NZ222723A - Fluoro-prostacyclines and pharmaceutical compositions - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £22723 '4A 22 2 7 2 3 .if?* •;*c • -tf/ I NO DRAWINGS Priority Oate(s): . A Complete Specification Filed:^7.".\ Close: s^o.'GSfSiJ^u fo^Kay.ssL.s.v Publication Date: .... .i£7.H0V| P.O. Journal, No: . 190 No.: Date: NEW ZEALAND PATENTS ACT, 1953 COMPLETE SPECIFICATION NOVEL PROSTACYCLINS -WWe. F. HOFFMANN-LA ROCHE & CO., AKTIENGESELLSCHAFT 124-184 Grenzacherstrasse, Basle, Switzerland, a Swiss Company -Mf hereby declare the invention for which t-/ we pray that a patent may be granted to me/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - - 1 (followed by page la) 11 222723 -la- The present invention relates to compounds of the formula -OR # 2 2 2 :—CHr—CH-r—CHr~CH, oR1 wherein Z represents a vinylene or ethylene group; R is hydrogen or lower alkyl; is lower alkanoyl; R2 is hydrogen, methyl or fluoro; and R2' is fluoro or trifluoromethyl: and with the proviso that when R 1 is trifluoromethyl. R is 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, *"Xv; 222723 %•?$<&> O their use in the manufacture of pharmaceutical preparations and to such pharmaceutical preparations per se.

As used throughout this specification, the term "lower alkyl" designates 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 terra "lower alkanoic acids" comprehends an alkanoic acid of 1 to 7 carbon atoms such as formic acid and acetic acid. The term "lower alkanoyl" 10 designates 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 20 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 25 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 ( ) 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. | -30CTI9903 "HSfrKZ&vli fly* 4 DOpAll*** .......... .... 22 2 7 2 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 5 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 10 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 prepara-15 tions. 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 20 with a non-toxic pharmceutical organic or inorganic carrier. Typical of pharmceutically acceptable carriers are, for example, water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly and other conventionally employed pharma-25 ceutically acceptable carriers. The pharmaceutical preparations may also contain non-toxic auxiliary substances such as emulsifying, preserving and wetting agents and the like, as for example, sorbitan monolaurate, triethanol amine oleate, polyoxyethylene sorbitan, dioctyl sodium sulfo-30 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 35 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- 22 2 7 2 3 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. 5 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 10 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 15 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 30 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. 3® 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 conventional 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-tocopherol-amine, 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 dispersed in an aqueous stabilizer-buffer solution. Stabilizers may be added to the topical preparation. Any conventional stabilizer can be utilized in accordance with 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 A = [3S[(Z),3alpha,3a alpha,4alpha.(IE,3R*)5beta, 6a alpha]]-5-[3-fluorohexahydro)-5-acetoxy-4-[3-acetoxy-4-fluoro-1-octenyl]-2H-cyclopenta[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 (Xylazine) 8.8 mg/kg. i.m. followed 10 minutes later by Ketaset (Ketamine HC1) 50 mg/kg, i.m. The animals are then anesthetized with Nembutal (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 ). The area was then washed with warm water, /Jm A 4 0 22 2 7 2 3 7 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 5 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 experiment. The greatest MABP change was at 2 hours and was only 15 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 20 by 2 hours. The peak inhibition of platelet aggregation was 65%. At 4 hours similar inhibition of platelet aggregation (65%) was observed. 2£> of formula I are prepared from compounds of the formula: In accordance with the present invention, the compounds II OH wherein Z, R, R and R 1 are as above. 2 2 222723 8 In producing a compound o£ 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 5 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 15 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 20 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 New Zealand Patent Specification No. 199912.

Compounds of formula II wherein Z is ethylene are either disclosed in New Zealand Patent Specification No. 216613 or 30 can be prepared in analogy to the processes disclosed therein. 22 2 7 2 3 Example 1 (52.7beta.9alpha.llalpha,13E.15R.16S)-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)-6.9-epoxy-7,16-difluoro-11,15-dihydroxyprost-5,13-dien-l-oic acid methyl ester in 2 ml of pyridine cooled to 0°C was added 300 jil of acetic anhydride. The reaction 10 mixture was stirred for one hour at 0°C 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 HC1. The resulting mixture was then extracted with ethyl acetate, the organic layer 15 separated, and then washed with a saturated sodium bicarbonate solution followed by a saturated sodium chloride solution. The ethyl acetate solution was then dried (MgSC>4) and the solvent removed under vacuum. The residue was then chromatographed on 12 g of silica gel and eluted 20 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-7,16-dif luoro-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 Example 2 (5Z.7 beta.9 alpha.11 alpha.15R.16S)-6.9-Epoxy-7,16- dif luoro-11.l5-diacetoxyprost-5-en-l-oic acid methyl ester By the procedure of Example 1, (5Z.7 beta,9 alpha,11 35 alpha.15R,16S)-6.9-epoxy-7,16-difluoro-11.15-dihydroxyprost-5-en-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- W ■f •»a r^s •., i /->, •- -) 22 2 7 | -lo ll | diacetoxyprost-5-en-l-oic acid methyl ester. f ! | Example A I O CAPSULE FORMULATION Ingredient mg/cap 1.

Compound of 0. 01 0.5 .0 .0 Example 1 or 2 2.

Lactose Hydrate 168. 99 168. 5 159 .0 123 .0 3.

Corn Starch . 0 .0 .0 .0 4.

Talc . 0 .0 .0 .0 .

Mg stearate 1. 0 1.0 1 .0 2.0 200. 0 200.0 200 .0 200.0 Manufacturing Procedure 1. 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. Fill in suitable capsule.

| ' Example B | 25 SOFT GELATIN CAPSULE FORMULATION J Ingredient mg/cap i . i > \ y I 1. Compound of 0.01 0.5 5.0 25.0 Example 1 or 2 ! 2. PEG 400 149.49 149.0 194.5 374.5 | (polyethylene •i j glycol molecule I at 400) I 3. Ascorbyl Palmitate 0.5 0.5 0.5 0•5 150.0 150.0 200.0 400.0 11 f' '•> U '■''I "4$ C?X\ /& - 11 - :1; # m „j_ ....

I . i -. i -fti . i © /"■> * ( -J llllll Manufacturing 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 Ingredient mg/cap 1. (5Z.7 beta.9 alpha. 0.01 0.5 5.0 25.0 11 alpha.15R, 16S)-6,9-Epoxy-7,16-dif luoro-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 . Magnesium stearate 1.0 1.0 1.0 2.0 130.0 130.0 130.0 130.0 Manufacturing 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. 22 2 7 2 3 4. Add magnesium stearate and mix for 3 minutes and compress.

Example D WET GRANULATION FORMULATION Ingredient mg/cap 1. (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 0 .01 in O .0 .0 2 .

Lactose Anhydrous 106 .99 106 .5 102 .0 118 .0 3 .

Avicel pH 102 .0 .0 .0 .0 4 .

Modified starch 7 .0 7 .0 7 .0 .0 .

Magnesium stearate 1 .0 1 .0 1 .0 2 .0 130 .0 130 .0 130 .0 130 .0 Manufacturing 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. 22 2 7 Example E Cream 0.25% The following is the quantitative composition of drug: Ingredients (5Z,7 beta,9 alpha. 11 alpha.15R,16S)- 6,9-Epoxy-7.16-difluoro- 11 .15-diacetoxyprost-S- en-l-oic acid methyl ester q/kg 2.575* Reasonable Variations Glyceryl Monostearate S.E. 100.00 80-120 2 Polysorbate 60 .00 -25 Cetyl Alcohol 50.00 40-60 Petrolatum 70.00 50-90 Methyl Paraben 1.50 1.25-1.75 Propyl Paraben 0.50 0.4-0.6 Propylene Glycol 200.00 150-250 Purified Water 571.395 500-600 Total 1015.97 gm 1. Arlacel 165 2. Tween 60 * 3% excess of drug ^r l-iti'J' i f) i ^ 222723 =6 I ■* ^ . ? O, ^ ■-—w' w -•■' '

Claims (16)

WHAT WE CLAIM IS:

1. Compounds of the formula: .CH—CHz—CHr~CHt-~C"-OR 7 2 2 2 a 10 'n Z "r" | CH^ ~'2 ~"2 ~"3 -H-r-CHTT-CH, 01^ 2 OR^ 15 wherein Z represents a vinylene or ethylene group; R is hydrogen or lower alkyl; R^ is lower alkanoyl; R2 is hydrogen, methyl or fluoro; and R2' is fluoro or trifluoromethyl; and with the proviso that when R ' is trifluoromethyl, R is H 6 20 hydrogen or methyl pharmaceutically acceptable salts, optical antipodes, racemates or diastereoisomers thereof.

2. The compounds of claim 1 wherein Z is a vinylene group. 25

3. The compounds of claim 2 where R^ is acetyl.

4. 6,9-Epoxy-7,16-difluoro-11,15-diacetoxyprosta-5,13-dien-l-oic acid methyl ester. 30

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

6. The compounds of claim 5 wherein R^ is acetyl. 35

7. 6 , 9-Epoxy-7 ,16-dif luoro-11,15-^j.acetoxypros t-5-en-l-oic acid methyl ester. \ ~3OCTI99o5fl 222723 - 15 -

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

9. Compounds of any one of claims 1-7 for use as blood platelet anti-aggregating 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 l which comprises esterifying a compound of formula ^-CHj-CH^-CH2~^~0R / \ II- 2 2 2 3 OH "2 OH wherein Z. R, R and R1 are as defined in claim 1, Ct M with a lower alkanoic acid or reactive derivative thereof.

13. Pharmaceutical preparations containing a compound of formula I,as defined in claim 1, or a pharmaceutically acceptable salt, optical antipode, diastereomer or racemate thereof, and a pharmaceutically acceptable carrier.

14. A process for the preparation of t^e_^compounds claimed in claim 1 substantially as described herein witlT-rei.erence to either Example 1 or Example 2. 222723 - 16 -

15. Compounds of any one of claims 1-7 whenever prepared by the process of claim 12 or claim 14.

16. Pharmaceutical preparations containing a compound of formula I, as defined in claim 1, or a pharmaceutically acceptable salt, optical isomer, diastereomer or racemate thereof/ substantially as described herein with reference to any one of Examples A to E. _ • OcXSOju- °f-o r*C 4 . * IA> < f -~4