clear indication is made to the contrary, formula (I) and like formulae in the specification and claims should be understood to embrace all stereoisomers represented by the appropriate twodimensional formulae. In particular such formulae include all the diestereoisomers thereof.

The compounds of formula (I) exhibit a potent anti-aggregatory action on blood platelets and therefore have particular utility in the treatment and/or prophylaxis of mammals as anti-thrombotic agents. They may also be used in mammals, including man, to reduce and control excessive gastric secretion, thereby reducing or avoiding gastrointestinal ulcer formation, and accelerating the healing of such ulcers already present in the gastrointestinal tract.

The compounds of formula (I) further exhibit a vasodilatory action on blood vessels and therefore have a particular utility as anti-hypertensives for the treatment of high blood pressure in mammals, including man. They also affect the biochemical co-operation between platelets and vascular endothelium which contributes to the repair of vascular endothelium. Therefore, the compounds of formula (I) have a further utility in the treatment of wound healing in mammals, including man. The halo compounds of formula (I) (R is bromine and iodine) may also be used as intermediates in the formation of prostacyclin (Johnson et al Prostaglandins, 12/6, 915-928, 1976 and our copending Application No, 19384/76. (Serial No, 1583961).

The compounds of formula I are useful whenever it is desired to inhibit platelet aggregation, to reduce the adhesive character of platelets, and to treat or prevent the formation of thrombi in mammals, including man. For example, these compounds are useful in the treatment and prevention of myocardial infarcts, to treat and prevent post-operative thrombosis, to promote patency of vascular grafts following surgery, and to treat complications of arteriosclerosis and conditions such as atherosclerosis, blood clotting defects due to lipemia, and other clinical conditions in which the underlying etiology is associated with lipid imbalance or hyperlipidemia.

The compounds of formula I are especially useful as additives to blood, blood products, blood substitutes, and other fluids which are used in artificial extra-corporeal circulation and perfusion of isolated body portions, e.g., limbs and organs, whether attached to the original body, detached and being preserved or prepared for transplant, or attached to a new body. During these circulations and perfusions, aggregated platelets tend to block the blood vessels and portions of the circulation apparatus. This blocking is avoided by the presence of these compounds. For this purpose, the compound is added gradually or in single or multiple portions to the circulating blood, to the blood of the donor animal, to the perfused body portion, attached or detached, to the recipient, or to two or all of those at a total steady state dose of 0.001 to 10 mg, per liter of circulating fluid. It is especially useful to use these compounds in laboratory animals, e.g. cats, dogs, rabbits, monkeys, and rats, for these purposes in order to develop new methods and techniques for organ and limb transplants.

The amount required of a compound of formula (I) (hereinafter referred to as the active ingredient) for therapeutic effect will, of course, vary both with the particular compound and with the route of administration.

In general a suitable dose for a mammal of a compound of formula (I) will lie in the range of 0.01 to 200 mg per kilogram bodyweight.

While it is possible for the active ingredients to be administered as the raw chemical it is preferable to present them as a pharmaceutical formulation preparation.

Unit doses of a formulation preferably contain between 0.5 mg. and 1.5 g. of the active ingredient.

The formulations, both for veterinary and for human medical use, of the present invention comprise an active ingredient, as above defined, together with one or more acceptable carriers therefor and optionally other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The formulations include those suitable for oral, rectal, vaginal, or parenteral (including subcutaneous, intramuscular and intravenous) administration, although the most suitable route in any given case will depend upon the active. ingredient.

The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired formulation.

Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, lozenges or tablets each containing a predetermined amount of the active ingredients; as a powder or granules; or as a solution or a suspension in an aqueous liquid or non-aqueous liquid; or as an oil-inwater emulsion or a water-in-oil liquid emulsion.

A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine, the active ingredient in a freeflowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine, a mixture of the powdered active ingredient and suitable carriers moistened with an inert liquid diluent.

Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter.

Formulations suitable for vaginal administration may be presented as pessaries, creams, pastes or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

Formulations suitable for parenteral administration conveniently comprise sterile aqueous solutions and suspensions of the active ingredient which are preferably isotonic with the blood of the recipient.

It should be understood that in addition to the aforementioned ingredients the formulations of this invention may include one or more additional ingredients such as diluents, buffers, flavouring agents, binders, surface active agents, thickeners, lubricants and preservatives (including antioxidants).

According to the present invention there are therefore provided: a) a novel compound of formula (I); b) the synthesis of the compounds of formula (I); c) a pharmaceutical formulation containing a compound of formula (I) d) method for the treatment or prophylaxis of thrombosis in a non-human mammal or non-human mammalian tissues comprising the administration of a non-toxic prophylactic thrombosis amount of a compound of formula (I).

e) method for inducing vasodilation in a non-human mammal comprising the administration of a non-toxic, vasodilatory amount of a compound of formula (I).

f) method for the prophylaxis and/or treatment of gastric lesions in a non-human mammal comprising the administration of a non-toxic prophylactic or thereapeutic amount of a compound of formula (I); and g) method for the treatment of wounds in a non-human mammal comprising the administration of a non-toxic, woundtreatment amount of a compound of formula (I).

The following Examples are provided by way of an illustration of the present invention and should in no way be construed as constituting a limitation thereof.

EXAMPLE 1 A well stirred solution of PGF2 methyl ester (1.489 g) in methylene chloride (30 ml) was treated with sodium bicarbonate (3.43 g; 10 molecular equivalents) and water (30 ml), cooled to OOC, and maintained thereat during the dropwise addition of a solution of iodine (1.132 g; 1.1 molecular equivalents) in methylene chloride (45 ml) during 4 hours. After stirring overnight at OOC, the mixture was treated with aqueous sodium thiosulphate (to remove excess iodine), diluted with methylene chloride and water, and the methylene chloride phase was separated, washed with water and dried over anhydrous magnesium sulphate.

Removal of the methylene chloride yielded a pale yellow gum (2.063 g) identified as 5g iodo - 9 - deoxy - 65,9a epoxyprostaglandin F1 methyl ester. This compound consisted essentially of one isomer, tentatively identified as having the following formula, which can be readily converted to prostacyclin methyl ester by treatment with sodium methoxide.

EXAMPLE 2 A stirred solution of PG F2 methyl ester (50 mg) in diethyl ether (1 ml) was treated with sodium bicarbonate (115 mg; 10 molecular equivalents) and water (1 ml) and then dropwise during 2 hours with aqueous potassium triiodide (0.8 molar; 0.261 ml).

After stirring overnight, the reaction mixture was shaken with ether and aqueous sodium thiosulphate; the etheral phase was separated, washed with water, dried with magnesium sulphate, and evaporated to leave a yellow gum of 55 - iodo - 9 deoxy - 6t,9a - epoxyprostaglandin F methyl ester.

EXAMPLE 3 A stirred solution of PGF2 (50 mg) in acetonitrile (2 ml) at room temperature was treated with N-bromosuccinimide (26.4 mg).

After 20 minutes, t.l.c. examination df the reaction solution indicated that reaction was complete, the product having rf 0.17 relative to 0.08 for the by-product (ca 5() on SiO2 in EtOAc saturated with 1120. After IT hours, the solvent was evaporated in vacuo and a solution of the residue in CH2CI2 was shaken with dilute. aqueous Na2S2O3; the CH2CI2 phase was washed (H2O), dried (MgSO4), and evaporated.

Column chromatography of the residual gum on SiO2, using EtOAc saturated with H2O as the developing liquid, yielded 5g bromo - 9 - deoxy - 6g,9a - epoxyprostaglandin Ft as a mixture of 2 diastereoisomers, rf 0.23 (double spot) on SiO2 in the system AIX (Hamberg and Samuelsson, J. Biol. Chem., 1965, 241 257).

Its 'H. n.m.r. spectrum in CDCl3 supported the conclusion that these compounds are isomers.

EXAMPLE 4 By treatment with tributyltin hydride the product of Example 1 was converted into 9 - deoxy - 6.t,9- epoxyprostaglandin F, methyl ester which was hydrolysed to the acid (R'=H in formula (I)).

See Corey et al., J. Am. Chem. Soc. 1969, 91 5675 and Cooper and Yankee, J. Am.

Chem. Soc. 1974, 96, 5876.

WHAT'WE CLAIM IS: 1. A compound of the formula:

wherein R is hydrogen, bromine or iodine, and R' is hydrogen, alkyl of 1 to 4 carbon atoms or a pharmacologically acceptable cation.

2. A compound as claimed in claim 1 wherein R is hydrogen.

3. A compound as claimed in claim I wherein R is bromine.

4. A compound as claimed in claim 1 wherein R is iodine.

5. A compound as claimed in claim 1 wherein R' is hydrogen.

6. A compound as claimed in claim 1 wherein R' is alkyl.

7. A compound as claimed in claim 6 wherein R' is methyl.

8. A compound corresponding to a compound of formula (I) (as defined in claim 1) wherein at least one of the 11- and 15- hydroxy groups is blocked by a hydroxy protecting group.

9. 55 - lodo - 9 - deoxy - 6g,9- epoxyprostaglandin F, methyl ester.

10. 55 - Bromo - 9 - deoxy - 65,9a - epoxyprostaglandin F1 .

11. A compound of the formula:

12. 9 - Deoxy - 65,9a epoxyprostaglandin F1 methyl ester.

13. 9 - Deoxy - 6,9a epoxyprostaglandin F 14. A process for preparing a compound as defined in any of claims 1 to 13 comprising oxidative attack with a halogenating agent upon a compound of the formula:

wherein Z' and Z2 are selected from hydrogen and a hydroxy protecting group, and optionally (a) (when R is bromine or iodine) reducing the resulting product to the corresponding compound wherein R is hydrogen, and/or (b) (when either or both of the groups Z' and Z2 are hydroxy protecting groups) removing the said protecting groups.

15. A process as claimed in claim 14 wherein Z1 and Z2 are hydrogen.

16. A process as claimed in claim 14 wherein the halogenating agent is iodine.

17. A process as claimed in claim 14 wherein the halogenating agent is Nbromosuccinimide.

18. A process as claimed in claim 15 wherein the halogenating agent is an alkali metal triiodide.

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **. then dropwise during 2 hours with aqueous potassium triiodide (0.8 molar; 0.261 ml). After stirring overnight, the reaction mixture was shaken with ether and aqueous sodium thiosulphate; the etheral phase was separated, washed with water, dried with magnesium sulphate, and evaporated to leave a yellow gum of 55 - iodo - 9 deoxy - 6t,9a - epoxyprostaglandin F methyl ester. EXAMPLE 3 A stirred solution of PGF2 (50 mg) in acetonitrile (2 ml) at room temperature was treated with N-bromosuccinimide (26.4 mg). After 20 minutes, t.l.c. examination df the reaction solution indicated that reaction was complete, the product having rf 0.17 relative to 0.08 for the by-product (ca 5() on SiO2 in EtOAc saturated with 1120. After IT hours, the solvent was evaporated in vacuo and a solution of the residue in CH2CI2 was shaken with dilute. aqueous Na2S2O3; the CH2CI2 phase was washed (H2O), dried (MgSO4), and evaporated. Column chromatography of the residual gum on SiO2, using EtOAc saturated with H2O as the developing liquid, yielded 5g bromo - 9 - deoxy - 6g,9a - epoxyprostaglandin Ft as a mixture of 2 diastereoisomers, rf 0.23 (double spot) on SiO2 in the system AIX (Hamberg and Samuelsson, J. Biol. Chem., 1965, 241 257). Its 'H. n.m.r. spectrum in CDCl3 supported the conclusion that these compounds are isomers. EXAMPLE 4 By treatment with tributyltin hydride the product of Example 1 was converted into 9 - deoxy - 6.t,9- epoxyprostaglandin F, methyl ester which was hydrolysed to the acid (R'=H in formula (I)). See Corey et al., J. Am. Chem. Soc. 1969, 91 5675 and Cooper and Yankee, J. Am. Chem. Soc. 1974, 96, 5876. WHAT'WE CLAIM IS:

1. A compound of the formula:

2. A compound as claimed in claim 1 wherein R is hydrogen.

3. A compound as claimed in claim I wherein R is bromine.

4. A compound as claimed in claim 1 wherein R is iodine.

5. A compound as claimed in claim 1 wherein R' is hydrogen.

6. A compound as claimed in claim 1 wherein R' is alkyl.

7. A compound as claimed in claim 6 wherein R' is methyl.

9. 55 - lodo - 9 - deoxy - 6g,9- epoxyprostaglandin F, methyl ester.

10. 55 - Bromo - 9 - deoxy - 65,9a - epoxyprostaglandin F1 .

11. A compound of the formula:

12. 9 - Deoxy - 65,9a epoxyprostaglandin F1 methyl ester.

13. 9 - Deoxy - 6,9a epoxyprostaglandin F

14. A process for preparing a compound as defined in any of claims 1 to 13 comprising oxidative attack with a halogenating agent upon a compound of the formula:

15. A process as claimed in claim 14 wherein Z1 and Z2 are hydrogen.

16. A process as claimed in claim 14 wherein the halogenating agent is iodine.

19. A process as claimed in claim 18

wherein the alkali metal triiodide is potassium triiodide.

20. A process as claimed in any of claims 14 to 19 wherein the reaction is carried out in the presence of a solvent.

21. A process as claimed in any of claims 14 to 20 wherein the reaction is carried out in the presence of a base.

22. A process as claimed in claim 20 wherein the solvent is a two-phase solvent system comprising water and an immiscible organic solvent for the prostaglandin starting material.

23. A process as claimed in claim 22 wherein the organic solvent is selected from methylene dichloride and diethyl ether.

24. A process as claimed in claim 14 or claim 15 (or the preparation of a compound of formula (I) wherein R is bromine.

25. A process as claimed in any of claims 14 to 23 (or the preparation of a compound of formula (I) wherein R is hydrogen.

26. A pharmaceutical composition comprising a compound of formula (I)

wherein R is hydrogen, bromine or iodine and R' is hydrogen, alkyl of 1 to 4 carbon atoms or a pharmacologically acceptable cation, in association with a pharmaceutically acceptable carrier therefor.

27. A composition as claimed in claim 26 wherein formula (I) R' is hydrogen.

28. A composition as claimed in claim 26 wherein in formula (I) R' is alkyl.

29. A composition as claimed in claim 26 wherein in formula (I) R' is methyl.

30. A composition as claimed in any of claims 26 to 29 wherein R in formula (I) is bromine.

31. A composition as claimed in any of claims 26 to 29 wherein R in formula (I) is hydrogen.

32. A composition as claimed in any one of claims 26 to 31 in the form of a unit dose.

33. A composition as claimed in claim 32 comprising from 0.5 mg to 1.5 g of the compound of formula (I).

34. A composition as claimed in any one of claims 26 to 33 in the form of a tablet, capsule, cachet, lozenge or suppository.

35. A composition as claimed in any one of claims 26 to 34 wherein the carrier is a solid.

36. A composition as claimed in any one of claims 26 to 33 wherein the carrier is a liquid.

37. A composition as claimed in claim 36 which is a sterile aqueous solution or suspension suitable for injection.

38. A composition as claimed in claim 26 wherein the compound of formula (I) is 9 deoxy - 6g,9a - epoxyprostaglandin F, .

39. A composition as claimed in claim 26 wherein the compound of formula (I) is 9 deoxy - 6g,9a - epoxyproståglandin F, methyl ester.

40. A method for the treatment or prophylaxis of thrombosis in a non-human mammal or non-human mammalian tissues, comprising the administration of an effective amount of a compound of formula (I).

41. A method for inducing vasodilation in a non-human mammal comprising the administration of an effective amount of a compound of formula (I).

42. A method forth prophylaxis or treatment of gastric lesions in a non-human mammal comprising the administration of an effective amount of a compound of formula (I).

43. A method for the treatment ofwounds in a non-human mammal comprising the administration of an effective amount of a compound of formula (I).