GB2198130A

GB2198130A - 7-fluro-prostacyclins

Info

Publication number: GB2198130A
Application number: GB08727991A
Authority: GB
Inventors: George William Holland; Hans Maag; Perry Rosen
Original assignee: F Hoffmann La Roche AG
Current assignee: F Hoffmann La Roche AG
Priority date: 1986-12-01
Filing date: 1987-11-30
Publication date: 1988-06-08
Anticipated expiration: 2007-11-30
Also published as: BE1001271A5; GB2198130B; DE3740595A1; SE8704770D0; AT391697B; AU8190787A; NZ222723A; SE8704770L; DK627787A; DK627787D0; ZA878947B; FR2607501A1; IT8722814A0; JPS63145275A; CH674363A5; GB8727991D0; ATA313887A; NL8702855A; AU597128B2; IT1223390B

Description

NOVEL PROSTACYCLINES 2198130 The present invention relates to compounds of

the formula CH-CH -CH---CH.----OR 2 2 0/ F CH7-CHH.5 H3 ER 1 2 - oR wherein Z represents a vinylene or ethylene group: R is hydrogen or lower alkyl; R 1 is lower alkanoyl; R 2 is hydrogen. methyl or fluoro; and R 2 1 is fluoro, hydrogen, trifluoromethyl or methyl; and with the proviso that when R 1 is trifluoromethyl, R is 2 2 hydrogen or methyl and salts thereof including optical antipodes, racemates, and diastereoisomers. The compounds of formula I are useful as a blood platelet anti-aggregating agents as well as anti-ulcerogenic agents. In particular. they provide a separation of properties since they exhibit strong blood platelet anti-aggregating effects without substantially reducing blood pressure. The compounds of formula I are particularly useful when administered topically to treat peripheral vascular disease. The compounds of formula I show a high degree of stability.

in a further aspect. the present invention relates to a process for the preparation of the compounds of formula I.

11 - 2 their use in the manufacture of pharmaceutical preparations and to such pharmaceutical preparations per se.

As used throughout this application, the term "lower alkyll' includes both straight chain and branched chain alkyl groups having from 1 to 7 carbon atoms such as methyl and ethyl. As also used herein, the term "lower alkanoic acids" comprehends an alkanoic acid of 1 to 7 carbon atoms such as formic acid and acetic acid. The term "lower alkanoyll, designate the monovalent radical formed from a lower alkanoic acid containing from 1 to 7 carbon atoms by removal of the -OH group from the - COOH moiety. Among the preferred alkanoyl groups. the acetyl, pivoloyl, butyryl and propionyl groups with acetyl having especially preferred.

The compounds of this invention, can be produced as racemic mixtures. These racemic mixtures can be resolved by methods well known in the art to obtain the corresponding optically pure enantiomers. On the other hand, the claimed optically active enantiomer or racemates of formula I can be produced depending upon the optical form of the compound of formula II utilized as a starting material.

In the pictorial representation of the compounds given throughout this application, a thickened taper line ( indicates a substituent which is in the beta-orientation (above the plane of the molecule), a broken line (MM) indicates a substituent which is in the alpha-orientation (below the plane of the molecule) and a wavy line indicates a substituent which is in either the alpha- or beta-orientation or mixtures of these isomers. It is to be understood that the pictorial representations of the compounds given throughout the specification are set forth for convenience and are to be construed as inclusive of other forms including enantiomers and racemates and are not to be construed as limited to the particular form shown.

1 The compounds of formula I above including their salts, optical antipodes. racemates and diastereoisomers thereof are active as blood platelet anti- aggregating agents, anti-ulcerogenic. vasodilating agents and are active- to prevent claudication. The compounds of formula I above including their salts, optical antipodes, racemates, and diastereoisomers thereof due to their inherent stability can be administered orally. topically or intravenously. They provide a prolonged therapeutic effect when administered either orally or topically.

When administered orally, the compounds of formula I or their pharmaceutically acceptable salts can be used in a variety of pharmaceutical preparations. In these preparations, these compounds or their salts are administerable in the form of tablets, pills, powders, capsules, and in other suitable forms. The pharmaceutical preparations which contain the compounds of formula I or their pharmaceutically acceptable salts are conveniently formed by admixing them with a non-toxic pharmceutical organic or inorganic carrier. Typical of pharmceutically acceptable carriers are, for example, water, gelatin, lactose, starch, magnesium stearate, tale, vegetable oils, polyalkylene glycols, petroleum jelly and other conventionally employed pharma- ceutically acceptable carriers. The pharmaceutical preparations may also contain non-toxic auxillary substances such as emulsifying, preserving and wetting agents and the like, as for example, sorbitan monolaurate, triethanol amine oleate, polyoxyethylene sorbitan, dioctyl sodium sulfo- succinate and the like.

The daily dose administered for the compounds will, of course, vary with the particular novel compound employed because of the very potency of the compounds. the chosen route of administration and the size of the recipient. The dosage administered is not subject to definite bounds but it will usually be in effective amounts of the pharmacologi- cally function of the prostacyclin. Representative of a typical method for administering the prostacyclin compounds of formula I or pharmaceutically acceptable salts thereof is by oral administration in the form of tablets or capsules. By this route, the prostacyclins of formula I or their salts can be administered at a dosage of 0.1 micrograms to 0.50 milligrams per day per kilogram of body weight.

The compounds of formula I and their salts including their optical antipodes and racemates can be administered topically. Topical administration is especially well suited for preventing or treating claudication and to enhance red blood cell deformability. In this manner these compounds enhance red blood cell circulation by promoting red blood cell deformability so that these cells can pass through nutrient vessels having small diameters. This activity makes these compounds useful in treating peripheral vascular diseases such as schleroderma. Also these compounds can be topically applied to lower blood pressure.

For topical administration to the skin the aforementioned compounds their optical antipodes, racemates, diastereoisomers or their salts are preferably prepared as ointments, tinctures. patches, creams. gels, solutions, lotions, sprays, suspensions. and the like. In fact. any conventional composition utilized for application to the scalp or skin can be utilized in accordance with this invention. Among the preferred methods of applying the composition containing the agents of this invention is in the form of gel, lotion, cream, solution and patch. The pharmaceutical preparation for topical administration to the skin can be prepared by mixing the aforementioned active ingredient with non-toxic, therapeutically inert. solid or liquid carriers customarily used in such preparations. These preparations should contain at least about 0.0005 percent by weight, of the active ingredient based upon the total weight of the composition. However, the active ingredient. the compound of formula I may be used in topical compositions in amounts significantly exceeding 10 percent i.e. up to 20% by weight. It is generally preferred that these preparations contain from about 0.01 to 10 percent by weight of the active ingredient based upon the total weight of the topical composition. While it is preferred to apply these preparations once or twice daily to the skin, these preparations can be applied according to the need of the patient. In carrying out this invention. the active ingredient can be applied in an aqueous solution or an alcohol solution such as ethyl alcohol.

in preparing the topical preparations described above additives such as preservatives. thickeners, perfumes, and the like conventional in the art of pharmaceutical compounding of topical preparations can be used. In addition, conventional antioxidants or mixtures of conven tional antioxidants can be incorporated into the topical preparations containing the aforementioned active agent.

Among the conventional antioxidants which can be utilized in these preparations are included N-methyl-alpha-tocopherolamine. tocopherols, butylated hydroxyanisole, butylated hydroxytoluene, ethoxyquin and the like. Cream-base topical formulations containing'the active agent. used in accordance with this invention. are composed of aqueous emulsions containing a fatty acid alcohol, a semi-solid petroleum hydrocarbon. 1,2-ethyleneglycol and an emulsifying agent.

Ointment formulations containing the active agent in accordance with this invention comprise admixtures of a semi-solid petroleum hydrocarbon with a solvent dispersion of the active material. Cream compositions containing the active ingredient for use in this invention preferably comprise emulsions formed from a water phase of a humectant, a viscosity stabilizer and water, an oil phase of fatty acid alcohol, a semi-solid petroleum hydrocarbon and an emulsifying agent and a phase containing the active agent 6 - dispersed in an aqueous stabilizer-buffer solution. Stabilizers may be added to the topical preparation. conventional stabilizer can be utilized in accordance this invention. In the oil phase. fatty acid alcohol components function as a stabilizer. These fatty acid alcohol components are derived from the reduction of a long-chain saturated fatty acid of at least 14 carbon atoms. Also. conventional perfumes and lotions generally utilized in topical preparation for the hair can be utilized in accordance with this invention. Furthermore. if desired. conventional emulsifying agents can be utilized in the topical preparations of this invention.

The effectiveness of the compounds of this invention to inhibit blood platelet aggregation while not effecting blood pressure can be seen when the following compound:

Compound H = Any Q with [3S[(Z).3alpha,3a alpha,4alpha,(1E.3R)5beta, 6a alpha]]-5-[3fluorohexahydro)-5-acetoxy-4[3-acetoxy-4-fluoro-loctenyl]-2Hcyclopenta[b] furan-2-ylidene]pentanoic acid methyl ester was tested in accordance with the following procedure:

Male New Zealand white rabbits are heavily sedated with a combination of Rompun (D (Xylazine) 8.8 mg/kg, i.m.

followed 10 minutes later by Ketaset (D (Ketamine HC1) 50 mg/kg, i.m. The animals are then anesthetized with Nembutal (D (pentobarbital sodium) 30 mg/kg, i.v. via the marginal ear vein. Blood pressure is monitored with a low volume displacement pressure transducer by means of a catheter inserted into the left common carotid artery. Heart rate was monitored continuously with an appropriate cardiotachometer. Animals were prepared for topical drug administration at least 1 hour prior to dosing. The left chest area was clipped and depilated with a hair remover (Neet 0). The area was then washed with warm water, 7 1 neutralized with phthalate buffer pH 4 and thoroughly dried. Compound A was formulated as a liquid in acetone and was administered topically in a single dose of 3 mg/kg to 4 animals. Acetone alone served as placebo control. Blood pressure and heart rate were monitored at 0.5, 1. 2, 3 and 4 hours following drug application. At these time intervals, a 1.0 ml arterial blood sample was taken to measure per cent inhibition of platelet aggregation.

The topical administration of Compound A when administered in accordance with the above procedure at 3 mg/kg.produced a slight but not significant decrease in arterial blood pressure (MABP) over the course of experi ment. The greatest MABP change was at 2 hours and was only decreased 10% of control value. The heart rate was increased significantly by 1 hour and continued to increase until it peaked at 3 hours. Topical administration of Compound A resulted in significant inhibition of platelet aggregation at 1 hour and reached a peak level of inhibition by 2 hours. The peak inhibition of platelet aggregation was 65%. At 4 hours similar inhibition of platelet aggregation (65%) was observed.

In accordance with the present invention, the compounds of formula I are prepared from compounds of the formula:

-CH=-CH=--OR 2 2 0 / / 2 Z -CH--CH---CH-CH 2 2 2 3 EH 2 CH wherein Z, R. R and R 1 are as above.

- 8 In producing a compound of formula I from a compound of formulas II a compound of formula II is esterified with a lower alkanoic acid or reactive derivative thereof such as halide or anhydride of a lower alkanoic acid. Any of the conventional means utilized for esterification with a lower alkanoyl acid, or reactive derivatives thereof can be utilized to carry out this conversion. The preferred lower alkanoyl group is acetyl.

In the practice of this invention, any pharmaceutically acceptable salts of the compound of formula I were R is hydrogen can be utilized. Among the preferred pharmaceutically acceptable salts are included the alkali metal salts such as lithium, sodium, and potassium, with sodium being especially preferred. Other salts which are also preferred are the alkaline earth metal salts such as calcium and magnesium, amine salts such as the lower alkyl amines, e.g. ethylamine and the hydroxy- substituted lower alkyl amine salts and tris(hydroxymethyl) amino-methane. Also preferred are the ammonium salts. Among the other salts are dibenzylamine, monoalkylamines or dialkylamine and salts with amino alpha-acids (i.e. salts with arginine and glycine).

Compounds of formula II wherein Z is vinylene are disclosed in U.S. Patent No. 4,558,142.

Compounds of formula II wherein Z is ethylene are either disclosed in European Patent Application No. Al-0209694 or can be prepared in analogy to the processes disclosed therein.

9 Example 1 l, (5Z.7beta.9alpha,llalpha,13E.15R,16-5)-6,9-Epoxy-7,16-difluoro 11,15-diacetoxyprost-5.13-dien-l-oic Acid Methyl Ester To a solution of 50 mg of (5Z,7 beta.9 alpha,11 alpha. 13E.15R,16S)-6,9epoxy-7.16-difluoro-11.15-dihydroxyprost5,13-dien-l-oic acid methyl ester in 2 ml of pyridine cooled to OOC was added 300 jil of acetic anhydride. The reaction mixture was stirred for one hour at OOC and then for two hours at room temperature. A small amount of methanol was then added to the chilled solution and the mixture then poured into 20 ml of 0.3 N HCl. The resulting mixture was then extracted with ethyl acetate, the organic layer separated, and then washed with a saturated sodium bicar bonate solution followed by a saturated sodium chloride solution. The ethyl acetate solution was then dried (MgSO 4) and the solvent removed under vacuum. The residue was then chromatographed on 12. g of silica gel and eluted with 30% ethyl acetate/hexane solution to give 46.7 mg of (5Z.7 beta.9 alpha.11 alpha.13E,15R,16S)-6,9-epoxy-7,16difluoro-11,15-diacetoxyprost-5.13-dien-l-oic acid methyl ester.

c H F Calc. 61.71 7.46 7.81 Found 61.31 7.49 7.77 Examj)le- 2 M.7 beta,9 alDha.11 alDha.15R,16S)-6,9-Epoxy-7,16difluoro-11,15-diacetoxyprost-S-en-l-oic acid methyl ester By the procedure of Example 1. (5Z.7 beta,9 alpha,11 alpha,15R,16S)-6,9-epoxy-7.16-difluoro-11,15-dihydroxyprost-.5en-l-oic acid methyl ester was converted to (5Z,7 beta, 9 alpha,11 alpha,15R.16S)-6,9-epoxy-7.16-difluoro-11.15- diacetoxyprost-5-en-l-oic acid methyl ester.

Example A

CAPSULE FORMULATION Inqredient mg/cap 1. Compound of 0.01 0.5 5.0 25.0 Example 1 or 2 2. Lactose Hydrate 168.99 168.5 159.0 123.0 3. Corn Starch 20.0 20.0 25.0 35.0 4. Talc 10.0 10.0 10.0 15.0 Mg stearate - 1.0 1.0 1.0 2.0 200.0 200.0 200.0 200.0 Manufacturinq Procedure Mix items 1. 2, and 3 in a suitable mixer for 30 minutes.

2. Add items 4 and 5 and mix for 3 minutes.

3.

Inqredient Compound of 0.01 0.5 Fill in suitable capsule.

1 Example B

SOFT GELATIN CAPSULE FORMULATION mg/ca2 5.0 25.0 Example 1 or 2 2. PEG 400 149.49 149.0 194.5 374.5 (polyethylene glycol molecule at 400) 3 Ascorbyl Palmitate - 0.5 0.5 150.0 150.0 0 0.5 0.5 200.0 400.0 - 11 Manufacturina Procedure 1. Dissolve item 3 in item 2.

2. Add item 1 to the solution in Step 1 and mix until dissolved.

3. Fill in soft gelatin capsule.

Example C

WET GRANULATION FORMULATION Inqredient mq/cap 1. (5Z.7 beta,9 alpha, 0.01 0.5 5.0 25.0 11 alpha.ISR, 16S)-6,9-Epoxy-7,16 difluoro-11.15 diacetoxyprost-5 en-l-oic acid methyl ester 2. Lactose anhydrous 106.99 106.5 102.0 118.0 3. Avicel pH 102 15.0 15.0 15.0 25.0 (microcrystalline cellulose) 4. Modified Starch 7.0 7.0 7.0 10.0 5. magnesium stearate 1.0 1.0 1.0 2.0 130.0 130.0 130.0 130.0 Manufacturinq Procedure 1. Dissolve item 1 in a suitable solvent such as alcohol.

2. Spread the solution in step 1 over item 2, dry.

3. Add items 3 and 4 and mix for 10 minutes.

- 12 4. Add magnesium stearate and mix for 3 minutes and compress.

Inqredient 1. (5Z.7 beta,9 alpha, 0.01 11 alpha,15R, 16S)-6,9-Epoxy-7,16difluoro-11,15diacetoxyprost-5- Example D WET GRANULATION FORMULATION ii-q. c a p 0.5 5.0 25.0 en-l-oic acid methyl ester 2. Lactose Anhydrous 106.99 106.5 102.0 118.0 3. Avicel pH 102 15.0 15.0 15.0 25.0 4. Modified starch 7.0 7.0 7.0 10.0 5. Magnesium stearate _ 1.0 1.0 1.0 2.0 130.0 130.0 130.0 130.0 Manufacturinc Procedure 1. Dissolve item 3 in item 2.

2. Add item 1 to the solution in Step 1 and mix until dissolved.

3. Fill in soft gelatin capsule.

Example E Cream 0.25% The following is the quantitative ComPosition of druq:

Incredients (5Z.7 beta.9 alpha, 11 alpha,15R.16S)6,9-Epoxy-7,16-difluoro11.15-diacetoxyprost-5 en-l-oic acid methyl ester Glyceryl Monostearate S.E. Polysorbate 60 2 15 Cetyl Alcohol Petrolatum Methyl Paraben Propyl Paraben Propylene Glycol 20 Purif ied Water 1. Arlacel 165 2. Tween 60 3% excess of drug c/kc 2.575 1 100.00 20.00 50.00 70.00 1.50 0.50 200.00 571.395 Total 1015.97 gm Reasonable Variations 80-120 15-25 40-60 50-90 1.25-1.75 0.4-0.6 150-250 500-600 14 -

Claims

CLAIMS:

1. Compounds of the formula:

O //CH 2 2 2 F z -CH---CH -- 2 1-CHFCH3 OR 1 2 - wherein Z represents a vinylene or ethylene group; R is hydrogen or lower alkyl; R 1 is lower alkanoyl; R 2 is hydrogen, methyl or fluoro; and R 2 1 is fluoro, hydrogen, trifluoromethyl or methyl; and with the proviso that when R 2' is trifluoromethyl, R 2 is hydrogen or methyl pharmaceutically acceptable salts, optical antipodes, racemates or diastereoisomers thereof.

2. The compounds of claim 1 wherein Z is a vinylene group.

3.

The compounds of claim 2 where R 1 is acetyl.

4. 6,9-Epoxy-7,16-difluoro-11,15-diacetoxyprosta-5,13-dien-loic acid methyl ester.

5. The compounds of claim 1 wherein Z is an ethylene group.

The compounds of claim 5 wherein R 1 is acetoxy.

7. 6,9-Epoxy-7,16-difluoro-11,15-diacetoxyprost-5-en-l-oi acid methyl ester.

-

8. Compounds of any one of claims 1-7 for use as a pharma- ceutical.

9. Compounds of any one of claims 1-7 for use as blood platelet antiaggregating agents. anti-ulcerogenic agents or vasodilating agents.

10. Compounds of any one of claims 1-7 for use in the manufacture of pharmaceutical preparations.

11. Compounds of any one of claims 1-7 for use in the manufacture of pharmaceutical preparations for the prevention and treatment of thrombosis. ulcers and claudication.

12. Process for the preparation of the compounds claimed in claim 1 which comprises esterifying a compound of formula 0 -CH --,CH.:--CH----OR J-"H 3 2 2 --- CHI-CHS-'CH3 --c "H2 2 / 1 400 z 5 1 EH 2 0 EH wherein Z. R, R and R' are as above with a lower alkanoic acid or reactive derivative thereof.

13. Pharmaceutical preparations containing a compound of formula I or a pharmaceutically acceptable salt, optical antipode, diastereomer or racemate thereof, and a pharmaceutically acceptable carrier.

14. Compounds of any one of claims 1-7 whenever prepared by the process of claim 12 or by an obvious chemical equivalent thereof.

16 -

15. The invention substantially as described herein.

1 Published 1988 at, The Patent Office, State House. 6671 High Holborn, London WCIR 4TP Further copies may be obtained from The Patent Office. Sales Branch, St Mary Cray. Orpington. Kent BR5 3RD Printed by Multiplex techxilques ltd. St Mary Cray. Kent Con. 1/87